摘要
离子交换树脂作为新型药物传递系统的载体,因其灵活多样的独特性质而日益受到关注。离子交换树脂能与药物通过离子交换反应形成药物树脂复合物。药物树脂复合物的物理性质与起始的离子交换树脂非常相似,都具有良好的流动性,可以进一步作制剂加工。本论文系统地对离子交换树脂复合物的药物传递系统与药物动力学进行了详尽的研究和阐述,主要内容包括:
1.本论文对药用离子交换树脂的质量特性进行了深入研究,为离子交换树脂在药物传递系统中的应用奠定了基础。实验结果表明,Amberlite IRP-64、Amberlite IRP-88、Amberlite IRP-69的平均粒径(d0.5)分别为52.95μm、57.33μm和62.31μm,属于中国药典(2005年版)规定的最细粉末,但其流动性良好,休止角都小于30°。离子交换树脂具有较强的吸湿性能,在水中可吸水膨胀,其中Amberlite IRP-69吸水膨胀后的平均粒径(d0.5)要增大约10μm。离子交换树脂是一类立体网状高分子聚合物,在水和大多数溶剂中均不溶解,但它能在水溶液中与药物离子等进行离子交换反应,形成药物树脂复合物。
2.本论文建立了模型药物——伪麻黄碱树脂复合物、阿奇霉素树脂复合物、可待因树脂复合物(微囊)及氯苯那敏树脂复合物(微囊)的质量分析方法,为下一步药物树脂复合物的制剂应用研究奠定了质量分析基础。为准确测定药物树脂复合物的载药量,必须首先对药物树脂复合物进行解离,让药物从树脂复合物中完全解离出来,才能准确测定其含量。实验结果表明,若解离1g伪麻黄碱树脂复合物(载药量约为15%),只要解离介质中可交换离子摩尔总量大于0.15 mol,则1小时之内即可达解离平衡,并且药物被充分解离出来。若解离1g阿奇霉素树脂复合物,需在250mL解离介质溶液[0.2 mol·L-1 KCl的甲醇-水(2:1)]中搅拌2小时,药物才能被充分解离出来。若解离其1g可待因和氯苯那敏药物树脂复合物,只要解离介质中可交换离子摩尔总量大于0.5 mol,则1小时之内即可达解离平衡,并且药物被充分解离出来。
3.本论文以吸湿药物——盐酸伪麻黄碱为模型药物,研究了药物树脂复合物的制备工艺。采用批式离子交换法,分别以Amberlite IRP 69、Amberlite IRP 64和Amberlite IRP 88为载体,制备了在高湿度下性能稳定的伪麻黄碱树脂复合物,解决解决了含伪麻黄碱胶囊剂的吸潮液化问题,以普通铝塑泡罩包装即可在有效期内保证产品质量。实验结果表明,离子交换树脂、盐酸伪麻黄碱和纯化水三者的用量比例对所得药物树脂复合物的载药量以及树脂对药物的利用率有着直接影响,从工业生产节约成本的角度考虑,三者的投料比宜为10:2:100。盐酸伪麻黄碱与树脂之间的离子交换反应为吸热反应,温度升高有利于交换反应的正向进行,因而有利于提高药物的利用率和药物树脂复合物的载药量。
4.本论文以离子交换树脂为载体制备的苦味药物——阿奇霉素树脂复合物,使药物的不良苦味得到了较好的掩蔽。由于阿奇霉素为非离子型药物,需在酸性条件下将其离子化后才能通过离子交换吸附到离子交换树脂上,制备出药物树脂复合物。实验表明,柠檬酸作为阿奇霉素离子化试剂的效果较好,其最佳用量比例为柠檬酸:阿奇霉素=0.37g:2g。阿奇霉素树脂复合物配以合适的助悬介质(0.2%黄原胶与1.0%微晶纤维素-羧甲基纤维素钠混合使用)即可制备出无苦味的阿奇霉素混悬剂。实验结果表明,影响药物与树脂的交换率的因素是多方面的,如药物浓度、介质体积、搅拌速度、搅拌时间等。
5.本论文以磷酸可待因和马来酸氯苯那敏为模型药物,详细考察了复方药物树脂复合物的制备工艺。磷酸可待因和马来酸氯苯那敏在Amberlite IRP-69上的离子交换过程都是一个放热过程,适当降低反应温度有利于离子交换反应行为的进行,也有利于提高离子交换树脂对药物的利用率和药物树脂复合物的载药量。实验结果表明,磷酸可待因和马来酸氯苯那敏对同一离子交换树脂存在竞争关系,氯苯那敏与离子交换树脂的结合能力强于可待因。因此,复方药物树脂复合物中氯苯那敏的载药量占有优先比例,但随着离子交换树脂用量的增大,磷酸可待因和马来酸氯苯那敏的利用率都有所提高,其药物树脂复合物的载药量与理论投料量也非常接近。磷酸可待因和马来酸氯苯那敏在临床上常作为复方制剂使用,将两者按比例混合投料,即可与离子交换树脂共同形成预定比例组合的可待因-氯苯敏树脂复合物,既简化了生产工艺,又提高了生产效率。
6.经X-ray衍射和DSC分析,药物树脂复合物所载药物是以化学键的形式结合到离子交换树脂上的,而且和离子交换树脂一样呈现无定型状态,不再出现药物的结晶峰。药物树脂复合物的释药动力学过程可用Viswanathan方程拟合,表明其释药动力学过程是粒扩散行为,主要与释放介质的组成及离子强度有关,其扩散系数影响药物的释放速率。
7.本论文以离子交换树脂复合物为囊心物,通过流化床包衣法、溶剂挥发法和表面包衣法,实现了对小粒径(<1001μm)药物树脂复合物的微囊化包衣,更好地控制药物的释放行为,并进一步制备了复方可待因树脂微囊缓释混悬液,实现了液体制剂的良好缓释性能。采用有机溶剂包衣系统和水分散体包衣系统,对可待因树脂复合物和氯苯那敏树脂复合物进行了流化床微囊化包衣,研究了囊心物性质、包衣液处方和流化床工艺参数对药物树脂复合物微囊释放度的影响。采用95%乙醇为囊材溶剂代替传统方法中的丙酮囊材溶剂,对可待因树脂复合物和氯苯那敏树脂复合物进行微囊化,利用单因素考察相似因子f2评价法和正交实验设计法对其处方工艺参数进行了优化。通过表面包衣法,采用含季铵基团的高分子聚合物(如Eudragit RS100等)对可待因树脂复合物和氯苯那敏树脂复合物进行微囊化,并优化表面包衣的工艺参数和处方参数。实验结果表明,药物树脂复合物的载药量、所用表面包衣材料的浓度、反应介质的用量以及反应温度等都对药物树脂复合物微囊的药物释放特性有着重要影响。
8.本论文以离子交换树脂复合物为基础,制备了复方可待因树脂微囊缓释混悬液。实验结果表明,以黄原胶和微晶纤维素-羧甲基纤维素钠为助悬介质制备的复方可待因树脂微囊缓释混悬液质地均匀,有较好的塑性和流动性,低剪切力时粘度高,使混悬微囊不易沉降,高剪切力时粘度低,有利用生产灌装。复方可待因树脂微囊缓释混悬液在体外具有良好的缓释性能,并采用HPLC-MS/MS分析测定血药浓度,进一步详细研究了其在Beagle犬体内的药物动力学过程。实验结果表明,本论文研制的复方可待因树脂微囊缓释混悬液与市售的马来酸氯苯那敏片和磷酸可待因片比较,该制剂的可待因和氯苯那敏具有明显的缓释特征,Tmax延长,Cmax显著降低,f1/2和MRT延长,但吸收程度相近,可以进一步开展健康成人体内的药物动力学研究。
