JP2020011999A - 組成物及び薬物送達方法 - Google Patents
組成物及び薬物送達方法 Download PDFInfo
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- JP2020011999A JP2020011999A JP2019193548A JP2019193548A JP2020011999A JP 2020011999 A JP2020011999 A JP 2020011999A JP 2019193548 A JP2019193548 A JP 2019193548A JP 2019193548 A JP2019193548 A JP 2019193548A JP 2020011999 A JP2020011999 A JP 2020011999A
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- albumin
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- paclitaxel
- human serum
- propofol
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Abstract
Description
本特許出願は、2002年12月9日出願の米国仮特許出願第60/432,317号、2003年12月3日出願の米国仮特許出願(弁理士整理番号225519)、2003年12月4日出願の米国仮特許出願(弁理士整理番号225549)、及び2003年12月5日出願の米国仮特許出願(弁理士整理番号225585)の利益を主張する。
本発明は、同様の薬剤の入手できる製剤と比較したとき、投与時の特定の非所望の副作用の減少効果を有する、非経口使用又は他の内服のための医薬活性剤を含有する医薬組成物に関する。
非経口使用の多数の薬剤、特に静脈内投与される薬剤が、静脈刺激、静脈炎、注射での焼灼や疼痛、静脈血栓、血管外漏出、及び他の投与関連副作用などの望ましくない副作用を引き起こすことはよく認識されている。これらの薬剤の多数は水不溶性であり、従って、患者に投与するときに刺激性、アレルギー性、又は毒性である、可溶化剤、界面活性剤、溶媒、及び/又は乳化剤と共に製剤化される(例えば、Briggsetal., Anesthesis 37, 1099 (1982)、及びWaugh et al., Am. J. Hosp. Pharmacists, 48,1520(1991)参照)。しばしば、製剤中に存在する遊離薬剤は、投与で疼痛又は刺激を引き起こす。例えば、進行性非小細胞肺癌の最前線化学療法としてイフォスファミドとビノレルビンの末梢静脈投与を受けた患者の50%で静脈炎が観察された(例えば、Vallejoetal., Am. J. Clin. Oncol., 19(6), 584−8 (1996)参照)。更に、バンコマイシンは、静脈炎などの副作用を誘導することが示されている(例えば、LopesRochaet al., Braz. J. Infect. Dis., 6(4), 196−200 (2002)参照)。固形腫瘍を有する患者でシスプラチン、ゲンシタビン、及びSU5416の使用により、深部静脈血栓や静脈炎などの有害事象が起こった(例えば、Kuenenetal., J. Clin. Oncol.,20(6), 1657−67 (2002)参照)。更に、麻酔剤であるプロポフォールは、特に、レシチン安定化脂肪エマルジョンとして投与されるとき、注射時疼痛、焼灼及び静脈刺激を引き起こしうる(例えば、Tanetal., Anathesia, 53, 468−76, (1998)参照)。投与関連副作用を示す他の薬剤として、例えば、タキソール(パクリタキセル)(例えば、タキソールI.V.用の添付文書参照)、コダロン(アミオダロン塩酸塩)(例えば、コダロンI.V.用の添付文書参照)、甲状腺ホルモンT3即ちリオチロニン(トリオスタットとして市販)、チオテパ、ブレオマイシン、及び診断用放射線造影剤が挙げられる。
本発明は、医薬組成物の様々な実施態様を提供する。種々の実施態様の性質の1つ、幾つか、又は全部は、本発明の様々な実施態様で見出すことができ、依然として添付の特許請求の範囲の範囲内である。
本発明は、医薬と医薬として許容できる担体を含有する医薬組成物を提供し、該医薬として許容できる担体は、ヒトへの医薬組成物の投与の1つ以上の副作用を減少するのに有効な量でアルブミンなどの蛋白質、好ましくはヒト血清アルブミンを含み、医薬として許容できる担体は、医薬組成物における微生物増殖を阻害するのに有効な量でデフェロキサミンを含む。本発明はまた、医薬と医薬として許容できる担体を含有する医薬組成物を提供し、医薬として許容できる担体は、ヒトへの医薬組成物の投与の1つ以上の副作用を減少するのに有効な量でアルブミンなどの蛋白質を含み、医薬として許容できる担体は、医薬組成物における酸化を阻害するのに有効な量でデフェロキサミンを含む。
