复方元胡止痛贴膏制剂研究
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摘要
目的:
研制具有良好皮肤黏贴性,含水量低,稳定性好的复方元胡止痛贴膏制剂,对其进行提取工艺、制备工艺、质量标准、释放度、离体透皮试验、初步稳定性及初步药效学等研究。
方法:
1提取工艺研究:以君药延胡索中有效成分延胡索乙素提取量作为考察指标,用高效液相色谱法测定延胡索乙素的含量,以乙醇浓度、乙醇用量、提取时间、提取次数为影响因素,采用L_9(3~4)正交试验优选延胡索、白芷乙醇回流提取工艺,其中对氧化铝柱法纯化供试品工艺进行考察研究;以豆蔻挥发油提取量为考察指标,采用水蒸气蒸馏法提取,以浸泡时间、加水量、提取时间为影响因素,采用L_9(3~4)正交试验优选豆蔻挥发油提取工艺。
2制剂成型工艺研究:在查阅文献及预实验的基础上确定基质的种类及用量范围,测定贴膏制剂的黏附性,并结合其平整性、光泽度、软硬度、均匀性、皮肤残留、背衬渗透情况等方面进行综合评分作为考察指标,采用L_(18)(3~7)正交试验优选复方元胡止痛贴膏剂基质的配比;以样品的黏性、涂展性、外观、剥离性等为考察指标,采用L_9(3~4)正交试验优选复方元胡止痛巴布剂的基质配比。
3释放度及离体透皮率研究:分别采用释放度装置及改良Fanz装置进行释放度及离体透皮吸收试验,用HPLC法测定接受液中延胡索乙素的含量,分别计算复方元胡止痛贴膏、复方元胡止痛巴布剂中延胡索乙素的释放度和离体透皮率,对两种不同剂型制剂的释放度与离体透皮率进行比较。
4制剂质量标准研究:采用薄层色谱法对制剂中延胡索、白芷及豆蔻进行定性鉴别,对贴膏剂、巴布剂、黑膏药3种剂型的薄层层析图谱进行比较;采用HPLC法测定制剂中延胡索乙素的含量,色谱条件:色谱柱:Agilent ZORBAXSB-C18(4.6mm×250mm,5μm);流动相:甲醇-0.1%磷酸溶液(三乙胺调pH值至6.0)(64:36);流速:0.8mL·min~(-1);检测波长:280nm;柱温:35℃;按照2005年版《中国药典》一部附录Ⅱ贴膏剂项下黏附性、重量差异检查方法,对制剂进行检查。
5加速初步稳定性研究:将复方元胡止痛贴膏制剂于温度37℃,相对湿度75%的条件下放置3个月,以制剂的性状、鉴别、含膏量、黏附力、延胡索乙素含量为考察项目,进行初步稳定性研究。
6初步药效学研究:采用缩宫素及氯前列醇引起大鼠痛经模型所致扭体实验,观察复方元胡止痛贴膏对于痛经的镇痛作用。
结果:
1优选的延胡索、白芷乙醇回流提取工艺为:以3倍量75%的乙醇回流提取3次,每次1.5小时。药材中延胡索乙素转移率可达82.7%;含量测定中优选的氧化铝柱纯化供试品工艺优于乙醚萃取工艺;优选的豆蔻挥发油的提取工艺为:药材(碾碎)加10倍量水,先浸泡2小时,再提取4小时。
2优选的复方元胡止痛贴膏的成型工艺为:石蜡1份,硬脂酸8份,三乙醇胺3份,明胶2份,聚丙烯酸(钠)(70%)1.5份,甘油0.5份,月桂基硫酸钠0.1份,浸膏3.2份,熔融搅拌法制备。优选的巴布剂的基质组方配比为:明胶:聚丙烯酸(钠)(70%):PVP K-30:甘油=3:4:2:1。
3释放度及离体透皮率研究:复方元胡止痛贴膏中,廷胡索乙素在水中150min的释放度为24.28%,48h的累计离体(小鼠)透皮吸收率为34.78%;复方元胡止痛巴布剂中,延胡索乙素在水中150min的释放度为82.63%,48h的累计离体(小鼠)透皮吸收率为40.95%。
4质量标准研究:薄层鉴别:制剂中各药材的薄层鉴别方法简便,图谱清晰,黑膏药制剂中延胡索生物碱和白芷中成分损失明显。含量测定:延胡索乙素的线性范围为0.1148μg～1.148μg(r=0.9999);精密度试验:RSD=0.495%;重复性试验:延胡索乙素平均含量0.04431mg/贴,RSD=2.45%;回收率试验:平均加样回收率为97.995%,RSD=2.89%。3批制剂中延胡索乙素含量分别为0.443mg/贴、0.378mg/贴、0.381mg/贴。本品的黏附力、重量差异等项目检查符合规定。
5加速初步稳定性研究结果表明:各项检测指标未见明显变化。
6初步药效学研究表明:复方元胡止痛贴膏能够减少缩宫素及氯前列醇所致痛经模型大鼠30min内扭体次数,有止痛作用,并且疗效优于原剂型元胡止痛片。
结论:
研制的复方元胡止痛贴膏具有良好的皮肤黏贴性,基质中含水量低,稳定性好。通过提取工艺、制剂成型工艺、制剂质量标准、释放度及离体透皮率试验、加速初步稳定性试验以及初步药效学试验研究,为中药新药复方元胡止痛贴膏的进一步开发奠定了良好的基础。
Objective:
To develope a type of patch preparation for Fufang Yuanhu Zhitong patch,which is not only have a nice stability and a good adhesion to skin,but also low in water content.This preparation would be studied systematicly on its extraction technology,manufacturing technology, quality standards,release rate,vitro percutaneous absorption, preliminary stable property and preliminary experiment on pharmacodynamics.
Methods:
1 The research of the extraction technology:The content of tetrahydropalmatine in the monarch Rhizoma Corydalis,which was regarded as one of the indexs of the chemical compositions extracted,was determined by HPLC.The content data determined were used to optimize the ethanol extraction process of both Rhizoma Corydalis and Radix Angelicae Dahuricae by orthogonal design experiment.In the experiment four influence factors such as ethanol density,amount of ethanol,time for extraction and number of times for extraction were considered and the L_9(3~4) table was used,and the craft of purifying the samples with neutral aluminum oxide column was inspected.The amount of volatile oil extracted from Fructus hmomi Rotundus by distillation method was regarded as the index of chemical compositions extracted to optimize the extraction process of Fructus Amomi Rotundus by or thogonal design experiment.In the experiment three influence factors such as amount of water,soaking time and extraction time were considered and the L_9(3~4)table was used.
2 The study on the manufacturing technology:Base on the results of the literature consulting and Pre-experiment,the kinds and the use range of matrixes were determined for Fufang Yuanhu Zhitong Patch and cataplasma respectively.The manufacturing technology for the patch was optimized by L_(18)(3~7)orthogonal design by determinating the adhesion and scoring synthetically on some other aspects such as the smoothness,glossiness, degree of softness,uniformity,quantity of remains on skin and permeability of back lining of the patchs together as index.The procedure of the Fufang Yuanhu Zhitong cataplasmata was optimized by L~9(3~4) orthogonal design with the adhesive ability,spreading ability,appearance and layer residue as indexes.
3 The study of the release rate and the vitro percutaneous absorption: Releasing installment and Franz permeating pull were used respectivelly to carry out the relative experiments.The content of tetrahydropalmatine of both released and percutaneous absorbed from Fufang Yuanhu Zhitong Patch and cataplasmata were determined by HPLC.
4 The study on the quality standards:The Rhizoma Corydalis,Radix Angelicae Dahuricae and Fructus Amomi Rotundus in the patch preparation were identified by TLC.The content of tetrahydropalmatine in the patch preparation was determined by HPLC.The chromatography conditions were that the Agilent ZORBAX SB-C_(18)(4.6mm×250mm,5μm)column was used;that mobile phase was compond of methanol-0.1%phosphoric acid solution(adjust the pH to 6.0 with triethylamine)(64:36);the flow rate was 0.8mL.min~(-1); with UV detection at 280nm and that the column temperature was 35℃.The adhesive ability and weight variation of the preparation were tested according to the method described for adhesive ointment in 2005 derision pharmacopeia below the ralative volumns of appendixⅠⅠ.
