前药--一种可靠的口服结肠靶向释药系统

综述了近年来前药的发展状况，并评价了各类前药的特点和发展前景。前药技术作为一种可靠的口服结肠靶向释药系统，不仅能减少药物的口服剂量，降低副作用并且增加了药效。     

地塞米松当归多糖前体药在大鼠体内的结肠靶向释药研究

目的:探讨以当归多糖为载体的地塞米松前体药在大鼠胃肠道内的转运及活性药物的释放情况。方法:地塞米松及其当归多糖前体药按1.96mg·kg-1(以地塞米松量计)给大鼠灌胃,采用高效液相色谱法检测地塞米松在大鼠胃肠道不同部位的分布及血药浓度变化。结果:地塞米松当归多糖前体药灌胃后,释放出的地塞米松只分布在盲肠和结肠的内容物及粘膜中,在胃和小肠的内容物及粘膜中未检测到地塞米松释放;释放出的地塞米松吸收缓慢,达峰时间(tmax)为7.2h,血浆药物峰浓度(Cmax)为42μg·L-1,曲线下面积(AUC)为334μg·h·L-1。地塞米松灌胃后,药物主要分布在胃、小肠近端及小肠远端的内容物和粘膜中,药物吸收迅速,tmax为2.2h,Cmax为2120μg·L-1,AUC为11875μg·h·L-1。结论:以当归多糖为载体的地塞米松前体药具有良好的结肠定位转释作用,有可能成为一种具有良好应用前景的结肠炎治疗药物。     

中药结肠靶向给药系统研究进展

目的对结肠靶向给药(CTDD)系统的相关进展全面综述,探讨其今后的发展方向,为研究人员提供参考与依据。方法查阅国内外19种期刊25篇相关文献,并进行分析、归纳。结果中药CTDD系统包括pH依赖型、时间依赖型、微生物酶解型、生物黏附型、压力依赖型、脉冲型和联合应用型。结论中药CTDD具有广阔的应用前景,但中药指标成分、体内评价等方面的研究还需加强。     

细菌触发型结肠靶向释药系统的研究进展

细菌触发型靶向释药系统是依据人体结肠独特的菌群分布，利用细菌具有的偶氮还原酶、糖苷酶及糖苷酸酶等多种酶，能生物降解药物载体，使药物在结肠定位释放。按释药机制和给药方式，细菌触发型结肠释药系统可分为4类：前体药物释药系统、多糖载体释药系统、联合pH依赖型或时滞型的复合释药系统、偶氮芳香族水性凝胶释药系统。它们需采用独特的溶出性试验评价药物的体外释放和γ-闪烁照相法观察药物的体内行为，本文对该领域的研究进展作一综述。     

结肠靶向给药系统研究进展

通过查阅国内外文献综述近年来国内外结肠靶向给药的研究动态,结肠靶向给药系统的几种类型：ｐＨ依赖型,时滞释药型和菌群触发型及其所使用的材料。介绍了结肠的特殊生理结构和功能,阐明药物在结肠的吸收和作用机理。     

环糊精在靶向给药系统中的应用

近年来,为了设计一种能在特殊器官、组织和细胞等部位集中有效释放药物的新型给药系统,国内外药剂工作者做了不懈的努力,其中利用环糊精(CD)制备靶向给药系统的研究也日渐增多。由于CD包合物在水中处于主客分子动态平衡状态,它的解离程度依赖于包合物稳定常数的大小。在吸收部位,包合物解离成游离的CD和药物分子,只有游离的药物分子能够进入体循环。然而,当我们需要将药物靶向定位的时候,这种包合平衡现象往往存在其不利之处,因为当药物到达靶器官或靶组织之前包合物往往已经解离了。为了有效阻止这种解离,国外文献报道最多的是将药物结…     

靶向结肠释药系统

靶向结肠释药系统盛杰古丽萍王晓文（中国人民解放军第４７３医院兰州７３００７０）时辰治疗学的新观点即选择在自身组织生物节律周期中适当时刻施以治疗方案，用最小的适宜剂量的药物力求达到高效、低毒、副作用少的目的。心血管病多在清晨发作；哮喘多发生在凌晨３～５...     

结肠靶向给药系统

本文介绍结肠的特殊生理结构和功能．综述3种结肠靶向给药系统的制备方法及其所用的材料。阐明药物在结肠的吸收和作用机理。     

基于纳米技术的结肠靶向给药系统研究进展

通过纳米技术将药物直接纳米化或包封于纳米载体后进行结肠靶向给药,可使药物在胃、十二指肠、空肠、回肠前端不释放药物,直至将药物运送至回盲部才释放,从而发挥结肠局部或全身治疗作用.这一纳米给药技术能消除体内生理环境的作用,防止药物进入结肠靶点前被破坏或降解.利用纳米药物载体比表面积大、界面活性高的特点,通过对其进行表面修饰,还可避免其被体内的免疫系统识别、吞噬,克服体内的"生物屏障",从而实现体内结肠靶向给药[1].     

结肠靶向给药系统研究概况

本文对结肠靶向给药系统的特点、当前制剂学手段进行介绍与分析，认为结肠靶向给药对便秘、结肠炎、大肠癌等肠道疾病的治疗以及蛋白多肽药物的口服给药都具有重要意义，是一个极具前景的新药研究领域。     

口服结肠靶向给药系统的研究进展

口服结肠靶向给药系统在药物转运和治疗结肠局部疾病方面具有重要作用。本文总结了口服结肠靶向给药系统近年来的研究概况,并对结肠靶向药物制剂的体内、外评价方法作一介绍。     

口服结肠定位给药系统的药剂学研究进展

目的:介绍近年来口服结肠定位给药方法药剂学方面的研究进展。方法:分析有关文献资料,对结肠的生理特点,口服结肠给药系统的原理和常用材料进行归纳和总结。结果:有多种药剂学方法可实现结肠给药的目的,目前主要应用的方法有时间依赖型、pH依赖型、酶解型等系统。结论:口服结肠定位给药系统作为现代药物剂型的高新技术之一,有重要的科研价值和市场前景。     

In vivo pharmacokinetic study for the assessment of poly(L-aspartic acid) as a drug carrier for colon-specific drug delivery

Glucocorticoids remain one of the mainstays of therapy for acute attacks of inflammatory bowel disease despite systemic side effects that limit their use. Prodrugs that selectively deliver glucocorticoids to the colon may lower the required dose and side effects. Because enzymes of gut microflora are able to cleave certain peptide and ester bonds, the ability of an ester prodrug consisting of dexamethasone (DX) as model drug and poly(L-aspartic acid) (weight-average mol wt=30,000) as drug carrier was investigated to selectively release the drug in the large intestine. Prodrug and drug solutions (1.18 mg DX/ml DMSO) were administered to two groups of male Sprague-Dawley rats by intragastric infusion using an ALZET^® osmotic pump. All rats were infused for sufficient time to achieve steady state in both blood and GI-tract tissues. DX concentrations in blood and tissue samples were measured with HPLC. The steady state DX concentrations at these sites were used to calculate a drug delivery index (DDI). DX blood concentrations were significantly lower (p<0.05) after intragastric administration of the prodrug. Moreover, prodrug administration resulted in significantly higher DX concentrations in the cecum and colon mucosa and the cecum muscle tissue compared to DX administration (p<0.05). The prodrug led to an increase of the DX concentration in the large intestinal tissues by factors of 1.3–2.0 and to an 1.3-fold decrease of DX blood concentrations. Thus, this novel conjugate should both increase efficacy and reduce toxicity to some extent.     

口服结肠定位给药系统

综述了近年来口服结肠定位给药系统的发展状况 ,并评价了各类结肠定位给药系统的优、缺点和发展前景     

Novel pH-sensitive hydrogels for colon-specific drug delivery

The purpose of this study is to develop novel intestinal specific drug delivery systems with pH-sensitive swelling and drug release properties. Acryloyl ester of 5-[4-(hydroxy phenyl) azo] salicylic acid (HPAS) as an azo derivative of 5-amino salicylic acid (5-ASA) was prepared under mild conditions. The HPAS was covalently linked with acryloyl chloride, abbreviated as APAS. Cubane-1,4-dicarboxylic acid (CDA), linked to two 2-hydroxyethyl methacrylate (HEMA) groups, was the cross-linking agent (CA). Methacrylic-type polymeric prodrugs were synthesized by free radical copolymerization of methacrylic acid, poly(ethyleneglycol monomethyl ether methacrylate), and APAS in the presence of cubane cross-linking agent. The effect of copolymer composition on the swelling behavior and hydrolytic degradation were studied in simulated gastric (SGF, pH 1) and intestinal fluids (SIF, pH 7.4). The composition of the cross-linked three-dimensional polymers was determined by FTIR spectroscopy. The hydrolysis of drug–polymer conjugates was carried out in cellophane membrane dialysis bags containing aqueous buffer solutions (pH 1 and pH 7.4) at 37°C. Detection of the hydrolysis product by UV spectroscopy shows that the azo prodrug (HPAS) was released by hydrolysis of the ester bond located between the HPAS and the polymer chain. Drug release studies showed that the increasing content of MAA in the copolymer enhances hydrolysis in SIF. These results suggest that pH-sensitive systems could be useful for preparation of a muccoadhesive system and controlled release of HPAS as an azo derivative of 5-amino salicylic acid (5-ASA).     

Drug glycosides: potential prodrugs for colon-specific drug delivery

The influence of prodrug structure on specificity of glycoside/glycosidase based colon-specific drug delivery was studied by preparing nine steroid glycosides, measuring their relative lipophilicities, and hydrolyzing them with bacterial glycosidases from rat intestines. The 21-yl beta-D-glucosides and galactosides of dexamethasone, prednisolone, hydrocortisone, and fludrocortisone and the 21-yl beta-D-cellobioside of prednisolone were prepared by a modified Koenigs-Knorr reaction. The deacetylated glycoside prodrugs, along with the P-nitrophenyl derivatives of beta-D-glucoside, galactoside, and cellobioside, were subjected to hydrolysis by the contents of the rat stomach, proximal small intestine (PSI), distal small intestine (DSI), and cecum. All the prodrugs were hydrolyzed slowly by PSI and stomach contents, more rapidly by contents of the DSI, and most rapidly by cecal contents. This is the basis of the site-specific drug delivery reported earlier (Friend, D. R.; Chang, G. W. J. Med. Chem. 1984, 27, 261). Furthermore, the prodrugs themselves had very different susceptibilities to hydrolysis. Hydrolysis rates catalyzed by DSI contents decreased in the following order: prednisolon-21-yl beta-D-galactoside (10) greater than prednisolon-21-yl beta-D-glucoside (2) greater than prednisolon-21-yl beta-D-cellobioside (13) greater than dexamethason-21-yl beta-D-galactoside (9) greater than dexamethason-21-yl beta-D-glucoside (1). Hydrolysis of cellobioside 13 was only half that of glucoside 2 and one-fourth that of galactoside 10. Hydrolysis of all the prodrugs in cecal contents was rapid, with the exceptions of hydrocortison-21-yl beta-D-glucoside (5) and fludrocortison-21-yl beta-D-glucoside (7), which were hydrolyzed more slowly than the other glucoside prodrugs. Eadie-Hofstee plots for hydrolysis of the glucoside compounds suggested that bacterial beta-D-glucosidase activity in the colon may be more heterogeneous in nature than beta-D-galactosidase activity. Relative lipophilicities of the prodrugs and free steroids were compared by measuring their octanol-buffer partition coefficients (P). The logarithm of the P of cellobioside 13 (-0.56) was considerably lower than that of the other prodrugs, which ranged from 0.11 to 0.84. Log P of the free steroids ranged from 1.54 to 1.73. These relative rates of hydrolysis and relative lipophilicities, along with previously reported animal experiments, enable one to estimate the site specificity of glycoside prodrugs prior to extensive animal studies.     

