Ab Hadi, H; (2012) Mechanistic studies of the permeation behaviour of a model hydrophilic compound. Doctoral thesis , UCL (University College London).

Abstract

Caffeine is commonly used as a model hydrophilic compound in skin research, and it also has pharmaceutical and cosmetic applications. Several topical products containing caffeine are currently being marketed, including anti-cellulite creams and gels, moisturizers, serums and shampoos. As the skin permeation of this compound is expected to be low, the aim of this work is to investigate how the topical delivery of caffeine may be optimized using chemical penetration enhancers. A range of penetration enhancers for caffeine were selected, namely ethanol (EtOH), propylene glycol (PG), isopropyl myristate (IPM), propylene glycol dipelargonate (DPPG), oleic acid (OA), dimethyl isosorbide (DMI), 1,2-pentanediol (1,2-PENT), propylene glycol monocaprylate (PGMC), propylene glycol monolaurate (PGML), Transcutol-P (TRANS), isostearylisostearate (ISIS), isopropyl isostearate (IPIS), geraniol (GER), d-limonene (LIM) and 1,8-cineole (CIN). Solubility and miscibility studies were conducted using these solvents. Based on the miscibility and solubility data, caffeine permeation using infinite dose studies in human skin was evaluated. The studies were performed for caffeine in simple single solvents namely, PG, DMI, 1,2-PENT and IPM. The effects of using more complex binary solvent systems and ternary solvent systems of these solvents were also studied. The highest flux values were observed from the ternary solvent system PG:1,2-PENT:IPM (50:45:5 v/v), which enhanced caffeine permeation up to 24 times, 43 times and 7 times compared with the single solvents PG, 1,2-PENT and IPM, respectively. Following infinite dose studies in human skin, caffeine permeation was evaluated in finite dose studies. Because of the high number of experiments required, this section of the work was conducted with porcine skin, which was easier to source compared to human skin. Porcine skin was chosen over other skin models because from the literature it has been shown that this skin model is the closest animal model to human skin. The enhancement effects on caffeine permeation by binary and ternary solvent systems were also evaluated in this study. Following the finite dose studies, mass balance studies were conducted in order to understand the distribution of the actives in the skin. After 24 hours of finite dose studies, the permeation profiles did not reach a plateau. However, the studies could not be prolonged to 48 hours with porcine skin since the solvents damaged the skin barrier, as shown by a sudden increase in permeation. Therefore, the two best ternary solvent systems were selected. It was found that the same trend of caffeine permeation was observed (PG:DMI:IPM> PG:1,2-PENT:IPM) from the finite dose studies using porcine skin and that obtained from human skin. These formulations were further evaluated in in vivo studies. The formulations were applied on human volunteers in order to investigate the effect of the formulations on the skin barrier in vivo. These studies were carried out by analysing the trans-epidermal water loss (TEWL), Attenuated Total Reflectance Fourier Transform Infrared(ATR-FTIR) scans and protein content. The TEWL measurements from the PG:1,2-PENT:IPM treated site showedsignificantly higher TEWL values up to the removal of 15 tape strips (p<0.05). It was speculated that this may be due to irritation caused by the formulation, which results in damage to the skin barrier as shown by the high TEWL values. However, no further macroscopic changes in the skin barrier were observed using the ATR-FTIR. Further evaluations of the effects of the formulations on caffeine permeation were assessed by using the tape-stripping technique. A general trend of higher protein content was observedin the stratum corneum removed from the PG:1,2-PENT:IPM treated site, compared with the PG:DMI:IPM treated site and the control site. It was noted from this study that a higher caffeine amount was detected from the PG:1,2-PENT:IPM treated site compared tothe PG:DMI:IPM treated site. In conclusion, this thesis presents evidence that caffeine permeation can be enhanced by using combinations of chemical permeation enhancers in increasingly complex combinations. The effects of the formulation on the skin barrier in vitro were successfully elucidated by modelling the permeationdata. Furthermore, in vivo data provides further insight into the effects of the formulations on caffeine permeation and on the skin barrier, which will be useful in taking forward these formulations for use in cosmetic or pharmaceutical preparations.

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