JP6309895B2 - Anagliptin-containing preparation - Google Patents
Anagliptin-containing preparation Download PDFInfo
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- JP6309895B2 JP6309895B2 JP2014538613A JP2014538613A JP6309895B2 JP 6309895 B2 JP6309895 B2 JP 6309895B2 JP 2014538613 A JP2014538613 A JP 2014538613A JP 2014538613 A JP2014538613 A JP 2014538613A JP 6309895 B2 JP6309895 B2 JP 6309895B2
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- Prior art keywords
- mass
- anagliptin
- formulation
- salt
- compression
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
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Description
本発明は医薬品分野に属するもので、具体的には、ジペプチジルペプチダーゼIVの阻害剤であるアナグリプチン又はその塩を含有する製剤に関する。 The present invention belongs to the pharmaceutical field, and specifically relates to a preparation containing anagliptin which is an inhibitor of dipeptidyl peptidase IV or a salt thereof.
一般的に、医薬品の有効成分として有用な化合物をそのまま投与することは、服用性の観点、投与量の正確性の確保の観点等から困難であり、通常何らかの剤形に製剤化されて投与される。中でも、散剤、顆粒剤、錠剤等の固形製剤は、液剤等に比べて取扱い易い、投与量の管理が容易である等のメリットを有し、汎用されている剤形である。固形製剤は、医薬品として有効性及び安全性が求められることは言うまでもないが、併せて化学的安定性及び市場流通時における製剤の物理安定性も重要である。ところが、一般に、固形製剤の取り扱い性及び物理安定性を向上させると溶出は遅延する。特に溶解度の高い薬物を高含量にて配合すると、製剤表面にママコを形成し、溶出が著しく遅延する現象が認められることがある。これに対して、錠剤化された製剤において、医薬品として有効性を高めるためには、崩壊剤を使用して有効成分の溶出を高めるという手法が一般的である。 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. Needless to say, a solid preparation is required to have efficacy and safety as a pharmaceutical product, but chemical stability and physical stability of the preparation at the time of market distribution are also important. However, elution is generally delayed when the handleability and physical stability of a solid preparation are improved. In particular, when a high-solubility drug is blended at a high content, there may be a phenomenon in which elution is remarkably delayed due to the formation of mamako on the preparation surface. On the other hand, in order to increase the effectiveness as a pharmaceutical in a tableted preparation, a technique of increasing the dissolution of an active ingredient using a disintegrant is common.
アナグリプチンについては、これまで固形製剤はおろか医薬品として上市可能な剤形・製剤化技術は何ら具体的に知られていない。構造類似のジペプチジルペプチダーゼIV（ＤＰＰ−ＩＶ）阻害剤であるビルダグリプチンについては、微結晶セルロース、ラクトース、デンプングリコール酸ナトリウム、及びステアリン酸マグネシウムを含む錠剤が報告されている（特許文献１）。この文献では、水による有効成分の不安定化を解消するため、直接打錠を採用している。また、同じくＤＰＰ−ＩＶ阻害剤であるリナグリプチンについては、通常の賦形剤を使用した直接圧縮製剤又は造粒後に圧縮成型して製造した製剤が報告されている（特許文献２）。この文献では、含有成分についての制限がなく、製剤化における課題が明らかではない。 Regarding anagliptin, there has been no specific known dosage form / formulation technology that can be marketed as a pharmaceutical product as well as a solid preparation. Regarding vildagliptin, a structurally similar dipeptidyl peptidase IV (DPP-IV) inhibitor, tablets containing microcrystalline cellulose, lactose, sodium starch glycolate, and magnesium stearate have been reported (Patent Document 1). In this document, direct tableting is employed to eliminate the destabilization of the active ingredient due to water. Moreover, about the linagliptin which is a DPP-IV inhibitor similarly, the direct compression formulation using a normal excipient | filler or the formulation manufactured by compression molding after granulation is reported (patent document 2). In this document, there are no restrictions on the components contained, and the problems in formulation are not clear.
他にも、打錠障害を誘引しやすい医薬活性成分として、ＤＰＰ−ＩＶ阻害剤であるアログリプチンについて製剤化の報告がある（特許文献３）。打錠障害とは、スティッキング（杵に粉末が付着する現象）、バインディング（臼と錠剤の摩擦が大きくなる現象）、キャッピング（錠剤が帽子状に剥離する現象）、ラミネーティング（錠剤が層状に剥離する現象）が挙げられている。この文献では、医薬活性成分、マンニトール、及び結晶セルロース等を含む顆粒に更に結晶セルロース等の賦形剤を添加し、圧縮成型して錠剤化する手法が開示されている。 In addition, there is a report of formulation of alogliptin, which is a DPP-IV inhibitor, as a pharmaceutically active ingredient that easily induces a tableting disorder (Patent Document 3). Tableting obstacles are sticking (a phenomenon in which powder adheres to the heel), binding (a phenomenon in which friction between the die and the tablet increases), capping (a phenomenon in which the tablet peels into a cap shape), and laminating (a tablet peels in a layer) Phenomenon). This document discloses a technique of further adding an excipient such as crystalline cellulose to granules containing a pharmaceutically active ingredient, mannitol, crystalline cellulose and the like, and compressing and molding into tablets.
しかしながら、同効のＤＰＰ−ＩＶ阻害剤といえども、化合物が異なれば、適正な剤形とするための製剤化技術は全く異なる。特に、ＤＰＰ−ＩＶ阻害剤の化学構造は相互に大きく相違するためその物理的・化学的性質も互いに大きく相違することが予想される。有効成分が錠剤中において不安定化する要因は様々であり、逐一、その原因を追究して、不安定化要因を排除して製剤化しなければならないため、他の有効成分についての先行技術は、アナグリプチンを製剤化するためには、あまり参考にならない。従って、アナグリプチンの製剤化においては、様々な検討が要求される。 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. There are various factors that cause the active ingredient to become unstable in the tablet, and since it is necessary to investigate the cause and eliminate the destabilizing factor for formulation, the prior art for other active ingredients is: It is not very helpful to formulate anagliptin. Therefore, various studies are required in the preparation of anagliptin.
アナグリプチンは、その有効用量から考えて100mg錠が最も適した錠剤となるが、取扱性を考慮した大きさの錠剤とするためには、アナグリプチンを高含量で含む高含量製剤となってしまう。この場合、有効成分の溶出特性と錠剤の物理的安定性（錠剤硬度及び摩損度）と有効成分の化学的安定性（有効成分の分解特性）とを、いずれも良好なものとして共存させることは困難であった。そこで、本発明は、有効成分であるアナグリプチンの高い化学的安定性及び速い溶出特性、並びに錠剤の優れた物理的安定性を兼ね備えたアナグリプチン製剤を製造する技術の提供を目的とする。 For anagliptin, a 100 mg tablet is the most suitable tablet in view of its effective dose. However, in order to obtain a tablet having a size in consideration of handleability, it becomes a high-content preparation containing anagliptin in a high content. In this case, the coexistence of the elution characteristics of the active ingredient, the physical stability of the tablet (tablet hardness and friability), and the chemical stability of the active ingredient (decomposition characteristics of the active ingredient) are all good. It was difficult. Therefore, an object of the present invention is to provide a technique for producing an anagliptin preparation having both high chemical stability and fast dissolution characteristics of an active ingredient anagliptin and excellent physical stability of a tablet.
本発明者らの検討により、アナグリプチンが製剤中において水に対して不安定であることが判明したため、まずは、直接打錠する方法で製剤化を試みた。ところが、アナグリプチン高含量製剤では、粉体の流動性が悪く、直接打錠では、打錠することすらできなかった。そこで、流動化剤を添加して打錠し、錠剤化に成功したが、今度は、アナグリプチンの化学的安定性が悪いことが判明した。その原因を究明したところ、流動化剤が原因であることが判明した。そこで、流動化剤の使用を断念し、造粒してから打錠することにした。ここで、アナグリプチンが製剤中において水に対して不安定であるにもかかわらず、あえて湿式造粒を採用したところ、アナグリプチンの化学的安定性に問題のない製剤を製造することができた。また、添加剤に関しては、結晶セルロース及びクロスポビドンを配合することにより、高い物理安定性と速い溶出性とを兼ね備えた製剤が得られることを見出し、本発明を完成させた。尚、本発明は、アナグリプチンと個々の添加剤との組み合わせについても言及するものである。 As a result of studies by the present inventors, it has been found that anagliptin is unstable with respect to water in the preparation. Therefore, preparation of the preparation was first attempted by direct tableting. However, with an anagliptin high-content preparation, the fluidity of the powder is poor, and even with direct tableting, even tableting was not possible. Therefore, although the tableting was successful by adding a fluidizing agent, it was found that the chemical stability of anagliptin was poor this time. When the cause was investigated, it became clear that a fluidizing agent was the cause. Therefore, we gave up using the fluidizing agent and decided to tablet after granulating. Here, despite the fact that anagliptin is unstable to water in the preparation, when wet granulation was used, a preparation without problems with the chemical stability of anagliptin could be produced. As for the additive, the inventors have found that a preparation having both high physical stability and fast dissolution can be obtained by blending crystalline cellulose and crospovidone, and completed the present invention. In addition, this invention mentions also about the combination of an anagliptin and each additive.