结肠定位释药瓜尔胶/乙基纤维素包衣小丸

体外研究瓜尔胶/乙基纤维素混合包衣小丸的结肠靶向性。以5-氟尿嘧啶为模型药， 采用流化包衣技术以瓜尔胶/乙基纤维素混合物的水/醇混悬液对载药小丸进行喷液包衣。瓜尔胶/乙基纤维素混合包衣小丸的释药行为取决于包衣处方中瓜尔胶与乙基纤维素的比例和包衣厚度。分别以混合包衣液中瓜尔胶与乙基纤维素的比例及包衣增重为自变量， 以T₅和T₉₀（药物释放5%和90%所需要的时间）为效应， 进行3×4析因设计/效应面优化， 筛选较优处方。结果表明随着乙基纤维素在衣层中所占比例的增大及包衣厚度的增加， 药物释放时滞增加。当瓜尔胶与乙基纤维素的比例在0.2~0.7， 并且包衣增重在250%~500%时， T_5%为5.1～7.8 h， T_90%为9.8～16.3 h。并且在释药时滞之后， 进入模拟结肠微菌群酶解作用的释放环境中(pH 6.5)药物释放速度加快， T_90%缩短到9.0～14.5 h。由此可以看出适当的瓜尔胶/乙基纤维素混合衣层既可以保护药物顺利通过上消化道而不释放， 达到结肠后药物开始释放， 并且可在结肠微菌群的酶解作用下加速药物的释放， 实现结肠定位释药的目的。     

Targeted prodrugs in oral drug delivery: the modern molecular biopharmaceutical approach

Introduction: The molecular revolution greatly impacted the field of drug design and delivery in general, and the utilization of the prodrug approach in particular. The increasing understanding of membrane transporters has promoted a novel ‘targeted-prodrug' approach utilizing carrier-mediated transport to increase intestinal permeability, as well as specific enzymes to promote activation to the parent drug.

Areas covered: This article provides the reader with a concise overview of this modern approach to prodrug design. Targeting the oligopeptide transporter PEPT1 for absorption and the serine hydrolase valacyclovirase for activation will be presented as examples for the successful utilization of this approach. Additionally, the use of computational approaches, such as DFT and ab initio molecular orbital methods, in modern prodrugs design will be discussed.

Expert opinion: Overall, in the coming years, more and more information will undoubtedly become available regarding intestinal transporters and potential enzymes that may be exploited for the targeted modern prodrug approach. Hence, the concept of prodrug design can no longer be viewed as merely a chemical modification to solve problems associated with parent compounds. Rather, it opens promising opportunities for precise and efficient drug delivery, as well as enhancement of treatment options and therapeutic efficacy.     

甲硝唑微囊口服结肠定位给药系统的制备

目的 :考察甲硝唑微囊口服结肠定位给药系统的制备工艺。方法 :采用液中干燥法制备微囊 ,应用均匀试验设计 ,考察各因素水平对微囊包封率、载药量的影响。按优化后的结果选择实验条件 ,进行重复实验 ,用体外溶出实验考察其结肠定位释放效果。结果 :制备的甲硝唑微囊包封率为 ( 62 .3± 1.3 ) % ,载药量为 ( 5 9.8± 2 .0 ) % ,所制备的片剂在 0 .1mol·L- 1 盐酸溶液和 pH6.8磷酸盐缓冲液中几乎不释放 ,而在 pH7.5磷酸盐缓冲液中 3 0min的平均累积释放量为 82 .13 %。结论 :优化后的制备工艺对甲硝唑微囊口服结肠定位给药系统的研究和应用具有一定的参考价值。     

新型茶碱口服结肠靶向给药系统的体内动力学

目的研究以时间为释药开关的结肠靶向给药系统。方法以非pH依赖型聚丙烯酸树脂Eu dragit NE 3 0D为膜材 ,制备茶碱薄膜衣片 ;用HPLC法进行体内血药浓度分析 ;以γ 闪烁照相研究该制剂体内胃肠道的转运情况。结果本制剂与参比制剂主要药代动力学参数分别为 :tlag( 8 67± 1 0 4 )h、( 0 67± 1 1 5 )h ;Cmax( 5 2 5± 1 2 1 )mg/L、( 4 0 9± 1 2 5 )mg/L ;AUC0 2 6 ( 2 7 5 0±7 2 0 )mg·h/L、( 3 9 0 4± 1 0 4 3 )mg·h/L ;体内γ 闪烁照相研究表明 ,体外 6 5h释放的制剂口服8 0h后到达升结肠处开始释药 ,且体内释药与体外释药有一定的相关性。结论本制剂能达到结肠靶向释药的设计要求