WO2009127922A2 - Pharmaceutical formulation for treating cardiovascular disease - Google Patents

Abstract

The present invention provides a pharmaceutical formulation containing an immediate-release compartment and an extended-release compartment. The immediate-release compartment comprises a statin lipid-lowering drug, its isomer, or its pharmaceutically acceptable salt as a pharmacologically active ingredient and the extended-release compartment contains a dihydropyridine calcium channel blocker, its isomer, or its pharmaceutically acceptable salt as a pharmacologically active ingredient. The combined formulation of immediate-release, statin lipid-lowering drug and extended-release dihydropyridine calcium channel blocker, is pharmacologically, clinically, scientifically, and economically more useful than the single formulation of each of the drugs or a simple combination of the drugs, in preventing and treating cardiovascular disease, cardiopulmonary disease, pulmonary disease, or kidney disease in patients with metabolic syndrome and insulin resistance and patients with diabetes or suspected prediabetes. médicamentsThe formulation of the present invention allows different release times for the statin lipid-lowering drug and the dihydropyridine calcium channel blocker, and thus prevents mutual antagonism and side effects between the two drugs, and provides easy administration for patients simultaneously taking the two drugs simultaneously.

Description

 【Specification】

 [Name of invention] Pharmaceutical preparation for the treatment of cardiovascular disease

【Field of Energy】

 The present invention is designed to control and release each drug at a specific rate by applying the so-called Chronotherapy principle and XenoMotics, which are administered by staggering the time of expression of pharmacological action in each body The present invention relates to a pharmaceutical formulation comprising, as an active ingredient, a controlled release dihydropyridine calcium channel blocker and a statin lipid lowering agent.

 Background Art

Hyperbaric pressure often coexists with coronary artery disease and is a major cause of heart disease. Hypertension is closely related to atherosclerosis due to hyperlipidemia. In other words, if the blood pressure rises, the arterial sclerosis worsens, and if the arteriosclerosis worsens, the blood pressure rises further to exacerbate each other. Such symptoms are recognized as a serious risk factor for developing cardiovascular disease. Hyperlipidemia in the ^"one type of gokol Leste ¾ increase is the my elevated serum low-density lipoprotein (LDL), and call test Te serum chongkol less hedge the increase of the specific. Therefore, lowering the level of serum lipids, especially LDL cholesterol, may lower the likelihood of developing cardiovascular disease, delay the progression of atherosclerosis, or induce regression of sinus sclerosis. [See American American associat ion, Diabetic care 2000; 23: S57].

 Hypercholesterolemia is involved in the early development of atherosclerosis, characterized by an uneven distribution of lipid deposits in the veins, including the coronary, jugular and peripheral arteries. This irregular distribution of atherosclerosis is characteristic of coronary artery injury and cardiovascular disease (Am J Cardiol 1987 59 (14): 91G).

Atherosclerosis and hypertension are cyclically exacerbating symptoms. Therefore, both hyperlipidemia patients and hypertensive patients should be treated for isochronism and hypertension isochronously and prevent exacerbations [Hypertens Res 2001; 24: 3-ll, Hyper tensRes2003; 6: 1-36, Hyper tensRes2003; 26: 979-990]. Clinical studies have shown that synergistic effects of co-administered statin-based lipid-lowering drugs are synergistic. Kramsch et al., Journal of Human Hyperteasion (1995) (Sup l. L), 53-59, have shown that a combination of amlodipine and lipid-lowering agents for the prophylaxis of atherosclerosis provides a better therapeutic effect. have. Jukema et al., Arteriosclerosis, Thr ombos i sand Vascu 1 arBio 1 ogy, voI .16No, 3, 1996,425-43 (), also showed the mutually beneficial effect by combining the chamomile channel blocker with a lipid lowering agent. Prove that can be obtained. In addition, the use of amlodipine in combination with a lipid lowering agent lovastatin for the treatment of ischemic sclerosis is known in Orthov et al. [Int J Cardiol, 62, p.67-77, 199]. Dihydropyridine calcium channel blockers are not only high-pressure drugs, but they are also known to be angina pectoris, and statin drugs are not only lipid lowering agents but also known for their anti-inflammatory effects in various conditions. that increased simvastatin is about the stability recognized so ⁱ be able to buy books in pharmacies without the Bahia spirit ^ [Cardiologyl992; 80 (Suppll) : S31-S36, JCardiovascPharmacol 1988; 12 (Suppl7): S110-S113, Lancet2000; 356: 359-365, Hypertens Res 2002; 25: 717-725, Hypertens Res 2002; 25: 329-333, Am J Manag Care. 2004 Oct; 10 (11 Suppl): S332-8.: Curr Control Trials Cardiovasc Med 2000, 1: 161165. Both drug groups can be developed in a dosage form that is administered once a day, which is a common feature that taking at dinner is the pharmacologically ideal dosage time. In many cases the drug is prescribed in combination of two yakmulgun may include simvastatin of the dihydropyridine calcium channel blocker of the ^'amlodipine and statin lipid-lowering drugs. In combination with these two drugs, amlodipine is synergistic with lipid lowering agents as well as its inherent anti-pressing action. . , Simvastatin to increase the lipid-lowering effect of simvastatin, Simvastatin also has a function to increase the blood pressure-lowering effect of the drug unique through synergistic action with Amlodi ¾ as well as intrinsic lipid-lowering action There is an advantage.

 Another combination of abusive prescriptions, amlodipine and atorvastatin, has the following advantages:

Patients with atherosclerosis, characterized by an uneven distribution of lipid deposits in the arteries, have an abnormal N0 production system (eNOs) in the vessel wall, resulting in This decrease increases blood pressure. Although general HMG ^- CoA reductase inhibitors have little NO release effects, amlodipine has a function of promoting NO release. However, the combination of amlodide and atorva-tatin has a much higher synergistic effect on NO. Unlike other statin drugs, atorvastatin has a phenoxy group, and this functional group catalyzes antioxidant activity due to proton donation and electron stabilization. This 02 the effect of amlodipine is that the vasodilating action that is, combined administration of amlodipine and atorvastatin is such a vessel wall is in eNOS lipid-lowering agent is atorvastatin because of a synergistic effect on kalseum channel antagonists - ^'- is a vasoconstriction action ^NO' [The American Journal of Medicine, 118, 54-61, 2005] The statin-based lipid lowering agent and the dihydrypyridine calm channel blocker are discussed in detail.

 Statin-based lipid lowering agents are ΗΜ (Η Α reductase inhibitors) and have the following general information, where statin-based lipid lowering agents and HMG-CoA reductase inhibitors are used interchangeably. Is the first choice for the prevention and treatment of heart disease caused by coronary atherosclerosis such as angina pectoris and myocardial infarction [Lancetl995; 346: 750-753, AmJCar dio 11998; 82: 57T-59T, AmJCardiol 1995; 76: 107C-112C, Hyper tensRes 2003; 26: 699-704, HypertensRes 2003; 26: 273-280, BrMedBul 12001; 59: 3-16, AmJMedl998; 104 (Suppl 1): 6S-8S, CI in Pharmacoki net 2002; 41: 343-370.] Statin-based hypolipidemia mainly consists of sylvastatin, atorvastated, fluvastatin, lovastated, pitavastatin, pravastatin, rosuvastatin and its pharmaceutically acceptable salts and isomers. This most representatively It is.

 Statin-based lipid-lowering agents have been recommended for use in the early evening, since lipid synthesis in the liver becomes vigorous after early dinner. [Arterioscler Thromb 11: 816-826, Am J Cardiol. 2006 Jan 1; 97 (1): 44-7. Epub 2005 Nov 8].

 Atherosclerotic or diabetic patients have abnormal N0 production (eNOs) in the vessel wall. This decreases N0 production and increases blood pressure. Statin-based lipid lowering agents, including simvastatin, increase the normal levels of eNOS in these ¾ tube walls. This is also one of the complex prescription effects in which lipid lowering action helps anti-pressure [Am J Physiol Renal Physiol Vol 281 Issue 5: F802-F809, 2001].

Metabolic enzymes that primarily activate statin-based lipid lowering agents are Cytokrum P450 3A4 And 2C9, metabolites are excreted from the liver through the biliary tract while acting in the liver

Drug Metab Disposl 990l 18: 138-145, Drug Metab Disposl 990; 18: 476-483 DrugMetabDisposl997; 25: 1191-1199 1997; 53: 828-847 C I inPharraacoki net 1996; 5: 348-371, Ar chB o ochemB i op ysl991; 290: 355-361

Drug etab Disposl 997; 25: 321-331: Drug Metab Dispos. 1999 Mar; 27 (3): 410-6. ].

 Therefore, if a drug used in combination with statin-based lipid lowering agents inhibits cytokine P450 enzymes that activate statins, the hepatic metabolism of statin-based lipid lowering agents is inhibited and statins and intermediate metabolites leak into the blood. The concentration will increase. The statin-based body metabolism and active metabolites liberated by hyperlipidemia can cause serious side effects of increased muscle lysis [Cl in Pharmacol Thar 1998; 63: 332-341, CI in Pharraacol Therl998; 64: 177-182, Physici ansDeskRef erence 2006 (Zocor), JPharmacolExpTher 1997; 282: 294-300, PharmacolExpTher 1999; 290: 1116-1125, L if eSc # 200; 76: 281-292 .: Drug Metab Dispos 1991; 19: 740-

748: Eur J Cl in P armaco 11996; 50: 209-215].

 In other words, when a simple combination of two drugs, the dihydropyridine-based chamomile antagonist first reaches the liver and induces * inhibition of cytokine P450 enzymes, and a large part of the starin-based lipid lowering agents that subsequently enter the liver or enter simultaneously Since it is not metabolized by cytokine P450 enzymes, a large amount of blood leaks out, delays excretion, or accumulates, and is not metabolized by the cytokine P450 enzyme. The hydroxy acid migrates to hypertension, causing blood levels to be higher than necessary, which can cause muscle disorders such as muscle solubility.

Simvastatin itself is a deactivated lactone-based compound and is primarily active in metabolites S, such as β-hydroxy acid of simvasta¾, an active form that has a hypolipidemic activity that enters the liver. Simvastatin is metabolized in several stages by the cytokine P450 3A4 in the liver, and activated metabolites exert potent lipid-lowering effects. It is well known that simvapatin has been shown to reduce the incidence of coronary heart disease 1 and reduce mortality in large clinical trials [Lancet 199; 34: 1383-1389. This is because simvastatin strongly inhibits HMG-CoA reductase, which plays a key role in the synthesis of cholesterol in the liver, and at the same time acts as an inhibitor of inflammation-inducing factors ["Scandinavian Simvastat in Survival Study "published in the Lancet, 1994, 344, 1383-89], Since pitavasta ¾ is metabolized by cytochrome P450 2C9 and acts in the liver, it is excreted, and when administered with a drug that inhibits cytokine P450 enzymes, phytavastatin inhibits intrahepatic metabolism, thereby increasing blood concentration, This can cause side effects such as muscle lysis.

 Staggered channel blockers are one of the most commonly used anticancer drugs in combination with statin-based lipid-lowering agents. There are dihydropyridine-based staggered channel blockers in calcium channel blockers, and dihydropyridine-based staggered channel blockers, such as amlodipine and lercanidipine. , Lacidipine, felodipine, vanidipine, benidipine, silinidipine, isradinine, manidipine, nicardipine, nifedipine, nimodipine, neilbodied, nisulodipine nitrenedipine, a¾nidipine and the like Salts and isomers are mainly used, among which amlodipine is most representatively prescribed. In particular, amlodipine is most commonly prescribed as an antihypertensive and angina treatment agent worldwide [Cardiologyl 992; 80 (StiE »pll): S31—S36, JCardi ovascPharmaco 11988; 12 (Suppl7): S110-S113, Lancet 2000; 356: 359 -365, Hyper tens Res 2002; 25: 717-725, Hyper tens Res 2002; 25: 329-333.

 The dihydropyridine-based chasm channel blocker is an antihypertensive drug that lowers blood pressure by blocking permeate in ¾ tubular smooth muscle and inducing peripheral artery dilation, and has common characteristics effective for angina due to convulsive vasoconstriction. It is also known that calcium channel blockers may have beneficial effects in the treatment of early cervical lesions [Lancet, 335, p. 1109-1139, 1990; and Circulation, 82, p.19401953, 1990].

 From a pathophysiological point of view, an increase in blood pressure during the morning, especially after morning waking, is a ¾ pressure increase due to ¾ wall wall spasm caused by stress stimulation, and dihydropyridine calcium channel blockers are primarily responsible for relaxing these spasms. Because of the action, especially in the morning after waking up in the morning, the blood pressure-lowering effect appears strongly. Therefore, if the dihydropyridine kill: sump channel blocker in the evening hours is reacted in the evening, it can reach the maximum concentration of ¾ before waking up, and the strongest blood pressure drop during the waking routine. Can be.

Amlodi ¾, a representative example of a dihydropyridine-based scab channel blocker, is an antihypertensive drug that lowers blood pressure by blocking peripheral vascular smooth muscle influx and inducing peripheral veins, which is effective in angina due to convulsive vasoconstriction. The chemical name is 3– to ¾-5-methyl ᅳ 2 ᅳ (2-aminoespecialime ¾) -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl ᅳ 3, 5 ᅳ pyridinedica As a carboxylate, the half-life is very consistent with 30 to 50 hours. It is a very useful chest channel blocker that shows activity over a long period of time [European Patent Publication No. 89, 167 and US Patent No. 4, 572, 909]. Oral administration of amlodipine as a single agent results in more than 40% breakdown in the small intestine, which leads to hypertension, leaving only a moderate blood pressure drop. In addition, amlodipine is a 24 hour daily lasting medicine, and taking it in the evening hours is the most powerful effect of lowering blood pressure from the morning of the next morning to midday.

Nitte dipin is when oral ruyeo a single drug mostly varies in the form of a metabolite of the inert type, 60-80% of the dose excreted in urine and ¾ the kidney, it is ^"arranged in byeoneu part via the bile duct. The metabolism of nifedipine is involved in the cytokine P450 enzyme system and has a potent inhibitory effect on cytokine P450 3A4. Nifedipine's excretion half-life is known to be about two hours. In order to have an all-day blood pressure-lowering effect upon administration, the nisinidipine formulations provided are provided in a slow release form throughout the day. In terms of pathophysiology ^' blown, especially morning weather. After that, the increase in ¾ pressure in the morning is the increase in blood pressure caused by vascular wall spasm caused by stress stimulation, nifedipine is the main action to relax this mild vascular contraction. Especially after morning waking, the blood pressure of morning sickness is effectively lowered. Para-on, when the nifedipine to taking the evening time (17 to 23 o'clock) and the highest reaches the blood concentration before the gas phase, it is possible to appear the most strongly ¾ mouth "lowering action in the work after the gas ^phase." The salpin described Likewise, when the cytokine P450 enzyme is already present, a dihydropyridine-based drug such as amlodipine may be partially inhibited by the enzyme, but it will soon act to inhibit the production of the Cytokrom P 450 3A4 enzyme. Most dihydropyridone drugs are mainly metabolized by cytokine P450 3A4 enzymes and also by cytokine P450 3A4 enzymes such as cytokine P450 2C9 [Arc lnternMed. 2002Feb25; 162 (4): 405-. 12., Dru ^ et abDi spos .2000Feb; 28 (2) ： 125-30.] Due to these characteristics, a combination of statin-based lipid lowering agents and dihydropyridine-based drugs requiring cytokine P450 appeal is required. Should be administered with a time delay to avoid interaction other drugs [MedCheml991; 34: 1838-1844,

EurJCl in Pharraacol 2000; 55: 843-852. ].

Thus, when administered in combination with drugs such as dihydropyridine-based kalseup channel blockers to inhibit the ^"Formation of torque flow P450 enzyme that activates the statin has particular administration method However, until now, no pharmaceutical preparations have been invented and approved which allow time-dependent action of dihydrolyridine calcium channel blockers and statin lipid lowering agents. In addition, prescribers are not able to co-prescribe the two drugs, but can't give the patient proper medication guidance such as taking the two drugs in time. If the two drugs are isochronically abused, the blood concentration of stard-based lipid lowering agent may be adversely induced, which may cause side effects, and it is difficult to obtain more effective blood pressure lowering action and effective lipid lowering action that can be obtained by using the two drugs together. [Hypertens Res, 2005, Vol. 28, No. 3], a study by Shinidiiro Nishio et al., Investigated the dihydropyridine calcium channel blocker amlodipine and the statin lipid lowering agent simovastatin in patients with hyperlipidemia. A case where a single agent is administered at the same time and a simvastatin single agent is compared is shown.

 According to the experimental results of Table 1 below, simultaneous administration of simvastatin and amlodisome inhibits cytokyl P450 3A4 enzyme due to amlodipine, and the concentration of simvastatin and the active metabolite is measured by the activity titer method. It has been found to have increased, and the possibility of side effects from this has been announced [Hypertension Research Vol. 28 (2005), No. 3 March 223-227.

 TABLE 1

 As shown in Table 1 above, when the blood concentration of the lipid-lowering component is combined with a single administration of simvasta¾ alone, the blood concentration at the time of the complex prescription is measured by the activity titer measurement.

30% higher. Nevertheless, lipid lowering activity did not rise. If the hepatic concentration of simvastatin-activated metabolites to act in the liver is higher than necessary, the inhibitory effect of cholesterol biosynthesis is reduced, and the likelihood of significant side effects such as muscle lysis is increased. Korean Registered Patent No. 582347 discloses ammodyne, a dihydropyridine calcium channel blocker, which is rapidly released and the mandrel is eluted, and the statin is gradually eluted over 24 hours, thereby preventing the statin drug from being eluted and absorbed at one time. Disclosed is a composite agent. In the present invention, it is considered as an irrational agent that reduces the efficacy of statins in the present invention as a complex system of concepts that are different from the concept of eluting statins first and metabolizing them in the liver first. If the amlodipine is introduced into the thrower liver, the production of cytochrome ί¾50 3A4 is inhibited in the liver, so that a small amount of statins, which are subsequently introduced into the liver, is not metabolized by the liver and is released into the blood. The patent only increases the side effects such as muscle lysis due to the release of statins, which should act in the liver, into ¾.

 In addition, Korean Patent No. 742432 is a patent for a pharmaceutical preparation including amlodicec ¾ sillate and simvastatin, and a method for preparing the same, but Cytok, which is required by simvastatin because both components are eluted simultaneously and absorbed into the liver Because comb P450 3A4 is inhibited by amlodipine, simvastatin is released in excess of 30% into the blood along with the activator, which is not sufficiently activated in the liver, resulting in decreased lipid lowering and increased side effects. Has also been demonstrated through clinical trials of the invention). Therefore, the present invention is a simple compounding concept, and this simple North compound is being removed due to the lack of progress. In addition, Pfizer's Korean Patent Publication No. 200,7002144, was also rejected by the Korean Intellectual Property Office because amlodipine and ato a vastatin are simple combinations.

 In other words, based on the above results, it is possible to prevent the mutual antagonism of the drug, which is a problem that is more likely to occur from simply prescribing a single agent or taking a dihydropyridine-based hem channel blocker than statin-based lipid lowering agents. There is a greater need for the development of viable dosing regimens or pharmaceutical formulations.

 Accordingly, the present inventors have completed the present invention to develop a pharmaceutical preparation effective for the prevention and treatment of hypertension and hyperlipidemia and thereby cardiovascular disease or metabolic syndrome.

 [Detailed Description of the Invention I

 [Technical problem]

The present invention controls the release of an agent comprising a dihydropyridine-based chamomile channel blocker containing several star ¾ lipid-lowering agents within about 2 hours of dissolution and absorption time in the gastrointestinal tract. To provide a pharmaceutical formulation that exhibits a difference of at least about 4 hours.

 The present invention also provides a preparation comprising a dihydropyridine-based chamois blocker and a statin-based lipid lowering agent, by optimizing the drug delivery time of the drug to prevent metabolic syndrome and insulin-resistant patients, and patients suspected of diabetes mellitus or diabetes mellitus. Maximize the effect of calcium channel blocker, which is the prevention or treatment of cardiovascular disease, cardiopulmonary disease, lung disease or kidney disease, and the effect of HMG-CoA reductase inhibitor, which is the prevention or treatment of heart disease caused by coronary atherosclerosis such as angina pectoris or myocardial infarction, It is intended to provide a pharmaceutical formulation that can avoid the interaction between the two drugs and the side effects thereby.

 Furthermore, the present invention is a preparation comprising a dihydropyridine-based chamomile channel blocker and a statin-based lipid lowering agent, which is added to convenience by taking one tablet once daily between evening hours and preferably 5 to 11 pm. In order to provide a pharmaceutical preparation that can further increase the patient's medication woowoonggi cold.

 Technical Solution

 The present invention relates to a pharmaceutical formulation designed to control and release each drug at a specific rate by applying the so-called Chronotherapy principle, which is administered at a time difference in the pharmacological action expression time of each complex component. In other words, the pharmaceutical formulation of the present invention applies the principle of GhronotheraDy and Xenobiotics of the drug to the expression of pharmacological action of each of the complex components, and is controlled at the specific rate and absorbed into the body. It is a specially designed drug delivery system that can produce an ideal effect.

 The present invention provides a pre-release compartment comprising a statin-based lipid lowering agent, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a dihydropyridine calcium channel blocker, an isomer thereof, as a pharmacologically active ingredient. Or a delayed-release compartment comprising a pharmaceutically acceptable salt thereof. The present invention is a dihydropyridine-based chamomile antagonist as an active ingredient, a delayed-release compartment made of granules, pellets or tablets, and a statin-based lipid lowering agent as an active ingredient. Provided is a pharmaceutical formulation with controlled release properties even with timed dissolution, which is a capsul formulation comprising an exudative compartment.

Formulation of the Invention The dihydropyridine-based scabin antagonist is lowered in starlin-based lipids The release can be adjusted to be absorbed by the liver 2 to 4 hours later.

 In the present invention, the dihydropyridine-based scab antagonist is amlodipine, lercanidipine, lassipinepine, felodipine, vanidipine, benidipine, silnidipine, isradinine, mandidi ¾, nicardidipine, nifedipine, nimodipine. , Nilvadipine, nisulodidi¾, nirenedipine, azanidipine may be selected from pharmaceutically acceptable salts thereof and isomerism thereof, and may be included in the range of 1 to 400 rag in the formulation.

 In the present invention, the delayed-release compartment may include at least one release controlling substance selected from an enteric polymer, a water-insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic membrane coating base, and an osmotic pressure-controlling agent. Silver polyvinylacetate phthalate, hydroxypropylmeth ¾ chlorocellulose phthalate, shellac, cello ώ acetate phthalate, salose propionate phthalate, pulley (methacrylate, methyl methacrylate) One or two or more mixtures selected from copolymers and poly (methacrylate, ethyl acrylate) copolymers. Semipermeable membrane coating base Coating base is polyvinyl acetate, a full methacrylate copolymer as a poly (ethyl acrylate- Meth ¾ methacrylate copolymer, ¾ (ethyl arc ¾rate-meth ¾ methacrylate-trimethyl meth) No ¾ decacrylate) copolymer, ethyl shellulose, saltose ester, ¾ chloro ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose One or two or more mixtures selected from acetate, salose acetate and cellulose triacetate; The third pressure regulating agent is magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, calcom sulfate, sodium sulfate, lithium sulfate and sodium sulfate selected one or two or more mixtures;

The statin-based lipid lowering agent is one or two selected from simvastatin, lovastat¾, atorvastatin, pitavastatin, rosuvastated, flu; vastatin, pravasta ¾, pharmaceutically acceptable salts thereof and isomers thereof. It may be a combination of the above. The present invention also relates to (a) a delayed-release compartment comprising a dihydropyridine base antagonist, a pharmaceutically acceptable salt thereof or an isomer thereof, a pharmaceutically acceptable carrier or diluent as an active ingredient (star as W active ingredient) A layer comprising a preservative-release compartment prepared using a base lipid lowering agent, a pharmaceutically acceptable salt thereof, or an isomer thereof, a pharmaceutically acceptable carrier or diluent, and (c) the first agent and the second agent Provided is a kit comprising container means for thickening.

 The present invention also provides a dihydropyridine-based calcium antagonist active ingredient, a delayed-release compartment prepared as a tablet, and a statin-based lipid lowering agent as an active ingredient.

The present invention provides a pharmaceutical formulation with controlled release, capable of dissolution of time, which is a coated tablet comprising a pre-release compartment coated on the surface of a single agent.

 The present invention also provides a delayed-release compartment comprising the dihydropyridine calcium antagonist as an active ingredient and constituting the inner core to release the drug by osmotic pressure, and a statin-based lipid lowering agent as the active ingredient, Provided is a pharmaceutical formulation with controlled release to allow monolithic timed dissolution of a dichroic layer comprising a radial release compartment. The present invention relates to a pre-release compartment comprising a statin-based lipid lowering agent, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a dihydropyridine calcium channel blocker, an isomer thereof, as a pharmacologically active ingredient. Or it provides a pharmaceutical formulation comprising a delayed-release compartment comprising a pharmaceutically acceptable salt thereof.

 The formulation according to the present invention is physically separated or partitioned to control the release property between the two active ingredients to obtain different release rates between the two ingredients, thereby improving the problem of co-administration or isoadministration of the existing single agent. It provides a more relaxing therapeutic effect.

 The agent of the present invention is a pre-release compartment and a dihydropyridine calcium antagonist that elutes statin-based lipid lowering agents to be absorbed in the small intestine so that they can be absorbed in the liver 2 to 4 hours later than statin-based lipid lowering agents. It is a pharmaceutical formulation comprising a delayed-release compartment.

 The present invention provides a delayed release compartment comprising simvastatin, an isomer thereof, or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and an amlodipine, other isomers or a pharmaceutically acceptable salt thereof, as a pharmacologically active ingredient. Pharmaceutical formulations comprising a release compartment (hereinafter referred to as simvastared / amlodipine formulations) are provided.

In addition, the present invention provides a prior-release compartment comprising atorvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and a pharmacological activity Pharmaceutical formulations comprising amlodipine, isomers thereof or pharmaceutically acceptable salts thereof as active ingredients provide a pharmaceutical formulation comprising a delayed-release compartment (hereinafter referred to as atorvastatin / amlodipine formulation).

The present invention also provides a prior-release compartment comprising atorvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and nifedipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. It provides a pharmaceutical formulation (hereinafter referred to as ' ¹ atorvastatin / nifedipine formulation') comprising a delayed-release compartment comprising.

 The present invention also provides a prior-release compartment comprising pitavastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as an pharmacologically active ingredient, and amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. A pharmaceutical formulation comprising a delayed-release compartment containing the following (hereinafter referred to as a 'pitavastatin / amlodipine formulation') is provided.

In addition, the present invention provides a prior-release compartment comprising Roschvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. It provides a pharmaceutical formulation ⁽ hereinafter referred to as "roschvastatin / amlodipine formulation") comprising a delayed-release compartment comprising a.

 In addition, the present invention provides that the pharmacologically active component of the lipophilic compartment and the pharmacologically active component of the prior-release compartment are bendipine several pitavastatin, nimodipine and pravastatin, nivaldi ¾ and pitavastatin, nisoldipine and lovastatin ni. Cardipine and rosuvastatin, nirenedipine and pravastatin, nifedipine and pullastatin, lashidipine and simvastatin, lercanidipine and simvastatin, manidipine and lovastat¾, vanidipine and lovastat¾, silnidipine and pravastatin, Pharmaceutical preparations that are amlodipine and lovastated, isradipine and quarustatin, ajunidipine and simvastatin or felodipine and atorvastatin.

 The present invention also preferably provides a statin-based lipid lowering agent release of statin-based lipid lowering agent, which is initiated after about 1 hour of statin lowering agent release * and is completed before about 8 hours. Providing a pharmaceutical agent which is then commenced and completed about 6 hours prior,

Nifedipine in the dihydropyridine-based calcium channel blocker as an active ingredient The preparation is delayed until the release of nifedipine is sufficiently delayed and the elution is initiated after about 1 to 8 hours. Preferably, atorvastatin elutes at least 90% of the drug within 1 hour, and nifedipine is sufficiently released. It is delayed and adjusted to begin dissolution about 2-6 hours after oral administration.

 For example, the release of simvastatin / amlodipine formulations, or pitavastatin / amlodipine formulations, amlodipine of the present invention is initiated about 1 hour after each statin-based lipid lowering agent and is completed before about 8 hours, or is preferred. Preferably about 2 hours later. Completed prior to 6 o'clock and atorvasta ¾ / amlodipine formulation of the present invention Amtodipine release is initiated about 1 hour after atorvastatin release and is completed before about 8 hours, or preferably after about 1 hour Rochevastatin / Amlodipine Formulation Completed before about 6 hours and amlodipine release can be initiated after about 1 hour of roschvastatin release, preferably after about 2 hours.

The pharmaceutical formulation of the present invention has a time for which release of less than about 40¾ of the total amount of dihydropyridine calcium channel blockers is maintained within about 2 hours, preferably within about 3 hours, more preferably after the start of release of the statin-based lipid lowering agent. Preferably, the drug is provided within about 4 hours, so that the effect of the dihydropyridine calcium channel blocker can be effectively generated after a certain delay time. For example, after the initiation of the release of the simvastatin / amlodipine formulation or the atorvastatin / amlodipine formulation, simvastatin or atorvastatin, the release of about 40¾ or less of the total amount of amlodipine is maintained within about 2 hours, preferably within about 3 hours. More preferably within about 4 hours and phytavastatin / amlodipine formulations or Roschvastarin / amlodipine formulations can dissolve up to 4 hours of amlodipine 1: 40% of this total, preferably not more than 30¾ . In a more preferred pharmaceutical formulation of the present invention, the statin-based lipid lowering agent is first released and 8M, preferably 90% or more of the elution is completed within 1 hour, and the dihydropyridine-based calm channel blocker starts to dissolve after about 2 hours. And less than 40%, preferably less than about 30%, of the total amount within about 4 hours. For example, in the simvastatin / amlodipine formulation, atorvastatin / amlodipine formulation, atorvastatin / nifedipine formulation, or pitavastatin / amlodipine formulation, each statin-based lipid lowering agent is at least 80¾ within 1 hour, preferably at least 90% This elutes and the amlodipine or nifedi ¾ starts to elute after 2 hours, and the dissolution rate up to 4 hours is 40%, preferably not more than 30¾. It is adjusted to be released to the level. In the Rochevastatin / Amlodyne formulation, Rochevastatin is released more than 80% within 30 minutes, preferably 15 minutes, and amlodipine release is delayed more than 40¾ within 4 hours after oral administration. And preferably a pharmaceutical formulation released below 3 ". In addition, in the atorvastatin / nifedi tube preparation, atorvastatin elutes at least 80% within 1 hour, and nifedipine is S-cutted so that elution is started after about 1 to 8 hours due to the delayed release. Atorvastatin elutes 90% or more within 1 hour, and nifedipine can be controlled to initiate elution approximately 2-6 hours after oral administration due to a significant delay in release. The pharmaceutical composition of the present invention exhibits the most effective effect when taken between 5 and 11 o'clock in the evening.

 In addition, the above-mentioned prior release compartment and controlled release compartment may be embodied in various formulations.

 Each component of the pharmaceutical formulation of the present invention is described in more detail as follows.

1. Pre-release block

Pre-release compartment refers to the compartment that is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention.

(1) pharmacologically active ingredients

The pharmacologically active ingredient of the prior release compartment comprises a statin-based lipid lowering agent or a pharmaceutically acceptable salt thereof, and may further comprise a pharmaceutically acceptable additive as necessary.

Statin-based lipid lowering agents of the present invention include simvastatin, lovastat¾, atorvastatin, pitavastar ¾, rosuvastatin fluvastatin, pravasta ¾, and the like, including its optical isomers, racemates It includes all of them. For example, isomers of atorvastatin include (RJ isomers, a, s) isomers, (s, s) isomers, or

The (S,) isomers and their racemates include, but are not limited to, the (ý, β) isomer (R, S) isomer, the (S, R) isomer, or the (S, S) isomer. Isomers are mentioned. The active ingredient in the pre-release compartment may comprise about 1 to about 160 mg, preferably about 2 to about 80 mg, as a unit dosage star ¾ lipid lowering agent. For example, simvastatin is about 1 ^{^} about 160 mg, preferably about 2 to about 80 rag, atorvastatin is about 1 to 160 mg, preferably 5 to 160 mg, more preferably 10 to 80 mg The tin may comprise about 1 to 2 (g Roschvastatin 1 to 160 mg, preferably 5 to 80 rag.

The prerelease compartmentalizing statin-based lipid lowering agent is at least about 80¾ of the total amount of the statin-based lipid lowering agent in the unit formulation within 1 hour, preferably within 30 minutes, more preferably within 15 minutes of the start of release. More than% is released, which can quickly indicate the efficacy. For example, simvastatin is at least about 80% of the total amount within 1 hour after initiation of release, preferably at least about go% and atorvastatin is at least about 80%, preferably at least 90% within 1 hour of onset of release. Pitavastatin is within 1 hour after initiation of release, preferably within ₃₀ minutes, more preferably within about ₁₅ % or more of the total amount Rochevastatin within 1 hour after initiation of release, preferably within 30 minutes, More preferably, at least about 80% of the total amount can be released within 15 minutes.

(2) pharmaceutically acceptable additives

The formulations of the present invention may also be formulated using additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, stabilizers, pH adjusting agents, dissolution aids, colorants, fragrances, etc. without departing from the effect of the present invention. have. Its content is preferably 100 to 30,000 parts by weight based on 100 parts by weight of the statin-based lipid lowering agent, more preferably 100 to 20,000 parts by weight. For example, in the simvastatin / amlodipine formulation, 100 to 100 parts by weight of simvastatin is added. 30,000 parts by weight, preferably 100-20,000 parts by weight, in the atorvastatin / amlodipine formulation, pitavastatin / amlodipine formulation, or atorvastatin / nisudipine formulation, 1 to 100 parts by weight for each .statin lipid lowering agent Preferably it is 1-30 parts by weight and the Roschvastatin / Amlodi ¾ preparation may contain 0.01-100 parts by weight per 1 part of Roschvastatin. The diluent is starch, microcrystalline ¾, lactose , Glucose, manny, alginate, alkaline earth metal salts, cleats, polyethylene glycols, dicalcium phosphate, or mixtures thereof. . The binder is starch, microcrystalline cellulose, highly dispersible silica, manny, sucrose, lactose, pulley ethylene glycol, pulley vinylpyridone, hydroxypropyl methyl salose, hydroxy propyl cellulose, Natural gums, synthetic gums, copovidones, l, or combinations thereof may be used.

The disintegrant is a starch or modified starch, such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch, bentonite, monmo ¾ lonite, or clay microcrystalline cell such as vegum, Cells such as oxypropylcellose or carboxymethyl ¾rose such as sodium alginate or alginic acid. Crosslinked cells such as alginate croscarmel lose sodium Crosslinked polymers such as guarose gum guar gum, xanthan gum and crosslinked polymers such as xanthan gum Polivinyl pyridone (crospovidone) Effervescent agents such as sodium bicarbonate and citric acid Or a combination thereof.

The lubricant is talc, stearic acid, magnesium stearate, calcium stearate, etc., lauryl sulfate sodium, hydrogenated vegetable oil, natzyl benzoate, sodium stearyl fumarate, glyceryl behanate, glycerol monomonate, glyceryl mono Stearate, glycer palmitostearate, polyethylene glycol and the like can be used.

The stabilizer may be a salt of an alkali metal, a salt of an alkaline earth metal, or an alkalizing agent thereof, and preferably, calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium oxide, magnesium carbonate, sodium citrate, and the like. Ascorbic acid, citric acid, butylated hydroxy anisole, butylated hydroxy toluene, tocope may be used as the derivative.

The pH adjusting agent may be an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid and a basicizing agent such as precipitated calcium carbonate, ammonia water, meglumine.

The dissolution aid may be a lauryl sulphate, polysorbate, such as pulley oxyethylene sorbitan fatty acid esters, docuate sodium, and the like.

In addition, the formulation of the present invention may be formulated using a pharmaceutically acceptable additive selected from various additives selected from colorants and fragrances.

The range of the additives usable in the present invention is not limited to the use of the above additives, and the above additives may be formulated to contain a range of dosages by selection. 2. Delayed-release compartment In the present invention, a delayed-release compartment means a compartment in which the active ingredient is released after a certain time of release of the active release compartment active ingredient. The delayed-release compartment comprises (1) the pharmacologically active amlodi ¾, an isomer thereof or a pharmaceutically acceptable salt thereof, and (2-1) a release controlling substance and / or (2-2) an osmotic regulator and a semipermeable membrane. A coating base, and, if necessary, (3) may further include a pharmaceutically acceptable additive. The delayed-release compartment according to the present invention comprises a commercially available statin-based lipid lowering agent. It can also be taken at the same time.

(1) Pharmacologically active ingredient

The pharmacologically active ingredient of the delayed-release compartment includes dihydropyridine-based chamomile channel blockers, isomers thereof and pharmaceutically acceptable salts.

Dihydropyridine calcium channel blockers can be used to select components that are inhibited by Cytokrum P450 enzymes, for example, amlodipine, lercanidipine, lassidipine, felodipine, vanidipine, benidipine, silinidi. ¾, device radio ¾, Mani dipin, you carboxylic dipin, nifedipine, Nemo dipin, carbonyl body pin, nisul Lodi pin nitrendipine, O ¾ you dipin but include ^", nor not they are limited in kind between, as set forth above It can be selected and used in dihydropyridine type antagonism which is inhibited by the torque P450 type enzyme. Preferably, amlodipine, nifedipine and pharmaceutically acceptable salts thereof can be used, and pharmaceutically acceptable salts of amlodipine include, specifically, maleic acid salts of amlodipine and besylate salts of amlodipine.

The active ingredient in the delayed-release compartment is a unit-depleted dihydropyridine-based scab channel blocker, which is based on a daily adult (65-75 kg adult male), about 1 to about 400 mg of unit dosage, and preferably about 2 "-about 120 mg may be included. The increase in amlodapine is about 1 to about 40 mg, preferably about 2 to about 20 mg, nifedipine may contain about 1 to about 90 mg per day. Dihydropyridine-based Calcium channel blockers have a release time of about 40% or less of the total amount of unit dosages reached release within about 2 hours, preferably within about 3 hours, more preferably about 4 hours after initiation of the star ¾ lipid lowering agent. Resulting in delayed time-to-effect, eg, simvastatin / amlodipine formulations or atorvastatin / nifedipine formulations, which require less than about 40% of the total amount of amlodipine or nifedipine to reach release. Within about 2 hours, preferably within about 3 hours, more preferably within about 4 hours The atorvastatin / amlodipine formulation has a time of less than 20¾ of the total amount of amlodi ¾ to reach release within about 2 hours, preferably Is within about 3 hours, more preferably about 4 hours, and the pitavastatin / amlodipine formulation is released up to 4 hours at 40% or less of the total amount of amplified amlodipine, preferably at 30% or less, and Rochevastatin / amlodipine. The formulations may release up to 3 hours of up to 30¾ of the total amount of amlodipine, preferably up to 20%.

(2-1) Release Control Substances

The delayed-release compartment in the pharmaceutical formulations of the present invention comprises at least one release agent selected from an elutable polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, and a mixture thereof. The release control material may be used in an amount of 10 to 3,000 parts by weight with respect to 100 parts by weight of dihydropyridine-based chamomile ¾ agent, the amount of which is used in the above range. If less than sufficient delayed release is not obtained, if the dose exceeds the above range drug release is excessively delayed to obtain a significant clinical effect.

The release-controlling material in the simvastatin / amlodipine formulation is preferably an enteric polymer comprising ^"and the common compounds of a hydrophilic ^polymer, or comprises a subeul soluble polymer, relative to 1 part amlodipine increase, 0.1 - comprises 100 parts by weight .

 In the atorvastatin / amlodipine formulation, the release controlling substance may include 0.05-100 parts by weight, preferably 0.05-30 parts by weight, with respect to 1 part by weight of amlodipine, and preferably may be a mixture of an enteric polymer and a hydrophilic polymer. The enteric polymer and the hydrophilic polymer mixture may be included in 0.5 to 10 parts by weight and 0.5 to 20 parts by weight, respectively, based on 1 part by weight of amlodipine.

The release controlling substance in the pitavastatin / amlodipine formulation is available at 0.05-100 parts by weight with respect to 1 part of amlodipine, and preferably includes water-insoluble polymers and polymers and hydrophilic polymers in the roschvastatin / amlodipine formulation. The release control material is available in an amount of 0.05 to 100 parts by weight based on 1 part by weight of amlodipine, preferably comprising at least one release control material selected from a water-insoluble polymer and a hydrophilic polymer, and in the atorvastatin / nifedipine formulation. The release control material may be used in an amount of 5 to 300 parts by weight with respect to 100 parts by weight of nifedipine, and may preferably include an enteric polymer and a hydrophilic polymer. In the delayed-release compartment of the present invention, an enteric polymer is one that is soluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under conditions of pH 5 or higher, such as an enteric cellulose derivative, an enteric acrylic acid system, and the like. It is selected from the group consisting of a co-polymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, and a combination thereof. Herein, the enteric cellulose derivatives include hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl decyl queryl phthalate, hydroxyspecific methyl ethyl cellulose phthalate, cellulose acetate phthalate, and cellulose. Acetate Succinate, Salose Acetate Maleate, Salose ¾ Zoate Phthalate ¾ Loose Propionate Phthalate, Methyl Cellulose Phthalate, Carboxymethylethyl Cellulose, Ethyl Hydroxy Cellulose One or more of the enteric acrylic acid co-polymers selected from phthalate, methyl hydroxyethyl cellulose and their mixtures include styrene-arc ¾ acid copolymers, methyl acrylate-acrylic acid copolymers, and methyl methacrylate acrylate. Acid Copolymers, Arc Butyl-Styrene-Acrylate Acid Copolymers, Methac- Acid-Methac Methyl acrylate copolymer (Example ¾ units, Eudragit L 100, Eudragit S, Degussa, Germany), Methacrylic acid, Ethyl acrylate copolymer (Example ¾ units, Eudragit L 100-55, Degussa Germany ), At least one of the above-mentioned enteric maleic acid-based co-polymers selected from methyl acrylate-methacrylic acid-acetic acid octyl co-polymer and their mixtures is selected from the group consisting of vinyl acetate-maleic anhydride co-polymer styrene-maleic anhydride copolymer, styrene Monoester maleic acid copolymer, vinyl methyl ether-maleic anhydride copolymer, ethylene-maleic anhydride co-polymer, vinylbutyl ether-maleic anhydride co-polymer, arc ¾-nitrile-methyl ¾ acid 'maleic anhydride co-polymer, The at least one enteric polyvinyl derivative selected from butyl arc butyl-styrene-maleic anhydride copolymer and mixtures thereof is polyvinyl alcohol phthalate, At least one selected from cetal phthalate, polyvinyl butyrate phthalate, polyvinyl acetal phthalate, and mixtures thereof.

Preferred enteric polymers for simvastatin / amlodipine formulations include polyvinylacetate phthalate, hydroxypropyltetylcelose phthalate, ¾ talc, cellulose acetate phthalate, cellulose propionate phthalate, poly (methacrylate, methyl Methacrate) Copolymer and pulley (methacrylate, Ethacrylate) Copolymer may be at least one selected from 0.1 to 20 parts by weight, preferably 0.5-10 parts by weight relative to 1 part by weight of amlodipine. Can be included ¾.

Preferred enteric polymers in atorvastatin / amlodipine formulations are hydroxypropylmethyl. Cell ¾ low phthalate, arc ¾ methyl-acrylic acid co-polymer, methacrylic acid-methyl methacrylate co-polymer, polyvinyl alcohol phthalate, polyvinylacetacetal phthalate are used, and more preferably hydroxypropyl methyl May be at least one selected from cellulose phthalate S, methacrylate acrylic acid-methacrylic acid copolymer, methacrylic acid-methacrylic acid ¾ acid tetramethyl co-polymerization, 0.1 to 20 parts by weight relative to 1 part by weight of amlodipine, preferably Can be included in 0.5 ᅳ: 10 increments.

Preferred enteric polymers in the pitavastatin / amlodipine formulations include arc ¾ acid copolymers, preferably methyl methacrylate acrylic acid copolymers (product name, acryl-is). It may be included in an amount of 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight.

Preferred enteric polymers in the Rochevastatin / Amlodipine formulation are at least one selected from methylmethacrylic acid co-polymer and hydroxypropylmethylcell of rosophthalate, and are included in an amount of 0.1-20 parts by weight, preferably 0.5-10 parts by weight, relative to amlodipine. If less than 0.1 parts by weight, there is a problem that is easily dissolved at pH ^' below 5, and if more than 20 parts by weight there is a problem that the total weight of the formulation is unnecessarily increased or excessively delayed dissolution.

In the atorvastatin / nifedipine preparations, enteric cellulose derivatives, enteric acrylic acid co-polymers, and enteric pulley vinyl derivatives are preferably used, and more preferably hydroxypropylme ¾¾rollosephthalate and hydroxypropylmerolo. Osacetate succinate, methacrylic acid-methacrylic acid ¾ copolymer may be used and may be included in an amount of 5 to 150 parts by weight, preferably 10 to 50 parts by weight, based on 100 parts by weight of nipadidi pin.

When the enteric polymer is included in the formulations below the lower limit of each of the formulations, there is a problem of dissolving easily at a pH of less than 5, and when included above each upper limit, the total weight of the formulation is unnecessarily increased or excessively delayed dissolution. There is a problem. In the delayed-release compartment of the present invention, a water-insoluble polymer is a polymer which is insoluble in pharmaceutically acceptable water to control the release of the drug. For example, polyvinylacetate, a polymethacylate copolymer, Poly (Ethyl Acrylate-Methyl Methacrylate) Copolymerization 쳬, Poly (Ethyl Arc ¾late-Cityl Methacrylate-Trimethylamino-Ethylmethacrylate) Copolymer, Ethyl Cellulose, Chlorose Ester , Cellulose ethe Le, ¾ loose acylate, cellulose diacrylate salorose triacylate, ¾ loose acetate, loose diacetate, ¾ loose triacetate, and mixtures thereof The above is mentioned.

In the simvastatin / amlodi ¾ preparation, the water-soluble polymer is preferably a polyvinylacetate; a polymethacrylate co-polymer; a pulley (ethyl acrylate-methyl methacrylate) co-polymer; a poly (ethyl arc 레이트 late-methyl methacrylate ¾late ᅳ trimethylaminoethyl methacrylate) copolymer, ethyl cellulose, cellulose acetate, more preferably polyvinyl acetate, poly (ethyl arc methacrylate—meth methacrylate Late trimethylamino ¾ methacrylate) copolymer, polybutak ¾ tate co-polymer, poly (¾ acrylate-methyl methacrylate) copolymer, and the like can be used. —30 parts by weight, preferably from 0.5 to 20 parts by weight.

In the atorvastatin / amlodipine formulation, the water-insoluble polymer is preferably polyvinyl acetate, Eudragit RS P0, ethyl shellose, sal-rose acetate, and more preferably polyvinylacetate, Eudragit RS. P0, ethyl cellulose may be used, and may be included in an amount of about 0.1-30 parts by weight, preferably 0.5-20 parts by weight, based on 1 part by weight of the active ingredient amlodipine.

In the pitavastatin / amlodipine formulation, the water-insoluble polymer may preferably be an acrylic copolymer roll, more preferably Eudragit RS30D, and 0.1-30 parts by weight, preferably 0.5-, based on 1 part by weight of amlodipine. It may be included in 20 parts by weight.

In the Rochevastatin / Amlodipine formulation, the soluble polymer is composed of ¾ribinal acetate (Collicott S 30D), saloose acetate and ply (ethyl arc ¾rate-methyl methacrylate-trimethylaminoethylmethac ¾). It is preferable that at least one selected from the rate) co-polymer (Eudragit RS30D), it can be included in the amount of 0.1-30 parts by weight, preferably 0.5-20 parts by weight relative to amlodipine.

In the atorvastatin / nizadipine formulation, the water-soluble polymer preferably uses an acrylic acid copolymer, more preferably a poly (¾H-acrylate-methyl methacrylate-trimetha¾aminoethylmethacrylate) copolymer ( Eudragit RS30D and Eudragit LR30D) and may be included in an amount of 5 to 200 parts by weight, preferably 10 to 100 parts by weight, based on 100 parts by weight of nifedipine. It is preferable to use 20 to 100 parts by weight of the poly (ethyl arc ¾-methyl meth ¾-trimeth ¾ aminoethyl meth ¾) copolymer with respect to 100 parts by weight of nifedipine. In the above formulations, when the water-soluble thickener is included below each lower limit, there is a problem in that the release of the drug is not controlled, and when included above each upper limit, unnecessarily excessive dissolution is delayed. In the delayed-release compartment of the present invention, hydrophobic compounds refer to substances which are insoluble in the pharmaceutically acceptable water controlling the release of the drug, such as fatty acids and fatty acid esters, fatty acid alcohols, waxes, inorganic substances, and And at least one selected from the group consisting of these mixtures. The exciple fatty acids and fatty acid esters are at least one selected from glyceryl palmitostearate, glycerol ¾ stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate, stearic acid, and combinations thereof; Fatty acid alcohols include one or more selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof; The waxes may be at least one selected from carnauba wax, beeswax, microcrystalline wax, and mixtures thereof. ^' Inorganic materials may be used at least one selected from talc, precipitated carbonated carbon, hydrogen hydrogen phosphate, zinc oxide, titanium oxide, carbonine, bentonite, ponmo ¾ ronite, non-gum and their common substances.

