pH-Sensitive nanospheres for colon-specific drug delivery in experimentally induced colitis rat model

Novel pH-sensitive nanospheres designed for colon-specific delivery were prepared using polymeric mixtures of poly (lactic-co-glycolic) acid (PLGA) and a pH-sensitive methacrylate copolymer. Budesonide (BSD), a topically active corticosteroid, was entrapped as a model drug. The therapeutic efficacy of the prepared nanospheres was assessed using the trinitrobenzenesulfonic acid (TNBS) colitis rat model, in comparison with conventional enteric microparticles. In addition, the colon targeting properties, systemic bioavailability, and specific uptake by the inflamed colon mucosa were evaluated using coumarin-6 (C-6)-loaded nanospheres. The prepared nanospheres showed strongly pH-dependent drug release properties in acidic and neutral pH values followed by a sustained release phase at pH 7.4. Animal experiments revealed the superior therapeutic efficiency of BSD-loaded nanospheres in alleviating the conditions of TNBS-induced colitis model. The in vivo studies using C-6-loaded nanospheres displayed higher colon levels and lower systemic availability of the fluorescent marker when compared with simple enteric coating. Moreover, quantitative analysis of the fluorescent marker and confocal laser scanning studies showed strong and specific adhesion of the nanospheres to the ulcerated and inflamed mucosal tissue of the rat colon. In conclusion, the proposed nanosphere system combined the properties of pH-sensitivity, controlled release, and particulate targeting that could be useful for colon-specific delivery in inflammatory bowel disease.     

Microbiota-sensitive drug delivery systems based on natural polysaccharides for colon targeting

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Cutting-edge technologies in colon-targeted drug delivery systems

Oral colon-targeted drug delivery systems have gained enormous attention among researchers in the last two decades. The significance of this site-specific drug delivery system can be measured by its usefulness for delivering a variety of therapeutic agents, both for the treatment of local diseases or for systemic therapies. With the arrival of newer innovations, a large number of breakthrough technologies have emerged for targeting a drug molecule to the colon. Researchers have attempted various approaches in the development of these formulation technologies, such as pH-dependent, time-dependent and microflora-activated systems. Recently, a number of approaches have been proposed that utilize a novel concept of di-dependent drug delivery systems, that is, the systems in which the drug release is controlled by two factors: pH and time, and pH and microflora of the colon. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the formulation technologies that have been developed for attaining colon-specific drug delivery.     

Sulfate-conjugated methylprednisolone as a colon-targeted methylprednisolone prodrug with improved therapeutic properties against rat colitis

Methylprednisolone (MP) is one of the most widely used corticosteroids for the treatment of inflammatory bowel disease (IBD). However, systemic adverse effects of MP limit its availability for the disease. In present study, sulfate-conjugated methylprednisolone (MPS) was evaluated in vivo as a colon-targeted prodrug of MP and its therapeutic properties against 2,4,6-trinitrobenzenesulfonic acid–induced rat colitis were investigated. Upon oral administration, a large fraction of MPS reached the large intestine, where MPS was converted to MP implying that MPS would deliver MP effectively to the large intestine. The fecal recovery of MP (after MPS administration) was much greater than that after MP administration and the urinary recovery of MP (after MPS administration) was much less than that after MP administration, suggesting that MPS should exhibit enhanced therapeutic activity and reduced systemic adverse effects. Consistent with this notion, MPS was more effective than MP in ameliorating rat colitis. Moreover, the adverse effects of MPS on adrenal function and thymus were much lower than those of MP. Taken together, MPS may be therapeutically superior to MP in IBD treatment.     

Susceptibility of glucocorticoids to colonic metabolism and pharmacologic intervention in the metabolism: implication for therapeutic activity of colon-specific glucocorticoid 21-sulfate sodium at the target site

Objectives The systemic side effects of glucocorticoids have prevented their long‐term use for treatment of inflammatory bowel disease. Colon‐specific delivery of glucocorticoids has been adopted as a strategy to circumvent the toxicological trouble. Glucocorticoids delivered to the large intestine might undergo metabolisms by colonic microflora, which should affect therapeutic availability at the target site. It was investigated whether the susceptibility of glucocorticoids to the colonic metabolisms and pharmacologic intervention in the metabolism could modulate the therapeutic availability of colon‐targeted glucocorticoids. Methods Various glucocorticoids and their derivatives, glucocorticoid 21‐sulfate sodium compounds, were incubated in the cecal contents in the presence or absence of reduction inhibitors and the change in the levels of the drugs was monitored. Key findings The accumulation profiles of the corresponding glucocorticoids liberated from glucocorticoid 21‐sulfate sodium compounds vary, depending on the metabolic susceptibility of glucocorticoids. Reduction inhibitors prevented the cecal metabolisms of glucocorticoids, which was most prominent for prednisolone (PD) and methylprednisolone (MP). Moreover, reduction inhibitors increased the accumulated amount of MP and PD released from PD‐ and MP‐21‐sulfate sodium in the cecal contents. Conclusions Our data provide information useful for selection of a glucocorticoid and a pharmacologic strategy for the design of an efficient colon‐specific glucocorticoid prodrug.     

