WO2010021473A2 - Pharmaceutical formulation - Google Patents

Abstract

The present invention provides a pharmaceutical formulation for mornings comprising: an immediate release compartment containing a dihydropyridine calcium channel blocker as a pharmacologically active ingredient, and a sustained release compartment containing an HMG-CoA reductase inhibitor as a pharmacologically active ingredient. The formulation of the present invention reduces side effects caused by interaction between drugs and is effective in treating and preventing hypertension and hyperlipidemia and cardiovascular diseases or metabolic syndrome caused thereby due to pharmacological synergism. Also, the formulation can enhance drug compliance.

Description

Pharmaceutical preparations

The present invention relates to a morning pharmaceutical formulation containing a dihydropyridine calcium channel blocker and an HMG-CoA reductase inhibitor.

Hypertension often coexists with coronary artery disease and is a major cause of heart disease. The expression of these risk factors is potentially due to the joint mechanism. Atherosclerosis due to hypertension and hyperlipidemia is a vicious cycle that worsens in parallel. As blood pressure rises, arteriosclerosis worsens, and when arteriosclerosis worsens, blood pressure rises and worsens each other. These symptoms are also considered as a serious risk factor for developing cardiovascular disease. For example, hypercholesterolemia and hyperlipidemia are involved in the early development of atherosclerosis, characterized by an uneven distribution of lipid deposits in arteries including coronary, carotid and peripheral arteries. Irregular lipid distribution is also a hallmark of coronary artery injury, cardiovascular disease and adversely affects left ventricular hypertrophy, a complication of diabetes, sex, smoking, and hypertension [Wilson et al., Am. J. Cardiol., Vol. 59 (14). (1987), p. 91G-94G]. Therefore, it is known that it is advantageous for patients to have a combination treatment to treat these symptoms, and it has become a clinically basic treatment guideline.

As a combination therapy for improving cardiovascular disease and metabolic syndrome caused by hypertension and hyperlipidemia, a combination therapy containing an HMG-CoA reductase inhibitor and a dihydropyridine-based calcium channel blocker has already been proposed.

According to Kramsch et al., Journal of Human Hypertension (1995) (Suppl. 1), 53-59, a combination of calcium channel blockers, amlodipine and lipid lowering agents, for the prevention and prevention of atherosclerosis, The effect is shown. Jukema et al., Arteriosclerosis, Thrombosis and Vascular Biology, vol. 16, No. 3, 1996, 425-430] also demonstrate that synergistic effects can be obtained by combining calcium channel blockers with lipid lowering agents. Orekhov et al., Int J Cardiol (1997) 62: S67-77, disclose the use of amlodipine in combination with a lipid lowering agent (lovastatin) for the treatment of atherosclerosis.

In atherosclerotic patients, the NO production system (eNOs) in the vessel wall is abnormal, which leads to a decrease in NO production resulting in increased blood pressure. While common HMG-CoA reductase inhibitors limit NO release, amlodipine has the function of promoting NO release. However, the combination of amlodipine and atorvastatin has a much more synergistic effect on NO. In other words, the complex administration of amlodipine and atorvastatin is a complex prescription of the lipid lowering agent atorvastatin to help the effect of amlodipine, a calcium channel blocker, due to the synergistic effect on eNOS in the vessel wall. [The American Journal of Medicine, Vol 118 (12A) , 54S-61S].

As described above, it is known that the combination and combination administration of HMG-CoA reductase inhibitor and dihydropyridine-based calcium channel blocker are advantageous in the treatment of cardiovascular diseases, but studies on the combination preparations have not been conducted sufficiently.

The present inventors have completed the present invention as a result of researches to develop an effective agent for the prevention and treatment of hypertension and hyperlipidemia and thereby cardiovascular disease or metabolic syndrome.

The problem to be solved by the present invention is to minimize side effects by minimizing the interaction between drugs, to exhibit a synergistic effect on the treatment and prevention of hypertension, hyperlipidemia and the resulting cardiovascular disease and metabolic syndrome, and can improve the medication compliance It is to provide a combination formulation.

The present invention provides a morning pharmaceutical formulation comprising a pre-release compartment comprising a dihydropyridine-based calcium channel blocker as a pharmacologically active ingredient, and a delayed-release compartment comprising a HMG-CoA reductase inhibitor as a pharmacologically active ingredient. to provide.

The dihydropyridine calcium channel blocker of the pre-release compartment in the preparation of the present invention is a rapid release, preferably 80% of the total amount of dihydropyridine calcium channel blocker within 1 hour after the release of the dihydropyridine calcium channel blocker. An anomaly is released, so that the desired drug can be produced quickly.

The HMG-CoA reductase inhibitor of the delayed-release compartment in the formulation of the present invention is released after a delay time, i.e., 6 to 12 hours after release of the dihydropyridine-based calcium channel blocker, preferably 9 hours after release. More preferably, the HMG-CoA reductase inhibitor is released within 20% from 6 hours to 9 hours after the release of the dihydropyridine calcium channel blocker, and at least 75% within 2 hours thereafter.

Dihydropyridine-based calcium channel blockers release 80% within 1 hour of oral administration, and are absorbed in the small intestine before HMG-CoA reductase inhibitors to block calcium inflow into vascular smooth muscle, leading to peripheral artery dilation and lowering blood pressure . In addition, HMG-CoA reductase inhibitor is released after a delay time (6 to 12 hours) after the release of the dihydropyridine calcium channel blocker and enters the liver. Therefore, the HMG-CoA reductase inhibitor is activated by cytochrome P450 3A4 without interfering with the calcium channel blocker. It is metabolized to fully perform the lipid lowering action in the liver.

The preparation of the present invention may include 1 to 400 mg of the dihydropyridine-based calcium channel blocker, and 1 to 160 mg of the HMG-CoA reductase inhibitor, and the dihydropyridine-based calcium channel blocker and HMG-CoA reductase inhibitor dose is based on a daily adult (65-75 kg adult male).

The formulation of the present invention is for morning use. That is, by taking the preparation of the present invention once a day in the morning time (7 to 10 am), the pre-release dihydropyridine calcium channel blocker can strongly lower the blood pressure during the day and delayed release. The HMG-CoA reductase inhibitor may act early in the evening to effectively perform the lipid-lowering action of the HMG-CoA reductase inhibitor even with a single dose.

Each compartment of the formulation of the present invention will be described in more detail as follows.

1.Preventive compartment

Pre-release compartment refers to the compartment in which the active ingredient is first released in comparison with the delayed-release compartment in the pharmaceutical formulation of the present invention, and may further include a pharmaceutically acceptable additive as necessary in addition to the pharmacologically active ingredient. .

(1) pharmacologically active ingredients

The pharmacologically active component of the prior-release compartment is a dihydropyridine calcium channel blocker. The dihydropyridine calcium channel blocker is an antihypertensive drug that lowers blood pressure by blocking calcium inflow into vascular smooth muscle and inducing peripheral artery dilation. , Lercanidipine, lassidipine, felodipine, nifedipine, benidipine, vanidipine, silnidipine, manidipine, nicardipine, isradipine, nisoldipine, nimodipine, and / or nitrendipine, and the like. Isomers thereof, and / or pharmaceutically acceptable salts.

A preferred example of the dihydropyridine-based calcium channel blocker is amlodipine. Amlodipine has the chemical name 3-ethyl-5-methyl-2 (2-aminoethoxymethyl) -4- (2-chloro phenyl) -1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate It is a very useful daily 24 hour sustained calcium channel blocker with a half-life of 30 to 50 hours and very active over a long period of time, and it lowers blood pressure by blocking peripheral calcium inflow and inducing peripheral artery expansion. It is a high blood pressure drug and is effective for angina due to convulsive vasoconstriction.

Amlodipine reduces myocardial ischemia by reducing Total Peripheral Resistance in patients with severe angina, or reduces myocardial oxygen demand at any particular level of exercise by reducing the rate pressure product after ingestion. . In patients with vasospasm angina, amlodipine blocks contraction and restores myocardial oxygen supply. Amlodipine is known to increase myocardial oxygen supply by dilatating coronary arteries.

In addition, amlodipine itself is an active form, and when it enters the liver, it is partially metabolized and inactivated by cytochrome P450 3A4 already present. Amlodipine is 60-90% active and maintains its highest blood concentration at 6-12 hours and inhibits the production of cytochrome P450 3A4.

(2) pharmaceutically acceptable additives

The formulations of the present invention may contain pharmaceutically acceptable additives such as diluents, binders, disintegrants, lubricants, stabilizers, coloring agents, flavoring agents, and the like, which do not impair the effects of the present invention. It may be formulated using additionally within the range not to be, the content thereof may be 1 to 70 parts by weight based on 1 part by weight of the dihydropyridine-based calcium channel blocker.

The diluent is starch, microcrystalline cellulose, lactose, sucrose, sugar seed, glucose, mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, and / or dicalcium phosphate. The binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, and / or Gelatin and the like. The disintegrant is a starch or modified starch, such as sodium starch glycolate, corn starch, potato starch, and / or pregelatinized starch, bentonite, montmorillonite, and / or clay microcrystalline cellulose such as vegum, hydroxypropyl Cross-linked celluloses such as sodium cellulose alginate and / or alginate such as cellulose and / or carboxymethyl cellulose such as alginate croscarmellose, guar gum, and / or gum crospovidone such as xanthan gum Effervescent agents, such as crosslinked polymer sodium bicarbonate and / or a citric acid, etc. can be mixed and used. The lubricants include talc, magnesium stearate and / or alkaline earth metal salts, zinc, lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, and or polyethylene glycol 3350, 4000 , 6000, and the like, ascorbic acid, citric acid, butylated hydroxy anisole, butylhydroxy toluene, propyl gallate and / or tocopherol derivatives and the like. In addition, a pharmaceutically acceptable additive may be selected and used as various additives selected from colorants and fragrances.

The scope of the present invention is not limited to the use of the additives, and the additives may contain a conventional range of doses by the choice of those skilled in the art.

2. Delayed release block

In the present invention, the delayed-release compartment refers to a compartment in which the active ingredient is released after a certain time of release of the prior-release compartment active ingredient. The delayed-release compartment comprises (1) a pharmacologically active ingredient and (2-1) a release control substance or (2-2) an osmotic pressure regulator and a semipermeable membrane coating base, and (3) a pharmaceutically acceptable It may further include an additive.

(1) pharmacologically active ingredients

The pharmacologically active component of the delayed-release compartment is the HMG-CoA reductase inhibitor, which is a mevalonate by HMG-CoA, its reductase, 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA). It is a drug that suppresses the reduction to reduce the production of cholesterol in the liver and lower the low density lipoprotein cholesterol (LDL-Cholesterol), the HMG-CoA reductase inhibitor is atorvastatin, lovastatin, simvastatin, pitavastatin, rosuvastatin, Fluvastatin, and / or pravastatin, and the like, and isomers thereof and / or pharmaceutically acceptable salts.

