JP2021527037A - ロフルミラスト皮膚浸透ラグタイムを改善する方法及び配合物 - Google Patents
ロフルミラスト皮膚浸透ラグタイムを改善する方法及び配合物 Download PDFInfo
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- JP2021527037A JP2021527037A JP2020567541A JP2020567541A JP2021527037A JP 2021527037 A JP2021527037 A JP 2021527037A JP 2020567541 A JP2020567541 A JP 2020567541A JP 2020567541 A JP2020567541 A JP 2020567541A JP 2021527037 A JP2021527037 A JP 2021527037A
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- roflumilast
- phosphate
- skin
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- FDGZUBKNYGBWHI-UHFFFAOYSA-N trioctadecyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCOP(=O)(OCCCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCCCC FDGZUBKNYGBWHI-UHFFFAOYSA-N 0.000 description 1
- SVETUDAIEHYIKZ-IUPFWZBJSA-N tris[(z)-octadec-9-enyl] phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCCOP(=O)(OCCCCCCCC\C=C/CCCCCCCC)OCCCCCCCC\C=C/CCCCCCCC SVETUDAIEHYIKZ-IUPFWZBJSA-N 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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Abstract
【選択図】図3
Description
の化合物である。
セテアリルアルコール(CAS−67762−30−0)、ジセチルホスフェート(CAS−2197−63−9)、及びセテス−10ホスフェート(CAS−50643−20−4)の乳化剤ブレンドは、商品名CRODAFOS(商標)CESでCrodaによって製造されている。この商業的に入手可能な乳化剤ブレンドは、10〜20%のジセチルホスフェート及び10〜20%のセテス−10ホスフェートと混合した、主としてワックス状物質のセテアリルアルコール(セチルアルコール(C16H34O)とステアリルアルコール(C18H38O)の混合物である)である自己乳化性ワックスである。自己乳化性ワックスは、水とブレンドするとエマルジョンを形成する。CRODAFOS(商標)CESを水に加えると、約3のpHを有するエマルジョンが自然に形成される。水酸化ナトリウム溶液を加えて、pHを所望の値に上昇させる。
DEGEEは、しばしば、局所用配合物中において10〜30%(w/w)、好ましくは15〜20%(w/w)として配合される。また、水は、局所用製品中において約20〜90%(w/w)として配合される。DEGEEと水のブレンドについては、比は1:10〜20:1の範囲であってよい。好ましくは、ロフルミラストを含む配合物において、DEGEE:水の比は1:4〜9:1である。
水中油型エマルジョン:この局所用製品は、不連続の疎水性相、並びにDEGEE−水のブレンド、及び場合により1種類以上の極性親水性賦形剤、並びに溶媒、共溶媒、塩、界面活性剤、乳化剤、及び他の成分を含む連続の水性相を含むエマルジョンであってよい。これらのエマルジョンには、エマルジョンの安定化を助ける水溶性又は水膨潤性ポリマーを含ませることができる。
