JP6283314B2 - Anagliptin-containing solid preparation - Google Patents

Description

  The present invention relates to a solid preparation containing anagliptin having dipeptidyl peptidase IV inhibitory action.

  A compound having a dipeptidyl peptidase IV (hereinafter sometimes abbreviated as DPP-IV) inhibitory activity (DPP-IV inhibitor) is a therapeutic agent for diseases involving DPP-IV, such as type 2 diabetes It is useful as an active ingredient. As such a DPP-IV inhibitor, Patent Document 1 discloses anagliptin (chemical name: N- [2-({2-[(2S) -2-cyanopyrrolidin-1-yl] -2-oxoethyl} amino). -2-methylpropyl] -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxamide) has an excellent DPP-IV inhibitory action.

  In general, it is difficult to administer a compound useful as an active ingredient of a pharmaceutical agent as it is from the viewpoint of ingestion and ensuring the accuracy of the dosage, and it is usually formulated and administered in some dosage form. The Among them, solid preparations such as powders, granules, tablets and the like have a merit that they are easier to handle and easier to manage the dose than liquids and the like, and are widely used dosage forms. However, for anagliptin, there has been no specific formulation or formulation technology that can be marketed as a pharmaceutical product as well as a solid preparation.

  By the way, as a DPP-IV inhibitor, besides anagliptin, for example, sitagliptin phosphate hydrate (trade name: Janubia, Gractive), vildagliptin (trade name: Equa), alogliptin benzoate (trade name: Nesina) Linagliptin (trade name: Trazenta) and teneligliptin hydrobromide hydrate (trade name: Tenelia) have been marketed or planned to be launched worldwide, including Japan.

  However, even if it is a DPP-IV inhibitor having the same effect, the formulation technique for obtaining an appropriate dosage form is completely different if the compound is different. In particular, since the chemical structures of DPP-IV inhibitors are greatly different from each other, it is expected that their physical and chemical properties are also greatly different from each other. Therefore, various studies are required in the preparation of anagliptin.

International Publication No. WO2004 / 067509 Pamphlet

  In order to obtain a solid preparation containing anagliptin, the inventors of the present invention first made extensive studies on the characteristics of anagliptin and found that the solubility of anagliptin in water was extremely high. In general, it is known that, in a solid preparation containing a highly soluble component, a spatter is formed on the surface of the preparation particularly when the content is high, and elution is delayed. The delay in elution associated with the formation of the pollen makes the release of the active ingredient unstable and uncertain. Therefore, in order to obtain a solid preparation containing anagliptin and having a stable release of active ingredients, it was considered desirable to add a disintegrant that promotes the disintegration of the preparation. Therefore, the present inventors conducted further diligent studies, and found that when anagliptin was allowed to coexist with various disintegrants, a change in formulation occurred and a large amount of anagliptin-derived degradation products were produced.

  Then, this invention makes it a subject to provide the solid formulation containing an anagliptin which is excellent in stability.

  As a result of further intensive studies to solve the above-mentioned problems, the present inventors have found that, among the components that can be used as a disintegrant, only hydroxypropylcellulose or a salt thereof specifically causes almost no anagliptin compounding change. Thus, it was found that a solid preparation containing anagliptin having excellent stability can be obtained by using this, and the present invention was completed.

That is, the main configuration of the present invention is as follows.
(1) A solid preparation containing anagliptin or a salt thereof and hydroxypropylcellulose.
(2) The solid preparation according to (1), wherein hydroxypropylcellulose is contained as a disintegrant.
(3) The solid preparation according to (1) or (2), wherein the hydroxypropylcellulose is a low-substituted hydroxypropylcellulose.
(4) The solid preparation according to any one of (1) to (3), wherein the solid preparation is a tablet, capsule, granule, fine granule or powder.

  According to the present invention, a solid preparation excellent in chemical stability of anagliptin can be obtained.

  Anagliptin is a compound described in Example 2 of Patent Document 1, and has a chemical name of N- [2-({2-[(2S) -2-cyanopyrrolidin-1-yl] -2-oxoethyl} amino. ) -2-Methylpropyl] -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxamide, which is a known compound, and can be produced with reference to the production method described in the document.

  In the present invention, “anagliptin or a salt thereof” includes not only anagliptin itself, but also a pharmaceutically acceptable salt of anagliptin, or a solvate of anagliptin or a pharmaceutically acceptable salt thereof, water, alcohol or the like. included. Examples of the pharmaceutically acceptable salt include a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. As preferable examples of salts with organic acids, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzoic acid, toluenesulfonic acid And the like. Preferable examples of the salt with basic amino acid include a salt with arginine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. In the present invention, anagliptin or a salt thereof is preferably an anagliptin free form.

