Stability and Bioavailability Enhancement of Telmisartan Ternary Solid Dispersions: the Synergistic Effect of Polymers and Drug-Polymer(s) Interactions
- 109 Downloads
The purpose of this study was to investigate the synergistic effect of polymers and drug-polymer(s) interactions on the improved stability and bioavailability of telmisartan (TEL) ternary solid dispersions. As a water-insoluble drug, 40 and 160 mg doses of TEL tablets exhibited bioavailabilities of 42% and 58%, respectively. Through polymer screening, PVP K30 and/or Soluplus were selected and used at different concentrations to prepare TEL amorphous solid dispersions by solvent evaporation. 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 in 90 days), and improved oral bioavailability (Cmax of 5535.819 ± 325.67 ng/mL and tmax of 1 h). These advantages were related to the complementarity of PVP K30 and Soluplus on TEL. PVP K30 had a better activity to solubilize TEL and achieved a high TEL initial concentration in dissolution media. Simultaneously, the ability of Soluplus to assist in the maintenance of supersaturation played an important role. PVP K30 and Soluplus together inhibited crystallization of the drug at different stages. The existence and intensity of drug-polymer interactions were also determined by DSC (Tg determination) and FT-IR. At the molecular level, a hypothesis was also proposed that the enhancements resulted from the contribution of the synergistic effect between PVP K30 and Soluplus. These results suggested that two polymers, in a combination and via a synergistic effect, could further enhance the bioavailability and amorphous stability of ternary solid dispersions.
KEY WORDStelmisartan ternary solid dispersions synergistic effect stability bioavailability
This work was supported by Project 21606203 of the Natural Science Foundation of China. Sincere thanks are given to Yehui Chen, Lin Yang, and Fuqi Fei (Zhejiang University of Technology) for assisting in the pharmacokinetic study.
- 9.Shah J, Vasanti S, Anroop B, Vyas H. Enhancement of dissolution rate of valdecoxib by solid dispersions technique with PVP K 30 & PEG 4000: preparation and in vitro evaluation. J Incl Phenom Macrocycl Chem. 2008;63(1–2):69–75.Google Scholar
- 23.Ueda H, Wu W, Lobmann K, Grohganz H, Mullertz A, Rades T. Application of a salt coformer in a co-amorphous drug system dramatically enhances the glass transition temperature: a case study of the ternary system carbamazepine, citric acid, and l-arginine. Mol Pharm. 2018;15(5):2036–44.CrossRefGoogle Scholar
- 33.Higuchi T, Connors K. Phase-solubility techniques. Adv Anal Chem Instrum. 1965;4:117–23.Google Scholar