JP2016513090A - 薬物送達キャリアとしての生分解性でかつ臨床上適合性のナノ粒子 - Google Patents
薬物送達キャリアとしての生分解性でかつ臨床上適合性のナノ粒子 Download PDFInfo
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Abstract
Description
本出願は、2013年2月5日に出願された同時係属中の米国仮特許出願第61/761,012号の優先権およびその利益を主張し、当該出願は、適用可能な法律および規則が許容する程度に、その全体が本明細書において参考として援用される。
該当なし。
本発明は、新規のナノ粒子組成物、それを製作する方法、および薬物送達キャリアとしてのその使用に関する。
高分子および小分子の両方を含めた治療的作用物質がますます豊富になるとともに、生物医学業界および製薬業界では、哺乳動物、特にヒト集団のための、これらの治療的作用物質の、安全で、実用的でかつ効果的な送達ビヒクルの重要性がますます認識されてきた。満足な送達ビヒクルについて所望される特徴は多数存在する:送達ビヒクルは、非毒性であること、したがって生体適合性であること、好ましくは合理的な時間以内で生分解可能または吸収可能である必要がある。全身投与については、送達ビヒクルは、治療物質を、体内で分解または消化から保護しながら標的部位まで循環させるに十分に安定である必要があり、そして、送達が著しい免疫応答を引き起こすように実際に設計されているのでない限り、そのような著しい免疫応答を回避する必要がある。送達ビヒクルは、標的の組織、細胞、細胞区画またはオルガネラにアクセスするためには、生理的障壁を透過することができる必要がある。送達ビヒクルはまた、標的部位の生理的条件下で、またはそれが運搬する作用物質を放出する標的時間の間、十分に可溶性である必要がある。さらに、治療的作用物質の経時的で制御された放出が、多くの場合強く所望される。
本発明は、RNAi技術に基づく治療的作用物質をはじめとする治療的作用物質の送達に用いることのできるナノ粒子の新しい材料および組成物を提供する。
本明細書において引用される全ての参考文献は、それぞれの個々の刊行物または特許または特許出願が、具体的かつ個別に、全ての目的についてその全体が参考として援用されると示されている場合と同じ程度に、かつ適用可能な法律が許容する程度に、全ての目的についてその全体が本明細書において参考として援用される。参考として援用された刊行物および特許もしくは特許出願が、本明細書に含まれる定義をはじめとする開示と矛盾する限りでは、いかなるそのような矛盾する事項についても、本明細書が取って代わる、および/または優先することが意図されている。
3’−AAUAAAUUCCAUCUUGUGAUC−5’ (配列番号2)
3’−AAUUUGAAAAUGUUGAUCUCC−5’ (配列番号4)
3’−AAUUUAAGGAGGGUGAUCUUC−5’(配列番号6)
3’−AACAUCGACUAUAACUACCUG−5’(配列番号8)
Claims (73)
- 医療的に有用な作用物質を送達するためのナノ粒子であって、以下:
マグネシウム塩を含む生分解性でかつ臨床上適合性のコア;および
医療的に有用な作用物質、を含むナノ粒子。 - 前記マグネシウム塩は無機マグネシウム塩である、請求項1に記載のナノ粒子。
- 前記マグネシウム塩はリン酸マグネシウムである、請求項2に記載のナノ粒子。
- 前記マグネシウム塩は有機マグネシウム塩である、請求項1に記載のナノ粒子。
- 前記作用物質は、核酸、タンパク質もしくはペプチド、および小分子からなる群より選択される、請求項1に記載のナノ粒子。
- 前記核酸は、アンチセンスDNA、RNA、DNA−RNAハイブリッド、PNA、およびアプタマーからなる群より選択される、請求項5に記載のナノ粒子。
- 前記RNAはaiRNAを含む、請求項6に記載のナノ粒子。
- 前記RNAはsiRNAを含む、請求項6に記載のナノ粒子。
- 前記aiRNAまたはsiRNAは、少なくとも、タンパク質をコードするか、または哺乳動物の疾患に関係する生体経路の一部分を調節するかのいずれかのRNAを標的とする、請求項7または8に記載のナノ粒子。
- 前記タンパク質もしくはペプチドは、抗体および抗体断片からなる群より選択される、請求項5に記載のナノ粒子。
- 前記作用物質は、前記コアの内部に配置される、請求項1に記載のナノ粒子。
- 前記作用物質は、前記コアの表面上に配置される、請求項1に記載のナノ粒子。
- 前記コアは、リン酸カルシウムをさらに含む、請求項1に記載のナノ粒子。
- 前記コアは、核酸、タンパク質もしくはペプチド、脂質、界面活性物質、アミノ酸、炭水化物、小分子、および/または生体適合性ポリマーからなる群より選択される添加物をさらに含む、請求項1に記載のナノ粒子。