Preferred examples of the HMG-CoA reductase inhibitor is atorvastatin, atorvastatin calcium is HMG-CoA is a 3-hydroxy-3-methyl glutaryl-coenzyme (HMG-CoA) is the reductase It is strongly inhibited from reducing to balonate, thereby suppressing the production of cholesterol in the liver and lowering the low density lipoprotein cholesterol (LDL-C). These effects are excellent for the treatment of complex hyperlipidemia, the treatment of clinically normal atherosclerosis, and prevention of its progression. Moreover, the action of reducing the levels of low density lipoprotein cholesterol is very effective in coronary heart disease.

In particular, low doses of atorvastatin reduce inflammation in patients with angina and low cholesterol levels.

Since lipid synthesis in the liver becomes vigorous after early dinner, HMG-CoA reductase inhibitors have been recommended for early evening use.

Atorvastatin is metabolized by the liver enzyme cytochrome P450 3A4 and excreted from the liver while acting in the liver. Therefore, atorvastatin, when used in combination with drugs that inhibit the cytochrome P450 3A4 enzyme, inhibits liver metabolism of atorvastatin, leading to increased blood levels, which can cause serious side effects such as myolysis.

 (2-1) Release Control Substances

The delayed-release compartment in the pharmaceutical formulation of the present invention comprises a release controlling substance, wherein the release controlling substance of the present formulation is selected from, for example, enteric polymers, water insoluble polymers, hydrophobic compounds, hydrophilic polymers, and mixtures thereof. At least one, preferably at least one selected from water-insoluble polymers and enteric polymers. The release controlling substance of the preparation contains 0.1 to 50 parts by weight, preferably 0.3 to 30 parts by weight, based on 1 part by weight of the HMG-CoA reductase inhibitor. If the release controlling substance is less than the above range, it may be difficult to have a sufficient delay time, and if it exceeds the above range, drug release may be excessively delayed to obtain a significant clinical effect.

The enteric polymer is insoluble or stable under acidic conditions, and refers to a polymer that is dissolved or decomposed under specific pH conditions of pH 5 or more. The enteric polymers usable in the present invention are, for example, polyvinylacetate phthalate, methacrylic acid copolymer, hydroxypropylmethyl cellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, poly (methacrylic acid-methylmeth) Acrylate) copolymer and poly (methacrylate-ethyl acrylate) copolymer, and mixtures thereof. Preferred examples of the enteric polymer are methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, poly (methacrylate-methylmethacrylate) copolymer or poly (methacrylate-ethyl acrylate) copolymer.

The water insoluble polymer refers to a polymer that is not soluble in pharmaceutically acceptable water that controls the release of the drug. The water insoluble polymers usable in the present invention are, for example, polyvinyl acetate, polymethacrylate copolymers, poly (ethylacrylate-methyl methacrylate) copolymers, poly (ethylacrylate-methyl methacrylate-trimethyl Aminoethyl methacrylate) copolymer, ethyl cellulose, cellulose acetate, and mixtures thereof, and at least one selected from polyvinyl acetate, ethyl cellulose, cellulose acetate, or poly (ethylacrylate-methyl). Methacrylate-trimethylaminoethyl methacrylate) copolymer.

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

The hydrophilic polymer refers to a polymeric material that is dissolved in pharmaceutically acceptable water that controls the release of the drug. Examples of hydrophilic polymers usable in the present invention include 1 selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl copolymers, and mixtures thereof. More than species. The saccharides include dextrins, polydextrins, dextran, pectin and pectin derivatives, alginates, polygalacturonic acids, xylans, arabinoxylans, arabinogalactans, starches, hydroxypropylstarches, amylose, amylopectins, and their The at least one cellulose derivative selected from the mixtures is hydroxypropylmethyl cellulose (or hypromellose), hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxy The at least one gum selected from propyl methylcellulose acetate succinate, hydroxyethylmethylcellulose, and mixtures thereof is guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, xanthan gum, And at least one protein selected from a mixture thereof The at least one polyvinyl derivative selected from gelatin, casein, zein, and mixtures thereof is at least one hydrophilic polymethacryl selected from polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate, and mixtures thereof. The rate copolymer is poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer (e.g. Eudragit E, Evonik, Germany), poly (methacrylate-methyl At least one polyethylene derivative selected from methacrylate) copolymer, poly (methacrylate-ethylacrylate) copolymer, and mixtures thereof, and at least one carboxyvinyl copolymer selected from polyethylene glycol, polyethylene oxide, and mixtures thereof. Is a carbomer. Preferred examples of the hydrophilic polymer are poly (butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate) copolymer, hydroxypropylmethylcellulose, poly (methacrylate-methylmethacrylate) Copolymer or poly (methacrylic acid-ethylacrylate) copolymer.

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

The delayed-release compartment of the present invention includes an osmotic pressure regulator and may be a compartment coated with a semipermeable membrane coating base.

The osmotic pressure control agent is at least one selected from the group consisting of, for example, magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, lithium sulfate, sodium sulfate, and mixtures thereof.

The semi-permeable membrane coating base refers to a material used to form a film that allows some components to pass but not others. In the present invention, the semipermeable membrane coating base may use the above-mentioned water-insoluble polymer.

The semipermeable membrane coating base in the present invention is, for example, polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate, methyl methacrylate) copolymer, poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate Late chloride) copolymer, ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose dicylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate and mixtures thereof The above is mentioned.

(3) pharmaceutically acceptable additives

The formulations of the present invention are diluents, binders, and borates other than those mentioned as pharmaceutically acceptable (2-1) release controlling substances and (2-2) osmotic pressure regulators and semipermeable membrane coating agents within the scope of not impairing the effects of the present invention. Commonly used additives such as releases, lubricants, stabilizers, colorants, and / or fragrances can be formulated further using within a range not departing from the nature of delayed release.

The diluent is starch, microcrystalline cellulose, lactose, calcium carbonate, sucrose, sugar seed, ascorbic acid, citric acid, glucose, pregelatinized starch, di-mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, potassium ratio Carbonate, magnesium oxide or anhydrous calcium phosphate. The binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone, gelatin, and the like. to be. The disintegrant is starch, such as sodium starch glyconate, corn starch, potato starch or pregelatinized starch, or clay microcrystalline cellulose, hydroxypropyl cellulose or carboxy such as modified starch bentonite, montmorillonite, or veegum. Cross-linked cellulose such as sodium cellulose such as methyl cellulose, alginate such as alginate, croscarmellose sodium such as guar gum, cross-linked polymer such as xanthan gum, cross-linked polymer insoluble ions such as crospovidone One or more selected from an effervescent agent such as exchange resin sodium bicarbonate or citric acid. The lubricant is talc, magnesium stearate, alkaline earth metal salts of stearate, zinc, lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, or polyethylene glycols. The stabilizer is butylated hydroxy anisole, butylhydroxy toluene, propyl gallate or tocopherol derivatives and the like. In addition, a pharmaceutically acceptable additive may be selected and used as various additives selected from colorants and fragrances.

In the formulation of the present invention, the pre-release compartment is mixed with a pharmaceutically acceptable additive in addition to the dihydropyridine-based calcium channel blocker, a mixture, granules, It may be prepared in the form of pellets or tablets. When the fluidity of the dihydropyridine-based calcium channel blocker mixture is not directly compressed, granulation may be performed by pressing, granulating, and sizing.

In addition, the delayed-release compartment in the formulation of the present invention may be used to prepare oral administration agents such as mixing, associating, drying, granulating or coating a release controlling substance in addition to an HMG-CoA reductase inhibitor, and a pharmaceutically acceptable additive as necessary. It can be prepared in the form of a mixture, granules, pellets, or tablets through conventional procedures.

The formulations of the present invention can be formulated using additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, etc., within the scope of not impairing the effects of the present invention in addition to the pre-release and delayed-release compartments prepared in the respective formulations. Can be.

Additives such as diluents, binders, disintegrants, lubricants, etc. may be suitably used depending on the purpose used in the formulation of the pre-release compartment, or delayed-release compartment, but is not limited thereto.

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

The formulation of the present invention is a tabletting by selectively mixing additives such as granules constituting the pre-release compartment and granules constituting the delayed-release compartment and the like to have a pre-release compartment and a delayed-release compartment in a single tablet, and thus the active ingredient of each compartment. This may be in the form of uncoated tablets will be eluted separately to show the respective effects.

The formulation of the present invention may be in the form of a two-phase matrix tablet obtained by tableting after the delayed-release compartment and the prior-release compartment are uniformly mixed.

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

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

In addition, the pharmaceutical formulation of the present invention may be in the form of a nucleus tablet consisting of an inner layer consisting of a delayed-release compartment and an outer layer consisting of a prior-release compartment surrounding the outer surface of the inner core tablet. The nucleated tablet may be an osmotic nucleated tablet, and the osmotic nucleated tablet contains an osmotic pressure-controlling agent inside the tablet for delayed release, followed by compression, and then coated the surface of the tablet with a semipermeable membrane coating agent to form an inner core. It is a dosage form in which the granules constituting the pre-release compartment are mixed with pharmaceutical additives and compressed into an outer layer to have a delayed-release inner core and the surface of the inner core is surrounded by a pre-release layer.

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

The tablet consisting of the delayed-release compartment of the capsule may include an osmotic pressure-controlling agent within the tablet and an osmotic coated tablet having a semipermeable membrane coating base on the surface of the tablet.

The base of the capsule may be one selected from gelatin, succinate gelatin, or hydroxypropylmethylcellulose, or a mixture thereof.

In addition, the pharmaceutical formulation of the present invention may be in the form of a kit comprising a delayed-release compartment, and a prior-release compartment, specifically, the kit comprises (a) a prior-release compartment (b) a delayed-release compartment and (c) the It may consist of a container for filling the pre-release compartment and the delayed-release compartment. The kit prepares the particles, granules, pellets, or tablets constituting the prerelease compartment, and separately prepares the granules, pellets, or tablets constituting the delayed release compartment, and fills them together with foil, blisters, bottles, and the like. It can be prepared in a form that can be taken at the same time.

The formulations of the present invention may further form a coating layer on the exterior of the delayed release compartment and / or the prior release compartment. In other words, the surface of the particles, granules, pellets, or tablets consisting of delayed-release compartments and / or pre-release compartments may be coated for the purpose of release control or formulation stability.

In addition, the formulation according to the present invention is also provided in a state such as uncoated tablets without additional coating, but may be in the form of a coated tablet containing a coating layer further by forming a coating layer on the outside of the formulation, if necessary. . By forming the coating layer, it is possible to further ensure the stability of the active ingredient.

The method of forming the coating layer may be appropriately selected by a person skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer, a method such as a fluidized bed coating method, a fan coating method may be applied, and preferably Fan coating can be applied.

