WO2010021473A2 - Formulation pharmaceutique - Google Patents

Formulation pharmaceutique Download PDF

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Publication number
WO2010021473A2
WO2010021473A2 PCT/KR2009/004565 KR2009004565W WO2010021473A2 WO 2010021473 A2 WO2010021473 A2 WO 2010021473A2 KR 2009004565 W KR2009004565 W KR 2009004565W WO 2010021473 A2 WO2010021473 A2 WO 2010021473A2
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Prior art keywords
release
tablet
delayed
formulation
pharmaceutical formulation
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PCT/KR2009/004565
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English (en)
Korean (ko)
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WO2010021473A3 (fr
Inventor
김성욱
전성수
구자성
김진욱
이영주
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한올제약주식회사
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Publication of WO2010021473A2 publication Critical patent/WO2010021473A2/fr
Publication of WO2010021473A3 publication Critical patent/WO2010021473A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • the present invention relates to a morning pharmaceutical formulation containing a dihydropyridine calcium channel blocker and an HMG-CoA reductase inhibitor.
  • Hypertension often coexists with coronary artery disease and is a major cause of heart disease.
  • the expression of these risk factors is potentially due to the joint mechanism.
  • Atherosclerosis due to hypertension and hyperlipidemia is a vicious cycle that worsens in parallel.
  • arteriosclerosis worsens, and when arteriosclerosis worsens, blood pressure rises and worsens each other.
  • These symptoms are also considered as a serious risk factor for developing cardiovascular disease.
  • hypercholesterolemia and hyperlipidemia are involved in the early development of atherosclerosis, characterized by an uneven distribution of lipid deposits in arteries including coronary, carotid and peripheral arteries.
  • Irregular lipid distribution is also a hallmark of coronary artery injury, cardiovascular disease and adversely affects left ventricular hypertrophy, a complication of diabetes, sex, smoking, and hypertension [Wilson et al., Am. J. Cardiol., Vol. 59 (14). (1987), p. 91G-94G]. Therefore, it is known that it is advantageous for patients to have a combination treatment to treat these symptoms, and it has become a clinically basic treatment guideline.
  • the NO production system (eNOs) in the vessel wall is abnormal, which leads to a decrease in NO production resulting in increased blood pressure.
  • eNOs NO production system
  • amlodipine has the function of promoting NO release.
  • the combination of amlodipine and atorvastatin has a much more synergistic effect on NO.
  • the complex administration of amlodipine and atorvastatin is a complex prescription of the lipid lowering agent atorvastatin to help the effect of amlodipine, a calcium channel blocker, due to the synergistic effect on eNOS in the vessel wall.
  • the present inventors have completed the present invention as a result of researches to develop an effective agent for the prevention and treatment of hypertension and hyperlipidemia and thereby cardiovascular disease or metabolic syndrome.
  • the problem to be solved by the present invention is to minimize side effects by minimizing the interaction between drugs, to exhibit a synergistic effect on the treatment and prevention of hypertension, hyperlipidemia and the resulting cardiovascular disease and metabolic syndrome, and can improve the medication compliance It is to provide a combination formulation.
  • the present invention provides a morning pharmaceutical formulation comprising a pre-release compartment comprising a dihydropyridine-based calcium channel blocker as a pharmacologically active ingredient, and a delayed-release compartment comprising a HMG-CoA reductase inhibitor as a pharmacologically active ingredient. to provide.
  • the dihydropyridine calcium channel blocker of the pre-release compartment in the preparation of the present invention is a rapid release, preferably 80% of the total amount of dihydropyridine calcium channel blocker within 1 hour after the release of the dihydropyridine calcium channel blocker. An anomaly is released, so that the desired drug can be produced quickly.
  • the HMG-CoA reductase inhibitor of the delayed-release compartment in the formulation of the present invention is released after a delay time, i.e., 6 to 12 hours after release of the dihydropyridine-based calcium channel blocker, preferably 9 hours after release. More preferably, the HMG-CoA reductase inhibitor is released within 20% from 6 hours to 9 hours after the release of the dihydropyridine calcium channel blocker, and at least 75% within 2 hours thereafter.
  • Dihydropyridine-based calcium channel blockers release 80% within 1 hour of oral administration, and are absorbed in the small intestine before HMG-CoA reductase inhibitors to block calcium inflow into vascular smooth muscle, leading to peripheral artery dilation and lowering blood pressure .
  • HMG-CoA reductase inhibitor is released after a delay time (6 to 12 hours) after the release of the dihydropyridine calcium channel blocker and enters the liver. Therefore, the HMG-CoA reductase inhibitor is activated by cytochrome P450 3A4 without interfering with the calcium channel blocker. It is metabolized to fully perform the lipid lowering action in the liver.
  • the preparation of the present invention may include 1 to 400 mg of the dihydropyridine-based calcium channel blocker, and 1 to 160 mg of the HMG-CoA reductase inhibitor, and the dihydropyridine-based calcium channel blocker and HMG-CoA reductase inhibitor dose is based on a daily adult (65-75 kg adult male).
  • the formulation of the present invention is for morning use. That is, by taking the preparation of the present invention once a day in the morning time (7 to 10 am), the pre-release dihydropyridine calcium channel blocker can strongly lower the blood pressure during the day and delayed release.
  • the HMG-CoA reductase inhibitor may act early in the evening to effectively perform the lipid-lowering action of the HMG-CoA reductase inhibitor even with a single dose.
  • Pre-release compartment refers to the compartment in which the active ingredient is first released in comparison with the delayed-release compartment in the pharmaceutical formulation of the present invention, and may further include a pharmaceutically acceptable additive as necessary in addition to the pharmacologically active ingredient. .
  • the pharmacologically active component of the prior-release compartment is a dihydropyridine calcium channel blocker.
  • the dihydropyridine calcium channel blocker is an antihypertensive drug that lowers blood pressure by blocking calcium inflow into vascular smooth muscle and inducing peripheral artery dilation.
  • a preferred example of the dihydropyridine-based calcium channel blocker is amlodipine.
  • Amlodipine has the chemical name 3-ethyl-5-methyl-2 (2-aminoethoxymethyl) -4- (2-chloro phenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate It is a very useful daily 24 hour sustained calcium channel blocker with a half-life of 30 to 50 hours and very active over a long period of time, and it lowers blood pressure by blocking peripheral calcium inflow and inducing peripheral artery expansion. It is a high blood pressure drug and is effective for angina due to convulsive vasoconstriction.
  • Amlodipine reduces myocardial ischemia by reducing Total Peripheral Resistance in patients with severe angina, or reduces myocardial oxygen demand at any particular level of exercise by reducing the rate pressure product after ingestion. .
  • amlodipine blocks contraction and restores myocardial oxygen supply.
  • Amlodipine is known to increase myocardial oxygen supply by dilatating coronary arteries.
  • amlodipine itself is an active form, and when it enters the liver, it is partially metabolized and inactivated by cytochrome P450 3A4 already present. Amlodipine is 60-90% active and maintains its highest blood concentration at 6-12 hours and inhibits the production of cytochrome P450 3A4.
  • the formulations of the present invention may contain pharmaceutically acceptable additives such as diluents, binders, disintegrants, lubricants, stabilizers, coloring agents, flavoring agents, and the like, which do not impair the effects of the present invention. It may be formulated using additionally within the range not to be, the content thereof may be 1 to 70 parts by weight based on 1 part by weight of the dihydropyridine-based calcium channel blocker.
  • the diluent is starch, microcrystalline cellulose, lactose, sucrose, sugar seed, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, and / or dicalcium phosphate.
  • the binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, and / or Gelatin and the like.
  • the disintegrant is a starch or modified starch, such as sodium starch glycolate, corn starch, potato starch, and / or pregelatinized starch, bentonite, montmorillonite, and / or clay microcrystalline cellulose such as vegum, hydroxypropyl Cross-linked celluloses such as sodium cellulose alginate and / or alginate such as cellulose and / or carboxymethyl cellulose such as alginate croscarmellose, guar gum, and / or gum crospovidone such as xanthan gum Effervescent agents, such as crosslinked polymer sodium bicarbonate and / or a citric acid, etc. can be mixed and used.
