JP5755878B2 - リファキシミンの薬剤組成物 - Google Patents
リファキシミンの薬剤組成物 Download PDFInfo
- Publication number
- JP5755878B2 JP5755878B2 JP2010515660A JP2010515660A JP5755878B2 JP 5755878 B2 JP5755878 B2 JP 5755878B2 JP 2010515660 A JP2010515660 A JP 2010515660A JP 2010515660 A JP2010515660 A JP 2010515660A JP 5755878 B2 JP5755878 B2 JP 5755878B2
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- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- controlled release
- release pharmaceutical
- rifaximin
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- NZCRJKRKKOLAOJ-XRCRFVBUSA-N rifaximin Chemical group OC1=C(C(O)=C2C)C3=C4N=C5C=C(C)C=CN5C4=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O NZCRJKRKKOLAOJ-XRCRFVBUSA-N 0.000 title claims description 80
- 229960003040 rifaximin Drugs 0.000 title claims description 72
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 58
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
生体接着性と粘膜接着性とは,交換可能に使用できる。
ある実施形態において,コーティングは薬物も含んで成る。
多層錠剤又は勾配錠剤は,数種類の方法で構成することができる。
放出調節ポリマーは,親水性,疎水性又はそれらの組み合わせであることができる。
i) 活性剤及び薬剤学的に許容しうる添加剤をブレンディングする工程;
ii) ブレンドを,スラッギング/圧縮に付して,コプライメート(coprimate)を形成する工程;
iii) コプライメートを顆粒に変換する工程;
iv) 顆粒を圧縮して,固体経口投与形態を形成する工程;
v) 圧縮顆粒を任意にコーティングする工程。
i) リファキシミン,希釈剤,HPMC及びポロキサマーを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を (iii)で潤滑にする。
次に,A及びBのブレンドを圧縮して,二層錠剤若しくは錠剤中錠剤にするか,又は個々に圧縮して,ミニ錠剤にし,カプセルに充填する。
次に,非コーティング錠剤を,下記の組成によって2〜3%の重量増加でフィルムコーティングした。
i) リファキシミン,希釈剤及びPEOを,特定の篩にかけ,ブレンダーで混合する;
ii) HPMCを撹拌下,水に添加する;
iii) (i)を(ii)で粒状化し,湿潤塊を流動床乾燥器で乾燥させる;
iv) (iii)の顆粒を,好適な篩にかける;
v) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
vi) (iv)を(v)で潤滑にする。
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
A及びBの両方を圧縮して,二層錠剤を形成するか,又は個々に圧縮して,ミニ錠剤を形成し,カプセルに充填する。
次に,非コーティング錠剤を,下記の組成によって5〜10%の重量増加で腸溶コーティングした。
i) リファキシミン,希釈剤及びPEOを,好適な篩にかけ,ブレンダーで混合する;
ii) HPMCを,撹拌下,IPA:塩化メチレンに添加する;
iii) (i)を(ii)で粒状化し,湿潤塊を流動床乾燥器で乾燥させる;
iv) (iii)の顆粒を,好適な篩にかける;
v) コロイド状二酸化珪素及びステアリン酸マグネシウムを,特定の篩にかける;
vi) (iv)を(v)で潤滑にする。
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
A及びBの両方を圧縮して二層錠剤を形成するか,又は個々に圧縮してミニ錠剤にし,カプセルに充填する。
i) リファキシミン,希釈剤,HPMC,SLS及びキサンタンガムを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする;
v) 次に,ブレンドを圧縮して,錠剤にする。
