JP5501553B2 - 同時押出逆作用剤粒子を含有する改変防止剤形およびその製造工程 - Google Patents
同時押出逆作用剤粒子を含有する改変防止剤形およびその製造工程 Download PDFInfo
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- JP5501553B2 JP5501553B2 JP2006513318A JP2006513318A JP5501553B2 JP 5501553 B2 JP5501553 B2 JP 5501553B2 JP 2006513318 A JP2006513318 A JP 2006513318A JP 2006513318 A JP2006513318 A JP 2006513318A JP 5501553 B2 JP5501553 B2 JP 5501553B2
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- 239000007787 solid Substances 0.000 description 1
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- 239000002195 soluble material Substances 0.000 description 1
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
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- 125000005270 trialkylamine group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Description
本発明は、隔離できるオピオイド拮抗薬のような逆作用剤(adverse agent)を含む同時押出(co-extruded)された医薬組成物と剤形に関する。医薬組成物と剤形は、オピオイドのような活性薬剤を含む剤形の異物混入、乱用、誤用または流用を回避または阻止するのに有益である。本発明は、また、そのような剤形で患者を治療する方法および患者を治療するための剤形使用説明書を持つ剤形を含むキットに関するものである。本発明は、さらに、そのような医薬組成物と剤形の調合のための押出工程に関する。
オピオイド作動薬としても知られるオピオイドは、アヘンまたはモルヒネのような性質を示す活性薬剤グループである。より具体的には、オピオイド作動薬はいくつかの形態のオピオイド受容体活性を示す。オピオイドは主に強力な鎮痛剤として適度に使用されている。
本発明は、同時押出された医薬組成物および隔離された逆作用剤を含有する剤形、およびそのような組成物と剤形を製造するための同時押出方法に関する。本発明はまた、そのような医薬組成物または剤形を用いた患者の治療方法と、そのような医薬組成物または剤形および患者の治療のためのそのような組成物または剤形の使用を目的とする説明書を含むキットに関する。
1 定義
活性剤、逆作用剤、オピオイド作動薬またはオピオイド拮抗薬のような薬剤についてのここでの言及は、特に明記しない限り、そのような薬剤のすべての薬学的に許容されうる型、例えば遊離型、すべての薬学的に許容されうる塩、すべての薬学的に許容されうる塩基、すべての薬学的に許容されうる水和物、すべての薬学的に許容されうる溶媒和物、すべての立体異性体、すべての光学異性体、ならびにそのような薬剤のプロドラッグ、そのような薬剤におけるすべての薬学的活性類似体、および上記のすべての混合物を含むものとする。
一実施態様では、逆作用剤は隔離されない。この実施態様では、逆作用剤は即時放出または制御放出に制限されず、いずれにしろ生体内に放出できる。
上述のように、本発明は同時押出された剤形および隔離された逆作用剤を含有する医薬組成物、ならびにそのような剤形と組成物の製造方法および投与方法を目的とする。一実施態様では、本発明は隔離された逆作用剤を含有する複数の同時押出された粒子を含む剤形に関する。
本発明の活性剤は複数の粒子で製剤されることもあれば、製剤されないこともある。
