KR20090114330A - Pharmaceutical preparations - Google Patents

Abstract

The present invention provides a pharmaceutical formulation comprising a prior release compartment comprising atorvastatin and a delayed release compartment comprising telmisartan. The pharmaceutical preparation of the present invention is a pharmaceutical preparation for the prevention and treatment of hypertension and hyperlipidemia and the prevention of complications in patients with hypertension and hyperlipidemia as well as metabolic syndrome, and the highest drug concentration at the optimal time of expression of each of atorvastatin and telmisartan. By releasing the two drugs in time so that they can have the most effective effect by reducing the side effects.

Description

Pharmaceutical Formulations

The present invention relates to a pharmaceutical formulation containing telmisartan and atorvastatin.

The present invention relates to a technology for formulating a functional combination that can suppress the decrease in drug efficacy due to drug interactions and prevent side effects from occurring when two drugs are simultaneously administered.

All drugs should be carefully reviewed for the characteristics of drug transporters, metabolic enzymes, and genes involved in the absorption, metabolism, distribution, drug expression and excretion of individual drugs when two or more components are taken. By determining the dissolution sequence and time difference of the components and maintaining the time difference of absorption, the antagonistic interaction between the drugs can be minimized. As a result, it is well known that side effects due to drug combinations can be reduced and drug efficacy can be enhanced.

More specifically, when drugs cross the barrier in the first stage, enter the liver in the secondary stage, metabolize and activate in liver cells in the tertiary stage, and biliary tract in the fourth stage, Efflux transporters, influx transporters, and metabolic enzymes are present everywhere, absorbing, metabolizing, and excreting drugs everywhere, such as when they exit the liver cells.

However, depending on the type of drug, it may also inhibit the action of these transporters, enzymes and genes.

Therefore, when two drugs pass through each step at the same time, one component may interfere with the absorption, distribution, and metabolism of the other, thereby reducing the efficacy or increasing the side effects. Therefore, one component must be passed first, and the other component must be passed at a time difference to eliminate drug interaction.

There are currently 300 such transporters, 500 metabolic enzymes, and 57 genes. Soon, gene genome analysis will find transporters and enzymes for all drugs.

Therefore, it is impossible to claim that there is no interaction between two or more drugs because it is a private return that any drug whose metabolic enzyme or transporter is currently unknown will be discovered soon. Therefore, even if a drug of two components for which metabolic enzymes or transporters are not known, it is reasonable to absorb it with a dissolution time difference between the two components.

As mentioned above, the background of the present invention is to determine the dissolution order between components and maintain the time difference based on those which are surely antagonistic interaction between two components for the purpose of realizing the ideal combination method when all drugs are heterogeneously administered. This enabled the functional combination to maximize drug efficacy and minimize side effects.

Examples of transporters and drug metabolizing enzymes that have been tested or reviewed for the preparation of the functional combination of the present invention are as follows.

1) Efflux Transporter: P-glycoprotein (P-gp), Multidrug resistance (MDR), Multidrug resistance associated protein (MRP)

2) Influx Transporter: Organic anion transport protein (OATP), Sodium taurocholate cotransporting polypeptide (NTCP), Organic cation transporter (OCT)

3) drug metabolism: Cytochrome P450 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4 / 5

4) Other metabolic enzymes: Uridine-5-phophate-glucuronosyltransferase (UDP-gt), Sulfatase, Sulfotransferase (1a1, 2a1, 1e1)

5) Nucleic Receptor: Pregnane-X-Receptor (PXR), Constitutive Androstane Receptor (CAR)

Hypertension refers to a condition in which blood pressure is maintained over a normal range, and when blood pressure does not drop, it causes various complications and eventually leads to death. This hypertension is one of the typical adult diseases of about 30% of the adult population in Korea, and about 95% of them are primary hypertension with no clear cause of blood pressure increase. Obesity, excessive salt intake, smoking, emotional and physical Lifestyle factors such as tension are considered to be the main cause.

Hyperlipidemia, like hypertension, is also one of the typical adult diseases, causing atherosclerosis in the arteries to make blood clots and close blood vessels. In addition, it causes changes in blood coagulation such as increased platelet aggregation function, shortening platelet coagulation time, and decreased function of the tolerant system, thereby increasing blood viscosity and eventually causing peripheral circulation disorder due to pathological changes in blood properties and condition. Hyperlipidemia is also considered to be a major cause of lifestyle factors such as obesity, poor eating habits, smoking, emotional and physical stress. As described above, hypertension and hyperlipidemia are not caused by definite causes of disease but adult disease caused by wrong lifestyles, and are often accompanied by each other. In particular, the disease accompanied by hypertension, hyperlipidemia, diabetes or impaired glucose tolerance is called metabolic syndrome. In the case of metabolic syndrome, not only hypertension and hyperlipidemia but also insulin resistance and consequent hyperinsulinemia have important pathophysiological factors. Many appear. Therefore, in the case of metabolic syndrome patients with hypertension and hyperlipidemia, it is an important factor to control not only hypertension and hyperlipidemia but also insulin resistance.

Therefore, hyperlipidemic agents as well as hypolipidemic agents are co-administered to hypertensive patients, and hyperlipidemic agents are co-administered as well as hyperlipidemic inhibitors. In addition, it is well known that metabolic patients with hypertension and hyperlipidemia use a combination of an antihypertensive agent and an antihyperlipidemic agent. Angiotensin II receptor blocker is an effective blood pressure lowering agent for patients with hyperlipidemia and those with metabolic syndrome because it has an excellent blood pressure lowering effect and does not cause lipid metabolism unlike beta blockers or diuretics. It is also well known that HMG-CoA reductase inhibitors are used as the primary selector to lower low density lipoprotein cholesterol (LDL-C), which not only lowers low density lipoprotein cholesterol (LDL-C) but also affects endothelial cell function. Enhance blood pressure lowering effect. Since the two drugs have a complementary effect on hypertension and hyperlipidemia, the combination of the two drugs may be used to treat and prevent hypertension and hyperlipidemia in patients with hypertension, hyperlipidemia, and metabolic syndrome, and to prevent complications. It is the best combination prescription.

Among the angiotensin II receptor blockers, telmisartan has an excellent antihypertensive effect and a glycemic control effect, making it an optimal choice for patients with hypertension and hyperlipidemia and metabolic syndrome. While other angiotensin II receptor blockers have similar molecular structures, telmisartan has a unique molecular structure that differs from other angiotensin II receptor blockers, and insulin can act on targeted receptors in controlling diabetes. In addition, the ability to activate PPARγ is significantly higher compared to other angiotensin II receptor blockers. This telmisartan is an optimal drug for lowering blood pressure in metabolic syndrome patients by inhibiting insulin resistance as well as lowering blood pressure when pioglitazone used as a diabetic agent is an agonist of PPARγ.

Atorvastatin is superior to other HMG-CoA reductase inhibitors in its long half-life and long-lasting efficacy, and has an amazing effect on suppressing cardiovascular disease such as coronary disease and stroke symptoms in patients with type 2 diabetes. [Diabetes Care, 28, 1151-1157 (2005)] Thus, atorvastatin is an optimal drug for the treatment of hyperlipidemia in patients with metabolic syndrome.

Combination therapy with telmisartan and atorvastatin is superior to conventional synergism. As a result, the use of telmisartan and atorvastatin as a combination prescription for hypertension and hyperlipidemia treatment and prevention in patients with hypertension, hyperlipidemia, and metabolic syndrome may have better efficacy than the combination of other drugs.

Regarding the combined prescription of these two drugs, International Publication No. 2004/062557 discloses a pharmaceutical combination of telmisartan and atorvastatin for the prevention or treatment of cardiovascular, cardiopulmonary, lung or kidney diseases. However, the International Patent Publication No. 2004/062557 discloses only the combination use through the combination formulation of telmisartan and atorvastatin, and a specific method regarding the formulation of the drug, the preparation method and administration method, and the administration time of the drug are disclosed. I'm not doing it.

The present invention is an oral preparation capable of simultaneously administering atorvastatin and telmisartan, and atorvastatin is immediately released upon evening administration, and telmisartan exhibits a fast medicinal effect, and telmisartan delays the release and absorption of the drug to maximize maximal efficacy at dawn. In view of the foregoing, it is intended to provide pharmaceutical formulations that have maximum efficacy with both drugs and minimize the interactions and side effects between these drugs.

The combination of telmisartan and atorvastatin shows good efficacy, but in order to obtain maximum efficacy and reduce side effects, the formulation, preparation method, administration method and administration time of the drug should be considered.

First of all, it should be an oral preparation that can be administered at the same time in consideration of patient compliance.

