摘要
丹黄凝胶剂由大黄、黄连、黄柏等中药组成,具有清热解毒、凉血化瘀、祛风杀虫、消肿散结之功,临床上用于治疗痤疮。本课题在中医药理论的指导下,采用现代科学技术方法,对丹黄凝胶方原药材质量、提取工艺、提取物溶解性能、成型工艺、体外释放与透皮、质量标准及稳定性进行了全面的研究和评价,具体研究及结果如下：
1.药材质量研究
参照《中国药典》2005版各药材项下鉴别方法对各味药材进行了鉴别,并对君药大黄中5个成分及臣药黄连和黄柏中的小檗碱进行了含量测定,结果所选药材均符合药典规定。
2.提取工艺研究
根据处方功效、临床用药及药物有效成分性质,将硫磺和冰片研成细粉备用,其余6味药材进行提取。在文献资料考查和预试验结果的基础上,以有效成分大黄酚及小檗碱的提取率为指标,同时兼顾干浸膏得率,采用单因素试验考察了提取温度,并运用均匀设计法对乙醇浓度、溶媒用量、提取时间和提取次数进行了考察,经多元统计分析和效应面分析优化,综合考虑选出了优化的提取工艺条件为：取处方比例药材适量,加入7倍量的65%乙醇,90℃条件下提取3次,2h/次,验证试验结果表明该提取工艺稳定、合理可行。以提取液中以大黄酚和小檗碱的转移率为指标,考察了浓缩、干燥方式和温度,最终确定的工艺为：提取液在温度为45℃的条件下减压回收溶剂,当浓缩至原提取液体积的10%时转移至50℃的真空干燥箱中干燥成干浸膏。
3.提取物溶解性能研究
提取物的基本理化性质决定了辅料的选择,同时决定了它在皮肽内的转运速率,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。实验中分别采用沉淀法和指标成分溶解量法考察了丹黄凝胶提取物及指标成分大黄酚和小檗碱在透皮制剂常用试剂中的溶解情况,并采用摇瓶法测定了提取物中大黄酚和小檗碱的油／水分配系数,结果提取物在丙二醇和水中有较大的溶解度,而大黄酚和小檗碱均在丙二醇、乙醇和异丙醇中有较好的溶解性,油／水分配系数测定结果表明提取物中大黄酚和小檗碱的脂溶性都比较低,且受pH值影响较大。
4.成型工艺研究
根据提取物溶解性研究结果,考察并确定了凝胶剂中提取物溶解的溶剂为由30%丙二醇、30%乙醇和40%水组成的混合溶液。分别以透皮性能和释药速率作为主要评价指标,采用透析膜扩散法和体外经皮渗透试验对凝胶剂基质种类及用量、促渗剂及用量和基质的载药量进行了考察,最后运用相关动力学模型和相似因子分析法筛选出用量为1.0%的卡波姆-940作为凝胶基质,用量为2%的氮酮作为透皮促渗剂,并确定凝胶基质的载药量为4.5%。在此基础上,运用正交设计法和体外释药速率试验考察了三乙醇胺用量、丙二醇用量、乙醇用量和甘油用量,结果以用量分别为1.5%、10.0%、10.0%、5.0%的处方组合释放效果最好,于是确定了丹黄凝胶剂的优化处方和制备工艺,并制备了三批小试凝胶样品。
5.体外释放透皮及相关性研究
对三批凝胶样品的体外释药特性和体外透皮渗透性进行了考察,运用多种动力学模型方程来描述指标成分在体外的释药规律和透皮渗透规律,并采用相似因子分析法来评价三批丹黄凝胶剂间释放和渗透的差异。释放试验结果表明大黄酚和小檗碱从凝胶剂中的释放动力学规律是扩散和溶蚀协同作用的结果,大黄酚以零级动力释放模型拟合优度最好,而小檗碱以Ritger-Peppas模型拟合优度最好；透皮试验结果表明大黄酚和小檗碱在体外皮肤均以一级动力学渗透吸收；体外释放速率与透皮速率相关性研究结果表明,体外释药特性与透皮渗透性有着较好的线性相关性,可用线性相关方程来描述,以相应取样时间点的透皮数据为Y、释放数据为X,得大黄酚的相关方程为Y=0.4687X+4.9722(R=0.9664),小檗碱的相关方程为Y=0.6669X+2.4874(R=0.9740),且两个指标成分的体外释放速率均大于体外透皮速率,提示影响丹黄凝胶剂透皮吸收的主要屏障可能是皮肤等生理因素。
6.质量标准初步研究
对丹黄凝胶剂进行外观性状考察和pH值检查,并采用薄层色谱法(TLC)和高效液相色谱法(HPLC)进行了定性鉴别、含量测定,建立了丹黄凝胶剂的质量标准。外观性状考察结果表明本品为淡黄棕色半固体、气微清香,pH值检查结果表明本品pH值约为6.8±0.2；采用TLC法建立了大黄、黄连、黄柏等6味药材的鉴别方法,结果表明各味药材色谱斑点清晰,专属性强,重现性好；采用HPLC测定建立了制剂中有效成分大黄酚和小檗碱含量测定的方法,并对其含量作了规定：每1g凝胶中以大黄酚计不得低于0.145mg,以小檗碱计不得低于0.907mg。
7.初步稳定性研究
分别以外观性状、pH值、含量测定等为考察指标,对丹黄凝胶进行了离心、高温、低温、光照、高湿等影响因素的稳定性试验,结果在高温和强光照射条件下外观颜色有所加深,其他各指标均无明显改变,而在低温和高湿条件下各指标均无明显改变,且离心无分层和沉淀现象,提示本品应避光低温保存；酸碱和盐的稳定性影响考察结果表明,本品的粘度受酸碱度影响较大,且金属盐对本品的凝胶特性和粘性有很强的破坏作用。在避光材料包装下,对3批凝胶样品进行了连续3个月的初步稳定性考察,结果表明丹黄凝胶剂在室温和避光条件下保存时性质比较稳定。
