Skip to main content
SpringerLink
Log in

Stability and Bioavailability Enhancement of Telmisartan Ternary Solid Dispersions: the Synergistic Effect of Polymers and Drug-Polymer(s) Interactions

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm. 2011;420(1):1–10.

    Article  CAS  Google Scholar 

  2. Paidi SK, Jena SK, Ahuja BK, Devasari N, Suresh S. Preparation, in-vitro and in-vivo evaluation of spray-dried ternary solid dispersion of biopharmaceutics classification system class II model drug. J Pharm Pharmacol. 2015;67(5):616–29.

    Article  CAS  Google Scholar 

  3. Scholz A, Abrahamsson B, Diebold SM, Kostewicz E, Polentarutti BI, Ungell A-L, et al. Influence of hydrodynamics and particle size on the absorption of felodipine in labradors. Pharm Res. 2002;19(1):42–6.

    Article  CAS  Google Scholar 

  4. Sigfridsson K, Ahlqvist M, Lindsjo M, Paulsson S. Salt formation improved the properties of a candidate drug during early formulation development. Eur J Pharm Sci. 2018;120:162–71.

    Article  CAS  Google Scholar 

  5. Tang P, Wang L, Ma X, Xu K, Xiong X, Liao X, et al. Characterization and in vitro evaluation of the complexes of posaconazole with beta- and 2,6-di-O-methyl-beta-cyclodextrin. AAPS PharmSciTech. 2017;18(1):104–14.

    Article  CAS  Google Scholar 

  6. Patel J, Dhingani A, Garala K, Raval M, Sheth N. Design and development of solid nanoparticulate dosage forms of telmisartan for bioavailability enhancement by integration of experimental design and principal component analysis. Powder Tech. 2014;258:331–43.

    Article  CAS  Google Scholar 

  7. Ellenberger DJ, Miller DA, Kucera SU, Williams RO. Improved vemurafenib dissolution and pharmacokinetics as an amorphous solid dispersion produced by KinetiSol® processing. AAPS PharmSciTech. 2018;19(5):1957–70.

    Article  CAS  Google Scholar 

  8. Sekiguchi K, Obi N. Studies on absorption of eutectic mixture I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem Pharm Bull. 1961;9:866–72.

    Article  CAS  Google Scholar 

  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 

  10. Jahan R, Islam MS, Tanwir A, Chowdhury JA. In vitro dissolution study of atorvastatin binary solid dispersion. J Adv Pharm Technol Res. 2013;4(1):18–24.

    Article  CAS  Google Scholar 

  11. Lavan M, Knipp G. Effects of dendrimer-like biopolymers on physical stability of amorphous solid dispersions and drug permeability across Caco-2 cell monolayers. AAPS PharmSciTech. 2018;19(6):2459–71.

    Article  CAS  Google Scholar 

  12. Alonzo DE, Zhang GGZ, Zhou D, Gao Y, Taylor LS. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27(4):608–18.

    Article  CAS  Google Scholar 

  13. Al-Obaidi H, Buckton G. Evaluation of griseofulvin binary and ternary solid dispersions with HPMCAS. AAPS PharmSciTech. 2009;10(4):1172–7.

    Article  CAS  Google Scholar 

  14. Xie T, Taylor LS. Effect of temperature and moisture on the physical stability of binary and ternary amorphous solid dispersions of celecoxib. J Pharm Sci. 2017;106(1):100–10.

    Article  CAS  Google Scholar 

  15. Chauhan H, Kuldipkumar A, Barder T, Medek A, Gu CH, Atef E. Correlation of inhibitory effects of polymers on indomethacin precipitation in solution and amorphous solid crystallization based on molecular interaction. Pharm Res. 2014;31(2):500–15.

    Article  CAS  Google Scholar 

  16. Trasi NS, Taylor LS. Effect of polymers on nucleation and crystal growth of amorphous acetaminophen. CrystEngComm. 2012;14(16):5188–97.

    Article  CAS  Google Scholar 

  17. Trasi NS, Abbou Oucherif K, Litster JD, Taylor LS. Evaluating the influence of polymers on nucleation and growth in supersaturated solutions of acetaminophen. CrystEngComm. 2015;17(6):1242–8.

