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WO2009134053A2 - Composition pharmaceutique contenant un composé à base de thiazidique à libération contrôlée et un bloqueur du récepteur d'angiotensine ii - Google Patents

Composition pharmaceutique contenant un composé à base de thiazidique à libération contrôlée et un bloqueur du récepteur d'angiotensine ii Download PDF

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Publication number
WO2009134053A2
WO2009134053A2 PCT/KR2009/002219 KR2009002219W WO2009134053A2 WO 2009134053 A2 WO2009134053 A2 WO 2009134053A2 KR 2009002219 W KR2009002219 W KR 2009002219W WO 2009134053 A2 WO2009134053 A2 WO 2009134053A2
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release
cellulose
angiotensin
group
delayed
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Korean (ko)
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WO2009134053A3 (fr
Inventor
김성욱
전성수
조영관
구자성
이아람
손재운
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Hanall Pharmaceutical Co Ltd
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Hanall Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form

Definitions

  • composition comprising controlled release of chiazide-based compound and angiotensin ⁇ ⁇ ⁇ receptor blocker
  • the present invention relates to pharmaceutical compositions of thiazide-based compounds and angiotensin-II ′ receptor blockers and their complex formulation techniques.
  • pharmacological and pharmacological effects can be obtained by taking a controlled formulation of a controlled release rather than taking a single formulation of a chiazide-based compound and an angiotensin ⁇ ⁇ ⁇ receptor blocker at the same time.
  • the present invention relates to a formulation technology that maximizes the clinical anti-pressure effect and the prevention of complications and further reduces side effects.
  • anti-pressure therapy is not the only purpose to lower blood pressure.
  • the purpose of anti-pressure therapy is to prevent myocardial infarction, heart failure, stroke, and premature death, which can be easily merged with hypertension patients, and to prevent the worsening of the condition.
  • Hypertension has a wide variety of causes. Various causes cause hypertension in the same patient. Therefore, it is difficult to determine in advance what results would result from the use of a single antipressant (Journal of human hypertension 1995: 9: 9: S33-S36).
  • the combination formulation makes it very easy for the patient to adhere to the medication. As the elderly population grows, the time spent on prescription medication guidance can be cut in half.
  • Hydrochlorothiazide a representative diazide compound, is chemically named 6-chloro-3, 4—dihydro-2H-1, 2,4-benzothiadiazine-7-sulfonamide 1,1— It is a dioxide, a diuretic effect lasting 6 ⁇ 12 hours when administered orally as a hypertension treatment adjuvant, with a half-life of 5.6-14.8 hours per day.
  • thiazide compound diuretics include chlorothiazide and bendroflumezigit.
  • Angiotensin ⁇ ⁇ ⁇ receptor blockers block the binding of angiotensin receptors, one of the sources of vasoconstriction, and have been shown to be effective in lowering blood pressure in both myocardial systolic and diastolic and are frequently used in clinical trials.
  • the group of compounds being applied has reached about 10 species, including salts that are pharmaceutically usable.
  • they are used alone with patients with symptoms ranging from mild to moderate in hypertension, and with angiotensin converting enzyme inhibitors that have anti-hypertensive effects with similar mechanisms.
  • Angiotension 2 Receptor Antagonist An Overview , Am J Health ⁇ Syst Pharm 57 (13): 1231-1238, 2000].
  • angiotensin ⁇ receptor receptors The anti-pressure and renal protective action of the angiotensin ⁇ receptor receptors is described, for example, in J. Wagner et al. : Effects of ATI receptor blockade on blood pressure and the renin angiotensin system in spontaneously hypertensive rats of the stroke prone strain, Clin, Exp. Hyper t ens. , vol. 20 (1998), p. 205-221; M. Bohm et al. : Angiotensin— ⁇ —receptor blockade in TGR (mREN2) 27: Effects of renin ⁇ angiotensin ⁇ system gene expression and cardiovascular functions, J. Hyper tens., Vol. 13 (8) (1995), p. 891-899.
  • Kidney protective effects are described in the following publications: S. Andersen et al. Renoprotective effects of angiotensin— ⁇ —receptor blockade in type 1 diabetic patients with diabetic nephropathy, Kidney Int. , vol. 57 (2) (2000), p. 601-606; LM Ruilope: Renoprotection and renin-angiotensin system blockade in diabetes mellitus, Am. J. Hyper t ens. , vol. 10 (12PT2) Suppl. (1997), p. 325-331.
  • Hypertension regardless of the type of disease, blood pressure during the day is most The effect of the medication should be expressed early in the morning, when it is rising, and more preferably, the angiotensin and the angiotensin, which are directly responsible for the increase in sleep time and the increase in blood pressure, are synthesized. Diseases in which evening medications are recommended to maintain blood pressure lowering until early morning, when aldosterone synthesis peaks. Patterns of blood pressure response: Day and night variations; American Journal of Hypertension April 2001 . 14, No.
  • Combination preparations product name: Hyzaar, manufacturer: MSD; product name: Diovan HCT, manufacturer: Novartis, etc.
  • hydrochlorothiazide and angiotensin ⁇ ⁇ ⁇ receptor blocker as active ingredients as a ziazide compound diuretic are commercially available, and these are clinically known combinations It has been applied to many hypertensive patients due to the additional blood pressure lowering effect when administered. See Combination Therapy in the Management of Hypertension: Focus on Angiotension Receptor blocker Combined with Diuretics, J Clin Hyper tens.
  • angiotensin ⁇ ⁇ receptor blocker which is a diuretic
  • the angiotensin ⁇ ⁇ receptor blocker not only lowers the blood pressure but also reduces the total plasma volume through diuresis.
  • An additional hypotensive effect can be obtained, thereby increasing the hypertension, which is difficult to recover to normal blood pressure by administration of a single agent of angiotensin ⁇ ⁇ receptor blocker as well as mild hypertensive patients. It has also been found that significant anti-pressure effects can be obtained in patients.
  • hydrochlorothiazide a diazide compound
  • hydrochlorothiazide is a side effect of the diuretic effect of long-term use, and may cause hypokalemia due to excretion of potassium through the kidneys, causing hypokalemia.
  • Angiotensin ⁇ ⁇ receptor receptor is angiotensin By suppressing the production of potassium, the loss of potassium can be prevented.
  • Angiotensin ⁇ ⁇ ⁇ receptor blockers reduce the side effects of long-term administration of hydrochlorothiazit, a thiazide compound diuretic.
  • morning doses of these simultaneous combinations can overcome side effects such as sleep disorders caused by night urination and suburinal urine administration in the evening of hydrochlorothiazide, a thiazide compound diuretic.
  • the pharmacological effect of angiotensin ⁇ ⁇ ⁇ receptor blocker cannot be maintained until the morning of the highest risk time, and evening doses can maximize the pharmacological effect of angiotensin ⁇ ⁇ receptor blocker, but it is not effective in the administration of hydrochlorothiazide, a ziazide-based diuretic.
  • Side effects such as sleep disturbance caused by night urination and night urination are inevitable.
  • the eluted hydrochlorothiazide is eluted first to maintain diuretic effect until bedtime, resulting in a blood pressure lowering effect, penetrating into the blood vessel wall, accumulating and then vasodilating while minimizing sleep disturbance caused by urination at night during sleep.
  • the angiotensin _ ⁇ ⁇ receptor blocker is eluted at a different time, resulting in the sleep time and blood pressure rise, which is the synthesis of renin, a source that causes vasoconstriction.
  • the present invention not only shows the best pharmacological effect of each component through the functional combination of the ziazide compound and angiotensin ⁇ ⁇ ⁇ receptor blocker, but also maximizes the pharmacological effect while reducing side effects of each component when the two components are used together. It is the world's first design of a delayed-release functional combination that makes patient compliance easier. To date, no complex composition that controls the release properties in consideration of pharmacological mechanisms such as absorption, distribution, metabolism and excretion of thiazide-based compounds and angiotensin-II-receptor blockers has not been considered. Detailed description of the invention
  • the present inventors solved the maximization of the effect of the combination of the chiazide compound and angiotensin- ⁇ -receptor blocker from the pharmaceutical point of view, inducing the optimal pharmacological effect according to the absorption ability of the body, and the pharmacological effect of each drug.
  • the present invention has been completed by studying a combination composition that can overcome sleep disorders due to night urination, which is a limitation of the composition, and can increase the patient's medication swelling rate by rational administration once daily in the morning time.
  • a delayed-release compartment comprising an angiotensin ⁇ ⁇ ⁇ receptor blocker or a pharmaceutically acceptable salt thereof as an active ingredient, and a prior-release compartment comprising a thiazide compound or a pharmaceutically acceptable salt thereof as an active ingredient
  • Composite composition with controlled release to enable time difference dissolution characterized in that it comprises a;
  • composition according to the above (1) wherein the active ingredient included in the pre-release compartment releases at least 85% by weight within 1 hour after the start of release;
  • the angiotensin ⁇ _receptor blocker or the pharmaceutically acceptable salt thereof is substantially released after 4 hours from the start of dissolution of the thiazide compound or the pharmaceutically acceptable salt thereof.
