JP6297481B2 - 粘液を通る輸送を増強するための組成物および方法 - Google Patents
粘液を通る輸送を増強するための組成物および方法 Download PDFInfo
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- JP6297481B2 JP6297481B2 JP2014256264A JP2014256264A JP6297481B2 JP 6297481 B2 JP6297481 B2 JP 6297481B2 JP 2014256264 A JP2014256264 A JP 2014256264A JP 2014256264 A JP2014256264 A JP 2014256264A JP 6297481 B2 JP6297481 B2 JP 6297481B2
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Description
この出願は、2006年9月8日に出願された、米国仮出願第60/843,282号(この明細書は、その全体が参考として本明細書に援用される)の利益を主張する。
本発明は、表面改変剤を使用することにより、物質の粘膜付着を減少させ、粘液中での流動性を高めることができるという知見に一部関係する。したがって、1つの態様においては、本発明により、粒子の粘液通過を促進する1つ以上の表面改変部分によって修飾された粒子が提供される。そのような粒子(例えば、ナノ粒子またはマイクロ粒子)は、これまで得られていたよりも高濃度の表面部分を有し、それにより、粘液を通って迅速に拡散するという予想外の特性が得られる。本発明にはさらに、そのような粒子の製造方法、および患者を処置するためのそのような粒子の使用方法が含まれる。
例えば、本発明は、以下の項目を提供する:
(項目1)
外表面と、粒子の粘膜付着を減少させるこの外表面に配置された1つ以上の表面改変部分とを含む粒子であって、この粒子が1秒の時間尺度で水を通って拡散する拡散率の1/1000よりも大きな拡散率でヒトの頸膣粘液を通って拡散する、粒子。
(項目2)
外表面と、この外表面に配置された1つ以上の表面改変部分とを含む粒子であって、それにより、1秒の時間尺度で4×10−2μm2/sより大きい拡散率でヒトの頸膣粘液中を移動する、粒子。
(項目3)
外表面と、粒子の粘膜付着を減少させるこの外表面に配置された1つ以上の表面改変部分とを含む粒子であって、10mV未満のゼータ電位を有する、粒子。
(項目4)
外表面と、粒子の粘膜付着を減少させるこの外表面に配置された1つ以上の表面改変部分とを含む粒子であって、この表面改変部分の質量が、この粒子の質量のうちの少なくとも1/3400を占める、粒子。
(項目5)
外表面と、粒子の粘膜付着を減少させるこの外表面に配置された1つ以上の表面改変部分とを含む粒子であって、平均最大蛍光強度によって計算される場合、この表面改変部分を含まない対応粒子によって吸着される蛍光標識されたアビジンの量の10%未満を吸着する、粒子。
(項目6)
外表面と、粒子の粘膜付着を減少させるこの外表面に配置された1つ以上の表面改変部分とを含む粒子であって、この表面改変部分が、1平方ナノメートルあたり0.01単位より大きい密度でこの外表面上に存在する、粒子。
(項目7)
0.067秒から3.0秒までの時間尺度の関数としての上記粒子集団の平均二乗変位の指数法則フィットの指数が0.5を超える、項目1から6のいずれかに記載の粒子。
(項目8)
上記粒子が、上記1つ以上の表面改変部分を含まない対応する大きさかつ密度のカルボキシル修飾されたポリスチレン(PS)粒子がヒトの頸膣粘液を通って拡散する拡散率よりも20倍超大きい1秒の時間尺度での拡散率でヒトの頸膣粘液を通って拡散し、このカルボキシル修飾が、1.77から6.69カルボキシル/nm2の密度で存在する、項目1から7のいずれかに記載の粒子。
(項目9)
上記粒子が、ヒトの頸膣粘液中で、上記1つ以上の表面改変部分が含まれていない対応する大きさかつ密度のカルボキシル修飾されたポリスチレン(PS)粒子についての幾何平均二乗変位よりも20倍超大きい1秒の時間尺度での頸膣粘液中での幾何平均二乗変位を有しており、このカルボキシル修飾が、1.77から6.69カルボキシル/nm2の密度で存在する、項目1から8のいずれかに記載の粒子。
(項目10)
上記粒子が、ヒトの頸膣粘液中で、上記1つ以上の表面改変部分が含まれていない対応する大きさかつ密度のカルボキシル修飾されたポリスチレン(PS)粒子よりも50倍超大きい1秒の時間尺度での拡散率でヒトの頸膣粘液を通って拡散し、このカルボキシル修飾が、1.77から6.69カルボキシル/nm2の密度で存在する、項目1から9のいずれかに記載の粒子。
(項目11)
上記粒子が粘液中を移動する1秒の時間尺度での幾何平均二乗変位は、上記1つ以上の表面改変部分を含まない対応する大きさかつ密度のカルボキシル修飾されたポリスチレン(PS)粒子がヒトの頸膣粘液中を移動する幾何平均二乗変位よりも100倍超大きく、このカルボキシル修飾が、1.77から6.69カルボキシル/nm2の密度で存在する、項目1から10のいずれかに記載の粒子。
(項目12)
コアが含まれている、項目1から11のいずれかに記載の粒子。
(項目13)
上記コアにポリマーが含まれている、項目12に記載の粒子。
(項目14)
上記ポリマーに、上記外表面に配置された表面改変部分が含まれている、項目13に記載の粒子。
(項目15)
上記ポリマーがコポリマーであり、上記1つ以上の表面改変部分に、上記粒子の上記外表面に局在化されたこのコポリマーの領域が含まれている、項目14に記載の粒子。
(項目16)
リポソーム、金属もしくは金属酸化物、または量子ドットである、項目1から11のいずれかに記載の粒子。
(項目17)
1つ以上の生物活性剤が上記粒子と会合している、項目1から16のいずれか1項に記載の粒子。
(項目18)
上記1つ以上の生物活性剤が上記粒子にカプセル化されている、項目17に記載の粒子。(項目19)
上記1つ以上の生物活性剤が上記粒子の表面上に配置されている、項目17に記載の粒子。
(項目20)
上記1つ以上の生物活性剤が上記粒子に共有結合されている、項目17に記載の粒子。
(項目21)
上記1つ以上の生物活性剤と上記粒子に非共有結合的に会合している、項目17に記載の粒子。
(項目22)
1nmを超える直径である、項目1から21のいずれかに記載の粒子。
(項目23)
20nmを超える直径である、項目1から22のいずれかに記載の粒子。
(項目24)
200nmを超える直径である、項目1から23のいずれかに記載の粒子。
(項目25)
500nmを超える直径である、項目1から24のいずれかに記載の粒子。
(項目26)
上記生物活性剤が造影剤または治療薬である、項目1から25のいずれかに記載の粒子。(項目27)
上記生物活性剤が診断薬である、項目26に記載の粒子。
(項目28)
上記生物活性剤が、検出可能標識をさらに含む造影剤である、項目26に記載の粒子。
(項目29)
上記生物活性剤が核酸、核酸アナログ、低分子、ペプチド模倣物、タンパク質、ペプチド、脂質、または界面活性剤である、項目26に記載の粒子。
(項目30)
1つ以上の標的部分がさらに含まれている、項目1から29のいずれかに記載の粒子。
(項目31)
上記1つ以上の表面改変部分が上記粒子の表面の親水性を高める、項目1から30のいずれかに記載の粒子。
(項目32)
上記1つ以上の表面改変部分に炭水化物が含まれている、項目1から31のいずれかに記載の粒子。
(項目33)
上記1つ以上の表面改変部分にポリエチレングリコールが含まれている、項目1から31のいずれかに記載の粒子。
(項目34)
項目1から33のいずれかに記載の粒子と、1つ以上の薬学的に許容される担体とが含まれている、薬学的組成物。
(項目35)
項目1から33のいずれかに記載の粒子が含まれている吸入器。
(項目36)
患者に対して、項目1から33のいずれかに記載の1つ以上の粒子を投与する工程が含まれる、患者の状態を処置、予防、または診断するための方法。
(項目37)
上記1つ以上の粒子を上記患者の粘膜組織に局所投与する、項目36に記載の方法。
(項目38)
上記粒子が、粘液でコートされている組織で長い滞留時間を示す、項目36に記載の方法。
(項目39)
患者に対して、項目34に記載の薬学的組成物を投与する工程が含まれている、患者の状態を処置、予防、または診断するための方法。
(項目40)
上記組成物を上記患者の粘膜組織に局所投与する、項目39に記載の方法。
(項目41)
上記粒子が、粘液でコートされている組織で長い滞留時間を示す、項目39に記載の方法。
(項目42)
組成物中の粒子のうちの少なくとも10%が、項目1から33のいずれかで定義された粒子である、複数の粒子が含まれている組成物。
(項目43)
上記粒子が上記組成物のうちの少なくとも20%を構成する、項目42に記載の組成物。
(項目44)
上記粒子が上記組成物のうちの少なくとも50%を構成する、項目42に記載の組成物。
(項目45)
上記粒子が上記組成物のうちの少なくとも90%を構成する、項目42に記載の組成物。
(項目46)
上記組成物に2以上のタイプの粒子の混合物が含まれている、項目42に記載の組成物。
(項目47)
項目1から33のいずれかで定義された第1の複数の粒子と、1秒の時間尺度で粒子が水を通って拡散する拡散率の1/1000未満の平均拡散率でヒトの頸膣粘液を通って拡散する第2の複数の粒子とが含まれている、項目46に記載の組成物。
(項目48)
上記第1の複数の粒子が上記組成物中の全粒子のうちの少なくとも15%を構成する、項目47に記載の組成物。
(項目49)
上記第1の複数の粒子が上記組成物中の全粒子のうちの少なくとも40%を構成する、項目48に記載の組成物。
(項目50)
上記第1の複数の粒子が上記組成物中の全粒子のうちの少なくとも70%を構成する、項目49に記載の組成物。
(項目51)
上記第1の複数の粒子中の粒子は、この第1の複数の粒子中の粒子が水を通って拡散する拡散率の100分の1よりも大きな拡散率でヒトの頸膣粘液を通って拡散する、項目47〜50のいずれかに記載の組成物。
(項目52)
上記第1の複数の粒子中の粒子は、この第1の複数の粒子中の粒子が水を通って拡散する拡散率の10分の1よりも大きな拡散率でヒトの頸膣粘液を通って拡散する、項目51に記載の組成物。
