WO2008010690A1

WO2008010690A1 - Gastric retention-type pellet and the preparation method thereof

Info

Publication number: WO2008010690A1
Application number: PCT/KR2007/003522
Authority: WO
Inventors: Kwon Yeon Weon; Dong Wook Kim; Jin Seok Kim; Kyungwoon Kim
Original assignee: Handok Pharmaceuticals Co., Ltd.
Priority date: 2006-07-21
Filing date: 2007-07-20
Publication date: 2008-01-24
Also published as: KR20080009016A

Abstract

Disclosed herein are a gastric retention pellet, comprising: (1) an inner layer, comprising a drug and a pharmaceutically acceptable carrier; and (2) an outer layer comprising a polymer having mucoadhesive and drug release-controlling properties, as well as a preparation method thereof.

Description

Gastric retention-type pellet and the preparation method thereof

Technical Field

The present invention relates to a gastric retention pellet and a preparation method thereof.

Background Art

Mucoadhesive polymers are synthetic or natural polymer that can adhere to mucosal surfaces. The concept of such mucoadhesive polymers was introduced into the pharmaceutical literature more than 40 years ago, and recently, such polymers have been studied as promising strategies to deliver drugs to the target sites through various mucous membranes. Up to date, a considerable number of studies focused on the mucoadhesive properties of various polymers have been conducted using other experimental methods and techniques. In the case of drugs whose absorption is limited to the upper portion of the small intestine, there have been attempts to increase the bioavailability of the drugs using gastric retention formulations. Korean Patent Registration No. KR0545480 discloses swelling and expanding systems. However, such systems have problems in that they are greatly influenced by the amount of gastric contents and the retention time thereof, and can cause gastrointestinal troubles, when swollen formulations are not easily degraded. Also, gastric mucoadhesive formulations are less influenced by such changes, but have disadvantages of poor adhesive performance and increased sizes. Because there was no technology of forming the mucoadhesive polymer layer on the outside of a drug layer, the gastric mucoadhesive formulation was prepared in the form of a matrix comprising a drug dispersed on a mucoadhesive polymer layer. For this reason, it is impossible to avoid the shortcoming in that the adhesive performance of the formulation surface is decreased due to the presence of drug particles on the surface. Meanwhile, the technology disclosed in US Patent Publication No.

US2006/0045865, assigned to Spherics, Inc., attempted to coat a mucoadhesive polymer on the outside of a drug layer using spray coating. However, said coating process has a shortcoming in that a long processing time is required, because a large amount of polymer must be dissolved or dispersed. Also, Spheromer™ (poly(fumaric anhydride- co-sebacic anhydride), used in said technology, has a short retention time in the stomach and the small intestine compared to alginates.

Disclosure of Invention

Technical Problem It is an object of the present invention to provide a novel gastric retention formulation system overcoming the above-described problems occurring in the prior art. Specifically, the objects of the present invention are to provide a gastric retention formulation system that is not influenced by the amount of gastric contents and the retention time thereof in the stomach and has good adhesion to the gastric mucosa without the need to increase the size of the formulation; and to provide a preparation method thereof.

Technical Solution

The present invention relates to a gastric retention pellet and a preparation method thereof. More particularly, the present invention relates to a pharmaceutical preparation, which can slowly release a drug for retention in the upper portion of the intestinal tract and, at the same time, allows the drug to reside in the gastrointestinal tract for a given time, as well as a preparation method thereof. In one aspect, the present invention provides a gastric retention pellet comprising:

(1) an inner layer, comprising a drug and a pharmaceutically acceptable carrier; and

(2) an outer layer, comprising a polymer having the mucoadhesive and drug release-controlling properties.

The polymer having mucoadhesive and drug release-controlling properties is preferably at least one selected from the group consisting of polyacrylates and their copolymers, alginic acids and their salts or derivatives, celluloses, such as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) or carboxymethyl cellulose (CMC), polyalkylene oxide such as polyethylene oxide, and chitosan and its derivatives.

The drug is preferably selected from the group consisting of metformin hydrochloride, ciprofloxacin hydrochloride, furosemide, cimetidine, ranitidine hydrochloride and famotidine. In particular, metformin hydrochloride can use greatly the advantages of the gastric retention pellet according to the present invention.

