复方对乙酰氨基酚口腔崩解片的研制
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摘要
背景及目的
口腔崩解片(orally disintegrating tablets,ODT)是近年来广泛为人们关注的一种新剂型,这种剂型有服用时不需用水、口感良好等特点,因此特别适合儿童使用,在国外已经有多个品种上市。国内对口腔崩解片的研究集中在其崩解机理方面,目前已经初步解决了快速崩解的问题,但由于缺乏对适用于口腔崩解片的可工业化掩味技术的研究,故上市品种很少,已上市品种的销量也很小。
口腔崩解片的开发的难点在于解决快速崩解、强度合适和掩味之间的平衡问题,因为这三者之间是互相影响的。本文以三种药物的复方组合物为模型,以Eudragit E100为包衣材料、流化床喷雾包衣掩味、直接压片法制备口腔崩解片,并对其质量及初步稳定性进行研究,目的在于解决上述三者的平衡问题,制备出可工业化的口腔崩解片。
方法与结果:
1、掩味及口腔崩解片的处方工艺研究
选用的包衣材料是一种口腔中不能迅速溶解而在胃内能迅速溶解的材料衣材料(甲基丙烯酸二甲氨基乙酯-中性甲基丙烯酸酯共聚物,国外商品名为)。以苦味掩蔽度、及有效包衣收率为指标,对包衣液的配方、包衣液的浓度、包衣增重量以及包衣温度等关键工艺参数进行研究,筛选出了最优的结果。为了防止包衣颗粒粘连,影响口腔崩解片的崩解,进行了防粘层包衣研究。以崩解时限和脆碎度等为指标,自制了多管静态崩解仪,并与单管的静态崩解法进行了对比研究,证明该方法能有效模拟口腔环境,具有较好的重复性,能作为本品崩解时限和粒度检查的有效的检查方法,结合脆碎度及硬度等指标,对口腔崩解片的处方进行了探索,最终得到崩解性能及硬度等指标理想的处方。
2、对制得的口腔崩解片样品进行了质量研究。参照新药研究指导原则及中国药典2000年版二部技术要求,进行了自制的对乙酰氨基酚口腔崩解片的的质量研究。
鉴别:该复方中对乙酰氨基酚占有较大比例,且该组分在243nm波长处有明显的特征吸收峰,在考查了辅料无干扰的情况下,确定了该制剂的紫外鉴别项。
检查:为控制制剂中杂质、降解产物,采用高效液相色谱法(HPLC)进行了相应方法研究。采用两个色谱系统分别考察了对乙酰氨基酚中有关物质和盐酸伪麻黄碱、氢溴酸右美沙芬中有关物质。此外对进行了本品溶出度、崩解时限、粒度、均作了研究。
含量:根据本品的性质并结合现有国家标准所采用的含量测定方法,采用专属性强的HPLC法同时测定本品中三组分的含量。结果表明含量测定方法精密度高,重现性好,三组分达到有效分离,能达到仪器分析要求。
3、对制得的口腔崩解片样品进行了初步稳定性考察,设置的稳定性研究为高温(60±2℃)、高湿(RH 75±5%和RH 90±5%)、光照(4500±500LX)等条件。并进行了6个月加速试验及12个月长期稳定性试验。试验结果表明本品对高湿(RH 75±5%和RH 90±5%)有吸湿,对崩解时限有影响外,强光、高温40℃、60℃质量稳定,加速6月及留样考察6月质量稳定。
结论
本文对口腔崩解片的关键因素进行了综合研究,首次对包衣颗粒对口腔崩解片的崩解及粒度的影响进行了研究,采用包防粘层的方法,解决了崩解、强度及掩味三者的平衡问题,经过质量研究和初步稳定性研究,可以满足临床使用及工业化生产的要求。
Object:
It is a wide-accepted combination of acetaminophen, pseudoephedrine hydrochloride and dextromethorphan hydrobromide to cure common cold and which has been proven to be effective and very safe through wide-range and long-term clinic application, so it is suitable to be prepared into orally disintegrating tablets (ODT) for children use. However, all of the three components have bitter taste, to be a children-use medicine; Unfavorable bitter taste will significantly affect the compliance of patient to take the medicine. To deal with this problem, only adding sweeting agent into the formulation will not achieve ideal effect. So we do the study to solve the problem taking advantage of modern bitter-masking technology.
