KR20170061219A

KR20170061219A - Controlled Released Hard Capsule Preparation

Info

Publication number: KR20170061219A
Application number: KR1020150165457A
Authority: KR
Inventors: 최연웅; 조상민; 장재상; 이남송; 기도형; 김보경
Original assignee: 한국유나이티드제약 주식회사
Priority date: 2015-11-25
Filing date: 2015-11-25
Publication date: 2017-06-05
Also published as: KR101869406B1

Abstract

[0001] The present invention relates to a controlled-release hard capsule preparation, and more particularly, to a capsule containing a first drug or a pharmaceutically acceptable salt thereof and a fast acting excipient; And a sustained release comprising a second drug or a pharmaceutically acceptable salt thereof and a release controlling polymer.

Description

[0001] Controlled Released Hard Capsule Preparation [

In the pharmaceutical industry, the drug delivery system technology that effectively transfers the necessary amount of drug to the action site in order to maximize the efficacy and the effect while minimizing the adverse effect of the drug along with the development of the new drug has been dramatically developed in order to create added value. In particular, the Controlled Released Drug Delivery System (DDS) technology, which slowly releases the drug and reduces the number of doses, is making rapid progress with this need. Drugs that are administered more than once a day may be converted to once-a-day dosing by this controlled-release drug delivery system technique to improve the patient's compliance with the medication. If the maximum blood concentration is above the effective blood level or the sudden drug Can increase the efficacy of the drug by increasing the effective blood concentration retention time.

However, despite the breakthrough of release-controlled drug delivery system technology, the application of conventional release-controlled drug delivery system techniques can achieve sustained release of the drug, There is a case that can not be done. Particularly, in the case of a drug which is poorly soluble and is administered into the body and the absorption is restricted to the small intestine, the bioavailability of the drug is markedly lowered when the drug is orally administered.

In view of the fact that it is difficult to maintain a rapid and constant pharmacological effect in a sustained-release pattern of a general drug, a two-phase elution is performed so as to allow release from the absorption site while exhibiting rapid drug efficacy after administration It is desirable to design formulations that not only have a profile (immediate release phase and delayed release phase) but also exhibit extended stagnation properties.

On the other hand, the development of a combination preparation having two or more pharmacological ingredients as one formulations to increase the convenience of taking and to reduce the content of each ingredient through synergistic action, thereby minimizing side effects and maximizing the therapeutic effect It is actively being done.

In the case of such a combination preparation, one ingredient may interfere with the absorption, distribution and metabolism of other ingredients during the absorption, metabolism, distribution, efficacy and excretion of the drug to reduce drug efficacy or increase side effects, It is required to develop an agent that can increase the drug efficacy and reduce the side effects, as compared with the case where the two components are separately administered as a single agent.

Thus, the present inventors have found that the present invention can provide a pharmaceutical composition which can exhibit an elongated stagnation property and a two-phase elution profile (immediate release phase and delayed release phase) so that the rapid pharmacological effect can be manifested and the pharmacological effect can be maintained for a long period, The present invention provides a pharmaceutical composition comprising a first drug or a pharmaceutically acceptable salt thereof and a fast acting excipient; And a sustained release comprising a second drug or a pharmacologically acceptable salt thereof and a release controlling polymer, wherein the preparation has a sustained uptake time and an initial effective blood concentration of the drug, And exhibits a specific elution profile capable of maintaining an effective blood concentration, thus completing the present invention.

It is an object of the present invention to provide a pharmaceutical composition which exhibits an extended stomach retention property and a two-phase elution profile (immediate release phase and delayed release phase) to enable rapid pharmacological effect development and long-term pharmacological effect maintenance, The present invention provides a release-controlled hard capsule preparation which can be eluted with a time difference.

In accordance with the above object,

A fastener comprising a first drug or a pharmaceutically acceptable salt thereof and a fast acting excipient; And

A second drug or a pharmaceutically acceptable salt thereof, and a release-controlling polymer including a release-controlling polymer.

Wherein the first drug is selected from the group consisting of rosacean, propranolol, metoprolol, verapamil, caberdiol, nimodipine, nicardipine, ferrodipine, amlodipine, enalapril, captopril, ramipril, lisinopril, , Tamsulosin, simvastatin, lovastatin, pravastatin, fluvastatin, cimetidine, famotidine, ranitidine, nizatidine, omeprazole, s omeprazole, lansoprazole, pantoprazole, rabeprazole, tenatoprazole, domperidone, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, Nitrofurantoin, atomocetin, tetracycline, oseltamivir, valacyclovir, diazepam, chlorodiaxanthide, imipramine, methylphenidate , May be selected from the trazodone, venlafaxine, Amit leaf ethylene, bupropion, gabapentin, quetiapine, zolpidem, saponite draw rate, cilostazol, non-carboxylic wave, levodopa and oxybutynin group consisting of.

The fast acting excipient may be selected from the group consisting of lactose, sucrose, dextrin, mannitol, xylitol, sorbitol, starch, microcrystalline cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, calcium hydrogenphosphate, And mixtures thereof.

Wherein the second drug is selected from the group consisting of rosatan, propranolol, metoprolol, verapamil, caberdiol, nimodipine, nicardipine, ferrodipine, amlodipine, enalapril, captopril, ramipril, lisinopril, , Tamsulosin, simvastatin, lovastatin, pravastatin, fluvastatin, cimetidine, famotidine, ranitidine, nizatidine, omeprazole, s omeprazole, lansoprazole, pantoprazole, rabeprazole, tenatoprazole, domperidone, But are not limited to, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, corticosteroids, Nitrofurantoin, atomocetin, tetracycline, oseltamivir, valacyclovir, diazepam, chlorodiaxanthide, imipramine, methylphenidate , May be selected from the trazodone, venlafaxine, Amit leaf ethylene, bupropion, gabapentin, quetiapine, zolpidem, saponite draw rate, cilostazol, non-carboxylic wave, levodopa and oxybutynin group consisting of.

The first drug and the second drug may be the same or different.

In the hard capsule preparation of the present invention wherein the first drug and the second drug are the same, the inner part comprises 20 to 40% by weight of the total weight of the active ingredient drug, and the western part comprises 60 to 80% Lt; / RTI >

The release controlling polymer may be at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carbomer, polyethylene oxide, carnenan, natural gum, guar gum, tragacanth, acacia gum, locust bean gum, xanthan gum, alginate , Polyvinyl alcohol, polyvinyl pyrrolidone, and mixtures thereof. The hydrophilic polymer may be at least one selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, and mixtures thereof.

In the hard capsule preparation of the present invention, the sustained-release part is formed from the group consisting of a methacrylic acid copolymer, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, and mixtures thereof as a release- And may further include a hydrophobic polymer selected from one or more species.

In the hard capsule preparation of the present invention, the extended part may contain 12 to 25% by weight, based on the total weight of the sustained release polymer, of the release-controlled polymer.

The sustained release may further comprise a pharmaceutically acceptable excipient.

The pharmaceutically acceptable excipient for use in the sustained release may be selected from lactose, sucrose, dextrin, mannitol, sorbitol, copovidone, methylcellulose, ethylcellulose, Calcium stearate, calcium stearate, croscarmellose sodium, crospovidone, carboxymethyl starch, methacrylate-divinylbenzene copolymer calcium, microcrystalline cellulose, starch, cyclodextrin, pregelatinized starch, Magnesium stearate, magnesium stearate, calcium stearate, glyceryl monostearate, sodium stearyl fumarate, talc, and mixtures thereof.

The inner zone may be in the form of granules and the middle zone may be in the form of pellets or mini tablets.

The pellet comprises a release coating layer comprising a) an inert core, b) a drug coating layer comprising a second drug formed on the surface of the inert core and a pharmaceutically acceptable excipient, and c) a polymer for release control formed on the surface of the drug coating layer May include.

In the pellet, the release-controlling layer formed on the surface of the drug coating layer may be a single layer or two or more multi-layered layers.

In the pellet, the release controlling layer may include a first release controlling layer formed on the surface of the drug coating layer and containing a mixture of a hydrophilic polymer and a hydrophobic polymer as a release controlling polymer, and a hydrophilic polymer as a release controlling polymer formed on the surface of the first release controlling layer. And the second emission control layer.

In the hard capsule preparation of the present invention, the mini tablet is prepared by mixing a) an inert core, b) a drug coating layer comprising a second drug formed on the surface of the inert core and a pharmaceutically acceptable excipient, and c) The pellet containing the release-controlling layer containing the polymer may be compression molded. The release control layer formed on the mini tablet surface may be a single layer or two or more multi-layered layers. In the mini tablet, the release control layer may include a first release control layer formed on the surface of the drug coating layer and including a mixture of a hydrophilic polymer and a hydrophobic polymer as a release control polymer, and a hydrophilic polymer as a release control polymer formed on the surface of the first release control layer. And the second emission control layer.

In the hard capsule preparation of the present invention, the mini-tablet may be a micro-tablet comprising a second drug and a pharmaceutically acceptable excipient and having a release-controlling layer containing a release-controlling polymer on the surface thereof. Wherein the release control layer comprises a first release control layer comprising a mixture of a hydrophilic polymer and a hydrophobic polymer as a release control polymer formed on the mini tablet surface, and a second release control layer formed on the surface of the first release control layer, the release control layer comprising a hydrophilic polymer 2 emission control layer.

The hard capsule preparation of the present invention may be administered once a day.

The controlled-release hard capsule preparation of the present invention comprises a first drug or a pharmaceutically acceptable salt thereof and a fast acting excipient; And a sustained release comprising a second drug or a pharmaceutically acceptable salt thereof and a release controlling polymer, thereby exhibiting an extended stomach retention and a two-phase elution profile (immediate release phase and delayed release phase) It is possible to exhibit a rapid pharmacological effect and to maintain the pharmacological effect for a long period of time.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic view showing a hard capsule preparation of controlled release type comprising a fast-release granule and a sustained-release pellet as one embodiment of the present invention.
Fig. 2 is a schematic diagram showing a controlled-release hard capsule preparation containing an immediate-preservative granule and a sustained-release mini-tablet as an embodiment of the present invention.

According to the present invention,

The hard capsule preparation of the present invention exhibits a two-phase elution profile in which the first phase comprises a first drug or a pharmaceutically acceptable salt thereof and an immediate-release excipient as an immediate release or immediate release phase, And the second phase is controlled by a sustained release containing a second drug or a pharmaceutically acceptable salt thereof and a release-controlling polymer as a delayed-release or sustained-release phase. In addition, since the hard capsule preparation according to the present invention can enhance the gastric adhesiveness of the western part by the release-controlling polymer contained in the western part, the residence time of the drug can be prolonged. Furthermore, it is possible to control the bioavailability by adjusting the content of the release-controlled polymer in the western part and the content of the immediate-release part and the western part to control the elution time and stagnation property. Accordingly, when the first drug and the second drug are the same, the hard capsule preparation of the present invention can be administered once a day by controlling the mechanism of release of the drug by the rapid and slow release phases and the gastric retentivity.

In the hard capsule preparation of the present invention wherein the first drug and the second drug are the same, the inner part comprises 20 to 40% by weight of the total weight of the active ingredient drug, and the western part comprises 60 to 80% .

Meanwhile, the hard capsule preparation of the present invention is capable of separating the dissolution pattern of the immediate-release phase and the sustained-release phase by each of the immediate-release and extended-release forms in one formulation, and thus exhibits different release patterns without affecting the mutual release Controlled release of the formulation is possible. When the first drug and the second drug are made into different combination preparations, time elution is enabled, which is more suitable for increasing the drug efficacy and reducing the side effects than when the two components are separately administered as a single drug.

The term " fast acting excipient " as used herein means a substance that rapidly elutes the drug of the immediate release and facilitates granulation. The fast acting excipients that can be used in the present invention include lactose, sucrose, dextrin, mannitol, xylitol, sorbitol, starch, microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, calcium hydrogen phosphate, But may be selected from the group consisting of hydrogen, calcium, calcium carbonate, and mixtures thereof, but is not limited thereto.

In the present invention, the immediate-release part may contain 30 to 70% by weight of the quick-acting excipient based on the total weight of the immediate-release part. When the quick-acting excipient is used in an amount less than 30% by weight based on the total weight of the sustained-release excipient, the elution of the active ingredient may be delayed and the rapid drug efficacy may be delayed. Which can cause side effects.

As used herein, the term "extended release " means a formulation that slowly dissolves in the body after administration and slowly elutes the drug.

The sustained release of the present invention is characterized by comprising a second drug or a pharmaceutically acceptable salt thereof and a release-controlling polymer.

The term "release controlling polymer " as used in the present invention means a substance that is used to release a drug over a long period of time. The release-controlling polymer may be a hydrophilic polymer that exhibits release control and mucoadhesiveness to improve sustained release and stagnation properties, or a pharmaceutically acceptable hydrophobic polymer that is not dissolved or hardly soluble in water together with such a hydrophilic polymer Can be used.

Examples of the hydrophilic polymer having mucoadhesive properties include hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carbomer, polyethylene oxide, carnenan, natural gum, guar gum, tragacanth, acacia gum, locust bean gum, But is not limited to, at least one selected from the group consisting of gum, alginate, polyvinyl alcohol, polyvinyl pyrrolidone, and mixtures thereof.

In the present invention, the release-controlling polymer is preferably a hydrophilic polymer which exhibits release control and adhesion to the mucous membranes and is capable of improving the release properties and stagnation properties. Specifically, the release-controlling hydrophilic polymer is capable of absorbing body fluids after oral administration to form a matrix to control the release of the drug, as well as allowing the slow outer layer to adhere to the gastric mucosa / So that it can stay on the floor until the adhesive strength is weakened by continuous shearing action.

In the present invention, the hydrophobic polymer which can be used as a polymer for emission control is selected from the group consisting of methacrylic acid copolymer, ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate and mixtures thereof And preferably a methacrylic acid copolymer or ethylcellulose can be used. However, any pharmaceutically acceptable hydrophobic polymer capable of controlling release according to the purpose of the present invention is not limited thereto.

