JP2017510625A - 医薬組成物 - Google Patents
医薬組成物 Download PDFInfo
- Publication number
- JP2017510625A JP2017510625A JP2016571474A JP2016571474A JP2017510625A JP 2017510625 A JP2017510625 A JP 2017510625A JP 2016571474 A JP2016571474 A JP 2016571474A JP 2016571474 A JP2016571474 A JP 2016571474A JP 2017510625 A JP2017510625 A JP 2017510625A
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- JP
- Japan
- Prior art keywords
- carrier
- active ingredient
- pharmaceutical composition
- trametinib
- weight
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 52
- 239000004480 active ingredient Substances 0.000 claims abstract description 67
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- 229960004066 trametinib Drugs 0.000 claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 66
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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Abstract
Description
(a1)前記有効成分および前記担体を溶媒に溶解する工程および
(b1)工程(a1)で得られた溶液を乾燥、好ましくは噴霧乾燥または凍結乾燥する工程
を含む乾燥法、具体的には噴霧乾燥法または凍結乾燥法に関する。
段階1:前記溶液を凍結し、好ましくは該溶液の三重点を下回るよう、減圧を行う。
段階2:温度を、好ましくは昇華曲線に示される温度まで上昇させ、昇華潜熱を与える。昇華が完了した後、凍結乾燥品を室温まで昇温させる。
(a2)前記有効成分と溶融した前記担体とを混合する工程および
(b2)工程(a2)で得られた混合物を押出する工程
を含む方法に関する。
(c2)前記押出物を医薬製剤用の型に射出して成形する工程
を含む。
(i)1〜40重量%、より好ましくは5〜35重量%、特に7〜35重量%の中間体および
(ii)1〜30重量%、より好ましくは2〜15重量%、特に4〜10重量%の崩壊剤
を含む。
(I)本発明の中間体および1以上の医薬品賦形剤(特に先に記載の賦形剤)を調製する工程、
(II)該中間体を圧縮してフレークとする工程、および
(III)該フレークを造粒するか、または粉砕により顆粒とする工程
を含む方法に関する。
(IV)顆粒、および任意に含んでいてもよい1以上の医薬品賦形剤を錠剤へと圧縮成形する工程
を含む方法を提供することである。
(I)本発明の中間体および1以上の医薬品賦形剤(特に先に記載の賦形剤)を調製し、任意に混合する工程、ならびに
(IV)該中間体および該1以上の医薬品賦形剤を錠剤へと圧縮成形する工程
を含む方法を提供することである。
比較例1において、米国で市販されているMekinist(登録商標)錠剤2mgを試験した。この錠剤は、有効成分としてトラメチニブのジメチルスルホキシド溶媒和物を含む。処方情報によると、Mekinist(登録商標)錠剤は、非有効成分としてマンニトール、微結晶性セルロース、ヒプロメロース、クロスカルメロースナトリウム、ステアリン酸マグネシウム、ラウリル硫酸ナトリウム、およびコロイド状二酸化ケイ素を錠剤コアに含む。2mg錠剤のコーティングには、ヒプロメロース、二酸化チタン、ポリエチレングリコール、ポリソルベート80、およびベンガラが使用される。前記方法に従って測定されるMekinist2mg錠剤の溶解プロファイルを図1に示す。
以下の成分を含む錠剤を調製した。
コポビドンをメタノールとジクロロメタンとの混合物に攪拌下で溶解した。トラメチニブを加え、完全に溶解するまで撹拌した。得られた溶液をBuchi B−290を使用して窒素雰囲気下で噴霧乾燥した(入口空気温度:90℃、アスピレーター:100%、ポンプ速度:6%)。得られた粉末を40℃、0.1ミリバールの真空棚式乾燥機で66時間乾燥した。
以下の成分を含む錠剤を調製した。
HPMCAS(ヒドロキシプロピルメチルセルロースアセテートサクシネート)をメタノールとジクロロメタンとの混合物に攪拌下で溶解した。トラメチニブを加え、完全に溶解するまで撹拌した。得られた溶液をBuchi B−290を使用して窒素雰囲気下で噴霧乾燥した(入口空気温度:90℃、アスピレーター:100%、ポンプ速度:6%)。得られた粉末を40℃、0.1ミリバールの真空棚式乾燥機で66時間乾燥した。
以下の成分を含む錠剤を調製した。
コポビドンおよびSDSをメタノールとジクロロメタンとの混合物に攪拌下で溶解した。トラメチニブを加え、完全に溶解するまで撹拌した。得られた溶液をBuchi B−290を使用して窒素雰囲気下で噴霧乾燥した(入口空気温度:90℃、アスピレーター:100%、ポンプ速度:6%)。得られた粉末を40℃、0.1ミリバールの真空棚式乾燥機で16時間乾燥した。
以下の成分を含む錠剤を調製した。
