一种新型载药液晶凝胶系统的研究

发布时间：2018-05-24 10:56

本文选题：醋酸奥曲肽 + 液晶凝胶　；参考：《湖北中医药大学》2017年硕士论文

【摘要】：药物载体作为药物的传递中介,能对药物起保护作用,并使之能够被人体吸收,同时可实现药物的靶向作用,使其释放速率可控。随着科学技术的不断发展,许多新剂型逐渐被开发出来,例如微乳、亚微乳、脂质体、醇质体、微球、纳米材料、凝胶等药物载体的研究已取得重大进展。溶致液晶(Lyotropic liquid crystals,LLCs)作为一种新型的药物载体,也开始受到关注。作为药物载体时,溶致液晶能够提高药物的稳定性,防止蛋白、多肽等生物活性分子的酶解,并实现其在体内的持续释放,从而减少给药次数,给患者带来极大的便利。胃肠胰内分泌肿瘤(gastroenteropancreatic neuroendocrine tumors,GEP-NETs)是由胃、肠和胰腺中的神经内分泌细胞,在致癌因素的作用下所引发的疾病。通过药物治疗的方法,缓解肿瘤所造成的疾病症状,并抑制肿瘤的增长,控制原发病灶向周围部位转移,对于胃肠胰内分泌肿瘤疾病的缓解和治疗有较好的作用。醋酸奥曲肽是治疗该类肿瘤的常用药物之一。醋酸奥曲肽(octreotide acetate,OA)是一种生长抑素类似物,能结合胃、肠、胰中的生长抑素受体,并抑制这些部位多种激素的过度分泌,停药后不会引起激素分泌的反弹现象。目前,醋酸奥曲肽上市的剂型主要为注射剂型,常通过皮下注射和静脉滴注方式给药,但药物在体内的半衰期较短,需要频繁给药,因此给患者带来不便和痛苦,也造成经济上的负担。为了延长药物在给药部位的作用时间,增加其生物利用度,并降低用药的次数,本课题拟以具有良好的生物相容性的天然物质大豆卵磷脂(soya phosphatidyl choline,SPC)和二油酸甘油酯(glycerol dioleate,GDO)为原材料,并添加乙醇以降低体系的黏度,研制出一种具有药物缓释作用、遇水可发生胶凝反应的醋酸奥曲肽液晶前体制剂。本研究通过单因素实验,考察了乙醇用量以及SPC/GDO的配比对醋酸奥曲肽液晶凝胶前体的性质的影响。通过所形成体系的外观性能,确定了体系中无水乙醇的用量为15wt%,并通过对体系的成胶能力、通针性、流变学性质等进行考察,初步筛选出SPC和GDO的质量比的范围在70:30至30:70之间。通过偏光显微镜对体系的液晶结构进行了表征,同时结合不同体系的体外释放性质,对处方进行优化,最终确定该体系中SPC/GDO的配比为7:3(wt/wt)。经过处方优化得到的醋酸奥曲肽液晶凝胶前体为淡黄色、澄清透明的液体,在贮存条件下,具有良好的流动性和注射性能,经皮下给药注射到体内后,与体液接触即可形成凝胶状的半固体,从而延缓药物释放。通过旋转流变仪测定结果发现,加水前后该制剂的复数黏度(η~*)值具有显著差异。在剪切应力为20Pa、频率为0.1Hz的条件下,加水前制剂的η~*值仅为9.86×10-2Pas,而加水相变后其η~*值可达到6.22×103Pas,表明该制剂在体内具有较好的粘附性。建立醋酸奥曲肽液晶凝胶前体的质量控制方法,采用HPLC方法测定制剂中的药物含量,并对该方法的专属性、精密度、重复性、回收率等进行考察,经检验,该方法专属性强,且具有较好的精密度和重复性,通过该方法测得的样品含量符合规定。影响因素试验显示,醋酸奥曲肽液晶凝胶前体受到温度和光照的影响比较大,因此,应将制剂在避光的条件下冷藏保存。同时,为了避免空气中的水分对制剂造成的细微影响,可将制剂置于干燥的环境中保存,使制剂能够有更好的稳定性。本研究通过影响因素实验和长期稳定性实验,对醋酸奥曲肽液晶凝胶前体的外观性状和制剂中药物的含量进行了考察,从而考察不同因素对制剂稳定性的影响情况。实验结果显示,光照和温度对醋酸奥曲肽液晶凝胶前体的稳定性有较大影响,同时结合制剂本身的性质,应将其密封避光冷藏保存在干燥的贮存环境中。综上所述,本研究所制备的醋酸奥曲肽液晶凝胶前体具有较好的注射性能,经皮下给药后,形成的凝胶结构稳定,具有良好的药物缓释性能。
[Abstract]:As the mediator of drug delivery, drug carrier can protect the drug and can be absorbed by the body, and can be absorbed by the human body. At the same time, it can target the drug and make the release rate controllable. With the continuous development of science and technology, many new dosage forms have been developed gradually, such as microemulsion, microemulsion, liposomes, alcohol plastids, microspheres, nanomaterials, and coagulation. Significant progress has been made in the research of drug carriers such as glue. Lyotropic liquid crystals (LLCs), as a new drug carrier, has also been paid attention to. As a drug carrier, lyotropic liquid crystal can improve the stability of the drug, prevent the enzymatic hydrolysis of protein, polypeptide and other bioactive molecules, and realize its continuous release in the body. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is a neuroendocrine cell in the stomach, the intestines, and the pancreas, caused by the carcinogenic factors, and alleviated the symptoms of the tumor by drug treatment. Octreotide acetate (OA) is a somatostatin similar to the growth of somatostatin, which combines the growth of the stomach, the intestines, and the pancreas. Inhibin receptor, which inhibits the excessive secretion of a variety of hormones in these parts, does not cause the rebound of hormone secretion after stopping. At present, the main dosage forms of octreotide acetate are injection type, often by subcutaneous injection and intravenous drip, but the drug is short in the body and needs frequent administration, thus giving the patient a bad effect. In order to prolong the action time of the drug in the drug delivery area, increase its bioavailability and reduce the number