Optimised topical delivery of 5–fluorouracil
Chinembiri, Tawona Nyasha
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Skin cancer is the most widely diagnosed form of cancer and it is split in to non-melanoma skin cancer (NMSC) and cutaneous malignant melanoma (CMM). Cutaneous melanoma has a high propensity for malignancy and it has the highest mortality rate of all skin cancers (de Gruijl, 1999:2004). The first line of treatment for most skin cancers is surgical excision but instances do arise in which surgery is not feasible due to the health of the patient or the location of the lesion. Therefore, viable alternatives are necessary in cases where surgery is not possible (Telfer et al., 2008:36). The skin is readily available for delivery of cytotoxic drugs to treat carcinomas and melanomas so the topical delivery of 5-fluorouracil was investigated in this study. 5-Fluorouracil is a pyrimidine anti-metabolite which interferes with deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis by inhibiting the nucleotide synthetic enzyme thymidylate synthase (TS) and by becoming misincorporated into RNA and DNA. Thymidylate is essential for replication as well as repair of DNA, in the event of TS inhibition thymidylate is not formed and “thymineless deaths” of cells occur (Chu & Sartorelli, 2009:935; Longley et al., 2003:330). This active pharmaceutical ingredient (API) causes death of atypical and rapidly dividing cells (Tsuji & Karasek, 1986:474). The intravenous and topical routes are approved for 5-fluorouracil and in the case of skin cancer the obvious choice would be topical application (Chu & Sartorelli, 2009:935). Topical application of 5-fluorouracil results in the occurrence of terrible side effects such as severe inflammation, stomatitis, photosensitivity and dermatitis. A reduction in side effects would reduce the stigma associated with topical 5-fluorouracil and in turn increase patient compliance. Topical drug delivery entails the delivery of an API onto or into the various layers of the skin (Flynn & Weiner, 1993:33) in order to treat conditions on or within the skin. Topical application of APIs is non-invasive, painless and simple plus the target site is readily accessible for topical therapy, thus the API is delivered directly to the site of action (Naik et al., 2000:318). In the case of skin cancer, 5-fluorouracil should be able to reach the epidermis because NMSC originates from the keratinocytes (Marks & Hanson, 2010:305) and CMM from melanocytes (de Gruijl, 1999:2004) which are both found in the epidermis. The barrier function of the skin limits the penetration of molecules into the skin and the rate-limiting step is usually penetration into the stratum corneum (Foldvari, 2000:418). The aim of this study was to investigate the diffusion of 5-fluorouracil from formulations into and through the skin. Two physico-chemical properties of 5-fluorouracil that influence skin permeation were determined (aqueous solubility and n-octanol-buffer partition coefficient (log D)). The Pheroid™ drug delivery system was used to enhance the delivery of 5-fluorouracil (Grobler et al., 2008:284). Pheroid™ is a novel technology that is used in the delivery of APIs in pharmaceutical products. It enhances the efficacy of delivered compounds while allowing for the reduction of unwanted adverse effects (Grobler et al., 2008:284). Franz cell skin diffusion studies and tape-stripping were conducted with Pheroid™ and non-Pheroid™ formulations to allow for comparison and determination of the effect of Pheroid™. The in vitro efficacy of 5-fluorouracil in inducing apoptosis of human melanoma cells was investigated using a flow cytometric apoptosis assay. Different concentrations of 5-fluorouracil in formulation were utilised in the experiments so as to observe the cytotoxic effect of 5-fluorouracil. The effect of the drug delivery vehicle on the efficacy of 5-fluorouracil was investigated by utilising API solutions in addition to Pheroid™ and non-Pheroid™ formulations in the experiments. Relatively high concentrations of 5-fluorouracil diffused into and through the skin with Pheroid™ formulations resulting in a greatly enhanced in vitro skin permeation of 5-fluorouracil. The tape-stripping revealed that the Pheroid™ lotions resulted in higher concentrations of 5-fluorouracil in the epidermis and dermis after 12 h as compared to the lotions. There was no deducible trend with respect to the distribution of 5-fluorouracil between the epidermis and dermis. Subsequent to the apoptosis assay it was found that 5-fluorouracil was able to induce apoptosis in A375 cells after a 24 h incubation period. The Pheroid™ treatment of cells resulted in a greater response (mean fluorescence intensity) as compared to treatments with the other drug delivery vehicles at three of the four concentrations. This showed that the drug delivery vehicle played a role in the in vitro efficacy of 5-fluorouracil. Further research must be done in order to combine these results. Optimum and highly effective topical formulations with low doses of 5-fluorouracil must be formulated for the purpose of treating cutaneous cancers with a reduced incidence of side effects.
- Health Sciences