Contribution of Formulation and Excipients Towards Enhanced Permeation of Curcumin

Abstract

Curcumin (CRM) (CAS number 458-37-07), a naturally-occurring molecule, has diverse pharmacological actions. Recently our research group demonstrated that poor permeability also contributes to its poor oral bioavailability. A self nano-emulsifying drug delivery system (CRM SNEDDS) consisting of Labrasol, Gelucire 44/14, Vitamin E TPGS and PEG 400 was designed and provided 16 times improvement in oral bioavailability in rats, at a dose of 250 mg/kg body weight. Caco-2 cell transport studies were conducted for CRM SNEDDS and CRM in the presence of individual excipients, to determine the extent of improvement in permeability. P_app values for CRM, CRM SNEDDS and CRM in combination with 4 individual excipients were calculated. Transepithelial electrical resistance value was assessed to evaluate the cell morphology and the cellular tight junctions. Permeation of a transcellular marker, Lucifer Yellow was used as a marker to assess monolayer integrity. The tested excipient concentrations were found to be non-toxic to the cell monolayer in 2 h incubation. Results showed that the P_app increased 6.35 times for curcumin in CRM SNEDDS as compared to CRM. Individual excipients enhanced permeation from 1.97 to 6.35 times, with Labrasol showing the highest enhancement of 6.35 times.

Key words

curcumin - oral bioavailability - permeability

• References

• 1 Maheshwari RK, Singh AK, Gaddipati J et al. Multiple biological activities of curcumin: A short review. Life Sci 2006; 78: 2081-2087
• 2 Kawamori T, Lubet R, Steele VE et al. Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer. Cancer Res 1999; 59: 597-601
• 3 Sharma S, Kulkarni SK, Chopra K. Curcumin, the active principle of turmeric (Curcuma longa), ameliorates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol 2006; 33: 940-945
• 4 Cole GM, Teter B, Frautschy SA. Neuroprotective effects of curcumin. Adv Exp Med Biol 2007; 595: 197-212
• 5 Wang Q, Sun AY, Simonyi A et al. Neuroprotective mechanisms of curcumin against cerebral ischemia-induced neuronal apoptosis and behavioral deficits. J Neurosci Res 2005; 82: 138-148
• 6 Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res 2003; 23: 363-398
• 7 Gao X, Kuo J, Jiang H et al. Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro. Biochem Pharmacol 2004; 68: 51-61
• 8 Varalakshmi C, Ali AM, Pardhasaradhi BVV et al. Immunomodulatory effects of curcumin: In-vivo. Int Immunopharmacol 2008; 8: 688-700
• 9 Tonnesen HH, Masson M, Loftsson T. Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. Int J Pharm 2002; 244: 127-135
• 10 Wang Y-J, Pan M-H, Cheng A-L et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal 1996; 15: 1867-1876
• 11 Garcea G, Jones DJ, Singh R et al. Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration. Br J Cancer 2004; 90: 1011-1015
• 12 Sou K, Inenaga S, Takeoka S et al. Loading of curcumin into macrophages using lipid-based nanoparticles. Int J Pharm 2008; 352: 287-293
• 13 Tiyaboonchai W, Tungpradit W, Plianbangchang P. Formulation and characterization of curcuminoids loaded solid lipid nanoparticles. Int J Pharm 2007; 337: 299-306
• 14 Bisht S, Feldmann G, Soni S et al. Polymeric nanoparticle-encapsulated curcumin (“nanocurcumin”): a novel strategy for human cancer therapy. J Nanobiotechnology 2007; 5: 3
• 15 Paradkar A, Ambike AA, Jadhav BK et al. Characterization of curcumin-PVP solid dispersion obtained by spray drying. Int J Pharm 2004; 271: 281-286
• 16 Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer 2005; 104: 1322-1331
• 17 Kumar V, Lewis SA, Mutalik S et al. Biodegradable microspheres of curcumin for treatment of inflammation. Indian J Physiol Pharmacol 2002; 46: 209-217
• 18 Gershanik T, Benzeno S, Benita S. Interaction of a self-emulsifying lipid drug delivery system with the everted rat intestinal mucosa as a function of droplet size and surface charge. Pharm Res 1998; 15: 863-869
• 19 Wang Z, Sun J, Wang Y et al. Solid self-emulsifying nitrendipine pellets: preparation and in vitro/in vivo evaluation. Int J Pharm 383: 1-6
• 20 Buyukozturk F, Benneyan JC, Carrier RL. Impact of emulsion-based drug delivery systems on intestinal permeability and drug release kinetics. J Control Release 2010; 142: 22-30
• 21 Volpe DA, Faustino PJ, Ciavarella AB et al. Classification of Drug Permeability with a Caco-2 Cell Monolayer Assay. Clinical Research and Regulatory Affairs 2007; 24: 39-47
• 22 Hou X-L, Takahashi K, Kinoshita N et al. Possible inhibitory mechanism of Curcuma drugs on CYP3A4 in 1[alpha], 25 dihydroxyvitamin D3 treated Caco-2 cells. Int J Pharm 2007; 337: 169-177
• 23 Wahlang B, Pawar YB, Bansal AK. Identification of permeability-related hurdles in oral delivery of curcumin using the Caco-2 cell model. Eur J Pharm Biopharm 2010; In Press
• 24 Schmiedlin-Ren P, Thummel KE, Fisher JM et al. Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1alpha,25-dihydroxyvitamin D3. Mol Pharmacol 1997; 51: 741-754
• 25 Fisher JM, Wrighton SA, Watkins PB et al. First-pass midazolam metabolism catalyzed by 1alpha,25-dihydroxy vitamin D3-modified Caco-2 cell monolayers. J Pharmacol Exp Ther 1999; 289: 1134-1142
• 26 Koga K, Kawashima S, Murakami M. In vitro and in situ evidence for the contribution of Labrasol and Gelucire 44/14 on transport of cephalexin and cefoperazone by rat intestine. Eur J Pharm Biopharm 2002; 54: 311-318
• 27 Sachs-Barrable K, Lee S, Thamboo A et al. Influence of the lipid excipient, Gelucire 44/14, on P-glycoprotein (P-gp) activity in an intestinal endothelial cell line (Caco-2) www.aapsj.org/abstracts/AM_2006/staged/AAPS2006-000193
• 28 Chang T, Benet LZ, Hebert MF. The effect of water-soluble vitamin E on cyclosporine pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1996; 59: 297-303
• 29 Yu L, Bridgers A, Polli J et al. Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability. Pharm Res 1999; 16: 1812-1817
• 30 Brown JR, Collett JH, Attwood D et al. Influence of monocaprin on the permeability of a diacidic drug BTA-243 across Caco-2 cell monolayers and everted gut sacs. Int J Pharm 2002; 245: 133-142