WO2014051024A1 - Anagliptin-containing drug composition - Google Patents
Anagliptin-containing drug composition Download PDFInfo
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- WO2014051024A1 WO2014051024A1 PCT/JP2013/076204 JP2013076204W WO2014051024A1 WO 2014051024 A1 WO2014051024 A1 WO 2014051024A1 JP 2013076204 W JP2013076204 W JP 2013076204W WO 2014051024 A1 WO2014051024 A1 WO 2014051024A1
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- anagliptin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a pharmaceutical composition containing anagliptin having dipeptidyl peptidase IV inhibitory action.
- DPP-IV inhibitor A compound having a dipeptidyl peptidase IV (hereinafter also 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.
- 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.
- a compound useful as an active ingredient of a pharmaceutical is formulated and administered as some pharmaceutical composition, but it is rare that it takes a long time from formulation to administration. Absent. Therefore, it is extremely important to ensure the stability of the active ingredient in the pharmaceutical composition from the viewpoint of exhibiting expected drug efficacy and avoiding unexpected side effects.
- the stability of an active ingredient is greatly influenced by its physical and chemical properties, and such properties are often unpredictable from its chemical structure, ensuring the stability of the active ingredient in pharmaceutical compositions. It takes a lot of trial and error to establish this technology.
- DPP-IV inhibitors 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 marketed worldwide, including Japan.
- sitagliptin phosphate hydrate trade name: Janubia, Gractive
- vildagliptin trade name: Equa
- alogliptin benzoate trade name: Nesina
- linagliptin Trade name: Trazenta
- Tenerigliptin hydrobromide hydrate Trade name: Tenelia
- An object of the present invention is to provide a pharmaceutical composition containing anagliptin which is excellent in stability.
- an anagliptin-containing pharmaceutical composition excellent in stability In order to provide an anagliptin-containing pharmaceutical composition excellent in stability, the present inventors first made extensive studies on the physical and chemical characteristics of anagliptin. The stability of the anagliptin is greatly influenced by the pH environment, and While it is extremely unstable in a high pH environment and rapidly decomposes, an anagliptin-containing pharmaceutical composition having excellent stability can be obtained by setting the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition containing anagliptin to 10 or less. The present invention has been completed.
- the main configuration of the present invention is as follows.
- the pharmaceutical composition according to (1) comprising a weakly acidic to weakly basic preparation additive.
- the pharmaceutical composition according to (5), wherein the solid preparation for oral administration is a tablet, capsule, granule, fine granule, or powder.
- a pharmaceutical composition excellent in the stability of anagliptin can be obtained.
- Anagliptin is a compound described in Example 2 of Patent Document 1, and has a chemical name of N- [2-( ⁇ 2-[(2S) -2-cyanopyrrolidin-1-yl] -2-oxoethyl ⁇ amino. ) -2-Methylpropyl] -2-methylpyrazolo [1,5-a] pyrimidine-6-carboxamide, which is a known compound, and can be produced with reference to the production method described in the document.
- 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.
- 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.
- the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- Suitable examples of salts with organic acids include acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzoic acid, and 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.
- anagliptin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user.
- anagliptin or a salt thereof can be contained in an amount that can be taken in an amount of 0.1 to 1000 mg, preferably 1 to 500 mg, particularly preferably 50 to 400 mg of anagliptin free form per day.
- the anagliptin or a salt thereof is preferably contained in an amount of 1 to 90% by mass, more preferably 3 to 80% by mass, in terms of the free form of anagliptin relative to the total mass of the pharmaceutical composition. It is particularly preferable to contain 70% by mass.
- the “pH value of an aqueous solution or aqueous dispersion” of a pharmaceutical composition is a ratio of 100 ml of a pharmaceutical composition containing anagliptin or a salt thereof to 625 mg (converted to free form) of anagliptin in the composition.
- the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition needs to be 10 or less, but is within the range of 2 to 9.9. More preferably, it is more preferably within the range of 3 to 9.8, even more preferably within the range of 4.5 to 9.7, and particularly preferably within the range of 6 to 9.6. .
- the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition is a weakly acidic to weakly basic formulation additive (specifically, the pH value when dissolved in water is about 6 to A value that can exhibit a value within the range of 10.
- weakly acidic to weakly basic preparation additive specifically, the pH value when dissolved in water is about 6 to A value that can exhibit a value within the range of 10.
- it is also referred to as “weakly acidic to weakly basic preparation additive”
- weakly acidic to weakly basic formulation additives include fructose, xylitol, D-sorbitol, lactose, anhydrous lactose, powdered sugar, sucrose, purified sucrose, glucose hydrate, D- Sugars and sugar alcohols such as mannitol, erythritol, trehalose, maltitol; pregelatinized starch, partially pregelatinized starch, dextrin, corn starch, potato starch, hydroxypropyl starch, reduced maltose syrup, wheat starch, rice starch, etc. And the like; celluloses such as hydroxypropylcellulose, powdered cellulose, crystalline cellulose, microcrystalline cellulose and the like.
