JP2013523780A - オピエートアゴニスト及びアゴニスト−アンタゴニストの乱用抑止性経皮製剤 - Google Patents
オピエートアゴニスト及びアゴニスト−アンタゴニストの乱用抑止性経皮製剤 Download PDFInfo
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- JP2013523780A JP2013523780A JP2013502921A JP2013502921A JP2013523780A JP 2013523780 A JP2013523780 A JP 2013523780A JP 2013502921 A JP2013502921 A JP 2013502921A JP 2013502921 A JP2013502921 A JP 2013502921A JP 2013523780 A JP2013523780 A JP 2013523780A
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Abstract
Description
本出願は2010年4月2日に出願した米国仮出願第61/320,526号の利益を主張し、その全体を参照により本明細書中に取り込む。
乱用抵抗性(abuse−resistant)製剤におけるオピオイドアゴニスト、オピオイドアゴニスト−アンタゴニスト又はそのプロドラッグならびにオピオイドアゴニスト、オピオイドアゴニスト−アンタゴニスト又はそのプロドラッグの経皮送達のための剤形を本明細書中に記載する。
疼痛(pain)は、最も頻繁に報告される症状であり、そして臨床医が直面する共通する臨床問題である。米国における数百万の人々は、多くの最近の報告によれば、慢性的に処置下にあるか又は不適切に管理されている重度の疼痛に悩まされている。
本明細書中に記載されるいくつかの実施形態は、オピオイドの経皮送達のための乱用抑止性組成物、製剤及び剤形(たとえば、パッチ)中に、オピオイドアゴニスト、アゴニスト−アンタゴニスト又はそのプロドラッグを含む。
本発明は種々の形で具体化され得るが、いくつかの実施形態の下記の記載は本開示が特許請求される内容の例示として考えられ、添付の特許請求の範囲を特定の実施形態に限定することが意図されないとの理解でなされている。この開示を通して使用される見出しは、単なる便利さのために提供され、そして特許請求の範囲をいかなる手段によっても限定するものと解釈されるべきでない。いずれかの見出しの下に示される実施形態は、いずれかの他の見出しの下に示される実施形態と組み合わされてよい。
(i)医学的疾患の阻止(inhibiting)、すなわち医学的疾患の開始、発生又は進行の停止(arresting)、減速(slowing)又は遅延(delaying);又は
(ii)医学的疾患の軽減(relieving)、すなわち医学的疾患の後退(regression)の誘発が挙げられる。
1つの実施形態において、オピオイドアゴニスト、オピオイドアゴニストプロドラッグ、オピオイドアゴニスト−アンタゴニスト又はオピオイドアゴニスト−アンタゴニストプロドラッグ及びオピオイドアンタゴニスト又はオピオイドアンタゴニストプロドラッグを含む第一の経皮剤形が対象に投与される。さらなる実施形態において、第1の経皮剤形は、対象に1回投与されるパッチであり、その後、それは廃棄される。第1の経皮剤形の1回の投与に続いて、オピオイドアゴニスト又はオピオイドアゴニスト−アンタゴニストの全身濃度をある時間にわたって測定し、そして最大濃度(「Cmax」)、投与後の最大濃度までの時間(「Tmax」)、及び時間対血漿又は血清濃度曲線下の面積(「AUC」)をそれから計算することができる。そのような実施形態において、AUCは0〜24時間、又は0時間〜無限で計算されうる。さらなる実施形態において、経皮剤形は、オピオイドアゴニスト又はオピオイドアゴニスト−アンタゴニストが定常状態の全身濃度に達するまで、対象に複数回投与される。定常状態に達した後に、オピオイドアゴニスト又はアゴニスト−アンタゴニストの全身濃度をある時間にわたって測定し、そしてオピオイドアゴニスト又はアゴニスト−アンタゴニストの最大定常状態濃度(「Cmax-ss」)及び最小定常状態濃度(「Cmin-ss」)を決定することができる。
