三七总皂苷油包水微乳的处方筛选及体内外评价

筛选口服油包水(W/O)微乳处方以提高三七总皂苷(panax notoginsenoside，PNS)中人参皂苷Rb₁的体内肠吸收，分别采用大鼠体内肠吸收、脂质体和平行人工膜(parallel artificial membrane permeability assay，PAMPA)等模型分别研究微乳的体内药代动力学及体外对膜流动性和药物膜转运性质的影响。主要以磷脂/乙醇(SP/EtOH)为表面活性剂，与PNS水溶液(400 mg·mL^-1)和不同油相分别制备11个W/O微乳处方。多数微乳处方可提高药物的大鼠体内肠吸收，其吸收促进作用除与所含表面活性剂有关外，不同油相的选用也会产生一定影响，其吸收促进作用大小为月桂酸甘油酯≈肉蔻豆酸异丙脂>棕榈酸异丙脂>棕榈酸异辛酯。长链(>C₁₄)脂肪酸酯的吸收促进作用低于中链脂肪酸酯(C₈~C₁₄)。多数微乳处方可不同程度的提高脂质体的膜流动性。PAMPA研究中，稀释后微乳(D-ME)中药物的有效透过系数(P_e)多数高于PNS对照溶液，表明微乳中的组分可以提高药物的膜透过能力，稀释前微乳(ME)的P_e与大鼠体内肠吸收具有相对较好的直线相关性(r=0.774 0)。W/O微乳可以促进人参皂苷Rb₁的肠吸收，吸收促进作用与其提高生物膜流动性有一定关系。PAMPA可以尝试引入制剂处方研究(如吸收促进剂等)的某些领域中。     

肝移植术后患者环孢素A药物动力学与红细胞膜脂流动性的动态观察

目的探讨肝移植术后患者细胞膜脂流动性与环孢素A(CsA)药物动力学相关性,减少药物引起的不良反应.方法采用FPLA法测定CsA全血药物浓度,DPH荧光探针法测定红细胞膜脂流动性.结果红细胞膜脂流动性的动态改变与血中CsA药物浓度的变化呈负相关.结论CsA可使细胞膜脂流动性降低,长期低水平的膜脂流动性是导致肝损害的病理学基础.     

山莨菪碱对红细胞膜流动性和膜内源荧光的影响

应用荧光探针DPH测定完整红细胞膜流动性。山茛菪碱显著增加红细胞膜流动性。山茛菪碱对红细胞膜内源荧光的焠灭呈药物浓度依赖,钙和山茛菪碱对红细胞膜内源荧光的焠灭有协同作用,提示山茛菪碱对膜疏水区有作用,并且直接与膜蛋白反应导致能量转移。     

山莨菪碱对红细胞膜流动性和膜内源荧光的影响

应用荧光探针DPH测定完整红细胞膜流动性。山茛菪碱显著增加红细胞膜流动性。山茛菪碱对红细胞膜内源荧光的焠灭呈药物浓度依赖,钙和山茛菪碱对红细胞膜内源荧光的焠灭有协同作用,提示山茛菪碱对膜疏水区有作用,并且直接与膜蛋白反应导致能量转移。     

山莨菪碱对红细胞膜流动性和膜内源荧光的影响

应用荧光探针DPH测定完整红细胞膜流动性。山莨菪碱显著增加红细胞膜流动性。山莨菪碱对红细胞膜内源我的粹灭呈药物浓度依赖。钙和山莨菪碱对细胞内源荧光的粹灭有协同作用，提示山莨菪碱对膜疏水区有作用，并且直接与膜蛋白反应导致能量转移。     

煤烟提取物致癌作用机制的研究

目的　从煤烟对细胞膜理化特性的影响 ,对DNA的损伤 ,诱导原癌基因表达方面研究其致癌作用机制。方法　利用 1,6 二苯基 1,3,5 己三烯 (DPH)和N 3芘 马来酰亚胺 (N 3P M)分别标记NIH3T3细胞膜脂和膜蛋白 ,不同剂量的煤烟作用后 ,通过其荧光偏振度的改变确定膜理化特性的变化 ;利用溴化乙锭 (EB)作荧光探针 ,通过DNA EB结合物荧光强度的变化确定基因组DNA损伤程度 ;利用地高辛标记的c myc癌基因作探针 ,运用斑点杂交的方法 ,检测c myc基因的表达情况。结果　不同剂量的煤烟作用后 ,能够引起膜脂流动性升高 ,膜蛋白运动度无显著变化 ,能够引起DNA的断裂损伤及c myc基因的高表达 ,且上述变化皆与剂量密切相关。结论　煤烟的诱变性与其对细胞膜、DNA及原癌基因的表达的影响密切相关。     

口服药物吸收促进剂应用与开发研究进展

目的 为口服药物吸收促进剂的合理使用及开发提供参考。方法 分析影响口服药物吸收的具体因素,结合国内外研究成果介绍吸收促进剂的常用种类及具体应用,阐述吸收促进剂增加肠道通透性、提高口服药物生物利用度的机制。结果与结论 口服药物生物利用度的影响因素包括消化道物理、化学屏障及药物处方组成等。口服药物吸收促进剂包括表面活性剂、螯合剂、壳聚糖及其衍生物、多肽类、聚酰胺-胺型树枝状大分子、生物黏附材料。表面活性剂为常用吸收促进剂,其一方面可提高药物的表观溶解度,进而提高亲脂性药物口服递送效率,另一方面可减少多种酶对药物的代谢作用,破坏消化道紧密连接、改善细胞膜流动性、促进肠淋巴转运吸收、增强药物与上皮细胞的亲和性,进而增加药物在消化道的渗透效率,从而提高口服生物利用度。目前能真正用于临床含吸收促进剂的药物仍较少,且安全性有待提高。     

肝移植术后患者环孢素A药物动力学与红细胞膜脂流动力性的 …

探讨肝移植术后患者细胞膜脂流动性与环孢素Ａ药物动力学相关性，减少药物引起的不良反应。方法：采用ＰＦＩＡ法测定ＣｓＡ全血药物浓度，ＤＰＨ荧光探针法测定红细胞膜脂流动性。结果红细胞膜脂流动性的动态改变与血中ＣｓＡ药物浓度的变化呈负相关。     

葛根素对谷氨酸所致大鼠原代神经细胞损伤的保护作用

目的从膜脂流动性等观察葛根素对谷氨酸所致大鼠原代神经细胞损伤的保护作用。方法建立大鼠原代神经细胞谷氨酸损伤模型,以1,6-二苯基-1,3,5-己三烯(DPH)为探针,用荧光偏振法测定荧光偏振度(P)值和微粘度(η),研究细胞膜脂流动性的改变;MTT(四甲基偶氮唑盐)法、培养介质乳酸脱氢酶(LDH)活力测定观察葛根素的保护作用。结果葛根素组荧光偏振度和微粘度低于谷氨酸损伤组,与尼莫地平作用相当,且呈现剂量依赖关系。葛根素组原代神经细胞LDH的释放减少,吸光度增加,但葛根素对正常细胞增殖无影响。结论葛根素对谷氨酸所致的大鼠原代神经细胞损伤具有保护作用,其保护作用可能与葛根素改善神经细胞膜脂流动性有关。     

两型拟除虫菊酯类杀虫剂对突触体膜流动性影响的研究

本研究利用荧光探剂DPH和ANS观察了六种根除虫菊酯类杀虫剂对大鼠脑突触体膜流动性的影响。发现带有α-氰基的拟除虫菊酯能降低突触体膜的流动性,且能增加脂双层极性头部的活动程度;而无α-氰基的拟除虫菊酯能增加突触体膜的流动性,但对脂双层极性头部的活动程度无明显影响。这六种杀虫剂对膜流动性的影响均发生在短时间内。     

Influence on intestinal mucous permeation of paclitaxel of absorption enhancers and dosage forms based on electron spin resonance spectroscopy

The aim of this paper is to investigate the permeation mechanism of the hydrophobic drug, paclitaxel in intestinal membranes of mice in relation to enhancers and preparation factors. The alteration fluidity of lipid and protein in mucous membrane were determined using electron spin resonance (ESR) when the membrane was treated with several enhancers including Pluronic F68, polyethylene glycol (PEG), Brij78 and lecithin. At the same time, the enhanced permeation of paclitaxel across the intestinal intercellular membrane of stratum corneum was studied for three formulations: inclusion complex, microemulsion and injection. The results showed that use of paclitaxel-hydroxypropyl-beta-cyclodextrin inclusion complexation and of paclitaxel microemulsion as vehicle and PEG 1500 as enhancer could significantly increase the permeation kinetics of paclitaxel in a fluid diffusion study. The effect on absorption characteristics of enhancing permeation of this hydrophobic drug in the intestinal mucosa was considered in the light of the change in membrane fluid.     

吸收促进剂对蚓激酶肠道吸收的影响

目的研究蚓激酶(YJM-I)和吸收促进剂合用时在大鼠肠道各段的吸收特点，寻找YJM-I经肠道吸收的最佳位置和考察吸收促进剂对YJM-I在肠道吸收过程中的影响。方法采用体外扩散池法、十二指肠部位直接给药、在体循环灌流及肠段原位结扎等方法对荧光标记的FITC-YJM-I在大鼠肠道的吸收情况进行了研究。结果十二指肠部位给药后的药代动力学和药效学评价结果显示YJM-I药物分子可被大鼠肠道吸收进入血液循环并保持生物学活性，但其绝对生物利用度较低。体外肠黏膜通透性试验及体内肠段吸收试验结果显示部分吸收促进剂表现出良好的促进YJM-I肠道吸收的作用。十二指肠、空肠和回肠段体外肠黏膜通透性均显示了相似的吸收促进剂作用强弱趋势： 1%壳聚糖>1%去氧胆酸钠>1% Na₂EDTA>1%十二烷基硫酸钠>1%辛酸钠>1%泊洛沙姆>1%羟丙基-β-环糊精。而在体内十二指肠部位给药则显示的强弱顺序为： 2.5%去氧胆酸钠>2.5% Na₂EDTA>2.0%壳聚糖>2.5%十二烷基硫酸钠>2.5%辛酸钠>2.5%泊洛沙姆>2.5%羟丙基-β-环糊精。结论吸收促进剂能有效地增加YJM-I肠道吸收程度，其中具有生物黏附作用的壳聚糖有望成为YJM-I肠道吸收的良好促进剂。     

胰岛素经口腔给药对正常大鼠的降血糖作用

目的　研究胰岛素溶液 (insulinsolution ,INS SOL)经正常大鼠口腔给药后的降血糖作用。方法　以血糖水平为指标 ,考察各种吸收促进剂经正常大鼠口腔给药后对INS SOL降血糖作用的影响 ,以皮下注射为对照 ,计算不同条件下INS SOL的药理生物利用度 (pharmacologicalbioavailability ,PA)。 结果　不加吸收促进剂的条件下 ,10U·kg-1的INS SOL经口腔给药后的生物利用较低 (PA =6 9% )。十二烷基硫酸钠 (5 % ,PA =14 5 % ) ,苄泽 78(5 % ,PA =2 0 6 % ) ,脱氧胆酸钠 (5 % ,PA =16 5 % )和卵磷脂(10 % ,PA =13 8% )均增加INS SOL的降血糖作用。苄泽78(5 % )可使INS SOL(5U·kg-1)的PA最高达到 33%。结论　在适当的吸收促进剂的作用下INS SOL经口腔给药后具有明显的降血糖效果。     

Permeation-enhancing effects of chitosan formulations on recombinant hirudin-2 by nasal delivery in vitro and in vivo

AIM: To investigate the enhancing effects of chitosan with or without enhancers on nasal recombinant hirudin-2 (rHV2) delivery in vitro and in vivo, and to evaluate the ciliotoxicity of these formulations. METHODS: The permeation-enhancing effect of various chitosan formulations was estimated by using the permeation coefficient of fluorescein isothiocyanate recombinant hirudin-2 (FITC-rHV2) across the excited rabbit nasal epithelium in vitro. The effect was further evaluated by measuring the blood concentration level after nasal absorption of FITC-rHV2 in rats. The mucosal ciliotoxicity of different formulations was evaluated with an in situ toad palate model. RESULTS: Chitosan at a concentration of 0.5% with or without various enhancers significantly increased the permeability coefficient (P) and relative bioavailability (Fr) of FITC-rHV2 compared with the blank control. The addition of 1% sodium dodecylsulfate, 5% Brij35, 5% Tween 80, 1.5% menthol, 1% glycyrrhizic acid monoammonium salt (GAM) or 4% Azone into the 0.5% chitosan solution resulted in a further increase in absorption (P<0.05) compared with 0.5% chitosan alone. But co-administration of chitosan with 5% hydroxyl-propyl-beta-cyclodextrin (HP-beta-CD), 5% lecithin or 0.1% ethylenediamine tetraacetic acid (EDTA) was not more effective than using the 0.5% chitosan solution alone. Chitosan alone and with 5% HP-beta-CD, 0.1% EDTA, 1% GAM or 5% Tween 80 was relatively less ciliotoxic. CONCLUSION: Chitosan with or without some enhancers was able to effectively promote the nasal absorption of recombinant hirudin, while not resulting in severe mucosal ciliotoxicity. A chitosan formulation system would be a useful approach for the nasal delivery of recombinant hirudin.     

胰岛素肺部给药对大鼠的降血糖作用

目的:研究胰岛素溶液(INS SOL)经正常大鼠肺部给药后的降血糖作用。方法:以血糖水平为指标,考察各种吸收促进剂以及酶抑制剂经正常大鼠肺部给药后对INS SOL降血糖作用的影响。同时比较了INS SOL在两种pH条件下的降血糖作用,并以皮下注射为对照,计算不同条件下INS SOL的药理生物利用度(pharmacologicalbioavailability,PBA)。结果:05u·kg^-1的INS SOL经肺部给药后即有明显的降血糖作用,在不加吸收促进剂的条件下的PA为260%。辛酸钠、胆酸钠、苄泽35、苄泽78和酶抑制剂杆菌肽均显著地增加INS SOL的降血糖作用。INS SOL在pH3时的降血糖效果比pH7时有显著的提高。结论:INS SOL经肺部给药后有显著的降血糖效果。     

Pulmonary Delivery of Salmon Calcitonin Dry Powders Containing Absorption Enhancers in Rats

Purpose. To evaluate the effects of absorption enhancers in dry powders and in liquids, pulmonary absorption of salmon calcitonin (sCT) in various formulations was measured. Methods. The dry powder of sCT was prepared by a freeze-drying method with a jet mill. After intratracheal administration of sCT dry powder and liquid (solution) preparations to rats, plasma sCT levels and calcium levels were measured. Results. After intratracheal administration without absorption enhancers, sCT in the dry powder and in the liquid were absorbed nearly to the same degree. Absorption enhancers (oleic acid, lecithin, citric acid, taurocholic acid, dimethyl-β-cyclodextrin, octyl-β-D-glucoside) were much more effective in the dry powder than in the solution. The reason may be that the enhancers added to the dry powder dissolved at high concentrations in a trace volume of the fluid lining the alveolar epithelium. Conclusions. The present results suggest that the pulmonary absorption of peptides and proteins can be greatly improved by formulating them into dry powders with smaller amounts of enhancers than in liquid dosage forms.     

吸收促进剂对人参皂苷Rg1鼻腔吸收的促进作用及鼻腔毒性

目的考察吸收促进剂对人参皂苷Rg1鼻腔黏膜的吸收促进作用以及对鼻腔黏膜毒性。方法采用大鼠在体鼻腔循环考察人参皂苷Rg1鼻腔吸收及吸收促进剂的促吸收作用，在体蟾蜍上腭纤毛法评价药物对纤毛运动的影响；考察吸收促进剂对家兔血红细胞的溶血作用、对鼻腔循环液中总蛋白和乳酸脱氢酶的影响及对鼻腔黏膜形态学的影响。结果人参皂苷Rg1鼻腔吸收必须加入吸收促进剂。各种吸收促进剂的促进作用为：1%去氧胆酸钠作用显著；1%甘草酸二钾和1%氮酮作用中等；1% Tween-80，2% β-环糊精、0.5%冰片、0.5%壳聚糖、5%羟丙-β-环糊精和0.1% EDTA等作用微弱。吸收促进剂对鼻腔黏膜毒性影响：1%去氧胆酸钠、1%氮酮和1%甘草酸二钾毒性大；1% Tween-80，2% β-环糊精及5%羟丙-β-环糊精等毒性中等；0.5%冰片、0.5%壳聚糖和0.1% EDTA毒性小。结论0.5%冰片与0.5%壳聚糖可安全有效地促进人参皂苷Rg1的鼻腔吸收。     

Absorption enhancement, mechanistic and toxicity studies of medium chain fatty acids, cyclodextrins and bile salts as peroral absorption enhancers

The objective of the present investigation was to evaluate an oral 'drug delivery' approach, which involves co-administration of absorption enhancers (AEs). The representative low permeable hydrophilic (biopharmaceutic classification system (BCS) Class III) drugs used in the study comprised of cefotaxime sodium and ceftazidime pentahydrate, whereas low permeable lipophilic (BCS Class IV) drugs include cyclosporin A and lovastatin. AEs from three different chemical classes, namely, medium chain fatty acids (sodium caprylate and caprate), cyclodextrins (beta-cyclodextrin, hydroxypropyl beta-cyclodextrin) and bile salts (sodium cholate and deoxycholate) were evaluated for absorption enhancement efficacy, mechanism of action and toxicity using in vitro everted intestinal sac model. These AEs were found to enhance intestinal permeability of drugs from 2- to 27-fold. Light microscopy studies of intestinal sac incubated with AEs for 120 min revealed morphological changes in absorptive mucosa and rank order of toxicity were cyclodextrins>bile salts congruent with medium chain fatty acids. Fluorescence polarization studies indicated that brush bordered membrane vesicles labeled with lipophilic (DPH, 12AS) and hydrophilic dyes (ANS), when treated with AEs exhibited concentration and time dependent decrease in fluorescence polarization. Total protein released in presence of AEs was more than control but considerably less than EDTA (0.58% w/v), which is known to cause toxic release of proteins from cell. Overall, AEs were found to significantly enhance drug permeability by decreasing lipid membrane fluidity and/or interacting with hydrophilic domains of membrane, and has the potential to improve oral delivery.     

Study on Pulmonary Delivery of Salmon Calcitonin in Rats: Effects of Protease Inhibitors and Absorption Enhancers

Effects of protease inhibitors and absorption enhancers on the absorption of salmon calcitonin (sCT) were evaluated after intratracheal coadministration to rats using the plasma Ca level as an index. Remarkable absorption enhancement could be attained with unsaturated fatty acids such as oleic acid and polyoxyethylene oleyl ether (absorption enhancers) and with chymostatin, bacitracin, potato carboxypeptidase inhibitor and phosphoramidon (protease inhibitors). sCT degrading enzymes had four times higher activity per total protein in membrane fraction of lung homogenates than the activity in cytosol fraction. These enzymes are thought to be serine proteases and metalloenzymes from the in vitro action profile of protease inhibitors. A good correlation between the in vitro activity of protease inhibitors and the in vivo enhancing effect on sCT activity suggested that membrane enzymes are responsible for the inactivation of sCT. Metabolic degradation and low permeability of sCT may be possible barriers to the absorption of sCT.     

Enhanced transbuccal salmon calcitonin (sCT) delivery: Effect of chemical enhancers and electrical assistance on in vitro sCT buccal permeation

This study investigates the combined effect of absorption enhancers and electrical assistance on transbuccal salmon calcitonin (sCT) delivery, using fresh swine buccal tissue. We placed 200 IU (40 μg/mL) of each sCT formulation—containing various concentrations of ethanol, N-acetyl-l-cysteine (NAC), and sodium deoxyglycocholate (SDGC)—onto the donor part of a Franz diffusion cell. Then, 0.5 mA/cm² of fixed anodal current was applied alone or combined with chemical enhancers. The amount of permeated sCT was analyzed using an ELISA kit, and biophysical changes of the buccal mucosa were investigated using FT-IR spectroscopy, and hematoxylin–eosin staining methods were used to evaluate histological alteration of the buccal tissues. The flux (J_s) of sCT increased with the addition of absorption enhancer groups, but it was significantly enhanced by the application of anodal iontophoresis (ITP). FT-IR study revealed that all groups caused an increase in lipid fluidity but only the groups containing SDGC showed statistically significant difference. Although the histological data of SDGC groups showed a possibility for tissue damage, the present enhancing methods appear to be safe. In conclusion, the combination of absorption enhancers and electrical assistance is a potential strategy for the enhancement of transbuccal sCT delivery.