Pulsatile systems for colon targeting of budesonide: in vitro and in vivo evaluation

The purpose of this study is to increase the lag time and prevent release of budesonide, a corticosteroid drug used in Crohn's disease for the first 5?h and efficiently deliver it to the colon. Eudragit S100 spray-coated capsules and pulsatile systems using tablet plugs of cellulose acetate butyrate (CAB), HPMC K4M, guar gum, and pectin were prepared. Eudragit S100-coated capsules released 80.62% after 5 h. In pulsatile systems, decreasing the ratio of the polymer significantly increased the rate and extent of drug release. Spray-coating with EUD S100 decreased the extent of drug release to 48.41%, 69.94%, 80.58%, and 45.23% in CAB, HPMC K4M, pectin, and guar gum, respectively; however, the entire amount was released in the target area. In the presence of bacterial enzymes, selected formulas showed nearly 100% release. X-ray imaging performed to monitor the capsules throughout the GIT in human volunteers of the capsules and spray-coated pulsatile systems with 25% guar gum in the plug showed bursting in the transverse and ascending colon, respectively. Both formulations showed marked reduction in induced rabbit colitis model.     

Bumadizone calcium dihydrate microspheres compressed tablets for colon targeting: formulation,optimization and in vivo evaluation in rabbits

Abstract

The objective of this study was the development of a colon-targeted microspheres which were compressed into tablets containing the non-steroidal anti-inflammatory bumadizone calcium dihydrate. A 3² full factorial design was adopted for the evaluation of the prepared microspheres. The effect of two independent variables namely polymer type (Eudragit RS100, ethyl cellulose and cellulose acetate butyrate), and drug: polymer ratio (1:1, 9:1 and 18:1) was studied on the entrapment efficiency and in vitro drug release for 12?h. Colon targeting aims to minimize the release of the drug off target area (pH 1.2 and 6.8) and to maximize the release of the drug in target area (pH 7.4). Candidate formulae were compressed into core tablets and colon targeting was achieved using the enzyme-dependent polymer (pectin) as coat in three different concentrations 50, 75 and 90%. Candidate formula F15 (microspheres prepared using BDZ:CAB in a ratio of 18:1 and compressed into tablets using 50% pectin and 50% Avicel in the coat) was able to adequately modulate drug release avoiding drug release in the gastric ambient, and reaching the colonic targeting where 99.7% release was achieved within 12?h following zero-order model. In vivo studies showed that F15 achieved significant decrease in myeloperoxidase activity and inflammation with delayed T_max (4?h) and lower C_max (2700?ng/ml) when compared to marketed product.     

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.     

Preparation and in vitro evaluation of mebeverine HCl colon-targeted drug delivery system

Mebeverine HCl is a water soluble drug commonly used to treat irritable bowel syndrome by acting directly on the smooth muscles of the colon. This work was aimed at the formulation and in vitro evaluation of a colon-targeted drug delivery system containing mebeverine HCl. Matrix tablets were prepared using ethyl cellulose (EC), Eudragit RL 100 either solely or in combination by wet granulation technique. Dissolution was carried out in 0.1 N HCl for 2?h followed by pH 6.8 phosphate buffer for eight hours. Uncoated forms released more than 5% drug in 0.1 N HCl therefore, Eudragit L100 was used as a coat. The results indicated very slow release profile. As a result, single retardant was used to prepare the matrix and coated by Eudragit L 100. The matrix containing 7% Eudragit RL 100 and 6% of binder was subjected to further studies to assess the effect of different coats (Eudragit L 100-55 and cellulose acetate phthalate) and different binders (pectin and sodium alginate) on the release profile. Eudragit L 100 and pectin were the best coating agent and binder, respectively. The final formula was stable and it can be concluded that the prepared system has the potential to deliver mebeverine HCl in vivo to the colon.     