Gynecology and Obstetrics,150, 811−816 (1980)参照)、そして、新生児の高ビリルビン血症の治療での交換輸血に関連して(例えば、Finlayson,Seminars in Thrombosis and Hemostasis, 6, 85−120, (1980)参照)記載された。
Bull.,46, 379−99(1999)、Kragh−Hansen,Dan. Med. Bull., 1441, 131−40 (1990)、Curry et al., Nat.Struct.Biol., 5, 827−35(1998)、Sugio et al., Protein. Eng., 12, 439−46 (1999)、He etal.,Nature, 358, 209−15(1992)、及びCarter et al., Adv. Protein. Chem., 45, 153−203 (1994)参照)。パクリタキセル及びプロポフォールはHSAと結合することが示されている(例えば、Paaletal., Eur. J. Biochem., 268(7), 2187−91 (2001)、Purcell et al., Biochim. Biophys.Acta,1478(1), 61−8 (2000)、Altmayer et al., Arzneimittelforschung, 45, 1053−6 (1995)、及びGarridoetal., Rev. Esp. Anestestiol. Reanim., 41, 308−12 (1994)参照))。更に、ドセタキセルは、ヒト血漿蛋白質に結合することが示されている(例えば、Urienetal.,Invest. New Drugs, 14(2), 147−51 (1996)参照)。従って、いずれの特定の理論にも縛られることは望まないが、本発明の医薬組成物中にアルブミンなどの蛋白質を含めることにより、医薬組成物の投与と関連した副作用における減少が起こる(減少は、少なくとも部分的には、組成物中に存在する任意の遊離薬剤へのヒト血清アルブミンの結合によるものである)と考えられる。
本実施例は、パクリタキセルとアルブミンを含む医薬組成物の製造を示す。パクリタキセル−アルブミン組成物の製造は、米国特許5,439,686及び5,916,596に記載されている(これらは、引用によりそれら全体が援用される)。詳細には、パクリタキセル30mgを塩化メチレン3.0mlに溶解した。溶液を、ヒト血清アルブミン溶液(2%w/v)27.0mlに加えた。デフェロキサミンを必要に応じ加えた。混合物を低RPM(Vitrisホモジナイザー、モデルTempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をロータリーエバポレーターに移し、塩化メチレンを、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じたパクリタキセル粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成できた。再構成後の粒子サイズは、凍結乾燥前と同じであった。
本実施例は、アミオダロンとアルブミンを含む医薬組成物の製造を示す。アミオダロン30mgを塩化メチレン3.0mlに溶解した。溶液を、ヒト血清アルブミン溶液(1%w/v)27.0mlに加えた。デフェロキサミンを必要に応じ加えた。混合物を低RPM(Vitrisホモジナイザー、モデルTempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をロータリーエバポレーターに移し、塩化メチレンを、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じたアミオダロン粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。
本実施例は、リオチロニンとアルブミン組成物を含む医薬組成物の製造を示す。リオチロニン(又は適切な塩)を、濃度0.5〜50mg/mlで水性アルコール性溶液又はアルカリ溶液に溶解した。アルコール性(又はアルカリ)溶液を、アルブミン溶液(0.1〜25%w/v)に加え、撹拌した。撹拌は、スターラーでの低い剪断、又は超音波処理器もしくはホモジナイザーでの高い剪断であった。リオチロニンの低濃度(5〜1000μg/ml)で清澄溶液が得られた。濃度が増加するにつれ、ミルク状安定懸濁液が得られた。これらの溶液又は懸濁液を、滅菌フィルターを通し濾過した。有機溶媒を蒸発又は他の適切な方法で除去した。
本実施例は、ラパマイシンとアルブミンを含む医薬組成物の製造を示す。ラパマイシン30mgをクロロホルム/エタノール2mlに溶解した。次いで、溶液を、ヒト血清アルブミン溶液(3%w/v)27.0mlに加えた。混合物を低RPM(Vitrisホモジナイザーモデル Tempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をRotavapに移し、溶媒を、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じた粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。本実施例で使用した薬剤、溶媒、蛋白質の量、型及び割合は、決して限定的ではないことを認識すべきである。
