JP4388143B2 - Antifungal persistent external preparation - Google Patents
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Description
【０００１】
【産業上の利用分野】
本発明は、硝酸オキシコナゾールからなる抗真菌持続性外用剤に関し、更に詳しくは抗真菌効果を長時間保つ組成物または低刺激で使用感が良く配合溶解助剤の選択により着色防止を施したクリーム剤に関する。
【０００２】
【従来の技術】
従来から、硝酸オキシコナゾール、硝酸ミコナゾール、クロトリマゾール、硝酸エコナゾール等のイミダゾール系抗真菌薬を主剤とする抗真菌剤は、水虫、タムシ等の皮膚真菌症の治療を目的として検討され使用されている（「化学療法の領域」１９９１年２月号５９７〜６０３頁）。
【０００３】
このうち、硝酸オキシコナゾール（以下、ＯＣＺと略す）は、強力な抗真菌作用と広範囲な抗菌スペクトルを有するとともにグラム陽性菌などの細菌に対しても抗菌作用を示す２’，４’−ジクロロ−２−イミダゾール−１−イルアセトフェノン（Ｚ）−［Ｏ−（２，４−ジクロロベンジル）オキシド］硝酸塩（分子式：Ｃ18Ｈ13Ｃ14Ｎ3Ｏ・ＨＮＯ3、分子量：４９２．１５）である。現在、ＯＣＺ製剤として、液剤、クリーム剤が市販され皮膚真菌症の治療に優れた効果を上げている。
【０００４】
更に、ＯＣＺと同様のイミダゾール系抗真菌薬物である硝酸ミコナゾール等について、抗真菌薬物の角質移行性を促進する物質と皮膚付着性高分子を配合し持続性を高める方法（特開平７−１２６１６４号公報）があるが、角質移行性を促進する物質としてあげられる一部の成分は、皮膚刺激性を有するものであったり、クリームの使用感及び質感に乏しくクリーム剤として不適当であること等の問題がある。
【０００５】
また、ＯＣＺが水にも油相基剤にも不溶であることから製剤化が難しかったが、液剤の場合はエタノール及びマクロゴール４００（日本薬局方第１３局収載、以下ＰＥＧ４００と略す）を高率に配合し液剤化し（オキナゾール液：製造販売・東京田辺製薬（株））、またクリーム剤の場合は、単味製剤であるが微細な結晶をベースクリームに分散させて製剤化しており（オキナゾールクリーム：製造販売・東京田辺製薬（株））、皮膚への薬物移行性を増すべく工夫をしているが、吸収性が未だ充分でなく１日数回の投与が必要である。
【０００６】
最近では特別にミリスチン酸イソプロピル等の常温において液状を呈する高級脂肪酸エステルを配合して患部への貯留性、吸収性を改善しているものもある（特許第２５５５５５５号、特開平９−２０８４６４号公報）。しかし、このＯＣＺ製剤は１日１回投与製剤であるがミリスチン酸イソプロピルの配合が必須であり、刺激性のある低級アルコールの配合が好ましいものである。皮膚真菌症治療において長期使用しなければならない薬剤であるため日常生活において患者に負担がかかっている。患者への負担を減らし且つ充分な治療効果を上げるために、ＯＣＺの角質移行性、薬効持続性及び使用感、質感について改善したクリーム剤は知られていない。
【０００７】
【解決しようとする課題】
ＯＣＺの液剤について、クロタミトンを結晶析出防止剤として配合することで、刺激性のあるエタノール並びに使用感及びＯＣＺの皮膚への吸収性を損なう溶解助剤を減ずる方法（特開平８−４０８９８号公報）があり、ＯＣＺの経時での安定性及びｉｎ ｖｉｔｒｏにおける代用皮膚（シリコーン膜）の透過性については優れた効果を示しているが、ｉｎ ｖｉｖｏでの皮膚中ＯＣＺ濃度の長時間にわたる有効濃度維持に関しては何等言及されていない。また、親水性及び親油性成分の２成分系でエマルションとし系のバランスをとるクリーム剤に液剤の処方をそのまま使うのは困難である。
【０００８】
前述のクリーム剤においてＯＣＺは易吸収性を期待し微粒子として用いられるが結晶状態にあるため、これが溶液でありその状態を安定して保つならば更に角質移行性、持続性が期待される。更に低級アルコール等の刺激性物質を低減することにより使用感も改善される。
【０００９】
そこで、本発明者らは、ＯＣＺ含有抗真菌外用剤において、充分な角質移行性、薬効の持続性、良好な使用感及び質感の確保を目的に鋭意研究を重ねた結果、クロタミトンと多価アルコールの特定の配合比率よりなる組成物を溶解助剤として用いてＯＣＺを油性基剤中に溶解させた後、適当な乳化剤と水を用いて常法により乳化し製した製剤が上記目的を満たした。更に、油相基剤中の炭化水素系油相基剤に代表される低極性油相基剤と、高級アルコールに代表される比較的極性の高い油相基剤との配合比率を変化させ、ＯＣＺを混合する油相の極性を変化させることで、ＯＣＺの角質移行性を制御できることを知り、本発明を完成した。また、クロタミトンと１，３−ブチレングリコールよりなる溶解助剤を用いた場合、クロタミトンを単独で用いた場合に比べ、製造時の加熱等に伴う成分の着色を極めて軽度に押さえることが可能であることを併せ知り、本発明によるクリーム剤を完成した。
【００１０】
【課題を解決するための手段】
本発明者らは、ＯＣＺ含有抗真菌持続性外用剤について鋭意研究を行ったところ、（ａ）クロタミトンと多価アルコールの配合比率が２：３〜４：１よりなる組成物を溶解助剤としてＯＣＺを油相基剤へ溶解させ、（ｂ）炭化水素系油相基剤及び高級アルコールを主成分とした油相基剤の配合比により極性を制御することによりＯＣＺの角質移行を改善することができることを見いだし、本発明を完成した。
【００１１】
また、添加される界面活性剤の種類、配合比率及び製剤の粘度等の物理化学的性質またはこれら要因の組み合わせにも何等影響を受けないことから、製剤の使用感及び安定性等を考慮し、クリーム剤、坐剤等の希望する剤形を得るために適当な界面活性剤、油相基剤、水溶性基剤を自由に選択することが可能である。
