(748f) Increasing Oral Bioavailability of SR 13668 by Using Polymeric Nanoparticles

Hao Shen¹, Aryamitra A. Banerjee², Alexander V Lyubimov^2,_*, Izet M. Kapetanovic³, Yoon Yeo^4,5 and Ying Liu^1,6,_*

¹ Department of Chemical Engineering, University of Illinois at Chicago, Chicago, IL 60607

² Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612

³National Cancer Institute, Bethesda, MD 20892

⁴ Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN 47907

⁵ Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907

⁶ Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60607

* To whom correspondence should be addressed.

SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole), is a new candidate cancer chemopreventive agent based on a naturally occurring anti-cancer agent indole-3-carbinol (I3C), which was found in cruciferous vegetables and had promising anti-cancer activity both in vitro and in vivo models. SR13668 has a safe preclinical toxicology profile (genotoxicity battery, acute and subchronic rat and dog studies). However, SR13668 showed a very poor oral bioavailability due to its limited aqueous solubility and permeability.

In this work, we have encapsulated the cancer chemopreventive drug, SR13668, into polymeric nanoparticles to increase its bioavailability, by using Flash NanoPrecipitation (FNP), a scalable process to prepare nanoparticles with controlled size distribution and a high drug loading rate. The effects of size of each block of the copolymer, ratio of the polymers to drug, supersaturation values of the polymers and the drug, presence of co-precipitator, and type of polymer on the size distribution of the nanoparticles and therapeutic loading is demonstrated. Drug loading rate up to 33% can be achieved by using FNP, which is more than twenty times higher compared to the traditional nanoprecipitation. Poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEG-b-PCL) and Poly(D,L-lactide-co-glycolide) (PLGA) were used to encapsulate SR13668. To increase the long-term stability of nanoparticles and to avoid Ostwald ripening and particle growth, nanoparticle suspensions were either freeze dried or spray dried to dry powders. Methods to redisperse the nanoparticles have been developed.

Pharmacokinetic (PK) analysis was performed in mice and dog models. High performance liquid chromatography (HPLC) - mass spectrometry (MS) was used to measure the SR13668 concentration in both whole blood and blood plasma. By comparing to SR13668 in methylcellulose formulation, polymeric nanoparticles encapsulating SR13668 dramatically enhanced the bioavailability of the drug.