本発明の組成物には、製品中における活性成分の所望のレベルの溶解度を得るために、1種類以上の溶媒又は共溶媒を含ませることができる。溶媒はまた、皮膚浸透性、又は局所用製品中に含まれる他の賦形剤の活性を改変することもできる。溶媒としては、アセトン、エタノール、ベンジルアルコール、ブチルアルコール、ジエチルセバケート、ジエチレングリコールモノエチルエーテル、ジイソプロピルアジペート、ジメチルスルホキシド、エチルアセテート、イソプロピルアルコール、イソプロピルイソステアレート、イソプロピルミリステート、N−メチルピロリジノン、プロピレングリコール、及びSDアルコールが挙げられるが、これらに限定されない。
本発明の組成物には、水和のレベルを増加させるために保湿剤を含ませることができる。エマルジョンに関しては、保湿剤は、しばしば不連続又は連続の疎水性相の成分である。保湿剤は、湿潤剤を含む親水性材料であってよく、又は皮膚軟化剤を含む疎水性材料であってよい。好適な保湿剤としては、1,2,6−ヘキサントリオール、2−エチル−1,6−ヘキサンジオール、ブチレングリコール、グリセリン、ポリエチレングリコール200−8000、ブチルステアレート、セトステアリルアルコール、セチルアルコール、セチルエステルワックス、セチルパルミテート、ココアバター、ココナッツ油、シクロメチコン、ジメチコン、ドコサノール、エチルヘキシルヒドロキシステアレート、脂肪酸、グリセリルイソステアレート、グリセリルラウレート、グリセリルモノステアレート、グリセリルオレエート、グリセリルパルミテート、グリコールジステアレート、グリコールステアレート、イソステアリン酸、イソステアリルアルコール、ラノリン、鉱油、リモネン、中鎖トリグリセリド、メントール、ミリスチルアルコール、オクチルドデカノール、オレイン酸、オレイルアルコール、オレイルオレエート、オリーブ油、パラフィン、ピーナッツ油、ワセリン、Plastibase-50W、及びステアリルアルコールが挙げられるが、これらに限定されない。
本発明による組成物には、場合により、組成物を乳化し、活性成分又は賦形剤の表面を湿潤させるのを助けるために、1種類以上の界面活性剤を含ませることができる。本明細書において使用する「界面活性剤」という用語は、水の表面張力及び/又は水と不混和性液体との間の界面張力を低下させることができる両親媒性物質(共有結合している極性領域及び非極性領域の両方を有する分子)を意味する。界面活性剤としては、アルキルアリールナトリウムスルホネート、Amerchol-CAB、ラウリル硫酸アンモニウム、杏仁油PEG−6エステル、アラセル、ベンザルコニウムクロリド、セテアレス−6、セテアレス−12、セテアレス−15、セテアレス−30、セテアリルアルコール/セテアレス−20、セテアリルエチルヘキサノエート、セテス−10、セテス−10ホスフェート、セテス−2、セテス−20、セテス−23、コレス−24、コカミドエーテルスルフェート、コカミンオキシド、ココベタイン、ココジエタノールアミド、ココモノエタノールアミド、ココ−カプリレート/カプレート、ジセチルホスフェート、ジナトリウムココアンホジアセテート、ジナトリウムラウレススルホスクシネート、ジナトリウムラウリルスルホアセテート、ジナトリウムラウリルスルホスクシネート、ジナトリウムオレアミドモノエタノールアミンスルホスクシネート、ドクサートナトリウム、ラウレス−2、ラウレス−23、ラウレス−4、ラウリン酸ジエタノールアミド、レシチン、メトキシPEG−16、メチルグルセス−10、メチルグルセス−20、メチルグルコースセスキステアレート、オレス−2、オレス−20、PEG−6−32ステアレート、PEG−100ステアレート、PEG−12グリセリルラウレート、PEG−120メチルグルコースジオレエート、PEG−15コカミン、PEG−150ジステアレート、PEG−2ステアレート、PEG−20メチルグルコースセスキステアレート、PEG−22メチルエーテル、PEG−25プロピレングリコールステアレート、PEG−4ジラウレート、PEG−4ラウレート、PEG−45/ドデシルグリコールコポリマー、PEG−5オレエート、PEG−50ステアレート、PEG−54水素化ヒマシ油、PEG−6イソステアレート、PEG−60水素化ヒマシ油、PEG−7メチルエーテル、PEG−75ラノリン、PEG−8ラウレート、PEG−8ステアレート、ペゴキソール7ステアレート、ペンタエリトリトールココエート、ポロキサマー124、ポロキサマー181、ポロキサマー182、ポロキサマー188、ポロキサマー237、ポロキサマー407、ポリグリセリル−3オレエート、ポリオキシエチレンアルコール、ポリオキシエチレン脂肪酸エステル、ポリオキシル20セトステアリルエーテル、ポリオキシル40水素化ヒマシ油、ポリオキシル40ステアレート、ポリオキシル6及びポリオキシル32、ポリオキシルグリセリルステアレート、ポリオキシルステアレート、ポリソルベート20、ポリソルベート40、ポリソルベート60、ポリソルベート65、ポリソルベート80、PPG−26オレエート、PROMULGENTM-12、プロピレングリコールジアセテート、プロピレングリコールジカプリレート、プロピレングリコールモノステアレート、ナトリウムキシレンスルホネート、ソルビタンモノオレエート、ソルビタンモノパルミテート、ソルビタンモノステアレート、ステアレス−2、ステアレス−20、ステアレス−21、ステアレス−40、獣脂グリセリド、及び乳化性ワックスが挙げられるが、これらに限定されない。配合物は、好ましくは1種類以上のホスフェートエステル界面活性剤を含む。配合物中に含ませることができるホスフェートエステル界面活性剤の例としては、リン酸セチルカリウム、C9−15アルキルリン酸カリウム、C11−15アルキルリン酸カリウム、C12−13アルキルリン酸カリウム、C12−14アルキルリン酸カリウム、ラウリルリン酸カリウム、C8−10アルキルエチルホスフェート、C9−15アルキルホスフェート、C20−22アルキルホスフェート、ヒマシ油ホスフェート、セテス−10ホスフェート、セテス−20ホスフェート、セテス−8ホスフェート、セテアリルホスフェート、セチルホスフェート、ジメチコンPEG−7ホスフェート、ジナトリウムラウリルホスフェート、ジナトリウムオレイルホスフェート、ラウリルホスフェート、ミリスチルホスフェート、オクチルデシルホスフェート、オレス−10ホスフェート、オレス−5ホスフェート、オレス−3ホスフェート、オレイルエチルホスフェート、オレイルホスフェート、PEG−26−PPG−30ホスフェート、PPG−5セテアレス−10ホスフェート、PPG−5セテス−10ホスフェート、ナトリウムラウリルホスフェート、ナトリウムラウレス−4ホスフェート、ステアリルホスフェート、DEA−セチルホスフェート、DEA−オレス−10ホスフェート、DEA−オレス−3ホスフェート、DEA−C8〜C18ペルフルオロアルキルエチルホスフェート、ジセチルホスフェート、ジラウレス−10ホスフェート、ジミリスチルホスフェート、ジオレイルホスフェート、トリセチルホスフェート、トリセテアレス−4ホスフェート、トリラウレス−4ホスフェート、トリラウリルホスフェート、トリオレイルホスフェート、及びトリステアリルホスフェートが挙げられるが、これらに限定されない。
幾つかの適用に関しては、アクリレートコポリマー、カルボマー1382、カルボマーコポリマータイプB、カルボマーホモポリマータイプA、カルボマーホモポリマータイプB、カルボマーホモポリマータイプC、カルボキシビニルコポリマー、カルボキシメチルセルロース、カルボキシポリメチレン、カラギーナン、グアーガム、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、微結晶質ワックス、及びメチルセルロースなど(しかしながらこれらに限定されない)の天然及び合成ポリマーのような可溶性、膨潤性、又は不溶性の有機ポリマー増粘剤或いは無機増粘剤で増粘された局所用製品を配合することが望ましい場合がある。
本発明による組成物には、化粧品及び局所用医薬品において通常見られる充填剤、キャリア、及び賦形剤のような更なる成分を配合することができる。更なる成分としては、消泡剤、噴射剤、防腐剤、酸化防止剤、金属イオン封鎖剤、安定剤、緩衝剤、pH調整溶液、皮膚浸透増強剤、フィルム形成剤、色素、顔料、香料、及び製品の安定性又は審美性を向上させるための他の賦形剤が挙げられるが、これらに限定されない。好ましい実施形態においては、ヘキシレングリコールを加えて、組成物の貯蔵寿命にわたる粒径分布の変化を抑制する。ヘキシレングリコールは、重量/重量基準で0.1%〜20%の間、好ましくは重量/重量基準で0.25%〜8%の間、最も好ましくは重量/重量基準で0.5%〜2%の間で加えることができる。
好適な医薬投与形態としては、エマルジョン、懸濁液、スプレー、油、軟膏、脂肪軟膏、クリーム、ペースト、ゲル、フォーム経皮パッチ、及び溶液(例えば、注射可能、経口)が挙げられるが、これらに限定されない。
本組成物は、急性及び慢性気道疾患;増殖性、炎症性、及びアレルギー性皮膚疾患;TNF及びロイコトリエンの過剰放出に基づく疾患;PDE阻害剤により治療可能な心臓の疾病;胃腸系又は中枢神経系における炎症;眼の疾病;関節炎性疾病;及びPDE阻害剤の組織弛緩作用により治療可能な疾病など(しかしながらこれらに限定されない)の、ロフルミラストを使用することにより治療可能又は予防可能とみなされる全ての疾患の治療及び予防のために獣医学及び人間医学において使用することができる。好ましくは、本組成物は、乾癬(尋常性)、湿疹、ざ瘡、単純性苔癬、日焼け、掻痒症、円形脱毛症、肥厚性瘢痕、円板状エリテマトーデス、及び膿皮症のような増殖性、炎症性、及びアレルギー性皮膚疾患を治療するために使用される。
480グラムの目標量の灌注用滅菌水−米国薬局方を1000mLのガラスビーカー中に正確に秤量し、20グラムの水酸化ナトリウムペレット−国民医薬品集を加え、完全に溶解するまで撹拌棒を使用して混合した。この溶液を保管して、1N水酸化ナトリウムとラベル付けした。
0.5%ロフルミラストクリームを得るのに十分な力価補正ロフルミラスト(50.69グラム)をAPI相溶液に加えたことを除いて、実施例3において使用したものと同じ製造プロセスを実施した。
Claims (23)
- 患者におけるロフルミラスト皮膚浸透ラグタイムを減少させる方法であって、ロフルミラスト及び乳化剤ブレンドを含む組成物を前記患者に局所投与することを含み、前記乳化剤ブレンドは、セテアリルアルコール、ジセチルホスフェート、及びセテス−10ホスフェートを含み、前記組成物は4.0〜6.5の間のpHを有する上記方法。
- 前記組成物が、ジエチレングリコールモノエチルエーテルを更に含む、請求項1に記載の方法。
- 前記ロフルミラスト組成物が0.005〜2%のロフルミラストを含む、請求項1に記載の方法。
- 前記ロフルミラスト皮膚浸透ラグタイムが60分未満である、請求項1に記載の方法。
- 前記ロフルミラスト皮膚浸透ラグタイムが45分未満である、請求項4に記載の方法。
- 前記患者が炎症症状に罹患している、請求項1に記載の方法。
- 前記患者がアトピー性皮膚炎に罹患している、請求項1に記載の方法。
- 患者におけるロフルミラスト皮膚浸透ラグタイムを減少させる方法であって、ロフルミラスト、並びに(a)ホスフェートエステル界面活性剤、(b)ジエチレングリコールモノエチルエーテル、(c)イソプロピルパルミテート、及びそれらの組み合わせからなる群から選択される薬剤を含む組成物を、そのような治療が必要な患者に局所投与することを含む上記方法。
- 前記組成物が4.0〜6.5の間のpHを有する、請求項8に記載の方法。
- 前記組成物が60分未満の皮膚浸透ラグタイムを有する、請求項9に記載の方法。
- ロフルミラスト及び乳化剤ブレンドを含む医薬組成物であって、前記乳化剤ブレンドは、セテアリルアルコール、ジセチルホスフェート、及びセテス−10ホスフェートを含み、前記組成物は4.0〜6.5の間のpHを有する上記医薬組成物。
- 前記ロフルミラストが0.005〜2%−w/wの量である、請求項11に記載の医薬組成物。
- 前記ロフルミラストが0.05〜1%−w/wの量である、請求項12に記載の医薬組成物。
- 前記ロフルミラストが0.1〜0.5%−w/wの量である、請求項13に記載の医薬組成物。
- 前記ロフルミラストが0.3%−w/wの量である、請求項14に記載の医薬組成物。
