Advanced oral breviscapine sustained-release tablets for improved ischemic stroke treatment.

Abstract

This study aimed to address the challenges associated with the low oral bioavailability and the necessity for frequent dosing of breviscapine (BRE), a mainstream drug in the treatment of cardiovascular and cerebrovascular diseases. The poor solubility and permeability of BRE in the gastrointestinal tract were identified as significant barriers to effective drug absorption, thereby impacting therapeutic efficacy and patient compliance. To enhance the gastrointestinal absorption of BRE, particles loaded with BRE were engineered utilizing Cremophor EL (CrEL), an absorption enhancer, in conjunction with mesoporous silica, a biocompatible drug delivery vector, formulating mesoporous silica particles loaded with BRE and CrEL (BRE-CrEL@SiO₂). The solubility and mucosal permeability of BRE were ameliorated, facilitating transepithelial transport and improving absorption kinetics. BRE-CrEL@SiO₂ were subsequently integrated to prepare sustained-release tablets. The finite element simulation method was utilized in the study of non-planar circular BRE tablet process to ensure tablet quality. The superior bioavailability and therapeutic index of the absorption-promoting sustained-release tablets, compared to commercial tablets, were validated through in vivo pharmacokinetic and pharmacodynamic assessments, while safety was maintained. The oral relative bioavailability of the absorption-enhancing sustained-release tablets was 160.7 % relative to the commercial tablets, demonstrated in Beagle dogs, indicating higher absorption. This innovative formulation represents a significant advancement in improving therapeutic efficacy of ischemic stroke and reducing the treatment burden on patients. The study provides new insights into the development of novel dosage forms for BRE and other drugs with poor solubility and permeability, suggesting a promising approach to enhance their therapeutic effectiveness and improve patient compliance in treatment.