Skip to main content

Advertisement

SpringerLink
Log in

Development of self-nanoemulsifying drug delivery system for oral bioavailability enhancement of valsartan in beagle dogs

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript

Abstract

Valsartan, an angiotensin II receptor antagonist, is widely used to treat high blood pressure in the clinical setting. However, its poor water solubility results in the low oral bioavailability. The aim of this study was to improve dissolution rate and oral bioavailability by developing a self-nanoemulsifying drug delivery system. Saturation solubility of valsartan in various oils, surfactants, and cosurfactants was investigated, and the optimized formulation was determined by central composite design-response surface methodology. The shape of resultant VAL-SNEDDS was spherical with an average diameter of about 27 nm. And the drug loading efficiency is approximately 14 wt%. Differential scanning calorimetry and XRD studies disclosed the molecular or amorphous state of valsartan in VAL-SNEDDS. The dissolution study indicated that the self-nanoemulsifying drug delivery systems (SNEDDS) exhibited significantly enhanced dissolution compared with market capsules (Diovan®) in various media. Furthermore, the stability of formulation revealed that valsartan SNEDDS was stable under low temperature and accelerated test condition. Furthermore, the pharmacokinetics demonstrated that C max and AUC(0-∞) of SNEDDS capsules were about three- and twofold higher than Diovan® in beagle dogs, respectively. Meanwhile, the safety evaluation implied that VAL-SNEDDS was innocuous to beagle dogs during 15 days of continuous administration. Our results suggested that VAL-SNEDDS was a potential and safe delivery system with enhanced dissolution rate and oral bioavailability, as well as offered a strategy for the engineering of poorly water-soluble drugs in the clinical setting.

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.

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

Similar content being viewed by others

References

  1. Luo C, Sun J, Du Y, He Z. Emerging integrated nanohybrid drug delivery systems to facilitate the intravenous-to-oral switch in cancer chemotherapy. J Control Release. 2014;176:94–103.

    Article  CAS  PubMed  Google Scholar 

  2. Tarate B, Chavan R, Bansal AK. Oral solid self-emulsifying formulations: a patent review. Recent Pat Drug Deliv Formul. 2014;8:126–43.

    Article  CAS  PubMed  Google Scholar 

  3. Harde H, Agrawal AK, Jain S. Tetanus toxoid-loaded layer-by-layer nanoassemblies for efficient systemic, mucosal, and cellular immunostimulatory response following oral administration. Drug Delivery and Translational Research. 2015;5:498–510.

    Article  CAS  PubMed  Google Scholar 

  4. Mooranian A, Negrulj R, Arfuso F, Al-Salami H. The effect of a tertiary bile acid, taurocholic acid, on the morphology and physical characteristics of microencapsulated probucol: potential applications in diabetes: a characterization study. Drug Delivery and Translational Research. 2015;5:511–22.

    Article  CAS  PubMed  Google Scholar 

  5. Brookman LJ, Rolan PE, Benjamin IS, Palmer KR, Wyld PJ, Lloyd P, et al. Pharmacokinetics of valsartan in patients with liver disease. Clin Pharmacol Ther. 1997;62:272–8.

    Article  CAS  PubMed  Google Scholar 

  6. Chadha R, Bala M, Arora P, Jain DV, Pissurlenkar RR, Coutinho EC. Valsartan inclusion by methyl-beta-cyclodextrin: thermodynamics, molecular modelling, tween 80 effect and evaluation. Carbohydr Polym. 2014;103:300–9.

    Article  CAS  PubMed  Google Scholar 

  7. Park YJ, Lee HK, Im YB, Lee W, Han HK. Improved pH-independent dissolution and oral absorption of valsartan via the preparation of solid dispersion. Arch Pharm Res. 2010;33:1235–40.

    Article  CAS  PubMed  Google Scholar 

  8. Ha NS, Tran TT, Tran PH, Park JB, Lee BJ. Dissolution-enhancing mechanism of alkalizers in poloxamer-based solid dispersions and physical mixtures containing poorly water-soluble valsartan. Chem Pharm Bull (Tokyo). 2011;59:844–50.