In another aspect, the present invention provides a pharmaceutical preparation, which is a capsule having the inventive pellet filled therein, or a tablet obtained by compressing the inventive pellet. In the pharmaceutical preparation of the present invention, said capsule or tablet may further comprise an immediate-release drug pellet, and the tablet may also further comprise an immediate-release drug layer. In this case, in order to maximize the advantages of the present invention, it is particularly preferable that the drug is metformin hydrochloride, and the drug of the additional pellet or layer (that is, the drug to be released immediately) is glimepiride.

In still another aspect, the present invention provides a method for preparing the pellet of the present invention, comprising the steps of: (1) preparing an inner layer, comprising a drug and a pharmaceutically acceptable carrier; and (2) spraying, on the inner layer, a polymer powder comprising a polymer having mucoadhesive and drug release-controlling properties, through one or more first nozzle(s), and, at the same time, spraying a binder solution through one or more second nozzle(s), thus forming an outer layer.

In the prior art, the polymer layer could not be separately formed, because the polymer having mucoadhesive and drug release-controlling properties is highly viscous, and thus it is very inefficient in terms of dilution ratio and preparation time to prepare a solution of the polymer. However, in the present invention, this limitation is overcome by adopting a novel preparation method, such that the polymer can be formed as a layer separate from the drug. Accordingly, the phenomenon that the adhesive performance of the formulation surface is decreased due to the presence of drug particles does not occur, and thus the content of the polymer in the formulation can be minimized.

Hereinafter, the present invention will be described in detail.

In one embodiment of the present invention, the present invention provides an oral pharmaceutical preparation of gastric retention system for the treatment of diabetes, which comprises metformin and glimepiride, wherein the pharmaceutical preparation maintains the effective blood concentration of each of the drugs, and at the same time, has an increased absorption rate of metformin. Also, the present invention provides the preparation method thereof.

Diabetic patients, who should be administered with drugs for a long period of time, are mostly treated with a combination of two or more drugs, but the drug compliance of the patients is low, because methods for administering these drugs are frequently different due to the different properties of these drugs. For this reason, there have been attempts to prepare a combination formulation comprising two or more drugs having different half-life in blood.

Among diabetes-treating agents, biguanides such as metformin, sulfonylureas such as glimepiride or glyburide, alpha-glucosidase inhibitors such as acarbose, voglibose or miglitol, thiazolidinedione such as troglitazone or rosiglitazone, or the like, may be used in this combination formulation.

It is known that the absorption rate of metformin in the gastrointestinal tract can be increased through an increase in the retention time thereof in the gastrointestinal tract, and there have been attempts to utilize such drug properties. Examples of such attempts include: a method of administering a formulation formed of a mixture of a drug and an adhesive material, such that the adhesion of the formulation to the mucosa is induced to cause the formulation to reside; a method of preparing a formulation having a specific gravity lower than that of gastric contents is prepared, such that the formulation floats in the stomach to have a relatively long retention time; and a method of preparing a formulation capable of swelling larger than the size of particle that can be released through the pylorus in the stomach, such that the release rate of the formulation in the stomach is reduced.

Among them, in the case of the matrix-type muco adhesive formulation formed of a mixture of a drug with an adhesive material, the drug and the mucoadhesive polymer are exposed to the surface of the formulation depending on the amount of use thereof, and thus the mucoadhesive polymer should be used at high concentration in order to the adhesion of the formulation to the mucosa. Also, because the water- soluble drug is exposed to the surface, the initial release of the drug is very high, such that the bioavailability thereof can be reduced or the risk of side effects can occur. In addition, the drug cannot be completely released and is sometimes excreted in a state in which it is encapsulated in the polymer.

However, the present inventors developed a method capable of applying a highly viscous mucoadhesive polymer in the solid state to a drug layer. According to the present invention, a mucoadhesive and release-controlling layer forms separately from a drug layer, unlike the prior method. In the prior art, a highly viscous mucoadhesive material was mixed with a drug to form a formulation because the highly viscous adhesive polymer cannot be applied to the surface of the drug layer by a generally known coating method due to its high viscosity. Thus, according to the present invention, it is possible to prepare a formulation that has the following advantages: that mucoadhesiveness can be maximized even with a small amount of a polymer; that the initial release of a drug can be controlled, because the drug can be exposed to body fluid only after the penetration of body fluid through the swelling of the polymer and the drug is slowly released; and that the drug can be completely released after a given time, because the drug and the highly viscous polymer layer are completely separate from each other.

