JP2004515455A - Opioid antagonist compositions and dosage forms - Google Patents

Abstract

The present invention provides novel dosage forms, pharmaceutical compositions, kits, and methods of administering opioid antagonists in amounts of at least about 0.0001 mg to less than about 1.0 mg (including about 0.0001 mg to less than about 0.5 mg). About. The solid oral dosage form is disclosed to consist essentially of or comprise the opioid antagonist and other active ingredients (eg, opioid agonists). Immediate release oral dosage forms are disclosed that release the opioid antagonist, and another active ingredient, if present, in all or a significant proportion at the desired time. Simultaneous release dosage forms are disclosed that provide for the simultaneous release of the opioid antagonist and another active ingredient.

Description

コーティングされた錠剤、ビーズ、ペレットまたは顆粒剤は、オピオイドアンタゴニストおよびオピオイドアゴニストの即時放出および／または同時放出を提供するように作製され得る。このような投薬形態は、本明細書中に記載される（例えば、実施例に記載されるような）組成物および投薬形態に従って作製される。コーティングされた固形物質は、その固形物質またはコーティング剤中にオピオイドアンタゴニストおよび／またはオピオイドアゴニストを独立して含む。例えば、特定の実施形態としては、以下の実施形態が挙げられる：１）別の活性な薬学的成分（例えばオピオイドアゴニスト）は、その中殻に存在し、そしてそのオピオイドアンタゴニストは、その中殻を少なくとも部分的に取り囲むコーティング剤中に存在し；２）別の活性な薬学的成分（例えば、オピオイドアゴニスト）、およびオピオイドアンタゴニストは両方とも中殻に存在し；３）別の活性な薬学的成分（例えば、オピオイドアゴニスト）、およびオピオイドアンタゴニストは両方とも、不活性な中殻を少なくとも部分的に取り囲むコーティング剤中に存在し；そして４）オピオイドアンタゴニストは中殻に存在し、そして別の活性な薬学的成分（例えば、オピオイドアゴニスト）は、その中殻を部分的に取り囲むコーティング剤中に存在する。
【０１４２】
用語「単位用量」とは、治療用化合物の量（この量は、１以上の規定の単位が単回の治療的投与として提供され得るような量である）を含む投薬形態を意味するように本明細書中で用いられる。特定の組合せならびに投薬形態中に含まれるアゴニストおよびアンタゴニストの量に依存して、改善された治療効果、相加的な治療効果または相乗的な治療効果が観察される。改善された治療効果とは、アンタゴニストが、アゴニスト単独で提供される治療効果（例えば、鎮痛効果）を増強する効果である。相加的な治療効果とは、アンタゴニストとおよびアゴニストのそれぞれが共通の治療効果を保有し、そしてこれら２つの薬物の組合せが、これらの個々の治療効果の総計に近い全体の治療効果を提供する効果である。相乗的な治療効果とは、これらの２つの薬物の組合せが、これら個々の治療効果の総計よりも大きい全体の治療効果を提供する効果である。
【０１４３】
図２は、本発明の非限定的実施形態を示す：コーティングされたノンパレイルな固形物質１およびコーティングされたノンパレイルな固形物質２の薬学的組成物（例えば、ペレットまたはビーズ）。コーティングされたペレット１は、１つ以上の薬学的賦形剤の不活性なノンパレイルな中殻３ならびに低用量のオピオイドアンタゴニストおよび１つ以上の薬学的賦形剤を有するコーティング剤４を含む。コーティングされたペレット２は、１つ以上の薬学的賦形剤の不活性なノンパレイルな中殻９ならびに低用量の活性な薬学的成分（この場合、オピオイドアゴニスト）および１つ以上の薬学的賦形剤を有するコーティング剤５を含む。薬学的賦形剤は、各生産時に独立して選択され得る。同様に、中殻３および中殻９は、同じかまたは異なる成分を含み得る。これらの２つの違う型のコーティングされたノンパレイルは、カプセル（例えば、硬質ゼラチンカプセル）中に充填され得るか、または錠剤の中殻に圧縮され得る。コーティングされたノンパレイルは、そのカプセル中に充填されるかまたはその錠剤の中殻に圧縮される前に、必要に応じて１つ以上の他の薬学的賦形剤と混合される。
【０１４４】
コーティングされたノンパレイル１またはコーティングされたノンパレイル２は、実施例１０のプロセスに従い、そして一般的に、少なくとも２つの異なるコーティングされたペレットの混合物を形成することによって作製され、ここで、第１ペレットは、第１ノンパレイルなペレット上にオピオイドアンタゴニストをコーティングすることによって作製され、そして第２ペレットは、第２ノンパレイルなペレット上にオピオイドアゴニストをコーティングすることによって作製される。
【０１４５】
カプセル中または錠剤中に含まれる場合、各々の投薬形態中に存在する各薬物の総量は、所望の治療的応答を提供するために必要とされる薬物の量または有用な薬物の量に依存する。
【０１４６】
図３は、１つ以上の薬学的賦形剤の不活性なノンパレイルな中殻８ならびに低用量のオピオイドアンタゴニスト、一用量の別の薬学的成分（この場合、オピオイドアゴニスト）および１つ以上の薬学的賦形剤を有するコーティング剤６を有するコーティングされたノンパレイルなビーズ７の薬学的組成物を示す。薬学的賦形剤は、各生産時に独立して選択され得る。コーティングされたノンパレイルは、カプセル（硬質ゼラチンカプセル）中に充填されるかまたは錠剤の中殻に圧縮され得る。コーティングされたノンパレイルは、カプセル中に充填されるかまたは錠剤の中殻に圧縮される前に、必要に応じて１つ以上の他の薬学的賦形剤と混合される。
【０１４７】
コーティングされたノンパレイルなビーズ７は、実施例１１のプロセスに従って、そして一般的に、オピオイドアンタゴニスト、オピオイドアゴニスト、少なくとも１つのポリマーまたはフィルム形成材料、および必要に応じて可塑剤を有する、組成物を調製し、そしてノンパレイルペレットにこの組成物を適用することによって作製される。
【０１４８】
図４は、オピオイドアンタゴニストおよび薬学的賦形剤の第１ブレンドを有する第１顆粒１１と別の薬学的成分（この場合、オピオイドアゴニスト）および薬学的賦形剤の第２ブレンドを有する第２顆粒１２とを有する混合顆粒１０を示す。薬学的賦形剤は、各生産時に独立して選択され得る。同様に、顆粒１１および顆粒１２は、同じかまたは異なる賦形剤を含み得る。２つの異なる顆粒は、カプセル（例えば、硬質ゼラチンカプセル）中に一緒に充填され得るか、または錠剤の中殻に一緒に圧縮され得る。これらの顆粒は、カプセル中に充填されるかまたは錠剤の中殻に圧縮される前に、１つ以上の薬学的賦形剤と必要に応じて混合される。
【０１４９】
混合顆粒１０は、一般に実施例１３のプロセスに従って、そして一般的には、オピオイドアンタゴニストおよび薬学的賦形剤の第１ブレンドを有する第１顆粒を形成し、オピオイドアゴニストおよび薬学的賦形剤の第２ブレンドを有する第２顆粒を形成し、そして第１顆粒および第２顆粒を混合することによって作製される。
【０１５０】
図５は、第１顆粒１７、低用量のオピオイドアンタゴニストおよび少なくとも１つの薬学的賦形剤を有する混合物１６を含む第２顆粒１５の薬学的組成物を示す。ここで、第１顆粒は、一用量の別の薬学的成分（この場合、オピオイドアゴニスト）および少なくとも１つ薬学的賦形剤を含む。これらの薬学的賦形剤は、各生産時に独立して選択される。複数の第２顆粒は、カプセル（例えば、硬質ゼラチンカプセル）中に充填され得るか、または錠剤の中殻に圧縮され得る。第２顆粒は、カプセル中に充填されるかまたは錠剤の中殻に圧縮される前に、１つ以上の他の薬学的賦形剤と必要に応じて混合される。
【０１５１】
第２顆粒１５は、実施例１４のプロセスに従って、そして一般的に、別の薬学的成分（この場合、オピオイドアゴニスト）および少なくとも１つの薬学的賦形剤を有する第１顆粒１７を形成し、そして第１顆粒と、オピオイドアンタゴニストおよび少なくとも１つの薬学的賦形剤の混合物１６、とを混合して、第２顆粒を形成することによって作製される。
【０１５２】
図６は、結合剤、オピオイドアンタゴニスト、別の薬学的成分（この場合、オピオイドアゴニスト）を有する結合組成物２１でコーティングされた薬学的賦形剤２３と、必要に応じて１つ以上の他の薬学的賦形剤２２との混合物のコーティングされた顆粒を有する薬学的組成物２０を示す。薬学的賦形剤は、各生産時に独立して選択され得る。薬学的組成物は、カプセル（例えば、硬質ゼラチンカプセル）中に充填され得るかまたは錠剤の中殻に圧縮され得る。
【０１５３】
薬学的組成物２０は、実施例１５のプロセスに従って、そして一般的に、結合剤、オピオイドアゴニストおよびオピオイドアンタゴニストを有する結合剤組成物を調製し、そして薬学的賦形剤の混合物を結合剤組成物でコーティングしてコーティングされた顆粒を形成することによって作製される。このコーティングされた顆粒を、次いで、１つ以上の薬学的賦形剤と必要に応じて混合して薬学的組成物２０を形成する。
【０１５４】
処置の異なる方法は、異なる投薬強度および投薬形態におけるアンタゴニストに対するアゴニストの異なる比を必要とする。組成物２および組成物１０は、アンタゴニストに対するアゴニストの実質的に異なる比を含む薬学的組成物バッチが、各々コーティングされたノンパレイル１およびノンパレイル２または顆粒１１および顆粒１２を再配合する必要なく、薬学的組成物中に各々含まれる、各コーティングされたノンパレイルの量、またはコーティングされた顆粒の量をそれぞれ変化させることによって簡単に、容易になされ得るという利点を有する。同様に、その各々のコーティングされたノンパレイルまたはコーティングされた顆粒内の各薬物の相対量を変化させて、特定の薬物強度の薬学的組成物を作製し得る。
【０１５５】
組合せ投薬形態の利点は、一単位用量形態中の活性な薬学的成分両方の存在が、一用量投与される毎に所望の用量比でコンプライアンスを保証することである。さらなる利点は、軽減された複雑性、軽減された服用間違いの可能性、および同時に複数の生成物のより簡便な投与、ならびに患者が有する付随する症状（例えば、悪心、嘔吐、不能または嚥下に起因する痛みの悪化）を調節し得る摂取量の低減を含み得る。
【０１５６】
例えば、図７は、薬物比と５００ｍｇ充填カプセル中に充填されたノンパレイルとの間の関係のグラフを示す。コーティングされたノンパレイル１は、５００ｍｇのコーティングされたノンパレイル１あたり１ｍｇのオピオイドアンタゴニストを含むよう作製され得る。同様に、コーティングされたノンパレイル２は、５００ｍｇのコーティングされたノンパレイル２あたり２００ｍｇのオピオイドアゴニスト（または別の薬学的成分）を含むよう作製され得る。従って、５００ｍｇのカプセルが重量比９０％のノンパレイル２および重量比１０％のノンパレイル１まで充填される場合、カプセルは、１８０ｍｇのオピオイドアンタゴニストおよび０．１ｍｇのオピオイドアンタゴニストを含み、そしてアンタゴニストに対するアゴニストの比は、１８００である。しかし、５００ｍｇのカプセルが、重量比５０％のノンパレイル２および重量比５０％のノンパレイル１まで充填される場合、そのカプセルは、１００ｍｇのオピオイドアゴニストおよび０．５ｍｇのオピオイドアンタゴニストを含み、そしてアンタゴニストに対するアゴニストの比は、２００である。一方、５００ｍｇのカプセルが、同量のノンパレイル２およびノンパレイル１で充填された場合、ノンパレイル１が５００ｍｇのノンパレイル１あたり０．５ｍｇのアンタゴニストを含むよう作製されるが、次いでこのカプセルは１００ｍｇのオピオイドアゴニストおよび０．２５ｍｇのオピオイドアンタゴニストを含み、そしてアンタゴニストに対するアゴニストの比は、４００である。図７に示される例示的な関係は、図２および図４の処方物についても一般にいえる。これらの関係は、用いられた処方物および特定の薬物中含まれる各薬物の量に従って変化する。
【０１５７】
しかし、図３、図５および図６の薬学的組成物は、オピオイドアゴニスト（または別の活性な薬学的成分）に対するオピオイドアンタゴニストの固定比率を、これらの薬学的組成物を含む投薬形態の総薬物強度にかかわらず提供するのに有用である。例えば、図８は、薬物比と５００ｍｇ充填カプセルに充填されたノンパレイルとの間の関係のグラフを示す。コーティングされたノンパレイル７（図３に示される）は、５００ｍｇのコーティングされたノンパレイル７あたり０．５ｍｇのオピオイドアンタゴニストおよび５００ｍｇのコーティングされたノンパレイル７あたり２００ｍｇのオピオイドアゴニストを含むように作製され得る。従って、５００ｍｇのカプセルが重量比１００％のノンパレイル７で充填される場合、カプセルは、２００ｍｇのオピオイドアゴニストおよび０．５ｍｇのオピオイドアンタゴニストを含み、そしてアンタゴニストに対するアゴニストの薬物比は、４００である。しかし、５００ｍｇのカプセルが、重量比５０％のノンパレイル７および重量比５０％の薬学的賦形剤まで充填される場合、このカプセルは１００ｍｇのオピオイドアゴニストおよび０．２５ｍｇのオピオイドアンタゴニストを含み、そしてアンタゴニストに対するアゴニストの割合は、４００のままである。しかし、コーティングされたノンパレイル７が５００ｍｇのコーティングされたノンパレイル７あたり０．２５ｍｇのオピオイドアンタゴニストおよび５００ｍｇのコーティングされたノンパレイル７あたり２００ｍｇのオピオイドアゴニストを含むよう作製され、そして５００ｍｇのカプセルが重量比１００％のノンパレイル７で充填される場合、このカプセルは、２００ｍｇのオピオイドアゴニストおよび０．２５ｍｇのオピオイドアンタゴニストを含み、そしてアンタゴニストに対するアゴニストの薬物比は、８００である。換言すれば、図３、図５および図６の薬学的組成物の相対量の減少は、薬物比を変更しないが、総薬物強度を減少させる。
【０１５８】
別の実施形態は、コーティングされた第１顆粒の薬学的組成物を提供し、ここで、この顆粒は、オピオイドアゴニスト（または別の活性な薬学的成分）および薬学的賦形剤の混合物を含み、そして、そのコーティング剤は、オピオイドアンタゴニストおよび１つ以上の薬学的賦形剤を含む。この顆粒は、実施例１６のプロセスに従って作製され得、そしてオピオイドアゴニストの組成物および薬学的賦形剤の混合物をコーティングすることによって、そしてオピオイドアンタゴニストのコーティングされた組成物および１つ以上の薬学的賦形剤を用いて一般的に作製される。
【０１５９】
本発明はまた、オピオイドアンタゴニスト、別の活性な薬学的成分（例えば、オピオイドアゴニスト）および少なくとも１つの薬学的賦形剤を有するスプレードライした顆粒の薬学的組成物を提供する。これらの顆粒は、実施例１７のプロセスに従って、そして一般的に、オピオイドアンタゴニスト、オピオイドアゴニストおよび少なくとも１つの薬学的賦形剤を有する溶液をスプレイドライしてスプレードライした顆粒を形成することによって作製され得る。
【０１６０】
投薬形態はまた、別の活性な薬学的成分（例えば、オピオイドアゴニスト）中のオピオイドアンタゴニストの懸濁液、および少なくとも１つの非水系のビヒクルを充填した軟質ゼラチンカプセルを含む。この投薬は、実施例１８のプロセスに従って、そして一般的に、オピオイドアンタゴニスト、オピオイドアゴニスト、および少なくとも１つの非水系ビヒクルから本質的に構成される分散物で軟質ゼラチンカプセルを充填することによって、作製され得る。
【０１６１】
吸入またはガス注入のための組成物としては、薬学的に受容可能な、水溶液もしくは有機溶媒、またはその混合物における溶液および懸濁液が挙げられ、散剤もまた意図される。液体または固形の組成物は、上記のような適切な薬学的に受容可能な賦形剤を含み得る。これらの組成物は、局所効果または全身効果のための経口経路または鼻腔呼吸経路によって一般的に投与される。好ましくは滅菌された薬学的に受容可能な溶媒中の組成物は、不活性なガスの使用によって噴霧されてもよい。噴霧される溶液は、噴霧するデバイスから直接吸息され得るか、または噴霧デバイスは、フェースマスク、テントもしくは間欠的陽圧呼吸装置に接続され得る。溶液組成物、懸濁液組成物または散剤組成物は、好ましくは、適切な様式における処方物を送達するデバイスから、経口投与または経鼻投与され得る。
【０１６２】
特定の条件の処置について、別の薬学的に活性な薬剤とともにオピオイドアンタゴニストを使用することが所望であり得る。例えば、本発明に従うオピオイドアンタゴニストは、同時使用、別々の使用または逐次使用のために、組合せ調製物として別の治療用薬剤とともに提供され得る。オピオイドアンタゴニストの固形組成物は単独で、オピオイドアゴニストが挙げられるがこれらに限定されない１つ以上の任意の他の治療用薬剤と組合せて投与され得る。このような組合せ調製物は、例えば、ツインパックの形態であり得る。一般に、このような組合せにおける使用のための他の治療用薬剤の現在利用可能な投薬形態は、適切である。
【０１６３】
単独のオピオイドアンタゴニスト、または他の活性な薬学的成分と組合せたオピオイドアンタゴニストは、以下が挙げられるがこれらに限定されない公知の手順によってヒト被験体に投与され得る：経口様式の投与、舌下様式の投与、筋内様式の投与、皮下様式の投与、静脈内様式の投与、気管内様式の投与、経粘膜様式の投与、または経皮様式の投与。これらの化合物の組合せが投与される場合、これらの化合物は、同じ組成物において一緒に投与され得るか、または別々の組成物において投与され得る。オピオイドアンタゴニストおよび別の活性な薬学的成分が別々の組成物において投与される場合、これらは類似の様式の投与または異なる様式の投与によって投与され得るか、互いに同時、または一方のすぐ前もしくはすぐ後に他方が投与され得る。
【０１６４】
オピオイドアンタゴニストまたはオピオイドアゴニストを投与するために現在用いられる市販の処方物は、記載されるように改変されて、本発明に従う薬学的組成物および処方物を提供し得る。ヒト投与のためのオピオイドアゴニストの市販の経口用量形態としては、以下が挙げられる：コデイン、ジヒドロコデイン（例えば、Ｗｙｅｔｈ−Ａｙｅｒｓｔ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ提供のＳＹＮＡＬＧＯＳ−ＤＣ（登録商標））、フェンタニール、（例えば、Ａｂｂｏｔｔ Ｌａｂｏｒａｔｏｒｉｅｓ提供のＡＣＴＩＱ（登録商標））、ヒドロコドン（例えば、Ｋｎｏｌｌ Ｌａｂｏｒａｔｏｒｉｅｓ提供のＶＩＣＯＤＩＮ（登録商標）およびＶＩＣＯＰＲＯＦＥＮ（登録商標）；Ｗａｔｓｏｎ Ｌａｂｏｒａｔｏｒｉｅｓ提供のＮＯＲＣＯ（登録商標）；Ｅｎｄｏ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ提供のＨＹＣＯＤＡＮ（登録商標）；Ａｂａｒａ提供のＮＯＲＣＥＴ（登録商標）；Ｍａｌｌｉｎｃｋｒｏｄｔ提供のＡＮＥＸＳＩＡ（登録商標）、ＨＹＤＲＯＣＥＴ（登録商標）、およびＬＯＲＣＥＴ−ＨＤ（登録商標）；ＵＣＢ Ｐｈａｒｍａ提供のＬＯＲＴＡＢ（登録商標）；Ａｓｃｈｅｒ提供のＨＹ−ＰＨＥＮ（登録商標）；Ｓｃｈｗａｒｚ Ｐｈａｒｍａ提供のＣＯ−ＧＥＳＩＣ（登録商標）；Ｚｅｎｉｔｈ Ｇｏｌｄｌｉｎｅ提供のＡＬＬＡＹ（登録商標））、ヒドロモルホン（例えば、Ｋｎｏｌｌ提供のＤＩＬＡＵＤＩＤ（登録商標））、レボルファノール（例えば、ＩＣＮ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ提供のＬＥＶＯ−ＤＲＯＭＯＲＡＮ（登録商標））、メぺリジン（例えば、Ｓａｎｏｆｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ提供のＤＥＭＥＲＯＬ（登録商標））、メタドン（例えば、Ｍａｌｌｉｎｃｋｒｏｄｔ提供のＭＥＴＨＡＤＯＳＥ（登録商標）；およびＲｏｘａｎｅ Ｌａｂｏｒａｔｏｒｉｅｓ提供のＤＯＬＯＰＨＩＮＥ（登録商標）ＨＣｌ）、モルフィン（例えば、Ｆａｕｌｄｉｎｇ Ｌａｂｏｒａｔｏｒｉｅｓ提供のＫＡＤＩＡＮ（登録商標）；Ｐｕｒｄｕｅ Ｆｒｅｄｅｒｉｃｋ提供のＭＳ ＣＯＮＴＩＮ（登録商標）；Ｒｏｘａｎｅ提供のＯＲＡＭＯＲＰＨ（登録商標）ＳＲ）、オキシコドン（例えば、Ｅｎｄｏ提供のＰＥＲＣＯＣＥＴ（登録商標）およびＰＥＲＣＯＤＡＮ（登録商標）；Ｍａｌｌｉｎｃｋｒｏｄｔ提供のＯＸＹＣＥＴ（登録商標）；Ｐｕｒｄｕｅ Ｆｒｅｄｅｒｉｃｋ提供のＯＸＹＣＯＮＴＩＮ（登録商標）；Ｏｒｔｈｏ−ＭｃＮｅｉｌ Ｐｈａｒｍａｃｅｕｔｉｃａｌ提供のＴＹＬＯＸ（登録商標）；Ｒｏｘａｎｅ提供のＲＯＸＩＣＯＤＯＮＥ（登録商標）、ＲＯＸＩＬＯＸ（登録商標）、およびＲＯＸＩＣＥＴ（登録商標））、ペンタゾシン（例えば、Ｓａｎｏｆｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ提供のＴＡＬＡＣＥＮ（登録商標）およびＴＡＬＷＩＮ（登録商標））、プロポキシフェン（例えば、Ｅｌｉ Ｌｉｌｌｙ＆Ｃｏ．提供のＤＡＲＶＯＣＥＴ−Ｎ（登録商標）およびＤＡＶＲＯＮ（登録商標）；Ｌｅｄｅｒｌｅ提供のＤＯＬＥＮＥ（登録商標）；Ｗｙｅｔｈ−Ａｙｅｒｓｔ提供のＷＹＧＥＳＩＣ（登録商標））、ならびにトラマドール（例えば、Ｏｒｔｈｏ−ＭｃＮｅｉｌ Ｐｈａｒｍａｃｅｕｔｉｃａｌ提供のＵＬＴＲＡＭ（登録商標））。ヒト投与のためのオピオイドアゴニストの市販の液体用量形態としては、以下が挙げられる：ヒドロコドン（例えば、Ｈａｌｓｅｙ提供のＨＹＤＲＯＰＨＡＮＥ（登録商標））、ヒドロモルホン（例えば、Ｋｎｏｌｌ提供のＤＩＬＡＵＤＩＤ（登録商標））、メペリジン（例えば、Ｓａｎｏｆｉ提供のＤＥＭＥＲＯＬ（登録商標））、メタドン（例えば、Ｒｏｘａｎｅ提供のＤＯＬＯＰＨＩＮＥ（登録商標））、オキシコドン（例えば、Ｋｎｏｌｌ提供のＨＹＣＯＭＩＮＥ（登録商標）；Ｒｏｘａｎｅ提供のＲＯＸＩＬＯＸ（登録商標））、およびプロポキシフェン（例えば、Ｅｌｉ Ｌｉｌｌｙ提供のＤＡＲＶＯＮ−Ｎ（登録商標））。ヒト投与のための市販の非経口用量形態としては、以下が挙げられる：アルフェンタニル（例えば、Ａｋｏｒｎ提供のＡＬＦＥＮＴＡ（登録商標））、ブプレノルフィン（例えば、Ｒｅｃｋｉｔｔ ＆ Ｃｏｌｍａｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ提供のＢＵＰＲＥＮＥＸ（登録商標））、ブトルファノール（例えば、Ａｐｏｔｈｅｃｏｎ提供のＳＴＡＤＯＬ（登録商標））、デゾシン（例えば、Ａｓｔｒａｚｅｎｅｃａ提供のＤＡＬＧＡＮ（登録商標））、フェンタニル、ヒドロモルホン（例えば、Ｋｎｏｌｌ提供のＤＩＬＡＵＤＩＤ−ＨＰ（登録商標））、レバロルファン（例えば、Ｒｏｃｈｅ提供のＬＯＲＦＡＮ（登録商標））、レボファノール（例えば、ＩＣＮ提供のＬＥＶＯ−ＤＲＯＭＯＲＡＮ（登録商標））、メペリジン（例えば、Ｓａｎｏｆｉ提供のＤＥＭＥＲＯＬ（登録商標））、メタドン（例えば、Ｒｏｘａｎｅ提供のＤＯＬＯＰＨＩＮＥ（登録商標）ＨＣＩ）、モルフェン（例えば、Ａｓｔｒａｚｅｎｅｃａ提供のＡＳＴＲＡＭＯＲＰＨ（登録商標）；Ｅｌｋｉｎｓ−Ｓｉｎｎ提供のＤＵＲＡＭＯＲＰＨ（登録商標）およびＩＮＦＵＭＯＲＰＨ（登録商標））、オキシモルホン（例えば、Ｅｎｄｏ提供のＮＵＭＯＲＰＨＡＮ（登録商標））、ナルブルフィン（例えば、Ｅｎｄｏ Ｐｈａｒｍａｃｅｕｔｉｃａｌ提供のＮＵＢＡＩＮ（登録商標））、ならびにペンタゾシン（Ａｂｂｏｔｔ提供のＴＡＬＷＩＮ（登録商標））。ヒト投与のためのオピオイドアゴニストの市販の経皮用量形態としては、フェンタニール（例えば、Ｊａｎｓｓｅｎ提供のＤＵＲＡＧＥＳＩＣ（登録商標））が挙げられる。ヒト投与のためのオピオイドアゴニストの市販の坐剤用量形態としては、オキシモルホン（例えば、Ｅｎｄｏ提供のＮＵＭＯＲＰＨＡＮ（登録商標））が挙げられる。
【０１６５】
本発明はまた、任意の他の治療用薬剤（オピオイドアゴニストが挙げられるがこれに限定されない）と一緒にオピオイドアンタゴニストを含む薬学的キットを含み、ここで、アンタゴニストは、上記で特定したような量で存在する。このキット中には、オピオイドアンタゴニストおよびオピオイドアゴニストまたは他の治療用薬剤が、化合物として任意の型の別個の容器（例えば、瓶またはパッケージ（例えば、カプセル剤、錠剤、丸薬またはパッチ））、および／または薬学的に受容可能な賦形剤またはキャリアと組合せた化合物として別個の容器に各々提供され得る。あるいは、オピオイドアンタゴニストおよびオピオイドアゴニストまたは他の治療用薬剤は、賦形剤またはキャリアと共にまたはこれらを含まずに、１つ以上の容器（例えば、瓶またはパッケージ）において、一緒に兼ね備えられ得る。従って、例えば、本発明はまた、本質的にオピオイドアンタゴニストからなる任意の型の容器（例えば、パッケージ、瓶、エンベロープ、ブリスターパック、バッグ、もしくはポーチ、シリンジ、吸入器もしくはチューブ）および本質的にオピオイドアゴニストまたは他の治療用薬剤からなる別個の容器を含む薬学的キットを含み、各容器は、所望の場合、賦形剤または他のキャリアを含む。
【０１６６】
薬学的組成物は、例えば、本明細書に記載される範囲内で、受容可能な薬学的有効性を提供する投薬形態におけるこのような処置を必要とするヒト被験体／患者に投与され得る。任意の特定の適用において使用に必要とされる特定の用量は、特定の化合物または選択された組成物のみならず、投与経路、処置される状態の性質、年齢、状態、疼痛耐性、および患者の他の特異体質、患者に伴う同時投薬または特定の食物、および当業者が認識する他の因子を、患者毎に最終的に担当医の裁量での適切な投薬量によって変化させることが理解される。
【０１６７】
好ましい実施形態において、オピオイドアンタゴニストが単独で投与される場合、投与されたオピオイドアンタゴニストの量は、オピオイドアゴニストの鎮痛性の作用強度を増強するかまたは維持するのに有効な量、および／あるいはオピオイドアゴニストの有害な副作用を減弱されるかまたは維持するのに有効な量、および／あるいは耐性、禁断症状、依存症および／または嗜癖を減弱するのに有効な量である。この量は、当業者によって容易に決定される、
本発明は、以下の実施例において記載され、これらは、本発明の理解を補助するために示されており、前述の特許請求の範囲において定義されるような本発明を多少なりとも限定するように解釈されるべきではない。実施例の処方物の調製において用いられた薬学的に活性な成分および薬学的に不活性な成分は、既存の研究論文が存在した場合、ＵＳＰ／ＮＦにおいて要約されていた。
【０１６８】
（実施例１）
製剤を、１単位用量（例えば、単一のカプセルまたは錠剤または丸薬またはパッチ）中にオピオイドアンタゴニストを含む複数の活性な化合物を含むように製造する。あるいは、オピオイドアンタゴニスト（例えば、ナルトレキソン）である１つの活性成分のみを含むように、製剤を製造する。塩酸ナルトレキソン（ナルトレキソン）は、本明細書に記載され、そして本発明に従う投薬形態において別々のカプセルとして投与されるように製造した。
【０１６９】
製剤原料の塩酸ナルトレキソンの概要、構造および物理的／化学的特性（ＵＳＰ）は、以下の通りである：
一般名： 塩酸ナルトレキソン
化学名： １７−シクロプロピルメチル−４，５α−エポキシ−３，１４−ジヒドロキシモルフィナン−６−一塩酸
分子式： Ｃ_２０Ｈ_２３ＮＯ_４・ＨＣｌ
分子量： ３７７．８６
（例えば、塩酸ナルトレキソンの物理的性質および化学的性質の詳細についてＵＳＰ概要を参照のこと）。
【０１７０】
（ナルトレキソンカプセル剤）
ナルトレキソンカプセル剤を、図１Ａ〜図１Ｂに例証され、そして以下に記載されるプロセスによって、代表的な濃度である、０．０１ｍｇ、０．１ｍｇおよび１．０ｍｇのナルトレキソンＨＣｌで製造した。
【０１７１】
【表２】

