萸连巴布膏的药学研究与评价
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摘要
萸连片出自《百一选方》,原方由黄连、吴茱萸按1:1的比例组成。现收载于中药部颁标准第五册中,用于治疗脘胁疼痛,嗳气吐酸,大便热泻。巴布剂是中药经皮给药系统研究的热点之一,其基质主要为水溶性高分子材料,具有载药量大、透皮效果好,贴服舒适、安全无刺激、可反复揭帖等优点,尤其适于中药制剂。课题依据“内病外治”理论,拟将萸连片改为巴布剂,探索经皮给药治疗胃肠疾病的可行性,以期能为中医治疗“胃脘痛”(胃溃疡)提供新的给药途径。课题对萸连巴布膏药材提取工艺、精制工艺、成型工艺、体外释放与透皮评价、药效与安全性评价、质量标准、初步稳定性等进行了系统研究。
1萸连巴布膏提取工艺研究采用L_9(3~4)正交试验设计,以黄连中盐酸巴马汀和盐酸小檗碱,吴茱萸中吴茱萸碱和吴茱萸次碱为指标,优选萸连巴布膏处方的提取工艺。最终确定萸连巴布膏处方的提取工艺为:黄连药材用5倍量70%的乙醇提取3次,每次1.5小时;吴茱萸、木香先用水蒸气蒸馏法提取挥发油,提油后的药渣用5倍量80%的乙醇提取3次,每次1.5小时。
2萸连巴布膏的精制工艺研究以药效学和盐酸巴马汀、盐酸小檗碱的含量为指标,对大孔树脂法,乙醇提取10%盐酸沉淀法、机械离心除杂等三种黄连精制方法,进行药效和有效成分的对比研究。结果显示:醇提酸沉法精制的黄连盐酸巴马汀和盐酸小檗碱的含量最高;药效学实验表明,三种不同精制方法制备的萸连巴布膏样品均对胃溃疡有一定的抑制作用,以醇提10%酸沉法精制黄连,醇沉法精制吴茱萸、木香所制备的萸连巴布膏样品效果最好。最终确定精制工艺为:黄连用乙醇提取,10%盐酸沉淀法精制;吴茱萸、木香提取挥发油的水溶液用2倍量95%乙醇沉淀精制。
3萸连巴布膏制备工艺研究在原研究基础上,采用L_9(3~4)正交试验设计,以巴布剂的黏性和感官指标作为综合评价指标,研究巴布剂基质配方,确定了赋形剂比例、保湿剂、溶剂的用量,优化了基质处方配比及制备工艺,并进行了验证试验,确定了萸连巴布膏的基质配方与制备工艺。
4萸连巴布膏的体外透皮研究建立了萸连巴布膏透皮接收液的HPLC测定方法并进行了方法学考察,首次实现了以一种流动相同时分离四种指标成分-吴茱萸碱、吴茱萸次碱、盐酸巴马汀和盐酸小檗碱,结果表明方法稳定、可行,可作为萸连巴布膏透皮接收液的含量测定方法。采用Franz扩散池,以PEG-95%乙醇-水(1:3:6)为接收液,以吴茱萸碱、吴茱萸次碱、盐酸巴马汀和盐酸小檗碱为指标,对萸连巴布膏的释放与透皮行为进行了研究,结果显示:萸连巴布膏中四种指标成分吴茱萸碱、吴茱萸次碱、盐酸巴马汀和盐酸小檗碱的体外释放均能符合经皮渗透对药物浓度的要求。萸连巴布膏中四种指标成分的体外经皮拟合方程分别为:Q=1.2561t-0.1016(r=0.9983),Q=1.0302t-1.0318(r=0.9985),Q=2.8029t-1.2159(r=0.9980),Q=20.919t-32.322(r=0.9909),经皮渗透速率为分别为:1.256,1.0302,2.8029,20.919μg·cm~(-2)·h~(-1),符合零级动力学过程。
5萸连巴布膏的药效学评价实验通过抗溃疡实验、镇痛抗炎实验和抗炎消肿实验,对萸连巴布膏进行了药效学评价。结果显示:萸连巴布膏对胃溃疡有一定得抑制作用;对角叉菜胶所致大鼠足趾肿胀有较明显的抗炎消肿作用;可以明显减少腹腔的炎性渗出和疼痛引起的扭体次数,对小鼠由化学刺激引发的腹腔炎症有一定的抗炎镇痛作用。表明萸连巴布膏能保持口服给药的药理作用。
6萸连巴布膏基质的安全性评价以优选的空白基质涂抹于家兔的完整和破损皮肤处,进行急性毒性、刺激性、过敏性研究,结果表明:对皮肤无明显刺激,无过敏反应;长毒试验结果安全。
7萸连巴布膏的质量评价建立了萸连巴布膏的质量标准,并对其药品原料(药材)的质量标准及药品成品质量标准研究的实验情况及起草标准的科学依据进行了详细的阐述。对制剂中黄连、吴茱萸、木香三味中药建立了薄层色谱鉴别方法。对制剂中黄连、吴茱萸药材及成品建立了高效液相色谱含量测定方法。并对含量测定方法进行了考察,结果表明四种指标成分的线性关系良好,线性范围分别为:0.01088-0.544;0.0088-0.44;0.0288-1.44;0.2896-14.48μg。精密度试验、稳定性试验、重复性试验、加样回收试验RSD%良好,符合相关规定,说明该方法稳定可行。制定了药材及成品中吴茱萸碱、吴茱萸次碱、盐酸巴马汀和盐酸小檗碱的含量限度。黄连药材中盐酸小檗碱(C_(20)H_(18)ClNO_4)和盐酸巴马汀(C_(21)H_(22)ClNO_4)的总量不得少于4.0%;吴茱萸药材中吴茱萸碱(C_(19)H_(17)N_3O)和吴茱萸次碱(C_(18)H_(13)N_3O)总量不得少于0.15%。萸连巴布膏中吴茱萸碱和吴茱萸次碱含量总和不得少于3.0mg,盐酸巴马汀和盐酸小檗碱的含量总和不得少于60.0mg。进行了3个月的初步稳定性实验研究,结果表明萸连巴布膏的含膏量、黏性均符合相关规定,指标成分的含量稳定,说明萸连巴布膏3个月的稳定性良好。
The prescription of Yulian Pian is made of Copt is chinensis Franch,Fructus Evodiae, Aucklandia lappa Decne,it mainly used for stomachache and hypochondriac,belching and acid regurgitation,diarrhea of heat pattern.Cataplasm has many advantages such as largely loaded,good effetcs,very comfortable,security and no irritation,it could be used for many times and especially fit for TTS of Chinese medicine.Cataplasm was developed with Yulian Pian prescription in our study,Otherwise,the systematic pharmaceutical reaearch on Yulian cataplasm has been performed,which included extraction technology,purification technology,releasing,percutaneous process, pharmacodynamics,toxicology,quality standard and preliminary stability.
