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Quality by Design Approach for Optimization of 5-Fluorouracil Microbeads Using Box–Behnken Design and Desirability Function for Colon Targeting

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Abstract

Purpose

The main objective was to develop and optimize a multiparticulate system of 5-fluorouracil through the Box–Behnken design (BBD) and desirability function and coating of the optimized batch for increased therapeutic efficacy and targeting for the treatment of colorectal cancer.

Method

It is essential to understand the factors and quality aspects involved in the formulation of a multiparticulate system through optimization. The ionotropic gel method was used to create an optimized batch, with selected independent factors such as sodium alginate, pectin concentrations, and curing time on the response variables such as particle size and entrapment efficiency of 5-fluorouracil-loaded microparticle. The relationship between the independent and dependent variables was examined by utilizing the contour, response surface designs, mathematical calculations, and desirability function produced by Design-Expert.

Result

The ionotropic gelation process was used to create an optimized batch, and the generated microparticles had a 674 µm particle size and a 90.81% drug entrapment efficiency. The observed answers were very similar with a bias of less than 5% when compared to the expected value and desirability function. A second layer of Eudragit S100 was applied to the improved formulation. The coated microbeads released pH 1.2 at a rate of less than 10%. After 10 h, more than 55.12% of the drug was released into the intestinal area (pH 6.8). The kinetics investigation demonstrated that the created formulation for the Higuchi and Korsmeyer-Peppas models possessed linearity, as shown by the plots, with R2 values of 0.9887 and 0.9236, respectively. This outcome supported the formulation’s extended-release behavior.

Conclusion

It was suggested that the drugs would be delivered to the desired place using the microbeads created in this study. The developed microbeads were probably made of small particles that contained a high percent drug entrapment. According to the findings, multiparticulate can be a possible carrier for the delivery of drugs to the colon, and the Box–Behnken design and desirability function can be an active strategy for optimizing the formulation. Its cytotoxicity is maintained by being formulated as a multiparticulate, and it is also suited for administration to patients with colorectal cancer.

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Availability of Data and Materials

All necessary data generated or analyzed during this study are included in this published article. Any additional data could be available from the corresponding author upon request.

Abbreviations

BBD:

Box–Behnken design

5-FU:

5-Fluorouracil

HCT:

Human colorectal carcinoma cell line

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide

TWG:

Total weight gain

References

  1. Ramanathan, Ramesh K, Clark, Jeffery W. Safety and toxicity analysis of oxaliplatin combined with fluorouracil or as a single agent in patients with previously treated advanced colorectal cancer. Am Soc Clin Oncol. 2003;2904–11.

  2. Dhawale SC, Bankar AS, Patro MN. Formulation and evaluation of porous microspheres of 5-fluorouracil for colon targeting. Int J Pharmtech Res. 2010;1112–18.

  3. Wong HL, Bendayan R, Rauth AM. Chemotherapy with anticancer drugs encapsulated in solid lipid nanoparticles. Adv Drug Deliv Rev. 2007;59:491–504.

    Article  CAS  PubMed  Google Scholar 

  4. Michor F, Iwasa Y, Lengauer C, Nowak NA. Dynamics of colorectal cancer. Semin Cancer Biol. 2013;15:484–93.

    Article  Google Scholar 

  5. Mohideen B, Ezhilmuthu RP, et al. Formulation and in vitro characterization of gliclazide-loaded polymeric nanoparticles. Int J Biol Pharm Res. 2005;4(7):533–40.

    Google Scholar 

  6. Krishnaiah YSR, Satyanarayan S. Colon-specific drug delivery systems: advances in controlled and novel drug delivery. CBS Publishers and Distributors. 2001;89–119.

  7. Levine DS, Raisys VA, Ainardi V. Coating oral beclomethasone dipropionate capsules with cellulose acetate phthalate enhances the delivery of topically active anti-inflammatory drug delivery to the terminal ileum. Gastroenterology. 1987;92:1037–44.

    Article  CAS  PubMed  Google Scholar 

  8. Rasmussen SN, Rondesen S, Hvidberg EF, Honore HS, Binder V, Halskov S. 5-Aminosalicylic acid in a slow-release preparation: bioavailability, plasma level, and excretion in humans. Gastroenterology. 1982;83:1062–7.

    Article  CAS  PubMed  Google Scholar 

  9. Arias JL, Ruiz MA, LopezViota M, Delgado AV. Poly (alkyl cyanoacrylate) colloidal particles as vehicles for antitumor drug delivery: a comparative study. Colloids Surf B. 2008;62:64–70.

