肠溶包衣材料羟丙甲纤维素邻苯二甲酸酯的研究
摘要
本文研制了肠溶包衣材料羟丙甲纤维素邻苯二甲酸酯（Hydroxypropyl
Methylcellulose phthalate，HPMCP），建立了HPMCP粘度及基团定量方法，
对HPMCP的理化性质及稳定性作了初步考察，研究了HPMCP游离膜的性
质，并以吲哚美辛和潘托拉唑钠为模型药物，进行了包衣研究。
以羟丙甲纤维素（HPMC）为主要原料合成了HPMCP。考察了HPMCP
的合成工艺条件、酯化剂、催化剂用量、反应温度及反应时间等影响酯化率
的因素，用均匀设计法优化了合成工艺条件，优化配比为羟丙甲纤维素100
份，邻苯二甲酸酐130份，无水醋酸钠100份，醋酸350份，氯酸钾4.5份，
反应温度85℃，反应时间3小时。按优化工艺所得产物平均酯化率为29.5％。
四种光谱分析结果表明，本品与日本信越公司HP-55化学结构一致。
粘度和取代基含量是控制聚合物质量的重要指标。参照中国药典测定甲
氧基及羟丙氧基含量的方法，根据实验具体情况，对其装置进行改进，用自
制仪器装置测定甲氧基及羟丙氧基的含量，结果证明该法的准确度与精密度
高于中国药典法。依据美国药典相应项下方法测定HPMCP的粘度和酯化率。
对三批HPMCP粘度、甲氧基、羟丙氧基及酯化率测定结果表明，所合成的
HPMCP符合美国药典HPMCP 200731基团含量要求，与信越公司HP-55为
同一规格。
采用电镜扫描法研究粒子形态，HPMCP为多孔实心不规则颗粒，HP-55
为外表完整、内部空虚的团状物，粒径较大。粒子形态的不同使两者的堆密
沈阳药科大学硕士学位论文 摘 要
度及溶解速度存在差异。HPMCP的堆密度为 0．453g／ffil，HP55为 0．265g／inl。
溶解度实验表明HPMCP可溶于丙酮、乙醇等有机混合溶剂，不溶于水及酸
性水溶液，在各种溶剂中的溶解行为与HP－55一致，但溶解速度比HP－55略
慢。差示扫描热分析（DSC）图谱显示HPMCP的玻璃化温度qg）为76oC，与信
越HP65相近。稳定性影响因素实验（光照4500Lx，温度60℃，湿度RH92．5％）
结果表明HPMCP在高湿条件下放置可明显吸潮O天吸湿增重6．56％，10天
为7．37％），吸潮后游离酸含量略有增加，酯化率略降。加速实验及室温留样
实验结果表明HPMCP在包装条件下对光、热、湿稳定。
采用“薄膜实验”法考察HPMCP游离膜的溶解性和透湿性。实验结果
表明，在人工肠液中HPMCP游离膜的溶解速率略快于HP－55膜，膜的透湿
系数与HP－55相近，但高于丙烯酸树脂类游离膜。成膜附加剂邻苯二甲酸二
乙酯、二氧化钛、滑石粉及色淀等对HPMCP膜的溶解性及透湿性均有不同
程度的影响，影响程度与用量有关。脂溶性增塑剂邻苯二甲酸二乙酯少量时
可降低膜的透湿性及溶解性，用量较多时，对膜的溶解性作用不大。水溶性
增塑剂PEG4OO及表面活性剂吐温－80可增加膜的透湿性和溶解性。成膜处方
中不溶性固体成份二氧化钛、滑石粉及色淀等，少量时起通透屏障作用，用
量30％以上时，使膜的通透性增加，溶解速度增快。采用乌＊‘）正交实验表
优化包衣膜组成，得到最佳组合为邻苯二甲酸二乙酯20％、二氧化钛20％、
滑石粉20％、色淀10％。
以MI％美辛（indometacin）为模型药物，以优化处方包衣液包衣，考察
HPMCP包衣膜的性质。研究吼跺美辛HPMCP包衣片的溶出行为，并与HP－
55包衣片及五种市售片进行比较。用相似因子法和ChoWb法对溶出实验数据
进行统计分析，相似因子F：70．l＊0＄F。＜100X 从而说明HPMCP包衣片与
HP－55包衣片溶出行为完全相似。溶出曲线表明，HPMCP包衣片片心药物溶
出速率明显快于五种市售片。
以潘托拉哇钠…antoprazole·Na·H。O）为模型药物，用HPMCP包衣制
2
沈阳药科大学硕士学位论文 摘 要
备肠溶衣片，通过“经典实验”来考察HPMCP作为肠溶材料的性能，。建立
了潘托拉哇钠肠溶片质量分析的高效液相色谱法，线性范围为
36．16－144石4mg／inl（r＝0．9999），高、中、低三个浓度的平均回收率为 100．二％。
耐酸力实验表明HPMCP包衣膜在酸中几乎不释放片心药物。溶出度实验表
明包衣片的溶出均一性良好，溶出速率明显快于市售潘托拉哇钠片。在采用
铝塑及纸铝袋密封包装条件下，加速实验及室温留样6个月包衣片质量未见
明显变化。
以上研究工作表明，本实验室合成的HPMCP与日本信越公司同类产品
HP55的主要理化性质一致，工艺成熟后，可望实现HPMCP的国产化。
A kind of enteric coating material - Hydroxypropyl Methylcellulose Phthalate (HPMCP) was studied in this thesis. The research covered synthetic technology quantitative analytical methods , properties of free film and coating film of
HPMCP.
HPMC was selected as a material to synthesize HPMCP , the synthetic process factors of this material such as esterifying reagent , catalyst ,temperature and time of reaction was studied and also optimized by uniform experiment . The optimum process were HPMC bOg , phthalic anhydride 130g , sodium acetate lOOg, acetic acid 350g , potassium chlorate 4.5g , reaction temperature 85 ~C, reaction time 3h the average estenfication degree of the products was 29.5% according to the optimum process . The synthetic substance was ascertained to have the same chemical structure as HP-55 (the product of Shin-Etsu in Japan ) by spectroscopic analysis
