Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Int J Pharm. 2011 Sep 20;416(2):493-8. doi: 10.1016/j.ijpharm.2011.02.062. Epub 2011 Mar 4.
The goal of this study was to compare the effects of liposomal and free glucocorticoid formulations on joint inflammation and activity of the hypothalamic-pituitary-adrenal (HPA) axis during experimental antigen-induced arthritis (AIA). A dose of 10mg/kg liposomal prednisolone phosphate (PLP) gave a suppression of the HPA-axis, as measured by plasma corticosterone levels in mice with AIA and in naïve mice. In a subsequent dose-response study, we found that a single dose of 1mg/kg liposomal prednisolone phosphate (PLP) was still equally effective in suppressing joint inflammation as 4 repeated once-daily injections of 10mg/kg free PLP. Moreover, the 1mg/kg liposomal PLP dose gave 22% less suppression of corticosterone levels than 10mg/kg of liposomal PLP at day 14 of the AIA. In order to further optimize liposomal glucocorticoids, we compared liposomal PLP with liposomal budesonide phosphate (BUP) (1mg/kg). At 1 day after treatment, liposomal BUP gave a significantly stronger suppression of joint swelling than liposomal PLP (lip. BUP 98% vs. lip. PLP 79%). Both formulations also gave a strong and lasting suppression of synovial infiltration in equal amounts. However, at day 21 after AIA, liposomal PLP still significantly suppressed corticosterone levels, whereas this suppression was not longer statistically significant for liposomal BUP.
Liposomal delivery improves the safety of glucocorticoids by allowing for lower effective dosing. The safety of liposomal glucocorticoid may be further improved by encapsulating BUP rather than PLP.
本研究旨在比较脂质体和游离糖皮质激素制剂对实验性抗原诱导关节炎（AIA）时关节炎症和下丘脑-垂体-肾上腺（HPA）轴活性的影响。在 AIA 小鼠和正常小鼠中，给予 10mg/kg 脂质体泼尼松龙磷酸酯（PLP）可抑制 HPA 轴，表现为血浆皮质酮水平降低。在随后的剂量反应研究中，我们发现 1mg/kg 脂质体泼尼松龙磷酸酯（PLP）单次给药与 10mg/kg 游离 PLP 每日重复 4 次同样有效抑制关节炎症。此外，在 AIA 的第 14 天，1mg/kg 脂质体 PLP 剂量比 10mg/kg 脂质体 PLP 对皮质酮水平的抑制作用低 22%。为了进一步优化脂质体糖皮质激素，我们比较了脂质体 PLP 与脂质体布地奈德磷酸酯（BUP）（1mg/kg）。在治疗后 1 天，脂质体 BUP 对关节肿胀的抑制作用明显强于脂质体 PLP（脂质体 BUP 98% vs. 脂质体 PLP 79%）。两种制剂均以等量强烈且持久地抑制滑膜浸润。然而，在 AIA 后第 21 天，脂质体 PLP 仍显著抑制皮质酮水平，而脂质体 BUP 的抑制作用不再具有统计学意义。
脂质体给药通过允许更低的有效剂量来提高糖皮质激素的安全性。通过封装 BUP 而不是 PLP，可能进一步提高脂质体糖皮质激素的安全性。
