Development of phospholipid complex loaded self-microemulsifying drug delivery system to improve the oral bioavailability of resveratrol
Abstract
Aim: The aim of this study was to develop a formulation that combines a phospholipid complex (PC) and self-microemulsifying drug delivery system (SMEDDS) to improve the bioavailability of poorly water-soluble resveratrol (RES), called RPC-SMEDDS. Methods: RES-PC (RPC) and RPC-SMEDDS were optimized by orthogonal experiment and central composite design, respectively. The characteristics and mechanism of intestinal absorption were studied by Ussing chamber model. The pharmacokinetics was evaluated in rats. Results: RES was the substrate of MRP2 and breast cancer resistance protein (BCRP) rather than P-gp. The prepared RPC-SMEDDS prevented the efflux mediated by MRP2 and BCRP and improved the bioavailability of RES. Conclusion: These results suggested that the combination system of PC and SMEDDS was a promising method to improve the oral bioavailability of RES.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Grape chemistry and the significance of resveratrol: an overview. Pharm. Biol. 36(5), 8–13 (1998).
- 2. . An organ system approach to explore the antioxidative, anti-inflammatory, and cytoprotective actions of resveratrol. Oxid. Med. Cell. Longev. 2015, 803971 (2015).
- 3. Resveratrol encapsulation in core-shell biopolymer nanoparticles: impact on antioxidant and anticancer activities. Food Hydrocolloids 64, 157–165 (2017).
- 4. . Antioxidant activity of resveratrol ester derivatives in food and biological model systems. Food Chem. 261, 267–273 (2018).
- 5. . Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim. Biophys. Acta 1852(6), 1155–1177 (2015).
- 6. . The potential therapeutic benefit of resveratrol on Th17/Treg imbalance in immune thrombocytopenic purpura. Int. Immunopharmacol. 73, 181–192 (2019).
- 7. . The pharmacology of resveratrol in animals and humans. Biochim. Biophys. Acta 1852(6), 1071–1113 (2015).
- 8. . Resveratrol – a comprehensive review of recent advances in anticancer drug design and development. Eur. J. Med. Chem. 200 (2020).
- 9. . A theoretical basis for a biopharmaceutic drug classification – the correlation of in-vitro drug product dissolution and in-vivo bioavailability. Pharm. Res. 12(3), 413–420 (1995). • Explanation of the classification scheme of biopharmaceutics drug based on the solubility and bioavailability of drugs.
- 10. . Administration of resveratrol: what formulation solutions to bioavailability limitations? J. Control. Release 158(2), 182–193 (2012).
- 11. . Increasing solubility of poorly water soluble drug resveratrol by surfactants and cyclodextrins. Adv. Mater. Res. 418–420, 2231–2234 (2012).
- 12. . Encapsulation of bioactive compounds in nanoemulsion-based delivery systems. Proc. Food Sci. 1, 1666–1671 (2011).
- 13. Therapeutic efficacy of thermosensitive pluronic hydrogel for codelivery of resveratrol microspheres and cisplatin in the treatment of liver cancer ascites. Int. J. Pharm. 582, 119334 (2020).
- 14. . Novel resveratrol nanodelivery systems based on lipid nanoparticles to enhance its oral bioavailability. Int. J. Nanomedicine 8, 177–187 (2013).
- 15. . Effect of resveratrol incorporated in liposomes on proliferation and UV-B protection of cells. Int. J. Pharm. 363(1–2), 183–191 (2008).
- 16. Enhancing topical delivery of resveratrol through a nanosizing approach. Planta Med. 83(5), 476–481 (2017).
- 17. Preparation of a nanoscale dihydromyricetin–phospholipid complex to improve the bioavailability: in vitro and in vivo evaluations. Eur. J. Pharm. Sci. 138 (2019).
- 18. . Curcumin-phospholipid complex: preparation, therapeutic evaluation and pharmacokinetic study in rats. Int. J. Pharm. 330(1–2), 155–163 (2007).
- 19. . Process optimization, characterization and evaluation in vivo of oxymatrine–phospholipid complex. Int. J. Pharm. 387(1–2), 139–146 (2010).
- 20. . Dual strategies to improve oral bioavailability of oleanolic acid: enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes. Eur. J. Pharm. Biopharm. 99, 65–72 (2016).
- 21. . Microemulsions as carriers for drugs and nutraceuticals. Adv. Colloid Interface Sci. 128, 47–64 (2006).
- 22. Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. Int. J. Pharm. 274(1–2), 65–73 (2004).
- 23. . Preparation and bioavailability assessment of SMEDDS containing valsartan. AAPS PharmSciTech 11(1), 314–321 (2010).
- 24. . Self-microemulsifying drug delivery system of phillygenin: formulation development, characterization and pharmacokinetic evaluation. Pharmaceutics 12(2), 130 (2020).
- 25. . Novel Solid self-nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of olmesartan medoxomil: design, formulation, pharmacokinetic and bioavailability evaluation. Pharmaceutics 8(3), 20 (2016).
- 26. . Self-microemulsifying drug delivery system for camptothecin using new bicephalous heterolipid with tertiary-amine as branching element. Int. J. Pharm. 541(1–2), 48–55 (2018).
- 27. . Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. Eur. J. Pharm. Sci. 16(4–5), 237–246 (2002).
- 28. . The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system. Pharm. Res. 13(4), 528–534 (1996). •• Discusses surfactants in pharmaceutical formulations may enhance the intestinal absorption of some drugs by inhibiting the efflux system.
