魔芋胶作为缓释骨架片载体材料应用的研究
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摘要
骨架片是缓释制剂的主要类型之一,它是将药物与一种或多种骨架材料和辅料通过制片工艺而成型的片状固体制剂。具有制备工艺简单,安全性能好,组方比较容易的特点,在缓释制剂开发中占有十分重要的地位。目前常用的缓控释材料根据来源和性质可分为天然与合成材料。与合成材料相比,天然材料具有廉价易得,安全性已被长期使用所证实等优点。
魔芋胶是一种从魔芋植物块茎中提取得到的水溶性、非离子型多糖材料,长期以来,被作为辅料用在食品及医药等行业,我国魔芋资源及其产量居世界第一,但其深加工及应用还比较缺乏,因此,如何开发其新的应用途径成为充分利用魔芋资源的关键。
本课题通过测定不同粘度规格KGM的休止角、临界相对湿度等物理常数对KGM理化性质行研究,结果发现,所用的三种粘度规格的KGM的流动性均符合粉末直接压片的要求,溶解性随粘度的增加而降低,溶胀性随黏度的增加而增加,介质的pH值、离子强度对KGM的溶解性、溶胀性、粘度影响均很小。环境湿度超过75 %以后,KGM吸湿量明显增加。
通过示差扫描量热分析对材料与其他处方成分的配伍性能进行研究发现,药物与辅料之间无相互作用。
建立了紫外分光光度法用于模型药物的溶解度,骨架片的体外释放度及主药含量的测定。
分别选择水溶性药物氨茶碱和微溶性药物阿司匹林作为模型药物,采用不同处方组成利用粉末直接压片和湿法制粒压片制得体外释放符合要求的亲水凝胶骨架片;通过体外释放试验考察了骨架片的处方组成,制备工艺,体外释放条件对药物释放的影响。体外释放度测定方法,释放介质pH及其离子强度、搅拌转速,辅助凝胶剂的种类及用量,凝胶剂比例,凝胶剂用量,填充剂种类对水溶性药物和水难溶性药物的体外释放均产生显著性影响;乳糖、MCC均加快药物释放,但影响程度不同;KGM粒度、主药粒度、制备工艺,压片压力对药物释放的影响相同。
采用不同的数学模型对骨架片的体外药物释放数据进行拟合,计算AIC值,并依据AIC值最小法筛选出药物释放的最佳拟合模型—Peppas方程;采用重量法对体外释放过程中骨架片的溶胀指数、溶蚀百分数及吸水百分数等参数进行测定,并结合Peppas方程拟合参数探讨骨架片的体外药物释放机理,发现骨架片药物释放机制均为非Fick扩散,即药物扩散和骨架溶蚀协同作用。
对骨架片进行加速试验,在温度为40℃、相对湿度为75%的条件下,骨架片6月内稳定性良好。
体外释放试验表明,KGM具有较好的缓释特性,与天然高分子材料合用,其缓释效果优于与合成高分子材料合用,可作为缓释骨架片载体材料使用。
Matrix tablet is the main kind of sustained-release preparation;it is a lamellar solid preparttion made by the technology of spring clip from the mixture of drug,one or more kind of matrix material and other adjuvants.With the characteristic of simply technology of spring clip, safe,and easy to be grouped, matrix tablet play an important role in the development of sustained-release preparation.At present,the simplest sustained-release and controlled release materials can be divided into natural and synthetic materials according to the origin and the nature. to the origin the materials.Compared with the synthetic materials,the natural material is economic,and its security has been confirmed by the long-term use and so on merits characteristic.
Konjac glucomannan(KGM) is a high-molecular weight water-soluble non-ionic polysaccharide derived from tubers of Amorphophallus rivieri. It has been used in food and pharmaceutical industry and so on. The resource and yield of Amorphophallus rivieri in our country are the richest and the biggest of the world, but it is deficient for its futher processing and application. So the key to make full use of its resource is that how to develop its new application.
