WO2013169007A1

WO2013169007A1 - Sustained-release complex preparations for treating diabetes with improved drug compliance and method for preparing same

Info

Publication number: WO2013169007A1
Application number: PCT/KR2013/004039
Authority: WO
Inventors: 어진; 정현근; 이종권; 윤주용; 신제용
Original assignee: 안국약품 주식회사
Priority date: 2012-05-11
Filing date: 2013-05-08
Publication date: 2013-11-14
Also published as: KR101409330B1; KR20130126253A

Abstract

The present invention relates to sustained-release complex preparations for the treatment of diabetes with improved drug compliance and to a method for preparing same. More particularly, the present invention relates to sustained-release complex oral preparations for the treatment of diabetes, which comprise: a) an inner layer that includes Metformin or pharmaceutically acceptable salts thereof, sustained-release carriers and a pharmaceutically acceptable excipient; b) an intermediate layer that does not include drugs and that includes a water-soluble polymer; and c) an outer layer that includes sulfonylurea-based drugs and a control release formulation, wherein Carbomer is used as the sustained-release carriers. According to the present invention, complex preparations for the treatment of diabetes, comprising the inner layer including Metformin, the intermediate layer and the outer layer including sulfonylurea-based drugs, use Carbomer as the sustained-release carriers of the inner layer, thus exhibiting the same release pattern as that of Amaryl Mex which has been used in conventional complex preparations for the treatment of diabetes. Furthermore, the greater part of the sustained-release carriers is decomposed after 24 hours, thus avoiding gastrointestinal tract disorders. The weight of the inner layer is minimized to reduce the size of a tablet to allow for ease of medicine taking, thus improving drug compliance of a patient.

Description

【Specification 】

【Name of Invention】

Administration of sustained release diabetes with improved compliance and preparation method

【Technical Fields】

The present invention relates to a combination preparation for treating sustained release diabetes mellitus with improved dose compliance and a preparation method thereof. Background technology