  • angiotensin ⁇ -receptor blocker is losartan, valsartan, telmisartan, irbesartan, candesartan, emmesartan, eprosartan, and Selected from the group consisting of their isomers, wherein the ziazide compound is hydrochlorothiazit;
  • a combination composition characterized in that it is selected from the group consisting of chlorothiazide, bendroflumezigit, and their isomers;
  • the angiotensin ⁇ ⁇ 1 receptor blocker or a pharmaceutically acceptable salt thereof according to the above (6) is contained in the range of 5 to 600 mg in the composition, and the thiazide compound or pharmaceutically acceptable thereof A composite composition characterized in that the salt is contained in the range of 2.5 to 100 mg in the composition;
  • the co-composition is characterized in that the sex.compartment is a formulation comprising an osmotic pressure-controlling agent and a coating coated with a semipermeable membrane coating base, and a formulation selected from the group consisting of a kit comprising a delayed-release compartment and a prior-release compartment.
  • the sex.compartment is a formulation comprising an osmotic pressure-controlling agent and a coating coated with a semipermeable membrane coating base, and a formulation selected from the group consisting of a kit comprising a delayed-release compartment and a prior-release compartment.
  • the present invention controls the release of the angiotensin- ⁇ -receptor blocker and the active ingredient of the ziazide-based compound, respectively, to reduce side effects from the therapeutic side and to increase the patient's medication compliance by once-daily administration in the morning. Can be provided.
  • angiotensin ⁇ ⁇ receptor blocker a representative hypotensive agent
  • the above adjustment is preferably performed for a delay of 4 hours or more.
  • the ziazide-based compound with blood half-life of 12 hours or more is released first, the hypotensive action expressed by reducing the total plasma volume through diuresis is maintained until the next administration time, and urination, which can cause sleep disorders, It takes place during the day (am) time and is metabolized in vivo before angiotensin ⁇ ⁇ receptor blockers to prevent further loss of electrolytes that can be caused by co-administration.
  • Angiotensin- ⁇ -receptor blockers which are subsequently released and absorbed, are designed to maintain the blood pressure-lowering action from the evening of the synthesis of vasoconstrictor-inducing substances to the early morning of peak blood pressure, leading to the best therapeutic effect. It will have a blood pressure lowering effect in the time zone.
  • Table 2 The advantages of the composite compositions according to the invention over simple composites are shown in Table 2.
  • Beam 1 is a graph showing the dissolution patterns of hydrochlorothiazide monotherapy, losartan monotherapy, and Example 1.
  • FIG. 2 is a graph showing the dissolution patterns of Coza Plus (hydrochlorothiazide, Losartan simple complex) and Example 2) in the market.
  • Figure 3 is a graph showing the dissolution patterns of Examples 5-8.
  • Figure 4 is a graph showing the dissolution patterns of Examples 7, 9-11.
  • Fig. 5 is a graph showing the dissolution patterns of Koza Fullus F (hydrochlorothiazide, Losartan simple combination), a formulation of Example 15, which is commercially available.
  • Fig. 6 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, losartan monotherapy, and the preparation of Example 16.
  • Fig. 7 is a graph showing the dissolution profiles of hydrochlorothiazide monotherapy, valsartan monotherapy, and formulations containing irbesartan as active ingredients in the formulation of Example 20.
  • Fig. 8 is a graph of the dissolution profiles of a hydrochlorothiazide monotherapy, an irbesartan monotherapy, and an formulation containing irbesartan as an active ingredient in the preparation of Example 21.
  • 9 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, losartan monotherapy, and formulations of Examples 23 and 24.
  • 10 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, telmisartan monotherapy, and formulation of Example 27.
  • FIG. 8 is a graph showing the dissolution profiles of hydrochlorothiazide monotherapy, valsartan monotherapy, and formulations containing irbesartan as active ingredients in the formulation of Example 20.
  • FIG. 11 is a graph of the elution profile of a hydrochlorothiazide monotherapy, an iprosartan monotherapy, and an formulation having Irbesartan as an active ingredient in the formulation of Example 29.
  • FIG. 11 is a graph of the elution profile of a hydrochlorothiazide monotherapy, an iprosartan monotherapy, and an formulation having Irbesartan as an active ingredient in the formulation of Example 29.
  • Fig. 12 is a graph of the dissolution profiles of hydrochlorothiazide monotherapy, cantesartan cilexetil monotherapy, and formulations containing irbesartan as active ingredients in the preparation of Example 30.
  • FIG. 13 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, olmesartan medoxomil monotherapy, and the preparation of Example 31.
  • FIG. 13 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, olmesartan medoxomil monotherapy, and the preparation of Example 31.
  • Fig. 14 is a graph showing the dissolution patterns of the hydrochlorothiazide monotherapy, olmesartan medoxomil monotherapy, and the preparation of Example 37.
  • 17 is a graph comparing the average blood pressure between administration routes as a result of the clinical trial according to Experiment 15.
  • the present invention relates to a composite composition
  • a composite composition comprising a pharmaceutically acceptable carrier, a cyanide compound, and an angiotensin ⁇ receptor receptor as an active ingredient, a delayed-release compartment comprising an angiotensin ⁇ receptor receptor as an active ingredient, and It is characterized by a composite composition having controlled release properties comprising a pre-release compartment containing a zed compound as an active ingredient.
  • the present invention relates to a composite composition designed to control and release each drug at a specific rate by applying the so-called time difference dosing theory (Chronotherapy) principle of staggering the time of pharmacological action in each of the complex components.
  • Chronotherapy time difference dosing theory
  • the combination of Zide-based compound and angiotensin _11 ⁇ receptor blocker provides synergistic effect and reduces side effects, and it is easy to take the medicine for the patient with the convenience of taking 1 tablet once daily in the morning.
  • the present invention relates to a delayed-release complex composition comprising a thiazide-based compound of the new concept and an angiotensin ⁇ receptor receptor.
  • the thiazide compound is rapidly absorbed in the gastrointestinal tract immediately after administration and the angiotensin-?-Receptor blocker is released after a certain time and is absorbed in the small intestine. Specifically, when oral administration, the thiazide compound is released immediately and more than 853 ⁇ 4 of the drug is eluted within 1 hour, and the angiotensin® ⁇ ⁇ receptor blocker delays the release from the gastrointestinal tract and releases up to 4 hours after oral administration.
  • the angiotensin ⁇ ⁇ receptor blocker is delayed in the gastrointestinal tract to release a total of 4 after oral administration
  • the dissolution rate by time is adjusted to release no more than 30%.
  • the angiotensin ⁇ ⁇ ⁇ receptor blocker is controlled to release so that it is absorbed in the liver 2-4 hours later than the thiazide compound, and more preferably, angiotensin ⁇ after 4 hours from the start of dissolution of the thiazide compound ⁇ —controlled to substantially release the receptor blocker.
  • This complex formulated formulation is taken only once in the morning to have an even blood pressure control action, complication inhibition and side effects reduction for 24 hours.
  • the reason for taking the present invention composite composition of the present invention in the morning time is as follows.
  • the thiazide compound since the thiazide compound lasts 12 hours, but only once in the morning, seeps into the blood vessel wall and accumulates a certain amount for 12 hours. This amount of accumulation is insufficient to sustain diuresis for 24 hours, but is adequate to sustain vasodilator for 24 hours. This is why the current 12-hour continuous dose is administered only once a day. It can also overcome side effects such as night urination and sleep disorders caused by night urine.
  • angiotensin ⁇ receptor receptor blockers have a strong blood pressure-lowering effect during the evening from 4 pm to 12 pm during evening sleep. It has a pharmacological rhythm that keeps your blood pressure even. This is because aldosterone and angiotensin ⁇ ⁇ , which are the blood-releasing substances of the renin system, are mainly produced and operated in the night, and angiotensin ⁇ ⁇ receptor blocker inhibits the production of aldosterone and inhibits the action of angiotensin ⁇ . to be.
  • Losartan a representative drug of angiotensin receptor receptor blockers, enters the liver primarily when absorbed. Some of them are the active form of losartan molecules, which are directly spilled into the blood and reach the highest concentration in the blood within 1 hour. However, some of the other enzymes in the liver are caused by two enzymes called cytokine P450 2C7 and 3A4. The metabolism leads to higher activity losartan carboxylic acid, which leads to peak hyperemia levels 3-4 hours later. That is, the pharmacological action of losartan is the pharmacological action of losartan and losartan carboxylic acid complex which is losartan active metabolite.
  • Loss rate in blood is 600 mL / min for losartan and 50 mL / min for active metabolite, which shows a slower loss rate for active metabolite.
  • Treatment of patients with hypertension should maintain blood pressure evenly, especially 24 hours, and suppress heart sympathetic excess erythema 24 hours evenly. This can be achieved only by the present federal formulation formulation technology of the present invention.
  • the pharmaceutical composition comprising the thiazide compound of the present invention and angiotensin ⁇ _ receptor blocker will be described in detail.
