JP2021155434A - アカンプロサートのスプリンクル製剤 - Google Patents
アカンプロサートのスプリンクル製剤 Download PDFInfo
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- JP2021155434A JP2021155434A JP2021103349A JP2021103349A JP2021155434A JP 2021155434 A JP2021155434 A JP 2021155434A JP 2021103349 A JP2021103349 A JP 2021103349A JP 2021103349 A JP2021103349 A JP 2021103349A JP 2021155434 A JP2021155434 A JP 2021155434A
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Abstract
Description
本明細書では次にように使用される。
本発明のペレットコアは1種類以上の有効成分を含む。本製品は、例えばアカンプロサートおよび少なくとも1種類の第二医薬を含む、またはこれらから基本的に構成される単回投与剤形単位を含み得る。一つの実施形態では、有効成分はアセチルアミノプロパンスルホン酸、アセチルアミノプロパンスルホン酸塩、タルトリミド、およびタウロムスチンからなる群から選択される少なくとも1種類のホモタウリンアナログを含む。好ましい有効成分はアカンプロサートである。
いくつかの実施形態では、本開示はグルタミン酸−GABA不均衡として特徴付けられるいずれかの神経伝達または認知障害、中断化または調節不全化したERKシグナル化経路によって特徴付けられるいずれかの障害、あるいは脳発達、学習、記憶、および認知に異常を生じるRAS病の治療方法で使用するための医薬品の製造におけるアカンプロサート経口ペレット製剤に関する。これらには、限定されないが、自閉症スペクトラム障害、広汎性発達障害−他に特定されない、特発性自閉症、脆弱X症候群、アスペルガー症候群、レット症候群、Diagnostic and Statistical Manual of Mental Disorders IV(精神障害の診断および統計学的マニュアルIV)でさらに参照される小児期崩壊性障害、アルコール依存、耳鳴り、睡眠時無呼吸、パーキンソン病、パーキンソン病におけるレボドパ誘発性ジスキネジー、アルツハイマー病、ハンチントン病、筋萎縮性側索硬化症、皮質拡延性抑制、偏頭痛、統合失調症、不安、遅発性ジスキネジー、痙攣、多発性硬化症、様々な型の痛み、または過食症が含まれ、加齢関連認知症、軽度認知症(MCI)、痴呆症、アルツハイマー病(AD)、前兆AD、心的外傷後ストレス障害(PTSD)、双極性障害、筋委縮性側索硬化症(ALS)、癌療法関連認知症、薬剤誘発性または毒素誘発性認知症、強迫行動、および物質依存症を有する、またはこれらのリスクのある被験体が含まれる。
被験体における疾患の治療に効果的である有効成分の量は、部分的には症状の性質に依存し、従来技術で知られている標準的な臨床技術によって判断することができる。さらに、インビトロまたはインビボの測定が、最適な投与量範囲を特定するのに役立てるために使用し得る。投与される有効成分の治療上効果的な量はまた、他の要因のなかで、治療される被検体、被験体の体重、疾患の重篤度、投与方法、および処方する医師の判断に依存し得る。
本発明の目的は、スプリンクル投与剤形用のアカンプロサートカルシウム腸溶性コーティングペレットを開発して、アルミニウムポーチ/小袋にパッキングしたこれらのプロトタイプスプリンクルの安定性を確立することである。アカンプロサートスプリンクル投与剤形の目標とする医薬品特性を表1にまとめる。
本発明のさらなる目的は、販売されている製品に匹敵するような、pH1.2で<10%放出(可能な限りゼロに近い薬剤放出)およびpH6.8で完全な放出を達成するスプリンクル製剤を開発することである。2種の異なるサイズ(No.16/20およびNo.25/30)を有するスプリンクルを製造して、薬剤放出プロファイル(溶解)に基づいて1つの製法に絞り込んだ。
