具有抗2型糖尿病活性的海洋药物HS203的制备及其初步药代动力学研究
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摘要
随着人们生活水平的提高，糖尿病的发病率迅速上升。据世界卫生组织公布，全世界已有3.47亿糖尿病患者。中国已成为世界糖尿病发病人数最多的国家，发病率达9.7%。2型糖尿病患者占糖尿病总患病人数的90%以上，以胰岛素分泌不足和胰岛素抵抗为主要特征。2型糖尿病的治疗不依赖胰岛素，主要通过口服降糖药治疗，现有的口服降糖药多存在着继发性失效，诱发低血糖及价格昂贵等缺点。因此，有必要开发新型口服降糖药。大量研究表明，糖尿病的发生和体内糖胺聚糖的改变有密切关系，补充铬可以显著改善糖尿病人的糖代谢和血脂代谢。海洋寡糖具有资源丰富，低毒和生物活性好等优点，具有良好的开发应用前景。基于以上几点，本文选择与糖胺聚糖结构类似的海洋酸性寡糖与铬离子进行配合，以期发挥两者的协同抗糖尿病作用，开发新型口服降糖药。
本论文在前期研究的基础上，优化了抗2型糖尿病海洋药物HS203的制备条件。通过核磁共振碳谱，紫外-可见全波长光谱，红外光谱等分析手段对制得的HS203进行了结构表征。然后对HS203胶囊剂的制备和质量标准进行了研究，确定了HS203胶囊制剂配方，并对药物在加速条件下6个月和室温条件下24个月的稳定性进行了考察，结果发现，HS203质量稳定，选用的包装材料也符合要求，对存储条件无苛刻要求。
采用Wistar大鼠2型糖尿病模型和KM小鼠2型糖尿病模型对HS203的降血糖活性及其机制进行了研究，结果表明HS203在糖尿病模型动物上表现出较好的降血糖活性，且没有急性降血糖作用，不存在一过性血糖降低的危险，其通过提高胰岛素敏感指数降低血糖，且具有一定的肾脏保护和减轻胰腺损伤作用，有较好的抗糖尿病应用前景。
对HS203药物在小鼠及beagle犬内的急性毒性试验进行了研究，结果表明HS203药物在动物体内毒性很小，在可给药的最大剂量下，动物仍无死亡情况发生，因此HS203安全性高，毒副作用小。采用柱后衍生-高效液相色谱法对HS203初步的药代动力学进行了研究，结果表明HS203药物注射给药后在大鼠体内代谢较快，t1/2α为3.35±0.78min。口服给药后，药物在大鼠体内代谢较慢，t1/2α为143.2±9.8min，在beagle犬内吸收较快。在beagle犬内的毒代动力学表明，药物连续给药后，在第8天和第30天血药浓度明显升高，且在雄犬内血药浓度较雌犬内高。说明药物经口服给药后，在大鼠和beagle犬内的代谢存在种属差异，且代谢过程可能与性别有关。
由于HS203属于口服用药，它属于非淀粉类糖类物质，该类物质对肠道微生物的影响，以及它是否被降解以及降解产物情况需要研究。本文采用厌氧发酵系统对HS203在不同人肠道微生物中的利用情况进行了研究，结果发现：HS203可被微生物降解为更低聚合度寡糖。采用PCR-DGGE的方法对HS203为底物发酵的样品菌群结构进行了研究，结果表明HS203可以明显影响肠道微生物的菌群结构。此外，对厌氧培养过程中微生物发酵产生的短链脂肪酸进行了测定，结果表明HS203能促进短链脂肪酸的产生。采用稀释涂板法进一步对细菌进行筛选分离，从肠道微生物中分离得到了两株可以利用HS203的细菌，分别为解木聚糖拟杆菌（Bacteroides xylanisolvens）和卵形拟杆菌(Bacteroides ovatus)，说明拟杆菌在利用HS203和褐藻胶及其寡糖寡糖过程中具有重要的作用。
综上所述，本论文对海洋寡糖药物HS203及其制剂的制备工艺，理化性质及稳定性进行了研究。对其在糖尿病动物模型上的降血糖活性进行了研究，然后对其急性毒性试验进行了考察，还对HS203在不同动物体内的药代毒代动力学进行了研究，最后对HS203及其类似物对肠道微生物的影响进行了研究，为将其开发成为抗2型糖尿病海洋寡糖药物提供了基础与依据。
The incidence of diabetes is rising rapidly along with the improvement of people'sliving standards. World health organization announced that347million people havediabetes all over the world. China has become the country with the largest number ofdiabetes, the prevalence is9.7%. Type2diabetes accounts for more than90%of thetotal number of diabetes patients, mainly associated with insufficient insulin secretionand insulin resistance. Treatment for type2diabetes is not dependent on insulin, mainlytreated by oral hypoglycemic drugs, however, current oral hypoglycemic drugs oftenhave many disadvantages such as secondary failure, hypoglycemia and expensive.Therefore, it is necessary to develop new oral hypoglycemic drugs. Many studies showthat there is a close relationship between the occurrence of diabetes and the changes inglycosaminoglycans structure, and chromium supplementation can significantlyimprove glucose metabolism and lipid metabolism in diabetic patients. Marineoligosaccharides have many advantages including abundant resources, low toxicity andgood bioactivity, show good application prospects in drug development. In this paper,the complex prepared from marine acidic oligosaccharide which is similar in structurewith glycosaminoglycans and chromium ions was studied, in order to develop a neworal hypoglycemic drug.
