JP2021505599A - 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性ヒドロゲル製剤 - 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性ヒドロゲル製剤 Download PDFInfo
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Abstract
Description
本出願は、2017年12月8日出願の米国仮出願第62/596,578号および2018年2月7日出願の米国仮出願第62/627,559号(これらは、その全体において本明細書に参考として援用される)に基づく利益および優先権を主張する。
本発明は、米国国立衛生研究所によって与えられた助成金番号RO1DK107806の下で政府から支援を得て行われた。政府は、本発明において一定の権利を有する。
本発明は一般に、増強された薬物送達、特に、粘膜表面での薬物送達のための製剤の分野にある。
粘膜は、身体の種々の腔、例えば、口腔、消化管、子宮、膣、結腸、肛門管、気管、肺、膀胱などを裏打ちする膜である。本明細書で使用される場合、皮膚は、粘膜表面とみなされ得る。その粘膜は、上皮自体、およびまた、その上皮の直ぐ下にある粘膜固有層といわれる支持性のゆるい結合組織からなる。その粘膜を支持するより深部の結合組織は、粘膜下組織といわれる。GI管には、粘膜と粘膜下組織との間の境界に薄い平滑筋層、粘膜筋板がある。
低張性ゲル化ビヒクルは、低い水溶性を有する薬物のための可溶化剤として使用される。このアプローチは、疎水性薬物の溶解度/溶解を改善するためにナノ粒子またはナノ結晶を使用することとは対照的である。薬物の可溶化は、粘膜透過を増強する一方で、低張性ゲル化ビヒクルは、分配および透過をさらに改善する。多くの薬物は、最小限の水溶性しかなく、粘膜表面へのそれらの送達が制限される。
I.定義
本明細書で一般的に使用される場合、「薬学的に受容可能な(pharmaceutically acceptable)」とは、妥当な医学的判断の範囲内で、合理的な利益/リスク比と釣り合う、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なしに、ヒトおよび動物の組織と接触した状態での使用に適したそれらの化合物、物質、組成物、および/または投与量形態に言及する。
ヒドロゲル形成ポリマーの、好ましくはポロキサマーを含む低張性製剤は、上皮組織への、治療薬剤、診断薬剤、予防薬剤または他の薬剤の粘液を介する増強された送達のために開発された。そのポリマーは、それらの通常の臨界ゲル化濃度(CGC)より低い濃度で投与される。そのCGCに等しいかまたはこれを上回る濃度で膣または結腸直腸へと投与されるポロキサマーゲルは、内腔にゲルの「プラグ(plug)」を形成する。対照的に、低張性で投与されたポロキサマー溶液からの流体は、そのポロキサマーがそのCGCを下回る濃度にある場合、粘膜組織へと吸収され、それによって、そのポロキサマーを、粘液ゲルを経て上皮に向かって引っ張り、それによって、身体への薬剤の送達を増強および促進する。水がその組織へと吸収されるにつれて、そのポロキサマーは、上皮組織表面近くで濃縮され、ゲル化し、それによって、薬物分子をその組織表面上の徐放性ゲルの中に捕捉する(むしろ、例えば、旧来の熱ゲル化(thermogelling)法で起こるように内腔の中で主に形成するゲルでは、それによってゲル化ポリマーが、それらのCGCにおいてまたはこれを上回る濃度で投与される)。内因性ムチングリコポリマーは、低張性ゲル化剤のゲル化特性(ゲル化するために必要とされるゲル化剤の濃度およびその得られるゲル/ムチン混合物の孔構造を含む)に影響を及ぼす。膣、結腸直腸、または眼適用の後に、その低張性ゲル化ビヒクルは、上皮(それらのひだまたは瞼の内側を含む)を被覆する。
その低張性ゲル形成組成物は、1種またはこれより多くのゲル形成ポリマーを含む。ゲル形成ポリマーは、そのポリマーの通常の臨界ゲル濃度(CGC)を下回る濃度、例えば、そのポリマー溶液が、37℃に加温した場合に試験管中でゲル化する濃度で利用される。
1)臨界ゲル化濃度(CGC)においてまたは上回る濃度で、および
2)その臨界ゲル化温度でまたはこれを上回る温度で。
