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AAPS PharmSciTech

, Volume 19, Issue 3, pp 1205–1218 | Cite as

ω-3 Fatty Acid Synergized Novel Nanoemulsifying System for Rosuvastatin Delivery: In Vitro and In Vivo Evaluation

  • Chandra Bhushan Tripathi
  • Neha Gupta
  • Pranesh Kumar
  • Ashok Kumar Singh
  • Vinit Raj
  • Poonam Parashar
  • Mahendra Singh
  • Jovita Kanoujia
  • Malti Arya
  • Shubhini A Saraf
  • Sudipta Saha
Research Article
  • 170 Downloads

Abstract

The present study was undertaken to improve rosuvastatin (RSV) bioavailability and pharmacological response through formation of SNES using Perilla frutescens oil as lipid carrier. The composition of oil was estimated by fatty acid methyl ester (FAME) analysis using gas chromatography. Solubility of RSV in Perilla frutescens oil and Cremophor EL was 25.0 ± 3.0 and 60.0 ± 5.0 mg/mL, respectively. Later, nanophasic maps and a central composite design were employed to determine the maximum nanoemulsion region and further optimize SNES in this study. Finally, the optimized formulation was evaluated in vitro and in vivo. FAME analysis revealed that PUFA content was 70.3% of total fatty acid. Optimized SNES formulation demonstrated particle size of 17.90 nm, dissolution 98.80%, cloud point 45°C, emulsification time 2 min, and viscosity 241.41 ± 5.52 cP. The hypolipidemic property of SNES was further explored using Triton X-100-induced hyperlipidemic rat model, and there were reductions of serum cholesterol, triglyceride, and LDL and VLDL levels in the SNES-treated group as compared to the toxic control. Pharmacokinetic study of SNES revealed significantly higher C max (60.13 ± 25.43 ng/mL) and AUC0–∞ (6195 ± 42.38 ng h/mL) vis-à-vis marketed tablet (284.80 ± 13.44 ng/mL, 3131.72 ± 51.93 ng h/mL, respectively). RSV was successfully incorporated into ω-3 fatty acid-based SNES with improved pharmacokinetic parameters (~ 2-fold improved bioavailability) and better hypolipidemic properties, owing to the synergistic effects of hepatic lipid regulation itself. The results clearly explicated that ω-3 fatty acid-based SNES effectively enhanced bioavailability and pharmacological responses of RSV, suggesting that these formulations may be useful as alternative for hyperlipidemia treatment in future drug design perspective.

KEY WORDS

rosuvustatin self-nanoemulsifying system ω-3 fatty acid hypolipidemic action Perilla frutescens oil 

Notes

Acknowledgements

The authors acknowledge the kind support of M/s IPCA Pharmaceuticals Pvt. Ltd., Mumbai and M/s BASF, Germany, for providing the ex gratis samples. The authors also acknowledge the SAIF Department, Babasaheb Bhimrao Ambedkar University for providing some evaluation facilities for this research work.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12249_2017_933_MOESM1_ESM.jpg (25 kb)
Suppl. Fig. 1A FTIR Spectrum of Rosuvastatin (JPEG 24 kb)
12249_2017_933_MOESM2_ESM.jpg (23 kb)
Suppl. Fig. 1B FTIR Spectrum of Cremophor EL (JPEG 22 kb)
12249_2017_933_MOESM3_ESM.jpg (33 kb)
Suppl. Fig. 1C FTIR Spectra of Perilla frutescens oil (JPEG 33 kb)
12249_2017_933_MOESM4_ESM.jpg (12 kb)
Suppl. Fig. 1D FTIR Spectra of rosuvastatin loaded SNES (JPEG 11 kb)
12249_2017_933_MOESM5_ESM.jpg (147 kb)
Suppl. Fig. 2 Standard HPLC chromatogram of Rosuvastatin with internal standard (Atorvastatin 100 ng/ml) in rat plasma (JPEG 147 kb)

