JP2019178176A - 有機ホスフェートを含有する液状タンパク質製剤 - Google Patents
有機ホスフェートを含有する液状タンパク質製剤 Download PDFInfo
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Abstract
Description
本願は、2014年7月29日出願の「Low-Viscosity Protein Formulations Containing Hydrophobic Salts」との表題の米国仮出願第62/030,521号;2014年7月18日出願の「Low-Viscosity Protein Formulations Containing GRAS Viscosity-Reducing Agents」との表題の米国仮出願第62/026,497号;2014年6月5日出願の「Low-Viscosity Protein Formulations Containing Ionic Liquids」との表題の米国仮出願第62/008,050号;2014年5月2日出願の「Low-Viscosity Protein Formulations Containing Organophosphates」との表題の米国仮出願第61/988,005号;2014年2月28日出願の「Concentrated, Low-Viscosity Infliximab Formulations」との表題の米国仮出願第61/946,436号;2014年2月21日出願の「Concentrated, Low-Viscosity, High-Molecular-Weight-Protein Formulations」との表題の米国仮出願第61/943,197号;2014年2月14日出願の「Concentrated, Low-Viscosity High-Molecular-Weight Protein Formulations」との表題の米国仮出願第61/940,227号、および2013年9月11日出願の「Concentrated, Low-Viscosity, High-Molecular-Weight Protein Formulations」との表題の米国仮出願第61,876,621号の優先権を主張し、かつその利益を主張する。これらの出願の開示は、本明細書に参考として明白に援用される。
本発明は、一般に、モノクローナル抗体などのタンパク質の注射可能な医薬製剤、ならびにその作製方法および使用方法の分野におけるものである。
モノクローナル抗体(mAb)は、がん、感染症、炎症および自己免疫疾患などの様々なヒト疾患を処置するための、重要なタンパク質をベースとする治療薬である。20種を超えるmAb製品が、米国食品医薬品局(FDA)によって承認されており、臨床試験において現在、評価されているバイオ医薬品の約20%が、mAbである(Daughertyら、Adv. Drug Deliv. Rev. 58巻:686〜706頁、2006年、およびBussら、Curr. Opinion in Pharmacol. 12巻:615〜622頁、2012年)。
(項目1)
(i)1種または複数のタンパク質;
(ii)1種または複数の粘度低下有機ホスフェート;および
(iii)薬学的に許容される溶媒;
を含む、注射用液状医薬製剤であって、
該タンパク質が、注射に適した体積で溶媒および有機ホスフェートと組み合わされる場合、該製剤が、円錐平板粘度計を使用して測定すると、25℃において絶対粘度約1cP〜約50cPを有しており、該製剤の該絶対粘度が、該有機ホスフェートの代わりに等量のリン酸ナトリウムを含む他は同じ該製剤の該絶対粘度よりも低く、
各場合において、該絶対粘度が外挿したゼロせん断粘度である、
注射用医薬製剤。
(項目2)
前記タンパク質(複数可)が、約70kDa〜100kDaまでの間、約100kDa〜約250kDa、または約250kDa〜約500kDaの間の分子量を有する高分子量タンパク質である、項目1に記載の製剤。
(項目3)
前記タンパク質が、約120kDa〜約250kDaの分子量を有する、項目1および2のいずれか一項に記載の製剤。
(項目4)
前記タンパク質の少なくとも1種が、酵素、抗体もしくは抗体断片、融合タンパク質、またはPEG化タンパク質である、項目1から3のいずれかに記載の製剤。
(項目5)
前記タンパク質(複数可)が、1mLあたり約100mg〜約2,000mg(mg/mL)、任意選択で約150mg/mLより多い合わせた量で存在する、項目1から4のいずれか一項に記載の製剤。
(項目6)
