JP2013136621A - ナノ粒子アリピプラゾール製剤 - Google Patents
ナノ粒子アリピプラゾール製剤 Download PDFInfo
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- JP2013136621A JP2013136621A JP2013042916A JP2013042916A JP2013136621A JP 2013136621 A JP2013136621 A JP 2013136621A JP 2013042916 A JP2013042916 A JP 2013042916A JP 2013042916 A JP2013042916 A JP 2013042916A JP 2013136621 A JP2013136621 A JP 2013136621A
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- aripiprazole
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- chloride
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Abstract
【解決手段】(a)約2000nm未満の平均有効粒度を有するアリピプラゾールの粒子;および(b)少なくとも1種類の表面安定剤を含む、安定なナノ粒子アリピプラゾールまたはその塩もしくは誘導体の組成物、および、これらの投与剤形。
【選択図】なし
Description
本出願は、米国特許法第119(e)項に従って、全体が参照により本明細書に組み入れられる、2005年9月15日に出願された米国仮出願第60/717,325号の恩典を主張する。
現在、CNSが関与する精神疾患および精神障害を治療するための薬物を含む、中枢神経系(「CNS」)の障害の治療に使用可能な多くの薬物が存在する。これらのなかには、抗精神病薬として知られる薬物がある。抗精神病薬は、統合失調症、双極性障害、および統合失調症様疾患などの重篤な精神疾患の治療に使用されることがしばしばある。
米国特許第5,145,684号(「'684特許」)に最初に記載されたナノ粒子組成物は、薬物の表面から吸収されるか、または表面に結合する、非架橋型の表面安定剤を有する、溶解度の低い治療剤または診断剤の粒子を含む。'684特許では、このようなナノ粒子活性作用物質組成物の作製法についても記載されているが、ナノ粒子アリピプラゾールを含む組成物については記載されていない。ナノ粒子活性作用物質組成物の作製法は例えば、いずれも「Method of Grinding Pharmaceutical Substances」と題する米国特許第5,518,187号および第5,862,999号;「Continuous Method of Grinding Pharmaceutical Substances」と題する米国特許第5,718,388号;ならびに「Process of Preparing Therapeutic Compositions Containing Nanoparticles」と題する米国特許第5,510,118号に記載されている。
本明細書に記載された組成物および方法は、約2000 nm未満の有効平均粒度を有するアリピプラゾールまたはその塩もしくは誘導体を含む組成物に関する。一般に組成物は、ナノ粒子アリピプラゾールの粒子、およびアリピプラゾール粒子の表面から吸収されるか、または表面に結合する少なくとも1種類の表面安定剤を含む。このようなナノ粒子は、結晶相、非晶質相、半結晶相、半非晶質相、またはこれらの混合物であってよい。
A. ナノ粒子アリピプラゾール組成物
本明細書に記載されたナノ粒子組成物は、アリピプラゾールまたはその塩もしくは誘導体などの抗精神病薬、および同薬物の表面に結合するか、または表面から吸収される少なくとも1種類の表面安定剤を含む。いくつかの態様では、平均有効粒度は約2000 nm未満でありうる。
1. 高い生物学的利用能
ナノ粒子アリピプラゾールまたはその塩もしくは誘導体を含む本発明の組成物は、高い生物学的利用能を示すと考えられており、過去または従来のアリピプラゾール製剤と比較して必要な用量がより少ない。
本明細書に記載されたナノ粒子アリピプラゾール組成物は、哺乳類対象に投与された場合に、望ましい薬物動態プロファイルを示しうる。アリピプラゾール組成物の望ましい薬物動態プロファイルは好ましくは、以下を含むが、これらに限定されない:(1)投与後に哺乳類対象の血漿において分析した、好ましくは、同じ投与量で投与された同じアリピプラゾールの非ナノ粒子製剤のCmaxより大きい、アリピプラゾールまたはその誘導体もしくは塩のCmax;および/または(2)投与後に哺乳類対象の血漿において分析した、好ましくは、同じ投与量で投与された同じアリピプラゾールの非ナノ粒子製剤のAUCより大きい、アリピプラゾールまたはその誘導体もしくは塩のAUC;および/または(3)投与後に哺乳類対象の血漿において分析した、好ましくは、同じ投与量で投与された同じアリピプラゾールの非ナノ粒子製剤のTmaxより小さい、アリピプラゾールまたはその誘導体もしくは塩のTmax。本明細書で用いる、望ましい薬物動態プロファイルとは、アリピプラゾールまたはその誘導体もしくは塩の初回量投与後に測定された薬物動態プロファイルである。
