KR101721831B1 - Pharmaceutical Compositions Comprising Lobeglitazone for Oral Administration - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration comprising robeglitazone. The pharmaceutical composition of the present invention includes a cellulose derivative and exhibits an action effect exhibiting an excellent dissolution rate and exhibiting a rapid pharmacological effect.

Description

Pharmaceutical Compositions Comprising Lobeglitazone for Oral Administration < RTI ID = 0.0 >

The present invention relates to a pharmaceutical composition for oral administration having improved solubility and dissolution rate containing robeglitazone.

Lobeglitazone is a glitazone-based drug developed in Chong Kun Dang and approved as a Korean New Drug No. 20. It is used as an oral diabetes remedy, especially for the treatment of type 2 diabetes, with an activity to improve insulin resistance. In addition, robeglitazone may be very useful for obese diabetic patients without the controversial cardiovascular side effects of conventional glitazone-based drugs, particularly GSK's rosiglitazone.

Robeeglitazone has a 2,4-thiazolidinedione group as shown by the following formula (1), and has a structure in which an N-methylaminoethoxybenzyl group is bonded as a linking ring bonded thereto, and a white to pale yellow powder .

[Chemical Formula 1]

On the other hand, robeglitazone was developed in the form of robeglitazone sulfate, but the robeglitazone sulfate was insoluble in water and was found to be aggregated between the robeglitazone sulfate molecules. After the robeglitazone sulfate was dissolved There is a problem that the solubility decreases at the time of recrystallization. Due to these problems, it has been found that when the rosiglitazone sulfate is formulated as an active ingredient, the dissolution rate of robeglitazone sulfate is lowered.

The dissolution rate problem of the drug is closely related to the solubility of the drug itself, and it is generally known that the lower the solubility of the drug, the lower the dissolution rate of the drug.

If the elution of the drug from the pharmaceutical preparation is too slow, the blood drug concentration can not reach the effective level, and the expected efficacy is not sufficiently exerted. Therefore, elution patterns that can maximize the efficacy of certain levels of dissolution rate and drug are very important issues in formulation.

Therefore, improvement of the dissolution rate is required for the rapid expression of the effect in the development of oral preparations. Methods for improving the dissolution rate of oral preparations include 1) milling the main component to reduce the particle size, 2) adding a surfactant or solubilizer, or 3) using a nanodization or 4) solid dispersion have. The most simple method is 1).

However, in the method of increasing the dissolution rate of the oral preparation by reducing the particle size of the main ingredient, the dissolution rate is generally improved as the particle size of the main ingredient is smaller. However, as the particle size of the active ingredient decreases, the surface area increases, thereby increasing the chance of reacting with other additives contained in oral preparations, resulting in decreased stability of oral preparations.

Korean Patent Laid-Open No. 10-2005-0084316 discloses that the dissolution rate is increased by using a water-soluble additive such as di-mannitol instead of lactose, Korean Patent Laid-Open No. 10-2007-0093259 discloses that methacrylate- It is disclosed that the dissolution rate can be improved by selectively using a specific polymer such as a methacrylic acid ester copolymer. However, when a solid dispersion is prepared using an excess of polymer to improve the dissolution rate, or when an excess amount of a surfactant is used, the ratio of the dissolved amount of the poorly soluble substance is lower than the amount of the surfactant used, The thing itself becomes meaningless.

In addition, it is possible to ensure stability by allowing a drug to be decomposed at a specific pH to exist in a stable pH range where the drug is decomposed at a specific pH using a pH adjusting agent. However, considering various pHs of the human body, There are limitations that apply only to liquid formulations.

Accordingly, the present inventors have studied how to maintain the solubility of robeglitazone and maintain the desired dissolution rate, while using a therapeutically effective amount of robeglitazone or a pharmaceutically acceptable salt thereof as a binding solvent in water And the solubility is maintained and the dissolution rate is improved remarkably when the cellulose derivative is used as the excipient. Thus, the present invention has been completed.