本论文通过以离子交换树脂为载体,研究解决了吸湿药物——盐酸伪麻黄碱胶囊剂的吸潮液化问题,研究改善了苦味药物——阿奇霉素口服混悬液的顺应性问题,研究实现了复方可待因液体制剂的良好缓释性能,建立了较为系统的药物树脂复合物实验研究方法和产业化工艺流程,为药物树脂复合物在药物传递系统中的应用研究奠定了基础,推动我国药物树脂制剂关键技术的进步,对于促进我国制剂技术水平的提高和药物制剂工业的发展具有重要的学术价值和现实意义。
Ion-exchange resin (IER), as a new drug-delivery vehicle, has been extensively studied in the development of novel drug delivery system (DDS) because of its versatile properties. The drug-resinate complex (DRC) can be formed when a drug is mixed with the appropriate IER. The DRC has the same good flowability as the initiative IER, and can be further applied in pharmaceutical process. This dissertation describes fundamental studies on DDS of IER and its Pharmacokinetics, including as followings:
1 The physical-chemical properties of pharmaceutical IER were thorough investigated, which laid a foundation for application of IER in the DDS.Results showed that the average diameter (do.5)of Amberlite IRP-64、Amberlite IRP-88 and Amberlite IRP-69 was 52.95μm,57.33μm and 62.31μm respectively. Those powders belong to the finest powders specified in the Chinese Pharmacopoeia (2005 edition). But, they have good flowability and their angle of repose is all less than 30°. IER has strong moisture absorption ability, it can swell in water. After it swells, the average particle size (do.5) of Amberlite IRP-69 increases by about 10μm. IRE, a kind of three-dimensional network polymer, is not soluble in water or the majority of solvents. But DRC can be formed by ion exchange reaction between IRE and drug-ions in water.
2 The quantitive analysis methods of model drugs-----pseudoephedrine-resinate complex, azithromycin-resinate complex, codeine-resinate complex (microcapsule) and chlorpheniramine-resinate complex (microcapsule) were established as a basis for the further quality analysis of the DRC preparation. In order to determine the drug-loading capacity of DRC accurately, DRC dissociation should be carried out firstly to make sure the drug dissociates from the drug-resinate complex completely. Results showed:1g pseudoephedrine-resinate complexes (the drug-loading capacity was about 15%), as long as the dissociation medium contained more than 0.15 mol exchange ion, reached a dissociation balance in an hour and the drug was sufficiently released; 1g azithromycin-resinate complexes should be stirred 2 hours in 250ml dissociation medium [0.2 mol·L-1 KCl methanol-water (2:1)solution] to make sure drug was fully released;1g codeine- and chlorpheniramine-resinate complexes, as long as the dissociation medium contained more than 0.5 mol exchange ion, reached a dissociation balance in an hour and the drug was sufficiently released.