【００１２】
本発明でＯＣＺは全製剤重量中、０．１〜２重量％含有する。好ましくは０．２から１重量％含有する。
【００１３】
溶解助剤はクロタミトン及び多価アルコールを用い、その組成重量比（クロタミトン：多価アルコール）は２：３から４：１で混合されたものであり、硝酸オキシコナゾールの重量に対し５から１５倍量用いるものである。
【００１４】
好ましくはクロタミトン及び多価アルコールの組成重量比（クロタミトン：多価アルコール）は１：１から２：１で混合されたものであり、硝酸オキシコナゾールの重量に対し５から１０倍量用いるものである。
【００１５】
更に好ましくはクロタミトン及び多価アルコールの組成重量比（クロタミトン：多価アルコール）は１：１から５：３で混合されたものであり、硝酸オキシコナゾールの重量に対し８から１０倍量用いるものである。
【００１６】
多価アルコールは１，３−ブチレングリコール、プロピレングリコール等が用いられる。
【００１７】
油相成分としては炭化水素系油相基剤と高級アルコールを混合して用い、その２成分の組成重量比（炭化水素系油相基剤：高級アルコール）は４：９から２：１で混合されたものであり、硝酸オキシコナゾールの重量に対し１５から４５倍量用いるものである。
【００１８】
好ましくは炭化水素系油相基剤と高級アルコールの２成分の組成重量比（炭化水素系油相基剤：高級アルコール）は１：１から８：５で混合されたものであり、硝酸オキシコナゾールの重量に対し２０から３０倍量用いるものである。
【００１９】
更に好ましくは炭化水素系油相基剤と高級アルコールの２成分の組成重量比（炭化水素系油相基剤：高級アルコール）は１：１から３：２で混合されたものであり、硝酸オキシコナゾールの重量に対し２０から２６倍量用いるものである。
【００２０】
炭化水素系油相基剤は白色ワセリン、流動パラフィン、スクワレン、スクワラン等を用い、高級アルコールはステアリルアルコール、セタノール等を用いることができる。
【００２１】
本発明に添加できる界面活性剤は、ポリオキシエチレン（２５）セチルエーテル、ポリオキシエチレン（３０）セチルエーテル、ポリオキシエチレン（４０）セチルエーテル、ポリオキシエチレン（３０）オレイルエーテル、ポリオキシエチレン（５０）オレイルエーテル等のポリオキシエチレンアルキルエーテル類、モノステアリン酸ポリエチレングリコール（２５ＥＯ）、モノステアリン酸ポリエチレングリコール（４０ＥＯ）等のポリエチレングリコール脂肪酸エステル類、ポリオキシエチレン（５０）硬化ヒマシ油、ポリオキシエチレン（６０）硬化ヒマシ油等の、ポリオキシエチレン硬化ヒマシ油類、モノステアリン酸ソルビタン、モノパルミチン酸ソルビタン、モノラウリン酸ソルビタン等のソルビタン脂肪酸エステル類、モノステアリン酸グリセリン等のグリセリン脂肪酸エステル類が挙げられ、好ましくはポリオキシエチレンアルキルエーテル及びグリセリン脂肪酸エステルである。
【００２２】
同じく、添加できるその他の油相基剤としては、ステアリン酸、パルミチン酸等の脂肪酸類、ミツロウ、ラノリン等の蝋類が挙げられる。
【００２３】
更に、治療効果を高めるための各種配合剤の添加が容易であり、例えばリドカイン、ジブカインの局所麻酔剤、アクリノール、塩化ベンザルコニウム、イソプロピルメチルフェノール等の殺菌防腐剤、グリチルレチン酸、アラントイン等の抗炎症剤、ｌ−メントール、ｄ−カンフル等の清涼化剤、尿素、フタル酸ジエチル等の角質溶解剤、アルミニウムクロロヒドロキシド、酸化亜鉛等の収斂保護剤等を必要に応じ配合することができる。
【００２４】
【効果】
本外用剤または実際に人に投与することを前提にしたものである製剤を経皮投与したときの皮膚中のＯＣＺ濃度及びその経時変化による持続性、訓練されたパネラーの官能検査による使用感、更にクリーム剤を長期間保存した場合の性状、ＯＣＺ残存率変化による製剤安定性について示す。
【００２５】
［ヘアレスラット皮膚中のＯＣＺ濃度及び経時変化］
（方法）
雄性ヘアレスラット（８週齢）１８０匹を１群１０匹の１８群に分け、それぞれ、比較例１〜７または実施例１〜１１の塗布群とし、ネンブタール麻酔下、ラット背部皮膚１ｃｍ2当たりＯＣＺの塗布量が０．１ｍｇとなるよう各製剤とも８０ｍｇを８ｃｍ2（２×４ｃｍ）に塗布した後、ラットが製剤塗布部位を舐めないように首かせをして８または２４時間放置した。
【００２６】
８または２４時間経過した時点で、各群とも１０匹中１／２の５匹ずつクロロホルムにて安楽死させ、製剤を塗布した皮膚表面に残存する製剤を、洗浄液（リン酸１％及びラウリル硫酸ナトリウム８％を含む７０％エタノール水溶液）を含ませた脱脂綿で良く拭き取り（１０回）、製剤を塗布した皮膚を摘出し、皮膚中に吸収されたＯＣＺの量をＨＰＬＣ法にて測定した。
【００２７】
（ＨＰＬＣ前処理）
摘出したラット背部皮膚１ｇを量り、内部標準物質としてｏ−ターフェニルの酢酸エチル溶液（３．６μｇ／ｍｌ）を０．５ｍｌ、酢酸エチル１０ｍｌを加え、ガラス製ホモジナイザーにて摩砕し、超音波洗浄機（ＵＴ−１０４、シャープ（株）製）を用い２分間超音波照射した。更に１％水酸化カリウム水溶液２ｍｌを加え激しく振り混ぜた後、遠心分離した。有機溶媒層を回収し濃縮乾固した後、乾固物にＨＰＬＣ用メタノール０．５ｍｌを加え溶解し、不溶物はポアサイズ０．４５μｍのメンブランフィルターで濾過して除き、ＨＰＬＣ検液を調製した。
【００２８】
また、製剤を塗布しないヘアレスラット背部皮膚１ｇに、濃度既知のＯＣＺ溶液を添加した後、同様に操作したものを標準液として分析して検量線を作成し、これを元に各製剤を塗布した動物皮膚中のＯＣＺ濃度を算出した。
【００２９】
（ＨＰＬＣ測定条件）
カラム ：Ｗａｋｏｓｉｌ ５Ｃ１８（φ４．６ｍｍ×２５０ｍｍ）
カラム温度 ：３５℃
