JP6290974B2 - R−バクロフェンプロドラッグの持効性放出経口投与形 - Google Patents
R−バクロフェンプロドラッグの持効性放出経口投与形 Download PDFInfo
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- JP6290974B2 JP6290974B2 JP2016109969A JP2016109969A JP6290974B2 JP 6290974 B2 JP6290974 B2 JP 6290974B2 JP 2016109969 A JP2016109969 A JP 2016109969A JP 2016109969 A JP2016109969 A JP 2016109969A JP 6290974 B2 JP6290974 B2 JP 6290974B2
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- methyl
- chlorophenyl
- propoxy
- carbonylamino
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Description
“薬物副作用”とは、所望しない、不快な、有害で又は潜在的に有害である薬物効果を言及する。薬物副作用は、軽い、中位い又は重度であり得る。軽い薬物副作用の例は、消化不良、頭痛、疲労、はっきりしない筋痛、倦怠感及び睡眠パターンにおける変化を包含するが、但しそれらだけには限定されない。中位の薬物副作用は、それらを経験する個人が厄介で、苦しく又は耐え難く思われる反応、例えば皮疹、視力障害、筋肉の震え、排尿困難、ムード又は精神的機能における知覚可能な変化、及び血液組成における一定の変化を表す。重度の薬物副作用の例は、持続的又は有意な障害又は入院をもたらし、そして先天性異常を引起す、生命の脅威である反応を包含する。バクロフィン療法に関連することが知られている副作用の例は、鎮静、認識的な機能の減失、精神錯乱、記憶喪失、眩暈感、衰弱、失調症、ぼけるか又は複視、嘔気、息切れ、痙攣及び体位性低血圧を包含する。
“患者”とは、哺乳類、例えばヒトを包含する。
“医薬的に許容できる”とは、U.S.薬局方に列挙されるか、又は哺乳類、例えばヒトへの使用のために他の一般的に認識される薬局方に列挙される、連邦又は州政府の規制局により許可されるか又は許可できることを言及する。
化合物(1)は、R−バクロフェンのプロドラッグである。
もう1つの観点においては、本発明の開示は、(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸及び医薬的に許容できる賦形剤を含んで成る持効性経口投与形を供給する。化合物(1)は、Gallop et al., アメリカ特許第7,109,239号; Gallop et al., アメリカ特許第7,227,028号; Gallop et al., US 2009/0192325号; Raillard et al., 2009年8月7日に出願されたアメリカ特許出願番号12/537,798号;及び/又は Raillard et al., 2009年8月7日に出願されたアメリカ特許出願番号12/537,764号(それらの全内容物は引用により本明細書に組込まれる)により記載される方法を用いて調製され得る。
種々の観点においては、乾燥粉末ブレンドからの錠剤製造を促進するためには、組合された化合物(1)及び医薬的に許容される賦形剤から形成される乾燥粉末が許容できる流動性質を示すことが所望される。乾燥粉末の流れは、多くのパラメーター、例えば粒度、粒度分布、粒子形状、粒子粗さ、、嵩密度、多孔度、粉末を通しての空気透過性、静電荷、湿度、沈殿効果及び粘着力、例えばLondon分散力及び水素結合力により影響され得る。
ある態様においては、投与形に使用される微晶性セルロースは、約10mmへの約14mmのFlodexを示す。
ある態様においては、投与形に使用されるヒドロキシプロピルメチルセルロースは、約26mmへの約32mmのFlodexを示す。
ある態様においては、投与形に使用されるニ塩基性リン酸カルシウム二水和物は、約4mm以下のFlodexを示す。
ある態様においては、投与形に使用されるニ塩基性無水リン酸カルシウムは、約4mm以下のFlodexを示す。
種々の観点においては、本発明の開示により供給される持効性経口投与形は錠剤として供給され得る。本発明の開示により供給される配合物は一般的に、直接的な圧縮により経口錠剤投与形を形成することにおいて有用である。
化合物(1)を含んで成る、本発明の開示により供給される投与形の放出特徴は、インビトロ溶解プロフィールにより一部特徴づけられ得る。投与形の溶解プロフィールを決定するための方法は、医薬業界の人々に良く知られている。米国薬局方に示される標準方法論が使用され得る。例えば、溶解プロフィールは、米国薬局方タイプI装置(バスケット)又は米国薬局方タイプII装置(パドル)のいずれかにおいて測定され得る。
