复方单硝酸异山梨酯双层缓释片的研制
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摘要
5-单硝酸异山梨酯是预防和治疗心绞痛、心肌梗塞最常用的药物之一,由于其起效快、作用强、疗效确切的特点,在临床上被广泛使用。大量研究发现,当其与阿司匹林合用时,具有协同作用并可以减少副作用的发生。本文以国外上市的复方双层片制剂Imazin XL(?)为参照,进行了含5-单硝酸异山梨酯和阿司匹林的双层片制剂的研究开发工作。
本品由两层组成,一层为阿司匹林常释层,另一层为单硝酸异山梨酯缓释层。在阿司匹林层处方工艺筛选中,以溶出度为指标,考察了崩解剂用量和加入方式对双层片常释层中溶出的影响,当崩解剂DISINT采用2.5%内加和2.5%外加时,阿司匹林溶出度与对照制剂基本一致。在单硝酸异山梨酯缓释层处方工艺筛选中,以释放度为指标,分别考察了缓释材料种类和用量、粘合剂种类和用量,片剂硬度等因素对释放度的影响,并选择EXP2、EXP3辅料用量以及粘合剂ETHO浓度作为因素进行了正交试验L9(34)优化,优化的处方为EXP2用量为80mg,EXP3用量为10mg,ETHO浓度为15%。以筛选和优化的处方工艺制备的双层片经体外溶出度和释放度验证,结果批内均一性好,批间差异小,并与对照制剂相似。
在质量标准研究中,建立了水杨酸的HPLC测定方法,线性范围为2.528～25.275μg／ml,平均回收率为99.5%,日内、日间精密度RSD分别为3.89%和3.10%；建立了无机硝酸盐的HPLC测定方法,线性范围为0.1245～6.225μg／ml,平均回收率为99.6%；建立了阿司匹林溶出度的紫外测定方法,线性范围为3.008～18.048μg／ml,平均回收率为101.4%,阿司匹林体外溶出度采用转篮法,转速为100rpm,根据测定结果,可将限度定为30min溶出量不低于8 0%；在5-单硝酸异山梨酯释放度研究中,考察了释放介质和转速对释放度的影响,结果选择水作为介质,转速为100rpm；建立了阿司匹林含量测定方法,采用HPLC法,以咖啡因作为内标,线性范围为30.16～90.48μg／ml,平均回收率为99.97%,日内、日间精密度RSD分别为1.36%和1.38%；建立了5-单硝酸异山梨酯的HPLC含量测定方法,线性范围为12.102～84.714μg／ml,平均回收率为99.7%,日内、日间精密度RSD分别为0.98%和1.04%。此外还对性状、鉴别等进行了研究,对生产的三批样品进行检验,结果各项指标均与国外对照片相似,产品质量可控。
进行了本品的影响因素试验,结果表明,样品对光、热均较为稳定,对高湿条件较为敏感。在RH92.5%条件下,阿司匹林含量从101.1%下降至95.3%,降解产物水杨酸从0.20%增加至1.53%,故样品的包装贮存条件应为密封、置干燥处保存；本品在加速试验6个月内及长期试验24个月内质量稳定,有效期可定为两年。
建立了血浆中5-单硝酸异山梨酯的GC-ECD测定方法,血浆中内源性物质不干扰测定,线性范围为2.72～696.5ng／ml,低、中、高浓度的日内精密度RSD分别13.3%、14.3%和11.4%,日间精密度RSD分别为14.3%、13.4%和11.7%,平均相对回收率分别为103.7%、105.9%和101.2%。低、中、高浓度的提取回收率分别为94.3%、92.4%和91.4%。在室温下,5-单硝酸异山梨酯在血浆中24h内稳定,在-20℃条件下30d内稳定,血浆样品经三次冻融试验,药物稳定性好。
研究了复方单硝酸异山梨酯双层缓释片与等剂量参比制剂单硝酸异山梨酯缓释片在人体单剂量口服后的生物等效性,结果两者5-单硝酸异山梨酯的吸收速度和吸收量无显著性差异,具有生物等效性,相对生物利用度为104.0%。
5-isosorbide mononitrate (5-ISMN) was one of the drugs widely used for prevention and treat of angina and heart infarction clinically for its rapid, strong and definite effect. Lots of studies proved that combination of 5-ISMN and aspirin could provide synergistic reaction and lead to reduced side effects. A double-layer tablet comprised of 5-ISMN and aspirin was developed in this dissertation according to overseas Imazin XL(?) tablet.
