Systemic absorption of ocular pilocarpine is modified by polymer matrices

Abstract

Systemic absorption of ocularly applied pilocarpine (1.2 mg) was studied after administration in aqueous solution, in hydroxypropylcellulose (HPC) matrix, and in a matrix of n-butyl half-ester of poly(methyl vinyl ether/maleic anhydride) (PVM/MA). In vitro release of pilocarpine from the HPC-matrix deviated slightly and positively from the diffusional square root of time dependence. The rate of drug release was independent of the phosphate buffer concentration of the dissolution medium with an initial pH of 7.4; the rate of release was 10.91 ± 0.59% min −0.5 in 1.3 mM buffer and 9.91 ±0.37% min −0.5 in 66.7 mM buffer. A matrix of n-butyl half-ester of PVM/MA released pilocarpine according to zero-order kinetics. The rate of drug release was 0.22 ± 0.02% min −1 in 1.3 mM phosphate buffer and 0.95 ± 0.06% min −1 in 66.7 mM phosphate buffer. From the 2% aqueous solution, pilocarpine was absorbed efficiently into the plasma (t max = 3.6 ± 0.9 min, c max = 0.384 ± 0.024 μg/ ml). Pharmacokinetic analysis of data for drug absorption revealed that the conjunctiva of the eye was the most important site for systemic absorption of pilocarpine. Both the HPC matrix (t max = 35.0 ± 7.9 min, c max = 0.256 ± 0.022 μg/ ml) and the matrix of n-butyl half-ester of PVM/MA (t max = 204 ± 17.5 min, c max = 0.112 ± 0.014 μg/ ml) delayed and decreased the peak concentrations of pilocarpine in general circulation. (AUC 0–6 h/AUC 0–6 h,i,v.) values were 0.72 ± 0.08, 0.67 ± 0.16, and 0.41 ± 0.05 for the aqueous solution, HPC matrix, and n-butyl half-ester of PVM/MA matrix, respectively. During the in vivo study, HPC matrices dissolved in 7–12 min in the tear fluid. n-Butyl half-ester of PVM/MA neither dissolved totally nor released all the drug from the matrix in the tear fluid during 8 h. Besides improving ocular drug absorption, as shown in earlier studies, the pilocarpine concentrations in systemic circulation can be decreased by administering the drug in polymer matrices.