十二指肠定位释药系统—盐酸黄连素生物粘附包衣片的研究

【作者】 郑玲利；

【导师】 张志荣； 黄园；

【作者基本信息】 四川大学 ， 药剂学， 2006， 硕士

【摘要】 本文以对消化性溃疡有效的常用广谱抗菌药物盐酸黄连素为模型药物，研究制备了盐酸黄连素生物粘附包衣片，对其释药行为及释药机理进行了较为深入的探讨，并对其在十二指肠的靶向性进行研究。十二指肠溃疡是消化系统常见的慢性病，多发病，是指发生在十二指肠粘膜的缺损，症状主要为反复的周期性发作，节律的上腹区疼痛，常并发出血、穿孔，甚至癌变。随着生活节奏的加快，近年来发现本病发病率有逐年增高的趋势。因此，寻找疗效好、价格低廉的抗溃疡病药物是近年全世界关注的热点，也是新药研究开发的热点。目前临床常以抗幽门螺旋杆菌（Hp）为中心的三联、四联方案治疗，尚无单一药物具备好的疗效。本课题利用十二指肠溃疡特殊的pH值环境，采用自制pH3．6敏感的高分子材料醋酸羟丙基甲基纤维素顺丁烯二酸酯（Hydroxypropyl methylcellulose Acetate Maleate，HPMCAM）作为包衣材料，以羟丙基甲基纤维素(HPMC K_4M)和卡波姆（CP 934P）为粘附材料，将盐酸黄连素模型药物制成具有生物粘附性的pH敏感包衣片，包衣片在胃中衣膜不溶解，而在十二指肠溃疡特殊的pH值环境下衣膜迅速溶解，生物粘附片暴露出来，粘附于十二指肠壁，并释出药物，浓集于溃疡部位在一定时间内达到有效杀菌浓度，清除幽门螺旋杆菌，从而构建一种十二指肠定位释药系统。以HPMC为骨架，用偏苯三酸酐或顺丁烯二酸酐对HPMC改性，制备了高分子材料羟丙甲纤维素偏苯三酸酯类（Hydroxypropyl methylcellulose Trimellitate，HPMCT）和醋酸羟丙基甲基纤维素顺丁烯二酸酯类（Hydroxypropyl methylcellulose Acetate Maleate，HPMCAM）。用红外光谱和核磁共振法进行结构表征，证实两种聚合物确已合成。课题着重对pH敏感包衣材料的常规性能指标，如：成膜性、溶解性、酸值、pH敏感值、膜的透湿性、抗拉强度、玻璃化转变温度进行了初步探讨。实验证明，HPMCT和HPMCAM两种材料成膜性良好，具备药剂学薄膜衣材料的有关性质。通过改变原料配比、催化剂用量、溶剂用量、反应时间等反应条件，得到了pH敏感点不同的产物。HPMCT的pH敏感值在3．8～4．2，HPMCAM的pH敏感值在3．2～4．4。在盐酸黄连素片芯的制备工艺条件的研究中，选用生物粘附片为片芯。HPMC K_4M为粘附材料，通过单因素试验，得到以乳糖为填充剂，PVPK₃₀为粘附剂的生物粘附片Ⅰ；以HPMC K_4M和CP 934P为粘附材料，通过单因素试验和正交试验设计得到生物粘附片Ⅱ。体外粘附力测定结果表明：生物粘附片Ⅱ＞生物粘附片Ⅰ＞普通片。体外释放试验表明：生物粘附包衣片Ⅰ的释药曲线的优化拟合模型为Weibull分布模型，释药机制为溶蚀机理；生物粘附包衣片Ⅱ的释药曲线的优化拟合模型为Hixson-Crowell方程，释药机制为以溶蚀为主的非Fick扩散。参照中国药典2005版，建立了盐酸黄连素生物粘附包衣片的质量评价方法并进行了初步稳定性研究，包括影响因素试验、加速试验与长期试验，结果表明盐酸黄连素生物粘附包衣片的贮存条件为：密闭、干燥处保存。以beagle犬为试验对象进行胃肠道分布及药物动力学研究，建立了一种具有较高灵敏度和精密度的RP-HPLC法测定胃、十二指肠、远端小肠、大肠内容物的盐酸黄连素的浓度。试验组口服给予盐酸黄连素生物粘附包衣片（CBT），对照组给予相当剂量的市售普通片（IBT），试验结果表明，试验组和对照组在十二指肠的药—时曲线下面积(AUC_0-Tn)分别为14．723 ug·h·g^-1和5．032 ug·h·g^-1；C_max分别为4．630 ug·mL^-1和2．345ug·mL^-1；t_1／2分别为1．626h和1．573h；CLs分别为7．407 mg·g／kg／h／μg和18．569 mg·g／kg／h／μg，说明生物粘附包衣片可提高药物在十二指肠的浓度，减缓药物在十二指肠的排空速度，利于十二指肠溃疡等疾病的治疗。相对摄取率Re、靶向效率TE、相对靶向效率RTE和峰浓度比Ce等靶向评价指标均表明，CBT具有较强的十二指肠靶向性，能延长药物在十二指肠的滞留。更多还原

