JP7079250B2 - リポソーム構築物を用いた黄斑細胞及び網膜細胞への尿素の送達 - Google Patents
リポソーム構築物を用いた黄斑細胞及び網膜細胞への尿素の送達 Download PDFInfo
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- JP7079250B2 JP7079250B2 JP2019530372A JP2019530372A JP7079250B2 JP 7079250 B2 JP7079250 B2 JP 7079250B2 JP 2019530372 A JP2019530372 A JP 2019530372A JP 2019530372 A JP2019530372 A JP 2019530372A JP 7079250 B2 JP7079250 B2 JP 7079250B2
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Description
本出願は、すべての目的のために、その内容全体が参照によって本願に組み込まれる、2016年8月18日に出願された米国仮特許出願番号62/376,862号の利点を主張するものである。
本明細書及び添付の特許請求の範囲で使用されているように、単数形「a」、「an」、及び「the」は、文脈が明らかにそうでないことを示さない限り、複数の指示対象を含む。用語「a」(または「an」)ならびに用語「1つ以上」及び「少なくとも1つ」は、互換的に使用され得る。
カプセル化%=100×[(カプセル化した活性剤の量)/(充填溶液中の活性剤の初期量)]
カプセル化効率は、重量、体積、または濃度に基づいて計算され得る。
本発明の実施形態のリポソーム構築物のサブユニットであるリポソームは、天然起源または合成起源の二重層によって囲まれたコアから構成されるSUVである。リポソームは、1つまたは複数のリン脂質の混合物を含み得る。リン脂質は、異なる鎖長、異なる電荷を有し得、そして飽和または不飽和であり得る。コレステロールの組み込みは、膜の剛性を向上させることによって、リポソームの安定性を高める。いくつかの実施形態において、リポソームは、コレステロール及び脂質が結合した親水性ポリマーを主成分として利用し得る。成分の選択及びそれらの相対比は、リポソームの構造安定性、それらの放出時間、カプセル化したカーゴ(すなわち尿素)の量、及びカプセル化に使用される方法に影響を与える。
SUVは、溶媒蒸発、逆相蒸発、脱水-再水和、界面活性剤透析、薄膜水和(Bangham法)、界面活性剤除去、溶媒(例えば、エーテル/エタノール)注入、エマルジョン法、濃密ガス法、超臨界流法などの、当該技術分野で公知の方法によって製造され得る。例えば、脂質混合物を有機溶媒に溶解し、次いで、乾燥して脂質フィルムを形成され得る。次いで、乾燥した脂質フィルムを、例えば、孔径を減少させるオリフィスを通して、それらを押し出すことによって水和及びサイズ調整することができ、その結果、ユニラメラリポソームからなり、標準化された均一直径を有するリポソーム構築物が得られる。
過去においては、活性剤が送達直後に硝子体内に分散し、十分な濃度が眼の裏側に到達しないので、活性剤を網膜の表面に投与することは非常に困難であった。尿素などの水溶性薬物は、この点に関して特別な課題を提起している。本発明の医薬組成物は、それらの物理的特性のために、この問題を解決する。特に、SUVは、それらが無菌濾過されることができるほど十分小さいが、それでもなお、治療有効量の尿素を捕捉することができる。それらは、注射時に十分に凝集し、投与されるとそれらは硝子体液全体に分散するのではなく、リポソーム構築物中に一緒にとどまり、それらは硝子体よりも密になり、網膜表面上に定着して覆うことができる。「空の」SUV(すなわち、カプセル化した尿素を含まない)は、硝子体内への注射後に凝集するが、それらは、硝子体液を穏やかに撹拌しながら容易に分散する。しかしながら、カプセル化した尿素を有する同じSUVは、硝子体内への注射後に凝集し、そして硝子体液の穏やかな撹拌下では分散しないリポソーム構築物を形成する。本発明の複数の異なる尿素を含有するリポソーム構築物は、硝子体液の穏やかな撹拌に耐える集塊を示し、これにより、硝子体全体に分散した位置からではなく、硝子体内で空間的に集塊から放出される。したがって、本発明の医薬組成物は、硝子体網膜界面に活性剤を効果的に送達するための新規製剤を提供する。
また、本開示の範囲内には、本明細書に提供されるリポソーム構築物及び/または組成物、ならびに使用説明書を含むキットがある。前記キットは、少なくとも1つの追加の試薬、または1つ以上の追加のリポソーム構築物をさらに含み得る。キットは通常、キットの内容物の意図された使用を示すラベルを含む。用語「ラベル」は、キットの上にまたはキットと共に供給されるか、そうでなければキットに付随する任意の筆記または記録された資料を含む。
尿素は、中等度から重度の糖尿病性網膜症の患者において、後部硝子体剥離(PVD)を誘発することが示されているが、臨床用途は、長期間にわたって、眼の後ろに十分な薬物を送達することができないことによって妨げられてきた。
粒径解析
Microtrac(Montgomeryville,PA)150装置、及びMicrotrac Particle Size Analyzerソフトウェア,バージョン10.1.3を使用して、粒径解析を実施した。尿素を含まない製剤2の粒径解析は、90%のリポソーム構築物が250nm未満であり、また、10%が100nm未満であることを示した。したがって、尿素を含まない製剤2のリポソーム構築物の粒径は、約100nmから約250nmの範囲であった。カプセル化した尿素を用いた製剤2の粒径解析は、リポソーム構築物の90%が300nm未満でありそして10%が90nm未満であることを示した。したがって、カプセル化した尿素を有する製剤2のリポソーム構築物の粒径は、約90nmから約300nmの範囲であった。
カプセル化効率、及びリポソーム構築物の安定性について、4℃で96時間、最適なバッファー組成物を評価した。カプセル化した尿素を有する製剤物2のリポソーム構築物を、表5に示される6つの異なるバッファー組成物を用いて作製した。
製剤2のリポソーム構築物を使用して、より高い体積対体積濃度のリポソーム構築物を用いて、リポソーム構築物の挙動を評価した。シリンジを通して、リポソーム構築物を吸引することの効果を試験するために、ペレットを上記のように調製し、2つのペレットを合わせ、全体の体積100μLの0.5×PBSに再懸濁し、27ゲージまたは30ゲージの針を通して吸引した。カプセル化した尿素及び遊離尿素の量を上記のように決定し、また、表7に示す。
上記のように調製及び解析した、製剤2のカプセル化した尿素のリポソーム構築物について、4℃、室温、及び37℃で、0.5×PBSにおいて温度を制御した安定性試験を7日間行った。結果を表8及び図3A~3Cに示し、そこでは、100μLの試料における全体のカプセル化した尿素(mg)を測定した。
1,2-ジオレオイル-sn-グリセロ-3-ホスホコリン(DOPC)及びコレステロールを使用して、尿素の存在下でリポソームを形成して、カプセル化した尿素のリポソーム構築物を作製した。使用した材料を表9にまとめる。
本実施例は、ニュージーランドホワイトラビットの眼内への硝子体内(IVT)注射後の、カプセル化した尿素の耐容性及び毒性、ならびにPVDを誘発するためのその有効性、ならびに硝子体内へ注射されたカプセル化した尿素のリポソーム構築物の沈降パターンの評価を提供する。
6匹の雌ニュージーランドホワイトラビット(サブグループ当たり2匹)に、カプセル化した尿素のリポソーム構築物(58mol%のDOPC、42mol%のコレステロール)を硝子体内(IVT)に両眼へ単回投与(OU)で投与した。塩酸ケタミン(30mg/kg)、キシラジン(5mg/kg)、及びアセプロマジン(3mg/kg)の筋肉内(IM)注射、続いて、酸素(1L/分)の吸入(1~2.5%)によるイソフルランで、動物を麻酔した。外科的処置の前に、1~2滴の局所用塩酸プロパラカイン麻酔薬(0.5%)を前記動物の眼に適用した。片眼を上にし、もう片方の眼を下に向けて、投与後3時間頭を安定させて動物を麻酔した。
2匹のさらなる動物(1サブグループにつき1匹)に、単回または2回投与量の遊離尿素の溶液IVTを右眼に(OD)、そして平衡塩溶液(BSS)を左眼に(OS)投与した。動物を、塩酸ケタミン(30mg/kg)及びキシラジン(5mg/kg)のIM注射で麻酔した。外科的処置の前に、1~2滴の局所用塩酸プロパラカイン麻酔薬(0.5%)を前記動物の眼に適用した。
カプセル化した尿素のリポソームまたは遊離尿素溶液のいずれかを投与された動物では、体重に対する有害事象、及び一般的な健康に対する重度の有害事象は観察されなかった。両群の動物において、眼内刺激及び腫脹がIVT注射直後に観察され、それは、投与日を過ぎて生き残った動物において数日後に消散した。
サブグループ2a及びサブグループ2bの両方の動物は、0日目から3日目までの間に、ODの硝子体に濁りを示した。いずれのサブグループのOSの硝子体においても、そのような濁りは観察されなかった。前記濁りは、ビヒクル処置をした眼には認められなかったので、前記濁りは、おそらく尿素による硝子体のタンパク質変化の影響であった。さらに、尿素で処置した眼の硝子体は、投与後3日後に透明になり始めたので、前記濁りは、おそらく感染によるものではなかった。