Methods and results:
1. According to the analysis of present bitter-masking technological methods, we decided to adopt the drug substance granule coating method, first granulate the principal agent into microparticles, then coat the microparticles.The coating material is a kind of material that won’t rapidly dissolve in oral cavity but will rapidly dissolve in stomach basing on its pH-dependent dissolubility. Because of its special property, the coating film can be maintained undissolved in oral cavity in certain time, thereby mask the unfavorable taste of the drug substance. Entering into the stomach, the coating film will dissolve in the acid gastric juice and release the active substance. Using bitter-taste masking rate and effective coating yield as index screen out the optimized formulation through studying on the crucial process parameters such as formulation and density of coating solution, coating increment and coating temperature. Moreover, have researched on the antistick layer for fear of the coated microparticles stick-together. According to the CDE conference summary about ODT on Aug. 2nd,2003, and with reference to disintegration-time determinator set in pharmacopoeia, designed the test method of disintegration time for ODT, and testified this method can mimic oral condition and has good reproducibility, and can be used as effective method to inspect disintegration time and particle size; At last, obtained optimized ODT formulation.
2. Have done quality control study towards the obtained ODT sample. To control the impurity and degradation in the preparation,we took advantage of HPLC to do corresponding method study. Using two chromatographic systems to investigate relevant substance in acetaminophen, pseudoephedrine hydrochloride and dextromethorphan hydrobromide. What’s more, have done experiments to investigate content, dissolution rate and so on.
3. Stability investigation on the ODT Sample. The conditions: high temperature(60±2℃), high humidity(RH 75±5%&RH 90±5%), illumination(4500±500LX); and completed 6 months accelerated test and 12 months long-term test. The result show that except showing moisture absorption under high humidity(RH 75±5%和RH 90±5%)condition, the ODT samples remain stable under highlight and high temperature(40℃、60℃) and in accelerated test as well as in long-term storage test.
口腔崩解片(orally disintegrating tablets,ODT)是近年来广泛为人们关注的一种新剂型,这种剂型有服用时不需用水、口感良好等特点,因此特别适合儿童使用,在国外已经有多个品种上市。国内对口腔崩解片的研究集中在其崩解机理方面,目前已经初步解决了快速崩解的问题,但由于缺乏对适用于口腔崩解片的可工业化掩味技术的研究,故上市品种很少,已上市品种的销量也很小。
口腔崩解片的开发的难点在于解决快速崩解、强度合适和掩味之间的平衡问题,因为这三者之间是互相影响的。本文以三种药物的复方组合物为模型,以Eudragit E100为包衣材料、流化床喷雾包衣掩味、直接压片法制备口腔崩解片,并对其质量及初步稳定性进行研究,目的在于解决上述三者的平衡问题,制备出可工业化的口腔崩解片。
方法与结果:
1、掩味及口腔崩解片的处方工艺研究
选用的包衣材料是一种口腔中不能迅速溶解而在胃内能迅速溶解的材料衣材料(甲基丙烯酸二甲氨基乙酯-中性甲基丙烯酸酯共聚物,国外商品名为)。以苦味掩蔽度、及有效包衣收率为指标,对包衣液的配方、包衣液的浓度、包衣增重量以及包衣温度等关键工艺参数进行研究,筛选出了最优的结果。为了防止包衣颗粒粘连,影响口腔崩解片的崩解,进行了防粘层包衣研究。以崩解时限和脆碎度等为指标,自制了多管静态崩解仪,并与单管的静态崩解法进行了对比研究,证明该方法能有效模拟口腔环境,具有较好的重复性,能作为本品崩解时限和粒度检查的有效的检查方法,结合脆碎度及硬度等指标,对口腔崩解片的处方进行了探索,最终得到崩解性能及硬度等指标理想的处方。
2、对制得的口腔崩解片样品进行了质量研究。参照新药研究指导原则及中国药典2000年版二部技术要求,进行了自制的对乙酰氨基酚口腔崩解片的的质量研究。
鉴别:该复方中对乙酰氨基酚占有较大比例,且该组分在243nm波长处有明显的特征吸收峰,在考查了辅料无干扰的情况下,确定了该制剂的紫外鉴别项。
检查:为控制制剂中杂质、降解产物,采用高效液相色谱法(HPLC)进行了相应方法研究。采用两个色谱系统分别考察了对乙酰氨基酚中有关物质和盐酸伪麻黄碱、氢溴酸右美沙芬中有关物质。此外对进行了本品溶出度、崩解时限、粒度、均作了研究。
含量:根据本品的性质并结合现有国家标准所采用的含量测定方法,采用专属性强的HPLC法同时测定本品中三组分的含量。结果表明含量测定方法精密度高,重现性好,三组分达到有效分离,能达到仪器分析要求。
3、对制得的口腔崩解片样品进行了初步稳定性考察,设置的稳定性研究为高温(60±2℃)、高湿(RH 75±5%和RH 90±5%)、光照(4500±500LX)等条件。并进行了6个月加速试验及12个月长期稳定性试验。试验结果表明本品对高湿(RH 75±5%和RH 90±5%)有吸湿,对崩解时限有影响外,强光、高温40℃、60℃质量稳定,加速6月及留样考察6月质量稳定。
结论
本文对口腔崩解片的关键因素进行了综合研究,首次对包衣颗粒对口腔崩解片的崩解及粒度的影响进行了研究,采用包防粘层的方法,解决了崩解、强度及掩味三者的平衡问题,经过质量研究和初步稳定性研究,可以满足临床使用及工业化生产的要求。
