JP5770582B2 - 経皮オキシブチニン療法のための組成物および方法 - Google Patents
経皮オキシブチニン療法のための組成物および方法 Download PDFInfo
- Publication number
- JP5770582B2 JP5770582B2 JP2011204430A JP2011204430A JP5770582B2 JP 5770582 B2 JP5770582 B2 JP 5770582B2 JP 2011204430 A JP2011204430 A JP 2011204430A JP 2011204430 A JP2011204430 A JP 2011204430A JP 5770582 B2 JP5770582 B2 JP 5770582B2
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- JP
- Japan
- Prior art keywords
- oxybutynin
- formulation
- gel formulation
- gel
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Description
本出願は、2000年4月26日に出願された米国特許出願シリアルNo.09/559,711の継続である2002年3月15日に出願された米国特許出願シリアルNo.10/098,752の一部継続である2002年11月1日に出願された米国特許出願シリアルNo.10/286,381の優先権を主張し、これらの各々は、参考とすることによって本明細書に組み込む。
本発明は、オキシブチニン療法に随伴する薬の副作用体験を最小化するための組成物および方法に関する。したがって、本発明は、薬科学、医学およびその他の健康科学の分野に該当する。
本発明の方法に関連して有用な供給配合物としては、経口、非経口、経皮、吸入または移植可能な配合物が挙げられるが、これらに限定するものではない。本発明の1つの態様にて、供給配合物は、経皮供給配合物であるのがよい。さらに詳細な態様にて、供給配合物は、咬合されないかまたはフリーの形で皮膚に局所投与されるゲル配合物であるのがよい。
A. 定義
本発明を説明しかつ特許請求するのに、以下の用語は、以降に記載する定義に従い使用する。
“皮膚(skin)”または“皮膚表面(skin surface)”という用語は、1つ以上の表皮層を含む被験者の外皮を含むのみならず、薬剤組成物が投与される粘膜表面をも含むことを意味する。粘膜表面の例としては、(鼻腔および肺を含め)呼吸器、口(口および口腔)、膣および直腸の粘膜が挙げられる。したがって、“経皮(transdermal)”という用語は、同様に、“経粘膜(transmucosal)”を包含する。
上記したように、本発明は、オキシブチニンを投与するための組成物および方法を提供する。これら組成物および方法は、オキシブチニン投与に随伴する副作用体験の発生率および/または重度を最小化したことを示すものの、治療学的利点を与えるのに十分なオキシブチニンを提供する。いずれかの特定の理論に結び付けようとする意図はないが、副作用体験の最小化は、慣用的な経口投与と比較する時、一部、本組成物および方法によるオキシブチニン代謝物、例えば、N-デスエチルオキシブチニンの血漿濃度の低下によると考えられる。“慣用的経口投与”という語句は、上記した経口配合物を含むことを意味し、例えば、オキシブチニンを含む直-レリースまたは持続性-レリース経口錠剤が挙げられる。1つのこのような慣用的な経口配合物は、5mg直レリース経口錠剤として入手可能である。
所望される薬物速度論的特性、例えば、オキシブチニン代謝物の血漿濃度低下は、とりわけ、1) 投与されるオキシブチニンの量の減少;2) オキシブチニンが体による代謝に利用可能となる速度の低下;および/または、3) オキシブチニンのファースト-パス(first-pass)肝および/または腸代謝の回避または最小化によって達成することができる。非経口投与ルートを使用するのがこれらの目的の1つ以上を達成する1つの方法である。あるいは、経口剤形は、本明細書に記載する血漿濃度およびその他の薬物速度論的データを達成するために、非経口投与をまねるように設計することができる。
本発明者らは、上記した態様をさらに探求し、本配合物および方法が、ある種のオキシブチニン代謝物の個々の異性体の有意に低いレベルを生じ、代謝物異性体のこれら低いレベルが、上記した薬の副作用体験を最小化するのに相関することを発見した。
過活動膀胱を有する72人のヒト被験者(患者)を使用し、非経口投与されるオキシブチニンに随伴する薬の副作用体験の発生率および重度の効能および最小化についての臨床的研究を行った。ほぼ半分の患者に、オキシブチニン塩酸塩を経口投与配合物にて投与した。残りの患者に、非経口供給ルート、例えば、約6週間かけての経皮接着マトリックスパッチを使用し、オキシブチニンを投与した。結果は、図4および5にグラフで示す。
