JP2010540468A - 高濃度キトサン−核酸ポリプレックス組成物 - Google Patents
高濃度キトサン−核酸ポリプレックス組成物 Download PDFInfo
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- JP2010540468A JP2010540468A JP2010526123A JP2010526123A JP2010540468A JP 2010540468 A JP2010540468 A JP 2010540468A JP 2010526123 A JP2010526123 A JP 2010526123A JP 2010526123 A JP2010526123 A JP 2010526123A JP 2010540468 A JP2010540468 A JP 2010540468A
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Abstract
Description
本出願は、2007年9月28日に出願された米国特許出願第60/976,376号の利益を請求し、そして本明細書に参照により完全に組み込まれる。
本発明は、均質なキトサン−核酸ポリプレックスに関する。本発明は、溶液中においてキトサン−核酸ポリプレックスを濃縮するための方法、及び均質なキトサン−核酸ポリプレックスの高濃縮調製物にさらに関する。
キトサンは、無毒性である、N−アセチル−D−グルコサミンとD−グルコサミンとの陽イオン性共重合体である。キトサンは、核酸と複合体を形成し得、そして細胞をトランスフェクトするためのDNA送達ビヒクルとして使用されている。
本発明者は、研究及び医薬の分野において多くの適用が見出されている、高濃縮キトサン−核酸ポリプレックス組成物を製造する分野における障害を克服した。好ましい実施形態において、当該組成物は、高濃度にもかかわらず凝集又は沈澱しない一定サイズのポリプレックスを含み、そして種々の条件下における安定性を示す。さらに、本発明の好ましい組成物はまた、形成されると等張的(isotonic)である。ポリプレックスの安定性を維持する一方で等張性を達することは、医薬における及び治療における適用のために非常に所望である。さらに、本発明者は、スタティック又はダイナミックミキサーを必要せず、そして当該ミキサーを含まないことによって改善されるインライン混合工程によって、キトサン−核酸ポリプレックスを製造する方法を発見した。さらにこれらの方法は、中性から著しく外れている電荷(すなわち、ゼータ電位)を有する安定なポリプレックスを製造するために使用され得る。驚くべきことに、本発明者はまた、混合溶液中におけるDNAとキトサンとの混合比を変えることなく、又はDNAとキトサンの濃度を実質的に変化させることなく、粒子のサイズ及び均質性が、インライン混合用の供給原料の体積を変化させることによって調節され得ることを見出した。
「キトサン−核酸ポリプレックス」、「キトサン−核酸ポリプレックス粒子」、又は「ポリプレックス」は、複数のキトサン分子(各々、グルコサミンモノマーのポリマー)、及び複数の核酸分子を含む複合体を意味する。キトサンモノマーは、リガンドと結合したキトサンを含む誘導体を含む。「誘導体」は、高範囲のカテゴリーの、共有結合性修飾されたN−アセチル−D−グルコサミン、及び/又はD−グルコサミンユニットを含むキトサン系(chitosan−based)ポリマー、及び他のユニットと結合した、又は他の部位と結合したキトサン型ポリマーを含むものとして理解されるだろう。誘導体は、グルコサミンのヒドロキシル基又はアミノ基の修飾に基づくものが多い。キトサン誘導体の例は、限定されないが、トリメチル化キトサン、PEG化されたキトサン、チオール化されたキトサン、ガラクトシル化されたキトサン、アルキル化されたキトサン、PEIの結合したキトサン、アルギニン修飾されたキトサン、ウロン酸修飾されたキトサンなどを含む。キトサン誘導体に関するさらなる教示は、例えば「Non−viral Gene Therapy」,K.Taira,K.Kataoka,T.Niidome(editors),Springer−Verlag Tokyo,2005,ISBN4−431−25122−7;Zhu et al.,Chinese Science Bulletin,December 2007,vol.52(23),pp.3207−3215;及びVarma et al.,Carbohydrate Polymers 55(2004)77−93を参照。
Claims (25)
- 水和したキトサン−核酸ポリプレックスを含む組成物であって、0.5mg/ml以上の核酸濃度を有する、前記組成物。
- ポリプレックス沈澱を実質的に含まない、請求項1に記載の組成物。
- 0.75mg/ml超の核酸濃度を含む、請求項1に記載の組成物。
- 1mg/ml超の核酸濃度を含む、請求項1に記載の組成物。
- 1.2mg/ml超の核酸濃度を含む、請求項1に記載の組成物。
- 1.5mg/ml超の核酸濃度を含む、請求項1に記載の組成物。
- 凝集阻害剤を含む、請求項1に記載の組成物。
- 約80mM未満の対アニオン濃度を含む、請求項1に記載の組成物。
- 前記ポリプレックスが750nm未満の平均直径を有する、請求項1に記載の組成物。
- 前記ポリプレックスが2:1以上のN:P比を有する、請求項1に記載の組成物。
- 前記ポリプレックスが、500kDa未満の平均分子量を有するキトサン分子を含む、請求項1に記載の組成物。
- 前記ポリプレックスが、3000個未満のグルコサミンモノマー単位を有するキトサン分子を含む、請求項1に記載の組成物。
- 本質的に前記水和したキトサン−核酸ポリプレックス及び凝集阻害剤からなる、請求項1に記載の組成物。
- 前記キトサン−核酸ポリプレックスが、0.5未満の平均多分散度を有する、請求項1に記載の組成物。
- 等張的である、請求項1に記載の組成物。
- キトサン−核酸ポリプレックスを濃縮する方法であって、キトサン−核酸ポリプレックスの非濃縮分散系を提供し、そしてキトサン−核酸ポリプレックスの濃縮分散系を形成するための濃縮手段を使用して、前記キトサン−核酸ポリプレックスの非濃縮分散系を濃縮することを含み、ここで前記組成物が0.5mg/ml以上の核酸濃度を有し、そして前記組成物が実質的にポリプレックス沈澱を含まない、前記方法。
- 前記非濃縮分散系が、最初の濃度で凝集阻害剤を含む、請求項16に記載の方法。
- 前記濃縮ステップが、前記濃縮分散系中における前記凝集阻害剤の前記最初の濃度を実質的に維持する、請求項17に記載の方法。
- 前記濃縮手段が、タンジェンシャルフロー濾過である、請求項16に記載の方法。
- インライン混合が、前記キトサン−核酸ポリプレックスの非濃縮分散系を調製するために使用される、請求項16に記載の方法。
- 請求項16に記載の方法によって製造される、キトサン−核酸ポリプレックスの濃縮分散系。
- 水和したキトサン−核酸ポリプレックスを含む医薬組成物であって、0.5mg/ml以上の核酸濃度を有し、そして前記キトサン−核酸ポリプレックスが治療用核酸コンストラクトを含む、前記組成物。
- 等張的である、請求項22に記載の医薬組成物。
- キトサン溶液及び核酸溶液を混合することによって製造される混合分散系中において形成される、キトサン−核酸ポリプレックスの直径を変化させるための方法であって、前記混合分散系中におけるキトサンと核酸との混合比を実質的に変化させることなく、かつキトサン又は核酸のいずれか一方の濃度を実質的に変化させることなく、キトサン又は核酸分散系の体積を変化させることを含む、前記方法。
- 前記混合溶液が、前記キトサン溶液及び前記核酸溶液のインライン混合により製造され、ここで前記キトサン溶液及び前記核酸溶液の流速が、混合流速を維持するように、並びにキトサン及び核酸の混合濃度を維持するように調節される、請求項24に記載の方法。
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