3 Pseudoephedrine hydrochloride with moisture absorbability, as a model drug, was applied to study the preparation process of DRC.With Amberlite IRP 69、Amberlite IRP 64 and Amberlite IRP 88 as the drug carriers respectively, a stable pseudoephedrine-resinate complex under high humidity environment has been prepared by batch method of ion exchange. The moisture absorption-liquefaction problem of the capsules containing pseudoephedrine hydrochloride (for example, paracetamol, pseudoephedrine hydrochloride and dexromethorphan hydrobromide capsules) has been successfully solved, so the usual aluminum-plastic blister packaging can ensure the product quality in validity period. Results showed that the amount of IRE, pseudoephedrine hydrochloride and purified water had a direct impact on the drug-loading capacity of DRC and the drug adsorption efficiency. From the prospective of saving industrial production costs, the ratio of the three material above is reasonable for 10:2:100. The rise of temperature can improve both the drug adsorption efficiency and the drug-loading capacity of DRC.The rise of temperature was conducive to promoting exchange reaction because the drug-ion exchange reaction is endothermic.
4 With IER as a drug carrier to prepare the bitter medicine-----azithromycin-resinate complexes, the drug bitterness was successful covered. Azithromycin, as a non-ionic drug, should be inonized in the acidic conditions, then absorbed to IER through ion-exchange reaction to prepare the DRC.The experiment showed that the citric acid was a good ionization reagent for azithromycin, and 0.37g:2g was the best ratio of citric acid to azithromycin. Azithromycin suspension without bitter taste could be prepared with azithromycin-resinate complexes and a suitable suspending medium [mixed 0.2% xanthan gum and 1.0% Avicel CL611 (microcrystalline cellulose and CMC-Na)].Results showed that the influence factors of drugs and ion exchange resins were miscellaneous, including the drug concentration, the reaction medium amount, mixing speed, mixing time, and so on.
5 With the codeine phosphate and chlorpheniramine maleate as model drugs, the detailed study on preparation process of the compound drug-resinate complexes were carried out. Ion exchange process of codeine phosphate and chlorpheniramine maleate on Amberlite IRP-69 is exothermic, so the lower reaction temperature is conducive to the progression of ion exchange reaction, enhancing the drug utilization rate and the drug-loading capacity of DRC.Results showed that codeine phosphate and chlorpheniramine maleate had competitive relationship on the same ion-exchange resins, and the latter one had stronger combination ability. Therefore, chlorpheniramine maleate had a higher proportion in the compound drug-resinate complexes. But, as the ion exchange resins amount increased, the utilization rate of both codeine phosphate and chlorpheniramine maleate was improved. At the same time, the theory inventory rating was quite close to the drug-loading capacity of DRC.In clinical practice, Codeine phosphate and chlorpheniramine maleate are often used as compound preparation. It not only simplified the production process, but also increased production efficiency, by combining them in a given ratio to form codeine-and chlorphenramine-resinate complexes.
6 Through X-ray diffraction and DSC analysis, it's found that the drug in DRC is combined with ion-exchange resins by chemical bond. The DRC, like ion exchange resin, is in amorphous state, with its crystallization peak disappearing. The DRC release dynamics can be defined by Viswanathan equation. It shows that the release kinetics is a diffusion process which is mainly correlated with composition and ionic strength of the release medium, and its diffusion coefficient affects the drug release.
7 With IRE as the core material, through fluidized bed coating, solvent evaporation and surface coating, microencapsulated coating of DRC a small size(<100μm) was achieved to control drug release better. Furthermore, a sustained-release suspension of compound drug-resinate complex microcapsules was prepared to obtain a good sustained-release performance of liquid formulations. With organic solvents coating systems and water dispersion coating systems, codeine-resinate complexes and chlorpheniramine-resinate complexes was microencapsulated coated by fluidized bed coating. The influences of core material prosperity、coating liquid formulation and fluidized bed process parameters on the release of drug-resinate complexes microcapsules were investigated. Ethanol (95%), instead of acetone, was used as solvent of encapsulation to microencapsule codeine-resinate complexes and chlorpheniramine-resinate complexes. The formulation and process parameters were optimized by methods of single-factor evaluation and orthogonal experimental design. The surface coating process parameters and fotmulation parameters of codeine-resinate complexes and chlorpheniramine-resinate complexes were optimized with materials containing quaternary ammonium group (such as Eudragit RS100, etc.). Results showed that the drug-loaded capacity of DRC, concentration of coating materials, amount of reaction medium and reaction temperature all had significant influence on drug release of the DRC microcapsules.