In the present invention, the sustained release part may contain 12 to 25% by weight of the release-controlled polymer based on the total weight of the sustained release part. When the release-controlled polymer is used in an amount less than 12% by weight based on the total weight of the sustained-release polymer, it may be difficult to exhibit sustained release due to accelerated dissolution of the active ingredient. When the polymer is used in an amount exceeding 25% by weight, There is a concern.

Such pharmaceutically acceptable excipients may include diluents, binders, lubricants, disintegrants, and the like. The diluent serves to increase the volume of the preparation and may be selected from one or more members selected from the group consisting of lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogenphosphate, anhydrous calcium hydrogenphosphate, Can be used. The binder may be dissolved in a solvent and used for increasing the binding force of the preparation. Examples of the binder include polyvinylpyrrolidone, copovidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose , Hydroxypropyl alkylcellulose, and mixtures thereof, may be used. The lubricant improves the fluidity of the granulate to increase the filling of the die, which is the lower part of the tablet machine, and reduces the friction between the granules and between the granules and the punch-die at the top of the tablet machine Examples of the lubricant include stearic acid, stearate, talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white lead, titanium oxide, microcrystalline cellulose, Macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, talc, and mixtures thereof. The disintegrant is used to absorb water and promote disintegration of the drug to improve dissolution of the drug, such as Croscamellose sodium, Sodium starch glycolate, microcrystalline cellulose, Crospovidone (cross-linked povidone) and other commercially available polyvinylpyrrolidone (PVP, Povidone), low-substituted hydroxypropyl cellulose (low substituted), alginic acid, powdered cellulose , Starch, sodium alginate, and mixtures thereof.

Preferably, the pharmaceutically acceptable excipient is selected from the group consisting of lactose, sucrose, dextrin, mannitol, sorbitol, copovidone, methylcellulose, ethylcellulose, hydroxypropylalkylcellulose, sodium croscarmellose cellulose, croscarmellose cellulose calcium, Starch, cyclodextrin, pregelatinized starch, light anhydrous silicic acid, stearic acid, magnesium stearate, sodium stearate, calcium stearate, calcium stearate, calcium stearate, sodium lauryl sulfate, sodium carboxymethylcellulose, sodium carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, carboxymethylstarch, methacrylate-divinylbenzene copolymer calcium, microcrystalline cellulose, At least one selected from the group consisting of calcium stearate, glyceryl monostearate, sodium stearyl fumarate, talc, and mixtures thereof.

In the hard capsule preparation of the present invention, the extended part may be in the form of a pellet or a mini tablet.

The pellet comprises a release coating layer comprising a) an inert core, b) a drug coating layer comprising a second drug formed on the surface of the inert core and a pharmaceutically acceptable excipient, and c) a polymer for release control formed on the surface of the drug coating layer .

As used herein, the term "inert core " refers to the core or nucleus of a drug-free pellet which is a pharmacologically active ingredient, and any conventional core material known as the inert core may be used without limitation. For example, sugar spheres, sugar, Di-tab (TM) Rhodia and spherical microcrystalline cellulose (JRS) may be used, but the present invention is not limited thereto.

In the pellet, the inert core is preferably 20 to 50% by weight based on the total weight of the pellets.

In the pellet, the drug coating layer is formed on the inert core surface in the form of a mixture of a second drug and a pharmaceutically acceptable excipient, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, copovidone, gelatin, starch, sucrose , Methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose, and mixtures thereof can be used. The amount of the binder to be used is not particularly limited and may be used in an amount sufficient to form a drug coating layer. The drug coating layer may further comprise a lubricant as a pharmaceutically acceptable excipient. Examples of the lubricant include stearic acid, stearic acid, talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white lead, titanium oxide, microcrystalline cellulose, macrogol 4000 and 6000, Calcium hydrogen phosphate, talc, and mixtures thereof.

In the pellet, the release-controlling layer formed on the surface of the drug coating layer may be one or two or more layers. Examples of the release-controlling polymer used in the release-controlling layer include a hydrophilic polymer that exhibits release control and mucoadhesiveness to improve release and sediment retention properties, or a pharmaceutical composition which is not dissolved or hardly dissolved in water together with such a hydrophilic polymer Can be used as the hydrophobic polymer. Preferably, the release-controlling layer may be formed on the surface of the drug coating layer as a single layer by mixing the hydrophilic polymer and the hydrophobic polymer. In the pellet, the release-controlling polymer may be present in an amount of 10 to 20% by weight of the hydrophilic polymer and 2 to 5% by weight of the hydrophobic polymer based on the total weight of the sustained-release part. When the content of the polymer is out of the above range, the above retention property and sustained release property may not be satisfactory.

Alternatively, the emission control layer may comprise a first emission control layer formed on the surface of the drug coating layer as a mixture of the hydrophilic polymer and the hydrophobic polymer, and a second emission control layer formed on the surface of the first emission control layer with a hydrophilic polymer have. The weight ratio of the hydrophilic polymer in the first release controlling layer and the second releasing controlling layer in the pellet may be 1 to 2: 1. If the weight ratio deviates from the above ratio, the above retention property and sustained release property may not be satisfactory.

Examples of the hydrophilic polymer include hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carbomer, polyethylene oxide, carnenan, natural gum, guar gum, tragacanth, acacia gum, locust bean gum, xanthan gum, alginate , Polyvinyl alcohol, polyvinylpyrrolidone, and mixtures thereof, and may be one selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone, polyvinylpyrrolidone, and mixtures thereof. But is not limited thereto.

The release-controlling hydrophilic polymer can absorb the body fluids after oral administration to form a matrix to regulate the release of the drug, as well as to allow the slow outer layer to adhere to the gastric mucosal / mucosal layer and the continuous hydration or continuous shear action So that the adhesive can be stood on until the adhesive strength is weakened.

In one embodiment of the present invention, when high viscosity hydroxypropyl methylcellulose is used as the hydrophilic polymer for emission control, excellent release controllability and stagnation properties are achieved, preferably 50,000 to 150,000 cps, more preferably 70,000 to 12,000 cps Of high viscosity hydroxypropyl methylcellulose can be used.

According to embodiments of the present invention, the release control layer may be formed from a mixture of high viscosity hydroxypropyl methylcellulose and ethylcellulose. The high viscosity hydroxypropylmethylcellulose may be present in an amount of 10 to 20% by weight and the ethylcellulose may be present in an amount of 2 to 5% by weight based on the total weight of the wax. If the weight ratio of hydroxypropylmethylcellulose and ethylcellulose is out of the above range, the above retention property and sustained release property may not be satisfactory.

In the present invention, by forming the release-controlling layer including the hydrophilic polymer for emission control in multiple layers, the release property and stagnation property can be further improved.