【Abstract】 Hydroxypropyl methylcellulose acetate maleate coated berberine chloride bioadhesive tablets were prepared in this research. Release behaviors and mechanism were investigated deeply. Furthermore, duodenum-specific drug delivery was studies.Duodenal ulcer （DU） is a kind of chronic disease commonly found in digesive system with the symptoms of repeated pain in the superior belly, periodically and regularly. It is believed as a defection occurred in the duodenal mucous membrane, usually followed by bleeding, perforation, and duodenal cancer. Up to now, there is no a single drug which can effectively deal with DU. Therefore, program about triple treatment or quadruple treatment was widely used in DU clinical therapy, which centered by drug eradicating the helicobacter pylori（Hp）.The aim of our study is establish a kind of duodenum-specific drug delivery system. Due to the special environmental pH of the ulcer duodenum, we synthesize pH sensitive polymer HPMCAM as a coating agent which dissolve at pH 3.6. On the basis, HPMCAM coated bioadhesive tablets were prepared which include HPMC-K_4M and carbopol-934P as bioadhesive materials. HPMCAM coated bioadhesive tablets can carry the therapeutics directly to the duodenum without drug release in the stomach, allowing the released drug to accumulate at the surface of the pathological ulcer, thereby achieving the function of a duodenum-specific and eradiation therapy for Hp.To obtain pH-sensitive HPMCT （Hydroxypropyl methylcellulose trimellitate） and HPMCAM （Hydroxypropyl methylcellulose acetate maleate） polymers, HPMC （Hydroxypropyl methylcellulose） as a base polymer was modified with trimellitic anhydride or maleic anhydrides at various degree of substitution. The structure of this polymer was characterized by FT-IR and ¹H-NMR. Its pharmaceutical properties such as film forming, dissolution behavior, acidity, pH-sensitive values, water vapor permeability of the free film, tensile strength and Tg were investigated. It proved that HPMCT and HPMCAM have good film forming and can be used as an ideal pharmaceutical coating material. Chang the reaction condition such as ration of reactants、the amount of the catalyst、the amount of solvents or reaction time, we can obtain HPMC derivatives that have slightly different pH sensitive point. The pH-sensitive value of HPMCAM can be controlled within the range 3.2-4.4 by adjusting the maleic anhydrides and acetic anhydrides ratios. However, the pH-sensitive value of HPMCT can be controlled within the range 3.8-4.2.Considering characteristics of berberine hydrochloride and the purpose of our project, we improve formulation and preparing method of tablet core on the basis of some preparing method of formulation. After HPMC-K4M was selected as bioadhesive polymer, the basic formulation of bioadhesive tablet I was formed, including lactose as fillers, PVP-K30 as adhesives. While HPMC-K_4M and carbopol-934P were selected, the basic formulation of bioadhesive tabet II was formed by orthogonal design. The result of adhesive force show that bioadhesive tabet II > bioadhesive tablet I > immediate released tablet. Study on drug release mechanism demonstrated that Weibull model could be used to the best describe the drug release curve of CBT I and Hixson-Crowell equation could be used to CBT II. The release mechanism of CBT I and II were proved to be erosion mechanism and non-Fickian diffusion, respectively.According to the regulations in Chinese Pharmacopoeia（2005）, a series of quality evaluation approaches were established for berberine hydrochloride HPMCAM coated bioadhesive tablets and a preliminary study on its stability, comprising influence factors test, accelerated test and long-term test, was also performed. It suggested that berberine hydrochloride HPMCAM coated bioadhesive tablet should be stored in a well-closed container, away from moisture.Distribution of berberine hydrochloride in the luminal contents of GI tract was measured after oral of CBT or equivalent dose of IBT to beagle. The pharmacokinetic parameters of test group and control group were as follows: AUC_0-Tn were 14.723 ug·h·g^-1 and 5.032 ug·h·g^-1 ;C_max were 4.630 ug·mL^-1 and 2.345ug·mL^-1; T_1/2 werel.626h and 1.573h; CLs were 7.407 mg·g/kg/h/μg and 18.569 mg·g/kg/h/μg, the result indicated that CBT could increase concentration of drug in duodenum, delay the time of evacuation in duodenum which is very important for the treatment of DU. Targeting index including Re、TE、RTE and Ce were evaluated, these results indicated that CBT had a good duodenum targeting efficiency in vivo and affect the extent of GI tract distribution.更多还原