JPWO2018038253A1 - 微小ナノ化薬剤およびその利用 - Google Patents
微小ナノ化薬剤およびその利用 Download PDFInfo
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Abstract
Description
しかし、腫瘍血管は前述のとおり、細かな血管網を形成しているため、腫瘍血管のみを選択的に塞栓することは困難であり、多くの場合腫瘍血管が分岐している元の血管を塞栓することで栄養の伝達を阻止する方法が採られる。しかしこの方法は正常な血管を塞栓させる必要があるため、正常組織への影響が懸念される。
(1)溶媒中に分散した有効成分の平均粒径が、1〜20nm径である、微小ナノ化薬剤。
(2)溶媒中に分散した有効成分の粒度分布が、1〜20nm径である、(1)の微小ナノ化薬剤。
(3)微小ナノ化が、放射線照射によるものである、(1)または(2)の微小ナノ化薬剤。
(4)有効成分が、抗がん剤である、(1)〜(3)に記載の微小ナノ化薬剤。
(5)腫瘍血管または炎症血管血流低減剤である、(1)〜(4)に記載の微小ナノ化薬剤。
(6)有効成分が、免疫チェックポイント阻害剤を含む、(5)の微小ナノ化薬剤。
(7)薬剤を微小ナノ化する方法であって、前記薬剤に100〜200μSv/hの放射線を10分〜60分照射することを含む、前記方法。
(8)放射線が、閃ウラン鉱石を放射線源とするものである、(7)の方法。
(9)薬剤が、ナノ化した抗がん剤である、(7)または(8)の方法。
(10)ナノ化した抗がん剤が、ゲムシタビン塩酸塩とグリチルリチン酸の混合物を含む、(9)の方法。
<1>本発明の微小ナノ化薬剤
本発明は、溶媒中に分散した有効成分の平均粒径が、約1〜20nm径である微小ナノ化薬剤を提供するものである。
本発明において、「薬剤」とは、特定の薬理学的効果を示す有効成分(化合物)そのものを意味するが、当該有効成分を含む製剤(組成物)を意味する場合もある。
本発明において、「微小ナノ化薬剤」とは、従来の薬剤よりも高い細胞膜透過性を示す程度に小さな粒径を有する薬剤を意味し、これに限定するものではないが、例えば40nm未満の粒径を有する薬剤である。微小ナノ化薬剤は、単独でまたは他の成分と組み合わせて溶媒に分散させることにより小さな粒径となるものであってもよいし、溶媒に分散させた後、粒径を小さくする処理を施したものであってもよい。粒径を小さくする方法としては、例えば振とう、希釈、撹拌など、当該技術分野において通常用いられる方法を用いることができる。
本発明において「炎症血管」とは、炎症部位で産生される炎症性サイトカインにより誘導された新生血管を意味し、典型的には、例えばリウマチにおいて滑膜で新生した血管網を構成する血管などが挙げられる。
本発明の微小ナノ化薬剤が高い薬効を示す理由はよくわかっていない。理論に拘束されるものではないが、例えば粒径が小さくなることにより、細胞表面レセプターとのマッチング性が向上するなどの理由が考えられる。
腫瘍血管血流低減剤に用いられる抗がん剤としては、好ましくはナノ化した抗がん剤などが挙げられる。本明細書において「ナノ化」とは、単独でまたは他の成分と組み合わせて溶媒に分散させることにより、または溶媒に分散させた後粒径を小さくする処理を施すことにより、約60〜120nm程度の粒度分布を有する薬剤とすることをいう。ナノ化した抗がん剤の例としては、限定することなく、ゲムシタビン塩酸塩(ジェムザール)とグリチルリチン酸アンモニウムの混合物(G−Gエマルジョン)のほか、アドリアマイシン、オキサリプラチン、ブレオマイシンなど他の抗がん剤とG−Gエマルジョンとの混合物などが挙げられる。
本発明は上述のとおり、薬剤を微小ナノ化することにより、従来の薬剤と比較して低用量で所望の効果を奏することを新たに見出したことに端を発するものである。したがって本発明は一側面において、薬剤を微小ナノ化する方法に関する。