そのゲル形成組成物は、低張性キャリアを含む。その低張性キャリアは、代表的には、好ましくは、ヒト被験体に投与される場合に、刺激の徴候をほとんどまたは全く引き起こさない生体適合性キャリアである。そのキャリアは、天然に存在し得るか、または天然に存在しない、合成および半合成両方を含むキャリアであり得る。好ましいキャリアは、水ベースである。他の溶液(糖ベース(例えば、グルコース、マンニトール)溶液を含む)および種々の緩衝液(ホスフェート緩衝液、トリス緩衝液、HEPES)も使用され得る。
その低張性ゲル形成組成物は、送達されるべき1種またはこれより多くの薬剤を含み得る。例としては、治療薬剤、予防薬剤、診断薬剤、および/または機能性栄養因子が挙げられる。生物学的に活性な薬剤は、処置に(例えば、治療薬剤)、防止に(例えば、予防薬剤)、診断に(例えば、診断薬剤)に使用されるか、または疾患もしくは病気の治癒もしくは軽減をもたらすか、身体の構造もしくは機能を質変化させる物質、あるいは生物学的に活性なるかもしくは所定の生理学的環境に置かれた後により活性になるプロドラッグである。これらは、低分子薬物(例えば、2000未満、1500未満、1000未満、750未満、または500未満の原子質量単位(amu)の分子量)、ペプチドもしくはタンパク質、糖もしくはポリサッカリド、ヌクレオチドもしくはオリゴヌクレオチド(例えば、アプタマー、siRNA、およびmiRNA)、脂質、糖タンパク質、リポプロテイン、またはこれらの組み合わせであり得る。
薬物可溶化は、貯蔵の際の増強された物理的安定性、身体への増大した薬物透過、および患者へ投与される場合のより再現性の高い薬物用量を含む潜在的な利点を提供する。
その低張性ゲル形成組成物は、原則として、ゲルを形成するために任意の水吸収表面(皮膚および粘膜組織を含む)に適用され得る。好ましくは、その製剤は、治療効果、予防効果、診断効果、または栄養上の効果の必要な被験体の上皮表面上の粘膜被覆に対して液体として適用され得る。そのゲル形成組成物は、その低張性溶液、または低張性溶液を形成する試薬が、表面と接触する限りにおいて、当業者に公知の任意の数の方法で適用され得る。
眼表面からの迅速な薬物排除は、局所的薬物送達の大きな障害であり、結果として、多くの点眼剤は、1日に数回の適用が処方される。
第1の例は、図3に模式的に示される方法を使用して調製した温度感受性ゲル化ビヒクル中でのシクロスポリンA(ドライアイに使用)(gelCsA)の可溶化を具現化する。シクロスポリンAおよびPluronic F127(10〜18% w/w)を、DMSO中にともに溶解し、塩(塩化ナトリウム,最終重量オスモル濃度 200mOsm)で平衡化した水に対して2日間透析して、DMSOを除去した。その全製剤におけるCsA濃度は、0.05%であった。涙液生成を、眼表面と接触した状態で保持されるSchirmer試験片を使用して測定した。薬物濃度を、LC−MSを使用して測定した。
シクロスポリンが健康な動物の眼において涙液生成を増大させることは、文献中で報告されている。図5Aは、種々の濃度のPluronic F127(10%、12%、15%、および18% w/wを含む)中で製剤化したシクロスポリンAの1回の点眼後に健康なウサギの眼においてシクロスポリンによって誘導された涙液生成の12時間にわたる累積増加を示す。シクロスポリンの低張性12% F127ビヒクルは、涙液生成において最大の増大を提供した。
材料および方法
ブリンゾラミドは、緑内障治療として眼圧(IOP)を下げるために使用される。ブリンゾラミドを、図4の方法を使用して、そのゲル化ビヒクル中に製剤化した(gelBRZ)。Pluronic F127は、10〜18%の範囲であり、塩を添加して、必要とされる場合、等張性(300mOsm/kg)になるまで重量オスモル濃度を調節した。正常血圧のウサギにおけるIOPに対するそのビヒクル自体(gelBRZビヒクル)およびブリンゾラミド点眼剤の効果を、10mg/mLにおいて50μLの1回の点眼剤を投与した後に試験した。
図6Aは、従来の(18% F127)ゲル化物質、または低張性もしくは等張性のいずれかであるように製剤化した低濃度(12% F127)のいずれかとして製剤化したgelBRZを示すグラフである。図6Bは、そのgelBRZビヒクルが、正常血圧のウサギにおける処置した眼または対側の眼のIOPに対して効果を有しなかったことを示す。これはさらに、その低張性gelBRZ製剤と、市販の点眼剤AZOPT(登録商標)(1% ブリンゾラミドの臨床用ブリンゾラミド眼用懸濁物)とを比較する。1% ブリンゾラミドの1用量は、AZOPT(登録商標)と比較して、gelBRZ(12%, 低張性)として送達した場合に、処置の8時間後までにわたって、IOP降下に対してより顕著な効果を有した。さらに、低張性gelBRZ(35mOsm)は、4時間までの早い時点で、等張性gelBRZ(300mOsm)より大きくIOPを下げた。