The coating layer may be formed by using a coating agent, a coating aid, or a mixture thereof. For example, the coating agent may be a cellulose derivative such as hydroxypropylmethylcellulose, hydroxypropylcellulose, sugar derivatives, polyvinyl derivatives, waxes, or fatty acids. , Gelatin, or a mixture thereof, and the like, and a coating aid may be polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, talc, diethyl phthalate, triethyl citrate or a mixture thereof.

The coating layer may be included in the range of 0.5 to 15% by weight (% w / w) based on the total weight of the tablet.

If it is less than 0.5% by weight, it may be difficult to secure stability depending on the protection and formulation of the product, and when it exceeds 15% by weight, it may affect the release pattern of the active ingredient.

Since the preparation of the present invention is for morning use, the preparation of the present invention is taken once a day in the morning time period (7 to 10 am) to strongly increase the blood pressure during the day by the pre-release dihydropyridine calcium channel blocker. It can be reduced, and HMG-CoA reductase inhibitor is released and enters the liver after a delay time (for example, 6 to 12 hours) after the release of the dihydropyridine calcium channel blocker. It is metabolized into active form by P450 3A4 without any action, thereby performing a hypolipidemic effect.

Dihydropyridine-based calcium channel blockers, such as amlodipine, have a duration of action of 24 hours and 6-12 hours after administration, and active forms reach the highest blood levels. This is especially effective for people whose daytime blood pressure rises are a problem.

Amlodipine, itself in active form, can inhibit P450 3A4 because it is partially metabolized and inactivated by cytochrome P450 3A4 already present, and atorvastatin is metabolized by cytochrome P450 3A4 and acts in the liver. Since it is excreted while being administered in combination with a drug that inhibits the cytochrome P450 3A4 enzyme, the liver metabolism of atorvastatin is inhibited to increase blood concentration, which may cause side effects such as muscle lysis. Such side effects can be avoided by using the formulation of the present invention.

In addition, since lipid synthesis in the liver becomes vigorous after early dinner, HMG-CoA reductase inhibitors have been recommended to be taken early in the evening. Therefore, if the formulation of the present invention is administered in the morning, the HMG-CoA reductase inhibitor may act in the early evening. It is possible to effectively perform the lipid lowering action of the HMG-CoA reductase inhibitor even with a single dose.

In addition, the formulation of the present invention can not only avoid side effects, but also excellent in compliance with medication because it is for morning use. This is the most common cause of non-compliance. Oblivion is the most likely to be forgotten. Lunch (44%), dinner (22%), before bedtime (6%), and morning (5%) are investigated in the following order. Patients' Use of Drugs and Problem Analysis and Countermeasure Direction: 2005: Shin Hyun-Taek], because it is the best way to take medication once a day in the morning.

In other words, the formulation of the present invention applies the principle of chronotherapy and the principle of Xenobiotics of the drug to the expression of pharmacological action of each of the complex components to control release in the body at a specific rate to achieve the most ideal effect upon absorption in the body. It can be, because the drug compliance is excellent, effectively express the drug.

The present invention provides a method for treating hypertension and hyperlipidemia, or a cardiovascular disease or metabolic syndrome, comprising administering the agent of the present invention to a mammal including a human once a day in the morning.

By the treatment method of administering the preparation of the present invention once a day, especially in the morning hours (7 am to 10 am), hypertension and hyperlipidemia, and the resulting cardiovascular disease or metabolic syndrome can be treated and prevented without side effects.

The cardiovascular disease includes hypertension in addition to hypertension.

Pharmaceutical formulations of the present invention may be prepared by any suitable method in the art, for example, with reference to methods disclosed in Chronotherapeutics (2003, Peter Redfern, PhP), Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA, and the like. It can be formulated preferably according to a disease or a component, and can be manufactured by the method containing the following steps specifically ,.

In the first step, the active ingredient of the delayed-release compartment is mixed with, or combined with, one or two release controlling substances selected from an enteric polymer, a water insoluble polymer, a hydrophobic compound, and a hydrophilic polymer, and a conventional additive used in pharmaceuticals. Delayed-release granules or tablets are obtained through drying, granulation or coating, and tableting, or the active ingredient is semipermeable after mixing, associating, drying, granulating or tableting by administering an osmotic agent and a conventional additive which is used pharmaceutically. It is a step of obtaining delayed-release granules or tablets by coating with a membrane coating base.

The second step involves the administration of the active ingredient of the prior-release compartment and the conventionally acceptable pharmaceutically acceptable additives to produce the oral solids through mixing, coalescing, drying, granulating or coating, and tableting to produce oral solids. Obtaining extruded granules or tablets.

In the third step, the granules or tablets obtained in the first step and the second step are mixed with pharmaceutical excipients, tableted or filled to obtain a preparation for oral administration.

The first step and the second step may be reversed or executed simultaneously.

The pharmaceutical formulation of the present invention may be prepared by the above process, and the formulation method of the third step is described in more detail as follows, but is not limited thereto.

[A] Preparation of two-phase matrix tablet

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

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

The coated tablets or granules obtained in the first step are additionally coated as they are or with a release control material, dried, and then compressed into a predetermined amount to prepare tablets as they are or additionally coated, and then the active ingredients of the pre-release compartments are separately coated with a water-soluble film coating solution. By dissolving and dispersing in a coating, the tablet outer layer obtained in step 1 can be used to prepare an orally administered film coating tablet containing the active ingredient in a film coating.

Preparation of multi-layered tablets

The granules obtained in the first step as they are or are additionally coated and dried with a release controlling substance and the granules obtained in the second step can be prepared in double tablets using a tablet press. Coated multi-layered tablets can be prepared by formulating or coating triple or more multi-layered tablets by adding a release aid layer as needed, or by formulation.

[D] Preparation of Nucleated Tablets

The coated tablet or granules obtained in the first step are additionally coated as it is or with a release control material, dried, and then compressed into a predetermined amount to be coated as it is or additionally to the inner core, followed by a nucleated tableting machine together with the granules obtained in the second step. The coated nucleated tablet may be prepared by preparing or coating a nucleated tablet having a form in which a pre-release layer is enclosed on the surface of the inner core.

[E] Preparation of Capsules (Granules or Tablets)

The granules obtained in the first step are additionally coated as is or with a release controlling substance, and the dried granules or tablets and the granules or tablets obtained in the second step are placed in a capsule charger and filled into capsules of a predetermined size by an effective amount of each active ingredient in an appropriate amount. Can be prepared.

[Bar] Preparation of capsules (pellets)

(1) Dissolve or suspend the active ingredients in the delayed-release compartments, controlled release substances and, if necessary, pharmaceutically acceptable additives in water, organic solvents or mixed solvents, coating them on sugar granules, drying them as necessary. After dissolving in water, organic solvent or mixed solvent using release control material alone or two or more, coating, drying, mixing with granules obtained in the second step or tablets obtained in the third step, and then filling the capsule with a capsule filler Capsules can be prepared.

(2) Activity of delayed-release compartment as described in (1) above after coating and drying the sugar spherical granules by dissolving or suspending the active ingredient and pharmaceutically acceptable additive in the pre-release compartment in water, organic solvent or mixed solvent. Capsules may be prepared by mixing the release control pellets containing the ingredients and filling the capsules with a capsule filling machine.

[Product] Kit Preparation

The delayed-release compartment preparation (beta-adrenergic blocker-containing formulation) obtained in the first stage and the prior-release compartment preparation (angiotensin-2 receptor antagonist-containing formulation) obtained in the second stage are filled together with a foil, blister, bottle, etc. It can be made into a kit that can be taken at the same time.

The human dosage of the formulation of the present invention is appropriately selected depending on the absorption rate, inactivation rate and excretion rate of the active ingredient in the body, the age, sex and condition of the patient, but in general, the daily dihydropyridine calcium channel blocker By containing 1 to 400mg in the formulation and administering HMG-CoA reductase inhibitor to include 1 to 160mg in the formulation, it is possible to exhibit the treatment and prophylaxis of hypertension, hyperlipidemia and the like.

The pharmaceutical preparations of the present invention can reduce side effects due to drug interactions, and are effective in the treatment and prevention of hypertension, hyperlipidemia and consequent cardiovascular diseases or metabolic syndrome due to pharmacological effect synergism, and can improve medication compliance. .

1 is a graph showing a comparative dissolution curve of the amlodipine / atorvastatin nucleated tablet of Example 5 and the reference drug.

Figure 2 is a graph showing the comparative dissolution curves of the silinidipine / rosuvastatin biphasic matrix tablets and the reference drug of Example 12.

Figure 3 is a graph showing a comparative dissolution curve of the amlodipine / fluvastatin capsules of Example 25 and the reference drug.

Figure 4 is a graph showing the atorvastatin elution pattern in Examples 3, 5, 6 formulations.

Figure 5 is a graph showing the atorvastatin elution pattern in Examples 21, 27 formulation.

Figure 6 is a blood concentration test result of Experimental Example 6, a graph showing the blood concentration-time profile of amlodipine in the formulation of Example 5.

7 is a blood concentration test result of Experimental Example 6, which is a graph showing the blood concentration-time profile of atorvastatin in the formulation of Example 5.

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

Example 1 Preparation of Nucleated Tablets

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

1) Preparation of pre-release compartment (dihydropyridine calcium channel blocker immediate release granule)

Amlodipine besylate (Cadila, India), microcrystalline cellulose (AvicelPH, FMC Biopolymer, USA), anhydrous calcium phosphate (RHODIA, USA) were attached and apologized as No. 35, and double cone mixer (MC / MIX-60, Ilsung Industrial, Korea) ) Was mixed for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose (HPC-L, Nippon Soda, Japan) was dissolved in purified water to prepare a binder solution (10% w / w), which was then mixed with a main ingredient mixture and a high speed mixer (Lab. Pharma mixer P, Diosna, Germany). United after input. After the association, granulation was carried out using an oscillator (AR402, ERWEKA, Germany) with No. 18 and dried at 60 ° C. using a hot water dryer (H-W-C, Samgye, Japan). After drying, it was established as No. 20 sieve again. The starch was mixed with sodium starch glyconate (Primojel, DMV, Germany), and magnesium stearate (Nitika Chemical, India) was added and mixed in a double cone mixer.

2) Preparation of delayed-release compartments (delayed-release tablets of HMG-CoA reductase inhibitors)

Atorvastatin calcium trihydrate (Dr. Reddy's, India), microcrystalline cellulose, calcium carbonate (NITTO FUNKA, Japan), crosslinked polyvinylpyrrolidone (Crospovidone, BASF, Germany), croscarmellose sodium (Acdisol, FMC Biopolymer, USA), pregelatinized starch (Starch 1500G, Colorcon, USA), di-mannitol (Pearlitol 200SD, Roquette, France), lauryl sulfate sodium (Miwon, Korea) apologize 35, and double cone mixer 5 Mixing was performed to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again. The sieved material is placed in a fluidized bed coater (GPCG-1, Glatt, Germany), separately cellulose acetate 320S (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate 398NF10 (acetal group 39.8%) (Eastman Chemical Company, USA ) Was dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granulated material was put into a fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate (Nitika Chemical, India) was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.