For simvastatin / amlodi ¾ preparations, the hydrophobic compounds preferably contain fatty acid esters, glyceryl palmitostearate, glyceryl stearate, glyceryl nonarate, more preferably gloxe ¾ stearate, glycerol bihe Nate may be used and may be included in an amount of 0, 1-20, and preferably 0,5-10, relative to 1 part of amlodipine.

In the atorvastatin / amlodipine formulation, the hydrophobic compound preferably uses fatty acid esters, fatty acid alcohols, waxes, inorganic materials, more preferably fatty acid esters, fatty acid alcohols, and amlodipine. 0.1-20 parts by weight, preferably 0, 5-10 parts by weight based on 1 part by weight.

In the pitavastatin / amlodipine formulation, the hydrophobic compound is preferably fatty acid esterolol, more preferably glycerol ¾ stearate, and 0.1 to 20 parts by weight, preferably 0.5 to 1 part by weight of amlodipine. It can be included in 40 increments.

In the rosuvastatin / amlodipine formulation, the hydrophobic compound may be included in an amount of 0.1-20 parts by weight, preferably 0.5-10 parts by weight, relative to amlodipine.

In atorvastatin / nifedipine formulations, the hydrophobic compounds are preferably in fatty acids. More preferably, glycerol ¾ stearate may be used, and may be included in an amount of 5 to 300 parts by weight, preferably 15 to 100 parts by weight, based on 100 parts by weight of nife dipine. When the hydrophobic compound is included below the lower limit in the above formulations, there is a problem in that the release of the drug is not controlled, and when included above each upper limit, the dissolution is unnecessarily excessively delayed. In the present invention, the hydrophilic polymer is a pharmaceutically acceptable water-soluble polymer that controls the release of the drug, sugars, ¾ roll derivatives, gums, proteins, poly bi¾ derivatives, polymethacrylate copolymers, ¾¾ derivatives and carboxyvinylated polyethers can be selected and used as the saccharides, specifically dextrins, ¾ liddextrins, dextrans, peck¾ and peck derivatives, alginates, pulligaltaxuronic acids, xylans, arabinoxylans, Arabinogalactan, starch, hydrated propyl starch, amylose, amylopected, etc. can be selected, and as cellulose derivatives, hydroxypropylme ¾cellose, hydroxypropylpropyl ** loose , Hydroxymethylcellose, hydroxy to ¾ 쎌 rose, methylsalorose, carboxymethylshell loose, romium, hydroxypropyl methylcell Osacetate succinate, hydroxyethylmethylsulloose, etc. can be selected and used as gums, guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum, etc. It can be used to select, gelatin, casein, zein and the like can be used as a protein, polyvinyl alcohol, polyvinyl pyrrolidone and polyvinyl acetal diethylamino acetate and the like can be selected and used as a polyvinyl derivative Poly (butyl methacrylate), (Φ 2-methacrylic ¾rate-methylmethacrylate) copolymer, Φ remethacrylate¾ copolymer, poly (methacrylate¾-meth ¾metha) Cr-tetra B) co-polymer, poly (¾-acrylate to methacrylic acid) copolymers can be selected and used as polyethylene derivatives, such as pulley terylene glycol, Lithium oxide and the like can be selected and used, and carbomer can be used as the carboxyvinyl pulley.

In the simvastatin / amlodi ¾ preparation, the hydrophilic polymer is preferably starch, hydroxypropylmethylshell, hydroxypropylshell, carboxymethiolose, sodium nitrate, xanthan gum, polyvinyl alcohol or Carbomer may be used and may be included as 0.05-30 parts by weight, preferably 0.5-20 parts by weight, relative to 1 part by weight of Amrodda ¾. In the atorvastatin / amlodi ¾ preparation, the hydrophilic polymer is preferably a cell using a loose derivative, a polyvinyl derivative, a carbocyvinyl polymer, a pulley ethylene derivative, more preferably hydroxypropyl 쩨 loose. , Hydroxypropyl methyl cell, cellulose acetate succinate, polyvinylpyridone, carbomer, pulley ethylene oxide can be used and 0.05 to 30 parts by weight, preferably 0.5 to 20 parts by weight relative to 1 part by weight of amlodipine. have.

In the pitavastatin / amlodipine formulation, the hydrophilic polymer may preferably be carboxyvinyl ¾ mer, more preferably carbomer, 0.05 to 30 parts by weight, preferably 1 part by weight of amlodipine, preferably It may be included in an amount of 0.5 to 20 parts by weight.

In the Rochevastatin / Amlodipine formulation, the hydrophilic polymer preferably comprises a hydroxypropylcelose and / or a polymethathirate copolymer, more preferably a pulley (methacrylic acid methylmethylmethacrylate). S) may be used and may be included in an amount of 0.05 to 30 parts by weight, preferably 0.5 to 20 parts by weight, for 1 part by weight of amlodipine.

In the atorvastatin / nifedipine formulation, the sing-group hydrophilic polymer preferably contains a cell as a loose derivative, a carboxyvinyl plymer, more preferably ¾ salicylate propylme loose, Carbomers may be used and may be included in an amount of from 5 to 200 parts by weight, preferably 10 to 100 parts by weight, based on the weight of nizadipine loo.

When the hydrophilic polymer is included in the above formulations below the lower limit, there is a problem that the release rate of the drug is not less than ≤, and when the hydrophilic polymer is included above the upper limit, the dissolution is excessively delayed. For simvastatin / amlodipine formulations, the preferred release control agents are polyvinylacetate, fullime 1-tacrylate co-concentration 쳬 poly (ethyl arc ¾rate, decyl methacrylate ¾tate, trimeth ¾ amino to ¾ methacrylate S ), Copolymer 쳬, Carboxy vinyl hornmer, ¾ Cellulose, "Loose Acetate, Carboxyme ¾ Cellulose Sodium, Polyethylene Oxide Hydroxypropyl Methyl Chloride, Hydroxylpropyl Cellulose, And at least one selected from the group consisting of hydroxypropyl methylcells and phthalates, or selected from the group consisting of carboxyvinal polymers, hydroxypropylmethylcells, and several hydroxypropyl.methcelloses It may be one or more, or one containing a carboxyvinyl pulleyr and hydroxypropyl cellulose. Preferred release control substances for atorbasin / tin / amlodipine formulations include polyvinylacetate, polymethacrylate co-polymer, carboxyvinyl polymer, hydroxypropylmetholose, hydroxypropyl¾ At least one selected from the group consisting of cellulose, ¾ roll acetate, ethyl cellulose, polyethylene oxide, and hydroxypropyl methyl pentose phthalate carboxyvinyl plymer, polymeth ¾late ^ polymer and And a mixture of carboxyvinyl plymer and hydroxypropylme ¾cell selected from the group consisting of hydroxypropylmethylcellose.

In the pitavastatin / amlodipine formulation, the preferred release control substances are hydroxypropylcellose, hydroxypropylmethylsalose, hydroxypropylmethylcellosephthalate, shell ^■ rose acetate, polyvinyl At least one selected from the group consisting of acetates, polymethacrylic acid copolymers, ethylcel ^' loose, li (methacrylate methylmethacrylate) copolymers and methyl methacrylate methacrylic acid copolymers, or One is selected from the group consisting of hydroxypropylcelose, cellulose acetate, ethylcellose, poly (meth¾late methylmethacrylate) copolymer.

In the Rochevastatin / Amlodisome formulations, the preferred release controlling substances are hydroxyspecificpropylsalose, hydroxyethoxypropylmerose, hydroxypropylmethyl ¾rollosephthalate, pylooseaceti 1, selected from the group consisting of eth, polyvinylacetate, fully methacrylate copolymer, ethyl ¾ loose, fully (methacrylate, methyl methacrylate) copolymer, and methacrylic acid ¾ terpacrylic acid copolymer Or the one or more selected from the group consisting of hydroxy propyl shellulose, salulose acetate, ethyl gelose, poly t decacrylate, and meth methacrylate). In the atorvastatin / nifedipine formulations, preferred release control substances are hydroxypropyl methyl ¾ cell cellulose phthalate, hydroxy propyl methyl cell cellulose acetate succinate, methac ¾ acid-methacrylate methyl copolymer, poly (ethylacryl Suntec from the group consisting of latex-methyl methacrylate-tritetyladinoethylmethacrylate), a glycerol ¾ stearate, hydroxy propylmethylshell, hydroxypropyl¾, and carbomer And one or more preferably, the release controlling substance is hydroxypropylmethylsal, loose phthalate, hydroxypropylmethylcell, loose acetate. One or more enteric polymers selected from succinate or methacrylic acid methacrylic acid methacrylic acid copolymers and ¾1 hydroxypropylmethelose, hydrophilic polymers selected from cellulose, hydroxypropyl¾ose, or carbomer . (2-2) Osmotic pressure regulator and semipermeable membrane coating base

The delayed-release compartment of the present invention includes an osmotic pressure control agent and may be a compartment coated with a semipermeable membrane coating base. In the delayed-release compartment of the present invention, osmotic seclective refers to components used to control the release rate of drugs using the principle of osmotic pressure, such as' magnesium sulfate, magnesium chloride, sodium chloride, calcium chloride, sodium phosphate, And at least one member selected from the group consisting of calcium phosphate, ammonium acetate, lithium chloride, sodium sulfate, sodium sulfate, sodium sulfate, and combinations thereof. Preferably sodium chloride, potassium chloride, sodium phosphate *, calcium phosphate can be used.

In simvastatin / amlodipine formulations, the osmotic pressure regulator is 0.01 to 10 parts by weight, preferably 0.05 to 5 parts by weight, based on 1 part by weight of amlodipine, atorvastatin / amlodipine formulations, pitavastatin / amlodipine formulations or roschvastatin / In the amlodipine formulation, 0.05 to 30 parts by weight, preferably 0.1-20 parts by weight, relative to 1 part by weight of amlodipine, in the atorvastatin / nifedipine formulation, in the amount of 5 to 150 ^, preferably 10 to 100 parts by weight may be included.

When the osmotic pressure control agent is impregnated to less than each lower limit in the above formulations, the osmotic pressure generating effect is insignificant, and when included above each upper limit, the total weight of the agent may be unnecessarily increased or an appropriate drug release rate may be realized. There is no problem. In the delayed-release compartment of the present invention, the semipermeable membrane coating base is a pharmaceutically usable coating base, which is used in the coating layer of the pharmaceutical formulation to form a membrane which allows some components to pass but does not pass other components. The above-mentioned water insoluble polymer may also be used. In the present invention, the semi-permeable membrane skipping agent is, for example, polyvinyl acetate, plymethac ¾ lay≤ copolymer, ply (ethyl arc ¾ rate, meth hexa decacrylate) copolymer, pulley (ethyl arc ¾ acetate, detyl meth ¾). , Trimeth ¾ aminoethyl meth ¾ rate) copolymer, ethyl cellulose, cellulose. Ester, Salloose Ether, ¾ Loose Acylate, ^ loose Diacylate, Cellulose Triacylate, Cellulose Acetate, Chlorose Diacetate, Chlorose Oust And at least one selected from the group consisting of liacetate, and combinations thereof.

In the preparation of simvastatin / amlodipine, the semipermeable membrane coating agent is preferably cellulose acetate, polyvinyl acetate, cellulose acetate, ethyl cellulose, polymethacrylate co-polymer, 1 part by weight of amlodipine. 0.01 to 10 parts by weight, preferably 0.05 parts by weight to 1.25 parts by weight.

In the Atorvasta ¾ / amlodipine formulation, the semipermeable membrane coating agent is preferably a poly (ethyl ac ¾, methyl methacrylate: trimethylaminoethyl methacrylate) co-polymer, cellulose ester, ethyl Salose, cellulose acetate may be used, and may be included in an amount of 0.5 to 2Q, preferably 1 to 10 parts by weight, relative to 1 part by weight of amlodipine.

In the pitavastatin / amlodipine formulation, the semipermeable membrane coating base may preferably be cellulose acetate and may be included in an amount of 0.1 to 20 parts by weight, preferably 1 to 10 parts by weight, based on 1 part by weight.

In the Rochevastatin / Amlodipine formulation, the semipermeable membrane coating agent may be included in an amount of 0.05 parts by weight, 30 parts by weight, preferably 0.1 parts by weight to 20 parts by weight, based on 1 part by weight of amlodipine.

In the atorvastatin / nifedipine formulation, the semipermeable membrane coating agent may preferably use ¾ rhorose acetate and may be included in an amount of 5 to 2000, and preferably 10 to 500, based on 100 parts by weight of nifedi ¾.

When the semi-permeable membrane coating base is included in the above formulations below the lower limit, there is a problem that the release rate is not controlled, such as difficult to have a layered delay time. Excessive (eg 9 hours or more) elution is delayed.

(3) pharmaceutically acceptable additives

The formulations of the present invention are referred to as pharmaceutically acceptable substances of (2-1) or (2 ᅳ 2) without diminishing the effects of the present invention, diluents, binders, disintegrants, lubricants, pH thereof. Commonly used additives such as crude agents, antifoams, and solubilizers can be formulated by further use without departing from the nature of delayed release. For example, starch, microcrystalline shellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene ¾ recall, decalum phosphate, or a combination thereof can be used as a diluent. As a binder, starch, microcrystalline salose, highly disperse silica, manny, sucrose, lactose, polyethylene glycol, polyvinylpyridin, hydroxypropylmethylcellose, hydroxypropylcellose, natural gum, synthetic Gum, copovidone, povidone, gelaline, or a combination thereof may be used,

As disintegrant, starch or modified ¾-minute starch, such as sodium starch glycolate, corn starch, potato starch or starch gelled starch, bentonite _> montmorillonite, or vegeum, etc. Cells such as salose or carboxymethyl gelose Crosslinked polyvinyl chloride such as sodium alginate or alginic acid Alginate croscarmel lose sodium such as alginic acid ¾ Gurose gum such as guar gum and xanthan gum Crosslinked polymers such as pyridone (crospovidone), effervescent agents such as sodium bicarbonate, citric acid, or a mixture thereof can be used.

Lubricant destearic acid, stearic acid magnesite, stearic acid kum, lauryl sulfur sulphate fl ", hydrogenated vegetable oil, natzoate, colloidal silicon dioxide, sodium stearyl fumarey S, glycerol ¾ behenate, glycerol Peel mono-rays, ^ riceryl monostearate, glyceryl gulmitostearate and polyethylene glycol may be used.

As a pharmaceutically acceptable additive of the present invention, the £ control agent is an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and a basic agent such as precipitated calcium carbonate, ammonia water, and meglumine. Etc. can be used.

As the pharmaceutically acceptable additive of the present invention, the antifoaming agent may use dimethicone, oleyl alcohol, propylene glycol alginate, simethicone such as simethicone emulsion, and the like.

In the pharmaceutically acceptable additive of the present invention, the dissolution aid can be used pleoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docuate or lithium.

In addition to the various additives selected from colorants, perfumes, pharmaceutically acceptable additives may be selected to formulate the formulations of the present invention. The range of additives that can be used in the present invention is not limited to the use of such additives, and one of the additives may be formulated to contain a range of dosages by selection, Further, in the delayed-release agent of the present invention, purified water, ethane, methylene chloride, and the like may be used as the solvent of the binder and the delayed-release additive, but preferably, purified water or ethane may be used.

In the pharmaceutically acceptable additives of the present invention, the available ¾ exclusion range is not limited to the use of such additives, and the above-mentioned additives may be formulated to contain a range of dosages by choice. The delayed-release compartment of the present invention consists of particles or granules obtained by mixing, granulating or coating a dihydropyridine-based calcium antagonist, a time difference controlling substance and a conventional additive used in pharmaceuticals.

The pre-release compartment of the present invention is made of granulated black granules through a conventional process for producing oral solids such as mixing, coalescing, drying and granulation, together with a statin-based lipid lowering agent, together with pharmaceutically acceptable additives. If the fluidity of the statin-based lipid-lowering agent mixture can be directly tableted, the composition can be obtained by mixing. If the fluidity is not *, the composition can be obtained by compression, granulation, and granulation. Thus it can be configured as a pre-release compartment.

The present invention provides a single tablet such as a biphasic matrix tablet, a multilayer tablet, a nucleated tablet containing a delayed-release dihydropyridine-based antagonist discontinuous phase in a continuous-release statin-based lipid lowering agent continuous phase as described below. It can be carried out by the production method and administration method, but is not limited thereto.

In addition, the granules constituting the delayed-release compartment and the prior-release compartment are mixed with pharmaceutical additives, and the tablets are compressed into double tablets or three tablets in parallel, using multiple tableting machines. Possible tablets for oral administration can be obtained. In addition, the granules constituting the delayed-release compartment may be mixed with a pharmaceutical additive and tableted to form a nucleus tablet, or the pharmaceutical coating may be applied to exhibit delayed-release properties. After mixing with a conventional additive and tableting as an outer layer, a tablet for oral administration can be obtained in the form of delayed release to the inner nucleus and a form in which the inner layer is surrounded by the inner layer.

In addition, the granules constituting the delayed-release compartment may be mixed and compressed with pharmaceutical additives or the drug layer constituting the prior-release compartment may be water-soluble after applying a special pharmaceutical coating even if it exhibits delayed release. After dissolving and dispersing in a film coating solution Tablets for oral administration can be obtained by coating the layers of the delayed-release tablet layer.

Also, to control the release of the dihydropyridine system, the osmotic material is contained in the tablet, and then compressed into tablets. Then, the surface of the tablet is coated with a semi-permeable polymer to form a nucleus tablet. By mixing with a pharmaceutical additive and tableting as an outer layer to obtain a tablet for oral administration in the form of a delayed-release compartment into the inner core and the immediate release layer on the surface of the inner core.

The present invention relates to a delayed-release compartment and a prior-release compartment comprising two-phase granules, radial granules or pellets and delayed-release tablets, delayed-release granules or pallets and pre-release tablets, and delayed-release tablets and pre-release tablets. It can be carried out by the production method and administration method of the layered camsul agent, but is not limited thereto.

Hereinafter, the present invention will be described in detail, the granules constituting the delayed-release second agent and immediate-release first agent according to the present invention are mixed with pharmaceutical additives as needed to layer the capsules in a controlled release. Possible capping agent can be obtained.

Further, the granules constituting the delayed-release compartment are coated as they are or tableted to show delayed release, and the tablets are compressed or coated after the tablets are granulated or coated. The tablets may be layered on the capsule to obtain a capsular agent capable of time release.

In addition, the granules constituting the open-release compartment are coated as they are or tableted to show delayed release, and the powder, granules or pellets constituting the pre-release compartment are laminated on the capsule to enable time lag release. I can get sage,

In addition, after the granules constituting the pre-release compartment is compressed into tablets and, if necessary, prepared into tablets, the granules and ¾¾ constituting the delayed-release compartment may be layered on the capsule to obtain a capsulant capable of time release.

In addition, the granules or pellets constituting the delayed-release compartment and the sacking or pellets constituting the prior-release compartment may be laminated on the capsule to obtain a capsulant capable of timed release. Also, to control the release of the dihydropyridine-based antagonist, the osmotic material is contained in the tablet, and then compressed into tablets. Then, the surface of the tablet is coated with a semipermeable polymer to form a nucleus tablet. Water can be mixed with pharmaceutical additives and then laminated to the capsule to obtain a timed release agent *.

The present invention separately prepares granule pellets or pre-release tablet layers constituting the prior release compartment, and calls for granules or delayed-release tablet layers constituting the delayed release compartment. It can be manufactured as a kit that can be layered together at work, blister, bottle, etc. The pharmaceutical preparations of the present invention can be formulated in a variety of formulations and can be formulated, for example, as viscous tablets, coated tablets, multilayer tablets, or nucleated tablets, powders, granules, or capsulants.

The pharmaceutical formulations of the present invention may be in the form of a two-phase matrix tablet consisting of delayed-release compartments—pre-releasing compartments surrounding them. The matrix of the delayed-release compartment and the prior-release compartment may be prepared as a preparation for oral administration by post-mixing or compressing the pharmaceutically acceptable additives in the material constituting the delayed-release compartment and the pre-release compartment. Two phase S present formulations. The pharmaceutical formulation of the present invention may be in the form of a two-phase matrix tablet obtained by slicing after uniformly mixing the delayed-release compartment and the prior-release compartment, and preferably, the delayed-release compartment is prepared in a granular form. It is.

In addition, the pharmaceutical formulation of the present invention may be in the form of a film skipping tablet consisting of a slow-release compartment and a film-coating layer consisting of a pre-release compartment surrounding the denture of the tablet, the film coating layer as the film coating layer is dissolved Simvastatin will be eluted.

In addition, the pharmaceutical formulation of the present invention is a delayed-release compartment obtained by mixing the pharmaceutical additives in the fruits and forests constituting the delayed-release compartment and the prior-release compartment, and tableting in two tablets or three tablets using a multiple tableting machine. And the pre-release compartment may be multi-layered form forming a multi-layer structure. This formulation is a tablet for oral administration specially formulated for pre-release and delayed release in layers.

In addition, the pharmaceutical formulation of the present invention may be a nucleated tablet consisting of the inner layer consisting of a delayed-release compartment and a layer consisting of a prior-release compartment enclosing the surface of the inner core, the nucleated tablet may be an osmotic nucleated tablet. The osmotic nucleus tablet is a tablet containing the osmotic pressure-controlling agent inside the tablet for delayed release and then tableted, and then the surface of the tablet is coated with a semi-permeable film coating base to form the inner core, and the granules constitute a pre-release compartment. It is a formulation in the form of having a delayed-release inner core and surrounding the surface of the inner core with a delayed-release inner core by mixing water with a pharmaceutical additive and then tableting the outer layer. The pharmaceutical formulations of the present invention may comprise particles, granules, pal¾, or It may be a capsular formulation comprising particles, granules, pellets, or tablets consisting of tablets and prerelease compartments.

The formulation of the present invention may further form a coating layer on the outside of the delayed-release compartment and / or the prior-release compartment. That is, the surface of the particles, granules, pellets, or tablets composed of delayed-release compartments and / or pre-release compartments may be coated for the purpose of release control or formulation stability.

In addition, the pharmaceutical formulation of the present invention may be in the form of a kit comprising a delayed-release compartment, and a prior-release compartment. Specifically, the present invention prepares particles, granules, ¾¾, or tablets constituting the pre-release compartment, separately prepares fruiting, ¾¾ or tablets constituting the delayed-release compartment, foils, blisters, bottles, etc. It may be in the form of a kit prepared in a form that can be filled together and taken simultaneously.

The formulation according to the present invention is also provided in a state such as uncoated tablets without additional coating, but may be a formulation in the form of a coated tablet further comprising a coating layer by forming a coating layer on the outside of the formulation, if necessary. By forming the coating layer, it is possible to provide a formulation that can further ensure the stability of the active ingredient.

The method of forming the coating layer can be appropriately selected by the choice of a person skilled in the art in the method of forming the coating layer outside the film on the surface of the tablet layer, a method such as a fluidized bed coating method, a fan coating method, can be applied, preferably For example, ¾ coating can be applied. The coating layer may be formed by using a coating agent, an auxiliary coating agent, or a combination thereof. Specifically, the coating agent may be a ¾ loose derivative such as hydroxypropyl methyl salose, hydroxy propyl propyl cellulose, a sugar derivative, or a ¾ lye. Vinyl derivatives, macrophages, fatty acids, gelatin, or mixtures thereof, and the like, and coating aids include polyethylene glycol, ethyl salose, ¾ riselides, titanium oxide, talc, diethyl phthalate, or mixtures thereof. A mixture or the like can be used. The coating layer may be included in the range of 0.5 to 15% by weight (% w / w) relative to the total tablet weight increase. The present invention also provides a pharmaceutical formulation according to the present invention for evening administration.

By taking the formulation of the present invention once a day, especially in the evening (17-23 hours), the effect of each active ingredient can be maximized and side effects can be minimized. In general, a critical factor to be considered in the treatment of hypertension and hyperlipidemia is biorhythm. For example, lipid synthesis in the liver becomes vigorous after early dinner, and the general population including people with hypertension Extravasation "falls between night and dawn, and blood pressure rises in the morning after waking, peaking during the day (active). Given this fact, the formulation of the present invention is used in the evening In this case, the pre-release simvastated liver enzyme is administered at the time of activating the enzyme, which shows more lipid lowering effect, and the delayed-release amlodipine effectively lowers the ¾ pressure after dawn, so that blood pressure can be equalized from morning to morning. It is possible to maintain a competitive mutual antagonism of the drug and to maximize the effect of each active ingredient The present invention is a method for treating cardiovascular diseases comprising administering a pharmaceutical formulation of the present invention to a mammal To provide.

The cardiovascular disease is applied to hypertension, or hypertension and complications of those with metabolic syndrome, such as diabetes mellitus, obesity, high altitudes, and coronary artery disease. Pharmaceutical formulations of the invention may be used in any suitable manner in the art, for example

Using the time-dose dosing principle disclosed in Chrontherpeut ics (2003, Peter Redfern, PhP), it can be preferably formulated according to each disease or component, and specifically can be prepared by the method comprising the following steps. .

In the first step, amalodipine is mixed with an enteric polymer, a water-insoluble polymer, a hydrophobic compound, or one or two selected release controlling substances selected from hydrophilic polymers, and a conventional ¾ gauze used in pharmacy. Delayed-release granules or tablets are obtained by granulation or coating, and tableting, or by mixing, combining, drying, granulating, or tableting amlodipine with osmotic pressure ≤ ablation and the usual additives used in pharmaceutical preparations. Coating to obtain delayed-release granules or tablets. The second step consists in administering simvastatin and conventionally acceptable pharmaceutically acceptable additives, followed by conventionally released granules through conventional processes for producing oral solids via mixing, association, drying, granulation, black coating, and tableting, or Obtaining tablets.

In the third step, the granules or tablets obtained in the first step and the second step are mixed with a pharmaceutical excipient, tableted or filled to obtain a preparation for oral administration. The first step and the second step may be reversed or executed simultaneously. The pharmaceutical formulation of the present invention may be prepared by the above process, and the formulation method of the third step will be described in more detail as follows, but is not limited thereto. [A] Preparation of two-phase matrix tablet

After further coating the particles or granules obtained in the first step as it is or with the release controlling substance, the tablets are obtained by mixing with the granules prepared in the second step and compressing them with a certain amount of weight. The resulting tablets may be film coated as needed for the purpose of improving stability or properties.

[B] Preparation of Film-Coated Tablets Containing Active Ingredients

The after-coated tablets or add the granules to a release-controlling material coating and appointed other by a predetermined amount and dried as black obtained in step 1 is manufactured to obtain the coating in addition, after the simvastatin to the film coating solution of the water-soluble corresponding ^'dissolution By dispersing and coating on the tablet layer obtained in step 1, an oral dosage form film-coated tablet containing the active ingredient in the film coating may be prepared.

Preparation of multi-layered tablets

The granules obtained in the first step can be prepared as is or in a double tablet using a tableting machine. Coated multilayer tablets can be prepared by formulating or coating triple or more multi-layered tablets by adding a release complement S layer as needed, or by formulation design.

[D] Preparation of Nucleated Tablets

The coated tablets or granules obtained in the first step are additionally coated as they are or with a release control material, dried, and then compressed into a predetermined amount, which is then further coated with black as an inner core, followed by a nucleated tableting machine together with the granules obtained in the second step. The coated nucleated tablet may be prepared by coating or preparing a nucleated tablet in the form of a pre-release layer submerged on the surface of the first-stage tablet by tableting. [Manufacture of capsules (containing granules or tablets) ^''

The granules obtained in the first step are additionally coated as is or with a release control material, and the dried granules or tablets and the granules or systems obtained in the second step are placed in a capsular bed electric machine and layered by an effective amount of each active ingredient in ¾ sul of a certain size. Capsules can be prepared.

[Bar] Preparation of ¾ Pellets

 (1) Dissolve or suspend amlodipine and release control substances, if necessary, as pharmaceutically acceptable additives in water, organic solvents, or mixed solvents, and coat the spherical granules with sugar; After dissolving in water, organic solvents, or mixed solvents using more than one species, coating, drying, granulation obtained in the second step or tablets obtained in the third step, and then mixing with the capsule filler to prepare the capsulant Can be.

 (2) Dissolve or suspend simvastatin and pharmaceutically acceptable additives in water, organic solvents, or mixed solvents, coat and sprinkle sugar spherical granules, and then mix with a controlled release ¾ containing amlodipine in (1). ¾ slabs can be prepared by layering the capsules with a capsul layered device.

[Product] Kit Preparation

The amlodipine-containing preparation obtained in the first step and the simvastatin-containing preparation obtained in the second step can be prepared as a kit that can be layered together in a foil, blister, bottle, or the like. The complex drug system of the present invention as described above is formulated into a complex formulation including a dihydropyridine-based Calm channel blocker and a statin-lipid lowering agent as an active ingredient to separately formulate each active ingredient by administering only one hour in the evening It is easier to guide the medication than to take it at the time of moxibustion, and it can reduce the side effects due to the metabolic interference action between drugs, and the shale control and lipid control effects of each drug are their own. Eggplant appears to be better than the effect. Advantageous Effects

The difference between the statin lipid lowering agent represented by simvastatin and the dihydropyridine type antagonist represented by amlodipine in gastrointestinal dissolution and scratch time If it is determined that statin-based hypolipidemic agents can prevent the increase in the concentration of blood than necessary and prevent the accumulation of side effects, it was confirmed that they could prevent the increase in the concentration of blood and prevent the side effects.

 As is apparent, the present invention is a so-called time difference dosing treatment (Chronotherapeutics) to maximize the therapeutic effect on the basis of heterogeneous pharmacokinetics Ofenobiotics to improve the side effects that can occur from the combination of different drugs from the pharmacokinetic point of view It is formulated as an effective active ingredient of dihydropyridine-calcin antagonist and statin-based lipid lowering agent, which affects or receives the same enzyme cytochrome P 450 system, and they are eluted from the body. Differential use of delayed-release substances to control the time allows the active ingredient to be delivered at a certain rate and at a certain rate, thus preventing and treating chronic circulatory disorders more often than in the case of a combination prescription in which the herbal ingredients are taken separately at the same time. Pharmacological, clinical, scientific and economic Yonghan may Kane realize pharmaceutical formulation.

 In addition, according to the present invention can be configured differently the release rate of the drug to prevent the antagonism and side effects between the drugs and at the same time can take the synergism of the drug.

 In addition, according to the present invention, since the complex preparation can be taken at a time, the medication guide for the patient and the patient's medication are easy.

 In addition, pharmaceutical preparations comprising a pre-release compartment containing a statin-based lipid lowering agent of the present invention and a delayed-release compartment containing a dihydropyridine-based calcium channel blocker may be used for patients with metabolic syndrome and insulin resistance and diabetes or diabetes mellitus. In the prevention or treatment of cardiovascular, cardiopulmonary, pulmonary or renal disease in patients suspected of being symptomatic, pharmacological, clinical, scientific and economical are more useful than single and simple combinations of individual drugs.

- Drawing simple ^'explanation of -

 1 is a graph showing the comparative elution curves of amlodipine / simvastatin nucleated tablets prepared in Example 1-1 and a control drug (Curve?: Simvastatin monotherapy, Novask: amlodipine monotherapy).

 Fig. 2 is a graph showing the curves of comparative coagulation between the combination preparation of amlodipine / simvastatin prepared in accordance with Examples 1-4 and 10 and the reference drug (Zoko: Simvastad single agent, Novask: Amlodipine single agent).

3 contrasts with the combination formulation of amlodipine / lovastatin prepared according to Examples 1-11 It is a graph showing the comparative elution curve of the drug (Mebaco: lovastatin monotherapy, Novasque: amlodipine monotherapy).

 Fig. 4 is a graph showing the comparative dissolution curves of the complex preparation of amlodipine / atorvastatin prepared in accordance with Examples 1-13 and the reference drug (lipitor: atorvastatin monotherapy, Novask: amlodipine monotherapy).

 FIG. 5 is a graph showing the comparative elution curves of the lercanidi ¾ / simvastatin complex preparation prepared according to Examples 1-16 and the control agent (Zoko: simvasta¾ monotherapy, zanidib: lercanidipine monotherapy).

 FIG. 6 is a graph showing the comparative elution curves of the laxidipine / simvastatin complex preparation prepared according to Examples 1-18 and the control drug (Zoko: simvapatin monoclonal, Dr.r: lacidipine monolith).

 Fig. 7 is a graph showing the curves of all the elution of amlodipine besylate / simvastarin nucleated tablets prepared according to Examples 1-20 and the comparative drug (Zoko: simvastatin monotherapy, MSD, Novasque: amlodipine monotherapy, Pfizer).

FIG. 8 is a comparative elution of a capsul agent containing an amlodipine pulsate / simvastatin combination tablet and a control agent (Zoko: simvastatin monotherapy, MSD, Novask: amlodipine monotherapy, Pfizer) prepared according to Example 1-22. ^{ᅵ This} is a graph showing the curve.

 Figure 9 is a combination preparation of amlodipine besylate / atorvastatin calcium prepared in accordance with Examples 1-30 and the control drug (lipitor: atorvasta ¾ single agent, Pfizer, Novask: amlodi ¾ single agent, Pfizer) A graph showing the comparative dissolution curves of.

 10 is a biphasic preparation in the form of pelodipine / atorvasta ¾ capsulant prepared in accordance with Examples 1-36 and the control drug (lipitor: atorvastatin monotherapy, Pfizer, non-novol: felodipine monotherapy, hand poison drug) A graph showing a comparative dissolution curve.

FIG. 11 is a biphasic preparation in the form of isradipine / lluvastatin capsules prepared according to Example 1 ′ ⁴ 0 and a control drug (Lescol: Polubasta ¾ single agent, Novartis, Dynazek: Sradipine Monolithic drug, Daewoong Pharmaceuticals).

Figure ¹ is a graph showing the dissolution test results * (S)-amlodipine / simvastatin complex formulation prepared according to Examples 1-51, 55.

 Figure 13 is a graph showing the dissolution test results of the (S) ᅳ amlodipine / simvastatin composite formulation prepared according to Examples 1-52, 53, 54.

£ 14 is the clinical trial result according to Experimental Example 1-14 above. It is a graph comparing the blood concentration of hydroxy acid.

 FIG. 15 is a graph comparing blood concentrations of simvastatin β-hydroxy acid and simvastatin between experimental groups as the clinical test results according to Experimental Examples 1-14.

 Figure 16 is a graph comparing the concentration of amlodipine in the time difference between the administration group and the co-administration group as a clinical test results except the experimental example Ι-Μ.

 Fig. 17 is a graph showing the comparative elution curves of amlodipine / simvastatin nucleated tablets prepared according to Example II-1 and the reference drug (2: Ko: simvastatin monotherapy, MSD, Novask: amlodipine monotherapy, Pfizer).

 FIG. 13 is a graph showing the comparative elution curves of the pharmaceutical preparation of amlodipine / simvastatin and the control agent (Zoko: simvastatin monotherapy, Novasque: amlodipine monotherapy) prepared according to Examples II-4 and 10. FIG.

 FIG. 19 is a graph showing the comparative elution curves of amlodapine besylate / simvastatin nucleated tablets prepared according to Example II-11 and a control drug (Zoko: simvastatin monotherapy, Novask: amlodipine monotherapy).

 FIG. 20 is a graphidi showing a comparative dissolution curve of a capsule containing an amlodi ¾ besylate / simvastatin complex tablet prepared according to Example 11-13 and a control agent (Zoko: simvastatin monotherapy, Novask: amlodipine monotherapy) .

 FIG. 21 is a graph showing the comparative elution of amlodipine / atorvastatin nucleated tablets prepared according to Example III-1 and a control agent (Ripto: atorvastatin monotherapy, Novask: Amlodi ¾ monotherapy). FIG. 22 is a graph showing the dissolution patterns of amlodipine of Examples III-1, 2 and 3, and FIG. 23 is a graph showing the dissolution profiles of Examples III-6 and 7. FIG.

 FIG. 24 is a graph showing the Atorvasta ¾ 3/4 concentration-time profile of Example III-1.

 25 is a graph showing the amlodi ¾ hyperemia concentration ᅳ time profile of Example III-1.

 26 according to example IV-2. It is a graph which shows the curve of the comparative elution of the manufactured pitavastatin / amlodipine nucleus tablet and the big treaty (Rivaro: pitavastatin single agent, Novask: amlodipine single agent).

27 is a graph showing the amlodipine elution aspect of Examples 2, 3. 28 is a graph showing the amlodipine elution pattern of Examples IV-17 and 18. FIG. FIG. 29 is a graph showing the comparative elution of Roschvastatin / Amlodi ¾ nucleated tablets prepared versus Example (Cresto: Roschvastatin Monotherapy, Novask: Amlodipine Monotherapy) prepared according to Example V-4.

 30 is a graph showing the dissolution profiles of Roschvastatin / Amlodipine in the formulations prepared according to Examples and Examples V-18,

 FIG. 31 is a graph showing the comparative elution of atorvastatin / nifedipon nucleated tablets prepared according to Example VI-1 and a control agent (lipitor: atorvastatin monotherapy, Procadia XL: nifedipine monotherapy).

 32 is a graph showing the elution aspect of Example VI-6.

 33 is a graph showing the dissolution aspect of the example.

34 is a graph showing the dissolution profiles of Example ^"VI-10.

 [Form for implementation of invention]

 Advantages and features of the present invention and methods for achieving them will be apparent with reference to the embodiments described below in detail. However, the present invention is not limited to the embodiments disclosed below, but may be embodied in various different forms, but the present embodiments only allow the disclosure of the present invention to be completed and to which the present invention pertains. It is provided to inform those skilled in the art to the fullest extent of the invention and the invention is defined only by the scope of the claims. Example 1-1 Preparation of Amlodipine-simvastatin Nucleated Tablets

 1) Preparation of Amlodipine Delayed-Release Compartments

As shown in Table 1-2, amlodipine malate and microcrystalline cell were apologized with No. 35 sieve, mixed with double cone mixer, and poured into a fluidized bed granulator (GPCG 1: Glatt), and separately Granules were formed by spraying a binding solution made by dissolving propylpropylcellulose in water, followed by drying. The carbomer 71G was added to the above-mentioned limbus in the form of powder, mixed with magnesium stearate, and mixed in a final double cone mixer, and the final pulverized mixture was subjected to a speed of 30 revolutions per minute using a rotary tableting machine (MRC-33: Sejong). The tablet was tableted with a hardness of 7 ~ 9kp, a thickness of 3.0 隨, and a diameter of 5.5 腿.

 2) Preparation of Simvastar¾ pre-release compartment

Following the ingredients and contents shown in Table r-2, simvastatin, microcrystalline salose, and manny were apologized with No. 35 and mixed with a high-molecular mixer. Separately hydroxypropyl cellulose and Dissolve citric acid in water to make a binding solution, put it in a high speed mixer with the main component mixture, and then combine it. Then, granulate it using an oscillator with No. 20 sieve and dry it at 60 ° C using a silver water dryer, and then return to No. 20 sieve. It was established. Butylated hydroxyanisole, starch glyconate nat ", and colloidal silicon dioxide were mixed here, and stearic acid magnesium was added and finally mixed with a double cone mixer.

3) tableting and coating

Using a nucleated tablet tableting machine (RUD-1: Ki lian) as the inner core of the amlodipine core tablet and the composition containing simvastatin at a rate of 30 revolutions per minute, hardness 7 ~ 9kp, thickness 6.0 聽, a ^'compressed into tablets with a diameter 9.5腿then using a Hi-coater (SFC- 30N, Sejong machinery Co., Ltd. Korea) to form a film-coated layer, thereby preparing a press-coated tablet. Example 1-2 ： Definition of amlodipine-simvastatin nucleated tablet ：

 1) Preparation of amlodipine delayed-release compartment (inner core)

Amodi ¾ malate and microcrystalline cell were apologized as No. 35 and mixed with a double cone mixer, and then added to a fluidized bed granulator (GPCG 1: Glatt) as shown in Table 1-2. Hydroxylpropyl ¾cell was sprayed to form a granule by spraying the binder solution prepared by dissolving cellulose in water and drying. Again, the granules were coated by spraying a hydroxypropylmethylcell solution containing a phthalate phthalate dissolved in 1: 1 shaker of ethane and methylene chloride. Magnesium stearate was added to this mixture and mixed with a final double cone mixer. The final mixture was then rotated at a speed of 30 revolutions per minute using a rotary tableting machine (MRC-33: Sejong), hardness 7 9 kp, thickness 3.0 kPa, diameter 5.5 The tablet was compressed into a nuclear tablet.

2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table 1-2 and 2) simvastatin pre-release compartment of Example 1-1.

 3) tableting and coating

Amlodipine-simvastatin nucleated tablets were prepared in the same manner as in Example 1-1, 3) Tableting and Coating. Example 1-3: Preparation of Amlodipon-Simvastatin Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

As shown in Table 1-2, amlodipine malate and microcrystalline cellulose were used as No. 35 Sieve apologies, mix with a double cone mixer, feed into a high-speed mixer, add Colicoat SR30D, combine, and granulate with a sieve No. 20 using an oscillator. It was sifted. Magnesium stearate was added to the final mixture in a double cone mixer, and the final mixture was used at a speed of 30 revolutions per minute using a rotary tablet press (M C-33: Sejong), hardness 7-9 kPa, thickness 3.0 kPa, diameter. A tablet of 5.5 mm was used to give a two-nuclear tablet.

 2) Preparation of Simvastar¾ pre-release compartment

It was prepared according to the ingredients and contents shown in Tables 1 to 2 and 2) simvastatin pre-release compartments of Shirci Example 1-1.

 3) tableting and coating

Amlodiated—simvastatin nucleated tablets were prepared by operating according to 3) Tableting and Coating Method of Example 1-1. Example 1-4: Preparation of Amlodipine-simvasta multilayered tablets

 1) Amlodipine lipophilic out-of-block manufacturing (inner core)

As shown in Table 1-2, the binding solution made by amplifying amlodipine maleate and microcrystalline shell loose with No. 35 sieve and mixing with a double cone mixer and dissolving hydroxypropyl methyl shellose in water separately The particles were sprayed to form granules and dried. When the granules were dissolved in 1: 1 shaker of ethane and methylene chloride, the granules were coated by spraying ¾ hydroxypropylmethylcell with a phthalate phthalate solution. Magnesium stearate was added to this and mixed with the final double conmixer.

 2) preparation of simvastatin prior-release compartments

Next, the ingredients and contents shown in Table 1-2 and 2) simvastatin pre-release compartment of Example 1-1 were prepared according to Method S.

 3 tableting and nose ¾

In this process, it was tableted using a multilayer tablet press (MRC-37T: Sejong). That is, the composition containing the simvastatin is put in the primary powder feeder, and the composition fire containing amlodipine in the secondary powder feeder in a condition that can minimize the extra-layer intermixing, at a rate of 30 ~ 18 per minute, hardness 7 ~ 9 It was compressed into 1φ, 6.0 mm thick and 9.5 mm in diameter, and a film coating layer was formed as a high coater to obtain a multi-layered tablet. Example 1-5: Preparation of Amlodi ¾-Simvastatin Multi-Layered Tablets

 1) Preparation of Amlodipine Delayed-Release Compartments

Next, as shown in Table 1-2, amalodipine malate and microcrystalline cell were apologized as No. 35, mixed with a double cone mixer, and Tato hydroxypropylmeth ¾¾ € -loose was dissolved in water. The liquid was sprayed to form granules and dried. Again, the granules were sprayed by spraying the Eudragit RS P0 solution in which ethane was dissolved in a 1: 1 mixture of ethane and detilene. Magnesium stearate was added here and mixed with the final double cone.

 2) 1st of simvastatin prior-release compartment

It was prepared according to the ingredients and contents shown in Tables 1 to 2 and the preparation method of 2) simvastatin prior * sex compartment of Example 1-1.

 3) Tableting and Nose

Amlodipine-simvastatin multi-layered tablets were prepared in the same manner as in Example 1-4, 3) Tableting and Coating. Example VII-6 Preparation of Amlodipine-simvastared Two-Phase Matrix Tablets

1) S ^' of the amlodipine delayed-release compartment

Following the ingredients and contents shown in Table 1-2, amlodipine malate and microcrystalline cells were mixed with apple No. 35 with apples, mixed with them, and colloidal SR30D was added to the high speed mixer. After the association, granulation was carried out using an oscillator with No. 20 sieve, and it was dried at 60 I;

2) preparation of simvastatin prior-release compartments

Following the ingredients and contents shown in Table 1-2, apples simvastatin, microcrystalline ¾, and Manny were No. 35, and were mixed with a high-speed Φ agitator. Separately, hydroxypropyl shellulose and citric acid were dissolved in the tulle to prepare a binding solution, and the mixture was added to a high speed shaker with the mixture of the main ingredients, and then granulated using an oscillator. ^It was dried at ^° C, and then sieved to No. 20 sieve, and butylated hydrated cyanuric sol was added thereto and mixed.

 3) Post-mixing, tableting and skipping

Each of the final S compounds prepared above was mixed with a double cone mixer, sodium starch glyconate, After colloidal silicon dioxide was mixed, stearic acid magnesium was added and mixed with a double cone.

Using the rotary tableting machine (MRC-33: Sejong) roll, the final mixture was compressed into tablets with a hardness of 7 to 9 kp, a thickness of 6,0 ram, and a diameter of 9.5 kW at a speed of 30 revolutions per minute, and then as a high coater Was formed to prepare a biphasic matrix tablet. Example 1-7: Preparation of Amlodiated-simvastatin Two-Phase Matrix Tablets

 1) Preparation of amlodipine delayed-release granules

The amlodipine malate and the microcrystalline cell rhodes were apologized as No. 35 and mixed in a Dubucon mixer as shown in the following Tables 1-2. The mixture was introduced into a fluidized bed granulator (GPCG 1: Glatt), and a binder solution, which was prepared by dissolving hydroxypropylmethyl ^ loose in water, was sprayed to form granules and dried. The granules were sprayed again by spraying Eudragit RS P0 solution dissolved in ethanol and 1: 1 shake solution of methylten chloride.

2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table 1-2 and 2) simvastatin pre-release compartments of Examples 1-6.

 3) tableting and coating

Amlodipine-simvastarin biphasic matrix tablets were prepared in the same manner as in Example 1-6, 3) Postmixing, Tableting and Coating. Example 1-8: Preparation of Amlodipine-Simvastatin Two-Phase Matrix Tablets

 1) Preparation of Amlodipine Delayed-Release Compartments

As shown in Table 1-2 below. Amlodipine malate and microcrystalline shell were apologized with Loose Roll 35 and combined with a double cone mixer. The above mixture was put into an EPC granule group (GPCG 1: Glatt), and separately a granule was formed by spraying a binder solution made by dissolving hydrate-specific-lofilmethylcellose in water and drying the granules. Again, the granules were coated by spraying a solution of hydroxyalcohol propyl sulphate phthalate, dissolved in a 1: 1 mixture of ethane and methylene chloride.

 2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table 1-2 and 2) simvastatin pre-release compartment of Example 1-6. 3) tableting and coating

Example I ^ 3) Amlodipine-simvastatin biphasic matrix tablets were prepared according to post mixing, tableting and coating methods. Examples 1-9: Amlodipine® simvastared two-phase capsular formulation

 1) Preparation of Amlodipine Delayed-Release Compartment (Gorim)

It was prepared according to the ingredients and contents shown in Table I-2 below and the preparation method of 1) amlodipine delayed-release compartment of Examples 1-8.

 2) Preparation of simvastatin prior-release compartments (granules)

It was prepared according to the ingredients and contents shown in Tables 1 to 2 and 2) simvastared pre-release compartments of Examples 1-6.

 3) Mixed and capped layers

The final compositions of steps 1) and 2) were mixed with a double cone mixer, and sodium starch glycolate was added thereto, followed by mixing with a fluorine mixer, colloidal silicon dioxide was mixed, and magnesium stearate was added to the final mixture. It was. The final mixed mixture was placed in a powder feeder and layered into No. 1 ¾ latin hard capsules using a capsul layer electric. Example 1-10: Amlodipine® Simvastatin Phase 2 Capsule Formulation

 1) Preparation of amlodipine delayed-release compartments (granules)

As shown in Table 1-2, amlodipine maleate and microcrystalline gelose were apologized with No. 35 and mixed in a double cone mixer, and then put into a layered granulator (GPCG 1: Glatt) and colicoat SR30D. Sprayed to form granules and dried.

 2) Preparation of simvastatin prior-release compartments (granules)

It was prepared according to the ingredients and contents shown in Table 1-2 and 2) simvastatin pre-release compartment of Example 1-6.

 3) mixing and capping layer

3) Amlodiche-simvastatin biphasic whiskey preparation was prepared by the procedure of Example 1-9, post mixing, tableting and coating. Example 1-11 Preparation of Amlodi ¾-lovastatin Multi-Layered Tablets

1) Preparation of Amlodipine Delayed-Release Compartments The amlodipine malate and the microcrystalline cell were apologized as No. 35 and mixed with a double cone mixer as shown in the following Tables I to 3, and the above mixture was added to a granular granulator (GPCG 1: Glatt). Injecting and separately hydroxypropyl methylcell was dissolved in water and sprayed the bonding liquid made to form granules, and dried. When the granules were dissolved in a 1: 1 mixture of ethane and methylene chloride, the granules were coated by spraying ¾ hydroxypropylmetalcell with a phthalate solution. Stearic acid magnesite was added to this and mixed with the final double cone.