The pharmaceutical preparation of the present invention may be formulated in the dosage form of pellet particles, capsules having pellet particles filled therein, or tablets obtained by press-molding pellet particles, and the prepared particles should be dispersed rapidly in the stomach after administration.

Another embodiment may be a structure in which the mucoadhesive polymer encloses the surface of the prior-art drug release formulation which uses osmotic pressure.

Unlike the prior method, in the present invention, a drug for gastric retention is divided into a plurality of small unit granules, and a highly mucoadhesive polymer layer in a dried state is coated on the surface of the drug granules. Thus, due to the flowability of a surface gel layer formed by body fluid, the formulation is relatively less influenced by the peristaltic movement of the gastrointestinal tract. Also, because the formulation of the present invention behaves as a plurality of unit formulations, the risk due to the failure of adhesion to the gastric mucosa or the small intestinal mucosa is much reduced compared to a single unit formulation. As a result, the surface adhesiveness of the inventive formulation can be greatly increased compared to a general matrix-type formulation so as to maximize the gastric retention time of the formulation, thus increasing the therapeutic effect of the drug in vivo.

Gastrointestinal mucoadhesive materials, which can be used in the present invention, polyacrylates and their copolymers; alginic acids and their salts or derivatives; celluloses, such as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) or carboxymethyl cellulose (CMC), and their salts or derivatives; polyalkylene oxide such as polyethylene oxide; and chitosan and its salts or derivatives. Such gastrointestinal mucoadhesive materials have the property of adhering to the gastrointestinal tract and also control the release of a soluble drug to reduce the diffusion rate of the drug. Accordingly, these materials perform a combination of the gastric retention and controlled delivery of a soluble drug, and thus provide a very useful method for the application of a drug which is absorbed mainly in the upper portion of the gastrointestinal tract. For example, the present invention allows more effective application of metformin, which is highly soluble in water and absorbed mainly in the upper portion of the gastrointestinal tract, and it will also be useful for the application of drugs which need to be applied directly to the gastric mucosa.

Specific examples of drugs, which can be effectively applied according to the present invention, include those which are absorbed mainly in the upper portion of the small intestine, for example, metformin hydrochloride, ciprofloxacin hydrochloride and furosemide, or H₂ antagonists which act directly in the gastrointestinal tract, for example, cimetidine, ranitidine hydrochloride, famotidine and nizatidine.

Metformin is a type 2 diabetes-treating agent belonging to the biguanide family and is conventionally administered orally at a dose of 500-1000 mg 2-3 times a day. It is known to be incompletely absorbed slowly in the gastrointestinal tract and be absorbed mainly in the upper portion of the intestinal tract. It is known to have a half- life of 2-6 hours in blood, and it has a very high solubility, a very low absorption rate and a very short half-life, and thus needs to be prepared into a sustained-release formulation.

On the other hand, glimepiride is a type-2 diabetes-treating agent belonging to the sulfonylurea family, and is conventionally administered orally at a dose of 1-2 mg one time a day. It is almost completely absorbed in the gastrointestinal tract and has a long half-life of about 9 hours in blood. For this reason, it needs to be absorbed with rapid release, but, because it has a very low solubility, the solubility thereof should be increased for rapid dissolution. However, a drug should generally be maintained at a concentration higher than the effective blood concentration thereof in vivo in order to maximize the therapeutic effects thereof.

Thus, in a combination formulation of metformin and glimepiride, the metformin, having a relatively short half-life in blood, should be continually released from the formulation, while glimepiride, having a relatively long half-life in blood, should be immediately released from the formulation, such that the concentration of each drug in blood can be maintained at a constant level, thus achieving suitable therapeutic effects.

In the present invention, a highly viscous adhesive material is applied on a pellet- or tablet-type drug formulation. For this purpose, a formulation such as a pellet or tablet is placed on a high-speed rotating plate to which hot air is continually supplied. While the rotating plate having the formulation placed thereon is rotated at a given speed, a small amount of a highly viscous mucoadhesive polymer is sprayed on the formulation and, at the same time, a solution of a given amount of binder in water or solvent such as alcohol is added to the formulation, thus instantaneously applying the highly viscous musoadhesive polymer on the formulation.

