WO2009127922A2 - Préparation pharmaceutique pour traiter une maladie cardio-vasculaire - Google Patents

Préparation pharmaceutique pour traiter une maladie cardio-vasculaire Download PDF

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Publication number
WO2009127922A2
WO2009127922A2 PCT/IB2009/000331 IB2009000331W WO2009127922A2 WO 2009127922 A2 WO2009127922 A2 WO 2009127922A2 IB 2009000331 W IB2009000331 W IB 2009000331W WO 2009127922 A2 WO2009127922 A2 WO 2009127922A2
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release
cellulose
amlodipine
pharmaceutical formulation
copolymer
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Korean (ko)
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WO2009127922A3 (fr
Inventor
김성욱
전성수
구자성
김진욱
박선우
장석영
이상주
조영관
이준영
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Hanall Pharmaceutical Co Ltd
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Hanall Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention is designed to control and release each drug at a specific rate by applying the so-called Chronotherapy principle and XenoMotics, which are administered by staggering the time of expression of pharmacological action in each body
  • the present invention relates to a pharmaceutical formulation comprising, as an active ingredient, a controlled release dihydropyridine calcium channel blocker and a statin lipid lowering agent.
  • Hyperbaric pressure often coexists with coronary artery disease and is a major cause of heart disease. Hypertension is closely related to atherosclerosis due to hyperlipidemia. In other words, if the blood pressure rises, the arterial sclerosis worsens, and if the arteriosclerosis worsens, the blood pressure rises further to exacerbate each other. Such symptoms are recognized as a serious risk factor for developing cardiovascular disease. Hyperlipidemia in the "one type of gokol Leste 3 ⁇ 4 increase is the my elevated serum low-density lipoprotein (LDL), and call test Te serum chongkol less hedge the increase of the specific.
  • LDL my elevated serum low-density lipoprotein
  • lowering the level of serum lipids, especially LDL cholesterol may lower the likelihood of developing cardiovascular disease, delay the progression of atherosclerosis, or induce regression of sinus sclerosis.
  • Hypercholesterolemia is involved in the early development of atherosclerosis, characterized by an uneven distribution of lipid deposits in the veins, including the coronary, jugular and peripheral arteries. This irregular distribution of atherosclerosis is characteristic of coronary artery injury and cardiovascular disease (Am J Cardiol 1987 59 (14): 91G).
  • Atherosclerosis and hypertension are cyclically exacerbating symptoms. Therefore, both hyperlipidemia patients and hypertensive patients should be treated for isochronism and hypertension isochronously and prevent exacerbations [Hypertens Res 2001; 24: 3-ll, Hyper tensRes2003; 6: 1-36, Hyper tensRes2003; 26: 979-990].
  • Clinical studies have shown that synergistic effects of co-administered statin-based lipid-lowering drugs are synergistic. Kramsch et al., Journal of Human Hyperteasion (1995) (Sup l.
  • Dihydropyridine calcium channel blockers are not only high-pressure drugs, but they are also known to be angina pectoris, and statin drugs are not only lipid lowering agents but also known for their anti-inflammatory effects in various conditions.
  • Both drug groups can be developed in a dosage form that is administered once a day, which is a common feature that taking at dinner is the pharmacologically ideal dosage time.
  • the drug is prescribed in combination of two yakmulgun may include simvastatin of the dihydropyridine calcium channel blocker of the 'amlodipine and statin lipid-lowering drugs.
  • amlodipine is synergistic with lipid lowering agents as well as its inherent anti-pressing action. .
  • Simvastatin to increase the lipid-lowering effect of simvastatin Simvastatin also has a function to increase the blood pressure-lowering effect of the drug unique through synergistic action with Amlodi 3 ⁇ 4 as well as intrinsic lipid-lowering action There is an advantage.
  • eNOs N0 production system
  • amlodipine has a function of promoting NO release.
  • atorvastatin has a phenoxy group, and this functional group catalyzes antioxidant activity due to proton donation and electron stabilization.
  • Statin-based lipid lowering agents are ⁇ ( ⁇ ⁇ reductase inhibitors) and have the following general information, where statin-based lipid lowering agents and HMG-CoA reductase inhibitors are used interchangeably.
  • Statin-based hypolipidemia mainly consists of sylvastatin, atorvastate
  • Atherosclerotic or diabetic patients have abnormal N0 production (eNOs) in the vessel wall. This decreases N0 production and increases blood pressure.
  • Statin-based lipid lowering agents including simvastatin, increase the normal levels of eNOS in these 3 ⁇ 4 tube walls. This is also one of the complex prescription effects in which lipid lowering action helps anti-pressure [Am J Physiol Renal Physiol Vol 281 Issue 5: F802-F809, 2001].
  • Metabolic enzymes that primarily activate statin-based lipid lowering agents are Cytokrum P450 3A4 And 2C9, metabolites are excreted from the liver through the biliary tract while acting in the liver
  • statin-based lipid lowering agents inhibit cytokine P450 enzymes that activate statins
  • statins and intermediate metabolites leak into the blood. The concentration will increase.
  • statin-based body metabolism and active metabolites liberated by hyperlipidemia can cause serious side effects of increased muscle lysis [Cl in Pharmacol Thar 1998; 63: 332-341, CI in Pharraacol Therl998; 64: 177-182, Physici ansDeskRef erence 2006 (Zocor), JPharmacolExpTher 1997; 282: 294-300, PharmacolExpTher 1999; 290: 1116-1125, L if eSc # 200; 76: 281-292 .: Drug Metab Dispos 1991; 19: 740-
  • the dihydropyridine-based chamomile antagonist when a simple combination of two drugs, the dihydropyridine-based chamomile antagonist first reaches the liver and induces * inhibition of cytokine P450 enzymes, and a large part of the starin-based lipid lowering agents that subsequently enter the liver or enter simultaneously Since it is not metabolized by cytokine P450 enzymes, a large amount of blood leaks out, delays excretion, or accumulates, and is not metabolized by the cytokine P450 enzyme.
  • the hydroxy acid migrates to hypertension, causing blood levels to be higher than necessary, which can cause muscle disorders such as muscle solubility.
  • Simvastatin itself is a deactivated lactone-based compound and is primarily active in metabolites S, such as ⁇ -hydroxy acid of simvasta3 ⁇ 4, an active form that has a hypolipidemic activity that enters the liver. Simvastatin is metabolized in several stages by the cytokine P450 3A4 in the liver, and activated metabolites exert potent lipid-lowering effects. It is well known that simvapatin has been shown to reduce the incidence of coronary heart disease 1 and reduce mortality in large clinical trials [Lancet 199; 34: 1383-1389.
  • simvastatin strongly inhibits HMG-CoA reductase, which plays a key role in the synthesis of cholesterol in the liver, and at the same time acts as an inhibitor of inflammation-inducing factors ["Scandinavian Simvastat in Survival Study "published in the Lancet, 1994, 344, 1383-89], Since pitavasta 3 ⁇ 4 is metabolized by cytochrome P450 2C9 and acts in the liver, it is excreted, and when administered with a drug that inhibits cytokine P450 enzymes, phytavastatin inhibits intrahepatic metabolism, thereby increasing blood concentration, This can cause side effects such as muscle lysis.
  • Staggered channel blockers are one of the most commonly used anticancer drugs in combination with statin-based lipid-lowering agents. There are dihydropyridine-based staggered channel blockers in calcium channel blockers, and dihydropyridine-based staggered channel blockers, such as amlodipine and lercanidipine.
  • amlodipine is most commonly prescribed as an antihypertensive and angina treatment agent worldwide [Cardiologyl 992; 80 (StiE »pll): S31—S36, JCardi ovascPharmaco 11988; 12 (Suppl7): S110-S113, Lancet 2000; 356: 359 -365, Hyper tens Res 2002; 25: 717-725, Hyper tens Res 2002; 25: 329-333.
  • the dihydropyridine-based chasm channel blocker is an antihypertensive drug that lowers blood pressure by blocking permeate in 3 ⁇ 4 tubular smooth muscle and inducing peripheral artery dilation, and has common characteristics effective for angina due to convulsive vasoconstriction. It is also known that calcium channel blockers may have beneficial effects in the treatment of early cervical lesions [Lancet, 335, p. 1109-1139, 1990; and Circulation, 82, p.19401953, 1990].
  • an increase in blood pressure during the morning is a 3 ⁇ 4 pressure increase due to 3 ⁇ 4 wall wall spasm caused by stress stimulation, and dihydropyridine calcium channel blockers are primarily responsible for relaxing these spasms. Because of the action, especially in the morning after waking up in the morning, the blood pressure-lowering effect appears strongly. Therefore, if the dihydropyridine kill: sump channel blocker in the evening hours is reacted in the evening, it can reach the maximum concentration of 3 ⁇ 4 before waking up, and the strongest blood pressure drop during the waking routine. Can be.
  • Amlodi 3 ⁇ 4 a representative example of a dihydropyridine-based scab channel blocker, is an antihypertensive drug that lowers blood pressure by blocking peripheral vascular smooth muscle influx and inducing peripheral veins, which is effective in angina due to convulsive vasoconstriction.
  • the chemical name is 3– to 3 ⁇ 4-5-methyl ⁇ 2 ⁇ (2-aminoespecialime 3 ⁇ 4) -4- (2-chlorophenyl) -1, 4-dihydro-6-methyl ⁇ 3, 5 ⁇ pyridinedica
  • the half-life is very consistent with 30 to 50 hours. It is a very useful chest channel blocker that shows activity over a long period of time [European Patent Publication No.
  • amlodipine is a 24 hour daily lasting medicine, and taking it in the evening hours is the most powerful effect of lowering blood pressure from the morning of the next morning to midday.
  • Nitte dipin is when oral ruyeo a single drug mostly varies in the form of a metabolite of the inert type, 60-80% of the dose excreted in urine and 3 ⁇ 4 the kidney, it is "arranged in byeoneu part via the bile duct.
  • the metabolism of nifedipine is involved in the cytokine P450 enzyme system and has a potent inhibitory effect on cytokine P450 3A4.
  • Nifedipine's excretion half-life is known to be about two hours.
  • the nisinidipine formulations provided are provided in a slow release form throughout the day. In terms of pathophysiology ' blown, especially morning weather.
  • the increase in 3 ⁇ 4 pressure in the morning is the increase in blood pressure caused by vascular wall spasm caused by stress stimulation, nifedipine is the main action to relax this mild vascular contraction. Especially after morning waking, the blood pressure of morning sickness is effectively lowered.
  • cytokine P450 3A4 enzymes are mainly metabolized by cytokine P450 3A4 enzymes and also by cytokine P450 3A4 enzymes such as cytokine P450 2C9 [Arc lnternMed. 2002Feb25; 162 (4): 405-. 12., Dru ⁇ et abDi spos .2000Feb; 28 (2) : 125-30.] Due to these characteristics, a combination of statin-based lipid lowering agents and dihydropyridine-based drugs requiring cytokine P450 appeal is required. Should be administered with a time delay to avoid interaction other drugs [MedCheml991; 34: 1838-1844,
  • Korean Registered Patent No. 582347 discloses ammodyne, a dihydropyridine calcium channel blocker, which is rapidly released and the mandrel is eluted, and the statin is gradually eluted over 24 hours, thereby preventing the statin drug from being eluted and absorbed at one time. Disclosed is a composite agent.
  • statins in the present invention it is considered as an irrational agent that reduces the efficacy of statins in the present invention as a complex system of concepts that are different from the concept of eluting statins first and metabolizing them in the liver first. If the amlodipine is introduced into the thrower liver, the production of cytochrome ⁇ 3 ⁇ 450 3A4 is inhibited in the liver, so that a small amount of statins, which are subsequently introduced into the liver, is not metabolized by the liver and is released into the blood.
  • the patent only increases the side effects such as muscle lysis due to the release of statins, which should act in the liver, into 3 ⁇ 4.
  • Korean Patent No. 742432 is a patent for a pharmaceutical preparation including amlodicec 3 ⁇ 4 sillate and simvastatin, and a method for preparing the same, but Cytok, which is required by simvastatin because both components are eluted simultaneously and absorbed into the liver
  • comb P450 3A4 is inhibited by amlodipine
  • simvastatin is released in excess of 30% into the blood along with the activator, which is not sufficiently activated in the liver, resulting in decreased lipid lowering and increased side effects.
  • the present invention is a simple compounding concept, and this simple North compound is being removed due to the lack of progress.
  • Pfizer's Korean Patent Publication No. 200,7002144 was also rejected by the Korean Intellectual Property Office because amlodipine and ato a vastatin are simple combinations.
  • the present inventors have completed the present invention to develop a pharmaceutical preparation effective for the prevention and treatment of hypertension and hyperlipidemia and thereby cardiovascular disease or metabolic syndrome.
  • the present invention controls the release of an agent comprising a dihydropyridine-based chamomile channel blocker containing several star 3 ⁇ 4 lipid-lowering agents within about 2 hours of dissolution and absorption time in the gastrointestinal tract.
  • an agent comprising a dihydropyridine-based chamomile channel blocker containing several star 3 ⁇ 4 lipid-lowering agents within about 2 hours of dissolution and absorption time in the gastrointestinal tract.
  • the present invention also provides a preparation comprising a dihydropyridine-based chamois blocker and a statin-based lipid lowering agent, by optimizing the drug delivery time of the drug to prevent metabolic syndrome and insulin-resistant patients, and patients suspected of diabetes mellitus or diabetes mellitus.
  • Maximize the effect of calcium channel blocker which is the prevention or treatment of cardiovascular disease, cardiopulmonary disease, lung disease or kidney disease, and the effect of HMG-CoA reductase inhibitor, which is the prevention or treatment of heart disease caused by coronary atherosclerosis such as angina pectoris or myocardial infarction, It is intended to provide a pharmaceutical formulation that can avoid the interaction between the two drugs and the side effects thereby.
  • the present invention is a preparation comprising a dihydropyridine-based chamomile channel blocker and a statin-based lipid lowering agent, which is added to convenience by taking one tablet once daily between evening hours and preferably 5 to 11 pm.
  • a pharmaceutical preparation that can further increase the patient's medication woowoonggi cold.
  • the present invention relates to a pharmaceutical formulation designed to control and release each drug at a specific rate by applying the so-called Chronotherapy principle, which is administered at a time difference in the pharmacological action expression time of each complex component.
  • the pharmaceutical formulation of the present invention applies the principle of GhronotheraDy and Xenobiotics of the drug to the expression of pharmacological action of each of the complex components, and is controlled at the specific rate and absorbed into the body. It is a specially designed drug delivery system that can produce an ideal effect.
  • the present invention provides a pre-release compartment comprising a statin-based lipid lowering agent, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a dihydropyridine calcium channel blocker, an isomer thereof, as a pharmacologically active ingredient.
  • a delayed-release compartment comprising a pharmaceutically acceptable salt thereof.
  • the present invention is a dihydropyridine-based chamomile antagonist as an active ingredient, a delayed-release compartment made of granules, pellets or tablets, and a statin-based lipid lowering agent as an active ingredient.
  • a pharmaceutical formulation with controlled release properties even with timed dissolution which is a capsul formulation comprising an exudative compartment.
  • the dihydropyridine-based scabin antagonist is lowered in starlin-based lipids
  • the release can be adjusted to be absorbed by the liver 2 to 4 hours later.
  • the dihydropyridine-based scab antagonist is amlodipine, lercanidipine, lassipinepine, felodipine, vanidipine, benidipine, silnidipine, isradinine, mandidi 3 ⁇ 4, nicardidipine, nifedipine, nimodipine.
  • Nilvadipine, nisulodidi3 ⁇ 4, nirenedipine, azanidipine may be selected from pharmaceutically acceptable salts thereof and isomerism thereof, and may be included in the range of 1 to 400 rag in the formulation.
  • the delayed-release compartment may include at least one release controlling substance selected from an enteric polymer, a water-insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic membrane coating base, and an osmotic pressure-controlling agent.
  • a release controlling substance selected from an enteric polymer, a water-insoluble polymer, a hydrophobic compound, a hydrophilic polymer, an osmotic membrane coating base, and an osmotic pressure-controlling agent.
  • Semipermeable membrane coating base Coating base is polyvinyl acetate, a full methacrylate copolymer as a poly (ethyl acrylate- Meth 3 ⁇ 4 methacrylate copolymer, 3 ⁇ 4 (ethyl arc 3 ⁇ 4rate-meth 3 ⁇ 4 methacrylate-trimethyl meth) No 3 ⁇ 4 decacrylate) copolymer, ethyl shellulose, saltose ester, 3 ⁇ 4 chloro ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose One or two or more mixtures selected from acetate, salose acetate and cellulose triacetate;
  • the third pressure regulating agent is magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, calcom sulfate, sodium sulfate, lithium sulfate and sodium sulfate selected one or two or more mixtures;
  • the statin-based lipid lowering agent is one or two selected from simvastatin, lovastat3 ⁇ 4, atorvastatin, pitavastatin, rosuvastated, flu; vastatin, pravasta 3 ⁇ 4, pharmaceutically acceptable salts thereof and isomers thereof. It may be a combination of the above.
  • the present invention also relates to (a) a delayed-release compartment comprising a dihydropyridine base antagonist, a pharmaceutically acceptable salt thereof or an isomer thereof, a pharmaceutically acceptable carrier or diluent as an active ingredient (star as W active ingredient)
  • a layer comprising a preservative-release compartment prepared using a base lipid lowering agent, a pharmaceutically acceptable salt thereof, or an isomer thereof, a pharmaceutically acceptable carrier or diluent, and
  • the first agent and the second agent Provided is a kit comprising container means for thickening.
  • the present invention also provides a dihydropyridine-based calcium antagonist active ingredient, a delayed-release compartment prepared as a tablet, and a statin-based lipid lowering agent as an active ingredient.
  • the present invention provides a pharmaceutical formulation with controlled release, capable of dissolution of time, which is a coated tablet comprising a pre-release compartment coated on the surface of a single agent.
  • the present invention also provides a delayed-release compartment comprising the dihydropyridine calcium antagonist as an active ingredient and constituting the inner core to release the drug by osmotic pressure, and a statin-based lipid lowering agent as the active ingredient,
  • the present invention relates to a pre-release compartment comprising a statin-based lipid lowering agent, an isomer thereof, or a pharmaceutically acceptable salt thereof, and a dihydropyridine calcium channel blocker, an isomer thereof, as a pharmacologically active ingredient.
  • it provides a pharmaceutical formulation comprising a delayed-release compartment comprising a pharmaceutically acceptable salt thereof.
  • the formulation according to the present invention is physically separated or partitioned to control the release property between the two active ingredients to obtain different release rates between the two ingredients, thereby improving the problem of co-administration or isoadministration of the existing single agent. It provides a more relaxing therapeutic effect.
  • the agent of the present invention is a pre-release compartment and a dihydropyridine calcium antagonist that elutes statin-based lipid lowering agents to be absorbed in the small intestine so that they can be absorbed in the liver 2 to 4 hours later than statin-based lipid lowering agents. It is a pharmaceutical formulation comprising a delayed-release compartment.
  • the present invention provides a delayed release compartment comprising simvastatin, an isomer thereof, or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and an amlodipine, other isomers or a pharmaceutically acceptable salt thereof, as a pharmacologically active ingredient.
  • Pharmaceutical formulations comprising a release compartment (hereinafter referred to as simvastared / amlodipine formulations) are provided.
