Pharmacokinetics of Topically Applied Metronidazole in Two Different Formulations

Abstract

Topical metronidazole is effective in the treatment of papulo-pustular rosacea, a common inflammatory disease of the face. In this study, a comparison of the bio-availability of two topical formulations (A and B) of 0.75% metronidazole has been made. Twenty-four subjects took part in a double-blind study where each was randomly allocated to four groups corresponding to 0.5, 1, 2 and 4 h of treatment. A single application was made to each forearm and after increasing times of contact, samples of stratum corneum were removed by the skin surface biopsy (SSB) technique. After SBB removal, a full-thickness skin biopsy was taken. The tissues were extracted and analysed by an HPLC method. Both formulations showed rapid percutaneous penetration. Formulation A gave the highest concentrations at the lowest levels of the stratum corneum at 4 h. Thus in SSB5, the mean drug concentrations at 4 h were as follows: A, 6.20 ± 1.16 μg cm^-2; B, 1.93 ± 0.98 μg cm-². A similar difference was observed when the levels in the punch biopsies were determined. At 4 h, the mean drug levels were: A, 6.07 ± 2.17 μgmg^-1; B, 0.95 ± 1.16 μgmg^-1. Formulation A clearly gives a higher rate of percutaneous penetration leading to higher tissue levels of drug. Whether this increase leads to a clinically more effective treatment has yet to be determined.

Mechanistic Modeling of In Vitro Skin Permeation and Extrapolation to In Vivo for Topically Applied Metronidazole Drug Products Using a Physiologically Based Pharmacokinetic Model

“…In vivo mean pharmacokinetic data reported by de Araujo et al are outside of 95th percentiles for the model-generated predictions even after the corneocyte permeability was set to a non-rate limiting value of 1 cm/h (it should be noted that metronidazole amounts in the corneocyte plateau at Pcell values of 1 × 10 –4 cm/h and aboverefer to Section 10 in the Supporting Information); however, the observed variability reported is quite high. On the contrary, the predicted metronidazole amounts in the stratum corneum at different time points were within two folds of the observed data as reported by Dykes et al…”

“…The in vitro verified Model II was further used to predict the metronidazole amount permeating across the skin of healthy volunteers following the application of metronidazole gel formulations (Dykes et al de Araujo et al). Dykes et al.…”

“…Hence, structural and physical characterization of Rosex were assumed to be similar to those of MetroGel. The diffusion coefficient of metronidazole in the stratum corneum for simulation of Dykes et al and de Araujo et al clinical studies was assumed to be 7.7 × 10 –4 cm 2 /h, identical to the diffusion coefficient used during the IVPT simulation of infinite and finite aqueous solutions (same as Model II). , This is because the volume of formulation used in the in vivo clinical studies is similar to the volume of aqueous solution used in finite dose IVPT experiments reported by Ajjarapu et al These two clinical studies served as independent verification data sets to evaluate the in vivo predictability of the developed model.…”

Solvent effects in permeation assessed in vivo by skin surface biopsy

“…This simple and versatile approach to the study of the stratum corneum was introduced by Goldschmidt and Kligman in the 1960's [19] and was later developed by Marks and Dawber [20]. If consecutive biopsies are performed in the same area it becomes possible to follow the permeation of a compound through the stratum corneum [21,22]. SSB alone does not provide any data regarding the amount of chemical permeated through the epidermis and dermis into systemic circulation, but it can be combined with the determination of blood and urine concentration in pharmacokinetic studies.…”

In vivo study of the physiological impact of stratum corneum sampling methods

“…A related technique, corneosurfametry, uses cyanoacrylate strippings to assess the interaction of surfactants present in personal care cleansing products with human stratum corneum [6]. One of the most interesting developments has been the application of SSB to the in vivo study of the pharmacokinetics of topically applied drugs [7–9]. The cutaneous drug levels can be determined at various intervals, which leads to a more precise knowledge of the rate of penetration and, therefore, the possibility of optimizing the dosage and the frequency of application.…”