The hard capsule preparation according to the present invention may further comprise a first release controlling layer formed on the surface of the drug coating layer as a mixture of the hydrophilic polymer and the hydrophobic polymer and a second release controlling layer formed on the surface of the first release controlling layer as a hydrophilic polymer The first release control layer plays a role of regulating the release of the drug so that the drug slowly dissolves and the second release control layer not only controls the drug release but also prevents the release of the drug from the gastric mucosa / Thereby increasing the stagnation resistance.

In one embodiment of the present invention, a first release controlling layer is formed using high viscosity hydroxypropyl methylcellulose as a hydrophilic polymer for emission control and ethyl cellulose as a hydrophobic polymer, and a second release controlling layer is formed using high viscosity hydroxypropyl methylcellulose Layer exhibited excellent stagnation and sustained release properties.

According to the present invention, the extended portion in the hard capsule preparation may be a mini tablet.

In the present invention, the mini-tablet refers to a tablet made by compressing a medicine into a certain shape, but it is possible to vary the diameter of the mini-tablet differently from the ordinary tablet without change in diameter, The smaller the number, the greater the number of mini tablets that can be injected into the capsule.

Said mini tablet comprising a) an inert core, b) a drug coating layer comprising a second drug formed on the surface of the inert core and a pharmaceutically acceptable excipient, and c) a release control layer comprising a release control polymer formed on the surface of the drug coating layer, The pellet may be compression molded. In the mini tablet, the release control layer may include a first release control layer formed on the surface of the drug coating layer and including a mixture of a hydrophilic polymer and a hydrophobic polymer as a release control polymer, and a hydrophilic polymer as a release control polymer formed on the surface of the first release control layer. And the second emission control layer.

Alternatively, the mini-tablet may be a mini-tablet comprising a second drug and a pharmaceutically acceptable excipient and having a release-controlling layer comprising a release-controlling polymer on the surface thereof. In the mini-tablet, the release-controlling layer may include a first release-controlling layer formed on the surface of the mini-tablet and containing a mixture of a hydrophilic polymer and a hydrophobic polymer as a release-controlling polymer, and a hydrophilic polymer as a release-controlling polymer formed on the surface of the first release- And the second emission control layer.

Such pharmaceutically acceptable excipients may include diluents, binders, lubricants, disintegrants, and the like. The diluent serves to increase the volume of the preparation and may be selected from the group consisting of lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogenphosphate, anhydrous calcium hydrogenphosphate, carbonate, saccharides and mixtures thereof . The binder may be dissolved in a solvent and used for increasing the binding force of the preparation. Examples of the binder include polyvinylpyrrolidone, copovidone, gelatin, starch, sucrose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose , Hydroxypropyl alkylcellulose, and mixtures thereof, may be used. The lubricant improves the fluidity of the granulate to increase the filling of the die, which is the lower part of the tablet machine, and reduces the friction between the granules and between the granules and the punch-die at the top of the tablet machine Examples of the lubricant include stearic acid, stearate, talc, corn starch, carnauba wax, light anhydrous silicic acid, magnesium silicate, synthetic aluminum silicate, hydrogenated oil, white lead, titanium oxide, microcrystalline cellulose, Macrogol 4000 and 6000, isopropyl myristate, calcium hydrogen phosphate, talc, and mixtures thereof. The disintegrant is used to absorb water and promote disintegration of the drug to improve dissolution of the drug, such as Croscamellose sodium, Sodium starch glycolate, microcrystalline cellulose, Crospovidone (cross-linked povidone) and other commercially available polyvinylpyrrolidone (PVP, Povidone), low-substituted hydroxypropyl cellulose (low substituted), alginic acid, powdered cellulose , Starch, sodium alginate, and mixtures thereof.

The size of the mini tablet may be 2 to 6 mm in size to be inserted into the hard capsule preparation.

The hard capsule preparation according to the present invention is characterized by being able to be administered once a day.

In one embodiment according to the present invention, a release-controlled hard capsule preparation comprising a fast-release and a slow-release containing cilostazol as the same active ingredient is prepared by using 900 ml of sodium laurylsulfate (0.5%) solution as a dissolution test medium , 20 to 30% after 2 hours, 60 to 70% after 8 hours, and 90% at 24 hours after the elution test (Experimental Example 1) was carried out according to Method 2 (paddle method, 50 rpm) (Table 6). &Lt; tb > < TABLE > Thus, the release-controlled hard capsule formulation of the present invention allows the rapidly released active ingredient to quickly reach the minimum effective treatment concentration, and the delayed-released active ingredient to maintain the effective blood concentration continuously for the scheduled time Not only is there an advantage, but it is also very useful in terms of pharmacology since dose and number of doses can be drastically reduced.

On the other hand, the hard capsule preparation of the present invention, in which the first drug and the second drug are different from each other, is capable of elution of time difference, so that it is more suitable for increasing the drug efficacy and decreasing side effects have.

In one embodiment of the present invention, a dissolution test was conducted on a combination preparation containing simvastatin and rosatan in the immediate-release part and the western part (Experimental example 2). As a result, the simvastatin ingredient in the immediate- (Table 9). However, it was confirmed that the dissolution of rosaceous component in the western part was delayed by 2 hours or more as compared with that of the comparative cosmetic preparation, and the preparation of the present invention showed a dissolution up to 120 minutes The dissolution rates were all within 10%, which was significantly lower than the dissolution rate (60%) of the control formulation (Table 10). Thus, the formulation of the present invention has the advantage that the time-controlled release of the two drugs can be effectively achieved, thereby reducing the side effects that can occur when the two drugs are taken at the same time.

The release-controlled hard capsule preparation according to the present invention comprises

Preparing a sustained-release formulation comprising a first drug or a pharmaceutically acceptable salt thereof and a fast acting excipient;

Preparing a sustained release comprising a second drug or a pharmaceutically acceptable salt thereof and a release controlling polymer; And

And filling the hard capsule with the inner and outer portions.

In the above production method, the step of preparing the sustained-release composition may be carried out by a method such as dry granulation, wet granulation, molten granulation, fluidized bed granule and the like. Preferably, the granules may be granulated by dry granulation, wet granulation, fluidized bed granulation, and the like.

In one embodiment of the present invention, the drug moiety is in the form of a granule and the sustained part comprises a) an inert core, b) a second drug formed on the surface of the inert core and a pharmaceutically acceptable excipient, and c) A hard capsule preparation in the form of a pellet comprising a release-controlling layer comprising a release-controlling polymer formed on a surface thereof,

Mixing and granulating a first drug or a pharmaceutically acceptable salt thereof and a rapid-acting excipient to prepare an immediate-release granule;

An inert core is coated with a coating liquid containing a second drug and a pharmaceutically acceptable excipient to form a drug coating layer,

Coating the drug coating layer with a coating solution containing a polymer for emission control to form a release controlling layer to prepare a sustained-release pellet; And

And filling the hard capsule with the sustained release granules and the sustained-release pellets.

The step of forming a release controlling layer in the manufacturing method may include forming a first release controlling layer including a mixture of a hydrophilic polymer and a hydrophobic polymer as a release controlling polymer on the surface of the drug coating layer, And forming a second emission control layer containing a hydrophilic polymer as a polymer.