Development and Evaluation of pH-Dependent Micro Beads for Colon Targeting

The purpose of this research was to develop and evaluate multiparticulates of alginate and chitosan hydrogel beads exploiting pH sensitive property for colon-targeted delivery of theophylline. Alginate and chitosan beads were prepared by ionotropic gelation method followed by enteric coating with Eudragit S100. All formulations were evaluated for particle size, encapsulation efficiency, swellability and in vitro drug release.In vitro dissolution studies performed following pH progression method demonstrated that the drug release from coated beads depends on coat weights applied and pH of dissolution media. Mechanism of drug release was found to be swelling and erosion-dependent. The studies showed that formulated alginate and chitosan beads can be used effectively for the delivery of drug to colon and a coat weight of 20% weight gain was sufficient to impart an excellent gastro resistant property to the beads for effective release of drug at higher pH values.     

Enzymatically degraded Eurylon 6 HP-PG: ethylcellulose film coatings for colon targeting in inflammatory bowel disease patients

Objectives Film coatings based on blends of Eurylon 6 HP‐PG (a hydroxypropylated and pregelatinized high amylose starch) and ethylcellulose were to be evaluated as promising coating materials for site‐specific drug delivery to the colon of patients suffering from inflammatory bowel diseases. Methods Pellet starter cores containing 60% 5‐aminosalicylic acid were prepared by extrusion/spheronization and coated with different Eurylon 6 HP‐PG : ethylcellulose blends at various coating levels. Drug release was measured in media simulating the contents of the upper gastrointestinal tract (in the presence and absence of enzymes) as well as in media simulating the contents of the colon. Key findings 5‐Aminosalicylic acid release could effectively be suppressed in 0.1 N HCl and phosphate buffer pH 6.8, optionally containing pepsin or pancreatin, but occurred as soon as the pellets came into contact with culture medium inoculated with faecal samples from inflammatory bowel disease patients. This can be attributed to the partial degradation of the starch derivative by enzymes secreted by bacteria present in the colon of these patients. Conclusions The presented drug delivery system is adapted to the pathophysiological conditions in inflammatory bowel disease patients. Furthermore, drug release remained unaltered upon 1 year open storage.     

苦参碱结肠靶向微丸的制备及体外释放性能评价

目的:优选苦参碱结肠靶向微丸的制备工艺。方法:采用挤出-滚圆法制备苦参碱载药丸芯,利用流化床包衣技术对苦参碱载药丸芯进行包衣,并进行体外释放度的考察。结果:苦参碱载药丸芯的优化处方工艺为:苦参碱10g,微晶纤维素40g,羧甲基纤维素钠0.5g,纯化水46mL。其包衣微丸外层衣尤特奇L30D-55增重20%,内层衣尤特奇EPO增重30%。体外释放度实验表明,苦参碱包衣微丸在模拟的胃液中基本不释放,在pH 5.0磷酸缓冲液中较快释放,在pH 6.8磷酸缓冲液中则释放缓慢。结论:苦参碱载药丸芯处方工艺简单稳定。苦参碱包衣微丸结肠靶向性较好,同时模拟实验提示在结肠pH发生明显下降时苦参碱结肠靶向微丸仍具有结肠靶向性。     

Methacrylate micro/nano particles prepared by spray drying: a preliminary in vitro/in vivo study

Delivery systems controlling drug release only in the colon holds great promises since they improve utilization of drug and decrease the dosing times comparison with conventional forms. The aim of the present study was to prepare polymeric microparticles on the basis of Ciprofloxacin via oral route for the treatment of inflammatory bowel disease. Ciprofloxacin was selected because of its extensive coverage for intestinal flora, relatively favorable side-effect profile and preliminary data suggesting its efficacy in the treatment of active Crohn's Disease. Microparticles were prepared using different acrylic compounds, namely Eudragit® RL (PO) and RS (PO) and a mixture of both. Spray-drying was used as a preparation method of Ciprofloxacin/Eudragit® microparticles using a Mini Spray Dryer B-290 (Büchi, Postfach, Switzerland). In vitro dissolution studies were performed to choose the best formulation and selected microparticles were characterized by size and morphology by environmental scanning electron microscopy. Yield and encapsulation efficiency were calculated and in vivo/ex vivo experiments were investigated both of which suggest that selected microparticles can be used for colon targeting of drugs increasing residence time of the drug in the affected area.     

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.     