First of all, the orthogonal experiments were carried out to optimize the preparationconditions of marine drug HS203from oligomannuronate and chromium, and theoptimal reaction conditions were determined. The structural characterization of HS203was performed by using Nuclear magnetic resonance (NMR) spectroscopy, fullwavelength UV-Vis scanning spectrametry, Infrared spectroscopy and other analyticaltechniques. Then the preparation of its capsule and the quality standards were studied, and the capsule formulations were determined. The stabilities of HS203capsules underaccelerated conditions for six months and room temperature for twenty-four monthswere investigated, the results indicated that the drug was stable and the packagingmaterials also meet the requirements, the drug did not need strict conditions for storage.
The hypoglycemic activity and its mechanism of HS203were also studied by usingtype2diabetic animal model in Wistar rats and in KM mice, the results showed thatHS203exhibited good hypoglycemic activity in animal models of diabetes mellitus, andhad no acute hypoglycemic effect, so there was no risk of a transient reduction of bloodglucose. The hypoglycemic activity of HS203was by improving insulin sensitivityindex, and also HS203could protect kidney and pancreas from damage caused byhyperglycemia, it showed good anti diabetic prospect.
The acute toxicity test of HS203in mice and beagle dogs was investigated, and theresults indicated that the toxicity of HS203was very little, no animal was dead even atthe highest dose by intravenous injection or intragastric administration, so it showedthat HS203was very safe, and with less toxic side effect. The preliminarypharmacokinetics in rats and toxicokinetic in beagle dogs of HS203were studied usingfluorescent labelling high-performance liquid chromatography with post-columnderivatization method, the results showed that HS203could be metabolized afterintravenous injection in rats, t1/2α was3.35±0.78min. After oral administration, HS203was absorbed slowly in rats but fast in beagle dogs. The toxicokinetic in beagle dogsshowed that the plasma concentration of HS203was significantly higher aftercontinuous oral administration for8days and30days than that in the first day, and theplasma concentration in the male dog was higher than that in the female dog. Theseresults showed that the metabolism was not only associated with species differences, butalso might related to gender.
The marine drug HS203will be developed as an oral preparation, and it belongs tonon-starchy carbohydrates, so it is necessary to study its effect to gut microbes. WhetherHS203was degraded or not, and what kinds of degradation products are produced, in order to know the metabolic process in vivo. The anaerobic fermentation system wasused to study the utilization of HS203, the results showed that HS203could be used bythe gut microbes. Polymerase chain reaction-denaturing gradient gel electrophoresis(PCR-DGGE) analysis was used to study the composition of the microbiota afterfermentation of HS203, the results indicated that HS203could significantly affect thecomposition of the microbiota, the intestinal microflora from different person weredistinctly different. The results also showed that the bacterias were mainly Bacteroides,and two strains were found in almost all the samples, they were Bacteroidesxylanisolvens and Clostridium clostridioforme respectively. The short chain fat acidsproduced during anaerobic fermentation process were determined. The isolation ofmicrobes was studied by using the gradient dilution and plate paint isolation methods,two strains could degrade HS203were isolated, they were Bacteroides xylanisolvensand Bacteroides ovatus, these results indicated that Bacteroides played an important rolein the use of HS203and its oligosaccharides.
