Murdan, S

UCL Discovery

Nail varnish as a drug delivery vehicleSudaxshina MurdanDepartment of Pharmaceutics, School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK.     Tel: +44-207-753-5810, Fax:+44-207-753-5942, email: sudax.murdan@ulsop.ac.ukNail varnish (enamel, lacquer) is an integral part of today=s beauty treatments.  It protects nail plates,  but  more importantly, it  enhances their  beauty, imparting colour and lustre.   It  is available in a myriad range of colours, it may be pearlised, some claim to be superdurable and chip-resistant, others claim to be fast-drying.  The basic nail varnish consists of solvents, film forming polymer, resins which enable the film to adhere to the nail plate and which convey luster  to  the  film,  plasticisers  which give flexibility and durability to  the film,  colouring agents and suspending agents.  Guanine crystals from fish scales and nacreous pigments may be included to give a pearlised effect; fibres e.g. silk, nylon, may also be included  to increase durability.Borrowing from the cosmetic industry....Incorporating drugs in nail varnish is an obvious step in the treatment of nail diseases, such as onychomycosis (fungal infections of the nail) and nail psoriasis, which are responsible for the bulk of nail disorders.  These two conditions are difficult to cure, need a long duration of treatment and relapse is common.  Side effects of oral anti-fungals include liver toxicity while treatment for nail psoriasis include monthly injection of corticosteroids into the nail  folds (skin around the nail plate).   Topical therapy, using nail varnish as a delivery vehicle, targets 1the drug to its site of action; thus, drug interactions and adverse events arising from systemic drug  exposure  can  be  avoided.   The technology to  manufacture,  package  and apply nail varnish has existed for a long time, most people are familiar with nail varnish, application is easy and pain-free.  Upon application of the lacquer onto the nail plate (the most visible part of the nail), the solvent evaporates, leaving a water-insoluble polymer film on the nail plate. The film acts as a drug depot from which drug can be released and penetrates into the nail for a desired duration, e.g. a week.  The film can then be removed using cosmetic nail polish remover  and fresh  lacquer  can  be  applied  to  renew the  drug depot.   Like  cosmetic  nail varnish, drug-containing nail lacquers must be stable, have the correct viscosity for ease of application; once applied, the lacquer must dry quickly (in 3-5 minutes) and form an even film which adheres well  to nail  plates and does not come off during daily activities,  but, which can be removed cleanly with enamel remover and is well-tolerated locally.  In addition, drug-containing lacquers must be colourless and non-glossy to be acceptable to male patients. Most importantly, the drug must be released from the film so that it can penetrate into the nail and achieve fungicidal concentrations.  The current drug-containing nail varnish formulations are pretty similar in composition to the cosmetic ones, except for the presence of the drug, the absence of colourants, nacreous pigments and suspending agents and the choice of the film-forming polymer; nitrocellulose (the main film-former in cosmetic nail varnish) is not used, presumably because of its explosive hazard. Commercially available drug-containing nail varnishThe first drug-containing nail varnish seems to be one that was used to treat nail mycoses, where   the  drug  was  the  anti-mycotic,  sulbentine  and  the  film-forming  polymer  was nitrocellulose.  This nail varnish was not universally accepted however, due to the fact that 2only mild nail mycoses could be treated, possibly as a result of poor drug bioavailability in the nail plate1.  Recent advances have resulted in more effective products, namely Loceryl7 and Penlac7, both of which are indicated for mild to moderate onychomycosis.  Loceryl7 - first marketed in 1992 - is a clear, colourless liquid and comprises the antifungal amorolfine (5%), Eudragit RL 100, glycerol triacetate, butyl acetate, ethyl acetate and ethanol.  The lacquer is applied 1-2 times weekly to infected nail plates for up to 6 months for fingernails or 9-12 months for toenails.  Penlac7 was  approved by the FDA in 1999.  A clear, colourless liquid, it is  composed  of  the  antifungal  agent  ciclopirox  (8%),  ethyl  acetate,  isopropanol  and butylmonoester of poly(methylvinyl ether/maleic acid).  