Synthesis of hybrid polymer blend nanoparticles and incorporation into in situ gel foam spray for controlled release therapy using a versatile synthetic purine nucleoside analogue antiviral drug

Abstract

Antiviral therapy requires desired intensity and duration of drug action at the site of infection to minimize adverse effects. The study aims to synthesize a nanoparticle based controlled release system for Acyclovir with required loading and maintenance doses to achieve steady-state plasma concentration for once-daily therapy. The amount of Acyclovir required for 24 h therapy was calculated to be 100 mg, which is approximately 10 fold reduced oral dose. Accordingly, nanoparticles with spherical and smooth surface were synthesized using hybrid polymer blends of polyvinyl pyrrolidone with ethyl cellulose or eudragit RSPO. Physical and chemical interactions between the drug and polymers favoured the formation of stable nanoparticles. Optimized nanoparticles with 80% entrapment exhibited size and surface charge of 100 nm and +26.1 mV respectively. In situ gels incorporated with 20% free drug and 80% Acyclovir loaded nanoparticles showed immediate sol–gel transition at 35 °C–37 °C with gel viscosity ranging between 1000 and 10 000 mPa s. The expected pH independent drug release profile was obtained in 0.1 N HCl, phosphate buffer, simulated vaginal and tear fluids. Ex vivo permeability was significantly higher through cornea than stomach and rectal membranes. Uptake of nanoparticles into human corneal epithelial cell lines was spontaneous. Foam spray was developed for optimized in situ gels for site specific action through vaginal or rectal administration. The bubble size, relative foam density, collapse time, drug content per puff and stability of the foam spray formulations proved its suitability for effective drug delivery. Hence, a unique dosage form achieving predicted release profile through diverse routes was well demonstrated.