JP2015522613A - 高置換ヒドロキシアルキルメチルセルロースを含む固体分散体 - Google Patents
高置換ヒドロキシアルキルメチルセルロースを含む固体分散体 Download PDFInfo
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- JP2015522613A JP2015522613A JP2015523138A JP2015523138A JP2015522613A JP 2015522613 A JP2015522613 A JP 2015522613A JP 2015523138 A JP2015523138 A JP 2015523138A JP 2015523138 A JP2015523138 A JP 2015523138A JP 2015522613 A JP2015522613 A JP 2015522613A
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- solid dispersion
- hydroxyalkylmethylcellulose
- water
- substitution
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- 239000002562 thickening agent Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
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- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A61K47/38—Cellulose; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
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Abstract
Description
現在周知の数多くの薬品は低水溶性であり、適切な剤形を調製するために複雑な技術を必要とする。多くの研究は、低水溶性の薬品と結合する薬学的に許容な水溶性ポリマーの使用に費やす。水溶性ポリマーの使用は薬品の結晶化を減衰させる狙いがあり、それによって、薬品の溶解のために必要な活性化エネルギーを最小化し、ならびに薬品分子のまわりで親水性状況を確立し、それによって生物学的利用能、すなわち、投与の際に個体によるその生体内吸収を増すために、薬品そのものの溶解度を向上させることである。しかしながら、低水溶性の薬品での水溶性ポリマーの単純な混合は、一般的に薬の結晶化度を減衰せず、一般的に前述薬品の可溶性も改善しない。
−a)1.0〜2.7のDSおよび0.40〜1.30のMSを有し、DSは、メトキシル基の置換度であり、MSはヒドロキシアルコキシル基のモル置換である、少なくとも1つのヒドロキシアルキルメチルセルロースと、b)1つ以上の有効成分と、c)1つ以上の任意の添加剤とを混合するステップと、
−混合物に対して押出を行うステップと、を含む。
−a)1.0〜2.7のDSおよび0.40〜1.30のMSを有し、DSは、メトキシル基の置換度であり、MSはヒドロキシアルコキシル基のモル置換である、少なくとも1つのヒドロキシアルキルメチルセルロースと、b)1つ以上の有効成分と、c)1つ以上の任意の添加剤と、d)液体組成物を調製するための有機液体希釈剤とを混合するステップと、
−液体組成物から液体希釈剤を除去するステップと、を含む。
米国薬局方(USP35、「ヒプロメロース」3467〜3469頁)に従って、ヒドロキシプロピルメチルセルロース(HPMC)の%メトキシルおよび%ヒドロキシプロピルの測定が実施される。得られる値は、%メトキシルおよび%ヒドロキシプロピルである。これらを、次にメチル置換基の置換度(DS)およびヒドロキシプロピル置換基のモル置換(MS)に換算する。残存する塩は、換算して検討した。
過飽和レベルの水溶液で薬品濃縮を維持する実施例1および2および比較実施例A〜CのHPMCの能力は、難溶性薬品グリセオフルビンおよびフェニトインで試験された。
グリセオフルビンで押出
