JP2022526196A - 浸透性が低いタンパク質、ペプチド、及び小分子の経口送達用の製剤 - Google Patents
浸透性が低いタンパク質、ペプチド、及び小分子の経口送達用の製剤 Download PDFInfo
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Abstract
Description
本出願は、2019年4月11日に出願された米国特許仮出願第62/832,508号の優先権を主張し、その全内容は、参照により本明細書に組み込まれる。
一部の実施形態では、製剤は、製剤の総質量の最大で約1wt%、約2wt%、約5wt%、約10wt%、約15wt%、又は約20wt%の量で合成若しくは天然の浸透性の低い分子、又はこれら浸透性の低い分子の任意の薬学的に許容される塩を含みうる。一部の実施形態では、製剤は、製剤の総質量の約0.01~30wt%、約0.1~30wt%、約0.01~20wt%、約0.1~20wt%、約0.1~15wt%、約0.1~10wt%、約0.1~5wt%、約0.1~2wt%、約0.1~1wt%、約0.1~0.5wt%、又は約0.5~1.5wt%の量で合成若しくは天然の浸透性の低い分子、又はこれら浸透性の低い分子の任意の薬学的に許容される塩を含みうる。
合成又は天然の浸透性の低い分子は、カルシトニン遺伝子関連ペプチド(CGRP)阻害剤でありうる。本明細書で使用される場合、用語「CGRP阻害剤」とは、CGRPリガンド又はCGRP受容体の阻害剤でありうる化学物質を指す。故に、用語「CGRP阻害剤」は、CGRP受容体阻害剤を包含する。CGRP阻害剤は、CGRP阻害剤又はCGRP受容体阻害剤でありうる。CGRP(カルシトニン遺伝子関連ペプチド)は、37個のアミノ酸の神経ペプチドであり、これは、カルシトニン、アドレノメデュリン、及びアミリンを含むペプチドのファミリーに属する。実質的な証拠は、CGRPが片頭痛の病理生理学に関係していることを示すために収集されている。臨床試験を実施して、CGRP阻害剤が片頭痛を処置するのに有効であることを示した。
一部の実施形態では、製剤は、製剤の総質量の最大で約50wt%、約55wt%、約60wt%、約65wt%、約70wt%、又は約80wt%の量で親油性相を含みうる。一部の実施形態では、製剤は、製剤の総質量の約50~80wt%、約55~75wt%、約60~70wt%、約62~68wt%、約64~66wt%、又は約65wt%の量で親油性相を含みうる。
を有しうる。
一部の実施形態では、製剤は、製剤の総質量の最大で約1wt%、約5wt%、約10wt%、約15wt%、約20wt%、約25wt%、約30wt%、約35wt%、約40wt%、約45wt%、又は約50wt%の量で少なくとも1つの親油性界面活性剤を含みうる。一部の実施形態では、製剤は、製剤の総質量の約10~50wt%、約15~35wt%、約20~30wt%、約22~28wt%、約24~26wt%、又は約25wt%の量で少なくとも1つの親油性界面活性剤を含みうる。製剤が、約10wt%未満の少なくとも1つの親油性界面活性剤を含む場合、動的な消化は、最適化することはできない。製剤が、50wt%超の少なくとも1つの親油性界面活性剤を含む場合、カプリン酸ナトリウムの放出に利用可能な親油性相の量は、最適ではない可能性がある。
一部の実施形態では、製剤は、製剤の総質量の最大で約2wt%、約5wt%、約8wt%、約10wt%、約15wt%、約20wt%、約25wt%、又は約30wt%の量で少なくとも1つの親水性界面活性剤を含みうる。一部の実施形態では、製剤は、製剤の総質量の約0~30wt%、約0~15wt%、約0~10wt%、約1~30wt%、約5~15wt%、約8~12wt%、約9~11wt%、又は約10wt%の量で少なくとも1つの親水性界面活性剤を含みうる。少なくとも1つの親水性界面活性剤の量が製剤の約30wt%超である場合、カプリン酸ナトリウムの放出に利用可能な親油性相の量に支障をきたす可能性がある。