In addition, biorhythmical pharmacological action should be taken into account in order to obtain optimal drug efficacy of the two active ingredients. Telmisartan has a strong blood pressure lowering effect at dawn when the RAIN (Renin and angiotensin system) is strongly activated, so it should be able to exhibit maximum efficacy at dawn. On the other hand, atorvastatin lowers low-density lipoprotein cholesterol (LDL-C) and triglycerides in the evening, raises high-density lipoprotein cholesterol (HDL-C), and is superior to morning administration even in cardiovascular complications such as myocardial infarction and angina. Inhibitory effect. [Am J Cardiol, 97,44-47 (2006)].

Accordingly, the present invention includes atorvastatin, a pharmaceutically acceptable salt thereof, or an isomer thereof (hereinafter, 'atorvastatin') as a pharmacologically active ingredient in a prior-release compartment, and telmisartan, a pharmacologically active ingredient thereof. A pharmaceutical formulation comprising a salt or isomer thereof (hereinafter, 'telmisartan') in a delayed-release compartment, wherein the ortho-atortomate in the prior-release compartment is rapidly absorbed from the stomach by oral administration. The telmisartan in the delayed-release compartment is absorbed after ˜4 hours, providing only a single dose in the evening to provide a pharmaceutical preparation that exhibits a blood pressure lowering effect and a complication prevention effect for patients with metabolic syndrome for 24 hours.

Hereinafter will be described in more detail for the pre-release and delayed-release compartment of the pharmaceutical formulation of the present invention.

1.Preventive compartment

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

The pre-release compartment comprises (1) atorvastatin, a pharmaceutically acceptable salt thereof, or an isomer thereof as the pharmacologically active ingredient, and (2) optionally further includes a pharmaceutically acceptable additive.

(1) pharmacologically active ingredients

Pre-release compartments include atorvastatin, pharmaceutically acceptable salts thereof, and / or isomers thereof as pharmacologically active ingredients.

The active ingredient atorvastatin in the prior release compartment comprises about 1-160 mg, preferably about 10-80 mg, in a single formulation, which is the reference dose per day of adult (65-75 kg adult male).

The atorvastatin of the pre-release compartment releases at least 75% of the total amount of atorvastatin within 1 hour, preferably 30 minutes, after the start of release, indicating the desired efficacy.

(2) pharmaceutically acceptable additives

Pre-release compartments may also be formulated to include additives such as pharmaceutically acceptable diluents, binders, disintegrants, stabilizers, pH adjusting agents, dissolution aids, lubricants, surfactants, and the like, without departing from the effects of the present invention.

The diluent may be used starch, microcrystalline cellulose, lactose (hydrate), glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, or a mixture thereof.

The binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hypromellose, hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatin, Or mixtures thereof.

The disintegrant may be a starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch; Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.

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

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, aqueous ammonia, meglumine and the like.

The dissolution aid can be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docusate sodium and the like.

The lubricant is talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, Magnesium metasilicate aluminate, polyethyleneglycol, etc. can be used.

As said surfactant, sodium lauryl sulfate, a cremophor, a poloxamer, a docuate, a pharmaceutically acceptable docuate salt, etc. can be used.

In addition, the formulation of the present invention may be formulated using various pharmaceutically acceptable additives selected from colorants and fragrances, and the additives usable in the present invention are not limited to the above additives. The additives may be formulated to contain a range of usual doses by selection.

2. Delayed release block

Delayed-release compartment refers to a compartment that is released after a certain time after release of the prior release compartment in the pharmaceutical formulation of the present invention.

The delayed-release compartment comprises (1) telmisartan, a pharmaceutically acceptable salt thereof, or an isomer thereof as a pharmacologically active ingredient; (2-1) release controlling substance or (2-2) osmotic pressure regulator and semipermeable coating base; And (3) pharmaceutically acceptable additives as necessary.

(1) pharmacologically active ingredients

Delayed-release compartments include telmisartan, pharmaceutically acceptable salts thereof, and / or isomers thereof as pharmacologically active ingredients.

The active ingredient telmisartan in the delayed-release compartment comprises about 1-200 mg, preferably about 10-160 mg, in a single formulation, which is the reference dose for an adult per day (65-75 kg adult male).

The telmisartan of the delayed-release compartment is released after 1 to 4 hours, preferably 2 to 3 hours after the start of atorvastatin release.

The release of telmisartan in the delayed-release compartment is delayed to release up to 20% of the total amount of telmisartan in the formulation until 2 hours after oral administration, and once release is initiated, the total amount of telmisartan is released within 2 hours thereafter. More than 75% is released, indicating the desired efficacy.

(2-1) Release Control Substances

The delayed-release compartment in the pharmaceutical formulation of the present invention comprises at least one release controlling substance selected from the group consisting of enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof for controlling the release of pharmacologically active ingredients. Include.

The release controlling substance comprises 0.1 to 100 parts by weight, preferably 1 to 50 parts by weight, relative to 1 part by weight of telmisartan. If the release control material is less than 0.1 parts by weight it may be difficult to have a sufficient delay time, there is a problem that the release of the drug does not occur or the delay time is more than 9 hours or longer when more than 100 parts by weight.

The enteric polymer refers to a polymer which is insoluble or stable under acidic conditions of less than pH 5, and is dissolved or decomposed under specific pH conditions of pH 5 or higher. The enteric polymers usable in the present invention are selected from the group consisting of enteric cellulose derivatives, enteric acrylic acid copolymers, enteric polymethacrylate copolymers, enteric maleic acid copolymers, enteric polyvinyl derivatives, and mixtures thereof. Cellulose derivatives include hypromellose acetate succinate, hypromellose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl At least one selected from cellulose phthalate, carboxymethylethyl cellulose, ethyl hydroxyethyl cellulose phthalate, and methyl hydroxyethyl cellulose; The enteric acrylic acid copolymers include styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylic acid copolymers (eg, acrylics (Acryl-eze, Colorcon, USA)), butyl-styrene-acrylic acid copolymers. At least one selected from copolymers and methyl acrylate-methacrylic acid-octyl acrylate copolymer; The enteric polymethacrylate copolymer may be a methacrylic acid-methyl methacrylate copolymer (e.g., Eudragit L 100, Eudragit S, Degussa) or a methacrylic acid-ethyl acrylate copolymer (e.g., Eudra L 100-55, degussa) at least one selected from; The enteric maleic acid copolymers include vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinylmethyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether At least one selected from maleic anhydride copolymer, acrylonitrile-methyl methacrylate-maleic anhydride copolymer, and butyl styrene-maleic-maleic anhydride copolymer; Or the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinylacetate phthalate, polyvinyl butyrate phthalate, and polyvinylacetacetal phthalate. Preferably enteric cellulose derivatives, enteric polyvinyl derivatives, enteric acrylic acid copolymers, or combinations thereof, more preferably hypromellose acetate succinate, hypromellose phthalate, polyvinylacetate phthalate, Acrylic acid methacrylic acid copolymer, or a combination thereof can be used.

The water insoluble polymer refers to a polymer that is insoluble in the pharmaceutically acceptable water that controls the release of the drug. The water insoluble polymers usable in the present invention are polyvinyl acetate, water insoluble polymethacrylate copolymers (e.g. poly (ethylacrylate-methyl methacrylate) copolymers (e.g. Eudragit NE30D), poly (ethylacrylic) Late-methyl methacrylate-trimethylaminoethylmethacrylate chloride) copolymer (e.g., Eudragit RS PO), etc., ethylcellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacyl Latex, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof. Preferably cellulose acetate can be used.

The hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug. The hydrophobic compounds usable in the present invention are selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof, and the fatty acids and fatty acid esters are glyceryl palmitostearate, glycerol. At least one selected from aryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and sleanic acid; The fatty acid alcohol is at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol; The waxes are at least one selected from carnauba wax, beeswax, and microcrystalline wax; Alternatively, the inorganic material may be at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and non-gum.

The hydrophilic polymer refers to a polymer dissolved in pharmaceutically acceptable water that controls the release of the drug. The hydrophilic polymer usable in the present invention is selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof. Is at least one selected from dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, and amylopectin; The cellulose derivative is one selected from hypromellose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, and hydroxyethyl methyl cellulose. More than; The gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, and xanthan gum; The protein is at least one selected from gelatin, casein, and zein; The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylamino acetate; The hydrophilic polymethacrylate copolymers include poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymers (eg Eudragit E100, Evonik, Germany); The polyethylene derivative is at least one selected from polyethylene glycol, and polyethylene oxide; Or the carboxyvinyl polymer is a carbomer. Preferably, a cellulose derivative, a carboxyvinyl polymer, or a combination thereof may be used, more preferably carbomer, hypromellose, or a combination thereof may be used.

