JP2006522149A - ドパミンアゴニストの徐放のための移植可能なポリマーデバイス - Google Patents
ドパミンアゴニストの徐放のための移植可能なポリマーデバイス Download PDFInfo
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- JP2006522149A JP2006522149A JP2006509657A JP2006509657A JP2006522149A JP 2006522149 A JP2006522149 A JP 2006522149A JP 2006509657 A JP2006509657 A JP 2006509657A JP 2006509657 A JP2006509657 A JP 2006509657A JP 2006522149 A JP2006522149 A JP 2006522149A
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- Prior art keywords
- implantable device
- dopamine agonist
- implantable
- administration
- dopamine
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Abstract
Description
この出願は、2003年3月31日に出願された米国仮出願第60/459,315号の利益を主張し、その仮出願は、その全体が本明細書中で参考として援用される。
本発明は、パーキンソン病およびドパミンアゴニストの投与が治療的に有益である他の状態の処置のためのドパミンアゴニストの皮下移植およびドパミンアゴニストの徐放のための非生物腐食性ポリマーデバイスを提供する。
進行性神経変性障害であるパーキンソン病は、ドパミンを合成し放出するニューロンの喪失により特徴付けられる。ドパミン作用性ニューロンのこの喪失は、硬直、安静時振せん(振せん)、運動の欠乏(運動不能)、運動の緩慢さ(運動緩徐)ならびに歩行および姿勢における変化のような症状に現れる。パーキンソン病の処置は、一般的には、ドパミンを分泌するニューロンの喪失に起因するドパミン作用性ニューロン伝達の欠如を補償し得る物質の治療投与に基づく。古典的な処置レジメンは、レボドパの慢性経口投与を含み、レボドパは、脳で脱カルボキシル化されドパミンを生成する。多くの場合、レボドパによる処置の数年後、異常性が現れ、この異常性としては、臨床的改善の「オン」相の間の不随意の動きおよび「オフ」相の間のパーキンソン病型症状の再出現が挙げられる。
本発明は、1つ以上のドパミンアゴニストの投与を必要とする哺乳動物への、その投与のための組成物(すなわち、移植可能なポリマーデバイス)、方法およびキットを提供する。
本発明は、生体適合性の非腐食性ポリマーデバイスを提供し、このデバイスは、処置を必要とする個体において皮下に移植された場合に、長期間にわたる、1つ以上のドパミンアゴニストの制御された徐放を可能にする。
本発明は、パーキンソン病またはドパミンアゴニストの投与が治療的に有益である他の状態の処置のための移植可能なデバイスを含む。本発明のデバイスば、ポリマーの非腐食性マトリクス中に封入された1つ以上のドパミンアゴニストを含む。
本発明は、特発性パーキンソン病または毒素誘起振せん麻痺もしくは疾患誘起振せん麻痺、あるいはドパミンアゴニストの投与が治療的に有益である任意の他の状態(例えば、勃起機能不全、不穏下肢症候群または過プロラクチン血症)の処置のための方法を提供する。「振せん麻痺」は、本明細書で使用される場合、中枢神経系への損傷から生じ、個体にパーキンソン病の症状に類似の症状を示させる状態を含む。振せん麻痺は、例えば、毒素曝露(例えば、一酸化炭素またはマンガン毒、またはMPTP投与)から生じ得るか、または脳炎のような疾患状態から生じ得る。
本発明はまた、パーキンソン病または、上記のように、ドパミンアゴニストの投与が治療的に有益である別の状態の処置における使用のためのキットを提供する。このキットは、本明細書中に記載される型の、長期の治療レベルのドパミンアゴニストを送達し得る少なくとも1つの移植可能な非腐食性デバイスを、使用者および/または衛生管理提供者に、ドパミンアゴニストの投与が治療的に有益である状態(例えば、パーキンソン病、毒素誘起振せん麻痺もしくは疾患誘起振せん麻痺、勃起機能不全、不穏下肢症候群または過プロラクチン血症)の処置のためのシステムの皮下移植および使用に関する情報を提供する指示書とともに、適切な容器内に含む。キットはまた、本発明の移植可能なデバイスの性能を論じる文献を含む。
(材料)