Korean Patent Registration No. 10-0450700

It is an object of the present invention to provide a pharmaceutical composition for oral administration with improved solubility and dissolution rate containing robeglitazone or a pharmaceutically acceptable salt thereof. Specifically, robeglitazone or a pharmaceutically acceptable salt thereof having low solubility is prepared by wet granulating purified water with a binding solvent and using a cellulose derivative as an excipient to maintain the solubility and improve the dissolution rate, And to provide a pharmaceutical composition for oral administration.

The present invention provides a pharmaceutical composition for oral administration of robeglitazone or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention maintains the solubility of the active ingredient robeglitazone and its pharmaceutically acceptable salts and exhibits an improved dissolution rate.

To achieve this, the pharmaceutical composition of the present invention may comprise 0.1 to 10 parts by weight of robeglitazone or a pharmaceutically acceptable salt thereof and 10 to 40 parts by weight of a cellulose derivative.

In the pharmaceutical composition of the present invention, the robeglitazone or a pharmaceutically acceptable salt thereof may be used as a free base or any pharmaceutically acceptable salt thereof. Preferably, robeglitazone sulfate is used. In addition, robeglitazone or a pharmaceutically acceptable salt thereof may be prepared as described in Korean Patent No. 10-0450700.

In addition, the above-mentioned robeglitazone or a pharmaceutically acceptable salt thereof may be administered in a pharmacologically effective amount, specifically 0.1 to 1000 mg, preferably 0.1 to 500 mg, most preferably 0.1 to 250 mg can do.

On the other hand, the cellulose derivative may contain one or more (e.g., one or more) cellulose groups which are present in at least one of the anhydroglucose repeating units of the cellulose polymer to provide one or more bonded groups on the cellulose polymer such as cellulose acetate, cellulose ether, cellulose ester, Means a derivative formed by the conversion of a hydroxy group.

In one embodiment of the invention, the cellulose ether is, for example, "a suitable ether-bonded group which may be present on the anhydroglucose repeating unit of the cellulose polymer" is hydroxy, carboxy, (C 1 -C 4) alkoxy and hydroxy (C1-C4) alkyl optionally substituted by one or more substituent (s) selected from (C1-C4) alkoxy. (C1-C4) alkyl, such as methyl or ethyl; Hydroxy (C1-C4) alkyl such as 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl; (C1-C4) alkoxy (C1-C4) alkyl such as 2-methoxyethyl, 3-methoxypropyl, 2-methoxypropyl or 2-ethoxyethyl; Hydroxy (C1-C4) alkoxy (C1-C4) alkyl such as 2- (2-hydroxyethoxy) ethyl or 2- (2-hydroxypropoxy) propyl; Carboxy (C1-C4) alkyl, such as carboxymethyl; Or _{H- [O-CH (CH 3} ) CH 2 -] m or _{H- [O-CH 2 CH 2} -] , such as the formula m H- [0- (C1-C4 ) alkyl -] m (where, m Is an integer from 1 to 5, such as 1, 2, or 3). For the sake of clarity, the term "ether bonded group" means one or more of the above functional groups bonded to the cellulose polymer by an oxygen atom. For example, when the ether-bonded group is methyl, at least one of the hydroxyl group of the anhydrous glucose repeat units is converted to a methoxy group.

In addition, the cellulose ether may have a methyl group in the case of the same ether-bonded group, such as methyl cellulose. Alternatively, the cellulose ether may have a plurality of different ether-bonded groups. For example, hydroxypropylmethylcellulose means cellulose having both a methyl group and a hydroxypropyl (e.g., 2-hydroxypropyl) ether-bonded group.

In the pharmaceutical composition of the present invention, it is preferable to use an ester of water-soluble cellulose ether or water-soluble cellulose ether as the cellulose derivative. Esters of water-soluble cellulose ethers or water-soluble cellulose ethers are preferred when the pH of the solution is increased, especially when the preparation is passed through the gastrointestinal tract, such as the high pH region of the topical area, where the preparation is supposed to be absorbed from the acidic environment above, May be present in the composition in an amount sufficient to inhibit the rate at which the formulation is precipitated from solution. Specifically, the ester of the water-soluble cellulose ether or the water-soluble cellulose ether is used in an amount of 0.1 to 90 parts by weight, preferably 1 to 80 parts by weight, based on 0.1 to 10 parts by weight of the active ingredient robeglitazone or a pharmaceutically acceptable salt thereof. More preferably 5 to 75 parts by weight, and most preferably 10 to 40 parts by weight based on 100 parts by weight of the composition.

