吸收促进剂对二种抗菌素类药物直肠粘膜吸收影响的研究

用离体外翻肠囊法,研究了两类吸收促进剂对氨苄青霉素及利福定肠吸收的影响。发现促进剂的作用与其浓度不成比例,有一最佳浓度范围,其中对氨基水杨酸钠能显著地提高利福定的直肠吸收,体内外相关,生物利用度提高了2.45倍。此外,本文初步探讨了促进剂的作用机制,发现促进剂水杨酸钠的肠通透性与促进作用相关;电泳实验表明促进剂未改变氨苄青霉素的荷电性质,通过测定吸收促进剂作用于肠粘膜后的粘膜静息电位,发现其变化规律与促进剂作用相关。     

胸腺肽胶囊的研制

目的:探讨胸腺肽胶囊的处方及研制.方法:建立在体肠吸收模型研究胸腺肽胃肠道吸收机理,以肠吸收参数指标筛选肠吸收促进剂,以药剂学指标筛选吸收剂和助流剂,设计制剂处方并制备之.结果:筛选出胆盐为吸收促进剂,淀粉为吸收剂,微粉硅胶为助流剂的处方.所制备的胸腺肽胶囊,具有工艺稳定、溶出速度快的特点.结论:以制剂学手段和生物学模型相结合的系统方法设计的口服胶囊,溶出速度明显优于肠溶胶囊,为提高胸腺肽生物利用度创造了条件.     

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。     

大鼠在体吸收连翘苷的机理研究

目的研究连翘苷在大鼠消化道内的吸收机理。方法采用HPLC测定大鼠在体实验中连翘苷的含量,分别进行大鼠原位胃吸收、结肠、小肠全肠段、分肠段(十二指肠、空肠、回肠)合用吸收促进剂(SDS、牛胆盐、冰片、卡波姆)的连翘苷吸收机理研究。结果连翘苷各时间点含量几乎不变。结论口服连翘苷在大鼠消化道内并无吸收。     

翻转肠囊法研究吸收促进剂对小肠吸收苦参碱的作用

目的 :研究不同吸收促进剂对苦参碱小肠吸收的促进作用。方法 :采用离体小肠翻转肠囊实验 ,考察了卵磷脂、脱氧胆酸钠、吐温 80、波洛沙姆 188和十二烷基硫酸钠对苦参碱小肠吸收的促进效果 ,并根据对计算苦参碱的表观渗透系数Papp和增渗比ER来选择最佳的吸收促进剂及用量。结果 :苦参碱在空肠、十二指肠、回肠吸收速率没有显著性差异 (Ρ >0 0 5 )。在几种促进剂中 ,以 0 2 %SDS对苦参碱的吸收促进作用最为明显 ,Papp =3 36×10 5cm s,ER =1 99。结论 :加入促进剂 0 2 %SDS可以增加苦参碱的离体小肠吸收。     

外翻肠囊法研究灯盏花素小肠吸收的影响因素

目的:研究灯盏花素在小肠的吸收情况,探索其吸收机制与影响因素。方法:采用离体外翻肠囊法,将大鼠肠囊浸泡在灯盏花素液体中,收集肠囊内溶液。以百分吸收率(P)、累积吸收量(Q)为指标,考察不同灯盏花素质量浓度(10.03、20.06、40.12μg/ml,以灯盏乙素计)、p H(6.0、6.8、7.4)、肠段(十二指肠、空肠、回肠)、吸收时间(15、30、60、90、120 min)、吸收促进剂(聚山梨酯80、大豆磷脂、亚油酸)对灯盏花素在小肠吸收情况的影响。结果:灯盏花素在小肠的累积吸收量Q随其质量浓度升高而增加;不同p H与肠段下,其P和Q无明显差异;在60 min内吸收情况稳定;加入聚山梨酯80与大豆磷脂后P、Q均明显高于未加吸收促进剂时。结论:灯盏花素在大鼠小肠内的吸收为被动扩散,p H对其吸收无影响;在各肠段均有吸收;聚山梨酯80与大豆磷脂能促进其吸收。本研究可为灯盏花素的合理用药以及设计合理的剂型提供试验依据。     

吸收促进剂对三七总皂苷小肠吸收的影响

目的:研究三七总皂苷(panax notoginseng saponins,PNS)的小肠吸收动力学及吸收促进剂对PNS在小肠吸收速率和表观渗透系数的影响。方法:以紫外分光光度法、高效液相色谱法分别测定酚红和PNS的质量浓度,采用大鼠在体肠灌注实验考察吸收过程。结果:当药物质量浓度为40.084～400.840μg.mL-1时,大鼠小肠吸收速率常数和表观渗透系数无显著性差异(P>0.05);部分吸收促进剂能提高PNS在小肠的吸收水平,促吸收强弱顺序为:冰片>卡波姆>聚山梨酯-80,牛胆盐促吸收效果不明显,壳聚糖在一定程度上会延缓PNS的吸收。结论:PNS在大鼠小肠吸收较差,部分吸收促进剂对其吸收有一定的促进作用。     

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。     

去甲斑蝥素及其壳聚糖纳米粒经大鼠肠黏膜的透过性研究

目的:研究去甲斑蝥素(NCTD)原料药及其壳聚糖纳米粒(NCTD-CS-NPs)经大鼠肠黏膜的透过性,并考察不同吸收促进剂对NCTD肠道吸收的影响。方法:采用体外扩散池法,考察NCTD原料药和NCTD-CS-NPs在十二指肠、空肠、回肠、结肠中不同方向即吸收方向(黏膜侧-浆膜侧,M-S)和分泌方向(S-M)的吸收情况;考察NCTD原料药和NCTD-CS-NPs不同质量浓度(70、80、90μg/ml)对十二指肠黏膜的表观渗透系数(Papp);比较0.1%、0.5%、1%的去氧胆酸钠、十二烷基硫酸钠、泊洛沙姆、低分子质量壳聚糖、高分子质量壳聚糖5种吸收促进剂对NCTD透过十二指肠黏膜的促进作用。结果:NCTD原料药和NCTD-CS-NPs透过4种肠段的Papp依次为十二指肠>空肠>回肠>结肠,在十二指肠和回肠中M-S和S-M的Papp无明显差异,在空肠中Papp(M-S)Papp(S-M);与NCTD原料药比较,NCTD-CS-NPs透过4种肠段的Papp均明显增加(P<0.05);NCTD原料药和NCTD-CS-NPs不同质量浓度对Papp无明显影响;吸收促进剂对促吸收作用的强弱为低分子质量壳聚糖>高分子质量壳聚糖>泊洛沙姆>十二烷基硫酸钠>去氧胆酸钠。结论:壳聚糖纳米粒有利于NCTD在肠段的吸收;NCTD原料药和NCTD-CS-NPs在空肠和结肠的转运可能受不同方向转运体的调控;吸收促进剂能有效促进NCTD的肠道吸收。     

胰岛素鼻腔粘膜吸收促进剂的研究进展

从胰岛素鼻腔粘膜吸收促进剂的种类、促进机理及毒性研究等方面介绍了国内外鼻粘膜吸收促进剂的最新研究进展,为进一步研究低毒高效的促进剂提供参考。     

Excellent absorption enhancing characteristics of NO donors for improving the intestinal absorption of poorly absorbable compound compared with conventional absorption enhancers

The characteristics of NO donors, NOC5 [3-(2-hydroxy-1-(1-methylethyl-2-nitrosohydrazino)-1-propanamine), NOC12 [N-ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino)-ethanamine] and SNAP [S-nitroso-N-acetyl-DL-penicillamine] as absorption enhancers for poorly absorbable drugs were examined in rats using an in situ closed loop method. They were compared with a group of conventional absorption enhancers including sodium glycocholate (NaGC), sodium caprate (NaCap), sodium salicylate (NaSal) and n-dodecyl-beta-D-maltopyranoside (LM). 5(6)-carboxyfluorescein (CF) was used as a model drug to investigate effectiveness, site-dependency, and concentration-dependency of the tested enhancers. Overall, the NO donors can improve the intestinal absorption of CF at low concentration (5 mM), whereas higher concentration was required for the conventional absorption enhancers to elicit the absorption enhancing effect. In the small intestine, SNAP was the most effective absorption enhancers, although its concentration (5 mM) was lower than the conventional absorption enhancers (20 mM). On the other hand, LM and NaCap as well as the three NO donors were effective to improve the colonic absorption of CF. In the regional difference in the absorption enhancing effects, the NO donors showed significant effects in all intestinal regions, whereas we observed a regional difference in the absorption enhancing effect of the other conventional absorption enhancers. In the conventional enhancers, the absorption enhancing effects were generally greater in the large intestine than those in the small intestine. LM and NaCap were ineffective in the jejunum, although they were effective for improving the absorption of CF in the colon. NaSal was ineffective in both the jejunum and the colon. The absorption enhancement produced by NO donors was greatly affected by increasing the enhancer concentration from 3 to 5 mM, but only a slight increase was obtained when the concentration was raised to 10 mM. Similar results were obtained for the other enhancers over the range of 10 to 20 mM, but the absorption enhancing effects of these enhancers were almost saturated above these concentrations. These results suggest that NO donors possess excellent effectiveness as absorption enhancers for poorly absorbable drugs compared with the conventional enhancers. They can enhance intestinal absorption of CF from all intestinal regions and they are effective at very low concentrations.     

Progress in absorption enhancers based on tight junction

Absorption enhancers have been investigated since the 1960s, in order to assist the transfer of drugs across the paracellular space in the intestinal epithelium. However, few absorption enhancers are presently used clinically, due to the difficulty of developing enhancers with high specificity and low toxicity. Using high-throughput genomic techniques, new drug candidates such as, non-Lipinski molecules, peptides, antibodies and nucleic acids, are being discovered, so the need for oral drug delivery strategies using absorption enhancers is gaining importance. The key to addressing this issue is to understand the molecular mechanism of the paracellular route in epithelial cell sheets. Towards this end, basic research in cell biology has revealed the components that regulate the paracellular route, and how the transport of substances is regulated. Based on these findings, novel strategies for enhancing drug absorption have been proposed. In this article, the authors first survey the development of absorption enhancers, then outline recent progress in the cell biology of tight junctions, and finally discuss novel approaches for absorption enhancers based on these advances.     

Progress in absorption enhancers based on tight junction

Absorption enhancers have been investigated since the 1960s, in order to assist the transfer of drugs across the paracellular space in the intestinal epithelium. However, few absorption enhancers are presently used clinically, due to the difficulty of developing enhancers with high specificity and low toxicity. Using high-throughput genomic techniques, new drug candidates such as, non-Lipinski molecules, peptides, antibodies and nucleic acids, are being discovered, so the need for oral drug delivery strategies using absorption enhancers is gaining importance. The key to addressing this issue is to understand the molecular mechanism of the paracellular route in epithelial cell sheets. Towards this end, basic research in cell biology has revealed the components that regulate the paracellular route, and how the transport of substances is regulated. Based on these findings, novel strategies for enhancing drug absorption have been proposed. In this article, the authors first survey the development of absorption enhancers, then outline recent progress in the cell biology of tight junctions, and finally discuss novel approaches for absorption enhancers based on these advances.     

各种吸收促进剂对黄芩苷鼻腔吸收的影响

目的研究黄芩提取物中黄芩苷的鼻腔吸收规律和9种吸收促进剂对黄芩苷鼻腔吸收的促进作用,寻找有效的鼻腔吸收促进剂。方法采用大鼠在体鼻腔循环法考察黄芩苷鼻腔吸收,以鼻腔吸收的一级动力学常数来衡量各种吸收促进剂促吸收作用的强弱。结果黄芩苷鼻腔吸收需加入吸收促进剂,各种不同质量分数吸收促进剂的促进作用为:1%去氧胆酸钠0.5%壳聚糖≈0.5%冰片≈5%甲基化-β-环糊精>5%HP-β-CD>5%β-CD>1%Tween-80≈0.1%EDTA-Na2≈1%磷脂,其中加入最后三者的促吸收效果与不加吸收促进剂时无显著性差异。结论质量分数为1%去氧胆酸钠促吸收效果最好,但鼻黏膜毒性较大,0.5%壳聚糖、0.5%冰片、5%甲基化-β-环糊精和5%HP-β-CD可安全有效地促进黄芩苷的鼻腔吸收。     

Absorption enhancers for nasal drug delivery

This paper describes the basic concepts for the transmucosal delivery of drugs, and in particular the use of the nasal route for delivery of challenging drugs such as polar low-molecular-weight drugs and peptides and proteins. Strategies for the exploitation of absorption enhancers for the improvement of nasal delivery are discussed, including consideration of mechanisms of action and the correlation between toxic effect and absorption enhancement. Selected enhancer systems, such as cyclodextrins, phospholipids, bioadhesive powder systems and chitosan, are discussed in detail. Examples of the use of these enhancers in preclinical and clinical studies are given. Methods for assessing irritancy and damage to the nasal membrane from the use of absorption enhancers are also described. Finally, the mucosal use of absorption enhancers (chitosan) for the improved nasal delivery of vaccines is reported with reference to recent phase I/II clinical studies.     

Absorption Enhancers: Applications and Advances

Absorption enhancers are functional excipients included in formulations to improve the absorption of a pharmacologically active drug. The term absorption enhancer usually refers to an agent whose function is to increase absorption by enhancing membrane permeation, rather than increasing solubility, so such agents are sometimes more specifically termed permeation enhancers. Absorption enhancers have been investigated for at least two decades, particularly in efforts to develop non-injection formulations for peptides, proteins, and other pharmacologically active compounds that have poor membrane permeability. While at least one product utilizing an absorption enhancer for transdermal use has reached the market, quite a few more appear to be at the threshold of becoming products, and these include oral and transmucosal applications. This paper will review some of the most advanced absorption enhancers currently in development and the formulation technologies employed that have led to their success. In addition, a more basic review of the barriers to absorption and the mechanisms by which those barriers can be surmounted is presented. Factors influencing the success of absorption-enhancing formulations are discussed. If ultimately successful, the products now in development should offer non-injection alternatives for several peptide or protein drugs currently only administered by injection. The introduction of new absorption enhancers as accepted pharmaceutical excipients, and the development of formulation technologies that afford the greatest benefit/risk ratio for their use, may create opportunities to apply these enabling technologies more broadly to existing drugs with non-optimal delivery properties.     

Overcoming Poor Tabletability of Bulky Absorption Enhancers by Spray Drying Technology

Absorption enhancers are often a major component of solid oral peptide formulations as compared to the active pharmaceutical ingredient and excipients. This commonly results in poor tabletability that is hard to mitigate in direct compaction by addition of small amounts of excipients. To improve the tabletability of bulky absorption enhancers, the model absorption enhancers, sodium cholate and deoxycholic acid, were co–spray-dried with hydroxypropyl methylcellulose E5, where the percentage of absorption enhancers was not lower than 90% (w/w). The physicochemical properties of the resulting powders were assessed by laser diffraction, scanning electron microscopy, X-ray powder diffraction, thermogravimetric analysis, and differential scanning calorimetry. The powders were compressed into tablets, and the tabletability was evaluated. Co–spray drying with 10% of hydroxypropyl methylcellulose significantly improved the tabletability of the both absorption enhancers. Moreover, it was demonstrated that small particle size and amorphous state rather than high moisture content contributed to the improved tabletability of the spray-dried powders. The study suggests that spray drying technology can be promising to overcome the poor tabletability of oral peptide formulation consisting of large amounts of absorption enhancers.     

吸收促进剂的作用机制及其在鼻腔给药中的研究进展

随着新的蛋白质及肽类治疗药物的开发,非侵入性给药途径-鼻腔给药日益受到关注。与口服给药和注射给药相比,鼻腔给药既可避免注射给药带来的生理和心理创伤,也可消除口服给药过程中肝脏的首过效应;且鼻腔黏膜下血管丰富,有助于药物的吸收,也更加便于患者的抢救和自救。然而,由于鼻黏膜屏障的存在,药物很难达到理想的治疗效果,因此需要加入鼻黏膜吸收促进剂来增强药物的吸收。该文主要探讨鼻黏膜吸收促进剂的作用机制及分类,并对FDA已上市鼻腔制剂中的吸收促进剂进行汇总,同时对新型黏膜吸收促进剂在鼻腔给药制剂中的应用进行阐述,以期为鼻腔给药制剂的开发提供依据。     

Enhancement of paracellular transport of heparin disaccharide across Caco-2 cell monolayers

The enhancement of paracellular transport of heparin disaccharide using several absorption enhancers across Caco-2 cell monolayers was tested. The cytotoxicity of these enhancers was also examined. The enhancing effects by Quillaja saponin, dipotassium glycyrrhizinate, 18beta-glycyrrhetinic acid, sodium caprate and taurine were determined by changes in transepithelial electrical resistance (TEER) and the amount of heparin disaccharide transported across Caco-2 cell monolayers. Among the absorption enhancers, 18beta-glycyrrhetinic acid and taurine decreased TEER and increased the permeability of heparin disaccharide in a dose-dependent and time-dependent manner with little or negligible cytotoxicity. Our results indicate that these absorption enhancers can widen the tight junction, which is a dominant paracellular absorption route of hydrophilic compounds. It is highly possible that these absorption enhancers can be applied as pharmaceutical excipients to improve the transport of macromolecules and hydrophilic drugs having difficulty in permeability across the intestinal epithelium.     

新型促吸收剂研究进展——以细胞间紧密连接为靶点

亲水性小分子药物、多肽和蛋白质主要通过胞旁通路吸收。这类药物膜通透性较差，口服生物利用度较低。紧密连接是构成胞旁通路的结构基础，传统的胞旁通路促吸收剂一般对黏膜损伤较大，限制了这些药物的临床应用。近年来，随着对紧密连接结构、功能认识日益加深，许多特异性的促吸收剂被发现，如NO供体、CPE和Zot等，实验表明，通过瞬间可逆的打开紧密连接，这些促吸收剂可显著增加胞旁转运标志物和亲水性药物的吸收，而其毒副作用较传统的促吸收剂大为降低。总之，新型促吸收剂提供了一个增加亲水性药物生物利用度的有益思路。