JP2022126766A - 活性薬剤の経口投与のための製剤 - Google Patents
活性薬剤の経口投与のための製剤 Download PDFInfo
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Abstract
Description
本発明のいくつかの実施形態の一態様によれば、治療活性剤を含む医薬組成物用の単位剤形であって、治療活性剤によって治療可能な病態の治療に使用するためのものであり、治療が、少なくとも2個の(本明細書に記載のそれぞれの実施形態のいずれかによる)単位剤形の同時経口投与を含むものが提供される。本明細書に記載の実施形態のいずれかの内の、いくつかの実施形態において、医薬組成物用の単位剤形は、本明細書に記載のそれぞれの実施形態のいずれかによる吸収促進剤をさらに含む。本明細書に記載の実施形態のいずれかによるいくつかの実施形態において、治療は、少なくとも3個の(本明細書に記載のそれぞれの実施形態のいずれかによる)これら単位剤形の同時経口投与を含む。
本発明のいくつかの実施形態の一態様によれば、単位剤形からなるセットを複数含むキットであって、単位剤形が、(本明細書に記載のそれぞれの実施形態のいずれかによる)治療活性剤および吸収促進剤を含み、各セットが少なくとも2個の単位剤形、所望により少なくとも3個の単位剤形、所望により少なくとも4個の単位剤形を含む、キットが提供される。1セットあたりの剤形の数は、所望により、(本明細書に記載のそれぞれの実施形態のいずれかによる)方法または使用を実行するための、本明細書に記載の単位剤形の範囲および/または数に従う。
本発明のいくつかの実施形態の一態様によれば、コーティングおよび/またはマトリックスによって互いに結合した少なくとも2つの別個の単位剤形を含む医薬組成物用の多重単位剤形であって、単位剤形のそれぞれが、(本明細書に記載のそれぞれの実施形態のいずれかによる)治療活性剤および吸収促進剤を含み、コーティングおよび/またはマトリックスが、経口投与の際に単位剤形を即時放出するように処方された、多重単位剤形が提供される。単位剤形が経口投与されたときの即時放出は、所望により、本明細書に記載のそれぞれの実施形態のいずれかによる少なくとも2個の単位剤形の経口投与によって実行することができる。
本明細書に記載の実施形態のいずれかの好ましい実施形態によれば、(本明細書に記載のそれぞれの実施形態のいずれかによる)少なくとも2個の剤形は、それらにおける吸収促進剤の総量が有効量となる量の吸収促進剤、すなわち治療活性剤の吸収を増強するのに有効な量の吸収促進剤を含む。
本明細書に記載の実施形態のいずれか1つに係わる複数の実施形態において、本明細書に記載の態様のいずれか1つによる少なくとも2個の単位剤形は、総量として、少なくとも50μgの治療活性剤を含む。いくつかの実施形態において、少なくとも2個の単位剤形は、総量として、少なくとも100μgの治療活性剤を含む。いくつかの実施形態において、少なくとも2個の単位剤形は、総量として、少なくとも200μgの治療活性剤を含む。いくつかの実施形態において、少なくとも2個の単位剤形は、総量として、少なくとも500μgの治療活性剤を含む。いくつかの実施形態において、単位剤形中の吸収促進剤の量は、本明細書に記載の治療活性剤に対する吸収促進剤の比率のいずれか1つに従う量である。いくつかの実施形態において、吸収促進剤は、NAC(8-N-(2-ヒドロキシベンゾイル)アミノカプリル酸)またはその塩(例えば、8-N-(2-ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)である。いくつかの実施形態において、単位剤形は、少なくとも1つのプロテアーゼ阻害剤を、本明細書に記載の治療活性剤に対するプロテアーゼ阻害剤の比率のいずれか1つに従う量でさらに含む。
(i)窒素-水素結合および酸素水素結合(これらは典型的には水素結合供与体である)の総数が5より多い、
(ii)窒素原子および酸素原子(これらは典型的には水素結合受容体である)の総数が5より多い、
