• JASWANTH GOWDA B. H. Department of Pharmaceutics, Vivekananda College of Pharmacy, Dr. Rajkumar road, Rajajinagar 2nd Stage, Bengaluru, India 560055
  • S. J. SHANKAR Department of Pharmaceutics, Vivekananda College of Pharmacy, Dr. Rajkumar road, Rajajinagar 2nd Stage, Bengaluru, India 560055
  • MURALI MUNISAMY Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal, India 576104
  • AKSHATHA R. S. Department of Pharmaceutics, PES College of Pharmacy, 50 feet Road, Hanumanth nagar, Srinagara, Bengaluru, India 560050
  • V. S. SAGAR Department of Pharmacy, Annamalai University, Annamalainagar, Chidambaram, India 608002



Colon cancer, Chronopharmaceutics, pH-dependent drug delivery, 5-fluorouracil,, Oxaliplatin, Eudragit S-100, Eudragit RSPO, FOLFOX regimen, Microspheres


Objective: To develop two different oral formulations such as 5-fluorouracil (5-FU) tablets and oxaliplatin (OX) microspheres which were further filled into capsules and coated with pH-sensitive polymer (eudragit S-100) for the chronotherapeutic treatment of colon cancer (Fluorouracil: Oxaliplatin regimen) to perform as a substitute for intravenous (IV) route based chronomodulated chemotherapy.

Methods: The 5-FU tablet formulation was prepared with alginate and guar gum polymers in varied concentrations using wet granulation technique in two varieties such as granules coated and tablet coated formulations using eudragit RSPO as coating material to achieve controlled drug release. Alongside OX microspheres were formulated using the ionotropic gelation methodology in combination with alginate and chitosan polymers in varying concentrations to accomplish a time-controlled drug release. Prepared formulations were evaluated for pre-compression and post-compression parameters, percentage yield, percentage drug entrapment, Fourier transformed infrared spectroscopy (FT-IR), Differential scanning calorimetry (DSC), Scanning electron microscopy (SEM), In vitro and Ex vivo dissolution studies.

Results: Pre-compression and post-compression parameters for 5-FU tablets were satisfied with Indian pharmacopeia specifications. The entrapment efficiency of OX microspheres were increased due to the elevated concentration of polymers up to a certain level as seen in A7M, further greater the concentration of polymer resulted in a decline of entrapment efficiency as seen in A4M and A8M. The optimized formulations A14T and A14M were shown in vitro drug release of 90.36 % by 24 h and 79.63 % by 9 h respectively.

Conclusion: The two different oral formulations of 5-FU (Tablets) and OX (Microspheres) were found to be successful in controlled drug release. Therefore they can be efficiently used to control the rate of drug release to the colon in synchronization with the circadian timing system in the belief of improved therapeutic efficacy, tolerability and overall survival rate of cancer patients. Hence it is promised to be a better alternative for intravenous route based chronomodulated chemotherapy.


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WHO Cancer Fact Sheet. Available from: [Last accessed on 11 Sep 2018]

Basini J, Rayadurgam S, Dakshinamurthy S. An overview of colorectal cancer: implication of two medicinal plants in their treatment. Asian J Pharm Clin Res 2019;12:47-52.

Chena Y, Li N, Xu B, Wu M, Yan X, Zhong L, et al. Polymer-based nanoparticles for chemo/gene-therapy: evaluation its therapeutic efficacy and toxicity against colorectal carcinoma. Biomed Pharmacother 2019;118:109-257.

Sunoqrot S, Abujamous L. pH-sensitive polymeric nanoparticles of quercetin as a potential colon cancer-targeted nanomedicine. J Drug Delivery Sci Tech 2019;52:670-6.

Neugut AI, Lin A, Raab GT, Hillyer GC, Keller D, Neil DSO, et al. FOLFOX and FOLFIRI use in stage IV colon cancer: analysis of SEER medicare data. Clin Colorectal Cancer 2019;18:133-40.

You X, Kang Y, Hollett G, Chen X, Zhao W, Gu Z, et al. Polymeric nanoparticles for colon cancer therapy: overview and perspectives. J Mater Chem B 2016;4:7779-92.

Shena MY, Liu T, Yu TW, Kv R, Chiang WH, Tsai YC, et al. Hierarchically targetable polysaccharide-coated solid lipid nanoparticles as an oral chemo/thermotherapy delivery system for local treatment of colon cancer. Biomaterials 2019;197:86-100.

Gupta SK, Huneza A, Patra S. Formulation, development and in vitro evaluation of tramadol extended-release tablets. Int J Pharm Pharm Sci 2019;11:63-73.

Li W, Liu D, Zhang H, Correia A, Makila E, Salonen J, et al. Microfluidic assembly of a nano-in-micro dual drug delivery platform composed of halloysite nanotubes and a pH-responsive polymer for colon cancer therapy. Acta Biomater 2017;48:238-46.

Lijun S, Liping L, Xiaoying S, Honglang C, Shumin Z, Wenfeng C, et al. Optimizing pH-sensitive and time-dependent polymer formula of colonic pH-responsive pellets to achieve precise drug release. Asian J Pharm Sci 2019;14:413-22.