(項目53)
上記第1の複数の粒子中の粒子は、この第1の複数の粒子中の粒子が水を通って拡散する拡散率の4分の1よりも大きな拡散率でヒトの頸膣粘液を通って拡散する、項目52に記載の組成物。
(項目54)
上記第1の複数の粒子中の粒子が、対応するカルボキシル修飾されたポリスチレン(PS)粒子がヒトの頸膣粘液を通って拡散する拡散率よりも20倍超大きい拡散率でヒトの頸膣粘液を通って拡散し、このカルボキシル修飾が、1.77から6.69カルボキシル/nm2の密度で存在する、項目47から50のいずれかに記載の組成物。
(項目55)
上記第1の複数の粒子中の粒子が、対応するカルボキシル修飾されたポリスチレン(PS)粒子がヒトの頸膣粘液を通って拡散する拡散率よりも50倍大きい拡散率でヒトの頸膣粘液を通って拡散し、このカルボキシル修飾が、1.77から6.69カルボキシル/nm2の密度で存在する、項目54に記載の組成物。
(項目56)
上記第2の複数の粒子が上記組成物中の全粒子のうちの少なくとも15%を構成する、項目47から54のいずれかに記載の組成物。
(項目57)
上記第2の複数の粒子が上記組成物中の全粒子のうちの少なくとも40%を構成する、項目47から54のいずれかに記載の組成物。
(項目58)
上記第2の複数の粒子のうちの20%未満が固定粒子である、項目47から57のいずれかに記載の組成物。
(項目59)
上記第2の複数の粒子のうちの70%未満が固定粒子または妨害された粒子である、項目47から57のいずれかに記載の組成物。
(項目60)
物質の粘膜付着を減少させる方法であって、粘液を通る拡散率を増大させる必要がある物質を同定する工程、この物質を表面改変部分で修飾する工程、および粘膜表面への局所投与に適している薬学的調製物中にこの修飾された物質を処方する工程を含む、方法。
(項目61)
上記修飾された物質を粒子として処方し、この粒子は、この粒子が1秒の時間尺度で水を通って拡散する拡散率の1/1000よりも大きな拡散率でヒトの頸膣粘液を通って拡散する、項目60に記載の方法。
(項目62)
上記物質に生物活性剤が含まれている、項目60に記載の方法。
(項目63)
上記生物活性剤が、造影剤、診断薬、治療薬、検出可能標識を有している因子、核酸、核酸アナログ、低分子、ペプチド模倣物、タンパク質、ペプチド、脂質、または界面活性剤である、項目62に記載の方法。
(項目64)
上記表面改変部分が上記物質の親水性を高める、項目60に記載の方法。
(項目65)
上記表面改変部分が炭水化物またはポリエチレングリコールである、項目60に記載の方法。
(項目66)
上記表面改変部分および上記生物活性剤が共有結合されている、項目61から65のいずれかに記載の方法。
(項目67)
上記表面改変部分および上記生物活性剤が非共有結合的に会合している、項目61から65のいずれかに記載の方法。
(項目68)
表面改変部分と会合している生物活性剤が含まれている、粘膜への局所投与に適している薬学的調製物。
(項目69)
上記生物活性剤が、造影剤、診断薬、治療薬、検出可能標識を有している因子、核酸、核酸アナログ、低分子、ペプチド模倣物、タンパク質、ペプチド、脂質、または界面活性剤である、項目68に記載の薬学的調製物。
(項目70)
上記表面改変部分が上記生物活性剤の親水性を増強する、項目68に記載の薬学的調製物。
(項目71)
上記表面改変部分が炭水化物またはポリエチレングリコールである、項目68に記載の薬学的調製物。
(項目72)
上記生物活性剤が上記表面改変部分に対して共有結合されている、項目68から71のいずれかに記載の薬学的調製物。
(項目73)
上記生物活性剤が上記表面改変部分と非共有結合的に会合している、項目68から71のいずれかに記載の方法。
(項目74)
表面改変部分が含まれている、エンベロープを持つウイルスであって、このウイルスが、表面改変部分を含まない対応ウイルスがヒトの頸膣粘液を通って拡散する拡散率よりも20倍超大きい1秒の時間尺度での拡散率でヒトの頸膣粘液を通って拡散する、ウイルス。
(項目75)
遺伝子操作されたウイルスである、項目74に記載のウイルス。
(項目76)
遺伝子治療用ベクターである、項目74に記載のウイルス。
本発明は、粘液を通る粒子の移動を促進する表面薬剤でコートされたナノ粒子またはマイクロ粒子に一部関する。上記ナノ粒子およびマイクロ粒子は、これまでに得られていた表面薬剤よりも高い濃度を有し、それにより、粘液を通って極めて早く拡散するという予想外の特性が導かれる。本発明にはさらに、上記粒子を製造する方法が含まれる。本発明にはさらに、患者を処置するために上記粒子を使用する方法が含まれる。
便宜上、本発明のさらなる記載の前に、本明細書、実施例、および添付の特許請求の範囲で使用される特定の用語がここに集められる。これらの定義は、本開示の残り部分を踏まえて読まれるべきであり、そして当業者に理解されるはずである。
本発明により、粒子、例えば、マイクロ粒子またはナノ粒子が提供される。特定の実施形態において、ポリマー粒子には、薬学的に許容されるポリマー、生物活性剤、およびポリマー粒子の表面を耐粘液性にする表面改変剤が含まれる。別の実施形態において、ポリマー粒子には、薬学的に許容されるポリマーと、生物活性剤でもある表面改変剤とが含まれる。特定のそのような実施形態において、粒子にはさらに、粒子の表面に対する表面改変剤の接着を促進する接着促進剤(例えば、臭化ジメチルジオクタデシル−アンモニウム、または他の陽イオン含有添加剤)がさらに含まれる。表面改変剤は、粘液中での粒子の輸送速度を大きくする場合がある。
Mは、それぞれの出現について独立して、置換または未置換のメチレン、例えば、CH2、CH(Me)、CF2、CH(OH)、C=Oなど、好ましくは、CH2、またはOに隣接しているMの出現については、C=Oを示し;
Xは、存在しないか、あるいは、それぞれの出現について独立して、NR、O、およびSから選択されるヘテロ原子、好ましくは、Oを示し;
Rは、それぞれの出現について独立して、Hまたは低級アルキルを示し;
jは、それぞれの出現について独立して、0から16までの整数、好ましくは、1から9までの整数を示し;
mは、それぞれの出現について独立して、4から20までの整数、好ましくは、8から14までの整数、なおさらに好ましくは、10を示し;
nは、それぞれの出現について独立して、4から500までの整数、好ましくは、10から200までの整数を示し;
pは、それぞれの出現について独立して、1から60までの整数、好ましくは、4から40までの整数を示し;そして、
qは、それぞれの出現について独立して、1から20までの整数、好ましくは、2から10までの整数、なおさらに好ましくは、2から6までの整数を示す。
York,1999に開示されているもの)(これらは全て参照により本明細書に組み込まれる)、ならびに、2種類以上のそのようなポリマーの混合物および/またはブロックコポリマーが挙げられる。ラクチド含有ポリマーおよびグリコリド含有ポリマーのカルボキシル末端は、状況に応じて、例えば、エステル化によってキャップされる場合があり、そしてヒドロキシル末端は、状況に応じて、例えば、エーテル化またはエステル化によってキャップされる場合がある。
一部において、本発明のポリマー粒子には、(上記の、もしくは当該分野で公知の、状況に応じた任意の他の生体適合性ポリマー、および状況に応じた生体分解性ポリマーを含む)上記で議論された任意のポリマーなどの生体適合性ポリマー、および好ましくは、生体分解性ポリマーが含まれる。本発明により、1つ以上の粒子を含む薬学的組成物が提供される。薬学的組成物は、治療用組成物、および/または診断用組成物もしくは画像化用組成物であり得る。
本発明の粒子(例えば、マイクロ粒子、または好ましくは、ナノ粒子)には、ポリマーマトリックスが含まれる場合がある。マイクロ粒子には、通常、生体分解性ポリマーマトリックスおよび生物活性剤が含まれる。例えば、生物活性剤は、ポリマーマトリックスにカプセル化されるか、または吸着される。マイクロ粒子は、当業者に公知の多種多様な技術によって形成することができる。マイクロ粒子形成技術の例としては、以下が挙げられるがこれらに限定されない:(a)乳化およびその後の有機溶媒の蒸発による相分離(油中水エマルジョン、水中油エマルジョン、および水油水エマルジョンなどの複雑な乳化方法を含む);(b)コアセルベーション相分離;(c)融解分散(melt dispersion);(d)界面蒸着(interfacial deposition);(e)インサイチュ重合;(f)噴霧乾燥、および噴霧凝固(spray−congealing);(g)気中懸濁コーティング(air−suspension coating);ならびに、(h)パンコーティング(pan coating)およびスプレーコーティング。これらの方法、ならびにマイクロ粒子の特性および特徴は、例えば、米国特許第4,652,441号;同第5,100,669号;同第4,526,938号;WO93/24150;EPA0258780 A2;米国特許第4,438,253号;および同第5,330,768号に開示されている(これらの開示全体が参照により本明細書に組み込まれる)。
ほとんどの実施形態においては、本発明のポリマーには、診断的、予防的、もしくは治療的処置の一部として、治療有効量の取り込まれた治療薬または他の物質を患者に送達するために十分な量で送達される物質が取り込まれるであろう。粒子中の活性化合物の所望される濃度は、薬物の吸収、不活化、および排泄速度、さらには、本発明の組成物からの化合物の送達速度に応じて様々であろう。投与量の値は、緩和される症状の重篤度に応じて変動してもよいことに留意されたい。さらに、任意の特定の被験体については、特異的な投薬レジメンは、個々の必要性、および組成物を投与するかまたは組成物の投与を監督する専門医の判断にしたがって、経時的に調整される必要があることがさらに理解される。通常、投薬は、当業者に公知の技術を使用して決定されるであろう。
本発明は、本明細書に概して記載され、単に本発明の特定の態様および実施形態の説明の目的で含まれる以下の実施例を参照すればさらに容易に理解されるであろう。これらは本発明を限定するようには意図されない。
1.1 頸膣粘液および嚢胞性線維症の粘液の収集および準備