以下の材料を使用した:
・塩酸アポモルヒネ、Hawkins, Inc.により供給
・トリアムシノロンアセトニド、Spectrumにより供給
・グルタチオン、Aldrich,St.Louis,MOにより供給
・エチレン酢酸ビニルコポリマー、33%酢酸ビニル、Southwest Research Institute,San Antonio,TXにより供給
・メタノール、ChromAR HPLC等級、Mallinckrodt,St.Louis,MOにより供給
・アセトニトリル、ChromAR HPLC等級、Mallinckrodt,St.Louis,MOにより供給
・トリフルオロ酢酸、99%、分光化学等級、Aldrich,St.Louis,MOにより供給
・ドデシル硫酸ナトリウム、99%、EM Scienceにより供給
・エタノール、Mallinckrodt,St.Louis,MOにより供給
(HPLCアッセイ)
HPLC方法を使用して、移植片からの塩酸アポモルヒネ(「ApoH」)またはロラチジン(「LA」)のインビトロ放出の速度を決定した。クロマトグラフィーを、Zorbax SB−C18(250mm×4.6mm)カラムおよび移動相としての水中の60% 0.1トリフルオロ酢酸、15%メタノール、25%のアセトニトリルおよび1ml/分の流量を用いて実施した。注入体積は。10μlであった。検出を、270nmの波長でのUV/VIS検出器によって達成した。装置制御およびデータ取得を、Waters Millennium(V2.15)ソフトウェアパッケージにより容易にした。外部較正をApoH標準溶液またはLA標準溶液を用いて得た。
移植可能なデバイスを、Microtruderデバイス(Rancastle,RC−025−CF−RF)中での押出し成型プロセスを用いて調製した。その押出し成型機への供給を助長し、アポモルヒネおよび移植片の中に組込まれるべき他の物質の混合を可能にするために、押出し成型の前に、EVAをより小さい粒径に砕いた。この押出し成型プロセスを、アルゴンガス下で実施し、アポモルヒネの酸化を防止した。コポリマーおよび薬物のすべてのブレンドを、120mlの褐色ビン中で、約10分間転がすことにより調製した。このブレンドを、次いでMicrotruderを通して供給した。ApoH/EVA移植片の押出し成型のために使用したパラメーターを表1に示し、トリアンシノロン(「TA」)、グルタチオン(「GSH」)、および/またはLAを含む移植片の押出し成型のために使用したパラメーターを表2に示す。
上記のように調製した押出し成型棒を、全薬物負荷量および薬物放出速度について特徴付けた。
70%ApoH:30%EVAで調製した移植片を2mm片に裁断し、正確に秤量し、そして250mlメスフラスコ中に置いた。約200mlのメタノールを各フラスコに添加し、その溶液を、移植片が溶解するまで室温で連続的に攪拌した。これらの溶液を、次いで薬物含量についてアッセイした。
実験を実施して、上記押出し成型棒から放出されるアポモルヒネの速度を決定した。これらの研究に対する媒体は、0.5%ドデシル硫酸ナトリウム(「SDS」)であった。前もって重量測定した棒を、50mlの媒体を含む100mlのスクリューキャップ広口ビン中に置き、回転式振盪機(orbital shaker)に置いた。この回転式振盪機を、37℃に維持したインキュベータ内に収容した。サンプリングを、媒体を周期的に置換することにより実施した。得たサンプルをHPLCで分析した。
4匹のMPTP障害の、L−DOPA未経験のカニクイザルに、上記のように調製し、各々が33%酢酸ビニルを含有し、98mg±10%塩酸アポモルヒネ(68.5%アポモルヒネ)を負荷した、3つの直径2.4mm×長さ2.6cmの棒状の移植可能なデバイスを投与した。デバイスを、肩甲骨の間に、トロカールを用いて移植した。比較のために、3匹のさらなるMPTP障害の、L−DOPA未経験のサルは、0.2mg/kgの投薬(これは、この動物で「オン」状態を達成するための最小有効用量である)で、間欠的な毎日のアポモルヒネの皮下注射を受けた。
Claims (56)
- ドパミンアゴニストの投与を必要とする哺乳動物へのドパミンアゴニストの投与のための移植可能なデバイスであって、該移植可能なデバイスは、ドパミンアゴニストおよび生体適合性の非腐食性ポリマーマトリクスを含み、
ここで、該ドパミンアゴニストは、該マトリクス内に封入され、そして該移植可能なデバイスが該哺乳動物において皮下に移植された場合に、該ドパミンアゴニストは、持続する期間にわたって、該マトリクスの表面に開口する孔を通して、定常状態で少なくとも約0.01ng/mlの血漿レベルをもたらす速度で、インビボで連続的に放出される、移植可能なデバイス。 - 前記ポリマーマトリクスが、エチレン酢酸ビニルコポリマー(EVA)を含む、請求項1に記載の移植可能なデバイス。
