JP2017075172A - Aripiprazole-containing powders in which stability is improved - Google Patents
Aripiprazole-containing powders in which stability is improved Download PDFInfo
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本発明は、原薬としてアリピプラゾール（日本医薬品一般名称）を含有する散剤に関する。 The present invention relates to a powder containing aripiprazole (Japanese pharmaceutical generic name) as a drug substance.
アリピプラゾールはドパミンD2 受容体部分アゴニスト作用、ドパミンD3 受容体部分アゴニスト作用、セロトニン5-HT1A 受容体部分アゴニスト作用及びセロトニン5-HT2A 受容体アンタゴニスト作用を併せ持つ薬剤である（非特許文献１参照）。アリピプラゾールと薬理学的に関連する化合物又は化合物群としては、ハロペリドール、リスペリドン、モサプラミン塩酸塩、ゾテピン、クロルプロマジン塩酸塩、オランザピン、クエチアピンフマル酸塩、ペロスピロン塩酸塩、ブロナンセリン、クロザピン等が挙げられる。 Aripiprazole is a drug having both a dopamine D2 receptor partial agonist action, a dopamine D3 receptor partial agonist action, a serotonin 5-HT1A receptor partial agonist action, and a serotonin 5-HT2A receptor antagonist action (see Non-Patent Document 1). Examples of compounds or compound groups that are pharmacologically related to aripiprazole include haloperidol, risperidone, mosapramine hydrochloride, zotepine, chlorpromazine hydrochloride, olanzapine, quetiapine fumarate, perospirone hydrochloride, blonanserin, clozapine and the like.
アリピプラゾールは錠剤、散剤、内用液等の形態で医療現場に上記の治療薬として提供されている。アリピプラゾールを含有する散剤に関しては、流動化剤である軽質無水ケイ酸を含有する処方が非特許文献１で記載されている。流動化剤は、粉体の流動性改善、湿度による固結防止等のために、一般的に用いられる医薬添加剤である。 Aripiprazole is provided as a therapeutic agent in the medical field in the form of tablets, powders, liquids for internal use and the like. Regarding the powder containing aripiprazole, Non-patent Document 1 describes a formulation containing light silicic acid which is a fluidizing agent. The fluidizing agent is a commonly used pharmaceutical additive for improving the fluidity of powder and preventing caking due to humidity.
アリピプラゾールを含有する散剤の化学的な安定性向上に関しては、特許文献１に過酸化物含有量の低いクロスポピドンを使用する技術が紹介されている。しかしながら、記載された技術だけで流動化剤を含有する散剤中のアリピプラゾールの安定性を十分問題がないレベルまで改善できるかどうかは不明であり、本発明者はそのアリピプラゾールの安定性を改善する新たな技術の開発が必要であると考えた。そこで本発明者は、前記の課題を解決するため、アリピプラゾールを含有する散剤の処方及び製造方法に関する検討を開始した。 Regarding the improvement of the chemical stability of powder containing aripiprazole, Patent Document 1 introduces a technique using crospovidone having a low peroxide content. However, it is unclear whether the described technique alone can improve the stability of aripiprazole in powders containing a fluidizing agent to a level that is sufficiently problematic, and the inventor has found a new improvement in the stability of aripiprazole. I thought that it was necessary to develop new technology. Therefore, in order to solve the above-mentioned problems, the present inventor has started investigation on a prescription and a production method of a powder containing aripiprazole.
本発明の課題は、アリピプラゾールを含有する散剤において、その安定性を改善し、アリピプラゾール由来の分解産物（類縁物質）の発生量を抑制することである。 The subject of this invention is improving the stability in the powder containing aripiprazole and suppressing the generation amount of the decomposition product (analogous substance) derived from aripiprazole.
本発明者は、アリピプラゾールの化学的な安定性を改善するため、アリピプラゾールを含有する散剤の処方や製造方法に関して鋭意検討を重ねた。その結果、塩基性の流動化剤を用いて製造されたアリピプラゾール含有散剤は、保存条件下でのアリピプラゾール由来の類縁物質の発生量が有意に低いことを発見した。その発見に基づいて、本発明者は更なる検討を重ね、安定性か改善された、アリピプラゾールを含有する散剤を完成させるに至った。 In order to improve the chemical stability of aripiprazole, the present inventor has intensively studied on the formulation and manufacturing method of powder containing aripiprazole. As a result, it was discovered that the aripiprazole-containing powder produced using a basic fluidizing agent has a significantly low generation amount of related substances derived from aripiprazole under storage conditions. Based on the findings, the present inventor conducted further studies and completed a powder containing aripiprazole having improved stability.
