药物缓释性载体用脱支淀粉的研究
发布时间：2018-07-21 15:33
【摘要】：淀粉及其衍生物是一类生物可降解性的天然高分子材料,具有良好的生物相容性,常作为药物高分子载体。利用淀粉含有多羟基基团,易于改性的特点,改变淀粉基载体的水解速度和分子结构,调控药剂中活性药物成分的溶解性和扩散速度,可构建具有缓释功能特性的载体材料,降低药物对胃肠等消化器官的毒副作用,从而提高活性药物成分的生物利用度。因此,研究淀粉作为药物缓释载体具有一定的理论意义和实际应用价值。本论文利用天然大分子淀粉为原料,采用生物酶法,对其适当的结构修饰,研究淀粉分子链结构和聚集态结构,改变其水解速度,将其作为片剂用载体,采用直接压片工艺制备淀粉基药片,调控淀粉基载体在人体消化道不同部位环境条件的消化性,提高活性药物成分的稳定性和生物利用度,从而达到缓释药物活性成分的目的;深入研究淀粉分子链结构和聚集态结构与活性药物成分缓释之间的构效关系,通过体内外实验初探淀粉基载体片剂活性药物成分的释放机制,主要研究内容包括以下几点:第一,研究了直链淀粉含量对脱支淀粉载体分子结构的影响。结果表明,由于普鲁兰酶主要作用位点是支链结构中的α-1,6-糖苷键,同时能水解直链结构中的α-1,6-糖苷键。而蜡质玉米淀粉含有较高的支链含量,经过普鲁兰酶酶解作用后,产生较多的线性短链淀粉,颗粒表面产生孔洞结构,有利于增加与水介质的接触面积,易形成凝胶层,样品的抗消化性增加;流变学特性显示:脱支蜡质玉米淀粉(DB-WMS)表现出较强的频率依赖性,分子链间的缠结点增多,使得分子链间的作用更强;凝胶渗透色谱(GPC)的分析结果进一步证实了脱支淀粉样品中低摩尔质量级分随着原淀粉中直链淀粉含量增加而呈现减少的趋势。第二,通过调节酶用量和酶解时间,调控样品脱支化程度,考察了脱支程度对淀粉消化性能和淀粉基载体片剂药物缓释性能的差异。结果发现:脱支度越高,形成一定聚合度的线性直链淀粉短链及低聚糖越多,线性短链分子通过两两碰撞、缠绕并形成双螺旋分子的几率增加,消化性降低,从而不易被水解;不同脱支程度的淀粉基片剂的药物缓释动力学有所不同,低脱支程度淀粉(L-DBS)基药片符合显示Higuchi方程,中等脱支程度淀粉(M-DBS)和高脱支程度淀粉(H-DBS)分别适合于零级释放和一级释放动力学;脱支淀粉基片剂药物释放机制都为药物分子自身扩散和载体溶蚀协同作用。第三,淀粉的溶胀性能和凝胶层的形成能力是影响淀粉基片剂中活性药物成分缓释的主要因素。论文考察了淀粉在具有一定溶胀特性后脱支样品的分子结构与释药性能。研究发现80℃条件下溶胀,样品的还原糖含量以及摩尔质量分布都显示获得较多的线性短链分子级分,持水性和溶解度增加;流变学凝胶特性则显示短链线性分子含量的增加,有利于淀粉分子形成稳定的凝胶网络结构;体外缓释性曲线证实80℃溶胀脱支淀粉基片剂具有较好的缓释药物行为,片剂药物释放过程属于Higuchi方程释放,并受到扩散作用和溶蚀作用共同控制。第四,通过大兔体内试验,以市售的速释盐酸普萘洛尔片剂为对照,运用荧光光谱法测定三种不同直链含量脱支淀粉基盐酸普萘洛尔片的释药性。研究发现,市售片剂的峰浓度Cmax为114.21 ng/m L,达到峰浓度时间Tmax为1.00 h,半衰期T1/2为1.43h。脱支蜡质玉米淀粉(DB-WMS)、脱支普通玉米淀粉(DB-NMS)、脱支高直链玉米淀粉(DB-HMS)基片剂的峰浓度Cmax分别为25.37 ng/m L,25.27 ng/m L,22.98ng/m L;达峰时间Tmax分别为3.33 h,3.67 h,3.00 h;半衰期T1/2分别为5.07 h,7.07h,5.33 h。结果可知,脱支淀粉基片剂的峰浓度Cmax降低,达到峰浓度的时间Tmax延长,表明脱支淀粉基作为片剂的药物载体,能够减缓盐酸普萘洛尔药物的释放速度,延长药物的释放时间,血药浓度趋于稳定化,可降低血药浓度的波动对治疗效果的影响。通过相关性分析,发现片剂体外药物溶出实验跟体内吸收实验具有较好的相关性,可通过体外实验预测药物成分在体内释放情况。最后,运用扫描电子显微镜(SEM)和X-摄像显微摄像仪(XMT)两种现代分析仪器研究了淀粉基片剂的内部结构。SEM显示普通玉米淀粉基药片表面有明显的裂缝,粒子大小不均匀,且互相之间较为紧凑,弹性较小,容易产生裂痕,显示出脆弱的多孔结构。相比之下,脱支淀粉基片剂没有发现裂纹,淀粉大粒子之间充满小粒子,表面较为光滑,分子之间结合紧密。Starch 1500基片剂的孔隙度和强度明显低于普通玉米淀粉和脱支淀粉基片剂。XMT通过断层成像技术清楚地诠释了药片内部的密度分布均匀性和孔隙度大小。结合体外溶出实验,证实了淀粉基药片的内部结构影响活性药物成分的扩散和溶出,脱支淀粉基药片中的小分子级分在水化过程中易形成凝胶,较少孔洞的存在,抑制药物的溶出和通过孔隙扩散至介质中,从而降低了片剂中药物的释放速度。
[Abstract]:Starch and its derivatives are a kind of biodegradable natural polymer materials, which have good biocompatibility and are often used as polymeric carriers of drugs. The hydrolysis rate and molecular structure of starch based carriers are changed by using starch containing polyhydroxy groups and easy to be modified. The solubility and diffusion of active drug components in the medicament are regulated. At the same time, the carrier material with the characteristics of sustained release function can be constructed to reduce the toxic and side effects of the drugs on digestive organs such as the gastrointestinal tract, thus improving the bioavailability of the active drug components. Therefore, the study of starch as a drug release carrier has certain theoretical significance and practical value. Using the biological enzyme method, the structure of the starch molecular chain and the aggregation state are studied, the hydrolysis speed of the starch is changed. The starch based tablets are prepared by the direct pressing process as the carrier of the tablets, and the digestion of the starch based carrier in different parts of the human digestive tract is regulated to improve the stability of the active drug components. And bioavailability, so as to achieve the purpose of releasing the active components of the drug, and to study the structure-activity relationship between the molecular chain structure and the aggregation structure of starch and the sustained release of active drug components. Through the experiments in vitro and in vivo, the release mechanism of the active drug components of the starch based carrier tablets is explored. The main contents include the following points: first, study The effect of amylose content on the molecular structure of debranched starch carrier. The result shows that the main action site of prulan enzyme is alpha -1,6- glycoside in the chain structure and can hydrolyze the alpha -1,6- glycoside bond in the direct chain structure. The waxy corn starch contains high branch chain content. After the enzymolysis of prulylase, it produces more. The linear short chain starch, which produces hole structure on the surface of the particle, is beneficial to increase the contact area with the water medium, easily form the gel layer and increase the anti digestibility of the sample. The rheological properties show that the