The extraction technology of effective component in Yulian prescription was explored.L_9(3~4) Orthogonal design was used for ethanol extraction process decision which is showing as follows:the Coptis chinensis Franch were extracted with 5-fold 70%ethanol for three times,which lasted for 1.5h each time;the Fructus Evodiae and Aucklandia lappa Decne were extracted with 5-fold of 80%ethanol for three times,which lasted for 1.5h each time.
The resin technology of Coptis chinensis Franch was determined by the experiment of choosing the kinds of resin,high-ratio,leakage curve,elution solvent,rate of elution flow and the eluton curve.To optimize the extraction and purification technology,we campared three methods,which were purified by X-5 resin,purified by the way of Centrifugal and extracting Coptis chinensis Franch with ethanol,precipitated by 10% HCl.The indicators were the content of huanglian alkaloid per gram and pharmacodynamics.The results were that to purify Coptis chinensis Franch is extracting Coptis chinensis Franch with 70%ethanol,precipitated by 10%HCL and to purify Fructus Evodiae and Aucklandia lappa Decne is precipitated by 2-fold 95%ethanol.
L_9(3~4) Orthogonal design was used to explore the prescription of cataplasm matrix with sensory index.It used stickiness as its evaluation indicator,the ratio of excipients,the dosage of Moisturizers and Solvent in the matrix of cataplasm were detemined, The quality of Yulian cataplasm will be better with using this proportion of matrix.
To explore the releasing and percutaneous process of Yulian Cataplasm,the indicators were mearsured by HPLC,and its methodology was explored.At the same time,Franz's diffusing cell was improved by PEG400-95%ethanol-water(1:3:6) as receptor liquid.The experiment also indicated that the releasing rate was very high.The releasing process was in accordance with Higuchi equation.The percutaneous process of four indicators(Evodiamine, Rutaecarpine,Palmatine and Berberine) was in accordance with zero-grade equation.
The pharmacodynamics experiment of Yulian Cataplasm showed that Yulian Cataplasm has a remarkable effect of gastric ulcier,anti-inflammatory,analgesic.
The toxicology experiment of matrix of Yulian Cataplasm showed that there was no obvious phenomenon of skin irritation,or skin allergy.The chronic toxicity test showed that it was safe.