本発明の具体的な構成は、下記（１）〜（５）によって記述されているものである。
（１）アリピプラゾール及びｐＨ８以上の塩基性流動化剤を含有する散剤。
（２）塩基性流動化剤が、ケイ酸カルシウム、タルク、ステアリン酸カルシウム、ステアリン酸マグネシウム、第三リン酸カルシウム、炭酸マグネシウム、ケイ酸マグネシウム、メタケイ酸アルミン酸マグネシウムより選ばれる、前記（１）に記載の散剤。
（３）塩基性流動化剤が、ケイ酸カルシウム又はタルクである、前記（１）に記載の散剤。
（４）散剤全重量に対して塩基性流動化剤が０．０５〜５．０重量％含有される、前記（１）〜（３）のいずれかに記載の散剤。
（５）さらに結合剤を散剤全重量に対して０．１〜５．０重量％含有し、結合剤がヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、可溶性デンプン、部分アルファー化デンプン、ヒプロメロース、メチルセルロース、ポビドン、エチルセルロース、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリエチレングリコールより選ばれる、前記（１）〜（４）のいずれかに記載の散剤。
The specific configuration of the present invention is described by the following (1) to (5).
(1) A powder containing aripiprazole and a basic fluidizing agent having a pH of 8 or higher.
(2) The basic fluidizing agent is selected from calcium silicate, talc, calcium stearate, magnesium stearate, tricalcium phosphate, magnesium carbonate, magnesium silicate, and magnesium aluminate metasilicate. Powder.
(3) The powder according to (1), wherein the basic fluidizing agent is calcium silicate or talc.
(4) The powder according to any one of (1) to (3), wherein the basic fluidizing agent is contained in an amount of 0.05 to 5.0% by weight based on the total weight of the powder.
(5) Further, a binder is contained in an amount of 0.1 to 5.0% by weight based on the total weight of the powder, and the binder is hydroxypropylcellulose, low-substituted hydroxypropylcellulose, soluble starch, partially pregelatinized starch, hypromellose, methylcellulose. , Povidone, ethyl cellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and powder according to any one of (1) to (4), selected from polyethylene glycol.
本発明によれば、アリピプラゾールを含有する散剤において、その安定性を改善し、アリピプラゾール由来の類縁物質の発生量を抑制することが可能である。 ADVANTAGE OF THE INVENTION According to this invention, in the powder containing aripiprazole, the stability can be improved and the generation amount of the related substance derived from aripiprazole can be suppressed.
以下で本発明のアリピプラゾールを含有する散剤の処方及び製造方法を詳細に説明する。但し、以下の記載は本発明を説明するための例示であり、本発明をこの記載範囲にのみ限定する趣旨ではない。 Hereinafter, the formulation and production method of the powder containing aripiprazole of the present invention will be described in detail. However, the following description is an example for explaining the present invention, and is not intended to limit the present invention to this description range.
本発明において使用されているアリピプラゾールのメディアン径(光散乱法による測定値）は５０μｍ以下のものが好ましく、より好ましくは０．１〜２０μｍである。必要に応じて適宜乾式又は湿式粉砕を行い、任意の粒子径に調整することも可能である。本発明の散剤において、アリピプラゾールは散剤全重量に対して０．５〜５．０重量％の範囲で含有されていることが好ましい。アリピプラゾールの結晶形には、無水物結晶形態(Ｉ型又はＩＩ型)、水和物結晶形態、非晶質形態等が挙げられるが、好ましくは無水物結晶形態(Ｉ型又はＩＩ型)である。 The median diameter (measured by a light scattering method) of aripiprazole used in the present invention is preferably 50 μm or less, more preferably 0.1 to 20 μm. If necessary, dry or wet pulverization can be appropriately performed to adjust the particle size to an arbitrary value. In the powder of the present invention, aripiprazole is preferably contained in the range of 0.5 to 5.0% by weight with respect to the total weight of the powder. The crystal form of aripiprazole includes an anhydrous crystal form (type I or type II), a hydrate crystal form, an amorphous form, etc., preferably an anhydrous crystal form (type I or type II) .
