JP2021536474A - 徐放性眼科用医薬組成物およびその使用 - Google Patents
徐放性眼科用医薬組成物およびその使用 Download PDFInfo
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Abstract
Description
本出願は2018年9月10日に出願された米国特許出願第62/729,038号の利益を主張し、その開示全体は、参照により本明細書に組み込まれる。
本発明は、少なくとも1つの捕捉剤を使用して、脂質に対する高い薬物比および高い薬物カプセル化効率を有する徐放性眼科用医薬組成物に関する。眼科用医薬組成物の脂質に対する高い薬物比、高いカプセル化効率および徐放性プロファイルは、薬物投与の頻度を減少させ、対象のコンプライアンスを増加させ、治療結果を改善する。
上記および開示全体を通して使用されるように、以下の用語は本明細書中で別段の指示がない限り、単数形「a」、「an」および「the」は文脈が別段の指示がない限り、複数の参照を含む。
用語「リポソーム」、「リポソームの」および関連する用語は、本明細書中で使用される場合、小胞を形成する1つ以上の二重層膜によって外部媒体から隔離された内部水性空間を特徴とする。特定の実施形態において、リポソームの内部水性空間は、トリグリセリドのような中性脂質、非水相(油相)、水−油エマルジョン、または非水相を含む他の混合物など、を実質的に含まない。リポソームの非限定的例には、平均直径が50〜500nm、50〜450nm、50〜400nm、50〜350nm、50〜300nm、50〜250nm、50〜200nm、100〜500nm、100〜450nm、100〜400nm、100〜350nm、100〜300nm、100〜250nmまたは100〜200nmの小さな単層小胞(SUV)、大きな単層小胞(LUV)、および多層小胞(MLV)があり、これらは全て滅菌フィルターを通過することが可能である。
本明細書で使用される「リモートローディング」という用語は、多原子イオン勾配によって、リポソームの二重層膜を横切って外部媒体から内部水性空間に薬物を移動させる手順を含む薬物充填方法である。このような勾配は、少なくとも1つの多原子イオンをリポソームの内部水性空間に捕捉剤としてカプセル化し、カラム分離、透析または遠心分離などの公知の技術によって、リポソームの外部媒体をより低い多原子イオン濃度、例えば、純水、スクロース溶液および生理食塩水で外部媒体に置き換えることによって生成される。多原子イオン勾配が、リポソームの内部水性空間と外部媒体との間に生成され、治療薬をリポソームの内部水性空間に捕捉する。捕捉剤としての例示的な多原子イオンとしては硫酸塩、亜硫酸塩、リン酸塩、リン酸水素塩、モリブデン酸塩、炭酸塩および硝酸塩が挙げられるが、これらに限定されない。例示的な捕捉剤としては、硫酸アンモニウム、リン酸アンモニウム、モリブデン酸アンモニウム、スクロースオクタ硫酸アンモニウム、スクロースオクタ硫酸トリエチルアンモニウム、硫酸デキストラン、またはそれらの組み合わせが挙げられるが、これらに限定されない。
本発明は(a)二重層膜を含む少なくとも1つのリポソーム;(b)捕捉剤;および(c)眼疾患を治療するための治療薬を含み、この際、二重層膜が少なくとも1つの脂質を含み、脂質に対する治療薬のモル比が0.2以上である徐放性眼科用医薬組成物に関する。いくつかの実施形態では、脂質に対する治療薬のモル比が0.2以上約20未満、約15未満、約10未満、約5未満である。