一部の実施形態では、製剤は、APIを可溶化するのを補助するために、製剤の総質量の最大で約15wt%、約10wt%、約5wt%、又は約1wt%の量で少なくとも1つの無水親水性溶媒を含みうる。一部の実施形態では、製剤は、少なくとも1つの親水性溶媒を含まない。一部の実施形態では、少なくとも1つの親水性溶媒は、例えば、増粘剤を可溶化するために添加される。
一部の実施形態では、製剤は、製剤の総質量の最大で約25wt%の量で少なくとも1つの化学的及び/又は物理的な安定剤を含みうる。一部の実施形態では、物理的な安定剤は、プロセスの間にAPI粉末の懸濁剤の均一性を維持するために添加しうる。以下で述べる通り、プラセボ製剤は、溶液中の脂質添加剤からなる単一相である場合、物理的に安定であるが、API粉末が懸濁剤として均質性を維持するために分散するので、増粘剤を添加する。
一部の実施形態では、製剤は、溶液の形態で液体でありうる。一部の実施形態では、製剤は、浸透性の低い分子(例えばAPI)が粉末として製剤において懸濁される溶液である。一部の実施形態では、製剤は、無水逆マイクロエマルジョン又は無水逆エマルジョンでありうる。一部の実施形態では、製剤は、均質である。均質な製剤は、1999年8月3日付けの産業に対するFDA指針、ANDAS:ブレンドの均一性に準拠したバルク充填製剤の製造、及び/若しくは、含量均一性試験判定基準(質量変動評価 - 欧州薬局方、投与単位の均一性2.9.40、USP一般章<905>、及び日本薬局方、6.02投与単位の均一性を除く)に準拠した実行可能な最終医薬剤形の製造に使用することができる、並びに/又は、製造プロセスにわたって得られる層状化されたサンプルでの安定した原薬のアッセイ結果のコンプライアンスを満たすことができる、任意の単一相又は多相の製剤でありうる。
本明細書に開示される製剤は、それに含有される浸透性の低い分子又はその塩と同じ治療活性を有することができる。故に、本開示はまた、薬物としての使用のための本明細書に開示される腸溶性医薬製剤に関する。
消化性成分(Miglyol 812N及びCapmul MCM)比について、85%超の製剤1(逆エマルジョン)及び製剤2(懸濁液中のAPI)は、消化性が高い。消化の30分後、製剤1は、製剤1g当たり2.3mmolの脂肪酸を放出し、製剤2は、製剤1g当たり2.1mmolの脂肪酸を放出する。3時間後、製剤1及び製剤2により放出される最大量の脂肪酸は、製剤1g当たり約2.8mmolであり、この放出量は、4つの製剤全てで可能な最大放出である。75%超の脂肪酸は、これら2つの製剤で30分未満で放出される。トリグリセリド(Miglyol 812N)を含まない製剤3(溶液中のAPI)は、最小量の脂肪酸を放出する:消化の3時間後、製剤1g当たり0.6mmolの脂肪酸。消化の30分後、製剤1g当たり0.3mmol(50%)の脂肪酸のみを放出する。製剤4は、他の3つと比較して、脂肪酸の中間計の量(消化の3時間後、製剤1g当たり2.0mmolの脂肪酸)を放出するので、消化成分のレベルは約70%である。1.7mmolの脂肪酸は、30分後に放出され、30分以内の放出の約85%に相当する。
研究された浸透性の低い分子の薬物動態学では、経口及び十二指腸内投与後のその薬物動態学パラメータ及び生物学的利用能を計算するために、静脈内投与後に調査している。
プラセボ製剤(F5)では、遊離脂肪酸の放出は速く、製剤の85%超の可消化部分は、腸管膜を通して浸透性を高めることが知られている遊離脂肪酸(主にC8及びC10脂肪酸)を放出する30分未満内で消化される。
プラセボ製剤を、所定比(table 4(表4)を参照)で3つの添加剤を共に添加することにより室温で調製し、単一相の溶液を達成するまで(即ち、撹拌せずに24時間後に相分離なし)、磁気撹拌しながら混合する。
1. 実験計画及び投与
各群に対して、3匹の雌のビーグル犬に、Table 6(表6)で示す通り、BHV-3500を一度投与した。
各投与後、BHV-3500の血漿レベルの決定用の血液サンプル(頚静脈からおよそ3mL)を、6時点(投与前、投与の15、30、及び60分後、並びに2及び4時間後)で、各イヌから得た。EDTAを、抗凝固剤として使用した。血漿サンプルを、解析までおよそ-70℃で凍結した。
