JP2012522791A - 組成物及びその使用 - Google Patents
組成物及びその使用 Download PDFInfo
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- JP2012522791A JP2012522791A JP2012503676A JP2012503676A JP2012522791A JP 2012522791 A JP2012522791 A JP 2012522791A JP 2012503676 A JP2012503676 A JP 2012503676A JP 2012503676 A JP2012503676 A JP 2012503676A JP 2012522791 A JP2012522791 A JP 2012522791A
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Abstract
【選択図】図1
Description
追加の側面及び態様は、以下の詳細な記載及び請求の範囲から明らかになるだろう。
側面及び態様によっては、化合物Iを含む固体分散体及び固体分子複合体を提供する。たとえば、化合物Iは、アモルファス形態で固定化されるように、その固体状態でポリマーによって形成されたマトリックス内に分散させることができる。態様によっては、化合物Iの二つ以上の薬剤分子間の分子間水素結合または弱い分散力を妨げるかもしれない。たとえばMatsumoro及びZografi、Pharmaceutical Research,第16巻、第11号、1722〜1728頁、1999年を参照されたい。特定の態様では、固体分散体は大きな表面積を提供するので、化合物Iの溶解及び生体利用効率を高めることができる。特定の態様では、固体分散体または固体分子複合体は化合物Iの治療的有効量を含む。
本明細書で開示の固体分子複合体及び前記固体分子複合体を含む組成物の製造法も提供する。本方法において、化合物Iは本明細書に開示のポリマー(たとえばHPMC−AS)で微小析出(microprecipitate)させることができる。微小析出は、当業界で公知の任意の手段、たとえば噴霧乾燥または凍結乾燥;溶媒制御沈殿形成;pH−制御沈殿形成;ホットメルト押出;及び超臨界流体技術により実施することができる。これらの方法はそれぞれ、以下に詳細を記載する。
化合物I及びポリマー(たとえばHPMC−AS)は、低沸点の一般的な溶媒、たとえばエタノール、メタノール、アセトンなどに溶かすことができる。噴霧乾燥または凍結乾燥により、溶媒は、その沸点に近い温度または高真空(低い蒸気圧)下でフラッシュ蒸発させて、ポリマーによって形成したマトリックス中に化合物Iを沈殿させたままにする。特定の態様において、化合物Iはメシル酸塩またはトシル酸塩の形態であるので、優れた溶解性をもつので好ましい。
化合物I及びポリマー(たとえばHPMC−AS)は、一般的な溶媒、たとえばジメチルアセトアミド、ジメチルホルムアミド、ジメチルスルホキシド(DMSO)、N−メチルピロリドン(NMP)などの中に溶かすことができる。化合物I/ポリマー溶液を冷水(0〜7℃、好ましくは2〜5℃)に添加して好適なpH(たとえば、多くの態様では好適なpHは3以下である)に調整する。これにより化合物Iは、ポリマー(たとえばHPMC−AS)により形成したマトリックス中に微小沈殿することとなる。微小沈殿物は、残存溶媒がその溶媒に関して許容可能な限界未満になるまで、水性媒体で数回洗浄することができる。それぞれの溶媒に関して「許容可能な限界」とは、ハーモナイゼーション国際会議(International Conference on Harmonization:ICH)ガイドラインに準じて決定する。
(a)化合物I及びHPMCASを同一有機溶媒に溶解させて、単一有機相とする;
(b)(a)で得られた前記有機相を、混合チャンバ内にある水性相に連続して加える、前記混合チャンバには高剪断混合装置と二つの追加の開口部が備えられており、この開口部は前記混合チャンバを閉鎖ループに接続し、ここで前記水性相が循環されて、前記混合チャンバを通過する;
(c)(b)で得られた水性相から、化合物I及びHPMCASのアモルファス形態からなる混合物を沈殿させる、同時に高剪断ミキサーを操作し、前記水性相を閉鎖ループ内の混合チャンバを通過させて、前記沈殿物の水性懸濁液を形成させる;
(d)(a)で製造した前記有機溶液を前記水性相に完全に添加した後、所定の粒径及び/または粒径分布が得られるまで、前記高剪断混合装置を操作しながら前記混合チャンバ内に前記水性懸濁液を連続循環させる;
(e)前記懸濁液から前記固相を単離する;
(f)単離した固相を水洗する;及び
(g)前記固相を砕塊及び乾燥させる;
の各段階を含む。
上記段階(a)における有機相はDMA中の化合物I及びHPMCASの35%溶液であり、化合物I対HPMCASの比は30%(w/w)〜70%(w/w)である;及び
段階(b)における連続添加は、前記高剪断ミキサーの縦軸に対して40〜50°の角度に向けられ且つ、約15〜約25m/秒の先端(tip)速度で操作している前記高剪断ミキサーの回転子から約1〜約10mmの距離があるインジェクタ・ノズルを介して操作される、各段階を含む。
上記段階(b)における連続添加は、前記高剪断ミキサーの縦軸に対して45°の角度に向けられ且つ、約25m/秒の先端速度で操作している前記高剪断ミキサーの回転子から約2〜約4mmの距離があるインジェクタ・ノズルを介して実施される、段階を含む。