化合物(1)を含んで成る持効性投与形は、R−バクロフェン及び/又はラセミ体の等用量形で投与される場合、R−バクロフェンの経口生物学的利用能に比較してR−バクロフェンとしての増強された経口生物学的利用能を示す。化合物(1)の増強された経口生物学的利用能は、受動的及び/又は活性輸送機能を通して、結腸を包含する胃腸管じゅうでの化合物(1)の効果的吸収のためであると思われる。本発明の開示により供給される投与形は、胃腸管を通しての投与形の通過の間、投与形からの化合物(1)の放出を提供する。
R−バクロフェンの持続した全身性濃度を提供する錠剤投与形は、現在、1日当たり3度、投与される即時放出性非プロドラッグ形、すなわち患者のために不便であり、そして患者にとって覚えるのが困難であるレジメに比較して、患者のコンプライアンスを増強するであろうと思われる。さらに、本発明の開示により供給される経口投与形錠剤の使用は、低められた副作用、例えば傾眠状態、衰弱、頭痛、発作、嘔気、嘔吐、低血圧、便秘、精神錯乱、呼吸抑制、不眠、及び頻尿又は尿閉を伴って、増強された効能を提供するであろうと思われる。
本発明の開示により供給される持効性経口投与形は、親薬物、すなわちR−バクロフェンが治療的有効であることが知られているか、治療的に有効であると思われるか、又はこの後、治療的有効であることが決定される、いずれかの疾病又は障害を有する患者に投与され得る。R−バクロフェンが処方されており、そして本発明の開示により供給される投与形がまた、効果的である徴候は、痙攣、胃食道逆流病、麻薬中毒又は乱用、アルコール中毒症又は乱用、ニコチン中毒又は乱用、嘔吐、咳嗽、神経因性疼痛、筋骨格痛及び尿失禁を包含する。
R−バクロフェン治療の必要な患者に投与される化合物(1)の適切な用量は、等価質量のR−バクロフェン、及び化合物(1)により供給されるR−バクロフェンの増強された経口生物学的利用能に基づいて評価され得る。
痙攣は、延伸に対する無意識の速度−依存性の高められた耐性である。痙攣は、上昇する延伸速度による外部的に付加された運動に対して高められた耐性が存在する筋肉緊張過渡により特徴づけられる。痙攣は、誕生の前、間又は後、脳への酸素の欠乏(脳性麻痺);物理的な損傷(脳又は脊髄損傷);脳血管からの出血の遮断(脳卒中); 一定の代謝性疾患; アドレノロイコジストロフィ; フェニルケトン尿症; 神経変性疾病、例えばパーキンソン病及び筋萎縮性側索硬化症;及び神経障害、例えば多発性硬化症により引起され得る。
胃食道逆流病(GERD)は、食道において異常逆流により生成される慢性症状又は粘膜損傷として定義される。GERDの症状は、胸焼け、食道炎、狭窄症、えん下障害、慢性的な胸の疼痛、咳嗽、 しわがれ声、声の変化、慢性的な耳痛、燃えるような胸痛、嘔気、及び副鼻腔炎を包含する。
悪心、嘔吐及び吐き気は、毒素の吸収に対する基本的なヒトの保護反射及び一定の刺激に対する応答である。悪心は、蒼白又は潮紅、頻拍、及び嘔吐に対する心拍の意識に関連する咽頭又は上胃部の背部における主観的に不快な波状感覚である。発汗、過度の唾液分泌、及び寒さ又は暑さの感覚がまた生じることができる。嘔吐は、腹筋の吸縮、融膜の降下、及び胃噴門の開口により特徴づけられ、口から胃内容物の強力な排除がもたらされる。吐き気は、胃内容物の排除を伴わないで、融膜、及び胸部及び腹筋の筋肉の痙攣性収縮を包含する。嘔吐は、悪心、嘔吐、及び/又は吐き気を言及するために本明細書において使用される。
呼吸気管に位置する咳受容体の活性化により誘発される咳反射は、呼吸気管からの吸入された刺激物及び外来性物質を清浄し、そして粘膜繊毛システムに関連して、呼吸気管からの異常状態下で生成される過剰の気道分泌物を排除することができる。咳は、軽い急性の上部呼吸気管感染、アレルギー、喘息、慢性閉塞性肺疾患、肺癌、胃食道逆流病、後鼻腔滴下、及び心臓又は耳疾患により引起され得る。しかしながら、同定できる原因を有さない慢性非生産性咳は、咳をする患者の数%である。慢性咳は喘息性徴候の増悪、肋骨骨折、息苦しさ、破裂脳動脈瘤腹部筋肉、気胸症、失神、 第2及び第3程度の心臓ブロック、及び意識喪失に関連している。永続的で且つ制御できない咳は、羅病率を導き、そしてそれらの患者の生命の質を重度に障害を与える。
咳の処理における効能は、適切な動物モデル及び臨床試験を用いて評価され得る。