【０１７２】
【表３】

【０１７３】
【表４】

１．列挙された量は、１２００カプセルバッチについてである。他のバッチの大きさは、同様の設備および処理工程を用いて、等量の処方物と共に用いられ得る。
２．ＦＭＣ Ｃｏｒｐｏｒａｔｉｏｎ，Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｄｉｖｉｓｉｏｎ，１７３５ Ｍａｒｋｅｔ Ｓｔ．Ｐｈｉｌａｄｅｌｐｈｉａ，ＰＡ １９１０３によりＡｖｉｃｅｌ（登録商標）として供給されている。
３．Ｗｈｉｔｔａｋｅｒ，Ｃｌａｒｋ ＆ Ｄａｎｉｅｌｄ，Ｉｎｃ．１０００ Ｃｏｏｌｉｄｇｅ Ｓｔ．，Ｓｏｕｔｈ Ｐｌａｉｎｆｉｅｌｄ，ＮＪ ０７０８０により供給されている。
【０１７４】
図１Ａおよび図１Ｂの製造スキームを用いて、ヒトの投与に有用なナルトレキソンカプセルを製造した。ナルトレキソンおよびプラシーボカプセルについての製造プロセスの工程の説明は以下の通りである：
ナルトレキソンカプセルの３つの選択された濃度（０．０１ｍｇ、０．１ｍｇ、１．０ｍｇ）について、一連のブレンドを作製し、そして充填のためにそれを合わせて規定の濃度を作製した。さらなるブレンドを作製し、そしてそれを合わせて０．０１ｍｇ未満（例えば、０．００１ｍｇ）の濃度を作製した。さらなるブレンドを、０．００１ｍｇ未満（０．０００１ｍｇ以下を含む）で作製し得る。
【０１７５】
（プラシーボブレンド）
プラシーボブレンドを、以下のプロセスに従い作製した。
【０１７６】
第１に図１Ａを参照し、ステアリン酸マグネシウム５０を新しい６０メッシュのステンレスふるいに通し、そして移動したステアリン酸塩５２をブレンダーボールに直接収集した。微結晶性セルロース５４の小部分を同一のふるいに通し、そして移動したステアリン酸５２に上乗せして収集し、次いで少なくとも１分間十分に混合した。これを、セルロースの別の小部分を用いて繰り返した。残りのセルロースをふるいに通し、そして１５分間十分に混合した。得られたブレンド５６を、肉眼で見える混入物について検査した。
【０１７７】
（１．０ｍｇ ナルトレキソンブレンド）
全量のナルトレキソン５８を、新しい６０メッシュのステンレスふるいに通し、そして移動したナルトレキソン６０をブレンダーボールに直接収集した。プラシーボブレンド５６の小部分を同一のふるいに通し、そしてナルトレキソンに上乗せして収集し、次いで少なくとも１分間十分に混合した。これを、プラシーボブレンドの別の小部分を用いて繰り返した。残りのプラシーボをふるいに通し、そして１５分間十分に混合した。結果は、１．０ｍｇ ナルトレキソンブレンド６２であった。このブレンドを、肉眼で見える混入物について検査した。このブレンド６２を、次の段落に記載されるようにさらに希釈するか、または１．０ｍｇの用量形態が最終産物として所望される場合、（以下にさらに記載されるように）カプセルを充填するために使用した。
【０１７８】
（０．１ｍｇ ナルトレキソンブレンド）
上述されるように作製された規定の量の１．０ｍｇ ナルトレキソンブレンド６２を、ブレンダーボールに移した。プラシーボブレンド５６の小部分を１．０ｍｇ ナルトレキソンブレンド６２に上乗せし、次いで少なくとも１分間十分に混合した。これを、プラシーボブレンド５６の別の小部分を用いて繰り返した。１０：１希釈物を提供するために必要なプラシーボブレンド５６の残りの部分を添加し、そして１５分間十分に混合した。結果は、０．１ｍｇ ナルトレキソンブレンド６４であった。このブレンド６４を、肉眼で見える混入物について検査した。このブレンド６４を、次の段落に記載されるようにさらに希釈するか、または０．１ｍｇ用量が最終産物として所望される場合、（以下にさらに記載されるように）カプセルを充填するために使用した。
【０１７９】
（０．０１ｍｇ ナルトレキソンブレンド）
上述されるように作製された規定の量の０．１ｍｇ ナルトレキソンブレンド６４を、ブレンダーボールに移した。プラシーボブレンド５６の小部分を０．１ｍｇ ナルトレキソンブレンド６４に上乗せし、次いで少なくとも１分間十分に混合した。これを、プラシーボブレンド５６の別の小部分を用いて繰り返した。１０：１希釈物を提供するために必要なプラシーボブレンド５６の残りの部分を添加し、そして１５分間十分に混合した。結果は、０．０１ｍｇ ナルトレキソンブレンド６６であった。このブレンド６６を、肉眼で見える混入物について検査した。
【０１８０】
０．００１ｍｇ ナルトレキソンブレンド７６（図１Ａおよび１Ｂに記載されるような）を達成するために、類似の希釈を、規定の量の０．０１ｍｇ ナルトレキソンブレンドを用いて実施した。より小さい用量が所望される場合、さらなる希釈もまた企図される。
【０１８１】
（カプセルの充填）
図１Ｂ（図１Ａの続き）に関して、以下の充填手順を用いて、各ナルトレキソン用量形態６２、６４、および６６をカプセル中に加えた。１２５０の空のカプセル殻６８を充填トレイに取り付けた。キャップを、工程７０に示すように、主要部から外した。
【０１８２】
１２５０のカプセルを充填するのに必要とされる１．０ｍｇ ナルトレキソンブレンド６２の量（１％の過剰量を含む）を決定した。規定の濃度のナルトレキソンブレンドのこの量を重量測定し、そしてカプセル機器に移した。このカプセル７０を全量のナルトレキソンブレンドを用いて充填し、各充填操作について圧力を３回適用した。このカプセルを、充填したカプセル７２を形成するために封鎖した。このカプセル７２をほこり除去し、そして磨き上げた。充填したカプセル７２を重量の変動について試験し、そして所定の範囲内のカプセル７２のみを最終産物−１．０ｍｇ ナルトレキソンカプセル７４として受け入れた。このカプセル７４を、安全な、標識された二重ポリエチレン袋に収集した。
【０１８３】
同様の様式で、０．１ｍｇ ナルトレキソンブレンド６４および０．０１ｍｇ ナルトレキソンブレンドを、再度、図１Ｂにおいて説明される通り、カプセル中に加え、そして仕上げた。
【０１８４】
連続希釈およびブレンドのプロセスを用いて、低濃度強ナルトレキソンカプセルを製造した。さらに、カプセルの充填重量における減少を用いて、例えば、０．０００１ｍｇ ナルトレキソンカプセルを製造するために必要なナルトレキソンカプセル強度における比例関係の減少を達成した。
【０１８５】
プラシーボを形成するために、プラシーボブレンド５６を、カプセルを充填するためにナルトレキソンブレンド６２と置き換えて使用し、再度、同様の様式で仕上げた。
【０１８６】
（実施例２）
この実施例は、固体経口投薬形態（実施例１の投薬形態のいくつかを含む）の臨床的使用および評価を実証する。実施例１において記載される手順に従って調製したナルトレキソンの薬学的組成物および投薬形態を、ヒト臨床試験において、モルヒネ、トラマドール、または炭化水素（ｈｙｄｒｏｃａｄｏｎｅ）／アセトアミノフェンと共に投与した。
【０１８７】
モルヒネ単独の研究およびモルヒネとナルトレキソンを組み合わせての研究は、本明細書で参考として援用される、米国出願番号６０／２０２，２６５（２０００年５月５日出願）の実施例１に記載される。例示的な研究結果の要約は以下の通りである。
【０１８８】
この臨床研究は、ＭＳ６０ｍｇ単独に対して、硫酸モルヒネ（以後、モルヒネまたはＭＳと呼ぶ）６０ｍｇと組み合わせた３つの異なる用量のナルトレキソン（ＮＴＸ）の鎮痛活性を比較するために設計された。試験被験体は、中程度から重度の手術後歯痛を有した。試験生成物は、ナルトレキソン（ＮＹＸ）１ｍｇとＭＳ ６０ｍｇ、ＮＴＸ ０．１ｍｇとＭＳ ６０ｍｇ、およびＮＴＸ ０．０１ｍｇとＭＳ ６０ｍｇであった。被験体が中程度から重度の手術後の疼痛を患っている場合、これらの処置のうちの１つの単一経口用量を投与した。研究集団は、２つ以上の埋伏した第３臼歯の抜歯後の中程度から重度の疼痛を伴う２０１人の男性および女性の外来患者であった。
【０１８９】
データ分析のために、特定の疼痛のパラメータを以下の通り算出した。各時点において疼痛が変化する程度を、疼痛解放スコア（ｐａｉｎ ｒｅｌｉｅｆ ｓｃｏｒｅ）（ＰＲ、０＝なし、１＝少ない、２＝いくらか、３＝多い、４＝完全な）および疼痛強度差スコア（ｐａｉｎ ｉｎｔｅｎｓｉｔｙ ｐａｉｎ ｄｉｆｆｅｒｅｎｃｅ ｓｃｏｒｅ）（ＰＩＤ、基底線と現時点との間の差、この疼痛強度スケールは、０＝なし、１＝穏やか、２＝中程度、３＝重度からなる）により測定した。試験期間全体にわたって疼痛が変化する程度を、総疼痛解放スコア（ＴＯＴＰＡＲ−８）、疼痛強度差の和（ＳＰＩＤ−８）、最大疼痛解放スコア（ＭＡＸＰＡＲ）、ピーク疼痛強度差（ＰＥＡＫＰＩＤ）、および全体的な評価（０＝乏しい、１＝十分、２＝良好、３＝非常に良好、４＝秀逸）により測定した。ＴＯＴＰＡＲ−８およびＳＰＩＤ−８を、隣接点間の時間差によって重みを加えた、全８時間の観察期間のそれぞれＰＲおよびＰＩＤの和（すなわち、台形法則を用いた曲線の下の領域）として定義する。ＭＡＸＰＡＲおよびＰＥＡＫＰＩＤを、それぞれＰＲおよびＰＩＤの最大値として定義する。効力および安全性の評価は、全体的な疼痛の評価、救出までの時間、救出薬剤を用いて再治療した患者の割合、意義のある疼痛の解放が生じるまでの時間、最初に認知される疼痛の解放および視覚的アナログスケール（ｖｉｓｕａｌ ａｎａｌｏｇ ｓｃａｌｅ）（ＶＡＳ）が生じるまでの時間、ならびに逆事象の評価に関した。
【０１９０】
プラシーボ処置群は、最も低い平均総疼痛解放スコアを有した。４つ全ての活性処置群は、プラシーボよりも数値的に高い平均総疼痛解放スコアを示した。組み合わせ処置は、平均総疼痛解放スコアにおいて逆の用量−応答関係を有した（すなわち、最も高い用量のＮＴＸが最も低い平均総疼痛解放スコアを有し、そして最も低い用量のＮＴＸが最も高い平均総疼痛解放スコアを有した）。このパターン（低用量（０．０１ｍｇ ＮＴＸ）＞中用量（１．０ｍｇ ＮＴＸ））を、この研究を通して全ての疼痛解放変数について観察した。０．０１ｍｇ ＮＴＸおよび０．１ｍｇ ＮＴＸの組み合わせ処置についての平均総疼痛解放スコアは、ＭＳ単独処置についての平均総疼痛解放スコアよりも高く、１．０ｍｇ ＮＴＸの組み合わせ処置の平均は、ＭＳ単独処置についての平均総疼痛解放スコアに匹敵するか、またはそれよりも低かった。
【０１９１】
プラシーボ処置は、最も低い４時間の疼痛強度差スコアの和の平均を有した。４つ全ての活性処置群は、疼痛強度差の和の平均においてプラシーボと比較して改善されたプロフィールを示した。０．０１ｍｇ ＮＴＸおよび０．１ｍｇ ＮＴＸの組み合わせ処置についての疼痛強度差スコアの和の平均は、ＭＳ単独処置についての疼痛強度差スコアの和の平均よりも高く、１．０ｍｇ ＮＴＸの組み合わせ処置は、ＭＳ単独処置についての疼痛強度差スコアの和の平均に匹敵した。６時間および８時間の疼痛強度差スコアの和のパターンは、４時間での疼痛強度差スコアの和に同様であった。
【０１９２】
有意な疼痛解放が生じるまでの治療時間は、０．０１ｍｇ ＮＴＸ（低用量）の組み合わせ処置群において最も短かった。プラシーボ処置は、意義のある疼痛解放に達した最小数の被験体を有した。
【０１９３】
報告された主な有害な副作用を、消化系（悪心または嘔吐）または神経系（めまい感または傾眠）として分類した。
【０１９４】
トラマドール単独の研究およびトラマドールとナルトレキソンを組み合わせての研究は、米国出願番号０９／５６６，０７１（２０００年５月５日出願）およびＰＣＴ／ＵＳ００／１２４９３［ＷＯ／００ ６７７３９］（２０００年５月５日出願）の継続である米国出願番号０９／７５６，３３１（２００１年１月８日出願）の実施例１０に記載される（これらの全開示は本明細書で参考として援用される）。例示的な研究結果の要約は以下の通りである。
【０１９５】
疼痛を伴うヒト被験体におけるこの研究において、塩酸トラマドール（トラマドール）を、単独でかまたは種々の量（用量）のオピオイドアンタゴニストであるナルトレキソンと組み合わせて投与した。この研究において、１つの目的は、オピオイドアンタゴニスト（例えば、塩酸ナルトレキソン（以後、この実施例において、ナルトレキソンまたはＮＴＸと呼ぶ））が、以下の歯科手術後の疼痛を伴うヒト被験体／患者において塩酸トラマドール（以後、この実施例において、トラマドールまたはＴと呼ぶ）の鎮痛性特性を増強するか否かを決定することであった。さらなる目的は、オピオイドアンタゴニスト（例えば、ＮＴＸ）がヒトにおいてトラマドールの有害な副作用を緩和（例えば、減少、遮断、または予防）するか否かを評価することであった。
【０１９６】
ヒト被験体を、以下の５つの処置群の１つに無作為化した：
・第１群：Ｔ（５０ｍｇ）およびＮＴＸ（１ｍｇ）
・第２群：Ｔ（５０ｍｇ）およびＮＴＸ（０．１ｍｇ）
・第３群：Ｔ（５０ｍｇ）およびＮＴＸ（０．０１ｍｇ）
・第４群：Ｔ（５０ｍｇ）およびプラシーボ
・第５群：プラシーボおよびプラシーボ。
【０１９７】
中程度から重度の疼痛を伴う全ての被験体は、研究薬剤の１つの用量を受けた。被験体は、経口摂取するための２つのカプセル（一方はトラマドールまたはプラシーボ、もう一方はナルトレキソンまたはプラシーボ）を受けた。
【０１９８】
疼痛の評価を、処置前に実施した。歯科手術後、被験体の疼痛レベルを、訓練を受けた観察者により評価した。この被験体は、（１）１つの疼痛カテゴリー（０＝なし、１＝穏やか、２＝中程度、３＝重度）を言葉で表わすこと、および（２）０〜１００ｍｍの視覚的アナログスケール（ＶＡＳ）（ここで、この尺度に１つのスラッシュを置くことにより、０＝疼痛なし、および１００＝考え得る最もひどい疼痛である）を用いること、の両方により初期疼痛強度を報告した。疼痛の評価を、処置後にも実施した。
【０１９９】
効力および安全性の評価は、疼痛の強度、疼痛の解放、全体的な疼痛の評価、有意な疼痛の解放までの時間の評価（ストップウォッチ）、視覚的スケールアナログ（ＶＡＳ）、および逆事象の評価を含んだ。データの分析のために、特定の疼痛パラメータを、一般的に上述されるように算出した。
【０２００】
プラシーボ処置群は、最も低い４時間の総疼痛解放スコアの平均を有した。活性処置群の４つ全てが、プラシーボよりも数字的に高い４時間の総疼痛解放スコアの平均を示した。組み合わせの処置は、４時間の総疼痛解放スコアの平均において、逆の用量−応答関係を有した（すなわち、最も高い用量のＮＴＸが最も低い４時間の総疼痛解放スコアの平均を有し、そして最も低い用量のＮＴＸが最も高い４時間の総疼痛解放スコアの平均を有した）。０．０１ｍｇ ＮＴＸおよび０．１ｍｇ ＮＴＸの組み合わせ処置についての４時間の総疼痛解放スコアの平均は、Ｔ単独での処置よりも高く、１．０ｍｇ ＮＴＸの組み合わせ処置の平均は、Ｔ単独での処置よりも低かった。
【０２０１】
プラシーボ処置は、最も低い４時間の疼痛強度差スコアの和の平均を有した。４つ全ての活性処置群は、４時間の疼痛強度差の和の平均においてプラシーボと比較して改善されたプロフィールを示した。０．０１ｍｇ ＮＴＸおよび０．１ｍｇ ＮＴＸの組み合わせ処置についての４時間の疼痛強度差スコアの和の平均は、Ｔ単独処置についての４時間の疼痛強度差スコアの和の平均よりも高く、１．０ｍｇ ＮＴＸの組み合わせ処置は、Ｔ単独処置についての４時間の疼痛強度差スコアの和の平均よりも低かった。６時間および８時間の疼痛強度差スコアの和のパターンは、４時間での疼痛強度差の和と同様であった。
【０２０２】
４時間、６時間、および８時間の疼痛強度差結果の視覚的アナログスケールの和は以下の通りである。プラシーボ処置は、最も低い４時間の疼痛強度差のＶＡＳの和の平均を有した。４つの活性処置群は、プラシーボについての疼痛強度差のＶＡＳの和の平均よりも高い疼痛強度差のＶＡＳの和の平均を示した。３つのＮＴＸの組み合わせ処置についての４時間の疼痛強度差のＶＡＳの和の平均は、Ｔ単独についての４時間の疼痛強度差のＶＡＳの和の平均よりも高かった。６時間および８時間の疼痛強度差スコアのＶＡＳの和の平均は、４時間での疼痛強度差スコアのＶＡＳの和の平均と同様であった。
【０２０３】
プラシーボ処置は、意義のある疼痛解放に達した最も少数の被験体を有した。さらに、全ての組み合わせ処置群は、Ｔ単独を受けた群よりも多い意義のある疼痛解放に達した被験体の数を有した。
【０２０４】
プラシーボ処置についての時間毎の疼痛解放スコアは、一般的に均一であるが、活性処置群についての時間毎の疼痛解放スコアは、一般的に時間経過と共に改善した。８時間の研究時間を通して続いたプラシーボ群と活性処置群との間の区別が存在した。
【０２０５】
報告された主な逆の事象を、胃腸障害（悪心または嘔吐）または神経系障害（めまい感、頭痛または鎮静）として分類した。
【０２０６】
モルヒネ単独の研究およびモルヒネとナルトレキソンを組み合わせての研究は、米国出願番号６０／２４５，１１０（２０００年１１月１日出願）の実施例２に記載される（この出願は本明細書で参考として援用される）。例示的な研究結果の要約は以下の通りである。
【０２０７】
用量範囲研究において、塩酸ナルトレキソン（０．１ｍｇ、０．０１ｍｇ、または０．００１ｍｇ）と組み合わせての硫酸モルヒネ（６０ｍｇ）の用量を、歯科手術後の中程度から重度の疼痛を有する患者に投与した。この研究は、モルヒネ単独、ナルトレキソン単独、モルヒネおよびプラシーボと組み合わせての３つの異なる用量のナルトレキソンの鎮痛効果（開始、ピーク、期間、および総合効果）を調査するために実施した。
【０２０８】
３００人の被験体の研究を、以下の６つの処置群を用いて設計した：Ａ）プラシーボ（５０ｐｔｓ）；Ｂ）モルヒネ６０ｍｇ（５０ｐｔｓ）；Ｃ）ナルトレキソン ０．０１ｍｇ（５０ｐｔｓ）；Ｄ）モルヒネ６０ｍｇおよびナルトレキソン０．１ｍｇ（５０ｐｔｓ）；Ｅ）モルヒネ６０ｍｇおよびナルトレキソン０．０１ｍｇ（５０ｐｔｓ）；Ｆ）モルヒネ６０ｍｇおよびナルトレキソン０．００１ｍｇ（５０ｐｔｓ）。この研究において、３つまたは４つの完全にかまたは部分的に骨と衝突した第３臼歯の抜歯後の中程度から重度の疼痛の処置において、被験体が中程度から重度の手術後の疼痛を患っている場合、これらの処置のうちの１つの単一経口用量を投与した。効力についての観察期間は処置後８時間であり、そして安全性についての観察期間は処置後２４時間であった。
【０２０９】
効力および安全性の評価は、疼痛の強度、疼痛の解放、全体的な疼痛の評価、意義のある疼痛の解放までの時間の評価（ストップウォッチ）、視覚的アナログスケール（ＶＡＳ）、および逆事象の評価に関した。データの分析のために、特定の疼痛パラメータを、一般的に上述されるように算出した。
【０２１０】
０．０１ｍｇ ＮＴＸ単独処置群およびプラシーボ処置群は、最も低い４時間の疼痛強度差の和（ＳＰＩＤ）のスコアの平均を有した。ＭＳ単独またはＮＴＸと組み合わせた活性処置群の４つ全てが、ＮＴＸ単独またはプラシーボと比較して、平均ＳＰＩＤにおいて改善されたプロフィールを示した。０．０１ｍｇ ＮＴＸおよび０．１ｍｇ ＮＴＸの組み合わせ処置についての４時間のＳＰＩＤスコアの平均は、ＭＳ単独での処置についての４時間のＳＰＩＤスコアの平均よりも高く、０．００１ｍｇ ＮＴＸの組み合わせ処置は、ＭＳ単独処置についての４時間のＳＰＩＤスコアの平均に匹敵した。６時間および８時間のＳＰＩＤスコアのパターンは、４時間でのＳＰＩＤスコアのパターンに同様であった。
【０２１１】
０．０１ｍｇ ＮＴＸ単独処置群およびプラシーボ処置群は、最も低い総疼痛解放スコアの平均を有した。活性処置群の４つ全てが、０．０１ｍｇ ＮＴＸ単独処置群およびプラシーボ処置群よりも数字的に高い総疼痛解放スコアの平均を示した。組み合わせの処置は、総疼痛解放スコアの平均において、逆の用量−応答関係を有した（すなわち、最も高い用量のＮＴＸが最も低い総疼痛解放スコアの平均を有し、そして最も低い用量のＮＴＸが最も高い総疼痛解放スコアの平均を有した）。このパターン（高用量（０．１ｍｇ ＮＴＸ）＞中用量（０．０１ｍｇ ＮＴＸ）＞低用量（０．００１ｍｇ ＮＴＸ））を、この研究を通して疼痛解放変数について一般的に観察した。０．０１ｍｇ ＮＴＸおよび０．１ｍｇ ＮＴＸの組み合わせ処置についての総疼痛解放スコアの平均は、ＭＳ単独処置についての総疼痛解放スコアの平均よりも高く、０．００１ｍｇ ＮＴＸの組み合わせ処置の平均は、ＭＳ単独処置についての総疼痛解放スコアの平均に匹敵するか、またはこれよりも低かった。
【０２１２】
ＮＴＸ単独およびプラシーボ処置群は、「乏しい」全体的な評価スコアを有する最も多い被験体の数を有した。全体的な評価スコアのプロフィールは、被験体の評価に基づく。
【０２１３】
意義のある疼痛の解放が生じるまでの治療時間は、０．１ｍｇ ＮＴＸの組み合わせ処置群において最も短かった。
【０２１４】
鎮痛が生じるまでの治療時間は、０．１ｍｇ ＮＴＸの組み合わせ処置群において最も短かった。
【０２１５】
基準の疼痛強度スコアおよび視覚的アナログスコアは、一般的に、処置群間で比較可能であった。
【０２１６】
報告された主な有害な副作用を、消化系（悪心または嘔吐）または神経系（めまい感または傾眠）として分類した。
【０２１７】
アセトアミノフェン（モルフィンの代わり）単独を用いたヒドロコドンの研究およびナルトレキソンと組み合わせての研究は、米国出願番号６０／２４５，１１０（２０００年１１月１日出願）の実施例３に記載される（この出願は明細書で参考として援用される）。例示的な研究結果の要約は以下の通りである。
【０２１８】
用量範囲研究において、アセトアミノフェン（５００ｍｇ）およびナルトレキソン（０．１ｍｇ、０．０１ｍｇ、および０．００１ｍｇ）を伴うヒドロコドン（５ｍｇ）の用量を、歯科手術後の中程度から重度の疼痛に対して投与した。この研究は、アセトアミノフェンとヒドロコドン、ヒドロコドン／アセトアミノフェンと組み合わせての４つの異なる用量のナルトレキソン、およびプラシーボの鎮痛効果を調査するために実施した。
【０２１９】
３００人の被験体の研究を、以下の６つの処置群を用いて設計した：Ａ）プラシーボ（５０ｐｔｓ）；Ｂ）ＨＣ ５ｍｇ／ＡＰＡＰ ５００ｍｇおよびプラシーボ（５０ｐｔｓ）；Ｃ）ＨＣ ５ｍｇ／ＡＰＡＰ ５００ｍｇおよびＮＴＸ １．０ｍｇ（５０ｐｔｓ）；Ｄ）ＨＣ ５ｍｇ／ＡＰＡＰ ５００ｍｇおよびＮＴＸ ０．１ｍｇ（５０ｐｔｓ）；Ｅ）ＨＣ ５ｍｇ／ＡＰＡＰ ５００ｍｇおよびＮＴＸ ０．０１ｍｇ（５０ｐｔｓ）；Ｆ）ＨＣ ５ｍｇ／ＡＰＡＰ ５００ｍｇおよびＮＴＸ ０．００１ｍｇ（５０ｐｔｓ）。この研究において、３つまたは４つの完全にかまたは部分的に骨と衝突した第３臼歯の抜歯後の中程度から重度の疼痛の処置において、被験体が中程度から重度の手術後の疼痛を患っている場合、これらの処置のうちの１つの単一経口用量を投与した。効力についての観察期間は処置後８時間であり、そして安全性についての観察期間は処置後２４時間であった。
【０２２０】
効力および安全性の評価は、疼痛の強度、疼痛の解放、全体的な疼痛の評価、有意な疼痛の解放までの時間の評価（ストップウォッチ）、視覚的アナログスケール、および逆事象の評価に関した。データの分析のために、特定の疼痛パラメータを、一般的に上述されるように算出した。
【０２２１】
プラシーボ処置群は、最も低い４時間の疼痛強度差の和（ＳＰＩＤ）のスコアの平均を有した。ＨＣ／ＡＰＡＰ単独またはＮＴＸと組み合わせた活性処置群の５つ全てが、プラシーボと比較して、平均ＳＰＩＤにおいて改善されたプロフィールを示した。０．００１ｍｇ ＮＴＸの組み合わせ処置についての４時間のＳＰＩＤスコアの平均は、ＨＣ／ＡＰＡＰ単独処置についての４時間のＳＰＩＤスコアの平均よりも高く、他のＮＴＸの組み合わせ処置は、ＨＣ／ＡＰＡＰ単独処置についての４時間のＳＰＩＤスコアの平均に匹敵するかまたはそれよりも低かった。６時間および８時間のＳＰＩＤスコアのパターンは、４時間でのＳＰＩＤスコアのパターンに同様であった。
【０２２２】
プラシーボ処置群は、最も低い総疼痛解放スコアの平均を有した。ＨＣ／ＡＰＡＰ単独を伴う活性処置群またはＮＴＸと組み合わせての活性処置群の５つ全てが、プラシーボよりも数字的に高い総疼痛解放スコアの平均を示した。０．００１ｍｇ ＮＴＸの組み合わせ処置についての総疼痛解放スコアの平均は、ＨＣ／ＡＰＡＰ単独処置についての総疼痛解放スコアの平均よりも高く、他のＮＴＸの組み合わせ処置の平均は、ＨＣ／ＡＰＡＰ単独処置についての総疼痛解放スコアの平均に匹敵するか、またはこれよりも低かった。
【０２２３】
プラシーボ処置群は、「乏しい」全体的な評価スコアを有する最も多い被験体の数を有した。０．００１ｍｇ ＮＴＸの組み合わせ処置群は、最も多い「秀逸な」、「非常に良好な」、および「良好な」全体的な評価スコアの合計を有する被験体の数を有した。全体的な評価スコアのプロフィールは、被験体の評価に基づく。
【０２２４】
意義のある疼痛の解放が生じるまでの治療時間は、０．００１ｍｇ ＮＴＸ（最も低い用量）の組み合わせ処置群において最も短かった。プラシーボおよび０．０１ｍｇ ＮＴＸの組み合わせ処置群は、最も低い意義のある疼痛解放に達した被験体の数を有した。
【０２２５】
基準の疼痛強度スコアおよび視覚的疼痛スコアは、一般的に、処置群間で比較可能であった。
【０２２６】
報告された主な逆事象を、消化系（悪心または嘔吐）または神経系（めまい感または傾眠）として分類した。
【０２２７】
モルヒネ単独およびナルトレキソンと組み合わせてモルヒネの別の研究を実施した。この用量範囲研究において、塩酸ナルトレキソン（０．１ｍｇ）と組み合わせた硫酸モルヒネの用量（３０ｍｇ、６０ｍｇ、および９０ｍｇ）を、歯科手術後の男性患者における中程度から重度の疼痛について投与した。この研究は、プラシーボと比較して、そしてモルヒネ単独と比較して、ナルトレキソン ０．１ｍｇを含むモルヒネの異なる用量の組み合わせの効力を調査するために、単独で投与した場合およびナルトレキソン ０．１ｍｇと同時投与した場合のモルヒネの用量−応答効果を評価するために、およびモルヒネと同時投与した場合の異なる用量のモルヒネに対するナルトレキソン ０．１ｍｇの効力の一貫性を試験するために実施した。
【０２２８】
２１０の被験体の研究を、以下の７つの処置群で設計した：Ａ）プラシーボ（３０ｐｔ）；Ｂ）モルヒネ ３０ｍｇ（３０ｐｔ）；Ｃ）モルヒネ ６０ｍｇ（３０ｐｔ）；Ｄ）モルヒネ ９０ｍｇ（３０ｐｔ）：Ｅ）モルヒネ ３０ｍｇおよびナルトレキソン ０．１ｍｇ（３０ｐｔ）；Ｆ）モルヒネ ６０ｍｇおよびナルトレキソン ０．１ｍｇ（３０ｐｔ）；Ｇ）モルヒネ ９０ｍｇおよびナルトレキソン ０．１ｍｇ（３０ｐｔ）。本研究では、３または４本の全てまたは一部が骨に埋伏した第３大臼歯の抜歯術後の中程度〜重篤な疼痛の処置において、この患者が術後の中程度〜重篤な疼痛に苦しんでいる場合に、これらの処置のうちの１つの経口単回用量を、投与した。効果についての観察期間は、処置後８時間であり、そして安全性についての観察期間は、処置後２４時間であった。
【０２２９】
効果の評価および安全性の評価は、ＰＩＤ、ＳＰＩＤ−４、ＳＰＩＤ−６およびＳＰＩＤ−８、ＰＥＡＫＰＩＤ、各評価でのＶＡＳ−ＰＩＤ、ＶＡＳ−ＳＰＩＤ−４、−６、および−８、ＰＥＡＫ−ＶＡＳ−ＰＩＤ、疼痛軽減（ＰＲ）スコア、ＴＯＴＰＡＲ−４、−６および−８、ＭＡＸＰＡＲ、総体的評価（ｇｌｏｂａｌ ｅｖａｌｕａｔｉｏｎ）、痛覚消失開始までの時間、再投薬までの時間、４、８、２４時間までに再投薬する患者の割合、そして有害反応事象の評価を含んだ。データ解析のために特定の疼痛パラメーターを、一般的に上に記載されるように算出した。
【０２３０】
プラシーボ処置群の平均ＰＩＤスコアは、一般的に平坦であったが、活性な処置群（３０ｍｇ ＭＳ、６０ｍｇ ＭＳ、および９０ｍｇ ＭＳ単独、またはこれらと０．１ｍｇのＮＴＸとの組合せ）の平均ＰＩＤスコアは、長期に渡って一般的に改善した。モルヒネ単独処置群およびモルヒネ／ナルトレキソンの組合せ処置群の、１〜８時間の時間毎の各評価時間の平均スコアは、プラシーボ群の平均ＰＩＤスコアよりも高かった。ＰＩＤスコアによって測定された最高の疼痛軽減は、９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸの組合せ処置群で観察された。
【０２３１】
プラシーボ処置群は、４時間目の疼痛強度差（Ｓｕｍ ｏｆ Ｐａｉｎ Ｉｎｔｅｎｓｉｔｙ Ｄｉｆｆｅｒｅｎｃｅ）（ＳＰＩＤ）スコアの最低値を有した。３０ｍｇ、６０ｍｇ、もしくは９０ｍｇ ＭＳ単独、またはこれらと０．１ｍｇのＮＴＸとの組合せを用いる、活性処置群の６つ全ては、プラシーボに対して改善された平均ＳＰＩＤプロフィールを示した。９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸの組合せ処置の４時間目の平均ＳＰＩＤスコアは、全ての処置群の中で最も高かった。３０ｍｇ、６０ｍｇ、および９０ｍｇ ＭＳ単独処置群の平均ＳＰＩＤスコアは、同等であった。対照的に、３０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ、６０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ、および９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸの組合せ処置群の平均ＳＰＩＤスコアは用量応答を示し、９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群が、最も高い平均ＳＰＩＤ−４スコアを有し、そして３０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群が、組合せ処置群の中で最も低い平均ＳＰＩＤ−４スコアを有した。
【０２３２】
プラシーボ処置群は、最も低い平均全疼痛改善スコア（Ｔｏｔａｌ Ｐａｉｎ Ｒｅｌｉｅｆ ｓｃｏｒｅ）を有した。３０ｍｇ、６０ｍｇ、もしくは９０ｍｇ ＭＳ単独、またはこれらと０．１ｍｇのＮＴＸとの組合せを用いる、活性処置群の６つ全ては、数的にプラシーボより高い平均全疼痛改善スコアを示した。９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸの組合せ処置の平均全疼痛改善スコアは、全ての処置群の中で最も高かった。３０ｍｇ、６０ｍｇ、および９０ｍｇ ＭＳ単独処置群の平均全疼痛改善スコアは、同等であった。対照的に、３０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ、６０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ、および９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸの組合せ処置群の平均全疼痛改善スコアは用量応答を示し、９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群が、最も高い平均全疼痛改善スコアを有し、そして３０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群が、組合せ処置群の中で最も低い平均全疼痛改善スコアを有した。
【０２３３】
平均ＰＥＡＫＰＩＤスコアは、処置群の間で変化し、６つ全ての活性処置群は、プラシーボ群と比較して、平均ＰＥＡＫＰＩＤスコアがより大きかった。他の全ての群と比較して、９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群の平均ＰＥＡＫＰＩＤスコアが、最も高かった。
【０２３４】
プラシーボ処置の平均疼痛軽減スコアは、長期に改善された活性処置群（３０ｍｇ、６０ｍｇ、９０ｍｇ ＭＳ単独、またはこれらと０．１ｍｇのＮＴＸとの組合せ）の平均疼痛軽減スコアよりも低かった。８時間の研究期間に渡ってプラシーボ処置群と活性処置群との間での分離が続いた。最も高い疼痛軽減スコアを、９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群で観察した。
【０２３５】
平均ＭＡＸＰＡＲスコアは、処置群の間で変化した。９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群の平均ＭＡＸＰＡＲスコアは、他の全ての群と比較して、最も高かった。６つ全ての活性処置群の平均スコアは、プラシーボ群の平均スコアよりも大きかった。
【０２３６】
プラシーボ処置群は、「乏しい」総体的評価スコアを有する被験体の数が最も多かった。９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群は、「秀逸」、「非常に良好」および「良好」の総体的評価スコアを有する被験体の総数が最も多かった。総体的評価スコアのプロフィールは、被験体の評価に基づいている。
【０２３７】
痛覚消失開始時間の中央値は、９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群で最短であった。
【０２３８】
プラシーボ群は、再投薬までの時間の中央値が最も短く、そして９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群では、再投薬までの時間の中央値が最も長かった。９０ｍｇ ＭＳ／０．１ｍｇ ＮＴＸ組合せ処置群の７０％を超える被験体は４時間目で、そして同じ組合せ群の６０％を超える被験体は８時間目で、再投薬の助けを必要としなかった。
【０２３９】
疼痛強度スコアのベースラインおよび可視的アナログスケールスコア（ｖｉｓｕａｌ ａｎａｌｏｇ ｓｃａｌｅ ｓｃｏｒｅ）は、一般的に、処置群全体で同等であった。
【０２４０】
報告された有害な事象の多数は、消化器系（悪心もしくは嘔吐）または神経系（めまい感もしくは傾眠）に分類された。
【０２４１】
（実施例３）
本実施例は、塩酸ナルトレキソン（これらの実施例において「ナルトレキソン」または「ＮＴＸ」といわれる）を含む投薬形態の調製を記載し、これを臨床的評価に使用した。本実施例はまた、この投薬形態の溶出の測定を記載する。
【０２４２】
本実施例の臨床的評価および溶出試験のための投薬形態を、オピオイドアンタゴニストおよび実施例１に従う賦形剤を含む硬質ゼラチンカプセル剤を調製することによって、提供した。このカプセル剤は、ナルトレキソンＨＣｌおよび２つの薬学的賦形剤を含んだ。以下の表は、ＮＴＸカプセル剤の質的組成物を示す。
【０２４３】
【表５】

空カプセル殻にＮＴＸ、微結晶性セルロース、およびステアリン酸マグネシウムの粉末ブレンドを充填することによって、ＮＴＸカプセル剤を調製した。充填重量は、作製したＮＴＸカプセルのそれぞれの強さについて一定であった。
【０２４４】
他に特定せず、そして特定の実施例について開示された特定の条件および特定のパラメーターに供さない限り、実施例３ならびに他の実施例における溶出試験は、米国薬局方２４（２０００）物理的試験＜７１１＞（これは、参考として本明細書中で援用される）の装置２（パドル攪拌要素）を採用する溶出試験を使用して行った。
【０２４５】
溶出試験を、溶出容器当たり２つのカプセルについて０．１Ｎの塩酸（ＨＣｌ）５００ｍｌの媒体中で実施した。試験媒体の温度を、約３７．０℃（＋／−０．５℃）で維持し、パドルの速度は、５０ｒｐｍであった。試験媒体のサンプルアリコートを、種々の時点で採取し、ナルトレキソン（および／または、溶出試験すべき別の成分）の量を決定した。試験した成分の放出を、時間に対する放出の割合として報告する。
【０２４６】
以下の表に、ＮＴＸカプセル剤の溶出試験について得られた結果を要約する。これらの結果は、６つの試験の平均値である。
【０２４７】
【表６】