即ち、本発明の主な構成は次のとおりである。
（１）有効成分としてアナグリプチン又はその塩、崩壊剤としてクロスポビドン、賦形剤として結晶セルロース、及び結合剤を含有し、流動化剤を含まず、前記有効成分及び前記含有成分の一部又は全部を前記結合剤にて湿式造粒した後に圧縮成型して製造される固形製剤。
（２）固形製剤の硬度が30Ｎ以上、固形製剤20錠を日本薬局方の錠剤の摩損度試験法記載のドラムを用いドラム回転数25rpmにて15分間試験し吸湿水分補正した後の摩損度が1%以下、及び、日本薬局方の溶出試験法による15分間の溶出率が85%以上を示す、（１）に記載の固形製剤。
（３）更に、温度60℃及び相対湿度75%の条件下で21日間の安定性試験の分解生成物量が3%以下を示す、（２）に記載の固形製剤。That is, the main configuration of the present invention is as follows.
(1) Anagliptin or a salt thereof as an active ingredient, crospovidone as a disintegrating agent, crystalline cellulose as an excipient, and a binder, without a fluidizing agent, and part or all of the active ingredient and the containing ingredient A solid preparation produced by compression molding after wet granulation with a binder.
(2) Hardness of solid preparation is 30N or more, 20 tablets of solid preparation were tested for 15 minutes at drum rotation speed of 25rpm using drum described in Japanese Pharmacopoeia tablet friability test method. The solid preparation according to (1), having a dissolution rate of 1% or less and a dissolution rate of 15 minutes according to the Japanese Pharmacopoeia dissolution test method of 85% or more.
(3) Further, the solid preparation according to (2), wherein the degradation product amount in the stability test for 21 days is 3% or less under conditions of a temperature of 60 ° C. and a relative humidity of 75%.
（４）前記結合剤が、ヒドロキシプロピルセルロース、ポビドン、ヒプロメロース、プルラン、及びデンプン糊からなる群から選択される１以上の結合剤である、（１）に記載の固形製剤。
（５）前記結合剤がヒドロキシプロピルセルロースである、（４）に記載の固形製剤。
（６）前記アナグリプチン又はその塩の含量が製剤全体の47質量%〜83質量%である、（１）に記載の固形製剤。
（７）前記アナグリプチン又はその塩の含量が製剤全体の55質量%〜75質量%である、（１）に記載の固形製剤。
（８）前記クロスポビドンの含量が製剤全体の7質量%〜35質量%である、（１）に記載の固形製剤。
（９）前記クロスポビドンの含量が製剤全体の8質量%〜25質量%である、（１）に記載の固形製剤。(4) The solid preparation according to (1), wherein the binder is one or more binders selected from the group consisting of hydroxypropylcellulose, povidone, hypromellose, pullulan, and starch paste.
(5) The solid preparation according to (4), wherein the binder is hydroxypropylcellulose.
(6) The solid preparation according to (1), wherein the content of the anagliptin or a salt thereof is 47% by mass to 83% by mass of the entire preparation.
(7) The solid preparation according to (1), wherein the content of the anagliptin or a salt thereof is 55% to 75% by weight of the whole preparation.
(8) The solid preparation according to (1), wherein the content of crospovidone is 7% to 35% by weight of the whole preparation.
(9) The solid preparation according to (1), wherein the content of crospovidone is 8% by mass to 25% by mass of the entire preparation.
（１０）前記結晶セルロースの含量が製剤全体の7質量%〜37質量%である、（１）に記載の固形製剤。
（１１）前記結晶セルロースの含量が製剤全体の15質量%〜30質量%である、（１）に記載の固形製剤。
（１２）前記結合剤の含量が製剤全体の0.1質量%〜5質量%である、（１）に記載の固形製剤。
（１３）更にフィルムコーティング層を有する、（１）に記載の固形製剤。
（１４）前記フィルムコーティング層に三二酸化鉄類を含有する、（１３）に記載の固形製剤。(10) The solid preparation according to (1), wherein the content of the crystalline cellulose is 7% to 37% by weight of the whole preparation.
(11) The solid preparation according to (1), wherein the content of the crystalline cellulose is 15% by mass to 30% by mass of the whole preparation.
(12) The solid preparation according to (1), wherein the content of the binder is 0.1% by mass to 5% by mass of the whole preparation.
(13) The solid preparation according to (1), further having a film coating layer.
(14) The solid preparation according to (13), wherein the film coating layer contains ferric oxide.
（１５）アナグリプチン又はその塩を含む粉体混合物を結合剤により造粒した後に圧縮成型して固形製剤を製造する方法であって、少なくともアナグリプチン又はその塩を、結合剤を含む溶液にて湿式造粒して得られた顆粒に、少なくとも、結晶セルロースとクロスポビドンとを添加混合し、得られた混合物を圧縮成型する工程、又は、少なくともアナグリプチン又はその塩と結晶セルロースとクロスポビドンとを混合して得られた混合物を、結合剤を含む溶液にて湿式造粒して得られた顆粒を圧縮成型する工程を含む、アナグリプチン又はその塩を含有する固形製剤の製造方法。
（１６）前記固形製剤のアナグリプチン又はその塩の含量が製剤全体の47質量%〜83質量%である、（１５）に記載の固形製剤の製造方法。
（１７）前記結合剤が、ヒドロキシプロピルセルロース、ポビドン、ヒプロメロース、プルラン、及びデンプン糊からなる群から選択される１以上の結合剤である、（１５）に記載の固形製剤の製造方法。(15) A method for producing a solid preparation by granulating a powder mixture containing anagliptin or a salt thereof with a binder and then compression-molding the mixture, and wet-making at least anagliptin or a salt thereof in a solution containing the binder. At least the crystalline cellulose and crospovidone are added and mixed to the granules obtained by granulation, and the step of compression molding the obtained mixture, or at least anagliptin or a salt thereof, crystalline cellulose and crospovidone are mixed. The manufacturing method of the solid formulation containing an anagliptin or its salt including the process of compression-molding the granule obtained by carrying out wet granulation of the obtained mixture in the solution containing a binder.
(16) The method for producing a solid preparation according to (15), wherein the content of anagliptin or a salt thereof in the solid preparation is 47% by mass to 83% by mass of the whole preparation.
(17) The method for producing a solid preparation according to (15), wherein the binder is one or more binders selected from the group consisting of hydroxypropylcellulose, povidone, hypromellose, pullulan, and starch paste.
（１８）アナグリプチン又はその塩、及び結晶セルロースを含有する固形製剤。
（１９）更に、クロスポビドンを含有する、（１８）に記載の固形製剤。
（２０）アナグリプチン又はその塩、及びクロスポビドンを含有する固形製剤。
（２１）アナグリプチン又はその塩、及び三二酸化鉄類を含有する固形製剤。
（２２）前記固形製剤が、錠剤、カプセル剤、顆粒剤、細粒剤、又は散剤である、（１８）〜（２１）のいずれかに記載の固形製剤。(18) A solid preparation containing anagliptin or a salt thereof and crystalline cellulose.
(19) The solid preparation according to (18), further comprising crospovidone.
(20) A solid preparation containing anagliptin or a salt thereof and crospovidone.
(21) A solid preparation containing anagliptin or a salt thereof and ferric oxides.
(22) The solid preparation according to any one of (18) to (21), wherein the solid preparation is a tablet, capsule, granule, fine granule, or powder.
本発明によれば、アナグリプチン又はその塩を有効成分として含有する製剤において、有効成分の優れた化学的安定性、有効成分の良好な溶出特性、及び／又は製剤の優れた物理安定性を得ることができ、特にアナグリプチン又はその塩の高含量製剤においても、それらの効果を十分に得ることができるので、アナグリプチン又はその塩を含有する製剤の医薬品としての高い品質を確保することができる。 According to the present invention, in a preparation containing anagliptin or a salt thereof as an active ingredient, excellent chemical stability of the active ingredient, good dissolution characteristics of the active ingredient, and / or excellent physical stability of the preparation are obtained. In particular, even in a high-content preparation of anagliptin or a salt thereof, those effects can be sufficiently obtained, so that high quality as a pharmaceutical product of a preparation containing anagliptin or a salt thereof can be ensured.
以下、本発明のアナグリプチン製剤（以下、「本製剤」という）及びその製造法について詳述する。アナグリプチンは、WO2004/067509の実施例2の化合物であり、同WO2004/067509の実施例1の製造方法を参考に合成することができる。本発明において、「アナグリプチン又はその塩」には、アナグリプチンそのもののほか、アナグリプチンの薬学上許容される塩、更には、アナグリプチンやその薬学上許容される塩と、水やアルコール等との溶媒和物も含まれる。薬学上許容される塩としては、例えば、無機酸との塩、有機酸との塩、塩基性又は酸性アミノ酸との塩等が挙げられる。無機酸との塩の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。また、有機酸との塩の好適な例としては、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、安息香酸、トルエンスルホン酸等との塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、アルギニン等との塩が挙げられる。酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸等との塩が挙げられる。本発明において、アナグリプチン又はその塩としては、フリー体のものが好ましい。 Hereinafter, the anagliptin preparation of the present invention (hereinafter referred to as “the preparation”) and the production method thereof will be described in detail. Anagliptin is the compound of Example 2 of WO2004 / 067509 and can be synthesized with reference to the production method of Example 1 of WO2004 / 067509. 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. Is also 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.
本製剤におけるアナグリプチンの含有量は、特に限定されるものではないが、製剤を服用しやすい大きさとし、かつ、期待する溶出特性及び製剤の物理安定性（硬度及び摩損性）を確保する観点から、好ましくは製剤全体の47質量%〜83質量%であり、更に好ましくは55質量%〜75質量%である。 The content of anagliptin in this preparation is not particularly limited, but from the viewpoint of ensuring that the preparation is easy to take, and ensuring the expected dissolution characteristics and physical stability (hardness and friability) of the preparation. Preferably it is 47 mass%-83 mass% of the whole preparation, More preferably, it is 55 mass%-75 mass%.