材料および方法
ブリモニジン酒石酸塩は、ゲル化ビヒクルへと直接溶解され得る水溶性薬物である(gelBT)。正常血圧のウサギにおいてIOPの低減によって測定される場合、低張性ゲル化ビヒクル中でブリモニジン酒石酸塩を眼に投与するための最適なF127濃度があるか否かを最初に試験した。次いで、IOP低減を、正常血圧のウサギにおいて低張性(塩なし)および等張性(塩で300mOsm/kgへと調節)で12〜18%の範囲に及ぶF127濃度に関して比較した。薬物濃度を、LC−MSによって測定した。
結果
材料および方法
ポリマー物質を、そのゲル化ビヒクル、ヒドロキシプロピルメチルセルロース(HPMC)へと、まばたき(眼投与)または潤滑(直腸投与)の場合に有利であり得るF127溶液(剪断減粘特性のため)へと組み込んだ。そのポリマー物質はまた、静止時(剪断なしの下)でのゲルの粘度を増大させ得、粘膜表面での保持時間を改善し得る。
図8Aに湿されるように、F127への0.5% HPMCの添加は、低剪断/剪断なしの下での粘度を増大させ、これは、標準的な潤滑点眼剤(GENTEAL(登録商標))より既に数千倍高い。図8Bは、剪断減粘特性(剪断下に配置された場合の粘度の減少)が、標準的な潤滑点眼剤(GENTEAL(登録商標))と比較して、HPMCを含むF127溶液に関して類似であることを示す。従って、F127溶液へのヒドロキシプロピルメチルセルロース(HPMC)の添加は、高剪断(まばたきする際の剪断速度に類似)下での標準的な潤滑点眼剤(例えば、GENTEAL(登録商標))において観察される低粘度を維持しながら、低剪断/剪断なしの下での粘度を増大させる。
ニュージーランドホワイトウサギに、潜在的な眼刺激を評価するために、5週間にわたって1日に2回、1回の点眼あたり50μLを局所投与した。試験薬剤は、添加した塩なしから300mOsm/kgまでの範囲に及ぶ最終重量オスモル濃度を生成するために、塩化ナトリウムを含有する12% F127溶液を含んだ。その陰性コントロールは、平衡化塩類溶液(BSS)であり、処置を受けない動物の群があった。非処置動物と比較して、いかなる製剤に関しても角膜染色(リサミングリーン(lisamine green) 1%)またはまばたき速度(3分間でのまばたきの回数)における差異はなかった。
C57/B6マウスを、3箇所でのブルッフ膜のレーザー誘導性破断後のマウスで脈絡膜血管新生(CNV)を防止するにあたって、スニチニブリンゴ酸塩(4mg/mLで5μL)およびアクリフラビン(5mg/mLで5μL)の局所送達を試験するために使用した。レーザー後、12% F127または水性ビヒクルコントロール(生理食塩水または水)のいずれかの中に溶解した両方の薬物を、7日間にわたって毎日投与した。12% F127を含む製剤のみが、脈絡膜での血管新生を抑制することにおいて有効であった。
ラットに、12% F127中のスニチニブリンゴ酸塩(4mg/mLで5μL)を、5日間一側に毎日局所投与した。次いで、その視神経頭を露出し、一側を押しつぶし、その対側の眼を比較のためにコントロールとして使用した。その神経を押しつぶして14日後に(さらなる局所投与なしで)、網膜神経節細胞(RGC)によって発現される遺伝子に関するqPCRのためにその組織を単離した。この投与スキームは、有色素のラット(Brown Norway)および有色素でないラット(Wistar)におけるRGCの防御をもたらした。これは、眼の中のメラニンへの結合が、長期の治療効果をもたらしたことを示唆する。
有色素のラット(Brown Norway)に、12% F127中のまたは生理食塩水中のスニチニブリンゴ酸塩を、1週間に1回、一側に局所投与した(4mg/mLで5μL)。視神経頭を露出し、8日目に一側を押しつぶし、その対側の眼を比較のためにコントロールとして使用した。その神経を押しつぶして14日後(22日目)に、網膜神経節細胞(RGC)によって発現される遺伝子に関するqPCRのためにその組織を単離した。RGCの防御は、スニチニブリンゴ酸塩を12% F127中で投与した場合に観察されたに過ぎず、スニチニブリンゴ酸塩を生理食塩水中で投与した場合には観察されなかった。
