Creation of a ready-to-use brexpiprazole suspension and the inflammation-mediated pharmacokinetics by intramuscular administration

• Published in: European journal of pharmaceutics and biopharmaceutics 2023-08, Vol.189, p.189-201
• Main Authors: Wang, Junji, Liu, Junfeng, Ding, Jingwen, Li, Qin, Zhao, Yuan, Gao, Dongxu, Su, Keyi, Yang, Yani, Wang, Zhefeng, He, Jun
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents; Brexpiprazole; Delayed-Action Preparations; Depressive Disorder, Major - drug therapy; Dogs; Foreign body reaction; Inflammation - drug therapy; Injections, Intramuscular; Pharmacokinetics; Rats; Ready-to-use Suspension; Schizophrenia; Suspensions
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2023.06.013

This graphical abstract was created by Adobe Photoshop 2020 containing the rat and muscle materials from BioRender.com. [Display omitted] Brexpiprazole (BPZ), which is approved for the treatment of schizophrenia and major depressive disorder, has the potential to meet diverse clinical needs. This study aimed to develop a long-acting injectable (LAI) formulation of BPZ that could provide sustained therapeutic benefits. A library of BPZ prodrugs was screened through esterification, and BPZ laurate (BPZL) was identified as an optimal candidate. To achieve stable aqueous suspensions, a pressure- and nozzle size-controlled microfluidization homogenizer was utilized. The pharmacokinetics (PK) profiles, considering dose and particle size modulation, were investigated following a single intramuscular injection in beagles and rats. BPZL treatment resulted in sustained plasma concentrations above the median effective concentration (EC50) for 2 ∼ 3 weeks, without exhibiting an initial burst release. Histological examination of foreign body reaction (FBR) in rats revealed the morphological evolution of an inflammation-mediated drug depot, confirming the sustained release mechanism of BPZL. These findings provide strong support for the further development of a ready-to-use LAI suspension of BPZL, which could potentially enhance treatment outcomes, improve patient adherence, and address the clinical challenges associated with long-term regimens of schizophrenia spectrum disorders (SSD).