| Objective:The colon is susceptible to a variety of disease states, of which the chronic inflammatory bowel diseases, ulcerative colitis and Crohn's disease, are the most serious. Colon-specific delivery of anti-inflammatory drug via the oral route would allow the local drug concentration higher and the systemic side effects fewer. A new pH and time-based oral colon-specific drug delivery system was developed by using multi-layer coating technology. The release profile in vitro, the stability of the formulation, the colonic targeting property in vivo and the pharmacodynamic characteristics of the system were investigated. Sodium 4-aminosalicylic acid, which has been employed since 1940s as a treatment for tuberculosis, was used as a model drug in this study. Being an anti-inflammatory agent as well, this drug was administered by rectal route to treat ulcerative colitis. The rectal route, however, is not convenient or acceptable for most patients, and therefore such patients would benefit from an oral alternative to chronic enema therapy. The purpose of this study was to develop a new oral colon-specific drug delivery system to treat inflammatory bowel diseases. Targeted delivery of this drug to the colon orally would therefore be advantageous, not only in terms of convenience, but also as a means of allowing topical treatment at the disease sites and fewer systemic side effects.Methods:Preparation of coated tablets (1) The effect on property of the core tablets ofseveral factors such as disintegrants> adhesive agents and pressure was investigated;(2) On the basis of mono-factor testing, an orthogonal experiment containing 3 factors and 3 levels was designed to study the content of microcrystalline cellulose^ lactose and cCMC-Na to optimize a formulation of the core tablets;(3) Several factors such as coating thickness of the sustained-release layer, combinations of Eudragit RL-RS, kind of the plasticizer, coating thickness of the enteric layer, drying time, diameter of core tablets, rotations were studied to evaluate the effect on the release profile of the coated tablets;? On the basis of mono-factor testing, an Lg(34) orthogonal design was used to investigate the impact on drug release of the factors such as combinations of Eudragit RL-RS -, coating. thickness of the sustained-released layer -, coating thickness of the enteric layer and drying time;(5) On the basis of the optimization of the prescription, the method to prepare coated tablets was confirmed;(6) The method of the main drug content was established.The release profile of coated tablets To compare the release profile of the colon-specific coated tablets and enteric-coated tablets in different media and to simulate the release data of the two formulations.Stability test of coated tablets ? To find the factors affecting stability by observing the change of out-look and the release profile of the coated tablet and contents of the main drug;(2) In the accelerated testing, the expiratory time was estimated by observing the change of appearance and determining release percentage of the coated tablets and the contents of the main drug.The colonic targeting property in vivo ? The coated tablets radiolabelled with 99mTc were prepared following the best formulation;(2) The colonic targeting property of sodium 4-aminosalicylic acid coated tablets was verified in vivo by Y -scintigraphy.pharmacodynamic study of the coated tablets ? Rats were treated by clyster with 500 u 1 of TNBS in 50% ethanol was applied;(2) Pharmacodynamics of the coated tablets was studied, using the traditional anti-UC drug SASP was used as the positive control, 4-ASANa tablets as the formulation control. The activity of MPOin the colon of rats was evaluated and the macroscopical and histological changes of the colon were observed. Results:Preparation of coated tablets (D The result of the mono-factor testing of core tablets was that there was effect on the property of core tablets when different disintegrants or adhesive agents were selected;(2) The result of the orthogonal experiment was that 13% microcrystalline cellulose and 20% lactose as filler, 6% cCMC-Na as disintegration;(3) The result of the mono-factor testing of coated tablets was: coating thickness of the sustained-release layer, combinations of Eudragit RL-R^ coating thickness of the enteric layer, drying time and size of the tablets could interfere the release profile dramatically;while the kind of plasticizer and rotations had less influence on drug releasing;@ The result of the orthogonal experiment of coated tablets showed that the best formulation was: coating thickness of sustained-release layer was 2.01%, combination of Eudragit RL-RS was 1:2, coating thickness of enteric layer was 6.02% and drying time was 4h. (5) On the basis of the optimization of the prescription, the method to prepare coated tablets was confirmed;? An HPLC method was established to determine the content of the coated tablets.The release profile of coated tablets The release profile of the colon-specific coated tablets followed zero-order kinetics or Higuchi equation, while which of the enteric-coated tablets followed Weibull equation.Stability test of dispersible tablets ? Stress test showed that high temperature, high humidity and lightening could make the outlook and release profile of the coated tablets changed, and high humidity can decrease the content of the main drug;(2) During the stage of the accelerated speed test, the content of the main drug decreased about 8% after 3 months, and drug released quicker than before because the enteric layer dissolved quicker. Therefore, sodium 4-aminosalicylic acid colon-specific delivery coated tablets should be packed in a sealed and light-resistant package and stored in a cool place.The colonic targeting property in vivo ? 99mTc was mixed with the main drugand expients and pressed into core tablets. The amount of 99mTc was 30mci per tablet as coating, and about 7-8mcj per tablet when y -scintigraphy study began;(2) The result showed that drug release did not occurred in the upper gastrointestinal, while began to occur when the tablets arrived at ascending colon in a sustained-release fashion. There was drug all over the colon until the tablets were eliminated out of the body after about 30 hours. It could be concluded that the system had good colon-specific property.Pharmacodynamic study of the coated tablets (T) Rats were catheterized 8 cm intrarectal and 0.85ml of TNBS in 50% ethanol was applied (dose was 150mg/kg of body weight of TNBS) to develop an inflammatory bowel disease model;(2) 4-ASA-Na colon-specific coated tablets showed a property of dose-dependent in dealing UC, and the drug with higher dose had similar pharmacodynamics with SASP. The ordinary tablets had similar effect on UC with the control group.Conclusion:In this study, by means of the multi-layer coating technology and orthogonal experiments to optimize the priscription of the core and coated tablets, we developed a new pH and time-controlled oral colon-specific delivery system, which was proved to have good colon targeting property by release experiment in vitro and colonic delivery study in vivo. Pharmacodynamic study also showed that this formulation had effect on ulcerative colitis in rats. This technology would therefore be advantageous, not only in terms of simple and practical, but also as a means of providing sustainable therapy for ulcerative colitis. This study established the principle of the use of permeable and enteric Eudragits coating as a feasible method to delivery drug to the colon. Being an ideal colon-specific delivery formulation, the system has extensive potential for development and application clinically.
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