中药凝胶贴膏成型工艺参数筛选和质量属性评价研究

发布时间：2018-05-04 16:14

本文选题：工艺参数 + 近红外　；参考：《北京中医药大学》2017年硕士论文

【摘要】：目的:凝胶贴膏是中药外用制剂的常用剂型,是中医儿科等临床优势病种广泛运用的现代中药制剂。然而,中药凝胶贴膏工艺参数通常采用感官和经验判断,缺乏客观和量化的评价体系,本文采用近红外技术、近红外成像技术和流变学等新技术,辨识凝胶贴膏制备过程的关键质量属性,分析中药提取物的加入对凝胶贴膏成型的影响,优选影响凝胶贴膏成型过程的关键工艺参数。方法:1.市售凝胶贴膏质量情况的研究(1)以6种不同品质等级市售凝胶贴膏为研究对象,采用黏附性指标实现不同品质等级市售凝胶贴膏的评价。(2)首次采用近红外成像技术,采用基础相关性分析方法(BACRA)对6种市售凝胶贴膏表面成像图进行分析,通过统计自相关的近红外成像光谱相关性计算结果,实现市售凝胶贴膏的表面均匀性评价。2.在课题组前期实验的基础上,以小儿退热处方为载体,采用外观性状结合高分子流变学技术以及近红外成像技术,研究中药浸膏的加入对中药凝胶贴膏成型的影响。(1)将提取所得的中药提取物浓缩成相对密度在1.0～1.4之间的浸膏,制备不同中药提取物密度的凝胶贴膏对其进行黏附力及感官评价。(2)采用流变学技术测定了不同相对密度中药提取物制成的凝胶贴膏膏体的线性粘弹区(LVR)、复数模量G*、弹性模量G'、粘性模量G"等指标,研究加入不同中药提取物制成的凝胶贴膏膏体的内部性质。(3)采用近红外成像技术对自制的加入不同相对密度中药提取物的凝胶贴膏表面近红外光谱扫描,通过近红外成像图及对膏体表面光谱进行统计,考察不同密度中药提取物制备的凝胶贴膏的表面均匀性。3.采用近红外技术监测中药凝胶贴膏成型过程中的的几个关键质量属性(1)采用近红外成像技术判断不同时间点物料混合的均匀性,确定了凝胶贴膏制备过程中的最佳搅拌时间。(2)采用近红外光谱技术,通过移动块标准偏差法(MBSD)计算方法,监测凝胶贴膏制备过程中基质的交联反应,确定了不同处方的快速交联反应时间,通过测定每隔24h胶强度变化率验证了用近红外光谱判断凝胶贴膏交联反应终点的科学性。(3)通过体外释放实验,测定凝胶贴膏基质不同交联时间药物释放度来判断凝胶贴膏基质的交联程度,验证采用近红外光谱技术判断交联反应终点的可靠性。结果:1.市售凝胶贴膏质量情况的调研(1)6个品牌的市售凝胶贴膏的初黏力和剥离强度差异较大;研究进一步得出初黏力在能粘住不小于9号小球的范围内均属合格,剥离强度在-0.11N--0.48N范围内属合格,以此获取了中药凝胶贴膏黏附力合格范围。(2)6个品牌成像图的可视化轮廓表达了不一样的均匀程度,品牌6光谱相关性的相对标准偏差高达23%,说明品牌6的凝胶贴膏表面分布非常不均匀,而品牌3的相对标准偏差最小,分布较均匀。本部分为后期自制中药凝胶贴膏的指标评价提供了方法和技术支撑。2.采用近红外成像结合高分子流变学技术,研究中药提取物的加入对中药凝胶贴膏成型的影响。(1)中药提取物的相对密度对凝胶贴膏成型的影响较大,提取物密度影响凝胶贴膏的粘接性能及交联强度。当中药提取物的相对密度为1.12时,凝胶贴膏的外观性状较好,不渗布,且黏性均较好。(2)当中药提取物的相对密度为1.12时,基质的复数模量G*值和线性粘弹区(LVR)较大,结果表明膏体结构强度大并且结构稳定,表现出"强凝胶"的特性。本部分发现了凝胶贴膏表面性质和内部性质存在相关性,获取了较优凝胶贴膏的系列指标,为后期中药凝胶贴膏制备提供了技术和指标支撑。(3)当加入的中药浸膏的相对密度为1.049和1.12时,凝胶贴膏表面光谱之间的相对标准偏差为1%,表面分布较均匀,此方法取代了只用肉眼观察的感官指标产生的差异,使中药凝胶贴膏的评价更标准化、客观化。3.采用近红外技术监测中药凝胶贴膏制备过程中的的几个关键质量属性(1)在膏体混合至20min时,膏体表面光谱的吸光度差别最小(RSD=0.01),中药浸膏膏体已经混合均匀,因此最终确定当物料混合20min后形成的凝胶膏体表面较均匀且利于涂布。(2)近红外光谱可以监测到胶强度24h变化率为10%左右光谱的变化,当胶强度24h的变化率低于10%时,即凝胶贴膏体系进入慢速反应期,近红外光谱测得的凝胶贴膏表面光谱无变化。通过对比不同处方制备的凝胶贴膏的胶强度及交联反应时间,发现得出了各物料对凝胶贴膏胶强度及交联反应速度的影响。(3)通过测定不同交联时间药物累积释放率,3个处方分别在72h,72h,120h时,所含药物的累积释放率最大,说明此时3个处方的凝胶贴膏在快速交联反应终点的附近。本实验的结果与采用近红外光谱技术监测得到的交联反应终点的时间基本一致,可以验证近红外光谱技术判断交联反应终点的可靠性。结论:本文采用多种新技术尝试构建了中药凝胶贴膏成型工艺参数筛选和成品的质量评价方法体系。采用近红外成像技术实现了市售凝胶贴膏和自制凝胶贴膏表面均匀性评价,使凝胶贴膏的评价更客观、准确;采用流变学技术发现了不同处方制备的凝胶贴膏的内部性质,找出了中药提取物的加入对凝胶贴膏基质的影响,比较了不同处方下凝胶贴膏的黏附性及粘弹性,并确定了最优处方;采用近红外光谱技术实现了凝胶贴膏成型过程中的关键质量参数监测并发现了最优参数值;本文构建的方法体系使中药凝胶贴膏的评价更加准确、客观,保证了凝胶贴膏的质量均一、稳定、可控。
[Abstract]:Objective: gel paste is a common dosage form of traditional Chinese medicine for external use. It is a modern traditional Chinese medicine preparation which is widely used by clinical dominant diseases such as pediatrics of traditional Chinese medicine. However, the technical parameters of gel paste are usually judged by sensory and experience and lack objective and quantitative evaluation system. Near infrared imaging technology, near infrared imaging technology and rheology are used in this paper. The new technology identifies the key quality attributes of the gel paste preparation process, analyzes the effect of the addition of Chinese medicine extract on the gelation of gel paste, and selects the key technological parameters that affect the gelation process of gel paste. Method: Study on the quality of gel plaster in the 1. cities (1) to study the gel plaster of 6 kinds of different quality grades. The adhesion index was used to evaluate the gel ointment of different quality grades. (2) the surface imaging of 6 kinds of gel paste was analyzed by the near infrared imaging technique and the basic correlation analysis method (BACRA) was used for the first time. The surface of the market gel paste surface was realized by the statistical autocorrelation calculation of correlation near infrared imaging spectra. On the basis