KR102070104B1 - Controlled release pharmaceutical formulation comprising Lobeglitazone and Metformin - Google Patents

Abstract

The present invention relates to a sustained release pharmaceutical formulation comprising metformin and lobeglitazone as active ingredients. Specifically, the present invention provides a composition comprising (i) a core layer comprising metformin or a pharmaceutically acceptable salt thereof; And (ii) an outer layer comprising lobeglitazone or a pharmaceutically acceptable salt thereof, wherein the metformin or pharmaceutically acceptable salt thereof is greater than 80% by weight relative to the total weight of the core layer. It relates to a pharmaceutical formulation.

Description

Controlled release pharmaceutical formulation comprising Lobeglitazone and Metformin}

The present invention relates to a sustained release pharmaceutical formulation comprising metformin and lobeglitazone as active ingredients. Specifically, the present invention provides a composition comprising (i) a core layer comprising metformin or a pharmaceutically acceptable salt thereof; And (ii) an outer layer comprising lobeglitazone or a pharmaceutically acceptable salt thereof, wherein the metformin or pharmaceutically acceptable salt thereof is greater than 80% by weight relative to the total weight of the core layer. It relates to a pharmaceutical formulation.

Structural formula of metformin, one of Biguanide-based drugs, is represented by Chemical Formula I below.

[Formula I]

Metformin is used as a therapeutic agent for non-insulin dependent diabetes mellitus (NIDDM), and the glucose regulation mechanism of metformin is known to act independently of insulin secretion and to activate glucose transporter in the liver. Metformin induces weight loss in diabetic patients, and decreases triglycerides and low density lipoproteins in blood and increases high density lipoproteins. Thus, metformin can be used as a primary agent in insulin-independent diabetic patients who exhibit insulin resistance.

Side effects associated with the use of metformin include loss of appetite, bloating, nausea, and diarrhea that occur in 20-30% of patients taking the medication. Most side effects are transient and usually disappear after two to three weeks of taking, but diarrhea or severe abdominal bloating is not lost if you stop taking it. These side effects can be ameliorated using sustained release formulations that can reduce the minimum and / or sustained dose or reduce the number of doses.

However, in general, sustained-release preparations have a disadvantage in that the tablet size is increased due to the higher excipient content than the general preparation, which may cause dysphagia in elderly patients and pediatric patients, which may lead to low medication compliance.

On the other hand, the glitazone-based drug is a PPARγ agonist (Peroxisome Proliferator Activated Receptor gamma agonist), which is expressed in adipocytes and promotes adiogenesis and glucose uptake. Stimulates PPARγ and has an effect of improving the sensitivity to insulin in the body.

Since glitazone-based drugs are not a mechanism for promoting insulin secretion, they are advantageous for protecting β-cells of the pancreas and improving insulin resistance, making them particularly effective for insulin-resistant diabetics. It slows the progression of, and is known to have a stronger therapeutic effect on early diabetes. Such glitazone-based drugs have a thiazolidinedione (TZD) structure, and the mainstream of the current market.

The structural formula of lobeglitazone (Lobeglitazone) of such a glitazone-based drug is represented by the formula (II).

[Formula II]

Robeglitazone not only has a stable molecular dynamic energy, but also has a structural characteristic that best matches the active site pocket of PPARγ. It is a drug that enhances the weak blood lipid lowering action, which was considered a disadvantage of the drug.

Glitazone-based drugs are known to be effective in co-administration with drugs of other mechanisms of action. In particular, in the case of insufficient glycemic control may be administered in combination with metformin. As a combination preparation of a glitazone-based drug and metformin, European Patent Publication No. 0749751 discloses a combination preparation of Pioglitazone and Metformin, and International Publication No. 98/57634 discloses Rosiglitazone and Metformin. The combination formulation of this is disclosed.

However, the therapeutic effects and side effects of the combination of new glitazone-based lobeglitazone and metformin have not been studied until now, and furthermore, they may show optimal dissolution patterns and reduce the frequency of administration. Combination formulations have also not been studied.

Korean Patent Publication No. 1750690 discloses an effect of improving medication compliance by providing a complex formulation including metformin and lobeglitazone, which can be administered once a day, but a combination of two or more layers contains a large amount of The use of sustained-release agents (15 to 25% by weight relative to the total weight of the core layer) has the disadvantage of large tablet size.

