Preparation And In Vivo Pharmacokinetic Of Lovastatin Solid Dispersion And Sustained-release Tablet

Objective:Lovastatin is a highly lipophilic drug considered to be one of the most effective cholesterol-lowering drugs.However,it is a BCS class II drug with low solubility and high permeability,and it has a strong affinity with P450 metabolizing enzymes in liver cells,and has a strong hepatic first-pass effect,resulting in its low oral bioavailability（<5%）.The objective of this study is to construct a stable solid dispersion system by screening suitable carriers to improve the bioavailability of lovastatin.At the same time,in order to reduce the adverse reactions caused by the fluctuation of blood drug concentration,improve the safety of medication and improve the compliance of patients,based on the optimal solid dispersion system constructed,the lovastatin sustained-release tablet was prepared by adding sustained-release excipients by direct compression method.Methods:The method for the analysis of LOV samples was established based on high performance liquid chromatography（HPLC）.The compatibility of the carriers（PVP K17,PVPK30,PVP VA64,Soluplus^?）with lovastatin was evaluated by the Hansen solubility parameter and the Flory-Huggins interaction parameter,and then the solid dispersion of different carriers was prepared by spray drying method.Fourier transform infrared transform（FTIR）was used to analyze the interaction between drugs and carriers,and X-ray diffraction（XRD）was used to explore the existence of drug in polymers.The morphology of the prepared solid dispersion was observed by scanning electron microscope（SEM）.The effects of different carriers and different drug loading ratios on drug dissolution were investigated.And the stability of the solid dispersion was investigated.The pharmacokinetic experiment in rats was investigated on the optimal solid dispersion formulation.On the basis of the optimal solid dispersion formulation,it was prepared into sustained-release tablets,and the powder fluidity,in vitro dissolution and stability were investigated.On the optimal formulation of sustained-release tablets,the pharmacokinetic experiments were carried out to verify after preparing lovastatin solid dispersion into sustained-release tablets,it can effectively improve the bioavailability while reducing the C_max and prolonging the Tmax.Results:The HPLC method was successfully established for the determination of LOV content.The result of compatibility showed that lovastatin has good compatibility with the carriers（Soluplus^?,PVP,PVP VA64）.The characterization of the prepared solid dispersion showed that the LOV was in an amorphous state after being prepared into a solid dispersion.There is a certain interaction force between the drug and the carrier in the solid dispersion.The in vitro dissolution results showed that the dissolution rate of the prepared solid dispersions was faster than the raw LOV.After placing the prepared solid dispersion at room temperature for 3 months,the LOV in the solid dispersion still exists in an amorphous state.The pharmacokinetic results in rats showed that after intragastric administration of LOV/Soluplus^?SD,the C_max increased by 1.92 times and the AUC_{0-24 h} increased by 1.48 times compared with the raw LOV.The LOV sustained-release tablet was successfully prepared by the direct compression method.Through single factor investigation,the sustained-release tablet with Kollidon^?SR as the skeleton material and pregelatinized starch as the filler was finally screened.The screened formulation of the tablet dissolves more than 80%within 12 hours,and the dissolution is stable and slow.When pregelatinized starch is used as the filler,the prepared sustained-release tablet can be stable stored for 3months under room temperature at a humidity of 75%;The in vivo pharmacokinetics results of LOV sustained-release tablets in New Zealand rabbits show that,compared with the domestic ordinary tablets,T_max was prolonged from 4 h to 8 h,C_max decreased by 29.46%,and AUC_{0-24 h}increased by 1.49 times.Conclusion:In this study,Soluplus^?was successfully selected as a carrier by calculating the Hansen solubility parameter and Flory-Huggins interaction parameter,and LOV solid dispersion was successfully prepared by spray drying method.The LOV in the solid dispersion is converted from the crystalline state to the amorphous state,and the dissolution rate of the drug in vitro is greatly accelerated.The prepared solid dispersion remained stable during the three-month stability test period at room temperature.The in vivo pharmacokinetics of LOV solid dispersion in rats indicated that preparation of LOV into solid dispersion could effectively improve its oral bioavailability.The prepared LOV solid dispersion has good fluidity and can be further prepared into sustained-release tablets by direct compression method.The results of pharmacokinetic experiments in New Zealand rabbits showed that compared with the domestic ordinary tablets,the self-made LOV sustained-release tablets can effectively improve the bioavailability while reducing the C_max and prolonging the T_max.The data obtained in this study have certain reference significance for improving the bioavailability of poorly soluble drugs and the development of new dosage forms.