  • the present invention provides a prior-release compartment comprising atorvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and a pharmacological activity
  • a prior-release compartment comprising atorvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and a pharmacological activity
  • Pharmaceutical formulations comprising amlodipine, isomers thereof or pharmaceutically acceptable salts thereof as active ingredients provide a pharmaceutical formulation comprising a delayed-release compartment (hereinafter referred to as atorvastatin / amlodipine formulation).
  • the present invention also provides a prior-release compartment comprising atorvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and nifedipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. It provides a pharmaceutical formulation (hereinafter referred to as ' 1 atorvastatin / nifedipine formulation') comprising a delayed-release compartment comprising.
  • the present invention also provides a prior-release compartment comprising pitavastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as an pharmacologically active ingredient, and amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient.
  • a pharmaceutical formulation comprising a delayed-release compartment containing the following (hereinafter referred to as a 'pitavastatin / amlodipine formulation') is provided.
  • the present invention provides a prior-release compartment comprising Roschvastatin, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient, and amlodipine, an isomer thereof or a pharmaceutically acceptable salt thereof as a pharmacologically active ingredient. It provides a pharmaceutical formulation ( hereinafter referred to as "roschvastatin / amlodipine formulation") comprising a delayed-release compartment comprising a.
  • the present invention provides that the pharmacologically active component of the lipophilic compartment and the pharmacologically active component of the prior-release compartment are bendipine several pitavastatin, nimodipine and pravastatin, nivaldi 3 ⁇ 4 and pitavastatin, nisoldipine and lovastatin ni.
  • the present invention also preferably provides a statin-based lipid lowering agent release of statin-based lipid lowering agent, which is initiated after about 1 hour of statin lowering agent release * and is completed before about 8 hours. Providing a pharmaceutical agent which is then commenced and completed about 6 hours prior,
  • Nifedipine in the dihydropyridine-based calcium channel blocker as an active ingredient
  • the preparation is delayed until the release of nifedipine is sufficiently delayed and the elution is initiated after about 1 to 8 hours.
  • atorvastatin elutes at least 90% of the drug within 1 hour, and nifedipine is sufficiently released. It is delayed and adjusted to begin dissolution about 2-6 hours after oral administration.
  • the release of simvastatin / amlodipine formulations, or pitavastatin / amlodipine formulations, amlodipine of the present invention is initiated about 1 hour after each statin-based lipid lowering agent and is completed before about 8 hours, or is preferred. Preferably about 2 hours later.
  • Amtodipine release is initiated about 1 hour after atorvastatin release and is completed before about 8 hours, or preferably after about 1 hour Rochevastatin / Amlodipine Formulation
  • Completed before about 6 hours and amlodipine release can be initiated after about 1 hour of roschvastatin release, preferably after about 2 hours.
  • the pharmaceutical formulation of the present invention has a time for which release of less than about 403 ⁇ 4 of the total amount of dihydropyridine calcium channel blockers is maintained within about 2 hours, preferably within about 3 hours, more preferably after the start of release of the statin-based lipid lowering agent.
  • the drug is provided within about 4 hours, so that the effect of the dihydropyridine calcium channel blocker can be effectively generated after a certain delay time.
  • the release of about 403 ⁇ 4 or less of the total amount of amlodipine is maintained within about 2 hours, preferably within about 3 hours. More preferably within about 4 hours and phytavastatin / amlodipine formulations or Roschvastarin / amlodipine formulations can dissolve up to 4 hours of amlodipine 1: 40% of this total, preferably not more than 303 ⁇ 4 .
  • statin-based lipid lowering agent is first released and 8M, preferably 90% or more of the elution is completed within 1 hour, and the dihydropyridine-based calm channel blocker starts to dissolve after about 2 hours. And less than 40%, preferably less than about 30%, of the total amount within about 4 hours.
  • each statin-based lipid lowering agent is at least 803 ⁇ 4 within 1 hour, preferably at least 90% This elutes and the amlodipine or nifedi 3 ⁇ 4 starts to elute after 2 hours, and the dissolution rate up to 4 hours is 40%, preferably not more than 303 ⁇ 4. It is adjusted to be released to the level.
  • Rochevastatin is released more than 80% within 30 minutes, preferably 15 minutes, and amlodipine release is delayed more than 403 ⁇ 4 within 4 hours after oral administration. And preferably a pharmaceutical formulation released below 3 ".
  • atorvastatin / nifedi tube preparation atorvastatin elutes at least 80% within 1 hour, and nifedipine is S-cutted so that elution is started after about 1 to 8 hours due to the delayed release. Atorvastatin elutes 90% or more within 1 hour, and nifedipine can be controlled to initiate elution approximately 2-6 hours after oral administration due to a significant delay in release.
  • the pharmaceutical composition of the present invention exhibits the most effective effect when taken between 5 and 11 o'clock in the evening.
  • Pre-release compartment refers to the compartment that is released earlier than the delayed-release compartment in the pharmaceutical formulation of the present invention.
  • the pharmacologically active ingredient of the prior release compartment comprises a statin-based lipid lowering agent or a pharmaceutically acceptable salt thereof, and may further comprise a pharmaceutically acceptable additive as necessary.
  • Statin-based lipid lowering agents of the present invention include simvastatin, lovastat3 ⁇ 4, atorvastatin, pitavastar 3 ⁇ 4, rosuvastatin fluvastatin, pravasta 3 ⁇ 4, and the like, including its optical isomers, racemates It includes all of them.
  • isomers of atorvastatin include (RJ isomers, a, s) isomers, (s, s) isomers, or
  • the (S,) isomers and their racemates include, but are not limited to, the ( ⁇ , ⁇ ) isomer (R, S) isomer, the (S, R) isomer, or the (S, S) isomer. Isomers are mentioned.
  • the active ingredient in the pre-release compartment may comprise about 1 to about 160 mg, preferably about 2 to about 80 mg, as a unit dosage star 3 ⁇ 4 lipid lowering agent.
  • simvastatin is about 1 ⁇ about 160 mg, preferably about 2 to about 80 rag
  • atorvastatin is about 1 to 160 mg, preferably 5 to 160 mg, more preferably 10 to 80 mg
  • the tin may comprise about 1 to 2 (g Roschvastatin 1 to 160 mg, preferably 5 to 80 rag.
  • the prerelease compartmentalizing statin-based lipid lowering agent is at least about 803 ⁇ 4 of the total amount of the statin-based lipid lowering agent in the unit formulation within 1 hour, preferably within 30 minutes, more preferably within 15 minutes of the start of release. More than% is released, which can quickly indicate the efficacy.
  • simvastatin is at least about 80% of the total amount within 1 hour after initiation of release, preferably at least about go% and atorvastatin is at least about 80%, preferably at least 90% within 1 hour of onset of release.
  • Pitavastatin is within 1 hour after initiation of release, preferably within 30 minutes, more preferably within about 15 % or more of the total amount Rochevastatin within 1 hour after initiation of release, preferably within 30 minutes, More preferably, at least about 80% of the total amount can be released within 15 minutes.
  • the formulations of the present invention may also be formulated using additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, stabilizers, pH adjusting agents, dissolution aids, colorants, fragrances, etc. without departing from the effect of the present invention.
  • additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, stabilizers, pH adjusting agents, dissolution aids, colorants, fragrances, etc.
  • Its content is preferably 100 to 30,000 parts by weight based on 100 parts by weight of the statin-based lipid lowering agent, more preferably 100 to 20,000 parts by weight.
  • simvastatin / amlodipine formulation 100 to 100 parts by weight of simvastatin is added.
  • atorvastatin / amlodipine formulation preferably 100-20,000 parts by weight, in the atorvastatin / amlodipine formulation, pitavastatin / amlodipine formulation, or atorvastatin / nisudipine formulation, 1 to 100 parts by weight for each .
  • statin lipid lowering agent Preferably it is 1-30 parts by weight and the Roschvastatin / Amlodi 3 ⁇ 4 preparation may contain 0.01-100 parts by weight per 1 part of Roschvastatin.
  • the diluent is starch, microcrystalline 3 ⁇ 4, lactose , Glucose, manny, alginate, alkaline earth metal salts, cleats, polyethylene glycols, dicalcium phosphate, or mixtures thereof. .
  • the binder is starch, microcrystalline cellulose, highly dispersible silica, manny, sucrose, lactose, pulley ethylene glycol, pulley vinylpyridone, hydroxypropyl methyl salose, hydroxy propyl cellulose, Natural gums, synthetic gums, copovidones, l, or combinations thereof may be used.
  • the disintegrant is a starch or modified starch, such as sodium starch glycolate, corn starch, potato starch or starch gelatinized starch, bentonite, monmo 3 ⁇ 4 lonite, or clay microcrystalline cell such as vegum, Cells such as oxypropylcellose or carboxymethyl 3 ⁇ 4rose such as sodium alginate or alginic acid.
  • Crosslinked cells such as alginate croscarmel lose sodium Crosslinked polymers such as guarose gum guar gum, xanthan gum and crosslinked polymers such as xanthan gum Polivinyl pyridone (crospovidone) Effervescent agents such as sodium bicarbonate and citric acid Or a combination thereof.
  • the lubricant is talc, stearic acid, magnesium stearate, calcium stearate, etc., lauryl sulfate sodium, hydrogenated vegetable oil, natzyl benzoate, sodium stearyl fumarate, glyceryl behanate, glycerol monomonate, glyceryl mono Stearate, glycer palmitostearate, polyethylene glycol and the like can be used.
  • the stabilizer may be a salt of an alkali metal, a salt of an alkaline earth metal, or an alkalizing agent thereof, and preferably, calcium carbonate, sodium carbonate, sodium bicarbonate, magnesium oxide, magnesium carbonate, sodium citrate, and the like.
  • Ascorbic acid, citric acid, butylated hydroxy anisole, butylated hydroxy toluene, tocope may be used as the derivative.
  • the pH adjusting agent may be an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid and a basicizing agent such as precipitated calcium carbonate, ammonia water, meglumine.
  • an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid and a basicizing agent such as precipitated calcium carbonate, ammonia water, meglumine.
  • the dissolution aid may be a lauryl sulphate, polysorbate, such as pulley oxyethylene sorbitan fatty acid esters, docuate sodium, and the like.
  • formulation of the present invention may be formulated using a pharmaceutically acceptable additive selected from various additives selected from colorants and fragrances.
  • a delayed-release compartment means a compartment in which the active ingredient is released after a certain time of release of the active release compartment active ingredient.
  • the delayed-release compartment comprises (1) the pharmacologically active amlodi 3 ⁇ 4, an isomer thereof or a pharmaceutically acceptable salt thereof, and (2-1) a release controlling substance and / or (2-2) an osmotic regulator and a semipermeable membrane.
  • a coating base, and, if necessary, (3) may further include a pharmaceutically acceptable additive.
  • the delayed-release compartment according to the present invention comprises a commercially available statin-based lipid lowering agent. It can also be taken at the same time.
  • the pharmacologically active ingredient of the delayed-release compartment includes dihydropyridine-based chamomile channel blockers, isomers thereof and pharmaceutically acceptable salts.
  • Dihydropyridine calcium channel blockers can be used to select components that are inhibited by Cytokrum P450 enzymes, for example, amlodipine, lercanidipine, lassidipine, felodipine, vanidipine, benidipine, silinidi. 3 ⁇ 4, device radio 3 ⁇ 4, Mani dipin, you carboxylic dipin, nifedipine, Nemo dipin, carbonyl body pin, nisul Lodi pin nitrendipine, O 3 ⁇ 4 you dipin but include ", nor not they are limited in kind between, as set forth above It can be selected and used in dihydropyridine type antagonism which is inhibited by the torque P450 type enzyme.
  • Cytokrum P450 enzymes for example, amlodipine, lercanidipine, lassidipine, felodipine, vanidipine, benidipine, silinidi. 3 ⁇ 4, device radio 3 ⁇ 4, Mani dipin, you carboxylic dipin
  • amlodipine, nifedipine and pharmaceutically acceptable salts thereof can be used, and pharmaceutically acceptable salts of amlodipine include, specifically, maleic acid salts of amlodipine and besylate salts of amlodipine.
  • the active ingredient in the delayed-release compartment is a unit-depleted dihydropyridine-based scab channel blocker, which is based on a daily adult (65-75 kg adult male), about 1 to about 400 mg of unit dosage, and preferably about 2 "-about 120 mg may be included.
  • the increase in amlodapine is about 1 to about 40 mg, preferably about 2 to about 20 mg, nifedipine may contain about 1 to about 90 mg per day.
  • Dihydropyridine-based Calcium channel blockers have a release time of about 40% or less of the total amount of unit dosages reached release within about 2 hours, preferably within about 3 hours, more preferably about 4 hours after initiation of the star 3 ⁇ 4 lipid lowering agent.
  • simvastatin / amlodipine formulations or atorvastatin / nifedipine formulations which require less than about 40% of the total amount of amlodipine or nifedipine to reach release.
  • the atorvastatin / amlodipine formulation has a time of less than 203 ⁇ 4 of the total amount of amlodi 3 ⁇ 4 to reach release within about 2 hours, preferably Is within about 3 hours, more preferably about 4 hours, and the pitavastatin / amlodipine formulation is released up to 4 hours at 40% or less of the total amount of amplified amlodipine, preferably at 30% or less, and Rochevastatin / amlodipine.
  • the formulations may release up to 3 hours of up to 303 ⁇ 4 of the total amount of amlodipine, preferably up to 20%.
  • the delayed-release compartment in the pharmaceutical formulations of the present invention comprises at least one release agent selected from an elutable polymer, a water insoluble polymer, a hydrophobic compound, a hydrophilic polymer, and a mixture thereof.
  • the release control material may be used in an amount of 10 to 3,000 parts by weight with respect to 100 parts by weight of dihydropyridine-based chamomile 3 ⁇ 4 agent, the amount of which is used in the above range. If less than sufficient delayed release is not obtained, if the dose exceeds the above range drug release is excessively delayed to obtain a significant clinical effect.
  • the release-controlling material in the simvastatin / amlodipine formulation is preferably an enteric polymer comprising "and the common compounds of a hydrophilic polymer, or comprises a subeul soluble polymer, relative to 1 part amlodipine increase, 0.1 - comprises 100 parts by weight .
  • the release controlling substance may include 0.05-100 parts by weight, preferably 0.05-30 parts by weight, with respect to 1 part by weight of amlodipine, and preferably may be a mixture of an enteric polymer and a hydrophilic polymer.
  • the enteric polymer and the hydrophilic polymer mixture may be included in 0.5 to 10 parts by weight and 0.5 to 20 parts by weight, respectively, based on 1 part by weight of amlodipine.
  • the release controlling substance in the pitavastatin / amlodipine formulation is available at 0.05-100 parts by weight with respect to 1 part of amlodipine, and preferably includes water-insoluble polymers and polymers and hydrophilic polymers in the roschvastatin / amlodipine formulation.
  • the release control material is available in an amount of 0.05 to 100 parts by weight based on 1 part by weight of amlodipine, preferably comprising at least one release control material selected from a water-insoluble polymer and a hydrophilic polymer, and in the atorvastatin / nifedipine formulation.
  • the release control material may be used in an amount of 5 to 300 parts by weight with respect to 100 parts by weight of nifedipine, and may preferably include an enteric polymer and a hydrophilic polymer.
  • an enteric polymer is one that is soluble or stable under acidic conditions of less than pH 5, and refers to a polymer that is dissolved or decomposed under conditions of pH 5 or higher, such as an enteric cellulose derivative, an enteric acrylic acid system, and the like. It is selected from the group consisting of a co-polymer, an enteric maleic acid copolymer, an enteric polyvinyl derivative, and a combination thereof.
  • the enteric cellulose derivatives include hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl decyl queryl phthalate, hydroxyspecific methyl ethyl cellulose phthalate, cellulose acetate phthalate, and cellulose.
  • enteric acrylic acid co-polymers selected from phthalate, methyl hydroxyethyl cellulose and their mixtures include styrene-arc 3 ⁇ 4 acid copolymers, methyl acrylate-acrylic acid copolymers, and methyl methacrylate acrylate.
  • Acid Copolymers Arc Butyl-Styrene-Acrylate Acid Copolymers, Methac- Acid-Methac Methyl acrylate copolymer (Example 3 ⁇ 4 units, Eudragit L 100, Eudragit S, Degussa, Germany), Methacrylic acid, Ethyl acrylate copolymer (Example 3 ⁇ 4 units, Eudragit L 100-55, Degussa Germany ), At least one of the above-mentioned enteric maleic acid-based co-polymers selected from methyl acrylate-methacrylic acid-acetic acid octyl co-polymer and their mixtures is selected from the group consisting of vinyl acetate-maleic anhydride co-polymer styrene-maleic anhydride copolymer, styrene Monoester maleic acid copolymer, vinyl methyl ether-maleic anhydride copolymer, ethylene-maleic anhydride co
  • enteric polymers for simvastatin / amlodipine formulations include polyvinylacetate phthalate, hydroxypropyltetylcelose phthalate, 3 ⁇ 4 talc, cellulose acetate phthalate, cellulose propionate phthalate, poly (methacrylate, methyl Methacrate) Copolymer and pulley (methacrylate, Ethacrylate) Copolymer may be at least one selected from 0.1 to 20 parts by weight, preferably 0.5-10 parts by weight relative to 1 part by weight of amlodipine. Can be included 3 ⁇ 4.
  • Preferred enteric polymers in atorvastatin / amlodipine formulations are hydroxypropylmethyl.
  • Cell 3 ⁇ 4 low phthalate, arc 3 ⁇ 4 methyl-acrylic acid co-polymer, methacrylic acid-methyl methacrylate co-polymer, polyvinyl alcohol phthalate, polyvinylacetacetal phthalate are used, and more preferably hydroxypropyl methyl May be at least one selected from cellulose phthalate S, methacrylate acrylic acid-methacrylic acid copolymer, methacrylic acid-methacrylic acid 3 ⁇ 4 acid tetramethyl co-polymerization, 0.1 to 20 parts by weight relative to 1 part by weight of amlodipine, preferably Can be included in 0.5 ⁇ : 10 increments.
  • enteric polymers in the pitavastatin / amlodipine formulations include arc 3 ⁇ 4 acid copolymers, preferably methyl methacrylate acrylic acid copolymers (product name, acryl-is). It may be included in an amount of 0.1 to 20 parts by weight, preferably 0.5 to 10 parts by weight.
  • Preferred enteric polymers in the Rochevastatin / Amlodipine formulation are at least one selected from methylmethacrylic acid co-polymer and hydroxypropylmethylcell of rosophthalate, and are included in an amount of 0.1-20 parts by weight, preferably 0.5-10 parts by weight, relative to amlodipine. If less than 0.1 parts by weight, there is a problem that is easily dissolved at pH ' below 5, and if more than 20 parts by weight there is a problem that the total weight of the formulation is unnecessarily increased or excessively delayed dissolution.
  • enteric cellulose derivatives In the atorvastatin / nifedipine preparations, enteric cellulose derivatives, enteric acrylic acid co-polymers, and enteric pulley vinyl derivatives are preferably used, and more preferably hydroxypropylme 3 ⁇ 43 ⁇ 4rollosephthalate and hydroxypropylmerolo.
  • Osacetate succinate, methacrylic acid-methacrylic acid 3 ⁇ 4 copolymer may be used and may be included in an amount of 5 to 150 parts by weight, preferably 10 to 50 parts by weight, based on 100 parts by weight of nipadidi pin.
