A risk assessment-based control strategy to formulate a potent, efficacious, and non-invasive topical onychomycotic dosage form

Abstract

This project involves the development of a strategy to formulate a novel dosage form with modified coconut oil (MCO) as the active pharmaceutical ingredient to treat onychomycosis caused by T. rubrum and C. albicans. The therapeutically effective concentration of the modified coconut oil towards T. rubrum has been established by preparing its dilutions in water-soluble and fat soluble bases separately and testing them against the organism. It was observed that modified coconut oil dilutions were more potent, efficacious, and advantageous than Naloc™ – a commercial dosage form available to treat onychomycosis caused by T. rubrum. The water-soluble modified coconut oil formulations were determined to be comparatively more efficient than either fat-soluble compositions or NalocTM with superior activity at lower concentrations and also within a short period of exposure. Therefore, developing a risk assessment-based strategy to formulate modified coconut oil into a water-soluble matrix to treat onychomycosis was targeted in this research. The principles of the tripartite guideline of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use – a collaboration of the regulatory authorities of the United States of America, Japan and Europe also known as ICH Q8 (R2) Pharmaceutical Development (2009) have been employed in this research for the development of dosage forms. Pre-formulation studies including a combination of spectroscopic and thermal analytical techniques and biological assays, were conducted on MCO to identify critical quality attributes to inform a quality targeted product profile. A matrix of chemical and biological tests had first been designed to characterize the compatibility of various established excipients with MCO. The best-in-class dosage form amongst them was discriminated by evaluating the extent of risk posed by the components of the formulation towards the stability of the dosage form. The stability of the finalised formulation towards induced stress conditions was evaluated for a period of 90 days. The stability was assessed using turbidity measurements, particle size distribution, conductivity and texture analysis. The antimicrobial efficiency of the samples from the ICH-mandated pull point intervals was assessed using microbiological assay and resistance towards microbial contamination conducted as per USP <61>. Based on the data generated from the pull point samples, quality control charts were constructed, and the optimum formulation developed using this risk assessment based strategy was shown to be stable over 90 days. Future research will include scaling up production of the prototype formulation to identify critical process parameters in order to improve yield and perform extended stability studies. Dissolution studies could be performed to establish the drug release profile of MCO and the development of chromatographic techniques to quantify the components of MCO will be required to further characterise the formulation.