本発明の散剤の製造に用いられる、医薬的に許容可能な添加剤としては、通常使用されている賦形剤、結合剤、流動化剤等であり、流動化剤は塩基性であることが好ましい。 Examples of the pharmaceutically acceptable additive used in the production of the powder of the present invention include commonly used excipients, binders, fluidizing agents, etc., and the fluidizing agent may be basic. preferable.
例えば賦形剤としては、トウモロコシデンプン、乳糖水和物、結晶セルロース、D-マンニトール、エリスリトール、キシリトール、ソルビトール、イソマルト、マルチトール、白糖、ショ糖、ブドウ糖等を挙げる事ができ、好ましくはトウモロコシデンプン又は乳糖水和物である。賦形剤は、散剤全重量に対して５０．０〜９９．５重量％、好ましくは９５．０〜９９．５重量％含有される。 Examples of excipients include corn starch, lactose hydrate, crystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, sucrose, sucrose, glucose, and preferably corn starch. Or lactose hydrate. The excipient is contained in an amount of 50.0 to 99.5% by weight, preferably 95.0 to 99.5% by weight, based on the total weight of the powder.
結合剤としては、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、可溶性デンプン、部分アルファー化デンプン、ヒプロメロース、メチルセルロース、ポビドン、エチルセルロース、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリエチレングリコール等を挙げる事ができ、好ましくはヒドロキシプロピルセルロースである。結合剤は、散剤全重量に対して０．１〜０．５重量％の範囲で含有されていることが好ましい。 As binders, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, soluble starch, partially pregelatinized starch, hypromellose, methylcellulose, povidone, ethylcellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyethylene glycol And hydroxypropyl cellulose is preferable. The binder is preferably contained in the range of 0.1 to 0.5% by weight based on the total weight of the powder.
流動化剤としては、ケイ酸カルシウム、タルク、ステアリン酸カルシウム、ステアリン酸マグネシウム、第三リン酸カルシウム、炭酸マグネシウム、ケイ酸マグネシウム、メタケイ酸アルミン酸マグネシウム等を挙げる事ができ、より好ましくはケイ酸カルシウム又はタルクであり、最も好ましくはケイ酸カルシウムである。流動化剤はｐＨ８以上の塩基性であることが好ましく、散剤全重量に対して０．０５〜５．０重量％、好ましくは０．１〜２．０重量％含有される。 Examples of the fluidizing agent include calcium silicate, talc, calcium stearate, magnesium stearate, tricalcium phosphate, magnesium carbonate, magnesium silicate, magnesium metasilicate aluminate, and more preferably calcium silicate or talc. And most preferably calcium silicate. The fluidizing agent is preferably basic having a pH of 8 or more, and is contained in an amount of 0.05 to 5.0% by weight, preferably 0.1 to 2.0% by weight, based on the total weight of the powder.
本発明の散剤の製造方法として具体的には、高速撹拌造粒法、流動層造粒法、乾式造粒法等が挙げられるが、好ましくは流動層造粒法である。前記の製造方法の操作法に困難はなく、常法にしたがって容易に目的の散剤を製造することができる。例えば流動層造粒法では、流動層造粒機中に投入した添加剤に結合剤及び原薬を含有する液を噴霧して造粒した造粒物を乾燥・篩過し、得られた整粒品と流動化剤を混合する、一般的な方法で行われる。 Specific examples of the method for producing the powder of the present invention include a high-speed stirring granulation method, a fluidized bed granulation method, a dry granulation method, and the like, and a fluidized bed granulation method is preferable. There is no difficulty in the operation method of the said manufacturing method, and the target powder can be manufactured easily according to a conventional method. For example, in the fluidized bed granulation method, a granulated product obtained by spraying a liquid containing a binder and a drug substance to an additive charged in a fluidized bed granulator is dried and sieved, and the obtained particle size is adjusted. It is carried out by a general method of mixing granule and fluidizing agent.
