藥物緩釋性載體用脫支淀粉的研究
發(fā)布時間：2018-07-21 15:33
【摘要】：淀粉及其衍生物是一類生物可降解性的天然高分子材料,具有良好的生物相容性,常作為藥物高分子載體。利用淀粉含有多羥基基團,易于改性的特點,改變淀粉基載體的水解速度和分子結(jié)構(gòu),調(diào)控藥劑中活性藥物成分的溶解性和擴散速度,可構(gòu)建具有緩釋功能特性的載體材料,降低藥物對胃腸等消化器官的毒副作用,從而提高活性藥物成分的生物利用度。因此,研究淀粉作為藥物緩釋載體具有一定的理論意義和實際應用價值。本論文利用天然大分子淀粉為原料,采用生物酶法,對其適當?shù)慕Y(jié)構(gòu)修飾,研究淀粉分子鏈結(jié)構(gòu)和聚集態(tài)結(jié)構(gòu),改變其水解速度,將其作為片劑用載體,采用直接壓片工藝制備淀粉基藥片,調(diào)控淀粉基載體在人體消化道不同部位環(huán)境條件的消化性,提高活性藥物成分的穩(wěn)定性和生物利用度,從而達到緩釋藥物活性成分的目的;深入研究淀粉分子鏈結(jié)構(gòu)和聚集態(tài)結(jié)構(gòu)與活性藥物成分緩釋之間的構(gòu)效關系,通過體內(nèi)外實驗初探淀粉基載體片劑活性藥物成分的釋放機制,主要研究內(nèi)容包括以下幾點:第一,研究了直鏈淀粉含量對脫支淀粉載體分子結(jié)構(gòu)的影響。結(jié)果表明,由于普魯蘭酶主要作用位點是支鏈結(jié)構(gòu)中的α-1,6-糖苷鍵,同時能水解直鏈結(jié)構(gòu)中的α-1,6-糖苷鍵。而蠟質(zhì)玉米淀粉含有較高的支鏈含量,經(jīng)過普魯蘭酶酶解作用后,產(chǎn)生較多的線性短鏈淀粉,顆粒表面產(chǎn)生孔洞結(jié)構(gòu),有利于增加與水介質(zhì)的接觸面積,易形成凝膠層,樣品的抗消化性增加;流變學特性顯示:脫支蠟質(zhì)玉米淀粉(DB-WMS)表現(xiàn)出較強的頻率依賴性,分子鏈間的纏結(jié)點增多,使得分子鏈間的作用更強;凝膠滲透色譜(GPC)的分析結(jié)果進一步證實了脫支淀粉樣品中低摩爾質(zhì)量級分隨著原淀粉中直鏈淀粉含量增加而呈現(xiàn)減少的趨勢。第二,通過調(diào)節(jié)酶用量和酶解時間,調(diào)控樣品脫支化程度,考察了脫支程度對淀粉消化性能和淀粉基載體片劑藥物緩釋性能的差異。結(jié)果發(fā)現(xiàn):脫支度越高,形成一定聚合度的線性直鏈淀粉短鏈及低聚糖越多,線性短鏈分子通過兩兩碰撞、纏繞并形成雙螺旋分子的幾率增加,消化性降低,從而不易被水解;不同脫支程度的淀粉基片劑的藥物緩釋動力學有所不同,低脫支程度淀粉(L-DBS)基藥片符合顯示Higuchi方程,中等脫支程度淀粉(M-DBS)和高脫支程度淀粉(H-DBS)分別適合于零級釋放和一級釋放動力學;脫支淀粉基片劑藥物釋放機制都為藥物分子自身擴散和載體溶蝕協(xié)同作用。第三,淀粉的溶脹性能和凝膠層的形成能力是影響淀粉基片劑中活性藥物成分緩釋的主要因素。論文考察了淀粉在具有一定溶脹特性后脫支樣品的分子結(jié)構(gòu)與釋藥性能。研究發(fā)現(xiàn)80℃條件下溶脹,樣品的還原糖含量以及摩爾質(zhì)量分布都顯示獲得較多的線性短鏈分子級分,持水性和溶解度增加;流變學凝膠特性則顯示短鏈線性分子含量的增加,有利于淀粉分子形成穩(wěn)定的凝膠網(wǎng)絡結(jié)構(gòu);體外緩釋性曲線證實80℃溶脹脫支淀粉基片劑具有較好的緩釋藥物行為,片劑藥物釋放過程屬于Higuchi方程釋放,并受到擴散作用和溶蝕作用共同控制。第四,通過大兔體內(nèi)試驗,以市售的速釋鹽酸普萘洛爾片劑為對照,運用熒光光譜法測定三種不同直鏈含量脫支淀粉基鹽酸普萘洛爾片的釋藥性。