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Cristofoli, Mignon (2025) The use of ion pairs to increase the percutaneous delivery of diclofenac. Doctoral thesis, London Metropolitan University.
Like many topically applied formulations, diclofenac (DF) preparations face delivery challenges due to the highly effective skin barrier. This research explored a novel amino acid-based ion pairing strategy to enhance percutaneous DF delivery through rational counterion selection and solvent optimisation. The investigation progressed through three phases. First, potential amino acid counterions were identified based on size, toxicity and charge compatibility. Distribution coefficient studies evaluated their effectiveness in enhancing DF partitioning from aqueous to organic phases. L-histidine hydrochloride monohydrate (LHSS) was identified as optimal, a finding validated through porcine skin in vitro permeation testing (IVPT). Next, solubility challenges were addressed by assessing diclofenac sodium (DNa) solubility in various pharmaceutical solvents. Transcutol® (TC), propylene glycol (PG), and dipropylene glycol (DiPG) were selected for high DNa solubility and water miscibility. A model binary system of TC and water was developed to evaluate novel ion pair formulations. Finally, formulation optimisation investigated solvent substitution effects and developed ternary systems incorporating PG, TC and water.
Mechanistic insights revealed that individual solvent properties, rather than overall system solubility parameters, governed formulation performance. The optimal formulation (PG:TC:water; 10:40:50; v/v/v) containing 5 mg/mL DNa and 25 mg/mL LHSS achieved 145% greater delivery than a commercial 1% DNa product, despite containing only half the active ingredient concentration (p < 0.05).
This work establishes a framework for amino acid ion pairing to address fundamental skin penetration challenges in topical pharmaceutical formulations. The approach employs non-toxic, economical and sustainably produced counterions. The methodology has potential applications for other ionisable pharmaceutical compounds, particularly NSAIDs and pharmaceutical salts facing similar topical delivery challenges.
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