The tablet developed in this dissertation comprised of two layers:one was aspirin normal release layer and the other was 5-ISMN sustained release layer. In the formulation and process researches of aspirin layer, influences of disintegrant amount and addition mode on dissolution of aspirin was investigated. The dissolution of aspirin was similar to reference tablet when DISINT was applied 2.5% inside and 2.5% outside the granule. In the formulation and process researches of 5-ISMN sustained release layer, impact of sustained release excipient category and amount, adhesive category and amount, and tablet hardness on release of 5-ISMN was investigated. Orthogonal experiment (L9 (34)) was carried out with EXP2 dosage, EXP3 dosage,ETHO concentration as factors. The optimized formulation was EXP2 80mg, EXP3 lOmg and ETHO concentration 15%. The dissolution (aspirin) and release(5-ISMN) of the double-layer tablets made by optimized formulation and process proved homogeneous, reproducible and similar to reference tablet.
In the specification study, determination of salicylic acid was developed using HPLC method. The linear range was 2.528～25.275 (a g/ ml, average recovery was 99.5%. Within-day and day-to-day precision (RSD) was 3.89% and 3.10%. Determination of nitrate was developed using HPLC method. The linear range was 0.1245～6.225μg/ml and average recovery was 99.6%. determination of aspirin in dissolution test was developed using UV method. The linear range was 3.008～18.048μg/ml and average recovery was 101.4%. Basket method was used in dissolution test of aspirin and rotation rate was 100rpm. And Limit of aspirin dissolution was formulated not less than 80% within 30min. In the study of 5-ISMN release, impact of mediator and rotation rate on 5-ISMN release was investigated. Water was determined as mediator and the rotation rate was determined as 100rpm. Determination of aspirin content was developed using HPLC method with caffeine as internal standard. The linear range was 30.16～90.48μg/ml, average recovery was 99.97%. Within-day and day-to-day precision (RSD) was 1.36% and 1.38%. Determination of 5-ISMN content was developed using HPLC method. The linear range was 12.102～84.714μg/ml, average recovery was 99.7%. Within-day and day-to-day precision (RSD) was 0.98% and 1.04%. Besides,the description and identification of the double-layer tablets were also investigated. Three batches of samples was produced and determined, and each specification was similar to reference tablet. The quality of the tablets were well controllable.
Influence factors test demonstrated that light, temperature had little effect on stability of the tablets.The tablet was sensitive to humidity.The content of aspirin dropped from 101.1% to 95.3% and the content of salicylic acid rised from 0.20% to 1.53% at RH92.5.As a result,the storage condition was:kept in tight container and placed in dry area. The accelerated stability test in 6 months and long-tem stability test in 24 months showed that the quality of the double-layer tablets were steady.And the validity of the product was 2 years.
Determinations of 5-ISMN in human plasma was developed using GC-ECD method. The study showed that endogenous substance in plasma had no impact on the determination. The linear range was 2.72～696.5ng/ml. Within-day precision(RSD) of low, medium, high concentration level was 13.3%、14.3% and 11.4% respectively, day-to-day precision (RSD) 14.3%、13.4% and 11.7% respectively, Average recovery 103.7%、105.9% and 101.2% respectively, extraction recovery 94.3%、92.4% and 91.4% respectively.5-ISMN was stable in plasma within 24h at room temperature,was stable in plasma within 30days at-20℃and was also stable in plasma under 3 circles of freezing and thawing.
The human bioequivalence of'compound isosorbide Mononitrate double-layer sustained release tablets'and reference'isosorbide Mononitrate sustained release tablets'was investigated after single oral administration. The study showed that there's no significant difference between the two preparations in the absorption speed and amount of 5-ISMN and they were bioequivalent. The relative bioavailability was 104.0%.
本品由两层组成,一层为阿司匹林常释层,另一层为单硝酸异山梨酯缓释层。在阿司匹林层处方工艺筛选中,以溶出度为指标,考察了崩解剂用量和加入方式对双层片常释层中溶出的影响,当崩解剂DISINT采用2.5%内加和2.5%外加时,阿司匹林溶出度与对照制剂基本一致。在单硝酸异山梨酯缓释层处方工艺筛选中,以释放度为指标,分别考察了缓释材料种类和用量、粘合剂种类和用量,片剂硬度等因素对释放度的影响,并选择EXP2、EXP3辅料用量以及粘合剂ETHO浓度作为因素进行了正交试验L9(34)优化,优化的处方为EXP2用量为80mg,EXP3用量为10mg,ETHO浓度为15%。以筛选和优化的处方工艺制备的双层片经体外溶出度和释放度验证,结果批内均一性好,批间差异小,并与对照制剂相似。
在质量标准研究中,建立了水杨酸的HPLC测定方法,线性范围为2.528～25.275μg／ml,平均回收率为99.5%,日内、日间精密度RSD分别为3.89%和3.10%；建立了无机硝酸盐的HPLC测定方法,线性范围为0.1245～6.225μg／ml,平均回收率为99.6%；建立了阿司匹林溶出度的紫外测定方法,线性范围为3.008～18.048μg／ml,平均回收率为101.4%,阿司匹林体外溶出度采用转篮法,转速为100rpm,根据测定结果,可将限度定为30min溶出量不低于8 0%；在5-单硝酸异山梨酯释放度研究中,考察了释放介质和转速对释放度的影响,结果选择水作为介质,转速为100rpm；建立了阿司匹林含量测定方法,采用HPLC法,以咖啡因作为内标,线性范围为30.16～90.48μg／ml,平均回收率为99.97%,日内、日间精密度RSD分别为1.36%和1.38%；建立了5-单硝酸异山梨酯的HPLC含量测定方法,线性范围为12.102～84.714μg／ml,平均回收率为99.7%,日内、日间精密度RSD分别为0.98%和1.04%。此外还对性状、鉴别等进行了研究,对生产的三批样品进行检验,结果各项指标均与国外对照片相似,产品质量可控。
进行了本品的影响因素试验,结果表明,样品对光、热均较为稳定,对高湿条件较为敏感。在RH92.5%条件下,阿司匹林含量从101.1%下降至95.3%,降解产物水杨酸从0.20%增加至1.53%,故样品的包装贮存条件应为密封、置干燥处保存；本品在加速试验6个月内及长期试验24个月内质量稳定,有效期可定为两年。
建立了血浆中5-单硝酸异山梨酯的GC-ECD测定方法,血浆中内源性物质不干扰测定,线性范围为2.72～696.5ng／ml,低、中、高浓度的日内精密度RSD分别13.3%、14.3%和11.4%,日间精密度RSD分别为14.3%、13.4%和11.7%,平均相对回收率分别为103.7%、105.9%和101.2%。低、中、高浓度的提取回收率分别为94.3%、92.4%和91.4%。在室温下,5-单硝酸异山梨酯在血浆中24h内稳定,在-20℃条件下30d内稳定,血浆样品经三次冻融试验,药物稳定性好。
研究了复方单硝酸异山梨酯双层缓释片与等剂量参比制剂单硝酸异山梨酯缓释片在人体单剂量口服后的生物等效性,结果两者5-单硝酸异山梨酯的吸收速度和吸收量无显著性差异,具有生物等效性,相对生物利用度为104.0%。
5-isosorbide mononitrate (5-ISMN) was one of the drugs widely used for prevention and treat of angina and heart infarction clinically for its rapid, strong and definite effect. Lots of studies proved that combination of 5-ISMN and aspirin could provide synergistic reaction and lead to reduced side effects. A double-layer tablet comprised of 5-ISMN and aspirin was developed in this dissertation according to overseas Imazin XL(?) tablet.