この投薬形態は、約５〜１０分間で、ナルトレキソンの理論量の９０％を超える迅速な放出を提供した。
【０２４８】
（実施例４）
本実施例は、臨床的評価のための硫酸モルヒネ五水和物（ＭＳ）を含む投薬形態の調製を記載する。本実施例はまた、この投薬形態の溶出の測定を記載する。臨床的評価および溶出試験のための本実施例の投薬形態は、硬質ゼラチンカプセル剤であった。ＭＳカプセルを、市販の１５ｍｇＭＳ即時放出型錠剤の１〜４個を、硬質ゼラチンカプセルに入れることによって調製した。次に、微結晶性セルロースおよびステアリン酸マグネシウムの混合物を、カプセル剤にかさを与え、そして加工を容易にするために加えた。以下の表は、ＭＳカプセル剤の質的な組成を示す。
【０２４９】
【表７】

本実施例におけるインビトロでの溶出速度を、米国薬局方２４（２０００）の装置２（パドル攪拌要素）（実施例３に記載ものと同じ条件およびパラメーターを使用する）を使用して決定した。
【０２５０】
溶出試験のために、１個の６０ｍｇＭＳカプセル剤を、試験溶媒に入れた。以下の表は、ＭＳカプセル剤の溶出試験について得られた結果を要約する。これらの結果は、６つの試験の平均値である。
【０２５１】
【表８】

これらの溶出の結果は、この投薬形態が、硫酸モルヒネ五水和物の迅速な放出を提供することを示す。
【０２５２】
（実施例５）
本実施例は、塩酸オキシコドン塩を含む投薬形態の調製を記載する。本実施例はまた、この投薬形態の溶出の測定を記載する。以下の一般的な手順を使用してＲｏｘｉｃｏｄｏｎｅ（登録商標）（Ｒｏｘａｎｅ Ｌａｂｏｒａｔｏｒｉｅｓ，Ｉｎｃ．）として供給される塩酸オキシコドン（本実施例においてオキシコドンといわれる）を異なる強さで含有するカプセル剤を調製した。Ｒｏｘｉｃｏｄｏｎｅ（登録商標）錠剤は、５．０ｍｇ（塩酸オキシコドン）の強さの錠剤で利用可能である。各Ｒｏｘｉｃｏｄｏｎｅ（登録商標）錠剤は、５．０ｍｇの塩酸オキシコドンの理論的薬物含量を有することが記載されているが、実際の量は、許容可能な範囲（例えば、約１０％）内で変化し得る。
【０２５３】
５．０ｍｇの塩酸オキシコドンのカプセル剤を、微結晶性セルロース（２２９．２ｍｇ）とステアリン酸マグネシウム（１．２ｍｇ）をブレンドが形成されるまで混合することによって作製した。このブレンドおよび１個のＲｏｘｉｃｏｄｏｎｅ（登録商標）錠剤を、別々に硬質ゼラチンカプセル殻のボディ部分に入れた。次に、このカプセル剤をこの殻のキャップ部分で閉じた。充填されたカプセル剤の重量は、おおよそ４２６．０ｍｇであった。
【０２５４】
１５．０ｍｇの塩酸オキシコドンのカプセル剤を、微結晶性セルロース（１３５．５ｍｇ）とステアリン酸マグネシウム（０．７ｍｇ）をブレンドが形成されるまで混合することによって作製した。このブレンドおよび３個のＲｏｘｉｃｏｄｏｎｅ（登録商標）錠剤を、別々に硬質ゼラチンカプセル殻のボディ部分の半体に入れた。次に、このカプセル剤をこの殻のキャップ部分で閉じた。充填されたカプセル剤の重量は、おおよそ５３３．０ｍｇであった。
【０２５５】
１５．０ｍｇのオキシコドンを含む充填したカプセルを、塩酸オキシコドンの錠剤についてＵＳＰ ２４ Ｍｏｎｏｇｒａｐｈに示された溶出試験と等価な溶出試験（使用した試験媒体がｐＨ４．５のＵＳＰグレードの緩衝液であったこと、および使用したパドル速度が７５ｒｐｍであったことを除く）に供した。さらに、紫外線吸光スペクトルにおける妨害を防ぐために、ゼラチンカプセル中の着色料からのオキシコドンのクロマトグラフィーでの分離を要した。塩酸オキシコドン錠剤についてのＵＳＰ ２４ Ｍｏｎｏｇｒａｐｈは、米国薬局方２４に示される一般的な溶出試験をいう。
【０２５６】
以下の表は、１５ｍｇの強さのオキシコドンカプセル剤について、試験された１２のサンプルに基づいて得られた溶出の結果を要約する。
【０２５７】
【表９】

これらの溶出の結果は、この投薬形態が、塩酸オキシコドンの迅速な放出を提供することを示す。
【０２５８】
溶出試験を、５０ｒｐｍでもまた企図したが、このパドル法では十分な攪拌が提供されず、錐型化が起こった。この５０ｒｐｍの低パドル速度では、このカプセル剤から、一杯に詰めた賦形剤が、溶出容器の底で錐型を形成し、錠剤の適切な溶出を妨げた。錐型化の発生は、溶出試験のパラメーターの改変を正当化する。錐型化を防ぐために、パドル速度を７５ｒｐｍまで増加させた。このパドル速度は、なおＵＳＰ溶出の規準内である。
【０２５９】
（実施例６）
本実施例は、塩酸トラマドール（本実施例において、「トラマドール」といわれる）を含む投薬形態の調製を記載し、これを臨床的評価で使用した。本実施例はまた、この投薬形態の溶出の測定を記載する。以下の一般的な手順を使用してＵｌｔｒａｍ（登録商標）（Ｊｏｈｎｓｏｎ ＲＷ）として供給される塩酸トラマドールを異なる強さで含有するカプセル剤を調製した。Ｕｌｔｒａｍ（登録商標）錠剤は、５０．０ｍｇ（塩酸トラマドール）の強さの錠剤で利用可能である。各Ｕｌｔｒａｍ（登録商標）錠剤は、５０．０ｍｇの塩酸トラマドールの理論的薬物含量を有することが記載されているが、それぞれの実際の量は、許容可能な範囲（例えば、約１０％）内で変化し得る。
【０２６０】
５０．０ｍｇの塩酸トラマドールのカプセル剤を、微結晶性セルロース（１６７．１６ｍｇ）とステアリン酸マグネシウム（０．８４ｍｇ）とのブレンドが形成されるまで混合することによって作製した。このブレンドおよび１個のＵｌｔｒａｍ（登録商標）錠剤を、別々に硬質ゼラチンカプセル殻のボディ部分に充填した。次に、このカプセル剤をこの殻のキャップ部分で閉じた。充填されたカプセル剤の重量は、おおよそ４９１．３ｍｇであった。
【０２６１】
充填したカプセル剤を、米国薬局方２４の装置２（パドル攪拌要素）を使用する溶出試験に供した。トラマドールカプセル剤の分析を、０．１Ｎの塩酸、９００ｍｌ中の充填したカプセル剤の溶出を実施することによって達成した。溶媒温度を、約３７．０℃（＋／−０．５℃）で維持し、パドル速度は、７５ｒｐｍであった。以下の表は、試験された６つのサンプルに基づいて得られた５０ｍｇの強さの塩酸トラマドールカプセルについての溶出データを要約する。
【０２６２】
【表１０】

再度、５０ｒｐｍで実施された溶出試験について錐型化が観察され、不確かな試験結果となった。錐型化を防ぐために、パドル速度を７５ｒｐｍに増加した。これはなお、許容可能なＵＳＰ溶出規準内である。
【０２６３】
これらの溶出の結果は、この投薬形態が塩酸トラマドールの迅速な放出を提供し、そして使用された賦形剤が、水性環境下においてオピオイドアゴニストに有意に結合しないことを示す。
【０２６４】
（実施例７）
本実施例は、コーティングされたノンパレイルのビーズまたはペレット（例えば、図２に示される、コーディングされたペレット１）上にオピオイドアンタゴニストを含む薬学的組成物を作製するために使用される一般的な手順を記載する。本実施例は、オピオイドアンタゴニストから実質的に構成される投薬形態を記載する。少なくとも結合剤、有機溶媒および／または水性溶媒、ならびにオピオイドアンタゴニストを含む結合剤溶液を調製する。適切な結合剤は、トリアセチン（例えば、Ｃｏｌｏｒｃｏｎ，Ｉｎｃ．からのＯｐａｄｒｙ（登録商標）ブランドの市販コーティング）で可塑化されたヒドロキシプロピルメチルセルロース（「ＨＰＭＣ」）である。結合剤溶液を不活性なノンパレイルペレットにコーティングし、コーティングされたペレットを形成した。このコーティングは、Ｗｕｒｓｔｅｒカラムインサートで下方向にスプレーするように設置された流動層装置中で実施する。可塑剤をコーティング分散物に添加して、コーティングの柔軟性を増大させ得る。ノンパレイルペレット上のコーティングの厚さ（重さ）は、所望のように変化させ得るが、一般的に総ペレット重量の約２〜５０重量％の範囲に入る。コーティングされたペレットの重量は、約１０ｍｇよりも少なく、約０．１〜５．０ｍｍの直径または長さを有する。コーティングされたこれらのペレットは、以下の成分をおおよそ示された量で含み得る。
【０２６５】
【表１１】

コーティングしたペレットおよびビーズの処方物に使用したノンパレイルのコアは、一般的に、乳糖、スクロース、およびデンプンのような薬学的に不活性な物質を含む。
【０２６６】
コーティングされたペレットを、硬質ゼラチンカプセルに充填するか、または錠剤に打錠し得る。
【０２６７】
（実施例８）
本実施例は、オピオイドアンタゴニストが、本実施例で使用される唯一の活性な薬学的成分のみであることを除いては、図６に示されているコーティング顆粒と同じものを含む薬学的組成物を作製するために使用する、一般的な手順を記載する。本実施例は、オピオイドアンタゴニストから実質的に構成される投薬形態を示す。オピオイドアンタゴニスト、１以上の結合剤、および水を、高剪断ミキサーを備える容器中で混合することによって、顆粒化溶液を作製する。適切な顆粒化溶液は、以下の成分をおおよそ示された量で含む。
【０２６８】
【表１２】

次に、不活性な薬学的賦形剤（例えば、以下の表中のもの）の第１のブレンドを、顆粒化溶液を用いて、流動層ユニットで造粒し、湿潤した顆粒化物質を形成した。この顆粒化物質を、１２番の篩いを通して同じ大きさに分ける。続いて、同じ大きさの顆粒を乾燥し、これによってコーティングされた顆粒化物を形成し、次にこれを３０番のメッシュスクリーンで篩う。
【０２６９】
【表１３】

次いで、顆粒をステアリン酸マグネシウム（０．５重量％）および低置換ヒドロキシプロピルセルロース（「Ｌ−ＨＰＣ」）（３．０重量％）と混ぜ、そしてさらに５分間混合した。次いで、このブレンドをロータリー打錠機で、錠剤に打錠する。
【０２７０】
（実施例９）
本実施例は、薬物の懸濁液を含む軟質ゼラチンカプセル投薬形態を作製するために使用される一般的な手順を記載する。懸濁液を、ミグリオール、ＰＥＧ、グリセリン、プロピレングリコール、または植物性油脂のような非水性ビヒクルとオピオイドアンタゴニストのような固体ならびに必要に応じて少なくとも１つの他の薬学的賦形剤とを混合することによって、作製する。非水性ビヒクルに添加された固体は、一般的に粉末または粒子であり、これらとして、例えば、ビーズ、ペレット、および顆粒が挙げられ得る。適切な懸濁液は、以下の成分をおおよそ示された量で含む。
【０２７１】
【表１４】

（実施例１０）
本実施例は、２つの異なるコーティングされたノンパレイルビーズまたはペレットの混合物を含む、図２の薬学的組成物を作製するために使用される、一般的な手順を記載する。本実施例は、オピオイドアンタゴニストおよび別の活性な薬学的成分（この場合においては、オピオイドタゴニスト）を含む投薬形態を記載する。ナルトレキソンおよび硫酸モルヒネ五水和物を含み、両方の薬物の同時放出のための、組合せカプセル投薬形態を調製した。本実施形態において使用される賦形剤が、水性環境下においてモルヒネまたはナルトレキソンと有意に結合しないことを見出した。
【０２７２】
少なくとも結合剤、有機溶媒および／または水性溶媒、ならびにオピオイドアンタアゴニストを含む第１の結合剤溶液を調製する。第１の結合剤溶液を、不活性なノンパレイルペレットにコーティングし、第１のコーティングペレットを形成する。適切な結合剤は、Ｏｐａｄｒｙ（登録商標）Ｃｌｅａｒのような可塑化されたＨＰＭＣである。このコーティングは、Ｗｕｒｓｔｅｒカラムインサートで下方向にスプレーするように設置された流動層装置中で実施した。コーティング溶液のスプレー速度を、加工中に調整し、加工中おおよそ以下の平衡状態を維持した；入口温度、７０〜８０℃、出口温度４２〜４７℃。
【０２７３】
【表１５】

類似の様式で、少なくとも結合剤、有機溶媒および／または水性溶媒、ならびにオピオイドアゴニストを含む第２の結合剤溶液を調製する。第２の結合剤溶液を、他の不活性なノンパレイルペレットにコーティングし、第２のコーティングペレットを形成する。可塑化剤をコーティング分散物に添加し、コーティングの柔軟性を増大させ得る。
【０２７４】
上に列挙される成分を含む水性コーティング溶液を使用して、薬物をコーティングしたノンパレイルのビーズを含むカプセル剤を製造した。このカプセル剤は、この投薬形態からオピオイドアゴニストおよびオピオイドアンタゴニストを迅速にかつ同時に放出する。
【０２７５】
【表１６】

所定の量の第１および第２のペレットを混合し、それにより、ペレットの混合物を形成する。ノンパレイルペレット上のコーティングの厚さ（重量）を、所望のように変化させ得るが、一般的に、全ペレット重量の約１〜７０重量％の範囲にある。コーティングしたペレットは、約１０ｍｇ未満の重さであり、そして約０．１〜５．０ｍｍの直径または長さを有する。
【０２７６】
この実施例に従って作製されたカプセルは、示されたおよその量で、以下の成分を含んだ。
【０２７７】
【表１７】

本発明のコーティングしたペレットおよびビーズ処方物において使用されるノンパレイルコアは、一般に、ラクトース、スクロース、および／またはデンプンのような薬学的に不活性の物質を含む。
【０２７８】
コーティングしたペレットの混合物を、硬質ゼラチンカプセル中に充填し、そして種々の異なる撹拌速度を使用したことを除いて、米国薬局方２４における装置２（パドル撹拌エレメント）を使用する溶解試験に供した。試験媒体は、３７℃（＋／−０．５℃）の一定媒体温度の、５００ｍｌの０．１Ｎ ＨＣｌであった。溶解試験のためのパドルの撹拌速度は、１分当り、５０、７５、または１００回転であった。以下の表は、それぞれのパドル速度での溶解試験について得られた結果を要約する。各パドル速度について各時間で報告された結果は、６回の試験の平均値である。
【０２７９】
【表１８】

これらの溶解試験は、この組み合わせ投薬形態が、オピオイドアゴニストおよびオピオイドアンタゴニストの同時放出を提供すること、そして使用された賦形剤が、水環境において、オピオイドアゴニストまたはオピオイドアゴニストと有意に結合しないことを示す。これらの溶解結果は、この組み合わせ投与形態において、５分、１０分、２０分、３０分、４５分、および６０分において、７５ｒｐｍおよび１００ｒｐｍで試験される場合、溶解プロフィールが、各撹拌速度において実質的に同じであり、オピオイドアゴニストおよびオピオイドアンタゴニストの割合が実質的に同じであることを示す。本実施例の投薬形態はまた、４５分で約９０％を超えて溶解する両方の活性な薬学的成分の即時放出を提供する。
【０２８０】
（実施例１１）
この実施例は、単一の型のコーティングしたノンパレイルペレットを含む、図３の薬学的組成物を作製するために使用された一般的な手順を示し、ここで、コーティングは、オピオイドアンタゴニストおよび別の活性な薬学的成分（この場合、オピオイドアゴニスト）を含む。少なくとも１つの結合剤、有機溶媒および／または水性溶媒、可塑剤、オピオイドアゴニストおよびオピオイドアンタゴニストを含む第１の結合剤溶液が、調製される。第１の結合剤溶液を、コーティングしたペレットを形成するために不活性のノンパレイルペレットにコーティングする。ノンパレイルペレット上のコーティングの厚さ（重量）は、所望のように変化し得るが、一般に、全ペレット重量の約２〜８０重量％の範囲に、通常１０〜５０％の間の範囲にある。コーティングしたペレットは、約１０ｍｇ未満の重さであり、そして約０．２〜２．０ｍｍの直径または長さを有する。これらのコーティングしたペレットは、示されたおよその量で、以下の成分を含む。
【０２８１】
【表１９】

（実施例１２）
この実施例は、両方の活性な薬学的成分の同時放出および即時放出のためのナルトレキソン塩およびモルヒネ塩の両方を含む組み合わせ錠剤投与形態を示す。この組み合わせ錠剤は、オピオイドアンタゴニストおよび別の活性な薬学的成分（この場合、オピオイドアゴニスト）を含む。この実施例において使用された賦形剤は、水環境においてモルヒネまたはナルトレキソンに有意には（例えば、治療効果または同時放出に干渉しない程度には）結合しないことが見出された。この錠剤は、３７℃での水性緩衝液に暴露された後、約５分以内に分解し、活性な薬学的成分の迅速な溶解を提供する。この実施例に従って作製された錠剤は、示されたおよその量で、以下の成分を含んだ。
【０２８２】
【表２０】

錠剤は、以下の一般的な手順に従って作製した。高剪断、湿式顆粒化方法を使用して、錠剤化のためのバルク粉末を調製した。
【０２８３】
【表２１】

オピオイドアゴニストおよび以下の薬学的賦形剤の乾燥物質ブレンドを、高剪断造粒機で調製した。
【０２８４】
【表２２】

混合する間、結合剤溶液を、乾燥物質ブレンドにゆっくりと添加して、顆粒を調製した。湿った顆粒を、２０メッシュスクリーンを通過させることによってサイズ分けした。サイズ分けした湿った顆粒を、乾燥重量が約５％未満の水分含有量を有するまで、流動床装置で乾燥した。乾燥した顆粒を、２０メッシュスクリーンを通過させた。以下の非顆粒化賦形剤を、二重コーンブレンダーを使用して、乾燥した顆粒にブレンドした。
【０２８５】
【表２３】

次いで、最終粉末ブレンドを、７ｍｍのまるい両凹の金型（ｔｏｏｌｉｎｇ）を使用して、回転式錠剤プレスで圧縮した。圧縮された錠剤圧粉体（ｃｏｍｐａｃｔ）を回収し、そして水性ベースのコーティングを、錠剤コーティング単位で適用した。
【０２８６】
可塑化したＨＰＭＣ（Ｏｐａｄｒｙ（登録商標））ベースの水性コーティング溶液の透明なシールコート、および可塑化ＨＰＭＣ（Ｏｐａｄｒｙ（登録商標））ベースの水性コーティング分散物着色トップコートを用いて、錠剤をコーティングした。
【０２８７】
錠剤は、米国薬局方２４（２０００）物理的試験＜７０１＞（これは、本明細書中に参考として援用される）における崩壊試験を使用して、３７℃（＋／−２℃）で脱イオン水中で３分未満で崩壊することが決定された。
【０２８８】
溶解媒体として５００ｍｌの０．１Ｎ ＨＣｌを用いて、コーティングしていない錠剤コアおよびコーティングした錠剤コアからのＭＳおよびＮＴＸの溶解を、米国薬局方２４における装置２（パドル撹拌エレメント）を使用して、評価した。２つの錠剤を、３７℃（＋／−０．５℃）で、５００ｍＬの溶解媒体中に配置した。パドル撹拌速度は、５０ｒｐｍであり、そして溶解されたＭＳおよびＮＴＸの割合を、試験媒体のサンプルから決定した。
【０２８９】
以下の表は、上記のように調製したコーティングしていない錠剤コアおよびコーティングした錠剤コアに関する溶解試験の結果を要約する。図９は、コーティングした錠剤コアの溶解プロフィールを示す。
【０２９０】
【表２４】

従って、本発明の実施形態は、オピオイドアンタゴニストおよびオピオイドアゴニストを含む即時放出型固体経口錠剤を提供する。活性な薬学的成分は、同時に放出される。さらに、この投薬形態のオピオイドアゴニストおよびオピオイドアンタゴニストの溶解割合は、各時間で実質的に同じである（コーティングしていない錠剤についての３０分を除く）。これらの溶解結果は、この組み合わせ投薬形態が、オピオイドアゴニストおよびオピオイドアンタゴニストの同時放出を提供すること、そして使用される賦形剤が、水環境でオピオイドアゴニストに有意には結合しないことを示す。
【０２９１】
（実施例１３）
この実施例は、２つの異なる型の顆粒の混合物を含む、図４の薬学的組成物を作製するために使用される一般的な手順を示す。１つの顆粒は、オピオイドアンタゴニストを含み、そして他方の顆粒は、別の活性な薬学的成分（この場合、オピオイドアゴニスト）を含む。
【０２９２】
第１の顆粒を、オピオイドアンタゴニスト、および薬学的賦形剤の第１のブレンドを顆粒溶液とブレンドすることによって作製し、篩を通過する湿った塊を形成し、引き続いて乾燥される湿った顆粒を形成する。適切な第１の顆粒は、示されるおよその量で、以下の成分を含む。
【０２９３】
【表２５】

同様に、第２の顆粒を、オピオイドアゴニスト、および薬学的賦形剤の第２のブレンドを顆粒溶液とブレンドすることによって作製し、篩を通過する湿った塊を形成し、引き続いて乾燥される湿った顆粒を形成する。適切な第２の顆粒は、示されるおおよその量で、以下の成分を含む。
【０２９４】
【表２６】

第１および第２の顆粒を引き続いてブレンドし、混合物を形成する。この顆粒を、Ｎｏ．２０メッシュスクリーンを通過させる。両方の活性な薬学的成分を、Ｎｏ．２０メッシュスクリーンを通過させ、そして回転式錠剤プレスでの圧縮の前に、ツインシェル（ｔｗｉｎ−ｓｈｅｌｌ）ブレンダー中で１０分間、崩壊剤（例えば、Ｌ−ＨＰＣ、３重量％）および滑沢剤（例えば、ステアリン酸マグネシウム、０．５重量％）とブレンドした。
【０２９５】
（実施例１４）
この実施例は、組み合わせ顆粒を含む、図５の薬学的組成物を作製するために使用される一般的な手順を示す。組み合わせ顆粒は、オピオイドアンタゴニストおよび別の活性な薬学的成分（この場合、オピオイドアゴニスト）を含む。
【０２９６】
第１の顆粒を、オピオイドアンタゴニスト、および薬学的賦形剤の第１のブレンドを、顆粒溶液とブレンドすることによって作製し、Ｎｏ．１２の篩を通過する湿った塊を形成し、引き続き乾燥される湿った顆粒を形成する。最終顆粒は、Ｎｏ．２０メッシュスクリーンを通過する。適切な第１の顆粒は、示されるおよその量で、以下の成分を含む。
【０２９７】
【表２７】

第２の顆粒を、オピオイドアゴニスト（薬学的賦形剤および第１の顆粒の第２のブレンド）を、顆粒溶液とブレンドすることによって作製し、篩を通過する湿った塊を形成し、引き続き乾燥される湿った顆粒を形成する。適切な第２の顆粒は、示されるおよその量で、以下の成分を含む。
【０２９８】
【表２８】

（実施例１５）
この実施例は、オピオイドアゴニストおよび別の活性な薬学的成分（この場合、オピオイドアゴニスト）を含むコーティングした顆粒を含む、図６の薬学的組成物を作製するために使用される一般的な手順を示す。顆粒溶液は、高剪断ミキサーを備えた容器中で、オピオイドアゴニスト、オピオイドアンタゴニスト、結合剤および溶媒をブレンドすることによって、作製される。適切な顆粒溶液は、示されるおおよその量で、以下の成分を含む。
【０２９９】
【表２９】

次いで、不活性な薬学的賦形剤の第１のブレンドを、流動床ユニット中の顆粒溶液と共に顆粒化して、湿った塊を形成し、Ｎｏ．１２の篩を通過させて引き続き乾燥させる湿った顆粒を形成する。それにより、コーティングした顆粒を形成する。
【０３００】
次いで、最終顆粒を、１つ以上の薬学的賦形剤と混合し、示されるおよその量で以下の成分を含む薬学的混合物を形成する。最終顆粒は、Ｎｏ．２０のスクリーンを通過する。
【０３０１】
【表３０】

（実施例１６）
この実施例は、オピオイドアゴニストが顆粒溶液に含まれず、その代わりに顆粒化された薬学的賦形剤が含まれることを除き、実施例１５の薬学的組成物を作製するための手順と類似した一般的手順を示す。
【０３０２】
顆粒溶液を、高剪断ミキサーを備えた容器中で、オピオイドアンタゴニスト、結合剤および溶媒をブレンドすることによって、作製する。適切な顆粒溶液は、示されるおよその量で、以下の成分を含む。
【０３０３】
【表３１】

次いで、不活性な薬学的賦形剤の第１のブレンドを、流動床ユニット中の顆粒溶液と共に顆粒化し、湿った塊を形成し、これを、Ｎｏ．１２の篩を通過させて引き続き乾燥させる湿った顆粒を形成する。それにより、コーティングした顆粒を形成し、そしてＮｏ．３０のメッシュスクリーンを通過させる。適切な顆粒は、示されるおよその量で、以下の成分を含む。
【０３０４】
【表３２】

コーティングした顆粒を、ステアリン酸マグネシウム（０．５重量％）およびＬ−ＨＰＣ（３．０重量％）と混合し、さらに５分間ブレンドする。次いでこのブレンドを、回転式錠剤プレスで錠剤に圧縮する。
【０３０５】
（実施例１７）
この実施例は、噴霧乾燥顆粒を含む薬学的組成物を作製するために使用された一般的手順を示す。オピオイドアンタゴニスト、別の活性な薬学的成分（例えば、オピオイドアゴニスト）、および少なくとも１つの薬学的賦形剤の溶液を、９０℃の入口温度および５０℃の出口温度を使用しながら、約１０ｍｌ／分の速度でＢＵＣＨＩ^ＴＭ噴霧乾燥機中で噴霧乾燥した。噴霧乾燥した顆粒を回収し、そしての顆粒は約２０メッシュ未満の粒子サイズを有する。適切な噴霧乾燥粒子は、示されるおよその量で、以下の成分を含む。
【０３０６】
【表３３】

噴霧乾燥の操作の特定のパラメーターは、上に詳しく述べられているが、噴霧乾燥機の操作は、必要に応じて行なわれ得、そしてこの装置の操作についてのパラメーターは、この実施例に従って生成物を調製するために、必要に応じて変化され得る。
【０３０７】
顆粒を乾燥し、ステアリン酸マグネシウム（０．５重量％）およびＬ−ＨＰＣ（３．０重量％）とブレンドし、さらに４〜６分間ブレンドする。次いでこのブレンドを、回転式錠剤プレスで錠剤に圧縮するか、または硬質ゼラチンカプセル中に充填する。
【０３０８】
（実施例１８）
この実施例は、薬物懸濁液を含む軟質ゼラチンカプセル投薬形態を作製するために使用される一般的な手順を示す。懸濁液を、ｍｉｇｌｙｏｌ、ＰＥＧ、グリセリン、プロピレングリコール、または植物油のような非水性ビヒクルと、オピオイドアンタゴニスト、別の活性な薬学的成分（例えば、オピオイドアゴニスト）、および必要に応じて少なくとも１つの他の薬学的賦形剤とを混合することによって作製する。非水性ビヒクルに添加する固体は、一般に粉末または粒子であり、そして例えば、ビーズ、ペレットおよび顆粒が挙げられる。適切な懸濁液は、示されるおよその量で、以下の成分を含む。
【０３０９】
【表３４】