臨床試験においては、バクロフェンは、コケイン中毒(Brebner et al., Alcohol 2002, 37(5), 478-84; 及び Haney et al., Neuropsychopharmacology 2006, 31, 1814-21);メトアンフェタミン依存性(Heinzerling et al., Drug Alcohol Depend 2006, 85(3), 177-84);オピオイド依存性(Assadi et al., BMC Psychiatry 2003, November 18, 3(16); 及び Ahmadi-Abhari et al., J Clin Pharm Therapeutics 2001, 26(1), 67-71);アルコール欲求及び摂取(Addolorato et al., Alcohol 2002, 37(5), 504-8; 及びFlannery et al., Alcohol Clin Exp Res 2004, 28(10), 1517-23);ニコチン使用(Markou et al., Ann N.Y. Acad Sci 2004, 1025, 491-503);及び薬物乱用(Cousins et al., Drug Alcohol Dependence 2002, 65(3), 209-20)の処理において効果的であることが示されている。
神経因性疼痛は、通常、神経組織への直接的な外傷又は損傷の後に生じる感覚入力の異常工程を包含する。神経因性疼痛は、異なった病因学、例えば感染、炎症、 疾病、例えば糖尿病及び多発性硬化症、主要末梢神経に対する損傷又は圧縮、及び化学物質又は照射-誘発された神経損傷により特徴づけられる障害の集積である。新規因性疼痛は典型的には、組織損傷が解決された後、長く持続する。
圧痛及び筋肉痙攣を引き起こす筋骨格状態は、線維筋痛症、緊張型頭痛、筋筋膜疼痛症候群、咬合局面関節痛、 内部椎間板離開、体性機能不全、脊椎骨折、化膿性脊椎炎、リウマチ性多発筋痛、環軸関節の不安定性、環椎後頭関節疼痛、骨粗鬆症の脊椎骨の圧縮破壊、ショイエルマン病、 脊椎分離症、脊椎辷り症、棘突起間関節形成症、仙腸関節疼痛、仙椎の圧力骨折、尾骨痛、 衰えた逆症候群、 及び機械的腰痛又は頸痛を包含する(Meleger and Krivickas, Neurol Clin 2007, 25, 419-438)。
化合物(1)は、頸部、胸部及び/又は腰背骨領域における背痛を包含する背痛みの処理に使用される。背痛は急性又は慢性であり得る。急性背痛は、4週よりも少ない間、存在する低背痛みとして定義され、時々、3ヶ月よりも少ない間、存在する症状を伴って、亜急性背痛により分類される。慢性低背痛は、3ヶ月以上の間、存在する低背痛として定義される。
腰痛は一般的に、腰椎L1−L5の位置における背部のコシ領域において発生する。腰痛は、捻挫、緊張、 又は筋、腱、面関節、 及び/又は背部における仙腸関節の1つに対する痙攣; 背骨捻挫又は過剰圧縮; 又は脊椎板破壊又は湾曲部により引起され得る。腰痛はまた、神経又は筋肉刺激又は骨損傷に影響を及ぼすことができる。ほとんどの腰痛は背部への損傷又は外傷を従えるが、しかし疼痛はまた、変性状態、例えば関節炎又は脊椎板疾患、骨粗鬆症、又は他の骨疾患、ウイルス感染,関節及び脊椎板に対する刺激、又は背骨における先天性異常により引起され得る。
筋肉痙攣は、苦痛を伴う急性筋骨格状態に関連している。腰痛及び頸痛はそのような状態の共通する表れである。背部の急性筋骨格痙攣は、局在化された疼痛、硬直、低められた移動性、毎日の生活の活動消出、及び睡眠障害を引起す共通する障害である。急性腰痛又は頚痛のほとんどのエピソードは、非特異的である。ほとんどの対象は、腰痛及び頸痛、例えば有意な痙攣、癌、感染又は運動衰弱を示す基準を満たさない。非特異的な腰痛は、機械的背痛、個眼関節痛、変形性関節炎、筋捻挫及び筋痙攣として定義される。腰痛は、傍脊椎筋群における反射性痙攣により引起され得る。急性背痛は不本意であり、そしてしばしば、頸部、胸部及び/又は腰髄部を包含する背部の筋肉の苦痛を伴った収縮である。腰椎に関連する痙攣はまた、下背痙攣としても言及される。
線維筋痛は、身体じゅう、但し特に背骨を通して、筋肉、腱及び関節における痛み及び疼痛により特徴づけられる状態である。身体はまた、圧点又はトリガー点として言及される特定領域において接触しにくい。線維筋痛の他の症状は、睡眠妨害、鬱病、昼間の疲労、頭痛、下痢便秘交代症、手足の麻痺及び刺痛、脱力感、 記憶困難、及び眩暈感を包含する。線維筋痛の病因学は知られていないが、ストレス、乱れた睡眼パターン、神経系における疼痛関連の化学物質の異常生成、及び/又は低レベルの成長ホルモンが、線維筋痛の開始に寄与していると思われる。
尿失禁は、尿のいずれかの不本意な漏れであり、そして切迫性尿失禁、ストレス性失禁、奇異性尿失禁、機能的な失禁、及び混合汚泥失禁を包含する状態のパターンに基づいて5種のタイプに分類され得る(Abrams et al., Neurology and Urodynamics 2002, 21, 167-178)。
尿失禁はまた、夜尿症又は遺尿を包含する。
