JP2022028041A - Pharmaceutial composition comprising dasatinib as active ingredient - Google Patents
Pharmaceutial composition comprising dasatinib as active ingredient Download PDFInfo
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- JP2022028041A JP2022028041A JP2021207695A JP2021207695A JP2022028041A JP 2022028041 A JP2022028041 A JP 2022028041A JP 2021207695 A JP2021207695 A JP 2021207695A JP 2021207695 A JP2021207695 A JP 2021207695A JP 2022028041 A JP2022028041 A JP 2022028041A
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- dasatinib
- pharmaceutical
- pharmaceutical composition
- active ingredient
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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Abstract
Description
本発明は、ダサチニブを有効成分とする医薬組成物及びそれを用いた医薬錠剤、並びにその製造方法に関する。 The present invention relates to a pharmaceutical composition containing dasatinib as an active ingredient, a pharmaceutical tablet using the same, and a method for producing the same.
ダサチニブは、化学名をＮ－（２－クロロ－６－メチルフェニル）－２－（｛６－［４－（２－ヒドロキシエチル）ピペラジン－１－イル］－２－メチルピリミジン－４－イル｝アミノ）－１、３－チアゾール－５－カルボキサミドとする、式（１）で示される構造を有する化合物である。 Dasatinib has the chemical name N- (2-chloro-6-methylphenyl) -2-({6- [4- (2-hydroxyethyl) piperazine-1-yl] -2-methylpyrimidine-4-yl}. Amino) -1,3-thiazole-5-carboxamide, which is a compound having a structure represented by the formula (1).
慢性骨髄性白血病（ＣＭＬ）及びＰｈｉｌａｄｅｌｐｈｉａ染色体陽性急性リンパ性白血病（Ｐｈ＋ＡＬＬ）は、いずれもＰｈｉｌａｄｅｌｐｈｉａ染色体上に形成されたｂｃｒ－ａｂｌキメラ遺伝子が産生するＢｃｒ－Ａｂｌ融合タンパクが、発症と白血病細胞の増殖に関与している疾患である。
現在、ＣＭＬ及び同種造血幹細胞移植の適応とならないＰｈ＋ＡＬＬに対する薬物療法としては、Ｂｃｒ－Ａｂｌチロシンキナーゼ活性を阻害するイマチニブメシル酸塩（以下、イマチニブと略す。）が用いられているが、Ｂｃｒ－Ａｂｌのキナーゼ領域内における点突然変異によりイマチニブの結合親和性が低下することが報告されており、当該変異がイマチニブへの治療抵抗性の要因の一つであると考えられている。
ダサチニブは、Ａｂｌキナーゼの立体構造への結合様式がイマチニブと一部異なることから、イマチニブ抵抗性ＣＭＬ及びＰｈ＋ＡＬＬの治療薬として用いられており、スプリセル（登録商標）の商品名にて提供されている。
In both chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph + ALL), the Bcr-Abl fusion protein produced by the bcr-abl chimeric gene formed on the Philadelphia chromosome develops and proliferates leukemia cells. It is a disease involved in.
Currently, imatinib mesylate (hereinafter abbreviated as imatinib), which inhibits Bcr-Abl tyrosine kinase activity, is used as a drug therapy for Ph + ALL, which is not indicated for CML and allogeneic hematopoietic stem cell transplantation. It has been reported that point mutations in the kinase region of Tyrosine reduce the binding affinity of imatinib, and the mutation is considered to be one of the factors of treatment resistance to imatinib.
Dasatinib is used as a therapeutic agent for imatinib-resistant CML and Ph + ALL because the mode of binding of Abl kinase to the three-dimensional structure is partially different from that of imatinib, and is provided under the trade name of Sprycel®. ..