of drugs, the subject is to use natural biocompatible soybean lecithin (soya phosphatidyl choline, SPC) and two oleate (glycerol dioleate, GDO) as raw materials. With the addition of ethanol in order to reduce the viscosity of the system, a liquid crystalline precursor preparation of octreotide acetate was developed with the drug release effect and a gelation reaction in water. The effect of the amount of ethanol and the ratio of SPC/GDO on the properties of the octreotide acetate precursor of the octreotide acetate was investigated by a single factor experiment. In appearance, the amount of anhydrous ethanol in the system was determined to be 15wt%, and the quality ratio of SPC and GDO was preliminarily screened from 70:30 to 30:70 by the sizing ability of the system, the needle property and the rheological properties. The structure of the liquid crystal of the system was characterized by polarizing microscope and combined with the body of different systems. The formulation was optimized, and the ratio of SPC/GDO was determined to be 7:3 (wt/wt) in the system. The precursor of octreotide acetate liquid crystal gel obtained by prescription was light yellow, clarified transparent liquid and had good fluidity and injection performance under storage conditions. After being injected subcutaneously into the body, the liquid was exposed to body fluid. The gelatinous semisolid can be formed to delay the drug release. The results of the rotation rheometer show that the value of the complex viscosity (ETA *) of the preparation before and after water is significant difference. Under the condition of the shear stress 20Pa and the frequency of 0.1Hz, the value of the ETA ~ * of the preparation before adding water is only 9.86 x 10-2Pas, and the value of the ETA * is 6.22 * 1 after the water adding phase change. 03Pas shows that the preparation has good adhesion in the body. The quality control method of the liquid crystal gel precursor of octreotide acetate is established, the content of the drug in the preparation is determined by HPLC method, and the specificity, precision, repeatability and recovery rate of the method are investigated. The method is highly specific and has good precision and good precision. Repeatability, the sample content measured by this method accords with the regulations. The influence factor test shows that the precursor of octreotide acetate liquid crystal is more affected by temperature and light, so the preparation should be kept under the condition of avoiding light. Meanwhile, in order to avoid the subtle influence of water in the air on the preparation, the preparation can be put into dry. The effect of different factors on the stability of the preparation of octreotide acetate liquid crystal gel was investigated by the influence factor experiment and the long-term stability test, and the effect of different factors on the stability of the preparation was investigated. The temperature has a great influence on the stability of the liquid crystal gel precursor of octreotide acetate. At the same time, it should be kept in a dry storage environment with the properties of the preparation itself. In summary, the precursor of the octreotide acetate liquid crystal gel prepared in this study has good injection performance and the gel junction formed after subcutaneous administration. It is stable and has good drug release properties.
【学位授予单位】：湖北中医药大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

【参考文献】