- the content of such weakly acidic to weakly basic formulation additive is not particularly limited, and may be determined by appropriate examination according to the pH value of the pharmaceutical composition.
- the content is preferably -99% by mass, more preferably 20-97% by mass, and particularly preferably 30-95% by mass.
- the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition can also be adjusted by selecting the content of anagliptin or a salt thereof in the pharmaceutical composition according to the pH value.
- the dosage form of the “pharmaceutical composition” is not particularly limited, and may be any of solid, semi-solid, and liquid forms, and is usually used as a medicine depending on the purpose of use and the like.
- the shape can be made. Since anagliptin is extremely soluble in water, its stability is greatly affected by the surrounding pH environment even in liquid, solid and semi-solid pharmaceutical compositions.
- the dosage form of the pharmaceutical composition specifically, for example, the dosage form described in the 16th revised Japanese Pharmacopoeia, General Rules for Formulation, etc., specifically tablets (ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets) Tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules, fine granules, powders and other solid preparations for oral administration; oral solutions (elixirs, suspensions, emulsions, limonades, etc.); oral jelly preparations; Oral tablets (troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.); oral sprays; oral solids, etc., but from the viewpoint of ease of administration, etc. A formulation is preferred. These solid preparations for oral administration may be coated with a film, sugar coating or the like, if necessary.
- the pharmaceutical composition of the present invention can be produced by a known method described in, for example, the 16th revised Japanese Pharmacopoeia, General Rules for Preparations, etc. according to the above dosage form.
- an appropriate formulation additive as described below may be mixed and then compression molded.
- 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.
- the granulation method include extrusion granulation, stirring granulation, rolling granulation, spray drying granulation, crushed granulation, fluidized bed granulation, and melt granulation.
- compositions of the present invention in addition to the above-mentioned components such as anagliptin and weakly acidic to weakly basic preparation additives, excipients, binders, fluidizing agents, corrigents, Appropriate formulation additives such as colorants can be used as appropriate.
- the pharmaceutical composition of the present invention contains anagliptin having a DPP-IV inhibitory action or a salt thereof, it is useful as a medicament for type 2 diabetes.
- the pharmaceutical composition of the present invention can be taken in one or two or more divided doses so as to achieve the above-mentioned daily dose.
- Example 1 A tablet containing 100 mg of anagliptin in one tablet was produced by the following method. That is, 100 parts by mass of anagliptin was fluidized-bed granulated using a hydroxypropylcellulose aqueous solution (1.5 parts by mass as hydroxypropylcellulose). The resulting granular product was dried and sized, and 15 parts by mass of crospovidone and 32 parts by mass of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) were added and mixed. Next, 1.5 parts by mass of magnesium stearate was added and mixed to obtain granules for tableting. The obtained granules for tableting were tableted to give 150 mg per tablet to obtain tablets.
- the obtained tablet was ground and an amount equivalent to 625 mg of anagliptin free body (937.5 mg) was dissolved in 100 ml of purified water at about 25 ° C., and its pH value was about 9.4.
- the obtained tablets were placed in a plastic petri dish and subjected to a 21-day stability test at a temperature of 60 ° C. and a relative humidity of 75%.
- the degradation product amount of anagliptin was 1.58%, and the stability of anagliptin was good.
- a pharmaceutical composition containing anagliptin having a DPP-IV inhibitory activity or a salt thereof and having excellent stability can be provided and used in the pharmaceutical industry and the like.
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Abstract
Provided is a drug composition containing anagliptin and having superior stability. The drug composition contains anagliptin or a salt thereof, and the pH value of an aqueous solution or aqueous dispersion thereof is no greater than 10.
Description
本発明は、ジペプチジルペプチダーゼＩＶ阻害作用を有するアナグリプチンを含有する医薬組成物に関する。
The present invention relates to a pharmaceutical composition containing anagliptin having dipeptidyl peptidase IV inhibitory action.
ジペプチジルペプチターゼＩＶ（以下、ＤＰＰ－ＩＶと略することもある。）阻害作用を有する化合物（ＤＰＰ－ＩＶ阻害剤）は、ＤＰＰ－ＩＶが関与する疾患、例えば、２型糖尿病等の治療剤の有効成分として有用である。このようなＤＰＰ－ＩＶ阻害剤として例えば、特許文献１にはアナグリプチン（化学名：N-[2-({2-[(2S)-2-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミド）が優れたＤＰＰ－ＩＶ阻害作用を有する旨、記載されている。
A compound having a dipeptidyl peptidase IV (hereinafter also 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.