 2) Preparation of lovastarin prior-release compartment

Next, as shown in Table 1-3, lovastatin, microcrystalline cellulose and manny were appled into No. 35 sieve and mixed with a high speed mixer. Separately, dissolve hydroxypropyl ¾ and citric acid in water to gradate the binder solution, and then combine it with a main component mixture in a high-speed mixer, combine it, and granulate it with a No. 20 sieve using an oscillator. After drying at ^° C it was again established as No. 20 sieve. In addition, butanated hydrated cyanosol, starch glycoic acid ^' natrop, colloidal silicon dioxide were mixed, and stearic acid magnesium was added to the final mixture in a double cone mixer.

 3) tableting and coating

In this step, the tablet was compressed using a multi-layer tablet press (MRC-37T: Sejong). That is, the composition containing the lovastarin is placed in the primary powder feeder, and the composition containing amlodipine is placed in the secondary powder feeder at a speed of 30 revolutions per minute at a speed of 30 revolutions per minute to minimize the infiltration of the layers. It was compressed into 9 kp, 6.0 mm thick, 9.5 mm diameter and formed a film coating layer as a high coater to prepare a multi-layer point. Example 1-12 Preparation of Amlodipine-Lovastatin Multi-Layered Tablets

 1) Preparation of Amlodipine Delayed-Release Compartments

As shown in Table 1-3, amlodipine malate and microcrystalline ¾ loose were apologized with No. 35 sieve, mixed with a Dubucon mixer, fed into a high-speed mixer, and colicoat S 30D was added. The granule was granulated using an oscillator, which was dried at 60 using a silver water dryer, and then again formed into a 20 sieve. Magnesium stearate was added thereto and finally mixed with a double cone mixer.

 2) Preparation of lovastar¾ pre-release compartment

2) Svastatin pre-release compartment of Example 1-11 and the ingredients and contents shown in Table 1-3 It was prepared according to the preparation method.

 3) tableting and skipping

The amlodipine-lovastatin multi-layered tablet was prepared in the same manner as in Example 1-11, 3) Tableting and coating method. Example 1-13: Preparation of amlodipine-atorvastad multilayered tablets

 1) Preparation of Amlodipine Delayed-Release Compartments

It was prepared according to the ingredients and contents shown in Table 1-3 and the preparation method of 1) amlodipine delayed-release compartment of Example 1-11.

 2) Preparation of the atorvastatin prior-release compartment

Following the ingredients and contents shown in Table 1-3, atorvastatin, microcrystalline ^ loose, and Manni were apologized as No. 35 and mixed with a high speed mixer. Separately, hydroxypropyl¾loose and citric acid are dissolved in water to prepare a binding solution, which is mixed with a main component: in a high-speed mixer, and fed together, and then granulated using a No. 20 ceto oscillator. After drying, it was established as No. 20 sieve again. Butyl hydroxyanisole, sodium starch glyconate, and colloidal silicon dioxide were mixed therein, and magnesium stearate was added to the final mixture in a double cone mixer.

 3) tableting and coating

In this process, it was tableted using a multilayer tablet press (MRC-37T: Sejong). That is, the S-form containing the atorvastatin is put in the primary powder feeder, and the composition containing amlodipine is placed in the secondary powder feeder in a condition that minimizes the infiltration of the layers between the hardness 7 ~ 9> A tablet having a thickness of 6.0 mm 3 and a diameter of 9.5 mm was formed, and a film coating layer was formed as a high coater to prepare a delayed-release multilayer tablet in the form of a multilayer tablet. Example 1-14 Manufacture of Amlodipine-Atorvastatin Multi-Layered Tablets

 1) Preparation of Amlodipine Delayed-Release Compartments

It was prepared according to the ingredients and contents shown in the following Table ί ~ 3 and the method of preparing 1) amlodipine delayed-release compartment of Examples 1-12.

 2) Preparation of the atorvastatin prior-release compartment

It was prepared according to the ingredients and contents shown in Table 1-3 and 2) the atorvastatin pre-release compartment of Examples 1-13. 3) tableting and coating

3) Tableting and coating method of Example 1-13, and the amlodipine pentato svastatin multi-layered tablet was prepared. Example 1-15: Preparation of Amlodipine-atorvastatin Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

It was prepared according to the ingredients and contents shown in Table 1-3 and the preparation method of 1) amlodipine delayed-release compartment of Example 1-1.

 2) Preparation of Atorvasta ¾ pre-release compartment

It was prepared according to the ingredients and contents shown in Table 1-3 and 2) Atorvasta ¾ pre-release compartment of Example 1-13.

 3) tableting and coating

Press-coated tablet tableting machine: at the rate of the inner core of amlodipine tablet core using (RUD-1 Ki Han) and atorvastatin on the ^'30 turns per minute to the composition in an outer layer comprising eu, hardness 7 ~ 9 kp, thickness of 6.0删After tableting to a diameter of 9.5 kPa, a coating layer was formed using a high coater roll to prepare a nucleated tablet. Example 1-16 ： Preparation of Lercanidipine-simvastatin Multi-Layered Tablet

 1) Preparation of lercanidipine delayed-release compartments

Apples with lercanidipine and microcrystalline salolosol No. 35 과 as shown in the following Tables 1 to 3 were mixed with a double cone mixer, and the above mixture was added to a granular granulator (GPCG 1: Glatt). Separately, hydroxypropylmethylshellulose was dissolved in water and sprayed to form a binder solution, which was then dried to form granules. Again, the granules were sprayed with a solution of hydrated propylpropyl 셀 ¾cell dissolved in 1: 1 shaker of ethanol and tertylene chloride, and then the granules were coated. Magnesium stearate was added to this and mixed with the final double conmixer.

 2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Tables 1 to 3 and 2) simvasta¾ pre-release compartments of Example 1-1.

 3) tableting and coating

In this step, the tablet was compressed using a multi-layer tablet press (MRC-37T: Sejong). That is The composition containing simvastatin is placed in the primary powder feeder, and the composition containing lercanidipine is placed in the secondary powder feeder at a speed of 30 revolutions per minute, at a speed of 7 to 9 kp, to minimize the incidence of filling. The film was hit with a thickness of 6,0 mm 3 and a diameter of 9.5 mm, and a film coating layer was formed as a high coater to prepare a multilayer tablet. Example IVII 17: Preparation of Lerke "Nidi ¾-Simvasta¾ Multi-Layered Tablets

 1) Preparation of lercanidipine delayed-release compartments

Following the ingredients and contents shown in Table 1-3, lercanidipine and the microcrystalline cell were apologized with a Rooseol No. 35 sieve, mixed with a debulcon mixer, fed into a high-speed mixer, and then added with Colicoat SR30D. Granulation was carried out using an oscillator, which was dried at 60 ° C. using a silver water dryer, and then re-formed as No. 20. Magnesium stearic acid was added thereto and finally mixed with a double cone mixer.

 2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table 1-3 and 2) simvastatin pre-release compartment of Example 1-1.

 3) tableting and skipping

Lercanidipine-simvastatin multi-layered tablets were prepared in the same manner as in Example 1-16, 3) Tableting and Coating Method. Example 1-18 Manufacture of Lacidipine-simvastatin Multi-Layered Tablets

 1) Preparation of Lacidipine Delayed-Release Compartments

Following the ingredients and contents shown in the following Table 1-3, the acedipine and the microcrystalline cellulose were apologized with a No. 35 sieve and mixed with a double cone mixer, and the above mixing tool was placed on a homogeneous layered granulator (GPCG 1: Glatt). The mixture was added and sprayed separately, hydroxypropylmethylcell was dissolved in cellulose roll water to form granules and dried. Again, the granules were sprayed with a hydroxypropylmeth ¾cell, which was dissolved in a 1: 1 mixture of ethane and methylene chloride, and sprayed with a phthalate phthalate solution to coat the granules. Magnesium stearate was added to this and mixed with the final double cone mixer.

 2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table 1-3 and the preparation method of 2) simvastatin pre-release compartments of Examples 1-11. 3) tableting and corrugated

In this process, it was tableted using a multilayer tablet press (MRC-37T: Sejong). That is, the composition containing the simvastatin in a primary powder feeder, and the composition containing the lacidipine in a secondary powder feeder at a speed of 30 revolutions per minute under conditions that can minimize the shaking between the layers, hardness 7 It was tableted at 9 kp, 6.0 mm thick, and 9.5 mm diameter, and a multi-layered tablet was prepared by forming a film coating layer as a high coater. Examples 1-19: Preparation of Rassidi ¾-Simvasta Multilayered Tablets

 1) Preparation of Lacidipine Delayed-Release Compartments

Following amplification of amlodipine malate and microcrystalline cell with No. 35 sieve as shown in Table VII-3, mixed with a double cone mixer, put into a high-speed mixer, add Colicoat SR30D, and then combine with No. 20 oscillator It was granulated using, and it was dried at 60 X: using a silver water dryer, and then sieved to No. 20 sieve again. Stearic acid magnesium was added to this and finally mixed with a double cone mixer.

 2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table I-3 below and the preparation method of 2) simvasterin pre-release compartment of Example 1-1.

 3) tableting and coating

Lacidipine-simvastatin multi-layered tablets were prepared in the same manner as in Example 1-18, 3) Tableting and Coating. Example I-20: Preparation of Amrodafine-Simvastatin Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

As shown in Table 1-4, amlodipine besylate and microcrystalline cells of aloe and decalom phosphate were apologized with No. 35 sieve, mixed with a double cone filter, and added to a fluidized bed granulator (GPCG 1: Glatt). The binding solution made by dissolving hydroxypropylmethylshellose in water was sprayed to form granules and dried. Carbomer 71G was added to the granules in a powder form, and then stearic acid was added to the granules, and the resultant mixture was mixed with a final double cone mixer, and the final mixture was mixed with Bundang (MRC-33: Sejong). At a rate of 30 miter, hardness 7-9 kp, thickness 3.0 mm, diameter 5.5 mm. Tableting. In the above purification, ¾¾ of hydroxypropylmeth dissolved in 1: 1 mixture of ethane and methylene chloride was added. Nuclear tablets were prepared by forming a film coating layer using a high coater of a roophthalate solution and an acetylated monoglyceride solution.

 2) Preparation of simvastatin pre-release compartments

Next, simvastatin, microcrystalline cellulose, corn starch, and lactose were apples in No. 35 as shown in Table 1-4 and mixed with a high speed mixer. Separately, prepare a binding solution by dissolving hydroxyaluminum salulose and citric acid in water, and incorporating it into a high-speed mixer with the main component mixture, and then coalescing it using an oscillator with a No. 20 sieve. It was dried at 60 ° C. and then sieved to No. 20 sieve again. Butylated hydroxyanisole, starch glyconate natate here. s colloidal silicon dioxide was mixed, and stearic acid magnesium was added and finally mixed in a double cone mixer.

 3) tableting and coating

Using a nucleated tablet tablet machine (RUD-1: Ki Han) as the inner core of the amlodipine core tablet and simvastatin-containing composition at a rate of 30 revolutions per minute, hardness 7 to 9 kp, thickness 6.0 mm, diameter 9.5 Nucleated tablets were prepared by tableting with a pan and then forming a film nose layer as a high coater. Example 1-21: Amlodipine-simvasta multilayered tablets

 1) Preparation of Amlodipine Delayed-Release Compartments

Next, as shown in Table 1-4, the aloe ¾ besylate and microcrystalline cell were apologized with S-ose and decalcium phosphate as No. 35 and mixed with a double cone mixer, and hydroxypropylmethylcellose was separately added to water. The binder solution was dissolved and sprayed to form granules. The granules were coated by spraying a coating solution consisting of ¾ hydroxypropylmethylshell loose phthalate and acetylated monoglycerides when the granules were dissolved in 1: 1 shaker of ethane and salt methylene. Stearic acid magnesite was added thereto and mixed in the final double cone mixer.

 2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table 1-3 and the preparation method of 2) simvasta¾ pre-release of Example 1-1.

 3) tableting and coating

In this shop, it was compressed using a multi-layer tablet press (MRC-37T: Sejong). That is, the composition containing the simvastatin is placed in a primary wheat flour: feeder, the crude containing amlodipine The material is placed in a secondary powder feeder and compressed to a hardness of 7 to 9 kp, a thickness of 6.0 mm and a diameter of 9,5 議 at a speed of 30 revolutions per minute under conditions that minimize the intrusion of layer¾, and the film coating layer as a high coater. To prepare a multilayer tablet, Example 1-22: Amlodipine tablets-3/4 tablet containing simvastatin tablets

 1) Preparation of amlodipine delayed-release compartment (purification)

As shown in Table 1-4, amlodipine besylate and microcrystalline ¾ rose were apologized as No. 35, mixed with a double cone mixer, and then added to a granular granulator (GPCG 1: Giatt), and then separately. Granules were formed and dried by spraying a binder solution made by dissolving hydroxypropylmethylcell ¾ rose in water. Carbomer 71G was added to the granules in powder form, and then stearic acid and magnesium were added to the final double cone mixer, and the final mixture was mixed with a rotary tablet press (MRC-33: Sejong). At the speed of rotation, tableting was carried out with a hardness of 7-9 kp, a thickness of 3.0 mm and a diameter of 5.0 mm. In the above tablets, hydroxypropyl methylcell (5 weight ¾) and acetylated monoglyceride solution dissolved in 1: 1 shaker of ethane and methylene chloride and acetylated monoglyceride solution were coated with a high coater. To form a tablet.

 2) Preparation of simvastatin pre-release compartments (tablets)

Following the ingredients and contents shown in Table 1-4, simvastatin, the crystalline salose, and Manny were apples with No. 35 and mixed with a high speed mixer. Separately, hydroxypropyl¾loose and citric acid are dissolved in water to prepare a binding solution, which is then added to a high-speed mixer combined with the main component mixture, which is then granulated using an oscillator with a No. 20 sieve. ^After drying at ^° C it was again established as No. 20 sieve. Add the mixed hydroxyanisole, sodium starch glyconate, and colloidal silicon dioxide, and add the stearic acid magnesium to the double-mixer for final mixing. 33: Sejong) was used to tablet tablets with a hardness of 7 to 9 kp, a thickness of 4.0 mm 3 and a diameter of 5.0 mm 3 at a speed of 30 revolutions per minute. The tablets were coated with a high coater using a coating solution prepared by dissolving and dispersing hydroxypropylsal, thiolenglycol 6000, titanium oxide and talc in 80% ethanol.

 3) ¾ charging

The amlodipine tablets of step 1) and the simvastatin tablets of step 2) were layered onto the hard gelatin capsulization of No. 3 using a capsule layer electric machine. Example 1-23: Amlodipine-simvastatin 3/4

 1) Preparation of amlodipine delayed-release compartment (purification)

It was prepared according to the ingredients and contents shown in Table 1-4 below and the preparation method of 1) amlodipine delayed-release compartment of Example 1-22.

 2) Preparation of simvastatin prior-release compartments' (granules)

Following the ingredients and contents shown in Table 1-4, simvasta¾, microcrystalline cellulose, lactose and starch starch were appled with No. 35 sieve and mixed with a high speed mixer. Separately, hydroxypropylcellolose and citric acid are dissolved in water to prepare a binding solution, which is added to a high-speed mixer with the main component mixture, and then combined.Then, it is granulated using an oscillator with a No. 20 sieve. After drying at 1C it was again established as No. 20 sieve. In addition, butylated hydroxyanisole, sodium starch glyconate and colloidal silicon dioxide were mixed, and a stearic acid magnesium was added to the final mixture in a double cone mixer.

 3) wine layer exhibition

The amlodipine tablet of step 1) and the simvastatin granules of step 2) were layered into hydroxypropylmethylcell No. 2 in the hard capsule of cellulose using a ¾ capsule layer electric machine. Example 1-24: Amlodipine-Simvastar ¾ Coated Tablets

 1) Preparation of Amlodi Delayed-Release Compartments (Tablets)

It was prepared according to the ingredients and contents shown in Tables 1 to 4 and the preparation method of 1) amlodipine delayed-release compartments of Examples 1-20.

 2) Simvastatin pre-release ^ herbicidal coating solution

As shown in Table 1-4, simvastatin, butyl tated hydroxyanisole, hydrated propylmethylsalose, colloidal silicon oxide, polyethylene glycol 6000, titanium oxide, talc and ethane A pre-release simvastatin coating solution was prepared by dissolving and dispersing in methylene chloride shake solution.

 3) Primary coating

The amlodipine tablets prepared above were administered to the high coater and then first coated with a simvastared coating solution.

 4) secondary coating

Dissolve the composition of the film coating layer in Table 1-4 in a solvent to prepare a film coating solution, and then complete the first coating. The coated tablet was subjected to secondary coating to prepare a film coated tablet. Examples 1-25 ： Preparation of Simvasta¾ Rapid-Amodi ¾ Osmotic Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartments (tablets)

Next, the ingredients and contents shown in Table 1-4 and ¾- apodipine besylate and microcrystalline salose a few sodium chloride ≤ cerium apology as No. 35, mixed with a double cone mixer, and added magnesium stearate to the final double cone The resultant mixture was mixed with a mixer and compressed using a rotary tablet press (MRC-33: Sejong, Korea) at a speed of 30 ¾ per minute, hardness 7-9 kp, thickness 3.0 mm, and diameter 5.5 mm. Collicode Si? As osmotic base after tableting? 30D and triethyl citrate were dispersed in purified water, and then coated with an inner core using a high coater to prepare an osmotic core tablet.

 2) Preparation of simvastatin pre-release compartments

The ingredients and contents shown in Tables 1 to 4 and 2) simvastatin pre-release compartments of Examples 1-20 were prepared in Para.

 3) tableting and coating

Simbastatin immediate-amlodipine osmotic nucleated tablets were prepared in the same manner as in Example 1-20, 3) Tableting and Coating. Example I-2 ⁶ ： Amlodipine-simvastatin blister packaging kit

Prepared according to the ingredients and contents shown in Tables 1 to 4 below, except that the amlodipine tablets and simvastatin tablets of Example I-22 were packaged in a blister package for simultaneous use in place of ¾ slot. Was prepared as in Example 1-22. Example 1-27: amlodipine-atorvastatin nucleated tablets

Except for using atorvastatin instead of simvastatin, according to the ingredients and contents of Table 1-4, according to the preparation method of Example 1-20, amlodipine-atorvastatin nucleated tablets were removed. Example 1-28: Amlodipine-atorvastatin multilayer tablet

Using atorvastated in place of simvastatin The alodipine-atorvastatin multilayered tablet was prepared according to the method and the ingredient of Table 1-4 according to the method S of Example 1-21. All. Example 1-29: Amlodipine-Atorvastatin Capsule

Except for using atorvastatin in simvastatin Daeshan according to the ingredients and contents of Table 1-4, according to the preparation method of Example 1-22, amlodipine-atorvastatin capsule was prepared. Example 1-30: Amlodipine-Atorvasta ¾ capsule

 1) Preparation of amlodipine delayed-release compartment (purification)

It was prepared according to the ingredients and contents shown in Table 1-4 and the preparation method of 1) amlodipine delayed-release compartment of Example 1-22.

 2) Preparation of atorvapatin pre-release compartments (granules)

It was prepared according to the ingredients and contents shown in Tables 1 to 4 and the preparation method of 2) atorvastatin pre-release compartments of Examples 1-23.

 3) Cap layer

Amlodied tablets of step 1) and atorvastatin granules of step 2) were layered onto hydrated hard capillary hydroxypropylmethol ¾¾ using a capsul layer electroroll. Example 1-31: Preparation of Amlodiated-Atorvastar Coated Tablets

Amlodipine-atorvastated coating according to the preparation method of Example 1-24, except for the use of atorvastatin instead of simvastatin and no colloidal silicon dioxide in the preparation of the prior release compartments. Tablets were prepared. Example 1-32: Preparation of Atorvastatin-Amtodipine Osmotic Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

As shown in Daum Table 1-5, amlodipine besylate, microcrystalline cellulose and sodium chloride were apologized with No. 35 sieve and mixed with a double cone mixer. The resultant mixture was mixed with a mixer, and the final mixture was compressed into tablets having a hardness of 7 to 9 kp, a hardness of 3.0 kPa, and a diameter of 5.5 kPa at a speed of 30 revolutions per minute using a Rota ^ grinder (MRC-33: Sejong). After tableting, the Eudragit RS 30D and triethyl citrate were dispersed in purified water as an osmotic machine, and then coated on the ^ using a high coater. Osmotic nuclear tablets were prepared.

 2) Preparation of Atorvasta ¾ pre-release compartment

It was prepared according to the ingredients and contents shown in Table 1-5 and 2) simvastatin pre-release compartments of Examples 1-25.

 3) tableting and coating

Using a nucleated tablet tableting machine (RUD—l: KHian) as the inner nucleus ^ and the composition containing ato 5vastatin as the inner core ^, at a rate of 30 revolutions per minute, hardness 7 ~ 9 kp, thickness The tablets were compressed into 6,0 mm 3 and 9.5 mm diameter, and then a film coating layer was formed as a high coater to prepare nucleated tablets. Realization ΐ 1-33 ： Amlodipine ᅳ Atorvasta ¾ Blister Packaging Kit

Prepared as ingredients and contents shown in the following Table 1-5, except that the amlodipine tablets and atorvastatin tablets of Example 1-29 can be simultaneously taken in a blister packaging container instead of isotropically layering on the capsule. And _? Was S as in Example 1-29. Example 1-34: Nifedipine-simvastatin Nucleated Tablets

 1) s of the nifedipine delayed-release compartment s (inner core)

By melting after the nifedipine Rie Ϊ ¾ glycol 6000 and honhyeop ¹ was prepared in the solid dispersion composition as shown in Table 1-5, the ingredients and contents shown in. The prepared solid dispersion was apologized with No. 35 sieve, and the microcrystalline cell apologized with No. 35 sieve was mixed with a double cone mixer with loose and lau ¾ sodium sulfate. Carbomer 71G was added to the granules in powder form, and magnesium stearate was added to the granules, and the resultant mixture was mixed with a final double cone mixer. The final mixture was 30 minutes per minute using a rotary tablet press (MRC— 33: Sejong). At the rate of abduction, tablets were made with a hardness of 7-9 kp, 3.0 mm thick, and 5.5 mm diameter. In the above purification, hydroxypropylmethyl¾-loose phthalate solution and acetylated monoglyceride solution dissolved in a 1: 1 mixture of ethane and methylene chloride were formed using a high coater to form a film coating layer. Was prepared.

 2) Preparation of Silvastar¾ pre-release compartment

Table 1-5 shows the ingredients and contents and the examples. 1-20, 2) "simvastatin pre-release compartments were prepared according to the preparation method.

3) Tableting and Nose Using a nucleated tablet tableting machine (RUD-1: Ki l ian) as the inner core of the nifedipine core tablet and the composition containing simvastatin as the outer layer at a speed of 30 revolutions per minute, hardness 7 — 9 3, thickness 6.0 画 ， Girum Nucleated tablets were prepared by tableting at 9.5 mm and then forming a film coating layer as a high coater.

Example 1-35: Nifedipine-atorvastated Nucleated Tablets

Except for using atorvastatin instead of simvastatin, according to the ingredients and contents of Table 1-5, according to the preparation method of Example 1-34 was prepared nipydipine- atorvastatin nucleated tablets. Examples 1-36: ¾ rhodipine-atorvasparated biphasic ¾ capsule formulation

 1) Preparation of Pelodipine Delayed-Release Compartment (Tablet)

Following the ingredients and contents shown in the following Table 1-6, apples pelped and microcrystalline cellulose were mixed with a sieve No. 35, mixed in a double cone mixer, and put into a fluidized bed granulator (GPCG. 1: Glatt), and hydroxy separately. A binder solution made by dissolving propyl cellulose in water was sprayed to form granules and dried. The granules were then coated with hydroxypropylmethylsalloosephthalate solution dissolved in 1: 1 shaker of ethane and methylene chloride to coat the granules. Here, the granules were mixed with 71G rolls of carbomer, and then mixed with a double cone mixer. The final mixture was used at a speed of 30 revolutions per minute using a rotary tableting machine (MRC-33: Sejong). ， Tablets with a hardness of 7 to 9 kp, a thickness of 3.0 mm and a diameter of 5.0 mm were tableted.

 2) Preparation of Atorvasta ¾ pre-release compartments (tablets)

Next, the ingredients and contents shown in Table 1-7 and 2) the atorvastatin pre-release compartment of Example 1-22 were prepared according to the method S.

 3) ¾ shot layer

The ¾ rhodipine tablet of step 1) and the atorvastared tablet of vacant spot 2) were layered into No. 2 ¾ latin hard capsules using Capsulphate 1 :. Example 1-37: Vanidipine-Lovastatin Two-Phase Capsule Formulation

 1) Preparation of vardy ¾ delayed-release compartments (tablets)

As shown in the following Table 1-6, vanidipine hydrochloride and microcrystalline cells were replaced with 35 Apples and common combined in a double cone mixer, open inflicting a then Kollicoat SR30D commitment to high-speed common stapler Union and then a No. 20 sieve and granulated using an oscillator, this hermit dryer this use at 60 X is dried again ²⁰ Issue It was sifted. Magnesium stearate was added to this mixture and finally mixed with a double cone mixer. The final mixture was used at a speed of 30 revolutions per minute using a rotary milling machine (MRC # 33: Sejong), hardness 7-9kp, thickness 3.0mm, diameter Tablets of 5.5 mm were compressed.

 2) Preparation of lovastatin prior-release compartments (tablets)

Following the ingredients and contents shown in Table 1-7, lovastatin, microcrystalline cellulose, and Manny were apologized to No. 35 and mixed with a high speed mixer. Separately, hydroxypropyl salulose and citric acid were dissolved in water to prepare a binding solution, which was added to a high-speed mixer with the main component mixture, and then united. After drying at C, it was established as No. 20 sieve again. Butylrate hydroxyanisole, starch glyconate sodium, colloidal silicon dioxide was mixed, and the final mixture was mixed with a double cone mixer after stearic acid magnesite was added to the rotary tableting machine (MRC-33 : Tablets of hardness 7-9 kp, thickness 5.0 kPa, and diameter 5.5 kPa were hit at a speed of 30 revolutions per minute using Sejong.

 3) Capsul layer exhibition

The vanidipine tablets of step 1) and the lovastatin tablets of step 2) were layered onto hydroxy hardcapsule of No. 2 by using a ¾ sulfa bed electrolysis. Example 1-38: Benidis ¾-Pitavastatin Two-Phase ¾ Knee

 1) Preparation of Tinidipine Delayed-Release Compartment (Tablet)

 The use of panidipine hydrochloride in place of lodipine, according to the napanan component and content in Table 1-6, and 1) Lodiphan delayed-release compartment of Example 1-36 was prepared according to S.

 2) Preparation of Pitavastatin Prior-Release Compartment (Granule)

In addition to the use of pitavastatin stag instead of simvastatin, it was prepared according to the preparation method of 2) simvastatin pre-release compartment of Example 1-1, as shown in the components and contents shown in Table 1-7.

 3) Cap layer

Benidin tablets of step 1) and the final composition of 2) were encapsulated in capsule layer electrophoresis # 1 gelatin It was stratified in hard cap surgery. Example 1-39: Silinidipine-Pravastar ¾ 2-Phase Capsule Preparation

 1) Preparation of silnidipine delayed-release compartments (viscosities)

Using silinidipine instead of vanidied, as prepared, according to the ingredient content shown in Table 1-6, was prepared according to the method of preparing a delayed-release layer of Example 1-37 1) vanidipine.

2) Preparation of Pravastatin Prior-Release Compartments (Granules)

Pravastatin sodium was used in place of simvastatin, according to the preparation method of Example 1-11, 2) simvastatin pre-release compartment, as shown in Table 1-7.

 3) Capsul layer exhibition

Hydroxypropylmethylcell of No. 1 was layered into a cellulose hard capsule by using the cynidipine tablet of step 1) and the final S-form ¾ sulf layer electrolysis of 2). Example 1-40 ： Isradin ᅳ Fluvastatin 2-Phase ¾ Formulation

 1) Preparation of Israd¾ Delayed-Release Pelhat

Isradipine and microcrystalline cells were apples as a No. 35 sieve as shown in Table 1-6, and the mixtures were prepared by mixing in a double cone mixer. Separately, hydroxypropyl cellulose was dissolved in water to prepare a binder solution. While spraying the defect solution to the crystalline sucrose seeds in the CF granulator, the mixed powder was dispersed in the crystalline sucrose seeds to prepare pellets. The obtained ¾ was dried at 50 ° C. until the water content was 2% or less, thereby preparing isoldipine-containing core ¾lets. Again, Pelhat was commented by spraying a solution of hydroxypropylmethyl ¾ rose phthalate dissolved in ¾¾ of ethane and acetone in 1: 1 shake solution.

 2) Preparation of fluvastatin prior-release compartments

Except for using fluvastatin nat instead of simvastatin, it was prepared according to the preparation method of 2) simvastatin pre-release compartment of Example 1-1 as shown in Table 1-7.

 3) Cap layer

The final compositions of steps 1) and 2) were layered into No. 1 ¾ la¾ hard caps using capsular bed electrolysis. Example 1-41 ： Manidipine-Lovastatin 2-Phase ¾ Capsule

 1) Preparation of Manidipine Delayed-Release Compartments (Granules)

As shown in Table 1-6, Mandihydrochloride ¾ and microcrystalline cell were apologized with No. 35 sieve and mixed with a double cone mixer, and then poured into a fluidized bed granulator (GPCG 1: Glatt), and separately The combined solution prepared by dissolving oxypropylmethylcell in water was sprayed to form granules and dried. Again, the granules were coated by spraying a hydroxypropylmexylsaloseophthalate solution dissolved in ethanol and 1: 1 shake solution of methylene chloride. Magnesium squalene was added to the mixture and the final mixture was mixed using a double cone mixer.

2) Preparation of lovastatin prior-release compartments (tablets)

Like the ingredients and contents shown in Table 1-7, lovastatin, microcrystalline cellulose and manny were apologized as No. 35 and mixed with a high speed mixer. Separately hydroxypropyl to prepare a binding solution by dissolving trehalose with citric acid in water saelreul and put in a high-speed common stapler with the main component mixture is granulated using an oscillator with a union and then sieve No. 20 and this, using a hermit dryer 60 ^° C It was dried at and then reconstituted with No. 20 sieve. Butylated hydric cyanosol, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were added thereto and finally mixed with a double cone mixer.

The tablet was tableted with a warning of 7 to 9 kp, a thickness of 3.0 mm, and a diameter of 5.5 mm at a speed of 30 revolutions per minute using the Rotary Mixer (MRC-33; Sejong).

 3) Mixed and ¾ layer warfare

The final compositions of steps 1) and 2) were layered onto No. 2 gelatin hard capsules using a capsul layer electroroll. Example 1-42: Preparation of Nicardipine-Rosuvastar Nucleated Tablets

 1) Preparation of Nicardipine Delayed-Release Compartment (Inner Core)

Nicardipine hydrochloride was used in place of the felodisome, which was prepared according to the ingredients and contents shown in the following Tables 1-6 and 1) ¾ rhodipine delayed-release compartment of Example I ′ 36.

 2) Preparation of Rosuvastatin Prior-Release Compartments

The use of rosuvastatin kite instead of simvastatin is shown in Table 1-7 below. It was prepared according to the preparation method of 2) simvastatin pre-release compartment of Example 1-1 as well as egg component and content.

3) tableting and coating

Using a nucleated tablet press (RUD-1: Ki l iaii) as the inner core of the nicardipine nucleus and the composition containing rosuvastatin as an outer layer at a speed of 30 revolutions per minute, hardness 7 to 9 kp, thickness 6.0 kPa After tableting with a diameter of 9.5 ram, a nucleus tablet was prepared by forming a film coating layer as a high coater. Example 1-43: Preparation of Nifedipine-Flubusted Nucleated Tablets

 1) Preparation of nifedipine delayed-release compartment (inner core)

In addition to using nifedipine instead of felodipine, it was prepared according to the ingredients and contents shown in the following Table 1-8 and 1) ¾ rhodipine delayed-release compartment of Examples 1-36.

2) S of fluvastatin prior-release compartment

Aside from using fluvastatin sodium instead of simvastatin, it was prepared according to the method for preparing 2) simvastatin pre-release compartments of Example 1-1 as shown in Table 1-9.

 3) tableting and coating

Using a nucleated tablet tablet machine (RUD-1: KHian) as the inner core of nifedipine core tablets and simvastatin-containing composition at a rate of 30 revolutions per minute, hardness 7 ~ 9 kp, thickness 6.0 kPa, diameter 9.5 mm Nucleated tablets were prepared by forming a film coating layer as a high coater after tableting. Example 1-44: Preparation of Amlodipine-Pitavastatin Nucleated Tablets

The use of pitavasta ¾ stilt instead of simvastatin, which according to the ingredients and contents of Tables 1-8 and 9, prepared Amlodi-Pitavastatin nucleated tablets according to the method S of Examples 1-20. Example 1-45: Preparation of amlodipine-rosuvastatin nucleated tablets

Amlodipine-rosuvastatin nucleated tablets were prepared according to the preparation method of Examples 1-20, except that rosuvastatin carsum was used instead of simvastatin. Example 1-46: Preparation of Nimodipine-pravastatin Coated Tablets

 1) Preparation of Nimodipine Delayed-Release Compartment (Tablet)

As shown in Table 1-8, Nimodibyun and microcrystalline cell were apologized with No. 35 sieve and common with a double cone mixer, which was then poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropyl separately. The binding solution made by dissolving methylcellose in water was sprayed to form granules and dried. Again, the granules were coated by spraying a hydroxypropylmethyl gel solution containing phthalate and ethanol in a 1: 1 mixture of ethylene chloride and methylene chloride. Here, the carbomer 71G was added to the granules in powder form, and then stear ¾ acid magnesium was added and mixed with a final double cone mixer. The final mixture was then used in a rotary tableting machine (MRC 33: Sejong) ¾ for 30 revolutions per minute. At the previous rate, tablets with a hardness of 7 to 9 kp, a thickness of 3.0 mm and a diameter of 7.0 mm were tableted.

 2) Coating of Pravastatin Sun-Release Part

Nimodipine tablet roll using a high coater Dissolves and disperses hydroxytitanium _τ titanium oxide and talc in ethanol and constant water, and dissolves pravastatin sodium salt as shown in the following Tables 1-9. A pre-release coating solution containing pullulvastatin nat salt was prepared, and the coating solution was prepared by forming a coating layer on the outer layer of the nimodipine delayed-release compartment with the coating solution.

 3) coating

2) Using the high coater (SFC-30N) on the coating portion of the pravastatin pre-emitting portion to form a coating layer as shown in the ingredients and contents shown in Table 1-7 to complete the film coating tablets. Example 1-47: Preparation of Nivaldipine-Pitavastatin Multi-Layered Tablets

 1) Preparation of Nivaldipine Delayed-Release Compartments and ¾

Next, as shown in Table 1-8, nibaldimun and microcrystalline cells were apologized with No. 35 sieve and mixed with a double cone mixer. Separately, hydroxypropylmethylcell was dissolved in water to spray a binder solution. The advent formed and dried. Again, the granules were coated by spraying a solution of hydroxyspitalymethylmethylcell dissolved in a 1: 1 shake solution of ol and methylene chloride. The granules were poured into carbomer 71G roll powder, and then stearic acid magnesium was added to the final double cone mixer.

2) Preparation of Pitavastatin Pre-Release Compartments It was prepared according to the preparation method of 2) simvastatin pre-release compartment of Example 1-1 as shown in Table 1-9, except for using pitavastatin sting instead of simvastatin.

3) tableting and coating

In this step, tableting was carried out using a multi-layer tablet press (ffiC-37T: Sejong). That is, the composition containing the pitavasta ¾ in the primary powder feeder, and the composition containing nibaldipine in the secondary powder feeder at a speed of 30 revolutions per minute to minimize the infiltration of the layers, hardness 7 It was tableted to ˜9 kp, 6.0 ram thick, 9,5 mm in diameter, and a film coating layer was formed as a high coater to prepare a tablet in a multi-layered form. Example 1-48: Nisoldipine-Lovastatin Multi-Layered Tablet S

 1) Preparation of Nisoldipine Delayed-Release Block Granules

Nisoldipine and the microcrystalline cell in a No. 35 sieve aprose with a No. 35 sieve and mixed with a double cone mixer, and separately sprayed the binder solution made by dissolving the hydrated propylmethylcellose in water as shown in Tables 1 to 8 below. Granules were formed and dried. Again, the granules were coated by spraying the Eudragit RS P0 solution dissolved in 1: 1 shaker of ethane and methylene chloride. Stearic acid magnesium was added to this and mixed with the final double cone mixer.

2) Preparation of lovastatin prior-release compartment

The use of lovastatin in place of simvastatin was prepared according to the method of preparation of 2) simvastatin pre-release compartment of Example 1-1 with the components and contents shown in the following Table 1-9.

 3) tableting and coating

In this process, it was tableted using a multilayer tablet press (MRC-37T: Sejong). That is, the S-form containing the lovastatin is put into the primary powder feeder, and the composition fire containing nisoldipine is put into the secondary powder feeder at a speed of 30 revolutions per minute at a speed of 30 revolutions per minute, hardness 7-9 The tablet was compressed into kp, 6.0 mm thick, and 9.5 mm in diameter, and a film coating layer was formed as a high coater to prepare a multi-layered tablet. Example I4949: Nirenedipine- Pravastatin Blister Packaging Kit

 1) Preparation of Nitrendipine Delayed-Release Compartments

In addition to the use of nirenedipine in place of felodipine, Content was prepared according to the preparation method of 1) felodipine delayed-release compartment of Example I-36.

 2) Preparation of Pravastatin Pre-Release Compartment

Following the ingredients and contents shown in Table 1-9, pravastad nat "salt, microcrystalline shellulose, manniolol apologies with 35 No. 35 and mixed with a high-speed mixer. Separately hydroxypropyl cellulose and citric acid in water It was prepared by dissolving in a binder solution, and putting it in a high speed mixer together with the main component mixture, and then granulating it with an oscillator using No. 20 sieve and drying it at 60 ^° C. using a silver water dryer, and then reconstituting it with No. 20 sieve. Butylated hydroxyanisole, sodium starch glyconate, and colloidal silicon dioxide were mixed, and finally mixed with a stearic acid magnesite with a double cone filter, and the final mixture was rotated by a tablet press (MRC-33: Sejong). Using a tablet at a rate of 30 revolutions per minute, a viscosity of 7 to 9 kp, 4.0 mm thick, and 8.5 mm in diameter was tableted.

 3) Packing

It was specified that the nirenedipine tablets of step 1) and pravastatin tablets of step 2) were packaged in one blister and taken at the same time. Examples 1-50: Preparation of (S) -Amlodipine-simvastatin Nucleated Tablets

 1) (Preparation of S Amlodipine Delayed-Release Block (Inner Core)

Following the ingredients and contents shown in Table 1-10, (s) -amlodipine besylate and microcrystalline cell cellulose were apologized as No. 35, mixed with a double cone mixer, and then added to the granular granulator (GPCG 1: Glatt). Separately, by spraying the binding solution prepared by dissolving hydroxypropylcellose in purified water to form granules, and dried. Carbomer 71G was added to the granules as a powder and mixed in a double cone mixer for 10 minutes. Then, stearic acid magnesium which was sieved through a No. 35 sieve was added and finally mixed for 4 minutes. (S) -Amlodipine core tablets were prepared by compressing the final mixture with a hardness of 6 to 10 kp, a thickness of 3.0 mm, and a diameter of 5.5 mm at a rate of 30 revolutions per minute using a rotary tablet press (MRC-33: tax). .

 2) Preparation of simvastatin pre-release compartments

As shown in Table 1-10, simvastatin, microcrystalline salulose and manni were sieved through a No. 20 sieve, and then mixed in a high-speed mixer for 10 minutes. Separately, hydrophilic prophyllose and citric acid were purified. It was dissolved in to prepare a binding solution. While adding the binding solution to the above mixed moles, the granulation was completed, the granulation was completed, and granulation was completed. Butylated hydroxyanisole, starch sodium glycolate, and colloidal silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a double cone mixer together with the above granules, and then mixed for about 10 minutes. Was passed through a sieve No. 35 and administered to a double cone mixer, followed by final mixing for about 4 minutes to complete the preparation of simvasta¾ layer granules.

3) tableting and coating

Using a nucleated tablet press (RUD-1: Ki lian) as the inner core of the Amlodi ¾ nuclear tablet and the composition containing simvastatin as the outer layer, at a speed of 30 revolutions per minute, hardness 7-13 kp, thickness 6.0 kPa, The inner core was prepared by tableting with a diameter of 9.5 mm 3. Separately, the film coating layer composition of Table 1-8 was dissolved in a solvent to prepare a film coating solution. The inner core prepared above was administered to a high coater and then coated with a film coating solution to complete nucleated tablet manufacturing. Example 1-51: Preparation of (S) -amlodipine-simvastatin nucleated tablets

Prepared according to the ingredients and contents shown in the following Table 1-10, except that enteric coating with a poly (methacrylate, methyl methacrylate) co-polymer after the preparation of the nuclear tablet of Example 1-50 Example 1-50 It was prepared in the same manner. Example 1-52: Preparation of (S) -amlodipine-simvastatin capsulant

 1) Preparation of (s) -amlodi duct delayed-release compartment (purification)

Next, as shown in Table 1-10, (S) -amlodipine besylate and microcrystalline cell loose were mixed with a No. 35 sieve and mixed with a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glati). After spraying the binding solution prepared by dissolving parohydroxypropylcellose in purified water to form granules, the granules were dried, and the resultant granules were infused with carbomer 71G in powder form for 10 minutes in a double cone mixer. After the addition, stearic acid magnesium which was sieved through a No. 35 sieve was added and mixed for 4 minutes. (S) -Amlodipine tablets prepared by tableting the final mixture with a hardness of 6 ᅳ 10 kp, a thickness of 3.0 誦 and a diameter of 5.5 画 at a speed of 30 revolutions per minute using a rotary tablet press (M C-33: Sejong). Was coated with a poly (methacrylate, methyl methacrylate) copolymer to complete the preparation of (S) -amlodipine tablets.

2) Preparation of simvastatin pre-release compartments (tablets)

Following the ingredients and contents shown in Table 1-10, Simvastar, microcrystalline ¾, mannyul, sieved through No. 20 sieve, and then mixed in a high speed mixer for 10 minutes. Separately, hydroxypropyl cellulose was dissolved in purified water to remove the binding solution. Binding to the above mixture While adding the liquid, the association was completed, then granulated, dried, and granulated to complete the granulation roll. Butylated hydroxyanisole, sodium starch glycolate, and colloidal silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a double cone mixer together with the above granules, and then mixed for about 10 minutes, and magnesium stearate was added thereto. After sieving through a No. 35 sieve and administering to a double cone mixer, the final mixture was finally mixed for about 4 minutes to complete the preparation of the simvasta layered granules. Simvastatin tablets were prepared by tableting the granules at a speed of 30 revolutions per minute using a rotary tableting machine (MRC-33: Sejong, Korea) at a hardness of 6 to 10 kp, a thickness of 3.0 mm and a diameter of 5.5 mm. Coating with a film layer component of 8 completed simvastatin tablet preparation.

3) Cap layer

Using the capsul layer, the above-mentioned (S) ᅳ amlodyne tablets and simvastatin tablets were layered onto the Latin hard cap capsules of No. 3 to complete the preparation of ¾ capsules. Example 1-53: Preparation of (S) -amlodipine-simvastatin ¾

 1) Article ≤ (purification) of the (S) -amlodipine delayed-release compartment

Next, as shown in Table 1-10, (S) —Amlodipine besylate and microcrystalline shell rollose were apples in No. 35, mixed in a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glatt). Separately, the binding solution made by dissolving hydroxypropylcellose in purified water was sprayed to form granules, and then dried. Carbomer 71G in powder form to the produced granules 10 minutes in a double cone mixer? } After mixing, Magnesium Stearate, which was sieved through No. 35, was added, followed by final mixing for 4 minutes. (S) amlodipine tablets prepared by tableting the final mixture with a hardness of 6 to 10 kp, a thickness of 3.0 mm and a diameter of 5.5 at a rate of 30 revolutions per minute using a rotary tableting machine (M C-33: Sejong). The preparation of the (S) -amlodi ¾ tablet was completed by co-coating with li (methacrylate, ¾ meth ¾ tate) copolymer.

2) s (granule) of the simvasta layer prior-release compartment

Following the ingredients and contents shown in Table 1-10, simvastatin, microcrystalline salose, and Manni were sieved through a No. 20 sieve and mixed for 10 minutes in a high speed mixer. Separately, the combined solution was prepared by dissolving hydrocyclopropyl cellulose and citric acid in purified water. While adding the binding solution to the mixture, granulation was completed by granulation, drying, and sizing to complete granulation. Butylated hydride cyanosol, starch glyconate sodium, and colloidal silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a Dubolcon mixer together with the above granules, and then mixed for about 10 minutes. The sieve was sifted through No. 35 sieve and then administered to the Dulon method Final mixing was completed for minutes to complete the preparation of the simvastatin layer granules.

3) Capsul layer exhibition

Capsule preparation was completed by simultaneously laminating the above-mentioned (S) -amlodipine tablets and simvastatin granules in the hydrophilic cipropylmethyl ¾ rollose hard cap capsule of No. 1 using a capsular layer electrolysis. Example 1-54: (S) —Amlodipine Tablet + Simvastar¾ Blister Packaging Kit

Prepared as shown in the following Table 1-10, and the contents, except that the (S)-amlodipine tablets and simvastatin tablets of Example 1-50 in a PTP packaging container instead of isothermal layering in capsule Except that prepared as in Example 1-52. Example 1-55: Preparation of (S) -amlodiated-simvastatin coated tablets

 1) Preparation of (S) -Amlodipine Delayed-Release Block (Tablet)

As shown in Table 1-10, (S) -Amlodipine and microcrystalline cell were apologized with No. 35 sieve and mixed with a double cone mixer, and then poured into a fluidized bed granulator (GPCG 1: Glatt). Separately, after forming a granule by spraying the binding solution prepared by dissolving hydroxypropyl shelle in purified water, it was dried after ¾. After the ^"to Carbomer 71G In a roll in the resulting powder-form granules combined shake for 10 minutes at a double cone mixer, placed into the thoracic chegwa a magnesium stearate sieved with a 35 mesh sieve, followed by final heunhap 4 minutes. (S) -Amlodipine tablets prepared by tableting the final mixture with a hardness of 6 ᅳ 10 kp, a thickness of 4.0 ma, and a diameter of 8.0 로 at a speed of 30 revolutions per minute using a rotary tablet press (MRC-33: Sejong). It was coated with a pulley (methacrylate, methyl methacrylate) copolymer below Table 1-10 to complete the preparation of (S)-amlodipine tablets.

2) preparation of simvastatin coating liquid

As shown in Table 1-10, simvastatin, butylated hydroxyanisole, hydroxypropyl decylose, and colloidal silicon oxide were dissolved in ethane and ethylene chloride shaker to prepare a simvastatin coating solution.

 3) Primary coating

The second step: Han (S) —Amlodipine tablets were administered to the high coater, followed by a first skip with a simvastatin coating solution.

 4) secondary coating

The film coating layer composition of Table 1-10 was dissolved in a solvent to prepare a film coating solution, and then a second coating was applied to the first coated tablet to prepare a film coated tablet. Example 1-56: Preparation of (S) -amlodipine-atorvastatin capsulant:

 1) Preparation of (S) -Amlodipine Delayed-Release Block (Tablet)

It was prepared according to the preparation method of 1) (S)-amlodipine delayed-release compartments of Examples 1-53 as shown in the following Table 1-11.

 2) second of atorvastatin layer prior-release compartment: (felhett)

Atorvastatin calum, butylated hydroxy anisole and microcrystalline salose were apologized as No. 35 as shown in Table 1-11, and mixed in a double cone mixer to prepare a mixture. Separately, hydroxypropyl ¾ was dissolved in water to prepare a binder solution. A pellet was prepared by spraying the mixed powder on the crystalline sucrose seed while spraying the binder solution on the crystalline sucrose seed in the CF granulator. The pel¾ obtained was dried at 50 ° C until the water content was 2¾> or less to prepare ¾¾ containing atorvastatin sting.

 3) Cap layer layering

Using the capsule layer electrophoresis, the above (S) -amlodipine tablets and ato 5vastatin calce pellets were layered on hydroxypropylmethylcell of No. 2 hard capsules to complete capsule preparation. Example 1-57: Preparation of (S) -amlodipine-atorvastatin capsules

 1) Preparation of (S) -Amlodipine Delayed-Release Compartments (Pel?

As the components and contents shown in Table 1-11, (S) -amlodi ¾ besylate and microcrystalline cellulose were apologized as No. 35, and mixed in a double cone mixer to prepare a mixed powder. Separately, the binder solution was prepared by dissolving hydroxyipropyl cellulose in water. While spraying the binder solution to the crystalline sucrose seed in the CF granulator ^' , the mixed powder was dispersed in the crystalline sucrose: seed to prepare pel¾. The pellets were dried under arc until the water content was below 2% to remove (s) -amlodipine besylate containing core ¾.