特許文献１は、ダサチニブの分解がコーティング剤中の可塑剤により引き起こされることを示唆するものであり、ポリエチレングリコールを可塑剤として含む非反応性コーティング剤を用いたダサチニブの医薬錠剤を記載している。具体的にはダサチニブ、並びに乳糖一水和物、微結晶セルロース、ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、ステアリン酸マグネシウムを含み、錠剤外部である被覆層にオパドライ（登録商標）ホワイトを含む薄層被覆錠剤が記載されている。オパドライ（登録商標）ホワイトは、可塑剤としてポリエチレングリコール、基剤としてヒドロキシプロピルメチルセルロース、隠蔽剤として二酸化チタンを含むプレミックスのコーティング剤である。 Patent Document 1 suggests that the decomposition of dasatinib is caused by the plasticizer in the coating agent, and describes a pharmaceutical tablet of dasatinib using a non-reactive coating agent containing polyethylene glycol as a plasticizer. .. Specifically, a thin layer coating containing dasatinib, lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, and opadry (registered trademark) white on the coating layer outside the tablet. Tablets are listed. Opadry® White is a premix coating agent containing polyethylene glycol as a plasticizer, hydroxypropylmethyl cellulose as a base, and titanium dioxide as a concealing agent.
本発明の目的は、ダサチニブを有効成分とする医薬組成物を提供することであって、ダサチニブと反応しない添加剤を含む医薬組成物を提供することを課題とする。特にダサチニブと反応しないフィルムコーティング剤に用いることができる可塑剤を含む医薬組成物を提供することを課題とする。 An object of the present invention is to provide a pharmaceutical composition containing dasatinib as an active ingredient, and an object of the present invention is to provide a pharmaceutical composition containing an additive that does not react with dasatinib. In particular, it is an object of the present invention to provide a pharmaceutical composition containing a plasticizer that can be used for a film coating agent that does not react with dasatinib.
ダサチニブはコーティング剤成分と反応してしまうことが知られており、可塑剤としてポリエチレングリコールを含むコーティング剤が唯一の非反応性材料として知られていた。しかしながら、更なるダサチニブの安定性に影響を及ぼさないコーティング剤、及びそれに用いることができるコーティング剤用の可塑剤が求められていた。本発明者は、ダサチニブに対する非反応性添加剤として、クエン酸トリエチル、Ｄ－ソルビトール、グリセリン、プロピレングリコール及び流動パラフィンからなる群より選択される１種以上の添加剤を見出し、これらを用いることによりダサチニブの安定性が担保された医薬組成物を提供できることを見出し、本発明を完成させた。すなわち、本発明は以下の［１］～［５］を要旨とする。 Dasatinib is known to react with the coating agent component, and coating agents containing polyethylene glycol as a plasticizer have been known as the only non-reactive material. However, there has been a demand for a coating agent that does not affect the stability of dasatinib, and a plasticizer for the coating agent that can be used therefor. The present inventor has found one or more additives selected from the group consisting of triethyl citrate, D-sorbitol, glycerin, propylene glycol and liquid paraffin as non-reactive additives to dasatinib, and by using these. The present invention has been completed by finding that it is possible to provide a pharmaceutical composition in which the stability of dasatinib is guaranteed. That is, the gist of the present invention is the following [1] to [5].
［１］ ダサチニブを有効成分とする医薬組成物であって、クエン酸トリエチル、Ｄ－ソルビトール、グリセリン、プロピレングリコール及び流動パラフィンからなる群より選択される１種以上の添加剤を含む医薬組成物。
［２］ 添加剤がグリセリン、プロピレングリコール及び流動パラフィンからなる群より選択される１種以上である前記［１］に記載の医薬組成物。
［３］ 添加剤がコーティング剤として含まれる前記［１］又［２］の何れか一項に記載の医薬組成物。
［４］ 前記［１］～［３］の何れか一項に記載の医薬組成物が成型された医薬錠剤であって、添加剤がコーティング剤に含まれているダサチニブを有効成分とする医薬錠剤。
［５］ ダサチニブを有効成分とする医薬錠剤の製造方法であって、ダサチニブ、並びに賦形剤、結合剤、崩壊剤、滑沢剤を含む混合物を圧縮成型して得られる錠剤に、クエン酸トリエチル、Ｄ－ソルビトール、グリセリン、プロピレングリコール及び流動パラフィンからなる群より選択される１種以上の添加剤を含むコーティング剤でコーティングする工程を含む医薬錠剤の製造方法。
[1] A pharmaceutical composition containing dasatinib as an active ingredient, which comprises one or more additives selected from the group consisting of triethyl citrate, D-sorbitol, glycerin, propylene glycol and liquid paraffin.