本明細書中の発明は、特定の実施形態を参照して記載されているが、これらの実施例は、本発明の種々の局面を単に例示するものであることが理解されるべきである。従って、多数の改変が、例示的な実施形態においてなされ得、そして他の構成が、本発明の精神および範囲から逸脱することなく考案され得ることが理解されるべきである。
【図面の簡単な説明】
【図１Ａ】
図１Ａは、開示される実施形態に従って、ナルトレキソンカプセル投薬形態を製造する方法を示した流れ図である。
【図１Ｂ】
図１Ｂは、開示される実施形態に従って、ナルトレキソンカプセル投薬形態を製造する方法を示した流れ図である。
【図２】
図２は、コーティングされたノンパレイルなペレットの２つの異なる型を有する、即時放出投薬形態の実施形態を示す。
【図３】
図３は、コーティングされたノンパレイルなペレットの単一型を有する、即時放出投薬形態の実施形態を示す。
【図４】
図４は、顆粒の２つの異なる型を含む混合物の、本発明の実施形態を示す。
【図５】
図５は、コーティングされた顆粒の、本発明の実施形態を示す。
【図６】
図６は、必要に応じた薬学的賦形剤組成物中に分散された顆粒の、本発明の実施形態を示す。
【図７】
図７は、本発明に従う薬学的組成物の総重量に関して、オピオイドアンタゴニストに対するオピオイドアゴニストの比と、処方物の量との間の関係を実証するグラフを示す。この関係は、図２および図４の実施形態に当てはまる。
【図８】
図８は、本発明に従う薬学的組成物の総重量に関して、オピオイドアンタゴニストに対するオピオイドアゴニストの比と、第１の処方物の量との間の関係を実証するグラフを示す。この関係は、図３、図５、および図６の実施形態に当てはまる。
【図９】
図９は、実施例１２の例示的なコーティングされた錠剤についてのインビトロ溶解プロフィールを示す。[0001]
(Citation of related application)
No. 60 / 202,227 (filed on May 5, 2000) (provisional); No. 60 / 202,268 (filed on May 5, 2000) (provisional) No. 09 / 756,331 (filed on Jan. 8, 2001) (this is a continuation of 09 / 566,071 (filed on May 5, 2000)); No. 60 / 244,482 No. 60 / 245,110 (proposed on November 1, 2000) (provisional); and No. 60 / 246,235 (provisional November 2, 2000) (Provisional application); and PCT / US00 / 12493 [WO 00/67739] (filed on May 5, 2000). The above application is incorporated herein by reference in its entirety and provides a series of disclosures.
[0002]
(Field of the Invention)
The present invention relates to novel dosage forms and pharmaceutical compositions comprising low dose opioid antagonists. The invention also relates to a dosage form comprising the opioid antagonist and another active pharmaceutical ingredient (eg, an opioid agonist).
[0003]
(Background of the Invention)
The pharmacology of opioid antagonist compounds is described in Goodman and Gillman's PHARMACOLOGICAL BASIS OF THERAPEUTICS, Chapter 22, "Opioid Antagonists", incorporated herein by reference. Opioid antagonists include, but are not limited to, naloxone, cyclazocine, nalmefene, naltrexone, nalorphine, nalbuphine, thebaine, levallorphan, pentazocine, oxymorphine, butorphanol, bupremorphine, and bupremorphine. Or an opioid antagonist compound having the same cyclic nucleus as norl, meptazinol, dezocine or pentazocine, or a pharmacologically effective salt or ester thereof (eg, their hydrochloride, maleate, tartrate and lactic acid) But not limited to).
[0004]
A generally accepted use of opioid antagonists is to treat overdose and prevent abuse of opioid agonists such as heroin or morphine. For these conventional uses, antagonists such as naloxone or naltrexone are used at relatively high concentrations to efficiently block the activity or effect of the opioid agonist. The high concentrations of opioid antagonists used so far are thought to antagonize opioid agonists at the biochemical level at opioid receptors on nociceptive neurons.
[0005]
Naloxone (4,5-epoxy-3,14-dihydroxy-17- (2-prophenyl) morphinan-6-one), an opioid antagonist compound first synthesized in 1960, was immediately "pure" It has been discovered that it has antagonist properties (ie, does not exhibit substantial agonist activity). Therefore, naloxone has become the preferred regimen for the treatment of acute anesthetic conditions (habitual use of anesthetics). However, since naloxone exhibits a relatively short duration in the body, longer acting drugs, also having the properties of "pure" antagonists, have proven to be more advantageous. Therefore, naltrexone (17- (cyclopropylmethyl) -4,5-epoxy-3,14-dihydroxy-morphinan-6-one) was developed in 1965 to meet this requirement and its N-allyl homologue It has been found to have stronger potency and longer action than the body, naloxone, and to have activity when administered orally. For example, a dosage form of 50 mg naltrexone is commercially available in the United States as ReVia® and in other countries as Trexan. Nalmefene (6-methylene-6-desoxy-N-cyclopropyl-methyl-14-hydroxydihydroxy-dihydronormorphine) has also been developed, which is a long-acting and orally available potent opioid antagonist And also has "pure" antagonist properties. These drugs are currently marketed in specific dosage forms and, to the best of our knowledge, are the only pure opioid antagonists with government approval for administration to humans.
[0006]
Crain and Shen (BRAIN RESEARCH 757: 176-190 (1997)) show that opioid agonists not only activate inhibitory opioid receptors that produce analgesic activity, but they also simultaneously excite opioids on sensory neurons. It has been shown to activate a smaller group of receptors. It has been proposed that these effects on excitatory opioid receptors attenuate opioid-induced analgesia and, under certain conditions, actually increase pain. Surprisingly, Crain and Shen (eg, US Pat. No. 5,512,578, reissued as RE 36,457) provide significantly lower doses of opioid antagonists (eg, on the order of nanograms / kilograms (ng / kg)). Naloxone or naltrexone) when administered to mice together with morphine or a similar opioid agonist, the opioid antagonist selectively blocks the effect of the opioid antagonist on excitatory opioid agonists, but not on inhibitory opioid agonists, Have shown to significantly increase the analgesic efficacy of opioid agonists. These findings of Grain and Shen are described in U.S. Patent Nos. 5,472,943; 5,512,578 (reissued as RE 36,457); 5,580,876; , 767, 125, which selectively increase the analgesic potency of bimodally-acting opioid agonists, and provide anti-hyperalgesia, hyperalgesia, hyperexcitability. ), Physical dependence, and / or a method of simultaneously mitigating tolerance effects associated with the administration of a dual-acting opioid agonist.
[0007]
These methods increase the analgesic efficacy of a sub-analgesic or sub-analgesic amount of a dual-acting opioid agonist, and increase the analgesic efficacy of the dual-acting opioid agonist, Administering to the subject an effective amount of an excitatory opioid receptor antagonist to attenuate hyperalgesia, hyperexcitability, physical dependence, and / or tolerance effects. Analgesic or sub-analgesic dual-acting opioid agonists, and increasing the analgesic efficacy of dual-acting opioid agonists, increasing analgesia, hyperalgesia, hyperexcitability, physical dependence, and / or dual-acting opioids Also included in these patents are methods for treating pain in a subject by administering to the subject an excitatory opioid receptor in an amount effective to simultaneously attenuate the agonist's tolerance effect.
[0008]
An effective amount of an excitatory opioid receptor antagonist to an opiate addict, alone or alone, to reduce the physical dependence caused by the binomially acting opioid agonist and to increase the analgesic efficacy of the dually acting opioid agonist Methods for treating opiate addicts by administering in combination with a dual-acting opioid agonist are also included in these patents. An analgesic or sub-analgesic dual-acting opioid agonist, as well as increasing the analgesic efficacy of a dual-acting opioid agonist in a subject to which the composition has been administered, including antihyperalgesia, hyperalgesia, hyperexcitability, physical Also included are compositions of the excitatory opioid receptor antagonist in an amount effective to attenuate the dependent and / or resistant effects of the dual-acting opioid agonist. In all of these studies, the antagonist mitigated such adverse effects while increasing potency.
[0009]
Two clinical studies on post-surgical patients (Joshi et al., ANESTHESIL. 90: 1007-1011 (1999); Gan et al., ANESTHESIOL. 87: 1075-1081 (1997)) are low-dose opioid antagonists. It has been demonstrated that co-treatment of patients with PCA / IV morphine together with naloxone (IV) or nalmefene (IV) significantly enhances efficacy with various cumulative daily doses of morphine. In these studies, this adverse side effect was attenuated.
[0010]
Various other uses for opioid antagonists are described or proposed for treatment of humans, where the opioid antagonist is used to treat relatively high concentrations (opioid overdose or opioid addiction) And similar amounts).
[0011]
US Patent No. 6,194,382 Bl describes a method of treating irritable bowel syndrome (IBS) by administering an effective amount of an opioid receptor antagonist to treat IBS. For example, daily doses of naltrexone ranging between 0.1 mg / day and about 5 mg / day and daily doses of nalmefene ranging between 0.01 mg / day and about 1 mg / day are described.
[0012]
U.S. Patent No. 6,187,782 B1 describes morphinan derivatives of certain formulas as compounds having the ability to bind to opioid C receptors, which opioid C receptors have agonistic or antagonistic activity . The results of an in vitro antagonist activity assay for eight compounds are shown.
[0013]
U.S. Patent No. 6,153,621 discloses a combination of antagonists of different excitatory systems (e.g., nicotine antagonists, opioid antagonists, serotonin antagonists, adrenergic antagonists), specifically the opioid antagonists naltrexone or naloxone. Compositions and methods for treating excitable system disorders, pain, and psychiatric disorders, including combinations with the nicotine antagonist mecamylamine.
[0014]
U.S. Patent No. 6,136,780 discloses that naltrexone, naloxone or [Met ⁵ ]-Describes a method of treating and preventing cancers, particularly gastrointestinal cancers, characterized by the presence of the ζ receptor, by administering enkephalin and thereby inhibiting or inhibiting the growth of the cancer. Subcutaneous injection of 0.1 mg / kg daily into mice inoculated with tumor cells reduced tumor incidence and tumor growth.
[0015]
U.S. Patent No. 6,110,926 discloses a form of a naloxone hydrochloride solution (e.g., 0.1-1% w / v) in a mixture of water and at least one pharmaceutically acceptable polyhydric alcohol. An ophthalmic composition for an opioid intoxication test having increased stability is described.
[0016]
U.S. Patent No. 6,103,734 describes a multi-step method for reducing patient dependence on opiates by administering an opiate antagonist in a number of steps. According to this method, naltrexone can be administered between 6 and 40 mg per hour, and naloxone can be administered between 0.4 and 1.5 mg per hour.
[0017]
U.S. Patent No. 6,103,258 teaches that homeostasis during administration of dopamine, an opioid analgesic, is achieved at the kappa opioid receptor with only minimal opposition of the opioid agonist and this agonist analgesic at the mu-opioid receptor. Methods are described for optimizing by administration of a kappa-preferring opioid antagonist, particularly nalmefene, in an amount sufficient to inhibit binding of the opioid agonist analgesic. Parenteral administration of nalmefene at 0.00025-0.00015 mg / kg is recommended.
[0018]
U.S. Patent No. 6,087,369 discloses indole derivative compounds of a specific formula having delta-opioid antagonist activity and methods of using the compounds in immunosuppressive, antiallergic, antiinflammatory, and brain cell protective amounts. Is described.
[0019]
U.S. Patent No. 6,071,918 teaches alcoholism and dependence by administering a therapeutically effective amount of a cooperatively acting combination of at least one opioid antagonist and at least one selective serotonin reuptake inhibitor. Methods and compositions for treating are described.
[0020]
U.S. Patent No. 6,034,091 discloses a method for treating depression with the need for depression associated with alcoholism by administering a pharmacologically effective dose of an opioid antagonist and a pharmacologically effective dose of an antidepressant compound. Is described.
[0021]
U.S. Patent No. 6,026,817 discloses a method of coronary administration comprising a stepwise dosing regimen that includes an opioid antagonist or a drug that substantially reduces the embodied amount of catecholamine at a higher initial dose and a lower maintenance dose. Described are methods of treating a human suffering from one or more conditions included in the symptom group of Arterial Heart Disease Risk Factor (CHDRF).
[0022]
U.S. Patent No. 6,004,970 describes a method of treating a human having nicotine dependence by administering an effective amount of an opioid antagonist and an effective amount of nicotine.
[0023]
U.S. Patent No. 6,004,962 describes a multi-step method of rapid detoxification of a patient's opioid, which detoxifies the patient by injection of an opioid antagonist while the patient is sedated. And then subjecting the patient to antagonist maintenance therapy.
[0024]
U.S. Patent No. 5,972,954 discloses methylnaltrexone by oral dosage of about 1.0-40.0 mg / kg or as enteric-coated tablets at a dosage of about 1.0-80.0 mg / kg. Methods of preventing or treating opioid-induced side effects and non-opioid-induced changes in gastrointestinal motility by administration are described.
[0025]
US Patent No. 5,958,962 describes a method of treating alcoholism and dependence with naltrexone and fluoxetine.
[0026]
U.S. Patent Nos. 5,922,705 and 5,783,583 describe a method for rapidly detoxifying opioid anesthetic addicts by injecting nalmefene.
[0027]
U.S. Patent No. 5,919,760 describes a method of rapid detoxification of anesthesia, where acute withdrawal symptoms are induced by nalmefene and where it induces clinically severe bradycardia Octreotide is administered in an amount sufficient to alleviate acute severe diarrhea without incident.
[0028]
US Patent No. 5,866,164 describes an osmotic dosage form for reducing the incidence of substance abuse, comprising a combination of an opioid antagonist and an opioid agonist, wherein the antagonist and the agonist are distinct Maintained in dosage form. This dosage form provides osmotic controlled release of the agonist, but not the antagonist, characterized by administration of the drug opioid composition without the antagonist.
[0029]
U.S. Patent No. 5,852,032 describes a method of treating a human subject suffering from nicotine dependence by administering nalmefene and reducing nicotine dependence.
[0030]
U.S. Patent No. 5,817,665 discloses a pharmacologically effective amount of an opioid antagonist having a pentacyclic nucleus structurally similar to naltrexone, naloxone, nalmefene, nalorphine, nalbuphine, oxymorphone, buprenorphine, and thebaine; Physiologically effective salts and esters, and combinations thereof, and pharmacologically effective doses of one or more non-tricyclic antidepressant compounds that exhibit serotonin reuptake activity inhibition at central synapses Described are methods and compositions for treating depression with these pharmacologically effective salts and esters, or combinations thereof.
[0031]
U.S. Patent No. 5,780,479 discloses a method for controlling impulse modulation, other than hair loss, by administering an amount of at least one opioid receptor antagonist effective to reduce or eliminate at least one symptom of impulse control disorder. A therapeutic method for treating a disorder is described.
[0032]
U.S. Patent No. 5,714,483 describes an antitussive compound of a specific formula that is a delta opioid antagonist and suppresses cough in a patient with an amount of such an antagonist effective to reduce the frequency of coughing Claim a way to do it. For oral administration, it is suggested that this dose be from 10 μg to 1 g per day, but the test compound was administered intraperitoneally to rats.
[0033]
US Patent No. 5,512,593 describes a method of treating depression with a pharmacologically effective dose of an opioid antagonist and a pharmacologically effective dose of a compound, wherein the opioid antagonist comprises naltrexone, naloxone Selected from the group consisting of pharmacologically effective salts and esters thereof, or a combination thereof, and wherein said compound has one or more non-tricyclic rings that exhibit serotonin reuptake inhibition at synapses of the central nervous system. Or a pharmacologically effective salt or ester thereof, or a combination thereof.
[0034]
U.S. Patent No. 5,426,112 discloses at least one opioid antagonist that provides a transient blockade of an opioid receptor site by administering at least one opioid antagonist in a cumulative amount of less than about 10 mg per day in humans. Methods for treating and ameliorating pain and addiction are described.
[0035]
U.S. Pat. No. 5,356,900 discloses that an amount of a delta receptor which is effective to exert a substantial opiate receptor blocking effect on a .mu. A method for treating a human suffering from chronic herpes virus infection with an essentially pure opiate receptor antagonist having a selectively higher blocking effect on the μ opiate receptor as compared to the effect of the drug on the opiate receptor.
[0036]
U.S. Patent No. 5,352,680 describes delta opioid receptor antagonists of certain formulas and administers an effective amount of such antagonists to block or reduce resistance to opioid mu receptor agonists Accordingly, a method for treating resistance in a human receiving an opioid agonist is claimed.
[0037]
US Pat. No. 5,272,149 describes a method of treating addiction (eg, against heroin), implemented by reducing the amount of a target addictive drug in a subject, wherein the method comprises: Encompassing multiple specific steps for the sequential administration of multiple therapeutic agents, each in an amount effective to reduce a physiological level of the target agent in the subject, and wherein: Therapeutic agents include naloxone, naltrexone, buprenorphine and hydroxyzine.
[0038]
U.S. Pat. No. 5,266,574 accelerates the growth of wound tissue and related cells by administering an amount of naltrexone sufficient to continuously block the receptor site of the wound tissue and related cells. Thus, methods for enhancing the wound healing process are described.
[0039]
U.S. Patent No. 5,025,018 discloses that an effective amount of kappa opiate suitable to allow induction of kappa opiate receptor antagonist activity in a patient suffering from ischemic or traumatic central nerve injury. Methods for inducing kappa opiate receptor antagonist activity by administering a drug receptor antagonist are described. In a preferred embodiment, the kappa opiate receptor antagonist is nalmefene.
[0040]
U.S. Pat. No. 5,013,739 discloses a method of administering a therapeutically effective dose of an essentially pure opiate receptor antagonist to a human patient suffering from chronic fatigue syndrome in a pharmacologically effective manner. Methods for treating such humans are described, wherein the dose corresponds to a therapeutic result produced by naltrexone ranging from about 1.0 mg to about 10.0 mg.
[0041]
U.S. Pat. No. 4,935,428 describes a method of treating an opiate-dependent patient, wherein poisoning is administered sublingually with buprenorphine in a daily dose of 2-8 mg for 1-4 weeks, Thereafter, as a maintenance treatment, treatment is performed by co-administration of 2 to 8 mg of buprenorphine and naltrexone in an amount such that the weight ratio of naltrexone to buprenorphine is in the range of 1: 4 to 1: 1 every day. You.
[0042]
U.S. Pat. No. 4,906,637 has the same disclosure as U.S. Pat. No. 5,025,018 and has an effective amount of a kappa opiate agent suitable to permit induction of kappa opiate receptor antagonist activity. A method for treating a patient suffering from ischemic or traumatic brain injury by parenterally administering a receptor antagonist is described.
[0043]
U.S. Patent No. 4,877,791 discloses a method of treating such patients by administering daily from about 1 mg to about 50 mg of nalmefene or naltrexone to a patient suffering from interstitial cystitis. Is described.
[0044]
U.S. Pat. No. 4,863,928 discloses that by administering daily from about 1 mg to about 100 mg of nalmefene or naltrexone to a patient suffering from an arthritic or concomitant inflammatory disease, Describe the method of treatment.
[0045]
U.S. Pat. No. 4,857,533 describes a method of treating a patient suffering from an autoimmune disease, comprising administering about 1 mg to about 100 mg of the anesthetic antagonist nalmefene or naltrexone. And daily administration. Oral dosage forms generally contain from about 0.5 mg to 50.0 mg of nalmefene or naltrexone per dosage unit.
[0046]
U.S. Pat. Nos. 4,769,372 and 4,785,000 describe opioid analgesics or selected opioids that, when administered orally, substantially lack systemic antagonistic activity when administered orally. Method of treating a patient suffering from chronic pain or suffering from chronic cough without orally inducing intestinal motility by orally administering a dosage unit comprising a combination with an antagonist Is described.
[0047]
U.S. Pat. No. 4,774,230 discloses to provide glucuronic acid derivatives of opioid antagonists that have a local therapeutic effect in the gastrointestinal tract while minimizing systemic effects, especially central nervous system effects (e.g., Methods and compositions for the treatment of gastrointestinal dysmotility). Such derivatives of the opioid antagonist are used in an amount sufficient to provide, for example, about 0.1 mg to 50 mg of the opioid antagonist to the gastrointestinal tract of a subject for gastrointestinal tract-specific drug delivery.
[0048]
U.S. Patent No. 4,767,764 describes compounds of certain formulas that are kappa and mu receptor antagonists, but are more selective as kappa opioid receptor antagonists. Methods for improving the effects of opioid drugs and / or providing an appetite controlling effect by the administration of such compounds are also described.
[0049]
U.S. Pat. No. 4,668,685 is a substituted benzoate prodrug derivative of 3-hydroxymorphinan of a specific formula, which is useful in an effective analgesic amount or an effective anesthetic antagonizing amount. , Compounds.
[0050]
U.S. Pat. No. 4,600,718 describes a method of treating a weight loss disorder, comprising an effective amount consisting essentially of at least 10 mg of at least one opiate antagonist per 37 kg body weight. Administering to a mammal having a weight loss disorder.
[0051]
U.S. Patent No. 4,582,835 discloses a parenterally effective dose or sublingual with a sufficient amount of naloxone (e.g., 0.1 mg per tablet) to prevent surrogate formation in patients with opiate dependence. A method for treating pain by administering an effective dose of buprenorphine is described.
[0052]
U.S. Pat. No. 4,464,378 describes a method of eliciting an analgesic or anesthetic response in a warm-blooded animal by intranasal administration of: (a) eliciting an analgesic response An analgesically effective dose of morphine, hydromorphone, methopone, oxymorphone, desomorphine, dihydromorphine, levorphanol, cyclazosin, phenozosine, levallorphan, 3-hydroxy-N-methylmorphinan, levofenacylmorphan, Metazosin, norlevorphanol, phenomorphan, nalorphine, nalbuphine, buprenorphine, butorphanol or pentazocine, or a non-toxic pharmaceutically acceptable acid addition salt thereof; or (b) for eliciting an anesthetic antagonistic response , Anesthetic antagonist effective amounts of naloxone, naltrexone, diprenorphine, nalmexone, cyprenorphine, levallorphan, alazosine, oxilophan, cyclolphane, nalorphine, nalbuphine, buprenorphine, butorphanol, cyclazosin pentazone Or their non-toxic pharmaceutically acceptable acid addition salts.
[0053]
U.S. Patent No. 4,181,726 discloses a method of alleviating severe pruritus by administering an effective dosage (e.g., a dosage of 0.4 mg to 1000 mg) of naloxone to a patient suffering from pruritus. Describe.
[0054]
U.S. Patent No. 3,966,940 describes a method of treating a subject during anesthesia by administering an orally effective but parenterally inert analgesic composition. Such compositions may contain from about 0.1 mg to about 10 mg of naloxone.
[0055]
U.S. Pat. No. 3,773,955 describes a method of treating a drug subject by administering an orally effective but parenterally inert analgesic composition, wherein the analgesic composition comprises Naloxone and opiates (eg, phenazosin and methadone).
[0056]
Opioid antagonists in relatively high dosage forms to treat opioid agonist overdose and / or to prevent abuse of such agonists (eg, REVIA® 50 mg naltrexone) Opioid antagonist compositions and dosage forms have not yet been manufactured for use at very low concentrations, as they have been manufactured for conventional use.
[0057]
In particular, the commercial production of an immediate release dosage form that provides a dose of a first active agent (eg, an opioid antagonist) and at the same time a substantially lower dose of a second active agent (eg, an opioid agonist) Difficulty is due to batch-to-batch variability in the amount of active agent present in individual unit dosages. Although various different methods have been developed to address this problem, none of the specific methods are widely applicable to all combinations of drugs. That is, issues such as undesired drug / excipient interactions, drug instability, formulation instability, and unexpected dosage form performance can cause the formulation and process to be tailored to a particular drug combination. Continuous demands arise.
[0058]
(Summary of the Invention)
The present invention relates to novel pharmaceutical compositions, dosage forms, and kits comprising an opioid antagonist. The present invention also relates to novel pharmaceutical compositions, dosage forms, and kits comprising an opioid antagonist and another active ingredient (eg, an opioid antagonist). The present invention further provides such pharmaceutical compositions, dosage forms, and kits comprising an opioid antagonist, alone or in combination with another active pharmaceutical ingredient (eg, an opioid agonist), in a human subject. To a method for administration. Preferred opioid antagonists include naltrexone, nalmefene, or naloxone. Particularly preferred is naltrexone. For pharmaceutical compositions, dosage forms, kits and methods according to the invention, the opioid antagonist is provided in the following amounts: at least about 0.0001 mg to about 1.0 mg, or at least about 0.001 mg to about 1.0 mg or less, or at least about 0.01 mg to about 1.0 mg or less, or at least 0.1 mg to about 1 mg or less. A preferred range of opioid antagonists also includes: about 0.0001 mg to less than 1.0 mg; about 0.001 mg to less than 1.0 mg; about 0.01 mg to less than 1.0 mg; or about 0.1 mg to 1 mg. Less than 0.0 mg. More preferred ranges of opioid antagonists include: about 0.0001 mg to about 0.1 mg; about 0.001 mg to about 0.1 mg; about 0.01 mg to about 0.1 mg; about 0.001 mg to about 0 mg. 0.1 mg; about 0.001 mg to about 0.01 mg; or about 0.01 mg to about 0.1 mg. More preferred opioid antagonist ranges include: at least about 0.0001 mg to less than about 0.5 mg; at least about 0.01 mg to less than about 0.5 mg, or at least about 0.1 mg to less than about 0.5 mg. .
[0059]
Each of these dosage forms can be a solid oral dosage form or another dosage form. Each of these pharmaceutical compositions may consist essentially of the opioid antagonist and a pharmaceutically acceptable carrier. Each of these kits may consist essentially of a solid oral dosage form of the antagonist and a container. Each of these pharmaceutical compositions or kits may be further comprised of another active pharmaceutical ingredient, such as an opioid agonist, optionally in a solid oral dosage form. Alternatively, the other active pharmaceutical ingredient (eg, agonist) is provided in an injectable, transdermal, transmucosal, oral solution, syrup, elixir or other dosage form as needed. Is done.
[0060]
Each of the pharmaceutical compositions may comprise or consist essentially of an opioid antagonist together with another active pharmaceutical ingredient (eg, an opioid agonist), which may comprise one or more pharmaceutically acceptable With the possible ingredients, it is formulated into dosage forms designed for the particular route of administration. Each kit may comprise or consist essentially of one or more containers of an agent, each of which may contain an opioid antagonist alone or may contain an opioid antagonist and other active pharmaceutical ingredients (eg, opioids). Has one or more dosage forms, either in combination with an agonist or both. Further, the dosage forms and kits, by design, provide a dosage system that provides for the administration of one or both agents in one or more dosage forms in the particular regimen required to achieve a therapeutic benefit. Can be configured.
[0061]
The maximum amount of antagonist in a dosage form is: 1 mg, or less than 1 mg, or 0.99 mg, or 0.98 mg, or 0.97 mg, or 0.96 mg, or 0.95 mg, or 0.94 mg, or 0.93 mg, or 0.92 mg, or 0.91 mg, or 0.90 mg, or 0.89 mg, or 0.88 mg, or 0.87 mg, or 0.86 mg, or 0.85 mg, or 0.84 mg, or 0.83 mg, or 0.82 mg, or 0.81 mg, or 0.80 mg, or 0.79 mg, or 0.78 mg, or 0.77 mg, or 0.77 mg, or 0.75 mg, or 0.74 mg, or 0. 3 mg, or 0.72 mg, or 0.71 mg, or 0.70 mg, or 0.69 mg, or 0.68 mg, or 0.67 mg, or 0.66 mg, or 0.65 mg, or 0.64 mg, or 0. 63 mg, or 0.62 mg, or 0.61 mg, or 0.60 mg, or 0.59 mg, or 0.58 mg, or 0.57 mg, or 0.56 mg, or 0.55 mg, or 0.54 mg, or 0.5 mg. 53 mg, or 0.52 mg, or 0.51 mg, or 0.50 mg.
[0062]
Further, the maximum amount of the antagonist in the dosage form is: less than 0.5 mg, or 0.49 mg, alternatively 0.48 mg, alternatively 0.47 mg, alternatively 0.46 mg, alternatively 0.45 mg, alternatively 0.44 mg, Or 0.43 mg, or 0.42 mg, or 0.41 mg, or 0.40 mg, or 0.39 mg, or 0.38 mg, or 0.37 mg, or 0.37 mg, or 0.36 mg, or 0.35 mg, or 0.34 mg; Or 0.33 mg, or 0.32 mg, or 0.31 mg, or 0.30 mg, or 0.29 mg, or 0.28 mg, or 0.27 mg, or 0.26 mg, or 0.25 mg, or 0.24 mg; Or 0.23 g, or 0.22 mg, or 0.21 mg, or 0.20 mg, or 0.19 mg, or 0.18 mg, or 0.17 mg, or 0.16 mg, or 0.16 mg, or 0.15 mg, or 0.14 mg, or 0.1 g. 13 mg, or 0.12 mg, or 0.11 mg, or 0.10 mg, or 0.09 mg, or 0.08 mg, or 0.07 mg, or 0.06 mg, or 0.05 mg, or 0.04 mg, or 0.03 mg; 03 mg, or 0.02 mg, or 0.01 mg, or 0.009 mg, or 0.008 mg, or 0.007 mg, or 0.006 mg, or 0.005 mg, or 0.005 mg, or 0.004 mg, or 0.003 mg, or .002mg or 0.001mg or 0.0009mg or 0.0008mg or 0.0007mg or 0.0006mg or 0.0005mg or 0.0004mg or 0.0003mg or 0.0002mg,,,,,,,,,.
[0063]
The minimum amount of antagonist in the dosage form is: 0.0001 mg, or 0.0002 mg, or 0.0003 mg, or 0.0004 mg, or 0.0005 mg, or 0.0006 mg, or 0.0007 mg, or 0.007 mg. 0008 mg, or 0.0009 mg, or 0.001 mg, or 0.002 mg, or 0.003 mg, or 0.004 mg, or 0.005 mg, or 0.006 mg, or 0.007 mg, or 0.008 mg, or 0. 009 mg, or 0.01 mg, or 0.011 mg, or 0.012 mg, or 0.013 mg, or 0.014 mg, or 0.015 mg, or 0.016 mg Is 0.017 mg, or 0.018 mg, or 0.019 mg, or 0.02 mg, or 0.021 mg, or 0.022 mg, or 0.023 mg, or 0.024 mg, or 0.025 mg, or 0.026 mg; Or 0.027 mg, or 0.028 mg, or 0.029 mg, or 0.03 mg, or 0.031 mg, or 0.032 mg, or 0.033 mg, or 0.034 mg, or 0.034 mg, or 0.036 mg; Or 0.037 mg, or 0.038 mg, or 0.039 mg, or 0.04 mg, or 0.041 mg, or 0.042 mg, or 0.043 mg, or 0.044 mg Is 0.045 mg, or 0.046 mg, or 0.047 mg, or 0.048 mg, or 0.049 mg, or 0.05 mg, or 0.051 mg, or 0.051 mg, or 0.052 mg, or 0.053 mg, or 0.054 mg; Or 0.055 mg, or 0.056 mg, or 0.057 mg, or 0.058 mg, or 0.059 mg, or 0.06 mg, or 0.061 mg, or 0.061 mg, or 0.062 mg, or 0.063 mg, or 0.064 mg; Or 0.065 mg, or 0.066 mg, or 0.067 mg, or 0.068 mg, or 0.069 mg, or 0.07 mg, or 0.071 mg, or 0.072 mg, or Is 0.073 mg, or 0.074 mg, or 0.075 mg, or 0.076 mg, or 0.077 mg, or 0.078 mg, or 0.079 mg, or 0.08 mg, or 0.081 mg, or 0.082 mg, Or 0.083 mg, or 0.084 mg, or 0.085 mg, or 0.086 mg, or 0.087 mg, or 0.088 mg, or 0.089 mg, or 0.09 mg, or 0.09 mg, or 0.091 mg, or 0.092 mg; Or 0.093 mg, or 0.094 mg, or 0.095 mg, or 0.096 mg, or 0.097 mg, or 0.098 mg, or 0.099 mg, or 0.1 mg, or .11 mg, or 0.12 mg, or 0.13 mg, or 0.14 mg, or 0.15 mg, or 0.16 mg, or 0.17 mg, or 0.18 mg, or 0.19 mg, or 0.20 mg, or 0 0.21 mg, or 0.22 mg, or 0.23 mg, or 0.24 mg, or 0.25 mg, or 0.26 mg, or 0.27 mg, or 0.28 mg, or 0.29 mg, or 0.3 mg, or 0 .31 mg, or 0.32 mg, or 0.33 mg, or 0.34 mg, or 0.35 mg, or 0.36 mg, or 0.37 mg, or 0.38 mg, or 0.39 mg, or 0.30 mg, or 0.40 mg, or 0 .41 g, or 0.42 mg, or 0.43 mg, or 0.44 mg, or 0.45 mg, or 0.46 mg, or 0.47 mg, or 0.47 mg, or 0.48 mg, or 0.49 mg, or 0.5 mg, or 0.5 mg. 51 mg, or 0.52 mg, or 0.53 mg, or 0.54 mg, or 0.55 mg, or 0.56 mg, or 0.57 mg, or 0.58 mg, or 0.59 mg, or 0.6 mg, or 0.5 mg. 61 mg, or 0.62 mg, or 0.63 mg, or 0.64 mg, or 0.65 mg, or 0.66 mg, or 0.67 mg, or 0.68 mg, or 0.69 mg, or 0.7 mg, or 0.7 mg. 71 mg, or 0.72 mg, or 0.73 mg, or 0.74 mg, or 0.75 mg, or 0.76 mg, or 0.77 mg, or 0.78 mg, or 0.79 mg, or 0.8 mg, or 0.81 mg, or 0.82 mg, or 0.83 mg, or 0.84 mg, or 0.85 mg, or 0.86 mg, or 0.87 mg, or 0.88 mg, or 0.89 mg, or 0.9 mg, or 0.91 mg, or 0.92 mg, or 0.93 mg, or 0.94 mg, or 0.95 mg, or 0.96 mg, or 0.97 mg, or 0.98 mg, or 0.99 mg.
[0064]
Any minimum and any maximum amount of the antagonist in the dosage form can be combined to define a range of amounts, as specified above, with the proviso that the selected minimum is equal to the selected maximum or Less than that. In an alternative embodiment of the invention, the amount of the antagonist in the dosage form is less than the effective amount to antagonize the exogenous or endogenous opioid agonist, but such an amount enhances the potency of the agonist, and And / or an amount that attenuates adverse effects, and / or an amount that attenuates tolerance, withdrawal symptoms, dependence and / or addiction.
[0065]
In one alternative embodiment of the invention, the antagonist is present in the form of a pharmaceutically acceptable salt. For example, a dosage form may include naltrexone hydrochloride as an antagonist. The antagonist may be provided in a form suitable for oral administration. The antagonist may be formulated as a capsule, tablet, pill, or solid sprinkle form.
[0066]
Yet another aspect of the invention is a method of administering a fixed dose of an opioid antagonist to a human subject by administering a solid dosage form as described above or a kit as described above, comprising, for example, The dose of the antagonist will be less than the amount effective to antagonize the exogenous or endogenous opioid agonist (eg, less than the amount of the effective antagonist), but such an amount will enhance potency and And / or an amount that attenuates the deleterious effects of the agonist, and / or an amount that attenuates tolerance, withdrawal symptoms, dependence and / or addiction. In one aspect of the invention, the method further comprises administering another active pharmaceutical ingredient (eg, an opioid agonist), either in a combined dosage form with the antagonist or in a separate dosage form. Steps. Such separate agonist dosage forms include solid oral forms, oral solution forms, syrup forms, elixir forms, injectable forms, transdermal forms, transmucosal forms, or other Dosage forms may be mentioned.
[0067]
Yet another aspect of the invention is a pharmaceutical kit comprising a dosage form of an opioid antagonist and a container. The kit may also optionally include a dosage form of the opioid agonist or other active pharmaceutical ingredient. The opioid antagonist and another active pharmaceutical ingredient can be combined in one dosage form or can be supplied in separate dosage forms that can be used together or sequentially. The opioid antagonist and another active pharmaceutical ingredient can be administered simultaneously with, before, or after the other.
[0068]
In another alternative embodiment of the invention, the agonist is present as another active pharmaceutical ingredient with the antagonist. The agonist may be in its original form or in the form of a pharmaceutically acceptable salt. The agonist may be present in an amount that is analgesic or subalgesic (eg, non-analgesic) in a human subject. The agonist may also be present in an amount that is anti-analgesic in a human subject. As agonists, alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, royalphanan, leuorphanol, meperidine, methadone, morphine, narbufen, narbufen, nalbufen, nalbufen, nalbufen Oxymorphone, pentazocine, propoxyphen, and tramadol. The agonist is preferably morphine, hydrocodone, tramadol, or oxycodone, or may include a combination thereof.
[0069]
In another alternative embodiment of the invention, the opioid antagonist is present with one or more other active ingredients. For example, other active pharmaceutical ingredients include acetaminophen, steroidal or non-steroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen), COX-1 and / or COX-2 inhibitors (eg, aspirin) , Rofecoxib (commercially available as VIOXX®), and celecoxib (CELEBREX) ^TM Commercially available as).
Yet another aspect of the invention is that one or more pharmaceutical excipients, a fixed dose of an opioid agonist and a low dose of an opioid antagonist, wherein when placed in an aqueous environment, the opioid agonist and opioid antagonist are (Released at the same time). A further preferred aspect of the present invention provides a solid oral dosage form comprising an opioid agonist and an opioid antagonist and essentially free of other active pharmaceutical ingredients.
[0070]
Yet another aspect of the invention is an immediate release combination solid substantially consisting of an opioid antagonist, another active pharmaceutical ingredient (eg, an opioid agonist), and one or more pharmaceutical excipients. Oral dosage form. The opioid antagonist is present in the following amounts: from about 0.0001 mg to about 1.0 mg, alternatively less than 1.0 mg, alternatively less than about 0.5 mg. The opioid agonist is present in an amount from about 0.1 mg to about 300 mg. The opioid antagonist and the opioid agonist are released simultaneously over a period of less than about 1.5 hours.
[0071]
Specific embodiments of the present invention include the following: 1) The dosage form is free of pharmaceutical excipients that significantly bind, adsorb, or complex opioid antagonists in an aqueous environment; The opioid antagonist is present in an amount of at least about 0.0001 mg to about 1.0 mg or less, or less than 1.0 mg or at least about 0.0001 mg to less than 0.5 mg, and the opioid agonist is optimally Present in an amount ranging from about 0.1 mg to about 300 mg; 3) the dosage form comprises at least two pharmaceutical excipients; 4) the dosage form is coated on a first nonpareil pellet. A first pellet of the isolated opioid antagonist and, optionally, a second nonpareil pellet. A second pellet of the coated opioid agonist (or another active pharmaceutical ingredient); 5) the dosage form comprises a composition of the opioid antagonist, optionally another active pharmaceutical ingredient (eg, an opioid Agonist), at least one polymer, and at least one plasticizer; 6) the dosage form is a first granule of another opioid antagonist and a first mixture of pharmaceutical excipients, and optionally another A second granulation of an active pharmaceutical ingredient (eg, an opioid agonist) and a second mixture of pharmaceutical excipients; 7) the dosage form comprises a first granulation, an opioid antagonist, and at least one pharmaceutical agent. A second granule comprising a mixture of active excipients, wherein the first granule comprises another active pharmaceutical ingredient (eg, opioid). Agonist) and at least one pharmaceutical excipient; 8) the dosage form comprises a binder, a pharmaceutical excipient coated with a binder composition, an opioid antagonist, and optionally another active Comprising a mixture of coated granules of a pharmaceutical ingredient (eg, an opioid agonist); 9) the dosage form comprises a coated first granule, wherein the granules comprise another active pharmaceutical ingredient ( For example, an opioid agonist), and a mixture of pharmaceutical excipients, the coating comprising an opioid antagonist; 10) a dosage form comprising spray-dried opioid antagonist opioid granules, optionally another active pharmaceutical agent. An active ingredient (eg, an opioid agonist) and at least one pharmaceutical excipient; The dosage form comprises a soft gelatin capsule filled with an opioid antagonist, optionally another active pharmaceutical ingredient (eg, an opioid agonist), and at least one non-aqueous vehicle.
[0072]
Another aspect of the invention provides a method of making an immediate release solid oral dosage form having a dose of an opioid antagonist and optionally a dose of another active pharmaceutical ingredient (eg, an opioid agonist). Wherein, the opioid antagonist, or the opioid antagonist and another active pharmaceutical ingredient, is released in greater than 90% in less than about 45 minutes after exposure to an aqueous environment. Immediate release solid oral dosage forms having antagonists and agonists include immediate release solid oral dosage forms where the opioid agonist and opioid antagonist are released simultaneously when placed in an aqueous environment.
[0073]
Other particular embodiments of the present invention include embodiments wherein the dosage form is made by: 1) forming a mixture of at least two different coated pellets, wherein: The first pellet is made by coating an opioid antagonist on a first non-pareil pellet, and the second pellet is coated with another active pharmaceutical ingredient on a second non-pareil pellet. Made by coating; 2) preparing a composition of an opioid antagonist, another active pharmaceutical ingredient, at least one polymer, and at least one plasticizer, and applying the composition to non-pareil pellets Step; 3) First Blend of Opioid Antagonist and Pharmaceutical Excipient Forming a first granule of the product, forming a second granule of a second mixture of another active pharmaceutical ingredient and a pharmaceutical excipient, and the first granule and the second granule 4) forming a first granule of the active pharmaceutical ingredient and at least one pharmaceutical excipient, and mixing the first granule, the opioid antagonist and the at least one pharmaceutical excipient 5) preparing a binding composition of a binding agent, an opioid antagonist, another active pharmaceutical ingredient, and coating the mixture of pharmaceutical excipients with the binding composition. 6) coating the composition of the mixture of the active pharmaceutical ingredient and the pharmaceutical excipient with the coating composition of the opioid antagonist. 7) spray drying the opioid antagonist, another active pharmaceutical ingredient and at least one pharmaceutical excipient to form spray-dried granules; or 8) opioid antagonist, another active pharmaceutical ingredient and Filling the soft gelatin capsule with at least one non-aqueous vehicle.
[0074]
The following figures form part of the present description and describe exemplary embodiments of the invention. One skilled in the art, in light of these figures and the description herein, will be able to implement the present invention without undue experimentation.
[0075]
(Detailed description)
The present disclosure relates to novel pharmaceutical compositions of very low dose opioid antagonists. New dosage forms of such antagonists are manufactured for the first time and are administered to human subjects with unexpected benefit. When such novel dosage forms are administered to a human subject, they increase the analgesic efficacy of the opioid agonist and / or reduce (eg, reduce, block, inhibit or prevent) adverse side effects, and / or Or reduce tolerance, withdrawal, dependence and / or addiction. For example, such novel dosage forms may simultaneously increase the analgesic efficacy of the opioid agonist, but reduce the side effects of the agonist, or increase the analgesic efficacy of the opioid agonist without reducing the side effects of the agonist, Or maintain the analgesic efficacy of the agonist, but reduce the side effects of the agonist, while at the same time, or reduce tolerance, withdrawal, dependence and / or addiction. For compositions and methods of the present invention that reduce (eg, reduce, block or prevent) the deleterious effects of an opioid agonist, the advantage is that analgesic efficacy is maintained without increasing or decreasing the cumulative daily dose of the agonist. There is.
[0076]
The present invention involves the manufacture and use of new dosage forms of very low amounts of opioid antagonists. Clinical trials have yielded surprising effects and benefits in humans. For example, using the novel pharmaceutical compositions or dosage forms according to the present invention, it has been unexpectedly demonstrated that the analgesic efficacy of opioid agonists can be offset from harmful effects in humans. Thus, initially, the present invention provides novel pharmaceutical composition compositions, dosage form kits and methods for administering an opioid antagonist to a human or treating a human with an opioid antagonist. The opioid antagonist is provided in the following amounts: at least about 0.0001 mg to about 1.0 mg or less or at least about 0.001 mg to about 1.0 mg or less or at least about 0.01 mg to about 1.0 mg or less or at least about 0.1 mg to about 1 mg or less. Preferred ranges of the opioid antagonist also include: about 0.0001 mg to less than 1.0 mg; about 0.001 mg to less than 1.0 mg; about 0.01 mg to less than 1.0 mg; or about 0.1 mg to less than 1.0 mg. Less than 1.0 mg. More preferred ranges of opioid antagonists include: about 0.0001 mg to about 0.1 mg; about 0.001 mg to about 0.1 mg; about 0.01 mg to about 0.1 mg; about 0.001 mg to about 0.1 mg. 0.1 mg; about 0.001 mg to about 0.01 mg; or about 0.01 mg to about 0.1 mg. More preferred ranges of opioid antagonists include: at least about 0.0001 to less than about 0.5 mg; at least about 0.01 to less than about 0.5 mg; or at least about 0.001 to about 0.5 mg. Less than.
