黄连素纳米乳给药系统的研究
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摘要
本研究利用纳米技术的优点,以纳米乳给药系统为载体,对传统的黄连素制剂进行改造。在建立分析方法、空白纳米乳的处方筛选及影响因素考察上,利用伪三元相图,制备出了黄连素纳米乳给药系统,并对其质量的稳定性、安全性、药效学、药动学和释药性能等进行了较为系统的研究。研究摘要如下:
1.黄连素纳米乳给药系统的分析方法建立
建立用于黄连素纳米乳给药系统含量检测的紫外(制剂)与高效液相色谱(制剂和动力学)分析方法。用紫外分光光度计和高效液相色谱仪,对其紫外吸收波长、标准曲线、回收率和精密度等进行研究。结果表明,黄连素在340 nm处有最大吸收,紫外的标准曲线在1～40μg/ml范围内线性关系良好,其平均回收率为99.7 %。回收率的相对标准偏差(RSD)为0.39 %、进样重复性的为2.5 %、日间和日内精密度的小于0.6 %;高效液相色谱(HPLC):制剂的标准曲线在50～1600 ng/mL范围内线性关系良好,检测限为2ng/mL,其平均回收率为99.4 %和平均保留时间为7.499 min。回收率的RSD为0.79%、进样重复性的为0.64 %和1.44 %、日间和日内精密度的小于0.6 %;血浆的标准曲线在10～1600 ng/mL范围内,线性关系良好,检测限为0.36 ng/mL,其平均回收率为95.6 %和平均保留时间为5.602 min。回收率的RSD为3.46 %、进样重复性的为0.42 %和1.42 %、日间和日内精密度的小于0.6 %。本研究建立的分析方法回收率高、精密度和重复性好,可用于其质量控制和动力学研究。
2.空白纳米乳给药系统的处方筛选及其影响因素考察
筛选出空白纳米乳处方并对其影响因素进行考察。用HLB值法和纳米乳的评价标准,筛选出形成纳米乳的处方;用伪三元相图,对纳米乳形成的影响因素进行考察;对黄连素的增溶作用也进行研究。结果表明,筛选出可形成纳米乳的处方是,表面活性剂为Tween类(80和60),Span类(80和60),EL-40和RH-40;助表面活性为无水乙醇、甘油、丙二醇、正丁醇和1,3丁二醇;油相为IPM和液体石蜡。影响因素考察结果显示,表面活性剂与油相的种类及比例是纳米乳形成最主要和关键的因素。在能形成纳米乳范围内,表面活性剂HLB值越大,纳米乳区越大;助表面活性剂的链越短,纳米乳区越大;油相的HLB值与混合表面活性剂的HLB值越匹配,纳米乳区越大;表面活性剂与助表面活性剂的比值(Km)越合适,纳米乳区越大;在一定范围内,药物加入量的增加,纳米乳区增大;增溶试验表明,黄连素在纳米乳中的溶解度比水溶液和胶束的高。本研究筛选出的空白纳米乳处方及影响因素考察结果,为后期制备工作奠定了基础。
3.黄连素纳米乳给药系统的制备及其质量评价
制备出黄连素纳米乳给药系统并对其质量进行评价。选择适宜的油相、表面活性剂和助表面活性剂,利用伪三元相图,制备出黄连素纳米乳给药系统。用包封率与载药量为评价指标,对其制备工艺进行优化;用透射电镜、激光粒度分布仪、黏度计、折光仪和电导仪等对其理化性质进行研究;用高效液相色谱仪检测该系统中黄连素的含量,对其稳定性进行检测。结果表明,制备出含EL40-甘油-IPM的黄连素纳米乳给药系统是澄清透明的球状液滴液体,其平均粒径为43.5 nm(空白纳米乳为17.9 nm);优化出的制备工艺是磁力搅拌、37 oC、150 r/min、分散12 h和第三种药物加入顺序。理化性质、稳定性参数、加速和光加速等研究结果表明,制备的黄连素纳米乳给药系统质量稳定;通过长期和经典恒温试验可推测出其有效期为2.5年。本研究制备出的黄连素给药系统质量稳定,符合纳米乳给药系统的要求。
4.黄连素纳米乳给药系统的安全性评价
对黄连素纳米乳给药系统的安全性进行评价。通过急性毒性、皮肤刺激和眼部刺激毒性(单次和多次)、细胞毒性试验对纳米乳的安全性进行评价。结果表明,黄连素纳米乳给药系统对小鼠的最大耐受量为875 mg/kg,折合成人的剂量(50 kg),是临床用量的21 875倍。根据Bliss法,用SAS6.0统计软件、自行编制程序,计算出其累积的LD50为3 055 mg/kg;对家兔皮肤和眼部(单次和多次)刺激均无毒性;对细胞毒性为1级,无明显毒性。本研究制备出的纳米乳给药系统的对小鼠、家兔皮肤和眼部、细胞均无毒性,临床用药安全,符合纳米乳给药系统的要求。