他の具体的な態様では、本方法は、
上記段階(g)における乾燥は、流動床乾燥により実施される、段階を含む。
さらなる態様において、上記方法により得られた固体分散体を提供する。
従って、このようにして得られた医薬製剤は本明細書に提供されたさらなる態様を形成する。
本プロセスは、イオン性ポリマー(たとえば、HPMC−AS)中に化合物Iを微小析出させることを含む。本プロセスにおいて、化合物I及びポリマーは、高pHで溶解させて、溶液のpHを低下させることにより、または低pHで溶解させて、溶液のpHを上昇させることによって沈殿形成させる。
ポリマー(たとえばHPMC−AS)中の化合物Iの微小析出化は、ホットメルト押出しプロセス(hot melt extrusion process)により特定の態様において実施することができる。化合物Iとポリマーとを混合し、次いで同時に温度制御した押出し機に供給して、化合物Iを溶融ポリマー中に分子的に分散させる。得られた押出物を室温に冷却し、粉砕して微粉末とする。
本プロセスにおいて、化合物I及びポリマー(たとえばHPMC−AS)を液体窒素または液体二酸化炭素などの超臨界流体中に溶かす。次いで超臨界流体は蒸発により除去して、ポリマーにより形成したマトリックス中に化合物Iを微小析出させたままにする。別の方法では、化合物I及びポリマー(たとえばHPMC−AS)を好適な溶媒に溶かす。次いで微小析出粉末は、逆溶媒(antisolvent)として作用する超臨界流体中にこの溶液を噴霧することにより形成することができる。
化合物Iがアモルファス形態にうまく固定化されているかどうかは、粉末X−線回折などの種々の手段により測定できる。さらに、複合体のガラス転移温度は変調DSCにより測定でき、これは分散体が多相または単一相(uniphase)であるかの情報も提供することができる。単一相は、そのような固定化の指標である。
(A)結晶多形1
プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド(化合物I)の結晶多形を提供する。一態様において、多形が約4.7、9.4、11.0、12.5及び15.4度2θ(degree 2θ)の特徴的なピーク位置をもつ粉末x−線回折パターンを示す、結晶多形1を提供する。一態様において、多形1は、約4.7、9.4、10.0、11.0、12.5、14.2、15.4、18.6及び22.2度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す。一態様において、結晶多形1は、約4.7、9.4、10.0、11.0、12.5、14.2、15.4、16.1、18.6、19.0、22.2及び26.8度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す。一態様において、結晶多形1は、図1の粉末x−線回折パターンと実質的に同じ粉末x−線回折パターンを示す。一態様において、精製結晶多形1を提供する。一態様において、精製結晶多形1は、プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミドのメシル酸塩(mesylate salt)またはトシル酸塩(tosylate salt)形態の製造で使用する。一態様において、結晶多形1及び少なくとも一種の賦形剤またはキャリヤを含む医薬組成物を提供する。
約8.8、9.2、13.5、19.1及び24.4度2θ(degree 2θ)の特徴的なピーク位置をもつ粉末x−線回折パターンを示す、プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミドの結晶多形2を提供する。一態様において、結晶多形2は、約6.7、8.8、9.2、13.5、15.0、17.7、19.1、19.7、21.4及び24.4度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す。一態様において、結晶多形2は、約6.7、8.8、9.2、13.5、14.1、14.5、15.0、16.2、17.0、17.7、19.1、19.7、21.4、22.2、24.1、24.4及び28.1度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す。一態様において、結晶多形2は、図2の粉末x−線回折パターンと実質的に同じ粉末x−線回折パターンを示す。一態様において、精製結晶多形2を提供する。一態様において、精製結晶多形2は、プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミドのメシル酸塩またはトシル酸塩形態の製造で使用する。一態様において、結晶多形2及び少なくとも一種の賦形剤またはキャリヤを含む医薬組成物を提供する。
プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミドのメシル酸塩形態を提供する。一態様において、プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミドのメシル酸塩形態を提供する。一態様において前記メシル酸形態は実質的に結晶質である。一態様において、前記メシル酸塩形態は部分的にアモルファスである。一態様において、前記メシル酸塩形態は実質的にアモルファスである。一態様において、前記メシル酸塩形態は、前記塩をアモルファス形態に調製(formulate)するために微小析出させたバルクプロセス(bulk process)で使用する。一態様において、前記メシル酸塩は、アモルファス形態の塩を調製するために微小析出させたバルクプロセスでin situで生成する。一態様において、前記メシル酸塩を含む組成物を提供する。
プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミドのトシル酸塩形態を提供する。一態様において、前記トシル酸塩形態は実質的に結晶質である。一態様において、前記トシル酸塩形態は部分的にアモルファスである。一態様において、前記トシル酸塩形態は実質的にアモルファスである。一態様において、前記トシル酸塩形態は、前記塩をアモルファス形態に調製するために微小析出させたバルクプロセスで使用する。一態様において、前記トシル酸塩は、アモルファス形態の塩を調製するために微小析出させたバルクプロセスでin situで生成する。一態様において、前記トシル酸塩を含む組成物を提供する。
蛋白質キナーゼは、生化学的シグナルを様々な生物学的経路に伝播する上で重要な役割を果たす。500を超えるキナーゼが記載されており,特定のキナーゼは、これらに限定されないが、癌、心臓血管疾患、炎症性疾患、神経学的疾患及び他の疾病などの広範な種類の疾病または症状(すなわち適応症:indication)に関与していた。それゆえ、キナーゼは小さな分子による治療介入のための重要な制御点である。本発明により企図される特定の標的蛋白質キナーゼについて以下に説明する。
標的キナーゼA−Raf(すなわち、v−rafマウス肉腫3611ウイルス癌遺伝子ホモログ1)は、染色体Xp11.4−p11.2(記号:ARAF)によりコードされる67.6kDaのセリン/スレオニンキナーゼである。成熟タンパク質は、RBD(すなわち、Ras結合ドメイン)及びホルボール−エステル/DAG型亜鉛フィンガードメインを含み、細胞膜から核への細胞分裂シグナル伝達に関与する。A−Raf阻害剤は、多発脳梗塞性認知症、頭部外傷、脊椎損傷、アルツハイマー病(AD)、パーキンソン病などの神経疾患;悪性黒色腫、神経膠腫、肉腫、癌腫(たとえば、結腸直腸、肺、乳房、膵臓、甲状腺、腎臓、卵巣)、リンパ腫(たとえば、組織球性リンパ腫)、神経線維腫症、骨髄異形成症候群、白血病、腫瘍血管形成を含むが、これらに限定されない腫瘍形成疾患;急性疼痛、慢性疼痛、癌関連の疼痛及び偏頭痛を含むが、これらに限定されない神経障害性または炎症性由来の疼痛;血管再狭窄、筋肉減弱症、筋ジストロフィー(デュシェーヌ、ベッカー、エメリー・ドレイフェス、肢帯型筋ジストロフィー、顔面肩甲上腕型筋ジストロフィー、筋緊張性、眼球咽頭性、遠位及び先天性の筋ジストロフィーを含むが、これらに限定されない)、運動ニューロン疾患(筋萎縮性側索硬化症、乳児進行性脊髄筋萎縮症、中間性脊髄筋萎縮症、小児脊髄筋萎縮症、球脊髄性筋萎縮症及び成人脊髄性筋萎縮症を含むが、これらに限定されない)、炎症性筋疾患(皮膚筋炎、多発性筋炎及び封入対筋炎を含むが、これらに限定されない)、神経筋接合部の疾患(重症筋無力症、ランバート・イートン症候群及び先天性筋無力症候群を含むが、これらに限定されない)、内分泌異常によるミオパシー(甲状腺機能亢進ミオパシー及び甲状腺機能低下性ミオパシーを含むが、これらに限定されない)、末梢神経の疾患(シャルコー・マリー・トゥース(Charcot−Marie−Tooth)病、デジェリン・ソッタス(Dejerine−Sottas)病及びフリードライヒ失調症(Friedreich’s ataxia)を含むが、これらに限定されない)、そのほかのミオパシー(先天性ミオトニー、先天性パラミオトニー、セントラルコア病、ネマリン・ミオパシー、管状筋細胞ミオパシー及び周期性四肢麻痺を含むが、これらに限定されない)、及び筋肉の代謝性疾患(ホスホリラーゼ欠損症、酸性マルターゼ欠損症、ホスホフルクトキナーゼ欠損症、脱分枝酵素欠損症、ミトコンドリア性筋障害、カルニチン欠損症、カルニチンパルマチル転移酵素欠損症、ホスホグリセレートキナーゼ欠損症、ホスホグリセレートムターゼ欠損症、乳酸脱水素酵素欠損症及びミオアデニレートデアミナーゼ欠損症を含むが、これらに限定されない)の疾患を治療するのに有用でありえる。
標的キナーゼB−Raf(すなわち、v−rafマウス肉腫ウイルス癌遺伝子ホモログB1)は、染色体7q34(記号:BRAF)によりコードされる84.4kDaのセリン/スレオニンキナーゼである。成熟タンパク質は、RBD(すなわち、Ras結合ドメイン)、C1(すなわち、タンパク質キナーゼC保存領域1)及びSTK(すなわち、セリン/スレオニンキナーゼ)ドメインを含む。
標的キナーゼc−Raf−1(すなわち、v−rafマウス肉腫ウイルス癌遺伝子ホモログ1)は、染色体3p25(記号:RAF1)によりコードされる73.0kDaのSTKである。c−Raf−1は、アポトーシス細胞死の調節因子であるBCL2(すなわち、癌遺伝子B細胞白血病2)によってミトコンドリアを標的とすることができる。活性c−Raf−1は、BCL2が介在するアポトーシスへの耐性を改善し、c−Raf−1はBAD(すなわち、BCL2結合タンパク質)をリン酸化する。c−Raf−1は、結腸直腸癌、卵巣癌、肺癌及び腎細胞癌などの癌に関与する。c−Raf−1はまた、腫瘍の血管形成の重要な媒介物(mediator)として関与する(Hood,J.D.ら、2002年,Science 296巻,2404頁)。c−Raf−1阻害剤は、急性骨髄性白血病及び骨髄異形成症候群の治療にも有用でありえる(Crump,Curr.Pharm.Des 2002年,8(25)巻:2243−8頁)。Raf−1活性化剤は、神経内分泌腫瘍、たとえば甲状腺髄様癌、カルチノイド、小細胞肺癌及び褐色細胞腫の治療として有用でありえる(Kunnimalaiyaanら、Anticancer Drugs 2006年,17(2)巻:139−42頁)。