debranched waxy corn starch (DB-WMS) shows a strong frequency dependence, the entanglement between the molecular chains is increased, and the effect of the molecular chain is stronger; gel is stronger; gel is stronger. The results of GPC analysis further confirmed that the low molar mass grade in the debranched starch showed a decreasing trend with the increase of amylose content in the original starch. Second, the debranching degree of the samples was regulated by adjusting the amount of enzyme and the time of enzymatic hydrolysis, and the debranching degree on the starch digestibility and starch based carrier tablets was investigated. The results showed that the higher the debranched degree, the more short chain and oligosaccharides of linear amylose, which formed a certain degree of polymerization, increased the probability of the linear short chain molecules through 22 collisions, twisted and formed the double helix molecules, reduced the digestibility and was not easy to be hydrolyzed; the drug release of the starch based tablets with different debranched degrees was slow release. The low debranched starch (L-DBS) based tablets accorded with the Higuchi equation, the medium debranched starch (M-DBS) and the high debranched starch (H-DBS) were suitable for the zero order release and the first order release kinetics, respectively. The release mechanism of the debranched starch based tablets was both the self diffusion of drug molecules and the synergistic effect of the carrier dissolution. Third The swelling properties of starch and the formation ability of the gel layer are the main factors affecting the sustained release of active drug components in the starch based tablets. The molecular structure and drug release properties of the debranched samples with certain swelling properties are investigated. The results show that the swelling, reducing sugar content and molar mass distribution of the samples at 80 degrees centigrade are all obvious. More linear short chain molecular grades were obtained, water holding and solubility increased, and the rheological gel properties showed an increase in the content of short chain linear molecules, which was beneficial to the formation of a stable gel network structure of starch molecules. In vitro release curves confirmed that the swelling and debranched starch based tablets at 80 C had good drug release behavior and tablets were released. The release process belongs to the release of Higuchi equation and is controlled by the effect of diffusion and dissolution. Fourth, the release of propranolol tablets from the marketed fast release propranolol tablets was controlled by a large rabbit experiment. The release of three kinds of amylopectin based Propranolol Hydrochloride Tablets with different direct chain content was measured by fluorescence spectrometry. The peak of the market was found to be the peak of the market. The concentration Cmax was 114.21 ng/m L, the peak concentration time Tmax was 1 h, the half life T1/2 was 1.43h. debranched waxy corn starch (DB-WMS), the debranched corn starch (DB-NMS), and the peak concentration of the high amylose corn starch (DB-HMS) base tablets of the debranched high amylose corn starch were 25.37 ng/m, and 25.27 were respectively 3.33, 3.67 and 3 respectively. 0 h; the half-life T1/2 was 5.07 h, 7.07h, and 5.33 H., the results showed that the peak concentration Cmax of the debranched starch based tablets decreased and the peak concentration time Tmax prolonged, indicating that the debranched amyloid was used as a drug carrier for tablets, which could slow down the release rate of propranolol hydrochloride and prolong the release time of the drug, and the concentration of the drug tended to be stable. The effect of reducing the fluctuation of blood concentration on the therapeutic effect is reduced. Through correlation analysis, it is found that the drug dissolution test in vitro has a good correlation with the absorption experiment in the body. It can be predicted by in vitro experiments to predict the release of drug components in the body. Finally, two kinds of modern scanning electron microscopy (SEM) and X- camera microscope camera (XMT) are used. The internal structure.SEM of the starch based tablets showed that there were obvious cracks on the surface of the common corn starch based tablets, the size of the particles was not uniform, and the size of the particles was compact, the elasticity