Method for producing formulated tablet containing vildagliptin and metformin hydrochloride

Abstract

To provide a formulated tablet containing vildagliptin and metformin hydrochloride, while avoiding the issues of delayed dissolution and impurity formation, and exhibiting superior manufacturability and stability.SOLUTION: Metformin hydrochloride is granulated by fluidization using a rolling fluidized bed granulation device while being sprayed with a binder, resulting in metformin hydrochloride granules. Then, vildagliptin and a specific lubricant are add and mixed with the metformin hydrochloride granules for compression molding.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a combination tablet containing vildagliptin and metformin hydrochloride, and in particular to a tablet which is free from problems of delayed dissolution and impurity generation even when stored under humid or heated conditions and has excellent manufacturability and stability. [Background technology]

[0002] Vildagliptin selectively and reversibly inhibits dipeptidyl peptidase-4 (DPP-4), an incretin decomposition enzyme secreted from the digestive tract into the blood upon intake of nutrients such as glucose. This inhibitory effect increases the concentration of endogenous incretin, promoting blood glucose-dependent insulin secretion and suppressing glucagon secretion, thereby exerting a blood glucose lowering effect. On the other hand, metformin exhibits a blood glucose lowering effect by suppressing hepatic glucose production and glucose absorption from the digestive tract, increasing insulin sensitivity and glucose consumption in peripheral tissues, and improving insulin resistance. Therefore, by administering vildagliptin and metformin to type 2 diabetes patients who exhibit hyperglycemia due to insulin secretion deficiency and insulin resistance, it is possible to improve both factors of insulin secretion deficiency and insulin resistance. Therefore, a combination tablet having the action mechanism of both vildagliptin and metformin has been developed, which reduces the number of medications taken by patients and contributes to improving medication adherence. (Non-Patent Document 1)

[0003] However, vildagliptin is hygroscopic, has stability problems, and is essentially non-compressible, so special ingenuity is required to make it into a tablet. For this reason, tablet technologies containing vildagliptin as an active ingredient are known (Patent Document 1, Patent Document 2, Patent Document 3).

[0004] In addition, metformin is usually used in the form of hydrochloride, and the content in one tablet is as high as 250 mg or 500 mg, and adding additives required for tableting makes the tablet large and difficult to take. Therefore, a technology for miniaturizing tablets containing metformin is known (Patent Document 4).

[0005] As described above, since vildagliptin and metformin hydrochloride are ingredients that each have problems in tableting, special ingenuity and technology are required to obtain a combination tablet containing these two ingredients. Therefore, technology related to a combination tablet containing vildagliptin and metformin hydrochloride is known.

[0006] For example, a technique has been disclosed in which metformin hydrochloride and a binder component are melt-granulated while being heated (Patent Document 5). However, this technique requires a special and expensive melt-granulation device called a twin-screw extruder, and strict and complicated temperature control is required during melt-granulation, such as increasing the temperature stepwise and ultimately controlling the temperature to a range not exceeding the melting point of metformin hydrochloride.

[0007] Also known is a technology for stabilizing tablets containing vildagliptin, a pharmaceutical additive that has little effect on the stability of vildagliptin, and metformin or a pharmacologically acceptable salt thereof (Patent Document 6). However, this technology relates to a multi-layer tablet in which a composition containing vildagliptin and a composition containing metformin are separated into different layers and compressed, and a special and expensive tablet press is required to manufacture the multi-layer tablet. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 5122144 [Patent Document 2] Patent No. 5739835 [Patent Document 3] Patent No. 5147399 [Patent Document 4] Patent No. 4848558 [Patent Document 5] Patent No. 5415762 [Patent Document 6] Patent Publication No. 2021-104988 [Non-patent literature]

[0009] [Non-Patent Document 1] Pharmaceutical Interview Form "Equmet Combination Tablets LD / HD", November 2022 revised (10th edition) Summary of the Invention [Problem to be solved by the invention]