3) tableting and coating

A nucleophilic tableting machine equipped with a 12 mm punch (RUD-1: Kilian, Germany) was used as the outer layer of the dihydropyridine calcium channel blocker rapid release granules of 1) as the outer layer, and the HMG-CoA reductase inhibitor of 2) The slow-release tablet was tableted using a nuclear tablet. Separately, a coating solution obtained by dissolving and dispersing hydroxypropylmethylcellulose 2910 (Shin-etsu, Japan), polyethylene glycol 6,000 (BASF, Germany), talc (Luzenac, France) and titanium oxide (Tioside Americas, USA) in ethanol and purified water The tablets were prepared to form a film coating layer as a high coater (SFC-30F, Sejong Machinery, Korea) to prepare tablets in the form of nucleated tablets.

Example 2: Nucleated Tablets Preparation

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

1) Preparation of pre-release compartment (dihydropyridine calcium channel blocker immediate release granule)

Lercanidipine (Daehee Chemical, Korea), microcrystalline cellulose, anhydrous calcium phosphate, corn starch (DMV, Germany) were weighed and appled in No. 35, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (delayed-release tablets of HMG-CoA reductase inhibitors)

Simvastatin (Biocon, India), microcrystalline cellulose, starch glyconate, di-mannitol, butylated hydroxyanisole (Merck, USA) were apples in No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. . Separately, hydroxypropyl cellulose and citric acid (Jungbunzlauer, Austria) were dissolved in purified water and combined, granulated and dried using a binder solution (10% w / w). After drying, it was established as No. 18 body again. Separately, the above granulated product was prepared by dissolving cellulose acetate 320S (acetal group 32%) and cellulose acetate 398NF10 (acetal group 39.8%) in a 1: 1 mixture of ethanol and methylene chloride (20% w / w). It was put in a coater (GPCG-1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.

3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).

Example 3: Nucleated Tablets Preparation

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

1) Preparation of pre-release compartment (dihydropyridine calcium channel blocker immediate release granule)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, weighed in apple No. 35, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (delayed-release tablets of HMG-CoA reductase inhibitors)

Atorvastatin calcium trihydrate, microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate in apples No. 35 and mixed for 5 minutes using a double cone mixer. A mixture was prepared. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again. The formulations are placed in a fluidized bed coater (GPCG-1, Glatt, Germany) and separately poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer (Evonik Degussa, Germany) and triethyl A solution of citrate (Vertellus, England) dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and coated. It was. After the coating was completed, magnesium stearate (Nitika Chemical, India) was added, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.

3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).

Example 4 Preparation of Nucleated Tablets

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

1) Preparation of pre-release compartment (dihydropyridine calcium channel blocker immediate release granule)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, weighed in apple No. 35, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (delayed-release tablets of HMG-CoA reductase inhibitors)

Rosuvastatin calcium (Glenmark Pharmaceutical Ltd, India), microcrystalline cellulose (Vivapur 12, JRS, Germany), lactose (Flowlac 100, Meggle, Germany), di-mannitol, sodium lauryl sulfate, calcium phosphate anhydrous And mixed for 5 minutes with a double cone mixer to prepare a mixture. Add crosslinked polyvinylpyrrolidone and butylated hydroxyanisole to the mixture, mix for 5 minutes, add magnesium stearate, mix for 2 minutes, and rotary tablet press equipped with a 6.5mm diameter punch (MRC-30, Sejong Machinery , Korea) to make a nuclear tablet. Separately, a coating solution of ethyl cellulose (HERCULES, USA) dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared, and the primary coating was performed using a high coater (SFC-30F, Sejong Machinery, Korea). It was. Thereafter, a coating solution obtained by dissolving poly (methacrylate, methyl methacrylate) copolymer (Evonik degussa, USA) and triethyl citrate in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared. The HMG-CoA reductase inhibitor coated tablets were coated with a high coater to form a coating layer, thereby completing the preparation of HMG-CoA reductase inhibitor nuclear tablets.

3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).

Example 5: Nucleated Tablets Preparation

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, weighed in apple No. 35, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (delayed-release tablets of HMG-CoA reductase inhibitors)

Atorvastatin calcium trihydrate, microcrystalline cellulose, calcium carbonate, croscarmellose sodium, pregelatinized starch, di-mannitol and sodium lauryl sulfate were mixed with apple No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried. After drying, the mixture was established as a No. 18 sieve again, and then cross-linked polyvinylpyrrolidone was added to the sieved material, mixed, and mixed for 4 minutes. Thereafter, magnesium stearate sieved through No. 35 sieve was added, mixed for 2 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet. Separately, a coating solution obtained by diluting polyvinylacetate 30% dispersant (colicoat SR 30D, BASF, Germany) and triethyl citrate in purified water was prepared and coated using a high coater (SFC-30F, Sejong Machinery, Korea). Was prepared. After the coating layer was formed, a coating solution in which acrylic-Iz (methacrylic acid copolymer type C, talc, PEG, colloidal silicon dioxide, sodium bicarbonate, SLS, Colorcon, USA) was dissolved and dispersed in purified water (10% w / w) To prepare the HMG-CoA reductase inhibitor coated tablets as a secondary coat layer as a high coater (SFC-30F, Sejong Machinery, Korea) to complete the preparation of HMG-CoA reductase inhibitor nuclear tablets.

3) tableting and coating

Slow release of HMG-CoA reductase inhibitor of 2) using dihydropyridine calcium channel blocker fast-release granules as outer layer in inner nuclear tableting machine equipped with 12 mm punch (RUD-1, Kilian, Germany) The tablet was compressed into nuclear tablets. Separately, a coating solution obtained by dissolving and dispersing hydroxypropylmethylcellulose 2910, polyethylene glycol 6,000, talc, and titanium oxide in ethanol and purified water was prepared, and the above-described nucleated tablet was used as a high coater (SFC-30F, Sejong Machinery, Korea). To form a tablet in the form of a film-coated nucleated tablets.

Example 6: Nucleated Tablets Preparation

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

With the composition and content of Table 1, fast-release granules were prepared in the same manner as in Example 1 1).

2) Preparation of delayed-release compartments (delayed-release tablets of HMG-CoA reductase inhibitors)

Atorvastatin calcium trihydrate, microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate in apples No. 35 and mixed for 5 minutes using a double cone mixer. A mixture was prepared. The mixture was added to a high-speed mixer, polyvinylacetate 30% dispersant in which hydroxypropyl cellulose was dissolved, polyvinylacetate 30% dispersant (BASF, Germany) was added, and then granulated using an oscillator with No. 20 sieve. After drying at 60 ° C to No. 18 sieve again. Magnesium stearate was added to the sieved material, mixed for 2 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet. Separately, HMG- was prepared by dissolving and dispersing hydroxypropylmethylcellulose phthalate (Shin-etsu, Japan) and triethyl citrate in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride. CoA reductase inhibitor tablets were formed as a coater as a high coater (SFC-30F, Sejong Machinery, Korea) to complete the preparation of HMG-CoA reductase inhibitor tablets.

3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).

Example 7 Nuclear Purification

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Amalodipine besylate, a dihydropyridine calcium channel blocker, anhydrous calcium phosphate, microcrystalline cellulose and corn starch were weighed and appled in a No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (delayed-release tablets of HMG-CoA reductase inhibitors)

Atorvastatin calcium anhydride (TEVA, Israel), microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate with 35 Mixing was carried out for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again. Separately, ethylcellulose was dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution, and was first coated using a fluidized bed granulator coater (GPCG-1; Glatt, Germany). After primary coating, the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and hydroxypropylmethylcellulose phthalate and triethylcitrate were mixed 1: 1 with ethanol and methylene chloride (20% w). final coating with the solution dissolved in / w). After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.

3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).

Example 8 Nuclear Tablet Preparation

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Pedidipine (Cipla, India), microcrystalline cellulose, corn starch, lactose, and propyl gallate (Spectrumchemical, USA), which are dihydropyridine-based calcium channel blockers, are apples in No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. It was. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator (AR402, ERWEKA, Germany) with No. 18 and dried at 60 ° C. using a hot water dryer (H-W-C, Samgye, Japan). After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (delayed-release tablets of HMG-CoA reductase inhibitors)

Simvastatin (Biocon, India), microcrystalline cellulose, starch glyconate, di-mannitol, butylated hydroxyanisole were apples in No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose and citric acid were dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again. Separately, ethylcellulose was dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution, and was first coated using a fluidized bed granulator coater (GPCG-1; Glatt, Germany). After primary coating, the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and hydroxypropylmethylcellulose phthalate and triethylcitrate were mixed 1: 1 with ethanol and methylene chloride (20% w). final coating with the solution dissolved in / w). After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.

3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).

Example 9: Nucleated Tablets Preparation

With the components and contents shown in Table 1, nucleated tablets were prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Lercanidipine, microcrystalline cellulose, anhydrous calcium phosphate, corn starch, apples in No. 35, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (delayed-release tablets of HMG-CoA reductase inhibitors)

HMG-CoA reductase inhibitor fluvastatin sodium, microcrystalline cellulose, potassium bicarbonate (Tomita, Japan), pregelatinized starch, lauryl sulfate sodium, croscarmellose sodium as apples No. 35 and 5 minutes with a double cone mixer Mixing gave a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again. Separately, ethylcellulose was dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution, and was first coated using a fluidized bed granulator coater (GPCG-1; Glatt, Germany). After primary coating, the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and hydroxypropylmethylcellulose phthalate and triethylcitrate were mixed 1: 1 with ethanol and methylene chloride (20% w). final coating with the solution dissolved in / w). After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6.5 mm diameter punch to prepare a nuclear tablet.

3) tableting and coating

Tableting in the form of nucleated tablets was prepared by tableting and coating in the same manner as in Example 3).

Example 10 Preparation of Two-Phase Matrix Tablets

With the components and contents shown in Table 2, two-phase matrix tablets were prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, weighed in apple No. 35, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.

2) Preparation of delayed-release compartment (delayed immediate layer granule of HMG-CoA reductase inhibitor)

Atorvastatin calcium trihydrate, microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate in apples No. 35 and mixed for 5 minutes using a double cone mixer. A mixture was prepared. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again. The sieved material is placed in a fluidized bed coater (GPCG-1, Glatt, Germany), separately cellulose acetate 320S (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate 398NF10 (acetal group 39.8%) (Eastman Chemical Company, USA ) Was dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granulated material was put into a fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated.

