Preparation Of Ternary Solid Dispersions And Tablets Of Telmisartan And Research Of Carriers Synergistic Effect

Telmisartan?TEL?,a nonpeptide angiotensin II-type 1 receptor?AT₁?blocker,is widely used to treat hypertension.However,as a BCS class II drug,it is especially insoluble between pH 3-9,resulting in bioavailability of 42%at 40 mg dose of tablet.For BCS class II drugs,solubility and dissolution are the rate-limiting steps for in-vivo absorption.Hence,it is necessary to increase solubility of TEL to improve bioavailability.The purpose of this study was to prepare TEL solid dispersions by solvent evaporation,and explore the influence of carriers on saturation solubility,in-vitro dissolution and in-vivo bioavailability.Furthermore,the synergistic effect of carriers and drug-carrier?s?interactions on the improved stability and bioavailability of TEL ternary solid dispersions were also investigated.And the preferred TEL ternary solid dispersion was prepared as a TEL tablet.Through ratios of drug/carrier and different kinds of carriers screening,PVP K30 and/or Soluplus were selected and used at different concentrations to prepare TEL binary and ternary solid dispersions.Compared to pure TEL and TEL-PVP K30/Soluplus binary solid dispersions,TEL-PVP K30-Soluplus ternary solid dispersions demonstrated significant advantages,including higher dissolution?over 90%release at 60 min?,better amorphous stability?physically stable at 40°C/75%RH conditions?and improved oral bioavailability(C_maxax was 16.85 times than pure TEL).Subsequently,single factor investigation were used to screen and optimize the preparation of telmisartan ternary solid dispersion tablets.The quality of the preferred tablets was evaluated by the difference in tablet weight,friability,content uniformity,disintegration time limit,and dissolution,and found to meet the all requirements.These advantages were related to the complementarity of PVP K30 and Soluplus on TEL,via analysis of saturation solubility,in-vitro dissolution,precipitation inhibition,T_g determination and FT-IR detection.On the one hand,PVP K30 had a better activity to solubilize TEL and achieve a high initial concentration in dissolution media.Simultaneously,the ability of Soluplus to assist in the maintenance of supersaturation played an important role.On the other hand,the amorphous stability maintenance at stability studies of TEL ternary solid dispersions was resulted from the higher T_g of PVP K30 and crystal inhibition ability of Soluplus,whereas TEL binary solid dispersions were unstable.Combined with results,a hypothesis was proposed that the existence of drug-carrier?s?interactions resulted to the synergistic effect of PVP K30 and Soluplus at molecular level.Therefore,the mechanism of carriers synergistic effect was discussed in this study.In present study,TEL ternary solid dispersions and tablets were successfully prepared by PVP K30 and Soluplus,which significantly improved the in-vitro dissolution and oral bioavailability of TEL.Simultaneously,the mechanism of synergistic effect of PVP K30 and Soluplus in TEL ternary solid dispersions was studied.Solid dispersions,which composed two or more kinds of carriers,have obvious potential to overcome shortcomings,such as precipitation in solution and amorphous unstable in solid state.Therefore,this study was in-depth and innovative,and more solid dispersion-based drugs were excepted to be prepared.