JP2023002687A - Peg化リポソームおよび血液凝固因子の製剤処方 - Google Patents
Peg化リポソームおよび血液凝固因子の製剤処方 Download PDFInfo
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Abstract
Description
clotting factor)の言及には、血液凝固因子(blood coagulation factor)が含まれる。
ることができる。一実施形態では、PEGの分子量は2000ダルトンであってもよい。ポリエチレングリコールは、分枝状であっても非分枝状であってもよい。
のでありうる(Arakawa、T. and Timasheff、SN、Biochemistry 24:6756-6762(1985);Lee、JC and Lee、LLY、J. Biol.Chem。226:625-631(1981))。そのようなポリマーの例としては、ポリエチレングリコール(PEG)である。
の使用に適した最も一般的なリン脂質はレシチン(ホスファチジルコリン(PC)とも呼ばれる)であり、リン酸のコリンエステルに結合したステアリン酸、パルミチン酸およびオレイン酸のジグリセリドの混合物である。レシチンは、卵、大豆、および動物組織(脳、心臓など)などのすべての動物および植物に見出され、また合成的に製造することもできる。リン脂質の供給源またはその合成方法は重要ではなく、任意の天然または合成のホスファチドを使用することができる。
1.リン脂質の薄膜を水性媒体で水和させた後、機械的に振とうおよび/もしくは超音波照射および/もしくは適当なフィルターを通して押し出しを行う;
2.リン脂質を適切な有機溶媒に溶解し、水性媒体と混合した後、溶媒を除去する。
3.その気体の臨界点を超える気体を使用する(すなわち、フレオンおよびCO2もしくはCO2と他のガス状炭化水素との混合物などの他のガス)または
4.次に、脂質と界面活性剤との混合ミセルを調製し、次いで、界面活性剤の濃度を、リポソームが形成されるその臨界濃度よりも低いレベルまで低下させる。
a)水と混和しない有機溶媒中にベシクルを形成するのに適した脂質などの両親媒性物質を混合する
b)固体支持体の存在下で溶媒を除去するか、あるいは乾燥した両親媒性物質またはその混合物は、任意の形態(粉末、顆粒など)で直接用いられうる
c)生理学的に適合する溶液中で工程b)の生成物を生体高分子物質の溶液に取り込む工程
d)可溶化または分散性を有する有機溶媒を加え、そして
e)工程d)で得られた画分を生体高分子物質の機能を保持する条件下で乾燥する工程。
第IX因子を含む場合、tert-ブタノールの量は約30%であるのに対して、第VIII因子についてはtert-ブタノールの量は10%未満が適切である(第VIII因子はtert-ブタノールの影響に対してはるかに敏感である)。これらの実施例におけるtert-ブタノールのパーセンテージは、最終濃度について計算された体積%に基づく。
この方法は、方法Aの工程a)、b)およびc)も含む。しかし、方法Aの工程d)およびe)は省略される。
方法Cにおいて、方法Aの工程d)は、少なくとも2回繰り返さなければならない凍結融解サイクルに置き換えられる。この工程は、リポソームを製造するための先行技術において周知である。
方法Dは浸透性成分の使用を除外する。方法Dでは、ベシクルの調製、導入される物質の実質的に塩を含まない溶液と混合、および得られたフラクションの共乾燥の工程が関与する。
方法Eは、上記の方法A~Dよりも簡単である。それは、リポソーム調製に使用される化合物(脂質酸化防止剤など)を、tert-ブタノールなどの極性プロトン性水混和性溶媒に溶解する必要がある。次いで、この溶液を血液因子を含有する水溶液または分散液と混合する。混合は、薬剤の生物学的および薬理学的活性を維持するために必要な最適な体積比で行われる。
が必要となるかもしれない。
。
本発明の一実施形態によれば、血液凝固因子を含む本発明の製剤は、正常な止血が少なくとも半週間維持されることができる。
-50mMクエン酸ナトリウム
-pH 7.0