Penlac7 is applied once daily, for up to 48 weeks. The film is  removed every 7 days with alcohol before re-application of the lacquer.  Following  application  of  Loceryl7 and  Penlac7 (which  contain  5%  amorolfine  and  8% ciclopirox respectively) to the nail plate, the solvents evaporate and a polymer film with a higher drug concentration (approximately 25% amorolfine or 35% ciclopirox) is left on the nail plate2-3.  This creates a high diffusion gradient for drug permeation into the nail plate. Formation of a film on the nail  plate also reduces water loss from the nail surface to the atmosphere; this results in hyperhydration of the upper nail plate layers4, which can also assist drug diffusion2.  Following application of the lacquers, amorolfine and ciclopirox were found to reach fungicidal concentrations in the nail plate3,5 and were found to be effective at treating the disease6.  The nail lacquers are also well-tolerated; adverse effects are rare and usually comprise mild irritation localised to the application site7-8.  Although Loceryl7 and Penlac7 are not usually used on their own for severe onychomycosis, there is a large body of literature showing  the  benefits  of  combining  the  nail  lacquers  with  conventional  oral  anti-fungal 3therapy in severe disease states.  These include a more effective treatment of the disease9, a reduction in oral drug intake and reduced cost of treatment10.  The nail lacquers could also be used to treat severe disease in special populations where oral therapy is contra-indicated, for example  in  children11,  in  pregnant  and  in  breastfeeding  women,  in  patients  with  hepatic and/or renal impairment and in those who perceive nail infection to be too trivial for systemic therapy.Factors which influence drug permeation into the nail and thereby, success of therapyThe drug must be released from the lacquer film and penetrate into the nail plate before it can act.  Drug permeation into the nail  plate is normally very low as the nail  plate is a good barrier; in an investigation in healthy volunteers, Van Hoogdalem et al calculated that less than 0.2% of applied dose was taken up into nail plates after 6 weeks of application12.  The nail plate is a dense structure (figure 1a) that is made up of approximately 25 layers of dead, keratinised, flattened cells which are tightly bound to one another.  The cells at the dorsal surface overlap (figure 1b), giving a smooth and poorly-permeable surface. Since the nail plate=s permeability is so low, a drug candidate must be effective at low concentrations i.e. have a very high potency. A small molecular size also helps; drug flux through the nail plate was found to be inversely proportional to molecular size13.  There are conflicting reports on the influence of drug hydrophilicity/hydrophobicity on its permeation14-15.As expected, increasing the drug concentration in the lacquer increases drug flux in the nail5 (figure 2). This is reflected in the increased cure rate from 12% to 38% when amorolfine concentration  in  the  lacquer  was  increased  from 2  to  5% in  a  double-blind,  randomised study16.   Increasing the duration of contact  also increases flux (figure 2).   This  was also 4reflected in a double-blind placebo-controlled studies,  where the therapeutic response was found to be directly related to the duration of treatment of nail psoriasis17.  Increasing the frequency  of  lacquer  application,  from  once  to  twice  weekly,  also  resulted  in  slightly increased (76.1 vs 70.6%), but not statistically significant, mycological cure rate7.  The nature of the drug formulation is expected to influence drug partitioning from the vehicle into the nail plate.  There are many conflicting reports, however, about the influence of the vehicle, for example, regarding the presence of water, the presence of an organic co-solvent such as dimethyl sulfoxide, the pH of formulation, and the nature of the solvent in the nail lacquer on drug flux into the nail18-21.  For example, Franz (1992) reported an increased drug flux through and into the nail plate from a methylene chloride lacquer compared to an ethanol lacquer21.   The author did  not  speculate  on  the  reasons  for  the different  permeation  and uptake; they could include effects of the solvent on the film that was formed after solvent evaporation, the affinity of drug for the lacquer formulation and the effect of solvent on the nail plate.  