BHV-3500及びBHV-3500-d8に対する標準品を準備し、室温で保管した。標準を、校正標準の調製用の更なる精製をせずに使用し、血漿サンプルのBHV-3500濃度の決定用の品質管理(QC)サンプルを本研究中に収集した。
校正物質、QC、及び研究サンプルを、Table 7(表7)に詳述したLC-MS/MS装置条件下で分析した。
指定された(公称)サンプリング時間での個々の動物の血漿BHV-3500濃度データを、Phoenix WinNonlinソフトウェア(バージョン8.1; Certara社、Princeton、NJ)で、血管外投与に対する区画分けしないモデルを使用して分析した。
・排出半減期(t1/2)
・最大血漿濃度の発生時間(Tmax)
・最大血漿濃度(Cmax)
・血漿濃度-時間曲線下面積[0から4時間時点まで; AUC0-4時間]
BHV-3500濃度の決定は、Table 9(表9)に表し、図1及び図2にグラフで示す。
BHV-3500を経口カプセル剤(1群、ビヒクルなし)として20mgでイヌにビヒクルなしで投与した場合、血漿レベルは、全ての時点で定量化限界未満(BQL)だった。20mgの用量をビヒクル6及びDDMと組み合わせて(それぞれ2群及び3群)送達する場合のみ、血漿中で測定可能なBHV-3500であった(図1参照)。この20mgの用量で、血漿BHV-3500は、2群及び3群に対して最初の15分の時点でのBQLであり、最高濃度は、それぞれ14.2及び18.9ng/mLの平均曝露を伴う投与の2時間後で見られ、これは、それぞれ956×(22nM)及び1,282×(29.5nM)によりヒトCGRP受容体(Ki=0.023nM)に対するBHV-3500親和性を超える。BHV-3500を経口カプセル剤として50mgでイヌにビヒクルなしで投与した場合(4群、ビヒクルなし)、血漿レベルは、1及び2時間で見られるが、4時間で見られない測定可能なレベルで、15及び30分の時点でのBQLであった。50mgの用量をビヒクル6と組み合わせて送達した場合(5群)、1及び2時間での血漿レベルは、それぞれ11.5及び40.6ng/mLの平均曝露で3.4×から6.6×へ上昇し、これは、それぞれ782×(18nM)及び2,763×(63.3nM)によりヒトCGRP受容体(Ki=0.023nM)に対するBHV-3500親和性を超える(図2参照)。ビヒクル6と共に、測定可能な血漿レベルは、(BHV-3500の血漿レベルが4時間でのBQLであった場合のビヒクルなしの条件(4群)とは異なる)7.97ng/mLの平均曝露での4時間で見出された。50mgの用量を、DDMと組み合わせて送達した場合(6群)、1及び2時間での血漿レベルは、ビヒクルなしの条件(4群)と同様であった。4時間でのDDM(6群)(4時間の血漿レベルがBQLであった場合のビヒクルなしの条件と対照的)と共に、BHV-3500の測定可能な血漿レベルは、8.67ng/mLの平均曝露での4時間で見出され、これは、590×(13.5nM)によりヒトCGRP受容体(Ki=0.023nM)に対するBHV-3500親和性を超える。
研究タイトル: イヌにおけるBHV-3500の単回用量の経口カプセル剤研究
同定。試験物質をBHV-3500として識別する。試験物質は、カプセル剤として供給される。
上記のTable 6(表6)を参照。
試験動物。3匹又は3匹の雌のビーグル犬を、本研究で使用するためにRidglan Farms社、Mount Horeb、WIから得る。全ての動物は、供給者により、ジステンパー、2型アデノウイルス、パラインフルエンザ、ボルデテラ、狂犬病、パピローマウイルス、及びパルボウイルスに対して免疫化される。イヌは、投与の開始時に、およそ1歳であり、体重およそ8~12kgである。同じ3匹の動物は、全ての試験物質の投与に使用される。
隔離。本試験に購入した動物は、試験物質の投与前の少なくとも2週間、隔離されて保持する。隔離期間にわたって、動物は、死亡又は瀕死の証拠を1日に少なくとも1回観察する。
・署名される本来のプロトコル、並びに任意の補正例及び/又は逸脱例;