3) Post-mixing, tableting and coating

The products of 1) and 2) were put into a double cone mixer and mixed. Starch, sodium glyconate, and magnesium stearate were added to the mixture, followed by final mixing in a double cone mixer. The final mixture was compressed into tablets using a rotary tablet press (MRC-33: Sejong Machinery, South Korea). Separately, a coating solution obtained by dissolving and dispersing hydroxypropylmethylcellulose 2910, polyethylene glycol 6,000, talc, and titanium oxide in ethanol and purified water was prepared, and a high coater (SFC-30F: Sejong Machinery, Korea) was used for the above purification. The film coating layer was formed to prepare a biphasic matrix tablet.

Example 11 Preparation of Two-Phase Matrix Tablets

With the components and contents shown in Table 2, two-phase matrix tablets were prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Nifedipine (Cadila, India), a dihydropyridine-based calcium channel blocker, microcrystalline cellulose, corn starch, lactose, lauryl sulfate sodium, weighed 35 apples and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using a No. 20 body oscillator, which was dried at 60 ° C. using a hot water dryer, and then re-established into No. 18 body.

2) Preparation of delayed-release compartments (delayed-release granules of HMG-CoA reductase inhibitors)

HMG-CoA reductase inhibitor lovastatin (Ranbaxy, India), microcrystalline cellulose, pregelatinized starch, di-mannitol, lactose, butylated hydroxyanisole as apples No. 35 and mixed for 5 minutes with a double cone mixer Prepared. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. Separately, a solution of poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate) copolymer and triethyl citrate in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared. The above granules were prepared and placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and coated.

3) Post-mixing, tableting and coating

In the same manner as 3) of Example 10, post-mixing, tableting, and coating were performed to prepare a tablet in the form of a two-phase matrix.

Example 12 Preparation of Two-Phase Matrix Tablets

With the components and contents shown in Table 2, two-phase matrix tablets were prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

A dihydropyridine-based calcium channel blocker, silinidipine, microcrystalline cellulose, anhydrous calcium phosphate, corn starch, weighed 35 apples and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using a No. 20 body oscillator, which was dried at 60 ° C. using a hot water dryer, and then re-established into No. 18 body.

2) Preparation of delayed-release compartment (delayed immediate layer granule of HMG-CoA reductase inhibitor)

Rohvastatin calcium, microcrystalline cellulose, anhydrous calcium phosphate, di-mannitol, cross-linked polyvinylpyrrolidone, lauryl sulfate sodium, lactose, butylated hydroxyanisole, which are HMG-CoA reductase inhibitors A mixture was prepared by mixing for 5 minutes with a double cone mixer. The mixture was added to a high-speed mixer, and the mixture was added by adding 30% of a polyvinylacetate dispersant in which hydroxypropyl cellulose was dissolved. Granulation was carried out using an oscillator using No. 20 sieve, and dried at 60 ° C. using a hot water dryer. It was. Hydroxypropylmethylcellulose phthalate and triethylcitrate were dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granules were prepared in a fluid bed granulation coater (GPCG-1; Glatt). , Germany) and coated.

3) Post-mixing, tableting and coating

In the same manner as in 3) of Example 10, post-mixing, tableting, and coating were performed to prepare a tablet in the form of a two-phase matrix.

Example 13: Two-Phase Matrix Tablet Preparation

With the components and contents shown in Table 2, two-phase matrix tablets were prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Nicardipine (Chemwerth Inc, Germany), a dihydropyridine-based calcium channel blocker, microcrystalline cellulose, corn starch, anhydrous calcium phosphate, lactose, weighed 35 apples and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using a No. 20 body oscillator, which was dried at 60 ° C. using a hot water dryer, and then re-established into No. 18 body.

2) Preparation of delayed-release compartment (delayed immediate layer granule of HMG-CoA reductase inhibitor)

Pragstatin sodium, microcrystalline cellulose, magnesium oxide (Tomita, Japan), di-mannitol, croscarmellose sodium, lactose, lauryl sulfate sodium, HMG-CoA reductase inhibitor 35 Mixing gave a mixture. Separately, polyvinylpyrrolidone was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried. Separately, a solution obtained by dissolving ethyl cellulose (HERCULES, USA) in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and coated using a fluidized bed granulation coater (GPCG-1; Glatt, Germany). Thereafter, a poly (methacrylate, methyl methacrylate) copolymer and triethyl citrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed. It was put in a granular coater (GPCG-1; Glatt, Germany) and coated.

3) Post-mixing, tableting and coating

In the same manner as 3) of Example 10, post-mixing, tableting, and coating were performed to prepare a tablet in the form of a two-phase matrix.

Example 14 Preparation of Multi-Layered Tablets

By the component and content shown in Table 2, the multilayer tablet was produced with the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, weighed in apple No. 35, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartments (delayed-release granules of HMG-CoA reductase inhibitors)

Atorvastatin calcium trihydrate, microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate in apples No. 35 and mixed for 5 minutes using a double cone mixer. A mixture was prepared. Separately, polyvinylpyrrolidone was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried. After drying, it was established as No. 18 body again. Separately, a solution obtained by dissolving ethyl cellulose (HERCULES, USA) in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and coated using a fluidized bed granulation coater (GPCG-1; Glatt, Germany). Thereafter, a poly (methacrylate, methyl methacrylate) copolymer and triethyl citrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed. It was put in a granular coater (GPCG-1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes.

3) Post-mixing, tableting and coating

It was compressed using a multi-layer tablet press (MRC-30T: Sejong, Korea). The final mixture of 1) was placed in a primary powder feeder, and the final mixture of 2) was placed in a secondary powder feeder, and compressed into a condition capable of minimizing incorporation between layers. Separately, hydroxypropylmethylcellulose 2910, polyethylene glycol 6,000, talc, and titanium oxide were prepared by dissolving and dispersing a coating solution in ethanol and purified water. The above tablets were coated with a high coater (SFC-30F: Sejong Machinery, Korea). To form a tablet in the form of a multi-layered tablet.

Example 15 Preparation of Multi-Layered Tablets

By the component and content shown in Table 2, the multilayer tablet was produced with the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

A dihydropyridine calcium channel blocker, vanidipine, microcrystalline cellulose, anhydrous calcium phosphate, weighed 35 apples, and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartment (delayed immediate layer granule of HMG-CoA reductase inhibitor)

The HMG-CoA reductase inhibitor Rovastatin (Ranbaxy, India), microcrystalline cellulose, di-mannitol, pregelatinized starch, lactose and butylated hydroxyanisole were apologized with No. 35 and mixed for 5 minutes with a double cone mixer. Prepared. Separately, polyvinylpyrrolidone was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried. After drying, it was established as No. 18 body again. The sieved material is placed in a fluidized bed coater (GPCG-1, Glatt, Germany), separately cellulose acetate 320S (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate 398NF10 (acetal group 39.8%) (Eastman Chemical Company, USA ) Was dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granulated material was put into a fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes.

3) Post-mixing, tableting and coating

In the same manner as in 3) of Example 14, post-mixing, tableting, and coating were carried out to form a tablet in the form of a multilayer tablet.

Example 16: Multilayer Tablet Preparation

By the component and content shown in Table 2, the multilayer tablet was produced with the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Benidipine, a dihydropyridine calcium channel blocker, microcrystalline cellulose, anhydrous calcium phosphate, corn starch and di-mannitol were weighed and appled in a No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartment (delayed immediate layer granule of HMG-CoA reductase inhibitor)

Rohvastatin calcium, microcrystalline cellulose, anhydrous calcium phosphate, di-mannitol, cross-linked polyvinylpyrrolidone, lauryl sulfate sodium, lactose, butylated hydroxyanisole, which are HMG-CoA reductase inhibitors A mixture was prepared by mixing for 5 minutes with a double cone mixer. The mixture was added to a high-speed mixer, polyvinylacetate 30% dispersant in which hydroxypropyl cellulose was dissolved, polyvinylacetate 30% dispersant was added and granulated. It was established as No. 18 body again. Hydroxypropylmethylcellulose phthalate and triethylcitrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated. Magnesium stearate was added to the coated granules and mixed with a double cone mixer.

3) Post-mixing, tableting and coating

In the same manner as in 3) of Example 14, post-mixing, tableting, and coating were carried out to form a tablet in the form of a multilayer tablet.

Example 17 Preparation of Multi-Layered Tablets

By the component and content shown in Table 2, the multilayer tablet was produced with the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Mandipine, microcrystalline cellulose, di-mannitol and corn starch, which were dihydropyridine calcium channel blockers, were appled in a No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again. The starch sodium starch glyconate was mixed, magnesium stearate was added, and finally mixed with a double cone mixer.

2) Preparation of delayed-release compartment (delayed immediate layer granule of HMG-CoA reductase inhibitor)

Pragstatin sodium, microcrystalline cellulose, magnesium oxide (Tomita, Japan), di-mannitol, croscarmellose sodium, lactose, and lauryl sulfate sodium, which are HMG-CoA reductase inhibitors, were appled with No. 35 and mixed for 5 minutes in a double cone mixer. To prepare a mixture. Separately, polyvinylpyrrolidone was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried. The dried product was separately dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride in poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer and triethylcitrate. The solution was prepared and the above granules were put into a fluid bed granulation coater (GPCG-1 Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added and mixed for 4 minutes.

3) Post-mixing, tableting and coating

In the same manner as in 3) of Example 14, post-mixing, tableting, and coating were carried out to form a tablet in the form of a multilayer tablet.

Example 18: Preparation of Capsules (Pellets-Granules)

With the components and contents shown in Table 2, a capsule was prepared by the following method.

1) Preparation of pre-release compartment (dihydropyridine calcium channel blocker pellet)

Sugar seed (NP Pharmaceutical, France) was added to a fluidized bed granulator (GPCG, Glatt, Germany), and polyvinylpyrrolidone and dihydropyridine calcium channel blocker, amlodipine besylate, were dissolved separately in ethanol. The binding solution (10% w / w) was sprayed to form pellets containing dihydropyridine calcium channel blocker and dried.

2) Preparation of delayed-release compartments (delayed-release granules of HMG-CoA reductase inhibitors)

HMG-CoA reductase inhibitor, pitavastatin calcium, microcrystalline cellulose, calcium carbonate, pregelatinized starch, butylated hydroxyanisole was apples in No. 35 and mixed for 5 minutes with a double cone mixer to prepare a mixture. The polyvinylacetate 30% dispersant in which polyvinylpyrrolidone was dissolved was added thereto, and then granulated using an oscillator. Hydroxypropylmethylcellulose phthalate and triethylcitrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated

3) capsule filling

The final product of 1) and 2) was mixed with a double cone mixer. Magnesium stearate was added to the mixture for final mixing. The final mixed mixture was put into a powder feeder and filled into a capsule (Seoheung capsule, Korea) using a capsule charger (SF 40N, Sejong Machinery, Korea) to complete the preparation of the capsule formulation.