Accordingly, the present inventors minimize the side effects of rapid release of metformin and at the same time, by using a minimum amount of sustained-release agent to reduce the size of conventional sustained-release tablets, sustained-release preparations that can improve the ease of taking and drug compliance The present invention has been completed by finding.

OBJECT OF THE INVENTION The present invention relates to a complex sustained release formulation comprising metformin or a pharmaceutically acceptable salt thereof, and another antidiabetic agent, in particular a medicament comprising lobeglitazone or a pharmaceutically acceptable salt thereof as another antidiabetic agent. To provide a pharmaceutical formulation.

In addition, the use of minimal sustained-release agent reduces the size of the sustained-release tablet provides convenience of the drug, while providing a pharmaceutical formulation comprising metformin that is sustained even with a small amount of sustained-release agent.

Also provided are pharmaceutical formulations comprising metformin that do not contain a disintegrant to maintain uniformity of quality.

In order to achieve the above object, the present invention provides a sustained-release pharmaceutical preparation containing metformin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient comprises more than 80% by weight of the pharmaceutical ingredient. It relates to a formulation.

That is, in sustained-release pharmaceutical formulations comprising metformin or a pharmaceutically acceptable salt thereof, it is necessary to increase the weight ratio of metformin and to reduce the content of excipients added in order to reduce the size of the formulation.

In addition, the pharmaceutical formulation of the present invention comprises a water-soluble polymer as a sustained release agent. The water-soluble polymer may be hydroxypropyl methylcellulose (HPMC), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polymethacrylate, and mixtures thereof, but is not limited thereto. The sustained release agent of the present invention is preferably hydroxypropylmethylcellulose.

In order to reduce the size of the formulation of the present invention, it is necessary to reduce the content of the sustained release base. However, the formulations of the present invention utilizing a gastroretentive drug delivery system that delivers the drug in the form of sustained release of the drug through swelling and dilatation of the agent using sustained release mechanisms, can be combined with conventional sustained release formulations. In comparison, since it is more difficult to minimize the sustained release mechanism, it is very important to find the optimum weight ratio of the sustained release agent that can reduce the size of the formulation while maintaining the sustained release.

The sustained-release agent of the present invention is preferably included in about 12 to 30% by weight, more preferably in about 15 to 25% by weight relative to the total weight of metformin or a pharmaceutically acceptable salt thereof.

In addition, the formulation of the present invention may not include a disintegrant, thereby maintaining uniformity of quality.

The present invention provides a sustained-release pharmaceutical preparation comprising (i) a core layer comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and (ii) an outer layer comprising an additional antidiabetic agent. A pharmaceutical formulation comprising more than 80% by weight of the active ingredient (methformin or a pharmaceutically acceptable salt thereof).

The additional antidiabetic agent is not particularly limited, and may be a glitazone family of drugs such as rosiglitazone, pioglitazone, and lobeglitazone, and in particular, lobeglitazone.

In addition, in the formulation of the present invention, the core layer may further include a water-soluble polymer as a sustained release agent, wherein the water-soluble polymer is hydroxypropylmethyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrroli It may be pig, polymethacrylate and mixtures thereof, preferably hydroxypropylmethylcellulose.

The sustained release agent in the core layer is preferably included in about 12 to 30% by weight, more preferably in about 15 to 25% by weight relative to the total weight of metformin or a pharmaceutically acceptable salt thereof.

In addition, the core layer may not include a disintegrant, thereby maintaining a uniformity of quality.

In the formulation of the present invention, a protective coating layer may be further included between the core layer and the outer layer, or outside the outer layer. The protective coating layer may include hydroxypropyl methyl cellulose.

In particular, the present invention includes (i) a core layer comprising metformin or a pharmaceutically acceptable salt thereof, and (ii) an outer layer comprising lobeglitazone or a pharmaceutically acceptable salt thereof, wherein the core layer is Greater than 80% by weight of metformin or a pharmaceutically acceptable salt thereof, and 15-25% by weight of hydroxypropylmethylcellulose relative to the total weight of metformin or a pharmaceutically acceptable salt thereof in the core layer It relates to a pharmaceutical formulation.