8 Based on the IRE, a sustained-release suspension of compound codeine-resinate and chlorpheniramine-resinate complexes microcapsules was prepared. Results showed that this suspension had good sustained-release properties in vitro. As ionic strength of release medium increased, the release of codeine-resinate complexes and chlorpheniramine-resinate complexes became faster. But they still maintained good sustained-release performance in a simulated human gastric juice and intestinal fluid medium. HPLC-MS/MS method was adopted to analyze blood drug concentration, and a detailed study of pharmacokinetics of the sustained-release suspension of compound codeine-resinate complex and chlorpheniramine-resinate complex microcapsules in beagle dogs was carried out. Results showed that, compared with chlorpheniramine maleate tablets and codeine phosphate tablets on the market, the sustained-release suspension of compound codeine-resinate complex and chlorpheniramine-resinate complex microcapsules had obvious sustained-release characteristics:longer Tmax, lower Cmax, extented t1/2 and MRT, but the extent of absorption was similar. The further study on its pharmacokinetics in the healthy adults is desirable.
With IER as carrier, researches in this dissertation solved the moisture absorption and liquefaction problem of the capsules containing the moisture absorbable drug----pseudoephedrine hydrochloride, and improved the compliance of oral suspensions containing the bitter drug----azithromycin. We carried out comprehensive and in-depth studies on the application of IER in drug delivery systems and the drug pharmacokinetics of DRC.Meanwhile, we established systematic experimental methods and industrialized preparation process. These studies have important academic value and practical significance, in improving the technology of pharmaceutical preparations and promoting the development of pharmacy industry in China.
引文
[1]B. A. Adams and E. L. Holmes.J. Soc. Chem. Ind.,54,1--6T(1935);British Patent,450,308-9(1936).
[2]G. F. Farben. French Patent,816448, August 7,1937.
[3]C.M. McBurney. U. S. Patent,2366007, December 26,1944.
[4]Rohm & Hass Corporatiom Website, http://www.rohmhaas.com/wcm/index.page.
[5]何炳林.离子交换树脂的介绍[J].化学通报,957,5:4-12.
[6]何炳林.离子交换吸附树脂[M].上海:上海科学教育出版社,1995:78-83.
[7]何炳林,史作清.大孔离子交换树脂及新型吸附树脂的结构与性能[J].高分子通报,2005,4:13-19.
[8]化学工业部人事教育司,化学工业部教育培训中心.离子交换[M].北京:化学工业出版社,1997:37-41.
[9]浦宇,王芝祥.吸附树脂及其在天然产物和抗生素中的应用[J].中国医药工业杂志,2003,34(12):636-644.
[10]Bellamy SA, Hughes L. Method for preparing resinates [P].US Pat:20020031490,2002-03-14.
[11]Mertin D, Daube G, Edingloh M. Pharmaceutical preparations for oral administration, containing ion-exchange resins loaded with active ingredients and intrinsically viscous gelling agents as thickening agents [P]. CA Pat:2487648,2003-12-11.
[12]Irwin WJ, MacHale R, Watts PJ. Drug-delivery by ion exchange. Part Ⅶ:Release of acidic drugs from anionic exchange resinate complexes[J].Drug Dev Ind Pharm,1990,16(6):883-898.
[13]Sriwongjanya M, Bodmeier R. Effect of ion exchange resins on the drug release from matrix tablets[J]. Eur J Pharm Biopharm,1998,46(3):321-327.
[14]刘宏飞,王铭洲,潘卫三.离子交换树脂在药物制剂中的应用,中国药剂学杂志,2007,5(4):216-219.
[15]Hughes L. Ion Exchange Resins. Unique Solutions to Formulation Problems [J].Pharmaceutical Technology,2004,28(6):20-25.
[16]李振华,平其能,刘国杰.离子交换树脂控制药物释放研究进展.离子交换与吸附,1997,13(6):613-619.
[17]Dirk M, Block W, Hamann HJ. Pharmaceutical preparations comprising iox exchange resins charged with active,ingrdients [P].US Pat:2004247560,2004-12-09.
[18]Gao R, Shao ZJ, Fan ACL,et al.Taste masking of oral quinolone liquid preparations using ion exchange resins[P].AU Pat:777993,2004-11-11.
[19]Sakamoto K, Tsubokura Y, Takamori Y.Aqueous glucosamine salt solution improved in taste and method for producing the same. [P].JP pat:2003204770,2003-07-22.
[20]Leonard GS, Cooper D. Oral liquid compositions coataining paraxetine [P].US Pat:5811436, 1998-09-22.
[21]Douglas SJ, Bird FR. Process for the preparation of a ranitidine resin absorbate [P].EP Pat:0431759, 1991-06-12.
[22]Fischer FX, Khanna SC. Resinate sustained release dextromethorphan composition [P].EP Pat:0225615, 1987-06-16.
[23]Edward FB, Ira JF, Roy JT. Vitamin B12 Products and Preparations Thereof [P].US Pat:2830933, 1958-04-15.
[24]Raghunathan Y.Prolonged release pharmaceutical preparations [P].US Pat:4221778,1980-09-09.
[25]Wen B, Ramsay MP, Scheurer H, et al. Antitussive drugs delivered by ion exchange [P].US Pat:6001392, 1999-12-14.
[26]贺芬,奚连,侯惠民.含药树脂微囊法制备口服缓释混悬液.Ⅰ.右美沙芬口服缓释混悬液.中国医药工业杂志,2003,34(6):276-279.