i) リファキシミン,希釈剤,HPMC及びPEOを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) (ii)を水で粒状化し,湿潤塊を流動床乾燥器で乾燥させる;
iv) (iii)で得た顆粒を,好適な篩にかける;
v) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
vi) (iv)を(v)で潤滑にする;
vii) 次に,工程(vi)のブレンドを圧縮して,錠剤にする。
i) リファキシミン,希釈剤,HPMC及びPEOを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) (ii)を,IPA:塩化エチレン(70:30)で粒状化し,湿潤塊を流動床乾燥器で乾燥させる;
iv) (iii)で得た顆粒を,好適な篩にかける;
v) コロイド状二酸化珪素及びステアリン酸マグネシウムを,特定の篩にかける;
vi) (iv)を(v)で潤滑にする;
vii) 次に,工程(vi)のブレンドを圧縮して,錠剤にする。
i) リファキシミン,希釈剤,HPMC及びPEOを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) (iii)の半分の量を(ii)に添加し,ブレンダーで混合する;
v) ローラーコンパクターをある圧力で使用して,(iv)のブレンドを圧縮する;
vi) (v)を好適な篩にかけて,顆粒を得る;
vii) 残りの量の(iii),及び(vi)を,ブレンダーで混合する;
viii) (vii)のブレンドを圧縮して,錠剤にする。
i) HPMC,キサンタンガム及びカルボポールを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
A及びBのブレンドを圧縮して,三層錠剤にする。
i) HPMC,キサンタンガム及びカルボポールを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
ii) (i)をブレンダーでドライブレンドする;
iii) HPMCを水中で撹拌下,混合する;
iii) (ii)を(iii)で粒状化し,湿潤塊を流動床乾燥器で乾燥させる;
iv) (iii)で得た顆粒を,好適な篩にかける;
v) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
vi) (iv)を(v)で潤滑にする;
vii) 次に,A及びBのブレンドを圧縮して,三層錠剤にする。
i) HPMC,キサンタンガム及びカルボポールを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
ii) (i)をブレンダーでドライブレンドする;
iii) HPMCを,IPA:塩化メチレン中で撹拌下,混合する;
iv) (ii)を(iii)で粒状化し,湿潤塊を流動床乾燥器で乾燥させる;
v) (iii)で得た顆粒を,好適な篩にかける;
vi) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
vii) (iv)を(v)で潤滑にする。
次に,A及びBのブレンドを圧縮して,三層錠剤にする。
i) アルギン酸ナトリウムを水に懸濁させ,リファキシミンをこのコロイド溶液に懸濁させる;
ii) 塩化カルシウムを水に溶解させ,別にしておく;
iii) 工程(i)を,撹拌下,工程(ii)に滴下して,ビーズを形成し,さらに,溶液を濾過してビーズを分離し,ビーズを乾燥させる;
iv) 乾燥ビーズを,キサンタンガム及びアルギン酸ナトリウと混合する;
v) 工程(iv)のビーズを,ステアリン酸マグネシウムで潤滑にし,カプセル若しくはサッシェに充填するか,又は甘味剤及び香味剤と共に懸濁剤用の粉末として水に入れる。
手順:
i) リファキシミン,希釈剤,CMCナトリウム及びPEOを,好適な篩にかける;
ii) 工程(i)のブレンドをIPAで粒状化する;
iii) 工程(ii)の顆粒を乾燥させ,好適な篩にかける;
iv) 工程(iii)の顆粒を,ステアリン酸マグネシウムで潤滑にする;
v) 好適な希釈剤及び潤滑剤を用いて工程(iv)の生体接着性顆粒をさらに圧縮して錠剤にするか,又はカプセル若しくはサッシェに充填するか,又は甘味剤及び香味剤と共に懸濁剤用の粉末としてビンに充填することができる。
球状化
i) MCC,リファキシミン,PEO及びHPMCを,好適な篩にかける;
ii) 工程(i)をIPAと混合する;
iii) 工程(ii)の湿潤塊を押出機に通し,さらに球状化して,丸いペレットを得る。
ホットメルト押出
i) MCC,リファキシミン,PEO及びHPMCを,好適な篩にかける;
ii) 工程(i)を充分に混合し,70℃で加熱する;
iii) このようにして得た軟質塊を押出機に通し,球状化して,ペレットを得る。
ペレットを,カプセル,サッシェに充填するか,又は甘味剤及び香味剤と共に懸濁剤用の粉末として,ビン,水に入れるか,又は錠剤に圧縮することができる。
