Bioadhesive patch-based delivery of 5-aminolevulinic acid to the nail for photodynamic therapy of onychomycosis
Introduction
Onychomycosis is a fungal infection of the keratinized tissue of the nail plate [1] that is notoriously difficult to diagnose and treat [2], [3], [4]. The condition accounts for approximately one-third of all fungal skin infections [5] and is increasing in prevalence [6], with a recent survey indicating that from 2–18% of the world population are affected [7]. More importantly, onychomycosis in immunocompromised patients, such as those infected with HIV, can pose a more serious health problem.
Once onychomycosis has been diagnosed, the available treatment modalities that may be considered are topical therapy, systemic (oral) therapy and surgical intervention [7], [8]. However, effective treatment of the condition is notoriously difficult. Topically-applied drugs are generally unable to penetrate the entire nail unit [9]. Systemically administered drugs, such as griseofulvin, ketoconazole and terbinafine, may require up to 12 months of treatment [10]. Furthermore, these agents may be associated with toxicity and potentially serious drug interactions [11], [12]. Development of resistance, especially when used on a long-term basis, also poses concern. Surgical therapy has generally been discontinued due to the pain, disfiguration and potential for permanent scarring that accompanies invasive intervention [13], [14].
Photodynamic therapy (PDT) is defined as a medical treatment by which a combination of a sensitising drug and visible light causes destruction of selected cells [15], [16]. Recently, the use of PDT, based on topical application of 5-aminolevulinic acid (ALA), has been extended from the oncological field to that of antimicrobial chemotherapy. ALA administration has been shown to induce accumulation of the photosensitiser protoporphyrin IX (PpIX) in, and allow subsequent photodynamic destruction of, bacteria [17], [18] and fungi [19]. This study, therefore, reports on a bioadhesive patch containing ALA, first developed in our laboratory for PDT of vulval intraepithelial neoplasia [20] and vulval Paget's Disease [21], as a potential delivery system for use in ALA-PDT of onychomycosis.
Section snippets
Chemicals
Gantrez® AN-139, a copolymer of methylvinylether and maleic anhydride (PMVE/MA), was provided by ISP, Guildford, UK. Plastisol® medical grade poly(vinyl chloride) emulsion containing diethylphthalate as plasticiser, was provided by BASF Coatings, Clwyd, UK. 5-aminolevulinic acid, hydrochloride salt, was purchased from Crawford Pharmaceuticals, Milton Keynes, UK. Radiolabelled 5-aminolevulinic acid solution, 3.7 MBq ml−1 and Ultima Gold® Liquid Scintillation Cocktail were obtained from
ALA penetration of human nail samples
The rate of ALA transfer across the nail was shown to remain constant with respect to time for a considerable portion of the total release time interval, as shown in Fig. 2. After 4 h, the ALA concentration in the receiver phase was approximately 0.5 mM, after 24 h, it was approximately 2.8 mM, after 48 h, it was approximately 4.5 mM and after 72 h, it was approximately 6.9 mM. The large standard deviations observed are typical of those seen in nail penetration experiments [29], [30], [31],
Discussion
The principal manifestations of onychomycosis are hyperkeratosis and discolouration of the nail with other symptoms incorporating onycholysis (detachment of the nail from the nail bed), brittle and damaged nails, paronychial inflammation and thickening of the nail plates [8], [13]. Contrary to common misconception, the condition is not merely a cosmetic affliction [6] but can result in severe pain and the risk of progression to total dystrophy of the nail plate, with a significant adverse
Acknowledgements
The authors gratefully acknowledge the technical assistance of Mrs. Stephanie McGrath with microbiological experiments.
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