- 前記添加物は、標的化リガンド、細胞透過性ペプチド、アルブミン、アルブミン誘導体、ヒストン、プロタミン、Cremophor EL、Solutol、シクロデキストリン、RGDトリペプチド、コレステロール、リン脂質、およびポリエチレングリコール(PEG)からなる群より選択される、請求項14に記載のナノ粒子。
- 前記コアの周囲にシェルをさらに含む請求項1に記載のナノ粒子であって、該シェルは、タンパク質もしくはペプチド、界面活性物質、脂質、リガンド、アミノ酸、炭水化物、核酸、小分子および生体適合性ポリマーからなる群より選択される成分を含む、請求項1に記載のナノ粒子。
- 前記成分は、標的化リガンド、細胞透過性ペプチド、アルブミン、アルブミン誘導体、ヒストン、プロタミン、Cremophor EL、Solutol、シクロデキストリン、RGDトリペプチド、コレステロール、リン脂質、およびポリエチレングリコール(PEG)からなる群より選択される、請求項16に記載のナノ粒子。
- 前記ナノ粒子の平均の直径は、約200ナノメートルであるかまたはそれより小さい、請求項1に記載のナノ粒子。
- 前記ナノ粒子は、約7.0またはそれより高いpHの溶液中より、約6.0と約7.0との間のpH値の溶液中でより溶解性が高い、請求項1に記載のナノ粒子。
- 前記ナノ粒子は、約7.0またはそれより高いpHの溶液中より、約6.0またはそれより低い酸性pHの溶液中で、さらにより溶解性が高い、請求項19に記載のナノ粒子。
- 前記ナノ粒子は、約−30mVと約+50mVとの間の表面電荷を特徴とする、請求項1に記載のナノ粒子。
- 前記ナノ粒子は、約−10mVと約+20mVとの間の表面電荷を特徴とする、請求項1に記載のナノ粒子。
- 前記コアは、実質的にマグネシウム塩、および1つまたは複数の医療的に有用な作用物質から構成される、請求項1に記載のナノ粒子。
- マグネシウム塩から実質的に構成されるコア、および該コアの表面上にコーティングされた医療的に有用な作用物質を含むナノ粒子。
- 前記マグネシウム塩は、リン酸マグネシウムである、請求項23に記載のナノ粒子。
- 前記作用物質は、核酸、タンパク質もしくはペプチド、および小分子からなる群より選択される、請求項23に記載のナノ粒子。
- 前記核酸はaiRNAを含む、請求項25に記載のナノ粒子。
- タンパク質もしくはペプチド、界面活性物質、脂質、リガンド、アミノ酸、炭水化物、核酸、小分子および生体適合性ポリマーからなる群より選択される成分を含むシェルを、前記コアの周囲にさらに含む、請求項23に記載のナノ粒子。
- 実質的にリン酸マグネシウムから構成されるコア、および前記コアの内部に配置された1つまたは複数の医療的に有用な作用物質を含むナノ粒子。
- 前記作用物質は、核酸、タンパク質もしくはペプチド、および小分子からなる群より選択される、請求項28に記載のナノ粒子。
- 前記核酸はaiRNAを含む、請求項29に記載のナノ粒子。
- タンパク質もしくはペプチド、界面活性物質、脂質、リガンド、アミノ酸、炭水化物、小分子、核酸および生体適合性ポリマーからなる群より選択される成分を含むシェルを、前記コアの周囲にさらに含む、請求項28に記載のナノ粒子。
- リン酸マグネシウム、リン酸カルシウム、および1つまたは複数の医療的に有用な作用物質から構成されるコアを含むナノ粒子。
- 前記作用物質は、核酸、タンパク質もしくはペプチド、および小分子からなる群より選択される、請求項32に記載のナノ粒子。
- 前記核酸はaiRNAを含む、請求項33に記載のナノ粒子。
- タンパク質もしくはペプチド、脂質、界面活性物質、リガンド、アミノ酸、炭水化物、小分子、核酸および生体適合性ポリマーからなる群より選択される成分を含むシェルを、前記コアの周囲にさらに含む、請求項32に記載のナノ粒子。
- リン酸マグネシウム、生体適合性添加物、および医療的に有用な作用物質を含むコアを含むナノ粒子。
- 前記作用物質は、核酸、タンパク質もしくはペプチド、および小分子からなる群より選択される、請求項36に記載のナノ粒子。
- 前記核酸はaiRNAを含む、請求項37に記載のナノ粒子。
- タンパク質もしくはペプチド、脂質、界面活性物質、リガンド、アミノ酸、炭水化物、小分子、核酸および生体適合性ポリマーからなる群より選択される成分を含むシェルを、前記コアの周囲にさらに含む、請求項36に記載のナノ粒子。
- 前記添加物は、脂質、界面活性物質、タンパク質もしくはペプチド、核酸、炭水化物、アミノ酸、生体適合性ポリマー、ポリアルギニン、ポリリシン、およびポリエチレングリコール(PEG)からなる群より選択される、請求項36に記載のナノ粒子。
- 前記脂質はコレステロールまたはリン脂質であり、前記タンパク質もしくはペプチドはアルブミンまたはその誘導体である、請求項40に記載のナノ粒子。