Advantageous Effects In the present invention, preliminary experiments for proving the effects of the present invention were carried out, and the mucoadhesive property and drug dissolution behavior of the formulation prepared using the above-described method were assessed. The assessment results are shown in the accompanying drawings. FIG. 1 shows that the strength of the prepared pellet is so high that the pellet can be applied in clinical practice. In the case of FIG. 2, about 250 mg of mucin (porcine stomach type III) powder having properties similar to those of the biological mucous membrane was pressed with a force of 3 tons for 10 seconds using IR press, to form a disc having a diameter of about 13 mm. After the prepared pellet was attached to the disc for a given time, the force at which the pellet was detached from the disc was measured to assess whether the prepared pellet would be actually attached to the mucosa in clinical applications. The assessment results revealed that the pellet had good adhesion. In the case of FIG. 3, the adhesion between a highly viscous adhesive polymer to be used and mucin (porcine stomach type III) was assessed at the molecular level using a surface potential measurement method, and the assessment results showed that the adhesive polymer had good adhesion. In the case of FIG. 4, while the prepared pellet was rotated in 900 ml of artificial gastric juice using a paddle at a revolution speed of 50 rpm at 37 ^°C , the behavior of dissolution of a drug from the pellet was assessed. The assessment results revealed that the release of the drug from the pellet could be controlled. In the case of FIG. 5, while the prepared pellet was rotated in 900 ml of artificial intestinal juice using a paddle at a revolution speed of 50 rpm at 37 ^°C, the behavior of dissolution of a drug from the pellet was assessed. The assessment results revealed that the release of the drug from the pellet could be controlled. FIG. 6 shows that the pellet prepared according to the present invention can release a drug slowly compared to a matrix-type pellet prepared in Comparative Example 1. FIG. 7 shows that the formulation of the present invention can have a clinically significantly high blood concentration of metformin compared to a general metformin formulation, suggesting that it has more effective therapeutic effects. Accordingly, it was demonstrated that the gastric mucoadhesive formulation prepared according to the present invention has strength suitable for application in clinical practice, can slowly release a drug, and has the property capable of adhering to the mucosa, and thus can be used as a gastric retention formulation.

Description of Drawings

FIG. 1 shows the measurement results of the granule strength of Example 1 (B), Example 2 (D), Example 3 (A) and Example 4 (C).

FIG. 2 shows the measurement results of gastric mucoadhesive properties of Example 1 (B), Example 2 (D), Example 3 (A) and Example 4 (C). FIG. 3 shows the measurement results of zeta potentials of Example 1 (B),

Example 2 (D), Example 3 (A) and Example 4 (C).

FIG. 4 shows the results of dissolution tests of Example 1 (B), Example 2 (D),

Example 3 (A) and Example 4 (C) in artificial gastric juice (pH 1.2). FIG. 5 shows the results of dissolution tests of Example 1 (B), Example 2 (D), Example 3 (A) and Example 4 (C) in artificial intestinal juice (pH 6.8).

FIG. 6 shows the results of dissolution tests of Example 1 (o) and Comparative Example 1 (•) in artificial gastric juice (pH 1.2). FIG. 7 shows the change in the blood concentrations of Example 1 (o),

Example 2 (•) and Comparative Example 1 (D) as a function of time.

FIG. 8 shows the change in the blood glucose concentrations of Example 1 (o) and Comparative Example 1 (■) as a function of time.

Mode for Invention

Hereinafter, the present invention will be described in further detail with reference to examples. It is to be understood, however, that these examples are illustrative only and the scope of the present invention is not limited thereto.

Comparative Example 1

Preparation of metformin-polvmer mixture pellet

Metformin HCL 1 .00 kg

PVP K-30 0, .09 kg

Na-alginate 1. .00 kg

A mixture of metformin and sodium alginate was granulated with a binder of 10% PVP alcohol solution in a CF-granulator to form pellets, which were then dried. Example 1

Preparation of metformin pellets

Nonpareil® 101 (20-25mesh) 0.50 kg

Metformin HCl 1.00 kg PVP K-30 0.09 kg

Ethanol q.s.

