WO2006080630A1

WO2006080630A1 - Pharmaceutical combination preparation for oral delivery for the treatment of diabetes mellitus

Info

Publication number: WO2006080630A1
Application number: PCT/KR2005/003134
Authority: WO
Inventors: Kwon Yeon Weon; Dong Wook Kim; Tae Han Kim; Jung Hoon Kim; Eun Jung Kim
Original assignee: Handok Pharmaceuticals Co., Ltd.
Priority date: 2004-09-23
Filing date: 2005-09-22
Publication date: 2006-08-03
Also published as: KR100705210B1; WO2006080630A8; KR20060051510A

Abstract

Disclosed are a combined pharmaceutical preparation for oral delivery for treatment of diabetes mellitus, comprising a) an inner layer comprising metformin or a pharmaceutically acceptable salt thereof, a swellable polymer and a pharmaceutically acceptable excipient, b) a drug-free intermediate layer comprising a water-soluble polymer, and c) an outer layer comprising glimepiride and a releasing controller; and a method for preparing the same.

Description

[DESCRIPTION]

PHARMACEUTICAL COMBINATION PREPARATION FOR ORAL DELIVERY FOR THE TREATMENT OF DIABETES

MELLITUS

[Technical Field]

The present invention relates to a combined pharmaceutical preparation for oral delivery for treatment of diabetes mellitus. More specifically, the present invention relates to a combined pharmaceutical preparation for oral delivery for treatment of diabetes mellitus, which is a combined preparation capable of rendering a retention time of an effective blood concentration of individual drugs constant even when two different drugs, requiring different release patterns, namely an immediate- release type and sustained-release type, are combined into a single dosage form.

[Background Art]

Although most antidiabetic drugs, requiring chronic administration thereof, have been used in treatment of diabetes mellitus via combined use of more than two drugs, compliance of long-term administration patients to drug-taking is poor due to various administration methods of drugs resulting from different characteristics thereof. In order to cope with such problems, attempts have been made to formulate drugs having a different blood retention time into a single combined preparation, and among antidiabetic drugs, for example, biguanides such as metformin, sulfonylureas such as glimepiride and glyburide, alpha-glucosidase inhibitors (AGIs) such as acarbose, voglibose and miglitol, or thiazolidinedione preparations such as troglitazone and rosiglitazone may be utilized in such combined drugs.

For example, metformin is a biguanides medication for treatment of type 2 diabetes mellitus, and a conventional dose for oral administration thereof is in the range of 500 to 1,000 mg twice or thrice a day. Metformin is slowly and incompletely absorbed into the gastrointestinal tract and is known to be mainly absorbed in the upper part of the intestinal tract. A blood half-life of metformin is known to be 2 to 6 hours, exhibits very high solubility and very low permeability, and very short half-life in itself. Therefore, there is needs for formulation thereof into a sustained-release type preparation that slowly releases the drug. Whereas, glimepiride, for example, is a sulfonylurea medication for treatment of type 2 diabetes mellitus and a conventional dose for oral administration thereof is in the range of 1 to 2 mg once a day. Glimepiride is almost completely absorbed into the gastrointestinal tract and half-life thereof via continuous administration is about 9 hours. As such, since glimepiride has a long half-life, there is a need for drug absorption by rapid release. However, glimepiride has very low solubility and thus should be made to be rapidly released by enhancing solubility thereof. Meanwhile, in general, in order to maximize therapeutic effects of drugs, drugs should be maintained at a constant blood concentration equal to or higher than a therapeutically effective concentration following administration thereof. Therefore, a combined preparation of metformin and glimepiride should be formulated into a combination in ^■ which metformin having a short retention time in the blood should be released sustainedly thereof from the preparation, and glimepiride having a long retention time in the blood should be released immediately thereof from the preparation, such that practical concentrations of the respective drugs can be maintained constant in the blood, thereby being capable of obtaining proper therapeutic effects.

