脱乙酰化葡甘露聚糖—海藻酸钠凝胶丸的研究
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摘要
黄芩苷是从黄芩根中提取分离出来的一种黄酮类化合物,具有显著的生物活性，具有抑菌、利尿、抗炎、抗变态及解痉作用，并且具有较强的抗癌反应等生理效能。由于其广泛的药理作用，药效高，毒性低，黄芩苷一直受到研究学者的关注。传统的黄芩苷制剂半衰期短，血药浓度波动范围大。为减少服药次数，提高患者顺应性，本论文将其制成凝胶丸，不仅克服以上缺点，还可以提高药物的稳定性、延长半衰期。
关于凝胶丸的制备已有很多报道，但各种凝胶骨架材料各有利弊，本文将两种骨架材料脱乙酰化的葡甘露聚糖和海藻酸钠进行物理混合，并分别对其处方、制备工艺进行优化，对体外和体内释放机理进行初步研究，为脱乙酰化葡甘露聚糖和海藻酸钠共混物作为凝胶骨架材料在药剂中的应用提供一定的理论依据。
葡甘露聚糖是一种具有水溶、增稠、凝胶、成膜、粘结等多种理化特性的杂多糖。对高血压、肥胖症、糖尿病、便秘有一定疗效，可以排除体内毒素和垃圾，预防结肠癌。葡甘露聚糖不仅是一种天然的保健食品、理想的食品添加剂还是优良的药物载体。海藻酸钠一种天然多糖，具有药物制剂辅料所需的稳定性、溶解性、粘性和安全性。其温和的溶胶凝胶过程、良好的生物相容性使海藻酸钠适于作为释放或包埋药物、蛋白与细胞的微胶囊。中低黏度的海藻酸钠适于用来制备胶丸。
本文以包封率和平均释放时间为指标，考察了处方及工艺因素：凝胶骨架材料脱乙酰化葡甘露聚糖与海藻酸钠比例、黄芩苷用量、乙醇用量、葡甘露聚糖脱乙酰化pH值、胶凝时间、干燥温度；通过星点设计，优化了处方及工艺，并对优化后的处方和工艺进行验证；考察了凝胶丸的物化性质：平均粒径、包封率、载药量、稳定性、在不同pH值介质中的溶胀率；考察了离子强度、pH等体外释放条件对凝胶丸体外释放的影响；考察了凝胶丸在SD大鼠体内药物代谢动力学。
实验结果表明：骨架材料脱乙酰化葡甘露聚糖与海藻酸钠比例对包封率和平均释放时间均有显著影响，脱乙酰化葡甘露聚糖与海藻酸钠比例为1：1时包封率最大，增大或者减小两者比例，包封率均变小，比例为5：1时，平均释放时间最短，随着海藻酸钠比例的升高，平均释放时间变长，比例为1：1时，平均释放时间最长，继续增加海藻酸钠比例，平均释放时间变化不明显；黄芩苷用量对包封率影响不明显，对平均释放时间影响显著，随着黄芩苷用量的增加，平均释放时间明显延长；乙醇用量对包封率影响不明显，对平均释放时间影响显著，乙醇用量为10%、15%时，平均释放时间最长，小于10%或大于15%均使平均释放时间缩短；葡甘露聚糖脱乙酰化pH值、凝胶时间、干燥温度对包封率和平均释放时间影响均不明显。选取对凝胶丸包封率和平均释放时间影响较显著的三个因素：凝胶骨架材料脱乙酰化葡甘露聚糖与海藻酸钠比例、黄芩苷用量、乙醇用量，以包封率和平均释放时间为指标，采用星点设计优化处方，最佳处方为：凝胶骨架材料脱乙酰化葡甘露聚糖与海藻酸钠比例为37:63、黄芩苷用量4.94%、乙醇用量13.97%。
依据最佳处方和工艺制备三批样品进行验证：包封率大于80%，平均释放时间大于2h，对释放数据进行方程拟合，药物释放模型与Peppas方程最相似，释放机制为药物扩散和骨架溶蚀协同作用。
凝胶丸物化性质结果显示：凝胶丸平均粒径为2.01mm，包封率为81.15%，载药量为66.95%，凝胶丸在蒸馏水、pH1.2HCl溶液、pH6.8磷酸盐缓冲液中6h的溶胀率分别为317%、338%、936%中。稳定性加速实验实验结果表明：在温度为40℃±1℃，相对湿度75%±5%的条件下存放6个月，凝胶丸外观、主药含量、体外释放速率均无明显变化，表明凝胶丸在以上条件下稳定。离子强度对平均释放时间有显著影响，在一定范围内，随着离子强度的增强，平均释放时间缩短。pH值对平均释放时间有显著影响，在pH1.2盐酸溶液中，6h累计释放率不足1%，在pH6.8磷酸盐缓冲液中，6h累计释放率可达80%以上。
凝胶丸在SD大鼠体内药物动力学实验结果表明，通过剂型的优化，药物动力学参数发生明显改变，AUC提高约1.37倍，CL由10.78mg/kg/h（/μg/ml）降低到7.84mg/kg/h/（μg/ml），t1/2beta由1.76h延长至2.58h，这表明了黄芩苷凝胶丸改变了黄芩苷的体内行为，使黄芩苷在体内维持较高血药浓度时间延长。经实验验证，设计凝胶丸符合最初设计需求。
The Baicalin is a kind of flavonoids isolated and extracted from Scutellaria root, has significantbiological activity, with the effect of antimicrobial, diuretic, anti-inflammatory, anti-metamorphosis andantispasmodic, and has a strong anti-cancer response and physical performance. Because of its wide rangeof pharmacological effects, high efficacy, low toxicity, Baicalin has been subject to the attention of scholars.The tradition Baicalin preparations has the short half-life,and with the large fluctuations in plasmaconcentration range. In order to reduce the number of medication, improve the patient compliance, wemade the gel pills from of Baicalin, not only to overcome the above disadvantages, and can also improvethe stability of the drug and extends it's half-life.