The preferred water-soluble cellulose ethers for the pharmaceutical composition of the present invention are, for example, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxybutyl methyl cellulose, hydroxyethyl ethyl cellulose and carboxymethyl cellulose. A salt (e.g., sodium carboxymethylcellulose) and a salt of carboxymethylhydroxyethylcellulose (e.g., carboxymethylhydroxyethylcellulose sodium). More preferably, it may be selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and salts of carboxymethylcellulose (e.g., carboxymethylcellulose sodium).

Further, in one embodiment of the present invention, the water-soluble cellulose ether may be selected from the group consisting of hydroxyethyl cellulose and hydroxypropyl cellulose. When the water-soluble cellulose ether is hydroxypropyl cellulose, the content of hydroxypropoxy may be 16% by weight or more, and preferably 20 to 40% by weight. Preferably, the hydroxypropyl cellulose has a kinematic viscosity of 100-600 cP (for example, 150-450 cP). The viscosity of the hydroxypropyl cellulose is measured in a 2% w / v aqueous solution of hydroxypropyl cellulose at 25 ° C. Alternatively, the hydroxypropyl cellulose may be a low-substituted hydroxypropyl cellulose having a content of hydroxypropoxy of about 5 to 16% by weight. Although low substituted hydroxypropyl cellulose is often referred to as water insoluble, it has surprisingly been found that the low substituted hydroxypropyl cellulose in the composition of the present invention is sufficiently hydrophilic to prevent the formulation from precipitating out of the solution, And thus found that low-substituted hydroxypropylcellulose is one of the water-soluble cellulose derivatives of the present invention. The low-substituted hydroxypropyl cellulose preferably has a degree of substitution of from about 0.1 to about 1.0, such as from about 0.2 to about 0.4 (e.g., about 0.2), and the substitution degree refers to the average number of hydroxypropyl groups per anhydrous glucose ring of cellulose do. The low-substituted hydroxypropyl cellulose may have a content of hydroxypropoxy groups of about 5 to 16% by weight, and preferably 9 to 13% by weight. In addition, the average particle size of the low-substituted hydroxypropyl cellulose is preferably 10 to 75 μm, more preferably 50 to 60 μm.

In addition, the pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable excipients. As the excipient, a diluent, a binder, a disintegrant, and / or a lubricant may be used.

In the present invention, it is preferable to use a water-soluble diluent as the diluent. Non-limiting examples of water-soluble diluents include sugars such as lactose, sucrose and dextrose, polysaccharides such as dextrates and maltodextrins, polyols such as mannitol, xylitol and sorbitol and cyclodextrins, Starch hydrolyzate or starch hydrolyzate or starch hydrolyzate which may be chemically modified, such as starch hydrolyzate or starch, microcrystalline starch, mannitol, sorbitol, trehalose, maltose, inorganic salts such as calcium carbonate, magnesium carbonate, dibasic calcium phosphate Dihydrate) 3 basic calcium phosphate), cellulose, microcrystalline cellulose, calcium sulfate, xylitol and lactitol. In the present invention, the aqueous diluent may be present in the formulation in an amount sufficient to provide a suitable volume for the formulation and to perform tablet preparation. In the present invention, the water-soluble diluent may comprise 1 to 25 parts by weight, preferably 1 to 20 parts by weight, in the composition, based on 0.1 to 10 parts by weight of robeglitazone or a pharmaceutically acceptable salt thereof And more preferably 2 to 15 parts by weight.

In the present invention, it is preferable to use a hydrophilic binder. The hydrophilic binder is provided in an amount sufficient to act together to support the active ingredient, robeglitazone, or a pharmaceutically acceptable salt thereof, and other excipients in the composition. The hydrophilic binder facilitates granule preparation and handling and enhances the stability of the active ingredient. Suitable hydrophilic binders for the present invention include, for example, polyvinylpyrrolidone (e.g., povidone K25-32, especially K29-32, where "K value" represents the average molecular weight range obtained from the Fikentscher equation), lactose (anhydride form or hydration Starch, modified starch, sugar, acacia gum, tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, copolyvidone, gelatin and alginate (e.g., lactose monohydrate) , Sodium alginate). Preferably, it may be selected from the group consisting of polyvinylpyrrolidone, starch, modified starch and microcrystalline cellulose. In the present invention, the hydrophilic binder may comprise 1 to 20 parts by weight, preferably 1 to 10 parts by weight, based on 0.1 to 10 parts by weight of robeglitazone or a pharmaceutically acceptable salt thereof, And more preferably 2 to 8 parts by weight.

In the present invention, the disintegrant may be selected from the group consisting of, for example, sodium croscarmellose, crospovidone, polyvinylpyrrolidone, sodium starch glycolate, starch, and alginic acid, using croscarmellose sodium or crospovidone . In the present invention, the disintegrant may comprise 0.1 to 20 parts by weight, preferably 0.1 to 10 parts by weight, of the composition, based on 0.1 to 10 parts by weight of robeglitazone or a pharmaceutically acceptable salt thereof, And more preferably 1 to 10 parts by weight.

Suitable lubricants for the present invention refer to pharmaceutically acceptable preparations commonly used in the art as lubricants or lubricants in the preparation of solid pharmaceutical preparations. Nonlimiting examples of such lubricants include but are not limited to talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, calcium silicate, starch, mineral oil, wax, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium stearyl fumarate And a hydrogenated vegetable oil. The lubricant is preferably selected from the group consisting of magnesium stearate, sodium stearyl fumarate and stearic acid, and it is most preferred to use magnesium stearate. The lubricant is preferably provided in an amount sufficient to reduce the die wall frictional force when compressing the formulation into tablets. Lubricants also facilitate handling of dry powder formulations of the formulation. In the present invention, it is preferable that the lubricant comprises 0.1 to 2 parts by weight of the composition, based on 0.1 to 10 parts by weight of robeglitazone or a pharmaceutically acceptable salt thereof.

According to a preferred embodiment of the present invention,

(a) 0.1 to 10 parts by weight of robeglitazone or its sulfate;

(b) 10 to 40 parts by weight of a cellulose derivative selected from the group consisting of hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and salts of carboxymethylcellulose;

(c) 2 to 15 parts by weight of at least one water-soluble diluent selected from lactose (particularly lactose monohydrate), mannitol and microcrystalline cellulose;

(d) 2 to 8 parts by weight of at least one hydrophilic binder selected from the group consisting of polyvinylpyrrolidone (e.g., povidone K25-32, especially K29-32), starch, modified starch, sugar and hydroxypropyl methylcellulose;

(e) 1 to 10 parts by weight of at least one disintegrant selected from croscarmellose sodium or crospovidone; And

(f) 0.1 to 2 parts by weight of a lubricant (for example, magnesium stearate)

The sum of the components (a) + (b) + (c) + (d) + (e) + (f) is 100 parts by weight.

Still further excipients that may be added to the pharmaceutical compositions of the present invention include preservatives, stabilizers, antioxidants, silica flow control agents, adhesion inhibitors, and the like, and any additional components, such as colorants or flavors, May be incorporated into the formulation in an amount sufficient to perform the intended function without adversely affecting the tablet or powder formulation being manufactured.

The pharmaceutical compositions of the invention may be administered by a variety of routes including, but not limited to, oral, ocular, transdermal, subcutaneous, intravenous or intramuscular routes. The pharmaceutical composition of the present invention can be formulated into oral or parenteral formulations according to the selected route of administration, but oral administration is most preferred.

The oral formulations may be formulated in the form of powders, granules, tablets, pills, tablets, capsules, solutions, gels, slurries, suspensions and the like using methods known in the art. For example, an oral preparation can be obtained by combining the active ingredient with a solid excipient, followed by pulverizing, mixing, adding suitable auxiliaries, and then processing the mixture into a granulated mixture.