    Article  CAS  Google Scholar 

  10. Malet, Martino M, Martino RL. Clinical studies of three oral prodrugs of 5-fluorouracil Capecitabine, UFT, S-1): a review. Oncologist. 2002;7:288–323.

  11. Mazumder R, Mahanti B, Majumdar S, Pal R, Chowdhury AD. Response surface method for optimization of prepared satranidazole powder layered pellet. Future J Pharm Sci. 2021;7:190.

    Article  Google Scholar 

  12. Tamara M. Drug targeting to the colon with lectins and neoglycoconjugates. Adv Drug Deliv Rev. 2004;56:491–509.

    Article  Google Scholar 

  13. Akram W, Navneet G. Design Expert as a statistical tool for optimization of 5-ASA-loaded biopolymer-based nanoparticles using Box Behnken factorial design. Future J Pharm Sci. 2021;7:146.

    Article  Google Scholar 

  14. Paharia A, Yadav AK, Rai G, Jain SK, Pancholi SS, Agrawal GP. Eudragit-coated pectin microsphere of 5-fluorouracil for colon targeting. AAPS PharmSciTech. 2007;8:E56.

    Article  Google Scholar 

  15. Kundlik M. Girhepunje K, Ranju S, Pal HB, Gevariya NT, Patel L. Celecoxib loaded microbeads: a targeted drug delivery for colorectal cancer. Int J Curr Pharm Res. 2010;2:46–55.

  16. Ghosal K, Das SK, Ghosh D. The preparation and evaluation of naringin-loaded polycaprolactone microspheres based on oral suspension using Box-Behnken design. J Mol Liq. 2018;256:49–57.

  17. Yadav P, Rastogi V, Verma A. Application of Box-Behnken design and desirability function in the development and optimization of self-nano emulsifying drug delivery system for enhanced dissolution of ezetimibe. Future J Pharm Sci. 2020;6:1–20.

    Google Scholar 

  18. Khan MS, Sridhar BK. Development and evaluation of pH-dependent microbeads for colon targeting. Indian J Pharm Sci. 2010;72(1):18–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pandey AK, Choudhary N, Rai V, Dwivedi H, Kymonil KM, Saraf SA. Fabrication and evaluation of tinidazole microbeads for colon targeting. Asian Pac J Trop Dis. 2012;S197–201.

  20. Patel HK, Nagle A, Murthy RSR. Characterization of calcium alginate beads of 5-fluorouracil for colon delivery. Asian J Pharm. 2008;241–45.

  21. Ramírez-Bergeron DL, Runge A, Adelman DM, Gohil M. Simon MC HIF-dependent hematopoietic factors regulate the development of the embryonic vasculature. Dev Cell. 2006;11(1):81–92.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55–63.

    Article  CAS  PubMed  Google Scholar 

  23. Weijia L, Jing Z, Yuyin Xu. Study of the in vitro cytotoxicity testing of medical devices (review), biomedicine. Report. 2015;3:617–20.

  24. Ferreira SL, Bruns RE, Ferreira HS, Matos GD, David JM, Brandão GC, da Silva EG, Portugal LA, dos Reis PS, Souza AS, dos Santos WN. Box-Behnken design: an alternative for the optimization of analytical methods. Anal Chim Acta. 2007;597:179–86.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author wishes to give thanks to the Department of Pharmaceutics, Faculty of Pharmacy, Hygia Institute of Pharmaceutical Education and Research, Ghaila Road, Gazipur Balram Rd, Lucknow, Uttar Pradesh 226020, India, for the completion of the research project work.

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  1. Department of Pharmaceutics, Faculty of Pharmacy, Hygia Institute of Pharmaceutical Education and Research, Lucknow, India

    Amit Kumar Pandey & Udaivir Singh Sara

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  1. Amit Kumar Pandey
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Contributions

We declare that this work was done by the authors named in this article: AKP and UVS conceived and designed the study. AKP carried out the laboratory work and collected and analyzed the data, and UVS drafted the manuscript. UVS supervised the work and assisted in the data analysis. All authors have read and approved the final manuscript.

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Correspondence to Amit Kumar Pandey.

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Pandey, A.K., Sara, U.S. Quality by Design Approach for Optimization of 5-Fluorouracil Microbeads Using Box–Behnken Design and Desirability Function for Colon Targeting. J Pharm Innov 18, 2054–2065 (2023). https://doi.org/10.1007/s12247-023-09772-z

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