Type 2 diabetes, also called adult diabetes, insulin-independent diabetes, or diabetes mellitus, is a disease in which the body processes and uses carbohydrates, fats, and proteins. Each of these nutrients is a source of glucose and serves as the body's most basic energy source. In our body, glucose enters the cells of the body with the help of insulin. Insulin, produced by the pancreas, acts as a gatekeeper. Glucose enters the cells of the body with the help of insulin, and without insulin, glucose cannot cross the cell wall. Thus, cells rely on inefficient fuels for energy. Crab type 2 diabetes occurs when cells do not effectively react to the insulin produced by the pancreas. This condition is called insulin resistance. People with insulin resistance initially produce more insulin to maintain normal blood sugar. However, insulin resistance eventually progresses, causing the pancreas to fail to meet its insulin requirements and raise blood sugar levels. About 95% of people with diabetes are type 2 diabetics, who develop over the age of 40 and develop in the family. Tend to. Type 2 diabetes, part of a disease known as metabolic syndrome, was originally called icicle X, a collection of symptoms that increase the risk of developing heart disease and stroke. Risk factors that constitute metabolic syndrome include obesity, insulin resistance accompanied by elevated blood glucose, elevated blood insulin levels, high blood pressure, elevated triglycerides, and low concentrations of high-density lipoproteins. These problems often occur simultaneously and Has a genetic or metabolic association Metabolic syndrome and type 2 diabetes are both risk factors for the development of heart disease, stroke and peripheral arterial disease. In the past, as a treatment for diabetes, sulfonyl urea drugs have been mainly used, and such drugs include drugs such as glyclazide and glimepiride. Sulfonylurea-based drugs have a mechanism to regulate hyperglycemia by gradually increasing insulin secretion from beta cells. However, long-term use of sulfonylurea-based drugs has side effects such as hypoglycemia, weight gain, and deterioration of blood lipid status. In addition, drug resistance occurs during long-term use, which requires co-administration of the drug. For this reason, sulfonylurea-based drugs have recently been coadministered with biguanide drugs, which confirm that synergistic control functions due to differences in pharmacological mechanisms are synergistic with each other. The method of administration was performed clinically. However, when two or more oral hypoglycemic agents are used, their drug characteristics are different, so the dosage method is often different. Thus, attempts have been made to prepare drugs with different blood retention times in one combination. In fact, according to the study comparing the patient's dose rate according to the administration method in the combination therapy of oral hypoglycemic agent, the patient's dose level was 54%, but the patient's dose level was 54%. Was 77%, demonstrating that the combination can provide substantial benefits for long-term combination therapy. Such a combination drug for treating diabetes may include aguanide-based metformin, sulfonylurea-based glimepiride, glyburide, acarbose, alpha-glucosidase inhibitors such as acarbose, bolibos, migrile, or thiazolidinedine, and troglitazone, Rosiglitazone and the like can be used. For example, metformin is a biguanide type 2 diabetes treatment, and a typical dosage is 500 to 1000 mg orally 2-3 times a day. It is known to be slowly and incompletely absorbed by the gastrointestinal tract and mainly absorbed in the upper intestine. The half-life of blood is known to be 2-6 hours. The drug itself has a very high solubility, very low absorption, and a short half-life. On the other hand, for example, glymepyride is a sulfonylurea type 2 diabetes treatment agent, and a typical dosage is orally administered 1 to 2 nig once a day. It is almost completely absorbed by the gastrointestinal tract, and the drug half-life by continuous administration is about 9 hours, and the half-life of the drug itself is long, so that the drug is absorbed by rapid drug release. However, in general, the drug is put into the body to maintain a constant blood concentration above the effective concentration can maximize the therapeutic effect of the drug. Therefore, the metformin-glymepiride combination should be a combination formulation that has a sustained release of the drug from the formulation in the case of metformin with a short blood retention time of the drug, and an immediate release of the drug from the formulation in the case of glymepiride, which has a long blood retention time. In fact, each drug concentration can be kept constant in the blood to obtain an appropriate therapeutic effect. ^"However, the conventional method of blood citron time of the drug is to prepare other drugs in a single preparation are short drug in the blood retention time is long portion and a blood retention time to allow the release of the drug can be slowly drug is rapid drug release This is made by separately preparing the parts to be made by compression molding into a single tablet. However, in the case of manufacturing separately and compression molding into a single tablet requires a special tableting machine to produce a multi-layered tablet, the use of more than necessary excipients for smooth compression molding, the size of the tablet becomes large. If the amount of the drug is very small, there was a problem that it is difficult to obtain a tablet having a constant drug content. Attempts have been made to solve this problem. US Pat. No. 6,682,759 discloses a tablet comprising two immediate release layers and a continuous release layer. A method for preparing an immediate release layer by coating a sustained release tablet is disclosed, and International Publication No. W02003 / 026637 adds an immediate release composition comprising a long-term functional sulfonylurea and a release control composition comprising a biguanide. A dosage form for treating diabetes and conditions associated therewith is disclosed. However, US Patent Nos. 6, 682 and 759 do not separate each drug layer so that drug release requiring rapid release of the outer layer is prevented by the high viscosity polymer of the inner layer to properly obtain the desired rapid release. There is a problem that can not be. International Publication No. W02003 / 026637 also provides dosage forms for treating diabetes and related conditions further comprising an immediate release composition comprising a long-acting sulfonylurea and a release control composition comprising a biguanide. Is disclosed. Although the patent mentions some of the water-insoluble polymer interlayer, substantially the presence of the water-insoluble interlayer is too slow to release the drug release of the inner layer is difficult to finally obtain the desired drug release pattern. In addition, the water-insoluble coating layer must use an organic solvent such as methanol, isopropyl alcohol, methylene chloride, acetone in order to dissolve or disperse the coating material, which is at least 100 times higher than the raw material price. In addition, facilities in the manufacturing process require explosion-proof facilities to prevent the risk of explosion caused by organic solvents.In addition to the discharge of organic solvents, facilities for treating organic solvents in air and organic solvents in sewage treatment facilities are required. This is necessary. This will cost several hundred million won. However, even after treatment, it can be a source of environmental pollution, and there is always a risk of fire, and the most deadly one can cause central nervous system and liver damage if long-term exposure to workers during manufacturing process. In addition, organic solvents do not disappear completely during the manufacturing process and remain very dangerous for those who take the preparations, especially those with long-term needs, such as diabetics. In addition, in order to solve this problem, Handok Pharmaceuticals in Korea Patent Publication No. 2006-0051510 discloses a) metformin or its pharmaceutical An inner layer comprising an acceptable salt, a swellable polymer and a pharmaceutically acceptable excipient; b) an interlayer comprising a water soluble polymer, free of drugs; And c) an outer layer comprising a sulfonylurea-based drug and a release modulator, wherein the swellable polymer is a high-viscosity cellulose derivative (example: hydroxymethyl sallo). Oss 100,000 cps), and as a product was released Handok Amaryl Mex, but since the product is large tablet size (diameter: 20.0 mm), it is difficult for the elderly to take, and the sustained release carrier does not dissolve after dissolution It is possible to cause gastrointestinal disorders by maintaining its form even after the release of the drug. Accordingly, the inventors of the present invention are effective in that each drug is effectively released without interfering with each other even if two different drugs requiring different dissolution patterns as immediate and sustained releases because of different blood retention times are used as one agent. It is possible to make the effective blood concentration maintenance time of constant, and to reduce the size of tablets, it is easy for elderly people to take it. ， By using carbomer as the optimum ratio of sustained release sustained release carrier produced in sustained release type, it is possible to maintain continuous drug release even when taking eleven times of 11 days. May increase the sustained release carrier within 24 hours after taking it, causing gastrointestinal disorders The present invention was completed. 【Detailed Description of the Invention】