本明細書で企図されるプロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミドは、具体的な化合物を参照して記載する。さらに、化合物Iは、多くの種々の形態または誘導体で存在し、そのすべてが本発明の範囲内である。代替の形態または誘導体としては、たとえば、(a)プロドラッグ及び活性代謝産物、(b)互変異性体、(c)薬学的に許容可能な塩並びに、(d)その水和物、溶媒和物及びその他の形態を含む、種々の結晶形態、多形またはアモルファス固体を含む固形形態が挙げられる。
プロドラッグは、生理的条件下で代謝された場合、または加溶媒分解(solvolysis)によって変換された場合に、所望の活性化合物を生成する化合物または薬学的に許容可能なその塩である。プロドラッグとしては、活性化合物のエステル、アミド、カルバメート、カーボネート、ウレイド、溶媒和物または水和物が挙げられるが、これらに限定されない。通常、プロドラッグは不活性であるか、または活性化合物よりも活性が低いが、一つ以上の好都合な取り扱い、投与及び/または代謝特性を提供することができる。たとえばプロドラッグは、化合物の−NH基、たとえば化合物I若しくはその薬学的に許容可能な塩のスルホンアミド基の窒素またはピロロ[2,3−b]ピリジン環の1−位置がアシル化を受けた変異体を含むことができ、ここでアシル基の切断により活性薬剤の遊離−NH基が提供される。プロドラッグの中には、酵素的に活性化されて当該活性化合物を得るか、またはさらに化学反応を受けて活性化合物が得られるものがある。プロドラッグは、単一段階でプロドラッグ形から活性形に進行させることができ、またはそれ自体活性であっても不活性であってもよい一つ以上の中間形を有することができる。
酸化反応としては、たとえばアルコール、カルボニル及び酸官能基の酸化、脂肪族炭素のヒドロキシル化、脂環式炭素原子のヒドロキシル化、芳香族炭素原子の酸化、炭素−炭素二重結合の酸化、窒素含有官能基の酸化、ケイ素、リン、ヒ素及び硫黄の酸化、酸化的N−脱アルキル化、酸化的O−及びS−脱アルキル化、酸化的脱アミノ化、並びにその他の酸化反応などの反応が例示されるが、これらに限定されない。
還元反応としては、たとえばカルボニル官能基の還元、アルコール官能基及び炭素−炭素二重結合の還元、窒素含有官能基の還元及びその他の還元反応などの反応が例示されるが、これらに限定されない。
酸化状態で変化のない反応としては、エステル及びエーテルの加水分解、炭素−窒素単結合の加水分解的切断、非芳香族複素環の加水分解的切断、複数の結合での水和及び脱水、脱水反応から生じる新しい原子の結合、加水分解的脱ハロゲン化、ハロゲン化水素分子の除去並びに他のそのような反応などの反応が例示されるが、これらに限定されない。
化合物によっては互変異性を示し得ることが理解される。そのような場合、本明細書で提供される式は、可能性のある互変異性体形のたった一つを明示的に描くにすぎない。従って、本明細書で提供される化合物Iは描かれた化合物の任意の互変異性体形を示すことを意図し、化合物の式の記述によって描かれる特定の互変異性体形のみに限定されるものではない。
これとは反対に規定されない限り、本明細書における化合物Iの明細には、そのような化合物の薬学的に許容可能な塩が含まれる。従って、化合物Iは、薬学的に許容可能な塩の形であることができるか、または薬学的に許容可能な塩として配合することができる。企図された薬学的に許容可能な塩の形には、モノ、ビス、トリス、テトラキスなどが挙げられるが、これらに限定されない。薬学的に許容可能な塩は、それらが投与される量及び濃度においては非毒性である。そのような塩の調製は、その生理的効果の発揮を妨げることなく化合物の物理的特性を変えることによって薬理学的使用を促進できる。物理学的特性の有用な変更としては、経粘膜投与しやすくするために融点を低下させること及び、高い薬剤濃度を投与しやすくするために溶解度を高めることが挙げられる。化合物Iは、十分に酸性の官能基及び十分に塩基性の官能基をもつので、多くの無機または有機塩基及び無機または有機酸と反応して薬学的に許容可能な塩を形成できる。
固体である薬剤の場合、化合物及び塩は、様々な結晶若しくは多形の形態で存在してもよく、または共結晶として製剤化してもよく、またはアモルファス形態であってもよく、またはそれらの任意の組み合わせ(たとえば、部分的に結晶質、部分的にアモルファス、若しくは多形の混合物)であってもよく、その全てが本発明及び特定の式の範囲内であると意図されることは当業者によって理解される。塩は酸/塩基の添加によって形成される、すなわち、対象化合物の遊離塩基または遊離酸がそれぞれ対応する付加塩基または付加酸と酸/塩基反応を形成して、イオン性荷電相互作用を生じるが、共結晶は中性化合物間で形成される新しい化学種であり、同一結晶構造の中で本化合物とさらなる分子種を生じる。
