Study On Budesonide Colon-targeted Site-specific Dosage Forms

Budesonide, a very potent corticosteroid used to treat inflammatory bowel disease (IBD), was selected as model to prepare the new colon-targeted site-specific dosage forms which were named as the microbially triggered colon-targeted osmotic pump (MTCT-OP) localization tablet and the microbially triggered colon-targeted microporous semipermeable membrane (MTCT-MSM) localization tablet, respectively. The drug delivery systems were designed by combining together the microflora-triggered colon-targeted principle and the microporous semipermeable membrane-controlled drug delivery technology in order to enhance the targeting drug to the colon, to increase the local concentration and the local bioavailability of budesonide in the colon, to improve the therapeutic efficacy of budesonide on the IBD and to decrease the general side effect.1,Cellulose acetate and PEG 400 were used as semipermeable membrane material and plasticizer, respectively. Chitosan was used as pore forming agent which could be specifically degraded by glycosidase secreted by microflora of the colon. Effects of formulation compositions and medium conditions on the physico-chemical properties of isolated membrane (including the appearance, water vapor transmission, swelling property, permeability, degradability, elastic modulus, tensile strength) were investigated and the ratio of formulation was optimized carefully. Preliminary assessments of the permeability, the effect of membrane formation and the colon targeting property on the isolated membrane were determined, respectively. It was demonstrated that the optimized microporous semipermeable membrane had fine water vapor permeability and membrane-forming characteristics. It was also observed to form the in situ pores in the membrane only with the presence of rat caecal medium and exhibited excellent colon targeting property.2,The controlled release technology of controlled porosity osmotic pumps which could deliver drug at a controllable way was applied for the colonic drug delivery systems. The water-soluble channeling additives in the coating membrane of conventional controlled porosity osmotic pump were replaced by the chitosan. The obvious gelation characteristic of chitosan at acid condition was utilized as a polymeric osmotic agent to increase the osmotic pressure in osmotic pump core. Swelling of tablet core forced drug out through the in situ microporous orifice which was formed because of the glycosidase-specific biodegradability of chitosan. The duplicate aims of the targeting drug to the colon by microflora-activated mechanism and controlled release procedure at a pre-programmed rate were achieved. The three step-dissolution experiment simulated the physiological conditions of gastrointestinal tract was designed to determine the accumulated drug release curves. Release profiles of various formulations were compared by the calculation of 'similarity factor' f₂. The drug core formulations, microporous semipermeable membrane formulations, enteric membrane formulations and the coating parameters and technology were screened and optimized. The budesonide MTCT-OP localization tablet with drug release characteristics of osmotic pump and colon-specific drug delivery was prepared successfully. Dissolution data of the optimized formulation was fitted to various mathematical models in order to describe the kinetics of drug release. Drug release from the in house formulation fitted well into first-order model. We calculated the microporous semipermeable membrane parameter L_Pσ=7.0×10^-6 cm²/h-atm. It was proved that the drug release characteristics of optimized formulation conformed to the drug release mechanism of controlled porosity osmotic pump where osmotic pressure was the main driving force for controlled delivery of drugs.Three experiments, including the determination of budesonide in gastrointestinal tissues after oral administration of the in house localization tablet, study on pharmacodynamics of budesonide from the in house localization tablet against 2, 4, 6-trinitrobenzenesulfonic acid-induced colitis in rats, and insight into the gastrointestinal transit of the radioactive nuclide ¹¹¹In labeled in house localization tablet using the technique ofγ-scintigraphy, were designed well to validate systematically the colon-targeted characteristics and in vivo drug release pattern of budesonide MTCT-OP localization tablet. It was demonstrated that the in house localization tablet possessed conspicuous specificity of targeting drug to the colon. Compared with the control groups, it could ameliorate obviously the inflammatory exosyndrome of colonic inflammation in rats and exhibit the best therapeutic effects and minimum adverse reactions. The in house localization tablet had good in vitro/in vivo correlation. The in vivo drag release took place persistently in the colon transit and the drug released from the novel dosage form was disseminated uniformly in all round the colon.3,The budesonide solid dispersion was explored in order to enhance the solubility of poorly soluble budesonide, to profit the preparation the microporous semipermeable membrane-controlled dosage form, and to allow a high topical concentration and topical bioavailability when coming into contact with inflamed colon tissue. The solid dispersion of budesonide in poly (ethylene oxide) was prepared by supercritical fluid technique, using poly (ethylene oxide) as a hydrophilic carrier and supercritical carbon dioxide as the processing medium. Effects of such the operation parameters as supercritical fluid conditions (including temperature and pressure), various molecular weights of poly (ethylene oxide), and the different ratio of budesonide and poly (ethylene oxide) of formations on solid dispersions were elucidated by scanning electron microscopy, powder X-ray diffractometry, differential scanning calorimetry, intrinsic dissolution method, and in vitro dissolution test. The theory and method for preparation of solid dispersions using supercritical fluid technique were established preliminarily. It was found that the optimum conditions of solid dispersions formation were as follows: temperature, 40℃; pressure, 20 MPa; the ratio of budesonide and poly (ethylene oxide) (MW: 300 000 Da), 1∶10 (W∶W). Budesonide existed in amorphous state in hydrophilic poly (ethylene oxide) carrier and the intrinsic solubility, drug release and dissolution rates of drug were significantly enhanced.The foregoing budesonide-poly (ethylene oxide) solid dispersion was used as drug core and the microporous semipermeable membrane containing chitosan as the channeling agent was used as microporous membrane-coating material. The single factor test was adopted to optimize the drug core formulation, microporous semipermeable membrane formulation and enteric membrane formulation. The budesonide MTCT-MSM localization tablet was designed successfully by means of microbially activated mechanism for colon-specific drug delivery. The in vitro dissolution procedure and the mechanism of the in house localization tablet were evaluated using modeling kinetics and similarity analysis. It was shown that the in vitro drug release from the in house formulation conformed to Higuchi model derived by Fick's diffusion and the drug was delivered from the in situ micropore which was formed by the specific biodegradation of chitosan (channeling agent) by microflora of the colon.