JP2019519543A - Pde−4阻害剤の局所処方物およびそれらの使用方法 - Google Patents
Pde−4阻害剤の局所処方物およびそれらの使用方法 Download PDFInfo
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Abstract
Description
本願は、全体の内容が参照により本明細書によって組み込まれる、2016年6月7日提出の米国仮特許出願第62/347,006号明細書、2017年1月24日提出の同第62/449,753号明細書、2017年4月21日提出の同第62/488,495号明細書の優先権を主張する。
本明細書中の実施形態は、式(I)により表される化合物、その塩またはその水和物を開示する。
式(I)により表される化合物は、例えば以下に記載の方法によって作製され得る。
本明細書中の実施形態は、式(I)により表される化合物、その塩、その誘導体またはその水和物と、溶媒と、ベースと、を含む局所処方物:
本明細書中の実施形態は、本明細書中の実施形態の局所処方物を使用して皮膚状態を処置する方法も対象とする。いくつかの実施形態において、皮膚状態を処置する方法は、本明細書中に記載の実施形態の局所処方物を投与することを含む。いくつかの実施形態において、本局所処方物は局所投与される。いくつかの実施形態において、皮膚状態は、例えばアトピー性皮膚炎、脂漏性皮膚炎、脱毛症、接触性皮膚炎、乾癬、蕁麻疹、湿疹、熱傷、日焼け、膵炎、肝炎、扁平苔癬、強膜炎、強皮症、皮膚筋炎またはそれらの組み合わせなどであるが限定されない皮膚炎から選択され得る。いくつかの実施形態において、皮膚状態は、上記状態の何れかに関連するそう痒であり得る。
この試験は、ヒト死体皮膚でのインビトロFranz有限用量モデル(Franz finite dose model)を用いて、4つの処方物および1つの薬物溶液からのヒト死体皮膚への、およびこれを横断する、有効成分、メチルN−[3−(6,7−ジメトキシ−2−メチルアミノキナゾリン−4−イル)フェニル]テレフタルアミド酸(RVT−501)の浸透を評価するために設計した。リン酸緩衝食塩水;pH7.4±0.1を受容液(receiving media)として使用した。ポジティブディスプレイスメント式ピペットを使用して各細胞に10μL/cm2の個々の処方物を1回与えた。用量適用後の予め選択した時間に、フランツセルの試料採取アームを通じて受容液の500μLアリコートを取り出し、等体積の新鮮な受容液と交換した。ガラス棒を使用して処方物を均一に広げて、皮膚の表面領域全体を被覆した。試験の最後に、セルを分解し、各セルから皮膚を慎重に取り出した。各皮膚切片を0.5mLの抽出溶液(受容液)で2回洗浄して、未吸収の処方物を皮膚表面から回収した。ピンセットを用いて皮膚を慎重に表皮および真皮に分離した。各表皮および真皮バイアルに、ホモジナイズ溶液(リン酸緩衝食塩水、pH7.4)を添加した。ビーズホモジナイザー(OMNI Bead Ruptor 24.)を使用して組織をホモジナイズした。
第4、7、10および13日に耳の背側皮膚および背中にジニトロクロロベンゼン(DNCB)を繰り返し塗布することによって、8〜12週齢の特定病原体除去(SPF)雌NC/Ngaマウス(n=8匹/群)においてアトピー性皮膚炎(AD)を誘発した。NC/Ngaマウスは、アトピー性皮膚炎に対する確立されたマウスモデルである。Sutoら、NC/Nga mice:a mouse model for atopic dermatitis;Int Arch Allergy Immunol.1999;120 Suppl 1:70−5;およびGaoら、Establishment of allergic dermatitis in NC/Nga mice as a model for severe atopic dermatitis,Biol.Pharm.Bull.2004 Sep;27(9):1376−81を参照。
1.予防試験:第1〜14日に、0.2%処方物(C1)、0.5%処方物(C2)、RVT−501プラセボ、タクロリムスプラセボ、0.1%タクロリムスまたは処置なし(AD対照)、またはADの偽誘発。
2.治療試験:第8〜14日に、0.2%処方物(C1)、0.5%処方物(C2)、有効成分プラセボ、タクロリムスプラセボ、0.1%タクロリムスまたは処置なし(AD対照)。図4参照。
Claims (24)
- 局所処方物であって、有効量の式(I)
溶媒およびベースと、を含み、約30重量%超の溶媒を含む、局所処方物。 - 前記ベースが、前記局所処方物の約0.001重量%〜約10重量%未満の量である、請求項1に記載の局所処方物。
- 前記式(I)により表される化合物が、前記局所処方物の約0.2重量%〜約0.9重量%の量である、請求項1に記載の局所処方物。
- 前記式(I)により表される化合物が、前記局所処方物の約0.5重量%の量である、請求項1に記載の局所処方物。