Also, preferably, the release controlling material may include an enteric polymer, a water insoluble polymer, or both and a hydrophilic polymer.

(2-2) Osmotic pressure regulator and semipermeable membrane coating base

The delayed-release compartment in the pharmaceutical formulation of the present invention may be a compartment containing an osmotic pressure control agent and coated with a semipermeable membrane coating agent for controlling the release of the active ingredient.

The semi-permeable membrane coating base is a pharmaceutically usable coating base, and refers to a substance used in forming a membrane which is blended into the coating layer of the pharmaceutical formulation and passes some components but does not pass other components.

Semi-permeable membrane coating bases usable in the present invention include polyvinyl acetate, water-insoluble polymethacrylate copolymers (eg, poly (ethylacrylate, methyl methacrylate) copolymers, poly (ethylacrylate, methyl methacrylate, Trimethylaminoethyl methacrylate chloride) copolymers, etc.), ethyl cellulose, cellulose esters, cellulose ethers, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and their It is selected from the group consisting of a mixture. Preferably ethyl cellulose can be used.

The semipermeable membrane coating base may be included in an amount of 0.5 to 10 parts by weight, preferably 1 to 5 parts by weight, based on 1 part by weight of telmisartan, and when less than 0.5 parts by weight, the release rate may not be controlled. If it is exceeded, there is a problem that excessive dissolution is delayed.

The osmotic pressure control agent refers to a component used to control the release rate of the drug by using the principle of osmotic pressure, the osmotic pressure control agent usable in the present invention is magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, Sodium sulfate, and mixtures thereof. Preferably sodium chloride can be used.

Osmotic pressure control agent may be included in 0.5 to 10 parts by weight, preferably 2 to 5 parts by weight with respect to 1 part by weight of telmisartan, when less than 0.5 parts by weight osmotic pressure generation effect is weak, there is more than 10 parts by weight In this case, there is a problem in that it is impossible to unnecessarily increase the total weight of the formulation or to realize a suitable drug release rate.

(3) pharmaceutically acceptable additives

Delayed-release compartments may also be formulated to include additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusting agents, antifoams, dissolution aids, surfactants, and the like, without departing from the effects of the present invention.

The diluents, binders, disintegrants, lubricants, pH adjusting agents, dissolution aids and surfactants may be used as mentioned in the "preventive compartment" above.

The antifoaming agent may be used such as dimethicone (dimethicone), oleyl alcohol, propylene glycol alginate, simethicone such as simethicone emulsion.

In addition to the various additives selected from colorants and flavorings, pharmaceutically acceptable additives may be selected and used to formulate the formulations of the present invention.

The additive usable in the present invention is not limited to the above additives. The additives may be formulated to contain a range of usual doses by selection.

The pharmaceutical preparations of the present invention can be prepared in a variety of formulations and can be formulated, for example, in tablets, powders, granules, capsules, and the like, such as uncoated tablets, coated tablets, multilayer tablets, or nucleated tablets.

The pharmaceutical formulations of the present invention may be in the form of a delayed-release compartment and a biphasic matrix tablet prepared by mixing and then pre-releasing the prior release compartment.

In addition, the pharmaceutical formulation of the present invention may be in the form of a film coated tablet consisting of a tablet consisting of a delayed-release compartment and a film coating layer consisting of a pre-release compartment surrounding the outside of the tablet, the film coating layer of the film coating layer as it is dissolved Atorvastatin is eluted first.

In addition, the pharmaceutical formulation of the present invention is a delayed-release compartment, obtained by mixing the pharmaceutical additives in the granules constituting the delayed-release compartment and the prior-release compartment, and tableting in a double or triple tablet using a multiple tableting machine and The pre-release compartment may be in the form of a multi-layered tablet forming a multi-layered structure. This formulation is a tablet for oral administration which is formulated to enable pre-release and delayed release in layers.

In addition, the pharmaceutical formulation of the present invention may be in the form of a tablet in which pharmaceutical additives are mixed with the pellets constituting the delayed-release compartment and the prior-release compartment, and the layers of the delayed-release compartment and the prior-release compartment are not divided using a tableting machine. have. This formulation is a tablet for oral administration that is formulated after pelleting by mixing pharmaceutical additives to allow delayed or prerelease release of each pellet.

In addition, the pharmaceutical formulation of the present invention may be in the form of a nucleated tablet consisting of an inner core consisting of a delayed-release compartment and an outer layer composed of a prior-release compartment surrounding the outer surface of the inner core.

In addition, the nucleated tablet may be an osmotic nucleated tablet, and the osmotic nucleated tablet contains an osmotic pressure-controlling agent inside the tablet for delayed release, followed by tableting, and then coated the surface of the tablet with a semipermeable membrane coating agent to obtain the inner nuclear tablet. The granules constituting the pre-release compartment are mixed with pharmaceutical additives and compressed into an outer layer, which is a tablet having a delayed-release inner core tablet and a surface of the inner core tablet surrounded by a prior release layer.

Pharmaceutical formulations of the invention may be in the form of particles, granules, pellets, or tablets comprising delayed-release compartments, or capsules comprising particles, granules, pellets, or tablets, consisting of pre-release compartments.

The pharmaceutical 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 to prepare the particles, granules, pellets, or tablets constituting the prior-release compartment, The granules, pellets or tablets constituting the delayed-release compartment may be separately prepared, and may be in the form of a kit prepared in a form that can be simultaneously taken by filling together with a foil, a blister, a bottle, and the like.

The pharmaceutical preparations according to the present invention may be provided in the form of uncoated tablets without additional coating, but may be in the form of coated tablets which further include a coating layer by forming a coating layer on the outside of the preparation, 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 a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer, a method such as fluidized bed coating method, fan coating method, dry coating method can be applied. Preferably, a pan coating method can be applied.

The coating layer may be formed using a coating agent, a coating aid, or a mixture thereof. Specifically, the coating agent may be a cellulose derivative such as hypromellose, hydroxypropyl cellulose, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatin, Or a mixture thereof, and the like, and a coating aid may be polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, or a mixture thereof.

The coating layer may comprise 0.5 to 15 weight percent (% w / w) relative to the total weight of the tablet.

Pharmaceutical formulations of the invention may be for evening administration. That is, the pharmaceutical preparation of the present invention can be taken once a day, especially in the evening (17 to 23 o'clock), thereby effectively lowering blood pressure and preventing complications of patients with metabolic syndrome for 24 hours.

Even when the pharmaceutical preparation of the present invention is taken once in the evening, the prior-release atorvastatin shows the efficacy in the evening, and the delayed-release telmisartan shows the blood pressure lowering effect during the dawn, so that both drugs can be used at the most suitable time. Absorption and efficacy can be shown to have optimal efficacy of the drug.

The pharmaceutical formulation of the present invention is for the prevention or treatment of cardiovascular diseases. The cardiovascular disease includes all of the hypertension and complications of those with metabolic syndrome, such as hypertension or diabetes, obesity, hyperlipidemia, coronary artery disease, etc., chronic stable angina pectoris, vascular spasms, stroke, myocardial infarction , Transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance, prediabetes, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive decline and dementia.

The present invention also provides a method for the prevention and treatment of metabolic syndrome and consequent hypertension and complications comprising administering a pharmaceutical formulation of the invention to a mammal.

The pharmaceutical formulation of the present invention may be formulated using a time difference dosage principle disclosed by Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, as an appropriate method in the art, and specifically by the following steps have.

In the first step, telmisartan is administered together with one or more release controlling substances selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, and a hydrophilic polymer, to be delayed-release granules through mixing, granulation, tableting, or coating. Obtaining pellets or tablets. If necessary, it may be prepared by administration with a pharmaceutically acceptable additive.

When the osmotic pressure control agent and the semipermeable membrane coating agent are used as the delayed-release compartment, the semipermeable membrane is mixed, combined, dried, granulated, or coated by administering telmisartan, an osmotic pressure control agent, or a conventional pharmaceutically usable additive. It is coated with a coating base to prepare delayed-release granules or tablets.

The second step is to obtain the prior-release granules, pellets or tablets obtained through conventional procedures used by those skilled in the art to produce atorvastatin as an oral solid.

In the third step, the granules, pellets or tablets obtained in the first step and the second step are mixed with a pharmaceutically acceptable 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 composite formulation of the present invention may be prepared by the above process, and the formulation method is described in more detail as follows, but is not limited thereto.