i) リファキシミン,希釈剤,キサンタンガム,ポロキサマー及びアルギン酸ナトリウムを,好適な篩にかける;
ii) 工程(i)を,ブレンダーでドライブレンドする;
iii) 潤滑剤を特定の篩にかけ,工程(ii)と混合する;
iv) 次に,工程(iii)のブレンドを,ミニ錠剤に圧縮する;
v) これらのミニ錠剤を,カプセルに充填することができる。
i) リファキシミン及びHPMCを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
次に,A及びBのブレンドを圧縮して,二層錠剤又は錠剤中錠剤にする。
i) リファキシミン,希釈剤及びPEOを,特定の篩にかけ,ブレンダーで混合する;
ii) 撹拌下,HPMCを水に添加する;
iii) (i)を(ii)で粒状化し,湿潤塊を流動床乾燥器で乾燥させる;
iv) (iii)の顆粒を,好適な篩にかける;
v) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
vi) (iv)を(v)で潤滑にする。
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
A及びBの両方を圧縮して,二層錠剤を形成する。
i) リファキシミン,希釈剤及びPEOを,好適な篩にかけ,ブレンダーで混合する;
ii) 撹拌下,HPMCを,IPA:塩化メチレンに添加する;
iii) (i)を(ii)で粒状化し,湿潤塊を流動床乾燥器で乾燥させる;
iv) (iii)の顆粒を,好適な篩にかける;
v) コロイド状二酸化珪素及びステアリン酸マグネシウムを,特定の篩にかける;
vi) (iv)を(v)で潤滑にする。
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ブレンダーにおいて,(ii)を(iii)で潤滑にする。
A及びBの両方を圧縮して,二層錠剤を形成する。
i) リファキシミン,希釈剤,HPMC,SLS及びキサンタンガムを,好適な篩にかける;
ii) (i)をブレンダーでドライブレンドする;
iii) コロイド状二酸化珪素及びステアリン酸マグネシウムを,好適な篩にかける;
iv) ドライブレンダーにおいて,(ii)を(iii)で潤滑にする;
v) 次に,ブレンドを錠剤に圧縮する。
PEO=ポリエチレンオキシド
DCP=リン酸二カルシウム
MCC=微結晶性セルロース
MA 1=メタクリル酸コポリマーL 100
MA2=メタクリル酸コポリマーS 100
IPA=イソプロピルアルコール
本発明の配合物は,長時間生体外放出を有する。本発明の配合物からの活性剤の放出速度を測定するのに使用した生体外試験は,以下の通りであった。6.8pHリン酸塩緩衝液900mL,1.5% SLSを,撹拌可能な装置に入れた。本発明に使用した装置は,II型パドル溶解装置であり,100rpmの速度で回転させた。錠剤を,装置に入れ,溶解を定期的に測定した。実施例3の生体外溶解試験は以下の通りである:約20%〜50%の薬物が約8時間で放出され,約30%〜約70%の薬物が約12時間で放出され,約70%以上の薬物が約24時間で放出される。
生体接着を張力法によって測定した。測定のために,高性能フォースゲージ装置(製造会社:Mecmesin,West ssex,England)を使用した。新しく切除したヒツジの腸の組織を採取し,実験に使用するまでタイロード溶液中において4℃で保存した。組織を断片にカットし(3x4cm),スライドガラスに載せ,糸で固定した。0.5mLのリン酸緩衝生理食塩水(PBS)を組織に載せた。本発明の生体接着性錠剤をこの組織に載せ,さらに0.5mLのPBSを錠剤に載せた。重さ10gのスライドガラスを錠剤に載せ,10分,30分,60分及び840分間にわたって水和させた。所定の時間間隔で,水和錠剤をスライドガラスと共に,生体接着力装置の台に載せた。次に,0.2mm/秒の固定速度でプローブを下げ,上方スライドを,糸によってプローブのフックに取り付けた。図1のグラフから明らかなように,ピーク剥離力を生体接着力とみなした。錠剤を生物学的物質から分離するのに必要とした力をmNで記録した。
無作為化,非盲検,多施設,比較パイロット臨床試験を,下記の物質を使用して行なった:被験物質としての,1日1回投与されるリファキシミン600gmを含有する長時間放出錠剤を含有する薬剤調製物,及び対照物質としての,1日3回投与されるリファキシミン200mgを含有する市販投与形態(Xifaxan(登録商標))。試験は,Xifaxan(登録商標)と比較して同様の臨床有効性を示すように設計された。
大腸菌は,Xifaxan(登録商標)と比較して同様の臨床有効性を測定するために充分な数の基準病原体である。
一次有効性エンドポイントは,最後の無形便に至るまでの時間(TLUS)であり,二次エンドポイントは,病原体の死滅であった。治療を3日間行なった。治療を意図する(ITT)集団は,治療に対して無作為化された全被験者として定義された。