本製剤においては、通常、崩壊剤としてクロスポビドンが使用される。クロスポビドンの含有量は、特に限定されないが、期待する溶出特性を確保し、かつ、製剤を服用しやすい大きさとする観点から、好ましくは製剤全体の7質量%〜35質量%であり、より好ましくは8質量%〜25質量%である。尚、クロスポビドンは、１−ビニル−２−ピロリドンの架橋重合物であり、本発明においては、分子量等の異なるいずれのクロスポビドンを用いてもよく、これらを単独で又は２種以上を組み合わせて用いてもよい。勿論、クロスポビドンとしては市販品を用いてもよく、具体的には例えば、コリドンＣＬ、コリドンＣＬ−Ｆ、コリドンＣＬ−Ｍ、コリドンＣＬ−ＳＦ（以上、ＢＡＳＦ社製）、ポリプラスドンＸＬ、ポリプラスドンＸＬ−１０、ポリプラスドンＩＮＦ−１０（以上、アイエスピー・ジャパン社製）等が挙げられる。また、本製剤においては、更に他の崩壊剤等を組み合わせて用いることもできる。このような、他の崩壊剤としては、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、カルボキシメチルスターチナトリウム、クロスカルメロースナトリウム、クロスポビドン、部分アルファー化デンプン等が挙げられる。 In this preparation, crospovidone is usually used as a disintegrant. The content of crospovidone is not particularly limited, but it is preferably 7% by mass to 35% by mass of the entire formulation, more preferably, from the viewpoint of ensuring the expected dissolution characteristics and making the formulation easy to take. Is 8% by mass to 25% by mass. Crospovidone is a crosslinked polymer of 1-vinyl-2-pyrrolidone, and in the present invention, any crospovidone having a different molecular weight or the like may be used, and these may be used alone or in combination of two or more. It may be used. Of course, a commercially available product may be used as crospovidone. Specifically, for example, Kollidon CL, Kollidon CL-F, Kollidon CL-M, Kollidon CL-SF (above, manufactured by BASF), polyplastidone XL, Polyplaston XL-10, Polyplastidone INF-10 (above, manufactured by IPS Japan Co., Ltd.) and the like can be mentioned. Further, in the present preparation, other disintegrants and the like can be used in combination. Examples of such other disintegrants include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, and partially pregelatinized starch.
本製剤においては、通常、湿式造粒をするために結合剤が使用される。結合剤としては、ヒドロキシプロピルセルロース、ポビドン、ヒプロメロース、プルラン、及びデンプン糊等が挙げられる。これらは、単独で又は二つ以上を合わせて使用してもよい。これらの結合剤の中でも、ヒドロキシプロピルセルロース、ポビドン、及びヒプロメロースが好ましいものとして挙げられる。結合剤の含有量は、特に限定されないが、打錠障害を回避し、かつ、期待する溶出特性を確保する観点から、好ましくは製剤全体の0.1質量%〜5質量%であり、より好ましくは0.3質量%〜3質量%、更に好ましくは0.5質量%〜2質量%である。 In this preparation, a binder is usually used for wet granulation. Examples of the binder include hydroxypropyl cellulose, povidone, hypromellose, pullulan, and starch paste. These may be used alone or in combination of two or more. Among these binders, hydroxypropylcellulose, povidone, and hypromellose are preferable. The content of the binder is not particularly limited, but is preferably 0.1% to 5% by mass, more preferably 0.3%, more preferably 0.3% by mass from the viewpoint of avoiding tableting troubles and ensuring the expected dissolution characteristics. The content is from 3% by mass to 3% by mass, and more preferably from 0.5% by mass to 2% by mass.
本製剤においては、通常、賦形剤として結晶セルロースを使用する。その含有量は、特に限定されないが、期待する物理安定性（硬度及び摩損性）を確保し、かつ、期待する溶出特性を確保する観点から、好ましくは製剤全体の7質量%〜37質量%であり、より好ましくは10質量%〜35質量%、更に好ましくは15質量%〜30質量%である。使用する結晶セルロースの性状等は特に限定されず、粉末状のものでも、微粒子状のもの（結晶セルロース（微粒子））でも、造粒したもの（結晶セルロース（粒））でもよく、これらを単独で、または２種以上を組み合わせて使用することもできる。また、結晶セルロースとしては、市販のものを用いることができ、具体的には、セオラスＫＧ−８０２、ＰＨ−１０１、ＰＨ−１０２、ＰＨ−３０１、ＰＨ−３０２、ＰＨ−Ｆ２０ＪＰ、ＲＣ、アビセルＦＤ−１０１、ＦＤ−３０１、ＦＤ−Ｆ２０、セルフィアＳＣＰ、ＣＰ（以上、旭化成ケミカルズ）、結晶セルロース（五協産業）、セオラス（三栄原エフ・エフ・アイ）等が挙げられる。 In this preparation, usually, crystalline cellulose is used as an excipient. The content is not particularly limited, but from the viewpoint of ensuring the expected physical stability (hardness and friability) and ensuring the expected dissolution characteristics, it is preferably 7 mass% to 37 mass% of the entire preparation. More preferably, it is 10 mass%-35 mass%, More preferably, it is 15 mass%-30 mass%. The properties of the crystalline cellulose to be used are not particularly limited, and it may be powdery, finely divided (crystalline cellulose (fine particles)), or granulated (crystalline cellulose (grains)), and these may be used alone. , Or a combination of two or more. Further, as the crystalline cellulose, commercially available ones can be used, and specifically, Theolas KG-802, PH-101, PH-102, PH-301, PH-302, PH-F20JP, RC, Avicel FD -101, FD-301, FD-F20, SELPHY SCP, CP (Asahi Kasei Chemicals), crystalline cellulose (Gokyo Sangyo), Theolas (Saneihara FFI) and the like.
本製剤においては、前記成分以外に、医薬品添加剤として一般的に使用され得る添加剤を配合してもよい。例えば、本製剤の質量を調整するための賦形剤や、打錠時の打錠障害改善のための滑沢剤を配合してもよい。賦形剤としては、例えば、乳糖水和物、D-マンニトール、トウモロコシデンプン、及び無水リン酸水素カルシウム等が、滑沢剤としては、例えば、ステアリン酸マグネシウム、タルク、ステアリン酸、ステアリン酸カルシウム、及びフマル酸ステアリルナトリウム等が挙げられる。これらの賦形剤等は、単独であるいは二つ以上を混合して使用してもよい。 In this preparation, in addition to the above components, additives that can be generally used as pharmaceutical additives may be blended. For example, you may mix | blend the excipient | filler for adjusting the mass of this formulation, and the lubricant for the tableting trouble improvement at the time of tableting. Examples of the excipient include lactose hydrate, D-mannitol, corn starch, and anhydrous calcium hydrogen phosphate, and examples of the lubricant include magnesium stearate, talc, stearic acid, calcium stearate, and Examples include sodium stearyl fumarate. These excipients may be used alone or in admixture of two or more.
他にも、本製剤は、着色剤として三二酸化鉄類を配合してもよい。三二酸化鉄類としては、三二酸化鉄を含む成分であればよく、例えば、黄色三二酸化鉄、褐色酸化鉄、及び三二酸化鉄等が挙げられ、中でも、黄色三二酸化鉄、三二酸化鉄が好ましい。これらは公知の化合物であり、公知の方法で製造することができるほか、市販のものを用いることができる。本製剤中における三二酸化鉄類の含有量は、特に限定されないが、製剤全体の0.005〜0.5質量%が好ましく、0.01〜0.1質量%がより好ましい。三二酸化鉄類は、圧縮成型物中ではなく、後述のフィルムコーティング層や糖衣層に存在させてもよい。 In addition, the present preparation may contain iron sesquioxide as a colorant. The iron sesquioxides may be any component containing iron sesquioxide, and examples thereof include yellow iron sesquioxide, brown iron oxide, and iron sesquioxide, among which yellow iron sesquioxide and iron sesquioxide are preferable. . These are known compounds, which can be produced by known methods, and commercially available products can be used. The content of ferric sesquioxide in the preparation is not particularly limited, but is preferably 0.005 to 0.5 mass%, more preferably 0.01 to 0.1 mass% of the entire preparation. The iron sesquioxides may be present not in the compression molded product but in the film coating layer or sugar coating layer described later.
本製剤においては、フィルムコーティング層又は糖衣層を設けることができる。フィルムコーティング層は、医薬品添加剤として使用される添加剤の組合せからなり、例えば、ヒプロメロース、マクロゴール、及び酸化チタン等から構成される。これらフィルムコーティング層又は糖衣層には、前述のような着色剤等を添加し、着色してもよい。更に、商品価値を高めるために光沢化剤を添加してもよい。 In this preparation, a film coating layer or a sugar coating layer can be provided. A film coating layer consists of the combination of the additive used as a pharmaceutical additive, for example, is comprised from a hypromellose, a macrogol, a titanium oxide, etc. The film coating layer or sugar coating layer may be colored by adding a colorant as described above. Further, a brightener may be added to increase the commercial value.