研究發(fā)現(xiàn),市售片劑的峰濃度Cmax為114.21 ng/m L,達到峰濃度時間Tmax為1.00 h,半衰期T1/2為1.43h。脫支蠟質(zhì)玉米淀粉(DB-WMS)、脫支普通玉米淀粉(DB-NMS)、脫支高直鏈玉米淀粉(DB-HMS)基片劑的峰濃度Cmax分別為25.37 ng/m L,25.27 ng/m L,22.98ng/m L;達峰時間Tmax分別為3.33 h,3.67 h,3.00 h;半衰期T1/2分別為5.07 h,7.07h,5.33 h。結(jié)果可知,脫支淀粉基片劑的峰濃度Cmax降低,達到峰濃度的時間Tmax延長,表明脫支淀粉基作為片劑的藥物載體,能夠減緩鹽酸普萘洛爾藥物的釋放速度,延長藥物的釋放時間,血藥濃度趨于穩(wěn)定化,可降低血藥濃度的波動對治療效果的影響。通過相關性分析,發(fā)現(xiàn)片劑體外藥物溶出實驗跟體內(nèi)吸收實驗具有較好的相關性,可通過體外實驗預測藥物成分在體內(nèi)釋放情況。最后,運用掃描電子顯微鏡(SEM)和X-攝像顯微攝像儀(XMT)兩種現(xiàn)代分析儀器研究了淀粉基片劑的內(nèi)部結(jié)構(gòu)。SEM顯示普通玉米淀粉基藥片表面有明顯的裂縫,粒子大小不均勻,且互相之間較為緊湊,彈性較小,容易產(chǎn)生裂痕,顯示出脆弱的多孔結(jié)構(gòu)。相比之下,脫支淀粉基片劑沒有發(fā)現(xiàn)裂紋,淀粉大粒子之間充滿小粒子,表面較為光滑,分子之間結(jié)合緊密。Starch 1500基片劑的孔隙度和強度明顯低于普通玉米淀粉和脫支淀粉基片劑。XMT通過斷層成像技術清楚地詮釋了藥片內(nèi)部的密度分布均勻性和孔隙度大小。結(jié)合體外溶出實驗,證實了淀粉基藥片的內(nèi)部結(jié)構(gòu)影響活性藥物成分的擴散和溶出,脫支淀粉基藥片中的小分子級分在水化過程中易形成凝膠,較少孔洞的存在,抑制藥物的溶出和通過孔隙擴散至介質(zhì)中,從而降低了片劑中藥物的釋放速度。
[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.
【學位授予單位】：江南大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：TS236.9;TQ460.1
本文編號：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.
【學位授予單位】：江南大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：TS236.9;TQ460.1
【參考文獻】
相關期刊論文 前4條
1 周中凱;張巖;陳曉姍;鄭排云;楊艷;;5種小麥淀粉的結(jié)構(gòu)與性質(zhì)的研究[J];糧食與飼料工業(yè);2013年04期
2 史苗苗;高群玉;;脫支蠟質(zhì)玉米抗性淀粉的制備及性質(zhì)[J];食品與發(fā)酵工業(yè);2010年08期
3 盧玉棟,吳宗華;糊化條件對淀粉溶解度及性能的影響[J];中國造紙學報;2003年01期
4 梁勇,張本山,楊連生,高大維;三偏磷酸鈉交聯(lián)馬鈴薯淀粉顆粒膨脹歷程及溶脹機理研究[J];中國糧油學報;2002年02期
相關博士學位論文 前2條
1 張雅媛;玉米淀粉與親水性膠體協(xié)效性和作用機理的研究[D];江南大學;2012年
2 范江洋;魔芋葡甘聚糖—黃原膠共混多糖作為釋藥載體的研究[D];天津大學;2007年
相關碩士學位論文 前1條
1 張斌;慢消化淀粉的制備、性質(zhì)及其形成機理研究[D];華南理工大學;2011年
，本文編號：2135973
本文鏈接：http://sikaile.net/shoufeilunwen/gckjbs/2135973.html
最近更新
教材專著