[A] Preparation of two-phase matrix tablet

The particles, pellets or granules obtained in the first step are further coated as they are or with a delayed-release material, and then mixed with the particles, pellets or granules prepared in the second step, and compressed into a certain amount of weight to prepare tablets. The obtained tablet can be film coated as necessary for the purpose of improving stability or property.

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

The final product obtained in the first step is further coated as such or with a delayed-release material or the like to prepare a final coated tablet. Separately, the atorvastatin may be dissolved or dispersed in a water-soluble film coating solution and then coated on the tablet outer layer obtained in the first step to prepare an orally administered film coating tablet containing the active ingredient in the film coating.

Preparation of multi-layered tablets

The particles, granules or pellets obtained in the first step may be additionally coated as they are or with a delayed-release material, and the dried granules and the particles, granules or pellets obtained in the second step may be added to produce a double tablet using a multi-layer tablet press. Coated multi-layered tablets can be prepared by formulating or coating triple or more multi-layered tablets by adding a release aid layer as needed, or by formulation design.

[D] Preparation of Nucleated Tablets

The final product obtained in the first step is prepared as it is or in the form of a finally coated tablet by additional coating with a delayed-release material or the like to make an inner core, and then compressed into a nucleated tableting machine with the granules obtained in the second step. A coated nucleated tablet may be prepared by preparing or coating a nucleated tablet in a form surrounded by a pre-emitting layer on its surface.

[E] Preparation of Capsules (Granules or Tablets)

The granules, granules, pellets or tablets obtained in the first step may be further coated as-is or with a delayed-release material, and the granules, granules, pellets or tablets obtained in the second step are placed in a capsule charger. Capsules may be prepared by filling the capsules with an effective amount of each active ingredient.

[Bar] kit manufacturing

The preparation obtained in the first step and the preparation obtained in the second step may be prepared into a kit that can be taken at the same time by filling together a foil, a blister, a bottle, or the like.

The pharmaceutical preparations of the present invention are formulated to allow timed uptake of drugs in the body to have the highest drug concentration at the optimal time of expression of each drug, increasing drug efficacy and reducing side effects, which is optimal for patients with metabolic syndrome. It is effective in preventing and treating hypertension and complications.

Examples are provided to help understand the present invention. The following examples are merely provided to more easily understand the present invention, but the contents of the present invention are not limited by the examples.

Example  One: Telmisartan - Atorvastatin  2-phase matrix tablet manufacturing

(1) Preparation of atorvastatin prior-release granules

Atorvastatin calcium anhydride, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), lactose, mannitol (Roquette, USA), and crospovidone are shown in Table 1. The apples were squeezed and mixed with a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany) for 60 minutes. Separately, hydroxypropyl cellulose (HPC-L, Nippon soda, Japan) and polysorbate 80 were dissolved in purified water to prepare a binding solution. The solution and the mixture were combined using a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany) and granulated using a No. 20 oscillator (AR402, ERWEKA, Germany), which was then heated to 60 ° using a hot water dryer. It was dried at C and sieved to No. 20 sieve again. Sodium starch glycolate was mixed thereto, and magnesium stearate (Nitika Chemical, India) was added thereto, followed by final mixing with a double cone mixer [Dasan Pharmatech, South Korea].

(2) preparation of telmisartan delayed-release granules

As shown in Table 1, cross-linked polyvinylpyrrolidone (Crosspovidone, Basf, Germany) and microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) were appled with No. 35 and fluid bed granulator GPCG-1 (Glatt, Germany). After mixing for 30 minutes, magnesium stearate (Nitika Chemical, India) was added and mixed for 4 minutes. Telmisartan, sodium hydroxide, meglumine and hypromellose (Pharmacoat645, Shin-etsu, Japan) were dissolved in purified water to prepare telmisartan liquid. The telmisartan liquid was assembled by adding a fluid bed granulator to the mixture using GPCG-1 (Glatt, Germany). Fluidized bed granulators used the Bottom-spray system of GPCG-1 (Glatt, Germany).

After the assembly was completed, the granulated material was dried using a fluid bed dryer. The fluid bed drier used GPCG-1 (Glatt, Germany).

Separately, cellulose acetate (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate (acetal group 39.8%) (Eastman Chemical Company, USA), hypromellose (Pharmacoat2910, Shin-etsu, Japan) The liquid dissolved in methylene was prepared, and the dried granules were placed in a fluidized bed coater (GPCG-1, Glatt, Germany) and coated. After the coating was completed, the coating material, meglumine and sodium starch glycolate were mixed in a double cone mixer (Dasan Pharmatech, Korea) for 10 minutes, mixed with magnesium stearate (Nitika Chemical, India), and then mixed for 4 minutes with telmisartan. Delayed-release granules were prepared.

(3) tableting and coating

The two granules of (1) and (2) were mixed and then compressed in a rotary tablet press (MRC-30, Sejong Pharmatech, Korea). After the tablet is finished, hypromellose (Pharmacoat2910, Shin-etsu, Japan), polyethylene glycol (Lutrol6000, Basf, Germany) are dissolved in ethanol and purified water, and the coating solution prepared by dispersing titanium oxide (Tioside Americas, USA) Coating was performed using a coater (SFC-30F, Sejong Pharmatech, Korea).

Example  2: Telmisartan - Atorvastatin  Double Tablet Manufacturing

(1) Preparation of atorvastatin prior-release

Atorvastatin calcium trihydrate, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), lactose and sodium lauryl sulfate (Texapon K12P, Cognis Corp, US) apples in No. 35 and mixed for 60 minutes in a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany). Separately, hydroxypropyl cellulose was dissolved in purified water to obtain a binding solution. The solution and the mixture were combined using a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany), followed by granulation using a No. 20 oscillator (AR402, ERWEKA, Germany) and 60 ° using a hot water dryer. After drying at C, it was established as No. 20 sieve again. Croscarmellose sodium was mixed therein, and magnesium stearate (Nitika Chemical, India) was added thereto, followed by final mixing with a double cone mixer [Dasan Pharmatech, Korea].

(2) preparation of telmisartan delayed-release granules

As shown in Table 1, telmisartan, sodium hydroxide, meglumine, and polyvinylpyrrolidone were dissolved in ethanol to prepare telmisartan liquid. The solution was spray dried using a Mini spray dryer B-290, Buchi, Switzerland to prepare telmisartan granules having an amorphous solid dispersion.

Separately, cellulose acetate (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate (acetal group 39.8%) (Eastman Chemical Company, USA), hypromellose (Pharmacoat2910, Shin-etsu, Japan) The liquid dissolved in methylene was prepared and the dried granules were placed in a fluidized bed coater (GPCG-1, Glatt, Germany) and coated. After the coating is completed, the coating material, cross-linked polyvinylpyrrolidone and silicified microcrystalline cellulose are added to a double cone mixer (Dasan Pharmatech, Korea) for 10 minutes, mixed with magnesium stearate (Nitika Chemical, India) and mixed for 4 minutes Carbon delayed release granules were prepared.

(3) tableting and coating

Put the two granules of (1) and (2) into the granule inlet of the rotary multi- tablet tableting machine [MRC-37T, Sejong Pharmatech, Korea], respectively, and then tableting the finished tablets with hypromellose (Pharmacoat2910, Shin -etsu (Japan), Polyethylene glycol (Lutrol 6000, BASF, Germany) is dissolved in ethanol and purified water, and the coating solution prepared by dispersing titanium oxide (Tioside Americas, USA) is applied to the coating machine (SFC-30F, Sejong Pharmatech, Korea). And coated.

Example  3: Telmisartan - Atorvastatin  Multilayer Tablet Manufacturing

(1) Preparation of atorvastatin prior-release granules

Atorvastatin strontium pentahydrate, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), lactose and sodium lauryl sulfate (Texapon K12P, Cognis Corp, US) apples in No. 35 and mixed for 60 minutes in a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany). Separately, hydroxypropyl cellulose was dissolved in purified water to obtain a binding solution. The solution and the mixture were combined using a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany), followed by granulation using a No. 20 oscillator (AR402, ERWEKA, Germany) and 60 ° using a hot water dryer. After drying at C, it was established as No. 20 sieve again. Croscarmellose sodium was mixed therein, and magnesium stearate (Nitika Chemical, India) was added thereto, followed by final mixing with a double cone mixer [Dasan Pharmatech, Korea].

(2) preparation of telmisartan delayed-release granules

Like the ingredients and contents shown in Table 1, cross-linked polyvinylpyrrolidone, microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) was weighed and appled in No. 35, and mixed for 30 minutes in a double mixer to prepare a mixture. Separately, sodium hydroxide, meglumine, telmisartan and hypromellose were dissolved in a mixture of ethanol and water to prepare telmisartan liquid. The solution and the mixture were dried after association and granulation using a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany).

