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Novel Gefitinib Formulation with Improved Oral Bioavailability in Treatment of A431 Skin Carcinoma

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Abstract

Purpose

Oral administration of anticancer agents presents a series of advantages for patients. However, most of the anticancer drugs have poor water solubility leading to low bioavailability.

Methods

Controlled released spray dried matrix system of Gefitinib with hydroxypropyl β-cyclodextrin, chitosan, hydroxy propyl methyl cellulose, vitamin E TPGS, succinic acid were used for the design of formulations to improve the oral absorption of Gefitinib. Spray drying with a customized spray gun which allows simultaneous/pulsatile flow of two different liquid systems through single nozzle was used to prepare Gefitinib spray dried formulations (Gef-SD). Formulation was characterized by in vitro drug release and Caco-2 permeability studies. Pharmacokinetic studies were performed in Sprague Dawley rats. Efficacy of Gef-SD was carried out in A431 xenografts models in nude mice.

Results

In Gef-SD group 9.14-fold increase in the AUC was observed compared to free Gef. Improved pharmacokinetic profile of Gef-SD translated into increase (1.75 fold compared to Gef free drug) in anticancer effects. Animal survival was significantly increased in Gef formulation treated groups, with superior reduction in the tumor size (1.48-fold) and volumes (1.75-fold) and also increase in the anticancer effects (TUNEL positive apoptotic cells) was observed in Gef-SD treated groups. Further, western blot, immunohistochemical and proteomics analysis demonstrated the increased pharmacodynamic effects of Gef-SD formulations in A431 xenograft tumor models.

Conclusion

Our studies suggested that Gefitinib can be successfully incorporated into control release microparticles based oral formulation with enhanced pharmacokinetic and pharmacodynamic activity. This study demonstrates the novel application of Gef in A431 tumor models.

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Abbreviations

EGFR:

Epidermal Growth Factor Receptor

Gef:

Gefitinib

Gef-SD:

Gefitinib Spray Dried Formulation

HPβ-CD:

Hydroxy Propyl Beta- Cyclodextrin

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors acknowledge the financial assistance of this research from the National Institute on Minority Health and Health Disparities (NIMHD) P20 program [Grant # 1P20MD006738-03; to M.S.]; and the Department of Defense (DOD) Breast Cancer Program [Grant # W81XWH-11-1-0211 to M.S] and the National Institutes of Health (NIH) SC-1 grant [Grant # 5SC1CA161676-03 to M.S]. The authors thanks for the support of Dr. Ramesh Katam, Assistant professor, FAMU for proteomic analysis and Dr. Jaganmohan Somagoni, Research associate, FAMU for pharmacokinetic experiments during this study. Chandraiah Godugu, Ravi Doddapaneni and Mandip Singh contributed equally to this work.

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Authors and Affiliations

  1. College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, USA

    Chandraiah Godugu, Ravi Doddapaneni, Apurva R Patel & Mandip Singh

  2. Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research, (NIPER), Hyderabad, Telangana, India

    Chandraiah Godugu

  3. Translational Science Laboratory, Florida State University, College of Medicine, Tallahassee, Florida, 32306, USA

    Rakesh Singh & Roger Mercer

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  1. Chandraiah Godugu
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  2. Ravi Doddapaneni
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  3. Apurva R Patel
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  6. Mandip Singh
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Correspondence to Mandip Singh.

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Godugu, C., Doddapaneni, R., Patel, A.R. et al. Novel Gefitinib Formulation with Improved Oral Bioavailability in Treatment of A431 Skin Carcinoma. Pharm Res 33, 137–154 (2016). https://doi.org/10.1007/s11095-015-1771-6

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