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.     

Multiparticulate System for Colon Targeted Delivery of Ondansetron

Targeted delivery of drugs to colon has the potential for local treatment of a variety of colonic diseases. The main objective of the study was to develop a multiparticulate system containing chitosan microspheres for the colon targeted delivery of ondansetron for the treatment of irritable bowel syndrome. This work combines pH-dependent solubility of eudragit S-100 polymers and microbial degradability of chitosan polymers. Chitosan microspheres containing ondansetron were prepared by emulsion cross linking method. The effect of process variables like chitosan concentration, drug-polymer ratio, emulsifier concentration and stirring speed were studied on particle size and entrapment efficiency of chitosan microspheres. In vitro drug release studies in simulated gastro intestinal fluids showed a burst drug release pattern in the initial hour necessitating microencapsulation around the chitosan microspheres. The optimized formulation was then subjected to microencapsulation with eudragit S-100 by solvent evaporation technique. The effect of different coat/core ratio on particle size, drug entrapment efficiency and in vitro drug release were studied. Formulation which contain 1:10 core/coat ratio released lesser amount of drug in the upper gastro intestinal conditions and so selected as best formulation and then subjected to in vitro drug release studies in presence of rat ceacal contents to assess biodegradability of chitosan microspheres in colon. In order to study the drug release mechanism in vitro drug release data was fitted into various kinetic models. Analysis of regression values suggested that the possible drug release mechanism was Peppas model.     

Development of Enteric-coated Pectin-based Matrix Tablets for Colonic Delivery of Theophylline

The present work was aimed at developing a new colonic drug delivery system which takes advantage of the combined approaches of a specifically colon-biodegradable pectin matrix with a pH-sensitive Eudragit_® S100 polymeric coating. The developed system was able to suitably retard the onset of drug release and to provide a colon-specific delivery, thus overcoming the problems of pectin solubility in the upper gastrointestinal tract and low site-specificity of simple pH-dependent systems. Due to the poor compactability properties of pectin, it was used in mixture with Emdex_®, a hydrophilic directly-compressible material, in order to make it possible to prepare tablets by direct compression. Theophylline (TP) was used as model drug due to its suitable pharmacokinetic properties for colonic delivery and good absorption in the large intestine. The effects of varying the type of pectin (low and high methoxylated, or amidated), the pectin:Emdex_® ratio and the level of the pH-dependent polymeric coating on drug release behavior were investigated. Release tests were performed using sequential liquids simulating the physiological variation of pH and the effect of the presence or not of pectinolytic enzymes into the simulated colonic medium was evaluated. Thirty percent (w/w) was the the minimum content of Emdex_® for obtaining directly compressible tablets with sufficient hardness to withstand the coating process and 27% (w/w) was the minimum coating amount for obtaining an adequate lag time before the onset of drug release. After lag time, linear nearly zero-order profiles were obtained whose slope (i.e. the drug release rate) depended on both the Emdex_® content and the pectin type. Comparison of the results obtained in the presence or not of pectynolitic enzymes allowed selection of the high methoxylated pectin as the most interesting candidate for specific colonic delivery since it was the least water-soluble and the most susceptible to enzymatic degradation, thus assuring a greater site-specificity of drug release. Finally, the importance of using appropriate dissolution test conditions to adequately characterize the drug release profiles from delivery systems endowed with a microflora-activated drug release triggering mechanism has been demonstrated.     

Development of a Modified-Release Formulation of Lovastatin Targeted to Intestinal Methanogens Implicated in Irritable Bowel Syndrome With Constipation

There is growing evidence that methane production, predominantly by Methanobrevibacter smithii, in the intestines is a cause of constipation, pain, and bloating in irritable bowel syndrome with constipation (IBS-C). M smithii resides primarily in the large intestine but can also colonize the small intestine. In vitro studies found that the prodrug lactone form of lovastatin, found in cholesterol-lowering drugs, inhibited methane production in stool samples from patients with IBS-C. However, the cholesterol-lowering lovastatin β-hydroxyacid was ineffective at inhibiting methane production in this system. A considerable amount of lovastatin is converted to hydroxyacid in the stomach and is absorbed. It was hypothesized that galenic innovations could protect lovastatin from the stomach and allow release in 2 strategic locations, the duodenum and the ileocecal region, to reach M smithii. The desired release profile was achieved by developing an oral dosage form containing lovastatin and coated with 2 different enteric polymers that enabled a pH-dependent “dual pulse” drug release. Combinations of the 2 coated tablets were encapsulated together to deliver the desired amount of lovastatin to the targeted intestinal locations. The capsules have been tested in vitro and in vivo and show promise in treating IBS-C.     