Separately, cellulose acetate (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate (acetal group 39.8%) (Eastman Chemical Company, USA), hypromellose (Pharmacoat2910, Shin-etsu, Japan) The liquid dissolved in methylene was prepared, and the dried granules were placed in a fluidized bed coater (GPCG-1, Glatt, Germany) and coated. After the coating is completed, add the coating material, meglumine, and croscarmellose sodium to a double cone mixer (Dasan Pharmatech, Korea) for 10 minutes, mix magnesium stearate (Nitika Chemical, India), and then mix for 4 minutes to delay telmisartan. Release granules were prepared.

(3) tableting and coating

Put the two granules of (1) and (2) into the granule inlet of the rotary multi- tablet tableting machine [MRC-37T, Sejong Pharmatech, Korea], respectively, and then tableting the finished tablets with hypromellose (Pharmacoat2910, Shin -etsu (Japan), Polyethylene glycol (Lutrol 6000, BASF, Germany) is dissolved in ethanol and purified water, and the coating solution prepared by dispersing titanium oxide (Tioside Americas, USA) is applied to the coating machine (SFC-30F, Sejong Pharmatech, Korea). And coated.

Example  4: Telmisartan - Atorvastatin Nucleus refining  Produce

(1) Preparation of atorvastatin prior-release granules

Atorvastatin calcium anhydride, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), lactose, corn starch and sodium lauryl sulfate (Texapon K12P, Cognis) as shown in Table 1 Corp., USA), apples in No. 35 and mixed for 60 minutes with a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany). Separately, hydroxypropyl cellulose was dissolved in purified water to obtain a binding solution. The solution and the mixture were combined using a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany), and then granulated using a No. 20 body oscillator (AR402, ERWEKA, Germany) and 60 ° using a hot water dryer. After drying at C, it was established as No. 20 sieve again. Croscarmellose sodium was mixed therein, and magnesium stearate was added thereto, followed by final mixing in a double cone mixer [Dasan Mapatech, South Korea].

(2) Preparation of telmisartan delayed-release inner core tablet

As shown in the following Table 1, telmisartan, sodium hydroxide, and meglumine were dissolved in purified water to prepare telmisartan liquid. Separately, hypromellose acetate succinate (HPMCAS) is dissolved in a mixture of ethanol and dichloromethane. The two liquids were prepared using a twin screw extruder to prepare telmisartan granules having an amorphous solid dispersion.

The granules, cross-linked polyvinylpyrrolidone and silicified microcrystalline cellulose were added to a double cone mixer (Dasan Pharmatech, Korea) for 10 minutes, mixed with magnesium stearate and mixed for 4 minutes to prepare telmisartan delayed-release granules. Inner core tablets were prepared by tableting in a tablet press (MRC-30, Sejong Pharmatech, Korea).

The prepared intranuclear tablet was administered to a coating machine (SFC-30F, Sejong Pharmatech, Korea), and separately cellulose acetate (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate (acetal group 39.8%) (Eastman Chemical Company , USA), hypromellose (Pharmacoat2910, Shin-etsu, Japan) using a solution dissolved in ethanol and methylene chloride was prepared as a coating solution.

(3) nucleated tablet manufacturing

After tableting with the inner core tablet of (2) and the atorvastatin pre-release granules of (1) in a nucleating tableting machine (RUD-1, Kilian, Germany), tablets having been tableted are prepared by pharmacoat 2910 (Pharmacoat2910, Shin-etsu). , Japan), polyethylene glycol was dissolved in ethanol and purified water, and then coated tablets were prepared using a coating solution prepared by dispersing titanium oxide.

Example  5: Telmisartan - Atorvastatin  Preparation of capsules (tablets + tablets)

(1) Preparation of atorvastatin prior-release tablet

As shown in Table 1, atorvastatin calcium trihydrate, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan) and microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) were apologized with No. 35 and a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany). Separately, hydroxypropyl cellulose (HPC-L, Nippon soda, Japan) and polysorbate 80 were dissolved in purified water to prepare a binding solution. The solution and the mixture were put into a high speed mixer and combined, and then granulated using an oscillator (AR402, ERWEKA, Germany) as a No. 20 sieve, dried at 60 ° C. using a hot water dryer, and then re-established as No. 20 sieve. Sodium starch glyconate (Primojel, DMV Pharma, The Netherlands) is mixed, and magnesium stearate is added and finally mixed with a double cone mixer [Dasan Pharmatech, South Korea], and the final mixture is a rotary tablet press (MRC-30, Sejong, Korea). Pharmatech, Korea). The tablets were dissolved in ethanol and purified water by dissolving hypromellose (Pharmacoat2910, Shin-etsu, Japan) and polyethylene glycol (Lutrol 6000, BASF, Germany) using the ingredients and contents described in the coating layer of Table 1, followed by titanium oxide (Tioside Americas, The coating solution prepared by dispersing the United States) was coated using a coater (SFC-30F, Sejong Pharmatech, Korea).

(2) Telmisartan delayed-release tablet preparation

The ingredients and contents shown in Table 1 were compressed in a rotary tablet press (MRC-30: Sejong Pharmatech, Korea) using the method of Example 1. The tablet is administered to a coating machine (SFC-30F, Sejong Pharmatech, Korea), and telmisartan delayed-release tablet is prepared by dissolving hypromellose phthalate (HPMCP, Shin-etsu, Japan) in 80% ethanol as a coating solution. Was prepared.

(3) charging

Two tablets were filled into capsules using a capsule filling machine (SFN-8N, Sejong Pharmatech, Korea) to prepare an atorvastatin-telmisartan capsule (tablet + tablet). However, in case of telmisartan delayed-release tablet, telmisartan capacity is 20mg per tablet, so 4 tablets are filled.

Example  6 Telmisartan - Atorvastatin  Preparation of Capsules (Granules + Tablets)

(1) Preparation of atorvastatin prior-release tablet

As shown in Table 1, atorvastatin strontium pentahydrate, calcium stearate, microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), lactose and corn starch were identified as No. 35 and high speed mixer (Lab. Pharma Mixer P, Diosna) , Germany) for 60 minutes. Separately, hydroxypropyl cellulose and polysorbate 80 were dissolved in purified water to obtain a binding solution. The solution and the mixture were combined using a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany), followed by granulation using a No. 20 oscillator (AR402, ERWEKA, Germany) and 60 ° using a hot water dryer. After drying at C, it was established as No. 20 sieve again. Sodium starch glycolate (Primojel, DMV Pharma, The Netherlands) is mixed, and magnesium stearate is added and finally mixed with a double cone mixer [Dasan Pharmatech, Korea], and the final mixture is a rotary tablet press (MRC-30, Sejong, Korea). Pharmatech, Korea).

After tableting is completed, dissolve hypromellose (Pharmacoat2910, Shin-etsu, Japan) and polyethylene glycol (Lutrol 6000, BASF, Germany) in ethanol and purified water using the ingredients and contents listed in the coating layer of Table 1. The coating solution prepared by dispersing Americas, USA) was coated using a coater (SFC-30F, Sejong Pharmatech, Korea).

(2) preparation of telmisartan delayed-release granules

Granules are prepared using the method of Example 1 with the ingredients and contents shown in Table 1.

(3) charging

Atorvastatin-telmisartan capsules (tablets + granules) were prepared by filling the capsules using a capsule filling machine (SFN-8N, Sejong Pharmatech, Korea).

Example  7: Telmisartan - Of atorvastatin (granule + granule)  Produce

(1) Preparation of atorvastatin prior-release granules

Atorvastatin calcium anhydride, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), lactose, corn starch and sodium lauryl sulfate (Texapon K12P, Cognis) as shown in Table 1 Corp., USA), apples in No. 35 and mixed for 60 minutes with a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany). Separately, hydroxypropyl cellulose was dissolved in purified water to obtain a binding solution. The solution and the mixture were combined using a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany), followed by granulation using a No. 20 oscillator (AR402, ERWEKA, Germany) and 60 ° using a hot water dryer. After drying at C, it was established as No. 20 sieve again.

(2) preparation of telmisartan delayed-release granules

Prepared in the same manner as the telmisartan delayed-release granules of Example 1 with the ingredients and contents shown in Table 1, the dried product was placed in a fluidized bed coater, cellulose acetate (acetal group 32%) (Eastman Chemical Company, USA), cellulose Acetate (acetal group 39.8%) (Eastman Chemical Company, USA) and hypromellose (Pharmacoat2910, Shin-etsu, Japan) were dissolved in ethanol and methylene chloride, instead of polyvinylacetate phthalate (Phthalavin, Colorcon, USA) The solution dissolved in the solution was prepared and placed in a fluidized bed granulator coater (GPCG-1, Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes to prepare telmisartan delayed-release granules.