[0010] The known techniques for combination tablets containing vildagliptin and metformin hydrochloride require special and expensive equipment for tableting and stabilization. Therefore, an object of the present invention is to provide a combination tablet containing vildagliptin and metformin hydrochloride that can be produced inexpensively using general production equipment, has good manufacturability, and is excellent in dissolution and stability. [Means for solving the problem]

[0011] As a result of intensive research, the present inventors have found that a stable combination tablet containing vildagliptin and metformin hydrochloride, which is easy to manufacture and has no problems of delayed dissolution after storage or generation of impurities, can be obtained by a simple and inexpensive method in which metformin hydrochloride is fluidized in a tumbling fluidized bed granulator while an aqueous solution of a binder is sprayed thereon to granulate, and then a granulated product of metformin hydrochloride is obtained by adding fixed amounts of vildagliptin and magnesium stearate as a lubricant to the metformin hydrochloride granules, mixing the mixture, and compression-molding, thereby completing the present invention.

[0012] The present invention includes the following inventions. (1) A method for producing a combination tablet containing vildagliptin and metformin hydrochloride, comprising the steps of granulating metformin hydrochloride and a binder in a tumbling fluidized bed granulator, mixing the granulated product with vildagliptin and magnesium stearate, and compressing the mixture. (2) A method for producing a combination tablet containing vildagliptin and metformin hydrochloride according to (1), characterized in that the content of magnesium stearate is 0.1% by weight to 1.5% by weight of the tablet. (3) A method for producing a combination tablet containing vildagliptin and metformin hydrochloride according to (2), wherein when the combination tablet is subjected to a dissolution test in accordance with the dissolution test of the Japanese Pharmacopoeia at 50 rotations using the paddle method in a test solution having a pH of 1.2, the dissolution rates after 30 minutes of each of vildagliptin and metformin hydrochloride are 80% or more. (4) The method for producing a combination tablet containing vildagliptin and metformin hydrochloride according to (3), wherein, when the combination tablet is stored at 25°C and a relative humidity of 75% for 2 weeks and then the dissolution test is performed, the change in dissolution rate of vildagliptin and metformin hydrochloride after 15 minutes from the dissolution rate before storage is within 15% for each. (5) The method for producing a combination tablet containing vildagliptin and metformin hydrochloride according to any one of (1) to (4), wherein the maximum amount of each impurity derived from vildagliptin and metformin hydrochloride is 0.5% or less after storing the combination tablet at 60°C in a tightly sealed glass bottle for 4 weeks. Effect of the Invention

[0013] The combination tablet containing vildagliptin and metformin hydrochloride in the present invention can be produced simply and inexpensively because the tablet powder obtained by mixing vildagliptin and magnesium stearate as a lubricant with the granulated product obtained by granulating metformin hydrochloride and a binder in a general tumbling fluidized bed granulator can be tableted in a general tablet press. Furthermore, since there is no problem of delayed dissolution or generation of impurities after storage, a high-quality and safe pharmaceutical preparation can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The combination tablet containing vildagliptin and metformin hydrochloride according to the present invention will be described below. However, the combination tablet containing vildagliptin and metformin hydrochloride according to the present invention should not be construed as being limited to the description of the following embodiments and examples.

[0015] In the present invention, a combination tablet containing vildagliptin and metformin hydrochloride contains the two ingredients, vildagliptin and metformin hydrochloride, in amounts of 50 mg and 250 mg, or 50 mg and 500 mg, respectively, and the ingredients are not separated into individual layers or fractions as in multi-layer tablets or dry-coated tablets, but are randomly dispersed throughout the tablet.

[0016] In the present invention, the tumbling fluidized bed granulation method is a method of granulation using a tumbling fluidized bed apparatus equipped with a rotating disk or blade at the bottom of the fluidized bed granulator. The feature of this apparatus is that it applies a swirling motion to the granulated material which is fluidized up and down by the airflow supplied from the bottom of the fluidized bed.

