In vitro-in vivo myotoxicity of intramuscular liposomal formulations.
OBJECTIVE
The first objective was to study the in vitro myotoxicity of empty liposomes and to examine whether liposome size, charge and fluidity affect of liposomal myotoxicity. The second objective was to investigate the effect of liposomal encapsulation on the in vitro and in vivo myotoxicity of loxapine compared to the loxapine commercial preparation (Loxitane).


METHODS
The in vitro myotoxicity of empty liposomes and loxapine liposomes was evaluated by the cumulative efflux of the cytosolic enzyme creatine kinase (CK) from the isolated rat extensor digitorum longus (EDL) muscle over a 2 hour period. In the in vivo studies, the area under plasma CK curve over 12 hours was used to evaluate muscle damage.


RESULTS
The in vitro myotoxicity for all empty liposomal formulations was not statistically different from negative controls (untreated control muscles and normal saline injected muscles). However, these empty liposomal formulations were significantly less myotoxic than the positive controls (muscles injected with phenytoin and muscle sliced in half). In vitro-in-vivo studies showed that the liposomal encapsulation of loxapine resulted in significant (P < 0.05) reduction in myotoxicity (80% in vitro and 60% in vivo) compared to the commercially available formulation which contains propylene glycol (70% V/V) and polysorbate 80 (5% W/V) prepared at equal concentration.


CONCLUSIONS
Results indicate that empty liposomes do not induce myotoxicity. Furthermore, liposomal size, charge and fluidity do not affect myotoxicity. In addition, in vitro and in vivo studies have demonstrated that liposomal encapsulation of loxapine can reduce myotoxicity compared to a formulation containing organic cosolvents.
Department of Pharmaceutics, University of Florida, College of Pharmacy, J. Hillis Miller Health Center Gainesville 32610, USA.
S A
SA
al-Suwayeh
I R
IR
Tebbett
D
D
Wielbo
G A
GA
Brazeau
D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D018492:Dopamine Antagonists / Q000633:toxicity*; D004337:Drug Carriers / Q000633:toxicity; D066298:In Vitro Techniques; D007273:Injections, Intramuscular; D008081:Liposomes / Q000633:toxicity; D008152:Loxapine / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology; D010672:Phenytoin / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
D018492:Dopamine Antagonists; D004337:Drug Carriers; D008081:Liposomes; D010672:Phenytoin; D003402:Creatine Kinase; D008152:Loxapine