[27]刘宏飞,聂淑芳,潘卫三,等.盐酸氨溴索药物树脂复合物体外释药动力学的研究.沈阳药科大学学报,2004,21(2):84-86.
[28]Raghunathan Y.Controlled release pharmaceutical preparations [P]:US Pat:4847077,1989-07-11.
[29]Chow SL,Raghunathan Y. Coatable ion exchange resins [P].US Pat:4859461,1989-08-22.
[30]Kelleher WJ, Carpanzano AE. Sustained release drug-resin complexes [P].US Pat:4996047, 1991-02-26.
[31]Hughes L, Bellamy SA, Hann C. Extended release of active ingredients [P].US Pat:20020176842, 2002-11-28.
[32]Safadi MS, Barder M, Golander Y, Yacobi A, et al. Process for preparing non-hygroscopic sodium valproate composition [P].US Pat:2004208927,2004-10-21.
[33]Hughes L, Bellamy SA. Pharmaceutical formulation including a resinate and aversive agent [P].US Pat: 2004126428,2004-07-01.
[34]Will JP, Hughes L.Ion exchange resins for alleviation of upper gastrointestinal irritation [P].EP Pat: 1396265,2004-03-10.
[1]陈永健.离子交换树脂的性质[J].华东电力,1976,(S2):79-86.
[2]钱庭宝.离子交换树脂[J].高分子通报,1989,(1):51-56.
[3]陈家威.离子交换树脂的新进展[J].湖北化工,1993,(3):35-38.
[4]何炳林,王林富.离子交换树脂发展概况和展望[J].离子交换与吸附,1986,(4):1-16.
[5]Anand V, Kandarapu R, Garg S. Ion-exchange resins:carrying drug delivery forward[J]. Res Focus,2001, 6(7);905-914.
[6]史作清,马建标.离子交换树脂和吸附树脂的开发与生产[J].离子交换与吸附,1989,(1):89-90.
[7]何炳林,史作清.大孔离子交换树脂及新型吸附树脂的结构与性能[J].高分子通报,2005,(4):13-19.
[8]江邦和,胡晓忠,邬行彦.离子交换与吸附树脂在中药有效成分提取中的应用[J].离子交换与吸附,2001,17(4):379-384.
[9]刘喜纲,刘翠哲,王栋.离子交换树脂在医药方面的应用[J].承德医学院学报,2004,21(3):243-244.
[10]解小刚,贺永莲,邓盛齐.离子交换树脂在药剂学中的应用进展[J].中国新药杂志,2006,15(2):83-86.
[11]陶祖贻.离子交换树脂酸碱性的测定[J].离子交换与吸附,1991,7(4):307-313.
[12]马凤国,廖双泉,周贵忠,等.超强吸水树脂的吸水性能研究[J].高分子材料科学与工程,2002,18(5):199-201.
[13]赵志祥.对离子交换树脂性能测定的分析[J].江苏电机工程,2005,24(1):56-57.
[14]曾环想,程刚,黄凯,等.磷酸可待因在安伯来特IRP-69上的离子交换平衡特性研究[J].离子交换与吸附,2008,24(1):64-72.
[15]高向阳,宁莲军,张平安,等.超声波处理快速测定离子交换树脂的交换容量[J].中国卫生检验杂志,2004,14(4):441-442.
[16]关美银.关于阴阳离子交换树脂处理方法的建议[J].中国卫生检验杂志,2002,12(6):652.
[1]郑萍,戴贵东,李汉青.麻黄碱及伪麻黄碱药理作用研究进展[J].宁夏医学杂志,2002,24(2):126-127.
[2]史宇翔,苏嫦娥.中美两国OTC药物中伪麻黄碱的应用[J]:中国药师,2001,4(3):225-226.
[3]洪琅.阿齐红霉素的基础研究与临床评价[J].中国药学杂志,1995,30(11):687.
[4]高春林,蒋明海。阿奇霉素制剂研究进展.齐齐哈尔大学学报,2007,23(5):14-18.
[5]国家药典委员会编.中国药典2005年版临床用药须知[M],北京:人民卫生出版社,2005,239-240.
[6]Thomson PDR. Physicians' Desk reference,60 edition, Thomson Healthcare, Inc., Montvale,2006, 1844-1852.
[7]张兴成.抗组胺药的临床应用[J].中国农村医学,1993,21(5):55-56.
[8]Sweetman S.C. Martindale:The Complete Drug Reference,34 edition, The Pharmaceutical Press, London, 2005,427-428.
[9]岳宁.防止盐酸伪麻黄碱成品结块的研究[J].中国医药工业杂志,1983,(1):19-21.
[10]李俐,支玲,陈坚.盐酸伪麻黄碱生产工艺改革[J].新疆医科大学学报,2003,26(6):544-545.
[11]庄愉.克拉霉素与阿奇霉素简介.中国药事,1995,(5):287-307.
[12]国内罗红霉素、克拉霉素、阿奇霉素药物不良反应回顾性分析.中国新药与临床杂志,2006,25(8):590-595.
[13]苏明寿.浅谈可待因在液体药物制剂中的稳定性[J].青海医药杂志,1995,25(8):65-67.
[14]洪明莹.我院2004年止咳类药物的应用分析[J].中国药物滥用防止杂志,2006,12(1):53-54.
[15]陈锡林,徐世松.抗组胺药对普通感冒的疗效[J].国外医学药学分册,1981,(6):372.
[16]辛伟,邹梅娟,郑东,等.复方盐酸伪麻黄碱缓释微丸的制备及其释放度考察[J].沈阳药科大学学报,2007,24(10):593-597.
[17]祝莉莎,马晓峰,胡军,等.盐酸伪麻黄碱中有关物质的HPLC测定[J].中国医药工业杂志,2004,35(2):101-102.
[18]王丽荣,王国兰,余立.阿奇霉素干混悬剂溶出度方法的建立.中国药品标准,2007,8(4):24-26.
[19]陈悦,俞忻璐,姜晓丽.反相HPLC法测定阿奇霉素软胶囊的含量.中国抗生素杂志,2007,32(7):414-418.
[20]盛俊泰,张瑞琛,周娟.HPLC法测定阿奇霉素葡萄糖注射液中阿奇霉素的含量.化学分析计量,2002,(3):17-18.
[21]马素英.分光光度法测定阿奇霉素片的含量.儿科药学杂志,2007,13(4):53-58.
[22]Patricia Zubata, Rita Ceresole, et al.A new HPLC method for azithromycin quantitation[J].J.Pharm Biomed. Anal.2002,27:833-836.
[23]Miguel L., Barbas C..LC determination of impurities in azithromycin tablets[J].J.Pharm Biomed. Anal. 2003,33:211-217.
[24]A.Sher et al. Spectroscopic and polarographic investigations of copper-azithromycin interactions under equilibrium conditions[J].Int J. Pharm.1996,133:237-244.
[25]王天鹅.尴尬可待因[J].中国社区医师,2006,22(21):3-6.
[26]李小清.高效液相色谱法测定复方磷酸可待因溶液中的扑尔敏含量[J].中国药业,2001,10(1):29-30.
[27]何伟,玉宁.小儿镇咳合剂中磷酸可待因的HPLC测定[J].中国医药工业杂志,1997,28(8):371-372.
[28]尹宁宁,习超鹏.HPLC法测定枇杷止咳含片中磷酸可待因的含量[J].山东中医杂志,2007,26(7):483-484.
[29]杜彦梅,张振华,张兰桐,等.高效液相色谱法测定联邦止咳露多组分含量[J].河北医科大学学报,2000,21(3):138-139.
[30]Darry J. H.,Cheung H.Y. A chromatographic method for rapid and simultaneous analysis of codeine phosphate, ephedrine HCl and chlorpheniramine maleate in cough-cold syrup formulation. J. Pharm. Biomed. Anal.,2003,30:1595-1601.
[1]Mertin D, Daube G, Edingloh M. Pharmaceutical preparations for oral administration, containing ion-exchange resins loaded with active ingredients and intrinsically viscous gelling agents as thickening agents [P].CA Pat:2487648,2003-12-11.
[2]Nasr Z. Misk. Adsorption isotherms in ion exchange reactions. Further treatments and remarks on the application of the Langmuir isotherm [J].Colloids and Surfaces,1995,97:129-140.
[3]Anand V, Kandarapu R, Garg S.Ion-exchange resins:carrying drug delivery forward [J].Res Focus,2001, 6(7);905-914.
[4]W.J. Irwin, K.A. Belaid, H.O. Alpar, Drug-delivery by ion-exchange:Part Ⅲ. Interaction of ester pro-drugs of propranolol with cationic exchange resins [J].Drug Dev. Ind. Pharm.1987,13:2047-2066.
[5]O.L. Sprockel, W. Prapaitrakul, Effect of eluant properties on drug release from cellulose acetate butyrate-coated drug resin complexes [J].Int. J. Pharm.1988,48:217-222.
[6]G.E. Boyd, A.W. Adamson, L.S. Mayers, The exchange adsorption of ions from aqueous solutions by organic zeolites:Ⅱ. Kinetics [J].J. Am. Chem. Soc.1947,69:2836-2848.
[7]Irwin WJ, MacHale R, Watts PJ. Drug-delivery by ion exchange. Part Ⅶ:Release of acidic drugs from anionic exchange resinate complexes[J].Drug Dev Ind Pharm,1990,16(6):883-898.
[8]Sriwongjanya M, Bodmeier R. Effect of ion exchange resins on the drug release from matrix tablets[J].Eur J Pharm Biopharm,1998,46(3):321-327.
[9]刘宏飞,王铭洲,潘卫三.离子交换树脂在药物制剂中的应用,中国药剂学杂志,2007,5(4):216-219.
[10]Hughes L. Ion Exchange Resins. Unique Solutions to Formulation Problems [J].Pharmaceutical Technology,2004,28(6):20-25.
[11]Pongjanyakul T., Prakongpan S.,Rungsardthong U.,et al. Characteristics and in vitro release of dextromethorphan resonates [J].Powder Technology,2005,152:100-106.