  The content of anagliptin or a salt thereof in the solid preparation of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, anagliptin or a salt thereof per day can be contained in an amount of 0.1 to 1000 mg, preferably 1 to 500 mg, particularly preferably 100 to 400 mg in terms of anagliptin free form. In the present invention, it is preferable to contain 1 to 90% by mass of anagliptin or a salt thereof in terms of free form of anagliptin, more preferably 3 to 80% by mass, based on the total mass of the solid preparation. The content by mass is particularly preferred.

  “Hydroxypropyl cellulose” is a hydroxypropyl ether of cellulose, and may be any hydroxypropyl cellulose having a different hydroxypropoxy group substitution rate and molecular weight, or a combination of two or more different hydroxypropyl celluloses. Good. The substitution rate of the hydroxypropoxy group is preferably in the range of 5 to 78%, more preferably in the range of 5 to 16% or 53 to 78%. Furthermore, from the viewpoint of the stability of anagliptin or a salt thereof, those having a low substitution degree, specifically, a low substitution degree hydroxypropyl cellulose in the range of 5 to 16% are particularly preferred. The hydroxypropoxy group substitution rate of hydroxypropyl cellulose is determined according to the hydroxypropoxy group quantification method of hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose described in the 16th revision Japanese Pharmacopoeia. In addition, the compounding purpose of the hydroxypropyl cellulose in the solid preparation of the present invention is not limited to the disintegrant, and the case where it is blended for other purposes is also included in the present invention.

  A commercially available hydroxypropyl cellulose can be used. Specifically, for example, L-HPC (Shin-Etsu Chemical), HPC-SSL (Nippon Soda), HPC-SL (Nippon Soda) HPC-L (Nippon Soda) ), HPC-M (Nippon Soda), HPC-H (Nippon Soda) and the like.

  In addition, in this invention, the hydroxypropyl cellulose should just be contained and the aspect used in combination with another disintegrating agent etc. is also contained in this invention. Such other disintegrants are not particularly limited, and specific examples include carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, and partially pregelatinized starch.

  The content of hydroxypropyl cellulose in the solid preparation of the present invention is not particularly limited, and may be determined by appropriate examination. In the present invention, from the viewpoint of the stability of anagliptin or a salt thereof, it is preferably contained in an amount of 0.05 to 40% by mass, more preferably 0.1 to 30% by mass relative to the total mass of the solid preparation. It is particularly preferable to contain 0.5 to 20% by mass. In particular, when the hydroxypropyl cellulose is a low-substituted hydroxypropyl cellulose (with a hydroxypropoxy group substitution rate in the range of 5 to 16%), the content is preferably 1 to 40% by mass, and 2 to 30% by mass. It is more preferable to contain, and it is especially preferable to contain 3-20 mass%. In addition, in the case of hydroxypropylcellulose having a hydroxypropoxy group substitution rate in the range of 53 to 78%, 0.05 to 30% by mass is preferable, and 0.1 to 20% by mass is more preferable. The content is preferably 0.5 to 10% by mass.

  The content ratio of anagliptin or a salt thereof and hydroxypropylcellulose contained in the solid preparation of the present invention is not particularly limited, and may be appropriately determined and determined according to the stability of anagliptin or a salt thereof, but anagliptin or a salt thereof From the viewpoint of stability, it is preferable that 0.5 to 50 parts by mass of hydroxypropyl cellulose is contained with respect to 100 parts by mass of anagliptin or a salt thereof in terms of free form of anagliptin, and 1 to 40 parts by mass is contained. Is more preferable, and it is particularly preferable to contain 3 to 30 parts by mass. In particular, when the hydroxypropyl cellulose is a low-substituted hydroxypropyl cellulose (with a hydroxypropoxy group substitution rate in the range of 5 to 16%), anagliptin or a salt thereof is converted to 1 part by mass in terms of free form of anagliptin. On the other hand, it is preferable to contain 0.5-50 mass parts of low substituted hydroxypropylcellulose, it is more preferable to contain 1-40 mass parts, and it is especially preferable to contain 3-30 mass parts. Moreover, in the case of hydroxypropyl cellulose having a hydroxypropoxy group substitution rate in the range of 53 to 78%, the substitution rate of hydroxypropoxy group is 1 part by mass of anagliptin or a salt thereof in terms of free form of anagliptin. It is preferable to contain 0.1 to 35 parts by mass of hydroxypropyl cellulose in a range of 53 to 78%, more preferably 0.5 to 25 parts by mass, and particularly preferably 1 to 15 parts by mass.

