Polymers for colon targeted drug delivery

The colon targeted drug delivery has a number of important implications in the field of pharmacotherapy. Oral colon targeted drug delivery systems have recently gained importance for delivering a variety of therapeutic agents for both local and systemic administration. Targeting of drugs to the colon via oral administration protect the drug from degradation or release in the stomach and small intestine. It also ensures abrupt or controlled release of the drug in the proximal colon. Various drug delivery systems have been designed that deliver the drug quantitatively to the colon and then trigger the release of drug. This review will cover different types of polymers which can be used in formulation of colon targeted drug delivery systems.     

壳聚糖在靶向制剂中的应用进展

壳聚糖是一种天然高分子化合物，壳聚糖及其衍生物具有优良的生物相容性和生物可降解性，在制药业有广阔的应用前景。综述了近几年来壳聚糖及其衍生物在靶向制剂中的应用。     

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。     

Design, development and optimization of a novel time and pH-dependent colon targeted drug delivery system

The aim of present study was to develop a time- and pH-dependent system for delivering mesalamine to the colon. The system consists of the core tablet of mesalamine which is compression coated with hydroxypropyl methylcellulose (HPMC K4M) (time-dependent factor). This is then coated with pH-dependent polymer Eudragit L100. The simplex lattice design was adopted to optimize the independent variables i.e. amount of HPMC (X1), dextrose (X2) and polyvinyl pyrollidone (PVP) (X3) and to study their effect on the dependent variables i.e. lag time and time for 50% drug dissolution (t50). The results of the linear interactive model and graphical representation revealed that as the amount of HPMC increases, the lag time and t50 value also increases and as the amount of dextrose and PVP were increased the lag time and t50 value decreases.     

口服结肠靶向释药系统的制备及应用

目的由于在治疗肠道或某些全身性疾病中具有特殊的优点,口服结肠靶向给药系统受到更多的关注。但消化道的复杂性导致影响药物在结肠靶向释药的因素较多,重现性不好。本文对经口服药物结肠靶向释药的生理因素、目前已有的制备技术及应用进行综述。     

口服结肠靶向纳米载体的研究进展

通过对近年来有关口服结肠靶向给药纳米载体的文献进行归纳和总结,列出了常用的新型口服结肠靶向纳米给药载体如纳米粒、纳米乳、胶束、脂质体纳米凝胶和纳米混悬液等。结肠靶向纳米载体可使药物选择性到达结肠部位,减少给药剂量、降低药物毒副作用,从而提高药物口服生物利用度,发挥治疗结肠相关疾病的作用。     

Design and development of multiparticulate system for targeted drug delivery to colon

A multiparticulate system combining pH-sensitive property and specific biodegradability for colon-targeted delivery of metronidazole has been investigated. Cross-linked chitosan microspheres were prepared from an emulsion system using liquid paraffin as the external phase and solution of chitosan in acetic acid as the disperse phase. The multiparticulate system was prepared by coating cross-linked chitosan microspheres exploiting Eudragit® L-100 and S-100 as pH-sensitive polymers. Morphology and surface characteristics of the formulations were determined by scanning electron microscopy. Particle size of the chitosan microspheres was determined by optical microscopy while that of coated microspheres was determined by particle size analyzer. In vitro drug-release studies were performed in conditions simulating stomach-to-colon transit in presence and absence of rat caecal contents. The size of the microspheres was small and they were efficiently microencapsulated within Eudragit® microspheres, forming a multireservoir system. By coating the microspheres with Eudragit® pH-dependant release profiles were obtained. No release was observed at acidic pH; however, when it reached the pH where Eudragit® starts solublizing there was continuous release of drug from the formulation. Further, the release of drug was found to be higher in the presence of rat caecal contents, indicating the susceptibility of chitosan matrix to colonic enzymes released from rat caecal contents.     

