A fundamental study to determine the difference in barrier properties of healthy and diseased nail in order to facilitate drug delivery

一项基础研究，旨在确定健康指甲和患病指甲的屏障特性差异，以促进药物输送

• 批准号: BB/H009922/1
• 负责人: Stuart Jones
• 金额: $ 14.03万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FH009922%2F1
• 关键词: fundamental; study; determine; difference; barrier

Nail disorders affect up to 10% of the population and range from innocuous discoloration of the nail plate, commonly seen in smokers, to chronic infections, which can be very painful and disfiguring for the sufferer. Nail infections are especially serious for immunocompromised patients and diabetics where they can cause major complications such as limb amputation. There are many highly effective compounds available to treat infections found in the nail but, the ungual keratin represents a highly effective barrier against absorption following topical drug administration, and therefore, the delivery of therapeutic agents to the site of action i.e. within the nail plate and the nail bed, represents a significant challenge. At present, topical treatments used for nail disorders such as fungal infections or psoriasis require long term application, hence patient compliance is often poor and relapse common. The treatments for nail disorders fall into three general categories; the first involves the surgical /chemical removal of all or part of the affected nail to expose the site of infection, which can then be treated topically. The second method of treatment is the oral administration of an appropriate drug and the third is topical drug administration. Although, at present, nail removal and oral administration are the most effective, the pain associated with nail removal and side-effects and potential drug interactions associated with oral drug therapy result in the direct application of a therapeutic agent to the nail plate being most popular with clinicians and patients. Two topical treatments are currently licensed for onychomycosis, Penlac marketed by Dermik in the USA, approved in late 1999 with reported sales of $142 million in 2003 and Loceryl available in Europe with sales of greater than $100 million in the same year). Topical treatments do not carry the risks of serious side effects (such as hepatotoxicity) associated with systemic antifungals and are less painful than treatments involving full or partial nail removal. However, the topical products currently marketed to treat onychomycosis have reported cure rates as low as 24% . Research has suggested the inefficiency of topical onychomycosis treatment is linked to the low penetration of the therapeutic into the nail, as some formulations only deliver 0.2% of their applied dose to the target site. To be effective, the drug must be able to penetrate the nail plate in sufficient quantities, to achieve an efficacious dose within the nail bed something that remains to be achieved with the current marketed products. One of the major reasons for this is that the nail is a more effective barrier to chemical permeation even compared to skin and the complete lack of fundamental understanding of structural properties of this barrier are preventing the effective design of drugs/formulations that can be used at this topical site. As such the aim of this study is to investigate the properties of healthy and onychomycotic nail plates, including their permeability to drugs. Such knowledge will be critical to identify new targets for enhancement strategies to improve the poor drug permeability of this biological barrier and further the ultimate goal of successfully treating onychomycosis topically.

指甲疾病影响高达10%的人口，范围从指甲盖的无害变色，常见于吸烟者，到慢性感染，这可能是非常痛苦和毁容的患者。指甲感染对于免疫功能低下的患者和糖尿病患者尤其严重，它们可能导致严重的并发症，如截肢。存在许多可用于治疗指甲中发现的感染的高效化合物，但是，甲角蛋白代表了在局部药物施用后针对吸收的高效屏障，因此，将治疗剂递送至作用部位，即在指甲板和甲床内，代表了重大挑战。目前，用于指甲疾病如真菌感染或银屑病的局部治疗需要长期应用，因此患者依从性通常较差，复发常见。指甲疾病的治疗分为三大类;第一类涉及手术/化学切除全部或部分受影响的指甲，以暴露感染部位，然后可以局部治疗。第二种治疗方法是口服适当的药物，第三种是局部给药。尽管目前，指甲去除和口服给药是最有效的，但与指甲去除相关的疼痛和与口服药物治疗相关的副作用和潜在的药物相互作用导致将治疗剂直接应用于甲板最受临床医生和患者欢迎。目前有两种局部治疗方法获得许可用于甲癣，Penlac由Dermik在美国上市，于1999年底获得批准，2003年报告的销售额为1.42亿美元，罗每乐在欧洲上市，同年销售额超过1亿美元。局部治疗不会带来与全身性抗真菌药相关的严重副作用（如肝毒性）的风险，并且比涉及全部或部分指甲切除的治疗疼痛更少。然而，目前市场上用于治疗甲真菌病的局部产品报告的治愈率低至24%。研究表明，局部甲真菌病治疗的无效性与治疗剂对指甲的渗透性低有关，因为一些制剂仅将其应用剂量的0.2%递送到目标部位。为了有效，药物必须能够以足够的量渗透甲板，以在甲床内达到有效剂量，这仍然是目前市售产品所要达到的。其主要原因之一是，即使与皮肤相比，指甲也是更有效的化学渗透屏障，并且完全缺乏对该屏障的结构性质的基本理解，这阻碍了可用于该局部部位的药物/制剂的有效设计。因此，本研究的目的是调查健康和甲肌甲板的特性，包括其对药物的渗透性。这些知识将是至关重要的，以确定新的目标，增强策略，以改善这种生物屏障的药物渗透性差，并进一步成功地局部治疗甲真菌病的最终目标。

项目成果

Human nail plate modifications induced by onychomycosis: implications for topical therapy.

• DOI: 10.1007/s11095-014-1562-5
• 发表时间: 2015-05
• 期刊: PHARMACEUTICAL RESEARCH
• 影响因子: 3.7
• 作者: Baraldi, A.;Jones, S. A.;Guesne, S.;Traynor, M. J.;McAuley, W. J.;Brown, M. B.;Murdan, S.
• 通讯作者: Murdan, S.

Advances in Dermatological Sciences: v. 1

皮肤科学进展：v. 1

• 发表时间: 2013
• 作者: Chilcott, Robert;Brain, K. R.;Anderson, Diana;Marrs, Tim;Waters, Mike D;Wilks, Martin F.
• 通讯作者: Wilks, Martin F.

An investigation of how fungal infection influences drug penetration through onychomycosis patient's nail plates.

• DOI: 10.1016/j.ejpb.2016.03.008
• 发表时间: 2016-05
• 期刊: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
• 作者: McAuley WJ;Jones SA;Traynor MJ;Guesné S;Murdan S;Brown MB
• 通讯作者: Brown MB