Systems approach to vaginal delivery of drugs IV: methodology for determination of membrane surface pH.

A physical model including a diffusional layer in series with the membrane was developed for studying the possible differences between the pH at the membrane surface and that in the bulk solution. Both the membrane-secreted substances (acids and bases) and buffer constituents in the bulk solutions are assumed to contribute to the surface pH. Equations derived for this situation, together with experimental determinations of the acidic dissociation constant of the secreted material, the total secretion flux, the flux of total secreted acidic species, and the diffusion layer thickness, allow estimates to be made of the pH at the membrane surface. With the rabbit vagina, the membrane surface pH was close to that of the bulk solution in most cases. These results were supported by the fact that the absorption of 1-alkanoic acids in pH 2.2 phosphate buffers was relatively constant over the buffer concentration range of 0.003-0.1 M phosphate.

Systems approach to vaginal delivery of drugs V: in situ vaginal absorption of 1-alkanoic acids.

The vaginal absorption of a homologous series of ionizable compounds, the 1-alkanoic acids, was studied using a perfusion method with a rib-cage cell surgically implanted in the rabbit vagina. The absorption rates of these compounds followed first-order kinetics. The physical model previously used for the 1-alkanols, but accounting for the pKa and pH effects in the present case was employed in the analysis of the carboxylic acid data. The aqueous diffusion layer thickness was 0.031 cm. The permeability coefficient for the lipoidal pathway increased 3.5-fold per methylene group. Both values agree reasonably well with those obtained in the alcohol study.

Vaginal drug absorption in rhesus monkeys I: development of methodology.

Earlier reports from these laboratories described a procedure for determining vaginal drug absorption in the rabbit based upon a perfusion system, and data on the vaginal absorption of the straight-chain aliphatic alcohols and carboxylic acids were given. These studies have been extended to the rhesus monkey. Rib-cage-type cells were designed for intravaginal insertion through the vulval orifice and to fit the specific dimensions of the monkey vagina. The general design of the cell was similar to that used in the rabbit vaginal absorption studies. The persusion system was checked by using 3H-polyethylene glycol 4000, and no significant leaks from the cell were found. The absorption of the alcohols followed first-order kinetics. The computed apparent permeability coefficients for the alcohols were of comparable magnitude to those previously reported for the rabbit vaginal membrane.

Systems approach to vaginal delivery of drugs II: In situ vaginal absorption of unbranched aliphatic alcohols.

The absorption of unbranched aliphatic alcohols in the rabbit vagina was studied using a perfusion method, and the absorption rates were found to be first order with respect to the drug concentration in the vagina from methanol to octanol. A physical model involving an aqueous diffusion layer in series with a membrane consisting of aqueous pores and lipoidal pathways was used for analyzing the data. The physically based parameters in the model were determined. An effective diffusion layer thickness ("unstirred layer") of around 0.035 cm was found. The increase in the permeability coefficient for the lipoidal pathway per methylene group was around 2.5 for this homologous series.

Systems approach to vaginal delivery of drugs III: Simulation studies interfacing steroid release from silicone matrix and vaginal absorption in rabbits.

A composite physical model involving the simultaneous receding boundary release of drug from a drug suspension-silicone polymer matrix system, diffusion across the aqueous layer, and passive transport across the vaginal membrane consisting of parallel lipoidal and aqueous pore pathways is described. Simulation studies with progesterone and hydrocortisone illustrate matrix release-limiting, membrane absorption, and aqueous diffusion layer-limiting cases when the cylindrical silicone delivery device is interfaced with the vaginal membrane of the rabbit.