A conventional manner to formulate drugs having different retention time in the blood into a single preparation form by the following manners. The conventional manners involve separately preparing a drug having a short blood retention time and a drug having a long blood retention time into a component capable of slowly releasing the drug and a component capable of rapidly releasing the drug, respectively. After then, the resulting components are compressed into a single tablet. However, such a method, involving separately preparing two drug components and then compressing them into a single tablet, requires a special tablet machine capable of manufacturing a multi-layer tablet, and employs an excessive amount of an excipient in order to achieve smooth compression of tablet materials into a tablet, thus leading to an increase in tablet size. In addition, when employing extremely low drug concentrations, it is difficult to obtain a tablet containing a constant amount of the active drug. A variety of attempts have been made to solve such problems. For example,

US Patent No. 6,682,759 discloses a method for manufacturing a tablet comprising an immediate-release layer and a sustained-release layer, it is prepared by coating the immediate-release layer on a sustained-release tablet. International Publication No. WO 2003/026637 discloses a dosage form for the treatment of diabetes mellitus and conditions associated therewith, comprising an immediate-release composition containing a long-acting sulfonylurea, and further comprising a controlled release composition containing a biguanide.

However, the present inventors have confirmed in US Patent No. 6,682,759 that release of the drug in the outer layer, requiring immediate release, is hampered by a high-viscosity, high-molecular polymer in the inner layer, thereby being incapable of obtaining desired immediate release, due to non-separation of respective drug layers.

In addition, International Publication No. WO 2003/026637 partly mentions "optionally, a coat comprising one or more water-insoluble polymer(s) surrounding the inner layer", namely a water-insoluble polymer intermediate layer, but does not mention the fact that the high-viscosity, high-molecular weight polymer(s) in the inner layer adversely affect release of the drug in the outer layer, requiring immediate release. In fact, the present inventors have confirmed that the presence of such a water-insoluble intermediate layer leads to excessively sustained-release of the drug in the inner layer, and finally it is difficult to obtain desired drug release profiles. Further, in order to dissolve or disperse coating materials, the water-insoluble coating layer requires use of organic solvents such as ethanol, methanol, isopropyl alcohol, methylene chloride and acetone etc., but this leads to an increase in raw material costs at least 100 times higher than use of water. In addition, facilities used during a manufacturing process require installation of explosion proof facilities in order to prevent the risk of explosion due to use of the organic solvents, and furthermore facilities for treatment of the organic solvents in the air and sewage are necessary associated with discharge of the organic solvents. Such facilities require enormous installation costs. However, even though the organic solvents are treated using such facilities, there still remains a risk of environmental contamination, and fire. Furthermore, the most serious risk is the probability of damage to the central nervous system and liver of workers, where they are exposed to the organic solvents for a long period of time during a manufacturing process of the drug preparations. Additionally, it is difficult to completely eliminate the organic solvents in the course of a manufacturing process, and the remaining solvents are very detrimental to patients taking drug preparations, particularly to diabetics requiring long-term administration of drug preparations. A possibility of danger of the organic solvents, which are conventionally used, is fully described in guidelines for residual solvents such as Tolerable Daily Intake (TDI) presented by the International Program on Chemical Safety (IPCS)₅ Acceptable Daily Intake (ADI) presented by the World Health Organization (WHO), and Permitted Daily Exposure (PDE) stipulated by the International Conference on Harmonization (ICH).

[Description of the Drawings] The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

Fig. 1 is a graph showing results of a dissolution test of glimepiride, present on outer layers of the respective preparations in Example 1 (•) and Comparative Example 1 (o) (n=6);

Fig. 2 is a graph showing results of an dissolution test at pH 6.8 of metformin, present on inner layers of the respective preparations in Example 1 (o) and Comparative Example 1 (T) and a reference preparation (•) (n=6); and

Fig. 3 is a graph showing results of a dissolution test in a 0.1N hydrochloric acid solution and at pH 6.8 of metformin, present on inner layers of the respective preparations in Example 1 (o) and Comparative Example 1 (T) and a reference preparation (•) (n=6).

[Disclosure of Invention] [Technical Problem]

Therefore, the present invention has been made in view of the above problems, and it is an object of the present invention to provide a combined pharmaceutical preparation for oral delivery for treatment of diabetes mellitus, which is capable of rendering a retention time of effective blood concentrations of individual drugs constant. It is accomplished via effective release of individual drugs without interference with release each other, even when two different drugs requiring different release patterns, namely an immediate-release type and sustained-release type, due to a different blood retention time from one another, are formulated into a single dosage form.

It is another object of the present invention to provide a combined pharmaceutical preparation for oral delivery for treatment of diabetes mellitus, which can be prepared at low production costs due to an easy manufacturing method and simplified facilities, and is capable of solving problems associated with environmental contamination and adverse side effects on workers and patients, due to the absence of organic solvents.