To explore the quality standard for Yulian cataplasm,the following methods were used:the content of four indactors(Evodiamine,Rutaecarpine,Palmatine,Berberine) were determined by HPLC,and its methodology was explored;the limitation of four indicators in herbs and Yulian Cataplasm was developed.the Coptis chinensis Franch,Fructus Evodiae and Aucklandia lappa Decne were identified by TLC.The results showed that the quality standard which had been explored was accurate,relible and could be for controlling the quality of Yulian cataplasm effectively.3 months' Prelimmary stability experiment indicated that Yulian cataplasm has good stability.
1萸连巴布膏提取工艺研究采用L_9(3~4)正交试验设计,以黄连中盐酸巴马汀和盐酸小檗碱,吴茱萸中吴茱萸碱和吴茱萸次碱为指标,优选萸连巴布膏处方的提取工艺。最终确定萸连巴布膏处方的提取工艺为:黄连药材用5倍量70%的乙醇提取3次,每次1.5小时;吴茱萸、木香先用水蒸气蒸馏法提取挥发油,提油后的药渣用5倍量80%的乙醇提取3次,每次1.5小时。
2萸连巴布膏的精制工艺研究以药效学和盐酸巴马汀、盐酸小檗碱的含量为指标,对大孔树脂法,乙醇提取10%盐酸沉淀法、机械离心除杂等三种黄连精制方法,进行药效和有效成分的对比研究。结果显示:醇提酸沉法精制的黄连盐酸巴马汀和盐酸小檗碱的含量最高;药效学实验表明,三种不同精制方法制备的萸连巴布膏样品均对胃溃疡有一定的抑制作用,以醇提10%酸沉法精制黄连,醇沉法精制吴茱萸、木香所制备的萸连巴布膏样品效果最好。最终确定精制工艺为:黄连用乙醇提取,10%盐酸沉淀法精制;吴茱萸、木香提取挥发油的水溶液用2倍量95%乙醇沉淀精制。
3萸连巴布膏制备工艺研究在原研究基础上,采用L_9(3~4)正交试验设计,以巴布剂的黏性和感官指标作为综合评价指标,研究巴布剂基质配方,确定了赋形剂比例、保湿剂、溶剂的用量,优化了基质处方配比及制备工艺,并进行了验证试验,确定了萸连巴布膏的基质配方与制备工艺。
4萸连巴布膏的体外透皮研究建立了萸连巴布膏透皮接收液的HPLC测定方法并进行了方法学考察,首次实现了以一种流动相同时分离四种指标成分-吴茱萸碱、吴茱萸次碱、盐酸巴马汀和盐酸小檗碱,结果表明方法稳定、可行,可作为萸连巴布膏透皮接收液的含量测定方法。采用Franz扩散池,以PEG-95%乙醇-水(1:3:6)为接收液,以吴茱萸碱、吴茱萸次碱、盐酸巴马汀和盐酸小檗碱为指标,对萸连巴布膏的释放与透皮行为进行了研究,结果显示:萸连巴布膏中四种指标成分吴茱萸碱、吴茱萸次碱、盐酸巴马汀和盐酸小檗碱的体外释放均能符合经皮渗透对药物浓度的要求。萸连巴布膏中四种指标成分的体外经皮拟合方程分别为:Q=1.2561t-0.1016(r=0.9983),Q=1.0302t-1.0318(r=0.9985),Q=2.8029t-1.2159(r=0.9980),Q=20.919t-32.322(r=0.9909),经皮渗透速率为分别为:1.256,1.0302,2.8029,20.919μg·cm~(-2)·h~(-1),符合零级动力学过程。
5萸连巴布膏的药效学评价实验通过抗溃疡实验、镇痛抗炎实验和抗炎消肿实验,对萸连巴布膏进行了药效学评价。结果显示:萸连巴布膏对胃溃疡有一定得抑制作用;对角叉菜胶所致大鼠足趾肿胀有较明显的抗炎消肿作用;可以明显减少腹腔的炎性渗出和疼痛引起的扭体次数,对小鼠由化学刺激引发的腹腔炎症有一定的抗炎镇痛作用。表明萸连巴布膏能保持口服给药的药理作用。
6萸连巴布膏基质的安全性评价以优选的空白基质涂抹于家兔的完整和破损皮肤处,进行急性毒性、刺激性、过敏性研究,结果表明:对皮肤无明显刺激,无过敏反应;长毒试验结果安全。
7萸连巴布膏的质量评价建立了萸连巴布膏的质量标准,并对其药品原料(药材)的质量标准及药品成品质量标准研究的实验情况及起草标准的科学依据进行了详细的阐述。对制剂中黄连、吴茱萸、木香三味中药建立了薄层色谱鉴别方法。对制剂中黄连、吴茱萸药材及成品建立了高效液相色谱含量测定方法。并对含量测定方法进行了考察,结果表明四种指标成分的线性关系良好,线性范围分别为:0.01088-0.544;0.0088-0.44;0.0288-1.44;0.2896-14.48μg。精密度试验、稳定性试验、重复性试验、加样回收试验RSD%良好,符合相关规定,说明该方法稳定可行。制定了药材及成品中吴茱萸碱、吴茱萸次碱、盐酸巴马汀和盐酸小檗碱的含量限度。黄连药材中盐酸小檗碱(C_(20)H_(18)ClNO_4)和盐酸巴马汀(C_(21)H_(22)ClNO_4)的总量不得少于4.0%;吴茱萸药材中吴茱萸碱(C_(19)H_(17)N_3O)和吴茱萸次碱(C_(18)H_(13)N_3O)总量不得少于0.15%。萸连巴布膏中吴茱萸碱和吴茱萸次碱含量总和不得少于3.0mg,盐酸巴马汀和盐酸小檗碱的含量总和不得少于60.0mg。进行了3个月的初步稳定性实验研究,结果表明萸连巴布膏的含膏量、黏性均符合相关规定,指标成分的含量稳定,说明萸连巴布膏3个月的稳定性良好。
The prescription of Yulian Pian is made of Copt is chinensis Franch,Fructus Evodiae, Aucklandia lappa Decne,it mainly used for stomachache and hypochondriac,belching and acid regurgitation,diarrhea of heat pattern.Cataplasm has many advantages such as largely loaded,good effetcs,very comfortable,security and no irritation,it could be used for many times and especially fit for TTS of Chinese medicine.Cataplasm was developed with Yulian Pian prescription in our study,Otherwise,the systematic pharmaceutical reaearch on Yulian cataplasm has been performed,which included extraction technology,purification technology,releasing,percutaneous process, pharmacodynamics,toxicology,quality standard and preliminary stability.
