Abstract 3361: Pharmacokinetic and pharmacodynamic evaluation of novel dual channel spray dried enteric coated self-emulsifying capsules for anti-cancer agents in dogs.

Abstract

Abstract Purpose: Oral administration of anti-cancer agents presents a series of advantages for patients. However, most of the anticancer agents are hydrophobic (poor water solubility) thus associated with low bioavailability. Self-emulsifying drug delivery systems (SEDDS), known to improve the oral absorption of highly lipophilic compounds, are normally prepared in a liquid form. However, solid-SEDDS has several advantages over conventional SEDDS. Thus we have incorporated spray drying for this purpose using customized spray gun system, which allows simultaneously/pulsatile flow of two different liquid systems through single nozzle. This modification allowed us to formulate Enteric coated SEDDS by using SEDDS as one liquid system and Enteric coating solution as second liquid system. Objective of this study was to design and evaluate this formulation in-vivo using DIM-C-pPhC6H5 (DIM-P), a novel anti-cancer agent, in dogs. Methods: SEDDS formulations were prepared as capsules and optimized based on pseudo-ternary phase diagram analysis as well as characteristics such as turbidity or phase separation prior to self-emulsification, emulsion droplet size and self-emulsification efficiency before/after spray drying. Evaluation for enteric coating was done by drug release of spray dried E-SEDDS. Pharmacokinetic and pharmacodynamic properties in dogs were determined following intravenous and oral administration of formulations. Pharmacokinetic parameters were determined using non-compartmental and compartmental techniques with WinNonlin® 5.0 software. Efficiency of anti-tumor activity was carried out using metastatic H1650 tumor model in nude mice using ‘M’ size capsules. Results: Three formulations of SEDDS were selected based on pseudo-ternary phase diagram and physicochemical properties of SEDDS. Droplet size of emulsion was in range of 5-10 μm. In-vitro drug release study showed < 2% release in acidic pH followed by burst release (80% at 6hr) in pH>5 suggesting coating of SEDDS particles. Pharmacokinetic evaluation in dogs showed improved absorption of SEDDS formulations compare to solution; increased Cmax (39.18 ± 7.34 vs 21.68 ± 6.3 μg dL-1), higher AUC0-t (34481.34 ± 1125.46 vs 14159.53 ± 702.20 μg min dL-1). The relative oral bioavailability of SEDDS calculated on the basis of AUC0-t was about 43% as compared to solution. Also, plasma concentration vs time profile following intravenous administration and tissue distribution analysis confirmed three compartment distribution of DIM-P. SEDDS formulation showed ∼20-25% tumor volume and weight reduction in-vivo H1650 tumor models. Conclusion: The results emanating from these studies demonstrate a potential use of dual channel spray dried enteric coated self-emulsifying capsules for enhanced oral absorption and thus increased anti-cancer activity for treatment of Lung cancer. Citation Format: Apurva R. Patel, Chandraiah Godugu, Wilson R. Heather, Stephen Safe, Mandip S. Sachdeva. Pharmacokinetic and pharmacodynamic evaluation of novel dual channel spray dried enteric coated self-emulsifying capsules for anti-cancer agents in dogs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3361. doi:10.1158/1538-7445.AM2013-3361