JP2022169600A - ジアセレインまたはレインの局所製剤およびその使用 - Google Patents
ジアセレインまたはレインの局所製剤およびその使用 Download PDFInfo
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- JP2022169600A JP2022169600A JP2022125318A JP2022125318A JP2022169600A JP 2022169600 A JP2022169600 A JP 2022169600A JP 2022125318 A JP2022125318 A JP 2022125318A JP 2022125318 A JP2022125318 A JP 2022125318A JP 2022169600 A JP2022169600 A JP 2022169600A
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- Prior art keywords
- composition
- skin
- compound
- diacerein
- rhein
- Prior art date
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Abstract
Description
本出願は、2015年7月1日出願の米国特許仮出願第62/187,743号の優先権を主張するものであり、前記仮出願はこの全体が参照により本明細書に組み込まれる。
ジアセレイン局所組成物の調製
3つの異なる形態(ゲル、クリームおよび軟膏)を有する7つのジアセレイン局所組成物(G1、C1、C2およびO1からO4)を表1から4に従って調製した。各組成物中の化合物の粒子径(Dv90)をMastersizer 2000バージョン5.60によって測定した。以下の表に列挙する賦形剤/成分は複数の機能を有してよく、例えば1つの賦形剤が界面活性剤および/または安定剤および/または乳化剤等として使用される。
局所ジアセレイン組成物の拡散セル試験
手順:マウスを頸椎脱臼によって犠死させた。全層側腹部皮膚を取り、30%PEG 300を含有するPBS(pH5.4)(37℃)である、レセプター相と接触させて拡散セル上に置いた。緩衝液を3から4mL/時の流速でレシーバー区画に送り込んだ。1%ジアセレインゲル(製剤G1)、1%ジアセレインクリーム(製剤C1およびC2)または1%ジアセレイン軟膏(製剤O1、O2およびO3)20μlの用量をドナー区画中の皮膚表面に添加した。レシーバー溶液を0、1、2、4、6および8時間目に採集した。製剤での処置の8時間後に、皮膚を拡散セルから取り外し、皮膚表面を3つのアルコールスワブで注意深く清浄にした(テープ剥離なし)。外科用メス刃を使用して表皮を真皮から分離した。分離した表皮および真皮の両方の重量を量って細かく刻み、1時間強く振とうすることによってアセトニトリル:酢酸:水(60:0.1:40)0.5mlで2回抽出した。次に皮膚抽出物を14,500rpmで20分間遠心分離した。すべての手順を減光下で実施した。皮膚抽出物およびレシーバー溶液の両方を、HPLCによるジアセレインおよびレイン濃度の分析に供するまで-20℃で保存した(ジアセレインは実験の間に容易にレインに変換される)。皮膚流入量を、レイン濃度の累積浸透量対時間の曲線の直線部分の勾配から計算した。結果は以下のように要約される。
透過性
図1に示すように、ゲルジアセレイン製剤(G1)は、クリームおよび軟膏製剤(C1およびO1)よりも良好に角質層に浸透する。投与から8時間後に、表皮1グラム当たりのレイン濃度は、G1については204.0μg、C1については16.1μgおよびO1については31.2μgであり、ならびに真皮1グラム当たりのレイン濃度は、G1については11.9μg、C1については2.53μgおよびO1については3.14μgである。
図2Aおよび2Bに示すように、レインは皮膚組織に浸透し、ゲル製剤(G1)については1時間後およびクリーム製剤(C1)については2時間後にレシーバー溶液中に放出されたが、軟膏製剤(O1)に関しては、レインは皮膚組織に浸透せず、4時間後までレシーバー溶液中に入らなかったので、軟膏製剤がゲルおよびクリーム製剤よりも高い保持率と長い保持時間を有することを示した。
図3は、より小さな粒子径を有する軟膏製剤(O2)がより大きな粒子径を有する製剤(O3)よりも速く浸透したことを示す。投与から8時間後に、表皮1グラム当たりのレイン濃度は、O2については10.7μgおよびO3については4.8μgであり、ならびに真皮1グラム当たりのレイン濃度は、O2については1.6μgおよびO3については0.7μgである。
比較実施例