一般的に、医薬品の有効成分として有用な化合物は、何らかの医薬組成物として製剤化されて投与されることとなるが、製剤化されてから投与されるまでに長期間を要することも珍しいことではない。そのため、期待する薬効の発揮の観点や予期せぬ副作用の回避の観点から、医薬組成物中での有効成分の安定性の確保が極めて重要となる。しかしながら、有効成分の安定性はその物理的・化学的特性に大きく左右されるところ、当該特性はその化学構造からは予測出来ないことが多く、医薬組成物中での有効成分の安定性を確保する技術の確立には多くの試行錯誤を要する。
In general, a compound useful as an active ingredient of a pharmaceutical is formulated and administered as some pharmaceutical composition, but it is rare that it takes a long time from formulation to administration. Absent. Therefore, it is extremely important to ensure the stability of the active ingredient in the pharmaceutical composition from the viewpoint of exhibiting expected drug efficacy and avoiding unexpected side effects. However, the stability of an active ingredient is greatly influenced by its physical and chemical properties, and such properties are often unpredictable from its chemical structure, ensuring the stability of the active ingredient in pharmaceutical compositions. It takes a lot of trial and error to establish this technology.
ところで、ＤＰＰ－ＩＶ阻害剤としては、アナグリプチン以外に例えば、シタグリプチンリン酸塩水和物（商品名：ジャヌビア、グラクティブ）、ビルダグリプチン（商品名：エクア）、アログリプチン安息香酸塩（商品名：ネシーナ）、リナグリプチン（商品名：トラゼンタ）、テネリグリプチン臭化水素酸塩水和物（商品名：テネリア）が、本邦を初めとして全世界的に上市されている。
By the way, as DPP-IV inhibitors, 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 marketed worldwide, including Japan.
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、その安定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・化学的特性も互いに大きく相違することが予想される。従って、上記のような他のＤＰＰ－ＩＶ阻害剤に関する情報は参考にならず、アナグリプチンの安定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 with the same effect, the stabilization technique is completely different for different compounds. In particular, since the chemical structures of DPP-IV inhibitors are greatly different from each other, their physical and chemical properties are expected to be greatly different from each other. Therefore, the information regarding the other DPP-IV inhibitors as described above is not helpful, and various studies are required for the stabilization of anagliptin.
本発明は、安定性に優れる、アナグリプチンを含有する医薬組成物を提供することを目的とする。
An object of the present invention is to provide a pharmaceutical composition containing anagliptin which is excellent in stability.
本発明者らは、安定性に優れるアナグリプチン含有医薬組成物を提供するため、まずアナグリプチンの物理的・化学的特性につき鋭意検討したところ、その安定性がｐＨ環境に大きく影響を受けること、そして、高ｐＨ環境では極めて不安定であり速やかに分解される一方、アナグリプチンを含有する医薬組成物の水溶液又は水分散液のｐＨ値を１０以下とすれば、安定性に優れるアナグリプチン含有医薬組成物が得られることを見出し、本発明を完成した。
In order to provide an anagliptin-containing pharmaceutical composition excellent in stability, the present inventors first made extensive studies on the physical and chemical characteristics of anagliptin. The stability of the anagliptin is greatly influenced by the pH environment, and While it is extremely unstable in a high pH environment and rapidly decomposes, an anagliptin-containing pharmaceutical composition having excellent stability can be obtained by setting the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition containing anagliptin to 10 or less. The present invention has been completed.
すなわち、本発明の主な構成は次の通りである。
（１）アナグリプチン又はその塩を含有し、その水溶液又は水分散液のｐＨ値が１０以下である医薬組成物。
（２）弱酸性～弱塩基性製剤添加物を含有する、（１）記載の医薬組成物。
（３）アナグリプチン又はその塩の含有量が、医薬組成物全質量に対し１～９０質量％である、（１）又は（２）記載の医薬組成物。
（４）その水溶液又は水分散液のｐＨ値が２～１０である（１）～（３）のいずれか１項記載の医薬組成物。
（５）経口投与用固形製剤である、（１）～（４）のいずれか１項記載の医薬組成物。
（６）前記経口投与用固形製剤が、錠剤、カプセル剤、顆粒剤、細粒剤、又は散剤である、（５）記載の医薬組成物。 That is, the main configuration of the present invention is as follows.
(1) A pharmaceutical composition containing anagliptin or a salt thereof and having an aqueous solution or aqueous dispersion having a pH value of 10 or less.
(2) The pharmaceutical composition according to (1), comprising a weakly acidic to weakly basic preparation additive.
(3) The pharmaceutical composition according to (1) or (2), wherein the content of anagliptin or a salt thereof is 1 to 90% by mass relative to the total mass of the pharmaceutical composition.
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the aqueous solution or aqueous dispersion has a pH value of 2 to 10.
(5) The pharmaceutical composition according to any one of (1) to (4), which is a solid preparation for oral administration.
(6) The pharmaceutical composition according to (5), wherein the solid preparation for oral administration is a tablet, capsule, granule, fine granule, or powder.
