JP2018506525A - 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 - Google Patents
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 Download PDFInfo
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Abstract
Description
本願は、Katharina Maisel、Laura Ensign、Justin HanesおよびRichard Coneによって2015年1月27日に出願された、米国特許出願第62/108,354号「Hypotonic Hydrogel Formulations for Enhanced Transport of Active Agents at Mucosal Surfaces」への米国特許法第119条のもとの優先権を主張する。
本発明は、国立衛生研究所によって授与された助成金第5R21AI079740号および助成金第5R21AI094519号のもと、政府支援により行われた。政府は、本発明に一定の権利を有する。
本明細書で一般に使用する場合、「薬学的に許容される」とは、合理的なリスク/ベネフィット比にふさわしい、過剰な毒性、刺激、アレルギー応答または他の問題もしくは合併症のない、ヒトおよび動物の組織と接触した使用に適切な、妥当な医学的判断の範囲内の化合物、材料、組成物および/または剤形を指す。
ヒドロゲル形成性ポリマー、好ましくはポロクサマーの低張製剤が、上皮組織、特に粘膜コーティングを有する上皮組織への、治療剤、診断剤、予防剤または他の薬剤の、粘液を介した増強された送達のために開発された。ポリマーは、それらの通常の臨界ゲル化濃度(CGC)またはそれよりも高い濃度で投与される。そのCGCにおいて膣または結腸直腸中に投与されたポロクサマーゲルは、管腔においてゲルの「プラグ」を形成する。対照的に、CGC未満の低張性に投与されたポロクサマー溶液からの流体は、上皮表面によって吸収され、ポロクサマーを粘液ゲル中に引き込みかつ上皮に対して引き寄せ、それによって、上皮細胞への薬剤の送達を増強および促進する。ポロクサマーが濃縮されると、これは粘液と混合する。内因性ムチン糖ポリマーは、ゲル化に必要なゲル化剤の濃度、および得られたゲル/ムチン混合物の孔構造を含む、低張ゲル化剤のゲル化特性に影響を与える。膣および結腸直腸適用後に、低張ゲル化ビヒクルは、ヒダを含む上皮をコーティングする。例は、CGCにおいて投与されたゲル化剤の場合と同様の、膣管腔の中央部において形成されたゲルのボーラスと比較して、低張ゲル化剤中で投与されたモデル薬物のより長い膣保持を実証している。
低張ゲル形成性組成物は、1つまたは複数のゲル形成性ポリマーを含有する。ゲル形成性ポリマーは、ポリマーの通常の臨界ゲル化濃度(CGC)未満の濃度で、例えば、37℃まで温められた場合にポリマー溶液が試験管中でゲル化する濃度で利用される。
ゲル形成性組成物は、低張担体を含む。低張担体は、典型的には、好ましくは、ヒト対象に投与された場合に刺激の兆候をほとんど〜全く引き起こさない生体適合性担体である。担体は、天然に存在するもの、または合成担体および半合成担体の両方を含む天然に存在しないものであり得る。好ましい担体は、ナトリウムベースである。糖ベースの(例えば、グルコース、マンニトール)溶液および種々の緩衝液(リン酸緩衝液、トリス緩衝液、HEPES)を含む他の溶液もまた使用され得る。
低張ゲル形成性組成物は、治療剤、予防剤、診断剤および/または栄養補助剤(nutraceutical)を含む、送達されるまたはヒドロゲル障壁中に取り込まれる1つまたは複数の薬剤を含有し得る。「生理活性薬剤」および「活性薬剤」は、相互交換可能に使用され、限定なしに、身体において局所的または全身的に作用する生理学的または薬理学的に活性な物質を含む。生物学的に活性な薬剤は、処置に使用される物質(例えば、治療剤)、予防に使用される物質(例えば、予防剤)、診断に使用される物質(例えば、診断剤)、疾患もしくは病気の治癒もしくは緩和に使用される物質、身体の構造もしくは機能に影響を与える物質、またはそれらが所定の生理学的環境中に置かれた後に生物学的に活性になるもしくはより活性になるプロドラッグである。例には、小分子薬物、ペプチド、タンパク質、抗体、糖、多糖、ヌクレオチド、オリゴヌクレオチド、アプタマー、siRNA、核酸、およびそれらの組合せが含まれ得るがこれらに限定されない。薬剤は、小分子(例えば、2000、1500、1000、750または500原子質量単位(amu)未満の分子量)もしくは生体分子、例えば、ペプチド、タンパク質、核酸、多糖、脂質、糖タンパク質、リポタンパク質、またはそれらの組合せであり得る。薬剤には、Martindale: The Complete Drug Reference、第37版(Pharmaceutical Press、London、2011年)に記載される薬剤のうち1つまたは複数が含まれ得る。