Wally et al.は、一般的に使用されるケアクリームultraphil(登録商標)中に1%ジアセレインを含有するクリーム製剤を開示する(Wally et al.,Orphanet Journal of Rare Diseases,2013,vol.8,issue 69)。このクリーム製剤(比較製剤)と本発明の軟膏製剤O3との間で比較試験を実施した。結果を図5および6に示す。
Claims (21)
- ジアセレイン、レイン、モノアセチルレインおよびその塩またはエステルまたはプロドラッグから成る群より選択される化合物の治療有効量、ならびに1つ以上の医薬として許容される賦形剤を含有する局所医薬組成物であって、ここで前記組成物が軟膏、クリームまたはゲルの形態であり、および前記化合物の少なくとも約90体積%が約0.5から約35μmの粒子径を有する、局所医薬組成物。
- 軟膏またはクリームの形態である、請求項1に記載の組成物。
- 軟膏の形態である、請求項1に記載の組成物。
- 前記化合物の少なくとも約90体積%が、約10から約30μmの粒子径を有する、請求項3に記載の組成物。
- 前記化合物の少なくとも約90体積%が、約12から約25μmの粒子径を有する、請求項4に記載の組成物。
- 前記組成物が被験体の皮膚に投与される場合、前記化合物の数の90%より多くが投与後少なくとも約4時間皮膚に保持される、請求項3に記載の組成物。
- 前記組成物が被験体の皮膚に投与される場合、前記化合物の数の90%より多くが投与後少なくとも約6時間皮膚に保持される、請求項6に記載の組成物。
- 前記組成物が被験体の皮膚に投与される場合、前記化合物の数の90%より多くが投与後少なくとも約8時間皮膚に保持される、請求項7に記載の組成物。
- アトピー性皮膚炎、乾癬、嚢胞性乾癬、酒さ、ケロイド、過形成性瘢痕、ざ瘡、ネザートン症候群、または結節性痒疹を含む他の掻痒性皮膚病から選択される炎症性および/または過剰増殖性および掻痒性皮膚疾患、高齢者の不特定のかゆみ、ならびに老化皮膚および表皮水疱症を含む表皮バリア機能障害を伴う疾患の処置における使用のための、請求項1に記載の組成物。
- 表皮水疱症の処置における使用のための、請求項9に記載の組成物。
- 前記化合物が、前記組成物全体の約0.1重量%から約10.0重量%の量で存在する、請求項1に記載の組成物。
- 前記化合物が、前記組成物全体の約0.1重量%から5.0重量%の量で存在する、請求項11に記載の組成物。
- 前記化合物が、前記組成物全体の約0.5重量%から約2.0重量%の量で存在する、請求項12に記載の組成物。
- 1日1回組成物または1日2回組成物である、請求項1に記載の組成物。
- ジアセレイン、レイン、モノアセチルレインおよびその塩またはエステルまたはプロドラッグから成る群より選択される化合物の治療有効量、ならびに1つ以上の医薬として許容される賦形剤を含有する局所組成物であって、ここで前記組成物がゲルの形態であり、および前記化合物の少なくとも約90体積%が約1μm未満の粒子径を有する、局所組成物。
- 前記組成物が被験体の皮膚に投与される場合、前記化合物が投与後約6時間以内に皮膚から体内に放出される、請求項15に記載の組成物。
- 変形性関節症、高尿酸血症、高尿酸血症に関連する障害および2型糖尿病の処置における使用のための、請求項15に記載の組成物。
- 変形性関節症の処置における使用のための、請求項15に記載の組成物。
- 処置を必要とする被験体に、請求項3に記載の組成物の有効量を投与することを含む、炎症性および/または過剰増殖性および掻痒性の皮膚疾患、ならびに表皮バリア機能障害を伴う疾患を処置する方法。
- 前記表皮バリア機能障害を伴う疾患が、老化皮膚および表皮水疱症を含む、請求項19に記載の方法。
- 処置を必要とする被験体に、請求項15に記載の組成物の有効量を投与することを含む、高尿酸血症、高尿酸血症に関連する障害、変形性関節症および2型糖尿病を処置する方法。
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IL256585B (en) | 2021-05-31 |
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AU2021229177A1 (en) | 2021-10-07 |
US20170000732A1 (en) | 2017-01-05 |
MX2018000264A (es) | 2018-05-23 |
TWI723032B (zh) | 2021-04-01 |
AU2016287636A1 (en) | 2018-02-08 |
KR20180023965A (ko) | 2018-03-07 |
AU2021229177B2 (en) | 2023-11-23 |
AU2016287636B2 (en) | 2021-09-16 |
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