利血康软胶囊的制备与质量标准的建立
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摘要
利血康软胶囊由三七、白及、白茅根和藕节四味中药组成,该制剂由临床使用的利血康颗粒研制而成,主要用于血小板减少症。本实验对利血康软胶囊的制备工艺、质量标准进行了研究与考察,确立了制剂工艺,质量检测指标,克服了颗粒剂本身存在诸多不足之处,提高了该处方的生物利用度,质量标准进一步提高,对利血康的临床应用具有较大现实意义。
本课题以干膏得率、乙酸乙酯提取物得率为考察指标,采用正交试验法对白茅根、藕节炭的水煎煮工艺进行优化研究；并以乙酸乙酯提取物得率为考察指标,优选水提物的醇沉工艺；该最佳工艺为：白茅根、藕节炭等二味,加水煎煮三次,每次加入10倍量水,煎煮沸2小时,滤液浓缩至相对密度为了1.10(75～80℃测)的清膏,加乙醇使含醇量达成50%,搅匀,静置于24小时,吸取上清液,减压回收乙醇,浓缩至相对密度为1.15(55～60℃测)的清膏；由于白及水提物粘度较大,采用单独提取并优化白及的提取及纯化工艺。为白及水煎3次,每次加入10倍量水,煎煮1小时,滤液浓缩至相对密度为1.20-1.25(75-80℃测)的清膏,加乙醇使醇沉浓度为60%,醇沉时间24小时,吸取上清液,减压回收乙醇,浓缩至相对密度为1.15(55～60℃测)的清膏；三七采用直接粉碎成细粉加入。
以混悬体系的稳定性为指标,选择软胶囊制剂中赋形剂和真空干燥好的药膏粉碎粒度。以真空干燥好的药膏粉碎、混匀后的流动性为指标,考察聚乙二醇400用量。以软胶囊囊材的柔韧度为指标,对囊材中甘油明胶的比例进行考察,使囊材的柔韧度适中,并符合崩解时限的要求。以明胶与甘油比例、水与明胶比例、溶胶温度为考察因素,进行正交试验,确定软胶囊囊壳最佳组成为明胶：甘油：水=1：0.6：1,溶胶温度为70℃。
利用TLC法对处方药材及利血康制剂中三七、白茅根、白及及藕节炭进行定性鉴别。采用HPLC法测定三七及其制剂中人参皂苷Rg1、人参皂苷Rb1和三七皂R1的含量。建立了人参皂苷Rg1、人参皂苷Rb1和三七皂R1线性方程,其线性范围、平均回收率分别为：Y=84397X+75745,R2=0.9986,平均回收率为98.12%,RSD为1.12；Y=57176X-187.1,R2=0.9988平均回收率为98.30%RSD为1.03；Y=12264X-1478.9,R2=0.9990平均回收率为98.35% RSD为1.30。本法简单可行、方法重现性好,可以作为利血康软胶囊质量控制方法。测得三批利血康软胶囊内容物中人参皂苷Rgl、人参皂苷Rbl和三七皂R1总和均大于8.5mg/粒对三批样品进行了常温留样考察12个月的稳定性试验,稳定性良好。
总之,优选的利血康软胶囊提取纯化和制剂成型工艺合理可行,建立的质量控制方法可以有效地控制制剂质量,产品质量稳定。
Lixuekang soft capsule is developed based on Lixuekang granules, which is composed of raw Panax notoginseng and extractions from Rhizoma bletillae, Rhizoma imperatae, Nodus nelumbinis rhizomatis. Lixuekang soft capsule is used in clinic for the treatment of Thrombocytopenia. In this study, the optimal preparation process and quality standards of LIxuekang soft capsule were investigated to overcome many shortcomings of Lixuekang granules and improve the bioavailability and quality standards of the formulation, which is very important for clinical application.
