WO2010008203A2 - Preparation pharmaceutique contenant un inhibiteur des canaux calciques - Google Patents

Preparation pharmaceutique contenant un inhibiteur des canaux calciques Download PDF

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Publication number
WO2010008203A2
WO2010008203A2 PCT/KR2009/003897 KR2009003897W WO2010008203A2 WO 2010008203 A2 WO2010008203 A2 WO 2010008203A2 KR 2009003897 W KR2009003897 W KR 2009003897W WO 2010008203 A2 WO2010008203 A2 WO 2010008203A2
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cellulose
release
pharmaceutical formulation
tablet
copolymer
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PCT/KR2009/003897
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English (en)
Korean (ko)
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WO2010008203A3 (fr
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김성욱
전성수
구자성
김진욱
이나영
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한올제약주식회사
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Publication of WO2010008203A2 publication Critical patent/WO2010008203A2/fr
Publication of WO2010008203A3 publication Critical patent/WO2010008203A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention relates to a pharmaceutical formulation comprising a calcium channel blocker.
  • Calcium channel blocker (Calcium channel blocker) is a drug commonly used in the treatment of hypertension. Hypertension is a major cause of death of cardiovascular disease and causes fatal diseases such as stroke, myocardial infarction, congestive heart failure, and peripheral vascular disease.
  • hypertension is not only a major disease of chronic disease in adults at home and abroad, but also a representative circulatory disease disease with a high prevalence regardless of gender.
  • One of the most prescribed drugs for the treatment of hypertension is a calcium channel antagonist that lowers blood pressure by blocking the calcium exchange pathway of cardiovascular smooth muscle.
  • dihydropyridine-based drugs such as amlodipine and lercanidipine. , Lacidipine, felodipine, vanidipine, benidipine, silinidipine, isradipine, manidipine, nicardipine, nifedipine, nimodipine, nilvadipine, nisoldipine, nirenedipine, azelenidipine, and the like.
  • bidihydropyridine-based drugs examples include diltiazem, verapamil, galopamil, cinnarizine, flunarizine, prenylamine, pendylin, mibepradyl, anipamil, and thiopamyl.
  • the characteristics of amlodipine are as follows.
  • Amlodipine belongs to calcium channel blockers and is a persistent drug [Clin Pharmacokinet 1992; 22: 22-31, Am Heart J 1989; 118: 1100-1103, Hypertens Res 2003; 26: 201-208.
  • Amlodipine has the chemical name 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methyl-3,5-pyridinedica It is a very useful calcium channel antagonist as a carboxylate which has a very long half life of 30-50 hours and shows activity over a long period of time (European Patent Publication No. 89,167 and U.S. Patent No. 4,572,909).
  • Amlodipine is effective in lowering blood pressure and blocking angina due to convulsive vasoconstriction by blocking calcium inflow into vascular smooth muscle and inducing peripheral artery dilation.
  • amlodipine When amlodipine is orally administered, it is absorbed by the small intestine and is metabolized by the liver metabolic enzyme cytochrome P450 3A4 40% or more, and only about 60% is released into the blood and exhibits sufficient blood pressure-lowering effect.
  • amlodipine is a 24 hour daily lasting drug, and it is known that taking it in the evening time has the most powerful blood pressure lowering effect from the morning of the next morning to midday.
  • Amlodipine which is a calcium channel antagonist drug that is effective for the symptoms of hypertension, is generally recommended to be taken during the evening hours (about 19 o'clock after dinner), but within 5 minutes after administration, disintegration is completed and the drug is absorbed.
  • the maximum time to reach peak blood concentration is expected to be 6-12 hours after administration. This is about 1 am to 7 am the next day when the patient is sleeping, and the maximum effect of the drug cannot be expected at 6 am to 12 am, when the patient is at the highest mortality rate.
  • the major onset age of the target disease is often older than 40 years, often accompanied by additional diseases.
  • Many drugs are taken simultaneously with other drugs to treat many other diseases, and many drugs that are taken at the same time are metabolized by cytochromes in the liver or are cytochrome suppressed.
  • cytochromes in the liver or are cytochrome suppressed.
  • antihypertensive agent such as simvastatin, atorvastatin
  • antihistamines such as losartan, valsartan, carvedilol, aliskiren, etc.
  • Anticoagulants such as pramin, bupropion and venlafaxine
  • anti-epileptics such as warfarin
  • Anti-convulsants such as chloropromazine and granitone
  • an acne treatment such as carbamazepine, etc.
  • antifungal agents such as forsam prenavir, and itazolidinediol-based diabetes treatment agents such as itraconazole
  • obesity treatment agents such as pioglitazone
  • erectile dysfunction treatment agents such as cibutramine
  • incontinence drugs such as sildenafil.
  • Drugs that are metabolized by cytochromes or inhibit cytochromes compete with each other in vivo by calcium channel antagonists co-administered and cytochromes in the liver, so that either drug is not sufficiently metabolized, resulting in decreased drug efficacy or non-metabolism. Increasing blood levels of the drug causes side effects such as drug interactions.
  • hepatic hepatitis is dose-dependent, it takes a role of destroying the liver several times when taking multiple drugs, and the chance of hepatitis is increased by taking calcium channel blockers for a long time alone. This hepatitis is the destruction of liver parenchymal cells and the destruction of the lobe.
  • the first condition caused by oxidative stress is fatty liver, in which more than 5% of the liver cell weight is increased by lipid peroxide. These fatty livers are soon exacerbated by hepatitis, which destroys the liver, leading to necrosis of the liver cells. When hepatocytes are necrotic, enzymes such as GPT and GOT that are active in hepatocytes are released and released into the blood. All types of liver toxicity are proportional to sGPT levels. Thus, the way to lower sGPT is the basis for treating liver disease [Cecil's text book of medicine]. In addition, in order to prevent hepatotoxicity of drugs, there is a method of lowering sGPT within the normal range by inhibiting lipid peroxide formation by administering an antioxidant or the like.
  • Lipid peroxide inhibition in the liver must first occur in the cell membrane. Because lipids are concentrated in the cell membrane, oxidative stress is concentrated. In these cell membranes, vitamin E removes Peroxyl and Hydroxyl radicals to protect the cell membranes from oxidative stress, and single oxygen is removed by carotenoids, vitamin A. Vitamin E, which performs antioxidant activity, is regenerated by vitamin C, the used vitamin C is regenerated by glutathione, and Glutathione is regenerated by cysteine. Therefore, a series of antioxidant activities require the antioxidant environment of connected systems such as vitamin E, vitamin C, Glutathione and Cysteine.
  • silymarin or biphenyl dimethyl dicarboxylate is a herbal ingredient known to detoxify pharmacological hepatitis by inhibiting oxidative stress on cell membranes.
  • microbiliary obstruction in the liver one of the conditions of drug hepatitis, is a condition in which cell destruction does not escape into the biliary tract and causes continuous hepatic cells to be destroyed.
  • Ursodesoxycholic acid is used for these drug liver disorders. ) Does not act as an antioxidant but acts as a surfactant, but prevents worsening of the condition caused by oxidative stress and increases liver cell regeneration ability.
  • the inventors of the present invention further enhance the drug efficacy when used as a single agent when administering calcium channel blockers, and reduce the side effects when co-administered with other drugs. Completed.
  • the present invention has been completed to develop a formulation that is excellent in patient compliance, can prevent drug interaction, and can prevent liver damage during long-term administration.
  • the technical problem to be solved by the present invention is to provide a formulation that can be excellent in patient compliance when the calcium channel blocker is administered, can prevent drug interaction, and can prevent liver damage during long-term administration.
  • the present invention provides a pharmaceutical formulation comprising a calcium channel blocker and a release controlling substance.
  • the active ingredient calcium channel antagonist in the formulation of the present invention is released within 40% by weight within 4 hours after oral administration, preferably within 30% by weight within 4 hours after oral administration.
  • Calcium channel antagonist in the formulation of the present invention is included 1 ⁇ 400mg per unit formulation, preferably 3 ⁇ 200 mg.
  • the preparation of the present invention further comprises a hepatitis preventive and inhibitor as an active ingredient, and the hepatitis preventive and inhibitor is included in the formulation of 0.01 ⁇ g to 1 g, preferably 0.1 ⁇ g to 200 mg.