本実施例は、エポチロンBとアルブミンを含む医薬組成物の製造を示す。エポチロンB30mgをクロロホルム/エタノール2mlに溶解した。次いで、溶液を、ヒト血清アルブミン溶液(3%w/v)27.0mlに加えた。デフェロキサミンを必要に応じ加えた。混合物を低RPM(Vitrisホモジナイザーモデル Tempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をRotavapに移し、溶媒を、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じた粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。本実施例で使用した薬剤、溶媒、蛋白質の量、型及び割合は、決して限定的ではないことを認識すべきである。クレモホール製剤に溶解したエポチロンBの毒性と比較したとき、アルブミン含有の医薬組成物はかなり低い毒性を示した。
本実施例は、コルヒチンダイマーとアルブミンを含む医薬組成物の製造を示す。コルヒチン−ダイマー30mgをクロロホルム/エタノール2mlに溶解した。次いで、溶液を、ヒト血清アルブミン溶液(3%w/v)27.0mlに加えた。デフェロキサミンを必要に応じ加えた。混合物を低RPM(Vitrisホモジナイザーモデル Tempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をRotavapに移し、溶媒を、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じた粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。本実施例で使用した薬剤、溶媒、蛋白質の量、型及び割合は、限定的ではないことを認識すべきである。ツウィーンに溶解したコルヒチンダイマーの毒性と比較したとき、アルブミン含有の医薬組成物はかなり低い毒性を示した。
本実施例は、ドセタキセルとアルブミンを含む医薬組成物の製造を示す。ドセタキセル30mgをクロロホルム/エタノール2mlに溶解した。次いで、溶液を、ヒト血清アルブミン溶液(3%w/v)27.0mlに加えた。デフェロキサミンを必要に応じ加えた。混合物を低RPM(Vitrisホモジナイザーモデル Tempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をRotavapに移し、溶媒を、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じた粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。本実施例で使用した薬剤、溶媒、及び蛋白質の量、型及び割合は、限定的ではないことを認識すべきである。ツウィーン/エタノール(これはこの薬剤用の標準的溶媒である)に溶解したドセタキセルの毒性と比較したとき、アルブミン含有の医薬組成物はかなり低い毒性を示した。
本実施例は、ドセタキセルとアルブミンを含む医薬組成物の製造を示す。ドセタキセル150mgを酢酸エチル/酢酸ブチル1ml及び油(例えば、ダイズ油又はビタミンE油)0.5mlに溶解した。溶媒と油の他の比を使用し、これらの組成物も本発明の一部と考えられる。少量の陰性荷電成分(例えば、安息香酸(0.001%〜0.5%))も場合によっては加えられた。次いで、溶液を、ヒト血清アルブミン溶液(5%w/v)27.0mlに加えた。デフェロキサミンを必要に応じ加えた。混合物を低RPM(Vitrisホモジナイザーモデル Tempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をRotavapに移し、溶媒を、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じた粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。本実施例で使用した薬剤、溶媒、蛋白質の量、型及び割合は、限定的ではないことを認識すべきである。ツウィーン/エタノール(これはこの薬剤用の標準的溶媒である)に溶解したドセタキセルの毒性と比較したとき、アルブミン含有の医薬組成物はかなり低い毒性を示した。