少なくとも2種の異なるタンパク質を含み、好ましくは、該タンパク質の両方が、少なくとも約50kDaの分子量を有する、項目1から5のいずれか一項に記載の製剤。
(項目7)
有機ホスフェートを添加する前の、同じ前記タンパク質濃度における初期絶対粘度が、約60cPを超える、約80cPを超える、または約100cPを超える、項目1から6のいずれか一項に記載の製剤。
(項目8)
液状の前記製剤が、約5.0〜約8.0の間のpHを有する水性である、項目1から7のいずれか一項に記載の製剤。
(項目9)
約0.01M〜約1.0Mの濃度で存在する前記有機ホスフェートを含む、項目1から8のいずれか一項に記載の製剤。
(項目10)
0.30M未満、または0.15M未満の量で存在する前記有機ホスフェートを含む、項目1から9のいずれか一項に記載の製剤。
(項目11)
皮下または筋肉注射用の1種または複数の薬学的に許容される賦形剤であって、糖または糖アルコール、緩衝剤、保存剤、担体、酸化防止剤、キレート剤、天然または合成ポリマー、凍結保護剤、凍結乾燥保護剤、界面活性剤、増量剤および安定化剤からなる群から選択される、1種または複数の薬学的に許容される賦形剤を含む、項目1から10のいずれか一項に記載の製剤。
(項目12)
前記賦形剤の1種または複数が、ポリソルベート、ポロキサマー188、ラウリル硫酸ナトリウム、マンニトールおよびソルビトールなどの糖アルコール、ポリ(エチレングリコール)、グリセロール、プロピレングリコールおよびポリ(ビニルアルコール)からなる群から選択されるポリオールからなる群から選択される、項目11に記載の製剤。
(項目13)
前記界面活性剤が、約10mg/mL未満の量で存在する、項目11に記載の製剤。
(項目14)
約2mg/mL〜約900mg/mLの量で存在しているポリオールを含む、項目12に記載の製剤。
(項目15)
前記絶対粘度が、25℃において、約5cP〜約50cPである、項目1から14のいずれか一項に記載の製剤。
(項目16)
前記絶対粘度が、前記有機ホスフェートをほぼ同じ濃度の適切な緩衝剤に置き換えた以外同一条件下で測定した場合、該有機ホスフェートを含まない製剤の該絶対粘度よりも少なくとも約30%低い、項目1から15のいずれか一項に記載の製剤。
(項目17)
前記絶対粘度が、前記有機ホスフェートをほぼ同じ濃度の適切な緩衝剤に置き換えた以外同一条件下で測定した場合、該有機ホスフェートを含まない製剤の該絶対粘度よりも少なくとも約2倍または4倍低い、項目1から16のいずれか一項に記載の製剤。
(項目18)
単位用量バイアル、容器またはプレフィルドシリンジ中の、項目1から17のいずれか一項に記載の製剤。
(項目19)
前記タンパク質、有機ホスフェートおよび/または賦形剤が乾燥形態にあり、好ましくは凍結乾燥されている、項目18に記載の製剤。
(項目20)
有機ホスフェート、タンパク質および溶媒を組み合わせた場合の前記製剤の体積が、SC注射の場合、約1.5mL未満であり、IM注射の場合、約3mL未満である、項目1から19のいずれかに記載の製剤。
(項目21)
ヒト血清に等張である、項目1から20のいずれか一項に記載の製剤。
(項目22)
それを必要とするヒトに投与される条件下で、レオロジー的に、本質的にニュートン液体として挙動する、項目1から21のいずれか一項に記載の製剤。
(項目23)
静脈内注入により投与される同じ用量の前記タンパク質と比べて、治療有効な投与量を実現する、項目1から22のいずれか一項に記載の製剤。
(項目24)
前記有機ホスフェートが、皮下注射または筋肉内注射により投与される場合、毒性または注射部位の刺激の臨床的に有意な徴候を引き起こさない濃度で存在する、項目1から23のいずれか一項に記載の製剤。
(項目25)
前記製剤の前記絶対粘度が、円錐平板粘度計を使用して測定される場合、少なくとも約0.5s−1のせん断速度で測定される、項目1から24のいずれかに記載の製剤。
(項目26)
前記製剤の前記絶対粘度が、マイクロ流体粘度計を使用して測定した場合、少なくとも約1.0s−1のせん断速度で、測定される、項目1から24のいずれか一項に記載の製剤。
(項目27)
項目1から26のいずれか一項に記載の製剤の、皮下注射または筋肉内注射を含む、治療有効量のタンパク質を投与する方法。
(項目28)
前記皮下注射または筋肉内注射が、加熱シリンジ、自己混合式シリンジ、オートインジェクター、プレフィルドシリンジ、およびそれらの組合せからなる群から選択されるシリンジを用いて行われる、項目27に記載の方法。
(項目29)
