褐藻胶钙离子交联体系肠溶空心硬胶囊制备技术

发布时间：2018-05-02 05:01

本文选题：褐藻胶 + 交联　；参考：《中国海洋大学》2013年硕士论文

【摘要】：随着制药业的不断发展,肠溶胶囊市场的需求量不断增大。植物肠溶空心硬胶囊,不仅可以解决明胶胶囊原料自身性质缺陷和原料安全性问题,而且具有生物利用度高、剂量小、保护药物免受胃内酶类或胃酸的破坏等特点。以褐藻胶为原料制备肠溶胶囊,不仅开辟了褐藻资源高值化利用的新途径,同时形成了具有自主知识产权的褐藻胶肠溶空心硬胶囊生产技术。本论文在研究褐藻胶生物膜水蒸气透过系数的基础上,利用褐藻胶和Ca2+的交联作用制备出褐藻胶肠溶空心硬胶囊,并对其药物释放度和性能进行检测。主要研究内容如下： 1、研究了褐藻胶生物膜的水蒸气透过系数(WVP)。将WVP作为指标,通过单因素实验确定了最佳条件：甘油浓度为5%,褐藻胶浓度为8%,CMC浓度为0.1%,在氯化钙中交联时间为12分钟,氯化钙浓度2%。综合考虑各方面因素,固定甘油浓度为5%,氯化钙浓度为2%,选取影响褐藻胶生物膜的WVP三个关键因素：褐藻胶浓度、羧甲基纤维素钠浓度和在氯化钙溶液中的交联时间,进行Box-Behnken Design和响应面(RSM)分析,得到最优工艺条件：褐藻胶浓度、CMC浓度和在氯化钙溶液中的交联时间分别为8.04%,0.13%和12分钟。在最优条件下,实际测得的平均WVP为0.3898,与理论预测值0.3974相比,表达了很高的相关性。为后续制作褐藻胶肠溶空心硬胶囊提供了一定的指导意义。 2、以褐藻胶为主要原料制备了褐藻胶肠溶空心硬胶囊。通过实验在一次钙化法和两次钙化法中确定用两次钙化法制备胶囊,并分别研究了两次钙化的钙源、时间、浓度、温度和烘干条件对胶囊成型性的影响,得到了最佳第一次钙化条件：钙源为葡萄糖酸钙,钙化温度、时间、浓度分别为40℃、4min和4%,烘干温度、时间分别为50℃、1h；最佳第二次钙化条件：钙源为乳酸钙,钙化温度、时间和浓度分别为25℃、20min和6%时,烘干温度、时间分别为50℃、1.5h。在此条件下获得的胶囊无顶星顶凹现象,且拔壳易、硬度好。为我国植物肠溶空心硬胶囊开辟了新的发展道路。 3、对自制的褐藻胶肠溶空心硬胶囊进行了药物释放度的研究,并对胶囊按照药典和中国医药包装协会的要求进行了理化指标的检测。 (1)确定了L-谷氨酰胺在模拟胃溶液和模拟肠溶液中的吸收光谱,最终确定模拟胃环境实验选用285nm作为最佳测定波长,模拟肠环境实验选用264nm作为最佳测定波长。在确定最佳测定波长的基础上,考察了其分别在模拟胃、肠环境中的精密度、回收率和稳定性,结果表明：在模拟胃、肠环境中的精密度实验中,RSD值分别低于1.13%和1.54%；在模拟胃环境中,回收率在99.81～100.19%之间,RSD均在0.7%以下,在模拟肠环境中,回收率在99.91～100.23%之间,RSD均在0.5%以下；在模拟胃环境下,12h内的稳定性实验的RSD值均低于1.17%,在模拟肠环境下,12h内的稳定性实验的RSD值均低于1.52%,说明本品在12h内稳定,本方法具有良好的稳定性。自制的复方谷氨酰胺肠溶胶囊,在模拟胃环境中2h无药物释放,在模拟肠环境中第35分钟时,累计释放度已达标示量的70%,在60分钟时,累积释放度达92%,符合药典规定。 (2)对自制肠溶胶囊的规格尺寸进行检测,其帽体长度、单壁厚、口部外径均符合中国医药包装协会的规定。对自制肠溶胶囊的外观缺陷进行检测,其外观色泽均匀、有光泽、无明显色差,无裂缝、气泡、夹皱、异色点、刮痕、褶皱、切丝现象,符合中国医药包装协会的规定；对自制肠溶胶囊的理化指标进行检测,未出现漏粉、破裂现象,符合药典规定；在人工胃液中,胶囊2h不崩解,在人工肠液中,2分55秒开始崩解,符合药典规定；干燥失重值为10.98%,小于药典标准,含水量更低,比明胶胶囊更具优势；灼烧残渣值为1.08%；重金属铅、铬的含量均为0,符合药典规定；对自制肠溶胶囊的微生物限度进行检测,细菌总数为10CFU/g,霉菌、酵母菌、大肠埃希菌均未检出,符合药典规定。
[Abstract]:With the continuous development of the pharmaceutical industry, the demand for the enteric capsule Market is increasing. The plant enteric coated hollow hard capsules can not only solve the defects of the properties of the gelatin capsules and the safety of the raw materials, but also have the characteristics of high bioavailability, small dosage, and protection from the internal enzymes of the stomach or the destruction of gastric acid. The preparation of enteric coated capsules not only opens a new way for the high value utilization of alga resources, but also forms the production technology of seaweed gelatin enteric hollow hard capsules with independent intellectual property rights.
In this paper, on the basis of the water vapor transmission coefficient of alginate biofilm, the gelatin enteric hollow hard capsule was prepared by the crosslinking of alginate and Ca2+, and the drug release and performance were detected. The main contents are as follows:
1, the water vapor permeation coefficient (WVP) of the alginate biofilm was studied. The optimum conditions were determined by WVP as an index. The concentration of glycerol was 5%, the concentration of alginate was 8%, the concentration of CMC was 0.1%, the crosslinking time in calcium chloride was 12 minutes, the concentration of calcium chloride concentration 2%. combined with various factors, the concentration of fixed glycerol was 5%, calcium chloride was obtained. The concentration of WVP was 2%, and three key factors affecting the biofilm of alga were selected: alginate concentration, carboxymethyl cellulose sodium concentration and crosslinking time in calcium chloride solution, Box-Behnken Design and response surface (RSM) analysis were carried out. The optimum technological conditions were obtained: alginate concentration, CMC concentration and crosslinking time in calcium chloride solution, respectively. It is 8.04%, 0.13% and 12 minutes. Under the optimal conditions, the actual measured WVP is 0.3898, and the correlation is very high compared with the theoretical prediction value 0.3974. It provides a certain guiding significance for the subsequent preparation of alginate enteric hollow hard capsules.