  • a water-insoluble polymer is a polymer which is insoluble in pharmaceutically acceptable water to control the release of the drug.
  • the water-soluble polymer is preferably a polyvinylacetate; a polymethacrylate co-polymer; a pulley (ethyl acrylate-methyl methacrylate) co-polymer; a poly (ethyl arc ⁇ late-methyl methacrylate 3 ⁇ 4late ⁇ trimethylaminoethyl methacrylate) copolymer, ethyl cellulose, cellulose acetate, more preferably polyvinyl acetate, poly (ethyl arc methacrylate—meth methacrylate Late trimethylamino 3 ⁇ 4 methacrylate) copolymer, polybutak 3 ⁇ 4 tate co-polymer, poly (3 ⁇ 4 acrylate-methyl methacrylate) copolymer, and the like can be used. —30 parts by weight, preferably from 0.5 to 20 parts by weight.
  • the water-insoluble polymer is preferably polyvinyl acetate, Eudragit RS P0, ethyl shellose, sal-rose acetate, and more preferably polyvinylacetate, Eudragit RS. P0, ethyl cellulose may be used, and may be included in an amount of about 0.1-30 parts by weight, preferably 0.5-20 parts by weight, based on 1 part by weight of the active ingredient amlodipine.
  • the water-insoluble polymer may preferably be an acrylic copolymer roll, more preferably Eudragit RS30D, and 0.1-30 parts by weight, preferably 0.5-, based on 1 part by weight of amlodipine. It may be included in 20 parts by weight.
  • the soluble polymer is composed of 3 ⁇ 4ribinal acetate (Collicott S 30D), saloose acetate and ply (ethyl arc 3 ⁇ 4rate-methyl methacrylate-trimethylaminoethylmethac 3 ⁇ 4). It is preferable that at least one selected from the rate) co-polymer (Eudragit RS30D), it can be included in the amount of 0.1-30 parts by weight, preferably 0.5-20 parts by weight relative to amlodipine.
  • the water-soluble polymer preferably uses an acrylic acid copolymer, more preferably a poly (3 ⁇ 4H-acrylate-methyl methacrylate-trimetha3 ⁇ 4aminoethylmethacrylate) copolymer ( Eudragit RS30D and Eudragit LR30D) and may be included in an amount of 5 to 200 parts by weight, preferably 10 to 100 parts by weight, based on 100 parts by weight of nifedipine.
  • an acrylic acid copolymer more preferably a poly (3 ⁇ 4H-acrylate-methyl methacrylate-trimetha3 ⁇ 4aminoethylmethacrylate) copolymer ( Eudragit RS30D and Eudragit LR30D) and may be included in an amount of 5 to 200 parts by weight, preferably 10 to 100 parts by weight, based on 100 parts by weight of nifedipine.
  • hydrophobic compounds refer to substances which are insoluble in the pharmaceutically acceptable water controlling the release of the drug, such as fatty acids and fatty acid esters, fatty acid alcohols, waxes, inorganic substances, and And at least one selected from the group consisting of these mixtures.
  • the exciple fatty acids and fatty acid esters are at least one selected from glyceryl palmitostearate, glycerol 3 ⁇ 4 stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate, stearic acid, and combinations thereof;
  • Fatty acid alcohols include one or more selected from cetostearyl alcohol, cetyl alcohol, stearyl alcohol, and mixtures thereof;
  • the waxes may be at least one selected from carnauba wax, beeswax, microcrystalline wax, and mixtures thereof.
  • Inorganic materials may be used at least one selected from talc, precipitated carbonated carbon, hydrogen hydrogen phosphate, zinc oxide, titanium oxide, carbonine, bentonite, ponmo 3 ⁇ 4 ronite, non-gum and their common substances.
  • the hydrophobic compounds preferably contain fatty acid esters, glyceryl palmitostearate, glyceryl stearate, glyceryl nonarate, more preferably gloxe 3 ⁇ 4 stearate, glycerol bihe Nate may be used and may be included in an amount of 0, 1-20, and preferably 0,5-10, relative to 1 part of amlodipine.
  • the hydrophobic compound preferably uses fatty acid esters, fatty acid alcohols, waxes, inorganic materials, more preferably fatty acid esters, fatty acid alcohols, and amlodipine. 0.1-20 parts by weight, preferably 0, 5-10 parts by weight based on 1 part by weight.
  • the hydrophobic compound is preferably fatty acid esterolol, more preferably glycerol 3 ⁇ 4 stearate, and 0.1 to 20 parts by weight, preferably 0.5 to 1 part by weight of amlodipine. It can be included in 40 increments.
  • the hydrophobic compound may be included in an amount of 0.1-20 parts by weight, preferably 0.5-10 parts by weight, relative to amlodipine.
  • the hydrophobic compounds are preferably in fatty acids. More preferably, glycerol 3 ⁇ 4 stearate may be used, and may be included in an amount of 5 to 300 parts by weight, preferably 15 to 100 parts by weight, based on 100 parts by weight of nife dipine.
  • glycerol 3 ⁇ 4 stearate may be used, and may be included in an amount of 5 to 300 parts by weight, preferably 15 to 100 parts by weight, based on 100 parts by weight of nife dipine.
  • the hydrophilic polymer is a pharmaceutically acceptable water-soluble polymer that controls the release of the drug, sugars, 3 ⁇ 4 roll derivatives, gums, proteins, poly bi3 ⁇ 4 derivatives, polymethacrylate copolymers, 3 ⁇ 43 ⁇ 4 derivatives and carboxyvinylated polyethers can be selected and used as the saccharides, specifically dextrins, 3 ⁇ 4 liddextrins, dextrans, peck3 ⁇ 4 and peck derivatives, alginates, pulligaltaxuronic acids, xylans, arabinoxylans, Arabinogalactan, starch, hydrated propyl starch, amylose, amylopected, etc.
  • cellulose derivatives can be selected, and as cellulose derivatives, hydroxypropylme 3 ⁇ 4cellose, hydroxypropylpropyl ** loose , Hydroxymethylcellose, hydroxy to 3 ⁇ 4 ⁇ rose, methylsalorose, carboxymethylshell loose, romium, hydroxypropyl methylcell Osacetate succinate, hydroxyethylmethylsulloose, etc.
  • gums guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum, etc.
  • gelatin, casein, zein and the like can be used as a protein
  • polyvinyl alcohol, polyvinyl pyrrolidone and polyvinyl acetal diethylamino acetate and the like can be selected and used as a polyvinyl derivative
  • poly (3 ⁇ 4-acrylate to methacrylic acid) copolymers can be selected and used as polyethylene derivatives, such as pulley terylene glycol, Lithium oxide and the like can be selected and used, and carbomer can be used as the carboxyvinyl pulley.
  • the hydrophilic polymer is preferably starch, hydroxypropylmethylshell, hydroxypropylshell, carboxymethiolose, sodium nitrate, xanthan gum, polyvinyl alcohol or Carbomer may be used and may be included as 0.05-30 parts by weight, preferably 0.5-20 parts by weight, relative to 1 part by weight of Amrodda 3 ⁇ 4.
  • the hydrophilic polymer is preferably a cell using a loose derivative, a polyvinyl derivative, a carbocyvinyl polymer, a pulley ethylene derivative, more preferably hydroxypropyl ⁇ loose.
  • Hydroxypropyl methyl cell Hydroxypropyl methyl cell, cellulose acetate succinate, polyvinylpyridone, carbomer, pulley ethylene oxide can be used and 0.05 to 30 parts by weight, preferably 0.5 to 20 parts by weight relative to 1 part by weight of amlodipine. have.
  • the hydrophilic polymer may preferably be carboxyvinyl 3 ⁇ 4 mer, more preferably carbomer, 0.05 to 30 parts by weight, preferably 1 part by weight of amlodipine, preferably It may be included in an amount of 0.5 to 20 parts by weight.
  • the hydrophilic polymer preferably comprises a hydroxypropylcelose and / or a polymethathirate copolymer, more preferably a pulley (methacrylic acid methylmethylmethacrylate).
  • S may be used and may be included in an amount of 0.05 to 30 parts by weight, preferably 0.5 to 20 parts by weight, for 1 part by weight of amlodipine.
  • the sing-group hydrophilic polymer preferably contains a cell as a loose derivative, a carboxyvinyl plymer, more preferably 3 ⁇ 4 salicylate propylme loose, Carbomers may be used and may be included in an amount of from 5 to 200 parts by weight, preferably 10 to 100 parts by weight, based on the weight of nizadipine loo.
  • the preferred release control agents are polyvinylacetate, fullime 1-tacrylate co-concentration ⁇ poly (ethyl arc 3 ⁇ 4rate, decyl methacrylate 3 ⁇ 4tate, trimeth 3 ⁇ 4 amino to 3 ⁇ 4 methacrylate S ), Copolymer ⁇ , Carboxy vinyl hornmer, 3 ⁇ 4 Cellulose, "Loose Acetate, Carboxyme 3 ⁇ 4 Cellulose Sodium, Polyethylene Oxide Hydroxypropyl Methyl Chloride, Hydroxylpropyl Cellulose, And at least one selected from the group consisting of hydroxypropyl methylcells and phthalates, or selected from the group consisting of carboxyvinal polymers
  • Preferred release control substances for atorbasin / tin / amlodipine formulations include polyvinylacetate, polymethacrylate co-polymer, carboxyvinyl polymer, hydroxypropylmetholose, hydroxypropyl3 ⁇ 4 At least one selected from the group consisting of cellulose, 3 ⁇ 4 roll acetate, ethyl cellulose, polyethylene oxide, and hydroxypropyl methyl pentose phthalate carboxyvinyl plymer, polymeth 3 ⁇ 4late ⁇ polymer and And a mixture of carboxyvinyl plymer and hydroxypropylme 3 ⁇ 4cell selected from the group consisting of hydroxypropylmethylcellose.
  • the preferred release control substances are hydroxypropylcellose, hydroxypropylmethylsalose, hydroxypropylmethylcellosephthalate, shell ⁇ rose acetate, polyvinyl At least one selected from the group consisting of acetates, polymethacrylic acid copolymers, ethylcel ' loose, li (methacrylate methylmethacrylate) copolymers and methyl methacrylate methacrylic acid copolymers, or One is selected from the group consisting of hydroxypropylcelose, cellulose acetate, ethylcellose, poly (meth3 ⁇ 4late methylmethacrylate) copolymer.
  • the preferred release controlling substances are hydroxyspecificpropylsalose, hydroxyethoxypropylmerose, hydroxypropylmethyl 3 ⁇ 4rollosephthalate, pylooseaceti 1, selected from the group consisting of eth, polyvinylacetate, fully methacrylate copolymer, ethyl 3 ⁇ 4 loose, fully (methacrylate, methyl methacrylate) copolymer, and methacrylic acid 3 ⁇ 4 terpacrylic acid copolymer Or the one or more selected from the group consisting of hydroxy propyl shellulose, salulose acetate, ethyl gelose, poly t decacrylate, and meth methacrylate).
  • preferred release control substances are hydroxypropyl methyl 3 ⁇ 4 cell cellulose phthalate, hydroxy propyl methyl cell cellulose acetate succinate, methac 3 ⁇ 4 acid-methacrylate methyl copolymer, poly (ethylacryl Suntec from the group consisting of latex-methyl methacrylate-tritetyladinoethylmethacrylate), a glycerol 3 ⁇ 4 stearate, hydroxy propylmethylshell, hydroxypropyl3 ⁇ 4, and carbomer
  • the release controlling substance is hydroxypropylmethylsal, loose phthalate, hydroxypropylmethylcell, loose acetate.
  • enteric polymers selected from succinate or methacrylic acid methacrylic acid methacrylic acid copolymers and 3 ⁇ 41 hydroxypropylmethelose, hydrophilic polymers selected from cellulose, hydroxypropyl3 ⁇ 4ose, or carbomer .
  • enteric polymers selected from succinate or methacrylic acid methacrylic acid methacrylic acid copolymers and 3 ⁇ 41 hydroxypropylmethelose, hydrophilic polymers selected from cellulose, hydroxypropyl3 ⁇ 4ose, or carbomer .
  • the delayed-release compartment of the present invention includes an osmotic pressure control agent and may be a compartment coated with a semipermeable membrane coating base.
  • osmotic seclective refers to components used to control the release rate of drugs using the principle of osmotic pressure, such as' magnesium sulfate, magnesium chloride, sodium chloride, calcium chloride, sodium phosphate, And at least one member selected from the group consisting of calcium phosphate, ammonium acetate, lithium chloride, sodium sulfate, sodium sulfate, sodium sulfate, and combinations thereof.
  • sodium chloride, potassium chloride, sodium phosphate *, calcium phosphate can be used.
  • the osmotic pressure regulator is 0.01 to 10 parts by weight, preferably 0.05 to 5 parts by weight, based on 1 part by weight of amlodipine, atorvastatin / amlodipine formulations, pitavastatin / amlodipine formulations or roschvastatin /
  • 0.05 to 30 parts by weight, preferably 0.1-20 parts by weight, relative to 1 part by weight of amlodipine, in the atorvastatin / nifedipine formulation, in the amount of 5 to 150 ⁇ , preferably 10 to 100 parts by weight may be included.
  • the semipermeable membrane coating base is a pharmaceutically usable coating base, which is used in the coating layer of the pharmaceutical formulation to form a membrane which allows some components to pass but does not pass other components.
  • the above-mentioned water insoluble polymer may also be used.
  • the semi-permeable membrane skipping agent is, for example, polyvinyl acetate, plymethac 3 ⁇ 4 lay ⁇ copolymer, ply (ethyl arc 3 ⁇ 4 rate, meth hexa decacrylate) copolymer, pulley (ethyl arc 3 ⁇ 4 acetate, detyl meth 3 ⁇ 4). , Trimeth 3 ⁇ 4 aminoethyl meth 3 ⁇ 4 rate) copolymer, ethyl cellulose, cellulose.
  • the semipermeable membrane coating agent is preferably cellulose acetate, polyvinyl acetate, cellulose acetate, ethyl cellulose, polymethacrylate co-polymer, 1 part by weight of amlodipine. 0.01 to 10 parts by weight, preferably 0.05 parts by weight to 1.25 parts by weight.
  • the semipermeable membrane coating agent is preferably a poly (ethyl ac 3 ⁇ 4, methyl methacrylate: trimethylaminoethyl methacrylate) co-polymer, cellulose ester, ethyl Salose, cellulose acetate may be used, and may be included in an amount of 0.5 to 2Q, preferably 1 to 10 parts by weight, relative to 1 part by weight of amlodipine.
  • the semipermeable membrane coating base may preferably be cellulose acetate and may be included in an amount of 0.1 to 20 parts by weight, preferably 1 to 10 parts by weight, based on 1 part by weight.
  • the semipermeable membrane coating agent may be included in an amount of 0.05 parts by weight, 30 parts by weight, preferably 0.1 parts by weight to 20 parts by weight, based on 1 part by weight of amlodipine.
  • the semipermeable membrane coating agent may preferably use 3 ⁇ 4 rhorose acetate and may be included in an amount of 5 to 2000, and preferably 10 to 500, based on 100 parts by weight of nifedi 3 ⁇ 4.
  • the formulations of the present invention are referred to as pharmaceutically acceptable substances of (2-1) or (2 ⁇ 2) without diminishing the effects of the present invention, diluents, binders, disintegrants, lubricants, pH thereof.
  • Commonly used additives such as crude agents, antifoams, and solubilizers can be formulated by further use without departing from the nature of delayed release.
  • starch, microcrystalline shellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene 3 ⁇ 4 recall, decalum phosphate, or a combination thereof can be used as a diluent.
  • starch As a binder, starch, microcrystalline salose, highly disperse silica, manny, sucrose, lactose, polyethylene glycol, polyvinylpyridin, hydroxypropylmethylcellose, hydroxypropylcellose, natural gum, synthetic Gum, copovidone, povidone, gelaline, or a combination thereof may be used,
  • starch or modified 3 ⁇ 4-minute starch such as sodium starch glycolate, corn starch, potato starch or starch gelled starch, bentonite > montmorillonite, or vegeum, etc.
  • Cells such as salose or carboxymethyl gelose Crosslinked polyvinyl chloride such as sodium alginate or alginic acid Alginate croscarmel lose sodium such as alginic acid 3 ⁇ 4 Gurose gum such as guar gum and xanthan gum
  • Crosslinked polymers such as pyridone (crospovidone), effervescent agents such as sodium bicarbonate, citric acid, or a mixture thereof can be used.
  • Lubricant destearic acid, stearic acid magnesite, stearic acid kum, lauryl sulfur sulphate fl ", hydrogenated vegetable oil, natzoate, colloidal silicon dioxide, sodium stearyl fumarey S, glycerol 3 ⁇ 4 behenate, glycerol Peel mono-rays, ⁇ riceryl monostearate, glyceryl gulmitostearate and polyethylene glycol may be used.
  • the £ control agent is an acidifying agent such as acetic acid, adipic acid, ascorbic acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and a basic agent such as precipitated calcium carbonate, ammonia water, and meglumine. Etc. can be used.
  • the antifoaming agent may use dimethicone, oleyl alcohol, propylene glycol alginate, simethicone such as simethicone emulsion, and the like.
  • the dissolution aid can be used pleoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate, polysorbate, docuate or lithium.
  • additives selected from colorants, perfumes may be selected to formulate the formulations of the present invention.
  • the range of additives that can be used in the present invention is not limited to the use of such additives, and one of the additives may be formulated to contain a range of dosages by selection,
  • purified water, ethane, methylene chloride, and the like may be used as the solvent of the binder and the delayed-release additive, but preferably, purified water or ethane may be used.
  • the available 3 ⁇ 4 exclusion range is not limited to the use of such additives, and the above-mentioned additives may be formulated to contain a range of dosages by choice.
  • the delayed-release compartment of the present invention consists of particles or granules obtained by mixing, granulating or coating a dihydropyridine-based calcium antagonist, a time difference controlling substance and a conventional additive used in pharmaceuticals.
  • the pre-release compartment of the present invention is made of granulated black granules through a conventional process for producing oral solids such as mixing, coalescing, drying and granulation, together with a statin-based lipid lowering agent, together with pharmaceutically acceptable additives. If the fluidity of the statin-based lipid-lowering agent mixture can be directly tableted, the composition can be obtained by mixing. If the fluidity is not *, the composition can be obtained by compression, granulation, and granulation. Thus it can be configured as a pre-release compartment.
  • the present invention provides a single tablet such as a biphasic matrix tablet, a multilayer tablet, a nucleated tablet containing a delayed-release dihydropyridine-based antagonist discontinuous phase in a continuous-release statin-based lipid lowering agent continuous phase as described below. It can be carried out by the production method and administration method, but is not limited thereto.
  • the granules constituting the delayed-release compartment and the prior-release compartment are mixed with pharmaceutical additives, and the tablets are compressed into double tablets or three tablets in parallel, using multiple tableting machines. Possible tablets for oral administration can be obtained.
  • the granules constituting the delayed-release compartment may be mixed with a pharmaceutical additive and tableted to form a nucleus tablet, or the pharmaceutical coating may be applied to exhibit delayed-release properties. After mixing with a conventional additive and tableting as an outer layer, a tablet for oral administration can be obtained in the form of delayed release to the inner nucleus and a form in which the inner layer is surrounded by the inner layer.
