CN102088957A - 用于治疗光化性角化病的局部性组合物 - Google Patents
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Abstract
本发明关于一种用于治疗光化性角化病的局部性凝胶组合物，包含：(a)用于治疗光化性角化病的活性剂、(b)角质层分离活性剂、(c)凝胶形成剂以及(d)有机溶剂。
Description
技术领域
本发明关于一种用作治疗光化性角化病的医药的局部性组合物。
背景技术
光化性角化病是一种表皮原位癌。其关系到局限于表皮的转化角质细胞的增殖，特征在于尤其是肿瘤抑制基因p53及端粒酶基因的高突变率。其进一步与通常也发生于浸润性皮肤鳞状细胞癌的特征性染色体畸变有关联。在所有罹患光化性角化病患者的约10％中，特别是还患有免疫抑制的患者的约30％中，该病况的进一步发展期间会成为皮肤鳞状细胞癌。因此，光化性角化病的确诊通常构成治疗的指标。
光化性角化病的疗法中，不同的外科手术及物理学方法诸如冷冻手术、刮除术、切除疗法、雷射疗法及软X射线疗法已被提出。并且，已知不同形式的用于治疗光化性角化病的药物疗法。例如，环加氧酶抑制剂诸如二克氯吩(diclofenac)、抗代谢物诸如5’-氟尿嘧啶以及免疫调节剂诸如咪喹莫特(imiquimod)已被用于治疗光化性角化病。
光化性角化病的药物疗法通常通过局部性施用对应药物来实行，特别是水性霜剂与胶剂形式或醇溶液的形式。
有关本领域目前已知的水性霜剂与胶剂制剂，已发现是有缺陷的，这些制剂必须被搓揉入皮肤中。在搓揉霜剂或胶剂制剂的过程，包含于其中的活性剂通常会被涂布于皮肤上一大块区域。因此，很难将以水性霜剂与胶剂制剂特定地施用在确实需要治疗的皮肤区域上。关于醇溶液，已发现这些配方易于流动，特别是施用在经常发生光化性角化病的头部与脸部区域时易流动。因此，醇溶液也不容易进行活性剂的准确给药。因为本领域目前的制剂不适于特定剂量给药，所以这些制剂与不需要给药的大面积的皮肤区域接触，从而增加了副作用的程度与危险。并且，已发现诸如5’-氟尿嘧啶的药物在含水或含醇制剂中以该制剂的形式保存一段期间(对应于这样的制剂的通常的保存期限)就会从制剂中结晶出来。
WO-A-96/32112公开用于治疗皮肤光化性损伤的组合物，其包含5’-氟尿嘧啶、浅表皮肤剥离剂及药学上可接受的载剂，特别为醇溶液形式。用于治疗急性光化性角化病时，建议5’-氟尿嘧啶含量为5％至10％。已发现局部性施用包含这些含量的5’-氟尿嘧啶的组合物会引发很多副作用。并且，所描述的醇溶液当局部地施用在皮肤表面时易于流动。
需要适于作为治疗光化性角化病的医药的局部性组合物，其在治疗中具有高效，而副作用极小，并且能够进行确切的剂量给药。
发明内容
本发明因此提供一种用于治疗光化性角化病的局部性凝胶组合物，包含：
(a)用于治疗光化性角化病的活性剂，
(b)角质层分离活性剂，
(c)凝胶形成剂，以及
(d)有机溶剂。
该组合物通常是直接施加至皮肤的形式。因此，该组合物优选不被封装，例如膏药(patch)或贴片。
该组合物优选包含少于5wt％，特定地少于1wt％，更优选少于0.5wt％的水。特别优选该组合物实质上不含水。
本发明组合物中成分的特定组合具有众多优点。特别是，该组合致使允许用于组合物中的活性剂具有高药理利用度，即使药物含量较低，所述组合物在治疗光化性角化病中也具有高效。并且，该组合物在所施加的量以及指定的皮肤区域两方面均可准确给药。该组合物进一步的优点是可快速吸收或干燥，而不需要搓揉入皮肤中，并且，甚至在施加至例如垂直的头部及/或脸部区域时不会流动。特别地，已发现本发明的组合物在使用时只有极小的副作用被观察到。并且，本发明的组合物在通常的储存期间(例如3年)是稳定的，甚至当使用诸如5’-氟尿嘧啶的活性剂时。
本发明组合物以凝胶形式存在。该凝胶通常具有适合利用例如刷子将产品施加至受光化性角化病影响的皮肤区域而该组合物不流动的任何黏度。特别优选组合物在20℃具有300mPas至1500mPas的范围的黏度，特别地，在20℃具有500mPas至1200mPas的黏度，最优选在20℃具有600mPas至900mPas的黏度。优选利用DIN测量系统Z3于D＝57.2sec-1及T＝20℃的条件下测定黏度。这样的凝胶被局部地施加时，能够特别准确地进行剂量给药，而不会流动。
