JP6516759B2 - 安定化エフィナコナゾール組成物 - Google Patents
安定化エフィナコナゾール組成物 Download PDFInfo
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- JP6516759B2 JP6516759B2 JP2016546886A JP2016546886A JP6516759B2 JP 6516759 B2 JP6516759 B2 JP 6516759B2 JP 2016546886 A JP2016546886 A JP 2016546886A JP 2016546886 A JP2016546886 A JP 2016546886A JP 6516759 B2 JP6516759 B2 JP 6516759B2
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- efinaconazole
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Description
本出願は、2013年10月3日に出願された米国特許仮出願第61/886,569号、および2014年1月1日に出願された米国特許仮出願第61/922,867号に対する優先権を主張し、これらの出願はその全体が参照により本明細書に組み入れられる。
ケトコナゾール、イトラコナゾールおよびフルコナゾールなどのトリアゾール系抗真菌化合物が知られており、科学的研究、医薬開発および医療用途の対象となっている。このクラスの化合物は抗真菌活性を示すことが多いが、異なる種類の医薬製剤および治療では有効性および有用性の点で異なる。エフィナコナゾール(CAS登録番号 164650-44-6)は、爪真菌症の治療において活性を示したトリアゾールである。爪真菌症の治療におけるエフィナコナゾールおよび他のトリアゾール系抗真菌薬の局所送達に有用な製剤は、例えば、米国特許第8,486,978号(特許文献1)に記載されている。トリアゾール系有効成分を含む一部の製剤は、保存時に様々な程度の不安定性を示す。ある種の製剤は、1日または2日という短い保存期間内に変色し、黄色から深紅色または茶色の範囲の組成物の色をもたらすことが知られている。このような変色は、変色した組成物を自己投与することに気が進まない患者による組成物の処方使用を妨げるおそれがある。そのため、エフィナコナゾールなどのトリアゾールの安定化製剤が必要とされる。本発明はこの必要性に応えるものである。
[本発明1001]
約0.5〜約15重量%のエフィナコナゾール、ブチル化ヒドロキシトルエン(BHT)、およびエチレンジアミン四酢酸(EDTA)の塩を含む、液体または半固体の組成物であって、BHTおよびEDTAの塩の量が、該組成物が(i)最初の製剤時に無色であること、および(ii)少なくとも約40℃の温度で少なくとも3週間の保存後に無色または淡黄色であることを確実にするのに十分な量である、前記組成物。
[本発明1002]
約65℃の温度で1ヶ月間の保存後に無色または淡黄色である、本発明1001の組成物。
[本発明1003]
エフィナコナゾールの量が約8%(w/w)〜約12%(w/w)の範囲内である、本発明1001または1002の組成物。
[本発明1004]
エフィナコナゾールの量が約10%(w/w)である、本発明1003の組成物。
[本発明1005]
エフィナコナゾールの量が約0.5%(w/w)〜約5%(w/w)の範囲内である、本発明1001または1002の組成物。
[本発明1006]
エフィナコナゾールの量が約2%(w/w)である、本発明1005の組成物。
[本発明1007]
BHTの量が約0.01%(w/w)〜約2%(w/w)の範囲内である、本発明1001〜1006のいずれかの組成物。
[本発明1008]
EDTAの塩の量が約0.0001%(w/w)〜約1.5%(w/w)の範囲内である、本発明1001〜1007のいずれかの組成物。
[本発明1009]
EDTAの塩の量が約0.0001%(w/w)〜約0.0005%(w/w)の範囲内である、本発明1008の組成物。
[本発明1010]
溶液として製剤化される、本発明1009の組成物。
[本発明1011]
EDTAの塩の量が約0.00025%(w/w)であり、かつBHTの量が約0.1%(w/w)である、本発明1009または1010の組成物。