[2] The pharmaceutical composition according to the above [1], wherein the additive is at least one selected from the group consisting of glycerin, propylene glycol and liquid paraffin.
[3] The pharmaceutical composition according to any one of the above [1] and [2], wherein the additive is contained as a coating agent.
[4] A pharmaceutical tablet obtained by molding the pharmaceutical composition according to any one of the above [1] to [3] and containing dasatinib, which contains an additive in a coating agent, as an active ingredient. ..
[5] Triethyl citrate is a method for producing a pharmaceutical tablet containing dasatinib as an active ingredient, which is obtained by compression molding a mixture containing dasatinib and an excipient, a binder, a disintegrant, and a lubricant. , A method for producing a pharmaceutical tablet comprising a step of coating with a coating agent containing one or more additives selected from the group consisting of D-sorbitol, glycerin, propylene glycol and liquid paraffin.
本発明のダサチニブと、クエン酸トリエチル、Ｄ－ソルビトール、グリセリン、プロピレングリコール及び流動パラフィンからなる群より選択される１種以上の添加剤を含む医薬組成物は、添加剤によるダサチニブの分解がなく、化学的安定性が確保された医薬組成物である。したって、ダサチニブを有効成分とする医薬製剤を調製する際に、当該医薬組成物を用いることにより安定な医薬製剤を提供することができる。 The pharmaceutical composition containing the dasatinib of the present invention and one or more additives selected from the group consisting of triethyl citrate, D-sorbitol, glycerin, propylene glycol and liquid paraffin does not decompose dasatinib by the additives. It is a pharmaceutical composition in which chemical stability is ensured. Therefore, when preparing a pharmaceutical preparation containing dasatinib as an active ingredient, a stable pharmaceutical preparation can be provided by using the pharmaceutical composition.
本願発明は、ダサチニブを有効成分とする医薬組成物であって、クエン酸トリエチル、Ｄ－ソルビトール、グリセリン、プロピレングリコール及び流動パラフィンからなる群より選択される１種以上の添加剤を含む医薬組成物、それを用いたコーティング錠剤、並びに医薬錠剤の製造方法に関する。以下にその詳細について説明する。 The present invention is a pharmaceutical composition containing dasatinib as an active ingredient, which comprises one or more additives selected from the group consisting of triethyl citrate, D-sorbitol, glycerin, propylene glycol and liquid paraffin. , A method for producing a coated tablet using the same, and a pharmaceutical tablet. The details will be described below.
本発明の医薬組成物は、有効成分としてダサチニブを用いる。ダサチニブは、化学名をＮ－（２－クロロ－６－メチルフェニル）－２－（｛６－［４－（２－ヒドロキシエチル）ピペラジン－１－イル］－２－メチルピリミジン－４－イル｝アミノ）－１、３－チアゾール－５－カルボキサミドとする化合物である。当該化合物は、特表２００２－５４２１９３号公報にて実施例４５５として開示されており、それに記載の方法により合成することができる。
ダサチニブは医薬品の有効成分として用いることができる品質レベルの化合物を用いることが望ましい。
本発明の医薬組成物は、有効成分としてダサチニブ水和物、有機溶媒和物又はその医薬的に許容な塩を用いても良い。
The pharmaceutical composition of the present invention uses dasatinib as an active ingredient. Dasatinib has the chemical name N- (2-chloro-6-methylphenyl) -2-({6- [4- (2-hydroxyethyl) piperazine-1-yl] -2-methylpyrimidine-4-yl}. Amino) -1,3-thiazole-5-carboxamide is a compound. The compound is disclosed as Example 455 in JP-A-2002-542193, and can be synthesized by the method described therein.
It is desirable to use dasatinib as a quality level compound that can be used as an active ingredient in pharmaceutical products.
The pharmaceutical composition of the present invention may use dasatinib hydrate, an organic solvate or a pharmaceutically acceptable salt thereof as an active ingredient.