was small, the cracks were easy to produce, and the fragile porous structure was shown. In contrast, the debranched starch based tablets did not find cracks and the starch was large particles. The surface is full of small particles, the surface is smooth, the porosity and strength of the close.Starch 1500 base tablets are obviously lower than that of the common corn starch and the debranched starch base tablet.XMT. The density distribution uniformity and the pore size inside the tablet are clearly explained by the tomography technique. The internal structure of the base tablet affects the diffusion and dissolution of the active drug components. The small molecular grade in the debranched starch based tablets is easy to form the gel during the hydration process, which reduces the dissolution of the drug and diffuses the pores into the medium, thus reducing the release rate of the tablets of the tablets.
【学位授予单位】：江南大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：TS236.9;TQ460.1
本文编号：2135973
[Abstract]:Starch and its derivatives are a kind of biodegradable natural polymer materials, which have good biocompatibility and are often used as polymeric carriers of drugs. The hydrolysis rate and molecular structure of starch based carriers are changed by using starch containing polyhydroxy groups and easy to be modified. The solubility and diffusion of active drug components in the medicament are regulated. At the same time, the carrier material with the characteristics of sustained release function can be constructed to reduce the toxic and side effects of the drugs on digestive organs such as the gastrointestinal tract, thus improving the bioavailability of the active drug components. Therefore, the study of starch as a drug release carrier has certain theoretical significance and practical value. Using the biological enzyme method, the structure of the starch molecular chain and the aggregation state are studied, the hydrolysis speed of the starch is changed. The starch based tablets are prepared by the direct pressing process as the carrier of the tablets, and the digestion of the starch based carrier in different parts of the human digestive tract is regulated to improve the stability of the active drug components. And bioavailability, so as to achieve the purpose of releasing the active components of the drug, and to study the structure-activity relationship between the molecular chain structure and the aggregation structure of starch and the sustained release of active drug components. Through the experiments in vitro and in vivo, the release mechanism of the active drug components of the starch based carrier tablets is explored. The main contents include the following points: first, study The effect of amylose content on the molecular structure of debranched starch carrier. The result shows that the main action site of prulan enzyme is alpha -1,6- glycoside in the chain structure and can hydrolyze the alpha -1,6- glycoside bond in the direct chain structure. The waxy corn starch contains high branch chain content. After the enzymolysis of prulylase, it produces more. The linear short chain starch, which produces hole structure on the surface of the particle, is beneficial to increase the contact area with the water medium, easily form the gel layer and increase the anti digestibility of the sample. The rheological properties show that the debranched waxy corn starch (DB-WMS) shows a strong frequency dependence, the entanglement between the molecular chains is increased, and the effect of the molecular chain is stronger; gel is stronger; gel is stronger. The results of GPC analysis further confirmed that the low molar mass grade in the debranched starch showed a decreasing trend with the increase of amylose content in the original starch. Second, the debranching degree of the samples was regulated by adjusting the amount of enzyme and the time of enzymatic hydrolysis, and the debranching degree on the starch digestibility and starch based carrier tablets was investigated. The results showed that the higher the debranched degree, the more short chain and oligosaccharides of linear amylose, which formed a certain degree of polymerization, increased the probability of the linear short chain molecules through 22 collisions, twisted and formed the double helix molecules, reduced the digestibility and was not easy to be hydrolyzed; the drug release of the starch based tablets with