[Technical Solution]

The present invention relates to a combined pharmaceutical preparation for oral delivery for treatment of diabetes mellitus. More specifically, the present invention relates to a combined pharmaceutical preparation for oral delivery for treatment of diabetes mellitus, which is a combined preparation capable of rendering a retention time of an effective blood concentration of individual drugs constant, even when two different drugs, requiring different release patterns, namely an immediate- release type and sustained-release type, are formulated into a single dosage form.

In accordance with an aspect of the present invention, the above and other objects can be accomplished by the provision of a combined pharmaceutical preparation for oral delivery for treatment of diabetes mellitus, comprising: a) an inner layer comprising metformin or a pharmaceutically acceptable salt thereof, a swellable polymer and a pharmaceutically acceptable excipient; b) a drug-free intermediate layer comprising a water-soluble polymer; and c) an outer layer comprising a sulfonylurea drug and a releasing controller. The content of metformin or the pharmaceutically acceptable salt thereof to be used is preferably in the range of 250 to 1,000 mg, and more preferably in the range of 500 to 1,000 mg per unit preparation.

The pharmaceutically acceptable salts of metformin include, for example, hydrochloride, succinate, fumarate, bromate, p-chlorophenoxy acetate and embonate. Preferred is a hydrochloride.

The sulfonylurea drug includes, for example, glimepiride, glyburide, gliclazide, glibornuride, glyhexamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, carbutamide, chlorpropamide and pharmaceutically acceptable salts thereof. In particular, glimepiride can be applied which is frequently used in a great deal of practical clinical application cases. The content of glimepiride is preferably included in the range of 1 to 8 mg, and more preferably in the range of 1 to 2 mg per unit preparation.

The sulfonylurea drug is very poorly water-soluble and therefore dissolution thereof can be improved by maximizing a surface area of the drug. In addition, since the sulfonylurea drug is contained in a tiny amount in the pharmaceutical preparation, it is preferred to decrease a particle size thereof and apply to the preparation to distribute uniformly in the preparation. Particularly preferably, the sulfonylurea drug has an average particle diameter of not more than 10 μm, with not less than 40% of particles being not more than 2.5 μm in diameter, and not less than 90% of particles being not more than 10 μm in diameter, and has a drug surface area of 5 to 8 g/m².

The swellable polymer is a release-controlling material that constitutes the inner layer of the preparation, and then serves to slowly release the drug from the inner layer. Therefore, any material can be employed as the swellable polymer, so long as it is swelled in a dissolution medium and then can exert the above-mentioned action. The swellable polymer is preferably a high-viscosity polymer having a viscosity of 1,000 to 100,000 cps, and more preferably a polymer having a viscosity of 4,000 to 100,000 cps.

As the preferred swellable polymer, mention may be made of exemplarily a high- viscosity cellulose derivative for controlled release of the drug. Examples of the high-viscosity cellulose derivative that can be used in the present invention include hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), crosslinked carboxymethyl cellulose, and derivatives thereof, methylcellulose (MC), ethylcellulose (EC), salts or derivatives thereof, carboxyvinyl polymers, polyvinyl alcohols, polymethacrylate polymers, and pharmaceutically acceptable biodegradable cellulose derivatives and any combination thereof, each having high viscosity. Particularly preferably, the high-viscosity cellulose derivative is hydroxypropyl methylcellulose with 8 to 12% hydroxypropyl substituent groups, having an average particle diameter of 40 to 60 μm, and a viscosity of 4,000 to 100,000 cps. The swellable polymer is preferably contained in the range of 1.0 to 90%, and more preferably in the range of 20 to 50%, based on the total weight of the combined pharmaceutically preparation. Meanwhile, in preparing the preparation, suitable release-controlling materials may be used depending upon characteristics of the drugs, and appropriate pharmaceutically acceptable excipients or additives may be employed as adjuvants for enhancing processability or controlling drug release.

