COLON SPECIFIC DELIVERY OF COMBINATION OF 5-FLUOROURACIL AND CELECOXIB: PREPARATION, CHARACTERIZATION, AND IN VITRO CYTOTOXICITY ASSAY

  • VIKAS BANSAL Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Punjab, India.
  • ANJOO KAMBOJ Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Punjab, India.
  • JITENDER MADAN Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Punjab, India.

Abstract

Objective: 5-Fluorouracil (5-FU) and celecoxib (Cel) combination offered additive effect in the treatment of colon cancer. However, physicochemical and biopharmaceutical attributes of both drugs deliver suboptimal concentration at the site of action. The objective of the current study is the development of a microparticulate drug delivery system loaded with a combination of 5-FU and Cel to achieve prolonged drug delivery in colon cancer.


Methods: 5-FU and Cel combination were loaded in Eudragit coated chitosan (CH) microspheres (MSs) and characterized.


Results: The average particle size of the MSs was in the range of 2.7±0.9μm to 4.8±1.1μm. A substantial drug encapsulation efficiency of 71.30±2.3% as obtained for 5-FU as compared to 35.20±1.9% of Cel in the tailored microparticles. The drug loading capacity of 6.5 mg/10 mg and 2.3 mg/10 mg was obtained for 5-FU and Cel, respectively. By Eudragit S 100 (Ed) coating, significant pH-dependent release profile was achieved, and no drug release was observed in simulated gastric and intestinal fluids. The developed MSs exhibited the release of 92.1±2.9% of 5-FU in 8h whereas 18.9±0.7% Cel was found to be released from the developed MSs. The drug-loaded MSs exhibited appreciable potency against HT-29 cells with an IC50 value of 35.9 μM.


Conclusion: The results indicated that these microparticles are a promising vehicle for selectively targeting drugs to the colon in the chemotherapy of colon cancer.

Keywords: 5-Fluorouracil, Celecoxib, Chitosan, Eudragit coating, Colon targeting, Cytotoxicity.

Author Biographies

VIKAS BANSAL, Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Punjab, India.

Faculty

Chandigarh College of Pharmacy, Landran, Mohali-140307

ANJOO KAMBOJ, Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Punjab, India.

Professor

Chandigarh College of Pharmacy, Landran, Mohali-140307

JITENDER MADAN, Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Punjab, India.