本発明においては、ロードセル式硬度計で測定した錠剤の硬度は少なくとも30Ｎ以上であれば、物理安定性が良好と言える。錠剤の硬度は、好ましくは40Ｎ以上である。加えて、錠剤の摩損度は1%未満であるのが好ましい。摩損度が1%未満である場合は、物理安定性が良好と言える。本発明において、摩損度とは、日本薬局方錠剤の摩損度試験法記載の摩損度試験器（ドラム）を用い、錠剤20錠の質量を測定し、ドラムに入れ、回転数25rpmにて15分間回転させた後、錠剤を取り出し、質量を測定する。別に錠剤20錠を対照としておき、その試験前後の質量より吸湿水分補正した後の摩損度である。 In the present invention, it can be said that the physical stability is good if the hardness of the tablet measured with a load cell hardness tester is at least 30 N or more. The tablet hardness is preferably 40 N or more. In addition, the friability of the tablet is preferably less than 1%. When the friability is less than 1%, it can be said that the physical stability is good. In the present invention, the friability means the mass of 20 tablets measured using a friability tester (drum) described in the Japanese Pharmacopoeia tablet friability test method, put in a drum, and rotated at 25 rpm for 15 minutes. After rotation, the tablet is taken out and the mass is measured. Separately, 20 tablets were used as controls, and the friability after correcting moisture absorption from the mass before and after the test.
本発明において、溶出特性評価は、第十六改正日本薬局方の中の「一般試験法」分類の「製剤試験法」分類の「溶出試験法」分類の「パドル法」において、水を試験液とし、パドル回転数50rpmにて、錠剤中の有効成分の溶出率を測定する。本製剤においては、前記試験方法による15分間の有効成分の溶出率は85%以上であるのが好ましい。溶出率がそれに満たないものは、アナグリプチンの錠剤からの溶出が悪いため、有効性の問題を生じる可能性がある。 In the present invention, the dissolution property evaluation is performed in the “paddle method” of the “dissolution test method” category of the “formulation test method” category of the “general test method” category in the 16th revised Japanese pharmacopoeia. And the dissolution rate of the active ingredient in the tablet is measured at a paddle rotation speed of 50 rpm. In this preparation, the dissolution rate of the active ingredient for 15 minutes according to the test method is preferably 85% or more. If the dissolution rate is less than that, the dissolution of anagliptin from the tablet is poor, which may cause efficacy problems.
本発明において、アナグリプチンの化学的安定性評価、すなわち安定性試験は、次のように行われる。製剤を温度60℃、相対湿度75%の環境下において、開放21日間の苛酷試験を実施する。アナグリプチン及びその分解生成物量を液体クロマトグラフィーで測定し、全ピーク面積値（アナグリプチン及びその分解生成物の総量に相当する）及びアナグリプチンのピーク面積値（アナグリプチンの総量に相当する）を求め、アナグリプチン以外のピーク面積値合計（アナグリプチンの分解生成物量に相当する）の全ピーク面積値に対する割合を計算する。その割合がアナグリプチンの分解生成物量の割合（%）であり、本製剤においては、当該数値が3%以下であることが好ましい。 In the present invention, the chemical stability evaluation of anagliptin, that is, the stability test is performed as follows. The formulation is subjected to an open 21-day severe test in an environment of a temperature of 60 ° C. and a relative humidity of 75%. Measure the amount of anagliptin and its degradation products by liquid chromatography and determine the total peak area value (corresponding to the total amount of anagliptin and its degradation products) and the peak area value of anagliptin (corresponding to the total amount of anagliptin). The ratio of the total peak area value (corresponding to the amount of degradation products of anagliptin) to the total peak area value is calculated. The ratio is the ratio (%) of the degradation product amount of anagliptin, and in this preparation, the value is preferably 3% or less.
本発明において「固形製剤」とは、特に圧縮成型して製造した錠剤に限定した記載のある場合を除き、カプセル剤、顆粒剤、細粒剤、散剤等の固形製剤を意味する場合もある。それぞれの形態の固形製剤は、技術常識に従って様々な方法で製造することができるが、中でも、本発明の主たる部分をなす圧縮成型して製造される錠剤は、少なくともアナグリプチンを含む粉体混合物を結合剤により湿式造粒してできた顆粒に、必要に応じて残りの成分を追加して、圧縮成型して製造することができる。例えば、アナグリプチンを、結合剤を含む溶液にて湿式造粒して得られた顆粒に、少なくとも、結晶セルロース及びクロスポビドン等を添加混合し、得られた混合物を圧縮成型することにより製造することができる。また、少なくともアナグリプチンと結晶セルロースとクロスポビドンとを混合して得られた混合物を、結合剤を含む溶液にて湿式造粒して得られた顆粒を圧縮成型することにより製造することもできる。尚、ここで、滑沢剤等は必要に応じて添加する。また、アナグリプチンはその全部を湿式造粒するのが好ましい。 In the present invention, the “solid preparation” may mean a solid preparation such as a capsule, a granule, a fine granule, a powder, and the like, except where there is a description limited to tablets produced by compression molding. Each form of solid preparation can be produced by various methods according to common general technical knowledge. Among them, tablets produced by compression molding, which constitutes the main part of the present invention, are combined with a powder mixture containing at least anagliptin. The remaining components can be added to the granules formed by wet granulation with an agent, if necessary, and compression-molded. For example, anagliptin can be produced by adding and mixing at least crystalline cellulose and crospovidone to granules obtained by wet granulation with a solution containing a binder, and compression-molding the resulting mixture. it can. It can also be produced by compression molding granules obtained by wet granulating a mixture obtained by mixing at least anagliptin, crystalline cellulose and crospovidone with a solution containing a binder. Here, a lubricant or the like is added as necessary. Moreover, it is preferable that the whole anagliptin is wet-granulated.
尚、前記湿式造粒法により錠剤を製造する場合、造粒により製造した造粒顆粒のサイズが小さいと、良好な錠剤硬度・摩損度が得られる反面、溶出が遅くなる傾向があり、逆に造粒顆粒のサイズが大きいと、速やかな溶出が得られる反面、硬度・摩損度で示される物理的安定性が悪くなる傾向がある。そのため、本発明においては、150〜1000μmくらいのサイズ（篩分けによる）を有する造粒顆粒の占める割合を多くすることで、所望の特性を有する本錠剤を容易に得ることができる。 In addition, when producing tablets by the wet granulation method, if the granulated granules produced by granulation are small in size, good tablet hardness and friability can be obtained, but elution tends to be slow, conversely When the granulated granule size is large, rapid elution can be obtained, but physical stability indicated by hardness and friability tends to deteriorate. Therefore, in this invention, this tablet which has a desired characteristic can be obtained easily by increasing the ratio for which the granulated granule which has a size (by sieving) about 150-1000 micrometers is occupied.
以下、実施例、比較例及び実験例を挙げて本発明を詳細に説明するが、これらは本発明をなんら制限するものではない。尚、以下の実験例における実施例及び比較例の表記は、現在の課題を解決するための手段に記載された（１）の発明に対するものであるため、他の発明に対しては、比較例が実施例となる、又はその逆になる場合がある。実験例における基本的な測定方法は、次の４つの方法による。また、いずれの実験においても、有効成分であるアナグリプチンは、積水メディカル(株)製のものを使用した。 EXAMPLES Hereinafter, although an Example, a comparative example, and an experiment example are given and this invention is demonstrated in detail, these do not restrict | limit this invention at all. In addition, since the description of the Example and the comparative example in the following experiment examples is for the invention of (1) described in the means for solving the present problem, it is a comparative example for other inventions. May be an example or vice versa. The basic measurement method in the experimental example is based on the following four methods. In all experiments, the active ingredient anagliptin was manufactured by Sekisui Medical Co., Ltd.
１，化学的安定性評価
アナグリプチン及びその全ての分解生成物をHPLCにて測定し、全ピーク面積からアナグリプチンのピーク面積を除いたピーク面積を全ピーク面積で除して分解生成物量（%）を算出した。これにより、有効成分であるアナグリプチンの化学的安定性の評価を行った。
２，物理的安定性評価：硬度測定方法
錠剤硬度計（岡田精工(株)製：ポータブルチェッカー PC-30）にて測定した。
３，物理的安定性評価：摩損度測定方法
日本薬局方錠剤の摩損度試験法記載の摩損度試験器（ドラム）を用い、錠剤20錠の質量を測定し、ドラムに入れ、回転数25rpmにて15分間回転させた後、錠剤を取り出し、質量を測定する。別に錠剤20錠を対照としておき、その試験前後の質量より吸湿水分補正して摩損度を算出した。
４，溶出特性評価方法
溶出試験機（富山産業(株)製：溶出試験システム）を用い、水900mL及びパドル回転数50rpmにて、UVフロー法で測定した。1. Chemical stability evaluation Anagliptin and all its degradation products were measured by HPLC, and the peak area obtained by removing the peak area of anagliptin from the total peak area was divided by the total peak area to obtain the amount of degradation product (%). Calculated. Thereby, the chemical stability of an anagliptin which is an active ingredient was evaluated.
2, Physical stability evaluation: Hardness measuring method It measured with the tablet hardness meter (Okada Seiko Co., Ltd. product: portable checker PC-30).
3. Physical stability evaluation: friability measurement method Using the friability tester (drum) described in the Japanese Pharmacopoeia tablet friability test method, measure the mass of 20 tablets, put in a drum, and rotate at 25 rpm. Rotate for 15 minutes, remove the tablets and measure the mass. Separately, 20 tablets were used as controls, and the friability was calculated by correcting moisture absorption from the mass before and after the test.