移動相 ：０．１％酢酸及び０．２％酢酸アンモニウム含有８０％メタノール水溶液
流速 ：０．８ｍｌ／ｍｉｎ
検出器 ：紫外吸光光度計（測定波長２４２ｎｍ）
（結果）
本発明である実施例と比較例を経皮投与したときの皮膚内濃度（８時間後、２４時間後）を表１及び図１に示した。
【００３０】
【表１】
【図１】
表１及び図１に示したように、実施例１〜１１のクリーム剤は、比較例１〜７に対し、極めて高い皮膚中ＯＣＺ濃度を示した。特に、いずれのクリーム剤も、塗布後２４時間後の皮膚中ＯＣＺ濃度において、比較例の８時間後の濃度を上回る濃度を示しており、実施例は２４時間後、いずれも高い濃度を維持していた。
【００３３】
これにより本発明品の持続性が確認された。
【００３４】
［使用感］
実施例と比較例について、その使用感に関する官能検査は、訓練されたパネラー１０名により実施した。結果を表２に示す。
【００３５】
使用感は、パネラー全員が良好と判断した場合を○で、７〜９名が良いと判断した場合を□で、４〜７名が良くないと判断した場合を△で、８名以上が良くないと判断した場合を×で示した。
【００３６】
【表２】
表２に示したように、実施例は良好な使用感であった。
【００３８】
これにより本発明品は製剤として適していると思われる。
【００３９】
［製剤安定性］
調製した製剤を密閉容器に入れ、４０℃・７５％ＲＨの条件下で３ヶ月保存した。ＯＣＺ含量を経時的に前記ＨＰＬＣ測定条件に準じＨＰＬＣ法で測定し、保存開始時を１００％として残存率を調べた。また、製剤の性状の変化として変色（黄色）の有無を目視にて確認した。変色がみられない場合を−で、わずかに変色が認められた場合を±で、明らかな変色が認められた場合を＋で示した。
【００４０】
【表３】
表３に示したように、本発明品は４０℃・７５％ＲＨ保存におけるＯＣＺ含量の低下及び性状の変化が無く、極めて安定な製剤である。
【００４２】
以上より、本発明品は長時間の薬効濃度を持続させることができ、また製剤の使用感及び安定性は良好であった。
【００４３】
また、角質移行を促進するための単一の特殊な成分等の添加は必要なく、軟膏基剤として安全であり充分な使用実績を持つ成分の組み合わせのみで目的を達成可能である。更に本発明においてＯＣＺは油相基剤中に存在するため、他の配合成分に由来するｐＨの変化の影響を受けにくく、実施例７〜１１に示す通り、リドカイン等の有機塩基を配合し、製剤としてのｐＨが７以上を示す場合も４０℃３ヶ月保存におけるＯＣＺの含量低下は認められず、極めて安定な製剤を得ることができる。
【００４４】
つまり、本発明品により、ＯＣＺの外用製剤においてＯＣＺの充分な角質移行性と皮膚中濃度の持続性を達成した製剤を、使用感及び製剤安定性を確保しつつ提供することが可能となった。
【００４５】
【実施例】
以下、本発明を製造例をもって示す。但し、これらは本発明を限定するものではない。併せて、比較例を示す。
【００４６】
【表４】
＜実施例 １＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００４８】
＜実施例 ２＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００４９】
＜実施例 ３＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００５０】
＜実施例 ４＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００５１】
＜実施例 ５＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００５２】
＜実施例 ６＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００５３】
＜実施例 ７＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００５４】
＜実施例 ８＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００５５】
＜実施例 ９＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００５６】
＜実施例 １０＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００５７】
＜実施例 １１＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００５８】
＜比較例 １＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しベースクリームを調製した。３０℃以下で、ＯＣＺを均一に懸濁した薬液を徐々に加えながら常法に従い撹拌混合しクリーム剤を得た。
【００５９】
＜比較例 ２＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しベースクリームを調製した。３０℃以下で、ＯＣＺ及びリドカインを均一に懸濁した薬液を徐々に加えながら常法に従い撹拌混合しクリーム剤を得た。
【００６０】
＜比較例 ３＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００６１】
＜比較例 ４＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００６２】
＜比較例 ５＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００６３】
＜比較例 ６＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。