いくつかの態様では、ナノ粒子アリピプラゾール組成物の薬物動態プロファイルは、組成物を摂取した対象の摂食状態または絶食状態に実質的に影響されない。これは、摂食状態と絶食状態におけるナノ粒子アリピプラゾール組成物の投与時に、薬物吸収量や薬物吸収速度にほとんど差がないか、または検出可能な差がないことを意味する。
いくつかの態様では、絶食状態の対象へのナノ粒子アリピプラゾール組成物の投与は、摂食状態の対象への組成物の投与と生物学的に同等である。摂食状態と絶食状態で投与された場合のナノ粒子アリピプラゾール組成物の吸収に見られる差は好ましくは、約100%未満、約90%未満、約80%未満、約70%未満、約60%未満、約55%未満、約50%未満、約45%未満、約40%未満、約35%未満、約30%未満、約25%未満、約20%未満、約15%未満、約10%未満、約5%未満、または約3%未満である。
ナノ粒子アリピプラゾール組成物は、予想外に劇的な溶解プロファイルを有すると考えられている。投与された活性作用物質は、速やかに溶解することが好ましい。というのは迅速な溶解は一般に、より迅速な作用発現、およびより大きな生物学的利用能につながるからである。加えて迅速な溶解速度は、薬物の有効性を高めると考えられる、吸収される薬物の用量を増やすことを可能とすると考えられる。アリピプラゾールの溶解プロファイルおよび生物学的利用能を改善するためには、100%に近いレベルに達するように薬物の溶解を高めることが有用であろう。
本明細書に記載されたアリピプラゾール組成物の追加的な特徴は、再分散したアリピプラゾール粒子の有効平均粒度が約2ミクロン未満となるような再分散を含みうる。投与時に本発明のアリピプラゾール組成物が、実質的にナノ粒子サイズまで再分散しない場合に、投与剤形が、アリピプラゾールをナノ粒子サイズに製剤化することでもたらされる利益を失う場合があることから、これは重要である。
ナノ粒子アリピプラゾールまたはその塩もしくは誘導体を含む組成物には追加的に、精神疾患や精神障害などのCNSの疾患または障害の治療に有用な1種類もしくは複数の化合物を含めることができる。加えて、有害な抗精神病薬の副作用の治療に有用な1種類もしくは複数の化合物も想定される。数種類の化合物の例は、クロルプロマジン、フルフェナジン、ペルフェナジン、プロクロルペラジン、チオリダジン、トリフルオペラジンなどの1種類もしくは複数のフェノチアジン;オランザピン、リスペリドン、クエチアピン、およびジプラシドンなどのブチロフェノンを含むが、これらに限定されない。
本発明は、アリピプラゾール粒子および少なくとも1種類の表面安定剤を含む組成物を提供する。表面安定剤は好ましくは、アリピプラゾール粒子の表面から吸収されるか、または表面に結合する。いくつかの態様では、表面安定剤は好ましくは、ナノ粒子アリピプラゾール粒子の表面に物理的に吸着するか、または表面に結合するが、アリピプラゾール粒子と、またはそれ自体では化学的に反応しない。他の態様では、個別に吸収された表面安定剤の分子は本質的に分子間の架橋結合を含まない。
本発明の組成物は、アリピプラゾールまたはその塩もしくは誘導体の粒子を含む。粒子は、結晶相、半結晶相、非晶質相、半非晶質相、またはこれらの組み合わせでありうる。
アリピプラゾールに対する表面安定剤の選択は重要であり、望ましい剤形を実現するためには、広範囲に及ぶ実験を必要とする。したがって本発明は、安定化されたナノ粒子アリピプラゾール組成物が作製可能であるという驚くべき発見に関する。
(i)R1〜R4がCH3ではなく;
(ii)R1〜R4の1つがCH3であり;
(iii)R1〜R4の3つがCH3であり;
(iv)R1〜R4の全てがCH3であり;
(v)R1〜R4の2つがCH3であり、R1〜R4の1つがC6H5CH2であり、かつR1〜R4の1つが炭素原子7個以下のアルキル鎖であり;
(vi)R1〜R4の2つがCH3であり、R1〜R4の1つがC6H5CH2であり、かつR1〜R4の1つが、炭素原子19個以上のアルキル鎖であり;
(vii)R1〜R4の2つがCH3であり、R1〜R4の1つが官能基C6H5(CH2)nであり(n>1);
(viii)R1〜R4の2つがCH3であり、R1〜R4の1つがC6H5CH2であり、かつR1〜R4の1つが少なくとも1個のヘテロ原子を含み;
(ix)R1〜R4の2つがCH3であり、R1〜R4の1つがC6H5CH2であり、かつR1〜R4の1つが少なくとも1個のハロゲンを含み;
(x)R1〜R4の2つがCH3であり、R1〜R4の1つがC6H5CH2であり、かつR1〜R4の1つが少なくとも1個の環状断片を含み;
