Design and evaluation of rhubarb total free anthraquinones oral colon-specific drug delivery granules to improve the purgative effect

Rhubarb is commonly used as a cathartic in Asian countries. However, researchers have devotedextensive concerns to the quality control and safety of rhubarb and traditional Chinese preparations composed of rhubarb due to the instable purgative effect and potential nephrotoxicity of anthraquinones. In this study, we aimed to prepare rhubarb total free anthraquinones (RTFA) oral colon-specific drug delivery granules (RTFA-OCDD-GN) to delivery anthraquinones to colon to produce purgative effect. RTFA-OCDD-GN were prepared using chitosan and Eudragit S100 through a double-layer coating process and the formulation was optimized. Continuous release studies were performed in a simulated gastric fluid (pH 1.2), followed by a small-intestinal fluid (pH 6.8) and a colonic fluid (pH 7.4, containing rat cecal contents). The purgative effect test was performed in rats. The dissolution profile of RTFA-OCDD-GN showed that the accumulative dissolution rate of RTFA was about 83.0% in the simulated colonic fluid containing rat cecal contents and only about 9.0% in the simulated gastrointestinal fluids. And the RTFA-OCDD-GN could produce the comparative purgative activity as rhubarb, suggesting it could deliver the free AQs to the colon. The RTFA-OCDD-GN was a useful media to enhance the purgative activity of free anthraquinones after administered orally.

Solid dispersion-based pellet for colon delivery of tacrolimus through time- and pH-dependent layer coating: preparation, in vitro and in vivo studies

The intent of the present investigation is to develop and evaluate colon-specific coated tacrolimus solid dispersion pellet (SDP) that retards drug release in the stomach and small intestine but progressively releases in the colon. Tacrolimus-SDP was prepared by extrusion-spheronization technology and optimized by the micromeritic properties including flowability, friability, yields and dissolution rate. Subsequently, the pH-dependent layer (Eudragit L30D55) and time-dependent layer (Eudragit NE30D and L30D55) were coated on the SDP to form tacrolimus colon-specific pellets (CSP) using a fluidized bed coater. Under in vitro gradient pH environment, tacrolimus only released from CSP after changing pH to 6.8 and then quickly released in the phosphate buffer solution of pH 7.2. The Cmax of CSP was 195.68 ± 3.14 ng/mL at Tmax 4.5 ± 0.24 h where as in case of SDP, the Cmax was 646.16 ± 8.15 ng/mL at Tmax 0.5 ± 0.03 h, indicating the ability of CSP targeted to colon. The highest area under the curve was achieved 2479.58 ± 183.33 ng·h/mL for SDP, which was 2.27-fold higher than tacrolimus suspension. However, the best biodistribution performance was achieved from CSP. In conclusion, SDP combining of pH- and time-dependent approaches was suitable for targeted delivery of tacrolimus to colon.

Advances of new excipients and technique in colon-specific preparations / 中国药科大学学报

The oral colon-specific drug delivery system (OCDDS) has gained more attention from investigators in recent years since it can increase local drug concentration and reduce dosage and side effects.The type of colonspecific drug delivery system consists of enzyme dependent,pH dependent,time dependent,pressure dependent system and CODEDSTM.The development of many new materials and technology is very important for the preparation of new type of precise positioning colon-specific preparation.This article summarizes the advances in excipients and technique for oral colon-specific drug delivery system in recent years.It may provide a reference and a basis for the researchers concerned.

Non-Starch Plant Polysaccharides: Physicochemical Modifications and Pharmaceutical Applications.