The effective therapy of cyclosporine A with drug delivery system in experimental colitis

Cyclosporine A (CyA) is a useful immunosuppressive agent for steroid-dependent or steroid-refractory ulcerative colitis. However, side effects have been reported in clinical trials of ulcerative colitis treated with CyA. Biodegradable microspheres (MS) have been investigated as drug delivery system. We evaluated the effect of a drug delivery system with poly(d,l-lactic acid)-MS containing CyA. Colitis was induced in C57BL/6 mice by 3% dextran sulfate sodium (DSS). Mice with DSS-induced colitis were treated with oral administration of CyA or CyA-MS: CyA (0.2?mg/kg/day)-MS; CyA (2?mg/kg/kg)-MS). Serum levels of CyA were significantly less elevated after oral administration of CyA (2?mg/kg/day)-MS compared with CyA (2?mg/kg/day) (CyA (2?mg/kg/day), 44.7 ± 0.8?ng/ml; CyA (2?mg/kg/day)-MS, 7.7 ± 1.3?ng/ml). The body weight at day 10 was significantly recovered in the mice treated with CyA (0.2?mg/kg/day)-MS and CyA (2?mg/kg/day)-MS compared with CyA (0). The histological score and myeloperoxidase activity in the mice treated with CyA-MS was significantly lower than CyA (0). Gene expressions of interleukin-1β (IL-1β), IL-6, and CXCL1 in the mice treated with CyA (0.2?mg/kg/day)-MS and CyA (2?mg/kg/day)-MS were downregulated compared with CyA (0)-MS. CyA-MS might be possible to treat ulcerative colitis effectively by decreasing the total dosage without the elevation of the serum level or the side effects of CyA.     

Protective effect of embelin against acetic acid induced ulcerative colitis in rats

The aim of the present study is to evaluate the effect of embelin isolated from Embelia ribes on acetic acid induced colitis in rats. Experimental animals received embelin (25 and 50 mg/kg, p.o.) and sulfasalazine (100 mg/kg, p.o.) for five consecutive days before induction of colitis by intra-rectal acetic acid (3% v/v) administration and the treatment continued up to 7 days. The colonic mucosal injury was assessed by clinical, macroscopic, biochemical and histopathological examinations. Embelin treatment significantly decreased clinical activity score, gross lesion score, percent affected area and wet colon weight when compared to acetic acid induced controls. The treatment also reduced significantly the colonic myeloperoxidase activity, lipid peroxides and serum lactate dehydrogenase and significantly increased the reduced glutathione. The histopathological studies also confirmed the foregoing findings. The protective effect may be due to its antioxidant and anti-inflammatory activities.     

基于炎症环境的口服结肠靶向给药系统研究进展

口服结肠靶向给药系统由于能改善结肠局部疾病的治疗效果和降低副作用而成为该领域的研究热点。口服给药系统设计方法的不断发展显著提高了药物在结肠部位的生物利用度,然而,要使药物在发病期能够发挥治疗效果,还须关注到结肠炎症时胃肠道出现生理条件变化的影响。纳米技术已经作为提高药物在结肠炎症病灶区摄取的新策略而应用于口服剂型设计中,本文主要介绍该纳米给药系统的设计方法和研究进展。     

溃结康对三硝基苯磺酸诱导大鼠炎症性肠病的作用研究

目的 观察溃结康经灌肠给药对三硝基苯磺酸(trinitrobenzene sulfonic acid,TNBS)诱导的炎症性肠病动物模型的作用,以明确溃结康对炎症性肠病的治疗作用,为探索药物应用于克罗恩病治疗的可行性。方法 采用TNBS灌肠的方法诱导大鼠溃疡性结肠炎模型,观察溃结康灌肠给药对大鼠疾病活动指数(DAI)评分、血清干扰素-γ(IFN-γ)、白介素-l(IL-1)、白介素-4(IL-4)、白介素-10(IL-10)和肠黏膜中谷氨酰胺(Glutamine,Gln)的含量的影响,并观察药物对大鼠结肠组织损伤评分以及病理学的影响。结果 TNBS诱导的结肠炎模型可引起动物体质量下降,肉眼血便或便潜血阳性,DAI评分增高,血清IFN-γ,IL-1升高,肠黏膜Gln降低,溃结康不同剂量组灌肠给药可改善TNBS引起的DAI评分增高以及降低血清IFN-γ、IL-1水平,升高肠黏膜Gln,缓解结肠炎组织学变化,其中尤以溃结康高剂量组作用更为明显。结论 溃结康灌肠给药对缓解TNBS诱导结肠炎模型有一定治疗作用。     