The tablet developed in this dissertation comprised of two layers:one was aspirin normal release layer and the other was 5-ISMN sustained release layer. In the formulation and process researches of aspirin layer, influences of disintegrant amount and addition mode on dissolution of aspirin was investigated. The dissolution of aspirin was similar to reference tablet when DISINT was applied 2.5% inside and 2.5% outside the granule. In the formulation and process researches of 5-ISMN sustained release layer, impact of sustained release excipient category and amount, adhesive category and amount, and tablet hardness on release of 5-ISMN was investigated. Orthogonal experiment (L9 (34)) was carried out with EXP2 dosage, EXP3 dosage,ETHO concentration as factors. The optimized formulation was EXP2 80mg, EXP3 lOmg and ETHO concentration 15%. The dissolution (aspirin) and release(5-ISMN) of the double-layer tablets made by optimized formulation and process proved homogeneous, reproducible and similar to reference tablet.
In the specification study, determination of salicylic acid was developed using HPLC method. The linear range was 2.528～25.275 (a g/ ml, average recovery was 99.5%. Within-day and day-to-day precision (RSD) was 3.89% and 3.10%. Determination of nitrate was developed using HPLC method. The linear range was 0.1245～6.225μg/ml and average recovery was 99.6%. determination of aspirin in dissolution test was developed using UV method. The linear range was 3.008～18.048μg/ml and average recovery was 101.4%. Basket method was used in dissolution test of aspirin and rotation rate was 100rpm. And Limit of aspirin dissolution was formulated not less than 80% within 30min. In the study of 5-ISMN release, impact of mediator and rotation rate on 5-ISMN release was investigated. Water was determined as mediator and the rotation rate was determined as 100rpm. Determination of aspirin content was developed using HPLC method with caffeine as internal standard. The linear range was 30.16～90.48μg/ml, average recovery was 99.97%. Within-day and day-to-day precision (RSD) was 1.36% and 1.38%. Determination of 5-ISMN content was developed using HPLC method. The linear range was 12.102～84.714μg/ml, average recovery was 99.7%. Within-day and day-to-day precision (RSD) was 0.98% and 1.04%. Besides,the description and identification of the double-layer tablets were also investigated. Three batches of samples was produced and determined, and each specification was similar to reference tablet. The quality of the tablets were well controllable.
Influence factors test demonstrated that light, temperature had little effect on stability of the tablets.The tablet was sensitive to humidity.The content of aspirin dropped from 101.1% to 95.3% and the content of salicylic acid rised from 0.20% to 1.53% at RH92.5.As a result,the storage condition was:kept in tight container and placed in dry area. The accelerated stability test in 6 months and long-tem stability test in 24 months showed that the quality of the double-layer tablets were steady.And the validity of the product was 2 years.
Determinations of 5-ISMN in human plasma was developed using GC-ECD method. The study showed that endogenous substance in plasma had no impact on the determination. The linear range was 2.72～696.5ng/ml. Within-day precision(RSD) of low, medium, high concentration level was 13.3%、14.3% and 11.4% respectively, day-to-day precision (RSD) 14.3%、13.4% and 11.7% respectively, Average recovery 103.7%、105.9% and 101.2% respectively, extraction recovery 94.3%、92.4% and 91.4% respectively.5-ISMN was stable in plasma within 24h at room temperature,was stable in plasma within 30days at-20℃and was also stable in plasma under 3 circles of freezing and thawing.
The human bioequivalence of'compound isosorbide Mononitrate double-layer sustained release tablets'and reference'isosorbide Mononitrate sustained release tablets'was investigated after single oral administration. The study showed that there's no significant difference between the two preparations in the absorption speed and amount of 5-ISMN and they were bioequivalent. The relative bioavailability was 104.0%.
