JP6576953B2 - リファキシミンの新規溶媒和物結晶形、生成物、組成物及びそれらの使用 - Google Patents
リファキシミンの新規溶媒和物結晶形、生成物、組成物及びそれらの使用 Download PDFInfo
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- JP6576953B2 JP6576953B2 JP2016566935A JP2016566935A JP6576953B2 JP 6576953 B2 JP6576953 B2 JP 6576953B2 JP 2016566935 A JP2016566935 A JP 2016566935A JP 2016566935 A JP2016566935 A JP 2016566935A JP 6576953 B2 JP6576953 B2 JP 6576953B2
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- rifaximin
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Description
リファキシミン(INN;メルクインデックス第13版(The Merck Index, XIII ed.), 8304, CAS No. 80621-81-4(非特許文献1)参照)、IUPAC命名法(2S,16Z,18E,20S,21S,22R、23R,24R,25S,26S,27S,28E)−5,6,21,23,25 ペンタヒドロキシ−27−メトキシ−2,4,11,16,20,22,24,26−オクタメチル−2,7−(エポキシペンタデカ−(1,11,13)トリエンイミノ)ベンゾフロ(4,5−e)ピリド(1,2,−a ベンズイミダゾール−1,15(2H)ジオン,25−アセテート)は、リファンピシン群に属する半合成抗生物質である。より正確には、リファキシミンは、イタリア国特許第1154655号(特許文献1)に記載のピリド−イミダゾ−リファマイシンであり、欧州特許第0161534号(特許文献2)には、リファマイシンO(メルクインデックス第13版(The Merck Index, XIII ed.), 8301(非特許文献2))を出発物質としてリファキシミンを製造する方法が記載されている。
第1の態様によると、本発明は、リファキシミンとジエチレングリコールモノエチルエーテル(DEGME)との溶媒和物の形態(solvated form)であることを特徴とするリファキシミンの新規結晶形(又は形態)に関し、この結晶形はリファキシミンτと称される。
・ジエチレングリコールモノエチルエーテル(DEGME)をリファキシミンに約4:1〜約500:1のモル比で、室温〜100℃の温度で5分〜5時間の間添加してリファキシミン溶液を得る工程;
・この溶液を室温〜−20℃の温度に冷却する工程;
・得られた沈殿物を濾過する工程;
・得られた沈殿物を室温〜40℃の温度、周囲圧力(大気圧)〜真空圧力下で5分〜1日間の間乾燥する工程。
添付の図面は、本明細書に組み入れられて本明細書の一部を構成するものであり、本開示の1又は複数の実施形態を例示し、そして実施例の記載とともに本開示の原理及び実施を説明する役割を果たす。
本開示には、リファキシミン結晶形並びに関連する組成物、方法及び系(システム)が記載されている。
・ジエチレングリコールモノエチルエーテル(DEGME):リファキシミンのモル比約4:1〜約500:1で、室温〜100℃の温度で5分〜5時間の間リファキシミンをDEGME中に溶解させてリファキシミン溶液を得る工程;
・この溶液を室温〜−20℃の温度で1時間〜20時間にわたって冷却する工程;
・この溶液を濾過してリファキシミン沈殿物を得る工程;
・この沈殿物を、必要に応じて脱水剤の存在下で、室温〜40℃の温度で周囲圧力〜0.001Torrの圧力下、10分〜1日間の間乾燥する工程。
本明細書に記載の組成物、方法及びシステムは、以下の実施例においてさらに説明されるが、これらの実施例は、例示の目的として提供されるものであって、限定を意図するものではない。
(リファキシミンτの調製方法(I))
ジエチレングリコールモノエチルエーテル(2−(2−エトキシエトキシ)エタノールとも称される。以下、DEGME)2300mgに相当する量を、20mgのリファキシミン多形αに添加し、この懸濁液を完全に溶解するまで室温で攪拌した。この溶液を室温で蒸発させ、4日後、着色した結晶が形成され、この結晶を単離して分析した。