Claims (23)
- a.治療有効量のリファキシミン又は薬剤学的に許容し得るその塩若しくは鏡像異性体,
b.ヒドロキシプロピルメチルセルロース及びポリエチレンオキシド,及び
c.薬剤学的に許容し得る賦形剤
を含んで成る制御放出性薬剤組成物であって,
II型パドル溶解装置において,1.5% SLSを含む6.8リン酸塩緩衝液中で100rpmで測定した場合に生体外溶解プロフィールを有し,20%〜50%の薬物が8時間で放出され,30%〜70%の薬物が12時間で放出され,70%を超える薬物が24時間で放出され,70%のリファキシミンが24時間で放出され,そして
高性能フォースゲージ装置(製造会社:Mecmesin, West Sussex, England)を使用して測定した場合に少なくとも100mNの剥離力として測定される接着強度を有するものである,制御放出性薬剤組成物。 - 消化管におけるリファキシミンの滞留時間を増加させるように調製された,請求項1に記載の制御放出性薬剤組成物。
- 生体接着によって,消化管におけるリファキシミン調製物の滞留時間の増加が得られる,請求項2に記載の制御放出性薬剤組成物。
- 生体接着が,ヒドロキシプロピルメチルセルロース及びポリエチレンオキシドによって得られる,請求項3に記載の制御放出性薬剤組成物。
- 水溶性又は水分散性ノニオン界面活性剤,半極性ノニオン界面活性剤,アニオン界面活性剤,カチオン界面活性剤,両性界面活性剤,又は両性イオン界面活性剤;シクロデキストリン;親油性物質;ビタミンE;クエン酸トリアルキル,ラクトン及び低級アルコール脂肪酸エステル;窒素含有溶媒;リン脂質;アセチン,ジアセチン及びトリアセチン;グリセロール脂肪酸エステル,モノグリセリド,ジグリセリド及びトリグリセリド並びにアセチル化モノグリセリド及びアセチル化ジグリセリド;プロピレングリコールエステル;エチレングリコールエステル,又はそれらの任意の組み合わせを含む群から選択される可溶化剤をさらに含んで成る,請求項1に記載の制御放出性薬剤組成物。
- 薬剤学的に許容し得る賦形剤が,結合剤,希釈剤,潤滑剤,界面活性剤及び流動促進剤を含む群から選択される,請求項1に記載の制御放出性薬剤組成物。
- 結合剤が,炭水化物,セルロース;デンプン;ガム;ポリビニルピロリドン,ポビドン,糖ミツ,ポリエチレンオキシド,ポリアクリルアミド,ポリ−N−ビニルアミド,カルボキシメチルセルロースナトリウム,ポリエチレングリコール,ゼラチン,ポリエチレンオキシド,ポリプロピレングリコール,トラガカント,アルギン酸,及びそれらの組み合わせを含む群から選択される1又は2以上の結合剤である,請求項6に記載の制御放出性薬剤組成物。
- 希釈剤が,炭水化物,炭水化物誘導体,ポリオール,糖アルコール,無機金属の炭酸塩,硫酸塩若しくはリン酸塩,又はそれらの混合物を含む群から選択される1又は2以上の希釈剤である,請求項6に記載の制御放出性薬剤組成物。
- 潤滑剤が,ステアリン酸マグネシウム,ステアリン酸アルミニウム,ステアリン酸亜鉛又はステアリン酸カルシウム,ステアリルフマル酸ナトリウム,ポリエチレングリコール,鉱油,ステアリン酸,水素添加植物油,グリセリルベヘネート,グリセリルパルミトステアレート,グリセリルステアレート,コーンスターチ,タルク,珪酸カルシウム,珪酸マグネシウム,コロイド状二酸化珪素,シリコンヒドロゲル,及びそれらの混合物を含む群から選択される1又は2以上の潤滑剤である,請求項6に記載の制御放出性薬剤組成物。
- 界面活性剤が,イオン界面活性剤又は非イオン界面活性剤又は両性イオン界面活性剤から選択される1又は2以上の界面活性剤である,請求項6に記載の制御放出性薬剤組成物。
- 流動促進剤が,二酸化珪素,コロイド状シリカ,粉末セルロース,タルク,第三リン酸カルシウム及びそれらの混合物を含む群から選択される1又は2以上の流動促進剤である,請求項6に記載の制御放出性薬剤組成物。
- 20〜2400mgのリファキシミンを含む1日1回投与形態である,請求項1に記載の制御放出性薬剤組成物。
- 550mgのリファキシミンを含む1日1回投与形態である,請求項1に記載の制御放出性薬剤組成物。
- 600mgのリファキシミンを含む1日1回投与形態である,請求項1に記載の制御放出性薬剤組成物。
- 旅行者下痢,肝性脳症,感染性下痢,憩室性疾患,結腸手術前の抗細菌予防措置,過敏性腸症候群,クローン病,クロストリジウムジフィシル関連下痢,小腸細菌異常増殖,旅行者下痢予防,赤痢,回腸嚢炎,消化性潰瘍疾患,外科的予防及び胃性消化不良の治療のために使用される,請求項1に記載の制御放出性薬剤組成物。
- 旅行者下痢の治療のために使用される,請求項1に記載の制御放出性薬剤組成物。
- 大腸菌による旅行者下痢の治療のために使用される,請求項1に記載の制御放出性薬剤組成物。
- クレブシエラ菌誘発性旅行者下痢の治療用の,請求項1の制御放出性薬剤組成物。