本実施例は、タキサンIDN5390とアルブミンを含む医薬組成物の製造を示す。IDN5390150mgを酢酸エチル/酢酸ブチル1ml及び油(例えば、ダイズ油又はビタミンE油)0.5mlに溶解した。溶媒と油の他の比を使用し、これらの組成物も本発明の一部と考えられる。少量の陰性荷電成分(例えば、安息香酸(0.001%〜0.5%))も場合によっては加えられた。次いで、溶液を、ヒト血清アルブミン溶液(5%w/v)27.0mlに加えた。デフェロキサミンを必要に応じ加えた。混合物を低RPM(Vitrisホモジナイザーモデル Tempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をRotavapに移し、溶媒を、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じた粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。本実施例で使用した薬剤、溶媒、蛋白質の量、型及び割合は、限定的ではないことを認識すべきである。ツウィーンに溶解したIDN5390の毒性と比較したとき、アルブミン含有の医薬組成物はかなり低い毒性を示した。
本実施例は、タキサンIDN5109とアルブミンを含む医薬組成物の製造を示す。IDN5109150mgをクロロホルム/エタノール2mlに溶解した。溶媒と油の他の比を使用し、これらの組成物も本発明の一部と考えられる。少量の陰性荷電成分(例えば、安息香酸(0.001%〜0.5%))も場合によっては加えられた。次いで、溶液を、ヒト血清アルブミン溶液(5%w/v)27.0mlに加えた。デフェロキサミンを必要に応じ加えた。混合物を低RPM(Vitrisホモジナイザーモデル Tempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をRotavapに移し、溶媒を、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じた粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。本実施例で使用した薬剤、溶媒、及び蛋白質の量、型及び割合は、限定的ではないことを認識すべきである。ツウィーンに溶解したIDN5109の毒性と比較したとき、アルブミン含有の医薬組成物はかなり低い毒性を示した。
本実施例は、10−ヒドロキシカンプトテシン(10HC)とアルブミンを含む医薬組成物の製造を示す。10−HC30mgをDMF/塩化メチレン/ダイズ油2.0mlに溶解した。次いで、溶液を、ヒト血清アルブミン溶液(3%w/v)27.0mlに加えた。混合物を低RPM(Vitrisホモジナイザーモデル Tempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をRotavapに移し、溶媒を、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じた粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。本実施例で使用した薬剤、溶媒、蛋白質の量、型及び割合は、決して限定的ではないことを認識すべきである。
本実施例は、シクロスポリンとアルブミンを含む医薬組成物の製造を示す。シクロスポリン30mgを塩化メチレン3.0mlに溶解した。次いで、溶液を、ヒト血清アルブミン溶液(1%w/v)27.0mlに加えた。混合物を低RPM(Vitrisホモジナイザーモデル Tempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をRotavapに移し、塩化メチレンを、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じた粒子の典型的平均直径は、範囲50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。再構成後の粒子サイズは、凍結乾燥前と同じであった。
本実施例は、油を含みかつシクロスポリンとアルブミンを含む医薬組成物の製造を示す。シクロスポリン30mgを適切な油(10%オレンジ油を含むゴマ油)3.0mlに溶解した。次いで、溶液を、ヒト血清アルブミン溶液(1%v/w)27.0mlに加えた。混合物を低RPM(Vitrisホモジナイザー、モデルTempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた分散液は、範囲50〜220nm(Z平均、MalvernZetasizer)の典型的平均直径を有した。分散液は直接使用するか、又は適切な凍結保護剤を場合によっては添加することによって48時間凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成された。本実施例で使用した薬剤、溶媒、及び蛋白質の量、型及び割合は、決して限定的ではないことを認識すべきである。