 2) Preparation of atorvastatin prior-release compartments (tablets)

As shown in Table 1-11, atorvastatin scabbard, microcrystalline cellulose and mannyul were sieved through No. 20 sieve, and then mixed in a high speed mixer for 10 minutes. Separately, the binder solution was prepared by dissolving hydroxyipropylpropylcellulose and citric acid in purified water. Combination of the above While adding the binder solution to the water, the association was completed, then granulated, dried, and granulated to complete the granulation roll. Butylated hydroxyanisole, sodium starch guliconate, and colloidal silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a double cone mixer with the above fruiting and sesame seeds, followed by mixing for about 10 minutes, and magnesium stearate 35 After sieving through a sieve and administering to a double cone mixer, and finally mixed for about 4 minutes to complete the preparation of atorpastatin granules. The Atorvastar calcium tablets were tableted using a rotary tablet press (MRC—33: Sejong) at a rate of 30 revolutions per minute, with a hardness of 6 to 10 kp, a thickness of 3.0 ram, and a diameter of 5.5 舰. Coating with the coating layer components of Table 1-11 completed the preparation of the atorvasta calder tablets.

 3) Capsul layer exhibition

Capsule preparation was completed by simultaneously laminating the above-mentioned (S) -amlodipine besylate felhett and atorvastatin Calm tablets on hydroxypropylmethol 3 Cellulose hard capsing using capsule layer electrolysis. Example 1-58: Preparation of (S) -amlodipine-atorvastatin capsule.

 1) Preparation of (S) -Amlodipine Delayed-Release Compartments (Pal ¾)

It was prepared according to the preparation method of 1) (S) ᅳ amlodipine delayed-release compartment of Examples 1-57 as shown in Table 1-11.

 2) Preparation of the atorvastatin prior-release compartment (pel ¾)

It was prepared according to the preparation method of Example 1-56 2) atorvastatin calcium pre-release compartment as shown in Table 1-11.

 3) Capsul layer exhibition

Using the capsular layer electrophoresis, the above (S) -amlodi fragment ¾¾ and atorvastarin pellets were layered on hydroxypropylmethylcell No. 2 in a hard capsule of capsule 2 to complete the preparation of the ¾ slot. Example 1-59: Preparation of (S) -Amlodipine Atorvastar Capsule

 1) (S) —the preparation of amlodipine delayed-release compartments (granules)

As shown in Table i-ii, (s) -amlodipine tesylate and microcrystalline ¾loose were apologized as No. 35, mixed with a double cone mixer, and then added to a fluidized bed granulator (GPCG 1: Glatt). The colicoat SR30D was sprayed to form granules and dried.

2) Preparation of Atorvasta ¾ pre-release compartments (pelvets) Following the ingredients and contents shown in Table 1-11 were prepared according to the preparation method of Example 1-56 2) atorvastatin pre-emitting compartment.

3) Capsul layer exhibition

Capsule preparation was completed by simultaneously laminating the above-mentioned (S) -amlodipine granules and atorvastatin ¾ on No. 1 hydrospecylmethylcellose hard capsule using a capsular layer electrolysis. Example 1-60: (S) Preparation of amlodipine-atorvastatin ¾ sludge

 1) Preparation of (S) -amlodi ¾ delayed release compartment (¾¾)

It was prepared according to the preparation method of Example 1-57 1) (S) -amlodied delayed-release compartment as in Table 1 11 and the contents thereof.

 2) Preparation of atorvastatin prior-release compartments (granules)

As shown in Table 1-11, atorvastatin calcium, microcrystalline cellulose and mannrol were sieved through No. 20 sieve, and then mixed in a high speed mixer for 10 minutes. Separately, the combined solution was prepared by dissolving hydroxypropylcellose and citric acid in purified water. Adding the binder solution to the mixture above, after completing the association, granulation, drying, and granulation were completed to complete the granulation. Butane-rated hydroxyanisole, sodium starch glycolate, and roidoid silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a double cone mixer together with the above granules, and then mixed for about 10 minutes. The sieved sieve was sieved through a No. 35 sieve and administered to a double cone mixer, followed by final mixing for about 4 minutes to complete the atorvasta layered granule production roll.

 3) ¾ thrust

Capsule preparation was completed by simultaneously filling the above (S) -amlodipine ¾¾ and atorvastatin granules with No. 1 hydroxypropylmethylcell in a hard capsule capsule.

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Table 1-5

Table 1-6

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 75

 Table 1–7

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-11]

실시예 II-1: 암로디 ¾~심바스타틴 유핵정의 제조

Example II-1 Preparation of Amlodi ¾-simvastatin Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment

Following amplification of amlodipine malate and microcrystalline cell with No. 35 sieve with the ingredients and contents shown in the following table Π-2, mixed with a double cone mixer and added to a fluidized bed granulator (GPCG 1 Glatt). The combined solution (10¾ w / w) dissolved in rhoroseol purified water was sprayed to form granules and dried. Carbomer 71G was added to the granules in powder form, and magnesium stearate was added and mixed in a final double cone mixer. The final mixture was tableted with a rotary tableting machine (MRC-30: Sejong), and the inner core was As All.

 2) Preparation of simvastatin pre-release compartments

In the following ingredients and contents shown in Table Π-2, simvastatin, microcrystalline cellulose and manny were apologized as No. 35 and mixed with a high speed mixer. Separately, hydroxypropylcell was dissolved in purified water and lutein was dissolved in purified water to prepare a binding solution (1W w / w), and the mixture was added to a high speed mixer with a main component mixture, and then granulated using an oscillator. After drying at 60 ^° C. using a silver water dryer, the product was found to be No. 20. Butylated hydrate cyanisole, ¾ minute sodium glyconate and colloidal silicon dioxide were mixed, and the stearic acid magnesium was added and finally mixed with a double cone mixer.

 3) tableting and coating

Using a nucleated tableting machine (RUD-1: Kilian) as a layer of amlodipine inner core as a composition containing simvastatin, and then using a high coater (SFC-30N, Sejong Machinery, Korea), the components described in Table II-2 and Nucleated tablets were prepared by forming a film coating layer by content. . Example II-2: Preparation of Amlodipine-simvastatin Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

Apology of the amlodipine maltate and microcrystalline cell with the No. 35 sieve with the ingredients and contents shown in the following table Π— 2, mixed with a double cone mixer, and put into an isocratic granulator (GPCG 1: Glatt), followed by hydroxy The granules were formed by spraying a binder solution (10% w / w) made by dissolving propylmethylcellose in purified water, and drying the dried granules. The granules were coated by spraying propyl sal ¾ salorose phthalate solution (20 / w). Magnesium stearate was added thereto, mixed with a final double cone mixer, and the final mixture was compressed into tablets using a rotary tableting machine (MRC—30: Sejong) and used as an inner core.

 2) the 1st of simvastatin prior-release block

Next, the ingredients and contents shown in Table II-2 were prepared according to the preparation method of Example 2-1 simvastared prior-release compartment.

 3) tableting and coating

Amlodipine-Simvasta¾ nucleated tablets were prepared according to 3) Tableting and coating method of Example II-1 with the ingredients and contents shown in Table II-2. 9 000331

 81

Example 11-3: Preparation of Amlodipine-simvastatin Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

Next, amplify amlodipine malate and microcrystalline salose into the No. 35 sieve with the contents shown in Table Π-2, mix it with a double cone mixer, add it to a high-speed mixer, and then combine it with Colicoat SR30D roll, and then oscillate with No. 20 sieve. It was granulated using, dried at 60 ° C using a silver water drier, and then sieved to No. 20 sieve again. Magnesium stearate was added thereto, followed by final mixing in a double cone mixer, and the final mixture was compressed into tablets using a rotary tableting machine (MRC-30: Sejong) and used as an inner core.

 2) Preparation of simvastatin pre-release compartments

It was prepared according to the preparation method of Example II-1 and 2) simvastatin pre-release compartment with the ingredients and contents shown in the following Table Π-2.

 3) tableting and coating

Amlodipine-simvastatin nucleated tablets were prepared according to 3) tableting and coating method of Example II-1 with the mechanical components and contents of Table II-1. Example II-4: Definition of amlodipine-simvastatin multilayer tablet 3:

 1) Preparation of amlodipine delayed-release compartment (inner core)

A binder solution prepared by amplifying amlodipine maltate and the crystalline cell with a Rooseol No. 35 sieve and mixing it with a glue paste mixer, and separately dissolving hydrated propylmethylsalose in purified water according to the ingredients and contents shown in the following Table II-2. 10% w / w) was sprayed to form granules and dried. Again, the granules were coated by spraying the hydroxypropyl methylcellolose phthalate solution dissolved in 1: 1 shaker of ethanol and methylene chloride. Stearic acid magnesium breath was added to the final double cone mixer.

 2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table II-2 and 2) simvastatin pre-release compartment of Example Π-1.

 3) tableting and nose ^

In this process, it was tableted using a multilayer tablet press (MRC-37T: Sejong). That is, the composition containing the simvastatin is put into the primary powder feeder, and the composition containing amlodipine is put into the secondary powder feeder, and the tableting is performed under conditions that can minimize the infiltration of the layers. A high-coater (SFC-30N, Sejong Machinery, Korea) was used to form a film coating layer to produce a multilayer tablet. Example II-5 ： Amlodipine-simvastatin

 1) Preparation of amlodipine delayed-release compartment

Next, the binding solution prepared by amplifying amlodipine malate and microcrystalline salulose with No. 35 according to the ingredients and contents shown in Table II ᅳ 2 and mixing with a double cone mixer and dissolving hydroxypropylmethylcellose in purified water (1 » wAv) was sprayed to form granules and dried. Again, the granules were coated by spraying Eudragit RS P0 solution (20% wAv) dissolved in a 1: 1 mixture of ethane and methylene chloride. Magnesium stearate was added thereto and mixed in a final double cone mixer.

 2) Preparation of simvastatin pre-release compartments

Next, the ingredients and contents shown in Table II-2 were prepared according to the preparation method of Example 2-1 simvastatin pre-release compartment.

 3) RBI and Coating

Amlodipine-simvastatin multi-layered tablets were prepared according to the method of Example II-4, 3) Tableting and Coating according to Table II-2. Examples II-6: Preparation of Amlodi ¾-simvastared two-phase matrix tablets

 1) Preparation of amlodipine delayed-release compartment

In the following ingredients and contents shown in Table II ᅳ 2, amlodi ¾ malate and microcrystalline cell were apologized with No. 35 sieve and mixed, and then fed into a high-speed mixer, and then added with Colicoat SR30D. After the association, granulation was carried out using an oscillator with No. 20 sieve, which was dried at 60 using a silver-dried dryer roll and then re-established with No. 20.

 2) Preparation of Simvastar¾ pre-release compartment

In the following ingredients and contents shown in Table II-2, simvastatin, microcrystalline cellulose, and manni were apologized with No. 35 and mixed with a high speed mixer. Separately, hydroxypropylcell was dissolved in purified water to prepare a binding solution (10% wAv) in purified water, and the mixture was added to a high-speed mixer with the above-mentioned mixture of main components, and then combined. This was dried at 60 ° C. using a silver water drier, and then immersed in No. 20 sieve again, and butylated hydroxyanisole was added thereto and mixed. 3) Post-mixing, tableting and coating

Each of the final compositions prepared above was mixed with a double cone mixer, starch glyconate natto, ¾-loid silicon dioxide, and mixed with stearic acid magnesium.

The final mixture was compressed using a rotary tablet press (MKC-30: Sejong) and then formed into a film coating layer with a high coater (SFC-30N, Sejong Machinery, South Korea) to prepare a two-phase matrix tablet. Example II-7 Preparation of Amlodi ¾-Simvastatin Two-Phase Matrix Tablets

 1) Preparation of granules as amlodipine delayed-release compartments

In the following ingredients and contents shown in Table 11-2, amlodipine maleate and microcrystalline cell were apologized as No. 35, which was common as a double cone mixer. The mixture was introduced into a fluidized bed granulator (GPCG 1: Glatt) and sprayed with a binder solution (10¾ w / w) prepared by dissolving hydrated propyl decylcellulose in purified water separately to form granules and dried. The granules were then sprayed with ¾ Eudragit RS P0 solution (20¾ΛΪ) when ethane was dissolved in 1: 1 shaker of permethylene chloride to coat the granules.

 2) Preparation of simvastatin pre-release compartments

2) Preparation of simvastatin pre-release compartment of Example Π-6 and the components and contents shown in the following Table Π-2; It was prepared according to the method.

 3) tableting and coating

Amlodipine—simvasta¾ two-phase matrix tablets were prepared according to 3) postmixing, tableting and coating methods of Example Π-6 with the ingredients and contents of Table ΙΙ-2. Example II-8: Preparation of Amlodipine-simvastatin Two-Phase Matrox Tablets

Preparation of Amlodipine Delayed-Release Compartments

To the ingredients and contents shown in Table 11-2, amlodipine wheat: rate and microcrystalline shell

Apology with No. 35 and mixed with a double cone mixer. The mixture was added to a fluidized bed granulator (GPCG 1: Glatt), and a combined solution (10 w / w) prepared by dissolving hydroxypropylmethicelose in purified water was sprayed to form granules and dried. Again, the granules were coated by spraying hydroxypropylmethylcell (2 w / w) with ethane dissolved in 1: 1 shaker of methylene chloride. 2) Preparation of Simvastatin Preservative Block

It was prepared according to the ingredients and contents shown in Table II-2 and 2) simvastatin pre-release compartments of Example II-6.

 3) tableting and coating

Table II-2 Amlodipine-simvastatin biphasic matrix tablets were prepared according to the method of Example II-6 in 3) Post-mixing Tableting and Coating. Example II-9: Amlodipine-Simvastar ¾ Biphasic Capsule Formulation

 1) Preparation of amlodipine delayed-release compartments (granules)

Next, several contents of the ingredients shown in Table 11-2 and 1) of Example II-8 were prepared according to the preparation method of the amlodipine delayed-release compartment.

 2) Preparation of simvastatin pre-release compartments (Firim)

Next, the ingredients and contents shown in Table II 표 2 and 2) Simvastar¾ pre-release compartment of Example Γ-6 were prepared according to the preparation method.

 3) mixing and capsulation

Mix the final compositions of steps 1) and 2) with a double cone mixer, add sodium starch ¾ lyconate and mix with a double cone mixer, mix colloidal silicon dioxide, and add stearic acid magnesium. Mixed. The final mixed mixture was placed in a powder feeder and layered into No. 1 hard capsules using a capsular bed electrolysis machine. Example 11-10 ： Amlodi ¾-Simvasta ¾ two-phase capsular formulation

 1) Preparation of amlodipine delayed-release compartments (granules)

Next, amplify the amlodipine malate and the microcrystalline cell into the Rhose »No. 35 sieve with the ingredients and contents shown in the following table 11-2, mix with a double cone mixer, put it into a fluidized bed granulator (GPCG 1: Glatt), and spray Colicoat SR30D To form granules.

 2) Preparation of simvastatin prior-release compartments (granules)

It was prepared according to the ingredients and contents shown in Table II-2 and 2) simvastatin pre-release compartments of Example Π-6.

 3) mixing and capping layer

Amtodipine-simvastared two-phase capsule formulations were prepared according to the 3) mixing and ¾ sludge preparation method of Example II-9 with the ingredients and contents shown in Table II-2. Example II-ll: Preparation of amlodi / 4-simvastatin nucleated tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

Following amplification of amlodipine besylate, microcrystalline ¾loose, and dicalcium phosphate as No. 35 with the ingredients and contents shown in Table 11-3, mixed with a double cone mixer, and then placed in an antagonist (GPCG 1: Glatt) In addition, the combined solution (1 «w / w) prepared by dissolving hydroxypropylmethyl ¾ in purified water was sprayed to form granules and dried. Carbomer 71G was added to the granules in powder form, and magnesium stearate was added to the granules, followed by mixing with a final Vorcon mixer. The final mixture was compressed into tablets using a rotary tableting machine (MRC-30: Sejong). It was.

Again, hydroxypropyl merlophthalate and acethiated monoglycerides were introduced into a 1: 1 mixture of ethane and chlorene chlorene chloride, and then dissolved as a coating solution (20fa / w). The inner core was prepared by forming a film coating layer using a coater (SFC-30N, Sejong Machinery, South Korea).

 2) Preparation of simvastatin pre-release compartments

The following Table 11-3 simvastatin, microcrystalline selreul as agarose, corn starch and lactose as ingredients and contents shown in heunhap was 35 hoche S apples and ^'high-speed common stapler. Separately, hydroxypropylcellulose and citric acid were dissolved in purified water to prepare a binder solution (10% w / w), which was added to a high-speed mixer combined with the main component mixture, and then granulated using an oscillator. It was dried at 60 ° C using a silver water dryer and then re-established as No. 20. Butylated hydration cyanisole, sodium starch glyconate, and colloidal silicon dioxide were mixed therein, and magnesium stearate was added thereto, followed by ^ condensation in a double cone mixer.

3) tableting and coating

Using a nucleated tableting machine (RUD-l: Ki lian), the amlodipine inner core was compressed into S-layers containing simvastatin as a layer, followed by a high coater (SFC-30N, ^' Sejong Machinery, Korea). Nucleated tablets were prepared by forming a film coating layer by content. Example II-12: Preparation of Amlodi ¾-simvasta multilayered tablets

 1) Article ≤ of amlodipine delayed-release compartment:

Next, amplify amlodipine besylate and microcrystalline shellulose and decalcium phosphate as No. 35 with the ingredients and contents shown in Table II-3, mixed with a Dubolcon mixer, and separately hydroxy. The combined solution (10% w / w) made by dissolving propylde¾ cellulose in purified water was sprayed to form granules and dried. Again, the granules were coated by spraying a coating solution (20¾ V) comprising hydroxyphthalate and acetylated mono ¾ riserite with hydrated propyl butyl acetylcell dissolved in 1: 1 shaker of ethane and methylene chloride. Magnesium stearate was added to this and mixed with the final double cone mixer.

 2) Preparation of simvastatin pre-release compartments

It was prepared according to the ingredients and contents shown in Table 11-3 and the preparation method of 2) simvasta¾ pre-release compartment of Example I-1.

 3) tableting and coating

In this shop, tableting was carried out using a multi-layer tablet press (MRC-37T: Sejong). That is, the composition containing simvastatin is placed in the primary powder feeder, and the composition containing amlodipine is placed in the secondary powder feeder, and tableted under conditions that can minimize the infiltration of the layers, and the high coater (SFC-30N, Sejong Machinery, Korea) to form a multi-layered tablet by forming a film coating layer with the ingredients and contents described in Table 3. Example I 13: Amtodipine Tablets—Preparation of Capsulfonate Containing Simvastatin Tablets

 1) Preparation of amlodipine delayed-release compartments (tablets)

next. Apology of amlodipine besylate and crystalline ¾rollose with No. 35 with the ingredients and contents shown in Table II-3 was mixed with a double cone mixer, and then mixed in a fluidized bed granulator (GPCG 1: Glatt), followed by separately hydrated propyl. The granules were sprayed by spraying the binding solution (10% w / w), which was made by tapping the tertylcel in purified water. Carbomer 71G was added to the above-mentioned limbus in powder form, and magnesium stearate was added thereto, which was common as a final double cone mixer, and the final mixture was compressed using a rotary tableting machine (MRC-30: Sejong). . To the above viscous solution, a solution of hydroxypropyl ¾ cells in a 1: 1 shaker solution of ethanol and methylene chloride was added to a solution of chloropropylphthalate and acetylated monoterminicete as a coating solution (20% w / w). To prepare a tablet by forming a film coating layer using a high coater (SFC-30N, Sejong Machinery, Korea).

 2) Preparation of simvastatin pre-release compartments (tablets)

Next, simvastar, microcrystalline cellulose, manny, which was synthesized with the ingredients and contents shown in Table Π-3, were appled into a No. 35 sieve and mixed with a high speed mixer. Separately, hydroxypropyl cellulose and citric acid were dissolved in purified water to prepare a binder solution (10¾ w / w), which was mixed with the main component mixture. The mixture was put into a fast mixer and softened, and then granulated with an oscillator using No. 20 sieve, which was dried at 60 ° C using a silver water dryer, and then reconstituted with No. 20 sieve. Butylated hydroxyanisole, sodium starch glyconate and colloidal silicon dioxide were mixed, and finally mixed with magnesium stearate in a double cone mixer, and the final mixture was mixed with a rotary tablet press (MRC-30: Sejong, Korea). ) Was compressed into tablets. The tablet is a high coater (SFC-30N, Sejong machine, Korea) by fusing a coating solution (20¼ / w) prepared by dissolving and dispersing hydroxy propylose 2910, polyethylene glycol 6000, titanium oxide and talc in 80¾ ethane. ),

3) Capsulation layer exhibition

The amlodipine tablets of step 1> and the simvastatin tablets of step 2) were layered onto No. 3 hard ¾ latin capsules using ¾ slabs. Example 11-14 Preparation of Amlodipine-Simvastatin Capsulant

 1) S (tablet) of amlodipine delayed-release compartment

It was prepared according to the ingredients and contents shown in Table 11-3 and 1) amlodipine delayed-release compartment of Example Π-13.

 2) Preparation of simvastatin prior-release compartments (granules)

In the following ingredients and contents shown in Table 11-3, simvastatin, microcrystalline cells, apples, lactose, and corn starch as No. 35 sieve were mixed with a high speed mixer. Separately, hydrated special propyl sal was dissolved in purified water, and a binder solution (10¾ w / w) was prepared, and the mixture was thrown into a high-speed mixer with a main ingredient mixture, and then granulated using an oscillator. After drying at 60 using was again established as No. 20 sieve. To this was added butylated hydroxyanisole, starch glyconate Na: trium, and colloidal silicon dioxide, and magnesium stearate was added for final mixing in a double cone mixer.

3) ¾ cup filling

The amlodipine tablet of step 1) and the simvastatin granules of step 2) were layered onto the hydroxy hard capsules of No. 2 hydroxypropylme ¾ cells using a capsular bed electric machine. Example 11-15 ： Amlodipine—simvastatin coated tablet S

1) Preparation of amlodipine delayed-release compartments (tablets)

Next, the ingredients and contents shown in Table 11-3 and 1) Amlodipine delayed-release sphere of Example 11-11 It was prepared according to the method for preparing the stroke.

 2) Preparation of simvastatin pre-release coating solution

80% of simvastatin, butylated hydride cyanosol, hydroxypropylmethylcellose 2910, colloidal silicon oxide, pulley ¾ lencholol 6000, titanium oxide, and talc as shown in Table 11-3. Ethane was dissolved and dispersed in to prepare a pre-release simvastatin coating solution (2W w).

 3) Primary coating

The amlodipine tablets prepared above were administered to a high coater (SFC-30N, Sejong Machinery, Korea), and then first coated with a simvastatin coating solution.

 4) secondary coating

The film coating layer composition of Table II-3 was dissolved in 80% E. coal and purified water shaker to prepare a film coating solution, and then a second coating was applied to the first coated tablet to prepare a film coated tablet. Example 11-16: Preparation S of Simvastar¾ Rapid-Amlodipine Osmotic Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartments (tablets)

Next, amplify amlodi ¾ besylate and microcrystalline cells of rhodes and sodium chloride in a No. 35 sieve with the ingredients and contents shown in the following Table 3. The final mixture was compressed using a rotary tablet press (MRC-30: Sejong). After tableting, colicoat S 30D as a semi-permeable membrane coating base and triethyl citrate as a plasticizer were dispersed in purified water (20% w / w), and then coated onto inner core using a high coater (SFC-30N, Sejong Machinery, Korea). Osmotic inner core was prepared.

 2) Preparation of simvastatin pre-release compartments

Next, the ingredients and contents shown in Table 11-3 and 2) simvastatin pre-release compartments of Example 11-11 were prepared according to the preparation method.

 3) tableting and coating

Example II—11) 3) Simvastatin immediate-amlodipine-invasive nucleated tablets were prepared according to the method of tableting and skipping. Example II 一 17: Amlodipine-simvastatin blister packaging kit

Prepared with the ingredients and contents shown in the following Table 11-3, tablets Amlodithi of Example A— Example II—13 And simvastatin tablets were prepared in the same manner as in Example 11-13, except that the blister packaging was packaged for isochronization instead of simultaneously filling in the capsule, Example 11-18: (S) -Amlodi ¾ ~ Preparation of Vastatin Nucleated Tablets

 1) Preparation of (S) -amlodipine delayed-release compartment (inner core)

Next, the (S) -amlodipine besylate and microcrystalline sal were apologized with a No. 35 sieve and mixed with a double cone mixer using the ingredients and contents shown in the following Table Π-4, and then immersed in an epilayer granulator (GPCG 1: Glatt). Separately, the binder solution (10% w was sprayed to form granules, and then dried. After mixing for about minutes, magnesium stearate, which was sieved through No. 35, was added, and finally mixed for 4 minutes.The final mixture was compressed into tablets at a rate of 30 revolutions per minute using a rotary tableting machine (MRC-30: Sejong). S) -nucleodiol in amlodipine was prepared.

 2) Preparation of simvastatin pre-release compartments

Next, sieved to simvastatin, microcrystalline cellulose, and Manniul with No. 20 sieve with the ingredients and contents shown in Table Π-4, and then mixed in a high speed mixer for 10 minutes. Separately, hydroxypropyl ^ was dissolved in distilled water and citric acid to prepare a binding solution (10% w / w). The binder was added to the above mixture, and then granulated, dried, and granulated to complete granulation. Butane-rated hydroxyanisole and starch glycolate sodium, which were previously sieved through No. 35, were administered to the double cone mixer together with the above granules, and then mixed for about 10 minutes. After passing through a sieve and administering to a double cone mixer, the final mixture was finally mixed for about 4 minutes to prepare simvastatin layer granules.

 3) tableting and coating.

Nucleating tablets were prepared by tableting at a rate of 30 revolutions per minute using a nucleated tableting machine (RUD-1: Kil iai *) as the outer layer of a composition containing amlodipine inner cores. The coating layer composition was dissolved in a solvent to prepare a film coating solution.The nucleated tablet prepared above was administered to a high coater (SFC-30N, Sejong Machinery, Korea) and coated with a film coating solution to complete nucleated tablet preparation. 19 ： (S) -Amlodipine-Zombatin Nucleated Tablets

Prepared with the ingredients and contents shown in the following Table Π-4 ᅳ After the preparation of the nuclear tablet of Example Π-18 A solution in which poly (decacrylate, methylmepark ¾rate) copolymer is dispersed in purified water

(20¼ / w) was prepared in the same manner as in Example II-18, except that it was additionally coated with (20¼ / w). Example 11-20: Preparation of (S) -Amlodipine-Simvastatin Capsulant

 1) Preparation of (s) -amlodipine delayed-release compartment (purification)

(S) —Amlodipine besylate and microcrystalline cell were mixed with a double cone mixer and appled with a double cone mixer using the ingredients and contents shown in the following table Π-4, and added to a fluidized granulator (GPCG 1: Glatt). Separately, after forming a granule by spraying a binding solution (10% w / iv) prepared by dissolving hydroxypropyl shellose in purified water, dry S was added. After mixing for W minutes in the mixer, the stearic acid magnesium which was sieved through a No. 35 sieve was added and finally mixed for 4 minutes. (S) -Ambro dipine tablets prepared by tableting at the speed of 30 revolutions per minute using a rotary tablet press (MRC-30: Sejong) rolls were prepared using a poly (methacrylate, methacrylate) copolymer. Coating with a solution (20taAr) dispersed in purified water to complete the preparation of (S)-amlodipine tablets.

 2) Preparation of simvastatin pre-release compartments (tablets)

After sieving simvastatin, microcrystalline cellulose and manny with No. 20 sieve with the ingredients and contents shown in the following table Π-4, they were mixed in a high-speed mixer for 10 minutes. Separately, hydroxypropylcell was dissolved in purified water and bound. 2: (10 3 w / w) was obtained. On the above complications. After adding the binding solution, the association was completed, and then granulation was completed by granulation, drying, and granulation. Butylated hydroxyanisole, starch glyconate natcom, and colloidal silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a double cone mixer together with the above granules, followed by mixing for about 10 minutes, and magnesium stearate. The sieve was passed through a sieve No. 35 and administered to a double cone mixer, followed by final mixing for about 4 minutes to complete the preparation of simvastar ¾ granules. Simvastar ¾ tablets prepared by tableting the granules at a rate of 30 revolutions per minute using a rotary tablet press (MRC-30: Sejong) were coated with the film layer components of Table 8 to complete the preparation of simvastatin tablets.

3) Capsulation layer exhibition

Capsule preparation was completed by layering the above (S) -amlodipine tablets and simvastatin tablets on the gelatine hard cap capsules of No. 3 using a capsular layer electrophoresis. Example 11-21: Preparation of (S) -Amlodipine-Simvasta ¾ capsulant 1) (S) —the ≥ (tablet) of the amlodied delayed-release compartment

Next, the preparation of dipine tablets by (S) -cancer was completed by the method of Example 11-20-1) with the ingredients and contents shown in Table II-4.

 2) Preparation of simvastatin layer prior-release compartment (granule)

Next, sivastatin, microcrystalline cellulose, and manni were sieved through a No. 20 sieve with the ingredients and contents shown in Table Π-4, followed by mixing for 10 minutes in a high speed mixer. Separately, the hydroxydemic propyl sal was dissolved in purified water of loose and citric acid to prepare a binding solution (10¾ w / w). The binder was added to the above mixture, granulation, drying, and granulation were completed to complete granulation rolls. It was then administered to a double cone mixer with granules on buhalated hydride cyanosol, starch glycolate, and colloidal silicon dioxide, which were previously sieved through No. 35, and then mixed for about 10 minutes. Magnesium acid was sieved through a No. 35 sieve and poured into a double cone mixer, followed by final mixing for about 4 minutes to complete the preparation of simvastatin layer granules.

 3) Capsule layer

 Using ¾ wine layer above. (S) -Amlodipine tablets and simvasparin granules were simultaneously layered on No. 1 hydroxypropylmethylcellulose hard cap surgery to complete the preparation of the capsulant. Example 11-22: (S) -Amlodi Equation + Simvasta Blister Packaging Kit

Prepared by the ingredients and contents shown in the following Table Π-4, but instead of co-layered in the (S)-amlodipine tablets and simvastatin tablet roll cap of Example II ᅳ 20 it is proposed to co-dock packaging in a PTP packaging container And prepared as in Example 11-20. Example II-23: (S) —Preparation of Amlodipine-Simvastar ¾ Coated Tablet

i) (s)-s (purification) of the amlodipine delayed-release compartment

Following the ingredients and contents shown in Table II-4, (S) -Amlodipine and the microcrystalline cell were anointed with No. 35 sieve, mixed with a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glatt). A combined solution (10¾ of hydroxypropylcellose was dissolved in purified water, sprayed to form a grove, and dried. Carbomer 71G was added to the granules in a powdered state: 10 minutes in a double cone mixer. After mixing, the stearic acid was passed through a No. 35 sieve, followed by final mixing for 4 minutes.The final mixture was prepared by tableting at a speed of 30 revolutions per minute using a rotary tableting machine (M C-30: Sejong). Purification of the (S) -amlodipine tablets from the following table Π-4 poly (methacrylate, methyl meth ¾) co-polymer Upon dispersal in aging, coating with ¾ solution (20¾v / w) completes the preparation of (S) -amlodipine tablets.

2) Preparation of Simvastatin Coating Liquid

To the components and contents shown in Table II-4, simvastar¾, butylated hydrated cyanuric sol, hydroxypropylmethylshellose 2910, and colloidal silicon oxide were added to a shake solution of ethane and methylene chloride 1: 1. Melt to prepare a simvastatin coating solution,

 3) Primary coating

The (S) -amlodipine tablets prepared above were administered to a high coater (SFC-30N, Sejong Machinery, South Korea), followed by primary codontification with a simvastar¾ coating solution.

 4) secondary coating

After dissolving the film coating layer composition of Table II-4 in a solvent to prepare a film coating solution to prepare a film coating tablet by the secondary coating on the first coating is completed.

 -2]

C6 ιεεοοο / 6θοζ9ΐχ3ί Table 11-3

[표 11-4]

Table 11-4

Example II I- Preparation of Amlodipine-atorvastatin Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

As shown in Table III-1, amlodipine besylate and microcrystalline cell were apologized as No. 35 sieve and mixed with a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropyl separately. Granules were formed by spraying the binding solution prepared by dissolving methyl salose in purified water and drying the granules. Carbomer 71G »powder was added to the granules and stearic acid was added to the final double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) and used as the inner core.

2) the 1st of the atorvastatin prior-release compartment

As shown in Table II 1-1, atorvastatin chamomile trihydrate, carbohydrate carbonate, microcrystalline cellulose, lactose, pregelatinized starch and lauryl sulfate; "(sodium lauryl sulfate) was appointed in No. 35 and mixed with a high-speed mixer. Loose was dissolved in purified water to prepare a binding solution, which was added together with the main ingredient mixture in a high speed mixer, and then granulated using an oscillator as a No. 20 sieve, dried at 60 X using a silver water dryer, and then re-established as No. 20 sieve. Croscarmellose sodium was added to the mixture, and magnesium stearate was added to the final mixture in a double cone mixer.

3) tableting and coating

Using a nucleated tablet tableting machine (RUD ᅳ 1: Ki lian), the composition containing amlodipine inner core and atorvastatin was used as an external insect, followed by rubbing using a high coater (SFC-30N, Sejong Machinery, Korea). A nucleated tablet was prepared by forming a film coating layer with an excess content. Example III-2 Preparation of Amlodiphan-Atorvastated Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

As shown in Table III-1, amlodipine besylate and unaffected cells were apologized as No. 35, mixed with double cones, and poured into a fluidized bed granulator (GPCG 1: Glatt). Roxypropylte ¾ gel was dissolved in purified water by spraying the binding solution to form granules, dried. The granules were then sprayed with hydroxypropyl decylcel dissolved in a 1: 1 shaker solution of ethane and methylene chloride, followed by spraying with a fluorophthalate solution. Magnesium stearate was added thereto, followed by mixing in a final double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) and used as the inner core.

 2) Preparation of atorvastatin prior-release compartment

It was prepared according to the method of Example III-1 with the ingredients and contents shown in the following Table II-1.

3) tableting and coating

Using a nucleated tablet tableting machine (RUD-1: Ki liai), the composition containing the amlodipine inner core and atorvastatin as an outer layer was compressed into tablets, and then used a high coater (SFC-30N, Sejong Machinery, Korea). Nucleated tablets were prepared by forming a film coat layer with an excess content. Example III-3: Preparation of Amlodipine-Atorvastated Nucleated Tablets

1) Preparation of amlodipine delayed-release compartment (inner core) The amlodipine besylate and microcrystalline ^ loose were apologized as No. 35 and mixed with a double cone mixer as shown in Table III-1 below. The above mixtures were mixed in a fluidized bed and a ¾ phase (GPCG 1: Giatt). The granules were injected and sprayed separately with hydroxypropylmethylcellose in purified water to form granules and dried. Then, the granules were sprayed with Eudragit RS P0 solution dissolved in methylene chloride to coat the granules. . Magnesium stearate was added thereto and finally mixed with a double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC—33: Sejong) and used as a nuclear tablet.

 2) Preparation of atorvastatin prior-release compartment

To the ingredients and contents shown in Table III-1 were prepared according to the method of Example ΙΠ-1-2).

 3) tableting and coating

Using a nucleated tablet tableting machine (RUD-1: Ki H an), the composition containing amlodipine inner core and atorvastatin as an outer layer was compressed into tablets, and then used a high coater (SFC-30N, Sejong Machinery, Korea). to form a film coating layer components and the content was prepared with a press-coated tablet ^{of example} ΙΠ-4: amlodipine-atorvastatin multi-layered manufacturing

 1) Preparation of amlodipine delayed-release compartment

The ingredients shown in Table III-1 below. And amlodi fragment maleate and microcrystalline cell were apologized and mixed with Loose Roll No. 35, and then fed into a high-speed mixer, and added with Colicoat SR30D. After the association, the No. 20 body was used with an oscillator. The granules were dried at 60 1 C using a dry water dryer and then tipped to No. 20 again. Magnesium stearate was added thereto and finally mixed with a double cone mixer.

 2) Preparation of atorvastatin prior-release compartment

As shown in Table III-1, the atorvastared stale anhydrous, calcium carbonate, microcrystalline cellulose, lactose and sodium lauryl sulfate were appled with a No. 35 sieve and mixed with a high speed mixer. . Separately, prepare a defect solution by dissolving hydroxypropyl ^ loose in purified water, add it to a high-speed mixer mixed with a main ingredient mixture, combine it, and granulate it with a No. 20 sieve using an oscillator, and dry it at 60 ¾ using a silver water dryer. Again it was determined as No. 20 body. Croscarmellose sodium was added to this mixture, and stearic acid magnesium was added to the final mixture using a double cone mixer. 3) tableting and coating

In this process, the tablet was compressed using a multi-layer tablet press (M4C-37T: Sejong). That is, the composition containing atorvastatin was placed in a primary powder feeder, and the composition containing amlodipine was placed in a secondary powder feeder. The tablets were compressed to minimize the infiltration between the layers, and a multi-layered tablet was prepared by forming a film coating layer using the ingredients and contents of Table III-1 as a high coater (SFC-30M, Sejong Machinery, Korea). Example II-5: Preparation of amlodipine-atorvastatin multilayer tablet S

 1) harvesting of amlodipine delayed-release compartments

As shown in Table III 1, amodipine malate and microcrystalline ¾loose were apologized with No. 35 and mixed with a double cone mixer, and hydroxypropylmethol¾¾loose was dissolved in purified water. The liquid was sprayed to form granules and dried. Again, the granules were sprayed with hydroxypropylmethylcelolo phthalate solution dissolved in 1: 1 shaker of ethane and methylene chloride, and co-coated with the team. Magnesium stearate was added to the final double cone mixer. .

 2) Preparation of atorvastatin prior-release compartment

As shown in Table III-1, atorvastatin calcium strontium pentahydrate, calcium carbonate, microcrystalline ¾-lose, lactose and sodium lauryl sul fate as apple No. 35 were used as apples. Mixed. Separately, a special liquid was prepared by dissolving the loose-special propyl shell in purified water, putting it in a high-speed mixer with a main component mixture, and then combining it with J1 and then granulating it using an oscillator in a No. 20 sieve. It was dried at and then reconstituted with No. 20 sieve. Croscarmellose sodium was added to the mixture, and magnesium stearate was added thereto, followed by final mixing with a double cone mixer.

 3) tableting and coating

In this process, the tablet was compressed using a multi-layer tablet press (MRC-37T: Sejong). That is, the composition containing Atorvasta ¾ was placed in a primary powder feeder, and the composition containing amlodipine was placed in a secondary powder feeder. The tablets were compressed to minimize the infiltration between the layers, and a multi-layered tablet was prepared by forming a fill # coating layer using the ingredients and contents of Table II 1-1 as a high coater (SFC-30N, Sejong Machinery, Korea). Example 6-6: Preparation of Amlodipine-Atorvastatin Biphasic Matrix Tablets

1) Preparation of amlodipine delayed-release compartment

As shown in Table II-1-1, amlodipine vasylate and microcrystalline shell loose were mixed with apple No. 35 and mixed, and then fed into a high-speed mixer, and co-coated SR30D was added. When the association was completed, granulated with 20 housings using an oscillator, dried at 60 using a silver water dryer, and then re-established as 20 :.

 2) Preparation of Atorvasta ¾ pre-release compartment

As shown in Table ΠΙ-1, atorvastatin calcium trihydrate, calcium carbonate, microcrystalline salose, lactose, mannose, and crospovidone were appled with No. 35 and mixed with a high-speed mixer. Loose and plysorbate 80 were dissolved in purified water to prepare a binding solution, and the mixture was introduced into a high-speed mixer with the common substance of the above-mentioned ingredients. Then, it was granulated using an oscillator. Dried at I; and back to 20.

 3) post-mixing, tableting and coating

Each of the final compositions prepared above was mixed with a double cone mixer, and sodium starch glycolate was mixed, and then a magnesium stearate was added thereto, followed by final mixing with a double cone mixer.

Rub the final mixture using a rotary tableting machine (MRC— 33: Sejong) and then form a film coating layer with the ingredients and contents listed in Table II-1-1 as a high coater (SFC-30N, Sejong Machinery, Korea). Phase matrix tablets were prepared. Example III-7 Preparation of Amlodimen-atorvastatin Two-Phase Matrix Tablets

 1) Preparation of Amlodi fragment delayed-release compartment

As shown in Table III-1, amlodipine besylate and microcrystalline shell loose were apologized as No. 35 and mixed with a double cone mixer. The above mixture was introduced into a fluidized bed granulator (GPCG 1: Glatt). Separately, granules were formed by spraying a binder solution made by dissolving ¾ cell cellulose in hydrated propyl-metholose in purified water, and drying the granules by spraying ¾ Eudragit RS P0 solution upon dissolving in granules. Was coated.

 2) Preparation of atorvastatin prior-release compartment

It was prepared by the crime prevention of Example III ᅳ 6-2) with the ingredients and contents shown in the following Table III-1

3) tableting and coating Each of the above-described final compositions was mixed with a double cone mixer, and sodium starch glycolate was mixed with a stearic acid magnesium and finally mixed with a double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) and formed into a film coating layer using the ingredients and contents of Table III-1 as a high coater (SFC-30N, Sejong Machinery, Korea). Biphasic matrix tablets were subtracted. Example III-8 Preparation of (S) -Amlodipine-Atorvastatin Two-Phase Matrix Tablets

 1) Preparation of amlodipine delayed-release compartment

In the following Table III-1, S-amlodipine besylate was used instead of amlodipine besylate in the same manner as in Example III-6-1).

2) Preparation of atorvastatin pre-release compartment

 In the same manner as in Example ΠΙ-6-2), except that atorvastatin calcium anhydride was used instead of atorvastatin chame trihydrate with the ingredients and contents shown in the following Table 111-1.

3) tableting and coating

 It was prepared in the same manner as in Example III-6-3) with the ingredients and contents shown in Table III-1 below. Example III-9: (S) -Amlodipine-Atorvastatin Phase 2 Capsule Preparation

 1) Preparation of amlodipine delayed-release compartments (granules)

Following the ingredients and contents shown in Table II 1-1, S-amlodipine besylate and microcrystalline cell were apologized with No. 35 sieve and mixed with a double cone mixer, and then added to the fluidized bed and ¾ (1 1: Glatt). ， Separately, the bonding liquid made by dissolving hydroxycell of hydroxy cellulose in purified water was sprayed to form granules and dried. Again, the granules were sprayed with hydroxypropylmethylsalloosephthalate solution dissolved in 1: 1 shaker of ethane and ethylene chloride to coat the granules.

 2) Granulation of Atorvasta ¾ prior-release compartment

Apples of atorvastatin calcium trihydrate, calcium carbonate, microcrystalline cellulose, lactose, pregelatinized starch, and sodium lauryl sulfate were identified as No. 35 as shown in Table III-1. Faro hydroxypropylcellose was dissolved in purified water to prepare a binder, which was added to a high-speed mixer with a mixture of the main ingredients, and then granulated using an oscillator roll. It dried at 60X: using the dryer roll, and it was made up again with No. 20 sieve.

3) mixing and capping

It was combined common a final composition of step 1) and 2) in a double cone mixer, and then tueop starch article Recliner acid sodium ^"here traces were combined in a double cone mixer all, were finally mixed into the aralkyl acid magnesium seudwe The final heunhap The mixed moles were placed in a powder feeder and layered in caps No. 1 using a capsular layer electric machine Example 111-10: Preparation of amlodipine-atorvastatin biphasic preparation

 1) Preparation of amlodipine delayed-release compartments (granules)

Following amplification of amlodipine malate and microcrystalline cellulose as No. 35, mixed with a Dubucon mixer as shown in the following table ΙΠ-1, it was added to a fluidized bed granulator (GPCG 1: Glatt) and colicoat SR30D Sprayed to form granules and dried.

 2) Preparation of atorvastared prior-release compartments (granules)

As shown in Table II 1-1, atorvastatin strontium pentahydrate, calcium ¾ acid, microcrystalline ¾ rate loose, lactose, manni and crospovidone were apologized by No. 35 and mixed with a high speed mixer. Dissolve the propylcellulose and pulley sorbate 80 in purified water to remove the defect solution, add it to the high-speed mixer together with the mixture of the main component, and then unite with the No. 20 sieve. It was dried at 60 ° C. and then sieved to No. 20 sieve again.

 3) mixing and capping layer

The final compositions of Steps 1) and 2) were mixed with a Dubucon mixer, sodium starch glycolate was added thereto, followed by mixing with a double cone mixer, and magnesium stearate was added for final mixing. The final mixed mixture was put into a powder feeder and layered into No. 1 ¾ liquor using a ¾ sul charger. Example II-11: Preparation of Amlodipine-Atorvasta ¾ Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (inner core)

Amlodipine besylate and microcrystalline shell as shown in the following Table ΙΠ-2 Aps, dicalcium phosphate was mixed with a No. 35 sieve, mixed with a double cone mixer, and then added to the granular layer granules 7) (GPCG 1: Glatt), and a binder solution prepared by dissolving hydroxypropylmethylgelulose in purified water was separately prepared. The granules were sprayed to form granules and dried. Carbomer 71G was added to the granules in a powder form, followed by adding a stearic acid magnesite to a final double cone mixer, followed by rotary tablet press (MRC). — 33: Sejong) tableted using>

In the above purification, a hydroxypropyl methyl salulose phthalate solution and acetylated monoglycerides dissolved in 1: 1 shaker of ethane and methylene chloride were added at a ratio of 100: 1 to a high coater (SFC-30N, Sejong Machinery, Korea) was used to form a film coating layer to remove the inner core.

 2) Preparation of atorvastatin prior-release compartment

Atorvastatin ¾: calcium trihydrate, stearic acid, chestnut, microcrystalline gellose, oak starch and lactose were apologized as No. 35 and mixed in a high-speed mixer as shown in the following table II- 2. Dissolve propyl-l-loose and plysorbate 80 in purified water to remove the binding solution, add it to a high-speed mixer with the main component mixture, combine it, and granulate it with the No. 20 sieve using an oscillator. The mixture was dried at 60'C, and then sieved to No. 20. Here, sodium starch glyconate was mixed, and magnesium stearate was added and finally mixed with a double cone mixer.

 3) tableting and coating

Using a nucleated tablet tableting machine (Rl -1: Ki l ian), the composition containing amlodipine inner core and atorvastatin as a layer was compressed into a layer, followed by a high coater (SFC-30N, Sejong Machinery, Korea). Nucleated tablets were prepared by forming a film coating layer with an excess content. Example II-12: (S) —Preparation of Amlodipine-Atorvasta multilayered tablets

 1) the preparation of amlodipine delayed-release compartment

Following the ingredients and contents shown in Table II 1-2, apples with S-amlodipine besylate and microcrystalline cell were identified as Loose and Dicalcium Phosphate as No. 35, and double-mixed with hydroxypropylmethylcellose in purified water. The dissolved binder solution was sprayed to form granules, followed by drying. Again, the hydroxypropylmeth¾¾ dissolved in ethane and methylene chloride in a 1: 1 solution was added to the phthalate solution and acetylated monoglycerides. The granules were coated by spraying a 100: 1 mixed solution, to which stearic acid magnesium And mixed into a final double cone mixer.

 2) Preparation of atorvastatin prior-release compartment

It was prepared by the method of Example II 1-11-2) with the ingredients and contents shown in Table II 1-2.

 3) tableting and coating

In this process, the tablets were compressed using a multi-layer tablet press (MRC) 37T: Sejong). That is, the composition containing the atorvastatin was placed in a primary powder feeder, and the composition containing amlodisome was transferred to a secondary powder feeder. Tablets were put in a condition that minimizes the intrusion between layers, and a multi-layered tablet was prepared by forming a film coating layer using the ingredients and contents of Table ΠΙ-2 as a high coater (SFC-30N, Sejong Machinery, Korea). Exemplary Example II 1-13: Preparation of Amlodipine-Atorvasta Caps

 1) Preparation of amlodipine delayed-release compartments (tablets)

Next, as shown in Table II 1-2, amlodipine besylate and microcrystalline salose were apologized with No. 35, mixed with a Dubucon mixer, and then added to a granular granulator (GPCG 1: Glatt). Granules were formed by spraying the combined solution obtained by dissolving hydroxypropyltetylshelle in purified water, and drying the carbomer 71G into the granules, and then adding magnesium stearate to the final granules. After mixing with a mixer, the final mixture was compressed using a rotary tablet press (MRC-33: Sejong). Again, hydroxypropylmethylcell was dissolved in 1: 1 shaker of ethane and methylene chloride. The tablet was prepared by forming a film coating layer using a high coater (SFC-30N, Sejong Machinery, Korea) using a solution mixed with a solution of acetylated monoglycerides in a ratio of 100: 1.

 2) Preparation of atorvastatin prior-release compartments (tablets)

In the following Table II 1-2, atorvastatin chamomile trihydrate, carbonate chamomile, and microcrystalline salose were apologized as No. 35 and mixed with a high speed mixer. Dissolve the sorbate 80 in purified water to make a binding solution, add it to a high speed mixer with the main component mixture and combine it, and granulate it using the oscillator with No. 20 sieve. Here, Nathium starch glyconate is mixed, and the final mixture is mixed with a stearic acid magnesium bosom with a double cone mixer, and the final mixture is placed into a rotary tablet press (MRC- 33: King Sejong). The tablet is a coating liquid prepared by dissolving and dispersing hydrated propyl cellulose, polystyrene glycol 6000, titanium oxide and talc ethane in. It was coated with a high coater (SFC-30N, Sejong Machinery, Korea).