表21及び図9はEVA及びHPC二層パッチからのナルトレキソンの放出を示す。
Claims (17)
- オピオイドを対象に経皮的に送達させるための乱用抑止性パッチであって:
(a)支持層;
(b)前記支持層の下にある第一の層であって、オピオイドを対象に経皮的に投与するためにパッチが使用されるときに治療レベルで経皮的に送達されないオピオイドアンタゴニスト又はオピオイドアンタゴニストのプロドラッグを含み、ここで、前記支持層は前記第一の層のオピオイドアンタゴニスト又はオピオイドアンタゴニストのプロドラッグに対して実質的に不透過性である、前記第一の層;
(c)前記第一の層の下にある第二の層であって:
(i)オピオイドアゴニスト、オピオイドアゴニストのプロドラッグ、オピオイドアゴニスト−アンタゴニスト及びオピオイドアゴニスト−アンタゴニストのプロドラッグからなる群より選ばれるオピオイド;並びに
(ii)感圧接着剤
を含み、ここで前記第二の層は、対象に治療有効量のオピオイドを経皮的に投与するために、対象の皮膚と拡散的に連絡するように(in diffusional communication)構成されている、前記第二の層;並びに、
(d) 前記第一の層と前記第二の層との間に配置されたバリア層であって、水不溶性ポリマー材料及び水溶性ポリマーを含む、前記バリア層
を含み、ここで、エタノール、水又はpH約6.5のリン酸緩衝液中に、約30秒を超える間、前記パッチを置いた後において、放出比が約1:60〜約60:1である、前記乱用抑止性パッチ。 - 前記オピオイドアゴニスト又はオピオイドアゴニストのプロドラッグは、アルフェンタニル、アリルプロジン、アルファプロジン、アニレリジン、ベンジルモルヒネ、ベンジトラミド、クロニタゼン、コデイン、デソモルヒネ、デキストロモラミド、デゾシン、ジアムプロミド、ジアモルホン、ジヒドロコデイン、ジヒドロモルヒネ、ジメノキサドール、ジメフェプタノール、ジメチルチアンブテン、ジオキサフェチルブチラート、ジピパノン、エプタゾシン、エトヘプタジン、エチルメチルチアンブテン、エチルモルヒネ、エトニタゼン、エトルフィン、ジヒドロエトルフィン、フェンタニル、ヒドロコドン、ヒドロモルホン、ヒドロキシペチジン、イソメタドン、ケトベミドン、レボルファノール、レボメタジル、レボフェナシルモルファン、ロフェンタニル、メペリジン、メタゾシン、メタドン、メトポン、モルヒネ、ミロフィン、ナルセイン、ニコモルフィン、ノルレボルファノール、ノルメタドン、ノルモルフィン、ノルピパノン、アヘン、オキシコドン、オキシモルフォン、パパベレタム、フェナドキソン、フェノモルファン、フェナゾシン、フェノペリジン、ピミノジン、ピリトラミド、プロフェプタジン(propheptazine)、プロメドール、プロペリジン、プロポキシフェン、スフェンタニル、チリジン、トラマドール及びそれらのいずれかのプロドラッグからなる群より選ばれ;
前記オピオイドアゴニスト−アンタゴニスト又はオピオイドアゴニスト−アンタゴニストのプロドラッグは、ブプレノルフィン、ブトルファノール、デゾシン、メプタジノール、ナルブフィン、ナロルフィン、ペンタゾシン及びそれらのいずれかのプロドラッグからなる群より選ばれ;そして
前記オピオイドアンタゴニスト又はオピオイドアンタゴニストのプロドラッグは、ナルトレキソン、6-ベータ-ナルトレキソール、ナルブフィン、ナルメフェン、ナロキソン、シクラゾシン、レバロルファン、シクロファン(cyclorphan)、オキシロルファン(oxilorphan)及びそれらのいずれかのプロドラッグからなる群より選ばれる、請求項1記載の乱用抑止性経皮パッチ。 - 前記オピオイドアゴニスト−アンタゴニストはブプレノルフィンである、請求項2記載の乱用抑止性経皮パッチ。