[0017] The dissolution test in the present invention is performed according to the 18th edition of the Japanese Pharmacopoeia, using 900 mL of dissolution test first fluid (pH 1.2) or second fluid (pH 6.8) as the test fluid, at 50 rotations by the paddle method, and the dissolution rates of vildagliptin and metformin hydrochloride 30 minutes after the start of the test are determined by liquid chromatography. Good dissolution is defined as 70% or more of vildagliptin and metformin hydrochloride dissolved 30 minutes after the start of the test, and more preferably 80% or more.

[0018] In the present invention, the absence of a problem of delayed dissolution means that, when the combination tablet containing vildagliptin and metformin hydrochloride of the present invention is stored in an open state under conditions of 25°C and 75% relative humidity for 2 weeks, and then the dissolution rates of vildagliptin and metformin hydrochloride at a test time of 15 minutes in the first dissolution test fluid (pH 1.2) are determined by liquid chromatography, the change in the dissolution rates of vildagliptin and metformin hydrochloride before and after 2 weeks of storage is within 15%.

[0019] In the present invention, the absence of a problem of impurity generation means that, when the combination tablet containing vildagliptin and metformin hydrochloride according to the present invention is stored in a sealed glass bottle at 60°C for 4 weeks and the impurities in the tablet are determined by liquid chromatography, the maximum amount of each impurity derived from vildagliptin and metformin hydrochloride is 0.5% or less, more preferably the maximum amount of each impurity is 0.2% or less.

[0020] The granulator according to the present invention is preferably a fluidized bed granulator, and more preferably a tumbling fluidized bed granulator.

[0021] The amount of magnesium stearate added to the tablet of the present invention is preferably 0.1 to 1.5% by weight, more preferably 0.3 to 0.7% by weight.

[0022] The combination tablet containing vildagliptin and metformin hydrochloride may contain various additives other than the binder and magnesium stearate, such as a filler, a disintegrant, a lubricant, and a coating agent.

[0023] (Binding Agent) In the combination tablet containing vildagliptin and metformin hydrochloride according to the present invention, the binder can be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, macrogol, etc. These binders can be used alone or in appropriate combination.

[0024] (Excipients) In the combination tablet containing vildagliptin and metformin hydrochloride according to the present invention, an excipient used for tableting may be added. For example, lactose, sugar alcohols such as D-mannitol, erythritol, sorbitol, and xylitol, trehalose, sucrose, etc. may be used alone or in appropriate combination.

[0025] (Disintegrant) A disintegrant may be added to the combination tablet containing vildagliptin and metformin hydrochloride according to the present invention. For example, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, etc. may be used alone or in appropriate combination.

[0026] (lubricant) In the combination tablet containing vildagliptin and metformin hydrochloride according to the present invention, the lubricant may contain ingredients other than magnesium stearate, and may be selected from stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol, etc. These lubricants may be used alone or in appropriate combination.

[0027] (Coating agent) The combination tablet containing vildagliptin and metformin hydrochloride according to the present invention may contain a coating agent, and any coating agent that can be used for medical purposes may be used. Examples of the coating agent include hypromellose, polyvinyl alcohol, ethyl cellulose, carboxymethylethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, PVA copolymer, ethyl acrylate-methyl methacrylate copolymer dispersion, aminoalkyl methacrylate copolymer, Opadry, carnauba wax, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and methacrylic acid copolymer. Ingredients such as light-shielding agents and colorants may also be added.

[0028] As described above, the combination tablet containing vildagliptin and metformin hydrochloride according to the present invention can be obtained by a simple and inexpensive production method, and a pharmaceutical preparation of excellent quality having excellent manufacturability, good dissolution properties, and good tablet stability during storage can be obtained.

[0029] The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.