of the preliminary experiment of the project group,.2. was used as the carrier of the antipyretic prescription of the children. The effect of the addition of the Chinese herbal extract on the gelation of the traditional Chinese medicine gel paste was studied by using the appearance character, the polymer rheology technology and the near infrared imaging technology. (1) the extract of the extracted Chinese medicine was condensed into a relative density of 1 to 1.4. The adhesive force and sensory evaluation of the gel ointment with the density of different Chinese herbal extracts were prepared. (2) the linear viscoelastic area (LVR), the complex modulus G*, the elastic modulus G'and the viscosity G "G" were measured by rheology. The internal properties of the gel paste paste made of the material. (3) near infrared scanning of the gel paste surface with different relative density of Chinese herbal extract with near infrared imaging technology, and the surface of the gel paste prepared by different density Chinese herbal extracts were investigated by the near infrared imaging and the statistics of the surface spectrum of the paste. The homogeneous.3. uses near infrared technology to monitor several key quality attributes in the forming process of traditional Chinese medicine gel plaster (1) using near infrared imaging technology to determine the uniformity of material mixing at different time points, and determine the optimum stirring time in the process of gel paste preparation. (2) using near infrared spectroscopy and mobile block standard deviation method (MBSD ) the calculation method was used to monitor the crosslinking reaction of the matrix in the gel paste preparation process and determine the rapid crosslinking reaction time of different prescriptions. By measuring the change rate of each 24h glue strength, the scientific character of the near infrared spectrum to judge the crosslinking reaction end point of gel paste was verified. (3) the different crosslinking of the gel paste matrix was determined by the release experiment in vitro. The degree of time drug release was used to determine the crosslinking degree of the gel paste matrix, and the reliability of the crosslinking reaction end was determined by near infrared spectroscopy. Results: 1. research on the quality of the gel plaster (1) the difference of the initial adhesion and stripping strength of the 6 brands of the market gel paste was different. The range of no less than No. 9 is qualified, and the peeling strength is qualified within the range of -0.11N--0.48N, so as to obtain the qualified scope of the adhesive force of the traditional Chinese medicine gel paste. (2) the visual contour of the 6 brand image maps expressed the different degree of uniformity, and the relative standard deviation of the brand 6 spectral correlation is as high as 23%, indicating the gel paste of the brand 6. The surface distribution of the paste is very uneven, while the relative standard deviation of the brand 3 is the smallest and the distribution is more uniform. This part provides a method and technical support for the index evaluation of the later homemade traditional Chinese medicine gel paste. The effect of the addition of Chinese medicine extract on the gelation of the traditional Chinese medicine gel has been studied by the method and technical support.2.. (1) The relative density of the extract of traditional Chinese medicine has great influence on the gelation of gel paste, and the density of the extract affects the adhesion and crosslinking strength of the gel paste. When the relative density of