In conclusion, the preparation, the properties and stability of marine oligosaccharidedrug HS203and its capsule were studied in this paper. And then the hypoglycemicactivity in animal models of diabetes and the acute toxicity test were investigated, thepharmacokinetics and the toxicokinetic in different animals were also studied. In the last,the effect on intestinal microflora of HS203was investigated by using anaerobicfermentation system. These useful data offered the basis for developing it to be apromising anti-type2diabetes marine oligosaccharide drug in the future.
本论文在前期研究的基础上，优化了抗2型糖尿病海洋药物HS203的制备条件。通过核磁共振碳谱，紫外-可见全波长光谱，红外光谱等分析手段对制得的HS203进行了结构表征。然后对HS203胶囊剂的制备和质量标准进行了研究，确定了HS203胶囊制剂配方，并对药物在加速条件下6个月和室温条件下24个月的稳定性进行了考察，结果发现，HS203质量稳定，选用的包装材料也符合要求，对存储条件无苛刻要求。
采用Wistar大鼠2型糖尿病模型和KM小鼠2型糖尿病模型对HS203的降血糖活性及其机制进行了研究，结果表明HS203在糖尿病模型动物上表现出较好的降血糖活性，且没有急性降血糖作用，不存在一过性血糖降低的危险，其通过提高胰岛素敏感指数降低血糖，且具有一定的肾脏保护和减轻胰腺损伤作用，有较好的抗糖尿病应用前景。
对HS203药物在小鼠及beagle犬内的急性毒性试验进行了研究，结果表明HS203药物在动物体内毒性很小，在可给药的最大剂量下，动物仍无死亡情况发生，因此HS203安全性高，毒副作用小。采用柱后衍生-高效液相色谱法对HS203初步的药代动力学进行了研究，结果表明HS203药物注射给药后在大鼠体内代谢较快，t1/2α为3.35±0.78min。口服给药后，药物在大鼠体内代谢较慢，t1/2α为143.2±9.8min，在beagle犬内吸收较快。在beagle犬内的毒代动力学表明，药物连续给药后，在第8天和第30天血药浓度明显升高，且在雄犬内血药浓度较雌犬内高。说明药物经口服给药后，在大鼠和beagle犬内的代谢存在种属差异，且代谢过程可能与性别有关。
由于HS203属于口服用药，它属于非淀粉类糖类物质，该类物质对肠道微生物的影响，以及它是否被降解以及降解产物情况需要研究。本文采用厌氧发酵系统对HS203在不同人肠道微生物中的利用情况进行了研究，结果发现：HS203可被微生物降解为更低聚合度寡糖。采用PCR-DGGE的方法对HS203为底物发酵的样品菌群结构进行了研究，结果表明HS203可以明显影响肠道微生物的菌群结构。此外，对厌氧培养过程中微生物发酵产生的短链脂肪酸进行了测定，结果表明HS203能促进短链脂肪酸的产生。采用稀释涂板法进一步对细菌进行筛选分离，从肠道微生物中分离得到了两株可以利用HS203的细菌，分别为解木聚糖拟杆菌（Bacteroides xylanisolvens）和卵形拟杆菌(Bacteroides ovatus)，说明拟杆菌在利用HS203和褐藻胶及其寡糖寡糖过程中具有重要的作用。
综上所述，本论文对海洋寡糖药物HS203及其制剂的制备工艺，理化性质及稳定性进行了研究。对其在糖尿病动物模型上的降血糖活性进行了研究，然后对其急性毒性试验进行了考察，还对HS203在不同动物体内的药代毒代动力学进行了研究，最后对HS203及其类似物对肠道微生物的影响进行了研究，为将其开发成为抗2型糖尿病海洋寡糖药物提供了基础与依据。
The incidence of diabetes is rising rapidly along with the improvement of people'sliving standards. World health organization announced that347million people havediabetes all over the world. China has become the country with the largest number ofdiabetes, the prevalence is9.7%. Type2diabetes accounts for more than90%of thetotal number of diabetes patients, mainly associated with insufficient insulin secretionand insulin resistance. Treatment for type2diabetes is not dependent on insulin, mainlytreated by oral hypoglycemic drugs, however, current oral hypoglycemic drugs oftenhave many disadvantages such as secondary failure, hypoglycemia and expensive.Therefore, it is necessary to develop new oral hypoglycemic drugs. Many studies showthat there is a close relationship between the occurrence of diabetes and the changes inglycosaminoglycans structure, and chromium supplementation can significantlyimprove glucose metabolism and lipid metabolism in diabetic patients. Marineoligosaccharides have many advantages including abundant resources, low toxicity andgood bioactivity, show good application prospects in drug development. In this paper,the complex prepared from marine acidic oligosaccharide which is similar in structurewith glycosaminoglycans and chromium ions was studied, in order to develop a neworal hypoglycemic drug.