（１）アナグリプチン又はその塩を含有し、その水溶液又は水分散液のｐＨ値が１０以下である医薬組成物。
（２）弱酸性～弱塩基性製剤添加物を含有する、（１）記載の医薬組成物。
（３）アナグリプチン又はその塩の含有量が、医薬組成物全質量に対し１～９０質量％である、（１）又は（２）記載の医薬組成物。
（４）その水溶液又は水分散液のｐＨ値が２～１０である（１）～（３）のいずれか１項記載の医薬組成物。
（５）経口投与用固形製剤である、（１）～（４）のいずれか１項記載の医薬組成物。
（６）前記経口投与用固形製剤が、錠剤、カプセル剤、顆粒剤、細粒剤、又は散剤である、（５）記載の医薬組成物。 That is, the main configuration of the present invention is as follows.
(1) A pharmaceutical composition containing anagliptin or a salt thereof and having an aqueous solution or aqueous dispersion having a pH value of 10 or less.
(2) The pharmaceutical composition according to (1), comprising a weakly acidic to weakly basic preparation additive.
(3) The pharmaceutical composition according to (1) or (2), wherein the content of anagliptin or a salt thereof is 1 to 90% by mass relative to the total mass of the pharmaceutical composition.
(4) The pharmaceutical composition according to any one of (1) to (3), wherein the aqueous solution or aqueous dispersion has a pH value of 2 to 10.
(5) The pharmaceutical composition according to any one of (1) to (4), which is a solid preparation for oral administration.
(6) The pharmaceutical composition according to (5), wherein the solid preparation for oral administration is a tablet, capsule, granule, fine granule, or powder.
本発明によれば、アナグリプチンの安定性に優れる医薬組成物を得ることができる。
According to the present invention, a pharmaceutical composition excellent in the stability of anagliptin can be obtained.
アナグリプチンは、特許文献１の実施例２に記載された化合物であり、化学名がN-[2-({2-[(2S)-2-シアノピロリジン-1-イル]-2-オキソエチル}アミノ)-2-メチルプロピル]-2-メチルピラゾロ[1,5-a]ピリミジン-6-カルボキサミドである公知の化合物であり、同文献記載の製造方法を参考にして製造することができる。
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.
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、さら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。
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. Suitable examples of salts with organic acids include acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzoic acid, and 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.
本発明の医薬組成物におけるアナグリプチン又はその塩の含有量は特に限定されず、服用者の性別、年齢、症状等に応じて適宜検討して決定すればよい。例えば、１日あたり、アナグリプチン又はその塩を、アナグリプチンのフリー体換算で０．１～１０００ｍｇ、好適には１～５００ｍｇ、特に好適には５０～４００ｍｇ服用できる量を含有せしめることができる。本発明においては、アナグリプチン又はその塩を医薬組成物全質量に対して、アナグリプチンのフリー体換算で１～９０質量％含有するのが好ましく、３～８０質量％含有するのがより好ましく、５～７０質量％含有するのが特に好ましい。
The content of anagliptin or a salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be determined by appropriately examining according to the sex, age, symptoms, etc. of the user. For example, anagliptin or a salt thereof can be contained in an amount that can be taken in an amount of 0.1 to 1000 mg, preferably 1 to 500 mg, particularly preferably 50 to 400 mg of anagliptin free form per day. In the present invention, the anagliptin or a salt thereof is preferably contained in an amount of 1 to 90% by mass, more preferably 3 to 80% by mass, in terms of the free form of anagliptin relative to the total mass of the pharmaceutical composition. It is particularly preferable to contain 70% by mass.
本発明において、医薬組成物の「水溶液又は水分散液のｐＨ値」とは、アナグリプチン又はその塩を含有する医薬組成物を、当該組成物中のアナグリプチン６２５ｍｇ（フリー体換算）に対し１００ｍｌの割合に相当する量の水に溶解・分散して得られる水溶液又は水分散液のｐＨを、２５℃で測定して得られる値を意味する。本発明においては、アナグリプチン又はその塩の安定性の観点から、医薬組成物の水溶液又は水分散液のｐＨ値が１０以下である必要があるが、２～９．９の範囲内であるのがより好ましく、３～９．８の範囲内であるのがさらに好ましく、４．５～９．７の範囲内であるのがさらにより好ましく、６～９．６の範囲内であるのが特に好ましい。
In the present invention, the “pH value of an aqueous solution or aqueous dispersion” of a pharmaceutical composition is a ratio of 100 ml of a pharmaceutical composition containing anagliptin or a salt thereof to 625 mg (converted to free form) of anagliptin in the composition. Means a value obtained by measuring the pH of an aqueous solution or aqueous dispersion obtained by dissolving and dispersing in an amount of water corresponding to In the present invention, from the viewpoint of the stability of anagliptin or a salt thereof, the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition needs to be 10 or less, but is within the range of 2 to 9.9. More preferably, it is more preferably within the range of 3 to 9.8, even more preferably within the range of 4.5 to 9.7, and particularly preferably within the range of 6 to 9.6. .
