Study On The Long Acting Injection Of Ginkgolide B

In recent years,Ginkgolides B（GB）,the most potent platelet-activating factor antagonist,has been shown to be effective in cerebral arterial thrombosis treatment.In this project,an S/O/W solid lipid microparticles（SLMs）was designed to address the shortcomings of existing long-acting injectable（LAI）and the problems of low water solubility and increased ring-opening solubility of GB in body environment.Two microcrystalline preparation methods of anti-solvent precipitation and ball milling,in terms of particle size control of GB-MCTS were first compared.The process and prescription were then screened according to GB release performance,and the optimized GB-SLMs were characterized and pharmacokinetically studied in rats.To address the problem of non-specific phagocytosis by local macrophages uptake when the intramuscular administration,the SLMs were modified with hydrophilic groups of PEG and HES by emulsification and"post-insertion"method.The relationship between the surface modification and the macrophages uptake was established by Raw264.7 cells and pharmacokinetic study in rats.The results showed that the GB-MCTS prepared by ball milling was more uniform with an average particle size of 1.2μm,and the in vitro/vivo studies showed that the oil phase MCT could effectively block the diffusion of GB microcrystals into the aqueous phase.GB-SLMs with D₅₀around 10μm were prepared according to the optimal process and prescription.In vitro/vivo studies showed that SLMs could effectively control the GB release less than 10%at 2 h and showed a slowly release.HES-SLMs reduced phagocytic uptake more effectively than PEG modified SLMs due to its low immunogenic phenotype and thick hydrophilic layer,and the highest AUC_0-t(12413.43±1595.24 ng·h·m L^-1)and sustained release were observed in rats.The S/O/W GB-SLMs constructed in this project can realize the dual regulation of matrix embedding and microcrystal dissolution strategy,and the HES hydrophilic group modification can make more drugs into blood and guarantee the system bioavailability,reducing the frequency of drug delivery and enhance the stability of blood concentration.The implementation of this project will not only provide a technical and theoretical basis for the development of GB formulation,but also lay the foundation for the research of other drugs LAI.