Morey Timothy E, Modell Jerome H, Shekhawat Dushyant, Grand Todd, Shah Dinesh O, Gravenstein Nikolaus, McGorray Susan P, Dennis Donn M
Department of Anesthesiology, University of Florida, Gainesville, 32610, USA.
Anesthesiology. 2006 Jun;104(6):1184-90. doi: 10.1097/00000542-200606000-00013.
The lipophilicity of propofol has required dispersion in a soybean macroemulsion. The authors hypothesized that the anesthetic properties of propofol are preserved when reformulated as a transparent microemulsion rather than as a turbid macroemulsion and that the dose-response relation can be selectively modified by altering the microemulsion's surfactant type and concentration.
Microemulsions of propofol were formulated using purified poloxamer 188 (3%, 5%, 7%), and sodium salt of fatty acids (C(8), C(10), C(12)) in saline and characterized using ternary/binary diagrams, particle sizing, and stability upon dilution. Rats received propofol (10 mg . kg(-1) . min(-1)) as either a microemulsion or a conventional macroemulsion to determine these end points: induction (dose; stunned; loss of lash reflex, righting reflex, withdrawal to toe pinch) and recovery (recovery of lash, righting, withdrawal reflexes). After a 14-day recovery period, rats were crossed over into the opposite experimental limb.
Forty-eight microemulsions (diameter, 11.9-47.7 nm) were formulated. Longer carbon chain length led to a marked increase in the volume of diluent necessary to break these microemulsions. All rats experienced anesthetic induction with successful recovery, although significantly greater doses of propofol were required to induce anesthesia with microemulsions irrespective of surfactant concentration or type than with macroemulsions. The sodium salt of C10 fatty acid microemulsion required the greatest dose and longest time for anesthetic induction.
Propofol microemulsions cause induction in rats similar to that from macroemulsions. The surfactant concentration and type markedly affect the spontaneous destabilization and anesthetic properties of microemulsions, a phenomenon suggesting a mechanism whereby dose-response relation can be selectively modified.
丙泊酚的亲脂性使其需分散于大豆大乳剂中。作者推测，将丙泊酚重新配制为透明微乳剂而非浑浊大乳剂时，其麻醉特性得以保留，且通过改变微乳剂的表面活性剂类型和浓度可选择性地改变剂量 - 反应关系。
使用纯化的泊洛沙姆188（3%、5%、7%）和脂肪酸钠盐（C8、C10、C12）在盐水中配制丙泊酚微乳剂，并使用三元/二元相图、粒度分析及稀释稳定性进行表征。大鼠接受丙泊酚（10 mg·kg⁻¹·min⁻¹），剂型为微乳剂或传统大乳剂，以确定以下终点：诱导（剂量；惊厥；睫毛反射消失、翻正反射消失、对趾捏取反应消失）和恢复（睫毛反射、翻正反射、退缩反射恢复）。经过14天的恢复期后，大鼠交叉进入相反的实验组。
配制了48种微乳剂（直径为11.9 - 47.7 nm）。碳链长度增加导致破坏这些微乳剂所需稀释剂体积显著增加。所有大鼠均经历麻醉诱导并成功恢复，尽管与大乳剂相比，无论表面活性剂浓度或类型如何，使用微乳剂诱导麻醉所需的丙泊酚剂量均显著更高。C10脂肪酸钠微乳剂诱导麻醉所需剂量最大且时间最长。
丙泊酚微乳剂在大鼠中引起的诱导作用与大乳剂相似。表面活性剂的浓度和类型显著影响微乳剂的自发失稳和麻醉特性，这一现象提示了一种可选择性改变剂量 - 反应关系的机制。