2, alginate gelatin enteric hollow hard capsules were prepared with algin as the main raw material. The capsules were prepared by two calcification methods in the one calcification and two calcification methods, and the effects of calcium sources, time, concentration, temperature and drying conditions on the formation of the capsules were studied, and the optimum conditions for the first calcification were obtained. Calcium gluconate, calcium gluconate, temperature, time, concentration of 40 degrees, 4min and 4%, drying temperature, 50 degrees centigrade, 1H, the optimum second calcification conditions: calcium source is calcium lactate, calcium temperature, time and concentration are 25, 20min and 6%, drying temperature, time respectively 50 degrees, 1.5h. under the condition of the capsule without the top star It is a new development way for Chinese plant enteric hollow hollow capsule.
3, the drug release degree of the self-made alginate enteric coated hollow hard capsules was studied, and the physical and chemical indexes of the capsules were tested according to the Pharmacopoeia and the requirements of the Chinese Medicine Packaging Association.
(1) the absorption spectrum of L- glutamine in simulated gastric solution and simulated intestinal solution was determined. Finally, 285nm was selected as the best wavelength for simulated gastric environment experiment, and 264nm was selected as the best measurement wavelength in simulated intestinal environment experiment. On the basis of determining the optimum determination wavelength, the precision of the experiment was investigated in the simulated stomach and intestinal environment. Degree, recovery and stability, the results showed that the RSD values were lower than 1.13% and 1.54% in the simulated stomach and intestinal environment. In the simulated gastric environment, the recovery rate was from 99.81 to 100.19%, and the RSD was below 0.7%. In the simulated intestinal environment, the recovery rate was 99.91 to 100.23%, RSD was below 0.5%, 1 in the simulated stomach environment, 1 The RSD value of the stability test in 2H was lower than 1.17%. In the simulated intestinal environment, the RSD value of the stability test in 12h was lower than 1.52%. It indicated that the product was stable in 12h and the method had good stability. The self-made Compound Glutamin Entersoluble Capsules was not released in the simulated stomach environment and 2H was not released in the simulated intestinal environment, and was tired in the simulated intestinal environment for thirty-fifth minutes. The release rate of the meter has reached 70% of the indicated quantity, and the cumulative release rate reaches 92% at 60 minutes, which is in conformity with the Pharmacopoeia regulations.
(2) to test the size and size of the self-made enteric capsule, the length of the cap, the thickness of the single wall and the outer diameter of the mouth all conform to the regulations of the Chinese Medical Packaging Association. The appearance defects of the self-made enteric capsule are detected. The appearance of the capsule is uniform and lustrous, without obvious color difference, no crack, bubble, crease, color point, scratch, wrinkle and shredding. The physical and chemical indexes of the Chinese Medicine Packaging Association, testing the physical and chemical indexes of the self-made enteric capsule, did not appear to leak powder, rupture, conformed to the Pharmacopoeia regulations; in the artificial gastric juice, the capsule 2H did not collapse and began to disintegrate in the artificial intestinal fluid for 2 minutes and 55 seconds, which was in accordance with the Pharmacopoeia regulations; the dry weight loss value was 10.98%, less than the pharmacopoeia standard, the water content was lower, and the ratio. Gelatin capsule has more advantages, burning residue value is 1.08%, heavy metal lead and chromium content are 0, in accordance with the Pharmacopoeia regulations, the microbial limit of self-made enteric capsule is detected, the total number of bacteria is 10CFU/g, mould, yeast, Escherichia coli are not detected, in line with the Pharmacopoeia regulations.

【学位授予单位】：中国海洋大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：TQ460.1

【参考文献】