(リファキシミンτの結晶構造の決定)
実施例1に従って得られたリファキシミンτの構造決定を、MoKα(λ=0,71073Å)放射線を用いるCCD領域検出器とグラファイト単色光分光器とを備えたOxford Diffraction Xcaliburによって行い、データを室温で収集した。構造を、プログラムSIR2008(M. C. Burla, R. Caliandro, M. Camalli, B. Carrozzini, G. L. Cascarano, L. De Caro, C. Giacovazzo, G. Polidori, D. Siliqi, R. Spagna (2007);Il Milione: a suite of computer programs for crystal structure solution of proteins J. Appl. Cryst. (2007), 40, 609-613)によって直接法により解明し、パッケージWingX(L. J. Farrugia, J. Appl. Cryst. (2012), 45, 849-854)によって実行されたプログラムSHELX97(Sheldrick, G.M. SHELX97, Program for Crystal Structure Determination; University of Gottingen: Gottingen, Germany, 1997)によって精緻化した。表1に、本開示の結晶の構造細部及び測定の詳細を示す。
(リファキシミンτの調製方法(II))
リファキシミンに対してモル比64:1の量のDEGMEを固体リファキシミンに添加した。この懸濁液を、透明な溶液が得られるまで60℃で攪拌し続けた。この溶液を室温まで放冷して一晩攪拌し続けた。固体沈殿物を濾過して、吸収紙を用いて過剰な溶媒を除去し乾燥した。結晶粉末を100μmの篩にかけて結晶生成物を得た。この生成物をHPLCにより一度分析して69.9%のリファキシミン含有量(滴定量)が得られ、GCにより一度分析して28.53%のDEGME含有量が得られ、カール・フィッシャー(Karl Fisher)法により一度分析して1.58%の含水量が測定された。
(リファキシミンτの調製方法(III))
実施例3と同様に実施した後、生成物を、約8×10−3atmの真空下でさらに真空乾燥し、この真空乾燥では、前記生成物を30℃で約30分ごとにプレート上に置き、この系を温度−82℃のコンデンサに接続した。
(リファキシミンτの調製方法(IV))
リファキシミンに対してモル比10:1の量のDEGMEを固体リファキシミンに添加した。この懸濁液を、透明な溶液が得られるまで60℃で約2時間攪拌した。この溶液を室温まで放冷して沈殿物を得た。この沈殿物を単離し、真空下65℃で一晩乾燥して結晶生成物を得た。生成物をHPLCにより一度分析して85.4%のリファキシミン含有量が得られ、GCにより一度分析して14.9%のDEGME含有量が得られ、カール・フィッシャー法により一度分析して0.3%の含水量が測定された。この粉末X線回折(XRPD)パターンは、実施例1の単結晶データに基づいて算出された図1のX線回折パターンに対応している。
(リファキシミンτの調製方法(V))
リファキシミンに対してモル比10:1の量のDEGEEを固体リファキシミンに添加した。この懸濁液を、透明な溶液が得られるまで60℃で約2時間攪拌し続けた。この溶液を室温まで放冷して沈殿物を得た。DEGEEと同体積の量のヘプタンをこの溶液に添加した。
(異なる湿度環境におけるリファキシミンτの安定性)
(a)実施例1に従って得られたリファキシミンτを、室温で、塩化リチウム(LiCl)飽和溶液による11%の湿度レベルに10日間の間曝露した。
(固有溶出性の決定)
実施例5に記載の方法に従って得られた粉末の固有溶出性の決定を、欧州薬局方第7.0版(European Pharmacopeia Ed. 7.0)、2010、2.9.3、第256頁(この文献の開示は、参照することによりその全体が本明細書に組み入れられる)に準じて行い、新規結晶のリファキシミンτと、無定形リファキシミンと、リファキシミン多形βとを比較した。
(中性pHにおけるリファキシミンτの溶出速度の決定)
500mgのリファキシミンτ、500mgのリファキシミン多形α及び500mgの無定形リファキシミンを、それぞれ、pH6.8、30±0.5℃の温度で750mlのリン酸緩衝液中に懸濁した。これらの溶液を、攪拌速度250rpmで120分間攪拌した。等容量のサンプルを所定の時間間隔で取り出し、濾過し、波長430nmで分光光度計によって分析した。サンプル中のリファキシミン濃度を、既知の濃度を有する溶液と比較して算出した。