Danhuang Gel was traditional Chinese medicines containing herbs:Rheum officinale Baill, Coptis chinensis Franch, Phellodendron chinense Schneid and so on, which had the effect of heat-clearing and detoxicating, cool the blood and stasis, eliminating wind and anthelminthic, detumescence and eliminating stagnation,was used for the Clinical treatment of acne. Under the guidance of TCM theory,the pharmaceutical researchs were performed in these aspects,including forrnulation,technology,the dissolvability of the extract,the release and transdermal penetration characteristics in vitro,quality tandard and stability using modern science and technology.
1. Study on the quality of herbs
Regarding the method of identifying of the Chinese Pharmacopoeia as reference, the selected herbs were identified, the content of five components in Rheum officinale Baill and berberine in Coptis chinensis Franch and Phellodendron chinense Schneid was determined, the results showed that the selected herbs meet the pharmacopoeia requirements.
2. Study on the optimized extaction process of Danhuang Gel
According to the effectiveness of prescription indications, clinical drug characteristics and the nature of the active ingredients of drugs, We ground the sulfur and borneol to fine powder, the remaining six herbs were extracted.Based on the results of literature and pre-test,with the extraction rate of the active ingredients berberine and chrysophanol as the indicators and taking the yield of dry extract into account,single factor test was used to investigate the extraction temperature,and the uniform design method was used to investigate the ethanol concen tration,solvent usage,extraction time and extraction times,the results were optimized by multi variate statistical analysis and response surface analysis, the final result showed that the best conditions are adding 7 times the amount of 65%ethanol to extract prescription medicine for 3 times under 90℃,2 hours once,the verification test results showed that the extraction process is stable, reasonable and feasible. With the transfer rate of chrysophanol and berberine as the index,the method and temperature of concentration and drying were studied,the final and the best conditions was that the extract liquid was concentrated at a temperature of 45℃under vacuum, transferred to vacuum oven and dried into dry extract at 50℃when the extract liquid was concentrated to 10%of the original extract volume.
