Preparation And Evaluation Of Three Insoluble Drug Solid Dispersions Based On Sodium Carboxymethyl Starch

Carboxy methyl starch sodium(CMS)has been widely used in medical and health fields due to its outstanding physicochemical properties,excellent biocompatibility and safety.Piperine(PIP),18-β-glycyrrhetinic acid(β-GA)and evodine(EVO)have many pharmacological activities,but they are insoluble in water and belong to insoluble drugs.Due to the low oral bioavailability,it is difficult to meet the requirements of drug treatment concentration,and its efficacy and clinical application are limited.In this study,CMS was used as the carrier,and three different types of drugs,namely,insoluble alkaloids active substance PIP,oleanolic acid pentacyclic triterpenoid compound β-GA,and highly oxidized tetracyclic triterpenoid compound EVO containing furan ring,which were alkaline,acidic,and neutral,were used as model drugs.PIP-CMS solid dispersion,β-GA-CMS solid dispersion and EVO-CMS solid dispersion were prepared by solvent evaporation method,and evaluated in vitro and in vivo.While improving the release of PIP,β-GA and EVO in vitro,increasing their solubility and bioavailability in vivo,the feasibility of CMS as a carrier material for the preparation of solid dispersion was investigated.In vitro dissolution test,hydrochloric acid solution with pH 1.2 and phosphate buffer solution with pH 6.8 were selected as dissolution medium conditions to simulate gastric and intestinal fluid environments,respectively.The dissolution results showed that the PIP-CMS SD,β-GA-CMS SD and EVO-CMS SD with three mass ratios(API:CMS mass ratios were 1:4,1:6 and 1:8,respectively)showed excellent dissolution behavior,and their solubility and dissolution rate were significantly improved compared with API and physical mixture.In terms of quality evaluation,phase identification,microstructure and intermolecular force of solid dispersions were investigated by DSC,XRPD,SEM and FTIR.The results showed that in PIP-CMS SD,β-GA-CMS SD and EVO-CMS SD,the three ingredients existed in amorphous form with high physical stability,and their crystal characteristics had disappeared.There was strong intermolecular interaction between the three ingredients and CMS.In addition,the in vitro dissolution results after 3 months and 6 months under accelerated conditions showed that the cumulative dissolution rates of the three solid dispersions had no significant change compared with those at 0 months,and the stability was good.In the pharmacokinetic study of rats,the oral bioavailability of the corresponding solid dispersion agents was studied with PIP,β-GA,EVO raw materials and their physical mixture with CMS as the control.The results showed that the Cmax of PIP in the PIP-CMS SD group was(17.51±8.15)μg/mL,which was increased to 1.85 and 2.41 times of the original drug and physical mixture,respectively.After β-GA was prepared into solid dispersion with CMS,the Cmax increased from 10.77 μ/mL to 32.17 μg/mL.The Cmax of EVO in EVO-CMS SD group was(158.55±91.22)ng/mL,which increased to 8.75 and 6.21 times of the original drug and physical mixture,respectively.The AUC0-24h of PIP-CMS SD,β-GA-CMS SD and EVO-CMS SD were 2.29 times,1.74 times and 8.75 times of the original drug,respectively,indicating that the bioavailability of PIP,β-GA and EVO in rats was significantly improved.In conclusion,the preparation of PIP,β-GA,EVO and CMS into solid dispersion can improve their in vitro release,significantly improve the solubility and bioavailability of the three APIs,promote the rational preparation development and accelerate the transition from in vitro system to in vivo application.It is feasible to apply CMS as a carrier material in the preparation of solid dispersions,which has a certain reference value and significance for the application of CMS in the development of solid dispersion preparations.