There are many reports on the preparation of the gel pills, but the gel matrix materials have avariety of advantages and disadvantages, in this paper we mix two kinds of reinforcing materials thedeacetylation of glucomannan and sodium alginate physically, and optimize its prescription, preparationprocess respectively, the preliminary studies on vitro and on vivo release mechanism was perform ed.finally provide a theoretical basis for the deacetylation of glucomannan and sodium alginate blends ashydrophilic matrix materials in the pharmaceutical.
Glucomannan is a kand of heteropolysaccharide,has the water-soluble, thickening, gel, film,adhesive and other physical and chemical characteristics. It has a certain effect on Hypertension, obesity,diabetes, constipation, and Can rid the body of toxins and waste, prevent the colon cancer. Glucomannan isnot only a natural health food, but an ideal food additive and an excellent drug carrier. Sodium alginate, anatural polysaccharide, has the required stability, solubility, viscosity and security of pharmaceuticalpreparations accessories. The Mild sol-gel process, good biocompatibility made sodium alginate suitablefor be made of Microcapsules that can release or embeddrugs, proteins and cells.The low viscosity ofsodium alginate suitable for use in the preparation of capsules.
In this paper,we use the Encapsulation efficiency and the average release time as an indicator tostudy the prescription and process factors: gel matrix material deacetylation of glucomannan and sodiumalginate ratio, the amount of Baicalin and ethanol, glucomannan deacetylation pH, gelling time, drying temperature; optimize the prescription and technology By the central composite design,and verifed theoptimized prescription and process; study the physicochemical properties of the gel pills: averageparticle size, encapsulation efficiency, drug loading, stability, swelling ratio in different pH media; studythe affection that vitro release conditions such as Ionic strength, pH, etc. in gel pill vitro release. of thecumulative release percentage in vitro release of ionic strength, pH and other conditions on the gel pill;study the dynamics of the gel pill drug metabolism in SD rats.
