JP2014098043A - 絹に基づく薬物送達システム - Google Patents
絹に基づく薬物送達システム Download PDFInfo
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- JP2014098043A JP2014098043A JP2014038624A JP2014038624A JP2014098043A JP 2014098043 A JP2014098043 A JP 2014098043A JP 2014038624 A JP2014038624 A JP 2014038624A JP 2014038624 A JP2014038624 A JP 2014038624A JP 2014098043 A JP2014098043 A JP 2014098043A
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- Prior art keywords
- silk
- pharmaceutical formulation
- product
- silk fibroin
- therapeutic agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
【解決手段】メタノールと接触、剪断(sheer)応力で処理、電場で処理、圧力で処理、又は塩を接触させることによりコンフォメーションを改変した絹フィブロインに基づく徐放性送達システム。
【選択図】図1
Description
本発明は概して、絹に基づく薬物送達システムに関する。特に、本システムは、デバイスから持続性かつ制御可能な速度で治療剤を放出することが可能である。
本発明はNIHによって支持され、かつ米国の政府がそこへ特定の権利を有する。
絹は、この用語が一般的に当技術分野において公知であるように、カイコまたはクモのような生物によって分泌される糸状の繊維産物を意味する。昆虫、すなわち、(i)カイコガ(Bombyx mori)カイコ、および(ii)クモ、典型的にはアメリカジョロウグモ(Nephilia clavipes)の腺から生産される絹は、最も多くの場合研究される材料の形態である;しかしながら、数百から数千もの絹の自然な変種が自然界には存在する。フィブロインは、カイコの2つの絹糸腺によって生産され、かつ分泌される。
絹に基づく薬物送達システムの調製方法が記載される。特に、薬物送達システムは、インビボでの治療剤の制御放出および徐放性を可能にする。一般に、絹フィブロイン溶液は、絹フィブロイン製品を形成するために治療剤と併用される。製品は次いで、そのコンフォメーションを改変するような方法で処理される。コンフォメーションの変化はその結晶化度を増加し、したがって製剤からの治療剤の放出を制御する。
材料および方法:絹の調製
絹繭は4等分に切断され、Na2CO3溶液中で1時間、洗浄された。絹は、温水で2回、冷水で20回、洗浄された。絹は、一晩乾燥され、9M LiBrに溶解されて、10%絹フィブロイン溶液となった。溶液は、27,000 gで30分間遠心分離され、上清は、透析カセット(NWCO 3,500)に移され、2日間透析された。絹フィブロイン濃度は、250 mbarおよび45℃での蒸発により5%(水中m/V)に調整された。結果として生じた絹溶液は、150 μl絹フィブロイン溶液対20 μlのFD4溶液の比率で、デキストランに連結したFITCの溶液(4kDaの分子量;FD4;濃度10 mg/ml、Sigma)と混合されるか、または対照群について、FD-4が後で添加された(表1を参照されたい)。さらなる群として、この溶液の部分は、50Hz、2A、10秒間で超音波処理された(Hielscher, UP200H)。170 μlの溶液(FD-4/絹混合物)が、96ウェルプレートの各ウェルへ添加された。対照について、ウェルは、150 μlの絹フィブロイン溶液で満たされた。水を、室温および250mbarで、一晩蒸発させた。20 μlのFD4溶液が、絹フィブロイン溶液のみを入れたウェルへ添加された(後の固体フィルムのインキュベーションに対する、薬物と溶解された絹フィブロインとの混合の効果を分析するために)。さらなるウェルは、絹とインキュベートされなかった(絹フィブロインフィルムそれ自身の可能な蛍光を分析するために)。フィルムは、水、メタノール20%、またはメタノール90%(V/V)のいずれかで、3時間処理された。溶液は、吸引され、薬物放出研究のために300 μl PBSに置き換えられた。全放出媒体は、24時間、48時間、130時間後、新鮮なPBSで置き換えられ、蛍光は、Lumicounter(Packard, 480V, Gain Level, 1, ex. 485nm, em. 530nm)で読み取られた。