- 吸収促進剤、浸出防止剤、水またはそれらの組み合わせをさらに含む、請求項1に記載の局所処方物。
- 前記浸出防止剤が、2つ以上の浸出防止剤である、請求項5に記載の局所処方物。
- 前記浸出防止剤の総量が前記局所処方物の約40重量%超である、請求項5に記載の局所処方物。
- 前記吸収促進剤が、前記局所処方物の約5重量%〜約20重量%の量である、請求項5に記載の局所処方物。
- 前記溶媒および吸収促進剤の合計が、前記局所処方物の約35重量%〜約70重量%である、請求項5に記載の局所処方物。
- 前記ベースが、ペトロラタム、パラフィン、流動パラフィン、微結晶ワックス、カルナウバろう、白色蜜ろうおよび任意のそれらの組み合わせからなる群から選択される、請求項1に記載の局所処方物。
- 前記溶媒が、約200〜約600の平均分子量を有するポリエチレングリコール、ジプロピレングリコール、ベンジルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル、ジエチレングリコールモノエチルエーテル、プロピレングリコール、ポリオキシエチレンオレイルエーテル、ポリオキシエチレンオクチルフェニルエーテル、ポリオキシエチレンラウリルエーテル、ポリオキシエチレンヒマシ油、オレイン酸および任意のそれらの組み合わせからなる群から選択される、請求項1に記載の局所処方物。
- 前記溶媒が約200〜約600の平均分子量を有するポリエチレングリコールである、請求項1に記載の局所処方物。
- 前記溶媒が、約400の平均分子量を有するポリエチレングリコールである、請求項1に記載の局所処方物。
- 前記吸収促進剤が、ミリスチン酸イソプロピル、ミリスチン酸エチル、ミリスチン酸オクチルドデシル、パルミチン酸イソプロピル、パルミチン酸イソステアリル、イソステアリン酸イソプロピル、ステアリン酸ブチル、オレイン酸エチル、オレイン酸デシル、セバシン酸ジイソプロピル、セバシン酸ジエチル、アジピン酸ジイソプロピル、アジピン酸ジエチル、フタル酸ジエチルおよび任意のそれらの組み合わせからなる群から選択される、請求項5に記載の局所処方物。
- 前記浸出防止剤が、1000〜50000の平均分子量を有するポリエチレングリコール、ポリオキシエチレン硬化ヒマシ油、ステアリン酸、オレイン酸、モノステアリン酸ソルビタン、モノオレイン酸ソルビタン、セスキオレイン酸ソルビタン、トリオレイン酸ソルビタン、脂肪酸のグリセロールエステルおよび任意のそれらの組み合わせからなる群から選択される、請求項5に記載の局所処方物。
- 前記浸出防止剤が、約3600〜約4400の平均分子量を有するポリエチレングリコールである、請求項5に記載の局所処方物。
- 前記浸出防止剤が、約4000の平均分子量を有するポリエチレングリコールである、請求項5に記載の局所処方物。
- 前記脂肪酸のグリセロールエステルが、モノステアリン酸グリセロール40〜55、モノグリセリドおよびジグリセリド、ステアリン酸モノ、ジまたはトリグリセロール、イソステアリン酸ジグリセリル、ポリリシノレイン酸ヘキサグリセリルおよび任意のそれらの組み合わせからなる群から選択される、請求項15に記載の局所処方物。
- 前記2つ以上の浸出防止剤が、1000〜50000の平均分子量を有するポリエチレングリコールおよび脂肪酸のグリセロールエステルである、請求項6に記載の局所処方物。
- 前記溶媒が、約50重量%の量であり、前記ベースが約4.4重量%の量であり、前記浸出防止剤が約33重量%の量であり、前記吸収促進剤が約10重量%の量である、請求項5に記載の局所処方物。
- 前記式(I)により表される化合物が、
- 治療的有効量の請求項1に記載の局所処方物を投与することを含む、対象において皮膚状態を処置する方法。
- 前記皮膚状態が、皮膚炎、アトピー性皮膚炎、脂漏性皮膚炎、脱毛症、接触性皮膚炎、乾癬、蕁麻疹湿疹、熱傷、日焼け、膵炎、肝炎、扁平苔癬、強膜炎、強皮症、皮膚筋炎、前述の状態の何れかに関連するそう痒および任意のそれらの組み合わせからなる群から選択される、請求項22に記載の方法。
- 前記局所処方物中の前記式(I)により表される化合物が:
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JP2013542994A (ja) * | 2010-11-16 | 2013-11-28 | アセチロン ファーマシューティカルズ インコーポレイテッド | 蛋白質脱アセチル化酵素抑制剤としてのピリミジン水酸基アミド化合物およびその利用方法 |
JP2015505543A (ja) * | 2012-01-26 | 2015-02-23 | アンジオン バイオメディカ コーポレーション | 抗線維化化合物及びその使用 |
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JPH11209350A (ja) | 1998-01-26 | 1999-08-03 | Eisai Co Ltd | 含窒素複素環誘導体およびその医薬 |