壳聚糖微/纳米粒在定向给药系统中的应用研究

目的：介绍壳聚糖微/纳米粒在新型定向给药系统中的应用,为发展安全高效的壳聚糖微/纳米粒定向给药系统提供参考。方法：综合近年来出版的有关文献,对壳聚糖基本性质,定位给药于各组织部位进行了探讨。结果：壳聚糖微/纳米粒可应用于脑、眼、鼻、口、肺、胃、小肠、结肠等器官靶向给药。结论：壳聚糖微/纳米粒作为一种新型药用辅料,在定位给药系统中已经得到了开发和应用。     

Formulation and evaluation of chitosan microspheres of aceclofenac for colon‐targeted drug delivery

The objective of this investigation was to develop novel colon specific drug delivery. Aceclofenac, a NSAID, was successfully encapsulated into chitosan microspheres. Various formulations were prepared by varying the ratio of chitosan, span‐85 and stirring speed and the amount of glutaraldehyde. The SEM study showed that microspheres have smooth surfaces. Microspheres were characterised by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) to confirm the absence of chemical interactions between drug and polymer and to know the formation of microspheres structure. The microspheres were evaluated for particle size, encapsulation efficiency, drug loading capacity, mucoadhesion studies, stability studies, in vitro and in vivo drug release studies. Particle sizes, as measured by the laser light scattering technique, were of an average size in the range 41–80 µm. The swelling index was in the range 0.37–0.82 and the entrapment efficiency range was 51–75% for all the formulations. The optimised batch ACM₁₃ released 83.6% at 8 h and 104% at 24 h in SCF containing rat caecal content. Eudragit coated chitosan microspheres prevented the release of the aceclofenac in the physiological environment of the stomach and small intestine and released 95.9±0.34% in the colon. With regard to release kinetics, the data were best fitted with the Higuchi model and showed zero order release with non‐Fickian diffusion mechanism. The in vivo findings suggest that aceclofenac microspheres exhibit a prolonged effect of aceclofenac in rats and produce a significant anti‐inflammatory effect. The findings of the present study conclusively state that chitosan microspheres are promising for colon targeting of aceclofenac to synchronise with chronobiological symptoms of rheumatoid arthritis. Copyright © 2010 John Wiley & Sons, Ltd.     

口服结肠靶向给药系统的研究概况

口服结肠靶向给药系统具有很多优点,尤其对肠病的治疗。本文综述了口服结肠靶向蛤药系统的机制、类型的研究概况。     

Design and in vitro evaluation of oral colon targeted drug delivery systems for tinidazole

The aim of the present investigation is to develop colon targeted drag delivery sytems for tinidazole using guar gum as a carrier in the treatment of amoebiasis. Fast-disintegrating tinidazole core tablets were compression-coated with 55, 65 and 75% of guar gum. All the formulations were evaluated for the hardness, drug content uniformity, and subjected to in vitro drug release studies. The amount of tinidazole released from tablets at different time intervals was estimated by HPLC method. The compression-coated formulations released < 0.5% of tinidazole in the physiological environment of stomach and small intestine. When the dissolution study was continued in simulated colonic fluids, the compression coated tablet with 55% of guar gum coat released 99% of tinidazole after degradation by colonic bacteria at the end of 24 h of the dissolution study. The compression coated tablets with 65 and 75% of guar gum coat released about 67 and 20% of tinidazole, respectively in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that compression coated tinidazole tablets with either 55 or 65% of guar gum coat is most likely to provide targeting of tinidazole for local action in the colon owing to its minimal release of the drug in the first 5 h of physiological environment of stomach and small intestine. The tinidazole compression coated tablets showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40 degrees C/75% RH for 6 months.     

肝靶向给药系统的研究进展

通过对近年来国内外报道的肝靶向研究相关文献进行检索,根据肝靶向药物的不同作用机制对肝靶向给药系统的研究进展进行分析和总结。有关肝靶向药物的研究结果表明,肝靶向给药系统能选择性地将药物输送至肝脏病变部位,通过提高其在肝脏病变组织的药物浓度,从而达到增强药物疗效、减少其毒副作用的目的。因此,肝靶向给药系统在肝脏疾病治疗方面具有广阔的应用前景。     

靶向给药研究的新进展

靶向给药可使治疗部位的药物浓度明显提高, 可减少用药量并使治疗费用降低, 降低药物对全身的毒副作用。因此, 靶向给药是目前研究的热点, 本文综述了近年来靶向给药的相关研究, 主要从被动靶向、主动靶向以及物理化学靶向3个方面阐述了靶向给药的研究进展。     

Design,optimization and evaluation of mesalamine matrix tablet for colon drug delivery system

The aim of the present investigation was to develop and evaluate matrix tablet of mesalamine for colonic delivery by using Eudragit RSPO, RLPO and combination of both. The tablets were further coated with different concentration of pH-dependent methacrylic acid copolymers (Eudragit S100), by dip immerse method. The physicochemical parameters of all the formulations were found to be in compliance with the pharmacopoeial standards. The in vitro drug release study was conducted using sequential dissolution technique at pH 1.2 (0.1N) HCl, phosphate buffers pH 6.8 and 7.4, with or without rat cecal content mimicking different regions of gastro intestinal tract. The result demonstrated that the tablet containing Eudragit RLPO coated with Eudragit S100 (1 %) showed a release of 94.91 % for 24 h whereas in the presence of rat cecal content the drug release increases to about 98.55 % for 24 h. The uncoated tablets released the drug within 6 h. The in vitro release of selected formulation was compared with marketed formulation (Octasa MR). In vitro dissolution kinetics followed the Higuchi model via non-Fickian diffusion controlled release mechanism. The stability studies of tablets showed less degradation during accelerated and room temperature storage conditions. The enteric coated Eudragit S100 coated matrix of mesalamine showing promising site specific drug delivery in the colon region.     

Pioglitazone hydrochloride: chemopreventive potential and development of site-specific drug delivery systems

Abstract

The aim of this study was to investigate the potential of pioglitazone hydrochloride as a promising anticancer agent and then to design and evaluate the colon-targeted delivery system. The role of pioglitazone hydrochloride as a promising anticancer agent was evaluated by in vitro cell line studies and in vivo 1,2-dimethylhydrazine-induced colon carcinogenesis in rats. In order to deliver the drug at site of action, i.e. colon, drug embedded in matrices containing a release retarding polymer (HPMC K4M) and a polysaccharide (locust bean gum) were prepared. These matrix systems were further enteric coated with Eudragit®S100 to minimize the premature drug release in the upper segments of the GIT. In vitro dissolution studies were performed in absence and presence of rat caecal contents on selected batches and samples were analyzed using a validated RP-HPLC method. Hence, the studies led to the conclusion that successful site-specific delivery systems of pioglitazone hydrochloride were developed to improve its therapeutic efficacy in the management of colorectal cancer.     

Water-soluble polymers for targeted drug delivery to human squamous carcinoma of head and neck

