Formulation, in vitro release and transdermal diffusion of Vitamin A and Zinc for the treatment of acne
Acne vulgaris is the single, most common disease that presents a significant challenge to dermatologists, due to its complexity, prevalence and range of clinical expressions. This condition can be found in 85% of teenage boys and 80% of girls (Gollnick, 2003:1580). Acne can cause serious psychological consequences (low self–esteem, social inhibition, depression, etc.), if left untreated, and should therefore be recognised as a serious disorder (Webster, 2001:15). The pathogenesis of acne is varied, with factors that include plugging of the follicle, accumulation of sebum, growth of Propionibacterium acnes (P. acnes), and inflammatory tissue responses (Wyatt et al., 2001:1809). Acne treatment focuses on the reduction of inflammatory and non–inflammatory acne lesions, and thus halts the scarring process (Railan & Alster, 2008:285). Non–inflammatory acne lesions can be expressed as open and closed comedones, whereas inflammatory lesions comprise of papules, pustules, nodules and cysts (Gollnick, 2003:1581). Acne treatment may be topical, or oral. Topical treatment is the most suitable first–line therapy for non–inflammatory comedones, or mildly inflammatory disease states, with the advantage of avoiding the possible systemic effects of oral medications (Federman & Kirsner, 2000:80). Topical retinoids were very successfully used for the treatment of acne in the 1980s. Their effectiveness in long–term therapies was limited though, due to local skin irritations that occurred in some individuals (Julie & Harper, 2004:S36). Vitamin A acetate presented a new approach in the treatment of acne, showing less side effects (Cheng & Depetris, 1998:7). In this study, vitamin A acetate and zinc acetate were formulated into semisolid, combination formulations for the possible treatment of acne. Whilst vitamin A controls the development of microcomedones, reduces existing comedones, diminishes sebum production and moderately reduces inflammation (Verschoore et al., 1993:107), zinc normalises hormone imbalances (Nutritional–supplements–health–guide.com, 2005:2) and normalises the secretion of sebum (Hostýnek & Maibach, 2002:35). Although the skin presents many advantages to the delivery of drugs, it unfortunately has some limitations. The biggest challenge in the transdermal delivery of drugs is to overcome the natural skin barrier. Its physicochemical properties are a good indication(s) of the transdermal behaviour of a drug. The ideal drug to be used in transdermal delivery would have sufficient lipophilic properties to partition into the stratum corneum, but it would also have sufficient hydrophilic properties to partition into the underlying layers of the skin (Kalia & Guy, 2001:159). Pheroid technology was also implemented during this study, in order to establish whether it would enhance penetration of the active ingredients across the skin. The Pheroid consists of vesicular structures that contain no phospholipids, nor cholesterol, but consists of the same essential fatty acids that are present in humans (Grobler et al., 2008:283). The aim of this study hence was to investigate the transdermal delivery of vitamin A acetate and zinc acetate, jointly formulated into four topical formulations for acne treatment. Vitamin A acetate (0.5%) and zinc acetate (1.2%) were formulated into a cream, Pheroid cream, emulgel and Pheroid emulgel. An existing commercial product, containing vitamin A acetate, was used to compare the results of the formulated products with. The transdermal, epidermal and dermal diffusion of the formulations were determined during a 6 h diffusion study, using Franz diffusion cells and tape stripping techniques. Experimental determination of the diffusion studies proved that vitamin A acetate did not penetrate through the skin. These results applied to both the formulations being developed during this study, as well as to the commercial product. Tape stripping studies were done to determine the concentration of drug present in the epidermis and dermis. The highest epidermal concentration of vitamin A acetate was obtained with the Pheroid emulgel (0.0045 ug/ml), whilst the emulgel formulation provided the highest vitamin A acetate concentration in the dermis (0.0029 µg/ml). Contrary, for the commercial product, the total concentration of vitamin A acetate in the epidermis was noticeably lower than for all the new formulations studied. Vitamin A acetate concentrations of the commercial product in the dermis were within the same concentration range as the newly developed formulations, with the exception of the emulgel that delivered approximately 31% more vitamin A acetate to the dermis, than the commercial product. Zinc acetate was able to diffuse through full thickness skin, although no flux values were obtained. To eliminate the possibility of endogenous zinc diffusion, placebo formulations (without zinc) were prepared for use as control samples during the skin diffusion investigation. The emulgel and Pheroid emulgel formulations were unable to deliver significant zinc acetate concentrations transdermally, although transdermal diffusion was attained from both the cream and Pheroid cream. Tape stripping experiments with placebo formulations relative to the formulated products revealed that zinc acetate concentrations in the epidermis and dermis were significantly higher when the placebo formulations were applied. However, the average zinc acetate concentration in the dermis, after application of the cream formulation, was significantly higher, compared to when the placebo cream was applied. It could therefore be concluded that no zinc acetate had diffused into the epidermis and dermis from the new formulations, except from the cream formulation. The zinc acetate concentration being measured in the epidermis thus rather represented the endogenous zinc acetate. The cream formulation, however, was probably able to deliver detectable zinc acetate concentrations to the epidermis. Stability of the formulated products was tested under a variety of environmental conditions to determine whether the functional qualities would remain within acceptable limits over a certain period of time. The formulated products were tested for a period of three months under storage conditions of 25°C/60% RH (relative humidity), 30°C/60% RH and 40°C/75% RH. Stability studies included stability indicating assay testing, the determination of rheology, pH, droplet size, zeta–potential, mass loss, morphology of the particles and physical assessment. The formulations were unstable over the three months stability test period. A change in viscosity, colour and concentration of the active ingredients were observed.
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