  • the thiazide compound may be used as one or two or more combinations selected from hydrochlorothiazide, chlorothiazide, bendroflumezigit and pharmaceutically acceptable salts thereof, but is not limited to these types and is shown above.
  • hydrochlorothiazide or a pharmaceutically acceptable salt thereof can be used.
  • the thiazide compound in the composition is 2.5 to 100 nig, preferably 10 to 50 mg.
  • the dose of each drug is a daily dose based on an adult (an adult male weighing 65 to 75 kg).
  • hydrochloroziazite As a ziazide-based compound exhibiting the above-described blood pressure lowering effect, hydrochloroziazite is described as a specific example in the specification of the present invention, but the present invention is not limited thereto.
  • the angiotensin ⁇ ⁇ receptor receptor blocker included as an active ingredient of the composite composition of the present invention performs a blood pressure lowering action, specific examples thereof are losartan, valsartan, irbesartan, cantesartan, telmisartan, if And one or two or more combinations selected from losartan, olmesartan and pharmaceutically acceptable salts or isomers thereof.
  • the amount of angiotensin ⁇ ⁇ ⁇ receptor blocker in the composition is 5 to 600 mg, preferably . 5 to 300 mg.
  • the dose of each drug is a daily dose based on an adult (65-75 kg adult male).
  • the pharmaceutically acceptable salts mean salts commonly used in the pharmaceutical industry, for example, inorganic ions, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, made of calcium, potassium, sodium and magnesium, Inorganic acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P-Truenesulfonic acid, naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, Oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glutonic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanic acid, Organic acid salts, methanesulfonic acid, ethanesulfonic
  • the anti-pressure (3) hydrochlorothiazide begins during the day when the action is diminished, penetrates into the blood vessel walls, accumulates in the lower blood pressure group, and becomes unsuitable for blood vessels and causes complications during sleep.
  • the risk of inadequate risk during the night time period (for post-weather and post-war concomitant seizures at 9 am) is also more effective for non-dippers than at the same time, as it reduces peak incidence at night.
  • novel compositions of the present invention are delayed-release compartments and thiazides consisting of angiotensin ⁇ ⁇ _receptor blockers, pharmaceutically acceptable salts thereof and the desired excipients so that they can be physically separated or partitioned to achieve different release rates of the two drugs.
  • the pre-release and delayed-release compartments presented above can be implemented in a variety of formulations. That is, the coating particles, granules, pellets or tablets obtained in this way can be coated by a conventional coating method comprising a release controlling substance selected from the group consisting of the delayed-release compartments presented above, multicomponent particles, granules,
  • the pellets can be layered in capsules or formulated into various tablets such as biphasic matrices, film coated tablets, multi-layer tablets nucleated tablets or osmotic nucleated tablets.
  • Such a pharmaceutical composition of the present invention is suitable for the prevention and treatment of kidney disease or for the treatment of cardiovascular diseases, and when taken in the morning time once a day between 6 am to 11 am exerts an effective effect.
  • Pre-release compartment refers to the compartment that is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention, and includes ziazide-based drugs as pharmacologically active ingredients, and further includes a pharmaceutically acceptable additive as necessary. It may include.
  • the delayed-release compartment refers to a compartment in which the active ingredient is released after a certain time of release of the prior-release compartment active ingredient. Delayed-release compartments Angiotensin ⁇ ⁇ receptor blocker, an isomer thereof, or a pharmaceutically acceptable salt thereof, and 1) a release controlling substance or osmotic pressure control agent and a semipermeable membrane coating agent, as necessary, 2) pharmaceutically acceptable Possible additives may further be included.
  • the delayed-release compartment of the present invention uses a material selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, and a combination of an osmotic semipermeable membrane coating base and an osmotic agent.
  • the release controlling substance of the delayed-release compartment may be used in an amount of 10 to 2,000 parts by weight based on 100 parts by weight of the active ingredient. If the amount is less than the above range, the delayed release property may not be obtained. Release is delayed and no significant clinical effect is obtained.
  • the enteric polymer is insoluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or higher.
  • the enteric polymer which can be used in the present invention is at least one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric polymethacrylate copolymer, an enteric maleic acid copolymer and an enteric polyvinyl derivative.
  • Cellulose derivatives include hydroxypropylmethylcellulose acetate succinate, hypromellose phthalate (hydroxypropylmethylcellulose phthalate), hydroxymethylethylcellulose phthalate, celluloseacetate phthalate, cellullo Osacetate Succinate, Cellulose Acetate Maleate, Cellulose Benzoate Phthalate Cell Loss Propionate Phthalate, Methyl Cellulose Phthalate, Carboxymethylethyl Cellulose and Ethylhydroxyethyl Cellulose Phthalate, Methyl Hydrate rock From the agarose with ethyl selreul
  • At least one of the selected i-type enteric acrylic acid copolymers may be selected from the group consisting of styrene-acrylic acid copolymer, methyl acrylate-acrylic acid copolymer, methyl methacrylate acrylic acid copolymer (e.g.
  • enteric polymethacrylate copolymer is a poly (methyl methacrylate) copolymer (e.g., Eudragit L, Eudragit S) , Evonik, Germany), one or more selected from poly (ethyl methacrylate) copolymer (e.g.
  • the enteric maleic acid copolymer is vinyl acetate-maleic anhydride copolymer , Styrene maleic anhydride copolymer, styrene maleic acid monoester copolymer, vinyl methyl ether maleic acid At least one selected from an anhydride copolymer, an ethylene-maleic anhydride copolymer, a vinylbutyl ether-maleic anhydride copolymer, an acrylonitrile-methyl acrylate maleic anhydride copolymer, and a butyl-styrene-maleic anhydride copolymer
  • the enteric polyvinyl derivative is at least one selected from polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinyl acetal phthalate.
  • the enteric polymer is preferably at least one selected from hydroxypropylmethyl cellulose phthalate or acrylic acid methacrylic acid copolymer.
  • the water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug.
  • the water-soluble polymers usable in the present invention include polyvinylacetates (eg, colicoat SR30D), water-insoluble polymethacrylate copolymers [eg, poly (ethylacrylate-methyl methacrylate) copolymers (eg, Eudra).
  • NE30D poly (ethyl acrylate- Methyl methacrylate—trimethylaminoethylmethacrylate chloride) copolymers (eg Eudragit RSP0), etc., ethyl cellulose, cellulose ester cellulose ether, cellulose acylate, cellulose dia At least one member selected from the group consisting of silates, cellulose triacylates, cellulose acetate, cellulose diacetate and cellulose triacetate.
  • the water-insoluble polymer is preferably one or more selected from ethyl cellulose, cellulose acetate, and polyvinylacetate.
  • 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 acid alcohols, waxes, inorganic substances, and mixtures thereof, and the fatty acids and fatty acid esters are glyceryl palmitostearate, At least one selected from glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and slearinic acid, and the fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol.
  • the wax is at least one selected from carnauba wax, beeswax, and microcrystalline wax
  • the inorganic material is selected from talc, precipitated carbonate, calcium hydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum. It is one or more selected.
  • the hydrophobic compound is preferably carnauba wax.
  • the hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug.
  • Hydrophilic polymers that can be used in the present invention Sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl polymers, and mixtures thereof, wherein the sugars are dextrins, polydextrins, At least one selected from dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, and amylopectin;
  • the derivative is at least one selected from hydroxypropylcellose, hydroxypropylcelose, hydroxymethylcellose, hydroxyethylcellose, hydroxyethylcellose, methylcellose and carboxymethylcellose sodium.
  • Gum, locust bean gum, tragacanta, carrageenan, acacia gum The at least one protein selected from ruby gum, gellan gum, and xanthan gum is gelatin, casein, and zein at least one polyvinyl derivative selected from polyvinyl alcohol, polyvinyl pyridone, and polyvinyl acetal diethyl.
  • At least one hydrophilic polymethacrylate copolymer selected from aminoacetates may be a poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (e.g.
  • the polyethylene derivative is at least one selected from polyethylene glycol, polyethylene oxide, and the carboxyvinyl polymer uses carbomer.
  • the hydrophilic polymer is preferably at least one selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyridone, and polyethylene glycol 6000.
  • the osmotic 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 semipermeable membrane coating base is, for example, polyvinyl acetate, polymethacrylate copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacyl And at least one selected from the group consisting of latex, cellulose acetate, cellulose diacetate, cellulose triacetate, and combinations thereof.
  • the semi-permeable coating agent is preferably at least one selected from ethyl cellulose and cellulose acetate.
  • Osmotic agents are selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, lithium sulfate, sodium sulfate, lithium sulfate, sodium sulfate and combinations thereof
  • the release control material is used alone or two or more, 5 to 10,000 parts by weight relative to 100 parts by weight of angiotensin ⁇ ⁇ ⁇ receptor blocker, preferably 20 to 5,000 parts by weight, most preferably 50 ⁇ 3,000 increments are used. At 5 parts by weight or less, it is difficult to have a delayed time, and at 10,000 parts by weight or more, no release of the drug occurs or the delay time exceeds 12 hours.