【００６４】
＜比較例 ７＞
表４の処方にて、油相成分及び水相成分をそれぞれ加温溶解し、８０℃にて油相成分中に水相成分を加え常法に従い乳化した後、室温まで冷却しクリーム剤を得た。[0001]
[Industrial application fields]
The present invention relates to an antifungal persistent external preparation composed of oxyconazole nitrate, and more specifically, a composition that keeps the antifungal effect for a long time or a low irritation and a good feeling in use, and coloring prevention is performed by selecting a blended dissolution aid. It relates to creams.
[0002]
[Prior art]
Conventionally, antifungal agents based on imidazole antifungals such as oxyconazole nitrate, miconazole nitrate, clotrimazole, and econazole nitrate have been studied and used for the treatment of dermatomycosis such as athlete's foot and beetle. ("Area of Chemotherapy", February 1991, pages 597-603).
[0003]
Among these, oxyconazole nitrate (hereinafter abbreviated as OCZ) has a strong antifungal action and a broad antibacterial spectrum, and also exhibits antibacterial action against bacteria such as Gram-positive bacteria. 2-Imidazol-1-ylacetophenone (Z)-[O- (2,4-dichlorobenzyl) oxide] nitrate (molecular formula: C 18 H 13 C 14 N 3 O.HNO 3 , molecular weight: 492.15) is there. Currently, liquid preparations and cream preparations are commercially available as OCZ preparations, and have excellent effects in the treatment of dermatomycosis.
[0004]
Further, for miconazole nitrate, which is an imidazole antifungal drug similar to OCZ, and the like, a method for enhancing the sustainability by blending a substance that promotes keratin migration of an antifungal drug and a skin-adhesive polymer (JP-A-7-126164) However, some of the ingredients listed as substances that promote keratin migration are skin irritants and are unsuitable as creams because of their poor cream feeling and texture. There's a problem.
[0005]
In addition, since OCZ is insoluble in water and oil phase bases, it was difficult to formulate it. However, in the case of liquid preparations, ethanol and Macrogol 400 (listed in the Japanese Pharmacopoeia 13th Office, hereinafter abbreviated as PEG400) are high. (Okinazole solution: Manufactured and sold by Tokyo Tanabe Seiyaku Co., Ltd.), and in the case of cream, it is a simple preparation, but it is formulated by dispersing fine crystals in the base cream (Okinazole) Cream: Manufactured and sold by Tokyo Tanabe Seiyaku Co., Ltd., has been devised to increase the drug transferability to the skin, but the absorbability is still not sufficient and administration several times a day is necessary.
