论文总字数：24538字

摘 要

洛索洛芬钠（Loxoprofen sodium) 为前体药物，属苯丙酸类非甾体消炎镇痛解热药，口服后能迅速吸收，以较高浓度分布于肝、肾及血浆中，镇痛作用强。临床上广泛用于治疗类风湿性关节炎、骨性关节炎、慢性风湿性关节炎等。原型药物口服达峰值时间约0.5h，t1 /2约1 ～ 1.5h，因此在临床应用中需频繁服用，给患者造成一定不便，因此，很适合制成缓控释制剂^[1]。目前制备洛索洛芬钠缓释，可使药物长时间释放，进而使体内血药浓度较长时间维持在有效浓度范围之内，从而减少了服药的次数，提高患者的顺应性。采用 HPMC 及 HPC 为主要骨架材料结合其他辅料制备体外释放12小时的洛索洛芬钠的缓释片^[2]。

本课题系统进行了洛索洛芬钠缓释片的制备;进行洛索洛芬纳缓释片释放度的测定，同时建立了高效液相色谱分析法，用于缓释片含量测定及处方前研究。在处方研究前，考察了洛索洛芬钠的理化性质。

1.洛索洛芬钠处方前研究

本文考察了洛索洛芬钠在不同溶媒中的溶解度及表观油水分配系数和洛索洛芬钠的稳定性，结果表明洛索洛芬钠对空气、光和热都很稳定，但吸湿性较强。洛索洛芬钠具有良好的水溶性；在磷酸盐缓冲液中的溶解度随pH增加而增大，而油水分配系数随pH增加而减小。这是因为在酸性条件下，洛索洛芬钠主要以共轭酸洛索洛芬的形式存在，其溶解度小而油水分配系数较大，因此给药体系的pH将直接影响洛索洛芬钠的经皮渗透速率和累计渗透量。

2.洛索洛芬钠缓释片处方筛选及工艺研究

按照中国药典2000年版附录XIXD中缓释、控释制剂指导原则，以缓释片在0-12h药物的释放度为判定标准，考察了处方因素、工艺因素及释放条件对释放的影响，制成了日服2次的缓释制剂。

关键词：洛索洛芬钠 缓释片 处方筛选 质量研究

Preparation of sustained-release tablets of sodium loxoprofen

Abstract

Loxoprofen sodium (Loxoprofen sodium) as a prodrug, is Phenylalanine non-steroidal anti-inflammatory analgesic antipyretic drugs, rapidly absorbed after oral administration, at a higher concentration distribution in the liver, kidney and plasma, the analgesic effect strong.Clinically widely used to treat rheumatoid arthritis, osteoarthritis, chronic rheumatoid arthritis.The prototype drug orally reached the peak time is about zero. 5h, t1 / 2 about 1 to 1. 5h, so the frequent need to take clinical applications, cause some inconvenience to the patient, so it is suitable for controlled release formulations prepared[1].Currently loxoprofen sodium sustained release preparation, can release the drug for a long time, and thus make the body a long time to maintain the plasma concentration within the effective concentration range, thereby reducing the number of medication to improve patient compliance.HPMC and HPC use as the main framework material in combination with other materials prepared in vitro release 12 hours of loxoprofen sodium tablets[2].

Measured before Lox sustained-release tablets, while the establishment of a high-performance liquid chromatography for the determination of sustained-release tablets and prescription; the subject system was prepared loxoprofen sodium sustained-release tablets the study. Before prescribing study investigated the physical and chemical properties of sodium loxoprofen.

Sodium prescription before loxoprofen

This paper examines the stability and solubility of sodium loxoprofen and apparent partition coefficient in different solvents. The results in Table sodium lox to air, light and heat are stable but hygroscopic. Loxoprofen sodium has a good water solubility; solubility in phosphate buffer with pH increase increases, but oil-water partition coefficient decreases with increasing pH. This is because under acidic conditions, sodium loxoprofen mainly loxoprofen conjugate acid form, its solubility and the larger partition coefficient, thus pH dosing system will directly affect sodium loxoprofen transdermal permeation rate and cumulative permeation amount.

Formulation and Preparation Sodium Sustained Release Tablets loxoprofen

According to Chinese Pharmacopoeia 2000 edition Appendix XIXD sustained release, controlled-release formulation of guidelines to sustained-release tablets of the drug in 0-12h criteria

investigated formulation factors affecting technical factors and conditions on the release of the release,made 2 times a day sustained-release formulation.

Key words: Sodium loxoprofen；Sustained Release Tablets；Formulation screening Quality Research；Phrmacokinetics

目 录

摘 要 I

Abstract II

第一章 文献综述 3

1.1研究背景 3

1.2洛索洛芬钠研究进展 3

1.2.1洛索洛芬钠的介绍 3

1.2.2 洛索洛芬钠的药理作用 4

1.2.3洛索洛芬钠的药代动力学研究 4

1.2.4洛索洛芬钠的临床应用 5

1.2.5 洛索洛芬钠制剂的研究进展 6

1.3 缓释片的研究进展 7

1.3.1 缓释片剂的分类 7

1.3.2缓释片剂中应用的辅料 8

1.3.3国内外缓释片的研究进展 8

1.4 立题依据及主要研究内容 8

1.4.1 立题依据 8

1.4.2 本课题研究内容 8

第二章 洛索洛芬钠理化性质及处方前研究 10

2.1 实验材料 10

2.1.1 仪器 10

2.1.2 试剂 10

2.2 实验部分 11

2.2.1洛索洛芬钠在不同溶剂中的紫外吸收 11

2.2.2洛索洛芬钠溶液的稳定性 11

2.2.3 洛索洛芬钠原料药的稳定性 11

2.2.4 洛索洛芬钠溶解度的测定 12

2.3 实验结果 12

2.3.1检测波长的确定 12

2.3.2洛索洛芬钠溶液的稳定性 12

2.3.2 洛索洛芬钠原料药的稳定性 13

2.3.4 洛索洛芬钠在不同溶剂中的溶解度 14

2.4 小结与讨论 15

第三章 洛索洛芬钠缓释片的处方及工艺研究 16

3.1 实验材料 16

3.1.1 仪器 16

3.1.2 试剂 16

3.2实验部分 17

3.2.1 释放度方法学的验证 17

3.2.2 洛索洛芬钠缓释片的制备工艺 18

3.2.3 洛索洛芬钠缓释片处方筛选 18

3.3 结果与讨论 18

3.3.1 释放度方法学的验证 18

3.3.2 洛索洛芬钠缓释片处方筛选 21

3.3结果与讨论 23

讨 论 25

参考文献 26

致谢 29

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