Chemical Engineering Science 64 (2009) 4341--4349 Contents lists available at ScienceDirect Chemical Engineering Science journal homepage: www.elsevier.com/locate/ces Paclitaxel release from micro-porous PLGA disks Lai Yeng Lee a,b , Sudhir Hulikal Ranganath b , Yilong Fu b , Jasmine Limin Zheng b , How Sung Lee c , Chi-Hwa Wang a,b, ∗ , Kenneth A. Smith a,d a Molecular Engineering of Biological and Chemical Systems (MEBCS), Singapore-MIT Alliance, 4 Engineering Drive 3, Singapore 117576, Singapore b Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576, Singapore c Department of Pharmacology, National University of Singapore, Clinical Research Center Bldg MD11, Level 5, #05-9, 10 Medical Drive, Singapore 117597, Singapore d Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA ARTICLE INFO ABSTRACT Article history: Received 5 March 2009 Received in revised form 25 June 2009 Accepted 4 July 2009 Available online 23 July 2009 Keywords: Supercritical fluid Foam Polymer processing Microstructure Paclitaxel Drug delivery Micro-porous biodegradable polymeric foams have potential applications in tissue engineering and drug delivery systems. A two-stage fabrication process combining spray drying and supercritical gas foaming is presented for the encapsulation of paclitaxel in micro-porous PLGA (poly lactic glycolic acid) foams. Encapsulation of paclitaxel in the PLGA polymer matrix was achieved and these foams have potential application as a new type of surgical implant for controlled release of paclitaxel. This technique may also be applied to other hydrophobic drugs which face problems of slow release when encapsulated in a compact polymeric device. The micro-porous structure helps to increase drug release rate due to a shorter diffusion path of the drug in the polymer. The final residual organic solvent content in the polymer was low and well within safety limits due to the high miscibility of supercritical CO 2 with the organic solvent. The pore size distribution, the phase behavior, and the in vitro swelling behavior of the foams were characterized. In vitro release results showed a nearly constant release rate for up to 8 weeks. The release profiles from micro-porous foam and from compressed disks were compared to assess the performance of micro-porous foams as sustained release implants. The foams implanted intracranially in mice showed therapeutic concentrations of paclitaxel at distant regions of the brain even after 28 days of implantation. © 2009 Elsevier Ltd. All rights reserved. 1. Introduction Supercritical fluid techniques have been explored for processing of polymeric materials due to their high liquid-like dissolving power and gas-like transport properties (Eckert et al., 1996). Supercritical carbon dioxide (CO 2 ) has been selected for many processes in phar- maceutical product fabrication due to its accessible critical temper- ature and pressure, abundance, and generally environmentally be- nign nature in comparison to many organic solvents. Different forms of polymeric devices such as particles, fibers and foams have been achieved with various supercritical fluid techniques (Reverchon and Cardea, 2007). With supercritical CO 2 as a foaming agent, polymeric foams with micro-porous structures can be obtained. Three-dimensional micro-porous biodegradable polymer struc- tures serve an important role in tissue engineering (Mooney et al., 1996; Lu et al., 2000; Singh et al., 2004) and have potential ∗ Corresponding author at: Molecular Engineering of Biological and Chemical Systems (MEBCS), Singapore-MIT Alliance, 4 Engineering Drive 3, Singapore 117576, Singapore. Tel.: +65 6516 5079; fax: +65 6779 1936. E-mail address: chewch@nus.edu.sg (C.-H. Wang). 0009-2509/$ - see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.ces.2009.07.016 applications in drug delivery systems (Hile et al., 2000; Hile and Pishko, 2004). Porous scaffolds with interconnected pores are useful in tissue engineering to maximize cell seeding, attachment, growth, vascularization and extracellular matrix production. Due to its bio- compatibility, poly dl lactide-co-glycolide (PLGA) has commonly been selected for use in these applications (Singh et al., 2004; Lu et al., 2000; Hile et al., 2000; Hile and Pishko, 2004; Mooney et al., 1997; Thomson et al. 1995, 1998). Conventional methods of micro-porous foam formation such as the solvent-casting, particulate leaching technique (Lu et al., 2000) are usually associated with the use of large amounts of organic sol- vents which may require extensive purification steps to remove the residual solvent. By using supercritical CO 2 as the foaming agent, the use of organic solvent may be minimized or even eliminated in the production of PLGA foams (Mooney et al., 1996). The supercriti- cal gas foaming technique is illustrated in Fig. 1: (i) polymer is first placed in a high pressure vessel; (ii) the polymer is contacted with supercritical CO 2 , which diffuses into the polymer matrix to produce a solution of CO 2 in PLGA; (iii) upon rapid depressurization, the ma- terial solidifies to form solid polymeric foam with a micro-porous structure (as shown in Fig. 1(iv)).