Cristofoli, Mignon; Hadgraft, Jonathan; Lane, Majella E; Sil, Bruno C; (2025) Ion pairing as a strategy to enhance the delivery of diclofenac. RSC Pharmaceutics 10.1039/d5pm00096c. (In press).

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Abstract

This study explores the use of ion pairing and solvent selection to enhance the percutaneous delivery of diclofenac (DF) from topical formulations. Previous investigations identified L-histidine monochloride monohydrate (LHSS) as an ion pair candidate for diclofenac sodium (DNa). Initial in vitro permeation tests (IVPT) demonstrated that while LHSS increased DF permeation, it caused DF precipitation at higher concentrations. As DNa is sparingly soluble in water, the only solvent in which LHSS dissolves, its solubility was tested in alternative solvents. The highest solubility was observed in Transcutol® (TC), dipropylene glycol (DiPG) and propylene glycol (PG). Building on earlier research using TC : water binary systems to evaluate ion pairs, this study assessed: (i) the substitution of TC with DiPG in binary formulations, (ii) the development of ternary systems comprising water, TC and either DiPG or PG, and (iii) their impact on DF delivery using finite dose IVPT with porcine skin. The inclusion of LHSS (10 mg mL−1) with DNa (10 mg mL−1) in a DiPG : water (60 : 40 v/v) binary system significantly enhanced DF delivery (2.69 ± 1.01%), relative to the LHSS-free control (1.02 ± 0.44%, p < 0.05.). However, this was significantly lower than in TC : water binary formulations (4.80 ± 1.08–5.41 ± 2.21%; p < 0.05). Similarly, the ternary formulation containing DiPG (5 mg mL−1 DNa; 12.5 mg mL−1 LHSS; DiPG : TC : water; 10 : 40 : 50 v/v/v) resulted in lower DF delivery (5.62 ± 2.78%) compared to the corresponding TC : water (50 : 50 v/v) binary formulation (12.26 ± 3.06%, 5 mg mL−1 DNa; 12.5 mg mL−1 LHSS, p < 0.05). Conversely, replacing DiPG with PG in the ternary formulation (PG : TC : water; 10 : 40 : 50 v/v/v) containing 25 mg mL−1 LHSS, significantly enhanced DF permeation (4.26 ± 1.41 μg cm−2) compared to all binary (0.14 ± 0.28–1.52 ± 0.32 μg cm−2) and ternary formulations (0.21 ± 0.36–1.72 ± 1.06 μg cm−2, p < 0.05). This formulation also outperformed a recognised commercial product (1.74 ± 0.6 μg cm−2) by 145%, despite containing only half the DNa concentration and resulted in the highest total DF uptake as a percentage of the applied dose (27.25 ± 2.61%). This work builds on previous findings, confirming that LHSS enhances DF delivery in combination with DNa. By examining solvent systems and counterion effects, it provides a deeper understanding of formulation strategies to optimise the percutaneous delivery of DF.

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