PLGA Microdevices for Retinoids Sustained Release Produced by Supercritical Emulsion Extraction: Continuous Versus Batch Operation Layouts GIOVANNA DELLA PORTA, 1,2 ROBERTA CAMPARDELLI, 1 NUNZIA FALCO, 1 ERNESTO REVERCHON 1 1 Dipartimento di Ingegneria Industriale, Universit` a di Salerno, Via Ponte don Melillo, 84084 Fisciano (SA), Italy 2 Laboratorio di Ingegneria Cellulare e Molecolare (DEIS), Universit` a di Bologna, Via Venezia 52, 47521 Cesena (FC), Italy Received 29 March 2011; revised 2 May 2011; accepted 11 May 2011 Published online 2 June 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22647 ABSTRACT: Retinyl acetate (RA) was selected as a model compound to be entrapped in poly(lactic-co-glycolic)acid (PLGA) microspheres using supercritical emulsion extraction (SEE). Several oil-in-water emulsions prepared using acetone and aqueous glycerol (80% glycerol, 20% water) were processed using supercritical carbon dioxide (SC-CO 2 ) to extract the oily phase and to induce microspheres formation. The characteristics of the microspheres obtained by conventional liquid emulsion extraction and SEE were also compared: SEE produced spheri- cal and free flowing microspheres, whereas the conventional liquid–liquid extraction showed large intraparticles aggregation. Emulsion extraction by SC-CO 2 technology was tested us- ing two different operation layouts: batch (SEE-B) and continuous (SEE-C). SEE-C was per- formed using a packed tower to produce emulsion/SC-CO 2 contact in countercurrent mode, allowing higher microsphere recovery and process efficiencies. Operating at 80 bar and 36 ◦ C, SEE-C produced PLGA/RA microspheres with mean sizes between 3.3 and 4.5 : m with an excellent encapsulation efficiency of 80%–90%. Almost all the drug was released in about 6 days when charged at 2.7% (w/w), whereas only 40% and 10% of RA were released in the same period of time when the charge was 5.2% and 8.8% (w/w), respectively. Release kinet- ics constants calculated from the experimental data, using a mathematical model, were also proposed and discussed. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4357–4367, 2011 Keywords: supercritical fluids; PLGA; microspheres; emulsion; controlled release INTRODUCTION All trans-retinoic acids (atRAs, or vitamin A complex) show a high therapeutic potential in the treatment of several diseases and, recently, they have also been included in anticancer therapeutical schemes. 1 How- ever, atRAs are very labile at ambient conditions and their degradation is a typical radical reaction, cat- alyzed by light, transition metals, or free radicals. 2 Because of their short half-life and hydrophobicity, retinoids parenteral administration is very difficult and to date no commercial formulations are available. Different formulations have been investigated to overcome fast metabolization of retinoids and to achieve their locally sustained release: encap- Correspondence to: Giovanna Della Porta (Telephone: +39-089- 964104; Fax: +39-089-964057; E-mail: gdellaporta@unisa.it) Journal of Pharmaceutical Sciences, Vol. 100, 4357–4367 (2011) © 2011 Wiley-Liss, Inc. and the American Pharmacists Association sulation into injectable microspheres, 3 emulsions, 4 nanodisks, 5 liposomes, 2 solid lipid nanoparticles, 6 and nanoparticles. 7 Retinoids encapsulation in poly(lactic-co-glycolic)acid (PLGA) microparticles with diameters ranging between 1 and 30 : m and narrow size distributions could be interesting for drug controlled release and/or targeting after local administration. 8–10 PLGA microparticles have also been suggested as biodegradable support for cell cul- ture in the so-called “injectable scaffolds,” 11–13 which may affect stem cells lineage restriction and, after polymer degradation, allow a complete integration of the grafted cells in the host tissue. For example, some authors 14,15 reported the possibility of pluripotent stem cell differentiation into neurons after cells adhe- sion and growth on the surface of PLGA microspheres loaded with retinoids, confirming the potential use of these microdevices as transplantation matrices for tissue engineering. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 100, NO. 10, OCTOBER 2011 4357