低剂量佐匹克隆延迟控释片治疗早醒性失眠的疗效研究

Low-dose Zopiclone Delayed Controlled-release Tablets for Dysphylaxia:an Experimental Study

背景 失眠可分为入睡困难、睡眠维持障碍和早醒等,目前药物治疗失眠存在局限性,尚缺乏对不同类型失眠的针对性治疗,对失眠分型治疗的研究鲜见报道.目的 探讨低剂量佐匹克隆延迟控释片治疗早醒性失眠的疗效.方法 本研究时间为2016年10月-2018年1月.将40只清洁级雄性SD大鼠随机分为对照1组、低剂量(2.5 mg/kg佐匹克隆)组、高剂量(5.0 mg/kg佐匹克隆)30 min组、高剂量60 min组,每组10只大鼠.采用戊巴比妥钠延长实验,观察并记录各组大鼠的睡眠潜伏期及睡眠时间,为佐匹克隆延迟控释片的制备奠定基础.将佐匹克隆与羧甲基淀粉钠、乳糖、5%聚维酮K30(PVPK30)、硬脂酸镁混匀后压片;将山嵛酸甘油酯、乳糖、5%PVPK30、硬脂酸镁混匀后得到包衣颗粒,将片芯置于包衣颗粒中央,压片制得佐匹克隆延迟控释片.将60只清洁级雄性SD大鼠随机分为对照2组、佐匹克隆延迟控释片组(2.5 mg/kg佐匹克隆)、佐匹克隆溶液组(5.0 mg/kg佐匹克隆),每组20只大鼠,观察并记录各组大鼠的睡眠潜伏期和睡眠时间.结果 对照1组〔(126.3±18.6)min〕、低剂量组〔(175.3±18.1)min〕、 高剂量30 min组〔(151.8±19.2)min〕和高剂量60 min组〔(181.5±15.6)min〕睡眠时间比较,差异有统计学意义(F=19.651,P<0.01);其中,低剂量组与高剂量30 min组、60 min组大鼠睡眠时间长于对照1组,高剂量30 min组大鼠睡眠时间短于低剂量组,高剂量60 min组大鼠睡眠时间长于高剂量30 min组(P<0.05).佐匹克隆延迟控释片组〔(188.3±25.0)min〕、佐匹克隆溶液组〔(194.0±28.1)min〕与对照2组〔(130.2±25.6)min〕 睡眠时间比较,差异有统计学意义(F=30.400,P<0.05),佐匹克隆延迟控释片组、佐匹克隆溶液组睡眠时间长于对照2组(P<0.05).结论 通过制备低剂量(2.5 mg/kg)佐匹克隆延迟控释片喂食实验大鼠,使之在大鼠入睡后释药,能达到高剂量(5.0 mg/kg)佐匹克隆睡前60 min灌胃延长大鼠睡眠时间的效果,显现了以低剂量佐匹克隆延迟控释片针对性治疗成人早醒性失眠的前景.

Background Insomnia is manifested by symptoms of difficulty falling asleep,sleep-maintenance disorder,and waking up too early in the morning,and so on.At present,the effects of available pharmacological treatments for insomnia are limited,and targeted pharmacological treatments for different types of insomnia as well as related reports are rare.Objective To study the effect of low-dose zopiclone delayed controlled-release tablets(ZDCT)in the treatment of dysphylaxia.Methods This study was carried out between October 2016 and January 2018.(1)40 male clean grade SD rats were equally divided into control groupⅠ,low-dose group(2.5 mg/kg zopiclone),high-dose(5.0 mg/kg zopiclone)30 minutes group and high-dose 60 minutes group.The sleep latency and sleep duration of rats in each group were observed by sleep time-prolongation test with pentobarbital sodium.(2)Evenly mixed zopiclone with sodium carboxymethyl starch,lactose,5%PVPK30 and magnesium stearate,the compressed the mixture into tablet cores.Next,by mixing evenly glycerol sorbate,lactose,5%PVPK30 and magnesium stearate,the coated granules were obtained.Then,placing the cores at the center of the coating and the delayed-release tablets were prepared by pressing.(3)60 male clean grade SD rats were randomly and evenly divided into control groupⅡ,ZDCT group(2.5 mg/kg zopiclone)and zopiclone solution group(5.0 mg/kg zopiclone).The sleep latency and sleep duration were compared across the groups.Results There were significant differences in sleep duration between the control groupⅠ〔(126.3±18.6)min〕,low-dose group〔(175.3±18.1)min〕,high-dose 30 minutes group〔(151.8±19.2)min〕and high-dose 60 minutes group〔(181.5±15.6)min〕(F=19.651,P<0.01).The sleep duration of the control groupⅠwas shorter than that of low-dose group,high-dose 30 minutes group,and high-dose 60 minutes group(P<0.05).Low-dose group had longer sleep duration than high-dose 30 min group(P<0.05).The sleep duration of high-dose 60 minutes group was longer than that in the high-dose 30 minutes group(P<0.05).The difference of sleep duration between ZDCT group〔(188.3±25.0)min〕,zopiclone solution group〔(194.0±28.1)min〕and controlⅡgroup〔(130.2±25.6)min〕was significant(F=30.400,P<0.05).Control groupⅡhad shorter sleep duration than that of ZDCT group and zopiclone solution group(P<0.05).Conclusion Low-dose(2.5 mg/kg dosage form)ZDCT prepared by us orally administered to SD rats can release zolpidem after the rats falling asleep,which showed the same effectiveness as highdose(5.0 mg/kg dosage form)ZDCT given to SD rats by gavage 60 minutes before sleep,indicating that low-dose ZDCT may be a promising drug for dysphylaxia in adults.