  • the granules constituting the delayed-release compartment may be mixed and compressed with pharmaceutical additives or the drug layer constituting the prior-release compartment may be water-soluble after applying a special pharmaceutical coating even if it exhibits delayed release. After dissolving and dispersing in a film coating solution Tablets for oral administration can be obtained by coating the layers of the delayed-release tablet layer.
  • the osmotic material is contained in the tablet, and then compressed into tablets. Then, the surface of the tablet is coated with a semi-permeable polymer to form a nucleus tablet.
  • a pharmaceutical additive and tableting as an outer layer to obtain a tablet for oral administration in the form of a delayed-release compartment into the inner core and the immediate release layer on the surface of the inner core.
  • the present invention relates to a delayed-release compartment and a prior-release compartment comprising two-phase granules, radial granules or pellets and delayed-release tablets, delayed-release granules or pallets and pre-release tablets, and delayed-release tablets and pre-release tablets. It can be carried out by the production method and administration method of the layered camsul agent, but is not limited thereto.
  • the granules constituting the delayed-release second agent and immediate-release first agent according to the present invention are mixed with pharmaceutical additives as needed to layer the capsules in a controlled release. Possible capping agent can be obtained.
  • the granules constituting the delayed-release compartment are coated as they are or tableted to show delayed release, and the tablets are compressed or coated after the tablets are granulated or coated.
  • the tablets may be layered on the capsule to obtain a capsular agent capable of time release.
  • the granules constituting the open-release compartment are coated as they are or tableted to show delayed release, and the powder, granules or pellets constituting the pre-release compartment are laminated on the capsule to enable time lag release. I can get sage,
  • the granules constituting the pre-release compartment is compressed into tablets and, if necessary, prepared into tablets
  • the granules and 3 ⁇ 43 ⁇ 4 constituting the delayed-release compartment may be layered on the capsule to obtain a capsulant capable of time release.
  • the granules or pellets constituting the delayed-release compartment and the sacking or pellets constituting the prior-release compartment may be laminated on the capsule to obtain a capsulant capable of timed release.
  • the osmotic material is contained in the tablet, and then compressed into tablets. Then, the surface of the tablet is coated with a semipermeable polymer to form a nucleus tablet. Water can be mixed with pharmaceutical additives and then laminated to the capsule to obtain a timed release agent *.
  • the present invention separately prepares granule pellets or pre-release tablet layers constituting the prior release compartment, and calls for granules or delayed-release tablet layers constituting the delayed release compartment. It can be manufactured as a kit that can be layered together at work, blister, bottle, etc.
  • the pharmaceutical preparations of the present invention can be formulated in a variety of formulations and can be formulated, for example, as viscous tablets, coated tablets, multilayer tablets, or nucleated tablets, powders, granules, or capsulants.
  • the pharmaceutical formulations of the present invention may be in the form of a two-phase matrix tablet consisting of delayed-release compartments—pre-releasing compartments surrounding them.
  • the matrix of the delayed-release compartment and the prior-release compartment may be prepared as a preparation for oral administration by post-mixing or compressing the pharmaceutically acceptable additives in the material constituting the delayed-release compartment and the pre-release compartment.
  • Two phase S present formulations The pharmaceutical formulation of the present invention may be in the form of a two-phase matrix tablet obtained by slicing after uniformly mixing the delayed-release compartment and the prior-release compartment, and preferably, the delayed-release compartment is prepared in a granular form. It is.
  • the pharmaceutical formulation of the present invention may be in the form of a film skipping tablet consisting of a slow-release compartment and a film-coating layer consisting of a pre-release compartment surrounding the denture of the tablet, the film coating layer as the film coating layer is dissolved Simvastatin will be eluted.
  • the pharmaceutical formulation of the present invention is a delayed-release compartment obtained by mixing the pharmaceutical additives in the fruits and forests constituting the delayed-release compartment and the prior-release compartment, and tableting in two tablets or three tablets using a multiple tableting machine.
  • the pre-release compartment may be multi-layered form forming a multi-layer structure.
  • This formulation is a tablet for oral administration specially formulated for pre-release and delayed release in layers.
  • the pharmaceutical formulation of the present invention may be a nucleated tablet consisting of the inner layer consisting of a delayed-release compartment and a layer consisting of a prior-release compartment enclosing the surface of the inner core
  • the nucleated tablet may be an osmotic nucleated tablet.
  • the osmotic nucleus tablet is a tablet containing the osmotic pressure-controlling agent inside the tablet for delayed release and then tableted, and then the surface of the tablet is coated with a semi-permeable film coating base to form the inner core, and the granules constitute a pre-release compartment.
  • the pharmaceutical formulations of the present invention may comprise particles, granules, pal3 ⁇ 4, or It may be a capsular formulation comprising particles, granules, pellets, or tablets consisting of tablets and prerelease compartments.
  • the formulation of the present invention may further form a coating layer on the outside of the delayed-release compartment and / or the prior-release compartment. That is, the surface of the particles, granules, pellets, or tablets composed of delayed-release compartments and / or pre-release compartments may be coated for the purpose of release control or formulation stability.
  • 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 present invention prepares particles, granules, 3 ⁇ 43 ⁇ 4, or tablets constituting the pre-release compartment, separately prepares fruiting, 3 ⁇ 43 ⁇ 4 or tablets constituting the delayed-release compartment, foils, blisters, bottles, etc. It may be in the form of a kit prepared in a form that can be filled together and taken simultaneously.
  • the formulation according to the present invention is also provided in a state such as uncoated tablets without additional coating, but may be a formulation in the form of a coated tablet further comprising a coating layer by forming a coating layer on the outside of the formulation, if necessary.
  • 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 can be appropriately selected by the choice of a person skilled in the art in the method of forming the coating layer outside the film on the surface of the tablet layer, a method such as a fluidized bed coating method, a fan coating method, can be applied, preferably For example, 3 ⁇ 4 coating can be applied.
  • the coating layer may be formed by using a coating agent, an auxiliary coating agent, or a combination thereof.
  • the coating agent may be a 3 ⁇ 4 loose derivative such as hydroxypropyl methyl salose, hydroxy propyl propyl cellulose, a sugar derivative, or a 3 ⁇ 4 lye.
  • Vinyl derivatives, macrophages, fatty acids, gelatin, or mixtures thereof, and the like, and coating aids include polyethylene glycol, ethyl salose, 3 ⁇ 4 riselides, titanium oxide, talc, diethyl phthalate, or mixtures thereof. A mixture or the like can be used.
  • the coating layer may be included in the range of 0.5 to 15% by weight (% w / w) relative to the total tablet weight increase.
  • the present invention also provides a pharmaceutical formulation according to the present invention for evening administration.
  • lipid synthesis in the liver becomes vigorous after early dinner, and the general population including people with hypertension Extravasation "falls between night and dawn, and blood pressure rises in the morning after waking, peaking during the day (active).
  • the formulation of the present invention is used in the evening
  • the pre-release simvastated liver enzyme is administered at the time of activating the enzyme, which shows more lipid lowering effect
  • the delayed-release amlodipine effectively lowers the 3 ⁇ 4 pressure after dawn, so that blood pressure can be equalized from morning to morning. It is possible to maintain a competitive mutual antagonism of the drug and to maximize the effect of each active ingredient
  • the present invention is a method for treating cardiovascular diseases comprising administering a pharmaceutical formulation of the present invention to a mammal To provide.
  • cardiovascular disease is applied to hypertension, or hypertension and complications of those with metabolic syndrome, such as diabetes mellitus, obesity, high altitudes, and coronary artery disease.
  • Pharmaceutical formulations of the invention may be used in any suitable manner in the art, for example
  • Chrontherpeut ics 2003, Peter Redfern, PhP
  • it can be preferably formulated according to each disease or component, and specifically can be prepared by the method comprising the following steps. .
  • amalodipine is mixed with an enteric polymer, a water-insoluble polymer, a hydrophobic compound, or one or two selected release controlling substances selected from hydrophilic polymers, and a conventional 3 ⁇ 4 gauze used in pharmacy. Delayed-release granules or tablets are obtained by granulation or coating, and tableting, or by mixing, combining, drying, granulating, or tableting amlodipine with osmotic pressure ⁇ ablation and the usual additives used in pharmaceutical preparations. Coating to obtain delayed-release granules or tablets.
  • the second step consists in administering simvastatin and conventionally acceptable pharmaceutically acceptable additives, followed by conventionally released granules through conventional processes for producing oral solids via mixing, association, drying, granulation, black coating, and tableting, or Obtaining tablets.
  • the granules or tablets obtained in the first step and the second step are mixed with a pharmaceutical excipient, tableted or filled to obtain a preparation for oral administration.
  • the first step and the second step may be reversed or executed simultaneously.
  • the pharmaceutical formulation of the present invention may be prepared by the above process, and the formulation method of the third step will be described in more detail as follows, but is not limited thereto. [A] Preparation of two-phase matrix tablet
  • the tablets are obtained by mixing with the granules prepared in the second step and compressing them with a certain amount of weight.
  • the resulting tablets may be film coated as needed for the purpose of improving stability or properties.
  • the after-coated tablets or add the granules to a release-controlling material coating and appointed other by a predetermined amount and dried as black obtained in step 1 is manufactured to obtain the coating in addition, after the simvastatin to the film coating solution of the water-soluble corresponding 'dissolution
  • an oral dosage form film-coated tablet containing the active ingredient in the film coating may be prepared.
  • the granules obtained in the first step can be prepared as is or in a double tablet using a tableting machine.
  • Coated multilayer tablets can be prepared by formulating or coating triple or more multi-layered tablets by adding a release complement S layer as needed, or by formulation design.
  • the coated tablets or granules obtained in the first step are additionally coated as they are or with a release control material, dried, and then compressed into a predetermined amount, which is then further coated with black as an inner core, followed by a nucleated tableting machine together with the granules obtained in the second step.
  • the coated nucleated tablet may be prepared by coating or preparing a nucleated tablet in the form of a pre-release layer submerged on the surface of the first-stage tablet by tableting.
  • the granules obtained in the first step are additionally coated as is or with a release control material, and the dried granules or tablets and the granules or systems obtained in the second step are placed in a capsular bed electric machine and layered by an effective amount of each active ingredient in 3 ⁇ 4 sul of a certain size. Capsules can be prepared.
  • 3 ⁇ 4 slabs can be prepared by layering the capsules with a capsul layered device.
  • the amlodipine-containing preparation obtained in the first step and the simvastatin-containing preparation obtained in the second step can be prepared as a kit that can be layered together in a foil, blister, bottle, or the like.
  • the complex drug system of the present invention as described above is formulated into a complex formulation including a dihydropyridine-based Calm channel blocker and a statin-lipid lowering agent as an active ingredient to separately formulate each active ingredient by administering only one hour in the evening It is easier to guide the medication than to take it at the time of moxibustion, and it can reduce the side effects due to the metabolic interference action between drugs, and the shale control and lipid control effects of each drug are their own. Eggplant appears to be better than the effect.
  • statin lipid lowering agent represented by simvastatin
  • dihydropyridine type antagonist represented by amlodipine
  • the present invention is a so-called time difference dosing treatment (Chronotherapeutics) to maximize the therapeutic effect on the basis of heterogeneous pharmacokinetics Ofenobiotics to improve the side effects that can occur from the combination of different drugs from the pharmacokinetic point of view
  • Chronotherapeutics a so-called time difference dosing treatment
  • It is formulated as an effective active ingredient of dihydropyridine-calcin antagonist and statin-based lipid lowering agent, which affects or receives the same enzyme cytochrome P 450 system, and they are eluted from the body.
  • according to the present invention can be configured differently the release rate of the drug to prevent the antagonism and side effects between the drugs and at the same time can take the synergism of the drug.
  • the complex preparation can be taken at a time, the medication guide for the patient and the patient's medication are easy.
  • compositions comprising a pre-release compartment containing a statin-based lipid lowering agent of the present invention and a delayed-release compartment containing a dihydropyridine-based calcium channel blocker may be used for patients with metabolic syndrome and insulin resistance and diabetes or diabetes mellitus.
  • a statin-based lipid lowering agent of the present invention may be used for patients with metabolic syndrome and insulin resistance and diabetes or diabetes mellitus.
  • a delayed-release compartment containing a dihydropyridine-based calcium channel blocker may be used for patients with metabolic syndrome and insulin resistance and diabetes or diabetes mellitus.
  • Example 1 is a graph showing the comparative elution curves of amlodipine / simvastatin nucleated tablets prepared in Example 1-1 and a control drug (Curve?: Simvastatin monotherapy, Novask: amlodipine monotherapy).
  • Fig. 2 is a graph showing the curves of comparative coagulation between the combination preparation of amlodipine / simvastatin prepared in accordance with Examples 1-4 and 10 and the reference drug (Zoko: Simvastad single agent, Novask: Amlodipine single agent).
  • Fig. 4 is a graph showing the comparative dissolution curves of the complex preparation of amlodipine / atorvastatin prepared in accordance with Examples 1-13 and the reference drug (lipitor: atorvastatin monotherapy, Novask: amlodipine monotherapy).
  • FIG. 5 is a graph showing the comparative elution curves of the lercanidi 3 ⁇ 4 / simvastatin complex preparation prepared according to Examples 1-16 and the control agent (Zoko: simvasta3 ⁇ 4 monotherapy, zanidib: lercanidipine monotherapy).
  • FIG. 6 is a graph showing the comparative elution curves of the laxidipine / simvastatin complex preparation prepared according to Examples 1-18 and the control drug (Zoko: simvapatin monoclonal, Dr.r: lacidipine monolith).
  • Fig. 7 is a graph showing the curves of all the elution of amlodipine besylate / simvastarin nucleated tablets prepared according to Examples 1-20 and the comparative drug (Zoko: simvastatin monotherapy, MSD, Novasque: amlodipine monotherapy, Pfizer).
  • FIG. 8 is a comparative elution of a capsul agent containing an amlodipine pulsate / simvastatin combination tablet and a control agent (Zoko: simvastatin monotherapy, MSD, Novask: amlodipine monotherapy, Pfizer) prepared according to Example 1-22.
  • ⁇ This is a graph showing the curve.
  • Figure 9 is a combination preparation of amlodipine besylate / atorvastatin calcium prepared in accordance with Examples 1-30 and the control drug (lipitor: atorvasta 3 ⁇ 4 single agent, Pfizer, Novask: amlodi 3 ⁇ 4 single agent, Pfizer) A graph showing the comparative dissolution curves of.
  • FIG. 10 is a biphasic preparation in the form of pelodipine / atorvasta 3 ⁇ 4 capsulant prepared in accordance with Examples 1-36 and the control drug (lipitor: atorvastatin monotherapy, Pfizer, non-novol: felodipine monotherapy, hand poison drug)
  • lipitor atorvastatin monotherapy, Pfizer, non-novol: felodipine monotherapy, hand poison drug
  • FIG. 11 is a biphasic preparation in the form of isradipine / lluvastatin capsules prepared according to Example 1 ′ 4 0 and a control drug (Lescol: Polubasta 3 ⁇ 4 single agent, Novartis, Dynazek: Sradipine Monolithic drug, Daewoong Pharmaceuticals).
  • Figure 1 is a graph showing the dissolution test results * (S)-amlodipine / simvastatin complex formulation prepared according to Examples 1-51, 55.
  • Figure 13 is a graph showing the dissolution test results of the (S) ⁇ amlodipine / simvastatin composite formulation prepared according to Examples 1-52, 53, 54.
  • £ 14 is the clinical trial result according to Experimental Example 1-14 above. It is a graph comparing the blood concentration of hydroxy acid.
  • FIG. 15 is a graph comparing blood concentrations of simvastatin ⁇ -hydroxy acid and simvastatin between experimental groups as the clinical test results according to Experimental Examples 1-14.
  • Figure 16 is a graph comparing the concentration of amlodipine in the time difference between the administration group and the co-administration group as a clinical test results except the experimental example ⁇ - ⁇ .
  • Fig. 17 is a graph showing the comparative elution curves of amlodipine / simvastatin nucleated tablets prepared according to Example II-1 and the reference drug (2: Ko: simvastatin monotherapy, MSD, Novask: amlodipine monotherapy, Pfizer).
  • FIG. 13 is a graph showing the comparative elution curves of the pharmaceutical preparation of amlodipine / simvastatin and the control agent (Zoko: simvastatin monotherapy, Novasque: amlodipine monotherapy) prepared according to Examples II-4 and 10.
  • FIG. 13 is a graph showing the comparative elution curves of the pharmaceutical preparation of amlodipine / simvastatin and the control agent (Zoko: simvastatin monotherapy, Novasque: amlodipine monotherapy) prepared according to Examples II-4 and 10.
  • FIG. 13 is a graph showing the comparative elution curves of the pharmaceutical preparation of amlodipine / simvastatin and the control agent (Zoko: simvastatin monotherapy, Novasque: amlodipine monotherapy) prepared according to Examples II-4 and 10.
  • FIG. 13 is a graph showing the comparative elution curves of the pharmaceutical preparation of amlodipine / simvastatin and the control agent
  • FIG. 19 is a graph showing the comparative elution curves of amlodapine besylate / simvastatin nucleated tablets prepared according to Example II-11 and a control drug (Zoko: simvastatin monotherapy, Novask: amlodipine monotherapy).
  • FIG. 20 is a graphidi showing a comparative dissolution curve of a capsule containing an amlodi 3 ⁇ 4 besylate / simvastatin complex tablet prepared according to Example 11-13 and a control agent (Zoko: simvastatin monotherapy, Novask: amlodipine monotherapy) .
  • FIG. 21 is a graph showing the comparative elution of amlodipine / atorvastatin nucleated tablets prepared according to Example III-1 and a control agent (Ripto: atorvastatin monotherapy, Novask: Amlodi 3 ⁇ 4 monotherapy).
  • FIG. 22 is a graph showing the dissolution patterns of amlodipine of Examples III-1, 2 and 3, and
  • FIG. 23 is a graph showing the dissolution profiles of Examples III-6 and 7.
  • FIG. 24 is a graph showing the Atorvasta 3 ⁇ 4 3/4 concentration-time profile of Example III-1.
  • Example III-1 is a graph showing the amlodi 3 ⁇ 4 hyperemia concentration ⁇ time profile of Example III-1.
  • FIG. 27 is a graph showing the amlodipine elution aspect of Examples 2, 3.
  • 28 is a graph showing the amlodipine elution pattern of Examples IV-17 and 18.
  • FIG. 29 is a graph showing the comparative elution of Roschvastatin / Amlodi 3 ⁇ 4 nucleated tablets prepared versus Example (Cresto: Roschvastatin Monotherapy, Novask: Amlodipine Monotherapy) prepared according to Example V-4.
  • FIG. 31 is a graph showing the comparative elution of atorvastatin / nifedipon nucleated tablets prepared according to Example VI-1 and a control agent (lipitor: atorvastatin monotherapy, Procadia XL: nifedipine monotherapy).
  • Example 32 is a graph showing the elution aspect of Example VI-6.
  • Example 34 is a graph showing the dissolution profiles of Example "VI-10.
  • nucleated tablet tableting machine (RUD-1: Ki lian) as the inner core of the amlodipine core tablet and the composition containing simvastatin at a rate of 30 revolutions per minute, hardness 7 ⁇ 9kp, thickness 6.0 ⁇ , a 'compressed into tablets with a diameter 9.5 ⁇ then using a Hi-coater (SFC- 30N, Sejong machinery Co., Ltd. Korea) to form a film-coated layer, thereby preparing a press-coated tablet.