本実施例は、アムホテリシンとアルブミンを含む医薬組成物の製造を示す。アムホテリシン30mgをメチルピロリジノン/塩化メチレン3.0mlに溶解した。溶液を、ヒト血清アルブミン溶液(1%w/v)27.0mlに加えた。混合物を低RPM(Vitrisホモジナイザー、モデルTempest I.Q.)で5分ホモジナイズし、粗エマルジョンを形成させ、次いで、高圧ホモジナイザー(Avestin)に移した。エマルジョンを少なくとも5サイクルの間リサイクルしつつ、乳化を9000〜40,000psiで行った。生じた系をロータリーエバポレーターに移し、溶媒を、20〜30分間、減圧下(30mmHg)、40℃で急速除去した。生じた分散液は半透明で、生じたアムホテリシン粒子の典型的平均直径は、50〜220nm(Z平均、MalvernZetasizer)であった。分散液を更に48時間、凍結乾燥した。生じたケーキは、滅菌水又は生理食塩水の添加によって、元の分散物に容易に再構成することができた。再構成後の粒子サイズは、凍結乾燥前と同じであった。本実施例で使用した薬剤、溶媒、及び蛋白質の量、型及び割合は、決して限定的ではないことを認識すべきである。脂質、胆汁塩などの他の成分の添加によっても、適切な製剤が得られた。
本実施例は、アルブミンとパクリタキセルを含む医薬組成物の前臨床の薬物動態学と薬力学を示す。
本実施例は、パクリタキセルとアルブミンを含む医薬組成物に関連する副作用の減少及び毒性の減少を示す。
本実施例は、ヒトでのパクリタキセルとアルブミンを含む医薬組成物の臨床効果を示す。
本実施例は、アルブミンとパクリタキセルを含む医薬組成物を用いる前臨床効能の増大を示す。
本実施例は、動脈内投与したアルブミンとパクリタキセルを含む医薬組成物を用いる臨床効能の増大を示す。
本実施例は、3%油を含みかつプロポフォールとアルブミンを含む医薬組成物の製造を示す。
本実施例は、5%油を含みかつプロポフォールとアルブミンを含む医薬組成物の製造を示す。
本実施例は、油非含有の、プロポフォールとアルブミンを含む医薬組成物の製造を示す。
本実施例は、油非含有の、プロポフォール、アルブミン、及びビタミンE−TPGSを含む医薬組成物の製造を示す。
本実施例は、プロポフォール、アルブミン、ビタミンE−TPGS、及び1%油を含む医薬組成物の製造を示す。
本実施例は、プロポフォール、アルブミン、ビタミンE−TPGS、1%油、及び陰性荷電成分を含む医薬組成物の製造を示す。
本実施例は、プロポフォール、アルブミン、ビタミンE−TPGS、1%油、及び陰性荷電成分(デオキシコール酸ナトリウム)を含む医薬組成物の製造を示す。
本実施例は、プロポフォール、アルブミン、ビタミンE−TPGS、1%油、及び陰性荷電成分(リン脂質、胆汁酸塩、ポリアミノ酸等)を含む医薬組成物の製造を示す。
本実施例は、アルブミンへのプロポフォールの結合を示す。
本実施例は、濾過/膜接触による医薬組成物中での遊離プロポフォールの減少を示す。
本実施例は、ヒトへのプロポフォールとアルブミンを含む医薬組成物の投与を示す。
冷蔵庫に元々は保存してあった製剤を室温にし、次いで、製剤10μLを、同時に被験体の両手の背面にゆっくりと配置した。製剤に関する彼らの手の全体反応及び感触を記録した。本研究の結果を表1に記載する。
本実施例は、プロポフォールを含む医薬組成物中の抗酸化剤としてのデフェロキサミンの使用を示す。
本実施例は、パクリタキセルとアルブミンを含む医薬組成物(ABI−007)の肺内送達を示す。
本実施例は、パクリタキセルとアルブミンを含む医薬組成物の肺送達でのAerotechII及びPariネブライザーの研究を示す。
本実施例は、アルブミンとラパマイシンを含む医薬組成物の肺内送達を示す。本研究の目的は、静脈内導入と比較した、SpragueDawleyラットへの気管内注入後の血中ラパマイシンの肺吸収を測定することであった。
本実施例は、本発明に従い製造したラパマイシンとアルブミンを含む医薬組成物の肺内投与後のアルブミン−ラパマイシンの組織分布を示す。本研究の目的は、静脈内導入と比較した、SpragueDawleyラットへの気管内注入後、組織中ラパマイシンの肺吸収を測定することであった。
本実施例は、パクリタキセルとアルブミンを含む医薬組成物(ABI−007)の経口送達を示す。
本実施例は、パクリタキセルとアルブミンを含む医薬組成物の投与で、赤血球と腫瘍細胞へのパクリタキセルの浸透の改善を示す。
本実施例は、マウスに投与した、パクリタキセルとアルブミンを含む医薬組成物の安全性を示す。
本実施例は、パクリタキセル−アルブミン組成物の微細血管内皮細胞(EC)を通る新規なパクリタキセル輸送機構を示す。
本実施例は、タキソールと比べて、パクリタキセルとアルブミンを含む医薬組成物の内皮トランスサイトーシスの増大を示す。
本実施例は、タキソールと比べた、パクリタキセルとアルブミンを含む医薬組成物による内皮細胞(EC)結合の改善を示す。
本実施例は、タキソールと比べて、パクリタキセルとアルブミンを含む医薬組成物によるアルブミン結合の改善を示す。
本実施例は、タキソールと比べて、パクリタキセルとアルブミンを含む医薬組成物についてのパクリタキセルのアルブミンへの輸送の増大を示す。
本実施例は、糖蛋白質gp60が、アルブミン−パクリタキセルの結合とトランスサイトーシスの責を担うことを示す。
本実施例は、アルブミン量の増加は、パクリタキセルの結合と競合しうることを示す。
本実施例は、本発明組成物中より少量のアルブミンが安定な組成物を生じることを示す。