(3) charging

Atorvastatin-telmisartan capsules (granules + granules) were prepared by filling the capsules using a capsule filling machine (SFN-8N, Sejong Pharmatech, Korea).

Example  8 : Telmisartan - Atorvastatin  Capsule ( Pellet  + Pellet Manufacturing

(1) Preparation of atorvastatin prior-release pellet

With the ingredients and contents shown in Table 1, the sugar seeds (Sugar shpere) was sieved through No. 16 sieve and placed in a fluidized bed coater (GPCG-1, Glatt, Germany), followed by hydroxypropylcellulose and atorvastatin calcium trihydrate separately in water and ethanol. A coating solution in which a cargo or calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan) was dissolved or suspended was prepared.

The coating solution was added to sugar seed (Sugar shpere) using a fluid bed granulator GPCG-1 (Glatt, Germany) to prepare atorvastatin pellets. Fluidized bed granulators used the Bottom-spray system of GPCG-1 (Glatt, Germany).

After the preparation of the atorvastatin pellets was completed, the atorvastatin pellets were dried using a fluid bed dryer. The fluid bed drier used GPCG-1 (Glatt, Germany).

(2) Preparation of Telmisartan Delayed-Release Pellets

With the ingredients and contents shown in Table 1, the sugar spheres were sieved through a No. 16 sieve and poured into a fluidized bed coater (GPCG-1, Glatt, Germany), followed by hypromellose (Pharmacoat910, Shin) in water and ethanol separately. -etsu, Japan) and a coating solution in which telmisartan, sodium hydroxide, and meglumine were dissolved or suspended.

The coating solution was added to Sugar seed (Sugar shpere) using a fluid bed granulator GPCG-1 (Glatt, Germany) to prepare telmisartan pellets. Fluidized bed granulators used the Bottom-spray system of GPCG-1 (Glatt, Germany).

After the preparation of telmisartan pellets was completed, telmisartan pellets were dried using a fluidized bed dryer. The fluid bed drier used GPCG-1 (Glatt, Germany).

Again, the pellets were sprayed in a fluidized bed coater GPCG-1 (Glatt, Germany), and sprayed with a solution of hypromellose phthalate (HPMCP, Shin-etsu, Japan) in ethanol and methylene chloride to give telmisartan delayed-release pellets. Manufactured.

(3) charging

Atorvastatin-telmisartan capsules (pellets + pellets) were prepared by filling the capsules using a capsule filling machine (SFN-8N, Sejong Pharmatech, Korea).

Example  9: Telmisartan - Atorvastatin Capsule  Produce( Pellet  + Tablets)

(1) Preparation of atorvastatin prior-release tablet

As shown in Table 1, atorvastatin calcium anhydride, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan) and microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) were apologized with No. 35 and a high speed mixer (Lab. Pharma Mixer) P, Diosna, Germany). Separately, hydroxypropyl cellulose (HPC-L, Nippon soda, Japan) and polysorbate 80 were dissolved in purified water to prepare a binding solution. The solution and the mixture were put into a high speed mixer and combined, and then granulated using an oscillator (AR402, ERWEKA, Germany) as a No. 20 sieve, dried at 60 ° C. using a hot water dryer, and then re-established as No. 20 sieve. To this, starch sodium glyconate (Primojel, DMV Pharma, The Netherlands) is mixed, and magnesium stearate is added and finally mixed with a double cone mixer [Dasan Pharmatech, Korea], and the final mixture is mixed with a rotary tableting machine (MRC-30, Tabletting using Sejong Pharmatech, Korea). The tablets were dissolved in ethanol and purified water by dissolving hypromellose (Pharmacoat2910, Shin-etsu, Japan) and polyethylene glycol (Lutrol 6000, BASF, Germany) using the ingredients and contents described in the coating layer of Table 1, followed by titanium oxide (Tioside Americas, The coating solution prepared by dispersing the United States was coated using a coater (SFC-30F, Sejong Pharmatech, Korea).

(2) Preparation of Telmisartan Delayed-Release Pellets

With the ingredients and contents shown in Table 1, telmisartan delayed-release pellets were prepared in the same manner as in Example 8.

(3) charging

Atorvastatin-telmisartan capsules (tablets-pellets) were prepared by filling the capsules using a capsule filling machine (SFN-8N, Sejong Pharmatech, Korea).

Example  10: Telmisartan - Atorvastatin  Preparation of Biphasic Matrix Tablets

(1) Preparation of atorvastatin prior-release granules

Atorvastatin strontium pentahydrate, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), lactose, mannitol (Roquette, USA), and crospovidone as shown in Table 1 Apples in No. 35 were mixed with a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany) for 60 minutes. Separately, hydroxypropyl cellulose (HPC-L, Nippon soda, Japan) and polysorbate 80 were dissolved in purified water to prepare a binding solution. The solution and the mixture were combined using a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany) and granulated using a No. 20 oscillator (AR402, ERWEKA, Germany), which was then heated to 60 ° using a hot water dryer. It was dried at C and sieved to No. 20 sieve again. Sodium starch glycolate was mixed and magnesium stearate was added and finally mixed with a double cone mixer [Dasan Pharmatech, Korea].

(2) preparation of telmisartan delayed-release granules

With the ingredients and contents shown in Table 1, telmisartan granules were prepared in the same manner as in Example 1, except that cellulose acetate (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate (acetal group 39.8%) ( Eastman Chemical Company (USA) and hypromellose (Pharmacoat2910, Shin-etsu, Japan) dissolved in ethanol and methylene chloride, hypromellose (Pharmacoat2910, Shin-etsu, Japan) dissolved in purified water and acrylic (Acryl-eze, Colorcon, USA) was dissolved in 80% ethanol to prepare a coating solution. After the preparation of the coating solution was completed, the granules were administered to the fluidized bed coater GPCG-1 (Glatt, Germany) and subjected to the primary coating (hypromellose coating solution), and then the secondary coating (acrylic coating solution). After the coating was completed, after adding magnesium stearate and mixing for 4 minutes, telmisartan delayed-release granules were prepared.

(3) tableting and coating

The two granules were mixed and compressed in a rotary tablet press (MRC-30, Sejong Pharmatech, Korea). A tablet solution prepared by dissolving hypromellose (Pharmacoat2910, Shin-etsu, Japan) and polyethylene glycol (Lutrol 6000, BASF, Germany) in ethanol and purified water and dispersing titanium oxide (Tioside Americas, USA). The coating was carried out using the Essop coater (SFC-30F, Sejong Pharmatech, Korea).

Example  11: Telmisartan - Atorvastatin Blaster  Packing Of kit  Produce

(1) Preparation of atorvastatin prior-release tablet

As shown in Table 1, atorvastatin calcium anhydride, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan) and microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) were apologized as No. 35 and a high speed mixer (Lab. Pharma Mixer) P, Diosna, Germany). Separately, hydroxypropyl cellulose (HPC-L, Nippon soda, Japan) and polysorbate 80 were dissolved in purified water to prepare a binding solution. The solution and the mixture were put into a high speed mixer and combined, and then granulated using an oscillator (AR402, ERWEKA, Germany) as a No. 20 sieve, dried at 60 ° C. using a hot water dryer, and then re-established as No. 20 sieve. Sodium starch glyconate (Primojel, DMV Pharma, The Netherlands) was mixed, and magnesium stearate was added and finally mixed with a double cone mixer [Dasan Pharmatech, South Korea] to prepare atorvastatin pre-release granules.

(2) Telmisartan Granules Manufacturing

As shown in Table 1, cross-linked polyvinylpyrrolidone (Crosspovidone, Basf, Germany) and microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) were appled with No. 35 and fluid bed granulator GPCG-1 (Glatt, Germany). After mixing for 30 minutes, magnesium stearate was added and mixed for 4 minutes. Telmisartan, sodium hydroxide, meglumine and hypromellose (Pharmacoat645, Shin-etsu, Japan) were dissolved in purified water to prepare telmisartan liquid. The telmisartan liquid was assembled by adding a fluid bed granulator to the mixture using GPCG-1 (Glatt, Germany). Fluidized bed granulators used the Bottom-spray system of GPCG-1 (Glatt, Germany).

After the assembly was completed, the granulated material was dried using a fluid bed dryer. The fluid bed drier used GPCG-1 (Glatt, Germany).