Oral dosage forms of the present invention can be produced by a number of techniques well known in the art. Examples of such techniques include, but are not limited to, wet granulation followed by dry granulation, milling with or without the use of a tablet, compression granulation followed by dry granulation, compression with tablets with or without a membrane coating, dry blending Tableting, tabletting, wet granulation, drying and filling with gelatin capsules, dry mixing with gelatin capsules, or filling of suspensions or solutions with gelatin capsules, etc. with or without membrane coating . Generally, the agent is labeled on the surface by debossing or engraving.

Preferably, the pharmaceutical composition of the present invention comprises wet granulating (S1) mixing robeglitazone or a pharmaceutically acceptable salt thereof, a diluent, a binder and a disintegrant, and (S2) wet granulating the wet granule, cellulose A binder, a disintegrant, and a lubricant.

It is most preferable to use purified water as the wet granulation solvent in the step (S1).

The pharmaceutical composition of the present invention produced by the production method of the present invention has excellent physical stability (hardness or malleability) and exhibits a remarkably excellent effect of dissolution rate.

The pharmaceutical composition of the present invention can improve the dissolution rate while maintaining the solubility of robeglitazone or a pharmaceutically acceptable salt thereof and exhibit a rapid pharmacological effect.

1 shows the results of a comparison of the results obtained when the content of the cellulose derivative (low-substituted hydroxypropyl cellulose) in the preparation was 5 wt% (Comparative Example 2), 10 wt% (Example 1), 15 wt% (Example 3), 40% by weight (Example 4), 50% by weight (Comparative Example 3) and 63% by weight (Comparative Example 4) Fig.
FIG. 2 is a graph showing the results of a comparison of the results of the wet granulation process of the wet granulation process of the preparation with the solvent used as the binding liquid in each of the purified water (Example 3), purified water: anhydrous ethanol = 1: 1 mixture (Comparative Example 5), purified water: (Comparative Example 6), purified water: dichloromethane = 1: 4 mixture (Comparative Example 7), purified water: isopropyl alcohol = 4: 1 mixture (Comparative Example 8), purified water: isopropyl alcohol = 9), and comparing the degree of leaching with the result of the purification.

Hereinafter, the present invention will be described in more detail with reference to the following specific examples. However, these embodiments are provided for illustrative purposes only to help understand the present invention, and the scope of the present invention is not limited by the following examples.

Example  1 to 4 and Comparative Example  1 to 4. According to the present invention Robe glitazone  Preparation of tablets containing sulfate

A pharmaceutical composition comprising robeglitazone sulfate in the composition of Table 1 was prepared.

1) The main component Redemption

Robeeglitazone sulfate was dissolved in lactose hydrate (spray dried) and mixed with Ac-di-sol (DMV-Fonterra Excipients GmBH, Germany).

2) Preparation of binding solution

The blue No. 2 dye was added to purified water and the mixture was pulverized and homogenized with a homogenizer (HG-150, Kagaku Kagaku Kogyo Co., Ltd.), and povidone K-30 (Daebong L To prepare a binding solution.

3) Preparation of granules

(FBCG-1, manufactured by Chungjin Industrial Technology Co., Ltd., Korea) after putting the mixture of the above 1) and the coupling solution of 2) into a high speed mixer (LFS-GS-2J, Fukae Powtec, Japan) And dried. After drying, Co-mil (U3, Quadro, Canada) was established.

4) final mixing and Tableting

The dried granules of 3) were put into a mixer and croscarmellose sodium and microcrystalline cellulose (Avicel PH 102, FMC BioPolymer, USA) and low-substituted hydroxypropyl cellulose (LH-11, Shin-Etsu, Japan) And the primary mixing was carried out. After completion of the primary mixing, magnesium stearate was sieved through 30 mesh, and the mixture was subjected to secondary mixing to prepare a final mixture, which was then tableted using an automatic tablet machine (XP1, Korsch, Germany) .

