title: Capreomycin oleate microparticles for intramuscular administration: Preparation, in vitro release and preliminary in vivo evaluation.
abstract: 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 solubility 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 encapsulate 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 electron 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 solvent emulsion-evaporation could represent an interesting therapeutic alternative for the treatment of MDR-TB.
authors.affiliation: Faculty of Pharmacy, University of Concepción, Concepción, Chile; Hospital Dr. Fernando Escalante Pradilla, CCSS, San José, Costa Rica.
authors.forename: Adrián
authors.initials: A
authors.lastname: Cambronero-Rojas
authors.affiliation: Faculty of Pharmacy, University of Concepción, Concepción, Chile. Electronic address: pabltorr@udec.cl.
authors.forename: Pablo
authors.initials: P
authors.lastname: Torres-Vergara
authors.affiliation: Faculty of Pharmacy, University of Concepción, Concepción, Chile.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Godoy
authors.affiliation: Faculty of Pharmacy, University of Concepción, Concepción, Chile.
authors.forename: Carlos
authors.initials: C
authors.lastname: von Plessing
authors.affiliation: Department of Pharmacology, Faculty of Biological Sciences, University of Concepción, Chile.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sepúlveda
authors.affiliation: Faculty of Pharmacy, University of Concepción, Concepción, Chile. Electronic address: cargomez@udec.cl.
authors.forename: Carolina
authors.initials: C
authors.lastname: Gómez-Gaete
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D002207:Capreomycin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004339:Drug Compounding; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005260:Female; D007273:Injections, Intramuscular; D008297:Male; D009132:Muscles / Q000033:anatomy & histology / Q000187:drug effects; D019301:Oleic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley
chemical_list: D000904:Antibiotics, Antitubercular; D003692:Delayed-Action Preparations; D002207:Capreomycin; D019301:Oleic Acid
keywords: Capreomycin oleate; DPPC; Intramuscular; Microparticles; PLGA; Spray drying; Tuberculosis