3) ¾ layer warfare

The amlodipine tablet of step 1) and the atorvastar ¾ tablet of step 2) were layered into capsule 3 using a ¾ sulfoner. Example 111-14 Preparation of Amlodi ¾ ᅳ atorvastatin ¾

 1) Preparation of amlodipine delayed-release compartments (tablets)

It was prepared by the method of Example III-13-1) with the ingredients and contents shown in the following Table III-2.

 2> Preparation of atorvapatin pre-release compartments (granules)

In the following Table II 1-2, the atorvastatin calcium trihydrate, calcium carbonate, microcrystalline cellulose, lactose, corn starch and lau ¾ sodium sulfate as apples No. 35 were apples and mixed with a high speed mixer. Separately, hydroxypropyl ¾ loose was added to purified water to prepare a binding solution, and the mixture was added to a high-speed mixer mixed with the main ingredient mixture. Then, the mixture was granulated using an oscillator with No. 20 sieve and dried at 60 13 using a silver water dryer. Again, No. 20 sieve was added. Here, sodium starch glyconate was mixed, and magnesium stearate was added and finally mixed with a double cone mixer.

3) ¾ charging

The amlodipine tablet of step 1) and the atorvastatin granules of step 2) were layered onto hydroxypropylmethylcellol.rose hard ¾ liquor of No. 2 using a capsular bed electric machine. Example 111-15 Preparation of Amlodi ¾-Atorvasta Coated Tablets

 1) Preparation of amlodipine delayed-release compartments (tablets)

Following amplification of amlodipine besylate and microcrystalline ¾ with rhodes, Decalum Phosphate ¾ 35 as shown in Table ΠΙ-2, mixed with a double cone mixer, and put into a fluidized bed granulator (GPCG 1: Glatt). Separately, hydroxypropylme ¾ · loose was dissolved in purified water and sprayed with a defect solution to form granules and dried.The carbomer 71G was added to the above-mentioned vinegar in powder form, and then magnesium stearate was added thereto. Put the final deconcone into a common place, and then use the rotary tableting machine (M C-33: Sejong) Again, the hydroxypropylmethylshellloosephthalate solution and acetylated monoglyceride solution dissolved in ethanol and 1: 1 benzene solution of decene chloride were 100: 1 mixed with a high coater (SFC). -30N, Sejong Machinery, Korea) to form a film coating layer to prepare a tablet.

 2) agent S of the atorvastatin prior-release coating liquid

As shown in Table II 1-2, the atorvastatin calcium trihydrate, hydrated propylpropylcellulose was dissolved and dispersed in 80¾ ethane to prepare a pre-release atorvastatin coating solution.

 3) car coating

The amlodipine tablets prepared above were administered to a high coater (SFC-30N, Sejong Machinery, Korea), followed by primary treatment with an atorvastatin coating solution.

 4) car coating

The film coating layer composition of Table ΠΙ-2 was dissolved in a solvent to prepare a film coating solution, and then a second coating was performed on the first coated tablet to prepare a film coated tablet. Example III—16: Preparation of Amlodipine-Atorvastated Seborrheic Nucleated Tablets

 1) Preparation of amlodipine delayed-release compartment (osmotic tablets)

As shown in Table III-2, amplify the amlodipine silicate, microcrystalline cell, and sodium chloride with No. 35 sieve and mix with a double cone mixer, and add magnesium stearate to the final double cone. The mixture was mixed with a mixer and compressed into tablets using a rotary tablet press (MRC-33: Sejong). After tableting, triethyl srate and Colicoat S 30D as an osmotic base were dispersed in purified water, followed by a high coater ( SFC-30N, Sejong Machinery, Korea) was coated on the inner core to produce an osmotic inner core.

 2) Preparation of atorvastatin prior-release compartments (granules)

It was prepared by the method of Example 111-14-2) with the ingredients and contents shown in Table III-3 below.

 3) tableting and coating

Using a nucleated tableting tablet press (RUD— 1: Kil ian), the composition containing amlodipine inner core and atorvastatin was externally swept and then a film coat layer was formed using a high coater (SFC-30N, Sejong Machinery, Korea). Osmotic nucleated tablets were prepared. Example I IIVII 17 Preparation of Amlodipine-Atorvasta ¾ Blister Packaging Kit

To prepare the amlodipine delayed-release compartment (tablet) and atorvastatin pre-release compartment (tablet) by the method of Examples III-13-1) and 13-2) as shown in the following components III and III. It was manufactured by packaging to allow simultaneous use in the bolister packaging.

 -One]

TABLE II 1-2

2) g¾ lot sreoD-Chu gsi m cwa¾s 3o¾ ¾ solution,-at s Example IV '1: Amlodipine-Pitavata ¾ Nucleated Tablets

The nucleation point was subtracted by the following method with the ingredients and contents listed in the table.

1) Manufacture of pre-release compartments (Pitavastatin pre-release granules)

Pitavastatin calcium, metasilicate aluminate, crystalline cellulose (AvkelPHlOl, FC Biopolymer, USA), lactose hydrate (DMV, Germany), pregelatinized starch (Starch 1500G, Colorcon, USA) Apples were mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropylcell was dissolved in purified water of cellulose OFC-L, Nippon Soda, Japan) * to prepare a binding solution, which was then combined with the main component mixture. When the union is finished, granulate with No. 18 sieve using Oscillator R402, ERWEKA, Gennany) * and dry it at 60 ^° C with a silver water dryer (HWC, Samgong, Japan). It was established. Low-substituted hydroxypropyl salose was mixed with the sintered material, and magnesium stearate (Nitika Chemical, India) was added and finally mixed with a double cone mixer.

2) Manufacture of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate, microcrystalline ¾ rose, anhydrous calcium hydrogen phosphate, pregelatinized starch (Starch 1500G, Colorcon, USA) were apples in No. 35 and mixed for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropylcell was dissolved in purified water roll to form a binding solution, which was then combined, granulated, and dried. After drying, it is established as No. 18 again. The sieved material is placed in a fluidized bed corrugator, and separately ¾ cellulose acetate: 巨 320S (32% acetal group) and saloseacetate S 398-10NF (acetal group 39.8%) are added to ethane and methylene chloride. The melted solution was prepared and the above granules were placed in a fluid bed granulation coater (GPC &-1; Glatt, Germany) and nosed. Coating completed. After that, magnesium stearate was added and mixed for 4 minutes, and the tablets were tableted with a rotary tablet press (MRC-37, Sejong Machinery, Korea) equipped with a 5 mm diameter bias.

3) honing coating

A nucleated tableting machine (RUTK1: i lian, Germany) equipped with 11 mm bias was used as phytavastatin calcium pre-release granules of 1) as the outer layer, and the amlodipine besylate delayed-release tablet of 2) was used as a nuclear tablet. Tableting. Separately hydroxypropylmethylcyclolose 2910 (Shin-etsu, Japan), pulley ¾ lenglycol 6,000 (BASF, Germany), ¾ 2 ^ 3 ⁽ : France), titanium oxide (Tioside Americas, USA) dissolved and dispersed in ethane and purified water The coating solution was prepared to form a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea) to prepare a tablet roll in the form of nucleated tablets. Example IV-2: Preparation of Amlodipine-Pitabatatin Nucleated Tablets

Nucleated tablets were prepared by the following method using the ingredients and contents shown in Table IV-1.

1) Manufacture of pre-release compartments (Pitavasta ¾ pre-release granules)

Pitavastatin knives, metasilicate aluminate magnesium, crystallized cellulose, lactose carbohydrates and starch starch were apologized with No. 35, and the mixture was common for 5 minutes in a double cone mixer. Separately, hydroxypropyl¾ was dissolved in purified water to prepare a binder solution, which was associated with the main ingredient mixture. After the association, granulate with No. 18 using an oscillator and dry it at 60¾ using a hot water dryer. After drying, it was established as No. 20 again. Low-substituted hydroxypropyl cellulose was mixed with the sieved material, stearic acid magnesium was added, and finally mixed with a double cone mixer.

2) Manufacture of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate, microcrystalline cellulose, anhydrous hydrogen phosphate, and pregelatinized starch were appointed as No. 35 and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropylcellulose was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it is established as No. 18 again. The granules were placed in a fluidized bed coater, and a solution obtained by dissolving Eudragit RS30D (ETOiiik Degussa, Germany) and triethyl citrate (Vert lus, England) in methylene chloride was prepared. GPCG-1; Glatt, Germany) and coated. After the coating was completed, the stearic acid was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-37: Sejong) equipped with a 5 mm diameter bias to prepare a nuclear tablet.

 3) tableting and coating

Tablets in the form of nucleated tablets were prepared by tableting and coating in the same manner as in Example IV-1 and 3). Example IV-3: Preparation of Amlodipine-Pitavata ¾ nucleated tablets Nucleated tablets were prepared by the following method using the ingredients and contents shown in Table IV-1.

1) Pre-release compartment (Pitavastatin pre-release granules> manufacture

Pitavastatin kalsup, meta-silicate silicate, microcrystalline salose, lactose hydrate, starch starch and apple with 35 pieces were mixed and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropyl sal was dissolved in purified water roll to prepare a defect solution, and the roll was combined with the main ingredient mixture. After the association, granules were formed into a No. 18 sieve using an oscillator, and the granules were formed using a silver water gun: a 6 (TC: from the TC. After drying, the sieve was formed into a No. 20 sieve again. Were mixed, and the stearic acid magnesium was added and finally mixed with a double cone mixer.

2) Manufacture of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine tesylate, microcrystalline shellulose, and di-mannee were apples with No. 35 sieve, and mixed with each other for 5 minutes to prepare a mixture. Separately, pulley vinylphyllolidon (Koll idon 30, BASF, Germany) was dissolved in purified water and combined, granulated, and dried as a binder. After drying, it is established as No. 18 again. The formulations are placed in a fluidized bed coater and separately placed in ¾ shell (HERCULES, USA) and poly (methachite, methyl methrate) copolymer (Evonik degussa, USA) with ethane and methylene chloride. Was prepared in a liquid-bed granulation coater (GPCG # 1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes, and the core tablet was removed by teeing with a ¾ rotary tableting machine (MRC-37: Sejong) equipped with a 5 mm diameter punch.

3) tableting and coating

 Tablets in the form of nucleated tablets were prepared by tableting and coating in the same manner as in Example IV-1, 3). Example IV-4: Preparation of Amlodipine-Pipavatatin Nucleated Tablets

Nucleated tablets were prepared by the following method, using ingredients and contents set forth in Table IV-1.

1) Pre-release compartment (Pitavastatin pre-release granules) et al.

Pita Basta ¾ kalseum, metasilicate aluminate magnesium deer, and the mixture to apple microcrystalline ¾ weighed agarose, lactose monohydrate, pregelatinized starch sieved with a 35 mesh sieve and the combined shake for 5 minutes in a double cone ^mixer, was Article. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution. Was associated with the main component mixture. After the association, granulate with No. 18 using an oscillator and transfer it to No. 18 using a silver-drying machine. After completion of Gun s, it is re-established with No. 20. Sodium starch glycate (DMV, Germany) ), into the thoracic magnesium stearate, followed by final mixing in a double cone mixer. ^"

2) Preparation of delayed-release compartments (amlodipine delayed-release excipients)

Amlodichet malate, microcrystalline shellose, anhydrous hydrogen phosphate, and di-mannee were appled in No. 35 and mixed for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cells were dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it is settled again with No. 18 sieve. Stearic acid magnesium sieved through No. 35 sieve was added to the sieved material, followed by mixing for 4 minutes to prepare amlodipine delayed-release layer granules. Nuclear tablets were prepared by tableting the amlodipine fed granules with a rotary tablet press (MRC—37: Sejong) equipped with a 5 mm diameter punch. Separately, dissolve and disperse arc ¾-ises (methac¾ acid copolymer type C, talc, PEG, colloidal silicon dihexaside, sodium bicarbonate, SLS, Colorcon, USA) in purified water to prepare a ¾ coating solution. Lodi ¾ tablet was formed as a coater as a high coater (SFC—30N, Sejong machine, Korea) to complete the amlodipine tablet manufacturing roll.

3) tableting and coating

Pitavaspartin immediate release and ¾ were used as the outer layer in a nucleating tableting machine (11-1, ilian, Germany) equipped with a 11-kilometer, and tableted as an amlodipine delayed-release tablet roll core tablet of 2) above. Separately, hydroxypropylmethylcellulose 2910, polyethylene glycol 6,000, talc, and titanium oxide are dissolved and dispersed in ethane and purified water to prepare a ¾ coating solution to coat the above core tablets (SFC-30N, Sejong Machinery, Korea) to form a film coating layer to prepare a tablet in the form of nucleated tablets. ^"Example IV-5: amlodipine-blood Tabata ¾ press-coated tablet prepared

Nucleated tablets were prepared by the following method with the ingredients and contents listed in the table. 1) Preparation of Prerelease Blocks (Pitavastatin Rapid Release Granules)

Pitavastatin ¾ calcium, metasilicate aluminate magnesium, microcrystalline shellulose, lactose monohydrate, corn starch (DMV, Germany) were added to apples with No. 35 and the mixture was removed for 5 minutes in a double cone mixer. . Separately, dissolve the hydrous propylcellose in purified water Was prepared and associated with the main component mixture. After the association, granulate with No. 18 using an oscillator and transfer it at 60t: using a silver water dryer. After drying, it was established as No. 20. Low-substituted hydroxypropyl shell was mixed with the sieved material, and stearic acid magnesium was added and finally mixed with a double cone mixer.

2) S of delayed-release compartment (amlodi fragment delayed-release tablet)

Amalodipine malate and microcrystalline mullose were apples in No. 35 and mixed for 5 minutes with a double cone mixer to prepare a mixture. The mixture was added to a double cone mixer and colicoat SR30D (30% suspension of main component pulley vinyl acetate, manufactured by BASF, Germany) was added and granulated using an oscillator. After drying at 60 1C it was again established as No. 18. Magnesium stearate, which was sieved through No. 35 sieve, was added to the sieved material, mixed for 4 minutes, and tableted with a rotary tableting machine (M C-37: Sejong) equipped with a 5 mm diameter bias to prepare a nuclear tablet. Separately, a coating solution was prepared by dissolving and dispersing hydroxypropylmethelloose phthalate (Shin— etsu, Japan) in ethane and methylene chloride.The above Amlodi ¾ tablets were coated on a high coater (SFC-30N, Sejong Machinery, Korea). ) To form a coating layer to complete the amlodipine oak preparation.

3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in 3) of Example IV-1. Example IV-6: Preparation of Amlodipine-Pitabatatin Nucleated Tablets

Nucleated tablets were prepared by the following method with the ingredients and contents shown in Table IV-1. 1) Preparation of Prerelease Blocks (Pitavastatin Rapid Release Granules)

Pitavastatin calcium, magnesium metasilicate aluminate, more crystalline cellulose, lactose hydrate, corn starch were added to apples in No. 35, and the mixture was mixed for 5 minutes in a double cone mixer to prepare a common substance. Separately, the hydrophilic propylcellose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulate with No. 18 using an oscillator and dry it in an arc using a dry water dryer. After drying, it was established as No. 20 again. Sodium starch glycolate (DMV, Germany) and magnesium stearate were added to the sieved material, followed by final mixing with a double cone mixer. 2) Preparation of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate, pregelatinized starch, corn starch were apples with No. 35 sieve and mixed for 5 minutes with a sticking mixer to prepare a mixture. Separately, hydroxypropylmethyl ^ loose was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After construction, it is established as No. 18 body again. The granules are placed in a fluidized bed cobalt, and separately hydrated propylmethylsalose phthalate is added to ethane and methalene chloride, and the above granules are added to a soft layer granulation coater (GPCG-1; Glatt, Germany ) And coated. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a Totari tableting machine (MRC-37: Sejong) equipped with a 5 mm diameter punch to prepare a core tablet.

3) tableting and coating

Tableting roll in the form of nucleated tablets was prepared by S tableting and coating in the same manner as 3) of Example IV-1. Example IV-7: Amlodipine-Pitavapatin Two-Phase Matrix Tablet Preparation

According to the ingredients and contents shown in Table IV-1, the following crime prevention-proof two-phase matrix tablets were prepared.

 1) Preparation of Sun-Release Compartments (Pitavasta ¾ Rapid Release Granules)

Pitavastatin scabbard, metasilicate aluminate magnesium, lactose monohydrate, pregelatinized starch, apples with No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare Φ compound. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution, which was then combined with the main component mixture. After the association was completed using the No. 20 oscillator, it was dried at 601C using a warm water dryer, and then re-established as No. 18.

2) Preparation of delayed-release compartments (amlodi¾ delayed immediate release granules)

Amlodipine besylate, microcrystalline cellulose, calcium hydrogen phosphate anhydrous apples with No. 35 sieve, and mixed for 5 minutes with a double cone chuck to prepare a mixture. Separately, hydroxypropylsal was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. The dried product was placed in a fluidized bed coater, and a solution obtained by dissolving Dalo Cell Acetate 320S (acetal group 32%) and Cellulose Acetate 398-10NF10 (acetal group 39.8%) in ethane and methylene chloride was prepared. The above granules were put into a coating of granular layer coating machine (GPCG-1: Glatt, Geramny) and coated.

3) posterior streak, tableting and nose ¾

The products of 1) and 2) were put into a double cone mixer and mixed. Nathium starch glycolate and magnesium stearate were added to this mixture, and finally mixed with a double cone mixer. The final mixture was compressed using a rotary scrambler (MRC-33: Sejong Machinery, South Korea). Separately Hydroxypropylmethyl ^■ € 2910, Polyethyleneglycol 6,000, Talc, and Titanium oxide are prepared by dissolving and dispersing titanium oxide in ethanol and purified water. Machine, Korea) to form a film coating layer to prepare a two-phase matrix tablets. Example IV-8: Amlodipine-Pitabatatin Biphasic Matrix Tablet Preparation

Two-phase medium: Rix tablets were prepared by the following method, with the components and contents listed in Table IV-1.

 1) Preparation of Sun-Release Compartments (Pitavasta ¾ Rapid Release Granules)

Pitavastatin kalseum ^', metasilicate aluminate magnesium thoracic, and sieved with a 35 mesh sieve apple put the microcrystalline cellulose and heunham for 5 minutes in a double cone mixer to prepare a heunham water. Separately, hydroxypropylose was dissolved in purified water to prepare a binding solution, which was then combined with the main component mixture. After softening, granulation was carried out using a No. 20 body oscillator, and it was formed into a No. 18 body after drying at 6 (C using a silver water dryer.

2) Preparation of delayed-release compartments (amlodipine delayed immediate release granules)

Amalodipine malate, microcrystalline ¾ rose, pregelatinized starch were apples in No. 35 sieve and double cone mixed with each other for 5 minutes to prepare a mixture. Separately, polyvinylpyridone was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. The dry granules were placed in a fluidized bed coater and separately prepared by dissolving in Eudragit RS30D and triethylcitrate methylene chloride, and the above granules were placed in a fluidized bed granular coronate (GPCG-1; Glatt, Germany) and coated.

3) post mixing, tableting and coating

Post-mixing, tableting and coating were carried out in the same manner as 3) of Example IV-7 to remove the tablet in the form of a two-phase matrix. Example IV-9: Amlodipine-Pitabatated Biphasic Matrix Tablet ≤

With the ingredients and contents shown in Table IV-2, two-phase metex tablets were prepared by the following methods.

 1) Preparation of Pre-Release Compartment (Pitavastatin Rapid Release Granules)

Pitavastatin calcium, magnesium metasilicate aluminate, microcrystalline cellulose and lactose hydrate were added to apple with No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl shell-rose was dissolved in purified water to prepare a binding solution, which was then combined with the major roll mixture. After the association, granulation was performed using a No. 20 oscillator, which was dried at 60 ^° C. using a silver water dryer, and then re-established as No. 18.

2) Preparation of delayed-release compartment (amlodipine delayed immediate release granule)

 A mixture of S-amlodipine tesylate, microcrystalline salose, and di-manny apples with No. 35 was mixed for 5 minutes with a double cone mixer. The mixture was added to a high-speed mixer, fed with Colicoat SR30D, and then granulated using No. 20 sieve using an oscillator. The roll was dried at 60 1 C using a dry water dryer and re-established into No. 18 sieve.

3) post-mix, tableting and skipping

In the same manner as in 3) of Example IV-7, post-mixing, tableting and coating were performed to prepare a tablet in the form of a two-phase matrix. Example IV-10 ： Amlodi ¾-Pitabatatin Biphasic Matrix Tablet Preparation

With the components and contents shown in Table IV-2, two-phase matrix tablets were prepared by the following method.

 1) Preparation of Pre-Release Compartment (Pitavastatin Rapid Release Granules)

Pitavastatin calcium, magnesium metasilicate aluminate, broth starch, and pregelatinized starch were apologized with No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare the mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulation was carried out using a No. 20 oscillator, which was dried at 60 using a silver water dryer, and then back to No. 18. 2) Preparation of delayed-release compartments (amlodipine delayed immediate release granules)

Amalodifun besylate, microcrystalline salose, anhydrous calcium hydrogen phosphate, pregelatinized starch were appled in a No. 35 sieve and mixed for 5 minutes with a double cone mixer to prepare a mixture. Separately, polyvinylpyridone was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. Put ¾ water in a fluidized bed coater, and separately prepare a solution of ethyl cellulose (HERCULES, USA) and poly (methacrylate, methyl meth ¾) co-polymer in ethane and methylene chloride. Of plantation was put into a coating of granular granules ½ «-1; Glatt, Germany) and coated.

3) Post-mixing, tableting and coating

A tablet in the form of a biphasic matrix was prepared by postmixing, tableting and coating in the same manner as 3) of Example IV-7. Example IV-11 Preparation of Amlodipine-Pitabata Multi-Layered Tablets

With the components and contents described in Table IV-2, a multilayer tablet was prepared by the following method.

1) Preparation of Pre-Release Compartments (Pitavastared Rapid Release Granules)

A mixture of pitavasta calder, meta metasilicate aluminate, microcrystalline cellulose, lactose hydrate and apple No. 35 was ap- plied and shaken in a double cone mixer for 5 minutes. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. When the coalition is received, the granules are granulated using the oscillator 20 and dried at 60 ° C using a hot water dryer. After drying, it was reestablished as No. 18. The starch sodium starch glycolate was mixed, magnesium stearate was added, and the final mixture was mixed with a double cone mixer.

2) Preparation of delayed-release compartments (amlodipine delayed immediate release granules)

Amalodipine besylate, microcrystalline shell loose, ¾ starch, corn starch were apples with No. 35 sieve and mixed for 5 minutes with a double cone filter to prepare a mixture. Separately, pulley vinylpy * ridone was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, the mixture was again sieved to No. 18 sieve. Place the rim in a fluidized bed coater, separate ¾-cell, poly (methacrylate, de¾ decacrylate) copolymer in ethane and methylene chloride to prepare a tip of the fluidized bed granulator (GPCG). -1; Glatt, Germany) and coated. After completion of the coating, stearic acid magnesium was added and mixed for 4 minutes. 3) Post-mixing, Crushing and Coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The final mixture of 1) was placed in a primary powder feeder, and the final mixture of 2) was placed in a secondary powder feeder, and tableted under conditions capable of minimizing infiltration between layers. Separately, the above tablet was prepared by preparing a coating solution in which hydroxypropylmethylcellulose 2910, ¾ Li ¾lenglycol 6,000, Tal 3, and titanium oxide were dissolved and dispersed in ethane and purified water (SFC-30N: Sejong Machinery, Korea) to form a film coating layer to prepare a tablet in the form of a multi-layered tablet. Example IV-12 ： Amlodipine-Pitabatatin Multilayer Tablet Preparation

With the components and contents shown in Table IV-2, a multilayer tablet was prepared by the following method.

1) Preparation of Pre-Release Compartment (Pitavastatin Rapid Release Granules)

Pitavastatin scabbard, metasilicate aluminate magnesium, microcrystalline ¾, corn starch, apples in No. 35 sieve, and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, the hydrophilic propylcellose was dissolved in purified water to prepare a binding solution, which was combined with the main ingredient mixture. After the association, granulate with No. 20 using an oscillator and dry it at 60'C using a hot water dryer. After drying, it was reestablished as No. 18. The starch was mixed with sodium starch glyrate, and a stearic acid magnesium was added to the mixture and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (amlodipine delayed immediate release granules)

Amalodipine malate, microcrystalline ^ ¾ose, pregelatinized starch, and di-manny were apologized with No. 35 sieve and mixed for 5 minutes with a double cone mixer to prepare a mixture. Separately, pulley vinylpyridone was bound to purified water and combined, granulated and dried. After drying, it was established as No. 18 sieve again. Place the sieved material in a fluidized bed coater, and separately prepare Cell # Rose Acetate 320S (Acetal group 32%) and ¾ Loose Acetate 398-10NF (Acetal group 39.8¾) * ethane and methylene chloride. The crude tip of was placed in a fluid bed granulation coater (GPCG-1: Glatt, Gerarany) and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes.

3) whiteness, tableting and coating The tablets in the form of multi-layered dots were prepared by post-mixing, tableting, and coating in the same manner as 3) of Example IV-11. Example IV—13 Preparation of Amrodafine-Pitabata ¾ Polyplyum Tablets

With the components and contents shown in Table IV-2, a multilayer tablet was prepared by the following method.

1) Preparation of Pre-Release Compartment (Pitavastatin Rapid Release Granules)

Pitavastatin calcium, magnesium metasilicate aluminate, mercury cellulose, lactose hydrate, corn starch, apples in No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, the hydrophobic propylcellose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After softening, use an oscillator to granulate with No. 20 sieve: a Dry it at 60 ° C using a hot water dryer. After drying, it was established as No. 18 sieve again. Low-substituted hydroxypropyl ¾ was mixed with the sieved material, and magnesium stearate was added and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (amlodipine delayed immediate release granules)

 S-amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, pregelatinized starch were appled with a No. 35 sieve, and mixed with a double cone mixer for 5 minutes to prepare a mixture. The mixture was added to a high-speed mixer, fed with a coat coat SR30D, and then granulated with a No. 20 sieve using an oscillator, which was dried at 60 'C using a silver water dryer, and then back to No. 18 sieve. After adding ¾ magnesium stearate, the mixture was mixed for 4 minutes.

3) Post-mixing, tableting and coating

In the same manner as 3) of Example IV-11, multimodal tablets were prepared by post-mixing, tableting, and coring. Example IV-14 ： Amlodiphan-Pitabata Multilayer Tablet Preparation

With the components and contents shown in Table IV-2, a multilayer tablet was produced by the following security. 1) Preparation of prior-release compartments (Pitavasterin immediate release and ¾)

Pitavastatin calcium, magnesium silicate aluminate, microcrystalline cellulose, pregelatinized starch, apples with No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Ta S. hydroxypropylshellose was dissolved in purified water to prepare a binding solution, United with the compound. After the association, granulate with No. 20 sieve using an oscillator and dry it at 60 ton using a silver water dryer. After drying, it was reestablished as No. 18. Low-substituted hydroxypropyl cellulose was mixed in the sizing, and magnesium stearate was added thereto, followed by final mixing in a double cone mixer.

2) Preparation of delayed-release compartments (amlodipine delayed immediate release granules>

Amlodipine besylate, anhydrous calcium hydrogen phosphate, and di-mannney were appointed as No. 35 and mixed with each other for 5 minutes to prepare a mixture. Separately, hydroxypropylcell was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it was established as No. 18 body again. The sieved material was placed in a gas-coated coater and separately prepared by dissolving Eudragit RS30D and triethyl citrate in methylene chloride. . After completion of the coating, magnesium stearate was thrown up and mixed for 4 minutes.

3) Post-mixing, tableting and coating

Example IV—The same method as 3) of 11) was followed by post-mixing, tableting, and coating to prepare tablets in the form of a multilayer tablet. Example IV-15: Amlodipine-Pitabatatin Capsule Preparation (Pallet-Granule)

With the ingredients and contents shown in Table IV-2, ¾ sulfone was prepared by the following method.

1) Preparation of Sun-Released Compartment (Pitavastatin ¾¾)

Sugar seed (NP Pharmaceutical, France) was added to a fluidized bed granulator (GPCG, Glatt, Germany) and sprayed separately with a combined solution of hydroxypropylcellose and pitavastar ¾ calcium in purified water. Pellets were formed and dried.

2) Preparation of delayed-release compartment (amlodi¾ delayed-release granules)

Amlodipine tesylate, microcrystalline cellulose and anhydrous hydrogen phosphate were mixed with 35 apples for 5 minutes with a JZ double cone mixer to prepare a mixture. Colicoat SR30D was added and combined with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 and dried using a hot water dryer. After drying, No. 18 body S was established again. 3) Post-mixing, tableting and coating

The final product of 1) and 2) was mixed with a double cone mixer. Magnesium stearate was added to the mixture for final mixing. The final mixed mixture was put into a powder feeder and layered onto a capsule (West Hong Gap Sal, Korea) using a capsule filling machine (SF 40N, Sejong Machinery, Korea) to complete the preparation of a time release formulation in the form of a capsul. Example ιν-16 ： Amlodipine-Pitabatatin Capsule Preparation

With the components and contents shown in Table I-2, a capsulant was prepared by the following method.

1) Preparation of a prior release compartment (Pitavastatin immediate release * ¾¾)

The sugar spheres were poured into a fluid bed granulator (GPCG1: Glatt), and then separately dissolved in hydrated propyl salulose and pitavastatin kalmos in water, sprayed with ¾ binding solution to form a pitavastatin-containing pellet. Formed and dried.

2) Preparation of delayed-release compartments (amlodipine delayed-release pellets)

Sugar seeds were added to a fluidized bed granulator (GPCG1: Glatt), and then sprayed with a binder solution of hydroxypropylsilose and amlodipine besylate in water, to form ammodipine-containing pelhat and dried. It was. Again, amlodipine retardant pel¾ was prepared by spraying a solution of hydroxyhexphthalate (Shin-etsu, Japan) in ethane and methane chloride in ¾ head.

3) post mixing, tableting and coating

The final product of step 1) and 2) was filled in capsul (Seheung capsal, Korea) using a capsul layered electric to complete the preparation of the timed release formulation in the form of capsule. Example IV-17 Preparation of Amlodipine-Pitabatatin Capsul (Pel Osmotic Tablets)

With the ingredients and contents shown in Table IV-3, capsules were prepared by the following method: 1) Preparation of a prerelease compartment (pitavastatin immediate release pellets)

Sugar seeds were added to a fluidized bed granulator (GPCG1: Glatt), and then sprayed with a combined solution of hydroxypropylcellose and pitavastatin staples in water to form ¾¾ containing pit¾statin. It was. 2) Preparation of delayed-release compartments (amlodipine osmotic tablets)

Amlodipine besylate, microcrystalline cellulose, anhydrous hydrogen phosphate, corn starch were apples with No. 35 sieve, and the mixture was prepared for 5 minutes in a double cone mixer. Separately, the hydrophilic cyclofilel was dissolved in purified water to form a binding solution, and then combined, granulated, and dried. Sodium chloride and magnesium stearate were added to the sieved material, followed by mixing for 4 minutes. The mixture was compressed into tablets using a rotary tableting machine (MRC-37: Sejong) equipped with a 5 mm diameter bias. Separately, a solution obtained by dissolving cellulose acetate 320S (acetal group 32%) and chlorocellulose acetate 398-10 F (acetal group 39.8%) in ethane and methylene chloride was prepared and used as a high coater (SFC-30N). : Sejong Machinery, Korea) to form a film coating layer to prepare an osmotic tablet of amlodipine.

3) post mixing, tableting and coating

The final product of 1) and 2) was layered in ¾ tassel (seohong capsule, Korea) by using a capsule layer electric (EXC 40F, Seoheung capsule, Korea) roll to complete the preparation of the delayed release agent in the form of a capsule. Example IV-18: Preparation of Amlodipine-Pitabatatin Capsule (¾¾-Tablet)

According to the components and contents described in Table IV-3, the preparation of a chelating agent was carried out by the following method.

1) Preparation of Prerelease Block (Pitavastatin Rapid Release Pel ¾)

Sugar seeds were added to a fluidized bed granulator (GPCG1: Watt), and then sprayed with a binder solution in which hydroxypropyl shellose and pitavastatin calcium were dissolved in water to form ¾¾ containing pitavastatin and dried. It was.

2) S of delayed-release compartment (amlodipine delayed-release tablets)

Amalodipine besylate, microcrystalline cellulose and pregelatinized starch were apples in No. 35 and mixed for 5 minutes using a double cone mixer. Separately, hydroxypropyl 쎌 was dissolved in purified water and combined to form a binding solution. Granulated and dried. When the case is over, clean it again with No. 18 sieve. Magnesium stearate, which was sieved through No. 35 sieve, was added to the sieved material, mixed for 4 minutes, and the mixture was compressed into tablets using a rotary tablet press (MRC-37: Sejong) equipped with a 5 mm diameter bias. Separately, the above-mentioned amlodipine tablets were prepared as a high coater (SFC-30N, Sejong Machinery, Korea) by preparing a nose ¾ solution in which ¾-ise was dissolved and dispersed in purified water. A coating layer was formed to complete the preparation of amlodipine oak,

3) Post-mixing, tableting and coating

The final product of 1) and 2) was layered on a capsule (Seoheung Kalsel, Korea) using a capsul layered electric to complete the preparation of the time-release formulation in the form of a capsule. Example IV-19: Preparation of Amlodipine-Pitabatatin Capsule (Tablet-¾¾)

With the ingredients and contents shown in Table IV-3, the capsule was prepared in the following manner.

1) Preparation of Pre-Release Compartment (Gottavastatin Rapid Release Tablet)

Pitavastatin kalmup, metasilicate aluminate magnesium, microcrystalline cellulose and corn starch in apple No. 35 were mixed with apples for 5 minutes to prepare a common substance. Separately, hydrated propylcellelose was dissolved in purified water to form condensate, combined, granulated, and dried. After preparing sodium starch glycolate and magnesium stearate, the mixture was mixed for 4 minutes, and tableted with a rotary tablet press (MSC-37, Sejong) equipped with a 5 mm diameter diameter.

2) Preparation of delayed-release compartments (HMG-CoA reductase inhibitors and delayed immediate release layer ¾¾) Sugar seed (Sugarsphere) was added to a fluidized bed granulator (GPCG1: Glatt), followed by pulley vinylpyridone, The binding solution in which S-amlodipine besylate was dissolved was sprayed to form ¾¾ containing amlodipine and dried. Again, the Amlodipine delayed pellets were sprayed on the PEL 95 by spraying a solution of Eudragit RS30D (Evonik Degussa, Germany) and triethercitrate (Vertel lus, England) to methylene chloride.

3) Post-mixing, tableting and coating

The product of 1) and 2) was laminated to capsule (Seoheung capsule, Korea) by using a ¾-layer electric device to complete the preparation of a timed release formulation in the form of capsule. Example IV-20: Amlodipine-Pitabatatin Capsule Manufacture (tablet-tablet)

With the components and contents shown in Table IV-3, a capsulant was prepared by the following method.

1) Preparation of Prerelease Blocks (Pitavastatin Rapid Release Tablets)

Pitavas starred, metasilicate aluminate, corn starch with apple The mixture was prepared by mixing in a double cone mixer for 5 minutes. Separately, the hydrophobic propylcellulose was dissolved in purified water to prepare a binding solution, which was associated with an irol main component mixture. When softness is finished, granulate with No. 20 sieve using an oscillator and dry it at 60 ° C using a silver water dryer. After drying, it was established as No. 18 body again. Starch glycolic acid nat Ϋ and stearic acid Magnesium sieved through No. 35 sieve were added to the sieved material, mixed for 4 minutes, and tableted with a rotary tableting machine (M¾> 37, Sejong Machinery, Korea) equipped with a 5-ram punch. Fidavastatin tablet preparation was completed.

2) Third part of delayed-release compartment (amlodipine delayed-release tablet):

 Apology of S-Amlodipine Tesylate, Microcrystalline Salose, and Anhydrous Staphylococcus with No. 35 Sieve and Mixing with a Double Cone Mixer for 5 Minutes. The mixture was prepared as 2: 2. Combined, granulated and dried with Colicoat SR30D as a binding solution. It was. After drying, it is established as No. 18 again. Magnesium stearate, which was sieved through No. 35 sieve, was added to the tablets, mixed for 4 minutes, and compressed into tablets using a rotary tablet press (M 37: Sejong) equipped with a 5 mm diameter diameter. The coating solution was prepared by dissolving and dispersing latex, meth methacrylate copolymer (Coiorcon, USA) in purified water to form a coating layer as a high coater (SPC-30N, Sejong Machinery Co., Ltd. Korea). Article was completed.

3) post-mix, tableting and nasal tongue

The product of 1) and 2) was laminated to the capsul (Seohong Gap ¾, Korea) using a capsul layered electric to complete the preparation of the capsule-type controlled release formulation. Example IV-21: Preparation of Amlodipine-Pitabatatin Capsule (Granules-Granules)

With the ingredients and contents set forth in Table IV-3, the capsule was prepared by the following jump. 1) Preparation of Prior-Release Compartments (Pitavastatin Immediate Release Granules)

Pitavastatin calcium, metasilicate aluminate, lactose monohydrate, apples in No. 35, and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropyl salulose was dissolved in purified water to form a binder 2: and combined with the main component mixture. United. When the association was completed, the granules were formed into a No. 20 sieve using an oscillator, and the granules were dried using 6 (TC) using a silver water drier. 2) Preparation of delayed-release compartments (amlodipine delayed granules)

Amlodipine besylate, microcrystalline cellulose, and di-mannee were apples with No. 35 sieve and mixed with each other for 5 minutes to prepare a mixture. Collicoat SR30D was added and associated with the main ingredient mixing mole. After the association, granulation was carried out using an oscillator in No. 20 and dried using a silver water dryer. After drying, it was established as No. 18 body again.

3) post mixing, tableting and coating

The products of 1) and 2) were mixed with a double cone mixer. Sodium starch ¾ glycolate was added to the mixture and mixed with a double cone mixer. Magnesium stearate was added to the mixture again for final mixing. The final mixed mixture was put into a powder feeder and filled into ¾ sul (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the time release agent in capsule form. Example IV-22: Amlodipan-Pitabatatin Capsulation Agent (Granules—Pel 3/4)

With the components and contents listed in Table IV-3, a capsul was prepared by the following method.

1) Preparation of Pre-Release Compartment (Pitavastatin Immediate Release Granules)

Pitavastatin calum, magnesium metasilicate aluminate, microcrystalline cellulose and pregelatinized starch were apologized to No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, it was dissolved in hydroxypropyl shell * rose * purified water to prepare a binding solution and associated with an irol main component mixture. After the association, granules were prepared using an oscillator * with a No. 20 sieve and dried in a 6 (rc using a silver water drier.

2) Preparation of delayed-release compartments (amlodi¾ delayed pellets)

Sugar seeds were introduced into a fluidized bed granulator (GPCG1: Glatt), and then separately sprayed with a defect solution in which polyvinylpyridone and amlodipine besylate were dissolved in purified water to form ¾¾ containing amlodipine. It was. The pellets were then sprayed with a solution of Eudragit RS30D and triethyl citrate dissolved in ¾ ¾ chloride to prepare amtodipine delayed pellets.

3) Post-mixing, tableting and coating The products of 1) and 2) were mixed with a double cone mixer. Sodium starch glycolate was added to the mixture and mixed with a double cone mixer. The stearic acid magnesium was added to the mixture again for final mixing. The final mixed mixture was introduced into the powder feeder and layered into capsule (Western capsule, South Korea) using capsular layer electrolysis to complete the preparation of the timed release formulation in the form of capsule. Example IV-23: Preparation of Amlodipine-Pitabatatin Capsule (Granule-Tablet)

With the ingredients and contents described in Table IV-3, ¾ knee was prepared by the following method.

1) Preparation of Prerelease Blocks (Pitavastatin Rapid Release Granules)

Pitavastatin calcium, magnesium silicate aluminate, lactose monohydrate, corn starch, and apples with No. 35 sieve, were mixed in a double cone mixer for 5 minutes to prepare a mixture. Purified water was added to the mixture. After the association, granulate with No. 18 using an oscillator roll and dry it at 60 ° C using a silver water dryer. After drying to constant lip sieve No. 20 again. Nathium starch glycolate was thrown up to the sieved material, and it mixed with a bulcon mixer. Magnesium stearate was again added to the mixture for final mixing.

2) Preparation of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate, anhydrous calcium phosphate and pregelatinized starch were apples in No. 35 sieve and mixed for 5 minutes using a double cone mixer to prepare a mixture. Separately, hydroxypropylsal was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it is settled again with No. 18 sieve. Magnesium stearate, which was sieved through No. 35 sieve, was put into the tablets, mixed for 4 minutes, and the mixture was compressed into tablets using a rotary tablet press (MRC-37: Sejong) equipped with a 5 mm diameter bias. Separately, dissolve and disperse the arc ¾-ize in purified water to prepare a ¾ coating solution to form a coating layer on the above Amlodi ¾ tablet as a high coater (SFC-30N, Sejong Machinery, Korea) to complete the preparation of amlodipine tablets.

3) Post-mix, tableting and nose ¾

The product of 1) and 2) was layered onto a capsule (Suhhongcapsal, South Korea) using capsul layered electrophoresis »to prepare a time-delayed release formulation in the form of dew. Example IV-24: Amlodipine-Pitabata ¾ Capsulant Preparation S (tablet-granule) Capsuljeol was prepared by the following method with the ingredients and contents shown in Table IV-3.

1) Preparation of Prerelease Blocks (Pitavastatin Rapid Release Tablets)

Pitavastatin calum, magnesium metasilicate aluminate, microcrystalline shellulose, pregelatinized starch, apples with No. 35 sieve, and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropylcellulose was dissolved in purified water to prepare a binding solution, which was associated with an Irol main component mixture. After the association, granulate using the oscillator at No. 20 and dry it at 60 ^° C using a dry dryer. After drying, it was reestablished as No. 18. A low-substituted hydroxypropyl ¾ sieved through No. 35 sieve was added to the formulation, mixed with magnesium stearate for 4 minutes, and then the mixture was fed into a rotary tableting machine equipped with a 5 mm diameter (MRC—37, Tableting with Sejong, Korea) to complete the manufacture of pitavastatin tablets.

2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

Amalodipine besylate, microcrystalline salose, anhydrous hydrogen phosphate, and hydroxypropylmethyl cellulose were apples in No. 35 and mixed for 5 minutes with a double cone filter to prepare a mixture. Purified water was added and combined with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, and it was dried using a dry roll of silver. After drying, it was again erected with No. 18 sieve. Magnesium stearate was added to the tablets for final mixing, and amlodipine delayed-release granules were prepared.

3) Post-mixing, tableting and coating

The product of 1) and 2) was laminated to a capsule (Seoheung Capsule, Korea) using a capsule layer electric to complete the preparation of the time-release formulation in the form of a capsule. Example IV-25: Preparation of Pitavastar ¾-Amlodipine Tesylate Blister Packaging Kit A pitavastatin-amlodi ¾ besylate blister packaging kit was prepared by the following security.

Each of the pitavastatin streak pre-release granules prepared in Example IV-7 and 1) and the amlodipine besylate delayed-release granules prepared in Example IV—7 2) were prepared using a rotary tablet press (MRC—33: Sejong Machinery, Korea After each tablet is purified using a blister packaging machine (Minister A, Heunga Engineer ¾), the blister packaging container (silver foil, the same good grade) is used. PVDC, Jeonmin industry) to prepare a blister packaging kit by packaging each tablet for simultaneous use.

Table IV-l

Table IV-2

Table IV-33

실시예 v-i: 암로디핀-로슈바스타¾ 유핵정 제조

Example vi: Preparation of Amlodipine-Roschvasta¾ Nucleated Tablets

Nucleated tablets were prepared by the following method, using ingredients and contents set forth in Table V-1.

 (1) Preparation of prior-release compartments (roschvastatin prior-release granules)

Roschvasta Calcium (MSN, INDIA), Tribasic Chest Phosphate, Microcrystalline Salose (Avicel PHlOl, FMC Biopolymer, USA), Lactose Hydrate (DMV, Germany), Pregelatinized Starch (Starch 1500G, Colorcon, USA) Sieve apologies, and mixed with a double cone mixer (Dasan and Martech, Korea) for 5 minutes in real, prepared a fire. Separately, hydroxypropyl salulose (HPC-L, Nippon Soda, Japan) was dissolved in purified water The binder solution was removed and associated with the main component mixture. After the association, granulation was carried out using an oscillator in No. 18 and dried in 6013 using a silver water drier (IHf— C, Samcheong, Japan) and then formed in No. 20. Crospovidone was mixed in the sieved material and stearic acid (Nitika Chemical, India) was added and finally mixed with a double cone mixer to give the titled prior-release compartment.

(2) Manufacture of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate, crystalline cellulose, anhydrous calcium hydrogen phosphate, pregelatinized starch (Starch 1500G, Colorcon, USA) were apples in No. 35, and mixed with a double cone mixer for 5 minutes in a real environment to prepare a mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a conjugated solution, which was associated with the main component mixture. After the coalition, it was granulated with an oscillator using No. 18 sieve, which was dried at using a silver water dryer (HW-C, Samgong, Japan) and erected with No. 20 sieve. Separately, ¾ loose acetate 320S (acetal group 32%) and shellloose acetate 398-10 F (acetal group 39.8%) were dissolved in a mixture of ethane and methylene chloride to prepare a fluidized bed granulation coater with the above formulation. (GPCG-1; Glatt, Germany) and coated. After completion of coating, magnesium stearate was added, mixed for 4 minutes, and equipped with a rotary tablet press (MRC-30, Sejong Pharmatech, Korea) equipped with a 5 mm diameter punch. Tableting gave a nuclear tablet, the titled delayed-release compartment. (3) tableting and coating

 Amlodipine pulsate delayed release of (2) above using a Rochevasta ¾ Calm pre-release granule of (1) as an outer layer with a nucleus tableting machine (RUD-1: Ri lian, Germany) equipped with 11 mm bias The tablets were compressed into nuclear tablets. Separately hydroxypropylme ¾¾rose 2910 (S in-ets, Japan), pulley ¾ lenglycol 6,000 (BASF, Germany), talc (Luzenac, France), titanium oxide (Tioside Americas, USA) and ethane. Upon dissolving and dispersing in purified water, a ¾ coating solution was prepared to form a coating layer as a high coater (SFC-30N, Sejong Machinery, Korea) to prepare a nucleated tablet. Example V-2: Preparation of Amlodipine-Roschvastatin Nucleated Tablets

With the components and contents shown in Table V-1, nucleated tablets were prepared by the following jump.

 (1) Preparation of prior-release compartments (roschvastatin prior-release granules)

Rochevastatin calum, tribasic calcium phosphate, microcrystalline ¾, lactose, and pregelatinized starch were apologized to No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulation was carried out using an oscillator roll with No. 18 sieve, dried at 6C C using this »hot water dryer, and then formed into No. 20 sieve. Crospovidone was mixed in the formulations, and magnesium stearate was added and finally mixed with a double cone feed to remove the titled prior-release compartment.

(2) Manufacture of delayed-release compartments (amlodipine delayed-release tablets)

Amalodipine besylate, microcrystalline cellulose, anhydrous hydrogen phosphate, and pregelatinized starch were appointed as No. 35, and mixed with a double cone mixer for 5 minutes in real time to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water and combined and granulated as a binding solution. Separately, a solution of Eudragit RS30D (Evomk Degussa, Germany) and ¾ citrus CVertellus, England) was prepared in methylene chloride and the above formulation was placed in a fluidized bed immersion coater and coated. After completion of the cobalt, magnesium stearate was added and mixed for 4 minutes, and tableted with a Totari tableting machine (MRC ᅳ 30, Sejong Pharmatech, Korea) equipped with a 5 舰 diameter diameter. ≤ (3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3-1 (3). Example V— 3: Preparation of Amlodi ¾-Roschvasta ¾ nucleated tablets

Nucleated tablets were prepared by the following method with the ingredients and contents shown in Table V-1.

(1) Preparation of pre-release compartments (Roschvasta ¾ pre-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, and pregelatinized starch were appled in a No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl ¾ was dissolved in purified water to prepare a binding solution, which was then combined with an Irol main component mixture. After the association, granules were prepared using an oscillator in No. 18 and dried at 60 2 using a silver water dryer. After drying, the mixture was stipulated as No. 20, and then the crospovidone was mixed with the sieved material. The stearic acid was added thereto, followed by final mixing with a double cone mixer to prepare the title-release compartment.

(2) Manufacture of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate S, microcrystalline cellulose, di-mannitol (Roquette, USA) was passed through a No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, pulley vinylpyrrolidone (Kol l idcm 30, BASF, Germany) was dissolved in purified water, combined and granulated as a binder, and dried in a silver water dryer at. Separately, ¾-Cellulose (HERCULES, USA) and Li (methacrylate, methyl methacrylate) co-polymer (Evonik degussa, USA) are dissolved in ethane and methylene chloride shaker. The grains were placed in a fluid bed granulator coater and coated. After the coating was completed, the stearic acid magnesium was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press equipped with a 5 mm diameter punch to prepare a titled delayed-release compartment.

(3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3-1 (3). Example V-4 Preparation of Amlodipine-Roschvastatin Nucleated Tablets

The nucleated tablet was manufactured by the following method with the component and the amount content of Table V-1.

