JP2018076372A - Anagliptin-containing solid formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a solid formulation containing anagliptin or a salt thereof, having excellent stability.SOLUTION: A solid formulation contains anagliptin or a salt thereof and has a moisture content of 3.4 mass% or less.SELECTED DRAWING: None

Description

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

  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, 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 However, for anagliptin, there are no specific known dosage forms / formulation techniques that can be marketed as pharmaceuticals.

  By the way, as a DPP-IV inhibitor, in addition to 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 on the market worldwide, including Japan.

  However, even if it is a DPP-IV inhibitor having the same effect, the formulation technique is completely different for different compounds. 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, the information regarding other DPP-IV inhibitors as described above is not helpful, and various studies are required in the preparation of anagliptin.

International Publication No. WO2004 / 067509 Pamphlet

The present inventor considered that a solid preparation having merits such as easy administration and administration of dosage is suitable as a dosage form of an anagliptin-containing preparation, and attempted to formulate anagliptin as a solid preparation. It was. However, it was revealed that anagliptin is unstable in a solid preparation and an anagliptin-derived degradation product is formed over time.
Then, this invention makes it a subject to provide the solid formulation containing an anagliptin or its salt which is excellent in stability.

  The present inventor has intensively studied to solve the above-mentioned problems, but anagliptin itself has a high stability against water, but the cause of destabilization in the solid preparation is water in the solid preparation, It has been found that if the water content of an anagliptin-containing solid preparation is kept below a certain value, the production of degradation products in the solid preparation can be suppressed even after long-term storage, and the present invention has been completed.

That is, the main configuration of the present invention is as follows.
(1) A solid preparation containing anagliptin or a salt thereof and having a water content of 3.4% by mass or less.
(2) The solid preparation according to (1), wherein the water content is 2.8% by mass or less.
(3) The solid preparation according to (1), wherein the water content is 2.5% by mass or less.
(4) The solid preparation according to any one of (1) to (3), comprising a hygroscopic disintegrant.
(5) Hygroscopic disintegrants from pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose potassium, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, crystalline cellulose, and partially pregelatinized starch The solid preparation according to (4), which is one or more selected from the group consisting of:
(6) The solid preparation according to any one of (1) to (5), which is produced through a step of wet granulating at least anagliptin or a salt thereof.
(7) The solid preparation according to any one of (1) to (6), wherein the solid preparation is a tablet.
(8) A pharmaceutical product comprising the solid preparation according to any one of (1) to (7) contained in an airtight package.
(9) The pharmaceutical product according to (8), wherein the hermetic package is at least one selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.

  According to the present invention, a solid preparation having excellent stability of anagliptin or a salt thereof 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. More preferably, it is contained by mass%.

  The solid preparation of the present invention needs to have a moisture content (the amount of free water in the solid preparation) of 3.4% by mass or less based on the total mass of the solid preparation in order to suppress the formation of anagliptin-derived degradation products. The amount is preferably 2.8% by mass or less, more preferably 2.5% by mass or less, and particularly preferably 2.0% by mass or less. In the region where the water content is 2.8% by mass or less, more preferably 2.5% by mass or less, and particularly preferably 2.0% by mass or less, an anagliptin-derived degradation product hardly occurs. However, if it exceeds 3.4% by mass, the production of anagliptin-derived degradation products increases, and especially if it exceeds 3.9%, the degradation products increase rapidly. Therefore, the boundary of 3.4% by mass is an important meaning. have.

  The water content of the solid preparation of the present invention is measured by a loss on drying test method. Specifically, in accordance with the 16th revision Japanese Pharmacopoeia, the loss on drying (mass of moisture in the specimen) of the specimen is measured, and the obtained moisture mass is compared to the specimen weight before drying. Calculated as a percentage (%). In addition, when the solid preparation contains a component having a low melting point or a component having bound water, the drying temperature condition during the test is an apparent increase in the water content value due to those components. In order to prevent this, it may be set by considering appropriately.