本発明の医薬組成物は、医薬用の添加剤として、クエン酸トリエチル、Ｄ－ソルビトール、グリセリン、プロピレングリコール及び流動パラフィンからなる群より選択される１種以上の添加剤を含むことを特徴とする。これらの添加剤は、医薬製剤の添加剤として認められており、特にコーティング剤の可塑剤として用いられているものである。これらは単独で用いても良く、２種以上を混合して用いても良い。これら添加剤の中でも、グリセリン、プロピレングリコール及び流動パラフィンからなる群から選択される１種以上がより好ましい。
当該添加剤は、医薬品添加剤として用いられる品質のものであれば、特に制限することなく用いることができる。
当該医薬組成物において、これらの添加剤はコーティング剤に含まれる可塑剤として用いても良い。当該添加剤がコーティング剤に含まれる場合、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、エチルセルロース等をコーティング基材とし、任意に遮光剤や着色剤と共に混合して用いられる。
また、当該添加剤を結合剤、可溶化剤等としてダサチニブと共に混合して用いても良い。その場合は、ダサチニブ及び当該添加剤を、任意の更なる医薬品用添加剤と共に混合することで調製されるものである。
The pharmaceutical composition of the present invention is characterized by containing, as a pharmaceutical additive, one or more additives selected from the group consisting of triethyl citrate, D-sorbitol, glycerin, propylene glycol and liquid paraffin. .. These additives are recognized as additives for pharmaceutical preparations, and are particularly used as plasticizers for coating agents. These may be used alone or in combination of two or more. Among these additives, one or more selected from the group consisting of glycerin, propylene glycol and liquid paraffin is more preferable.
The additive can be used without particular limitation as long as it is of a quality that can be used as a pharmaceutical additive.
In the pharmaceutical composition, these additives may be used as a plasticizer contained in the coating agent. When the additive is contained in the coating agent, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, ethylcellulose or the like is used as a coating base material, and is optionally mixed with a light-shielding agent or a coloring agent.
Further, the additive may be mixed with dasatinib as a binder, a solubilizer, or the like and used. In that case, it is prepared by mixing dasatinib and the additive with any further pharmaceutical additives.
本発明の医薬組成物において、ダサチニブは５質量％以上６０質量％以下で含有することが好ましい。好ましくは１０質量％以上５０質量％以下である。
一方、当該添加剤は０．０５質量％以上１０質量％以下で使用することが好ましい。好ましくは０．１質量％以上質量５％以下である。
In the pharmaceutical composition of the present invention, dasatinib is preferably contained in an amount of 5% by mass or more and 60% by mass or less. It is preferably 10% by mass or more and 50% by mass or less.
On the other hand, the additive is preferably used in an amount of 0.05% by mass or more and 10% by mass or less. It is preferably 0.1% by mass or more and 5% or less by mass.
ダサチニブはイマチニブ抵抗性ＣＭＬ及びＰｈ＋ＡＬＬの治療薬として経口的に服用されて用いられる。このため、本発明の医薬組成物は、これを成型して調製される医薬錠剤であることが好ましい。医薬錠剤としては、通常の錠剤の他、口腔内崩壊錠といった錠剤形態も含まれる。すなわち本発明の医薬錠剤は、有効成分としてダサチニブと任意の賦形剤、結合剤、崩壊剤、滑沢剤等の錠剤成型用添加剤と併せて混合し、成型することで調製される錠剤であって、クエン酸トリエチル、Ｄ－ソルビトール、グリセリン、プロピレングリコール及び流動パラフィンからなる群より選択される１種以上の添加剤を可塑剤として含むコーティング剤によりコーティングされた医薬錠剤であることが好ましい。
本発明の医薬錠剤において、有効成分であるダサチニブは、医薬錠剤総量に対し５質量％以上６０質量％以下で使用することが好ましい。好ましくは１０質量％以上５０質量％以下である。
また、可塑剤としての当該添加剤は、医薬錠剤総量に対し０．０５質量％以上１０質量％以下で使用することが好ましい。好ましくは０．１質量％以上質量５％以下である。
Dasatinib is taken orally as a therapeutic agent for imatinib-resistant CML and Ph + ALL. Therefore, the pharmaceutical composition of the present invention is preferably a pharmaceutical tablet prepared by molding the pharmaceutical composition. Pharmaceutical tablets include not only ordinary tablets but also tablet forms such as orally disintegrating tablets. That is, the pharmaceutical tablet of the present invention is a tablet prepared by mixing and molding dasatinib as an active ingredient together with any excipient, binder, disintegrant, lubricant and other tablet molding additives. Therefore, it is preferable that the tablet is coated with a coating agent containing one or more additives selected from the group consisting of triethyl citrate, D-sorbitol, glycerin, propylene glycol and liquid paraffin as a plasticizing agent.