  • the hepatitis preventive and inhibitors are beta-carotene ( ⁇ -carotene), riboflavin (riboflavin), riboflavin tetrabutyrate (riboflavin tetrabutyrate), riboflavin rocoat (riboflavin phosphate sodium), ascorbic acid ( ascorbic acid, ascorbyl palmitate, calcium ascorbate, ascorbate nicotinamide ascorbate, sodium ascorbate, dehydroascorbic acid, cholecal Cholecalciferol, cholecalciferolic acid, ergocalciferol, tocopherol, tocopherol acetate, tocopherol calcium, tocopherol calcium uccinate Amino acids such as cysteine, cysteine hydorchlori, and / or tocopherol succinate de, cysteine malate, methyl cysteine, carboxymethyl cysteine, methyl cysteine hydrochloride,
  • the formulation of the present invention contains a calcium channel blocker represented by amlodipine as an active ingredient.
  • the calcium channel blocker include dihydropyridine-based amlodipine, lercanidipine, lassipinepine, felodipine, vanidipine, benidipine, silinidipine, isradinine, manidipine, nicadipine, nifedipine, nimodipine, and nilbadi Fin, nisoldipine, nirenedipine, azelnidipine, bidihydropyridine series include diltiazem, verapamil, galopamil, cinnarizine, flunarizine, prenylamine, pendylin, mibepradilla, anifamil, and / Or thiafamil and the like, and isomers thereof and pharmaceutically acceptable salts thereof, and prodrugs thereof, preferably amlodipine maleic acid salts and
  • amlodipine is described as a specific example, but the present invention is not limited thereto.
  • the release controlling substance of the formulation of the present invention is, for example, at least one selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, and a hydrophilic polymer, and preferably at least one selected from a water insoluble polymer and an enteric polymer.
  • the release controlling substance of the formulation may be used in an amount of 0.1 to 50 parts by weight based on 1 part by weight of the calcium channel antagonist. However, when the amount is less than the above range, sufficient controlled release property cannot be obtained. It may be delayed to obtain significant clinical effects.
  • 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 polymer usable in the present invention is at least one selected from the group consisting of an enteric cellulose derivative, an enteric acrylic acid copolymer, an enteric polymethacrylate copolymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, and a mixture thereof. .
  • the enteric cellulose derivative may be hydroxypropylmethylcellulose acetate succinate (or hypromellose acetate succinate), hydroxypropylmethyl cellulose phthalate (or hypromellose phthalate), hydroxymethylethyl cellulose phthalate , Cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethyl hydroxyethyl cellulose phthalate, methyl hydroxyethyl cellulose and their At least one selected from a mixture;
  • the enteric acrylic acid copolymers include styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl methacrylate acrylates, butyl acrylate-styrene-acrylic acid copolymers, methyl acrylate-methacrylic acid-o
  • the enteric maleic acid copolymer is vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinyl methyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether- At least one selected from maleic anhydride copolymer, acrylonitrile-methyl acrylate maleic anhydride copolymer, butyl styrene-maleic-maleic anhydride copolymer and mixtures thereof;
  • the enteric polyvinyl derivative is preferably at least one selected from polyvinyl alcohol phthalate, polyvinylacetate phthalate,
  • the enteric polymer may be included in an amount of 0.1 parts by weight to 20 parts by weight, preferably 0.5 parts by weight to 10 parts by weight with respect to 1 part by weight of the active ingredient, and less than 0.1 parts by weight may be easily dissolved at a pH of less than 5, If the amount exceeds 20 parts by weight, the total weight of the preparation may be unnecessarily increased or the elution may be excessively delayed.
  • 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 include polyvinyl acetate, water-insoluble polymethacrylate copolymers (e.g. poly (ethylacrylate, methyl methacrylate) copolymers (e.g. Eudragit NE30D), poly (ethylacrylic) Latex, methyl methacrylate, trimethylaminoethyl methacrylate chloride) copolymer (e.g.
  • Eudragit RS, RL etc.
  • ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose tri At least one selected from the group consisting of acylate, cellulose acetate, cellulose diacetate, cellulose triacetate, and mixtures thereof is preferred, and more preferably polyvinylacetate, ethyl cellulose, poly (ethyl acrylate, methyl methacrylate). Trimethylaminoethyl methacrylate Yit chloride) copolymer, and cellulose acetate.
  • the water-insoluble polymer may be included in an amount of 0.1 parts by weight to 30 parts by weight, preferably 0.5 parts by weight to 20 parts by weight, and less than 0.1 parts by weight based on 1 part by weight of the active ingredient. If the content is more than 30 parts by weight, the dissolution may be excessively delayed.
  • the hydrophobic compound refers to a substance that does not dissolve in pharmaceutically acceptable water that controls the release of the drug.
  • the hydrophobic compound usable in the present invention is, for example, at least one selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof.
  • fatty acids and fatty acid esters are selected from glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate, stearic acid and mixtures thereof Species or more;
  • Fatty acid alcohols are at least one selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol and mixtures thereof;
  • the waxes are at least one selected from carnauba wax, beeswax, microcrystalline wax, and mixtures thereof;
  • the inorganic material is preferably at least one selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, bum and mixtures thereof.
  • a more preferred example of the hydrophobic compound is carnauba wax.
  • the hydrophobic compound may be included in an amount of 0.1 parts by weight to 20 parts by weight, preferably 0.5 parts by weight to 10 parts by weight with respect to 1 part by weight of the active ingredient, and when less than 0.1 parts by weight, the release of the drug may not be controlled. In case of more than 20 parts by weight, excessive elution may be delayed.
  • 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.
  • sugars are dextrins, polydextrins, dextran, pectin and pectin derivatives, alginates, polygalacturonic acids, xylans, arabinoxylans, arabinogalactan, starch, hydroxypropylstarches, amylose, amylopectin, and their At least one selected from mixtures;
  • Cellulose derivatives include hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, hydroxypropyl methylcellulose acetate succinate, At least one selected from hydroxyethyl methyl cellulose, and mixtures thereof;
  • the gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, arabic gum, gellan gum, xanthan gum, and mixtures thereof;
  • the protein is at least one selected from gelatin, case
  • the polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate, and mixtures thereof;
  • Hydrophilic polymethacrylate copolymers include poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymers (eg Eudragit E, Evonik, Germany), poly (meth At least one selected from methacrylic acid-methylmethacrylate) copolymer, poly (methacrylic acid-ethylacrylate) copolymer, and mixtures thereof;
  • the polyethylene derivative is at least one selected from polyethylene glycol, polyethylene oxide and mixtures thereof;
  • the carboxyvinyl copolymer is preferably a carbomer.
  • hydrophilic polymer are selected from polyvinyl pyrrolidone, hydroxypropyl cellulose, hypromellose, and poly (ethyl acrylate-methyl methacrylate-triethylaminoethyl-methacrylate chloride) copolymer. More than species.
  • the hydrophilic polymer may be included in an amount of 0.05 parts by weight to 30 parts by weight, preferably 0.5 to 20 parts by weight with respect to 1 part by weight of the active ingredient, and when less than 0.05 parts by weight, the release rate may not be controlled. If the excess is excessive, there is a fear that excessive dissolution is delayed.
  • the formulations of the present invention may be used in the form of pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusters, dissolution aids, etc., if necessary, within the scope of not impairing the effects of the present invention. It can be formulated using further within the range which does not interfere with.
  • the additive includes 0.1 to 300 parts by weight based on 1 part by weight of the active ingredient.
  • the diluent may be starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, dicalcium phosphate, or a mixture thereof.
  • the binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, sucrose, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, polyvinylpyrrolidone Copolymers, povidone, gelatin, mixtures thereof, and the like.
  • the disintegrant may be starch or modified starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch (starch starch); Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; Algins such as sodium alginate or alginic acid; Crosslinked celluloses such as croscarmellose sodium; Gums such as guar gum and xanthan gum; Crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof can be used.
  • starch starch such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch (starch starch); Clay such as bentonite, montmorillonite, or veegum; Celluloses such as microcrystalline cellulose, hydroxypropyl cellulose
  • the lubricant is talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monorate, glyceryl monostearate, Glyceryl palmitostearate, polyethylene glycol or mixtures thereof, and the like.
  • the stabilizer may be ascorbic acid, citric acid, butylated hydroxy anisole, butylated hydroxy toluene, tocopherol derivatives and the like.
  • an alkalizing agent which is a salt of an alkali metal, a salt of an alkaline earth metal, or a mixture thereof, may be used.
  • calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium oxide, magnesium carbonate, sodium citrate, or the like may be used. Can be.
  • the pH adjusting agent may be an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and a basicizing agent such as precipitated calcium carbonate, aqueous ammonia, and meglumine.
  • an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and a basicizing agent such as precipitated calcium carbonate, aqueous ammonia, and meglumine.
  • the dissolution aid may be used polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, sodium docusate and the like.
  • a pharmaceutically acceptable additive may be selected and used in the preparation of the present invention as various additives selected from colorants and fragrances.