  • the lubricants include talc, magnesium stearate and / or alkaline earth metal salts, zinc, lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, and or polyethylene glycol 3350, 4000 , 6000, and the like, ascorbic acid, citric acid, butylated hydroxy anisole, butylhydroxy toluene, propyl gallate and / or tocopherol derivatives and the like.
  • a pharmaceutically acceptable additive may be selected and used as various additives selected from colorants and fragrances.
  • the scope of the present invention is not limited to the use of the additives, and the additives may contain a conventional range of doses by the choice of those skilled in the art.
  • 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.
  • the delayed-release compartment comprises (1) a pharmacologically active ingredient and (2-1) a release control substance or (2-2) an osmotic pressure regulator and a semipermeable membrane coating base, and (3) a pharmaceutically acceptable It may further include an additive.
  • the pharmacologically active component of the delayed-release compartment is the HMG-CoA reductase inhibitor, which is a mevalonate by HMG-CoA, its reductase, 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA). It is a drug that suppresses the reduction to reduce the production of cholesterol in the liver and lower the low density lipoprotein cholesterol (LDL-Cholesterol), the HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, pitavastatin, rosuvastatin, Fluvastatin, and / or pravastatin, and the like, and isomers thereof and / or pharmaceutically acceptable salts.
  • HMG-CoA reductase inhibitor is a mevalonate by HMG-CoA, its reductase, 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA). It is a drug that suppresses the reduction to reduce the production
  • HMG-CoA reductase inhibitor is atorvastatin
  • atorvastatin calcium is HMG-CoA is a 3-hydroxy-3-methyl glutaryl-coenzyme (HMG-CoA) is the reductase It is strongly inhibited from reducing to balonate, thereby suppressing the production of cholesterol in the liver and lowering the low density lipoprotein cholesterol (LDL-C).
  • HMG-CoA 3-hydroxy-3-methyl glutaryl-coenzyme
  • LDL-C low density lipoprotein cholesterol
  • atorvastatin reduce inflammation in patients with angina and low cholesterol levels.
  • HMG-CoA reductase inhibitors Since lipid synthesis in the liver becomes vigorous after early dinner, HMG-CoA reductase inhibitors have been recommended for early evening use.
  • Atorvastatin is metabolized by the liver enzyme cytochrome P450 3A4 and excreted from the liver while acting in the liver. Therefore, atorvastatin, when used in combination with drugs that inhibit the cytochrome P450 3A4 enzyme, inhibits liver metabolism of atorvastatin, leading to increased blood levels, which can cause serious side effects such as myolysis.
  • the delayed-release compartment in the pharmaceutical formulation of the present invention comprises a release controlling substance, wherein the release controlling substance of the present formulation is selected from, for example, enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof. At least one, preferably at least one selected from water-insoluble polymers and enteric polymers.
  • the release controlling substance of the preparation contains 0.1 to 50 parts by weight, preferably 0.3 to 30 parts by weight, based on 1 part by weight of the HMG-CoA reductase inhibitor. If the release controlling substance is less than the above range, it may be difficult to have a sufficient delay time, and if it exceeds the above range, drug release may be excessively delayed to obtain a significant clinical effect.
  • the enteric polymer is insoluble or stable under acidic conditions, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or more.
  • the enteric polymers usable in the present invention are, for example, polyvinylacetate phthalate, methacrylic acid copolymer, hydroxypropylmethyl cellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, poly (methacrylic acid-methylmeth) Acrylate) copolymer and poly (methacrylate-ethyl acrylate) copolymer, and mixtures thereof.
  • enteric polymer examples include methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, poly (methacrylate-methylmethacrylate) copolymer or poly (methacrylate-ethyl acrylate) 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 insoluble polymers usable in the present invention are, for example, polyvinyl acetate, polymethacrylate copolymers, poly (ethylacrylate-methyl methacrylate) copolymers, poly (ethylacrylate-methyl methacrylate-trimethyl Aminoethyl methacrylate) copolymer, ethyl cellulose, cellulose acetate, and mixtures thereof, and at least one selected from polyvinyl acetate, ethyl cellulose, cellulose acetate, or poly (ethylacrylate-methyl). Methacrylate-trimethylaminoethyl methacrylate) copolymer.
  • 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 palmito At least one fatty acid alcohol selected from stearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and stearic acid is 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 at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum. to be.
  • Preferred examples of the hydrophobic compound are glyceryl palmitostearate, or glyceryl stearate.
  • the hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug.
  • hydrophilic polymers usable in the present invention include 1 selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl copolymers, and mixtures thereof. More than species.
  • the saccharides include dextrins, polydextrins, dextran, pectin and pectin derivatives, alginates, polygalacturonic acids, xylans, arabinoxylans, arabinogalactans, starches, hydroxypropylstarches, amylose, amylopectins, and their
  • the at least one cellulose derivative selected from the mixtures is hydroxypropylmethyl cellulose (or hypromellose), hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxy
  • the at least one gum selected from propyl methylcellulose acetate succinate, hydroxyethylmethylcellulose, and mixtures thereof is guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum, And at least one protein selected from a mixture thereof
  • the rate copolymer is poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (e.g. Eudragit E, Evonik, Germany), poly (methacrylate-methyl At least one polyethylene derivative selected from methacrylate) copolymer, poly (methacrylate-ethylacrylate) copolymer, and mixtures thereof, and at least one carboxyvinyl copolymer selected from polyethylene glycol, polyethylene oxide, and mixtures thereof. Is a carbomer.
  • hydrophilic polymer examples include poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer, hydroxypropylmethylcellulose, poly (methacrylate-methylmethacrylate) Copolymer or poly (methacrylic acid-ethylacrylate) copolymer.
  • the delayed-release compartment of the present invention includes an osmotic pressure regulator and may be a compartment coated with a semipermeable membrane coating base.
  • the osmotic pressure control agent is at least one selected from the group consisting of, for example, magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, lithium sulfate, sodium sulfate, and mixtures thereof.
  • the semi-permeable membrane coating base refers to a material used to form a film that allows some components to pass but not others.
  • the semipermeable membrane coating base may use the above-mentioned water-insoluble polymer.
  • the semipermeable membrane coating base in the present invention is, for example, polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate Late chloride) copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate and mixtures thereof The above is mentioned.
  • the formulations of the present invention are diluents, binders, and borates other than those mentioned as pharmaceutically acceptable (2-1) release controlling substances and (2-2) osmotic pressure regulators and semipermeable membrane coating agents within the scope of not impairing the effects of the present invention.
  • Commonly used additives such as releases, lubricants, stabilizers, colorants, and / or fragrances can be formulated further using within a range not departing from the nature of delayed release.
  • the diluent is starch, microcrystalline cellulose, lactose, calcium carbonate, sucrose, sugar seed, ascorbic acid, citric acid, glucose, pregelatinized starch, di-mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, potassium ratio Carbonate, magnesium oxide or anhydrous calcium phosphate.
  • the binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, gelatin, and the like. to be.
  • the disintegrant is starch, such as sodium starch glyconate, corn starch, potato starch or pregelatinized starch, or clay microcrystalline cellulose, hydroxypropyl cellulose or carboxy such as modified starch bentonite, montmorillonite, or veegum.
  • Cross-linked cellulose such as sodium cellulose such as methyl cellulose, alginate such as alginate, croscarmellose sodium such as guar gum, cross-linked polymer such as xanthan gum, cross-linked polymer insoluble ions such as crospovidone
  • an effervescent agent such as exchange resin sodium bicarbonate or citric acid.
  • the lubricant is talc, magnesium stearate, alkaline earth metal salts of stearate, zinc, lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, or polyethylene glycols.
  • the stabilizer is butylated hydroxy anisole, butylhydroxy toluene, propyl gallate or tocopherol derivatives and the like.
  • a pharmaceutically acceptable additive may be selected and used as various additives selected from colorants and fragrances.