本発明において、医薬組成物の水溶液又は水分散液のｐＨ値は、製剤添加物として弱酸性～弱塩基性のもの（具体的には、水に溶解させたときｐＨ値が常温において約６～１０の範囲内の値を示し得るもの。以下、「弱酸性～弱塩基性製剤添加物」ともいう。）を適宜選択して配合することにより調整できる。このような、弱酸性～弱塩基性製剤添加物としては、具体的には例えば、果糖、キシリトール、Ｄ－ソルビトール、乳糖、無水乳糖、粉糖、白糖、精製白糖、ブドウ糖水和物、Ｄ－マンニトール、エリスリトール、トレハロース、マルチトール等の糖類・糖アルコール類；アルファー化デンプン、部分アルファー化デンプン、デキストリン、トウモロコシデンプン、バレイショデンプン、ヒドロキシプロピルスターチ、還元麦芽糖水アメ、コムギデンプン、コメデンプン等のデンプン類；ヒドロキシプロピルセルロース、粉末セルロース、結晶セルロース、微結晶セルロース等のセルロース類等が挙げられる。
In the present invention, the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition is a weakly acidic to weakly basic formulation additive (specifically, the pH value when dissolved in water is about 6 to A value that can exhibit a value within the range of 10. Hereinafter, it is also referred to as “weakly acidic to weakly basic preparation additive”), and can be adjusted by appropriately selecting and blending. Specific examples of such weakly acidic to weakly basic formulation additives include fructose, xylitol, D-sorbitol, lactose, anhydrous lactose, powdered sugar, sucrose, purified sucrose, glucose hydrate, D- Sugars and sugar alcohols such as mannitol, erythritol, trehalose, maltitol; pregelatinized starch, partially pregelatinized starch, dextrin, corn starch, potato starch, hydroxypropyl starch, reduced maltose syrup, wheat starch, rice starch, etc. And the like; celluloses such as hydroxypropylcellulose, powdered cellulose, crystalline cellulose, microcrystalline cellulose and the like.
このような、弱酸性～弱塩基性製剤添加物の含有量は特に限定されず、医薬組成物のｐＨ値に応じて適宜検討して決定すればよいが、医薬組成物全質量に対して１０～９９質量％含有するのが好ましく、２０～９７質量％含有するのがより好ましく、３０～９５質量％含有するのが特に好ましい。また、本発明において、医薬組成物の水溶液又は水分散液のｐＨ値は、医薬組成物中のアナグリプチン又はその塩の含有量を当該ｐＨ値に応じて選択することによっても調整できる。
The content of such weakly acidic to weakly basic formulation additive is not particularly limited, and may be determined by appropriate examination according to the pH value of the pharmaceutical composition. The content is preferably -99% by mass, more preferably 20-97% by mass, and particularly preferably 30-95% by mass. In the present invention, the pH value of the aqueous solution or aqueous dispersion of the pharmaceutical composition can also be adjusted by selecting the content of anagliptin or a salt thereof in the pharmaceutical composition according to the pH value.
本発明において、「医薬組成物」の剤形は特に限定されるものではなく、固形状、半固形状、液状のいずれの形状であってもよく、その利用目的等に応じて医薬として通常利用される形状とすることができる。アナグリプチンは水に極めて溶けやすいため、液状はおろか固形状、半固形状の医薬組成物中においても、その安定性は周囲のｐＨ環境に大きく影響を受ける。医薬組成物の剤形としては、具体的には例えば、第十六改正日本薬局方 製剤総則等に記載の剤形、具体的には錠剤（通常錠、口腔内崩壊型錠剤、チュアブル錠、発泡錠、分散錠、溶解錠など）、カプセル剤、顆粒剤、細粒剤、散剤等の経口投与用固形製剤；経口液剤（エリキシル剤、懸濁剤、乳剤、リモナーデ剤など）；経口ゼリー剤；口腔用錠剤（トローチ剤、舌下錠、バッカル錠、付着錠、ガム剤など）；口腔用スプレー剤；口腔用半固形剤等が挙げられるが、服用の容易性等の観点から経口投与用固形製剤が好ましい。なお、これらの経口投与用固形製剤は、必要に応じてフィルム、糖衣等でコーティングされていてもよい。
In the present invention, the dosage form of the “pharmaceutical composition” is not particularly limited, and may be any of solid, semi-solid, and liquid forms, and is usually used as a medicine depending on the purpose of use and the like. The shape can be made. Since anagliptin is extremely soluble in water, its stability is greatly affected by the surrounding pH environment even in liquid, solid and semi-solid pharmaceutical compositions. As the dosage form of the pharmaceutical composition, specifically, for example, the dosage form described in the 16th revised Japanese Pharmacopoeia, General Rules for Formulation, etc., specifically tablets (ordinary tablets, orally disintegrating tablets, chewable tablets, effervescent tablets) Tablets, dispersible tablets, dissolving tablets, etc.), capsules, granules, fine granules, powders and other solid preparations for oral administration; oral solutions (elixirs, suspensions, emulsions, limonades, etc.); oral jelly preparations; Oral tablets (troches, sublingual tablets, buccal tablets, adhesive tablets, gums, etc.); oral sprays; oral solids, etc., but from the viewpoint of ease of administration, etc. A formulation is preferred. These solid preparations for oral administration may be coated with a film, sugar coating or the like, if necessary.