The physical constants of KGM which have different viscosity specification were studied by measuring the angle and critical relative humidity in this thesis,and the result is that,all the three kind of viscosity specification's KGM have met the requirements of the powder direct sheeting requirement. The solubility increases along with the viscosity reduces, the solubility of KGM increases along with the viscosity reduces while the swelling capacity increases . The pH value of the medium and the ionic strength has little effect on the solubility and the swelling capacity of KGM. With an environment humidity over 75%, the KGM hygroscopic moisture content increases obviously;
It is found that the drug and the supplementary material has no interaction, through the different scanning calorimetry analysis between the medicine and the supplementary material.
The ultraviolet spectrophotometric method has been established to test the solubility of model medicine,the amount of the drug release in vitro ,and to determinate the content of the main medicine in different media, the skeleton piece release and the main medicine content.
Water-soluble drug aminophylline and the infusibile drug aspirin were selected as the model drug, hydrophilic matrix tablets meet the requirement of in vitro release were made by direct powder compression and the wet legal system grain of sheeting with different prescription,the effect of prescription composition,the preparation craft and in vitro release condition to the drug release from hydrophilic matrix tablet.Different test methods,pH values of dissolution media,rotation speeds,the type and the amount of assist gels,the ratio of gels and assist gels,the amount of matrix materials, the kind of bulking agent,ionic strength of dissolution media,the amount of Eudragit L100 all has the significance influence on the drug release of both Water-soluble drug and the infusibility drug have a great impact.Lactose and MCC can accelerate the rate of drug release,but have no significant influence.The particle size of KGM and the model drug, technology of spring clip,pressure of spring clip have the same influence on the drug release.
The amount of drug release was confirmed in different mathematical model, calculate the AIC value ,base on the AIC value smallest method, the release of drug exhibited Peppas equation.
Uses of the weight method to calculate the swelling index,water uptake,polymer eroded,to study the release mechanism of drug from hydrophilic matrix tablets though the fitting parameter of Peppas equation.It is found that the release mechanism of drug from hydrophilic matrix tablets is non-Fickian release that coupled diffusion and erosion model.
The results of stability test indicated that the hydrophilic matrix tablets were stable under acceleration conditions for 6 months.
In vitro release tests have indicated that KGM has good sustained release character, it is better to use KGM couple together with natural polymer than synthetical polymer ,KGM can be used in sustained delivery systems as a good candidate for hydrophilic polymer.
魔芋胶是一种从魔芋植物块茎中提取得到的水溶性、非离子型多糖材料,长期以来,被作为辅料用在食品及医药等行业,我国魔芋资源及其产量居世界第一,但其深加工及应用还比较缺乏,因此,如何开发其新的应用途径成为充分利用魔芋资源的关键。
本课题通过测定不同粘度规格KGM的休止角、临界相对湿度等物理常数对KGM理化性质行研究,结果发现,所用的三种粘度规格的KGM的流动性均符合粉末直接压片的要求,溶解性随粘度的增加而降低,溶胀性随黏度的增加而增加,介质的pH值、离子强度对KGM的溶解性、溶胀性、粘度影响均很小。环境湿度超过75 %以后,KGM吸湿量明显增加。
通过示差扫描量热分析对材料与其他处方成分的配伍性能进行研究发现,药物与辅料之间无相互作用。
建立了紫外分光光度法用于模型药物的溶解度,骨架片的体外释放度及主药含量的测定。
分别选择水溶性药物氨茶碱和微溶性药物阿司匹林作为模型药物,采用不同处方组成利用粉末直接压片和湿法制粒压片制得体外释放符合要求的亲水凝胶骨架片;通过体外释放试验考察了骨架片的处方组成,制备工艺,体外释放条件对药物释放的影响。体外释放度测定方法,释放介质pH及其离子强度、搅拌转速,辅助凝胶剂的种类及用量,凝胶剂比例,凝胶剂用量,填充剂种类对水溶性药物和水难溶性药物的体外释放均产生显著性影响;乳糖、MCC均加快药物释放,但影响程度不同;KGM粒度、主药粒度、制备工艺,压片压力对药物释放的影响相同。
采用不同的数学模型对骨架片的体外药物释放数据进行拟合,计算AIC值,并依据AIC值最小法筛选出药物释放的最佳拟合模型—Peppas方程;采用重量法对体外释放过程中骨架片的溶胀指数、溶蚀百分数及吸水百分数等参数进行测定,并结合Peppas方程拟合参数探讨骨架片的体外药物释放机理,发现骨架片药物释放机制均为非Fick扩散,即药物扩散和骨架溶蚀协同作用。
对骨架片进行加速试验,在温度为40℃、相对湿度为75%的条件下,骨架片6月内稳定性良好。
体外释放试验表明,KGM具有较好的缓释特性,与天然高分子材料合用,其缓释效果优于与合成高分子材料合用,可作为缓释骨架片载体材料使用。