[0077]
The term "opioid" includes metabolites of such compounds or compositions that bind to specific opioid receptors and have agonistic (activating) or antagonistic (inactivating) effects on these receptors For example, compounds or compositions that refer to opioid alkaloids (including the agonist morphine and metabolite morphine-6-glucuronide and the antagonist naltrexone and its metabolites) and opioid peptides (including enkephalin, dynorphin and endorphin). The opioid may be present in the compositions of the present invention as an opioid base, an opioid pharmaceutically acceptable salt or a combination thereof. Pharmaceutically acceptable salts include inorganic or organic salts. Representative salts include: hydrobromide, hydrochloride, mucate, citrate, n-oxide, sulfate, malonate, acetate, dibasic phosphate, Monobasic phosphate, acetic acid trihydrate, bi (heprafluorobutyrate), maleate, bi (methyl carbamate), bi (pentafluoropropionate), mesylate, bi (pyridine-3-carboxylate) ), Bi (trifluoronate), hydrogen bitartrate, chlorhydrate, fumarate and pentahydrate sulfate. The term "opiate" refers to an opiate-derived drug or related natural or synthetic analog.
[0078]
An “opioid receptor agonist” or “opioid agonist” is an opioid compound or composition that comprises any active metabolite of such a compound or composition that binds and activates the opioid receptor in nociceptive neurons that mediate pain. Things. Such opioid agonists have analgesic activity (having a measurable onset, peak, duration and / or total effect) and can produce analgesia. Opioid agonists according to the present invention include: alfentanil, allylprozine, alphaprozine, anileridine, apomorphine, apocodeine, benzylmorphine, benzitolamide, buprenorphine, butorphanol, clonitazen, codeine, cyclazosin, cyclorphene, cyprenorphine, dezomorphine. Dextromolamide, desozin, diapromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxafetyl, butyrate, dipipanone, eptazocine, ethyl, ethheptazine, ethyl Morphine, etonitazene , Fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levallorphan, levorphanol, levorfenacyl norphan, lofentanil, meperidine, meptazinol, metazodine, methazone, methylmorphine, methopone, Morphine, myrophin, nalbuphine, narcein, nicomorphine, norlevorphenol, normethad, nalorphine, normorphine, norpipanone, ohmefentanil, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenadoxone, phenadoxone , Phenoperidine, phorcodine, pimino , Pyritramide, propeptazine, promedol, propadole, properidine, propiram, propoxyphene, remifentanil, safentanil, tamaramadol, thyridine, salts thereof, a mixture of any of the foregoing, a mixed mu-agonist / antagonist, Combinations of mu-antagonists or others known to those skilled in the art. Preferred opioid agonists for human use are morphine, hydrocodone, oxycodone, codeine, fentanyl (and related), hydromorphone, meperidine, methadone, oxamorphone, propoxyphen or tramadol or mixtures thereof. Certain preferred possible agonists include morphine, hydrocodone, oxycodone or trador. Opioid agonists include exogenous or endogenous opioids.
[0079]
A "binary-acting opioid agonist" is an opioid agonist that binds and activates both inhibitory and excitatory opioid receptors in nociceptive neurons that mediate pain. Activation of the inhibitory receptor by this agonist causes analgesia. Activation of excitatory receptors by this agonist results in anti-analgesic, hyperexcitatory, hyperalgesic and the development of physiological dependence, tolerance and other undesirable side effects. Binomial-acting opioid agonists can be identified by measuring the effect of opioids on the duration of action (APD) of spinal ganglion (DRG) neurons in tissue culture. In this regard, binomial opioid agonists are compounds that induce prolongation of APD in DRG neurons at pM-nM concentrations (ie, excitatory sclerosis) and shortening of APD in DRG neurons at μM concentrations (ie, inhibitory effects). .
[0080]
An "opioid antagonist" refers to an opioid compound or opioid composition that includes any active metabolite of such a compound or composition that reduces (eg, blocks, inhibits, prevents or competes for) the action of the opioid agonist in sufficient amount. Say. An amount of an “effective antagonist” is an amount that effectively reduces the analgesic activity of the opioid agonist. For example, it is recognized that 50 mg of naltrexone is an effective antagonist amount. Such relief is demonstrated when the compound or composition is used at an effective antagonist dose. Opioid antagonists bind and block (eg, inhibit) opioid receptors in nociceptive neurons that mediate pain. Opioid antagonists include: naltrexone (commercially available in 50 mg dosage form as Revia® or Trexan®), nalokirin (commercially available as Narcan®), nalmefene, methyl Naltrexone, nalokirin methiodide, nalorphine, naloxanodine, nadide, nalomexone, nalobfen, nalofin, dinicotinate, naltriindole (NTI), naltriindole iotisocyanate (NTII), naltriben (NTB), nor-binal tolfimine (Nor-BNI), b-funaltrexamine (b-FNA), BNTX, cyprodim, ICI-174,864, LY117413, MR2266 Or the same 5-cyclic nucleic acids such as nalmefene, naltrexone, nalorphine, nalbuphine, nalobufine, thebaine, levallorphan, oxymorphone, butorphanol, buprenorphine, levorphanol, meptazinol, pentazocine, dezocine or a pharmaceutically effective ester or salt) An opioid antagonist having the formula: In some embodiments, the opioid antagonist is naltrexone, nalomephan, naloxone, or a mixture thereof. A particularly contemplated antagonist is naltrexone.
[0081]
"Excitatory opioid receptor antagonists" are opioids that bind to and act as antagonists to excitatory opioid receptors, rather than inhibitory opioid receptors in nociceptive neurons that mediate pain. That is, excitatory opioid receptor antagonists bind DRG excitatory opioid receptors and block DRG neurons at 1,000 to 10,000-fold lower concentrations required to block inhibitory opioid receptor function in these neurons. It is a compound that selectively blocks nociceptive excitatory opioid receptor function. The excitatory opioid receptor antagonisd can also be identified by measuring the effect of opioids on the duration of potency (APD) of spinal ganglion (DRG) neurons in tissue culture. In this regard, excitatory opioid receptor antagonists select for prolongation of APD of DRG neurons (ie, excitatory effects) rather than shortening (ie, inhibitory effects) of APD of DRG neurons induced by a binomial-acting opioid receptor agonist. It is a compound that blocks specifically. Suitable excitatory opioid receptor antagonists include: nalmefene, naltrexone, naloxone, etorphine and dihydroethorphine and similar acting opioid alkaloids and opioid peptides. The excitatory opioid receptor antagonists are preferably naltrexone and nalomephan because of their longer duration of action and higher viability after oral administration compared to naloxone.
[0082]
The opioid antagonist or opioid agonist (if used) or another active pharmaceutical ingredient can be provided in free base or pharmaceutically acceptable acid, as well as salt form. As used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound. Here, the therapeutic compounds are modified by making their acid or base salts. Pharmaceutically acceptable salts include inorganic or organic salts.
[0083]
Examples of pharmaceutically acceptable salts include, but are not limited to: metal or organic acid salts of an opioid antagonist or opioid agonist. Pharmaceutically acceptable salts include the conventional non-toxic salts made from, for example, non-toxic inorganic or non-toxic organic salts. For example, such conventional non-toxic salts include those derived from the following inorganic acids: hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric, and the like. Others known to the art; and salts prepared from organic acids such as: amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, malonic, tartaric, citric, Ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfone, methanesulfone, ethanedisulfuric acid, oxalic acid , Isethionic acid, glucuronic acid and other acids. Other pharmaceutically acceptable salts and variants include: mucate, phosphate (monobasic), phosphate (dibasic), acetic acid trihydrate, di (heprafluorobutyi). Rates), bi (methyl carbamate), bi (pentafluoropropionate), mesylate, bi (pyridine-3-carboxylate), bi (trifluoroacetate), bitartrate, chlorohydrate and pentahydrate sulfate. Oxides (although not usually referred to by chemists as salts) are also "pharmaceutically acceptable salts" for this purpose. For acidic compounds, the salt may include an amine base (primary, secondary tertiary or quaternary amine) counter ion, an alkali metal cation or a metal cation. A list of suitable salts is found in texts such as: Remington's Pharmaceutical Sciences, 18th Edition (eds. Alfonson R. Gennaro; Mack Publishing Company, Easton, PA, 1990); Remington: the same cinema; Pharmacy, 19th Edition (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd Edition (Arthur H. Klebes, Pharmaceuticals, Inc .; Amer. Pharmaceuticals; Pharmaceuticals, Inc .; actice of Pharmaceutics 12th edition (Walter Lund eds; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird eds .; McGraw Hill, 1992) (the disclosures of which are incorporated herein by reference).
[0084]
The phrase "pharmaceutically acceptable" is used herein to refer to these compounds, substances, compositions and / or dosage forms. They are suitable for use in contact with human and animal tissues, within the scope of sound medical judgment, have no undue toxicity, irritation, allergic response or other problems or complications, and It is proportional to the risk ratio.
[0085]
The maximum amount of antagonist in the dosage form is: 1 mg, or less than 1 mg, or 0.99 mg, or 0.98 mg, or 0.97 mg, or 0.96 mg, or 0.95 mg; Alternatively, 0.94 mg, or 0.93 mg, or 0.92 mg, or 0.91 mg, or 0.90 mg, or 0.89 mg, or 0.88 mg, or 0.87 mg, or 0.86 mg, 0.85 mg, 0.84 mg, 0.83 mg, 0.82 mg, 0.81 mg, 0.80 mg, 0.79 mg, or 0.7 mg 78mg or 0.77mg or 0.76mg or 0.75 mg, 0.74 mg, 0.73 mg, 0.72 mg, 0.71 mg, 0.70 mg, 0.69 mg, 0.68 mg, or 0 .67 mg, or 0.66 mg, or 0.65 mg, or 0.64 mg, or 0.63 mg, or 0.62 mg, or 0.61 mg, or 0.60 mg, or 0.59 mg Or 0.58 mg, or 0.57 mg, or 0.56 mg, or 0.55 mg, or 0.54 mg, or 0.53 mg, or 0.52 mg, or 0.51 mg, or 0.50 mg.
[0086]
Further, the maximum amount of antagonist in the dosage form is: less than 0.5 mg, alternatively 0.49 mg, alternatively 0.48 mg, alternatively 0.47 mg, alternatively 0.46 mg, alternatively 0.45 mg, Alternatively, 0.44 mg, or 0.43 mg, or 0.42 mg, or 0.41 mg, or 0.40 mg, or 0.39 mg, or 0.38 mg, or 0.37 mg, or 0.36 mg, 0.35 mg, 0.34 mg, 0.33 mg, 0.32 mg, 0.31 mg, 0.30 mg, 0.29 mg, or 0.3 mg 28 mg, or 0.27 mg, or 0.26 mg, or 0 25 mg, or 0.24 mg, or 0.23 mg, or 0.22 mg, or 0.21 mg, or 0.20 mg, or 0.19 mg, or 0.18 mg, or 0.17 mg; Alternatively, 0.16 mg, or 0.15 mg, or 0.14 mg, or 0.13 mg, or 0.12 mg, or 0.11 mg, or 0.10 mg, or 0.09 mg, or 0.08 mg, 0.07 mg, 0.06 mg, 0.05 mg, 0.04 mg, 0.03 mg, 0.02 mg, 0.01 mg, or 0.1 mg 009 mg, or 0.008 mg, or 0.007 mg, Or 0.006 mg, or 0.005 mg, or 0.004 mg, or 0.003 mg, or 0.002 mg, or 0.001 mg, or 0.0009 mg, or 0.0008 mg; or 0.0007 mg, 0.0006 mg, 0.0005 mg, 0.0004 mg, 0.0004 mg, 0.0003 mg, or 0.0002 mg.
[0087]
The minimum amount of antagonist in the dosage form is: 0.0001 mg, or 0.0002 mg, or 0.0003 mg, or 0.0004 mg, or 0.0005 mg, 0.0006 mg, or 0.0007 mg. Or 0.0008 mg, or 0.0009 mg, or 0.001 mg, or 0.002 mg, or 0.003 mg, or 0.004 mg, or 0.005 mg, or 0.006 mg, or 0.007 mg, or 0.008 mg, or 0.009 mg, or 0.01 mg, or 0.011 mg, or 0.012 mg, or 0.013 mg, or 0.014 mg, or 0 .01 mg, or 0.016 mg, or 0.017 mg, or 0.018 mg, or 0.019 mg, or 0.02 mg, or 0.021 mg, or 0.022 mg, or 0.023 mg; Alternatively, 0.024 mg, or 0.025 mg, or 0.026 mg, or 0.027 mg, or 0.028 mg, or 0.029 mg, or 0.03 mg, or 0.031 mg, or 0.032 mg, or 0.033 mg, or 0.034 mg, or 0.035 mg, or 0.036 mg, or 0.037 mg, or 0.038 mg, or 0.038 mg, or 0.039 mg; 04 mg or 0. 41 mg, or 0.042 mg, or 0.043 mg, or 0.044 mg, or 0.045 mg, or 0.046 mg, or 0.047 mg, or 0.048 mg, or 0.049 mg; Alternatively, 0.05 mg, or 0.051 mg, or 0.052 mg, or 0.053 mg, or 0.054 mg, or 0.055 mg, or 0.056 mg, or 0.057 mg, or 0.058 mg, or 0.059 mg, or 0.06 mg, or 0.061 mg, or 0.062 mg, or 0.063 mg, or 0.064 mg, or 0.065 mg, or 0.0. 066 mg, or 0.067 mg, or 0.068 mg, or 0.069 mg, or 0.07 mg, or 0.071 mg, or 0.072 mg, or 0.072 mg, or 0.073 mg, or 0.04 mg; 075mg, or 0.076mg, or 0.077mg, or 0.078mg, or 0.079mg, or 0.08mg, or 0.081mg, or 0.082mg, or 0.083mg, Alternatively, 0.084 mg, or 0.085 mg, or 0.086 mg, or 0.087 mg, or 0.088 mg, or 0.089 mg, or 0.09 mg, or 0.091 mg, or 0.092mg, or 0.093 mg, or 0094 mg, or 0.095 mg, or 0.096 mg, or 0.097 mg, or 0.098 mg, or 0.098 mg, or 0.1 mg, or 0.11 mg , Or 0.12 mg, or 0.13 mg, or 0.14 mg, 0.15 mg, or 0.16 mg, or 0.17 mg, or 0.18 mg, or 0.19 mg, or 0 0.2 mg, 0.21 mg, 0.22 mg, 0.23 mg, 0.24 mg, 0.25 mg, 0.26 mg, 0.27 mg, or 0.28 mg Or 0.29mg or 0.3mg Is 0.31 mg, or 0.32 mg, or 0.33 mg, or 0.34 mg, or 0.35 mg, or 0.36 mg, or 0.37 mg, or 0.38 mg, or 0.39 mg, or 0.40 mg, or 0.41 mg, or 0.42 mg, or 0.43 mg, or 0.44 mg, or 0.45 mg, or 0.46 mg, or 0.4 g 47 mg, or 0.48 mg, or 0.49 mg, or 0.5 mg, or 0.51 mg, or 0.52 mg, or 0.53 mg, or 0.54 mg, or 0.55 mg; Alternatively, 0.56 mg, 0.57 mg, or 0.58 mg, Or 0.59 mg, or 0.6 mg, or 0.61 mg, or 0.62 mg, or 0.63 mg, or 0.64 mg, or 0.65 mg, or 0.66 mg, or 0.67 mg or 0.68 mg or 0.69 mg or 0.7 mg or 0.71 mg or 0.72 mg or 0.73 mg or 0.74 mg or 0 0.75 mg, or 0.76 mg, or 0.77 mg, or 0.78 mg, or 0.79 mg, or 0.8 mg, or 0.81 mg, or 0.82 mg, or 0.83 mg Or 0.84 mg or 0.85 mg or 0.86 mg Or 0.87 mg, or 0.88 mg, or 0.89 mg, or 0.9 mg, or 0.91 mg, or 0.92 mg, or 0.93 mg, or 0.94 mg, or 0.95 mg, or 0.96 mg, or 0.97 mg, or 0.98 mg, or 0.99 mg.
[0088]
As specified above, any minimum and any maximum amount of the antagonist in the dosage form can be tailored to define a range of amounts. However, the selected minimum amount is equal to or less than the selected maximum amount. In one alternative embodiment of the invention using opioid antagonists and opioid agonists, the amount of antagonist in the dosage form is less than the effective amount to antagonize exogenous or endogenous opioid agonists, but such amounts , Increase potency and / or reduce the deleterious effects of agonists and / or reduce tolerance, withdrawal, dependence and / or addiction.
[0089]
When used in combination with an opioid antagonist, the opioid agonist is administered in a dosage form containing from about 0.1 to about 300 mg of the opioid agonist. Opioid antagonists (opioid agonists alone or in combination) include dosage forms in an amount sufficient to produce the desired effect on a process or condition, including various conditions and diseases in a mammal.
[0090]
When the opioid antagonist is used in combination with an opioid agonist, the amount of opioid agonist administered can be an analgesic or sub-analogesic amount. As used herein, an "analgesic" amount is an amount of an opioid agonist that causes analgesia in a subject that is administered with the opioid agonist alone, and is typically administered to cause analgesia. Includes standard doses of agonist (eg, mg dose). A "sub-analgesic" amount is an amount that does not cause analgesia in a subject receiving the opioid agonist alone, but produces an analgesic when used in combination with an opioid antagonist. An “non-analgesic” amount is an amount that does not cause analgesia when administered to a subject, while an “anti-analgesic” amount is an analgesic (ie, pain) amount when administered to a subject. The amount to cause. The amount of the opioid antagonist is an amount effective to increase the analgesic efficacy of the opioid agonist and / or reduce adverse side effects, while at the same time or reducing tolerance, withdrawal, dependence and / or addiction. Can be The amount of opioid antagonist can be less than the amount of effective agonist, ie, the amount of agonist that is not effective, or additionally provides some or all of the benefits described above. The optimal amount of the opioid antagonist administered alone or in combination with the opioid agonist or other therapeutic agent will, of course, depend on the particular agonist and antagonist used, the excipient chosen, the route of administration and / or the treatment. Depends on the pharmacokinetic characteristics of the patient.
[0091]
The dosage form can be in the form of a pharmaceutical preparation, for example, a solid, semi-solid or liquid form, which comprises the active ingredient (alone or in combination with one or more additional active pharmaceutical ingredients (eg, an opioid agonist)) (Including one or more opioid antagonists).
[0092]
The dosage form according to the invention may comprise a specified active pharmaceutical ingredient, which may also be an active ingredient or a therapeutic, either alone or in combination with pharmaceutical excipients and other pharmaceutical ingredients. Referred to as a target drug. An “active pharmaceutical ingredient” is intended to be used in the manufacture of a drug (medical) product, and when used in the manufacture of a drug, becomes any substance or substance that becomes the active ingredient of a drug product. Defined as a mixture of substances. Such substances are intended to provide other direct effects in the diagnosis, treatment, metastasis, treatment or prevention of pharmacological activity or disease, or to affect body structure and function . Draft Consensus Guideline for Good Manufacturing Practice Guide for Active Pharmacrutical Ingredient International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceutical for Human Use (transfer with respect to consultation of July 19, 2000) See. Other dosage forms may consist essentially of one or more pharmaceutical ingredients. A dosage form “consisting essentially of” one or more active pharmaceutical ingredients is a dosage form that contains only the active pharmaceutical ingredient and one or more pharmaceutical excipients, but does not include any other Contains no active pharmaceutical ingredients. By way of example, a drug dose consisting essentially of an opioid antagonist may also include a binder and a lubricant, but no active pharmaceutical composition other than an opioid agonist. As another example, a dosage form consisting essentially of an opioid agonist and an opioid antagonist may also include a binder and a lubricant, but no active pharmaceutical ingredient other than the opioid agonist and the opioid antagonist.
[0093]
Any opioid antagonist or opioid agonist can be administered enterally or parenterally (eg, orally, topically, transdermally, by inhalation spray, rectally, subcutaneously, intravenously, It can be mixed with suitable organic or inorganic carriers and excipients for administration intramuscularly, subcutaneously or by intrasternal injection or infusion techniques).
[0094]
The opioid antagonist may be formulated alone or in combination with another active pharmaceutical ingredient, such as an opioid agonist, for example, with conventional non-toxic pharmaceutically acceptable excipients, carrier diluents or other adjuvants. The choice of adjuvant depends on the active ingredient used, the physiological form of the composition, the route of administration and other factors.
[0095]
Excipients, binders, carriers and diluents that can be used include, among others: water, glucose, lactose, natural sugars (eg, sucrose, glucose or corn sweeteners), sorbitol, Natural and synthetic rubbers (eg, gum acaia, tragacanth, sodium alginate and gum arabic), gelatin, mannitol, starch (eg, starch paste, corn starch or potato starch), magnesium trisilicate, Talc, keratin, colloidal silica, urea, stearic acid, magnesium stearate, dibasic calcium phosphate, cellulose crystals, methylcellulose, carboxymethylcellulose, polyclonal ethylene glycol, wax, Serine and saline.
[0096]
Suitable dispersing or suspending agents for aqueous suspensions include: synthetic and natural gums (eg, tragacanth, acacia, alginic acid, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin). .
[0097]
The dosage form may also comprise one or more acidifying agents, adsorbents, alkalizing agents, antiadherents, antioxidants, binders, buffers, coloring agents, complexing agents, diluents or fillers, Direct compression excipients, disintegrants, flavorants, fragrances, glidants, lubricants, lubricants, opaquants, plasticizers, abrasives, preservatives, sweeteners or pharmaceuticals It may contain other ingredients known for use in the preparation.
[0098]
As used herein, the term "acidifying agent" is intended to mean a compound used to provide an acidic medium for product stability. Such compounds include, by way of example and not limitation, acetic acid, amino acids, citric acid, fumaric acid and other alpha hydroxy acids, hydrochloric acid, ascorbic acid, nitric acid, phosphoric acid, and other compounds known to those skilled in the art. Is mentioned.
[0099]
As used herein, the term "sorbent" is intended to mean an agent capable of retaining other molecules on its surface by physical or chemical (chemisorption) means. Such compounds include, by way of example and not limitation, powdered and activated carbons, zeolites, and other materials known to those skilled in the art.
[0100]
As used herein, the term "alkalizing agent" is intended to mean a compound used to provide an alkaline medium for product stability. Such compounds include, by way of example and not limitation, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium boride, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, And trolamine and other compounds known to those skilled in the art.
[0101]
As used herein, the term "anti-adhesion agent" is intended to mean an agent that prevents the adhesion of a solid dosage formulation component to a punch and die in a tableting machine during manufacture. Is done. Such compounds include, by way of example and not limitation, magnesium stearate, talc, calcium stearate, glyceryl behenate, PEG, hydrogenated vegetable oils, mineral oil, stearic acid, and other materials known to those of skill in the art. No.
[0102]
As used herein, the term "antioxidant" is intended to mean an agent that inhibits oxidation and thus is used to prevent deterioration of the preparation by oxidative processes. Such compounds include, by way of example and not limitation, ascorbic acid, ascorbic acid palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sulfurous acid Examples include sodium hydrogen, sodium sulfoxylate formaldehyde and sodium metabisulfite and other materials known to those skilled in the art.
[0103]
As used herein, the term "binder" is intended to mean a substance used to cause the adhesion of powder particles in a solid dosage formulation. Such compounds include, by way of example and not limitation, acacia, alginic acid, sodium carboxymethylcellulose, poly (vinylpyrrolidone), compressible sugars (eg, NuTab), ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone, And pregelatinized starch and other materials known to those skilled in the art.
[0104]
If necessary, a binding agent may also be included in the dosage form. Exemplary binders include acacia, tragacanth, gelatin, starch, cellulosic materials (eg, methylcellulose, HPMC, HPC, HEC and sodium carboxymethylcellulose), alginic acid and its salts, polyethylene glycol, guar gum, polysaccharides, bentonite, sugar, Invert sugar, poloxamer (PLURONIC) ^TM F68, PLUONIC ^TM F127), collagen, albumin, gelatin, cellulose derivatives in non-aqueous solvents, combinations thereof, and other materials known to those skilled in the art. Other binders include, for example, polypropylene glycol, polyoxyethylene-polypropylene copolymers, polyethylene esters, polyethylene sorbitan esters, polyethylene oxide, combinations thereof, and other materials known to those skilled in the art.
[0105]
As used herein, the term "buffering agent" is intended to mean a compound used to resist changes in pH upon dilution or addition of an acid or alkali. Such compounds include, by way of example and not limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and anhydrous sodium citrate and sodium citrate dihydrate, and other materials known to those skilled in the art. Is mentioned.
[0106]
As used herein, the term "sweetener" is intended to mean a compound used to impart sweetness to a preparation. Such compounds include, by way of example and not limitation, aspartame, dextrose, glycerin, mannitol, sodium saccharin, sorbitol, sucrose, and other materials known to those skilled in the art.
[0107]
As used herein, the term "diluent" or "filler" refers to an inert substance used to produce the desired bulk, flow, and compression characteristics in the preparation of a solid dosage form. It is intended to mean. Such compounds include, by way of example and not limitation, dibasic calcium phosphate, kaolin, lactose, dextrose, magnesium carbonate, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, calcium sulfate, sorbitol, And starch and other materials known to those skilled in the art.
[0108]
As used herein, the term "direct compression excipient" is intended to mean a compound used in a compressed solid dosage form. Such compounds include, by way of example and not limitation, dibasic calcium phosphate (eg, Ditab) and other materials known to those of skill in the art.
[0109]
As used herein, the term "disintegrant" refers to a compound used in a solid dosage form to facilitate the disintegration of a solid mass into smaller particles that are more easily dispersed or dissolved. Is intended to mean. Exemplary disintegrants include, by way of example and not limitation, starch (eg, corn starch, potato starch, pregelatinized starch and modified starches thereof), sweeteners, clay (eg, bentonite), microcrystalline cellulose (eg, bentonite). For example, Avicel), methylcellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, alginic acid, sodium alginate, cellulose polyacrylin potassium (eg, Amberlite), alginate, sodium starch glycolate, gum, agar, guar, carob, karaya , Xanthan, pectin, tragacanth, agar, bentonite, and other materials known to those skilled in the art.
[0110]
As used herein, the term "glidant" is intended to mean an agent used in a solid dosage formulation to enhance the flow of a solid mass. Such compounds include, by way of example and not limitation, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, colloidal silicon, tribasic calcium phosphate, silicon hydrogel, and others known to those skilled in the art. Substances.
[0111]
As used herein, the term "lubricant" is intended to mean a substance used in solid dosage formulations to reduce friction during compression. Such compounds include, by way of example and not limitation, sodium oleate, sodium stearate, calcium stearate, zinc stearate, magnesium stearate, polyethylene glycol, talc, mineral oil, stearic acid, sodium benzoate, sodium acetate , Sodium chloride, and other materials known to those of skill in the art.
[0112]
As used herein, the term "opaquer" is intended to mean a compound used to make a coating opaque. Opacifiers can be used alone or in combination with colorants. Such compounds include, by way of example and not limitation, titanium dioxide, talc, and other materials known to those of skill in the art.
[0113]
As used herein, the term "abrasive" is intended to mean a compound used to impart an attractive sheen to a solid dosage form. Such compounds include, by way of example and not limitation, carnauba wax, white wax, and other materials known to those of skill in the art.
[0114]
As used herein, the term "colorant" is intended to mean a compound used to impart color to a solid (eg, tablet) pharmaceutical preparation. Such compounds include, for example, without limitation, FD & C Red No. 3, FD & C Red No. 20, FD & C Yellow No. 6, FD & C Blue No. 2, D & C Green No. 5, D & C Orange No. 5 5, D & C Red No. 8. Caramel, ferric oxide, other FD & C pigments, and natural colorants (eg, grape hull extract, sugar beet red powder, β-carotene, annatto, carmine, turmeric, paprika, and others known to those skilled in the art. The amount of colorant used will vary as desired.
[0115]
As used herein, the term "perfume" is intended to mean a compound used to impart a pleasant aroma, and often an odor, to a pharmaceutical preparation. Exemplary flavors or flavors include synthetic fragrance oils and flavor fragrance oils and / or natural oils, extracts from plants, leaves, flowers, fruits, and the like, and combinations thereof. These also include cinnamon oil, wintergreen oil, peppermint oil, clove oil, laurel oil, anise oil, eucalyptus oil, thyme oil, scented oil, nutmeg oil, sage oil, gentian oil, cinnamon oil. obtain. Other useful fragrances include vanilla, citrus oil (including lemon, orange, grape, lime and grapefruit), and fruit essences (apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc.) Including). Flavors which have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof. The amount of perfume can depend on many factors, including the desired sensory effect. The fragrance is present in any amount desired by those skilled in the art. Particularly contemplated flavors are grape and cherry flavors and citrus flavors such as oranges.
[0116]
Complexing agents include, for example, disodium EDTA or other salts of EDTA and other agents known to those skilled in the art.
[0117]
Exemplary fragrances include those generally accepted as FD & C quality grades.
[0118]
Exemplary preservatives include substances that inhibit bacterial growth, such as Nipagin, Nipasol, alcohol, antimicrobial agents, benzoic acid, sodium benzoate, benzyl alcohol, sorbic acid, parabens, isopropyl alcohol, and known to those skilled in the art. Other substances.
[0119]
The solid dosage forms of the present invention may also employ one or more surfactants or co-solvents that improve the wetting or disintegration of the core and / or layer of the solid dosage form.
[0120]
Plasticizers may also be included in the tablets to modify the properties and characteristics of the polymer used in the tablet coating or core. As used herein, the term "plasticizer" includes any compound that can plasticize or soften the polymer or binder used in the present invention. The plasticizer should be able to lower the melting or glass transition temperature (softening point temperature) of the polymer or binder. Plasticizers (eg, low molecular weight PEG) generally increase the average molecular weight of the polymer in which the plasticizer is included, thereby lowering the glass transition temperature or softening point. Plasticizers also generally reduce the viscosity of the polymer. Plasticizers can impart some particularly advantageous physical properties to the dosage forms of the present invention.
[0121]
Plasticizers useful in the present invention include, by way of example and not limitation, low molecular weight polymers, oligomers, copolymers, oils, low organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester plasticizers, glycol esters, polyesters. (Polyethylene glycol), multi-block polymers, single-block polymers, low molecular weight poly (ethylene glycol), citrate plasticizers, triacetin, polyethylene glycol and glycerin. Such plasticizers also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, and other poly (ethylene glycol) compounds, Propylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetylbutyl citrate, triethyl citrate, citrate Acetyl triethyl citrate, tributyl citrate, and allyl glycolate may be mentioned. All such plasticizers are available from Aldrich or Sigma Chemical Co. Commercially available from sources such as It is also contemplated that combinations of plasticizers may be used in the formulations of the present invention and are within the scope of the present invention. PEG-based plasticizers are commercially available or available in a variety of ways (eg, Poly (ethylene glycol) Chemistry: Biotechnical and Biomedical Applications (JM Harris, eds .; Plenum Press, NY). ), Which is incorporated herein by reference).
[0122]
The solid dosage forms of the present invention also include oils (eg, fixed oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil); fatty acids (eg, oleic acid, stearic acid and isostearic acid); (Eg, ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides). It also includes alcohols (e.g., ethanol, isopropanol, hexadecyl alcohol, glycerol and propylene glycol); glycerol ketals (e.g., 2,2-dimethyl-1,3-dioxolan-4-methanol); ethers (e.g., poly ( Ethylene glycol) 450; petroleum hydrocarbons (eg, mineral oil and petrolatum); water; or mixtures thereof (with or without the addition of pharmaceutically suitable surfactants, suspending or emulsifying agents). obtain.
[0123]
Soaps and synthetic detergents can be used as surfactants and as vehicles for solid pharmaceutical compositions. Suitable soaps include fatty acid alkali metal, fatty acid ammonium, and fatty acid triethanolamine salts. Suitable detergents include cationic detergents (eg, dimethyldialkylammonium halide, alkylpyridinium halide and alkylamine acetate); anionic detergents (eg, alkyl sulfonate, aryl sulfonate and sulfonate olefin, alkyl sulfate, olefin sulfate, Ether sulfates and monoglycerides, and sulfosuccinates; nonionic detergents (e.g., oxidized fatty amines, fatty acid alkanolamides, and poly (oxyethylene) -block-poly (oxypropylene) copolymers); and amphoteric detergents ( For example, quaternary ammonium salts of alkyl β-aminopropionates and 2-alkylimidazolines); and other substances known to those skilled in the art; and mixtures thereof.
[0124]
A water-soluble coating or layer can be formed to surround the solid dosage form or a portion thereof. The water-soluble coating or layer can be either inert or drug-containing. Such coatings or layers generally include inert and non-toxic materials that are at least partially, and optionally substantially completely, soluble or corrosive in the environment of use. Selection of the appropriate substance depends on the desired behavior of the dosage form. The rapidly dissolving coating or layer is soluble in the oral cavity and / or above the gastrointestinal tract (eg, above the stomach, duodenum, jejunum, or small intestine). Exemplary materials are US Pat. No. 4,576,604 to Guittard et al., And US Pat. No. 4,673,405 to Guittard et al., And US Pat. No. 6,004,582 to Faour et al., And textbooks. Pharmaceutical Dosage Forms: Tables Volume I, Second Edition (A. Lieberman, eds. 1989, Marcel Dekker, Inc.), the disclosures of which are hereby incorporated by reference. In some embodiments, the rapidly dissolving coating or layer is soluble in saliva, gastric juice, or acidic fluid.
[0125]
Materials suitable for making water-soluble coatings or layers include, by way of example and not limitation, water-soluble polysaccharide gums (eg, carrageenan, fucoidan, gatch gum, tragacanth, arabinogalactan, pectin) And xanthan); water-soluble salts of polysaccharide gums (e.g., sodium alginate, sodium tragacanth, and sodium Gatchi gum); water-soluble hydroxyalkyl cellulose (where the alkyl member is a straight chain of 1 to 7 carbons). Chain or branched) (eg, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; synthetic, water-soluble, cellulose-based laminar forming agents (eg, methylcellulose and its hydroxyalkyl methylcellulose cellulose). Loose derivatives (eg, members selected from the group consisting of hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and hydroxybutylmethylcellulose); croscarmellose sodium; other cellulose polymers (eg, sodium carboxymethylcellulose; and one of skill in the art). Other thin layer forming materials that can be used for this purpose include poly (vinyl alcohol), poly (ethylene oxide), gelatin, glucose and sugars. The coating may include other pharmaceutical excipients in a manner that may or may not alter the behavior of the water-soluble coating, and those skilled in the art will recognize that the materials described above include lamellar forming polymers.
[0126]
The water-soluble coating or layer may also include hydroxypropylmethylcellulose, supplied by Dow under the trademark Methocel E-15. This material can be prepared in a solution with different concentrations of polymer, depending on the desired solution viscosity. For example, Methocel ^TM A 2% W / V aqueous solution of E-15 has a viscosity of about 13 to 18 cps at 20 ° C.
[0127]
For transdermal administration, these compounds include a skin penetration enhancer (eg, propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, or other compounds known to those of skill in the art). These can be combined, which increase the permeability of the skin to the compound and allow the compound to penetrate through the skin and into the bloodstream. The compound / enhancer composition can also be further combined with a polymeric material such as ethyl cellulose, hydroxypropyl cellulose, ethylene / vinyl acetate or other materials known to those skilled in the art to provide a composition in gel form. The composition can be dissolved in a solvent such as methylene chloride, evaporated to the desired viscosity, and then applied to a backing material to provide a patch.
[0128]
For intravenous, intramuscular, or subcutaneous administration, the active ingredient may be combined with a sterile aqueous solution, which is preferably isotonic with the blood of the recipient. Such formulations include a physiologically acceptable substance (eg, sodium chloride, glycine, or other substance known to those of skill in the art) and / or are compatible with physiological conditions to produce an aqueous solution. Prepared by dissolving one or more solid active ingredients in water having a buffered pH and / or sterilizing the solution. These formulations may be presented in unit-dose containers, such as sealed ampules or vials.
[0129]
The solid dosage forms of the present invention can be coated with a finish coating, as commonly done in the art, to provide the desired gloss, color, taste, or other aesthetic feature. Suitable materials for the preparation of a finish coating are well known in the art and are found in the disclosure of a number of references which are incorporated herein by reference.
[0130]
Various other compounds (in some cases, other than those listed above) can be added to the formulations of the present invention to optimize the release profile of the desired active agent. These include, by way of example and not limitation, glyceryl monostearate, nylon, butylated cellulose acetate, d, l-poly (butyric acid), 1,6-hexanediamine, diethylenetriamine, starch, derivatized starch, acetylated Monoglyceride, gelatin coacervate, poly (styrene-maleic acid) copolymer, glycowax, castor wax, stearyl alcohol, glycerol palmitostearate, poly (ethylene), poly (vinyl acetate), poly (vinyl acetate) ), 1,3-butylene-glycol dimethacrylate, ethylene glycol-dimethacrylate and methacrylate hydrogels.
[0131]
It is to be understood that compounds used in the field of pharmaceutical formulation generally perform a variety of functions or purposes. Thus, regardless of whether a compound specified herein is referred to only once or used herein to define more than one term, its purpose or function is to It should not be construed as limited only to the specified purpose or function.
[0132]
To prepare a solid composition such as a tablet, the opioid antagonist, alone or conjugated with an opioid agonist, can be used as a pharmaceutical carrier or excipient (eg, conventional tableting ingredients) and It is mixed with another pharmaceutical diluent (eg, water) to form a solid preformulation composition containing a homogeneous mixture of the compound or a non-toxic pharmaceutically acceptable salt thereof. If these preformulation compositions are said to be homogeneous, the opioid antagonist, alone or conjugated to an opioid agonist, will be uniformly dispersed throughout the composition, so that the composition is equally effective Means that it can be easily subdivided into different unit dosage forms (eg, capsules, tablets, caplets, or pills). This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing the above dosages (alone or conjugated with opioid agonists).
[0133]
A solid composition of an opioid antagonist alone can be administered in combination with any other therapeutic agent, including but not limited to an opioid agonist.
[0134]
Capsules, tablets, caplets or pills of the novel pharmaceutical compositions can be coated or otherwise mixed to provide a dosage form that offers the advantage of prolonged action. For example, a tablet or pill may include an inner dosage component and an outer dosage component, the latter being in a more mantle form than the former. The two components can be separated by an enteric layer, which prevents disintegration in the stomach and allows the internal components to pass intact into the duodenum or to be delayed in release Work like that. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids, as well as polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. Mixtures are mentioned.
[0135]
Controlled release (eg, slow or sustained release) dosage forms and rapid release dosage forms are specifically contemplated. Controlled release compositions in liquid form, in which the therapeutic agent can be incorporated for oral administration or for administration by injection, are also contemplated.
[0136]
The pharmaceutical composition or dosage form of the invention may be used in the form of a pharmaceutical preparation, which comprises one or more opioid antagonists, alone or one or more opioid agonists or other active pharmaceutical ingredients. Including in combination.
[0137]
It has been unexpectedly discovered that some opioid antagonists bind significantly less favorably with certain pharmaceutical excipients in the environment of use. These pharmaceutical excipients generally result in incomplete amounts of the opioid antagonist to be released from the rapid release dosage form within the specific time allotted for release in a dissolution test or clinical use. For example, if naltrexone hydrochloride in solution was mixed with croscarmelol sodium in suspension, croscarmelol sodium bound more than 90% of naltrexone hydrochloride. Morphine sulfate also bound to this excipient. However, when lactose, dibasic calcium phosphate, dextrose or sucrose was tested in combination with the above drug, the drug was not significantly bound by the excipient. Accordingly, some embodiments of the present invention include certain combinations of opioid antagonists and pharmaceutical excipients, wherein the excipients do not bind the opioid antagonist to a significant degree in the environment of use. Other embodiments include a combination of an opioid agonist, an opioid antagonist and a pharmaceutical excipient, wherein the excipient binds as effectively as the opioid agonist and the opioid antagonist so that they Are released continuously and / or have substantially the same dissolution rate.
[0138]
The combination dosage forms of the invention can be formulated to provide for simultaneous release of the opioid agonist and the opioid antagonist, generally over at least a majority of the delivery profile for the formulation. As used herein, the terms “co-release” and “co-release” mean that the agonist and antagonist are released in an overlapping manner in an in vitro dissolution assay. The respective onset of each drug release can be, but need not be, simultaneous. Simultaneous release occurs when the majority of the release of the first drug overlaps with the majority of the release of the second drug. According to one exemplary embodiment, the release of the agonist and antagonist begins and ends at approximately the same time. In some embodiments of the formulation comprising the opioid antagonist and the opioid agonist, the dissolution rates of the antagonist and the agonist are substantially the same. A desired portion of each of the active pharmaceutical ingredients can be released within a desired time. This desired portion can be, for example, 5%, 50% or 90%, or some other percentage. This desired time can be, for example, 10, 20, 30, or 45 minutes.
[0139]
Generally, the entire charge of each active pharmaceutical ingredient is released in less than 120 minutes, less than 90 minutes, less than 60 minutes, less than 45 minutes, less than 30 minutes, less than 20 minutes or less than 10 minutes. Preferably, the entire charge of each active pharmaceutical ingredient is released in less than 45 minutes.
[0140]
According to a particular embodiment of the invention, each active pharmaceutical ingredient is released as follows:
[0141]
[Table 1]