化合物Iまたは本明細書に記載のその任意の形態(固体分子複合体を含む)は、通常、ヒト被験者のための治療法で使用される。しかしながら、化合物Iまたはその組成物は、他の動物被験者における同様のまたは同一の適応を処置するのに使用されてもよく、注射(すなわち、静脈内、腹腔内、皮下及び筋肉内を含む非経口)、経口、経皮、経粘膜、直腸または吸入を含む様々な経路で投与できる。そのような剤形は、本化合物が標的細胞に到達するようにすべきである。その他の因子は当業界で公知であり、毒性、及び化合物または組成物がその効果を発揮するのを遅らせる剤形の考慮が含まれる。技法及び製剤化は一般に、The Science and Practice of Pharmacy,第21版、Lippincott,Williams及びWilkins,フィラデルフィア,PA,2005年に知見される(本明細書中、参照として含まれる)。
本実施例では、化合物I及びHPMC−ASを含む固体分子複合体の形成について記載する。
得られた固体分子複合体の特性は以下のようであった。
化合物I及びHPMC−ASを含む固体分子複合体は、実施例1で使用したものと類似の方法を使用して製造すると、固体分子複合体中、それぞれ3:7、5:5、5:5、4:6、4:6及び2:8のプロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド対イオン性ポリマーの重量比であった。
この実施例は、プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及びEUDRAGIT(登録商標)L 100を含む固体分子複合体の製造について記載する。Eudragit L100は別のアニオン性ポリマー、官能基としてメタクリル酸をもつポリメチルメタクリレートエステルであり、pH6.0以上で溶解する。
この実施例は、プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及びEUDRAGIT(登録商標)L 100を実施例8の3:7の代わりに4:6(化合物40%及びポリマー60%)の比でジメチルアセトアミド(DMA)に溶解したことを除いては、実施例8と全て同じ段階で実施した。この実施例の結果は以下の表2に示す。
プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及びEudragit(登録商標)L 100−55をそれぞれ4:6及び5:5の比で含む固体分子複合体を実施例1と同一の微小析出プロセスを使用して製造した。Eudragit(登録商標) L100−55はpH5.5以上で溶解するので、そのpH溶解性プロフィールにおいてHPMC−ASに酷似していることを除いては、L−100と同様である。製造し、貯蔵したサンプルを粉末XRDで評価した。この実施例の結果は以下の表2に示す。
本実施例は、プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及び腸溶性目的のために使用する別のアニオン性ポリマー、ヒドロキシプロピルメチルセルロースフタレート(HPMCP)を含む固体分子複合体の製造について記載する。HPMCPはヒドロキシル基の幾つかがフタリルエステル27〜35%で置き換えられているセルロースポリマーである。これはpH5.5以上で溶解し始める。プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及びHPMCPを1:1比で含む固体分子複合体を実施例1で使用したものと同一プロセスで製造した。製造し、貯蔵したサンプルを粉末XRDで評価した。この実施例の結果は以下の表2に示す。
4:6の比でプロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及びHPMC−ASを含有する固体分子複合体は、製造直後にアモルファスであることが判明し(表3)、40℃/75%RHで4週間の貯蔵に暴露した。
固体分子複合体のXRDを評価した。
4:6の比でプロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及びHPMCPを含有する固体分子複合体は、製造直後にアモルファスであることが判明し(表3)、40℃/75%RHで4週間の貯蔵に暴露した。
4:6の比でプロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及びEudragit L100−55を含有する固体分子複合体は、製造直後にアモルファスであることが判明し(表3)、40℃/75%RHで4週間の貯蔵に暴露した。
4:6の比でプロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及びポリビニルアセテートフタレート(PVAP)を含有する固体分子複合体は、製造直後に結晶質であったので、さらなる試験にはかけなかった。PVAPは、ポリ酢酸ビニルのフタレートエステルとして形成されたアニオン性腸溶性ポリマーであり、フタリル基55〜62%を含む。これは、42.5℃という低いTgをもつので、PVAPを安定化ポリマーマトリックスとして不適当にする。これはpH>5で溶解する。
4:6の比でプロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド及びセルロースアセテートフタレート(CAP)を含有する固体分子複合体は、製造直後に結晶質であったので、さらなる試験にはかけなかった。
製造直後の初期段階での実施例12〜16の粉末XRDプロフィールは、表3に示す。
実施例12及び14で製造したサンプルは、貯蔵最大4週間終了時まで、粉末XRDプロフィールで結晶質ピークを全く示さなかった。