- ジエチレングリコールモノエチルエーテルを更に含む、請求項11に記載の医薬組成物。
- 前記ロフルミラスト組成物が、水中油型エマルジョン、増粘水性ゲル、増粘ヒドロアルコールゲル、親水性ゲル、及び親水性又は疎水性軟膏からなる群から選択される、請求項11に記載の医薬組成物。
- 前記ロフルミラスト組成物が、溶媒、保湿剤、界面活性剤又は乳化剤、ポリマー又は増粘剤、消泡剤、防腐剤、酸化防止剤、金属イオン封鎖剤、安定剤、緩衝剤、pH調整液、皮膚浸透増強剤、膜形成剤、色素、顔料、及び香料からなる群から選択される少なくとも1種類の更なる成分を更に含む、請求項11に記載の医薬組成物。
- 前記ロフルミラスト組成物が、アントラリン、アザチオプリン、タクロリムス、コールタール、メトトレキサート、メトキサレン、サリチル酸、乳酸アンモニウム、尿素、ヒドロキシ尿素、5−フルオロウラシル、プロピルチオウラシル、6−チオグアニン、スルファサラジン、ミコフェノール酸モフェチル、フマル酸エステル、コルチコステロイド、コルチコトロピン、ビタミンD類似体、アシトレチン、タザロテン、シクロスポリン、レゾルシノール、コルヒチン、アダリムマブ、ウステキヌマブ、インフリキシマブ、気管支拡張薬、及び抗生物質からなる群から選択される更なる活性剤を更に含む、請求項11に記載の医薬組成物。
- ロフルミラスト及び少なくとも1種類の乳化剤を含む医薬組成物であって、前記組成物は4.0〜6.5の間のpHを有する上記医薬組成物。
- ジエチレングリコールモノエチルエーテルを更に含む、請求項20に記載の医薬組成物。
- 前記乳化剤が、セテアリルアルコール、ジセチルホスフェート、及びセテス−10ホスフェートを含む乳化剤ブレンドである、請求項20に記載の医薬組成物。
- ロフルミラスト、並びに(a)セテアリルアルコール、ジセチルホスフェート、及びセテス−10ホスフェートを含む乳化剤ブレンド、(b)ジエチレングリコールモノエチルエーテル、(c)イソプロピルパルミテート、及びそれらの組合せからなる群から選択される薬剤を含む医薬組成物。
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US20200155524A1 (en) | 2018-11-16 | 2020-05-21 | Arcutis, Inc. | Method for reducing side effects from administration of phosphodiesterase-4 inhibitors |
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WO2019236374A2 (en) | 2019-12-12 |
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US20230346690A1 (en) | 2023-11-02 |
AU2019281888B2 (en) | 2024-05-02 |
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US20230338275A1 (en) | 2023-10-26 |
WO2019236374A3 (en) | 2020-01-16 |
BR112020024768A8 (pt) | 2022-12-13 |
CA3102689A1 (en) | 2019-05-30 |
EP3801461A2 (en) | 2021-04-14 |
BR112020024768A2 (pt) | 2021-03-30 |
CA3102689C (en) | 2023-08-29 |
US20190365642A1 (en) | 2019-12-05 |
AU2019281888A1 (en) | 2021-01-14 |
US20230346689A1 (en) | 2023-11-02 |
CN112384199A (zh) | 2021-02-19 |
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