KR100812538B1 - Drug-controlled metformin-glymepiride combination - Google Patents

Abstract

The present invention relates to a drug-controlled metformin-glymepiride combination formulation, and more particularly, to a sustained release layer by specifically selecting and designing a release controlling substance so that the release of metformin having a high water solubility and a high unit dosage is continuously performed for 24 hours. And the immediate release layer so that the content of glymepiride with low water solubility and low unit dose is maintained uniformly, and the rapid release layer is configured so that the excipient constituting the sustained release layer cannot affect the rapid release of glymepiride. By implementing a multi-layered formulation that completely blocks the release layer of the immediate release layer, the phase separation between metformin and glymepiride is minimized, minimizing the interaction of each drug and the effects of each drug are complementary. Drugs for oral administration effective for type diabetes Air-release metformin relates to a combined preparation glimepiride.

Description

Pharmacologically controlled release of metformin-glymepiride

1 is a graph showing the dissolution curve of the metformin layer of the multilayer tablet prepared according to Example 1 and the dissolution curve of the reference drug (glucophage XAL).

Figure 2 is a graph showing the dissolution curves of the metformin layer of the multilayer tablet prepared according to Example 5 and the dissolution curve of the reference drug (glucophage XAL).

FIG. 3 is a graph showing an elution curve of the glymepiride layer and an elution curve of the reference drug (Amaryl) in the multilayer tablet prepared according to Example 1. FIG.

The present invention relates to a drug controlled-release metformin-glymepiride combination for oral administration, which is particularly effective for type 2 diabetes since the interaction between metformin and each drug of glymepire is minimized and the effects of these drugs are complementary.

Type 2 Diabetes (DM), or insulin-independent diabetes, is diabetes caused by lifestyle, not inherited or autoimmune diseases. It is a disease caused by insulin secretion but insufficient or poor use, and the main therapeutic direction is to control hyperglycemia due to insulin resistance and insulin secretion deficiency, altered lipidemia, glucose metabolism disorder, and disturbance of other factors, and It is to prevent hypoglycemia due to treatment.

To this end, it is currently clinically demonstrated that combination therapy of diabetic modulators with different mechanisms has a synergistic effect and can achieve more useful control than when using high doses of a single active ingredient.

As the anti-diabetic agent, sulfonyl urea (SU-based) drugs have been mainstream in the past.

The pharmacologic mechanism of the sulfonylurea system is to control hyperglycemia by gradually increasing insulin secretion from beta cells. However, in the treatment of diabetes, there is a problem that side effects such as hypoglycemia, weight gain, deterioration of blood lipid status, etc. occur during long-term use of sulfonylurea-based drugs. In addition, 10-20% of diabetic patients who received sulfonylurea-based drug therapy did not show a therapeutic effect from the initial administration, and when it was taken for 1 to 2 years, there was no therapeutic effect at a frequency of 5-20%. At the end of this decade, there is a 50% frequency of ineffectiveness. Thus, co-administration of other therapeutic agents was considered.

Other therapeutic agents in combination with sulfonylureas have been considered three new classes of treatments, represented by biguanides, thiazolidinediones, and alpha-glucosidase inhibitors.

Among the coadministered therapeutic agents, the biguanide system exhibits a mechanism for controlling hyperglycemia by reducing insulin resistance by inhibiting hepatic glucose production and enhancing peripheral glucose absorption.

Recently, it has been confirmed that the glycemic control function due to the difference in the pharmacological mechanism of the sulfonylurea-based drug and the biguanide-based drug is synergistic with each other. .

A typical example of a biguanide-based therapeutic agent is metformin, and a typical case of using a combination of metformin with glyburide or glymepiride among sulfonylurea-based therapeutic agents is typical. In addition, the combination of sulfonylurea-based drugs with metformin in combination with sulfonylurea-based drugs in patients who failed to successfully control the sulfonylurea-based treatments was found to have an excellent effect on glycemic control.

Therefore, the combined use of the two drugs that complement the blood glucose control through different mechanisms of action tends to increase, and according to prescription data, about 60% of metformin use is combined with sulfonylurea treatment It is out.

Examples of the combined use of glyburide in metformin and sulfonylureas are well illustrated in the following literature. Vigneri et al. Described 15 mg / l in Treatment of NIDDM Patients with secondary failure to Glyburide: Comparison of the Addition of Either Metformin of Bed-Time NPH Insulin to Gluburide, Diabete & Metabolism, 1991, 17, 232-234. A combination use of 1500 mg / day metformin and 15 mg / day glyburide is disclosed to treat patients with type 2 diabetes who have secondary failure with one dose of glyburide.

WO2001 / 32158 discloses the use of low-dose pharmaceutical preparations of metformin and sulfonylurea-based drugs, glyburide, for the first treatment of diabetes in patients who do not have experience with medication, and in the first treatment of diabetes in patients with early diabetes. It is disclosed that when combined dosages of less than a single dose of such drugs generally prescribed in approved medical practice have substantially reduced side effects.

