Topical bio(in)equivalence of metronidazole formulations in vivo

Abstract

The topical bioavailabilities of metronidazole from a commercially available 'reference' product (Rozex®) and two extemporaneous test formulations were compared. With the reference drug product, a full skin pharmacokinetic profile, in vivo in human volunteers (following a 6-h uptake and clearance over the subsequent 22 h), was obtained using an improved stratum corneum (SC) sampling procedure. Then, a two-time point SC sampling method enabled the bio(in)equivalence of the test formulations to Rozex® to be evaluated. One test formulation was shown to be bioequivalent to Rozex®, both for uptake and clearance, whereas the other (more viscous and less spreadable) formulation was not. The delivery of metronidazole into the underlying viable epidermal tissue from Rozex® and from the equivalent test formulation was 2.5 to 3.5-fold higher than that from the inequivalent extemporaneous vehicle. The results highlight that the quantitative composition of a formulation, as well as its physical properties that influence events that take place at the vehicle-skin interface, can have a dramatic impact on the delivery of drug into the SC and subsequently to the viable skin layers below. The reproducible, sensitive and facile in vivo methodology employed may prove of particular value where regulatory approval of generic formulations lacks objective rigour.

Application of a dermatopharmacokinetic (DPK) method for bioequivalence assessment of topical metronidazole creams

“…Importantly, it was seen that the duration of contact with the formulation or the position of the site on the arm did not influence the percentage of SC removed. The exponential increase in the penetration of MTZ observed was in accordance with the study conducted by de Araujo et al (33), which indicated uptake up to 6 h application. Measurements were continued for various times at sites after removal of the dose at 6 h where the amount of MTZ decreased which the authors describe as the clearance phase.…”

“…The cost of prescription medicines is an ongoing concern leading to unaffordability and, consequently, patients often defer or even abandon treatment. The availability of generic products provide lower-priced competing versions of medications and therefore facilitate patient access to marketed medicines (1,2). However, demonstration of bioavailability/ bioequivalence (BA/BE) of topical semi-solid dosage forms intended for local action has been a major challenge amongst scientific researchers and regulatory agencies around the world (3).…”

“…Several studies have demonstrated the utility of TS to establish bioequivalence between products (18,21,(33)(34)(35)(36)(37)(38). N'Dri-Stempfer et al (18) identified the sources of variabilities in the DPK approach and designed an improved method that minimised the influence of these variables to assess bioequivalence between topical products containing 1% econazole nitrate.…”

Stratum Corneum Sampling to Assess Bioequivalence between Topical Acyclovir Products

“…The use of tape-stripping to sample the SC has been fully described in the literature (13,14,17). All sites on the designated uptake forearm were tape-stripped immediately after drug removal.…”

“…As a result, there is an ongoing and intensifying effort to identify and validate surrogate methods for the assessment of topical bioequivalence. Recent work has focussed upon (a) in vivo microdialysis (and, specifically, open-flow microperfusion) (12), (b) in vivo SC sampling (i.e., tape-stripping) (13,14), and (c) in vitro permeation testing (IVPT) using excised human skin mounted on diffusion cells (e.g., Franz cells) (13,15).…”