4. Elution characteristic evaluation method Using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd .: dissolution test system), measurement was performed by the UV flow method at 900 mL of water and a paddle rotation speed of 50 rpm.
＜実験１＞
アナグリプチンの分解に及ぼす水分量の影響を評価した。ここでは、結晶セルロース（旭化成ケミカルズ(株)製：セオラスPH-302）を様々な温度（70〜105℃）で乾燥し、含有水分量の異なる結晶セルロースサンプルを作成し、それぞれの結晶セルロースサンプルに、アナグリプチンの配合比が5%となるようにアナグリプチンをビニール袋混合した後、速やかにガラス瓶に充填（30mL瓶に約13g）し密閉した。このような試験検体について、60、70、及び80℃にて7、14、及び21日の安定性試験を行い、安定性試験前後の分解生成物量（%）を測定した。尚、安定性試験前の各試験検体の水分量%を表１に示した。<Experiment 1>
The effect of water content on the degradation of anagliptin was evaluated. Here, crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas PH-302) is dried at various temperatures (70 to 105 ° C.) to prepare crystalline cellulose samples with different water contents. The anagliptin was mixed in a plastic bag so that the blending ratio of anagliptin was 5%, and then quickly filled into a glass bottle (about 13 g in a 30 mL bottle) and sealed. Such test specimens were subjected to stability tests at 60, 70, and 80 ° C. for 7, 14, and 21 days, and the amount of degradation products (%) before and after the stability test was measured. The moisture content% of each test specimen before the stability test is shown in Table 1.
安定性試験前後の分解生成物量（%）を表２に示した。このように、保存温度が高いほど、また、水分の多い検体ほど、分解生成物の増加が著しく、アナグリプチンが水分の影響により不安定化することが確認された。この結果からは、アナグリプチンを製剤化するにあたって、直接打錠法を選択することになり、湿式造粒という選択は通常では考えられないことになる。 Table 2 shows the amount (%) of decomposition products before and after the stability test. Thus, it was confirmed that the higher the storage temperature and the higher the moisture content, the more the degradation products increased and the anagliptin was destabilized by the influence of moisture. From this result, in formulating anagliptin, the direct compression method is selected, and the selection of wet granulation is not normally considered.
＜実験２＞
アナグリプチンの直接打錠の可否について評価した。表３（試験検体1〜5）に示す割合（質量比）にて、アナグリプチン、クロスポビドン（BASF社製：コリドンCL）、及び結晶セルロース（旭化成ケミカルズ(株)製：セオラスPH-302）をビニール袋混合し、次いでステアリン酸マグネシウム（太平化学工業(株)製：ステアリン酸マグネシウム植物性）を添加し、ビニール袋混合した。得られた混合粉体を、φ8mm標準R杵を用い、ロータリー打錠機（(株)菊水製作所製：VIRG）にて打錠圧10kN/杵で1錠質量160mgとして打錠し、錠剤を製造した。<Experiment 2>
The possibility of direct tableting of anagliptin was evaluated. Anagliptin, crospovidone (BASF Co., Ltd .: Kollidon CL), and crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas PH-302) were used in the proportions (mass ratio) shown in Table 3 (test samples 1-5). After bag mixing, magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd .: magnesium stearate vegetable) was added and mixed in a plastic bag. The obtained mixed powder was tableted using a φ8mm standard R 杵 with a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRG) at a tableting pressure of 10 kN / 杵 to give a tablet weight of 160 mg to produce tablets. did.
結果は表３に示す。このように、アナグリプチンが高含量配合されている場合は、混合粉体の流動性不良により、表３の打錠の可否に示す通り打錠できず、アナグリプチン含量45%質量以下で打錠可能であった。アナグリプチン含量がそれより多い錠剤を製造するには、流動化剤を添加するか、又は造粒する必要があることが判明した。 The results are shown in Table 3. Thus, when anagliptin is blended in a high content, tableting cannot be performed as shown in Table 3 for possible tableting due to poor flowability of the mixed powder, and tableting is possible with an anagliptin content of 45% by mass or less. there were. It has been found that to produce tablets with higher anagliptin content it is necessary to add a fluidizing agent or granulate.
＜実験３＞
流動化剤を添加して直接打錠したアナグリプチン高含量の錠剤及び、湿式造粒して打錠したアナグリプチン高含量の錠剤について、アナグリプチンの化学的安定性を評価した。すなわち、以下の比較例1〜4及び実施例1〜4の錠剤をプラスチックシャーレに入れ、温度60℃、相対湿度75%にて、21日間の安定性試験を実施した。<Experiment 3>
The chemical stability of anagliptin was evaluated for the anagliptin-rich tablets directly compressed by adding a fluidizing agent and the anagliptin-rich tablets tableted by wet granulation. That is, the tablets of the following Comparative Examples 1 to 4 and Examples 1 to 4 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%.
[比較例1〜4]
表４に示す割合で、アナグリプチン、クロスポビドン（BASF社製：コリドンCL）、結晶セルロース（旭化成ケミカルズ(株)製：セオラスPH-302）、及び流動化剤である軽質無水ケイ酸（フロイント産業(株)製：アドソリダー101）又は含水二酸化ケイ素（フロイント産業(株)製：アドソリダー102）をビニール袋混合し、ついでステアリン酸マグネシウム（太平化学工業(株)製：ステアリン酸マグネシウム植物性）を添加し、ビニール袋混合した。得られた混合粉体を、φ8mm標準R杵を用い、ロータリー打錠機にて打錠圧10kN/杵で打錠した。これらの錠剤は、錠剤中、アナグリプチンを100mg（66〜68質量%）含有する。[Comparative Examples 1 to 4]
In the proportions shown in Table 4, anagliptin, crospovidone (BASF: Kollidon CL), crystalline cellulose (Asahi Kasei Chemicals: Theolas PH-302), and light anhydrous silicic acid (Freund Sangyo ( Co., Ltd .: Adsolider 101) or hydrous silicon dioxide (Freund Sangyo Co., Ltd .: AdSolider 102) is mixed in a plastic bag, and then magnesium stearate (Taihei Chemical Industry Co., Ltd .: Magnesium stearate vegetable) is added. Mixed plastic bags. The obtained mixed powder was tableted with a tableting pressure of 10 kN / 杵 using a rotary tableting machine using a φ8 mm standard R 杵. These tablets contain 100 mg (66-68% by mass) of anagliptin in the tablet.
[実施例1]
アナグリプチン100質量部をヒドロキシプロピルセルロース（日本曹達(株)製：HPC-L）1.5質量部の水溶液にて、流動層造粒乾燥機（フロイント産業(株)製：フローコーター FLO-5）を用い流動層造粒し、乾燥後、整粒機（ダルトン(株)製：パワーミル P-04S）にて整粒し、当該顆粒にクロスポビドン（BASF社製：コリドンCL）15質量部及び結晶セルロース（旭化成ケミカルズ(株)製：セオラスKG-802）30質量部を添加してビニール袋混合し、ついでステアリン酸マグネシウム（太平化学工業(株)製：ステアリン酸マグネシウム植物性）1.5質量部を添加し、更にビニール袋混合した。得られた顆粒を、φ8mm標準R杵を用い、ロータリー打錠機（(株)菊水製作所製：VIRG）にて打錠圧10kN/杵で1錠質量148mgとして打錠した。当該錠剤は、錠剤148mg中、アナグリプチンを100mg（ほぼ68%）含有する。[Example 1]
Using 100 parts by mass of anagliptin in an aqueous solution of 1.5 parts by mass of hydroxypropylcellulose (Nippon Soda Co., Ltd .: HPC-L) using a fluidized bed granulator (Freund Sangyo Co., Ltd .: Flow coater FLO-5) Fluidized bed granulated, dried, and then sized with a sizing machine (Dalton Co., Ltd .: Power Mill P-04S). The granules were mixed with 15 parts by mass of crospovidone (BASF: Kollidon CL) and crystalline cellulose ( Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) 30 parts by mass was added and mixed in a plastic bag, then magnesium stearate (Tahei Chemical Industry Co., Ltd .: magnesium stearate vegetable) 1.5 parts by mass was added. Furthermore, the plastic bag was mixed. The obtained granules were tableted with a tableting pressure of 10 kN / kg and a tablet weight of 148 mg using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRG) using a φ8 mm standard R 杵. The tablet contains 100 mg (almost 68%) of anagliptin in 148 mg of the tablet.
[実施例2]
実施例1において、ヒドロキシプロピルセルロース（日本曹達(株)製：HPC-L）1.5質量部をポビドン（BASF社製：コリドンK30）1.5質量部に置き換え、流動層造粒乾燥機（フロイント産業(株)製：フローコーター FLO-5）を流動層造粒乾燥機（フロイント産業(株)製：フローコーター FLO-2）に置き換えて、実施例1と同様に製造した。[Example 2]
In Example 1, 1.5 parts by mass of hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd .: HPC-L) was replaced with 1.5 parts by mass of povidone (manufactured by BASF: Kollidon K30), and fluidized bed granulator / dryer (Freund Sangyo Co., Ltd.) ): Flow coater FLO-5) was replaced with a fluidized bed granulator (Freund Sangyo Co., Ltd .: Flow coater FLO-2).
[実施例3]
実施例2において、ポビドン1.5質量部をヒプロメロース（信越化学工業(株)製：TC-5R）1.5質量部に置き換えて、実施例2と同様に製造した。[Example 3]
In Example 2, 1.5 parts by mass of povidone was replaced with 1.5 parts by mass of hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd .: TC-5R).