[本発明1012]
EDTAの塩の量が約0.01%(w/w)〜約1%(w/w)の範囲内である、本発明1008の組成物。
[本発明1013]
ゲルとして製剤化される、本発明1012の組成物。
[本発明1014]
EDTAの塩の量が約0.1%(w/w)であり、かつBHTの量が約0.1%(w/w)である、本発明1012または1013の組成物。
[本発明1015]
約0.01%(w/w)クエン酸〜約1%(w/w)クエン酸をさらに含む、本発明1001〜1014のいずれかの組成物。
[本発明1016]
約0.05%(w/w)クエン酸〜約0.25%(w/w)クエン酸を含む、本発明1015の組成物。
[本発明1017]
約0.075%(w/w)クエン酸〜約0.15%(w/w)クエン酸を含む、本発明1016の組成物。
[本発明1018]
前記組成物の色が目視検査により決定される、本発明1001〜1017のいずれかの組成物。
[本発明1019]
色がUV-vis吸光度値の評価により決定される、本発明1001〜1017のいずれかの組成物。
[本発明1020]
65℃で少なくとも1ヶ月間の保存後に、400 nmで0.4吸光度単位(AU)以下、500 nmで0.1 AU以下、および/または600 nmで0.1 AU以下のUV-vis吸光度値を示す、本発明1019の組成物。
[本発明1021]
65℃で少なくとも1ヶ月間の保存後に、400 nmで0.4 AU以下、500 nmで0.1 AU以下、および600 nmで0.1 AU以下のUV-vis吸光度値を示す、本発明1020の組成物。
[本発明1022]
65℃で少なくとも1ヶ月間の保存後に、400 nmで0.2 AU以下、500 nmで0.03 AU以下、および/または(iii)600 nmで0.03 AU以下のUV-vis吸光度値を示す、本発明1019の組成物。
[本発明1023]
65℃で少なくとも1ヶ月間の保存後に、400 nmで0.2 AU以下、500 nmで0.03 AU以下、および600 nmで0.03 AU以下のUV-vis吸光度値を示す、本発明1022の組成物。
[本発明1024]
65℃で少なくとも1ヶ月間の保存後に、400 nmで0.1 AU以下、500 nmで0.01 AU以下、および/または(iii)600 nmで0.01 AU以下のUV-vis吸光度を示す、本発明1019の組成物。
[本発明1025]
65℃で少なくとも1ヶ月間の保存後に、400 nmで0.1 AU以下、500 nmで0.01 AU以下、および(iii)600 nmで0.01 AU以下のUV-vis吸光度値を示す、本発明1024の組成物。
[本発明1026]
爪の治療において効果的に吸収される薬学的に許容される製剤である、本発明1001〜1025のいずれかの組成物。
[本発明1027]
以下の段階を含む、真菌感染を治療または予防する方法:
本発明1026の製剤の治療的有効量をそのような治療を必要とする患者に投与する段階。
I. 定義
本明細書で用いられる「薬学的組成物」という用語は、エフィナコナゾールなどの薬学的有効成分と、1つまたは複数の薬学的に許容される賦形剤(抗酸化剤、保存剤、担体等)とを含む混合物を指す。局所投与用の組成物は、溶液、スプレー、軟膏、ローション、ゲル、およびシャンプー等として製剤化される。「薬学的に許容される」組成物は、その中で担体、希釈剤および賦形剤などの置換成分が相互におよび有効成分と混合されている組成物である。薬学的に許容される組成物は、医薬品グレードの活性作用物質および賦形剤で作製されることが多い。薬学的に許容される組成物はその受容者に有害でないことが理解されよう。
第1の局面において、本発明は、約0.5〜約15重量%のエフィナコナゾール、ブチル化ヒドロキシトルエン(BHT)、およびエチレンジアミン四酢酸(EDTA)の塩を含む組成物を提供する。当該組成物は、着色剤がない場合(通常このケースである)、最初の製剤時に無色であり、少なくとも3週間の保存期間の後、無色であるかまたは淡黄色を有する。本発明の文脈における組成物は典型的には、液体組成物(例えば、溶液)または半固体組成物(例えば、ゲル、軟膏、ローション、クリームまたは他の形態)である。
好ましい態様において、当該組成物は、約0.5%(w/w)〜約15%(w/w)のエフィナコナゾール(すなわち、KP-103としても知られる、(2R,3R)-2-(2,4-ジフルオロフェニル)-3-(4-メチレンピペリジン-1-イル)-1-(1H-1,2,4-トリアゾール-1-イル)ブタン-2-オール)を含む。
