新鱼腥草素钠滴眼液的研究
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摘要
目的:1.通过建立金黄色葡萄球菌和绿脓杆菌引起的细菌性角膜炎溃疡的动物模型,观察新鱼腥草素钠(Sodium New Houttuyfonate ,SNH)对细菌性角膜炎的治疗效果及安全性,初步评估新鱼腥草素钠(SNH)在眼科感染性疾病的应用价值。2.制备新鱼腥草素钠滴眼液(Sodium New Houttuyfonate Eye Drops,SNHED),并对其进行了质量标准的评价,对制剂的稳定性进行了初步考察。
方法:1.新鱼腥草素钠(SNH)的眼刺激性试验。记录眼部反应,包括分泌物、结膜充血、结膜水肿,角膜实质病变和虹膜炎症,并给予评分。2.动物模型的建立。分别将金黄色葡萄球菌液和绿脓杆菌液注射于角膜实质层间的1/3-2/3深处,建立金葡菌性和绿脓杆菌性角膜溃疡的动物模型。3.观察0.05%、0.1%和0.15%新鱼腥草素钠对兔眼金葡菌性和绿脓杆菌性角膜溃疡的疗效。以生理盐水为阴性对照,以诺氟沙星滴眼液作为阳性对照,以角膜溃疡面积及角膜炎症综合评分作为观察疗效的主要指标。4.用正交试验初筛新鱼腥草素钠滴眼液的处方,对处方和工艺进行系统的研究。5.按照中国药典2005版二部附录有关要求,对实验室三批制剂进行了质量标准的考察。6.参考药典附录XIXC《原料药与药物制剂稳定性实验指导原则》,对制剂进行了稳定性考察,包括影响因素试验:高温40℃和60℃、光照试验和低温冻融试验;40℃6个月加速试验和长期试验。
结果:1.眼刺激性实验结果表明,0.05%、0.1%和0.15%新鱼腥草素钠均无任何刺激性。2.动物模型实验表明,金黄色葡萄球菌液和绿脓杆菌液注射于角膜实质层间的1/3-2/3深处,24小时后即可建立金葡菌性和绿脓杆菌性角膜溃疡的动物模型。3.观察0.05%、0.1%和0.15%新鱼腥草素钠对兔眼金葡菌性和绿脓杆菌性角膜溃疡的疗效结果表明,0.05%、0.1%和0.15%SNHED对兔眼金葡菌性和绿脓杆菌性角膜溃疡均有治疗作用,对金葡菌性角膜溃疡的抑制更为强大。0.1%、0.15%新鱼腥草素钠对细菌性角膜炎的疗效相当,均优于0.05%新鱼腥草素钠。对金葡菌性角膜炎,0.1%、0.15%新鱼腥草素钠与诺氟沙星滴眼液的效果相当;对绿脓杆菌性角膜炎,诺氟沙星滴眼液均优于各浓度的新鱼腥草素钠。4.制备了处方合理、工艺简单、质量稳定的新鱼腥草素钠滴眼液。5.在测定方法的建立中,根据附录XIXA《药品质量标准分析方法验证指导原则》的规定,确定了HPLC法,并摸索出适宜的流动相、温度等色谱条件,用以鉴别药物及精密稳定的测定样品,并用精密度、线性、稳定性等验证内容对该方法进行验证。6.制剂为澄明无色液体;pH值为6.5;有关物质<1%;含量在95%-105%之间。
结论:1.初步动物实验表明,新鱼腥草素钠在0.1%浓度下可显著改善金黄色葡萄球菌和绿脓杆菌所致家兔细菌性角膜炎的症状,并可抑制病原菌的局部增殖,对于由金葡菌引起的细菌性角膜溃疡,其作用与诺氟沙星滴眼液的治疗效果相当。2.通过正交实验和各种因素的考察,制备了处方合理的新鱼腥草素钠滴眼液,工艺重复性良好,质量稳定,含量测定快速、准确,加速实验和长期实验表明,稳定性良好。
Objective:1. To observe the topical effects of sodium new houttuynia (SNH) on experimental bacterial keratitis models caused by stapHylococcus aureus and bacillus pyocyaneus. The safety and efficacy of SNH have been primarily evaluated, and the rusult showed potential clinical use. 2. To prepare the sodium new houttuynia eye drops, and the quality standard and the stability have been evaluated.