In another embodiment of the present invention, when the western part is in mini-tablet form, the mini-tablet comprises a) an inert core, b) a drug coating layer comprising a second drug formed on the surface of the inert core and a pharmaceutically acceptable excipient, and c ) A pellet containing a release-controlling layer containing a release-controlling polymer formed on the surface of the drug coating layer may be compression molded. Said mini tablet comprising a) an inert core, b) a drug coating layer comprising a second drug formed on the surface of the inert core and a pharmaceutically acceptable excipient, and c) a release control layer comprising a release control polymer formed on the surface of the drug coating layer, To the pellet containing the additional pharmaceutically acceptable excipient, followed by mixing and molding. The emission control layer may be a single layer or two or more multi-layers. Wherein the emission control layer comprises a first emission control layer comprising a mixture of a hydrophilic polymer and a hydrophobic polymer as a emission control polymer on the surface of the drug coating layer and a second emission control layer comprising a hydrophilic polymer as a emission control polymer 2 release controlling layer.

Alternatively, the mini-tablet may be a mini-tablet comprising a second drug and a pharmaceutically acceptable excipient and having a release-controlling layer comprising a release-controlling polymer on the surface thereof. The mini-tablet may be prepared by granulating a mixture comprising a second drug and a pharmaceutically acceptable excipient, followed by tableting with a mini-tablet by adding an additional diluent, a binder, a disintegrant, and a lubricant, And a release controlling layer containing a release controlling polymer. The emission control layer may be a single layer or two or more multi-layers. Wherein the emission control layer comprises a first emission control layer comprising a mixture of a hydrophilic polymer and a hydrophobic polymer as a emission control polymer on the surface of the mini tablet and forming a first emission control layer on the surface of the first emission control layer comprising a hydrophilic polymer as a emission control polymer 2 release controlling layer.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example 1 to 3 and Comparative Example 1 and 2: Depending on the active ingredient content Internal preservation Granule and western part Pellet Preparation of a Hard Capsule Formulation Containing

According to the ingredients and contents shown in the following Table 1, cilostazol hard capsule preparations containing the immediate-release granules and the sustained-release pellets were prepared as follows.

One. Internal preservation Manufacture of granules

Cilostazol and lactose hydrate were put in a high-speed aliquot and mixed. Then, povidone K-30 solution previously dissolved in ethanol was added to prepare granules by a coalescence and granulation process. Magnesium stearate was mixed with the granules to form a fast- .

2. Western Pellet Produce

1) Formation of drug coating layer

Spherical microcrystalline cellulose having a size of 15 to 25 mesh was placed in a fluidized bed coater and coated with a coating solution prepared by dissolving cilostazol and hydroxypropylmethylcellulose as a binder in a mixed solution of water and ethanol (1: 2, weight ratio) To prepare a pellet having a coating layer formed thereon.

2) Formation of controlled release layer

The pellet formed with the drug coating layer was coated with a coating solution prepared by dissolving ethyl cellulose and hydroxypropyl methylcellulose in a mixed solution (1: 41.5, weight ratio) of water and ethanol in a fluidized bed coater to form a release controlling layer.

3. Hard capsule Filling

The prepared fast-release granules and the sustained-release pellets were filled into a No. 1 capsule using a capsule filling machine (DMF 1500, Daesan Pharmatech).

division Classification ingredient Example Comparative Example One 2 3 One 2 genus

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part chief ingredient Cilostazol 20.00 30.00 40.00 10.00 50.00 Excipient Lactose baggage 45.00 35.00 25.00 55.00 15.00 Binder Povidone K-30 4.50 4.50 4.50 4.50 4.50 Lubricant Magnesium stearate 0.5 0.5 0.5 0.5 0.5 Total (mg / capsule) 70.00 70.00 70.00 70.00 70.00 book

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part chief ingredient Cilostazol 80.00 70.00 60.00 90.00 50.00 Excipient Spherical microcrystalline cellulose 45 55 65 35 75 Binder Hydroxypropylmethylcellulose 7 7 7 7 7 Westernization
Mechanism Ethyl cellulose 3 3 3 3 3 Westernization
Mechanism High viscosity
Hydroxypropylmethylcellulose
(HPMC 2208) 15 15 15 15 15 Total (mg / capsule) 150 150 150 150 150 Total (mg / capsule) 220 220 220 220 220

Example 4 to 6 and Comparative Example 3 to 5: Depending on the polymer content for emission control Internal preservation Granules and Western Pellet Preparation of a Hard Capsule Formulation Containing

According to the ingredients and contents shown in Table 2 below, cilostazol hard capsule preparations containing the immediate-preservative granules and the sustained-release pellets were prepared in the same manner as in Examples 1 to 3 and Comparative Examples 1 and 2.

division Classification ingredient Example Comparative Example 4 5 6 3 4 5 genus

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part chief ingredient Cilostazol 30.00 30.00 30.00 30.00 30.00 30.00 Excipient Lactose baggage 35.00 35.00 35.00 35.00 35.00 35.00 Binder Povidone K-30 4.50 4.50 4.50 4.50 4.50 4.50 Lubricant Magnesium stearate 0.5 0.5 0.5 0.5 0.5 0.5 Total (mg / capsule) 70.00 70.00 70.00 70.00 70.00 70.00 book

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part chief ingredient Cilostazol 70.00 70.00 70.00 70.00 70.00 70.00 Excipient Spherical microcrystalline cellulose 40 50.5 35.5 33 59 35 Binder Hydroxypropylmethylcellulose 7 7 7 7 7 7 Westernization
Mechanism Ethyl cellulose 3 7.5 7.5 3 2 8 Westernization
Mechanism High viscosity
Hydroxypropylmethylcellulose
(HPMC 2208) 30 15 30 37 12 30 Total (mg / capsule) 150 150 150 150 150 150 Total (mg / capsule) 220 220 220 220 220 220

Example 7 to 10: Internal preservation Granules and Western Pellet Preparation of a Hard Capsule Formulation Containing

The cilostazol hard capsule preparation containing the immediate-preservative granules and the sustained-release pellets was prepared according to the methods described in Examples 1 to 3 and Comparative Examples 1 and 3 according to the ingredients and contents shown in the following Table 3, 10 was prepared by coating a coating solution prepared by dissolving hydroxypropyl methylcellulose in a mixed solution of water and ethanol (1: 41.5, weight ratio) after forming a release controlling layer (first release controlling layer) on the drug coating layer, A step of forming a release controlling layer was further performed.

division Classification ingredient Example 7 8 9 10 genus

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part chief ingredient Cilostazol 30.00 30.00 30.00 30.00 Excipient Lactose baggage 35.00 35.00 35.00 35.00 Binder Povidone K-30 4.50 4.50 4.50 4.50 Lubricant Magnesium stearate 0.5 0.5 0.5 0.5 Total (mg / capsule) 70.00 70.00 70.00 70.00 book

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part chief ingredient Cilostazol 70.00 70.00 70.00 70.00 Excipient Spherical microcrystalline cellulose 45 45 45 45 Binder Hydroxypropylmethylcellulose 7 7 7 7 Westernization
Mechanism
(First emission control layer)
Ethyl cellulose 4 4 4 4 High viscosity
Hydroxypropyl methylcellulose (HPMC 2208) 24 12 16 14 Westernization
Mechanism
(Second emission control layer) High viscosity
Hydroxypropylmethylcellulose
(HPMC 2208) 0 12 8 10 Total (mg / capsule) 150 150 150 150 Total (mg / capsule) 220 220 220 220

Example 11 and 12: Internal preservation Granules and Western Preparation of Hard Capsule Preparations Containing Mini Tablets

According to the ingredients and contents shown in Table 4 below, cilostazol hard capsule preparations were prepared as follows, comprising the immediate-preservative granules and the sustained-release mini-tablets as follows.