Example 19 Preparation of Capsules (Pellets-Pellets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release pellet)

A sugar solution (Sugar sphere) was added to a fluidized bed granulator (GPCG-1: Glatt), and then a binder solution (10% w /) in which polyvinylpyrrolidone and amlodipine besylate, a dihydropyridine calcium channel blocker, were dissolved in ethanol. w) was sprayed to form pellets containing dihydropyridine calcium channel blocker and dried.

2) Preparation of delayed-release compartments (delayed-release pellets of HMG-CoA reductase inhibitors)

Sugar seeds were added to a fluidized bed granulator (GPCG-1: Glatt), and then ethanol was prepared using polyvinylpyrrolidone, citric acid, butylated hydroxyanisole and simvastatin, which are HMG-CoA reductase inhibitors. The dispersed and dissolved binding solution (10% w / w) was sprayed to form pellets containing HMG-CoA reductase inhibitor and dried. The pellets were sprayed with HMG-CoA by spraying a solution of hydroxypropylmethylcellulose phthalate (Shin-etsu, Japan) and triethyl citrate in a 1: 1 mixture of ethanol and methylene chloride (20% w / w). Reductase inhibitor delayed-release pellets were prepared.

3) capsule filling

The final product of step 1) and 2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule formulation.

Example 20 Preparation of Capsules (Pellets-Osmotic Tablets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release pellet)

A sugar solution (Sugar sphere) was added to a fluidized bed granulator (GPCG-1: Glatt), and a binder solution (10% w / d) in which polyvinylpyrrolidone and dihydropyridine calcium channel blocker, amlodipine besylate, were dissolved in ethanol. w) was sprayed to form pellets containing dihydropyridine calcium channel blocker and dried.

2) Preparation of delayed-release compartments (osmotic purification of HMG-CoA reductase inhibitors)

HMG-CoA reductase inhibitor fluvastatin sodium, microcrystalline cellulose, potassium bicarbonate, pregelatinized starch, lauryl sulfate sodium, croscarmellose sodium was appled with No. 35 sieve and mixed for 5 minutes with a double cone mixer to prepare a mixture. It was. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 again. Sodium chloride and magnesium stearate were added to the formulation and mixed for 4 minutes. The mixture was tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6 mm diameter punch to prepare a tablet. Separately, a solution obtained by dissolving cellulose acetate 320S (acetal group 32%) and cellulose acetate 398NF10 (acetal group 39.8%) in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared. SFC-30F: Sejong Machinery, Korea) to form a film coating layer to prepare an osmotic tablet of HMG-CoA reductase inhibitor.

3) Capsule filling

The final product of 1) and 2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.

Example 21 Preparation of Capsules (Pellets-Tablets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release pellet)

A sugar solution (Sugar sphere) was added to a fluidized bed granulator (GPCG-1: Glatt), and a binder solution in which polyvinylpyrrolidone and dihydropyridine calcium channel blocker nisoldipine (Lusochimica, Italy) was dissolved in ethanol ( 10% w / w) was sprayed to form pellets containing dihydropyridine calcium channel blocker and dried.

2) Preparation of a delayed release compartment (delayed rapid release tablet of HMG-CoA reductase inhibitor)

Atorvastatin calcium anhydride (TEVA, Israel), microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate with 35 Mixing was carried out for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again.

The formulations are placed in a fluidized bed coater (GPCG-1, Glatt, Germany) and separately poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer (Evonik Degussa, Germany) and triethyl A solution of citrate (Vertellus, England) dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and coated. It was. After the coating was completed, magnesium stearate (Nitika Chemical, India) was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6 mm diameter punch to prepare a nuclear tablet.

A coating solution (10% w / w) obtained by dissolving and dispersing acryl-isolated in purified water was prepared to form a coating layer using the HMG-CoA reductase inhibitor tablet as a high coater (SFC-30F, Sejong Machinery, Korea). CoA reductase inhibitor tablet preparation was completed.

3) Capsule filling

The final product of 1) and 2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.

Example 22 Preparation of Capsules (Tablets-Pellets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

1) Preparation of prior-release compartment (dihydropyridine calcium channel blocker rapid release tablet)

Dihydropyridine channel blocker lercanidipine, microcrystalline cellulose, anhydrous calcium phosphate, corn starch were apples in No. 35 sieve and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again. Starch sodium glyconate and magnesium stearate were added to the sieved material, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong) equipped with a 5 mm diameter punch to prepare a tablet.

2) Preparation of delayed-release compartments (delayed-release rapid release pellets of HMG-CoA reductase inhibitors)

Sugarsphere was added to a fluidized bed granulator (GPCG-1: Glatt), and then polyvinylpyrrolidone, citric acid, butylated hydroxyanisole and simvastatin, HMG-CoA reductase inhibitors, were separately dispersed in ethanol. The dissolved binding solution (10% w / w) was sprayed to form pellets containing the HMG-CoA reductase inhibitor and dried. In the pellet, poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate) copolymer (Evonik Degussa, Germany) and triethyl citrate (Vertellus, England) were prepared by ethanol and methylene chloride. 1: Spray a solution dissolved in a mixed solution (20% w / w), and add hydroxypropyl methyl cellulose phthalate (Shin-etsu, Japan) and triethyl citrate to the pellet. HMG-CoA reductase inhibitor delayed-release pellets were prepared by spraying the solution dissolved in the mixed solution (20% w / w).

3) Capsule filling

The product of 1) and 2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the time difference release formulation of the capsule form.

Example 23 Preparation of Capsules (Tablets-Tablets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

1) Preparation of prior-release compartment (dihydropyridine calcium channel blocker rapid release tablet)

Ishydrin (Shasun Chemicals, India), a dihydropyridine calcium channel blocker, microcrystalline cellulose, anhydrous calcium phosphate and corn starch were weighed and appled in No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again. Starch sodium glyconate and magnesium stearate sieved through No. 35 sieve were added to the sieved material, mixed for 4 minutes, and then compressed with a rotary tableting machine (MRC-30, Sejong Machinery, Korea) equipped with a 5 mm diameter punch. The preparation of pyridine calcium channel blocker tablets was completed.

2) Preparation of delayed-release compartments (delayed purification of HMG-CoA reductase inhibitors)

HMG-CoA reductase inhibitor simvastatin, microcrystalline cellulose, croscarmellose sodium, pregelatinized starch and di-mannitol, butylated hydroxyanisole apologized in 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture It was. Separately, citric acid and hydroxypropyl cellulose were dissolved in a polyvinylacetate 30% dispersant to form a binding solution (10% w / w), followed by granulation and drying. After drying, it was established as No. 18 body again. Magnesium stearate sieved through a No. 35 sieve was added to the sieved material, mixed for 4 minutes, and compressed into tablets using a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 5 mm diameter punch. Separately, poly (methacrylate, methyl methacrylate) copolymer (Evonik degussa, USA) and triethyl citrate were prepared in a 1: 1 mixture of ethanol and methylene chloride (20% w / w). The HMG-CoA reductase inhibitor tablets of the high coater (SFC-30F, Sejong Machinery, Korea) to form a coating layer to complete the preparation of HMG-CoA reductase inhibitor tablets.

3) Capsule filling

The product of 1) and 2) was filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of a controlled release formulation in the form of a capsule.

Example 24 Preparation of Capsules (Granules-Granules)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker immediate release layer granules)

Nimodipine (Lusochimica, Italy), a dihydropyridine calcium channel blocker, microcrystalline cellulose, corn starch, anhydrous calcium phosphate, weighed 35 apples, and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again.

2) Preparation of delayed-release compartments (delayed granules of HMG-CoA reductase inhibitors)

HMG-CoA reductase inhibitor rosuvastatin calcium, microcrystalline cellulose, anhydrous calcium phosphate, di-mannitol, cross-linked polyvinylpyrrolidone, lauryl sulfate sodium, butylated hydroxyanisole in apple 35 and double cone The mixture was prepared by mixing for 5 minutes with a mixer. The mixture was added to a high-speed mixer, and the mixture was added by adding 30% of a polyvinylacetate dispersant in which hydroxypropyl cellulose was dissolved. Granulation was carried out using an oscillator using No. 20 sieve, and dried at 60 ° C. using a hot water dryer. It was. Hydroxypropylmethylcellulose phthalate and triethylcitrate were dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) to prepare a solution of the above granulated fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated.

3) Post mixing and capsule filling

The products of 1) and 2) were mixed in a double cone mixer. Sodium starch glyconate was added to the mixture and mixed with a double cone mixer. Magnesium stearate was added to the mixture, followed by final mixing. The final mixed mixture was put into a powder feeder and filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.

Example 25 Preparation of Capsules (Granules-Pellets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker immediate release layer granules)

Amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate, weighed in apple No. 35, and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binding solution (10% w / w), which was fed to the main component mixture and a high speed mixer and then combined. After association, granulation was carried out using an oscillator in No. 18 and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 20 sieve again.

2) Preparation of delayed-release compartments (delayed pellets of HMG-CoA reductase inhibitors)

Sugar seeds were added to a fluidized bed granulator (GPCG-1: Glatt), and then polyvinylpyrrolidone in ethanol and fluvastatin sodium, potassium bicarbonate, and lauryl sulfate in inhibitors of HMG-CoA. The binding solution (10% w / w) in which sodium was dispersed and dissolved was sprayed to form pellets containing the HMG-CoA reductase inhibitor and dried. In the pellet, a poly (ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer and triethylcitrate were mixed in a 1: 1 mixture of ethanol and methylene chloride (20% w / w). After spraying the dissolved solution, HMG was sprayed with a solution of poly (methacrylate, methyl methacrylate) copolymer and triethyl citrate in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride. -CoA reductase inhibitor delayed pellets were prepared.

3) Post mixing and capsule filling

The products of 1) and 2) were mixed in a double cone mixer. Sodium starch glycolate was added to the mixture and mixed with a double cone mixer. Magnesium stearate was added to the mixture, followed by final mixing. The final mixed mixture was put into a powder feeder and filled into capsules (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the time release formulation in capsule form.

Example 26 Preparation of Capsules (Granules-Tablets)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

1) Preparation of a prerelease compartment (dihydropyridine calcium channel blocker rapid release granules)

Pedidipine (Cipla, India), microcrystalline cellulose, corn starch, lactose, and propyl gallate (Spectrumchemical, USA), which are dihydropyridine-based calcium channel blockers, are apples in No. 35 and mixed for 5 minutes in a double cone mixer to prepare a mixture. It was. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture.

The granules were dried at 60 ° C. using a hot water dryer (H-W-C, Samkok, Japan). After drying, it was established as No. 20 sieve again. Sodium starch glyconate was added to the sieved material and mixed with a double cone mixer. Magnesium stearate was added to the mixture for final mixing.