  • the range of additives usable in the present invention is not limited to the use of such additives, and the above additives may be formulated to contain a range of dosages, usually by selection.
  • the formulations of the invention can be implemented in a variety of formulations. That is, the preparation of the present invention can be formulated into tablets, powders, granules, capsules and the like such as uncoated tablets, film coated tablets, multilayer tablets, nucleated tablets and the like.
  • the uncoated tablet may be formed by compressing a granule containing a calcium channel blocker and a release control material with a tableting machine or the like.
  • the uncoated tablet may be prepared by coating particles, granules or pellets containing a calcium channel blocker with a release controlling material, and then mixing the same with a pharmaceutically acceptable excipient and tableting the tablet with a certain amount of weight.
  • the film coating tablet may be a tablet coated with a film coating layer containing a release control material using a tablet or the like tablet containing a calcium channel blocker.
  • the film-coated tablet is prepared by tableting particles, granules and pellets containing calcium channel blocker in a predetermined amount, and then coating the tablet with a release control material and drying to prepare a film-coated tablet, or to obtain a stable film-coated tablet.
  • the uncoated tablet tablets with delayed-release granules may be prepared by coating with a coating liquid for the purpose of improving stability or delaying drug release.
  • the multilayer tablet may be a tablet in which a layer including a calcium channel blocker and an emission control material and a layer including an emission control material are layered.
  • the layer comprising the release controlling substance can be formulated to not contain a calcium channel blocker.
  • the multilayer tablet comprises one layer comprising particles, granules, pellets and a pharmaceutically acceptable excipient coated with a release control material comprising a calcium channel blocker and a pharmaceutically acceptable excipient together with a release control material.
  • the nucleated tablet may be a tablet comprising an inner core tablet including a calcium channel blocker and a release control material, and an outer layer including a release control material surrounding an outer surface of the inner core tablet. That is, the nucleated tablet is a tablet comprising a coating layer surrounding the outer surface of a tablet including a calcium channel blocker and including a release control material, and an outer layer surrounding the outer surface of the coating layer and including a release control material, or releasing a drug by osmotic pressure. It may be an osmotic nucleated tablet containing an osmotic inner core tablet as an inner core.
  • the capsule may be in the form of one or more selected from particles, granules, pellets and tablets filled into the capsule.
  • the capsule includes a calcium channel blocker and fills the granules coated with the release control material into the capsule charger as it is, or by filling and filling the capsule charger with particles, granules containing the pharmaceutically acceptable excipient or release control material. Capsules can be prepared.
  • the capsule includes a calcium channel blocker and the pellet coated with the release control material as it is or filled into the capsule charger with particles, granules containing a pharmaceutically acceptable excipient or release control material Capsules can be prepared.
  • the capsule is filled into the capsule as a film coated tablet coated with a release control material containing a calcium channel blocker, or into a capsule charger with particles, granules containing a pharmaceutically acceptable excipient or release control material.
  • Capsules can be prepared by filling.
  • the formulation according to the present invention may be provided in a state such as uncoated tablet without additional coating, but may be in the form of a coated tablet further comprising a coating layer by forming a coating layer on the outside of the formulation, if necessary.
  • a coating layer By forming the coating layer, it is possible to provide a formulation that can further ensure the stability of the active ingredient.
  • the method of forming the coating layer 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 formulation of the present invention includes an osmotic pressure control agent and may be coated with a semipermeable membrane coating base.
  • the osmotic pressure regulator is preferably at least one selected from the group consisting of magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, lithium sulfate, sodium sulfate and mixtures thereof.
  • the osmotic pressure control agent may be included in an amount of 0.01 parts by weight to 10 parts by weight, preferably 0.05 parts by weight to 0.5 parts by weight with respect to 1 part by weight of the active ingredient, and there is a concern that it is difficult to obtain sufficient time difference release property at less than 0.01 parts by weight, Drug release may be delayed at more than 10 parts by weight, making it difficult to obtain a significant clinical effect.
  • the semi-permeable membrane coating base is a substance to be blended into the coating layer of the pharmaceutical formulation, and refers to a substance used to form a membrane that allows some components to pass but does not pass other components.
  • 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 semi-permeable membrane coating base may be included in an amount of 0.01 parts by weight to 10 parts by weight, preferably 0.05 parts by weight to 1.25 parts by weight, with respect to 1 part by weight of the active ingredient, and when less than 0.01 parts by weight, it may be difficult to have a sufficient delay time. And, if more than 10 parts by weight there is a problem that the release of the drug does not occur or the delay time is long.
  • the formulation of the present invention may be administered for evening administration, once a day between 5 and 11 pm. That is, in the preparation of the present invention, the calcium channel antagonist administered in the evening time period such as amlodipine reaches the highest blood concentration during the morning from 6 am to 12 pm, that is, the optimal effect.
  • formulation of the present invention can be co-administered with drugs that are metabolized by cytochromes.
  • the drug metabolized by the cytochrome may be a lipid inhibitor which is at least one selected from simvastatin and atorvastatin; Antihypertensive agents that are one or more selected from amlodipine, felodipine, carvedilol, and aliskiren; An antihistamine, which is at least one selected from loratatin, and azelastine; Analgesics which are at least one selected from acetaminophen, and tramadol; Antidepressant, which is at least one selected from amitriptyline, and imipramine; Anticoagulants that are warfarin; An anti-emetic agent which is at least one selected from chloropromazine, and granistron; Anticonvulsants that are carbamazepine; Isotretinoin acne treatment (retinoids); Antipsychotics that are risperidone; Antidepressants at least one selected from bupropine, and venlafaxine; HIV (human immunodefici
  • the present invention also provides a pharmaceutical formulation comprising a prior-release compartment comprising a hepatitis preventive and inhibitor as a pharmacologically active ingredient, and a delayed-release compartment comprising a calcium channel blocker as a pharmacologically active ingredient.
  • the active ingredient included in the delayed-release compartment is released 1 hour to 4 hours after the release of the active ingredient included in the prior-release compartment, and 40% or less of the active ingredient included in the delayed-release compartment is prerelease. Release within 4 hours after the start of release of the active ingredient included in the compartment.
  • the active ingredient included in the pre-release compartment is released at least 85% by weight within 1 hour after the start of release.
  • Hepatitis prophylaxis and inhibitors in the formulations of the present invention are included in the formulation 0.01 ⁇ g ⁇ 1g.
  • the calcium channel blocker in the formulation of the present invention contains 1 to 400 mg of the formulation.
  • 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 ingredient of the prior-release compartment is a hepatitis preventive and inhibitor, the same as described above in the pharmaceutical formulation comprising the calcium channel blocker and the release controlling substance.
  • formulations of the present invention do not interfere with the release of pharmacologically active ingredients from commonly used additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusters, dissolution aids and the like without departing from the effect of the present invention. It can be formulated using additionally within the scope of, and the details described above apply to pharmaceutical formulations comprising the calcium channel blocker and the release controlling substance.
  • 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) release controlling 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 ingredient of the delayed-release compartment is a calcium channel blocker, and may further comprise a hepatitis preventive and inhibitor of the prior-release compartment as needed.
  • the active ingredient of the delayed-release compartment releases less than 40% by weight of the total amount of the active ingredient of the delayed-release compartment until 2 hours after the release of the active ingredient of the prior-release compartment.
  • the active ingredient is released within 20% by weight of the total amount of the active ingredient of the delayed-release compartment until 2 hours after the start of the release of the active ingredient of the prior-release compartment.
  • the delayed-release compartment of the pharmaceutical formulation of the present invention includes a release controlling substance, and the details of the release controlling substance are the same as those described above in the pharmaceutical preparation including the calcium channel blocker and the release controlling substance. There is only a difference between the compartment and the formulation.
  • 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.
  • osmotic pressure control agent and the semipermeable membrane coating base are the same as those described above in the pharmaceutical preparation including the calcium channel blocker and the release controlling substance.
  • the formulations of the present invention are diluents, binders, disintegrating agents 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 release, lubricants, pH adjusters, antifoams, dissolution aids and the like can be formulated further using within a range not departing from the nature of delayed release.
  • 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 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 it is possible to provide a formulation which can further secure the stability of the active ingredient, the details of the coating is the same as described above in the pharmaceutical formulation comprising the calcium channel blocker and the release control material.
  • the formulation of the present invention may be administered once a day between 5 to 11 o'clock in the evening, and may be co-administered with drugs that are metabolized by cytochromes.
  • the foregoing applies in pharmaceutical formulations comprising control substances.