  • diluents As a pharmaceutically acceptable additive of the delayed-release compartment within the scope of not impairing the effects of the present invention, diluents, binders, disintegrants, lubricants, pH adjusting agents, stabilizers, coloring agents, flavoring agents, surfactants, etc. are suitable. Its content is preferably 100 to 30,000 parts by weight based on 100 parts by weight of the active ingredient.
  • a pharmaceutically acceptable diluent within the scope of not impairing the effects of the present invention sugar, starch, microcrystalline cellulose, lactose, glucose, manny, alginate alkaline earth metal salt, clay, polyethylene glycol and dicalcium phosphate, etc. of Can be used.
  • starch starch, microcrystalline cellulose, highly disperse silica, manny, lactose, polyethylene glycol, polyvinylpyridone, polyvinylpyridone copolymer, hydroxypropyl methylcellose, hydroxypropylcell Acetic acid, natural gum synthetic gum, gelatin and the like can be used.
  • Starch or modified starch such as sodium starch glycolate, potato starch or pregelatinized starch, clays such as bentonite, montmorillonite, veegum, and microcrystalline cellulose low-substituted hydroxypropyl cellulose as disintegrants Or crosslinked cells such as alginic acid and croscarmellose sodium, gums such as guar gum xanthan gum, crosslinked polymers such as crospovidone, and effervescent agents such as sodium bicarbonate and citric acid. It can be used in combination.
  • clays such as bentonite, montmorillonite, veegum, and microcrystalline cellulose low-substituted hydroxypropyl cellulose as disintegrants
  • crosslinked cells such as alginic acid and croscarmellose sodium
  • gums such as guar gum xanthan gum
  • crosslinked polymers such as crospovidone
  • effervescent agents such as sodium bicarbonate and citric acid. It
  • lubricants examples include talc, stearic acid, magnesium stearate, stearic acid calum, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, and glyceryl palmi.
  • Tostearate colloidal silicon dioxide polyethylene glycol 4000 or a combination thereof may be used, and pharmaceutically acceptable additives may be selected and used as various additives selected from pH adjusting agents, stabilizers, surfactants, colorants, and flavoring agents.
  • microcrystalline cellulose pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide, stearic acid magnesium and the like are used. It is not limited, and the above additives may contain a conventional range of dosages by the choice of those skilled in the art. Pharmaceutically, except for the active ingredient constituting the pre-release compartment
  • acceptable additives diluents, binders, disintegrants, lubricants, pH adjusting agents, stabilizers, coloring agents, flavoring agents, surfactants and the like are suitable, and the content thereof is preferably 100 to 30,000 parts by weight based on 100 parts by weight of the active ingredient.
  • Sugar, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol and decalum phosphate may be used as a pharmaceutically acceptable diluent within the scope of not impairing the effects of the present invention. Can be.
  • Starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch as a disintegrating agent, clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose and low-substituted hydroxypropyl and agarose or alginate in selreul, croscarmellose (croscarmellose) and a cross-linked selreul agarose acids such as sodium and gums such as guar gum, xanthan gum, cross-povidone (crospovidone), the cross-linked polymer such as, sodium bicarbonate, citric acid, etc. Can be used in combination.
  • clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose and low-substituted hydroxypropyl and agarose or alginate in selreul, croscarmellose (croscarmellose) and a cross-linked selreul agarose acids
  • talc As lubricants, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, glyceryl palmi Tostearate, colloidal silicon dioxide, polyethylene glycol 4000, or a combination thereof may be used, and pharmaceutically acceptable additives may be selected as various additives selected from pH adjusters, stabilizer surfactants, and colorant flavors.
  • lactose lactose, microcrystalline cellulose, Corn starch, pregelatinized starch, polyvinylpyridone copolymer, sugar, hydroxypropylmethylcellose, hydroxypropylcellose, low-substituted hydroxypropylcellose, colloidal silicon dioxide, magnesium stearate, etc.
  • the scope of the present invention is used is not limited to the use of the additives, the additives may contain a conventional range of capacity by the choice of those skilled in the art.
  • the formulation may form a film-like coating layer on the outer surface of the tablet, if necessary. That is, the thiazide compound / angiotensin ⁇ ⁇ receptor blocker composite composition of the present invention can be used in the form of uncoated tablets without a coating layer, to form a coating layer on the surface of the tablet containing the active ingredient to be formulated into a coated tablet. In this case, there is an advantage of further securing 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 using the above-described components, and can be applied to methods such as a fluidized bed coating method and a fan coating method. Can be. It is preferable to use a pan coating method.
  • the coating layer may be a coating agent, a coating aid or a combination thereof.
  • the coating layer may be used as a coating agent, such as cellulose derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatin, and the like.
  • a coating agent such as cellulose derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatin, and the like.
  • the polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, diethyl phthalate and the like one or two or more kinds thereof may be used.
  • the coating layer is preferably included in the range of 0.5 to 15% by weight of the total weight of the tablet.
  • an angiotensin ⁇ ⁇ receptor blocker is used in one or two or more release control substances selected from enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, osmotic semipermeable membrane coating bases and osmotic agents, and pharmaceutically. It is a step of obtaining a composition designed to enable delayed release in combination with conventional additives.
  • the second step is to use the particles, granules and pellets as they are obtained through the usual procedures for producing oral solids such as mixing, coalescing, drying and granulation from thiazide compounds and conventional pharmaceutically acceptable additives or It is a step of obtaining a composition designed to be capable of pre-release using particles, granules, pellets coated using a coating solution dissolved or suspended with a film coating agent.
  • the third step is to obtain a delayed-release oral combination using a composition designed to be delayed-release and a composition designed to be prior-release obtained in each of steps 1 and 2.
  • the particles, granules or pellets obtained in the first step may be used as is or in an enteric polymer, a water-insoluble polymer or a hydrophobic compound, a hydrophilic polymer, or an osmotic semipermeable membrane.
  • Tablets are prepared by coating with a release controlling substance comprising one or two or more selected from a coating base and an osmotic agent, then mixing with the granules prepared in the second step and tableting to a certain amount of weight.
  • the obtained tablet can be film-coated as necessary for the purpose of improving stability or properties.
  • a release controlling substance comprising particles, granules, pellets or tablets obtained in the first step comprising an enteric polymer, a water-insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent.
  • the outer layer may be coated with a coating solution containing the drug obtained in the second step to prepare a film coated tablet. All. Multilayer Tablet Preparation
  • the particles, granules and pellets obtained in the first step may be used as they are or as an emission control material comprising at least one selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent.
  • the granules and pellets obtained in the second step may be added to prepare double tablets using a multilayer tablet press. If necessary, a triple layer or more multilayered tablets may be prepared or coated by adding an emission auxiliary layer to prepare a coated multilayer tablet.
  • the tablet obtained in the sieve step 1 is used as an inner core tablet, and the enteric polymer and the water insoluble Coating with a release control material comprising one or more selected from polymers, hydrophobic compounds, hydrophilic polymers, osmotic semipermeable membrane coating bases, and osmotic agents, and then using a nucleated tablet press with granules obtained in the second step.
  • Nucleated tablets can be prepared or coated to produce coated nucleated tablets. hemp.
  • the particles, granules and tablets obtained in the first step may be used as they are or as an emission control material comprising at least one selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent.
  • Coated and dried granules, pellets, tablets and granules and tablets obtained in the second step can be put into the capsule layer electrophoresis layered capsule to a certain size capsule by the effective amount of the footnote component. bar.
  • Angiotensin ⁇ ⁇ receptor blockers and release control substances or pharmaceutically acceptable additives are dissolved or suspended in water or organic solvents or mixed solvents, coated on sugar spherical granules, dried and, if necessary, enteric polymers, water insoluble polymers, hydrophobic
  • the release control material comprising one or two or more selected from a compound, a hydrophilic polymer, an osmotic semipermeable membrane coating base, and an osmotic agent is dissolved in water, an organic solvent or a mixed solvent, coated, dried, and then obtained in the second step.
  • Pellets coated with the coating liquid may be layered as they are on the capsule, or a capsule may be layered after film coating. Also, do the above.
  • Delayed-release granules, pellets, Tablets, pre-release granules, pellets, and tablets can be mixed with each other to produce delayed-release (pre-release) granules, granules-pellets, granules-tablets, pellets-granules, tablets-granules. four. Manufacture of kit
  • the angiotensin-containing receptor blocker preparation obtained in the first step and the zigzide compound-containing preparation obtained in the second step can be prepared as a kit that can be simultaneously layered on a foil, a blister or a bed.
  • the complex drug system of the present invention as described above is formulated with a compound containing an ziazide-based compound and angiotensin ⁇ ⁇ ⁇ receptor blocker as an active ingredient, and is administered only once a day in the morning hours to separately formulate each active ingredient.
