WO2008050987A1

WO2008050987A1 - Combination formulation with controlled release comprising metformin and glimepiride

Info

Publication number: WO2008050987A1
Application number: PCT/KR2007/005197
Authority: WO
Inventors: Sung Wuk Kim; Sung Soo Jun; Young Gwan Jo; Ja-Seong Koo; Yoon-Sik Jun
Original assignee: Hanall Pharmaceutical Co., Ltd.
Priority date: 2006-10-23
Filing date: 2007-10-23
Publication date: 2008-05-02
Also published as: KR100812538B1

Abstract

The present invention relates to a controlled-release metformin-glimepiride combination formulation, and particularly to a controlled-release metformin- glimepiride combination formulation for oral administration, where a controlled- release layer is constructed so that the release of metformin having high water solubility and high unit dose may be maintained for 24 hours by selectively designing a release-controlling material and an immediate-release layer is constructed so that the content of glimepiride having low water solubility and low unit dose may be maintained uniform and it may also be immediately released. In particular, a controlled-release metformin-glimepiride combination formulation herein may be embodied into a multi-layered tablet, where a controlled-release layer and an immediate-release layer are separated to completely separate metformin and glimepiride so that excipients constructing the controlled-release layer may not affect an rapid release of glimepiride, thereby minimizing the interaction of drugs and maintaining the complementary activities of the drugs, thus being efficacious for especially type 2 diabetes.

Description

[DESCRIPTION]

[Invention Title]

Combination formulation with controlled-release comprising metformin and glimepiride

[Technical Field]

The present invention relates to a controlled-release metformin-glimepiride combination formulation for oral administration, which minimizes the interaction between metformin and glimepiride and maintains complementary activities of the drugs, thus being efficacious for especially type 2 diabetes.

[Background Art]

Type 2 diabetes (DM), is a non-insulin-dependent diabetes that can be aggravated by a person's life pattern even though it is related to genetic inheritance or an autoimmune disease. It develops when the body produces an insufficient amount of insulin or when the insulin produced does not work properly(known as insulin resistance). A most common treatment is to control hyperglycemia caused by insulin resistance and insulin secretory defect, dyslipidemia, disorders of glucose metabolism and disorders of other factors, while preventing hypoglycemia from the drug therapy.

For this purpose, it is clinically ascertained that a combination therapy of drugs having a different mechanism may result in a synergistic efficacy, and control the level of blood glucose more effectively than high dose of a single component.

Of the antidiabetic drugs, sulfonylurea derivatives have been used almost exclusively in the type 2 diabetes. They control hyperglycemia by increasing the secretion of insulin from the beta cells in the pancreas. However, when administered for a long period of time, sulfonylureas can induce side effects such as hypoglycemia, weight gain, aggravated plasma lipid profile, no secretion of insulin, while showing frequent incidence of hypoglycemia. Further, 10-20% of diabetes patients taking sulfonylureas show no therapeutic efficacy from the beginning. Therapeutic efficacy decreases by 5-20% after its administration for a period of 1-2 years, and by 50% 10 years later. Thus, a combination therapy with other oral antidiabetics is considered to overcome this problem.

Biguanides, thiazolidinediones and alpha-glucosidase inhibitors are considered as a drug that may be used in combination with sulfonylureas.

The biguanides control hyperglycemia by suppressing glucose production and increasing peripheral glucose uptake by decreasing insulin resistance.

It was recently ascertained that sulfonylureas and biguanides synergistically act in the control of blood glucose level by using a different pharmacological mechanism, and the combination therapy has been clinically conducted.

A representative example of biguanides is metformin and, among sulfonylureas, glyburide or glimepiride is usually administered in combination with metformin. It is reported that the administration of metformin in combination with sulfonylureas is remarkably efficacious in controlling the level of blood glucose even for patients who have failed in using a single therapy of sulfonylureas.

Therefore, a combination therapy of drugs having a different mechanism is on an increase for complementarily controlling the level of blood glucose. According to the prescription data, about 60% of prescribed metformin has been used in combination with sulfonylureas. The combination use of metformin and glyburide, one of sulfonylureas, is reported in the following references. Vigneri et al. discloses a combination use of 1500 mg/day of metformin and 15 mg/day of glyburide for a patient, who suffers from type 2 diabetes and has failed in the therapy of 15 mg/day of glyburide [Treatment of NIDDM Patients with secondary failure to Glyburide: Comparison of the Addition of Either Metformin or Bed-Time NPH Insulin to Glyburide, Diabete & Metabolism, 1991, 17, 232-234].

WO 01/032158 discloses the use of a low dose of antidiabetics comprising metformin and glyburide (i.e., sulfonylureas) as first line therapy for treating diabetes in drug-naive patients. This publication describes that a mixture formulation which contains lower dose of drugs that in the generally used dose in the clinical for the first line therapy in treatment of diabetes.

However, the mixture of single pills may be useful not only for first line diabetes patients taking a thrice-daily administration of metformin hydrochloride or an once-daily administration of sulfonylureas, but also for second line diabetes patients who take both metformin and sufnoylureas.

Meanwhile, in current clinical practice metformin and glimepiride would be used to be co-administered when needed. In this case, metformin is generally administered three times a day and a long-acting glimepiride is administered once a day. This difference in medication frequency may cause confusion. If metformin and glimepiride are administered once a day, it is difficult to maintain the level of blood glucose constantly because metformin is rapidly eliminated in the body and the synergistic action with glimepiride does not work effectively for a long period of time.