5.黄连素纳米乳给药系统的药效学评价
对黄连素纳米乳给药系统的药效学进行评价。用体外抑菌、对大肠杆菌所致细菌性腹泻的预防和治疗作用、对正常和高糖耐受量小鼠血糖的影响和对急性高血脂模型小鼠血脂的影响试验对其药效学进行评价。黄连素纳米乳给药系统对金黄色葡萄球菌、大肠杆菌、沙门氏菌和无乳链球菌具有相似的抗菌活性,其抑菌圈直径分别是片剂、胶囊和水溶液的4倍、3.83倍、3.83倍和3.66倍。用大肠杆菌所致细菌性腹泻,黄连素纳米乳减少腹泻次数是黄连素水溶液、黄连素片剂、黄连素胶囊和泻痢停的2倍、2.2倍、2倍、1.93倍(预防试验)和2.7倍、2.13倍、1.88倍、2.22倍(治疗试验)。用50 mg/kg,1次/d,连续给药6 d后,它可降低正常小鼠的血糖值,但与各试验组间差异不显著(P>0.05)。用上述方法给药,2.0 g/kg腹腔注射葡萄糖造成的高糖耐受量模型,对降低小鼠相对的血糖值的平均值(0、30、60、120 min),黄连素纳米乳是黄连素片剂、黄连素胶囊和格列苯脲的4.48倍、3.57倍、3.88倍。用上述方法给药后,0.25 mL/10g腹腔注射75%的蛋黄乳造成的急性高血脂模型,对降低小鼠的总甘油三酯、总胆固醇、动脉硬化指数的相对值,黄连素纳米乳是黄连素片剂、黄连素胶囊和非诺倍特的4.51倍、2.18倍、4.60倍和2.08倍、1.06倍、1.27倍和2.64倍、1.64倍和1.44倍。药效学结果表明,制备的黄连素纳米乳药效比黄连素黄连素片剂和黄连素胶囊显著提高。
6.黄连素纳米乳给药系统的药动学及其释药性能研究
对黄连素纳米乳的药动学和体外释药性能进行研究。给家兔灌50 mg/kg黄连素后,在0、0.16、0.33、0.5、0.75、1、2、4、8、12、18、24 h,用HPLC法测定家兔血浆中的黄连素含量,用残数法对药时曲线进行拟合,计算出药动学参数。用透析袋法,考察黄连素纳米乳、黄连素片剂和黄连素胶囊在人工胃液、人工肠液和pH6.8的磷酸盐缓冲液(PBS)的释药性能,用七种常用的释放模型方程对释药曲线进行拟合。在家兔体内,黄连素纳米乳、黄连素片剂和黄连素胶囊均符合有吸收的二室开放模型。黄连素纳米乳的平均达峰时间Tmax(4.205 h)比黄连素片剂(1.379 h)和黄连素胶囊(1.117 h)延长2.826 h和3.088 h;其理论的平均最高血药浓度Cmax(113.699μg/L)是黄连素片剂(62.466μg/L)和黄连素胶囊(60.021μg/L)的1.820倍和1.894倍;其相对生物利用度是黄连素片剂和黄连素胶囊的339%和332%。释药结果表明,黄连素纳米乳在人工胃液和PBS中符合Hixon-crowell方程;在人工肠液中符合一级释放方程。动力学结果揭示,黄连素纳米乳的相对生物利用度明显增加,且具有一定的缓释作用。释药性能曲线显示,黄连素纳米乳在人工肠液中的释放浓度最高,药物释放属于被动扩散。
In this research, for the merits of nanotechnology, the traditional berberine was recasted by using the nanoemulsion drug delivery system as a new carrier. At first, the establishment of analytical method, screening of blank nanoemulsion prescription and the inspection of influence factor were studied. Nanoemulsion drug delivery system of berberine was prepared by pseudotertiary phase diagram. And the quality stability, security, pharmacodynamics, pharmacokinetics and release properties were systemically studied. The abstracts are as follows:
1. The establishment of analytical method on nanoemulsion drug delivery system of berberine.
To establish the analytical method for content determining of berberine nanoemulsion drug delivery system, Ultraviolet was used in preparation and HPLC was used in preparation and dynamic. The Ultraviolet absorption wavelength, standard curve, recovery and accuracy were studied by Ultraviolet spectrophotometer and HPLC. Results shown that berberine has the maximal absorption in 340 nm. The good linear range was 1～40μg/ml.The mean recovery is 99.7 %.RSD of the recovery is 0.39 %,the type duplication is 2.5 %,the accuracies with-day and between-day are lesss than 0.6 %.HPLC:The good linear range of the preparation was 50～1 600 ng/ml, The examination limit is 2 ng/mL, the mean recovery is 99.4% and the mean retention time is 7.499 min. RSD of the recovery is 0.79 %,the type duplication is 0.64 % and 1.44 %, the accuracies with-day and between-day are is less than 0.6 %; The good linear range of the blood plasma was 10～1 600 ng/ml.The examination limits is 0.36 ng/mL, the mean recovery is 95.6% and the mean retention time is 5.602 min. RSD of the recovery is 3.64 %, the type duplication is 0.42 % and 1.42 %、the accuracies with-day and between-day are lesss than 1%.The analysis method we established in this study have high recovery, accuracy and repeatable, it can be used in quality control and dynamics research.
2. The prescription screening and the influence factors inspection of blank nanoemulsion drug delivery system
The prescriptions of the blank nanoemulsion were screened and its influence factors were observed. Prescriptions of nanoemulsion were screened with the HLB and the nanoemulsion evaluation standard, pseudoternary phase diagrams were used to be observed the formula of nanoemulsion; the enhanced solubility was studied also. Results show that the prescriptions of screening that can form nanoemulsion are: the surfactant is: the Tween kind (80 and 60), Span kind (80 and 60), EL-40and RH-40; the cosurfactant is: the absolute ethyl alcohol, the glycerine, synth eticnbutyl alcohol, n-Butanol and 1, 3-butyleneglycol. The oil phase is: IPM and liquid paraffin. The influence factors inspection result shows that surfactant and the type and retio of the oil phase are the main and the key factors for the formula of nanoemulsion. In some distance, the higher HLB of surfactant, the bigger area of nanoemulsion is. The shorter chain of cosurfactant, the bigger area of nanoemulsion is. The HLB of the oil phase and the mixed surfactant more matches, the bigger area of nanoemulsion. The the ratio (Km) to surfactant and cosurfactant be more appropriate, the bigger area of nanoemulsion. Within limits, the amount of the medicine added increase, the area of nanoemulsion increased; the solubilization effect shows that the berberine has higher solubility in nanoemulsion than in water and micelle. The prescription of the blank nanoemulsion of being screened and the influence factors inspection results laid a good foundation for further study preparation.
3. The preparation and quality evaluation on nanoemulsion drug delivery system of berberine.
The nanoemulsion drug delivery system of berberine was prepared and its quality was evaluated. The suitable oil phase, surfactant and cosurfactant were choused, the nanoemulsion drug delivery system of berberine were optimized by studying the pseudoternary phase diagram. The preparation method was optimized by entrapment efficiency and drug loading as evaluation standard. Their characters were detected by electron microscope, photon correlation spectroscope, the viscosity statement, refraction and electric conductivity, the content of berberine was determined by HPLC, its’stability was also detected. Results show that the nanoemulsion drug delivery system of berberine that contains EL40-glycerine-IPM was transparent spherical bubble. Its average diameter is 43.5 nm (blank nanoemulsion is 17.9 nm); the optimal preparation method was magnetic stirring, 37 oC, and 150 r/min, disperses 12 h and the order of the third kind of medicine. The physical and chemistry characters, stability parameter, acceleration and light acceleration indicate that the quality of berberine nanoemulsion drug delivery systerm was stable, its term of validity can be conjected to be 2.5 years by long-term and the classical constant temperature experiment. The quality on nanoemulsion drug delivery system of berberine was stable. It conforms to the request of nanoemulsion drug delivery system.