Polysaccharides of natural, synthetic or semi-synthetic origin have been used from time immemorial in the development of drug delivery systems designed to achieve tailored and site-specific drug release. Starch-based polysaccharides derived from plants have been extensively studied in this regard. Natural polymeric excipients are preferred over their synthetic counterparts owing to their low cost, availability, biocompatibility, biodegradability and non-toxicity. The present review attempts to provide a new direction and a comprehensive insight on the physical properties, rheological behavior, toxicity profile, pharmaceutical applications, swelling behavior and drug diffusion kinetics from dosage forms based on non-starch polysaccharides of plant origin such as, psyllium, pectin, arabinoxylan, xyloglucan, guar gum galactomannan and konjac glucomannan. It has been observed from the current review that non-starch polysaccharides are safe for human consumption and can be successfully employed to deliver drugs specifically to stomach and colon in a sustained fashion. They have thus widened the scope of natural polymeric excipients and demand better industrial utilization on a commercial scale to minimize cost of production and to satisfy therapeutic needs in safe and effective manner.

Optimize preparation parameters of colon-specific pellets of Angelica Sinensis Radix supercritical fluid extraction with response surface analysis methodology / 中国中药杂志

To prepare pellets of supercritical fluid extraction (SFE) of Angelica Sinensis Radix by using the ionic crosslinking method, and the drug loading and encapsulation efficiency were used as the index to investigate the multiple factors which may impact the drug loading and encapsulation efficiency. Box-Behnken design and response surface analysis method were then taken to optimize the prescription of pellets and study the coating technology. Through the study on the release of pellets in vitro, an optimal coating technology and prescription of colon-specific pellets of Angelica Sinensis Radix SFE were selected and their colon targeting was evaluated. The optimal preparation parameters of pellets were determined as follows： 3% pectin; 4∶1 for pectin/lecithin; 4∶5 for pectin/SFE of Angelica Sinensis Radix; 4% zinc acetate solution as crosslinking agent, blending temperature 35 ℃, crosslinking temperature 35 ℃, crosslinking time 30 min; coating technology： coating material Eudragit FS 30D, 1.5% triethyl citrate and polyoxyethylene sorbitan monooleate（tween-80）, 1.2% monostearin and 15% coating weight gained. The colon-specific pellets of Angelica Sinensis Radix SFE prepared with optimized conditions were almost not released in simulated gastric fluid in 2 h, released less than 20% in simulated intestine fluid in 4 h, and released more than 90% in simulated colon fluid in 6 h, indicating that the colon-specific pellets of Angelica Sinensis Radix SFE had an excellent colon targeting property.

Preparation of Eudragit-chitosan bilayer colon-specific multi-dosage mini tablets / 中国药学杂志

OBJECTIVE: To develop colon-targeting multi-dosage oral delivery system (mini tablet) using chitosan as the material for treatment of colon cancer. METHODS: Indomethacin (IN) was chosen as a model drug. Firstly, IN solid dispersion was prepared, then Eudragit-chitosan bilayer coated colon targeting mini tablets were prepared by direct compression method and coating technology. The release profiles of the targeting mini tablets in different release media were studied. Small animal in vivo fluorescence imaging investigation was used to sudy the transport and absorption in rats. Beagle dogs were used as animal model to study the pharmacokinetics and bioavailability of the mini tablets. RESULTS: The Eugragit-chitosan bilayer coated mini tablets maintained complete form when passing through the stomach and small intestine of rats, and targeted to the colon. The pharmacokinetic data in Beagle dogs showed that the mini tablets had delayed release and preserved steady absorption. CONCLUSION: The prepared Eudragit-chitosan bilayer coated multi dosage oral colon mini tablets showed good colon targeting effect and sustained release, which can provide important reference for the treatment of colon diseases.

Preparation of Colon-specific and Synchronous Release Pellet Containing Total Alkaloids of Sophora alopecuroides / 中草药·英文版

Objective: To deliver multiple component drugs to colon site and sustain a synchronous release for better therapeutic effect. For achieving this purpose, colon specific pellet containing total alkaloids of Sophora alopecuroides (TASA) was prepared. Methods: The pellet was prepared by extrasion-spheronizing and subsequently coated with three layers of two polymers. Results: The pellet core consisted of 40% TASA, 1:2 in ratio of Bletilla striata polysaccharide (BSP), an enzyme-degradable material, to microcrystalline cellulose (MCC), filler, and 1% CMC-Na solution as binder by optimization. Concerning of the three coated layers, the outer layer was coated with Eudragit RS30D for controlling drug release in colon, the intermediate layer and the inner layer were coated with same polymer, Eudragit S100, for preventing drug release in upper gastrointestinal tract, which required 23.2%, 21.7%, and 9.3% weigh gain, respectively. The coated pellets released 1.20% of sophoridine and 1.98% of matrine in media mimicking the stomach condition for 2 h, and 23.88% of sophoridine and 22.91% of matrine in media mimicking the intestine for 3 h and finally 90.25% of sophoridine and 89.94% of matrine in colonic conditions within 24 h. And the similarity factor f of sophoridine and matrine of release curve for investigated formulation was internal in (50-100) and > 80, demonstrating that sophoridine and matrine in formulation achieved a synchronous release. Conclusion: The coated pellets achieve a certain colon-specific release and synchronous release.

Optimization of preparation technology of colon-specific chitosan microspheres of rhubarb total anthraquinones / 中草药

Objective: To optimize the preparation technology of colon-specific chitosan microspheres of rhubarb total anthraquinones (RTA-CMS). Methods: With chitosan as material, RTA was made into microspheres. According to the entrapment efficiency (EE) and particle diameter, the best preparation technology was selected using orthogonal design. The enteric material Eudragit S100 was used to coat the CMS. Results: The best preparation technology was as follows: The concentration of chitosan was 2.5%; The mass ratio of RTA and chitosan was 1:4; The ratio of paraffin and dichloromethane was 1:1; The amount of span-80 was 2%. The EE of CMS was 64.5%. The particle diameter of the CMS was (248.8 ± 54.2) μm, and the mean diameter was (269.3 ± 172.7) μm after coating. Conclusion: RTA-CMS prepared with the best preparation technology has a high EE. And the microspheres form is good. The technology could be used to prepare colon-specific RTA-CMS.

Evaluation in vitro of Cecum and Colon-specific Drug Delivery System of 4-aminosalicylic Acid-maltoside / 中国药房

OBJECTIVE:To investigate the characteristics of cecum and colon-specific drug delivery system of 4-aminosalicyl-ic acid-maltoside (4-ASA-Mal) in vitro. METHODS:With the cumulative release rate of 4-ASA as the index,HPLC was em-ployed to observe the delivery of 4-ASA-Mal (equivalent to 250 μg/ml 4-ASA) in the buffer solutions of different pH (1.2,6.8 and 7.4)and in the aqueous contents in different parts(stomach,small intestine,cecum and colon)of normal rats and the rat mod-els of ulcerative colitis. RESULTS:4-ASA-Mal was hardly released in the buffer solutions of different pH. 12 h cumulative release rates were less than 8% in the aqueous contents in the stomachs and small intestines of normal rats and rat models,and were 55%and 81% in the aqueous contents in the cecum and colons of normal rats,and 55% and 74% in the aqueous contents in the cecum and colons of model rats with ulcerative colitis. CONCLUSIONS:4-ASA-Mal can release a lot of 4-ASA in aqueous contents in ce-cum and colon,targeting cecum and colon in vitro.

A suppository-base-matrix tablet for time-dependent colon-specific delivery system

Our research has focused on the main design features and release performances of time-dependent colon-specific (TDCS) delivery tablets, which relies on the relative constancy that is observed in the small intestinal transit time of dosage forms. But inflammatory bowel disease（IBD）can affect the transit time, and usually results in watery stool. Compared to the TDCS and wax-matrix TDCS tablet, a promising time-dependent colon-specific delivery system was investigated. In our study, a suppository-base-matrix coated tablet was evaluated. Water soluble suppository-base helps the expansion of tablet, facilitates uniform film dissolution and achives high osmotic pressure. Combining the expansion of carboxymethyl starch sodium (CMS-Na) and the moisture absorption of NaCl, the coated TDCS tablet obtained a burst and targeted drug delivery system. A very good correlation between in vitro drug release and in vivo outcome was observed. This TDCS coated tablet provides a promising strategy to control drug release to the desired lower gastrointestinal region.