(xi)R1〜R4の2つがCH3であり、かつR1〜R4の1つがフェニル環であり;または
(xii)R1〜R4の2つがCH3であり、かつR1〜R4の2つが純粋な脂肪族断片である。
**Mvは粘度-平均分子量であり、Mnは数値-平均分子量であり、Mwは重量-平均分子量である。MwおよびMnは光散乱法および超遠心法によって決定され、Mvは粘度測定によって決定された。
本発明の薬学的組成物は、1種類もしくは複数の結合剤、充填剤、潤滑剤、懸濁剤、甘味剤、香味剤、保存剤、緩衝剤、湿潤剤、崩壊剤、発泡剤、および他の賦形剤を含んでもよい。このような賦形剤は当技術分野で既知である。
本明細書に開示された組成物はナノ粒子アリピプラゾールを含み、ここで、アリピプラゾール粒子は、光散乱法、顕微鏡法、流動場沈降分画法、光子相関分光法、ディスク遠心法、または他の適切な方法で測定時に約2000 nm(すなわち2ミクロン)未満、約1900 nm未満、約1800 nm未満、約1700 nm未満、約1600 nm未満、約1500 nm未満、約1400 nm未満、約1300 nm未満、約1200 nm未満、約1100 nm未満、約1000 nm未満、約900 nm未満、約800 nm未満、約700 nm未満、約600 nm未満、約500 nm未満、約400 nm未満、約300 nm未満、約250 nm未満、約200 nm未満、約150 nm未満、約100 nm未満、約75 nm未満、または約50 nm未満の有効平均粒度を有しうる。
アリピプラゾールまたはその塩もしくは誘導体と、1種類もしくは複数の表面安定剤の相対量は変動しうる。個々の成分の最適量は例えば、選択されるアリピプラゾールの種類、親水親油バランス(HLB)、融点、および安定剤の水溶液の表面張力などに依存する可能性がある。
いくつかの態様では、注射用のナノ粒子アリピプラゾール製剤が提供される。以下の例は、ナノ粒子注射可能な製剤の範囲を、いかなる点でも制限する意図はなく、むしろ本明細書に記載されたようにかつ当技術分野で既知の方法によって利用可能な、例示的な製剤を提供する。いくつかの態様では、注射可能な製剤は、低注射容量で高濃度の薬物を含んでよい。さらに作用持続期間は、粒度を、ひいては溶解度を操作することで制御可能であり、結果的に長期間、例えば2日以上、5日以上、7日以上、10日以上、または14日以上、1か月以上、2か月以上、3か月以上、もしくは4か月以上にわたって有効な血中レベルが得られる。説明目的の非制限的な組成物を重量比(%w/w)で以下に示す:
アリピプラゾール 5〜50%
安定剤ポリマー 0.1〜50%
保存剤(任意選択) 0.05〜0.25%
pH調整剤 pHは約6〜約7
注射用水 適量
複数の例示的なアリピプラゾールの錠剤製剤を以下に示す。これらの例は、本発明の範囲をいかなる点においても制限する意図はなく、むしろ本明細書に記載された手順および当技術分野で既知の方法で利用可能な、アリピプラゾールの例示的な錠剤製剤を提供する。このような例示的な錠剤は、コーティング剤を含んでもよい。
本発明の別の局面は、ナノ粒子アリピプラゾール製剤の作製法を含む。ナノ粒子アリピプラゾールまたはその塩もしくは誘導体の組成物は例えば、ミル粉砕、均質化、沈殿、凍結、鋳型エマルジョン技術、または超臨界流体法で作製することができる。ナノ粒子組成物の例示的な作製法は、いずれも特異的に参照により組み入れられる、'684特許、「Method of Grinding Pharmaceutical Substances」と題する米国特許第5,518,187号;「Continuous Method of Grinding Pharmaceutical Substances」と題する米国特許第5,718,388号;「Method of Grinding Pharmaceutical Substances」と題する米国特許第5,862,999号;「Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers」と題する米国特許第5,665,331号;「Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers」と題する米国特許第5,662,883号;「Microprecipitation of Nanoparticulate Pharmaceutical Agents」と題する米国特許第5,560,932号;「Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles」と題する米国特許第5,543,133号;「Method of Preparing Stable Drug Nanoparticles」と題する米国特許第5,534,270号;「Process of Preparing Therapeutic Compositions Containing Nanoparticles」と題する米国特許第5,510,118号;「Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation」と題する米国特許第5,470,583号に記載されている。
