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

Lead Research Organisation: School of Pharmacy
Department Name: Pharmaceutics

Abstract

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.

Technical Summary

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. 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 represents a significant challenge. 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. However, topical treatments used for nail disorders such as fungal infections or psoriasis. Topical treatments do not carry the risks of serious side effects (hepatotoxicity) associated with systemic antifungals. The topical products currently marketed to treat onychomycosis have reported cure rates as low as 24% and require long term application, hence patient compliance is often poor and relapse common. 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. 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.

Planned Impact

The proposed study is timely in that the incidence of onychomycosis appears to be on the increase which has been attributed to a growing elderly population (prevalence of onychomycosis being higher in older people), the spread of HIV infection and AIDS, a higher frequency of iatrogenic immunosuppression due to the use of immunosuppressant drugs, lifestyle factors such as the wearing of tight-fitting clothing and shoes and the use of communal recreational facilities and health clubs, as well as improved detection and higher public awareness. Thus demand for effective therapy is on the increase. This project will generate basic knowledge on the properties of healthy and diseased nail plates and on the physicochemical properties of drugs which influence their permeation into such nail plates which will be of interest to anybody working in diseases of the nail. As such the knowledge generated will have a significant impact on the treatment of nail diseases and hence on the quality of life of sufferers. Thus, this project fits with the BBSRC's mission to support high quality basic and strategic research, to provide trained scientists, and thereby contribute to the quality of life. Beneficiaries will contribute to this project by donating their fungally infected nails for analysis. In addition, the techniques developed in this study will have a wider application in other areas of drug delivery and the healthcare industry where little is known about the barrier properties of some biological membranes (e.g. the eye). The techniques and understanding developed could provide a fundamental insight into how topical disease treatment can be improved. The findings could also be applied to other scientific disciplines where a more fundamental understanding of membrane properties is required (e.g. polymer science, material science, plant science, food science, cosmetic science, microbiology, veterinary medicine, nanotechnology) and as such could be ubiquitous in is application. The applicants have already established a reputation in maximizing the impact of their work. For example, Prof Brown and Dr Jones applied the fundamental knowledge they developed in a particle engineering project and received translational funding in collaboration with MedPharm Ltd to develop a drug delivery technology named MedSpray which has recently successfully complete a phase IIB clinical trial in the treatment of athlete's foot. Dr Jones and Prof Brown are also the co-inventors on 11 patents between them over three quarters of which have been licensed to industry. Industry have already expressed interest in the findings of these results and as such once any potential intellectual property issues have been addressed by the relevant technology transfer groups of the three institutions formal meetings between all interested parties (e.g. academia, industry, equipment companies and healthcare professionals ) will be organised in order to discuss the findings and their potential application. Obviously, it is policy to publish and present the findings of these studies in peer-reviewed articles and conference proceedings for dissemination to the rest of the scientific community and the general public. The applicants are also members of the organising committees of Perspectives of Percutaneous Penetration which is organised in France every 2 years and Skin Forum which is arranged in Europe in the alternative years and these will provide other potential opportunities to disseminate the results from this study. The resultant data will also be included on the relevant web sites of the 3 partner institutions and any associated meetings.

Publications

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publication icon
McAuley WJ (2016) An investigation of how fungal infection influences drug penetration through onychomycosis patient's nail plates. in European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V

 
Description We found that diseased nails are significantly different from healthy nails, in terms of their appearance and properties. Diseased nails are 2-3 times thicker, less dense, more porous (about twice), mechanically less strong. Very importantly, diseased nails are more permeable to hydrophilic drugs compared to healthy nails. However, the permeability of hydrophobic drugs is the same in healthy and diseased nails.
Exploitation Route Other researchers are now more aware that when testing drug permeation into the nail, diseased nails should be used, as these nails are different to healthy nails and are the nails that will be treated
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

URL https://iris.ucl.ac.uk/iris/publication/996038/2
 
Description Evaluation of anti-fungal efficacy of nail medicines and of new drugs and of drug combinations. Further evaluation of the diseased nail 
Organisation Birkbeck, University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution With Birkbeck, We have developed a simple, rapid and accurate assay to test the susceptibility of dermatophytes to antifungals based on the SPOTi assay. The work is now published. We have also tested the anti-fungal efficacy of the patches developed in this project. This collaboration has led to further collaboration on the testing of other products for their fungal efficacy, and the related papers have been published. with Monash and University of Havana, we are testing new compounds that have anti-fungal activity, which would be able to treat onychomycotic nails With Hospital Tor Vegata Roma, we are studying the diseased nail in more detail With UCL, we are investigating drug combinations for the treatment of onychomycotic nails
Collaborator Contribution THe partners at Birkbeck are experts in fungi and antimicrobial testing. They were the developers of SPOTi assay (for mycobacteria) which we then adapted for fungus. THe partners provided the expertise and laboratory facilities for the work.
Impact THe papers are published and are included in 'publications' THe collaboration is multi-disciplinary, in pharmaceutical sciences, infection, microbiology
Start Year 2014
 
