SUSTAINED RELEASE TABLETS OF SORAFENIB-SILIBININ COMBINATIONS FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA
Keywords:Sustained release, Pullulan, Combinational treatment, Silibinin, Silymarin, Sorafenib, Hepatocellular Carcinoma
Objective: The aim of this study was to develop polymer coated sustained release tablet using sorafenib and silibinin combination for the treatment of hepatocellular carcinoma.
Methods: The qualitative analysis such as weight variation, friability, hardness, interaction studies, disintegration and in vitro release were performed to validate formulated tablets. We have maintained the acceptable official limits for weight variation, friability, hardness and disintegration time according to prescribed pharmacopoeial recommendation. In vitro drug release studies were performed using USP-II (paddle type) dissolution apparatus. The MTT assay was performed for assessment of Cell viability of drug combination for tablet formulation. Molecular docking studies have been performed to determine the combinatorial mode of action for the tablet formulation.
Results: Friability and weight variation were less than 1% for each formulation, which were within range of prescribed pharmacopoeial recommendation. The hardness of 20 tablets showed 5-6.5Kg/cm2 for all formulations 5-6.5Kg/cm2. The optimized formulation resulted in 98% drug release after 28 h. The present study reports the synergistic effects of drug combination to inhibit cell growth in HepG2 cell line. Molecular docking studies showed that sorafenib has high binding affinity for B-Raf vascular endothelial growth factor receptor Î² and protein kinase B. Silibinin showed binding affinity with MAP kinase-11, protein phosphatase 2 A and tankyrase.
Conclusion: The present study reports for the first time a novel formulation for sustained release and reduced toxicity of sorafenib with enhanced inhibitory effect of the drug combination on cancerous hepatic cell line as well collaborative mechanism of action for the formulation.
Zhu RX, Seto WK, Lai CL, Yuen MF. Epidemiology of hepatocellular carcinoma in the asia-pacific region. Gut Liver 2016;10:332.
Yang X, Zhang XF, Lu X, Jia HL, Liang L, Dong QZ, et al. MicroRNAâ€26a suppresses angiogenesis in human hepatocellular carcinoma by targeting hepatocyte growth factorâ€cMet pathway. Hepatology 2014;59:1874-85.
Malik S, Bhatnagar S, Chaudhary N, Katare DP, Jain S. DEN+2-AAF-induced multistep hepatotumorigenesis in Wistar rats: supportive evidence and insights. Protoplasma 2013;250:175-83.
Qun W, Tao Y, Yi D, Weijun L, Fu W. Effective personalized treatment of advanced hepatic carcinoma based on sorafenib. J Integr Oncol 2016;5:2.
Van Malenstein H, Dekervel J, Verslype C, Van Cutsem E, Windmolders P, Nevens F, et al. Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. Cancer Lett 2013;329:74-83.
Hellerbrand C, Schattenberg JM, Peterburs P, Lechner A, Brignoli R. The potential of silymarin for the treatment of hepatic disorders. Clin Phytosci 2016;2:1.
Lu K, Bhat M, Basu S. Plants and their active compounds: natural molecules to target angiogenesis. Angiogenesis 2016;19:287-95.
Zhang Z, Niu B, Chen J, He X, Bao X, Zhu J, et al. The use of lipid-coated nanodiamond to improve bioavailability and efficacy of sorafenib in resisting metastasis of gastric cancer. Biomaterials 2014;35:4565-72.
Wang XQ, Zhang Q. pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs. Eur J Pharm Biopharm 2012;82:219-29.
Gajjar DG PR, Patel VA, Patel PK. Novel hydroxyl terminated dendrimers as potential drug carriers: sustained release, hemolysis and cytotoxicity study. Int J Appl Pharm 2015;7:5-9.
Carpenter MK. Design of oral sustain release drug delivery of quetiapine fumarate. J Drug Discovery Ther 2014;2:7-11.
Boateng J, Okeke O, Khan S. Polysaccharide based formulations for mucosal drug delivery: a review. Curr Pharm Des 2015;21:4798-821.
Pai GK, Reddy SM. Design, fabrication and evaluation of ss 316 punch die set for accurate sizing of sodium cromoglycate ocular inserts. Int J Pharm Pharm Sci 2014;6:244-7.
Rekha M, Sharma CP. Pullulan as a promising biomaterial for biomedical applications: a perspective. Trends Biomater Artif Organs 2007;20:116-21.
Prajapati VD, Jani GK, Khanda SM. Pullulan: an exopolysaccharide and its various applications. Carbohydr Polym 2013;95:540-9.
Singh RS, Kaur N, Kennedy JF. Pullulan and pullulan derivatives as promising biomolecules for drug and gene targeting. Carbohydr Polym 2015;123:190-207.
Dragojevic S, Ryu JS, Raucher D. Polymer-based prodrugs: improving tumor targeting and the solubility of small molecule drugs in cancer therapy. Molecules 2015;20:21750-69.
K Maurya A, Singh M, Dubey V, Srivastava S, Luqman S, U Bawankule D. Î±-(-)-bisabolol reduces pro-inflammatory cytokine production and ameliorates skin inflammation. Curr Pharm Biotechnol 2014;15:173-81.
Wei JC, Qu K, Wang ZX, Wu QF, Zhang LQ, Pang Q, et al. Sorafenib inhibits proliferation and invasion of human hepatocellular carcinoma cells via up-regulation of p53 and suppressing FoxM1. Acta Pharmacol Sin 2015;36:241-51.
Surai PF. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants 2015;4:204-47.
Mishra S, Katare D. Synergistic combination for chemoprevention of hepatocellular carcinoma: an inâ€silico and inâ€vitro approach. Basic Clin Pharmacol Toxicol 2017;120:532-40.
Gazak R, Walterova D, Kren V. Silybin and silymarin-new and emerging applications in medicine. Curr Med Chem 2007;14:315-38.
Tres F, Treacher K, Booth J, Hughes LP, Wren SA, Aylott JW, et al. Indomethacin-kollidon VA64 extrudates: a mechanistic study of pH-dependent controlled release. Mol Pharm 2016;13:1166-75.
Na K, Lee ES, Bae YH. Adriamycin loaded pullulan acetate/sulfonamide conjugate nanoparticles responding to tumor pH: pH-dependent cell interaction, internalization and cytotoxicity in vitro. J Controlled Release 2003;87:3-13.
Gu HR, Park SC, Choi SJ, Lee JC, Kim YC, Han CJ, et al. Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells. Clin Mol Hepatol 2015;21:49-59.
Shoichet BK, McGovern SL, Wei B, Irwin JJ. Lead discovery using molecular docking. Curr Opin Chem Biol 2002;6:439-46.
Mani RJ, Mittal K, Mishra S, Kharkwal H, Ahmad S, Katare DP. In silico approach to evaluate the efficacy of dietary flavonoids and their role in alzheimer's disease. Int J Pharm Sci Rev Res 2015;34:94-102.
Huang SMA, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009;461:614-20.
Stamos JL, Weis WI. The Î²-catenin destruction complex. Cold Spring Harbor Perspect Biol 2013;5:a007898.
Li L, Zeng J, Gao Y, He D. Targeting silibinin in the antiproliferative pathway. Expert Opin Investig Drugs 2010;19:243-55.
Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099-109.