依据本发明，优选组合物中的用于治疗光化性角化病的活性剂是选自于下述物质所构成的组：环加氧酶抑制剂、局部免疫调节剂、抗代谢物、及上述几种物质的混合物。合适的环加氧酶抑制剂的实例为：布洛芬(ibuprofen)、双氯芬酸(diclofenac)、依托度酸(etodolac)、塞来昔布(celecoxib)以及吡罗昔康(piroxicam)。局部免疫调节剂的实例包括：咪喹莫特(imiquimod)、雷西莫特(resimiquimod)及索替莫特(sotirimod)。较佳的抗代谢物是具有嘧啶结构的抗代谢物，特别是5’-氟尿嘧啶。
特别优选用于治疗光化性角化病的活性剂是选自于具有嘧啶结构的抗代谢物所构成的组，其中特别优选5’-氟尿嘧啶。并且，优选该组合物包含0.1wt％至10wt％，特别地0.25wt％至4.5wt％的用于治疗光化性角化病的活性剂。本发明的优选具体例中，该组合物包含少于2wt％的用于治疗光化性角化病的活性剂。最佳地，该组合物包含0.4wt％至1wt％的用于治疗光化性角化病的活性剂。令人惊奇的是，本发明组合物即使以相对低的药物含量，仍高效地治疗光化性角化病。
该组合物包含至少一种角质层分离活性剂。此处使用的术语“角质层分离活性剂”是指适于实现角质细胞(korneocyte)自角质层解离及脱离的药剂。
优选，该角质层分离活性剂是选自于下述物质所构成的组：类视黄醇受体激动剂、尿素(urea)、有机酸(特别是羟基羧酸)以及上述几种物质的混合物。适当的类视黄醇受体激动剂的实例包括：阿达帕林(adapalene)及类视黄醇(retinoid)，特别是维A酸(tretinoin)、异维A酸(isotretinoin)、莫维A胺(motretinide)、他扎罗汀(tazarotene)及/或视黄醇(retinol)。特别优选有机酸是乙醇酸(glycolicacid)、乙酸、乳酸及/或水杨酸。水杨酸是特佳的。并且，优选该组合物包含0.025wt％至30wt％，特别是0.1wt％至20wt％，更优选2wt％至20wt％，最优选5wt％至15wt％的角质层分离活性剂。
该组合物进一步包含至少一种凝胶形成剂。此处使用的术语“凝胶形成剂”是指该组合物的成分与有机溶剂一起形成由胶体悬浮液所构成的黏弹性物质。不同的凝胶形成剂都适合用于本发明组合物中。特别优选组合物中的凝胶形成剂是选自于下述物质所构成的组：乙烯基均聚物及共聚物、纤维素衍生物、及上述几种物质的混合物。
该乙烯基均聚物及共聚物特别优选是以丙烯酸或甲基丙烯酸或其酯类和甲基丙烯酸甲酯为基础的共聚物。以丙烯酸或甲基丙烯酸或其酯类和甲基丙烯酸甲酯为基础的适当共聚物的实例是：丙烯酸乙酯-甲基丙烯酸甲酯共聚物(Eudragit NE)、甲基丙烯酸-甲基丙烯酸甲酯共聚物(Eudragit L，Eudragit S或Rohagit S)以及甲基丙烯酸丁酯-甲基丙烯酸甲酯共聚物(Plastoid B)，优选PlastoidB。
较佳的纤维素衍生物是纤维素酯，诸如硝酸纤维素。依据本发明的优选具体例，本发明的组合物包含至少一种选自于由以丙烯酸或甲基丙烯酸或其酯类及甲基丙烯酸甲酯为基础的共聚物所构成的组中的凝胶形成剂，以及至少一种选自于由纤维素衍生物所构成的组中的凝胶形成剂。已发现如此的凝胶形成剂组合尤其能够与有机溶剂一起形成一种凝胶，该凝胶可被准确地进行剂量给药，而无需搓揉入皮肤中，并且局部性施加时不会流动。
特别优选本发明组合物包含1wt％至30wt％，特别地2wt％至20wt％，最优选5wt％至15wt％的凝胶形成剂。
本发明组合物包含至少一种有机溶剂。优选该有机溶剂选自于下述物质所构成的组：C1-C10醇类、C1-C10醇类与C1-C10羧酸形成的酯、C3-C8烷基酮、及上述几种物质的混合物。适当的溶剂的实例包括：乙醇、异丙醇、丁醇、乙酸乙酯、乙酸丁酯以及丙酮。优选该有机溶剂包含C1-C6醇以及C1-C6醇类与C2-C6羧酸形成的酯。特别优选该有机溶剂具有低于100℃，优选低于90℃，最优选低于80℃的沸点。
进一步优选该组合物包含1wt％至90wt％，特别是50wt％至80wt％，最优选60wt％至75wt％的有机溶剂。惊奇地发现本发明所使用的溶剂与凝胶形成剂的组合使活性剂获得高可利用度，并且进一步使组合物能够准确地进行剂量给药，而无需搓揉入皮肤中，并且局部性施加时不会流动。