[0030] (Test Example 1) Impact of manufacturing methods on manufacturability and stability of combination tablets

[0031] Example 1: Tumbling fluidized bed granulation method 300 g of metformin hydrochloride was placed in a fluidized bed granulator (Multiplex MP-01, Powrex Corp.) equipped with a rolling plate, and the mixture was tumbled and fluidized with an air current heated to 60°C. 352.5 g of an 8% aqueous solution of hydroxypropylcellulose (HPC-L, molecular weight 140,000, Japan) was sprayed onto the mixture at a rate of 7.0 g per minute, and the mixture was dried to 45°C after spraying. The dried product was granulated using a granulator (Comil QC197S, Powrex Corp.) equipped with a 0.813 mm screen. 328.2 g of the granulated product and 30 g of vildagliptin were placed in a plastic bag and mixed for 3 minutes, after which 3.6 g of magnesium stearate was added and mixed for 1 minute to prepare tablet powder. This powder was compressed and molded using a tablet press (HT-EX18SS2, manufactured by Hata Iron Works) equipped with an elliptical punch having a major axis of 16.9 mm and a minor axis of 6.6 mm, to give tablets with a mass of 603 mg each and a thickness of 6.0 mm.

[0032] Comparative Example 1 Dry Granulation Method 400g of metformin hydrochloride, 35.1g of hydroxypropylcellulose, and 2.43g of magnesium stearate were mixed in a plastic bag, and compressed in a dry granulation device (roller compactor TF-LABO, manufactured by Freund Corporation) under conditions of roll pressure of 7.0MPa, roll rotation speed of 1.5rpm, and screw rotation speed of 15rpm to obtain a molded product. This molded product was granulated using an oscillator equipped with a 1mm mesh screen. 40.0g of vildagliptin was placed in a plastic bag with 437.53g of this granulated product and mixed for 3 minutes, and 7.27g of magnesium stearate was added to this mixture and mixed for 1 minute to obtain tablet powder. This tablet powder was compressed and molded in a tablet press (HT-EX18SS2, manufactured by Hata Iron Works Co., Ltd.) equipped with an oval punch with a major axis of 16.3mm and a minor axis of 7.6mm so that each tablet had a mass of 606mg and a thickness of 6.1mm, to obtain tablets.

[0033] Comparative Example 2: Stirring granulation method 300g of metformin hydrochloride and 27.2g of hydroxypropyl cellulose were placed in a stirring granulator (vertical granulator VG-01 type, manufactured by Powrex Corporation), and 24g of a 4% aqueous solution of hydroxypropyl cellulose was added while stirring under the conditions of a blade rotation speed of 250 rpm and a cross screw rotation speed of 1600 rpm. After granulation for 3 minutes, the granulated product was sized using a granulator (Comil QC197S, manufactured by Powrex Corporation) equipped with a 3.962 mm screen. The sized product was dried at 80 ° C. using a fluidized bed dryer (Multiplex MP-01, manufactured by Powrex Corporation). The obtained dried product was granulated using a granulator (Comil QC197S, manufactured by Powrex Corporation) equipped with a 1.575 mm screen. 328.2g of this granulated product and 30g of vildagliptin were placed in a plastic bag and mixed for 3 minutes, and then 3.6g of magnesium stearate was added and mixed for 1 minute to obtain tablet powder. This powder was compressed and molded using a tablet press (HT-EX18SS2, manufactured by Hata Iron Works) equipped with an elliptical punch having a major axis of 16.9 mm and a minor axis of 6.6 mm, to give tablets with a mass of 603 mg each and a thickness of 6.0 mm.

[0034] Comparative Example 3 Fluidized Bed Granulation Using a fluidized bed granulator (Multiplex MP-01, manufactured by Powrex Corp.), 400 g of metformin hydrochloride was fluidized with an airflow heated to 60°C, and 495 g of an 8% aqueous solution of hydroxypropylcellulose was sprayed onto it at 7 g per minute, and then dried to 45°C after spraying. This dried product was granulated using a granulator (Comil QC197S, manufactured by Powrex Corp.) equipped with a 1.575 mm screen. 439.6 g of this granulated product and 40 g of vildagliptin were placed in a plastic bag and mixed for 3 minutes, after which 5.2 g of magnesium stearate was added and mixed for 1 minute to obtain tablet powder. This tablet powder was compressed and molded using a tablet press (HT-EX18SS2, manufactured by Hata Iron Works Co., Ltd.) equipped with an oval punch with a major axis of 16.3 mm and a minor axis of 7.6 mm, so that each tablet had a mass of 606 mg and a thickness of 6.2 mm, and tablets were obtained.

