Original article Development of thalidomide-loaded biodegradable devices and evaluation of the effect on inhibition of inflammation and angiogenesis after subcutaneous application Bruno Gonc ¸alves Pereira a,b , Leandro Flores Batista a , Pedro Alca ˆntara Fonseca de Souza a , Gisele Rodrigues da Silva c , Silvia Passos Andrade d , Roge ´ ria Serakides e , Wagner da Nova Mussel f , Armando Silva-Cunha b , Sı ´lvia Ligo ´ rio Fialho a, * a Pharmaceutical Research and Development, Ezequiel Dias Foundation – Funed, Belo Horizonte, Brazil b Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil c Faculty of Pharmacy, Federal University of Sa˜o Joa˜o Del Rei, Divino ´polis, Brazil d Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil e School of Veterinary, Federal University of Minas Gerais, Belo Horizonte, Brazil f Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, Brazil 1. Introduction Thalidomide (THD) was initially indicated as a sedative drug and the use by pregnant women led to severe infant limb defects probably because of its anti-angiogenic effect [1]. Besides, thalidomide presents important pharmacological properties, that include anti-inflammatory, immunomodulatory and antiangio- genic effects that shows remarkable value in the control or treatment of several diseases, even cancer [2,3]. Regarding its pharmacokinetics, thalidomide has physical– chemical properties that may be troublesome for bioavailability after oral administration. It is practically insoluble in water and presents a rapid and spontaneous hydrolysis that leads to an erratic and incomplete absorption after oral administration and even injectable formulations are limited face to thalidomide physicochemical properties [4–6]. Furthermore, thalidomide has severe adverse effects that limit its use, which includes peripheral neuropathy, constipation, sedation, somnolence, rash and deep vein thrombosis, resulting sometimes in treatment withdrawal [7]. A drug delivery system, in the form of biodegradable implants, may be an effective dosage form for the delivery of thalidomide since they may promote: (1) controlled drug release, that allows maintenance of effective therapeutic levels for a prolonged period of time without frequent doses dependent of patient adherence; (2) drug release directly to the site of action, avoiding adverse effects caused by systemic distribution; Biomedicine & Pharmacotherapy 71 (2015) 21–28 A R T I C L E I N F O Article history: Received 15 January 2015 Accepted 9 February 2015 Keywords: PLGA Delivery system Sponge model Anti-angiogenic Anti-inflammatory A B S T R A C T Purpose: To develop thalidomide-loaded poly-lactide-co-glycolide implants and evaluate its in vivo release and biological activity against inflammation and angiogenesis after subcutaneous administration. Methods: Implants were prepared by the hot molding technique and characterized using stereomicro- scopy, thermal analysis and X-ray diffraction. Swiss mice, divided in groups 1–3, received a subcutaneous implant containing 25% (w/w), 50% (w/w) or 75% (w/w) of thalidomide, respectively (n = 6). The drug levels were determined during a 28-day study period. The toxicity associated with the implants was evaluated by light microscopy. The potential of the developed implant in the inhibition of inflammation and angiogenesis was evaluated in vivo using the sponge model. Results: Thalidomide implant was developed and its characterization proved the stability of the drug and the polymer during preparation. Release profiles in vivo demonstrated an extended release of thalidomide from the implants during the 28 days. Histological evaluation did not show any sign of intense local inflammatory response to the presence of the implants in the subcutaneous pouch. The thalidomide implant reduced the number of vessels and N-acetyl-b-glucosaminidase (NAG) in vivo. Conclusion: The biodegradable implants delivered safe doses of thalidomide that were also effective to induce angiogenesis and inflammation regression. ß 2015 Elsevier Masson SAS. All rights reserved. * Corresponding author at: Pharmaceutical Research and Development, Ezequiel Dias Foundation, Rua Conde Pereira Carneiro, 80, Gameleira, CEP 30510-010, Belo Horizonte, MG, Brazil. Tel.: +55 31 3314 4986; +55 31 3314 4766. E-mail address: silvia.fialho@funed.mg.gov.br (S.L. Fialho). Available online at ScienceDirect www.sciencedirect.com http://dx.doi.org/10.1016/j.biopha.2015.02.003 0753-3322/ß 2015 Elsevier Masson SAS. All rights reserved.