胃溃疡靶向给药系统的构建及评价---以左金“有效组分”为例

The common problem faced by Chinese and Western medicines in the treatment of gastric ulcer diseases is the existence of gastric emptying phenomenon, ordinary preparations are difficult to stay in the stomach for a long time, and can’t form an effective and long-term drug concentration on the ulcer surface. Based on this, Our technical team has researched Zuojin gastric floating drug delivery system from 2010 to the present, the purpose is to prolong the retention time of drug in the stomach, the previous research results show that the new drug delivery system can better floating sustained 12 hours, the effect is also improved, but still can’t reach the ideal state.After we have repeated analysis, we believe that in the formulation of the design also has the following problems: firstly, we believe mistakenly that "gastric retention" is "gastric ulcer targeting". In fact, the drug "gastric retention" is far less than the effective concentration and the corresponding therapeutic concentration of the ulcer site, that is, "gastric retention" is not what we hope for "gastric ulcer targeting".secondly, the comprehensive advantages of traditional Chinese medicine composition did not play out, especially" Zuojin effective components "are not clear, resulting in extraction process can not be" effective components "to maximize the extraction.thirdly,The evaluation system of traditional Chinese medicine ulcerative target preparation with traditional Chinese Medicine.Based on this, we take the Zuojin pill as a model drug, the design of this project is the construction and evaluation of gastric ulcer targeted drug delivery system.

中西药制剂在治疗胃溃疡疾病中共同面临的问题是：由于“胃排空现象”的存在，普通制剂难以在胃内滞留较长时间，不能在溃疡表面形成有效的、长久的药物浓度。基于此，课题组从2010年起开始研究左金胃漂浮给药系统，其目的是延长药物在胃内的滞留时间，前期的研究成果表明，新的给药系统能较好地漂浮缓释12小时、疗效也有所增强，但仍然达不到理想状态。经反复分析，我们认为在剂型设计上还存在如下问题：首先，我们误认为“胃内滞留”就是“胃溃疡靶向”，其实，药物“胃内滞留”远达不到溃疡病灶部位的有效富集和相应的治疗浓度，即“胃内滞留”不是我们希望的“胃溃疡靶向”；其次，没有将中药多成分的综合优势发挥出来，尤其是左金“有效组分”不明确，造成提取过程不能将“有效组分”最大限度地提取出来；其三，中药溃疡靶向制剂缺乏具有中医特色的评价体系。基于此，我们以左金丸为模型药物，设计了本项目----胃溃疡靶向给药系统的构建及评价。

在中医防治胃溃疡疾病的研究中，课题组早期制备了左金胃漂浮缓释片，发现此类胃滞留制剂只能达到延长药物胃内滞留时间，而不具备胃溃疡靶向性，难以实现药物在溃疡病灶部位的有效富集和特异性释药，导致治疗效果不令人满意。由此，我们提出胃溃疡靶向的概念。另外，传统经方左金丸在治疗胃溃疡方面具有显著疗效，但由于化学成分复杂，方中多个组分对疗效的“贡献系数”无法量化，导致在工艺过程、质量标准、体内外研究中往往因缺乏“有效组分”及权重系数的客观依据而无法深入研究。.本项目首先建立左金及单味药材体外化学指纹图谱和体内血清药物化学指纹图谱，进行体内药效学实验，获得左金抗胃溃疡的药效学数据，建立“谱-效关系”数学模型，明确与药效作用密切相关的指纹峰族即“有效组分”，确定各组分对整个复方药效作用的贡献系数，在明确了有效组分的前提下，优化精制提取工艺，将有效组分最大限度地提取出来。然后，利用胃溃疡损伤部位与非损伤部位的电性差异原理以及EPR效应，优选高分子材料，以“左金方多成分”为模型药物进行胃溃疡靶向纳米粒的制备工艺研究，实现“左金方多成分”特异性的富集于胃溃疡病灶部位，在胃溃疡病灶部位靶向释药，提高药物生物利用度。建立符合中医诊断的胃溃疡动物模型，采用活体荧光成像技术、免疫指标检测技术、组织病理学等方法对胃溃疡靶向给药制剂进行靶向性、药效学研究，构建具有中医药特色的评价体系。.该研究通过体内外指纹图谱及药效学研究，建立谱效关联数学模型，阐明左金丸抗胃溃疡的“有效组分”，为完善左金丸的质量评价标准及进一步诠释其抗胃溃疡的药效物质基础提供科学依据。利用PLGA及其与mPEG的嵌段聚合物为载体，制备了左金方多成分纳米粒，表征结果均满足设计要求，具有一定的胃溃疡病灶部位的靶向性能。药效结果表明，左金方多成分纳米粒对乙醇刺激型胃溃疡有显著治疗作用，能够为今后中药复方多组分制备纳米制剂及胃溃疡靶向给药系统的研究提供一定的实验参考。