However, the combination of the above-mentioned single tablets is useful when applied to primary patients with diabetes, i.e., patients taking metformin hydrochloride three times a day or patients taking sulfonylurea-based drugs once a day. In other words, diabetes has already progressed and it is not useful for patients taking metformin and sulfonylureas.

In practice, when metformin and glymepiride are to be administered in combination, they are administered as each single agent. In this case, the general method of taking is metformin three times a day, and in the case of long-acting glymepiride is taken once a day. This difference in doses can cause confusion. When metformin and glymepiride are administered once a day to prevent such confusion, it is difficult to maintain blood sugar by sustained synergy with glymepiride because metformin is rapidly lost in the body.

Korean Patent Laid-Open No. 2006-6469 proposes a mixed single-dose administration of metformin and glimepiride, which shows a clinical synergistic effect on a patient by a combination administration of metformin and glimepiride. However, the elution form of metformin in the patent is designed as a general tablet, not having controlled release sustained release properties, where metformin released in the general definition elution pattern disappears relatively rapidly in the blood and is continuously elevated with glycepiride after taking. Hard to expect effects

Korean Patent Laid-Open No. 2004-79980 relates to a method for preparing an oral dosage form for delivering both immediate release and sustained release drugs, comprising a sustained release layer containing metformin hydrochloride and an immediate release layer containing glymepiride, In order to induce rapid release, the drug constituting the immediate release layer is formulated into particles of less than 10 microns, or a technique of forming a coating layer is mentioned. However, since the amount of the main component to use the outer coating layer as the glymepiride layer as described above is very small, it is difficult to match the uniformity of the content. In addition, controlled release of the sustained release layer only mentions the elution form within 8 hours, so it is difficult to maintain a sustained synergistic effect with glymepiride, which exhibits 24-hour action.

On the other hand, metformin is 250-1000 mg per dose, and glymepyride is 1-8 mg per dose, and there is a big difference in the unit dose of each component. In addition, there is a big difference in physical properties. Metformin shows high solubility and low drug absorption, while glymepiride shows low solubility and high drug absorption.

Due to the characteristics of each of these drugs, high formulation technology is required to induce maximum drug efficacy through continuous controlled release of metformin and rapid release of glymepiride. In other words, inducing a 24-hour sustained release of metformin with high solubility and very high doses is a difficult task in view of the size of the tablet itself. It is also a difficult task to induce the rapid release of glymepiride with low solubility and long duration of action. The general formulation technique is that the excipients used for controlled release of metformin can be captured by the glymepiride component, which can slow the release of the drug.

That is, in order to formulate two components having a large difference in release properties as described above, the following points must be overcome.

Since metformin has a very large unit dose, an agent that can be orally administered should be designed to maintain a sustained controlled release for 24 hours. In the case of glimepiride, since the unit dosage is very small, a formulation which can solve the problem of content uniformity should be designed. There is also a need for suitable formulation designs that do not affect the release of mutual drugs due to active ingredients having opposite mechanisms of release of drugs, and formulation designs where the release of glymepiride is not affected by the controlled release of metformin.

The inventors of the present invention have tried to solve the above problems.

As a result, the release control material was specifically designed and designed to sustain the release of metformin with high water solubility and high unit dose continuously for 24 hours, thereby forming a slow release layer, and having low water solubility and low unit dose of glymepiride. The rapid release layer is configured to be released quickly while maintaining uniformity. In particular, the excipient constituting the sustained release layer has a multi-layered formulation that completely blocks the release layer of the sustained release layer and the immediate release layer such that the excipient constituting the sustained release layer cannot be affected. This was achieved by completely separating the phase where metformin and glymepire were located, thus completing a combination formulation with minimal interaction between drugs.

That is, unlike the conventional metformin sustained-release tablets, by using a hydrophilic polymer mixture and a hydrophobic material in selecting the release control material constituting the sustained release layer containing metformin, the tablet size can be made small so that oral administration is possible. In addition, the size of metformin was continuously released for 24 hours, so that the medicinal effect could be continued.The immediate release layer containing glymepiride constitutes the sustained release layer and the multi-layered tablet so that the contact surface between them is minimized, so that the release layer containing metformin swells. Glymepiride is not trapped, but quickly disintegrates to express the drug.

 According to the present invention, unlike the conventional metformin formulations administered three times a day, effective once-daily administration can maintain effective blood levels for 24 hours, and metformin, which maintains a constant concentration in the body, thus loses body velocity May have a sustained synergistic effect with slow glymepiride, and thus no side effects such as hypoglycemia can be effectively and continuously blocked since there is no sudden rise or decrease in blood levels due to glymepireid.

In addition, unlike the administration of these drugs in combination with glymepiride, metformin and glymepireide can be administered in a single tablet, so it is easy to guide the medication, and side effects due to the difference in the patient's compliance and the blood concentration during high-dose frequency administration Problems such as occurrence can be solved.