アリピプラゾールまたはその塩もしくは誘導体をミル粉砕してナノ粒子分散剤を得る方法は、アリピプラゾール粒子を、アリピプラゾールの溶解度が低い液体分散媒中に分散させ、次に機械的な手段によって粉砕媒体の存在下で、アリピプラゾールの粒度を望ましい有効平均粒度に低減する段階を含む。分散媒は例えば、水、ベニバナ油、エタノール、t-ブタノール、グリセリン、ポリエチレングリコール(PEG)、ヘキサン、またはグリコールでありうる。いくつかの態様では、好ましい分散媒は水である。
望ましいナノ粒子アリピプラゾール組成物を作製する別の方法は、ミクロ沈殿法(microprecipitation)である。これは、溶解度の低い活性作用物質の安定な分散液を、任意の微量の毒性溶媒または可溶化した重金属不純物を含まない1種類もしくは複数の表面安定剤、および1種類もしくは複数のコロイド状の安定性促進性の表面活性作用物質の存在下で調製する方法である。このような方法は例えば、以下の段階を含む:(1)アリピプラゾールを適切な溶媒に溶解する段階;(2)段階(1)で得られた製剤を、少なくとも1種類の表面安定剤を含む溶液に添加する段階;および(3)段階(2)に由来する製剤を、適切な非溶媒を使用して沈殿させる段階。この方法には、形成された任意の塩(存在する場合)の透析またはダイアフィルトレーションによる除去、および従来の手段による分散液の濃縮を続けることができる。
活性作用物質のナノ粒子組成物を調製する例示的な均質化法は、「Process of Preparing Therapeutic Compositions Containing Nanoparticles」と題する米国特許第5,510,118号に記載されている。このような方法は、アリピプラゾールまたはその塩もしくは誘導体の粒子を液体分散媒中に分散させた後に、分散液を均質化して、アリピプラゾールの粒度を望ましい有効平均粒度に減ずる段階を含む。アリピプラゾール粒子は、少なくとも1種類の表面安定剤の存在下で粒度を減ずることが可能である。またはアリピプラゾール粒子は、1種類もしくは複数の表面安定剤に、摩擦の前または後のいずれかにおいて接触させることが可能である。希釈剤などの他の化合物を、アリピプラゾール/表面安定剤組成物に、粒度低下過程の前、最中、またはその後のいずれかの時点で添加することができる。分散液は連続的に、またはバッチモードで作製することができる。
望ましいナノ粒子アリピプラゾール組成物の別の作製法は、液体中への噴霧凍結(「SFL」)による。この手法では、安定剤を含む有機溶液または有機性水溶液のアリピプラゾールを、液体窒素などの低温液体中に注入する。アリピプラゾール溶液の液滴は、結晶化および粒子成長を最小化するために、ひいてはナノ構造を有するアリピプラゾール粒子を製剤化するのに十分な速度で凍結する。溶媒系および処理条件の選択によって、ナノ粒子アリピプラゾール粒子は、多様な粒子形態を取り得る。単離段階では、アリピプラゾール粒子の凝集または成長を避ける条件で、窒素および溶媒が除去される。
望ましいナノ粒子アリピプラゾールまたはその塩もしくは誘導体の組成物を作る別の方法は、鋳型エマルジョン技術による。鋳型エマルジョン技術では、粒度の分布が制御されかつ溶解挙動が迅速である、ナノ構造を有するアリピプラゾール粒子が作られる。この方法は、調製後にアリピプラゾールおよび安定剤を含む非水溶液によって膨潤される水中油型のエマルジョンを含む。アリピプラゾール粒子の粒度の分布は、制御可能で、かつ同過程で最適化可能な特性をアリピプラゾールに付与する前のエマルジョン液滴のサイズの直接的な結果である。さらに、溶媒および安定剤を選択的に使用することで、エマルジョンの安定性が、オストワルド成長なしに、またはオストワルド成長を抑えながら達成される。続いて溶媒および水が除去され、安定化されたナノ構造を有するアリピプラゾール粒子が回収される。さまざまなアリピプラゾール粒子の形状は、処理条件を適切に制御することで達成できる。
1997年4月24日に公開された、Pace et al.による、国際公開特許出願WO 97/144407では、化合物を溶液に溶解後に、適切な表面修飾剤の存在下で溶液を圧縮ガス、液体、または超臨界流体に吹き付けることで調製される、平均粒度が100 nm〜300 nmの、水に不溶性の生物学的に活性のある化合物の粒子について開示されている。
注射可能な組成物の開発には、無菌製品の製造が必要である。本発明の製造過程は、無菌懸濁液に関する典型的な既知の製造過程と似ている。典型的な無菌懸濁物の製造過程の流れ図を以下に示す:
本発明のさらに別の局面は、本明細書に記載された組成物を使用する方法を提供する。本発明の組成物は、統合失調症、双極性障害に伴う急性躁病エピソードおよび混合エピソード、ならびに他の統合失調症様疾患を含むがこれらに限定されない精神疾患や精神障害などのCNSの疾患および障害の治療に有用であると考えられている。したがって、いくつかの態様では、このような方法は、精神疾患や精神障害などの中枢神経系の障害についてヒトを含む哺乳類を治療する段階を含んでよく;このような治療は精神科療法を含みうる。いくつかの態様では治療は、ナノ粒子アリピプラゾール組成物を含む組成物を哺乳類に投与する段階を含みうる。
以下の実施例を、本発明を説明する目的で供する。しかしながら、本発明の趣旨および範囲は、これらの実施例に記載された特定の条件または詳細に制限されないと理解されたい。
この実施例の目的は、アリピプラゾールの適切なナノ粒子製剤を同定する手順を説明することにある。
Claims (30)
- (a) 約2000 nm未満の平均有効粒度を有するアリピプラゾールの粒子;および
(b) 少なくとも1種類の表面安定剤
を含む、安定なナノ粒子アリピプラゾールまたはその塩もしくは誘導体の組成物。 - アリピプラゾールが、結晶相、非晶質相、半結晶相、半非晶質相、およびこれらの混合物からなる群より選択される形状である、請求項1記載の組成物。
- アリピプラゾール粒子の有効平均粒度が、約1900 nm未満、約1800 nm未満、約1700 nm未満、約1600 nm未満、約1500 nm未満、約1400 nm未満、約1300 nm未満、約1200 nm未満、約1100 nm未満、約1000 nm未満、約900 nm未満、約800 nm未満、約700 nm未満、約600 nm未満、約500 nm未満、約400 nm未満、約300 nm未満、約250 nm未満、約200 nm未満、約100 nm未満、約75 nm未満、および約50 nm未満からなる群より選択される、請求項1記載の組成物。
- (a)非経口投与、経口投与、肺投与、静脈内投与、直腸投与、眼内(ophthalmic)投与、結腸投与、大槽内投与、膣内投与、腹腔内投与、眼(ocular)投与、耳投与、局所投与、舌下投与、鼻投与、生体接着剤投与、および局所投与からなる群より選択される投与のために;
(b)液体分散剤、ゲル、エアロゾル、軟膏、クリーム剤、凍結乾燥製剤、錠剤、カプセル剤からなる群より選択される投与剤形へと;
(c)制御放出製剤、即時溶解製剤、遅延放出製剤、徐放性製剤、パルス放出製剤、即時放出と制御放出の混合型製剤からなる群より選択される投与剤形へと;または
(d)(a)、(b)、および(c)の任意の組み合わせ
で製剤化される、請求項1記載の組成物。 - 1種類または複数の薬学的に許容される賦形剤、担体、またはこれらの組み合わせをさらに含む、請求項1記載の組成物。
- (a)アリピプラゾールの量が、他の賦形剤を含まないアリピプラゾールおよび少なくとも1種類の表面安定剤の全合計重量に基づき、重量比で約99.5%〜約0.001%、約95%〜約0.1%、および約90%〜約0.5%からなる群より選択され;
(b)少なくとも1種類の表面安定剤が、他の賦形剤を含まないアリピプラゾールおよび少なくとも1種類の表面安定剤の全合計乾燥重量に基づき、重量比で約0.5%〜約99.999%、重量比で約5.0%〜約99.9%、および重量比で約10%〜約99.5%からなる群より選択される量で存在し;または
(c)(a)および(b)の組み合わせ
である、請求項1記載の組成物。 - 少なくとも1種類の第1の表面安定剤、および少なくとも1種類の第2の表面安定剤をさらに含む、請求項1記載の組成物。
- 表面安定剤が、陰イオン性表面安定剤、陽イオン性表面安定剤、両性イオン性表面安定剤、非イオン性表面安定剤、およびイオン性表面安定剤からなる群より選択される、請求項1記載の組成物。
- 少なくとも1種類の表面安定剤が、塩化セチルピリジニウム、ゼラチン、カゼイン、ホスファチド、デキストラン、グリセロール、アラビアゴム、コレステロール、トラガカント、ステアリン酸、塩化ベンザルコニウム、ステアリン酸カルシウム、グリセロールモノステアレート、セトステアリルアルコール、セトマクロゴール乳化ワックス、ソルビタンエステル、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンヒマシ油誘導体、ポリオキシエチレンソルビタン脂肪酸エステル、ポリエチレングリコール、ドデシルトリメチルアンモニウムブロミド、ステアリン酸ポリオキシエチレン、コロイド状二酸化ケイ素、リン酸塩、ドデシル硫酸ナトリウム、カルボキシメチルセルロースカルシウム、ヒドロキシプロピルセルロース、ヒプロメロース、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシエチルセルロース、フタル酸ヒプロメロース、非結晶セルロース、ケイ酸マグネシウムアルミニウム、トリエタノールアミン、ポリビニルアルコール、ポリビニルピロリドン、酸化エチレンおよびホルムアルデヒドを含む4-(1,1,3,3-テトラメチルブチル)-フェノールポリマー、ポロキサマー;ポロキサミン、荷電性リン脂質、ジオクチルスルホコハク酸塩(スルホコハク酸ジオクチルナトリウム)、スルホコハク酸ナトリウムのジアルキルエステル、ラウリル硫酸ナトリウム、スルホン酸アルキルアリールポリエーテル、ステアリン酸ショ糖とジステアリン酸ショ糖の混合物、C18H37CH2C(O)N(CH3)-CH2(CHOH)4(CH2OH)2、p-イソノニルフェノキシポリ-(グリシドール)、デカノイル-N-メチルグルカミド;n-デシルβ-D-グルコピラノシド;n-デシルβ-D-マルトピラノシド;n-ドデシルβ-D-グルコピラノシド;n-ドデシルβ-D-マルトシド;ヘプタノイル-N-メチルグルカミド;n-ヘプチル-β-D-グルコピラノシド;n-ヘプチルβ-D-チオグルコシド;n-ヘキシルβ-D-グルコピラノシド;ノナノイル-N-メチルグルカミド;n-ノイルβ-D-グルコピラノシド;オクタノイル-N-メチルグルカミド;n-オクチル-β-D-グルコピラノシド;オクチルβ-D-チオグルコピラノシド;リゾチーム、PEG-リン脂質、PEG-コレステロール、PEG-コレステロール誘導体、PEG-ビタミンA、PEG-ビタミンE、リゾチーム、酢酸ビニルとビニルピロリドンのランダム共重合体、陽イオン性ポリマー、陽イオン性生体ポリマー、陽イオン性多糖、陽イオン性セルロース誘導体、陽イオン性アルギン酸塩、陽イオン性非ポリマー化合物、陽イオン性リン脂質、陽イオン性脂質、ポリメチルメタクリレートトリメチルアンモニウムブロミド、スルホニウム化合物、ジメチル硫酸ポリビニルピロリドン-2-ジメチルアミノエチルメタクリレート、ヘキサデシルトリメチルアンモニウムブロミド、ホスホニウム化合物、四級アンモニウム化合物、ベンジル-ジ(2-クロロエチル)エチルアンモニウムブロミド、ココナツトリメチルアンモニウムクロリド、ココナツトリメチルアンモニウムブロミド、ココナツメチルジヒドロキシエチルアンモニウムクロリド、ココナツメチルジヒドロキシエチルアンモニウムブロミド、デシルトリエチルアンモニウムクロリド、デシルジメチルヒドロキシエチルアンモニウムクロリド、デシルジメチルヒドロキシエチルアンモニウムクロリドブロミド、C12-15ジメチルヒドロキシエチルアンモニウムクロリド、C12-15ジメチルヒドロキシエチルアンモニウムクロリドブロミド、ココナツジメチルヒドロキシエチルアンモニウムクロリド、ココナツジメチルヒドロキシエチルアンモニウムブロミド、ミリスチルトリメチルアンモニウムメチルサルフェート、ラウリルジメチルベンジルアンモニウムクロリド、ラウリルジメチルベンジルアンモニウムブロミド、ラウリルジメチル(エテノキシ)4アンモニウムクロリド、ラウリルジメチル(エテノキシ)4アンモニウムブロミド、N-アルキル(C12-18)ジメチルベンジルアンモニウムクロリド、N-アルキル(C14-18)ジメチル-ベンジルアンモニウムクロリド、N-テトラデシルジメチルベンジルアンモニウムクロリド一水和物、ジメチルジデシルアンモニウムクロリド、N-アルキル(C12-14)ジメチル1-ナフチルメチルアンモニウムクロリド、トリメチルアンモニウムハライド、アルキル-トリメチルアンモニウム塩、ジアルキル-ジメチルアンモニウム塩、ラウリルトリメチルアンモニウムクロリド、エトキシル化アルキルアミノアルキルジアルキルアンモニウム塩、エトキシル化トリアルキルアンモニウム塩、ジアルキルベンゼンジアルキルアンモニウムクロリド、N-ジデシルジメチルアンモニウムクロリド、N-テトラデシルジメチルベンジルアンモニウムクロリド一水和物、N-アルキル(C12-14)ジメチル1-ナフチルメチルアンモニウムクロリド、ドデシルジメチルベンジルアンモニウムクロリド、ジアルキルベンゼンアルキルアンモニウムクロリド、ラウリルトリメチルアンモニウムクロリド、アルキルベンジルメチルアンモニウムクロリド、アルキルベンジルジメチルアンモニウムブロミド、C12トリメチルアンモニウムブロミド、C15トリメチルアンモニウムブロミド、C17トリメチルアンモニウムブロミド、ドデシルベンジルトリエチルアンモニウムクロリド、ポリ-ジアリルジメチルアンモニウムクロリド(DADMAC)、ジメチルアンモニウムクロリド、ハロゲン化アルキルジメチルアンモニウム、トリセチルメチルアンモニウムクロリド、デシルトリメチルアンモニウムブロミド、ドデシルトリエチルアンモニウムブロミド、テトラデシルトリメチルアンモニウムブロミド、メチルトリオクチルアンモニウムクロリド、POLYQUAT 10(商標)、テトラブチルアンモニウムブロミド、ベンジルトリメチルアンモニウムブロミド、コリンエステル、塩化ベンザルコニウム、塩化ステアラルコニウム化合物、臭化セチルピリジニウム、塩化セチルピリジニウム、四級化ポリオキシエチルアルキルアミンのハライド塩、MIRAPOL(商標)、ALKAQUAT(商標)、アルキルピリジニウム塩;アミン、アミン塩、アミンオキシド、イミドアゾリニウム塩、プロトン化四級アクリルアミド、メチル化四級ポリマー、ならびにカチオン化グアーからなる群より選択される、請求項1記載の組成物。