[0035] Table 1 shows the results of the manufacturability and stability of the combination tablets containing vildagliptin and metformin hydrochloride in Example 1 and Comparative Examples 1 to 3. In the table, metformin means metformin hydrochloride.

[0036] [Table 1] Evaluation of granulation: Good; ◯, slightly bad; △, bad; × Evaluation of tableting: Good; ◯, slightly bad; △, bad; × Dissolution evaluation (pH 1.2, 30 minutes after the start of the test): Dissolution rate 80% or more; : Dissolution rate is less than 80%; × Evaluation of dissolution delay (pH 1.2, 15 minutes after the start of the test): The change in dissolution rate of vildagliptin and metformin hydrochloride between before and after 2 weeks of storage was within 15%; Yes : The change in dissolution rate of vildagliptin and metformin hydrochloride between before and after two weeks of storage exceeds 15%; ×

[0037] As shown in Table 1, the combination tablet of vildagliptin and metformin hydrochloride obtained in Example 1 using the tumbling fluidized bed granulation method had good manufacturability, such as granulation properties of the metformin hydrochloride granules and compression properties during tablet molding, and the obtained tablets had excellent dissolution properties and stability after storage.

[0038] (Test Example 2) Addition amount of magnesium stearate and dissolution delay

[0039] Example 2 300 g of metformin hydrochloride was placed in a fluidized bed granulator (Multiplex MP-01, Powrex Corp.) equipped with a rolling plate, and the mixture was tumbled and fluidized with an air current heated to 60°C. 352.5 g of an 8% aqueous solution of hydroxypropylcellulose (HPC-L, molecular weight 140,000, Japan) was sprayed onto the mixture at a rate of 6.0 g per minute, and the mixture was dried to 45°C after spraying. The dried product was granulated using a granulator (Comil QC197S, Powrex Corp.) equipped with a 0.813 mm screen. 328.2 g of the granulated product and 30 g of vildagliptin were placed in a plastic bag and mixed for 3 minutes, after which 1.8 g of magnesium stearate was added and mixed for 1 minute to prepare tablet powder. This powder was compressed and molded using a tablet press (HT-EX18SS2, manufactured by Hata Iron Works) equipped with an oval punch having a major axis of 16.9 mm and a minor axis of 6.6 mm, to give tablets with a mass of 600 mg each and a thickness of 6.0 mm.

[0040] Comparative Example 4 300g of metformin hydrochloride was placed in a fluidized bed granulator (Multiplex MP-01, Powrex Corp.) equipped with a rolling plate, and tumbled and fluidized with air heated to 60°C. 352.5g of an 8% aqueous solution of hydroxypropylcellulose (HPC-L, molecular weight 140,000, Japan) was sprayed onto the mixture at 6.0g / min, and the mixture was dried to 45°C after spraying. The dried product was granulated using a granulator (Comil QC197S, Powrex Corp.) equipped with a 0.813mm screen. 328.2g of the granulated product and 30g of vildagliptin were placed in a plastic bag and mixed for 3 minutes, after which 7.2g of magnesium stearate was added and mixed for 1 minute to prepare tablet powder. This powder was compressed and molded using a tablet press (HT-EX18SS2, manufactured by Hata Iron Works) equipped with an elliptical punch having a major axis of 16.9 mm and a minor axis of 6.6 mm, to give tablets with a mass of 609 mg each and a thickness of 6.0 mm.

[0041] Table 2 shows the results of the productivity, dissolution property, and stability of the combination tablets containing vildagliptin and metformin hydrochloride in Examples 1 and 2 and Comparative Example 4. In the table, metformin means metformin hydrochloride.

