Paavola Anne, Bernards Christopher M, Rosenberg Per H
Faculty of Pharmacy, University of Helsinki, Finland; Department of Anesthesiology, University of Washington, Seattle, USA.
Department of Anesthesiology, University of Washington, Seattle, USA.
Eur J Pharm Biopharm. 2016 Nov;108:180-186. doi: 10.1016/j.ejpb.2016.09.006. Epub 2016 Sep 9.
In order to avoid the risks of sideeffects of epidural local anesthetics and opioids, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) epidurally would be an interesting option of analgesic therapy. The fairly short duration of action of spinally administered NSAIDs, e.g., ibuprofen, may be prolonged by using controlled release poloxamer gel formulation. Using a microdialysis technique we studied the epidural and intrathecal pharmacokinetics of ibuprofen after its epidural administration as a poloxamer 407 formulation or a solution formulation. In addition, plasma ibuprofen concentrations were analyzed from central venous blood samples. Ibuprofen concentrations in the epidural space were significantly higher and longer lasting after the epidural gel injection compared with the epidural solution injection. The epidural AUC of ibuprofen was over threefold greater after epidural ibuprofen gel injection compared with the ibuprofen solution injection (p<0.001). The systemic absorption of ibuprofen from 25% poloxamer 407 gel was very low. The in situ forming poloxamer gel acted as a reservoir allowing targeted ibuprofen release at the epidural injection site and restricted ibuprofen molecules to a smaller spinal area. Ibuprofen diffusion from the epidural space to the intrathecal space was steady and prolonged. These results demonstrate that the use of epidurally injectable poloxamer gel can increase and prolong ibuprofen delivery from epidural space to the CSF enhancing thus ibuprofen entry into the central neuroaxis for spinal analgesia. Further toxicological and dose-finding studies are justified.
为避免硬膜外局部麻醉药和阿片类药物的副作用风险，硬膜外使用非甾体抗炎药（NSAIDs）将是一种有趣的镇痛治疗选择。脊髓给予的NSAIDs（如布洛芬）作用持续时间相当短，使用控释泊洛沙姆凝胶制剂可能会延长其作用时间。我们采用微透析技术研究了布洛芬以泊洛沙姆407制剂或溶液制剂硬膜外给药后的硬膜外和鞘内药代动力学。此外，还分析了中心静脉血样本中的血浆布洛芬浓度。与硬膜外溶液注射相比，硬膜外凝胶注射后硬膜外间隙中的布洛芬浓度显著更高且持续时间更长。硬膜外注射布洛芬凝胶后，布洛芬的硬膜外AUC比注射布洛芬溶液后高出三倍多（p<0.001）。25%泊洛沙姆407凝胶中布洛芬的全身吸收非常低。原位形成的泊洛沙姆凝胶起到了储库的作用，使布洛芬在硬膜外注射部位靶向释放，并将布洛芬分子限制在较小的脊髓区域。布洛芬从硬膜外间隙向鞘内间隙的扩散稳定且持续时间长。这些结果表明，硬膜外注射泊洛沙姆凝胶可增加并延长布洛芬从硬膜外间隙向脑脊液的递送，从而增强布洛芬进入中枢神经轴用于脊髓镇痛的效果。进一步的毒理学和剂量探索研究是合理的。