Description Evaluation of anti-fungal efficacy of nail medicines and of new drugs and of drug combinations. Further evaluation of the diseased nail 
Organisation Hospital Tor Vergata Roma
PI Contribution With Birkbeck, We have developed a simple, rapid and accurate assay to test the susceptibility of dermatophytes to antifungals based on the SPOTi assay. The work is now published. We have also tested the anti-fungal efficacy of the patches developed in this project. This collaboration has led to further collaboration on the testing of other products for their fungal efficacy, and the related papers have been published. with Monash and University of Havana, we are testing new compounds that have anti-fungal activity, which would be able to treat onychomycotic nails With Hospital Tor Vegata Roma, we are studying the diseased nail in more detail With UCL, we are investigating drug combinations for the treatment of onychomycotic nails
Collaborator Contribution THe partners at Birkbeck are experts in fungi and antimicrobial testing. They were the developers of SPOTi assay (for mycobacteria) which we then adapted for fungus. THe partners provided the expertise and laboratory facilities for the work.
Impact THe papers are published and are included in 'publications' THe collaboration is multi-disciplinary, in pharmaceutical sciences, infection, microbiology
Start Year 2014
 
Description Evaluation of anti-fungal efficacy of nail medicines and of new drugs and of drug combinations. Further evaluation of the diseased nail 
Organisation Monash University
Department Institute of Pharmaceutical Sciences
Country Australia 
Sector Academic/University 
PI Contribution With Birkbeck, We have developed a simple, rapid and accurate assay to test the susceptibility of dermatophytes to antifungals based on the SPOTi assay. The work is now published. We have also tested the anti-fungal efficacy of the patches developed in this project. This collaboration has led to further collaboration on the testing of other products for their fungal efficacy, and the related papers have been published. with Monash and University of Havana, we are testing new compounds that have anti-fungal activity, which would be able to treat onychomycotic nails With Hospital Tor Vegata Roma, we are studying the diseased nail in more detail With UCL, we are investigating drug combinations for the treatment of onychomycotic nails
Collaborator Contribution THe partners at Birkbeck are experts in fungi and antimicrobial testing. They were the developers of SPOTi assay (for mycobacteria) which we then adapted for fungus. THe partners provided the expertise and laboratory facilities for the work.
Impact THe papers are published and are included in 'publications' THe collaboration is multi-disciplinary, in pharmaceutical sciences, infection, microbiology
Start Year 2014
 
Description Evaluation of anti-fungal efficacy of nail medicines and of new drugs and of drug combinations. Further evaluation of the diseased nail 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution With Birkbeck, We have developed a simple, rapid and accurate assay to test the susceptibility of dermatophytes to antifungals based on the SPOTi assay. The work is now published. We have also tested the anti-fungal efficacy of the patches developed in this project. This collaboration has led to further collaboration on the testing of other products for their fungal efficacy, and the related papers have been published. with Monash and University of Havana, we are testing new compounds that have anti-fungal activity, which would be able to treat onychomycotic nails With Hospital Tor Vegata Roma, we are studying the diseased nail in more detail With UCL, we are investigating drug combinations for the treatment of onychomycotic nails
Collaborator Contribution THe partners at Birkbeck are experts in fungi and antimicrobial testing. They were the developers of SPOTi assay (for mycobacteria) which we then adapted for fungus. THe partners provided the expertise and laboratory facilities for the work.
Impact THe papers are published and are included in 'publications' THe collaboration is multi-disciplinary, in pharmaceutical sciences, infection, microbiology
Start Year 2014
 
Description Evaluation of anti-fungal efficacy of nail medicines and of new drugs and of drug combinations. Further evaluation of the diseased nail 
Organisation University of Havana
PI Contribution With Birkbeck, We have developed a simple, rapid and accurate assay to test the susceptibility of dermatophytes to antifungals based on the SPOTi assay. The work is now published. We have also tested the anti-fungal efficacy of the patches developed in this project. This collaboration has led to further collaboration on the testing of other products for their fungal efficacy, and the related papers have been published. with Monash and University of Havana, we are testing new compounds that have anti-fungal activity, which would be able to treat onychomycotic nails With Hospital Tor Vegata Roma, we are studying the diseased nail in more detail With UCL, we are investigating drug combinations for the treatment of onychomycotic nails
Collaborator Contribution THe partners at Birkbeck are experts in fungi and antimicrobial testing. They were the developers of SPOTi assay (for mycobacteria) which we then adapted for fungus. THe partners provided the expertise and laboratory facilities for the work.
Impact THe papers are published and are included in 'publications' THe collaboration is multi-disciplinary, in pharmaceutical sciences, infection, microbiology
Start Year 2014
 
Description Presentation at UCL Ageing event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Approximately 200 older people, who are study participants on a different research programme attended the event. The intended purpose of my presentation was to raise awareness of nail diseases and medicines, and ask the attendees how they view and treat (or not) their nail diseases, if they have any. we also asked if the attendees at the event would want to be involved in my future studies on nails, nail diseases and medicines. Several attendees gave me their contact details.
Year(s) Of Engagement Activity 2016