- 少なくとも1種類の表面安定剤が、ポビドン、ポビドンポリマー、Plasdone(登録商標)、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルピロリドンポリマー、高分子量ポリオキシアルキレンエーテル、Pluronic(商標)、ポリオキシエチレンソルビタン脂肪酸エステル、ポリエチレングリコールのリン脂質、ジオキシコール酸、ジオクチルスルホコハク酸、ラウリル硫酸ナトリウム、B20-5000(登録商標)およびスルホン酸化B20-5000などのトリブロック共重合体表面修飾剤、チロキサポール、ならびにレシチンからなる群より選択される、請求項1記載の組成物。
- 皮下注射または筋肉内注射用に製剤化される、請求項1記載の組成物。
- 注射後にデポ(depot)を形成するように製剤化される、請求項11記載の組成物。
- 組成物の薬物動態プロファイルが、該組成物を摂取する対象の摂食状態または絶食状態に有意に影響されない、請求項1記載の組成物。
- 絶食状態と比較して、摂食状態で投与された場合に、有意に異なる吸収レベルを生じない、請求項1記載の組成物。
- 絶食状態に対して絶食状態で投与された場合の、本発明の活性作用物質組成物の吸収の差が、約100%未満、約90%未満、約80%未満、約70%未満、約60%未満、約50%未満、約40%未満、約30%未満、約25%未満、約20%未満、約15%未満、約10%未満、約5%未満、および約3%未満からなる群より選択される、請求項14記載の組成物。
- 絶食状態の対象への組成物の投与が、摂食状態の対象への該組成物の投与と生物学的に同等である、請求項1記載の組成物。
- 「生物学的同等性」が、
(a)CmaxおよびAUCの両方に関する90%信頼区間が0.80〜1.25であること;または
(b)AUCに関する90%信頼区間が0.80〜1.25であり、およびCmaxに関する90%信頼区間が0.70〜1.43であること
によって確立される、請求項16記載の組成物。 - (a)投与後に哺乳類対象の血漿において分析したアリピプラゾールのTmaxが、同じ投与量で投与された同じアリピプラゾールの非ナノ粒子組成物のTmaxより小さい;
(b)投与後に哺乳類対象の血漿において分析したアリピプラゾールのCmaxが、同じ投与量で投与された同じアリピプラゾールの非ナノ粒子組成物のCmaxより大きい;
(c)投与後に哺乳類対象の血漿において分析したアリピプラゾールのAUCが、同じ投与量で投与された同じアリピプラゾールの非ナノ粒子組成物のAUCより大きい;または
(d)(a)、(b)、および(c)の任意の組み合わせ
である、請求項1記載の組成物。 - (a)Tmaxが、同じ投与量で投与された同じアリピプラゾールの非ナノ粒子組成物によって示されるTmaxの約90%以下、約80%以下、約70%以下、約60%以下、約50%以下、約30%以下、約25%以下、約20%以下、約15%以下、約10%以下、および約5%以下のTmaxからなる群より選択されるか;
(b)Cmaxが、同じ投与量で投与された同じアリピプラゾールの非ナノ粒子組成物によって示されるCmaxより少なくとも約50%、少なくとも約100%、少なくとも約200%、少なくとも約300%、少なくとも約400%、少なくとも約500%、少なくとも約600%、少なくとも約700%、少なくとも約800%、少なくとも約900%、少なくとも約1000%、少なくとも約1100%、少なくとも約1200%、少なくとも約1300%、少なくとも約1400%、少なくとも約1500%、少なくとも約1600%、少なくとも約1700%、少なくとも約1800%、または少なくとも約1900%大きいCmaxからなる群より選択されるか;
(c)AUCが、同じ投与量で投与された同じアリピプラゾールの非ナノ粒子製剤によって示されるAUCより少なくとも約25%、少なくとも約50%、少なくとも約75%、少なくとも約100%、少なくとも約125%、少なくとも約150%、少なくとも約175%、少なくとも約200%、少なくとも約225%、少なくとも約250%、少なくとも約275%、少なくとも約300%、少なくとも約350%、少なくとも約400%、少なくとも約450%、少なくとも約500%、少なくとも約550%、少なくとも約600%、少なくとも約750%、少なくとも約700%、少なくとも約750%、少なくとも約800%、少なくとも約850%、少なくとも約900%、少なくとも約950%、少なくとも約1000%、少なくとも約1050%、少なくとも約1100%、少なくとも約1150%、または少なくとも約1200%大きいAUCからなる群より選択されるか;または
(d)(a)、(b)、および(c)の任意の組み合わせ
である、請求項18記載の組成物。 - 精神疾患または精神障害の治療に有用な1種類もしくは複数の活性作用物質を追加的に含む、請求項1記載の組成物。