  • the pre-release compartment is mixed with a pharmaceutically acceptable additive in addition to the dihydropyridine-based calcium channel blocker, a mixture, granules, It may be prepared in the form of pellets or tablets.
  • a pharmaceutically acceptable additive in addition to the dihydropyridine-based calcium channel blocker, a mixture, granules, It may be prepared in the form of pellets or tablets.
  • granulation may be performed by pressing, granulating, and sizing.
  • the delayed-release compartment in the formulation of the present invention may be used to prepare oral administration agents such as mixing, associating, drying, granulating or coating a release controlling substance in addition to an HMG-CoA reductase inhibitor, and a pharmaceutically acceptable additive as necessary. It can be prepared in the form of a mixture, granules, pellets, or tablets through conventional procedures.
  • formulations of the present invention can be formulated using additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, etc., within the scope of not impairing the effects of the present invention in addition to the pre-release and delayed-release compartments prepared in the respective formulations.
  • additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, etc.
  • Additives such as diluents, binders, disintegrants, lubricants, etc. may be suitably used depending on the purpose used in the formulation of the pre-release compartment, or delayed-release compartment, but is not limited thereto.
  • 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 formulation of the present invention is a tabletting by selectively mixing additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like to have a pre-release compartment and a delayed-release compartment in a single tablet, and thus the active ingredient of each compartment.
  • additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like to have a pre-release compartment and a delayed-release compartment in a single tablet, and thus the active ingredient of each compartment.
  • This may be in the form of uncoated tablets will be eluted separately to show the respective effects.
  • the formulation of the present invention may be in the form of a two-phase matrix tablet obtained by tableting after the delayed-release compartment and the prior-release compartment are uniformly mixed.
  • 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
  • the active ingredient dihydropyridine calcium channel blocker is eluted first.
  • 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-emitting compartments may be in the form of a multi-layered tablet with a layered structure.
  • This formulation is a tablet for oral administration which is formulated to enable pre-release and delayed release in layers.
  • the pharmaceutical formulation of the present invention may be in the form of a nucleus tablet consisting of an inner layer consisting of a delayed-release compartment and an outer layer consisting of a prior-release compartment surrounding the outer surface of the inner core tablet.
  • 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 compression, and then coated the surface of the tablet with a semipermeable membrane coating agent to form an inner core.
  • compositions of the present invention may be in the form of capsules comprising particles, granules, pellets, or tablets consisting of delayed-release compartments, and particles, granules, pellets, or tablets consisting of prior release compartments.
  • the tablet consisting of the delayed-release compartment of the capsule may include an osmotic pressure-controlling agent within the tablet and an osmotic coated tablet having a semipermeable membrane coating base on the surface of the tablet.
  • the base of the capsule may be one selected from gelatin, succinate gelatin, or hydroxypropylmethylcellulose, or a mixture thereof.
  • 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
  • the kit comprises (a) a prior-release compartment (b) a delayed-release compartment and (c) the It may consist of a container for filling the pre-release compartment and the delayed-release compartment.
  • the kit prepares the particles, granules, pellets, or tablets constituting the prerelease compartment, and separately prepares the granules, pellets, or tablets constituting the delayed release compartment, and fills them together with foil, blisters, bottles, and the like. It can be prepared in a form that can be taken at the same time.
  • the formulations of the present invention may further form a coating layer on the exterior of the delayed release compartment and / or the prior release compartment.
  • the surface of the particles, granules, pellets, or tablets consisting of delayed-release compartments and / or pre-release compartments may be coated for the purpose of release control or formulation stability.
  • the formulation according to the present invention is also provided in a state such as uncoated tablets without additional coating, but may be in the form of a coated tablet containing a coating layer further by forming a coating layer on the outside of the formulation, if necessary. .
  • a coating layer By forming the coating layer, it is possible to further ensure the stability of the active ingredient.
  • the method of forming the coating layer may 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 a fluidized bed coating method, a fan coating method may be applied, and preferably Fan coating can be applied.
  • the coating layer may be formed by using a coating agent, a coating aid, or a mixture thereof.
  • the coating agent may be a cellulose derivative such as hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar derivatives, polyvinyl derivatives, waxes, or fatty acids. , Gelatin, or a mixture thereof, and the like, and a coating aid may be polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, triethyl citrate or a mixture thereof.
  • the coating layer may be included in the range of 0.5 to 15% by weight (% w / w) based on the total weight of the tablet.
  • the preparation of the present invention is for morning use, the preparation of the present invention is taken once a day in the morning time period (7 to 10 am) to strongly increase the blood pressure during the day by the pre-release dihydropyridine calcium channel blocker. It can be reduced, and HMG-CoA reductase inhibitor is released and enters the liver after a delay time (for example, 6 to 12 hours) after the release of the dihydropyridine calcium channel blocker. It is metabolized into active form by P450 3A4 without any action, thereby performing a hypolipidemic effect.
  • Dihydropyridine-based calcium channel blockers such as amlodipine, have a duration of action of 24 hours and 6-12 hours after administration, and active forms reach the highest blood levels. This is especially effective for people whose daytime blood pressure rises are a problem.
  • Amlodipine itself in active form, can inhibit P450 3A4 because it is partially metabolized and inactivated by cytochrome P450 3A4 already present, and atorvastatin is metabolized by cytochrome P450 3A4 and acts in the liver. Since it is excreted while being administered in combination with a drug that inhibits the cytochrome P450 3A4 enzyme, the liver metabolism of atorvastatin is inhibited to increase blood concentration, which may cause side effects such as muscle lysis. Such side effects can be avoided by using the formulation of the present invention.
  • HMG-CoA reductase inhibitors have been recommended to be taken early in the evening. Therefore, if the formulation of the present invention is administered in the morning, the HMG-CoA reductase inhibitor may act in the early evening. It is possible to effectively perform the lipid lowering action of the HMG-CoA reductase inhibitor even with a single dose.
  • the formulation of the present invention can not only avoid side effects, but also excellent in compliance with medication because it is for morning use. This is the most common cause of non-compliance. Oblivion is the most likely to be forgotten. Lunch (44%), dinner (22%), before bedtime (6%), and morning (5%) are investigated in the following order. Patients' Use of Drugs and Problem Analysis and Countermeasure Direction: 2005: Shin Hyun-Taek], because it is the best way to take medication once a day in the morning.
  • the formulation of the present invention applies the principle of chronotherapy and the principle of Xenobiotics of the drug to the expression of pharmacological action of each of the complex components to control release in the body at a specific rate to achieve the most ideal effect upon absorption in the body. It can be, because the drug compliance is excellent, effectively express the drug.
  • the present invention provides a method for treating hypertension and hyperlipidemia, or a cardiovascular disease or metabolic syndrome, comprising administering the agent of the present invention to a mammal including a human once a day in the morning.
  • the cardiovascular disease includes hypertension in addition to hypertension.
  • compositions of the present invention may be prepared by any suitable method in the art, for example, with reference to methods disclosed in Chronotherapeutics (2003, Peter Redfern, PhP), Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA, and the like. It can be formulated preferably according to a disease or a component, and can be manufactured by the method containing the following steps specifically ,.
  • the active ingredient of the delayed-release compartment is mixed with, or combined with, one or two release controlling substances selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, and a hydrophilic polymer, and a conventional additive used in pharmaceuticals.
  • Delayed-release granules or tablets are obtained through drying, granulation or coating, and tableting, or the active ingredient is semipermeable after mixing, associating, drying, granulating or tableting by administering an osmotic agent and a conventional additive which is used pharmaceutically. It is a step of obtaining delayed-release granules or tablets by coating with a membrane coating base.
  • the second step involves the administration of the active ingredient of the prior-release compartment and the conventionally acceptable pharmaceutically acceptable additives to produce the oral solids through mixing, coalescing, drying, granulating or coating, and tableting to produce oral solids. Obtaining extruded granules or tablets.
  • the granules or tablets obtained in the first step and the second step are mixed with pharmaceutical excipients, tableted or filled to obtain a preparation for oral administration.
  • the first step and the second step may be reversed or executed simultaneously.