上記した薬物速度論的データから、本発明の以下の態様が提供されうる。1つの態様にて、オキシブチニン代謝物の平均ピーク血漿濃度は、約8ng/ml未満である。もう1つの態様にて、代謝物の平均ピーク血漿濃度は、約0.5ng/ml〜約8ng/mlであり;なおもう1つの態様にて、その濃度は、約5ng/ml未満であり;なおもう1つの態様にて、その濃度は、約1.0ng/ml〜約3ng/mlである。幾つかの態様にて、オキシブチニンの代謝物は、N-デスエチルオキシブチニンである。
いずれの薬学的に許容可能な組成物およびこのような組成物を投与するための方法も、本発明の所望される態様を達成するために使用することができる。例えば、経口および非経口組成物ならびに投与方法を使用することができる。非経口組成物および投与方法としては、腸管外(parenteral)、移植、吸入および経皮組成物ならびに方法が挙げられる。
込む。
の詳細な態様にて、クリーム配合物中の乳化剤は、非イオン性、アニオン性、カチオン性または両性界面活性剤であってもよい。
が、これらに限定するものではない。本発明のもう1つの態様にて、ゲル化剤は、CARBOPOLである。本発明の1つのさらに詳細な態様にて、ゲル化剤は、アルキルアクリレートポリマーである。本発明のなおもう1つの態様にて、ゲル化剤は、CARBOPOLとアルキルアクリレートポリマーとの混合物である。
が挙げられるが、これらに限定するものではない。
上記した臨床研究に使用される非経口オキシブチニン供給デバイスは、13および/または39cm2経皮接着マトリックスパッチであった。経皮接着マトリックスパッチを製造する一般的な方法は、U.S.特許Nos.5,227,169および5,212,199によって記載されており、これらの特許は、それらの全体を参考とすることによって組み込む。この一般的な方法に従い、本発明のオキシブチニンパッチを以下のようにして製造した:
オキシブチニン遊離塩基、トリアセチン(Eastoman Chemical Co.,Kingsport,NY)および87-2888アクリル系コポリマー接着剤(National Starch and Chemical Co.,Bridgewater,NJ)を混合して、均質な溶液にし、二域塗布/乾燥/ラミネートオーブン(Kraemer Koating,Lakewood,NJ)を使用して、6mg/cm2(乾燥させた重量)でシリコーン処理したポリエステルレリースライナー(Raxham Release,Chicago.IL)上に塗布して、それぞれ、15.4重量%、9.0重量%および75.6重量%のオキシブチニン、トリアセチンおよびアクリル系コポリマー接着剤を含有する最終的なオキシブチニン接着マトリックスを用意した。オキシブチニン含有マトリックスの乾燥させた接着剤表面上に、50ミクロン厚さのポリエチレン裏装フィルム(3M,St.Paul,MN)を逐次積層し、最終ラミネート構造部材を打ち抜いて、約13cm2〜39cm2サイズの範囲のパッチを用意した。
持続性レリースデポー注射を行うための生物分解性ミクロスフェアを使用して、本発明の方法に従いオキシブチニンを供給した。以下の方法によりミクロスフェアを調製した:
12,000分子量のポリ-、d,l乳酸(“PLA”,Birmingham Polymers,Birmingham,Alabama)を最終濃度20重量%で塩化メチレンに溶解させた。最終溶液にて4重量%で、オキシブチニン遊離塩基をPLA溶液に溶解させた。Teflonタービン攪拌機に固定したツルーボア攪拌機を備えた(5℃に制御した温度の)水ジャケット反応容器に、0.1%Tween 80を含有する脱イオン水を装填した。
局所施用オキシブチニン含有ゲルを使用して、本発明の方法に従い、オキシブチニンを供給した。局所ゲルを調製する一般的な方法は、当分野公知である。この一般的な方法に従い、オキシブチニンを含む局所ゲルを以下のように調製した:
95%エタノール(USP)を水(USP)、グリセリン(USP)およびグリセロールモノオレエート(Eastman Chemical,Kingsport NY)で希釈すると、それぞれ、エタノール/水/グリセリン/グリセロールモノオレエートのパーセント比35/59/5/1で最終溶液を生じた。ついで、オキシブチニン遊離塩基を上記溶液に溶解させ、10mg/グラムの濃度とした。生ずる溶液を、ついで、1%ヒドロキシプロピルセルロース(Aqualon,Wilmington,Delaware)でゲル化すると、最終的なオキシブチニンゲルを生じた。上記ゲル1〜2グラムを、胸、胴および/または腕上ほぼ200cm2の表面積に局所施用すると、オキシブチニンの局所投与を生ずる。
16人の健康なボランティアにての臨床研究は、クロスオーバー方式で、オキシブチニン、N-デスエチルオキシブチニンおよびそれらのそれぞれの(R)-および(S)-エナンチオマー成分の比較血漿濃度および薬物速度論を比較した。