4. The safety evaluation on nanoemulsion drug delivery system of berberine.
To the safety evaluate of berberine nanoemulsion drug delivery system. Evaluate the safety of berberine nanoemulsion drug delivery systerm by acute toxicity, skin irritation, eye irritation (single and several), cell toxicity experiment. Results show that the maximal tolerance dose test on mice of the berberine nanoemulsion drug delivery systerm was 875mg/kg. Converts into adult's dosage (50 kg), is 21,875 times of clinical amount used. According to Bliss, counts software with SAS6.0, self-procedure, calculates its accumulation LD50 is 3 055 mg/kg. The stimulation to the party of rabbit’s skin and eye are all non-toxic. The cell toxicity is 1 level, not obvious toxicity. The berberine nanoemulsion drug delivery system is non-toxic to mouse, domestic rabbit skin and eye, cell, clinical with medicine security, conforms to the request of nanoemulsion drug delivery system.
5. The pharmacodynamics evaluation on nanoemulsion drug delivery system of berberine.
The pharmacodynamics on nanoemulsion drug delivery system of berberine was evaluated. The pharmacodynamics on nanoemulsion drug delivery system of berberine was evaluated by antibacterial activity in vitro, preventing and treating effect on bacterial diarrhea caused by E.coli, the mice blood sugar influence by normal and high glucose tolerance, the mice serum lipids influence experiment by acute hyperlipemia. Results show that the nanoemulsion drug delivery system of berberine had the same antibacterial activity to Staphylococcus aureus, E.coli, S.agalactae, Sam onellal, its antibacterial diameter is respectively 4, 3.83, 3.83, 3.66 times as that of tablet, capsule, watery solution, and blanking nanoemulsion. Bacterial diarrhea caused by E.coli, The diarrhea times that berberine nanoemulsion decreased is respectively2,2.2,2,1.93 times(Preventing tests) and 2.7,2.13,1.88,2.22 times(Treating tests) that of watery solution, tablet, capsule, Xieliting tablets. Continuously administrated for 6d, with 50mg/kg, 1 time/d, the normal blood sugar of mice reduced.But there is no remarkable differences between each experimental group(P>0.05). high glucose tolerance model caused by ip 2.0 g/kg glucose,administere the drug as the method above, berberine nanoemulsion is respectively 4.48,3.57,3.88 times that of tablet, capsule, glibenclamide for decreasing the average of mice ralitive blood glucose(0, 30, 60, 120min). The drug and the method above were administered. The acute yperlipemia model caused by ip 0.25 ml/10 g yolk emulsion (75 %). After administrated using the method above, the reduction of the total cholesterol and the arteriosclerosis index relative value of rats caused by berberine nanoemulsion is 4.51, 2.18, 4.60:2.08, 1.06, 1.27; 2.64, 1.64, 1.44 times as that of tablet, capsule and enofibrate. The pharmacodynamics results show that the berberine nanoemulsion is better than tablet and capsule.
6. The pharmacokinetics and release study on nanoemulsion drug delivery system of berberine.
The pharmacokinetics and in vitro release of berberine nanoemulsion were studied. The berberine nanoemulsion was administered to the rabbit by ig with 50 mg/kg,in the time of 0,0.16,0.33,0.5,0.75,1,2,4,8,12,18,24 h, berberine was determined through HPLC in its plasma. The medicine kinematics parameter was calculated. The release behavior of berberine nanoemulsion,tablet and capsule in SGF、SIF、PBS (pH6.8)was inspected by dialysis seven normal release model carve were used to fitting the release curve. Results show that berberine nanoemulsion, tablet and capsule are all fit for the two room open model, in rabbit. The average peak time values of berberine nanoemulsion (4.205 h) enhance 2.826 h,3.088 h than tablet(1.379 h) and capsule(1.117 h).The average highest plasma concentration of its (113.699μg/L)is 1.820,1.894 times of ablet (62.466μg/L)and capsule(60.021μg/L), The relative bioavailability is339% and 332% that of tablet and capsule.The release result shows that berberine nanoemulsion fit for Hixon-crowell equation in SGF and PBS.Fit for one level release equation in SIF. The pharmacokinetics indicated that the relative bioavailability of nanoemulsion increased obviously and there is some controlled release effect. The release behavior shows that the release content of erberine nanoemulsion is highest in SIF and the release of the drug is passive diffusion.