The experimental results show that: reinforcing material de-acetylated glucomannan and sodiumalginate ratio had significant effects on the encapsulation efficiency and the average release time,when thedeacetylation of glucomannan and sodium alginate ratio was1:1,it has the Maximum encapsulationefficiency,the longest average release time, increase or reduce the ratio between the two, the encapsulationefficiency got smaller, the average release time got longer; the effect of amount of Baicalin on theencapsulation efficiency was not significant,but has the significantly affect on the average release time,with the increase amount of Baicalin, the average release time was significantly prolonged; the effect ofamount of ethanol on the encapsulation efficiency was not significant, but has the significantly affect onthe average release time, when the amount of Ethanol was10%,15%, it has the longest Averagerelease,Less than10%or greater than15%both Shorten the average release time;the effect ofglucomannan deacetylation pH value, gel time, drying temperature on the encapsulation efficiency and theaverage release time both has no significant impact. Select the three factors that more significant on thegel pill encapsulation efficiency and the average release time: the gel matrix material deacetylation ofglucomannan and sodium alginate ratio, the amount of Baicalin and ethanol. the encapsulation efficiencyand average release time as an index, using central composite design to optimize the prescription, The bestformula: gel matrix material deacetylation of glucomannan and sodium alginate ratio of37:63, Baicalinamount of4.94%,13.97%of the ethanol dosage.
Authentication: Three batches of samples based on the best prescription and Process:encapsulation efficiency greater than80%, the average release time is greater than2h, the release data werefitted by equation,Drug release model were similar to Peppas equation,the release mechanism is theSynergies of the diffusion of the drug and the Skeleton dissolution.
The gel pill pHysicochemical properties: gel pill average particle size of2.01mm, the encapsulation efficiency was81.15%, theDrug loading was66.95%, the swelling ratiosgel of pills indistilled water,pH1.2HCL solution, pH6.8phosphate buffer were317%、338%、936%. Acceleratedstability experiment experimental results show that: Store the Gel pills at a temperature of40°C±1°C,relative humidity conditions of75%±5%for6months, Gel pills appearance, the main ingredients, in vitrorelease rate did not change significantly indicating that gel Pill stable under the above conditions. Ionicstrength has the significant effect on the average release time, within a certain range, with the enhancementof the ionic strength, the average release time got shorter. pH value has the significant effect on the averagerelease time,in pH1.2hydrochloric acid solution, the6h cumulative release rate less than1%, in pH6.8phosphate buffer, the6h cumulative release rate can up to80%.
