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 usin
g the isolated rodent skeletal muscle model by measuring the cumulative cre
atine kinase (CK) efflux. For the in-vivo study, following intramuscular in
jection (i.m.) into male Sprague Dawley rats, the area under the plasma CK-
curve was used to evaluate muscle damage. The formulations included ISM-sys
tems la poly (lactide)-solvent phase dispersed into an external oil phase a
nd poly (lactide) solutions (in-situ implant systems). Phenytoin and normal
saline served as positive and negative controls, respectively. Poly (lacti
de) in different solvents (in-situ implant systems) resulted in 14.4-24.3 t
imes higher CK-values compared to normal saline, indicating a high myotoxic
potential. With the ISM-system, the CK-release was significantly lower, de
creased with a lower polymer phase: oil phase ratio, and approached the val
ues of normal saline at a ratio of 1:4. Bupivacaine HCl- and Buserelin acet
ate- containing ISM-systems resulted in significantly lower CK-levels when
compared to the corresponding drug formulation in normal saline. The in-viv
o studies confirmed the in-vitro data and showed good muscle compatibility
of the ISM-systems. (C) 2001 Elsevier Science B.V. All rights reserved.