The present invention

(a) a core layer comprising metformin or a pharmaceutically acceptable salt thereof;

(b) a primary protective coating layer coated on the core layer;

(c) an outer layer comprising lobeglitazone or a pharmaceutically acceptable salt thereof on the primary protective coating layer; And

(d) relates to a pharmaceutical formulation comprising a secondary protective coating layer coated on the outer layer.

Pharmaceutical formulations of the present invention may further comprise diluents, glidants and the like.

In addition, the diluent is an additive used for the purpose of dilution or increase, preferably at least one selected from the group consisting of sugars, lactose, cellulose and starch. More preferably, lactose monohydrate, microcrystalline cellulose, microcrystalline cellulose-lactose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose salt (e.g., carboxy cellulose calcium, carboxy cellulose) Sodium), other substituted and unsubstituted cellulose, corn starch, gelatinized starch, lactose, acrylate polymers and copolymers, dexrate, dextrin, dextrose, maltodextrin, pectin, gelatin, and other diluents known in the art, It is not limited to this.

In addition, the lubricant is an additive for smoothing the compression operation of the granules, may be any one or more selected from the group consisting of magnesium stearate, sodium stearyl fumarate and glyceryl behenate, but is not limited thereto. .

In addition, other additives that may be incorporated into the formulation may include lubricants, preservatives, surfactants, antioxidants, colorants, flavors, flavor enhancers, or any other additives commonly used in the art.

Sustained release formulations of the present invention can improve medication compliance by minimizing side effects that occur in immediate release and at the same time increasing the ease of taking to a smaller size than conventional sustained release tablets. In addition, it is possible to achieve a uniformity of quality without including a disintegrant.

Figure 1 shows the dissolution rate with time at pH 1.2 of Comparative Example 1, and Examples 1 to 4.
Figure 2 shows the results of the expansion confirmation test of Example 3 and Example 4.
Figure 3 shows the dissolution rate with time at pH 1.2 of Example 2 and Comparative Example 2.
Figure 4 shows the concentration of the geometric mean of metformin in the blood.

Metformin or its pharmaceutically acceptable salts are very well soluble in water and, when formulated into conventional tablets, can cause excessive blood sugar drop with rapid release and lead to gastrointestinal disorders. In addition, since metformin or a pharmaceutically acceptable salt thereof is administered at a high dose, a sudden change in blood concentration due to rapid release has a problem of intensifying side effects and resistance to metformin. Furthermore, it is necessary to release sustained release of metformin or its pharmaceutically acceptable salts because the half-life of metformin in the blood is short, from 2 to 6 hours.

In addition, since the sustained release formulation includes a sustained release agent, a sustained release formulation including a high dose of metformin is inevitably large in size.

Accordingly, the present invention relates to a pharmaceutical preparation comprising sustained release pharmaceutical preparation containing metformin or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the active ingredient comprises more than 80% by weight of the active ingredient.

In addition, the present invention provides a sustained-release pharmaceutical preparation comprising (i) a core layer comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient, and (ii) an outer layer comprising an additional diabetes therapeutic agent. In the present invention relates to a pharmaceutical formulation comprising more than 80% by weight of the active ingredient (methformin or a pharmaceutically acceptable salt thereof).

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

EXAMPLE

Preparation of Examples 1-4

The tablets of Examples 1 to 4 were prepared by the preparation methods described below.

1. Union and Establishment

Metformin hydrochloride and HPMC were added to a high speed mixer, mixed, purified water was added, and then the granulation process was performed.

2. Dry

The granulated material was put into a fluidized bed granulator and a dryer and a drying process was performed.

3. Formulation

The dried product was put into a sizing machine and a sizing process was performed.

4. Final mixing and tableting

Hard silicate and magnesium stearate were added to the sieved material and mixed to prepare a final mixture, followed by tableting using a tableting machine.

5. Coating

Spraying the primary coating solution (ethanol, purified water, triethyl citrate, HPMC) prepared in the tablets is subjected to the first protective coating. The drug coating solution (ethanol, purified water, lobeglitazone sulfate, triethyl citrate, povidone, lactose, HPMC) prepared on the dried primary coating is sprayed to proceed with drug coating. Finally, the secondary coating solution (ethanol, purified water, titanium oxide, blue No. 2 aluminum lake, triethyl citrate, HPMC) prepared by the drug coating and drying is completed, and then the secondary protective coating is performed.