 (1) Preparation of a prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic phosphate, microcrystalline 로 rose, lactose monohydrate, and pregelatinized starch were apologized with No. 35 sieve, and the mixture was prepared by mixing for 5 minutes in a double cone mixer. Separately, hydroxypropylcellulose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture in the real silver. After the association, granulation was carried out using an oscillator in No. 18 and dried in 60 ^ using an Irol silver water dryer, and then No. 20 was established. A sized product to put the sodium starch glycolate (DMV, Germany), are seutte acid Marg neseum double cone mixer at room ^temperature, the final traces were combined to prepare a prior-release compartment of the title.

(2) Preparation of delayed-release compartment (amlodi fragment delayed-release tablet)

Amlodipine malate (Daehee Chemical, Korea) A microcrystalline cellulose, anhydrous calcium hydrogen phosphate, di-manny was apologized with No. 35, and a mixture was mixed with a double cone mixer for 5 minutes in a real batch. Separately, hydroxypropyl salose was dissolved in purified water to prepare a binding solution, and then it was combined and granulated with a mixture of the main components, which were dried at 60 C using a silver water dryer, and then formed into No. 20 sieve. Magnesium stearate, which was sieved through No. 35 sieve, was added to the sieved material, followed by mixing for 4 minutes, thereby preparing HMG-CoA-reducing inhibitor inhibitor delayed-elution layer granules. HMG-CoA reductase inhibitor delayed fast-dissolving granules were tableted with a rotary tableting machine equipped with a 5 mm diameter bias to remove nuclear tablets. Separately, dissolve acryl-Ize (methacrylic acid copolymer type C, talc, PEG, colloidal silicon dioxide, sodium bicarbonate, SLS, Colorcon, USA) in purified water and dissolve ¾ coating solution in a few dispersions. The coating layer was formed as a high coater to prepare amlodipine tablets of the titled delayed-release compartment. ^' -

(3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in (3) of Example V-1. Example V-5: Preparation of Amlodi ¾-Rochevastarin Nucleated Tablets With the components and contents shown in Table Vl, nucleated tablets were prepared by the following security.

(1) Preparation of prerelease compartments (roschvastatin prerelease granules)

Rochevastatin, Chestnut Tribasic, Microcrystalline Cellulose, Lactose Carb, Corn Starch

(Colorcon, USA) was added and appled with No. 35, and the mixture was prepared by mixing in a double cone mixer for 5 minutes at room temperature. Separately, hydroxypropylcellose was dissolved in purified water to prepare a conjugate solution, which was then mixed with the main component mixture. United together. After association, granules were prepared by using an oscillator with No. 18 sieve, and then dried at 6 (C. using a silver water dryer. After drying, the No. 20 was re-established. The breast was put in a double cone mixer for final mixing to prepare the title-releasing compartment.

(2) Preparation of delayed-release compartments (amlodipine delayed-release tablets)

Amalodi fragment maleate and microcrystalline cellulose were apples in No. 35 sieve and mixed in a silver for 5 minutes in a double cone mixer to prepare a mixture. The mixture was added to a double cone mixer, colicoat SR30D (BASF, Germany) was added, the mixture was granulated using an oscillator roll with No. 18 sieve, and dried at 60 ° C. using a silver water dryer, and then, the mixture was refined to No. 20 sieve. ¾ granules were steared in a 35-sieve, ¾-mounted magnesite, mixed for 4 minutes, and compressed into a rotary tableting machine equipped with a 5 mm diameter bias to prepare nuclear tablets ¾. Separately, a hydroxy phthalate (Shin-etsu, Japan) was dissolved and dispersed in ethane and methylene chloride shake solution to prepare a coating solution. Using this cotim solution, a coating layer was formed on amlodipine core tablets with a high coater to prepare amlodipine tablets, which are the titled delayed-release compartments.

(3) tableting and coating

Example V— Tablets in the form of nucleated tablets were prepared by tableting and coating in the same manner as in (1). Example V-6 Preparation of Amlodipine—Rochevastatin Nucleated Tablets

Nucleated tablets were prepared by the following method with the ingredients and contents shown in Table V-1. (1) Preparation of prerelease compartments (Roschvasta ¾ prerelease granules)

Rochevastatin Stag, Tribasic Calsum Phosphate, Microcrystalline Salose, Lactose Carb, Corn Starch Weighed apples with a No. 35 sieve, using a double cone eater was mixed for 5 minutes at the real to prepare a mixture. Separately, hydroxypropylsalose was dissolved in purified water to prepare a binding solution, which was then combined with the main ingredient mixture, granulated using No. 18 sieve using an oscillator, and dried at 6 C using a hot water dryer. At the end, it was again formed into a No. 20 sieve, and starch glytoolic acid natcum (DMV, Germany) and stearic acid magnesium were added to the sizing tool and finally mixed in a double cone mixer to prepare a title-release compartment.

(2) Preparation of delayed-release compartments (amlodipine delayed-release tablets)

Amalodipine besylate, pregelatinized starch, corn starch were apples with No. 35 sieve, and mixed with a bulbyon mixer for 5 minutes in real plants to prepare a mixture. Separately, hydroxypropylmethylcellose was dissolved in purified water to prepare a defect solution, and the main component mixture was added thereto, and then combined and granulated. The resultant was dried at 60 ° C using a silver water dryer, and then formed into No. 20 sieve. Separately, hydroxypropyl decyl ¾ loose phthalate was dissolved in ethane and methylene chloride shake solution to prepare a coating solution, which was then placed in a keratinous coating machine (GPCG-1; Glatt, Germany) and commanded with the coating solution. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press equipped with a 5 mm diameter bias to prepare a core tablet having a titled delayed-release compartment.

 (3) tableting and coating

 Tableting in the form of nucleated tablets was carried out by tableting and coating in the same manner as (3) of Example v-i. Example V-7 Preparation of Amlodipine-Rochevastatin Biphasic Matrix Tablets

With the components and contents shown in Table V-1, two-phase matrix viscosities were prepared by the following method.

 (1) Preparation of prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calumum 'tribasic calcine phosphate, lactose monohydrate, pregelatinized starch and apples in No. 35 were mixed and mixed with a double cone mixer for 5 minutes in real time to prepare a mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution, which was then combined with the main ingredient mixture. After the association, granulation was carried out using a No. 20 oscillator, and dried at 60 ^° C. using a water dryer, and then re-established as No. 18 to prepare a title discharge compartment. (2) Preparation of delayed-release compartments (amlodipine delayed-release granules)

Amlodipine besylate, mercury cellulose, and hydrogen phosphate-free calum were apples in a No. 35 sieve and mixed for 5 minutes in a silver cone with a double cone mixer to prepare a mixture. Separately, hydroxypropyl¾ was dissolved in purified water to form a binding solution, and then combined and granulated with the main ingredient mixture, which was dried at 6C C using a silver water dryer, and then formed into No. 20 sieve. Separately, cellulose acetate 320S (acetal group 32%) and cellulose acetate 398-10NF (acetal group 39.8%) were dissolved in ethane and methylene chloride shake solution to prepare a coating solution. It was placed in a fluid bed granulation coater (GPCG-1: Glatt, Geratnny) and coated to prepare the titled delayed release compartment.

(3) post mixing, tableting and coating

The products of (1) and (2) were placed in a double cone mixer and mixed at the actual solution. To this mixture was added sodium starch glycolate, and magnesium stearate and finally mixed in a double cone mixer. The final mixture was excised using a rotary tablet press equipped with a 10 mm diameter pinch. Separately, hydroxypropylme ¾-cell cellulose 2910, pulley ethylene glycol 6,000, talc, and titanium oxide were dissolved and dispersed in ethane and purified water to prepare a coating solution, and a high coater (SFC—30N: Sejong Machinery Co., Ltd.) , Korea) to form a film coating layer to prepare a bi-phase meth tablets. Example V-8 Preparation of Amlodipine-Roschvastared Two-Phase Matrix Tablets

The two-phase matrix purification was performed by the following method with the component and content which were machined in Table V-1.

 (1) Preparation of a prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline · ¾ * loose were apologized with No. 35 sieve and mixed for 5 minutes in a double cone mixer at room temperature to prepare a mixture. Separately, hydroxypropyl salulose was dissolved in purified water to prepare a binding solution, which was combined with the main component mixture. After the association, granulation was carried out using a No. 20 oscillator, which was then dried using 6 ⁽ TC) using a silver water drier and erected as No. 18 again to prepare the title-release compartment. (2) Preparation of delayed-release compartment (amlodipine delayed-release granules)

Amlodipine maleate, microcrystalline cellulose and pregelatinized starch were appointed with No. 35 sieve and mixed with each other for 5 minutes at room temperature to prepare a mixture. Separately, polyvinylpyridone was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. The dried material was put in a fluidized bed coating machine, and separately a solution of Eudragit RS30D and triethyl citrate dissolved in methylene chloride was prepared. The above granulated material was put in a fluidized bed immersion coater and coated to prepare a titled delayed-release compartment.

(3) postmixing, tableting and coating 、

After mixing, tableting and coating in the same manner as in (3) of Example V-7 to prepare a tablet in the form of a two-phase matrix. Example V-9: (S) -Amlodipine—Rochevastatin Biphasic Matrix Tablet Preparation

According to the ingredients and contents shown in Table V-2, two-phase matrix tablets were prepared by the following method.

 (1) Preparation of prior-release compartments (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic calcium phosphate, the crystalline cell ¾ rose, and lactose hydrate were appled with No. 35 sieve and mixed with a double cone mixer for 5 minutes at room temperature to prepare a mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulation was carried out using a No. 20 oscillator roll, which was dried at 6 CTC using a silver water dryer, and then re-established as No. 18 to prepare the title-release compartment.

(2) Preparation of delayed-release compartment (amlodipine delayed-release granules>

S-amlodipine besylate (Glochem, INDIA), unblemished cellulose, di-manny apples with No. 35 sieve and mixed with a double cone mixer for 5 minutes in a real mixture to prepare a mixture, the mixture was put into a high speed mixer Then, after adding Colicoat SR30D, they were granulated using an oscillator with No. 20 sieve, dried at 60 ^° C. using a silver water drier, and then reconstituted with No. 18 sieve to prepare a titled delayed-release compartment.

(3) post mixing, tableting and coating In the same manner as in (3) of Example V-7, post-mixing, tableting, and coating were carried out to prepare a tablet in the form of a two-phase matrix. Example V-10 Preparation of Amlodipine-Rochevastatin Two-Phase Matrix Tablets

According to the ingredients and contents shown in Table V-2, two-phase matrix tablets were prepared by the following method.

 (1) Preparation of a prior-release compartment (roschvastatin prior-release granules)

Rochevastatin calcium, tribasic phosphate, corn starch, pregelatinized starch and apples in 35 sieves were mixed with a double cone mixer at room temperature for 5 minutes to prepare a mixture. Separately, hydroxypropylcellose was added to purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulation was carried out using a No. 20 oscillator, and this was settled to 6 (TC dry to No. 18 in a TC using a silver water drier to prepare a title-release compartment.

(2) Preparation of delayed-release compartments (amlodipine delayed-release granules)

Amlodipine besylate, microcrystalline ¾ rose, anhydrous calcium hydrogen phosphate, and pregelatinized starch were apologized with No. 35 sieve, and the mixture was mixed with a double cone mixer for 5 minutes at real silver to prepare a common substance. Separately, polyvinylpyridone was dissolved in purified water to prepare a binding solution, which was combined and granulated with the main component mixture, which was dried at 60¾ using a silver-water dryer, and was formed into No. 20 sieve. Put the sieved material in the larvae coater, and separately prepare a coating solution of ethyl cellulose (HERCULES, USA), poly (methacrylate, methyl methacrylate) co-polymer dissolved in ethane and methylene chloride trace liquid, Using this as a coating liquid, the above granules were coated with a fluid bed granulation coater (GPCG-1; Glatt, Germany) to prepare the titled delayed-release compartment.

(3) post mixing, tableting and coating

In the same manner as in (3) of Example V-7, post-mixing, tableting, and coating were carried out to prepare a biphasic matrix tablet. Exhibit V-11: Preparation of Amlodipine-Rochevastatin Multiplying Tablets

With the components and contents shown in Table V-2, a multilayer tablet was prepared by the following method. (1) Preparation of a prior-release compartment (roschvastatin prior-release granules) Rochevastatin calum, tribasic calcium phosphate, the crystallized cellulose, lactose hydrated, apples in No. 35 sieve, and mixed in a double cone mixer at room temperature for 5 minutes to prepare a mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator roll at No. 20 쳬 and dried at 60t; Thereafter, the formulations were mixed with sodium starch glyconate, and the stearic acid magnesium was added thereto, followed by final mixing with each other to prepare the title-releasing compartment of the title.

(2) Preparation of delayed-release compartments (amlodipine delayed-release granules)

Amlodi ¾ besylate, microcrystalline shell loose, pregelatinized starch, broth and starch were apologized with No. 35 sieve, and a mixture was prepared by mixing with a double cone mixer for 5 minutes at real. Separately, plybinylpyridone was dissolved in purified water to prepare a binding solution, and then combined and granulated. The dried solution was dried at 60¾ using a dry water dryer, and then sieved to No. 20. The teaming solution is poured into a fluidized bed coating machine, and a ethyl acetate, poly (methacrylate, methyl methacrylate) co-polymer is dissolved in ethane and methylene chloride shaker to prepare a coating solution. The above granules were coated with a fluidized bed granulator coater.After completion of the coating, stearic acid magnesium was added and mixed for 4 minutes to prepare the titled delayed-release compartment.

(3) post mixing, tableting and coating

The final product of (1) was put into the primary powder feeder of a multi-layer tablet press (MRC-37T: Sejong) and the final product of (2) was put into the secondary powder feeder to minimize the infiltration of the layers. Tableting. Separately, dissolve and disperse hydrated propylmethylcellose 2910, pulleylylene glycol 6,000, talc, and titanium oxide in ethane and purified water to prepare a coating solution, and use the above tablets as a high coater. The film coating layer was formed to prepare tablets in the form of the title multilayer tablet. Example V-12 Preparation of Amlodipine-Tosvastatin Multi-Layered Tablets

With the components and contents shown in Table V-2, a multilayer tablet was prepared by the following method. (1) Article S of the prior-release compartment (Roschvapatin prior-release granules)

Rochevastatin calum, tribasic calcium phosphate salt, microcrystalline cellulose, corn starch were apples with No. 35 sieve, and mixed with a double cone mixer at room temperature for 5 minutes to prepare a mixture. Separately Deoxypropyl¾ was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulate with No. 20 sieve using an oscillator and use hot water dryer to dry it at 6 (C, and set it as No. 18. Mixture of starch glycelic acid sodium and mixed with stearic acid magnesium Final mixing with a conmixer produced the title-releasing compartment.

(2) delayed-release ^"Preparation of a block (amlodipine delayed-release gwarim)

Amalodipine malate, microcrystalline cellulose, pregelatinized starch, and Dijonmanni were apologized with No. 35 sieve and mixed for 5 minutes in a double cone mixer at room temperature to prepare a mixture. Separately, polyvinyl pyridone was dissolved in purified water to prepare a binding solution, and then the main component common substance was combined and granulated, and dried at 60 ^' C using a hot water dryer, and then formed into No. 20 sieve. The granules were placed in a fluidized bed coater, and a solution of shell cellulose acetate 320S (acetal group 32%) and cellulose acetate 398-10NF (acetal group 39.8%) in ethane and methylene chloride 1: 1 mixture was prepared. The above granules were placed in a fluid bed granulator coater and coated. After coating is finished. Magnesium stearate was added and then mixed for 4 minutes 3/4 to give the titled delayed-release compartment.

(3) posterior streak, tableting and nose ¾

In the same manner as in (3) of Example V-11, thick, tableted and coated to prepare a tablet in the form of a multilayer tablet. Example V-13: Preparation of (S) -Amlodipine-Roschvastar Multilayer Tablet

With the components and contents shown in Table V-2, a multilayer tablet was prepared by the following method.

(1) Preparation of prior-release compartments (roschvastatin immediate release granules)

Rochevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, lactose hydrate, broth and starch were apples in No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separate S hydroxypropylcellose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulation was carried out using an oscillator with No. 20 sieve, and it was established as No. 18 after ¾ when dried at 6013 using a silver water dryer. Crospovidone was mixed with the granules, and magnesium stearate was added and finally mixed with a double cone mixer to prepare the title-releasing compartment of the title. C2) Preparation of delayed-release compartments (amlodipine delayed-release granules)

 S-amlodipine besylate, microcrystalline cellulose, anhydrous hydrogen phosphate, pregelatinized starch were appled with a No. 35 sieve, and mixed with a double cone mixer for 5 minutes at real silver to prepare a mixture. The mixture was introduced into a high-speed mixer, softened by adding Colicoat SR30D, and granulated using No. 20 sieve using an oscillator, which was dried at 60 using a silver water dryer, and then re-established into No. 18 sieve. After the sieving of the stearic acid magnesium was added, the mixture was mixed for 4 minutes to prepare a titled delayed-release compartment.

(3) post mixing, tableting and coating

In the same manner as in Example (3), after mixing, tableting and coating were prepared in a tablet roll of a multi-layered tablet form. Example V-14: Preparation of Amlodipine-Rochevastatin Multi-Layered Tablets

Multi-layered tablets were prepared by the following method, with the components and contents listed in Table V-2.

(1) Preparation of prior-release compartments (Roschva ώ-Tatin prior-release granules)

Rochevastatin calcium, tribasic phosphate, microcrystalline cellulose, and pregelatinized starch were apologized with No. 35, and mixed with a double cone mixer for 5 minutes at room temperature to remove the mixture. Was prepared by binding to the purified water and then combined with the main component mixture 후 granulated using the oscillator in No. 20 sieve, it was made at 60 ° C. using a silver water dryer and then established as No. 18 sieve. Crospovidone was mixed with the sieved material, and the final mixture was mixed by adding a stearic acid magnesite with a double cone mixer to prepare a title-releasing compartment.

 (2) Article S of delayed-release compartment (amlodipine delayed-release granules)

Amlodipine besylate, anhydrous hydrogen phosphate, and di-mannney were apologized with No. 35, and double cones were mixed with each other for 5 minutes at room temperature to obtain a second mixture. Separately, hydroxypropyl¾rose was dissolved in purified water and combined, granulated and dried as a binding solution. After drying, it was reestablished as No. 18. The granules were put in a fluidized bed coater and separately prepared by dissolving ¾ citrate in methylene chloride in Eudragit RS30D and Tri, and the above granules were put in a fluidized bed granulator coater and coated. After ^'complete coating, then mouth-to-thoracic magnesium stearate, 4 minutes traces were combined to prepare a delayed-release compartment of the title.

(3) post mixing, tableting and coating Example V- 11 (3) and the like by post-mixing, tableting and coating to prepare a tablet in the form of a multi-layered tablet. Exhibit V-15: Amlodipine—Manufacture of Rochevastatin Capsule (Pellets-Granules)

With the ingredients and contents shown in Table V-2, a capsulant was prepared by the following method.

 (1) Preparation of a prior release compartment (Rochevastatin ¾¾)

Sugar seeds (NP Pharmaceutical, France) were introduced into a fluid bed granulator (GPCG, Glatt, Germany), and then sprayed with ¾ binding solution when hydroxypropylcellose and Roche-vastatin scab were applied separately in purified water. To form ¾¾, and dried to prepare the title-releasing compartment.

 (2) Preparation of delayed-release compartments (amlodipine delayed-release granules)

Amlodipine xylate, microcrystalline ¾ rose, and anhydrous calcium hydrogen phosphate were apologized with a No. 35 sieve, and then mixed at a room temperature for 5 minutes with a stick cone mixer to prepare a ¾ mixture. Collicoat SR30D was added and associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, dried using a silver water drier, and then erected in No. 18 to prepare a delayed-release compartment of the title.

 (3) post mixing, tableting and coating

The final products of (1) and (2> above were mixed with a double cone mixer in the seal, and the mixture was finally mixed with a stearic acid magnesium.The final mixed mixture was put into a powder feeder and capsular charger (SF 40N, Sejong Machine, Korea) was used to layer the capsul (Seheung Kalcel, Korea) to prepare a capsule of the title Example V— 16: Preparation of amlodipine-Rochevastatin capsule

With the ingredients and contents described in Table V-2, the following capsules were prepared.

 (1) Preparation of a prior release compartment (Roschvastatin prior release pel ¾)

Sugar seeds were introduced into a fluidized bed granulator and then sprayed with ¾ binding liquid and dried to form ¾¾, the title-releasing compartment, ¾, when hydroxypropyl and rhorosevastatin kum were dissolved in water separately. .

 (2) Preparation of delayed-release compartments (amlodipine delayed-release pellets)

After throwing up the sugar seed roll fluidized bed granulator, spraying the combined solution of hydroxy ^' propylcellose and amlodisome besylate in purified water was sprayed to obtain amlodiphen-containing pel¾. Formed and dried. Again in the above pel¾ hydroxypropyl merophthalate

(Shin-etsu, Japan) was sprayed with a solution of ethane and methylene chloride shake solution to prepare a delayed-release pellet of amlodipine, the title sustained release compartment.

 (3) post mixing, tableting and coating

The final product of the steps (1) and (2) was laminated to the slab (Seoheung Kap, Korea, Korea) using a capsul layered electrolysis to complete the preparation of the pharmaceutical formulation in the form of ¾-sulphine Example V-17: Amlodipine -Rochevastatin Capsule Preparation (Pelta- Osmotic Tablets)

With the components and contents shown in Table V-3, a capsule was prepared by the following method.

(1) Preparation of a prior release compartment (Rochevastatin prior release ¾¾)

Sugar seed was introduced into a fluidized bed granulator and sprayed and dried by separately dissolving the hydroxypropylcellulose and roschvastatin calum in purified water, thereby preparing Rosvastarin-containing pel¾, the title-releasing compartment.

 (2) Preparation of delayed-release compartments (amlodipine osmotic tablets)

Amalodipine besylate, microcrystalline ¾ lot, anhydrous hydrogen phosphate, corn starch were apples with No. 35 sieve, and mixed with a double cone mixer for 5 minutes at real silver to prepare a mixture. Separately, hydroxypropylsalose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried in 60¾ using a dry roll of silver. Nathium chloride and stearic acid magnesium were added to the formulation, followed by mixing for 4 minutes. The mixture was 5 mm in diameter. Tablets were prepared by tableting with a rotary tableting machine equipped with bias. Separately, cellulose acetate 320S (acetal group 32 ¾) and cellulose acetate 398-10NF (acetalizer 39.8%) were dissolved in ethane and methylene chloride shaker to prepare a coating solution. Using this to form a film coating layer on the tablet with a high coater to prepare an osmotic tablet * of amlodipine, the delayed-release compartment of the title.

 (3) post mixing, tableting and coating

The final product of (1) and (2) was layered on capsule (Seoheung capsule, Korea) using capsule layer electrolysis (EXC 40F, Seoheung Capsule, Korea) to prepare a delayed eluent in the form of the title capsule. Example i V-18: Preparation of Amlodipine-Roschvastatin Capsul (Pel ¾-Tablet)

According to the ingredients and contents described in Table V-3, a capsule was prepared by the following method. (1) Preparation of prior-release compartments (roschvastatin prior-release pellets)

Sugar seed was added to an epilayer granulator and sprayed separately with hydroxypropyl cellulose and roche-vastated calcium in water, followed by drying to prepare the title-releasing roche-vastatin-containing pellets.

 (2) Preparation of delayed-release compartments (amlodipine lipophilic ointments).

Amalodymium besylate, microcrystalline gelose, and pregelatinized starch were apples in No. 35, and mixed with a bulbylon mixer for 5 minutes at real silver to prepare a mixture. Separately, the hydroxypropyl shell was dissolved in purified water to prepare a binding solution, and then combined with the main component mixture. After the association, granules were prepared using an oscillator with No. 20 sieve, dried at 6CTC using a hot water dryer, and then formed into No. 18. Magnesium stearate, which was sieved through a No. 35 sieve, was added to the sieved material, mixed for 4 minutes, and then a mixture; i: Tablets were prepared by tableting rotary tablets equipped with a 5 mm diameter bias. Separately, a coating solution obtained by dissolving and dispersing Arc ¾-S in purified water was prepared, and the tablets were coated with a high coater to form a titled delayed-release amlodipine tablet.

 (3) post mixing, tableting and coating

The final product of (1) and (2) was layered into capsules (Seoheung capsule, Korea) using capsul layer electrolysis to prepare ¾suljeol of the title. Example V-19: (S) —Preparation of Amlodi ¾-Rochevastatin Capsule (Tablet-¾¾)

With the components and contents shown in Table V-3, a capsulant was prepared by the following method.

 (1) Preparation of a prior release compartment (Rochebusted Prerelease Tablet)

Toschvastatin calcium, tribasic phosphate, microcrystalline cellulose, corn starch were apples with No. 35 sieve and mixed for 5 minutes in a double cone mixer at room temperature to prepare a mixture. Separately, hydroxypropyl shelle was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a silver water drier to form No. 18 sieve. Starch sodium glyconate and magnesium stearate were added to the lysate, mixed for 4 minutes, and then compressed into a rotary tableting machine equipped with a 5 mm diameter bias to prepare the title-release compartment.

(2) Preparation of delayed-release compartment (delayed-release ¾¾ of amlodipine)

Sugar Seed (Sugarsphere) was added to a fluidized bed granulator and then separately A binder solution in which lydonone and S ᅳ amlodipine besylate was dissolved was sprayed to form ¾ of amlodipine and dried. Again, the pellet was sprayed with a solution of Eudragit RS30D (Evonik: Degussa, Germany) and triethyl citrate (Vertellus, England) in ¾¾ of chloride to prepare the titled delayed-release compartment.

(3) post mixing, tableting and coating

The final product of (1) and (2) was layered on Capsul (Seoheung Cap¾, Korea) using Capsul layer electrolysis to prepare the title capsule. Example V-20: Preparation of (S) -Amlodipine-Rochebuster Capsules (Tablets-Tablets)

With the components and contents shown in Table V-3, a capsulant was prepared by the following method.

 (1) Preparation of a prior release compartment (roschvastatin prior release tablet)

Rochevastatin calcium, tribasic phosphate and corn starch were apples with No. 35 sieve, and mixed with each other for 5 minutes at room temperature to prepare a mixture. Separately, hydroxypropyl¾rose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulation was carried out using an oscillator with No. 20 sieve, and dried at 601C using a hot water dryer, and then established with No. 18 sieve. Nathium starch glycolate and stearic acid magnesium which were sieved through No. 35 sieve were added to the sieved material, which was common for 4 minutes, and then compressed into a rotary tableting machine equipped with a 5 mm diameter punch to prepare the title-release compartment.

(2) Preparation other than delayed-release compartment (amlodipine delayed-release tablet)

 S-amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate were apologized with No. 35 sieve, and mixed with a double cone mixer for 5 minutes at real silver to prepare a mixture. Separately, colicoat SR30D was used as the binding solution and associated with the main component mixture. The coalition was completed in No. 20, which was granulated using an oscillator. Magnesium stearate, which was sieved through No. 35 sieve, was added to the sieved material, mixed for 4 minutes, and compressed into tablets using a rotary tableting machine equipped with a 5 mm diameter bias. Separately, a coating solution obtained by dissolving and dispersing poly (methacrylate, methyl methacrylate) copolymer (Colorcon, USA) in purified water was used to form a coat layer as a high coater. The delayed-release compartment of was prepared.

(3) post mixing, tableting and coating The final product of (1) and (2) was layered on capsul (Seheung capshell, Korea) using capsul layer electrolysis to prepare the title capsulant, Example V-21: Amlodi ¾-Rochevastatin Cap Seulje Manufacturing (Granules-Granules)

With the components and contents shown in Table V-3, a capsule was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin immediate release granule)

Rochevastatin calceum, tribasic calcium phosphate and lactose hydrate were weighed and appled with No. 35, and the mixture was mixed for 5 minutes in a silkworm with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granules were formed into a No. 20 sieve using an oscillator roll, which was formed into a No. 18 sieve after drying in a silver water dryer to prepare a pre-release compartment of the title.

 (2) Preparation of delayed-release compartment (amlodipine delayed granules)

Amlodipine besylate, microcrystalline cellulose, and di-manny were apples in a No. 35 sieve, and mixed with each other for 5 minutes at a double cone mixed mixture to prepare a mixture. Colicoat SR30D was added and combined with the main ingredient mixture, No. 20 was used to make a No. 20 sieve using an oscillator roll, which was dried at 60 ^° C. using a silver water dryer.

(3) post mixing, tableting and coating

The final product of (1) and (2) was mixed with a double cone mixer. Sodium starch glycolate was added to the mixture and mixed with a double cone mixer. Magnesium stearate was added ^' to the mixture again and finally mixed. The final mixed mixture was placed in a powder feeder and layered in capsul (Seoheung ^" Shell, Korea) using Capsul caterpillar to prepare the capsulant of the title. Example V-22: Preparation of amlodipine hydrosvastatin capsula ( Granule-pellets ¾)

With the components and contents shown in Table V-3, a capsulant was prepared by the following method.

(1) Preparation of prior-release compartment (roschvastatin prior-release granules):

Rochevastatin chamomile, tribasic calcium phosphate, microcrystalline salose, and ¾ starch starch were apples with No. 35 sieve and mixed for 5 minutes in a double cone eater. Separately, the hydrophilic propylcellose was dissolved in purified water to prepare a binding solution, which was then combined with the main component mixture. When the union is over, it is granulated using the oscillator with No. 20 body. Is dried at 601: using a silver towel S roll. After drying, it was reestablished as No. 18 to prepare the title-release compartment.

(2) Preparation of delayed-release compartment (amlodi¾ delayed-release ¾¾)

Then put the sugar seeds in a fluidized bed granulator groups, to form a separately by spraying a binder solution on the plastic pulley P ⁱ of purified water were dissolved and the pyrrolidone-containing amlodipine besylate cancer Lodi pin ¾ leg, the key was crude. Again spraying a solution of Eudragit RS30D and triethyl citrate in methylene chloride to ¾¾ above to prepare the delayed-release compartment of the title.

 (3) post mixing, tableting and coating

The final product of (1) and (2) was mixed with a double cone mixer. Nathrum of starch glycolic acid was added to the mixture and mixed with a double cone mixer. Magnesium stearate was again added to the mixture for final mixing. The final mixed mixture was put into a powder feeder and layered into capsule (Seoheung capsule, Korea) using a capsule layering device * to prepare the title capsule. Example V-23: Amlodipine-Rochevastatin Capsulation Agent ： (Granules Tablet)

Capsules were prepared by the following method, with the ingredients and amounts listed in Table V-3.

(1) Preparation of a prior release compartment (roschvastatin rapid release granule)

Rojuvastatin knife, tribasic calcium phosphate, lactose monohydrate, corn starch, and apples with No. 35 sieve, and the mixture was mixed for 5 minutes in a real cone with a double cone mixer to prepare a mixture. Purified water was added to the mixture, followed by granulation with an oscillator using No. 18 sieve and dried at 60 tons using an early dry towel. After that, the mixture was established with No. 20 sieve and sodium starch glycolate was added to the formulation. The mixture was mixed in. A stearic acid magnesium was added to the mixture and finally mixed to prepare a pre-release compartment made of S.

 (2) Preparation of delayed-release compartments (amlodipine delayed-release tablets)

Amlodipine besylate, anhydrous hydrogen phosphate, pregelatinized starch were apples in No. 35, and mixed with a double cone mixer for 5 minutes at real silver to prepare a mixture. Separately, hydroxypropylcell was dissolved in purified water and combined, granulated, and dried as a binding solution. After drying, it is established as a No. 18 sieve again, Magnesium stearate obtained by sifting No. 35 into the formulation is mixed, mixed for 4 minutes, and the mixture is tableted with a rotary scouring machine equipped with a 5 mm diameter punch to prepare a tablet. It was. Separately, a coating solution obtained by dissolving and dispersing acryl-isolated in purified water was prepared, and the coating layer was formed by using ^' Amodi ¾ tablet * high coater ^{' using} the same. The title delayed release compartment was prepared.

(3) post-mixing, tableting and coating

The product of (1) and (2) was laminated to Camsul (Seoheung Capsule, Korea) using a sulf bed electrolysis to obtain the title capsule. Example V-24: Preparation of Amlodipine-Rochevastatin ¾ Sludge (Tablet-Granules)

With the ingredients and contents set forth in Table V-3, ¾ slabs were removed by the following method.

 (1) Preparation of a prior release compartment (Rochevastatin immediate release tablet)

Roachevastatin calcium, tribasic calcium phosphate, microcrystalline cellulose, pregelatinized starch and apples in No. 35 sieve were mixed with a double cone mixer for 5 minutes in real plants to prepare a mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After coalescence, the granules were formed into a No. 20 sieve using an oscillator, and when they were dried at 60¾ using a hot water gun S, they were formed into No. 18 sieve. Crospovidone and stearic acid magnesium, which were sieved at 35 ° C, were added to the rim and mixed for 4 minutes, and the mixture was compressed into a rotary tablet press equipped with a 5 _m diameter punch to prepare the title-release compartment.

 (2) Preparation of delayed-release compartments (amlodipine delayed-release granules)

Amalodipine besylate, microcrystalline salulose, anhydrous hydrogen phosphate and hydroxypropylmeth ¾ cells were apples in No. 35 and mixed with a double cone mixer for 5 minutes to prepare a mixture. Purified water was added and combined with the main ingredient mixture. After the association, granules were formed by using an oscillator with No. 20 sieve. Magnesium stearate was added to the sieved material and finally mixed to remove the delayed-release compartment of the title.

(3) post mixing, tableting and coating

The final product of (1) and (2) was laminated to a capsule (Seoheung Gap ¾, Korea) by using a capsul layered electrolysis to prepare a capsule of the title. Example V-25: Preparation of Rochevastar ¾-Amlodi¾ Toxylate Blister Packaging Kit Rochevastatin-Amlodipine Besylate Blister Packaging Kit was prepared by the following procedure. It was.

Each of the Roschvastatin streak pre-eluting granules prepared in Example V-7, (1) and the amlodipine besylate delayed-dissolution granules prepared in Example V-7, (2) were prepared using a rotary tablet press equipped with 7ι. Each tablet was manufactured by tableting using the blister packaging machine (Minister A, Heunga Engineering), and then packaged to allow simultaneous use of each tablet roll in a blister packaging container (silver foil, Dongyang, Jeonmin Industries). Trolley Packaging Trolls were manufactured.

[^ V-l]

TABLE V-2

TABLE V ᅳ 3

Composition (mg / tablet)

In component implementation

 V-17 V-18 V-19 V-20 V-21 V-22 V-23 V-24 Rochebaslatin ¾ 10,4 10.4 10.4 10.4 10.4 10.4 10.4 10.4 Shampoo ¾ Approved Mountain--20 20 30 £ 0 30 20 口 1 Crystalline Cell s Loose ᅳ-50--40-41 Wire Lactose ¾--―-22.6-20 ᅳ Room Corn Starch--15.6 61.6--15.6-

Sg starch-----20.6-30.6

 50 50

castle

 ： C: Roxy to ¾ ^ ΐ ^

 2 2 1 1 1 1 2 Starch ¾¾¾ ^

 Crospovidone---ᅳ 4 s ειιοι ・ Lessan Di Win ᅳ-ᅳ 1 1 1 1 tablet 1 number 48 48 50 50 20 50 30 50 Cancer ≥ E! Hil Silate 6.94 6.94 6.94 6.94 6.94 6.94 s-Angry as Ηΐι Sil eii 3.74 3.74

0 ^' | Crystalline cellulosic 30 50-50 30 25 Hydrogen phosphate anhydrous 10-25.26 23.06 22.06 s Starch-25.66---40

18 ^' .6

Jade "4 ^» starch---

6

 D-Manny §--13.06

 .Si si.Duroin i as a cell

 2 2 ᅳ

Smoking--2-

1.26 1.06

^• § l Drone I pro galls cells

 -----20 Lo-Os

castle

 Sud 50 50

phrase

 Arc a-Ease ᅳ 9--Stroke--9.-

^ Yuloose o Aiigi

 12 ᅳ--―---

320S (0U-1IS ^ | 32%)

 Cellulose · ί) ᅡ세 ΕΙΙΟί

 398-10IF (0 i) ia 39.8 12-------%)

 Sri Sri SR 30D---10 20---

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¾ dew ^{63- 63 63 63 63 63 63 '} 63 if system 220 220 233 263 202 233 224 247 Example VI-1: nifedipine - atorvastatin press-coated tablet prepared

Nucleated tablets were prepared by the following method with the ingredients and contents shown in Table vi-i.

 1) Preparation of prior release compartments (atorvastatin prior release granules)

Atorvastatin calcium anhydride, Precipitated calcium carbonate (Nitto Funka, Japan), microcrystalline cellulose (Avicel PH101, FMC Biopolymer, USA), lactose hydrate (DMV, Germany), pregelatinized starch (Starch 1500G, Colorcon, USA) ), Lau ¾ sodium sulfate (Texapon 12P, Cognis Corp, USA), weighed and appled with No. 35 sieve, and mixed for 5 minutes in a debulcon mixer (Dasan Pharmatech, Korea) to prepare a mixture. Separately, hydroxypropyl¾ rose (HPC-L, Nippon Soda, Japan) was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, the unit 18 is made using an oscillator (AR402, Erweka, Germany), and it is dried at 60 ° C using a silver dry machine (H-C, Samco, Japan). After drying, it was established as No. 20 sieve again. Cros carmelo Osnacht (Primellose, D V, Germany) was added to the sieved material and stearic acid magnesium CNitika Chemical (India) was added and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartment (nifedipine delayed-release sustained-release tablet)

Nifedipine, microcrystalline cellulose and lau ¾ sodium sulfate were apologized with No. 35 sieve and mixed with a double cone mixer for 5 minutes, and then added to a petroleum bed granulator (GPCG 1, Glatt, Germany). Spray the binding solution made by dissolving the osmotic water in water to form granules It was. After collidone SR (Basf, Dukil) was mixed, the final mixture was mixed with stearic acid magnesium, and the final mixture was compressed into a rotary tablet press (MRC-30, Sejong Machinery, Korea) to make a nuclear tablet.

Using the coating machine (SFC—30F, Sejong Machinery, Korea), the Eudragit L 100 solution dissolved in 80% ethane was prepared as a coated core tablet.

3) tableting and coating

The atorvastatin calcium pre-release granules of 1) above were used as a nucleus tablet tableting machine (RUE L, Kilian, Deukil), and the nifedipine delayed-release sustained-release tablet of 2) was tableted using a nuclear tablet. Separately, 80% ethane was dissolved in hydroxypropylmethyl ¾rose 2910 (Stiin-etsu, Japan), polyethyleneglycol 6000 (Basf, Germany), talc (Luz ac, France), titanium oxide (Tioside Americas, After dispersing the United States) to prepare a coating solution to form a coating layer as a coating on the nucleated tablets to prepare a tablet in the form of film-coated nucleated tablets. Example VI-2: Preparation of Nifedipine-Atorvastated Nucleus ¾

Nucleated tablets were prepared by the following method with the ingredients and contents listed in the table.

1) Manufacture of pre-release compartment (atorvastatin pre-release)

Atorvastatin chamomile trihydrate, calcium carbonate, microcrystalline cellulose, lactose carbohydrate, pregelatinized starch, lau ¾ sulphate, weighed 35 apples: a, a mixture was prepared by mixing in a double cone mixer for 5 minutes. Separately, hydroxypropyl¾ was dissolved in purified water to prepare a defect solution, which was associated with the main component mixture. After softening, granulate with No. 18 using an oscillator and dry it at 60t: using a silver water dryer. After drying, it was established as No. 20 sieve again. "Crosscardello loath" was mixed, and a stearic acid magnesite was added and finally mixed with a double cone mixer.

2) Manufacture of delayed-release compartments (nifedipine delayed-release sustained-release tablets)

Nifedipine, microcrystalline cellulose, sodium lauryl sulfate, and apples were mixed with No. 35, mixed with a double cone mixer for 5 minutes, and added to a granular bed granulator. Separately, a binder solution prepared by dissolving hydroxypropyl methyl cell in water was used. Sprayed to form granules and dried. Combined with hydroxy propyl metal gelloose (Benecel, Hercules, USA) and hydroxypropylcelose (Klucel, Hercules, USA), and the final mixture with stearic acid The final mixture was then compressed with a rotary tableting machine to make it a nuclear tablet.

Second: using the coating machine in a tablet core, oil in purified water driver did RS 30D _(. EVO Nick, Germany) and Eudragit RL 30D by spraying a coating solution prepared by dispersing (EVO Nick, Germany) noses ¾ nuclear Prepared by tablets.

3) tableting and coating

Example VI-1 Tablets in the same manner as 3) were coated and coated to prepare tablets in the form of film-coated nucleated tablets. Example VI-3 ： Nifedipine-Atorvasta ¾ nucleated tablet preparation

Nucleated tablets were prepared by the following method, using the ingredients and contents shown in the table.

1) Manufacture of pre-release compartments (atorvastatin pre-release granules)

Atorvastatin strontium pentahydrate, carbonate carbon, microcrystalline salose, lactose carbohydrate, starch starch, sodium lauryl sulfate were added to apples in No. 35, and mixed in a double cone mixer for 5 minutes to prepare a mixed fire. Separately, the hydrophilic propyl sal was dissolved in purified water roll to prepare a defect solution, which was associated with the main component mixture. After the association, granules were prepared using an oscillator in No. 18 and dried in a roll using a mercury dryer. After drying, it was established as No. 20 sieve again. The croscarmellose sodium was mixed with the grains, stearic acid magnesium was added, and the final mixture was mixed with a double cone mixer.

2) Manufacture of delayed-release compartments (nifedipine delayed-release sustained-release tablets)

Nifedipine, microcrystalline cellulose, sodium lauryl sulfate in apple No. 35 sieve, mixed with a double cone mixer for 5 minutes, put into a fluidized bed granulator, and separately sprayed with a special liquid made by dissolving the hydroxypropylpropyl cellulose in water. Granules were formed and dried. Combine the Eudragit RS P0 (Evonik, Germany), Eudragit RL P0 (Evonik, Germany) and Nathium Chloride, add final stearate with Magnesium Stearate, and then add the final mixture to a rotary tableting machine. The tablet was compressed into a nuclear tablet.

Using a coated group in the nuclear tablet prepared above, cellulose acetate phthalate (Aquacoat cPD, FMC, Meruk), polyethylene glycol 6000 (Basf, Ind.) And triethyl citrate (Vertel lus, UK) were added to purified water. The coating solution prepared by distillation was sprayed to prepare a coating core point. 3) tableting and coating

Tableting and coating in the same manner as 3) of Example VI-1 to prepare a tablet in the form of a film-coated nucleated tablet. VI Example VI-4 ： Nifediphan ᅳ atorvastatin nucleated tablet preparation

Nucleated tablets were prepared by the following method using the ingredients and contents shown in Table VI-1.

1) Preparation of a prior release compartment (atorvastatin prior release granules)

Atorvastatin calcium trihydrate, ¾ acid chamomile, undefected cellulose, lactose carbohydrate, pregelatinized starch, apples with No. 35 sieve, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropylcellose and T een 80 (AkzoNobel, Netherlands) were dissolved in purified water to prepare a binding solution, which was then combined with the main component mixture. After the association, granulate using an oscillator in No. 18 and dry at 60 ^° C using a silver roll dryer. After drying, it was established as No. 20 sieve again. Sodium starch glycolate ζ 丽, Dukil) and stearic acid magnesium were added to the sieved material, followed by final mixing with a double cone mixer.

2) Jecho of delayed-release compartment (nifedipine delayed-release sustained-release tablet)

Nifedi, microcrystalline salose, and lauryl sulfate nitrate were mixed with No. 35 sieve, mixed with a double cone mixer for 5 minutes, and then put into an equilayer granulator, and hydroxypropylmethylcell was dissolved in water. The liquid was sprayed to form granules and dried. Here again, ethylcellulose (Aquacoat ECD, FMC, USA) was diluted in purified water, and the granules were coated and dried by spraying a solution prepared by dissolving polyetherene glycol 6000. Magnesium stearate was added to the granules thus prepared for final mixing, followed by tableting with a rotary tableting machine to obtain the core tablet.

Using a coating machine in the above-described core tablet, dissolved hydroxyspecialpropylmethylcellulose acetate succinate (Shin® etsu, Japan) and triethyl citrate in purified water and sprayed the coating solution; Prepared.

3) tableting and coating

Tableting and coating in the same manner as 3) of Example VI-1 to prepare a tablet in the form of a film-coated nucleated tablet. Example VI-5 ： Nifedipine (Atorvastatin) nucleated tablet preparation

By using the ingredients and contents shown in Table VI-1, a pseudonucleated tablet was prepared by the following method.

1) Preparation of the prior release compartment (atorvastatin prior release granules)

Atorvastatin calum trihydrate, carbonate carbon, microcrystalline cellulose lactose monohydrate, corn starch (DMV, Germany) and sodium lauryl sulfate were added to apples in No. 35, and the mixture was mixed for 5 minutes in a debulcon mixer to prepare a mixture. Separately, hydroxypropyl "loose was dissolved in purified water to prepare a binding solution, which was then combined with the main component mixture. After the association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C using a silver water dryer. After drying, the mixture was again formed into a No. 20 body. The cross matter was mixed with cross-key "lemeloose or thromium, and a stearic acid magnesium was added and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (nifedipine delayed-release sustained-release tablets)

Nifedipine microcrystalline cells were mixed with 35 pieces of loose and sodium lauryl sulfate, mixed with a double cone mixer for 5 minutes, and then poured into a fluidized bed granulator, and separately hydroxypropylmethyl ^ lose phthalate (Shin-etsu (Japan)) was rolled into water. The sprayed melt was sprayed to form and dry. The carbomer 71G was mixed with the prepared limbus, and the final mixture was added with stearic acid magnesite, and then compressed into a rotary tableting machine to make a nuclear tablet.

 3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as 3) of Example VI-1. Example VI-6 Nifedipine-atorvastatin biphasic matrix tablets

With the components and contents shown in Table VI-1, two-phase matrix tablets were prepared by the following method.

 1) Preparation of the prior release compartment (atorvastatin prior release granules)

Atorvastatin calcium anhydride, calcium carbonate, lactose monohydrate, pregelatinized starch and apologies as a No. 35 sieve and common in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropyl ¾ and Tween 80 were dissolved in purified water to prepare a binding solution, which was then combined with the main ingredient mixture. After the association, the granules were formed using a No. 20 oscillator and dried at 60 tons using a silver water dryer, and then re-established as No. 18.

2) preparation of delayed-release compartments (nifedipine delayed-release sustained-release granules) Nifedipine, microcrystalline cellulose, and lauryl sulfate natto were apologized with No. 35, mixed with a double cone mixer for 5 minutes, and then put into a granular bed granulator. Separately, a binder solution prepared by dissolving hydroxypropylmethylcellulose in water was used. Sprayed to form granules and dried. To this was diluted ethyl 쎌 loose (Aquacoat ECD, FMC, USA) in purified water and sprayed with a solution prepared by dissolving ethylene glycol 6000 to dry the granules. The granules were sprayed onto the granules separately by spraying a coating solution prepared by dissolving hydroxypropylmethylshell cellulose acetate succinate (Shin- etsu, Japan) and triethyl citrate in purified water separately.

 3) post mixing, tableting and coating

The products of 1) and 2) were put into a double cone mixer and mixed. Sodium starch glyconate was mixed with this mixture and the stearic acid magnesium was put in the final mixture. The final mixture was compressed into tablets using a rotary tablet press to prepare two-phase matte tablets. Separately, ethanol and hydroxy methmethol ¾¾ 910 2910 in ethane and purified water were dissolved 6,000 lene glycol 6, 000, talc, titanium oxide dispersion coating solution was prepared, and the prepared 2 using the coating machine A film coating layer was formed on the phase matrix tablet. Example VI-7: Nifedipine-atorvastatin Biphasic Matrix Tablet Preparation

With the components and contents shown in Table VI-1, two-phase matrix purification was obtained by the following method. -

1) Preparation of a prior release compartment (atorvastatin prior release granules)

Atorvastatin calcium trihydrate, calcium carbonate, microcrystalline cellulose, sodium lauryl sulfate were weighed and appled with No. 35, and the mixture was mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulation was carried out using a No. 20 oscillator, and it was formed into No. 18 after drying in 6 ⁽ VC) using a silver water dryer.

 2) Preparation of delayed-release compartments (nifedipine delayed-release sustained-release granules)

Nifedipine was mixed with ¾ ethylene glycol 6000 and melted to prepare a solid dispersion. The prepared solid dispersion was apples in No. 35, and the mercury crystals apples in No. 35 were mixed with a double cone mixer together with loose, sodium lauryl sulfate, and Carbomer 71G. The above-mentioned mixture was sprayed with a bonding liquid prepared by dissolving hydroxypropylmethylthiolose in a fire to form granules and dried. Hydroxypropylmethylcell, in which ethane was dissolved in purified water The granules were coated by spraying a rhoose phthalate solution and ace ¾ graded monoglyceride (Riken, Japan) solution.

3) post mixing, tableting and coating

Post-mixing, tableting and coating were carried out in the same manner as in 3) of Example 6 to prepare a biphasic matrix tablet. Example VI-8: Nifedipine-atorvastatin Multilayer Tablet Preparation

With the components and contents shown in Table VI-2, a multilayer tablet was prepared by the following method.

1) Preparation of a prior release compartment (atorvastatin prior release granules)

Atorvastatin Kalum anhydride 킬 Kilcarbonate: Chem, microcrystalline salose, lactose hydrate, sodium lauryl sulfate, weighed 35 apples and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulate with the No. 20 sieve using an oscillator and dry it at 6CTC using a silver water dryer. After drying, it was again formed into a No. 18 sieve. The starch glyconate natsim was mixed with the formulation, and magnesium stearate was added to the final mixture with a double cone mixer.