One. Internal preservation Manufacture of granules

2. Western Manufacture of mini tablets

1) Formation of drug coating layer

2) Formation of controlled release layer

The pellet formed with the drug coating layer was coated with a coating solution prepared by dissolving ethyl cellulose and hydroxypropyl methylcellulose in a mixed solution (1: 41.5, weight ratio) of water and ethanol in a fluidized bed coater to form a release controlling layer. In Example 12, hydroxypropylmethylcellulose was coated with a coating solution prepared by dissolving hydroxypropylmethylcellulose in a mixed solution (1: 41.5, weight ratio) of water and ethanol after formation of the emission control layer (first emission control layer) A step of forming a release controlling layer was further performed.

3) Mini tablet tablets

Low-substituted propylcellulose as a disintegrant and magnesium stearate as a lubricant were added to the pellet having the release-controlling layer formed thereon, and the mixture was compressed with a single-handed tableting machine to prepare a mini tablet having a diameter of 4-6 mm.

3. Hard capsule Filling

The prepared fast-release granules and the western-side mini-tablets were filled into a No. 1 capsule using a capsule filling machine (DMF 1500, Daesan Pharmatech).

division Classification ingredient Example 11 12 genus

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part chief ingredient Cilostazol 30.00 30.00 Excipient Lactose baggage 35.00 35.00 Binder Povidone K-30 4.50 4.50 Lubricant Magnesium stearate 0.5 0.5 Total (mg / capsule) 70.00 70.00 book

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part chief ingredient Cilostazol 70.00 70.00 Excipient Spherical microcrystalline cellulose 40 40 Binder Hydroxypropylmethylcellulose 7 7 Westernization
Mechanism
(First emission control layer)
Ethyl cellulose 4 4 High viscosity
Hydroxypropyl methylcellulose (HPMC 2208) 24 16 Westernization
Mechanism
(Second emission control layer) High viscosity
Hydroxypropylmethylcellulose
(HPMC 2208) 0 8 Disintegration Low-substituted propyl cellulose 4.5
4.5 Lubricant Magnesium stearate 0.5
0.5 Total (mg / capsule) 150 150 Total (mg / capsule) 220 220

Example 13 and 14: Internal preservation Granules and Western Preparation of Hard Capsule Preparations Containing Mini Tablets

According to the ingredients and contents shown in Table 5 below, cilostazol hard capsule preparations containing the immediate-preservative granules and the sustained-release mini-tablets were prepared as follows.

One. Internal preservation Manufacture of granules

2. Western Manufacture of mini tablets

1) Tablets in the western part of the mini tablet

After mixing cilostazol with microcrystalline cellulose, hydroxypropylmethyl cellulose, high viscosity hydroxypropyl methylcellulose (100,000 cps, HPMC 2208) and low-substituted hydroxypropyl cellulose (LHPC), povidone K-30 The resulting solution was combined and granulated. After drying and sizing, magnesium stearate was added and mixed, and the tablets were tableted with a single tablet machine.

2) Formation of controlled release layer of the western part mini tablet

The mini tablet was placed in a pan coater and coated with a coating solution prepared by dissolving ethyl cellulose and hydroxypropyl methylcellulose in a mixed solution of water and ethanol (1: 41.5, weight ratio) to form a release controlling layer. In the case of Example 14, hydroxypropylmethylcellulose was coated with a coating solution prepared by dissolving hydroxypropylmethylcellulose in a mixed solution (1: 41.5, weight ratio) of water and ethanol after formation of the emission control layer (first emission control layer) A step of forming a release controlling layer was further performed.

3. Hard capsule Filling

division Classification ingredient Example 13 14 genus

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part chief ingredient Cilostazol 30.00 30.00 Excipient Lactose baggage 35.00 35.00 Binder Povidone K-30 4.50 4.50 Lubricant Magnesium stearate 0.5 0.5 Total (mg / capsule) 70.00 70.00 book

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part chief ingredient Cilostazol 70.00 70.00 Excipient Spherical microcrystalline cellulose 40 40 Binder Hydroxypropylmethylcellulose 7 7 Westernization
Mechanism
(First emission control layer)
Ethyl cellulose 4 4 High viscosity
Hydroxypropyl methylcellulose (HPMC 2208) 24 16 Westernization
Mechanism
(Second emission control layer) High viscosity
Hydroxypropylmethylcellulose
(HPMC 2208) 0 8 Disintegration Low-substituted propyl cellulose 4.5
4.5 Lubricant Magnesium stearate 0.5
0.5 Total (mg / capsule) 150 150 Total (mg / capsule) 220 220

Experimental Example One: Cilostazol Dissolution test of preparation

Dissolution tests were conducted to evaluate the dissolution rates of the cilostazol preparations of Examples 1 to 14 and Comparative Examples 1 to 5.

The dissolution test was carried out by using 900 ml of sodium lauryl sulfate (0.5%) as a dissolution test medium, 50 rotations per minute according to the Korean Pharmacopoeia dissolution assay method (paddle method), and a dissolution temperature of 37 ± 0.5 ° C . 5 ml of the eluate was taken from each of the vessels at 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours after initiation of the elution test and filtered through a 0.45 탆 membrane filter. Was used as the sample solution, and the absorbances At and As were measured at a wavelength of 257 nm using a UV (spectrophotometer, Shimadzu, Japan). The results of the dissolution test are shown in Table 6.