Core pellets were rotated in a CF-granulator and, at the same time, supplied with air, which was warmed such that the temperature of the product was maintained at 15-30 ^°C . Metformin hydrochloride powder was supplied at a rate of about 10 g/min to the core pellets that rotate, while a binder of 10% PVP alcohol solution was sprayed thereto, so that the metformin hydrochloride was attached to the surface of the core pellets. The resulting pellets were dried for a given time.

Preparation of metformin pellets encapsulated in polymer

Metformin HCl pellets 25O g

Na alginate 500 g

PVP K-30 30 g

Ethanol q.s.

The metformin HCl pellets were rotated in a CF-granulator and, at the same time, supplied with air, which was warmed such that the temperature of the product was maintained at 15-30 ^°C . Na alginate was supplied at a rate of about 10 g/min to the metformin HCl pellets that rotate, while a binder of 10% PVP alcohol solution was sprayed thereto, so that the Na alginate was attached to the surface of the metformin HCl pellets. The resulting pellets were dried for a given time.

Example 2

Preparation of metformin pellets

NonpareiKDIOl (20-25 mesh) 0.50 kg

Metformin HCl 1.00 kg

PVP K-30 0.09 kg Ethanol q.s.

Preparation of metformin pellets encapsulated in polymer Metformin HCl pellets 250 g

Na carboxymethylcellulose 500 g

PVP K-30 30 g

Ethanol q.s. The metformin HCl pellets were rotated in a CF-granulator and, at the same time, supplied with air, which was warmed such that the temperature of the product was maintained at 15-30 "C . Sodium carboxymethylcellulose was supplied at a rate of about 10 g/min to the metformin HCl pellets that rotate, while a binder of 10% PVP alcohol solution was sprayed thereto, so that the Na carboxymethylcellulose was attached to the surface of the metformin HCl pellets. The resulting pellets were dried for a given time.

Example 3

Preparation of metformin pellets

Nonpareil® 101 (20-25 mesh) 0.50 kg

Metformin HCl 1.00 kg

PVP K-30 0.09 kg Ethanol q.s.

Core pellets were rotated in a CF-granulator and, at the same time, supplied with air, which was warmed such that the temperature of the product was maintained at 15-30 ^°C . Metformin hydrochloride powder was supplied at a rate of about 10 g/min to the core pellets that rotate, while a binder of 10% PVP alcohol solution was sprayed thereto, so that the metformin hydrochloride was attached to the surface of the core pellets. The resulting pellets were dried for a given time. Preparation of metformin pellets encapsulated in polymer Metformin HCl pellets 250 g

Hydroxypropylmethylcellulose 500 g PVP K-30 30 g Ethanol q.s.

The metformin HCl pellets were rotated in a CF-granulator and, at the same time, supplied with air, which was warmed such that the temperature of the product was maintained at 15-30 °C . Hydroxypropylmethylcellulose was supplied at a rate of about 10 g/min to the metformin HCl pellets that rotate, while a binder of 10% PVP alcohol solution was sprayed thereto, so that the hydroxypropylmethylcellulose was attached to the surface of the metformin HCl pellets. The resulting pellets were dried for a given time.

Example 4

Preparation of metformin pellets

Nonρareil®101 (20-25 mesh) 0.50 kg

Metformin HCl 1.00 kg

PVP K-30 0.09 kg Ethanol q.s.

Preparation of metformin pellets encapsulated in polymer

Metformin HCl pellets 250 g

Carbomer 934P 500 g

PVP K-30 30 g Ethanol q.s.

The metformin HCl pellets were rotated in a CF-granulator and, at the same time, supplied with air, which was warmed such that the temperature of the product was maintained at 15-30 ^°C . Carbomer 934P was supplied at a rate of about 10 g/min to the metformin HCl pellets that rotate, while a binder of 10% PVP alcohol solution was sprayed thereto, so that Carbomer 934P was attached to the surface of the metformin HCl pellets. The resulting pellets were dried for a given time.

Example 5 Preparation of metformin pellets

Nonpareil®101 (20-25 mesh) 0.50 kg Metformin HCl 1.00 kg

PVP K-30 0.09 kg Ethanol q.s.