    Article  CAS  Google Scholar 

  18. Sheng X, Tang J, Bao J, Shi X, Su W. Enhancement of in vitro dissolution and in vivo performance/oral absorption of FEB-poloxamer-TPGS solid dispersion. Journal of Drug Delivery Science and Technology. 2018;46:408–15.

    Article  CAS  Google Scholar 

  19. Wairkar S, Gaud R, Jadhav N. Enhanced dissolution and bioavailability of Nateglinide by microenvironmental pH-regulated ternary solid dispersion: in-vitro and in-vivo evaluation. J Pharm Pharmacol. 2017;69(9):1099–109.

    Article  CAS  Google Scholar 

  20. Alaziz DMA, Sammour OA, Elshamy AEAA, Neseem DI. Formulation and evaluation of binary and ternary solid dispersions of domperidone by solvent evaporation method. Afr J Pharm Pharmacol. 2014;8(3):66–80.

    Article  Google Scholar 

  21. Mooter GV, Wuyts M, Blaton N, Busson R, Grobet P, Augustijns P, et al. Physical stabilization of amorphous ketoconazole in solid dispersions with polyvinylpyrrolidone K25. Eur J Pharm Sci. 2001;12:261–9.

    Article  Google Scholar 

  22. Song Y, Yang X, Chen X, Nie H, Byrn S, Lubach JW. Investigation of drug-excipient interactions in lapatinib amorphous solid dispersions using solid-state NMR spectroscopy. Mol Pharm. 2015;12(3):857–66.

    Article  CAS  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.

    Article  CAS  Google Scholar 

  24. Prasad D, Chauhan H, Atef E. Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: combination of polymers showing drug-polymer interaction for synergistic effects. J Pharm Sci. 2014;103(11):3511–23.

    Article  CAS  Google Scholar 

  25. Prasad D, Chauhan H, Atef E. Role of molecular interactions for synergistic precipitation inhibition of poorly soluble drug in supersaturated drug-polymer-polymer ternary solution. Mol Pharm. 2016;13(3):756–65.

    Article  CAS  Google Scholar 

  26. Albadarin AB, Potter CB, Davis MT, Iqbal J, Korde S, Pagire S, et al. Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus® processed by hot melt extrusion. Int J Pharm. 2017;532(1):603–11.

    Article  CAS  Google Scholar 

  27. Zhong L, Zhu X, Yu B, Su W. Influence of alkalizers on dissolution properties of telmisartan in solid dispersions prepared by cogrinding. Drug Dev Ind Pharm. 2014;40(12):1660–9.

    Article  CAS  Google Scholar 

  28. Dukeck R, Sieger P, Karmwar P. Investigation and correlation of physical stability, dissolution behaviour and interaction parameter of amorphous solid dispersions of telmisartan: a drug development perspective. Eur J Pharm Sci. 2013;49(4):723–31.

    Article  CAS  Google Scholar 

  29. Singh G, Sharma S, Gupta GD. Extensive diminution of particle size and amorphization of a crystalline drug attained by eminent technology of solid dispersion: a comparative study. AAPS PharmSciTech. 2017;18(5):1770–84.

    Article  CAS  Google Scholar 

  30. Borba PAA, Pinotti M, de Campos CEM, Pezzini BR, Stulzer HK. Sodium alginate as a potential carrier in solid dispersion formulations to enhance dissolution rate and apparent water solubility of BCS II drugs. Carbohydr Polym. 2016;137:350–9.

    Article  CAS  Google Scholar 

  31. Enose AA, Dasan P, Sivaramakrishanan H, Kakkar V. Formulation, characterization and pharmacokinetic evaluation of telmisartan solid dispersions. J Mol Pharm Org Process Res. 2016;4(1):1–8.

    Article  Google Scholar 

  32. Das S, Vegesna NSKV. H. G S. Design and development of a dual-drug loaded pulsatile capsule for treatment of hypertension – in vitro and ex vivo studies. RSC Adv. 2015;5(122):100424–33.