Example Average dissolution rate (%) 0.5 hours 1 hours 2 hours 3 hours 4 hours 6 hours 8 hours 12 hours 16 hours 24 hours Example 1 5.2 10.1 20.5 30.6 43.6 55.5 67.0 80.2 93.1 99.8 Example 2 8.9 15.1 25.6 36.5 44.2 56.3 65.9 80.5 92.3 101.8 Example 3 13.5 18.5 30.1 40.3 50.1 59.1 68.8 83.2 92.5 103.5 Example 4 8.5 12.3 26.5 34.5 44.5 54.4 67.8 82.4 90.6 106.7 Example 5 8.6 11.2 27.7 35.6 45.1 56.1 69.5 85.6 93.2 104.1 Example 6 9.0 12.5 27.3 36.7 46.1 53.2 67.4 81.0 92.5 102.5 Example 7 8.5 13.5 26.2 36.5 44.2 56.2 66.7 82.5 93.1 106.1 Example 8 8.7 14.2 27.4 36.2 42.1 55.6 65.8 81.1 92.2 103.2 Example 9 8.8 12.8 28.3 36.7 43.9 55.5 65.5 80.6 92.3 105.1 Example 10 7.9 12.5 26.1 35.6 42.2 56.0 66.7 82.1 93.1 101.0 Example 11 8.5 13.3 27.1 34.5 42.0 56.2 67.5 83.0 93.2 101.9 Example 12 8.7 13.5 27.5 35.0 43.0 55.5 66.2 83.5 92.7 99.9 Example 13 8.2 12.7 26.5 36.5 44.2 56.2 67.5 82.5 92.1 99.8 Example 14 8.6 12.8 28.1 37.5 43.2 57.2 68.9 84.5 93.2 100.1 Comparative Example 1 3.2 9.8 17.2 22.3 32.8 45.5 55.0 68.7 79.8 88.1 Comparative Example 2 15.9 25.6 32.7 36.8 42.1 49.5 58.0 72.1 78.2 90.1 Comparative Example 3 8.1 16.1 22.5 33.5 42.1 47.2 57.0 68.9 72.9 95.1 Comparative Example 4 8.6 13.4 24.5 38.5 52.5 60.1 69.5 83.0 95.1 101.0 Comparative Example 5 7.8 12.1 23.6 37.5 40.1 55.5 68.2 80.0 90.2 99.8

The release-controlled hard capsule preparation according to the present invention was prepared by dissolving 900 ml of sodium lauryl sulfate (0.5%) in a dissolution test medium and performing a dissolution test according to Korean Pharmacopoeia dissolution assay method 2 (paddle method, 50 rpm) , 20-30% after 2 hours, 60-70% after 8 hours and 90% or more at 24 hours. In Comparative Example 1, the initial dissolution rate was too low, the active ingredient eluted slowly, and in Comparative Example 2, excessive drug eluted in the early stage, but the overall dissolution rate was low. In Comparative Examples 3, 4 and 5, the late dissolution rate was low and did not satisfy the dissolution criterion.

Example 15 and 16: Internal preservation Granules and Western Pellet Preparation of a Hard Capsule Agent (Composite) Containing

In the same manner as in Examples 1 to 3 and Comparative Examples 1 and 2, according to the ingredients and contents described in the following Table 7, except that the sustained-release drug was used as simvastatin and the sustained- A hard capsule preparation containing granules and sustained-release pellets was prepared. In the case of Example 16, hydroxypropylmethylcellulose was dissolved in a mixed solution of water and ethanol (1: 41.5, weight ratio) to form a release controlling layer (first release controlling layer) on the drug coating layer Thereby forming a second emission control layer.

division Classification ingredient Example 15 16 genus

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part chief ingredient Simvastatin 30.00 30.00 Excipient Lactose baggage 35.00 35.00 Binder Povidone K-30 4.50 4.50 Lubricant Magnesium stearate 0.5 0.5 Total (mg / capsule) 70.00 70.00 book

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part chief ingredient Rosatan 70.00 70.00 Excipient Spherical microcrystalline cellulose 45 45 Binder Hydroxypropylmethylcellulose 7 7 Westernization
Mechanism
(First emission control layer)
Ethyl cellulose 4 4 High viscosity
Hydroxypropylmethylcellulose
(HPMC 2208) 24 16 Westernization
Mechanism
(Second emission control layer) High viscosity
Hydroxypropylmethylcellulose
(HPMC 2208) 0 8 Total (mg / capsule) 150 150 Total (mg / capsule) 220 220

Example 17: Internal preservation Granules and Western Preparation of Hard Capsule Formulation (Composite) Containing Mini Tablets

In accordance with the components and contents shown in Table 8 below, except that the sustained-release drug was used as simvastatin and the sustained-release drug was used as rosavast, the sustained-release granules and the sustained-release mini-tablets were contained in the same manner as in Example 11 Lt; RTI ID = 0.0 > capsule. &Lt; / RTI > However, in the case of Example 18, hydroxypropyl methylcellulose was prepared by dissolving hydroxypropylmethylcellulose in a mixed solution (1: 41.5, weight ratio) of water and ethanol after formation of a release controlling layer (first release controlling layer) Coating with a coating liquid to form a second emission control layer.

division Classification ingredient Example 17 18 genus

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part chief ingredient Simvastatin 30.00 30.00 Excipient Lactose baggage 35.00 35.00 Binder Povidone K-30 4.50 4.50 Lubricant Magnesium stearate 0.5 0.5 Total (mg / capsule) 70.00 70.00 book

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part chief ingredient Rosatan 70.00 70.00 Excipient Spherical microcrystalline cellulose 45 45 Binder Hydroxypropylmethylcellulose 7 7 Westernization
Mechanism
(First emission control layer)
Ethyl cellulose 4 4 High viscosity
Hydroxypropylmethylcellulose
(HPMC 2208) 24 16 Westernization
Mechanism
(Second emission control layer) High viscosity
Hydroxypropylmethylcellulose
(HPMC 2208) 0 8 Total (mg / capsule) 150 150 Total (mg / capsule) 220 220

Experimental Example 2: Combination Dissolution test

In order to evaluate the dissolution rates of the combination preparations of Examples 15 to 18, a dissolution test was carried out.

The dissolution test method for each component was as follows. Simvastatin single agent (Zocor®, Korean MSD) and Rosatane single agent (Kozan®, Korea MSD) were used as control agents, and the results are shown in Tables 9 and 10 .

[Simvastatin dissolution test]

Dissolution test basis: Dissolution test method of Korean Pharmacopoeia

Test method: paddle method, 50 revolutions per minute

Test solution:

1) 0.01 M hydrochloric acid solution, 750 mL (0-2 hours)

2) pH 6.8 artificial intestinal fluid, 1,000 mL (after 2 hours)

Analytical method: Extracellular absorption spectrophotometry (detection wavelength up to 244 nm)

[How to test Rosa Tan]

Dissolution test basis: Dissolution test method of Korean Pharmacopoeia

Test method: paddle method, 50 revolutions per minute

Test solution:

1) 0.01 M hydrochloric acid solution, 750 mL (0-2 hours)

2) pH 6.8 artificial intestinal fluid, 1,000 mL (after 2 hours)

Analytical method: Extracellular absorption spectrophotometry (detection wavelength up to 240 nm)

Time (minutes) Simvastatin dissolution rate (%) Example 15 Example 16 Example 17 Example 18 Treaty 0 0 0 0 0 0 5 60.0 62.5 61.5 62.4 72.5 10 77.5 78.5 77.4 76.2 83.5 15 79.5 80.5 82.1 80.1 80.1 30 83.5 83.2 84.5 83.5 85.5 45 90.1 91.2 92.1 90.1 95.2 60 94.6 96.5 96.5 93.5 96.5 120 99.1 98.0 97.8 97.2 98.2 130 99.8 99.2 99.3 99.2 99.2 150 99.8 99.8 99.7 99.8 99.8 180 100.1 99.8 99.9 99.8 99.8 240 100.1 99.9 100.0 99.9 99.9 300 100.1 100.1 100.1 100.0 100.0 360 100.2 100.1 100.1 100.1 100.0 480 100.3 100.1 100.1 101.2 100.0