3. Study on dissolvability of the extract
The dissolvability affeets the preparation,stallility and the pharmacodynamic action and the study of the dissolvability was important for performulation.We used the methods of precipi tation and dissolved load of the index components to investigate the dissolvability condition of the extract and the index components chrysophanol and berberine in some different reagents often used in the transdermal preparation,and the shake flask method was established to determine the apparent n-octanol/water partition cofficieent of the index components chrysop hanol and berberine.The research results showed that the extract had better solubility in the propylene glycol and water,while the index components had a good solubility in the propylene glycol, ethanol and isopropanol.The results of n-octanol/water partition cofficieent test showed that the liposolubility of chrysophanol and berberine in the extract is not good, and easily influenced by the pH value.
4. Study on the proeessing technology of Danhuang Gel
According to the researh results of solubility of the extracts, the solvent used to dissolve the extract of gel was investigated,finding that the mixed solution composed by 30%propylene glycol,30%ethanol and 40%water was the best selection. Taking the transdermal penetration rate and release rate as the main index,we used the dialysis membrane diffusion method and transdermal penetration test in vitro to study the type and amount of gel matrix, penetration agents and the amount of penetration agents, drug loading of gel matrix,1.0%Carbomer-940 was selected as gel matrix,2%Azone was selected as transdermal penetration enhancers and the drug loading of gel matrix selected 4.5%by the use of related dynamic model analysis and the similarity factor analysis. On this basis, orthogonal design method was applied to investigate the amount of triethanolamine, propylene glycol dosage, the amount of ethanol and glycerol, the results of the amount were 1.5%,10.0%,10.0%,5.0%when the prescription had the best release. Then we determine the optimal Danhuang Gel formulation and preparation process,and three batches of sample gel were prepared.
5. Study on the characteristics of release and transdermal penetration in vitro
The characteristics of release and transdermal penetration in vitro were investigated by using a variety of kinetic model equations to describe the law rules of release and transdermal penetration of the index components, and adopted the similar factor analysis to evaluate the differences of release and permeation between three batches of Danhuang Gel.The results showed that release of chrysophanol and berberine from the gel was the result of the synergy of diffusion and dissolution, release of chrysophanol can be described by zero-power kinetics model,while berberine by Ritger-Peppas model. The results of penetration test showed that penetration of chrysophanol and berberine in vitro skin was better fitted for the one-power kinetics model.The results of study on the correlation of release rate and penetration rate in vitro showed that the release and the transdermal penetration had a good linear correlation, taking the penetration datas for Y and the release datas for the X, the relevant linear equation of chrysophanol can be described as Y= 0.4687X+4.9722 (R= 0.9664), berberine as Y= 0.6669X +2.4874 (R= 0.9740), and the release rate was higher than the transdermal rate for two index components in Danhuang Gel,suggested that skin and other physiological factors may be he primary barrier for transdermal absorption of Danhuang Gel.
6. Study on the quality standard
We checked on the appearance of Danhuang Gel and determined the pH value of Danhuang gel,the methods of TLC and high performance liquid chromatography (HPLC) were established for the qualitative identification, determination of preparation. Appearance inspection results showed that the Gel is yellowish brown semi-solid, gas micro fragrance,the results of pH value test showed that the pH value of Danhuang gel was 6.8±0.2; TLC method was established to identify the whole herbs in Danhuang gel, the results showed that the spots are clear on the TLC picture and the negative control was non-interference, so we could use it as the qualition identification; The determination methods of chrysophanol and berberine had been established using HPLC.As an important quality standard,the content of chrysophanol can not be less than 0.145mg in lg Danhuang gel,and berberine 0.907mg either.
7. Study on the stability of Danhuang Gel
With appearance, pH value, contents of Danhuang Gel as the indicators, influencing factors including centrifugalization,high temperature, low temperature,light radiation,high humidity on the stability of Danhuang Gel were investigated. The results showed that color of Gel deepened under high temperature and strong light radiation, the other indexs had no significant change, while the indicators had no significant changes at low temperatures and high humidity conditions, and no stratification and sedimentation, suggesting that the Gel should be stored under dark and low temperature. The stability study results of the effect of PH and salt on Gel showed that the viscosity of Danhuang Gel was influenced by pH and salts, salts has a strong role in the destruction of the features and viscosity of gel. Packaging Danhuang Gel in dark materials, the initial stability study of 3 months was carried out, the result showed that the nature of Danhuang Gel was stable.
引文
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