As examples of the pharmaceutically acceptable excipients, mention may be made of microcrystalline cellulose, lactose, polyvinyl pyrrolidone, magnesium stearate and any combination thereof. The intermediate layer comprising a water-soluble polymer peels off the outer layer before drug release of the outer layer is inhibited by the high- viscosity polymer of the inner layer when the preparation is exposed to the dissolution medium, thereby rapidly separating the two layers, and then controls the rapid drug release from the outer layer, thus minimizing effects of the inner and outer layers on release of drugs therebetween. In addition, the intermediate layer minimizes effects of the inner and outer layers on drug stability therebetween, which may occur when two different drugs are formulated through various processes and are stored for extended periods of time. Further, when the drug in the inner layer is water-labile, permeability of water into the inner layer can be lowered by sufficient coating the intermediate layer within the range which does not affect drag release of the inner layer, thus being capable of further enhancing drug stability of the inner layer.

Therefore, the water-soluble polymer, a main ingredient of the intermediate layer, which will exert such action, is preferably a polymer having viscosity of not more than 6 cps. Examples of the water-soluble polymer that can be used in the present invention include cellulose derivatives such as hydroxypropyl methylcellulose

(HPMC), carboxymethyl cellulose (CMC), microcrystalline cellulose (MCC)₃ ethylcellulose (EC), methylcellulose (MC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) etc., and polymethacrylate polymers. These materials may be used alone or in any combination thereof.

Any material can be employed as the releasing controller, so long as it is a polymer that constitutes the outer layer of the preparation and is capable of rapidly releasing the drug from the outer layer. Therefore, the releasing controller is preferably a polymer having a viscosity of not more than 6 cps. In addition, the releasing controller is preferably a water-soluble or hydrophilic polymer. Particularly preferred is a water-soluble polymer. Examples of the releasing controller that can be used in the present invention include cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), microcrystalline cellulose (MCC), ethylcellulose (EC), methylcellulose (MC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) etc., and polymethacrylate polymer. These materials may be used alone or in any combination thereof. When forming the intermediate layer and outer layer of the preparation in accordance with the present invention, aqueous coating is preferably carried out using water as water-soluble coating solution. Upon forming the outer layer, in order to attain homogeneous dispersion of a hydrophobic drug in the solution and rapid release thereof, surfactants, fatty acids, oils, polyethylene glycol, alcohols or propylene glycol etc. may be employed in admixture with a coating material. As the surfactant, sodium lauryl sulfate (SLS) may be preferably used in the range of 0.1 to 10%, and more preferably in the range of 0.1 to 5%. The coating solution may be prepared by conventional methods well-known in the art. Where the material included in the inner layer needs to be blocked from light, pigments and screening agents may be included in the coating solution.

Further, in the combined pharmaceutical preparation in accordance with the present invention, in order to make active ingredients of the combined pharmaceutical preparation release after passage of a predetermined period of time, or in order to enhance stability of the drug in the outer layer, the outer part of the drug coating layer may be re-coated with a material selected from cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), microcrystalline cellulose (MCC), ethylcellulose (EC), methylcellulose (MC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP) etc. and hydroxypropyl methylcellulose acetate succinate (HPMCAS) etc., and polymethacrylate polymer.

The combined preparation in accordance with the present invention enables far rapid release of the drug from the outer layer due to no effects of the respective layers on drug release therebetween, by the presence of the intermediate layer made of the water-soluble polymer, thus resulting in effective drug release of individual layers, and consequently, is capable of rendering a retention time of an effective blood concentration of individual drugs constant. In addition, it is possible to further enhance drug stability. The intermediate layer using an insoluble film, partly disclosed in International

Publication No. WO 2003/026637, inevitably affects drug release of the inner core. In this fashion, where release of the drug is controlled by an external film, it is difficult to exhibit uniform dissolution of individual tablets unless the thickness of the insoluble film in the manufacturing process is kept constant, and an initial release amount of the drug is very small, thus making it difficult to express immediate drug action. Moreover, in case of the above, unexpected conditions in vivo lead to rupture of the tablets, thus having risk factors which renders proper control of drug release difficult, such as occurrence of dose-dumping. In contrast, the preparation of the present invention takes a matrix-type formulation, via use of a water-soluble film as the intermediate layer, instead of the insoluble film. Unlike a reservoir-type preparation exhibiting the above-mentioned disadvantages, the matrix-type preparation is a formulation in which the polymer is uniformly distributed in the preparation and thus forms a network capable of controlling release of the drug. As such, this matrix-type preparation exhibits very constant patterns in control of initial release and overall release of the drug, thus enabling safer administration of drugs, and therefore, from the past to the present time, most sustained-release preparations are formulated into matrix-type formulations.