[12]Raghunathan Y., Amsel L., Hinsvark O., Bryant W.Sustained-release drug delivery system:I. Coated ion-exchange resin system for phenylpropanolamine and other drugs[J].J. Pharm. Sci.,1981,70:379-384.
[13]李莉,陈坚,李新霞.硫酸伪麻黄碱的研制[J].中国药学杂志,2005,40(23):1829-1831.
[14]Martindale:the complete drug reference[M],34 edition, published by the Pharmaceutical Press in 2005. Pseudoephedrine:1129-1130.
[15]曾环想,程刚,潘卫三.离子交换树脂在药物传递系统中的应用[J].中国现代应用药学杂志,2006,23(8):762-764.
[16]Bhaskar R., Murthy R.S.R., Miglani B.D., et al. Novel method to evaluate diffusion controlled release of drug from resinate, Int. J. Pharm.1986,28:59-66.
[17]洪琅.阿齐红霉素的基础研究与临床评价[J].中国药学杂志,1995,30(11):687.
[18]Martindale:the complete drug reference[M],34 edition, published by the Pharmaceutical Press in 2005. Azithromycin:159-160.
[19]王优杰,冯怡,徐德生等,药物掩味技术的研发进展与应用[J].中国药学杂志,2006,41(19):1444-1448
[20]张小滨,侯新朴,掩盖药物不良臭味的研发进展[J].中国医院药学杂志,2003,23(1):43-45
[21]何琪莹,吕万良,张强.注射用阿奇霉素的成盐剂的研究[J].中国抗生素杂志,2005,30(4):204-207.
[22]黎玲,王东凯.盐酸阿奇霉素注射液的处方及制备工艺研究[J].中国药剂学杂志,2005,3(4):176-179.
[23]Fiese E. F..Comparision of the acid stability of azithromycin and erythromycin A [J].Antimicrob Chemother,1990,25(S-A):39-47.
[24]邹龙贵,抗生素粉体掩味包衣工艺及设备[J].医药工程设计,2006,27(5):48-51.
[25]Gao R, Shao ZJ, Fan ACL,et al.Taste masking of oral quinolone liquid preparations using ion exchange resins [P].AU Pat:777993,2004-11-11.
[26]Sakamoto K, Tsubokura Y, Takamori Y.Aqueous glucosamine salt solution improved in taste and method for producing the same. [P].JP pat:2003204770,2003-07-22.
[27]Cotterill JV, Massei G, Cowan DP. Masking the taste of the conditioned taste aversion agent levamisole using an ion-exchange resin, for practical application in wildlife management [J].Pest Manag Sci,2006,62(2):120-125.
[28]Hughes L. Ion Exchange Resins:Unique Solutions to Formulation Problems [J].Pharmaceutical Technology,2004,28(6):20-25.
[29]Anand V, Kandarapu R, Garg S. Ion-exchange resins:carrying drug delivery forward [J].Res Focus,2001, 6(7):905-914.
[30]姜志新.离子交换动力学及其应用[J].离子交换与吸附,1989,5:54-73,221-233.
[31]国家药典委员会编.中华人民共和国药典临床用药须知[M],2005年版.北京:人民卫生出版社,磷酸可待因:239-240.
[32]国家药典委员会编.中华人民共和国药典临床用药须知[M],2005年版.北京:人民卫生出版社,马来酸氯苯那敏:734-735.
[33]Garwal R., Mital R., Singh A.. Studies of ion exchange resin complex of chloroquine phosphate[J].Drug Dev Ind Pharm,2000,26(7):773-776.
[34]Bhaskar R, Murthy RSR,Miglani BD,et al.Novel method to evaluate diffusion-controlled release of drug from resinate[J].Int. J. Pharm.,1986,28(1),59-66.
[35]Higuchi T.Mechanism of sustained action medication:theoretical analysis of rate of release of solid drugs dispersed in solid matrices[J].J Pharm Sci,1963,52(12):1145-1149.
[36]Hiroki Tamura. Theorization on ion-exchange equilibria:activity of species in 2-D phases. J. Colloid Interface Sci.2004,279:1-22.
[37]Frenning G., Stromme M.. Drug release modeled by dissolution, diffusion, and immobilization, Int. J. Pharm.2003,250(1):137-145.
[38]Goran Frenning. Theoretical analysis of the release of slowly dissolving drugs from spherical matrix systems. J. Control. Release,2004,95:109-117.
[1]周松,陈腾.微囊化技术在药物研究中的应用[J].医药导报,2007,26(2):179-181.
[2]刘怡,冯怡,徐德生.微囊机械性质评价方法的研究进展[J].华西药学杂志,2007,22(2):195-197.
[3]Jones DS, Pearce KJ. An investigation of the effects of some process variables on the microencapsulation of propranolol hydrochloride by the solvent evaporation method [J].Int J Pharm.1995,118:199-205.
[4]Torres D, Seijo B, Garcia-Encina G, et al. Microencapsulation of ion-exchange resins by interfacial nylon polymerization [J].Int J Pharm.1990,59:9-17.
[5]Alex R, Bodmeier R. Encapsulation of water soluble drugs by modified solvent evaporation method, I: effect of process and formulation variables on drug entrapment [J].J Microencapsul.1990,7:347-355.