Object:
It is a wide-accepted combination of acetaminophen, pseudoephedrine hydrochloride and dextromethorphan hydrobromide to cure common cold and which has been proven to be effective and very safe through wide-range and long-term clinic application, so it is suitable to be prepared into orally disintegrating tablets (ODT) for children use. However, all of the three components have bitter taste, to be a children-use medicine; Unfavorable bitter taste will significantly affect the compliance of patient to take the medicine. To deal with this problem, only adding sweeting agent into the formulation will not achieve ideal effect. So we do the study to solve the problem taking advantage of modern bitter-masking technology.
Methods and results:
1. According to the analysis of present bitter-masking technological methods, we decided to adopt the drug substance granule coating method, first granulate the principal agent into microparticles, then coat the microparticles.The coating material is a kind of material that won’t rapidly dissolve in oral cavity but will rapidly dissolve in stomach basing on its pH-dependent dissolubility. Because of its special property, the coating film can be maintained undissolved in oral cavity in certain time, thereby mask the unfavorable taste of the drug substance. Entering into the stomach, the coating film will dissolve in the acid gastric juice and release the active substance. Using bitter-taste masking rate and effective coating yield as index screen out the optimized formulation through studying on the crucial process parameters such as formulation and density of coating solution, coating increment and coating temperature. Moreover, have researched on the antistick layer for fear of the coated microparticles stick-together. According to the CDE conference summary about ODT on Aug. 2nd,2003, and with reference to disintegration-time determinator set in pharmacopoeia, designed the test method of disintegration time for ODT, and testified this method can mimic oral condition and has good reproducibility, and can be used as effective method to inspect disintegration time and particle size; At last, obtained optimized ODT formulation.
2. Have done quality control study towards the obtained ODT sample. To control the impurity and degradation in the preparation,we took advantage of HPLC to do corresponding method study. Using two chromatographic systems to investigate relevant substance in acetaminophen, pseudoephedrine hydrochloride and dextromethorphan hydrobromide. What’s more, have done experiments to investigate content, dissolution rate and so on.
3. Stability investigation on the ODT Sample. The conditions: high temperature(60±2℃), high humidity(RH 75±5%&RH 90±5%), illumination(4500±500LX); and completed 6 months accelerated test and 12 months long-term test. The result show that except showing moisture absorption under high humidity(RH 75±5%和RH 90±5%)condition, the ODT samples remain stable under highlight and high temperature(40℃、60℃) and in accelerated test as well as in long-term storage test.
引文
[1] 张建春,蒋雪涛,邓明德.口腔速释给药系统研究进展[J],解放军药学学报,2000,16(4):206
[2] 中成药口腔速溶片发展前景广阔[J].中国中医药信息杂志,2001,8,(5): 26
[3] 邓英贤,张晓东 口腔崩解片的概况与制备工艺[J],解放军药学学报 2006,22(3):213
[4] 曹环想,陈济民 粉末包衣的制剂参数[J],中国医药工业杂志,l997,28(9):462
[5] 周淳,刘春城 多层振动流化床干燥机工作原理及特点[J]沈阳化工 1995 (1) P34-35
[6] 邹龙贵,流化床包衣技术特点及应用[J],机电信息(南京),2003,000(018):20
[7] 氨酚麻美糖浆国家标准(WS1-(X-096)-2002Z)
[1] Billany, M.R.J. In; Aulton M.E., Eds; Pharmaceutics; The science of Dosage form Design[M], International Edition, Churchill Livingstone, New York, 1996, 263.
