Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas - UNICAMP, Campinas, São Paulo, Brazil.
Department of Structural and Functional Biology, Institute of Biology, UNICAMP, Brazil.
Biomater Sci. 2021 May 4;9(9):3378-3389. doi: 10.1039/d1bm00077b.
The most frequently used local anesthetics (LA) for local infiltration have an ionizable amine in the range of pH 7.6-8.9. Effective anesthesia of inflamed tissues is a great challenge, especially because the induced local acidosis decreases the fraction of the neutral (more potent) LA species in situ. To solve this limitation, the butyl-substituted benzocaine analogue butamben (BTB) - that has no ionizable amine group close to the physiological pH - could be useful if it was not for its low solubility. To overcome the solubility problem, an optimized formulation for BTB using nanostructured lipid carriers (NLC) was developed by a factorial design and characterized using DLS, XRD, DSC and cryo-EM. The release kinetics and cytotoxicity of the new formulation were measured in vitro, while the in vivo tests assessed its effectiveness on healthy and inflamed tissues, in rats. The optimized NLCBTB formulation showed desirable physicochemical properties (size = 235.6 ± 3.9 nm, polydispersity = 0.182 ± 0.006 and zeta potential = -23.6 ± 0.5 mV), high (99.5%) encapsulation efficiency and stability during 360 days of storage at room temperature. NLCBTB prolonged the release of butamben and decreased its in vitro cytotoxicity without inducing any in vivo toxic alteration. In the inflammatory hyperalgesia model, the NLCBTB formulation showed potential for the management of inflammatory pain, displaying greater analgesic effectiveness (40%) and a prolonged effect.
最常被用于局部浸润麻醉的局部麻醉剂（LA）在 pH 值 7.6-8.9 范围内具有可电离的胺。对发炎组织进行有效的麻醉是一个巨大的挑战，特别是因为诱导的局部酸中毒会降低中性（更有效）局部麻醉剂物种在局部的比例。为了解决这个限制，如果没有无离子化胺基团接近生理 pH 值的丁基取代苯佐卡因类似物丁卡因（BTB） - 可以使用，如果不是因为它的低溶解度。为了克服溶解度问题，通过因子设计开发了一种使用纳米结构化脂质载体（NLC）的 BTB 优化配方，并使用 DLS、XRD、DSC 和冷冻 EM 进行了表征。新配方的释放动力学和细胞毒性在体外进行了测量，而体内测试评估了其在健康和发炎组织中的有效性，在大鼠中。优化的 NLCBTB 配方表现出理想的物理化学性质（大小 = 235.6 ± 3.9nm、多分散性 = 0.182 ± 0.006 和 zeta 电位 = -23.6 ± 0.5mV）、高（99.5%）包封效率和在室温下储存 360 天的稳定性。NLCBTB 延长了丁卡因的释放并降低了其体外细胞毒性，而不会引起任何体内毒性改变。在炎症性痛觉过敏模型中，NLCBTB 配方显示出管理炎症性疼痛的潜力，表现出更大的镇痛效果（40%）和更长的作用时间。