依据优选具体例，本发明组合物进一步包含皮肤渗透促进剂。优选该皮肤渗透促进剂选自于下述物质所构成的组：多元脂肪族C2-C10醇、具有C2-C4亚烷基的聚亚烷基二醇、多元脂肪族C2-C10醇与具有C2-C4亚烷基的聚亚烷基二醇的非烷氧基化醚、氮酮(azone)、萜类(terpene)、类萜(terpenoid)、吡咯烷酮(pyrrolidone)、亚砜(sulfoxide)、及上述几种物质的混合物。已发现本发明组合物中皮肤渗透促进剂的存在进一步改善活性剂的可利用度，且能减少该活性剂的量同时维持药效。
特别优选该皮肤渗透促进剂包含亚砜，特别是二甲基亚砜。此外，皮肤渗透促进剂的例子是多元醇，特别是C2-C8二醇，诸如丙二醇或丁二醇以及甘油。进一步优选该组合物包含1wt％至50wt％，特别地3wt％至15wt％，最佳地5wt％至10wt％的皮肤渗透促进剂。
依据特别优选的具体例，该组合物包含：
(a)0.25wt％至4.5wt％，特别是0.4wt％至1wt％的用于治疗光化性角化病的活性剂，优选5’-氟尿嘧啶，
(b)2wt％至20wt％，特别是5wt％至15wt％的角质层分离活性剂，优选水杨酸，
(c)2wt％至20wt％，特别是5wt％至15wt％的凝胶形成剂，优选(甲基)丙烯酸酯均聚物或共聚物和纤维素衍生物的组合，
(d)40wt％至70wt％，特别是50wt％至60wt％的C1-C4醇类与C2-C4羧酸形成的酯，
(e)5wt％至30wt％，特别是10wt％至20wt％的C1-C4醇类，以及
(f)3wt％至15wt％，特别是5wt％至10wt％的皮肤渗透促进剂，优选二甲基亚砜。
该组合物可另外包含惯用的药学上可接受的成分。然而，油成分诸如矿物油一般地是不希望存在于该组合物中，原因在于所述油成分可能导致不希望的皮肤感觉，并且可能会造成粉刺(comedogenic)。因此，该组合物一般优选包含少于5wt％，特别地少于1wt％，更佳地少于0.1wt％的油成分。该组合物特别优选实质上无油。
本发明还关于一种用于治疗患者的光化性角化病的方法，该方法包含将本发明的局部性凝胶组合物施加至患病的皮肤区域。
本发明还关于本发明组合物于制造用于治疗光化性角化病的医药中的用途。
具体实施方式
进一步参照随后的实例详细描述本发明，但该实例无论如何并未限制本发明的范畴：
实例1：
制备了具有下述组成(wt％)的产品：
| 5’-氟尿嘧啶 | 0.50 |
| 水杨酸 | 10.00 |
| 聚(甲基丙烯酸丁酯，甲基丙烯酸甲酯) | 4.00 |
| 硝酸纤维素 | 5.00 |
| 二甲基亚砜 | 8.00 |
| 乙酸乙酯 | 56.50 |
| 乙醇 | 16.00 |
实例2：
制备了具有下述组成(wt％)的产品：
| 5’-氟尿嘧啶 | 0.50 |
| 水杨酸 | 10.00 |
| 聚(甲基丙烯酸丁酯，甲基丙烯酸甲酯) | 5.00 |
| 硝酸纤维素 | 4.00 |
| 二甲基亚砜 | 10.00 |
| 乙酸乙酯 | 54.50 |
| 乙醇 | 16.00 |
实例3：
制备了具有下述组成(wt％)的产品：
| 5’-氟尿嘧啶 | 0.50 |
| 水杨酸 | 10.00 |
| 聚(甲基丙烯酸丁酯，甲基丙烯酸甲酯) | 5.00 |
| 硝酸纤维素 | 4.00 |
| 二甲基亚砜 | 8.00 |
| 乙酸乙酯 | 56.50 |
| 乙醇 | 16.00 |
实例4：
制备了具有下述组成(wt％)的产品：
| 5’-氟尿嘧啶 | 0.50 |
| 乳酸 | 10.00 |
| 聚(甲基丙烯酸丁酯，甲基丙烯酸甲酯) | 5.00 |
| 硝酸纤维素 | 4.00 |
| 二甲基亚砜 | 8.00 |
| 乙酸乙酯 | 56.50 |
| 乙醇 | 16.00 |
实例5：
制备了具有下述组成(wt％)的产品：
| 5’-氟尿嘧啶 | 0.50 |
| 乳酸 | 5.00 |
| 水杨酸 | 5.00 |
| 聚(甲基丙烯酸丁酯，甲基丙烯酸甲酯) | 5.00 |
| 硝酸纤维素 | 4.00 |
| 二甲基亚砜 | 8.00 |
| 乙酸乙酯 | 56.50 |
| 乙醇 | 16.00 |
实例6：
制备了具有下述组成(wt％)的产品：
| 布洛芬(Ibuprofen) | 0.50 |
| 水杨酸 | 10.00 |
| 聚(甲基丙烯酸丁酯，甲基丙烯酸甲酯) | 5.00 |
| 硝酸纤维素 | 4.00 |
| 二甲基亚砜 | 8.00 |
| 乙酸乙酯 | 56.50 |
| 乙醇 | 16.00 |
实例7：
制备了具有下述组成(wt％)的产品：
| 5’-氟尿嘧啶 | 0.50 |
| 水杨酸 | 10.00 |
| 聚(甲基丙烯酸丁酯，甲基丙烯酸甲酯) | 4.00 |