In the pharmaceutical tablet of the present invention, dasatinib, which is an active ingredient, is preferably used in an amount of 5% by mass or more and 60% by mass or less based on the total amount of the pharmaceutical tablet. It is preferably 10% by mass or more and 50% by mass or less.
Further, the additive as a plasticizer is preferably used in an amount of 0.05% by mass or more and 10% by mass or less with respect to the total amount of pharmaceutical tablets. It is preferably 0.1% by mass or more and 5% or less by mass.
当該添加剤を、可塑剤として含むコーティング剤によりコーティングされた医薬錠剤を用いる場合、該コーティング剤は、当該添加剤及びコーティング基材、並びに任意に遮光剤や着色剤と共に混合して調製されたものである。
コーティング基材としては、医薬製剤用のコーティング剤として用いられるものであれば特に限定されるものではなく、例えば、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースフタレート、エチルセルロース等のセルロース系コーティング基材が挙げられる。
また、遮光剤や着色剤としては、酸化チタン、黄酸化鉄、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、酸化亜鉛、褐色酸化鉄、タルク、食用黄色素類、食用青色素類、食用赤色素類等が挙げられる。
When a pharmaceutical tablet coated with a coating agent containing the additive as a plasticizer is used, the coating agent is prepared by mixing with the additive and the coating base material, and optionally a light-shielding agent or a colorant. Is.
The coating base material is not particularly limited as long as it is used as a coating agent for pharmaceutical formulations, and examples thereof include cellulosic coating base materials such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and ethylcellulose.
In addition, as light-shielding agents and colorants, titanium oxide, yellow iron oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, zinc oxide, brown iron oxide, talc, edible yellow elements, edible blue pigments, and edible Examples include red pigments.
ダサチニブを有効成分とする医薬錠剤を調製するためには、任意に賦形剤、結合剤、崩壊剤、滑沢剤、可溶化剤、流動化剤、安定化剤、保存剤、矯味剤、着色剤等の医薬製剤を調製するための通常の医薬製剤用添加剤を用いても良い。 In order to prepare pharmaceutical tablets containing dasatinib as an active ingredient, optionally, excipients, binders, disintegrants, lubricants, solubilizers, fluidizers, stabilizers, preservatives, flavoring agents, and coloring agents are used. Ordinary additives for pharmaceutical preparations for preparing pharmaceutical preparations such as agents may be used.
本発明において賦形剤としては、乳糖、マンニトール、マルトース、スクロース、ソルビトール、キシリトール、イノシトール、トウモロコシデンプン等が挙げられ、これらの単独使用、若しくは２種以上を組み合せて用いることが好ましい。
賦形剤を用いる場合は、当該医薬錠剤総量に対し５質量％以上９０質量％以下で使用することが好ましい。好ましくは１０質量％以上８０質量％以下である。
In the present invention, examples of the excipient include lactose, mannitol, maltose, sucrose, sorbitol, xylitol, inositol, corn starch and the like, and it is preferable to use these alone or in combination of two or more.
When an excipient is used, it is preferable to use it in an amount of 5% by mass or more and 90% by mass or less with respect to the total amount of the pharmaceutical tablets. It is preferably 10% by mass or more and 80% by mass or less.