[0042] [Table 2] Evaluation of tableting: Good; ◯, slightly bad; △, bad; × Dissolution evaluation (pH 1.2, 30 minutes after the start of the test): Dissolution rate is 80% or more; Yes : Dissolution rate is less than 80%; × Evaluation of dissolution delay (pH 1.2, 15 minutes after the start of the test): The change in dissolution rate of vildagliptin and metformin hydrochloride between before and after 2 weeks of storage was within 15%; Yes : The change in dissolution rate of vildagliptin and metformin hydrochloride between before and after two weeks of storage exceeds 15%; ×

[0043] As shown in Table 2, the vildagliptin and metformin hydrochloride combination tablets of Examples 1 and 2, to which 1.0% by weight and 0.5% by weight of magnesium stearate were added, respectively, had good compression properties during tablet formation, and the obtained tablets had excellent dissolution properties and stability after storage.

[0044] (Test Example 3) Example of a film-coated combination tablet

[0045] Preparation of Coating Solution of Example 3 Dissolve 846 g of hydroxypropylmethylcellulose 2910 and 78 g of macrogol 6000 in 5,400 g of purified water. Add 78 g of talc, 78 g of titanium oxide, 2.58 g of ferric oxide, and 0.39 g of ferric oxide dispersed in 750 g of purified water to this solution, stir and mix, and pass through a 140M sieve to obtain a coating solution.

[0046] Preparation of Coating Solution of Example 4 Dissolve 1,152 g of hydroxypropyl methylcellulose 2910 and 96 g of macrogol 6000 in 7,296 g of purified water. Add 96 g of talc, 96 g of titanium oxide, 3.444 g of yellow ferric oxide, and 0.432 g of ferric oxide dispersed in 1,008 g of purified water to this solution, stir and mix, and pass through a 140M sieve to obtain a coating solution.

[0047] Example 3 10,000 g of metformin hydrochloride was placed in a fluidized bed granulator (Flocoater NFLO-15, Freund Corporation) equipped with a rolling plate, and the mixture was tumbled and fluidized with an air current heated to 80°C. 14,500 g of an 8% aqueous solution of hydroxypropylcellulose (HPC-L, Nippon Sotatsu) was sprayed onto the mixture at a rate of 50 g per minute, and the mixture was dried to 45°C after spraying. The metformin hydrochloride was granulated and dried twice. The resulting dried product was granulated using a granulator (Comil QC197S, Powrex Corporation) equipped with a 0.813 mm screen, and 22,320 g of the granulated product and 2,000 g of vildagliptin were placed in a 60 L V-type mixer (TCV-60, Tokuju Seisakusho Co., Ltd.) and mixed for 15 minutes at 26 revolutions per minute. After that, 120 g of magnesium stearate was added and mixed for another minute to obtain tablet powder. This tablet powder was compressed and molded using a tablet press (HT-AP18SS-II, Hata Iron Works) equipped with an elliptical punch with a major axis of 16.9 mm and a minor axis of 7.4 mm, so that each tablet had a mass of 611 mg and a thickness of 5.7 mm, to obtain tablets. These tablets were sprayed with the above-mentioned coating solution using a coating device (Hi-Coater HCT-80, Freund Corporation), to obtain film-coated tablets with an average tablet mass of 629 mg. A small amount of carnauba wax powder was applied as a polishing agent to these film-coated tablets to give them a glossy finish.

[0048] Example 4 10,000 g of metformin hydrochloride was placed in a fluidized bed granulator (Flocoater NFLO-15, Freund Corporation) equipped with a rolling plate, and the mixture was tumbled and fluidized with an air current heated to 60°C. 17,600 g of an 8% aqueous solution of hydroxypropylcellulose (HPC-L, Nippon Sotatsu) was sprayed onto the mixture at a rate of 50 g per minute, and the mixture was dried to 45°C after spraying. The metformin hydrochloride was granulated and dried twice. The resulting dried product was granulated using a granulator (Comil QC197S, Powrex Corporation) equipped with a 0.813 mm screen, and 22,816 g of the granulated product and 4,000 g of vildagliptin were placed in a 60 L V-type mixer (TCV-60, Tokuju Kosakusho Co., Ltd.) and mixed for 15 minutes at 26 revolutions per minute. After that, 144 g of magnesium stearate was added and mixed for another minute to obtain tablet powder. This tableting powder was compressed and molded using a tablet press (Hata Iron Works, HT-AP18SS-II) equipped with an elliptical punch with a major axis of 14 mm and a minor axis of 6.3 mm, so that each tablet had a mass of 337 mg and a thickness of 4.6 mm, to obtain tablets. These tablets were sprayed and coated with the above-mentioned coating solution using a coating device (Hi-Coater HCT-80, Freund Corporation), to obtain film-coated tablets with an average tablet mass of 349 mg. A small amount of carnauba wax powder was applied as a polishing agent to these film-coated tablets to give them a glossy finish.