5 The study on the preliminary stable property:The Fufang Yuanhu Zhitong Patch was placed under the conditions of 37℃and relative humidity of 75%for 3 months.The preliminary stable property was studied with the investigation items such as characteristics、identification and the content of extraction、adhesive ability、the content of tetrahydropalmatine.
6 The study of the preliminary pharmacodynamics:The analgesic effect of Fufang Yuanhu Zhitong Patch for dysmenorrhea was evaluated by ip oxytocin or cloprostenol to cause dysmenorrhea and incur contortion on rats as test model.
Results:
1 The optimum ethanol extraction technology of both Rhizoma Corydalis and Radix Angelicae Dahuricae was as follows:The medicinal materials was extracted for 3 times with 3 times amount of 75%ethanol and for 1.5 hours per time.The transfer rate of tetrahydropalmatine in the medical material was 82.7%.The craft of using alumina column to purify the samples is better than that of ether extraction in the process of assaying.The optimium volatile oil extraction technology for Fructus Amomi Rotundus was as follows:The coarse powder was soaked for 2 hours and then extracted with 10 times of water for 4 hours continuously.The rate of oil extracted was 5.23%.
2 The optimum manufacturing technology for Fufang Yuanhu Zhitong Patch was that the patch was prepared by the melted method and the matrix was made of paraffin wax lg,stearic acid 8g,triethanolamine 3g,gelatin 2g,PAA(S)(70%)1.5g,glycerol 0.5g,sodium dodecyl sulphate(SDS)0.1g and extractive 3.2g.The optimum ingredients of the matrix of the cataplasmatawere gelatin:PAA(S)(70%):PVP K-30:glycerol =3:4:2:1.
3 The released rate and the vitro percutaneous absorption:the content of tetrahydropalmatine released from Fufang Yuanhu Zhitong Patch in water was 24.28%and the cumulative vitro permeation(mouse)rate within 48 hours was 34.78%;the content of tetrahydropalmatine released from Fufang Yuanhu Zhitong Cataplasmata in water was 82.63%,and the cumulative vitro permeation(mouse)rate within 48 hours was 40.95%.
4 The quality standards:The TLC identification methods for each medical material in the patch preparation were simple,and the spots on TLC pictures were clear.Study on determination had shown that the linear rang of the concengtration of tetrahydropalmatine was 0.1148μg～1.148μg(r=0.9999);that the precision test indicated that RSD was equal to 0.495%;that the repeatition test indicated that the average content of tetrahydropalmatine in the patch was 0.04431mg per patch and the RSD was 2.45%;that the average recovery was 97.995%and the RSD was 2.89%and that he content of tetrahydropalmatine in 3 batch of patches were 0.443mg per patch,0.378mg per patch and 0.381mg per patch respectively.The adhesive ability and the weight variation of the patch preparation were accord with the regulation.
5 The accelerated preliminary stable property:all the detection indexes examined unchanged evidently.
6 The preliminary pharmacodynamics:Fufang Yuanhu Zhitong Patch could reduce the contortion frequency caused by oxytocin or cloprostenol in model rats.And the result of the test also showed that the patch is more effective in therapying dysmenorrhea than the dosage form of Yuanhu Zhitong Tablet.
Conclusions:
The Fufang Yuanhu Zhitong Patch possesses good stability,super adhesive property to skin,and low water content in matrix.Many research have been done in many different aspects,such as extraction technology, manufacturing technology,quality standards of the preparation,test of released rate and the cumulative permeation rate,the accelerated preliminary stable property,and the preliminary pharmacodynamics.All of these reseaches lay a good foundation for the further development of new traditional Chinese medicine Fufang Yuanhu Zhitong Patch.