コポビドンおよびSDS(4)をメタノールとジクロロメタンとの混合物に攪拌下で溶解した。トラメチニブを加え、完全に溶解するまで撹拌した。イソマルトを溶液中に懸濁し、UltraTurraxを使用してホモジナイズした。得られた懸濁液を攪拌下で、Buchi B−290を使用して窒素雰囲気下で噴霧乾燥した(入口空気温度:85℃、アスピレーター:100%、ポンプ速度:6%)。得られた粉末を40℃、0.1ミリバールの真空棚式乾燥機で32時間乾燥した。
以下の成分を含む錠剤を調製した。
トラメチニブ、Soluplus、およびSDS(3)を加熱板上で溶融し、撹拌によってホモジナイズした。得られた溶融物を、室温に冷却し、粉砕し、篩過した(メッシュサイズ:500μm)。
実施例2、3、4の医薬組成物、および対照としてMekinist(登録商標)錠剤を用いて、バイオアベイラビリティに関する研究(ビーグル犬を使用した研究)を行った。結果を以下の表に要約する。
群1:対照
群2:実施例3に相当
群3:実施例4に相当
群4:実施例2に相当
Claims (15)
- 有効成分としてのトラメチニブまたはその薬学的に許容される塩と、担体とを含む医薬組成物であって、該担体が、該有効成分を包み込むマトリックスを形成し、該有効成分に含有されるジメチルスルホキシドが、該組成物中に存在する、塩を形成せずかつ溶媒和されていない形態におけるトラメチニブの総重量に対して1重量%未満であることを特徴とする医薬組成物。
- 請求項1に記載の医薬組成物であって、該組成物に含有されるジメチルスルホキシドが、該組成物中に存在する、塩を形成せずかつ溶媒和されていない形態におけるトラメチニブの総重量に対して1重量%未満であることを特徴とする組成物。
- 前記担体がポリマー、脂肪類、蝋類、糖類、糖アルコール類、グリコール、脂肪酸類、脂肪酸類の塩、脂肪酸エステル類、および脂肪族アルコール類から選択されることを特徴とする、請求項1または2に記載の医薬組成物。
- 前記有効成分が固溶体または固体分散体の形態で前記担体中に含まれることを特徴とする、先行する請求項のいずれかに記載の医薬組成物。
- 前記担体のガラス転移温度(Tg)が20℃以上であることを特徴とする、先行する請求項のいずれかに記載の医薬組成物。
- 前記担体が親水性または両親媒性であることを特徴とする、先行する請求項のいずれかに記載の医薬組成物。
- 前記担体がポリビニルピロリドン、ポリビニルアセテート(PVAC)、ポリビニルアルコール(PVA)、アクリル酸ポリマーおよびそれらの塩、ポリアクリルアミド、ポリメタクリレート類、ビニルピロリドン−ビニルアセテートコポリマー、ポリアルキレングリコール類、ポリエチレングリコールとポリプロピレングリコールとのコブロックポリマー、ポリエチレンオキシド、ヒドロキシプロピルメチルセルロース(HPMC)、ヒドロキシプロピルメチルセルロースアセテートサクシネート(HPMCAS)、ポリビニルカプロラクタム−ポリビニルアセテート−ポリエチレングリコールグラフトコポリマー、ならびにこれらの混合物からなる群から選択されることを特徴とする、先行する請求項のいずれかに記載の医薬組成物。
- 固体経口剤形、好ましくは顆粒、カプセル、または錠剤であることを特徴とする、先行する請求項のいずれかに記載の医薬組成物。
- 即放性製剤であることを特徴とする、先行する請求項のいずれかに記載の医薬組成物。
- 有効成分としてのトラメチニブまたはその薬学的に許容される塩と、担体とを含む中間体であって、該担体が、該有効成分を包み込むマトリックスを形成し、該有効成分に含有されるジメチルスルホキシドが、該組成物中に存在する、塩を形成せずかつ溶媒和されていない形態におけるトラメチニブの総重量に対して1重量%未満であることを特徴とする中間体。
- 前記担体がポリマー、脂肪類、蝋類、糖類、糖アルコール類、グリコール、脂肪酸類、脂肪酸類の塩、脂肪酸エステル類、および脂肪族アルコール類から選択されることを特徴とする、請求項10に記載の中間体。
- ガラス転移温度(Tg)が20℃以上であることを特徴とする、請求項10または11に記載の中間体。
- 前記有効成分と前記担体との重量比が1:1〜1:150、好ましくは1:1〜1:100であることを特徴とする、請求項10〜12のいずれかに記載の中間体。
- 請求項10〜13のいずれかに記載の中間体を含み、少なくとも1つのさらなる医薬品賦形剤を任意に含んでいてもよいことを特徴とする、請求項1〜9のいずれかに記載の医薬組成物。
- 請求項1〜9のいずれかもしくは14に記載の医薬組成物または請求項10〜13のいずれかに記載の中間体を調製する方法であって、
(a1)前記有効成分および前記担体を溶媒に溶解する工程および
(b1)工程(a1)で得られた溶液を、好ましくは噴霧乾燥または凍結乾燥により乾燥する工程、または
(a2)前記有効成分と溶融した前記担体とを混合する工程および
(b2)工程(a2)で得られた混合物を押出する工程
を含む方法。
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Application Number | Priority Date | Filing Date | Title |
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EP14157041.6A EP2913048A1 (en) | 2014-02-27 | 2014-02-27 | Pharmaceutical composition comprising trametinib |
EP14157041.6 | 2014-02-27 | ||
PCT/EP2015/053764 WO2015128298A1 (en) | 2014-02-27 | 2015-02-24 | Pharmaceutical composition |
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EP (2) | EP2913048A1 (ja) |