本実施例は、水性系における固体分子複合体の安定性を示す。薬剤−HPMC−ASの固体分子複合体は、2%ヒドロキシプロピルセルロース(Klucel LF)を含む水性ビヒクル中に懸濁させる。>0.5%w/wコロイド状二酸化ケイ素を添加すると、得られた懸濁液は、通常条件下では最大8時間まで、冷蔵条件下では最大24時間まで安定であることが知見された。
プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミドは、たとえば多形1または2として、多形で存在することができ、ここでそのような多形は実質的に純粋な多形として単離することができる。所望の多形は、好適な結晶化条件を使用することによって製造することができる。たとえば多形1は、たとえば本明細書中に詳細を説明したように、アセトン/無水エタノール(たとえば1:1〜5:1、好ましくは2:1体積で)から再結晶することにより単離した。多形2は、ジメチルアセトアミド/メタノールからの結晶化により直接、または種々の再結晶化条件下で形成することができ、たとえばメチル−t−ブチルエーテル/テトラヒドロフラン、酢酸エチル、アセトンからの再結晶化により形成することができるか、または多形1などの任意の固体形若しくは固体形の混合物を加熱/溶融及び再固化することにより形成することができる。実質的に純粋な単離多形は、X−線粉末回折(XRPD)、示差走査熱量計(DSC)及び赤外線分光法により特徴付けした(以下の実施例20参照)。
プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド多形1及び多形2は、X−線粉末回折、赤外線分光法及び示差走査熱量法により特徴付けした。サンプルは、Shimadzu XRD−6000 X−線粉末回折計を使用し、Cu Kα放射線を使用してX−線粉末回折(XRPD)で分析した。チューブ電圧及び電流は、それぞれ40kV及び40mAであった。発散(divergence)及び散乱スリットは1°に設定し、受けスリットは0.15mmに設定した。回折される放射線はNaIシンチレーション検出器により検出した。2.5°〜40°2θの3°/mmにおけるθ−2θ連続スキャン(0.4秒/0.02°段階)を使用した。シリコン標準を分析して、装置の位置合わせをチェックした。データを収集し、XRD−6100/7000 v5.0を使用して分析した。サンプルは、シリコンインサートのついたアルミニウムホルダー中にサンプルを設置することによって、分析用に調製した。結果は、図1(多形1)及び図2(多形2)並びに以下の表4に示す。
プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミドは、有機塩複合体を形成することができ、優れた溶解性となる弱い塩基性及び弱い酸性中心のいずれをも提供する官能基をもつものとして特徴つけられる。たとえばアザインドール位置のN−7は弱塩基性(pKa約4〜5)であり、ベンゼンスルホン酸、メチルスルホン酸またはトルエンスルホン酸、好ましくはメタンスルホン酸またはトルエンスルホン酸などの有機酸と酸付加塩複合体を形成することができる。そのようなメシル酸塩またはトシル酸塩は、遊離塩基よりも改善された溶解性、改善された固有溶解速度(intrinsic dissolution rate)、及び低い融点などの遊離塩基よりも好都合な点を提供する。改善された固有溶解速度は、上記実施例で記載の方法によりアモルファス形態での配合物など、塩の形成で好都合な点を提供する。改善された溶解性はより効率的で、且つ費用効率が高い製剤を提供し、たとえば、固有溶解により、ずっと少ない溶媒体積を使用して噴霧乾燥または微小析出バルクプロセスを実施することができる。そのような好都合な点は、たとえば噴霧乾燥、溶媒制御沈殿形成、またはpH制御沈殿形成のプロセスなどの、処理の間にin situでメシル酸塩またはトシル酸塩を形成することもできる。また、塩形の低い融点により、より効率的なホットメルト押出しプロセスが提供されるので、低温で溶融物を処理することができる。
本実施例は、HPMCAS中のアモルファス化合物Iの固体分散体(MBP)の製造について記載する。
有機溶媒中の化合物I及びHPMCASの濃度は35%(w/w)であり、化合物I及びHPMCASの比は30:70であった。溶液の温度は70℃に調節した。
図5に示したような二重ジャケット化2.0リットル反応器で、0.01N HCl1210gを5℃に調節した。反応器の底部バルブから、水性相を高剪断ミキサーまたは補助ポンプ、好ましくはロータリーローブポンプにより、続いて高剪断ミキサーで再循環させて、反応器上部に戻した。反応器への循環入口は、発泡を防ぐために流体レベル下であった(図5参照)。
高剪断ミキサー(HSM)
高剪断ミキサー中の回転子の先端速度は25m/秒に設定した。回転子及び固定子それぞれに関して一つの歯列で回転子/固定子を使用した。
70℃に調節したDMA溶液を、高剪断ミキサーの混合チャンバへ向いているインジェクタ・ノズルを介してギアポンプで循環している水性相に投与した。
DMA溶液を水性相に投入すると、高剪断ミキサーの混合チャンバ内で、100/1のHCl/DMAの比になった。
DMA溶液を添加した後、得られたMBP懸濁液を、高剪断ミキサーを通過する同量のバッチに相当する追加の時間、分散させた。時間は、6回のバッチの計算上の再循環時間のターンオーバーに相当した。
