Reduced In vivo burst release of ginkgolide B microcrystals achieved by polymeric H+ depot

Drug microcrystal (MC) is an important category of long acting injections (LAIs), whose release profile is controlled mainly by particle size, crystal form, drug solubility, and other parameters. In this study, a polymeric H+ depot composed of alginate was combined with drug MC using ginkgolide B (GB) as model drug to reduce the initial burst release of the drugs with elevated solubility in body fluid. The parameters of GB MC preparation by precipitation, including stabilizer type and amount, phase volume ratio, and stirring rate were investigated. And the particle size/distribution, particle morphology, crystallinity, in vitro release of optimized GB MC were characterized. The in vivo dissolution retardation effect of acidified alginate (SAA) was first confirmed by live imaging using fluorescein as probe. And the pharmacokinetic profiles of different GB MC-polymer blends were investigated by UPLC-MS/MS. The prepared GB MC was spherical-like particles with a mean particle size of 5.863 μm and a span value of 1.634. The crystallinity of GB MC was lowered by the precipitation process compared with that of the crude drug, which resulted in a faster in vitro dissolution with more than 90% of drugs dissolved in 20 min. When administered with SAA, an alginate amount-dependent reduction in Cmax (1243.5 ± 281.4 ng/mL of GB-SAA, 1:5, 820.9 ± 84.0 ng/mL of GB-SAA, 1:10, 2850.9 ± 1059.3 ng/mL of GB alone and 2476.9 ± 396.4 ng/mL of GB-HPMC E5, 1:10) and prolongation in Tmax (3.2 ± 1.1 h of GB-SAA, 1:5, 6.4 ± 2.2 h of GB-SAA, 1:10, 1.2 ± 0.45 h of GB alone and 1.4 ± 0.55 h of GB-HPMC E5, 1:10) was noticed, indicating the capability of polymeric H+ depot in controlling GB release in vivo. In conclusion, the polymeric H+ depot strategy influenced drug dissolution and outward drug diffusion sequentially to retard the initial burst release of drugs with elevated solubility in body fluid.