[Technical Challenges]

An object of the present invention is to maintain the effective blood concentration of the drug by taking only once a day, the two drugs with different release patterns do not interfere with each other in the drug release effectively and elute effectively, reducing the size of the elderly The present invention is to provide a sustained release diabetes mellitus formulation that is easy for patients to take the drug.

【Technical Solution】

In order to achieve the above object, the present invention

a) metformin or a pharmaceutically acceptable salt thereof sustained release An inner layer comprising a carrier and a pharmaceutically acceptable excipient;

b) an intermediary layer comprising a water soluble polymer, free of drugs;

For sustained release treatment of diabetes, characterized in ^that: C) a sulfonylurea-based drugs, and in a combined preparation for the treatment of diabetes for oral administration comprising an outer layer comprising a controlled release material, to use a carbomer as the sustained release carrier Provide a combination formulation.

Advantageous Effects

According to the present invention, in a combination preparation for treating diabetes comprising an inner layer, an intermediate layer containing metformin, and an outer layer containing a sulfonylurea-based drug, a combination preparation for treating diabetes, which is conventionally used by using a carbomer as a sustained release carrier of the inner layer It shows an emission pattern equivalent to that of Jane Amaryl Mex, and the sustained release carriers are mostly decomposed after 24 hours, and do not cause gastrointestinal disorders.

【Brief Description of Drawings】

1 is a photograph showing a sustained release tablet prepared according to Example 1 of the present invention and a conventional preparation for treating diabetes mellitus.

Figure 2 is a graph showing the dissolution test results for metformin in eluate pH 6.8 of the sustained-release tablet prepared in Example 1 of the present invention and the conventional combination therapy for diabetes treatment

Figure 3 is a graph showing the dissolution test results for glymepiride in the eluate pH 6.8 of the sustained-release tablet prepared in Example 1 of the present invention and the conventional preparation for treating diabetes mellitus.

