Novel pH-Responsive Structural Rearrangement of Myristic Acid-Conjugated Quetiapine Nanosuspension for Enhanced Long-Acting Delivery Performanceoa mark
Quetiapine myristate (QM), an ester-bonded lipophilic prodrug of quetiapine (QTP), is synthesized and converted into an amphiphilic structure in acidic pH to trigger a novel self-assembled QM nanosuspension (QMN). Following injection, this QMN rearranges within physiological pH to form nanoaggregates in structure, resulting in enhanced physicochemical properties and in vivo therapeutic performance without an initial burst release. The 200-nm-sized QMN exhibits less invasive injection, higher drug content, and better storage stability profile than conventional poly(lactide-co-glycolide) (PLGA) nanosuspensions containing QTP or QM. Following a single intramuscular injection to beagle dogs (35 mg kg−1 QTP), QMN undergoes pH-responsive nanoaggregation to form the lipophilic prodrug, providing esterase-oriented sustained release for five weeks compared with the two-week period of PLGA nanosuspensions. Notably, QMN exhibits improved in vivo pharmacokinetic performance with long-acting delivery while minimizing issues associated with polymeric PLGA formulations, including the initial massive burst release, cellular toxicity, and adverse side effects. These results support the further development of QMN as a novel long-acting injectable to improve patient compliance and dosing frequency.
This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (RS\\u20102023\\u201000208240) and the NRF Grant and Commercialization Promotion Agency for R&D Outcomes (COMPA, 2021M3A9G1015618), Republic of Korea. The authors would like to thank the staff of Ajou Central Laboratory for allowing them to use the FE\\u2010SEM and FE\\u2010TEM. They sincerely thank Professor Kim Ju Min at the Department of Energy Systems Research, Ajou University, for his support in performing rheology measurements.