(iii)オクタノール-水の分配係数(logP)が5より大きい、および/または
(iv)分子量が少なくとも500Da(0.5kDa)。
本明細書に記載の実施形態のいずれか1つに係わる複数の実施形態において、本明細書に記載のそれぞれの実施形態のいずれかによる単位剤形は、少なくとも1つのプロテアーゼ阻害剤を含む。いくつかの実施形態において、少なくとも1つのプロテアーゼ阻害剤は、少なくとも1つのトリプシン阻害剤を含む。いくつかの実施形態において、少なくとも1つのプロテアーゼ阻害剤は、1つまたは複数のトリプシン阻害剤から実質的になる。
多重単位剤形、多重単位剤形中の個々の単位投薬量および単位剤形を含む本明細書に記載の医薬組成物の剤形は、いずれも、所望により、上記で説明した機能的な成分(例えば、治療活性剤、吸収促進剤、崩壊剤および/またはプロテアーゼ阻害剤)から実質的になるものである。または上記の代わりに、剤形は、好適な薬学的に許容される担体および/または添加剤をさらに含むものである。
本明細書では、用語「ポリペプチド」は、ペプチド結合によって連結された少なくとも4つのアミノ酸残基またはそれらの類似体を含む、(本明細書に記載の)ポリマーであり、所望によりペプチド結合のみを含むものを指す。いくつかの実施形態において、ポリペプチドは、少なくとも10個のアミノ酸残基またはそれらの類似体を含む。いくつかの実施形態において、ポリペプチドは、少なくとも20個のアミノ酸残基またはそれらの類似体を含む。いくつかの実施形態において、ポリペプチドは、少なくとも30個のアミノ酸残基またはそれらの類似体を含む。いくつかの実施形態において、ポリペプチドは、少なくとも50個のアミノ酸残基またはそれらの類似体を含む。用語「ポリペプチド」は、本来の(native)ポリペプチド(例えば、分解産物、合成法により合成されたポリペプチドおよび/または組換えポリペプチド)を含み、本来のタンパク質、本来のタンパク質の断片および本来のタンパク質の相同体および/またはその断片が挙げられるが、これらに限定されるものではない。さらには、ペプチド模倣物(典型的には、合成法によって合成したポリペプチド)およびポリペプチド類似体であるペプトイドおよびセミペプトイドなどの、例えば、ポリペプチドを、体内中でより安定にするか、または細胞に浸透しやすくするような修飾を有するものも包含する。そのような修飾としては、N末端修飾、C末端修飾、ペプチド結合修飾、骨格修飾、および残基修飾が挙げられるが、これらに限定されるものではない。ペプチド模倣化合物を製造するための方法は、当業界で周知であり、例えば、Quantitative Drug Design, C.A. Ramsden Gd., Chapter 17.2, F. Choplin Pergamon Press (1992)に特定されている。この文献の記載は、ここに完全に記載されたのと同等に、本参照をもって本願に組み込まれたものとする。これに関するさらなる詳細は、本明細書に記載される。
8-アミノカプリル酸を、Alfa-Aesar社から入手した。
ステアリン酸マグネシウムを、Merck社から入手した。
O-アセチルサリチロイルクロリドを、Alfa-Aesar社から入手した。
ダイズトリプシン阻害剤(SBTI)を、BBI solutions Ltd社から入手した。
テリパラチドを、Bachem社から購入した。
SNAC(8-N-(2-ヒドロキシベンゾイル)アミノカプリル酸ナトリウム)は、O-アセチルサリチロイルクロリドと8-アミノカプリル酸とを反応させることによって製造した。
薬物動態の変動に対する、多重単位製剤の作用
副甲状腺ホルモン(PTH)の多重単位経口製剤の、薬物動態の変動に対する作用を評価するために、第I相薬物動態研究を実施した。
副甲状腺ホルモン(PTH)の薬物動態および薬力学に対する、多重単位製剤の作用
副甲状腺ホルモン(PTH)の多重単位経口製剤の、薬物動態の変動およびバイオアベイラビリティに対する作用に加え、血清カルシウムレベルの増加などの薬力学的作用についても評価するために、第Ib相薬物動態研究を実施した。
薬物動態の変動に対する、多重単位製剤の作用
薬物動態の変動および/または血清カルシウムレベルの増加などの薬力学的作用への副甲状腺ホルモン(PTH)の多重単位経口製剤の作用を評価するために、第I相薬物動態研究を行う。
Claims (21)
- コーティングおよび/またはマトリックスによって互いに結合した少なくとも3個の別個の単位製剤を含む、医薬組成物用の多重単位製剤であって、前記単位製剤のそれぞれが、治療活性剤および吸収促進剤を含み、前記単位製剤における前記治療活性剤の総量が治療有効量となり、且つ前記吸収促進剤の総量が有効量となり、前記コーティングおよび/またはマトリックスが、経口投与の際に前記単位製剤を即時放出するように処方され、前記吸収促進剤が、NAC(8-N-(2-ヒドロキシベンゾイル)アミノカプリレート)、NAD(10-N-(2-ヒドロキシベンゾイル)アミノデカン酸)、5-CNAC(8-N-(5-クロロサリチルオイル)アミノカプリル酸)、4-MOAC(8-N-(2-ヒドロキシ-4-メトキシベンゾイル)アミノカプリル酸)、4-CNAB(4-N-(2-ヒドロキシ-4-クロロベンゾイル)アミノブタン酸)およびそれらの塩からなる群から選択され、
前記単位製剤の少なくとも50重量%が前記吸収促進剤からなる、多重単位製剤。 - 胃液および/または唾液中で崩壊することが可能であり、それにより前記単位製剤を放出する、請求項1に記載の多重単位製剤。
- 前記別個の単位製剤を3~10個含む、請求項1または2に記載の多重単位製剤。
- 前記治療活性剤の分子量が、0.5kDa~100kDaである、請求項1~3のいずれか一項に記載の多重単位製剤。
- 前記治療活性剤が、BCS クラスIIIの薬剤である、請求項1~4のいずれか一項に記載の多重単位製剤。
- 前記治療活性剤が、ポリペプチドである、請求項1~4のいずれか一項に記載の多重単位製剤。
- 前記ポリペプチドが、副甲状腺ホルモンおよびその断片からなる群から選択される、請求項6に記載の多重単位製剤。
- 前記治療活性剤の経口投与によって治療可能な病態の治療を必要とする対象において、前記病態を治療するためのキットの製造における、請求項1~7のいずれか一項に記載の多重単位製剤の使用。
- 前記治療が、前記治療活性剤の血漿濃度のCmaxおよび/またはAUCの変動を低下させることを含む、請求項8に記載の使用。
- 前記治療が、前記治療活性剤のCmaxおよび/またはバイオアベイラビリティを増加させることを含む、請求項8または9に記載の使用。
- 治療活性剤および吸収促進剤を含む医薬組成物用の単位製剤の、前記治療活性剤によって治療可能な病態を治療するためのキットの製造における使用であって、前記治療が、少なくとも3個の前記単位製剤の同時経口投与を含み、前記少なくとも3個の単位製剤が多重単位製剤に含まれておらず、且つ前記治療活性剤の総量が治療有効量となり、前記吸収促進剤の総量が有効量となり、前記吸収促進剤が、NAC(8-N-(2-ヒドロキシベンゾイル)アミノカプリレート)、NAD(10-N-(2-ヒドロキシベンゾイル)アミノデカン酸)、5-CNAC(8-N-(5-クロロサリチルオイル)アミノカプリル酸)、4-MOAC(8-N-(2-ヒドロキシ-4-メトキシベンゾイル)アミノカプリル酸)、4-CNAB(4-N-(2-ヒドロキシ-4-クロロベンゾイル)アミノブタン酸)およびそれらの塩からなる群から選択され、
前記単位製剤の少なくとも50重量%が前記吸収促進剤からなる、使用。 - 前記治療が、3~10個の前記単位製剤の同時経口投与を含む、請求項11に記載の使用。
- 前記治療が、前記治療活性剤の血漿濃度のCmaxおよび/またはAUCの変動を低下させることを含む、請求項11または12に記載の使用。
- 前記治療が、前記治療活性剤のCmaxおよび/またはバイオアベイラビリティを増加させることを含む、請求項11~13のいずれか一項に記載の使用。
- 前記治療活性剤の分子量が、0.5kDa~100kDaである、請求項8~14のいずれか一項に記載の使用。
- 前記治療活性剤が、BCS クラスIIIの薬剤である、請求項8~14のいずれか一項に記載の使用。