the extract of Chinese medicine is 1.12, the appearance of the gel paste is better, and the stickiness is better. (2) when the relative density of the extract of Chinese medicine is 1.12, the matrix is recovered. The G* value of modulus and the linear viscoelastic zone (LVR) are large. The results show that the structure of the paste is strong and the structure is stable, showing the characteristics of "strong gel". This part found the correlation between the surface properties and the internal properties of the gel paste, and obtained a series of better gel paste, which provides the technology and index for the preparation of the later gelatin plaster. Support. (3) when the relative density of the Chinese herbal extract is 1.049 and 1.12, the relative standard deviation between the surface spectrum of the gel paste surface is 1% and the surface distribution is more uniform. This method takes the place of the difference of the sensory indexes only observed by the naked eye, so that the evaluation of the gel paste is more standardized, and the objective.3. is used in the near infrared technology monitoring. Several key quality attributes in the preparation of the gel paste (1) when the paste is mixed to 20min, the absorbance difference of the surface spectrum of the paste is minimal (RSD=0.01), and the extract paste has been mixed evenly. Therefore, the surface of the gel paste formed when the material is mixed with 20min is more uniform and is beneficial to coating. (2) near infrared spectroscopy can be used. The change rate of the adhesive strength 24h is about 10%. When the change rate of the adhesive strength 24h is below 10%, the gel paste system enters the slow reaction period and the gel paste surface spectrum of the gel paste has no change. The effect of the material on the strength of gel adhesive and the rate of cross-linking reaction. (3) the cumulative release rate of the drugs was the largest by measuring the cumulative release rate of drugs at different crosslinks at 72h, 72h and 120h, indicating that the gel paste of 3 prescriptions was near the fast crosslinking reaction end point at this time. The results of this experiment and the use of the near infrared light were the result of this experiment. The time of the cross-linking reaction end of the spectrum technology is basically the same, it can verify the reliability of the near infrared spectroscopy to determine the crosslinking reaction end point. Conclusion: in this paper, a variety of new technologies are used to construct the method of screening the processing parameters of the gelatin plaster and the quality evaluation method of the finished product. The near infrared imaging technology is implemented. The evaluation of the surface uniformity of the gel paste and the homemade gel paste made the evaluation of the gel paste more objective and accurate. The internal properties of the gel paste prepared by different prescriptions were found by the rheology technology, and the effects of the addition of the extract on the gel paste matrix were found out, and the adhesion and adhesion of the gel paste under different prescriptions were compared. The optimal prescription was determined by elasticity, and the key quality parameters in the gelation process were monitored by near infrared spectroscopy and the optimal parameter was found. The method system constructed in this paper made the evaluation of the gel paste more accurate and objective, and the quality of gel paste was guaranteed, stable and controllable.

【学位授予单位】：北京中医药大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R283.6

【参考文献】