そのままの絹フィブロインフィルムは蛍光を示さない。MeOH処理無しかまたは20%MeOHでの処理で、放出は、高い最初のバーストおよび24時間後のわずかな時間の放出に特徴付けられるが(群I+0およびI+20)、20%MeOHで処理された場合、より多いFD4が放出された。これは、おそらく、MeOHの存在下におけるFD4の溶解性の低下による。90%MeOHで処理された場合、48時間後および130時間後、有意により多いFD4が放出され、変形的変化を誘導することにより絹ポリマーからの徐放性を得る可能性を実証した(I+90)。群I+0およびI+20での観察と同様に、90%へのMeOH濃度の増加は、結果として、全FD4のより高い封入を生じる。調製されたフィルムのFD4との3時間のインキュベーション(I-90)は、I+0およびI+20と同様に、結果として、高い最初のバーストを生じる。実質的な徐放性の欠如は、おそらく、(アモルファス)絹フィブロインフィルムにおける薬物拡散の妨害による。それゆえに、コンフォメーション変化は、フィルムの表面へ吸収されたFD4に実質的には影響を及ぼさない。本質的には、超音波処理でも処理された群について、同じ結果が得られた。しかしながら、超音波による処理は、非超音波処理群と比較して、薬物放出へ影響を及ぼさない。
本発明者らは、絹フィブロインに基づいた薬物送達システムを製剤化する可能性を評価した。実験は、水性フィブロイン-薬物溶液から開始し、続いて、水のゆっくりした蒸発が、結果として、懸濁された薬物分子を有する固体フィブロインフィルムを生じた。フィブロインのコンフォメーション変化は、メタノール処理を通して誘導され、結果として結晶化度の増加を生じた。結晶化度は、薬物の放出を支配した。
蛍光色素に連結したデキストランは、モデル薬物として選択された。それらは、膨潤ゲル上で薬物分子量の影響の直接的な評価を可能にする。本概要で用いられる用語FD4は、4,000 g/モルの分子量を有するデキストラン(D)に連結したFITC(F)を記載する。第1セットの実験は、水および上昇するメタノール濃度で処理されたフィブロインゲルからのFD4放出を比較した(図2)。
絹フィルムのメタノールへの曝露は、FTIR分析により測定されているように(図7A)、結晶化度における増加を示唆した。この発見は、1540cm-1から1535cm-1へのアミドII結合シフト、β結晶構造における増加に典型的な発見に基づいていた。同様に、追加の肩が、1630cm-1(アミドI)および1265cm-1(アミドIII)においてメタノール処理に応答して現れた。
絹フィルムのメタノール処理は、結果として、結晶化度(βシート)の増加、疎水性の増加、水溶性の減少、および表面トポロジーの変化を生じた。
異なる分子量を有する蛍光でマークされたデキストランの放出が、メタノール処理の関数として評価された。
絹フィルムからの薬物放出は、薬物分子量およびメタノールでのフィルム処理の関数であった。生物活性タンパク質の直線的放出を有する徐放性プロフィールが、HRPおよびLysについて観察され、結果として、3日目から8日目までほとんど零次カイネティクスを生じた(水処理されたフィルム)が、一方、実質的により少ないタンパク質薬物活性がメタノール処理において観察された。この活性の減少は、Lysのメタノール感受性と(およびHRPについて、より少ない程度で)相関した。または、結晶性は、薬物負荷フィルムの25℃での飽和Na2SO4溶液の上での24時間の水蒸気処理により誘導され得る(データ示さず)。タンパク質活性(LysまたはHRP)の損失は、予備的知見により確証される仮定から、これらの蒸気条件下では予想されない。
Claims (52)
- 以下の段階を含む、少なくとも1つの治療剤の放出制御のための薬学的製剤を生産する方法:
a.絹フィブロイン溶液と治療剤を接触させる段階;
b. 治療剤を含む絹フィブロイン製品を形成する段階;および
c.結晶化度または液体結晶化度を増大するために、製品のコンフォメーションを改変し、したがって絹フィブロイン製品からの治療剤の放出を制御する段階。 - 治療剤が、タンパク質、ペプチド、核酸、PNA、アプタマー、抗体、および小分子からなる群より選択される、請求項1記載の方法。
- 絹フィブロイン溶液が水性絹フィブロインを含む、請求項1記載の方法。
- 絹フィブロイン溶液が有機溶媒中の絹フィブロインを含む、請求項1記載の方法。
- 有機溶媒がHFIPである、請求項4記載の方法。
- 絹フィブロイン製品が、糸、繊維、フィルム、泡、メッシュ、ヒドロゲル、三次元骨格、錠剤充填材料、錠剤コーティング、およびマイクロスフェアからなる群より選択される、請求項1記載の方法。
- コンフォメーションの改変が、製品とメタノールを接触させることにより誘導される、請求項1記載の方法。
- コンフォメーションの改変が、製品を剪断(sheer)応力で処理することにより誘導される、請求項1記載の方法。
- コンフォメーションの改変が、製品を電場で処理することにより誘導される、請求項1記載の方法。
- コンフォメーションの改変が、製品を圧力で処理することにより誘導される、請求項1記載の方法。