Improving the therapeutic efficiency of ginger extract for treatment of colon cancer using a suitably designed multiparticulate system

Abstract

Ginger extract (GE), a potential natural anticancer agent, has compromised therapeutic utilization due to poor bioavailability and physicochemical properties. Present study aimed at assigning GE with a pharmaceutical couture so as to improve its biopharmaceutical performance by monitoring its localized (though prolonged) delivery in the distal parts of gastrointestinal tract for the treatment of colon cancer. Alginate beads entrapping 85.9?±?1.78% GE were subjected to Eudragit S100 coating. Latter is insoluble at acidic and near neutral (6.8) pH of stomach and upper part of small intestine and it led to 50% retardation (upto 12?h) in release of GE. However, it was solubilised at pH?>?7.0 resulting in colon targeted system. Developed beads were free flowing, showed a particle size of 0.9?±?0.006?mm and super class-II release controlled by swelling and polymer relaxation. Preclinical evaluation using 1,2-dimethylhydrazine-induced colon cancer, in male Wistar rats, in terms of histopathology, oxidative stress, mitochondrial complex activity, β-glucuronidase and ammonia concentration determinations indicated GE loaded beads (50?mg/kg) to be significantly better (p?<?0.05) than free GE. Highlight of the study was that GE loaded coated alginate beads were administered after the induction of colon cancer and significant recession of the cancers was observed after 4 weeks of treatment.     

Statistical optimization and in vivo evaluation of colon specific delivery system of herbal rhubarb extract

The present research effort was aimed to develop colon targeted drug delivery system (CTDDS) of rhubarb, herbal drug using a mixed film of pectin and ethyl cellulose (EC). Pectin and ethyl cellulose were mixed in various proportions to coat the core tablet to target colon. The methanolic extract of rhubarb was used and the dose of the extract in each formulation was finalized by estimating the emodin content in it by high performace thin layer chromatography (HPTLC). In vitro drug release, erosion study in presence and absence of pectinase enzyme and release constant (K) of zero order was measured for each formulation. The formulation was optimized by using 3² full factorial design. Formulation having 50% pectin as a coating polymer with 12% coat weight was selected as an optimized formulation (OF) on the basis of % similarity with maximum desirability but this formulation was not able to retard the release of drug in stomach and upper intestine fully. So it was further coated with Eudragit S100 (ES) (3% coat weight). The optimized formulation, coated with ES indicated significant laxative activity on loperamide induced constipation in rats. The results revealed that CTDDS of rhubarb using two combined approaches of biodegrable microflora-activated system and pH-sensitive system exhibited a promising colon targeting performance.     

地塞米松-葡聚糖酯大鼠体内结肠靶向性

目的：建立地塞米松—葡聚糖酯(DSD)体内含量测定方法，并考察DSD体内结肠靶向性。方法：以Sprague-Daule雄性大鼠为实验动物，灌胃给药法分别给予DSD(实验组)和相当剂量的地塞米松(DEX)(对照组)，高效液相色谱法(HPLC)考察血液、胃、近端小肠、运端小肠、育肠、结肠内容物中DEX分布情况。结果：DSD给药后，血液及胃内容物中游离DEX含量显著低于对照组，盲肠、结肠中药物含量百分率分别为44．35％-83.31％，10．22％-20．52％，远过错高于对照组(盲肠，结肠药物含量百分率分别为0．05％-24．67％，0．79％-3．15％)。结论：DSD经盲肠、结肠中特异性酶类水解后释放出游离DEX，大大降低了DEX的全身吸收，具有良好的结肠靶向性。     

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.     

Design,in vitro and in vivo evaluation of glipizide Eudragit microparticles

Glipizide microparticles made with Eudragit (RS 100 and RL 100), prepared by emulsion solvent evaporation technique were evaluated for various in-vitro properties viz. encapsulation efficiency, particle size and surface morphology, drug release pattern and in-vivo hypoglycaemic activity. The optimized formulation parameters were used to prepare smooth and spherical microparticles (2–32 µm) with higher entrapment efficiency (67–89%). Drug release patterns of glipizide microparticles of Eudragit RS 100 and Eudragit RL 100 with drug-to-polymer ratio of 1 : 4 (i.e. EGM14 and ELGM14) have shown gradual and extended release for 24 h with cumulative release of glipizide to the extent of 72.3% and 83.9%, respectively. However, EGM14 showed a significant in-vivo hypoglycaemic effect up to 12 h in rabbits while ELGM14 showed for 9 h. Hence, glipizide microparticles of Eudragit RS 100 (glipizide: polymer 1 : 4) is better suited for oral sustained release formulation.     

