Ready-to-use, spheronized drug particles-embedded iron(III)-reinforced carboxymethyl cellulose hydrogels as novel long-acting injectable platform with reduced local inflammation.

Abstract

This study aimed to construct a ready-to-use, spheronized drug particle-embedded iron(III)-reinforced carboxymethyl cellulose hydrogel (Fe3+-CMC HG) as a novel long-acting injectable (LAI) platform for hydrophobic drugs. Dutasteride (DTS), a lipophilic 5α-reductase inhibitor prescribed for benign prostatic hyperplasia, was selected as a model compound. Uniform spherical DTS particles (∼180 μm) were fabricated using a dual centrifugation technique, with excellent flowability. Low-molecular-weight CMC (90 kDa, 100 mg/mL) formed a mechanically reinforced HG with 0.1% (w/v) Fe3⁺ (designated 90K-0.1) through coordination with carboxyl and hydroxyl groups, yielding high viscoelasticity and restricted spreading. Prior to administration, the spherical drug particles were homogeneously incorporated into the CMC HG via hydrogen bonding through two-syringe mixing process, preserving their original particle size and crystallinity. In vivo studies in rats exhibited that intramuscular administration of 90K-0.1 provided a markedly prolonged pharmacokinetic profile over 56 days, comparable to that of native high-molecular-weight CMC HG (700 kDa, 20 mg/mL) and a poly(lactic-co-glycolic acid)-based in situ forming implant (ISFI). Furthermore, Fe3⁺-CMC HG elicited substantially reduced local inflammation at the injection site compared with native CMC HG and ISFI. Collectively, these findings support Fe3⁺-CMC HG as an effective and biocompatible LAI platform for hydrophobic drugs such as DTS.