Preparation Of Ritonavir Solid Dispersion By Hot Melt Extrusion

Hot melt extrusion is a new pharmaceutical technology,which is characterized of sustainability,neither water nor solvents,with the drug well dispersed.The preparation of ritonavir solid dispersion by hot melt extrusion was researched and the dissolution in vitro also was studied.Objective: Ritonavir is an effective oral inhibitor of human immunodeficiency aspartic protease which is developed by Abbott.It can be used alone or combined with antiretroviral nucleoside drugs for treatment of advanced or non-AIDS patients.At present,most of the Ritonavir formulation which are approved by China are prepared by hot melt extrusion technology by Abbott's,and domestically developed tablets have not been developed in China.Therefore,this study is aimed to explore the the excipients and process conditions of ritonavir solid dispersion which is prepared by hot melt extrusion,and provide references for the subsequent preparation of ritonavir generic drugs.Methods:(1)Study on pre-formulation.The thermal stability of ritonavir,Soluplus,Kollidon VA64 and mixtures of different mass ratios was investigated by high performance liquid chromatography and ultraviolet spectrophotometry,miscibility between the drug and the carriers was investigated,and establish the method of ritonavir dissolution in vitro.(2)The effects of different types of substances(water,Griseofulvin,Ritonavir,Modified Phospholipids,Cholesterol)on Tg of Soluplus and Kollidon VA64 were investigated by thermal analysis.(3)Screening Hot-melt Extrusion formulations by Film Method.The effects of different additives,modified soybean phospholipids,DOPC,DPPC,Span20 and PEG-6000 on the glass transition temperature and dissolution of ritonavir solid dispersions were studied.(4)Preparation of ritonavir solid dispersion by Hot Melt Extrusion.Preparation of Ritonavir Solid Dispersion by Hot Melt Extrusion.The solid dispersions of ritonavir-kollidon VA64,ritonavir-kollidon VA64-modified Phospholipids,ritonavir-kollidon VA64-Span20 were prepared and their properties were identified.Results:(1)A simple and sensitive high performance liquid chromatography and ultraviolet spectrophotometry were set up and used to determine the in vitro dissolution ofritonavir.The analysis of the dissolution point,melting point and glass transition temperature of the drugs and excipients showed that the two kinds of excipients could be used as the carrier s of ritonavir.(2)It was found that the five substances could be used as plasticizers to reduce the Tg of Soluplus,Kollidon VA64.2.Water content of 2.4%Soluplus Tg reduced by about 12.4?,water content of 4% Kollidon VA64 Tg decreased by about 57.6?.50% griseofulvin / ritonavir / modified soybean phospholipid /cholesterol-Soluplus Tg decreased by 3.6,20.8,15.5 and 30.5?;50% griseofulvin /ritonavir / modified The decrease in the Tg of the phospholipid / cholesterol-Kollidon VA64 was 11.0,41.1,8.9 and 35.4 ?,respectively.Ritonavir,cholesterol on the Soluplus,Kollidon VA64 plasticization effect is stronger than griseofulvin and modified soybean phospholip.(3)The dissolution results of the solid formulations of ritonavir in various formulations prepared by the thin film method showed that the dissolution of the modified solid suspension and Span20 was higher.(4)The solid dispersion of ritonavir-Kollidon VA64-modified soybean phospholipid / Span20 prepared by hot-melt extrusion solid dispersion has a lower Tg and a better dissolution.Conclusion: The solid solution of ritonavir prepared by hot melt extrusion using Kollidon VA64 as carrier,modified asprolide and Span20 as additives have a better dissolution,Which provided the basis for the subsequent preparation of ritonavir imitation tablets.