Here, Examples 1 to 4 were prepared by varying the content of sustained-release agent (HPMC), as shown in Table 1 below.

Example 1 Example 2 Example 3 Example 4 mg / tablet % (w / w) mg / tablet % (w / w) mg / tablet % (w / w) mg / tablet % (w / w) HPMC to main ingredient (%) 21% 19% 15% 10% Metformin hydrochloride 1,000 81.04 1,000 82.37 1,000 85.2 1,000 88.97 HPMC 210 17.02 190 15.65 150 12.8 100 8.90 Light anhydrous silicic acid 12 0.97 12 0.99 12 1.0 12 1.07 Magnesium stearate 12 0.97 12 0.99 12 1.0 12 1.07 Inner core 1,234 100.0 1,214 100.0 1,174 100.0 1,124 100.0 Primary coating total 24 100.0 24 100.0 24 100.0 24 100.0 Total amount of drug coating 100 100.0 100 100.0 100 100.0 100 100.0 2nd total coating 40 100.0 40 100.0 40 100.0 40 100.0 Tablet total amount 1,398 100.0 1,378 100.0 1,338 100.0 1,288 100.0

[Comparative Example]

Preparation of Comparative Examples 1 and 2

Comparative Example 1 was prepared by the same production method as in Examples 1 to 4, Comparative Example 2 was prepared by the following manufacturing method.

1. Union and Establishment

Metformin and HPMC were put in a high speed mixer, mixed, purified water was added, and then the granulation process was performed.

2. Dry

The granulated material was put into a fluidized bed granulator and a dryer and a drying process was performed.

3. Formulation

The dried product was put into a sizing machine and a sizing process was performed.

4. Final mixing and tableting

Sodium croscarmellose sodium, light silicic anhydride and magnesium stearate were added to the sieved material, mixed to prepare a final mixture, and then compressed using a tableting machine.

5. Coating

Spraying the primary coating solution (ethanol, purified water, triethyl citrate, HPMC) prepared in the tablets is subjected to the first protective coating. The drug coating solution (ethanol, purified water, lobeglitazone sulfate, triethyl citrate, povidone, lactose, HPMC) prepared on the dried primary coating is sprayed to proceed with drug coating. Finally, the secondary coating solution (ethanol, purified water, titanium oxide, blue No. 2 aluminum lake, triethyl citrate, HPMC) prepared by the drug coating and drying is completed, and then the secondary protective coating is performed.

Comparative Examples 1 and 2 were prepared by varying the addition of disintegrants in final mixing, as shown in Table 2 below.

Comparative Example 1 Comparative Example 2 mg / tablet % (w / w) mg / tablet % (w / w) HPMC to main ingredient (%) 29% 19% Metformin hydrochloride 1,000 75.87 1,000 80.00 HPMC 290 22.00 190 15.20 Light anhydrous silicic acid 14 1.06 12 0.96 Magnesium stearate 14 1.06 12 0.96 Croscarmellose sodium - - 36 2.88 Inner core 1,318 100.0 1,250 100.00 Primary coating total 24 100.0 24 100.0 Total amount of drug coating 100 100.0 100 100.0 2nd total coating 40 100.0 40 100.0 Tablet total amount 1,482 100.0 1,414 100.0

[Test Example 1]

Dissolution test according to the content of sustained release mechanism (HPMC)

For the formulations of Examples 1 to 4 and Comparative Example 1 prepared by varying the content of the sustained-release agent (HPMC) with respect to 1000 mg of the main component metformin, the dissolution test was performed by the following method, and the analysis conditions were as follows.