引文
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[18]王玉,王洪光。压制包衣法制备二甲双胍脉冲缓释片。西北药学杂志,2009,24(1)：38-40
[19]单铮,霍美蓉,周建平等。盐酸索他洛尔爆破型脉冲片的制备及释放度研究。药学与临床研究,2009,17(3)：186-190
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[21]糜志远,张迎庆,王忆娟等。阿昔洛韦口腔缓释膜的制备及其体外释放。药物研究,2008,5(23)：25-33
[22]王兰,葛雪梅,易定峰。奥硝唑双层缓释膜的制备工艺及其体外释放度研究。中国药房,2009,20(7)：525-527[23]梁红云。复方奥硝唑缓释膜的制备与临床应用。医药导报,2007,26(5)：
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[1]张玉祥,邱蔚芬,王林。复方丹参骨架缓释片的研制。中医药导报,2007,13(8)：85-86
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[3]谢虹虹,饶晓玲,鲁联等。酒石酸美托洛尔骨架缓释片的制备及释放度测定。中国医院药学杂志,2008,28(8)：626-629
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[7]李伟,张志宏,聂淑芳等。格列齐特推拉式渗透泵的制备。中国新药杂志,2008,17(3)：233-236
[8]唐蕾,张文彬,唐仕炜等。枸橼酸坦度螺酮渗透泵型控释片的制备及体外释药因素的考察。华西药学杂志,2009,24(3)：232-234
[9]Yakubu R, Peh KK, Tan YT, et al. Design of a 24-hour controlled porosity osmotic pump system containing PVP:formulation variables. Drug Development and Industrial Pharmacy,2009,35(12):1430-1438
[10]侯陆星。蕨麻素缓释微丸制备及相关质量控制研究[硕士学位论文]。北京,首都师范大学,2008
[11]陈丽华,徐德生,冯怡等。流化床包衣法制备芍药总苷缓释微丸的研究。中草药,2009,40(3)：379-383
[12]刘扬,游本刚,周志杰等。去甲斑蝥素缓释微丸的制备工艺研究。中国新药杂志,2009,18(6)：549-552
[13]王宝华,陈阳,伍丹。氧化苦参碱膜控缓释包衣微丸的制备。北京中医药大学学报,2009,32(2)：128-131
[14]翟小玲,倪健,谷雨龙。地稔总酚胃内漂浮片制备工艺的研究。中国中药杂志,2008,33(1)：31-34
[15]丁秀芹,刘涛,张翠玲等。石杉碱甲胃漂浮片的研制及体外释放。中国现代中药,2007,9(7)：26-27
[16]Bomma R, Swamy Naidu RA, Yamsani MR, et al. Development and evaluation of gastroretentive norfloxacin floating tablets. Acta Pharm. 2009,59(2):211-221
[17]李元波,薛立安,殷建华等。中国中药杂志,2009,34(1)：30-34
[18]王玉,王洪光。压制包衣法制备二甲双胍脉冲缓释片。西北药学杂志,2009,24(1)：38-40
[19]单铮,霍美蓉,周建平等。盐酸索他洛尔爆破型脉冲片的制备及释放度研究。药学与临床研究,2009,17(3)：186-190
[20]Fan. T, Wei. S, Yan. W, et al. An investigation of pulsatile release tablets with ethylcellulose and Eudragit L as film coating materials and cross-linked polyvinylpyrrolidone in the core tablets. Journal of Controlled Release.2001,77 (3):245-251
[21]糜志远,张迎庆,王忆娟等。阿昔洛韦口腔缓释膜的制备及其体外释放。药物研究,2008,5(23)：25-33
[22]王兰,葛雪梅,易定峰。奥硝唑双层缓释膜的制备工艺及其体外释放度研究。中国药房,2009,20(7)：525-527[23]梁红云。复方奥硝唑缓释膜的制备与临床应用。医药导报,2007,26(5)：
537-538
[24]陈永顺,陈芳,方侃等。吲哚美辛缓释栓的研制及其生物利用度的测定。中国医院药学杂志,2009,29(4)：296-299
[25]龙利红,黄群,侯淑贤等。黄体酮缓释栓的制备及药动学。中国医院药学杂志,2006,26(2)：156-160
[26]谢斌,丁玉峰,贺国芳。右旋布洛芬缓释栓的制备工艺及其体外释放特性 研究。医药导报,2008,27(5)：522-525
[27]Ozguney S, Ozcan I,Ertan G, et al. The preparation and evaluation of sustained release suppositories containing ketoprofen and Enduagit RL 100 by using factorial design. Pharmaceutical Development and Technology. 2007,12(1):97
[28]江华,翟所迪,王晓民。雷公藤内酯醇缓释微球的制备及体内外释放规律研究。中国药房,2009,20(3)：176-179
[29]王莹。苦参碱磁性微球的制备及实验研究[硕士学位论文]。湖北武汉,武汉理工大学,2006
[30]王彦卿,张朝平。诺氟沙星明胶磁性微球的研制及表征。无机材料学报,2005,20(1)： 77-82