[実施例4]
アナグリプチン100質量部、クロスポビドン（BASF社製：コリドンCL）15質量部、及び結晶セルロース（旭化成ケミカルズ(株)製：セオラスKG-802）30質量部をヒドロキシプロピルセルロース（日本曹達(株)製：HPC-L）1.5質量部の水溶液にて、流動層造粒乾燥機（フロイント産業(株)製：フローコーター FLO-2）を用いて混合後、流動層造粒し、乾燥後、整粒機（ダルトン(株)製：パワーミル P-04S）にて整粒し、更にステアリン酸マグネシウム（太平化学工業(株)製：ステアリン酸マグネシウム植物性）1.5部を添加しビニール袋混合した。得られた顆粒を、φ8mm標準R杵を用い、ロータリー打錠機（(株)菊水製作所製：VIRG）にて打錠圧10kN/杵で1錠質量148mgとして打錠した。[Example 4]
100 parts by mass of anagliptin, 15 parts by mass of crospovidone (manufactured by BASF: Kollidon CL), and 30 parts by mass of crystalline cellulose (manufactured by Asahi Kasei Chemicals Corporation: Theolas KG-802) are produced by hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.): HPC-L) After mixing with 1.5 parts by mass of aqueous solution using a fluidized bed granulator (Freund Sangyo Co., Ltd .: Flow coater FLO-2), fluidized bed granulated, dried and granulated The size was adjusted with a Dalton Co., Ltd. product: Power Mill P-04S, and 1.5 parts of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd .: Magnesium stearate vegetable) was added and mixed in a plastic bag. The obtained granules were tableted with a tableting pressure of 10 kN / kg and a tablet weight of 148 mg using a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VIRG) using a φ8 mm standard R 杵.
試験の結果は以下の表５に示す。このように、湿式造粒により製造した実施例1〜4の錠剤は、21日間の安定性試験後でも分解生成物量（%）は3%以下であるが、流動化剤を用いて直接打錠した比較例1〜4の錠剤は、分解生成物量（%）はいずれも3%を超えていた。この結果から、アナグリプチンの化学的安定性に、流動化剤が悪影響を及ぼしていることが判明した。 The test results are shown in Table 5 below. Thus, the tablets of Examples 1 to 4 produced by wet granulation have a degradation product amount (%) of 3% or less even after 21 days of stability test, but directly compressed using a fluidizing agent. In the tablets of Comparative Examples 1 to 4, the degradation product amount (%) exceeded 3%. From this result, it was found that the fluidizing agent had an adverse effect on the chemical stability of anagliptin.
＜実験４＞
本製剤において使用可能な結合剤の検討を行った。すなわち、前記実施例1〜4の錠剤、並びに下記実施例5及び6の錠剤について、その物理的安定性評価及び溶出特性評価を行った。<Experiment 4>
Binders that can be used in this preparation were examined. That is, the physical stability and dissolution characteristics of the tablets of Examples 1 to 4 and the tablets of Examples 5 and 6 below were evaluated.
[実施例5]
ポビドン（BASF社製：コリドンK30）1.5質量部をプルラン（(株)林原製：プルラン）1.5質量部に置き換えて、実施例2と同様に製造した。[Example 5]
The same production as in Example 2 was carried out by replacing 1.5 parts by mass of povidone (BASF: Kollidon K30) with 1.5 parts by mass of pullulan (Hayashibara Co., Ltd .: pullulan).
[実施例6]
ポビドン（BASF社製：コリドンK30）1.5質量部の水溶液をデンプン（日本食品化工(株)製：コーンスターチ）1.5質量部を水に懸濁させ80℃以上で30分以上アルファー化させたデンプン糊に置き換えて、実施例2と同様に製造した。[Example 6]
A starch paste obtained by suspending 1.5 parts by weight of an aqueous solution of povidone (BASF: Kollidon K30) in 1.5 parts by weight of starch (Nihon Shokuhin Kako Co., Ltd .: corn starch) and watering it at 80 ° C or higher for 30 minutes or more. It replaced and manufactured similarly to Example 2.
試験の結果は以下の表６に示した。いずれの錠剤も、硬度40Ｎ以上及び摩損度1%以下の良好な物理安定性を示すとともに、溶出特性は15分値が85%以上となり、良好であった。これらの結果から、結合剤は特に限定されず、どのような結合剤でも使用できることが判明した。 The results of the test are shown in Table 6 below. All tablets showed good physical stability with a hardness of 40 N or more and a friability of 1% or less, and the dissolution characteristics were good with a 15-minute value of 85% or more. From these results, it was found that the binder is not particularly limited, and any binder can be used.
＜実験５＞
崩壊剤であるクロスポビドンの配合量の検討を行った。すなわち、以下に示す実施例7〜12の錠剤について、その物理的安定性評価及び溶出特性評価を行った。<Experiment 5>
The amount of crospovidone, a disintegrant, was examined. That is, physical stability evaluation and dissolution characteristic evaluation were performed on the tablets of Examples 7 to 12 shown below.
[実施例7〜12]
クロスポビドン（BASF社製：コリドンCL）の添加量及び1錠質量を表７に示す割合に設定し、実施例1と同様に錠剤を製造した。[Examples 7 to 12]
The addition amount of crospovidone (manufactured by BASF: Kollidon CL) and the mass of one tablet were set to the ratios shown in Table 7, and tablets were produced in the same manner as in Example 1.
試験結果を表８に示した。クロスポビドンの添加量が増えるに従って硬度は低下し、摩損度に関しては一貫した結果は得られなかったが、いずれも硬度40Ｎ以上、摩損度1%以下の良好な物理安定性を示した。一方、溶出特性は、クロスポビドンの添加量が増えるに従って速くなったが、クロスポビドンの添加量5質量%の場合のみ、期待する溶出特性（15分値85%以上）を有していなかった。以上の結果から、クロスポビドンの含量は7質量%以上が好ましく、15質量%程度が最も好ましいことがわかった。尚、30質量%を超える量のクロスポビドンを用いると、錠剤が大きくなって飲み込みにくくなるため、好ましくない。 The test results are shown in Table 8. As the amount of crospovidone added increased, the hardness decreased and consistent results were not obtained with respect to the friability, but all showed good physical stability with a hardness of 40 N or more and a friability of 1% or less. On the other hand, the elution characteristics increased as the amount of crospovidone added increased, but only when the amount of crospovidone added was 5% by mass, the expected elution characteristics (15 minutes value of 85% or more) were not obtained. From the above results, it was found that the content of crospovidone is preferably 7% by mass or more, and most preferably about 15% by mass. Use of crospovidone in an amount exceeding 30% by mass is not preferable because the tablet becomes large and difficult to swallow.
＜実験６＞
本製剤において使用可能な崩壊剤の検討を行った。すなわち、実施例１の錠剤において、崩壊剤のクロスポビドンを別の崩壊剤に置換した以下の比較例5〜11の錠剤（いずれも崩壊剤を実施例１と同じ10質量%含有する）について、その物理的安定性評価及び溶出特性評価を行った。<Experiment 6>
The disintegrant that can be used in this preparation was examined. That is, in the tablet of Example 1, the tablet of the following Comparative Examples 5 to 11 in which disintegrant crospovidone was replaced with another disintegrant (all containing 10% by mass of the disintegrant as in Example 1), The physical stability and elution characteristics were evaluated.
[比較例5〜11]
クロスポビドン15質量部をそれぞれ表9に示す崩壊剤15質量部に置き換えて、実施例1と同様に製造した。尚、崩壊剤は次の７種類で、クロスカルメロースナトリウム（FMC Biopolymer社製：Ac-Di-Sol）、カルメロースカルシウム（五徳薬品(株)製：ECG-505）、カルメロース（五徳薬品(株)製：NS-300）、低置換度ヒドロキシプロピルセルロース（信越化学工業(株)製：L-HPC LH-21）、カルボキシメチルスターチナトリウム（ROQUTTE社製：グリコリス）、部分アルファー化デンプン（旭化成ケミカルズ(株)製：PCS）、及びトウモロコシデンプン（日本食品化工(株)製：コーンスターチ）を使用した。[Comparative Examples 5 to 11]
Production was carried out in the same manner as in Example 1, except that 15 parts by mass of crospovidone was replaced with 15 parts by mass of the disintegrant shown in Table 9, respectively. There are the following seven disintegrants: croscarmellose sodium (FMC Biopolymer: Ac-Di-Sol), carmellose calcium (Gotoku Pharmaceutical Co., Ltd .: ECG-505), carmellose (Gotoku Pharmaceutical Co., Ltd.) NS-300), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd .: L-HPC LH-21), sodium carboxymethyl starch (ROQUTTE: Glycoris), partially pregelatinized starch (Asahi Kasei Chemicals) Corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd .: corn starch) was used.
試験結果を表９に示した。このように、いずれの錠剤も物理的安定性は基準を満たしていたが、溶出特性については、崩壊剤としてクロスポビドンを添加した実施例1のみ、期待する溶出特性（15分値85%以上）を有していた。 The test results are shown in Table 9. Thus, although all tablets met the standard of physical stability, the dissolution characteristics were expected only in Example 1 in which crospovidone was added as a disintegrant (15 minutes value of 85% or more). Had.