R−バクロフェンの持続した全身性濃度を提供する錠剤投与形は、現在、1日当たり3度、投与される即時放出性非プロドラッグ形、すなわち患者のために不便であり、そして患者にとって覚えるのが困難であるレジメに比較して、患者のコンプライアンスを増強するであろうと思われる。さらに、本発明の開示により供給される経口投与形錠剤の使用は、低められた副作用、例えば傾眠状態、衰弱、頭痛、発作、嘔気、嘔吐、低血圧、便秘、精神錯乱、呼吸抑制、不眠、及び頻尿又は尿閉を伴って、増強された効能を提供するであろうと思われる。
本発明の開示により供給される投与形はさらに、化合物(1)の他に、1又は複数の医薬的化合物を含んで成ることができる。そのような化合物は、化合物(1)により処理される疾病と同じ疾病又は異なった疾病を処理するために供給され得る。
神経因性疼痛の処理のための非薬理学的療法は、経皮的電気刺激、経皮の電気的神経刺激、及び刺鍼術を包含する。
化合物(1)ロット70を、次の方法を用いて結晶化した。機械撹拌機、テフロン(登録商標)被覆されたサーモカップル、還流冷却器及び窒素入口を備えた、5Lの三ツ首丸底フラスコに、化合物(1)(72g)、アセトン(186ml)及びヘキサン(672ml)を添加した。その混合物を、撹拌し(60%の速度)、そして50℃に1時間、加熱した。すべての材料は溶解した。追加のヘキサン(1081ml)を、50℃で温度を維持しながら、1時間にわたって添加した。その溶液を45℃に冷却し、そして45℃で5時間、維持し、この時点で固形物が形成した。溶液をさらに、40℃に12時間、次に35℃に12時間、冷却した。次に、その溶液を22〜25℃に2時間、冷却した。生成物を焼結ガラス漏斗を通しての濾過(早い)により集め、そしてアセトン(100ml)及びヘキサン(900ml)の溶液によりすすいだ。湿ったフィルターケークを真空オーブンに移し、そして40℃で12時間、乾燥し、白色固形物として結晶性化合物(1)(ロット70、70g、97%)を得た。
遅い結晶化(ロット70)、早い結晶化(ロット71)、及び中間速度の結晶化(ロット4)により調製された結晶性化合物(1)の種々の性質が表2に示されている。
乾燥粉末の流れを、FLODEX(商標) Powder Flowability Index Test Instrument (Hanson Research Corporation, Chatsworth, CA)を用いて特徴づけた。その器具は、流動試験の前、試験粉末を保持する円柱状の金属貯蔵物を備えた。その円柱状貯蔵物は、5.7cmの内径及び7.4mmの長さを有する。貯蔵物の底端は、取りはずせる金属ディスクにより密封され得る。個々のディスクは、そのディスクの中心に丸型開口部を有する。開口部の直径は、1mmの増分で4mm〜10mmの範囲であり、そして2mmの増分で10mm〜34mmの範囲である。流動試験の前、その開口部は閉じられる。
純粋化合物(1)及び種々の純粋錠剤化賦形剤の3種のロットについてのFlodexが表3に示される。純粋化合物(1)の3種のロットは化学的に同等であるが、しかし個々のロットの粒子サイズ及び形状により異なる(例1、図1及び2を参照のこと)。表3に示されるように、ロット4は最低のFlodexを示す。低いFlodexは丸型の粒子形状に寄与し、それは、もつれるロット70の特徴的な繊維状粒子塊状物、又は運動下で高い粒子間摩擦力を付与するロット71の特徴的な不規則形状の粒子よりも、より滑らかに流れる。それらの測定は、Flodexが、異なった形状学を有する粒子を含んで成る粉末の流動性質における差異を検出し、そして定量化するために十分に異なることを示す。
錠剤化賦形剤の2種の乾燥ブレンドを調製し、そして流動性質を決定した。ブレンドA08−011を、1インチ当たり20のワイヤを有する篩を通して、42.0 gの AVICEL(商標) PH200、43.4 g のMETHOCELTM K4M (SP)及び25.7 gのEUDRAGIT(商標) RLPOを容器中に連続的に通すことにより調製した。36gのDI−TAB(商標)及び1.5gのコロイド状二酸化珪素(CAB-O-SILTM M-5P, Cabot Corporation, Billerica, MA)を予備混合し、そして次に、同じスクリーンを通して容器中に通した。コロイド状二酸化珪素は、流動促進剤としてブレンドに含まれた。
賦形剤及び単一ロットの化合物(1)により配合された2種の乾燥粉末ブレンドを調製し、そして流動性質を決定した。30.0gの化合物(1)、69.0 g の AVICEL(商標) PH200、86.7 g のMETHOCELTM K4M SP、及び51.3 g のEUDRAGIT(商標) RLPOを、20メッシュの篩を通してボウル中に連続的に通した。57.0gのDI-TAB(商標)及び3.0gの二酸化珪素を予備混合し、そして同じ20メッシュの篩を通してボウル中に通した。得られるサイズ分けされた粉末を、2クオートのV−ブレンダにおいて5分間タンブル−ブレンドした。最終的に、40メッシュの篩を通して前もってサイズ分けされた、3.0gのステアリン酸マグネシウムを、前記混合された粉末に添加し、そして5分間タンブル混合した。得られるブレンドA08−020のFlodexは22mmであった。