- 前記オピオイドアゴニスト−アンタゴニストのプロドラッグはブプレノルフィンのプロドラッグである、請求項2記載の乱用抑止性経皮パッチ。
- 前記オピオイドアンタゴニストはナルトレキソン又はナロキソンである、請求項2記載の乱用抑止性経皮パッチ。
- 前記オピオイドアンタゴニストのプロドラッグはナルトレキソンのプロドラッグ又はナロキソンのプロドラッグである、請求項2記載の乱用抑止性経皮パッチ。
- 前記水不溶性ポリマー材料は、エチルセルロース、セルロース誘導体、セルロースエステル、エチレン−酢酸ビニルコポリマー、ポリオレフィン、ポリエチレン、低密度ポリエチレン、中密度ポリエチレン、高密度ポリエチレン、ポリプロピレン、エチレン−プロピレンコポリマー、スチレン系ポリマー、ポリスチレン、ビニルポリマー、ポリ酢酸ビニル、アクリル系ポリマー、エチレンメチルアクリレートコポリマー、ポリメチルアクリレート、ポリエチルアクリレート、エチレン−アクリル酸コポリマー、エチレン−エチルアクリレートコポリマー、アクリル酸のホモポリマー、アクリル酸、メタクリル酸メチル、第四級アンモニウム基を含むメチルアクリル酸エステルのコポリマー、及び、それらの組み合わせからなる群より選ばれ;そして
前記水溶性ポリマーはセルロース誘導体、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、メチルセルロース、セルロースガム、ナトリウムカルボキシメチルヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース、カルボキシアルキルセルロース、カルボキシメチルセルロース、ポリビニルピロリドン、ポリエチレンオキシド、多糖類、デキストラン、ポリシアル酸、トウモロコシデンプン、寒天、アガロース、アルギン酸塩、キサンタンガム、ヘパリン、キチン、キトサン、ポリビニルアルコール、ポリエチレングリコール、ポリオキサゾリン、ポリアクリロイルモルホリン及びそれらの組み合わせからなる群より選ばれる、請求項1記載の乱用抑止性経皮パッチ。 - 前記水不溶性ポリマー材料はエチルセルロースである、請求項1記載の乱用抑止性経皮パッチ。
- 前記水溶性ポリマーはヒドロキシプロピルセルロースである、請求項1記載の乱用抑止性経皮パッチ。
- 前記第一の層は、さらに:
(a)場合により、エチルセルロース、セルロース誘導体、セルロースエステル、エチレン−酢酸ビニルコポリマー、ポリオレフィン、ポリエチレン、低密度ポリエチレン、中密度ポリエチレン、高密度ポリエチレン、ポリプロピレン、エチレン−プロピレンコポリマー、スチレン系ポリマー、ポリスチレン、ビニルポリマー、ポリ酢酸ビニル、アクリル系ポリマー、エチレンメチルアクリレートコポリマー、ポリメチルアクリレート、ポリエチルアクリレート、エチレン−アクリル酸コポリマー、エチレン−エチルアクリレートコポリマー、アクリル酸のホモポリマー、アクリル酸、メタクリル酸メチル、第四級アンモニウム基を含むメチルアクリル酸エステルのコポリマー、及び、それらの組み合わせからなる群より選ばれる水不溶性ポリマー材料;並びに、
(b)場合により、セルロース誘導体、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、メチルセルロース、セルロースガム、ナトリウムカルボキシメチルヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース、カルボキシアルキルセルロース、カルボキシメチルセルロース、ポリビニルピロリドン、ポリエチレンオキシド、多糖類、デキストラン、ポリシアル酸、トウモロコシデンプン、寒天、アガロース、アルギン酸塩、キサンタンガム、ヘパリン、キチン、キトサン、ポリビニルアルコール、ポリエチレングリコール、ポリオキサゾリン、ポリアクリロイルモルホリン及びそれらの組み合わせからなる群より選ばれる水溶性ポリマー