Professor

Chandigarh College of Pharmacy, Landran, Mohali-140307

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7-30.
2. Patel MM. Getting into the colon: Approaches to target colorectal cancer. Expert Opin Drug Deliv 2014;11:1343-50.
3. Gulbake A, Jain A, Jain A, Jain A, Jain SK. Insight to drug delivery aspects for colorectal cancer. World J Gastroenterol 2016;22:582-99.
4. Gupta RA, Dubois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 2001;1:11-21.
5. Ashwanikumar N, Kumar NA, Nair SA, Kumar GV. Methacrylic-based nanogels for the pH-sensitive delivery of 5-fluorouracil in the colon. Int J Nanomedicine 2012;7:5769-79.
6. Zhang DQ, Guo Q, Zhu JH, Chen WC. Increase of cyclooxygenase-2 inhibition with celecoxib combined with 5-FU enhances tumor cell apoptosis and antitumor efficacy in a subcutaneous implantation tumor model of human colon cancer. World J Surg Oncol 2013;11:16.
7. Wacker A, Lersch C, Scherpinski U, Reindl L, Seyfarth M. High incidence of angina pectoris in patients treated with 5-fluorouracil. A planned surveillance study with 102 patients. Oncology 2003;65:108-12.
8. Jensen SA. On 5-fluorouracil therapy of colorectal cancer. Dan Med J 2013;60:B4603.
9. Giovannucci E, Rimm EB, Stampfer MJ, Colditz GA, Ascherio A, Willett WC, et al. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 1994;121:241-6.
10. Goldman AP, Williams CS, Sheng H, Lamps LW, Williams VP, Pairet M, et al. Meloxicam inhibits the growth of colorectal cancer cells. Carcinogenesis 1998;19:2195-9.
11. Rahman M, Selvarajan K, Hasan MR, Chan AP, Jin C, Kim J, et al. Inhibition of COX-2 in colon cancer modulates tumor growth and MDR-1 expression to enhance tumor regression in therapy-refractory cancers in vivo. Neoplasia 2012;14:624-33.
12. Steinbach G, Lynch PM, Phillips RK, Wallace MH, Hawk E, Gordon GB, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000;342:1946-52.
13. Ruiz JF, Kedziora K, Keogh B, Maguire J, Reilly M, Windle H, et al. A double prodrug for colon targeting of benzenesulfonamide COX-2 inhibitors. Bioorgan Med Chem Lett 2011;21:6636-40.
14. Finckh A, Aronson MD. Cardiovascular risks of cyclooxygenase-2 inhibitors: Where we stand now. Ann Intern Med 2005;142:212-4.
15. Lin C, Ng HL, Pan W, Chen H, Zhang G, Bian Z, et al. Exploring different strategies for efficient delivery of colorectal cancer therapy. Int J Mol Sci 2015;16:26936-52.
16. Rajesh K, Deveswaran R, Bharath S, Basavaraj BV. Development of mesalazine microspheres for colon targeting. Int J Appl Pharm 2017;9:1-9.
17. Jain A, Jain SK. Optimization of chitosan nanoparticles for colon tumors using experimental design methodology. Artif Cells Nanomed Biotechnol 2016;44:1917-26.
18. Shaima C, Moorthi PV, Kutty SN. In vitro anticancer activity of 5-fluorouracil coated chitosan nanoparticle. Int J Curr Pharm Res 2016;8:6-8.
19. Thakral NK, Ray AR, Majumdar DK. Eudragit S-100 entrapped chitosan microspheres of valdecoxib for colon cancer. J Mater Sci Mater Med 2010;21:2691-9.
20. Paharia A, Yadav AK, Rai G, Jain SK, Pancholi SS, Agrawal GP, et al. Eudragit-coated pectin microspheres of 5-fluorouracil for colon targeting. AAPS PharmSciTech 2007;8:12.
21. Raj BS, Nair RS, Samraj PI, Vidya. Formulation and evaluation of coated microspheres for colon targeting. J Appl Pharm Sci 2013;3:S68-74.
22. Jyoti K, Bhatia RK, Martis EA, Coutinho EC, Jain UK, Chandra R, et al. Soluble curcumin amalgamated chitosan microspheres augmented drug delivery and cytotoxicity in colon cancer cells: In vitro and in vivo study. Colloids Surf B Biointerfaces 2016;148:674-83.
23. Wang QS, Wang GF, Zhou J, Gao LN, Cui YL. Colon targeted oral drug delivery system based on alginate-chitosan microspheres loaded with icariin in the treatment of ulcerative colitis. Int J Pharm 2016;515:176-85.
24. Cerchiara T, Abruzzo A, di Cagno M, Bigucci F, Bauer-Brandl A, Parolin C, et al. Chitosan based micro-and nanoparticles for colon-targeted delivery of vancomycin prepared by alternative processing methods. Eur J Pharm Biopharm 2015;92:112-9.
25. Patel KS, Patel MB. Preparation and evaluation of chitosan microspheres containing nicorandil. Int J Pharm Investig 2014;4:32-7.
26. Garud N, Garud A. Preparation and in vitro evaluation of metformin microspheres using non-aqueous solvent evaporation technique. Trop J Pharm Res 2012;11:577-83.
27. Sareen R, Jain N, Rajkumari A, Dhar KL. PH triggered delivery of curcumin from eudragit-coated chitosan microspheres for inflammatory bowel disease: Characterization and pharmacodynamic evaluation. Drug Deliv 2016;23:55-62.
28. Kumar M, Awasthi R. Development of metronidazole-loaded colon-targeted microparticulate drug delivery system. Polim Med 2015;45:57-65.
29. Glavas Dodov M, Calis S, Crcarevska MS, Geskovski N, Petrovska V, Goracinova K, et al. Wheat germ agglutinin-conjugated chitosan-ca-alginate microparticles for local colon delivery of 5-FU: Development and in vitro characterization. Int J Pharm 2009;381:166-75.
30. Kotla NG, Gulati M, Singh SK, Shivapooja A. Facts, fallacies and future of dissolution testing of polysaccharide based colon-specific drug delivery. J Control Release 2014;178:55-62.
31. Sharma A, Jyoti K, Bansal V, Jain UK, Bhushan B, Madan J, et al. Soluble telmisartan bearing poly (ethylene glycol) conjugated chitosan nanoparticles augmented drug delivery, cytotoxicity, apoptosis and cellular uptake in human cervical cancer cells. Mater Sci Eng C Mater Biol Appl 2017;72:69-76.
32. Lim YJ, Rhee JC, Bae YM, Chun WJ. Celecoxib attenuates 5-fluorouracil-induced apoptosis in HCT-15 and HT-29 human colon cancer cells. World J Gastroenterol 2007;13:1947-52.
33. Saini J, Bansal V, Chandra A, Madan J, Jain UK, Chandra R, et al. Bleomycin sulphate loaded nanostructured lipid particles augment oral bioavailability, cytotoxicity and apoptosis in cervical cancer cells. Colloids Surf B Biointerfaces 2014;118:101-10.
34. Rai G, Yadav AK, Jain NK, Agrawal GP. Eudragit-coated dextran microspheres of 5-fluorouracil for site-specific delivery to colon. Drug Deliv 2016;23:328-37.
35. Chakra BK, Karan S, Das B, Debnath S, Chatterjee TK. A controlled release microsphere formulation of an anti-diabetic drug and characterization of the microsphere. Int J Pharm Pharm Sci 2018;10:30-8.
36. Arafat M. Approaches to achieve an oral controlled release drug delivery system using polymers: A recent review. Int J Pharm Pharm Sci 2015;7:16-21.
Statistics
23 Views | 107 Downloads
How to Cite
BANSAL, V., A. KAMBOJ, and J. MADAN. “COLON SPECIFIC DELIVERY OF COMBINATION OF 5-FLUOROURACIL AND CELECOXIB: PREPARATION, CHARACTERIZATION, AND IN VITRO CYTOTOXICITY ASSAY”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 12, no. 3, Feb. 2019, pp. 193-8, https://innovareacademics.in/journals/index.php/ajpcr/article/view/29876.
Section
Original Article(s)