研制具有良好皮肤黏贴性,含水量低,稳定性好的复方元胡止痛贴膏制剂,对其进行提取工艺、制备工艺、质量标准、释放度、离体透皮试验、初步稳定性及初步药效学等研究。
方法:
1提取工艺研究:以君药延胡索中有效成分延胡索乙素提取量作为考察指标,用高效液相色谱法测定延胡索乙素的含量,以乙醇浓度、乙醇用量、提取时间、提取次数为影响因素,采用L_9(3~4)正交试验优选延胡索、白芷乙醇回流提取工艺,其中对氧化铝柱法纯化供试品工艺进行考察研究;以豆蔻挥发油提取量为考察指标,采用水蒸气蒸馏法提取,以浸泡时间、加水量、提取时间为影响因素,采用L_9(3~4)正交试验优选豆蔻挥发油提取工艺。
2制剂成型工艺研究:在查阅文献及预实验的基础上确定基质的种类及用量范围,测定贴膏制剂的黏附性,并结合其平整性、光泽度、软硬度、均匀性、皮肤残留、背衬渗透情况等方面进行综合评分作为考察指标,采用L_(18)(3~7)正交试验优选复方元胡止痛贴膏剂基质的配比;以样品的黏性、涂展性、外观、剥离性等为考察指标,采用L_9(3~4)正交试验优选复方元胡止痛巴布剂的基质配比。
3释放度及离体透皮率研究:分别采用释放度装置及改良Fanz装置进行释放度及离体透皮吸收试验,用HPLC法测定接受液中延胡索乙素的含量,分别计算复方元胡止痛贴膏、复方元胡止痛巴布剂中延胡索乙素的释放度和离体透皮率,对两种不同剂型制剂的释放度与离体透皮率进行比较。
4制剂质量标准研究:采用薄层色谱法对制剂中延胡索、白芷及豆蔻进行定性鉴别,对贴膏剂、巴布剂、黑膏药3种剂型的薄层层析图谱进行比较;采用HPLC法测定制剂中延胡索乙素的含量,色谱条件:色谱柱:Agilent ZORBAXSB-C18(4.6mm×250mm,5μm);流动相:甲醇-0.1%磷酸溶液(三乙胺调pH值至6.0)(64:36);流速:0.8mL·min~(-1);检测波长:280nm;柱温:35℃;按照2005年版《中国药典》一部附录Ⅱ贴膏剂项下黏附性、重量差异检查方法,对制剂进行检查。
5加速初步稳定性研究:将复方元胡止痛贴膏制剂于温度37℃,相对湿度75%的条件下放置3个月,以制剂的性状、鉴别、含膏量、黏附力、延胡索乙素含量为考察项目,进行初步稳定性研究。
6初步药效学研究:采用缩宫素及氯前列醇引起大鼠痛经模型所致扭体实验,观察复方元胡止痛贴膏对于痛经的镇痛作用。
结果:
1优选的延胡索、白芷乙醇回流提取工艺为:以3倍量75%的乙醇回流提取3次,每次1.5小时。药材中延胡索乙素转移率可达82.7%;含量测定中优选的氧化铝柱纯化供试品工艺优于乙醚萃取工艺;优选的豆蔻挥发油的提取工艺为:药材(碾碎)加10倍量水,先浸泡2小时,再提取4小时。
2优选的复方元胡止痛贴膏的成型工艺为:石蜡1份,硬脂酸8份,三乙醇胺3份,明胶2份,聚丙烯酸(钠)(70%)1.5份,甘油0.5份,月桂基硫酸钠0.1份,浸膏3.2份,熔融搅拌法制备。优选的巴布剂的基质组方配比为:明胶:聚丙烯酸(钠)(70%):PVP K-30:甘油=3:4:2:1。
3释放度及离体透皮率研究:复方元胡止痛贴膏中,廷胡索乙素在水中150min的释放度为24.28%,48h的累计离体(小鼠)透皮吸收率为34.78%;复方元胡止痛巴布剂中,延胡索乙素在水中150min的释放度为82.63%,48h的累计离体(小鼠)透皮吸收率为40.95%。
4质量标准研究:薄层鉴别:制剂中各药材的薄层鉴别方法简便,图谱清晰,黑膏药制剂中延胡索生物碱和白芷中成分损失明显。含量测定:延胡索乙素的线性范围为0.1148μg～1.148μg(r=0.9999);精密度试验:RSD=0.495%;重复性试验:延胡索乙素平均含量0.04431mg/贴,RSD=2.45%;回收率试验:平均加样回收率为97.995%,RSD=2.89%。3批制剂中延胡索乙素含量分别为0.443mg/贴、0.378mg/贴、0.381mg/贴。本品的黏附力、重量差异等项目检查符合规定。
5加速初步稳定性研究结果表明:各项检测指标未见明显变化。
6初步药效学研究表明:复方元胡止痛贴膏能够减少缩宫素及氯前列醇所致痛经模型大鼠30min内扭体次数,有止痛作用,并且疗效优于原剂型元胡止痛片。
结论:
研制的复方元胡止痛贴膏具有良好的皮肤黏贴性,基质中含水量低,稳定性好。通过提取工艺、制剂成型工艺、制剂质量标准、释放度及离体透皮率试验、加速初步稳定性试验以及初步药效学试验研究,为中药新药复方元胡止痛贴膏的进一步开发奠定了良好的基础。
Objective:
To develope a type of patch preparation for Fufang Yuanhu Zhitong patch,which is not only have a nice stability and a good adhesion to skin,but also low in water content.This preparation would be studied systematicly on its extraction technology,manufacturing technology, quality standards,release rate,vitro percutaneous absorption, preliminary stable property and preliminary experiment on pharmacodynamics.
Methods:
1 The research of the extraction technology:The content of tetrahydropalmatine in the monarch Rhizoma Corydalis,which was regarded as one of the indexs of the chemical compositions extracted,was determined by HPLC.The content data determined were used to optimize the ethanol extraction process of both Rhizoma Corydalis and Radix Angelicae Dahuricae by orthogonal design experiment.In the experiment four influence factors such as ethanol density,amount of ethanol,time for extraction and number of times for extraction were considered and the L_9(3~4) table was used,and the craft of purifying the samples with neutral aluminum oxide column was inspected.The amount of volatile oil extracted from Fructus hmomi Rotundus by distillation method was regarded as the index of chemical compositions extracted to optimize the extraction process of Fructus Amomi Rotundus by or thogonal design experiment.In the experiment three influence factors such as amount of water,soaking time and extraction time were considered and the L_9(3~4)table was used.
2 The study on the manufacturing technology:Base on the results of the literature consulting and Pre-experiment,the kinds and the use range of matrixes were determined for Fufang Yuanhu Zhitong Patch and cataplasma respectively.The manufacturing technology for the patch was optimized by L_(18)(3~7)orthogonal design by determinating the adhesion and scoring synthetically on some other aspects such as the smoothness,glossiness, degree of softness,uniformity,quantity of remains on skin and permeability of back lining of the patchs together as index.The procedure of the Fufang Yuanhu Zhitong cataplasmata was optimized by L~9(3~4) orthogonal design with the adhesive ability,spreading ability,appearance and layer residue as indexes.
3 The study of the release rate and the vitro percutaneous absorption: Releasing installment and Franz permeating pull were used respectivelly to carry out the relative experiments.The content of tetrahydropalmatine of both released and percutaneous absorbed from Fufang Yuanhu Zhitong Patch and cataplasmata were determined by HPLC.
4 The study on the quality standards:The Rhizoma Corydalis,Radix Angelicae Dahuricae and Fructus Amomi Rotundus in the patch preparation were identified by TLC.The content of tetrahydropalmatine in the patch preparation was determined by HPLC.The chromatography conditions were that the Agilent ZORBAX SB-C_(18)(4.6mm×250mm,5μm)column was used;that mobile phase was compond of methanol-0.1%phosphoric acid solution(adjust the pH to 6.0 with triethylamine)(64:36);the flow rate was 0.8mL.min~(-1); with UV detection at 280nm and that the column temperature was 35℃.The adhesive ability and weight variation of the preparation were tested according to the method described for adhesive ointment in 2005 derision pharmacopeia below the ralative volumns of appendixⅠⅠ.
