Investigation On Huperzine A-Ligustrazine Phosphate Formula In Interfering Alzheimer's Disease

The aim of this paper was to research and develop a kind of drug combination named huperzine A-ligustrazine phosphate formula, which could interfere the Alzheimer's disease from multiple targets, based on the platforms of pharmaceutics, animal ethology, biochemistry, and pharmacokinetics-pharmacodynamics (PK-PD), and to investigate this formula deeply and thoroughly, providing an innovative formula delivery system in fight against the Alzheimer's disease.Scopolamine induced memory deficits rat model and D-galactose induced aging rat model were established as the animal models to simulate the Alzheimer's disease, and the reliability of the models was validated in the animal ethologic, biochemical, and metabonomic investigations. The influence of this formula, administrated orally, on the ethology and biochemistry in these two animal models was studied, which indicated that this formula was superior to the mono-therapy in interfering the Alzheimer's disease, and its mechanism was explained preliminarily. Taking the influence of the formula, administrated orally, on the scopolamine induced memory deficits rat model as the investigative target, the metabonomic studies of rat brain after administration were conducted based on the UPLC-TOF MS metabonomic research platform. Several potential biomarkers were gained, and the advantage of this formula in the fight against the Alzheimer's disease was further validated. Moreover, the metabonomic studies showed that huperzine A-ligustrazine phosphate formula could interfere various mechanisms related to the etiological factors of the Alzheimer's disease, which identified the mechanisms of this formula in the molecular level.The assay methods of huperzine A and ligustrazine phosphate in the plasma of rat were constructed, respectively, using HPLC-TOF MS and UPLC analytical technologies. Furthermore, a PK-PD model was established to correlate the blood drug level, drug effect, and drug action time of huperzine A and ligustrazine phosphate, respectively, which realized the transducer process between dosage and effectiveness.The combined penetration enhancer was gained after the penetration enhancement effects of different terpene enhancers on the in vitro transdermal delivery of huperzine A and ligustrazine phosphate in the formula were compared. Furthermore, the synergic penetration enhancement effect of the combined penetration enhancer was investigated by attenuated total reflectance-Fourier transform infrared (ATR-FTIR), and its penetration enhancement mechanisms were also identified. The basic constituents of the formula microemulsion were determined using pseudo-ternary phase diagram. The microeulsion had small particle size with satisfied dispersity and stability, with high entrapment efficiency for huperzine A as well. The in vitro transdermal penetration kinetics of the microemulsion was in a zero order process. The formula microemulsion-based patch were thereafter constructed to overcome the disadvantages of microemulsion in strong fluidity and poor viscosity to skin, and the ratio of drugs as well as the administration dosage in the patch was optimized. The novel, safe and effective transdermal delivery system of huperzine A-ligustrazine phosphate formula, interfering the Alzheimer's disease, was eventually gained.In conclusion, in this paper, the huperzine A-ligustrazine phosphate formula has been applied in the prevention and treatment of Alzheimer's disease for the first time, providing an innovative transdermal delivery system of formula in interfering Alzheimer's disease.