  • the pharmaceutical preparations of the present invention may be formulated according to the respective diseases or according to the ingredients, using the time-dose dosing principle disclosed by Chronotherapeutics (2003, Peter Redfern, PhP), as an appropriate method in the art, Specifically, it may be produced by a method comprising the following steps.
  • 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 formulation of the present invention is based on Chronotherapy taking into account the time of expression of pharmacological action in the body, and is formulated to delay release than when taking a single calcium channel blocker which is released in vivo. Maximize pharmacological and clinical anti-pressure effects and prevent complications.
  • the pharmaceutical formulation of the present invention is based on the theory of metabolic (Xenobiotics) in consideration of metabolic enzyme interactions, and is formulated so as to delay release than drugs that are metabolized by cytochromes in the liver. It does not compete with the metabolism by cytochromes, so that time difference is maximized, pharmacological and clinical anti-pressure effects and complication prevention effects are maximized, and side effects are further reduced.
  • the pharmaceutical preparations of the present invention can prevent and inhibit the development of pharmacologic hepatitis due to prolonged or excessive drug administration.
  • the formulation of the present invention maximizes the pharmacological and clinical anti-pressure effects and complication prevention effects when taken, avoids interaction with drugs metabolized by the same enzyme in the liver, and prevents the development of drug hepatitis due to long-term administration And can be suppressed.
  • Figure 1 is a graph showing the dissolution patterns of amlodipine single agent, and Example 1 formulation.
  • Figure 2 is a graph showing the dissolution patterns of lecanidipine single agent, and Example 2 formulation.
  • Fig. 5 is a graph showing the dissolution patterns of the (S) -amlodipine single agent and the Example 32 formulation.
  • Amlodipine besylate, microcrystalline cellulose, and sorbitol are sieved through a No. 35 sieve in a content of Table 1 and mixed for 5 minutes using a high speed mixer to prepare a mixture.
  • citric acid, succinic acid and polyvinylpyrrolidone are dissolved in purified water (70 mg per tablet) to form a binding solution, which is then combined, granulated and dried.
  • the dried product was placed in a fluidized bed coater, and a solution of polyvinylacetate dissolved in a mixed solvent of ethanol and methylene chloride (2: 8) (240 mg per tablet) was prepared. ) And coat. Drying after completion of the coating prepared a calcium channel blocker delayed-release granules.
  • the calcium channel blocker delayed-release granules prepared in 1) and magnesium stearate were placed in a double cone mixer and mixed for 4 minutes, followed by final mixing.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare delayed-release uncoated tablets of calcium channel blockers.
  • Lecanidipine hydrochloride , pregelatinized starch, lactose and croscarmellose sodium were sieved through a No. 35 sieve in a content of Table 1 and mixed for 5 minutes using a high speed mixer to prepare a mixture.
  • poloxamer 188 is dissolved in purified water (90 mg per tablet) to form a binding solution, which is then combined, granulated and dried.
  • the dried product was placed in a fluidized bed coater, and cellulose acetate (acetyl group 32.0%) and cellulose acetate (acetyl group 39.8%) were dissolved in ethanol and methylene chloride (2: 8) mixed solvent (800 mg per tablet).
  • the granules are placed in a fluid bed granulation coater (GPCG-1: Glatt, Germany) and coated. After the completion of the coating was dried and the dried microcrystalline cellulose, colloidal silicon dioxide was added to the double cone mixer and mixed to prepare a calcium channel blocker delayed-release granules.
  • GPCG-1 fluid bed granulation coater
  • the calcium channel blocker delayed-release granules prepared in 1) and magnesium stearate were placed in a double cone mixer and mixed for 4 minutes, followed by final mixing.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare uncoated tablets containing calcium channel blockers.
  • (S) -Amlodipine besylate, microcrystalline cellulose, crosslinked polyvinylpyrrolidone in a content of Table 1 was sieved through a No. 35 sieve, and mixed with a high speed mixer for 5 minutes to prepare a mixture.
  • polyvinylpyrrolidone is dissolved in purified water (100 mg per tablet) to form a binding solution, which is then combined, granulated and dried.
  • the dried product was placed in a fluidized bed coater, and separately a solution of hypromellose dissolved in purified water (70 mg per tablet) and hypromellose phthalate in ethanol and purified water (8: 2) mixed solvent (120 mg per tablet) were prepared.
  • the granules are put in a fluid bed granulation coater (GPCG-1: Glatt, Germany) and coated sequentially. Drying after completion of the coating prepared a calcium channel blocker delayed-release granules.
  • the calcium channel blocker delayed-release granules prepared in 1) and magnesium stearate were placed in a double cone mixer and mixed for 4 minutes, followed by final mixing.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare delayed-release uncoated tablets of calcium channel blockers.
  • Lecanidipine hydrochloride, microcrystalline cellulose, sodium starch glycolate and lactose in a content of Table 1 were sieved through a No. 35 sieve and mixed for 5 minutes with a high speed mixer to prepare a mixture. Separately, hydroxypropyl cellulose is dissolved in purified water (40 mg per tablet) to form a binding solution, which is then combined, granulated and dried. The dried product was placed in a fluidized bed coater, and separately prepared by dissolving hypromellose phthalate (HP-55) and triethyl citrate in a mixed solvent of ethanol and methylene chloride (2: 8) (1200 mg per tablet).
  • HP-55 hypromellose phthalate
  • triethyl citrate in a mixed solvent of ethanol and methylene chloride (2: 8) (1200 mg per tablet).
  • the water is placed in a fluid bed granulation coater (GPCG-1: Glatt, Germany) and coated. After the completion of the coating was dried and the colloidal silicon dioxide was added to the double cone mixer in the dry and mixed to prepare a calcium channel blocker delayed-release granules.
  • GPCG-1 fluid bed granulation coater
  • the calcium channel blocker delayed-release granules prepared in 1) and magnesium stearate were placed in a double cone mixer and mixed for 4 minutes, followed by final mixing.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare delayed-release uncoated tablets of calcium channel blockers.
  • the uncoated tablet prepared in 1) was put into a high coater (SFC-30N: Sejong Machinery, Korea), and hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc were prepared using ethanol and purified water (8: 2)
  • a film-coated tablet containing calcium channel blocker was prepared by dissolving and dispersing in a mixed solvent (400 mg per tablet) to prepare a coating solution.
  • a calcium channel blocker delayed-release uncoated tablet was prepared in the same manner as in the preparation of 1) and 2) of Example 4, except that lassidipine was used instead of lecanidipine hydrochloride.
  • a film-coated tablet including delayed-release granules was prepared in the same manner as in the method of preparing the film coating layer 2) of Example 5 and in the composition and content of Table 1.
  • a film-coated tablet including delayed-release granules was prepared in the same manner as in the method of preparing the film coating layer 2) of Example 5 and in the composition and content of Table 1.
  • Example 8 ammodipine besylate, microcrystalline cellulose, pregelatinized starch, polyvinylpyrrolidone copolymer, and colloidal silicon dioxide were sieved through the composition of Table 2 to prepare a calcium channel blocker delayed-release film-coated tablet. And mixed for 30 minutes with a double cone mixer to prepare a mixture. After adding magnesium stearate to the mixture, the mixture was mixed for 4 minutes, and the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare a calcium channel blocker uncoated tablet.
  • MRC-33 Sejong
  • a calcium channel blocker uncoated tablet was prepared in the same composition and content as in Table 1 above.
  • Examples 8-11 respectively, the uncoated tablet prepared in 1) was put into a high coater (SFC-30N: Sejong Machinery, Korea), and Eudragit RL 30 D (Eudragit RL 30 D, Degussa) and Eudragit RS 30 D (Degussa) and triethyl citrate were mixed in the ratios of Table 2 and prepared as a coating solution to prepare a calcium channel blocker delayed release film coated tablet containing a delayed release film. .
  • a high coater SFC-30N: Sejong Machinery, Korea
  • Eudragit RL 30 D Eudragit RL 30 D, Degussa
  • Eudragit RS 30 D Degussa
  • the delayed-release film-coated tablet prepared in 2) was put into a high coater (SFC-30N: Sejong Machinery, Korea), the same method as the method of manufacturing the film coating layer of Example 5, 2) and the composition and content of Table 2 It was coated with to prepare a film-coated tablet comprising a delayed release film.
  • SFC-30N Sejong Machinery, Korea
  • Example 12 a calcium channel blocker uncoated tablet was prepared by the composition and the content of Table 2 in the same manner as in 1) of Example 8.
  • the uncoated tablet prepared in 1) was put into a high coater (SFC-30N: Sejong Machinery, Korea), and polyvinylpyrrolidone, triethyl citrate, and Eudra in the contents of Table 2.
