Transdermal delivery of Acyclovir and Ketoconazole by PheroidTM technology
Van der Walt, Magdalena Elizabeth
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The aim of this study was to investigate in vitro transdermal delivery of the antiviral drug, acyclovir and the antifungal drug, ketoconazole, with the aid of the novel Pheroid™ drug delivery system. Since its appearance in the early 1980's, human immunodeficiency virus (HIV) infection has had a major impact on the field of dermatology. The skin is amongst the organs where HIV disease and immunosuppression usually manifest, and diseases that were once rare have become more common. HIV is associated with a variety of infectious diseases, some of which are of viral and fungal origin. Acyclovir, an antiviral drug is active against numerous viruses of the herpes viridae family including herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella zoster virus, and to a lesser extent against Epstein-Barr virus and cytomegalovirus. Ketoconazole, an antifungal drug, is effective against the majority of pathogenic fungi, including dermatophytes and yeasts and has in vitro activity against a number of gram-positive bacteria. When combined with acyclovir, ketoconazole also displays antiviral activity against HSV-1 and HSV-2 and synergistic antiviral activity. It would be appropriate to design a single topical dosage form containing both an antiviral and antifungal drug, which could be used in the treatment of the cutaneous manifestations commonly seen in HIV and acquired immunodeficiency syndrome (AIDS). The application of transdermal delivery to a wide variety of drugs is however limited due to the significant barrier to penetration across the skin that is associated mainly with the outermost stratum corneum (SC) layer of the epidermis. The systemic absorption of acyclovir and ketoconazole after topical administration is minimal. Acyclovir therapy has insufficient effectiveness due to the failure of the drug to traverse the SC, lack of its reach at the target site; the basal epidermis and diverse distribution of the drug in the skin layers. In contrast to acyclovir, the target site for ketoconazole is the SC. In order to inhibit the growth of fungal pathogens, sufficient concentrations of the drug should be delivered to this layer. A large variety of additives have been tested to enhance transdermal penetration. Usually, penetration enhancers promote drug diffusion by disturbing the structure of the SC and/or deeper layers of the skin. Improved antiviral results have been achieved for acyclovir by using dimethyl sulfoxide (DMSO), modified aqueous cream (MAC) and the addition of oleic acid and oleyl alcohol in 5% concentrations to propylene glycol bases. Transdermal penetration of ketoconazole has also been enhanced by 10% lauramide-diethanolamine. Pheroid™ technology can enhance the absorption and/or efficacy of a selection of active ingredients and other compounds. Pheroids™ contain ethyl esters of the essential fatty acids, linoleic acid and linolenic acid, as well as oleic acid. Penetration enhancement of acyclovir has been achieved by addition of oleic acid to drug formulations, therefore it was hypothesized that it could be possible to achieve at least the same results by using Pheroids™. Vertical Franz cell diffusion studies were conducted over 12 hours, using female abdominal skin. As donor phase, 5% acyclovir and 2% ketoconazole in phosphate buffered solution was compared with 5% acyclovir and 2% ketoconazole in Pheroids™. In vitro penetration of acyclovir and ketoconazole was directly assayed by high pressure liquid chromatography (HPLC). The Pheroids™ proved to be advantageous for transdermal diffusion of acyclovir but not for ketoconazole when used as delivery system.
- ETD@PUK