Separately, a solution obtained by dissolving polyvinylacetate phthalate (Phthalavin, Colorcon, USA) in ethanol was prepared, and the granulated product was put in a fluidized bed granulation coater (GPCG-1, Platt, Germany) and coated under the same conditions as in (1) of Example 1. It was.

After the coating was completed, the telmisartan delayed-release granules were dried using a fluid bed dryer. Fluid bed dryer GPCG-1 (Glatt, Germany) was used.

The dried telmisartan delayed-release granules were granulated using an F-type sizer equipped with No. 20, and the powder and carbomer 71G (Carboxyvinylpolymer, Lubrizole, USA) were powdered in a double cone mixer (Dasan Pharmatech, Korea). After 10 minutes of mixing, magnesium stearate was added and mixed for 4 minutes to prepare telmisartan delayed-release granules.

(3) Manufacture of packaging kits after tableting and coating

As the granules of (1) and (2), telmisartan delayed-release tablets and atorvastatin pre-release tablets were respectively compressed with a rotary tablet press (MRC-30, Sejong Pharmatech, Korea). A tablet solution prepared by dissolving hypromellose (Pharmacoat2910, Shin-etsu, Japan) and polyethylene glycol (Lutrol 6000, BASF, Germany) in ethanol and purified water and dispersing titanium oxide (Tioside Americas, USA). The coating was carried out using the Essop coater (SFC-30F, Sejong Pharmatech, Korea). Each coated tablet was packaged in one PTP (Press Through Pack) packaging container to prepare a packaging kit that can be used at the same time.

Example  12: Telmisartan - Atorvastatin  contain Definition of film coating  Produce

(1) Preparation of Atorvastatin Prior-Release Coating Liquid

As shown in Table 1, atorvastatin calcium trihydrate, hypromellose (Pharmacoat2910, Shin-etsu, Japan), polyethylene glycol 6000, titanium oxide, and talc were added to the mixed solution of ethanol and water in the amount described in the coating layer of Table 1. Dissolved and dispersed to prepare a pre-release atorvastatin coating solution.

(2) Preparation of Chamtelmisartan delayed-release tablet

As shown in Table 1, cross-linked polyvinylpyrrolidone (Crosspovidone, Basf, Germany) and microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA) were appled with No. 35 and fluid bed granulator GPCG-1 (Glatt, Germany). After mixing for 30 minutes, magnesium stearate was added and mixed for 4 minutes. Telmisartan, sodium hydroxide, meglumine and hypromellose (Pharmacoat645, Shin-etsu, Japan) were dissolved in purified water to prepare telmisartan liquid. The telmisartan liquid was assembled by adding a fluid bed granulator to the mixture using GPCG-1 (Glatt, Germany). The fluid bed granulator used the Bottom-spray system of GPCG-1 (Glatt, Germany).

After the assembly was completed, the granulated material was dried using a fluid bed dryer. The fluid bed drier used GPCG-1 (Glatt, Germany).

After completion of drying, add the dried product and meglumine, sodium starch glycolate, and carbomer 71G (Carboxyvinylpolymer, Lubrizole, USA) to the double cone mixer (Dasan Pharmatech, Korea), mix for 10 minutes, add magnesium stearate, and mix for 4 minutes. The telmisartan delayed-release granules were prepared and then compressed using a rotary tablet press (MRC-30: Sejong Machinery, Korea).

Separately, hypromellose (Pharmacoat2910, Shin-etsu, Japan) was dissolved in purified water and acrylic acid (Acryl-eze, Colorcon, USA) was dissolved in 80% ethanol to prepare a coating solution. After the preparation of the coating solution is completed, the tablet is administered to the coating machine (SFC-30F, Sejong Pharmatech, Korea) and the first coating (hypromellose coating solution), and then the second coating (acrylic coating solution) and telmisartan Delayed-release tablets were prepared.

(3) coating

Telmisartan uncoated tablets were administered to a coating machine (SFC-30F, Sejong Pharmatech, Korea) and coated with an atorvastatin coating solution. After drug coating, hypromellose (Pharmacoat2910, Shin-etsu, Japan) and polyethylene glycol (Lutrol 6000, BASF, Germany) are dissolved in ethanol and purified water, and the coating solution is prepared by dispersing titanium oxide (Tioside Americas, USA). The coating was carried out using the Essop coater (SFC-30F, Sejong Pharmatech, Korea).

Example  13: Telmisartan - Atorvastatin Osmotic Nuclear Justice  Produce

(1) Preparation of atorvastatin prior-release granules

Atorvastatin strontium pentahydrate, calcium carbonate (Precipitaed calcium carbonate, Nitto Funka, Japan), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), lactose, corn starch and sodium lauryl sulfate (Texapon K12P,) as shown in Table 1 Cognis Corp. (USA) apologizes for the 35th issue and a high speed mixer [Lab. Pharma Mixer P, Diosna, Germany]. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution. The solution and the mixture were combined using a high speed mixer (Lab. Pharma Mixer P, Diosna, Germany) and granulated using a No. 20 oscillator (AR402, ERWEKA, Germany), which was then heated to 60 ° using a hot water dryer. It was dried at C and sieved to No. 20 sieve again. Sodium starch glycolate was mixed and magnesium stearate was added thereto, followed by final mixing with a double cone mixer [Dasan Pharmatech, Korea].

(2) Preparation of telmisartan delayed-release inner core tablet

As shown in Table 1, cross-linked polyvinylpyrrolidone (Crosspovidone, Basf, Germany), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), sodium chloride as a No. 35 sieve and fluid bed granulator GPCG-1 (Glatt) , Germany) for 30 minutes and then magnesium stearate was added and mixed for 4 minutes. Telmisartan, sodium hydroxide, meglumine and hypromellose (Pharmacoat645, Shin-etsu, Japan) were dissolved in purified water to prepare telmisartan liquid. The telmisartan liquid was assembled by adding a fluid bed granulator to the mixture using GPCG-1 (Glatt, Germany). Fluidized bed granulators used the Bottom-spray system of GPCG-1 (Glatt, Germany).

After the assembly was completed, the granulated material was dried using a fluid bed dryer. The fluid bed drier used GPCG-1 (Glatt, Germany).

After completion of drying, dry matter, meglumine and sodium starch glycolate were mixed in a double cone mixer (Dasan Pharmatech, Korea), mixed for 10 minutes, magnesium stearate was added and mixed for 4 minutes to prepare telmisartan delayed-release granules, and then rotary Tableting machine (MRC-30: Sejong Machinery, Korea) was compressed.

After tableting, ethyl cellulose was dissolved in ethanol and methylene chloride as a semipermeable membrane coating base, and then coated with an inner core tablet using a coater (SFC-30F, Sejong Pharmatech, Korea) to prepare an osmotic core tablet.

(3) tableting and coating

A nucleated tablet tablet machine (RUD-1: Kilian, Germany) was used to tablet the telmisartan osmotic nuclear tablet as the inner core and the atorvastatin prior-release granules as the outer layer. A tablet solution prepared by dissolving hypromellose (Pharmacoat2910, Shin-etsu, Japan) and polyethylene glycol (Lutrol 6000, BASF, Germany) in ethanol and purified water and dispersing titanium oxide (Tioside Americas, USA). Was coated using a coating machine (SFC-30F, Sejong Pharmatech, Korea).

TABLE 1

[ Experimental Example  1] Dissolution aspect test ( dissolution profile test )

Comparative dissolution tests were performed using telmisartan single agent (Mikadis, Boehringer Ingelheim) and atorvastatin single agent (Lipitor, Pfizer) as the test preparations and the control preparations obtained in Examples 1 to 9 and 11 to 13. In the case of the test preparation, the dissolution test was carried out by changing the eluate from pH 1.2-hydrochloric acid solution (artificial gastric solution) to pH 6.8-phosphate solution (phosphate solution) for telmisartan and atorvastatin. The results are shown in FIGS. 1 to 6.

[Telmisartan / Atorvastatin Dissolution Test Method]

Dissolution test basis: The complex preparations obtained in the above examples are carried out according to the dissolution test method of the nine general test methods of the Korean Pharmacopoeia.

Detailed test methods were performed in artificial gastric fluid (warmed at No. 9) and then in artificial intestinal fluid (warmed at No. 9). Dissolution test was conducted.

Test method: Paddle method, 50 revolutions / minute

Test solution: Test solution: pH 1.2 artificial gastric fluid (0.1 N hydrochloric acid solution) (0-2 hours),

pH 6.8 artificial intestine solution, (0.1 N phosphate solution) (after 2 hours)

Analysis method: High performance liquid chromatography analysis

Column: C-18, 4.6mm X 25cm, 5μm,

Detection wavelength (telmisartan / atorvastatin) = 230/240 nm

As shown in Figures 1 to 6, the formulations of the various formulations obtained in the examples all show a consistent dissolution pattern, telmisartan it can be seen that both have a constant dissolution delay time according to the formulation and formulation.