頸膣粘液の収集手順は、これまでに公開されているように行った(参照により本明細書に組み込まれる、Boskey,ER,Moench,TR,Hees,PS & Cone,RA(2003)Sexually Transmitted Diseases 30,107−109)。収集した粘液は、4時間以内に顕微鏡試験に使用した。新しい試料の粘性は、Brookfield円錐平板粘度計(CP−40スピンドルを有しているModel HADV−III;Brookfield Engineering Lab,Middleboro,MA.)において、37℃で剪断速度の関数として観察した。
100〜500nmの黄色−緑色の蛍光のカルボキシル修飾されたポリスチレン(PS)粒子(Molecular Probes,Eugene,OR)を、製造業者によって示唆されているプロトコールにしたがって、3:1の過剰量でのカルボキシル−アミン反応によって、ジアミンPEG(MW約2kDa;Nektar Therapeutics,San Carlos,CA)で共有結合的に修飾した。分子量3,400ダルトンのジアミンポリエチレングリコール(PEG)(Nektar Therapeutics,San Carlos,CA)を、pH6.0の50mMの2−(N−モルホリノ)エタンスルホン酸(MES,Sigma,St Louis,MO)緩衝剤中に溶解した。ジアミンPEGの使用によって、表面結合したPEG鎖の末端に遊離のアミン基が生じる場合がある。黄色−緑色の蛍光のポリスチレンナノスフェア(Molecular Probes,Eugene,OR)を溶液に添加すると、10mgのPEG/mlおよび1%の固体/mlの最終濃度が得られた。ナノスフェアは100nmの直径を有しており、カルボキシル修飾されていた。室温で15分間のインキュベーションの後、EDAC(1−エチル−3−(3−ジメチルアミノプロピル)−カルボジイミド)(Sigma,St Louis,MO)を、4mg/mlの濃度になるように混合物に添加した。溶液のpHを希NaOHで6.5に調整し、室温で2時間、オービタル振とう器(orbital shaker)にてインキュベートした。反応を停止させるために、グリシン(JT Baker,Phillipsburg,NJ)を、100mMの最終濃度となるように添加した。溶液を室温で30分間インキュベートし、その後、300,000kDaのMWCO Float−a−lyzer(Spectrum Laboratories,Rancho Dominguez,CA)でDulbeccoのリン酸緩衝化生理食塩水(PBS)に対して十分に透析した。未修飾のマイクロスフェアを同様に透析して、製造業者によってもともと加えられていたアジ化ナトリウムを全量除去した。
PEGの付着を確認し、PEGによるタンパク質吸着に抵抗する効力を定量するために、10μLのCOOH−粒子およびPEG修飾粒子(約0.04質量%)を、200μLの0.1mg/mLのローダミン蛍光NeutrAvidin(Molecular Probes,Eugene,OR)に添加し、オービタル振とう器で1時間インキュベートした。その後、粒子をPBS中で2回洗浄し、0.008質量%の最終濃度になるように再懸濁し、100×/1.4 NA油浸レンズを備えた共焦点顕微鏡(Zeiss LSM 510,Carl Zeiss Inc.,Thornwood,NY)を使用して観察し、密封したガラススライド/カバーガラス上で観察した。試料を488および543レーザーで励起させ、ピンホールを0.7〜0.8μm未満の範囲の光学的切片が得られるように調整した。同じ励起および検出の設定を維持し、全ての試料を連続して試験した。アビジンインキュベーションを行っていない粒子をネガティブ対照として、無視できる程度の漂白を超えることを確実にした(to ensure negligible bleach over)。グレースケールへの変換の後、それぞれの粒子についての最大ピクセル強度を、SCION Image 4.03bを使用して分析した。
粒子の運搬速度は、100×の油浸対物レンズ(開口数1.3)が備え付けられている倒立落射蛍光顕微鏡に取り付けたSITカメラ(silicon−intensified target camera)(VE−1000,Dage−MTI,Michigan,IN)を使用して記録した、蛍光粒子の軌跡を分析することによって測定した。実験は、8ウェルのガラスチャンバ(LabTek,Campbell,CA)で行い、希釈した粒子溶液(0.0082%w/v)を、250−500μLの新しい粘液に対して3%v/vの最終濃度となるように添加し(最終粒子濃度8.25×10−7w/v)、顕微鏡観察の前に2時間インキュベートした。n>100個の粒子の軌跡をそれぞれの実験について分析し、3回の実験を個々の条件について行った。動画を、66.7msの時間分解能で20秒間、Metamorphソフトウェア(Universal Imaging Corp.)で捕捉した。軌跡の解像度は、強い接着で固定された粒子の移動を追跡することによって決定した場合には10nmであった。ナノ粒子の重心の座標を、時間平均二乗変位(MSD)に変換した<Δr2(τ)>=[x(t+τ)−x(t)]2+[y(t+τ)−y(t)]2(τ=時間尺度またはタイムラグ)。これから、MSDの分布および有効拡散係数を、以前に明らかにされているように計算した(Dawson,M,Wirtz,D & Hanes,J(2003)Journal of Biological Chemistry 278,50393−50401.,Valentine,MT,Perlman,ZE,Gardel,ML,Shin,JH,Matsudaira,P,Mitchison,TJ & Weitz,DA(2004)Biophys J 86,4004−14,Mason,TG,Ganesan,K,vanZanten,JH,Wirtz,D & Kuo,SC(1997)Physical Review Letters 79,3282−3285,これらは全て参照により本明細書に組み込まれる)。2D粒子の追跡により3Dの運搬を測定するためのさらに別の情報は、最近のレビュー(参照により本明細書に組み込まれる、Suh,J,Dawson,M & Hanes,J(2005)Adv Drug Deliv Rev 57,63−78)に提供されている。
短い時間尺度および長い時間尺度にわたる粒子の運搬機構を、有効拡散係数(Deff)の相対的変化(RC)の概念に基づいて分類した。簡単に説明すると、短い時間尺度および長い時間尺度での粒子のRC値を、最も早い参照時間尺度でのDeffで、調べた時間尺度での粒子のDeffを割ることによって計算した。2種類の時間レジメン(すなわち、短い時間尺度および長い時間尺度)についてRC値を計算することによって、様々な長さおよび時間尺度にわたる粒子の運搬特性を記載する運搬形式を得ることができる。RCshortは、τref=0.2sおよびτprobe=1sで定義し、一方、RClongは、参照値τref=1sおよびτprobe=2sで見られた。RC標準曲線(時間尺度全体にわたって純粋なBrownian粒子についてのDeffの95%の分布範囲をプロットする)をモンテカルロシミュレーションに基づいて作成し、グリセロール中のポリスチレンナノ粒子を追跡することによって確認した(データは示さない)。短い時間尺度または長い時間尺度のいずれかについて97.5%の範囲を下回るRC値を示す粒子の運搬形式は、被妨害と分類し、残りを拡散と分類した。固定粒子は、1秒の時間尺度で10nm未満の解像度の平均MSDを示すものと定義した。運搬形式の分類の厳密性を、MSD対時間尺度のプロットの傾きから確認し、拡散粒子はおよそ1の傾きを有しており、妨害された粒子の傾きは、時間尺度が大きくなるに伴い1から徐々に小さくなった。
2.1 ヒトの頸膣粘液およびそのレオロジー
頸膣(CV)粘液は、典型的なヒトの粘液分泌物(肺、GI管、鼻、眼、および精巣上体を含む)の範囲(高いほうの端点以内)の微視的粘性を示す。これは、それらの化学的組成の類似性に一部寄与する。例えば、ムチンの糖形態MUC5Bは、CV管、肺、鼻、および眼を保護している粘膜層中のムチンの主要な分泌形態である。ムチンの含有量はおよそ1〜3重量%であり、これもまた、子宮頸粘液、鼻粘液、および肺粘液の間で類似している。上記の粘液のタイプ中の水の組成は全て、90〜98%の範囲に入る。
本発明者らは、ヒトボランティアから得た頸膣(CV)粘液中での運搬速度に対する粒子の大きさの影響を決定した。動的光散乱によって特性決定した、水中に懸濁させた粒子の流体力学直径を図8に列挙する。CV粘液への比較的高濃度(2重量%の粒子)のコートされていない粒子の添加によって、粒子を捕捉した束状構造への粘液の繊維の崩壊が生じ、それらの運搬が妨げられる(データは示さない)。しかし、低濃度の粒子(0.008重量%の粒子)は、束状になることを引き起こすことはなく、粒子の移動を可能にした。予想したとおり、粒子の運搬は、それらの低い平均二乗変位(MSD)から明らかであるように、粘液の網目によって大きく妨害された(図1A)。COOH−PS粒子のアンサンブル平均有効拡散係数(Deff)は、粘液において予想したとおり、短い時間尺度では小さくなる(図2B)。粒子のMSD対時間尺度(τ)を方程式MSD=4D0τα(式中、D0は、時間尺度に依存する拡散係数である)に対してフィットさせることによって、αの平均値を得ることができ、これは、粒子の運動の妨害の程度についての知見を提供する(注:水中の粒子などの、妨げられていない純粋なBrownian拡散についてはα=1)。平均α値は、100、200、および500nmのCOOH−PS粒子について、それぞれ、0.16、0.36、および0.43であった。全体的には、(τ=1sで)粘液中の100、200、および500nmのCOOH−PS粒子のアンサンブル平均Deffは、水中の同じ粒子と比較すると、44000倍、590倍、および4600倍低くなった(図8)。