  One feature of the present invention is to suppress the formation of degradation products by adjusting the water content of the solid preparation. Here, examples of means for adjusting the water content of the solid preparation include a humidifying means and a drying means, and these means may be appropriately combined to adjust the water content according to the present invention.

Examples of the humidifying means include means using a hydrous solvent as a kneading liquid in wet granulation operation.
Examples of the drying means include a means using a drying apparatus and a means using a desiccant. Here, as a drying apparatus, what is usually used in the field of medicines and foods can be used. Specifically, for example, a box-type dryer, a fluidized bed dryer, a spray dryer, a freeze dryer, A vacuum dryer, a high frequency dryer, etc. are mentioned. Moreover, as a desiccant, what is normally used in the field | area of a pharmaceutical or foodstuff can be used, For example, a silica gel, a silica alumina gel (for example, allophane), a natural zeolite, a synthetic zeolite (for example, for example) Molecular sieves), quicklime (calcium oxide), bentonite clay (for example, montmorillonite), calcium chloride, magnesium chloride, magnesium oxide, and the like, and a mixture of these with activated carbon may be used. In the present invention, a method using a drying apparatus is preferable because of easy adjustment of the water content of the solid preparation.
The moisture content by these humidifying means and drying means may be adjusted during the production of the solid preparation (for example, before and after granulation operation) or after the production of the solid preparation. The adjustment of the water content by the drying means is preferably performed at least after the production of the solid preparation in order to accurately adjust the water content of the solid preparation.

The solid preparation of the present invention preferably contains a hygroscopic disintegrant in addition to anagliptin or a salt thereof.
Anagliptin or its salts are very soluble in water. In general, solid preparations containing highly soluble components, especially when the content is high, form a splint on the surface of the preparation and slow dissolution. It is known to be. 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 the active ingredient, it is desirable to incorporate a disintegrant that promotes the disintegration of the preparation. However, most of the disintegrants have hygroscopicity, which increases the moisture in the solid preparation and destabilizes anagliptin. Therefore, coexistence in a solid formulation of anagliptin or a salt thereof and a hygroscopic disintegrant has been difficult.
However, according to the present invention, it is possible to suppress the production of a degradation product derived from anagliptin or a salt thereof while blending such a hygroscopic disintegrant, so that the stability of anagliptin or a salt thereof is excellent, and the release thereof is It has a remarkable effect that a stable solid preparation can be obtained.

  The hygroscopic disintegrant that can be suitably blended in the present invention is not particularly limited as long as it is a hygroscopic component that can be used as a disintegrant in a solid preparation. Specific examples of hygroscopic disintegrants include pregelatinized starch, sodium carboxymethyl starch, carmellose, carmellose potassium, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, crystalline cellulose, and partial alpha. Examples thereof include modified starch. In addition, in this invention, these can be used individually or in combination of 2 or more types. Among these, in the present invention, crospovidone and crystalline cellulose are preferable, and crospovidone is particularly preferable from the viewpoint of disintegration of the solid preparation.

The content of the hygroscopic disintegrant that can be suitably blended 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 disintegration property of the solid preparation, it is preferable to contain the hygroscopic disintegrant in a total amount of 0.5 to 30% by mass, based on the total mass of the solid preparation, and 1 to 25% by mass It is more preferable to contain 3 to 20% by mass.
Further, the content ratio of the hygroscopic disintegrant that can be suitably blended in the solid preparation of the present invention with anagliptin or a salt thereof is not particularly limited, and may be determined by appropriate examination. In the present invention, from the viewpoint of disintegration of the solid preparation, 0.005 to 0.3 parts by mass of a hygroscopic disintegrant is contained in total with respect to 1 part by mass of anagliptin or a salt thereof (in terms of free form of anagliptin). It is preferable to contain 0.01 to 0.25 parts by mass, more preferably 0.01 to 0.1 parts by mass, and even more preferably 0.02 to 0.2 parts by mass. The content is preferably 0.03 to 0.2 parts by mass.