Mahto A, Mishra S. Design, development and validation of guar gum based pH sensitive drug delivery carrier via graft copolymerization reaction using microwave irradiations. Int J Biol Macromol 2019;138:278-91.

Vemula SK. Formulation and pharmacokinetics of colon-specific double-compression coated mini-tablets: chronopharmaceutical delivery of ketorolac tromethamine. Int J Pharm 2015;491:35-41.

Sen SO, Devbhuti P, Sen KK, Ghosh A. Development and evaluation of sustain release microparticles of metoprolol succinate. Int J Appl Pharm 2019;11:166-72.

Cerciello A, Auriemma G, Gaudio PD, Sansone F, Aquino RP, Russo P. A novel coreeshell chronotherapeutic system for the oral administration of ketoprofen. J Drug Delivery Sci Tech 2016;32:126-31.

Jose S, Prema MT, Chacko AJ, Thomas AC, Souto EB. Colon specific chitosan microspheres for chronotherapy of chronic stable angina. Colloids Surf B 2011;83:277-83.

Levi F. Circadian chronotherapy for human cancers. Lancet Oncol 2001;2:307-15.

Youan BBC. Chronopharmaceutics: gimmick or clinically relevant approach to drug delivery? J Controlled Release 2004;98:337-53.

Oishi K, Koyanagi S, Matsunaga N, Kadota K, Ikeda E, Hayashida S, et al. Bezafibrate induces plasminogen activator inhibitor-1 gene expression in a CLOCK dependent circadian manner. Mol Pharmacol 2010;78:135-41.

Marra G, Anti M, Percesepe A, Armelao F, Ficarelli R, Coco C, et al. Circadian variations of epithelial cell proliferation in human rectal crypts. Gastroenterology 1994;106:982-7.

Levi F, Schibler U. Circadian rhythms: mechanisms and therapeutic implications. Annu Rev Pharmacol Toxicol 2007;47:593-628.

Innominato PF, Levi FA, Bjarnason GA. Chronotherapy and the molecular clock: clinical implications in oncology. Adv Drug Delivery Rev 2010;62:979-1001.

Levi F, Focan C, Karaboue A, De la Valette V, Henrard DF, Baron B, et al. Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Delivery Rev 2007;59:1015-35.

Takimoto CH. Chronomodulated chemotherapy for colorectal cancer: failing the test of time? Eur J Cancer 2006;42:574-81.

Kiran HC, Venkatesh DN, Kumar RR. Formulation and characterisation of sustained release microbeads loaded with zaltoprofen. Int J Appl Pharm 2019;11:173-80.

Venkatesh DN, Kumar SS, Rajeshkumar R. Sustained release microbeads of ritonavir: in vitro and in vivo evaluation. Int J Appl Pharm 2019;11:189-98.

Venkatesh DN, Rao P, Rajeshkumar R. Enhanced oral bioavailability of tenofovir from ionotropically gelled microbeads. Int J Appl Pharm 2019;11:242-50.

Rodriguez MLG, Holgado MA, Lafuente CS, Rabasco AM, Fini A. Alginate/chitosan particulate systems for sodium diclofenac release. Int J Pharm 2002;232:225-34.

Shankar SJ, Gowda JBH, Nimitha AG, Metikurki B. Formulation and evaluation of hydroxyapatite microspheres of an antimicrobial drug for the treatment of osteomyelitis. Indo Am J Pharm Res 2019;7:3145-56.

Indian Pharmacopoeia, Government of India, Ministry of health and family welfare. 8th ed. New Delhi: The Controller of Publications; 2018.

Karthika C, Sureshkumar R, Suhail A. Formulation development and in vitro evaluation of curcumin-loaded solid self-nanoemulsifying drug delivery system for colon carcinoma. Asian J Pharm Clin Res 2019;12:243-7.

Wang QS, Wang GF, Zhou J, Gao LN, Cui YL. Colon targeted oral drug delivery system based on chitosan/alginate microspheres loaded with icariin in the treatment of ulcerative colitis. Int J Pharm 2016;515:176-85.

Sharma S, Seth N. Exploring the potential of eudragit for development of microparticles of water-soluble drug using quality by design approach. Int J Appl Pharm 2019;11:110-6.

Al-tahami K. Preparation, characterization, and in vitro release of ketoprofen loaded alginate microspheres. Int J Appl Pharm 2014;6:9-12.

Alange VV, Birajdar RP, Kulkarni RV. Functionally modified polyacrylamide-graft-gum karaya pH-sensitive spray dried microspheres for colon targeting of an anti-cancer drug. Int J Biol Macromol 2017;102:829-39.

Dodov MG, Calis S, Crcarevska MS, Geskovski N, Petrovska V, Goracinova K. 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.

Jain A, Jain SK, Ganesh N, Barve J, Beg AM. Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer. Nanomed: Nanotechnol Biol Med Food Hydrocolloids 2010;6:179-90.

Aulton ME. Pharmaceutics the science of dosage form design. Bangalore, India: Sapna Book House; 2002. p. 247.

Lachman L, Liberman HA, Kanig JL. The theory and practice of industrial pharmacy. Bangalore, India: Sapna Book House; 1987. p. 293-345.



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