Korean patent application publication No. 2006-6469 discloses a combination product comprising metformin and glimepiride for a clinically synergistic effect. However, in this publication, the metformin formulation is to be designed as a short-acting tablet without having controlled-release property, and therefore metformin is to be released following a dissolution pattern of a short-acting tablet to be rapidly absorbed and eliminated, resultly in the failure of a daily long-term synergistic effect with glimepiride.

Korean patent application publication No. 2004-79980 discloses a process of preparing an orally administered formulation which is delivering both an immediate-release drug and a controlled-release drug. Specifically, the formulation therein comprises a controlled-release layer including metformin hydrochloride and an immediate-release layer containing glimepiride. This publication mentions two techniques as a way to release glimepiride immediately. One is to formulate a drug in an immediate-release layer into powders with a size of less than 10 μm, and the other is to form a coating layer. However, it is difficult to ensure the content uniformity because the amount of main ingredient in the glimepiride layer is too small to be used as an outer coating layer. Further, this publication only reports a dissolution pattern in the controlled-release layer up to 8 hours, and it is difficult to expect a long-term synergistic effect together with glimepiride which is effective for 24 hours.

Meanwhile, there is found a discrepancy in the combination ratio of two drug components of metformin (a daily dose of 250-1,000 mg) and glimepiride (a daily dose of 1-8 mg). Moreover, the two drugs are also different in properties that metformin has relatively high water solubility and low drug absorption, while glimepiride shows relatively low water solubility and high drug absorption.

Due to the aforementioned differences, an appropriate formulation technique is required for maximizing the drug efficacy by means of a controlled-release of metformin and an immediate-release of glimepiride. To be specific, it is difficult to ensure the controlled-release of metformin_? for 24 hours considering the large size of a tablet having relatively high water solubility and unit dose. Further, it is also difficult to release glimepiride component immediately after administration, which has a relatively low water solubility and a relatively long acting time because an excipient used for the controlled-release of metformin according to a general formulation technique may seize the glimepiride component and retard the drug release.

That is, the followings should be overcome for formulating combination of the two components considering the apparent difference in their releasing pattern.

Due to a relatively high unit dose, metformin should have a size fit for oral administration and be designed into a formulation that may ensure the controlled- release for 24 hours. Further, due to a low unit dose, glimepiride should be designed into a formulation that can include its unit dose uniformly the glimepiride- containing layer. Furthermore, it is required to design a formulation where one drug does not affect the release of the other drug, and particularly the release of glimepiride is not affected by the controlled-release of metformin.

To overcome the aforementioned problems, the present inventors have exerted extensive research. As a result, the present invention has been completed by (i) constructing a controlled-release layer so that the release of metformin having high water solubility and high unit dose may be maintained for 24 hours by selectively designing a controlled release layer and (ii) constructing an immediate-release layer so that the content of glimepiride having low water solubility and low unit dose may be included uniformly and it may also be immediately released, particularly by preparing a multi-layered tablet, which a controlled-release layer and an immediate- release layer are separated to completely separate metformin and glimepiride so that excipients used in constructing the controlled-release layer may not affect a rapid release of glimepiride, thereby minimizing the interaction of each drug and maintaining the complementary activities of the drugs.

That is, a mixture of a hydrophilic polymer mixture and a hydrophobic material is used in the present invention to construct controlled release layer of metformin, thereby allowing a relatively small tablet enough for oral administration and releasing metformin for 24 hours. Further, an immediate-release layer of glimepiride is separated from metformin layer through multi-layers of the tablet, thereby minimizing the contact surface of the two drugs and inducing glimepiride to be immediately released without being incorporated when a controlled-release layer of metformin swells.

According to the present invention, the thrice-daily administration of the conventional metformin formulation may be changed to once-daily administration while maintaining the effect of metformin for 24 hours. Further, metformin may act synergistically with glimepiride having a relatively low elimination rate in a body, thereby enabling to effectively control the abrupt increase or decrease of the plasma insulin concentration caused by glimepiride and to prevent side effects such as hypoglycemia.

Further, as compared to the conventional medication of separately coadministering metformin and glimepiride, a single combination tablet of metformin and glimepiride according to the present invention can facilitate the medication instruction, increase the medication compliance and prevent various side effects caused by difference in plasma concentration of drugs when frequently administered in ahigh dose.

Therefore, the present invention aims to provide a novel controlled-release metformin-glimepiride combination formulation, which offers a once- dailycombination therapy of glimepiride and metformin to a patient suffering from diabetes, thereby effectively controlling the blood glucose level.

[Disclosure]

[Description of Drawings]

Figure 1 compares a dissolution curve of the metformin layer in a multi-layered tablet prepared in Example 1 with that of a control drug (Glucophage XR).

Figure 2 compares a dissolution curve of the metformin layer in a multi-layered tablet prepared in Example 5 with that of a control drug (Glucophage XR).

Figure 3 compares a dissolution curve of the glimepiride layer in a multi- layered tablet prepared in Example 1 with that of a control drug (Amaryl).

[Mode for Invention]

The present invention relates to a controlled-release combination formulation comprising metformin and glimepiride as active ingredients and a pharmaceutically acceptable excipient, where the formulation is a multi-layered tablet comprising (i) a controlled-release layer comprising metformin or its pharmaceutically acceptable salt as an active ingredient and a mixture of pharmaceutically acceptable hydrophilic polymers and a hydrophobic material as a release-controlling material, and (ii) an immediate-release layer comprising glimepiride or its pharmaceutically acceptable salt as an active ingredient and at least one excipient selected from the group consisting of a disintegrant, a diluent, a binder and a lubricant. Hereunder is provided a detailed description of the present invention. The present invention relates to a controlled-release metformin-glimepiride combination formulation for oral administration, where a controlled-release layer is constructed so that the release of metformin having high water solubility and high unit dose may be maintained for 24 hours by selectively designing a release- controlling material, and an immediate-release layer is constructed so that the content of glimepiride having low water solubility and low unit dose may be maintained uniform and it may also be immediately released. In particular, a controlled-release metformin-glimepiride combination formulation herein may be embodied into a multi-layered tablet, where a controlled-release layer and an immediate-release layer are completely separated glimepiride from metformin so that excipients constructing the controlled-release layer may not affect the rapid release of glimepiride, thereby minimizing the interaction of drugs and maintaining the complementary activities of the drugs, thus being efficacious for especially type 2 diabetes.