The coated tablets, beads, pellets or granules can be made to provide immediate and / or simultaneous release of the opioid antagonist and opioid agonist. Such dosage forms are made according to the compositions and dosage forms described herein (eg, as described in the Examples). The coated solid material independently comprises an opioid antagonist and / or opioid agonist in the solid material or coating. For example, certain embodiments include the following embodiments: 1) Another active pharmaceutical ingredient (eg, an opioid agonist) is present in its core, and the opioid antagonist is associated with its core. 2) another active pharmaceutical ingredient (eg, an opioid agonist) and an opioid antagonist are both present in the inner shell; 3) another active pharmaceutical ingredient (at least partially surrounding the coating); For example, opioid agonists), and opioid antagonists are both present in a coating that at least partially surrounds the inert core; and 4) the opioid antagonist is present in the core and another active pharmaceutical agent The component (eg, opioid agonist) is a coating agent that partially surrounds its core Exist in.
[0142]
The term "unit dose" is intended to mean a dosage form containing an amount of the therapeutic compound, the amount being such that one or more defined units can be provided as a single therapeutic administration. Used herein. Depending on the particular combination and the amount of agonist and antagonist included in the dosage form, an improved, additive or synergistic therapeutic effect is observed. An improved therapeutic effect is an effect in which the antagonist enhances the therapeutic effect provided by the agonist alone (eg, an analgesic effect). An additive therapeutic effect is that each of the antagonist and agonist possesses a common therapeutic effect, and the combination of the two drugs provides an overall therapeutic effect that approximates the sum of these individual therapeutic effects The effect is. A synergistic therapeutic effect is one in which the combination of these two drugs provides an overall therapeutic effect that is greater than the sum of these individual therapeutic effects.
[0143]
FIG. 2 shows a non-limiting embodiment of the present invention: a pharmaceutical composition of coated non-pareil solid substance 1 and coated non-pareil solid substance 2 (eg, pellets or beads). The coated pellet 1 comprises an inert nonpareil core 3 of one or more pharmaceutical excipients and a coating 4 with a low dose of an opioid antagonist and one or more pharmaceutical excipients. The coated pellet 2 comprises an inert non-pareil core 9 of one or more pharmaceutical excipients and a low dose of active pharmaceutical ingredient (in this case, an opioid agonist) and one or more pharmaceutical excipients. And a coating agent 5 having an agent. Pharmaceutical excipients can be chosen independently at each production. Similarly, the inner shell 3 and the inner shell 9 may include the same or different components. These two different types of coated nonpareils can be filled into capsules (eg, hard gelatin capsules) or compressed into tablet cores. The coated nonpareil is optionally mixed with one or more other pharmaceutical excipients before being filled into the capsule or compressed into the tablet core.
[0144]
Coated nonpareil 1 or coated nonpareil 2 is made according to the process of Example 10 and generally by forming a mixture of at least two different coated pellets, where the first pellet is , Made by coating an opioid antagonist on a first nonpareil pellet, and a second pellet is made by coating an opioid agonist on a second nonpareil pellet.
[0145]
When included in a capsule or tablet, the total amount of each drug present in each dosage form will depend on the amount of drug required or the amount of useful drug required to provide the desired therapeutic response. .
[0146]
FIG. 3 shows an inert nonpareil inner shell 8 of one or more pharmaceutical excipients and a low dose of an opioid antagonist, one dose of another pharmaceutical ingredient (in this case, an opioid agonist) and one or more pharmaceutical agents. 1 shows a pharmaceutical composition of coated non-pareil beads 7 having a coating agent 6 with a specific excipient. Pharmaceutical excipients can be chosen independently at each production. The coated nonpareils can be filled into capsules (hard gelatin capsules) or compressed into tablet cores. The coated nonpareil is optionally mixed with one or more other pharmaceutical excipients before filling into capsules or compressing into tablet cores.
[0147]
The coated non-pareil beads 7 are prepared according to the process of Example 11 and generally comprise an opioid antagonist, an opioid agonist, at least one polymer or film-forming material, and optionally a plasticizer. And applying this composition to non-pareil pellets.
[0148]
FIG. 4 shows a first granule 11 having a first blend of an opioid antagonist and a pharmaceutical excipient and a second granule having a second blend of another pharmaceutical ingredient (in this case, an opioid agonist) and a pharmaceutical excipient. 12 shows a mixed granule 10 comprising Pharmaceutical excipients can be chosen independently at each production. Similarly, granules 11 and 12 may include the same or different excipients. The two different granules can be filled together in a capsule (eg, a hard gelatin capsule) or compressed together into a tablet core. These granules are optionally mixed with one or more pharmaceutical excipients before filling into capsules or compressing into tablet cores.
[0149]
The mixed granules 10 generally follow the process of Example 13 and generally form a first granule having a first blend of an opioid antagonist and a pharmaceutical excipient, and a second granule of the opioid agonist and a pharmaceutical excipient. It is made by forming a second granule having two blends and mixing the first granule and the second granule.
[0150]
FIG. 5 shows a pharmaceutical composition of a second granule 15 comprising a first granule 17, a mixture 16 having a low dose of an opioid antagonist and at least one pharmaceutical excipient. Here, the first granule comprises a dose of another pharmaceutical ingredient (in this case, an opioid agonist) and at least one pharmaceutical excipient. These pharmaceutical excipients are independently selected at each production. The plurality of second granules can be filled into a capsule (eg, a hard gelatin capsule) or compressed into a tablet core. The second granulate is optionally mixed with one or more other pharmaceutical excipients before being filled into a capsule or compressed into a tablet shell.
[0151]
The second granules 15 follow the process of Example 14 and generally form first granules 17 with another pharmaceutical ingredient (in this case, an opioid agonist) and at least one pharmaceutical excipient, and It is made by mixing a first granule with a mixture 16 of an opioid antagonist and at least one pharmaceutical excipient to form a second granule.
[0152]
FIG. 6 shows a pharmaceutical excipient 23 coated with a binding composition 21 having a binder, an opioid antagonist, another pharmaceutical ingredient (in this case, an opioid agonist), and optionally one or more other excipients. Shown is a pharmaceutical composition 20 having coated granules of a mixture with a pharmaceutical excipient 22. Pharmaceutical excipients can be chosen independently at each production. The pharmaceutical compositions can be filled in capsules (eg, hard gelatin capsules) or compressed into tablets.
[0153]
Pharmaceutical composition 20 is prepared according to the process of Example 15, and generally comprises a binder composition having a binder, an opioid agonist and an opioid antagonist, and a mixture of pharmaceutical excipients. And to form coated granules. The coated granules are then optionally mixed with one or more pharmaceutical excipients to form a pharmaceutical composition 20.
[0154]
Different methods of treatment require different dosage strengths and different ratios of agonist to antagonist in the dosage form. Compositions 2 and 10 can be formulated without requiring the pharmaceutical composition batches containing substantially different ratios of agonist to antagonist to re-formulate coated nonpareil 1 and nonpareil 2 or granules 11 and 12, respectively. It has the advantage that it can be done simply and easily by varying the amount of each coated non-pareil or the amount of coated granules respectively contained in the target composition. Similarly, the relative amount of each drug within its respective coated non-pareil or coated granules can be varied to create a pharmaceutical composition of a particular drug strength.
[0155]
The advantage of a combined dosage form is that the presence of both active pharmaceutical ingredients in a single unit dosage form ensures compliance with the desired dose ratio between doses administered. Additional advantages include reduced complexity, reduced likelihood of ingestion, and easier administration of multiple products at the same time, as well as associated symptoms that the patient has (eg, due to nausea, vomiting, inability or swallowing) Worsening pain).
[0156]
For example, FIG. 7 shows a graph of the relationship between drug ratio and nonpareil filled in a 500 mg filled capsule. Coated nonpareil 1 can be made to contain 1 mg of opioid antagonist per 500 mg of coated nonpareil. Similarly, coated nonpareil 2 can be made to contain 200 mg opioid agonist (or another pharmaceutical ingredient) per 500 mg coated nonpareil 2. Thus, if 500 mg capsules are filled to 90% nonpareil 2 by weight and 10% nonpareil 1 by weight, the capsules will contain 180 mg opioid antagonist and 0.1 mg opioid antagonist and the ratio of agonist to antagonist Is 1800. However, if a 500 mg capsule is filled to 50% non-pareil 2 by weight and 50% non-pareil 1 by weight, the capsule will contain 100 mg opioid agonist and 0.5 mg opioid antagonist, and the agonist to the antagonist Is 200. On the other hand, if a 500 mg capsule is filled with the same amount of nonpareil 2 and nonpareil 1, then nonpareil 1 will be made to contain 0.5 mg of antagonist per 500 mg of nonpareil, and then this capsule will contain 100 mg of opioid agonist And 0.25 mg of the opioid antagonist, and the ratio of agonist to antagonist is 400. The exemplary relationships shown in FIG. 7 also apply generally to the formulations of FIGS. 2 and 4. These relationships vary according to the formulation used and the amount of each drug included in the particular drug.
[0157]
However, the pharmaceutical compositions of FIGS. 3, 5 and 6 show a fixed ratio of the opioid antagonist to the opioid agonist (or another active pharmaceutical ingredient), the total drug in the dosage form comprising these pharmaceutical compositions. Useful to provide regardless of strength. For example, FIG. 8 shows a graph of the relationship between drug ratio and nonpareil filled into a 500 mg filled capsule. Coated nonpareil 7 (shown in FIG. 3) can be made to contain 0.5 mg opioid antagonist per 500 mg coated nonpareil 7 and 200 mg opioid agonist per 500 mg coated nonpareil 7. Thus, if 500 mg capsules are filled with 100% non-pareil 7 by weight, the capsules will contain 200 mg opioid agonist and 0.5 mg opioid antagonist, and the drug to agonist ratio of antagonist to antagonist is 400. However, if a 500 mg capsule is filled with 50% by weight non-pareil 7 and 50% by weight pharmaceutical excipient, the capsule will contain 100 mg opioid agonist and 0.25 mg opioid antagonist and the antagonist The ratio of agonists to remains at 400. However, coated nonpareil 7 was made to contain 0.25 mg opioid antagonist per 500 mg coated nonpareil 7 and 200 mg opioid agonist per 500 mg coated nonpareil 7, and 500 mg capsules were 100% by weight The capsule contains 200 mg opioid agonist and 0.25 mg opioid antagonist and the drug ratio of agonist to antagonist is 800. In other words, reducing the relative amount of the pharmaceutical compositions of FIGS. 3, 5 and 6 does not change the drug ratio, but decreases the total drug strength.
[0158]
Another embodiment provides a pharmaceutical composition of a coated first granule, wherein the granule comprises a mixture of an opioid agonist (or another active pharmaceutical ingredient) and a pharmaceutical excipient. And, the coating comprises an opioid antagonist and one or more pharmaceutical excipients. The granules can be made according to the process of Example 16 and by coating a mixture of the composition of an opioid agonist and a pharmaceutical excipient, and by coating the composition of an opioid antagonist and one or more pharmaceutical agents Generally made with excipients.
[0159]
The present invention also provides a pharmaceutical composition of spray-dried granules having an opioid antagonist, another active pharmaceutical ingredient (eg, an opioid agonist) and at least one pharmaceutical excipient. These granules are made according to the process of Example 17 and generally by spray-drying a solution having an opioid antagonist, an opioid agonist and at least one pharmaceutical excipient to form spray-dried granules. obtain.
[0160]
Dosage forms also include a suspension of the opioid antagonist in another active pharmaceutical ingredient (eg, an opioid agonist), and a soft gelatin capsule filled with at least one non-aqueous vehicle. This dosage is made according to the process of Example 18 and generally by filling a soft gelatin capsule with a dispersion consisting essentially of an opioid antagonist, an opioid agonist, and at least one non-aqueous vehicle. obtain.
[0161]
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders are also contemplated. Liquid or solid compositions may include suitable pharmaceutically acceptable excipients as described above. These compositions are generally administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be connected to a face mask, tent or intermittent positive pressure breathing apparatus. Solution, suspension or powder compositions may be preferably administered orally or nasally from devices which deliver the formulation in an appropriate manner.
[0162]
For the treatment of certain conditions, it may be desirable to use an opioid antagonist with another pharmaceutically active agent. For example, an opioid antagonist according to the present invention may be provided with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use. The solid composition of an opioid antagonist can be administered alone, in combination with one or more any other therapeutic agent, including but not limited to an opioid agonist. Such a combined preparation may be, for example, in the form of a twin pack. In general, the currently available dosage forms of other therapeutic agents for use in such combinations are suitable.
[0163]
The opioid antagonist alone, or in combination with other active pharmaceutical ingredients, can be administered to a human subject by known procedures, including but not limited to: administration in oral mode, administration in sublingual mode Administration, intramuscular, subcutaneous, intravenous, intratracheal, transmucosal, or transdermal administration. When a combination of these compounds is administered, the compounds may be administered together in the same composition, or may be administered in separate compositions. When the opioid antagonist and another active pharmaceutical ingredient are administered in separate compositions, they can be administered by similar or different modes of administration, simultaneously with each other, or immediately before or immediately after one The other can be administered.
[0164]
Commercially available formulations currently used to administer opioid antagonists or agonists can be modified as described to provide pharmaceutical compositions and formulations according to the present invention. Commercial oral dosage forms of opioid agonists for human administration include the following: codeine, dihydrocodeine (eg, SYNALGOS-DC® from Wyeth-Ayerst Pharmaceuticals), fentanyl, (eg, provided by Abbott Laboratories) ACTIQ®), hydrocodone (e.g., VICO DIN® and VICOPROFEN® provided by Knoll Laboratories; NORCO® provided by Watson Laboratories; HYCODA provided by Endo Pharmaceuticals; HYCODA provided by Endo Pharmaceuticals; NORCET® from ANEXSI provided by Mallinckrodt (Registered trademark), HYDROCET (registered trademark), and LORSET-HD (registered trademark); LORTAB (registered trademark) provided by UCB Pharma; HY-PHEN (registered trademark) provided by Ascher; CO-GESIC (registered trademark) provided by Schwarz Pharma Trademark); ALLAY (registered trademark) provided by Zenith Goldline), hydromorphone (for example, DILAUDID (registered trademark) provided by Knoll), levorphanol (for example, LEVO-DROMORAN (registered trademark) provided by ICN Pharmaceuticals), merizolidine (For example, DEMEROL (registered trademark) provided by Sanofi Pharmaceuticals), methadone (for example, METHADOSE (registered trademark) provided by Mallinckrodt); DOLOPHINE (R) HCl provided by Roxane Laboratories and morphine (e.g., KADIAN (R) provided by Fouling Laboratories; MS CONTIN (R) provided by Purdue Frederick; ORAMORPH (R) Oxoron® SR provided by Roxane Laboratories) (E.g., PERCOCET (R) and PERCODN (R) from Endo; OXYCET (R) from Mallinckrodt; OXYCONTIN (R) from Purdue Frederick; TYLO (R) from Ortho-McNeil Pharmaceutical (R); ROXICODONE (registered trademark), ROX provided LOX (R), and ROXICET (registered trademark)), pentazocine (e.g., Sanofi Pharmaceuticals providing TALACEN (R) and TALWIN (registered trademark)), propoxyphene (e.g., Eli Lilly & Co. DARVOCET-N (R) and DAVRON (R) provided by Lederle; DOLENE (R) provided by Lederle; WYGESIC (R) provided by Wyeth-Ayerst), and Tramadol (e.g., ULRAM provided by Ortho-McNeil Pharmaceutical). Registered trademark)). Commercial liquid dosage forms of opioid agonists for human administration include: hydrocodone (eg, HYDROPHANE® from Halsey), hydromorphone (eg, DILAUDID® from Knoll), meperidine (E.g., DEMEROL (R) from Sanofi), methadone (e.g., DOLOPHINE (R) from Roxane), oxycodone (e.g., HYCOMINE (R) from Knoll; ROXILOX (R) from Roxane), And propoxyphene (eg, DARVON-N® from Eli Lilly). Commercially available parenteral dosage forms for human administration include: alfentanil (eg, ALFENTA® provided by Akorn), buprenorphine (eg, BUPRENEX® provided by Reckitt & Colman Pharmaceuticals) , Butorphanol (e.g., STADOL (R) provided by Apothecon), dezocin (e.g., DALGAN (R) provided by AstraZeneca), fentanyl, hydromorphone (e.g., DILAUDID-HP (R) provided by Knoll), levallorphan (e.g., LORPANAN® from Roche, Levophanol (eg, LEVO-DROMORAN® from ICN), meperidine (eg DEMEROL® from Sanofi, methadone (eg, DOLOPHINE® HCI from Roxane), morphene (eg, ASTRAMORPH® from AstraZeneca; DURAMORPH® from Elkins-Sinn) and INFUMORPH (R)), oxymorphone (e.g., NUMORPHAN (R) from Endo), nalbulfin (e.g., NUBAIN (R) from Endo Pharmaceutical), and pentazocine (TALWIN (R) from Abbott)). Commercially available transdermal dosage forms of opioid agonists for human administration include fentanyl (eg, DURAGESIC® from Janssen). Commercially available suppository dosage forms of opioid agonists for human administration include oxymorphone (eg, NUMORPHAN® from Endo).
[0165]
The invention also includes a pharmaceutical kit comprising an opioid antagonist together with any other therapeutic agent, including, but not limited to, an opioid agonist, wherein the antagonist is in an amount as specified above. Exists in. In this kit, the opioid antagonist and the opioid agonist or other therapeutic agent are provided as compounds in separate containers of any type (eg, bottles or packages (eg, capsules, tablets, pills or patches)), and / or Alternatively, each may be provided in a separate container as a compound in combination with a pharmaceutically acceptable excipient or carrier. Alternatively, the opioid antagonist and the opioid agonist or other therapeutic agent may be combined together in one or more containers (eg, bottles or packages) with or without excipients or carriers. Thus, for example, the invention also relates to any type of container (eg, package, bottle, envelope, blister pack, bag, or pouch, syringe, inhaler or tube) consisting essentially of an opioid antagonist and essentially opioids Includes a pharmaceutical kit comprising separate containers of the agonist or other therapeutic agent, each container containing an excipient or other carrier, if desired.
[0166]
The pharmaceutical composition can be administered to a human subject / patient in need of such treatment in a dosage form that provides acceptable pharmaceutical efficacy, for example, within the ranges described herein. The particular dose required for use in any particular application will depend not only on the particular compound or selected composition, but also on the route of administration, the nature of the condition being treated, the age, the condition, the pain tolerance, and the It is understood that other idiosyncratic properties, co-medication or specific foods associated with the patient, and other factors recognized by those skilled in the art, will vary from patient to patient with the appropriate dosage at the discretion of the attending physician. .
[0167]
In a preferred embodiment, when the opioid antagonist is administered alone, the amount of opioid antagonist administered will be an amount effective to enhance or maintain the analgesic potency of the opioid agonist, and / or an opioid agonist. An amount effective to attenuate or maintain the harmful side-effects of and / or to attenuate tolerance, withdrawal symptoms, dependence and / or addiction. This amount is easily determined by one skilled in the art,
The present invention is described in the following examples, which have been set forth to assist in understanding the invention, and which may in any way limit the invention as defined in the following claims. Should not be interpreted as The pharmaceutically active and inactive ingredients used in the preparation of the example formulations were summarized in the USP / NF, if there were existing research papers.
[0168]
(Example 1)
The formulations are prepared so as to include a plurality of active compounds, including opioid antagonists, in a unit dose (eg, a single capsule or tablet or pill or patch). Alternatively, the formulation is prepared to include only one active ingredient that is an opioid antagonist (eg, naltrexone). Naltrexone hydrochloride (naltrexone) was described herein and was prepared to be administered as a separate capsule in a dosage form according to the present invention.
[0169]
The overview, structure and physical / chemical properties (USP) of the drug substance naltrexone hydrochloride are as follows:
Generic name: Naltrexone hydrochloride
Chemical name: 17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-monohydrochloric acid
Molecular formula: C ₂₀ H ₂₃ NO ₄ ・ HCl
Molecular weight: 377.86
(See, eg, USP Summary for details of the physical and chemical properties of naltrexone hydrochloride).
[0170]
(Naltrexone capsule)
Naltrexone capsules were made at typical concentrations of 0.01 mg, 0.1 mg and 1.0 mg of naltrexone HCl by the process illustrated in FIGS. 1A-1B and described below.
[0171]
[Table 2]

