Sutton S C, Evans L A, Rinaldi M T, Norton K A
Pharmaceutical R & D Department, Pfizer Incorporated, Groton, Connecticut 06340, USA.
Pharm Res. 1996 Oct;13(10):1514-8. doi: 10.1023/a:1016027528937.
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.
ER formulations (danofloxacin oily and aqueous suspensions) were evaluated in RbLV, rat and rabbit plasma creatine phosphokinase (CK), and rat foot edema (RFE) models as described in the companion article.
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 RbLVdays1-3 was marked and greater (p < 0.05) for 60 mg/ml (6.0 +/- 3.1) than vehicle (2.2 +/- 2.9) formulations. Furthermore, RbLVdays 1-3) 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.
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.
本研究的目的是找到一种资源节约型替代方法，以替代兔损伤模型（RbLV），用于评估缓释（ER）肌肉注射（IM）制剂筛选中的注射部位耐受性。
如配套文章所述，在RbLV、大鼠和兔血浆肌酸磷酸激酶（CK）以及大鼠足部水肿（RFE）模型中评估ER制剂（达氟沙星油性和水性混悬液）。
没有一个短期模型能够始终如一地预测其急性和慢性影响。例如，RFE预测水性载体（0.03±0.03 g）和60 mg/ml（0.08±0.03 g）制剂对肌肉损伤较小；而RbLV第1 - 3天，60 mg/ml（6.0±3.1）制剂的损伤明显更大（p < 0.05），高于载体（2.2±2.9）制剂。此外，载体（6.5±7.5）和60 mg/ml（4.9±4.6）达氟沙星油性制剂的RbLV第1 - 3天情况比单独的油（1.4±2.2）更差（p < 0.05）；CK模型未预测到这一观察结果，因为它们显然仅反映了注射时周围组织中立即可用的制剂成分的急性肌肉损伤。
CK模型可能有助于筛选那些因立即可用成分而具有不可接受急性损伤的ER制剂。然而，为了评估ER制剂的潜在延迟效应，仍推荐使用长期模型RbLV。