本発明において結合剤としては、結晶セルロース、ヒドロキシプロピルセルロース、ヒプロメロース、ポビドン、部分アルファー化デンプン等が挙げられ、これらの単独使用、若しくは２種以上を組み合せて用いることが好ましい。
結合剤を用いる場合は、当該医薬錠剤総量に対し１質量％以上６０質量％以下で使用することが好ましい。好ましくは２質量％以上５０質量％以下である。
In the present invention, examples of the binder include crystalline cellulose, hydroxypropyl cellulose, hypromellose, povidone, partially pregelatinized starch and the like, and it is preferable to use these alone or in combination of two or more thereof.
When a binder is used, it is preferably used in an amount of 1% by mass or more and 60% by mass or less with respect to the total amount of the pharmaceutical tablets. It is preferably 2% by mass or more and 50% by mass or less.
本発明において崩壊剤としては、カルボキシメチルスターチナトリウム、クロスポビドン、カルメロース、カルメロースナトリウム、カルメロースカルシウム、クロスカルメロースナトリウム、低置換度カルボキシメチルスターチナトリウム等が挙げられ、これらの単独使用、若しくは２種以上を組み合せて用いることが好ましい。
崩壊剤を用いる場合は、当該医薬錠剤総量に対し１質量％以上２０質量％以下で使用することが好ましい。好ましくは２質量％以上１０質量％以下である。
Examples of the disintegrant in the present invention include sodium carboxymethyl starch, crospovidone, carmellose, sodium carmellose, calcium carmellose, sodium croscarmellose, sodium carboxymethyl starch having a low degree of substitution, and the like, and these may be used alone or 2 It is preferable to use a combination of seeds or more.
When a disintegrant is used, it is preferably used in an amount of 1% by mass or more and 20% by mass or less with respect to the total amount of the pharmaceutical tablets. It is preferably 2% by mass or more and 10% by mass or less.
本発明において滑沢剤としては、ステアリン酸、ステアリン酸マグネシウム、ステアリン酸亜鉛、ステアリン酸アルミニウム、モノステアリン酸グリセリン、フマル酸ステアリルナトリウム、ステアリン酸カルシウム、タルク、カルナウバロウ等が挙げられ、これらの単独使用、若しくは２種以上を組み合せて用いることが好ましい。
滑沢剤を用いる場合は、当該医薬錠剤総量に対し０．１質量％以上５質量％以下で使用することが好ましい。好ましくは０．２質量％以上３質量％以下である。
Examples of the lubricant in the present invention include stearic acid, magnesium stearate, zinc stearate, aluminum stearate, glycerin monostearate, sodium stearyl fumarate, calcium stearate, talc, carnauba wax and the like, and these are used alone. Alternatively, it is preferable to use two or more in combination.
When a lubricant is used, it is preferably used in an amount of 0.1% by mass or more and 5% by mass or less with respect to the total amount of the pharmaceutical tablets. It is preferably 0.2% by mass or more and 3% by mass or less.
本発明において可溶化剤としては、ラウリル硫酸ナトリウム、大豆レシチン、精製大豆レシチン、ソルビタン脂肪酸エステル、ダイズ油、ラウロマクロゴール等が挙げられる。
本発明において流動化剤としては、軽質無水ケイ酸、タルク、含水二酸化ケイ素等が挙げられる。
本発明において安定化剤としては、ジブチルヒドロキシトルエン、トコフェロール、亜硫酸塩等が挙げられる。
本発明において保存剤としては、パラオキシ安息香酸エステル類等が挙げられる。
本発明において矯味剤としては、白糖、Ｄ－ソルビトール、キシリトール等が挙げられる。
本発明において着色剤としては、酸化チタン、黄酸化鉄、三二酸化鉄、黄色三二酸化鉄、黒酸化鉄、酸化亜鉛、褐色酸化鉄、タルク、食用黄色素類、食用青色素類、食用赤色素類等が挙げられる。
これらの添加剤は、医薬品製剤用途で許容される純度であれば特に制限されることなく用いることができる。これらの添加剤は１種のみを用いても良く、これらの混合物として用いても良い。当該医薬組成物又は医薬製剤を調製する際に、任意に使用される。
Examples of the solubilizer in the present invention include sodium lauryl sulfate, soybean lecithin, purified soybean lecithin, sorbitan fatty acid ester, soybean oil, lauromacrogol and the like.
