Abstract 5673: Controlled-release systemic delivery of chemopreventive agents - An update
Authors: Vadhanam Manicka V. , Aqil Farrukh , Bansal Shyam S. , Cao Pengxiao , Jeyabalan Jeyaprakash , Ravoori Srivani , Gupta Ramesh C. 
Published: February 2011

Abstract
Controlled release systemic delivery of chemopreventive agents bypasses all the hurdles of oral delivery, including issues with absorption, liver first-pass effect and fast clearance by kidneys. We had previously demonstrated the effectiveness of controlled release of chemopreventive agents by systemic route using subcutaneous implants of polycaprolactone (PCL):F68 (9:1). This implant concept reduced the effective dose by two-orders of magnitude and increased bioavailability. However, there were several issues that required further optimization. Specifically, i) the rate of release of lipophilic compounds such as curcumin was not high enough to achieve biologically-effective dose; ii) the implant formulation gave an undesirable burst release, followed by a more sustained release; and iii) lack of correlation between in vitro and in vivo release. Different drugs require varying release kinetics in order to achieve biologically-effective dose. To achieve this, the formulation of the polymer matrix was modified by replacing the water-soluble polymer F68 with polyethylene glycol (PEG; Mol. Wt. 8,000). By varying the composition of the two polymers, a ratio of PCL:PEG of 65:35 increased the initial release by nearly 4-fold and an average 2-fold increase in daily release was achieved at the end of one month. Thus, adding eight to ten coatings of a 10% PCL solution prevented the immediate release of the surface-bound drug and essentially abolished the burst release phenomenon. These modifications in the implant formulation with curcumin have resulted in near zero-order kinetics over one month tested. Finally, we previously reported the short-term release of phytochemicals from subcutaneous implants in a rat model. We have now measured the release up to 16 months and found that the polymeric implants are still continuing to release the compounds. After 10 and 16 months, respectively punicalagin showed a release of 20.8 and 8.2 µg/day, curcumin 28 and 18.5 µg/day and green tea polyphenols 42 and 4.7 µg/day. We also observed a tissue depot of test agent at the site of implant that seems to contribute to the release of the drug systemically. This tissue depot may facilitate the release kinetics to be of zero-order. Based on our standardized ‘sink’ conditions, curcumin released on an average 3.6 ± 0.14 fold higher amounts in vivo than in vitro, when tested at various time intervals. Thus, our controlled-release, systemic-delivery system circumvents major limitations of oral delivery, provides continuous (“24/7”) delivery of drug for long duration, lowers the total amount of drug required, enables delivery of biologically-effective dose at the target site. This essentially allows testing of several minor phytochemicals and synthetic structural analogs that may remain uninvestigated in animal models due to insufficient quantities (Supported from the USPHS grants CA-118114 and CA-125152 and Agnes Brown Duggan Endowment).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5673.