スプリンクルの製造のための製剤組成を表10に示す。スプリンクルはAPI+Avicel PH101の浸潤塊を1.2mmのメッシュサイズに通す押し出しによって製造した。押し出した材料を造粒装置に2.1のプレートRPMで10分間加えて球体形状スプリンクルを得た。
小さいサイズのスプリンクルも、大きいサイズのスプリンクルと同様にAPIおよびAveicel PH101を1:1混合で用いて製造した。小さいスプリンクル用のメッシュサイズは、大きいサイズのスプリンクル用の1.2mmに対して0.8mmだった。
プロトタイプを安定性について設定し、試験の詳細は下記の通りである。
バッチ番号:SF14000999
パッキング:スプリンクルをアルミ小袋に秤量してシーリングした。
充填重量:バッチ番号SF14000999のスプリンクルが1080mg
(スプリンクルをアカンプロサートカルシウムAPIの300mg相当秤量した)
条件:25℃/60%相対湿度および40℃/75%相対湿度
試験時期:開始時、1、3、および6ヶ月
評価:測定、関連物質、および溶解
アカンプロサートカルシウム腸溶性コーティングスプリンクルをNo.25/30ASTMスプリンクルを用いて製造した。コーティングは20%エチルセルロース(持続放出)次いで50%腸溶性コーティング(Eudragit L100 55)によって実施し、目標とした溶解プロファイルを達成した。同一コーティング処理は製剤組成を含むエチルセルロースおよび腸溶性コーティングに関する前セクションで示されるものに従った。PKバッチのバッチ番号はSF14001404である。
プロトタイプを安定性について設定し、試験の詳細は下記の通りである。
バッチ番号:SF14001404
パッキング:スプリンクルをアルミ小袋に秤量してシーリングした。
充填重量:バッチ番号SF14001404のスプリンクルが1199mg
(スプリンクルをアカンプロサートカルシウムAPIの333mg相当秤量した)
条件:25℃/60%相対湿度および40℃/75%相対湿度
試験時期:開始時、1、3、および6ヶ月
評価:測定、関連物質、および溶解
スプリンクル投与剤形のためにアカンプロサートカルシウム腸溶性ペレットを、薬剤添加量、エチルセルロースおよびEudragitコーティング割合に関して開発して最適化し、アルミニウムポーチ/小袋にパッケージングしたこれらのプロトタイプスプリンクルの安定性を確立することが、なお本発明のさらなる目的である。
押し出し
ステップ1:アカンプロサートおよびAvicel PH101を60:40比で、ボウル中で混合した。
ステップ2:水を徐々に加えて湿潤塊を調製した。
ステップ3:湿潤塊を0.8mm単一円錐スクリーンによって100rpm押し出し速度で押し出し装置に通した。
ステップ4:押し出し物を造粒用にさらに使用した。
造粒化
ステップ1:2.11mmチェックプレートを造粒化で使用した。
ステップ2:押し出し物を造粒装置のボウルに加えた。
ステップ3:造粒装置を500〜800rpmの速度で作動させた。
ステップ4:5〜10mLの水を造粒化の際に液滴として加えた。
ステップ5:ペレットをさらに加温空気オーブンで乾燥させた。
腸溶性コーティングスプリンクルのpH1.2緩衝液における30%の薬剤放出は、30%コーティングが薬剤放出を<10%までに制御するには十分でなかったことを示す。従って、40〜50%のようなEudragitコーティングの高い割合が考えられた。
40%腸溶性コーティングスプリンクルを伴う5%エチルセルロースの薬剤放出は、pH1.2で8%であることが認められ、50%腸溶性コーティングを伴う5%エチルセルロースの薬剤放出はpH1.2で4%であることが認められた。しかし、緩衝液段階における薬剤放出が迅速であることが認められた。
30%、40%、および50%腸溶性コーティングを伴う10%エチルセルロースの薬剤放出は、酸段階で2時間後にそれぞれ15%、9%、および6%であることが認められた。10%エチルセルロースコーティングペレットでは緩衝液段階において完全な薬剤放出は認められなかった。
SF14000999に関する安定性試験の際、特に40℃/75%相対湿度で、薬剤の迅速な放出が緩衝液段階で時間とともに認められた。このことは、エチルセルロースコーティング層の表面への可塑剤の移動、それによる高温での迅速な薬剤放出に起因すると考えられ、仮定された。同様なことを迅速に評価するため、スプリンクルを開口したペトリ皿で40℃/75%相対湿度に2週間暴露した。