本発明に従って、逆作用剤は同時押出された多層粒子に製剤される。好ましい特定の実施態様では、逆作用剤は、少なくとも部分的にコアを囲む、好ましくはコアの大部分を囲むシースを含む、同時押出された二層の粒子で隔離される。例えば、図1は、同時押出された円筒形の粒子(10)を含む、限定されていない本発明の一実施態様の透視図である。隔離された逆作用剤はコア(12)内部に含まれる。大部分のコアはシース(14)に覆われている。例えば、コアは、放射状にコアの外曲面(13)を覆うシースを有し、軸方向に覆われていないコアの少なくとも一端(17)をそのままにしている円筒形である。図1では、円筒形粒子(16)の一端でコアの覆われていない部分は斜線部分(17)で示されている。
隔離された逆作用剤を含む本発明のコアは、好ましくは疎水性マトリックス物質を包含する。本発明で有益な疎水性マトリックス物質には、胃腸管で不溶性または低溶解度を有する当業者に既知のものが含まれる。そのような物質には、アクリル酸ポリマーおよびコポリマーとメタクリル酸ポリマーとコポリマー、およびアルキルセルロースから成る群から選択される疎水性物質が含まれるが、これらに限定されない。該マトリックスはまた、ゼイン(zein)、シェラック、硬化ヒマシ油、硬化植物油のような追加の疎水性物質またはその混合物が含まれる。不溶性のそのような疎水性物質は自然に分解でき、最終的に逆作用剤のある部分を放出する。薬学的な技術における通常の技術の一つでは、例えば隔離された逆作用剤の生体内放出を制限または大幅に制限するため、逆作用剤コア中の疎水性マトリックス物質の含量を変化させることにより、そのような放出速度を制御することができる。逆作用剤を隔離するこの方法およびその他の方法は当業者に既知であり、通常の実験により決定することができる。
本発明の同時押出され、隔離された逆作用剤を含む粒子は、少なくとも部分的に逆作用剤を含むコアを囲む、好ましくは大部分の逆作用剤を含むコアを囲むシースを含有する。好ましい一実施態様では、シースは全てではないが、大部分のコアを囲む。シースは、好ましくは疎水性マトリックス物質、および任意に結合剤、追加された遅延剤、可塑剤、および賦形剤を含む。シースが少量の逆作用剤を含むことができる場合、シースは逆作用剤を全く含まないことが好ましい。
本発明は、限定はされないが、活性剤を含む粒子を含む適切な剤形に製剤することができる活性剤を包含する組成物と剤形を含む。本発明の組成物と剤形は、経口投与に続いて、生体内への活性剤のいかなる放出速度、例えば即時放出または制御放出をも提供できる。好ましい実施態様では、活性剤を含む粒子は、オピオイド作動薬のような活性剤の制御放出を提供する。オピオイド拮抗薬の制御放出剤形の製剤および製造方法は技術的に知られている。例えば、米国特許第5,958,452号、第5,965,161号、第5,968,551号、第6,294,195号、第6,335,033号は、それぞれ参照して明確に本明細書に取り込まれるが、制御放出経口オピオイド作動薬剤形を開示する。1つまたはそれ以上のそのような特許の開示には、製剤、マトリックス物質、コーティング物質、疎水性物質、遅延剤、結合剤、可塑剤、賦形剤、ならびにビーズのコーティング方法、スフェロイドの成形方法、造粒方法(湿乾)、オピオイド作動薬の制御放出経口剤形のための錠剤、カプレット、多粒子カプセル形成のための押出方法の詳細が記載されている。
(a)ゴム、セルロースエーテル、タンパク質に由来する物質、ナイロン、アクリル樹脂、ポリ乳酸、ポリビニルクロライド、デンプン、ポリビニルピロリドン、および酢酸フタル酸セルロースのような親水性ポリマーまたは疎水性ポリマー。これらのポリマーのうちセルロースエーテル、例えばアルキルセルロース(例:エチルセルロース)、 C1-C6 ヒドロアルキルセルロース(例:ヒドロキシプロピルセルロースおよびヒドロキシエチルセルロース)、およびアクリル樹脂(例:メタクリル酸コポリマーなどのメタクリレート)のような置換セルロースエーテルが用いられる。制御放出マトリックスは好都合に、約1(重量)%〜約80(重量)%の疎水性ポリマーおよび/または親水性ポリマーを含む。
(b)消化できる長鎖(C8-C40、一実施態様ではC8-C50)の、脂肪酸のような置換炭化水素または非置換炭化水素;硬化植物油;ラウリル、ミリスチル、ステアリル、セチルのような脂肪アルコール、または一実施態様ではセトステリアルアルコール;脂肪酸、例えばグリセリルモノステアラートのグリセリルエステル;鉱油;および蜜ろう、グリコろう、キャスターろう、カルナバろうなどのワックス。約25℃〜約90℃の融点を持つ炭化水素は一実施態様で使用される。これらの長鎖炭化水素物質のうち、脂肪(脂肪族)アルコールは一実施態様において有益である。制御放出マトリックスは少なくとも一つの消化できる長鎖の炭化水素を約60(重量)%まで含むことができる。
