A model binary system for the evaluation of novel ion pair formulations of diclofenac

Diclofenac (DF) is well established as a topical treatment option for conditions such as osteoarthritis. In investigating novel DF ion pairs for topical delivery, studies to determine the impact of various amino acids on the distribution of DF between octanol and aqueous environments were conducted. These studies identified the amino acid L-histidine hydrochloride monohydrate (LHSS) as an ion pair candidate for diclofenac sodium (DNa). Preliminary porcine skin permeation studies indicated that the addition of LHSS to DNa solutions increased the amount of DF that permeated through porcine skin. With increasing amounts of LHSS added, greater amounts of DF precipitated out of solution. In the present work, the solubility of DNa in various solvents was assessed, with the intention of identifying solvents in which DNa was most soluble. Binary systems comprising water and selected solvents were tested for both miscibility and the solubility of DNa and LHSS. The model system selected to evaluate novel ion pair formulations using porcine skin in vitro permeation studies under finite dose (10 μL) conditions comprised Transcutol® (TC) and water. The tested formulations contained DNa at concentrations of 5, 7.5 and 10 mg mL⁻¹. Higher LHSS concentrations were possible when the DNa concentrations were lower, and ranged from 10–25 mg mL⁻¹. However, increasing the DNa concentration to 10 mg mL⁻¹, without adding LHSS, resulted in a significant reduction in the amount of DF that partitioned and permeated, relative to formulations that contained either 5 mg mL⁻¹ DNa in combination with LHSS (at 12.5 or 25 mg mL⁻¹), or 7.5 mg mL⁻¹ DNa together with 12.5 mg mL⁻¹ LHSS. The current work confirms previous investigations, suggesting that the addition of LHSS to DNa in a formulation may increase the partition and permeation of DF.