  • Eurdragit RL 30 D, Degussa and Eudragit RS 30 D, Degussa are dissolved and dispersed in purified water (80 mg per tablet) and coated with a coating solution to contain a delayed release film. Calcium channel blocker delayed release film coated tablets were prepared.
  • Example 12 to 14 the delayed-release film-coated tablet prepared in 2) above was introduced into a high coater (SFC-30N: Sejong Machinery, Korea), and the same method as the method of manufacturing the film coating layer of 2) of Example 5 It was coated with the composition and content of the method and Table 2 to prepare a film coated tablet comprising a delayed release film.
  • SFC-30N Sejong Machinery, Korea
  • Azenidipine, microcrystalline cellulose and pregelatinized starch were sieved through a No. 35 sieve in a content of Table 3 and mixed for 5 minutes with a high speed mixer to prepare a mixture.
  • hydroxypropyl cellulose is dissolved in purified water (30 mg per tablet) to form a binding solution, followed by association, granulation, and drying.
  • the dried product was placed in a fluidized bed coater, and a solution of polyvinylacetate dissolved in a mixed solvent of ethanol and methylene chloride (2: 8) (240 mg per tablet) was prepared. Germany) and coated to prepare calcium channel blocker delayed-release granules.
  • Magnesium stearate was added to the granules prepared in 1) and finally mixed with a double cone mixer.
  • the final mixed mixture was put into a powder feeder and filled into No. 1 capsule (Seheung Capsule) using a capsule charger (SF-40N, Sejong Pharmatech, Korea) to prepare a delayed-release preparation in capsule form.
  • the sugar spheres were sieved through a No. 35 sieve and poured into a fluidized bed granulator (GPCG 1: Glatt), and then separately in ethanol and purified water (8: 2) mixed solvent (750 mg per tablet) and hypromellose and isradi
  • GPCG 1 Glatt
  • ethanol and purified water 8: 2 mixed solvent (750 mg per tablet) and hypromellose and isradi
  • the binding solution in which the pin was dissolved was sprayed to form pellets containing calcium channel blocker and dried.
  • the granules were sprayed with hypromellose phthalate (HP-55) dissolved in a mixed solvent of ethanol and methylene chloride (2: 8) (1200 mg per tablet) to prepare calcium channel blocker delayed-release pellets.
  • HP-55 hypromellose phthalate
  • Magnesium stearate was added to the pellet prepared in 1) and finally mixed with a double cone mixer. The final mixed mixture was put into a powder feeder and filled into No. 1 capsule using a capsule charger to complete the preparation of the capsule form preparation.
  • a calcium channel blocker delayed-release uncoated tablet was prepared in the same manner as in Example 8 1) and in the composition and content of Table 3, except that isradipine was used instead of amlodipine besylate.
  • the uncoated tablet was put into a high coater (SFC-30N: Sejong Machinery, Korea), and the mixed solvent of hypromellose phthalate (HP-55) and polyethylene glycol 6000 with ethanol and purified water (8: 2) according to the contents of Table 3 It was coated with a coating solution dissolved and dispersed in 80mg per tablet) to prepare a calcium channel blocker film coated tablet containing a delayed release film.
  • the final product of 1) was put into a powder feeder and filled into No. 1 capsule using a capsule charger to complete the preparation of a capsule form preparation.
  • Nicardipine hydrochloride, alpha-lipoic acid, microcrystalline cellulose, sorbitol in a content of Table 3 was sieved through a No. 35 sieve and mixed for 5 minutes with a high speed mixer to prepare a mixture. Separately, citric acid, ascorbic acid and polyvinylpyrrolidone are dissolved in purified water (70 mg per tablet) and combined, granulated and dried as a binding solution.
  • the dried product was put in a fluidized bed coater, and a solution of polyvinylacetate dissolved in a mixed solvent of ethanol and methylene chloride (2: 8) (1200 mg per tablet) was prepared, and the above granules were poured into a fluidized bed granulator (GPCG-1: Glatt, Germany) and coated. Granules were prepared by drying after the coating was completed.
  • a fluidized bed granulator GPCG-1: Glatt, Germany
  • Magnesium stearate was added to a double cone mixer in the delayed-release granules prepared in 1) and Table 3, followed by mixing for 4 minutes, followed by final mixing.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare uncoated tablets containing alpha-lipoic acid and nicardipine hydrochloride.
  • the delayed-release granules prepared in 1) and colloidal silicon dioxide and magnesium stearate were added to a double cone mixer in the amounts shown in Table 3 and mixed for 4 minutes, followed by final mixing.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare uncoated tablets containing beta-carotene and vanidipine hydrochloride.
  • Benidipine hydrochloride, silymarin, microcrystalline cellulose, crosslinked polyvinylpyrrolidone in a content of Table 3 was sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture.
  • polyvinylpyrrolidone is dissolved in purified water (70 mg per tablet) to form a binding solution, which is then combined, granulated and dried.
  • the dried product was placed in a fluidized bed coater.
  • a solution of hypromellose dissolved in purified water (70 mg per tablet) and hypromellose phthalate (HP-55) were mixed in ethanol and purified water (8: 2) mixed solvent (120 mg per tablet).
  • the melted solution is prepared and the above granulated material is put into a fluid bed granulation coater (GPCG-1: Glatt, Germany) and coated. After the completion of the coating was dried to prepare a delayed-release granules.
  • Magnesium stearate was added to a double cone mixer in the delayed-release granules prepared in 1) and Table 3, followed by mixing for 4 minutes, followed by final mixing.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare uncoated tablets containing silymarin and benidipine hydrochloride.
  • Isadipine, biphenyl dimethyldicarboxylate, microcrystalline cellulose, sodium starch glycolate, lactose in a content of Table 3 was sieved through a No. 35 sieve and mixed for 5 minutes with a high speed mixer to prepare a mixture.
  • hydroxypropyl cellulose is dissolved in purified water (40 mg per tablet) to form a binding solution, which is then combined, granulated and dried.
  • the dried product was placed in a fluidized bed coater, and a liquid obtained by dissolving hypromellose phthalate (HP-55) and polyethylene glycol 6000 in ethanol and purified water (8: 2) mixed solvent (120 mg per tablet) was prepared.
  • a granulation coater (GPCG-1: Glatt, Germany) and coat. After the completion of the coating was dried and the colloidal silicon dioxide was added to the double cone mixer in the dry and mixed to prepare a biphenyl dimethyl dicarboxylate and isadipine delayed-release granules.
  • Magnesium stearate was added to the delayed-release granules prepared in 1) in Table 3, followed by mixing for 4 minutes, followed by final mixing. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare delayed release uncoated tablets.
  • Example 22 Film-coated tablet preparation comprising calcium channel blocker delayed-release granules and hepatitis preventive and inhibitor-release film
  • a delayed-release uncoated tablet was prepared by the same method as the preparation method of Example 21, 1) and 2), and the composition and content of Table 3, except for not including biphenyldimethyldicarboxylate.
  • the uncoated tablet prepared in 1) was introduced into a high coater (SFC-30N: Sejong Machinery, Korea), and acetyl cysteine, hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc were used in the composition shown in Table 3. It was coated with a coating solution dissolved and dispersed in 260mg per tablet) to prepare a film-coated tablet comprising a pre-release film layer containing acetyl cysteine and delayed-release granules containing isradipine.
  • Example 23 film-coated tablet preparation comprising calcium channel blocker delayed-release granules and hepatitis preventive and inhibitor pre-release film
  • Nimodipine, selenium-containing yeast, microcrystalline cellulose, sodium starch glycolate, and lactose in a content of Table 3 were sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture.
  • hydroxypropyl cellulose is dissolved in purified water (40 mg per tablet) to form a binding solution, which is then combined, granulated and dried.
  • the dried product was placed in a fluidized bed coater, and separately, a solution obtained by dissolving hypromellose phthalate (HP-55) and polyethylene glycol 6000 in ethanol (220 mg per tablet) and methylene chloride (980 mg per tablet) was prepared. Place in a granulation coater (GPCG-1: Glatt, Germany) and coat. After the completion of the coating was dried and colloidal silicon dioxide was added to the double cone mixer in the dry and mixed to prepare a delayed-release granules.
  • GPCG-1 Glatt, Germany
  • Magnesium stearate was added to a double cone mixer in the delayed-release granules prepared in 1) and Table 3, followed by mixing for 4 minutes, followed by final mixing.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare untreated selenium-containing yeast and nimodipine.
  • the uncoated tablet prepared in 1) was introduced into a high coater (SFC-30N: Sejong Machinery, Korea), and the composition of Table 3 is ATSO (unpolysaccharide), hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc.