| 硝酸纤维素 | 5.00 |
| 二甲基亚砜 | 10.00 |
| 乙酸乙酯 | 56.50 |
| 乙醇 | 14.00 |
所获得的产品是凝胶形式，且在20℃具有约770mPas的黏度。可以利用细刷将所述产品准确地应用于光化性角化病。由于溶剂挥发，该凝胶快速地在皮肤上形成薄膜而不会流动。
Claims (32)
1.一种用于治疗光化性角化病的局部性凝胶组合物，包含：
(a)用于治疗光化性角化病的活性剂，
(b)角质层分离活性剂，
(c)凝胶形成剂，以及
(d)有机溶剂。
2.如权利要求1所述的组合物，其中所述组合物包含少于5wt％的水。
3.如权利要求2所述的组合物，其中所述组合物包含少于1wt％的水。
4.如权利要求3所述的组合物，其实质上不含水。
5.如前述权利要求中任一项所述的组合物，其中所述凝胶在20℃具有300mPas至1500mPas的范围的黏度。
6.如权利要求5所述的组合物，其中所述凝胶在20℃具有600mPas至900mPas的范围的黏度。
7.如前述权利要求中任一项所述的组合物，其中所述用于治疗光化性角化病的活性剂选自于如下组：环加氧酶抑制剂、局部免疫调节剂、抗代谢物、及上述几种物质的混合物。
8.如权利要求7所述的组合物，其中所述用于治疗光化性角化病的活性剂是5’-氟尿嘧啶。
9.如前述权利要求中任一项所述的组合物，其中所述组合物包含0.25wt％至4.5wt％的所述用于治疗光化性角化病的活性剂。
10.如权利要求9所述的组合物，其包含0.4wt％至1wt％的所述用于治疗光化性角化病的活性剂。
11.如前述权利要求中任一项所述的组合物，其中所述角质层分离活性剂选自于如下组：类视黄醇受体激动剂、尿素、有机酸、及上述几种物质的混合物。
12.如权利要求11所述的组合物，其中所述角质层分离活性剂选自于如下组：乙醇酸、乙酸、乳酸、水杨酸、及上述几种物质的混合物。
13.如权利要求11所述的组合物，其中所述角质层分离活性剂是水杨酸。
14.如前述权利要求中任一项所述的组合物，其包含0.025wt％至30wt％的所述角质层分离活性剂。
15.如权利要求14所述的组合物，其包含5wt％至15wt％的所述角质层分离活性剂。
16.如前述权利要求中任一项所述的组合物，其中所述凝胶形成剂选自于如下组：乙烯基均聚物、乙烯基共聚物、纤维素衍生物、及上述几种物质的混合物。
17.如前述权利要求中任一项所述的组合物，其包含1wt％至30wt％的所述凝胶形成剂。
18.如权利要求17所述的组合物，其包含5wt％至15wt％的所述凝胶形成剂。
19.如前述权利要求中任一项所述的组合物，其中所述有机溶剂选自于如下组：C1-C10醇类、C1-C10醇类与C1-C10羧酸形成的酯、及上述几种物质的混合物。
20.如权利要求19所述的组合物，其中所述有机溶剂包含C1-C6醇及C1-C6醇与C2-C6羧酸形成的酯。
21.如前述权利要求中任一项所述的组合物，其中所述有机溶剂具有低于100℃的沸点。
22.如权利要求21所述的组合物，其中所述有机溶剂具有低于80℃的沸点。
23.如前述权利要求中任一项所述的组合物，其包含1wt％至90wt％的所述有机溶剂。
24.如权利要求23所述的组合物，其包含60wt％至75wt％的所述有机溶剂。
25.如前述权利要求中任一项所述的组合物，其进一步包含皮肤渗透促进剂。
26.如权利要求25所述的组合物，其中所述皮肤渗透促进剂选自于如下组：多元脂肪族C2-C10醇、具有C2-C4亚烷基的聚亚烷基二醇、多元脂肪族C2-C10醇与具有C2-C4亚烷基的聚亚烷基二醇的非烷氧基化醚、氮酮、萜类、类萜、吡咯烷酮、亚砜、及上述几种物质的混合物。
27.如权利要求26所述的组合物，其中所述皮肤渗透促进剂是二甲基亚砜。
28.如权利要求25～27中任一项所述的组合物，其包含1wt％至50wt％的所述皮肤渗透促进剂。
29.如权利要求28所述的组合物，其包含5wt％至10wt％的所述皮肤渗透促进剂。
30.如权利要求1所述的组合物，其包含：
(a)0.25wt％至4.5wt％的所述用于治疗光化性角化病的活性剂，
(b)2wt％至20wt％的所述角质层分离活性剂，
(c)2wt％至20wt％的所述凝胶形成剂，
(d)40wt％至70wt％的C1-C4醇与C2-C4羧酸形成的酯，
(e)5wt％至30wt％的C1-C4醇，以及
(f)3wt％至15wt％的所述皮肤渗透促进剂。
