Formulation and in-vitro anticancer activity of nilotinib immediate release and ibrutinib sustained release pellets

Vishal Gupta; Jitendra Gupta

doi:10.69857/joapr.v12i4.571

Authors

Vishal Gupta Institute of Pharmaceutical Research, GLA University, Mathura-281406, U. P., India https://orcid.org/0009-0003-1704-0519
Jitendra Gupta Institute of Pharmaceutical Research, GLA University, Mathura-281406, U. P., India

DOI:

https://doi.org/10.69857/joapr.v12i4.571

Keywords:

Ibrutinib, Nilotinib, Pellets, Anticancer, Cytotoxicity test, immediate release, Sustained release

Abstract

Background: Blood cancer is a significant contributor to mortality rates worldwide, and its prevalence is projected to rise on a global scale. This trend places considerable strain on healthcare systems and necessitates the expedited development of innovative treatments by pharmaceutical firms to remain competitive. Conventional pellets produce rapid plasma drug levels, but they might cause side effects, decrease effectiveness, and lead to poor therapeutic management. Ibrutinib and Nilotinib are employed to treat leukemia patients. Methodology: The current research aims to formulate, characterize, and anticancer effect of Nilotinib immediate release (NIR) and Ibrutinib sustained release (ISR) seal sugar-coated pellets. Micrometric properties estimated the characterization of the drug pellets, and surface morphology was estimated using scanning electron microscopy. Drug excipient compatibility studies, stability studies, and in-vitro drug release were accessed. Result & Discussion: The results of pellet formulations FNI-1 to FNI-5 showed that FNI-5 formulations showed 100±6.0 µm size and possessed excellent mechanical strength for giving pellets a good self-life; also, due to the higher drug content up to 99%, FNI-5 was the best suited for pellet formulation and because NIR showed 99.18 ± 2.12 drug release at 2h and ISR 99.03±3.74% up to 12h so that anticancer concentration maintained for prolonged period. The standard dose for cytotoxicity against the THP-1 cell line of Nilotinib was found to be 200 mg, and the maintenance oral dose of Ibrutinib was 140mg, with four times the intake of the drug up to 560 mg. In an in vitro study in FNI-5 (final formulation), the dose of Ibrutinib was reduced to 420 mg. Conclusion: A synergistic effect of Ibrutinib and nilotinib drugs was observed in the inhibition of cancer cell growth, with an IC50 value of 4.585 µg/mL

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References

Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Wang MD, Fu L, Li J, Wu K, Cohen A, Shadman M. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med, 388, 319-32 (2023).

Dores GM, Linet MS, Curtis RE, Morton LM. Risks of therapy-related hematologic neoplasms beyond myelodysplastic syndromes and acute myeloid leukemia. Blood, 141, 951-5 (2023).

Iyer SG, Elias L, Stanchina M, Watts J. The treatment of acute promyelocytic leukemia in 2023: Paradigm, advances, and future directions. Front Oncol, 12, 1062524 (2022).

Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, Kolibaba KS, Furman RR, Rodriguez S, Chang BY, Sukbuntherng J, Izumi R, Hamdy A, Hedrick E, Fowler NH. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol, 31, 88-94 (2013).

Wang Q, Bian X, Chen X, Han Y, Yan C. Mechanism and structure of the interaction of water-soluble pillar[5]arene and ibrutinib that enhances the anticancer activity of ibrutinib. Journal of Molecular Structure, 1210, 128004, (2020).

Ahmad S, Khan JA, Kausar TN, Mahnashi MH, Alasiri A, Alqahtani AA, Alqahtani TS, Walbi IA, Alshehri OM, Elnoubi OA, Mahmood F, Sadiq A. Preparation, Characterization and Evaluation of Flavonolignan Silymarin Effervescent Floating Matrix Tablets for Enhanced Oral Bioavailability. Molecules, 28, 2606 (2023).

Philipova I, Mihaylova R, Momekov G, Angelova R, Stavrakov G. Ferrocene modified analogues of imatinib and nilotinib as potent anti-cancer agents. RSC Med Chem, 14, 880-9 (2023).

Visan AI, Cristescu R. Polysaccharide-Based Coatings as Drug Delivery Systems. Pharmaceutics, 15, 2227 (2023).

Patel M, Desai A, Kansara V, Vyas B. Core Shell Lipid-Polymer Hybrid Nanoparticles for Oral Bioavailability Enhancement of Ibrutinib via Lymphatic Uptake. AAPS PharmSciTech, 24, 142 (2023).

Zhu Y, Bai Y, He J, Qiu X. Advances in the stimuli-responsive mesoporous silica nanoparticles as drug delivery system nanotechnology for controlled release and cancer therapy. 3 Biotech, 13, 274 (2023).

Radha G, Kumar SR, Kumar SB. Dual therapeutic 5-fluorouracil and hesperidin loaded chitosan nanocarrier system Understanding its synergism on anti-cancer activity. Journal of Drug Delivery Science and Technology, 80, 104184 (2023).

Zolotov SA, Sazonov GK, Dain IA, Ponomarev ES, Zolotova AS. Production of the Amorphous Form of Ibrutinib and Study of its Physicochemical Properties. Pharm. Chem. J, 57(2), 300 (2023)

Rangaraj N, Pailla SR, Chowta P, Sampathi S. Fabrication of Ibrutinib Nanosuspension by Quality by Design Approach: Intended for Enhanced Oral Bioavailability and Diminished Fast Fed Variability. AAPS PharmSciTech, 20, 326 (2019).

Roy SK, Das P, Mondal A, Kuotsu K. Design, formulation and evaluation of multiparticulate time programmed system of Ramipril for pulsed release: An approach in the management of early morning surge in blood pressure. Journal of Drug Delivery Science and Technology, 62, 102344 (2021).

Wu S, Fu L. Tyrosine kinase inhibitors enhanced the efficacy of conventional chemotherapeutic agent in multidrug resistant cancer cells. Mol Cancer, 17, 25 (2018).

Cheng M, Yang F, Liu J, Yang D, Zhang S, Yu Y, Jiang S, Dong M. Tyrosine Kinase Inhibitors-Induced Arrhythmias: From Molecular Mechanisms, Pharmacokinetics to Therapeutic Strategies. Front Cardiovasc Med, 8, 758010 (2021).

Kenda M, Avsec D, Zore T, Kogovšek E, Pečar Fonović U, Kos J, Bozovičar K, Bratkovič T, Karas Kuželički N, Žegura B, Filipič M, Sollner Dolenc M. Effects of tyrosine kinase inhibitors on androgen, estrogen α, glucocorticoid and thyroid receptors. Toxicol Appl Pharmacol, 434, 115818 (2022).