 2) Preparation of delayed-release compartment (nifedipine delayed-release sustained release)

Nifedipine delayed-release sustained-release granules were prepared in the same manner as 2) of Example VI-6.

 3) post mixing, tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T, Sejong Pharmatech, Korea). The final mixture of 1) was placed in a primary powder feeder, and the final mixture of 2) was placed in a secondary powder feeder, and compressed into conditions that minimize the incorporation between layers. Separately, a coating solution was prepared by dissolving and dispersing hydrated propyl methylcellose 2910, polyethylene glycol 6,000, talc, and titanium oxide in ethane and purified water to form a film coating layer using the above tablet as a coating machine. Tablets in the form were prepared. - ^"Example VI-9: Needle paddy ¾-Atorva Spa tin multi-layered tablet prepared

With the components and contents shown in Table VI-2, a multilayer tablet was prepared by the following method. 1) Preparation of the prior release compartment (atorvastatin prior release granules)

Atorvastarted venom trihydrate, carbonated venom, microcrystalline ^■ § With loose, corn starch Apples No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropylshellulose was dissolved in purified water to prepare a binding solution, which was associated with the main component mixture. After the association, granulate with No. 20 sieve using an oscillator and dry it at 60 ° C using a silver water dryer. After drying, it was established as No. 18 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

 2) Preparation of delayed-release compartment (nifedipine delayed-release sustained-release granules)

Nipadidipine delayed-release sustained-release granules were prepared in the same manner as in Example VI-7.

 3) post mixing, tableting and coating

In the same manner as in Example VI-8, 3), after mixing, tableting and coating, a tablet in the form of a multilayer tablet was prepared. Example VI-10 ： Nifepin-atorvastatin Capsule Preparation (Pellet-Granule)

According to the ingredients and contents shown in Table VI-2, capsules were prepared by the following security.

1) Preparation of sun-release compartment (atorvastatin ¾¾)

Sugar seeds (Sugar sphere, MP Pharmaceutical, France) were sieved through a No. 35 sieve and poured into a fluid bed granulator. Separately, a combined solution in which hydroxypropylcellose and atorvastatin calci trihydrate was dissolved in purified water was sprayed to form a pellet and dried.

 2) Preparation of delayed-release compartments (Nizadipine delayed-release sustained-release granules)

Nifedipine delayed-release sustained-release granules were prepared in the same manner as in Example VI-7.

 3) Postmixing and Capsulation

The final products of 1) and 2) above were combined with a double cone mixer. Magnesium stearate was added to the mixture for final mixing. The final mixture was put into a powder feeder and layered into ¾ cup (West Honggaxel, Korea) using a ¾ cup filler (SF 40N, Sejong Pharma, Korea) to complete the preparation of a delayed-release sustained-release formulation in the form of a capsul. . Example VI-11 ： Nifedipine-atorvastatin Capsule Preparation (Pel ¾-¾let)

With the components and contents shown in Table VI-2, a formulation was prepared by the following method.

1) Preparation of the prior release compartment (atorvastatin prior release ¾¾) Sugar seeds were poured into a No. 35 sieve, poured into a fluidized bed granulator, and then sprayed with a combined solution of hydroxypropyl ¾ and atorvastatin calum trihydrate in water to form atorvastatin-containing ¾ and dried.

 2) Manufacture of delayed-release compartment (nifedipine delayed ¾¾)

Sieve the sugar seeds through a sieve No. 35, put them in an equalizer supernatant, and spray nifedipine-containing pellets by separately spraying a water solution of hydroxypropylmethylcellose, polyethylene glycol 6000, lau ¾ sodium sulfate, and nifedipine in water. ¾ was formed and dried. In addition, nitrodipine retardant ¾¾ was prepared by spraying a solution of * Ricoat 30D (Basf, Germany) dissolved in ethane and mexylene chloride in ¾¾. Again, the pellet was sprayed with a solution of arc ¾-ise (Colorcon, USA) dissolved in ethanol and purified water to prepare nifedipine delayed-release sustained-release ¾.

 3) Capsular layering-The final products of steps 1) and 2) were layered onto the capsules using a capsule layering machine to complete the preparation of the ¾ slot type preparation. Example VI-12 Nifedi ¾-atorvastatin Capsule Preparation: (Pel 5-osmotic tablet) A capsule was prepared by the following method with the components and contents set forth in Table VI-II.

1) Preparation of a prior release compartment (atorvastatin prior release felhett)

The sugar spheres were sieved through a No. 35 sieve, and poured into a fluidized bed granulator, and then sprayed with a combined solution of hydroxypropyl salulose and atorvastatin ¾ breast trihydrate in water to form atorvastatin-containing pel¾ and dried. .

 2) S of delayed-release compartment (nifedipine osmotic tablets)

Example VI-3 Nipedipine delayed-release sustained-release tablets were prepared in the same manner as in 2).

 3) ¾ full layer

The final products of 1) and 2) were layered into capsules using a capsular layer pendulum. Example VI-13: Preparation of Nifedi ¾—atorvastar ¾ Knee (Pel ¾-Tablet)

With the components and contents shown in the table, a capsule was prepared by the following method.

1) Preparation of the prior release compartment (atorvastatin prior release ¾¾)

The sugar seeds were sieved through a No. 35 sieve, placed in a homogeneous granulator, and then hydroxypropyl chloride in water. By spraying with ropil saelreul agarose and a binding solution prepared by dissolving atorvastatin calcium trihydrate Atorva form containing statins have ^■, and dried.

 2) S of delayed-release compartment (nipeded delayed-release sustained-release tablet.)

Nifedipine delayed-release sustained-release tablets were prepared in the same manner as in Example VI-1, 2).

 3) Capsul layered

The final product of 1) and 2) was layered on the capsule using a camsule layer electric machine. Example VI-14: Nifedi ¾-A Servastatin Capsule Preparation (Tablet-Pellets)

With the components and contents shown in Table VI-3, a capsulant was prepared by the following method.

1) Article S of the prior release compartment (atorvastatin prior release tablet)

Atorvastarin sorghum trihydrate, calcium carbonate, microcrystalline ¾rose, corn starch, lauryl sulfate Nat. Apples in a No. 35 sieve and mixed with a double cone mixer for 5 minutes to prepare a mixture. Propylcell was dissolved in viscous water to form a binding solution, which was then combined, granulated, and dried.After drying, the mixture was again formed into No. 18. Sodium starch glyconate and magnesium stearate were added to the formulation, which was then shaken for 4 minutes. After combining, the tablets were prepared by tableting with a rotary tablet press (MRC-37, Sejong) equipped with a 5 mm diameter punch.

 2) Preparation of delayed-release compartment (delayed-release sustained-release Pal ¾ of nifedipine)

Example VI—Nifedipine paper was prepared in the same manner as 2) of 11). Emissive sustained release pellets were prepared.

 3) Capsul layered

The products of 1) and 2) were layered in capsules using a capsular layer roll. Example VI-15 ： Nifedipon-atorvastatin Capsule Preparation (Tablet-Tablet)

With the components and contents shown in Table VI-3, a camsulant was prepared by the following method. 1) Preparation of a prior release compartment (atorvastatin prior release tablet)

Atorvastatin sorghum trihydrate, carbonate carbonate, corn starch, lau ¾ sodium sulfate were weighed and appled with No. 35, and then mixed in a double cone shaker for 5 minutes to prepare a mixture. Was prepared and associated with the main component mixture. After the association is completed, granulate using the oscillator in No. 20 and dry at 60t! Using this roll hot water dryer. After gun a is finished, it goes back to 18 It was. Into the formulation, sodium starch glycolate and magnesium stearate, which were sieved through a No. 35 sieve, were mixed for 4 minutes, and then compressed into a rotary tableting machine equipped with a 5 mm diameter bias. First roll was completed.

 2) the delayed release compartment (nifedipine delayed-release sustained-release tablet)

Nifedipine delayed-release sustained-release tablets were prepared in the same manner as in Example 2).

 3) Capsular stratification.

The products were layered into capsules using the three-layer single layer electric products of Xinggi 1) and 2). Example VI-16 ： Nifedipine-atorvastatin Capsule Preparation (Garim-Garim)

According to the ingredients and contents described in Table VI-3, a capsule was prepared according to the following method.

1) Gradation of the prior release compartment (Atorvasta¾ prerelease granules)

Atorvastatin chamomile trihydrate, calcium carbonate, lactose monohydrate, lauryl sulfate sulphate was affixed to apple No. 35, and the mixture was mixed for 5 minutes in a double cone mixer to prepare a mixture. Sodium croscarmellose sodium was added to the mixture for final mixing.

 2) Preparation of delayed-release compartments (nifedipine delayed-release sustained-release granules)

Nifedipine delayed-release sustained-release granules were prepared in the same manner as 2) of Example VI-6.

 3) Cap layer stratification

The products of 1) and 2) were combined with a double cone mixer. Starch and sodium glyconate were added to the mixture and mixed with a double cone mixer. Magnesium stearate was added to the mixture again for final mixing. The final mixed mixture was placed in a powder feeder and layered in ¾ sul using a capsular layer roll. Example VI-17: Preparation of nifedi ¾-atorvastatin capsulant (granule-¾)

With the components and contents shown in Table VI-3, capszelol was produced by the following method.

1) Preparation of a prior release compartment (atorvastatin prior release layer granules)

Atorvastatin calcium trihydrate, calcium carbonate, microcrystalline cellulose, pregelatinized starch, lau ¾ sodium sulphate and apples in No. 35 were mixed and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, the hydrous propyl ¾ was dissolved in purified water to prepare a binding solution, which was combined with the main component mixture. When the union is over, move the oscillator to 20. Granules were dried and dried in a 6-rc using a silver-water drier. When the drying was completed, the mixture was returned to No. 18, and the cross carmellose nat was added thereto.

 2) Preparation of delayed-release compartment (nifedipine delayed-release slow release ¾¾)

Niphi dipine delayed-release sustained-release pel¾ was prepared in the same manner as in Example 2).

 3) Cap Filling

The products of 1) and 2) above were combined with a double cone mixer. Sodium starch glycolate was added to the mixture and mixed with a double cone mixer. Magnesium stearate was added to the mixture again for final mixing. The final mixed mixture was placed in a powder feeder and layered into ¾ sul using a capsul layered electric. ^"Example VI-18: Nifedipine-o tor Basta ¾ cap sulje prepared (granules-tablets)

A capsule was prepared by the following method with the components and contents shown in Table VI-3.

1) Preparation of the prior release compartment (atorvastatin prior release granules)

Atorvastatin carcass trihydrate, carbohydrate, lactose carbide and corn starch were weighed and appled in 35 soda, and the mixture was mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, Tween 80 was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. After the association, granulate with No. 18 using an oscillator and dry it at 60 using a silver water dryer. After drying, it was established as No. 20 sieve again. Sodium starch glyconate was added to the sieved material and mixed with a double cone mixer. Stearic acid magnesium was added to the mixture again for final mixing.

 2) Preparation of delayed-release compartments (nifedipine delayed-release sustained-release tablets)

Nifedipine delayed-release sustained-release tablets were prepared in the same manner as in Example VI-1, 2).

 3) ¾ tiers

The product of 1) and 2) was layered on the capsul using capsul layer electric. Example VI-19: Preparation of nifedipine-atorvastar capsules (tablets-granules)

With the ingredients and contents shown in Table VI-3, ¾ sulfone was prepared by the following method.

1) Second of prior-release compartment (atorvastatin prior-release tablet):

Atorvastatin Calhum Trihydrate, Dehydrated Stem of Carbonate, and Pregelatinized Starch Apples in No. 35 were mixed and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl gelloose and Tween 80 were dissolved in constant water to prepare a binding solution, which was associated with the main component mixture. After the association, granules were formed using No. 20 sieve using an oscillator roll, and the granules were dried at 6 (TC using a silver water dryer. After drying, the sieve was formed into No. 18 again. After mixing ¾ for stearic acid and mixing for 4 minutes, the mixture was compressed with a rotary tablet press (MRC-37, Sejong, Korea) equipped with a 5 mm diameter diameter to complete the preparation of atorvastatin tablets.

 2) number a of the delayed-release compartment (nifedipine delayed-release granules)

Nifedipine delayed-release sustained-release granules were prepared in the same manner as in Example VI-1, 2).

 3) Capsul layered

The products of 1) and 2) were layered in capsules using a ¾ slot electric machine. Example VI-20: Preparation of Atorvastatin-Nifed Dipine Blister Packaging Kit

The atorvastatin-nifedipine blister packaging kit was prepared by the following method. Each tablet was prepared by tableting each of the atorvastatin carsum trihydrate prior-release granules prepared in Example VI-7 and Nifedi ¾ delayed-release sustained-release granules prepared in Example VI-7 and 2) with a rotary tablet press. Then, each blister is packed in a blister packaging container (silver foil, Dongyang, PTOC, Jeonmin industry, Korea) using a blister packaging machine (Minister A, Heunga Engineering). Was prepared.

[table

TABLE VI 一 2

S¾ (mg / tablet)

？ Sex ingredient

 VI-1 V! -1 Vl-I VI-1

Vl-8 VI-9

 0 1 2 3

10,3

 Atorvas Efg Horsefighter g

 5

 10,8 10.8 10.8 10.8 10.8

01.Tor iXtra ¾ ¾ calcium trihydrate

 5 S 5 5 5

& Mountain S 60 60

 01 side cell BS 27 36.5

 Lactose ae 40

 ! Room * Sung section

 Uk ^ Suijeon C 30

 Acid 50 50 50 50 Ramyl sulphur ^ nat g 3 3

 SI rod ^ AI pro cell shell 2.65 2.65 3.15 2,15 3,15 S.15 starch § S acid i S ^ 6 6

 Summer 1 Ah ΞSan Ag Ul¾ 1 1

 uffli ia 30 30 30 30 30 30

* Gasid 50, αι§Jecell BRoess 65 39 39 28 27 Lau 3/4 3 3 3 3 3 3

SI deurok Λ | Ξ £ §0ΙΙ§¾§Ε £ 23 Scotland 32 22 hydroxy! ^'In a particular AIS S0 «mwopseol醫£ ^2' soup with g¾ Sites 12 12

 오스 ¾ to £ 2 o'clock 아 日 아 | | |

 ίθ

 T

 SR 58 delayed room β Sunggu

 Brico SR 30D 12

 10 10

 Eudra S UOO 15 Euphora 5 RS-PO 15 Euphora ¾ RL PO 25

0 | -3¾-012; 10 to west iE | K ⁾ | Gifts ¾21 days 12

OiiSS Loose 15 Tan 촐 6000 3 30 30 30 3 s sheet allite 2 2 asm = g 15 owi @ B) I 曰 α ≤ 리 세 3 3 3

 S¾ acid magnesium 1 1 after s¾ ss HIah s acid οwh ui¾ 1

 SWI S! To the side Λ | ≥ 2910 3.2 3.2

 Plié a! Gai 書 ΘΟΟΟ 3.2 3.2

 3 S #

 Mountain & Tan 2 2

 1.6 1.6

¾ wine 63 63 63 63 Total 890 290 258 263 263 263

[^ VI-3]

실험예 1-1 ： 암로디핀 -심바스타틴 유핵정의 비교 용출시험 (comparative dissolution prof i le test)

Experimental Example 1-1 ： Comparative dissolution test of amlodipine-simvastatin nucleated tablets (comparative dissolution prof i le test)

A comparative dissolution test of the amlodi tube Malay S / simvastatin nucleated tablet prepared in accordance with Example 1-1 and the reference drug (Zoko: simvastatin monotherapy, MSD, Novasque: amlodipine monosaccharide, Pfizer) was performed. In the case of the amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial serous at 2 hours. The dissolution test method for each component is as follows, and the results are shown in the accompanying drawings.

According to Figure 1, the nucleated tablet of the present invention was confirmed that the simvastatin component in the dissolution test under the following conditions showed almost the same dissolution characteristics as compared to the control preparation Joko, the amlodipine component is very late dissolution compared to the control formulation Novasque You can check the speed. The nucleated tablets of amlodipine maleate / simvastatin of the present invention have a dissolution rate of the amlodipine component up to 1 hour in all 50%, which is ¾ times slower than the dissolution of the large S formulation (about 99%).

Nucleus ¾ nucleotablet of amlodipine maleate / simvastatin of the present invention, unlike the control drug amlodipine single agent, since the initial release of amlodipine is much slower than simvastatin, the chance of metabolism in the liver before the simba statin is lowered. Experimental Example 1-2 ： Comparative dissolution test of amlodipine-simvastarin multilayer tablet (comparative dissolution prof i le test)

Comparative dissolution test of the combination preparation of amlodipine malate / simvastatin prepared in accordance with Examples 1-4, 10 and the reference drug (Zoko: simvastatin single, Novask: amlodipine single). The dissolution characteristics of simvastatin and amlodipine components were measured by the following method. In the dissolution test of amlodipine components, elution was changed from artificial gastric fluid to artificial intestinal fluid for 2 hours. As a result, as shown in Figure 2 attached to the roll.

According to Figure 2 Examples 1-4, 10 of the present invention in the following two cases in the dissolution test Simvastar ^' components were confirmed to show almost the same elution characteristics compared to the control agent Zoko, but the amlodipine component is a control formulation A very slow elution rate can be seen when compared to innovava, and the multilayer tablet of amlodipine malate / simvastatin of the present invention has a dissolution rate of the control formulation of about 50% of the amlodipine component up to 1 hour. Much slower than 99¾).

As such multi-layer tablet of amlodipine maleate / simvastatin of the present invention due to the very ^slow, than the initial release of the amlodipine is simvastatin unlike the reference product amlodipine single drug is metabolized in the liver to receive hwakreul deonjeo than Shimbashi Spa tin is ^lowered,

Experimental Example 1-3 ： Comparative dissolution test of amlodipine hydrostatin multilayer tablet (comparat ive dissolution prof i le test)

Comparative dissolution test of the combination of amlodipine maleate / lovastatin prepared in accordance with Example 1-11 and the treaties (mebaco: lovastatin single agent, Novask: amlodi ¾ single agent, Pfizer). In the case of amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid from 2 hours. The dissolution test method for each component is as follows, and the results are shown in the accompanying drawings.

According to Figure 3, Example 1-11 of the present invention was confirmed that the lovastatin component in the dissolution test in the following conditions compared to the control agent mebaco almost the same dissolution characteristics, the amlodipine component of the Novask and the control formulation In comparison, very slow elution rates can be seen. The multilayer tablets of amlodipine malate / lovastatin of the present invention have a dissolution rate of the amlodipine component up to 1 hour all within 5, slower than the dissolution rate of the control formulation (about 99%).

As described above, the multilayer tablet of amlodipart maltate / lovastatin according to the present invention, unlike the cancer S-dipine single agent, the initial release of amlodipine is much slower than lovastatin, thereby lowering the chance of metabolism in the liver before lovastatin. Experimental Example 1-4: Comparative dissolution profi le test of amlodipine-atorvastatin

The comparative dissolution test of the combination preparation of amlodipine maleate / atorvastatin prepared according to Example 1-13 and the reference drug (lipitor: atorvastatin monotherapy, Pfizer, Novasque: amlodipine monotherapy, Pfizer) was performed. In the dissolution test of amlodipine component, the dissolution test was performed by changing the solution * from artificial gastric juice to artificial intestinal fluid from 2 hours. As a result «as shown in Figure 4,

Except for Fig. 4, Examples 1-13 of the present invention, when the dissolution test under the following conditions Atorvasta It was confirmed that the tin component showed almost the same elution characteristics as the control agent Lipitor, but the amlodipine component showed a very slow dissolution rate compared to the control agent Novasque. The multilayer tablets of amlodipine malate / atorvastatin of the present invention have a dissolution rate of the amlodipine component up to 1 hour all within 50¾, which is much slower than that of the control formulation (about 99%).

As described above, the multilayer tablet of amlodipine maleate / atorvastatin of the present invention, unlike the amlodipine monoclonal drug, has a slower initial release of amlodipine than atorvastatin, thus lowering the chance of metabolism in the liver before atorvasta ¾. do. Experimental Example 1-5 ： Comparat ive dissolution profi le test

The comparative dissolution test of the combination of lercanidipine / simvasta¾ prepared according to Example 1-16 and the reference drug (zoco: simvastatin single, MSD, Janidib: lercanidipine single, LG Life Sciences). In the case of lercanidipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid from 2 hours. The results are shown in FIG. 5.

According to FIG. 5, Examples 1-16 of the present invention showed that the simvastatin component exhibited almost the same elution characteristics as compared to the control formulation joco in the dissolution test under the following conditions. In comparison, very slow dissolution rates can be seen. The multilayer tablets of lercardidipine / simvastatin of the present invention have a dissolution of the lercardidipine component by one hour all within 50¾, which is ¾ slower than the dissolution of the control formulation (about 99%).

As described above, the multilayer tablet of lercardidipine / simvastatin according to the present invention has a lower rate of metabolism in the liver of simvastar than the simvastated because the initial release of lercardidipine is much slower than simvastatin, unlike the lercardidipine monotherapy. Experimental Example 1-6: Comparative dissolution profile test of lacidipine-simvastatin multilayer tablets (comparat ive dissolution profile test)

The comparative dissolution test of the combination formulation of lacidipine / simvastatin prepared in accordance with Example 1-18 and the reference drug (co: simvastatin monosaccharide, MSD, Dr. lacidipine monosaccharide, glaxo smith kline) was performed. Elution solution for 2 hours in the case of lacidipine component dissolution test Dissolution test was carried out by changing from artificial gastric fluid to artificial intestinal fluid. The results are shown as shown in FIG.

According to Figure 6, Examples 1-18 of the present invention was confirmed that the simvastatin component in the dissolution test under the following conditions compared to the control chocolate, almost the same dissolution characteristics, but the Rassidi ¾ component Dr. le Compared with, the elution rate is very slow. The multilayer tablets of the lacidipine / simvastatin of the present invention are less than 50% of the dissolution of the lacidipine component up to 1 hour, which is ¾ times slower than the elution of the control formulation (about 99%).

As described above, the multilayer tablets of lacidipine / simvastatin in addition to the present invention are unlikely to receive the metabolite in the liver before simvastatin, because the initial release of lacidipine is significantly slower than simvastatin, unlike the control agent lacidipine single agent. Example 1-7 ： Comparative dissolution profi le test of amlodime—simvastatin nucleated tablets

The comparative dissolution test of the amlodipine besylate / simvastatin nucleated tablet prepared according to Example 1-20 and the control drug (Zoko: simvastatin single, MSD, Novasque: amlodipine single, Pfizer) was performed. In the case of amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid for 2 hours. The dissolution test method for each component is as follows, and the results are shown as shown in FIG.

According to Figure 7, the nucleated tablet of the present invention was confirmed that the simvastatin component in the dissolution test under the following conditions showed almost the same dissolution characteristics compared to the control preparation Zoko, the amlodipine component was very late compared to the control formulation Novasque The dissolution rate can be checked. The nucleated tablets of amlodipine besylate / simvastatin of the present invention have a dissolution of the amlodipine component up to 1 hour all within 50%, which is much slower than the dissolution of the control formulation.

As described above, the nucleotablet of amlodipine besylate / simvastatin of the present invention, unlike the control drug amlodipine single agent, is initially slower than simvastatin, and thus lowers the possibility of metabolism in the liver before simvastatin. Experimental Example 1-8: Comparative dissolution profi le test of amlodipine-simvastatin two-phase capsule preparation A comparative dissolution test of the capsule containing the amlodipine besylate / simvastatin complex tablet prepared according to Example 1-22 and the reference drug (Zoko: simvastatin monotherapy, MSD, Novasque: amlodipine monotherapy, Pfizer) was performed. In the case of the # test for amlodisome components, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid for 2 hours. The dissolution test method for each component is as follows, and the results are shown as shown in FIG.

According to Figure 8, the two-phase capsule formulation of the present invention was confirmed that the simvastatin component in the dissolution test under the following conditions showed almost the same dissolution characteristics as compared to the control preparation Zoko, the amlodipine component is very compared to the control formulation Novasque The slow elution rate can be seen. The capsule containing the amlodi ¾ besylate / simvastatin composite tablet of the present invention has a dissolution rate of the amlodipine component up to 1 hour within 50¾, which is much slower than the dissolution rate of the control agent.

As described above, the capsule containing the amlodipine besylate / simvastatin complex tablet of the present invention is unlikely to be metabolized in the liver before simvastatin because the initial release of maldodipine is slower than simvastatin, unlike the amlodipine single agent, which is a major treaty. do. Experimental Example 1-9 ： Comparative dissolution test of amlodipine-atorvastatin biphasic capsule preparation

Comparative dissolution test of the combination preparation of amlodipine besylate / atorvastatin scabbark prepared in accordance with Example I-30 and the reference drug (lipitor: atorvastatin single agent, Pfizer, Novasque: amlodipine single agent, Pfizer) was performed. In the dissolution test of amlodipine component, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid for 2 hours. The results are shown in FIG. 9.

According to FIG. 9, Examples 1-30 of the present invention showed that the atorvastatin component exhibited almost the same elution characteristics as the control agent Lipitor in the dissolution test under the following conditions, but the amlodipine component was the Novask control. Compared with, the elution rate is very slow. The combination formulation of amlodipine besylate / atorvastatin scabies of the present invention has a dissolution rate of the amlodipine component up to 1 hour in all 50%, which is much slower than the dissolution rate of the control agent.

As such, the combination formulation of amlodipine besylate / atorvastatin calcium of the present invention is very slower than the atorvastatin in the initial release of amlodipine, unlike the amlodipine single agent, which is the reference Therefore, the chance of metabolism in the liver is lowered before the atorvastatin, Experimental Example 1-10: Comparative dissolution profi le test of felodipine-atorvastatin biphasic capsule preparation

Example prepared according to the 1-36 ^'felodipine / atorvastatin two-phase system and the reference product kaepseul a comparison of the dissolution test (Lipitor: atorvastatin single drug, Pfizer, non-Solano ¾ Lodi pin single drug, Handok Pharmaceuticals) was performed. In the case of Pelodipine elution test, the elution test was performed by changing the eluate from artificial gastric juice containing sodium lauryl sulfate as surfactant to artificial serous solution containing lau ¾ sodium sulfate as surfactant. It was. The dissolution test method for each component is as follows, and the results are shown as shown in FIG.

According to Figure 10, the two-phase capsule formulation of the present invention was confirmed that when the dissolution test under the following conditions, the atorvastatin component exhibits almost the same dissolution characteristics as compared to the control lipid Lipitor, the ¾ rhodipine component is the control formulation Comparing the phosphorus exposure and the dissolution results, it can be seen that the initial drug release was delayed.

As described above, the two-phase capsular formulation of ¾-loaded / atorvastatin of the present invention, unlike the pelodipine single agent, the initial release of ¾ rhodipine is much slower than atorvasta ¾, so that the metabolism in the liver is lower than that of atorvastatin. do. Experimental Example 1-11 ： Comparative dissolution profile test of isradipine-Pulubastar¾ 2-phase capsular preparation

Comparative Elution of Isradipine / Fluvastatin Two-Phase Capsule Preparation Prepared According to Examples 1-40 and a Control (Lescol: Fluvastatin Monotherapy, Novartis, Dynacirc: Isadipine Monotherapy, Daewoong Drug) The test was conducted. In the case of isradipine component deposition test, the eluate was changed from artificial gastric juice containing lau ¾ sodium sulfate as a surfactant to artificial intestinal fluid containing lau ¾ sulfate as a surfactant. . The dissolution test method for each component is as follows, and the results are shown as shown in FIG.

According to Figure 11, the two-phase capsule formulation of the present invention was confirmed that the fluvastatin component in the dissolution test under the following conditions compared to the control agent Lescol almost the same dissolution characteristics, the isradipine component is a control formulation Very late compared to DynaCirc The elution rate can be checked. Isradiffin component of the present invention can be seen that the initial drug release is delayed when comparing the dissolution results with dynacque, a control formulation. As described above, the biphasic capsular formulation of isradipine / rubovastatin according to the present invention is unlikely to receive metabolism in the liver before fluvastatin because the initial release of isradi 3 is much slower than fluvastatin, unlike the isradipine monotherapy. The probability is lowered. Experimental Example 1-12: (S) ᅳ Disintegration test of amlodipine-simvastatin formulations (Disintegration test) The formulations obtained in Examples 1-51, 52, and 54 were carried out according to the disintegration test method during the 8 general test runs of the Korean Pharmacopoeia. Test conditions such as test solution are as follows.

The detailed test method was contracted and placed in a beaker and adjusted for up and down movement with 29 ~ 32 round trip and amplitude 53 ~ 57 mm for 1 minute. When the tester was moved to the bottom, the bottom surface of the beaker was The amount of test liquid placed in the beaker was 25 으로부터 from, so that the top of the tester coincided with the surface of the liquid when the tester was lowest. The temperature of the liquid was maintained at 37.2 ^° C. As the test solution, one solution of disintegration test method (pH about 1.2) and two solutions of disintegration test method ( _P H 6.8) were used.

Take 6 specimens from each example and put them into the glass tube of the tester one by one, immerse the tester in the test liquid in the beaker with the silver and liquid volume adjusted in advance, and then up and down for a certain period of time, and then take the tester out of the test liquid and place the sample in the glass tube. Rolls were observed. Disintegration time and the like results are shown in Table 1-12.

As shown in the results of Tables 1-12, the simvastatin layer tablets or granules of this example according to the present invention showed rapid disintegration under all conditions. On the other hand, the purification of the (S) -amlodipine layer did not disintegrate for 2 hours in the pH 1.2 disintegration test solution, and disintegration started after a certain delay time at pH 6.8. The results of the above experiments showed that when a patient takes a pharmaceutical preparation other than the present invention, simvastatin component is first disintegrated and eluted to be absorbed, and after some time, the amlodipine component is eluted and absorbed. This is consistent with the purpose of the pharmaceutical formulation to be developed by the present invention.

실험예 1-13 ： (S)-암로디핀 /심바스타된 약제학적 제제의 용출시험 (Dissolution profile test) Table 1-12

Experimental Example 1-13: Dissolution profile test of (S) -amlodipine / simvastad pharmaceutical formulation

(S) -Amlodipine / simvastatin pharmaceutical preparations prepared according to Examples 1-51, 52, 53, 54, 55 were eluted. The dissolution test was performed for 2 hours in an acidic solution of hydrochloric acid, and then further dissolution test was performed in a pH 6.8 (phosphate) solution. However, in the case of simvastatin components, it is difficult to detect the low solubility under general dissolution conditions, so the dissolution test was conducted under separate conditions, and the dissolution test method for each component is as follows. , As shown in FIG. 13.

According to Figure 12 and 13 (S)-amlodipine / simvastatin pharmaceutical formulation of the present invention, simvasta¾ is eluted and absorbed as quickly as the present invention intended, (S)-amlodipine is eluted after being absorbed by simvasta It is formulated to be absorbable. In addition, while it is possible to prepare a variety of formulations to ease the patient's dose, as shown in the dissolution graph, the dissolution rate difference of each component due to the difference in formulation hardly occurred. Experimental Example 1-14 ： clinical study

This experiment was carried out with 'Sco-coated' and 'Novask-coated' as the test group and the co-administration group 'Zokoco ¹ ' (wanvastatin 20 rag, MSD) and 'Novask' (Texyl acid amlodipine 6.944 mg, Pfizer). To have the same release time as in the compositions provided by the examples. The clinical trials were carried out as shown in Table 1-13 in addition to having the effect as a composition according to the present invention by administering the time difference.

Table 1-13

This experiment was conducted to reduce the clinical trial criteria and the number of trials for the approval of medicines for marketing purposes. Was carried out. Detailed results of the comparative clinical trials are shown in Table 1-14 and FIGS. 14 to 16.

 Table 1-14

 ^ Pharmacokinetics / Pharmacodynamics of Comparative Clinical Results ¾ and Clinical Results Revealed

 At the time of blood pressure drop, the time-difference group showed lower blood pressure than the co-administration group in the shale measurement on day 41 in systolic and diastolic blood pressure.

 2. The lower level of total cholesterol and LDL-cholesterol showed the lowest lipid level at 41 days than the simultaneous treatment group.

3. The most important lipid of hyperlipidemia, the neutral lipid lowering state, was superior to the timed group, and the concurrent group showed no hyperlipidemic effect. Statins are cholesterol synthetic inhibitors, but cholester ^' synthetic reaction itself is a lipid protein Because of the rate-controlling effects of synthetic reactions, the effect of thickening lipids is known as the 8¾-2 range. Compared with this figure, the hypolipidemic effect in this clinical trial was 20% in the time-differentiated group, whereas the concurrent-treated group showed little effect.

 This can be interpreted that the isoluite group is antagonistic by the enzyme in the liver, and simvastatin is released into the blood, so that the lowering effect is not even lowered to neutral lipid lowering.

 4. Also, it is well known that lipid improvement requires an increase in HDL levels.

 5. Changes in the biomarker in the blood at day 41 of dosing to evaluate the safety of drug therapy

 1) S-GPT, S-GOT, CPK, y-GPT and alkaline phosphatase levels showed safer biomarks.

 2) This may be inferred due to the unnecessary inflammation-induced reaction of simvastatin because more simvastatin spills into the bloodstream than the co-administration group.

 6. Clinical adverse events were observed in 3 of the mild side effects in only 2 patients. One case of diarrhea was found in the time-administered group, and one case of fatigue and cough in the isochronous group.

 Changes in blood plasma concentrations of drugs through this comparative clinical trial are as follows.

 1) Simvastatin β-Hydroxylate concentrations: Simvasu, which should be low in the blood, is 40% higher than other co-therapy or simvastatin monotherapy. It can be seen that it is reduced (Table I '15 and FIG. 14).

This is a pharmacological proof that timed dosing can provide better lipid-lowering effects and lower side effects. Table 1-15

 Increase the blood concentration of simvastatin P-hydroxy acid

 2) Sum of simvastatin and simvastatin β-hydric acid: As shown in Table 1-16 and FIG. 15, the sum of ¾ median concentrations of simvastatin and simvastatin-hydroxy acid is different from the time of administration of simvastatin in the liver. It can be seen that the case of overwhelmingly high, which demonstrates that the time-diffusion method is superior to the lipid-lowering effect and low side effect expression compared to the simultaneous administration.

 Table 1-16

Padding bath pretzel ¾ and Shimbashi seutarin ρ- sum Hi ^ ¾ blood at the time of ^slaughter: increased bieul

3) ¾ concentration of amlodipine: The concentration of amlodipine in blood is directly related to the lowering of blood pressure and has the additional effect of increasing lipid lowering effect. Table 1-17

 Blood concentration of amlodipine

As shown in FIGS. 14 to 15, statin-based lipid lowering agents (simvastatin) and statin-based lipid lowering agents represented by wanvastatin and dihydropyridine-based antagonists represented by amlodipine, respectively, are to be differentiated from each other. It has been confirmed that the hyperglycemic concentration of the active transformant (simvastar β-hydroxy acid) is significantly lowered than that of the control group, thereby preventing the side effects of myolysis due to its accumulation. Statin-based lipid-lowering agents are first absorbed by timed administration and converted to the active form in the liver. Inactive metabolites are metabolized and excreted by cytoktom Ρ450 3Α4, followed by dehydrogenated staples. Cyridine-based calcium antagonists, ie, amlodipine, are absorbed by the gastrointestinal tract Inhibitory action on Ρ450 3Α4 this shows no effect does not have to the simvastatin.

In addition, as shown in FIG. 16, the time-difference group had a Tmax (maximum blood concentration attainment time of drug) delayed by about 4 to 5 hours in the dihydropyridine-based chamomile agent represented by amlodipine. At the same time it was taken at 7 o'clock, but it showed the same delayed blood pressure lowering effect as that administered at 12 o'clock in the evening. Thus, the composition according to the present invention, unlike the conventional simultaneous administration group, it can be seen that the average blood pressure has an optimal external blood pressure lowering effect from the morning of the morning to the day of the highest dose ^ hours.

Thus, as in the pharmaceutical preparations of the dihydropyridine-based hem Antagonist and the statin-based lipid lowering agent according to the present invention, when a timed administration is performed, each of the single agents of the dihydropyridine-based hem Antagonist and the statutory lipid-lowering agent It can be seen that not only does it significantly reduce the side effects of statin-based lipid lowering agents, but also results in the clinically optimal effect of dihydroglydine-based calcium antagonists administered for the purpose of lowering blood pressure. Table I-18 shows the results of measurement of lipids between the co-administration group of amlodipine and simvastatin and the time-division group according to the present invention. The time-difference group used the LDL-cholteste of simvastatin administered as a lipid-lowering agent and total compared to the isochronous group of 'Novask tablets (amlodipine 6.944 rag) and' zoco-tablet '(simvastatin 20 mg). It can be seen that it significantly lowered the concentration level of cholesterol. This is not affected by the inhibition of cytokine P450 3A4 enzyme by amlodipine, a dihydropyridine-based calcium antagonist co-administered with the composition according to the present invention, and the total amount of the administered drug is converted into the bowel formation in the liver. This is due to the inhibition of HMG-CoA reductase, which increases cholesterol levels.

 Table 1-18

 Cholesterol rate, HDL, LDL and thick lipid cross-linking girls with inter-dose ¾ foci administration <0.05, p <0.01 vs screening;)

On the other hand, Table 1-19 and Table 1-20 is the result of measuring the blood pressure between the co-administered group of amlodi ¾ and simvastatin and the time difference administration group according to the present invention. The hypotensive action of the dihydropyridine calcium antagonist, amlodipine, was found to significantly decrease the mean left systolic blood pressure and mean left diastolic ¾ pressure in the test group provided by the present invention. The increase in amlodipine hypertension in the administration group was shown to be the actual blood pressure drop in the patient group. As a result of the delayed drug release of amlodipine administered for the purpose of lowering blood pressure with a time difference of about 4 hours as intended by the present invention, it was proved that the time-differentiated group had an excellent blood pressure-lowering effect as compared with the simultaneous-dose group. One

 195

Table 1-19

 Shigin 'Tea Lung and Simultaneous Dialysis Blood Pressure Comparison

(* ρ <0.05, ** p <0.01 va Scr)

Table 1-20

 Pulse rate and pulse rate button

(* p <Q.D5, ** p <O.Oi vs swim ^' )

In conclusion, when the pharmaceutical preparation of the dihydropyridine calcium antagonist and the statin-based lipid lowering agent according to the present invention was administered over time, the single agent of the dihydropyridine-based antagonist and the statin-lowering lipid was simultaneously administered. In addition, the antihyperlipidemic effect of statin-based lipid lowering drugs was more excellent at the same dose than when administered, and the elevated blood pressure-lowering effect of dihydropyridine calcium antagonists administered for the purpose of lowering blood pressure was demonstrated. It can be seen that the optimal effect expression is expected by prolonging the release time. Experimental Example Π-l: Comparative dissolution profile test Nucleic acid tablets (Comparative dissolution profile test) Amlodipine maleate / simvastatin nucleated tablets and the control drug of Example 11-1 above (Zoko: simvastatin monosaccharide, MSD, Novask: amlodipine monosaccharide, Pfizer's comparative dissolution test was carried out. In the case of amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial fluid for 2 hours. The dissolution test method for each component is as follows, and the results are shown in FIG. 17.

According to FIG. 17, simvastatin component of the nucleated tablet of the present invention showed almost the same elution characteristics as the large preparation 2: nose, while the amlodipine component had a dissolution up to 3 hours within this 30¾, and the control formulation was in 1 hour. Compared with the nearly 99% eluted already, the delay was remarkably delayed.

As described above, the nucleotablet of amlodipine maleate / simvastatin of the present invention, unlike the control drug amlodipine single agent, is significantly slower than simvastatin because the initial release of amlodipine is significantly slower than that of simvastarin. Example II-2: Multi-layered Comparative Dissolution Profile Test Example Π—4, 5 and other pharmaceutical preparations of amlodipine malate / simvastatin versus S drug (Cho nose: simvastatin monotherapy, Novasque: Comparative dissolution test of amlodipine single agent) was performed. The dissolution characteristics of the simvastatin and amlodipine components were measured by the following method. In the dissolution test of the amlodipine components, the dissolution test was performed by changing the eluent from artificial gastric fluid to artificial intestine at 2 hours. The results are shown in Fig. 18 and the accompanying drawings.

According to Figure 18, the multi-layered simvastatin component of the present invention showed almost the same dissolution characteristics as compared to the control drug Zoco, while the amlodipine component had a dissolution rate of up to 3 hours all within 40%. Compared with the already eluted 99% eluted it can be seen that significantly delayed elution.

As described above, the multilayer tablet of amlodipine maleate / simvastatin of the present invention has a lower probability of being metabolized in the liver before simvastatin because the initial release of amlodipine is significantly slower than simvastatin, unlike the amlodipine single agent, which is a reference drug. Experimental Example II-3 Comparative Dissolution Profiling Test Comparable Dissolution Profiling Test of Amlodi ¾ Besylate / Simvasta¾ Nucleated Tablets and Reference Agents of Example ii-ii (Zoko: Simvastatin Monotherapy, MSD, Novask: Amlodipine monolith, Pfizer) were tested for dissolution. In the case of amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid from 2 hours. The dissolution test method for each component is as follows, and as a result, it is shown in FIG.

According to FIG. 19, simvastatin component of the nucleated tablet of the present invention showed nearly equivalent dissolution characteristics compared to that of control, whereas amlodi ¾ component showed up to 3 hours of elution within 40% of the control formulation compared to 1 hour. Compared to the already eluted 99% of elution, the elution was significantly delayed.

As described above, the nucleotablet of amlodipine tesylate / simvastatin of the present invention, unlike the control drug amlodipine single agent, because the initial release of amlodipine is much slower than simvastatin, the stroke ** is lowered in the liver before simvastatin.

Experimental Example II-4 ： Comparative dissolution profile test of the two-phase capsule preparation

A comparative dissolution test of the capsule containing the amlodipine besylate / simvastatin complex tablet of Example Π-13 and the reference drug (Zoko: simvastatin monotherapy, MSD, Novask: amlodipine monotherapy, Pfizer) was carried out. In the case of amlodipine component dissolution test, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid for 2 hours. Dissolution test method for each component is shown below, and as a result shown in Figure 20 and the attached drawing.

According to FIG. 20, the simvastatin component of the two-phase capsular formulation of the present invention showed almost the same elution characteristics as that of the control preparation, zoco, whereas the amlodipine component had an elution * of up to 3 hours within 30¾, and the control formulation was used for 1 hour. Compared with the already eluted 99% eluted it can be seen that significantly delayed elution.

As such, the rapeseul containing amlodipine tesylate / wanvasta¾ composite tablet of the present invention is unlikely to receive metabolism in liver cells before simvastatin because the initial release of amlodipine is very slower than simvastatin, unlike the amlodi ¾ single drug, which is a treaty. You lose. Experimental Example III-l: Comparative dissolution profile test of amlodipine-atorvastatin nucleated tablets

Comparative dissolution test of the amlodipine / atorvastatin nucleated tablet prepared in accordance with Example III-1 and the reference drug (lipitor: atorvastatin monolith, Pfizer, Novask: amlodipine monolith, Pfizer) was performed for 2 hours in the amlodipine component dissolution test. The dissolution test was carried out by changing the eluate from artificial gastric fluid to artificial intestinal fluid. The dissolution test method for each component is as follows, and the results are shown in FIG. 21.

According to Figure 21, the nucleated tablet of the present invention was confirmed that the atorvastatin component in the dissolution test under the following conditions almost the same dissolution characteristics compared to the control lipid Lipitor, the amlodipine component is very late dissolution compared to the control formulation Novasque You can check the speed. The nucleated tablet of amlodi ¾ / atorvastatin of the present invention exhibits an excellent delayed-release effect as the dissolution rate of the amlodipine component up to 4 hours is less than 2, which is much lower than the dissolution of the control agent which has already reached about 99% in one hour. Afterwards, it was confirmed that the emission showed a drastic emission up to 80¾ level in about 2 hours.

As described above, the nucleotablet of amlodipine / atorvastatin according to the present invention is significantly delayed in the initial release of amlodipine from atorvastatin, unlike the amlodipine single agent, which is a reference drug, and thus, amlodipine is metabolized in the liver prior to the preparation of atorvastatin. It can be seen that the probability is significantly lowered. Experimental Example II 1-2: Comparative Dissolution Profile Test of Atorvasta ¾-Amlodi ¾ Nucleated Tablets

The comparative dissolution test of amlodipine was performed on the formulations of Example II-1, 2, and 3 above. Dissolution test method of amlodipine was the same as in Example III-1, the results are shown in Figure 22.

22 shows that the controlled release nucleated tablet of the present invention in the dissolution test under the conditions of Example III-1 was coated with enteric polymer after tableting, rather than after mixing the hydrophilic polymer before tableting (Example ΠΙ-1). (Example I II-2) and when coated with water-insoluble polymer after tableting (Example III ᅳ 3), it can be seen that the amlodipine component is released more rapidly after having a delay until the intended time. there was. The elution of the amlodipine component is within 90% for a total of 480 minutes, depending on the type of release control and release control coating. The besylate component was released rapidly.

As described above, the nucleated tablet of atorvastatin / amlodipine of the present invention can rapidly release amlodipine after having a delay time to the intended time by using a release controlling substance. In addition, the nucleated tablet of atorvastatin / amlodipine of the present invention is a atorvastatin single agent and amlodi fragment single agent as a reference. Unlike the elution pattern when taken isochronous, the initial release of amlodipine is much slower than atorvastatin, so that atorvastatin can be metabolized in the liver and the time to regenerate the metabolic enzyme Cytokrum P450 This can reduce the likelihood of side effects. Experimental Example III-3: Comparative Dissolut Ion Profil Test of Atorvastatin-Amlodiphan Two-Phase Matrix Tablets

A comparative dissolution test was conducted for the formulations of Examples 111-6 and 7. Each component solar dissolution test method is the same as Example III-1, and the results are shown in FIG.

23 shows that the controlled release biphasic matrix tablet of the present invention was prepared using a water-insoluble polymer (Example ΙΠ-6) as a binder in the dissolution test under the conditions of Example II-l and coated with a water-soluble polymer after preparation of granules. When (Example ΠΙ-7), the amlodipine besylate component was confirmed to be released relatively rapidly after a delay until the intended time. The elution of the amlodipine besylate component was less than 9 for a total of 480 minutes, and the amlodipine besylate component was rapidly released depending on the release control material and the release control coating.

As described above, the biphasic matrix tablet of the atorvastatin stale / amlodipine besylate of the present invention can rapidly release amlodipine besylate after having a delay time to the intended time by using a release controlling substance.

In addition, the nucleated tablet of atorvastatin calcium / amlodipine besylate of the present invention is different from the dissolution of the atorvastatin calcium monoclonal agent and amlodipine besillay S monoclonal agent, since the initial release of amlodipine besylate is much slower than atorvastatin. The atorvastatin calm is first metabolized in the liver, and thus, it is possible to secure enough time for the metabolism-related enzyme cytokine Ρ450 to be regenerated, thus reducing the possibility of side effects. Experimental Example II 1-4: Blood Concentration Test In this experiment, as a control group, lipitor tablets (atorvastatin scabbard 10.85mg, Pfizer) and Novasque tablets (Besilic acid amlodipine 6.9 ng, Pfizer) were used as the control group. A blood concentration test was performed to confirm the delayed release effect according to the present invention by administering the prepared formulations.

On the other hand, the control group 1, control group 2, the test group for each test group was conducted in six subjects, a total of 18 people, the details are shown in Table ΙΠ-3.

 Table III-3

 Blood concentration test results of atorvastatin by the control group 1 and the test group are shown in Table III-4 (hematoma concentration of atorvastatin) and FIG. 24.

 TABLE ΠΙ-4

 There was no difference in the mean Tmax values between the test and control groups, and there was no significant difference in the Cn x and AUC (0-∞) values.

The blood concentration test result of amlodipine by the control group 2 and the test group is shown in Table III-5 (blood concentration of amlodipine) and FIG. Table πι-5

 It was found that 3 of the amlodipine by the control group 2 was 6.5 hours, and the Tmax of the amlodipine of the test group was delayed by about 3 hours or more compared to the Tma of the amlodipine by the control group 2.

 On the other hand, the Qnax and AUC values of amlodipine were not significantly different between the test and control groups.

 As a result, it was confirmed that by administering the pharmaceutical preparations according to the present invention (Example III-1) at one evening per day, drug interaction depending on the combination prescription could be excluded. Experimental Example IV-1: Comparison of amlodi ¾-Pitavastatin Nucleated Tablets * Experimental (comparative dissolution profile test)

Comparative dissolution experiments of the pitavastatin / amlodi ¾ besylate nucleated tablet prepared in accordance with Example IV-1 and the control drug (Rivaro: Pitavastatin single agent, Chinese medicine, Novasque: amlodipine single agent, Pfizer) were performed. In the dissolution test of the amlodipine component, the dissolution test was carried out by changing the eluate from artificial gastric fluid to artificial intestinal fluid for 2 hours. The dissolution test method for each component is as follows, and ¾ is shown in FIG.

According to FIG. 26, the nucleated tablet of the present invention was found to exhibit almost the same elution characteristics as the atorvastar component in the dissolution test in the following case compared to the reference drug Rivaro, but the amlodipine component compared to the reference drug Novasque. The elution rate of the amlodipine besylate / pitavasti "tin of the present invention is less than 50% of all amlodi ¾ components up to 1 hour of dissolution of the reference drug (about 99%). Much slower than

Thus, the nucleated tablet of amlodipine besylate / pitavasta ¾ of the present invention has a lower rate of metabolism in the liver before pitavastatin because the initial release of amlodipine is much slower than pitavastatin, unlike the amlodipine single agent, which is a reference drug. You lose. Experimental Example IV-2: Comparative dissolution profi le test of Pitavasta ¾-amlodipine nucleated tablets

Comparative dissolution experiments were carried out for the formulations of Examples IV-1, 2 and 3. The dissolution test method for each component was the same as Experimental Example IV-1, and the results are shown in FIG. 27.

27 shows that the nucleated tablets of the controlled release property of the present invention in the dissolution test under the conditions of Experimental Example IV-1 were prepared by enteric coating after tablet tableting (Examples IV-1 and 2) and by preparation of granules by enteric base. (Example IV-3) When the amlodipine component had a delay time to the intended time, it was confirmed that it was released relatively rapidly. The elution of the amlodipine component was less than 9 W for a total of 480 minutes, and the amlodipine component was rapidly released depending on the type of enteric base and enteric coating.

As described above, the nucleated tablet of pitavastatin calcium / amlodipine besylate of the present invention may have a delay time until the intended time by enteric coating and rapidly release amlodipine.

In addition, unlike the dissolution of the phytavastatin scab / amlodipine besylate and other nucleated tablets of the present invention, when phytavastatin stool and amlodipine single agent were taken isochronously, the initial release of the methavastatin besylate was phytavastatin. Since it is much slower than calcium, phytavastatin stag can be metabolized in the liver first, and then the time for regeneration of metabolic enzyme cytokine P450 can be secured, thus reducing the possibility of side effects. Experimental Example IV-3 ： Comparative dissolution procedure of pitavastatin-amlodipine capsule

Comparative dissolution experiments were carried out for the formulations of Examples IV-17 and 18. The dissolution test method for each component is the same as in Example IV-1, and the results are shown in FIG. 28.

According to FIG. 28, the controlled release tablet of the present invention in the dissolution test under the conditions of Experimental Example IV-1 was treated with an osmotic tablet (Example IV-17) and an enteric coating after tablet tableting (Example IV-18). It was confirmed that the Rhodi ¾ component was released relatively rapidly after having a delay until the intended time. The dissolution rate of amlodipine component was within 90% for a total of 480 minutes, and the amlodipine component was rapidly released depending on the type of enteric base and enteric coating.

As described above, the multilayered enteric coating of the pitavastatin scab / amlodipine besylate of the present invention This allows for a rapid delay in the release of amlodipine after having a delay until the intended time.

In addition, the multi-layered tablet of the pitavastatin chame / amlodipine besylate of the present invention, unlike the dissolution of the case of the simultaneous use of the pitavastatin chame single drug and amlodipine besylate monotherapy, the initial release of amlodi ¾ besylate is pitta Since it is much slower than vastatin, phytavastatin calcium is first metabolized in the liver, and thus the time to regenerate the metabolic enzyme cytokrum P450 can be secured, thus reducing the possibility of side effects and the like. V-1: Comparative dissolution profile test of amlodipine-roschvastatin nucleated tablets

Comparative dissolution test of Rochevastared / amlodited besylate nucleated tablets prepared according to Example V-4 and the control drug (Cresto: Roschvasta ¾ single agent, AstraZenecaky, Nosque: amlodipine single agent, Pfizer) In the dissolution test of the amlodipine component, the dissolution test was performed by changing the eluate from artificial gastric fluid to artificial intestinal fluid for 2 hours. The dissolution test method for each component was as follows.

The results are shown in Fig. 29 and the accompanying drawings.

According to FIG. 29, the Roschvastatin component of the nucleated tablet of the present invention was found to exhibit almost equal dissolution characteristics compared to the control formulation Cresto, but the amlodipine component was found to be very slow in dissolution rate compared to the control formulation Novasque. have. Specifically, the nucleophilic tablet of amlodipine / roschvastatin of the present invention had almost no elution of the amlodipine component up to 1 hour after the start of the dissolution test. Could confirm.

As described above, the harmful tablets of amlodipine / roschvastatin of the present invention, unlike the amlodipine single agent, the initial dissolution of amlodipine is much slower than roschvastated, so the chance of metabolism in the liver is lowered before roschvastatin. Experimental Example V-2: Comparative dissolution profi le test of Rochevastatin-Amlodipine Cam

The dissolution test was carried out in the same manner as in Experimental Examples V-1 for the formulations of Examples V-17 and 18, and the dissolution rate of amlodipine in each formulation was measured and shown in FIG. 30. According to FIG. 30, amlodipine in Example V-17 (when semi-permeable coating was applied after tableting) and Jill V-18 (when enteric coating after tableting) was used 1 hour and 30 minutes after the start of elution of roschvastatin. It was only confirmed that the solution eluted rapidly. In addition, the dissolution rate of the amlodipine component was eluted at least 90% within a total of 480 minutes.

Thus Roche bar statin of the present invention / amlodipine kaepseul is then output for the sudden amlodipine besylate and then with a delay by the time the intended also as a semi-permeable membrane coating and an enteric ^coating.

In addition, in the case of Roschvastatin calcium / amlodi ¾ besylate ¾ knee of the present invention, unlike the dissolution of the rosuvastatin calcium monotherapy and amlodipine besylate monotherapy simultaneously, the initial dissolution of amlodipine besylate is Since it is much slower than rochevastatin, Rochevastatin calcium can be metabolized in the liver first, and thus the time for regeneration of the metabolic enzyme cytokine P450 can be secured. . Experimental example ： Comparative dissolution profile test of nifedi piece-atorvastatin nucleated tablets (comparative dissolution profile test)

A comparative dissolution test of the atorvastatin / nifedipine nucleated tablets prepared according to Example VI-1 and the control drug (Lipto: atorvastatin monoclonal procadia XL: nifedipine monolith, abnormal Pfizer) was performed. The dissolution test method for each component is as follows, and the results are shown in FIG.

According to FIG. 31, it was confirmed that the atorvastatin component in the nucleated tablet of the present invention exhibited almost the same elution characteristics as that of the lipitor which is a large preparation, but the nifedipine component was released when compared to the control agent Procadia XL. You can see the time delay.

As described above, the nucleated tablet of atorvastatin / nifedipine of the present invention is different from the dissolution of the atorvastatin monotherapy and nifedipine monoglycerol, which are the reference drugs, so that the initial release of nifedipine is restarted with a time difference between atorvastatin and liver. This isochron may be introduced to prevent metabolic interactions from occurring. Experimental Example VI-2: Comparative dissolution experiment of nifedipine-atorvastatin two-phase matrix tablet The dissolution test of the atorvastatin / nifedipine biphasic matrix tablet prepared according to the above embodiment was carried out. The dissolution test method of nittedipine is as follows, the results are shown as shown in FIG.

32, the biphasic matrix tablet of the present invention can be confirmed that the release delay time is lower when the nifedipine component compared to the control agent Procadia XL (see the release mode of Figure 31) in the dissolution test under the following conditions.

As described above, the two-phase matrix tablet of atorvastatin / nizadipine of the present invention can be prevented by introducing two drugs into the liver and isotopic metabolism because the initial release of nifedipine is initiated with a more time difference than atorvastatin. Experimental Example VI-3 ： Comparative dissolution profile test of nifedi tube-atorvastatin multilayer tablets

Was the display room to Example VI- 8 of atorvastatin / Your jjedi piece multilayer jeongoe elution prepared in accordance with the test, - the test method for the nifedipine is "same dyeo below are shown the same as a result scattered ^Fig 3 attached.

33 shows that the multi-layered tablet of the present invention exhibited a delayed release time when compared to the control agent Procadia XL (see the release mode of FIG. 31) in the dissolution test under the following conditions.

Nature ¾ The multi-layered tablet of atorvastatin / nifedipine of the present invention, since the initial room ¾ of nifedipine is initiated with a much longer time difference than atorvastatin, two drugs may be simultaneously introduced into the liver to prevent metabolic interactions from occurring. Experimental Example VI-4: Comparative dissolut ion profi le test of nifedipine-atorvastatin capsulant

The dissolution test of the atorvastatin / nifedipon capsule prepared according to Example VI-10 was carried out. The dissolution test method of nifedipine is shown below.

_It is shown as ₃₄ .

According to FIG. 34, the capsulicide of the present invention can be confirmed that the release delay time of the nifedipine component is lower than that of the control agent, Profodia XL (see release of FIG. 31), in the dissolution test under the following conditions.

As such, the capsular agent of atorvasta ¾ / nifedipine of the present invention is not an early-release of nidipine. Since it is initiated with a time lag greater than torvastatin, it is possible to prevent two metabolic interactions from taking place simultaneously in the liver.

[Elution test method of each active ingredient]

 [Amlodipine Test Method]

Dissolution test basis ： Dissolution test of the General Test Method of the 8th Amendment of KP ¾

Test crime prevention ： Paddle method, 75 revolutions / minute

Test solution ： 0.01M hydrochloric acid solution, 750mL (0 2 hours)

 H 6.8 artificial intestine, l, OO0mL (after 2 hours)

Analysis method ： Self-visible absorption spectroscopy (sword * wavelength = maximum 240 nm)

[Lercanidipine Test Method]

Dissolution test basis ： Dissolution test method of General Test Method

Test method ： Paddle method, 75 revolutions / minute

Test solution ： 0.01M hydrochloric acid solution, 750inL (0 ~ 2 hours)

 pH 6.8 artificial intestine, l, 000 mL (after 2 hours)

Analysis method ： High speed liquid chromatography method

Detection wavelength: 356 nra

Secondary phase ： Acetonitrile] ¾ ： 0.0IM Phosphate complete solution = 45 ： 55 (pH = 4.0)

 ¾ lum: octadecylylated into a stainless steel tube of 4.6 mm in diameter and 250 mm in length

Flow rate: 1.0 mL / min

[Racidipine Test Method]

Dissolution test basis ： Dissolution test method of General Test Method

Test method ： Paddle method, 75 revolutions / minute

Test solution ： 0.01M hydrochloric acid solution, 750mL (0 ~ 2 hours)

 PH6.8 intestinal fluid, l, 000mL (after 2 hours)

Analysis method ： High speed liquid chromatography method

Detection Wavelength: 282iM

Mobile phase ： Acetonitrile ： 0.05M ammonium acetate buffer = 80 ： ² 0

Column: ¾ octadecylsilylated into a stainless steel tube of 4.6 mm in diameter and 250 mm in length Flow rate ： l.OmL / min

[Pelodipine Test Method]

Dissolution test basis ： Dissolution test method of General Test Method

Test method ： Paddle method, 50 revolutions / minute

Test solution ： 0.01M hydrochloric acid solution, 750 mL sodium lauryl sulfate, 2¾ (0-2 hours)

 pH 6.8 artificial intestinal fluid, l, 000nL-sodium lauryl sulfate, 2% (after 2 hours) Analytical method: UV-visible absorption spectroscopy (detection wavelength = max. 254nm)

[Isradipine Test]

Dissolution test basis ： Dissolution test method of General Test Method in the 8th Amendment of KP

Test method ： Paddle method, 50 hee / min

Test solution ： 0.011 hydrochloric acid solution, 750 mL sodium lauryl sulfate, 2¾ (0-2 hours)

 pH 6,8 artificial intestine, l, 000aiL-lauryl sulfate, 2% (after 2 hours) Analytical method: UV-visible photometry (detection wavelength = maximum 328 nm)

[Nifed D¾ test method]

Dissolution Test Basis ： Condensation Test Method of General Test Method

Test method ： Paddle method, 100 revolutions / minute

Test solution ： 1% Lau ¾ sodium sulfate, pH 6.8 phosphoric acid complete solution, 900mL (0 ~ 24 hours)

Analysis method ： High speed liquid chromatograph method (detection wavelength: 350 nm)

[Simvastatin test method]

Dissolution Test Basis ： 'Simvastatin tablet ¹ of the US Pharmacopeia (USP 29)

Test Method: Paddle method, 50 revolutions / minute

Test solution ： pH = 7.0 complete layer solution (composition = 0.0M sodium dihydrogen phosphate solution containing 0.5% increase / increase in sodium lauryl sulfate as surfactant), 900 mL

Analysis method ： Self-visible absorption spectroscopy (detection wavelength = maximum 247, minimum 257 nm)

[Lovastatin Test Method]

Dissolution test basis ： 'Lovastatin tablet' in US Pharmacopoeia JSF 29) Test method ： Paddle method, 50 revolutions / minute

Test solution ： pH = 7.0 complete layer solution (composition = 0.01M sodium dihydrogen phosphate solution containing about an increase / extension of sodium lauryl sulfate as a surfactant), 900 mL

Analysis method ： High speed liquid chromatography method

Detection wavelength ： 230nra

Secondary phase ： Acetonite ¾ ： 0.02M Sodium dihydrogen phosphate complete solution (pH-4.0) ： Methane = 5 ： 3 ： 1

 ¾Rum ¾ octadecyl ¾ in a stainless steel pipe with a diameter of 4.6 麵 and a length of 250 mm ¾ flow rate ： 1.5raL / min

[Atorvastatin test method!

Dissolution test basis ： Dissolution test method of General Test Method

Test method ： Paddle method, 50 revolutions / minute

Test solution ： PH = 7.0 complete layer solution (composition = 0.01M sodium dihydrogen phosphate solution containing sodium lauryl sulfate increase / increase as surfactant), 900mL

Analysis method ： High speed liquid chromatography method

Detection wavelength ： 247

Secondary phase: Methane: 0.025M sodium dihydrogen phosphate complete solution (pH-4.0) = 67:33 (pH = 4.0) Column: ¾ velocity of octadecylsil ¾ in a stainless steel tube with inner diameter of 4 · 6ΙΜ and length of 250 匪： 1.5mL / min

[Fluvastatin Test Method]

Dissolution test basis ： 'Fluvastat in capsules' in USP 30

Test method ： Paddle method, 50 revolutions / minute

Test solution ： Purified water, 900mL

Analysis method ： High speed liquid chromatography method

Detection wavelength: 235nm

Secondary phase: Methane / acetonitrile (3: 2) mixture: 0.016 M Ammonium dihydrogen phosphate complete solution (pH 3.5) = 7: 3

Column ： 4.6 瞧 of inner diameter, gel flow rate of octadecyl ¾ in a stainless steel tube of length 100mm: 2.0mLJ min [Pitavastatin Test Method]

Dissolution test basis ： Dissolution test method of General Test Method

Test method ： Paddle method, 50 ghee / min

Test solution ： 0.0 hydrochloric acid solution, 750 mL (0-2 hours)

pH 6.8 artificial intestine, l, 000 mL (after 2 hours)

Analysis method ： Ultraviolet-visible absorption spectrophotometry (detection wavelength-254 nra)

[Rochevastatin Test Chamber ¾]

Dissolution test basis ： Dissolution test method of General Test Method

Test method ： Paddle method, 50 revolutions / minute

Test solution ： 0.01M hydrochloric acid solution, 750mL (0 ~ 2 hours)

 6.8 artificial intestine, l.OOOmL (after 2 hours)

Analysis method ： Self-visible absorption spectrophotometry (detection section = 220 nm)

 【¾ Business Availability】

 As described above, the present invention is a so-called time difference dosing therapy (Chronotherapeutics) that maximizes the therapeutic effect on the basis of heterogeneous drug metabolism (Xenobiotics) to improve the side effects that can occur in combination with heterologous drugs from the pharmaco-isotopic perspective (Chronotherapeutics) ), Which is a compound that affects or inhibits the same enzyme cytokine P 450-based enzyme or inhibits enzyme activity, and reacts with a combination of dihydropyridine-based calm antagonist and statin-lipid lowering agent as an active ingredient, Differential use of time-releasable substances and immediate-release substances to control the elution time in the body allows the active ingredient to be delivered at a specific rate at a timed interval. Pharmacology and prevention in the prevention and treatment of chronic circulatory diseases Chemical, useful functionality than the time difference in scientific and economic ruyeo may Kane realize pharmaceutical pharmaceutical preparations.

 . In addition, according to the present invention by configuring the release rate of the drug differently can prevent the effect of ¾ anti-action and side effects between the weak fire and obtain synergistic effect of isochronism. In addition, according to the present invention, since the complex preparation can be taken at a time, it is easy to guide the medication and the medication of the patient.

Claims

 [Range of request]  [Claim 1] Dihydropyridine-based kalseum holding ¾ blockers, and his reason jilchye, or a pharmaceutically coming ^"acceptable salt thereof as an active ingredient, and the prepared granules The delayed-release compartment and a star tingye lipid-lowering agent as an active ingredient, pel ¾ Or a capsular agent comprising a prior release compartment made into a tablet.  [Claim 2]  As a dihydropyridine-based chamomile channel blocker, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, or as a delayed-release compartment and a star ¾ type hypolipidemic active ingredient prepared as a tablet, granules, ¾ A pharmaceutical formulation which is a capsulting agent comprising a pre-release compartment prepared from a let, or tablet.  [Claim 3]  (a) a delayed-release compartment comprising, as an active ingredient, a dihydropyridine-based calcium antagonist, an isomer thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  (b) a pre-release compartment comprising a statin-based lipid lowering agent, an isomer thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and (c) the delayed-release compartment and the pre-release compartment together. A pharmaceutical formulation which is a kit comprising a container means for stratification.  [Claim 4]  It contains dihydropyridine-based chamois blocker as an active ingredient, a sustained-release compartment made of tablets and a statin-based lipid lowering agent as an active ingredient, and a pre-release compartment coated on the surface of the delayed-release compartment. A pharmaceutical formulation that is a coating tablet consisting of.  [Claim 5]  The active ingredient is a dihydric apyridine calcium channel blocker as an active ingredient, and a delayed-release compartment and a statin-based lipid lowering agent as an active ingredient, including an osmotic pressure-controlling agent, which constitute an inner core that releases wastewater by osmotic cancer. A pharmaceutical formulation that is an osmotic nucleated tablet comprising a prerelease compartment constituting an outer layer.  [Claim 6] The said dihydropyridine-based knife chest in any one of Claims 1-5. Channel Blocker A pharmaceutical formulation with controlled release to be absorbed in the liver 2 to 4 hours later than gastatin-based lipid lowering agents. [Claim 7]  The dihydropyridine-based chamomile ¾ blocker according to any one of claims 1 to 5, wherein the dihydropyridine-based chamomile ¾ blocker is amlodipine, lercanidipine, lassidipine, ¾-rhodipine, vanidipine, benidipine, silnidipine, isradipine, and mani. A pharmaceutical formulation which is at least one selected from dipine, nicardipine, nifedipine, nimodipine, nilvadipine, nisulodipine, nirenedipine a¾nidi ¾ an isomer thereof, and pharmaceutically acceptable.  [Claim 8]  The pharmaceutical preparation according to claim 7, wherein the dihydropyridine-based calm channel blocker is included in the range of 1 to 400 mg of the agent.  【Claim 9 ½  The method according to any one of claims 1 to 5, wherein the star ¾ lipid lowering agent is simvastatin, lovastatin, atorvastated, pitavastatin, rosuvastated, flutvastatin, pravastatin, isomers thereof, and A pharmaceutical formulation which is a combination of at least one selected from pharmaceutically acceptable salts thereof.  [Claim 10]  A releasing compartment comprising simvastatin, an isomer thereof, or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and a releasing compartment comprising amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient; Pharmaceutical formulations comprising.  [Claim 11]  A pharmaceutical formulation comprising a prior-release compartment comprising atorvastatin as a pharmacologically active ingredient, or a pharmaceutically acceptable salt thereof, and a federally-released compartment comprising amlodipine or a pharmacologically acceptable salt thereof as the pharmacologically active ingredient. [Claim 12] Pharmaceutical formulation comprising a prior-release compartment comprising pitavastatin or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient and a federally-released compartment comprising amlodipine or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient . [Claim 13] Delayed-release compartments comprising roschvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient and delayed-release compartments comprising amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient Pharmaceutical preparations comprising the compartments.  [Claim 14]  A pharmaceutical formulation comprising a sustained release compartment comprising atorvastatin or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient and a delayed release compartment comprising nifedipine or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. [Claim 15]  15. The release control according to any one of claims 1 to 5 and 10 to 14, wherein the delayed-release compartment is selected from enteric polymers, soluble polymers, hydrophobic compounds, hydrophilic polymers and mixtures thereof. Pharmaceutical formulations comprising one or more substances.  [Claim 16]  The pharmaceutical preparation according to claim 15, wherein the enteric high difference is at least one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric maleic acid copolymer, an enteric pulley vinyl derivative, and a mixture thereof. . [Claim 17] 17. The method of claim 16, wherein the enteric salulose derivative is hydroxypropyl methyl gel cellulose acetate succinate, hydroxy propyl metal sal cellulose phthalate, hydroxy propyl methyl cellulose cellulose phthalate, cellulose acetate phthalate, ^ Cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxy methethyl cellulose, ethyl hydrate At least one selected from ¾ ¾ hydroxyphthalate in hydroxy, ¾ ¾ in methyl hydroxy and mixtures thereof; The enteric acrylic acid-based co-polymers include sty¾-acrylic acid copolymer, arc ¾ acid ¾-acrylic acid copolymer, arc ¾ acid methyl methacrylate ¾ acid copolymer, butyl acrylate-styrene-acrylic acid copolymer, detac ¾ acid-meta At least one selected from methacrylic acid ¾ copolymer, methacrylic acid '' ethyl acrylate copolymer, methyl acrylate-methacrylic acid-acetic acid octyl copolymer and mixtures thereof; remind The enteric maleic acid-based co-polymerization is composed of vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride co-polymer, styrene-maleic acid monoester copolymer, vinyl methyl ether monomaleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl ether-end lane anhydride copolymer, acrylonitrile-methyl methacrylate-maleic anhydride copolymers, acrylic acid portion ¾- ^Stevenage, alkylene-maleic anhydride copolymers, and represents at least one member selected from mixtures thereof increased; The enteric polyvinyl derivative is at least one pharmaceutical agent selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, and polyvinylacetate: acetal phthalate and other combinations thereof.  [Claim 18] 16. The method of claim 15, wherein the water-insoluble polymer is selected from the group consisting of 리 livinyl acetate, fully methacrylate co-polymers, * li (ethylacrylic≤-methyl methacrylate) co-polymers, pulleys (ethyl acrylate ¾-methyl 쩨). Tac ¾-trimethylaminoethyl methacrylate), a notary copolymer, ¾ cellulose, cellulose ester, ¾ cellulose ether, cellulose acylate, ¾ ose dicylate, cellulose triacyl A pharmaceutical formulation which is at least one selected from the group consisting of latex, cellulose acetate _> salulose diacetate, cellulose triacetate, and combinations thereof.  [Claim 19]  The pharmaceutical preparation according to claim 15, wherein the hydrophobic compound is at least one selected from fatty acids and fatty acid esters, fatty acid alcohols, waxes, inorganic substances, and common substances thereof.  [Claim 20]  20. The method according to claim 19, wherein the fatty acid and fatty acid esters are selected from glyceryl gulmito stearate, glycerol ¾ stearate, glyceryl bilatenate, cetyl gulmitate, glyce ¾ monoacrylate, stearic acid and combinations thereof. At least one; The fatty acid alcohols are at least one selected from cetostea ¾ alcohol, three ¾ alcohols, stearyl alcohols, and mixtures thereof; The waxes are at least one selected from carnauba wax, beeswax, microcrystalline wax, and combinations thereof. The inorganic materials include talc, precipitated calcium carbonate, hydrogen dihydrogen phosphate, zinc oxide, titanium oxide, chlorine, At least one pharmaceutical agent selected from bentonite, montmorillonite, non-gum and combinations thereof, [Claim 211 The method of claim 15, wherein the hydrophilic polymer is a saccharide, cellulose derivative, gum, Proteins, pulley vinyl derivatives, plymethac ¾late co-polymers, polyethyl¾ derivatives. A pharmaceutical formulation which is at least one selected from carboxyvinyl copolymers and mixtures thereof. [Claim 22]  22. The method of claim 21, wherein the sugar is dextrin, plydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogal lactan, starch, hydroxypropylstarch, amylose At least one selected from, amylopectin and combinations thereof; The cellulose derivatives are hydroxypropyl methyl cellulose, hydroxy propyl cellulose, hydroxy metal cellulose, hydroxy ether cellulose, methyl cellulose, carboxymethyl cellulose, hydroxy hydroxy. At least one selected from propylmethyl¾rose acetate succinate, hydroxyethylmethylcellose and mixtures thereof; The gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, xanthan gum and other mixtures; The protein is at least one selected from casein, casein, and combinations thereof; The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyridone, polyvinyl acetaldie ¾amino acetate and mixtures thereof; The polymethacrylate copolymer is ple (butyl methacrylate ¾, (2-dimethylaminoethyl) methacrylate-methyl methacrylate) co-polymer, ple (methacrylate-meth ¾ methacrylate) notarization At least one selected from coalescing and pulley (methacrylic acid-ethylacrylate) co-polymers, and mixtures of isopium; The lyethylene derivative is at least one selected from boleyethylene glycol, polyethylene oxide and other complications; The carboxyvinyl polymer is a carbomer.  [Claim 23]  The pharmaceutical formulation according to any one of claims 10 to 14, wherein the formulation is in the form of a two-phase matrix tablet obtained by tableting after the delayed-release compartment and the prior-release compartment are uniformly mixed.  [Claim 241  The pharmaceutical formulation according to any one of claims 10 to 14, wherein the pharmaceutical formulation is in the form of a peel-coated tablet consisting of a tablet consisting of a delayed-release compartment and a film-coating layer consisting of a prior-release compartment surrounding the denture of the tablet. Pharmaceutical preparations.  [Claim 25] The method according to any one of claims 10 to 14, wherein the pharmaceutical formulation is A pharmaceutical formulation in the form of a multi-layered tablet in which the federally-released compartment and the prior-release compartment are layered. [Claim 26]  15. The pharmaceutical composition according to any one of claims XX to 14, wherein the preparation is in the form of a nucleated tablet consisting of the inner nucleus tablet consisting of a delayed-release compartment and a prior-release compartment enclosing the outer surface of the inner core. Formulation.  [Claim 27]  The pharmaceutical formulation of claim 26, wherein the nucleated tablet is an osmotic nucleated tablet.  [Claim 281  The method of claim 10, wherein the pharmaceutical agent comprises particles, granules, 3/4, or tablets consisting of delayed-release compartments and particles, granules, 3/4, or tablets composed of prior-release compartments. A pharmaceutical formulation in the form of a capsule containing. [Claim 29]  The pharmaceutical formulation according to any one of claims 10 to 14, further comprising a coating layer on at least one exterior of said delayed-release compartment or said prior-release compartment syndrome.  [Claim 30]  The pharmaceutical formulation of claim 10, wherein the delayed-release compartment comprises an osmotic pressure modifier and is coated with a semipermeable membrane coating base.  [Claim 31]  31. The method of claim 30, wherein the osmotic pressure regulator is magnesium sulfate, magnesium chloride, sodium chloride, potassium chloride, sodium phosphate, calcium phosphate, ammonium acetate, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate product, And at least one selected from the group consisting of a mixture of idols.  [Claim 32] 31. The method of claim 30, wherein the semipermeable membrane coating base is * rivinyl acetate, ply methacrylate co-polymer, poly (ethyl arc ¾ate, meth meth ¾ hydrate) copolymer, poly (ethyl acrylate, meth) ¾ methacrylate ¾tate, trimethylaminoethyl waste methacrylate), not only acerose, aryl salose, cell 1 "rose ester, cellulose ether, cellulose acylate, ^■ € diacetate , Cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and combinations thereof. [Claim 33]  The pharmaceutical formulation according to any one of claims 10 to 14, which is in the form of a coated tablet further comprising a coating layer on the outside.  [Claim 34]  The pharmaceutical formulation according to any one of claims 10 to 14, wherein the formulation is in the form of a kit comprising a open release compartment and a prior release compartment.  [Claim 35]  The pharmaceutical formulation according to any one of claims 10 to 14, wherein the formulation is for evening administration.  [Claim 36]  15. A method for treating cardiovascular disease, comprising administering a pharmaceutical agent of any one of claims 1 to 5 and 10 to 14 to a mammal.  [Claim 37]  The pharmaceutical formulation of claim 10, wherein simvastatin releases at least 80¾ of the total amount of simvastatin in the formulation within 1 hour after the start of release thereof.  [Claim 38]  The pharmaceutical formulation of claim 10, wherein the amlodipine is released 1 hour after the start of simvastatin release and release is complete within 8 hours.  [Claim 39]  The pharmaceutical formulation of claim 38, wherein the amlodipine is released within 40% of the total amount of the unit formulation within 3 hours after initiation of simvastatin release.  ί claim 40】  The pharmaceutical formulation of claim 10, wherein the simvastatin is in the range of 1 to 160 mg in the pharmaceutical formulation. -Claim 41  The pharmaceutical formulation of claim 10, wherein the amlodipine is in the range of 1-40 mg of the pharmaceutical formulation.  [Claim 42]  The pharmaceutical formulation of claim 10, wherein the delayed-release compartment comprises an enteric polymer and a hydrophilic polymer as release controlling substances. [Claim 43] 16. The enteric polymer of claim 10, wherein the enteric polymer is polyvinylacetate phthalate, hydroxypropylmethylcellose phthalate, shellac, ¾looseacetate phthalate, ¾loosepropionate phthalate fleece (methacrylyl). A pharmaceutical formulation which is at least one selected from a mixture of latex, methylmethacrylate) copolymers and poly (decacrylate), ethylacrylate) copolymers and idols.  [Claim 44]  43. The method of claim 42, wherein the enteric polymer is polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, «lac, cell * looseacetate: phthalate, salose propionate phthalate, * li (meth). Pharmaceutical formulations of at least one selected from acrylate, methylmethacrylate) copolymers and poly (methacrylate, ethylacrylate) copolymers and their common condition.  [Claim 45]  The water-insoluble polymer of claim 10, wherein the water-insoluble polymer of claim 10 is selected from the group consisting of polyvinyl acetate, polymethacrylate co-polymer, pulley (ethacrylate-methyl decacrylate) copolymer, pulley (ethyl arc ¾tate, meth). A pharmaceutical formulation which is at least one selected from methacrylate, ¾ meth ¾ rate) copolymer of trimethylamino, ethyl cellulose, cellulose acetate, and combinations thereof.  I claim 46]  The hydrophilic polymer of claim 10, wherein the hydrophilic polymer of claim 10 is starch, hydroxypropyl methyl cellulose, hydroxyspecific propyl cellulose, carboxy ¾ ¾ sodium, xanthan gum, polyvinyl alcohol, carboxy A pharmaceutical formulation selected from the group consisting of vinyl polymers and combinations thereof.  [Claim 471]  43. The method of claim 42, wherein the hydrophilic polymer is starch hydroxypropylmethylcellulose, hydroxypropyl cellulose, carboxymethylshell natsucom, xanthan gum, polyvinyl alcohol, carboxyvinyl polymer and mixtures thereof Pharmaceutical agents selected from the group consisting of.  (Claim 48)  The pharmaceutical preparation according to claim 15, wherein the release controlling substance of claim 10 is contained in an amount of 0.1 to 100 parts by weight based on 1 part by weight of amlodipine. [Claim 49] 16. The method of claim 15, wherein the release controlling material of claim 10 is selected from the group consisting of ¾ vinyl acetate, poly meth ¾ copolymer, poly (ethyl acrylate, methyl meth acrylate, trimethyl aminoethyl meth acrylate) copolymer, Carbocyvinyl Plymer, Ethyl Cellulose, Cellulose Loose Acetate, Cartuxylmethyl Cellulose Sodium, Polyethylene Oxide, Hydroxypropylmethyl Cell ^■ Looset Hydroxypropyl ^ Loose, and Hydroxy At least one pharmaceutical agent selected from the group consisting of propylmethylshello-osphthalate. [Claim 50]  50. The pharmaceutical formulation of claim 49, wherein the release controlling substance is at least one selected from the group consisting of carboxyvinyl plymer, hydroxypropyl methylzelotose, and hydroxypropylmethylsalosephthalate.  [Claim 51]  50. A pharmaceutical formulation according to claim 42 or 49 wherein the release controlling substance is a mismatch of carboxyvinyl polymer and hydroxypropylmethylcellose.  [Claim 52]  The pharmaceutical formulation of claim 11, wherein the atorvastatin releases at least 90% of the total amount of atorvastatin in the unit formulation within 1 hour after the release of the atorvastatin.  [Claim 53]  The pharmaceutical formulation of claim 11, wherein the amlodipine is released after 1 hour of atorvastatin release and completes release before 8 hours.  [Claim 54]  54. The pharmaceutical formulation of claim 53, wherein the amlodi ¾ is released one hour after atorvastatin release and completes release 6 hours prior.  [Claim 55]  55. The pharmaceutical formulation of claim 53, wherein the pharmaceutical formulation releases within 20% of the total amount of amlodipine in the unit formulation within 4 hours after initiation of atorvastatin release. (Claim 56)  12. The pharmaceutical formulation of claim 11, wherein the amlodipine is selected from the group consisting of (S) isomers, (R) isomers, and racemates.  [Claim 57] The pharmaceutical composition of claim 11, wherein the atorvastatin is selected from the group consisting of (RI?) Isomer, (RS) isomer (SR) isomer, (SS) isomer, and racemate. Preparations.  [Claim 58]  The pharmaceutical formulation of claim n wherein the delayed-release compartment comprises a release controlling substance that is a mixture of an enteric polymer and a hydrophilic polymer. [Claim 59] ^'  The pharmaceutical preparation according to claim 58, wherein the enteric polymer and the hydrophilic polymer are included in an amount of 0.5 to 10 parts by weight and 0.5 to 20 parts by weight relative to 1 part by weight of amlodipine, respectively.  [Claim 60] 60. The enteric polymer according to claim 58 or 59, wherein the enteric polymer is hydroxypropylme ¾cell as a enteric cellulose derivative, hydroxyacetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxymeth ¾ethylcello Phthalate, rhorose acetate phthalate, ¾ loose acetate succinate, cellulose acetate maleate, ¾ loose benzoate phthalate, cellulose looxate phthalate, methyl cellulose loose phthalate, carboxymethyl One or more selected from ethyl ¾, ethoxy-specific ethyl salose, cellulose phthalate, and methyl hydrate specialty salose; Enteric acrylic acid copolymers include styrene-arc ¾ acid copolymer, methyl acrylate-arc acid copolymer, methyl methacrylate acrylate, arc ¾ butyl-styrene-acrylic acid copolymer, methacrylic acid-methacrylic ¾ sanme ¾ notary hapchae, straighten] ^■ other methacrylic acid ethyl acrylate copolymer, and methyl acrylate-methacrylic acid - at least one selected from the group consisting of octyl acrylate copolymer; Enteric maleic acid-based copolymers, vinyl acetate-maleic anhydride co-polymers, styrene-maleic anhydride co-polymers, styrene-maleic acid monoester copolymers, vinyl methyl ether-maleic anhydride co-polymers, ^' ¾- maleic anhydride copolymers At least one selected from a portion of ¾ether-maleic anhydride copolymer, an acrylonitrile ¾-methyl methacrylate maleic anhydride copolymer, and an arc ¾ acid ¾-styrene-maleic anhydride copolymer; And an enteric polyvinyl derivative ¾ ^«■ polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl replicon butynyl ray bit phthalate and polyvinyl least one selected from acetaminophen acetal phthalate and the common at least one selected from the compounds increase, The hydrophilic polymer is a cellulose derivative as hydroxypropylmethylcellose, hydroxypropylcellose, hydroxymethylgelose, hydroxyethylcellose, methylcellose, carboxymethylyl Osmote 1 ", hydrisopropyl tertylcellose acete Two or more selected from succinate, and hydroxyethyl de¾¾; At least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, and xanthan gum; At least one selected from ¾ Latin, Casein, and Jane's as proteins; At least one selected from polyvinyl alcohol, polyvinyl pyridone, and polyvinylacetal to ¾aminoacetate as the polyvinyl derivative; Pulley (part ¾ methacrylate— (2-dimethylaminoethyl) methacrylate ¾ latexetyl decacrylate) copolymer, poly (methacrylate acid- methyl methacrylate) co-polymer as polymethacrylate notary At least one selected from the group consisting of Ply (detax-acid-ethylarc ¾rate) copolymer; A pharmaceutical formulation comprising at least one selected from polyethylene glycol as a ¾ polyethylene derivative, and polyethylene oxide, and at least one selected from carbomer and combinations thereof.  [Claim 61]  The pharmaceutical formulation of claim 11, wherein the Amlodi ¾ comprises 1 to 20iii g of unit dosage.  [Claim 62]  The pharmaceutical formulation of claim 11, wherein the atorvastatin is comprised between 5 and 160 mg in unit dosage form.  [Claim 63] The method of claim 15, wherein the release control material of claim 11 is polyvinylacetate, poly meth ¾ copolymer, carboxyvinyl polymer, hydroxy propyl metal cellulose, hydroxy propyl 프로필 € 쎌, chloro the pharmaceutical preparations agarose acetate, ethyl ssaelreul as agarose, polyethylene oxide, and hydroxypropyl methyl group consisting selreul by agarose phthalate is from ^"over one selected species.  [Claim 64] _R the release-controlling material is Murray carboxyvinyl pulleys, poly greater ¾ les sites Notary pharmaceutical preparation copolymers and hydroxypropyl methoxy ¾ from the group consisting of agarose in selreul least one selected according to claim 63.  [Claim 65]  64. The pharmaceutical formulation according to claim 58 or 63, wherein the release controlling substance is carboxyvinyl polymer and hydroxypropyl methcellose. [Claim 66] 13. The pharmaceutical formulation of claim 12, wherein the pitavastatin of the prior-release compartment releases at least 80¾ of the total amount of pitavastatin within 15 minutes after initiation of release.  [Claim 67]  The pharmaceutical formulation of claim 12, wherein the amlodi ¾ is released 2 to 4 hours after initiation of pitavastatin release.  [Claim 68]  13. The pharmaceutical formulation of claim 12, wherein the pitavastatin is comprised between 1 and 20 mg of the formulation.  [Claim 69]  13. The pharmaceutical formulation of claim 12, wherein Sing 'group Pitavasta ¾ is an isomer thereof and said amlodipine is selected from the group consisting of (S) isomer, (R) isomer, and racepiche.  Claim Port 701  13. The pharmaceutical formulation of claim 12, wherein the amlodide is comprised between 1 and 20 mg of a formulation.  [Claim 71]  The pharmaceutical formulation of claim 12, wherein the amlodi ¾ is released up to 40¾ of the total amount of the unit dosage up to 4 hours after initiation of pitavastatin release.  [Claim 72]  13. The pharmaceutical formulation of claim 12, wherein the delayed-release compartment comprises a controlled release hook which is a combination of a soluble polymer and a hydrophilic polymer.  [Claim 73]  The pharmaceutical preparation according to claim 15, wherein the release controlling substance of claim 12 is contained in an amount of 0.05 to 100 parts by weight based on 1 part by weight of amlodipine.  [Claim port ¾] 73. The method of claim 72, wherein the water-insoluble polymer is polyvinyl acetate, pullimethac ¾late copolymer, poly (ethylacrylate-methyl methacrylate) copolymer, ¾ ((¾acrylate-methyl methacrylate). ¾ methacrylate ¾) copolymer, ethyl cellulose, cellulose ester, ¾ ether, loose acylate, cellulose dicylate, cellulose triacylate, Shellloose Acetate, Cellulose Diacetate, ¾ Loose Triacetate and mixtures thereof Was chosen from the ruined army, The hydrophilic polymer is a hydroxypropyl methyl cellulose, a hydroxy propyl cellulose, a hydroxy methyl cellulose, a hydroxy methyl cellulose, a cellulose methyl cellulose, a carboxymethyl cellulose as a cellulose derivative. sodium, ^■ & ideu hydroxypropyl methyl "for a trehalose acetoxy Te byte succinate, and a ¾ methoxy ¾ selreul the hydroxy ethoxy one or more selected from the agarose increases; as gum guar gum, locust bean gum, tragacanth, carrageenan, acacia One or more selected from gums, gum arabic, gellan gum, and xanthan gum; one or more selected from gelatin, casein, and zeinosis as proteins; polyvinyl alcohol, pulley vinyl pyridone, and polyvinyl as polyvinyl derivatives At least one selected from acetaldiethylaminoacetate solution; as a polymethacrylate copolymer, ple (butyl methacrylate ¾- (2-dimethylamino Butyl) methac ¾ late-methylmethacrylate) co-polymer, pulley (methacrylic acid—methyl methacrylate) co-polymer, and poly (waste ¾-ethyl acrylate) ^ At least one selected from the group consisting of polypropylene ethylene, a polyethylene derivative, and at least one selected from several polyethylene oxides; a pharmaceutical formulation comprising at least one selected from carbomers and combinations thereof as carboxyvinyl polymers.  [Claim 75]  16. The method of claim 15, wherein the emission control material of claim 12 is a hydroxy propyl cellulose, hydroxy propylmethyl ¾, hydroxy propyl methyl cellulose phthalate, cellulose acetate, polyvinylacetate, Polyvinylpyridone, ¾ ethylene oxide, polymeth ethylene ¾ copolymer, ethyl cellulose, pulley (meth acrylate methyl methacrylate) copolymer and methyl methacrylate methacrylic acid copolymer One or more pharmaceutical agents selected.  [Claim 76]  76. The method of claim 72 or 75, wherein the controlled release material comprises a group consisting of hydroxyelethane, ¾, cellulose, cellulose, and poly (methacrylate methylmethacrylate ¾) copolymer. At least one pharmaceutical agent selected from.  [Claim 77]  14. The pharmaceutical formulation of claim 13, wherein said Roschvastatin releases at least 80¾ of the total amount of Roschvastatin within 15 minutes after initiation of release. [Claim 78] 14. The pharmaceutical formulation of claim 13, wherein said amlodipine is released 2 hours after initiation of roschvastatin.  [Claim 791  The pharmaceutical formulation of claim 13, wherein the amlodipine is released within 20¾ of the total amount of amlodi ¾ in unit dosage form within 3 hours after the start of elution of roschvastatin.  [Claim port 80J  The pharmaceutical formulation of claim 13, wherein the amlodi ¾ is released within 8 hours.  [Claim 81]  The pharmaceutical formulation of claim 13, wherein the rochevastatin is 5 to 80 mg in the formulation.  [Claim 82] The pharmaceutical formulation of claim 13, wherein the amlodipine is 1-20 m in the formulation. [Claim 83]  The pharmaceutical formulation of claim 13, wherein the delayed-release compartment is at least one selected from enteric polymers and soluble polymerases.  ί claim 84】  The pharmaceutical body according to claim 15, wherein the release controlling substance of claim 13 is included in an amount of 0-05 to 100 parts by weight based on 1 part by weight of amlodi ¾.  [Claim 85]  The pharmaceutical formulation according to claim 15, wherein the enteric polymer of claim 13 is at least one selected from arc ¾ methyl meth ¾ acid copolymer and hydroxypropylmethyl ¾ rossosphthalate.  [Claim 86]  The pharmaceutical preparation according to claim 15, wherein the enteric polymer of claim 13 is 0.1 part by weight to 20 parts by weight with respect to 1 part by weight of amlodipine.  [Claim 87] 16. The method of claim 15, wherein the water-insoluble copolymer of claim 13 is a polyvinylacetate, cell cellulose acetate and pulleys (ethyl arc ¾ rate- meth meth ¾ rate- trimethylamerno ethyl methacrylate ¾) copolymer At least one pharmaceutical agent selected from among. [Claim 88]  The pharmaceutical formulation of claim 15, wherein the water-soluble polymer of claim 13 is included in an amount of 0.1 to 30 parts by weight based on 1 part by weight of amlodipine.  [Claim 891  The pharmaceutical preparation according to claim 15, wherein the hydrophobic compound of claim 13 is 1 to 20 parts by weight based on 1 part by weight of amlodipine.  [Claim 901  16. The pharmaceutical formulation of claim 15 wherein the hydrophilic polymer of claim 13 is from 0.05 to 30 parts by weight relative to 1 part by weight of amlodi ¾.  [Claim 911  16. The method of claim 15, wherein the release control material of claim 13 is hydroxyspecific methyl cellulose, hydroxypropyl methyl cellulose, hydroxy propyl methyl cellulose phthalate, cellulose acetate, polyvinylacetate, polymeta At least one member selected from the group consisting of acrylate copolymers, ethyl sullose, poly (decacylate-methyl meth ¾) copolymer, and methyl methacrylate ¾ acid copolymer. Formulation.  [Claim 92]  The pharmaceutical formulation of claim 14, wherein the atorvastatin of the prior-release compartment releases at least 8 (»or more) of the total amount of atorvastatin within 1 hour after the start of release.  [Claim 93]  The method of claim 14, wherein the nipadidipine is. A pharmaceutical formulation released 2 to 6 hours after the start of atorvastatin release.  [Claim 94]  117. The pharmaceutical formulation according to claim 114, wherein Atorvasta ¾ comprises S from 1 to 160 mg of formulation.  [Claim 95]  The pharmaceutical formulation of claim 14, wherein the atorvastatin is an isomer thereof. [Claim 96]  The pharmaceutical preparation according to claim 14, wherein nifedipine comprises 1 to 90 mg of preparation.  [Claim 97] The method of claim 14, wherein the delayed-release compartment is enteric polymer and hydrophilic polymer Pharmaceutical formulations comprising a jar.  [Claim 98]  The pharmaceutical formulation according to claim 15, wherein the release controlling substance of claim 14 is contained in an amount of 5 to 300 parts by weight with respect to 100 parts by weight of nifedipine.  [Claim 99]  98. The pharmaceutical formulation of claim 97 wherein the release controlling substance of claim 14 is contained in an amount of 5 to 300 parts by weight relative to 100 parts by weight of nifedipine.  [Claim 100]  99. The method according to claim 97 or 98, wherein the enteric polymer is hydroxypropylme ¾-cell as hydroxypropylme cellulose, hydroxyacetate succinate, hydroxypropylmethyl salophthalate, hydroxymeth ¾ to ¾-sallo. Osphthalate, cellulose acetate phthalate, low cellulose acetate succinate, chloroacetate maleate, cellulose benzoate phthalate, ¾ loose propionate phthalate S, methyl cell toosphthalate, At least one selected from carboxymethylethyl cellose, ethyl hydroxy, ¾ cell, ose phthalate, and meth hydroxyethyl cellose; Enteric arc ¾ acid-based co-condensate soils Styrene-arc ¾ acid copolymer, methacrylate ¾ ᅳ arc ¾ acid copolymer, methyl methacrylate acrylate, arc ¾-styrene-acrylic acid copolymer, methacrylic acid-methacryl At least one selected from methyl acid copolymer, methacrylic acid, ethyl acrylate copolymer, and methyl methacrylate acrylate-acrylic acid octyl co-polymerisation; As an enteric malthenic acid type copolymer, a vinyl acetate- maleic acid anhydride copolymer, a styrene- maleic acid anhydride non-copolymer, a styrene- maleic acid monoester copolymer, a vinyl methyl ether ether- maleic anhydride copolymer. At least one selected from an ethylene ethylene maleic anhydride copolymer, a vinyl ¾ ether-maleic anhydride copolymer, an acrylonitrile-methyl xylate maleic anhydride co-polymer, and an acrylic acid butyl- styrene maleic anhydride copolymer; Or an enteric polyvinyl derivative, at least one selected from ribinal alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butytate phthalate, and polyvinyl acetal phthalate, The hydrophilic polymer is cellulose derivative S hydroxypropylmeth ¾ cellulose, hydroxypropyl ¾ cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, meth cellulose, carboxy At least one selected from methyl ¾ rhodium naphthium, hydroxypropyl methylcellose ose acetate succinate, and ¾ methcellel in hydroxyose; sword As one or more proteins selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, and xanthan gum, as one or more polyvinyl derivatives selected from gelatin, casein, and zeinosis. At least one selected from polyvinyl alcohol, polyvinyl pyridone, and pulley vinyl acetal diethylamino acetate; Flea meta-methacrylate copolymer as a poly (butyl methacrylate- (2-dimethylaminoethyl) meth greater Relate-methyl methacrylate) copolymer, a replicon (methacrylic acid-methyl jje Tacna relay ^"sites) notary copolymer At least one selected from poly (methacrylic acid-ethylacrylate) and copolymerisation; A pharmaceutical preparation comprising at least one selected from cariemers and combinations thereof as at least one carboxyvinyl polymer selected from pulley ethylene glycol, and polyethylene oxide as a pulley derivative.  [Claim 101]  16. The method of claim 15, wherein the release controlling substance of claim 14 is selected from the group consisting of hydroxyspecyl methyl cellulose oslolate, hydroxypropyl mexyl cellulose acetate succinate, methacrylic acid—methacrylate ¾ copolymer, glycerol ¾ stearate. , Hydroxypropylme ¾cellulose, hydroxypropylsulose, carbomer, and combinations thereof.  [Claim 102]  102. The method of claim 97 or 101, wherein the release controlling substance is hydroxypropylmethylcello phthalate, hydroxypropylmethylshelloseacetate succinate, methacrylic acid-methyl methacrylate copolymer, hydroxypropylmethyl A pharmaceutical agent selected from the group consisting of cellulose, hydricopropylcelulose, carbomer, and combinations thereof.