前記シリンジが、加熱シリンジであり、前記製剤が、25℃〜40℃の間の温度で投与される、項目28に記載の方法。
(項目30)
前記製剤が、ドレイズ評点システムを使用して評価した場合、3未満の一次刺激インデックスを惹起する、項目27から29のいずれかに記載の方法。
(項目31)
射出力が、前記有機ホスフェートを含まないがそれ以外は同じ製剤を同じ様式で投与した場合の射出力よりも、少なくとも10%または20%小さい、項目27から30のいずれか一項に記載の方法。
(項目32)
前記注射が、直径がゲージ27〜31の間の針を使用して施行され、かつ該ゲージ27の針を使用した場合、前記射出力が30N未満である、項目27から31のいずれか一項に記載の方法。
(項目33)
項目1から26のいずれかに記載のタンパク質、溶媒および有機ホスフェートを合わせるステップを含む、医薬製剤を調製する方法。
(項目34)
前記製剤が、プレフィルドシリンジまたはカートリッジ内にある、項目33に記載の方法。
(項目35)
項目1、または7から10のいずれかに記載の有機ホスフェートの有効量を、タンパク質溶液に加えて、該タンパク質溶液の前記粘度を低下させることを含む、タンパク質の精製を容易にする方法。
(項目36)
前記タンパク質−有機ホスフェート溶液が、限外ろ過/ダイアフィルトレーション、タンジェンシャルフローろ過、遠心濃縮、および透析からなる群から選択される方法を使用して精製または濃縮される、項目35に記載の方法。
発明の概要
タンパク質の、低粘度で低体積の濃縮液状医薬製剤を開発した。こうした製剤は、長時間の静脈内注入によるよりもむしろ、皮下(SC)または筋肉内(IM)注射によって、迅速かつ便利に投与することができる。これらの製剤は、mAbなどの低分子量および/または高分子量タンパク質、および有機ホスフェートを含む。代表的な有機ホスフェートには、チアミンピロリン酸(TPP)、アデノシン三リン酸(ATP)、デオキシアデノシン三リン酸(dATP)、デオキシグアノシン三リン酸(dGTP)、デオキシチミジン三リン酸(dTTP)、デオキシシチジン三リン酸(dCTP)、環状アデノシン一リン酸(cAMP)、ニコチンアミドアデニンジヌクレオチドリン酸(NADP+)およびピリドキサールリン酸、ならびにそれらの塩が、好ましくは約0.01M〜約0.50Mの間、最も好ましくは約0.05M〜約0.25Mの間の濃度で含まれる。
本明細書において一般に使用される、用語「タンパク質」とは、ペプチド結合により互いに連結されて、その鎖長が少なくとも検出可能な三次元構造を生じるのに十分な、ポリペプチドを形成する、アミノ酸のポリマーを指す。約100kDaを超える分子量(kDaで表され、ここで、「Da」は「ダルトン」を表し、1kDa=1,000Daである)を有する、タンパク質は、「高分子量タンパク質」と称することができる一方、約100kDa未満の分子量を有するタンパク質は、「低分子量タンパク質」と称することができる。用語「低分子量タンパク質」は、タンパク質と見なすのに必要な少なくとも三次元の構造という要件を欠く、小さなペプチドを除外する。タンパク質の分子量は、質量分析法(例えば、ESI、MALDI)または公知のアミノ酸配列およびグリコシル化からの計算を含むがこれらに限定されない、当業者に公知の標準方法を使用して決定することができる。タンパク質は、天然に存在するかまたは天然に存在しないもの、合成によるものまたは半合成によるものとすることができる。
有機ホスフェートは、バイオシミラーAVASTIN(登録商標)の濃縮水溶液の粘度を低下させる
バイオシミラーAVASTIN(登録商標)の水溶液の粘度低下は、有機ホスフェートの濃度に依存する
有機ホスフェートは、治療関連性のあるモノクローナル抗体の多くの粘度を低下させる。
Claims (26)
- (i)抗体;
(ii)1種または複数の粘度低下有機ホスフェートであって、
環状アデノシン一リン酸(cAMP)もしくはその薬学的に許容される塩;または
アデノシン三リン酸(ATP)もしくはその薬学的に許容される塩
を含む、1種または複数の粘度低下有機ホスフェート;および
(iii)薬学的に許容される溶媒;
を含む、注射用液状医薬製剤であって、
該液状医薬製剤は、注射に適した体積にある場合、円錐平板粘度計またはマイクロ流体粘度計を使用して測定すると、25℃において約1cP〜約100cPの絶対粘度を有しており、該液状医薬製剤の該絶対粘度が、該抗体および該薬学的に許容される溶媒を含むが、該1種または複数の粘度低下有機ホスフェートを含まない対照組成物の絶対粘度よりも低く、
該絶対粘度が外挿したゼロせん断粘度である、