Examples of the fluidizing agent in the present invention include light anhydrous silicic acid, talc, and hydrous silicon dioxide.
Examples of the stabilizer in the present invention include dibutylhydroxytoluene, tocopherol, sulfite and the like.
Examples of the preservative in the present invention include paraoxybenzoic acid esters and the like.
Examples of the flavoring agent in the present invention include sucrose, D-sorbitol, xylitol and the like.
In the present invention, the colorants include titanium oxide, yellow iron oxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, zinc oxide, brown iron oxide, talc, edible yellow elements, edible blue pigments, and edible red pigment. Kind and the like.
These additives can be used without particular limitation as long as the purity is acceptable for pharmaceutical pharmaceutical use. Only one of these additives may be used, or a mixture thereof may be used. It is optionally used when preparing the pharmaceutical composition or pharmaceutical product.
本発明は当該添加剤を可塑剤として含むコーティング剤によりコーティングされた医薬錠剤の製造方法を含む。その製造方法は、まず、ダサチニブ及び任意の賦形剤、結合剤、崩壊剤、滑沢剤等の医薬製剤用添加剤を配合し、これを場合によって顆粒体を調製した後に、任意に滑沢剤を別に添加して圧縮成型することにより素錠を調製する。次に、クエン酸トリエチル、Ｄ－ソルビトール、グリセリン、プロピレングリコール及び流動パラフィンからなる群より選択される１種以上の添加剤を可塑剤としてコーティング基材、並びに任意の隠蔽剤や着色剤を、水又は水と任意の割合で混合し得る有機溶剤を含む水性溶剤にて溶解又は懸濁させてコーティング剤水性溶液を調製し、前記の圧縮成型した素錠に、スプレー等により錠剤表面付着させ、熱風を送り錠剤表面から溶媒を除去乾燥させる方法により、調製することができる。 The present invention includes a method for producing a pharmaceutical tablet coated with a coating agent containing the additive as a plasticizer. The production method is as follows: first, dasatinib and an additive for pharmaceutical preparation such as an optional excipient, a binder, a disintegrant, and a lubricant are blended, and if this is used, granules are prepared in some cases, and then the lubricant is arbitrarily prepared. An uncoated tablet is prepared by adding an agent separately and compression-molding. Next, a coating substrate using one or more additives selected from the group consisting of triethyl citrate, D-solvitol, glycerin, propylene glycol and liquid paraffin as a plasticizer, and any concealing agent or coloring agent with water. Alternatively, a coating agent aqueous solution is prepared by dissolving or suspending it in an aqueous solvent containing an organic solvent that can be mixed with water at an arbitrary ratio, and the solution is adhered to the tablet surface by spraying or the like on the compression-molded uncoated tablet, and hot air is used. It can be prepared by a method of removing the solvent from the surface of the tablet and drying it.
本発明の医薬組成物及びそれを用いた医薬錠剤は、添加剤によるダサチニブの類縁物質の生成が抑制されており保存安定性に優れた特性を有する。具体的には、コーティング剤の可塑剤として汎用されているポリエチレングリコールを含む医薬組成物又は医薬錠剤よりもダサチニブの含量低下が抑制されていることを特徴とする。 The pharmaceutical composition of the present invention and a pharmaceutical tablet using the same have excellent storage stability because the production of dasatinib-related substances due to additives is suppressed. Specifically, it is characterized in that the decrease in the content of dasatinib is suppressed as compared with a pharmaceutical composition or a pharmaceutical tablet containing polyethylene glycol, which is widely used as a plasticizer for a coating agent.
以下、本発明を実施例により更に説明する。ただし、本発明がこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be further described with reference to Examples. However, the present invention is not limited to these examples.
［実施例１］
ダサチニブ２００ｍｇ、クエン酸トリエチル２００ｍｇを混合し、実施例１の医薬組成物を調製した。
［実施例２～５、並びに比較例１、２］
実施例１におけるクエン酸トリエチル２００ｍｇに代えて、表１に挙げる添加剤を用い、その他は実施例１と同様の操作を行うことにより実施例２～５、並びに比較例１、２に係る医薬組成物を調製した。
[Example 1]
200 mg of dasatinib and 200 mg of triethyl citrate were mixed to prepare the pharmaceutical composition of Example 1.