[6]Motycka S.,Nairn J. G.Preparation and evaluation of microencapsulated ion-exchange resin beads [J].J Pharm Sci,1978,68(2):211-215.
[7]Zhang Z-Y, Ping Q-N, Xiao B.Microencapsulation and characterization of Tramadol-resin complexes [J].J Control Release.2000,66(2-3):107-113.
[8]Torres D, Boado L, Blanko D,et al. Comparison between aqueous and non-aqueous solvent evaporation methods for micro-encapsulation of drug-resin complexes [J].Int J Pharm.1998,173:171-182.
[9]Motycka S..Newth J. L,Nairn J. G.. Preparation and evaluation of microencapsulated and coated ion-exchange resin beads containing theophylline [J].J Pharm Sci,1985,74:643-646.
[10]Martindale:the complete drug reference[M],34 edition, published by the Pharmaceutical Press in 2005. Codeine:27-28.
[11]Martindale:the complete drug reference[M],34 edition, published by the Pharmaceutical Press in 2005. Chlorpheniramine maleate:427-428.
[12]史宁,崔光华.流化床包衣制备微囊技术的发展及应用[J].国外医学药学分册,2002,29(6):336-340.
[13]Knezevic Z, Gosak D,Hraster M, et al.Fluid-bed microencapsulation of ascorbic acid [J].J Microencapsul,1998,15(2):237-252.
[14]Rubino OP. Fluid2bed technology overview and criteria for process selection[J].Pharm Tech,1999,23 (6):104-113.
[15]Watano S,Suzuki T, Taira T, et al.Continuous monitoring and mechanism of electrostatic charge of powder in fluidized bed process [J].Chem Pharm Bull,1998,46(9):1438-1441.
[16]Sprockel OL, Price J.C. Evaluation of sustained release aqueous suspensions containing microencapsulated drug resin complexes. Drug Dev. Ind. Pharm,1989,15:1275-1287.
[17]Sprockel OL, Price JC. Development of an emulsion-solvent evaporation technique for microencapsulation of drug-resin complex. Drug Dev Ind Pharm.1990,16:361-376.
[18]乔吉超,胡小玲,张团红等.溶剂蒸发法制备药物微胶囊研究进展[J].化工进展,2006,(8):42-46.
[19]邢福保,成国祥,杨炳兴,等.微囊微球的物理化学制备技术及其应用研究进展[J].胶体与聚合物,2003,21(2):39-42.
[20]熊迎新,尹宗宁.表面修饰对药物靶向性的影响[J].中国新药杂志,2004,13(12):1275-1279.
[21]胡云霞,原续波,张晓金,等.聚乳酸载药纳米微粒的表面修饰及体外评价[J].中国生物医学工程学报,2004,23(1):33-39.
[22]朱子春,光洁,李春梅.载药纳米粒子的表面修饰与改性[J].池州师专学报,2007,21(3).43-46.
[23]何朝辉,孔桦,许海燕.药物和基因载体树枝状大分子的生物学效应及表面修饰研究进展[J].中国医学科学院学报,2006,28(4):590-595.
[1]Leon Shargel, Andrew B. C. Yu. Applied Biopharmaceutics & Pharmacokinetics[M].Fouth edition. USA: Prentice Hall International,1999.
[2]王广基主编.药物代谢动力学[M],第1版.北京:化学工业出版社,2005.
[3]赵香兰主编.临床药代动力学基础与应用[M],第1版.郑州:郑州大学出版社,2002.
[4]魏树礼.生物药剂与药物动力学[M],第1版.北京:北京医科大学出版社,1997.
[5]孙瑞元,郑青山.数学药理学新论[M],第1版.北京:人民卫生出版社,2004.
[6]任斌,何林,胡继承,等.磷酸可待因缓释片人体药物动力学及生物利用度[J].中国临床药学杂志,1999,8(6):343-346.
[7]夏春华,熊玉卿.反相高效液相色谱法测定人体血浆中氯苯那敏的浓度[J].药物分析杂志,2002,22(6):443-445.
[8]刘蕾,孙春华.液质联用测定人血浆中氯雷他定的浓度及人体药动学研究[J].药物分析杂志,2003,23(5):325-327.
[9]李小燕,陈笑艳,顾琦,等.LC/MS/MS法测定比格犬血将中特拉唑嗪及其在药物动力学研究中的应用[J].药物分析杂志,2004,24(1):14-17.
[10]肇丽梅,赵立,孙亚欣.LC/MS/MS法测定血浆中左羟丙哌嗪浓度用其药代动力学[J].药学学报,2004,39(12):993-996.
[11]Salem 1.1., Saif W.A., Jmeian Y., et al. A selective and rapid method for the quantification of captopril in human plasma using liquid chromatography/selected reaction monitoring mass spectrometry[J].J. Pharm. Biomed. Anal.2005,37:1073-1080.
[12]Zhu Y.X., Chiang H., Radcliffe M.W, et al. Liquid chromatography/tandem mass spectrometry for the determination of carbamazepine and its main metabolite in rat plasma utilizing an automated blood sampling system[J]. J. Pharm. Biomed. Anal.2005,38:119-125.