    Article  CAS  Google Scholar 

  33. Higuchi T, Connors K. Phase-solubility techniques. Adv Anal Chem Instrum. 1965;4:117–23.

    CAS  Google Scholar 

  34. Venkateskumar K, Parasuraman S, Gunasunderi R, Sureshkumar K, Nayak MM, Shah SAA, et al. Acyclovir-polyethylene glycol 6000 binary dispersions: mechanistic insights. AAPS PharmSciTech. 2017;18(6):2085–94.

    Article  CAS  Google Scholar 

  35. Panda T, Das D, Panigrahi L. Formulation development of solid dispersions of bosentan using gelucire 50/13 and poloxamer 188. J Appl Pharm Sci. 2016;6(9):027–33.

    Article  CAS  Google Scholar 

  36. Chen J, Chen Y, Huang W, Wang H, Du Y, Xiong S. Bottom-up and top-down approaches to explore sodium dodecyl sulfate and Soluplus on the crystallization inhibition and dissolution of felodipine extrudates. J Pharm Sci. 2018;107(9):2366–76.

    Article  CAS  Google Scholar 

  37. Chae JS, Chae BR, Shin DJ, Goo YT, Lee ES, Yoon HY, et al. Tablet formulation of a polymeric solid dispersion containing amorphous alkalinized telmisartan. AAPS PharmSciTech. 2018;19(7):2990–9.

    Article  CAS  Google Scholar 

  38. Patel DD, Anderson BD. Adsorption of polyvinylpyrrolidone and its impact on maintenance of aqueous supersaturation of indomethacin via crystal growth inhibition. J Pharm Sci. 2015;104(9):2923–33.

    Article  CAS  Google Scholar 

  39. Patel DD, Anderson BD. Effect of precipitation inhibitors on indomethacin supersaturation maintenance: mechanisms and modeling. Mol Pharm. 2014;11(5):1489–99.

    Article  CAS  Google Scholar 

  40. Tran PH, Tran HT, Lee BJ. Modulation of microenvironmental pH and crystallinity of ionizable telmisartan using alkalizers in solid dispersions for controlled release. J Control Release. 2008;129(1):59–65.

    Article  CAS  Google Scholar 

  41. Frank DS, Matzger AJ. Probing the interplay between amorphous solid dispersion stability and polymer functionality. Mol Pharm. 2018;15(7):2714–20.

    Article  CAS  Google Scholar 

  42. Aso Y, Yoshioka S, Kojima S. Molecular mobility-based estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly (vinylpyrrolidone) solid dispersions. J Pharm Sci. 2004;93(2):384–91.

    Article  CAS  Google Scholar 

  43. Gordon M, Taylor JS. Ideal copolymers and the second-order transitions of synthetic rubbers. I. Non-crystalline copolymers. J Appl Chem. 1952;2:493–500.

    Article  CAS  Google Scholar 

  44. Brostow W, Chiu R, Kalogeras IM, Vassilikou-Dova A. Prediction of glass transition temperatures: binary blends and copolymers. Mater Lett. 2008;62(17–18):3152–5.

    Article  CAS  Google Scholar 

  45. Moura Ramos JJ, Diogo HP. Thermal behavior and molecular mobility in the glassy state of three anti-hypertensive pharmaceutical ingredients. RSC Adv. 2017;7(18):10831–40.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, People’s Republic of China

    Xiangjun Shi, Tiantian Xu, Wan Huang & Baibai Fan

  2. Soli Pharma Sci-Tech Co., Ltd, Economic & Technical Development Zone, Hangzhou, People’s Republic of China

    Xiaoxia Sheng

Authors
  1. Xiangjun Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiantian Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Baibai Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoxia Sheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiangjun Shi.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, X., Xu, T., Huang, W. et al. Stability and Bioavailability Enhancement of Telmisartan Ternary Solid Dispersions: the Synergistic Effect of Polymers and Drug-Polymer(s) Interactions. AAPS PharmSciTech 20, 143 (2019). https://doi.org/10.1208/s12249-019-1358-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-019-1358-3

KEY WORDS

Search

Navigation