31.如权利要求30所述的组合物，其包含：
(a)0.25wt％至4.5wt％的5’-氟尿嘧啶，
(b)2wt％至20wt％的水杨酸，
(c)2wt％至20wt％的凝胶形成剂，其是(甲基)丙烯酸酯均聚物或共聚物和纤维素衍生物的组合，
(d)40wt％至70wt％的C1-C4醇与C2-C4羧酸形成的酯，
(e)5wt％至30wt％的C1-C4醇，以及
(f)3wt％至15wt％的二甲基亚砜。
32.一种治疗患者光化性角化病的方法，包括将前述权利要求中任一项所述的局部性凝胶组合物施加到受到感染的皮肤区域。
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510185320.3A CN104825384A (zh) | 2008-07-07 | 2009-06-29 | 用于治疗光化性角化病的局部性凝胶组合物及其制药用途 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08012237A EP2143421A1 (en) | 2008-07-07 | 2008-07-07 | Topical composition for the treatment of actinic keratosis |
| EP08012237.7 | 2008-07-07 | ||
| PCT/EP2009/004682 WO2010003568A1 (en) | 2008-07-07 | 2009-06-29 | Topical composition for the treatment of actinic keratosis |
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| CN201510185320.3A Pending CN104825384A (zh) | 2008-07-07 | 2009-06-29 | 用于治疗光化性角化病的局部性凝胶组合物及其制药用途 |
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| US (1) | US8569320B2 (zh) |
| EP (2) | EP2143421A1 (zh) |
| JP (2) | JP5654987B2 (zh) |
| KR (1) | KR101689898B1 (zh) |
| CN (2) | CN102088957A (zh) |
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| AU (1) | AU2009267471B2 (zh) |
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| DK (1) | DK2315581T3 (zh) |
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| PL (1) | PL2315581T3 (zh) |
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| JP5798561B2 (ja) * | 2009-10-08 | 2015-10-21 | エムエスディー コンシューマー ケア， インコーポレイテッド | 低エーテル組成物およびデリバリー装置 |
| JP5950528B2 (ja) * | 2011-09-30 | 2016-07-13 | 小林製薬株式会社 | 皮膜形成性外用製剤 |
| WO2013088380A1 (en) * | 2011-12-12 | 2013-06-20 | Leo Laboratories Limited | Gel compositions |
| NZ606177A (en) * | 2012-01-30 | 2014-03-28 | Dolorgiet Gmbh & Co Kg | Compositions for the treatment of actinic keratosis |
| GB201222405D0 (en) * | 2012-12-12 | 2013-01-23 | Leo Lab Ltd | Gel compositions |