[0006]
Recently, there are specially formulated higher fatty acid esters that are liquid at room temperature, such as isopropyl myristate, to improve the retention and absorption in the affected area (Japanese Patent No. 2555555, JP-A-9-208464). ). However, this OCZ preparation is a once-daily preparation, but it must contain isopropyl myristate and is preferably an irritating lower alcohol. Since it is a drug that must be used for a long time in the treatment of dermatomycosis, there is a burden on patients in daily life. In order to reduce the burden on the patient and increase the sufficient therapeutic effect, there is no known cream preparation that improves the keratin transfer property, sustained drug efficacy, feeling of use, and texture of OCZ.
[0007]
[Problems to be solved]
About the OCZ solution, crotamiton is blended as a crystal precipitation inhibitor to reduce irritating ethanol and solubilizing agents that impair the feeling of use and absorbability of OCZ into the skin (Japanese Patent Laid-Open No. Hei 8-40898). Although it shows excellent effects on the stability of OCZ over time and the permeability of the skin substitute (silicone membrane) in vitro, it maintains the effective concentration of OCZ in the skin over a long period of time in vivo. Is not mentioned at all. Moreover, it is difficult to use the formulation of the liquid as it is for a cream that balances the system by forming an emulsion with a two-component system of hydrophilic and lipophilic components.
[0008]
In the above-mentioned cream preparation, OCZ is used as fine particles because it is expected to be easily absorbable. However, since it is in a crystalline state, if this is a solution and the state is kept stable, further keratin migration and sustainability are expected. Furthermore, the feeling of use is improved by reducing stimulating substances such as lower alcohols.
[0009]
Therefore, the present inventors have conducted extensive research on the OCZ-containing antifungal topical preparation for the purpose of ensuring sufficient keratin transfer, sustained drug efficacy, good usability and texture, and as a result, crotamiton and polyhydric alcohol A formulation prepared by dissolving OCZ in an oily base using a composition comprising a specific blending ratio of the following as a solubilizing agent and then emulsifying by a conventional method using an appropriate emulsifier and water fulfilled the above purpose. . Furthermore, the blending ratio of the low polarity oil phase base represented by the hydrocarbon-based oil phase base in the oil phase base and the relatively polar oil phase base represented by the higher alcohol is changed, The present invention was completed by knowing that the polarity of the oil phase mixed with OCZ can be controlled to control the keratin migration of OCZ. In addition, when a solubilizing agent composed of crotamiton and 1,3-butylene glycol is used, it is possible to suppress the coloring of components accompanying heating at the time of manufacture extremely lightly compared to the case where crotamiton is used alone. The cream preparation according to the present invention was completed.
[0010]
[Means for Solving the Problems]
The present inventors conducted extensive research on the OCZ-containing antifungal persistent external preparation, and (a) a composition comprising a mixing ratio of crotamiton and polyhydric alcohol of 2: 3 to 4: 1 as a dissolution aid. OCZ is dissolved in an oil phase base, and (b) OCZ keratin migration is improved by controlling the polarity by the blending ratio of a hydrocarbon-based oil phase base and an oil phase base composed mainly of a higher alcohol. The present invention has been completed.
[0011]
In addition, since it is not affected at all by the combination of the physicochemical properties such as the type of surfactant added, the mixing ratio and the viscosity of the preparation, or the combination of these factors, the usability and stability of the preparation are taken into consideration. In order to obtain a desired dosage form such as a cream or a suppository, it is possible to freely select an appropriate surfactant, oil phase base, and water-soluble base.
[0012]
In the present invention, OCZ is contained in an amount of 0.1 to 2% by weight in the total preparation weight. Preferably 0.2 to 1% by weight is contained.
[0013]
The dissolution aid used was crotamiton and polyhydric alcohol, and the composition weight ratio (crotamiton: polyhydric alcohol) was mixed at 2: 3 to 4: 1, and 5 to 15 based on the weight of oxyconazole nitrate. Double the amount.
[0014]
Preferably, the composition weight ratio of crotamiton and polyhydric alcohol (crotamiton: polyhydric alcohol) is mixed from 1: 1 to 2: 1, and is used in an amount 5 to 10 times the weight of oxyconazole nitrate. is there.
[0015]
More preferably, the composition weight ratio of crotamiton and polyhydric alcohol (crotamiton: polyhydric alcohol) is mixed at 1: 1 to 5: 3, and used in an amount 8 to 10 times the weight of oxyconazole nitrate. It is.
[0016]
As the polyhydric alcohol, 1,3-butylene glycol, propylene glycol or the like is used.