  • Angiotensin® ⁇ ⁇ Receptor Blocker Delayed-Release Inner Core Tablets Angiotensin ⁇ ⁇ ⁇ Receptor Blocker Delayed-release inner core tablets were prepared in the following compositions and contents as shown in Table 4 with potassium losartan, microcrystalline cellulose, pregelatinized starch, polyvinylpyrrolidone copolymer, and colloidal silicon dioxide * 35. Sieve and mix for 5 minutes with a high-speed mixer to prepare a mixture. After adding magnesium stearate to the mixture, mix for 4 minutes, and use the rotary tableting machine (MRC-33: Sejong) to tablet the species mixture.
  • MRC-33 Sejong
  • the inner core tablet thus prepared was introduced into a high coater (SFC-30N: Sejong Machinery, South Korea), and hydroxypropylmethylcell was dissolved and dispersed in cellulose and acrylic acid methacrylic acid copolymer (acrylate) to be delayed as a coating solution. Ejective inner core tablets were prepared.
  • Preparation of the thiazide compound-releasing layer was carried out in a No. 35 sieve with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, and low-substituted hydroxypropyl cellulose with the composition and contents shown in Table 4. Mix for minutes to prepare the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer Preferably use a fluid bed dryer.
  • Fluid bed granulation drier was used GPCG-l (Glatt, Germany).
  • the dry matter is established using an oscillator equipped with a No. 18 body. Add colloidal silicon dioxide to the formulation and mix with a double cone mixer. Magnesium stearate was added to the above mixture and finally mixed with a double cone mixer. 3) tableting and coating
  • nucleated tablet tableting machine (RUD-1: Kilian) to make the losartan inner core tablet as the inner core tablet and the composition containing the thiazide compound as the outer layer
  • hydroxypropylmethylcellose was separately prepared.
  • 2910, titanium oxide and talc were prepared by dissolving and dispersing a coating solution in 80% ethanol.
  • the above nucleated tablets were put into a high coater (SFC-30N: Sejong Machinery, Korea) and then coated with a coating solution to complete coating nucleated tablets.
  • SFC-30N Sejong Machinery, Korea
  • angiotensin ⁇ ⁇ receptor blocker delayed-release layer was prepared by sieving potassium losartan, microcrystalline cellulose, sodium starch glycolate, and lactose into a No. 35 sieve with a composition and content as shown in Table 6, followed by mixing for 5 minutes using a high speed mixer. Prepare the mixture. Separately, hydroxypropylcell is dissolved, dispersed in hydroxypropylcell, and cellulose phthalate (HP-50), which is combined, granulated and dried. The dried product was placed in a fluidized bed coater, and a solution of hydroxypropylcellulose phthalate (HP-55) and polyethylene glycol 6000 in 220 mg of ethane and 980 mg of methylene chloride was prepared.
  • Preparation of the thiazide-based compound pre-release layer was sieved through the hydrochloricitate, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide with No. 35 in a composition and content as shown in Table 6. By mixing for 5 minutes to prepare a mixture. After the stearic acid magnesium was added to the mixture, the mixture was finally mixed with a double cone mixer for 4 minutes.
  • MRC-37T Sejong Tablet using a multi-layer tablet press
  • the pre-release layer composition containing the ziazide-based compound was placed in the primary powder feeder, and the delayed-release layer composition containing the angiotensin ⁇ ⁇ receptor receptor was placed in the secondary powder feeder, and the tableting was performed under conditions that minimize the infiltration of the layers. do.
  • hydroxypropylmethylcellose 2910, hydroxypropylcelose, hydroxypropylcellose, titanium oxide, and talc were prepared by dissolving and dispersing in 803 ⁇ 4 ethanol.
  • Example 23 Film Coated Tablet Preparation
  • potassium losartan, microcrystalline cellulose, sodium starch glycolate and lactose were sieved through a No. 35 sieve and mixed with a high speed mixer for 5 minutes to prepare a mixture.
  • hydroxypropylcell and hydroxypropylcell are dissolved in purified water and dissolved in purified water to combine, granulate and dry.
  • the dried material was placed in a fluidized bed coater, and a solution obtained by dissolving hydroxypropylcellulose phthalate (HP-55) and polyethylene glycol 6000 in 220 mg of ethane and 980 rag of methylene chloride was prepared. -1: Glatt, Germany) and coated. After the coating was completed, the colloidal silicon dioxide was added and mixed, followed by the addition of stearic acid magnesium, followed by mixing for 4 minutes to prepare angiotensin ⁇ receptor receptor delayed-release granules.
  • hydrochlorothiazide, hydroxyspecific propylmethylcellose 2910, hydroxypropylcelose, titanium oxide, and talc were dissolved and dispersed in 80% ethanol to form a pre-release coating solution containing a thiazide compound.
  • Film coated tablet preparation comprising angiotensin ⁇ receptor receptor delayed release layer and a pre-release layer of a cyanide compound
  • angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release granules of 1) were compressed into tablets using a rotary tablet press, tableting tablets were injected into a high coater (SFC-30N: Sejong Machinery, Korea) and then 2) ziazide System-based pre-release coating solution The coating was completed to prepare a delayed-release compartment in the form of a film-coated tablet including an angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release layer and a thiazide compound pre-release layer.
  • Example 24 Preparation of Capsules (Granules-Particles)
  • potassium losar, microcrystalline cellulose, sodium starch glycolate and lactose were sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture.
  • hydroxypropylcell and hydroxypropylcell are dissolved in purified water and dissolved in purified water to combine, granulate and dry.
  • the dried product was placed in a fluidized bed coater, and a liquid obtained by dissolving hydrated propyl cellulose (HP-55) and polyethylene glycol 6000 in 220 mg of ethanol and 980 mg of methylene chloride was prepared. 1: Glatt, Germany) and coated. After the coating was completed, the colloidal silicon dioxide was added and mixed, followed by the addition of stearic acid magnesium, followed by mixing for 4 minutes to prepare angiotensin ⁇ receptor receptor delayed-release granules.
  • hydrochlorothiazide, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide were sieved through a No. 35 sieve and mixed for 5 minutes with a high speed mixer to prepare a mixture.
  • irbesartan, lactose, croscarmellose sodium and sodium chloride were sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture.
  • pregelatinized starch and poloxamer 188 were dissolved in purified water to form a binder, and then combined and dried.
  • the dried material was placed in a fluidized bed coater, and separately cellulose acetate (32% acetyl), cellulose acetate (39.8% acetyl), and hydroxypropylmethylcellose were dissolved in 220 mg of ethanol and 980 mg of methylene chloride, and Dispersed coating solution was prepared and the above granules were put in a fluidized bed granulation coater (GPCG- 1: Glatt, Germany) and coated.
  • Angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release granules were prepared by adding microcrystalline cells to the coating and adding colloidal silicon dioxide.
  • the zigzide compound hydrochlorothiazide and the excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer.
  • a biphasic matrix tablet was prepared with the composition and content shown in Table 7 according to the same biphasic matrix tablet manufacturing method as in Example 25.
  • Example 28 Preparation of Capsules (Pellets-Granules)
  • the sugar seeds were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellose and losartan potassium were separately added to water and ethane.
  • the dissolved binder solution was sprayed to form pellets containing angiotensin® receptor blocker.
  • the granules were then sprayed with a solution of hydroxypropyl methylcellulose phthalate dissolved in 220 mg of ethane and 980 mg of methylene chloride to prepare angiotensin® receptor receptor blocker delayed-release pellets.
  • the thiazide compound pre-release layer is as shown in Table 8 Hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxypropyl cellulose were added, sieved through a No. 35 sieve, and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer is used.
  • Fluid bed granulation dryer was used GPCG-l (Glatt, Germany).
  • the dry matter is established using an oscillator equipped with a No. 18 body. Colloidal silicon dioxide is added to the formulation and mixed with a double cone mixer.
  • the sugar sphere was sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellose and iprosartan were separately added to water and ethanol.
  • the dissolved binder solution was sprayed to form pellets containing angiotensin ⁇ i receptor receptor blocker and dried. Again, 220 mg of ethane and methylene chloride with hydroxypropylmethylcelloseophthalate were added to the granules.
  • Angiotensin-? Receptor receptor blocker delayed-release pellets were prepared by spraying a solution dissolved in 980 mg.
  • the sugar seeds were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcell was dissolved in water and ethanol. The solution was sprayed and dried to form a thiazide compound pre-release pellet.
  • GPCG 1 Glatt
  • sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and then hydroxypropylmethylcellose and candesartan were dissolved separately in water and ethanol.
  • the binder solution was sprayed to form pellets containing angiotensin ⁇ i ⁇ receptor blocker and dried.
  • the back angiotensin eu ⁇ eu receptor blocker delayed-release pellets by spraying a liquid obtained by dissolving the ethane agarose phthalate with hydroxypropyl methylcellulose selreul in the granules through 220m g and 980 mg of methylene chloride was prepared.
  • the zigzide compound hydrochlorothiazide and the excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer. Magnesium stearate was added to this mixture and finally mixed. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a thiazide compound-release tablet.