In order to control the qualities of HPMCP , the quantitative methods were established referring to Ch.P and USP . New apparatus were designed to determine the contents of hydroxypropoxy and methoxy . The methods with these new apparatus were proved to be more efficient than the methods of Ch.P . The viscosity and phthalyl content of HPMCP were determined according to the
4
~4k4~ L~{~tiri ABSTRACT
methods of USP . The determination results indicated that the qualities of the three batches of HPMCP were in accord with the demands of HPMCP 200731 in USP and equaled to HP-55 in Japan.
The scanning electron microscope was used to study the morphological characters of HPMCP particles . Compared with HP-55 in Shin-Etsu , HPMCP were multipore solid-core particles , but HP-55 were bigger empty-core particles with integral surfaces . The morphological differences made them have different bulk densities and dissolution rate . The bulk densities of HPMCP and HP-55 were
?0.453 g!ml and 0.265 g/ml respectively . Solubility experiments suggested that HPMCP can be dissolved in most organic solvent mixtures such as acetone and ethylalcohol , but not in water and acid water solutions , its dissolution behavior was similar to HP-55 ,but dissolution rate was slower than that of HP-55 . The DSC curve of HPMCP appeared a near Tg with HP-55 at about 76C . The stability of HPMCP was monitored under the condition of 4500Lx , 60 0C and 92.5% respectively , the results indicated that HPMCP had a perfect-stability except for absorbing moisture in the air of RH 92.5%.
The film properties such as permeability and solubility were evaluated by a method of?free film? In simulated intestinal juice , HPMCP free film had a faster dissolution rate than HP-55 , and the additives within the film could affect the permeability and solubility of HPMCP free film . The effect degrees of the additives on the free film were different according to the kinds and concentrations of additives . In general , a water-insoluble plasticizer could decrease the permeability coefficient and the soluble time of free film in lower concentration but had no significant effect on solubility of free film in higher concentration for its lipophilicity . A water-soluble plasticizer such as PEG 400 can increase the permeability and solubility of free film with an increasing concentration . Insoluble solid additives acted as humidity defences in lower concentration but increased permeability of free film in higher concentration . The L9(34) orthogonal design table was used to optimize the compositions of film coating liquids and the best
;4)~ L1Z~ ABSTRACF
combinations were Diethyl phthalate 20% , Tb2 20% , Talc 20% , pigment 10%.