Figure 4 is a graph showing the dissolution test results for metformin in the eluate pH 6.8 of the sustained-release tablet prepared in accordance with Examples 1 and 4-7 of the present invention and the conventional combination therapy for diabetes treatment.

Figure 5 is a graph showing the dissolution test results for metformin in the eluate pH 6.8 according to the sustained release carrier of the sustained release tablet prepared according to the present invention.

6 is a time-dependent dissolution test in the eluate pH 6.8 of the sustained-release tablet prepared in accordance with the present invention and the conventional preparation for treating diabetes mellitus It is a photograph showing the change of the shape of a sustained release tablet.

【Best Mode for Implementation of Invention】

Hereinafter, the present invention will be described in detail. The present invention,

a) an inner layer comprising metformin or a pharmaceutically acceptable salt thereof, a sustained release carrier and a pharmaceutically acceptable excipient;

b) an interlayer comprising a water soluble polymer, free of drugs; And

c) A combination preparation for diabetes treatment for oral administration comprising an outer layer comprising a sulfonylurea-based drug and a release control agent, wherein the combination preparation for treating sustained-release diabetes is characterized in that a carbomer is used as the sustained release carrier. To provide. In the combination according to the present invention, the amount of metformin or a pharmaceutically acceptable salt thereof is preferably 55 바람직 60 weight _¾ to the total weight of the inner layer ᅳ more preferably, _{250 mg} to oo mg is added, Even more preferably, 1000 mg of 500 i _j fl may be added. In this case, the pharmaceutically acceptable salt of metformin is, for example, hydrochloride, succinate, fumarate, bromate, P-chlorophenoxyacetate or embonate, preferably hydrochloride. In the co-formulation according to the present invention, the sulfonylurea-based drug is, for example, glymepiride glyburide, glyclagit, glyborneuride, glynuxamide, fenbutamide, llaramide, ebutamide , Cyclamide, carbutamide, chlorpropamide or pharmaceutically acceptable salts thereof can be used. In particular, glymepiride with a high frequency of clinical application can be used. The glymepyride is preferably included in an amount of 1 mg to 8 mg, more preferably 1 mg to 2 mg.

The sulfonylurea-based drug is very difficult to dissolve in water due to the characteristics of the drug, thereby maximizing the surface area of the drug to improve the dissolution of the drug, and the amount contained in the preparation is small, so when applied to the preparation by reducing the particle size of the drug Uniform distribution in this formulation In the co-formulation according to the present invention, the sustained release carrier is a release controlling substance for releasing drugs in the inner layer by constituting the inner layer, and it is preferable to use a hydrophilic carbomer as the sustained release carrier. In the dissolution rate experiment of the drug according to the sustained release carrier, the carbomer was found to release the drug slowly in the inner layer than other sustained release carriers (hydroxypropylmethylcellose (HPMC), polyethylene oxide (PE0), etc.), Since the drug is released within 24 hours after drug release, it does not cause gastrointestinal disorders and the like, and thus can be usefully used as a sustained release carrier.

At this time, the carbomer used as the hydrophilic sustained release carrier in the present invention is preferably a granular carbomer having a viscosity of 4,00 11,000 centipoas (cps). If a powder type carbomer is used, there is a problem in that the fluidity is low and the machine is disturbed during mass production.

The carbomer may be used in an amount of 10 to 25% by weight relative to the total weight of the inner layer.