- 錠剤,ペレット,ビーズ,顆粒剤,持続放出剤,カプセル剤,マイクロカプセル剤,カプセル中錠剤,ミクロスフェア,又は懸濁剤用の粉末/ペレット/ビーズ/顆粒である,請求項1に記載の制御放出性薬剤組成物。
- a.治療有効量のリファキシミン又は薬剤学的に許容し得るその塩若しくは鏡像異性体,
b.ヒドロキシプロピルメチルセルロース及びポリエチレンオキシド,及び
c.薬剤学的に許容し得る賦形剤
を含んで成り,
II型パドル溶解装置において,1.5% SLSを含有する6.8リン酸塩緩衝液中で100rpmで測定した場合に生体外溶解プロフィールを有し,20%〜50%の薬物が8時間で放出され,30%〜70%の薬物が12時間で放出され,70%を超える薬物が24時間で放出される,1日1回投与用制御放出性薬剤組成物であり,
高性能フォースゲージ装置(製造会社:Mecmesin, West Sussex, England)を使用して測定した場合に少なくとも100mNの剥離力として測定される接着強度を有するものである,制御放出性薬剤組成物。 - 乾式造粒,湿式造粒,溶融造粒,直接圧縮,二重圧縮,押出球状化又は層状化により形成されるものである,請求項1〜20の何れかに記載の制御放出性薬剤組成物。
- 0.1%〜90%w/wのリファキシミンを含有するものである,請求項1〜21の何れかに記載の制御放出性薬剤組成物。
- ポロキサマー,スルホ琥珀酸ジオクチルナトリウム(DSS),トリエタノールアミン,ラウリル硫酸ナトリウム(SLS),ポリオキシエチレンソルビタン及びポロキサルコル誘導体,第四級アンモニウム塩,及びこれらの組み合わせからなる群より選ばれる界面活性剤を更に含むものである,請求項1〜22の何れかに記載の制御放出性薬剤組成物。
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Families Citing this family (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7906542B2 (en) * | 2004-11-04 | 2011-03-15 | Alfa Wassermann, S.P.A. | Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin |
US20080262024A1 (en) * | 2003-11-07 | 2008-10-23 | Giuseppe Claudio Viscomi | Rifaximin compositions and method of use |
ITMI20032144A1 (it) * | 2003-11-07 | 2005-05-08 | Alfa Wassermann Spa | Forme polimorfe di rifaximina, processi per ottenerle e |
US7902206B2 (en) * | 2003-11-07 | 2011-03-08 | Alfa Wassermann, S.P.A. | Polymorphic forms α, β and γ of rifaximin |
US7923553B2 (en) * | 2003-11-07 | 2011-04-12 | Alfa Wassermann, S.P.A. | Processes for the production of polymorphic forms of rifaximin |
SI1698630T1 (sl) | 2005-03-03 | 2015-01-30 | Alfa Wassermann S.P.A. | Nove polimorfne oblike rifaksimina, postopki za njihovo pripravo in njihova uporaba v medicinskih pripravkih |
ITBO20050123A1 (it) * | 2005-03-07 | 2005-06-06 | Alfa Wassermann Spa | Formulazioni farmaceutiche gastroresistenti contenenti rifaximina |
NZ587099A (en) | 2008-02-25 | 2012-08-31 | Salix Pharmaceuticals Ltd | Forms of rifaximin and uses thereof |
US8486956B2 (en) | 2008-02-25 | 2013-07-16 | Salix Pharmaceuticals, Ltd | Forms of rifaximin and uses thereof |
US11779571B2 (en) | 2008-02-26 | 2023-10-10 | Salix Pharmaceuticals, Inc. | Methods for treating irritable bowel syndrome (IBS) |