製剤は、投与のために液体として調製され得る。典型的には、これらは、適切なアプリケーター中の単一または複数の投薬単位として調製される。粉末単位は、二重チャンバーにされ得、一方は、張度を調整するための賦形剤ありまたはなしで溶媒を含有し、他方は、ヒドロゲル形成性材料を含有し、典型的には、投与すべき1つまたは複数の薬剤もまた含む。複数の投薬単位は典型的に、粉末を充填したバレル(barrel)、およびその上に投薬量増分を有するプランジャーを含む。これらは典型的に、無菌化され、貯蔵および流通のために、密封無菌包装中に包装される。
低張ゲル形成性組成物は、主に、任意の水吸収性表面に適用され得る。一実施形態では、製剤は、治療的、予防的、診断的または栄養学的効果を必要とする対象の上皮表面上の粘膜コーティングに、液体として適用される。ゲル形成性組成物は、低張溶液、または低張溶液を形成する試薬が表面と接触する限り、当業者に公知のいくつもの方法で適用され得る。ゲル形成性組成物を低張製剤として適用することによって、水は、上皮組織中に吸収される。水吸収は、表面におけるゲル形成性ポリマーの濃縮を提供し、表面において均一なゲル形成を生じる。別の実施形態では、ゲルは、それが凝固する際に、または部分的に固体の形態で適用され、それによって、障壁、レザーバーもしくはデポ、またはそれらの組合せとして作用する。ゲル形成性組成物中の薬剤または賦形剤は、ゲル中に封入され得、表面においてまたは表面中に放出され得る。
材料および方法
非付着性ナノ粒子(PSPEG)を使用して、複数の熱感受性PLURONIC(登録商標)ゲルの孔構造を、それらのCGCにおいて評価した。試験した熱感受性PLURONIC(登録商標)ゲルは、15%F68、24%P104、18%F68/15%F127、24%F98および18%F127を含んだ。多粒子追跡(MPT)を使用して、37℃に設定した温度制御チャンバー中でインキュベートしたゲル中のPSPEGの運動を観察した。データを、秒(s)での時間尺度の関数としての、アンサンブル平均した平均二乗変位(<MSD>、μm2)として報告した。
図1に示すように、100nm PSPEGのMSDは、試験した異なるゲルについて有意に変動し、粒子の拡散は、15%F68ゲルにおいて最も速く、18%F127ゲルにおいて最も緩慢であった。図2A〜2Eは、各ゲル中のナノ粒子について計算した平均MSD値の範囲を支持する、種々のゲル中の100nm PSPEGについての典型的な軌跡を示す。PSPEGは、15%F68ゲルにおいて比較的迅速に拡散できたが、ナノ粒子は、18%F127ゲルにおいては完全に不動化された(表1)。このサイズの粒子を不動化するゲルは、ナノサイズの物体(ウイルスを含む)に対する立体障壁特性を有し得るが、ナノ粒子拡散に対して許容的なゲルは、上皮に送達され細胞によって取り込まれる必要があるナノ粒子を投与するのに適切であり得る。
通常の投与の場合のようにそれらの臨界ゲル化濃度(CGC)にあるポロクサマーゲルと、それらのCGC未満の低張溶液中のポロクサマーゲルとの間の差異を調査した。そのCGCにおいて膣または結腸直腸中に投与されたポロクサマーゲルは、管腔においてゲルの「プラグ」を形成する。対照的に、CGC未満で低張性に投与されたポロクサマー溶液からの流体は、上皮表面によって吸収され、ポロクサマーを粘液ゲル中に引き込み、かつ上皮に対して引き寄せる。ポロクサマーが濃縮されると、これは粘液と混合する。内因性ムチン糖ポリマーと混合することは、ゲル化に必要なゲル化剤の濃度、および得られたゲル/ムチン混合物の孔構造を含む、低張ゲル化剤のゲル化特性に影響を与えると仮定された。
非付着性ナノ粒子(PSPEG)を使用して、15%F68、24%P104、18%F68/15%F127、24%F98および18%F127を含む複数の熱感受性ポロクサマーゲルの孔構造を、それらのCGCにおいて評価した。多粒子追跡(MPT)を使用して、37℃に設定した温度制御チャンバー中でインキュベートしたゲル中のPSPEGの運動を観察した。
図3に示すように、18%F127ゲルの構造は、ポリマーをムチンまたは粘液と混合することによって有意に影響を受けた。100nm PSPEGは、ムチン/粘液の存在下でより可動性になり、ゲルの孔サイズにおける増加を示した。対照的に、24%F98ゲルの孔構造は、ムチンによっても粘液によっても有意に影響を受けなかった(図4)が、それは、粒子の可動性が、ムチン/粘液の存在下で変化しなかったからである。100nm PSPEGの軌跡は、18%F127をムチン/粘液と混合した場合にはより拡散性になったが、100nm PSPEGは、ムチン/粘液を有する24%F98中では同様に不動化された。