(リファキシミンτを含む錠剤形態の医薬組成物の調製(組成物A))
実施例5で得られた2340mgの結晶粉末リファキシミンτと、デンプングリコール酸、ジステアリン酸グリセロール、タルク及び微結晶セルロースとを混合した。この混合物をV−ミキサー中で30分間攪拌した後、圧縮成形して顆粒剤を得た。次いで、篩にかけた顆粒剤と、顆粒外物質であるパルミトステアリン酸グリセリル、タルク、微結晶セルロース、シリカとを混合し、均質な混合物を圧縮して固形を得た。次いで、この錠剤を、ヒドロキシプロピルメチルセルロース、二酸化チタン、エデト酸ナトリウム及び酸化鉄を含むフィルムコーティング剤でコーティングした。
(リファキシミンτを含む錠剤形態の医薬組成物の調製(組成物B))
実施例5で得られた2340mgの結晶粉末リファキシミンτと、微結晶セルロース、アルファー化デンプン、タルク及びステアリン酸マグネシウムとを、ミキサー中、16rpmで20分間混合した。次いで、この混合物を打ち抜き機(punch)で圧縮して錠剤を得た。次いで、この錠剤をコーティングした。錠剤の単位組成を表5に示す。
(リファキシミンτを含む錠剤形態の医薬組成物の調製(組成物C))
実施例5に従って調製された2340mgのリファキシミンτと、微結晶セルロース、パルミトステアリン酸グリセリル、タルク及びデンプングリコール酸ナトリウムとをV−ミキサー中で混合した。均質な混合物を、3.15及び1.45mmメッシュで乾燥造粒し、造粒物と、微結晶セルロース、パルミトステアリン酸グリセリル、タルク及び無水コロイダルシリカによって形成された顆粒外賦形剤とを混合した。この混合物を16rpmで20分間攪拌し、次いで圧縮した。得られた錠剤をフィルムコーティング剤でコーティングした。水溶液中に懸濁したフィルムコーティング剤を、温度45℃で錠剤上に噴霧(sprayed)した。得られた錠剤の単位組成を表6に示す。
(放出制御性リファキシミンτを含む錠剤形態の医薬組成物の調製)
実施例5に従って得られた2340mgのリファキシミンτと、微結晶セルロース、パルミトステアリン酸グリセリル、タルク及びデンプングリコール酸ナトリウムとをV−ミキサー中で混合した。次いで、この混合物を、3.15及び1.45mmメッシュで乾燥造粒プロセスによって造粒した。次いで、この造粒物と、顆粒外賦形剤(微結晶セルロース、パルミトステアリン酸グリセリル、タルク及び無水コロイダルシリカ)とを混合した。この混合物を圧縮した後、得られたコアを、メタクリル酸とアクリル酸エチルとのコポリマー(Eudargit L30 D−55)、クエン酸トリエチル、ポリソルベート80及びモノステアリン酸グリセリルを水溶液中に懸濁させたコーティング剤でコーティングした。次いで、コーティング溶液を、45℃で予熱したリファキシミンコア上に噴霧(sprayed)した。リファキシミンτ錠剤の単位組成を表7に示す。
(放出制御性顆粒剤中にリファキシミンτを含むサシェ形態の医薬組成物の調製)
流動床装置に、実施例5に従って得られた468gのリファキシミンτを、2.5gのコロイダルシリカとともに導入した。同時に、ミキサーで攪拌しながら、1385gの脱塩水中に267.3gのメタクリル酸−アクリル酸エチルコポリマー(Kollicoat(コリコート)(登録商標)MAE100P)、40.1gのプロピレングリコール、71gのタルク及び18gの二酸化チタンを含む懸濁液を調製した。この懸濁液を流動装置に仕込み、供給通気量(incoming air flow)15m3/hを温度65℃で適用することによってリファキシミン造粒物上に噴霧(nebulised)した。次いで、得られた胃抵抗性顆粒剤を、温度75℃で1時間乾燥した。
(リファキシミンτを含む錠剤の溶出の決定)
リファキシミン錠剤の溶出の決定を、欧州薬局方第8.0版(European Pharmacopeia ED. 8.0);2.9.3、第288頁、2014に準じて行った。200mgのリファキシミン多形αを含むNormix(登録商標)の錠剤を、実施例10に従って調製したリファキシミンτを含む錠剤及び無定形リファキシミンを含む錠剤と比較した。無定形リファキシミン錠剤は、リファキシミンτ代わりに無定形リファキシミンを用いたこと以外は実施例10の記載と同じ条件下で調製した。
(噴霧乾燥によって調製されたリファキシミンを用いるイヌへのPK試験)