[0017]
The oil phase component is a mixture of a hydrocarbon oil phase base and a higher alcohol, and the composition weight ratio of the two components (hydrocarbon oil phase base: higher alcohol) is mixed from 4: 9 to 2: 1. It is used in an amount of 15 to 45 times the weight of oxyconazole nitrate.
[0018]
Preferably, the composition weight ratio of the two components of the hydrocarbon-based oil phase base and the higher alcohol (hydrocarbon-based oil phase base: higher alcohol) is mixed from 1: 1 to 8: 5. The amount used is 20 to 30 times the weight of nazole.
[0019]
More preferably, the composition weight ratio of the two components of the hydrocarbon-based oil phase base and the higher alcohol (hydrocarbon-based oil phase base: higher alcohol) is a mixture of 1: 1 to 3: 2, and oxynitrate oxynitrate. 20 to 26 times the amount of conazole is used.
[0020]
As the hydrocarbon-based oil phase base, white petrolatum, liquid paraffin, squalene, squalane and the like can be used, and as the higher alcohol, stearyl alcohol, cetanol and the like can be used.
[0021]
Surfactants that can be added to the present invention include polyoxyethylene (25) cetyl ether, polyoxyethylene (30) cetyl ether, polyoxyethylene (40) cetyl ether, polyoxyethylene (30) oleyl ether, polyoxyethylene ( 50) Polyoxyethylene alkyl ethers such as oleyl ether, polyethylene glycol fatty acid esters such as polyethylene glycol monostearate (25EO), polyethylene glycol monostearate (40EO), polyoxyethylene (50) hydrogenated castor oil, polyoxy Polyoxyethylene hydrogenated castor oil such as ethylene (60) hydrogenated castor oil, sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, mono Glycerol fatty acid esters such as stearic acid glyceryl and the like, preferably a polyoxyethylene alkyl ether and glycerin fatty acid esters.
[0022]
Similarly, other oil phase bases that can be added include fatty acids such as stearic acid and palmitic acid, and waxes such as beeswax and lanolin.
[0023]
Furthermore, it is easy to add various kinds of compounding agents for enhancing the therapeutic effect, for example, local anesthetics such as lidocaine and dibucaine, bactericidal antiseptics such as acrinol, benzalkonium chloride, isopropylmethylphenol, and anti-antibacterial agents such as glycyrrhetinic acid and allantoin. Inflammatory agents, refreshing agents such as l-menthol and d-camphor, keratolytic agents such as urea and diethyl phthalate, astringent protecting agents such as aluminum chlorohydroxide and zinc oxide, and the like can be blended as necessary.
[0024]
【effect】
OCZ concentration in the skin when the external preparation or a preparation that is supposed to be actually administered to humans is administered transdermally and its persistence due to changes over time, feeling of use by a sensory test of trained panelists, Furthermore, the properties when the cream is stored for a long period of time and the preparation stability due to the change in OCZ residual rate are shown.
[0025]
[OCZ concentration in hairless rat skin and changes with time]
(Method)
180 male hairless rats (8 weeks old) were divided into 18 groups of 10 per group, and each group was applied as Comparative Examples 1-7 or Examples 1-11, and under the Nembutal anesthesia, OCZ per 1 cm 2 of rat back skin In each preparation, 80 mg of each preparation was applied to 8 cm 2 (2 × 4 cm) so that the amount of application was 0.1 mg, and then the rat was placed on the neck so as not to lick the preparation application site and left for 8 or 24 hours.
[0026]
When 8 or 24 hours had elapsed, ½ of 10 mice in each group were euthanized with chloroform, and the preparation remaining on the skin surface to which the preparation was applied was washed with washing solution (1% phosphoric acid and lauryl sulfate). Wipe well with absorbent cotton containing 70% ethanol solution containing 8% sodium) (10 times), the skin to which the preparation was applied was removed, and the amount of OCZ absorbed in the skin was measured by HPLC.
[0027]
(HPLC pretreatment)
1 g of the extracted rat back skin was weighed, 0.5 ml of an ethyl acetate solution (3.6 μg / ml) of o-terphenyl and 10 ml of ethyl acetate were added as an internal standard substance, and ground with a glass homogenizer. Ultrasonic irradiation was performed for 2 minutes using a washing machine (UT-104, manufactured by Sharp Corporation). Further, 2 ml of 1% aqueous potassium hydroxide solution was added and shaken vigorously, followed by centrifugation. After the organic solvent layer was collected and concentrated to dryness, 0.5 ml of HPLC methanol was added to the dried solid to dissolve it, and the insoluble matter was filtered off through a membrane filter having a pore size of 0.45 μm to prepare an HPLC test solution.
[0028]
In addition, after adding an OCZ solution of known concentration to 1 g of hairless rat back skin to which the formulation was not applied, a standard curve was prepared by analyzing the same operation, and each formulation was applied based on this The OCZ concentration in the animal skin was calculated.