親水性であり、電荷を有していないポリマーであるポリエチレングリコール(PEG)を、CV粘液と粒子との相互作用を減少させるための試みにおいて、100、200、および500nmの粒子の表面に共有結合させた。PEGの付着の程度は、それらのほぼ中性の表面電荷、および蛍光標識されたアビジンの吸着への抵抗における類似する効力によって示されるように、全ての粒子について同程度であった(図8)。PEG化によって、同じ大きさの対応するCOOH−PS粒子と比較して、100、200、および500nmのPEG化粒子(PEG−PS)の、20倍、400倍、そして1100倍高いアンサンブルMSD(τ=1s)によって明らかであるように、粒子の運搬速度が大幅に大きくなった(図2A)。100nm、200nm、および500nmのPEG−PS粒子についてのDeff(τ=1s)は、水中でのそれらの拡散についての予想される値のものと比較して、わずか2000倍、6倍、および4倍低くなった。3種類の全ての大きさのPEG−PS粒子のアンサンブルDeffは、時間尺度が大きくなるに伴い、なおも低くなったが(図2B)、100nmのPEG−PS粒子だけは、運搬が大幅に妨害された(100nm、200nm、および500nmのPEG−PS粒子について、それぞれ、α=0.31、0.81、0.89)。PEG化によって、大きなPEG−PS粒子(200nmおよび500nm)についての妨害が減少しただけではなく、同様の大きさのCOOH−PS粒子と比較して、運搬の均一性が増大した(図2C)。
高MWのPEGは、粘膜付着剤として広く使用されている(Bures,P.,Y.Huang,E.Oral,and N.A.Peppas,Surface modifications and molecular imprinting of polymers in medical and pharmaceutical applications.J Control Release,2001.72(1−3):p.25−33,Huang,Y.,W.Leobandung,A.Foss,and
N.A.Peppas,Molecular aspects of muco− and bioadhesion:tethered structures and site−specific surfaces.J Control Release,2000.65(1−2):p.63−71.,LeIe,B.S.and A.S.Hoffman,Mucoadhesive drug carriers based on complexes of poly(acrylic acid) and PEGylated drugs having hydrolysable PEG−anhydride−drug linkages.J Control Release,2000.69(2):p.237−48.,Peppas,N.A.,K.B.Keys,M.Torres−Lugo,and A.M.Lowman,Poly(ethylene glycol)−containing hydrogels in drug delivery.J Control Release,1999.62(1−2):p.81−7.)。ナノ粒子についてのコーティングとしてのその効果を試験するために、10kDaのPEGを200nmの粒子の表面に共有結合させた(PEG10kDa−PS)。PEG2kDa−PS対応物と明確に対比するために、密度の高い10kDaのPEGでのコーティングを有している粒子は、2kDaのPEGで修飾された粒子と比較される2300倍低いアンサンブルMSD(τ=1s)によって明らかであるように、新しいヒトCV粘液において粒子の運搬速度の大幅な低下を示した(図3A)。実際、PEG10kDa−PSの運搬についての広範囲に及ぶ妨害によって、同様の大きさのCOOH−PS粒子のアンサンブルMSDよりもほぼ6倍小さいアンサンブルMSD(τ=1s)が生じた。これは、固定粒子と強く妨害された粒子(すなわち粘膜付着性)の両方の高い割合に大きな原因がある(図3B)。理論に束縛されることは望ましくないが、低MWのPEGは、水素結合と、粘液ゲルへのPEG鎖の相互浸透との両方を最小にすることによって粘膜付着を排除し、一方、粒子の表面からさらに延びる長い可撓性の鎖を有している高MWのPEGは、拡散を遅らせる様式で粘液ゲルに浸透する。しかし、高MWのPEGで粒子を修飾するための別のアプローチでは、ペンダントPEG鎖の長さおよび可撓性を制御することができ、それによって、耐粘液性の表面特性が得られる。
CV粘液中を運搬される粒子の典型的な軌跡を記録し、顕微鏡によって定量化した。粒子を3つの一般的なカテゴリーに分けた:固定(図6A)、被妨害(図6B)、および拡散(図6C)。
未希釈のヒト粘液中でのポリマーナノ粒子の迅速な運搬は、おそらく、PEGの改良された表面コーティングの直接的な結果である。これまでに、低いPEG密度を有している、500nmのPEGでコートされた粒子(WO2005/072710 A2の実施例6Bに開示されている)(調製物A、図7)は、同様の大きさのコートされていない粒子と比較して、約10倍、運搬を改善することが明らかにされている。対照的に、より高い表面PEG密度(調製物B、図7)は、同様の大きさのコートされていない対応物と比較すると、最大で約1100倍の、500nmの粒子の運搬の改善を媒介することができた。このことは、粘液中での粒子の輸送を決定付けることにおける、高密度の表面のPEGコーティングの重要性を直接強調している。
本明細書に記載した全ての刊行物および特許は、それぞれの個々の刊行物または特許が、具体的かつ個別に参照により本明細書に組み込まれることが示されるかのように、それらの全体が参照により本明細書に組み込まれる。
当業者は、本明細書に記載された本発明の特異的な実施形態に対する多くの等価物を認識し、またはそれらを常套の実験以上のものを使用することなく確認できるであろう。そのような等価物は、以下の特許請求の範囲に含まれるように意図される。
Claims (23)
- コアおよび該コアの外表面に非共有結合的に吸着している1つ以上の表面改変部分を含む粒子であって、
該粒子は、150nmから750nmの間の直径であり;
該コアは疎水性であるか、水素結合ドナーもしくはアクセプターを有するか、または電荷を有しており;
該コアは、ポリ(D,L−乳酸−コ−グリコール酸)、ポリエチレンイミン、ジオレイルトリメチルアンモニウムプロパン/ジオレイル−sn−グリセロホスホエタノールアミン、および、ポリセバシン酸無水物から選択される薬学的に許容されるポリマーを含み;
該表面改変部分の質量が、該粒子の質量の少なくとも1/3400、1/2000、1/1000、1/500、1/200、1/100、1/50、1/20、1/5、1/2、または9/10を構成し;
該表面改変部分が、ポリ(エチレン)グリコールを含み;そして
該表面改変部分における各ポリ(エチレン)グリコール鎖が、300Da、600Da、1kDa、2kDa、3kDaまたは4kDaの分子量を有する、粒子。 - 前記表面改変部分における各ポリ(エチレン)グリコール鎖が、300Da、600Da、1kDaまたは2kDaの分子量を有する、請求項1に記載の粒子。
- 前記表面改変部分がポロキサマーである、請求項1または2に記載の粒子。
- 前記粒子が200nmから500nmの間の直径である、請求項1〜3のいずれか1項に記載の粒子。
- 前記粒子が、500nmの直径であるか、または200nmの直径である、請求項1〜3のいずれか1項に記載の粒子。
- 前記コアが生物活性剤を含む、請求項1〜5のいずれか1項に記載の粒子。
- 前記生物活性剤が造影剤または治療薬である、請求項6に記載の粒子。
- 前記生物活性剤が造影剤であり、そして該造影剤が診断薬である、請求項6に記載の粒子。
- 前記生物活性剤が造影剤であり、そして該造影剤が検出可能標識である、請求項6に記載の粒子。
- 前記生物活性剤が、核酸、核酸アナログ、低分子、ペプチド模倣物、タンパク質、ペプチド、脂質または界面活性剤である、請求項6に記載の粒子。
- さらに標的部分を含む、請求項6に記載の粒子。
- 前記粒子が、該粒子の表面上に配置された生物活性剤を含む、請求項1〜5のいずれか1項に記載の粒子。
- 前記生物活性剤が造影剤または治療薬である、請求項12に記載の粒子。
- 前記生物活性剤が造影剤であり、そして該造影剤が診断薬である、請求項12に記載の粒子。
- 前記生物活性剤が造影剤であり、そして該造影剤が検出可能標識である、請求項12に記載の粒子。
- 前記生物活性剤が、核酸、核酸アナログ、低分子、ペプチド模倣物、タンパク質、ペプチド、脂質または界面活性剤である、請求項12に記載の粒子。
- さらに標的部分を含む、請求項12に記載の粒子。
- 請求項1〜17のいずれか1項に記載の複数の粒子と、薬学的に許容される担体とを含む、薬学的組成物。
- 請求項18に記載の薬学的組成物を含む、吸入器。
- 患者の状態を処置、予防、または診断するための、請求項19に記載の吸入器。
- 患者の状態を処置、予防、または診断するための、請求項1〜17のいずれか1項に記載の複数の粒子を含む組成物。
- 前記患者の粘膜組織への局所投与のための、請求項21に記載の組成物。
- 薬学的に許容される担体をさらに含む、請求項21または22に記載の組成物。
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JP2013110583A Withdrawn JP2013163697A (ja) | 2006-09-08 | 2013-05-27 | 粘液を通る輸送を増強するための組成物および方法 |
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JP2013110583A Withdrawn JP2013163697A (ja) | 2006-09-08 | 2013-05-27 | 粘液を通る輸送を増強するための組成物および方法 |
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Families Citing this family (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005072710A2 (en) * | 2004-01-28 | 2005-08-11 | Johns Hopkins University | Drugs and gene carrier particles that rapidly move through mucous barriers |