本発明の医薬組成物は、上記の剤形に応じ、例えば第十六改正日本薬局方 製剤総則等に記載の公知の方法により製造することができる。具体的には例えば、医薬組成物が錠剤である場合、アナグリプチン又はその塩に加えて、下記のような適当な製剤添加物を混合し、次いで、圧縮成型すればよい。圧縮成型の方法としては、乾式顆粒圧縮法、半乾式顆粒圧縮法、湿式顆粒圧縮法等のように造粒後に圧縮成形して製造する方法や、直接粉末圧縮法等が挙げられる。造粒方法としては、押出し造粒、撹拌造粒、転動造粒、噴霧乾燥造粒、破砕造粒、流動層造粒、溶融造粒等が挙げられる。
The pharmaceutical composition of the present invention can be produced by a known method described in, for example, the 16th revised Japanese Pharmacopoeia, General Rules for Preparations, etc. according to the above dosage form. Specifically, for example, when the pharmaceutical composition is a tablet, in addition to anagliptin or a salt thereof, an appropriate formulation additive as described below may be mixed and then compression molded. Examples of the compression molding method include a method of compression molding after granulation such as a dry granule compression method, a semi-dry granule compression method, and a wet granule compression method, and a direct powder compression method. Examples of the granulation method include extrusion granulation, stirring granulation, rolling granulation, spray drying granulation, crushed granulation, fluidized bed granulation, and melt granulation.
本発明の医薬組成物の製造においては、上記したアナグリプチン、弱酸性～弱塩基性製剤添加物などの成分以外にも、剤形に応じて賦形剤、結合剤、流動化剤、矯味剤、着色剤等の適当な製剤添加物を適宜用いることができる。
In the production of the pharmaceutical composition of the present invention, in addition to the above-mentioned components such as anagliptin and weakly acidic to weakly basic preparation additives, excipients, binders, fluidizing agents, corrigents, Appropriate formulation additives such as colorants can be used as appropriate.
本発明の医薬組成物は、ＤＰＰ－IV阻害作用を有するアナグリプチン又はその塩を含有することから、２型糖尿病に対する医薬等として有用である。この場合において、本発明の医薬組成物は、上記した１日投与量となるよう１回又は２回以上の複数回に分けて服用することができる。
Since the pharmaceutical composition of the present invention contains anagliptin having a DPP-IV inhibitory action or a salt thereof, it is useful as a medicament for type 2 diabetes. In this case, the pharmaceutical composition of the present invention can be taken in one or two or more divided doses so as to achieve the above-mentioned daily dose.
次に、実施例を挙げて本発明を更に説明するが、本発明はこれらに限定されるものではない。
［試験例］アナグリプチンの各種ｐＨ条件下での安定性の検討
アナグリプチン６２５ｍｇを、２５℃の条件下でｐＨ２、３、７、１０、１１又は１２に調整したＢｒｉｔｔｏｎ－Ｒｏｂｉｎｓｏｎ緩衝液１００ｍｌに溶解し、２５℃にて１日間保存し、試験開始時及び１日保存後のアナグリプチンを定量することにより、各種ｐＨ条件下での安定性を評価した。
なお、アナグリプチンの定量値（％）は、ＨＰＬＣを用いて、濃度既知の標準溶液とピーク面積を比較することにより算出した。 Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these.
[Test Example] Examination of stability of anagliptin under various pH conditions 625 mg of anagliptin was dissolved in 100 ml of Britton-Robinson buffer adjusted to pH 2, 3, 7, 10, 11 or 12 under the condition of 25 ° C. It was stored at 25 ° C. for 1 day, and the stability under various pH conditions was evaluated by quantifying anagliptin at the start of the test and after storage for 1 day.
The quantitative value (%) of anagliptin was calculated by comparing the peak area with a standard solution with a known concentration using HPLC.
［試験例］アナグリプチンの各種ｐＨ条件下での安定性の検討
アナグリプチン６２５ｍｇを、２５℃の条件下でｐＨ２、３、７、１０、１１又は１２に調整したＢｒｉｔｔｏｎ－Ｒｏｂｉｎｓｏｎ緩衝液１００ｍｌに溶解し、２５℃にて１日間保存し、試験開始時及び１日保存後のアナグリプチンを定量することにより、各種ｐＨ条件下での安定性を評価した。
なお、アナグリプチンの定量値（％）は、ＨＰＬＣを用いて、濃度既知の標準溶液とピーク面積を比較することにより算出した。 Next, although an Example is given and this invention is further demonstrated, this invention is not limited to these.