different debranched degrees was slow release. The low debranched starch (L-DBS) based tablets accorded with the Higuchi equation, the medium debranched starch (M-DBS) and the high debranched starch (H-DBS) were suitable for the zero order release and the first order release kinetics, respectively. The release mechanism of the debranched starch based tablets was both the self diffusion of drug molecules and the synergistic effect of the carrier dissolution. Third The swelling properties of starch and the formation ability of the gel layer are the main factors affecting the sustained release of active drug components in the starch based tablets. The molecular structure and drug release properties of the debranched samples with certain swelling properties are investigated. The results show that the swelling, reducing sugar content and molar mass distribution of the samples at 80 degrees centigrade are all obvious. More linear short chain molecular grades were obtained, water holding and solubility increased, and the rheological gel properties showed an increase in the content of short chain linear molecules, which was beneficial to the formation of a stable gel network structure of starch molecules. In vitro release curves confirmed that the swelling and debranched starch based tablets at 80 C had good drug release behavior and tablets were released. The release process belongs to the release of Higuchi equation and is controlled by the effect of diffusion and dissolution. Fourth, the release of propranolol tablets from the marketed fast release propranolol tablets was controlled by a large rabbit experiment. The release of three kinds of amylopectin based Propranolol Hydrochloride Tablets with different direct chain content was measured by fluorescence spectrometry. The peak of the market was found to be the peak of the market. The concentration Cmax was 114.21 ng/m L, the peak concentration time Tmax was 1 h, the half life T1/2 was 1.43h. debranched waxy corn starch (DB-WMS), the debranched corn starch (DB-NMS), and the peak concentration of the high amylose corn starch (DB-HMS) base tablets of the debranched high amylose corn starch were 25.37 ng/m, and 25.27 were respectively 3.33, 3.67 and 3 respectively. 0 h; the half-life T1/2 was 5.07 h, 7.07h, and 5.33 H., the results showed that the peak concentration Cmax of the debranched starch based tablets decreased and the peak concentration time Tmax prolonged, indicating that the debranched amyloid was used as a drug carrier for tablets, which could slow down the release rate of propranolol hydrochloride and prolong the release time of the drug, and the concentration of the drug tended to be stable. The effect of reducing the fluctuation of blood concentration on the therapeutic effect is reduced. Through correlation analysis, it is found that the drug dissolution test in vitro has a good correlation with the absorption experiment in the body. It can be predicted by in vitro experiments to predict the release of drug components in the body. Finally, two kinds of modern scanning electron microscopy (SEM) and X- camera microscope camera (XMT) are used. The internal structure.SEM of the starch based tablets showed that there were obvious cracks on the surface of the common corn starch based tablets, the size of the particles was not uniform, and the size of the particles was compact, the elasticity was small, the cracks were easy to produce, and the fragile porous structure was shown. In contrast, the debranched starch based tablets did not find cracks and the starch was large particles. The surface is full of small particles, the surface is smooth, the porosity and strength of the close.Starch 1500 base tablets are obviously lower than that of the common corn starch and the debranched starch base tablet.XMT. The density distribution uniformity and the pore size inside the tablet are clearly explained by the tomography technique. The internal structure of the base tablet affects the diffusion and dissolution of the active drug components. The small molecular grade in the debranched starch based tablets is easy to form the gel during the hydration process, which reduces the dissolution of the drug and diffuses the pores into the medium, thus reducing the release rate of the tablets of the tablets.
【学位授予单位】：江南大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：TS236.9;TQ460.1
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