红霉素纳米乳的制备及其药效学研究
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摘要
本试验旨在制备出水包油型红霉素纳米乳,并初步考察红霉素纳米乳的理化性、稳定性、安全性及有效性,为红霉素纳米乳的进一步研究提供理论依据。
本试验用非离子型表面活性剂吐温-80、助表面活性剂无水乙醇、油相乙酸乙酯和去离子水为原料,结合伪三元相图筛选出红霉素纳米乳的最佳处方;用透射电镜和粒度测定仪检测红霉素纳米乳的形态、粒径及其分布;通过恒温加速试验及在不同温度下的贮存试验考察红霉素纳米乳的稳定性;用紫外分光光度计测定红霉素纳米乳的药物含量;用急性毒性试验对红霉素纳米乳的安全性进行了评价;通过体内、外抑菌试验及临床治疗试验考察红霉素纳米乳的药效。
结果显示,表面活性剂吐温-80?助表面活性剂无水乙醇(km=3:1),它们质量之和与油相乙酸乙酯质量之比为9:1时,形成的红霉素纳米乳区最大,所制备的红霉素纳米乳外观上均为粘度较小的淡黄色澄清透明液体;透射电镜下红霉素纳米乳液滴呈球形;经粒度测定仪检测,其粒径为5～20nm;红霉素纳米乳经10 000 rpm/min离心20 min后仍为澄清透明均一的液体;红霉素纳米乳在-4℃冰箱、室温和60℃条件下放置6个月后,仍为透明均一的体系,未见分层;红霉素纳米乳中红霉素的含量为8.557 mg /ml,在75～175 ug·mL-1浓度范围内,线性关系良好, r=0.9932,平均回收率为98.85%,RSD为0.19%,日内和日间的精密度均小于1%;急性毒性试验结果表明红霉素纳米乳是低毒级的药物;体外抑菌试验结果表明,红霉素纳米乳、红霉素肠溶片、罗红霉素片对金黄色葡萄球菌的最小抑菌浓度分别是0.01563、0.03125和0.01563 mg/mL,对链球菌的最小抑菌浓度分别是0.0625、0.25和0.25 mg/mL,表明红霉素纳米乳对金黄色葡萄球菌和溶血性链球菌有较强的抑菌效果;体内抑菌试验表明,红霉素纳米乳对人工感染的鸡金黄色葡萄球菌病的治疗效果强于红霉素肠溶片;临床试验结果表明红霉素纳米乳治疗鸡慢性呼吸道病具有较好的疗效。
综上可知,本研究制备的红霉素纳米乳符合纳米乳的各种特性,且稳定性好、安全高、有效性强。
The objective of this experiment is to prepare oil-in-water erythromycin nanoemulsion and investigate its physicochemical property, stability, security and effect, accordingly offer academic gist for futher investigation of erythromycin nanoemulsion.
In the experiment, Tween-80 as surfactants, absolute ethyl alcohol as cosurfactants and acetic ether as oil and deionized water were chosen to sieve the best recipe which was used to prepare erythromycin nanoemulsion by pseudoternary phase diagrams. The particle shape, size and distribution of erythromycin nanoemulsion were detected with transmission electron microscope and Zetasizer Nano ZS. The stability of erythromycin nanoemulsion was investigated by accelerated test in constant temperature and reserved test in different temperature. The content of erythromycin in erythromycin nanoemulsion was measured with ultraviolet spectrophotometry. Its security was evaluated by acute toxicity experiment. Its drug effect was tested by anti - bacterial experiments in vitro and in vivo and clinical test.
The results showed that the nanoemulsion area was the largest when the ratio of Tween-80 and absolute ethyl alcohol was 3:1, the ratio of the gross of them and ethyl acetate was 8:2. The nanoemulsion that had been prepared is low viscosity, straw yellow and transparent liquid in appearance, and it presented as small spherical drops under Transmission Electron Microscope (TEM), the diameter of erythromycin nanoemulsion was about 5-20 nm by Zetasizer Nano ZS testing. Erythromycin nanoemulsion was still homogeneous and transparent. Moreover, it didn’t stratify and subside after centrifuging for 20min with 10 000rpm and reserving under -4℃, room temperature and 60℃for 6 months.Linear relation was all right and r was 0.9932 when the concentration ranged from 75 to 175 ug·mL-1, the average recovery rate was 98.85%, and RSD was 0.19%, the inter-day and intra-day precision of determination of erythromycin was less than 1%. And the content of erythromycin in nanoemulsion was 8.557 mg /ml. Acute toxicity experiment showed that the toxicity of erythromycin microemulsion belonged to practically low-toxic substance; Anti-bacterial experiments in vitro showed that the MICs of erythromycin nanoemulsion on staphylococcus and streptococcus were respectively 0.01563 and 0.125 mg/mL,the MICs of erythromycin Enteric-coated tablets on staphylococcus and streptococcus were respectively 0.03125 and 0.25 mg/mL,the MICs of roxithromycin tablets on staphylococcus and streptococcus were respectively 0.01563 and 0.25 mg/mL,which showed that the antibacterial effect of erythromycin nanoemulsion on staphylococcus and streptococcus in vitro was remarkable; Anti - bacterial experiments in vivo showed that the efficacy of erythromycin nanoemulsion against experimentally induced staphy-locosis in chicken was better than erythromycin enteric-coated tablets;Clinical test showed that the the clinical effect of erythromycin nanoemulsion on avian chronic respiratory disease was good.