＜実験７＞
実験６と同様に、本製剤において使用可能な崩壊剤の検討を行った。すなわち、実施例13の錠剤において、崩壊剤のクロスポビドンを別の崩壊剤に置換した以下の比較例12〜16の錠剤（いずれも崩壊剤を実施例13と同じ10質量%含有する）について、その物理的安定性評価（硬度）及び溶出特性評価を行った。<Experiment 7>
As in Experiment 6, the disintegrant that can be used in this preparation was examined. That is, in the tablet of Example 13, the tablet of the following Comparative Examples 12 to 16 in which the disintegrant crospovidone was replaced with another disintegrant (both containing 10% by mass of the disintegrant as in Example 13), The physical stability (hardness) and elution characteristics were evaluated.
[実施例13]
アナグリプチン100質量部を、ヒドロキシプロピルセルロース水溶液（ヒドロキシプロピルセルロースとして1.6質量部）を用いて造粒した。得られた粒状物を乾燥し、クロスポビドン（BASF社製：コリドンCL）16質量部、D-マンニトール24質量部及び結晶セルロース16質量部を添加し、混合した。次いで、ステアリン酸マグネシウム2.4質量部を添加し混合して、打錠用顆粒を得た。得られた打錠用顆粒を１錠当たり160mgとなるように打錠した。なお、得られた錠剤は１錠当たりアナグリプチンを100mg、クロスポビドンを16mg含有し、錠剤１錠当たりの含有量はそれぞれアナグリプチンが62.5質量%、クロスポビドンが10質量%となる。[Example 13]
100 parts by mass of anagliptin was granulated using an aqueous hydroxypropylcellulose solution (1.6 parts by mass as hydroxypropylcellulose). The obtained granular material was dried, 16 parts by mass of crospovidone (manufactured by BASF: Kollidon CL), 24 parts by mass of D-mannitol and 16 parts by mass of crystalline cellulose were added and mixed. Next, 2.4 parts by mass of magnesium stearate was added and mixed to obtain tableting granules. The obtained granules for tableting were tableted to 160 mg per tablet. The obtained tablet contains 100 mg of anagliptin and 16 mg of crospovidone per tablet, and the content per tablet is 62.5% by mass of anagliptin and 10% by mass of crospovidone, respectively.
[比較例12〜16]
実施例13において、クロスポビドン16質量部の代りに、表10に示す崩壊剤16質量部に置き換えて、実施例13と同様に製造した。尚、崩壊剤は次の5種で、カルボキシメチルセルロース（五徳薬品（株）製：NS-300）、カルボキシメチルスターチナトリウム（ROQUTTE社製：グリコリス）、クロスカルメロースナトリウム（FMC Biopolymer社製：Ac-Di-Sol）、低置換度ヒドロキシプロピルセルロース（信越化学工業（株）製：L-HPC LH-21）、及びカルメロースカルシウム（五徳薬品(株)製：ECG-505）を使用した。[Comparative Examples 12-16]
In Example 13, it replaced with 16 mass parts of crospovidone, and replaced with 16 mass parts of disintegrating agents shown in Table 10, and it manufactured similarly to Example 13. The following five disintegrants are carboxymethyl cellulose (manufactured by Gotoku Pharmaceutical Co., Ltd .: NS-300), sodium carboxymethyl starch (manufactured by ROQUTTE: Glicolis), croscarmellose sodium (manufactured by FMC Biopolymer: Ac- Di-Sol), low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical Co., Ltd .: L-HPC LH-21), and carmellose calcium (Gotoku Pharmaceutical Co., Ltd .: ECG-505) were used.
試験結果を表10に示す。このように、比較例12〜16の錠剤においては、15分後においても溶出率は70%以下であったのに対し、実施例13の錠剤においては10分後において溶出率が80%を超え、15分後においては100%に近い溶出が見られた。なお、実施例13及び比較例12〜16の錠剤において、硬度は全て60Ｎ前後とほぼ同程度であることから、実施例13において見られた良好な溶出は単なる錠剤物性に基づくものでは無く、崩壊剤としてクロスポビドンを用いたことによるものであることが明らかとなった。
以上実験6及び7の試験結果から、アナグリプチンを含有する固形製剤においては、他の崩壊剤では溶出促進作用が得られず、クロスポビドンのみが特異的に、単なる製剤物性の面からでは説明できない顕著に優れた溶出促進作用を示すことが明らかとなった。したがって、アナグリプチン又はその塩、及び崩壊剤としてクロスポビドンを含有する固形製剤は、溶出性の大変優れた製剤となる。この結果から、我々は、アナグリプチン又はその塩、及びクロスポビドンを含有する固形製剤という、課題を解決するための手段の（２０）に記載の発明を成すに至った。The test results are shown in Table 10. Thus, in the tablets of Comparative Examples 12 to 16, the dissolution rate was 70% or less even after 15 minutes, whereas in the tablet of Example 13, the dissolution rate exceeded 80% after 10 minutes. After 15 minutes, elution close to 100% was observed. In the tablets of Example 13 and Comparative Examples 12 to 16, the hardness was almost the same as around 60 N, so the good dissolution seen in Example 13 was not based on the physical properties of the tablet but was disintegrated. It was revealed that this was due to the use of crospovidone as an agent.
From the test results of Experiments 6 and 7 above, in solid preparations containing anagliptin, other disintegrants do not provide an elution promoting effect, and crospovidone alone is not specifically explained from the standpoint of mere formulation properties It was revealed that it exhibited an excellent elution promoting action. Therefore, a solid preparation containing anagliptin or a salt thereof and crospovidone as a disintegrant is a preparation with excellent dissolution properties. From this result, we have made the invention described in (20) of the means for solving the problem of a solid preparation containing anagliptin or a salt thereof and crospovidone.
＜実験８＞
本製剤において使用される結晶セルロースの含有量について検討した。すなわち、以下の実施例14〜17の錠剤について、その物理的安定性評価及び溶出特性評価を行った。<Experiment 8>
The content of crystalline cellulose used in this preparation was examined. That is, the physical stability evaluation and dissolution characteristic evaluation of the tablets of Examples 14 to 17 below were performed.
[実施例14〜17]
結晶セルロース（旭化成ケミカルズ(株)製：セオラスKG-802）の添加量及び1錠質量を表11に示す割合に設定し、実施例1と同様に錠剤を製造した。[Examples 14 to 17]
The amount of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) added and the mass of one tablet were set to the ratio shown in Table 11, and tablets were produced in the same manner as in Example 1.
試験結果を表12に示した。結晶セルロースの添加量が増えるに従って、硬度は増加し、摩損度は低下し、物理的安定性は改善されたが、溶出特性は遅くなり悪化した。すなわち、結晶セルロースの添加量5質量%の実施例14では、期待する物理的安定性を示さず、結晶セルロースの添加量40質量%では、期待する溶出特性（15分値85%以上）を示さなかった。以上の結果から、結晶セルロースの含量は、7〜37質量%が適切であることがわかった。 The test results are shown in Table 12. As the added amount of crystalline cellulose increased, the hardness increased, the friability decreased, and the physical stability was improved, but the elution characteristics were delayed and deteriorated. That is, in Example 14 where the addition amount of crystalline cellulose was 5% by mass, the expected physical stability was not shown, and when the addition amount of crystalline cellulose was 40% by mass, the expected dissolution characteristics (15 minutes value 85% or more) were shown. There wasn't. From the above results, it was found that 7 to 37% by mass is appropriate for the content of crystalline cellulose.
＜実験９＞
本錠剤において、結晶セルロースに置き換え可能な賦形剤について検討した。すなわち、実施例１の錠剤において、結晶セルロースを代替物に置換した以下の比較例17〜19の錠剤（結晶セルロース代替物を実施例１と同じ20質量%含有する）について、その物理的安定性評価及び溶出特性評価を行った。<Experiment 9>
In this tablet, an excipient that can be replaced with crystalline cellulose was examined. That is, in the tablet of Example 1, the physical stability of the tablets of Comparative Examples 17 to 19 below (in which 20% by mass of the crystalline cellulose substitute is contained as in Example 1), in which the crystalline cellulose is substituted with the substitute. Evaluation and elution characteristics were evaluated.
[比較例17〜19]
実施例１において、結晶セルロース30質量部を表13に示すように、それぞれ、乳糖水和物（DMV社製：乳糖200M）30質量部、D-マンニトール（三菱商事フードテック(株)製：マンニット-P）30質量部、無水リン酸水素カルシウム（協和化学工業(株)製：無水リン酸水素カルシウム）30質量部に置き換えて、実施例1と同様に製造した。[Comparative Examples 17-19]
In Example 1, 30 parts by mass of crystalline cellulose, as shown in Table 13, 30 parts by mass of lactose hydrate (DMV: lactose 200M), D-mannitol (Mitsubishi Corporation Foodtech Co., Ltd .: Man Knit-P) 30 parts by mass and anhydrous calcium hydrogen phosphate (manufactured by Kyowa Chemical Industry Co., Ltd .: anhydrous calcium hydrogen phosphate) were replaced with 30 parts by mass.
試験結果を表13に示した。結晶セルロース以外の賦形剤を使用した比較例17〜19の錠剤では、期待する物理的安定性が得られず、特に摩損度1%以下の基準を満たさなかった。尚、これら比較例の錠剤においては、打錠圧を上げて摩損度の改善が可能かどうか検討したが改善されず、結晶セルロースが好適な賦形剤であることが判明した。この結果から、我々は、アナグリプチン又はその塩、及び結晶セルロースを含有する固形製剤という、課題を解決するための手段の（１８）に記載の発明を成すに至った。 The test results are shown in Table 13. In the tablets of Comparative Examples 17 to 19 using excipients other than crystalline cellulose, the expected physical stability was not obtained, and in particular, the standard of friability of 1% or less was not satisfied. In addition, in the tablets of these comparative examples, it was investigated whether the tableting pressure could be increased to improve the friability, but it was not improved, and it was found that crystalline cellulose is a suitable excipient. From this result, we have made the invention described in (18) of the means for solving the problem of a solid preparation containing anagliptin or a salt thereof and crystalline cellulose.