  The solid preparation of the present invention is also preferably produced through a step of granulating an anagliptin or a salt thereof by adding a binder or other various additives in some cases and wet granulating. In this case, when the solid preparation is a tablet, various additives are preferably added after granulation, and the mixed granulation / powder mixture is preferably compressed and formed into a tablet.

  As described above, the solid preparation of the present invention preferably contains a hygroscopic disintegrant and is produced through a process of wet granulation and granulation to increase the water content in the solid preparation. Therefore, it is extremely important to adjust the water content to 3.4% by mass or less. On the other hand, the solid preparation of the present invention is a preparation in which conflicting factors of adjusting the water content to a low level are made compatible with many factors that increase the water content in the preparation.

In the present invention, the solid preparation may contain additives usually used in the technical field depending on its specific form (dosage form). Examples of the additive include an excipient, a binder, a fluidizing agent, a corrigent, a coloring agent, and the like, and these can be used alone or in combination of two or more.
The excipient is not particularly limited, and specific examples include saccharides such as lactose hydrate, sucrose, and glucose; mannitol; anhydrous calcium hydrogen phosphate and the like.
The binder is not particularly limited, and specific examples include hydroxypropylcellulose, hypromellose, pullulan and the like.
The fluidizing agent is not particularly limited, and specific examples include calcium stearate, magnesium stearate, titanium oxide, sodium stearyl fumarate and the like.
The corrigent is not particularly limited, and specific examples include aspartame, saccharin, saccharin sodium hydrate, dl-menthol, and l-menthol.
Although a coloring agent is not specifically limited, For example, yellow iron sesquioxide, brown iron oxide, iron sesquioxide etc. are mentioned.
In addition, the usage-amount of each additive can be determined suitably.

In the present invention, the solid preparation can be formulated into various dosage forms according to known methods described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations and the like. The dosage form is not particularly limited as long as it is a solid preparation, and the dosage form described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations, specifically tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets) ), Capsules, pills, granules, fine granules, powders, etc. Oral solid preparations and oral tablets (troches, sublingual tablets, buccal tablets, adhesive tablets, gums) And the like, and the like.), Etc., but solid preparations for oral administration are preferred. In addition, these solid preparations may be coated with a film, a sugar coating, etc. as needed.
In the present invention, the dosage form of the solid preparation is preferably a tablet, capsule, pill, granule, fine granule or powder, more preferably a tablet, granule, fine granule or powder, and particularly preferably a tablet.

  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 may be mixed in addition to anagliptin or a salt thereof, and if necessary, a hygroscopic disintegrant, 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.

  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.

Moreover, this invention provides the pharmaceutical in which said solid formulation is accommodated in an airtight package. As a result of containing the solid preparation in an airtight package, the intrusion of moisture from outside the package is hindered. As a result, the moisture content of the solid preparation existing inside the package is stable over a long period of time even in a high humidity environment. As a result, the production of the degradation product derived from anagliptin in the solid preparation is suppressed over a long period of time.
The “pharmaceutical product” of the present invention contains 3.4% by mass or less, preferably 2.8% by mass or less, more preferably 2.5% by mass or less, particularly preferably 2% of the solid preparation inside the hermetic package. The water content may be 0.0 mass% or less. That is, immediately after taking out the solid preparation from the hermetic package, the water content may be within the above-described range. For example, the moisture content of the solid preparation deviates from the above-mentioned range before being contained in the hermetic package. Even if the moisture content of the solid preparation is within the above-mentioned range inside the hermetic package by means such as enclosing a desiccant, it is included in the “medicament” of the present invention.

  In the present invention, the term “airtight package” means a package capable of suppressing substantial intrusion of moisture from outside the package in a normal handling, transport or storage state, and the 16th revised Japanese Pharmacopoeia General Rules It is a concept including “airtight container” and “sealed container” defined in the above. As the package, any of regular and irregular shapes can be used. Specifically, for example, bottle packaging, SP (Stripe Package) packaging, PTP (Press Through Package) packaging, pillow packaging, stick packaging, and the like. Is mentioned. In the present invention, a combination of a plurality of these may be used. Specifically, for example, a solid preparation is first packaged in PTP packaging and further packaged in pillow packaging.