1.黄连素纳米乳给药系统的分析方法建立
建立用于黄连素纳米乳给药系统含量检测的紫外(制剂)与高效液相色谱(制剂和动力学)分析方法。用紫外分光光度计和高效液相色谱仪,对其紫外吸收波长、标准曲线、回收率和精密度等进行研究。结果表明,黄连素在340 nm处有最大吸收,紫外的标准曲线在1～40μg/ml范围内线性关系良好,其平均回收率为99.7 %。回收率的相对标准偏差(RSD)为0.39 %、进样重复性的为2.5 %、日间和日内精密度的小于0.6 %;高效液相色谱(HPLC):制剂的标准曲线在50～1600 ng/mL范围内线性关系良好,检测限为2ng/mL,其平均回收率为99.4 %和平均保留时间为7.499 min。回收率的RSD为0.79%、进样重复性的为0.64 %和1.44 %、日间和日内精密度的小于0.6 %;血浆的标准曲线在10～1600 ng/mL范围内,线性关系良好,检测限为0.36 ng/mL,其平均回收率为95.6 %和平均保留时间为5.602 min。回收率的RSD为3.46 %、进样重复性的为0.42 %和1.42 %、日间和日内精密度的小于0.6 %。本研究建立的分析方法回收率高、精密度和重复性好,可用于其质量控制和动力学研究。
2.空白纳米乳给药系统的处方筛选及其影响因素考察
筛选出空白纳米乳处方并对其影响因素进行考察。用HLB值法和纳米乳的评价标准,筛选出形成纳米乳的处方;用伪三元相图,对纳米乳形成的影响因素进行考察;对黄连素的增溶作用也进行研究。结果表明,筛选出可形成纳米乳的处方是,表面活性剂为Tween类(80和60),Span类(80和60),EL-40和RH-40;助表面活性为无水乙醇、甘油、丙二醇、正丁醇和1,3丁二醇;油相为IPM和液体石蜡。影响因素考察结果显示,表面活性剂与油相的种类及比例是纳米乳形成最主要和关键的因素。在能形成纳米乳范围内,表面活性剂HLB值越大,纳米乳区越大;助表面活性剂的链越短,纳米乳区越大;油相的HLB值与混合表面活性剂的HLB值越匹配,纳米乳区越大;表面活性剂与助表面活性剂的比值(Km)越合适,纳米乳区越大;在一定范围内,药物加入量的增加,纳米乳区增大;增溶试验表明,黄连素在纳米乳中的溶解度比水溶液和胶束的高。本研究筛选出的空白纳米乳处方及影响因素考察结果,为后期制备工作奠定了基础。
3.黄连素纳米乳给药系统的制备及其质量评价
制备出黄连素纳米乳给药系统并对其质量进行评价。选择适宜的油相、表面活性剂和助表面活性剂,利用伪三元相图,制备出黄连素纳米乳给药系统。用包封率与载药量为评价指标,对其制备工艺进行优化;用透射电镜、激光粒度分布仪、黏度计、折光仪和电导仪等对其理化性质进行研究;用高效液相色谱仪检测该系统中黄连素的含量,对其稳定性进行检测。结果表明,制备出含EL40-甘油-IPM的黄连素纳米乳给药系统是澄清透明的球状液滴液体,其平均粒径为43.5 nm(空白纳米乳为17.9 nm);优化出的制备工艺是磁力搅拌、37 oC、150 r/min、分散12 h和第三种药物加入顺序。理化性质、稳定性参数、加速和光加速等研究结果表明,制备的黄连素纳米乳给药系统质量稳定;通过长期和经典恒温试验可推测出其有效期为2.5年。本研究制备出的黄连素给药系统质量稳定,符合纳米乳给药系统的要求。
4.黄连素纳米乳给药系统的安全性评价
对黄连素纳米乳给药系统的安全性进行评价。通过急性毒性、皮肤刺激和眼部刺激毒性(单次和多次)、细胞毒性试验对纳米乳的安全性进行评价。结果表明,黄连素纳米乳给药系统对小鼠的最大耐受量为875 mg/kg,折合成人的剂量(50 kg),是临床用量的21 875倍。根据Bliss法,用SAS6.0统计软件、自行编制程序,计算出其累积的LD50为3 055 mg/kg;对家兔皮肤和眼部(单次和多次)刺激均无毒性;对细胞毒性为1级,无明显毒性。本研究制备出的纳米乳给药系统的对小鼠、家兔皮肤和眼部、细胞均无毒性,临床用药安全,符合纳米乳给药系统的要求。
5.黄连素纳米乳给药系统的药效学评价
