An investigation into the influence of binary drug solutions upon diffusion and partition processes in model membranes

Abstract

Few studies have assessed the impact of binary systems on the fundamental mathematical models that describe drug permeation. The aim of this work was to determine the influence of varying the proportions of prilocaine and lidocaine in a binary saturated solution on mass transfer across synthetic membranes. Infinite-dose permeation studies were performed using Franz diffusion cells with either regenerated cellulose or silicone membranes, and partition coefficients were determined by drug loss over 24 h. There was a linear relationship between the flux of prilocaine and lidocaine through regenerated cellulose membrane (R(2) >or= 0.985, n = 5) and their normalised ratio in solution. This linear model was also applicable for the permeation of prilocaine through silicone membrane (R(2) = 0.991, n = 5), as its partition coefficient was independent of the drug ratio (15.84 +/- 1.41). However, the partition coefficient of lidocaine increased from 27.22 +/- 1.68 to 47.03 +/- 3.32 as the ratio of prilocaine increased and this resulted in a non-linear relationship between permeation and drug ratio. Irrespective of the membrane used, the permeation of one drug from a binary system was hindered by the presence of the second, which could be attributed to a reduction in available membrane diffusion volume.

A fundamental investigation into the effects of eutectic formation on transmembrane transport

“…The drug permeation was dependent on its ratio in the applied eutectic; increasing the proportion of an individual agent in the applied mixture increased its steady-state flux. This trend was similar to the results previously reported for the binary lidocaine-prilocaine phosphate buffer solutions hence they imply a similar competition phenomenon was occurring at the membrane surface (Fiala et al, 2008). The overall permeation of lidocaine from the mixtures was higher than that of prilocaine.…”

“…Previously published data, which employed a similar set up but delivering the drugs with an aqueous vehicle, showed a different permeation behaviour compared to the pure eutectics (Fiala et al, 2008). Enhancement ratios (ER) for the eutectic mixtures when compared to two drug-containing aqueous solutions showed that prilocaine permeation was increased by 1.8-2.6-fold (a statistically significant difference in the enhancement degree existed between the different drug ratios, p ≤ 0.05, ANOVA, Table 1) and lidocaine permeation was increased by 2.9-4.1 fold (a statistically significant difference in the enhancement degree existed between the different drug ratios, p ≤ 0.05, ANOVA, Table 1).…”

“…The binary saturated solutions were prepared from single lidocaine base or procaine base solutions in phosphate buffer (0.172 M, final pH 9.57 ± 0.09, concentration ranged from 1 to 4 mg ml −1 ) to which excess of the counter drug was added. The resulting suspensions were stirred for 24 h in order to reach equilibrium and then filtered using 0.2 m cellulose acetate syringe filters (recovery was > 0.99) to obtain clear binary solutions; this method was described elsewhere (Fiala et al, 2008). In order to measure the solubility in the membrane, it was cut into squares of 1.5 cm, weighed and placed into vials.…”

“…The column temperature was maintained at 50 • C using a thermostat oven (Jones Chromatography, Mid Glamorgan, UK). The method was previously shown to be fit for purpose in terms of precision (<3%), accuracy (>99%), linearity (r 2 > 0.999) and sensitivity (the limits of detection were 7.10 g ml −1 and 4.45 g ml −1 and the limits of quantification were 23.68 g ml −1 and 14.82 g ml −1 , for prilocaine and lidocaine, respectively) (Fiala et al, 2008).…”

“…Similarly, the rate of ibuprofen-terpene eutectic permeation through human epidermis was compared to an ibuprofen saturated solution (Stott et al, 1998). The permeation of one drug can dramatically inhibit the permeation of the second when applying binary drug solutions to topical membranes means that simply saturating a single agent in an application vehicle is not an ideal control when attempting to measure the permeation of agents from eutectic systems (Fiala et al, 2008).…”