In addition, the preparation in accordance with the present invention can be prepared at low production facility costs as compared to multi-layer tablets, due to formation of the respective drug layers for different drugs in the form of a coating, instead of a multi-layer tablet form. In addition, upon preparing the preparation, since it is possible to employ aqueous coating without use of organic solvents due to characteristics of the composition, there is no need for installation of explosion proof facilities, and it is possible to reduce production costs. Further, it is possible to prepare the preparation without environmental contamination and detrimental effects upon worker health, and it is also possible to administer the preparation to patients requiring chronic administration, without adverse side effects of residual solvents. Hereinafter, a method for producing a combined preparation in accordance with the present invention will be described by way of example. As the inner layer of the combined preparation in accordance with the present invention, metformin preparations such as granules, tablets and pills and the like can be used. Such metformin preparations can be prepared via conventional methods for preparing sustained-release type preparations, well-known in the art. That is, as the inner layer, metformin or a pharmaceutically acceptable salt thereof, a swellable polymer and a pharmaceutically acceptable excipient, together with water are introduced and homogeneously dispersed in a mixer. The resulting mixture is granulated and dried, thereby preparing granules having a predetermined size. The thus-prepared granules may be used directly or may be further compressed to use.

The intermediate layer can be prepared by coating a solution of a water- soluble polymer which was previously dissolved in water on the inner layer which was introduced in a coating apparatus.

The outer layer can be prepared as follow. First, a drug of interest, a surfactant and a pigment or screening agent (opacifier) are homogeneously dispersed in water using a dispersion apparatus. The resulting dispersion is mixed and homogeneously dispersed in the solution of the water-soluble polymer. As stirring continuously, the resulting mixture is coated until a final amount of the drug is coated, in the coating apparatus to which the inner layer having the intermediate layer applied thereon was introduced, thereby preparing an outer layer.

The combined preparation composition in accordance with the present invention may be administered in the form of a tablet, capsule or granule. Preferably, the composition takes the form of a compressed tablet.

The pharmaceutical composition in accordance with the present invention is orally administered. The preferred amount of a compound in accordance with the present invention to be administered may depend upon conditions, weight of patients, severity of disease, dosage form, administration routes and a period of time for administration, but may be appropriately determined by person skilled in the art. The preferred amount of the compound to be administered is as indicated hereinbefore. Administration may be effected once or multiple times a day.

[Advantageous Effects] The present invention enables rapider drug release of an outer drug layer than the inner drug layer and further enhanced stability of the drug due to no effects of different drug layers on drug release therebetween, via additional coating of a polymer material containing no drug between two or more different drug layers having different blood retention times (immediate-release layers and sustained-release layers) in a single preparation, such that the respective layers can be readily separated. In addition, the present invention is more preferred for patients requiring chronic administration due to the absence of problems associated with residual solvents which may occur upon coating using organic solvents, via use of an aqueous coating only without use of organic solvents in drug coating layers, and is also capable of reducing process costs.

Unlike US Patent No. 6,682,759, the present invention was capable of achieving rapider dissolution results of a glimepiride layer than the pharmaceutical preparation comprising no intermediate coating layer, via interposition of an additional intermediate coating layer between the core and drug coating layers. Therefore, the present invention provides a preferred combined preparation of an immediate-release type sulfonylurea drug and sustained-release type metformin.

[Mode for Invention]

Now, the present invention will be described in more detail with reference to the following examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.

Example 1

1-a. Preparation of metformin inner layer

Metformin hydrochloride : 500 mg

Hydroxypropyl methylcellulose, 100,000 cps : 430 mg Lactose : 30 mg

Polyvinyl pyrrolidone K-30 : 35 mg

Magnesium stearate : 5 mg

Total : 1000 mg Metformin hydrochloride, hydroxypropyl methylcellulose (viscosity: 100,000 cps), lactose and polyvinyl pyrrolidone K-30 were homogenized in a mixer, and a predetermined amount of water was added thereto, as a binding solution to obtain humidified granules. The resulting granules were sieved through a 50-mesh screen and the thus-sieved granules were dried in a fluidized bed dryer. Magnesium stearate was then added and mixed with the dried granules for a predetermined period of time, thereby obtaining granules having superior fluidity and compressibility. The granules were subjected to a given compression force, thereby gradually obtaining a metformin inner layer.