Development and Evaluation of Microbial Degradation Dependent Compression Coated Secnidazole Tablets for Colonic Delivery

The present paper describes development of a polysaccharide based compression coated tablets of secnidazole for colon delivery. Core tablet containing secnidazole was compression coated with various proportions of guar gum, xanthan gum and chitosan, either alone or in combinations. Drug release studies were performed in simulated gastric fluid (SGF) for 2 h followed by simulated intestinal fluid (SIF, pH 7.4) up to 24 h. Secnidazole release from the prepared formulations was dependent on the type and concentration of polymer used in the formulation. Tablets coating containing either guar gum or xanthan gum showed ~30-40% drug release in 8 h. Further, in vitro dissolution studies of selected formulations performed in the dissolution media with rat caecal contents showed 54.48±0.24 - 60.42±0.16% of drug release. Formulations with single polymer in coating layer were unsuitable for targeting secnidazole release to colon region. Combination of chitosan with guar gum or xanthan gum exhibited control over secnidazole release.     

Development of novel budesonide pellets based on CODES(TM) technology: In vitro/in vivo evaluation in induced colitis in rats

Background and the purpose of the study

Budesonide is the drug of choice for treatment of active inflammatory bowel disease (IBD). The aim of this study was to develop budesonide pellets based on a novel colon drug delivery system (CODES).

Methods

Pellet cores containing lactulose or mannitol were prepared by extrusion/spheronization and coated with an acid soluble polymer (Eudragit E100), hydroxypropylmethyl cellulose (HPMC) and an enteric coat (Eudragit FS 30D) sequentially. In vitro drug release of coated pellets was studied using USP dissolution apparatus type II in buffers of pH 1.2 (2 hrs), pH of 7.4 (4 hrs) and pH of 6.8 containing 8% rat cecal contents (RCC) (18 hrs). The efficacy of the optimized formulation (containing 50% lactulose coated with Eudragit E (30% w/w) and Eudragit FS 30D (12% w/w)) was evaluated against 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats.

Results

The results of the kind of bacteria in vitro dissolution tests indicated absence of drug release in pHs of 1.2 and 7.4 and controlled release in buffer of pH 6.8 containing RCC. It was found that release rate was controlled by the type and amount of polysaccharide and the thickness of the acid soluble layer. The prepared formulation showed promising results in alleviating the conditions of experimental model of colitis.

Conclusion

The results of this study suggest that pellets based on CODES technology could be useful for colonic delivery of budesonide.     

Sophoridine-loaded PLGA microspheres for lung targeting: preparation,in vitro,and in vivo evaluation

Lung-targeting sophoridine-loaded poly(lactide-co-glycolide) (PLGA) microspheres were constructed by a simple oil-in-oil emulsion-solvent evaporation method. The obtained microspheres were systematically studied on their morphology, size distribution, drug loading, encapsulation efficiency, in vitro release profile, and biodistribution in rats. The drug-loaded microparticles showed as tiny spheres under SEM and had an average size of 17?μm with 90% of the microspheres ranging from 12 to 24?μm. The drug loading and encapsulation efficiency were 65% and 6.5%, respectively. The in vitro drug release behavior of microspheres exhibited an initial burst of 16.6% at 4?h and a sustained-release period of 14 days. Drug concentration in lung tissue of rats was 220.10?μg/g for microspheres and 6.77?μg/g for solution after intraveneous injection for 30?min, respectively. And the microsphere formulation showed a significantly higher drug level in lung tissue than in other major organs and blood samples for 12 days. These results demonstrated that the obtained PLGA microspheres could potentially improve the treatment efficacy of sophoridine against lung cancer.     

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