＜実験10＞
アナグリプチンの含量がどこまで上げられるか検討した。すなわち、アナグリプチンの含量を変えた以下の実施例18，19、及び比較例20について、その物理的安定性評価及び溶出特性評価を行った。<Experiment 10>
To what extent the content of anagliptin could be increased. That is, physical stability evaluation and elution characteristic evaluation were performed on the following Examples 18 and 19 and Comparative Example 20 in which the content of anagliptin was changed.
[実施例18，19]
実施例1において、クロスポビドン（BASF社製：コリドンCL）の添加量、結晶セルロース（旭化成ケミカルズ(株)製：セオラスKG-802）の添加量、ステアリン酸マグネシウム（太平化学工業(株)製：ステアリン酸マグネシウム植物性）の添加量、及び1錠質量を表14に示す割合に設定し、実施例1と同様に製した。[Examples 18 and 19]
In Example 1, the addition amount of crospovidone (BASF Corporation: Kollidon CL), crystalline cellulose (Asahi Kasei Chemicals Corporation: Theolas KG-802), magnesium stearate (Taihei Chemical Industry Co., Ltd.): The amount of magnesium stearate vegetable) and the mass of 1 tablet were set to the ratios shown in Table 14 and were produced in the same manner as in Example 1.
[比較例20]
実施例1において、クロスポビドン（BASF社製：コリドンCL）の添加量、結晶セルロース（旭化成ケミカルズ(株)製：セオラスKG-802）の添加量、ステアリン酸マグネシウム（太平化学工業(株)製：ステアリン酸マグネシウム植物性）の添加量、及び1錠質量を表14に示す割合に設定し、実施例1と同様に製した。[Comparative Example 20]
In Example 1, the addition amount of crospovidone (BASF Corporation: Kollidon CL), crystalline cellulose (Asahi Kasei Chemicals Corporation: Theolas KG-802), magnesium stearate (Taihei Chemical Industry Co., Ltd.): The amount of magnesium stearate vegetable) and the mass of 1 tablet were set to the ratios shown in Table 14 and were produced in the same manner as in Example 1.
試験結果は表15に示す。このように、アナグリプチン含量が増えるに従って硬度は低下、摩損度は増加し、物理的安定性は悪化した。アナグリプチン含量が85%以上では、硬度及び／又は摩損度が基準（それぞれ30Ｎ以上、1.0%以下）を満たさなかった。本結果から、アナグリプチン含量の上限は83%程度とすることが好ましいと考えられる。 The test results are shown in Table 15. Thus, as the anagliptin content increased, the hardness decreased, the friability increased, and the physical stability deteriorated. When the anagliptin content was 85% or more, the hardness and / or friability did not satisfy the standard (30N or more and 1.0% or less, respectively). From this result, it is considered that the upper limit of the anagliptin content is preferably about 83%.
＜実験11＞
本発明の錠剤にフィルムコーティングを施し、素錠との物性比較を行った。<Experiment 11>
Film coating was applied to the tablet of the present invention, and the physical properties of the tablet were compared.
[実施例20，21]
表16の配合割合で、実施例１と同様に錠剤を製造した。実施例20が素錠部であり、更にフィルムコーティングを行ったフィルムコーティング錠が実施例21である。[Examples 20 and 21]
Tablets were produced in the same manner as in Example 1 at the blending ratios in Table 16. Example 20 is an uncoated tablet part, and a film-coated tablet on which film coating is further performed is Example 21.
試験結果は表17に示す。このように、フィルムコーティングを施すことにより、溶出特性は若干遅くなったが、目標値（15分値85%以上）は十分満たしていた。しかし、フィルムコーティング錠とする場合は、溶出特性を早めるために、クロスポビドンの含量を多めにした方が好ましいことがわかる。 The test results are shown in Table 17. Thus, although the elution characteristics were slightly delayed by applying the film coating, the target value (15 minutes value of 85% or more) was sufficiently satisfied. However, in the case of film-coated tablets, it can be seen that it is preferable to increase the content of crospovidone in order to accelerate the dissolution characteristics.
＜実験12＞
本発明の錠剤にフィルムコーティングを施した、以下の実施例22〜26の錠剤各々6錠につき、色彩についての安定性評価を行い、着色剤の効果について調べた。試験は、以下の３つの条件について行った。
条件１：温度40℃、90%相対湿度、開放条件下で5日間保存
条件２：温度60℃、75%相対湿度、開放条件下で3週間保存
条件３：温度40℃、75%相対湿度、無可塑硬質塩化ビニル単層PTP包装して1か月間保存
保存前後の錠剤につき、色差計を用いて、SCE（正反射光除去方式）、L*a*b*表色系にて反射率を測定し、保存後と開始時との差から色差（ΔE=（（ΔL*）２＋（Δa*）２＋（Δb*）２）１/2）を求めた。 <Experiment 12>
The stability of the color was evaluated for each of the 6 tablets of Examples 22 to 26 below, which were film-coated on the tablets of the present invention, and the effect of the colorant was investigated. The test was conducted under the following three conditions.
Condition 1: Temperature 40 ° C, 90% relative humidity, storage for 5 days under open conditions 2: Temperature 60 ° C, 75% relative humidity, storage for 3 weeks under open conditions 3: Temperature 40 ° C, 75% relative humidity, Use a color difference meter to measure the reflectivity of SCE (regular reflection light removal method) and L * a * b * color system for tablets before and after storage and storage for 1 month with non-plastic rigid polyvinyl chloride single layer PTP. The color difference (ΔE = ((ΔL * ) 2 + (Δa * ) 2 + (Δb * ) 2 ) 1/2 ) was determined from the difference between after storage and at the start.
[実施例22〜26]
前記実験11の実施例20の素錠を使用して、１錠につき次の表18の組成となるフィルムコーティングを施した。
Using the uncoated tablet of Example 20 of Experiment 11, a film coating having the composition shown in Table 18 below was applied to each tablet.
試験結果を表19に示す。表19から明らかなように、三二酸化鉄類を含む実施例25及び26の錠剤は、いずれの条件においても保存前後における色差は極めて少なかった。一方、着色剤不含の実施例22、食用黄色5号アルミニウムレーキを含む実施例23、食用黄色5号を含む実施例24は、保存前後の色差が大きかった。しかも、食用黄色5号等を含む実施例23及び24においては、着色剤を含まないとき以上に色差が大きかった。この結果から、三二酸化鉄類は、アナグリプチンを含有する錠剤において、特異的に錠剤の変色を防止する効果を示したものと考えられる。したがって、アナグリプチン又はその塩、及び三二酸化鉄類を含有する固形製剤は、長期保存安定性に優れたものである。 The test results are shown in Table 19. As can be seen from Table 19, the tablets of Examples 25 and 26 containing ferric oxides had very little color difference before and after storage under any conditions. On the other hand, Example 22 containing no colorant, Example 23 containing edible yellow No. 5 aluminum lake, and Example 24 containing edible yellow No. 5 had large color differences before and after storage. Moreover, in Examples 23 and 24 containing Food Yellow No. 5, etc., the color difference was larger than when no colorant was contained. From these results, it is considered that iron sesquioxides exhibited an effect of specifically preventing discoloration of tablets in tablets containing anagliptin. Therefore, a solid preparation containing anagliptin or a salt thereof and ferric sesquioxide is excellent in long-term storage stability.
＜実験13＞
実験12の結果に基づき、製剤中の三二酸化鉄類の含有量につき検討した。以下の実施例につき、実験12と同様に、温度60℃、75%相対湿度、開放条件下で１週間保存して、色彩についての安定性評価を行った。<Experiment 13>
Based on the results of Experiment 12, the content of ferric oxides in the preparation was examined. In the same manner as in Experiment 12, the following examples were stored at a temperature of 60 ° C., 75% relative humidity, and open conditions for 1 week to evaluate the stability of colors.
[実施例27〜29]
前記実験11の実施例20の素錠を使用して、１錠につき次の表20の組成となるフィルムコーティングを施し、フィルムコーティング錠を作製した。[Examples 27 to 29]
Using the uncoated tablet of Example 20 of Experiment 11, film coating having the composition shown in Table 20 below was applied to each tablet to prepare film-coated tablets.
結果を表21に示した。表21から明らかなように、三二酸化鉄を含むいずれの錠剤も、保存安定性に優れることが判明した。以上の実験12及び13の結果から、我々は、アナグリプチン又はその塩、及び三二酸化鉄を含有する固形製剤という、課題を解決するための手段の（２１）に記載の発明を成すに至った。当該発明を更に具体的に述べると、アナグリプチン又はその塩を含有し、更に三二酸化鉄を含有するフィルムコーティングを有する固形製剤となる。 The results are shown in Table 21. As is clear from Table 21, it was found that any tablet containing iron sesquioxide is excellent in storage stability. From the results of the above experiments 12 and 13, we have achieved the invention described in (21) of the means for solving the problem of a solid preparation containing anagliptin or a salt thereof and iron sesquioxide. More specifically, the invention is a solid preparation having a film coating containing anagliptin or a salt thereof and further containing iron sesquioxide.
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