US20100317681A1 (en) * | 2009-06-15 | 2010-12-16 | Salix Pharmaceuticals, Ltd. | Modulation of systemic exposure to rifaximin |
US7928115B2 (en) * | 2008-10-02 | 2011-04-19 | Salix Pharmaceuticals, Ltd. | Methods of treating travelers diarrhea and hepatic encephalopathy |
US20110035232A1 (en) | 2008-10-02 | 2011-02-10 | Salix Pharmaceuticals, Ltd. | Methods of treating hepatic encephalopathy |
WO2010040020A1 (en) | 2008-10-02 | 2010-04-08 | Salix Pharmaceuticals, Ltd. | Methods of treating hepatic encephalopathy |
WO2010093776A1 (en) * | 2009-02-11 | 2010-08-19 | Cedars-Sinai Medical Center | Antibiotic therapy to reduce the likelihood of developing post-infectious irritable bowel syndrome |
ES2656850T3 (es) | 2009-02-11 | 2018-02-28 | Cedars-Sinai Medical Center | Diagnóstico del síndrome intestinal inflamatorio con base en la toxina de distensión citoletal |
EP2432437A4 (en) * | 2009-05-21 | 2012-12-19 | Bionex Pharmaceuticals Llc | TWO- AND ONE-LAYER DOSAGE FORMS |
AU2010260089B2 (en) * | 2009-06-15 | 2015-05-14 | Salix Pharmaceuticals, Inc. | Modulation of systemic exposure to rifaximin |
JP2013504597A (ja) | 2009-09-13 | 2013-02-07 | サリックス ファーマスーティカルズ,リミテッド | 過敏性腸症候群(ibs)の治療方法 |
CN102665693A (zh) * | 2009-10-27 | 2012-09-12 | 鲁平有限公司 | 利福昔明固体分散体 |
IT1398550B1 (it) | 2010-03-05 | 2013-03-01 | Alfa Wassermann Spa | Formulazioni comprendenti rifaximina utili per ottenere un effetto prolungato nel tempo |
CA2800235C (en) * | 2010-03-10 | 2018-10-16 | Lupin Limited | Rifaximin ready-to-use suspension |
WO2012009387A1 (en) * | 2010-07-12 | 2012-01-19 | Salix Pharmaceuticals, Ltd | Formulations of rifaximin and uses thereof |
BR112013005772A2 (pt) * | 2010-09-13 | 2019-09-24 | Cipla Ltd | composição compreendendo rifaximina na forma de pertículas, composição farmacêutica, uso de uma composição, método para tratar uma infecção bacteriana e processo para preparar uma composição farmacêutica |
IT1403847B1 (it) * | 2010-09-22 | 2013-11-08 | Alfa Wassermann Spa | Composizioni farmaceutiche comprendenti rifaximina e loro uso. |
WO2012071220A1 (en) * | 2010-11-23 | 2012-05-31 | Transcept Pharmaceuticals, Inc. | Compositions and methods for once-daily administration of a trilayer osmotic tablet |