1-b. Preparation of intermediate layer Hydroxypropyl methylcellulose, 4.5 cps : 8.4 mg Polyethylene glycol : 1.6 mg Purified water : q.s.

Hydroxypropyl methylcellulose (viscosity : 4.5 cps) was added to an aqueous solution of polyethylene glycol, and mixed until a homogeneous drug coating solution was obtained.

The thus-prepared coating solution was sprayed to coat the inner layer in a coating machine.

1-c. Preparation of glimepiride outer layer

Glimepiride : 2 mg

Hydroxypropyl methylcellulose, 4.5 cps : 25 mg Polyethylene glycol : 5 mg

Sodium lauryl sulfate ; 1.5 mg Titanium dioxide : 1.7 mg Purified water : q.s.

Glimepiride, titanium dioxide and sodium lauryl sulfate were homogeneously dispersed in a predetermined amount of water, and the resulting dispersion was added and mixed with the separately prepared aqueous solution of hydroxypropyl methylcellulose (viscosity : 4.5 cps) and polyethylene glycol until a homogeneous drug coating solution was obtained.

1-d. The prepared drug coating solution was sprayed on the inner layer, which was previously coated with the intermediate layer, in a coating machine, such that the inner layer is finally coated to contain 2 mg of glimepiride, thereby obtaining a combined preparation.

Example 2

A pharmaceutical preparation was prepared in the same method as in Example 1 , using the following formula for the respective layers.

2-a. Preparation of sustained-release metformin inner layer

Metformin hydrochloride : 750 mg Hydroxymethyl cellulose, 100,000 cps : 400 mg Magnesium stearate : 6 mg Total : 1156 mg

2-b. Preparation of coating layer between inner and outer layers

Hydroxymethyl cellulose, 4.5 cps : 8.4 mg Polyethylene glycol : 1.6 mg

Purified water : q.s.

2-c. Preparation of immediate-release glimepiride outer layer

Glimepiride : 2 mg Hydroxymethyl cellulose, 4.5 cps : 25 mg

Polyethylene glycol : 5 mg

Sodium lauryl sulfate : 1.5 mg

Titanium dioxide : 1.7 mg

Purified water : q.s.

Example 3

A pharmaceutical preparation was prepared in the same method as in Example , using the following formula for the respective layers.

3-a. Preparation of sustained-release metformin inner layer

Metformin hydrochloride : 500 mg Hydroxymethyl cellulose, 100,000 cps : 280 mg Lactose : 30 mg Polyvinyl pyrrolidone K-30 : 35 mg Magnesium stearate : 5 mg

Total : 1000 mg

3-b. Preparation of coating layer between inner and outer layers Hydroxymethyl cellulose, 3 cps : 8.4 mg

Polyethylene glycol : 1.6 mg Purified water : q.s.

3-c. Preparation of immediate-release glimepiride outer layer Glimepiride : 1 mg

Hydroxymethyl cellulose, 4.5 cps : 25 mg

Polyethylene glycol : 5 mg

Sodium lauryl sulfate : 1.5 mg

Titanium dioxide : 1.7 mg Purified water : q.s.

Comparative Example 1

A pharmaceutical preparation was prepared in the same composition and manner as in Example 1 , except that an intermediate layer was not formed.

Comparative Example 2

Unlike the present invention using a water-soluble intermediate layer, the pharmaceutical preparation was prepared according to Example 5 of the cited invention, International Publication No. WO 2003/026637, using an insoluble intermediate layer.

Experimental Example 1. Dissolution test 1: Dissolution of drug from outer layer In order to confirm effects of the presence of the intermediate layer, which is a feature of the present invention, on drug dissolution from the outer layer, an dissolution test of glimepiride was performed on pharmaceutical preparations of Example 1 and Comparative Example 1, according to the following procedure. Comparative Example 1 corresponds to Examples of US Patent No. 6,682,759, which is a cited invention disclosing a dosage form comprising a core and a drug coating layer only, without the intermediate layer.

The dissolution test was carried out at 50 rpm in 900 ml of pH 9.0 Tris buffer at 37^°C , according to an dissolution method (Method II) described in the United States Pharmacopeia (USP). The each sample was withdrawn at the respective time points, and the contents of glimepiride were measured according to high pressure liquid chromatography described in USP (n=6).

