A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia
A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia
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DOI：
10.1097/00000542-200407000-00021
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发表时间：
2004-07-01
期刊：
影响因子：
8.8
通讯作者：
Davidson, EM
中科院分区：
文献类型：
--
作者：
Grant, GJ;Barenholz, Y;Davidson, EM
背景。目前可用的局部麻醉剂的作用时间相对较短。超长效局麻药对急性和慢性疼痛患者都有好处。作者制备并表征了一种新型布比卡因脂质体制剂，采用沿硫酸铵梯度远程装载布比卡因，并评估了其在人体中的功效。方法：采用单层小泡连续冻融的方法制备布比卡因多泡大脂质体制剂。然后沿硫酸铵梯度([(NH4)(2)SO4)]（脂质体内）/ [(NH4)（2)SO4)]（中）> 1000）将盐酸布比卡因远程加载到脂质体中。然后对脂质体的大小分布进行表征；drug-to-phospholipid比率;4℃、21℃和37℃的体外释放曲线；不育;和pyrogenicity。6名受试者分别在腰背部皮下注射0.5 ml浓度为0.5、1.0和2%的布比卡因脂质体；0.5%标准布比卡因；生理盐水;和“空”脂质体。用针刺法直接在注射部位的皮肤上进行测试来评估镇痛的持续时间。结果采用log-rank检验进行比较。结果：大多泡囊泡的平均大小为2439±544 nm，药物与磷脂的比值为1.8，是先前报道结果的5倍。体外释放最慢，为4度。0.5%标准布比卡因的中位镇痛持续时间为1小时。0.5%、1.0和2.0%布比卡因脂质体的中位镇痛持续时间分别为19、38和48小时。生理盐水和“空”脂质体均不能产生镇痛作用。结论：该新型脂质体制剂具有良好的药磷脂比，并以剂量依赖性方式延长布比卡因镇痛持续时间。如果这些结果在健康志愿者身上可以在临床环境中复制，这种配方有可能显著影响疼痛的管理。
Background. Currently available local anesthetics have relatively brief durations of action. An ultralong-acting local anesthetic would benefit patients with acute and chronic pain. The authors prepared and characterized a novel liposomal bupivacaine formulation using remote loading of bupivacaine along an ammonium sulfate gradient and assessed its efficacy in humans.Methods: A large multivesicular liposomal bupivacaine formulation was prepared by subjecting small unilamellar vesicles to successive freeze-and-thaw cycles. Bupivacaine hydrochloride was then remotely loaded into the liposomes along an ammonium sulfate gradient ([(NH4)(2)SO4)](intraliposome)/ [(NH4)(2)SO4)](medium) > 1,000). The liposomes were then characterized for size distribution; drug-to-phospholipid ratio; in vitro release profile at 4degrees, 21degrees, and 37degreesC; sterility; and pyrogenicity. Six subjects each received six intradermal injections in the lower back with 0.5 ml of 0.5, 1.0, and 2% liposomal bupivacaine; 0.5% standard bupivacaine; saline; and "empty" liposomes. Duration of analgesia was assessed using pinprick testing of the skin directly over the injection sites. Results were compared using the log-rank test.Results: The mean large multivesicular vesicle size was 2,439 +/- 544 nm, with a drug-to-phospholipid ratio of 1.8, fivefold greater than results previously reported. In vitro release was slowest at 4degreesC. The median duration of analgesia with 0.5% standard bupivacaine was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, respectively. Neither saline nor "empty" liposomes produced analgesia.Conclusions: This novel liposomal formulation had a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this formulation has the potential to significantly impact the management of pain.