JP6125547B2 - 無定形レボノルゲストレル、固体分散体及びそれらの製造方法 - Google Patents
無定形レボノルゲストレル、固体分散体及びそれらの製造方法 Download PDFInfo
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- JP6125547B2 JP6125547B2 JP2014561677A JP2014561677A JP6125547B2 JP 6125547 B2 JP6125547 B2 JP 6125547B2 JP 2014561677 A JP2014561677 A JP 2014561677A JP 2014561677 A JP2014561677 A JP 2014561677A JP 6125547 B2 JP6125547 B2 JP 6125547B2
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- levonorgestrel
- solid dispersion
- amorphous
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- polymer
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—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
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Description
無定形レボノルゲストレルは、粉末X線回折スペクトルにおいて、結晶構造に由来する回折ピークを実質的に有しておらず、入射X線の散乱に由来するハロー回折パターンを示す。
(製造方法)
無定形レボノルゲストレルは、例えば、レボノルゲストレルの3位のオキソ基(=O)をアンモニア又は第1級アミンによりイミノ化し、生成したイミノ体を加水分解することにより製造できる。
本発明の固体分散体は、レボノルゲストレルがポリマーに無定形(アモルファス)の形態で分散している。前記ポリマーは、水溶性ポリマーであってもよく、水不溶性ポリマーであってもよい。また、水不溶性ポリマーは、不溶性ポリマー、胃溶性ポリマーあるいは腸溶性ポリマーであってもよい。
本発明の固体分散体は、レボノルゲストレルと前記ポリマーとを、前記と同様の割合で溶媒に溶解し、結晶化を防ぎつつ溶媒を除去することにより製造することができる。溶媒は、前述の無定形レボノルゲストレルの製造方法で使用可能な溶媒を用いることができ、例えば、アルコール類(エタノール、プロパノール、イソプロパノールなど)、ハロゲン化炭化水素類(塩化メチレン、クロロホルムなど)、エーテル類(ジオキサン、テトラヒドロフランなど)、アミド類(N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミドなど)、スルホキシド類(ジメチルスルホキシドなど)、ニトリル類(アセトニトリル、ベンゾニトリルなど)、又はこれらの混合溶媒であってもよい。
本発明の無定形レボノルゲストレル及び固体分散体は、緊急避妊薬として好適に用いられ、単独で医薬として用いてもよく、担体(薬理学的又は生理学的に許容可能な担体など)と組み合わせて医薬組成物(又は製剤)として用いてもよい。
粉末X線回折スペクトルは、線源:Cu K(α1)、管電圧:40kV、管電流:40mA、サンプリング間隔:0.01°、スキャン速度10°/分の条件で測定した。なお、粉末X線回折チャートにおいて、回折ピークは、ピーク幅の閾値を0.1°として、二次微分法によりサーチした。
示差走査熱量スペクトルは、示差走査熱量計(型式:DSC8230L)を用いて、昇温速度10℃/分の条件で測定した。
レボノルゲストレル(Industriale Chimica社製)200mgにプロピルアミン2mLを加え、40℃に加熱してレボノルゲストレルを溶解させた後、室温で4日間放置して、プロピルアミンを自然蒸発させた。
レボノルゲストレル(Industriale Chimica社製)1gにプロピルアミン15mLを加え、2時間加熱還流して溶液を得た。この溶液を室温で2日間放置した後、溶液中のプロピルアミンを減圧留去して、レボノルゲストレルのプロピルイミノ体を得た。
レボノルゲストレル(Industriale Chimica社製)30mgをクロロホルム3mLに溶解し、ヒドロキシプロピルメチルセルロース(信越化学工業(株)社製「TC−5R」、濃度2重量%及び温度20℃における水溶液粘度6mPa・s)90mgを添加して溶解した。その後、クロロホルムを減圧留去し、残渣を減圧乾燥した後、乳鉢で粉砕することにより、白色粉末を得た。
市販のレボノルゲストレル(Industriale Chimica社製)の結晶を比較例1とした。
レボノルゲストレル(Industriale Chimica社製)1gをエタノール500mLに溶解した。その後、噴霧乾燥装置(ヤマト科学株式会社製「Pluvis Mini-Spray Model GS-31」)を用いて、乾燥媒体:窒素ガス、乾燥温度:90℃の条件で溶液を噴霧乾燥し、白色粉末を得た。
実施例3の固体分散体の粉末10mg(レボノルゲストレルを2.5mg含む)又は比較例1の結晶粉末2.5mgとヒドロキシプロピルメチルセルロース7.5mgとを均一にした混合物10mgを、37℃の1%Tween80水溶液40mLに添加し、試験液を攪拌しつつ、添加から一定時間毎に2mLをサンプリングし、クロマトディスク(孔径0.2μm)でろ過し、高性能液体クロマトグラフ(装置:島津製作所製「LC−2010AHT」、検出器:UV240nm、カラム:ウォーターズ社製「XBridge C18 5μm」、カラム温度:35℃付近の一定温度、移動相:アセトニトリル/0.1%トリフルオロ酢酸水溶液の混液(3:2))によりろ液のレボノルゲストレル濃度を測定した。結果を表1及び図4に示す。
Claims (7)
- 水溶性セルロースエーテル類にレボノルゲストレルが無定形の形態で分散している固体分散体であって、前記水溶性セルロースエーテル類が、ヒドロキシプロピルメチルセルロース及びヒドロキシプロピルセルロースから選択された少なくとも一種を含む固体分散体。
- 水溶性セルロースエーテル類が、濃度2重量%及び温度20℃において500mPa・s以下の溶液粘度を有する請求項1記載の固体分散体。
- 水溶性セルロースエーテル類とレボノルゲストレルとの重量比が、水溶性セルロースエーテル類/レボノルゲストレル=90/10〜50/50である請求項1又は2記載の固体分散体。
- アンモニア又は第1級アミンによりイミノ化したレボノルゲストレルのイミノ体を加水分解して、示差走査熱量スペクトルにおいて、51〜61℃に発熱ピークを有する無定形レボノルゲストレルを製造する方法。
- レボノルゲストレルと、水溶性セルロースエーテル類と、溶媒とを含む溶液から前記溶媒を除去して、請求項1〜3のいずれかに記載の固体分散体を製造する方法であって、前記水溶性セルロースエーテル類が、ヒドロキシプロピルメチルセルロース及びヒドロキシプロピルセルロースから選択された少なくとも一種を含む、製造方法。
- 請求項1〜3のいずれかに記載の固体分散体を含む医薬組成物。
- 緊急避妊剤である請求項6記載の医薬組成物。
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