WO2006085127A1 (en) * | 2005-02-08 | 2006-08-17 | Antibe Therapeutics, Inc. | Topical compositions |
MX2008010774A (es) | 2006-02-21 | 2008-09-01 | Eisai R&D Man Co Ltd | Derivados de 4-(3-benzoilaminofenil)-6, 7-dimetoxi-2-metilaminoqui nazolina. |
RU2348423C2 (ru) * | 2006-09-25 | 2009-03-10 | Государственное учреждение Научно-исследовательский институт клинической иммунологии Сибирского отделения Российской академии медицинских наук(ГУНИИ КИ СО РАМН) | Способ лечения атопического дерматита у детей |
RU2402776C2 (ru) * | 2007-01-24 | 2010-10-27 | Светлана Николаевна Козлова | Способ лечения атопического дерматита у детей при диагностированной цитомегаловирусной инфекции |
EP2123641A4 (en) * | 2007-02-16 | 2011-06-22 | Eisai R&D Man Co Ltd | CRYSTAL, AMORPHOUS FORM AND METHYL N-Ý3- (6,7-DIMETHOXY-2-METHYLAMINOQUINAZOLINE-4-YL) PHENYLENE TEREPHTALIC ACID SALT |
JP5043945B2 (ja) * | 2007-08-17 | 2012-10-10 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | キナゾリン誘導体の製造方法 |
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WO2009025239A1 (ja) * | 2007-08-17 | 2009-02-26 | Eisai R & D Management Co., Ltd. | 新規外用剤 |
JP2011529048A (ja) * | 2008-07-23 | 2011-12-01 | プレジデント アンド フェローズ オブ ハーバード カレッジ | デアセチラーゼ阻害剤およびその使用 |
JP2013542994A (ja) * | 2010-11-16 | 2013-11-28 | アセチロン ファーマシューティカルズ インコーポレイテッド | 蛋白質脱アセチル化酵素抑制剤としてのピリミジン水酸基アミド化合物およびその利用方法 |
JP2015505543A (ja) * | 2012-01-26 | 2015-02-23 | アンジオン バイオメディカ コーポレーション | 抗線維化化合物及びその使用 |
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RU2018145676A (ru) | 2020-07-09 |
IL263506A (en) | 2019-01-31 |
US10206925B2 (en) | 2019-02-19 |
RU2768826C2 (ru) | 2022-03-24 |
RU2018145676A3 (ja) | 2020-07-09 |
CA3026763A1 (en) | 2017-12-14 |
AU2017277524B2 (en) | 2021-07-29 |
CN109475555A (zh) | 2019-03-15 |
WO2017214289A1 (en) | 2017-12-14 |
US10357495B2 (en) | 2019-07-23 |
US20170348311A1 (en) | 2017-12-07 |
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AU2017277524A1 (en) | 2018-12-13 |
US20190134036A1 (en) | 2019-05-09 |
MX2018015114A (es) | 2019-12-05 |
EP3463366A1 (en) | 2019-04-10 |
EP3463366A4 (en) | 2020-01-08 |
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