JP6856948B2 - 眼科薬物徐放装置 - Google Patents
眼科薬物徐放装置 Download PDFInfo
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- JP6856948B2 JP6856948B2 JP2018515421A JP2018515421A JP6856948B2 JP 6856948 B2 JP6856948 B2 JP 6856948B2 JP 2018515421 A JP2018515421 A JP 2018515421A JP 2018515421 A JP2018515421 A JP 2018515421A JP 6856948 B2 JP6856948 B2 JP 6856948B2
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
- A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
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- A—HUMAN NECESSITIES
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Description
少なくとも一つの開口部を備える中空の容器内に、薬物封入部及びそれに隣接する眼内滞留性ガス封入部が備えられ、
前記薬物封入部は、前記眼内滞留性ガス封入部が間に介在することによって前記開口部から隔絶されている、眼科薬物徐放装置。
中空の容器内に、薬物封入部及びそれに隣接する眼内滞留性ガス封入部からなるユニットが複数備えられ、
複数の前記ユニットは隔壁によって区画されており、
各ユニットの眼内貯留性ガス封入部の外壁部には、移植後に開口部が形成される領域が設けられている、眼科薬物徐放装置を提供する。
(a)水晶体嚢内に挿入又は毛様溝に固定(図2の1)
(b)眼内へ埋植し、毛様体扁平部に固定(図2の2)
(c)眼内に挿入(図2の3)
(d)眼外に留置(図2の4)
眼内滞留性ガスを利用した薬物徐放システムの有効性を検討するため以下の実験を行った。尚、眼内滞留性ガスによる、封印及び徐放の効果の評価を容易にするため、薬物封入部と眼内滞留性ガス封入部で構成されるユニットの数が1の装置(中空デバイス)を試作し、その特性を調べることにした。
酸素透過性の低いアクリル樹脂のポリメタクリル酸メチル樹脂(Polymethyl methacrylate: PMMA)製の中空デバイスを作製するために、試作品として、2枚のPMMA製眼内レンズの光学部の外縁部分を接着剤で接合した。内腔容積は計算上、11.3μLであった。1箇所、接着剤を用いずに開口部(矢印)とした(図3左、図4)。
薬物放出特性を検討するために、低分子量の水溶性の蛍光色素である10%フルオレセインナトリウム水溶液をPMMA中空デバイス内腔に充填し、風乾させた(図3右)。
固形フルオレセインナトリウム封入PMMA中空デバイスを100% SF6ガス内に留置し、中空部分にガスを充填した(図3右)。家兎にケタラールとセラクタールの筋肉内注射により麻酔後、右眼を0.05%トロピカミド・0.05%フェニレフリン塩酸塩点眼液(ミドリンP(登録商標)、参天製薬)にて散瞳した。術野を消毒、ドレープをかけて、開瞼器にて開瞼し、0.4%オキシブプロカイン塩酸塩点眼液(ベノキシール(登録商標)、参天製薬)にて局所麻酔を行った。角膜穿刺の上、前房内を粘弾性物質で置換し、屈曲させた27G針にて前嚢切開を施行した。その後、2.4 mmの強角膜切開を行い、超音波乳化吸引とinfusion & aspirationにて水晶体を摘出し、再度、前房内を粘弾性物質で満たした後、SF6ガスで内腔を満たした固形フルオレセインナトリウム封入PMMA中空デバイスを嚢内に挿入した。粘弾性物質を除去し、灌流液にて眼圧を調整して、抗生剤眼軟膏を結膜嚢に塗布して手術を終了した。
術後、定期的に散瞳して前眼部写真を撮影し、前房水を吸引採取した。前眼部写真からガスの残留量を計測し、前房水サンプル内のフルオレセインナトリウムの含有量を蛍光強度計にて測定した。2ヶ月の段階でSF6ガスは3割以上残存していた。初期バーストの後、1週目からは安定した薬物徐放を認めた(図5)。このように、2ヶ月以上のガスの残存、安定した薬物徐放効果が確認された。尚、初期バーストは装置(中空デバイス)のデザインによって制御可能である。