  In the present invention, “solid preparation” refers to the dosage form described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations, such as tablets (ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets). Etc.), solid preparations for oral administration such as capsules, granules, fine granules, powders, and oral tablets (troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.) A solid formulation for administration is preferred. In addition, these solid preparations may be coated with a film, a sugar coating, etc. as needed.

  The solid preparation of the present invention can be produced by a known method described in, for example, the 16th revised Japanese Pharmacopoeia General Rules for Preparations according to the above dosage form. For example, when the solid preparation is a tablet, an appropriate preparation additive as described below may be mixed in addition to anagliptin or a salt thereof and hydroxypropylcellulose, and then compression molded. Examples of the compression molding method include a method of compression molding after granulation such as a dry granule compression method, a semi-dry granule compression method, and a wet granule compression method, and a direct powder compression method. Examples of the granulation method include extrusion granulation, stirring granulation, rolling granulation, spray drying granulation, crushed granulation, fluidized bed granulation, and melt granulation.

In the production of the solid preparation of the present invention, in addition to the above-mentioned components, appropriate preparation additives such as excipients, binders, fluidizing agents, corrigents, and coloring agents can be used as appropriate.
Examples of excipients include sugars such as lactose hydrate, sucrose, and glucose; sugar alcohols such as erythritol, xylitol, sorbitol, and mannitol; celluloses such as crystalline cellulose, microcrystalline cellulose, and powdered cellulose; Examples include starches such as wheat starch and corn starch; anhydrous calcium hydrogen phosphate.
Examples of the binder include starch (soluble), hypromellose, pullulan, povidone, polyvinyl alcohol and the like.
Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, titanium oxide and the like.
Examples of the corrigent include aspartame, saccharin, saccharin sodium hydrate, dl-menthol, and L-menthol.
Examples of the colorant include yellow iron sesquioxide, brown iron oxide, and iron sesquioxide.

  Since the solid preparation of the present invention contains anagliptin having a DPP-IV inhibitory action or a salt thereof, it is useful as a medicament for type 2 diabetes. In this case, the solid preparation of the present invention can be taken in one or two or more divided doses so as to achieve the above-mentioned daily dose.

Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these.
[Test Example 1] Examination of interaction between anagliptin and various disintegrants Samples 1 to 6 shown below were prepared, stored for 1 week under conditions of 60 ° C and 75% relative humidity, and stored immediately before the start of storage and for 1 week. The interaction between anagliptin and various disintegrants was examined by evaluating the chemical stability of anagliptin in later samples.

  The chemical stability was evaluated by measuring anagliptin and all degradation products thereof by HPLC, and removing the peak area of anagliptin from the total peak area (the peak area derived from the degradation product). The amount of decomposition products (%) was calculated by dividing by.

[Sample 1]
1 part by mass of anagliptin and 9 parts by mass of low-substituted hydroxypropylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd .: L-HPC LH-21) were mixed to obtain a sample 1 mixture.
[Sample 2]
1 part by mass of anagliptin and 4 parts by mass of hydroxypropylcellulose (manufactured by Nippon Soda Co., Ltd .: HPC-L) were mixed to obtain a mixture of sample 2.

[Sample 3]
1 part by mass of anagliptin and 9 parts by mass of carboxymethyl cellulose (manufactured by Gotoku Pharmaceutical Co., Ltd .: NS-300) were mixed to obtain a mixture of Sample 3.
[Sample 4]
1 part by mass of anagliptin and 9 parts by mass of carmellose calcium (manufactured by Gotoku Pharmaceutical Co., Ltd .: ECG-505) were mixed to obtain a sample 4 mixture.

[Sample 5]
1 part by mass of anagliptin and 9 parts by mass of croscarmellose sodium (manufactured by FMC Biopolymer: Ac-Di-Sol) were mixed to obtain a mixture of sample 5.
[Sample 6]
1 part by mass of anagliptin and 9 parts by mass of crospovidone (manufactured by BASF: Kollidon CL) were mixed to obtain a mixture of sample 6.

The results are shown in Table 1. From the test results shown in Table 1, when anagliptin was combined with carboxymethylcellulose (sample 3), carmellose calcium (sample 4), croscarmellose sodium (sample 5) or crospovidone (sample 6), It was found that changes occurred and as much as 10% or more of degradation products were produced after storage for 1 week.
On the other hand, when anagliptin and low-substituted hydroxypropylcellulose (sample 1) or hydroxypropylcellulose (sample 2) coexist, the amount of degradation product hardly changed before and after storage, and anagliptin is stable. It became clear that.
From the above test results, it was revealed that anagliptin or a salt thereof and a solid preparation containing hydroxypropylcellulose are excellent in chemical stability of anagliptin.