[Test Example] Examination of stability of anagliptin under various pH conditions 625 mg of anagliptin was dissolved in 100 ml of Britton-Robinson buffer adjusted to pH 2, 3, 7, 10, 11 or 12 under the condition of 25 ° C. It was stored at 25 ° C. for 1 day, and the stability under various pH conditions was evaluated by quantifying anagliptin at the start of the test and after storage for 1 day.
The quantitative value (%) of anagliptin was calculated by comparing the peak area with a standard solution with a known concentration using HPLC.
結果を表１に示す。表１記載の試験結果より、アナグリプチンはｐＨ１０以下の環境では極めて安定である一方、ｐＨ１０を超えると大きく不安定化し、ｐＨ１２の条件下では１日保存後においてアナグリプチンの残存量は大よそ１０％を割り込む結果となった。
以上の試験結果から、アナグリプチン又はその塩を含有する医薬組成物の水溶液又は水分散液のｐＨを１０以下とすることにより、アナグリプチン又はその塩の安定性に優れる医薬組成物が得られることが明らかとなった。 The results are shown in Table 1. From the test results shown in Table 1, anagliptin is extremely stable in an environment of pH 10 or lower, but greatly destabilized when the pH exceeds 10, and the residual amount of anagliptin is about 10% after storage for 1 day under the condition of pH 12. The result was interrupted.
From the above test results, it is clear that a pharmaceutical composition having excellent stability of anagliptin or a salt thereof can be obtained by setting the pH of the aqueous solution or aqueous dispersion of the pharmaceutical composition containing anagliptin or a salt thereof to 10 or less. It became.
以上の試験結果から、アナグリプチン又はその塩を含有する医薬組成物の水溶液又は水分散液のｐＨを１０以下とすることにより、アナグリプチン又はその塩の安定性に優れる医薬組成物が得られることが明らかとなった。 The results are shown in Table 1. From the test results shown in Table 1, anagliptin is extremely stable in an environment of pH 10 or lower, but greatly destabilized when the pH exceeds 10, and the residual amount of anagliptin is about 10% after storage for 1 day under the condition of pH 12. The result was interrupted.
From the above test results, it is clear that a pharmaceutical composition having excellent stability of anagliptin or a salt thereof can be obtained by setting the pH of the aqueous solution or aqueous dispersion of the pharmaceutical composition containing anagliptin or a salt thereof to 10 or less. It became.
［実施例１］
以下の方法により、１錠中にアナグリプチンを１００ｍｇ含有する錠剤を製造した。
すなわち、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１．５質量部）を用いて、流動層造粒した。得られた粒状物を乾燥後整粒し、整粒物にクロスポビドン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）３２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１．５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１５０ｍｇとなるように打錠して、錠剤を得た。 [Example 1]
A tablet containing 100 mg of anagliptin in one tablet was produced by the following method.
That is, 100 parts by mass of anagliptin was fluidized-bed granulated using a hydroxypropylcellulose aqueous solution (1.5 parts by mass as hydroxypropylcellulose). The resulting granular product was dried and sized, and 15 parts by mass of crospovidone and 32 parts by mass of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) were added and mixed. Next, 1.5 parts by mass of magnesium stearate was added and mixed to obtain granules for tableting. The obtained granules for tableting were tableted to give 150 mg per tablet to obtain tablets.
以下の方法により、１錠中にアナグリプチンを１００ｍｇ含有する錠剤を製造した。
すなわち、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１．５質量部）を用いて、流動層造粒した。得られた粒状物を乾燥後整粒し、整粒物にクロスポビドン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）３２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１．５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１５０ｍｇとなるように打錠して、錠剤を得た。 [Example 1]
A tablet containing 100 mg of anagliptin in one tablet was produced by the following method.
That is, 100 parts by mass of anagliptin was fluidized-bed granulated using a hydroxypropylcellulose aqueous solution (1.5 parts by mass as hydroxypropylcellulose). The resulting granular product was dried and sized, and 15 parts by mass of crospovidone and 32 parts by mass of crystalline cellulose (Asahi Kasei Chemicals Co., Ltd .: Theolas KG-802) were added and mixed. Next, 1.5 parts by mass of magnesium stearate was added and mixed to obtain granules for tableting. The obtained granules for tableting were tableted to give 150 mg per tablet to obtain tablets.
得られた錠剤をすりつぶし、アナグリプチンのフリー体６２５ｍｇに相当する量（９３７．５ｍｇ）をほぼ２５℃にて精製水１００ｍｌに溶解させたところ、そのｐＨ値は約９．４であった。
また、得られた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。アナグリプチンの分解生成物量は1.58％であり、アナグリプチンの安定性は良好であった。 The obtained tablet was ground and an amount equivalent to 625 mg of anagliptin free body (937.5 mg) was dissolved in 100 ml of purified water at about 25 ° C., and its pH value was about 9.4.
The obtained tablets were placed in a plastic petri dish and subjected to a 21-day stability test at a temperature of 60 ° C. and a relative humidity of 75%. The degradation product amount of anagliptin was 1.58%, and the stability of anagliptin was good.