WO2012076832A1 (en) | 2010-12-09 | 2012-06-14 | Cipla Limited | Suppositories comprising rifaximin |
KR20140016260A (ko) * | 2011-02-03 | 2014-02-07 | 루핀 리미티드 | 베포타스틴의 경구용 방출 조절 약제 조성물 |
EA201391171A1 (ru) | 2011-02-11 | 2014-11-28 | Сэликс Фармасьютиклз, Лтд. | Формы рифаксимина и их применение |
ITBO20110461A1 (it) | 2011-07-29 | 2013-01-30 | Alfa Wassermann Spa | Composizioni farmaceutiche comprendenti rifaximina, processi per la loro preparazione e loro uso nel trattamento di infezioni vaginali. |
US20130184302A1 (en) | 2011-11-02 | 2013-07-18 | Enoch Bortey | Methods for treating irritable bowel syndrome (ibs) and infections |
CA2861104A1 (en) * | 2012-01-25 | 2013-08-01 | Salix Pharmaceuticals, Ltd. | Rifaximin derivative and uses thereof |
ITBO20120368A1 (it) | 2012-07-06 | 2014-01-07 | Alfa Wassermann Spa | Composizioni comprendenti rifaximina e amminoacidi, cristalli di rifaximina derivanti da tali composizioni e loro uso. |
KR102203568B1 (ko) | 2012-09-17 | 2021-01-15 | 세다르스-신나이 메디칼 센터 | 장 및 방광의 운동 장애 및 섬유근육통의 진단 및 치료 |
US10835495B2 (en) | 2012-11-14 | 2020-11-17 | W. R. Grace & Co.-Conn. | Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same |
CA2900763C (en) * | 2013-02-13 | 2021-04-06 | Reza Fathi | Pharmaceutical compositions for the treatment of helicobacter pylori |
ES2675305T3 (es) | 2014-04-15 | 2018-07-10 | Novintethical Pharma Sa | Composiciones a base de xiloglucano y proteínas para el tratamiento de trastornos intestinales |
CN106795192B (zh) | 2014-05-04 | 2020-06-16 | 萨利克斯药品公司 | Ibs微生物群及其用途 |
NZ723571A (en) | 2014-05-12 | 2020-02-28 | Alfasigma Spa | New solvated crystal form of rifaximin, production, compositions and uses thereof |
GB2536037A (en) * | 2015-03-05 | 2016-09-07 | Atlantic Inertial Systems Ltd | Anti-vibration mounting system |
WO2017058869A1 (en) | 2015-09-29 | 2017-04-06 | Acorda Therapeutics, Inc. | Sustained release compositions of 4-aminopyridine |
RS63751B1 (sr) | 2016-09-30 | 2022-12-30 | Salix Pharmaceuticals Inc | Čvrsti disperzioni oblici rifaksimina |
MX2018010065A (es) * | 2017-04-26 | 2019-02-07 | Sandoz Ag | Forma de dosificacion oral que comprende rifaximina en forma beta. |