Carbomer use in this range can improve the patient's medication mileage by reducing the increase in total co-formulation. In addition, the present invention may further include polyethylene oxide and / or hydroxypropylmetholose in the carbomer as an auxiliary substance for improving processability or controlling drug release. In this case, the polyethylene oxide may be used having an average molecular weight of 100, 000-7,000, 000, it may be used by mixing two or more polyethylene oxide of different molecular weight. The hydroxypropyl methyl cellulose may be used a polymer having a viscosity of 4,000-100,000 centipoise. In the co-formulation according to the present invention, the pharmaceutically acceptable excipient may be at least one component selected from microcrystalline cellulose, di-mannitol, lactose and magnesium stearate. In the composite preparation according to the present invention, the intermediate layer containing the water-soluble polymer is formed in the outer layer before the drug release of the outer layer is inhibited by the high viscosity polymer in the inner layer when the agent is exposed to the dissolution medium. By stripping, the two cases are quickly separated and the release of the drug from the outer layer is controlled quickly to minimize the effect of the inner and outer layers on each other's release. The intermediate layer also minimizes the effects on the drug stability of each other that can occur when the two drugs are formulated and stored for a long time.

Accordingly, the water polymer, which is the main component of the intermediate layer to perform this action, is preferably a polymer having a viscosity of 6 centipoise or less. Examples of the water-soluble polymer

Hydroxypropylmethyl Cellulose (HPMC), Carboxymethyl Cellulose (CMC) Microcrystalline Cellulose (MCC), Ethyl Cellulose (EC), Methyl Salulose (MC), Hydroxypropyl Cellulose ( HPC)

Cellulose Acetate Phthalate (CAP) I

As hydroxypropylmethyl saelreul O soup Frontale ^'Sites (HPMCP),

One or more components selected from cellulose derivatives, such as hydroxypropylmethylcelloseroseacetatesuccinate (HPMCAS), and polymethacrylate polymers can be used. In the co-formulation according to the present invention, any one of the polymers that can release the drug from the outer layer by constituting the external agent can be used. Therefore, the release controlling agent is preferably a polymer having a viscosity of 6 centipoise or less. Also preferred are water soluble to hydrophilic polymers, particularly preferably water soluble polymers. As the release control agent, for example, a cotton noodle, hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) microcrystalline cellulose (MCC), ethyl cellulose (EC), methyl cellulose ( MC), hydroxypropyl cellulose (HPC),

Cellulose acetate phthalate (CAP),

Hydroxypropylmethylcellulose phthalate (HPMCP),

One or more components selected from cellulose derivatives such as hydroxypropylmethylmethyl cellulose acetate succinate (HPMCAS) and polymethacrylate can be used. It is preferable to use the water-based coating which uses water as a water-soluble coating liquid at the time of forming a thick layer and forming an outer layer of the formulation of this invention. In forming the outer layer, the hydrophobic drug is homogeneously dispersed in the solution, Surfactants, fatty acids, oils, polyethylene glycols, alcohols, or propylene glycols may be used in combination with the coating material for rapid release. Preferably, the surfactant is 0.1 to 10% by weight of sodium lauryl sulfate, Preferably it can be used in the range of 0.1 to 5% by weight. Preparation of the coating liquid may be carried out according to a conventional method for preparing a coating liquid. When the material included in the inner layer requires the blocking of light, the coating solution may include a pigment and a shielding agent. ;

， ^■

The co-formulation according to the present invention has an intermediate layer of water-soluble polymers, and thus does not affect the release of drugs of different layers, so that the drug release from the vortex is much faster, and the drug release from each other becomes effective, resulting in effective use of individual drugs. The blood concentration maintenance time can be made constant, and also the stability of the drug can be maintained higher.

In addition, the formulation of the present invention is not a multi-layered tablet, but forms a drug layer for different drugs in the form of a coating, which is less expensive to produce than the multi-layered tablets. The use of waterborne coatings eliminates the need for explosion-proof facilities, reduces production costs, and can be manufactured without environmental pollution and without adverse effects on workers, and can be administered to long-term patients without the side effects of residual solvents.

Furthermore, the preparation of the present invention exhibits a release pattern equivalent to that of Amaryl Mex, which is a conventional combination therapy for diabetes treatment, by using carbomer as a sustained release carrier, and does not cause gastrointestinal tract obstruction as most of the sustained release carriers are decomposed after 24 hours, By minimizing the weight of the tablet to reduce the size of the tablet is easy to take, thus increasing the patient's dose. Referring to the manufacturing method of the composite preparation according to the present invention, for example.