Accordingly, the present invention provides a novel drug-controlled release of metformin-glymepiride combination that enables the use of glycepiide and metformin in combination with once-daily treatment for diabetic patients who have a combination therapy of glycepiride and metformin. There is this.

The present invention provides a combination formulation comprising metformin and glymepiride as an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient contains metformin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable hydrophilic polymer mixture. A sustained release layer comprising a hydrophobic substance as a release controlling substance, and an immediate release layer containing glymepiride or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the sustained release layer and the immediate release layer are tablets formed of a multi-layered tablet. It is characterized by a release metformin-glymepiride co-formulation.

Hereinafter, the present invention will be described in detail.

The present invention constitutes a sustained release layer by specifically designing a release control material so that the release of metformin having a high water solubility and a high unit dose continuously for 24 hours, and a low water solubility and a low unit dose of glymepiride are uniform. The immediate release layer is configured to be rapidly released while maintaining the release, and in particular, the excipient constituting the sustained release layer implements a multi-layered formulation to completely block the release layer of the sustained release layer and the immediate release layer so that the excipient constituting the sustained release layer cannot be affected. By completely separating the phase where metformin and glymepire are located, the interaction of each drug is minimized, and the effects of each drug are complementary to each other. Therefore, the drug controlled-release metformin-glymepiride complex for oral administration, particularly effective for type 2 diabetes, It is about.

Hereinafter, the drug controlled-release metformin-glymepiride complex preparation of the present invention will be described in detail by component.

The present invention encompasses dosage forms comprising delayed release metformin compositions and glymepiride compositions for immediate release so that they can be physically separated or partitioned to achieve different release rates of the two drugs. The novel composition of the present invention consists of a sustained release layer consisting of metformin, its pharmaceutically acceptable salts and the desired excipients so that each active ingredient can be physically separated or partitioned to obtain different release rates, and glymepiride and the desired excipients. It consists of immediate layers. Such physical compartments may be embodied in a multi-layered formulation.

The sustained release layer and the immediate release layer is most preferably composed of 100: 10 to 30% by weight in consideration of the dosage of each active ingredient and the size of the tablet after tableting. In addition, the drug-controlled release metformin-glymepiride complex preparation of the present invention may be composed of a bilayer tablet in which the sustained release layer and the immediate release layer are compressed and laminated into two layers, and the release rate of the drug including the sustained release layer is differently controlled. The sustained release layer and the single immediate release layer of the layer are compression laminated, and the immediate release layer may be composed of three-layered tablets constituting the outermost layer of the formulation.

The metformin may be used in the form of metformin or a pharmaceutically acceptable salt thereof, and preferably hydrochloride salt of metformin.

Metformin in the co-formulation may be used in the amount of 250 to 1000 mg, preferably 500 to 750 mg, and glymepyride may be 1 to 8 mg, preferably 1 to 2 mg, in terms of hydrochloride.

Such metformin is best suited to exhibit a desired delayed release of metformin to be comprised of 55 to 75% by weight of the sustained release layer, and glymepyride is contained in the matrix base of the slow release layer to contain 0.05 to 10% by weight of the immediate release layer. Most preferred to exhibit rapid release.

Hereinafter, the composite preparation of the present invention will be described based on two-layered tablets.

When the composite preparation of the present invention is composed of two-layered tablets, the sustained-release layer and the immediate release layer may be configured to have a compressed layer structure in parallel.

The sustained release layer contains metformin or a pharmaceutically acceptable salt thereof as the active ingredient, and is composed of a pharmaceutically acceptable hydrophilic polymer mixture and a hydrophobic substance containing a release controlling substance. At this time, it is obvious that can be used in combination with conventional excipients that are commonly accepted in the art.

In the present invention, in the sustained release layer, the release control material comprises 10 to 45% by weight of the total composition of the sustained release layer, and a hydrophilic polymer mixture and a hydrophobic material are mixed and used.

That is, by selecting the hydrophilic polymer can adjust the pore size of the gel layer formed by its water expansion can be controlled primarily the release rate of the drug component, by selecting the hydrophobic material can block the pores of the gel layer drug Since the rate of release of the ingredient can be controlled secondarily, it is superior to conventional western information, so it shows excellent dissolution characteristics that can slowly release the drug ingredient in the body at a constant rate even with the use of a small amount of release control substance. To maintain a constant blood level for 24 hours. In addition, it is possible to solve the problem that the release is delayed by trapping the glymepiride contained in the immediate release layer by the selective use of the emission control material as described above.

The hydrophilic polymer may be a mixture of two or more selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, and carboxyvinyl polymers. The hydrophilic polymer is a water-expandable substance that is in contact with the eluate and expands in water to undergo gelation.