- 前記治療活性剤が、ポリペプチドである、請求項8~14のいずれか一項に記載の使用。
- 前記ポリペプチドが、副甲状腺ホルモンおよびその断片からなる群から選択される、請求項17に記載の使用。
- 医薬組成物用の単位剤形であって、5μg以上200μg未満の副甲状腺ホルモンまたはその断片と、NAC(8-N-(2-ヒドロキシベンゾイル)アミノカプリレート)、NAD(10-N-(2-ヒドロキシベンゾイル)アミノデカン酸)、5-CNAC(8-N-(5-クロロサリチルオイル)アミノカプリル酸)、4-MOAC(8-N-(2-ヒドロキシ-4-メトキシベンゾイル)アミノカプリル酸)、4-CNAB(4-N-(2-ヒドロキシ-4-クロロベンゾイル)アミノブタン酸)およびそれらの塩からなる群から選択される吸収促進剤とを含み、且つ前記単位剤形が多重単位剤形に含まれていない、単位剤形。
- 前記副甲状腺ホルモンまたはその断片によって治療可能な病態の治療に使用するためのキットの製造における、請求項19に記載の単位剤形の使用であって、前記治療が少なくとも3個の前記単位剤形の同時経口投与を含み、前記少なくとも3個の前記単位剤形における前記副甲状腺ホルモンまたはその断片の総量が治療有効量となり、且つ前記吸収促進剤の総量が有効量となる、使用。
- 少なくとも3個の単位剤形からなるセットを複数含むキットであって、前記単位剤形が治療活性剤および吸収促進剤を含み、前記少なくとも3個の単位剤形が多重単位剤形に含まれておらず、前記少なくとも3個の単位剤形における前記治療活性剤の総量が治療有効量となり、且つ前記吸収促進剤の総量が有効量となり、前記吸収促進剤が、NAC(8-N-(2-ヒドロキシベンゾイル)アミノカプリレート)、NAD(10-N-(2-ヒドロキシベンゾイル)アミノデカン酸)、5-CNAC(8-N-(5-クロロサリチルオイル)アミノカプリル酸)、4-MOAC(8-N-(2-ヒドロキシ-4-メトキシベンゾイル)アミノカプリル酸)、4-CNAB(4-N-(2-ヒドロキシ-4-クロロベンゾイル)アミノブタン酸)およびそれらの塩からなる群から選択される、キット。
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KR20240093678A (ko) | 2024-06-24 |
CN116850132A (zh) | 2023-10-10 |
JP2024054222A (ja) | 2024-04-16 |
CN116831978A (zh) | 2023-10-03 |
CN116831977A (zh) | 2023-10-03 |
MX2019001850A (es) | 2019-05-15 |
EP3500291A1 (en) | 2019-06-26 |
IL312218A (en) | 2024-06-01 |
SG11201901070YA (en) | 2019-03-28 |
WO2018033927A1 (en) | 2018-02-22 |
CA3033259A1 (en) | 2018-02-22 |
NZ751668A (en) | 2022-07-29 |
US20190209657A1 (en) | 2019-07-11 |
KR20190039768A (ko) | 2019-04-15 |
KR20230088854A (ko) | 2023-06-20 |
IL264880B1 (en) | 2024-05-01 |
BR112019003136A2 (pt) | 2019-05-21 |
EP3500291A4 (en) | 2020-03-11 |
CN109862906A (zh) | 2019-06-07 |
AU2017311698A1 (en) | 2019-04-04 |
IL264880A (en) | 2019-04-30 |
JP2019524836A (ja) | 2019-09-05 |
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