雷公藤微乳凝胶经皮给药系统的设计与评价
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摘要
雷公藤治疗类风湿性关节炎效果显著,口服制剂的疗效最为明确,然而其毒副作用十分严重,使用受到限制。本课题本研究为降低雷公藤毒副作用,提高患者顺应性,丰富临床剂型,充分发挥其疗效,对雷公藤微乳凝胶经皮给药系统进行研究,并对该系统进行体内外相关评价。
本文的具体研究内容如下:
1.雷公藤提取物溶解性能研究
提取物原料的基本物理化学性质决定了辅料的选择,同时决定了它在皮肤内的转运速度,以及制剂的稳定性和药效,因此对药物的基本性质—溶解性能进行考察,能为进一步开展药物处方设计和筛选提供依据。实验中首先考察了中药提取物溶解性能的测定方法,然后测定了雷公藤提取物在不同的油相、表面活性剂、助表面活性剂中的溶解性能,研究结果表明,雷公藤甲素在油相中的溶解能力为:油酸>辛癸酸甘油酯>三辛酸癸酸甘油酯>油酸乙酯>IPM>棕榈酸异辛酯>Gemseal40;在表面活性剂Tween 80中的溶解性能较Crempphor 40好;助表面活性剂以无水乙醇的溶解性能较好。
2.雷公藤微乳的制备工艺研究
以油酸为油相、Tween80:平平加0(9∶1)为表面活性剂、无水乙醇为助表面活性剂,在不同的Km值下绘制伪三元相图,筛选微乳处方;根据对不同处方制成的微乳理化性质、粒子形态和经皮渗透性研究,确定处方为:吐温80为7.52%,平平加0为0.84%,油酸为1.10%,无水乙醇为12.54%,水为77.50%,药物为0.5%。该处方制成的微乳理化性质均符合要求,相对于相同载药量的软膏制剂的增渗比为8.35,表明雷公藤微乳能促进雷公藤甲素的透皮吸收。
3.雷公藤微乳凝胶制备工艺研究
以凝胶的黏度、外观为指标,对凝胶的常用基质进行筛选,结果表明卡波姆-934基质制得的凝胶外观,稠度最为适宜,载药量最高;对药物的加入对卡波姆凝胶体系流变性能的影响进行了研究,结果表明药物的加入降低了原凝胶体系的表观粘度,且随凝胶浓度的增加,降低越明显;实验用Franz扩散池法,对促渗剂氮酮的浓度进行了筛选,结果以2.5%的氮酮促渗效果最好。通过以上研究得出雷公藤微乳凝胶的工艺处方为:雷公藤微乳:80%,3%卡波姆934:17%,三乙醇胺:0.6%,氮酮:2.5%。
4.雷公藤微乳凝胶体外质量评价
对雷公藤微乳凝胶的性状、鉴别、检查,根据实验结果对制剂的性状、pH值、黏度进行了规定;体外释药规律符合一级模型,效果稳定,透皮速率J值约为2.6378μg/cm~2·h;采用白色家兔测定其对皮肤的刺激性,结果表明对完整皮肤无刺激性,对损伤皮肤有轻度刺激;采用HPLC法测定雷公藤甲素含量为0.28mg/g;稳定性试验结果表明,在室温条件下放置6个月,该制剂基本稳定。
5.雷公藤微乳凝胶的体内质量评价
采用小鼠醋酸扭体实验法进行了镇痛实验研究,结果表明,与模型组比,阿司匹林片剂组、雷公藤片组、雷公藤微乳凝胶剂高剂量组、中剂量组均有抑制小鼠醋酸所致的扭体作用(p＜0.01),雷公藤微乳凝胶剂低剂量组无明显抑制作用。雷公藤微乳凝胶剂高中剂量的镇痛作用和临床上阿司匹林阳性阳物组无显著性差异(p＞0.05),说明雷公藤有较好的镇痛作用,且中剂量即达到镇痛效果,疗效与剂量相关;
通过建立大鼠佐剂性关节炎(AA)模型,观察雷公藤微乳凝胶对AA大鼠的足肿胀的抑制作用,结果表明雷公藤微乳凝胶对类风湿性关节炎有很好的治疗和预防作用,其作用于其剂量有一定的关系,且经皮给药系统与口服制剂相比,降低了肾毒性;急性毒性研究结果提示,雷公藤微乳凝胶经皮给药系统能在一定程度上降低雷公藤毒副作用,并保证疗效,说明经皮给药系统是减少雷公藤毒副作用的一个较好的途径。
建立了LC/MS检测大鼠血浆中雷公藤甲素浓度的方法,研究并比较了单次口服给予雷公藤多甙片和和经皮给予雷公藤微乳凝胶后雷公藤甲素在大鼠体内的药物动力学过程。结果表明,雷公藤微乳凝胶经皮给药及口服给药在大鼠体内均为二室模型,其中经皮给药Tmax为6.667±1.633h,Cmax为82.963±17.626ng/ml,T_(1/2)(Ka)为0.39±0.384,T_(1/2)(α)7.314±7.869h,T_(1/2)(β)56.7172±26.5155h。表明该药具有维持稳定血药浓度时间长,药效稳定的优点,能达到持效、长效的目的。
6.鼠表皮郎格罕氏细胞的研究
采用ATP酶法对鼠表皮的郎格罕氏细胞进行了检测,考察了两种不同的表皮分离方法:EDTA法和分离酶法,分离酶分离表皮的效果较好,减少了成纤维细胞的污染,细胞的结构观察较清晰。
The traditional Chinese herb Tripterygium wilfordii Hook.f.(TWHF) has been reported to be effective in treating patients with a variety of autoimmune and inflammatory diseases.The oral preparation of the herb is effective especially,but it's side effects all over the body is so serious that limits its use.At present its external preparation has therapeutic effect and few side effects,but the osmosis per cutem is difficult and can't utilized enough.
We made the microemulsion as drug delivery vehicles to prepare the transdermal drug delivery systems of TWHF to improve the suffers' acclimatization,reduce its side effects,enrich clinic dosage forms to serve people better.We evaluated the system in vitro and in vivo relatively. The dissertation is summarized as follows:
1.Study on dissolvability of extract of Tripterygium