乾燥前に、(湿潤)MBPをシーブミル(sieve mill)を使用して砕塊した。(湿潤)MBPをキャビネット乾燥機中で乾燥した。MBPの乾燥プロセスの間、APIの再結晶化を防ぐために生成物の温度は40℃未満であった。キャビネット乾燥機内部の圧力は20mbar未満であった。乾燥後のMBPの含水量は2.0%未満であり、XRPDパターンでアモルファスを示した。
本実施例では、化合物I及びHPMC−ASを含む固体分子複合体の噴霧乾燥による形成について記載する。
さらなる態様は本発明の範囲内であり、付記特許請求の範囲の範囲内である。
Claims (50)
- 固体状態にイオン性ポリマーによって形成されたポリマーマトリックス内に分子状に分散された化合物Iを含む固体分散体。
- 前記イオン性ポリマーが、ヒドロキシプロピルメチルセルロースアセテートスクシネート、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースフタレート及びメタクリル酸コポリマーからなる群から選択される、請求項1に記載の固体分散体。
- 前記イオン性ポリマーが、ヒドロキシプロピルメチルセルロースアセテートスクシネート、ヒドロキシプロピルメチルセルロース及びメタクリル酸コポリマーからなる群から選択される、請求項2に記載の固体分散体。
- 前記ポリマーがヒドロキシプロピルメチルセルロースアセテートスクシネート(HPMCAS)である、請求項1〜3のいずれかに記載の固体分散体。
- 前記ポリマーがメタクリル酸コポリマーを含む、請求項1〜3のいずれかに記載の固体分散体。
- 前記ポリマーがEUDRAGIT(登録商標)L100−55を含む、請求項1に記載の固体分散体。
- 前記固体分散体中の化合物Iの重量対前記イオン性ポリマーの重量比が約1:9〜約1:1である、請求項1〜6のいずれかに記載の固体分散体。
- 前記固体分散体中の化合物Iの重量対前記イオン性ポリマーの重量比が約2:8〜約4:6である、請求項1〜7のいずれかに記載の固体分散体。
- 前記固体分散体中の化合物Iの重量対前記イオン性ポリマーの重量比が約3:7である、請求項1〜8のいずれかに記載の固体分散体。
- 化合物Iが主としてアモルファス形態である請求項1〜9のいずれかに記載の固体分散体。
- ヒドロキシプロピルメチルセルロースアセテートスクシネート(HPMCAS)が固体分散体の約20重量%以上の量で存在する、請求項4に記載の固体分散体。
- ヒドロキシプロピルメチルセルロースアセテートスクシネートが、前記固体分散体の約20重量%〜約95重量%の量で存在する、請求項11に記載の固体分散体。
- ヒドロキシプロピルメチルセルロースアセテートスクシネートが前記固体分散体の約20重量%〜約70重量%の量で存在する、請求項11に記載の固体分散体。
- 請求項1〜13のいずれかに記載の固体分散体と、薬学的に許容可能なキャリヤとを含む組成物。
- 水性ビヒクル中に懸濁させた請求項1〜13のいずれかに記載の固体分散体または請求項14に記載の組成物を含む製剤。
- コロイド状二酸化ケイ素をさらに含む、請求項15に記載の製剤。
- 前記コロイド状二酸化ケイ素が前記組成物の少なくとも0.5重量%の量で存在する、請求項16に記載の製剤。
- 前記水性ビヒクルがヒドロキシプロピルセルロースを2重量%含む、請求項15〜17のいずれかに記載の製剤。
- 請求項1〜13のいずれかに記載の固体分散体の製造法であって、化合物I及びイオン性ポリマーを微小析出(microprecipitate)させることを含む、前記方法。
- 化合物I及び前記イオン性ポリマーが同時に沈殿して、前記イオン性ポリマー中に化合物Iの分子分散体を形成する、請求項19に記載の方法。
- 前記固体分散体が噴霧乾燥により製造される、請求項19に記載の方法。
- 前記固体分散体がホットメルト押出し(hot melt extrusion)により製造される、請求項19に記載の方法。
- 前記方法が溶媒制御沈殿(solvent controlled precipitation)の段階法を含む、請求項19に記載の方法。
- 前記ポリマーがヒドロキシプロピルメチルセルロースアセテートスクシネートである、請求項19〜23のいずれかに記載の方法。
- 化合物I及びヒドロキシプロピルメチルセルロースアセテートスクシネートを有機溶媒中に溶かす、請求項24に記載の方法。
- 前記溶媒がジメチルホルムアミド、ジメチルアセトアミド、ジメチルスルホキシド及びN−メチルピロリドンからなる群から選択される、請求項25に記載の方法。
- 得られた溶液を水に加え、これによって化合物I及びヒドロキシプロピルメチルセルロースアセテートスクシネートが同時に析出して、前記ポリマーにより形成したマトリックス中に埋め込まれた化合物Iを含む固体分子複合体を形成する、請求項25及び26のいずれかに記載の方法。
- 得られた溶液を塩酸(HCl)水溶液に加え、これによって化合物I及びヒドロキシプロピルメチルセルロースアセテートスクシネートが同時に析出して、前記ポリマーにより形成したマトリックス中に埋め込まれた化合物Iを含む固体分子複合体を形成する、請求項25及び26のいずれかに記載の方法。
- 得られた固体分子複合体を水洗して前記有機溶媒を除去する、請求項19〜28のいずれかに記載の方法。
- 以下の:
(a)前記同一有機溶媒中に化合物I及びHPMCASとを溶解させて、単一有機相とする;
(b)(a)で得られた前記有機相を、混合チャンバ内にある水性相に連続して加える、前記混合チャンバには高剪断混合装置と二つの追加の開口部が備えられており、この開口部は前記混合チャンバを閉鎖ループに接続し、ここで前記水性相が循環されて、前記混合チャンバを通過する;