The extraction technology of effective component in Yulian prescription was explored.L_9(3~4) Orthogonal design was used for ethanol extraction process decision which is showing as follows:the Coptis chinensis Franch were extracted with 5-fold 70%ethanol for three times,which lasted for 1.5h each time;the Fructus Evodiae and Aucklandia lappa Decne were extracted with 5-fold of 80%ethanol for three times,which lasted for 1.5h each time.
The resin technology of Coptis chinensis Franch was determined by the experiment of choosing the kinds of resin,high-ratio,leakage curve,elution solvent,rate of elution flow and the eluton curve.To optimize the extraction and purification technology,we campared three methods,which were purified by X-5 resin,purified by the way of Centrifugal and extracting Coptis chinensis Franch with ethanol,precipitated by 10% HCl.The indicators were the content of huanglian alkaloid per gram and pharmacodynamics.The results were that to purify Coptis chinensis Franch is extracting Coptis chinensis Franch with 70%ethanol,precipitated by 10%HCL and to purify Fructus Evodiae and Aucklandia lappa Decne is precipitated by 2-fold 95%ethanol.
L_9(3~4) Orthogonal design was used to explore the prescription of cataplasm matrix with sensory index.It used stickiness as its evaluation indicator,the ratio of excipients,the dosage of Moisturizers and Solvent in the matrix of cataplasm were detemined, The quality of Yulian cataplasm will be better with using this proportion of matrix.
To explore the releasing and percutaneous process of Yulian Cataplasm,the indicators were mearsured by HPLC,and its methodology was explored.At the same time,Franz's diffusing cell was improved by PEG400-95%ethanol-water(1:3:6) as receptor liquid.The experiment also indicated that the releasing rate was very high.The releasing process was in accordance with Higuchi equation.The percutaneous process of four indicators(Evodiamine, Rutaecarpine,Palmatine and Berberine) was in accordance with zero-grade equation.
The pharmacodynamics experiment of Yulian Cataplasm showed that Yulian Cataplasm has a remarkable effect of gastric ulcier,anti-inflammatory,analgesic.
The toxicology experiment of matrix of Yulian Cataplasm showed that there was no obvious phenomenon of skin irritation,or skin allergy.The chronic toxicity test showed that it was safe.
To explore the quality standard for Yulian cataplasm,the following methods were used:the content of four indactors(Evodiamine,Rutaecarpine,Palmatine,Berberine) were determined by HPLC,and its methodology was explored;the limitation of four indicators in herbs and Yulian Cataplasm was developed.the Coptis chinensis Franch,Fructus Evodiae and Aucklandia lappa Decne were identified by TLC.The results showed that the quality standard which had been explored was accurate,relible and could be for controlling the quality of Yulian cataplasm effectively.3 months' Prelimmary stability experiment indicated that Yulian cataplasm has good stability.
引文
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[1]李宇,韩凤梅,柳伟等.反相高效液相色谱法测定加味左金丸中盐酸小檗碱和吴茱萸次碱的含量[J].中国药学杂志,2006,41(8):631-633.
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