本実施例は、高いパクリタキセルに対するアルブミンの比を有するアルブミンとパクリタキセルを含む医薬組成物を示す。
本実施例は、低いパクリタキセルに対するアルブミンの比を有するアルブミンとパクリタキセルを含む医薬組成物を示す。
本実施例は、中間のパクリタキセルに対するアルブミンの比を有するアルブミンとパクリタキセルを含む医薬組成物を示す。
本実施例は、アルブミン−パクリタキセル組成物を用いた動物モデルでの慢性関節リウマチの治療を示す。
本実施例は、心臓血管再狭窄を治療するためのアルブミン−パクリタキセル組成物の使用を示す。
Claims (34)
- パクリタキセルと医薬として許容できる担体とを含有する注射用医薬組成物であって、該医薬として許容できる担体は、アルブミンを含み、該組成物中の該アルブミンと該パクリタキセルとは粒子として調製され、該粒子は200nm未満の粒子サイズを有し、該組成物中のアルブミンとパクリタキセルとの重量比が1:1〜9:1である、医薬組成物。
- 前記アルブミンがヒト血清アルブミンである、請求項1に記載の医薬組成物。
- クレモホール非含有である、請求項1に記載の医薬組成物。
- 前記医薬組成物中のアルブミンとパクリタキセルとの比(w/w)が1:1〜5:1である、請求項1に記載の医薬組成物。
- 前記医薬組成物中のアルブミンとパクリタキセルとの比(w/w)が1:1〜9:1である、請求項1に記載の医薬組成物。
- 前記医薬組成物中のアルブミンとパクリタキセルとの比(w/w)が、9:1である請求項1に記載の医薬組成物。
- パクリタキセルと医薬として許容できる担体とを含有する注射用液体医薬組成物であって、該医薬として許容できる担体は、アルブミンを含み、該組成物中の該アルブミンと該パクリタキセルは粒子として調製され、該粒子は200nm未満の粒子サイズを有し、該組成物中のアルブミンとパクリタキセルの重量比が1:1〜9:1であり、該液体医薬組成物が重量で0.5%〜5%のアルブミンを含み、さらに生理食塩水を含む、液体医薬組成物。
- 前記アルブミンがヒト血清アルブミンである、請求項7に記載の液体医薬組成物。
- クレモホール非含有である、請求項7に記載の液体医薬組成物。
- 前記医薬組成物中のアルブミンとパクリタキセルとの重量比が1:1〜9:1である、請求項7に記載の液体医薬組成物。
- 前記医薬組成物中のアルブミンとパクリタキセルとの重量比が、9:1である請求項7に記載の液体医薬組成物。
- 重量で5%アルブミンを含有する、請求項7に記載の液体医薬組成物。
- 前記組成物中のpHが5.0〜8.0である、請求項7に記載の液体医薬組成物。
- 前記アルブミンがヒト血清アルブミンである、請求項13に記載の液体医薬組成物。
- 前記医薬組成物中のアルブミンとパクリタキセルとの重量比が1:1〜9:1である、請求項13に記載の液体医薬組成物。
- 前記医薬組成物中のアルブミンとパクリタキセルとの重量比が、9:1である請求項13に記載の液体医薬組成物。
- 前記アルブミンがヒト血清アルブミンである、請求項10に記載の液体医薬組成物。
- 前記アルブミンがヒト血清アルブミンである、請求項11に記載の液体医薬組成物。
- 前記アルブミンがヒト血清アルブミンである、請求項15に記載の液体医薬組成物。
- 前記アルブミンがヒト血清アルブミンである、請求項16に記載の液体医薬組成物。
- パクリタキセルと医薬として許容できる担体とを含有する注射用医薬組成物を含む密封容器であって、該医薬として許容できる担体は、アルブミンを含み、該組成物中の該アルブミンと該パクリタキセルは粒子として調製され、該粒子は200nm未満の粒子サイズを有し、該組成物中のアルブミンとパクリタキセルの重量比が1:1〜9:1である、密封容器。
- 前記アルブミンがヒト血清アルブミンである、請求項21に記載の密封容器。
- 前記医薬組成物中のアルブミンとパクリタキセルとの重量比が1:1〜9:1である、請求項21に記載の密封容器。
- 前記医薬組成物中のアルブミンとパクリタキセルとの重量比が、9:1である請求項21に記載の密封容器。
- 単回投与用容器である、請求項21に記載の密封容器。
- 多回投与用容器である、請求項21に記載の密封容器。
- 前記医薬組成物が液体組成物である、請求項21に記載の密封容器。
- 前記医薬組成物が乾燥組成物である、請求項21に記載の密封容器。
- 前記医薬組成物が凍結乾燥されている、請求項21に記載の密封容器。
- 前記アルブミンがヒト血清アルブミンである、請求項29に記載の密封容器。
- 前記医薬組成物中のアルブミンとパクリタキセルとの重量比が1:1〜9:1である、請求項29に記載の密封容器。
- 前記医薬組成物中のアルブミンとパクリタキセルとの重量比が、9:1である請求項29に記載の密封容器。
- 前記アルブミンがヒト血清アルブミンである、請求項31に記載の密封容器。
- 前記アルブミンがヒト血清アルブミンである、請求項32に記載の密封容器。
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