  • ATSO unpolysaccharide
  • hypromellose 2910 hypromellose 2910
  • hydroxypropyl cellulose titanium oxide
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • talc hydroxypropyl cellulose
  • Example 24 film-coated tablets containing calcium channel blocker granules and hepatitis preventive and inhibitor prior release film
  • a delayed-release uncoated tablet was prepared in the same manner as in the preparation of 1) and 2) of Example 1, except that nicardipine hydrochloride was used instead of amlodipine besylate and ascorbic acid was used instead of succinic acid. It was.
  • the uncoated tablet prepared in 1) was introduced into a high coater (SFC-30N: Sejong Machinery, Korea), and the composition of Table 3 was purified by using cytilon, hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc. 260 mg per tablet) was dissolved and dispersed and coated with a coating solution to prepare a film-coated tablet including a pre-release film layer containing cytilon and delayed-release granules containing nicardipine hydrochloride.
  • (S) -Amlodipine besylate, riboflavin, microcrystalline cellulose, pregelatinized starch, polyvinylpyrrolidone copolymer and colloidal silicon dioxide were sieved through a No. 35 sieve and mixed for 30 minutes using a double cone mixer. Prepared. Magnesium stearate was added to the mixture, followed by mixing for 4 minutes, and the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) to prepare uncoated tablets containing riboflavin and (S) -amlodipine besylate.
  • the uncoated tablet prepared in 1) was added to a high coater (SFC-30N: Sejong Machinery, Korea), and polyethylene glycol 6000 and Eudragit L100 55 were dissolved and dispersed in purified water (400 mg per tablet) and coated with a coating solution to delayed release.
  • a delayed release film coated tablet was prepared comprising riboflavin comprising a film and (S) -amlodipine besylate.
  • Uncoated tablets were prepared by the same method as in Example 25 1) and the compositions and contents shown in Table 4, including the fraction of riboflavin and a fine purified flavonoid fraction.
  • Example 25 A delayed-release film-coated tablet was prepared in the same manner as in the preparation method of 2) and in the composition and content of Table 4, including the fine-purified flavonoid fraction and (S) -amlodipine besylate.
  • Example 25 A delayed-release film-coated tablet containing cyclosilic acid and (S) -amlodipine besylate was prepared in the same manner as in the preparation method of Example 2 2).
  • Example 25 A delayed-release film-coated tablet comprising (S) -amlodipine besylate was prepared in the same manner as in the preparation method of Example 2).
  • Uncoated tablets were prepared according to the compositions and contents shown in Table 4 in the same manner as in Example 25 1), including agaro-oligosaccharides and melatonin instead of riboflavin.
  • the uncoated tablet prepared in 1) was put into a high coater (SFC-30N: Sejong Machinery, Korea), and polyvinylpyrrolidone, poly (methacrylic acid ethyl acrylate) copolymer (Eudragit L100 55, Degussa), Polyethylene glycol 6000 (PEG6000, Duksan) was coated with a coating solution prepared by dissolving and dispersing in purified water (400 mg per tablet) to prepare a delayed-release film-coated tablet including agar oligosaccharide, melatonin, and (S) -amlodipine besylate.
  • uncoated tablets were prepared using the composition and contents shown in Table 4 in the same manner as in Example 25 1) using ursodeoxycholic acid.
  • Example 29 A delayed-release film-coated tablet containing ursodeoxycholic acid and (S) -amlodipine besylate was prepared in the same manner as in the preparation method of Example 2) and in the composition and content of Table 4.
  • Example 29 Delayed-release containing naphthyl acetate, butylated hydroxyanisole butylated hydroxyanisole and (S) -amlodipine besylate in the same manner as in preparation of Example 2) and in the composition and content of Table 4 Film coated tablets were prepared.
  • Example 32 Preparation of a Multi-Layered Tablet Including Hepatitis Prevention and Inhibitor Pre-Release Layer and Calcium Channel Antagonist Delayed-Release Layer
  • (S) -Amlodipine besylate, microcrystalline cellulose, crosslinked polyvinylpyrrolidone in a content of Table 5 was sieved through a No. 35 sieve and mixed for 5 minutes by a high speed mixer to prepare a mixture.
  • polyvinylpyrrolidone is dissolved in purified water (80 mg per tablet) to form a binding solution, which is then combined, granulated and dried.
  • the dried material was placed in a fluidized bed coater, and the above granulated product was first poured into a fluidized bed granule coater (GPCG-1: Glatt, Germany) by dissolving hypromellose in purified water (32 mg per tablet).
  • GPCG-1 fluidized bed granule coater
  • ubide carenone, hamatopolpyrin and microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer. Separately, hydroxypropyl cellulose was dissolved in purified water (60 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After the drying was finished again by using the F-type sizer equipped with No. 20 sieve to prepare a hepatitis preventive and inhibitor-release layer granules.
  • the semi-finished product of 1) is mixed with magnesium stearate and put into the primary powder feeder, and the semi-finished product of 2) is mixed with magnesium stearate and put into the secondary powder feeder to minimize the mixing between the layers.
  • Multi-layer tablets were prepared by tableting using MRC-37T: Sejong).
  • Example 33 Preparation of a Multi-Layered Tablet Comprising Hepatitis Prevention and Inhibitor Pre-Release Layer and Calcium Channel Antagonist Delayed-Release Layer
  • Amlodipine besylate, microcrystalline cellulose, sodium starch glycolate and lactose in a content of Table 5 were sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture. Separately, hydroxypropyl cellulose is dissolved in purified water (40 mg per tablet) to form a binding solution, which is then combined, granulated and dried. The dried product was placed in a fluidized bed coater, and separately hypromellose, cellulose acetate (acetyl group 32%) and cellulose acetate (acetyl group 39.8%) were mixed with ethanol and methylene chloride (2: 8) mixed solvent (820 mg per tablet).
  • the melted solution is prepared and the above granulated material is put into a fluid bed granulation coater (GPCG-1: Glatt, Germany) and coated. After the coating was completed, it was dried to prepare granules for amlodipine besylate delayed-release layer.
  • GPCG-1 fluid bed granulation coater
  • Arginine hydrochloride, ornithine hydrochloride and microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer according to the ingredients and contents shown in Table 5.
  • hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and combined.
  • granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After the drying was finished again by using the F-type sizer equipped with No. 20 sieve to prepare a hepatitis preventive and inhibitor-release layer granules.
  • the semi-finished product of 1) is mixed with magnesium stearate and put into the primary powder feeder, and the semi-finished product of 2) is mixed with magnesium stearate and put into the secondary powder feeder to minimize the mixing between the layers.
  • Multi-layer tablets were prepared by tableting using MRC-37T: Sejong).
  • Example 34 Preparation of a Multi-Layered Tablet Comprising Hepatitis Prevention and Inhibitor Pre-Release Layer and Calcium Channel Antagonist Delayed-Release Layer
  • Amlodipine besylate, microcrystalline cellulose, sodium starch glycolate and lactose in a content of Table 5 were sieved through a No. 35 sieve and mixed for 5 minutes using a high speed mixer to prepare a mixture.
  • hydroxypropyl cellulose is dissolved in purified water (40 mg per tablet) to form a binding solution, which is then combined, granulated and dried.
  • the dried product was placed in a fluidized bed coater, and separately, hypromellose phthalate (HP-50) and triethyl citrate were dissolved in ethanol and purified water (8: 2) mixed solvent (600 mg per tablet). Place in a fluid bed granulation coater (GPCG-1: Glatt, Germany) and coat. Drying was completed after the coating to prepare granules for the delayed release layer.
  • GPCG-1 Glatt, Germany
  • Erdostein, guayachol, creatine and microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer in the ingredients and contents shown in Table 5.
  • hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After the drying was finished again by using the F-type sizer equipped with No. 20 sieve to prepare a hepatitis preventive and inhibitor-release layer granules.
  • the semi-finished product of 1) is mixed with magnesium stearate and put into the primary powder feeder, and the semi-finished product of 2) is mixed with magnesium stearate and put into the secondary powder feeder to minimize the mixing between the layers.
  • Tableting using MRC-37T: Sejong Separately, a coating solution was prepared by dissolving and dispersing hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc in a mixed solvent of ethanol and purified water (8: 2) (600 mg per tablet). 30N: Sejong Machinery, South Korea) to form a film coating layer to prepare a multilayer tablet.
  • nitrified dipine, lactose, corn starch and carboxymethyl cellulose calcium were sieved through a No. 35 sieve and mixed with a high speed mixer. Separately, hydroxypropyl cellulose was dissolved in purified water (300 mg per tablet) to prepare a binding solution, which was fed to a high speed mixer together with the main ingredient mixture and combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After drying, it was established using an F-type sizer equipped with No. 20 body again.