The dissolvability affects the preparation,stability and the pharmacodynamic action and the study of the dissolvability was important for performulation.We studied the method as precipitation,dissolvability of active component and mean diameters and determined the dissolvability of Tripterygium Wilfordii extract in oil phase,surfactant and cosurfactant respectively.The dissolvability of extract in oril phase is as follows:oleic acid,MCT,labrafac, ethyl oleate,IPM,2EHP,Germseal-40 and the dissolvability was better in Tween-80 than in Crempphor 40 for surfactant and dehydrated alcohol for cosurfactant.
2.The preparation of tripterygium microemulsion
With the oleic acid as oil phase,Tween-80 and paregal O(1:1) as surfactant,dehydrated alcohol as cosurfactant the optimum formulation was investigated by using titration to prepare the Pseudo-ternary phase diagram,testing the size distribution,stability physico-chemical property, and osmosis per cutem of the microemulsion;the formula of the TWHF was 7.52%Tween-80, 0.84%paregal O 1.1%oleic acid,12.54%dehydrated alcohol,77.50%water,0.5%the extract and the osmosis per cutem of the microemulsion is significantly higher than the ointment in vitro.
3.The preparation technique of tripterygium microemulsion gel
The viscosity and the shape were determined to select the adjuvant of the gel and Carbomer 934 was chosen for its suitable viscosity and characteristics.The dependence of apparent viscosity of Carbomer gel from various concentrations on shear rate was studied by rheometer,and discuss the influence of drug to the carbomer gel's rheology property.The results are the higher carbomer content,the higher apparent viscosity of carbomer gel,and after addition the drug,the apparent viscosity of carbomer gel decrease.The Franz diffusion cells were utilized to characterize the permeation behaviour of triptolide in microemulsion gels and the results is 2.5%azone can remarkably enhance the percutaneous absorption of triptolide in vitro.The selected formulation of the tripterygium microemulsion gel is:80%tripterygium microemulsion,17%carbomer (concentration is 3%),0.6%trolamine,2.5%azone.
4.Quality Evaluation of tripteryginm mieroemulsion gel in-vitro
The character,identification,examination were studied and the quality control of the preparation by the character,pH value,viscosity was determined according to the experimental results.Determination of in vitro Percutaneous Rate and in vitro of Release of the preparation were did in use of the Franz diffusion cell and the gel permeated in vitro at the speed of 2.6378μg/cm~2·h by first-order kinetics.The skin irritation test was performed on the skin of rabbit and result was the microemulsion gel had no irritation to the intact skin of rabbits,but the mild irritation to the damaged skin was observed.The content of triptolide was 0.28mg/g in HPLC As the result of the stability test shows,the gel stability is good after storing at room temperature for 6 months and the appearance,content,viscosity and permeation rates had hardly any change.