Indometacin was selected as a model drug to study 1-IPMCP coating film which coating film was also compared with Shin-Etsu HP-55 coating film . The drug release data of HPMCP coated tablets and HP-55 coated tablets in simulated intestinal juice were analyzed by statistical methods. The results suggested that the drug release behaviour of HPMCP coated tablets was perfectly similar with HP-55 coated tablets (F2=
Methylcellulose phthalate，HPMCP），建立了HPMCP粘度及基团定量方法，
对HPMCP的理化性质及稳定性作了初步考察，研究了HPMCP游离膜的性
质，并以吲哚美辛和潘托拉唑钠为模型药物，进行了包衣研究。
以羟丙甲纤维素（HPMC）为主要原料合成了HPMCP。考察了HPMCP
的合成工艺条件、酯化剂、催化剂用量、反应温度及反应时间等影响酯化率
的因素，用均匀设计法优化了合成工艺条件，优化配比为羟丙甲纤维素100
份，邻苯二甲酸酐130份，无水醋酸钠100份，醋酸350份，氯酸钾4.5份，
反应温度85℃，反应时间3小时。按优化工艺所得产物平均酯化率为29.5％。
四种光谱分析结果表明，本品与日本信越公司HP-55化学结构一致。
粘度和取代基含量是控制聚合物质量的重要指标。参照中国药典测定甲
氧基及羟丙氧基含量的方法，根据实验具体情况，对其装置进行改进，用自
制仪器装置测定甲氧基及羟丙氧基的含量，结果证明该法的准确度与精密度
高于中国药典法。依据美国药典相应项下方法测定HPMCP的粘度和酯化率。
对三批HPMCP粘度、甲氧基、羟丙氧基及酯化率测定结果表明，所合成的
HPMCP符合美国药典HPMCP 200731基团含量要求，与信越公司HP-55为
同一规格。
采用电镜扫描法研究粒子形态，HPMCP为多孔实心不规则颗粒，HP-55
为外表完整、内部空虚的团状物，粒径较大。粒子形态的不同使两者的堆密
沈阳药科大学硕士学位论文 摘 要
度及溶解速度存在差异。HPMCP的堆密度为 0．453g／ffil，HP55为 0．265g／inl。
溶解度实验表明HPMCP可溶于丙酮、乙醇等有机混合溶剂，不溶于水及酸
性水溶液，在各种溶剂中的溶解行为与HP－55一致，但溶解速度比HP－55略
慢。差示扫描热分析（DSC）图谱显示HPMCP的玻璃化温度qg）为76oC，与信
越HP65相近。稳定性影响因素实验（光照4500Lx，温度60℃，湿度RH92．5％）
结果表明HPMCP在高湿条件下放置可明显吸潮O天吸湿增重6．56％，10天
为7．37％），吸潮后游离酸含量略有增加，酯化率略降。加速实验及室温留样
实验结果表明HPMCP在包装条件下对光、热、湿稳定。
采用“薄膜实验”法考察HPMCP游离膜的溶解性和透湿性。实验结果
表明，在人工肠液中HPMCP游离膜的溶解速率略快于HP－55膜，膜的透湿
系数与HP－55相近，但高于丙烯酸树脂类游离膜。成膜附加剂邻苯二甲酸二
乙酯、二氧化钛、滑石粉及色淀等对HPMCP膜的溶解性及透湿性均有不同
程度的影响，影响程度与用量有关。脂溶性增塑剂邻苯二甲酸二乙酯少量时
可降低膜的透湿性及溶解性，用量较多时，对膜的溶解性作用不大。水溶性
增塑剂PEG4OO及表面活性剂吐温－80可增加膜的透湿性和溶解性。成膜处方
中不溶性固体成份二氧化钛、滑石粉及色淀等，少量时起通透屏障作用，用
量30％以上时，使膜的通透性增加，溶解速度增快。采用乌＊‘）正交实验表
优化包衣膜组成，得到最佳组合为邻苯二甲酸二乙酯20％、二氧化钛20％、
滑石粉20％、色淀10％。
以MI％美辛（indometacin）为模型药物，以优化处方包衣液包衣，考察
HPMCP包衣膜的性质。研究吼跺美辛HPMCP包衣片的溶出行为，并与HP－
55包衣片及五种市售片进行比较。用相似因子法和ChoWb法对溶出实验数据
进行统计分析，相似因子F：70．l＊0＄F。＜100X 从而说明HPMCP包衣片与
HP－55包衣片溶出行为完全相似。溶出曲线表明，HPMCP包衣片片心药物溶
出速率明显快于五种市售片。
以潘托拉哇钠…antoprazole·Na·H。O）为模型药物，用HPMCP包衣制
2
沈阳药科大学硕士学位论文 摘 要
备肠溶衣片，通过“经典实验”来考察HPMCP作为肠溶材料的性能，。建立
了潘托拉哇钠肠溶片质量分析的高效液相色谱法，线性范围为
36．16－144石4mg／inl（r＝0．9999），高、中、低三个浓度的平均回收率为 100．二％。
耐酸力实验表明HPMCP包衣膜在酸中几乎不释放片心药物。溶出度实验表
明包衣片的溶出均一性良好，溶出速率明显快于市售潘托拉哇钠片。在采用
铝塑及纸铝袋密封包装条件下，加速实验及室温留样6个月包衣片质量未见
明显变化。
以上研究工作表明，本实验室合成的HPMCP与日本信越公司同类产品
HP55的主要理化性质一致，工艺成熟后，可望实现HPMCP的国产化。