  • Example 1-2 Definition of amlodipine-simvastatin nucleated tablet :
  • Amodi 3 ⁇ 4 malate and microcrystalline cell were apologized as No. 35 and mixed with a double cone mixer, and then added to a fluidized bed granulator (GPCG 1: Glatt) as shown in Table 1-2.
  • Hydroxylpropyl 3 ⁇ 4cell was sprayed to form a granule by spraying the binder solution prepared by dissolving cellulose in water and drying. Again, the granules were coated by spraying a hydroxypropylmethylcell solution containing a phthalate phthalate dissolved in 1: 1 shaker of ethane and methylene chloride.
  • Magnesium stearate was added to this mixture and mixed with a final double cone mixer. The final mixture was then rotated at a speed of 30 revolutions per minute using a rotary tableting machine (MRC-33: Sejong), hardness 7 9 kp, thickness 3.0 kPa, diameter 5.5 The tablet was compressed into a nuclear tablet.
  • Amlodipine-simvastatin nucleated tablets were prepared in the same manner as in Example 1-1, 3) Tableting and Coating.
  • Example 1-3 Preparation of Amlodipon-Simvastatin Nucleated Tablets
  • amlodipine malate and microcrystalline cellulose were used as No. 35 Sieve apologies, mix with a double cone mixer, feed into a high-speed mixer, add Colicoat SR30D, combine, and granulate with a sieve No. 20 using an oscillator. It was sifted. Magnesium stearate was added to the final mixture in a double cone mixer, and the final mixture was used at a speed of 30 revolutions per minute using a rotary tablet press (M C-33: Sejong), hardness 7-9 kPa, thickness 3.0 kPa, diameter. A tablet of 5.5 mm was used to give a two-nuclear tablet.
  • Example 1-4 Preparation of Amlodipine-simvasta multilayered tablets
  • the binding solution made by amplifying amlodipine maleate and microcrystalline shell loose with No. 35 sieve and mixing with a double cone mixer and dissolving hydroxypropyl methyl shellose in water separately The particles were sprayed to form granules and dried.
  • the granules were dissolved in 1: 1 shaker of ethane and methylene chloride, the granules were coated by spraying 3 ⁇ 4 hydroxypropylmethylcell with a phthalate phthalate solution. Magnesium stearate was added to this and mixed with the final double conmixer.
  • Amlodipine-simvastatin multi-layered tablets were prepared in the same manner as in Example 1-4, 3) Tableting and Coating.
  • Example VII-6 Preparation of Amlodipine-simvastared Two-Phase Matrix Tablets
  • amlodipine malate and microcrystalline cells were mixed with apple No. 35 with apples, mixed with them, and colloidal SR30D was added to the high speed mixer. After the association, granulation was carried out using an oscillator with No. 20 sieve, and it was dried at 60 I;
  • apples simvastatin, microcrystalline 3 ⁇ 4, and Manny were No. 35, and were mixed with a high-speed ⁇ agitator.
  • hydroxypropyl shellulose and citric acid were dissolved in the tulle to prepare a binding solution, and the mixture was added to a high speed shaker with the mixture of the main ingredients, and then granulated using an oscillator. It was dried at ° C, and then sieved to No. 20 sieve, and butylated hydrated cyanuric sol was added thereto and mixed.
  • Each of the final S compounds prepared above was mixed with a double cone mixer, sodium starch glyconate, After colloidal silicon dioxide was mixed, stearic acid magnesium was added and mixed with a double cone.
  • Example 1-7 Preparation of Amlodiated-simvastatin Two-Phase Matrix Tablets
  • the amlodipine malate and the microcrystalline cell rhodes were apologized as No. 35 and mixed in a Dubucon mixer as shown in the following Tables 1-2.
  • the mixture was introduced into a fluidized bed granulator (GPCG 1: Glatt), and a binder solution, which was prepared by dissolving hydroxypropylmethyl ⁇ loose in water, was sprayed to form granules and dried.
  • the granules were sprayed again by spraying Eudragit RS P0 solution dissolved in ethanol and 1: 1 shake solution of methylten chloride.
  • Amlodipine-simvastarin biphasic matrix tablets were prepared in the same manner as in Example 1-6, 3) Postmixing, Tableting and Coating.
  • Example I Amlodipine-simvastatin biphasic matrix tablets were prepared according to post mixing, tableting and coating methods. Examples 1-9: Amlodipine® simvastared two-phase capsular formulation
  • amlodipine maleate and microcrystalline gelose were apologized with No. 35 and mixed in a double cone mixer, and then put into a layered granulator (GPCG 1: Glatt) and colicoat SR30D. Sprayed to form granules and dried.
  • lovastatin, microcrystalline cellulose and manny were appled into No. 35 sieve and mixed with a high speed mixer. Separately, dissolve hydroxypropyl 3 ⁇ 4 and citric acid in water to gradate the binder solution, and then combine it with a main component mixture in a high-speed mixer, combine it, and granulate it with a No. 20 sieve using an oscillator. After drying at ° C it was again established as No. 20 sieve. In addition, butanated hydrated cyanosol, starch glycoic acid ' natrop, colloidal silicon dioxide were mixed, and stearic acid magnesium was added to the final mixture in a double cone mixer.
  • the tablet was compressed using a multi-layer tablet press (MRC-37T: Sejong). That is, the composition containing the lovastarin is placed in the primary powder feeder, and the composition containing amlodipine is placed in the secondary powder feeder at a speed of 30 revolutions per minute at a speed of 30 revolutions per minute to minimize the infiltration of the layers. It was compressed into 9 kp, 6.0 mm thick, 9.5 mm diameter and formed a film coating layer as a high coater to prepare a multi-layer point.
  • MRC-37T Sejong
  • Example 1-11 Svastatin pre-release compartment of Example 1-11 and the ingredients and contents shown in Table 1-3 It was prepared according to the preparation method.
  • amlodipine-lovastatin multi-layered tablet was prepared in the same manner as in Example 1-11, 3) Tableting and coating method.
  • Example 1-13 Preparation of amlodipine-atorvastad multilayered tablets
  • atorvastatin, microcrystalline ⁇ loose, and Manni were apologized as No. 35 and mixed with a high speed mixer.
  • hydroxypropyl3 ⁇ 4loose and citric acid are dissolved in water to prepare a binding solution, which is mixed with a main component: in a high-speed mixer, and fed together, and then granulated using a No. 20 ceto oscillator. After drying, it was established as No. 20 sieve again.
  • Butyl hydroxyanisole, sodium starch glyconate, and colloidal silicon dioxide were mixed therein, and magnesium stearate was added to the final mixture in a double cone mixer.
  • Example 1-15 Preparation of Amlodipine-atorvastatin Nucleated Tablets
  • Press-coated tablet tableting machine at the rate of the inner core of amlodipine tablet core using (RUD-1 Ki Han) and atorvastatin on the '30 turns per minute to the composition in an outer layer comprising eu, hardness 7 ⁇ 9 kp, thickness of 6.0 ⁇ After tableting to a diameter of 9.5 kPa, a coating layer was formed using a high coater roll to prepare a nucleated tablet.
  • Example 1-16 Preparation of Lercanidipine-simvastatin Multi-Layered Tablet
  • Apples with lercanidipine and microcrystalline salolosol No. 35 ⁇ as shown in the following Tables 1 to 3 were mixed with a double cone mixer, and the above mixture was added to a granular granulator (GPCG 1: Glatt).
  • GPCG 1 Glatt
  • hydroxypropylmethylshellulose was dissolved in water and sprayed to form a binder solution, which was then dried to form granules.
  • the granules were sprayed with a solution of hydrated propylpropyl ⁇ 3 ⁇ 4cell dissolved in 1: 1 shaker of ethanol and tertylene chloride, and then the granules were coated.
  • Magnesium stearate was added to this and mixed with the final double conmixer.
  • the tablet was compressed using a multi-layer tablet press (MRC-37T: Sejong). That is The composition containing simvastatin is placed in the primary powder feeder, and the composition containing lercanidipine is placed in the secondary powder feeder at a speed of 30 revolutions per minute, at a speed of 7 to 9 kp, to minimize the incidence of filling.
  • the film was hit with a thickness of 6,0 mm 3 and a diameter of 9.5 mm, and a film coating layer was formed as a high coater to prepare a multilayer tablet.
  • Example IVII 17 Preparation of Lerke "Nidi 3 ⁇ 4-Simvasta3 ⁇ 4 Multi-Layered Tablets
  • lercanidipine and the microcrystalline cell were apologized with a Rooseol No. 35 sieve, mixed with a debulcon mixer, fed into a high-speed mixer, and then added with Colicoat SR30D.
  • Granulation was carried out using an oscillator, which was dried at 60 ° C. using a silver water dryer, and then re-formed as No. 20.
  • Magnesium stearic acid was added thereto and finally mixed with a double cone mixer.
  • Lercanidipine-simvastatin multi-layered tablets were prepared in the same manner as in Example 1-16, 3) Tableting and Coating Method.
  • Example 1-18 Manufacture of Lacidipine-simvastatin Multi-Layered Tablets
  • the acedipine and the microcrystalline cellulose were apologized with a No. 35 sieve and mixed with a double cone mixer, and the above mixing tool was placed on a homogeneous layered granulator (GPCG 1: Glatt).
  • GPCG 1 Glatt
  • the mixture was added and sprayed separately, hydroxypropylmethylcell was dissolved in cellulose roll water to form granules and dried.
  • the granules were sprayed with a hydroxypropylmeth 3 ⁇ 4cell, which was dissolved in a 1: 1 mixture of ethane and methylene chloride, and sprayed with a phthalate phthalate solution to coat the granules.
  • Magnesium stearate was added to this and mixed with the final double cone mixer.
  • Lacidipine-simvastatin multi-layered tablets were prepared in the same manner as in Example 1-18, 3) Tableting and Coating.
  • Example I-20 Preparation of Amrodafine-Simvastatin Nucleated Tablets
  • amlodipine besylate and microcrystalline cells of aloe and decalom phosphate were apologized with No. 35 sieve, mixed with a double cone filter, and added to a fluidized bed granulator (GPCG 1: Glatt).
  • GPCG 1 Glatt
  • the binding solution made by dissolving hydroxypropylmethylshellose in water was sprayed to form granules and dried.
  • Carbomer 71G was added to the granules in a powder form, and then stearic acid was added to the granules, and the resultant mixture was mixed with a final double cone mixer, and the final mixture was mixed with Bundang (MRC-33: Sejong).
  • simvastatin, microcrystalline cellulose, corn starch, and lactose were apples in No. 35 as shown in Table 1-4 and mixed with a high speed mixer.
  • prepare a binding solution by dissolving hydroxyaluminum salulose and citric acid in water, and incorporating it into a high-speed mixer with the main component mixture, and then coalescing it using an oscillator with a No. 20 sieve. It was dried at 60 ° C. and then sieved to No. 20 sieve again.
  • Butylated hydroxyanisole, starch glyconate natate here. s colloidal silicon dioxide was mixed, and stearic acid magnesium was added and finally mixed in a double cone mixer.
  • nucleated tablet tablet machine (RUD-1: Ki Han) as the inner core of the amlodipine core tablet and simvastatin-containing composition at a rate of 30 revolutions per minute, hardness 7 to 9 kp, thickness 6.0 mm, diameter 9.5 Nucleated tablets were prepared by tableting with a pan and then forming a film nose layer as a high coater.
  • the aloe 3 ⁇ 4 besylate and microcrystalline cell were apologized with S-ose and decalcium phosphate as No. 35 and mixed with a double cone mixer, and hydroxypropylmethylcellose was separately added to water.
  • the binder solution was dissolved and sprayed to form granules.
  • the granules were coated by spraying a coating solution consisting of 3 ⁇ 4 hydroxypropylmethylshell loose phthalate and acetylated monoglycerides when the granules were dissolved in 1: 1 shaker of ethane and salt methylene. Stearic acid magnesite was added thereto and mixed in the final double cone mixer.
  • Example 1-22 Amlodipine tablets-3/4 tablet containing simvastatin tablets
  • amlodipine besylate and microcrystalline 3 ⁇ 4 rose were apologized as No. 35, mixed with a double cone mixer, and then added to a granular granulator (GPCG 1: Giatt), and then separately.
  • Granules were formed and dried by spraying a binder solution made by dissolving hydroxypropylmethylcell 3 ⁇ 4 rose in water.
  • Carbomer 71G was added to the granules in powder form, and then stearic acid and magnesium were added to the final double cone mixer, and the final mixture was mixed with a rotary tablet press (MRC-33: Sejong).
  • tableting was carried out with a hardness of 7-9 kp, a thickness of 3.0 mm and a diameter of 5.0 mm.
  • hydroxypropyl methylcell (5 weight 3 ⁇ 4) and acetylated monoglyceride solution dissolved in 1: 1 shaker of ethane and methylene chloride and acetylated monoglyceride solution were coated with a high coater. To form a tablet.
  • simvastatin, the crystalline salose, and Manny were apples with No. 35 and mixed with a high speed mixer. Separately, hydroxypropyl3 ⁇ 4loose and citric acid are dissolved in water to prepare a binding solution, which is then added to a high-speed mixer combined with the main component mixture, which is then granulated using an oscillator with a No. 20 sieve. After drying at ° C it was again established as No. 20 sieve. Add the mixed hydroxyanisole, sodium starch glyconate, and colloidal silicon dioxide, and add the stearic acid magnesium to the double-mixer for final mixing.
  • amlodipine tablets of step 1) and the simvastatin tablets of step 2) were layered onto the hard gelatin capsulization of No. 3 using a capsule layer electric machine.
  • simvasta3 ⁇ 4, microcrystalline cellulose, lactose and starch starch were appled with No. 35 sieve and mixed with a high speed mixer.
  • hydroxypropylcellolose and citric acid are dissolved in water to prepare a binding solution, which is added to a high-speed mixer with the main component mixture, and then combined.Then, it is granulated using an oscillator with a No. 20 sieve. After drying at 1C it was again established as No. 20 sieve.
  • butylated hydroxyanisole, sodium starch glyconate and colloidal silicon dioxide were mixed, and a stearic acid magnesium was added to the final mixture in a double cone mixer.
  • amlodipine tablet of step 1) and the simvastatin granules of step 2) were layered into hydroxypropylmethylcell No. 2 in the hard capsule of cellulose using a 3 ⁇ 4 capsule layer electric machine.
  • Example 1-24 Amlodipine-Simvastar 3 ⁇ 4 Coated Tablets
  • simvastatin As shown in Table 1-4, simvastatin, butyl tated hydroxyanisole, hydrated propylmethylsalose, colloidal silicon oxide, polyethylene glycol 6000, titanium oxide, talc and ethane A pre-release simvastatin coating solution was prepared by dissolving and dispersing in methylene chloride shake solution.
  • amlodipine tablets prepared above were administered to the high coater and then first coated with a simvastared coating solution.
  • Example I-2 6 Amlodipine-simvastatin blister packaging kit
  • Example 1-22 amlodipine-atorvastatin nucleated tablets
  • Example 1-28 Amlodipine-atorvastatin multilayer tablet
  • Example 1-22 amlodipine-atorvastatin capsule was prepared.
  • Example 1-30 Amlodipine-Atorvasta 3 ⁇ 4 capsule
  • nucleated tablet tableting machine (RUD—l: KHian) as the inner nucleus ⁇ and the composition containing ato 5vastatin as the inner core ⁇ , at a rate of 30 revolutions per minute, hardness 7 ⁇ 9 kp, thickness
  • the tablets were compressed into 6,0 mm 3 and 9.5 mm diameter, and then a film coating layer was formed as a high coater to prepare nucleated tablets.
  • Realization ⁇ 1-33 Amlodipine ⁇ Atorvasta 3 ⁇ 4 Blister Packaging Kit
  • Example 1-34 Nifedipine-simvastatin Nucleated Tablets
  • tablets were made with a hardness of 7-9 kp, 3.0 mm thick, and 5.5 mm diameter.
  • hydroxypropylmethyl3 ⁇ 4-loose phthalate solution and acetylated monoglyceride solution dissolved in a 1: 1 mixture of ethane and methylene chloride were formed using a high coater to form a film coating layer.
  • Table 1-5 shows the ingredients and contents and the examples. 1-20, 2) "simvastatin pre-release compartments were prepared according to the preparation method.
  • nucleated tablet tableting machine (RUD-1: Ki l ian) as the inner core of the nifedipine core tablet and the composition containing simvastatin as the outer layer at a speed of 30 revolutions per minute, hardness 7 — 9 3, thickness 6.0 ⁇ , Girum Nucleated tablets were prepared by tableting at 9.5 mm and then forming a film coating layer as a high coater.
  • Example 1-34 Except for using atorvastatin instead of simvastatin, according to the ingredients and contents of Table 1-5, according to the preparation method of Example 1-34 was prepared nipydipine- atorvastatin nucleated tablets.
  • apples pelped and microcrystalline cellulose were mixed with a sieve No. 35, mixed in a double cone mixer, and put into a fluidized bed granulator (GPCG. 1: Glatt), and hydroxy separately.
  • a binder solution made by dissolving propyl cellulose in water was sprayed to form granules and dried.
  • the granules were then coated with hydroxypropylmethylsalloosephthalate solution dissolved in 1: 1 shaker of ethane and methylene chloride to coat the granules.
  • the granules were mixed with 71G rolls of carbomer, and then mixed with a double cone mixer.
  • the final mixture was used at a speed of 30 revolutions per minute using a rotary tableting machine (MRC-33: Sejong). , Tablets with a hardness of 7 to 9 kp, a thickness of 3.0 mm and a diameter of 5.0 mm were tableted.
  • Example 1-22 the ingredients and contents shown in Table 1-7 and 2) the atorvastatin pre-release compartment of Example 1-22 were prepared according to the method S.
  • vanidipine hydrochloride and microcrystalline cells were replaced with 35 Apples and common combined in a double cone mixer, open inflicting a then Kollicoat SR30D commitment to high-speed common stapler Union and then a No. 20 sieve and granulated using an oscillator, this hermit dryer this use at 60 X is dried again 20 Issue It was sifted.
  • Magnesium stearate was added to this mixture and finally mixed with a double cone mixer. The final mixture was used at a speed of 30 revolutions per minute using a rotary milling machine (MRC # 33: Sejong), hardness 7-9kp, thickness 3.0mm, diameter Tablets of 5.5 mm were compressed.
  • lovastatin, microcrystalline cellulose, and Manny were apologized to No. 35 and mixed with a high speed mixer.
  • hydroxypropyl salulose and citric acid were dissolved in water to prepare a binding solution, which was added to a high-speed mixer with the main component mixture, and then united. After drying at C, it was established as No. 20 sieve again.
  • Butylrate hydroxyanisole, starch glyconate sodium, colloidal silicon dioxide was mixed, and the final mixture was mixed with a double cone mixer after stearic acid magnesite was added to the rotary tableting machine (MRC-33 : Tablets of hardness 7-9 kp, thickness 5.0 kPa, and diameter 5.5 kPa were hit at a speed of 30 revolutions per minute using Sejong.
  • Example 1-36 Lodiphan delayed-release compartment of Example 1-36 was prepared according to S.
  • Benidin tablets of step 1) and the final composition of 2) were encapsulated in capsule layer electrophoresis # 1 gelatin It was stratified in hard cap surgery.
  • silinidipine instead of vanidied, as prepared, according to the ingredient content shown in Table 1-6, was prepared according to the method of preparing a delayed-release layer of Example 1-37 1) vanidipine.