[Test Example 2] Examination of stability of tablets containing anagliptin and hydroxypropyl cellulose After preparing the film-coated tablets of Example 1 shown below after PTP packaging, the obtained PTP sheet was further packaged with aluminum pillow, It was stored for 6 months under the conditions of 40 ° C. and 75% relative humidity, and the chemical stability of anagliptin in the tablets immediately after the start of storage, after 2 months of storage, after 4 months of storage and after 6 months of storage was evaluated. . The chemical stability was evaluated by calculating the decomposition product amount (%) in the same manner as in Test Example 1.

[Example 1]
To 25 parts by mass of anagliptin, 37.4 parts by mass of mannitol, 8 parts by mass of crystalline cellulose, and 8 parts by mass of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd .: L-HPC LH-21) were added and mixed. . Next, 1.6 parts by mass of magnesium stearate was added and mixed to obtain tableting powder. The obtained powder for tableting was tableted so that it might become 80 mg per tablet, and the tablet was obtained.
One tablet obtained was film-coated with a solution obtained by dissolving and dispersing 3.5 parts by mass of hypromellose, 0.65 parts by mass of macrogol 6000, and 0.85 parts by mass of titanium oxide in water. The film coating was applied. The obtained film-coated tablets contain 25 mg of anagliptin per tablet.

  The results are shown in Table 2. From the test results shown in Table 2, it was revealed that the tablets containing anagliptin and hydroxypropyl cellulose maintained chemical stability even after long-term storage.

[Test Example 3] Examination of stability of tablets containing anagliptin and hydroxypropylcellulose Part 2
The following film-coated tablets of Example 2 shown below were prepared, packaged in bottles with a desiccant, stored for 6 months under conditions of 40 ° C. and 75% relative humidity, stored immediately before the start of storage, stored for 2 months, and stored for 4 months. The chemical stability of anagliptin in the tablets after and after 6 months storage was evaluated. The chemical stability was evaluated by calculating the decomposition product amount (%) in the same manner as in Test Example 1.

[Example 2]
To 50 parts by mass of anagliptin, 74.8 parts by mass of mannitol, 16 parts by mass of crystalline cellulose, and 16 parts by mass of low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd .: L-HPC LH-21) were added and mixed. Next, 3.2 parts by mass of magnesium stearate was added and mixed to obtain a tableting powder. The obtained powder for tableting was tableted to 160 mg per tablet to obtain tablets.
One tablet obtained was film-coated with a solution obtained by dissolving and dispersing 7 parts by mass of hypromellose, 1.3 parts by mass of macrogol 6000 and 1.7 parts by mass of titanium oxide in water, and 10 mg of film. Coating was applied. The film-coated tablets obtained contain 50 mg of anagliptin per tablet.

  The results are shown in Table 3. From the test results shown in Table 3, as in Test Example 2, it was found that the tablets containing anagliptin and hydroxypropylcellulose maintained chemical stability even after long-term storage.

Example 3
Tablets containing 100 mg of anagliptin per tablet were produced by the following method. That is, 100 parts by mass of anagliptin was fluidized-bed granulated using a hydroxypropylcellulose aqueous solution (1.5 parts by mass as hydroxypropylcellulose). The obtained granular material was sized after drying, and 15 parts by mass of low-substituted hydroxypropylcellulose and 30 parts by mass of crystalline cellulose were added to the sized product and mixed. Next, 1.5 parts by mass of magnesium stearate was added and mixed to obtain granules for tableting. The obtained granules for tableting were tableted to give 148 mg per tablet to obtain tablets.

  ADVANTAGE OF THE INVENTION According to this invention, the solid formulation which contains an anagliptin which has DPP-IV inhibitory activity, or its salt, and is excellent in stability can be provided, and it can utilize in pharmaceutical industry etc.

Claims (4)

  A solid preparation containing anagliptin or a salt thereof and hydroxypropylcellulose.   The solid preparation according to claim 1, wherein hydroxypropylcellulose is contained as a disintegrant.   The solid preparation according to claim 1 or 2, wherein the hydroxypropylcellulose is a low-substituted hydroxypropylcellulose.   The solid preparation according to any one of claims 1 to 3, wherein the solid preparation is a tablet, capsule, granule, fine granule or powder.