2) Preparation of a delayed release compartment (delayed rapid release tablet of HMG-CoA reductase inhibitor)

Pragstatin sodium, microcrystalline cellulose, magnesium oxide (Tomita, Japan), di-mannitol, croscarmellose sodium, and lauryl sulfate sodium, which are HMG-CoA reductase inhibitors, were appled with No. 35 and mixed for 5 minutes with a double cone mixer. Was prepared. Separately, polyvinylpyrrolidone was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried. Separately, a solution of ethyl cellulose (HERCULES, USA) dissolved in a 1: 1 mixture of ethanol and methylene chloride (20% w / w) was prepared and the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany). Coated. Magnesium stearate sieved through No. 35 sieve was added to the coated formulation, mixed for 4 minutes, and the mixture was compressed into tablets using a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 5 mm diameter punch. .

A coating solution (10% w / w) obtained by dissolving and dispersing acryl-isolated in purified water was prepared to form a coating layer using the HMG-CoA reductase inhibitor tablet as a high coater (SFC-30F, Sejong Machinery, Korea). CoA reductase inhibitor tablet preparation was completed.

3) Capsule filling

The product of 1) and 2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.

Example 27 Preparation of Capsules (Tablets-Granules)

With the components and contents shown in Table 3, a capsule was prepared by the following method.

1) Preparation of prior-release compartment (dihydropyridine calcium channel blocker rapid release tablet)

A dihydropyridine calcium channel blocker, lacidipine (Fine Chem Trading, UK), microcrystalline cellulose, anhydrous calcium phosphate, corn starch, weighed 35 apples and mixed for 5 minutes in a double cone mixer to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again. Into the formulation, sodium starch glycolate and magnesium stearate, which were sieved through a No. 35 sieve, were added, mixed for 4 minutes, and the mixture was compressed into a rotary tableting machine (MRC-30, Sejong, Korea) equipped with a 5 mm diameter punch. Dihydropyridine calcium channel blocker tablet preparation was completed.

2) Preparation of delayed-release compartments (delayed-release granules of HMG-CoA reductase inhibitors)

Atorvastatin calcium trihydrate, microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate in apples No. 35 and mixed for 5 minutes using a double cone mixer. A mixture was prepared. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), followed by association, granulation, and drying. After drying, it was established as No. 18 body again. Separately, ethylcellulose was dissolved in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and prepared by first coating by using a fluidized bed granulation coater (GPCG-1; Glatt, Germany). After primary coating, the above granules were placed in a fluid bed granulation coater (GPCG-1; Glatt, Germany) and hydroxypropylmethylcellulose phthalate and triethylcitrate were mixed 1: 1 with ethanol and methylene chloride (20% w). final coating with the solution dissolved in / w). Magnesium stearate was added to the coating for final mixing.

3) Capsule filling

The product of 1) and 2) was filled in a capsule (Seoheung capsule, Korea) using a capsule charger to complete the preparation of the capsule form preparation.

Example 28 Preparation of Amlodipine-Atorvastatin Blister Packaging Kit

The amlodipine-atorvastatin blister packaging kit was manufactured by the following method.

1) Preparation of prior-release compartment (dihydropyridine calcium channel blocker rapid release tablet)

Dihydropyridine calcium channel blocker, amlodipine besylate, microcrystalline cellulose, anhydrous calcium phosphate was added to apple No. 35 and mixed in a double cone mixer for 5 minutes to prepare a mixture. Separately, hydroxypropyl cellulose was dissolved in purified water to prepare a binder solution (10% w / w), which was associated with the main ingredient mixture. After the association, granulation was carried out using an oscillator in No. 20 sieve and dried at 60 ° C. using a hot water dryer. After drying, it was established as No. 18 body again. Starch sodium glyconate and magnesium stearate sieved through No. 35 sieve were added to the sieved material, mixed for 4 minutes, and then compressed with a rotary tableting machine (MRC-30, Sejong Machinery, Korea) equipped with a 5 mm diameter punch. The preparation of pyridine calcium channel blocker tablets was completed.

2) Preparation of delayed-release compartments (delayed purification of HMG-CoA reductase inhibitors)

Atorvastatin calcium trihydrate, microcrystalline cellulose, calcium carbonate, cross-linked polyvinylpyrrolidone, croscarmellose sodium, pregelatinized starch, di-mannitol, sodium lauryl sulfate in apples No. 35 and mixed for 5 minutes using a double cone mixer. A mixture was prepared. Separately, hydroxypropyl cellulose was dissolved in purified water to form a binding solution (10% w / w), and the mixture was granulated and dried. After drying, it was established as No. 18 body again. The sieved material is placed in a fluidized bed coater (GPCG-1, Glatt, Germany), separately cellulose acetate 320S (acetal group 32%) (Eastman Chemical Company, USA), cellulose acetate 398NF10 (acetal group 39.8%) (Eastman Chemical Company, USA ) Was prepared in a 1: 1 mixture (20% w / w) of ethanol and methylene chloride, and the above granulated material was put into a fluidized bed granulator coater (GPCG-1; Glatt, Germany) and coated. After the coating was completed, magnesium stearate was added thereto, mixed for 4 minutes, and tableted with a rotary tablet press (MRC-30, Sejong Machinery, Korea) equipped with a 6 mm diameter punch to prepare a tablet.

(3) blister packing

After each tablet is manufactured, the blister packaging machine (Minister A, Heung-A Engineering) is used to package each tablet in a blister packaging container (silver foil, Dongyang, PVDC, Jeonmin Industries) for simultaneous use. The packaging kit was prepared.

Table 1

[Table 2]

Table 3

Experimental Example 1: Comparative Dissolution Profile Test

Comparative dissolution test of the amlodipine / atorvastatin calcium nucleated tablet prepared in Example 5 and the reference drug (Novask (Pfizer): amlodipine single agent, Lipitor (Pfizer): atorvastatin calcium single agent). In the case of amlodipine component dissolution, the dissolution test was carried out based on the nine amendments to the Korean Pharmacopoeia General Test Method. In the case of atorvastatin dissolution test, the dissolution was changed from artificial gastric fluid to artificial intestinal fluid for 120 minutes. . The dissolution test method for each component is as follows, and the results are shown in FIG.

According to Figure 1, the nucleated tablet of Example 5 was confirmed that the amlodipine component in the dissolution test exhibited almost the same elution characteristics as compared to the control formulation Novasque under the following conditions, the atorvastatin calcium component release compared to the control agent Lipitor You can see the delay. In the dissolution test results of the atorvastatin component, it was confirmed that the dissolution rate of the atorvastatin component up to 120 minutes, which is the artificial gastric juice section, was all within 10% of the nucleated tablets of amlodipine / atorvastatin of Example 5, but the control formulation was about 50%. Since the dissolution rate of the atorvastatin component in the artificial intestinal section was 97% at 360 minutes in the control agent, the nucleated tablet of amlodipine / atorvastatin of Example 5 was found to be much delayed to about 5% at 360 minutes.

As described above, the amlodipine / atorvastatin nucleated tablet of the present invention has a metabolite associated with metabolism first after metabolism in the liver since the initial release of atorvastatin is much slower than that of amlodipine, unlike the dissolution of the amlodipine monotherapy and the atorvastatin monotherapy simultaneously. Enough time to regenerate the enzyme cytochrome P450 can be secured.

[Amlodipine Test Method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 75 revolutions / minute

Test solution: 0.01M hydrochloric acid solution, 750 mL

Analysis method: high performance liquid chromatography

[Atorvastatin Calcium Test Method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 50 revolutions / minute

Test solution: 0.01N hydrochloric acid solution, 750mL (artificial gas solution)

        pH 6.8 phosphate buffer, total 1,000mL (phosphoric acid solution)

Analysis method: high performance liquid chromatography

Experimental Example 2: Comparative Dissolution Profile Test

A comparative dissolution test of the silinidipine / rosuvastatin calcium biphasic matrix tablets prepared in Example 12 and the control drug (cinnaron (Boryeong Pharmaceuticals): single silinipine, Crestor (Astrazeneca: rosuvastatin calcium single agent) It was. In the case of silinidipine component dissolution, the dissolution test was carried out based on 9 amendments to the Korean Pharmacopoeia General Test Method. For the rosuvastatin dissolution test, the dissolution solution was changed from artificial gastric to artificial intestinal fluid for 120 minutes. Proceeded. The dissolution test method for each component is as follows, and the results are shown in FIG.

According to FIG. 2, the biphasic matrix tablet of Example 12 was found to exhibit almost the same elution characteristics as the cinnarone, the control formulation, in the dissolution test under the following conditions, but the rosuvastatin component was the crest, the control formulation. It can be seen that the release is very slow compared to. In the dissolution test results of the rosuvastatin component, the dissolution rate of the rosuvastatin component up to 120 minutes, which is the artificial gastric juice section, was within 5% in the two-phase matrix tablet of the silinidipine / rosuvastatin of Example 12. The dissolution rate of the rosuvastatin component in the artificial intestine section was 95% at 360 minutes in the control formulation, but the two-phase matrix tablet of silinidipine / rosuvastatin of Example 12 was about 360 minutes. It was confirmed that the release was delayed even more by 10%.

As described above, the two-phase matrix tablets of the silinidipine / rosuvastatin of the present invention, unlike the dissolution of the simultaneous injection of the silinidipine monotherapy and the rosuvastatin monotherapy, showed that the initial release of rosuvastatin calcium was much higher than that of the silinidipine. Because of its slowness, cynidipine is first metabolized in the liver, allowing ample time to regenerate the metabolic enzyme cytochrome P450.

[Silnidipine test method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 75 revolutions / minute

Test solution: 0.01M hydrochloric acid solution, 750 mL

Analysis method: high performance liquid chromatography

[Rosuvastatin Calcium Test Method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 50 revolutions / minute

Test solution: 0.01N hydrochloric acid solution, 750mL (artificial gas solution)

        pH 6.8 phosphate buffer, total 1,000mL (phosphoric acid solution)

Analysis method: high performance liquid chromatography

Experimental Example 3: Dissolution Test

A comparative dissolution test of the amlodipine / fluvastatin sodium capsule preparation prepared in Example 25 and the reference drug (Novask: amlodipine monotherapy, rescol (Novartis): fluvastatin sodium monotherapy) was performed. In the case of amlodipine component dissolution, the dissolution test was carried out based on the nine amendments of the Korean Pharmacopoeia General Test Method of Experimental Example 1. In the case of fluvastatin sodium component dissolution test, the eluate was changed from artificial gastric to artificial intestine at 120 minutes The dissolution test was carried out for 600 minutes as shown in FIG. 3.