・動物の受領記録;
・動物の飼育記録;
・試験物質データ;
・採血データ;
・TKデータ
ToxData(登録商標)を使用して電子的に獲得されるデータ(例えば、用量投与、毎日の瀕死/死亡及び環境データ、診療観察、体重等)は、コンピュータシステムのデータベース内に維持され、ToxData(登録商標).htmのファイルの電子コピーもまた、CD-ROMにバックアップし、ディスクは、生データで維持される。
・任意の補正例及び/又は逸脱例を含む、承認されたプロトコルのコピー
・使用した動物の種及び系統
・臨床観察データ
・体重データ
・血漿薬物レベルデータ
・薬物動態的データ
別段定義しない限り、本明細書に使用される全ての技術用語、表記法、並びに他の技術的及び科学的用語又は専門用語は、特許請求される主題が関連する当業者が通常理解するのと同じ意味を有することを意図する。一部の例では、通常理解される意味を有する用語は、明確さ及び/又は容易な参照のために本明細書で定義され、本明細書でのこのような定義を含めることは、当該技術分野で一般に理解されるものとの実質的な相違を表すと解釈される必要はない。
Claims (20)
- 製剤の総質量の0.01~20wt%の量で合成若しくは天然の浸透性の低いカルシトニン遺伝子関連ペプチド(CGRP)阻害剤又はその塩若しくは溶媒和物;
製剤の総質量の50~80wt%の量で脂肪酸のトリグリセリドを含む親油性相;並びに
製剤の総質量の10~50wt%の量でポリオール及び脂肪酸の部分エステルを含む少なくとも1つの親油性界面活性剤
を含む、医薬製剤。 - 合成又は天然の浸透性の低いCGRP阻害剤が、CGRP抗体、CGRP受容体抗体、CGRP抗体若しくはCGRP受容体抗体由来の抗原結合フラグメント、CGRP注入阻害性タンパク質、CGRP生体中和剤、小分子CGRP受容体アンタゴニスト、小分子CGRP阻害剤、又はポリペプチドCGRP阻害剤である、請求項1に記載の製剤。
- 合成又は天然の浸透性の低いCGRP阻害剤が、小分子CGRP受容体アンタゴニストである、請求項1に記載の製剤。
- 小分子CGRP受容体アンタゴニストが、(R)-N-(3-(7-メチル-1H-インダゾール-5-イル)-1-(4-(1-メチルピペリジン-4-イル)ピペラジン-1-イル)-1-オキソプロパン-2-イル)-4-(2-オキソ-1,2-ジヒドロキノリン-3-イル)ピペリジン-1-カルボキサミド(BHV-3500)である、請求項3に記載の製剤。
- 製剤の総質量の1~30wt%の量で10超の親水親油バランス(「HLB」)を有する少なくとも1つの親水性界面活性剤を更に含む、請求項1に記載の製剤。
- 少なくとも1つの親水性界面活性剤が、ポリオキシエチレン(20)モノオレエート、PEG 8カプリル酸/カプリン酸グリセリド、PEG 6カプリル酸/カプリン酸グリセリド、ポリ(オキシエチレン)(4)ラウリルエーテル、及びその混合物からなる群から選択される、請求項5に記載の製剤。
- 脂肪酸のトリグリセリドが、中鎖脂肪酸である、請求項1に記載の製剤。
- 親油性界面活性剤が、中鎖脂肪酸のモノグリセリド及びジグリセリドの混合物を含む、請求項1に記載の製剤。
- 水を含まない、請求項1に記載の製剤。
- 製剤の総質量の0.01~20wt%の量で合成若しくは天然の浸透性の低いCGRP阻害剤又はその塩若しくは溶媒和物;
製剤の総質量の50~80wt%の量で脂肪酸のトリグリセリドを含む親油性相;並びに
製剤の総質量の10~50wt%の量でポリオール及び脂肪酸の部分エステルを含む少なくとも1つの親油性界面活性剤
を含む医薬製剤を含む、遅延放出性の医薬剤形であって、
その放出がpH依存性であるコーティングされた剤形である、
遅延放出性の医薬剤形。 - 患者を処置するための方法であって、
製剤の総質量の0.01~20wt%の量で合成若しくは天然の浸透性の低いCGRP阻害剤又はその塩若しくは溶媒和物;
製剤の総質量の50~80wt%の量で脂肪酸のトリグリセリドを含む親油性相;並びに
製剤の総質量の10~50wt%の量でポリオール及び脂肪酸の部分エステルを含む少なくとも1つの親油性界面活性剤