  • the pharmaceutical formulation of the present invention may be prepared by the above process, and the formulation method of the third step is described in more detail as follows, but is not limited thereto.
  • the particles or granules obtained in the first step are further coated as they are or with a release controlling material, and then mixed with the granules prepared in the second step and compressed into a certain amount of weight to prepare a tablet.
  • the obtained tablet can be film coated as necessary for the purpose of improving stability or property.
  • the coated tablets or granules obtained in the first step are additionally coated as they are or with a release control material, dried, and then compressed into a predetermined amount to prepare tablets as they are or additionally coated, and then the active ingredients of the pre-release compartments are separately coated with a water-soluble film coating solution.
  • the tablet outer layer obtained in step 1 can be used to prepare an orally administered film coating tablet containing the active ingredient in a film coating.
  • the granules obtained in the first step as they are or are additionally coated and dried with a release controlling substance and the granules obtained in the second step can be prepared in double tablets using a 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.
  • the coated tablet or granules obtained in the first step are additionally coated as it is or with a release control material, dried, and then compressed into a predetermined amount to be coated as it is or additionally to the inner core, followed by a nucleated tableting machine together with the granules obtained in the second step.
  • the coated nucleated tablet may be prepared by preparing or coating a nucleated tablet having a form in which a pre-release layer is enclosed on the surface of the inner core.
  • the granules obtained in the first step are additionally coated as is or with a release controlling substance, and the dried granules or tablets and the granules or tablets obtained in the second step are placed in a capsule charger and filled into capsules of a predetermined size by an effective amount of each active ingredient in an appropriate amount.
  • Capsules may be prepared by mixing the release control pellets containing the ingredients and filling the capsules with a capsule filling machine.
  • the delayed-release compartment preparation (beta-adrenergic blocker-containing formulation) obtained in the first stage and the prior-release compartment preparation (angiotensin-2 receptor antagonist-containing formulation) obtained in the second stage are filled together with a foil, blister, bottle, etc. It can be made into a kit that can be taken at the same time.
  • the human dosage of the formulation of the present invention is appropriately selected depending on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, but in general, the daily dihydropyridine calcium channel blocker
  • the daily dihydropyridine calcium channel blocker By containing 1 to 400mg in the formulation and administering HMG-CoA reductase inhibitor to include 1 to 160mg in the formulation, it is possible to exhibit the treatment and prophylaxis of hypertension, hyperlipidemia and the like.
  • the pharmaceutical preparations of the present invention can reduce side effects due to drug interactions, and are effective in the treatment and prevention of hypertension, hyperlipidemia and consequent cardiovascular diseases or metabolic syndrome due to pharmacological effect synergism, and can improve medication compliance. .
  • Example 1 is a graph showing a comparative dissolution curve of the amlodipine / atorvastatin nucleated tablet of Example 5 and the reference drug.
  • Figure 2 is a graph showing the comparative dissolution curves of the silinidipine / rosuvastatin biphasic matrix tablets and the reference drug of Example 12.
  • Figure 3 is a graph showing a comparative dissolution curve of the amlodipine / fluvastatin capsules of Example 25 and the reference drug.
  • Figure 4 is a graph showing the atorvastatin elution pattern in Examples 3, 5, 6 formulations.
  • Figure 5 is a graph showing the atorvastatin elution pattern in Examples 21, 27 formulation.
  • Figure 6 is a blood concentration test result of Experimental Example 6, a graph showing the blood concentration-time profile of amlodipine in the formulation of Example 5.
  • Example 7 is a blood concentration test result of Experimental Example 6, which is a graph showing the blood concentration-time profile of atorvastatin in the formulation of Example 5.
  • nucleated tablets were prepared by the following method.
  • Amlodipine besylate (Cadila, India), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), anhydrous calcium phosphate (RHODIA, USA) were attached and apologized as No. 35, and double cone mixer (MC / MIX-60, Ilsung Industrial, Korea) ) was mixed for 5 minutes to prepare a mixture.
  • hydroxypropyl cellulose HPC-L, Nippon Soda, Japan
  • was dissolved in purified water to prepare a binder solution (10% w / w) was then mixed with a main ingredient mixture and a high speed mixer (Lab. Pharma mixer P, Diosna, Germany). United after input.
  • granulation was carried out using an oscillator (AR402, ERWEKA, Germany) with No. 18 and dried at 60 ° C. using a hot water dryer (H-W-C, Samgye, Japan). After drying, it was established as No. 20 sieve again.
  • the starch was mixed with sodium starch glyconate (Primojel, DMV, Germany), and magnesium stearate (Nitika Chemical, India) was added and mixed in a double cone mixer.
  • Atorvastatin calcium trihydrate (Dr. Reddy's, India), microcrystalline cellulose, calcium carbonate (NITTO FUNKA, Japan), crosslinked polyvinylpyrrolidone (Crospovidone, BASF, Germany), croscarmellose sodium (Acdisol, FMC Biopolymer, USA), pregelatinized starch (Starch 1500G, Colorcon, USA), di-mannitol (Pearlitol 200SD, Roquette, France), lauryl sulfate sodium (Miwon, Korea) apologize 35, and double cone mixer 5 Mixing was performed to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again.
  • the sieved material is placed in a fluidized bed coater (GPCG-1, Glatt, Germany), separately cellulose acetate 320S (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate 398NF10 (acetal group 39.8%) (Eastman Chemical Company, USA ) was dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granulated material was put into a fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated.
  • GPCG-1 fluidized bed granulator coater
  • magnesium stearate (Nitika Chemical, India) was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.
  • a nucleophilic tableting machine equipped with a 12 mm punch (RUD-1: Kilian, Germany) was used as the outer layer of the dihydropyridine calcium channel blocker rapid release granules of 1) as the outer layer, and the HMG-CoA reductase inhibitor of 2)
  • the slow-release tablet was tableted using a nuclear tablet.
  • a coating solution obtained by dissolving and dispersing hydroxypropylmethylcellulose 2910 (Shin-etsu, Japan), polyethylene glycol 6,000 (BASF, Germany), talc (Luzenac, France) and titanium oxide (Tioside Americas, USA) in ethanol and purified water
  • the tablets were prepared to form a film coating layer as a high coater (SFC-30F, Sejong Machinery, Korea) to prepare tablets in the form of nucleated tablets.
  • nucleated tablets were prepared by the following method.
  • Lercanidipine (Daehee Chemical, Korea), microcrystalline cellulose, anhydrous calcium phosphate, corn starch (DMV, Germany) were weighed and appled in No. 35, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • the above granulated product was prepared by dissolving cellulose acetate 320S (acetal group 32%) and cellulose acetate 398NF10 (acetal group 39.8%) in a 1: 1 mixture of ethanol and methylene chloride (20% w / w). It was put in a coater (GPCG-1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.
  • a rotary tablet press MRC-30, Sejong Machinery, Korea
  • Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).
  • nucleated tablets were prepared by the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.
  • the starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • the formulations are placed in a fluidized bed coater (GPCG-1, Glatt, Germany) and separately poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer (Evonik Degussa, Germany) and triethyl
  • GPCG-1 fluidized bed coater
  • Triethyl ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer
  • triethyl A solution of citrate (Vertellus, England) dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and coated. It was.
  • magnesium stearate (Nitika Chemical, India) was added, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.
  • Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).
  • nucleated tablets were prepared by the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.
  • the starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • Rosuvastatin calcium (Glenmark Pharmaceutical Ltd, India), microcrystalline cellulose (Vivapur 12, JRS, Germany), lactose (Flowlac 100, Meggle, Germany), di-mannitol, sodium lauryl sulfate, calcium phosphate anhydrous And mixed for 5 minutes with a double cone mixer to prepare a mixture.
  • a coating solution of ethyl cellulose (HERCULES, USA) dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared, and the primary coating was performed using a high coater (SFC-30F, Sejong Machinery, Korea). It was. Thereafter, a coating solution obtained by dissolving poly (methacrylate, methyl methacrylate) copolymer (Evonik degussa, USA) and triethyl citrate in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared.
  • the HMG-CoA reductase inhibitor coated tablets were coated with a high coater to form a coating layer, thereby completing the preparation of HMG-CoA reductase inhibitor nuclear tablets.
  • Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).
  • nucleated tablets were prepared by the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.
  • the starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • Atorvastatin calcium trihydrate, microcrystalline cellulose, calcium carbonate, croscarmellose sodium, pregelatinized starch, di-mannitol and sodium lauryl sulfate were mixed with apple No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried. After drying, the mixture was established as a No. 18 sieve again, and then cross-linked polyvinylpyrrolidone was added to the sieved material, mixed, and mixed for 4 minutes. Thereafter, magnesium stearate sieved through No.
  • a coating solution in which acrylic-Iz (methacrylic acid copolymer type C, talc, PEG, colloidal silicon dioxide, sodium bicarbonate, SLS, Colorcon, USA) was dissolved and dispersed in purified water (10% w / w)
  • acrylic-Iz methacrylic acid copolymer type C, talc, PEG, colloidal silicon dioxide, sodium bicarbonate, SLS, Colorcon, USA
  • purified water 10% w / w
  • nucleated tablets were prepared by the following method.
  • a mixture was prepared. The mixture was added to a high-speed mixer, polyvinylacetate 30% dispersant in which hydroxypropyl cellulose was dissolved, polyvinylacetate 30% dispersant (BASF, Germany) was added, and then granulated using an oscillator with No. 20 sieve. After drying at 60 ° C to No. 18 sieve again.
  • HMG-CoA reductase inhibitor tablets were formed as a coater as a high coater (SFC-30F, Sejong Machinery, Korea) to complete the preparation of HMG-CoA reductase inhibitor tablets.
  • Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).
  • nucleated tablets were prepared by the following method.
  • Amalodipine besylate, a dihydropyridine calcium channel blocker, anhydrous calcium phosphate, microcrystalline cellulose and corn starch were weighed and appled in a No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.
  • the starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • Atorvastatin calcium anhydride (TEVA, Israel), microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate with 35 Mixing was carried out for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again.
  • ethylcellulose was dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution, and was first coated using a fluidized bed granulator coater (GPCG-1; Glatt, Germany). After primary coating, the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and hydroxypropylmethylcellulose phthalate and triethylcitrate were mixed 1: 1 with ethanol and methylene chloride (20% w). final coating with the solution dissolved in / w). After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.
  • a rotary tablet press MRC-30, Sejong Machinery, Korea
  • Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).
  • nucleated tablets were prepared by the following method.
  • Pedidipine (Cipla, India), microcrystalline cellulose, corn starch, lactose, and propyl gallate (Spectrumchemical, USA), which are dihydropyridine-based calcium channel blockers, are apples in No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. It was. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator (AR402, ERWEKA, Germany) with No. 18 and dried at 60 ° C. using a hot water dryer (H-W-C, Samgye, Japan). After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).
  • nucleated tablets were prepared by the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.
  • the starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again.
  • ethylcellulose was dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution, and was first coated using a fluidized bed granulator coater (GPCG-1; Glatt, Germany). After primary coating, the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and hydroxypropylmethylcellulose phthalate and triethylcitrate were mixed 1: 1 with ethanol and methylene chloride (20% w). final coating with the solution dissolved in / w). After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.
  • a rotary tablet press MRC-30, Sejong Machinery, Korea
  • Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).
  • two-phase matrix tablets were prepared by the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.
  • the sieved material is placed in a fluidized bed coater (GPCG-1, Glatt, Germany), separately cellulose acetate 320S (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate 398NF10 (acetal group 39.8%) (Eastman Chemical Company, USA ) Was dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granulated material was put into a fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated.
  • GPCG-1 fluidized bed coater
  • the products of 1) and 2) were put into a double cone mixer and mixed. Starch, sodium glyconate, and magnesium stearate were added to the mixture, followed by final mixing in a double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong Machinery, South Korea). Separately, a coating solution obtained by dissolving and dispersing hydroxypropylmethylcellulose 2910, polyethylene glycol 6,000, talc, and titanium oxide in ethanol and purified water was prepared, and a high coater (SFC-30F: Sejong Machinery, Korea) was used for the above purification. The film coating layer was formed to prepare a biphasic matrix tablet.
  • two-phase matrix tablets were prepared by the following method.
  • Nifedipine (Cadila, India), a dihydropyridine-based calcium channel blocker, microcrystalline cellulose, corn starch, lactose, lauryl sulfate sodium, weighed 35 apples and mixed for 5 minutes in a double cone mixer to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using a No. 20 body oscillator, which was dried at 60 ° C. using a hot water dryer, and then re-established into No. 18 body.
  • HMG-CoA reductase inhibitor lovastatin Rosbaxy, India
  • microcrystalline cellulose pregelatinized starch
  • di-mannitol lactose
  • butylated hydroxyanisole as apples No. 35 and mixed for 5 minutes with a double cone mixer
  • hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying.
  • a solution of poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate) copolymer and triethyl citrate in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared.
  • the above granules were prepared and placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and coated.
  • Example 10 In the same manner as 3) of Example 10, post-mixing, tableting, and coating were performed to prepare a tablet in the form of a two-phase matrix.
  • two-phase matrix tablets were prepared by the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture.
  • granulation was carried out using a No. 20 body oscillator, which was dried at 60 ° C. using a hot water dryer, and then re-established into No. 18 body.
  • Rohvastatin calcium, microcrystalline cellulose, anhydrous calcium phosphate, di-mannitol, cross-linked polyvinylpyrrolidone, lauryl sulfate sodium, lactose, butylated hydroxyanisole, which are HMG-CoA reductase inhibitors A mixture was prepared by mixing for 5 minutes with a double cone mixer. The mixture was added to a high-speed mixer, and the mixture was added by adding 30% of a polyvinylacetate dispersant in which hydroxypropyl cellulose was dissolved. Granulation was carried out using an oscillator using No. 20 sieve, and dried at 60 ° C. using a hot water dryer. It was.
  • Hydroxypropylmethylcellulose phthalate and triethylcitrate were dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granules were prepared in a fluid bed granulation coater (GPCG-1; Glatt). , Germany) and coated.
  • GPCG-1 fluid bed granulation coater
  • Example 10 In the same manner as in 3) of Example 10, post-mixing, tableting, and coating were performed to prepare a tablet in the form of a two-phase matrix.
  • two-phase matrix tablets were prepared by the following method.
  • Nicardipine (Chemwerth Inc, Germany), a dihydropyridine-based calcium channel blocker, microcrystalline cellulose, corn starch, anhydrous calcium phosphate, lactose, weighed 35 apples and mixed for 5 minutes in a double cone mixer to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using a No. 20 body oscillator, which was dried at 60 ° C. using a hot water dryer, and then re-established into No. 18 body.
  • polyvinylpyrrolidone was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried.
  • a solution obtained by dissolving ethyl cellulose (HERCULES, USA) in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and coated using a fluidized bed granulation coater (GPCG-1; Glatt, Germany).
  • a poly (methacrylate, methyl methacrylate) copolymer and triethyl citrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed. It was put in a granular coater (GPCG-1; Glatt, Germany) and coated.
  • Example 10 In the same manner as 3) of Example 10, post-mixing, tableting, and coating were performed to prepare a tablet in the form of a two-phase matrix.
  • the multilayer tablet was produced with the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.
  • the starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • a solution obtained by dissolving ethyl cellulose (HERCULES, USA) in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and coated using a fluidized bed granulation coater (GPCG-1; Glatt, Germany).
  • GPCG-1 fluidized bed granulation coater
  • a poly (methacrylate, methyl methacrylate) copolymer and triethyl citrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed. It was put in a granular coater (GPCG-1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes.
  • a multi-layer tablet press (MRC-30T: Sejong, Korea).
  • the final mixture of 1) was placed in a primary powder feeder, and the final mixture of 2) was placed in a secondary powder feeder, and compressed into a condition capable of minimizing incorporation between layers.
  • hydroxypropylmethylcellulose 2910, polyethylene glycol 6,000, talc, and titanium oxide were prepared by dissolving and dispersing a coating solution in ethanol and purified water.
  • the above tablets were coated with a high coater (SFC-30F: Sejong Machinery, Korea). To form a tablet in the form of a multi-layered tablet.
  • the multilayer tablet was produced with the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture.
  • granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again.
  • the starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • HMG-CoA reductase inhibitor Rovastatin Rosbaxy, India
  • microcrystalline cellulose di-mannitol
  • pregelatinized starch lactose
  • butylated hydroxyanisole were apologized with No. 35 and mixed for 5 minutes with a double cone mixer.
  • polyvinylpyrrolidone was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried. After drying, it was established as No. 18 body again.
  • the sieved material is placed in a fluidized bed coater (GPCG-1, Glatt, Germany), separately cellulose acetate 320S (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate 398NF10 (acetal group 39.8%) (Eastman Chemical Company, USA ) was dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granulated material was put into 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.
  • GPCG-1 fluidized bed coater
  • Example 14 In the same manner as in 3) of Example 14, post-mixing, tableting, and coating were carried out to form a tablet in the form of a multilayer tablet.
  • the multilayer tablet was produced with the following method.
  • Benidipine, a dihydropyridine calcium channel blocker, microcrystalline cellulose, anhydrous calcium phosphate, corn starch and di-mannitol were weighed and appled in a No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again.
  • the starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • Rohvastatin calcium, microcrystalline cellulose, anhydrous calcium phosphate, di-mannitol, cross-linked polyvinylpyrrolidone, lauryl sulfate sodium, lactose, butylated hydroxyanisole, which are HMG-CoA reductase inhibitors A mixture was prepared by mixing for 5 minutes with a double cone mixer. The mixture was added to a high-speed mixer, polyvinylacetate 30% dispersant in which hydroxypropyl cellulose was dissolved, polyvinylacetate 30% dispersant was added and granulated. It was established as No. 18 body again.
  • Hydroxypropylmethylcellulose phthalate and triethylcitrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated. Magnesium stearate was added to the coated granules and mixed with a double cone mixer.
  • GPCG-1 granulated fluidized bed granulator coater
  • Example 14 In the same manner as in 3) of Example 14, post-mixing, tableting, and coating were carried out to form a tablet in the form of a multilayer tablet.
  • the multilayer tablet was produced with the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture.
  • granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again.
  • the starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.
  • Pragstatin sodium, microcrystalline cellulose, magnesium oxide (Tomita, Japan), di-mannitol, croscarmellose sodium, lactose, and lauryl sulfate sodium, which are HMG-CoA reductase inhibitors, were appled with No. 35 and mixed for 5 minutes in a double cone mixer. To prepare a mixture. Separately, polyvinylpyrrolidone was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried.
  • the dried product was separately dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride in poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer and triethylcitrate.
  • the solution was prepared and the above granules were put into a fluid bed granulation coater (GPCG-1 Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes.
  • Example 14 In the same manner as in 3) of Example 14, post-mixing, tableting, and coating were carried out to form a tablet in the form of a multilayer tablet.
  • a capsule was prepared by the following method.
  • HMG-CoA reductase inhibitor pitavastatin calcium, microcrystalline cellulose, calcium carbonate, pregelatinized starch, butylated hydroxyanisole was apples in No. 35 and mixed for 5 minutes with a double cone mixer to prepare a mixture.
  • the polyvinylacetate 30% dispersant in which polyvinylpyrrolidone was dissolved was added thereto, and then granulated using an oscillator.
  • Hydroxypropylmethylcellulose phthalate and triethylcitrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated
  • the final product of 1) and 2) was mixed with a double cone mixer. Magnesium stearate was added to the mixture for final mixing.
  • the final mixed mixture was put into a powder feeder and filled into a capsule (Seoheung capsule, Korea) using a capsule charger (SF 40N, Sejong Machinery, Korea) to complete the preparation of the capsule formulation.
  • a capsule was prepared by the following method.
  • a sugar solution (Sugar sphere) was added to a fluidized bed granulator (GPCG-1: Glatt), and then a binder solution (10% w /) in which polyvinylpyrrolidone and amlodipine besylate, a dihydropyridine calcium channel blocker, were dissolved in ethanol. w) was sprayed to form pellets containing dihydropyridine calcium channel blocker and dried.
  • GPCG-1 fluidized bed granulator
  • step 1) and 2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule formulation.
  • a capsule was prepared by the following method.
  • a sugar solution (Sugar sphere) was added to a fluidized bed granulator (GPCG-1: Glatt), and a binder solution (10% w / d) in which polyvinylpyrrolidone and dihydropyridine calcium channel blocker, amlodipine besylate, were dissolved in ethanol. w) was sprayed to form pellets containing dihydropyridine calcium channel blocker and dried.
  • GPCG-1 fluidized bed granulator
  • HMG-CoA reductase inhibitor fluvastatin sodium, microcrystalline cellulose, potassium bicarbonate, pregelatinized starch, lauryl sulfate sodium, croscarmellose sodium was appled with No. 35 sieve and mixed for 5 minutes with a double cone mixer to prepare a mixture. It was. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 again. Sodium chloride and magnesium stearate were added to the formulation and mixed for 4 minutes.
  • the mixture was tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6 mm diameter punch to prepare a tablet.
  • a solution obtained by dissolving cellulose acetate 320S (acetal group 32%) and cellulose acetate 398NF10 (acetal group 39.8%) in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared.
  • SFC-30F Sejong Machinery, Korea) to form a film coating layer to prepare an osmotic tablet of HMG-CoA reductase inhibitor.
  • the final product of 1) and 2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.
  • a capsule was prepared by the following method.
  • a sugar solution (Sugar sphere) was added to a fluidized bed granulator (GPCG-1: Glatt), and a binder solution in which polyvinylpyrrolidone and dihydropyridine calcium channel blocker nisoldipine (Lusochimica, Italy) was dissolved in ethanol ( 10% w / w) was sprayed to form pellets containing dihydropyridine calcium channel blocker and dried.
  • GPCG-1 fluidized bed granulator
  • a binder solution in which polyvinylpyrrolidone and dihydropyridine calcium channel blocker nisoldipine (Lusochimica, Italy) was dissolved in ethanol ( 10% w / w) was sprayed to form pellets containing dihydropyridine calcium channel blocker and dried.
  • Atorvastatin calcium anhydride (TEVA, Israel), microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate with 35 Mixing was carried out for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again.
  • the formulations are placed in a fluidized bed coater (GPCG-1, Glatt, Germany) and separately poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer (Evonik Degussa, Germany) and triethyl
  • GPCG-1 fluidized bed coater
  • Triethyl ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer
  • triethyl A solution of citrate (Vertellus, England) dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and coated. It was.
  • magnesium stearate (Nitika Chemical, India) was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6 mm diameter punch to prepare a nuclear tablet.
  • a coating solution (10% w / w) obtained by dissolving and dispersing acryl-isolated in purified water was prepared to form a coating layer using the HMG-CoA reductase inhibitor tablet as a high coater (SFC-30F, Sejong Machinery, Korea). CoA reductase inhibitor tablet preparation was completed.
  • the final product of 1) and 2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.
  • a capsule was prepared by the following method.
  • Dihydropyridine channel blocker lercanidipine, microcrystalline cellulose, anhydrous calcium phosphate, corn starch were apples in No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again.
  • Starch sodium glyconate and magnesium stearate were added to the sieved material, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong) equipped with a 5 mm diameter punch to prepare a tablet.
  • MRC-30, Sejong rotary tablet press
  • Sugarsphere was added to a fluidized bed granulator (GPCG-1: Glatt), and then polyvinylpyrrolidone, citric acid, butylated hydroxyanisole and simvastatin, HMG-CoA reductase inhibitors, were separately dispersed in ethanol.
  • the dissolved binding solution (10% w / w) was sprayed to form pellets containing the HMG-CoA reductase inhibitor and dried.
  • poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate) copolymer (Evonik Degussa, Germany) and triethyl citrate (Vertellus, England) were prepared by ethanol and methylene chloride.
  • 1 Spray a solution dissolved in a mixed solution (20% w / w), and add hydroxypropyl methyl cellulose phthalate (Shin-etsu, Japan) and triethyl citrate to the pellet.
  • HMG-CoA reductase inhibitor delayed-release pellets were prepared by spraying the solution dissolved in the mixed solution (20% w / w).
  • the product of 1) and 2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the time difference release formulation of the capsule form.
  • a capsule was prepared by the following method.
  • Ishydrin (Shasun Chemicals, India), a dihydropyridine calcium channel blocker, microcrystalline cellulose, anhydrous calcium phosphate and corn starch were weighed and appled in No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again. Starch sodium glyconate and magnesium stearate sieved through No. 35 sieve were added to the sieved material, mixed for 4 minutes, and then compressed with a rotary tableting machine (MRC-30, Sejong Machinery, Korea) equipped with a 5 mm diameter punch. The preparation of pyridine calcium channel blocker tablets was completed.
  • HMG-CoA reductase inhibitor simvastatin, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch and di-mannitol, butylated hydroxyanisole apologized in 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture It was. Separately, citric acid and hydroxypropyl cellulose were dissolved in a polyvinylacetate 30% dispersant to form a binding solution (10% w / w), followed by granulation and drying. After drying, it was established as No. 18 body again. Magnesium stearate sieved through a No.
  • the product of 1) and 2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of a controlled release formulation in the form of a capsule.
  • a capsule was prepared by the following method.
  • Nimodipine (Lusochimica, Italy), a dihydropyridine calcium channel blocker, microcrystalline cellulose, corn starch, anhydrous calcium phosphate, weighed 35 apples, and mixed in a double cone mixer for 5 minutes to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again.
  • HMG-CoA reductase inhibitor rosuvastatin calcium, microcrystalline cellulose, anhydrous calcium phosphate, di-mannitol, cross-linked polyvinylpyrrolidone, lauryl sulfate sodium, butylated hydroxyanisole in apple 35 and double cone
  • the mixture was prepared by mixing for 5 minutes with a mixer. The mixture was added to a high-speed mixer, and the mixture was added by adding 30% of a polyvinylacetate dispersant in which hydroxypropyl cellulose was dissolved. Granulation was carried out using an oscillator using No. 20 sieve, and dried at 60 ° C. using a hot water dryer. It was.
  • Hydroxypropylmethylcellulose phthalate and triethylcitrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated.
  • GPCG-1 granulated fluidized bed granulator coater
  • the products of 1) and 2) were mixed in a double cone mixer.
  • Sodium starch glyconate was added to the mixture and mixed with a double cone mixer.
  • Magnesium stearate was added to the mixture, followed by final mixing.
  • the final mixed mixture was put into a powder feeder and filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.
  • a capsule was prepared by the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.
  • HMG was sprayed with a solution of poly (methacrylate, methyl methacrylate) copolymer and triethyl citrate in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride.
  • -CoA reductase inhibitor delayed pellets were prepared.
  • the products of 1) and 2) were mixed in a double cone mixer.
  • Sodium starch glycolate was added to the mixture and mixed with a double cone mixer.
  • Magnesium stearate was added to the mixture, followed by final mixing.
  • the final mixed mixture was put into a powder feeder and filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the time release formulation in capsule form.
  • a capsule was prepared by the following method.
  • Pedidipine (Cipla, India), microcrystalline cellulose, corn starch, lactose, and propyl gallate (Spectrumchemical, USA), which are dihydropyridine-based calcium channel blockers, are apples in No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. It was. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture.
  • the granules were dried at 60 ° C. using a hot water dryer (H-W-C, Samkok, Japan). After drying, it was established as No. 20 sieve again. Sodium starch glyconate was added to the sieved material and mixed with a double cone mixer. Magnesium stearate was added to the mixture for final mixing.
  • Pragstatin sodium, microcrystalline cellulose, magnesium oxide (Tomita, Japan), di-mannitol, croscarmellose sodium, and lauryl sulfate sodium, which are HMG-CoA reductase inhibitors, were appled with No. 35 and mixed for 5 minutes with a double cone mixer. Was prepared. Separately, polyvinylpyrrolidone was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried.
  • a solution of ethyl cellulose (HERCULES, USA) dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany). Coated. Magnesium stearate sieved through No. 35 sieve was added to the coated formulation, mixed for 4 minutes, and the mixture was compressed into tablets using a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 5 mm diameter punch. .
  • a coating solution (10% w / w) obtained by dissolving and dispersing acryl-isolated in purified water was prepared to form a coating layer using the HMG-CoA reductase inhibitor tablet as a high coater (SFC-30F, Sejong Machinery, Korea). CoA reductase inhibitor tablet preparation was completed.
  • the product of 1) and 2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.
  • a capsule was prepared by the following method.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture.
  • granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again.
  • sodium starch glycolate and magnesium stearate which were sieved through a No. 35 sieve, were added, mixed for 4 minutes, and the mixture was compressed into a rotary tableting machine (MRC-30, Sejong, Korea) equipped with a 5 mm diameter punch.
  • Dihydropyridine calcium channel blocker tablet preparation was completed.
  • ethylcellulose was dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and prepared by first coating by using a fluidized bed granulation coater (GPCG-1; Glatt, Germany). After primary coating, the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and hydroxypropylmethylcellulose phthalate and triethylcitrate were mixed 1: 1 with ethanol and methylene chloride (20% w). final coating with the solution dissolved in / w). Magnesium stearate was added to the coating for final mixing.
  • GPCG-1 fluidized bed granulation coater
  • the product of 1) and 2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.
  • amlodipine-atorvastatin blister packaging kit was manufactured by the following method.
  • Dihydropyridine calcium channel blocker, amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate was added to apple No. 35 and mixed in a double cone mixer for 5 minutes to prepare a mixture.
  • hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture.
  • granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again.
  • Starch sodium glyconate and magnesium stearate sieved through No. 35 sieve were added to the sieved material, mixed for 4 minutes, and then compressed with a rotary tableting machine (MRC-30, Sejong Machinery, Korea) equipped with a 5 mm diameter punch.
  • MRC-30 Sejong Machinery, Korea
  • the sieved material is placed in a fluidized bed coater (GPCG-1, Glatt, Germany), separately cellulose acetate 320S (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate 398NF10 (acetal group 39.8%) (Eastman Chemical Company, USA ) was prepared in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granulated material was put into a fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6 mm diameter punch to prepare a tablet.
  • a rotary tablet press MRC-30, Sejong Machinery, Korea
  • the blister packaging machine (Minister A, Heung-A Engineering) is used to package each tablet in a blister packaging container (silver foil, Dongyang, PVDC, Jeonmin Industries) for simultaneous use.
  • the packaging kit was prepared.
  • the nucleated tablet of Example 5 was confirmed that the amlodipine component in the dissolution test exhibited almost the same elution characteristics as compared to the control formulation Novasque under the following conditions, the atorvastatin calcium component release compared to the control agent Lipitor You can see the delay.
  • the dissolution test results of the atorvastatin component it was confirmed that the dissolution rate of the atorvastatin component up to 120 minutes, which is the artificial gastric juice section, was all within 10% of the nucleated tablets of amlodipine / atorvastatin of Example 5, but the control formulation was about 50%.
  • the nucleated tablet of amlodipine / atorvastatin of Example 5 was found to be much delayed to about 5% at 360 minutes.
  • the amlodipine / atorvastatin nucleated tablet of the present invention has a metabolite associated with metabolism first after metabolism in the liver since the initial release of atorvastatin is much slower than that of amlodipine, unlike the dissolution of the amlodipine monotherapy and the atorvastatin monotherapy simultaneously. Enough time to regenerate the enzyme cytochrome P450 can be secured.