| MX2017001331A (es) * | 2014-07-31 | 2017-05-23 | Sun Pharmaceutical Ind Ltd | Composicion farmaceutica oral de isotretinoina. |
| BR112017004889A2 (pt) | 2014-09-12 | 2017-12-05 | Antibiotx Aps | uso antibacteriano de salicilanilidas halogenadas |
| GB201509326D0 (en) | 2015-05-29 | 2015-07-15 | Antibio Tx Aps | Novel use |
| RU2706234C2 (ru) * | 2015-07-10 | 2019-11-15 | Инфектофарм Арцнаймиттель Унд Консилиум Гмбх | Применение гидроксида калия при лечении актинического кератоза |
| GB201604484D0 (en) * | 2016-03-16 | 2016-04-27 | Antibiotx Aps And Københavns Uni University Of Copenhagen | Topical antibacterial compositions |
| BR112019018687A2 (pt) | 2017-03-10 | 2020-04-07 | Athenex Inc | métodos de tratamento e/ou prevenção da ceratose actínica |
| US11419834B2 (en) | 2019-02-25 | 2022-08-23 | Rhode Island Hospital | Methods for treating diseases or infections caused by or associated with H. pylori using a halogenated salicylanilide |
| US20220175769A1 (en) * | 2020-12-08 | 2022-06-09 | Ankh Life Sciences Limited | Method of treatment of actinic keratoses |
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| US4234599A (en) * | 1978-10-04 | 1980-11-18 | Scott Eugene J Van | Treatment of skin keratoses with α-hydroxy acids and related compounds |
| US5091171B2 (en) * | 1986-12-23 | 1997-07-15 | Tristrata Inc | Amphoteric compositions and polymeric forms of alpha hydroxyacids and their therapeutic use |
| US5167649A (en) * | 1988-08-22 | 1992-12-01 | Zook Gerald P | Drug delivery system for the removal of dermal lesions |
| US5093360A (en) * | 1989-04-07 | 1992-03-03 | Yu Ruey J | Retinal, derivatives and their therapeutic use |
| GB9023701D0 (en) * | 1990-10-31 | 1990-12-12 | Efamol Holdings | Medical treatment |
| JP3117502B2 (ja) * | 1991-08-27 | 2000-12-18 | 株式会社資生堂 | 皮膚外用剤 |
| US5627187A (en) | 1995-04-12 | 1997-05-06 | Katz; Bruce E. | 5-FU for treating actinic kerotoses |