を含む有効量の医薬製剤を、それを必要とする人に投与する工程を含む、方法。 - 合成又は天然の浸透性の低いCGRP阻害剤が、CGRP抗体、CGRP受容体抗体、CGRP抗体若しくはCGRP受容体抗体由来の抗原結合フラグメント、CGRP注入阻害性タンパク質、CGRP生体中和剤、小分子CGRP受容体アンタゴニスト、小分子CGRP阻害剤、又はポリペプチドCGRP阻害剤である、請求項11に記載の方法。
- 合成又は天然の浸透性の低いCGRP阻害剤が、小分子CGRP受容体アンタゴニストである、請求項11に記載の方法。
- 小分子CGRP受容体アンタゴニストが、(R)-N-(3-(7-メチル-1H-インダゾール-5-イル)-1-(4-(1-メチルピペリジン-4-イル)ピペラジン-1-イル)-1-オキソプロパン-2-イル)-4-(2-オキソ-1,2-ジヒドロキノリン-3-イル)ピペリジン-1-カルボキサミド(BHV-3500)である、請求項13に記載の方法。
- 医薬組成物が、製剤の総質量の1~30wt%の量で10超の親水親油バランス(「HLB」)を有する少なくとも1つの親水性界面活性剤を含む、請求項11に記載の方法。
- 少なくとも1つの親水性界面活性剤が、ポリオキシエチレン(20)モノオレエート、PEG 8カプリル酸/カプリン酸グリセリド、PEG 6カプリル酸/カプリン酸グリセリド、ポリ(オキシエチレン)(4)ラウリルエーテル、及びその混合物からなる群から選択される、請求項15に記載の方法。
- 脂肪酸のトリグリセリドが、中鎖脂肪酸である、請求項11に記載の方法。
- 親油性界面活性剤が、中鎖脂肪酸のモノグリセリド及びジグリセリドの混合物を含む、請求項11に記載の方法。
- 製剤が、水を含まない、請求項11に記載の方法。
- 医薬製剤が、その放出がpH依存性であるコーティングされた剤形を含む遅延放出剤形である、請求項11に記載の方法。
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BR112021020287A2 (pt) | 2021-12-14 |
CA3134550A1 (en) | 2020-10-15 |
CA3136485A1 (en) | 2020-10-15 |
MX2021012356A (es) | 2021-11-04 |
CN113784722A (zh) | 2021-12-10 |
KR20210151187A (ko) | 2021-12-13 |
BR112021018817A2 (pt) | 2021-11-23 |
WO2020210722A1 (en) | 2020-10-15 |
CO2021012462A2 (es) | 2021-09-30 |
CO2021014899A2 (es) | 2021-11-19 |
US20220143188A1 (en) | 2022-05-12 |
AR118654A1 (es) | 2021-10-20 |
EA202192792A1 (ru) | 2022-01-11 |
US11185589B2 (en) | 2021-11-30 |
WO2020210723A1 (en) | 2020-10-15 |
SG11202111251SA (en) | 2021-11-29 |
AU2020272059A1 (en) | 2021-12-09 |
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EA202192793A1 (ru) | 2022-01-12 |
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EP3952900A1 (en) | 2022-02-16 |
US20220249468A1 (en) | 2022-08-11 |
TW202103726A (zh) | 2021-02-01 |
IL287084A (en) | 2021-12-01 |
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