Nossa pesquisa focou-se nas principais características de planejamento e de desempenho de liberação cólon-específica tempo-dependente (TDCS) de comprimidos, que leva em conta a constância relativa observada no tempo de trânsito intestinal das formas de dosagem. A doença inflamatória do intestino (IBD) pode afetar o tempo de trânsito e, geralmente, resulta em fezes aquosas. Comparando ao TDCS e a comprimidos TDCS com matriz-cerosa, investigou-se sistema promissor de liberação cólon-específica tempo-dependente. Em nosso estudo, avaliou-se comprimido revestido com matriz base de supositório. A base de supositório solúvel em água auxilia a expansão do comprimido, facilita a dissolução uniforme do filme e atinge alta pressão osmótica. Associando a expansão do carboximetil amido sódico (CMS-Na) à absorção de umidade do NaCl, o comprimido revestido TDCS originou sistema de liberação direcionado e de erupção. Observou-se correlação muito boa entre a liberação in vitro e a in vivo do fármaco. Este comprimido revestido TDCS representa estratégia promissora para o controle da liberação do fármaco na região gastrintestinal mais baixa.

Preparation of astragalus polvsaccharides-Eudragit S100 colon-specific spray drying powder and evaluation on its in vitro release / 中草药

Objective: To prepare the pH-dependent astragalus polvsaccharides colon-specific spray drying powder, with the intention of controlling drug release in the colon. Methods: Eudragit S100 water dispersion was used as a carrier to prepare astragalus polvsaccharides colon-specific spray drying powder by spray drying method and the in vitro dissolution of spray drying powder was performed. The structure characteristics of spray drying powder was analyzed by SEM. Results: When the ratio of drug to Eudragit S100 was 1:10, the drug in simulated gastric fluid did not release nearly and the accumulative drug-release percent in vitro at 4 h was less than 30.0%; But in the simulated colonic fluid, the accumulated drug release percent reached 90.0% within 1 h. Conclusion: The astragalus polysaccharides colon-specific spray drying powder had the characteristics as a colon-specific delivery system. The preparation process is simple and feasible.

Levan in the developing of new colon-specific polymer material: evaluation of the permeability, moisture and thermal analyses in free films of Eudragit® FS 30 D / Levana no desenvolvimento de novo material polimérico cólon-específico: avaliação da permeabilidade, intumescimento e análises térmicas de filmes isolados de Eudragit® FS 30 D

Levan was used as agent in the synthesis of new colon-specific polymeric matrix together with Eudragit® FS 30 D. Eudragit® FS 30 D films incorporated with levan were made by casting process and characterized to: water vapour transmission, sweeling index, differential scanning calorimetry and thermogravimetric. The levan increased the films permeability (p < 0.001) however did not influenced in the sweeling index of the formulations (p > 0.05). The thermal analyses of the films indicated a glass transition temperature approximate at 47°C and thermal decomposition at 400°C. The results indicated that there is potential for using such site-specificity blend as pharmaceutical coating material.

Levana foi utilizada na síntese de novo material polimérico cólon-específico conjuntamente com o Eudragit® FS 30 D. Filmes de Eudragit® FS 30 D aditivados de levana foram feitos pelo método de "casting process" e caracterizados quanto à transmissão de vapor de água, índice de intumescimento, calorimetria diferencial de varredura e termogravimetria. A levana aumentou a permeabilidade dos filmes (p < 0,001), entretanto não influenciou no índice de intumescimento das formulações (p > 0,05). As análises térmicas dos filmes indicaram uma temperatura de transição vítrea aproximada de 47°C e temperatura de decomposição de 400°C. Os resultados indicaram que há potencial de uso desta nova blenda sítio-específica como material de revestimento farmacêutico.

Colon Specific Drug Delivery Systems: A Review on Various Pharmaceutical Approaches.