The packaging material (material) of the hermetic package is not particularly limited as long as it can suppress the change in the moisture content of the solid preparation that is the packaging content. In the field of pharmaceuticals and foods, moisture-proof contents that are sensitive to moisture, etc. A material used for the purpose can be appropriately used.
Examples of the material of the bottle body used for the bottle packaging include plastics such as polyester, polyethylene (including low density (LDPE) and high density (HDPE)), polycarbonate, polystyrene, and polypropylene; glass; metals such as aluminum, and the like. Can be mentioned. In addition, examples of the material of the stopper and the lid include the above-described plastic and metal. When packaging the bottle, for example, an appropriate quantity of the solid preparation of the present invention may be stored in a commercially available bottle and then sealed with an appropriate stopper or lid. In addition, what is necessary is just to select the thing of the magnitude | size according to the quantity of the solid formulation to store suitably, and as a capacity | capacitance of a bottle, it is about 10-500 mL, for example, 14-400 mL is preferable, and 24-350 mL is preferable. More preferred. Among the plastics, polyethylene and polypropylene are preferable as the material for the bottle packaging, low density polyethylene (LDPE) and high density polyethylene (HDPE) are more preferable, and high density polyethylene (HDPE) is particularly preferable.

  Examples of packaging materials used for SP packaging, PTP packaging, pillow packaging, stick packaging, and the like include biaxially oriented polypropylene (OPP), biaxially oriented polyester (PET), glucose-modified PET (PET-G), and biaxially. Stretched nylon (ONy, PA), cellophane, paper, low density polyethylene (LDPE), linear low density polyethylene (L-LDPE), ethylene-vinyl acetate copolymer (EVA), unstretched polypropylene (CPP, IPP) , Ionomer resin (IO), ethylene-methacrylic acid copolymer (EMAA), polyacrylonitrile (PAN), biaxially stretched polyvinylidene chloride (PVDC), ethylene-vinyl alcohol copolymer resin (EVOH), polyvinyl chloride (PVC) ), Cyclic polyolefin (COC), unstretched nylon (CNy) Resin such as polycarbonate (PC), polystyrene (PS), hard vinyl chloride (VSC), metal foil such as aluminum foil (AL), and the like. Good. As such a multilayer structure, for example, a laminate of PVC and PVDC (PVC / PVDC, hereinafter abbreviated as well), PVC / PVDC / PE / PVC, PVC / PVDC / PE / PVDC / PVC, CPP / COC / CPP, PVC / AL, CPP / AL, CPP / CPP / CPP, etc. are mentioned. Examples of a method for forming such a multilayer structure include known lamination methods such as extrusion lamination, dry lamination, coextrusion lamination, thermal lamination, wet lamination, non-solvent lamination, and heat lamination. As a packaging material used for SP packaging, PTP packaging, pillow packaging, stick packaging and the like, polyvinyl chloride and aluminum foil are preferable.

As a form of PTP packaging, the solid preparation of the present invention is stored one by one or one dosage unit in a pocket formed by a known method on a resin sheet or the like, and then a metal foil such as an aluminum foil is used as a constituent material. It is possible to use a sheet as a lid material and cover the sheet. In addition, it is good also as what is called double-sided aluminum PTP packaging using the sheet | seat which uses aluminum foil as a constituent material as a sheet | seat which forms a pocket. In the present invention, from the viewpoint of suppressing a change in the water content of the solid preparation, it is preferable that the PTP packaging is further packaged by pillow packaging (for example, aluminum pillow packaging).
Examples of forms of SP packaging, pillow packaging, and stick packaging include packaging of a solid preparation one by one or one dosage unit by using a sheet having a resin sheet or aluminum foil as a constituent material by a known method. In this invention, it is preferable to use the sheet | seat which uses aluminum foil from a viewpoint of suppressing the change of the moisture content of a solid formulation.

