(524c) Fabrication of Controlled Release Devices for Anticancer Agents Using Supercritical Antisolvent Method

Lee, L. Y. - Presenter, Singapore-MIT Alliance
Smith, K. A. - Presenter, Massachusetts Institute of Technology
Wang, C. - Presenter, National University of Singapore

There are currently a number of anticancer agents approved for use in chemotherapy. These include cisplatin, doxorubicin, and paclitaxel. A major complication of most anticancer agents is that the cytotoxicity effects apply to both cancerous and normal cells. Long term administration of the drugs to the cancer patient also brings about some serious side effects such as hair loss, weight loss, and nausea. A delivery system that allows sustained release of drugs in the vicinity of target cells is desirable in the chemotherapy process to improve the overall quality of life of the patient. In the past few decades, much research has been carried out to develop micro-/nanoparticles of biodegradable polymers as drug delivery systems for chemotherapy.

We are interested in developing controlled delivery devices which give high yield of product and permit facile control of the product size and morphology through tuning of process parameters. In particular, the use of supercritical fluid techniques in the processing and fabrication of drugs and pharmaceutical products is examined in this research. CO2 is the supercritical fluid of choice in our study and many other researches because it is environmentally benign, easily available and its low critical temperature (Tc = 31.1 deg C) makes it ideal for processing most thermally labile biological and pharmaceutical compounds. This study focuses mainly on the Supercritical Antisolvent (SAS) [1-6] method of producing drug-loaded particles with high yield, controllable size and good morphology.

Several research groups have been working on the SAS process for semiconductor and catalytic materials, polymeric materials and drugs. Some studies have been done on the application to controlled release devices, mainly for antibiotic and protein drugs. Few studies explore the in vitro release profile of the encapsulated polymeric devices [2-4]. In this work, we extend the application to the controlled release of the anticancer agents paclitaxel and doxorubicin. The efficacy of drug release is studied and optimized for applications in systemic administration for chemotherapy.

Biodegradable polymers poly L lactide (PLLA), poly DL lactide-co-glycolide (PLGA) and polycaprolactone (PCL) have been used to encapsulate paclitaxel and doxorubicin delivery devices in the form of nanoparticles using a process similar to the SASEM process. An ultrasonic vibrating probe (3/8" probe tip diameter) is fitted into the high pressure vessel to generate mixing and turbulence within the vessel. The organic phase is introduced into the high pressure vessel via a 440 micron ID stainless steel capillary. The spray is directed away from the ultrasonic vibrating probe tip. The high pressure vessel used has borosilicate glass windows which allow observation of the SAS process.

The ultrasonic vibration amplitude (30 - 210 micron peak-to-peak amplitude) is varied to control the size of the resulting particles. For co-precipitates of PLLA and paclitaxel, nanoparticles in the range 200 - 500 nm have been obtained. As in the studies of Chattopadhyay and Gupta [4-7], the particle size varies with sonication power. The encapsulation efficiency and in vitro release profile were determined by Scanning Electron Microscope (SEM) and High Performance Liquid Chromatography (HPLC) respectively.

We also investigate the effects of using various polymer blends to control the surface properties and in vitro release profile of the drugs. The effect of PLLA/PCL and PLLA/PLGA ratios is explored in this work.

References: [1]. Tom, J.W. and Debenedetti, P.G. "Particle Formation with Supercritical Fluids - A review", J. Aerosol Sci. 22, 555 - 584, 1991 [2]. Debenedetti, P.G., Tom, J. W. Yeo, S.D. and Lim, G.B. "Application of Supercritical Fluids for the Production of Sustained Delivery Devices", J. Control. Rel. 24, 27 - 44, 1993 [3]. Caliceti, P., Salmaso, S., Elvassore, N. and Bertucco, A. "Effective protein release from PEG/PLA nanoparticles produced by compressed gas antisolvent precipitation techniques", J. Control. Rel. 94, 195 - 205, 2004 [4]. Chattopadhyay, P. and Gupta, R.B. "Production of antibiotic nanoparticles using supercritical CO2 as antisolvent with enhanced mass transfer", Ind. Eng Chem. Res. 40, 3530 - 3539, 2001 [5]. Chattopadhyay, P. and Gupta, R.B. "Production of griseofulvin nanoparticles using supercritical CO2 antisolvent with enhanced mass transfer", Int. J. Pharma. 228, 19 - 31, 2001 [6]. Chattopadhyay, P. and Gupta, R.B. "Protein nanoparticles formation by supercritical antisolvent with enhanced mass transfer", AIChE Journal. 48 (2), 235 - 244, 2002 [7]. Chattopadhyay, P. and Gupta, R.B. "Supercritical CO2 based production of magnetically responsive micro- and nanoparticles for drug targeting", Ind. Eng. Chem. Res. 41, 6049 - 6058, 2002


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