JP (1) | JP2017510625A (ja) |
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US11273126B2 (en) | 2017-03-15 | 2022-03-15 | Sun Pharma Advanced Research Company Limited | Amorphous dispersion of cyclopropanecarboxylic acid (5-{5-[N′-(2-chloro-6-methylbenzoyl) hydrazinocarbonyl]-2-methyl-phenylethynyl}-pyridin-2-yl) amide |
JP7234129B2 (ja) * | 2017-03-15 | 2023-03-07 | サン・ファーマ・アドバンスド・リサーチ・カンパニー・リミテッド | 4-メチル-3-キノリン-3-イルエチニル-安息香酸n’-(2-クロロ-6-メチル-ベンゾイル)ヒドラジドの新規非晶質分散体 |
ES2968399T3 (es) | 2017-03-30 | 2024-05-09 | Merck Patent Gmbh | Formulación farmacéutica |
WO2023219465A1 (ko) * | 2022-05-12 | 2023-11-16 | 주식회사 지뉴브 | 안정한 액상 제약 제제 |
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JPH11116502A (ja) * | 1997-08-11 | 1999-04-27 | Pfizer Prod Inc | 噴霧乾燥固体分散系を含む組成物 |
WO2006087919A1 (ja) * | 2005-01-28 | 2006-08-24 | Takeda Pharmaceutical Company Limited | 難水溶性物質含有微細化組成物 |
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US7378423B2 (en) | 2004-06-11 | 2008-05-27 | Japan Tobacco Inc. | Pyrimidine compound and medical use thereof |
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JP2013505939A (ja) | 2009-09-23 | 2013-02-21 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | 組合せ |
WO2011146712A1 (en) | 2010-05-21 | 2011-11-24 | Glaxosmithkline Llc | Combination |
WO2012027438A1 (en) * | 2010-08-26 | 2012-03-01 | Glaxosmithkline Llc | Pharmaceutical combination of a vegfr inhibitor and a mek inhibitor useful for treating cancer |
TWI505828B (zh) | 2010-12-20 | 2015-11-01 | 葛蘭素史克智慧財產(第二)有限公司 | 新穎醫藥組成物 |
-
2014
- 2014-02-27 EP EP14157041.6A patent/EP2913048A1/en not_active Withdrawn
-
2015
- 2015-02-24 WO PCT/EP2015/053764 patent/WO2015128298A1/en active Application Filing
- 2015-02-24 EP EP15705830.6A patent/EP3110406B1/en active Active
- 2015-02-24 US US15/120,426 patent/US20170014414A1/en not_active Abandoned
- 2015-02-24 EA EA201691741A patent/EA031607B1/ru not_active IP Right Cessation
- 2015-02-24 CA CA2934586A patent/CA2934586A1/en not_active Abandoned
- 2015-02-24 JP JP2016571474A patent/JP2017510625A/ja active Pending
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Also Published As
Publication number | Publication date |
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EP2913048A1 (en) | 2015-09-02 |
WO2015128298A1 (en) | 2015-09-03 |
EA031607B1 (ru) | 2019-01-31 |
EA201691741A1 (ru) | 2017-02-28 |
EP3110406B1 (en) | 2018-04-04 |
EP3110406A1 (en) | 2017-01-04 |
CA2934586A1 (en) | 2015-09-03 |
US20170014414A1 (en) | 2017-01-19 |
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