TY - JOUR
T1 - Topical bio(in)equivalence of metronidazole formulations in vivo
AU - Pedon de Araujo, Thalita
AU - Moura Fittipaldi, Isabelle
AU - Galindo Bedor, Danilo Cesar
AU - Ludna Duarte, Maira
AU - Cordery, Sarah
AU - Guy, Richard
AU - Delgado-Charro, Maria
AU - Pereira de Santana, Davi
AU - Bastos Leal, Leila
PY - 2018/4/25
Y1 - 2018/4/25
N2 - 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.
AB - 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.
KW - topical bioavailability
KW - skin pharmacokinetics
KW - stratum corneum sampling in vivo
KW - metronidazole
KW - skin
KW - topical bioequivalence
UR - http://www.scopus.com/inward/record.url?scp=85042473608&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2018.02.032
DO - 10.1016/j.ijpharm.2018.02.032
M3 - Article
SN - 0378-5173
VL - 541
SP - 167
EP - 172
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
IS - 1-2
ER -