JP7378391B2 - 有効成分としてオピオイド受容体アゴニストを含む医薬製剤、その製造方法および治療的使用 - Google Patents
有効成分としてオピオイド受容体アゴニストを含む医薬製剤、その製造方法および治療的使用 Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、より具体的には、新生児薬物離脱症候群の治療のための治療的に有効な用量を提供する、頬側/舌下投与用のブプレノルフィン製剤に関する。
主な症状には、筋肉の緊張の増加、自律神経の不安定性、過敏性、しゃぶり反射の低下、体重増加の障害などがある。
疫学研究では、母体のオピオイド乱用が一般的であり、出生の約1%で使用の毒性学的証拠がある(Vega WA et al N Engl J Med 1993, 16:329(12), 850-854)。
さらに、米国小児科学会の薬物委員会によると、NASはオピオイド依存の母親から生まれた乳児の55%~94%に発生する。
NASの最適な処理はまだ確立されていない。
使用される特定のオピオイド剤としては、硫酸モルヒネ、新生児アヘン溶液の形態のモルヒネ、アヘンの脱臭チンキ、およびメタドンが挙げられる。
モルヒネベースの組成物の投与は、治療期間が8~79日であり、コンセンサス期間が約30日であると報告されている。
前記入院期間は、母体の結合の妨害、院内感染の可能性、および資源の使用のために最適ではない。
ブプレノルフィンは、高用量でのオピオイド中毒の治療、低用量での非オピオイド耐性の個人の中等度の急性疼痛の制御、さらに低用量での中等度の慢性疼痛の制御への使用が増加している部分的μ-オピオイド受容体アゴニストである。
ブプレノルフィンには、NASの治療における魅力的な薬剤となる多くの特徴がある。例えば、その長い半減期と作用の持続時間は、離脱症状を引き起こす可能性がある受容体占有の急速な変化を防ぐ。
ただし、新生児または小児集団におけるブプレノルフィンの使用に関する経験はほとんどなく、新生児における舌下製剤の使用に関する情報は限られている。
著者らは、舌下ブプレノルフィンは安全であり、経口モルヒネによる標準的なケア療法よりも実質的な有効性の利点があると結論付けた。
しかし、注射用の塩酸ブプレノルフィンを30%エタノールとスクロース単一シロップに混合することにより、即用溶液製剤を使用した。最終濃度は、ブプレノルフィン遊離塩基として0.075mg/mlであった。
エタノールの存在のために、前記製剤はヒト新生児における反復投与には適さないかもしれない。
さらに、粘度が適切でない場合、溶液状の舌下/頬側剤形は、適用部位での保持が不十分であるため、さまざまな量の薬物を送達する可能性がある。
特に、投与後に新生児の横臥位で投与されそうな量およびおしゃぶりの使用を考えると、薬物は、舌下経路ではなく、胃腸管を通して飲み込まれて吸収されるリスクがある。
上記の事項を考慮すると、保存および使用のための適切な貯蔵寿命を有する新生児への舌下投与のためのより安全で効果的な製剤を開発する必要が依然としてある。
新生児または治療を必要とする対象の舌の下に保持し、粘膜と密接に接触し、嚥下および胃腸管からの吸収を回避するのに充分な粘度の製剤を提供することも有利である。
i)唯一の有効成分としてのブプレノルフィンまたはその薬学的に許容される塩を0.005~0.02%w/v、
ii)増粘剤を0.5~10%w/v、および
iii)5.0~7.0のpHを提供する量の緩衝剤。
その粘度は、25±2℃で500~2300mPas、好ましくは700~2100mPasとすべきである。
本発明の好ましい態様では、増粘剤は、セルロース誘導体、より好ましくはヒドロキシエチルセルロース(HEC)またはナトリウムカルボキシメチルセルロース(NaCMC)、さらにより好ましくはヒドロキシエチルセルロースである。
好ましくは、患者は、新生児オピオイド離脱症候群に罹患した新生児である。
ブプレノルフィンに関して、「薬物」、「有効成分」および「活性物質」という用語は互換的に使用される。
したがって、本発明の目的は、オピエート離脱症候群(OWS)に罹患した患者、好ましくは新生児OWS(以下NOWS)に罹患した新生児に舌下投与することによる効果的な治療のための安全な医薬製剤を提供することである。
前記安全な製剤は、水性ビヒクルに溶解したブプレノルフィンを含むものとする。
本発明の製剤は、新生児ならびに子供または青年に投与することができる。
本発明の製剤は、使用前に即座に溶解される乾燥粉末の形態、または即時使用可能製剤の形態であり得る。
即時使用可能製剤を使用することが好ましい。
i)適切な量のブプレノルフィンまたはその薬学的に許容される塩、好ましくはその塩酸塩を適切な容器内で水に溶解して、濃縮された透明な溶液を得る工程、