Method: 1. The irritation of SNH have been observed in this experiment. The reactions of each eye, such as conjunctivitis, corneablur and iritis are scored daily. 2. To establish experimental models of stapHylococcus aureus and bacillus pyocyaneus in rabbits, stapHylococcus aureus and bacillus pyocyaneus are inoculated into the stroma of cornea. 3. To observe the therapeutic efficacy of 0.05% SNH, 0.1% SNH and 0.15% SNH on experimental bacterial corneal ulcer, compared with pHysiological saline solution (as negative control) and norfloxacin eye drops (as positive control). The therapeutic efficacy are juded by the area of corneal ulcer and the conjunctivitis scores of the infected eyes.
4. To study the prescription and craftwork. 5. According to the related requests of the appendices of Chinese PHarmacopoeia (2005 edition, II part), we perform the quality analysis to the three batches of preparation. 6.With the reference to the appendix of CP, we have investigated the stability of the preparation, including the experiment for the stress testing of preparation: at 60℃and 40℃, light exposure, accelerated test of at 40℃for 6 months and the long-term testing.
Results: 1. No irration have been observed at the ocular irritation test. 2. The experimental model of stapHylococcus aureus and bacillus pyocyaneus in rabbits can be successfully established by intrasteomally injection of stapHylococcus aureus and bacillus pyocyaneus. 3. SNH have evident thetapeutic efficacy on stapHylococcus aureus and bacillus pyocyaneus. The thetapeutic efficacy on stapHylococcus aureus is stronger than that on bacillus pyocyaneus. 4. The procedure of preparation was simple, and the quantitative determination was quick, and accurate while was reliable. 5. During the establishment of the detective method, the HPLC method, as well as the proper mobile pHase and temperature were determined to identify the drug and to detect the content of the sample accurately and precisely. The method is validated in the aspects of accuracy, stability and linearity. 6. In the research of quality standard, content limit, character, detection, determination, etc were detected in accordance with related regulation.
Conclusions: 1. The results show that SNH have no ocular irrition, and it has good therapeutic efficacy on stapHylococcus aureus and bacillus pyocyaneus. SNHED proved to be an effective acular medication for the therapy of experimental stapHylococcus aureus and bacillus pyocyaneus.The effecitiveness of SNHED in this experiment suggests a role of this drug as a useful ocular antibiotic. 2. The procedure of preparation was simple, and the quantitative determination was quick, and accurate while was reliable.
方法:1.新鱼腥草素钠(SNH)的眼刺激性试验。记录眼部反应,包括分泌物、结膜充血、结膜水肿,角膜实质病变和虹膜炎症,并给予评分。2.动物模型的建立。分别将金黄色葡萄球菌液和绿脓杆菌液注射于角膜实质层间的1/3-2/3深处,建立金葡菌性和绿脓杆菌性角膜溃疡的动物模型。3.观察0.05%、0.1%和0.15%新鱼腥草素钠对兔眼金葡菌性和绿脓杆菌性角膜溃疡的疗效。以生理盐水为阴性对照,以诺氟沙星滴眼液作为阳性对照,以角膜溃疡面积及角膜炎症综合评分作为观察疗效的主要指标。4.用正交试验初筛新鱼腥草素钠滴眼液的处方,对处方和工艺进行系统的研究。5.按照中国药典2005版二部附录有关要求,对实验室三批制剂进行了质量标准的考察。6.参考药典附录XIXC《原料药与药物制剂稳定性实验指导原则》,对制剂进行了稳定性考察,包括影响因素试验:高温40℃和60℃、光照试验和低温冻融试验;40℃6个月加速试验和长期试验。
结果:1.眼刺激性实验结果表明,0.05%、0.1%和0.15%新鱼腥草素钠均无任何刺激性。2.动物模型实验表明,金黄色葡萄球菌液和绿脓杆菌液注射于角膜实质层间的1/3-2/3深处,24小时后即可建立金葡菌性和绿脓杆菌性角膜溃疡的动物模型。3.观察0.05%、0.1%和0.15%新鱼腥草素钠对兔眼金葡菌性和绿脓杆菌性角膜溃疡的疗效结果表明,0.05%、0.1%和0.15%SNHED对兔眼金葡菌性和绿脓杆菌性角膜溃疡均有治疗作用,对金葡菌性角膜溃疡的抑制更为强大。0.1%、0.15%新鱼腥草素钠对细菌性角膜炎的疗效相当,均优于0.05%新鱼腥草素钠。对金葡菌性角膜炎,0.1%、0.15%新鱼腥草素钠与诺氟沙星滴眼液的效果相当;对绿脓杆菌性角膜炎,诺氟沙星滴眼液均优于各浓度的新鱼腥草素钠。4.制备了处方合理、工艺简单、质量稳定的新鱼腥草素钠滴眼液。5.在测定方法的建立中,根据附录XIXA《药品质量标准分析方法验证指导原则》的规定,确定了HPLC法,并摸索出适宜的流动相、温度等色谱条件,用以鉴别药物及精密稳定的测定样品,并用精密度、线性、稳定性等验证内容对该方法进行验证。6.制剂为澄明无色液体;pH值为6.5;有关物质<1%;含量在95%-105%之间。
