JP2009539804A - Tmc125の噴霧乾燥された調製物の調製方法 - Google Patents
Tmc125の噴霧乾燥された調製物の調製方法 Download PDFInfo
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- JP2009539804A JP2009539804A JP2009513696A JP2009513696A JP2009539804A JP 2009539804 A JP2009539804 A JP 2009539804A JP 2009513696 A JP2009513696 A JP 2009513696A JP 2009513696 A JP2009513696 A JP 2009513696A JP 2009539804 A JP2009539804 A JP 2009539804A
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Abstract
Description
製薬学的剤形に転換することにより、さらに加工することができる。
しても顕著な活性を示す。例えば噴霧−乾燥により、TMC125を固体分散系に転換することは、そのバイオアベイラビリティーを向上させる。
(a)微結晶性セルロースならびに水溶性ポリマーとTMC125の溶液の供給混合物を準備し;
(b)霧散(atomizing)手段を介して噴霧−乾燥室中に供給混合物を液滴として導入することにより、段階(a)からの供給混合物を噴霧−乾燥して製薬学的作用剤とポリマーの固体分散系を形成する
段階を含んでなる、固体製薬学的粉末の製造方法を提供する。
提供する。
JRS Pharmaから入手可能な微結晶性セルロース製品、特にVivapurTM
105(20μm)、VivapurTM 101(50μm)、EmcocelTM
SP 15(15μm)、EmcocelTM 50M 105(50μm)、ProsolvTM SMCC 50(50μm);
DMVから入手可能な微結晶性セルロース製品、特にPharmacelTM 105(20μm)、PharmacelTM 101(50μm);
Blanverから入手可能な微結晶性セルロース製品、特にTabulose(Microcel)TM101(50μm)、Tabulose(Microcel)TM103(50μm);
Asahi Kasei Corporationから入手可能な微結晶性セルロース製品、例えばCeolusTM PH−F20JP(20μm)、CeolusTM PH−101(50μm)、CeolusTM PH−301(50μm)、CeolusTM KG−802(50μm)
を含む。
である。
15mPa.sである。ヒドロキシプロピルメチルセルロースは、ヒプロメロースに関する合衆国採択名(United States Adopted Name)である(Martindale,The Extra Pharmacopoeia,29th edition,1435頁を参照されたい)。4個の数字「2910」において、最初の2個の数字はメトキシ基の大体のパーセンテージを示し、第3及び第4の数字はヒドロキシプロポキシル基の大体のパーセンテージ組成を示す;15mPa.s又は5mPa.sは、20℃における2%水溶液の見掛粘度を示す値である。
混合物、より好ましくは9:1の重量比におけるジクロロメタンとエタノールの混合物であり、特に後者が無水エタノールである混合物である。ポリマーがポリビニルピロリドン又はコポリビドンである場合、溶媒は、好ましくはアセトンである。供給混合物中に存在する溶媒の量は、TMC125及び水溶性ポリマーが溶解され、且つ供給混合物が、それが噴霧されるのに十分に低い粘度を有するような量であろう。1つの態様において、供給混合物中の溶媒の量は少なくとも80%、特に少なくとも90%、好ましくは少なくとも95%であり、パーセンテージは供給混合物の合計重量に対する溶媒の重量を表す。
(i)14.57gのジクロロメタン エクストラピュア及び1.619gのエタノール96%(v/v)中の200mgのTMC125、200mgのHPMC 2910 5mPa.s、100mgの微結晶性セルロース(Avicel PH 105(R));(ii)14.57gのジクロロメタン エクストラピュア及び1.619gのエタノール96%(v/v)中の200mgのTMC125、400mgのHPMC 2910 5mPa.s、100mgの微結晶性セルロース(Avicel PH 105(R));
(iii)14.57gのジクロロメタン エクストラピュア及び1.619gのエタノール96%(v/v)中の200mgのTMC125、600mgのHPMC 2910
5mPa.s、100mgの微結晶性セルロース(Avicel PH 105(R));
(iv)16.19gのジクロロメタン エクストラピュア及び1.8gの無水エタノール中の222mgのTMC125、667mgのHPMC 2910 5mPa.s、111mgの微結晶性セルロース(Avicel PH 105(R));
を含んでなるものである。
う用語は、数値の関係におけるその通常の意味を有するものとする。必要なら、「約」という用語を数値±10%又は±5%又は±2%又は±1%により置き換えることができる。本明細書で引用したすべての文書は、引用することによりその記載事項全体が本明細書の内容となる。
1)MCCを用いる及び用いない噴霧−乾燥された粉末の製造