Hereunder is provided a detailed description of each component of a controlled-release metformin-glimepiride combination formulation herein.

The present invention also relates to a formulation comprising a metformin composition for the controlled release of metformin and a glimepiride composition for the immediate release of glimepiride, which are physically separated or partitioned so that the two drugs can be released at different release rates. A novel composition of the present invention comprises a metformin controlled-release layer comprising metformin or its pharmaceutically acceptable salt and suitable excipients and a glimepiride immediate-release layer comprising glimepiride and appropriate excipients, which are physically separated or partitioned so that each of the active ingredients may be released at a different release rate. Such physical separation or partition may be embodied by a formulation such as a multi-layered tablet.

The controlled-release layer and the immediate-release layer are preferred to be contained in the weight ratio of 100 : 10-30 considering the input amount of each active ingredient and the size of a compressed tablet. Further, a controlled-release metformin-glimepiride combination formulation of the present invention may be formulated into a double-layered tablet, where a controlled-release layer and an immediate-release layer are compressed into the double layers. Alternatively, a controlled-release metformin-glimepiride combination formulation herein may also be formulated into a triple-layered tablet, where controlled-release double layers with different release rates and an immediate-release layer are compressed into the triple-layered tablet with the immediate-release layer to become an outer layer.

Metformin may be used in the form of metformin per se or its pharmaceutically acceptable salt, preferably metformin hydrochloride. Metformin may be contained in the combination formulation herein in the amount of 250-1,000 mg, preferably 500-750 mg as calculated on a basis of the weight of hydrochloride salt. Glimepiride may be contained in the formulation herein in the amount of 1-8 mg, preferably 1-2 mg. Metformin is preferred to be contained in the amount of 55-75 wt% of a controlled-release layer considering the release control of metformin. Glimepiride is preferred to be contained in the amount of 0.05-10 wt% of an immediate-release layer considering the immediate release of glimepiride without being incorporated into a matrix. Hereunder is provided a detailed description of a double-layered combination formulation herein.

When a combination formulation is formulated into a double-layered tablet, it may comprise a layer structure where a controlled-release layer and an immediate- release layer are pressed in parallel. The controlled-release layer comprises metformin or its pharmaceutically acceptable salt as an active ingredient, and also comprises a mixture of pharmaceutically acceptable hydrophilic polymers and a hydrophobic material as a release-controlling material. Any conventional excipient may also be contained in the layer. A release-controlling material is contained in the amount of 10-45wt% of the total composition of the controlled-release layer, and a mixture of a hydrophilic polymer mixture and a hydrophobic material is used in the present invention.

That is, a combination formulation controls the release rate of drugs by two mechanisms. First, the hydrophilic polymer controls the pore size of a gel layer formed by the water-swelling, thus primarily controlling the release rate of drugs. Second, the hydrophobic material blocks the pores of gel layer, thereby secondarily controlling the release rate of drugs. Therefore, a combination formulation gradually releases a drug at a constant rate by using a less amount of the release- controlling material than the conventional sustained-release tablet, and may offer a once-daily combination therapy of glimepiride and metformin to a patient suffering from diabetes, thereby effectively controlling the blood glucose level.

Examples of the hydrophilic polymer include saccharides, cellulose derivative, gums, proteins, polyvinyl derivative, polymethacrylate copolymer, polyethylene derivative and carboxyvinyl polymer and a mixture thereof. The hydrophilic polymer is a water-swelling material that swells and gels when in contact with a dissolution solution.

Examples of the hydrophilic polymer include saccharides selected from the group consisting of dextrin, polydextrin, dextran, pectin and pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose and amylopectin; a cellulose derivative selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate and hydroxyethylmethyl cellulose; a gum selected from the group consisting of guar gum, locust bean gum, tragacanth, carrageenan, gum acacia, gum arabic and gellan gum; a protein selected from the group consisting of gelatin, casein and sein; a polyvinyl derivative selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone and polyvinylacetaldiethylaminoacetate; a polymethacrylate copolymer selected from the group consisting of poly(butyl methacrylate,(2-dimethylaminoethyl) methacrylate, methyl methacrylate) copolymer, poly(methacrylic acid, methyl methacrylate) copolymer and poly(methacrylic acid, ethylacrylate) copolymer; a polyethylene derivative selected from the group consisting of polyethylene glycol and polyethylene oxide; carbomer as carboxyvinyl polymer; and a mixture thereof. Examples of the hydrophobic material include a water-insoluble polymer, hydrophobic compound and a mixture thereof.

Examples of the water-insoluble polymer include pharmaceutically acceptable polyvinyl acetate; poly(ethylacrylate, methyl methacrylate) copolymer, poly(ethylacrylate, methyl methacrylate, trimethylaminoethylmethacrylate) copolymer; a cellulose derivative selected from the group consisting of a polymethacrylate copolymer selected from the group consisting of ethyl cellulose and cellulose acetate; and a mixture thereof.

Examples of the hydrophobic compound include a fatty acid and fatty acid esters selected from the group consisting of glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and stearic acid; a fatty acid alcohol selected from the group consisting of cetostearyl alcohol, cetylalcohol and stearylalcohol; a wax selected from the group consisting of

Carnauba wax, beewax and microcrystalline wax; an inorganic material selected from the group consisting of talc, precipitated calcium carbonate, calcium hydrogen phosphate, zinc oxide, titanium oxide, caolin, bentonite, montmorillonite and veegum; and a mixture thereof.

The hydrophilic polymer and the hydrophobic material are preferred to be contained in the weight ratio of between 2:1 and 20:1 considering the release control.

The immediate-release layer comprises glimepiride or its pharmaceutically acceptable salt as an active ingredient. Any conventional excipient may also be contained in the layer.

A combination formulation herein may comprise a mixture of appropriately selected excipients as a pharmaceutically acceptable carrier, and may further comprise other pharmaceutically acceptable additives such as a coloring agent and a flavoring agent. A combination formulation herein may comprise a mixture of at least two excipients or additives.

Examples of the excipient include a disintegrant, a diluent, a binder and a lubricant. Examples of the disintegrant include a starch or a modified starch selected from the group consisting of sodium starch glyconate, corn starch, potato starch and pregelatinized starch; a clay selected from the group consisting of bentonite, montmorillonite and veegum; a cellulose selected from the group consisting of microcrystalline cellulose and low-substituted hydroxypropyl cellulose; alginic acid; a crosslinked cellulose such as croscarmellose sodium; a gum selected from the group consisting of guar gum and xanthan gum; a crosslinked polymer such as crospovidone; effervescent agent such as sodium bicarbonate and citric acid; and a mixture thereof. A preferable example of the disintegrant is sodium starch glycolate. A disintegrant may be contained in the amount of 0.01-40 wt% on a basis of the unit weight of a tablet.

Examples of the diluent include corn starch, modified corn starch, lactose, glucose, mannitol, sorbitol, alginate, alkaline earth metal salt, clay, an inorganic salt such as calcium carbonate, cellulose derivative such as ligno cellulose, microcrystalline cellulose, polyethyleneglycol, dicalcium phosphate and a mixture thereof. A diluent or an excipient may be contained in the amount of 0.1-90 wt%, preferably 0.1-50 wt% on a basis of the unit weight of a tablet.

Examples of the binder include starch, highly-dispersed silica, mannitol, lactose, Carnauba wax, paraffin, spermaceti, polyethylene wax, polyethylene glycol, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatin and a mixture thereof. A binder may be contained in the amount of 3-30 wt%, preferably 3-10 wt % on a basis of the unit weight of a tablet.

Examples of the lubricant include talc, magnesium stearate, alkaline earth metal, calcium stearate, zinc stearate, lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol, glyceryl behenate and a mixture thereof. A lubricant may be contained in the amount of 0.05-20 wt%, preferably 0.05-2 wt% on a basis of the unit weight of a tablet.

A combination formulation herein may further comprise other optional ingredient such as an antiseptic, a stabilizing agent, anti-adhesive agent, colloidal silicon dioxide, a fluidizing agent and a coloring agent.

A tablet of the present invention may comprise a coating layer in the amount of 0.1-15 wt%. A coating layer, which is formed on an outer solid phase that may incorporate inner solid-phase particles, may further comprise any conventional coating agent.

A coating agent, a coating-forming adjuvant or a mixture thereof may be used as the coating layer. Examples of the coating agent include cellulose derivative, saccharide derivative, polyvinyl derivative, waxes, fat and gelatin. Examples of the coating-forming adjuvant include polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, diethyl phthalate and a mixture thereof.

A solvent may also be contained as a film-forming agent, and examples of the film-forming agent include water; alcohols such as methyl alcohol, ethyl alcohol and isopropyl alcohol; ketones such as acetone and ethylmethylketone; chlorohydrocarbon such as methylene chloride, dichloroethane and 1,1,1- trichloroethane; and a mixture thereof. A combination formulation herein is usually administered for a long period of time, and an aqueous coating is preferred for minimizing the effect of the remaining solvent. A combination formulation herein may comprise at least one hydrophilic polymer such as hydroxypropylmethyl cellulose and at least one plasticizer such as polyethylene glycol. A coloring agent may be used optionally in combination with a film-forming agent, a plasticizer and solvents.

Hereunder is provided a process of preparing formulating a combination formulation herein into a multi-layered tablet. First, a controlled-release layer is prepared by mixing a pharmaceutical composition comprising metformin or its pharmaceutically acceptable salt as an active ingredient, a release-controlling material for sustaining the release of the active ingredient, and other ingredients such as a disintegrant, a diluent, an excipient, a binder and a lubricant. Metformin, hydrophilic polymer and hydrophobic material form a matrix for controlling the release rate in a matrix. The hydrophilic polymer has a swelling property, thus inducing the delay of gastric retention time, and gradually releases metformin that is incorporated into the matrix. The hydrophobic material controls the release of a drug by blocking the pores in a matrix layer with the lapse of time.

In a separate step, an immediate-release layer is prepared by preparing and granulating a pharmaceutical composition comprising glimepiride or its pharmaceutically acceptable salt as an active ingredient and other ingredients such as a disintegrant, a diluent, an excipient, a binder and a lubricant. The controlled-release layer mixture and the immediate-release layer granules are compressed in a compressor, thus preparing a tablet. If the mixture has sufficient fluidity, it may be directly compressed. If the fluidity is not sufficient, the compression may be conducted by compacting, granulating and sieving the mixture.