    Article  CAS  Google Scholar 

  9. Patel A, Shelat P, Lalwani A. Development and optimization of solid self-nanoemulsifying drug delivery system (S-SNEDDS) using Scheffe's design for improvement of oral bioavailability of nelfinavir mesylate. Drug Delivery and Translational Research. 2014;4:171–86.

    Article  CAS  PubMed  Google Scholar 

  10. Constantinides PP. Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res. 1995;12:1561–72.

    Article  CAS  PubMed  Google Scholar 

  11. Fagir W, Hathout RM, Sammour OA, ElShafeey AH. Self-microemulsifying systems of Finasteride with enhanced oral bioavailability: multivariate statistical evaluation, characterization, spray-drying and in vivo studies in human volunteers. Nanomedicine (Lond). 2015;10:3373–89.

    Article  CAS  Google Scholar 

  12. Feher P, Ujhelyi Z, Vecsernyes M, Fenyvesi F, Damache G, Ardelean A, et al. Hepatoprotective effects of a self-micro emulsifying drug delivery system containing Silybum marianum native seed oil against experimentally induced liver injury. Pharmazie. 2015;70:231–8.

    CAS  PubMed  Google Scholar 

  13. Ujhelyi Z, Kalantari A, Vecsernyes M, Roka E, Fenyvesi F, Poka R, et al. The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells. Molecules. 2015;20:13226–39.

    Article  CAS  PubMed  Google Scholar 

  14. Beg S, Sandhu PS, Batra RS, Khurana RK, Singh B. QbD-based systematic development of novel optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with enhanced biopharmaceutical performance. Drug Deliv. 2015;22:765–84.

    Article  CAS  PubMed  Google Scholar 

  15. C.B. Tripathi, S. Beg, R. Kaur, G. Shukla, S. Bandopadhyay and B. Singh. Systematic development of optimized SNEDDS of artemether with improved biopharmaceutical and antimalarial potential. Drug Deliv. 2016;1–15.

  16. Bandyopadhyay S, Beg S, Katare OP, Sharma G, Singh B. QbD-oriented development of self-nanoemulsifying drug delivery systems (SNEDDS) of valsartan with improved biopharmaceutical performance. Curr Drug Deliv. 2015;12:544–63.

    Article  CAS  PubMed  Google Scholar 

  17. Ghosh PK, Murthy RS. Microemulsions: a potential drug delivery system. Curr Drug Deliv. 2006;3:167–80.

    Article  CAS  PubMed  Google Scholar 

  18. Setthacheewakul S, Mahattanadul S, Phadoongsombut N, Pichayakorn W, Wiwattanapatapee R. Development and evaluation of self-microemulsifying liquid and pellet formulations of curcumin, and absorption studies in rats. Eur J Pharm Biopharm. 2010;76:475–85.

    Article  CAS  PubMed  Google Scholar 

  19. F. Carriere. Impact of gastrointestinal lipolysis on oral lipid-based formulations and bioavailability of lipophilic drugs. Biochimie. 2015

  20. Xiumin LI, Man GE, Minzi LU, Yinghua J, Dongqin Q. The in vitro and in vivo evaluation of fenofibrate with a self-microemulsifying formulation. Curr Drug Deliv. 2015;12:308–13.

    Article  CAS  PubMed  Google Scholar 

  21. Poudel BK, Marasini N, Tran TH, Choi HG, Yong CS, Kim JO. Formulation, characterization and optimization of valsartan self-microemulsifying drug delivery system using statistical design of experiment. Chem Pharm Bull (Tokyo). 2012;60:1409–18.

    Article  CAS  Google Scholar 

  22. Dixit AR, Rajput SJ, Patel SG. Preparation and bioavailability assessment of SMEDDS containing valsartan. AAPS PharmSciTech. 2010;11:314–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. K. Zhao, Y. Yuan, H. Wang, P. Li, Z. Bao and Y. Li. Preparation and evaluation of valsartan by a novel semi-solid self-microemulsifying delivery system using Gelucire 44/14. Drug Dev Ind Pharm. 2016;1–8.