The vivo pharmacokinetic experiments of Gel pills in SD rats studies showed that theoptimization of the formulations, the pharmacokinetic parameters changed significantly, the AUCincreased by about1.5times,CL was reduced from3.9ml/min to2.6ml/min, t1/2beta extend from1.76h to2.58h, which indicates that the the Baicalin gel pill changed the In vivo behavior of Baicalin, made theBaicalin in the body to maintain higher plasma concentration for longer time. The experiments prove thatthe designed gel pill conform to the original design requirements.
关于凝胶丸的制备已有很多报道，但各种凝胶骨架材料各有利弊，本文将两种骨架材料脱乙酰化的葡甘露聚糖和海藻酸钠进行物理混合，并分别对其处方、制备工艺进行优化，对体外和体内释放机理进行初步研究，为脱乙酰化葡甘露聚糖和海藻酸钠共混物作为凝胶骨架材料在药剂中的应用提供一定的理论依据。
葡甘露聚糖是一种具有水溶、增稠、凝胶、成膜、粘结等多种理化特性的杂多糖。对高血压、肥胖症、糖尿病、便秘有一定疗效，可以排除体内毒素和垃圾，预防结肠癌。葡甘露聚糖不仅是一种天然的保健食品、理想的食品添加剂还是优良的药物载体。海藻酸钠一种天然多糖，具有药物制剂辅料所需的稳定性、溶解性、粘性和安全性。其温和的溶胶凝胶过程、良好的生物相容性使海藻酸钠适于作为释放或包埋药物、蛋白与细胞的微胶囊。中低黏度的海藻酸钠适于用来制备胶丸。
本文以包封率和平均释放时间为指标，考察了处方及工艺因素：凝胶骨架材料脱乙酰化葡甘露聚糖与海藻酸钠比例、黄芩苷用量、乙醇用量、葡甘露聚糖脱乙酰化pH值、胶凝时间、干燥温度；通过星点设计，优化了处方及工艺，并对优化后的处方和工艺进行验证；考察了凝胶丸的物化性质：平均粒径、包封率、载药量、稳定性、在不同pH值介质中的溶胀率；考察了离子强度、pH等体外释放条件对凝胶丸体外释放的影响；考察了凝胶丸在SD大鼠体内药物代谢动力学。
实验结果表明：骨架材料脱乙酰化葡甘露聚糖与海藻酸钠比例对包封率和平均释放时间均有显著影响，脱乙酰化葡甘露聚糖与海藻酸钠比例为1：1时包封率最大，增大或者减小两者比例，包封率均变小，比例为5：1时，平均释放时间最短，随着海藻酸钠比例的升高，平均释放时间变长，比例为1：1时，平均释放时间最长，继续增加海藻酸钠比例，平均释放时间变化不明显；黄芩苷用量对包封率影响不明显，对平均释放时间影响显著，随着黄芩苷用量的增加，平均释放时间明显延长；乙醇用量对包封率影响不明显，对平均释放时间影响显著，乙醇用量为10%、15%时，平均释放时间最长，小于10%或大于15%均使平均释放时间缩短；葡甘露聚糖脱乙酰化pH值、凝胶时间、干燥温度对包封率和平均释放时间影响均不明显。选取对凝胶丸包封率和平均释放时间影响较显著的三个因素：凝胶骨架材料脱乙酰化葡甘露聚糖与海藻酸钠比例、黄芩苷用量、乙醇用量，以包封率和平均释放时间为指标，采用星点设计优化处方，最佳处方为：凝胶骨架材料脱乙酰化葡甘露聚糖与海藻酸钠比例为37:63、黄芩苷用量4.94%、乙醇用量13.97%。
依据最佳处方和工艺制备三批样品进行验证：包封率大于80%，平均释放时间大于2h，对释放数据进行方程拟合，药物释放模型与Peppas方程最相似，释放机制为药物扩散和骨架溶蚀协同作用。
凝胶丸物化性质结果显示：凝胶丸平均粒径为2.01mm，包封率为81.15%，载药量为66.95%，凝胶丸在蒸馏水、pH1.2HCl溶液、pH6.8磷酸盐缓冲液中6h的溶胀率分别为317%、338%、936%中。稳定性加速实验实验结果表明：在温度为40℃±1℃，相对湿度75%±5%的条件下存放6个月，凝胶丸外观、主药含量、体外释放速率均无明显变化，表明凝胶丸在以上条件下稳定。离子强度对平均释放时间有显著影响，在一定范围内，随着离子强度的增强，平均释放时间缩短。pH值对平均释放时间有显著影响，在pH1.2盐酸溶液中，6h累计释放率不足1%，在pH6.8磷酸盐缓冲液中，6h累计释放率可达80%以上。
凝胶丸在SD大鼠体内药物动力学实验结果表明，通过剂型的优化，药物动力学参数发生明显改变，AUC提高约1.37倍，CL由10.78mg/kg/h（/μg/ml）降低到7.84mg/kg/h/（μg/ml），t1/2beta由1.76h延长至2.58h，这表明了黄芩苷凝胶丸改变了黄芩苷的体内行为，使黄芩苷在体内维持较高血药浓度时间延长。经实验验证，设计凝胶丸符合最初设计需求。
The Baicalin is a kind of flavonoids isolated and extracted from Scutellaria root, has significantbiological activity, with the effect of antimicrobial, diuretic, anti-inflammatory, anti-metamorphosis andantispasmodic, and has a strong anti-cancer response and physical performance. Because of its wide rangeof pharmacological effects, high efficacy, low toxicity, Baicalin has been subject to the attention of scholars.The tradition Baicalin preparations has the short half-life,and with the large fluctuations in plasmaconcentration range. In order to reduce the number of medication, improve the patient compliance, wemade the gel pills from of Baicalin, not only to overcome the above disadvantages, and can also improvethe stability of the drug and extends it's half-life.
There are many reports on the preparation of the gel pills, but the gel matrix materials have avariety of advantages and disadvantages, in this paper we mix two kinds of reinforcing materials thedeacetylation of glucomannan and sodium alginate physically, and optimize its prescription, preparationprocess respectively, the preliminary studies on vitro and on vivo release mechanism was perform ed.finally provide a theoretical basis for the deacetylation of glucomannan and sodium alginate blends ashydrophilic matrix materials in the pharmaceutical.