[0172]
[Table 3]

[0173]
[Table 4]

1. The amounts listed are for a 1200 capsule batch. Other batch sizes can be used with equal amounts of the formulation, using similar equipment and processing steps.
2. FMC Corporation, Pharmaceutical Division, 1735 Market St. It is supplied as Avicel® by Philadelphia, PA 19103.
3. Whitaker, Clark & Daniel, Inc. 1000 Coolidge St. , South Plainfield, NJ 07080.
[0174]
Using the manufacturing scheme of FIGS. 1A and 1B, naltrexone capsules useful for human administration were manufactured. A description of the steps in the manufacturing process for naltrexone and placebo capsules follows:
For the three selected concentrations of naltrexone capsules (0.01 mg, 0.1 mg, 1.0 mg), a series of blends were made and combined for filling to make the defined concentrations. Additional blends were made and combined to make a concentration of less than 0.01 mg (eg, 0.001 mg). Additional blends can be made with less than 0.001 mg (including 0.0001 mg or less).
[0175]
(Placebo blend)
A placebo blend was made according to the following process.
[0176]
First, referring to FIG. 1A, magnesium stearate 50 was passed through a fresh 60 mesh stainless sieve, and the transferred stearate 52 was collected directly in a blender bowl. A small portion of the microcrystalline cellulose 54 was passed through the same sieve and collected on top of the transferred stearic acid 52, and then mixed well for at least 1 minute. This was repeated with another small portion of the cellulose. The remaining cellulose was passed through a sieve and mixed well for 15 minutes. The resulting blend 56 was inspected for macroscopic contaminants.
[0177]
(1.0mg naltrexone blend)
The entire amount of naltrexone 58 was passed through a new 60 mesh stainless sieve, and the transferred naltrexone 60 was collected directly on a blender ball. A small portion of the placebo blend 56 was passed through the same sieve and collected over naltrexone and then mixed well for at least 1 minute. This was repeated with another small portion of the placebo blend. The remaining placebo was passed through a sieve and mixed well for 15 minutes. The result was 1.0 mg naltrexone blend 62. The blend was inspected for macroscopic contaminants. This blend 62 may be further diluted as described in the next paragraph, or filled with capsules (as described further below) if a 1.0 mg dosage form is desired as the final product. Used for
[0178]
(0.1mg naltrexone blend)
A defined amount of 1.0 mg naltrexone blend 62 made as described above was transferred to a blender ball. A small portion of placebo blend 56 was added to 1.0 mg naltrexone blend 62 and then mixed well for at least 1 minute. This was repeated with another small portion of the placebo blend 56. The remaining portion of placebo blend 56 required to provide a 10: 1 dilution was added and mixed well for 15 minutes. The result was 0.1 mg naltrexone blend 64. The blend 64 was inspected for macroscopic contamination. This blend 64 may be further diluted as described in the next paragraph, or used to fill capsules (as described further below) if a 0.1 mg dose is desired as the final product. did.
[0179]
(0.01mg naltrexone blend)
A defined amount of 0.1 mg naltrexone blend 64, made as described above, was transferred to a blender ball. A small portion of placebo blend 56 was added to 0.1 mg naltrexone blend 64 and then mixed well for at least 1 minute. This was repeated with another small portion of the placebo blend 56. The remaining portion of placebo blend 56 required to provide a 10: 1 dilution was added and mixed well for 15 minutes. The result was 0.01 mg naltrexone blend 66. This blend 66 was inspected for macroscopic contaminants.
[0180]
A similar dilution was performed with a defined amount of 0.01 mg naltrexone blend to achieve 0.001 mg naltrexone blend 76 (as described in FIGS. 1A and 1B). Further dilutions are also contemplated if a smaller dose is desired.
[0181]
(Filling capsules)
Referring to FIG. 1B (continuation of FIG. 1A), each naltrexone dosage form 62, 64, and 66 was added into a capsule using the following filling procedure. 1250 empty capsule shells 68 were attached to the filling tray. The cap was removed from the main part as shown in step 70.
[0182]
The amount of 1.0 mg naltrexone blend 62 required to fill 1250 capsules (including a 1% excess) was determined. This amount of the specified concentration of naltrexone blend was weighed and transferred to a capsule machine. The capsule 70 was filled with the entire volume of the naltrexone blend and three pressures were applied for each filling operation. The capsule was sealed to form a filled capsule 72. The capsule 72 was dusted and polished. The filled capsules 72 were tested for variation in weight, and only those capsules 72 within the given range were accepted as the final product-1.0 mg naltrexone capsule 74. The capsule 74 was collected in a secure, labeled double polyethylene bag.
[0183]
In a similar manner, 0.1 mg naltrexone blend 64 and 0.01 mg naltrexone blend were again added and finished in capsules as described in FIG. 1B.
[0184]
Low strength naltrexone capsules were manufactured using a process of serial dilution and blending. In addition, a reduction in the capsule fill weight was used to achieve a proportional reduction in naltrexone capsule strength required to produce, for example, a 0.0001 mg naltrexone capsule.
[0185]
To form a placebo, placebo blend 56 was used in place of naltrexone blend 62 to fill the capsules and was again finished in a similar manner.
[0186]
(Example 2)
This example demonstrates the clinical use and evaluation of a solid oral dosage form (including some of the dosage forms of Example 1). Pharmaceutical compositions and dosage forms of naltrexone prepared according to the procedure described in Example 1 were administered in human clinical trials with morphine, tramadol, or hydrocadone / acetaminophen.
[0187]
Studies of morphine alone and in combination with morphine and naltrexone are described in Example 1 of US Application No. 60 / 202,265 (filed May 5, 2000), which is incorporated herein by reference. . A summary of exemplary study results follows.
[0188]
This clinical study was designed to compare the analgesic activity of three different doses of naltrexone (NTX) in combination with morphine sulfate (hereinafter morphine or MS) 60 mg versus MS 60 mg alone. The test subjects had moderate to severe postoperative toothache. The test products were naltrexone (NYX) 1 mg and MS 60 mg, NTX 0.1 mg and MS 60 mg, and NTX 0.01 mg and MS 60 mg. If the subject suffered from moderate to severe post-operative pain, a single oral dose of one of these treatments was administered. The study population was 201 male and female outpatients with moderate to severe pain following extraction of two or more impacted third molars.
[0189]
For data analysis, specific pain parameters were calculated as follows. The extent to which pain changed at each time point was determined by the pain relief score (PR, 0 = none, 1 = less, 2 = somewhat, 3 = more, 4 = complete) and the pain intensity score (pain intensity). pain difference score (PID, difference between baseline and current time, this pain intensity scale was measured as 0 = none, 1 = mild, 2 = moderate, 3 = severe). The extent to which pain changes over the entire test period is measured by the total pain relief score (TOTPAR-8), the sum of pain intensity differences (SPID-8), the maximum pain relief score (MAXPAR), the peak pain intensity difference (PEAKPID), and (0 = poor, 1 = sufficient, 2 = good, 3 = very good, 4 = excellent). Define TOTPAR-8 and SPID-8 as the sum of the PR and PID, respectively, for the entire 8 hour observation period, weighted by the time difference between adjacent points (ie, the area under the curve using the trapezoidal rule). . MAXPAR and PEAKPID are defined as the maximum values of PR and PID, respectively. Efficacy and safety assessments include overall pain assessment, time to rescue, percentage of patients re-treated with rescue medication, time to significant pain relief, initial perceived pain Release and the time until visual analog scale (VAS) occurred, and the evaluation of adverse events.
[0190]
The placebo treatment group had the lowest average total pain relief score. All four active treatment groups showed numerically higher mean total pain relief scores than placebo. The combination treatment had an inverse dose-response relationship in the mean total pain release score (ie, the highest dose of NTX had the lowest mean total pain release score, and the lowest dose of NTX had the highest mean total pain release score). Had a pain relief score). This pattern (low dose (0.01 mg NTX)> medium dose (1.0 mg NTX)) was observed for all pain relief variables throughout the study. The average total pain relief score for the 0.01 mg NTX and 0.1 mg NTX combination treatments was higher than the average total pain relief score for the MS alone treatment, and the average for the 1.0 mg NTX combination treatment was Was comparable to or lower than the average total pain release score of
[0191]
Placebo treatment had the average of the sum of the lowest 4 hour pain intensity difference scores. All four active treatment groups showed an improved profile in comparison to placebo in the mean of the sum of pain intensity differences. The average of the sum of the pain intensity difference scores for the combination treatment of 0.01 mg NTX and 0.1 mg NTX is higher than the average of the sum of the pain intensity difference scores for the MS alone treatment; It was comparable to the average of the sum of the pain intensity difference scores for MS alone treatment. The pattern of the sum of the pain intensity difference scores at 6 hours and 8 hours was similar to the sum of the pain intensity difference scores at 4 hours.
[0192]
The time to treatment before significant pain relief occurred was the shortest in the 0.01 mg NTX (low dose) combination treatment group. Placebo treatment had the minimum number of subjects who reached significant pain relief.
[0193]
The major adverse side effects reported were categorized as digestive (nausea or vomiting) or nervous (vertigo or somnolence).
[0194]
Studies of tramadol alone and in combination with tramadol and naltrexone are described in U.S. Application No. 09 / 566,071 (filed May 5, 2000) and PCT / US00 / 12493 [WO / 0067739] (May 5, 2000). No. 09 / 756,331 (filed Jan. 8, 2001), which is a continuation of US Patent Application No. 09 / 756,331, the entire disclosure of which is incorporated herein by reference. A summary of exemplary study results follows.
[0195]
In this study in human subjects with pain, tramadol hydrochloride (tramadol) was administered alone or in combination with various amounts (doses) of the opioid antagonist naltrexone. In this study, one objective was to use an opioid antagonist (eg, naltrexone hydrochloride (hereinafter referred to as naltrexone or NTX in this example)) in the following human subjects / patients with pain after dental surgery: tramadol hydrochloride (Hereinafter referred to as tramadol or T in this example) was to determine whether to enhance the analgesic properties. A further objective was to evaluate whether opioid antagonists (eg, NTX) alleviate (eg, reduce, block, or prevent) the deleterious side effects of tramadol in humans.
[0196]
Human subjects were randomized into one of the following five treatment groups:
Group 1: T (50 mg) and NTX (1 mg)
Group 2: T (50 mg) and NTX (0.1 mg)
Group 3: T (50 mg) and NTX (0.01 mg)
Group 4: T (50 mg) and placebo
Group 5: placebo and placebo.
[0197]
All subjects with moderate to severe pain received one dose of study drug. Subjects received two capsules for oral ingestion, one for tramadol or placebo and the other for naltrexone or placebo.
[0198]
Pain assessments were performed prior to treatment. After dental surgery, the subject's pain level was assessed by a trained observer. The subject had (1) verbalized one pain category (0 = none, 1 = mild, 2 = moderate, 3 = severe), and (2) a visual analog scale (VAS) of 0-100 mm. ) (Where a single slash on this scale puts 0 = no pain and 100 = the worst pain possible), both reported initial pain intensity. Pain assessment was also performed post-treatment.
[0199]
Efficacy and safety assessments included pain intensity, pain relief, global pain assessment, time to significant pain relief (stopwatch), visual scale analog (VAS), and inverse event Including ratings. For analysis of the data, certain pain parameters were calculated as generally described above.
[0200]
The placebo treatment group had the lowest mean 4 hour total pain release score. All four of the active treatment groups showed a numerically higher 4-hour average total pain release score than placebo. The combination treatment had an inverse dose-response relationship in the mean of the 4-hour total pain release score (ie, the highest dose of NTX had the lowest mean of the 4-hour total pain release score, and The lowest dose of NTX had the highest average of 4 hours total pain relief score). The average 4-hour total pain relief score for the 0.01 mg NTX and 0.1 mg NTX combination treatments was higher than for the T alone treatment, and the average for the 1.0 mg NTX combination treatment was the T alone treatment. Was lower than.
[0201]
Placebo treatment had the average of the sum of the lowest 4 hour pain intensity difference scores. All four active treatment groups showed an improved profile compared to placebo in the mean of the sum of the four hour pain intensity differences. The average of the sum of the 4-hour pain intensity difference scores for the combination treatment of 0.01 mg NTX and 0.1 mg NTX is higher than the average of the sum of the 4-hour pain intensity difference scores for the T-only treatment, 1.0 mg The combination treatment with NTX was lower than the average of the sum of the 4 hour pain intensity difference scores for the T alone treatment. The pattern of the sum of the pain intensity difference scores at 6 hours and 8 hours was similar to the sum of the pain intensity differences at 4 hours.
[0202]
The sum of the visual analog scales of the 4, 6 and 8 hour pain intensity difference results is as follows. The placebo treatment had the average of the lowest four hour pain intensity difference VAS sums. The four active treatment groups showed an average of the sum of the VAS of pain intensity differences higher than the average of the VAS of pain intensity differences for the placebo. The average of the four hour pain intensity difference VAS sum for the three NTX combination treatments was higher than the average of the four hour pain intensity difference VAS sum for T alone. The average of the sum of the VAS of the pain intensity difference scores at 6 hours and 8 hours was similar to the average of the sum of the VAS of the pain intensity difference scores at 4 hours.
[0203]
Placebo treatment had the fewest subjects achieving significant pain relief. In addition, all combination treatment groups had a greater number of subjects achieving significant pain relief than the group receiving T alone.
[0204]
The hourly pain release scores for the placebo treatment were generally uniform, while the hourly pain release scores for the active treatment group generally improved over time. There was a distinction between the placebo and active treatment groups that continued throughout the 8 hour study period.
[0205]
The major adverse events reported were classified as gastrointestinal disorders (nausea or vomiting) or nervous system disorders (vertigo, headache or sedation).
[0206]
Studies of morphine alone and in combination with morphine and naltrexone are described in Example 2 of US Application No. 60 / 245,110, filed November 1, 2000, which is incorporated herein by reference. Incorporated). A summary of exemplary study results follows.
[0207]
In a dose range study, a dose of morphine sulfate (60 mg) in combination with naltrexone hydrochloride (0.1 mg, 0.01 mg, or 0.001 mg) was administered to patients with moderate to severe pain after dental surgery . This study was conducted to investigate the analgesic effects (onset, peak, duration, and overall effects) of three different doses of naltrexone in combination with morphine alone, naltrexone alone, morphine and placebo.
[0208]
A study of 300 subjects was designed with the following six treatment groups: A) placebo (50 pts); B) morphine 60 mg (50 pts); C) naltrexone 0.01 mg (50 pts); D) morphine 60 mg. And naltrexone 0.1 mg (50 pts); E) morphine 60 mg and naltrexone 0.01 mg (50 pts); F) morphine 60 mg and naltrexone 0.001 mg (50 pts). In this study, in the treatment of moderate to severe pain after extraction of three or four third or full bone impacted third molars, subjects experienced moderate to severe postoperative pain. If so, a single oral dose of one of these treatments was administered. The observation period for efficacy was 8 hours after treatment and the observation period for safety was 24 hours after treatment.
[0209]
Efficacy and safety assessments include pain intensity, pain relief, global pain assessment, time to meaningful pain relief (stopwatch), visual analog scale (VAS), and inverse events Regarding evaluation. For analysis of the data, certain pain parameters were calculated as generally described above.
[0210]
The 0.01 mg NTX alone and placebo treatment groups had the lowest mean sum of the four hour pain intensity difference (SPID) scores. All four of the active treatment groups with MS alone or in combination with NTX showed an improved profile in mean SPID compared to NTX alone or placebo. The average 4-hour SPID score for the 0.01 mg NTX and 0.1 mg NTX combination treatments was higher than the average 4-hour SPID score for the MS alone treatment, and the 0.001 mg NTX combination treatment was It was comparable to the average of the 4 hour SPID score for MS alone treatment. The pattern of SPID scores at 6 hours and 8 hours was similar to the pattern of SPID scores at 4 hours.
[0211]
The 0.01 mg NTX alone and placebo treatment groups had the lowest mean total pain release scores. All four of the active treatment groups showed numerically higher averages of total pain release scores than the 0.01 mg NTX alone treatment group and the placebo treatment group. The combination treatments had an inverse dose-response relationship in the mean total pain release score (ie, the highest dose of NTX had the lowest mean total pain release score, and the lowest dose of NTX Had the highest total pain relief score average). This pattern (high dose (0.1 mg NTX)> medium dose (0.01 mg NTX)> low dose (0.001 mg NTX) was generally observed for pain relief variables throughout the study. The average total pain relief score for the 0.01 mg NTX and 0.1 mg NTX combination treatments was higher than the average total pain relief score for the MS alone treatment, and the average for the 0.001 mg NTX combination treatment was MS alone. It was comparable to or lower than the average total pain release score for the treatment.
[0212]
The NTX alone and placebo treatment groups had the highest number of subjects with a "poor" overall rating score. The overall rating score profile is based on the subject's rating.
[0213]
The time to treatment before significant pain relief occurred was the shortest in the 0.1 mg NTX combination treatment group.
[0214]
The treatment time until analgesia occurred was the shortest in the combination treatment group with 0.1 mg NTX.
[0215]
Baseline pain intensity scores and visual analog scores were generally comparable between treatment groups.
[0216]
The major adverse side effects reported were categorized as digestive (nausea or vomiting) or nervous (vertigo or somnolence).
[0219]
A study of hydrocodone with acetaminophen (instead of morphine) alone and in combination with naltrexone is described in Example 3 of US Application No. 60 / 245,110, filed November 1, 2000 ( This application is incorporated herein by reference). A summary of exemplary study results follows.
[0218]
In a dose range study, a dose of hydrocodone (5 mg) with acetaminophen (500 mg) and naltrexone (0.1 mg, 0.01 mg, and 0.001 mg) was administered for moderate to severe pain after dental surgery. Administration. This study was conducted to investigate the analgesic effects of acetaminophen and hydrocodone, four different doses of naltrexone in combination with hydrocodone / acetaminophen, and placebo.
[0219]
A study of 300 subjects was designed with the following six treatment groups: A) placebo (50 pts); B) HC 5 mg / APAP 500 mg and placebo (50 pts); C) HC 5 mg / APAP 500 mg and NTX. 1.0 mg (50 pts); D) HC 5 mg / APAP 500 mg and NTX 0.1 mg (50 pts); E) HC 5 mg / APAP 500 mg and NTX 0.01 mg (50 pts); F) HC 5 mg / APAP 500 mg and NTX 0. 001 mg (50 pts). In this study, in the treatment of moderate to severe pain after extraction of three or four third or full bone impacted third molars, subjects experienced moderate to severe postoperative pain. If so, a single oral dose of one of these treatments was administered. The observation period for efficacy was 8 hours after treatment and the observation period for safety was 24 hours after treatment.
[0220]
Efficacy and safety assessments related to pain intensity, pain relief, overall pain assessment, time to significant pain relief (stopwatch), visual analog scale, and adverse event assessment . For analysis of the data, certain pain parameters were calculated as generally described above.
[0221]
The placebo-treated group had the lowest sum of the four hour pain intensity difference (SPID) scores. All five of the active treatment groups, HC / APAP alone or in combination with NTX, showed an improved profile in mean SPID compared to placebo. The average 4-hour SPID score for the 0.001 mg NTX combination treatment was higher than the average 4-hour SPID score for the HC / APAP alone treatment, while the other NTX combination treatments were higher for the HC / APAP alone treatment. Was equal to or lower than the average of the 4 hour SPID score. The pattern of SPID scores at 6 hours and 8 hours was similar to the pattern of SPID scores at 4 hours.
[0222]
The placebo treatment group had the lowest mean total pain release score. All five of the active treatment groups with HC / APAP alone or in combination with NTX showed an average numerically higher total pain release score than placebo. The average total pain relief score for the 0.001 mg NTX combination treatment was higher than the average total pain relief score for the HC / APAP alone treatment, while the average for the other NTX combination treatments was higher for the HC / APAP alone treatment. Was equal to or lower than the average total pain release score of
[0223]
The placebo treatment group had the highest number of subjects with a "poor" overall rating score. The 0.001 mg NTX combination treatment group had the largest number of subjects with the sum of "excellent", "very good", and "good" overall rating scores. The overall rating score profile is based on the subject's rating.
[0224]
The time to treatment before significant pain relief occurred was the shortest in the 0.001 mg NTX (lowest dose) combination treatment group. The combination treatment group of placebo and 0.01 mg NTX had the number of subjects that achieved the lowest significant pain relief.
[0225]
Baseline pain intensity scores and visual pain scores were generally comparable between treatment groups.
[0226]
The major adverse events reported were classified as digestive (nausea or vomiting) or nervous (vertigo or somnolence).
[0227]
Further studies of morphine alone and in combination with naltrexone were performed. In this dose range study, doses of morphine sulfate (30 mg, 60 mg, and 90 mg) in combination with naltrexone hydrochloride (0.1 mg) were administered for moderate to severe pain in male patients after dental surgery. This study was conducted to investigate the efficacy of different dose combinations of morphine containing 0.1 mg of naltrexone when administered alone and simultaneously with 0.1 mg naltrexone compared to placebo and compared to morphine alone. It was performed to evaluate the dose-response effect of morphine when administered and to test the consistency of the efficacy of naltrexone 0.1 mg against different doses of morphine when co-administered with morphine.
[0228]
A study of 210 subjects was designed with the following seven treatment groups: A) placebo (30 pt); B) morphine 30 mg (30 pt); C) morphine 60 mg (30 pt); D) morphine 90 mg (30 pt): E A) morphine 30 mg and naltrexone 0.1 mg (30 pt); F) morphine 60 mg and naltrexone 0.1 mg (30 pt); G) morphine 90 mg and naltrexone 0.1 mg (30 pt). In this study, in the treatment of moderate to severe pain after extraction of a third molar, all or part of which was impacted by 3 or 4 bones, the patient was treated with moderate to severe postoperative Oral single doses of one of these treatments were given when suffering from pain. The observation period for effect was 8 hours after treatment and the observation period for safety was 24 hours after treatment.
[0229]
The effect evaluation and the safety evaluation were performed for PID, SPID-4, SPID-6 and SPID-8, PEAKPID, VAS-PID, VAS-SPID-4, -6, and -8 for each evaluation, and PEAK-VAS. -PID, pain relief (PR) score, TOTPAR-4, -6 and -8, MAXPAR, global evaluation, time to onset of analgesia, time to remedication, up to 4, 8, 24 hours Included were the proportion of patients who remedicated and the assessment of adverse reaction events. Certain pain parameters were calculated for data analysis generally as described above.
[0230]
The mean PID scores of the placebo treated groups were generally flat, but the mean PID scores of the active treatment groups (30 mg MS, 60 mg MS, and 90 mg MS alone or in combination with 0.1 mg NTX) Generally improved over time. The average score at each evaluation time every hour from 1 to 8 hours for the morphine alone treatment group and the morphine / naltrexone combination treatment group was higher than the average PID score for the placebo group. The highest pain relief measured by the PID score was observed in the 90 mg MS / 0.1 mg NTX combination treatment group.
[0231]
The placebo treatment group had the lowest sum of pain intensity difference (SPID) score at 4 hours. All six of the active treatment groups using 30 mg, 60 mg, or 90 mg MS alone, or a combination of these with 0.1 mg of NTX, showed an improved average SPID profile over placebo. The average SPID score at 4 hours for the 90 mg MS / 0.1 mg NTX combination treatment was the highest among all treatment groups. The average SPID scores for the 30 mg, 60 mg, and 90 mg MS alone treatment groups were comparable. In contrast, the mean SPID scores of the 30 mg MS / 0.1 mg NTX, 60 mg MS / 0.1 mg NTX, and 90 mg MS / 0.1 mg NTX combination treatment groups indicate a dose response, with the 90 mg MS / 0.1 mg NTX combination. The treatment group had the highest mean SPID-4 score, and the 30 mg MS / 0.1 mg NTX combination treatment group had the lowest mean SPID-4 score among the combination treatment groups.
[0232]
The placebo treatment group had the lowest mean total pain improvement score (Total Pain Relief score). All six of the active treatment groups using 30 mg, 60 mg, or 90 mg MS alone, or a combination of these with 0.1 mg of NTX, showed a mean overall pain improvement score numerically higher than placebo. The mean total pain improvement score for the 90 mg MS / 0.1 mg NTX combination treatment was the highest among all treatment groups. The mean total pain improvement scores for the 30 mg, 60 mg, and 90 mg MS alone treatment groups were comparable. In contrast, the mean total pain improvement scores for the 30 mg MS / 0.1 mg NTX, 60 mg MS / 0.1 mg NTX, and 90 mg MS / 0.1 mg NTX combination treatment groups indicate a dose response, with 90 mg MS / 0.1 mg The NTX combination treatment group had the highest mean total pain improvement score, and the 30 mg MS / 0.1 mg NTX combination treatment group had the lowest mean total pain improvement score among the combination treatment groups.
[0233]
Mean PEAKPID scores varied between treatment groups, and all six active treatment groups had higher mean PEAKPID scores compared to the placebo group. Compared to all other groups, the 90 mg MS / 0.1 mg NTX combination treatment group had the highest mean PEAKPID score.
[0234]
The average pain relief score for the placebo treatment was lower than the average pain relief score for the long-term improved active treatment groups (30 mg, 60 mg, 90 mg MS alone or in combination with 0.1 mg NTX). Separation between the placebo and active treatment groups continued over the 8 hour study period. The highest pain relief scores were observed in the 90 mg MS / 0.1 mg NTX combination treatment group.
[0235]
Mean MAXPAR scores varied between treatment groups. The average MAXPAR score of the 90 mg MS / 0.1 mg NTX combination treatment group was the highest compared to all other groups. The average score for all six active treatment groups was greater than the average score for the placebo group.
[0236]
The placebo treatment group had the highest number of subjects with a "poor" overall rating score. The 90 mg MS / 0.1 mg NTX combination treatment group had the highest total number of subjects with an overall rating score of "excellent", "very good" and "good". The overall rating score profile is based on the subject's rating.
[0237]
The median time to onset of analgesia was the shortest in the 90 mg MS / 0.1 mg NTX combination treatment group.
[0238]
The placebo group had the shortest median time to re-dose, and the 90 mg MS / 0.1 mg NTX combination treatment group had the longest median time to re-dose. More than 70% of subjects in the 90 mg MS / 0.1 mg NTX combination treatment group at 4 hours, and more than 60% of subjects in the same combination group at 8 hours did not need remedy assistance.
[0239]
The baseline and visual analog scale scores of pain intensity scores were generally comparable across treatment groups.
[0240]
Many of the reported adverse events were classified as gastrointestinal (nausea or vomiting) or nervous (vertigo or somnolence).
[0241]
(Example 3)
This example describes the preparation of a dosage form containing naltrexone hydrochloride (referred to in these examples as "naltrexone" or "NTX"), which was used for clinical evaluation. This example also describes the measurement of dissolution of this dosage form.
[0242]
The dosage form for the clinical evaluation and dissolution test of this example was provided by preparing a hard gelatin capsule containing the opioid antagonist and the excipient according to Example 1. This capsule contained naltrexone HCl and two pharmaceutical excipients. The table below shows the qualitative composition of the NTX capsules.
[0243]
[Table 5]

NTX capsules were prepared by filling an empty capsule shell with a powder blend of NTX, microcrystalline cellulose, and magnesium stearate. The filling weight was constant for each strength of the produced NTX capsules.
[0244]
Unless otherwise specified and subjected to the specific conditions and parameters disclosed for the particular example, the dissolution tests in Example 3 and other examples were performed according to the United States Pharmacopeia 24 (2000) Physical Test <711> (which is incorporated herein by reference) was performed using a dissolution test employing apparatus 2 (paddle stirring element).
[0245]
Dissolution tests were performed on 500 capsules of 0.1 N hydrochloric acid (HCl) for two capsules per dissolution vessel. The temperature of the test medium was maintained at about 37.0 ° C. (+/− 0.5 ° C.) and the paddle speed was 50 rpm. Sample aliquots of the test medium were taken at various time points to determine the amount of naltrexone (and / or another component to be tested for dissolution). The release of the tested component is reported as a percentage of the release over time.
[0246]
The following table summarizes the results obtained for the dissolution test of NTX capsules. These results are the average of six tests.
[0247]
[Table 6]

This dosage form provided a rapid release of over 90% of the theoretical amount of naltrexone in about 5-10 minutes.
[0248]
(Example 4)
This example describes the preparation of a dosage form containing morphine sulfate pentahydrate (MS) for clinical evaluation. This example also describes the measurement of dissolution of this dosage form. The dosage form of this example for clinical evaluation and dissolution testing was a hard gelatin capsule. MS capsules were prepared by placing 1-4 of the commercially available 15 mg MS immediate release tablets into hard gelatin capsules. Next, a mixture of microcrystalline cellulose and magnesium stearate was added to bulk the capsules and to facilitate processing. The table below shows the qualitative composition of the MS capsules.
[0249]
[Table 7]

The in vitro dissolution rates in this example were determined using USP 24 (2000) Apparatus 2 (paddle stirring element) (using the same conditions and parameters as described in Example 3).
[0250]
For dissolution testing, one 60 mg MS capsule was placed in the test solvent. The following table summarizes the results obtained for the dissolution test of MS capsules. These results are the average of six tests.
[0251]
[Table 8]

The results of these dissolutions indicate that this dosage form provides for rapid release of morphine sulfate pentahydrate.
[0252]
(Example 5)
This example describes the preparation of a dosage form comprising oxycodone hydrochloride salt. This example also describes the measurement of dissolution of this dosage form. The following general procedure was used to prepare capsules containing different strengths of oxycodone hydrochloride (referred to as oxycodone in this example) supplied as Roxicodone® (Roxane Laboratories, Inc.). Roxicodone® tablets are available in tablets with a strength of 5.0 mg (oxycodone hydrochloride). Although each Roxicodone® tablet is stated to have a theoretical drug content of 5.0 mg oxycodone hydrochloride, the actual amount may vary within an acceptable range (eg, about 10%). obtain.
[0253]
A capsule of 5.0 mg oxycodone hydrochloride was made by mixing microcrystalline cellulose (229.2 mg) and magnesium stearate (1.2 mg) until a blend was formed. The blend and one Roxidone® tablet were placed separately in the body part of the hard gelatin capsule shell. The capsule was then closed with the shell cap. The weight of the filled capsule was approximately 426.0 mg.
[0254]
A capsule of 15.0 mg oxycodone hydrochloride was made by mixing microcrystalline cellulose (135.5 mg) and magnesium stearate (0.7 mg) until a blend was formed. The blend and three Roxicodone® tablets were separately placed in the body half of the hard gelatin capsule shell. The capsule was then closed with the shell cap. The weight of the filled capsule was approximately 533.0 mg.
[0255]
Filled capsules containing 15.0 mg of oxycodone were treated with a dissolution test equivalent to the dissolution test shown in USP 24 Monograph for tablets of oxycodone hydrochloride (the test medium used was a USP grade buffer of pH 4.5. , And the paddle speed used was 75 rpm). In addition, chromatographic separation of oxycodone from the colorant in the gelatin capsule was required to prevent interference in the UV absorption spectrum. USP 24 Monograph for oxycodone hydrochloride tablets refers to the general dissolution test set forth in USP 24.
[0256]
The following table summarizes the dissolution results obtained based on the 12 samples tested for 15 mg strength oxycodone capsules.
[0257]
[Table 9]

The results of these dissolutions indicate that this dosage form provides for rapid release of oxycodone hydrochloride.
[0258]
Dissolution testing was also contemplated at 50 rpm, but this paddle method did not provide sufficient agitation and pyramidalization occurred. At this low paddle speed of 50 rpm, from the capsule, the filled excipient formed a cone at the bottom of the dissolution vessel, preventing proper dissolution of the tablet. The occurrence of cones justifies the modification of the parameters of the dissolution test. The paddle speed was increased to 75 rpm to prevent cones. This paddle speed is still within the criteria for USP elution.
[0259]
(Example 6)
This example describes the preparation of a dosage form containing tramadol hydrochloride (referred to in this example as "tramadol"), which was used in clinical evaluations. This example also describes the measurement of dissolution of this dosage form. The following general procedure was used to prepare capsules containing tramadol hydrochloride supplied at different strengths supplied as Ultram® (Johnson RW). Ultram® tablets are available in tablets with a strength of 50.0 mg (tramadol hydrochloride). Although each Ultram® tablet is stated to have a theoretical drug content of 50.0 mg tramadol hydrochloride, the actual amount of each is within an acceptable range (eg, about 10%). Can change.
[0260]
A capsule of 50.0 mg tramadol hydrochloride was made by mixing until a blend of microcrystalline cellulose (167.16 mg) and magnesium stearate (0.84 mg) was formed. The blend and one Ultram® tablet were separately filled into the body portion of a hard gelatin capsule shell. The capsule was then closed with the shell cap. The weight of the filled capsule was approximately 491.3 mg.
[0261]
The filled capsules were subjected to a dissolution test using USP 24 device 2 (paddle stirring element). Analysis of tramadol capsules was achieved by performing elution of the filled capsules in 900 ml of 0.1 N hydrochloric acid. The solvent temperature was maintained at about 37.0 ° C. (+/− 0.5 ° C.) and the paddle speed was 75 rpm. The following table summarizes the dissolution data for 50 mg strength tramadol hydrochloride capsules obtained based on the six samples tested.
[0262]
[Table 10]

Again, cone formation was observed for the dissolution test performed at 50 rpm, resulting in uncertain test results. Paddle speed was increased to 75 rpm to prevent cones. This is still within acceptable USP elution criteria.
[0263]
The results of these dissolutions indicate that this dosage form provides a rapid release of tramadol hydrochloride and that the excipients used do not significantly bind to opioid agonists in an aqueous environment.
[0264]
(Example 7)
This example describes a general procedure used to make a pharmaceutical composition comprising an opioid antagonist on coated nonpareil beads or pellets (eg, coded pellet 1 shown in FIG. 2). Is described. This example describes a dosage form consisting essentially of an opioid antagonist. A binder solution comprising at least a binder, an organic and / or aqueous solvent, and an opioid antagonist is prepared. A suitable binder is hydroxypropyl methylcellulose ("HPMC") plasticized with triacetin (e.g., a commercial coating of the Opadry (R) brand from Colorcon, Inc.). The binder solution was coated on inert non-pareil pellets to form coated pellets. The coating is performed in a fluidized bed apparatus set up to spray down with a Wurster column insert. Plasticizers can be added to the coating dispersion to increase the flexibility of the coating. The thickness (weight) of the coating on the non-pareil pellets can vary as desired, but generally falls in the range of about 2 to 50% by weight of the total pellet weight. The weight of the coated pellets is less than about 10 mg and has a diameter or length of about 0.1-5.0 mm. These coated pellets may contain the following components in approximately indicated amounts.
[0265]
[Table 11]

The non-pareil cores used in the coated pellet and bead formulations generally include pharmaceutically inert substances such as lactose, sucrose, and starch.
[0266]
The coated pellets can be filled into hard gelatin capsules or compressed into tablets.
[0267]
(Example 8)
This example provides a pharmaceutical composition comprising the same coated granules shown in FIG. 6, except that the opioid antagonist is the only active pharmaceutical ingredient used in this example. The general procedure used to make is described. This example shows a dosage form consisting essentially of an opioid antagonist. A granulation solution is made by mixing the opioid antagonist, one or more binders, and water in a vessel equipped with a high shear mixer. Suitable granulation solutions include the following ingredients in approximately indicated amounts.
[0268]
[Table 12]

Next, a first blend of an inert pharmaceutical excipient (eg, in the table below) is granulated in a fluid bed unit using a granulation solution to form a wet granulated material. did. The granulated material is sized through a # 12 sieve. Subsequently, the same size granules are dried, thereby forming a coated granulate, which is then sieved through a # 30 mesh screen.
[0269]
[Table 13]

The granules were then mixed with magnesium stearate (0.5% by weight) and low substituted hydroxypropyl cellulose ("L-HPC") (3.0% by weight) and mixed for an additional 5 minutes. The blend is then compressed into tablets on a rotary tablet press.
[0270]
(Example 9)
This example describes the general procedure used to make a soft gelatin capsule dosage form containing a suspension of the drug. The suspension is mixed with a non-aqueous vehicle, such as miglyol, PEG, glycerin, propylene glycol, or vegetable oil, and a solid, such as an opioid antagonist, and optionally, at least one other pharmaceutical excipient. By doing so, it is produced. Solids added to non-aqueous vehicles are generally powders or particles which may include, for example, beads, pellets, and granules. Suitable suspensions contain the following ingredients in approximately indicated amounts.
[0271]
[Table 14]

(Example 10)
This example describes a general procedure used to make the pharmaceutical composition of FIG. 2, comprising a mixture of two different coated non-pareil beads or pellets. This example describes a dosage form comprising an opioid antagonist and another active pharmaceutical ingredient, in this case, an opioid agonist. A combination capsule dosage form was prepared containing naltrexone and morphine sulfate pentahydrate for simultaneous release of both drugs. The excipient used in this embodiment was found not to bind significantly to morphine or naltrexone in an aqueous environment.
[0272]
A first binder solution comprising at least a binder, an organic and / or aqueous solvent, and an opioid antagonist is prepared. The first binder solution is coated on inert non-pareil pellets to form first coated pellets. A suitable binder is a plasticized HPMC such as Opadry® Clear. The coating was performed in a fluid bed apparatus set up to spray down with a Wurster column insert. The spray rate of the coating solution was adjusted during processing and maintained approximately the following equilibrium during processing; inlet temperature, 70-80 ° C, outlet temperature 42-47 ° C.
[0273]
[Table 15]

