JP6283313B2 - Anagliptin-containing pharmaceutical composition - Google Patents

Description

  The present invention relates to a pharmaceutical composition 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, for example, 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, a compound useful as an active ingredient of a pharmaceutical is formulated and administered as some pharmaceutical composition, but it is rare that it takes a long time from formulation to administration. Absent. Therefore, it is extremely important to ensure the stability of the active ingredient in the pharmaceutical composition from the viewpoint of exhibiting expected drug efficacy and avoiding unexpected side effects. However, the stability of an active ingredient is greatly influenced by its physical and chemical properties, and such properties are often unpredictable from its chemical structure, ensuring the stability of the active ingredient in pharmaceutical compositions. It takes a lot of trial and error to establish this technology.

  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 Tenerigliptin hydrobromide hydrate (Trade name: Tenelia) are marketed worldwide, including Japan.

  However, even if it is a DPP-IV inhibitor having the same effect, the stabilization technique is completely different if the compound is different. In particular, since the chemical structures of DPP-IV inhibitors are greatly different from each other, their physical and chemical properties are expected to be greatly different from each other. Therefore, the information regarding other DPP-IV inhibitors as described above is not helpful, and various studies are required for the stabilization of anagliptin.

International Publication No. WO2004 / 067509 Pamphlet

  An object of this invention is to provide the pharmaceutical composition containing anagliptin which is excellent in stability.

  In order to provide an anagliptin-containing pharmaceutical composition excellent in stability, the present inventors first made extensive studies on the physical and chemical characteristics of anagliptin. The stability of the anagliptin is greatly influenced by the pH environment, and While it is extremely unstable in a high pH environment and rapidly decomposes, an anagliptin-containing pharmaceutical composition having excellent stability can be obtained by setting the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition containing anagliptin to 10 or less. The present invention has been completed.

That is, the main configuration of the present invention is as follows.
(1) A pharmaceutical composition containing anagliptin or a salt thereof and having an aqueous solution or aqueous dispersion having a pH value of 10 or less.
(2) The pharmaceutical composition according to (1), which contains a weakly acidic to weakly basic preparation additive.
(3) The pharmaceutical composition according to (1) or (2), wherein the content of anagliptin or a salt thereof is 1 to 90% by mass relative to the total mass of the pharmaceutical composition.
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the aqueous solution or aqueous dispersion has a pH value of 2 to 10.
(5) The pharmaceutical composition according to any one of (1) to (4), which is a solid preparation for oral administration.
(6) The pharmaceutical composition according to (5), wherein the solid preparation for oral administration is a tablet, capsule, granule, fine granule, or powder.

  According to the present invention, a pharmaceutical composition excellent in the 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 free.

  The content of anagliptin or a salt thereof in the pharmaceutical composition 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 50 to 400 mg in terms of anagliptin free form. In this invention, it is preferable to contain 1-90 mass% of anagliptin or its salt with respect to pharmaceutical composition total mass in conversion of the free form of anagliptin, and it is more preferable to contain 3-80 mass%. It is particularly preferable to contain 70% by mass.

  In the present invention, the “pH value of an aqueous solution or aqueous dispersion” of a pharmaceutical composition is a ratio of 100 ml of a pharmaceutical composition containing anagliptin or a salt thereof to 625 mg (converted to free form) of anagliptin in the composition. Means a value obtained by measuring the pH of an aqueous solution or aqueous dispersion obtained by dissolving and dispersing in an amount of water corresponding to In the present invention, from the viewpoint of the stability of anagliptin or a salt thereof, the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition needs to be 10 or less, but is within the range of 2 to 9.9. More preferably, it is more preferably within the range of 3 to 9.8, even more preferably within the range of 4.5 to 9.7, and particularly preferably within the range of 6 to 9.6. .

  In the present invention, the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition is weakly acidic to weakly basic as a formulation additive (specifically, the pH value when dissolved in water is about 6 to It can be adjusted by appropriately selecting and blending “a weakly acidic to weakly basic preparation additive”) that can exhibit a value within the range of 10. Specific examples of such weakly acidic to weakly basic preparation additives include fructose, xylitol, D-sorbitol, lactose, anhydrous lactose, powdered sugar, sucrose, purified sucrose, glucose hydrate, D- Sugars and sugar alcohols such as mannitol, erythritol, trehalose, maltitol; pregelatinized starch, partially pregelatinized starch, dextrin, corn starch, potato starch, hydroxypropyl starch, reduced maltose starch candy, wheat starch, rice starch, etc. And the like; celluloses such as hydroxypropylcellulose, powdered cellulose, crystalline cellulose, microcrystalline cellulose and the like.