Colonic Drug Delivery: Enhanced Release of Indomethacin from Cross-Linked Chondroitin Matrix in Rat Cecal Content

Pharmaceutical Research -     

替硝唑结肠给药系统的研制

依据时控型结肠给药系统原理，以替硝唑为模型药物．利用于压包衣和薄膜包衣双层包衣的方法制备了结肠给药系统，并对影响药物释放的因素(如EC粒度，HPMC粘度，时控层厚度，片刑硬度等)、肠衣层性能和药物释放稳定性等进行了考查。结果表明，HPMC粘度增加使药物释放滞后时间延长,但高粘度HPMC会导致药物释放无明显突跃点；包芯片硬度40～60N、片重0．26～0．28g的片剂药物释放较稳定。加速试验(3个月)结果表明,药物释放稳定性良好。     

盐酸地尔硫(艹卓)结肠释药片的研制

以丙烯酸树脂 和乙基纤维素为包衣材料 ,采用锅包衣法制得盐酸地尔硫口服结肠释药片。通过正交设计和体外释放度实验 ,考察处方和工艺对结肠定位释药的影响。结果表明影响片子释药时滞的主要因素是包衣液处方中丙烯酸树脂 与乙基纤维素的比例 ,比例越小 ,时滞效应越强。通过调整处方和工艺 ,可制得在酸性条件下不释药 ,在模拟胃肠液 p H条件下经 5～ 6 h时滞后形成爆破释药的结肠释药片。     

Guar gum as platform for the oral controlled release of therapeutics

Introduction: The past decade of research has witnessed a huge advancement in research efforts on guar gum (GG)-based polymers as controlled release (CR) formulations for the delivery of therapeutics.

Areas covered: The unique structure and beneficial properties of GG makes it an attractive biomaterial in CR applications. Current status on GG-based polymers has been addressed as a CR formulation in the form of microspheres, nanoparticles, hydrogels and matrix tablets for the delivery of various types of therapeutics having a wide range of physicochemical properties. Majority of literature on GG as a platform technology has dealt with oral route of drug administration as it is the most convenient, patient-compliant and preferred approach. Recent reports on GG-based polymers are summarized and critically discussed to narrate their usefulness as oral delivery systems.

Expert opinion: The research on GG-based formulations has been focused on optimization of the therapy by designing CR dosage forms with a minimum number of excipients. In this context, GG-based polymers are quite attractive. The present review summarizes published reports on these systems and offers expert opinion relevant to oral delivery of therapeutics.     

壳聚糖包覆脂质体递药系统的研究进展

脂质体在药物传递方面被广泛研究,但因结构稳定性差等因素使其应用受到了限制.壳聚糖是一种阳离子多糖,具有良好的生物相容性、生物降解性以及生物黏附性,并且可经化学改性成为性能更佳的壳聚糖衍生物.近年来,壳聚糖及其衍生物包覆脂质体在载药方面的研究得到了越来越多学者的关注.壳聚糖或其衍生物修饰脂质体,可提高其稳定性、黏附渗透性...     

胃粘附片及粘附辅料的体外评价

用改良的粘附力测定法,测定了片剂中常用的添加剂对几种辅料粘附性的影响,并以阿莫西林为模型药物进行了体外粘附性及药物释放的研究。     

The Relation Between Swelling Properties and Enzymatic Degradation of Azo Polymers Designed for Colon-Specific Drug Delivery

Copolymers of 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA), and terpolymers of HEMA, MMA, and methacrylic acid (MA) were synthesized in the presence of N,N-bis(methacryloyloxyethyloxycarbonylamino)azobenzene (B(MOEOCA)AB) and evaluated as coating materials for colonic targeting. The release of ibuprofen, a model drug, from capsules coated with the azo polymers was investigated in vitro. The release medium was made up of sonicated rat cecal content, benzyl viologen, glucose-6-phosphate, glucose-6-phosphate dehydrogenase, and nicotine amide dinucleotide phosphate (NADP) in phosphate buffer (pH 6.8, 0.05M). The drug-release profiles indicate that the degradation of the azo polymer coatings depends on their degree of swelling, due to a higher accessibility of the azo bonds for the bacterial azo reductase. The best results were obtained with azo polymers containing MA: 98.7 (±1.1) % of ibuprofen was released after 19 hours residence in the release medium, while only 26.2 (± 4.9) % in the control experiment. These findings demonstrate that azo polymers are promising materials for delivering drugs selectivity to the colon.     