[Dissolution test condition]

-Dissolution Act: Korean Medicines Pact 1 (Rotational Sampling Act)

Eluent: pH 1.2 solution, 900 mL

-Elution temperature: 37 ± 0.5 ℃

-Speed: 100 rpm

[Operating conditions]

-Detector: ultraviolet absorbance photometer (wavelength: 255 nm)

Column: Phenomenex Luna SCX (4.6 × 50 mm, 5 μm) or equivalent column

Injection volume: 5 μL

Flow rate: 2.0 mL / min

-Column temperature: Constant temperature around 40 ℃

-Sample temperature: Constant temperature around 20 ℃

Analysis time: 4 minutes

-Mobile phase: a mixture of 50 mM ammonium acetate solution 1) and acetonitrile (300: 700)

The dissolution test results are shown in Table 3 and FIG. 1.

pH 1.2 Dissolution rate at each time point (%) Hours (hr) 0.25 0.5 One 1.5 2 3 5 6 8 10 12 Comparative Example 1 4.6 14.5 28.9 36.4 45.4 56.1 73.6 78.6 85.7 88 90.4 Example 1 4.8 15.4 28.5 37.5 45.2 57.6 74.5 78.8 86.1 89.5 91.0 Example 2 3.8 14.8 29.3 38.7 46.3 58.1 74.8 79.6 87.3 90 90.2 Example 3 9.5 19.4 34.5 44.5 53.2 63.4 78.6 83.2 90.6 93.3 93.8 Example 4 21 29 43.7 55.7 62.4 73.4 86.4 90.4 94 96.5 97.4

As shown in Table 3 and FIG. 1, it can be seen that Example 4 having the lowest weight ratio of sustained-release agent to metformin is very fast compared to other examples.

As the weight ratio of the sustained-release agent to metformin decreases, the dissolution rate is faster. As a result, when the weight ratio is 10% or less, it was confirmed that it is difficult to maintain the sustained release drug release pattern.

[Test Example 2]

Inflation confirmation test

Since the present invention maintains sustained release of the drug through gastric swelling system, it is important to maintain the high strength without disintegrating the form of the formulation formed through swelling after dissolution test. In the case of inflation system formulations, insufficient inflation size and strength can easily pass through the pylorus, making it difficult to maintain the release pattern of the sustained release drug.

Therefore, the dissolution test was carried out in the pH 1.2 test solution for up to 12 hours for the formulations of Examples 3 and 4 having a low content of sustained-release agent among Examples prepared by varying the sustained-release agent content with respect to 1000 mg of the main component metformin, followed by dissolution. The state of the tablets remaining in the vessel was confirmed.

As shown in FIG. 2, in the case of the formulation of Example 3, the expanded formulation was maintained even after 12 hours dissolution test, but in the case of the formulation of Example 4, it was confirmed that it collapsed. As a result, it can be seen that Example 4 contained a sustained-release agent of a content which is not suitable for gastrointestinal release system.

[Test Example 3]

Dissolution test with or without disintegrant

For Example 2 and Comparative Example 2 without the addition of a disintegrant (crosamelose sodium), dissolution test was carried out by the following method, the analysis conditions are as follows.

The test was carried out under the same conditions as the dissolution test according to the content of the sustained-release agent (HPMC).

The dissolution test results are shown in Table 4 and FIG. 3.

pH1.2 Dissolution rate ± deviation (%) at each time point (time) minute 15 30 60 90 120 180 300 360 480 600 720 Example 2 3.8 ± 0.6 14.8 ± 1.0 29.3
± 0.8 38.7
± 0.4 46.3
± 0.4 58.1
± 0.6 74.8
± 1.1 79.6
± 0.8 87.3
± 1.6 90.0
± 1.6 90.2
± 1.8 Comparative Example 2 5.9 ± 3.8 18.2
± 5.3 32.7
± 4.5 42.4
± 4.0 49.5
± 5.9 63.9
± 7.5 79.9
± 5.4 86.3
± 5.6 92.5
± 4.6 91.9
± 5.2 94.9
± 5.6

As shown in Table 4 and Figure 3, Comparative Example 2 using a disintegrant was confirmed to show a large dissolution deviation compared to Example 2 not used. Therefore, it can be seen that when the disintegrant does not contain a small deviation and uniform sustained release of the drug, thereby maintaining the uniformity of the formulation quality.

[Test Example 4]

Equivalence test for metformin

PK test was performed as follows.

For purification of Example 1 (Test) and Comparative Example 1 (Reference), a PK test was performed as follows.