A kind of enteric coating material - Hydroxypropyl Methylcellulose Phthalate (HPMCP) was studied in this thesis. The research covered synthetic technology quantitative analytical methods , properties of free film and coating film of
HPMCP.
HPMC was selected as a material to synthesize HPMCP , the synthetic process factors of this material such as esterifying reagent , catalyst ,temperature and time of reaction was studied and also optimized by uniform experiment . The optimum process were HPMC bOg , phthalic anhydride 130g , sodium acetate lOOg, acetic acid 350g , potassium chlorate 4.5g , reaction temperature 85 ~C, reaction time 3h the average estenfication degree of the products was 29.5% according to the optimum process . The synthetic substance was ascertained to have the same chemical structure as HP-55 (the product of Shin-Etsu in Japan ) by spectroscopic analysis
In order to control the qualities of HPMCP , the quantitative methods were established referring to Ch.P and USP . New apparatus were designed to determine the contents of hydroxypropoxy and methoxy . The methods with these new apparatus were proved to be more efficient than the methods of Ch.P . The viscosity and phthalyl content of HPMCP were determined according to the
4
~4k4~ L~{~tiri ABSTRACT
methods of USP . The determination results indicated that the qualities of the three batches of HPMCP were in accord with the demands of HPMCP 200731 in USP and equaled to HP-55 in Japan.
The scanning electron microscope was used to study the morphological characters of HPMCP particles . Compared with HP-55 in Shin-Etsu , HPMCP were multipore solid-core particles , but HP-55 were bigger empty-core particles with integral surfaces . The morphological differences made them have different bulk densities and dissolution rate . The bulk densities of HPMCP and HP-55 were
?0.453 g!ml and 0.265 g/ml respectively . Solubility experiments suggested that HPMCP can be dissolved in most organic solvent mixtures such as acetone and ethylalcohol , but not in water and acid water solutions , its dissolution behavior was similar to HP-55 ,but dissolution rate was slower than that of HP-55 . The DSC curve of HPMCP appeared a near Tg with HP-55 at about 76C . The stability of HPMCP was monitored under the condition of 4500Lx , 60 0C and 92.5% respectively , the results indicated that HPMCP had a perfect-stability except for absorbing moisture in the air of RH 92.5%.