- 前記EVAが、約33%の酢酸ビニルを含む、請求項2に記載の移植可能なデバイス。
- 約10%〜約85%のドパミンアゴニストを含む、請求項1〜3のいずれかに記載の移植可能なデバイス。
- 前記ドパミンアゴニストが、アポモルヒネ、リスリド、ペルゴリド、ブロモクリプチン、プラミペキソール、ロピニロール(ropinerole)、およびロチゴチンからなる群より選択される、請求項1〜4のいずれかに記載の移植可能なデバイス。
- 前記ドパミンアゴニストが、アポモルヒネである、請求項5に記載の移植可能なデバイス。
- 前記持続する期間が、少なくとも約3ヶ月である、請求項1〜6のいずれかに記載の移植可能なデバイス。
- 前記移植可能なデバイスが、押出し成形プロセスにより製造される、請求項1〜7のいずれかに記載の移植可能なデバイス。
- 直径が約2〜約3mmおよび長さが約2〜約3cmの寸法を備える、請求項1〜8のいずれかに記載の移植可能なデバイス。
- 前記移植可能なデバイスが、インビトロで、定常状態で1日あたり約0.1〜約10mgのドパミンアゴニストを放出する、請求項1〜9のいずれかに記載の移植可能なデバイス。
- 前記マトリクス内に封入された抗炎症剤をさらに含む、請求項1〜10のいずれかに記載の移植可能なデバイス。
- 前記抗炎症剤が、ステロイドである、請求項11に記載の移植可能なデバイス。
- 前記抗炎症剤が、非ステロイド系抗炎症性薬物(「NSAID」)である、請求項11に記載の移植可能なデバイス。
- 前記抗炎症剤が、抗ヒスタミン薬である、請求項11に記載の移植可能なデバイス。
- 前記マトリクス内に封入された酸化防止剤をさらに含む、請求項1〜14のいずれかに記載の移植可能なデバイス。
- ドパミンアゴニストの投与を必要とする哺乳動物へのドパミンアゴニストの投与のための移植可能なデバイスであって、該移植可能なデバイスは、ドパミンアゴニストおよび生体適合性の非腐食性ポリマーマトリクスを含み、
ここで、該ドパミンアゴニストは、該マトリクス内に封入され、そして
該移植可能なデバイスが哺乳動物において皮下に移植された場合に、該ドパミンアゴニストが、持続する期間にわたって、該マトリクスの表面に開口する孔を通して、定常状態で、1日あたり少なくとも約0.1mgのドパミンアゴニストの速度で、インビボで連続的に放出される、移植可能なデバイス。 - 前記ポリマーマトリクスが、EVAを含む、請求項16に記載の移植可能なデバイス。
- 前記EVAが、約33%の酢酸ビニルを含む、請求項17に記載の移植可能なデバイス。
- 約10%〜約85%のドパミンアゴニストを含む、請求項16〜18のいずれかに記載の移植可能なデバイス。
- 前記ドパミンアゴニストが、アポモルヒネ、リスリド、ペルゴリド、ブロモクリプチン、プラミペキソール、ロピニロール(ropinerole)、およびロチゴチンからなる群より選択される、請求項16〜19のいずれかに記載の移植可能なデバイス。
- 前記ドパミンアゴニストが、アポモルヒネである、請求項20に記載の移植可能なデバイス。
- 前記持続する期間が、少なくとも約3ヶ月である、請求項16〜21のいずれかに記載の移植可能なデバイス。
- 前記移植可能なデバイスが、押出し成形プロセスにより製造される、請求項16〜22のいずれかに記載の移植可能なデバイス。
- 前記マトリクス内に封入された抗炎症剤をさらに含む、請求項16〜23のいずれかに記載の移植可能なデバイス。
- 前記抗炎症剤が、ステロイドである、請求項24に記載の移植可能なデバイス。
- 前記抗炎症剤が、NSAIDである、請求項24に記載の移植可能なデバイス。
- 前記抗炎症剤が、抗ヒスタミン薬である、請求項24に記載の移植可能なデバイス。
- 前記マトリクス内に封入された酸化防止剤をさらに含む、請求項18〜27に記載の移植可能なデバイス。
- ドパミンアゴニストの投与を必要とする哺乳動物へのドパミンアゴニストの投与のための方法であって、該方法は、少なくとも1つの該移植可能なデバイスを皮下投与する工程を包含し、
ここで、該少なくとも1つの該移植可能なデバイスの各々が、生体適合性の非腐食性ポリマーマトリクス内に封入されるドパミンアゴニストを含み、
該ドパミンアゴニストは、該少なくとも1つの移植可能なデバイスの各々から、持続する期間にわたって、該マトリクスの表面に開口する孔を通して、定常状態で、少なくとも約0.01ng/mlの血漿レベルをもたらす速度で、インビボで連続的に放出される、方法。 - 前記少なくとも1つの移植可能なデバイスが、複数の個々の移植可能なデバイスを含み、該移植可能なデバイスの組合せが、ドパミンアゴニストを、持続する期間にわたって、定常状態で少なくとも約0.05ng/mlの血漿レベルをもたらす速度で、インビボで連続的に放出する、請求項29に記載の方法。。