-100mMリン脂質 パルミトイル-オレオイルホスファチジルコリン(POPC)および1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン-N-[ポリ(エチレングリコール)-2000](DSPE-PEG 2000)の97:3モル比
-凍結乾燥rFVIII(Helixate NexGen)。
実施例1:リポソームの合成
パルミトイル-オレオイルホスファチジルコリン(POPC)およびPEG-2000(PEGの分子量 2000ダルトン)で誘導体化された1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノールアミン-N-[ポリ(エチレングリコール)-2000](DSPE-PEG 2000)から以下のようにして混合脂質を調製した:
POPCの分子量:760.08g/mol
DSPE-2kPEGの分子量:2789.5g/mol
最終調製物は、100mMのリン脂質の濃度を有していた。POPC:DSPE-2kPEGの97:3モル比で脂質の15%w/v混合物を作製した。以下のものを計量し、混合した:
POPC 2.04g
DSPE-2kPEG 0.232g
14.9mLのtert-ブタノール(35℃の水浴中で融解)を、全て100mLのSchottボトルに入れた。
GF/D)で覆った。エマルジョンをハウジングに注ぎ、4バールの窒素ガス下で押出し、ろ液を50mLチューブに集めた。各押し出しの継続時間は計測され、記録された。
血友病Aを有するイヌ(イヌ番号「1」と識別される)は、第VIII因子に関連するPEG化リポソーム(PEGLip FVIII SQ)の皮下用量を以下のように受けた:
この研究の目的は、皮下投与(SQ)されたPEG化リポソーム中で再構成された完全長rFVIIIの血友病AイヌにおけるPKおよびPDを決定することであった。
凍結乾燥した完全長rFVIII(Helixate NexGen、Lot 270LR8WB)を試験品として使用した。
クエン酸緩衝液中のPEG化リポソームを、Baru等(2005)の方法による上記実施例1に従って製造した。リポソーム製剤は以下の組成を有していた;パルミトイル-オレオイルホスファチジルコリン(POPC)と1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノール-アミン-N-[ポリ(エチレングリコール)-2000](DSPE-PEG 2000)との97:3モル比の混合物を含有するリン脂質100mMを含む、pH7.0の50mMクエン酸ナトリウム。
Alabama Medical School)に収容された血友病Aコロニーからのものであった。全ての犬は先天性重度血友病Aを有する。試験被験体は体重16.4kgであり、ヒトのタンパク質にはナイーブであった。
投与量(ml)=(a×b)/c
ここで、aはターゲット用量(100IU/kg)であり、
bはイヌの体重(kg)であり、
cはrFVIII活性(150IU/ml)である。
whole blood)に対して行った。
(i)非クエン酸処理全血:全血凝固アッセイ
血液試料を2つの真空管(2×0.5ml)の間で分割し、完全に水平な位置での流れの中断によって血栓が決定されるまで、チューブの定期的かつ賢明なレべリングにより慎重に観察した。血栓の質は、チューブを完全に反転した位置に保持することによって観察された。全血液凝固時間は、サンプル抽出から両方のサンプルの血栓の目視観察までの総時間の平均として記録し、逆位の血栓の質を記録した。
製造元の推奨に従って、止血分析装置モデル5000(Haemoscope Corporation)トロンボエラストグラフを用いて、再石灰化したクエン酸処理全血を用いてTEGを実施した。簡潔には、カオリンを含有する市販の(Teg(登録商標)造血システムカオリン、Haemonetics)バイアルに1mlのクエン酸処理全血を入れた。混合は、カオリン含有バイアルを5回穏やかに反転させることによって確実に行った。ピンおよびカップは、製造業者によって推奨される標準的な手順に従ってTEG分析器に配置された。各標準TEGカップを37℃の予熱した器具ホルダーに置き、20μlの塩化カルシウム(0.2M)で満たした。次いで、340μlのカオリン活性化クエ
ン酸処理全血を全容量の360μlで添加した。