- リン酸マグネシウムを含むコアであって、aiRNAが該コアの内部に配置されているコア;
該コアの周囲のシェルであって、タンパク質もしくはペプチド、脂質、界面活性物質、リガンド、アミノ酸、炭水化物、小分子、核酸および生体適合性ポリマーからなる群より選択される成分を含むシェル;
を含むナノ粒子であって、
該ナノ粒子の平均の直径が約2ナノメートルと約200ナノメートルとの間である、ナノ粒子。 - 前記タンパク質もしくはペプチドはアルブミンまたはアルブミン誘導体であり、前記脂質はコレステロールまたはリン脂質である、請求項42に記載のナノ粒子。
- 前記ナノ粒子の平均の直径は、約5ナノメートルと約100ナノメートルとの間である、請求項42に記載のナノ粒子。
- 前記ナノ粒子の平均の直径は、約5.5ナノメートルと約80ナノメートルとの間である、請求項42に記載のナノ粒子。
- 前記界面活性物質は、Cremophor EL、Solutol、TweenおよびTritonからなる群より選択される、請求項42に記載のナノ粒子。
- 前記ナノ粒子は、約7.0より低いpHにおいてより溶解性が高い、請求項42に記載のナノ粒子。
- 前記タンパク質もしくはペプチドは、プロタミンまたはヒストンである、請求項42に記載のナノ粒子。
- 前記ナノ粒子は、約−10mVと約+20mVとの間の表面電荷を特徴とする、請求項42に記載のナノ粒子。
- それぞれが請求項1〜49のいずれかに記載のナノ粒子である複数のナノ粒子を含む、医薬組成物。
- 薬学的に許容可能な賦形剤、キャリアまたは希釈剤をさらに含む、請求項50に記載の医薬組成物。
- 経口投与のために製剤化される、請求項50に記載の医薬組成物。
- ナノ粒子および活性医薬成分を含む医薬組成物であって、該組成物は、経口投与された後に、少なくとも1つの疾患または状態を処置する医療的効果を引出すことができ、その結果、該組成物は、臨床適用のための通常の要件に適合する医薬候補として適格である、医薬組成物。
- 哺乳動物被験体に活性作用物質を送達する方法であって、該方法は、該哺乳動物被験体に、活性作用物質を負荷された少なくとも1つのナノ粒子を経口投与することを含む、方法。
- 前記活性作用物質は、活性医薬成分である、請求項54に記載の方法。
- 前記ナノ粒子は、マグネシウム塩を含むコアを含み、前記活性作用物質は、aiRNAまたはsiRNAのいずれかである、請求項54に記載の方法。
- 哺乳動物被験体における疾患を処置する方法であって、該方法は、該哺乳動物被験体に、複数のナノ粒子により運搬される活性医薬成分の治療的有効量を、経口投与することを含む、方法。
- 前記ナノ粒子は、マグネシウム塩を含むコアを含む、請求項57に記載の方法。
- 哺乳動物被験体の疾患を処置する方法であって、該方法は、該哺乳動物被験体に、請求項50〜53のいずれかに記載の医薬組成物の治療的有効量を投与することを含む、方法。
- 前記医薬組成物は、前記哺乳動物被験体に経口投与される、請求項59に記載の方法。
- 哺乳動物被験体に活性作用物質を送達する方法であって、該方法は、該哺乳動物被験体に、それぞれが請求項1〜49のいずれかに記載のナノ粒子である複数のナノ粒子を投与することを含む、方法。
- 前記ナノ粒子は、前記哺乳動物被験体に経口投与される、請求項61に記載の方法。
- アルブミンベースのコアおよび医療的に有用な作用物質を含むナノ粒子。
- 前記コアは、改変アルブミン、アルブミン断片およびアルブミンの誘導体からなる群より選択されるペプチドをさらに含む、請求項63に記載のナノ粒子。
- マグネシウム塩をさらに含む、請求項63に記載のナノ粒子。
- 前記作用物質は、アンチセンスDNA、RNA、DNA−RNAハイブリッド、PNA、アプタマー、抗体、抗体断片および小分子からなる群より選択される、請求項63に記載のナノ粒子。
- 金およびaiRNAを含むコアを含むナノ粒子。
- 前記コアは、リン酸マグネシウムをさらに含む、請求項67に記載のナノ粒子。
- タンパク質もしくはペプチド、脂質、界面活性物質、リガンド、アミノ酸、炭水化物、小分子、核酸および生体適合性ポリマーからなる群より選択される材料を含むシェルを、前記コアの周囲にさらに含む、請求項67に記載のナノ粒子。
- 前記aiRNAは、少なくとも、タンパク質をコードするか、または自己免疫疾患もしくは炎症疾患に関係する生体経路の一部分を調節するかのいずれかのRNAを標的とする、請求項67に記載のナノ粒子。
- 前記aiRNAは、ヒトTNF−α(腫瘍壊死因子−α)機能を標的とする、請求項67に記載のナノ粒子。
- 前記aiRNAは、ヒトIL−6(インターロイキン−6)機能を標的とする、請求項67に記載のナノ粒子。
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