  24. Lian H, Zhang T, Sun J, Liu X, Ren G, Kou L, et al. Enhanced oral delivery of paclitaxel using acetylcysteine functionalized chitosan-vitamin E succinate nanomicelles based on a mucus bioadhesion and penetration mechanism. Mol Pharm. 2013;10:3447–58.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang Q, Sun J, Lu T, Zhang J, Wu C, Li L, et al. A rapid and sensitive LC-MS/MS method for evaluation of the absolute oral bioavailability of a novel c-Met tyrosine kinase inhibitor QBH-196 in rats. Biomed Chromatogr. 2015;29:1650–6.

    Article  CAS  PubMed  Google Scholar 

  26. Liu M, Cao W, Sun Y, He Z. Preparation, characterization and in vivo evaluation of formulation of repaglinide with hydroxypropyl-beta-cyclodextrin. Int J Pharm. 2014;477:159–66.

    Article  CAS  PubMed  Google Scholar 

  27. Wang M, Sun J, Zhai Y, Lian H, Luo C, Li L, et al. Enteric polymer based on pH-responsive aliphatic polycarbonate functionalized with vitamin E to facilitate oral delivery of tacrolimus. Biomacromolecules. 2015;16:1179–90.

    Article  CAS  PubMed  Google Scholar 

  28. Wang J, Sun J, Chen Q, Gao Y, Li L, Li H, et al. Star-shape copolymer of lysine-linked di-tocopherol polyethylene glycol 2000 succinate for doxorubicin delivery with reversal of multidrug resistance. Biomaterials. 2012;33:6877–88.

    Article  CAS  PubMed  Google Scholar 

  29. Li Z, Han X, Zhai Y, Lian H, Zhang D, Zhang W, et al. Critical determinant of intestinal permeability and oral bioavailability of pegylated all trans-retinoic acid prodrug-based nanomicelles: chain length of poly (ethylene glycol) corona. Colloids Surf B Biointerfaces. 2015;130:133–40.

    Article  CAS  PubMed  Google Scholar 

  30. Yang R, Huang X, Dou J, Zhai G, Su L. Self-microemulsifying drug delivery system for improved oral bioavailability of oleanolic acid: design and evaluation. Int J Nanomedicine. 2013;8:2917–26.

    PubMed  PubMed Central  Google Scholar 

  31. Han SD, Jung SW, Jang SW, Son M, Kim BM, Kang MJ. Reduced food-effect on intestinal absorption of dronedarone by self-microemulsifying drug delivery system (SMEDDS). Biol Pharm Bull. 2015;38:1026–32.

    Article  CAS  PubMed  Google Scholar 

  32. He S, Cui Z, Wang X, Zhang H, Dai W, Zhang Q. Cremophor-free intravenous self-microemulsions for teniposide: safety, antitumor activity in vitro and in vivo. Int J Pharm. 2015;495:144–53.

    Article  CAS  PubMed  Google Scholar 

  33. Z. Li, M. Zhang, C. Liu, S. Zhou, W. Zhang, T. Wang, et al. Development of liposome containing sodium deoxycholate to enhance oral bioavailability of itraconazole. Asian Journal of Pharmaceutical Sciences. 2016;

  34. Jaiswal P, Aggarwal G, Harikumar SL, Singh K. Development of self-microemulsifying drug delivery system and solid-self-microemulsifying drug delivery system of telmisartan. Int J Pharm Investig. 2014;4:195–206.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mu S, Li M, Guo M, Yang W, Wang Y, Li J, et al. Spironolactone nanocrystals for oral administration: different pharmacokinetic performances induced by stabilizers. Colloids Surf B Biointerfaces. 2016;147:73–80.

    Article  CAS  PubMed  Google Scholar 

  36. Guo M, Fu Q, Wu C, Guo Z, Li M, Sun J, et al. Rod shaped nanocrystals exhibit superior in vitro dissolution and in vivo bioavailability over spherical like nanocrystals: a case study of lovastatin. Colloids Surf B Biointerfaces. 2015;128:410–8.