More specifically, the hydrophilic polymer is dextrin, polydextrin, dextran, pectin and pectin derivatives, alginates, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose and amylopectin Sugars selected from among others; Hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, cellulose acetate phthalate, hydroxypropylmethylcellulose succinate and hydroxyethylmethyl Cellulose derivatives selected from cellulose and the like; Gum selected from guar gum, locust bean gum, tragacantha, carrageenan, acacia gum, arabic gum and gellan gum; Proteins selected from gelatin, casein, zein and the like; Polyvinyl derivatives selected from polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethyl amino acetate, and the like; Poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methylmethacrylate) copolymer, poly (methacrylic acid, methylmethacrylate) copolymer and poly (methacrylic acid, ethylacrylate) Polymethacrylate copolymers selected from copolymers and the like; Polyethylene derivatives selected from polyethylene glycol, polyethylene oxide and the like; As the carboxyvinyl polymer, one or a mixture of two or more selected from carbomer and the like can be used.

The hydrophobic material uses a water insoluble polymer, a hydrophobic compound or a mixture thereof.

The water insoluble polymer may be a pharmaceutically acceptable polyvinyl acetate; Polymethacrylate copolymers selected from poly (ethyl acrylate, methyl methacrylate) copolymer, poly (ethyl acrylate, methyl methacrylate, trimethylamino ethyl methacrylate) copolymer and the like; One or a mixture of two or more selected from cellulose derivatives selected from ethylcellulose, cellulose acetate and the like can be used.

The hydrophobic compound may be selected from fatty acids and fatty acid esters selected from glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and sleanic acid; Fatty acid alcohols selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol; Waxes selected from carnauba wax, beeswax and microcrystalline wax; One or a mixture of two or more selected from inorganic materials selected from talc, precipitated calcium carbonate, calcium dihydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and non-gum can be used.

It is preferable that the hydrophilic polymer and the hydrophobic material be included in a weight ratio of 2: 1 to 20: 1 in terms of controlled release.

The immediate release layer consists of glymepiride or a pharmaceutically acceptable salt thereof as the active ingredient. At this time, it is obvious that can be used in combination with conventional excipients that are commonly accepted in the art.

The co-formulation of the present invention can be appropriately blended excipients as necessary as a pharmaceutically acceptable carrier, and in addition to the pharmaceutically acceptable additives can be selected as various additives selected from colorants and flavorings. Excipients or additives that may be used in addition to the active ingredient may each be used one or more.
The excipient may be selected from disintegrants, diluents, binders and lubricants.

As a disintegrant, starch or modified starch, such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch, clays such as bentonite, montmorillonite, non-gum, microcrystalline cellulose, hydroxypropyl cellulose or algins And crosslinked celluloses such as croscarmellose sodium, gums such as guar gum and xanthan gum, crosslinked polymers such as crospovidone, and boiling agents such as sodium bicarbonate and citric acid. As the disintegrant, sodium starch glycolate is preferably used. The disintegrant may be mixed in the range of 0.01 to 40% by weight based on the unit weight of the tablet.

Diluents include corn starch, modified corn starch, lactose, glucose, mannitol, sorbitol, alginate, alkaline earth metal salts, clays, inorganic salts such as calcium carbonate and / or cellulose derivatives such as wood cellulose, microcrystalline cellulose polyethylene glycol and dicalcium phosphate And one or more. The diluent may be mixed in the range of 0.1 to 90% by weight based on the unit weight of the tablet, preferably 0.1 to 50% by weight can be used.

As binders, starch, highly dispersible silica, mannitol, lactose, carnauba wax, paraffin, braze, polyethylene wax polyethylene glycol, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, natural gum , Synthetic gums, copovidone, gelatin and the like can be used. The binder may be mixed in the range of 3 to 30% by weight based on the unit weight of the tablet, and preferably includes an amount of 3 to 10% by weight.

As lubricant, talc, magnesium stearate and alkaline earth metal, calcium stearate, zinc, lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and polyethylene glycol, glyceryl behenate, etc. One or more selected from the group consisting of can be used. The lubricant may be mixed in the range of 0.05 to 20% by weight based on the unit weight of the tablet, and preferably includes an amount of 0.05 to 2% by weight.

Other conventional ingredients that may optionally be present may include preservatives, stabilizers, anti-tackifiers or light silicic anhydrides or glidants, colorants, and the like.

Tablets of the compositions of the present invention may comprise a coating layer constituting 0.1 to 15% by weight. The coating layer applied on the outer solid phase capable of embedding the inner solid particles therein may comprise a conventional coating agent.

The coating layer may be a coating agent, a coating aid or a mixture thereof. Specifically, the coating layer may be used as a coating agent, cellulose derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats and gelatin, and polyethylene glycol as coating aids. Or a mixture of one or more selected from ethyl cellulose, glycerides, titanium oxide, diethyl phthalate and the like can be used.

Film forming agents include water, alcohols such as methyl alcohol, ethyl alcohol or isopropyl alcohol, ketones such as acetone, ethyl methyl ketone, methylene chloride, dichloroethane, and chlorolated hydrocarbons such as 1,1,1-trichloroethane The above solvent may be included. Preferably based on water-based coating in order to minimize the effect of the residual solvent in the long-term use of the problem in the long-term use of the formulation. One or more hydrophilic polymers, such as hydroxypropylmethylcellulose, and one or more plasticizers, such as polyethylene glycol. When a colorant is used, the colorant may be applied with a film forming agent, a plasticizer, a solvent composition, and the like.