  • Pravastatin sodium was used in place of simvastatin, according to the preparation method of Example 1-11, 2) simvastatin pre-release compartment, as shown in Table 1-7.
  • Isradipine and microcrystalline cells were apples as a No. 35 sieve as shown in Table 1-6, and the mixtures were prepared by mixing in a double cone mixer. Separately, hydroxypropyl cellulose was dissolved in water to prepare a binder solution. While spraying the defect solution to the crystalline sucrose seeds in the CF granulator, the mixed powder was dispersed in the crystalline sucrose seeds to prepare pellets. The obtained 3 ⁇ 4 was dried at 50 ° C. until the water content was 2% or less, thereby preparing isoldipine-containing core 3 ⁇ 4lets. Again, Pelhat was commented by spraying a solution of hydroxypropylmethyl 3 ⁇ 4 rose phthalate dissolved in 3 ⁇ 43 ⁇ 4 of ethane and acetone in 1: 1 shake solution.
  • simvastatin pre-release compartment of Example 1-1 was prepared according to the preparation method of 2) simvastatin pre-release compartment of Example 1-1 as shown in Table 1-7.
  • Mandihydrochloride 3 ⁇ 4 and microcrystalline cell were apologized with No. 35 sieve and mixed with a double cone mixer, and then poured into a fluidized bed granulator (GPCG 1: Glatt), and separately The combined solution prepared by dissolving oxypropylmethylcell in water was sprayed to form granules and dried. Again, the granules were coated by spraying a hydroxypropylmexylsaloseophthalate solution dissolved in ethanol and 1: 1 shake solution of methylene chloride. Magnesium squalene was added to the mixture and the final mixture was mixed using a double cone mixer.
  • lovastatin, microcrystalline cellulose and manny were apologized as No. 35 and mixed with a high speed mixer.
  • Separately hydroxypropyl to prepare a binding solution by dissolving trehalose with citric acid in water saelreul and put in a high-speed common stapler with the main component mixture is granulated using an oscillator with a union and then sieve No. 20 and this, using a hermit dryer 60 ° C It was dried at and then reconstituted with No. 20 sieve.
  • Butylated hydric cyanosol, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate were added thereto and finally mixed with a double cone mixer.
  • the tablet was tableted with a warning of 7 to 9 kp, a thickness of 3.0 mm, and a diameter of 5.5 mm at a speed of 30 revolutions per minute using the Rotary Mixer (MRC-33; Sejong).
  • MRC-33 Rotary Mixer
  • Nicardipine hydrochloride was used in place of the felodisome, which was prepared according to the ingredients and contents shown in the following Tables 1-6 and 1) 3 ⁇ 4 rhodipine delayed-release compartment of Example I ′ 36.
  • rosuvastatin kite instead of simvastatin is shown in Table 1-7 below. It was prepared according to the preparation method of 2) simvastatin pre-release compartment of Example 1-1 as well as egg component and content.
  • nucleated tablet press (RUD-1: Ki l iaii) as the inner core of the nicardipine nucleus and the composition containing rosuvastatin as an outer layer at a speed of 30 revolutions per minute, hardness 7 to 9 kp, thickness 6.0 kPa
  • a nucleus tablet was prepared by forming a film coating layer as a high coater.
  • nifedipine instead of felodipine, it was prepared according to the ingredients and contents shown in the following Table 1-8 and 1) 3 ⁇ 4 rhodipine delayed-release compartment of Examples 1-36.
  • nucleated tablet tablet machine (RUD-1: KHian) as the inner core of nifedipine core tablets and simvastatin-containing composition at a rate of 30 revolutions per minute, hardness 7 ⁇ 9 kp, thickness 6.0 kPa, diameter 9.5 mm Nucleated tablets were prepared by forming a film coating layer as a high coater after tableting.
  • ROD-1 KHian
  • Example 1-44 Preparation of Amlodipine-Pitavastatin Nucleated Tablets
  • Amlodipine-rosuvastatin nucleated tablets were prepared according to the preparation method of Examples 1-20, except that rosuvastatin carsum was used instead of simvastatin.
  • Example 1-46 Preparation of Nimodipine-pravastatin Coated Tablets
  • Nimodibyun and microcrystalline cell were apologized with No. 35 sieve and common with a double cone mixer, which was then poured into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropyl separately.
  • the binding solution made by dissolving methylcellose in water was sprayed to form granules and dried.
  • the granules were coated by spraying a hydroxypropylmethyl gel solution containing phthalate and ethanol in a 1: 1 mixture of ethylene chloride and methylene chloride.
  • the carbomer 71G was added to the granules in powder form, and then stear 3 ⁇ 4 acid magnesium was added and mixed with a final double cone mixer.
  • Nimodipine tablet roll using a high coater Dissolves and disperses hydroxytitanium ⁇ titanium oxide and talc in ethanol and constant water, and dissolves pravastatin sodium salt as shown in the following Tables 1-9.
  • a pre-release coating solution containing pullulvastatin nat salt was prepared, and the coating solution was prepared by forming a coating layer on the outer layer of the nimodipine delayed-release compartment with the coating solution.
  • nibaldimun and microcrystalline cells were apologized with No. 35 sieve and mixed with a double cone mixer.
  • hydroxypropylmethylcell was dissolved in water to spray a binder solution.
  • the granules were coated by spraying a solution of hydroxyspitalymethylmethylcell dissolved in a 1: 1 shake solution of ol and methylene chloride.
  • the granules were poured into carbomer 71G roll powder, and then stearic acid magnesium was added to the final double cone mixer.
  • tableting was carried out using a multi-layer tablet press (ffiC-37T: Sejong). That is, the composition containing the pitavasta 3 ⁇ 4 in the primary powder feeder, and the composition containing nibaldipine in the secondary powder feeder at a speed of 30 revolutions per minute to minimize the infiltration of the layers, hardness 7 It was tableted to ⁇ 9 kp, 6.0 ram thick, 9,5 mm in diameter, and a film coating layer was formed as a high coater to prepare a tablet in a multi-layered form.
  • Example 1-48 Nisoldipine-Lovastatin Multi-Layered Tablet S
  • Granules were formed and dried. Again, the granules were coated by spraying the Eudragit RS P0 solution dissolved in 1: 1 shaker of ethane and methylene chloride. Stearic acid magnesium was added to this and mixed with the final double cone mixer.
  • lovastatin in place of simvastatin was prepared according to the method of preparation of 2) simvastatin pre-release compartment of Example 1-1 with the components and contents shown in the following Table 1-9.
  • pravastad nat "salt, microcrystalline shellulose, manniolol apologies with 35 No. 35 and mixed with a high-speed mixer Separately hydroxypropyl cellulose and citric acid in water It was prepared by dissolving in a binder solution, and putting it in a high speed mixer together with the main component mixture, and then granulating it with an oscillator using No. 20 sieve and drying it at 60 ° C. using a silver water dryer, and then reconstituting it with No. 20 sieve.
  • Butylated hydroxyanisole, sodium starch glyconate, and colloidal silicon dioxide were mixed, and finally mixed with a stearic acid magnesite with a double cone filter, and the final mixture was rotated by a tablet press (MRC-33: Sejong). Using a tablet at a rate of 30 revolutions per minute, a viscosity of 7 to 9 kp, 4.0 mm thick, and 8.5 mm in diameter was tableted.
  • (S) -Amlodipine core tablets were prepared by compressing the final mixture with a hardness of 6 to 10 kp, a thickness of 3.0 mm, and a diameter of 5.5 mm at a rate of 30 revolutions per minute using a rotary tablet press (MRC-33: tax). .
  • simvastatin, microcrystalline salulose and manni were sieved through a No. 20 sieve, and then mixed in a high-speed mixer for 10 minutes. Separately, hydrophilic prophyllose and citric acid were purified. It was dissolved in to prepare a binding solution. While adding the binding solution to the above mixed moles, the granulation was completed, the granulation was completed, and granulation was completed. Butylated hydroxyanisole, starch sodium glycolate, and colloidal silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a double cone mixer together with the above granules, and then mixed for about 10 minutes. Was passed through a sieve No. 35 and administered to a double cone mixer, followed by final mixing for about 4 minutes to complete the preparation of simvasta3 ⁇ 4 layer granules.
  • nucleated tablet press (RUD-1: Ki lian) as the inner core of the Amlodi 3 ⁇ 4 nuclear tablet and the composition containing simvastatin as the outer layer, at a speed of 30 revolutions per minute, hardness 7-13 kp, thickness 6.0 kPa
  • the inner core was prepared by tableting with a diameter of 9.5 mm 3.
  • the film coating layer composition of Table 1-8 was dissolved in a solvent to prepare a film coating solution.
  • the inner core prepared above was administered to a high coater and then coated with a film coating solution to complete nucleated tablet manufacturing.
  • Example 1-51 Preparation of (S) -amlodipine-simvastatin nucleated tablets
  • Example 1-50 It was prepared in the same manner.
  • Example 1-52 Preparation of (S) -amlodipine-simvastatin capsulant
  • (S) -amlodipine besylate and microcrystalline cell loose were mixed with a No. 35 sieve and mixed with a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glati).
  • GPCG 1 fluidized bed granulator
  • the binding solution prepared by dissolving parohydroxypropylcellose in purified water to form granules
  • the granules were dried, and the resultant granules were infused with carbomer 71G in powder form for 10 minutes in a double cone mixer.
  • stearic acid magnesium which was sieved through a No. 35 sieve was added and mixed for 4 minutes.
  • (S) -Amlodipine tablets prepared by tableting the final mixture with a hardness of 6 ⁇ 10 kp, a thickness of 3.0 ⁇ and a diameter of 5.5 ⁇ at a speed of 30 revolutions per minute using a rotary tablet press (M C-33: Sejong).
  • M C-33: Sejong a rotary tablet press
  • simvasta layered granules 35 sieve and administering to a double cone mixer, the final mixture was finally mixed for about 4 minutes to complete the preparation of the simvasta layered granules.
  • Simvastatin tablets were prepared by tableting the granules at a speed of 30 revolutions per minute using a rotary tableting machine (MRC-33: Sejong, Korea) at a hardness of 6 to 10 kp, a thickness of 3.0 mm and a diameter of 5.5 mm. Coating with a film layer component of 8 completed simvastatin tablet preparation.
  • (S) —Amlodipine besylate and microcrystalline shell rollose were apples in No. 35, mixed in a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glatt).
  • GPCG 1 Glatt
  • the binding solution made by dissolving hydroxypropylcellose in purified water was sprayed to form granules, and then dried.
  • Magnesium Stearate which was sieved through No. 35, was added, followed by final mixing for 4 minutes.
  • (S) amlodipine tablets prepared by tableting the final mixture with a hardness of 6 to 10 kp, a thickness of 3.0 mm and a diameter of 5.5 at a rate of 30 revolutions per minute using a rotary tableting machine (M C-33: Sejong).
  • the preparation of the (S) -amlodi 3 ⁇ 4 tablet was completed by co-coating with li (methacrylate, 3 ⁇ 4 meth 3 ⁇ 4 tate) copolymer.
  • simvastatin, microcrystalline salose, and Manni were sieved through a No. 20 sieve and mixed for 10 minutes in a high speed mixer. Separately, the combined solution was prepared by dissolving hydrocyclopropyl cellulose and citric acid in purified water. While adding the binding solution to the mixture, granulation was completed by granulation, drying, and sizing to complete granulation. Butylated hydride cyanosol, starch glyconate sodium, and colloidal silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a Dubolcon mixer together with the above granules, and then mixed for about 10 minutes. The sieve was sifted through No. 35 sieve and then administered to the Dulon method Final mixing was completed for minutes to complete the preparation of the simvastatin layer granules.
  • Capsule preparation was completed by simultaneously laminating the above-mentioned (S) -amlodipine tablets and simvastatin granules in the hydrophilic cipropylmethyl 3 ⁇ 4 rollose hard cap capsule of No. 1 using a capsular layer electrolysis.
  • Example 1-54 (S) —Amlodipine Tablet + Simvastar3 ⁇ 4 Blister Packaging Kit
  • Example 1-55 Preparation of (S) -amlodiated-simvastatin coated tablets
  • (S) -Amlodipine tablets prepared by tableting the final mixture with a hardness of 6 ⁇ 10 kp, a thickness of 4.0 ma, and a diameter of 8.0 ⁇ at a speed of 30 revolutions per minute using a rotary tablet press (MRC-33: Sejong). It was coated with a pulley (methacrylate, methyl methacrylate) copolymer below Table 1-10 to complete the preparation of (S)-amlodipine tablets.
  • simvastatin, butylated hydroxyanisole, hydroxypropyl decylose, and colloidal silicon oxide were dissolved in ethane and ethylene chloride shaker to prepare a simvastatin coating solution.
  • the second step Han (S) —Amlodipine tablets were administered to the high coater, followed by a first skip with a simvastatin coating solution.
  • Example 1-56 Preparation of (S) -amlodipine-atorvastatin capsulant:
  • Atorvastatin calum, butylated hydroxy anisole and microcrystalline salose were apologized as No. 35 as shown in Table 1-11, and mixed in a double cone mixer to prepare a mixture.
  • hydroxypropyl 3 ⁇ 4 was dissolved in water to prepare a binder solution.
  • a pellet was prepared by spraying the mixed powder on the crystalline sucrose seed while spraying the binder solution on the crystalline sucrose seed in the CF granulator.
  • the pel3 ⁇ 4 obtained was dried at 50 ° C until the water content was 23 ⁇ 4> or less to prepare 3 ⁇ 43 ⁇ 4 containing atorvastatin sting.
  • (S) -amlodi 3 ⁇ 4 besylate and microcrystalline cellulose were apologized as No. 35, and mixed in a double cone mixer to prepare a mixed powder.
  • the binder solution was prepared by dissolving hydroxyipropyl cellulose in water. While spraying the binder solution to the crystalline sucrose seed in the CF granulator ' , the mixed powder was dispersed in the crystalline sucrose: seed to prepare pel3 ⁇ 4. The pellets were dried under arc until the water content was below 2% to remove (s) -amlodipine besylate containing core 3 ⁇ 4.
  • atorvastatin scabbard, microcrystalline cellulose and mannyul were sieved through No. 20 sieve, and then mixed in a high speed mixer for 10 minutes.
  • the binder solution was prepared by dissolving hydroxyipropylpropylcellulose and citric acid in purified water. Combination of the above While adding the binder solution to the water, the association was completed, then granulated, dried, and granulated to complete the granulation roll. Butylated hydroxyanisole, sodium starch guliconate, and colloidal silicon dioxide, which were previously sieved through a No.
  • Capsule preparation was completed by simultaneously laminating the above-mentioned (S) -amlodipine besylate felhett and atorvastatin Calm tablets on hydroxypropylmethol 3 Cellulose hard capsing using capsule layer electrolysis.
  • Example 1-58 Preparation of (S) -amlodipine-atorvastatin capsule.
  • Example 1-56 It was prepared according to the preparation method of Example 1-56 2) atorvastatin calcium pre-release compartment as shown in Table 1-11.
  • Capsule preparation was completed by simultaneously laminating the above-mentioned (S) -amlodipine granules and atorvastatin 3 ⁇ 4 on No. 1 hydrospecylmethylcellose hard capsule using a capsular layer electrolysis.
  • Example 1-60 (S) Preparation of amlodipine-atorvastatin 3 ⁇ 4 sludge
  • atorvastatin calcium, microcrystalline cellulose and mannrol were sieved through No. 20 sieve, and then mixed in a high speed mixer for 10 minutes. Separately, the combined solution was prepared by dissolving hydroxypropylcellose and citric acid in purified water. Adding the binder solution to the mixture above, after completing the association, granulation, drying, and granulation were completed to complete the granulation. Butane-rated hydroxyanisole, sodium starch glycolate, and roidoid silicon dioxide, which were previously sieved through a No. 35 sieve, were administered to a double cone mixer together with the above granules, and then mixed for about 10 minutes. The sieved sieve was sieved through a No. 35 sieve and administered to a double cone mixer, followed by final mixing for about 4 minutes to complete the atorvasta layered granule production roll.
  • Capsule preparation was completed by simultaneously filling the above (S) -amlodipine 3 ⁇ 43 ⁇ 4 and atorvastatin granules with No. 1 hydroxypropylmethylcell in a hard capsule capsule.
  • nucleated tableting machine (RUD-1: Kilian) as a layer of amlodipine inner core as a composition containing simvastatin, and then using a high coater (SFC-30N, Sejong Machinery, Korea), the components described in Table II-2 and Nucleated tablets were prepared by forming a film coating layer by content.
  • SFC-30N Sejong Machinery, Korea
  • Amlodipine-Simvasta3 ⁇ 4 nucleated tablets were prepared according to 3) Tableting and coating method of Example II-1 with the ingredients and contents shown in Table II-2. 9 000331
  • Amlodipine-simvastatin nucleated tablets were prepared according to 3) tableting and coating method of Example II-1 with the mechanical components and contents of Table II-1.
  • the binding solution prepared by amplifying amlodipine malate and microcrystalline salulose with No. 35 according to the ingredients and contents shown in Table II ⁇ 2 and mixing with a double cone mixer and dissolving hydroxypropylmethylcellose in purified water (1 » wAv) was sprayed to form granules and dried. Again, the granules were coated by spraying Eudragit RS P0 solution (20% wAv) dissolved in a 1: 1 mixture of ethane and methylene chloride. Magnesium stearate was added thereto and mixed in a final double cone mixer.
  • Amlodipine-simvastatin multi-layered tablets were prepared according to the method of Example II-4, 3) Tableting and Coating according to Table II-2.
  • Each of the final compositions prepared above was mixed with a double cone mixer, starch glyconate natto, 3 ⁇ 4-loid silicon dioxide, and mixed with stearic acid magnesium.
  • Amlodipine—simvasta3 ⁇ 4 two-phase matrix tablets were prepared according to 3) postmixing, tableting and coating methods of Example ⁇ -6 with the ingredients and contents of Table ⁇ -2.
  • amlodipine wheat rate and microcrystalline shell
  • Example II-2 Amlodipine-simvastatin biphasic matrix tablets were prepared according to the method of Example II-6 in 3) Post-mixing Tableting and Coating.
  • Example II-9 Amlodipine-Simvastar 3 ⁇ 4 Biphasic Capsule Formulation
  • Example II-8 several contents of the ingredients shown in Table 11-2 and 1) of Example II-8 were prepared according to the preparation method of the amlodipine delayed-release compartment.
  • Example II-ll Preparation of amlodi / 4-simvastatin nucleated tablets
  • hydroxypropyl merlophthalate and acethiated monoglycerides were introduced into a 1: 1 mixture of ethane and chlorene chlorene chloride, and then dissolved as a coating solution (20fa / w).
  • the inner core was prepared by forming a film coating layer using a coater (SFC-30N, Sejong Machinery, South Korea).
  • simvastatin, microcrystalline selreul as agarose, corn starch and lactose as ingredients and contents shown in heunhap was 35 navale S apples and 'high-speed common stapler.
  • hydroxypropylcellulose and citric acid were dissolved in purified water to prepare a binder solution (10% w / w), which was added to a high-speed mixer combined with the main component mixture, and then granulated using an oscillator. It was dried at 60 ° C using a silver water dryer and then re-established as No. 20.
  • Butylated hydration cyanisole, sodium starch glyconate, and colloidal silicon dioxide were mixed therein, and magnesium stearate was added thereto, followed by ⁇ condensation in a double cone mixer.