過活動膀胱を有する72人の患者にて、効能および副作用の発生率の臨床研究を行った。これらの患者は、U.S.A.の種々の地域に位置する独立した臨床研究者によって募られた。これら患者のほぼ半数に、直-レリース経口投薬配合物にてオキシブチニン塩酸塩を投与した。残りの患者には、各場合、1つ以上の13cm2のオキシブチニン含有経皮接着マトリックスパッチを使用して、オキシブチニンを投与した。これらの処置群の各々にて、処置のプラシーボ形を合致させる並行投与により投薬をブラインドした。活性経口処置の場合に、患者には、活性薬剤オキシブチニンを除外して活性経皮系の全ての成分を含有させたプラシーボ経皮系を施用した。同様に、活性経皮処置群に、活性オキシブチニン成分を含まない合致する経口配合物を受容させた。
見られるように、本発明の非経口法によって処置した個体についての失禁症状出現の発生率数は、経口配合物で処置した固体についての数とほぼ同等である。これは、本方法および組成物が慣用的な経口配合物、例えば、5mg経口オキシブチニン錠剤に匹敵する尿失禁および過活動膀胱のための治療学的に有効な処置を提供することを明らかに示す。薬の副作用体験の発生率および/または重度も、また、上記のように投与したオキシブチニンの慣用的な経口錠剤配合物と経皮配合物との間で比較した。抗コリン作働性副作用体験、例えば、口の渇きの発生率および重度をいずれかの配合物の投与に随伴しうる副作用体験のインジケータとして使用すると、抗コリン作働性副作用を表す。臨床研究参加者に、標準化した質問紙に従いその体験を報告するように依頼した。質問紙から誘導されるデータは、図5にグラフで示す。口の渇きを報告した参加者のパーセンテージは、垂直軸に示し、口の渇きの重度は、水平軸に示す。
ことを示す。
局所施用オキシブチニン含有ゲルを使用して、本発明の方法に従いオキシブチニンを供給することができる。本発明のゲルおよび実施例9〜11に記載するゲルは、グリセリン(またはその他の湿潤剤および皮膚軟化剤)を6オンスのジャーに秤取し、ついで、予め秤量した水を加え、続いて、予め秤量した (オキシブチニンクロライドゲルについて) 2N 水酸化ナトリウムを、または、 (オキシブチニン遊離塩基ゲルについて) 2N 塩酸を加えた。水酸化ナトリウムまたはナトリウムヒドロクロライドは、合計遊離形ゲルの0重量%〜約5重量%存在する。予め秤量したエタノールを6オンスジャーに加えた。活性成分(オキシブチニン遊離塩基かまたはオキシブチニンクロライド)を化学天秤上の秤量皿に秤取し、ついで、6オンスのジャーに移した。緊密に蓋をした後、活性成分とグリセリンとの両方が完全に溶解されるまで、ジャーをハンドシェイクした。次に、予め秤量したゲル化剤を前記ジャーに移した(ゲル化剤の凝集は、ジャー内でゲル化剤粒子を緩やかに分散させることによって回避することができる)。各成分の実際の量は、移し容器(transfer container)の重量の差によって測定した。ジャーは、キャップし、パラフィンでラップし、リストシェ−カー(wrist shaker)に一晩かけると、ゲル化剤を完全に溶解した。
実施例9〜11のインビトロ皮膚フラックス研究は、スキンバンクから入手した十分に厚い(ほぼ500μmの)皮膚試料を使用して行った。十分に厚い皮膚試料は、実験を行うまで-5℃にて貯蔵した。各供与者についてのジェンダー(gender)、性、年齢および解剖部位情報は、入手可能である時、記録した。
わたってほぼ7μLの投薬量を負荷した。施用する投薬量は、拡散表面1cm2当りほぼ11μLのゲルであり、これは、局所施用について典型的である。
実施例8〜10の研究について、典型的には、4つの反復試験区が、パー皮膚パー系当り得られた。各皮膚からの所定の系について得られる値の平均値の比較は、皮膚内の較差による浸透の差を示した。
実施例8.1
中のオキシブチニンの濃度を増加させることによるオキシブチニンフラックス速度を増加させる方法が提供される。
実施例9.1
組成:73.3重量%のエタノール、18.0重量%の水、1.0重量%のグリセリン、2.0重量%のKLUCEL HF、4.4重量%のオキシブチニンクロライドおよび1.3重量%の水酸化ナトリウムを有する遊離形のオキシブチニンクロライドゲルを調製した。生ずるゲルは、pH6を有した。9個の別々の皮膚試料を48時間にわたりフラックスについて試験し、結果を表10に示す。採取24時間後、皮膚の頂部に残ったゲルを除去し、ついで、30時間試料(ゲル除去後6時間)および48時間試料(ゲル除去後24時間)を採取した。
各相に表11に示すような組成物を含有する遊離形のオキシブチニンクリームを製造することができる。オキシブチニンは、配合物中に約1〜約10% w/wにて存在する。
各相に表12に示すような組成物を含有する遊離形のオキシブチニンローションを製造することができる。オキシブチニンは、配合物中に約1〜約10% w/wにて存在する。
各相に表13に示すような組成物を含有する遊離形のオキシブチニンゲルを製造することができる。オキシブチニンは、配合物中に約1〜約10% w/wにて存在する。乳化させたゲル担体を使用して、遊離形のオキシブチニンゲルを製造することができる。オキシブチニンは、配合物中に約1〜約20% w/w存在する。前述に基づき、他の適用可能な実施例にて示したpH効果が、これら配合物のある種の態様にて観測されうることが予想される。さらに、乳化させたゲル基体は、上記した実施例と同様にして、その遊離塩基形、薬学的に許容可能な塩の形またはそれらの混合物の形のいずれかにてオキシブチニンを供給することができ、供給速度はそれらに等しいことが期待される。また、オキシブチニンがそのR-またはS-異性体形で存在しうることを理解するべきである。