  The content of such weakly acidic to weakly basic preparation additives is not particularly limited, and may be determined by appropriate examination according to the pH value of the pharmaceutical composition. It is preferable to contain -99 mass%, it is more preferable to contain 20-97 mass%, and it is especially preferable to contain 30-95 mass%. In the present invention, the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition can also be adjusted by selecting the content of anagliptin or a salt thereof in the pharmaceutical composition according to the pH value.

  In the present invention, the dosage form of the “pharmaceutical composition” is not particularly limited, and may be any of solid, semi-solid, and liquid forms, and is usually used as a medicine depending on the purpose of use and the like. The shape can be made. Since anagliptin is extremely soluble in water, its stability is greatly affected by the surrounding pH environment even in liquid, solid and semi-solid pharmaceutical compositions. As the dosage form of the pharmaceutical composition, specifically, for example, the dosage form described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations, specifically tablets (ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets) Tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules, fine granules, powders and other solid preparations for oral administration; oral solutions (elixirs, suspensions, emulsions, limonades, etc.); oral jelly preparations; Oral tablets (troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.); oral sprays; oral solids, etc., but from the viewpoint of ease of administration, etc. A formulation is preferred. These solid preparations for oral administration may be coated with a film, sugar coating or the like, if necessary.

  The pharmaceutical composition 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. Specifically, for example, when the pharmaceutical composition is a tablet, in addition to anagliptin or a salt thereof, an appropriate formulation additive as described below may be mixed 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 pharmaceutical composition of the present invention, in addition to the components such as the above-mentioned anagliptin and weakly acidic to weakly basic formulation additives, excipients, binders, fluidizing agents, corrigents, Appropriate formulation additives such as colorants can be used as appropriate.

  Since the pharmaceutical composition 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 pharmaceutical composition 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] Examination of stability of anagliptin under various pH conditions Anagliptin 625 mg was dissolved in 100 ml of Britton-Robinson buffer adjusted to pH 2, 3, 7, 10, 11 or 12 under the condition of 25 ° C. It was stored at 25 ° C. for 1 day, and the stability under various pH conditions was evaluated by quantifying anagliptin at the start of the test and after storage for 1 day.
The quantitative value (%) of anagliptin was calculated by comparing the peak area with a standard solution with a known concentration using HPLC.

The results are shown in Table 1. From the test results shown in Table 1, anagliptin is extremely stable in an environment of pH 10 or lower, but greatly destabilized when the pH exceeds 10, and the residual amount of anagliptin is about 10% after storage for 1 day under the condition of pH 12. The result was interrupted.
From the above test results, it is clear that a pharmaceutical composition having excellent stability of anagliptin or a salt thereof can be obtained by setting the pH of the aqueous solution or aqueous dispersion of the pharmaceutical composition containing anagliptin or a salt thereof to 10 or less. It became.

[Example 1]
A tablet containing 100 mg of anagliptin in one tablet was 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 product was sized after drying, and 15 parts by mass of crospovidone and 32 parts by mass of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) were added 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 150 mg per tablet to obtain tablets.

The obtained tablet was ground and an amount equivalent to 625 mg of anagliptin free body (937.5 mg) was dissolved in 100 ml of purified water at about 25 ° C., and its pH value was about 9.4.
The obtained tablets were placed in a plastic petri dish and subjected to a 21-day stability test at a temperature of 60 ° C. and a relative humidity of 75%. The degradation product amount of anagliptin was 1.58%, and the stability of anagliptin was good.

  ADVANTAGE OF THE INVENTION According to this invention, the pharmaceutical composition which contains 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 (6)

Containing Anaguripuchi emissions, pH value of the aqueous solution or dispersion is 9.4 or less, the pharmaceutical composition is a solid formulation for oral administration.   The pharmaceutical composition according to claim 1, comprising a weakly acidic to weakly basic preparation additive. Anaguripuchi content of emissions is, the pharmaceutical composition is the total mass to 1 to 90 wt%, according to claim 1 or 2 pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 3, wherein the aqueous solution or aqueous dispersion has a pH value of 2 to 9.4 . The pharmaceutical composition according to any one of claims 1 to 4, wherein the aqueous solution or aqueous dispersion has a pH value of 2 to 7. The pharmaceutical composition according to any one of claims 1 to 5 , wherein the solid preparation for oral administration is a tablet, capsule, granule, fine granule, or powder.