DE112008003727T5 (de) * | 2008-02-18 | 2011-04-21 | Csir | Nanopartikel-Träger für Wirkstoffverabreichung und Verfahren für ihre Herstellung |
WO2011106702A2 (en) | 2010-02-25 | 2011-09-01 | The Johns Hopkins University | Sustained delivery of therapeutic agents to an eye compartment |
CN102985131B (zh) | 2010-04-28 | 2016-06-29 | 金伯利-克拉克环球有限公司 | 用于递送siRNA的医疗装置 |
WO2011135533A2 (en) | 2010-04-28 | 2011-11-03 | Kimberly-Clark Worldwide, Inc. | Nanopatterned medical device with enhanced cellular interaction |
US9522263B2 (en) | 2010-04-28 | 2016-12-20 | Kimberly-Clark Worldwide, Inc. | Device for delivery of rheumatoid arthritis medication |
US9586044B2 (en) | 2010-04-28 | 2017-03-07 | Kimberly-Clark Worldwide, Inc. | Method for increasing the permeability of an epithelial barrier |
EP3578205A1 (en) | 2010-08-06 | 2019-12-11 | ModernaTX, Inc. | A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof |
US10307372B2 (en) * | 2010-09-10 | 2019-06-04 | The Johns Hopkins University | Rapid diffusion of large polymeric nanoparticles in the mammalian brain |
CN104531812A (zh) | 2010-10-01 | 2015-04-22 | 现代治疗公司 | 设计核酸及其使用方法 |
WO2012061703A1 (en) * | 2010-11-05 | 2012-05-10 | The Johns Hopkins University | Compositions and methods relating to reduced mucoadhesion |
WO2012109363A2 (en) * | 2011-02-08 | 2012-08-16 | The Johns Hopkins University | Mucus penetrating gene carriers |
JP2014511687A (ja) | 2011-03-31 | 2014-05-19 | モデルナ セラピューティクス インコーポレイテッド | 工学操作された核酸の送達および製剤 |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
ES2911677T3 (es) | 2011-10-03 | 2022-05-20 | Modernatx Inc | Nucleósidos, nucleótidos y ácidos nucleicos modificados, y sus usos |
US9550053B2 (en) | 2011-10-27 | 2017-01-24 | Kimberly-Clark Worldwide, Inc. | Transdermal delivery of high viscosity bioactive agents |
US20170246439A9 (en) | 2011-10-27 | 2017-08-31 | Kimberly-Clark Worldwide, Inc. | Increased Bioavailability of Transdermally Delivered Agents |
KR20140079429A (ko) | 2011-10-27 | 2014-06-26 | 킴벌리-클라크 월드와이드, 인크. | 생체활성 제제를 전달하기 위한 이식형 기구 |
RU2631599C2 (ru) * | 2011-12-14 | 2017-09-25 | Дзе Джонс Хопкинс Юниверсити | Наночастицы, легче проникающие в слизистую оболочку или вызывающие меньше воспаления |
RS63244B1 (sr) | 2011-12-16 | 2022-06-30 | Modernatx Inc | Kompozicije modifikovane mrna |
EP2804632B1 (en) * | 2012-01-19 | 2019-09-18 | The Johns Hopkins University | Nanoparticle formulations with enhanced mucosal penetration |
CA2867381C (en) | 2012-03-16 | 2016-09-20 | The Johns Hopkins University | Controlled release formulations for the delivery of hif-1 inhibitors |
US10159743B2 (en) | 2012-03-16 | 2018-12-25 | The Johns Hopkins University | Non-linear multiblock copolymer-drug conjugates for the delivery of active agents |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9878056B2 (en) | 2012-04-02 | 2018-01-30 | Modernatx, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
US20140010861A1 (en) | 2012-04-02 | 2014-01-09 | modeRNA Therapeutics | Modified polynucleotides for the production of proteins associated with human disease |
CA2868391A1 (en) | 2012-04-02 | 2013-10-10 | Stephane Bancel | Polynucleotides comprising n1-methyl-pseudouridine and methods for preparing the same |
US9895437B2 (en) | 2012-04-18 | 2018-02-20 | Valneva Austria Gmbh | Aluminum compounds for use in therapeutics and vaccines |
US11596599B2 (en) | 2012-05-03 | 2023-03-07 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US10864219B2 (en) * | 2012-05-03 | 2020-12-15 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
EP2844227B1 (en) | 2012-05-03 | 2020-11-18 | Kala Pharmaceuticals, Inc. | Pharmaceutical nanoparticles showing improved mucosal transport |
CA2871778C (en) | 2012-05-03 | 2022-09-13 | Kala Pharmaceuticals, Inc. | Pharmaceutical nanoparticles showing improved mucosal transport |
WO2013166498A1 (en) * | 2012-05-04 | 2013-11-07 | The Johns Hopkins University | Lipid-based drug carriers for rapid penetration through mucus linings |
US9533068B2 (en) | 2012-05-04 | 2017-01-03 | The Johns Hopkins University | Drug loaded microfiber sutures for ophthalmic application |
LT2922554T (lt) | 2012-11-26 | 2022-06-27 | Modernatx, Inc. | Terminaliai modifikuota rnr |
AU2013374345A1 (en) | 2013-01-17 | 2015-08-06 | Moderna Therapeutics, Inc. | Signal-sensor polynucleotides for the alteration of cellular phenotypes |
WO2014124006A1 (en) | 2013-02-05 | 2014-08-14 | The Johns Hopkins University | Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof |
CA2900652C (en) | 2013-02-15 | 2021-05-04 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