空のリポソームを、脂質フィルム水和−押出法または溶媒注入法によって調製した。脂質膜水和法では、二重層膜成分(例えば、66.7/33.3のモルパーセントのDOPC/コレステロール)を有機溶媒、例えば、クロロホルムおよびジクロロメタンに溶解した。有機溶媒をロータリーエバポレーター中、真空下で除去することにより、薄い脂質フィルムを形成した。乾燥脂質を、捕捉剤、300mM硫酸アンモニウム(AS)中で、転移温度より高い温度で30分間水和して、MLVを形成した。リン酸アンモニウム(AP)またはスクロースオクタ硫酸トリエチルアンモニウム(TEA−SOS)などの他の捕捉剤も使用した。溶媒注入法では、二重層膜成分(66.7/33.3のモルパーセントでのDOPC/コレステロール)を有機溶媒に溶解し、次いで捕捉剤を含有する撹拌水溶液に注入してMLVを形成した。押出後、カプセル化されていない捕捉剤を9.4%のスクロース溶液または0.9%のNaClに対する透析法または透析ろ過法によって除去して、空のリポソームの内側水相と外側水相との間に多原子イオン勾配を作り出した。
10.0mg/mLのスニチニブ(LC Laboratories, USA)、空のリポソーム(実施例1に従って調製した20.0mMの脂質を含む)、および40mMのヒスチジン緩衝液(pH7)を含む反応混合物を、40℃で15分間インキュベートした。Sephadex(登録商標) G−50ファインゲル(GE Healthcare,USA)または透析袋(Spectrum Labs,USA)を用いて、9.4%のスクロース液に対して反応混合物のカプセル化されていないスニチニブを除去し、リポソームのスニチニブ製剤を得た。カプセル化スニチニブ濃度およびリポソームのスニチニブ製剤の脂質濃度を、紫外/可視(UV/Vis)分光光度計を用いて測定し、リポソームのスニチニブ製剤の脂質に対する薬物モル比(D/L)を計算した。
種々の二重層膜および種々の捕捉剤によって構成される空のリポソームを、実施例1に記載の方法に従って調製した。4.0mg/mLのスニチニブまたはリンゴ酸スニチニブの初期充填濃度を、実施例2の手順に従って空のリポソームと混合した。表1は、異なる二重層膜および捕捉剤を有するリポソームの薬物充填プロファイルを示す。
この実施例で使用したチロシンキナーゼ阻害剤には、アキシチニブ(LC Laboratories, USA)およびメシル酸イマチニブ(Sigma−Aldrich, USA)が含まれた。空のリポソームを実施例1に従って調製し、実施例2の充填手順に従って薬物を充填した。アキシチニブ充填研究のために、2mg/mLのアキシチニブを含有する反応混合物、空のリポソーム(300mM ASを含有する)および50mMクエンの酸緩衝液(pH 4.0)を40℃で30分間インキュベートした。イマチニブ充填研究のために、2mg/mLのメシル酸イマチニブを含有する反応混合物、空のリポソーム(300mM ASを含有する)および20mMヒスチジン緩衝液(pH6.5)を25℃で30分間インキュベートした。カプセル化されていない薬物を、Sephadex(登録商標) G−50ファインゲル(GE Healthcare,USA)によって除去して、リポソームの受容体型チロシンキナーゼ阻害剤製剤を得た。リポソームの受容体型チロシンキナーゼ阻害剤製剤のD/L比を、実施例2の工程に従って計算した。表2は、異なる二重層膜および受容体型チロシンキナーゼ阻害剤を有するリポソームの薬物充填プロファイルを示す。
in vitro放出システムを設定するために、(a)50μLの遊離スニチニブ、(b)実施例2に従って調製した50μLのリポソームスニチニブ製剤A(DOPC/コレステロール=66.7/33.3および300mMのASからなる二重層膜)、および(c)実施例3に従って調製した50μLのリポソームのスニチニブ製剤B(HSPC/コレステロール=60/40および75mMのTEA−SOSからなる二重層膜)を別々の透析バッグに入れた。各透析バッグは950μLのウサギ硝子体液(Pel−Freez Biologicals, USA)を含み、次いで、透析バッグの両端を密封した。各透析バッグを、50mLの遠心管中のpH7.4の25mLのPBSに浸漬し、37±1℃の水浴中で24時間インキュベートした。インキュベーション後の指定された時点(1、2、4、6、24、48、122、146および168時間)で、各遠心管内の25mLのPBSからの0.5mLアリコートをサンプリングし、0.5mLの新鮮なPBSを添加して、サンプリングされたアリコートを補充した。各時点でのサンプリングしたアリコートの薬物濃度を高速液体クロマトグラフィー(HPLC)を用いて分析し、リポソーム組成物のin vitro放出プロファイルを作成した。