PK試験用に製造したプロトタイプを安定性試験で使用し、詳細は次の通りである。
バッチ番号:SF15000679、SF15000775
パッキング:スプリンクルをアルミ小袋に秤量してシーリングした。
充填重量:バッチ番号SF15000679のスプリンクルを874mg
バッチ番号SF15000775のスプリンクルを816mg
(スプリンクルをアカンプロサートカルシウムAPIの333mg相当秤量した)
条件:25℃/60%相対湿度および40℃/75%相対湿度
試験時期:開始時、1、3、6ヶ月、および12ヶ月
評価:測定、関連物質、および溶解
a.Campral試験
薬物動態試験‘537をビーグル犬においてCovance’s Madison,Wisconsin facilityで実施した。この容認された動物モデルは本薬剤有効成分がどのように吸収、分布、および消失されるかを理解するために使用される。ビーグル犬はCampralの動物モデルとして使用され、公開されている研究が比較のために利用可能であることに留意されるべきである(Kathleen Haberny−FDA Review, Adam Wasserman−FDA review and Rhee et al.,2008a,b)。試験‘537によって、いくつかの用量範囲のなかで現存の333mg腸溶性コーティングに関するベースラインプロファイルを立証することができ、同時に有効成分が水性溶液に溶解されたときに添加剤のない単なる「裸にされた」製剤と比較することができた。
2種の小児に適した製剤技術について次の目標製品プロファイルを、経口関連問題(咀嚼、吐き気、および飲み込み不能)ならびにこのBCSIII化合物の投与に適応させる際の色、感触、および味覚に対する感受性に起因して、ピルの摂取に困難さを経験している脆弱X症候群患者集団の特定の要求に、どちらが適合できるか展開させた。2種の投与剤形が、表44に示すように、アカンプロサートカルシウムの微小サイズ粒子および小粒子のスプリンクル剤形に関する目標製品プロファイルで考えられた。
プロトタイプSF14000999から学び、2種の新規製剤プロトタイプであるSF15000679およびSF15000775を開発した。両新規プロトタイプは、CampralおよびSF14000999と比べて好ましい放出プロファイルを示した。両スプリンクル製剤の可塑剤および腸溶性コーティングを低下させることによって、SF15000679およびSF15000775はスプリンクルあたりに高い薬剤添加量をもたらしながら、同一または小さい粒子サイズを維持した。
Claims (28)
- 経口投与可能な医薬製剤であって、複数のペレットを含み、前記ペレットはコア、持続放出コーティング、および腸溶性コーティングを含み、前記コアはアカンプロサートカルシウムおよび希釈剤を含む、上記医薬製剤。
- 前記希釈剤が微細結晶セルロース(MCC)またはセルロースゲルを含む、請求項1に記載の医薬製剤。
- 前記希釈剤がAvicel PH101を含む、請求項2に記載の医薬製剤。
- 前記持続放出コーティングが熱可塑性セルロースエーテルを含む、請求項1〜3のいずれか一項に記載の医薬製剤。
- 前記持続放出コーティングがエチルセルロース20スタンダードを含む、請求項4に記載の医薬製剤。
- 前記腸溶性コーティングがメタクリル酸およびエチルアクリラートをベースとしたアニオン性コポリマーを含む、請求項1〜5のいずれか一項に記載の医薬製剤。
- 前記腸溶性コーティングがEudragit L100 55を含む、請求項6に記載の医薬製剤。
- 前記複数のペレットが、スプリンクルと表示される医薬品に関する最大ビーズサイズ(最新US−FDAガイダンス文書による)について測定されたとき、サイズが約0.5〜約3.1mmの範囲である、請求項1〜7のいずれか一項に記載の医薬製剤。
- 前記複数のペレットが、ASTMメッシュを用いて測定されたき、サイズが約0.6〜約1.5mmの範囲である、請求項1〜7のいずれか一項に記載の医薬製剤。
- 有効成分が前記ペレット中に均一に分散されている、請求項1〜9のいずれか一項に記載の医薬製剤。