References

  1. 1.
    Benito-Gallo P, Marlow M, Zann V, Scholes P, Gershkovich P. Linking in vitro lipolysis and microsomal metabolism for the quantitative prediction of oral bioavailability of BCS II drugs administered in lipidic formulations. Mol Pharm. 2016;13(10):3526–40.  https://doi.org/10.1021/acs.molpharmaceut.6b00597.CrossRefPubMedGoogle Scholar
  2. 2.
    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(5):544–63.  https://doi.org/10.2174/1567201812666150227125639.CrossRefPubMedGoogle Scholar
  3. 3.
    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:S93–8.  https://doi.org/10.1016/S0928-0987(00)00167-6.CrossRefPubMedGoogle Scholar
  4. 4.
    Kale AA, Patravale VB. Design and evaluation of self-emulsifying drug delivery systems (SEDDS) of nimodipine. AAPS PharmSciTech. 2008;9(1):191–6.  https://doi.org/10.1208/s12249-008-9037-9.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Elgart A, Cherniakov I, Aldouby Y, Domb AJ, Hoffman A. Improved oral bioavailability of BCS class 2 compounds by self nano-emulsifying drug delivery systems (SNEDDS): the underlying mechanisms for amiodarone and talinolol. Pharm Res. 2013;30(12):3029–44.  https://doi.org/10.1007/s11095-013-1063-y.CrossRefPubMedGoogle Scholar
  6. 6.
    Singh B, Beg S, Khurana RK, Sandhu PS, Kaur R, Katare OP. Recent advances in self-emulsifying drug delivery systems (SEDDS). Crit Rev Ther Drug Carrier Syst. 2014;31(2):121–85.  https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2014008502.CrossRefPubMedGoogle Scholar
  7. 7.
    Beg S, Katare OP, Singh B. Formulation by design approach for development of ultrafine self-nanoemulsifying systems of rosuvastatin calcium containing long-chain lipophiles for hyperlipidemia management. Colloids Surf B Biointerfaces. 2017;159:869–79.  https://doi.org/10.1016/j.colsurfb.2017.08.050.CrossRefPubMedGoogle Scholar
  8. 8.
    Luvai A, Mbagaya W, Hall AS, Barth JH. Rosuvastatin: a review of the pharmacology and clinical effectiveness in cardiovascular disease. Clin Med Insights Cardiol. 2012;6:17–33.  https://doi.org/10.4137/CMC.S4324.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Martin PD, Warwick MJ, Dane AL, Hill SJ, Giles PB, Phillips PJ, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther. 2003;25(11):2822–35.  https://doi.org/10.1016/S0149-2918(03)80336-3.
  10. 10.
    Tripathi CB, Beg S, Kaur R, Shukla G, Bandopadhyay S, Singh B. Systematic development of optimized SNEDDS of artemether with improved biopharmaceutical and antimalarial potential. Drug Deliv. 2016;23(9):3209–23.  https://doi.org/10.3109/10717544.2016.1162876.CrossRefPubMedGoogle Scholar
  11. 11.
    Singh M, Kanoujia J, Singh P, Tripathi CB, Arya M, Parashar P, et al. Development of an α-linolenic acid containing soft nanocarrier for oral delivery: in vitro and in vivo evaluation. RSC Adv. 2016;6(81):77590–602.  https://doi.org/10.1039/C6RA15166C.
  12. 12.
    Khattab A, Hassanin L, Zaki N. Self-nanoemulsifying drug delivery system of coenzyme (Q10) with improved dissolution, bioavailability, and protective efficiency on liver fibrosis. AAPS PharmSciTech. 2017;18(5):1657–72.  https://doi.org/10.1208/s12249-016-0632-x.CrossRefPubMedGoogle Scholar
  13. 13.
    Yu H, Qiu JF, Ma LJ, Hu YJ, Li P, Wan JB. Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional edible-medicinal herb in China. Food Chem Toxicol. 2016;S0278-6915(16):30439–2.Google Scholar
  14. 14.