を含む、請求項1記載の乱用抑止性経皮パッチ。 - 前記オピオイドアンタゴニストはナルトレキソンであり、前記オピオイドはブプレノルフィン又はブプレノルフィンのプロドラッグであり、ここで放出比は約1:1〜約0.01:1であり;
前記オピオイドアンタゴニストはナルトレキソンのプロドラッグであり、前記オピオイドはブプレノルフィン又はブプレノルフィンのプロドラッグであり、ここで放出比は約1:1〜約0.01:1であり;
前記オピオイドアンタゴニストはナロキソンであり、前記オピオイドはブプレノルフィン又はブプレノルフィンのプロドラッグであり、ここで放出比は約4:1〜約0.01:1であり;又は、
前記オピオイドアンタゴニストはナロキソンのプロドラッグであり、前記オピオイドはブプレノルフィン又はブプレノルフィンのプロドラッグであり、ここで放出比は約4:1〜約0.01:1である、請求項1記載の乱用抑止性経皮パッチ。 - オピオイド依存症、アルコール依存症、多剤中毒、疼痛、コカイン中毒、摂食障害及び治療抵抗性うつ病を治療するのに使用するための、請求項1記載の対象にオピオイドを経皮送達させるための乱用抑止性パッチ。
- 前記オピオイドアゴニスト又はオピオイドアゴニストのプロドラッグは、アルフェンタニル、アリルプロジン、アルファプロジン、アニレリジン、ベンジルモルヒネ、ベンジトラミド、クロニタゼン、コデイン、デソモルヒネ、デキストロモラミド、デゾシン、ジアムプロミド、ジアモルホン、ジヒドロコデイン、ジヒドロモルヒネ、ジメノキサドール、ジメフェプタノール、ジメチルチアンブテン、ジオキサフェチルブチラート、ジピパノン、エプタゾシン、エトヘプタジン、エチルメチルチアンブテン、エチルモルヒネ、エトニタゼン、エトルフィン、ジヒドロエトルフィン、フェンタニル、ヒドロコドン、ヒドロモルホン、ヒドロキシペチジン、イソメタドン、ケトベミドン、レボルファノール、レボメタジル、レボフェナシルモルファン、ロフェンタニル、メペリジン、メタゾシン、メタドン、メトポン、モルヒネ、ミロフィン、ナルセイン、ニコモルフィン、ノルレボルファノール、ノルメタドン、ノルモルフィン、ノルピパノン、アヘン、オキシコドン、オキシモルフォン、パパベレタム、フェナドキソン、フェノモルファン、フェナゾシン、フェノペリジン、ピミノジン、ピリトラミド、プロフェプタジン(propheptazine)、プロメドール、プロペリジン、プロポキシフェン、スフェンタニル、チリジン、トラマドール及びそれらのいずれかのプロドラッグからなる群より選ばれ;
前記オピオイドアゴニスト−アンタゴニスト又はオピオイドアゴニスト−アンタゴニストのプロドラッグはブプレノルフィン、ブトルファノール、デゾシン、メプタジノール、ナルブフィン、ナロルフィン、ペンタゾシン及びそれらのいずれかのプロドラッグからなる群より選ばれ;そして
前記オピオイドアンタゴニスト又はオピオイドアンタゴニストのプロドラッグはナルトレキソン、6-ベータ-ナルトレキソール、ナルブフィン、ナルメフェン、ナロキソン、シクラゾシン、レバロルファン、シクロファン(cyclorphan)、オキシロルファン(oxilorphan)及びそれらのいずれかのプロドラッグからなる群より選ばれる、請求項14記載の乱用抑止性経皮パッチ。 - オピオイドを対象に送達させるための乱用抑止性経皮パッチの製造方法であって、以下のステップ:
(a)オピオイドを経皮的に投与するためにパッチを使用したときに治療レベルで経皮的に送達されないオピオイドアンタゴニスト又はオピオイドアンタゴニストのプロドラッグを含む、第一の層を、支持層を含む基材に適用するステップ;
(b)水不溶性ポリマー材料及び水溶性ポリマーを含むバリア層を前記第一の層に適用するステップ;そして、
(c) 第二の層を前記バリア層に適用するステップであって、ここで前記第二の層は:
(i)オピオイドアゴニスト、オピオイドアゴニストのプロドラッグ、オピオイドアゴニスト−アンタゴニスト及びオピオイドアゴニスト−アンタゴニストのプロドラッグからなる群より選ばれるオピオイド;並びに、
(ii)感圧接着剤
を含み、ここで前記第二の層は、対象に治療有効量のオピオイドを経皮的に投与するために、対象の皮膚と拡散的に連絡するように構成されている、前記ステップ
を含み、
ここで、エタノール、水又はpH約6.5のリン酸緩衝液中に、約30秒間を超える間、前記パッチを置いた後において、放出比が約1:60〜約60:1である、前記方法。 - 前記オピオイドアゴニスト又はオピオイドアゴニストのプロドラッグは、アルフェンタニル、アリルプロジン、アルファプロジン、アニレリジン、ベンジルモルヒネ、ベンジトラミド、クロニタゼン、コデイン、デソモルヒネ、デキストロモラミド、デゾシン、ジアムプロミド、ジアモルホン、ジヒドロコデイン、ジヒドロモルヒネ、ジメノキサドール、ジメフェプタノール、ジメチルチアンブテン、ジオキサフェチルブチラート、ジピパノン、エプタゾシン、エトヘプタジン、エチルメチルチアンブテン、エチルモルヒネ、エトニタゼン、エトルフィン、ジヒドロエトルフィン、フェンタニル、ヒドロコドン、ヒドロモルホン、ヒドロキシペチジン、イソメタドン、ケトベミドン、レボルファノール、レボメタジル、レボフェナシルモルファン、ロフェンタニル、メペリジン、メタゾシン、メタドン、メトポン、モルヒネ、ミロフィン、ナルセイン、ニコモルフィン、ノルレボルファノール、ノルメタドン、ノルモルフィン、ノルピパノン、アヘン、オキシコドン、オキシモルフォン、パパベレタム、フェナドキソン、フェノモルファン、フェナゾシン、フェノペリジン、ピミノジン、ピリトラミド、プロフェプタジン(propheptazine)、プロメドール、プロペリジン、プロポキシフェン、スフェンタニル、チリジン、トラマドール及びそれらのいずれかのプロドラッグからなる群より選ばれ;
前記オピオイドアゴニスト−アンタゴニスト又はオピオイドアゴニスト−アンタゴニストのプロドラッグはブプレノルフィン、ブトルファノール、デゾシン、メプタジノール、ナルブフィン、ナロルフィン、ペンタゾシン及びそれらのいずれかのプロドラッグからなる群より選ばれ;そして
前記オピオイドアンタゴニスト又はオピオイドアンタゴニストのプロドラッグはナルトレキソン、6-ベータ-ナルトレキソール、ナルブフィン、ナルメフェン、ナロキソン、シクラゾシン、レバロルファン、シクロファン(cyclorphan)、オキシロルファン(oxilorphan)及びそれらのいずれかのプロドラッグからなる群より選ばれる、
請求項16記載の方法。
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Also Published As
Publication number | Publication date |
---|---|
EP2552425B1 (en) | 2016-07-27 |
CA2795158C (en) | 2019-10-22 |
JP6212104B2 (ja) | 2017-10-11 |
ES2592277T3 (es) | 2016-11-29 |
JP2016053085A (ja) | 2016-04-14 |
EP2552425A1 (en) | 2013-02-06 |
EP3064199A1 (en) | 2016-09-07 |
WO2011123866A1 (en) | 2011-10-06 |
EP3064199B1 (en) | 2023-12-20 |
US8481560B2 (en) | 2013-07-09 |
CA2795158A1 (en) | 2011-10-06 |
US20110245783A1 (en) | 2011-10-06 |
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