マウス膣への投与後に、低張PLURONIC(登録商標)ゲル化剤が上皮に対してゲル化し、ウイルスを捕捉する能力を調査した。捕捉は、上皮による流体吸収が、PLURONIC(登録商標)溶液をそれらのCGCに濃縮し、ゲル化を誘導するのに十分なほど顕著であった場合にのみ生じ、結腸直腸中に存在する粘液と混合しても、ゲル中の孔がウイルスよりも大きい直径まで大きくなることはなかった。
蛍光標識されたヒト免疫不全ウイルス(HIV、約120nm)および単純ヘルペスウイルス1型(HSV、約180nm)の両方の捕捉を試験した。
図5に示すように、HIVは、ゲルがない場合、マウス膣粘液中で拡散する。10%および15%F127(CGCは18%である)の投与は、MSDにおける中程度の減少を生じる。図3に示すように、粘液と混合したF127ゲルは、ウイルスサイズの粒子を効率的に捕捉しない。対照的に、18%F98(CGCは24%である)の投与は、膣において引き続いて投与されたHIVの有効な捕捉を生じる。サイズがより大きいHSVについて、15%F127および18%F98は共に、HSVの拡散を低減させるが、18%F98は、HSVを捕捉するのにより有効であった(図6)。
材料および方法
結腸直腸において低張ゲル化剤によってPSPEGナノ粒子またはHIVを捕捉するさらなる試験を実施した。PSPEGナノ粒子を、実施例1に記載したように調製した。HIVを、実施例3に記載したように調製した。
蛍光標識されたHIVは、マウス結腸直腸粘液を通じて迅速に拡散したが、CGC未満のゲル化剤の低張溶液(10%F127)をウイルスの前に導入した場合、ウイルスは、粘液中に付着により捕捉されるナノ粒子、100nm PSナノ粒子と同様に、不動化された(ゲルなしの場合のウイルスよりも>500倍緩慢な動き)(図8)。
膣適用後に、低張ゲル化ビヒクルは、膣ヒダを含む上皮をコーティングし、膣管腔の中央部において形成されたゲルのボーラス(CGCにおいて投与されたゲル化剤の場合と同様)と比較して、より長い膣保持をもたらし得る。
フルオレセインを、脱イオン(DI)水、CGCにある熱ゲル(18%F127)または低張熱ゲル(10%F127)のいずれか中で投与し、保持を24時間の時点で評価した。パーセント蛍光保持(%)を、投与直後の蛍光に基づいて正規化した。データは、各n≧3のマウスを用いたn=3実験の代表であった。
図11に示すように、10%における低張ゲル化剤F127は、そのCGC(18%)において投与したF127中のフルオレセインと比較して、24時間後に、モデル薬物フルオレセインの増加した膣保持を提供した。両方のゲルが、水中での投与よりも、膣においてより長くフルオレセインを保持した。
毒性は、粘膜表面への適用のための製品を設計する場合の重要な懸念である。ある特定の殺菌剤製品からの膣毒性および刺激は、保護を提供するのではなく、性感染症に対する感受性を事実上増加させる(Segarraら、PLoS One、6巻(11号)、e27675頁、2011年)。膣HIV感染に対する感受性を増加させることが公知の製品ノノキシノール−9(N9)は、マウスにおける7日間の毎日の膣投与後に、サイトカインIL−1β(上皮傷害に応答して放出される)の放出を引き起こす(Ensignら、Sci Transl Med、4巻(138号):138ra79頁、2012年)。
20μLの各試験薬剤を、7日間1日1回、プロゲスチン誘導性発情間期(DP)マウスモデルに膣内投与した(L.M. Ensign、B.C. Tang、Y.Y. Wang、T.A. Tse、T. Hoen、R. Cone、J. Hanes、Mucus−penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus、Science Translational Medicine、4巻(2012年)138ra179頁)。8日目に、各マウスを、50μLのPBSで2回洗浄した。各洗浄試料を、さらなる200μLのPBSで希釈し、遠心分離して粘液プラグを除去した。上清(50μL)を使用して、Quantikine ELISAキット(R&D Systems)を使用してIL−1βの濃度を測定した。ELISAを、製造業者の指示に従って実施した。
18%F127の7日間の毎日の適用は、5%N9と類似したIL−1β放出を引き起こしたことが見出され、これは、感染に対する感受性における増加をもたらし得る上皮刺激が存在したことをおそらくは示している。対照的に、HIV臨床試験においてプラセボとしてしばしば使用されるヒドロキシエチルセルロースプラセボゲルなどの製品および1%F127溶液は、処置なし対照からは識別不能なサイトカイン放出を有した(図12)。この結果は、低張1%F127溶液が、CGC超のF127濃度を含有する製品よりも、より安全な膣in situゲル化製品であることを示した。