结论:1.初步动物实验表明,新鱼腥草素钠在0.1%浓度下可显著改善金黄色葡萄球菌和绿脓杆菌所致家兔细菌性角膜炎的症状,并可抑制病原菌的局部增殖,对于由金葡菌引起的细菌性角膜溃疡,其作用与诺氟沙星滴眼液的治疗效果相当。2.通过正交实验和各种因素的考察,制备了处方合理的新鱼腥草素钠滴眼液,工艺重复性良好,质量稳定,含量测定快速、准确,加速实验和长期实验表明,稳定性良好。
Objective:1. To observe the topical effects of sodium new houttuynia (SNH) on experimental bacterial keratitis models caused by stapHylococcus aureus and bacillus pyocyaneus. The safety and efficacy of SNH have been primarily evaluated, and the rusult showed potential clinical use. 2. To prepare the sodium new houttuynia eye drops, and the quality standard and the stability have been evaluated.
Method: 1. The irritation of SNH have been observed in this experiment. The reactions of each eye, such as conjunctivitis, corneablur and iritis are scored daily. 2. To establish experimental models of stapHylococcus aureus and bacillus pyocyaneus in rabbits, stapHylococcus aureus and bacillus pyocyaneus are inoculated into the stroma of cornea. 3. To observe the therapeutic efficacy of 0.05% SNH, 0.1% SNH and 0.15% SNH on experimental bacterial corneal ulcer, compared with pHysiological saline solution (as negative control) and norfloxacin eye drops (as positive control). The therapeutic efficacy are juded by the area of corneal ulcer and the conjunctivitis scores of the infected eyes.
4. To study the prescription and craftwork. 5. According to the related requests of the appendices of Chinese PHarmacopoeia (2005 edition, II part), we perform the quality analysis to the three batches of preparation. 6.With the reference to the appendix of CP, we have investigated the stability of the preparation, including the experiment for the stress testing of preparation: at 60℃and 40℃, light exposure, accelerated test of at 40℃for 6 months and the long-term testing.
Results: 1. No irration have been observed at the ocular irritation test. 2. The experimental model of stapHylococcus aureus and bacillus pyocyaneus in rabbits can be successfully established by intrasteomally injection of stapHylococcus aureus and bacillus pyocyaneus. 3. SNH have evident thetapeutic efficacy on stapHylococcus aureus and bacillus pyocyaneus. The thetapeutic efficacy on stapHylococcus aureus is stronger than that on bacillus pyocyaneus. 4. The procedure of preparation was simple, and the quantitative determination was quick, and accurate while was reliable. 5. During the establishment of the detective method, the HPLC method, as well as the proper mobile pHase and temperature were determined to identify the drug and to detect the content of the sample accurately and precisely. The method is validated in the aspects of accuracy, stability and linearity. 6. In the research of quality standard, content limit, character, detection, determination, etc were detected in accordance with related regulation.
Conclusions: 1. The results show that SNH have no ocular irrition, and it has good therapeutic efficacy on stapHylococcus aureus and bacillus pyocyaneus. SNHED proved to be an effective acular medication for the therapy of experimental stapHylococcus aureus and bacillus pyocyaneus.The effecitiveness of SNHED in this experiment suggests a role of this drug as a useful ocular antibiotic. 2. The procedure of preparation was simple, and the quantitative determination was quick, and accurate while was reliable.
引文
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