[Table 1]

Experimental Example  1. Hardness of the prepared tablet, Masondo's  Measure

The hardness, the degree of malleability and the angle of repose of the tablets obtained in Examples 1 to 4 and Comparative Examples 1 to 4 according to the present invention were measured according to the following methods, and the results are shown in Table 2.

[Measurement of hardness]

- Hardness tester: TBH-225 (Pharmatest Apparatebau, GmbH, Germany)

- Measurement method: Average calculation after 10 repetitions

[Measuring the degree of wear]

- Marsonometer: SVM-102 ((Pharmatest Apparatebau, GmbH, Germany)

- Measuring method: Measuring 20 marks, 100 marks after measuring the degree of wear

[Table 2]

As can be seen from Table 2 above, when the water-soluble cellulose derivative is contained in an amount of 10% by weight or more, it shows high hardness and low degree of scratching. In Comparative Example 1, it was impossible to form tablets by compression due to insufficient binding force in the granules, so that measurement was impossible and it was confirmed that the composition was not suitable as a composition for oral administration. In Comparative Example 2, the hardness was 5 kp and the degree of scratching was as low as 0.7%. On the other hand, Examples 1 to 4 or Comparative Examples 3 and 4 containing not less than 10% by weight of the water-soluble cellulose derivative showed hardness and degree of warpage remarkably improved to not less than 10 kp in hardness and less than 0.1% in warpage.

Experimental Example  2. Dissolution test

The preparations obtained in Examples 1 to 4 and Comparative Examples 2 to 4 were subjected to a dissolution test according to the dissolution test method 2 of the Korean Pharmacopoeia 10 (paddle method) and analyzed according to the following method, The results are shown in Table 3 and Fig.

[Dissolution Test Method]

- Elution test apparatus: Hanson SR 8 (Hanson Research, USA)

- eluent: pH 1.2 medium 900 mL

- Temperature of eluent: 37 ± 0.5 ℃

- Rotation speed: 50 rpm

- Amount of sample: 1 tablet per vessel

[Assay: HPLC Liquid Chromatography Method]

- Detector: UV absorptiometer (measuring wavelength: 250 nm)

Column: X-Terra RP 18 (4.6 × 250 mm, 5 μm) or equivalent column

- mobile phase: 50 mM ammonium acetate (pH 5.0) Buffer: acetonitrile = 55: 45

- Injection volume: 100 μL

- Flow rate: 1.5 mL / min

- Column temperature: 40 ° C

[Table 3]

As can be seen from Table 3 and FIG. 1, in Examples 1 to 4 and Comparative Examples 3 and 4 in which sufficient hardness and flaws were secured in the formation of tablets, in the case of Examples 1 to 4, The dissolution rate was about 95% while the dissolution rate of Comparative Examples 3 and 4 was remarkably lower than about 70% even at 45 minutes. The present invention relates to a pharmaceutical composition containing robeglitazone, which contains a cellulose derivative of 10 to 40% by weight, and has a dissolution profile suitable for pharmacokinetics of robeglitazone sulfate having a maximum blood concentration within 1 hour Respectively.

Example  3, Comparative Example  5 to 9. According to the present invention Robe glitazone  Preparation of tablets containing sulfate

Example 3 and Comparative Examples 5 to 9 were prepared by varying the types of coupling solvents on the basis of Example 3 showing the elution behavior suitable for the pharmacokinetics as shown above. The production method was the same as in Example 1.

[Table 4]

Experimental Example  3. Dissolution test

The preparations obtained in Example 3 and Comparative Examples 5 to 9 were subjected to a dissolution test according to the dissolution test method 2 of the Korean Pharmacopoeia 10 (paddle method), and analysis was carried out according to the following method, Are shown in Table 5 and Fig.