Colon specific drug delivery system has attracted considerable attention for the past few years in order to develop drug delivery systems that are able to release drugs specifically in the colon in a predictable and reproducible manner. The colon is a site where both local and systemic delivery of drugs can take place. To achieve successful colon targeted drug delivery, a drug need to be protected from degradation, release and absorption in the upper portion of the gastric intestinal tract (GIT) and then to be ensured abrupt or controlled release in the proximal colon. This review is aimed at understanding recent approaches for dosage forms which is targeting to colon through pH sensitive system, microbially triggered system i.e., prodrugs and polysaccharide based system, timed release system, osmotically controlled drug system, pressure dependent release system.

Guar gum/ethylcellulose coated pellets for colon-specific drug delivery / 药学学报

The aim of this work was to investigate guar gum/ethylcellulose mix coated pellets for potential colon-specific drug delivery. The coated pellets, containing 5-fluorouracil as a model drug, were prepared in a fluidized bed coater by spraying the aqueous/ethanol dispersion mixture of guar gum and ethylcellulose. The lag time of drug release and release rate were adjustable by changing the ratio of guar gum to ethylcellulose and coat weight gain. In order to find the optimal coating formulation that was able to achieve drug targeting to the colon, the effect of two independent variables (the ratio of guar gum to ethylcellulose and the coat weight gain) on drug release characteristics was studied using 3×4 factorial design and response surface methodology. Results indicated that drug release rate decreased as the proportion of ethylcellulose in the hybrid coat and the coat weight gain increased. When the ratio of guar gum to ethylcellulose was kept in the range of 0.2 to 0.7, and the coat weight gain in the range of 250% to 500%, the coated pellets can keep intact for about 5 h in upper gastrointestine and achieve colon-specific drug delivery. The pellets prepared under optimal conditions resulted in delayed-release sigmoidal patterns with T5% (time for 5% drug release) of 5.1-7.8 h and T90% (time for 90% drug release) of 9.8-16.3 h. Further more, drug release was accelerated and T90% of the optimum formulation pellets decreased to 9.0-14.5 h in pH 6.5 phosphate buffer with hydrolase. It is concluded that mixed coating of guar gum and ethylcellulose is able to provide protection of the drug load in the upper gastrointestinal tract, while allowing enzymatic breakdown of the hybrid coat to release the drug load in the colon.

Colon-specific delivery tablets of sodium 4-aminosalicylic acid / 药学学报

Aim To prepare a new oral colon-specific delivery formulation and to investigate the release profile in vitro and the colon-specific delivery property in vivo in dogs. Methods Sodium 4-aminosalicylic acid was selected as the model drug. The combination of Eudragit RL30D and RS30D were used as sustained-release film, and Eudragit FS30D used as enteric film, which was expected to release drug depending on pH and time. The release profile of tablets was studied in three phosphate buffers with the pH 6.5, 7.0 or 7.4 for 12 h after a simulated gastric presoak for 2 h in 0.1 mol · L-1 HCl. The tablets were radiolabelled with 99mTc to make their release times and positions in the gastrointestinal tract be followed using a gamma camera. Results For the in vitro study, there was no drug released in 0. 1 mol ·L- 1 HCl for 2 h, and release occurred slowly when pH was above 6.5. Drug was released faster while pH was higher. For the in vivo study, the coated tablets remained intact in the upper gastrointestinal tract, and drug release began after the colonic arrival. The uncoated tablets, however, disintegrated in the stomach of the dogs rapidly. Conclusion The coating could protect the drug until the tablets reached the ascending colon, where drug was released slowly for over 10 h.

Preparation of 4-Paramisan Sodium Colon-specific Delivery Coated Tablets and the Determination of Its Drug-releasing Rate / 中国药房

0.05).CONCLUSION:4-paramisan sodium oral colon-specific delivery coated tablets coated in turn with permeable and enteric soluble acrylic resin has ideal specific delivery and slow-release properties,the coating technology was stable and the reproducibility is good.