US11129862B2 (en) * | 2017-08-30 | 2021-09-28 | Johnson & Johnson Consumer Inc. | Ophthalmic compositions |
EP3501503A1 (en) * | 2017-12-22 | 2019-06-26 | Cosmo Technologies Ltd. | Solid delivery composition |
EP3902528A1 (en) * | 2018-12-19 | 2021-11-03 | Friulchem SpA | Process for the manufacture of a tablet of rifaximin and tablet of rifaximin |
CN112057629A (zh) * | 2019-06-10 | 2020-12-11 | 苏州兰鼎生物制药有限公司 | 一种药物组合物 |
BR112022003500A2 (pt) * | 2019-09-24 | 2022-05-24 | Bausch Health Ireland Ltd | Formulações líquidas de rifaximina |
US20230116647A1 (en) * | 2020-03-24 | 2023-04-13 | Bausch Health Ireland Limited | Methods of treating covid-19 with rifaximin |
US11878011B2 (en) | 2020-05-07 | 2024-01-23 | Redhill Biopharma Ltd. | Method for eradicating Helicobacter pylori infection in patients regardless of body mass index |
EP4171520A1 (en) * | 2020-06-26 | 2023-05-03 | Bausch Health Ireland Limited | Targeted release rifaximin compositions |
CN112121172B (zh) * | 2020-09-26 | 2022-05-20 | 北京英茂药业有限公司 | 缓释型薄膜包衣预混剂及其制备方法 |
CN115252566B (zh) * | 2022-08-10 | 2023-07-25 | 广州白云片片康药业有限公司 | 一种养胃护肝的中药复合片剂及其制备方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1154655B (it) | 1980-05-22 | 1987-01-21 | Alfa Farmaceutici Spa | Derivati imidazo-rifamicinici metodi per la loro preparazione e loro uso come sostanza ad azione antibatterica |
IT1253711B (it) * | 1991-12-17 | 1995-08-23 | Alfa Wassermann Spa | Formulazioni farmaceutiche vaginali contenenti rifaximin e loro uso nel trattamento delle infezioni vaginali |
ITMI20032144A1 (it) * | 2003-11-07 | 2005-05-08 | Alfa Wassermann Spa | Forme polimorfe di rifaximina, processi per ottenerle e |
ITBO20050123A1 (it) * | 2005-03-07 | 2005-06-06 | Alfa Wassermann Spa | Formulazioni farmaceutiche gastroresistenti contenenti rifaximina |
WO2008021089A2 (en) * | 2006-08-07 | 2008-02-21 | Middlebrook Pharmaceuticals, Inc. | Once-a-day (rna-polymerase inhibiting or phenazine)-dihydropteroate synthase inhibiting-dihydrofolate reductase inhibiting antibiotic pharmaceutical product, formulation thereof, and use thereof in treating infection caused by methicillin-resistant staphylococcus aureus |
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