[0029]
(HPLC measurement conditions)
Column: Wakosil 5C18 (φ4.6 mm × 250 mm)
Column temperature: 35 ° C
Mobile phase: 80% aqueous methanol solution containing 0.1% acetic acid and 0.2% ammonium acetate Flow rate: 0.8 ml / min
Detector: UV absorption photometer (measurement wavelength 242 nm)
(result)
Table 1 and FIG. 1 show the concentrations in the skin (after 8 hours and 24 hours) when the Examples and Comparative Examples of the present invention were transdermally administered.
[0030]
[Table 1]
[Figure 1]
As shown in Table 1 and FIG. 1, the creams of Examples 1 to 11 showed extremely high OCZ concentration in the skin as compared with Comparative Examples 1 to 7. In particular, all creams showed a concentration exceeding the concentration after 8 hours of the comparative example in the OCZ concentration in the skin 24 hours after application, and all the examples maintained a high concentration after 24 hours. It was.
[0033]
Thereby, the sustainability of the product of the present invention was confirmed.
[0034]
[Usage feeling]
About the Example and the comparative example, the sensory test regarding the usability was implemented by 10 trained panelists. The results are shown in Table 2.
[0035]
The feeling of use is ○ when all panelists judge good, □ when 7-9 people are judged good, and △ when 4-7 people are judged not good, 8 or more people are good The case where it was judged that it was not indicated by x.
[0036]
[Table 2]
As shown in Table 2, the examples had a good feeling in use.
[0038]
Thus, the product of the present invention seems to be suitable as a preparation.
[0039]
[Formulation stability]
The prepared preparation was put in a sealed container and stored for 3 months under the conditions of 40 ° C. and 75% RH. The OCZ content was measured over time by the HPLC method according to the above HPLC measurement conditions, and the residual rate was examined with the start of storage as 100%. Moreover, the presence or absence of discoloration (yellow) was confirmed visually as a change of the property of a formulation. The case where no discoloration was observed was indicated by −, the case where slight discoloration was observed was indicated by ±, and the case where clear discoloration was observed was indicated by +.
[0040]
[Table 3]
As shown in Table 3, the product of the present invention is an extremely stable preparation with no reduction in OCZ content and no change in properties when stored at 40 ° C. and 75% RH.
[0042]
From the above, the product of the present invention was able to maintain a long-term medicinal concentration, and the usability and stability of the preparation were good.
[0043]
In addition, it is not necessary to add a single special component or the like for promoting keratin migration, and the object can be achieved only by a combination of components that are safe as an ointment base and have a sufficient record of use. Furthermore, in the present invention, since OCZ is present in the oil phase base, it is not easily affected by changes in pH derived from other ingredients, and as shown in Examples 7 to 11, an organic base such as lidocaine is blended, Even when the pH of the preparation is 7 or more, a decrease in the content of OCZ during storage at 40 ° C. for 3 months is not observed, and an extremely stable preparation can be obtained.
[0044]
That is, according to the present invention, it has become possible to provide a preparation that achieves OCZ sufficient keratin transfer and sustained skin concentration in an OCZ preparation for external use while ensuring a feeling of use and preparation stability. .
[0045]
【Example】
Hereinafter, this invention is shown with a manufacture example. However, these do not limit the present invention. A comparative example is also shown.
[0046]
[Table 4]
<Example 1>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0048]
<Example 2>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0049]
<Example 3>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0050]
<Example 4>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0051]
<Example 5>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0052]
<Example 6>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0053]
<Example 7>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0054]
<Example 8>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0055]
<Example 9>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0056]
<Example 10>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0057]
<Example 11>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0058]
<Comparative Example 1>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were heated and dissolved respectively, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method, and then cooled to room temperature to prepare a base cream. did. A cream was obtained by stirring and mixing according to a conventional method while gradually adding a chemical solution in which OCZ was uniformly suspended at 30 ° C. or lower.
[0059]
<Comparative Example 2>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were heated and dissolved respectively, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method, and then cooled to room temperature to prepare a base cream. did. A cream was obtained by stirring and mixing according to a conventional method while gradually adding a chemical solution in which OCZ and lidocaine were uniformly suspended at 30 ° C. or lower.
[0060]
<Comparative Example 3>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0061]
<Comparative Example 4>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0062]
<Comparative Example 5>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0063]
<Comparative Example 6>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
[0064]
<Comparative Example 7>
In the formulation shown in Table 4, the oil phase component and the aqueous phase component were respectively heated and dissolved, and the aqueous phase component was added to the oil phase component at 80 ° C. and emulsified according to a conventional method. It was.