5.Quality Evaluation of Tripterygium Microemulsion gel in vivo
The analgesic effect was studied by using acetic acid-induced wringing text and the result was the aspirin group,Tablet of Tripterygium Wilfordii,Microemulsion gel of Tripterygium high dose group and middle dose group could inhibit body's turning reaction times significantly compared with model group(p＜0.01);So its manifests a positive correlation in effect with the dosage. Between the middle and high dose group of Microemulsion gel and the the aspirin group in analgesic effect was found no significant difference,so its manifests the analgesic effect of the preparation was very good and the middle dose was efficient.
The model of arthritis was developed by Freund's complete adjuvant and the inhibitory effect of Microemulsion gel on the rat's foot swelling was determined in the rats with arthritis.The result illustrated that the preparation could exert therapeutic effect on primary inflammation and preventive effect on secondary inflammation in rats with arthritis induced by Freund's complete adjuvant,and its manifested a positive correlation in effect with the dosage.The preparation could decrease the renal toxicity of Tripterygium.The result of the experiment on acute toxicity indicated that Microemulsion gel could decrease the side effects in some degree and keep therapeutic effect.Then we could predicate that transdermal drug delivery system was a good way of lowing the side effects of Tripterygium.
We established a method for the determination of triptolide in rat plasma by HPLC/MS and studied pharmacokinetics of Microemulsion gel and Tablet of Tripterygium in rats by transdermal and oral administration respectively.The outcome indicated that the patch was a two-compartment model,and its druggery dynamics parameters were:Tmax=6.667±1.633h,Cmax =82.963±17.626ng/ml,T_(1/2)(Ka) = 0.39±0.384,T_(1/2)(α) = 7.314±7.869h,T_(1/2)(β) =56.7172±26.5155h.The above means that this drug has the advantange of lang time keeping stable blood-drug concentration and steady effects.
6.Study on the LCs cell
ATP enzyme method is deployed to detected the epidermal LC of the mouse.Two different epidermis disjunction methods are used:EDTA and dispase,the result suggests that dispase method is better.
本文的具体研究内容如下:
1.雷公藤提取物溶解性能研究
提取物原料的基本物理化学性质决定了辅料的选择,同时决定了它在皮肤内的转运速度,以及制剂的稳定性和药效,因此对药物的基本性质—溶解性能进行考察,能为进一步开展药物处方设计和筛选提供依据。实验中首先考察了中药提取物溶解性能的测定方法,然后测定了雷公藤提取物在不同的油相、表面活性剂、助表面活性剂中的溶解性能,研究结果表明,雷公藤甲素在油相中的溶解能力为:油酸>辛癸酸甘油酯>三辛酸癸酸甘油酯>油酸乙酯>IPM>棕榈酸异辛酯>Gemseal40;在表面活性剂Tween 80中的溶解性能较Crempphor 40好;助表面活性剂以无水乙醇的溶解性能较好。
2.雷公藤微乳的制备工艺研究
以油酸为油相、Tween80:平平加0(9∶1)为表面活性剂、无水乙醇为助表面活性剂,在不同的Km值下绘制伪三元相图,筛选微乳处方;根据对不同处方制成的微乳理化性质、粒子形态和经皮渗透性研究,确定处方为:吐温80为7.52%,平平加0为0.84%,油酸为1.10%,无水乙醇为12.54%,水为77.50%,药物为0.5%。该处方制成的微乳理化性质均符合要求,相对于相同载药量的软膏制剂的增渗比为8.35,表明雷公藤微乳能促进雷公藤甲素的透皮吸收。
3.雷公藤微乳凝胶制备工艺研究
以凝胶的黏度、外观为指标,对凝胶的常用基质进行筛选,结果表明卡波姆-934基质制得的凝胶外观,稠度最为适宜,载药量最高;对药物的加入对卡波姆凝胶体系流变性能的影响进行了研究,结果表明药物的加入降低了原凝胶体系的表观粘度,且随凝胶浓度的增加,降低越明显;实验用Franz扩散池法,对促渗剂氮酮的浓度进行了筛选,结果以2.5%的氮酮促渗效果最好。通过以上研究得出雷公藤微乳凝胶的工艺处方为:雷公藤微乳:80%,3%卡波姆934:17%,三乙醇胺:0.6%,氮酮:2.5%。