The film properties such as permeability and solubility were evaluated by a method of?free film? In simulated intestinal juice , HPMCP free film had a faster dissolution rate than HP-55 , and the additives within the film could affect the permeability and solubility of HPMCP free film . The effect degrees of the additives on the free film were different according to the kinds and concentrations of additives . In general , a water-insoluble plasticizer could decrease the permeability coefficient and the soluble time of free film in lower concentration but had no significant effect on solubility of free film in higher concentration for its lipophilicity . A water-soluble plasticizer such as PEG 400 can increase the permeability and solubility of free film with an increasing concentration . Insoluble solid additives acted as humidity defences in lower concentration but increased permeability of free film in higher concentration . The L9(34) orthogonal design table was used to optimize the compositions of film coating liquids and the best
;4)~ L1Z~ ABSTRACF
combinations were Diethyl phthalate 20% , Tb2 20% , Talc 20% , pigment 10%.
Indometacin was selected as a model drug to study 1-IPMCP coating film which coating film was also compared with Shin-Etsu HP-55 coating film . The drug release data of HPMCP coated tablets and HP-55 coated tablets in simulated intestinal juice were analyzed by statistical methods. The results suggested that the drug release behaviour of HPMCP coated tablets was perfectly similar with HP-55 coated tablets (F2=
引文
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25. Tommy Andersson. Pharmacokinetics,Metabolism and interactions of acid pump inhibitors. Drug Disposition, 1996, 31(1): 9-28
26. Jan Gunnar Hatlebakk, Arnold Berstad. Pharmacokinetic optimisation in the treatment of gastro-oesophageal reflux disease. Disease Management, 1996, 31(5): 386-406
27．陈寿坡主编．胃肠病临床药理学．北京：科学出版社，1998，107-126
28．杨藻寰主编．临床用药的药理学基础．北京：科学技术文献出版社，1997，467
29. Andrew Fitton, Lynda Wiseman. Pantoprazole A review of its pharmacological properties and therapeutic use in acid-related disorders. Drug Evaluation, 1996, 51(3): 460-482
30. Evans DF, Pye G, Bramley R, etal. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut, 1988, 29:1035-1041
31. Peter J, Lisbeth I. Colonic drug delivery. Drug Dev. Ind. Pharm., 1997, 23(9): 893-913
32．小柳俊一，小川钡也，山本昭．低聚合度的羟丙甲纤维素酞酸酯的制造方法．JP 71 43， 104
33. Chiba,Tohru,sckigawa. Fujio, Muto. Hiroaki, et al. A method for the preparation of an acidic dicarboxylic acid ester of cellulose ether. EP 219, 426
34. NFXⅦ.1990, 1938-1940
35．JP．第十三改正，1330-1332
36．中华人民共和国药典委员会．中华人民共和国药典．北京：化学工业出版社，2000，附录51-52
37．NFXⅦ．1990，1450
38．中华人民共和国药典委员会．中华人民共和国药典．北京：化学工业出版社，2000，附录180
39．中华人民共和国药典委员会．中华人民共和国药典．北京：化学工业出版社，2000，附录178
40．中华人民共和国药典委员会．中华人民共和国药典．北京：化学工业出版社，2000，附录181
41．毕殿洲主编．药剂学(第四版)北京：人民卫生出版社，54
42. Leon laclunan, Arge Drubulis. Factors influencing the properties of films used for tablet coating I Effects of plasticizers on the water vapor transmission of cellulose acetate phthalate films. J.Pharm. Sci., 1964, 53(6): 639-643
43. Bill.J.Munden, H.George Dekay, Gilbert S. Banker. Screening of selected polymers as film coating agents. J.Pharm. Sci., 1964, 53(4): 394-401
