Differential permeation of propranolol enantiomers across human skin in vitro from formulations containing an enantioselective excipient.
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.
Suedee
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R
Welsh School of Pharmacy, Cardiff, UK.
Brain
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Heard
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CM
D002851:Chromatography, High Pressure Liquid; D005079:Excipients / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D010539:Permeability; D011433:Propranolol / Q000737:chemistry / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism*; D013237:Stereoisomerism
D005079:Excipients; D011433:Propranolol