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method Paddle method, 75 revolutions / minute
  • Test solution 0.01M hydrochloric acid solution, 750 mL
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.01N hydrochloric acid solution, 750mL (artificial gas solution)
  • the biphasic matrix tablet of Example 12 was found to exhibit almost the same elution characteristics as the cinnarone, the control formulation, in the dissolution test under the following conditions, but the rosuvastatin component was the crest, the control formulation. It can be seen that the release is very slow compared to.
  • the dissolution rate of the rosuvastatin component up to 120 minutes, which is the artificial gastric juice section was within 5% in the two-phase matrix tablet of the silinidipine / rosuvastatin of Example 12.
  • the dissolution rate of the rosuvastatin component in the artificial intestine section was 95% at 360 minutes in the control formulation, but the two-phase matrix tablet of silinidipine / rosuvastatin of Example 12 was about 360 minutes. It was confirmed that the release was delayed even more by 10%.
  • the two-phase matrix tablets of the silinidipine / rosuvastatin of the present invention unlike the dissolution of the simultaneous injection of the silinidipine monotherapy and the rosuvastatin monotherapy, showed that the initial release of rosuvastatin calcium was much higher than that of the silinidipine. Because of its slowness, cynidipine is first metabolized in the liver, allowing ample time to regenerate the metabolic enzyme cytochrome P450.
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method Paddle method, 75 revolutions / minute
  • Test solution 0.01M hydrochloric acid solution, 750 mL
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.01N hydrochloric acid solution, 750mL (artificial gas solution)
  • a comparative dissolution test of the amlodipine / fluvastatin sodium capsule preparation prepared in Example 25 and the reference drug (Novask: amlodipine monotherapy, rescol (Novartis): fluvastatin sodium monotherapy) was performed.
  • amlodipine component dissolution the dissolution test was carried out based on the nine amendments of the Korean Pharmacopoeia General Test Method of Experimental Example 1.
  • fluvastatin sodium component dissolution test the eluate was changed from artificial gastric to artificial intestine at 120 minutes The dissolution test was carried out for 600 minutes as shown in FIG. 3.
  • the capsules of Example 25 were found to exhibit almost the same elution characteristics as the control formulation of the amlodipine component in the dissolution test under the following conditions, and the fluvastatin component compared to the control formulation leschols. It can be seen that the elution is very slow.
  • the dissolution test results of the fluvastatin component showed that the dissolution rate of the fluvastatin component up to 120 minutes, which is the artificial gastric juice section, was all within 10% in the capsules of amlodipine / fluvastatin of Example 25, but the control formulation was about 30%.
  • the dissolution rate of fluvastatin components in the artificial intestinal fluid section was about 98% at 360 minutes in the control formulation, but the amlodipine / fluvastatin capsule of Example 25 was released at about 5% in total 360 minutes. This delay was confirmed.
  • amlodipine / fluvastatin capsules of the present invention differ from the dissolution of the amlodipine monoclonal and fluvastatin monoclonal drugs, and thus the amlodipine is treated first because the initial release of fluvastatin sodium is much slower than that of amlodipine. After the metabolism in the metabolic enzyme cytochrome P450 can be obtained enough time to regenerate.
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method Paddle method, 50 revolutions / minute
  • Test solution 0.01N hydrochloric acid solution, 750mL (artificial gas solution)
  • Example 4 shows that the controlled release nucleated tablet of the present invention was prepared using an enteric base as a binder (Example 3) and an enteric coating after nuclear tableting (Example 5, Example 6) in the dissolution test under the conditions of Experimental Example 1. ), All of the atorvastatin calcium components were released relatively rapidly after the delayed time to the intended time. Depending on the type of enteric base and enteric coating, the atorvastatin calcium component was rapidly released after a certain delay time.
  • the formulations of the present invention may rapidly release HMG-CoA reductase inhibitors after a delay to the intended time.
  • the release of atorvastatin calcium is much slower than that of amlodipine. It is possible to secure enough time for the related enzyme cytochrome P450 to be regenerated, thereby reducing the possibility of side effects and the like.
  • a comparative dissolution test was performed on the atorvastatin calcium in the capsules of Examples 21 and 27.
  • the dissolution test method was the same as Experimental Example 1, and the results are shown in FIG. 5.
  • the capsule of the present invention can rapidly release the HMG-CoA reductase inhibitor component after a delay time until the intended time.
  • the capsule of the present invention has sufficient time to regenerate the metabolic enzyme cytochrome P450 after the dihydropyridine calcium channel blocker is first metabolized in the liver. can do.
  • control group 1 control group 2
  • test group for each test group was conducted in six people, a total of 18 people, the details are shown in Table 4.
  • the difference between the mean Tmax value of the test group and the control group was about 0.1 hours, and there was no significant difference between the Cmax value and the AUC (0- ⁇ ) value.
  • amlodipine showed similar blood levels between the two groups.
  • the atorvastatin Tmax of the control group was about 0.5 hours, and the atorvastatin Tmax of the test group was delayed by about 9 hours or more compared to the Tmax of the atorvastatin of the control group 2.
  • the preparation of the present invention reduces the side effects of drug interactions and is effective in the treatment and prevention of hypertension, hyperlipidemia and the resulting cardiovascular disease or metabolic syndrome due to pharmacological effect synergism, and can increase medication compliance.

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Abstract

La présente invention concerne une formulation pharmaceutique pour une administration matinale comportant : un compartiment de libération spontanée contenant un bloqueur de canaux calciques à base de dihydropyridine en tant que principe pharmacologiquement actif, et un compartiment de libération prolongée contenant un inhibiteur de HMG-CoA réductase en tant que principe pharmacologiquement actif. La formulation selon la présente invention réduit les effets secondaires provoqués par l’interaction entre médicaments et est efficace dans le traitement et la prévention de l’hypertension et de l’hyperlipidémie et de maladies cardio-vasculaires ou du syndrome métabolique provoqué par cette interaction due au synergisme pharmacologique. La formulation peut également améliorer l’observance médicamenteuse.
PCT/KR2009/004565 2008-08-19 2009-08-14 Formulation pharmaceutique WO2010021473A2 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2014015672A1 (fr) * 2012-07-24 2014-01-30 兆科药业（广州）有限公司 Préparation d'un composé de lercanidipine et d'atorvastatine

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WO2006040085A2 (fr) * 2004-10-12 2006-04-20 Boehringer Ingelheim International Gmbh Comprime bicouche
WO2006071077A1 (fr) * 2004-12-30 2006-07-06 Hanmi Pharm. Co., Ltd. Formulation de complexe d'inhibiteur de reductase coa de 3-hydroxy-3-methylglutaryle et agent anti-hypertensif, et procede de preparation correspondant
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
WO2008054123A1 (fr) * 2006-10-30 2008-05-08 Hanall Pharmaceutical Company, Ltd. Composition complexe à libération contrôlée comprenant des bloqueurs des récepteurs de l'angiotensine ii et des inhibiteurs de la hmg-coa réductase

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Publication number Priority date Publication date Assignee Title
WO2006040085A2 (fr) * 2004-10-12 2006-04-20 Boehringer Ingelheim International Gmbh Comprime bicouche
WO2006071077A1 (fr) * 2004-12-30 2006-07-06 Hanmi Pharm. Co., Ltd. Formulation de complexe d'inhibiteur de reductase coa de 3-hydroxy-3-methylglutaryle et agent anti-hypertensif, et procede de preparation correspondant
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
WO2008054123A1 (fr) * 2006-10-30 2008-05-08 Hanall Pharmaceutical Company, Ltd. Composition complexe à libération contrôlée comprenant des bloqueurs des récepteurs de l'angiotensine ii et des inhibiteurs de la hmg-coa réductase

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014015672A1 (fr) * 2012-07-24 2014-01-30 兆科药业（广州）有限公司 Préparation d'un composé de lercanidipine et d'atorvastatine
JP2015522626A (ja) * 2012-07-24 2015-08-06 兆科薬業（広州）有限公司Ｚｈａｏｋｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ（Ｇｕａｎｇｚｈｏｕ） Ｃｏｍｐａｎｙ Ｌｉｍｉｔｅｄ レルカニジピンとアトルバスタチンの複合製剤

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