(c)ポリアルキレングリコール。制御放出マトリックスは少なくとも一つのポリアルキレングリコールを約60(重量)%まで含むことができる。
本発明はまた、逆作用剤を含むコアと少なくとも部分的にコアを囲むシースを溶融同時押出のような同時押出することにより隔離された逆作用剤を包含する医薬組成物または剤形の調製方法に関する。一実施態様では、本発明は、a)押出ストランドを形成するために、逆作用剤を包含するコア、および少なくとも部分的、好ましくはコアの大部分を囲むシースを同時押出し;b)複数の隔離された逆作用剤粒子を形成するための押出ストランドを切断することによる、複数の隔離された逆作用剤粒子の製造方法に関する。一実施態様では、コアは逆作用剤および疎水性物質を含み、シースは疎水性物質を包含する。
本発明はまた、治療を必要としている患者に本発明の剤形を投与することを含む、患者の病態を治療する方法をを目的としている。剤形は例えば、錠剤またはカプセルのような経口剤形、または座薬のような直腸または膣にいれる剤形である。一実施態様では、症状が痛みであり、剤形にはオピオイドおよび隔離されたオピオイド拮抗薬が含まれる。特定の実施態様では、剤形は一日に2回患者に投与され、別の実施態様では一日に1回投与される。
本発明の剤形では、一投与あたりの活性剤量は特定の指示に対して効果的な量であり、逆の効果を有する剤の量に依存しない。例えば、治療剤がオピオイド作動薬の場合、本発明の剤形におけるオピオイド作動薬量は一般的に約1〜約800mg、一実施態様では約5〜約160mgである。当業者は、過度の実験なしで、特定の指示に必要な治療剤の量を容易に決定できる。
上述のように、本発明はまた、同時押出され、隔離された逆作用剤粒子と活性剤粒子を含む剤形の、それを必要とする患者への、直腸から吸収する座薬の形態での投与を目的とする。座薬として投与される場合、好ましくは、組成物は原料物質(base material)を含む。もし微粒子を溶解しないのであれば、いかなる原料物質も用いることができる。例えば、カカオバターは従来からの座薬の原料物質であるが、ワックスの添加により、わずかに融点をあげるように修飾される。特に多種の分子量を持つポリエチレングリコールを含む水混和性の座薬の原料物質が含まれる。座薬として投与される場合、座薬製剤中の複数の第1と第2の粒子の合計濃度は一般的に組成物の約5.0〜約80重量%である。
本発明はまた、本発明の少なくとも1つの剤形を含むキットを対象としている。一実施態様では、剤形は、例えばボトルまたは箱のような容器中に存在する。別の実施態様では、キットはさらに、患者の、例えば痛みを治療するために剤形を使用することを対象とする一組の説明書を含む。一実施態様では、説明書は印刷されたラベルを容器に貼付するか、またはコンテナに印刷することができる。別の実施態様では、説明書は容器または容器を包含する包装に挿入された印刷シートを含む。説明書はまた、剤形および/またはその使用法が剤形の乱用、誤用または流用を軽減するために設計されたことを記載する。
実施例1は、シースで覆われず隔離されたオピオイド拮抗薬粒子の調製を記述する。オピオイド拮抗薬を含む粒子の調製に使用される押出機へ供給される製剤を以下の表1に示す。
実施例2は、コアが隔離されたオピオイド拮抗薬であるナルトレキソン塩酸を含み、コアの大部分がナルトレキソンを含まないシースによって囲まれる場合、溶融同時押出によるシースで覆われ、隔離されたオピオイド拮抗薬粒子の調製に適切な工程の予言的な例を記載している。より具体的には、コアは円筒形で、シースはコアの両端が軸方向に曝される一方、放射状にコアの長さが囲まれる。この予言的な例に使用されるコア押出機とシース押出機に仕込まれる製剤が表3に示されている。
Claims (11)
- 活性剤を含む複数の第1粒子と、逆作用剤を含むコアと少なくとも部分的に前記コアを囲むシースを含む複数の同時押出第2粒子とを含有する剤形であって、