[0049] The results of the productivity, dissolution property, and stability of the film-coated combination tablets containing vildagliptin and metformin hydrochloride of Examples 3 and 4 are shown in Table 3. In the table, metformin means metformin hydrochloride.

[0050] [Table 3] Evaluation of granulation: Good; ◯, slightly bad; △, bad; × Evaluation of tableting: Good; ◯, slightly bad; △, bad; × Coating property evaluation: good; ◯, slightly bad; △, bad; × Dissolution evaluation (pH 1.2, 30 minutes after the start of the test): Dissolution rate is 80% or more; Yes : Dissolution rate is less than 80%; × Dissolution evaluation (pH 6.8, 30 minutes after the start of the test): Dissolution rate is 80% or more; Yes : Dissolution rate is less than 80%; × Evaluation of dissolution delay (pH 1.2, 15 minutes after the start of the test): The change in dissolution rate of vildagliptin and metformin hydrochloride between before and after 2 weeks of storage was within 15%; Yes : The change in dissolution rate of vildagliptin and metformin hydrochloride between before and after two weeks of storage exceeds 15%; ×

[0051] The combination tablets of vildagliptin and metformin hydrochloride produced by the tumbling fluidized bed granulation method of the present invention were easy to manufacture and had excellent storage stability, even in the case of tablets coated with a film coating.

[0052] Examples 5 to 10 The tablet compositions shown in Tables 4 and 5 can be obtained by carrying out granulation, drying, granulation, mixing, tableting, preparation of film coating solution, film coating and polishing using each binder (hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol) in the same manner as in Examples 3 and 4.

[0053] [Table 4]

[0054] [Table 5] [Industrial Applicability]

[0055] The present invention provides a combination tablet containing vildagliptin and metformin hydrochloride which can be produced at low cost by a simple production method, has good manufacturability, and has excellent storage stability.

Claims

1. A method for producing a combination tablet containing vildagliptin and metformin hydrochloride, comprising the steps of granulating metformin hydrochloride and a binder in a tumbling fluidized bed granulator, mixing the granulated product with vildagliptin and magnesium stearate, and compressing the mixture.

2. 2. The method for producing a combination tablet containing vildagliptin and metformin hydrochloride according to claim 1, characterized in that the content of magnesium stearate is 0.1 to 1.5% by weight of the tablet.

3. 3. The method for producing a combination tablet containing vildagliptin and metformin hydrochloride according to claim 2, wherein when the combination tablet is subjected to a dissolution test in accordance with the dissolution test of the Japanese Pharmacopoeia at 50 rotations by the paddle method in a test solution having a pH of 1.2, the dissolution rates after 30 minutes of each of vildagliptin and metformin hydrochloride are 80% or more.

4. 4. The method for producing a combination tablet containing vildagliptin and metformin hydrochloride according to claim 3, characterized in that, when the combination tablet is stored at 25°C under a relative humidity of 75% for 2 weeks and then the dissolution test is performed, the change in dissolution rate of vildagliptin and metformin hydrochloride after 15 minutes from the dissolution rate before storage is within 15% for each.

5. 5. The method for producing a combination tablet containing vildagliptin and metformin hydrochloride according to any one of claims 1 to 4, wherein the maximum amount of each impurity derived from vildagliptin and metformin hydrochloride is 0.5% or less after storing the combination tablet at 60°C in a tightly sealed glass bottle for 4 weeks.

Images