    Dubois V, Breton S, Linder M, Fanni J, Parmentier M. Fatty acid profiles of 80 vegetable oils with regard to their nutritional potential. Eur J Lipid Sci Technol. 2007;109(7):710–32.  https://doi.org/10.1002/ejlt.200700040.CrossRefGoogle Scholar
  15. 15.
    Ferrazzi P, Vercelli M, Chakir A, Romane A, Mattana M, Consonni R. Pollination effects on antioxidant content of Perilla frutescens seeds analysed by NMR spectroscopy. Nat Prod Res. 2017;20:1–7.CrossRefGoogle Scholar
  16. 16.
    Scorletti E, Byrne CD. Omega-3 fatty acids, hepatic lipid metabolism, and nonalcoholic fatty liver disease. Annu Rev Nutr. 2013;33(1):231–48.  https://doi.org/10.1146/annurev-nutr-071812-161230.CrossRefPubMedGoogle Scholar
  17. 17.
    Asif M. Health effects of omega-3,6,9 fatty acids: Perilla frutescens is a good example of plant oils. Orient Pharm Exp Med. 2011;11(1):51–9.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Peirett PG. Fatty acid content and chemical composition of vegetative parts of Perilla (Perilla frutescens) after different growth lengths. Res J Med Plants. 2011;5:72–8.CrossRefGoogle Scholar
  19. 19.
    Calder PC. n-3 Fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clin Sci (Lond). 2004;107(1):1–11.  https://doi.org/10.1042/CS20040119.CrossRefGoogle Scholar
  20. 20.
    Yu H, Qiu JF, Ma LJ, Hu YJ, Li P, Wan JB. Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional edible-medicinal herb in China. Food Chem Toxicol. 2017;108(Pt B):375–91.CrossRefPubMedGoogle Scholar
  21. 21.
    Porter CJ, Pouton CW, Cuine JF, Charman WN. Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev. 2008;60(6):673–91.  https://doi.org/10.1016/j.addr.2007.10.014.CrossRefPubMedGoogle Scholar
  22. 22.
    Weerapol Y, Limmatvapirat S, Kumpugdee-Vollrath M, Sriamornsak P. Spontaneous emulsification of nifedipine-loaded self-nanoemulsifying drug delivery system. AAPS PharmSciTech. 2015;16(2):435–43.  https://doi.org/10.1208/s12249-014-0238-0.CrossRefPubMedGoogle Scholar
  23. 23.
    Singh M, Ganggwar N, Parashar P, Tripathi CB, Arya M, Saraf SA, et al. Topical delivery of fluconazole via microemulsion incorporated hydrogel for the management of fungal dermatophytosis. Curr Drug Ther. 2016;11(2):129–41.  https://doi.org/10.2174/1574885511666160822143148.
  24. 24.
    Folch J, Lees M, Sloane Stanley GHA. Simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem. 1957;226(1):497–509.PubMedGoogle Scholar
  25. 25.
    Liu KS. Preparation of fatty acid methyl esters for gas-chromatographic analysis of lipids in biological materials. J Am Oil Chem Soc. 1994;71(11):1179–87.  https://doi.org/10.1007/BF02540534.CrossRefGoogle Scholar
  26. 26.
    Singh B, Kapil R, Nandi M, Ahuja N. Developing oral drug delivery systems using formulation by design: vital precepts, retrospect and prospects. Expert Opin Drug Deliv. 2011;8(10):1341–60.  https://doi.org/10.1517/17425247.2011.605120.CrossRefPubMedGoogle Scholar
  27. 27.
    Abo Enin HA. Self-nanoemulsifying drug-delivery system for improved oral bioavailability of rosuvastatin using natural oil antihyperlipdemic. Drug Dev Ind Pharm. 2015;41(7):1047–56.  https://doi.org/10.3109/03639045.2014.983113.CrossRefPubMedGoogle Scholar
  28. 28.
    Kumar TR, Shitut NR, Kumar PK, Vinu MC, Kumar VV, Mullangi R, et al. Determination of rosuvastatin in rat plasma by HPLC: validation and its application to pharmacokinetic studies. Biomed Chromatogr. 2006;20(9):881–7.  https://doi.org/10.1002/bmc.611.CrossRefPubMedGoogle Scholar
  29. 29.