各相に表14に示すような組成物を含有する遊離形のオキシブチニン軟膏を製造することができる。
表15は、クロライドおよび遊離塩基形のRおよびS異性体の各々について24時間かけて測定した皮膚フラックスを示す。オキシブチニン遊離塩基およびオキシブチニンクロライドの両方とも、2つの形RおよびSにて存在するキラル分子であり、表15にて示すように、本発明に従いそれらの光学的に活性な形で各々試験した。
これに限定されるわけではないが、本発明は以下の発明を包含する。
(1)局所施用のためのオキシブチニンゲル配合物であって、
治療学的に有効量のオキシブチニン;および、
ゲル担体;
を含み;
該配合物が、pH約4〜約11を有し、オキシブチニンが、オキシブチニン遊離塩基、薬学的に許容可能なオキシブチニン塩またはそれらの混合物として存在し、該配合物が、皮膚表面に咬合されることなく局所施用されるように調製されるオキシブチニンゲル配合物。
(2)配合物のpHが、約4〜約11である、(1)のオキシブチニンゲル配合物。
(3)配合物のpHが、約5〜約11である、(1)のオキシブチニンゲル配合物。
(4)配合物のpHが、約6〜約11である、(1)のオキシブチニンゲル配合物。
(5)配合物のpHが、約4〜約10である、(1)オキシブチニンゲル配合物。
(6)配合物のpHが、約5〜約10である、(1)のオキシブチニンゲル配合物。
(7)配合物のpHが、約6〜約10である、(1)のオキシブチニンゲル配合物。
(8)配合物のpHが、約6である、(1)のオキシブチニンゲル配合物。
(9)配合物のpHが、約9である、(1)のオキシブチニンゲル配合物。
(10)オキシブチニンが、オキシブチニン遊離塩基である、(1)のオキシブチニンゲル配合物。
(11)オキシブチニンが、オキシブチニンクロライドである、(1)のオキシブチニンゲル配合物。
(12)オキシブチニンが、オキシブチニン遊離塩基とオキシブチニンクロライドとの組み合わせである、(1)のオキシブチニンゲル配合物。
(13)局所施用のためのオキシブチニンゲル配合物であって、
ゲル担体中に治療学的に有効量のオキシブチニンを含み、それが、咬合することなく局所投与される際に、少なくとも約24時間にわたってオキシブチニン皮膚浸透速度少なくとも約10ug/cm2を生ずるのに十分であるオキシブチニンゲル配合物。
(14)皮膚浸透速度が、少なくとも約24時間にわたって少なくとも約20ug/cm2である、(13)のオキシブチニンゲル配合物。
(15)配合物が、皮膚への配合物の咬合することなく局所投与される際にオキシブチニン皮膚浸透を高めるpHを有する、(13)のオキシブチニンゲル配合物。
(16)配合物が、浸透増強剤を含む、(13)のオキシブチニンゲル配合物。
(17)オキシブチニンが、オキシブチニン遊離塩基である、(13)のオキシブチニンゲル配合物。
(18)オキシブチニンが、オキシブチニンクロライドである、(13)のオキシブチニンゲル配合物。
(19)オキシブチニンが、オキシブチニン遊離塩基とオキシブチニンクロライドとの混合物である、(13)のオキシブチニンゲル配合物。
Claims (15)
- 皮膚表面への局所施用のための咬合されていないオキシブチニンゲル配合物であって、
0.1重量%〜10重量%のオキシブチニン;
0.05重量%〜10重量%のヒドロキシプロピルセルロース;
60重量%〜85重量%のエタノール;
1重量%〜30重量%の水;および
0.01重量%〜20重量%の乳化剤、ここで該乳化剤は、プロピレングリコール、ポリエチレングリコール、グリコールヘキシレングリコール、エチレングリコール、グリセロール、ブタンジオール、ポリエチレングリコールモノラウレートおよびアルギン酸プロピレングリコールエステルからなる群から選択される;
を含み、
該配合物が、pH6〜9を有し、
オキシブチニンが、オキシブチニン遊離塩基、薬学的に許容可能なオキシブチニン塩またはそれらの混合物として存在し、
そして咬合することなく皮膚表面へ局所投与される際に:
少なくとも24時間にわたってオキシブチニン累積量少なくとも10μg/cm2;
投与後少なくとも3時間内にオキシブチニン血漿濃度少なくとも0.5ng/ml;および
投与後24時間でオキシブチニン血漿濃度8ng/mlより下;
を提供することができ、