(c)(b)で得られた水性相から、化合物I及びHPMCASのアモルファス形態からなる混合物を沈殿させる、同時に高剪断ミキサーを操作し、前記水性相を閉鎖ループ内の混合チャンバを通過させて、前記沈殿物の水性懸濁液を形成させる;
(d)(a)で製造した前記有機溶液を前記水性相に完全に添加した後、所定の粒径及び/または粒径分布が得られるまで、前記高剪断混合装置を操作しながら前記混合チャンバ内に前記水性懸濁液を連続循環させる;
(e)前記懸濁液から前記固相を単離する;
(f)単離した固相を水洗する;及び
(g)前記固相を砕塊(delump)及び乾燥させる;
各段階を含む、請求項19に記載の方法。 - (a)における有機相はDMA中の化合物I及びHPMCASの35%溶液であり、化合物I対HPMCASの比は30%(w/w)〜70%(w/w)である;及び
段階(b)における連続添加は、前記高剪断ミキサーの縦軸に対して40〜50°の角度に向けられ且つ、約15〜約25m/秒の先端速度で操作している前記高選断ミキサーの回転子から約1〜約10mmの距離があるインジェクタ・ノズルを介して操作される、請求項30に記載の方法。 - 約4.7、9.4、11.0、12.5及び15.4度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す化合物Iの結晶多形1。
- 前記多形が約4.7、9.4、10.0、11.0、12.5、14.2、15.4、18.6及び22.2度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す、請求項32に記載の結晶多形。
- 前記多形が約4.7、9.4、10.0、11.0、12.5、14.2、15.4、16.1、18.6、19.0、22.2及び26.8度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す、請求項32に記載の結晶多形。
- 前記多形が図1の粉末x−線回折パターンと実質的に同じ粉末x−線回折パターンを示す、請求項32に記載の結晶多形。
- 化合物Iが請求項32〜35のいずれかに記載の結晶多形である、請求項19〜29のいずれかに記載の方法。
- 請求項32の結晶多形の精製形。
- 約8.8、9.2、13.5、19.1及び24.4度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す、化合物Iの結晶多形2。
- 前記多形が約6.7、8.8、9.2、13.5、15.0、17.7、19.1、19.7、21.4及び24.4度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す、請求項38に記載の結晶多形。
- 前記多形が約6.7、8.8、9.2、13.5、14.1、14.5、15.0、16.2、17.0、17.7、19.1、19.7、21.4、22.2、24.1、24.4及び28.1度2θの特徴的なピーク位置をもつ粉末x−線回折パターンを示す、請求項38に記載の結晶多形。
- 前記多形が図2の粉末x−線回折パターンと実質的に同じ粉末x−線回折パターンを示す、請求項38に記載の結晶多形。
- 化合物Iが請求項38〜41のいずれかに記載の結晶多形である、請求項19〜29のいずれかに記載の方法。
- 請求項38の結晶多形の精製形。
- 化合物Iのアモルファス形態を含む組成物。
- 化合物Iのメシル酸塩。
- 化合物Iのトシル酸塩。
- 化合物Iのマレイン酸塩。
- 化合物Iのシュウ酸塩。
- 化合物Iのジクロロ酢酸塩。
- 化合物Iの新規多形、塩及び組成物、並びに実質的に上記に記載のこれらを製造する方法。
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JP2013510813A (ja) * | 2009-11-11 | 2013-03-28 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | プロパン−1−スルホン酸{3−[5−(4−クロロ−フェニル)−1H−ピロロ[2,3−b]ピリジン−3−カルボニル]−2,4−ジフルオロ−フェニル}−アミド組成物とその用途 |
JP2014505740A (ja) * | 2011-02-21 | 2014-03-06 | プレキシコン インコーポレーテッド | 医薬活性物質の固体形態 |
JP2016505029A (ja) * | 2013-01-22 | 2016-02-18 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 改良されたバイオアベイラビリティを有する薬学的組成物 |
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JP2016507574A (ja) * | 2013-02-12 | 2016-03-10 | ベンド・リサーチ・インコーポレーテッドBend Research,Incorporated | 低水溶性活性物質の固体分散体 |
JP2015057380A (ja) * | 2013-08-12 | 2015-03-26 | 信越化学工業株式会社 | 加熱溶融押出担体用ヒプロメロース酢酸エステルコハク酸エステル、加熱溶融押出用組成物及び加熱溶融押出成型物の製造方法 |
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