抗HP中药鸦胆子油胃内滞留微丸的制剂关键技术研究

The elimination of Helicobacter pylori (HP) is a clinical problem in the treatment and precaution of chronic gastric ulcer and gastric cancer. At present there has appeared different degrees of drug tolerance phenomena in the clinical practice of eradicating HP with antibiotics alone or with the standard triple therapy scheme. It has been found that Brucea javanica oil, a kind of unsaturated fatty oil extracted from fruits of Brucea javanica (L.) Merr. , can effectively inhibit HP, which suggested that it could be prepared as gastric retention preparation to extend its residence time in gastric areas, increase local drug concentration and promote its therapeutic effects. In this study, agar diffusion method is used to investigate the anti-HP effects of Brucea javanica oil in vitro. The design and screening of prescription includes the selection of hydrophilic gel matrix, erosion matrix, foaming agent and other accessories. Melt granulation technology is used to discuss the solidification conditions of Brucea javanica oil to explore an one-step process, with solidification and forming preparation. With the absorption fraction of physical process of the preparations and absorption process of the drugs, the correlation between an absorption behaviors in vivo and a release performance in vitro is to be explored, by which an objective evaluation method, suitable to gastric retention preparations with Chinese medicine will be established. The study is of positive significance to establish the key technology of the solidification of liquid oil and the preparation of multi-unit gastric retention preparations with Chinese medicine, and to seek a safer alternative option to solve the problem of HP tolerance with Chinese medicine.

根除幽门螺杆菌（HP）是临床慢性胃溃疡、胃癌的治疗和预防难点，目前抗生素单用或三联疗法已出现不同程度的耐药性问题。文献及前期研究表明鸦胆子油对HP有较好的抑制作用，将其制成胃内滞留制剂，可延长其胃内滞留时间，增加局部药物浓度，进而提高疗效。 课题以琼脂扩散法研究鸦胆子油体外抗HP作用，采用亲水凝胶骨架、溶蚀型骨架及起泡剂等辅料进行处方设计与筛选，以熔融制粒技术考察鸦胆子油固化工艺，探索实现鸦胆子油固化与制剂成型的一步化工艺，采用制剂体内物理过程与药物体内吸收分数，将制剂的体内数据分别与制剂体外释放行为之间进行体内外相关性研究，建立适用于中药胃内滞留制剂的体内外相关性客观评价方法。 课题对于液态油性中药的固化、多单元中药胃内滞留制剂等关键制剂技术的建立有积极意义，还将为临床上解决HP耐药性问题提供安全性好的中药替代性选择方案。

中药鸦胆子为苦木科（Simaroubaceae）植物鸦胆子Brucea jaranica (L.) Merr.的灰褐色长圆形或卵形果实。鸦胆子油为鸦胆子药材提取物，具有清热解毒、抗疟、抗炎和抗肿瘤的作用，可以治疗消化系统肿瘤、慢性胃炎、尖锐湿疣等疾病，对胃癌及胃溃疡的治疗有较好的临床表现。目前上市的鸦胆子油制剂有鸦胆子油口服乳液，鸦胆子油乳注射液和鸦胆子油软胶囊，但是鸦胆子油为植物脂肪油，其吸收差，生物利用度低，且上市剂型为全身吸收后再分布于治疗部位，治疗效果差，故本课题拟将其改制为胃内滞留制剂以提高其局部浓度，提高其治疗胃部疾病的局部靶向治疗作用。. 本课题建立了鸦胆子药材的HPLC-CAD测定法，对14批次药材中脂肪酸含量进行了指纹图谱、聚类分析及主成分分析研究。体外药效表明，鸦胆子油对于体外培养人胃癌细胞株BGC823、HGC27和SGC7901有明显的抑制生长作用，对乙醇致大鼠胃溃疡的预防程度与雷尼替丁相似，且具有一定的胃溃疡治疗作用。本课题摒弃了常规的β-环湖精包合固化技术，采用离子凝胶交联技术方法，实现鸦胆子油固化与制剂成型的一步化工艺；实验结果表明，适当浓度的海藻酸盐经交联后可以有效地将液态药物包裹，在加速条件下放置两个月后，微球外观性态圆整，无油性物渗出，胃内滞留型漂浮微球稳定性均良好。扫描电镜显示胃内滞留微球是一种内部中空、多孔道的结构体系，具有自漂浮能力，能够在胃组织内长时间滞留。体内示踪实验表明，胃滞留微球在大鼠胃内滞留时间均可达6 h以上，与参比制剂相比，在口服两种制剂6 h后，有超过一半的胃滞留微丸仍滞留于胃内。建立鸦胆子油的LC/MS/MS体内分析方法，考察了鸦胆子油中主要成分三油酸甘油酯在大鼠血浆和胃组织分布，评价了制剂的胃靶向性，表明其具有良好的缓释效果，能够达到6 h完全释放；同时，与普通市售制剂相比，该制剂在胃组织中的药物浓度6 h后达到最大值，是普通参比制剂的3倍，胃滞留制剂的血浆最高浓度是参比制剂的1000倍，表明胃滞留微球在胃组织具有良好的分布及靶向作用。