44. Gilbert S.Banker. Film coating theory and practice, J.Pharm. Sci, 1966, 55(1): 81-89
45. Dane O.Kildsig, Ronald L. Nedich, Gilbert S.Banker. Theoretical justification of keciprocal rate plots in studies of water vapor transmission through films. J.Pharm. Sci., 1970, 59(11): 1634-1637
46. Nutan B.Shah, Bhogi B.Sheth. A method for study of timed-release films. J.Pharm. Sci., 1972, 61(3): 412-416
47. D.J.Allen, J.D.DeMarco, K.C.Kwan. Free films I: Apparatus and preliminary evaluation. Int. J.Pharm., 1972, 61:106-110
48. J.Spitoel, R.Kinget. Preparation and evaluation of free film: influence of method preparation and solvent composition upon the permeability. Pharm.Acta.Helv., 1977, 52(3): 47-50
49. J.T.Heinamaki, A. Iraizoz Colarte, A.J.Nordstrom, et al. Comparative evaluation of ammoniated aqueous and organic-solvent-based cellulose ester enteric cating systems: a study on free films. Int.J.Pharm., 1994, 109:9-16
50. Chang R.K. A comparision of theological and enteric properties among organic solutions, ammonium salt aqueous solutions, and latex systems of some enteric polymers. Pharm. Tech., 1990, 11:62-70
51. Plaizier-Vercammen J.A., steppe K. Evaluation of enteric coated capsules coated with ammoniated water solutions of cellulose acetate phthalate and cellulose acetate trimellitate. Pharm.Iad., 1992, 54:1050-1052
52. O' Connor R.E. and Berryman W.H., Evaluation of enteric film permeability: tablet swelling method and capillary rise method. Drug Dev.Ind.pharm., 1992, 18:2123-2133
53．平其能等编著．现代药剂学．北京：中国医药科技出版社，1998，386
54. Davis M, I chikawa I, williams EJ, et al. Comparison and evaluation of enteric polymer properties in aqueous solutions. Int.J.Pharm., 1986, 28(2-3): 157
55．牟晓红，祝红杰，陈大为，等．羟丙氧基甲基纤维素酞酸酯游离膜的溶解性及附加剂的影响．中国药学杂志，1995，30(8)：467-469
56. S.C.Pocter, K. Ridrway. The permeability of enteric coatings and the dissolution rates of coated tablets. J.Pharm. Pharmacol., 1982, 34:5-8
57．牟晓红，张汝华，祝红杰．羟丙氧基甲基纤维素酞酸酯游离膜的透湿性及附加剂的影响．中国药学杂志，1994，29：470-472
58．林均柱，张汝华，王洪光，等．糖衣片隔离层的透湿性及强度考察．医药工业，1985，16(3)108-112
59．夏锦辉，刘昌孝．固体药物制剂的体外溶出度的统计学评价分析．中国药学杂志，2000，35(2)：130-131
60. Center for drug evaluation an research, FDA. Guidance for industry bioavailability and bioequivalences studies for orally administered drug products: General Considerations. 1999:10-14
61. Hall GY, Chow SC. Dissolution profile comparison versus bioequivalence. Drug clinical development and application of statistics, Beijing, 1997(session IV): 49
62. Graham Cole, John Hogan, Michael Aulton. Pharmaceutical Coating Technology, 391
63. Dietrich Rango, Ney Hartmut. Pantoprazol enthaltende orale darreichungsformen. Germany. EP 0519365, 1992, 6, 13
64．郑俊民主编．经皮给药新剂型．北京：人民卫生出版社，1997：215
2．上海医药工业研究院药物制剂研究室编著．药用辅料应用技术．北京：中国医药科技出版社，1991，129-146
3．郑俊民主编．药用高分子材料学．北京：中国医药科技出版社，2000，114-115
4．药用辅料手册．英美药学会联合出版．上海医药管理局科技情报局研究所编译．1988，280-286
5. Samy, E.M., Formulation and evaluation of sustained release ibuprofen granules. Saudi Pharm. J., 1995, 3:48-55
6. Hema Venkatesh, N.M. Sanghavi. Controlled drug delivery of pH dependent soluble drugpindolol. Drug Develepment And Industrial Pharmacy, 1994, 20(1): 111-118
7. Dilek Ermis, Nilufer Tarimci. Ketoprofen sustained-release suppositories containing HMCP in polyethylene glycol-bases. Int.J.Pharm., 1995, 113:65-71