本発明の組成物は典型的には、長い保存期間にわたって色安定性を示す。当該組成物は、約2週間から数ヶ月間さらには数年続く期間(例えば、室温保存にて約1年、約2年、さらには約3年またはそれより長期間)、安定でありうる。当該組成物は、例えば、少なくとも1ヶ月間、または少なくとも3ヶ月間、または少なくとも6ヶ月間、または少なくとも9ヶ月間、または少なくとも1年間、少なくとも約35℃、少なくとも約45℃、少なくとも約50℃、少なくとも約55℃、少なくとも約60℃またはそれを上回る温度など室温(RT)より高い温度で、保管可能でありうる。間組成物は、およそ室温(すなわち、25℃)、およそ40℃、およそ65℃、または他の適当な温度で保存することができる。
概して、本発明の組成物は、局所に投与されるように製剤化される。当該組成物は、例えば、溶液、スプレー、軟膏、ローション、ゲル、およびシャンプー等として製剤化されうる。当該組成物はまた、その全体が参照により本明細書に組み入れられる、米国特許第8,486,978号ならびに米国特許出願第2009/0175810号および同第2014/0228403号にしたがって製剤化されうる。一方で、本発明の組成物は概して、公知の製剤と比較すると安定性の増強を示す。好ましい態様において、当該組成物は溶液として製剤化される。いくつかの態様において、好ましい構成成分には、揮発性溶媒、不揮発性溶媒、および湿潤剤が含まれる。
アルコール−10%から80%(w/w);
シクロメチコン−0.01%から25%(w/w)未満;および
C12-15アルキル ラクタートおよびイソプロピル ミリスタートのいずれかまたはその両方を加えたジイソプロピル アジパート−5%から90%(w/w)
をさらに含む、爪または爪床の障害の治療のための薬学的組成物を提供する。
アルコール−50%から70%(w/w);
シクロメチコン−10%から15%(w/w);
ジイソプロピル アジパート−8%から15%(w/w);および
C12-15アルキル ラクタートおよびイソプロピル ミリスタートのいずれかまたはその両方−8%から15%(w/w)
をさらに含む、爪または爪床の障害の治療のための薬学的組成物を提供する。
別の局面において、本発明は、皮膚または爪の病態を治療するための方法を提供する。当該方法には、本発明の組成物をそれを必要とする患者に局所的に投与する段階が含まれる。一般に、皮膚および爪の病態は、カンジダ・アルビカンス、クリプトコッカス・ネオフォルマンス、アスペルギルス・フミガーツス、およびトリコフィトン・メンタグロフィテス等を含む真菌により引き起こされる。皮膚および爪の病態の例には、これらに限定されないが、足白癬(アスリートフット)、頭部白癬(頭皮白癬)、爪真菌症(爪白癬)、股部白癬(いんきん)、体部白癬(白癬)、およびイースト菌感染症が含まれる。
エフィナコナゾールおよび種々の溶媒を混合して、以下に記載のように抗酸化剤、ヒドロキシ酸、およびキレート剤を添加した混合物をもたらすことにより、溶液を調製した。結果として生じた溶液は、全ての構成成分を最初に混合した時、透明かつ無色であった。当該溶液を65℃で保存した。保存期間にわたって、いくつかの溶液は淡黄色に変化するのを観察した。いくつかの溶液の色は、黄色、明るい橙色、暗い橙色、ピンク色、銅色、明るい赤色、および暗い赤色の色合へと深まった。種々の色を呈する溶液の写真を図1に示す。UV可視光吸光度スペクトルを、Varian Cary 50 Bio Spectrophotometerを用いて種々の時点で記録した。サンプルを300 nmから800 nmにわたってスキャンした。吸光度値を400、500および600 nmで記した。吸光度読み取りに基づき、400 nmで0.1407吸光度単位(AU)、500 nmで0.0290 AU、および600 nmで0.0290 AUのカットオフ値を用いて、「不良となるまでの時間」を決定した。
Claims (24)
- 約0.5〜約15重量%のエフィナコナゾール、ブチル化ヒドロキシトルエン(BHT)、エチレンジアミン四酢酸(EDTA)の塩、水、C12-15アルキル ラクタート、ジイソプロピル アジパート、シクロメチコン、およびエタノールを含む、組成物であって、
該組成物が、溶液として製剤化され、および