バッチ調製:0.65グラムのグリセオフルビン(220℃の融解温度を有する)および5.85グラムの実施例1、3〜5および比較実施例CのHPMCを正確に計量し、小さなプロピレン袋に移送した。袋を密封され、製剤を振動により20秒間手動で混合した。続いて、材料を押出機への簡単な移送のために、袋から秤量ボートへ移送した。
0.6グラムのグリクラジドを除いて、実施例5および比較実施例Cは繰り返され、5.4グラムのHPMCは正確に計量され、押出パラメータは下記表4に記載された。
溶液調製:2%の溶解された固体を含む噴霧乾燥の溶液を、テフロン(登録商標)で被覆した撹拌子でガラス槽に90/10(w/w)のテトラヒドロフラン/水混合物の9.8gを計量することによって調製した。撹拌した溶剤混合物に対し、グリセオフルビンを十分に溶解するまで追加し撹拌した。グリセオフルビンを十分に溶解した後、HPMCを撹拌した溶液に追加した。溶液をHPMCが溶解するまで撹拌するようにした。調製された溶液は表5に詳述される。
サンプル調製:実施例6または比較実施例Bの6グラムのダナゾールおよび14グラムのHPMCを磁気撹拌子で一晩撹拌することによって180g塩化メチレンを溶解した。結果として生じる溶液をバーの下で50mil(1.27mm)ドローダウンバーを使用するガラス板の上に流延した。結果として生じるフィルムをヒュームフードで室温で乾燥するようにした。乾燥したフィルムをガラス板から徐々に剥がし、Alpine粉砕を使用して粉末へと粉砕した。
Claims (13)
- 1.0〜2.7のDSおよび0.40〜1.30のMSを有する少なくとも1つのヒドロキシアルキルメチルセルロース中に少なくとも1つの有効成分を含む固体分散体であって、DSが、メトキシル基の置換度であり、MSがヒドロキシアルコキシル基のモル置換である、固体分散体。
- 前記少なくとも1つのヒドロキシアルキルメチルセルロースが1.0〜2.1のDSを有する、請求項1に記載の固体分散体。
- 前記少なくとも1つのヒドロキシアルキルメチルセルロースが0.50〜1.20のMSを有する、請求項1または2に記載の固体分散体。
- 前記少なくとも1つのヒドロキシアルキルメチルセルロースが1.6〜2.1のDSおよび0.60〜1.10のMSを有する、請求項1〜3のいずれか一項に記載の固体分散体。
- 前記DSおよびMSの合計が1.8〜3.2である、請求項1〜4のいずれか一項に記載の固体分散体。
- ストランド、ペレット、細粒、丸剤、錠剤、カプレット、微小粒子、カプセルの充填物、もしくは射出成形カプセルの形態、または粉末、フィルム、ペースト、クリーム、懸濁液、もしくはスラリーの形態である、請求項1〜5のいずれか一項に記載の固体分散体。
- 請求項1〜6のいずれか一項に記載の押出固体分散体。
- 固体分散体を生成するプロセスであって、
a)1.0〜2.7のDSおよび0.40〜1.30のMSを有し、DSが、メトキシル基の置換度であり、MSがヒドロキシアルコキシル基のモル置換である、少なくとも1つのヒドロキシアルキルメチルセルロースと、b)1つ以上の有効成分と、c)1つ以上の任意の添加剤とを混合するステップと、
前記混合物に対して押出を行うステップと、を含む、プロセス。 - 前記少なくとも1つのヒドロキシアルキルメチルセルロースa)および前記1つ以上の有効成分b)の総量が、前記混合物の総重量に基づき、少なくとも70パーセントである、請求項8に記載のプロセス。
- 固体分散体を生成するプロセスであって、
a)1.0〜2.7のDSおよび0.60〜1.30のMSを有し、DSが、メトキシル基の置換度であり、MSがヒドロキシアルコキシル基のモル置換である、少なくとも1つのヒドロキシアルキルメチルセルロースと、b)1つ以上の有効成分と、c)1つ以上の任意の添加剤と、d)液体組成物を調製するための有機液体希釈剤とを混合するステップと、
前記液体組成物から液体希釈剤を除去するステップと、を含む、プロセス。 - 前記液体組成物が、噴霧乾燥を行う、請求項10に記載のプロセス。
- 前記組成物が任意の添加剤として水を含み、前記組成物が、有機液体希釈剤および水の総重量に基づき、50重量パーセントを超える有機液体希釈剤および50重量パーセント未満の水を含み、有機液体希釈剤および水が前記液体組成物から除去される、請求項10または11に記載のプロセス。
- 請求項1〜7のいずれか一項に記載の固体分散体を調製するための、請求項8〜12のいずれか一項に記載のプロセス。
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