Matrix tablet is the main kind of sustained-release preparation;it is a lamellar solid preparttion made by the technology of spring clip from the mixture of drug,one or more kind of matrix material and other adjuvants.With the characteristic of simply technology of spring clip, safe,and easy to be grouped, matrix tablet play an important role in the development of sustained-release preparation.At present,the simplest sustained-release and controlled release materials can be divided into natural and synthetic materials according to the origin and the nature. to the origin the materials.Compared with the synthetic materials,the natural material is economic,and its security has been confirmed by the long-term use and so on merits characteristic.
Konjac glucomannan(KGM) is a high-molecular weight water-soluble non-ionic polysaccharide derived from tubers of Amorphophallus rivieri. It has been used in food and pharmaceutical industry and so on. The resource and yield of Amorphophallus rivieri in our country are the richest and the biggest of the world, but it is deficient for its futher processing and application. So the key to make full use of its resource is that how to develop its new application.
The physical constants of KGM which have different viscosity specification were studied by measuring the angle and critical relative humidity in this thesis,and the result is that,all the three kind of viscosity specification's KGM have met the requirements of the powder direct sheeting requirement. The solubility increases along with the viscosity reduces, the solubility of KGM increases along with the viscosity reduces while the swelling capacity increases . The pH value of the medium and the ionic strength has little effect on the solubility and the swelling capacity of KGM. With an environment humidity over 75%, the KGM hygroscopic moisture content increases obviously;
It is found that the drug and the supplementary material has no interaction, through the different scanning calorimetry analysis between the medicine and the supplementary material.
The ultraviolet spectrophotometric method has been established to test the solubility of model medicine,the amount of the drug release in vitro ,and to determinate the content of the main medicine in different media, the skeleton piece release and the main medicine content.
Water-soluble drug aminophylline and the infusibile drug aspirin were selected as the model drug, hydrophilic matrix tablets meet the requirement of in vitro release were made by direct powder compression and the wet legal system grain of sheeting with different prescription,the effect of prescription composition,the preparation craft and in vitro release condition to the drug release from hydrophilic matrix tablet.Different test methods,pH values of dissolution media,rotation speeds,the type and the amount of assist gels,the ratio of gels and assist gels,the amount of matrix materials, the kind of bulking agent,ionic strength of dissolution media,the amount of Eudragit L100 all has the significance influence on the drug release of both Water-soluble drug and the infusibility drug have a great impact.Lactose and MCC can accelerate the rate of drug release,but have no significant influence.The particle size of KGM and the model drug, technology of spring clip,pressure of spring clip have the same influence on the drug release.
The amount of drug release was confirmed in different mathematical model, calculate the AIC value ,base on the AIC value smallest method, the release of drug exhibited Peppas equation.
Uses of the weight method to calculate the swelling index,water uptake,polymer eroded,to study the release mechanism of drug from hydrophilic matrix tablets though the fitting parameter of Peppas equation.It is found that the release mechanism of drug from hydrophilic matrix tablets is non-Fickian release that coupled diffusion and erosion model.
The results of stability test indicated that the hydrophilic matrix tablets were stable under acceleration conditions for 6 months.
In vitro release tests have indicated that KGM has good sustained release character, it is better to use KGM couple together with natural polymer than synthetical polymer ,KGM can be used in sustained delivery systems as a good candidate for hydrophilic polymer.
引文
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