对黄连素纳米乳给药系统的药效学进行评价。用体外抑菌、对大肠杆菌所致细菌性腹泻的预防和治疗作用、对正常和高糖耐受量小鼠血糖的影响和对急性高血脂模型小鼠血脂的影响试验对其药效学进行评价。黄连素纳米乳给药系统对金黄色葡萄球菌、大肠杆菌、沙门氏菌和无乳链球菌具有相似的抗菌活性,其抑菌圈直径分别是片剂、胶囊和水溶液的4倍、3.83倍、3.83倍和3.66倍。用大肠杆菌所致细菌性腹泻,黄连素纳米乳减少腹泻次数是黄连素水溶液、黄连素片剂、黄连素胶囊和泻痢停的2倍、2.2倍、2倍、1.93倍(预防试验)和2.7倍、2.13倍、1.88倍、2.22倍(治疗试验)。用50 mg/kg,1次/d,连续给药6 d后,它可降低正常小鼠的血糖值,但与各试验组间差异不显著(P>0.05)。用上述方法给药,2.0 g/kg腹腔注射葡萄糖造成的高糖耐受量模型,对降低小鼠相对的血糖值的平均值(0、30、60、120 min),黄连素纳米乳是黄连素片剂、黄连素胶囊和格列苯脲的4.48倍、3.57倍、3.88倍。用上述方法给药后,0.25 mL/10g腹腔注射75%的蛋黄乳造成的急性高血脂模型,对降低小鼠的总甘油三酯、总胆固醇、动脉硬化指数的相对值,黄连素纳米乳是黄连素片剂、黄连素胶囊和非诺倍特的4.51倍、2.18倍、4.60倍和2.08倍、1.06倍、1.27倍和2.64倍、1.64倍和1.44倍。药效学结果表明,制备的黄连素纳米乳药效比黄连素黄连素片剂和黄连素胶囊显著提高。
6.黄连素纳米乳给药系统的药动学及其释药性能研究
对黄连素纳米乳的药动学和体外释药性能进行研究。给家兔灌50 mg/kg黄连素后,在0、0.16、0.33、0.5、0.75、1、2、4、8、12、18、24 h,用HPLC法测定家兔血浆中的黄连素含量,用残数法对药时曲线进行拟合,计算出药动学参数。用透析袋法,考察黄连素纳米乳、黄连素片剂和黄连素胶囊在人工胃液、人工肠液和pH6.8的磷酸盐缓冲液(PBS)的释药性能,用七种常用的释放模型方程对释药曲线进行拟合。在家兔体内,黄连素纳米乳、黄连素片剂和黄连素胶囊均符合有吸收的二室开放模型。黄连素纳米乳的平均达峰时间Tmax(4.205 h)比黄连素片剂(1.379 h)和黄连素胶囊(1.117 h)延长2.826 h和3.088 h;其理论的平均最高血药浓度Cmax(113.699μg/L)是黄连素片剂(62.466μg/L)和黄连素胶囊(60.021μg/L)的1.820倍和1.894倍;其相对生物利用度是黄连素片剂和黄连素胶囊的339%和332%。释药结果表明,黄连素纳米乳在人工胃液和PBS中符合Hixon-crowell方程;在人工肠液中符合一级释放方程。动力学结果揭示,黄连素纳米乳的相对生物利用度明显增加,且具有一定的缓释作用。释药性能曲线显示,黄连素纳米乳在人工肠液中的释放浓度最高,药物释放属于被动扩散。
In this research, for the merits of nanotechnology, the traditional berberine was recasted by using the nanoemulsion drug delivery system as a new carrier. At first, the establishment of analytical method, screening of blank nanoemulsion prescription and the inspection of influence factor were studied. Nanoemulsion drug delivery system of berberine was prepared by pseudotertiary phase diagram. And the quality stability, security, pharmacodynamics, pharmacokinetics and release properties were systemically studied. The abstracts are as follows:
1. The establishment of analytical method on nanoemulsion drug delivery system of berberine.
To establish the analytical method for content determining of berberine nanoemulsion drug delivery system, Ultraviolet was used in preparation and HPLC was used in preparation and dynamic. The Ultraviolet absorption wavelength, standard curve, recovery and accuracy were studied by Ultraviolet spectrophotometer and HPLC. Results shown that berberine has the maximal absorption in 340 nm. The good linear range was 1～40μg/ml.The mean recovery is 99.7 %.RSD of the recovery is 0.39 %,the type duplication is 2.5 %,the accuracies with-day and between-day are lesss than 0.6 %.HPLC:The good linear range of the preparation was 50～1 600 ng/ml, The examination limit is 2 ng/mL, the mean recovery is 99.4% and the mean retention time is 7.499 min. RSD of the recovery is 0.79 %,the type duplication is 0.64 % and 1.44 %, the accuracies with-day and between-day are is less than 0.6 %; The good linear range of the blood plasma was 10～1 600 ng/ml.The examination limits is 0.36 ng/mL, the mean recovery is 95.6% and the mean retention time is 5.602 min. RSD of the recovery is 3.64 %, the type duplication is 0.42 % and 1.42 %、the accuracies with-day and between-day are lesss than 1%.The analysis method we established in this study have high recovery, accuracy and repeatable, it can be used in quality control and dynamics research.
2. The prescription screening and the influence factors inspection of blank nanoemulsion drug delivery system
The prescriptions of the blank nanoemulsion were screened and its influence factors were observed. Prescriptions of nanoemulsion were screened with the HLB and the nanoemulsion evaluation standard, pseudoternary phase diagrams were used to be observed the formula of nanoemulsion; the enhanced solubility was studied also. Results show that the prescriptions of screening that can form nanoemulsion are: the surfactant is: the Tween kind (80 and 60), Span kind (80 and 60), EL-40and RH-40; the cosurfactant is: the absolute ethyl alcohol, the glycerine, synth eticnbutyl alcohol, n-Butanol and 1, 3-butyleneglycol. The oil phase is: IPM and liquid paraffin. The influence factors inspection result shows that surfactant and the type and retio of the oil phase are the main and the key factors for the formula of nanoemulsion. In some distance, the higher HLB of surfactant, the bigger area of nanoemulsion is. The shorter chain of cosurfactant, the bigger area of nanoemulsion is. The HLB of the oil phase and the mixed surfactant more matches, the bigger area of nanoemulsion. The the ratio (Km) to surfactant and cosurfactant be more appropriate, the bigger area of nanoemulsion. Within limits, the amount of the medicine added increase, the area of nanoemulsion increased; the solubilization effect shows that the berberine has higher solubility in nanoemulsion than in water and micelle. The prescription of the blank nanoemulsion of being screened and the influence factors inspection results laid a good foundation for further study preparation.
3. The preparation and quality evaluation on nanoemulsion drug delivery system of berberine.
The nanoemulsion drug delivery system of berberine was prepared and its quality was evaluated. The suitable oil phase, surfactant and cosurfactant were choused, the nanoemulsion drug delivery system of berberine were optimized by studying the pseudoternary phase diagram. The preparation method was optimized by entrapment efficiency and drug loading as evaluation standard. Their characters were detected by electron microscope, photon correlation spectroscope, the viscosity statement, refraction and electric conductivity, the content of berberine was determined by HPLC, its’stability was also detected. Results show that the nanoemulsion drug delivery system of berberine that contains EL40-glycerine-IPM was transparent spherical bubble. Its average diameter is 43.5 nm (blank nanoemulsion is 17.9 nm); the optimal preparation method was magnetic stirring, 37 oC, and 150 r/min, disperses 12 h and the order of the third kind of medicine. The physical and chemistry characters, stability parameter, acceleration and light acceleration indicate that the quality of berberine nanoemulsion drug delivery systerm was stable, its term of validity can be conjected to be 2.5 years by long-term and the classical constant temperature experiment. The quality on nanoemulsion drug delivery system of berberine was stable. It conforms to the request of nanoemulsion drug delivery system.