Haemachron Jr凝固分析器(International Technidyne Corps.)を製造者の指示に従って使用して、ACTおよびaPTT試験を行った。
FVIII血漿活性は、Coatest Assay(Dia Pharma、West Chester、OH)を用いて測定した。血漿サンプルをアッセイ希釈剤で1:20から1:80に希釈し、製造者の指示に従ってアッセイした。正常な止血参照血漿(american diagnostica inc、Stamford、CT)および精製PEG-FVIIIタンパク質を用いて標準曲線を確立した。
血漿サンプル中のFVIII抗原の濃度は、Affinity Biologicals(Ancaster、Ontario、Canada)のVisulize FVIII抗原キットを製造者の指示に従って使用してELISAによって測定する。
試験血漿をFVIII欠損ヒト血漿中への1:4、1:10および1:20希釈でベセスダ(Bethesda)アッセイを行った。等量の希釈試験血漿および正常ヒト参照血漿を37℃で2時間インキュベートし、上述のようにaPTTアッセイおよび正常ヒト血漿標準曲線を用いてベセスダ力価を測定した。
Claims (13)
- 血液因子と、生体適合性親水性ポリマーで誘導体化された0.5~20モル%の両親媒性脂質を含有するコロイド粒子と、を含み、
前記血液因子が前記コロイド粒子に封入されておらず、
前記コロイド粒子が、パルミトイル-オレオイルホスファチジルコリン(POPC)および1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノール-アミン(DSPE)を、(POPC:DSPE)=85:15~99:1のモル比で含む、皮下投与用医薬組成物。 - 前記コロイド粒子が実質的に中性であり、および前記ポリマーが実質的に正味の電荷を有さない、請求項1に記載の医薬組成物。
- 前記コロイド粒子が、0.03~0.4ミクロン(μm)の平均粒径を有する、請求項1または2に記載の医薬組成物。
- 前記コロイド粒子が、パルミトイル-オレオイルホスファチジルコリン(POPC)および1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノール-アミン(DSPE)を、(POPC:DSPE)=90:10~99:1のモル比で含む、請求項1~3のいずれか1項に記載の皮下投与用医薬組成物。
- 前記コロイド粒子が、パルミトイル-オレオイルホスファチジルコリン(POPC)および1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノール-アミン(DSPE)を、(POPC:DSPE)=97:3のモル比で含む、請求項4に記載の皮下投与用医薬組成物。
- コレステロールが前記組成物に補充される、請求項1~5のいずれか1項に記載の医薬組成物。
- 前記生体適合性親水性ポリマーが、ポリアルキルエーテル、ポリ乳酸、ポリエチレングリコールおよびポリグリコール酸からなる群より選択される、請求項1~6のいずれか1項に記載の医薬組成物。
- 前記ポリエチレングリコールが500~5000ダルトンの分子量を有する、請求項7に記載の医薬組成物。
- 前記誘導体化された両親媒性脂質が、1,2-ジステアロイル-sn-グリセロ-3-ホスホエタノール-アミン-N-[ポリ-(エチレングリコール)]である、請求項7または8に記載の医薬組成物。
- 前記血液因子タンパク質またはポリペプチドが、第VIII因子、第VIIa因子、第VII因子、第IX因子、第X因子、第Xa因子、第XI因子、第V因子、第XII因子、第XIII因子、フォン・ヴィレブランド因子(vWF)、プロトロンビンもしくはプロテインCおよび/またはそれらのフラグメントからなる群より選択される、請求項1~9のいずれか1項に記載の医薬組成物。
- 前記組成物が、他の治療的に活性な化合物をさらに含む、請求項1~10のいずれか1項に記載の医薬組成物。
- 血液凝固疾患または外傷の治療のために使用される、請求項1~11のいずれか1項に
記載の医薬組成物。 - 血液因子に対する抗体ができている患者に皮下投与されることによって使用される、請求項12に記載の医薬組成物。
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