[2] Hussein, M.M.; Bareclon, S.A. Taste-Masking Agents for Bitterness of Volatile Oils.[P]US Patent4,983,394, January 8, 1991.
[3] Lankford, B.L.; Becker, C.H. The use of some imitation flavors for masking distasteful drugs. I. Ammonium chloride.[J], J. Am. Pharm. Assoc. 1951,XL (2), 77–82.
[4] Pandya, E.; Harish, B.; Callahan; Thomas, P.Taste Masking for Unpalatable Formulations[P],USPatent 5,837,286, November 17, 1998.
[5] TAZUKO, TOMOKO N, ERIKO T, et al. The combination effect of L-arginine and NaCl on bitterness suppression of amino acid solution [J].Chern Pharm Bull, 2004,52(2):17
[6] HUANG S Y. Bitter blockers[J] . Shanghai Med Ph- J(上海医药),2004, 25 (10): 446-447
[7] Gowan, W.G.; Bruce, R.D. Aliphatic Esters as a Solvent less Coating Pharmaceuticals.[P],Can. Pat. Appl. CA2082137, November 4, 1993.
[8] Mozada, R.F. Medicament Adsorbates and Their Preparation [P],Eur. Pat. Appl. EP0219458, April 22,1987.
[9] Chau, T.L.; Cherukuri, S.R. Delivery System for Cyclic Amino Acids with Improved Taste, Texture and Compressibility[P],Eur. Pat. Appl.EP0458751, November 27, 1991.
[10] Kinoshita, Y.; Shibuya, M. Preparation Composition for Suppressing Bitterness.[P],J,P 62,265,234, November 11, 1987.
[11] Motola, S.; Mogavero, A.; Agesim, G.R.;Panopoulos, P.N. Orally Administrable Ibuprofen Compositions[P],Can. Pat. Appl. CA1336819, August 29, 1995.
[12] HOU S G, WANG P Y. The preparation of inclusion compound of ranitidine-β-cyclodextrin [ J ] . Chin Pharnz J(中国药学杂志),1996, 31(8):480.
[13] Kurasumi, T.; Imamori, K.; Iwasa, A. Carbetapentane Citrate Containing Composition.[P] JP 03,236,316, October 22, 1991.
[14] Borodkin, S., Sundberg, [J]D.P., J. Pharm. Sci., 1971, 60(10), 1523
[15] GAO R, SHAO Z J, FAN A C L, et al. Taste Masking of quinolone Liquid Preparations Using Ion Exchange Resins: US Patent, 6,514,492[P].2003-02-04
[16] Morella, A.M.; Lucas, S. Microcapsule Compositions and Process. [P] Can. Pat. Appl. CA2068366,November 11, 1992.
[17] Tabata, T.; Yoshimi, A. Taste-Improving OralAgent. [P] JP 04,327,529, November 17, 1992.
[18] GE J L, FANG Y D, UU J A, et al. Preparation of taste-masking Orally Disintegrating Tablets: China: 200310108459.5[P].2005-5-1
[19] Roche, E.J.; Freeman, E.M.; Papile, S.M. TasteMask Coatings for Preparing Chewable PharmaceuticalTablets[P] Eur. Pat. Appl. EP0538034,April 21, 1993.
[20] Mapelli, L.G.; Markoni, M.G.R.; Zema, M. Pharmaceutical Formulations.[P] PCT Int. Appl. WO 9116043, October 31, 1991.
[21] LIU L G, ZHOU J F, QI N X. Research and preparation of shuanghuanglian granules (swallowing type) [ J ] . Chin Tradit Patent Med(中成药),2001,23(5):37
[22] Takagi, S., Toko, K., Wada, K., Yamada, H., Toyashima, K., 1998. Detection of suppression of bitterness by sweet substance using multichannel taste sensor.[J]J. Pharm. Sci. 87, 552–555.
[23] J.Y. Zheng, M.P. Keeney / [J]International Journal of Pharmaceutics 310 (2006) 118–124
[2] 中成药口腔速溶片发展前景广阔[J].中国中医药信息杂志,2001,8,(5): 26
[3] 邓英贤,张晓东 口腔崩解片的概况与制备工艺[J],解放军药学学报 2006,22(3):213
[4] 曹环想,陈济民 粉末包衣的制剂参数[J],中国医药工业杂志,l997,28(9):462
[5] 周淳,刘春城 多层振动流化床干燥机工作原理及特点[J]沈阳化工 1995 (1) P34-35
[6] 邹龙贵,流化床包衣技术特点及应用[J],机电信息(南京),2003,000(018):20
[7] 氨酚麻美糖浆国家标准(WS1-(X-096)-2002Z)
[1] Billany, M.R.J. In; Aulton M.E., Eds; Pharmaceutics; The science of Dosage form Design[M], International Edition, Churchill Livingstone, New York, 1996, 263.
