Long-acting injectable delivery system comprising ordered mixed drug aggregates with deaggregating and uniformly embeddable viscoelastic -polysaccharide solutions

Abstract

This study aimed to construct a ready-to-use, two-syringe mixing (TM) system comprising free-flowing drug aggregates with deaggregating and uniformly embeddable polysaccharide solutions as a new approach for long-acting parenteral delivery. Rotigotine (RG) and donepezil (DP), approved for the treatment of Parkinson's and Alzheimer's diseases, respectively, were employed as model compounds. For syringe filling, free-flowing drug aggregates were engineered using ordered mixing, adhering pulverized RG (1.1 ± 0.3 μm) or DP particles (0.8 ± 0.2 μm) to hydrophilic polyvinylpyrrolidone K17 particles (120 to 150 μm). Drug aggregates were effectively deaggregated and distributed as individual fine drug particles in hyaluronate (HA) or carboxymethyl cellulose (CMC) matrices via electrostatic interactions during TM process. TM systems of RG with HA or CMC and DP with HA provided extended drug release with decreased in vivo spread following subcutaneous injection. TM systems of RG and DP provided protracted pharmacokinetic profiles over 4 weeks with decreased initial exposure compared to drug suspensions and even profiles comparable to those of biodegradable polymer-based in situ forming implants (ISFI). Moreover, RG-loaded HA- or CMC-TM systems alleviated the local inflammation compared to the ISFI. Therefore, this polysaccharide-based TM system is expected to serve as a simple and effective long-acting delivery system for water-insoluble therapeutic agents.