Test design: 2 × 2 crossover, randomized, postprandial, single, oral administration

-Number of test subjects: 30 healthy adult test subjects

-Blood collection points: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 and 24 hours (13 points) before and after dosing

The experimental results are shown in FIG. 4.

90% confidence interval Test / Ref ratio AUC _t 0.9651-1.0589 1.0109 C _max 1.0196-1.1290 1.0729

As shown in FIG. 4, the Phase 1 clinical trial for Example 1 was conducted using the phase 1 clinical trial before the size reduction formulation demonstrating the sustained release drug release pattern as a control (Comparative Example 1). By confirming that both AUC and Cmax meet the 90% confidence interval criteria (0.8 to 1.25), it can be seen that sustained-release drug release patterns are maintained through size reduction.

Claims (20)

In an extended release pharmaceutical formulation comprising metformin or a pharmaceutically acceptable salt thereof as an active ingredient and a sustained release agent,
Contains more than 80% by weight of the active ingredient,
The sustained release agent comprises at least 15% by weight relative to the total weight of the active ingredient,
The sum of the active ingredient and the sustained release agent does not exceed 100% by weight,
Does not additionally contain disintegrants,
Pharmaceutical formulation, characterized in that the intragastric retention type is expanded in the stomach.
The pharmaceutical formulation of claim 1 wherein the sustained release agent is a water soluble polymer.
The method of claim 2, wherein the water-soluble polymer is selected from the group consisting of hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polymethacrylate, and mixtures thereof. Pharmaceutical formulations.
The pharmaceutical formulation of claim 3 wherein the water soluble polymer is hydroxypropylmethylcellulose.
delete delete delete (i) a core layer comprising metformin or a pharmaceutically acceptable salt thereof, and a sustained release agent; And
(ii) a pharmaceutical formulation comprising an outer layer comprising an additional antidiabetic agent,
More than 80% by weight of metformin or a pharmaceutically acceptable salt thereof in the core layer relative to the total weight of the core layer,
The sustained release agent in the core layer comprises at least 15% by weight relative to the total weight of metformin or a pharmaceutically acceptable salt thereof,
The sum of the metformin or a pharmaceutically acceptable salt thereof and a sustained release agent does not exceed 100% by weight,
The core layer further does not include a disintegrant,
The formulation is a pharmaceutical preparation, characterized in that the gastric retention type to expand in the stomach.
The pharmaceutical formulation of claim 8 wherein the sustained release agent of the core layer is a water soluble polymer.
The method of claim 9, wherein the water-soluble polymer is selected from the group consisting of hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polymethacrylate, and mixtures thereof. Pharmaceutical formulations.
The pharmaceutical formulation of claim 10, wherein the water soluble polymer is hydroxypropylmethylcellulose.
delete delete delete The pharmaceutical formulation of claim 8, wherein the additional antidiabetic agent is selected from the group consisting of rosiglitazone, pioglitazone, lobeglitazone, and pharmaceutically acceptable salts thereof.
The pharmaceutical formulation of claim 15, wherein the additional antidiabetic agent is lobeglitazone or a pharmaceutically acceptable salt thereof.
The pharmaceutical formulation of claim 8, further comprising a protective coating layer between the core layer and the outer layer.
The pharmaceutical formulation of claim 8, further comprising a protective coating layer on the outside of the outer layer.
The pharmaceutical formulation according to claim 17 or 18, wherein the protective coating layer comprises hydroxypropylmethylcellulose.
(i) a core layer comprising metformin or a pharmaceutically acceptable salt thereof, and hydroxypropylmethylcellulose, and
(ii) a pharmaceutical formulation comprising an outer layer comprising lobeglitazone or a pharmaceutically acceptable salt thereof
More than 80% by weight of metformin or a pharmaceutically acceptable salt thereof in the core layer relative to the total weight of the core layer,
Hydroxypropylmethylcellulose in the core layer at least 15% by weight relative to the total weight of metformin or a pharmaceutically acceptable salt thereof,
The sum of the metformin or a pharmaceutically acceptable salt thereof and hydroxypropylmethylcellulose does not exceed 100% by weight,
The core layer further does not include a disintegrant,
The formulation is a pharmaceutical preparation, characterized in that the gastric retention type to expand in the stomach.

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