Oral colon-specific therapeutic approaches toward treatment of inflammatory bowel disease

Introduction: Inflammatory bowel disease (IBD) is a chronic relapsing idiopathic disease. In clinical terms, most patients require lifelong medication associated with possible unpleasant adverse effects. Oral colon-specific drug delivery systems are designed to deliver therapeutic drugs to the inflamed colon to target pathophysiological manifestations of IBD. The aim is to maintain the drug with proper concentration in the inflamed colon, to enhance drug residence time and to minimize drug absorption by healthy tissues.

Areas covered: This review addresses the main barriers for colon-specific drug delivery from organism, tissue and cell levels, respectively. It also summarizes novel colon-specific therapeutic strategies using microparticles and nanoparticles.

Expert opinion: Oral colon-specific drug delivery represents a possible approach toward efficient treatment of IBD. As the environment of the gastrointestinal tract is harsh and intricate, this approach requires that drug carriers can respond to specific environmental factors of the inflamed colon, permitting stimulus-responsive release of loaded drugs to specific cells or even into specific organelles within cells.     

Novel drug delivery strategies for the treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD) encompasses two idiopathic inflammatory diseases of the intestinal tract: Crohn’s disease and ulcerative colitis. Existing therapy for IBD consists mainly of orally or rectally administered small drug molecules, such as 5-aminosalicylates and corticosteroids, or potent systemic immune suppressants. IBD presents a challenging target for drug delivery, particularly by the oral route, as, contrary to most therapeutic regimens, minimal systemic absorption and maximal intestinal wall drug levels are desired. Several delivery strategies are employed to achieve this goal, including the chemical modification of the drug molecules, the use of controlled- and delayed-release formulations and the use of bioadhesive particles. The goal of this review is to summarise existing IBD therapy and examine novel approaches in intestinal drug delivery.     

Polymer-based drug delivery: the quest for local targeting of inflamed intestinal mucosa

Colon-specific drug delivery has found important applications in the wide array of diseases affecting the lower intestinal tract. Recent developments and advancements in the polymer-based colonic delivery ensure targeted therapeutics with reduced systemic adverse effects. Latest progress in the understanding of polymer science has decorated a polymer-based formulation with a number of special features, which may prove effective in the localized drug targeting at specific sites of the intestine. Upon oral administration, polymeric vehicles or polymer-coated formulations serve to protect the drug from premature release and degradation in the upper gastrointestinal tract. Moreover, it also facilitates the selective accumulation and controlled release of the drug at inflamed sites of the colon. This review article focuses on a wide coverage of major polymers, their modifications, pros and cons, mechanism of colon targeting and applications as a vehicle system for colonic drug delivery, with a special emphasis on the inflammatory bowel disease.     

褪黑激素调节巨噬细胞功能减轻结肠免疫损伤

目的:研究褪黑素(MT)对大鼠结肠免疫损伤的影响及与巨噬细胞功能的关系.方法:利用2,4,6-三硝基苯磺酸(TNBS)和乙醇灌肠制备大鼠结肠炎模型.实验设正常对照组、模型对照组、5-氨基水杨酸给药组(100 mg/kg)和MT给药组(2.5,5.0,10.0 mg/kg),每大灌肠给药一次,从制备模型d 7开始共21 d.测定结肠粘膜损伤指数(CMDI)、粘膜病理组织学评分(HS)、粪便隐血实验(OBT)和髓过氧化物酶(MPO)、IL-1、TNF-α、NO水平.结果:大鼠经TNBS和乙醇处理后CMDI、HS、OBT和MPO水平以及结肠和血浆中IL-1、TNF-α和NO水平明显高于正常,MT可不同程度逆转上述变化,减轻大鼠结肠免疫损伤.结论:MT灌肠能减轻结肠炎大鼠粘膜损伤,此与MT调节巨噬细胞功能有关.     