  • Example I 13 Amtodipine Tablets—Preparation of Capsulfonate Containing Simvastatin Tablets
  • a solution of hydroxypropyl 3 ⁇ 4 cells in a 1: 1 shaker solution of ethanol and methylene chloride was added to a solution of chloropropylphthalate and acetylated monoterminicete as a coating solution (20% w / w).
  • a high coater SFC-30N, Sejong Machinery, Korea.
  • Butylated hydroxyanisole, sodium starch glyconate and colloidal silicon dioxide were mixed, and finally mixed with magnesium stearate in a double cone mixer, and the final mixture was mixed with a rotary tablet press (MRC-30: Sejong, Korea). ) was compressed into tablets.
  • the tablet is a high coater (SFC-30N, Sejong machine, Korea) by fusing a coating solution (201 ⁇ 4 / w) prepared by dissolving and dispersing hydroxy propylose 2910, polyethylene glycol 6000, titanium oxide and talc in 803 ⁇ 4 ethane. ),
  • amlodipine tablets of step 1> and the simvastatin tablets of step 2) were layered onto No. 3 hard 3 ⁇ 4 latin capsules using 3 ⁇ 4 slabs.
  • Example 11-14 Preparation of Amlodipine-Simvastatin Capsulant
  • simvastatin, microcrystalline cells, apples, lactose, and corn starch as No. 35 sieve were mixed with a high speed mixer. Separately, hydrated special propyl sal was dissolved in purified water, and a binder solution (103 ⁇ 4 w / w) was prepared, and the mixture was thrown into a high-speed mixer with a main ingredient mixture, and then granulated using an oscillator. After drying at 60 using was again established as No. 20 sieve. To this was added butylated hydroxyanisole, starch glyconate Na: trium, and colloidal silicon dioxide, and magnesium stearate was added for final mixing in a double cone mixer.
  • amlodipine tablet of step 1) and the simvastatin granules of step 2) were layered onto the hydroxy hard capsules of No. 2 hydroxypropylme 3 ⁇ 4 cells using a capsular bed electric machine.
  • Example 11-15 Amlodipine—simvastatin coated tablet S
  • amlodipine tablets prepared above were administered to a high coater (SFC-30N, Sejong Machinery, Korea), and then first coated with a simvastatin coating solution.
  • Example 11-16 Preparation S of Simvastar3 ⁇ 4 Rapid-Amlodipine Osmotic Nucleated Tablets
  • Example II—11) 3) Simvastatin immediate-amlodipine-invasive nucleated tablets were prepared according to the method of tableting and skipping.
  • Example 11-3 Tablets Amlodithi of Example A— Example II—13 And simvastatin tablets were prepared in the same manner as in Example 11-13, except that the blister packaging was packaged for isochronization instead of simultaneously filling in the capsule, Example 11-18: (S) -Amlodi 3 ⁇ 4 ⁇ Preparation of Vastatin Nucleated Tablets
  • Nucleating tablets were prepared by tableting at a rate of 30 revolutions per minute using a nucleated tableting machine (RUD-1: Kil iai *) as the outer layer of a composition containing amlodipine inner cores.
  • the coating layer composition was dissolved in a solvent to prepare a film coating solution.
  • the nucleated tablet prepared above was administered to a high coater (SFC-30N, Sejong Machinery, Korea) and coated with a film coating solution to complete nucleated tablet preparation. 19 : (S) -Amlodipine-Zombatin Nucleated Tablets
  • Example 11-20 Preparation of (S) -Amlodipine-Simvastatin Capsulant
  • (S) -Ambro dipine tablets prepared by tableting at the speed of 30 revolutions per minute using a rotary tablet press (MRC-30: Sejong) rolls were prepared using a poly (methacrylate, methacrylate) copolymer. Coating with a solution (20taAr) dispersed in purified water to complete the preparation of (S)-amlodipine tablets.
  • Capsule preparation was completed by layering the above (S) -amlodipine tablets and simvastatin tablets on the gelatine hard cap capsules of No. 3 using a capsular layer electrophoresis.
  • Example 11-21 Preparation of (S) -Amlodipine-Simvasta 3 ⁇ 4 capsulant 1) (S) —the ⁇ (tablet) of the amlodied delayed-release compartment
  • sivastatin, microcrystalline cellulose, and manni were sieved through a No. 20 sieve with the ingredients and contents shown in Table ⁇ -4, followed by mixing for 10 minutes in a high speed mixer.
  • the hydroxydemic propyl sal was dissolved in purified water of loose and citric acid to prepare a binding solution (103 ⁇ 4 w / w).
  • the binder was added to the above mixture, granulation, drying, and granulation were completed to complete granulation rolls. It was then administered to a double cone mixer with granules on buhalated hydride cyanosol, starch glycolate, and colloidal silicon dioxide, which were previously sieved through No. 35, and then mixed for about 10 minutes.
  • Magnesium acid was sieved through a No. 35 sieve and poured into a double cone mixer, followed by final mixing for about 4 minutes to complete the preparation of simvastatin layer granules.
  • Example II-23 (S) —Preparation of Amlodipine-Simvastar 3 ⁇ 4 Coated Tablet
  • (S) -Amlodipine and the microcrystalline cell were anointed with No. 35 sieve, mixed with a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glatt).
  • GPCG 1 Glatt
  • a combined solution 103 ⁇ 4 of hydroxypropylcellose was dissolved in purified water, sprayed to form a grove, and dried.
  • Carbomer 71G was added to the granules in a powdered state: 10 minutes in a double cone mixer. After mixing, the stearic acid was passed through a No.
  • simvastar3 ⁇ 4 butylated hydrated cyanuric sol, hydroxypropylmethylshellose 2910, and colloidal silicon oxide were added to a shake solution of ethane and methylene chloride 1: 1. Melt to prepare a simvastatin coating solution,
  • the (S) -amlodipine tablets prepared above were administered to a high coater (SFC-30N, Sejong Machinery, South Korea), followed by primary codontification with a simvastar3 ⁇ 4 coating solution.
  • amlodipine besylate and microcrystalline cell were apologized as No. 35 sieve and mixed with a double cone mixer, and then put into a fluidized bed granulator (GPCG 1: Glatt), and hydroxypropyl separately.
  • Granules were formed by spraying the binding solution prepared by dissolving methyl salose in purified water and drying the granules.
  • Carbomer 71G »powder was added to the granules and stearic acid was added to the final double cone mixer.
  • the final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong) and used as the inner core.
  • atorvastatin chamomile trihydrate, carbohydrate carbonate, microcrystalline cellulose, lactose, pregelatinized starch and lauryl sulfate; "(sodium lauryl sulfate) was appointed in No. 35 and mixed with a high-speed mixer. Loose was dissolved in purified water to prepare a binding solution, which was added together with the main ingredient mixture in a high speed mixer, and then granulated using an oscillator as a No. 20 sieve, dried at 60 X using a silver water dryer, and then re-established as No. 20 sieve. Croscarmellose sodium was added to the mixture, and magnesium stearate was added to the final mixture in a double cone mixer.
  • nucleated tablet tableting machine (RUD ⁇ 1: Ki lian)
  • the composition containing amlodipine inner core and atorvastatin was used as an external insect, followed by rubbing using a high coater (SFC-30N, Sejong Machinery, Korea).
  • a nucleated tablet was prepared by forming a film coating layer with an excess content.
  • Example III-2 Preparation of Amlodiphan-Atorvastated Nucleated Tablets
  • nucleated tablet tableting machine (RUD-1: Ki liai)
  • the composition containing the amlodipine inner core and atorvastatin as an outer layer was compressed into tablets, and then used a high coater (SFC-30N, Sejong Machinery, Korea).
  • Nucleated tablets were prepared by forming a film coat layer with an excess content.
  • Example III-3 Preparation of Amlodipine-Atorvastated Nucleated Tablets
  • nucleated tablet tableting machine (RUD-1: Ki H an)
  • the composition containing amlodipine inner core and atorvastatin as an outer layer was compressed into tablets, and then used a high coater (SFC-30N, Sejong Machinery, Korea). to form a film coating layer components and the content was prepared with a press-coated tablet of example ⁇ -4: amlodipine-atorvastatin multi-layered manufacturing
  • the atorvastared stale anhydrous, calcium carbonate, microcrystalline cellulose, lactose and sodium lauryl sulfate were appled with a No. 35 sieve and mixed with a high speed mixer. .
  • prepare a defect solution by dissolving hydroxypropyl ⁇ loose in purified water add it to a high-speed mixer mixed with a main ingredient mixture, combine it, and granulate it with a No. 20 sieve using an oscillator, and dry it at 60 3 ⁇ 4 using a silver water dryer. Again it was determined as No. 20 body. Croscarmellose sodium was added to this mixture, and stearic acid magnesium was added to the final mixture using a double cone mixer. 3) tableting and coating
  • the tablet was compressed using a multi-layer tablet press (M4C-37T: Sejong). That is, the composition containing atorvastatin was placed in a primary powder feeder, and the composition containing amlodipine was placed in a secondary powder feeder. The tablets were compressed to minimize the infiltration between the layers, and a multi-layered tablet was prepared by forming a film coating layer using the ingredients and contents of Table III-1 as a high coater (SFC-30M, Sejong Machinery, Korea).
  • Example II-5 Preparation of amlodipine-atorvastatin multilayer tablet S
  • atorvastatin calcium strontium pentahydrate, calcium carbonate, microcrystalline 3 ⁇ 4-lose, lactose and sodium lauryl sul fate as apple No. 35 were used as apples.
  • a special liquid was prepared by dissolving the loose-special propyl shell in purified water, putting it in a high-speed mixer with a main component mixture, and then combining it with J1 and then granulating it using an oscillator in a No. 20 sieve. It was dried at and then reconstituted with No. 20 sieve. Croscarmellose sodium was added to the mixture, and magnesium stearate was added thereto, followed by final mixing with a double cone mixer.
  • the tablet was compressed using a multi-layer tablet press (MRC-37T: Sejong). That is, the composition containing Atorvasta 3 ⁇ 4 was placed in a primary powder feeder, and the composition containing amlodipine was placed in a secondary powder feeder. The tablets were compressed to minimize the infiltration between the layers, and a multi-layered tablet was prepared by forming a fill # coating layer using the ingredients and contents of Table II 1-1 as a high coater (SFC-30N, Sejong Machinery, Korea).
  • Example 6-6 Preparation of Amlodipine-Atorvastatin Biphasic Matrix Tablets
  • amlodipine vasylate and microcrystalline shell loose were mixed with apple No. 35 and mixed, and then fed into a high-speed mixer, and co-coated SR30D was added.
  • association was completed, granulated with 20 housings using an oscillator, dried at 60 using a silver water dryer, and then re-established as 20 :.
  • atorvastatin calcium trihydrate, calcium carbonate, microcrystalline salose, lactose, mannose, and crospovidone were appled with No. 35 and mixed with a high-speed mixer.
  • Loose and plysorbate 80 were dissolved in purified water to prepare a binding solution, and the mixture was introduced into a high-speed mixer with the common substance of the above-mentioned ingredients. Then, it was granulated using an oscillator. Dried at I; and back to 20.
  • Each of the final compositions prepared above was mixed with a double cone mixer, and sodium starch glycolate was mixed, and then a magnesium stearate was added thereto, followed by final mixing with a double cone mixer.
  • amlodipine besylate and microcrystalline shell loose were apologized as No. 35 and mixed with a double cone mixer.
  • the above mixture was introduced into a fluidized bed granulator (GPCG 1: Glatt).
  • granules were formed by spraying a binder solution made by dissolving 3 ⁇ 4 cell cellulose in hydrated propyl-metholose in purified water, and drying the granules by spraying 3 ⁇ 4 Eudragit RS P0 solution upon dissolving in granules.
  • GPCG 1 Glatt
  • Example III ⁇ 6-2 It was prepared by the crime prevention of Example III ⁇ 6-2) with the ingredients and contents shown in the following Table III-1
  • Example ⁇ -6-2 In the same manner as in Example ⁇ -6-2), except that atorvastatin calcium anhydride was used instead of atorvastatin chame trihydrate with the ingredients and contents shown in the following Table 111-1.
  • Example III-9 (S) -Amlodipine-Atorvastatin Phase 2 Capsule Preparation
  • Apples of atorvastatin calcium trihydrate, calcium carbonate, microcrystalline cellulose, lactose, pregelatinized starch, and sodium lauryl sulfate were identified as No. 35 as shown in Table III-1.
  • Faro hydroxypropylcellose was dissolved in purified water to prepare a binder, which was added to a high-speed mixer with a mixture of the main ingredients, and then granulated using an oscillator roll. It dried at 60X: using the dryer roll, and it was made up again with No. 20 sieve.
  • atorvastatin strontium pentahydrate, calcium 3 ⁇ 4 acid, microcrystalline 3 ⁇ 4 rate loose, lactose, manni and crospovidone were apologized by No. 35 and mixed with a high speed mixer. Dissolve the propylcellulose and pulley sorbate 80 in purified water to remove the defect solution, add it to the high-speed mixer together with the mixture of the main component, and then unite with the No. 20 sieve. It was dried at 60 ° C. and then sieved to No. 20 sieve again.
  • Steps 1) and 2) were mixed with a Dubucon mixer, sodium starch glycolate was added thereto, followed by mixing with a double cone mixer, and magnesium stearate was added for final mixing.
  • the final mixed mixture was put into a powder feeder and layered into No. 1 3 ⁇ 4 liquor using a 3 ⁇ 4 sul charger.
  • Example II-11 Preparation of Amlodipine-Atorvasta 3 ⁇ 4 Nucleated Tablets
  • a hydroxypropyl methyl salulose phthalate solution and acetylated monoglycerides dissolved in 1: 1 shaker of ethane and methylene chloride were added at a ratio of 100: 1 to a high coater (SFC-30N, Sejong Machinery, Korea) was used to form a film coating layer to remove the inner core.
  • Atorvastatin 3 ⁇ 4 calcium trihydrate, stearic acid, chestnut, microcrystalline gellose, oak starch and lactose were apologized as No. 35 and mixed in a high-speed mixer as shown in the following table II- 2. Dissolve propyl-l-loose and plysorbate 80 in purified water to remove the binding solution, add it to a high-speed mixer with the main component mixture, combine it, and granulate it with the No. 20 sieve using an oscillator. The mixture was dried at 60'C, and then sieved to No. 20. Here, sodium starch glyconate was mixed, and magnesium stearate was added and finally mixed with a double cone mixer.
  • Example II 1-11-2 It was prepared by the method of Example II 1-11-2) with the ingredients and contents shown in Table II 1-2.
  • the tablets were compressed using a multi-layer tablet press (MRC) 37T: Sejong). That is, the composition containing the atorvastatin was placed in a primary powder feeder, and the composition containing amlodisome was transferred to a secondary powder feeder. Tablets were put in a condition that minimizes the intrusion between layers, and a multi-layered tablet was prepared by forming a film coating layer using the ingredients and contents of Table ⁇ -2 as a high coater (SFC-30N, Sejong Machinery, Korea).
  • MRC multi-layer tablet press
  • atorvastatin chamomile trihydrate, carbonate chamomile, and microcrystalline salose were apologized as No. 35 and mixed with a high speed mixer.
  • Dissolve the sorbate 80 in purified water to make a binding solution add it to a high speed mixer with the main component mixture and combine it, and granulate it using the oscillator with No. 20 sieve.
  • Nathium starch glyconate is mixed, and the final mixture is mixed with a stearic acid magnesium bosom with a double cone mixer, and the final mixture is placed into a rotary tablet press (MRC- 33: King Sejong).
  • the tablet is a coating liquid prepared by dissolving and dispersing hydrated propyl cellulose, polystyrene glycol 6000, titanium oxide and talc ethane in. It was coated with a high coater (SFC-30N, Sejong Machinery, Korea).
  • amlodipine tablet of step 1) and the atorvastar 3 ⁇ 4 tablet of step 2) were layered into capsule 3 using a 3 ⁇ 4 sulfoner.
  • Example 111-14 Preparation of Amlodi 3 ⁇ 4 ⁇ atorvastatin 3 ⁇ 4
  • the atorvastatin calcium trihydrate, calcium carbonate, microcrystalline cellulose, lactose, corn starch and lau 3 ⁇ 4 sodium sulfate as apples No. 35 were apples and mixed with a high speed mixer. Separately, hydroxypropyl 3 ⁇ 4 loose was added to purified water to prepare a binding solution, and the mixture was added to a high-speed mixer mixed with the main ingredient mixture. Then, the mixture was granulated using an oscillator with No. 20 sieve and dried at 60 13 using a silver water dryer. Again, No. 20 sieve was added. Here, sodium starch glyconate was mixed, and magnesium stearate was added and finally mixed with a double cone mixer.
  • amlodipine tablet of step 1) and the atorvastatin granules of step 2) were layered onto hydroxypropylmethylcellol.rose hard 3 ⁇ 4 liquor of No. 2 using a capsular bed electric machine.
  • Example 111-15 Preparation of Amlodi 3 ⁇ 4-Atorvasta Coated Tablets
  • Decalum Phosphate 3 ⁇ 4 35 as shown in Table ⁇ -2, mixed with a double cone mixer, and put into a fluidized bed granulator (GPCG 1: Glatt).
  • GPCG 1 Glatt
  • hydroxypropylme 3 ⁇ 4 ⁇ loose was dissolved in purified water and sprayed with a defect solution to form granules and dried.
  • the carbomer 71G was added to the above-mentioned vinegar in powder form, and then magnesium stearate was added thereto.
  • the atorvastatin calcium trihydrate, hydrated propylpropylcellulose was dissolved and dispersed in 803 ⁇ 4 ethane to prepare a pre-release atorvastatin coating solution.
  • amlodipine tablets prepared above were administered to a high coater (SFC-30N, Sejong Machinery, Korea), followed by primary treatment with an atorvastatin coating solution.
  • Example III—16 Preparation of Amlodipine-Atorvastated Seborrheic Nucleated Tablets
  • Example 111-14-2 It was prepared by the method of Example 111-14-2) with the ingredients and contents shown in Table III-3 below.
  • amlodipine delayed-release compartment (tablet) and atorvastatin pre-release compartment (tablet) by the method of Examples III-13-1) and 13-2) as shown in the following components III and III. It was manufactured by packaging to allow simultaneous use in the bolister packaging.
  • the nucleation point was subtracted by the following method with the ingredients and contents listed in the table.
  • Amlodipine besylate, microcrystalline 3 ⁇ 4 rose, anhydrous calcium hydrogen phosphate, pregelatinized starch (Starch 1500G, Colorcon, USA) were apples in No. 35 and mixed for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropylcell was dissolved in purified water roll to form a binding solution, which was then combined, granulated, and dried. After drying, it is established as No. 18 again. The sieved material is placed in a fluidized bed corrugator, and separately 3 ⁇ 4 cellulose acetate: ⁇ 320S (32% acetal group) and saloseacetate S 398-10NF (acetal group 39.8%) are added to ethane and methylene chloride.
  • the melted solution was prepared and the above granules were placed in a fluid bed granulation coater (GPC &-1; Glatt, Germany) and nosed. Coating completed. After that, magnesium stearate was added and mixed for 4 minutes, and the tablets were tableted with a rotary tablet press (MRC-37, Sejong Machinery, Korea) equipped with a 5 mm diameter bias.