Preparation of metformin pellets encapsulated in polymer

Metformin HCl pellets 25O g

Chitosan 500 g

PVP K-30 30 g

Ethanol q.s.

The metformin HCl pellets were rotated in a CF-granulator and, at the same time, supplied with air, which was warmed such that the temperature of a product was maintained at 15-30 ^°C . Chitosan was supplied at a rate of about 10 g/min to the metformin HCl pellets that rotate, while a binder of 10% PVP alcohol solution was sprayed thereto, so that the chitosan was attached to the surface of the metformin HCl pellets. The resulting pellets were dried for a given time.

Experimental Examples Materials

Metformin HCl: Farmhispania (Spain).

Hydroxypropylmethylcellulose (Metolose 90SH-100,000 SR; Shin-Etsu, Japan). Carbomer 934P (Cabopol®934 NF; Noveon, USA).

Na-alginate (Protanal®LF 240D; FMC biopolymer).

Sodium carboxymethylcellulose (Blanose®7M8SF; Hercules).

Core seed (Pareil®101, 20-40 mesh; Freund).

Mucin (from porcine stomach type III; SIGMA).

Experimental Example 1: Preparation of metformin pellets

Highly viscous mucoadhesive polymers were coated on metformin pellets using a method of applying the polymer slowly on the pellets in a CF-granulator.

This method is a very preferable method for coating highly viscous polymers. Four highly viscous mucoadhesive polymers were applied thereby to form metformin pellets, and a povidone-ethanol solution was used to induce the adhesion between the highly viscous mucoadhesive polymers and the metformin pellets. The theoretical amounts of drugs in the prepared pellets were 33% for HPMC, Na- Alginate and Carbomer 934P and 31.3% for Na-CMC.

Experimental Example 2: Strength measurement

A texture analyzer (Stable Micro Systems, UK) was used to measure the strength of the prepared pellets. For this purpose, a probe (type, P20) was lowered toward the pellet at a speed of 0.1 mm/sec, and after it was brought into contact with the pellet, the force at which the thickness of the pellet was reduced to 50% was measured. The arithmetic mean of the measured forces was recorded as the strength of the pellet. All measurements were repeated at least four times.

Experimental Example 3: Gastric mucoadhesive properties

To measure the adhesive properties of the prepared pellets, a texture analyzer

(Stable Micro Systems, UK) was used. Mucin (porcine stomach type III, Sigma) having properties similar to those of the biological mucous membrane was pressed with a force of about 3 tons using an IR press for 10 seconds to prepare a thin disc having a diameter of 13 mm. The prepared disc was attached to the lower end of a TPA probe using a double-sided adhesive tape, and the prepared pellet was swollen in artificial gastric juice (pH 1.2) for 5 min. and then placed below the mucin disc. The probe was lowered such that the mucin disc was in contact with the pellet, and then a pressing force of 0.1 N was maintained for about 3 minute to induce the bonding between the mucin disc and the pellet. Then, while the probe was moved upward at a speed of 0.5 mm/sec, the magnitude of force required for the mucin disc to be detached from the pellet was examined through a graph of time-force correlation. All measurements were repeated at least four times.

Experimental Example 4: Interaction between mucin particles and polymers In order to examine whether the bonding between the highly viscous mucoadhesive polymers used in the experiment and mucin particles occurs in the particle level, the following test was carried out. In this test, mucin (porcine stomach type III, Sigma) particles were dispersed in a buffer solution at a concentration of 0.005 w/v%, and each of the highly viscous mucoadhesive polymers was dispersed therein at a concentration of 0.005 w/v%. Herein, if the highly viscous mucoadhesive polymers had the property of adhering to the surface of the mucin particles, the surface properties of the mucin particles would be changed due to the adhesion, and such changes could be converted into numerical values by measuring zeta-potentials using the electrophoretic light scattering M/C (ELS-8000, Otsuka).

Experimental Example 5: Dissolution test

The dissolution properties of the metformin pellets coated with the highly viscous mucoadhesive polymers were evaluated. Dissolution tests were conducted by rotating the pellets in 900 ml of artificial gastric juice for about 2 hours and 900 ml of artificial intestinal juice for about 4 hours at a revolution of 50 rpm at a temperature of 37 ^°C using a paddle according to the dissolution test method of USP XXII.