In this thesis, the yield rates of ethyl acetate extraction proportion and dry extract were used as indexes to optimize the parameters of water extraction process of Rhizoma imperatae and Nodus nelumbinins rhizomatis by orthogonal design. Aqueous extract sedimentation with alcohol was also used as the index of ethyl acetate extraction proportion.The optimal process is:Rhizoma imperatae and Nodus nelumbinins rhizomatis were decocted 2 hours with 10-fold volume water by 3 times. The filtrate was concentrated to the relative density of 1.10 (75～80℃measured), and added ethanol into extraction until the alcohol content reached 50% under stirring, then desposited for 24 hours. The supernatant solution was collected and concentrated to the relative density of 1.15 (55～60℃measured). Because aqueous extract of Rhizoma bletillae is very glutinous, its extraction and purification was proceeded alone. The optimal decocted process of Rhizoma bletillae was lhours with 10-fold water by 3 times. The filtrate was concentrated to the relative density of 1.20～1.22 (75 80℃measured), then added ethanol into extraction until the alcohol content reached 60%. After stirred, it was desposited for 24 hours. The supernatant solution was collected and concentrated to the relative density of 1.15 (55～60℃measured); Raw Panax notoginseng was crushed into powder and added to based on the formulation indication. According to stability of the suspension system, excipients of soft capsules and granularity of dry extraction were selected. The amount of PEG400 was investigated on the basis of liquidity of the suspension system and granularity of dry extraction. In order to determine the optimal composition for capsule shells, orthogonal tests are carried out to explore the effects of the ratio of gelatin to glycerin, the ratio of water to gelatin, and the melt temperature. The observed optimal composition is:gelatin:glycerin:water= 2:1.2:2, with a melting temperature of 70℃.
TLC technique is utilized to identify qualitatively the Panax notoginseng, Rhizoma bletillae, Rhizoma imperatae and Nodus nelumbinis rhizomatis. Moreover, the HPLC technique is used to determine notoginsenoside R1, ginsenoside Rgland ginsenoside Rb1, and their linear equation are proposed by using the external standard method. The results displayed that ginsenoside Rgl, ginsenoside Rbl and notoginsenoside R1 linear relationship were well in the range of Y=84397X+75745, R2=0.9986; Y=57176X-187.1, R2=0.9988;Y 12264X-1478.9, R2=0.9990, respectively. The recovery rates of Lixuekang soft capsule were 98.12%, RSD1.12; 98.30%, RSD 1.03 and 98.35%, RSD 1.30 This method is simple, reproducible, and can be used as a quality control route for Lixuekang soft capsule. The total content of notoginsenoside R1, ginsenoside Rg1and ginsenoside Rb1 in Lizuekang soft capsule was above 8.5mg/g.
Stability is well exhibited by performing the 12-months stability tests in normal temperature on three batches of samples.
In conclusion, in this study the preparation technique of Lixuekang soft capsule has been optimized and an effective quality control method has been proposed as well.
本课题以干膏得率、乙酸乙酯提取物得率为考察指标,采用正交试验法对白茅根、藕节炭的水煎煮工艺进行优化研究；并以乙酸乙酯提取物得率为考察指标,优选水提物的醇沉工艺；该最佳工艺为：白茅根、藕节炭等二味,加水煎煮三次,每次加入10倍量水,煎煮沸2小时,滤液浓缩至相对密度为了1.10(75～80℃测)的清膏,加乙醇使含醇量达成50%,搅匀,静置于24小时,吸取上清液,减压回收乙醇,浓缩至相对密度为1.15(55～60℃测)的清膏；由于白及水提物粘度较大,采用单独提取并优化白及的提取及纯化工艺。为白及水煎3次,每次加入10倍量水,煎煮1小时,滤液浓缩至相对密度为1.20-1.25(75-80℃测)的清膏,加乙醇使醇沉浓度为60%,醇沉时间24小时,吸取上清液,减压回收乙醇,浓缩至相对密度为1.15(55～60℃测)的清膏；三七采用直接粉碎成细粉加入。
以混悬体系的稳定性为指标,选择软胶囊制剂中赋形剂和真空干燥好的药膏粉碎粒度。以真空干燥好的药膏粉碎、混匀后的流动性为指标,考察聚乙二醇400用量。以软胶囊囊材的柔韧度为指标,对囊材中甘油明胶的比例进行考察,使囊材的柔韧度适中,并符合崩解时限的要求。以明胶与甘油比例、水与明胶比例、溶胶温度为考察因素,进行正交试验,确定软胶囊囊壳最佳组成为明胶：甘油：水=1：0.6：1,溶胶温度为70℃。
利用TLC法对处方药材及利血康制剂中三七、白茅根、白及及藕节炭进行定性鉴别。采用HPLC法测定三七及其制剂中人参皂苷Rg1、人参皂苷Rb1和三七皂R1的含量。建立了人参皂苷Rg1、人参皂苷Rb1和三七皂R1线性方程,其线性范围、平均回收率分别为：Y=84397X+75745,R2=0.9986,平均回收率为98.12%,RSD为1.12；Y=57176X-187.1,R2=0.9988平均回收率为98.30%RSD为1.03；Y=12264X-1478.9,R2=0.9990平均回收率为98.35% RSD为1.30。本法简单可行、方法重现性好,可以作为利血康软胶囊质量控制方法。测得三批利血康软胶囊内容物中人参皂苷Rgl、人参皂苷Rbl和三七皂R1总和均大于8.5mg/粒对三批样品进行了常温留样考察12个月的稳定性试验,稳定性良好。
