Colon drug delivery has received a significant interest for local treatment of large bowel diseases as well as for systemic delivery of the drug. Colon-specific drug delivery systems exploit specific conditions of gastrointestinal tract; therefore, they can be classified into pH-, time-, enzyme- and pressure-controlled drug delivery systems. The aim of this work was to develop, optimize, and evaluate drug delivery system - microcapsules, which would provide an optimal therapeutic efficacy of antiinflammatory drug LK-423 in treating inflammatory bowel disease. For this purpose, interactions between the components of the drug delivery system were studied and the influence of various parameters of the preparation method of the delivery system evaluated. Additionally, the drug as well as drug delivery system was investigated from the physico-chemical, biopharmaceutical, and pharmacokinetic point of view. The starting point of our research work were microcapsules, developed in the scope of the research work on colon drug delivery taking place at the Chair of Biopharmacy and Pharmacokinetics. Microcapsules represented one of possible technological approaches to realize the idea of colon drug delivery, based on combination of enzyme, time and pH controlled drug release mechanisms in drug delivery system. In accordance with this idea, the microcapsules are composed of polysaccharide core, specifically degraded in colon by enzymes of resident bacteria, inner retard coating, which delays drug release in the small intestine, and outer enteric coating protecting the drug delivery system in the stomach.Firstly, we focused into optimization of the production of polysaccharide cores prepared by ionotropic gelation. Using a model system of theophylline and sodium alginate, the influence of various formulation (drug, additives) as well as process parameters (hardening time, concentration, temperature, and pH of calcium chloride solution, mode of drying) on the core properties such as drug content, drug release kinetics, shape and morphology was evaluated. By means of instrumental techniques like differential dynamic calorimetry, infrared spectroscopy, and X-ray powder diffraction analysis, the interactions between the components of the system were studied and the impact of different additives and process parameters on physical state of the drug and on core properties was investigated. Based on these findings, we were able to define the critical parameters of ionotropic gelation and to develop a simple and automated procedure for preparation of LK-423 containing polysaccharide cores with high encapsulation efficiency and acceptable shape characteristics for coating. To assure colon delivery, the conditions of in vitro dissolution method simulating in vivo gastrointestinal conditions and the criteria of drug release kinetics from microcapsules were determined in accordance with gastrointestinal conditions of each animal species (rat and dog). The release kinetics was adjusted to these criteria by varying the compostion (ratio of polymers Eudragit® RS and RL) and the amount of inner retard coating, which delays drug release along the small intestine, and outer enetric coting protecting drug delivery system in the stomach. To develop drug delivery system, providing optimal therapeutic activity of the drug, the physico-chemical, biopharmaceutical as well as pharmacokinetic properties of the drug and drug delivery system have to be understood in details. Pharmacokinetic study following intravenous administration of LK-423 solution to rats and dogs revealed limited distribution and rapid elimination of LK-423. Following oral administration, LK-423 demonstrated poor oral bioavailability, which could most likely be ascribed to low permeability related to its physicochemical characteristics. Based on the microcapsules’ in vitro drug release profiles, LK-423 plasma concentration profiles, obtained following oral administration of the microcapsules, and debris of microcapsules’ insoluble coatings in faeces it is anticipated that microcapsules delay drug release in upper parts of gastrointestinal tract and that drug is being released predominantly in distal parts of gastrointestinal tract. All these findings imply that microcapsules are an effective colon-specific drug delivery system. Rationality of development and optimization of LK-423 colon delivery microcapsules was confirmed in in vivo experiment of treating ulcerative colitis in rats, in which therapeutic efficacy of optimized microcapsules was compared to orally and rectally administered LK-423 in the form of suspension. The study revealed that LK-423 ameliorates the symptoms of colitis when compared to untreated colitis control group. However, in animals receiving LK-423 microcapsules the most physiologic regeneration of mucosa was observed what is probably related to local drug delivery near the site of inflammation achieved using microcapsules. These results imply that LK-423 colon delivery microcapsules appear to be an effective drug delivery system for treatment of inflammatory bowel disease.In conclusion, based on the results of studying interaction between the components of the system, as well as on findings of biopharmaceutical and pharmacokinetic evaluation of the drug and drug delivery system, LK-423 colon delivery microcapsules for rats and dogs were optimized and their beneficial therapeutic efficacy in treating ulcerative colitis in rats was demonstrated. This work presents an important scientific contribution to the field of ionotropic gelation as well as colon-specific drug delivery.
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