Differential permeation of propranolol enantiomers across human skin in vitro from formulations containing an enantioselective excipient

Abstract

This work tested the hypothesis that a stereospecific topical formulation could be used to engineer differential permeation rates for each enantiomer of an applied racemate across human skin in vitro. Racemic and enantiomerically pure R or S propranolol HCI were formulated with cellulose tris(3,5‐dimethyl phenyl carbamate) (CDMPC) and applied to excised human skin using side‐by‐side Franz‐type diffusion cells. When the pure enantiomers were used, there was a marked difference between the penetration rates of R and S propranolol (flux ratio: 2.06; P = 0.04). When racemic propranolol was used, the difference was reduced, although still statistically significant (flux ratio: 1.2; P = 0.08), particularly in view of the differential activities of the two enantiomers. Control experiments, in which no CDMPC was present, produced equal permeation rates. The results can be rationalised in terms of differential adsorption onto CDMPC within the vehicle, whereby S‐propranolol is preferentially bound relative to R‐propranolol. This causes an imbalance in the apparent donor phase concentrations that (in accordance with Fickian diffusion laws and thermodynamic activity) gives rise to differences in permeation rates. The diminished differential observed when the racemate was used, rather than individual enantiomers, is less easily rationalised. In this work, it was the permeation of the eutomer (S‐propranolol) that was retarded, although the general principle of stereoselectively retarded skin permeation has been established. Chirality 11:680–683, 1999. © 1999 Wiley‐Liss, Inc.

Percutaneous absorption of the montoterpene carvone: implication of stereoselective metabolism on blood levels

“…Plasma level differences of enantiomers based on enzymatic bioconversion is in accordance with the literature, as stereoselectivity of phase-I and phase-II metabolizing enzymes for many compounds is linked to altered pharmacokinetics (Williams & Lee 1985 ;Drayer 1986). In addition to enzymatic bioconversion, stereoselectivity in transdermal penetration may also influence plasma levels as recently shown for propranolol (Suedee et al 1999). Whether this may also apply to R-(k)-and S-(j)-carvone has yet to be determined.…”

Development of a reversed‐phase high‐performance liquid chromatographic method for the determination of propranolol in different skin layers

“…Despite the optical isomerism of PPN, both R and S enantiomeric forms present therapeutic interest (Sasaki et al, 2019; Suedee, Brain, & Heard, 1999) and exhibit the same skin penetration rate (Heard, Watkinson, Brain, & Hadgraft, 1993). Thus, the proposed method was developed to determine PPN stereoisomers together from a racemic mixture, which is the commercialized form of the drug product.…”

“…Despite the optical isomerism of PPN, both R and S enantiomeric forms present therapeutic interest (Sasaki et al, 2019;Suedee, Brain, & Heard, 1999) and exhibit the same skin penetration rate (Heard, Watkinson, Brain, & Hadgraft, 1993). Thus, the proposed The composition of the mobile phase was changed using different proportions of acidic aqueous phase/acetonitrile.…”