Time (minutes) Lossa solubility (%) Example 15 Example 16 Example 17 Example 18 Treaty 0 0 0 0 0 0 5 0 0 0 0 2 10 0 0 0 0 5 15 0 0 0 0 8 30 0 0 0 0 17 45 0 0 0 0 22 60 0 0 0 0 29 120 2 0 One 0 60.1 130 5 3 3 One 73.5 150 9 7 5 3 80.2 180 13 10 7 5 83.7 240 20 18 15 10 86.5 300 50 48 45 46 87.2 360 70 68 69 70 88.9 480 90 88 89 90 90

The simvastatin ingredient of the immediate-preservative was found to exhibit almost the same dissolution characteristics as compared with the control drug, Zocor® (Table 9), but the dissolution of rosatan in the western part was delayed by more than 2 hours (Table 10). In the formulation of the present invention, the dissolution rate of the losartan component was all within 10% until 120 minutes, which was significantly lower than the dissolution rate (60%) of the control preparation. Thus, it can be seen that the formulation of the present invention effectively achieves time-controlled release of the two drugs.

Claims

A fastener comprising a first drug or a pharmaceutically acceptable salt thereof and a fast acting excipient; And
A second drug or a pharmaceutically acceptable salt thereof, and a release-controlling polymer.

The method of claim 1, wherein the first drug is selected from the group consisting of rosatan, propranolol, metoprolol, verapamil, carvediol, nimodipine, nicardipine, ferrodipine, amlodipine, enalapril, captopril, The present invention relates to a pharmaceutical composition comprising at least one compound selected from the group consisting of folliculose, sertosuccine, terazosin, tamsulosin, simvastatin, lovastatin, pravastatin, fluvastatin, cimetidine, famotidine, lanitidine, nizatidine, omeprazole, s omeprazole, lansoprazole, pantoprazole, But are not limited to, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, But are not limited to, doxycycline, levocloxacin, nitrofurantoin, atomocetin, tetracycline, oseltamivir, valacyclovir, diazepam, chlorodiaxanthide, imipramine , Methylphenidate, trazodone, venlafaxine, amitriptyline, bupropion, gabapentin, quetiapine, zolpidem, sapoglylate, cilostazol, carbidopa, levodopa and oxybutynin In hard capsules.

The method of claim 1, wherein the second drug is selected from the group consisting of rosatan, propranolol, metoprolol, verapamil, carvediol, nimodipine, nicardipine, ferrodipine, amlodipine, enalapril, captopril, The present invention relates to a pharmaceutical composition comprising at least one compound selected from the group consisting of folliculose, sertosuccine, terazosin, tamsulosin, simvastatin, lovastatin, pravastatin, fluvastatin, cimetidine, famotidine, lanitidine, nizatidine, omeprazole, s omeprazole, lansoprazole, pantoprazole, But are not limited to, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, thiazolidinediones, But are not limited to, doxycycline, levocloxacin, nitrofurantoin, atomocetin, tetracycline, oseltamivir, valacyclovir, diazepam, chlorodiaxanthide, imipramine , Methylphenidate, trazodone, venlafaxine, amitriptyline, bupropion, gabapentin, quetiapine, zolpidem, sapoglylate, cilostazol, carbidopa, levodopa and oxybutynin In hard capsules.

The hard capsule preparation according to claim 1, wherein the first drug and the second drug are the same or different.

The hard capsule preparation of claim 4, wherein the at least one portion comprises from 20 to 40% by weight of the total weight of the active ingredient, and the western portion comprises from 60 to 80% by weight of the total weight of the active ingredient.

The method of claim 1, wherein the release-controlling polymer is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carbomer, polyethylene oxide, carnenan, natural gum, guar gum, tragacanth, Wherein the hydrophilic polymer is at least one hydrophilic polymer selected from the group consisting of polyvinyl alcohol, polyvinyl alcohol, polyvinyl pyrrolidone, and mixtures thereof.

[7] The release-controlling polymer according to claim 6, wherein at least one selected from the group consisting of methacrylic acid copolymer, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, &Lt; / RTI > wherein the hydrophobic polymer further comprises a hydrophobic polymer.

The hard capsule preparation according to claim 1, wherein the western part contains 12 to 25% by weight based on the total weight of the sustained release polymer.

The hard capsule preparation according to claim 1, wherein the extended part further comprises a pharmaceutically acceptable excipient.

10. The composition of claim 9 wherein the pharmaceutically acceptable excipient is selected from the group consisting of lactose, sucrose, dextrin, mannitol, sorbitol, copovidone, methylcellulose, ethylcellulose, hydroxypropylalkylcellulose, croscarmellose sodium, But are not limited to, cellulose calcium, croscarmellose sodium, crospovidone, carboxymethyl starch, methacrylate-divinylbenzene copolymer calcium, microcrystalline cellulose, starch, cyclodextrin, pregelatinized starch, At least one selected from the group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, sodium stearyl fumarate, talc, and mixtures thereof.

The hard capsule preparation according to claim 1, wherein the inner portion is in the form of granules and the outer portion is in the form of pellets or mini tablets.

12. The method of claim 11, wherein the pellet comprises: a) a drug coating layer comprising a) an inert core, b) a second drug formed on the surface of the inert core and a pharmaceutically acceptable excipient, and c) &Lt; / RTI > wherein the release control layer comprises a release control layer.

13. The hard capsule preparation according to claim 12, wherein the release-controlling layer formed on the surface of the drug coating layer is a single layer or two or more layers.

14. The release-controlling layer of claim 13, wherein the release-controlling layer comprises a first release-controlling layer formed on the surface of the drug coating layer and comprising a mixture of a hydrophilic polymer and a hydrophobic polymer as a release-controlling polymer, And a second release control layer containing a polymer.

12. The pharmaceutical composition according to claim 11, wherein the mini-tablet comprises: a) a drug coating layer comprising a) an inert core, b) a second drug formed on the surface of the inert core and a pharmaceutically acceptable excipient, and c) Wherein the pellet comprising the release-controlling layer is compression molded.

12. The hard capsule preparation according to claim 11, wherein the mini tablet has a release control layer comprising a release-controlling polymer on the surface of a mini-tablet comprising a second drug and a pharmaceutically acceptable excipient.

[15] The composition of claim 15, wherein the release control layer comprises a first release control layer comprising a mixture of a hydrophilic polymer and a hydrophobic polymer as a release control polymer formed on the surface of the drug coating layer, and a release control polymer formed on the surface of the first release control layer, And a second release control layer containing a polymer.

17. The release-controlling layer of claim 16, wherein the release-controlling layer comprises a first release-controlling layer comprising a mixture of a hydrophilic polymer and a hydrophobic polymer as a release-controlling polymer formed on the mini-tablet surface, and a hydrophilic polymer And a second release control layer containing a polymer.

19. The hard capsule preparation according to any one of claims 1 to 18, wherein the preparation is administered once a day.