[2] Hussein, M.M.; Bareclon, S.A. Taste-Masking Agents for Bitterness of Volatile Oils.[P]US Patent4,983,394, January 8, 1991.
[3] Lankford, B.L.; Becker, C.H. The use of some imitation flavors for masking distasteful drugs. I. Ammonium chloride.[J], J. Am. Pharm. Assoc. 1951,XL (2), 77–82.
[4] Pandya, E.; Harish, B.; Callahan; Thomas, P.Taste Masking for Unpalatable Formulations[P],USPatent 5,837,286, November 17, 1998.
[5] TAZUKO, TOMOKO N, ERIKO T, et al. The combination effect of L-arginine and NaCl on bitterness suppression of amino acid solution [J].Chern Pharm Bull, 2004,52(2):17
[6] HUANG S Y. Bitter blockers[J] . Shanghai Med Ph- J(上海医药),2004, 25 (10): 446-447
[7] Gowan, W.G.; Bruce, R.D. Aliphatic Esters as a Solvent less Coating Pharmaceuticals.[P],Can. Pat. Appl. CA2082137, November 4, 1993.
[8] Mozada, R.F. Medicament Adsorbates and Their Preparation [P],Eur. Pat. Appl. EP0219458, April 22,1987.
[9] Chau, T.L.; Cherukuri, S.R. Delivery System for Cyclic Amino Acids with Improved Taste, Texture and Compressibility[P],Eur. Pat. Appl.EP0458751, November 27, 1991.
[10] Kinoshita, Y.; Shibuya, M. Preparation Composition for Suppressing Bitterness.[P],J,P 62,265,234, November 11, 1987.
[11] Motola, S.; Mogavero, A.; Agesim, G.R.;Panopoulos, P.N. Orally Administrable Ibuprofen Compositions[P],Can. Pat. Appl. CA1336819, August 29, 1995.
[12] HOU S G, WANG P Y. The preparation of inclusion compound of ranitidine-β-cyclodextrin [ J ] . Chin Pharnz J(中国药学杂志),1996, 31(8):480.
[13] Kurasumi, T.; Imamori, K.; Iwasa, A. Carbetapentane Citrate Containing Composition.[P] JP 03,236,316, October 22, 1991.
[14] Borodkin, S., Sundberg, [J]D.P., J. Pharm. Sci., 1971, 60(10), 1523
[15] GAO R, SHAO Z J, FAN A C L, et al. Taste Masking of quinolone Liquid Preparations Using Ion Exchange Resins: US Patent, 6,514,492[P].2003-02-04
[16] Morella, A.M.; Lucas, S. Microcapsule Compositions and Process. [P] Can. Pat. Appl. CA2068366,November 11, 1992.
[17] Tabata, T.; Yoshimi, A. Taste-Improving OralAgent. [P] JP 04,327,529, November 17, 1992.
[18] GE J L, FANG Y D, UU J A, et al. Preparation of taste-masking Orally Disintegrating Tablets: China: 200310108459.5[P].2005-5-1
[19] Roche, E.J.; Freeman, E.M.; Papile, S.M. TasteMask Coatings for Preparing Chewable PharmaceuticalTablets[P] Eur. Pat. Appl. EP0538034,April 21, 1993.
[20] Mapelli, L.G.; Markoni, M.G.R.; Zema, M. Pharmaceutical Formulations.[P] PCT Int. Appl. WO 9116043, October 31, 1991.
[21] LIU L G, ZHOU J F, QI N X. Research and preparation of shuanghuanglian granules (swallowing type) [ J ] . Chin Tradit Patent Med(中成药),2001,23(5):37
[22] Takagi, S., Toko, K., Wada, K., Yamada, H., Toyashima, K., 1998. Detection of suppression of bitterness by sweet substance using multichannel taste sensor.[J]J. Pharm. Sci. 87, 552–555.
[23] J.Y. Zheng, M.P. Keeney / [J]International Journal of Pharmaceutics 310 (2006) 118–124