前記コアが疎水性物質を含有し、前記シースが疎水性物質を含有し、前記コアに含まれる疎水性物質が、前記シースに含まれる疎水性物質と同じであり、該疎水性物質が、アクリル・メタクリル酸ポリマーおよびコポリマー、並びにアルキルセルロースからなる群より選択される、前記剤形。 - 前記逆作用剤が隔離され、前記逆作用剤が前記同時押出第2粒子のコアにのみ存在し、前記逆作用剤は、シクラゾシン、ナロキソン、ナルトレキソン、ナルメフェン、ナルブフィン、ナロルフィン、シクラゾシン、レバロルファン、それらの薬剤的に許容可能な塩、及び前述の2つ以上の混合物からなる群より選択されるオピオイド拮抗薬であり、前記活性剤が、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、ベジトラミド、ブプレノルフィン、ブトルファノール、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、ジアムブロミド、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、ジメチルチアムブテン、ジオキサフェチルブチレート、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、フェンタニール、ヘロイン、ヒドロコドン、ヒドロモルフォン、ヒドロキシペチジン、イソメタドン、ケトベミドン、レバロルファン、レボルファノール、レボフェナシルモルフィン、ロフェンタニル、メペリジン、メプタジノール、メタゾシン、メタドン、メタフォン、モルヒネ、ミロヒネ、ナルブフィン、ナルセイン、ニコモルヒネ、ノルレボファノール、ノルメタドン、ナロルフィン、ノルモルヒネ、ノルピパノン、アヘン、オキシコドン、オキシモルホン、パパベレタム、ペンタゾシン、フェナドソン、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、ピリトラミデ、プロヘプタジン、プロメドール、プロペリジン、プロピラム、プロポキシフェン、スフェンタニル、トラマドール、チリジン、それらの薬剤的に許容可能な塩、及び前述の2つ以上の混合物からなる群より選択されるオピオイド作動薬であり、該剤形は経口投与剤形であり、かつ、該剤形は前記第1粒子および前記同時押出第2粒子を包含するカプセルを含む請求項1に記載の剤形。
- 前記剤形が、痛みの治療に有用な経口投与剤形の乱用、誤用または流用を軽減する、請求項1又は2に記載の剤形。
- 複数の第1粒子及び複数の同時押出第2粒子を含む経口投与剤形であって、前記複数の第1粒子はオピオイド作動薬を含み、患者への経口投与によって前記オピオイド作動薬の制御放出を提供し、前記複数の同時押出第2粒子はオピオイド拮抗薬を含有するコアと、少なくとも部分的に前記コアを囲むシースを含み、前記オピオイド拮抗薬は隔離され、前記第1粒子と前記同時押出第2粒子は互いに0.1mm〜3.0mmの大きさを有し、前記コアと前記同時押出第2粒子の前記シースは互いに少なくとも疎水性物質を含み、該疎水性物質はアクリル・メタクリル酸ポリマーおよびコポリマー、並びにアルキルセルロースからなる群より選択され、前記コアに含まれる疎水性物質が、前記シースに含まれる疎水性物質と同じである、前記剤形。
- 前記オピオイド作動薬がアルフェンタニル、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、ベジトラミド、ブプレノルフィン、ブトルファノール、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、ジアムブロミド、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、ジメチルチアムブテン、ジオキサフェチルブチレート、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、フェンタニール、ヘロイン、ヒドロコドン、ヒドロモルフォン、ヒドロキシペチジン、イソメタドン、ケトベミドン、レバロルファン、レボルファノール、レボフェナシルモルファン、ロフェンタニル、メペリジン、メプタジノール、メタゾシン、メタドン、メタフォン、モルヒネ、ミロヒネ、ナルブフィン、ナルセイン、ニコモルヒネ、ノルレボファノール、ノルメタドン、ナロルフィン、ノルモルヒネ、ノルピパノン、アヘン、オキシコドン、オキシモルホン、パパベレタム、ペンタゾシン、フェナドソン、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、ピリトラミデ、プロヘプタジン、プロメドール、プロペリジン、プロピラム、プロポキシフェン、スフェンタニル、トラマドール、チリジン、それらの薬剤的に許容可能な塩、及び前述の2つ以上の混合物からなる群より選択され、前記オピオイド拮抗薬はシクラゾシン、ナロキソン、ナルトレキソン、ナルメフェン、ナルブフィン、ナロルフィン、シクラザシン、レバロルファン、それらの薬剤的に許容可能な塩、及び前述の2つ以上の混合物からなる群より選択される請求項4に記載の経口投与剤形。