According to FIG. 3, the capsules of Example 25 were found to exhibit almost the same elution characteristics as the control formulation of the amlodipine component in the dissolution test under the following conditions, and the fluvastatin component compared to the control formulation leschols. It can be seen that the elution is very slow. The dissolution test results of the fluvastatin component showed that the dissolution rate of the fluvastatin component up to 120 minutes, which is the artificial gastric juice section, was all within 10% in the capsules of amlodipine / fluvastatin of Example 25, but the control formulation was about 30%. The dissolution rate of fluvastatin components in the artificial intestinal fluid section was about 98% at 360 minutes in the control formulation, but the amlodipine / fluvastatin capsule of Example 25 was released at about 5% in total 360 minutes. This delay was confirmed.

As described above, the amlodipine / fluvastatin capsules of the present invention differ from the dissolution of the amlodipine monoclonal and fluvastatin monoclonal drugs, and thus the amlodipine is treated first because the initial release of fluvastatin sodium is much slower than that of amlodipine. After the metabolism in the metabolic enzyme cytochrome P450 can be obtained enough time to regenerate.

[Fluvastatin Sodium Test Method]

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 50 revolutions / minute

Test solution: 0.01N hydrochloric acid solution, 750mL (artificial gas solution)

        pH 6.8 phosphate buffer, total 1,000mL (phosphoric acid solution)

Analysis method: high performance liquid chromatography

Experimental Example 4: Dissolution Test

A comparative dissolution test was conducted for atorvastatin calcium in the formulations of Examples 3, 5, and 6. Dissolution test method is the same as Experimental Example 1, the results are shown in FIG.

4 shows that the controlled release nucleated tablet of the present invention was prepared using an enteric base as a binder (Example 3) and an enteric coating after nuclear tableting (Example 5, Example 6) in the dissolution test under the conditions of Experimental Example 1. ), All of the atorvastatin calcium components were released relatively rapidly after the delayed time to the intended time. Depending on the type of enteric base and enteric coating, the atorvastatin calcium component was rapidly released after a certain delay time.

As such, the formulations of the present invention may rapidly release HMG-CoA reductase inhibitors after a delay to the intended time.

Therefore, unlike the dissolution of a single dihydropyridine calcium channel blocker and a single HMG-CoA reductase inhibitor, the release of atorvastatin calcium is much slower than that of amlodipine. It is possible to secure enough time for the related enzyme cytochrome P450 to be regenerated, thereby reducing the possibility of side effects and the like.

Experimental Example 5: Dissolution Test

A comparative dissolution test was performed on the atorvastatin calcium in the capsules of Examples 21 and 27. The dissolution test method was the same as Experimental Example 1, and the results are shown in FIG. 5.

According to Figure 5 it was confirmed that the release of the HMG-CoA reductase inhibitor components of the present invention during the dissolution test under the conditions of Experimental Example 1 is very delayed.

As such, the capsule of the present invention can rapidly release the HMG-CoA reductase inhibitor component after a delay time until the intended time.

Therefore, since the early release of HMG-CoA reductase inhibitors is very slow, the capsule of the present invention has sufficient time to regenerate the metabolic enzyme cytochrome P450 after the dihydropyridine calcium channel blocker is first metabolized in the liver. can do.

Experimental Example 6: Blood Concentration Test

In this experiment, as a control group, commercially available 'Novask's tablets (amlodipine besylate 6.944 mg, Pfizer) and' Lipitor tablets' (atorvastatin calcium 10.85 mg, Pfizer) were administered alone, and the preparations prepared in Example 5 were used as experimental groups. In order to confirm the delayed-release effect of the preparations according to the present invention, blood concentration tests were performed.

On the other hand, the control group 1, control group 2, the test group for each test group was conducted in six people, a total of 18 people, the details are shown in Table 4.

Table 4

Blood concentration test results of amlodipine by the control group 1 and the test group are shown in Table 5 (blood concentration of amlodipine) and FIG. 6.

Table 5

The difference between the mean Tmax value of the test group and the control group was about 0.1 hours, and there was no significant difference between the Cmax value and the AUC (0-∞) value.

In conclusion, amlodipine showed similar blood levels between the two groups.

The blood concentration test results of atorvastatin by the control group 2 and the test group are shown in Table 6 FIG.

Table 6

It was found that the atorvastatin Tmax of the control group was about 0.5 hours, and the atorvastatin Tmax of the test group was delayed by about 9 hours or more compared to the Tmax of the atorvastatin of the control group 2.

On the other hand, the Cmax and AUC values of atorvastatin were not significantly different between the test group and the control group.

As a result, it was confirmed that the drug interaction according to the combination prescription can be excluded by dosing once a day in the morning with the time release release preparation according to the present invention (Example 5).

The preparation of the present invention reduces the side effects of drug interactions and is effective in the treatment and prevention of hypertension, hyperlipidemia and the resulting cardiovascular disease or metabolic syndrome due to pharmacological effect synergism, and can increase medication compliance.

Claims (28)

A morning pharmaceutical formulation comprising a pre-release compartment comprising a dihydropyridine calcium channel blocker as a pharmacologically active ingredient, and a delayed-release compartment comprising a HMG-CoA reductase inhibitor as a pharmacologically active ingredient. The pharmaceutical preparation according to claim 1, wherein the dihydropyridine calcium channel blocker of the pre-release compartment releases at least 80% of the total amount of the dihydropyridine calcium channel blocker within 1 hour after the start of release. The pharmaceutical formulation of claim 1, wherein the HMG-CoA reductase inhibitor is released 6 hours to 12 hours after the release of the dihydropyridine calcium channel blocker. The dihydropyridine calcium channel blocker according to claim 1, wherein the dihydropyridine calcium channel blocker is amlodipine, lercanidipine, lassidipine, felodipine, nifedipine, benidipine, vanidipine, silnidipine, manidipine, nicardidipine, isradypine, A pharmaceutical formulation selected from the group consisting of nisoldipine, nimodipine, nirenedipine, isomers thereof, and pharmaceutically acceptable salts. The method of claim 1, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, lovastatin, simvastatin, pitavastatin, rosuvastatin, fluvastatin, pravastatin, isomers thereof, and pharmaceutically acceptable salts Pharmaceutical preparations. The pharmaceutical formulation of claim 1, wherein the dihydropyridine-based calcium channel blocker comprises 1 to 400 mg of the formulation. The pharmaceutical formulation of claim 1, wherein the HMG-CoA reductase inhibitor comprises 1 to 160 mg of the formulation. The pharmaceutical formulation of claim 1, wherein the delayed-release compartment comprises one or more release controlling substances selected from enteric polymers, water insoluble polymers, hydrophobic compounds, and hydrophilic polymers. The pharmaceutical formulation of claim 8, wherein the release controlling substance is included in an amount of 0.1 to 50 parts by weight based on 1 part by weight of the HMG-CoA reductase inhibitor. The method of claim 8, wherein the enteric polymer is polyvinylacetate phthalate, methacrylic acid copolymer, hydroxypropyl methyl cellulose phthalate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, poly (methacrylate-methyl methacrylate) A pharmaceutical formulation, which is at least one selected from a copolymer and a poly (methacrylate-ethyl acrylate) copolymer. 10. The method of claim 8, wherein the water-insoluble polymer is polyvinyl acetate, polymethacrylate copolymer, poly (ethylacrylate-methyl methacrylate) copolymer, poly (ethylacrylate-methyl methacrylate-trimethylaminoethyl Methacrylate) copolymer, ethylcellulose, cellulose acetate, and mixtures thereof. The pharmaceutical formulation of claim 8, wherein the hydrophobic compound is at least one selected from the group consisting of fatty acids and fatty acid esters, fatty alcohols, waxes, inorganic substances, and mixtures thereof. 13. The fatty acid and fatty acid ester according to claim 12, wherein the fatty acid and fatty acid ester are at least one selected from glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and slearic acid. Or at least one selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol, the wax is at least one selected from carnauba wax, beeswax, and microcrystalline wax, or the inorganic substance is talc, precipitated calcium carbonate, calcium monohydrogen phosphate. A pharmaceutical formulation comprising at least one selected from zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and non-gum. According to claim 8, wherein the hydrophilic polymer is a drug selected from the group consisting of sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, hydrophilic polymethacrylate copolymers, polyethylene derivatives, carboxyvinyl copolymers, and mixtures thereof Pharmaceutical preparations. 15. The method of claim 14, wherein the saccharide is dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose And at least one cellulose derivative selected from amylopectin is hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, hydroxypropyl methylcellulose acetate succinate, and At least one of the gums selected from hydroxyethyl methyl cellulose is guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, gum arabic, gellan gum, and xanthan gum. The protein is gelatin, casein, and At least one selected from Jane The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone, and polyvinyl acetal diethylamino acetate. The polymethacrylate copolymer is poly (butyl methacrylate- (2-dimethylaminoethyl) meth One or more of the polyethylene derivatives selected from methacrylate-methylmethacrylate) copolymer, poly (methacrylate-methylmethacrylate) copolymer, and poly (methacrylate-ethylacrylate) copolymer are polyethylene glycol, and At least one carboxyvinyl polymer selected from polyethylene oxides is a carbomer. The pharmaceutical formulation of claim 1, wherein the formulation is in uncoated form. The pharmaceutical formulation according to claim 1, wherein the formulation is in the form of a two-phase matrix tablet obtained by tableting after the delayed-release compartment and the prior-release compartment are uniformly mixed. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a film-coated tablet consisting of a tablet consisting of a delayed-release compartment and a film-coating layer consisting of a prior-release compartment surrounding the exterior of the tablet. The pharmaceutical formulation according to claim 1, wherein the formulation is in the form of a multilayer tablet having a multilayer structure in which the delayed-release compartment and the prior-release compartment are layered. The pharmaceutical preparation according to claim 1, wherein the preparation is in the form of a nucleated tablet consisting of an inner core consisting of a delayed-release compartment and an outer layer consisting of a prior-release compartment surrounding an outer surface of the inner core tablet. The pharmaceutical formulation of claim 20, wherein the nucleated tablet is an osmotic nucleated tablet. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a capsule comprising particles, granules, pellets, or tablets consisting of delayed-release compartments, and particles, granules, pellets, or tablets consisting of prior release compartments. The pharmaceutical formulation of claim 22, wherein the tablet comprising the delayed-release compartment comprises an osmotic pressure-controlling agent within the tablet and an osmotic coated tablet having a semipermeable membrane coating base on the surface of the tablet. The pharmaceutical formulation of claim 1, further comprising a coating layer on the exterior of at least one of the delayed-release compartment or the prior-release compartment. The pharmaceutical formulation of claim 1, wherein the formulation further comprises a coating layer on the outside. The pharmaceutical formulation of claim 25, wherein the coating layer comprises a coating agent, a coating aid, or a mixture thereof. The pharmaceutical formulation of claim 1, wherein the formulation is in the form of a kit comprising a delayed release compartment and a prior release compartment. 28. A method of treating hypertension and hyperlipidemia, or thereby a cardiovascular disease or metabolic syndrome, comprising administering to a mammal a morning time-releasing agent of any one of claims 1 to 27.

Images