In a similar manner, a second binder solution comprising at least a binder, an organic and / or aqueous solvent, and an opioid agonist is prepared. The second binder solution is coated on another inert non-pareil pellet to form a second coated pellet. Plasticizers can be added to the coating dispersion to increase the flexibility of the coating.
[0274]
An aqueous coating solution containing the components listed above was used to produce capsules containing drug-coated nonpareil beads. The capsule releases the opioid agonist and opioid antagonist quickly and simultaneously from the dosage form.
[0275]
[Table 16]

Predetermined amounts of the first and second pellets are mixed, thereby forming a mixture of pellets. The thickness (weight) of the coating on the non-pareil pellets can be varied as desired, but generally ranges from about 1 to 70% by weight of the total pellet weight. The coated pellets weigh less than about 10 mg and have a diameter or length of about 0.1-5.0 mm.
[0276]
Capsules made according to this example contained the following ingredients in the approximate amounts indicated.
[0277]
[Table 17]

The non-pareil core used in the coated pellet and bead formulations of the present invention generally comprises a pharmaceutically inert substance such as lactose, sucrose, and / or starch.
[0278]
The mixture of coated pellets was filled into hard gelatin capsules and subjected to dissolution tests using apparatus 2 (paddle stirring element) in USP 24, except that a variety of different stirring speeds were used. The test medium was 500 ml of 0.1N HCl at a constant medium temperature of 37 ° C. (+/− 0.5 ° C.). The stirring speed of the paddle for the dissolution test was 50, 75, or 100 revolutions per minute. The following table summarizes the results obtained for the dissolution tests at each paddle speed. The results reported at each hour for each paddle speed are the average of six tests.
[0279]
[Table 18]

These dissolution studies demonstrate that this combination dosage form provides for the simultaneous release of the opioid agonist and the opioid antagonist, and that the excipients used do not significantly bind to the opioid agonist or opioid agonist in an aqueous environment. Show. When these dissolution results are tested at 75 rpm and 100 rpm in this combination dosage form at 5, 10, 20, 30, 45, and 60 minutes, the dissolution profile is substantially different at each agitation speed. , Indicating that the proportions of the opioid agonist and the opioid antagonist are substantially the same. The dosage form of this example also provides for immediate release of both active pharmaceutical ingredients that dissolve in excess of about 90% in 45 minutes.
[0280]
(Example 11)
This example illustrates the general procedure used to make the pharmaceutical composition of FIG. 3, comprising a single type of coated non-pareil pellets, wherein the coating comprises an opioid antagonist and another Active pharmaceutical ingredients (in this case, opioid agonists). A first binder solution comprising at least one binder, an organic and / or aqueous solvent, a plasticizer, an opioid agonist and an opioid antagonist is prepared. The first binder solution is coated on inert non-pareil pellets to form coated pellets. The thickness (weight) of the coating on the non-pareil pellets can vary as desired, but generally ranges from about 2-80% by weight of the total pellet weight, usually between 10-50%. . The coated pellets weigh less than about 10 mg and have a diameter or length of about 0.2-2.0 mm. These coated pellets contain the following ingredients in the approximate amounts indicated.
[0281]
[Table 19]

(Example 12)
This example shows a combined tablet dosage form containing both naltrexone and morphine salts for simultaneous and immediate release of both active pharmaceutical ingredients. The combination tablet comprises an opioid antagonist and another active pharmaceutical ingredient, in this case, an opioid agonist. The excipient used in this example was found not to bind significantly (eg, to the extent that it did not interfere with the therapeutic effect or co-release) to morphine or naltrexone in an aqueous environment. The tablets disintegrate within about 5 minutes after exposure to the aqueous buffer at 37 ° C., providing rapid dissolution of the active pharmaceutical ingredient. Tablets made in accordance with this example contained the following ingredients in the approximate amounts indicated.
[0282]
[Table 20]

Tablets were made according to the following general procedure. A bulk powder for tableting was prepared using a high shear, wet granulation method.
[0283]
[Table 21]

Dry matter blends of the opioid agonist and the following pharmaceutical excipients were prepared on a high shear granulator.
[0284]
[Table 22]

While mixing, the binder solution was slowly added to the dry matter blend to prepare granules. The wet granules were sized by passing through a 20 mesh screen. The sized wet granules were dried in a fluid bed apparatus until the dry weight had a moisture content of less than about 5%. The dried granules were passed through a 20 mesh screen. The following non-granulated excipients were blended into the dried granules using a double cone blender.
[0285]
[Table 23]

The final powder blend was then compressed on a rotary tablet press using a 7 mm round bi-concave tooling. The compressed tablet compact was recovered and an aqueous-based coating was applied on a tablet coating basis.
[0286]
Tablets were coated using a clear seal coat of a plasticized HPMC (Opadry®) based aqueous coating solution and a plasticized HPMC (Opadry®) based aqueous coating dispersion tinted topcoat. .
[0287]
Tablets are extruded at 37 ° C. (+/− 2 ° C.) using the disintegration test in USP 24 (2000) Physical Test <701>, which is incorporated herein by reference. It was determined to disintegrate in ionic water in less than 3 minutes.
[0288]
Dissolution of MS and NTX from uncoated and coated tablet cores using 500 ml 0.1N HCl as dissolution medium was performed using Apparatus 2 (paddle stirring element) in USP 24 evaluated. The two tablets were placed at 37 ° C. (+/− 0.5 ° C.) in 500 mL dissolution medium. The paddle agitation speed was 50 rpm and the percentage of dissolved MS and NTX was determined from a sample of the test medium.
[0289]
The following table summarizes the dissolution test results for the uncoated and coated tablet cores prepared as described above. FIG. 9 shows the dissolution profile of the coated tablet core.
[0290]
[Table 24]

Accordingly, embodiments of the present invention provide an immediate release solid oral tablet comprising an opioid antagonist and an opioid agonist. The active pharmaceutical ingredients are released simultaneously. In addition, the dissolution rates of the opioid agonist and opioid antagonist in this dosage form are substantially the same each time (except for 30 minutes for uncoated tablets). These dissolution results indicate that the combination dosage form provides for the simultaneous release of the opioid agonist and the opioid antagonist, and that the excipients used do not bind significantly to the opioid agonist in an aqueous environment.
[0291]
(Example 13)
This example illustrates the general procedure used to make the pharmaceutical composition of FIG. 4, comprising a mixture of two different types of granules. One granule contains the opioid antagonist and the other granule contains another active pharmaceutical ingredient, in this case an opioid agonist.
[0292]
A first granule is made by blending a first blend of an opioid antagonist and a pharmaceutical excipient with a granule solution to form a wet mass that passes through a sieve and is subsequently dried To form Suitable first granules include the following ingredients in the approximate amounts indicated.
[0293]
[Table 25]

Similarly, a second granule is made by blending a second blend of an opioid agonist and a pharmaceutical excipient with the granule solution to form a wet mass that passes through a sieve and is subsequently dried Form wet granules. Suitable second granules include the following ingredients in the approximate amounts indicated.
[0294]
[Table 26]

The first and second granules are subsequently blended to form a mixture. The granules are Pass through a 20 mesh screen. Both active pharmaceutical ingredients are designated No. Disintegrant (e.g., L-HPC, 3% by weight) and lubricant (10%) in a twin-shell blender for 10 minutes before passing through a 20 mesh screen and compression on a rotary tablet press. For example, magnesium stearate (0.5% by weight).
[0295]
(Example 14)
This example illustrates the general procedure used to make the pharmaceutical composition of FIG. 5, including the combined granules. The combination granules comprise an opioid antagonist and another active pharmaceutical ingredient (in this case, an opioid agonist).
[0296]
A first granule was made by blending a first blend of an opioid antagonist, and a pharmaceutical excipient with a granule solution. It forms a wet mass passing through 12 sieves and then forms wet granules that are dried. The final granules are no. Pass through a 20 mesh screen. Suitable first granules include the following ingredients in the approximate amounts indicated.
[0297]
[Table 27]

The second granule is made by blending the opioid agonist (a second blend of the pharmaceutical excipient and the first granule) with the granule solution to form a wet mass that passes through a sieve and then is dried To form wet granules. Suitable second granules include the following ingredients in the approximate amounts indicated.
[0298]
[Table 28]

(Example 15)
This example illustrates the general procedure used to make the pharmaceutical composition of FIG. 6, comprising coated granules comprising an opioid agonist and another active pharmaceutical ingredient, in this case, an opioid agonist. Show. Granule solutions are made by blending the opioid agonist, opioid antagonist, binder and solvent in a container equipped with a high shear mixer. Suitable granule solutions include the following ingredients in the approximate amounts indicated.
[0299]
[Table 29]

The first blend of the inert pharmaceutical excipient is then granulated with the granule solution in the fluidized bed unit to form a wet mass, Pass through 12 sieves to form wet granules that are subsequently dried. Thereby, coated granules are formed.
[0300]
The final granule is then mixed with one or more pharmaceutical excipients to form a pharmaceutical mixture containing the following ingredients in the approximate amounts indicated. The final granules are no. Pass through 20 screens.
[0301]
[Table 30]

(Example 16)
This example is similar to the procedure for making the pharmaceutical composition of Example 15, except that the opioid agonist was not included in the granule solution, but instead a granulated pharmaceutical excipient was included. The general procedure is shown.
[0302]
A granule solution is made by blending the opioid antagonist, binder and solvent in a container equipped with a high shear mixer. Suitable granule solutions include the following ingredients in the approximate amounts indicated.
[0303]
[Table 31]

The first blend of inert pharmaceutical excipient is then granulated with the granule solution in the fluidized bed unit to form a wet mass, which is Pass through 12 sieves to form wet granules that are subsequently dried. Thereby forming coated granules, and no. Pass through a 30 mesh screen. Suitable granules include the following ingredients in the approximate amounts indicated.
[0304]
[Table 32]

The coated granules are mixed with magnesium stearate (0.5% by weight) and L-HPC (3.0% by weight) and blended for another 5 minutes. The blend is then compressed into tablets on a rotary tablet press.
[0305]
(Example 17)
This example illustrates the general procedure used to make a pharmaceutical composition comprising spray-dried granules. A solution of the opioid antagonist, another active pharmaceutical ingredient (e.g., an opioid agonist), and at least one pharmaceutical excipient is treated at about 10 ml / min using an inlet temperature of 90 <0> C and an outlet temperature of 50 <0> C. BUCHI at the speed of ^TM Spray dried in a spray dryer. The spray dried granules are recovered, and the granules have a particle size of less than about 20 mesh. Suitable spray-dried particles include the following ingredients in the approximate amounts indicated.
[0306]
[Table 33]

Although the specific parameters of the spray drying operation are detailed above, the operation of the spray dryer can be performed as needed, and the parameters for the operation of the apparatus are the product according to this example. Can be varied as needed to prepare
[0307]
The granules are dried, blended with magnesium stearate (0.5% by weight) and L-HPC (3.0% by weight) and blended for another 4-6 minutes. The blend is then compressed into tablets on a rotary tablet press or filled into hard gelatin capsules.
[0308]
(Example 18)
This example illustrates the general procedure used to make a soft gelatin capsule dosage form containing a drug suspension. The suspension may be combined with a non-aqueous vehicle such as miglyol, PEG, glycerin, propylene glycol, or vegetable oil, an opioid antagonist, another active pharmaceutical ingredient (eg, an opioid agonist), and optionally at least one other. By mixing with a pharmaceutical excipient. Solids added to non-aqueous vehicles are generally powders or particles and include, for example, beads, pellets and granules. Suitable suspensions contain the following ingredients in the approximate amounts indicated.
[0309]
[Table 34]

Although the invention herein has been described with reference to specific embodiments, it is to be understood that these examples are merely illustrative of various aspects of the invention. Therefore, it should be understood that numerous modifications can be made in the exemplary embodiments and other configurations can be devised without departing from the spirit and scope of the invention.
[Brief description of the drawings]
FIG. 1A
FIG. 1A is a flowchart illustrating a method of manufacturing a naltrexone capsule dosage form according to a disclosed embodiment.
FIG. 1B
FIG. 1B is a flowchart illustrating a method of manufacturing a naltrexone capsule dosage form according to a disclosed embodiment.
FIG. 2
FIG. 2 illustrates an embodiment of an immediate release dosage form having two different types of coated nonpareil pellets.
FIG. 3
FIG. 3 shows an embodiment of an immediate release dosage form having a single form of coated nonpareil pellets.
FIG. 4
FIG. 4 shows an embodiment of the present invention of a mixture comprising two different types of granules.
FIG. 5
FIG. 5 shows an embodiment of the present invention of coated granules.
FIG. 6
FIG. 6 shows an embodiment of the present invention of granules dispersed in an optional pharmaceutical excipient composition.
FIG. 7
FIG. 7 shows a graph demonstrating the relationship between the ratio of opioid agonist to opioid antagonist and the amount of formulation with respect to the total weight of the pharmaceutical composition according to the invention. This relationship applies to the embodiments of FIGS.
FIG. 8
FIG. 8 shows a graph demonstrating the relationship between the ratio of opioid agonist to opioid antagonist and the amount of the first formulation with respect to the total weight of the pharmaceutical composition according to the invention. This relationship applies to the embodiments of FIGS. 3, 5, and 6.
FIG. 9
FIG. 9 shows the in vitro dissolution profile for the exemplary coated tablet of Example 12.

Claims (171)

A dosage form comprising the opioid antagonist in an amount from about 0.0001 mg to about 1 mg or less than 1 mg. The dosage form of claim 1, wherein the amount of the antagonist is about 1 mg. The dosage form according to claim 1, wherein the amount of the antagonist is less than 1 mg. The dosage form of claim 1, wherein the amount of the antagonist is less than about 0.5 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is about 0.1 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is less than 0.1 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is greater than 0.1 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is about 0.01 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is less than 0.01 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is more than 0.01 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is about 0.001 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is less than 0.001 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is greater than 0.001 mg. 5. The dosage form according to claim 1, wherein the amount of the antagonist is about 0.0001 mg. The dosage form according to claim 1 or 4, wherein the amount of the antagonist is greater than 0.0001 mg. 5. The dosage form according to claim 1 or 4, wherein said antagonist is present as a pharmaceutically acceptable salt. The dosage form according to claim 1 or 4, wherein the antagonist is naltrexone, nalmefene, or naloxone. 5. The dosage form according to claim 1 or 4, further comprising an opioid agonist. 19. The dosage form of claim 18, wherein the agonist is at or below the analgesic amount. 19. The dosage form according to claim 18, wherein the agonist is morphine, hydrocodone, oxycodone, codeine, fentanyl, alfentanil, hydromorphone, meperidine, methadone, oxymorphone, propoxyphene, or tramadol. 19. The dosage form according to claim 18, wherein said agonist is morphine, hydrocodone, oxycodone, or tramadol. 5. The dosage form according to claim 1 or 4, wherein the antagonist is formulated as a capsule, tablet, or pill. A pharmaceutical composition comprising an opioid antagonist in an amount from about 0.0001 mg to about 1 mg or less than 1 mg, and a pharmaceutically acceptable carrier. 24. The pharmaceutical composition according to claim 23, wherein the amount of the antagonist is about 1 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of the antagonist is less than 1 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of the antagonist is about 0.1 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of the antagonist is less than 0.1 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of said antagonist is greater than 0.1 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of the antagonist is about 0.01 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of the antagonist is less than 0.01 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of said antagonist is greater than 0.01 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of said antagonist is about 0.001 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of the antagonist is less than 0.001 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of said antagonist is greater than 0.001 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of the antagonist is about 0.0001 mg. 24. The pharmaceutical composition according to claim 23, wherein the amount of said antagonist is greater than 0.0001 mg. 24. The pharmaceutical composition according to claim 23, wherein said antagonist is present as a pharmaceutically acceptable salt. 24. The pharmaceutical composition according to claim 23, wherein said antagonist is naltrexone, nalmefene, or naloxone. 24. The pharmaceutical composition according to claim 23, further comprising an opioid agonist. 40. The pharmaceutical composition of claim 39, wherein the agonist is at or below the analgesic amount. 40. The dosage form of claim 39, wherein the agonist is morphine, hydrocodone, oxycodone, codeine, fentanyl, alfentanil, hydromorphone, meperidine, methadone, oxymorphone, propoxyphene, or tramadol. 40. The pharmaceutical composition according to claim 39, wherein the agonist is morphine, hydrocodone, oxycodone, or tramadol. 40. The pharmaceutical composition according to claim 23 or 39, wherein the antagonist is formulated as a capsule, tablet, or pill. A method of administering a therapeutic dose of an opioid antagonist to a human subject, said method comprising administering a dosage form according to claim 1 or 4. 19. A method of administering a therapeutic dose of an opioid antagonist to a human subject, said method comprising administering a dosage form according to claim 18. A pharmaceutical kit comprising the dosage form according to claim 1. A pharmaceutical kit comprising a dosage form and a container according to claim 18. A solid oral dosage form consisting essentially of the opioid antagonist in an amount of about 0.0001 mg to less than 0.5 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is less than about 0.4 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is less than about 0.3 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is less than about 0.2 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is about 0.1 mg. 49. The solid oral dosage form of claim 48, wherein the amount of the antagonist is less than 0.1 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is greater than 0.1 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is about 0.01 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is less than 0.01 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is greater than 0.01 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is about 0.001 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is less than about 0.001 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is greater than 0.001 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is about 0.0001 mg. 49. The solid oral dosage form of claim 48, wherein the amount of said antagonist is greater than 0.0001 mg. 49. The solid oral dosage form according to claim 48, wherein said antagonist is naltrexone or nalmefene. A solid oral dosage form consisting essentially of naltrexone in an amount from about 0.0001 mg to less than about 0.5 mg. 65. The solid oral dosage form of claim 64, wherein the amount of naltrexone is less than the effective antagonist amount. A solid oral dosage form consisting essentially of nalmefene in an amount from about 0.0001 mg to less than about 0.5 mg. 67. The solid oral dosage form of claim 66, wherein the amount of nalmefene is less than the effective antagonist amount. A solid oral dosage form comprising the opioid antagonist in an amount of about 0.0001 mg to less than about 0.5 mg, and the opioid agonist in an amount of about 0.1 mg to about 300 mg. 70. The solid oral dosage form of claim 68, wherein said antagonist is present in an effective antagonist amount. 69. The solid oral dosage form of claim 68, wherein the amount of said antagonist is about 0.1 mg. 69. The solid oral dosage form of claim 68, wherein the amount of said antagonist is less than 0.1 mg. 69. The solid oral dosage form of claim 68, wherein the amount of the antagonist is greater than 0.1 mg. 69. The solid oral dosage form of claim 68, wherein the amount of said antagonist is about 0.01 mg. 69. The solid oral dosage form of claim 68, wherein the amount of the antagonist is less than 0.01 mg. 69. The solid oral dosage form of claim 68, wherein the amount of said antagonist is greater than 0.01 mg. 69. The solid oral dosage form of claim 68, wherein the amount of said antagonist is about 0.001 mg. 69. The solid oral dosage form of claim 68, wherein the amount of the antagonist is less than about 0.001 mg. 69. The solid oral dosage form of claim 68, wherein the amount of the antagonist is greater than 0.001 mg. 69. The solid oral dosage form of claim 68, wherein the amount of said antagonist is about 0.0001 mg. 69. The solid oral dosage form of claim 68, wherein the amount of said antagonist is greater than 0.0001 mg. 69. The solid oral dosage form of claim 68, wherein said antagonist is present as a pharmaceutically acceptable salt. 69. The solid oral dosage form of claim 68, wherein said antagonist is naltrexone or nalmefene. 69. The solid oral dosage form of claim 68, comprising naltrexone as an antagonist. 69. The solid oral dosage form of claim 68, comprising nalmefene as an antagonist. 69. The solid oral dosage form of claim 68, wherein said agonist is present in a sub-analgesic amount. 69. The dosage form of claim 68, wherein the agonist is morphine, hydrocodone, oxycodone, codeine, fentanyl, alfentanil, hydromorphone, meperidine, methadone, oxymorphone, propoxyphene, or tramadol. 69. The solid oral dosage form of claim 68, wherein said agonist is morphine, hydrocodone, oxycodone, or tramadol. 69. The solid oral dosage form of claim 68, wherein said antagonist is naltrexone and said agonist is morphine. 69. The solid oral dosage form of claim 68, wherein said antagonist is naltrexone and said agonist is oxycodone. 69. The solid oral dosage form of claim 68, wherein said antagonist is naltrexone and said agonist is hydrocodone. 69. The solid oral dosage form of claim 68, wherein said antagonist is naltrexone and said agonist is tramadol. 69. The solid oral dosage form of claim 68, wherein said antagonist is nalmefene and said agonist is morphine. 69. The solid oral dosage form of claim 68, wherein said antagonist is nalmefene and said agonist is oxycodone. 69. The solid oral dosage form of claim 68, wherein said antagonist is nalmefene and said agonist is tramadol. 69. The solid oral dosage form of claim 68, wherein said antagonist is nalmefene and said agonist is hydrocodone. 69. The solid oral dosage form of claim 68, wherein said antagonist is formulated as a capsule, tablet, or pill. 69. The method of claim 68, further comprising another active pharmaceutical ingredient selected from the group consisting of acetaminophen, a steroidal anti-inflammatory drug, a non-steroidal anti-inflammatory drug, a COX-1 inhibitor, and a COX-2 inhibitor. Solid oral dosage form. 23. A method of administering a therapeutic dose of an opioid antagonist to a human subject, said method essentially comprising administering the solid oral dosage form of claim 22. 24. A method of administering a therapeutic dose of an opioid antagonist to a human subject, said method essentially comprising administering the solid oral dosage form of claim 23. 43. A method of administering a therapeutic dose of an opioid antagonist to a human subject, said method essentially comprising administering a solid oral dosage form according to claim 42. 44. A method of administering a therapeutic dose of an opioid antagonist to a human subject, said method essentially comprising administering the solid oral dosage form of claim 43. 47. A method of administering a therapeutic dose of an opioid antagonist to a human subject, said method essentially comprising administering the solid oral dosage form of claim 46. 63. A method of administering a therapeutic dose of an opioid antagonist to a human subject, said method essentially comprising administering a solid oral dosage form according to claim 62. 69. A method of administering a therapeutic dose of an opioid antagonist to a human subject, said method essentially comprising administering a solid oral dosage form according to claim 68. A pharmaceutical kit comprising the dosage form according to claim 1, 4, or 46. 106. The kit of claim 105, further comprising an opioid agonist dosage form. 107. The kit of claim 106, wherein the agonist dosage form and the antagonist dosage form are separate dosage forms. 5. The solid oral dosage form according to claim 1 or 4, provided as an immediate release formulation. 23. The solid oral dosage form of claim 22, provided as an immediate release formulation. 44. The solid oral dosage form according to claim 43, provided as an immediate release formulation. 50. The solid oral dosage form according to claim 48, provided as an immediate release formulation. 65. The solid oral dosage form of claim 64, provided as an immediate release formulation. 69. The solid oral dosage form of claim 68, provided as an immediate release formulation. An immediate release solid oral dosage form comprising: an opioid antagonist present in an amount of from about 0.0001 to less than about 0.5 mg; at least one pharmaceutical excipient; wherein 90 of the opioid antagonist is present. An immediate release solid oral dosage form that is released in less than about 45 minutes after being exposed to an aqueous environment. 115. An immediate release solid oral dosage form according to claim 114, wherein more than 90% of the opioid antagonist is released in less than about 30 minutes after exposure to an aqueous environment. -Type solid oral dosage forms. 115. An immediate release solid oral dosage form according to claim 114, wherein more than 90% of the opioid antagonist is released in less than about 20 minutes after exposure to an aqueous environment. -Type solid oral dosage forms. 115. The solid oral dosage form of claim 114, wherein the dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises a coated solid substrate, wherein the solid substrate comprises: An active substrate; comprising a coating at least partially surrounding the inert substrate; and wherein the coating comprises a solid comprising an opioid antagonist and at least one pharmaceutical excipient, and optionally a binder and a plasticizer. Oral dosage form. 118. The solid oral dosage form of claim 117, wherein the coating comprises about 1-70% by weight of the coated solid substrate. 119. The dosage form of claim 118, wherein said pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with said coated solid substrate. 119. The solid oral dosage form of claim 118, wherein said dosage form is a capsule or a tablet. 115. The solid oral dosage form of claim 114, wherein the dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises coated granules, wherein the coated granules comprise: A granule comprising a mixture of one or more pharmaceutical excipients; and a coating at least partially surrounding each of the granules; and wherein the coating comprises a solid oral dosage form comprising the pharmaceutical excipient and the opioid antagonist. Form. 122. The solid oral dosage form of claim 121, wherein said pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with said coated granules. 123. The solid oral dosage form of claim 122, wherein the coated granules comprise about 10-85% by weight of the solid pharmaceutical composition. 124. The solid oral dosage form of claim 123, wherein said dosage form is a capsule or a tablet. 115. The solid oral dosage form of claim 114, wherein the solid oral dosage form comprises a spray-dried pharmaceutical composition comprising a mixture of at least one pharmaceutical excipient and an opioid antagonist. . 126. The dosage form of claim 125, wherein said pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with said spray dried pharmaceutical composition. 127. The solid oral dosage form of claim 126, wherein the spray dried pharmaceutical composition comprises about 5-99% by weight dosage form. 130. The solid oral dosage form of claim 127, wherein said dosage form is a capsule or a tablet. 129. The solid oral dosage form of claim 128, wherein the solid dosage form comprises a soft gelatin capsule filled with a suspension, the capsule comprising: a soft gelatin capsule; and a suspension within the capsule. Wherein the suspension comprises a non-aqueous vehicle in liquid form and an opioid antagonist in solid form. 129. The dosage form of claim 128, wherein said suspension further comprises at least one pharmaceutical excipient. An immediate release solid oral dosage form comprising: an opioid antagonist present in an amount from about 0.0001 to less than about 0.5 mg; another active pharmaceutical ingredient; at least one pharmaceutical excipient. An immediate release solid oral dosage form wherein the opioid antagonist and the other active ingredient are released in less than about 1.5 minutes after exposure to an aqueous environment. 134. The solid oral dosage form of claim 131, wherein the other active pharmaceutical ingredient is an opioid antagonist present in an amount from about 0.1 mg to about 300 mg. A simultaneous release combined solid oral dosage form comprising: an opioid antagonist present in an amount of about 0.0001 to less than 0.5 mg; another active pharmaceutical ingredient; at least one pharmaceutical excipient, A solid oral dosage form wherein the opioid antagonist and the other active pharmaceutical ingredient are released simultaneously. 135. A solid oral dosage form according to claim 133, wherein more than 90% of each of the opioid antagonist and the other active pharmaceutical ingredient is less than 45 minutes after exposure to an aqueous environment. , A solid oral dosage form. 143. The solid oral dosage form of claim 133, wherein said other active ingredient is an opioid agonist present in an amount from about 0.1 mg to about 300 mg. 134. The solid oral dosage form of claim 131 or 133, wherein said dosage form is a capsule or a tablet. 134. The solid oral dosage form of claim 131 or 133, wherein greater than 90% of the opioid antagonist is released in less than about 45 minutes after exposure to an aqueous environment. 134. The solid oral dosage form of claim 131 or 133, wherein greater than 90% of said other active pharmaceutical ingredient is released in less than about 45 minutes after exposure to an aqueous environment. 143. The solid oral dosage form of claim 133, wherein a majority release of said opioid antagonist overlaps a majority release of said other active pharmaceutical ingredient. 140. The solid oral dosage form of claim 133, wherein about 90% of the opioid antagonist is released within a time period when about 90% of the other active pharmaceutical ingredient is released. 144. A solid oral dosage form according to claim 133, wherein the dosage form provides an antagonist dissolution profile and a dissolution profile of the other active pharmaceutical ingredient, and wherein the dissolution profiles are substantially the same. Oral dosage form. A combined solid oral dosage form comprising: an opioid agonist; an opioid antagonist; at least one pharmaceutical excipient; wherein the dosage form is at about 37 ° C. in 500 ml of 0.1 HCl medium. Provides agonist and antagonist lysis percentages as measured by USP Paddle Method at 75 rpm, and the agonist and antagonist lysis percentages are substantially the same at any time from 5 minutes to 30 minutes. Oral dosage form. 143. The solid oral dosage form of claim 142, wherein said agonist dissolution percentage and said antagonist dissolution percentage are substantially the same at any of 5, 10, 15, 20, and 30 minutes. 143. The solid oral dosage form of claim 142, wherein said agonist lysis percentage and said antagonist lysis percentage are the average of at least six measurements. 153. The solid oral dosage form of claim 144, wherein the difference between the agonist lysis percentage and the antagonist lysis percentage is about 10% or less. A combination solid oral dosage form comprising: an opioid antagonist present in an amount of about 0.0001 to less than about 0.5 mg; an opioid agonist present in an amount of about 0.1 mg to about 300 mg; and at least one pharmaceutical agent Wherein the dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises a coated solid substrate, the coated solid substrate comprising: the opioid agonist and at least A solid substrate comprising one pharmaceutical excipient; and a coating that at least partially surrounds the solid substrate, and wherein the coating is a combination solid oral comprising the opioid antagonist and at least one pharmaceutical excipient. Dosage form. 147. The solid oral dosage form of claim 146, wherein said solid substrate is a pellet, bead, or granule. A combination solid oral dosage form comprising: an opioid antagonist present in an amount of about 0.0001 to less than about 0.5 mg; an opioid agonist present in an amount of about 0.1 mg to about 300 mg; and at least one pharmaceutical agent Wherein the dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises a coated solid matrix, wherein the coated solid matrix comprises: A bead or pellet; a coating that at least partially surrounds the bead or pellet, and wherein the coating comprises the opioid antagonist, opioid agonist, binder, plasticizer, and at least one pharmaceutical excipient; Combination solid oral dosage form. A combination solid oral dosage form comprising: an opioid antagonist present in an amount of about 0.0001 to less than about 0.5 mg; an opioid agonist present in an amount of about 0.1 mg to about 300 mg; and at least one pharmaceutical agent Wherein the solid dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises first and second coated solid substrates, and wherein the first coated The solid substrate comprises a non-substantial pellet or bead and a first coating at least partially surrounding the pellet or bead, and wherein the first coating comprises a binder and an opioid antagonist; The solid substrate coated with non-substantial pellets or beads and the pellets or beads Both include a second coating surrounding partially and the coating of said second binding agent and comprising an opioid agonist, a combined solid oral dosage forms. 149. The solid oral dosage form of claim 149, wherein the first coated solid matrix comprises about 0.5-80% by weight of the solid pharmaceutical composition; and the second coated solid matrix. A solid oral dosage form comprising about 20-95% by weight of the solid pharmaceutical composition. 163. The solid oral dosage form of claim 150, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the first and second coated substrates. Dosage form. A combination solid oral dosage form comprising: an opioid antagonist present in an amount of about 0.0001 to less than about 0.5 mg; an opioid agonist present in an amount of about 0.1 mg to about 300 mg; and at least one pharmaceutical agent Wherein the solid dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises first and second granules; and wherein the first granules comprise a binder. And said opioid antagonist; and said second granule is a combined solid oral dosage form comprising a binder and said opioid agonist. 153. The method of claim 152, wherein the first granules comprise about 0.5-50% by weight of the solid pharmaceutical composition; and the second granules comprise about 20-95% by weight of the solid pharmaceutical composition. A solid oral dosage form as described. 153. The solid oral dosage form of claim 153, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the first and second granules. 157. The solid oral dosage form of claim 154, wherein said dosage form is a capsule or a tablet. A combination solid oral dosage form comprising: an opioid antagonist present in an amount of about 0.0001 to less than about 0.5 mg; an opioid agonist present in an amount of about 0.1 mg to about 300 mg; and at least one pharmaceutical agent Wherein the dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises coated granules, wherein the coated granules comprise two or more pharmaceutical excipients. And a coating that at least partially surrounds the mixture, wherein the coating comprises a binder, an opioid agonist, and an opioid agonist. 157. The solid oral dosage form of claim 156, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the coated granules. 157. The solid oral dosage form of claim 157, wherein the coated granules comprise about 10-85% by weight of the solid pharmaceutical composition. 159. The solid oral dosage form of claim 158, wherein said dosage form is a capsule or a tablet. A combination solid oral dosage form comprising: an opioid antagonist present in an amount of about 0.0001 to less than about 0.5 mg; an opioid agonist present in an amount of about 0.1 mg to about 300 mg; and at least one pharmaceutical agent Wherein the solid dosage form comprises a pharmaceutical composition, wherein the pharmaceutical composition comprises coated granules comprising a mixture of two or more pharmaceutical excipients and an opioid agonist; And a coating that at least partially surrounds the mixture, and wherein the coating comprises a binder and the opioid antagonist. 163. The solid oral dosage form of claim 160, wherein said pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with said coated granules. 163. The solid oral dosage form of claim 161, wherein the coated granules comprise about 10-75% by weight of the solid pharmaceutical composition. 163. The solid oral dosage form of claim 162, wherein said dosage form is a capsule or a tablet. A combined solid oral dosage form comprising: an opioid antagonist present in an amount of about 0.0001 to less than about; an opioid agonist present in an amount of about 0.1 mg to about 300 mg; and at least one pharmaceutical excipient Wherein the solid dosage form comprises a spray-dried pharmaceutical composition, wherein the pharmaceutical composition comprises a mixture of at least one pharmaceutical excipient, the opioid agonist, and the opioid antagonist. A combined solid oral dosage form. 169. The solid oral dosage form of claim 164, wherein the pharmaceutical composition further comprises at least one pharmaceutical excipient in admixture with the spray dried pharmaceutical composition. 170. The solid oral dosage form of claim 165, wherein the spray dried pharmaceutical composition comprises about 5-99% by weight dosage form. 169. The solid oral dosage form of claim 166, wherein the dosage form is a capsule or a tablet. A combination solid oral dosage form comprising: an opioid antagonist present in an amount of about 0.0001 to less than about 0.5 mg; an opioid agonist present in an amount of about 1.0 mg to about 300 mg; and at least one pharmaceutical agent Wherein the solid dosage form comprises a suspension-filled soft gelatin capsule, the gelatin capsule comprises a soft gelatin capsule; and the suspension in the capsule comprises A combined solid oral dosage form comprising an aqueous vehicle, the solid form of the opioid agonist, and the solid form of the opioid antagonist. 168. The solid oral dosage form of claim 168, wherein said suspension further comprises at least one pharmaceutical excipient. A method for administering a therapeutic dose of an opioid antagonist to a human subject, the method comprising essentially: an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg; Administering a solid oral dosage form comprising an opioid agonist present in an amount from 0.1 mg to less than about 300 mg. A pharmaceutical kit, comprising: a dosage form comprising: an opioid antagonist present in an amount from about 0.0001 mg to less than about 0.5 mg; and an opioid agonist present in an amount from about 0.1 mg to less than about 300 mg. kit.

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