In Vitro Evaluation of Calcium Pectinate: A Potential Colon-Specific Drug Delivery Carrier

Calcium pectinate (CaP)—the insoluble salt of pectin—can potentially be used as a colon-specific drug delivery system. The use of CaP as a carrier was based on the assumption that, like pectin, it can be decomposed by specific pectinolytic enzymes in the colon but that it retains its integrity in the physiological environment of the small bowel. The biodegradation of the carrier was characterized by monitoring the percent cumulative release of the insoluble drug indomethacin, incorporated into pectin or CaP matrices. Compressed tablets of pectin and indomethacin were analyzed for degradation in the presence of Pectinex 3XL, a typical pectinolytic enzyme mixture, and in the presence of the human colonic bacterium Bacteroides ovatus. The degradation of CaP-indomethacin tablets was assessed in the presence of Pectinex 3XL and in rat cecal contents. The release of indomethacin was significantly increased (end-time percentage cumulative release vs control) in the presence of Pectinex 3XL (89 ± 20 vs 16 ± 2 for CaP tablets), Bacteroides ovatus (12 and 22 vs 5.2 for pectin tablets), and rat cecal contents (61 ± 16 vs 4.9 ± 1.1 for CaP tablets). The weight loss of tablet mass was significantly higher (end-time dry weight vs control) in the presence of Pectinex 3XL (0 vs 75 ± 6% of initial weight for CaP tablets). These findings indicate the potential of CaP, compressed into tablets with insoluble drug, to serve as a specific drug delivery system to the colon.     

PEG-PLGA包裹的介孔碳纳米给药系统的制备和表征

目的:利用一种简便易行的方法改善介孔碳(MCN)的分散性,并以其为载体构建纳米给药系统,探索其生物应用的效果。方法:利用TEM观察聚乙二醇-聚乳酸-羟基乙酸共聚物(PEG-PLGA)包裹前后MCN的大小和形态变化。稳定性检测用于评估PEG-PLGA包裹的MCN纳米粒(MCNP)的分散性。热效应实验评价MCNP的近红外(NIR)光热转化能力。构建PEG-PLGA包裹的载阿霉素(DOX)的介孔碳给药系统(MCNPD),从Zeta电荷、载药量、释放以及细胞摄取实验对其进行表征。结果:溶液静置24h后,原始MCN几乎完全聚集沉降,而MCNP仍均匀分散;NIR照射后,MCNP表现出很好的热效应;构建的给药系统MCNPD具有较高的载药量,并且呈p H-依赖释放和NIR-触发释放,同时能够很好地摄取进入细胞。结论:PEG-PLGA包裹以提高MCN分散性的方法简单可行,成功构建了一种具有良好分散性的MCN递药载体,利于生物应用。     

pH依赖—缓释型美沙拉秦结肠靶向小丸的制备与体外评价

以肠溶型和渗透型丙烯酸树脂为包衣材料制备ｐＨ依赖－缓释型美沙拉秦结肠靶向小丸,评价其体外释放特性。结果表明,包衣小丸在０．１ｍｏｌ／ＬＨＣｌ中２ｈ几乎不释放药物,在ｐＨ７．５缓冲液中具有较好的缓释作用。在模拟胃肠道各区段最高的和最低的ｐ变化的释放度试验中,均在对应小肠区段时开始缓慢释药。分别有４０％和７０％的药物进入结肠后释放。优于单独的肠溶或缓释制剂。     

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.     