As the inner layer in the formulation of the present invention, metformin preparations such as granules, tablets and pills can be used. It may be prepared by a conventional method for preparing a sustained release formulation. That is, the inner layer may contain metformin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient with water. It can be prepared by adding a mixer to the homogenous dispersion, homogeneously dispersing it, forming it into granules, drying and preparing granules of a predetermined size and then compression-mixing the sustained release carrier and a pharmaceutically acceptable excipient after mixing.

The intermediate layer may be prepared by coating a waterborne polymer solution previously dissolved in water on an inner layer introduced into a coating apparatus.

The outer layer is first disperse the drug, surfactant, and pigment or shielding agent in water through a dispersing device and then uniformly disperse it in a water-soluble polymer solution dissolved in water, and then stir the insects coated with intermediate insects while continuing stirring. Can be prepared by coating until the final amount of drug in the coating device

_, A combined preparation of the invention composition is preferably administered orally in the form of a tablet.

Preferred dosages of the co-formulations of the invention vary depending on the condition and weight of the patient, the extent and duration of the disease, but may be appropriately selected by those skilled in the art. Administration is preferably performed once a day.

【Mode for Implementation of the Invention】

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Preparation of a metformin limepiride complex preparation according to the invention;

(i) Preparation of Metformin Inner Layer

Metformin hydrochloride 500 g hydroxypropylmethyl cellulose (Methocel 165 g microcrystalline cellulose 20 g polyethylene oxide 25 g carbomer (Type A) 180 g magnesium stearate 10 g

900 g metformin

Homogeneously mix hydroxypropylmethylcellose, microcrystallinecelloseose, A portion of hydroxypropylmethylsalose was mixed with a binder solution dissolved in purified water to form granules. The resulting granules were dried in a fluid bed dryer and sieved through a No. 30 mesh sieve. Carbomer and polyethylene oxide were added thereto and mixed for 30 minutes. Finally, magnesium stearate was mixed with a No. 30 mesh sieve in a mixer for 10 minutes and then compressed to obtain a metformin inner layer.

(2) Preparation of Interlayer

Hydroxypropylmethylcellose (Pharmacoat 645)

Polyethylene Glycol (PEG 6000)

Ethane and hydroxypropyl methylcellose and polyethylene glycol were dissolved in purified water to prepare a coating solution. The mixed composition was sprayed to the inner layer in a tablet coating machine after passing through No. 120 mesh sieve and coated

(3) Preparation of Glimepiride Outer Layer

Glymepiride 2.0 g Sodium lauryl sulfate 2.0 g Hydroxypropylmethylcellose (Pharmacoat 645) 23.1 g Titanium oxide 2.9 g Polyethylene glycol (PEG 5.0 g

35 g of glymepiride, sodium lauryl sulfate, hydroxypropylmethylcellose, titanium oxide, and polyethylene glycol were mixed with purified water and passed through a Crab No. 120 mesh sieve. Composite formulations were prepared.

The metformin-glymepiride complex preparation was prepared in the same manner as in Example 1 except for using the composition shown in Table 1 below. Table 1

In the preparation of the composite preparation according to the present invention, except that the composition shown in Table 2 was used for the inner layer, it was carried out in the same manner as in Example 1 to prepare a metforminopenlymphide complex preparation.

Table 2

Experimental Example 1 Size Comparison

The Amaryl Mex tablet of Handok Pharmaceutical Co., Ltd. used as a conventional formulation for treating diabetes as a combination formulation of Example 1 prepared according to the present invention is shown in FIG. 1, and the sizes of the two tablets were measured and compared. 1 is a photograph showing a sustained-release tablet prepared according to Example 1 of the present invention and a conventional preparation for treating diabetes (Amaryl Mex).

