Predicting Injection Site Muscle Damage II: Evaluation of Extended Release Parenteral Formulations in Animal Models

Abstract

Purpose. The goal of this study was to find a resource sparing alternative to the rabbit lesion model (RbLV) for assessing injection site toleration in extended release (ER) intramuscular (IM) formulation screening.

Methods. ER formulations (danofloxacin oily and aqueous suspensions) were evaluated in RbLV, rat and rabbit plasma creatine phospho-kinase (CK), and rat foot edema (RFE) models as described in the companion article.

Results. None of the short term models could consistently predict acute and chronic effects of the. For example, RFE predicted little muscle damage from aqueous vehicle (0.03 ± 0.03 g) and 60 mg/ml (0.08 ± 0.03 g) formulation; while RbLV_{days l–3} was marked and greater (p < 0.05) for 60 mg/ml (6.0 ± 3.1) than vehicle (2.2 ± 2.9) formulations. Furthermore, RbLV_{days l–3} for vehicle (6.5 ± 7.5) and 60 mg/ml (4.9 ± 4.6) danofloxacin oily formulations were worse (p < 0.05) than oil alone (1.4 ± 2.2); an observation not predicted by CK models, since they apparently reflected only the acute muscle damage of formulation components immediately available to surrounding tissue at the time of injection.

Conclusions. The CK models may be useful to screen those ER formulations with unacceptable acute damage due to immediately available components. However, to evaluate potential delayed effects from ER formulations, the long-term model RbLV was still recommended.