  • the angiotensin ⁇ ⁇ receptor blocker delayed-release granules were sieved with oligosarthan medoxomil microcrystalline cell as No. 35 and mixed with a high speed mixer as shown in Table 8. Colicoat SR30D was associated with the main component mixture. After the union is completed, the granules are granulated by using an oscillator in No. 18 and dried in a fluid bed dryer or a hot water dryer. Preferably a fluid bed dryer is used. Fluid bed granulation dryer was used GPCG-l (Glatt, Germany). When the drying was completed, it was reestablished as No. 20 sieve to prepare angiotensin ⁇ ⁇ receptor receptor delayed-release granules. 2) Preparation of Chiazide Compound Pre-Release Granules
  • the thiazide-based compound pre-release layer was sieved with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxypropyl cellulose, and sieved through a No. 35 sieve. Combine to produce the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer is used.
  • the fluid bed granule dryer used GPCG-1 (Glatt; Germany).
  • the dry matter is established using an oscillator equipped with a No. 18 body. Add colloidal silicon dioxide to the formulation and mix with a double cone mixer.
  • Angiotensin ⁇ ⁇ ⁇ Receptor blocker delayed-release granules were sieved through a No. 35 sieve with valsartan, microcrystalline cellulose, cross-linked polyvinylpyridone, and mixed in a double cone mixer for 5 minutes, as shown in Table 8, to prepare a mixture.
  • do. seperately Polyvinylpyridone is dissolved in purified water to prepare a binding solution.
  • the mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution.
  • fluid bed granulators are used.
  • the fluid bed granulator used GPCG - l (Glatt; Germany).
  • the granules are dried in a fluid bed dryer or a silver dryer.
  • a fluid bed dryer is used.
  • Fluid bed granulation dryer was used GPCG-l (Glatt, Germany).
  • the granules were sprayed with carnauba wax ethane dissolved in 220 mg of ethane and 980 mg of methylene chloride to prepare angiotensin ⁇ receptor blocker delayed-release granules.
  • sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellose and hydrochlorothiazide were dissolved separately in water and ethane.
  • the binder solution was spray dried to form a thiazide compound pre-release pellet.
  • Angiotensin _ ⁇ receptor blocker delayed-release granules are shown in Table 8.
  • telmisartan, microcrystalline cellulose, and meglumine were added, sieved through a No. 35 sieve, and mixed in a double cone mixer for 5 minutes to prepare a mixture.
  • Solbi, polyvinylpyridone, and sodium hydroxide are dissolved in purified water to prepare a binding solution.
  • the mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution.
  • fluid bed granulators are used. Fluid bed granulator (GPCG-KGlatt, Germany) was used.
  • the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer is used.
  • Fluid bed granulation drier was used GPCG-l (Glatt, Germany).
  • the granules were sprayed again with carnauba wax dissolved in 220 mg of ethanol and 980 mg of methylene chloride, thereby preparing angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release granules.
  • zigzide compound hydrochlorothiazide and excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer. Magnesium stearate was added to this mixture and finally mixed. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a thiazide compound-release tablet.
  • angiotensin ⁇ ⁇ receptor blocker delayed-release tablets were sieved through Losartan potassium, microcrystalline cellulose, pregelatinized starch, polyvinylpyridone copolymer, and colloidal silicon dioxide with No. 35.
  • the mixture is prepared by mixing in a mixer for 5 minutes. After adding magnesium stearate to the mixture, mix for 4 minutes and tablet the final mixture using a rotary tablet press (MRC-33: Sejong).
  • the tablet thus prepared is put into a high coater (SFC-30N: Sejong Machinery, Korea).
  • the tablet was sprayed with a solution of polyethylene glycol 6000 and hydroxypropyl methylcellose phthalate in 220 mg of ethanol and 980 mg of methylene chloride to prepare an angiotensin receptor blocker delayed-release tablet.
  • the thiazide compound pre-release layer was sieved with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxypropyl cellulose and sieved through a No. 35 sieve, and then shaken for 5 minutes in a double cone mixer. Combine to produce the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high speed granulator and granulated by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • the granules are dried in a fluid bed dryer or a silver dryer.
  • a fluid bed dryer is used.
  • Fluidized bed granulation dryers are available from GPCG-l (Glatt, Germany). Used.
  • the dry matter is established using an oscillator equipped with a No. 18 body. Colloidal silicon dioxide is added to the formulation and mixed with a double cone mixer.
  • Angiotensin ⁇ ⁇ receptor blocker delayed-release tablets were sieved through valsartan, microcrystalline cellulose, and crosslinked polyvinylpyridone as No. 35, and mixed for 5 minutes using a high-speed mixer to prepare a mixture. .
  • polyvinylpyridone is dissolved in purified water to prepare a binding solution.
  • the mixture is put into a fluidized bed granulator or a high speed granulator and granulated by adding a binder solution.
  • fluid bed granulators are used.
  • the fluid bed granulator used GPCG-l (Glatt, Germany). After the assembly is completed, the granulated material is dried in a fluidized bed dryer or a hot water dryer.
  • a fluid bed dryer is used.
  • GPCG-l (Glatt, Germany) was used for the evaporated granule dryer.
  • the dry matter is established using an oscillator equipped with a No. 18 body.
  • Magnesium stearate is added to the formulation and finally mixed with a double cone mixer.
  • the final mixture is compressed using a rotary tablet press (MRC-33: Sejong).
  • the tablet thus prepared is put into a high coater (SFC-30N: Sejong Machinery, Korea).
  • SFC-30N Sejong Machinery, Korea.
  • Angiotensin-? Receptor receptor blocker delayed-release tablets were prepared by spraying a solution of hydroxypropylmethylcelloose phthalate in 220 mg of ethanol and 980 mg of methylene chloride.
  • the sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropylmethylcellulose and hydrochlorothiazide were dissolved separately in water and ethanol. The liquid was spray dried to form a thiazide compound pre-release pellet.
  • GPCG 1 Glatt
  • steps 1) and 2) were combined with a double cone mixer.
  • the mixture was placed in a powder feeder and filled using capsule bed electricity to complete the preparation of the controlled release formulation in capsule form.
  • Angiotensin ⁇ ⁇ ⁇ receptor blocker delayed-release tablets were sieved with telmisartan, microcrystalline cellulose, and meglumine as No. 35, and then mixed with a No. 35 sieve for 5 minutes in a double cone mixer to prepare a mixture. .
  • sorbetle, polyvinylpyridone, and sodium hydroxide are dissolved in purified water to prepare a binding solution.
  • the mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution.
  • fluid bed granulators are used. Fluid bed granulator (GPCG-KGlatt, Germany) was used.
  • Fluidized dryer or after assembly Dry the assembly in a hot water dryer.
  • a fluid bed dryer is used.
  • Fluid bed granulation dryer was used GPCG ⁇ l (GIatt, Germany).
  • the dry matter is established using an oscillator equipped with a No. 18 body.
  • Magnesium stearate is added to the formulation and finally mixed with a double cone mixer.
  • the final mixture is compressed using a rotary tablet press (MRC-33: Sejong).
  • the tablet thus prepared is put into a high coater (SFC-30N: Sejong Machinery, Korea).
  • angiotensin _ ⁇ ⁇ receptor blocker delayed-release tablet To the above tablets, a solution of ethylcellose and methacrylic acid co-polymer type C dissolved in 220 mg of ethanol and 980 mg of methylene chloride was sprayed to prepare angiotensin _ ⁇ ⁇ receptor blocker delayed-release tablet.
  • ziazide-based compound hydrochlorothiazide and excipient microcrystalline cellulose, pregelatinized starch, polyvinylpyridone co-polymer, and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed with a high speed mixer. Stearic acid magnesium was added to this mixture for final mixing. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a thiazide compound-release tablet.
  • a rotary tableting machine (MRC-33: Sejong).
  • MRC-33 Sejong
  • ethylcellose was dispersed in purified water, and then coated with an inner core tablet using a high coater (SFC-30N, Sejong Machinery, Korea) to prepare an osmotic inner core tablet.
  • thiazide compound-release layer Preparation of the thiazide compound-release layer was carried out with hydrochlorothiazide, microcrystalline cellulose, lactose, corn starch, low-substituted hydroxylpropyl cellulose as shown in Table 9 and sieved through No. 35 sieve for 5 minutes in a double cone mixer. Are mixed to produce the mixture. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution. The mixture is put into a fluidized bed granulator or a high-speed rotary granulator and assembled by adding a binder solution. Preferably fluid bed granulators are used. The fluid bed granulator used GPCG-l (Glatt, Germany).
  • fluid bed dryers Preferably fluid bed dryers are used. Fluid bed granulation drier was used GPCG-l (Glatt, Germany).
  • GPCG-l Gelatt, Germany.
  • the dry matter is established using an oscillator equipped with a No. 18 body. Add colloidal silicon dioxide to the formulation and mix with a double cone mixer. Magnesium stearate was added to the above mixture, and the final mixture was mixed with a debulcon mixer.
  • Osmotic nucleated tablets were prepared according to the composition and contents of Table 9 according to the same method for preparing the osmotic nucleated tablets as in Example 37.
  • Example 40 Blaster Packaging Kit
  • Example 15 The granules of Example 15, Step 1) and Example 15, Step 2) of Example 15 instead of mixing 1) angiotensin ⁇ i ⁇ receptor blocker delayed-release granules of Example 15 and 2) thiazide-based compound prior-release granules
  • the final composition of each process was compressed into tablets using a rotary tablet press (MRC-33: Sejong) and packaged for simultaneous use in a blister packaging container.
  • composition ratio (mg / t ablet)
  • Irbesi-Letan 150 Valsartan 80 Microcrystalline Cellulose 150 100 25 137 123 40 75 Sodium starch glycolate 8 8
  • Collicoat SR 30D (ingredient name: 30% suspension of polyvinyl acetate, bran 1: BASF) Table 71
  • the hydrochlorothiazide component of the nucleated tablet of the present invention was found to have almost the same elution characteristics as that of the control preparation dichroic tablet in the dissolution test, but the losartan component was very delayed in dissolution compared to the control agent Koza. You can check the speed.
  • the dissolution of the losartan component up to 120 minutes which is the artificial gastric juice section, was found to be within 10% of the nucleated tablet of losartan / hydrochlorothiazide of the present invention, but the control agent was about 60%.
  • the loss of losartan in the artificial serous section Elution was 100% in the total 150 minutes in the control agent, it was confirmed that much slower to about 2 in 240 minutes in the nucleated tablet functional combination of losartan / hydrochlorothiazide of the present invention.
  • the nucleated tablet formulation of losartan / hydrochlorothiazit of the present invention is different from the dissolution of the losartan monotherapy and the hydroclohozigit single agent, so that the initial release of losartan is much slower than hydrochlorothiazit. It is a pharmaceutical composition that is very effective in treating hypertension because it can be injected at the time when the secondary blood pressure lowering effect occurs. [Test Method of Thiazide-Based Compound Pre-Emission Layer]
  • Dissolution test basis Test method for 'hydrochlorothiazide purification' in USP 30: Apparatus 1 [Paddle method], 100 revolutions / minute
  • Test solution 0. IN—hydrochloric acid, 900 mL
  • Dissolution test basis Dissolution test method of General Test Method
  • Test Method Paddle Method, 50 Turns / Min
  • Test drug 0.1M hydrochloric acid solution, 750mL (artificial gas solution)
  • Experimental Example 2 Comparative Dissolution Profile Test The comparative dissolution test of the losartan / hydrochlorothiazide inner core tablet prepared in Example 2 and the composite control (coza plus tablet, MSD: losartan / hydrochlorothiazide composite) were carried out. . Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • hydrochlorothiazide component of the nucleated tablet of the present invention exhibited faster dissolution characteristics when compared to the control formulation Coza plus tablet when the dissolution test was carried out under the conditions of Experimental Example 1, but the hydrochlorothiazide elution of Coza plus tablet was the single agent or the present invention.
  • hydrochlorothiazide is affected by losartan, which has a slow elution rate in acid, because it is a simple complex without division. Elution rates are different from those of monoliths. In order to achieve the best effect of hydrochlorothiazide, it is necessary to show a fast dissolution rate similar to that of a single agent, not the delayed dissolution rate of a simple combination.
  • Losartan component can confirm a very delayed dissolution rate as in Experimental Example 1 compared to the control formulation Coza Plus.
  • the nucleated tablet formulation of losartan / hydrochlorothiazit of the present invention has a faster release rate of hydrochlorothiazit than Cozaplus, unlike the dissolution of the case of simultaneous administration of the losartan / hydrochlorothiazit simple combination without a compartment, which is a reference. Since the initial release is much slower than hydrochlorothiazide, it can be applied at the time when the second hypotensive effect of hydrochlorothiazide occurs, which is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 3 Comparative Dissolution Profile Test The comparative dissolution test of Examples 5 to 8 was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the nucleated tablet formulation of losartan / hydrochlorothiazide of the present invention can delay the initial release of losartan by an intended time by controlling the amount of ethylcell used in the coating. Therefore, losartan can be injected at the time when the second hypotensive effect of hydrochlorothiazide occurs. It is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 4 Comparative Dissolution Profile Test The comparative dissolution test of Examples 7 and 9 to 11 was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the nucleated tablet of the present invention has a delay time until the intended time of the lossartan component when polyvinylpyridone is present in the delayed release layer coated with ethylcellose. After it was confirmed that the release is relatively rapid. The dissolution of the losartan component was within 20% for a total of 240 minutes, and the losartan component was rapidly released as the amount of the polyvinylpyridone was increased.
  • the nucleated tablet formulation of losartan / hydrochlorothiazide of the present invention rapidly releases losartan after having a delay time until the intended time by controlling the amount of polyvinylpyrrolidone used in the delayed release layer coated with ethylcellose. You can. Therefore, losartan can be added at the time when the secondary blood pressure lowering effect of hydrochlorothiazide occurs, which is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 5 Comparative dissolution profile test The comparative dissolution test of the losartan / hydrochlorothiazide multilayer tablet and the composite control (coza plus F tablet, MSD: losartan / hydrochlorothiazide complex) prepared according to Example 15 was carried out. It was. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • Losartan component can confirm a very delayed dissolution rate as in Experimental Example 1 compared to the coza plus F tablets.
  • the multi-layered tablet formulation of losartan / hydrochlorothiazit of the present invention exhibits a faster release rate of hydrochlorothiazit than Coza plus F tablet, unlike the dissolution of co-administration of losartan / hydrochlorothiazide simple combination without a compartment. Since the initial release of losartan is much slower than hydrochlorothiazit, it can be applied at the time of the second hypotensive effect of hydrochlorothiazide, which is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 6 Comparative dissolution profile test Losartan / hydrochlorothiazide multilayer tablet prepared according to Example 16 and each component mono-control (coza-crystal, MSD: Losartan mono-I dichroic tablet, finite positive: hydrochlorothiazide Comparative dissolution test of a single agent) was performed.
  • the dissolution test method for each component is the same as in Experimental Example 1, and the nodules thereof are shown in FIG. 6.
  • the hydrochlorothiazide component of the multi-layered tablet of the present invention was almost equivalent to that of the control drug dichromatin tablet. It was confirmed that the dissolution characteristics, but the losartan component was confirmed to be very delayed dissolution rate compared to the control agent Koza.
  • the multi-layered tablet of losartan / hydrochlorothiazide of the present invention has a secondary blood pressure of hydrochlorothiazit because the initial release of losartan is much slower than that of hydrochlorothiazide, unlike the dissolution of co-administration of losartan monotherapy and hydrochlorothiazine monotherapy. It is a pharmaceutical composition that can be injected at the time of the lowering effect and is very effective in treating hypertension.
  • Experimental Example 7 Comparative dissolution profile test Valsartan / hydrochlorothiazide multilayer tablet prepared according to Example 20 and each component monotherapy control (dioban tablet, MSD: Valsartan monosaccharide I dichroic tablet, finite positive: hydrochlorothiazine monolith) A comparative dissolution test of was conducted. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG. According to FIG. 7, in the dissolution test under the conditions of Experimental Example 1, the hydrochlorothiazide component of the multi-layered tablet of the present invention was found to exhibit almost the same dissolution characteristics as that of the control, dichroic tablet, but the valsartan component was compared with the diovan, the control formulation.
  • the dissolution rate of the valsartan component in the artificial serous section was found to be much slower in the valsartan / hydrochlorothiazit of the present invention, about 20% in 240 minutes in total, compared to the control agent.
  • the multi-layered tablet formulation of valsartan / hydrochlorothiazide of the present invention has a secondary blood pressure lowering effect of hydrochlorothiazit because the initial release of valsartan is much slower than that of hydrochlorothiazide, unlike the dissolution of the valsartan monohydrochloride and the hydrochlorothiazide monotherapy simultaneously. Occurring It can be added at a point in time is a very effective pharmaceutical composition for treating hypertension.
  • Experimental Example 8 Comparative dissolution profile test ((X) mparative dissolution profile test) Irbesartan / hydrochlorothiazit multilayer tablets prepared according to Example 21 above and each component monoclonal control drug (Aprobel tablet, MSD: Irbesartan monosaccharide I Dike Rosin tablet, Yuhan Corporation: A comparative dissolution test of hydrochlorothiazide single agent) was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the hydrochlorothiazide component of the multi-layered tablet of the present invention was found to exhibit almost the same dissolution characteristics as that of the control, dichroic tablet, and the Irbesartan component was a control formulation. Compared with Diovan, we found very delayed dissolution rate. According to the dissolution test results of the irbesartan component, the dissolution rate of the irbesartan component in the artificial serous section was about 20% in 240 minutes in the multi-layered functional complex of irbesartan / hydrochlorothiazide of the present invention, unlike the control agent. It was confirmed that much slower.
  • the multi-layered tablet formulation of irbesartan / hydrochlorothiazide of the present invention is obtained when the irbesartan single agent and the hydrochlorothiazit single agent are simultaneously administered.
  • the initial release of irbesartan is much slower than hydrochlorothiazide, so it can be injected at the time of the secondary hypotensive effect of hydrochlorothiazide, which is a very effective pharmaceutical composition for the treatment of hypertension.
