Capreomycin oleate microparticles for intramuscular administration: Preparation, in vitro release and preliminary in vivo evaluation Adrián Cambronero-Rojas a,b , Pablo Torres-Vergara a, ⁎ ,1 , Ricardo Godoy a , Carlos von Plessing a , Jacqueline Sepúlveda c , Carolina Gómez-Gaete a, ⁎ ,1 a Faculty of Pharmacy, University of Concepción, Concepción, Chile b Hospital Dr. Fernando Escalante Pradilla, CCSS, San José, Costa Rica c Department of Pharmacology, Faculty of Biological Sciences, University of Concepción, Chile abstract article info Article history: Received 28 July 2014 Received in revised form 24 April 2015 Accepted 3 May 2015 Available online 5 May 2015 Keywords: Capreomycin oleate PLGA DPPC Microparticles Spray drying Intramuscular Tuberculosis Capreomycin sulfate (CS) is a second-line drug used for the treatment of multidrug-resistant tuberculosis (MDR- TB). The adverse effects profile and uncomfortable administration scheme of CS has led to the development of formulations based on liposomes and polymeric microparticles. However, as CS is a water-soluble peptide that does not encapsulate properly into hydrophobic particulate matrices, it was necessary to reduce its aqueous sol- ubility by forming the pharmacologically active capreomycin oleate (CO) ion pair. The aim of this research was to develop a new formulation of CO for intramuscular injection, based on biodegradable microparticles that encap- sulate CO in order to provide a controlled release of the drug with reduced local and systemic adverse effects. The CO-loaded microparticles prepared by spray drying or solvent emulsion-evaporation were characterized in their morphology, encapsulation efficiency, in vitro/in vivo kinetics and tissue tolerance. Through scanning elec- tron microscopy it was confirmed that the microparticles were monodisperse and spherical, with an optimal size for intramuscular administration. The interaction between CO and the components of the microparticle matrix was confirmed on both formulations by X-ray powder diffraction and differential scanning calorimetry analyses. The encapsulation efficiencies for the spray-dried and emulsion-evaporation microparticles were 92% and 56%, respectively. The in vitro kinetics performed on both formulations demonstrated a controlled and continuous release of CO from the microparticles, which was successfully reproduced on an in vivo rodent model. The results of the histological analysis demonstrated that none of the formulations produced significant tissue damage on the site of injection. Therefore, the results suggest that injectable CO microparticles obtained by spray drying and sol- vent emulsion-evaporation could represent an interesting therapeutic alternative for the treatment of MDR-TB. © 2015 Elsevier B.V. All rights reserved. 1. Introduction Tuberculosis (TB) is an infectious bacterial disease considered as a major cause of illness and death in many countries [1,2]. In humans, this disease is mainly caused by contagion with Mycobacterium tubercu- losis [3] and pulmonary TB is the commonest clinical presentation [4,5]. Pharmacological treatment of TB is basically a combination of drugs that must be given (orally or via injection) under a strict scheme, which varies according to the degree of resistance held by the bacterial strain that infects the patient [6]. Total compliance to TB treatments is difficult to achieve because of their length, the amount of drugs administered, the severity of certain adverse effects and the route of administration of some drugs, which can be very uncomfortable for most of patients [7]. Failure to comply can lead to the apparition of M. tuberculosis strains that are resistant to first-line drugs. Multidrug-resistant tuberculosis (MDR-TB) is often the result of a failed treatment with first line drugs due to patient non-compliance, prescription of a wrong/incomplete drug scheme, or an ineffective directly observed treatment short course (DOTS) therapy. Treatment of MDR-TB involves the use of second-line drugs, which are more expensive and have more adverse effects than first-line drugs [8]. Capreomycin sulfate (CS), a peptide obtained from strains of Strepto- myces capreolum, is a second-line drug used to treat patients infected with isoniazid and rifampicin-resistant M. tuberculosis strains [9,10]. Despite its efficacy, the adverse effects profile of CS and administration route, based on repeated intramuscular injections for several days, reduce the probabilities of achieving a full recovery from the disease [11]. As CS is an effective drug when tolerated by the patient, this subject has been a matter of interest for many research groups that have addressed the issue with the current advances in microparticle Journal of Controlled Release 209 (2015) 229–237 ⁎ Corresponding authors at: Facultad de Farmacia, Universidad de Concepción, Barrio Universitario s/n, Concepción, Chile. E-mail addresses: pabltorr@udec.cl (P. Torres-Vergara), cargomez@udec.cl (C. Gómez-Gaete). 1 Carolina Gómez-Gaete and Pablo Torres-Vergara are both senior authors. http://dx.doi.org/10.1016/j.jconrel.2015.05.001 0168-3659/© 2015 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel