人参皂苷Rg3鼻腔给药微球制剂的研究
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摘要
人参皂苷Rg3是存在于天然药物人参中的一种四环三萜皂苷,具有多方面的药理作用,如抗肿瘤、提高免疫、促进记忆、抗血管增生等。而人参皂苷Rg3的抗疲劳作用也随着抗疲劳新药参百益胶囊临床应用的增加进一步得到肯定。但是人参皂苷Rg3口服后血浆浓度很低,3.2mg/kg口服后的C_(max)值仅为(16.0±6.0)ng/ml,t_(max)值为(0.66±0.10)h。一般认为,口服后血药浓度很低的原因大致有三:一是口服后经胃肠道吸收的药量少;二是口服后进入胃肠道内的药物被其中的酶或肠道细菌所代谢;三是药物虽可被胃肠黏膜吸收,但药物被肠壁或肝脏的酶所代谢,即首过效应。
鼻腔作为药物吸收部位是因为鼻黏膜上有大量的细微绒毛,可大大增加上皮细胞的药物吸收面积,上皮细胞下分布着丰富的血管网,流经鼻腔的静脉血不经过肝脏可直接进入体循环。鼻腔中pH为6.5～7.1,对药物吸收影响很小。分子量较大的药物也可通过鼻黏膜吸收。因此,鼻黏膜给药特别适合在胃肠道不稳定、在胃肠道内不易被吸收或首过作用强的药物。但鼻腔中纤毛的正常生理摆动能将滴入的药物很快清除,影响药物吸收。若将药物制成亲水性凝胶微球制剂,能延长药物在鼻腔中滞留时间,以提高药物的吸收。
本文首先研究人参皂苷Rg3原料药经鼻给药后的抗疲劳作用并探讨其抗疲劳作用机制。旨在为Rg3抗疲劳鼻腔给药制剂提供动物实验依据及确定有效剂量。以低、中、高(0.05、0.1、0.5mg/kg)三个剂量的人参皂苷Rg3经鼻给予小鼠两周,观察小鼠负重游泳时间,测定一系列与疲劳相关的生化指标如血清尿素氮、血乳酸、肝糖原、肌糖原、肝总SOD活力、肝MDA含量及乳酸脱氢酶。结果与空白对照组比较,中、高剂量组可显著延长小鼠负重游泳时间(p＜0.05;p＜0.01)且肝糖原含量有显著增加(p＜0.05);三个剂量组对小鼠运动时产生的血清尿素氮含量均有显著降低(p＜0.01);低、中剂量组对小鼠运动后血乳酸值有显著降低(p＜0.05);但是对于肌糖原、肝总SOD含量、肝MDA含量及乳酸脱氢酶含量没有显著性影响。由此可以推断鼻腔给予人参皂苷Rg3后具有抗疲劳作用,作用机制可能与降低血乳酸浓度及提高肝糖原贮量有关。
其次对Rg3进行了处方前性质研究,为之后的制剂制备奠定基础。并且应用大鼠在体鼻腔滞留法,通过给予不同浓度相同体积及不同体积相同浓度的人参皂苷Rg3,考察Rg3的鼻腔吸收性质.然后选用三种不同吸收促进剂:壳聚糖、β-环糊精和冰片考察促进剂对药物鼻黏膜吸收的促进作用,同时结合在体蟾蜍纤毛毒性的实验对吸收促进剂进行了筛选,最终选择促吸收效果好而毒性小的壳聚糖作为载体材料,并由此作为微球制剂载体材料选择的依据。
第三对Rg3鼻用壳聚糖微球制剂的处方工艺进行了研究。通过对乳化交联、复乳化交联两种方法制备微球的比较,发现复乳化交联法制备的微球从微球形态到微球的载药量和包封率方面均好于乳化交联法,所以选择复乳化交联法作为微球的制备方法。在影响因素考察中,以单因素法考察了微球制备工艺的独立影响因素,包括油相的选择:壳聚糖的脱乙酰度、浓度:交联剂种类、用量;乳化剂种类、用量及乳化速度等。在此基础上,通过星点设计—效应面优化法,考察了具有交互作用的影响因素,包括投药比、有机相与水相体积比及初乳与油相体积比。以粒径、包封率和载药量作为指标,对处方进行了优化,确定了最佳处方:投药比:0.45;有机相与水相比:0.5;初乳与油相比:0.15。按此处方制备的微球形态良好,大小较均匀。平均粒径为(44.99±12.59)μm,载药量为(10.25±0.08)%,包封率为(30.61±1.46)%。预测值与实验测定值基本一致。同时对制备的Rg3壳聚糖微球粉雾剂进行了质量评价和安全性评价。建立了Rg3壳聚糖微球的体外释放度测定方法,初步探讨了释药机理,以pH为6.5的含3%十二烷基硫酸钠(SDS)的生理盐水为释放介质,在37℃,100 rpm条件下用溶出仪浆法进行体外释放实验,结果符合要求。之后对Rg3壳聚糖微球粉雾剂的安全性及微球的黏膜黏附力进行了考察,将粉雾剂鼻腔给予大鼠,对大鼠进行刺激性试验,每天给药一次,连续给药2周后,未发现对鼻腔局部产生明显红肿等现象。剥离大鼠鼻中隔黏膜,扫描电镜观察纤毛形态,进一步判断制剂对大鼠鼻纤毛的毒性。同时应用在体蟾蜍上腭模型考察了Rg3壳聚糖微球粉雾剂对黏膜纤毛运动的影响,通过测定纤毛摆动持续时间评价微球制剂的鼻纤毛毒性,并且测定纤毛输送速率评价微球的黏膜黏附力。
最后评价了Rg3壳聚糖微球鼻腔粉雾剂对小鼠的抗疲劳药效作用。实验动物分为3组:空白对照组,阳性对照组及Rg3壳聚糖微球粉雾剂组,经鼻给予小鼠两周,每天给药一次。观察小鼠负重游泳时间,测定一系列与疲劳相关的生化指标如血清尿素氮、血乳酸、肝糖原、肌糖原,肝总SOD活力、肝MDA含量及乳酸脱氢酶。结果与空白对照组比较,Rg3壳聚糖粉雾剂组可显著延长小鼠负重游泳时间(P＜0.05),能显著降低运动后小鼠的SUN水平及抑制小鼠运动后乳酸的堆积,对肝SOD含量有升高趋势,且对肝总MDA含量也有降低趋势;能提高肝、肌糖原含量,促进糖原储备,加速机体代谢产物清除。由此可以推断鼻腔给予人参皂苷Rg3壳聚糖粉雾剂后具有抗疲劳作用。
Ginsenoside Rg3(3β,12β,20(R)-dihydroxydammar-24-ene-O-[β-D-glucopyranosyl (1→2)-β-D-glucopyranoside]),a minor ginsenoside from the Panax ginseng,has been shown multiple pharmacological activities,including anti-fatigue,anti-tumor, platelet aggregation inhibition enhance immunity and memory improvement and so on. However,the plasma concentration of Rg3 after oral administration in human is very low.Previous researches obtained some human pharmacokinetic(PK) parameters, including Cmax of(16.00±6.00) ng/ml and tmax of(0.66±0.10) h at 3.2 mg/kg from the oral experiments.It is widely accepted that the short half-life and low plasma concentration of drugs had many reasons,firstly,the drug absorbed by gastrointestinal was low;secondly,the drug is metabolized quickly by the enzymes and bacterias in the gastrointestinal tract;thirdly,the drug can be absorbed by the gastrointestinal mocosal,but is metabolized by the enzymes in intestinal or liver,which is called first-pass effect.
Recently,the interest arises from the different possible advantages presented by the nasal cavity,such as:the direct transport of absorbed drugs into the systemic circulation thereby avoiding the first-pass effect in peroral administration,the lower enzymatic activity compared with the gastrointestinal tract and the liver,the convenience for administration when there is no water.For all these reasons the nasal route can be considered as an useful alternative both to parenteral and oral routes.
In this study,we used chitosan as the carrier material to prepare ginsenoside Rg3 microspheres,which was considered to have a bioadhesive effect and also have an absorption enhance effect as the carrier material.
Firstly,in order to provide an animal experimental evidence of Rg3 intranasal administrated preparation,in this study,we investigated the anti-fatigue effect of Rg3 after intranasal administration.In the present study,we investigated the effects of Rg3 on performance of the weight-loaded swimming test and on biochemical parameters related to fatigue:serum urea nitrogen(SUN),lactic dehydrogenase(LDH),superoxide dismutase(SOD),malondialdehyde(MDA),blood lactic acid(LA) and hepatic glycogen.Ginsenoside Rg3 was administrated intranasally to mice for two weeks at three different doses.Compared with the negative control group,the intermediate-dose and the high-dose groups significantly prolonged the weight-loaded swimming time(p＜0.05;p＜0.01);and the hepatic glycogen levels were significantly increased(p＜0.05) in these two groups;SUN levels were significantly decreased in three Rg3-treated groups(p＜0.01);in addition,the low-dose group obviously decreased the content of blood LA(p＜0.05).However,the levels of LDH,SOD and MDA did not show a significant change.The results predict a benefit of Rg3 as an anti-fatigue treatment by intranasal administration.The mechanism is related to increase the storage of hepatic glycogen,and decrease the accumulation of metabolite such as lactic acid and SUN.
Secondly,we investigated the physical and chemical properties of Rg3 before prescription.Then we used rat in vivo in-situ method as an experimental model to investigate the regulation of nasal absorption,The effects of drug volume and concentration on nasal absorption of Rg3 were studied.Then we studied the effects of three different absorption enhancers such as:chitosan,β-cyclodextrin and bomeol through rats in-situ nasal cavity stagnation method,combined with the results of ciliotoxity experiments,we finally chose chitosan as a carrier material because of its good promotion effect and low ciliotoxity.
Thirdly,a detailed investigation of the preparation of chitosan microspheres was carried out.It was found that the loading efficiency of multiple emulsion method was higher than emulsion method,so the multiple emulsion method was selected to prepare microspheres.The effects of processing parameters,including concentration of chitosan,emulsifying agents and speed of emulsifying and so on were also investigated according to the Single-factor Experimental Design.In order to optimize the formulation,a Central Composite Design(CCD) was employed for three independent variables,the ratio of drug to chitosan,the ratio of organic phase to water phase and ratio of first emulsion to oil phase.The dependent response variables were measured as particle size,drug loading and loading efficiency.Consequently,when the drug ratio was 0.45,the ratio of organic phase to water phase was 0.5 and the ratio of first emulsion to oil phase was 0.15,microspheres with a good shape were prepared. The average diameter was(44.99±12.59)μm,the drug loading capacity was (10.25±0.08)%,the encapsulation efficiency was(30.61±1.46)%.At the same time, we established the method to determine the in-vitro release of Rg3 chitosan microspheres and approached the release mechanism,then investigated the influencing factors related to drug release.The test was carried out under 37℃and constantly stirred at the rate of 100 rounds per minute.The media for release was saline(pH=6.5) contained 3%SDS.Then,we studied the ciliotoxicity and mucoadhesion of Rg3 chitosan microspheres.Rats were used for irritation tests.No obvious flare on the nasal region was found in three dosage levels after successive intranasal administered for 2 weeks.To evaluate the ciliotoxicity of Rg3 chitosan microspheres,the lasting time of ciliary movement was recorded with in situ toad palate model.The degree of mucoadhesion was also investigated by determining the mucociliary transport rate(MTR)of the microspheres.The results showed that Rg3 chitosan microspheres could effectively reduce ciliotoxicity and had a good mucoadhesive property.
Finally,we evaluated the anti-fatigue effect of Rg3 chitosan microspheres.The test animals were divided into three groups:negative control group,positive control group and Rg3-treated group.We investigated the effects of Rg3 on performance of the weight-loaded swimming test and on biochemical parameters related to fatigue: serum urea nitrogen(SUN),lactic dehydrogenase(LDH),superoxide dismutase(SOD), malondialdehyde(MDA),blood lactic acid(LA) and hepatic glycogen.The results suggested that the Rg3 chitosan microsphere had an anti-fatigue effect.
鼻腔作为药物吸收部位是因为鼻黏膜上有大量的细微绒毛,可大大增加上皮细胞的药物吸收面积,上皮细胞下分布着丰富的血管网,流经鼻腔的静脉血不经过肝脏可直接进入体循环。鼻腔中pH为6.5～7.1,对药物吸收影响很小。分子量较大的药物也可通过鼻黏膜吸收。因此,鼻黏膜给药特别适合在胃肠道不稳定、在胃肠道内不易被吸收或首过作用强的药物。但鼻腔中纤毛的正常生理摆动能将滴入的药物很快清除,影响药物吸收。若将药物制成亲水性凝胶微球制剂,能延长药物在鼻腔中滞留时间,以提高药物的吸收。
本文首先研究人参皂苷Rg3原料药经鼻给药后的抗疲劳作用并探讨其抗疲劳作用机制。旨在为Rg3抗疲劳鼻腔给药制剂提供动物实验依据及确定有效剂量。以低、中、高(0.05、0.1、0.5mg/kg)三个剂量的人参皂苷Rg3经鼻给予小鼠两周,观察小鼠负重游泳时间,测定一系列与疲劳相关的生化指标如血清尿素氮、血乳酸、肝糖原、肌糖原、肝总SOD活力、肝MDA含量及乳酸脱氢酶。结果与空白对照组比较,中、高剂量组可显著延长小鼠负重游泳时间(p＜0.05;p＜0.01)且肝糖原含量有显著增加(p＜0.05);三个剂量组对小鼠运动时产生的血清尿素氮含量均有显著降低(p＜0.01);低、中剂量组对小鼠运动后血乳酸值有显著降低(p＜0.05);但是对于肌糖原、肝总SOD含量、肝MDA含量及乳酸脱氢酶含量没有显著性影响。由此可以推断鼻腔给予人参皂苷Rg3后具有抗疲劳作用,作用机制可能与降低血乳酸浓度及提高肝糖原贮量有关。
其次对Rg3进行了处方前性质研究,为之后的制剂制备奠定基础。并且应用大鼠在体鼻腔滞留法,通过给予不同浓度相同体积及不同体积相同浓度的人参皂苷Rg3,考察Rg3的鼻腔吸收性质.然后选用三种不同吸收促进剂:壳聚糖、β-环糊精和冰片考察促进剂对药物鼻黏膜吸收的促进作用,同时结合在体蟾蜍纤毛毒性的实验对吸收促进剂进行了筛选,最终选择促吸收效果好而毒性小的壳聚糖作为载体材料,并由此作为微球制剂载体材料选择的依据。
第三对Rg3鼻用壳聚糖微球制剂的处方工艺进行了研究。通过对乳化交联、复乳化交联两种方法制备微球的比较,发现复乳化交联法制备的微球从微球形态到微球的载药量和包封率方面均好于乳化交联法,所以选择复乳化交联法作为微球的制备方法。在影响因素考察中,以单因素法考察了微球制备工艺的独立影响因素,包括油相的选择:壳聚糖的脱乙酰度、浓度:交联剂种类、用量;乳化剂种类、用量及乳化速度等。在此基础上,通过星点设计—效应面优化法,考察了具有交互作用的影响因素,包括投药比、有机相与水相体积比及初乳与油相体积比。以粒径、包封率和载药量作为指标,对处方进行了优化,确定了最佳处方:投药比:0.45;有机相与水相比:0.5;初乳与油相比:0.15。按此处方制备的微球形态良好,大小较均匀。平均粒径为(44.99±12.59)μm,载药量为(10.25±0.08)%,包封率为(30.61±1.46)%。预测值与实验测定值基本一致。同时对制备的Rg3壳聚糖微球粉雾剂进行了质量评价和安全性评价。建立了Rg3壳聚糖微球的体外释放度测定方法,初步探讨了释药机理,以pH为6.5的含3%十二烷基硫酸钠(SDS)的生理盐水为释放介质,在37℃,100 rpm条件下用溶出仪浆法进行体外释放实验,结果符合要求。之后对Rg3壳聚糖微球粉雾剂的安全性及微球的黏膜黏附力进行了考察,将粉雾剂鼻腔给予大鼠,对大鼠进行刺激性试验,每天给药一次,连续给药2周后,未发现对鼻腔局部产生明显红肿等现象。剥离大鼠鼻中隔黏膜,扫描电镜观察纤毛形态,进一步判断制剂对大鼠鼻纤毛的毒性。同时应用在体蟾蜍上腭模型考察了Rg3壳聚糖微球粉雾剂对黏膜纤毛运动的影响,通过测定纤毛摆动持续时间评价微球制剂的鼻纤毛毒性,并且测定纤毛输送速率评价微球的黏膜黏附力。
最后评价了Rg3壳聚糖微球鼻腔粉雾剂对小鼠的抗疲劳药效作用。实验动物分为3组:空白对照组,阳性对照组及Rg3壳聚糖微球粉雾剂组,经鼻给予小鼠两周,每天给药一次。观察小鼠负重游泳时间,测定一系列与疲劳相关的生化指标如血清尿素氮、血乳酸、肝糖原、肌糖原,肝总SOD活力、肝MDA含量及乳酸脱氢酶。结果与空白对照组比较,Rg3壳聚糖粉雾剂组可显著延长小鼠负重游泳时间(P＜0.05),能显著降低运动后小鼠的SUN水平及抑制小鼠运动后乳酸的堆积,对肝SOD含量有升高趋势,且对肝总MDA含量也有降低趋势;能提高肝、肌糖原含量,促进糖原储备,加速机体代谢产物清除。由此可以推断鼻腔给予人参皂苷Rg3壳聚糖粉雾剂后具有抗疲劳作用。
Ginsenoside Rg3(3β,12β,20(R)-dihydroxydammar-24-ene-O-[β-D-glucopyranosyl (1→2)-β-D-glucopyranoside]),a minor ginsenoside from the Panax ginseng,has been shown multiple pharmacological activities,including anti-fatigue,anti-tumor, platelet aggregation inhibition enhance immunity and memory improvement and so on. However,the plasma concentration of Rg3 after oral administration in human is very low.Previous researches obtained some human pharmacokinetic(PK) parameters, including Cmax of(16.00±6.00) ng/ml and tmax of(0.66±0.10) h at 3.2 mg/kg from the oral experiments.It is widely accepted that the short half-life and low plasma concentration of drugs had many reasons,firstly,the drug absorbed by gastrointestinal was low;secondly,the drug is metabolized quickly by the enzymes and bacterias in the gastrointestinal tract;thirdly,the drug can be absorbed by the gastrointestinal mocosal,but is metabolized by the enzymes in intestinal or liver,which is called first-pass effect.
Recently,the interest arises from the different possible advantages presented by the nasal cavity,such as:the direct transport of absorbed drugs into the systemic circulation thereby avoiding the first-pass effect in peroral administration,the lower enzymatic activity compared with the gastrointestinal tract and the liver,the convenience for administration when there is no water.For all these reasons the nasal route can be considered as an useful alternative both to parenteral and oral routes.
In this study,we used chitosan as the carrier material to prepare ginsenoside Rg3 microspheres,which was considered to have a bioadhesive effect and also have an absorption enhance effect as the carrier material.
Firstly,in order to provide an animal experimental evidence of Rg3 intranasal administrated preparation,in this study,we investigated the anti-fatigue effect of Rg3 after intranasal administration.In the present study,we investigated the effects of Rg3 on performance of the weight-loaded swimming test and on biochemical parameters related to fatigue:serum urea nitrogen(SUN),lactic dehydrogenase(LDH),superoxide dismutase(SOD),malondialdehyde(MDA),blood lactic acid(LA) and hepatic glycogen.Ginsenoside Rg3 was administrated intranasally to mice for two weeks at three different doses.Compared with the negative control group,the intermediate-dose and the high-dose groups significantly prolonged the weight-loaded swimming time(p＜0.05;p＜0.01);and the hepatic glycogen levels were significantly increased(p＜0.05) in these two groups;SUN levels were significantly decreased in three Rg3-treated groups(p＜0.01);in addition,the low-dose group obviously decreased the content of blood LA(p＜0.05).However,the levels of LDH,SOD and MDA did not show a significant change.The results predict a benefit of Rg3 as an anti-fatigue treatment by intranasal administration.The mechanism is related to increase the storage of hepatic glycogen,and decrease the accumulation of metabolite such as lactic acid and SUN.
Secondly,we investigated the physical and chemical properties of Rg3 before prescription.Then we used rat in vivo in-situ method as an experimental model to investigate the regulation of nasal absorption,The effects of drug volume and concentration on nasal absorption of Rg3 were studied.Then we studied the effects of three different absorption enhancers such as:chitosan,β-cyclodextrin and bomeol through rats in-situ nasal cavity stagnation method,combined with the results of ciliotoxity experiments,we finally chose chitosan as a carrier material because of its good promotion effect and low ciliotoxity.
Thirdly,a detailed investigation of the preparation of chitosan microspheres was carried out.It was found that the loading efficiency of multiple emulsion method was higher than emulsion method,so the multiple emulsion method was selected to prepare microspheres.The effects of processing parameters,including concentration of chitosan,emulsifying agents and speed of emulsifying and so on were also investigated according to the Single-factor Experimental Design.In order to optimize the formulation,a Central Composite Design(CCD) was employed for three independent variables,the ratio of drug to chitosan,the ratio of organic phase to water phase and ratio of first emulsion to oil phase.The dependent response variables were measured as particle size,drug loading and loading efficiency.Consequently,when the drug ratio was 0.45,the ratio of organic phase to water phase was 0.5 and the ratio of first emulsion to oil phase was 0.15,microspheres with a good shape were prepared. The average diameter was(44.99±12.59)μm,the drug loading capacity was (10.25±0.08)%,the encapsulation efficiency was(30.61±1.46)%.At the same time, we established the method to determine the in-vitro release of Rg3 chitosan microspheres and approached the release mechanism,then investigated the influencing factors related to drug release.The test was carried out under 37℃and constantly stirred at the rate of 100 rounds per minute.The media for release was saline(pH=6.5) contained 3%SDS.Then,we studied the ciliotoxicity and mucoadhesion of Rg3 chitosan microspheres.Rats were used for irritation tests.No obvious flare on the nasal region was found in three dosage levels after successive intranasal administered for 2 weeks.To evaluate the ciliotoxicity of Rg3 chitosan microspheres,the lasting time of ciliary movement was recorded with in situ toad palate model.The degree of mucoadhesion was also investigated by determining the mucociliary transport rate(MTR)of the microspheres.The results showed that Rg3 chitosan microspheres could effectively reduce ciliotoxicity and had a good mucoadhesive property.
Finally,we evaluated the anti-fatigue effect of Rg3 chitosan microspheres.The test animals were divided into three groups:negative control group,positive control group and Rg3-treated group.We investigated the effects of Rg3 on performance of the weight-loaded swimming test and on biochemical parameters related to fatigue: serum urea nitrogen(SUN),lactic dehydrogenase(LDH),superoxide dismutase(SOD), malondialdehyde(MDA),blood lactic acid(LA) and hepatic glycogen.The results suggested that the Rg3 chitosan microsphere had an anti-fatigue effect.
引文
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[4]Park.I.H.,Piao L.Z.,Kwon S.W.,Lee Y.J.,Cho S.Y.,Park M.K.,et ai.;Cytotoxic Dammarane Glycosides from Processed Ginseng[J];Chem.Pharm.Bull.2002,50(4):538-540
[5]Keμm Y.S.,Han S.S.,Chun K.S.,Park K.K.,Park J.H.,Lee S.K.,et ai.;Inhibitory effects of the ginsenoside Rg3 on phorbol ester-induced cyclooxygenase-2 expression,NF-KB activation and tμmor promotion[J];Mutat.Res.-Fund.Mol.M.,2003,523-524:75-85
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[7]Patrick Y.K.,Daisy Y.L.,Wong P.K.,Leung N.K.,Wu P.Y.,Mak H.W.,et ai.;The angiosuppressive effects of20(R)-ginsenoside Rg3[J];Biochemical Pharmacology,2006(72):437-445
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[9]蒋新国:药物的鼻腔黏膜吸收[J];中国新药杂志,2003,12(11):902-905
[10]王东兴,高永良;鼻腔给药新剂型研究进展[J]:中国新药杂志,2002,11(8):589-592,
[11]Hirai S,Yashiki T,Matsuzawa T,et ai;Absorption of drμgs from the nasal mucosa of rat[J];Int J Pharm,1981,7(4):217-325
[12]陈建明,毛世瑞,毕殿洲;退黑激素明胶微球的鼻腔给药[J];药学学报,2000,35(10):786-789
[13]Chen Y,Kong LD,Xia X,Kung HF,Zhang L.Behavioral and biochemical studies of total furocoμmarins from seeds ofPsoralea corylifolia in the forced swimming test in mice[J]:Journal of Ethnopharmacology:2005,96(3):451-459
[14]Morris AC:Jacobs I:McLellan TM:Klμgerman A;Wang LC;Zamecnik J;No ergogenic effect of ginseng ingestion[J];Int J Sport Nutr;,1996,6(3):263-71
[15]Engels H J,Said JH,Wirth JC.Failure of chronic ginseng supplementation to affect work performance and energy metabolism in health adμlt femaies[J].Nutr Res 1999;16:1295-305
[16]Dong TTX,Zhao KJ,Huang WZ,Leung KW,Tsim KWK,Orthogonal array design in optimizing the extraction efficiency of active constituents from roots of Panax notoginseng[J], Phytother.Res.,2005,19:684-688
[17]付克翠,陈菊平,陈元武:运动疲劳概述[J];四川体育科学,2004,6(2):31-34
[18]Casteil LM,Newsholme EA.The relation between glutamine and the immunodepression observed in exercise[J].Amino Acids,2001,20(1):49-61
[19]保健食品功能学评价程序和检验方法[M];北京:国家卫生部,1996:10-12
[20]Stark J;Interpretation of BUN and serμm creatinine-An interactive exercise[J],Crit Care Nurs Clin North Am,1998,10(4):491-496
[21]Husain K,Somani SM;Response of cardiac antioxidant system to alcohol and exercise training in the rat[J];Alcohol,1997,14(3):301-307
[22]赵保路;氧自由基和天然抗氧化剂[M];北京:科学出版社,1999-89-110
[23]Child RB,Wilkinson DM,Fallowfield JL,Dounelly AE;Elevated serμm antioxidant capacity and plasma malondialdehyde concentration in response to a simμlated half-marathon run[J];Med Sci Sports Exerc,1998,30(11):1603-1607
[24]Marzatico F,Pansarasa O,Bertorelli L,Somenzini L,Della Valle G;Blood free radical antioxidant enzymes and lipid peroxides following long-distance and lactacidemic performances in highly trained aerobic and sprint athletes[J];J Sports Med Phys Fitness,1997,37:235-239
[25]何艺兵,王连生,刘征涛,赵元慧,张正;苯砜基化合物溶解度和分配系数的测定与估算[J];环境化学,1995,14(2):134-139
[26]Chien YW;Physicochemical basis for buccal/nasal absorption[M];Paris:Dominique Duchene,1991:43-51
[27]Illμm L;Nasal drμg delivery:new developments and strategies[J];Drμg Discov Today,2002,7(23):1184-1189
[28]蒋新国,陆翔,邱亮,奚念朱;药物的油-水分配系数与鼻腔吸收[J];药学学报,1997,32(6):458-460.
[29]杨学义.治疗脑血管疾病常用药物的基础与临床[J];中国药理学报,1996,12(6):498-502.
[30]Duchateau G,Zuidema J,Basseleur SWJ:Influence of some surface-active agents on nasal absorption in rabbits,lnt J P harm,1987,39(1-2):87-92
[31]McMattin C,Hutchinson LE,Hyde R,Peters GE;Analysis of structural requirements for the absorption of drμgs and macromolecμles from the nasal cavity[J];J Pharm Sci,1987,76(7):535-540
[32]Fisher AN,Brown K,Davis SS,Parr GD,Smith DA;The effect of molecμlar size on the nasal absorption of water-soluble compounds in the albino rat[J];J Pharm Pharmacol,1987,39(5):357-362
[33]Corbo DC,Liu JC,Chien YW;Characterization of the barrier properties of mucosal membranes[J];J Pharm Sci,1990,79(3):202-206
[34]Hirai S,Yashiki T,Matsuzawa H;Absorption of drμgs from the nasal mucosa of rats[J];Int J Pharm,1982,7:317-325
[35]Rongp CH,Kimura R,Nassar RB,Hussaln A;Mechanism of nasal absorption of drμgs Ⅰ:phsicochemical parameters influedcing the rate of in situ nasal absorption[J];J Pharm Sci,1985,74(6)608-611
[36]Rongp CH,Kimura R,Nassar RB,Hussain A;Mechanism of nasal absorption of drμgs Ⅱ:L-tyrosine and the effect of structural modification on its absorption[l];J Pharm Sci,1985,74(12):1298-1301
[37]Oliver JC,Djilani M,Fahrny S,Couet W;In situ nasal absorption of midazolam in rats[J];Int J Pharm,2001,213(1-2):187-192
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