RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology Sustained Release of Naltrexone from Poly(N-Isopropylacrylamide) Microgels ANNA-LENA KJØNIKSEN, 1,2 MARIA TERESA CALEJO, 1,3 KAIZHENG ZHU, 4 ANA MARIA S. CARDOSO, 5 MARIA C. PEDROSO DE LIMA, 5,6 AM ´ ALIA S. JURADO, 5,6 BO NYSTR ¨ OM, 4 SVERRE ARNE SANDE 1 1 Department of Pharmacy, School of Pharmacy, University of Oslo, Blindern, N-0316 Oslo, Norway 2 Faculty of Engineering, Østfold University College, N-1757 Halden, Norway 3 Department of Electronics and Communications Engineering, Tampere University of Technology, FI-33101 Tampere, Finland 4 Department of Chemistry, University of Oslo, Blindern, N-0315 Oslo, Norway 5 CNC – Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal 6 Department of Life Sciences, University of Coimbra, Coimbra, Portugal Received 12 September 2013; revised 17 October 2013; accepted 18 October 2013 Published online 11 November 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23780 ABSTRACT: The release of the opioid antagonist naltrexone from neutral poly(N-isopropylacrylamide) (PNIPAAM) microgels and negatively charged PNIPAAM microgels containing acrylic acid groups (PNIPAAM-co-PAA) has been studied at various microgel and drug concen- trations. The release curves were found to be well represented by the Weibull equation. The release rates were observed to be dependent on the microgel concentration. At most conditions, the release from the charged microgels was slower than for the neutral microgels. In addition, the charged microgels exhibited a release lag time, which was dependent on the microgel concentration. No significant lag time could be observed for the neutral microgels. Increasing the naltrexone concentration did not significantly affect the release rates from the neutral microgels, but the release from the charged microgels became faster. The microgels did not exhibit any significant cytotoxic effect on HeLa cells at the tested concentrations. C  2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:227–234, 2014 Keywords: controlled release; drug delivery systems; macromolecular drug delivery; microencapsulation; microparticles; polymeric drug delivery systems INTRODUCTION Naltrexone (Fig. 1) is an opioid antagonist, and has been used to treat heroin and alcohol addiction. However, oral naltrexone formulations have drawbacks such as patient noncompliance, 1 fluctuating plasma levels, 2 and the exten- sive first-pass metabolism of naltrexone. 3 Injectable de- pot formulations that can give a sustained release of nal- trexone over an extended period of time could prevent the problems encountered with oral dosage forms. Sev- eral systems such as poly(L-lactide) microspheres, 4,5 poly lactide-co-glycolide (PLGA) microspheres, 6 poly(D,L-lactide- co-glycolide) microspheres, 7 polyethylene glycol-graft-methyl methacrylate crosslinked nanoparticles, 8 and nanoparti- cles produced from a blend of poly(N-isopropylacrylamide- acrylamide-vinylpyrrolidone) and PLGA 9 have been suggested for sustained release dosage forms for naltrexone. There is how- ever still need for improving the release profile and drug loading capacity of the systems. Utilizing new kinds of thermosensitive in situ gelling microgels might therefore be of interest. The release of a drug that is encapsulated into micro- or nanoparticles is dependent on a number of factors such as particle size, 10–13 drug size, 14,15 the degree of swelling of the particles, 16–18 erosion of the particles, 19 and associative inter- actions between the drug and the particles, for example, hy- Correspondence to: Anna-Lena Kjøniksen (Telephone: +47-69104095; Fax: +47-69215002; E-mail: anna.l.kjoniksen@hiof.no) Journal of Pharmaceutical Sciences, Vol. 103, 227–234 (2014) C  2013 Wiley Periodicals, Inc. and the American Pharmacists Association drophobic interactions, 15 hydrogen bonds, 20,21 or electrostatic interactions. 14 Nano- and microparticles that are formed using thermosen- sitive polymers with a lower critical solution temperature (LCST) have a swollen structure at temperatures below the transition temperature and a more compact (collapsed) struc- ture at higher temperatures. This effect can be utilized both to increase the loading capacity and modulate the release of a drug from the particles. Increased loading rate and capac- ity may be expected for drug loading in the swollen state, whereas the drug release is often found to be slower when the systems are heated to temperatures above the LCST of the particles due to reduced porosity. This phenomenon has been observed for several different systems such as: core–shell nanoparticles containing a poly(L-lactic acid) core and a poly(N- isopropylacrylamide) (PNIPAAM) thermosensitive shell, 22 alginate-hydroxypropylcellulose microbeads, 23 poly(N-vinyl caprolactam) nanoparticles, 24 poly(N-isopropylacrylamide-co- caprolactam) microspheres, 25 and PNIPAAM microspheres grafted with poly(itaconic acid) groups. 14 Interestingly, micro- spheres of elastin-like polypeptides (ELP) exhibited faster re- lease rates above the LCST due to the opening of micropores in the microspheres by the contraction of the thermosensitive ELP molecules. 26 Faster release rates above the LCST was also ob- served for chitosan-g-poly(N-vinylcaprolactam) and chitosan-g- PNIPAAM nanoparticles. 20,21 This was explained by the ability of the drug to form hydrogen bonds with the nanoparticles at temperatures below the LCST. This capacity was lost above the LCST, and hence faster release rates are promoted. Kjøniksen et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:227–234, 2014 227