  In the pharmaceutical product of the present invention, the occupation ratio (volume ratio) of the solid preparation inside the package is usually 25 to 90%, preferably 28 to 75%, preferably 30 to 30% when the package is a bottle package. 50% is more preferable. When the package is SP packaging, PTP packaging, pillow packaging, or stick packaging, it is usually 30 to 98%, preferably 40 to 95%, more preferably 45 to 93%, and particularly preferably 50 to 90%. . In this case, the occupancy rate means the occupancy rate of the solid preparation relative to the volume inside the package, and the filling or inner plug etc. for preventing breakage of the solid preparation stored inside the package, It is not taken into consideration when calculating the space occupancy.

  In the present invention, a commercially available package may be used as it is as an airtight package, or a commercially available packaging material may be processed and used. Examples of such commercially available products include Z-series (manufactured by Hanshin Kasei Kogyo Co., Ltd.) as a package for bottle packaging. Also, as packaging materials for SP packaging, PTP packaging, pillow packaging and stick packaging, Sumilite VSS, Sumilite VSL, Sumilite NS, Sumilite FCL (above, manufactured by Sumitomo Bakelite Co., Ltd.), TAS series (manufactured by Taisei Kako Co., Ltd.), PTP Vinyl foil for use, super foil for PTP (manufactured by Mitsubishi Plastics Co., Ltd.), nippaku aluminum foil (manufactured by Nippon Foil Co., Ltd.), and silver foil plain silver (manufactured by Yamato Chemical Co., Ltd.).

  In the present invention, the method for accommodating the solid preparation in the hermetic package is not particularly limited, and can be achieved by placing the solid preparation in the package by an appropriate means such as charging the solid preparation into the package. . In this case, a means for putting a desiccant (for example, a cylindrical shape, a tablet shape, or a sheet shape) into the package together with the solid preparation may be used.

Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these.
[Test Example 1] Examination of stability of anagliptin in solid preparation <Production of anagliptin-containing tablet>
200 parts by mass of anagliptin was subjected to fluidized bed granulation using an aqueous solution of hydroxypropylcellulose (2 parts by mass as hydroxypropylcellulose). The obtained granular material was dried, and 30 parts by mass of crospovidone and 65 parts by mass of crystalline cellulose were added to the dried product and mixed. Next, 3 parts by mass of magnesium stearate was added and mixed to obtain granules for tableting. The obtained granules for tableting were tableted to give 300 mg per tablet to obtain a plain tablet.
For each obtained uncoated tablet, 15 mg of film coating was applied using a solution obtained by dissolving and dispersing 15 parts by mass of a coating base (Opadry: Colorcon) in water to produce an anagliptin-containing tablet.
Each anagliptin-containing tablet contains 200 mg of anagliptin.

<Examination of stability of anagliptin>
The moisture content of the anagliptin-containing tablet produced by the above-described method was adjusted to various moisture contents shown in Table 1 by coexisting with the desiccant for a certain period of time. The moisture content (%) in the tablet was measured according to the Japanese Pharmacopoeia 16th revision of the Japanese Pharmacopoeia, and after crushing the tablet into powder, weighed about 5 g to prepare a sample and heated to 105 ° C. The decrease in the mass (the mass of water in the specimen) was measured, and this was measured as a percentage (%) with respect to the mass of the specimen before heating. Thereafter, various tablets (10 tablets each) with adjusted water content were placed in brown glass bottles (2K standard bottles), sealed with metal lids, and packaged in bottles.

  The package thus obtained was stored for 1 month under a temperature condition of 60 ° C., and the amount of degradation product (%) derived from anagliptin in the tablet immediately before the start of storage and after storage for 1 month was evaluated. Further, a value obtained by subtracting the amount of degradation product immediately before the start of storage from the amount of degradation product after storage for 1 month was calculated as the degradation product increase amount (%). The degradation product amount (%) was determined by measuring anagliptin and all of its degradation products by HPLC, and dividing the peak area excluding the anagliptin peak area from the total peak area (the degradation product-derived peak area) by the total peak area. It was calculated by doing. The results are shown in Table 1.