The results thus obtained are shown in FIG. 1 and Table 1 below. The pharmaceutical preparation of Comparative Example 1, which was prepared without formation of the intermediate layer, exhibited very low dissolution of glimepiride present in the outer layer, while the pharmaceutical preparation of Example 1 exhibited rapid dissolution of glimepiride. Consequently, it can be confirmed that the presence of the intermediate layer in accordance with the present invention enables rapid dissolution of the drug from the outer layer requiring rapid drug release. In more detail, the polymer in the inner layer - a high viscosity, high content polymer used to induce slow release of metformin in the inner layer - contacts an dissolution medium, and swells, thereby presenting adverse effects such as trapping the drug of the outer layer. In this connection, it is presumed that the reason why such rapid dissolution of the drug is achieved is because the presence of the intermediate layer blocks such adverse effects.

Table 1

Experimental Example 2. Dissolution test 2: Dissolution of drug from inner layer In order to confirm effects of the presence of the intermediate layer, which is a feature of the present invention, on drug dissolution from the inner layer, an dissolution test of metformin was performed on pharmaceutical preparations of Example 1 and Comparative Example 2, and Glucophage XR preparation on the market as a reference preparation, according to the following procedure. Glucophage XR is a sustained-release version preparation of metformin of which therapeutic effects are clinically verified, thus being coming into the market. Comparative Example 2 corresponds to Example 5 of a cited invention, International Publication No. WO 2003/026637 utilizing an insoluble intermediate layer, unlike the present invention utilizing the water-soluble intermediate layer. The dissolution test of metformin was carried out at 37 "C in 900 ml of simulated intestinal fluid (pH 6.8), according to Method II described in USP. The each sample was withdrawn at the respective time points, and the contents of metformin were measured with high pressure liquid chromatography described in USP (n=6). The results thus obtained are shown in FIG. 2 and Table 2 below. The pharmaceutical preparation of Comparative Example 2 having the insoluble intermediate layer exhibited inordinate dissolution delay of metformin present in the inner layer, and thereby very low % dissolution of metformin at each time point, showing more than 10% difference in % dissolution of metformin until passage of 4 hours, and 7.2% difference after passage of 8 hours, as compared with the reference preparation, Glucophage XR. According to bioequivalence tests (BE Test), where differences in % dissolution therebetween are greater than 10% at any one of at least 3 time points for confirmation of dissolution in comparison with the pharmaceutical preparation of which therapeutic effects are already acknowledged, it is determined that therapeutic effects are not equivalent therebetween for determination of bioequivalence. Based on results of determination of bioequivalence according to the above test, it is considered that the preparation of Comparative Example 2 is incongruent. Whereas, in the pharmaceutical preparation of Example 1 , dissolution profiles of metformin were almost consistent with the reference preparation, Glucophage XR, over all of the time points. Therefore, it was confirmed that the presence of the insoluble intermediate layer in the preparation of Comparative Example 2 leads to excessive sustained-release effects on drug dissolution from the inner layer, but the presence of the water-soluble intermediate layer in accordance with the present invention exhibits moderate effects on drug dissolution from the inner layer without causing inordinate delay of drug release.

Table 2

Experimental Example 3. Dissolution test 3: dissolution of drug from inner layer

After administration, a sustained-release preparation releases a portion of drugs in the stomach, and then migrates to the small intestine after about 2 hours, thus continuing to release the drugs. Therefore, in order to examine release patterns of the drugs more suited for in vivo conditions, an dissolution test of Experimental Example 2 was re-coήducted on pharmaceutical preparations of Example 1 and Comparative Example 2 and a reference preparation according to the following test method.

The dissolution test was carried out at 37 ^°C , utilizing 900 ml of 0.1N HCl (for 0 to 2 hours) and 900 ml of simulated intestinal fluid (pH 6.8, for 2 to 12 hours), as sample withdrawn, according to USP Method I described in USP. The each sample was withdrawn at the respective time points and the contents of metformin were measured with high pressure liquid chromatography described in USP (n=6). The results thus obtained are shown in FIG. 3 and Table 3 below. Similar to the results obtained in Experimental Example 2, the preparation of Example 1 exhibited release profiles of metformin which are almost consistent with the reference preparation, Glucophage XR. In contrast, the preparation of Comparative Example 2 having the insoluble intermediate layer exhibited very poor dissolution of metformin from the initial time point to the time point 4 hours have passed. Therefore, it represented a maximum difference of 22% in % dissolution of metformin, as compared to the reference preparation. Further, the preparation of Comparative Example 2 hardly accomplished the dissolution of metformin until the dissolution time of 1 hour, and thus it is difficult to achieve immediate drug action and expression of drug action following administration thereof takes significant time. Because of these reasons, it was concluded that there were limitations to practical clinical application thereof.