また、得られた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。アナグリプチンの分解生成物量は1.58％であり、アナグリプチンの安定性は良好であった。 The obtained tablet was ground and an amount equivalent to 625 mg of anagliptin free body (937.5 mg) was dissolved in 100 ml of purified water at about 25 ° C., and its pH value was about 9.4.
The obtained tablets were placed in a plastic petri dish and subjected to a 21-day stability test at a temperature of 60 ° C. and a relative humidity of 75%. The degradation product amount of anagliptin was 1.58%, and the stability of anagliptin was good.
本発明によれば、ＤＰＰ－IV阻害活性を有するアナグリプチン又はその塩を含有し、安定性に優れる医薬組成物を提供でき、医薬品産業等において利用できる。
According to the present invention, a pharmaceutical composition containing anagliptin having a DPP-IV inhibitory activity or a salt thereof and having excellent stability can be provided and used in the pharmaceutical industry and the like.
Claims (6)
- アナグリプチン又はその塩を含有し、その水溶液又は水分散液のｐＨ値が１０以下である医薬組成物。 A pharmaceutical composition containing anagliptin or a salt thereof and having an aqueous solution or aqueous dispersion having a pH value of 10 or less.
- 弱酸性～弱塩基性製剤添加物を含有する、請求項１記載の医薬組成物。 The pharmaceutical composition according to claim 1, comprising a weakly acidic to weakly basic preparation additive.
- アナグリプチン又はその塩の含有量が、医薬組成物全質量に対し１～９０質量％である、請求項１又は２記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the content of anagliptin or a salt thereof is 1 to 90% by mass relative to the total mass of the pharmaceutical composition.
- その水溶液又は水分散液のｐＨ値が２～１０である、請求項１～３のいずれか１項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3, wherein the pH value of the aqueous solution or aqueous dispersion is 2 to 10.
- 経口投与用固形製剤である、請求項１～４のいずれか１項記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, which is a solid preparation for oral administration.
- 前記経口投与用固形製剤が、錠剤、カプセル剤、顆粒剤、細粒剤、又は散剤である、請求項５記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the solid preparation for oral administration is a tablet, capsule, granule, fine granule, or powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014538614A JP6283313B2 (en) | 2012-09-27 | 2013-09-27 | Anagliptin-containing pharmaceutical composition |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012214891 | 2012-09-27 | ||
| JP2012-214891 | 2012-09-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014051024A1 true WO2014051024A1 (en) | 2014-04-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2013/076204 WO2014051024A1 (en) | 2012-09-27 | 2013-09-27 | Anagliptin-containing drug composition |
Country Status (2)
| Country | Link |
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| JP (1) | JP6283313B2 (en) |
| WO (1) | WO2014051024A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019004447A1 (en) * | 2017-06-30 | 2019-01-03 | 興和株式会社 | Pharmaceutical composition |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004067509A1 (en) * | 2003-01-31 | 2004-08-12 | Sanwa Kagaku Kenkyusho Co., Ltd. | Compound inhibiting dipeptidyl peptidase iv |
| JP2009535376A (en) * | 2006-05-04 | 2009-10-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | DPPIV inhibitor preparation |
| WO2009139362A1 (en) * | 2008-05-14 | 2009-11-19 | 株式会社 三和化学研究所 | Pharmaceutical preparation comprising dpp-iv inhibitor and other diabetes therapeutic agent in concomitant or combined form |
| WO2010147768A1 (en) * | 2009-06-15 | 2010-12-23 | Merck Sharp & Dohme Corp. | Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with pioglitazone |
-
2013
- 2013-09-27 WO PCT/JP2013/076204 patent/WO2014051024A1/en active Application Filing
- 2013-09-27 JP JP2014538614A patent/JP6283313B2/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004067509A1 (en) * | 2003-01-31 | 2004-08-12 | Sanwa Kagaku Kenkyusho Co., Ltd. | Compound inhibiting dipeptidyl peptidase iv |
| JP2009535376A (en) * | 2006-05-04 | 2009-10-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | DPPIV inhibitor preparation |
| WO2009139362A1 (en) * | 2008-05-14 | 2009-11-19 | 株式会社 三和化学研究所 | Pharmaceutical preparation comprising dpp-iv inhibitor and other diabetes therapeutic agent in concomitant or combined form |
| WO2010147768A1 (en) * | 2009-06-15 | 2010-12-23 | Merck Sharp & Dohme Corp. | Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with pioglitazone |
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| Title |
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| KATO N. ET AL.: "Discovery and pharmacological characterization of N-[2-({2-[(2S)-2- cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2- methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine -6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 19, no. 23, 2011, pages 7221 - 7227 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019004447A1 (en) * | 2017-06-30 | 2019-01-03 | 興和株式会社 | Pharmaceutical composition |
| US11344535B2 (en) | 2017-06-30 | 2022-05-31 | Kowa Company, Ltd. | Pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6283313B2 (en) | 2018-02-21 |
| JPWO2014051024A1 (en) | 2016-08-22 |
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