Hereinafter, the method for producing the multi-layered tablet of the present invention will be described in detail.

First, a pharmaceutical composition comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient of a sustained release layer, a controlled release material for sustained release of the active ingredient, a disintegrant, a diluent, an excipient, a binder and a lubricant, and the like. Mix the composition.

In the base, metformin, a hydrophilic polymer, and a hydrophobic material, which are active ingredients, form a matrix for controlled release. Hydrophilic polymers have the property of swelling, thus prolonging gastrointestinal retention time and slowly controlling release of metformin entrapped in the matrix. Hydrophobic materials delay the release of the drug by blocking the voids in the matrix layer over time.

Apart from this, the immediate release layer is a step of mixing and granulating a pharmaceutical composition comprising a glimepiride or a pharmaceutically acceptable salt thereof as an active ingredient and a disintegrant, a diluent, an excipient, a binder, a lubricant, and the like.

The mixture of the sustained release layer and the granules of the immediate release layer were put into each hopper of the tableting machine and compressed to form a tablet layer. In the case of the mixture, the fluidity can be tableted by direct hitting when it is possible to tablet, and when the fluidity is not good, it can be compressed by compression, granulation and formulation.

Although the method of manufacturing the two-layered tablet has been described above, the multilayered tablet is a three-layered tablet in which the sustained-release layer and the single-release layer in which the drug release rate is controlled differently are compressed and laminated, and the immediate-release layer forms the outermost layer of the formulation. It can be formulated into a three-layered tablet.

The complex preparation of the present invention may be composed of uncoated tablets, and may be composed of a coated tablet in which a film-like coating layer is formed on the outer surface of the tablet layer as necessary. There is an advantage to be secured.

The method of forming the coating layer can be appropriately selected by the choice of those skilled in the art from the method of forming a film-like coating layer on the surface of the tablet layer using the above-described components, applying a method such as fluidized bed coating method, fan coating method can do. It is preferable to use a pan coating method.

Preferred dosages of metformin and glymepiride, the active ingredients of the present invention, range from 250 to 1000 mg and 1 to 8 mg, respectively, depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration of time. Can be appropriately selected.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

Example  1: metformin and Glimepiride Two-story  Controlled release formulations in the form of

1) Metformin western layer

As shown in Table 1, metformin hydrochloride, hydroxypropylmethylcellulose and polyvinylpyrrolidone and hydroxypropyl cellulose were mixed and mixed in a double cone mixer. Compritol was added to the mixture and post-mixed.

2) Glymepyride Immediate Layer

As shown in Table 1, it was mixed with glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate in a high speed mixer. The mixture was granulated with polyvinylpyrrolidone binding solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules were lubricated with magnesium stearate.

3) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into two different hoppers of the tableting machine and then compressed into bilayer tablets. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  2: metformin and Glimepiride Two-story  Controlled release formulations in the form of

1) Metformin western layer

As shown in Table 1, metformin hydrochloride, hydroxypropylmethylcellulose, collidone SR and hard silicic anhydride were added and mixed in a double cone mixer. Compritol was added to the mixture and post-mixed.

2) Glymepyride Immediate Layer

As shown in Table 1, it was mixed with glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate in a high speed mixer. The mixture was granulated with polyvinylpyrrolidone binding solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules are lubricated with magnesium stearate.

3) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into two different hoppers of the tableting machine and then compressed into bilayer tablets. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example 3 Controlled Release Formulations in Two-Layered Forms of Metformin and Glimepiride

1) Metformin western layer

As shown in Table 1, metformin hydrochloride, hydroxypropylmethylcellulose and hydroxypropylcellulose were added and mixed in a double cone mixer. Magnesium stearate is added to the mixture and then mixed.

2) Glymepyride Immediate Layer

As shown in Table 1, it was mixed with glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate in a high speed mixer. The mixture was granulated with polyvinylpyrrolidone binding solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules are lubricated with magnesium stearate.

3) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into two different hoppers of the tableting machine and then compressed into bilayer tablets to minimize incorporation. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  4: metformin and Glimepiride Two-story  Controlled release formulations in the form of

1) Metformin western layer

As shown in Table 1, metformin hydrochloride, hydroxypropylmethylcellulose, hydroxypropylcellulose, and hard silicic anhydride were mixed in a double cone mixer. Magnesium stearate was added to the mixture, followed by post-mixing.

2) Glymepyride Immediate Layer

As shown in Table 1, it was mixed with glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate in a high speed mixer. The mixture was granulated with polyvinylpyrrolidone binding solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules are lubricated with magnesium stearate.

3) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into two different hoppers of the tableting machine and then compressed into bilayer tablets on conditions that minimize incorporation. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  5: metformin and Glimepiride Three story  Controlled release formulations in the form of

1) Metformin West 1F

To the amount of the drug shown in Table 1 was prepared in the same manner as the manufacturing method of the metformin sustained layer of Example 1.

2) Metformin West 2nd Floor

Metformin hydrochloride and collidone SR were added and mixed in a double cone mixer. Compritol was added to the mixture and post-mixed.

3) Glymepyride Immediate Layer

Glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate were mixed in a high speed mixer. The mixture was granulated with polyvinylpyrrolidone binding solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules are added with magnesium stearate and finally mixed.

4) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into three different hoppers of the tableting machine and then compressed into three layer tablets to minimize incorporation. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  6: metformin and Glimepiride Three story  Controlled release formulations in the form of

1) Metformin West 1F

Next, the amount of the drug shown in Table 1 was prepared in the same manner as in the preparation method of metformin sustained layer of Example 1.

2) Metformin West 2nd Floor

Metformin hydrochloride and lactose were added and mixed in a double cone mixer. Compritol was added to the mixture and post-mixed.

3) Glymepyride Immediate Layer

Glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate were mixed in a high speed mixer. The mixture was granulated with polyvinylpyrrolidone binding solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules were added with magnesium stearate and finally mixed.

4) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into three different hoppers of the tableting machine and then compressed into three layer tablets to minimize incorporation. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  7: metformin and Glimepiride Three story  Controlled release formulations in the form of

1) Metformin West 1F

To the amount of the drug shown in Table 1 was prepared in the same manner as in the preparation method of the metformin sustained layer of Example 1.

2) Metformin West 2nd Floor

Metformin hydrochloride, microcrystalline cellulose, and hydroxypropyl cellulose were placed in a double cone mixer and mixed. Magnesium stearate was added to the mixture, followed by post-mixing.

3) Glymepyride Immediate Layer

Glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate were mixed in a high speed mixer. The mixture was granulated with polyvinylpyrrolidone binding solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules were added with magnesium stearate and finally mixed.

4) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into three different hoppers of the tableting machine and then compressed into three layer tablets to minimize incorporation. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  8: metformin and Glimepiride Three story  Controlled release formulations in the form of

1) Metformin West 1F

Next, the amount of the drug shown in Table 1 was prepared in the same manner as in the preparation method of metformin sustained layer of Example 1.

2) Metformin West 2nd Floor

Metformin hydrochloride, collidone SR, sodium starch glycolate, hydroxypropyl cellulose, and hard silicic anhydride were added and mixed in a double cone mixer. Magnesium stearate was added to the mixture, followed by post-mixing.

3) Glymepyride Immediate Layer

Glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate were mixed in a high speed mixer. The mixture is granulated with polyvinylpyrrolidone binder solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules were added with magnesium stearate and finally mixed.

4) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into three different hoppers of the tableting machine and then compressed into three layer tablets. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  9: metformin and Glimepiride Three story  Controlled release formulations in the form of

1) Metformin West 1F

Next, the amount of the drug shown in Table 1 was prepared in the same manner as in the preparation method of metformin sustained layer of Example 1.

2) Metformin West 2nd Floor

Metformin hydrochloride and collidone SR were added and mixed in a double cone mixer. Compritol was added to the mixture, followed by post-mixing.

3) Glymepyride Immediate Layer

Glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate were mixed in a high speed mixer. The mixture is granulated with polyvinylpyrrolidone binder solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules were added with magnesium stearate and finally mixed.

4) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into three different hoppers of the tableting machine and then compressed into three layer tablets. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  10: metformin and Glimepiride Three story  Controlled release formulations in the form of

1) Metformin West 1F

Next, the amount of the drug shown in Table 1 was prepared in the same manner as in the preparation method of metformin sustained layer of Example 1.

2) Metformin West 2nd Floor

Metformin hydrochloride and polyvinylpyrrolidone were added and mixed in a double cone mixer. Compritol was added to the mixture, followed by post-mixing.

3) Glymepyride Immediate Layer

Glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate were mixed in a high speed mixer. The mixture is granulated with polyvinylpyrrolidone binder solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules were added with magnesium stearate and finally mixed.

4) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into three different hoppers of the tableting machine and then compressed into three layer tablets. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  11: metformin and Glimepiride Three story  Controlled release formulations in the form of

1) Metformin West 1F

Next, the amount of the drug shown in Table 1 was prepared in the same manner as in the preparation method of metformin sustained layer of Example 1.

2) Metformin West 2nd Floor

Metformin hydrochloride, collidone SR, and polyvinylpyrrolidone were added and mixed in a double cone mixer. Compritol was added to the mixture, followed by post-mixing.

3) Glymepyride Immediate Layer

Glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate were mixed in a high speed mixer. The mixture is granulated with polyvinylpyrrolidone binder solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules were added with magnesium stearate and finally mixed.

4) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into three different hoppers of the tableting machine and then compressed into three layer tablets. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Example  12: metformin and Glimepiride Three story  Controlled release formulations in the form of

1) Metformin West 1F

Next, the amount of the drug shown in Table 1 was prepared in the same manner as in the preparation method of metformin sustained layer of Example 1.

2) Metformin West 2nd Floor

Metformin hydrochloride, collidone SR, and polyvinylpyrrolidone were added and mixed in a double cone mixer. Compritol was added to the mixture, followed by post-mixing.

3) Glymepyride Immediate Layer

Glymepiride, lactose and microcrystalline cellulose and sodium starch glycolate were mixed in a high speed mixer. The mixture is granulated with polyvinylpyrrolidone binder solution. The granules were dried at a temperature of 60 ° C. and sieved to the 18 mesh range. The sieved granules were added with magnesium stearate and finally mixed.

4) tableting and coating

It was compressed using a multi-layer tablet press (MRC-37T: Sejong). The granules containing metformin and glymepiride were fed into three different hoppers of the tableting machine and then compressed into three layer tablets. It was manufactured by forming a film coating layer as a high coater (SFC-30N, Sejong Machinery, Korea).

Experimental Example 1. Comparative Dissolution Test

The comparative dissolution test of metformin was carried out in two-layered tablets of metformin sustained-release tablets and glymepiride prepared according to Examples 1 and 5. The control drug used was a product commercially available in the United States (glucophage 750 xal, BMS).

The dissolution characteristics were measured by paddle method in the dissolution test term of the KEPCO general test method, and the results are shown as shown in FIGS. 1 and 2, respectively. According to the test results, the elution characteristics of metformin multi-layered sustained-release tablets were similar to those of general sustained-release tablets.

Experimental Example  2. Comparative Dissolution Test

The comparative dissolution test of glymepiride was carried out in a bilayer tablet of metformin sustained-release tablet and glymepiride prepared according to Example 1. The reference drug used was a commercially available product (Amaryl, Handok Aventis).

The dissolution characteristics were measured by paddle method in the dissolution test term of the KEPCO general test method, and the results are shown in the accompanying drawings. According to the test results, glymepiride in the double-layered tablet of the present invention showed faster dissolution characteristics than general glymepiride.

As described above, according to the present invention, the multi-layered tablet of metformin and glymepiride is used in the diabetic patients taking metformin and glymepiride. This can prevent confusion and increase medication compliance.

In addition, according to the present invention, the multi-layer tablet of metformin sustained-release layer and glymepiride immediate release layer can be expected to have a faster medicinal effect due to the rapid release of glymepiride compared to the conventional formulation to diabetic patients taking metformin and glymepiride together, and due to the sustained release of metformin. More sustainable effects can be expected.

In addition, when taking multi-layered tablets of the metformin sustained-release layer and the glymepiride immediate release layer according to the present invention, the slow disappearing glymepiride and sustained-release metformin can be expected to have a sustained drug synergistic effect during the drug retention time, thereby increasing the usefulness of blood glucose control. Can have

In addition, by constructing a multi-layered tablet according to the present invention, it is possible to prevent the glymepiride layer from being captured by the swelling phenomenon of metformin controlled release. The glymepiride layer, which is not captured and rapidly released, has greater utility in managing blood glucose at the beginning of administration.

In addition, according to the present invention, it is possible to solve the content non-uniformity caused by the mixing of metformin and glymepiride, which occupy a large mass ratio in a single tablet, by constructing a multilayer tablet.

Claims (22)