Table 3

From the experimental results as described above, it can be confirmed that the presence of the water-soluble intermediate layer, which is a feature of the preparation in accordance with the present invention, blocks inhibition of drug release from the outer layer by the high-viscosity polymer present in the inner layer, in the course of an dissolution process. On this account, intermediate layer enables rapid-release of the drug of the outer layer while not interfering with moderate sustained-release of metformin in the inner layer.

Claims

[CLAIMS]

1. A combined pharmaceutical preparation for oral delivery for treatment of diabetes mellitus, comprising: a) an inner layer comprising metformin or a pharmaceutically acceptable salt thereof, a swellable polymer and a pharmaceutically acceptable excipient; b) a drug-free intermediate layer comprising a water-soluble polymer; and c) an outer layer comprising a sulfonylurea drug and a releasing controller.

2. The preparation according to claim 1, wherein the content of metformin or a pharmaceutically acceptable salt thereof is in the range of 250 to 1,000 mg per unit preparation.

3. The preparation according to claim 1, wherein the sulfonylurea drug is a drug selected from the group consisting of glimepiride, glyburide, gliclazide, glibornuride, glyhexamide, phenbutamide, tolazamide, tolbutamide, tolcyclamide, carbutamide, chlorpropamide and pharmaceutically acceptable salts thereof.

4. The preparation according to claim 3, wherein the sulfonylurea drug is glimepiride.

5. The preparation according to claim 4, wherein the content of glimepiride is in the range of 1 to 8 mg per unit preparation.

6. The preparation according to claim 1, wherein the sulfonylurea drug has an average particle diameter of not more than 10 μm, wherein particles having a diameter of not more than 2.5μm make up not less than 40% of the particles, and particles having a diameter of not more than 10 μm make up not less than 90% of the particles, and a surface area of 5 to 8 g/m².

7. The preparation according to claim 1, wherein the swellable polymer is a polymer having a viscosity of 1,000 to 100,000 cps.

8. The preparation according to claim 7, wherein the swellable polymer is a polymer having a viscosity of 4,000 to 100,000 cps.

9. The preparation according to claim 1, wherein the swellable polymer is a high- viscosity cellulose derivative for controlled release of the drug.

10. The preparation according to claim 9, wherein high- viscosity cellulose derivative is at least one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), cross-linked carboxymethyl cellulose, and derivatives thereof, methylcellulose (MC), ethylcellulose (EC), and salts or derivatives thereof, carboxyvinyl polymers, polyvinyl alcohols, polymethacrylate polymers and pharmaceutically acceptable biodegradable cellulose derivatives, each having high viscosity.

11. The preparation according to claim 9, wherein the high- viscosity cellulose derivative is hydroxypropyl methylcellulose with 8 to 12% hydroxypropyl substituent groups, having an average particle diameter of 40 to 60 μm, and a viscosity of 4,000 to 100,000 cps.

12. The preparation according to claim 1, wherein the content of the swellable polymer is in the range of 20 to 50%, based on the total weight of the combined pharmaceutical preparation.

13. The preparation according to claim 1, wherein the pharmaceutically acceptable excipient is at least one selected from the group consisting of microcrystalline cellulose, lactose, polyvinyl pyrrolidone, and magnesium stearate.

14. The preparation according to claim 1, wherein the water-soluble polymer is a polymer having a viscosity of not more than 6 cps.

15. The preparation according to claim 1, wherein the water-soluble polymer of the intermediate layer is at least one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), microcrystalline cellulose (MCC), ethylcellulose (EC), methylcellulose (MC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polymethacrylate polymer.

16. The preparation according to claim 1, wherein the releasing controller is a polymer having a viscosity of not more than 6 cps.

17. The preparation according to claim 1, wherein the releasing controller of the outer layer is at least one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), microcrystalline cellulose (MCC), ethylcellulose (EC), methylcellulose (MC), hydroxypropyl cellulose (HPC), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polymethacrylate polymers.