·

As shown in FIG. 1, the combination preparation according to the present invention was found to reduce the size of the tablet compared to Amaryl Mex tablet of Handok Pharmaceutical by minimizing the weight of the inner layer using a carbomer having a low molecular weight as a sustained release carrier. As a result of measuring the size of tablets, the Amaryl Mex tablet of Handok Pharmaceutical Co., Ltd. was 20.0 mm in length and 8.9 mm in width, whereas the combined preparation according to the present invention was 18.5 mm in length and 8.4 mm in width. The size was probably smaller than the € Mex tablet. Since the combination preparation prepared according to the present invention is smaller in size than the conventional preparation for treating diabetes, it is also taken by elderly patients. It is easy.

Experimental Example 2 Comparative Dissolution Test

In the case of sustained-release preparations, some of the drug is ^released from the ^{stomach after} it has been eluted and moved to the small intestine for about 2 hours to release the drug from the small intestine. Therefore, the dissolution test was performed on the formulation and the reference agent of Example 1 using the eluate of 1 6.8 under the condition of 50 rpm of paddle (Paddle) by the comparative dissolution test method of the drug equivalence criteria to see the drug release pattern according to the biological conditions. It was. The dissolution test was carried out by diluting the metformin and glymepiride dissolution rate, as a reference formulation was used 'Amaryl Mex' of Handok medicine used as a conventional combination therapy for diabetes treatment.

2 and 3 to the measurement results! Indicated. Figure 2 is a graph showing the dissolution test results for metformin in the eluate pH 6.8 of the sustained release tablet prepared according to Example 1 of the present invention and a conventional combination therapy for treating diabetes. Figure 3 is a graph showing the dissolution test results for glymepiride in the eluate pH 6.8 of the sustained-release tablet prepared in Example 1 of the present invention and the conventional combination therapy for diabetes treatment. As shown in Figures 2 and 3, the composite formulation prepared according to the present invention showed an elution pattern equivalent to the reference formulation. In addition, the dissolution rate for metformin in Examples 1 and 4 ′ 7 was also measured and shown in FIG. 4. Figure 4 is a graph showing the dissolution test results for metformin in the eluate pH 6.8 of the sustained-release tablet prepared in accordance with Examples 1 and 4-7 of the present invention and the conventional combination therapy for diabetes treatment. As shown in FIG. 4, the combination preparation prepared according to the present invention exhibits an elution pattern equivalent to that of the reference preparation (Amaryl Mex), thereby controlling rapid release of the drug over time and enabling continuous release. It can be seen that the emission concentration increases up to 12 hours.

Experimental Example 3 Comparative Dissolution Test According to Sustained Release Carrier Type

In the preparation of the composite preparation according to the present invention, the following test was carried out to determine the change in the dissolution rate of the inner layer (sustained release layer) according to the type of the sustained release carrier.

When preparing a composite preparation according to the present invention as shown in Table 3 below as a type of sustained release carrier, the composite preparation containing a carbomer (A) and hydroxypropylmethylcellulose or polyethylene oxide alone instead of carbomer The prepared composite formulation (B, C) was prepared in the same manner as in Example 1, and the dissolution test was performed using an eluate having a pH of 6.8 at a paddle of 50 rpm by a comparative dissolution test method of drug equivalence criteria, The results are shown in FIG.

Table 3

Figure 5 is a graph showing the dissolution test results for metformin in the eluate pH 6.8 according to the sustained release carrier of the sustained release tablet prepared according to the present invention. As shown in Fig. 5, when the carbomer is used as the sustained release carrier of the inner layer in the preparation of the composite formulation, the same weight of other hydrophilic sustained release carriers (hydroxypropylmethylcellose polyethylene oxide) It has been shown to delay dissolution rate. Therefore, it can be seen that the use of carbomer as a sustained release carrier in the composite preparation according to the present invention is effective in lowering the dissolution rate. Experimental Example 4 Formulation Degradation Test According to Sustained Release Carrier Type

In the preparation of the composite preparation according to the present invention, the following test was performed to determine the degree of degradation after administration of the preparation according to the type of sustained release carrier.