材料および方法
スニチニブリンゴ酸塩を、12% F127中に4mg/mlの濃度で溶解し、有色素のウサギ(ダッチ種)および有色素のブタ(若い家畜のブタ)に、それぞれ、合計14日間または5日間にわたって、1日に1回局所投与した。ウサギおよびブタノ両方での投与を麻酔なしで行い、それぞれ、50μLまたは50〜100μLの点眼剤を投与した。しかし、ブタにおける投与は、餌で注意を逸らしている間に行った。ウサギに関しては最後の投与の6時間後に、およびブタに関しては最後の投与の1時間後に組織を集めた。その薬物濃度を、LC−MSによって測定した。
スニチニブリンゴ酸塩を、(図9A)ダッチ種のウサギに14日間毎日、および(図9B)家畜のブタに5日間毎日、その低張性ゲル化ビヒクル中で局所投与した。組織を単離し、スニチニブおよび主な代謝産物(N−デスエチルスニチニブ)レベルを、種々の眼組織および流体において定量した。薬物の治療上関連するレベルを、前眼部および後眼部において見出した。
Claims (20)
- 治療薬剤、予防薬剤、診断薬剤または機能性栄養因子の送達のための製剤であって、前記製剤は、
治療薬剤、予防薬剤、機能性栄養因子または診断薬剤、
粘膜組織または皮膚への適用のためのゲル形成ポリマーであって、前記ゲル形成ポリマーが等張性条件および室温と体温との間の(約25〜約37℃)の温度の下で、前記ポリマーの臨界ゲル濃度(CGC)未満の濃度にあるように、製剤化されたゲル形成ポリマー、ならびに
必要性のある個体への送達のために適した前記ポリマーの薬学的に受容可能な低張性製剤を形成するための賦形剤、
を含む製剤。 - 乾燥形態または液体形態にある、請求項1に記載の製剤。
- 前記ゲル形成ポリマーは、温度感受性ゲル形成ポリマーである、請求項1〜2のいずれか1項に記載の製剤。
- 前記温度感受性ゲル形成ポリマーは、30℃未満、好ましくは21℃未満の下限臨界溶液温度を有する、請求項3に記載の製剤。
- 前記ポリマーはポロキサマーである、請求項1〜4のいずれか1項に記載の製剤。
- 賦形剤との組み合わせでの前記ポリマーは、口腔、咽頭、食道、肺、眼、耳、鼻、口内、舌、膣、子宮頚、尿生殖器、消化管、肛門直腸、および皮膚の表面からなる群より選択される粘膜表面または上皮表面上にゲルを形成する、請求項1〜5のいずれか1項に記載の製剤。
- 前記上皮表面は、眼の上または眼の中にある、請求項6に記載の製剤。
- 前記薬剤は水溶性である、請求項1〜7のいずれか1項に記載の製剤。
- 前記薬剤は、水溶性が不十分である、請求項1〜7のいずれか1項に記載の製剤。
- 前記製剤は、前記治療薬剤、予防薬剤、または診断薬剤を、少なくとも12時間の期間にわたって前記上皮表面において放出する、請求項1〜9のいずれか1項に記載の製剤。
- 前記製剤は、前記治療薬剤、予防薬剤、または診断薬剤を、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放出する、請求項10に記載の製剤。
- 前記ゲル形成ポリマーは、水性賦形剤中に12%超〜24%未満の間のF98である、請求項1〜11のいずれか1項に記載の製剤。
- 前記ゲル形成ポリマーは、10〜18%の間のF127である、請求項1〜11のいずれか1項に記載の製剤。
- 前記ゲル形成ポリマーは、前記上皮表面上への投与のときに、均一に厚い層を形成する、請求項1〜13のいずれか1項に記載の製剤。
- 乾燥粉末、ゲル、または液体の形態における投与のための、請求項1〜14のいずれか1項に記載の製剤。
- 前記製剤は、投与に関して単一投与量単位または複数投与量単位で提供される、請求項15に記載の製剤。
- 前記薬剤は、タンパク質もしくはペプチド、低分子、糖もしくはポリサッカリド、脂質、糖脂質、糖タンパク質、核酸、そのオリゴマーもしくはポリマー、または低分子である、請求項1〜16のいずれか1項に記載の製剤。
- 前記薬剤は、ステロイド、緑内障薬剤、チロシンキナーゼインヒビター、免疫抑制剤、抗線維化薬剤、抗感染剤、ホルモンおよび化学療法剤からなる群より選択される、請求項1〜15のいずれか1項に記載の製剤。
- 粘膜表面または上皮表面に薬剤を投与するための方法であって、前記方法は、請求項1〜18のいずれかに記載の製剤を必要性のある部位に投与する工程を包含する方法。
- 前記表面は、眼上または眼の中にある、請求項19に記載の方法。
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