总之,优选的利血康软胶囊提取纯化和制剂成型工艺合理可行,建立的质量控制方法可以有效地控制制剂质量,产品质量稳定。
Lixuekang soft capsule is developed based on Lixuekang granules, which is composed of raw Panax notoginseng and extractions from Rhizoma bletillae, Rhizoma imperatae, Nodus nelumbinis rhizomatis. Lixuekang soft capsule is used in clinic for the treatment of Thrombocytopenia. In this study, the optimal preparation process and quality standards of LIxuekang soft capsule were investigated to overcome many shortcomings of Lixuekang granules and improve the bioavailability and quality standards of the formulation, which is very important for clinical application.
In this thesis, the yield rates of ethyl acetate extraction proportion and dry extract were used as indexes to optimize the parameters of water extraction process of Rhizoma imperatae and Nodus nelumbinins rhizomatis by orthogonal design. Aqueous extract sedimentation with alcohol was also used as the index of ethyl acetate extraction proportion.The optimal process is:Rhizoma imperatae and Nodus nelumbinins rhizomatis were decocted 2 hours with 10-fold volume water by 3 times. The filtrate was concentrated to the relative density of 1.10 (75～80℃measured), and added ethanol into extraction until the alcohol content reached 50% under stirring, then desposited for 24 hours. The supernatant solution was collected and concentrated to the relative density of 1.15 (55～60℃measured). Because aqueous extract of Rhizoma bletillae is very glutinous, its extraction and purification was proceeded alone. The optimal decocted process of Rhizoma bletillae was lhours with 10-fold water by 3 times. The filtrate was concentrated to the relative density of 1.20～1.22 (75 80℃measured), then added ethanol into extraction until the alcohol content reached 60%. After stirred, it was desposited for 24 hours. The supernatant solution was collected and concentrated to the relative density of 1.15 (55～60℃measured); Raw Panax notoginseng was crushed into powder and added to based on the formulation indication. According to stability of the suspension system, excipients of soft capsules and granularity of dry extraction were selected. The amount of PEG400 was investigated on the basis of liquidity of the suspension system and granularity of dry extraction. In order to determine the optimal composition for capsule shells, orthogonal tests are carried out to explore the effects of the ratio of gelatin to glycerin, the ratio of water to gelatin, and the melt temperature. The observed optimal composition is:gelatin:glycerin:water= 2:1.2:2, with a melting temperature of 70℃.
TLC technique is utilized to identify qualitatively the Panax notoginseng, Rhizoma bletillae, Rhizoma imperatae and Nodus nelumbinis rhizomatis. Moreover, the HPLC technique is used to determine notoginsenoside R1, ginsenoside Rgland ginsenoside Rb1, and their linear equation are proposed by using the external standard method. The results displayed that ginsenoside Rgl, ginsenoside Rbl and notoginsenoside R1 linear relationship were well in the range of Y=84397X+75745, R2=0.9986; Y=57176X-187.1, R2=0.9988;Y 12264X-1478.9, R2=0.9990, respectively. The recovery rates of Lixuekang soft capsule were 98.12%, RSD1.12; 98.30%, RSD 1.03 and 98.35%, RSD 1.30 This method is simple, reproducible, and can be used as a quality control route for Lixuekang soft capsule. The total content of notoginsenoside R1, ginsenoside Rg1and ginsenoside Rb1 in Lizuekang soft capsule was above 8.5mg/g.
Stability is well exhibited by performing the 12-months stability tests in normal temperature on three batches of samples.
In conclusion, in this study the preparation technique of Lixuekang soft capsule has been optimized and an effective quality control method has been proposed as well.
引文
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