Interestingly, Polak (1993) showed totally opposite effects of the two solvents; amorolfine concentration in human nail layers were higher following a 24-hour contact with ethanol lacquer compared to contact with a methylene chloride lacquer22. The futureThe future for manufacturers of drug-containing lacquers, especially of anti-fungal containing lacquers is bright, given the increasing prevalence of onychomycosis, and a large number of patents covering anti-fungal nail lacquers have been filed. A review of the patent literature reveals that future pharmaceutical lacquer formulations could include, among others,:$ ungual  permeation  enhancers,  such  as,  oxacyclohexadecan-2-one,  which  could increase drug flux into the nail (e.g. US 2003049307, US 2003232070, US 6224887)5$ keratolytic  agents such as urea,  salicylic acid, enzymes, which could also increase drug flux into the nail (e.g. US 5264206, US 5346692),$ acidified  formulations  (acidification  was  found  to  enhance  drug  uptake  into  nail, probably via increased drug solubilisation in the nail lacquer (WO 9949835), $ drug combinations e.g. anti-mycotic and a steroidal anti-inflammatory agent (it has been suggested that the overall effectiveness of antimycotic agents may be improved by combining  an anti-fungal with a steroidal anti-inflammatory agent (US 6224887), $ vitamins which are thought to possess therapeutic activities against keratinic/psoriatic disorders (WO 9614048)$ colourants,  included  to  hide  unsightly  manifestations  of  nail  disorders  (US 2003232070), $ water-based  nail  lacquers,  which  would  be  environmentally-friendly  and  whose manufacture would be cheaper and safer, given the avoidance of flammable organic solvents. ConclusionsThe permeation of topically applied drugs into the nail is low due to the poor permeability of the nail plate.  This has limited the success of topical therapy of nail diseases.  Also, the field of  ungual  drug  delivery is  young and  work  needs  to  be  done  to  resolve  the  conflicting reports23.  Nevertheless, the very large number of papers on the commercially available nail lacquers, expounding the latter=s virtues, indicates great enthusiasm for the lacquers and for the topical therapy of onychomycosis.  In contrast, research into lacquers for nail psoriasis seems to be scant.  I am sure there is untapped potential and a market out there.6References1. US Patent 52642062. Marty, J.P., 1995.  J. Eur. Acad. Dermatol. Venereol., 4, Suppl 1, S17-S21.3. Bohn M, Kraemer K T, 2000.  J. Am. Acad. Dermatol., 43, 4, S57-S69.4. Spruit, D., 1972.  Amer. Cosmet. Perf. 87, 57-58.5.  Pittrof F, Gerhards J, Erni W, Klecak G, 1992.  Clin. Exp. Dermatol., 17, 26-28.6.  Gupta A K, Ryder J E, Baran R, 2003.  Dermatol. Clinics, 21, 3, 481.7. Reinel, D., Clarke, C., 1992. Clin. Exp. Dermatol. 1992, 17, Suppl. 1, 44-49.8.  Gupta, A.K., Fleckman, P., Baran, R., 2000. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J.Am. Acad. Dermatol. S70-S80.9.  Lecha M, Alsina M, Rodriguez JMT, de Erenchun FR, Mirada A, Rossi AB, 2002. Curr. Ther. Res. - Clin. Exp., 63, 6, 366-379.10.  Lambert J, 2003.  British Journal of Dermatology, 149, 19-22.11.  Pena-Penabad C, Garcia-Silva J, Almagro M, del Pozo J, Fonseca E, 2001. J. Eur. Acad. Dermatol. Venereol., 15, 1, 51-53.12.  Van Hoogdalem, E.J., Van den Hoven, W.E., Terpstra, I.J., Van Zijtveld, J., Verschoor, J.S.C., Visser, J.N., 1997. Eur. J. Pharm. Sci. 5, 119-127.13.  Mertin, D., Lippold, B.C., 1997a. J. Pharm. Pharmacol. 49, 866-872.14. Walters, K.A., Flynn, G.L., Marvel, J.R., 1983. J. Pharm. Pharmacol. 35, 28-33.15.  Mertin, D., Lippold, B.C., 1997b. J. Pharm. Pharmacol. 49, 30-34.16.  Lauharanta, J., 1992. Clin. Exp. Dermatol. 17, 41-43.17. Baran, R., Tosti, A., 1999. J. Dermatol. Treat. 10, 201-204.18.  Walters, K.A., Flynn, G.L., Marvel, J.R., 1985a. J. Pharm. Pharmacol. 37, 771-775.19.  Mertin, D., Lippold, B.C., 1997c. J. Pharm. Pharmacol. 49, 241-245.720.  Stuttgen, G. and Bauer, E., 1982.  Bioavailability, Skin- and Nail- penetration of topically applied antimycotics. Mycosen, 25, 74-8021.  Franz, T. J., 1992. Dermatology. 184, Suppl 1, 18-20.22. Polak, A., 1993.  JAMA South East Asia, 9, Suppl 4, 11-18.23.  Murdan, S., 2002.  Int. J. Pharm. 236, 1-26.Figure 1a: nail cross-section8Figure 1b: dorsal nail surface90102030400 1 2 3 4 5 6drug concentration in lacquer (%)mcg/cm26h6dFigure 210

Nail varnish as a drug delivery vehicle

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Nail varnish as a drug delivery vehicle

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