Claims (18)
- 徐放性眼科用医薬組成物であって、
(a)二重層膜を含む少なくとも1つのリポソームであって、前記二重層膜は、少なくとも1つの脂質を含む、リポソーム;
(b)捕捉剤;および
(c)眼の病気を治療するための治療薬、
を含み、脂質に対する治療薬のモル比は0.2以上である、徐放性眼科用医薬組成物。 - 前記リポソームの平均粒径が約50nm〜500nmである、請求項1に記載の徐放性眼科用医薬組成物。
- 前記二重層膜がコレステロールをさらに含む、請求項1に記載の徐放性眼科用医薬組成物。
- 前記二重層膜中の前記コレステロールのモルパーセンテージが約15〜約55%である、請求項3に記載の徐放性眼科用医薬組成物。
- 前記捕捉剤が、スクロースオクタ硫酸トリエチルアンモニウム、硫酸アンモニウム、リン酸アンモニウムおよびそれらの組み合わせからなる群から選択される、請求項1に記載の徐放性眼科用医薬組成物。
- 前記スクロースオクタ硫酸トリエチルアンモニウムの濃度が約10〜200mMである、請求項5に記載の徐放性眼科用医薬組成物。
- 前記硫酸アンモニウムの濃度が約100〜600mMである、請求項5に記載の徐放性眼科用医薬組成物。
- 前記リン酸アンモニウムの濃度が約100〜600mMである、請求項5に記載の徐放性眼科用医薬組成物。
- 前記眼疾患を治療するための治療薬が受容体型チロシンキナーゼ阻害剤である、請求項1に記載の徐放性眼科用医薬組成物。
- 前記受容体型チロシンキナーゼ阻害剤が、スニチニブ、ニンテダニブ、アキシチニブ、イマチニブ、レンバチニブ、ソラフェニブ、バンデタニブ、レゴラフェニブおよびこれらの組合せから実質的になる群より選択される、請求項9に記載の徐放性眼科薬学的組成物。
- 前記眼疾患を治療するための治療薬が、約50%より高いカプセル化効率でリポソーム中にカプセル化されている、請求項1に記載の徐放性眼科用医薬組成物。
- 前記眼疾患を治療するための方法であって、
徐放性眼科用医薬組成物を、それを必要とする対象に投与することを含み、前記眼科用医薬組成物は:
(a)二重層膜を含む少なくとも1つのリポソームであって、前記二重層膜は、少なくとも1つの脂質を含む、リポソーム;
(b)捕捉剤;および
(c)眼の病気を治療するための治療薬、
を含み、前記脂質に対する治療薬のモル比は、0.2以上である、方法。 - 前記対象の硝子体液中の治療薬の半減期が、前記対象の硝子体液中の遊離治療薬の半減期と比較して、少なくとも2倍、少なくとも5倍、少なくとも7.5倍、少なくとも10倍、または少なくとも20倍延長される、請求項12に記載の方法。
- 前記徐放性眼科用医薬組成物が、少なくとも1週間に1回、少なくとも2週間に1回、少なくとも1ヶ月に1回、または少なくとも3ヶ月に1回投与される、請求項12に記載の方法。
- 前記徐放性眼科用医薬組成物が、注射または局所投与によって投与される、請求項12に記載の方法。
- 前記注射が、硝子体内投与、脈絡膜上投与、網膜下投与または眼周囲投与を含む、請求項15に記載の方法。
- 前記局所投与が点眼剤または軟膏による、請求項15に記載の方法。
- 前記眼疾患が加齢性黄斑変性または糖尿病性眼疾患である、請求項12に記載の方法。
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