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。     

Early detection of renal injury using urinary vanin‐1 in rats with experimental colitis

Renal complications are often detected in patients with inflammatory bowel disease (IBD). Because conventional markers such as serum creatinine and β2‐microglobulin are not sensitive and/or specific, a new renal biomarker is needed. We have recently identified urinary vanin‐1 as an early biomarker for the detection of nephrotoxicant‐induced renal injury. In this study, we compared the usefulness of urinary vanin‐1 with other newly developed biomarkers [urinary monocyte chemoattractant protein‐1 (MCP‐1), kidney injury molecule‐1 (Kim‐1) and N‐acetyl‐beta‐D‐glucosaminidase (NAG)] for the detection of renal complications in rats with experimental colitis. On day 2 after intracolonic injection of 2,4,6‐trinitrobenzene sulfonic acid (TNBS), male Wistar rats developed not only colitis, but histologically evident renal injury. Urinary vanin‐1 started to elevate on day 1, whereas serum creatinine and urinary excretions of glucose, total protein, albumin, Kim‐1, MCP‐1 and NAG significantly increased only on day 2. The mRNA expressions of vanin‐1 and Kim‐1 significantly increased in the kidney, but not in the colon. In addition, vanin‐1 did not appear in the blood. On the other hand, colonic mRNA expression and the serum concentration of MCP‐1 were significantly higher in the TNBS‐treated rats than in the control animals. These results suggest that, in contrast to MCP‐1, urinary vanin‐1 and Kim‐1 mainly originated from the kidney rather than the colon in this model. Compared with Kim‐1 and MCP‐1, vanin‐1 might be an earlier biomarker for the detection of renal injury in rats with experimental colitis. Copyright © 2013 John Wiley & Sons, Ltd.     

Investigation of the effect of intracolonic melatonin gel formulation on acetic acid-induced colitis

The aims of the present study were to develop a colon-specific gel formulation of melatonin with sodium alginate and to evaluate its in vitro characteristics and intracolonic performance on oxidative stress parameters, such as nitric oxide (NOx), malondialdehyde (MDA) and glutathione (GSH) levels in rats with acetic acid-induced colitis. The melatonin-alginate gel formulations were prepared and their physico-pharmaceutical properties were determined. Formulation M5, which contained 3% of sodium alginate and 20% polyethylene glycol, was used for in vivo studies. The in vivo studies were conducted in rats with acetic acid-induced colitis. NOx, MDA and GSH levels were determined and histological investigations were performed. It was found that formulation M5 was the most suitable formulation for the colon-specific melatonin gel, in terms of pH, viscosity, drug release and mucoadhesion properties. The MDA levels in the tissues of Group 2 (treated with an intracolonic gel formulation without melatonin) were found to be significantly higher than in Group 1 (the untreated group). NOx levels decreased with the intracolonic and systemic melatonin treatment in the colitis-induced rats. Neither intracolonic nor intra-peritoneal (IP) melatonin treatment affected GSH levels. The epitelization of the colon tissues in groups administered with intracolonic melatonin, IP melatonin, and the intracolonic gel formulation without melatonin was much better than that found in the untreated group. It was concluded that melatonin participated in various defense mechanisms against the colonic inflammatory process, and that the dose, route and formulation type were the most important parameters in the effectiveness of melatonin.     

龙胆苦苷对结肠炎小鼠的治疗作用

目的探究龙胆苦苷对结肠炎小鼠的治疗作用。方法采用2,4,6-三硝基苯磺酸(TNBS)-乙醇溶液诱导结肠炎小鼠模型,测定龙胆苦苷给药后对小鼠体质量、结肠指数、胸腺质量、结肠组织中髓过氧化物酶(MPO)活性以及血清炎症细胞因子TNF-α和IL-8的影响,并通过免疫组化法观察龙胆苦苷对小鼠结肠组织中环氧合酶-2(COX-2)蛋白表达的影响。结果给药1周后,龙胆苦苷各剂量组小鼠体质量与模型组相比显著改善;小鼠结肠指数、结肠组织中MPO活性以及炎性细胞因子TNF-α和IL-8与模型组相比均显著降低(P<0.05);免疫组化结果显示,龙胆苦苷能降低结肠炎小鼠组织中环氧合酶-2(COX-2)的蛋白表达。结论龙胆苦苷能修复TNBS-乙醇溶液诱导的小鼠结肠损伤,对小鼠结肠炎有显著的治疗作用。     

Microencapsulation of budesonide with dextran by spray drying technique for colon-targeted delivery: an in vitro/in vivo evaluation in induced colitis in rat

The aim of this study was developing colon targeted-delivery of budesonide for ulcerative colitis. Microcapsules were prepared using spray drying technique by different drug-to-dextran ratios and three molecular weights (MWs) of polymer. Differential scanning calorimetry, X-ray diffraction (XRD), drug release and loading efficiency of microcapsules were studied. In vivo efficacy of the selected formulation prepared by 1?:?10 drug-to-polymer ratio and dextran with MW 500?000 (D10M500) against acetic acid-induced colitis in rats was evaluated and compared to the control and reference groups (mesalasine and budesonide suspensions). The results showed that D10M500 microcapsules could target the drug to colon and its efficacy in reducing macroscopic damage score was higher than mesalasine suspension. Treatment with D10M500 decreased the scores of crypt damage and total colitis significantly compared to the control group which just received the vehicle and the groups treated with mesalasine and budesonide suspension which could not reduce the colitis parameters significantly.