- 前記製剤が持続放出製剤であり、アカンプロサートカルシウムの約90%未満がpH6.8で30分以内に放出される放出プロファイルによって特徴付けられる、請求項1〜10のいずれか一項に記載の医薬製剤。
- アカンプロサートカルシウムの約50%未満がpH1.2で120分以内に放出される放出プロファイルによって特徴付けられる、請求項12に記載の医薬製剤。
- 前記製剤が改良された放出製剤であり、アカンプロサートカルシウムの約10%超がpH1.2で120分以内に放出されることによって特徴付けられる、請求項1〜10のいずれか一項に記載の医薬製剤。
- 前記アカンプロサートカルシウムが前記コアの約5〜約60w/w%含まれる、請求項1〜13のいずれか一項に記載の医薬製剤。
- 前記アカンプロサートカルシウムが前記コアの約45〜約65w/w%含まれる、請求項14に記載の医薬製剤。
- 前記アカンプロサートカルシウムが前記コアの約50〜約60w/w%含まれる、請求項15に記載の医薬製剤。
- 前記複数のペレットが小袋またはカプセルに含まれる、請求項1〜16のいずれか一項に記載の医薬製剤。
- 前記小袋がアカンプロサートカルシウムの単位用量を含む、請求項17に記載の医薬製剤。
- 前記単位用量が約100mg〜約2500mgである、請求項18に記載の医薬製剤。
- 患者における医学的状態を治療する方法であって、この方法を必要とする患者に請求項1〜19のいずれか一項による医薬製剤を効果的な量投与することを含む、上記方法。
- 前記医学的状態が加齢関連認知症、軽度認知症(MCI)、痴呆症、アルツハイマー病(AD)、前兆AD、心的外傷後ストレス障害(PTSD)、総合失調症、双極性障害、筋委縮性側索硬化症(ALS)、癌療法関連認知症、薬剤誘発性または毒素誘発性認知症、精神遅滞、パーキンソン病(PD)、自閉症、強迫行動、または物質依存症である、請求項20に記載の方法。
- 前記医学的状態がアルコール依存、耳鳴り、睡眠時無呼吸、パーキンソン病、パーキンソン病におけるレボドパ誘発性ジスキネジー、アルツハイマー病、ハンチントン病、筋萎縮性側索硬化症、皮質拡延性抑制、偏頭痛、統合失調症、不安、遅発性ジスキネジー、痙攣、多発性硬化症、様々な型の痛み、または過食症である、請求項20に記載の方法。
- 前記医学的状態が自閉症スペクトラム障害、広汎性発達障害−他に特定されない、特発性自閉症、脆弱X症候群、アスペルガー症候群、レット症候群、またはDiagnostic and Statistical Manual of Mental Disorders IV(精神障害の診断および統計学的マニュアルIV)でさらに参照される小児期崩壊性障害である、請求項20に記載の方法。
- 前記医学的状態が脆弱X症候群である、請求項20に記載の方法。
- 前記医学的状態がグルタミン酸−GABA不均衡として特徴付けられる神経伝達または認知障害、中断化または調節不全化したERKシグナル化経路によって特徴付けられる障害、あるいは脳発達、学習、記憶、または認知に異常を生じるRAS病である、請求項20に記載の方法。
- 前記投与が、前記医薬製剤を摂取前にpH<5.5を有する食物上または食物中に混ぜて散在させる、請求項20〜25のいずれか一項に記載の方法。
- 前記食物がアップルソース、プディング、ヨーグルト、または他のpHが適切な食物マトリックスである、請求項26に記載の方法。
- 前記アカンプロサートカルシウムの1回単位用量が1日に1〜4回投与される、請求項20〜27のいずれか一項に記載の方法。
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AU2016258624B2 (en) | 2021-07-29 |
US20190046458A1 (en) | 2019-02-14 |
JP7026347B2 (ja) | 2022-02-28 |
SG11201708393UA (en) | 2017-11-29 |
IL255343A0 (en) | 2017-12-31 |
US10709668B2 (en) | 2020-07-14 |
AU2016258624A1 (en) | 2017-11-02 |
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