In a combination formulation comprising metformin and glymepiride as an active ingredient and a pharmaceutically acceptable excipient, A sustained release layer containing metformin or a pharmaceutically acceptable salt thereof as an active ingredient and comprising a pharmaceutically acceptable hydrophilic polymer mixture and a hydrophobic material as an emission control material, An immediate release layer containing, as an active ingredient, glymepiride or a pharmaceutically acceptable salt thereof and at least one excipient selected from disintegrants, diluents, binders and glidants, A drug-controlled release metformin-glymepiride complex preparation, characterized in that the sustained-release layer and the immediate release layer is a multi-layer tablet formed by tableting. The method of claim 1, The sustained release layer and the immediate release layer is a drug controlled release metformin-glymepiride complex preparation, characterized in that consisting of 100: 10 to 30 by weight. The method of claim 1, The multi-layered tablet is a drug-controlled release metformin-glymepiride complex formulation, characterized in that the sustained-release layer and the immediate release layer is compressed laminated in two layers. The method of claim 1, The multilayer tablet is a drug-released metformin-glymepiride complex, wherein the sustained-release layer and the single-release layer in which the drug release rate is controlled differently are compressed and laminated, and the immediate release layer constitutes the outermost layer of the preparation. Formulation. The method of claim 1, The pharmaceutically acceptable salt of metformin is a drug controlled release metformin-glymepiride combination, characterized in that the hydrochloride of metformin. The method of claim 1, The metformin is a drug controlled release metformin-glymepiride complex preparation, characterized in that 55 to 75% by weight of the sustained release layer. The method of claim 1, Glymepyride is a drug controlled release metformin-glymepiride complex preparation, characterized in that 0.05 to 10% by weight of the immediate release layer. The method of claim 1, The hydrophilic polymer is a drug controlled release metformin, characterized in that one or two or more selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives, and carboxyvinyl polymers. Glymepiride combinations. The method of claim 8, The hydrophilic polymer is a saccharide selected from dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin ; Among hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate and hydroxyethylmethylcellulose Selected cellulose derivatives; Gum selected from guar gum, locust bean gum, tragacantha, carrageenan, acacia gum, arabic gum and gellan gum; Proteins selected from gelatin, casein and zein; Polyvinyl derivatives selected from polyvinyl alcohol, polyvinyl pyrrolidone and polyvinylacetal ethylaminoacetate; Poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methylmethacrylate) copolymer, poly (methacrylic acid, methylmethacrylate) copolymer and poly (methacrylic acid, ethylacrylate) Polymethacrylate copolymers selected from copolymers; Polyethylene derivatives selected from polyethylene glycol and polyethylene oxide; A carboxyvinyl polymer, a drug controlled-release metformin-glymepiride complex preparation, characterized in that one or a mixture of two or more selected from carbomers. The method of claim 1, The hydrophobic material is a water-insoluble polymer, a hydrophobic compound or a mixture thereof, drug controlled release metformin-glymepiride complex preparation. The method of claim 10, The water insoluble polymer may be a pharmaceutically acceptable polyvinyl acetate; Polymethacrylate copolymers selected from poly (ethyl acrylate, methyl methacrylate) copolymers, poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate) copolymers; A drug-controlled-release metformin-glymepiride complex preparation, characterized in that it is one or a mixture of two or more selected from cellulose derivatives selected from ethyl cellulose and cellulose acetate. The method of claim 10, The hydrophobic compounds include fatty acids and fatty acid esters selected from glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate and sleanic acid; Fatty acid alcohols selected from cetostearyl alcohol, cetyl alcohol and stearyl alcohol; Waxes selected from carnauba wax, beeswax and microcrystalline wax; Drug controlled release metformin-glymepiride complex, characterized in that the mixture is one or two or more selected from inorganic materials selected from talc, precipitated calcium carbonate, calcium hydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and non-gum. Formulation. The method of claim 1, The hydrophilic polymer and hydrophobic material is a drug controlled release metformin-glymepiride complex preparation, characterized in that it comprises a 2: 1 to 20: 1 weight ratio range. The method of claim 1, The controlled release of the sustained release layer is a drug controlled release metformin-glymepiride complex formulation, characterized in that it comprises 10 to 45% by weight of the total composition of the sustained release layer. The method according to any one of claims 1 to 14, The combination preparation is a drug-controlled release metformin-glymepiride complex preparation, characterized in that the coating tablet with a coating layer on the uncoated tablet or film. The method of claim 15, The coating layer is a drug controlled release metformin-glymepiride complex, characterized in that it comprises a coating agent, coating aid or a mixture thereof. The method of claim 15, The coating layer is a drug control, characterized in that it comprises one or two or more selected from cellulose derivatives, sugar derivatives, polyvinyl derivatives, waxes, fats, gelatin, polyethylene glycol, ethyl cellulose, titanium oxide and diethyl phthalate Release Metformin-Glymepyride Co-Formulations. The method of claim 15, The coating layer is a drug controlled release metformin-glymepiride complex preparation, characterized in that contained in the range of 0.1 to 15% by weight of the total weight of the multilayer tablet. The disintegrant of the immediate release layer is sodium starch glycolate, starch, modified starch, bentonite, montmorillonite, non-gum, microcrystalline cellulose, hydroxypropyl cellulose, algins, cross-linked cellulose, gum, A drug-controlled release metformin-glymepiride complex preparation, characterized in that at least one selected from crospovidone, sodium bicarbonate and citric acid. The diluent of the immediate release layer is corn starch, modified corn starch, lactose, glucose, mannitol, sorbitol, alginate, alkaline earth metal salt, clay, calcium carbonate, wood cellulose, microcrystalline cellulose, polyethylene glycol And dicalcium phosphate at least one selected from the group consisting of controlled release metformin-glymepiride. The method of claim 1, wherein the binder of the immediate release layer is starch, highly dispersible silica, mannitol, lactose, carnauba wax, paraffin, light lead, polyethylene wax polyethylene glycol, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropyl. A drug controlled-release metformin-glymepiride complex preparation, characterized in that at least one selected from methyl cellulose, hydroxypropyl cellulose, natural gum, synthetic gum, copovidone and gelatin. The lubricant of claim 1, wherein the lubricant of the immediate release layer is talc, magnesium stearate, calcium stearate, zinc, lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and polyethylene glycol, Drug-controlled release metformin-glymepiride complex preparation, characterized in that at least one selected from glyceryl behenate.

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