  • the film-coated tablets or capsules of losartan / hydrochlorothiazit of the present invention are different from the dissolution of the losartan monohydrochloride and the hydrochlorothiazine monoclonal drug, and thus the initial release of losartan is much slower than that of hydrochlorothiazide. It is a pharmaceutical composition that is very effective in treating hypertension because it can be injected at the time when the primary blood pressure lowering effect occurs.
  • Experimental Example 10 Comparative dissolution profile test Telmisartan / hydrochlorothiazit biphasic matrix tablets prepared according to Example 27 above, and each component of the single-agent reference drug (Micadis, Boehringer: I dichroic tablets, Yuhan Corporation: hydrochlorothiazide mono-)) was subjected to a comparative dissolution test. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • telmisartan / hydrochlorothiazit two-phase matrix tablet of the present invention is different from the dissolution of the telmisartan monohydrochloride and the hydrochlorothiazit monotherapy simultaneously, so that the initial release of telmisartan is much slower than that of the hydrochlorothiazit.
  • the hydrochlorothiazide component of the capsule (pelt-pellet) of the present invention was found to have almost the same dissolution characteristics as compared to the dichromat tablet, a control formulation, butyprosartan The component can identify a very delayed dissolution rate when compared to the control drug tebeten.
  • iprosartan / hydrochlorothiazide capsulicide pellet-pellet
  • the initial release of iprosartan is higher than that of hydrochlorothiazide.
  • hydrochlorothiazide because it is very slow It is a pharmaceutical composition that is very effective in the treatment of hypertension because it can be injected at the time when the hypotensive effect occurs.
  • the candesartan cilexetil / hydrochlorothiazit capsule (pellet-tablet) of the present invention has a very slow initial release of losartan, unlike the dissolution of the candesartan monotherapy and the hydrochlorothiazit monotherapy simultaneously. Therefore, it can be injected at the time when the secondary blood pressure lowering effect of hydrochlorothiazide is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 13 Comparative Dissolution Profile Test The emmesartan medoxomil / hydrochlorothiazide capsul agent (granule-granule) prepared according to Example 31 above and each component mono-control (olmetec tablet, Daewoong Pharma: A comparative dissolution test of olmesartan medoxomil single agent / dichroic tablet, Yuhan Corporation: hydrochlorothiazide single agent) was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the hydrochlorothiazide component of the capsulant (granule-granule) of the present invention was found to exhibit almost the same dissolution characteristics as compared to the dichromat tablet as a control formulation. Compared to Olmetec, a control formulation, very slow dissolution rates can be observed.
  • the olmesartan medoxomil / hydrochlorothiazit capsule (granule-granule) of the present invention has a very slow initial release of olmesartan, unlike the dissolution of the co-administration of losartan monotherapy and hydrochlorothiazit monotherapy. Therefore, it can be injected at the time when the secondary blood pressure lowering effect of hydrochlorothiazide is a very effective pharmaceutical composition for the treatment of hypertension.
  • Experimental Example 14 Comparative Dissolution Profile Test Losartan Potassium / Hydrochlorothiazit Osmotic Nucleus Tablets Prepared According to Example 37 and a Single-Component Reference (Coza Tablet, MSD: Losartan Potassium Monochloride I Dichroic Tablet) , Yuhan Corporation: A comparative dissolution test of hydrochlorothiazide single agent) was performed. Dissolution test method for each component is the same as Experimental Example 1, the results are shown as shown in FIG.
  • the hydrochlorothiazide component of the osmotic nucleated tablet of the present invention was found to exhibit almost the same dissolution characteristics as that of the control, dichroic tablet, but the losartan component was controlled. Compared to co-crystal, the formulation, very slow dissolution rates can be identified.
  • the losartan potassium / hydrochlorothiazit osmotic nucleus tablet of the present invention has a secondary effect of hydrochlorothiazide because the initial release of losartan is much slower than that of hydrochlorothiazide, unlike the dissolution of the losartan monotherapy and the hydrochlorothiazit monotherapy simultaneously. It is a pharmaceutical composition that is very effective in the treatment of hypertension because it can be injected at the time of the hypotensive effect.
  • Experimental Example 15 Animal Study
  • This test is a rat model animal test. It is designed by dividing light condition and dark condition. The biorhythms of rats and humans are opposite, so when applied to humans, the time zone is reversed. > 1. In terms of blood pressure drop, systolic and diastolic blood pressures were lower than those of the screening group at 5 days.
  • the blood pressure level was lower in the hourly group compared to the concurrent group and the hourly group.
  • the hourly group showed the lowest blood pressure level in the morning (cancer) than in the evening (dark). .
  • the blood pressure drop effect of each time slot is as shown in Figs. 15-17.
  • the morning time difference group was confirmed to have the best blood pressure lowering effect among the four groups.
  • composition according to the present invention has an optimal blood pressure lowering effect during the time from the morning of the morning until the middle of the day after the administration of the average blood pressure, unlike the conventional simultaneous administration group.
  • the time-administrated case was administered for the purpose of lowering blood pressure than when the single agent of angiotensin _ receptor receptor and hydrochlorothiazide was administered simultaneously. It can be seen that the optimal effect of the clinical antihypertensive effect of angiotensin ⁇ ⁇ receptor blocker and hydrochlorothiazit is expressed.
  • Table 9 is a result of measuring the blood pressure and the pulse rate between the co-administered group of losartan and hydrochlorothiazide and the morning time difference group (cancer condition) according to the present invention.
  • the hypotensive action of losartan and hydrochlorothiazide is The mean time of systolic blood pressure drop was 5.83 ⁇ 4, mean diastolic pressure drop was 5.6%, and mean blood pressure drop was 9.9% in the time-difference group, which was provided by the test group.
  • the pulse rate increased to 0.08%, indicating no significant difference.
  • the delayed drug release of losartan administered for the purpose of lowering blood pressure with a time difference of 4 hours as intended by the present invention has an excellent blood pressure lowering effect compared to the time-administered group.
  • Table 13 is according to the administration time of losartan and hydrochlorothiazit It is the result of measuring blood pressure.
  • the mean systolic blood pressure lowering effect was 4.0%, and the average sin: gastric diastolic blood pressure was higher than the evening time difference group (dark condition).
  • the drop in blood pressure was 2.2%, mean blood pressure drop was 3.1%, and pulse rate was 7.0%.

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Abstract

L'invention concerne une composition pharmaceutique dans laquelle la libération d'un composé à base de thiazidique et d'un bloqueur du récepteur d'angiotensine II est contrôlée, et une technique de préparation de combinaison de celle-ci. Elle concerne, plus particulièrement, une technique de préparation capable de maximiser les effets de régulation de pression sanguine pharmacologique et clinique et les effets de prévention de complication et de réduire de manière significative les effets secondaires par administration d'une préparation de combinaison à libération contrôlée plutôt que par administration simultanée d'une préparation contenant uniquement un composé à base de thiazidique et d'une préparation contenant uniquement un bloqueur du récepteur d'angiotensine II.
PCT/KR2009/002219 2008-04-29 2009-04-28 Composition pharmaceutique contenant un composé à base de thiazidique à libération contrôlée et un bloqueur du récepteur d'angiotensine ii Ceased WO2009134053A2 (fr)

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US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers
US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides

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US20050013863A1 (en) * 2003-07-18 2005-01-20 Depomed, Inc., A Corporation Of The State Of California Dual drug dosage forms with improved separation of drugs
KR100648825B1 (ko) * 2005-02-22 2006-11-24 한국유나이티드제약 주식회사 당뇨병 환자의 동맥경화증 예방을 위한 혈당강하제, 에이치엠지이-씨오에이 환원효소 저해제 및 장용코팅된 아스피린을 함유하는 복합 펠렛
KR100762847B1 (ko) * 2006-01-27 2007-10-04 씨제이 주식회사 멀티플 유닛 타입 서방성 경구 제제 및 그 제조방법
WO2008023869A1 (fr) * 2006-08-24 2008-02-28 Hanall Pharmaceutical Co., Ltd. PRÉPARATION PHARMACEUTIQUE COMBINÉE À LIBÉRATION CONTRÔLÉE COMPRENANT DES INHIBITEURS CALCIQUES À BASE DE DIHYDROPYRIDINE ET DES INHIBITEURS DE HMG-CoA RÉDUCTASE

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US12109223B2 (en) 2020-12-03 2024-10-08 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12433910B2 (en) 2020-12-03 2025-10-07 Battelle Memorial Institute Polymer nanoparticle and DNA nanostructure compositions and methods for non-viral delivery
US12031128B2 (en) 2021-04-07 2024-07-09 Battelle Memorial Institute Rapid design, build, test, and learn technologies for identifying and using non-viral carriers
US12458606B2 (en) 2023-09-29 2025-11-04 Battelle Memorial Institute Polymer nanoparticle compositions for in vivo expression of polypeptides
US12441996B2 (en) 2023-12-08 2025-10-14 Battelle Memorial Institute Use of DNA origami nanostructures for molecular information based data storage systems

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