    Article  CAS  PubMed  Google Scholar 

  37. Luo C, Sun J, Liu D, Sun B, Miao L, Musetti S, et al. Self-assembled redox dual-responsive prodrug-Nanosystem formed by single thioether-bridged paclitaxel-fatty acid conjugate for cancer chemotherapy. Nano Lett. 2016;16:5401–8.

    Article  CAS  PubMed  Google Scholar 

  38. C. Luo, J. Sun, B. Sun, D. Liu, L. Miao, T.J. Goodwin, et al. Facile fabrication of tumor redox-sensitive nanoassemblies of small-molecule oleate prodrug as potent chemotherapeutic nanomedicine. Small. 2016;

  39. Patel AR, Vavia PR. Preparation and in vivo evaluation of SMEDDS (self-microemulsifying drug delivery system) containing fenofibrate. AAPS J. 2007;9:E344–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pouton CW. Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and 'self-microemulsifying' drug delivery systems. Eur J Pharm Sci. 2000;11(Suppl 2):S93–8.

    Article  CAS  PubMed  Google Scholar 

  41. Flesch G, Muller P, Lloyd P. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol. 1997;52:115–20.

    Article  CAS  PubMed  Google Scholar 

  42. Dintaman JM, Silverman JA. Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). Pharm Res. 1999;16:1550–6.

    Article  CAS  PubMed  Google Scholar 

  43. Kawakami K, Yoshikawa T, Moroto Y, Kanaoka E, Takahashi K, Nishihara Y, et al. Microemulsion formulation for enhanced absorption of poorly soluble drugs. I Prescription design J Control Release. 2002;81:65–74.

    Article  CAS  PubMed  Google Scholar 

  44. Matsuoka K, Kuranaga Y, Moroi Y. Solubilization of cholesterol and polycyclic aromatic compounds into sodium bile salt micelles (part 2). Biochim Biophys Acta. 2002;1580:200–14.

    Article  CAS  PubMed  Google Scholar 

  45. O'Driscoll CM. Lipid-based formulations for intestinal lymphatic delivery. Eur J Pharm Sci. 2002;15:405–15.

    Article  PubMed  Google Scholar 

  46. Karpf DM, Holm R, Kristensen HG, Mullertz A. Influence of the type of surfactant and the degree of dispersion on the lymphatic transport of halofantrine in conscious rats. Pharm Res. 2004;21:1413–8.

    Article  CAS  PubMed  Google Scholar 

  47. Han X, Li Z, Sun J, Luo C, Li L, Liu Y, et al. Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery: probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation. J Control Release. 2015;197:29–40.

    Article  CAS  PubMed  Google Scholar 

  48. Williams JK, Eckman D, Dean A, Moradi M, Allickson J, Cline JM, et al. The dose-effect safety profile of skeletal muscle precursor cell therapy in a dog model of intrinsic urinary sphincter deficiency. Stem Cells Transl Med. 2015;4:286–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was financially supported from state key scientific research programs (2014ZX09507001-009).

Author information

Authors and Affiliations

  1. School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China

    Zhenbao Li, Wenjuan Zhang, Yan Gao, Yan Liu, Mingming Hu, Xiaohong Liu, Yongjun Wang, Zhonggui He, Yinghua Sun & Jin Sun

  2. School of Medical Devices, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China

    Rongwu Xiang

  3. School of further education, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China

    Mei Zhou

  4. Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China

    Jin Sun

Authors
  1. Zhenbao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wenjuan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rongwu Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mingming Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiaohong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yongjun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhonggui He
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yinghua Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jin Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yinghua Sun or Jin Sun.

Ethics declarations

The animal study was approved by the Institute Animal Ethics Committee (IAEC) and Shenyang Pharmaceutical University Animal Care

Conflict of interest

No conflict of interest exits in the manuscript, and the article is approved by all authors.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, Z., Zhang, W., Gao, Y. et al. Development of self-nanoemulsifying drug delivery system for oral bioavailability enhancement of valsartan in beagle dogs. Drug Deliv. and Transl. Res. 7, 100–110 (2017). https://doi.org/10.1007/s13346-016-0342-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13346-016-0342-7

Keywords

Search

Navigation