[Examples 2 to 5 and Comparative Examples 1 and 2]
By using the additives listed in Table 1 in place of 200 mg of triethyl citrate in Example 1 and performing the same operations as in Example 1, the pharmaceutical compositions according to Examples 2 to 5 and Comparative Examples 1 and 2. The thing was prepared.
実施例１～５、並びに比較例１、２の添加剤を表１にまとめた。
［試験例１］
実施例１～５並びに比較例１、２の医薬組成物を、４０℃、７５％ＲＨ及び６０℃の条件下で、１カ月保存した。
１カ月後に液体クロマトグラフィーによりダサチニブ含量を分析し、開始時からの含量低下率を以下の式により算出した。
（開始時のピーク面積％）－（１カ月後のダサチニブのピーク面積％）
得られた結果を表２に示す。
[Test Example 1]
The pharmaceutical compositions of Examples 1-5 and Comparative Examples 1 and 2 were stored at 40 ° C., 75% RH and 60 ° C. for 1 month.
One month later, the dasatinib content was analyzed by liquid chromatography, and the rate of decrease in content from the start was calculated by the following formula.
(Peak area% at the start)-(Peak area% of dasatinib one month later)
The results obtained are shown in Table 2.
実施例１～５は、比較例１、２と比較し、苛酷条件下での１カ月保存後において、ダサチニブの含量低下が少ないことが確認された。特に、特表２００８－５４０４４０号にて記載されるポリエチレングリコールよりもダサチニブ含量の低下が大きく抑制される物性であった。したがって本発明の医薬組成物は、ダサチニブと反応しない添加剤であることが示された。
It was confirmed that Examples 1 to 5 had less decrease in dasatinib content after storage under harsh conditions for 1 month as compared with Comparative Examples 1 and 2. In particular, the physical characteristics were such that the decrease in dasatinib content was greatly suppressed as compared with the polyethylene glycol described in Japanese Patent Publication No. 2008-540440. Therefore, the pharmaceutical composition of the present invention has been shown to be an additive that does not react with dasatinib.
Claims (4)
A method for producing a pharmaceutical tablet containing dasatinib as an active ingredient, which is obtained by compression-molding a mixture containing dasatinib and an excipient, a binder, a disintegrant and a lubricant, and glycerin, propylene glycol and fluidized tablets. A method for producing a pharmaceutical tablet, which comprises a step of coating with a coating agent containing one or more additives selected from the group consisting of paraffin.
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| JP2008540440A (en) * | 2005-05-05 | 2008-11-20 | ブリストル−マイヤーズ スクイブ カンパニー | SRC / ABL inhibitor |
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| WO2015011578A1 (en) * | 2013-07-22 | 2015-01-29 | Shilpa Medicare Limited | Dasatinib glucuronate salt and process for preparation thereof |
| WO2017134615A1 (en) * | 2016-02-03 | 2017-08-10 | Dr. Reddy's Laboratories Limited | Solid state forms of dasatinib and processes for their preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2008540440A (en) * | 2005-05-05 | 2008-11-20 | ブリストル−マイヤーズ スクイブ カンパニー | SRC / ABL inhibitor |
| JP2010539156A (en) * | 2007-10-23 | 2010-12-16 | テバ ファーマシューティカル インダストリーズ リミティド | Dasatinib polymorph and its preparation process |
| JP2013516442A (en) * | 2010-01-07 | 2013-05-13 | アクロン・モレキュールズ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Small molecules for obesity |
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| WO2015011578A1 (en) * | 2013-07-22 | 2015-01-29 | Shilpa Medicare Limited | Dasatinib glucuronate salt and process for preparation thereof |
| WO2017134615A1 (en) * | 2016-02-03 | 2017-08-10 | Dr. Reddy's Laboratories Limited | Solid state forms of dasatinib and processes for their preparation |
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