- 29. . Mechanistic roles of neutral surfactants on concurrent polarized and passive membrane transport of a model peptide in Caco-2 cells. J. Pharm. Sci. 86(7), 813–821 (1997).
- 30. . Solid self-microemulsifying dispersible tablets of celastrol: formulation development, charaterization and bioavailability evaluation. Int. J. Pharm. 472(1–2), 40–47 (2014).
- 31. . Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine. Int. J. Pharm. 167(1–2), 155–164 (1998).
- 32. Preparation and evaluation of self-microemulsifying drug delivery system of baicalein. Fitoterapia 83(8), 1532–1539 (2012).
- 33. Preparation and evaluation of kaempferol-phospholipid complex for pharmacokinetics and bioavailability in SD rats. J. Pharm. Biomed. Anal. 114, 168–175 (2015).
- 34. . Resveratrol encapsulation: designing delivery systems to overcome solubility, stability and bioavailability issues. Trends Food Sci. Tech. 38(2), 88–103 (2014).
- 35. Development and evaluation of docetaxel-phospholipid complex loaded self-microemulsifying drug delivery system: optimization and in vitro/ex vivo studies. Pharmaceutics 12(6), 544 (2020).
- 36. . Formulation of self-microemulsifying drug delivery system (SMEDDS) by D-optimal mixture design to enhance the oral bioavailability of a new cathepsin K inhibitor (HL235). Int. J. Pharm. 573, 118772 (2020).
- 37. . Solidified phospholipid-TPGS as an effective oral delivery system for improving the bioavailability of resveratrol. J. Drug Deliv. Sci. Technol. 52, 769–777 (2019).
- 38. Design and development of permeation enhancer containing self-nanoemulsifying drug delivery system (SNEDDS) for ceftriaxone sodium improved oral pharmacokinetics. J. Mol. Liq. 289, 111098 (2019).
- 39. . Self microemulsifying drug delivery system of lurasidone hydrochloride for enhanced oral bioavailability by lymphatic targeting: in vitro, Caco-2 cell line and in vivo evaluation. Eur. J. Pharm. Sci. 138, 105027 (2019).
- 40. . Resveratrol - A multitargeted agent for age-associated chronic diseases. Cell Cycle 7(8), 1020–1035 (2008).
- 41. . Bioavailability of resveratrol. Ann. NY Acad. Sci. 1215, 9–15 (2011).
- 42. A review on phospholipids and their main applications in drug delivery systems. Asian J. Pharm. Sci. 10(2), 81–98 (2015).
- 43. . Recent advances and future prospects of phyto–phospholipid complexation technique for improving pharmacokinetic profile of plant actives. J. Control. Release 168(1), 50–60 (2013).
- 44. . Biodegradable nanoparticles loaded with insulin–phospholipid complex for oral delivery: preparation, in vitro characterization and in vivo evaluation. J. Control. Release 114(2), 242–250 (2006).
- 45. A dabigatran etexilate phospholipid complex nanoemulsion system for further oral bioavailability by reducing drug-leakage in the gastrointestinal tract. Nanomedicine 14(4), 1455–1464 (2018).
- 46. . Enhanced therapeutic potential of naringenin-phospholipid complex in rats. J. Pharm. Pharmacol. 58(9), 1227–1233 (2006).
- 47. . Long chain lipid based tamoxifen NLC. Part I: preformulation studies, formulation development and physicochemical characterization. Int. J. Pharm. 454(1), 573–583 (2013).
- 48. . Preparation and in vitro characterization of a eutectic based semisolid self-nanoemulsified drug delivery system (SNEDDS) of ubiquinone: mechanism and progress of emulsion formation. Int. J. Pharm. 235(1–2), 247–265 (2002).
- 49. . Polymeric micelles and alternative nanonized delivery vehicles for poorly soluble drugs. Int. J. Pharm. 453(1), 198–214 (2013).
- 50. . Study of cosurfactant effect on nanoemulsifying area and development of lercanidipine loaded (SNEDDS) self nanoemulsifying drug delivery system. Colloid Surface B 86(2), 327–338 (2011).
- 51. . Role of components in the formation of self-microemulsifying drug delivery systems. Indian J. Pharm. Sci. 77(3), 249–257 (2015).
- 52. . Food-grade nanoemulsions: formulation, fabrication, properties, performance, biological fate, and potential toxicity. Crit. Rev. Food Sci. 51(4), 285–330 (2011).
- 53. . Double-coated poly (butylcynanoacrylate) nanoparticulate delivery systems for brain targeting of dalargin via oral administration. J. Pharm. Sci. 94(6), 1343–1353 (2005).
- 54. . Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J. Pharm. Sci. 10(1), 13–23 (2015).
- 55. Regional levels of drug transporters along the human intestinal tract: co-expression of ABC and SLC transporters and comparison with Caco-2 cells. Eur. J. Pharm. Sci. 29(3–4), 269–277 (2006).
- 56. . The bioavailability and distribution of trans-resveratrol are constrained by ABC transporters. Arch Biochem Biophys 527(2), 67–73 (2012). •• Representative review paper on the role of ABC transporters in the intestinal absorption of trans-resveratrol.
- 57. . Paeonol nanoemulsion for enhanced oral bioavailability: optimization and mechanism. Nanomedicine (Lond). 13(3), 269–282 (2018).