4.雷公藤微乳凝胶体外质量评价
对雷公藤微乳凝胶的性状、鉴别、检查,根据实验结果对制剂的性状、pH值、黏度进行了规定;体外释药规律符合一级模型,效果稳定,透皮速率J值约为2.6378μg/cm~2·h;采用白色家兔测定其对皮肤的刺激性,结果表明对完整皮肤无刺激性,对损伤皮肤有轻度刺激;采用HPLC法测定雷公藤甲素含量为0.28mg/g;稳定性试验结果表明,在室温条件下放置6个月,该制剂基本稳定。
5.雷公藤微乳凝胶的体内质量评价
采用小鼠醋酸扭体实验法进行了镇痛实验研究,结果表明,与模型组比,阿司匹林片剂组、雷公藤片组、雷公藤微乳凝胶剂高剂量组、中剂量组均有抑制小鼠醋酸所致的扭体作用(p＜0.01),雷公藤微乳凝胶剂低剂量组无明显抑制作用。雷公藤微乳凝胶剂高中剂量的镇痛作用和临床上阿司匹林阳性阳物组无显著性差异(p＞0.05),说明雷公藤有较好的镇痛作用,且中剂量即达到镇痛效果,疗效与剂量相关;
通过建立大鼠佐剂性关节炎(AA)模型,观察雷公藤微乳凝胶对AA大鼠的足肿胀的抑制作用,结果表明雷公藤微乳凝胶对类风湿性关节炎有很好的治疗和预防作用,其作用于其剂量有一定的关系,且经皮给药系统与口服制剂相比,降低了肾毒性;急性毒性研究结果提示,雷公藤微乳凝胶经皮给药系统能在一定程度上降低雷公藤毒副作用,并保证疗效,说明经皮给药系统是减少雷公藤毒副作用的一个较好的途径。
建立了LC/MS检测大鼠血浆中雷公藤甲素浓度的方法,研究并比较了单次口服给予雷公藤多甙片和和经皮给予雷公藤微乳凝胶后雷公藤甲素在大鼠体内的药物动力学过程。结果表明,雷公藤微乳凝胶经皮给药及口服给药在大鼠体内均为二室模型,其中经皮给药Tmax为6.667±1.633h,Cmax为82.963±17.626ng/ml,T_(1/2)(Ka)为0.39±0.384,T_(1/2)(α)7.314±7.869h,T_(1/2)(β)56.7172±26.5155h。表明该药具有维持稳定血药浓度时间长,药效稳定的优点,能达到持效、长效的目的。
6.鼠表皮郎格罕氏细胞的研究
采用ATP酶法对鼠表皮的郎格罕氏细胞进行了检测,考察了两种不同的表皮分离方法:EDTA法和分离酶法,分离酶分离表皮的效果较好,减少了成纤维细胞的污染,细胞的结构观察较清晰。
The traditional Chinese herb Tripterygium wilfordii Hook.f.(TWHF) has been reported to be effective in treating patients with a variety of autoimmune and inflammatory diseases.The oral preparation of the herb is effective especially,but it's side effects all over the body is so serious that limits its use.At present its external preparation has therapeutic effect and few side effects,but the osmosis per cutem is difficult and can't utilized enough.
We made the microemulsion as drug delivery vehicles to prepare the transdermal drug delivery systems of TWHF to improve the suffers' acclimatization,reduce its side effects,enrich clinic dosage forms to serve people better.We evaluated the system in vitro and in vivo relatively. The dissertation is summarized as follows:
1.Study on dissolvability of extract of Tripterygium
The dissolvability affects the preparation,stability and the pharmacodynamic action and the study of the dissolvability was important for performulation.We studied the method as precipitation,dissolvability of active component and mean diameters and determined the dissolvability of Tripterygium Wilfordii extract in oil phase,surfactant and cosurfactant respectively.The dissolvability of extract in oril phase is as follows:oleic acid,MCT,labrafac, ethyl oleate,IPM,2EHP,Germseal-40 and the dissolvability was better in Tween-80 than in Crempphor 40 for surfactant and dehydrated alcohol for cosurfactant.
2.The preparation of tripterygium microemulsion
With the oleic acid as oil phase,Tween-80 and paregal O(1:1) as surfactant,dehydrated alcohol as cosurfactant the optimum formulation was investigated by using titration to prepare the Pseudo-ternary phase diagram,testing the size distribution,stability physico-chemical property, and osmosis per cutem of the microemulsion;the formula of the TWHF was 7.52%Tween-80, 0.84%paregal O 1.1%oleic acid,12.54%dehydrated alcohol,77.50%water,0.5%the extract and the osmosis per cutem of the microemulsion is significantly higher than the ointment in vitro.