Glucomannan is a kand of heteropolysaccharide,has the water-soluble, thickening, gel, film,adhesive and other physical and chemical characteristics. It has a certain effect on Hypertension, obesity,diabetes, constipation, and Can rid the body of toxins and waste, prevent the colon cancer. Glucomannan isnot only a natural health food, but an ideal food additive and an excellent drug carrier. Sodium alginate, anatural polysaccharide, has the required stability, solubility, viscosity and security of pharmaceuticalpreparations accessories. The Mild sol-gel process, good biocompatibility made sodium alginate suitablefor be made of Microcapsules that can release or embeddrugs, proteins and cells.The low viscosity ofsodium alginate suitable for use in the preparation of capsules.
In this paper,we use the Encapsulation efficiency and the average release time as an indicator tostudy the prescription and process factors: gel matrix material deacetylation of glucomannan and sodiumalginate ratio, the amount of Baicalin and ethanol, glucomannan deacetylation pH, gelling time, drying temperature; optimize the prescription and technology By the central composite design,and verifed theoptimized prescription and process; study the physicochemical properties of the gel pills: averageparticle size, encapsulation efficiency, drug loading, stability, swelling ratio in different pH media; studythe affection that vitro release conditions such as Ionic strength, pH, etc. in gel pill vitro release. of thecumulative release percentage in vitro release of ionic strength, pH and other conditions on the gel pill;study the dynamics of the gel pill drug metabolism in SD rats.
The experimental results show that: reinforcing material de-acetylated glucomannan and sodiumalginate ratio had significant effects on the encapsulation efficiency and the average release time,when thedeacetylation of glucomannan and sodium alginate ratio was1:1,it has the Maximum encapsulationefficiency,the longest average release time, increase or reduce the ratio between the two, the encapsulationefficiency got smaller, the average release time got longer; the effect of amount of Baicalin on theencapsulation efficiency was not significant,but has the significantly affect on the average release time,with the increase amount of Baicalin, the average release time was significantly prolonged; the effect ofamount of ethanol on the encapsulation efficiency was not significant, but has the significantly affect onthe average release time, when the amount of Ethanol was10%,15%, it has the longest Averagerelease,Less than10%or greater than15%both Shorten the average release time;the effect ofglucomannan deacetylation pH value, gel time, drying temperature on the encapsulation efficiency and theaverage release time both has no significant impact. Select the three factors that more significant on thegel pill encapsulation efficiency and the average release time: the gel matrix material deacetylation ofglucomannan and sodium alginate ratio, the amount of Baicalin and ethanol. the encapsulation efficiencyand average release time as an index, using central composite design to optimize the prescription, The bestformula: gel matrix material deacetylation of glucomannan and sodium alginate ratio of37:63, Baicalinamount of4.94%,13.97%of the ethanol dosage.
Authentication: Three batches of samples based on the best prescription and Process:encapsulation efficiency greater than80%, the average release time is greater than2h, the release data werefitted by equation,Drug release model were similar to Peppas equation,the release mechanism is theSynergies of the diffusion of the drug and the Skeleton dissolution.
The gel pill pHysicochemical properties: gel pill average particle size of2.01mm, the encapsulation efficiency was81.15%, theDrug loading was66.95%, the swelling ratiosgel of pills indistilled water,pH1.2HCL solution, pH6.8phosphate buffer were317%、338%、936%. Acceleratedstability experiment experimental results show that: Store the Gel pills at a temperature of40°C±1°C,relative humidity conditions of75%±5%for6months, Gel pills appearance, the main ingredients, in vitrorelease rate did not change significantly indicating that gel Pill stable under the above conditions. Ionicstrength has the significant effect on the average release time, within a certain range, with the enhancementof the ionic strength, the average release time got shorter. pH value has the significant effect on the averagerelease time,in pH1.2hydrochloric acid solution, the6h cumulative release rate less than1%, in pH6.8phosphate buffer, the6h cumulative release rate can up to80%.
The vivo pharmacokinetic experiments of Gel pills in SD rats studies showed that theoptimization of the formulations, the pharmacokinetic parameters changed significantly, the AUCincreased by about1.5times,CL was reduced from3.9ml/min to2.6ml/min, t1/2beta extend from1.76h to2.58h, which indicates that the the Baicalin gel pill changed the In vivo behavior of Baicalin, made theBaicalin in the body to maintain higher plasma concentration for longer time. The experiments prove thatthe designed gel pill conform to the original design requirements.
引文
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