8. I Chikawa, Massaki. A new multiple-unit oral floating dosage system. I: preparation and in vitro evaluation of floating and sustained-release characteristics. J.Pharm. Sct., 1991, 80(11): 1062-1066
9. A.K.Walduck, J.P.Opdebeeck, H.E.benson, et al. Biodegradable implants for the delivery of veternary vaccines design manufacture and antibody responses in sheep. J.Control.Release, 1998, 51:269-280
10. Chen,Chin Ming. Pulsatile particle drug delivery system. US.US, 5,260,069
11. Nomurna,Tatswo. Bitterness-free bffemelane hydrochloride dry syrups. JP 05 97, 664 [9397, 664]
12. G.WeiB, A. Knoch, A.Laicher, et al. Simple coacervation of HPMCP Ⅱ Microencapsulation of ibuprofen. Int.J.Pharm., 1995, 124:97-105
13. D.Torres, G.Garcia-Encina, B.Seijo, et al. Formulation and in vitro evaluation of HPMCP-microencapsulated drug-resin complexes for sustained release of diclofenac. Int.J.Pharm., 1995, 121:239-243
14. D.Torres, G.Garcia-Encina, B.Seijo, et al. Biopharmaceutical evaluation of microencapsulated ion-exchange resin containing diclofenac. EUr. J.Pharm.Biopharm, 1995, 41(2): 127-131
15. H.C.Zaniboni, J.T.Fell, J.H.Collett. Production and Characterisation of enteric beads. Int. J.Pharm., 1995, 125:151-155
16. J.Varshosaz, R.A. Kennedy, E.M.Gipps. Use of enteric polymers for production of microspheres by extrusion-spheronization. Pharm.Acta Helvetiae, 1997, 72:145-152
17. Yamamura, Keiko. A multi-layered pharmaceutical films containing water-soluble high molecular weight substances. EP 781,546
18. K. Goracinova, Li. Klisarova, A. Simov.Physical Characterization and dissolution properties of varapumiL. Hcl coprecipitates. Drug Dev: And Industrial Pharm., 1995, 21(3): 383-391
19. Toshiya Kai, Yukiyo Akiyama, shigeyuki Nomura, et al. Oral absorption improvemeat of poorly solulde drug using solid dispersion technique. Chem. Pharm. Bull., 1996, 44(3): 568-571
20. Yamamoto, Hiroshi. Encapsulation of containing fish grouth hormone in enteric-soluble polymers for feed. JP 05 85, 941
21. Ikemori, Yutaka. Passage of chicken egg yolk antibody treated with HPMCP in the gastrointestional tract of calves. J.Vet. Med. Sci., 1996, 58(4): 365-367
22．赵丽琴，张守芳．环氧化酶-2选择性抑制剂研究进展．中国药物化学杂志，1999，9(2)：138-139
23．李端主编．药理学第四版．北京：人民卫生出版社，1999，150
24．中华人民共和国药典委员会．中华人民共和国药典．北京：化学工业出版社，2000，291-292
25. Tommy Andersson. Pharmacokinetics,Metabolism and interactions of acid pump inhibitors. Drug Disposition, 1996, 31(1): 9-28
26. Jan Gunnar Hatlebakk, Arnold Berstad. Pharmacokinetic optimisation in the treatment of gastro-oesophageal reflux disease. Disease Management, 1996, 31(5): 386-406
27．陈寿坡主编．胃肠病临床药理学．北京：科学出版社，1998，107-126
28．杨藻寰主编．临床用药的药理学基础．北京：科学技术文献出版社，1997，467
29. Andrew Fitton, Lynda Wiseman. Pantoprazole A review of its pharmacological properties and therapeutic use in acid-related disorders. Drug Evaluation, 1996, 51(3): 460-482
30. Evans DF, Pye G, Bramley R, etal. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut, 1988, 29:1035-1041
31. Peter J, Lisbeth I. Colonic drug delivery. Drug Dev. Ind. Pharm., 1997, 23(9): 893-913
32．小柳俊一，小川钡也，山本昭．低聚合度的羟丙甲纤维素酞酸酯的制造方法．JP 71 43， 104
33. Chiba,Tohru,sckigawa. Fujio, Muto. Hiroaki, et al. A method for the preparation of an acidic dicarboxylic acid ester of cellulose ether. EP 219, 426
34. NFXⅦ.1990, 1938-1940
35．JP．第十三改正，1330-1332
36．中华人民共和国药典委员会．中华人民共和国药典．北京：化学工业出版社，2000，附录51-52