異なったロットの化合物(1)によりそれぞれ配合された、3種の乾燥粉末ブレンドを調製し、そして得られるブレンドの流動性質を比較した。ブレンドを調製するために使用されるサイズ分け及び混合方法は、例5に記載されるのと同じであった。組成及び対応するFlodex数が表6に要約されている。ブレンドB08-019及びBO8-020はそれぞれ、21mm及び13mmのFlodex数を示した。化合物(1)の個々のロットについてのFlodex数に基づいて(表3)、化合物(1)ロット70により調製されたブレンドが、化合物(1)ロット71により調製されたブレンドのFlodexに相当するFlodexを示したことが予測される。しかしながら、ロット71により配合されたブレンドのFlodexは、ロット70により配合されたブレンドのFlodexよりも有意に良好であり;それぞれ13mm対21mmであった。
異なった品質のEUDRAGIT(商標)によりそれぞれ配合された2種の乾燥粉末ブレンドを調製した。16.5gのAVICEL(商標) PH200、32.9 g の METHOCELTM K4M DC、及び22.1 gのEUDRAGIT(商標) RLPOを、20メッシュの篩を通して通常の容器中に連続的に通した。16.5gのDI-TAB(商標)及び1.0gのコロイド状二酸化珪素を予備混合し、20メッシュの篩を通してサイズ分けし、そしてそのサイズ分けされた粉末に添加した。
例5及び6に記載されるブレンドを、1/4−インチの丸型標準量凸錠剤型押し及びダイスを用いて、100mgの重量の錠剤に圧縮した。個々のタイプの錠剤を、37℃の温度で、50mMの一塩基性リン酸ナトリウム(pH6.8)900mlにおけるUSA櫂装置(タイプII)における薬物の溶解性について試験した。櫂撹拌速度は75回転/分であった。溶解試験の間、錠剤は、個々の容器の底で錠剤を位置決定するためにステンレス鋼製カゴ内に含まれた。
錠剤バッチを、パイロット規模で製造し、ブレンド及び錠剤化操作において許容できる錠剤重量及び薬物含有率の維持の実行可能性を評価した。粉末ブレンドを、20メッシュのスクリーンを備えたRussell Finex 篩 (Russell Finex, Pineville, NC)を通して、順に1,140 g の AVICEL(商標) PH200、1,974 g のMETHOCELTM K4M DC、1,026 g のEUDRAGIT(商標) RLPO、1,140 gのDI-TAB(商標)、及び60gのコロイド状二酸化珪素を通すことにより調製した。
例9に記載されるブレンドの 3,600gを、3/8−インチの標準の丸型凹パンチ用具を備えたKilian T100 回転錠剤プレスのホッパーに移した。錠剤を、1分当たり180個の錠剤の速度で圧縮し、それらは錠剤当たり300mg(錠剤当たり30mgの化合物(1))の呼称重量を有する。錠剤のサンプルを約5分ごとに集め、そして錠剤の重量を測定した。10個の錠剤の平均重量を個々の時点で決定した。図8における錠剤重量ヒストグラムは、錠剤重量が300mgの標的重量の5%以内に維持されたことを示す。
10mgの化合物(1)を含んで成り、そして約175.1mgの重量の持効性放出錠剤を例9及び10に記載される方法に類似する方法を用いて調製した。SR4錠剤投与形の組成物は、表8に要約されている。
化合物(1)及びアンモニオアルキルメタクリレートポリマー、EUDRAGIT(商標) RL 30D, (SR3)を含んで成る持効性放出錠剤を、300gのバッチサイズで調製した。
温度及び湿度の種々の条件下での化合物(1)の開放皿化学安定性を、SR3-10及びSR4-10錠剤配合物について決定した。錠剤を、温度及び湿度に対して3ヶ月までの間、暴露し、そしてR−バクロフェンの量及びラクタム分解(R−(4−クロロ−フェニル)−ピロリジン−2−オン)を決定した。結果は表10に示される。SR4-10配合物は、3ヶ月での個々の貯蔵条件で一定した低いラクタムレベルにより示されるように、SR3-10配合物に比較して、卓越した化学安定性を示した。
健康な成人ボランティアにおける10mgのSR3及び10mg、20mg及び30mgのSR4錠剤配合物の定常状態薬物力学を比較する、ランダム化された、多重投与、4−処理、4−期間クロスオーバー研究を実施した。
処理B:朝食の完結後10分以内に1日1度(QD)、4日間、6×10mgの化合物(1)SR4-10錠剤;
処理C:朝食の完結後10分以内に1日1度(QD)、4日間、3×20mgの化合物(1)SR4-20錠剤;及び
処理D:朝食の完結後10分以内に1日1度(QD)、4日間、2×30mgの化合物(1)SR4-30錠剤。