乳糖水和物８８３ｇ（ｐｈａｒｍａｔｏｓｅ（登録商標）１００Ｍ／ＤＦＥ Ｐｈａｒｍａ製）及びトウモロコシデンプン１００ｇ（局方コーンスターチホワイト／日本コーンスターチ製)を流動層造粒機（パウレック製／ＭＰ−０１型）に投入し、ヒドロキシプロピルセルロース２ｇ（ＨＰＣ‐Ｍ／日本曹達製）を精製水１９８ｇに溶解した液にアリピプラゾール１０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目３０ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品４９７．５ｇをケイ酸カルシウム２．５ｇ（フローライトＲＥ／富田製薬製）と共に混合し散剤を得た。 Lactose hydrate 883g (Pharmacatose (registered trademark) 100M / DFE Pharma) and corn starch 100g (Pharmacopoeia Cornstarch White / Nihon Cornstarch) were charged into a fluidized bed granulator (Pauleck / MP-01). A solution obtained by dispersing 10 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) in a solution obtained by dissolving 2 g of hydroxypropyl cellulose (HPC-M / manufactured by Nippon Soda) in 198 g of purified water was granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 30 mesh. 497.5 g of the obtained sized product was mixed with 2.5 g of calcium silicate (Florite RE / Tonda Pharmaceutical) to obtain a powder.
乳糖水和物８６８ｇ（ｐｈａｒｍａｔｏｓｅ（登録商標）１００Ｍ／ＤＦＥ Ｐｈａｒｍａ製）及びトウモロコシデンプン１００ｇ（局方コーンスターチホワイト／日本コーンスターチ製)を流動層造粒機（パウレック製／ＭＰ−０１型）に投入し、ヒドロキシプロピルセルロース２ｇ（ＨＰＣ‐Ｍ／日本曹達製）を精製水１９８ｇに溶解した液にアリピプラゾール１０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目３０ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品４９０ｇをタルク１０ｇ（クラウンタルク／松村産業製）と共に混合し散剤を得た。 Lactose hydrate 868 g (Pharmacatose (registered trademark) 100M / DFE Pharma) and corn starch 100g (Pharmacopoeia Cornstarch White / Nihon Cornstarch) were charged into a fluidized bed granulator (Paurek / MP-01). A solution obtained by dispersing 10 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) in a solution obtained by dissolving 2 g of hydroxypropyl cellulose (HPC-M / manufactured by Nippon Soda) in 198 g of purified water was granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 30 mesh. 490 g of the obtained sized product was mixed with 10 g of talc (Crown Talc / Matsumura Sangyo) to obtain a powder.
〔比較例１〕
乳糖水和物８７８ｇ（ｐｈａｒｍａｔｏｓｅ（登録商標）１００Ｍ／ＤＦＥ Ｐｈａｒｍａ製）及びトウモロコシデンプン１００ｇ（局方コーンスターチホワイト／日本コーンスターチ製)を流動層造粒機（パウレック製／ＭＰ−０１型）に投入し、ヒドロキシプロピルセルロース２ｇ（ＨＰＣ‐Ｍ／日本曹達製）を精製水１９８ｇに溶解した液にアリピプラゾール１０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目３０ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品４９５ｇを軽質無水ケイ酸５ｇ（アドソリダー（登録商標）１０１／フロイント産業製）と共に混合し散剤を得た。
[Comparative Example 1]
878 g of lactose hydrate (Pharmacatose (registered trademark) 100M / DFE Pharma) and 100 g of corn starch (Pharmacopoeia Cornstarch White / Nippon Cornstarch) were charged into a fluidized bed granulator (Paurek / MP-01). A solution obtained by dispersing 10 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) in a solution obtained by dissolving 2 g of hydroxypropyl cellulose (HPC-M / manufactured by Nippon Soda) in 198 g of purified water was granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 30 mesh. 495 g of the obtained granulated product was mixed with 5 g of light anhydrous silicic acid (ADSOLIDER (registered trademark) 101 / Freund Sangyo) to obtain a powder.
〔比較例２〕
乳糖水和物８７８ｇ（ｐｈａｒｍａｔｏｓｅ（登録商標）１００Ｍ／ＤＦＥ Ｐｈａｒｍａ製）及びトウモロコシデンプン１００ｇ（局方コーンスターチホワイト／日本コーンスターチ製)を流動層造粒機（パウレック製／ＭＰ−０１型）に投入し、ヒドロキシプロピルセルロース２ｇ（ＨＰＣ‐Ｍ／日本曹達製）を精製水１９８ｇに溶解した液にアリピプラゾール１０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目３０ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品４９５ｇを含水二酸化ケイ素５ｇ（カープレックス（登録商標）＃８０／エボニック製）と共に混合し散剤を得た。
[Comparative Example 2]
878 g of lactose hydrate (Pharmacatose (registered trademark) 100M / DFE Pharma) and 100 g of corn starch (Pharmacopoeia Cornstarch White / Nippon Cornstarch) were charged into a fluidized bed granulator (Paurek / MP-01). A solution obtained by dispersing 10 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) in a solution obtained by dissolving 2 g of hydroxypropyl cellulose (HPC-M / manufactured by Nippon Soda) in 198 g of purified water was granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 30 mesh. 495 g of the obtained sized product was mixed with 5 g of hydrous silicon dioxide (Carplex (registered trademark) # 80 / Evonik) to obtain a powder.
〔比較例３〕
乳糖水和物８８８ｇ（ｐｈａｒｍａｔｏｓｅ１００Ｍ／ＤＦＥ Ｐｈａｒｍａ製）及びトウモロコシデンプン１００ｇ（局方コーンスターチホワイト／日本コーンスターチ製)を流動層造粒機（パウレック製／ＭＰ−０１型）に投入し、ヒドロキシプロピルセルロース２ｇ（ＨＰＣ‐Ｍ／日本曹達製）を精製水１９８ｇに溶解した液にアリピプラゾール１０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目３０ｍｅｓｈのステンレス製篩で篩過し散剤を得た。
[Comparative Example 3]
Lactose hydrate 888 g (manufactured by pharmamatase 100M / DFE Pharma) and corn starch 100 g (manufactured by Pharmacopoeia Cornstarch White / manufactured by Nippon Cornstarch) were charged into a fluidized bed granulator (manufactured by Paulek / MP-01 type), and 2 g of hydroxypropylcellulose ( A solution obtained by dispersing 10 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) in a solution obtained by dissolving HPC-M / manufactured by Nippon Soda Co., Ltd. in 198 g of purified water was granulated at a supply temperature of 85 ° C. Subsequently, the mixture was dried at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., and then sieved with a stainless steel screen having a mesh of 30 mesh to obtain a powder.
＜試験例１＞
（安定性評価試験）
実施例１及び２、比較例１〜３で得られた各散剤を用い、そのＩｎｉｔｉａｌ（製造直後）品および６０℃７５％ＲＨガラス瓶開放１週間保存品について、アリピプラゾールの類縁物質の生成量をそれぞれ調べた。類縁物質の測定は散剤を水/アセトニトリル/酢酸（１００）混液（６０：３０：１０：１）で抽出してＨＰＬＣ法で行い、その詳細な試験条件は以下に示す。Ｉｎｉｔｉａｌおよび６０℃７５％ＲＨガラス瓶開放１週間保存後のアリピプラゾール類縁物質含有率を測定した結果は表２に示す。
<Test Example 1>
(Stability evaluation test)
Using each powder obtained in Examples 1 and 2 and Comparative Examples 1 to 3, the amount of aripiprazole related substances produced for the Initial product (immediately after production) and the 60 ° C. 75% RH glass bottle opened one week storage product was determined. Examined. The related substances were measured by extracting the powder with a water / acetonitrile / acetic acid (100) mixture (60: 30: 10: 1) by the HPLC method, and detailed test conditions are shown below. Table 2 shows the results of measuring the aripiprazole analog content after initial and storage at 60 ° C. and 75% RH glass bottle for 1 week.