[Dissolution Test Method]

- Elution test apparatus: Hanson SR 8 (Hanson Research, USA)

- eluent: pH 4.0 medium 900 mL

- Temperature of eluent: 37 ± 0.5 ℃

- Rotation speed: 50 rpm

- Amount of sample: 1 tablet per vessel

[Assay: HPLC Liquid Chromatography Method]

- Detector: UV absorptiometer (measuring wavelength: 250 nm)

Column: X-Terra RP 18 (4.6 × 250 mm, 5 μm) or equivalent column

- mobile phase: 50 mM ammonium acetate (pH 5.0) Buffer: acetonitrile = 55: 45

- Injection volume: 100 μL

- Flow rate: 1.5 mL / min

- Column temperature: 40 ° C

[Table 5]

In the dissolution test at the pH 1.2 medium, there was no significant difference in the dissolution rate by the solvent used as the binding solvent during the wet granulation process of the preparation. As shown in Table 5 and FIG. 2, in the dissolution test at the pH 4.0 medium, In Example 3 using purified water alone as a solvent, the dissolution rate was about 97% at 45 minutes. On the other hand, Comparative Examples 5 to 9 in which an organic solvent or a mixture of purified water and an organic solvent were used as coupling solvents showed a significantly lower dissolution rate of 60 to 70%. As a result, it was confirmed that when the purified water and organic solvent were mixed and used as the binding solution, the dissolution rate was remarkably lowered compared with the case of single wetting with purified water. In the present invention, solubility and dissolution rate of robeglitazone due to poor solubility were remarkably improved by wet granulation using only purified water as a binding agent.

Claims (16)

0.1 to 10 parts by weight of robeglitazone or a pharmaceutically acceptable salt thereof and 10 to 40 parts by weight of a cellulose derivative, wherein the cellulose derivative is hydroxypropylcellulose. The pharmaceutical composition for oral administration according to claim 1, wherein the robeglitazone or a pharmaceutically acceptable salt thereof is robeglitazone sulfate. delete The pharmaceutical composition for oral administration according to claim 1, wherein the hydroxypropyl cellulose is a low-substituted hydroxypropyl cellulose having a hydroxypropoxy content of 5 wt% to 16 wt%. The pharmaceutical composition for oral administration according to claim 4, wherein the low-substituted hydroxypropyl cellulose has a hydroxypropoxy content of 9 wt% to 13 wt%. The pharmaceutical composition for oral administration according to claim 4, wherein the low-substituted hydroxypropyl cellulose has an average particle size of 10 to 75 μm. The pharmaceutical composition for oral administration according to claim 6, wherein the low-substituted hydroxypropyl cellulose has an average particle size of 50 to 60 μm. The pharmaceutical composition for oral administration according to claim 1, further comprising 2 to 15 parts by weight of a water-soluble diluent, 2 to 8 parts by weight of a hydrophilic binder, 1 to 10 parts by weight of a disintegrant and 0.1 to 2 parts by weight of a lubricant. The pharmaceutical composition for oral administration according to claim 8, wherein the aqueous diluent is selected from the group consisting of sugars, polysaccharides, polyols, cyclodextrins and mixtures thereof. The pharmaceutical composition for oral administration according to claim 8, wherein the hydrophilic binder is selected from the group consisting of polyvinylpyrrolidone, starch, modified starch, saccharides, microcrystalline cellulose, and mixtures thereof. The pharmaceutical composition for oral administration according to claim 8, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, and mixtures thereof. The lubricant composition of claim 8, wherein the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, calcium silicate, mineral oil, wax, glyceryl behenate, polyethylene glycol, sodium benzoate, Sodium fumarate, and mixtures thereof. ≪ RTI ID = 0.0 > The pharmaceutical composition for oral administration according to claim 1, which is a tablet. 14. The pharmaceutical composition according to claim 13, wherein rovetyltazone or a pharmaceutically acceptable salt thereof is contained in a first composition for wet granulation and the cellulose derivative is contained in a second composition for said wet granulation and postmixing ≪ / RTI > 15. The pharmaceutical composition for oral administration according to claim 14, wherein the wet granulation solvent is purified water. 15. The method of claim 14,
(S1) wet granulation by mixing robeglitazone or a pharmaceutically acceptable salt thereof, a diluent, a binder and a disintegrant; And
(S2) mixing the wet granulated product, the cellulose derivative, the binder, the disintegrant and the lubricant;
≪ / RTI > or a pharmaceutically acceptable salt thereof.

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