Human squamous cell carcinoma of the head and neck (SCCHN) is characterized by over expression of a tumor cell surface-specific receptor namely Hsp47/CBP2 that makes it a favorable candidate for targeted delivery of anticancer drugs. Several synthetic peptides have been identified as effective ligands for binding to CBP2. The purpose of this study is to investigate the potential of water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (Dox) conjugates containing a Hsp47/CBP2 binding peptide sequence, namely WHYPWFQNWAMA for targeted delivery to SCCHN. An HPMA copolymer containing Dox and CBP2 targeting peptide conjugated via lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer was synthesized by free radical precipitation copolymerization. A control polymer without targeting moiety was also synthesized. The conjugates were characterized for drug content, peptide content, molecular weight and molecular weight distribution. The uptake of polymeric conjugates by both drug resistant and drug sensitive SCCHN cells were determined in vitro by flow cytometry using FACS scan analysis. Cytotoxicity of the conjugates towards drug sensitive as well as multidrug resistant SCCHN cells were evaluated by a clonal survival assay and compared to free Dox. The cytotoxicity of the free peptide was similarly evaluated. The internalization and subcellular fate of the conjugates in drug sensitive SCCHN cells was monitored using confocal microscopy. The new targetable copolymer contained 0.16 mmole peptide/g polymer. Studies on drug sensitive SCCHN cells demonstrated lesser uptake of both targeted and non-targeted conjugates compared to free Dox suggesting a slower endocytic mechanism of uptake for the conjugates as opposed to rapid diffusion of free Dox. At higher Dox equivalent concentrations (>20 μM) the targeted conjugate showed significantly higher uptake (p≤0.028) than the non-targeted conjugate. The uptake of the targeted conjugate was inhibited in the presence of an anti Hsp47 antibody suggesting the involvement of active receptor mediated endocytosis in cell entry of the conjugate. Compared to free Dox, the targeted and non-targeted conjugates caused marginally lower inhibition (p≤0.01) of the drug sensitive SCCHN cells. In contrast, the same conjugates showed significantly higher uptake (p≤0.004) by drug resistant SCCHN cells and caused significantly higher inhibition (p≤0.02) of drug resistant SCCHN cells when compared to free Dox. Results suggest that the polymeric conjugates were able to overcome drug resistance. Confocal microscopy studies demonstrated the uptake of the polymeric conjugates, followed by internalization, intralysosomal localization and subsequent release of Dox. HPMA copolymer-Dox-peptide conjugates targeted to SCCHN cells were able to overcome drug resistance and increase efficacy in vitro. The results suggest that targetable polymeric conjugates have potential to improve systemic head and neck cancer chemotherapy by increasing tumor localization and reducing dose-limiting toxicity.     

核苷酸适体在靶向给药系统中的应用进展

适体,即体外合成筛选得到的能特异性地与靶分子结合的一段寡核苷酸序列。由于其独特的性质,在靶向给药系统中有着广阔的应用前景,目前已成为靶向给药研究领域的热点。综述了适体在靶向给药系统中的优势及其应用进展,并对其应用前景和面临的问题进行分析。     

Optimization and pharmacotechnical evaluation of compression‐coated colon‐specific drug delivery system of triphala using factorial design

The purpose of the present investigation was to achieve successful delivery specifically to the colon using guar gum as a compression coat over a core tablet of triphala. In this study, guar gum along with hydroxy propyl methyl cellulose (HPMC) was used as a compression‐coating polymer. The drug delivery system was based on the gastrointestinal transit time concept, assuming colon arrival time to be 6 h. Rapidly disintegrating core tablets containing 100‐mg triphala extract were compression coated with guar gum and HPMC. A 3² full factorial design was applied for optimization of the formulation. Both variables, the proportion of guar gum in polymer blend (X₁) and coat weight of the tablet (X₂), had an influence on the percent drug release after 4 h of dissolution of tablet in the presence of rat cecal content (Y240) and difference in percent drug release between 4 h and 10 h of dissolution of tablet in the presence of rat cecal content (YD).The results revealed that for protecting the rapidly disintegrating core of triphala in the physiological conditions of stomach and upper intestine, the core tablet should be coated with 50% of guar gum in coat formulation and higher coat weight. The proportion of guar gum exhibited predominant action as compared to coat weight. In vivo performance was assessed via an x‐ray roentgenography study by placing barium sulfate as an x‐ray opaque material instead of triphala. The guar gum–HPMC coating was found to be a promising drug delivery system for drugs such as triphala and sennosides to be delivered to the colon. Drug Dev. Res. 65:34–42, 2005. © 2005 Wiley‐Liss, Inc.     

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。     

国内靶向制剂的研究现状

目的：研究靶向制剂在中国的发展现状。方法：通过大量国内文献检索，从靶向制剂（主动靶向，被动靶向，物理化学靶向）三方面进行探讨。结果与结论：发现国内靶向制剂潜力巨大，具有较广阔的开发及应用前景。