上述のとおり本発明の微小ナノ化薬剤は、種々の疾患における微小血管の血流を低減させることができ、その結果として微小血管の密度を低減することができる。したがって本発明の微小ナノ化薬剤は微小血管の血流低減方法、および微小血管の過形成が認められる疾患や症状の処置方法に好適に用いることができる。すなわち本発明は、一側面において、本発明の微小ナノ化薬剤を用いた微小血管の血流低減方法、および微小血管の過形成が認められる疾患や症状の処置方法が包含される。本発明の微小血管血流低減方法により処置可能な疾患や症状としては、固形腫瘍、リウマチ、3か月以上継続する慢性の痛みを主訴とした変形性骨関節症、腱症、筋膜症、脊椎管狭窄症や慢性疼痛症候群とされる各種の痛みなどが挙げられる。
本発明の微小ナノ化薬剤は、腫瘍血管に投与した場合、当該腫瘍血管の血流を低減させ、それにより低酸素状態を改善し、腫瘍血管密度を低下させる腫瘍血管血流低減剤として好適に用いることができる。したがって本発明の微小ナノ化薬剤は、固形腫瘍周辺の微小環境(ニッチ)を改善することにより、固形腫瘍を処置する方法に用いることができる。すなわち本発明は、好ましい一側面において、腫瘍血管の血流を低減させることによる固形腫瘍の処置方法に関する。
(1)ナノ化した抗がん剤の粒度分布の計測
ジェムザール(日本イーライリリー株式会社より入手)200mg、グリチルリチン酸モノアンモニウム(株式会社ミノファーゲン製薬より入手)80mgおよびアブラキサン(大鵬薬品工業株式会社より入手)5mgを混合して、エマルジョンを調製した。また、同様にして、アブラキサンに代えてアドリアマイシン10mg、タキソテール10mg、オキサリプラチン50mg、オキサリプラチン50mg+マイトマイシン4mg、オキサリプラチン50mg+マイトマイシン4mg+アドリアマイシン10mgまたはブレオマイシン15mgを加えたものも調製した。
結果を表1に示す。
ナノ化抗がん剤(上記(1)においてアブラキサン5mgに代えてオキサリプラチン50mg+マイトマイシン4mg+5−フルオロウラシル250mgを加えたカクテルに、アブラキサン25mg、マキサカルシトール10μg、ボルテゾミブ0.35mg、プロプラノロール2mg、ニューロトロピン36NU、エタネルセプト25mg、トロンボモデュリン3200Uを加えて製剤化したもの)を入れた容器の近傍に、約150μSv/hのγ線を放射する閃ウラン鉱を設置し、30分放置した後、粒度分布を計測した。粒度分布の計測は、DelsaMax Pro(Beckman Coulter社製)を用いて行った。結果を図1に示す。約60nm付近に存在していたピークが、放射線照射することにより微小ナノ化され、約4nm付近に遷移した。
ニボルマブ20mg、ペンブロリズマブ10mgおよびベバシズマブ50mgを生理食塩水100mlに分散させ、微小ナノ化免疫チェックポイント治療(CBT)製剤Aを調製した。また、ニボルマブ20mg、ペンブロリズマブ10mgおよびイピリムマブ2mgを生理食塩水100mlに分散させ、微小ナノ化CBT製剤Bを調製した。DelsaMax Pro(Beckman Coulter社製)で表2の条件を用いて粒度分布を測定した。結果を図1に示す。
Claims (10)
- 溶媒中に分散した有効成分の平均粒径が、1〜20nm径である、微小ナノ化薬剤。
- 溶媒中に分散した有効成分の粒度分布が、1〜20nm径である、請求項1に記載の微小ナノ化薬剤。
- 微小ナノ化が、放射線照射によるものである、請求項1または2に記載の微小ナノ化薬剤。
- 有効成分が、抗がん剤である、請求項1〜3のいずれか一項に記載の微小ナノ化薬剤。
- 腫瘍血管または炎症血管血流低減剤である、請求項1〜4のいずれか一項に記載の微小ナノ化薬剤。
- 有効成分が、免疫チェックポイント阻害剤を含む、請求項5に記載の微小ナノ化薬剤。
- 薬剤を微小ナノ化する方法であって、前記薬剤に100〜200μSv/hの放射線を10分〜60分照射することを含む、前記方法。
- 放射線が、閃ウラン鉱石を放射線源とするものである、請求項7に記載の方法。
- 薬剤が、ナノ化した抗がん剤である、請求項7または8に記載の方法。
- ナノ化した抗がん剤が、ゲムシタビン塩酸塩とグリチルリチン酸の混合物を含む、請求項9に記載の方法。
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