Colon-specific delivery release mechanism of prednisolone-dextran prodrug / 中国药理学通报

AIM: To study the mechanism of colonic delivery of prednisolone dextran and provide scencific basis for seeking new drug to treat inflammatory bowel disease. METHODS: After the prodrug was incubated at 37°C with buffers of different pH, buffers with dextranase and with culture medium containing bacterium coli respectively, the release of prednisolone(PL) from prodrug were determined by HPLC. RERULTS: The release of active drug could increase at the pH close to that of lower GI tract; The dextranase and the Bacterium coli could facilitate the release of active drug. CONCLUSION: The effects of colon-specific delivery by PL-dextran prodrug may be explained as follows. When the prodrug reached colon, the active drugs are released by multiple factors such as a special pH of colon, microorganism and the enzyme produced by microorganism.

Determination of oxymatrine in Compound Kushen Colon-specific Capsula by capillary electrophoresis / 中草药

Objective To establish an HPCE method for the determination of oxymatrine in Compound Kushen Colon-specific Capsula.Methods Amphetamine sulfate was used as the internal standard.The separation was obtained with silica capillary column(50 cm ? 50 ?m,effective length 45 cm),30 mmol/L phosphate buffer(pH 5.8)at a constant voltage of 20 kV,and temperature at(25?1)℃,the detective wavelength 214 nm.Results The linear determination range was 30—240 ?g/mL and the average recovery and RSD were 99.54% and 1.85%,respectively.Conclusion The method is simple and accurate,and can be used for quality control of Compoud Kusheng Colon-specific Capsula.

Preparation and releasing evaluation in vivo and in vitro of pH-dependent Yuchangning Tablet for colon-specific delivery / 中草药

Objective To prepare the pH-dependent Yuchangning Tablet for colon-specific delivery(PYTCSD) used in treating the ulcerative colitis and evaluating the releasing property in vivo and in vitro.Methods The coating prescription was screened by the in vitro delivery of matrine and oxymatrine.The in vitro releasing property of the preparation was examined by the method of in vitro delivery. The in vivo releasing property of the preparation was evaluated by the shadowgraph technique of barium sulfate.Results The preparation method of the PYTCSD was obtained.The core of the tablet was coated by the alcohol solution mixed with 3.70%(g/mL) Eudragit Ⅲ,0.37%(g/mL) DEP,and 0.93%(g/mL) talcum power.The weight of the core was increased 8%.From the in vitro delivery,matrine and oxymatrine were not detected in the simulated gastric fluid after 2 h.The quantities of matrine and oxymatrine were less 10% in the simulated intestinal fluid after 4 h.The quantities of matrine and oxymatrine were 86.5% and 86.8% in the simulated colon fluid after 1 h.On the basis of the in vivo delivery by treating eight volunteers,the PYTCSD could completely get to the ileocecum or ascending colon and disintegrate in that part.Conclusion The PYTCSD can be prepared and the preparation is significantly delivered in the specific colon.

Coating technique of pH-time lag colon-specific matrine delivery mini-pill / 中成药

AIM:To study the coating technique of pH-time lap colon-specific matrine delivery mini-pill consisted of the time lag release coating (inner layer) and enteric coating (out layer). METHODS:To filter the coating composition based on the index of dissolution of matrine and oxymatrine in vitro and the appearance rating of miui-pill. RESULTS:4 The coating composition of inner layer was the alcoholic solution,consisted of 2% EC,0.4% DEP and 2% talc powder. Then the coating composition of out layer was the alcoholic solution consisted of 5% Eudragit S100,3% talc powder and 0.5% TEC. The dissolution tests in vitro indicated that matrine and oxymatrine were not dissolved in the simulated gastric juice in 2 h. The accumulative amount of matrine and oxymatrine were less than 15% in the simulated intestinal fluid in 4 h. The amount of matrine and oxymatrine were 80.7% and 83.5% in the simulated colon juice in 2 h. CONCLUSION:The mini-pill could achieve the goal of delivering in the specific colon.