The composite preparation of Example 1 prepared according to the present invention and Amaryl Mex tablet of Handok Pharmaceutical Co., Ltd., which is used as a conventional combination preparation for diabetes treatment, were placed in an eluate having a pH of 6.8 to observe the form of the preparation over time. Shown in Figure 6 is a photograph showing the change in the shape of the sustained-release tablet over time during the dissolution test in the eluate pH 6.8 of the sustained-release tablet prepared in accordance with the present invention and the conventional formulation for treating diabetes. As shown in Figure 6, the Amaryl Mex tablet of Handok Pharmaceuticals expands without melting over time, and may maintain gastrointestinal disorders by maintaining its form after 24 hours, but the combination preparation according to the present invention The use of carbomer as a sustained release carrier causes the preparation to dissolve and decompose upon release of the drug and most of the decompose after 24 hours, causing no concern for gastrointestinal disorders. Therefore, the present invention is a combination preparation for treating diabetes, comprising an inner layer, an intermediate layer, and an outer layer, including a sulfonylurea-based drug, including metformin, wherein the carbomer is used as a sustained release carrier of the inner layer. It shows an emission pattern equivalent to that of Jane Amaryl Mex and does not cause gastrointestinal disorders because most of the sustained release carriers are decomposed after 24 hours, and the size of the tablet is reduced by minimizing the weight of the inner layer, which makes it easy to take the patient. . 【Industrial Availability】

According to the present invention, in a combination preparation for treating diabetes comprising an inner layer, an intermediate layer containing metformin, and an outer layer containing a sulfonylurea-based drug, a combination preparation for treating diabetes, which is conventionally used by using a carbomer as a sustained release carrier of an inner insect, It shows an emission pattern equivalent to that of Jane Amaryl Mex and does not cause gastrointestinal tract obstruction as most of the sustained release carriers are decomposed after 24 hours. Therefore, it may be useful for the preparation of sustained-release diabetes combinations.

Claims

19 【Scope of claim】

[Claim 1]

b) an interlayer comprising a water soluble polymer, free of drugs; c) a combination preparation for diabetes treatment for oral administration comprising an outer layer comprising a sulfonylurea-based drug and a release control agent, wherein the combination preparation for treating sustained-release diabetes is characterized in that a carbomer is used as the sustained release carrier. .

[Claim 2]

The method of claim 1,

The carbomer is a combination preparation for the treatment of sustained release diabetes, characterized in that the granular carbomer having a viscosity of 4,000-11,000 centipois.

[Claim 3]

According to claim 1,

The carbomer is a combination for the treatment of sustained-release diabetes, characterized in that to reduce the weight of the total combination to improve medication compliance.

[Claim 4]

The method of claim 1,

The carbomer is a combination formulation for treating sustained release diabetes, characterized in that 10-25% by weight relative to the total weight of the inner layer of the combination.

[5.] ^"

The method of claim 1,

A composite preparation for the treatment of sustained-release diabetes, wherein the carbomer further comprises polyethylene oxide and hydroxypropylmethylcellose.

[Claim 6]

The method of claim 1,

Metformin as an active ingredient is a combination formulation for the treatment of sustained-release diabetes, characterized in that 55 to 60% by weight relative to the total weight of the inner layer containing metformin.

[Claim 7]

The method of claim 1,

Wherein the pharmaceutically acceptable excipient is microcrystalline cellulose, Dijon Manni, lactose and magnesium stearate, characterized in that at least one component selected from the combination for the treatment of sustained-release diabetes.

[Claim 8]

The method of claim 1,

The water-soluble polymer of the intermediate layer and the release control agent of the outer layer is a composite preparation for the treatment of sustained-release diabetes, characterized in that the polymer having a viscosity of 6 centipois or less.