●TMC125:HPMC(1:3)
MCCを用いない調製物の供給混合物は、540kgのジクロロメタン及び60kgの無水エタノール(99.9%)中に8.64kgのTMC125、25.0kgのHPMC 2910 5mPa.sを含有した。この供給混合物を次いで下記の表に示す条件下で、共−流モードにおける高圧ノズルを介してSD−12.5−N、閉鎖サイクル噴霧−乾燥室に入れた。
●TMC125:HPMC:MCC(1:3:0.5)
2.1)溶解試験
●採取される試料の重量:200mg
●溶解媒体:750ml FeSSIF+250ml 0.01M HCl
●溶解法:100RPM,5分毎に試料を集めた,実験時間 180分
●温度:37℃
3ミリモル/lのタウロコール酸ナトリウム(NaTC)及び0.75ミリモル/lのレシチンを含有し、6.50のpH及び270ミリオスモル/kgの容量オスモル濃度を有するFassifを以下の通りに調製した:
5リットルの脱イオン水中に1.74gのNaOH(ペレット)、19.77gのNaH2PO4.H2O(又は17.19gの無水NaH2PO4)及び30.93gのNaClを溶解した。1N NaOH又は1N HClを用いて、pHを正確に6.5に調整した。
1.500mlのブランクFaSSIF中に3.3g*のタウロコール酸ナトリウム(NaTC)を溶解した。
2.約12ml*の塩化メチレン中に1.18g*のレシチンを溶解した。
3.レシチン溶液をタウロコール酸ナトリウム溶液に加え、エマルションを形成した。
4.真空下に40℃において塩化メチレンを除去した(例えば回転蒸発器を用いて)。徐々に真空を構成することにより、回転蒸発器のフラスコから泡が出るのを避けるように注意した。これは、感知し得る塩化メチレンの臭いを有していないほとんど透明なミセル溶液を生じた。
5.室温に冷ました後、ブランクFaSSIFを用いて体積を2リットルに調整した。
*より大きい体積のFaSSIFの調製のために(6リットルまで)、NaTCの量を倍増させることができ、それでもこれを500mlのブランクFaSSIFに溶解する。それに従ってレシチン及び塩化メチレンの量を調整する。
カラム:50*3mm 内径,Xterra MS−C18,5Mm粒度
溶離モード:アイソクラチック
流量:0.5ml/分
移動相:35%A及び65%B
A:リン酸0.5%
B:アセトニトリル
検出:260nmにおけるUV
注入体積:100μl
実験時間:3分
カラム温度:35℃
0.1mlの濾過された試料を溶解媒体から集め、0.9mlの35/65 リン酸(0.5%)/アセトニトリル中で希釈した。次いで試料を直接注入し、分析した。すべての試料を二重に分析し、再現性に関して調べた。各分析に関し、20μl〜25μlの濃度範囲で2つの標準を作り、二重に分析した。HPLCからのAUCデータを集め、計算し、Microsoft Excelにおいてプロッティングした。
図1における溶解の結果は、調製の直後(保存なし)の噴霧乾燥された粉末を用いる溶解試験から得られた。
約300mgの各調製物(TMC125:HPMC(1:3)及びTMC125:HPMC:MCC(1:3:0.5)を10mlのアンプル中に装填し、飽和塩溶液を含有する25℃におけるデシケーター中に装入し、以下の相対湿度雰囲気を与えた:
●22%RH
●43%RH
●59%RH
●91%RH
図1:2つの寸法分別された試料、すなわち粒度分別された(45<x<100μm)TMC125:HPMC(1:3)及び粒度分別された(45<x<100μm)TMC125:HPMC:MCC(1:3:0.5)の、得られる溶解放出速度論。
図2−9:種々の相対湿度における2週間又は4週間の安定性保存の後のTMC125:HPMC(1:3)及びTMC125:HPMC:MCC(1:3:0.5)(乾燥された)の試料に関して得られた溶解分布。
Claims (11)
- (a)微結晶性セルロースならびに水溶性ポリマーとTMC125の溶液の供給混合物を準備し;
(b)霧散手段を介して噴霧−乾燥室中に供給混合物を液滴として導入することにより、段階(a)からの供給混合物を噴霧−乾燥して製薬学的作用剤とポリマーの固体分散系を形成する
段階を含んでなる、固体製薬学的粉末の製造方法。 - 微結晶性セルロースが5〜50μm、特に10〜30μmの平均有効粒度を有する請求項1の方法。
- 水溶性ポリマーがヒドロキシプロピルメチルセルロース、ポリビニルピロリドン及びコポリビドンから選ばれる請求項1〜2のいずれかの方法。
- ポリマーがヒドロキシプロピルメチルセルロースである請求項3の方法。
- ポリマー対製薬学的作用剤の比が10:1〜1:1の範囲内、特に5:1〜1:1の範囲内である請求項1〜4のいずれかの方法。
- MCC対TMC125の比が1:1〜1:3の範囲内、特に約1:2である請求項5の方法。
- 溶媒がアセトン、ジクロロメタン、エタノール、メタノール及びそれらの組み合わせから選ばれる請求項1〜6のいずれかの方法。
- 霧散手段が高圧ノズルを含む請求項1〜7のいずれかの方法。
- 請求項1〜8のいずれかの方法により得ることができる粉末形態におけるTMC125の固体分散系。
- 請求項9で定義される粉末及びさらなる賦形剤を含んでなる製薬学的調製物。
- 請求項9で定義される粉末及びさらなる賦形剤を含んでなる固体剤形。
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