1.薬物含有徐放装置の作製と薬物・眼内滞留性ガスの封入
三次元(3D)プリンター(Projet 3510HD plus)で材質がVisiJet(登録商標) Crystal(紫外線硬化型アクリル樹脂)の中空デバイス(図6)を作製した。中空デバイス内に抗体医薬のセツキシマブ溶液を充填した後、凍結乾燥処理に供した。このようにして作製された、多孔質体としてセツキシマブが充填された徐放装置10の特性を調べた。充填する気体は空気の場合と、移植直前に十分量のSF6で内部の気体を空気からSF6に置換したもの(SF6封入)も使用し、空気封入した場合と比較した。
家兎にケタラールとセラクタールの筋肉内注射により麻酔後、右眼を0.05%トロピカミド・0.05%フェニレフリン塩酸塩点眼液(ミドリンP(登録商標)、参天製薬)にて散瞳した。次に、オキシブプロカイン塩酸塩(ベノキシール点眼液、参天製薬)点眼にて表面麻酔の後、結膜を切開して強膜を露出し、強角膜トンネルを作製して、管状部を強角膜トンネルに挿入して、管状部の先端が前房の周縁部に位置するように徐放装置を眼外に埋植した(図7)。
術後、定期的に前房水を吸引採取し、前房水サンプル中のセツキシマブをELISAキットで定量した。その結果、6ヶ月以上の徐放が確認できた(図8)。また、空気よりもSF6で封入した場合の方が長期徐放に適していることが示された。
a 薬物封入部
b 眼内滞留性ガス封入部
c 開口部
d 管状部
w 部分隔壁
1〜4 移植部位
10 徐放装置
11 開口部
12 管状部
13 本体部
Claims (15)
- 少なくとも一つの開口部を備える中空の容器内に、薬物封入部及びそれに隣接する眼内滞留性ガス封入部が備えられ、
前記薬物封入部は、前記眼内滞留性ガス封入部が間に介在することによって前記開口部から隔絶されており、
前記眼内滞留性ガスが、六フッ化硫黄及び/又は八フッ化プロパンからなる、
眼科薬物徐放装置。 - 前記薬物封入部と前記眼内滞留性ガス封入部からなるユニットが複数備えられ、
前記開口部から前記薬物封入部までの距離がユニット間で異なり、
各ユニットの前記眼内滞留性ガス封入部は直接又は他のユニットを介して前記開口部に連通している、請求項1に記載の眼科薬物徐放装置。 - 複数の前記ユニットを区画する、複数の部分隔壁が備えられている、請求項2に記載の眼科薬物徐放装置。
- 複数の前記ユニットが、前記開口部から離れる方向に沿って直列状に設けられている、請求項2に記載の眼科薬物徐放装置。
- 前記容器が管状であり、その長手軸方向に沿って、複数の前記ユニットが直列状に並んでいる、請求項2に記載の眼科薬物徐放装置。
- 前記眼内滞留性ガス封入部の容積がユニット間で異なる、請求項2に記載の眼科薬物徐放装置。
- 中空の容器内に、薬物封入部及びそれに隣接する眼内滞留性ガス封入部からなるユニットが複数備えられ、
複数の前記ユニットは隔壁によって区画されており、
各ユニットの眼内貯留性ガス封入部の外壁部には、移植後に開口部が形成される領域が設けられており、
前記眼内滞留性ガスが、六フッ化硫黄及び/又は八フッ化プロパンからなる、眼科薬物徐放装置。 - 前記開口部がYAGレーザー、色素レーザー又はダイオードレーザーによって形成される、請求項7に記載の眼科薬物徐放装置。
- 前記容器内が、複数の前記薬物封入部と複数の前記眼内滞留性ガス封入部が混在する多孔質状態である、請求項1に記載の眼科薬物徐放装置。
- 前記容器内に注入した薬物溶液を凍結乾燥することにより前記多孔質状態が形成される、請求項9に記載の眼科薬物徐放装置。
- 前記容器が、前記眼内滞留性ガスの透過性が低く、生体適合性の高い材質からなる、請求項1〜10のいずれか一項に記載の薬物徐放装置。
- 前記材質が、アクリル樹脂、ガラス、Ti、Ti合金又はNi合金である、請求項12に記載の眼科薬物徐放装置。
- 前記薬物封入部に封入される薬物が水溶性である、請求項1〜10、12、13のいずれか一項に記載の眼科薬物徐放装置。
- 薬物が液体状又は固体状で前記薬物封入部に封入される、請求項1〜8、12〜14のいずれか一項に記載の眼科薬物徐放装置。
- 以下の(a)〜(d)のいずれかの移植方法によって生体に移植される、請求項1〜10、12〜15のいずれか一項に記載の眼科薬物徐放装置、
(a)水晶体嚢内に挿入又は毛様溝に固定、
(b)眼内へ埋植し、毛様体扁平部に固定、
(c)眼内に挿入、
(d)眼外に留置。
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