ここで、該咬合されていないオキシブチニンゲル配合物が、オキシブチニン療法に随伴する副作用を最小化することができる、上記咬合されていないオキシブチニンゲル配合物。 - 配合物のpHが、6である、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- 配合物のpHが、9である、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- オキシブチニンが、オキシブチニン遊離塩基である、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- オキシブチニンが、オキシブチニンクロライドである、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- オキシブチニンが、オキシブチニン遊離塩基とオキシブチニンクロライドとの組み合わせである、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- 少なくとも24時間にわたって少なくとも20μg/cm2のオキシブチニン累積量を提供することができる、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- 配合物が、浸透増強剤を含む、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- オキシブチニンが、オキシブチニン遊離塩基とオキシブチニンクロライドとの混合物である、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- オキシブチニン血漿濃度が投与から6時間後に2.0ng/mlより下である、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- 1.4ng/mlと8ng/mlの間のオキシブチニン濃度を提供することができる、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- 1.42ng/mlと4ng/mlの間のオキシブチニン濃度を提供することができる、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- 1.8ng/mlと4ng/mlの間のオキシブチニン濃度を提供することができる、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- 1.8ng/mlと3ng/mlの間のオキシブチニン濃度を提供することができる、請求項1に記載の咬合されていないオキシブチニンゲル配合物。
- 浸透増強剤が、脂肪酸、脂肪酸エステル、脂肪アルコール、グルセロールトリ−、ジ−およびモノエステル、トリアセチンおよびそれらの混合物からなる群から選択される、請求項8に記載の咬合されていないオキシブチニンゲル配合物。
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US10/286,381 | 2002-11-01 | ||
US10/286,381 US7029694B2 (en) | 2000-04-26 | 2002-11-01 | Compositions and methods for transdermal oxybutynin therapy |
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JP2011204430A Expired - Lifetime JP5770582B2 (ja) | 2002-11-01 | 2011-09-20 | 経皮オキシブチニン療法のための組成物および方法 |
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US (1) | US7029694B2 (ja) |
EP (4) | EP1565136B1 (ja) |
JP (4) | JP2006513161A (ja) |
KR (4) | KR20110043725A (ja) |
CN (2) | CN1708269A (ja) |
AU (2) | AU2003287377B2 (ja) |
BR (1) | BR0315867A (ja) |
CA (2) | CA2504021C (ja) |
DK (1) | DK1565136T3 (ja) |
ES (2) | ES2532495T3 (ja) |
MX (1) | MXPA05004110A (ja) |
NO (2) | NO339626B1 (ja) |
NZ (2) | NZ586108A (ja) |
RU (1) | RU2311170C2 (ja) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2015131826A (ja) * | 2002-11-01 | 2015-07-23 | ワトソン ファーマシューティカルズ, インコーポレイテッド | 経皮オキシブチニン療法のための組成物および方法 |
JP2017031191A (ja) * | 2002-11-01 | 2017-02-09 | アクタビス,インコーポレイテッド | 経皮オキシブチニン療法のための組成物および方法 |
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