The metformin pellets could be successfully coated with the highly viscous mucoadhesive polymers. Such pellets had strength suitable for handling in the preparation process, and in this experiment, the pellet coated with HPMC had the highest strength.

Experimental Example 6

7-week-old SD rats (230-270 g) were anesthetized with ketamine and xylazine HCl, and then the center of the chest at the collarbone was incised and the vein of the upper portion of the heart was incised in a V shape. Then, a polyethylene tube containing heparin-0.9% NaCl solution was inserted and fixed in the vein. A hole was made in the back of the rats, and the other end of the polyethylene tube was taken out through the hole. Then, the rats were fasted, stabilized, and administered with an aqueous solution of metformin HCl or the pellets in an amount corresponding to 100 mg/kg (bodyweight) of metformin HCl. After 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 9, 24 and 48 hours, blood was collected from the rats, the plasma was separated from the collected blood and diluted in heparin-0.9% NaCl solution, and then the concentration of metformin in the solution was measured by HPLC.

Experimental Example 7

Example 1 and Comparative Example 1 were administered to diabetes-induced rats to measure the blood glucose lowering effect thereof. Herein, the animal model was prepared as follows: 9-week-old Sprague-Dawley male rats were acclimatized for 1 week and then fasted for 1 day. Then, 25 mg/kg of streptozotocin was injected intra- abdominally into the rats to make a diabetes-induced animal model. The animal model was fasted for 24 hours while feeding only water, and then allowed to feed and water ad libitum. After 48 hours, the blood glucose levels of the rats were measured in the no- hungry state, and only rats having a blood glucose level of 200-250 mg/dl were selected for use in the test. The rats were administered with each of the pellets in an amount corresponding to 100 mg/kg (bodyweight) of metformin HCl, and after 0, 1, 2, 3, 4, 6 and 9 hours, blood was collected from the rats and measured for blood glucose levels using ACCU-CHEK Active Glucose® (ROCHE diagnostics GmbH, Germany). Industrial Applicability

As described above, the present invention provides a novel gastric retention formulation system, which overcomes the problems occurring in the prior art, is not influenced by the amount of gastric contents and the retention time thereof in the stomach, and has excellent gastric mucoadhesive properties without a need to increase the size of the formulation.

Furthermore, the present invention provides an excellent combination formulation, which rapidly releases glimepiride and, at the same time, releases metformin in a gastric retention state, thus greatly increasing the bioavailability of metformin.

Claims

1. A gastric retention pellet comprising:

(1) an inner layer, comprising a drug and a pharmaceutically acceptable carrier; and (2) an outer layer, comprising a polymer having mucoadhesive and drug release-controlling properties.

2. The gastric retention pellet of Claim 1, wherein the polymer having mucoadhesive and drug release-controlling properties is one or more selected from the group consisting of polyacrylates and their copolymers; alginic acids and their salts or derivatives; celluloses, such as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) or carboxymethyl cellulose (CMC), and their salts or derivatives; polyalkylene oxide such as polyethylene oxide; and chitosan and its salts or derivatives.

3. The gastric retention pellet of Claim 1, wherein the drug is selected from the group consisting of metformin hydrochloride, ciprofloxacin hydrochloride, furosemide, cimetidine, ranitidine hydrochloride and famotidine.

4. The gastric retention pellet of Claim 3, wherein the drug is metformin hydrochloride.

5. A pharmaceutical preparation, which is a capsule containing the pellet of Claim 1 filled therein, or a tablet obtained by tableting the pellet of Claim 1.

6. The pharmaceutical preparation of Claim 5, wherein said capsule or tablet further comprises an immediate-release drug pellet, or the tablet further comprises an immediate-release drug layer.

7. The pharmaceutical preparation of Claim 6, wherein the drug is metformin hydrochloride, and the drug of the immediate-release drug pellet or the immediate- release drug layer is glimepiride.

8. A method for preparing the pellet of Claim 1, the method comprising the steps of:

(1) preparing an inner layer, comprising a drug and a pharmaceutically acceptable carrier; and (2) spraying, on the inner layer, a polymer powder comprising a polymer having mucoadhesive and drug release-controlling properties, through one or more first nozzle(s), and, at the same time, spraying a binder solution through one or more second nozzle(s), thus forming an outer layer.