Claims (8)
（ａ）は、クロタミトン：多価アルコールの組成重量比が２：３から４：１で混合された溶解助剤であって、
（ｂ）は、炭化水素系油相基剤：高級アルコールの組成重量比が４：９から２：１で混合された油相成分であって、
（ａ）を硝酸オキシコナゾールの重量に対し５から１５倍量、かつ、（ｂ）を硝酸オキシコナゾールの重量に対し１５から４５倍量含有し、
（ａ）の多価アルコールが１，３−ブチレングリコール、プロピレングリコールまたはこれらの混合物である抗真菌持続性外用剤。 Containing an oil phase containing oxyconazole nitrate , (a) a dissolution aid composed of crotamiton and a polyhydric alcohol, and (b) an oil phase component composed of a hydrocarbon-based oil phase base and a higher alcohol,
(A) is a dissolution aid mixed with a composition weight ratio of crotamiton: polyhydric alcohol of 2: 3 to 4: 1,
(B) is an oil phase component in which the composition weight ratio of hydrocarbon-based oil phase base: higher alcohol is mixed from 4: 9 to 2: 1,
Containing (a) 5 to 15 times the weight of oxyconazole nitrate, and (b) 15 to 45 times the weight of oxyconazole nitrate,
The antifungal persistent external preparation whose polyhydric alcohol of (a) is 1, 3- butylene glycol, propylene glycol, or a mixture thereof.
（ａ）は、クロタミトン：多価アルコールの組成重量比が１：１から２：１で混合された溶解助剤であって、
（ｂ）は、炭化水素系油相基剤と高級アルコールの組成重量比が１：１から８：５で混合された外用剤中の油相成分であって、
（ａ）を硝酸オキシコナゾールの重量に対し５から１０倍量、かつ、（ｂ）を硝酸オキシコナゾールの重量に対し２０から３０倍量含有し、
（ａ）の多価アルコールが１，３−ブチレングリコール、プロピレングリコールまたはこれらの混合物である抗真菌持続性外用剤。 Oxyconazole nitrate , (a) a solubilizing agent composed of crotamiton and a polyhydric alcohol, and b) an oil phase containing an oil phase component composed of a hydrocarbon-based oil phase base and a higher alcohol,
(A) is a dissolution aid mixed with a composition weight ratio of crotamiton: polyhydric alcohol of 1: 1 to 2: 1,
(B) is an oil phase component in an external preparation in which the composition weight ratio of the hydrocarbon-based oil phase base and the higher alcohol is mixed from 1: 1 to 8: 5,
Containing (a) 5 to 10 times the weight of oxyconazole nitrate, and (b) 20 to 30 times the weight of oxyconazole nitrate,
The antifungal persistent external preparation whose polyhydric alcohol of (a) is 1, 3- butylene glycol, propylene glycol, or a mixture thereof.
（ａ）クロタミトンと１，３−ブチレングリコールとからなり、その組成重量比（クロタミトン：１，３−ブチレングリコール）が１：１から５：３で混合された溶解助剤、及び、（ｂ）炭化水素系油相基剤と高級アルコールからなり、その組成重量比（炭化水素系油相基剤：高級アルコール）が１：１から３：２で混合された油相成分を含有し、
硝酸オキシコナゾールの重量に対し８から１０倍量の（ａ）を、硝酸オキシコナゾールの重量に対し２０から２６倍量の（ｂ）に溶解し、製することを特徴とする抗真菌持続性外用剤。0.2 to 1% by weight of oxyconazole nitrate in the total formulation weight ,
(A) a dissolution aid comprising crotamiton and 1,3-butylene glycol, the composition weight ratio of which (crotamiton: 1,3-butylene glycol) is mixed from 1: 1 to 5: 3, and (b) It comprises an oil phase component composed of a hydrocarbon oil phase base and a higher alcohol, the composition weight ratio of which (hydrocarbon oil phase base: higher alcohol) is mixed from 1: 1 to 3: 2 .
8 relative to the weight of nitric oxiconazole 10-fold amount of the (a), was dissolved in 20 by weight of nitric acid oxiconazole of 26 times (b), antifungal duration, characterized in that Seisuru Sexual topical agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP00208098A JP4388143B2 (en) | 1998-01-08 | 1998-01-08 | Antifungal persistent external preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP00208098A JP4388143B2 (en) | 1998-01-08 | 1998-01-08 | Antifungal persistent external preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH11199485A JPH11199485A (en) | 1999-07-27 |
| JP4388143B2 true JP4388143B2 (en) | 2009-12-24 |
Family
ID=11519379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP00208098A Expired - Fee Related JP4388143B2 (en) | 1998-01-08 | 1998-01-08 | Antifungal persistent external preparation |
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| Country | Link |
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| JP (1) | JP4388143B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5743375B2 (en) * | 2008-09-30 | 2015-07-01 | 小林製薬株式会社 | Candidiasis preventive or therapeutic agent |
| CN112957314A (en) * | 2016-08-16 | 2021-06-15 | 湖南中威制药有限公司 | Oxiconazole nitrate cream preparation and production method thereof |
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1998
- 1998-01-08 JP JP00208098A patent/JP4388143B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11199485A (en) | 1999-07-27 |
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