- 前記オピオイド拮抗薬は隔離され、前記剤形は前記第1粒子と前記同時押出第2粒子を包含する錠剤、または前記第1粒子と前記同時押出第2粒子を包含するカプセルを含み、前記同時押出第2粒子は生体内の投与で0.5 mg以下のオピオイド拮抗薬を放出する請求項4又は5に記載の経口投与剤形。
- 前記経口投与剤形が、痛みの治療に有用な経口投与剤形の乱用、誤用または流用を軽減する、請求項4から6のいずれかに記載の経口投与剤形。
- (a)活性剤を含む複数の第1粒子を形成する工程と、
(b)コア組成物とシース組成物とを同時押出することによって、押出ストランドを形成し、ここで、前記シース組成物は前記コア組成物の一部を半径方向に囲み、前記コア組成物は逆作用剤と疎水性物質を含み、前記シース組成物は疎水性物質を含み、前記コアに含まれる疎水性物質が、前記シースに含まれる前記疎水性物質と同じであり、該疎水性物質が、アクリル・メタクリル酸ポリマーおよびコポリマー、並びにアルキルセルロースからなる群より選択され、前記押出ストランドを所定の長さに切断し、複数の第2粒子を形成することによって、逆作用剤を含む複数の第2粒子を形成する工程と、
(c)患者への投与に適切な形態で、前記第1粒子と前記第2粒子を加える工程を有する、剤形の製造方法。 - 前記第1粒子と前記第2粒子が外見上実質的にお互いに同じであり、前記活性剤はオピオイド作動薬であり、前記逆作用剤はオピオイド拮抗薬であり、前記剤形は経口投与剤形であり、前記第1粒子と前記第2粒子の大きさはそれぞれ0.1mm〜3.0mmであり、前記第1粒子と前記第2粒子は患者への投与用のカプセル内に入れられ、前記逆作用剤が隔離されている請求項8に記載の製造方法。
- 患者の痛みを治療するため、オピオイド作動薬を含有する複数の第1粒子と、オピオイド拮抗薬を包含するコア、及び少なくとも部分的に前記コアを囲むシースを含む複数の同時押出第2粒子とを含む経口投与剤形であって、前記オピオイド拮抗薬は隔離されており、かつ、前記オピオイド拮抗薬は前記同時押出第2粒子の前記コアにのみ存在し、前記コアが疎水性物質を含有し、前記シースが疎水性物質を含有し、前記コアに含まれる疎水性物質が、前記シースに含まれる疎水性物質と同じであり、該疎水性物質が、アクリル・メタクリル酸ポリマーおよびコポリマー、並びにアルキルセルロースからなる群より選択される、前記経口投与剤形。
- a)オピオイド作動薬を含む複数の第1粒子と、オピオイド拮抗薬を包含するコア、及び少なくとも部分的に前記コアを囲むシースを含む複数の同時押出第2粒子とを含む少なくとも一回分の経口投与剤形、ここで、前記コアが疎水性物質を含有し、前記シースが疎水性物質を含有し、前記コアに含まれる疎水性物質が、前記シースに含まれる疎水性物質と同じであり、該疎水性物質が、アクリル・メタクリル酸ポリマーおよびコポリマー、並びにアルキルセルロースからなる群より選択される、及び
b)痛みを治療するために前記経口投与剤形の使用取り扱いを説明する印刷された説明書を含み、前記オピオイド拮抗薬が隔離されている、患者の痛みを治療するキット。
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AU2004232370B2 (en) | 2009-12-10 |
CA2519556A1 (en) | 2004-11-04 |
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CA2519556C (en) | 2011-01-18 |
WO2004093819A3 (en) | 2005-03-03 |
US20070065364A1 (en) | 2007-03-22 |
JP2006524261A (ja) | 2006-10-26 |
AU2004232370A1 (en) | 2004-11-04 |
JP2011157384A (ja) | 2011-08-18 |
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