3.The preparation technique of tripterygium microemulsion gel
The viscosity and the shape were determined to select the adjuvant of the gel and Carbomer 934 was chosen for its suitable viscosity and characteristics.The dependence of apparent viscosity of Carbomer gel from various concentrations on shear rate was studied by rheometer,and discuss the influence of drug to the carbomer gel's rheology property.The results are the higher carbomer content,the higher apparent viscosity of carbomer gel,and after addition the drug,the apparent viscosity of carbomer gel decrease.The Franz diffusion cells were utilized to characterize the permeation behaviour of triptolide in microemulsion gels and the results is 2.5%azone can remarkably enhance the percutaneous absorption of triptolide in vitro.The selected formulation of the tripterygium microemulsion gel is:80%tripterygium microemulsion,17%carbomer (concentration is 3%),0.6%trolamine,2.5%azone.
4.Quality Evaluation of tripteryginm mieroemulsion gel in-vitro
The character,identification,examination were studied and the quality control of the preparation by the character,pH value,viscosity was determined according to the experimental results.Determination of in vitro Percutaneous Rate and in vitro of Release of the preparation were did in use of the Franz diffusion cell and the gel permeated in vitro at the speed of 2.6378μg/cm~2·h by first-order kinetics.The skin irritation test was performed on the skin of rabbit and result was the microemulsion gel had no irritation to the intact skin of rabbits,but the mild irritation to the damaged skin was observed.The content of triptolide was 0.28mg/g in HPLC As the result of the stability test shows,the gel stability is good after storing at room temperature for 6 months and the appearance,content,viscosity and permeation rates had hardly any change.
5.Quality Evaluation of Tripterygium Microemulsion gel in vivo
The analgesic effect was studied by using acetic acid-induced wringing text and the result was the aspirin group,Tablet of Tripterygium Wilfordii,Microemulsion gel of Tripterygium high dose group and middle dose group could inhibit body's turning reaction times significantly compared with model group(p＜0.01);So its manifests a positive correlation in effect with the dosage. Between the middle and high dose group of Microemulsion gel and the the aspirin group in analgesic effect was found no significant difference,so its manifests the analgesic effect of the preparation was very good and the middle dose was efficient.
The model of arthritis was developed by Freund's complete adjuvant and the inhibitory effect of Microemulsion gel on the rat's foot swelling was determined in the rats with arthritis.The result illustrated that the preparation could exert therapeutic effect on primary inflammation and preventive effect on secondary inflammation in rats with arthritis induced by Freund's complete adjuvant,and its manifested a positive correlation in effect with the dosage.The preparation could decrease the renal toxicity of Tripterygium.The result of the experiment on acute toxicity indicated that Microemulsion gel could decrease the side effects in some degree and keep therapeutic effect.Then we could predicate that transdermal drug delivery system was a good way of lowing the side effects of Tripterygium.
We established a method for the determination of triptolide in rat plasma by HPLC/MS and studied pharmacokinetics of Microemulsion gel and Tablet of Tripterygium in rats by transdermal and oral administration respectively.The outcome indicated that the patch was a two-compartment model,and its druggery dynamics parameters were:Tmax=6.667±1.633h,Cmax =82.963±17.626ng/ml,T_(1/2)(Ka) = 0.39±0.384,T_(1/2)(α) = 7.314±7.869h,T_(1/2)(β) =56.7172±26.5155h.The above means that this drug has the advantange of lang time keeping stable blood-drug concentration and steady effects.
6.Study on the LCs cell
ATP enzyme method is deployed to detected the epidermal LC of the mouse.Two different epidermis disjunction methods are used:EDTA and dispase,the result suggests that dispase method is better.
引文
[1]Mads Kreilgaard,Influence of microemulsions on cutaneous drug delivery.Advanced Drug Delivery Reviews,2002,54 Suppl.1:S77-S98
[2]张立超,胡进红.Foreign medical science section on pharmacy 2004 Feb;31(1)
[3]朱晓燕,等.经皮肤使用的雷公藤制剂概况.四川中医,2004,22(3):32
[4]沈子龙,李爽,谢启昆.雷公藤巴布剂透皮吸收研究.中国药科大学学报,1994,25(3):141-144
[5]王本祥.现代中药药理研究.天津:天津科技翻译出版公司,2004:1601
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