BR112015020139A2 (pt) | 2013-02-20 | 2017-07-18 | Kala Pharmaceuticals Inc | compostos terapêuticos e usos dos mesmos |
US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
WO2014159813A1 (en) | 2013-03-13 | 2014-10-02 | Moderna Therapeutics, Inc. | Long-lived polynucleotide molecules |
US10258698B2 (en) | 2013-03-14 | 2019-04-16 | Modernatx, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
PT3019619T (pt) | 2013-07-11 | 2021-11-11 | Modernatx Inc | Composições que compreendem polinucleótidos sintéticos que codificam proteínas relacionadas com crispr e sgarn sintéticos e métodos de utilização |
WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
JP2016530294A (ja) | 2013-09-03 | 2016-09-29 | モデルナ セラピューティクス インコーポレイテッドModerna Therapeutics,Inc. | キメラポリヌクレオチド |
KR20160067219A (ko) | 2013-10-03 | 2016-06-13 | 모더나 세라퓨틱스, 인코포레이티드 | 저밀도 지단백질 수용체를 암호화하는 폴리뉴클레오타이드 |
US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
US9458169B2 (en) | 2013-11-01 | 2016-10-04 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
WO2015127368A1 (en) | 2014-02-23 | 2015-08-27 | The Johns Hopkins University | Hypotonic microbicidal formulations and methods of use |
US10335500B2 (en) | 2014-05-12 | 2019-07-02 | The Johns Hopkins University | Highly stable biodegradable gene vector platforms for overcoming biological barriers |
CA2955250A1 (en) | 2014-07-16 | 2016-01-21 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
EP3171895A1 (en) | 2014-07-23 | 2017-05-31 | Modernatx, Inc. | Modified polynucleotides for the production of intrabodies |
US10253045B2 (en) | 2014-11-26 | 2019-04-09 | Kala Pharmaceuticals, Inc. | Crystalline forms of a therapeutic compound and uses thereof |
AU2015360438C1 (en) | 2014-12-10 | 2019-02-07 | Kala Pharmaceuticals, Inc. | 1 -amino-triazolo(1,5-a)pyridine-substituted urea derivative and uses thereof |
EA201791337A1 (ru) | 2014-12-15 | 2017-11-30 | Дзе Джонс Хопкинс Юниверсити | Составы сунитиниба и способы их применения в лечении глазных нарушений |
JP6846351B2 (ja) | 2015-01-27 | 2021-03-24 | ザ・ジョンズ・ホプキンス・ユニバーシティー | 粘膜表面における活性薬剤の増強された輸送のための低張ヒドロゲル製剤 |
WO2017035408A1 (en) | 2015-08-26 | 2017-03-02 | Achillion Pharmaceuticals, Inc. | Compounds for treatment of immune and inflammatory disorders |
AR106018A1 (es) | 2015-08-26 | 2017-12-06 | Achillion Pharmaceuticals Inc | Compuestos de arilo, heteroarilo y heterocíclicos para el tratamiento de trastornos médicos |
BR112018005589A2 (pt) | 2015-09-22 | 2018-10-09 | Graybug Vision Inc | “composto, composição farmaceuticamente aceitável, e, uso de um composto” |
JP6921833B2 (ja) | 2015-10-22 | 2021-08-18 | モデルナティーエックス, インコーポレイテッド | ヒトサイトメガロウイルスワクチン |
EP3364980A4 (en) | 2015-10-22 | 2019-07-10 | ModernaTX, Inc. | NUCLEIC ACID VACCINES AGAINST VARICELLA-ZONA VIRUS (VZV) |
CA3003103A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Broad spectrum influenza virus vaccine |
MA46024A (fr) | 2015-10-22 | 2019-07-03 | Modernatx Inc | Vaccin contre le virus de l'herpès simplex |
MD3718565T2 (ro) | 2015-10-22 | 2022-09-30 | Modernatx Inc | Vaccinuri împotriva virusului respirator |
JP2019501208A (ja) | 2015-10-22 | 2019-01-17 | モデルナティーエックス, インコーポレイテッド | 呼吸器合胞体ウイルスワクチン |
CA3003733C (en) * | 2015-10-30 | 2021-04-20 | The Johns Hopkins University | Mucus penetrating particles with high molecular weight and dense coatings |
BR112018009644A2 (pt) | 2015-11-12 | 2018-11-06 | Graybug Vision Inc | micropartículas agregantes sólidas modificadas na superfície, material injetável, processo para preparação de micropartículas agregantes sólidas modificadas na superfície, método para tratamento de um distúrbio ocular, e, uso de micropartículas agregantes sólidas modificadas na superfície |
HRP20220525T1 (hr) | 2015-12-23 | 2022-05-27 | Modernatx, Inc. | Postupci uporabe polinukleotida koji kodiraju ligand ox40 |
EP3400023A1 (en) | 2016-01-10 | 2018-11-14 | ModernaTX, Inc. | Therapeutic mrnas encoding anti ctla-4 antibodies |
KR101741977B1 (ko) * | 2016-04-26 | 2017-05-31 | 한국교통대학교산학협력단 | 경구 투여용 유전자 전달을 위한 나노입자 및 이를 포함하는 약학 조성물 |
KR20190036520A (ko) | 2016-06-27 | 2019-04-04 | 아칠리온 파르마세우티칼스 인코포레이티드 | 의학적 장애를 치료하기 위한 퀴나졸린 및 인돌 화합물 |
US10253036B2 (en) | 2016-09-08 | 2019-04-09 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
WO2018048750A1 (en) | 2016-09-08 | 2018-03-15 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
CA3036065A1 (en) | 2016-09-08 | 2018-03-15 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