| EP1210937A3 (en) * | 1996-06-20 | 2003-02-05 | Lavipharm S.A. | Device for topical treatment of acne and its method of manufacture |
| US5993787A (en) * | 1996-09-13 | 1999-11-30 | Johnson & Johnson Consumer Products, Inc. | Composition base for topical therapeutic and cosmetic preparations |
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| US6462071B1 (en) * | 2000-03-02 | 2002-10-08 | Vitreo-Retinal Technologies, Inc. | Agents for intravitreal administration to treat or prevent disorders of the eye |
| ES2223277B1 (es) * | 2003-06-19 | 2006-03-01 | Fernando Bouffard Fita | Composicion anestesica para administracion topica. |
| KR20060113657A (ko) * | 2003-08-25 | 2006-11-02 | 포믹스 리미티드 | 침투성 약제용 거품제 |
| US20050137164A1 (en) * | 2003-09-22 | 2005-06-23 | Moshe Arkin | Diclofenac compositions for the treatment of skin disorders |
| EP1765293B1 (en) * | 2004-06-24 | 2014-10-01 | Idexx Laboratories, Inc. | Pharmaceutical compositions for drug delivery and methods of treating or preventing conditions using same |
| US20070053984A1 (en) | 2005-03-03 | 2007-03-08 | Monique Spann-Wade | Topical gels compositions |
| WO2006134406A1 (en) * | 2005-06-14 | 2006-12-21 | Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. | Stable pharmaceutical gel of diclofenac sodium |
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| US20070264317A1 (en) * | 2006-05-15 | 2007-11-15 | Perrigo Israel Pharmaceuticals Ltd. | Imiquimod cream formulation |
| WO2008047857A1 (fr) * | 2006-10-18 | 2008-04-24 | Fujifilm Corporation | Procédé de production d'une composition comprenant un composé difficilement soluble dans l'eau incorporé dans une matrice hydrophile et préparation pour une utilisation externe comprenant un agent ou médicament anticancéreux ayant un coefficient de partage octanol/eau (log p) de -3,0 ou plus mais pas plus de 3,0, incorporé |
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