図12Aに示すように、100nm PSPEGのMSDは、試験した異なるゲルについて有意に変動し、粒子の拡散は、15%F68ゲルにおいて最も速く、18%F127ゲルにおいて最も緩慢であった。図12Bは、各ゲル中のナノ粒子について計算した平均MSD値の範囲を支持する、種々のゲル中の100nm PSPEGについての典型的な軌跡を示す。PSPEGは、15%F68ゲルにおいて比較的迅速に拡散できたが、ナノ粒子は、18%F127ゲルにおいては完全に不動化された(表2)。このサイズの粒子を不動化するゲルは、ナノサイズの物体(ウイルスを含む)に対する立体障壁特性を有し得るが、ナノ粒子拡散に対して許容的なゲルは、上皮に送達され細胞によって取り込まれる必要があるナノ粒子を投与するのに適切であり得る。
Claims (20)
- 等張条件および室温と体温との間の温度(25〜37℃)の下での、ポリマーの臨界ゲル化濃度(CGC)またはそれ超の濃度にあるゲル形成性ポリマー、ならびに
前記ポリマーの低張製剤を形成するための賦形剤
を含む、障壁としての、および/または治療剤、予防剤、診断剤もしくは栄養補助剤の送達における使用のための製剤。 - 前記ゲル形成性ポリマーが、前記ポリマーの最小ゲル化濃度(MGC)超の濃度で存在する、請求項1に記載の製剤。
- 前記ゲル形成性ポリマーが熱感受性ゲル形成性ポリマーである、請求項1から2のいずれか1項に記載の製剤。
- 前記熱感受性ゲル形成性ポリマーが、30℃未満、好ましくは21℃未満の下部臨界溶液温度を有する、請求項3に記載の製剤。
- 前記ポリマーがポロクサマー(polaxmer)である、請求項1から4のいずれか1項に記載の製剤。
- 賦形剤と組み合わされる前記ポリマーが、口腔、咽頭、食道、肺、眼、耳、鼻、頬、舌、膣、子宮頸部、尿生殖器、消化器、肛門直腸および皮膚の表面からなる群から選択される粘膜表面または上皮表面上でデポまたは障壁ゲルを形成する、請求項1から5のいずれか1項に記載の製剤。
- 前記上皮表面が膣表面であり、予防効果が、避妊、性行為感染疾患に対する保護、またはがんもしくは子宮内膜症などの異常な増殖の処置である、請求項6に記載の製剤。
- 低張溶液が、治療剤、予防剤または診断剤をさらに含む、請求項1から7のいずれか1項に記載の製剤。
- 前記ゲルが、少なくとも24時間の期間にわたって、前記上皮表面において前記治療剤、予防剤または診断剤を放出する、請求項8に記載の製剤。
- 前記ゲル形成性ポリマーが、水性賦形剤中、12%超と24%未満との間のF98である、請求項1から9のいずれか1項に記載の製剤。
- 前記ゲル形成性ポリマーが、10%と18%との間のF127である、請求項1から9のいずれか1項に記載の製剤。
- 前記ゲルが、前記上皮表面上で均一な層を形成する、請求項1から11のいずれか1項に記載の製剤。
- 前記ゲルが、前記上皮表面上において刺激の顕著な兆候を引き起こさない、請求項1から12のいずれか1項に記載の製剤。
- 乾燥粉末、ゲルまたは液体の形態の、請求項1から13のいずれかに記載の製剤。
- ポリマー製剤が、単一または複数の投薬単位での投与で提供される、請求項1から14のいずれか1項に記載の製剤。
- 請求項1から15のいずれかに記載の製剤を、それを必要とする部位に投与するステップを含む、粘膜表面または上皮表面に薬剤を投与するための方法。
- 前記製剤が、等張条件および室温と体温との間の温度(25〜37℃)の下でポリマーの臨界ゲル化濃度(CGC)またはそれ超で投与される、請求項16に記載の方法。
- 前記製剤が、等張条件および室温と体温との間の温度(25〜37℃)の下でポリマーの臨界ゲル化濃度(CGC)未満で投与される、請求項16に記載の方法。
- 治療剤、予防剤、診断剤または栄養補助剤の送達のための、請求項16から18のいずれか1項に記載の方法。
- 障壁の形成のための、請求項16から19のいずれか1項に記載の方法。
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CN107635545A (zh) | 2018-01-26 |
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WO2016123125A1 (en) | 2016-08-04 |
US20200138700A1 (en) | 2020-05-07 |
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CA2974715C (en) | 2020-05-05 |
US10485757B2 (en) | 2019-11-26 |
AU2016211696B2 (en) | 2018-05-10 |
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