LIPOSOMAL LOCAL ANESTHETICS FOR OROFACIAL PAIN

脂质体局部麻醉剂治疗口面部疼痛

• 批准号: 2430135
• 负责人: GILBERT J GRANT
• 金额: $ 3.78万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2430135
• 关键词: acidity /alkalinity; antiseptic sterilization; articular cartilage; biomaterial development /preparation; body temperature; chemical hydration; chemical stability; cytotoxicity; drug delivery systems; drug screening /evaluation; glycoprotein biosynthesis; laboratory mouse; laboratory rabbit; laboratory rat; light microscopy; liposomes; local anesthesia; membrane model; oral facial pain; phospholipids; piperidine; proteoglycan; pyrogens; radiotracer; solutions

DESCRIPTION: This is a application proposes experiments designed to prepare and characterize a stable, non-toxic andefficacious liposomal bupivacaine formulation that can be used in the clinical setting. The principal investigator, has proposed fourspecific aims.The first aim is to prepare various dehydrated-rehydratedliposomalvesicle formulations and to characterize these vesicles with respectto concentration of entrapped drug and in vitro release kinetics. The investigator will prepare a number of different dehydrated-rehydrated vesicles by altering the concentration of two saturated matrix lipids, the concentration of bupivacaine in the hydrating solution and the pH at which hydration occurs. The eight formulations with the highest drug/phospholipid ratios will then be used to measure the release of the entrapped drug over time. The second aim will be to evaluate the sterility, apyrogenicity and stability of these eight bupivacaine preparations. The liposomal bupivacaine formulations will be prepared under aseptic conditions and the sterility of each formulation will be tested by culturing under aerobic and anaerobic conditions. Apyrogenicity will be evaluated by injecting known aliquots IV in rabbits and monitoring body temperature. Formulations found to be sterile and apyrogenic will be stored at 4 degrees Celsius and assessed for physical and chemical stability at 3 month intervals. The third aim will be to determine the local and systemic toxicity of the liposomal bupivacaine preparations using in vivo and in vitro techniques. Metabolic perturbations of cartilage will be assessed by incubating bupivacaine preparations with bovine articular cartilage in the presence of radiolabeled sulfate and measuring sulfate incorporation as an indicator of proteoglycan synthesis. The in vivo local toxicity will be evaluated by injecting the formulations into the sciatic nerve in rats and the articular cartilage of rabbits and examining the tissue using light and electron microscopy. Systemic toxicity will be evaluated by injecting the liposomal bupivacaine preparations IP into mice and measuring LD50. Systemic organ toxicity will be determined by examining the liver, spleen, kidneys and lungs for pathologic changes. Finally, the fourth aim will be to evaluate the efficacy of the liposomal preparations. The formulations exhibiting optimal stability and lack of toxicity will be tested for efficacy and duration of analgesia using the mouse tail-flick test. The four formulations exhibiting the most prolonged analgesia will be further tested in a rabbit tooth pulp model.

描述：这是一个应用程序，旨在准备实验 并表征了稳定、无毒且有效的布比卡因脂质体 可用于临床环境的制剂。 校长 研究者提出了四个具体目标。第一个目标是准备 各种脱水-再水化脂质体囊制剂和 根据包埋药物的浓度来表征这些囊泡 和体外释放动力学。 调查员将准备一些 通过改变不同的脱水-再水化囊泡的浓度 两种饱和基质脂质中布比卡因的浓度 水合溶液和水合发生时的 pH 值。 八个 然后将使用具有最高药物/磷脂比率的制剂 测量包埋药物随时间的释放。 第二个目标将是 评估这八种物质的无菌性、无热原性和稳定性 布比卡因制剂。 布比卡因脂质体制剂是 在无菌条件下制备，每种制剂的无菌性将 通过在有氧和厌氧条件下培养进行测试。 将通过向兔子注射已知的等分试样来评估无热原性 并监测体温。 发现制剂是无菌的并且 无热源将储存在 4 摄氏度下并评估物理和 化学稳定性以 3 个月为间隔。 第三个目标是确定 布比卡因脂质体制剂的局部和全身毒性 使用体内和体外技术。 软骨的代谢紊乱 将通过将布比卡因制剂与牛一起孵育来进行评估 存在放射性标记硫酸盐的关节软骨并测量 硫酸盐掺入作为蛋白多糖合成的指示剂。 在 通过将制剂注射到体内来评估体内局部毒性 大鼠坐骨神经和兔关节软骨并检查 使用光学和电子显微镜观察组织。 会产生全身毒性 通过将脂质体布比卡因制剂IP注射到小鼠体内进行评估 并测量LD50。 系统器官毒性将通过检查来确定 肝、脾、肾、肺有无病理变化。 最后， 第四个目标是评估脂质体制剂的功效。 表现出最佳稳定性且无毒性的制剂将是 使用小鼠甩尾测试镇痛效果和持续时间 测试。 表现出最长镇痛时间的四种制剂是 在兔牙髓模型中进行了进一步测试。