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


CONCLUSIONS
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.
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, USA.|Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research, (NIPER), Hyderabad, Telangana, India.
Chandraiah
C
Godugu
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, USA.
Ravi
R
Doddapaneni
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, USA.
Apurva R
AR
Patel
Translational Science Laboratory, Florida State University, College of Medicine, Tallahassee, Florida, 32306, USA.
Rakesh
R
Singh
Translational Science Laboratory, Florida State University, College of Medicine, Tallahassee, Florida, 32306, USA.
Roger
R
Mercer
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, USA. mandip.sachdeva@famu.edu.
Mandip
M
Singh
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D005079:Excipients; D000077156:Gefitinib; D006801:Humans; D008819:Mice, Nude; D040901:Proteomics; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D012995:Solubility; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D005079:Excipients; D011799:Quinazolines; D000077156:Gefitinib
A431; control release formulations; epidermal growth factor receptor; gefitinib; spray drying