- 精神疾患または精神障害が、統合失調症様疾患、統合失調症、双極性障害、およびこれらの組み合わせからなる群より選択される、請求項20記載の組成物。
- 1種類もしくは複数の活性作用物質が、クロルプロマジン、フルフェナジン、ペルフェナジン、およびプロクロルペラジン、クロザピン、オランザピン、クエチアピン、ジプラシドン、ならびにこれらの組み合わせからなる群より選択される、請求項20記載の組成物。
- (a)哺乳類に投与された場合にアリピプラゾール粒子が、約2ミクロン未満、約1900 nm未満、約1800 nm未満、約1700 nm未満、約1600 nm未満、約1500 nm未満、約1400 nm未満、約1300 nm未満、約1200 nm未満、約1100 nm未満、約1000 nm未満、約900 nm未満、約800 nm未満、約700 nm未満、約600 nm未満、約500 nm未満、約400 nm未満、約300 nm未満、約250 nm未満、約200 nm未満、約150 nm未満、約100 nm未満、約75 nm未満、および約50 nm未満からなる群より選択される有効平均粒度を有するように再分散するか;
(b)アリピプラゾール粒子が約2ミクロン未満、約1900 nm未満、約1800 nm未満、約1700 nm未満、約1600 nm未満、約1500 nm未満、約1400 nm未満、約1300 nm未満、約1200 nm未満、約1100 nm未満、約1000 nm未満、約900 nm未満、約800 nm未満、約700 nm未満、約600 nm未満、約500 nm未満、約400 nm未満、約300 nm未満、約250 nm未満、約200 nm未満、約150 nm未満、約100 nm未満、約75 nm未満、および約50 nm未満からなる群より選択される有効平均粒度を有するように、組成物が生体関連媒体中に再分散するか;または
(c)(a)および(b)の組み合わせ
である、請求項1記載の組成物。 - アリピプラゾールの粒子に、少なくとも1種類の表面安定剤を、約2000 nm未満の有効平均粒度を有するナノ粒子アリピプラゾール組成物を提供するのに十分な時間および条件で接触させる段階を含む、ナノ粒子アリピプラゾールまたはその塩もしくは誘導体の組成物を調製する方法。
- 接触させる段階が、ミル粉砕、均質化、凍結、エマルジョン技術、超臨界流体粒子作成技術、沈殿、およびこれらの組み合わせからなる群より選択される方法を含む、請求項22記載の方法。
- (a)約2000 nm未満の平均有効粒度を有するアリピプラゾールまたはその塩もしくは誘導体の粒子;および
(b)少なくとも1種類の表面安定剤
を含む有効量の組成物を対象に投与する段階を含む、対象における統合失調症、双極性障害、統合失調症様疾患、および関連状態を治療する方法。 - 統合失調症、双極性障害、および関連状態の治療に有用な1種類もしくは複数の活性作用物質をさらに含む、請求項26記載の方法。
- 関連状態が、錐体外路症状、薬剤誘発性のパーキンソニズム、急性ジストニア反応、アカシジア、遅発性ジスキネジア、遅発性ジストニア、およびこれらの組み合わせからなる群より選択される、請求項27記載の方法。
- 皮下注射用または筋肉内注射用に製剤化される、請求項26記載の組成物。
- 組成物が経口錠剤の形状である、請求項26記載の方法。
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EP (2) | EP2279727A3 (ja) |
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- 2006-09-13 EP EP06814574A patent/EP1933814A2/en not_active Ceased
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JP2017524021A (ja) * | 2014-08-18 | 2017-08-24 | アルカーメス ファーマ アイルランド リミテッド | アリピプラゾールプロドラッグ組成物 |
Also Published As
Publication number | Publication date |
---|---|
WO2007035348A2 (en) | 2007-03-29 |
EP1933814A2 (en) | 2008-06-25 |
WO2007035348A3 (en) | 2007-05-31 |
CA2622758A1 (en) | 2007-03-29 |
EP2279727A2 (en) | 2011-02-02 |
US20070148100A1 (en) | 2007-06-28 |
JP2009508859A (ja) | 2009-03-05 |
EP2279727A3 (en) | 2011-10-05 |
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