OCT画像処理は、3日目に、サブグループ2aの動物の右眼(OD)にPVDを示した。サブグループ2bの動物において、4日目(AM及びPM)、7日目、及び14日目に、PVDが観察された。他の画像処理時点で、これらの動物のODにPVDは認められなかった。しかしながら、PVDは不可逆的であるので、臨床的な眼科検査の間に、両動物のPVDがODに認められた場合、最も可能性が高いのは、これらの日におけるOCT画像処理は、PVDを示す領域をとらえていなかっことであり、2日目以降のすべての時点で、PVDが実際に両動物のODに存在したと仮定され得る。いずれの動物も、任意の時点において、左眼(OS)にPVDを示さなかった。
本実施例は、ニュージーランドホワイトラビット(非GLP)の眼へのIVT注射後、(実施例5と比較して)減少した濃度の遊離尿素の耐容性の評価、及び様々な用量強度の各々の注射後に、PVDを誘発するのにかかる時間の決定を提供する。
一般的な健康の観察を0日目から始めて毎日行い、体重を投与前及び終了前に記録した。すべての動物は、試験の過程にわたって、軽度の体重減少を経験した。体重減少は、度重なる麻酔処置、度重なる対処及び拘束からのストレス、または試験品に関連する不快感、またはこれらの要因の組み合わせから生じた可能性がある。一般的な動物の健康に対する薬物及び/または試験処置のその他の有害事象は、観察されなかった。
眼底の画像を、-3日目または0日目(薬物またはBSS投与前の基準)、1日目、4日目、7日目または8日目、14日目、21日目、及び35日目に撮影した。4日目の画像を、就業日の初めに撮影した。21日目の画像は、グループ1、グループ2、及びグループ5のみを撮影した。画像処理のために、動物に麻酔をかけなかった。
-3日目または0日目(試験/コントロールの製品の投与前の基準)、1日目、4日目、7日目または8日目、14日目、21日目、及び35日目にOCTを実施した。4日目の画像は、就業日の初めに撮影した。21日目の画像は、グループ1、グループ2、及びグループ5のみを撮影した。上記のように、動物に麻酔した。ウサギ1匹当たり/1日当たりの画像を合計8枚取得した。
Bスキャンの超音波画像を、-3日目または0日目(試験/コントロール製品の投与前の基準)、及び35日目に撮影した。グループ4の動物の35日目のBスキャンの画像は、右眼(OD)にPVDの証拠を示したが、左目(OS)には認められなかった。他の動物のBスキャンの画像では、PVDは、検出されなかった。代表的な画像を図11A~11Bに示す。
回収された組織の病理組織学的な解析は、眼に対する尿素またはBSSの有害事象の証拠を全く見い出さなかった。網膜からの硝子体液の分離は、組織の取り扱い及び処理手順の間の機械的な破壊のために、容易に起こり得るので、PVDは、組織病理学的な解析の間に最終的に評価することが困難であった。
本実施例は、用量濃度の広範囲の硝子体内への注射直後に、後眼部空間におけるリポソーム構築物の物理的な位置の観察を、また、治療後の薬物の局所効果の評価を提供する。
Claims (14)
- リポソーム構築物及び薬学的に許容される担体を含み、
前記リポソーム構築物は、小単層小胞(SUV)の凝集体を含み、
前記SUVが、本質的に58mol%のDOPC及び42mol%のコレステロールからなるラメラを含み、
前記SUVは、前記SUV内にカプセル化した尿素を含み、
前記SUVは、約1.05より大きい比重、約220nmより小さいz平均直径、及び
約0.150より小さい多分散性指数値(PdI)を有する、
対象の眼の硝子体網膜界面に送達するための医薬組成物。 - 前記SUVが、約200nm未満のz平均直径を有する、請求項1に記載の医薬組成物
。 - 前記SUVが、表面修飾基を含む、請求項1または2に記載の医薬組成物。
- 前記表面修飾基が、ポリエチレングリコール(PEG)である、請求項3に記載の医薬組成物。
- 前記SUVが、少なくとも20%のカプセル化効率を有する、請求項1~4のいずれか1項に記載の医薬組成物。
- 前記SUVの充填されたペレットが、充填されたペレット1mL当たり少なくとも約1
00mgのカプセル化した尿素を含む、請求項1~5のいずれか1項に記載の医薬組成物。 - 前記薬学的に許容される担体が、尿素を含む、請求項1~6のいずれか1項に記載の医薬組成物。
- 前記薬学的に許容される担体が、450mg/mLの尿素を含む、請求項7に記載の医薬組成物。
- 40%の前記SUV及び60%の前記薬学的に許容される担体を含む(容量比)、請求項1~8のいずれか1項に記載の医薬組成物。
- エマルジョンまたは懸濁液の形態である、請求項1~9のいずれか1項に記載の医薬組成物。
- 対象の前記眼において、後部硝子体剥離(PVD)を誘発するための請求項1~10のいずれか1項に記載の医薬組成物。
- 糖尿病性網膜症または硝子体黄斑癒着(VMA)を治療するための請求項1~10のいずれか1項に記載の医薬組成物。
- 硝子体内への注射により投与される、請求項11または12に記載の医薬組成物。
- 前記対象が、前記医薬組成物の投与中に仰向けに位置する、請求項11~13のいずれか一項に記載の医薬組成物。
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