ii)必要に応じて、工程i)で得られた溶液を濾過により滅菌する工程、
iii)並行して、透明な溶液が得られるまで、適切な容量の容器で適切な量の緩衝剤を水に溶解する工程、
iv)必要に応じて、工程iii)で得られた溶液を加熱により滅菌する工程、
v)連続攪拌下で混合しながら、ブプレノルフィン濃縮溶液の適切な量を緩衝剤溶液に添加して、ブプレノルフィンの最終的な望ましい濃度、好ましくは0.05~0.01mg/mL(遊離塩基として)を得る工程、および
vi)増粘剤が完全に溶解し、透明で均質な溶液が得られるまで、連続攪拌下で、工程iii)の溶液に適切な量の増粘剤をゆっくりと加える工程。
本発明を、以下の実施例を参照して説明する。
最初の一連の実験は、適切な粘度とpHのブプレノルフィン水溶液製剤を、吸収の良好なプロファイルを維持しながら物理的および化学的に安定であることが判明するように調製する可能性を評価することを目的とした。
0.01%w/vのブプレノルフィン濃度の実施例1の製剤1、2、3および4を、物理的および化学的安定性を評価するために、長期条件下、すなわち25±2℃および相対湿度60%、および加速条件下、すなわち50±2℃で1か月貯蔵した。
塩基で表して0.075mg/mlのブプレノルフィン濃度の製剤1および2、および参照製剤を、舌下投与によってイヌに投与した。
この研究は、Kraft参照製剤に対する製剤1、2、3、4および5のインビトロ性能をスクリーニングするように設計した。
クプロファン(セルロースベースの膜)には、保湿剤としてグリセリンが含まれている(乾燥およびひび割れを防ぐために)。これを、蒸留水に長時間浸すことで除去した。メンブレン(あらかじめトリミングされた直径22mmの円を準備)を500mlのDuranボトルに入れて浸漬し、内容物を回転(20rpm)により混合した。グリセリンを除去するために、さらに2回の完全な水の交換を行った。合計の浸漬/すすぎ時間は、放出試験前に約46時間であった。
(粘膜付着特性の評価)
本発明の製剤の粘膜付着特性を、Pescina, S., et al.,. Drug Dev Ind Pharm, 2017. 43(9): p. 1472-1479に報告されている「傾斜面」装置によって試験した。
Claims (10)
- i)唯一の有効成分として塩酸塩の形態のブプレノルフィンを0.075mg/mL、
ii)増粘剤を15mg/mL、および、
iii)6.0±0.3のpHを提供する量の緩衝剤、
を含んでなる舌下および頬側投与用の水溶液状の即時使用可能医薬製剤であって、
前記製剤は、25±2℃において、500~2300mPasの間の粘度を有し、
増粘剤がヒドロキシエチルセルロースであり、
緩衝剤がクエン酸およびクエン酸ナトリウムからなる、製剤。 - 25±2℃で700~2100mPasの間の粘度を有する、請求項1に記載の製剤。
- 甘味料および/または香味料をさらに含む、請求項1または2に記載の製剤。
- 塩基として表して0.0075%w/vのブプレノルフィン塩酸塩、1.5%w/vのヒドロキシエチルセルロース、0.12%w/vの無水クエン酸、1.13%w/vの無水クエン酸ナトリウム、および注射用水から本質的になる、請求項1~3のいずれか一項に記載の製剤。
- i)適切な量のブプレノルフィン塩酸塩を適切な容器内で水に溶解して、濃縮された透明な溶液を得る工程、
ii)必要に応じて、工程i)で得られた溶液を濾過により滅菌する工程、
iii)並行して、透明な溶液が得られるまで、適切な容量の容器で適切な量の緩衝剤を水に溶解する工程、
iv)連続攪拌下で混合しながら、ブプレノルフィン濃縮溶液の適切な量を緩衝剤溶液に添加して、ブプレノルフィンの最終的な望ましい濃度を得る工程、
v)必要に応じて、工程iii)で得られた溶液を加熱により滅菌する工程、および
vi)増粘剤が完全に溶解し、透明で均質な溶液が得られるまで、連続攪拌下で、工程iii)の溶液に適切な量の増粘剤をゆっくりと加える工程
を含んでなる、請求項1~4のいずれか一項に記載の即時使用可能製剤を調製するための方法。 - オピオイド離脱症候群の治療に使用するための、請求項1~4のいずれか一項に記載の製剤。
- 症候群が新生児オピオイド離脱症候群である、請求項6に記載の製剤。
- 請求項1~4のいずれか一項に記載の製剤が予め充填された注射器。
- 注射器、およびオピオイド離脱症候群に罹患した患者に前記医薬製剤を経口投与するための説明書と組み合わせて、請求項1~4のいずれか一項に記載の製剤を含んでなる、パッケージ。
- 患者が新生児オピオイド離脱症候群に罹患している新生児である、請求項9に記載のパッケージ。
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