From the results above, conclusion can be achieved that the nanoemulsion prepared correspond to the standard of nanoemulsion and has fine stability, security, effect.
本试验用非离子型表面活性剂吐温-80、助表面活性剂无水乙醇、油相乙酸乙酯和去离子水为原料,结合伪三元相图筛选出红霉素纳米乳的最佳处方;用透射电镜和粒度测定仪检测红霉素纳米乳的形态、粒径及其分布;通过恒温加速试验及在不同温度下的贮存试验考察红霉素纳米乳的稳定性;用紫外分光光度计测定红霉素纳米乳的药物含量;用急性毒性试验对红霉素纳米乳的安全性进行了评价;通过体内、外抑菌试验及临床治疗试验考察红霉素纳米乳的药效。
结果显示,表面活性剂吐温-80?助表面活性剂无水乙醇(km=3:1),它们质量之和与油相乙酸乙酯质量之比为9:1时,形成的红霉素纳米乳区最大,所制备的红霉素纳米乳外观上均为粘度较小的淡黄色澄清透明液体;透射电镜下红霉素纳米乳液滴呈球形;经粒度测定仪检测,其粒径为5～20nm;红霉素纳米乳经10 000 rpm/min离心20 min后仍为澄清透明均一的液体;红霉素纳米乳在-4℃冰箱、室温和60℃条件下放置6个月后,仍为透明均一的体系,未见分层;红霉素纳米乳中红霉素的含量为8.557 mg /ml,在75～175 ug·mL-1浓度范围内,线性关系良好, r=0.9932,平均回收率为98.85%,RSD为0.19%,日内和日间的精密度均小于1%;急性毒性试验结果表明红霉素纳米乳是低毒级的药物;体外抑菌试验结果表明,红霉素纳米乳、红霉素肠溶片、罗红霉素片对金黄色葡萄球菌的最小抑菌浓度分别是0.01563、0.03125和0.01563 mg/mL,对链球菌的最小抑菌浓度分别是0.0625、0.25和0.25 mg/mL,表明红霉素纳米乳对金黄色葡萄球菌和溶血性链球菌有较强的抑菌效果;体内抑菌试验表明,红霉素纳米乳对人工感染的鸡金黄色葡萄球菌病的治疗效果强于红霉素肠溶片;临床试验结果表明红霉素纳米乳治疗鸡慢性呼吸道病具有较好的疗效。
综上可知,本研究制备的红霉素纳米乳符合纳米乳的各种特性,且稳定性好、安全高、有效性强。
The objective of this experiment is to prepare oil-in-water erythromycin nanoemulsion and investigate its physicochemical property, stability, security and effect, accordingly offer academic gist for futher investigation of erythromycin nanoemulsion.
In the experiment, Tween-80 as surfactants, absolute ethyl alcohol as cosurfactants and acetic ether as oil and deionized water were chosen to sieve the best recipe which was used to prepare erythromycin nanoemulsion by pseudoternary phase diagrams. The particle shape, size and distribution of erythromycin nanoemulsion were detected with transmission electron microscope and Zetasizer Nano ZS. The stability of erythromycin nanoemulsion was investigated by accelerated test in constant temperature and reserved test in different temperature. The content of erythromycin in erythromycin nanoemulsion was measured with ultraviolet spectrophotometry. Its security was evaluated by acute toxicity experiment. Its drug effect was tested by anti - bacterial experiments in vitro and in vivo and clinical test.
The results showed that the nanoemulsion area was the largest when the ratio of Tween-80 and absolute ethyl alcohol was 3:1, the ratio of the gross of them and ethyl acetate was 8:2. The nanoemulsion that had been prepared is low viscosity, straw yellow and transparent liquid in appearance, and it presented as small spherical drops under Transmission Electron Microscope (TEM), the diameter of erythromycin nanoemulsion was about 5-20 nm by Zetasizer Nano ZS testing. Erythromycin nanoemulsion was still homogeneous and transparent. Moreover, it didn’t stratify and subside after centrifuging for 20min with 10 000rpm and reserving under -4℃, room temperature and 60℃for 6 months.Linear relation was all right and r was 0.9932 when the concentration ranged from 75 to 175 ug·mL-1, the average recovery rate was 98.85%, and RSD was 0.19%, the inter-day and intra-day precision of determination of erythromycin was less than 1%. And the content of erythromycin in nanoemulsion was 8.557 mg /ml. Acute toxicity experiment showed that the toxicity of erythromycin microemulsion belonged to practically low-toxic substance; Anti-bacterial experiments in vitro showed that the MICs of erythromycin nanoemulsion on staphylococcus and streptococcus were respectively 0.01563 and 0.125 mg/mL,the MICs of erythromycin Enteric-coated tablets on staphylococcus and streptococcus were respectively 0.03125 and 0.25 mg/mL,the MICs of roxithromycin tablets on staphylococcus and streptococcus were respectively 0.01563 and 0.25 mg/mL,which showed that the antibacterial effect of erythromycin nanoemulsion on staphylococcus and streptococcus in vitro was remarkable; Anti - bacterial experiments in vivo showed that the efficacy of erythromycin nanoemulsion against experimentally induced staphy-locosis in chicken was better than erythromycin enteric-coated tablets;Clinical test showed that the the clinical effect of erythromycin nanoemulsion on avian chronic respiratory disease was good.
From the results above, conclusion can be achieved that the nanoemulsion prepared correspond to the standard of nanoemulsion and has fine stability, security, effect.
引文
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