  • This formulation was placed in a double cone mixer, magnesium stearate was added, and finally mixed, and then compressed using a rotary tablet press (MRC-33: Sejong). Tablets that have been tableted are added to a high coater (SFC-30N: Sejong Machinery, Korea), and then hypromellose acetate succinate and triethyl citrate are mixed with ethanol and purified water (8: 2) in a mixed solvent (550 mg per tablet). It was coated with a coating solution prepared by dissolving to prepare a delayed-release coating inner core tablet.
  • MRC-33 Sejong
  • Tablets that have been tableted are added to a high coater (SFC-30N: Sejong Machinery, Korea), and then hypromellose acetate succinate and triethyl citrate are mixed with ethanol and purified water (8: 2) in a mixed solvent (550 mg per tablet). It was coated with a coating solution prepared by dissolving to prepare a delayed-release coating inner core tablet.
  • Urazamide, microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer according to the ingredients and contents shown in Table 5.
  • cholecalciferol and hydroxypropyl cellulose were dissolved in purified water (80 mg per tablet) under shading to prepare a binding solution, which was added to a high speed mixer with a main ingredient mixture and fed together. After association, granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After drying, it was established using an F-type sizer equipped with No. 20 body again. This formulation was placed in a double cone mixer and magnesium stearate was added and finally mixed to prepare hepatitis preventive and inhibitor-release outer layer granules.
  • Nitrandipine delayed-release uncoated tablet prepared in 1) is brought into the tablet, and the hepatitis preventive and inhibitor pre-release granules prepared in 2) are tableted with a nucleated tablet tableting machine (RUD-1: Kilian) to come out of the tablet. The preparation was completed.
  • ROD-1 nucleated tablet tableting machine
  • Nisoldipine, microcrystalline cellulose, sodium starch glycolate, and lactose in a content of Table 5 were sieved through a No. 35 sieve and mixed for 5 minutes by a high speed mixer to prepare a mixture. Separately, hydroxypropyl cellulose is dissolved in purified water (40 mg per tablet) to form a binding solution, which is then combined, granulated and dried. After drying, it was established using an F-type sizer equipped with No. 20 body again. This formulation was placed in a double cone mixer, magnesium stearate was added, and finally mixed, and then compressed using a rotary tablet press (MRC-33: Sejong).
  • Glutathione, glutamine and microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer by the ingredients and contents shown in Table 5.
  • hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After drying, it was established using an F-type sizer equipped with No. 20 body again. This formulation was placed in a double cone mixer and magnesium stearate was added and finally mixed to prepare hepatitis preventive and inhibitor-release outer layer granules.
  • the nisoldipine delayed-release inner core tablet prepared in 1) is introduced into the tablet, and the hepatitis preventive and inhibitor prior-release granules prepared in 2) are tableted with a nucleated tablet tableting machine (RUD-1: Kilian) to come out of the tablet.
  • ROD-1 nucleated tablet tableting machine
  • the preparation was completed. Separately, a coating solution in which hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc was dissolved and dispersed in ethanol and purified water (8: 2) mixed solvent (800 mg per tablet) was prepared.
  • the nucleated tablet of 3) was added to a high coater (SFC-30N: Sejong Machinery, Korea) and then coated with a coating liquid to complete coating nucleated tablet manufacturing.
  • Example 8 Tableting uncoated tablet in the same manner as in the production method of 1) and the composition and content of Table 5. After tableting, the tablet is put into a high coater (SFC-30N: Sejong Machinery, Korea), and the first coating is applied with a solution of hypromellose dissolved in purified water (10 mg per tablet), and acrylic acid is purified water (80 mg per tablet). The secondary coating with a coating solution dissolved in) to prepare a delayed-release coating inner core tablet.
  • a high coater SFC-30N: Sejong Machinery, Korea
  • sodium selenite, ginkgo biloba extract and microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer.
  • hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and combined.
  • granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After drying, it was established using an F-type sizer equipped with No. 20 body again. This formulation was placed in a double cone mixer and magnesium stearate was added and finally mixed to prepare hepatitis preventive and inhibitor-release outer layer granules.
  • the amlodipine besylate delayed-release inner core tablet prepared in 1) is introduced into the tablet, and the hepatitis preventive and inhibitor pre-release granules prepared in 2) are tableted with a nucleated tablet tablet press (RUD-1: Kilian) to come out of the tablet. Nuclear tablet production was completed.
  • ROD-1 nucleated tablet tablet press
  • citric acid, succinic acid and polyvinylpyrrolidone are dissolved in purified water (70 mg per tablet) to form a binding solution, which is then combined, granulated and dried. After drying, it was established using an F-type sizer equipped with No. 20 body again. This formulation was placed in a double cone mixer, magnesium stearate was added, and finally mixed, and then compressed using a rotary tablet press (MRC-33: Sejong).
  • Ajintamide, ornithine and microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer according to the ingredients and contents shown in Table 5.
  • hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After drying, it was established using an F-type sizer equipped with No. 20 body again. This formulation was placed in a double cone mixer and magnesium stearate was added and finally mixed to prepare hepatitis preventive and inhibitor-release outer layer granules.
  • the nibadipine delayed-release inner core prepared in 1) is introduced into the tablet, and the hepatitis preventive and inhibitor pre-release granules prepared in 2) are compressed into tablets using a nucleated tablet tableting machine (RUD-1: Kilian) to come out of the tablets.
  • ROD-1 nucleated tablet tableting machine
  • the preparation was completed. Separately, a coating solution in which hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc was dissolved and dispersed in ethanol and purified water (8: 2) mixed solvent (350 mg per tablet) was prepared.
  • the nucleated tablet was added to a high coater (SFC-30N: Sejong Machinery, Korea) and then coated with a coating solution to complete coating nucleated tablet manufacturing.
  • Pelodipine, microcrystalline cellulose, and sodium chloride were sieved through a No. 35 sieve according to the composition and content of Table 6, and mixed for 30 minutes using a double cone mixer to prepare a mixture. After adding magnesium stearate to the mixture, the mixture was mixed for 4 minutes, and the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong). After tableting, ethyl cellulose was dispersed in purified water (50 mg per tablet), and then coated with an inner core tablet using a high coater (SFC-30N, Sejong Machinery, Korea) to prepare an osmotic inner core tablet.
  • MRC-33 Sejong
  • ethyl cellulose was dispersed in purified water (50 mg per tablet), and then coated with an inner core tablet using a high coater (SFC-30N, Sejong Machinery, Korea) to prepare an osmotic inner core tablet.
  • Arginine sodium, microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer by the ingredients and contents shown in Table 6.
  • hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After drying, it was established using an F-type sizer equipped with No. 20 body again. This formulation was placed in a double cone mixer and magnesium stearate was added and finally mixed to prepare hepatitis preventive and inhibitor-release outer layer granules.
  • the felodipine delayed-release osmotic inner core tablet prepared in 1) above was used as a nucleus tablet tableting machine (RUD-1: Kilian), and the hepatitis preventive and inhibitor pre-release outer layer granules prepared in 2) were taken out of the tablet.
  • ROD-1 nucleus tablet tableting machine
  • a coating solution in which hypromellose 2910, hydroxypropyl cellulose, titanium oxide, and talc was dissolved and dispersed in 80% ethanol was prepared.
  • the nucleated tablet was added to a high coater (SFC-30N: Sejong Machinery, Korea) and then coated with a coating solution to complete the preparation of the coated osmotic nucleated tablet.
  • azelnidipine, microcrystalline cellulose and pregelatinized starch were sieved through a No. 35 sieve and mixed for 5 minutes with a high speed mixer to prepare a mixture.
  • hydroxypropyl cellulose is dissolved in purified water (40 mg per tablet) to form a binding solution, which is then combined, granulated and dried.
  • the dried product was put in a fluidized bed coater, and a solution of polyvinylacetate dissolved in a mixed solvent of ethanol and methylene chloride (2: 8) (240 mg per tablet) was prepared to prepare the above granules in a fluidized bed granulator coater (GPCG-1: Glatt, Germany) and coated. Drying after completion of the coating produced delayed release granules.
  • GPCG-1 fluidized bed granulator coater
  • Erdostein, Protoporphyrin disodium, microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer by the ingredients and contents shown in Table 6.
  • hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and combined.
  • granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After the drying was again established using a No. 20 sieve
  • F-type granulator was prepared hepatitis preventive and inhibitor-release granules.
