Solubility and in vitro percutaneous absorption of tetracaine from solvents of propylene glycol and saline

Abstract

To gain a better understanding of the factors that govern the percutaneous penetration of topically applied local anesthetics, several properties of a proposed topical formulation of tetracaine were studied. Tetracaine solubility in propylene glycol-saline mixtures is measured for use in developing a topical, local anesthetic formulation. Solubilities of tetracaine free base, tetracaine acid salt, and a 60% free base/40% acid salt mixture are presented as a function of water and propylene glycol content. The solubility of the acid salt remains nearly constant (0.5–0.8 M) as the solvent varies from pure propylene glycol to pure saline. Free base solubility is negligible in saline, but peaks at 2.65 M in 70% propylene glycol (v/v) before falling to 2.17 M in pure propylene glycol. The solubility of the mixture exceeds those of either the free base or acid salt alone at nearly all solvent combinations (maximum 3.00 M in 50% propylene glycol v/v). This increased solubility is attributed to the degree of dissociation and differences in the surface activity of tetracaine free base and tetracaine acid salt. Partitioning data of a 60% free base/40% acid salt (w/w) mixture (7.3 ≦ pH ≦ 8.4) into 1-octanol or n-octane are presented as a function of water and propylene glycol ratio. The results from the two lipophilic solvents are in general agreement and suggest that partitioning into lipid phases is optimum between 0 and 30% propylene glycol (v/v). The diffusion of tetracaine mixtures (60% free base/40% acid salt w/w) in solvents of propylene glycol and saline was studied through synthetic polycarbonate membranes and hairless-mouse skin. The flux of tetracaine through the synthetic membrane was greatest from an aqueous solution, but also showed a local maximum at 40% propylene glycol. The flux continued to decrease as propylene glycol content increased. Wetting phenomena were assumed to be responsible for the maximum flux at the aqueous limit. The flux of tetracaine through hairless-mouse skin was greatest at 40% propylene glycol, but also showed a high flux at 10% propylene glycol. As with the synthetic membrane, the flux continued to decrease as the propylene glycol content rose to 70% (v/v). The effects of animal age, formulation pH, drug concentration, and formaldehyde (as a preservative) on tetracaine diffusion from solvents of propylene glycol and saline were also studied. The permeability of full-thickness hairless-mouse skin to tetracaine was found to decrease with the age of the mice. Specifically, the skins of mice 6–8 months old are found to have a permeability to tetracaine of only 20% that of mice 6–8 weeks old. The existence of a minimum pH for significant skin permeation of tetracaine is confirmed. A minimum pH value is consistent with the generally accepted idea that the anesthetic free base (favored at higher pH values) is the prominent species diffusing through the skin. Tetracaine concentration does not affect its transdermal flux. This is assumed to be a micellar phenomenon since tetracaine has previously been shown to be capable of forming micelles which are not assumed to contribute significantly to drug diffusion because of their size. Dilute solutions of formaldehyde (sometimes used as a preservative for in vitro skin permeation experiments) show a tendency to decrease the skin flux permeation of tetracaine. Furthermore, this inhibition seems to be a result of an interaction between formaldehyde and the skin.