リファキシミン無定形及びリファキシミン多形αと比較したリファキシミンτのバイオアベイラビリティ試験を、4匹の雄性ビーグル犬に、これらの多形又は無定形の1つを100mg/kgの用量で与えることによって行った。各動物に、リファキシミンτ、無定形リファキシミン及びリファキシミンαの1つの経口カプセルを投与し、各形態を同じ動物に投与する間に7日間の洗い流し(washout)期間を設けた。投薬は、サイズ13のゼラチンカプセルの後に10mlの飲料水を与えることにより行った。
tmax:投与からCmaxを得るまでの時間(中央値として表す);
AUC0−8h:0時間(最初の実験時点)から8時間までの濃度−時間曲線下面積;
AUC0−tlast:0時間(最初の実験時点)から最後の定量可能濃度までの濃度−時間曲線下面積。
Claims (12)
- リファキシミンとジエチレングリコールモノエチルエーテルとの溶媒和物形であって、正方晶結晶系を有し、空間群がP4 1 2 1 2であり、かつ単位格子定数が、a=b=16.51(1)Å;c=36.80(1)Å;α=β=γ=90°;V=10027(1)Å 3 であることを特徴とするリファキシミンτ結晶。
- 角度2θ±0.1°の値が、5.9°;9.0°及び12.9°;又は5.9°;12.9°及び18.8°;又は5.9°;15.4°及び23.4°;又は9.0°;15.4°及び23.4°;又は12.9°、22.8°及び23.4°にピークを有するX線回折スペクトルを特徴とする請求項1記載のリファキシミンτ結晶。
- 角度2θ±0.1°の値が、5.9°;9.0°;12.9°;15.4°;18.8°;22.8°及び23.4°にピークを有するX線回折スペクトルを特徴とする請求項1又は2記載のリファキシミンτ結晶。
- リファキシミンとジエチレングリコールモノエチルエーテルとの化学量論比(モル比)が1:1であることを特徴とする請求項1〜3のいずれかに記載のリファキシミンτ結晶。
- 以下の工程を含む方法:
・ジエチレングリコールモノエチルエーテルをリファキシミンに10:1〜100:1のモル比で、室温〜100℃の温度で5分〜5時間の間添加してリファキシミンをジエチレングリコールモノエチルエーテルに溶解し、リファキシミン溶液を得る工程;
・この溶液を室温〜−20℃の温度であって、前記溶解温度よりも低い温度に冷却する工程;
・得られた沈殿物を濾過する工程;及び
・得られた沈殿物を室温〜40℃の温度、周囲圧力〜真空圧力下で5分〜1日間の間乾燥する工程
を含み、
乾燥工程前の沈殿物を、必要に応じて、無極性溶媒であるC3−C7直鎖状又は環状又は芳香族炭化水素で洗浄する、方法、
若しくは以下の工程を含む方法:
・前記リファキシミン溶液を得る工程;及び
・この溶液を室温で蒸発させて結晶を得る工程;
を含む、方法により、
請求項1〜4のいずれかに記載のリファキシミンτ結晶を製造する方法。 - 沈殿物を凍結乾燥又は真空乾燥によって乾燥する請求項5記載の方法。
- 有効量の請求項1〜4のいずれかに記載のリファキシミンτ結晶と薬学的に許容可能な賦形剤とを含む医薬組成物。
- 感染症又は炎症の治療又は予防に有効な20〜1200mgの量でリファキシミンτ結晶を含む請求項7記載の医薬組成物。
- 錠剤、カプセル剤、クリーム剤、又は懸濁剤用顆粒剤の形態である請求項7又は8記載の医薬組成物。
- 錠剤又は顆粒剤であって、この錠剤又は顆粒剤が、アクリルポリマー、メタクリル酸とアクリル酸エステル又はメタクリル酸エステルとのコポリマー、ポリビニルアセテートフタレート、ヒドロキシプロピルセルロースアセテートフタレート、セルロースアセテートフタレート及びヒドロキシプロピルメチルセルロースフタレートからなる群より選択される少なくとも一種を含むコーティング剤でコーティングされており、4.5よりも高いpH値で放出制御性、時限放出性又は速放性を有する請求項7〜9のいずれかに記載の医薬組成物。
- 細菌エシェリキア コリ又はクロストリジウム ディフィシルによって生じる腸感染症;旅行者下痢症;感染性下痢症;クローン病、過敏性腸症候群(IBS)、腸炎、全腸炎、憩室炎、小腸における細菌の過剰増殖の症候群(SIBO)、大腸炎、膵不全、慢性膵炎、肝性脳症、機能性胃腸障害及び下痢症を伴う機能性消化不良から選択された腸障害;並びに膣感染症の治療又は予防のための請求項7〜10のいずれかに記載の医薬組成物。
- X線分析における解析基準としての請求項1〜4のいずれかに記載のリファキシミンτ結晶の使用。
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