個々の処理グループは、16人の健康な成人ボランティアを含んだ。
4種の処理の間、定常状態で決定される、血液中のR−バクロフェンについての平均薬物力学的パラメーターが表1に要約され、そして薬物力学的パラメーターが図11に示される。3種のSR4配合物についてのAUCss, 24値は、SR3配合物について約1500ng×時/mlのAUCss, 24に比較して、約1750ng×時/ml〜約1850ng×時/mlの範囲であった。
500gの粉末ブレンドを調製した。最初に、28.6gの化合物(1)中、ヘラにより20−メッシュ篩に通し、そして得られるサイズ分けされた薬物をそばに置いた。次に、105.7 g のAVICEL(商標) PH200、164.5 gのMETHOCELTM K4M 直接圧縮グレード(DC)、85.4 g のEUDRAGIT(商標) RLPO、 5.2 g の二酸化珪素グレード M5P、 及び105.7 g のDI-TAB(商標)としての二塩基性リン酸カルシウム・二水和物を、ヘラを用いて、20−メッシュ篩に連続的に通した。次に、サイズ分けされた賦形剤粉末を、2クォーツのツイン−シェルブレンダーに移し、そして25回転/分の回転速度で5分間タンブル混合した。
整構造の粉末ブレンドを調製した。最初に、33.0gのバクロフェンプロドラッグ化合物(1)、5.94gの二酸化珪素M5P、及び122.1gの DI-TAB(商標)を、ポリエチレンバッグに配置し、そして2分間タンブル混合した。次に、予備混合された粉末を、円錐状ミル(Quadro Comil Model U5, Quadro Engineering Corp., Waterloo, Ontario, Canada)に通した。その円錐上ミルは、457ミクロンの直径を有する丸型メッシュ開口部を有するスクリーンを固定され、そして3000rpmのインペラ速度で作動した。
次の工程を用いて、6kgの不統一粉末ブレンドを調製した。最初に、0.340kgの化合物(1)を、1インチ当たり20のワイヤのメッシュを有する篩を通してスクリーンした。次に、1.258 kg のAVICEL(商標)PH200、0.061 kgのコロイド状二酸化珪素、 1.958 kgのMETHOCELTM K4M (DC)、1.258 kgのDI-TAB(商標)、及び 1.017 kgのEUDRAGIT(商標)RLPOを、20メッシュ篩を備えたFinex電気シフター(Russell Finex Inc.)に通した。サイズ分けされた賦形剤を、1立方フィートのV−ブレンダー中に充填し、そして25rpmの回転速度で5分間タンブル混合した。得られる賦形剤ブレンドの半分を除いた。
次の工程を用いて、6kgの整構造粉末ブレンドを調製した。A−TAB(商標)の粒子を、次の方法を用いて、化合物(1)により被覆した。最初に、0.600kgのA−TAB(商標)を、8クオートのV−ブレンダーに充填した。次に、0.350kgの化合物(1)を、A-TAB(商標)上に積層した。0.695kgの追加のA-TAB(商標)を、化合物(1)上に1つの層として適用した。次に、3層組成物を、25rpmで4分間、ブレンダーによりタンブル混合した。得られる混合物を、813ミクロンの直径を有する丸形開口部を有するスクリーン、長方形のインペラー及び0.225インチのインペラースペーサーを備えたQuadro Comil Model 197円錐形ミルに通した。インペラーは、2000rpmの速度で回転した。混合物を、1分当たり約0.3kgの速度でミルにすくい取り、A−TAB(商標)により被覆された化合物(1)を生成した。
錠剤を、丸形標準凹形装置を備えたKorsch XL100錠剤プレスを用いて、10kN〜20kNの圧力で調製した。10mg、20mg、30mg及び40mgの化合物(1)を含むSR4錠剤の組成が表13に要約されている。SR4錠剤についての溶解プロフィールが表14に要約されている。
Claims (28)
- 約5mg〜約50mgの(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩;
投与剤の合計重量に基づいて;
約15重量%〜約40重量%の微晶性セルロース;
約15重量%〜約40重量%のヒドロキシプロピルメチルセルロース;
約3重量%〜約30重量%の放出速度−制御ポリマー;及び
二塩基性リン酸カルシウム二水和物又は二塩基性無水リン酸カルシウム;
を含んで成る経口錠剤投与剤。 - 投与剤の合計重量に基づいて;
約20重量%〜約35重量%のヒドロキシプロピルメチルセルロース;及び
約5重量%〜約20重量%の放出速度−制御ポリマーを含んで成る、請求項1記載の投与剤。 - 希釈剤、充填剤、滑剤及びそれらのいずれかの組合せから選択された1又は複数の賦形剤を含んで成る、請求項1又は2記載の投与剤。
- 前記(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸が遊離酸形で存在する、請求項1〜3のいずれか1項記載の投与剤。
- 前記遊離酸形で存在する(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸が結晶性である、請求項4記載の投与剤。
- 前記放出速度−制御ポリマーが、乾燥物質基準に基づいて約8.8%〜約12.0%のアンモニオメタクリレート単位を有するポリ(エチルアクリレート、メチルメタクリレート、トリメチルアンモニオエチルメタクリレートクロライド)コポリマーである、請求項1〜5のいずれか1項記載の投与剤。
- 前記放出速度−制御ポリマーが、乾燥物質基準に基づいて約4.4%〜約6.8%のアンモニオメタクリレート単位を有するポリ(エチルアクリレート、メチルメタクリレート、トリメチルアンモニオエチルメタクリレートクロライド)コポリマーである、請求項1〜5のいずれか1項記載の投与剤。
- 前記投与剤の合計重量が約100mg〜約600mgである、請求項1〜7のいずれか1項記載の投与剤。
- 前記経口投与剤からの(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩の放出が、75rpm(USP, Type II )で撹拌される、37℃での50mMのリン酸ナトリウム緩衝液(pH6.8)において、次の通りにインビトロ溶解プロフィールを示し:
約10%〜約30%の(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩が約4時間以内に放出され;
約15%〜約35%の(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩が約8時間以内に放出され;
約20%〜約50%の(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩が約12時間以内に放出され;そして
約30%〜約80%の(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩が約18時間以内に放出される、請求項1〜8のいずれか1項記載の投与剤。 - 前記経口投与剤からの(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩の放出が、75rpm(USP, Type II )で撹拌される、37℃での50mMのリン酸ナトリウム緩衝液(pH6.8)において、次の通りにインビトロ溶解プロフィールを示し:
約10%〜約20%の(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩が約4時間以内に放出され;
約20%〜約30%の(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩が約8時間以内に放出され;
約25%〜約45%の(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩が約12時間以内に放出され;そして
約35%〜約55%の(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩が約18時間以内に放出される、請求項1〜8のいずれか1項記載の投与剤。 - 約60mgの(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸の用量での16人の健康な成人患者への経口投与に続いて、約202±56ng/mlのCss, max;約3.9±1.0時間のTss, max;約19ng/mlのCss, 12;約10.9±3.8時間のTss, 1/2;及び1803±420ng・時/mlのAUCss, 24により特徴づけられる、前記患者の血液における(R)−3−アミノ−3−(4−クロロフェニル)ブタン酸の平均定常状態薬物力学プロフィールが提供される、請求項1〜10のいずれか1項記載の経口投与剤。
- 約60mgの(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸の用量での16人の健康な成人患者への経口投与に続いて、約8〜約15のCss, max/Css,12により特徴づけられる、前記患者の血液における(R)−3−アミノ−3−(4−クロロフェニル)ブタン酸の平均定常状態薬物力学プロフィールが提供される、請求項1〜11のいずれか1項記載の経口投与剤。
- USP(米国薬局方)1216に従って決定される場合、約0.5重量%以下の破砕性を有する、請求項1〜12のいずれか1項記載の経口投与剤。
- 約5mg〜約50mgの(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩;
約15重量%〜約40重量%の微晶性セルロース;
約15重量%〜約40重量%のヒドロキシプロピルメチルセルロース;
約3重量%〜約30重量%の放出速度−制御ポリマー;及び
二塩基性リン酸カルシウムに水和物又は二塩基性無水リン酸カルシウム(ここで前記重量%は投与形の合計重量に基づく)、を含んで成る配合物を乾式ブレンドし、そして
前記ブレンドされた配合物を圧縮し、経口錠剤投与剤を供給することを含んで成る、経口錠剤投与剤の調製方法。 - 前記(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩の乾燥粉末が、約20μm〜約60μmの直径を有する丸型凝集体により特徴づけられる、請求項14記載の方法。
- 前記ブレンドされた配合物が、約22mm以下のFlodexを示す、請求項14又は15記載の方法。
- 前記(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸が遊離酸形で存在する、請求項14〜16のいずれか1項記載の方法。
- リン酸二カルシウム及び(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸又は医薬的に許容できるその塩をブレンドし、第1ブレンドを供給し;
前記第1ブレンドを円錐型ミルに通し;
ヒドロキシプロピルメチルセルロース及びコロイド状二酸化珪素を乾燥ブレンドし、第2ブレンドを形成し;
前記第2ブレンドを円錐形ミルに通し;
前記第1ブレンド、前記第2ブレンド、微晶性セルロース、及び放出速度−制御ポリマーを、高剪断ブレンダーにおいてブレンドし、第3ブレンドを形成し;
前記第3ブレンドと共にステアリン酸マグネシウムをブレンドし;そして
前記第3ブレンドを圧縮し、経口錠剤投与形を供給することを含んで成る、経口錠剤投与剤の調製方法。 - 前記(3R)−4−{[(1S)−2−メチル−1−(2−メチルプロパノイルオキシ)プロポキシ]カルボニルアミノ}−3−(4−クロロフェニル)ブタン酸が遊離酸形及び結晶形で存在する、請求項18記載の方法。
- 痙攣、胃食道逆流病、嘔吐、咳嗽、麻薬中毒又は乱用、アルコール中毒症又は乱用、ニコチン中毒又は乱用、神経因性疼痛、筋骨格痛及び尿失禁から選択された、患者における疾病の処理のための、請求項1〜13のいずれか1項記載の経口投与剤。
- 前記疾病が痙攣である、請求項20記載の経口投与剤。
- 前記疾病が胃食道逆流病である、請求項20記載の経口投与剤。
- 前記疾病が神経因性疼痛であり、そして前記神経因性疼痛が帯状疱疹後神経痛、末梢ニューロパシー、三叉神経痛、苦痛性糖尿病性神経障害、HIV関連の神経因性疼痛、癌関連の疼痛及び線維筋痛症から選択される、請求項20記載の経口投与剤。
- 前記疾病が尿失禁である、請求項20記載の経口投与剤。
- 前記放出速度−制御ポリマーが、エチルアクリレート、メチルメタクリレート、及び第四アンモニウム基を有する低含有率のメタクリル酸エステルのコポリマーである、請求項1〜13及び20〜24のいずれか1項記載の経口投与剤。
- 0.1重量%〜2重量%のコロイド状二酸化ケイ素;及び
0.1重量%〜2重量%のステアリン酸マグネシウム;
を含んで成る、請求項1〜13及び20〜25のいずれか1項記載の経口投与剤。 - 前記放出速度−制御ポリマーが、エチルアクリレート、メチルメタクリレート、及び第四アンモニウム基を有する低含有率のメタクリル酸エステルのコポリマーである、請求項14〜19のいずれか1項記載の方法。
- 前記投与剤が、
0.1重量%〜2重量%のコロイド状二酸化ケイ素;及び
0.1重量%〜2重量%のステアリン酸マグネシウム;
を含んで成る、請求項14〜19のいずれか1項記載の方法。
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IL214628A0 (en) | 2011-09-27 |
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AU2010221270A1 (en) | 2011-09-08 |
WO2010102071A1 (en) | 2010-09-10 |
CN102341099A (zh) | 2012-02-01 |
WO2010102071A8 (en) | 2011-04-21 |
NZ594648A (en) | 2013-12-20 |
EP2403486A1 (en) | 2012-01-11 |
CA2753057A1 (en) | 2010-09-10 |
JP2012519212A (ja) | 2012-08-23 |
US20100255093A1 (en) | 2010-10-07 |
IL214628A (en) | 2016-08-31 |
JP2015108014A (ja) | 2015-06-11 |
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