First of all, the orthogonal experiments were carried out to optimize the preparationconditions of marine drug HS203from oligomannuronate and chromium, and theoptimal reaction conditions were determined. The structural characterization of HS203was performed by using Nuclear magnetic resonance (NMR) spectroscopy, fullwavelength UV-Vis scanning spectrametry, Infrared spectroscopy and other analyticaltechniques. Then the preparation of its capsule and the quality standards were studied, and the capsule formulations were determined. The stabilities of HS203capsules underaccelerated conditions for six months and room temperature for twenty-four monthswere investigated, the results indicated that the drug was stable and the packagingmaterials also meet the requirements, the drug did not need strict conditions for storage.
The hypoglycemic activity and its mechanism of HS203were also studied by usingtype2diabetic animal model in Wistar rats and in KM mice, the results showed thatHS203exhibited good hypoglycemic activity in animal models of diabetes mellitus, andhad no acute hypoglycemic effect, so there was no risk of a transient reduction of bloodglucose. The hypoglycemic activity of HS203was by improving insulin sensitivityindex, and also HS203could protect kidney and pancreas from damage caused byhyperglycemia, it showed good anti diabetic prospect.
The acute toxicity test of HS203in mice and beagle dogs was investigated, and theresults indicated that the toxicity of HS203was very little, no animal was dead even atthe highest dose by intravenous injection or intragastric administration, so it showedthat HS203was very safe, and with less toxic side effect. The preliminarypharmacokinetics in rats and toxicokinetic in beagle dogs of HS203were studied usingfluorescent labelling high-performance liquid chromatography with post-columnderivatization method, the results showed that HS203could be metabolized afterintravenous injection in rats, t1/2α was3.35±0.78min. After oral administration, HS203was absorbed slowly in rats but fast in beagle dogs. The toxicokinetic in beagle dogsshowed that the plasma concentration of HS203was significantly higher aftercontinuous oral administration for8days and30days than that in the first day, and theplasma concentration in the male dog was higher than that in the female dog. Theseresults showed that the metabolism was not only associated with species differences, butalso might related to gender.
The marine drug HS203will be developed as an oral preparation, and it belongs tonon-starchy carbohydrates, so it is necessary to study its effect to gut microbes. WhetherHS203was degraded or not, and what kinds of degradation products are produced, in order to know the metabolic process in vivo. The anaerobic fermentation system wasused to study the utilization of HS203, the results showed that HS203could be used bythe gut microbes. Polymerase chain reaction-denaturing gradient gel electrophoresis(PCR-DGGE) analysis was used to study the composition of the microbiota afterfermentation of HS203, the results indicated that HS203could significantly affect thecomposition of the microbiota, the intestinal microflora from different person weredistinctly different. The results also showed that the bacterias were mainly Bacteroides,and two strains were found in almost all the samples, they were Bacteroidesxylanisolvens and Clostridium clostridioforme respectively. The short chain fat acidsproduced during anaerobic fermentation process were determined. The isolation ofmicrobes was studied by using the gradient dilution and plate paint isolation methods,two strains could degrade HS203were isolated, they were Bacteroides xylanisolvensand Bacteroides ovatus, these results indicated that Bacteroides played an important rolein the use of HS203and its oligosaccharides.
In conclusion, the preparation, the properties and stability of marine oligosaccharidedrug HS203and its capsule were studied in this paper. And then the hypoglycemicactivity in animal models of diabetes and the acute toxicity test were investigated, thepharmacokinetics and the toxicokinetic in different animals were also studied. In the last,the effect on intestinal microflora of HS203was investigated by using anaerobicfermentation system. These useful data offered the basis for developing it to be apromising anti-type2diabetes marine oligosaccharide drug in the future.
引文
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