- 前記ポリマーマトリクスが、EVAを含む、請求項29または30に記載の方法。
- 前記EVAが、約33%の酢酸ビニルを含む、請求項31に記載の方法。
- 前記少なくとも1つの移植可能なデバイスの各々が、約10%〜約85%のドパミンアゴニストを含む、請求項29〜32のいずれかに記載の方法。
- 前記ドパミンアゴニストが、アポモルヒネ、リスリド、ペルゴリド、ブロモクリプチン、プラミペキソール、ロピニロール(ropinerole)、およびロチゴチンからなる群より選択される、請求項29〜33のいずれかに記載の方法。
- 前記ドパミンアゴニストが、アポモルヒネである、請求項34に記載の方法。
- 前記哺乳動物が、パーキンソン病を有する、請求項29〜35のいずれかに記載の方法。
- 前記哺乳動物が、毒素誘起振せん麻痺または疾患誘起振せん麻痺を有する、請求項29〜35のいずれかに記載の方法。
- 前記哺乳動物が、勃起機能不全および不穏下肢症候群からなる群より選択される状態を有する、請求項29〜35のいずれかに記載の方法。
- 前記持続する期間が、少なくとも約3ヶ月である、請求項29〜38のいずれかに記載の方法。
- 前記少なくとも1つの移植可能なデバイスの各々が、押出し成形プロセスにより製造される、請求項29〜39のいずれかに記載の方法。
- 各移植可能なデバイスが、直径が約2〜約3mmおよび長さが約2〜約3cmの寸法を備える、請求項40に記載の方法。
- 各移植可能なデバイスが、インビトロで、1日あたり、少なくとも約0.1mgのドパミンアゴニストを放出する、請求項41に記載の方法。
- 前記少なくとも1つの移植可能なデバイスの各々が、上腕、背、および腹腔からなる群より選択される部位で皮下移植される、請求項29〜42のいずれかに記載の方法。
- 抗炎症剤の投与をさらに包含する、請求項29〜43のいずれかに記載の方法。
- 前記抗炎症剤が、前記少なくとも1つの移植可能なデバイスの少なくとも1つの中に封入される、請求項44に記載の方法。
- 前記抗炎症剤が、前記ドパミンアゴニストを含まない生体適合性の非腐食性ポリマーマトリクス中に封入され、そして前記方法が、該抗炎症剤を含む該ポリマーマトリクスの皮下投与を包含する、請求項44に記載の方法。
- 前記抗炎症剤が、局所注入、全身注入、皮下注射、および経口投与からなる群より選択される経路を介して投与される、請求項44に記載の方法。
- 前記少なくとも1つの移植可能なデバイスが、酸化防止剤をさらに含む、請求項29〜47のいずれかに記載の方法。
- 少なくとも1つの移植可能なデバイス、ならびにドパミンアゴニストの投与を必要とする哺乳動物へのドパミンアゴニストの投与の方法における使用のための指示書を含むキットであって、該少なくとも1つの移植可能なデバイスは、生体適合性の非腐食性ポリマーマトリクス内に封入されるドパミンアゴニストを含み、該少なくとも1つの移植可能なデバイスが、哺乳動物において皮下に移植される場合に、該ドパミンアゴニストは、インビボで、該少なくとも1つの移植可能なデバイスの各々から、該マトリクスの表面に開口する孔を通して、定常状態で少なくとも約0.01ng/mlの血漿レベルをもたらす速度で、持続する期間にわたって連続的に放出される、キット。
- 前記少なくとも1つの移植可能なデバイスが、複数の個々の移植可能なデバイスを含み、該移植可能なデバイスの組合せが哺乳動物において皮下に移植される場合に、該移植可能なデバイスは、持続する期間にわたって、定常状態で少なくとも約0.05ng/mlの血漿レベルをもたらす速度で、インビボで、連続的にドパミンアゴニストを放出する、請求項49に記載のキット。
- 前記移植可能なデバイスが、インビトロで、1日あたり少なくとも約0.1mgの速度でドパミンアゴニストを放出する、請求項49または50に記載のキット。
- 前記移植可能なデバイスの各々が、EVAを含む、請求項49〜51のいずれかに記載のキット。
- 前記EVAが、約33%の酢酸ビニルを含む、請求項52に記載のキット。
- 前記移植可能なデバイスの各々が、約10〜約85%のドパミンアゴニストを含む、請求項49〜53のいずれかに記載のキット。
- 前記ドパミンアゴニストが、アポモルヒネ、リスリド、ペルゴリド、ブロモクリプチン、プラミペキソール、ロピニロール(ropinerole)、およびロチゴチンからなる群より選択される、請求項49〜54のいずれかに記載のキット。
- 前記ドパミンアゴニストが、アポモルヒネである、請求項55に記載のキット。
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