BHTおよびEDTAの塩の量が、該組成物が(i)最初の製剤時に無色であること、および(ii)少なくとも約40℃の温度で少なくとも3週間の保存後に無色または淡黄色であることを確実にするのに十分な量であり、
該エタノールの量が、50%から70%(w/w)の範囲内であり、
該シクロメチコンの量が、10%から15%(w/w)の範囲内であり、
該ジイソプロピル アジパートの量が、8%から15%(w/w)の範囲内であり、および
該C12-15アルキル ラクタートの量が、8%から15%(w/w)の範囲内である、
前記組成物。 - 約65℃の温度で1ヶ月間の保存後に無色または淡黄色である、請求項1に記載の組成物。
- エフィナコナゾールの量が約8%(w/w)〜約12%(w/w)の範囲内である、請求項1または2に記載の組成物。
- エフィナコナゾールの量が約10%(w/w)である、請求項3に記載の組成物。
- エフィナコナゾールの量が約0.5%(w/w)〜約5%(w/w)の範囲内である、請求項1または2に記載の組成物。
- エフィナコナゾールの量が約2%(w/w)である、請求項5に記載の組成物。
- BHTの量が約0.01%(w/w)〜約2%(w/w)の範囲内である、請求項1〜6のいずれか一項に記載の組成物。
- EDTAの塩の量が約0.0001%(w/w)〜約1.5%(w/w)の範囲内である、請求項1〜7のいずれか一項に記載の組成物。
- EDTAの塩の量が約0.0001%(w/w)〜約0.0005%(w/w)の範囲内である、請求項8に記載の組成物。
- EDTAの塩の量が約0.00025%(w/w)であり、かつBHTの量が約0.1%(w/w)である、請求項9に記載の組成物。
- 約0.01%(w/w)クエン酸〜約1%(w/w)クエン酸をさらに含む、請求項1〜10のいずれか一項に記載の組成物。
- 約0.05%(w/w)クエン酸〜約0.25%(w/w)クエン酸を含む、請求項11に記載の組成物。
- 約0.075%(w/w)クエン酸〜約0.15%(w/w)クエン酸を含む、請求項12に記載の組成物。
- 前記組成物の色が目視検査により決定される、請求項1〜13のいずれか一項に記載の組成物。
- 色がUV-vis吸光度値の評価により決定される、請求項1〜13のいずれか一項に記載の組成物。
- 65℃で少なくとも1ヶ月間の保存後に、400 nmで0.4吸光度単位(AU)以下、500 nmで0.1 AU以下、および/または600 nmで0.1 AU以下のUV-vis吸光度値を示す、請求項15に記載の組成物。
- 65℃で少なくとも1ヶ月間の保存後に、400 nmで0.4 AU以下、500 nmで0.1 AU以下、および600 nmで0.1 AU以下のUV-vis吸光度値を示す、請求項16に記載の組成物。
- 65℃で少なくとも1ヶ月間の保存後に、400 nmで0.2 AU以下、500 nmで0.03 AU以下、および/または600 nmで0.03 AU以下のUV-vis吸光度値を示す、請求項15に記載の組成物。
- 65℃で少なくとも1ヶ月間の保存後に、400 nmで0.2 AU以下、500 nmで0.03 AU以下、および600 nmで0.03 AU以下のUV-vis吸光度値を示す、請求項18に記載の組成物。
- 65℃で少なくとも1ヶ月間の保存後に、400 nmで0.1 AU以下、500 nmで0.01 AU以下、および/または600 nmで0.01 AU以下のUV-vis吸光度を示す、請求項15に記載の組成物。
- 65℃で少なくとも1ヶ月間の保存後に、400 nmで0.1 AU以下、500 nmで0.01 AU以下、および600 nmで0.01 AU以下のUV-vis吸光度値を示す、請求項20に記載の組成物。
- エフィナコナゾールの量が、約8%(w/w)〜約12%(w/w)の範囲内であり、
BHTの量が、約0.01%(w/w)〜約2%(w/w)の範囲内であり、
EDTAの塩の量が、約0.0001%(w/w)〜約1.5%(w/w)の範囲内であり、および
該組成物が、約0.05%(w/w)〜約0.25%(w/w)の範囲内の量のクエン酸をさらに含む、請求項1に記載の組成物。 - 爪の治療において効果的に吸収される薬学的に許容される製剤である、請求項1〜22のいずれか一項に記載の組成物。
- 真菌感染を治療または予防するための、請求項23に記載の組成物を含む医薬。
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