37．NFXⅦ．1990，1450
38．中华人民共和国药典委员会．中华人民共和国药典．北京：化学工业出版社，2000，附录180
39．中华人民共和国药典委员会．中华人民共和国药典．北京：化学工业出版社，2000，附录178
40．中华人民共和国药典委员会．中华人民共和国药典．北京：化学工业出版社，2000，附录181
41．毕殿洲主编．药剂学(第四版)北京：人民卫生出版社，54
42. Leon laclunan, Arge Drubulis. Factors influencing the properties of films used for tablet coating I Effects of plasticizers on the water vapor transmission of cellulose acetate phthalate films. J.Pharm. Sci., 1964, 53(6): 639-643
43. Bill.J.Munden, H.George Dekay, Gilbert S. Banker. Screening of selected polymers as film coating agents. J.Pharm. Sci., 1964, 53(4): 394-401
44. Gilbert S.Banker. Film coating theory and practice, J.Pharm. Sci, 1966, 55(1): 81-89
45. Dane O.Kildsig, Ronald L. Nedich, Gilbert S.Banker. Theoretical justification of keciprocal rate plots in studies of water vapor transmission through films. J.Pharm. Sci., 1970, 59(11): 1634-1637
46. Nutan B.Shah, Bhogi B.Sheth. A method for study of timed-release films. J.Pharm. Sci., 1972, 61(3): 412-416
47. D.J.Allen, J.D.DeMarco, K.C.Kwan. Free films I: Apparatus and preliminary evaluation. Int. J.Pharm., 1972, 61:106-110
48. J.Spitoel, R.Kinget. Preparation and evaluation of free film: influence of method preparation and solvent composition upon the permeability. Pharm.Acta.Helv., 1977, 52(3): 47-50
49. J.T.Heinamaki, A. Iraizoz Colarte, A.J.Nordstrom, et al. Comparative evaluation of ammoniated aqueous and organic-solvent-based cellulose ester enteric cating systems: a study on free films. Int.J.Pharm., 1994, 109:9-16
50. Chang R.K. A comparision of theological and enteric properties among organic solutions, ammonium salt aqueous solutions, and latex systems of some enteric polymers. Pharm. Tech., 1990, 11:62-70
51. Plaizier-Vercammen J.A., steppe K. Evaluation of enteric coated capsules coated with ammoniated water solutions of cellulose acetate phthalate and cellulose acetate trimellitate. Pharm.Iad., 1992, 54:1050-1052
52. O' Connor R.E. and Berryman W.H., Evaluation of enteric film permeability: tablet swelling method and capillary rise method. Drug Dev.Ind.pharm., 1992, 18:2123-2133
53．平其能等编著．现代药剂学．北京：中国医药科技出版社，1998，386
54. Davis M, I chikawa I, williams EJ, et al. Comparison and evaluation of enteric polymer properties in aqueous solutions. Int.J.Pharm., 1986, 28(2-3): 157
55．牟晓红，祝红杰，陈大为，等．羟丙氧基甲基纤维素酞酸酯游离膜的溶解性及附加剂的影响．中国药学杂志，1995，30(8)：467-469
56. S.C.Pocter, K. Ridrway. The permeability of enteric coatings and the dissolution rates of coated tablets. J.Pharm. Pharmacol., 1982, 34:5-8
57．牟晓红，张汝华，祝红杰．羟丙氧基甲基纤维素酞酸酯游离膜的透湿性及附加剂的影响．中国药学杂志，1994，29：470-472
58．林均柱，张汝华，王洪光，等．糖衣片隔离层的透湿性及强度考察．医药工业，1985，16(3)108-112
59．夏锦辉，刘昌孝．固体药物制剂的体外溶出度的统计学评价分析．中国药学杂志，2000，35(2)：130-131
60. Center for drug evaluation an research, FDA. Guidance for industry bioavailability and bioequivalences studies for orally administered drug products: General Considerations. 1999:10-14
61. Hall GY, Chow SC. Dissolution profile comparison versus bioequivalence. Drug clinical development and application of statistics, Beijing, 1997(session IV): 49
62. Graham Cole, John Hogan, Michael Aulton. Pharmaceutical Coating Technology, 391
63. Dietrich Rango, Ney Hartmut. Pantoprazol enthaltende orale darreichungsformen. Germany. EP 0519365, 1992, 6, 13
64．郑俊民主编．经皮给药新剂型．北京：人民卫生出版社，1997：215