Although a process of preparing a double-layered tablet is described above, a multi-layered tablet herein may also be formulated into a triple-layered tablet, where controlled-release double layers with different release rates and an immediate- release single layer are compressed into the triple-layered tablet with the immediate- release layer to become an outer layer.

The aforementioned combination formulation herein may be formulated into an uncoated tablet, and may also comprise a film-phase coating layer on the outer surface of the tablet. The coating layer has an advantage of increasing the stability of an active ingredient.

The coating layer may be formed by using any conventional method, such as a fluidized-bed coating method and preferably a pan coating method. Preferable dose of active ingredients herein, i.e., metformin and glimepiride, are

250-1,000 mg and 1-8 mg, respectively, and appropriate dosage level may be determined considering physical conditions and body weight of a patient, severeness of a disease, formulation type and route and period of administration.

The present invention is described more specifically by the following Examples.

Examples herein are meant only to illustrate the present invention, but they should not be construed as limiting the scope of the claimed invention.

Example 1: Controlled-release double-layered tablet comprising metformin and glimepiride

1) Controlled-release layer comprising metformin

Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and hydroxypropyl cellulose as shown in Table 1 were mixed in a double-cone mixer. The mixture was added with compritol and mixed. 2) Immediate-release layer comprising glimepiride

Predetermined amounts of glimepiride, lactose and microcrystalline cellulose and sodium starch glyconate as shown in Table 1 were mixed in a high-speed mixer.

The mixture was granulated by using a binder solution contatining polyvinylpyrrolidone. The granules were dried at 60 ⁰C, and sieved with No. 18 sieve. The sieved granules were lubricated with magnesium stearate.

3) Compression and coating

The granules were compressed by using a compressor for the production of multi-layered tablet (MRC-37T: Sejong) into a double-layered tablet. Film coating layer was formed on the compressed tablets using Hi-coater (SFC-30N, Sejong mechanics, Korea), thus providing a multi-layered tablet.

Example 2: Controlled-release double-layered tablet comprising metformin and glimepiride 1) Controlled-release layer comprising metformin

Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose, Kollidon SR and colloidal silicon dioxide as shown in Table 1 were mixed in a double-cone mixer. The mixture was added with magnesium stearate, and compressed. 2) Immediate-release layer comprising glimepiride

An immediate-release layer comprising glimepiride was prepared as described in Example 1.

3) Compression and coating

The granules were compressed into a double-layered tablet by using a compressor for the production of multi-layered tablet (MRC-37T: Sejong). Film coating layer was formed on the compressed tablets using Hi-coater (SFC-30N, Sejong mechanics, Korea), thus providing a multi-layered tablet.

Example 3: Controlled-release double-layered tablet comprising metformin and glimepiride

1) Controlled-release layer comprising metformin

Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose and hydroxypropyl cellulose as shown in Table 1 were mixed in a double- cone mixer. The mixture was added with magnesium stearate, and compressed. 2) Immediate-release layer comprising glimepiride

3) Compression and coating

Example 4: Controlled-release double-layered tablet comprising metformin and glimepiride

1) Controlled-release layer comprising metformin

Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose, hydroxypropyl cellulose and colloidal silicon dioxide as shown in Table 1 were mixed in a double-cone mixer. The mixture was added with magnesium stearate, and compressed. 2) Immediate-release layer comprising glimepiride

3) Compression and coating The granules were compressed into a double-layered tablet by using a compressor for the production of multi-layered tablet (MRC-37T: Sejong). Film coating layer was formed on the compressed tablets using Hi-coater (SFC-30N, Sejong mechanics, Korea), thus providing a multi-layered tablet.

Example 5: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin

Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, and hydroxypropyl cellulose as shown in Table 1 were mixed in a double-cone mixer. The mixture was added with compritol and mixed.

2) Second immediate-release layer comprising metformin

Metformin hydrochloride, Kollidon SR were mixed in a double-cone mixer. The mixture was added with compritol and mixed. 3) Immediate-release layer comprising glimepiride

4) Compression and coating

The granules were compressed into a triple-layered tablet by using a compressor for the production of multi-layered tablet (MRC-37T: Sejong). Film coating layer was formed on the compressed tablets using Hi-coater (SFC-30N, Sejong mechanics, Korea), thus providing a multi-layered tablet.

Example 6: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin

A first immediate-release layer comprising metformin was prepared as described in Example 5.

2) Second immediate-release layer comprising metformin Metformin hydrochloride and lactose were mixed in a double-cone mixer. The mixture was added with compritol and mixed.

3) Immediate-release layer comprising glimepiride

An immediate-release layer comprising glimepiride was prepared as described in Example 1. 4) Compression and coating

Example 7: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin

A first immediate-release layer comprising metformin was prepared as described in Example 5. 2) Second immediate-release layer comprising metformin

Metformin hydrochloride, microcrystalline cellulose and hydroxypropyl cellulose were mixed in a double-cone mixer. The mixture was added with magnesium stearate, and compressed. 3) Immediate-release layer comprising glimepiride

4) Compression and coating

Example 8: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin

2) Second immediate-release layer comprising metformin Metformin hydrochloride, Kollidon SR, sodium starch glyconate, hydroxypropyl cellulose and colloidal silicon dioxide were mixed in a double-cone mixer. The mixture was added with magnesium stearate, and compressed.

3) Immediate-release layer comprising glimepiride

Example 9: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose and polyvinylpyrrolidone as shown in Table 1 were mixed in a double- cone mixer. The mixture was added with compritol and magnesium stearate, and compressed.

2) Second immediate-release layer comprising metformin Metformin hydrochloride and Kollidon SR were mixed in a double-cone mixer.