It can be seen that the Chamtelmisartan component in the formulation of the present invention exhibits a very slow dissolution rate and sufficiently delayed dissolution time when compared to the control formulation, and the atorvastatin component exhibits similar dissolution results as the control formulation.

In the case of the test agent of the present invention, the dissolution rate of the telmisartan component was less than 30% by 2 hours, indicating a sufficiently delayed dissolution rate and time compared to the dissolution rate of the telmisartan (about 99%) of the control formulation. You can check it.

Thus, it can be seen that according to the pharmaceutical formulation of the present invention, time-controlled controlled release of atorvastatin and telmisartan can be achieved.

1 is a graph showing the comparative elution curve of Mycardis and Lipitor single agent as a test agent and a control agent of Example 1 according to the experimental example.

Figure 2 is a graph showing the comparative elution curve of Mycardis and Lipitor single agent as a test agent (capsule) and a control agent of Examples 5 to 7 according to the experimental example.

Figure 3 is a graph showing the comparative elution curve of Mycardis and Lipitor single agent as a test agent (capsule) and a control agent of Examples 8 to 9 according to the experimental example.

Figure 4 is a graph showing the comparative elution curve of the Mycardis and Lipitor single agent as a test agent (double tablet, multi-layered tablet, nucleated tablet) of Example 2, 3, and 4 according to the experimental example.

FIG. 5 is a graph showing comparative elution curves of Mycardis and Lipitor single agents as test agents (kits and film-coated tablets) of Example 11 and 12 according to Experimental Example.

FIG. 6 is a graph showing a comparative dissolution curve of Mycardis and Lipitor single agent as a test agent (osmotic nucleated tablet) and a control agent of Example 13 according to the experimental example.

Claims (33)

A delayed-release compartment comprising telmisartan, a pharmaceutically acceptable salt thereof, or an isomer thereof as a pharmacologically active ingredient, and atorvastatin, a pharmaceutically acceptable salt thereof, or an isomer thereof as a pharmacologically active ingredient A controlled release pharmaceutical formulation comprising a prior release compartment. The pharmaceutical formulation of claim 1, wherein the atorvastatin of the prior-release compartment releases at least 75% of the total amount of atorvastatin within 1 hour after initiation of release. The pharmaceutical formulation of claim 1, wherein the telmisartan is released 1 hour to 4 hours after the start of atorvastatin release. 4. The pharmaceutical formulation of claim 3, wherein the pharmaceutical formulation is a telmisartan released amount within 2 hours after the start of atorvastatin release, wherein the pharmaceutical formulation is 0-20% of the total amount of telmisartan. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises a release controlling substance selected from the group consisting of enteric polymers, water insoluble polymers, hydrophilic polymers, hydrophobic compounds, and mixtures thereof. The pharmaceutical formulation of claim 5, wherein the release controlling substance is included in an amount of 0.1 to 100 parts by weight based on 1 part by weight of telmisartan. 6. The enteric polymer according to claim 5, wherein the enteric polymer is selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric polymethacrylate copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, and a mixture thereof. Pharmaceutical preparations. The method of claim 7, wherein the enteric cellulose derivative is hypromellose acetate succinate, hypromellose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate At least one selected from cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethyl hydroxyethyl cellulose phthalate, and methyl hydroxyethyl cellulose; The enteric acrylic acid copolymer is selected from the group consisting of styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylate, butyl styrene-acrylic acid acrylate, and methyl methacrylate-octyl acrylate copolymer. At least one selected; The enteric polymethacrylate copolymer may be at least one selected from methacrylic acid-methyl methacrylate copolymer or methacrylic acid-ethyl acrylate copolymer; The enteric maleic acid-based copolymer may be a vinyl acetate-maleic anhydride copolymer, a styrene-maleic anhydride copolymer, a styrene-maleic acid monoester copolymer, a vinyl methyl ether-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, or a vinyl butyl ether At least one selected from maleic anhydride copolymer, acrylonitrile-methyl methacrylate-maleic anhydride copolymer, and butyl styrene-maleic-maleic anhydride copolymer; Or the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinylacetate phthalate, polyvinyl butyrate phthalate and polyvinylacetacetal phthalate. The method of claim 5, wherein the water-insoluble polymer is polyvinyl acetate, water-insoluble polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, A pharmaceutical formulation selected from the group consisting of cellulose diacetate, cellulose triacetate and mixtures thereof. The pharmaceutical composition of claim 5, wherein the hydrophilic polymer is selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof. Formulation. The saccharide according to claim 10, wherein the saccharide is dextrin, polydextrin, dextran, pectin and pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose At least one selected from amylopectin, and amylopectin; The cellulose derivative is selected from hypromellose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose, acetate succinate, and hydroxyethyl methyl cellulose. One or more; The gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, and xanthan gum; The protein is at least one selected from gelatin, casein, and zein; The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylamino acetate; The hydrophilic polymethacrylate copolymer may be a poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer; The polyethylene derivative is at least one selected from polyethylene glycol, and polyethylene oxide; Or the carboxyvinyl polymer is a carbomer. The pharmaceutical formulation of claim 5, wherein the hydrophobic compound is selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof. 6. A pharmaceutical according to claim 5, wherein the release controlling substance comprises an enteric polymer, and the enteric polymer is hypromellose acetate succinate, hypromellose phthalate, polyvinylacetate phthalate, methacrylate acrylic acid copolymer, or a mixture thereof. Pharmaceutical preparations. 6. The pharmaceutical formulation of claim 5, wherein the release controlling substance comprises a water insoluble polymer and the water insoluble polymer is cellulose acetate. 6. The pharmaceutical formulation of claim 5 wherein the release controlling agent comprises a hydrophilic polymer and the hydrophilic polymer is carbomer, hypromellose, or mixtures thereof. 6. The pharmaceutical formulation of claim 5, wherein the release controlling substance comprises an enteric polymer, a water insoluble polymer, or both and a hydrophilic polymer. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises an osmotic pressure regulator and is coated with a semipermeable membrane coating base. 18. The method of claim 17, wherein the semipermeable membrane coating base is polyvinyl acetate, water insoluble poly methacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate , Cellulose diacetate, cellulose tri acetate, and mixtures thereof. 18. The pharmaceutical formulation of claim 17, wherein the osmotic pressure regulator is selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, lithium sulfate, sodium sulfate, and mixtures thereof. 18. The pharmaceutical formulation of claim 17, wherein the semipermeable membrane coating base is ethyl cellulose and the osmotic pressure control agent is sodium chloride. The pharmaceutical formulation of claim 1, wherein the atorvastatin is comprised between 1 and 160 mg in the formulation. The pharmaceutical formulation of claim 1, wherein the telmisartan is comprised between 1 and 200 mg of the formulation. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a delayed-release compartment and a biphasic matrix tablet prepared by mixing and then pre-releasing the prior-release compartment. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a multi-layered tablet in which the delayed-release compartment and the prior-release compartment are layered. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a nucleus tablet consisting of a nuclear tablet consisting of delayed-release compartments and an outer layer consisting of a prior-release compartment surrounding the outer surface of the nuclear tablet. The pharmaceutical formulation of claim 25, wherein the nucleated tablet is an osmotic nucleated tablet. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a capsule comprising particles, granules, pellets, or tablets consisting of delayed-release compartments, and particles, granules, pellets, or tablets consisting of prior-release compartments. The pharmaceutical formulation of claim 1, further comprising a coating layer on the exterior of at least one of the delayed-release compartment or the prior-release compartment. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a coated tablet further comprising a coating layer on the outside. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a kit comprising a delayed release compartment and a prior release compartment. The pharmaceutical formulation of claim 1, wherein the formulation is for evening administration. 32. A pharmaceutical formulation according to any one of claims 1 to 31 for the prevention or treatment of cardiovascular diseases. 33. The cardiovascular system of claim 32, wherein the cardiovascular disease is hypertension, diabetes, obesity, hyperlipidemia, coronary artery disease, chronic stable angina, vasoconstrictive angina, stroke, myocardial infarction, transient ischemic attack, congestive heart failure, insulin resistance, impaired glucose tolerance A pharmaceutical agent, the disease being selected from prediabetes, type 2 diabetes mellitus, diabetic nephropathy, dyslipidemia, cognitive decline, dementia, and combinations thereof.

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