A Novel Self-Microemulsifying System for the Simultaneous Delivery and Enhanced Oral Absorption of Curcumin and Resveratrol

Abstract

The use of curcumin and resveratrol in combination has now become increasingly of interest because of their synergistic effects as therapeutic agents for various diseases, especially cancer. To overcome the poor oral bioavailability of both compounds and improve patient compliance, a novel self-microemulsifying formulation containing curcumin together with resveratrol was developed. Capryol 90, Cremophor EL, and Labrasol were selected as the oil, surfactant, and co-surfactant in the formulation, respectively, based on the solubility study of both compounds. More than 70 % and 80 % of curcumin and resveratrol, respectively, were released in 20 min. The formulation formed a fine oil in water microemulsion with droplet sizes in aqueous media of 15–20 nm. In addition, the formulation containing curcumin and resveratrol showed greater antioxidant activity than that of the formulations with individual compounds, while the cytotoxic activity against HT-29 of the co-formulation (IC₅₀ = 18.25 µM; curcumin and resveratrol in the ratio 1 : 1) was less than the formulation with only curcumin (IC₅₀ = 30.1 µM) and only resveratrol (IC₅₀ = 25.4 µM). After oral administration to rabbits, the self-microemulsifying formulation containing curcumin together with resveratrol increased the total plasma concentrations of curcumin and resveratrol by 10-fold and 6-fold, respectively, compared to the unformulated combination. This study clearly demonstrated the potential use of the self-microemulsifying formulation for co-delivery, and enhanced oral absorption of poorly water-soluble natural compounds. In addition, the combination was found to produce synergistic antioxidant activity and cytotoxicity against HT-29 cells.

Key words

self-microemulsifying drug delivery system - curcumin - resveratrol - oral absorption - co-delivery

• References

• 1 Bayet-Robert M, Kwiatkowski F, Leheurteur M, Gachon F, Planchat E, Abrial C, Mouret-Reynier MA, Durando X, Barthomeuf C, Chollet P. Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol Ther 2010; 9: 8-14
• 2 Chen Y, Tseng SH, Lai HS, Chen WJ. Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery 2004; 136: 57-66
• 3 Majumdar AP, Banerjee S, Nautiyal J, Patel BB, Patel V, Du J, Yu Y, Elliott AA, Levi E, Sarkar FH. Curcumin synergizes with resveratrol to inhibit colon cancer. Nutr Cancer 2009; 61: 544-553
• 4 Singh SK, Verma PR, Razdan B. Glibenclamide-loaded self-nanoemulsifying drug delivery system: development and characterization. Drug Dev Ind Pharm 2010; 36: 933-945
• 5 Pathak A, Jain V, Nagariya AK, Singh R, Nayak S, Bansal P, Gupta V, Kumar S, Singh H. Recent advances in self emulsifying drug delivery system – A review. Drug Inv Today 2010; 2: 123-129
• 6 Rajesh BV, Reddy TK, Srikanth G, Mallikarjun V, Nivethithai P. Lipid based self-emulsifying drug delivery system (SEDDS) for poorly water-soluble drugs: A review. J Global Pharma Tech 2009; 2: 47-55
• 7 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: 475-485
• 8 Haukvik T, Bruzell E, Kristensen S, Tønnesen HH. Photokilling of bacteria by curcumin in selected polyethylene glycol 400 (PEG 400) preparations studies on curcumin and curcuminoids, XLI. Pharmazie 2010; 65: 600-606
• 9 Gaumet M, Gurny R, Delie F. Localization and quantification of biodegradable particles in an intestinal cell model: the influence of particle size. Eur J Pharm Sci 2009; 36: 465-473
• 10 Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated curcumin. In vitro and in vivo effects on proliferation, apoptosis, signaling and angiogenesis. Cancer 2005; 106: 1322-1330
• 11 Queimada AJ, Mota FL, Pinho SP, Macedo EA. Solubilities of biologically active phenolic compounds: measurements and modeling. J Phys Chem B 2009; 113: 3469-3476
• 12 Lestari ML, Indrayanto G. Curcumin. Profiles Drug Subst Excip Relat Methodol 2014; 39: 113-204
• 13 Yamaguchi JY, Nishimura Y, Kanada A, Kobayashi M, Mishima K, Tatsuishi T, Iwase K, Oyama Y. Cremophor EL, a non-ionic surfactant, promotes Ca(2+)-dependent process of cell death in rat thymocytes. Toxicology 2005; 211: 179-186
• 14 Rice-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 1996; 20: 933-956
• 15 Aggarwal BB, Bhatt ID, Ichikawa H, Ahn KS, Sethi G, Sandur SK, Sundaram C, Seeram N, Shishodia S. Curcumin – biological and medicinal properties. In: Ravindran PN, Nirmal Babu K, Sivaraman K. editors Turmeric: The genus Curcuma . Boca Raton, FL: CRC Press; 2007: 297-368
• 16 Smoliga JM, Blanchard O. Enhancing the delivery of resveratrol in humans: if low bioavailability is the problem, what is the solution?. Molecules 2014; 19: 17154-17172
• 17 Singh AK, Chaurasiy A, Awasthi A, Mishra G, Asati D, Khar RK, Mukherjee R. Oral bioavailability enhancement of exemestane from self-microemulsifying drug delivery system (SMEDDS). AAPS PharmSciTech 2009; 10: 906-916
• 18 Narayanan KN, Nargi D, Randolph C, Narayanan BA. Liposome encapsulation of curcumin and resveratrol in combination reduces prostate cancer incidence in PTEN knockout mice. Int J Cancer 2009; 125: 1-8
• 19 Stagni G, Shukla C. Pharmacokinetics of methotrexate in rabbit skin and plasma after iv-bolus and iontophoretic administrations. J Control Release 2003; 93: 283-292