The mixture was added with compritol and mixed.

3) Immediate-release layer comprising glimepiride

The granules were compressed into a triple-layered tablet by using a compressor for the production of multi-layered tablet (MRC-37T: Sejong). Film coating layer was formed on the compressed tablets using Hi-coater (SFC-30N, Sejong mechanics, Korea), thus providing a multi-layered tablet. Example 10: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin

First immediate-release layer comprising metformin was prepared as described in Example 9.

2) Second immediate-release layer comprising metformin

Metformin hydrochloride and polyvinylpyrrolidone were mixed in a double- cone mixer. The mixture was added with compritol and mixed.

3) Immediate-release layer comprising glimepiride An immediate-release layer comprising glimepiride was prepared as described in Example 1.

4) Compression and coating

Example 11: Controlled-release triple-layered tablet comprising metformin and glimepiride 1) First immediate-release layer comprising metformin

2) Second immediate-release layer comprising metformin

Metformin hydrochloride, Kollidon SR and, polyvinylpyrrolidone were mixed in a double-cone mixer. The mixture was added with compritol and mixed. 3) Immediate-release layer comprising glimepiride

4) Compression and coating The granules were compressed into a triple-layered tablet by using a compressor for the production of multi-layered tablet (MRC-37T: Sejong). Film coating layer was formed on the compressed tablets using Hi-coater (SFC-30N, Sejong mechanics, Korea), thus providing a multi-layered tablet.

Example 12: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin

First immediate-release layer comprising metformin was prepared as described in Example 9. 2) Second immediate-release layer comprising metformin

Metformin hydrochloride, Kollidon SR and polyvinylpyrrolidone were mixed in a double-cone mixer. The mixture was added with compritol and mixed.

3) Immediate-release layer comprising glimepiride

4) Compression and coating

The granules were compressed into a triple-layered tablet by using a compressor for the production of multi-layered tablet (MRC-37T: Sejong). Film coating layer was formed on the compressed tablets using Hi-coater (SFC-30N, Sejong mechanics, Korea), thus providing a multi-layered tablet. Example 13: Controlled-release double-layered tablet comprising metformin and glimepiride

1) Controlled-release layer comprising metformin Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and hydroxypropyl cellulose as shown in Table 2 were mixed in a double-cone mixer. The mixture was added with compritol and mixed.

2) Immediate-release layer comprising glimepiride Predetermined amounts of glimepiride, lactose and microcrystalline cellulose and sodium starch glyconate as shown in Table 2 were mixed in a high-speed mixer. The mixture was granulated by using a binder solution contatining polyvinylpyrrolidone. The granules were dried at 60 ⁰C and sieved with No. 18 sieve. The sieved granules were lubricated with magnesium stearate.

3) Compression and coating

Example 14: Controlled-release double-layered tablet comprising metformin and glimepiride

1) Controlled-release layer comprising metformin First immediate-release layer comprising metformin was prepared as described in Example 13.

2) Immediate-release layer comprising glimepiride

An immediate-release layer comprising glimepiride was prepared as described in Example 13 by using predetermined amounts of the ingredients as shown in Table 2.

3) Compression and coating

Example 15: Controlled-release double-layered tablet comprising metformin and glimepiride

2) Immediate-release layer comprising glimepiride

3) Compression and coating

The granules were compressed into a double-layered tablet by using a compressor for the production of multi-layered tablet (MRC-37T: Sejong). Film coating layer was formed on the compressed tablets using Hi-coater (SFC-30N, Sejong mechanics, Korea), thus providing a multi-layered tablet. Example 16: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and hydroxypropyl cellulose as shown in Table 2 were mixed in a double-cone mixer. The mixture was added with compritol and mixed.

The mixture was added with compritol and mixed.

3) Immediate-release layer comprising glimepiride

4) Compression and coating

Example 17: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin First immediate-release layer comprising metformin was prepared as described in Example 16.

2) Second immediate-release layer comprising metformin

Second immediate-release layer comprising metformin was prepared as described in Example 16. 3) Immediate-release layer comprising glimepiride

Example 18: Controlled-release triple-layered tablet comprising metformin and glimepiride

1) First immediate-release layer comprising metformin

First immediate-release layer comprising metformin was prepared as described in Example 16. 2) Second immediate-release layer comprising metformin

Second immediate-release layer comprising metformin was prepared as described in Example 16.

3) Immediate-release layer comprising glimepiride

4) Compression and coating

Comparative Example 1: Controlled-release layer comprising metformin and coating layer comprising glimepiride 1) Controlled-release layer comprising metformin

Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and hydroxypropyl cellulose as shown in Table 2 were mixed in a double-cone mixer. The mixture was added with compritol, and mixed. 2) Compression

Compression was conducted by using a rotary compressor (MRC-33: Sejong).

3) Coating of immediate-release layer comprising glimepiride Predetermined amounts of glimepiride, PEG 6000, hydroxypropylmethyl cellulose and titanium dioxide as shown in Table 2 were dispersed and dissolved in purified water, and a coating layer comprising glimepiride was prepared by using Hi-coater (SFC-30N, Sejong mechanics, Korea).

4) Coating

Film coating layer was formed by using Hi-coater (SFC-30N, Sejong mechanics, Korea), thus providing a tablet. Comparative Example 2: Controlled-release double layers comprising metformin and coating layer comprising glimepiride

1) First immediate-release layer comprising metformin

Predetermined amounts of metformin hydrochloride, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and hydroxypropyl cellulose as shown in Table 2 were mixed in a double-cone mixer. The mixture was added with compritol and mixed.

