微乳碘的制备、质量评价及抗菌性与安全性评价

发布时间：2018-07-05 16:31

本文选题：微乳碘 + 伪三元相图　；参考：《山西医科大学》2017年硕士论文

【摘要】：目的:本文以微乳作为药物载体,制备微乳碘,优化其制备工艺,并对微乳碘制剂进行质量评价、抗菌性评价和安全性评价。方法:(1)从主药碘的化学性质出发,通过伪三元相图筛选合适的油相(Oil)、表面活性剂(Surfactant,SF)、助表面活性剂(Cosurfactant,CoSF);确定微乳中油相、表面活性剂、助表面活性剂和水相的最适组成比例及制备工艺,将单质碘制备成O/W型微乳碘。(2)根据2002版《消毒技术规范》项下有关规定对所得制剂进行质量评价,通过外观形态、pH、黏度、密度、粒径等指标进行微乳碘的理化性质评价;利用高效液相色谱法(HPLC)建立微乳碘中碘的含量测定方法并对该方法进行方法学考察;进行药物制剂稳定性试验,考察其储存条件、时间等。(3)考察制备所得微乳碘对金黄色葡萄球菌、大肠杆菌、白色念珠球菌和铜绿假单胞菌的抗菌活性,为微乳碘中碘的有效浓度确定及其抗菌效果提供科学依据;通过耐药菌试验,进一步考察微乳碘对耐药菌的杀灭效果;通过生物被膜试验,初步探究微乳碘的抗菌机理。(4)以家兔皮肤为受试对象,进行完整皮肤、破损皮肤试验及皮内刺激性试验,对微乳碘进行安全性考察及评价。结果:(1)通过伪三元相图,筛选得到微乳碘的油相(Oil)为乙酸丁酯、表面活性剂(SF)为吐温-80、助表面活性剂(CoSF)为无水乙醇。处方组成为Km=1:1,SF/CoSF:Oil=8:2,SF/CoSF+Oil=55%,即乙酸丁酯为11%、吐温-80为22%、无水乙醇为22%、蒸馏水为44.5%、碘为0.5%(g/100 mL)。制备工艺为:吐温-80与无水乙醇混合均匀后,加入乙酸丁酯,再次加入主药,最后加入水相。在25℃条件下,1300~2000 r/min磁力搅拌速度,搅拌30 min制备所得。(2)微乳碘的外观为酒红色澄清透明液体;粒径分布均在10~100 nm之间;平均黏度值为35.8 mPa.s;平均密度值为1.0095 g/cm3;pH为3.30~4.00。采用HPLC测定微乳碘中有效碘的含量:I3-的线性范围为0.08~0.50 mg/m L,日内精密度的RSD值为0.5%~1.0%,日间精密度的RSD值为0.8%~1.3%,回收率结果在97.2%~105.6%之间,平均回收率为100.8%,RSD值为3.1%,自制微乳碘以碘二分子计有效碘的含量约为1.383~1.472 mg/mL,每批次之间含量测定结果的RSD值0.5%~1.0%。稳定性试验结果表明,微乳碘除在高温、强光条件下含量稍有下降外,在低温条件及加速试验中稳定性良好,各组分外观均无明显变化。(3)自制微乳碘对金黄色葡萄球菌、铜绿假单胞菌的最小抑菌浓度(MIC)为0.012mg/m L,对白色念珠菌和大肠杆菌的MIC为0.023 mg/m L;四种菌的最小杀菌浓度(MBC)不大于0.094 mg/mL;有效碘含量在0.012~0.090 mg/m L范围,于2 min内对四种菌的抑菌率、杀菌率均达100%。耐药菌试验中微乳碘对耐咪唑类药物的克柔念珠菌的MIC、MBC均为0.125 mg/m L。生物被膜试验结果初步显示,微乳碘能有效抑制白色念珠菌菌体生物被膜的生长,从而达到杀菌或抑菌的作用。(4)有效碘含量为1.500 mg/m L时对家兔完整皮肤、破损皮肤及皮内均无刺激性反应。结论:本文从处方筛选、制备工艺考察、质量评价、抗菌性评价和安全性评价等方面进行探讨,成功制备出微乳碘。该制剂将碘包裹具有增加水溶性、掩盖碘刺激性气味、减少碘挥发等特点。各项指标完全符合2002版《消毒技术规范》“2.1.1”项下消毒剂杀微生物试验,“2.3.3”项下皮肤刺激试验及2015版《中国药典》第四部“原料药与药物制剂稳定性试验指导原则”项下操作的有关规定。是一种有效碘的起效浓度低、杀菌抑菌时间短、皮肤无刺激、杀菌谱广的安全高效的皮肤外用消毒制剂。拟为皮肤外用含碘消毒制剂提供一种新的剂型,具有一定的实际应用价值。
[Abstract]:Objective: microemulsion was used as a drug carrier to prepare microemulsion iodine and optimize its preparation technology. The quality evaluation, antibacterial evaluation and safety evaluation of microemulsion iodine preparation were carried out. Methods: (1) screening suitable oil phase (Oil), surface active agent (Surfactant, SF), and surfactant (Cosu) from the chemical properties of the main drug iodine. Rfactant, CoSF); determine the optimum composition ratio and preparation process of oil phase, surfactant, surfactant and water phase in microemulsion, and prepare iodine to form O/W microemulsion iodine. (2) evaluate the quality of the obtained preparation according to the regulations of the 2002 edition < disinfection technical specification > by appearance morphology, pH, viscosity, density, particle size and so on. The physicochemical properties of microemulsion iodine were evaluated, the determination method of iodine content in microemulsion iodine was established by high performance liquid chromatography (HPLC) and the method was investigated. The stability test of drug preparation was carried out to investigate the storage conditions and time. (3) the microemulsion iodine was investigated for Staphylococcus aureus, Escherichia coli, Candida albicans and Candida albicans. The antibacterial activity of Pseudomonas aeruginosa provides a scientific basis for the determination of the effective concentration of iodine in microemulsion iodine and its antibacterial effect. Through the test of resistant bacteria, the killing effect of microemulsion iodine on the resistant bacteria is further investigated. Through the biofilm test, the antibacterial mechanism of microemulsion iodine is preliminarily explored. (4) the skin of rabbit is taken as the subject of the skin, and the whole skin is carried out. The safety of microemulsion iodine was investigated and evaluated in damaged skin test and intradermal stimulation test. Results: (1) through the pseudo three element phase diagram, the oil phase of microemulsion (Oil) was selected as butyl acetate, surface active agent (SF) was Twain -80, and surface active agent (CoSF) was anhydrous ethanol. The formulation was Km=1:1, SF/CoSF:Oil=8:2, SF/CoSF+Oil=55%, that is, Butyl acetate is 11%, Twain -80 is 22%, anhydrous ethanol is 22%, distilled water is 44.5%, iodine is 0.5% (g/100 mL). The preparation process is that Twain -80 and anhydrous ethanol are mixed evenly, adding butyl acetate, adding the main drug and adding the water phase. At 25 centigrade conditions, 1300~2000 r/min magnetic stirring speed and stirring 30 min are prepared. (2) microemulsion iodine The appearance is wine red clear clear liquid; the particle size distribution is between 10~100 nm, the average viscosity value is 35.8 mPa.s, the average density value is 1.0095 g/cm3; pH is 3.30~4.00. using HPLC to determine the content of effective iodine in microemulsion iodine: the linear range of I3- is 0.08~0.50 mg/m L, the RSD value of the intra day precision is 0.8%, and the value of the day precision is 0.8% ~1.3%, the recovery rate is between 97.2%~105.6%, the average recovery rate is 100.8%, the RSD value is 3.1%. The content of effective iodine for the self-made microemulsion iodine two molecular meter is about 1.383~1.472 mg/mL, and the RSD value 0.5%~1.0%. stability test results of the content determination results between each batch show that the content of microemulsion iodine is slightly lower than that under high temperature and strong light condition. The stability was good in low temperature and accelerated test. (3) the minimum inhibitory concentration (MIC) of self-made microemulsion for Staphylococcus aureus and Pseudomonas aeruginosa was 0.012mg/m L, MIC of Candida albicans and Escherichia coli was 0.023 mg/m L, and the minimum bactericidal concentration (MBC) of four bacteria was not more than 0.094 mg/mL; The iodine content was in the range of 0.012~0.090 mg/m L, the bacteriostasis rate of four bacteria in 2 min, the bactericidal rate reached MIC of microemulsion iodine to imidazole resistant Candida krilicus in the test of 100%. resistant bacteria, and MBC was 0.125 mg/m L. biological membrane test results preliminarily showed that microemulsion iodine could effectively inhibit the growth of the biofilm of Candida albicans. The effect of bactericidal or bacteriostasis was achieved. (4) when the effective iodine content was 1.500 mg/m L, there was no irritation response to the intact skin of the rabbit, the damaged skin and the skin. Conclusion: in this paper, the microemulsion iodine was successfully prepared from the prescription screening, preparation process, quality evaluation, antibacterial evaluation and safety evaluation. It has the characteristics of increasing water solubility, covering iodine irritating odor, reducing iodine volatilization and so on. Each index is fully in conformity with the 2002 edition of disinfectant microbicide test under "disinfection technical specification >" "2.1.1", skin irritation test under "2.3.3" and "guidelines for the stability test guiding principle of 2015 editions of Chinese Pharmacopoeia," "Chinese Pharmacopoeia" and "drug preparation". It is a kind of safe and efficient skin disinfectant preparation with low concentration of effective iodine, short time of bacteriostasis and bacteriostasis, no irritation of skin and wide sterilization spectrum. It will provide a new dosage form for iodine containing iodine disinfection preparation, which has certain practical application value.
【学位授予单位】：山西医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

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