<Test results>
From the test results shown in Table 1, it has been clarified that when the moisture content of the tablet is 3.4% by mass or less, the increase in the amount of decomposed product is remarkably suppressed. In particular, the moisture content of the tablet is 2. When the content was 8% by mass or less, the amount of degradation product did not substantially increase even after storage at 60 ° C. for 1 month, and it was revealed that the stability of anagliptin in the solid preparation was extremely good. On the other hand, when the moisture content of the tablet exceeds 3.4% by mass, the production of anagliptin-derived degradation products increases, and particularly when it exceeds 3.9% by mass, the degradation products increase rapidly, exceeding 1% after one month. It was found that a decomposition product was formed.

  From the above test results, solids containing anagliptin or a salt thereof and having a moisture content of 3.4% by mass or less, more preferably 2.8% by mass or less, and particularly preferably 2.5% by mass or less. In the preparation, it was revealed that the formation of degradation products was suppressed. In addition, it has also been clarified that the pharmaceutical product in which the solid preparation is accommodated in an airtight package can suppress the generation of degradation products over a long period of time as a result of stably maintaining the water content.

[Test Example 2]
The disintegrant that can be used in this preparation was examined. That is, the following anagliptin-containing tablets and tablets in which disintegrant crospovidone was replaced with another disintegrant were produced, and the dissolution characteristics were evaluated. The elution characteristics were evaluated by a UV flow method using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd .: dissolution test system) at 900 mL of water and a paddle rotation speed of 50 rpm.

<Manufacture of anagliptin-containing tablets>
100 parts by mass of anagliptin is granulated in an aqueous solution of 1.5 parts by mass of hydroxypropylcellulose using a fluidized bed granulator / dryer (Freund Sangyo Co., Ltd .: Flow coater FLO-5), dried, and adjusted. Particle size is adjusted with a granulator (Dalton Co., Ltd .: Power Mill P-04S), and 15 parts by mass of crospovidone and 30 parts by mass of crystalline cellulose are added to the granules and mixed, and then 1.5 parts by mass of magnesium stearate. Was added and further mixed. The obtained granules were tableted using a φ8 mm standard R punch with a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRG) at a tableting pressure of 10 kN / 杵 with a mass of 148 mg per tablet. The tablet contains 100 mg (almost 68%) of anagliptin in 148 mg of the tablet.
Tablets substituted with the disintegrant were produced in the same manner by replacing 15 parts by mass of crospovidone with 15 parts by mass of the disintegrant shown in Table 2, respectively. In addition, the following four disintegrants were used, and croscarmellose sodium, carmellose calcium, carmellose, and carboxymethyl starch sodium were used.

<Test results>
The test results are shown in Table 2. Thus, in the tablet containing anagliptin, the dissolution property of anagliptin could be ensured by using a disintegrant having high hygroscopicity. Among them, crospovidone showed the most excellent dissolution property of anagliptin.

  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 (7)

  A solid preparation containing anagliptin or a salt thereof and having a water content of 3.4% by mass or less.   The solid preparation according to claim 1, wherein the water content is 2.8% by mass or less.   The solid preparation according to claim 1, wherein the water content is 2.5% by mass or less.   Contains one or more hygroscopic disintegrants selected from the group consisting of alpha starch, carboxymethyl starch sodium, carmellose, carmellose potassium, carmellose calcium, carmellose sodium, croscarmellose sodium, and partially pregelatinized starch The solid preparation according to any one of claims 1 to 3.   The solid preparation according to any one of claims 1 to 4, wherein the solid preparation is a tablet.   A pharmaceutical product comprising the solid preparation according to any one of claims 1 to 5 contained in an airtight package.   The pharmaceutical product according to claim 6, wherein the airtight package is at least one selected from the group consisting of bottle packaging, SP packaging, PTP packaging, pillow packaging, and stick packaging.