US20190216726A1 (en) * | 2016-09-16 | 2019-07-18 | Kala Pharmaceuticals, Inc. | Particles, Compositions and Methods for Ophthalmic and/or Other Applications |
AU2018240462C1 (en) | 2017-03-23 | 2022-12-08 | Graybug Vision, Inc. | Drugs and compositions for the treatment of ocular disorders |
WO2018209155A1 (en) | 2017-05-10 | 2018-11-15 | Graybug Vision, Inc. | Extended release microparticles and suspensions thereof for medical therapy |
US20210186880A1 (en) * | 2018-08-03 | 2021-06-24 | Brown University | Oral formulations with increased uptake |
JP2021535112A (ja) | 2018-08-20 | 2021-12-16 | アキリオン ファーマシューティカルズ,インコーポレーテッド | 補体d因子の医学的障害の治療のための医薬化合物 |
JP7504088B2 (ja) | 2018-10-16 | 2024-06-21 | ジョージア ステイト ユニバーシティー リサーチ ファウンデーション インコーポレイテッド | 医学的障害の治療のための一酸化炭素プロドラッグ |
US20220175690A1 (en) * | 2020-11-17 | 2022-06-09 | Phosphorex, Inc. | Novel drug delivery composition and process for blood-brain barrier crossing |
WO2023161350A1 (en) | 2022-02-24 | 2023-08-31 | Io Biotech Aps | Nucleotide delivery of cancer therapy |
Family Cites Families (54)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4996335A (en) * | 1980-07-10 | 1991-02-26 | Nicholas S. Bodor | Soft steroids having anti-inflammatory activity |
US4906474A (en) * | 1983-03-22 | 1990-03-06 | Massachusetts Institute Of Technology | Bioerodible polyanhydrides for controlled drug delivery |
US4757128A (en) * | 1986-08-01 | 1988-07-12 | Massachusetts Institute Of Technology | High molecular weight polyanhydride and preparation thereof |
CH671402A5 (ja) * | 1985-10-02 | 1989-08-31 | Sandoz Ag | |
GB8601100D0 (en) * | 1986-01-17 | 1986-02-19 | Cosmas Damian Ltd | Drug delivery system |
US4789724A (en) * | 1986-10-17 | 1988-12-06 | Massachusetts Institute Of Technology | Preparation of anhydride copolymers |
US5718921A (en) * | 1987-03-13 | 1998-02-17 | Massachusetts Institute Of Technology | Microspheres comprising polymer and drug dispersed there within |
US4839343A (en) * | 1987-03-13 | 1989-06-13 | Debiopharm, S.A. | Preparation containing hexatriacontapeptides and methods of use |
US4868274A (en) * | 1988-05-23 | 1989-09-19 | Hoechst Celanese Corp. | Polyanhydride from carboxy aryloxy alkanoic acid |
US4999417A (en) * | 1989-03-30 | 1991-03-12 | Nova Pharmaceutical Corporation | Biodegradable polymer compositions |
US5145684A (en) * | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5552160A (en) * | 1991-01-25 | 1996-09-03 | Nanosystems L.L.C. | Surface modified NSAID nanoparticles |
US5696298A (en) * | 1991-03-19 | 1997-12-09 | Cytrx Corporation | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity |
US6197346B1 (en) * | 1992-04-24 | 2001-03-06 | Brown Universtiy Research Foundation | Bioadhesive microspheres and their use as drug delivery and imaging systems |
US5916596A (en) * | 1993-02-22 | 1999-06-29 | Vivorx Pharmaceuticals, Inc. | Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof |
US5565215A (en) * | 1993-07-23 | 1996-10-15 | Massachusettes Institute Of Technology | Biodegradable injectable particles for imaging |
US5543158A (en) * | 1993-07-23 | 1996-08-06 | Massachusetts Institute Of Technology | Biodegradable injectable nanoparticles |
US5540930A (en) * | 1993-10-25 | 1996-07-30 | Pharmos Corporation | Suspension of loteprednol etabonate for ear, eye, or nose treatment |
US5665331A (en) * | 1995-01-10 | 1997-09-09 | Nanosystems L.L.C. | Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers |
US5612053A (en) * | 1995-04-07 | 1997-03-18 | Edward Mendell Co., Inc. | Controlled release insufflation carrier for medicaments |
US5985309A (en) * | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
ZA9711732B (en) * | 1996-12-31 | 1998-12-28 | Quadrant Holdings Cambridge | Methods and compositions for improvement bioavailability of bioactive agents for mucosal delivery |
GB9713980D0 (en) * | 1997-07-03 | 1997-09-10 | Danbiosyst Uk | New conjugates |
CA2361421A1 (en) * | 1999-02-03 | 2000-08-10 | Biosante Pharmaceuticals, Inc. | Therapeutic calcium phosphate particles and methods of manufacture and use |
US20040258763A1 (en) * | 1999-02-03 | 2004-12-23 | Bell Steve J.D. | Methods of manufacture and use of calcium phosphate particles containing allergens |
US20020068090A1 (en) * | 1999-02-03 | 2002-06-06 | Bell Steve J. D. | Calcium phosphate particles as mucosal adjuvants |
US6270806B1 (en) * | 1999-03-03 | 2001-08-07 | Elan Pharma International Limited | Use of peg-derivatized lipids as surface stabilizers for nanoparticulate compositions |
CN1174741C (zh) * | 1999-09-21 | 2004-11-10 | Rtp药品公司 | 生物活性物质的表面改性微粒组合物 |
