title: Myotoxicity studies of injectable biodegradable in-situ forming drug delivery systems.
abstract: The objective of the study was to investigate the potential in-vitro and in-vivo myotoxicity of different in-situ forming biodegradable drug delivery systems, namely in-situ Microparticle (ISM) systems and polymer solutions (in-situ implant systems). The acute myotoxicity was evaluated in-vitro using the isolated rodent skeletal muscle model by measuring the cumulative creatine kinase (CK) efflux. For the in-vivo study, following intramuscular injection (i.m.) into male Sprague Dawley rats, the area under the plasma CK-curve was used to evaluate muscle damage. The formulations included ISM-systems [a poly (lactide)-solvent phase dispersed into an external oil phase] and poly (lactide) solutions (in-situ implant systems). Phenytoin and normal saline served as positive and negative controls, respectively. Poly (lactide) in different solvents (in-situ implant systems) resulted in 14.4-24.3 times higher CK-values compared to normal saline, indicating a high myotoxic potential. With the ISM-system, the CK-release was significantly lower, decreased with a lower polymer phase: oil phase ratio, and approached the values of normal saline at a ratio of 1:4. Bupivacaine HCl- and Buserelin acetate- containing ISM-systems resulted in significantly lower CK-levels when compared to the corresponding drug formulation in normal saline. The in-vivo studies confirmed the in-vitro data and showed good muscle compatibility of the ISM-systems.
authors.affiliation: College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169, Berlin, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Kranz
authors.forename: G A
authors.initials: GA
authors.lastname: Brazeau
authors.forename: J
authors.initials: J
authors.lastname: Napaporn
authors.forename: R L
authors.initials: RL
authors.lastname: Martin
authors.forename: W
authors.initials: W
authors.lastname: Millard
authors.forename: R
authors.initials: R
authors.lastname: Bodmeier
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D007273:Injections, Intramuscular; D019344:Lactic Acid / Q000633:toxicity; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects*; D011091:Polyesters / Q000633:toxicity; D011100:Polyglycolic Acid / Q000633:toxicity; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011091:Polyesters; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); D003402:Creatine Kinase