2) Second immediate-release layer comprising metformin

Metformin hydrochloride and Kollidon SR were mixed in a double-cone mixer. The mixture was added with compritol and mixed.

3) Compression

Compression was conducted by using a compressor for the production of multi- layered tablet (MRC-37T: Sejong).

4) Coating of immediate-release layer comprising glimepiride Predetermined amounts of glimepiride, PEG 6000, hydroxypropylmethyl cellulose and titanium dioxide as shown in Table 2 were dispersed and dissolved in purified water, and a coating layer comprising glimepiride was prepared by using Hi-coater (SFC-30N, Sejong mechanics, Korea).

5) Coating Film coating layer was formed by using Hi-coater (SFC-30N, Sejong mechanics,

Korea), thereby providing a tablet. [Table 1]

Content (mg )

Layer Major ingredients Examples

1 2 3 4 5 6 7 8 9 10 11 12

[Table 2]

Experimental Example 1: Comparative dissolution profile test

Comparative dissolution profile test of metformin was conducted among the controlled-release tablet comprising metformin and the double-layered tablet comprising glimepiride prepared in Examples 1 and 5. Glucophage 750 XR (BMS) commercially available in U. S. was used as a control drug. Dissolution test was conducted according to a paddle method based on the general dissolution test method described in Korea Pharmacopoeia, and the results are provided in Figure 1 and 2. The controlled-release multi-layered tablet comprising metformin showed a similar dissolution behavior to the controlled- release control drug.

Experimental Example 2: Comparative dissolution profile test

Comparative dissolution profile test of glimepiride was conducted among the controlled-release tablet comprising metformin and the double-layered tablet comprising glimepiride prepared in Example 1. Commercially available Amaryl was used as a control drug (Handok Aventis).

Dissolution test was conducted according to a paddle method based on the general dissolution test method described in Korea Pharmacopoeia, and the results are provided in Figure 3. The double-layered according to the present invention released glimepiride more rapidly than the control drug.

Experimental Example 3: Content uniformity test

Content uniformity test was conducted by using the metformin-glimepiride combination formulations prepared in Example 1 and Comparative Example 1 based on the general dissolution test method described in Korea Pharmacopoeia (8^th edition). Content uniformity is considered as appropriate when the result is less than 15%. As shown in Table 3, the double-layered tablets according to the present invention show relatively higher content uniformity than the glimepiride coating tablets [Table 3]

Experimental Example 4: Stability test

Stability test was conducted by using the controlled-release tablet comprising metformin and a double-layered tablet comprising glimepiride prepared in Example 1. Content test and dissolution test were conducted under accelerated test conditions, i.e., at the temperature of 40 ⁰C and the humidity of 75±5% for 12 months. When the change in content is higher than 5% or the dissolution exceeds the standard, it is considered as significant under accelerated conditions.

There was no intercalation observed between the controlled-release layer comprising metformin and the immediate-release layer comprising glimepiride, and the release of metformin did not affect the dissolution of glimepiride.

As shown Tables 4 and 5, the results of accelerated stability test were ascertained as excellent.

[Table 4] Dissolution test

[Table 5] Content test twelve-month stabilit test

[Industrial applicability]

As described above, a patient suffering diabetes has taken metformin three times a day and glimepiride once daily. A multi-layered tablet comprising metformin and glimepiride according to the present invention may increase medication compliance by simplifying the medication method. Further, a multi- layered tablet of the present invention comprises a controlled-release layer comprising metformin and an immediate-release layer comprising glimepiride, thereby ensuring both the immediate efficacy of metformin and the gradual activity of glimepiride.

Moreover, a multi-layered tablet herein comprising a controlled-release layer comprising metformin and an immediate-release layer comprising glimepiride is useful for controlling the blood glucose level by maintaining the synergistic effect of glimepiride having low elimination rate and metformin that is released gradually.

Furthermore, a multi-layered tablet of the present invention may prevent the incorporation of glimepiride layer due to the swelling phenomenon of controlled- release of metformin. The glimepiride layer that is rapidly released without being incorporated increases the usefulness of a combination formulation herein for the initial control of blood glucose level.

Moreover, the present invention also solves the problem of the content non- uniformity between relatively large amount of metformin and relatively small amount of glimepiride by means of a multi-layered tablet.

Claims

[CLAIMS]

[Claim 1]

A controlled-release combination formulation comprising metformin and glimepiride as an active ingredients and a pharmaceutically acceptable excipient, wherein the formulation is a multi-layered tablet comprising (i) a controlled- release layer comprising metformin or its pharmaceutically acceptable salt as an active ingredient and a mixture of pharmaceutically acceptable hydrophilic polymers and a hydrophobic material as a release-controlling material, and (ii) an immediate-release layer comprising glimepiride or its pharmaceutically acceptable salt as an active ingredient and at least one excipient selected from the group consisting of a disintegrant, a diluent, a binder and a lubricant.

[Claim 2]

The controlled-release combination formulation of claim 1, which comprises metformin in the amount of 250-1,000 mg.

[Claim 3]

The controlled-release combination formulation of claim 1, which comprises glimepiride in the amount of 1-8 mg.

[Claim 4]

The controlled-release combination formulation of claim 1, which comprises a controlled-release layer and an immediate-release layer in the weight ratio of 100 : 10-30.

[Claim 5]

The controlled-release combination formulation of claim 1, wherein the multi- layered tablet is compressed into a double-layered tablet comprising a controlled- release layer and an immediate-release layer.

[Claim 6]

The controlled-release combination formulation of claim 1, wherein the multi- layered tablet is compressed into a table comprising a double-layered controlled- release layer where each drug has different release rates and a single-layered immediate-release layer, and the immediate-release layer forms an outer layer in the tablet.