Potential of Guar Gum Microspheres for Target Specific Drug Release to Colon

Various approaches for colon targeted drug delivery have been studied over the last decade including, pro-drugs, timed-released systems, coating of pH-dependant polymer and the use of polysaccharides. In the present work, a novel formulation consisting of cross-linked microspheres of guar gum has been investigated for colon-targeted delivery of metronidazole. An emulsification method involving the dispersion of aqueous solution of guar gum in castor oil was used to prepare spherical microspheres. Process parameters were analyzed in order to optimize the formulation. Shape and surface morphology of the microspheres were examined using scanning electron microscopy. Placebo microspheres exhibited a smooth surface while the incorporation of drug imparted a slight roughness to the surface texture. Particle size of the microspheres was determined using laser diffraction particle size analyzer. The in vitro drug release studies were performed in simulated gastric fluid for 2 h and intestinal fluid for 3 h, which revealed that the drug was retained comfortably inside the microspheres and that only 15.27±0.56% of the drug was released in 5 h. In vitro release rate studies were also carried out in simulated colonic fluid (SCF) in the presence of rat cecal contents, which showed improved drug release. Moreover, to induce the enzymes that specifically act on guar gum, the rats were treated with 1 ml of 1% w/v dispersion of guar gum for 2, 4 and 6 days and release rate studies were repeated in SCF in the presence of 2 and 4% w/v of cecal matter. A marked improvement in the drug release was observed in presence of cecal matter obtained after induction when compared to those without induction. In vitro release studies exhibited 31.23±1.49% drug release in 24 h in dissolution medium without rat cecal matter. However, the incorporation of 4% w/v cecal matter obtained after 6 days of enzymes induction increased the drug release to 96.24±4.77%.     

Self-double-emulsifying drug delivery system incorporated in natural hydrogels: a new way for topical application of vitamin C

This study aimed at the in vitro evaluation of topical hydrogels containing vitamin C-loaded self-double-emulsifying drug delivery system (SDEDDS). The liquid SDEDDS was converted into suitable unmodified xanthan gum hydrogels formulation and the prepared semi-solid hydrogels provided appropriate gel characteristics like pH, viscosity, spreadability, etc. The 5-week storage test displayed that the prepared hydrogels possessed good physicochemical stability. In addition, no significant cytotoxicity to L929 cells was observed for the vitamin C-loaded SDEDDS-based hydrogels, and the prepared hydrogels depicted a sustained drug release over an 8-h period. In vitro permeation study showed that the vitamin C-loaded SDEDDS-based hydrogels could significantly enhance vitamin C retention in the skin and permeation through the skin. The overall results demonstrated that the hydrogels containing vitamin C-loaded SDEDDS could be considered as a promising formulation for topical application.     

水飞蓟素自乳化给药系统处方设计及溶出度评价

目的: 设计水飞蓟素自乳化系统处方并评价其溶出度.方法: 采用正交设计进行水飞蓟素自乳化系统处方设计,以溶解状况、乳化速度及透光率为指标进行综合评价,确定最佳处方.结果: 水飞蓟素自乳化系统除主药外,主要由吐温85、橄榄油、甘油组成.结论: 按最佳处方制备的水飞蓟素自乳化系统在人工胃液及人工肠液的溶出度均与德国的对照胶囊基本相同.     

Chitosan and its derivatives as vehicles for drug delivery

Abstract

Chitosan and its derivatives as vehicles for drug delivery can achieve the purpose of sustained release and controlled release for drugs, improve the stability of drugs, and reduce adverse drug reactions. So, the bioavailability of drugs can be enhanced. Therefore, chitosan and its derivatives have become a hotspot in the field of drug delivery. Their characteristics as drug delivery vectors were introduced, the types and applications were summarized. The development direction of chitosan and its derivatives in this field was also forecasted.     

Development of Nanoparticles for Drug Delivery to Brain Tumor: The Effect of Surface Materials on Penetration Into Brain Tissue

Surface-modified poly(d,l-lactic-co-glycolic acid) PLGA nanoparticles (NPs) were fabricated via nanoprecipitation for obtaining therapeutic concentration of paclitaxel (PTX) in brain tumor. The cellular uptake and cytotoxicity of NPs were evaluated on C6 glioma cells in vitro, and BALB/c mice were used to study the brain penetration and biodistribution upon intravenous administration. Results showed that by finely tuning nanoprecipitation parameters, PLGA NPs coated with surfactants with a size around 150 nm could provide a sustained release of PTX for >2 weeks. Surface coatings could increase cellular uptake efficiency when compared with noncoated NPs, and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) showed the most significant enhancement. The in vivo evaluation of TPGS-PLGA NPs showed amplified accumulation (>800% after 96 h) of PTX in the brain tissue when compared with bare NPs and Taxol^®. Therefore, PLGA-NPs with PLGA-TPGS coating demonstrate a promising approach to efficiently transport PTX across blood-brain barrier in a safer manner, with the advantages of easy formulation, lower production cost, and higher encapsulation efficiency.