5 The study on the preliminary stable property:The Fufang Yuanhu Zhitong Patch was placed under the conditions of 37℃and relative humidity of 75%for 3 months.The preliminary stable property was studied with the investigation items such as characteristics、identification and the content of extraction、adhesive ability、the content of tetrahydropalmatine.
6 The study of the preliminary pharmacodynamics:The analgesic effect of Fufang Yuanhu Zhitong Patch for dysmenorrhea was evaluated by ip oxytocin or cloprostenol to cause dysmenorrhea and incur contortion on rats as test model.
Results:
1 The optimum ethanol extraction technology of both Rhizoma Corydalis and Radix Angelicae Dahuricae was as follows:The medicinal materials was extracted for 3 times with 3 times amount of 75%ethanol and for 1.5 hours per time.The transfer rate of tetrahydropalmatine in the medical material was 82.7%.The craft of using alumina column to purify the samples is better than that of ether extraction in the process of assaying.The optimium volatile oil extraction technology for Fructus Amomi Rotundus was as follows:The coarse powder was soaked for 2 hours and then extracted with 10 times of water for 4 hours continuously.The rate of oil extracted was 5.23%.
2 The optimum manufacturing technology for Fufang Yuanhu Zhitong Patch was that the patch was prepared by the melted method and the matrix was made of paraffin wax lg,stearic acid 8g,triethanolamine 3g,gelatin 2g,PAA(S)(70%)1.5g,glycerol 0.5g,sodium dodecyl sulphate(SDS)0.1g and extractive 3.2g.The optimum ingredients of the matrix of the cataplasmatawere gelatin:PAA(S)(70%):PVP K-30:glycerol =3:4:2:1.
3 The released rate and the vitro percutaneous absorption:the content of tetrahydropalmatine released from Fufang Yuanhu Zhitong Patch in water was 24.28%and the cumulative vitro permeation(mouse)rate within 48 hours was 34.78%;the content of tetrahydropalmatine released from Fufang Yuanhu Zhitong Cataplasmata in water was 82.63%,and the cumulative vitro permeation(mouse)rate within 48 hours was 40.95%.
4 The quality standards:The TLC identification methods for each medical material in the patch preparation were simple,and the spots on TLC pictures were clear.Study on determination had shown that the linear rang of the concengtration of tetrahydropalmatine was 0.1148μg～1.148μg(r=0.9999);that the precision test indicated that RSD was equal to 0.495%;that the repeatition test indicated that the average content of tetrahydropalmatine in the patch was 0.04431mg per patch and the RSD was 2.45%;that the average recovery was 97.995%and the RSD was 2.89%and that he content of tetrahydropalmatine in 3 batch of patches were 0.443mg per patch,0.378mg per patch and 0.381mg per patch respectively.The adhesive ability and the weight variation of the patch preparation were accord with the regulation.
5 The accelerated preliminary stable property:all the detection indexes examined unchanged evidently.
6 The preliminary pharmacodynamics:Fufang Yuanhu Zhitong Patch could reduce the contortion frequency caused by oxytocin or cloprostenol in model rats.And the result of the test also showed that the patch is more effective in therapying dysmenorrhea than the dosage form of Yuanhu Zhitong Tablet.
Conclusions:
The Fufang Yuanhu Zhitong Patch possesses good stability,super adhesive property to skin,and low water content in matrix.Many research have been done in many different aspects,such as extraction technology, manufacturing technology,quality standards of the preparation,test of released rate and the cumulative permeation rate,the accelerated preliminary stable property,and the preliminary pharmacodynamics.All of these reseaches lay a good foundation for the further development of new traditional Chinese medicine Fufang Yuanhu Zhitong Patch.
引文
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