[Claim 7]

The controlled-release combination formulation of claim 1, wherein the pharmaceutically acceptable salt of the metformin is metformin hydrochloride.

[Claim 8]

The controlled-release combination formulation of claim 1, wherein metformin is contained in the controlled-release layer in the amount of 55-75 wt%.

[Claim 9]

The controlled-release combination formulation of claim 1, wherein glimepiride is contained in the immediate-release layer in the amount of 0.05-10 wt%.

[Claim 10] The controlled-release combination formulation of claim 1, wherein the hydrophilic polymer is at least one selected from the group consisting of saccharides, cellulose derivative, gums, proteins, polyvinyl derivative, polymethacrylate copolymer, polyethylene derivative, carboxyvinyl polymer and a mixture thereof.

[Claim 11]

The controlled-release combination formulation of claim 10, wherein the hydrophilic polymer is selected from the group consisting of: a saccharide selected from the group consisting of dextrin, polydextrin, dextran, pectin and pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose and amylopectin; a cellulose derivative selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate and hydroxyethylmethyl cellulose; a gum selected from the group consisting of guar gum, locust bean gum, tragacanth, carrageenan, gum acacia, gum arabic and gellan gum; a protein selected from the group consisting of gelatin, casein and sein; a polyvinyl derivative selected from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone and polyvinylacetal diethylaminoacetate; a polymethacrylate copolymer selected from the group consisting of poly(butyl methacrylate,(2-dimethylaminoethyl)methacrylate, methyl methacrylate) copolymer, poly(methacrylic acid, methyl methacrylate) copolymer and poly(methacrylic acid, ethylacrylate) copolymer; a polyethylene derivative selected from the group consisting of polyethylene glycol and polyethylene oxide; a carbomer as carboxyvinyl polymer; and a mixture thereof.

[Claim 12]

The controlled-release combination formulation of claim 1, wherein the hydrophobic material is selected from the group consisting of a water-insoluble polymer, a hydrophobic compound and a mixture thereof.

[Claim 13]

The controlled-release combination formulation of claim 12, wherein the water- insoluble polymer is selected from the group consisting of: a pharmaceutically acceptable polyvinyl acetate; a polymethacrylate copolymer selected from the group consisting of poly(ethylacrylate, methyl methacrylate) copolymer, poly(ethyl acrylate, methyl methacrylate, trimethyl aminoethyl methacrylate) copolymer; a cellulose derivative selected from the group consisting of ethyl cellulose and cellulose acetate; and a mixture thereof.

[Claim 14]

The controlled-release combination formulation of claim 12, wherein the hydrophobic compound is selected from the group consisting of: a fatty acid or a fatty acid ester selected from the group consisting of glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and stearic acid; a fatty acid alcohol selected from the group consisting of cetostearyl alcohol, cetylalcohol and stearylalcohol; a wax selected from the group consisting of Carnauba wax, beewax and microcrystalline wax; an inorganic material selected from the group consisting of talc, precipitated calcium carbonate, calcium hydrogen phosphate, zinc oxide, titanium oxide, caolin, bentonite, montmorillonite and veegum; and a mixture thereof.

[Claim 15]

The controlled-release combination formulation of claim 1, which comprises the hydrophilic polymer and the hydrophobic material in the weight ratio of between 2:1 and 20:1.

[Claim 16]

The controlled-release combination formulation of claim 1, wherein the controlled-release layer comprises the release-controlling material in the amount of 10-45 wt% relative to a total composition in the controlled-release layer.

[Claim 17]

The controlled-release combination formulation of any of claims 1-16, which is formulated into an uncoated tablet or a coated tablet comprising a film-phase coating layer.

[Claim 18]

The controlled-release combination formulation of claim 17, wherein the coating layer comprises a coating agent, a coating-forming adjuvant or a mixture thereof.

[Claim 19]

The controlled-release combination formulation of claim 17, wherein the coating layer comprises a cellulose derivative, a saccharide derivative, a polyvinyl derivative, a wax, a fat, gelatin, polyethyleneglycol, ethyl cellulose, titanium oxide, diethylphthalate and a mixture thereof.

[Claim 20]

The controlled-release combination formulation of claim 17, wherein the coating layer is contained in the amount of 0.1-15 wt% of a multi-layered tablet.

[Claim 21]

The controlled-release combination formulation of claim 1, wherein the immediate-release layer comprises at least one disintegrant selected from the group consisting of sodium starch glyconate, starch, modified starch, bentonite, montmorillonite, veegum, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, alginic acid, crosslinked celluloses, gums, crospovidone, sodium bicarbonate and citric acid.

[Claim 22] The controlled-release combination formulation of claim 1, wherein the immediate-release layer comprises at least one diluents selected from the group consisting of corn starch, modified corn starch, lactose, glucose, mannitol, sorbitol, alginate, alkaline earth metal salt, clay, calcium carbonate, ligno cellulose, microcrystalline cellulose, polyethyleneglycol and dicalcium phosphate.

[Claim 23]

The controlled-release combination formulation of claim 1, wherein the immediate-release layer comprises at least one binder selected from the group consisting of starch, highly-dispersed silica, mannitol, lactose, Carnauba wax, paraffin, spermaceti, polyethylenewax polyethyleneglycol, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, natural gum, synthetic gum, copovidone and gelatin.

[Claim 24] The controlled-release combination formulation of claim 1, wherein the immediate-release layer comprises at least one lubricant selected from the group consisting of talc, magnesium stearate, calcium stearate, zinc stearate, lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate, polyethylene glycol and glyceryl behenate.