US20040102197A1 (en) * | 1999-09-30 | 2004-05-27 | Dietz Timothy Alan | Dynamic web page construction based on determination of client device location |
PE20020146A1 (es) * | 2000-07-13 | 2002-03-31 | Upjohn Co | Formulacion oftalmica que comprende un inhibidor de ciclooxigenasa-2 (cox-2) |
GB0027357D0 (en) * | 2000-11-09 | 2000-12-27 | Bradford Particle Design Plc | Particle formation methods and their products |
GB2370839A (en) * | 2001-01-06 | 2002-07-10 | Benedikt Timmerman | Immunogenic complex useful for disease control |
JP4758607B2 (ja) * | 2001-06-22 | 2011-08-31 | ジョンズ ホプキンズ ユニヴァーシティー スクール オブ メディシン | 生分解性ポリマー組成物、及びその使用方法 |
GB0200289D0 (en) * | 2002-01-08 | 2002-02-20 | Koninkl Philips Electronics Nv | Switched-current integrator |
AU2006220411B2 (en) * | 2002-03-20 | 2008-06-26 | Alkermes, Inc. | Inhalable Sustained Therapeutic Formulations |
CA2488498A1 (en) * | 2002-06-10 | 2003-12-18 | Elan Pharma International Limited | Nanoparticulate polycosanol formulations and novel polycosanol combinations |
JP4513007B2 (ja) * | 2002-09-26 | 2010-07-28 | アステラス製薬株式会社 | 薬物吸収性改善剤 |
BR0316685A (pt) * | 2002-12-17 | 2005-11-01 | Nastech Pharm Co | Composições e métodos para a administração aperfeiçoada por via mucosal de peptìdeos fixadores ao receptor de y2 e métodos para tratar e prevenir a obesidade |
US7060299B2 (en) * | 2002-12-31 | 2006-06-13 | Battelle Memorial Institute | Biodegradable microparticles that stabilize and control the release of proteins |
US7314959B2 (en) * | 2003-08-07 | 2008-01-01 | Wisconsin Alumni Research Foundation | Amino thiol compounds and compositions for use in conjunction with cancer therapy |
US20090148527A1 (en) * | 2007-12-07 | 2009-06-11 | Robinson Michael R | Intraocular formulation |
WO2005072710A2 (en) * | 2004-01-28 | 2005-08-11 | Johns Hopkins University | Drugs and gene carrier particles that rapidly move through mucous barriers |
WO2005076998A2 (en) * | 2004-02-05 | 2005-08-25 | Intradigm Corporation | Rnai therapeutics for treatment of eye neovascularization diseases |
ES2246694B1 (es) * | 2004-04-29 | 2007-05-01 | Instituto Cientifico Y Tecnologico De Navarra, S.A. | Nanoparticulas pegiladas. |
CA2571899A1 (en) * | 2004-07-01 | 2006-08-03 | Yale University | Targeted and high density drug loaded polymeric materials |
DE602005012289D1 (de) * | 2004-09-14 | 2009-02-26 | Nanodel Technologies Gmbh | Abgabevehikel mit nanoteilchen |
US20060083781A1 (en) * | 2004-10-14 | 2006-04-20 | Shastri V P | Functionalized solid lipid nanoparticles and methods of making and using same |
US8663639B2 (en) * | 2005-02-09 | 2014-03-04 | Santen Pharmaceutical Co., Ltd. | Formulations for treating ocular diseases and conditions |
WO2007067978A1 (en) * | 2005-12-09 | 2007-06-14 | Invitrogen Corporation | Optical in vivo imaging contrast agents and methods of use |
BRPI0619890A2 (pt) * | 2005-12-14 | 2011-10-25 | Hoffmann La Roche | composição farmacêutica e processo para preparação de uma suspensão sólida |
US20080102128A1 (en) * | 2006-07-28 | 2008-05-01 | Flamel Technologies, Inc. | Modified-release microparticles based on amphiphilic copolymer and on active principles(s) and pharmaceutical formulations comprising them |
WO2008033924A2 (en) * | 2006-09-12 | 2008-03-20 | Board Of Regents Of The University Of Nebraska | Methods and compositions for targeted delivery of therapeutic agents |
US20090226531A1 (en) * | 2008-03-07 | 2009-09-10 | Allergan, Inc. | Methods and composition for intraocular delivery of therapeutic sirna |
WO2012061703A1 (en) * | 2010-11-05 | 2012-05-10 | The Johns Hopkins University | Compositions and methods relating to reduced mucoadhesion |
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CA2663003C (en) | 2018-02-13 |
EP2061433A2 (en) | 2009-05-27 |
ES2360538T3 (es) | 2011-06-06 |
JP2013163697A (ja) | 2013-08-22 |
CA2663003A1 (en) | 2008-03-13 |
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JP2010502713A (ja) | 2010-01-28 |
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US20130164343A1 (en) | 2013-06-27 |
JP2015057438A (ja) | 2015-03-26 |
US20230108636A1 (en) | 2023-04-06 |
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WO2008030557A3 (en) | 2008-05-02 |
AU2007292902A8 (en) | 2013-09-05 |
AU2007292902A1 (en) | 2008-03-13 |
AU2007292902B8 (en) | 2013-09-05 |
US20200345864A1 (en) | 2020-11-05 |
ATE498393T1 (de) | 2011-03-15 |
US20100215580A1 (en) | 2010-08-26 |
US20180264135A1 (en) | 2018-09-20 |
WO2008030557A9 (en) | 2008-06-26 |
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