注射用液状医薬製剤。 - 前記抗体がモノクローナル抗体である、請求項1に記載の液状医薬製剤。
- 前記抗体が、約120kDa〜約250kDaの分子量を有する、請求項1または2に記載の液状医薬製剤。
- 約150mg/ml〜約250mg/mlの前記抗体を含む、請求項1から3のいずれか一項に記載の液状医薬製剤。
- 約156mg/ml〜約235mg/mlの前記抗体を含む、請求項4に記載の液状医薬製剤。
- 前記薬学的に許容される溶媒が、水性である、請求項1から5のいずれか一項に記載の液状医薬製剤。
- 前記1種または複数の粘度低下有機ホスフェートが、約0.10M〜約0.5Mの濃度で存在する、請求項1から6のいずれか一項に記載の液状医薬製剤。
- 1種または複数の薬学的に許容される賦形剤であって、糖、糖アルコール、緩衝剤、保存剤、担体、酸化防止剤、キレート剤、天然ポリマー、合成ポリマー、凍結保護剤、凍結乾燥保護剤、界面活性剤、増量剤、安定化剤またはこれらの組合せを含む、1種または複数の薬学的に許容される賦形剤をさらに含む、請求項1から7のいずれか一項に記載の液状医薬製剤。
- 前記1種または複数の薬学的に許容される賦形剤が、ポリソルベート、ポロキサマー188、ラウリル硫酸ナトリウム、ポリオール、ポリ(エチレングリコール)、グリセロール、プロピレングリコールまたはポリ(ビニルアルコール)である、請求項8に記載の液状医薬製剤。
- 前記糖アルコールがソルビトールまたはマンニトールである、請求項8に記載の液状医薬製剤。
- 単位用量バイアル、複数回用量バイアル、カートリッジ、またはプレフィルドシリンジ中の、請求項1から10のいずれか一項に記載の液状医薬製剤。
- ヒト血清に等張である、請求項1から11のいずれか一項に記載の液状医薬製剤。
- 前記絶対粘度が、円錐平板粘度計を使用して測定される場合、少なくとも約0.5s−1のせん断速度で測定される、請求項1から12のいずれか一項に記載の液状医薬製剤。
- 前記絶対粘度が、マイクロ流体粘度計を使用して測定した場合、少なくとも約1.0s−1のせん断速度で、測定される、請求項1から12のいずれか一項に記載の液状医薬製剤。
- 前記液状医薬製剤が、凍結乾燥組成物から再構成される、請求項1から14のいずれか一項に記載の液状医薬製剤。
- 前記液状医薬製剤が対象に投与され、ここで該投与が皮下注射または筋肉内注射を含むことを特徴とする、請求項1から15のいずれか一項に記載の液状医薬製剤。
- 前記注射が、シリンジを用いて行われる、請求項16に記載の液状医薬製剤。
- 前記シリンジが、加熱シリンジ、自己混合式シリンジ、オートインジェクター、プレフィルドシリンジ、またはそれらの組合せである、請求項17に記載の液状医薬製剤。
- 前記シリンジが、加熱シリンジであり、前記液状医薬製剤が、25℃〜40℃の間の温度を有する、請求項17または18に記載の液状医薬製剤。
- 前記液状医薬製剤が、ドレイズ評点システムを使用して評価した場合、3未満の一次刺激インデックスを惹起する、請求項16から19のいずれかに記載の液状医薬製剤。
- 前記液状医薬製剤が、前記抗体および前記薬学的に許容される溶媒を含むが前記1種または複数の粘度低下有機ホスフェートを含まない液状医薬製剤の射出力よりも、少なくとも10%小さい射出力によって注射される、請求項16から20のいずれか一項に記載の液状医薬製剤。
- 前記液状医薬製剤が、前記抗体および前記薬学的に許容される溶媒を含むが前記1種または複数の粘度低下有機ホスフェートを含まない液状医薬製剤の射出力よりも、少なくとも20%小さい射出力によって注射される、請求項16から20のいずれか一項に記載の液状医薬製剤。
- 前記注射が、直径がゲージ27〜31の間の針を使用して行われ、かつ該ゲージ27の針を使用した場合、前記射出力が30N未満である、請求項16から22のいずれか一項に記載の液状医薬製剤。
- 前記抗体、前記薬学的に許容される溶媒および前記1種または複数の粘度低下有機ホスフェートを合わせるステップを含む、請求項1から15のいずれか一項に記載の液状医薬製剤を調製する方法。
- (i)抗体;
(ii)1種または複数の粘度低下有機ホスフェートであって、
cAMPもしくはその薬学的に許容される塩;または
ATPもしくはその薬学的に許容される塩
を含む、1種または複数の粘度低下有機ホスフェート;および
(iii)薬学的に許容される賦形剤
を含む、凍結乾燥組成物。 - 再構成されると、前記抗体が少なくとも100mg/mlの濃度を有する、請求項25に記載の凍結乾燥組成物。
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