- コンフォメーションの改変が、製品と塩を接触させることにより誘導される、請求項1記載の方法。
- メタノール濃度が少なくとも50%である、請求項7記載の方法。
- メタノール濃度が少なくとも70%である、請求項7記載の方法。
- メタノール濃度が少なくとも90%である、請求項7記載の方法。
- メタノール濃度が少なくとも100%である、請求項7記載の方法。
- 剪断応力が、製品を針に通すことにより加えられる、請求項8記載の方法。
- 薬学的製剤が、少なくとも2つの層を含み、少なくとも1つの層は、少なくとも1つの他の層とは異なる誘導されたコンフォメーション変化を含む、請求項1記載の方法。
- 薬学的製剤が生物分解性である、請求項1記載の方法。
- 薬学的製剤が、製剤を特定の細胞または組織型に特異的に標的化するターゲティング薬剤をさらに含む、請求項1記載の方法。
- ターゲティング薬剤が、糖、ペプチド、および脂肪酸からなる群より選択される、請求項19記載の方法。
- 絹フィブロイン溶液が、溶解したカイコ絹を含む溶液より得られる、請求項1記載の方法。
- カイコ絹がカイコガ(Bombyx mori)より得られる、請求項21記載の方法。
- 絹フィブロイン溶液が、溶解したクモ絹を含む溶液より得られる、請求項1記載の方法。
- クモ絹がアメリカジョロウグモ(Nephila clavipes)より得られる、請求項23記載の方法。
- 絹フィブロイン溶液が、遺伝的に操作された絹を含む溶液より得られる、請求項1記載の方法。
- 遺伝的に操作された絹が治療剤を含む、請求項25記載の方法。
- 請求項1記載の方法によって生産された、少なくとも1つの治療剤の放出制御のための薬学的製剤。
- 製品のコンフォメーションの改変が誘導される、治療剤を伴う絹フィブロイン製品を含む、少なくとも1つの治療剤の放出制御のための薬学的製剤。
- 治療剤が、タンパク質、ペプチド、核酸、PNA、アプタマー、抗体、および小分子からなる群より選択される、請求項28記載の薬学的製剤。
- 治療剤が、10キロダルトンに等しいかまたはそれ以上である、請求項28記載の薬学的製剤。
- 絹フィブロイン製品が、糸、繊維、フィルム、泡、メッシュ、ヒドロゲル、三次元骨格、錠剤充填材料、錠剤コーティング、およびマイクロスフェアからなる群より選択される、請求項28記載の薬学的製剤。
- コンフォメーションの改変が、製品とメタノールを接触させることにより誘導される、請求項28記載の薬学的製剤。
- コンフォメーションの改変が、製品を剪断応力で処理することにより誘導される、請求項28記載の薬学的製剤。
- コンフォメーションの改変が、製品を電場で処理することにより誘導される、請求項28記載の薬学的製剤。
- コンフォメーションの改変が、製品を圧力で処理することにより誘導される、請求項28記載の薬学的製剤。
- コンフォメーションの改変が、製品と塩を接触させることにより誘導される、請求項28記載の薬学的製剤。
- メタノール濃度が少なくとも50%である、請求項32記載の薬学的製剤。
- メタノール濃度が少なくとも70%である、請求項32記載の薬学的製剤。
- メタノール濃度が少なくとも90%である、請求項32記載の薬学的製剤。
- メタノール濃度が少なくとも100%である、請求項32記載の薬学的製剤。
- 剪断応力が、製品を針に通すことにより加えられる、請求項33記載の薬学的製剤。
- 薬学的製剤が、複数の絹フィブロイン製品をさらに含み、少なくとも1つの絹フィブロイン製品は、少なくとも1つの他の絹フィブロイン製品とは異なる誘導されたコンフォメーション変化を含む、請求項28記載の薬学的製剤。
- 生物分解性である、請求項28記載の薬学的製剤。
- デバイスを特定の細胞または組織型に特異的に標的化するターゲティング薬剤をさらに含む、請求項28記載の薬学的製剤。
- ターゲティング薬剤が、糖、ペプチド、および脂肪酸からなる群より選択される、請求項44記載の薬学的製剤。
- 絹フィブロイン製品が、溶解したカイコ絹を含む溶液より得られる、請求項28記載の薬学的製剤。
- カイコ絹がカイコガより得られる、請求項46記載の薬学的製剤。
- 絹フィブロイン製品が、溶解したクモ絹を含む溶液より得られる、請求項28記載の薬学的製剤。
- クモ絹がアメリカジョロウグモより得られる、請求項48記載の薬学的製剤。
- 絹フィブロイン溶液が、遺伝的に操作された絹を含む溶液より得られる、請求項28記載の薬学的製剤。
- 遺伝的に操作された絹が治療剤を含む、請求項50記載の薬学的製剤。
- 治療剤が、10キロダルトンに等しいかまたはそれ以上である、請求項1記載の方法。
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JP2012144553A (ja) | 2012-08-02 |
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