  • a fluid bed granulation coater GPC &-1; Glatt, Germany
  • a nucleated tableting machine (RUTK1: i lian, Germany) equipped with 11 mm bias was used as phytavastatin calcium pre-release granules of 1) as the outer layer, and the amlodipine besylate delayed-release tablet of 2) was used as a nuclear tablet. Tableting.
  • Amlodipine besylate, microcrystalline cellulose, anhydrous hydrogen phosphate, and pregelatinized starch were appointed as No. 35 and mixed in a double cone mixer for 5 minutes to prepare a mixture.
  • hydroxypropylcellulose was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it is established as No. 18 again.
  • the granules were placed in a fluidized bed coater, and a solution obtained by dissolving Eudragit RS30D (ETOiiik Degussa, Germany) and triethyl citrate (Vert lus, England) in methylene chloride was prepared. GPCG-1; Glatt, Germany) and coated. After the coating was completed, the stearic acid was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-37: Sejong) equipped with a 5 mm diameter bias to prepare a nuclear tablet.
  • MRC-37 Sej
  • Example IV-3 Preparation of Amlodipine-Pitavata 3 ⁇ 4 nucleated tablets Nucleated tablets were prepared by the following method using the ingredients and contents shown in Table IV-1.
  • Amlodipine tesylate, microcrystalline shellulose, and di-mannee were apples with No. 35 sieve, and mixed with each other for 5 minutes to prepare a mixture.
  • pulley vinylphyllolidon (Koll idon 30, BASF, Germany) was dissolved in purified water and combined, granulated, and dried as a binder. After drying, it is established as No. 18 again.
  • the formulations are placed in a fluidized bed coater and separately placed in 3 ⁇ 4 shell (HERCULES, USA) and poly (methachite, methyl methrate) copolymer (Evonik degussa, USA) with ethane and methylene chloride.
  • Example IV-4 Preparation of Amlodipine-Pipavatatin Nucleated Tablets
  • Nucleated tablets were prepared by the following method, using ingredients and contents set forth in Table IV-1.
  • Amlodichet malate, microcrystalline shellose, anhydrous hydrogen phosphate, and di-mannee were appled in No. 35 and mixed for 5 minutes with a double cone mixer to prepare a mixture. Separately, hydroxypropyl cells were dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it is settled again with No. 18 sieve. Stearic acid magnesium sieved through No. 35 sieve was added to the sieved material, followed by mixing for 4 minutes to prepare amlodipine delayed-release layer granules.
  • Nuclear tablets were prepared by tableting the amlodipine fed granules with a rotary tablet press (MRC—37: Sejong) equipped with a 5 mm diameter punch. Separately, dissolve and disperse arc 3 ⁇ 4-ises (methac3 ⁇ 4 acid copolymer type C, talc, PEG, colloidal silicon dihexaside, sodium bicarbonate, SLS, Colorcon, USA) in purified water to prepare a 3 ⁇ 4 coating solution. Lodi 3 ⁇ 4 tablet was formed as a coater as a high coater (SFC—30N, Sejong machine, Korea) to complete the amlodipine tablet manufacturing roll.
  • a rotary tablet press MRC—37: Sejong
  • arc 3 ⁇ 4-ises metalhac3 ⁇ 4 acid copolymer type C, talc, PEG, colloidal silicon dihexaside, sodium bicarbonate, SLS, Colorcon, USA
  • Lodi 3 ⁇ 4 tablet was formed as a coater as a high
  • Amalodipine malate and microcrystalline mullose were apples in No. 35 and mixed for 5 minutes with a double cone mixer to prepare a mixture.
  • the mixture was added to a double cone mixer and colicoat SR30D (30% suspension of main component pulley vinyl acetate, manufactured by BASF, Germany) was added and granulated using an oscillator. After drying at 60 1C it was again established as No. 18.
  • Magnesium stearate which was sieved through No. 35 sieve, was added to the sieved material, mixed for 4 minutes, and tableted with a rotary tableting machine (M C-37: Sejong) equipped with a 5 mm diameter bias to prepare a nuclear tablet.
  • a coating solution was prepared by dissolving and dispersing hydroxypropylmethelloose phthalate (Shin— etsu, Japan) in ethane and methylene chloride.
  • the above Amlodi 3 ⁇ 4 tablets were coated on a high coater (SFC-30N, Sejong Machinery, Korea). ) To form a coating layer to complete the amlodipine oak preparation.
  • Example IV-6 Preparation of Amlodipine-Pitabatatin Nucleated Tablets
  • Amlodipine besylate, pregelatinized starch, corn starch were apples with No. 35 sieve and mixed for 5 minutes with a sticking mixer to prepare a mixture.
  • hydroxypropylmethyl ⁇ loose was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After construction, it is established as No. 18 body again.
  • the granules are placed in a fluidized bed cobalt, and separately hydrated propylmethylsalose phthalate is added to ethane and methalene chloride, and the above granules are added to a soft layer granulation coater (GPCG-1; Glatt, Germany ) And coated. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a Totari tableting machine (MRC-37: Sejong) equipped with a 5 mm diameter punch to prepare a core tablet.
  • MRC-37 Sejong
  • Example IV-7 Amlodipine-Pitavapatin Two-Phase Matrix Tablet Preparation
  • hydroxypropylsal was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried.
  • the dried product was placed in a fluidized bed coater, and a solution obtained by dissolving Dalo Cell Acetate 320S (acetal group 32%) and Cellulose Acetate 398-10NF10 (acetal group 39.8%) in ethane and methylene chloride was prepared.
  • the above granules were put into a coating of granular layer coating machine (GPCG-1: Glatt, Geramny) and coated.
  • Rix tablets were prepared by the following method, with the components and contents listed in Table IV-1.
  • Amalodipine malate, microcrystalline 3 ⁇ 4 rose, pregelatinized starch were apples in No. 35 sieve and double cone mixed with each other for 5 minutes to prepare a mixture.
  • polyvinylpyridone was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried.
  • the dry granules were placed in a fluidized bed coater and separately prepared by dissolving in Eudragit RS30D and triethylcitrate methylene chloride, and the above granules were placed in a fluidized bed granular coronate (GPCG-1; Glatt, Germany) and coated.
  • Example IV-9 Amlodipine-Pitabatated Biphasic Matrix Tablet ⁇
  • a mixture of S-amlodipine tesylate, microcrystalline salose, and di-manny apples with No. 35 was mixed for 5 minutes with a double cone mixer.
  • the mixture was added to a high-speed mixer, fed with Colicoat SR30D, and then granulated using No. 20 sieve using an oscillator.
  • the roll was dried at 60 1 C using a dry water dryer and re-established into No. 18 sieve.
  • Example IV-10 Amlodi 3 ⁇ 4-Pitabatatin Biphasic Matrix Tablet Preparation
  • Amalodifun besylate, microcrystalline salose, anhydrous calcium hydrogen phosphate, pregelatinized starch were appled in a No. 35 sieve and mixed for 5 minutes with a double cone mixer to prepare a mixture.
  • polyvinylpyridone was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried.
  • Example IV-11 Preparation of Amlodipine-Pitabata Multi-Layered Tablets
  • a multilayer tablet was prepared by the following method.
  • a mixture of pitavasta calder, meta metasilicate aluminate, microcrystalline cellulose, lactose hydrate and apple No. 35 was ap- plied and shaken in a double cone mixer for 5 minutes. Separately, hydroxypropylcellose was dissolved in purified water to prepare a binding solution, which was associated with the main ingredient mixture. When the coalition is received, the granules are granulated using the oscillator 20 and dried at 60 ° C using a hot water dryer. After drying, it was reestablished as No. 18. The starch sodium starch glycolate was mixed, magnesium stearate was added, and the final mixture was mixed with a double cone mixer.
  • Amalodipine besylate, microcrystalline shell loose, 3 ⁇ 4 starch, corn starch were apples with No. 35 sieve and mixed for 5 minutes with a double cone filter to prepare a mixture.
  • pulley vinylpy * ridone was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, the mixture was again sieved to No. 18 sieve.
  • GPCG fluidized bed granulator
  • the above tablet was prepared by preparing a coating solution in which hydroxypropylmethylcellulose 2910, 3 ⁇ 4 Li 3 ⁇ 4lenglycol 6,000, Tal 3, and titanium oxide were dissolved and dispersed in ethane and purified water (SFC-30N: Sejong Machinery, Korea) to form a film coating layer to prepare a tablet in the form of a multi-layered tablet.
  • SFC-30N Sejong Machinery, Korea
  • a multilayer tablet was prepared by the following method.
  • Example IV 13 Preparation of Amrodafine-Pitabata 3 ⁇ 4 Polyplyum Tablets
  • a multilayer tablet was prepared by the following method.
  • S-amlodipine besylate, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, pregelatinized starch were appled with a No. 35 sieve, and mixed with a double cone mixer for 5 minutes to prepare a mixture.
  • the mixture was added to a high-speed mixer, fed with a coat coat SR30D, and then granulated with a No. 20 sieve using an oscillator, which was dried at 60 'C using a silver water dryer, and then back to No. 18 sieve. After adding 3 ⁇ 4 magnesium stearate, the mixture was mixed for 4 minutes.
  • Example IV-11 In the same manner as 3) of Example IV-11, multimodal tablets were prepared by post-mixing, tableting, and coring.
  • Example IV-14 Amlodiphan-Pitabata Multilayer Tablet Preparation
  • Amlodipine besylate, anhydrous calcium hydrogen phosphate, and di-mannney were appointed as No. 35 and mixed with each other for 5 minutes to prepare a mixture.
  • hydroxypropylcell was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it was established as No. 18 body again.
  • the sieved material was placed in a gas-coated coater and separately prepared by dissolving Eudragit RS30D and triethyl citrate in methylene chloride. . After completion of the coating, magnesium stearate was thrown up and mixed for 4 minutes.
  • Example IV The same method as 3) of 11) was followed by post-mixing, tableting, and coating to prepare tablets in the form of a multilayer tablet.
  • Example IV-15 Amlodipine-Pitabatatin Capsule Preparation (Pallet-Granule)
  • a capsulant was prepared by the following method.
  • the sugar spheres were poured into a fluid bed granulator (GPCG1: Glatt), and then separately dissolved in hydrated propyl salulose and pitavastatin kalmos in water, sprayed with 3 ⁇ 4 binding solution to form a pitavastatin-containing pellet. Formed and dried.
  • GPCG1 fluid bed granulator
  • step 1) and 2) was filled in capsul (Seheung capsal, Korea) using a capsul layered electric to complete the preparation of the timed release formulation in the form of capsule.
  • Example IV-17 Preparation of Amlodipine-Pitabatatin Capsul (Pel Osmotic Tablets)
  • capsules were prepared by the following method: 1) Preparation of a prerelease compartment (pitavastatin immediate release pellets)
  • Amlodipine besylate, microcrystalline cellulose, anhydrous hydrogen phosphate, corn starch were apples with No. 35 sieve, and the mixture was prepared for 5 minutes in a double cone mixer. Separately, the hydrophilic cyclofilel was dissolved in purified water to form a binding solution, and then combined, granulated, and dried. Sodium chloride and magnesium stearate were added to the sieved material, followed by mixing for 4 minutes. The mixture was compressed into tablets using a rotary tableting machine (MRC-37: Sejong) equipped with a 5 mm diameter bias.
  • MRC-37 Sejong
  • a solution obtained by dissolving cellulose acetate 320S (acetal group 32%) and chlorocellulose acetate 398-10 F (acetal group 39.8%) in ethane and methylene chloride was prepared and used as a high coater (SFC-30N). : Sejong Machinery, Korea) to form a film coating layer to prepare an osmotic tablet of amlodipine.
  • Amalodipine besylate, microcrystalline cellulose and pregelatinized starch were apples in No. 35 and mixed for 5 minutes using a double cone mixer. Separately, hydroxypropyl ⁇ was dissolved in purified water and combined to form a binding solution. Granulated and dried. When the case is over, clean it again with No. 18 sieve. Magnesium stearate, which was sieved through No. 35 sieve, was added to the sieved material, mixed for 4 minutes, and the mixture was compressed into tablets using a rotary tablet press (MRC-37: Sejong) equipped with a 5 mm diameter bias.
  • MRC-37 Sejong
  • amlodipine tablets were prepared as a high coater (SFC-30N, Sejong Machinery, Korea) by preparing a nose 3 ⁇ 4 solution in which 3 ⁇ 4-ise was dissolved and dispersed in purified water. A coating layer was formed to complete the preparation of amlodipine oak,
  • the capsule was prepared in the following manner.
  • Example IV-20 Amlodipine-Pitabatatin Capsule Manufacture (tablet-tablet)
  • a capsulant was prepared by the following method.
  • the coating solution was prepared by dissolving and dispersing latex, meth methacrylate copolymer (Coiorcon, USA) in purified water to form a coating layer as a high coater (SPC-30N, Sejong Machinery Co., Ltd. Korea). Article was completed.
  • Example IV-21 Preparation of Amlodipine-Pitabatatin Capsule (Granules-Granules)
  • Amlodipine besylate, microcrystalline cellulose, and di-mannee were apples with No. 35 sieve and mixed with each other for 5 minutes to prepare a mixture.
  • Collicoat SR30D was added and associated with the main ingredient mixing mole. After the association, granulation was carried out using an oscillator in No. 20 and dried using a silver water dryer. After drying, it was established as No. 18 body again.
  • a capsul was prepared by the following method.
  • 3 ⁇ 4 knee was prepared by the following method.
  • Amlodipine besylate, anhydrous calcium phosphate and pregelatinized starch were apples in No. 35 sieve and mixed for 5 minutes using a double cone mixer to prepare a mixture. Separately, hydroxypropylsal was dissolved in purified water to form a binding solution, which was then combined, granulated, and dried. After drying, it is settled again with No. 18 sieve. Magnesium stearate, which was sieved through No. 35 sieve, was put into the tablets, mixed for 4 minutes, and the mixture was compressed into tablets using a rotary tablet press (MRC-37: Sejong) equipped with a 5 mm diameter bias.
  • MRC-37 Sejong
  • Capsuljeol was prepared by the following method with the ingredients and contents shown in Table IV-3.
  • Amalodipine besylate, microcrystalline salose, anhydrous hydrogen phosphate, and hydroxypropylmethyl cellulose were apples in No. 35 and mixed for 5 minutes with a double cone filter to prepare a mixture. Purified water was added and combined with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve, and it was dried using a dry roll of silver. After drying, it was again erected with No. 18 sieve. Magnesium stearate was added to the tablets for final mixing, and amlodipine delayed-release granules were prepared.
  • Example IV-25 Preparation of Pitavastar 3 ⁇ 4-Amlodipine Tesylate Blister Packaging Kit A pitavastatin-amlodi 3 ⁇ 4 besylate blister packaging kit was prepared by the following security.
  • Example IV-7 and 1) and the amlodipine besylate delayed-release granules prepared in Example IV—7 2) were prepared using a rotary tablet press (MRC—33: Sejong Machinery, Korea After each tablet is purified using a blister packaging machine (Minister A, Heunga Engineer 3 ⁇ 4), the blister packaging container (silver foil, the same good grade) is used. PVDC, Jeonmin industry) to prepare a blister packaging kit by packaging each tablet for simultaneous use.
  • Nucleated tablets were prepared by the following method, using ingredients and contents set forth in Table V-1.
  • Roschvasta Calcium (MSN, INDIA), Tribasic Chest Phosphate, Microcrystalline Salose (Avicel PHlOl, FMC Biopolymer, USA), Lactose Hydrate (DMV, Germany), Pregelatinized Starch (Starch 1500G, Colorcon, USA) Sieve apologies, and mixed with a double cone mixer (Dasan and Martech, Korea) for 5 minutes in real, prepared a fire.
  • hydroxypropyl salulose HPC-L, Nippon Soda, Japan
  • HPC-L hydroxypropyl salulose
  • Amlodipine besylate, crystalline cellulose, anhydrous calcium hydrogen phosphate, pregelatinized starch (Starch 1500G, Colorcon, USA) were apples in No. 35, and mixed with a double cone mixer for 5 minutes in a real environment to prepare a mixture.
  • hydroxypropylcellose was dissolved in purified water to prepare a conjugated solution, which was associated with the main component mixture. After the coalition, it was granulated with an oscillator using No. 18 sieve, which was dried at using a silver water dryer (HW-C, Samgong, Japan) and erected with No. 20 sieve.
  • 3 ⁇ 4 loose acetate 320S (acetal group 32%) and shellloose acetate 398-10 F (acetal group 39.8%) were dissolved in a mixture of ethane and methylene chloride to prepare a fluidized bed granulation coater with the above formulation. (GPCG-1; Glatt, Germany) and coated. After completion of coating, magnesium stearate was added, mixed for 4 minutes, and equipped with a rotary tablet press (MRC-30, Sejong Pharmatech, Korea) equipped with a 5 mm diameter punch. Tableting gave a nuclear tablet, the titled delayed-release compartment. (3) tableting and coating
  • the tablets were compressed into nuclear tablets. Separately hydroxypropylme 3 ⁇ 43 ⁇ 4rose 2910 (S in-ets, Japan), pulley 3 ⁇ 4 lenglycol 6,000 (BASF, Germany), talc (Luzenac, France), titanium oxide (Tioside Americas, USA) and ethane.
  • Example V-2 Preparation of Amlodipine-Roschvastatin Nucleated Tablets

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Abstract

La présente invention concerne une préparation pharmaceutique contenant un compartiment à libération immédiate et un compartiment à libération prolongée. Le compartiment à libération immédiate comprend un médicament statine à effet hypolipémiant, son isomère ou un sel pharmaceutiquement acceptable utilisé comme principe pharmacologiquement actif et le compartiment à libération prolongée contient une dihydropyridine inhibitrice des canaux calciques, son isomère ou son sel pharmaceutiquement acceptable utilisée comme principe pharmacologiquement actif. La préparation combinée de médicament statine à effet hypolipémiant à libération immédiate et de dihydropyridine inhibitrice des canaux calciques à libération prolongée, est pharmacologiquement, cliniquement, scientifiquement et économiquement plus utile que la préparation simple de chacun de ces médicaments ou qu'une combinaison simple de ces médicaments, dans la prévention et le traitement de maladie cardio-vasculaire, de maladies cardio-pulmonaire, de maladie pulmonaire, ou de maladie rénale, chez des patients atteints de syndrome métabolique et résistants à l'insuline et chez des patients souffrant de diabète ou dont on soupçonne un prédiabète. La préparation de la présente invention permet différentes durées de libération pour le médicament statine à effet hypolipémiant et pour la dihydropyridine inhibitrice des canaux calciques, et empêche ainsi l'antagonisme mutuel et les effets indésirables entre les deux médicaments et permet une administration facile aux patients prenants simultanément les deux médicaments.
PCT/IB2009/000331 2008-02-22 2009-02-23 Préparation pharmaceutique pour traiter une maladie cardio-vasculaire Ceased WO2009127922A2 (fr)

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RU2715771C2 (ru) * 2015-02-27 2020-03-03 ЭКОЛАБ ЮЭсЭй ИНК. Композиции для улучшения нефтеотдачи
US10808165B2 (en) 2016-05-13 2020-10-20 Championx Usa Inc. Corrosion inhibitor compositions and methods of using same
US11203709B2 (en) 2016-06-28 2021-12-21 Championx Usa Inc. Compositions for enhanced oil recovery
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KR101181172B1 (ko) 2012-09-18
WO2009127922A3 (fr) 2009-12-10
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