（試験例１におけるＨＰＬＣ法測定条件）
検出器 ：紫外吸光光度計（測定波長：２５４ｎｍ）
カラム ：ＹＭＣ−Ｐａｃｋ ＯＤＳ−Ａ、３μｍ、４．６ｍｍ ｉ．ｄ．×１００ｍｍ （ワイエムシィ製）
カラム温度：２５℃付近の一定温度
移動相Ａ ：薄めたトリフルオロ酢酸（１→２０００）／アセトニトリル混液（９：１）
移動相Ｂ ：アセトニトリル／薄めたトリフルオロ酢酸（１→２０００）混液（９：１）
移動相の送液 ：移動相Ａ及び移動相Ｂの混合比を次のように変えて濃度勾配制
（表１）
(HPLC method measurement conditions in Test Example 1)
Detector: UV absorption photometer (measurement wavelength: 254 nm)
Column: YMC-Pack ODS-A, 3 μm, 4.6 mm i. d. × 100mm (manufactured by YMC)
Column temperature: constant temperature around 25 ° C. Mobile phase A: diluted trifluoroacetic acid (1 → 2000) / acetonitrile mixture (9: 1)
Mobile phase B: acetonitrile / diluted trifluoroacetic acid (1 → 2000) mixture (9: 1)
Mobile phase feeding: Concentration gradient control (Table 1) by changing the mixing ratio of mobile phase A and mobile phase B as follows
試験例２（固結評価試験）
実施例１及び２、比較例１〜３で調製した各散剤を用い、Ｉｎｉｔｉａｌ（製造直後）品および６０℃７５％ＲＨガラス瓶開放１週間保存品について、ビンを逆さまにした際に粉体が落下するか否かで固結状況を確認した。評価基準を以下に示した。固結状況（○：ほとんどが固結せずガラスビン内で粉体が容易に落下した。×：固結によりガラスビン内で粉体が容易に落下しなかった。）を確認し、表２に示した。
Test example 2 (consolidation evaluation test)
Using the powders prepared in Examples 1 and 2 and Comparative Examples 1 to 3, powder was dropped when the bottle was turned upside down for the Initial product (immediately after production) and the 60 ° C 75% RH glass bottle opened one week storage product. The consolidation status was confirmed by whether or not to do so. The evaluation criteria are shown below. Table 2 shows the caking condition (○: almost no caking and powder easily dropped in the glass bottle. ×: powder did not fall easily in the glass bottle due to caking). It was.
（表２）
＜実施例及び比較例の処方例と、其の安定性及び固結評価試験結果＞
中性〜酸性の流動化剤である軽質無水ケイ酸又は含水二酸化ケイ素添加では６０℃７５％ＲＨガラス瓶開放１週間保存において類縁物質の増加を認めた。また、流動化剤無添加では６０℃７５％ＲＨガラス瓶開放における類縁物質の増加は認めなかったものの、湿度により固結を生じた。一方で、塩基性流動化剤であるケイ酸カルシウム又はタルク添加においては６０℃７５％ＲＨガラス瓶開放１週間保存においても類縁物質の増加をほとんど認めず、湿度による固結も認めなかった。
(Table 2)
<Prescription Examples of Examples and Comparative Examples, and Stability and Consolidation Evaluation Test Results>
Addition of light anhydrous silicic acid or hydrous silicon dioxide, which is a neutral to acidic fluidizing agent, showed an increase in related substances when stored at 60 ° C. and 75% RH glass bottle for 1 week. Further, when no fluidizing agent was added, an increase in related substances was not observed when the glass bottle was opened at 60 ° C. and 75% RH, but caking occurred due to humidity. On the other hand, when calcium silicate or talc, which is a basic fluidizing agent, was added, there was almost no increase in related substances even when stored at 60 ° C. and 75% RH glass bottle for 1 week, and no caking due to humidity was observed.
本発明によれば、アリピプラゾール含有散剤を製剤操作上一般的な方法で製造しながら、アリピプラゾール由来の類縁体の発生量が抑制された高品質なアリピプラゾール含有散剤を医療現場に提供することが可能である。
According to the present invention, it is possible to provide a high-quality aripiprazole-containing powder with reduced generation of aripiprazole-derived analogs to the medical site while producing aripiprazole-containing powder by a general method in terms of formulation operation. is there.
Claims (5)
Further, the binder is contained in an amount of 0.1 to 5.0% by weight based on the total weight of the powder, and the binder is hydroxypropylcellulose, low-substituted hydroxypropylcellulose, soluble starch, partially pregelatinized starch, hypromellose, methylcellulose, povidone, The powder according to any one of claims 1 to 4, which is selected from ethyl cellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and polyethylene glycol.
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