  • Himecromon, microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve with the ingredients and contents shown in Table 6 and mixed with a high speed mixer. Separately, hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After drying, it was established using an F-type sizer equipped with No. 20 body again. The tablets and magnesium stearate were added to a double cone mixer and finally mixed, followed by tableting with a rotary tablet press (MRC-33, Sejong Machinery, Korea) to prepare a hepatitis preventive and inhibitor-release tablet.
  • MRC-33 Sejong Machinery, Korea
  • the final product of the process 1) and 2) was filled into No. 1 capsule using a capsule charger to complete the preparation of the capsule form.
  • the sugar spheres were sieved through a No. 35 sieve with the ingredients and contents shown in Table 6, and introduced into a fluidized bed granulator (GPCG 1: Glatt), and separately in a mixture of ethanol and purified water (8: 2) (500 mg per tablet). Pellets were formed by spraying a binding solution in which hypromellose and amlodipine besylate were dissolved, and dried. Again, the granules were sprayed with hypromellose phthalate (HP-55) dissolved in a mixed solvent of ethanol and methylene chloride (2: 8) (1200 mg per tablet) to prepare amlodipine delayed-release pellets.
  • GPCG 1 Glatt
  • Microcrystalline cellulose, pregelatinized starch, corn starch, hematopopyrine were sieved through a No. 35 sieve with the ingredients and contents shown in Table 6 and mixed with a high speed mixer.
  • Ginkgo biloba extract was added thereto, mixed for 1 minute, and separately, hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer with the main ingredient mixture and combined.
  • granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After drying, it was established by using the F-type sizer equipped with No. 20 body again to prepare hepatitis preventive and inhibitor-release granules.
  • step 1) and 2) and magnesium stearate were added to a double cone mixer and mixed for 2 minutes, and then filled into the hard gelatin capsule of No. 1 using a capsule charger to complete preparation of a capsule.
  • Iprosartan delayed-release pellets were prepared in the same manner as in Example 42 1) and in the same composition and content as in Example 43 of Table 6, except that recidipine was used instead of amlodipine besylate.
  • the final product of the process 1) and 2) was filled into No. 1 capsule using a capsule charger to complete the preparation of the capsule form.
  • Uncoated tablet was prepared by the same method as the preparation method of 1) of Example 8 and the composition and content of Table 6.
  • the uncoated tablet is put into a high coater (SFC-30N: Sejong Machinery, Korea), and delayed release by coating with a coating solution made by dissolving and dispersing hypromellose phthalate (HP-55) and polyethylene glycol 6000 as shown in Table 6. Tablets were prepared.
  • Glutamine, ginkgo biloba extract, arginine sodium and microcrystalline cellulose, pregelatinized starch and corn starch were sieved through a No. 35 sieve and mixed with a high speed mixer. Separately, hydroxypropyl cellulose was dissolved in purified water (80 mg per tablet) to prepare a binding solution, which was added to a high speed mixer together with the main ingredient mixture and fed. After association, granulation was carried out using an oscillator in No. 18 and dried at 30 ° C. using a hot water dryer. After the drying was again established using a No. 20 sieve F-type granulator was prepared hepatitis preventive and inhibitor-release granules.
  • the final product of the process 1) and 2) was filled into No. 1 capsule using a capsule charger to complete the preparation of the capsule form.
  • Example 2 In the same manner as in the preparation method of Example 2, an uncoated tablet including nifedipine was prepared in the same composition and content as in Example 45 of Table 6.
  • Example 41 2 Prevention of hepatitis in the same manner as in Example 41 2) and in the same composition and content as in Example 45 of Table 6, using erdostaine, cholecalciferol, butylated hydroxyanisole instead of hymecromon, and Inhibitor pre-release tablets were prepared.
  • the final product of the process 1) and 2) was filled into No. 1 capsule using a capsule charger to complete the preparation of the capsule form.
  • a comparative dissolution test of the amlodipine besylate delayed-release uncoated tablet prepared according to Example 1 and the reference drug (Novask tablet, Pfizer: amlodipine besylate monosaccharide) was performed.
  • the eluate was changed from artificial gastric juice to artificial intestinal fluid for 120 minutes.
  • the dissolution test method for each component is as follows, and the results are shown in FIG.
  • the x-axis of the figure represents time (minutes), and the y-axis represents dissolution rate (Drug Released,%).
  • the unmodified amlodipine besylate of Example 1 showed a very delayed dissolution rate when compared to the control formulation Novask tablet, and it was confirmed that less than 20% of the drug eluted after 2 hours.
  • amlodipine besylate delayed-release uncoated tablet is very effective in treating hypertension because it is able to absorb amlodipine besylate at night during the evening administration because the initial release is very slow, unlike the dissolution pattern of the single-agent counterpart.
  • Dissolution test basis Dissolution test method of General Test Method
  • Test method paddle method, 50 revolutions / min
  • Test drug 0.01M hydrochloric acid solution, 750mL (artificial gas solution)
  • Example 2 shows that the film-coated tablet of Example 2 exhibits a very delayed dissolution rate when compared to the control preparation ZaniDip in the dissolution test under the conditions of Experimental Example 1, and it can be confirmed that less than 20% of the drug is eluted after 120 minutes. .
  • the film-coated tablet of the present invention has a very slow initial release of lecanidipine hydrochloride, unlike the dissolution of a single-preparative drug, so that it can absorb lecanidipine at night during the evening and is very effective in treating hypertension. have.
  • the comparative dissolution test was conducted for the formulations of Examples 10 and 14.
  • Dissolution test method is the same as Experimental Example 1, the results are shown in FIG.
  • the x-axis of the figure represents time (minutes), and the y-axis represents dissolution rate (Drug Released,%).
  • the film-coated tablet containing the delayed-release film of the present invention in the dissolution test under the conditions of Experimental Example 1 exhibited a dissolution rate within 20% up to 120 minutes, confirming that the release of the active ingredient is delayed for at least 2 hours It was confirmed that the release time was relatively rapid after having a delay time to the intended time.
  • Dissolution test method is the same as Experimental Example 1, the results are shown in FIG.
  • the x-axis of the figure represents time (minutes), and the y-axis represents dissolution rate (Drug Released,%).
  • the multilayered tablet including the delayed-release layer provided by the present invention can absorb (S) -amlodipine at night during the evening administration because the initial release is very slow, unlike the dissolution of the mono-controlled control drug, thereby treating hypertension. It is very effective for.
  • Comparative dissolution tests of the formulations of Examples 35, 36, 38, 39, 40, 43 and 45 were carried out to know the respective dissolution patterns according to the composition of the release controlling substance and the active ingredient.
  • Dissolution test method is the same as Experimental Example 1, the results are shown in FIG.
  • the x-axis of the figure represents time (minutes), and the y-axis represents dissolution rate (Drug Released,%).
  • the formulation of the present invention maximizes the pharmacological and clinical anti-pressure effects and complication prevention effects when taken, avoids interaction with drugs metabolized by the same enzyme in the liver, and prevents the development of drug hepatitis due to long-term administration And can be suppressed.

Abstract

L’invention concerne une préparation pharmaceutique contenant un inhibiteur des canaux calciques comme principe pharmacologiquement actif et un matériau à libération contrôlée, ainsi qu’une préparation pharmaceutique comprenant un compartiment à libération immédiate contenant un agent préventif de l’hépatite et un inhibiteur comme principe pharmacologiquement actif, ainsi qu’un compartiment à libération prolongée contenant un inhibiteur des canaux calciques comme principe pharmacologiquement actif. La préparation selon l’invention présente l’avantage : d’augmenter au maximum les effets de résistance à la pression pharmacologique et clinique et les effets de prévention des complications ; d’éviter une interaction avec les médicaments métabolisés par la même enzyme dans le foie ; et d’empêcher et d’inhiber l’hépatite d’origine médicamenteuse causée par un traitement médicamenteux au long cours.
PCT/KR2009/003897 2008-07-15 2009-07-15 Preparation pharmaceutique contenant un inhibiteur des canaux calciques WO2010008203A2 (fr)

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KR20200063858A (ko) 2018-11-28 2020-06-05 건양대학교산학협력단 니페디핀 함유 나노입자를 포함하는 지방간 질환 및 인슐린 저항성 예방 또는 치료용 조성물
CN114712319A (zh) * 2022-03-25 2022-07-08 北京诺康达医药科技股份有限公司 一种非洛地平盐酸普萘洛尔复方制剂及其制备方法
CN115381791A (zh) * 2022-09-21 2022-11-25 迪沙药业集团有限公司 一种盐酸氟桂利嗪药物组合物

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KR102414285B1 (ko) * 2020-06-02 2022-06-28 이화여자대학교 산학협력단 플루나리진 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 골질환의 예방 또는 치료용 약학적 조성물

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