4. The safety evaluation on nanoemulsion drug delivery system of berberine.
To the safety evaluate of berberine nanoemulsion drug delivery system. Evaluate the safety of berberine nanoemulsion drug delivery systerm by acute toxicity, skin irritation, eye irritation (single and several), cell toxicity experiment. Results show that the maximal tolerance dose test on mice of the berberine nanoemulsion drug delivery systerm was 875mg/kg. Converts into adult's dosage (50 kg), is 21,875 times of clinical amount used. According to Bliss, counts software with SAS6.0, self-procedure, calculates its accumulation LD50 is 3 055 mg/kg. The stimulation to the party of rabbit’s skin and eye are all non-toxic. The cell toxicity is 1 level, not obvious toxicity. The berberine nanoemulsion drug delivery system is non-toxic to mouse, domestic rabbit skin and eye, cell, clinical with medicine security, conforms to the request of nanoemulsion drug delivery system.
5. The pharmacodynamics evaluation on nanoemulsion drug delivery system of berberine.
The pharmacodynamics on nanoemulsion drug delivery system of berberine was evaluated. The pharmacodynamics on nanoemulsion drug delivery system of berberine was evaluated by antibacterial activity in vitro, preventing and treating effect on bacterial diarrhea caused by E.coli, the mice blood sugar influence by normal and high glucose tolerance, the mice serum lipids influence experiment by acute hyperlipemia. Results show that the nanoemulsion drug delivery system of berberine had the same antibacterial activity to Staphylococcus aureus, E.coli, S.agalactae, Sam onellal, its antibacterial diameter is respectively 4, 3.83, 3.83, 3.66 times as that of tablet, capsule, watery solution, and blanking nanoemulsion. Bacterial diarrhea caused by E.coli, The diarrhea times that berberine nanoemulsion decreased is respectively2,2.2,2,1.93 times(Preventing tests) and 2.7,2.13,1.88,2.22 times(Treating tests) that of watery solution, tablet, capsule, Xieliting tablets. Continuously administrated for 6d, with 50mg/kg, 1 time/d, the normal blood sugar of mice reduced.But there is no remarkable differences between each experimental group(P>0.05). high glucose tolerance model caused by ip 2.0 g/kg glucose,administere the drug as the method above, berberine nanoemulsion is respectively 4.48,3.57,3.88 times that of tablet, capsule, glibenclamide for decreasing the average of mice ralitive blood glucose(0, 30, 60, 120min). The drug and the method above were administered. The acute yperlipemia model caused by ip 0.25 ml/10 g yolk emulsion (75 %). After administrated using the method above, the reduction of the total cholesterol and the arteriosclerosis index relative value of rats caused by berberine nanoemulsion is 4.51, 2.18, 4.60:2.08, 1.06, 1.27; 2.64, 1.64, 1.44 times as that of tablet, capsule and enofibrate. The pharmacodynamics results show that the berberine nanoemulsion is better than tablet and capsule.
6. The pharmacokinetics and release study on nanoemulsion drug delivery system of berberine.
The pharmacokinetics and in vitro release of berberine nanoemulsion were studied. The berberine nanoemulsion was administered to the rabbit by ig with 50 mg/kg,in the time of 0,0.16,0.33,0.5,0.75,1,2,4,8,12,18,24 h, berberine was determined through HPLC in its plasma. The medicine kinematics parameter was calculated. The release behavior of berberine nanoemulsion,tablet and capsule in SGF、SIF、PBS (pH6.8)was inspected by dialysis seven normal release model carve were used to fitting the release curve. Results show that berberine nanoemulsion, tablet and capsule are all fit for the two room open model, in rabbit. The average peak time values of berberine nanoemulsion (4.205 h) enhance 2.826 h,3.088 h than tablet(1.379 h) and capsule(1.117 h).The average highest plasma concentration of its (113.699μg/L)is 1.820,1.894 times of ablet (62.466μg/L)and capsule(60.021μg/L), The relative bioavailability is339% and 332% that of tablet and capsule.The release result shows that berberine nanoemulsion fit for Hixon-crowell equation in SGF and PBS.Fit for one level release equation in SIF. The pharmacokinetics indicated that the relative bioavailability of nanoemulsion increased obviously and there is some controlled release effect. The release behavior shows that the release content of erberine nanoemulsion is highest in SIF and the release of the drug is passive diffusion.
引文
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