    Singh B, Bandopadhyay S, Kapil R, Singh R, Katare OP. Self-emulsifying drug delivery systems (SEDDS): formulation development, characterization, and applications. Crit Rev Ther Drug Carrier Syst. 2009;26(5):427–521.  https://doi.org/10.1615/CritRevTherDrugCarrierSyst.v26.i5.10.CrossRefPubMedGoogle Scholar
  30. 30.
    Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176(8):1113–20.  https://doi.org/10.1503/cmaj.060963.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci. 2003;18(2):113–20.CrossRefPubMedGoogle Scholar
  32. 32.
    Weintraub MS, Zechner R, Brown A, Eisenberg S, Breslow JL. Dietary polyunsaturated fats of the W-6 and W-3 series reduce postprandial lipoprotein levels. Chronic and acute effects of fat saturation on postprandial lipoprotein metabolism. J Clin Invest. 1988;82(6):1884–93.  https://doi.org/10.1172/JCI113806.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Bordin P, Bodamer OA, Venkatesan S, Gray RM, Bannister PA, Halliday D. Effects of fish oil supplementation on apolipoprotein B100 production and lipoprotein metabolism in normolipidaemic males. Eur J Clin Nutr. 1998;52(2):104–9.  https://doi.org/10.1038/sj.ejcn.1600522.CrossRefPubMedGoogle Scholar
  34. 34.
    Chan DC, Watts GF, Barrett PH, Beilin LJ, Mori TA. Effect of atorvastatin and fish oil on plasma high-sensitivity C-reactive protein concentrations in individuals with visceral obesity. Clin Chem. 2002;48(6):877–83.PubMedGoogle Scholar
  35. 35.
    Al-Kuraishy HM, Al-Gareeb AI. Effects of rosuvastatin alone or in combination with omega-3 fatty acid on adiponectin levels and cardiometabolic profile. J Basic Clin Pharm. 2016;8(1):8–14.  https://doi.org/10.4103/0976-0105.195080.CrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Mindrescu C, Gupta RP, Hermance EV, DeVoe MC, Soma VR, Coppola JT, et al. Omega-3 fatty acids plus rosuvastatin improves endothelial function in South Asians with dyslipidemia. Vasc Health Risk Manag. 2008;4(6):1439–47.  https://doi.org/10.2147/VHRM.S4001.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Gao F, Zhang Z, Bu H, Huang Y, Gao Z, Shen J, et al. Nanoemulsion improves the oral absorption of candesartan cilexetil in rats: performance and mechanism. J Control Release. 2011;149(2):168–74.  https://doi.org/10.1016/j.jconrel.2010.10.013.
  38. 38.
    Hu L, Wu H, Niu F, Yan C, Yang X, Jia Y. Design of fenofibrate microemulsion for improved bioavailability. Int J Pharm. 2011;420(2):251–5.  https://doi.org/10.1016/j.ijpharm.2011.08.043.CrossRefPubMedGoogle Scholar
  39. 39.
    Singh M, Kanoujia J, Singh P, Tripathi CB, Arya M, Parashar P, et al. Development of an a-linolenic acid containing soft nanocarrier for oral delivery part II: buccoadhesive gel. RSC Adv. 2016;6(103):101602–12.  https://doi.org/10.1039/C6RA20896G.
  40. 40.
    Singh AP, Saraf SK, Saraf SASLN. Approach for nose-to-brain delivery of alprazolam. Drug Deliv Transl Res. 2012;2(6):498–507.  https://doi.org/10.1007/s13346-012-0110-2.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Chandra Bhushan Tripathi
    • 1
  • Neha Gupta
    • 1
  • Pranesh Kumar
    • 1
  • Ashok Kumar Singh
    • 1
  • Vinit Raj
    • 1
  • Poonam Parashar
    • 1
  • Mahendra Singh
    • 1
  • Jovita Kanoujia
    • 1
  • Malti Arya
    • 1
  • Shubhini A Saraf
    • 1
  • Sudipta Saha
    • 1
  1. 1.Department of Pharmaceutical SciencesBabasaheb Bhimrao Ambedkar UniversityLucknowIndia

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