| Ibuprofen, a non-steroidal antipyretic and anti-inflammatory drug, has a shorthalf-life and low bioavailability, which can lead to excessive drug dosage and adversereactions. Although the high permeability though gastric mucosa, the ibuprofen haslow absorption in the stomach due to the poor solubility in water or acidic solutions.In the small intestine, the solubility of ibuprofen increases as the pH of the intestinalfluid increases. But ibuprofen also has low absorption in the small intestine because ofthe low permeability of the intestinal mucosa. It can be found that the dissolution ofibuprofen is thus the rate-limiting step for its absorption. In addition, Ibuprofen hasshort biological half-life. In order to maintain effective treatment in medicine, oraladministration of ibuprofen frequently is needed to the patient. As a result,gastrointestinal stimulation effects are appeared. The dissolution of poorwater-soluble drugs that undergo dissolution rate-limited gastrointestinal absorptioncan generally be improved by many techniques, such as solid dispersion (SD)techniques. This technique provides a means of reducing particle size to nearlymolecular levels. As the soluble carrier dissolves, the insoluble drug becomes exposedto the dissolution medium as very fine particles for quick dissolution and absorption.Chitosan-based microspheres can control the drug delivery, improve the drug stabilityand reduce the stimulation of the drugs on the gastrointestinal mucosa. In this study,SD-loaded chitosan microspheres are prepared to improve the drug stability, the drugsolubility, and the anti-inflammatory effect, reduce the administration frequency ofdrug and also reduce the stimulation of the drug on the intestinal mucosa.The solubilities of ibuprofen in the cosolvents (urea, mannitol, and PEG4000) arestudied in order to select the appropriate water-soluble carrier to prepare SD whichcan improve the solubility of ibuprofen. The results indicate that the solubility ofibuprofen in the aqueous solution of urea is significantly higher than that in the aqueous solution of mannitol and PEG4000. The Gibbs free energy of transferindicates the spontaneity of the solubilization process. Thus, urea is selected as thecarrier for the preparation of SDs. SDs are characterized in terms of dissolution,differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electronmicroscopy (SEM), and Fourier transform infrared (FTIR) spectroscopy. The resultsof in vitro release indicate that the ibuprofen dissolution rate is improved by the SD,and the dissolution rate of ibuprofen increased with the ratio of ibuprofen to carrierdecreased. Results from FTIR of SD suggest that no interaction between ibuprofenand urea is appeared. The DSC thermograms indicate that a small crystalline portionof ibuprofen existed in this SD and no interaction between ibuprofen and urea isappeared. The XRD patterns indicate that the ibuprofen diffraction peak intensity isdecreased and there is no physicochemical interaction between ibuprofen and urea.The SEM pictures indicate that SD alters the solid state of the drug. From all above,SD characterization results suggest that ibuprofen partly precipitates in crystalline andamorphous forms after SD preparation and that ibuprofen and urea do not interact.According to mathematical modeling of in vitro dissolution data, it can be find thatthe best fitting with Korsemeyer–Peppas model and the drug release kineticsprimarily as quasi-Fickian diffusion. SD-based (SDBT) and conventional (CT) tabletsare prepared by the wet granulation method and their anti-inflammatory effects areevaluated using the mouse ear edema test with xylene in this study. The resultsindicate that the SDBT displayed better anti-inflammatory effects than CT. Theseresults indicate that the preparation of SD with urea significantly improve thesolubility and anti-inflammatory effect of ibuprofen.Chitosan has non-toxicity, no stimulation, biocompatibility, biodegradablility, highcharge density, and mucoadhesion. The chitosan-based microspheres can improve thedrug stability and control the drug release. In order to maintain effective treatment inmedicine, oral administration of ibuprofen is needed frequently to the patient becauseof the short half-life of ibuprofen. As a result, the digestive tract mucosa will bedamaged. Molecular attractive forces are formed by the electrostatic interactionbetween the positively charged of chitosans’ amino groups and negatively charged mucosal surfaces. Hence, chitosan microsphere can control the release of drugs andprolong the action time of them, such as ibuprofen. In another word, chitosanmicrosphere can control drug release rate and maintain a certain blood drugconcentration. Thus, the side effects caused by high blood drug concentration can beavoided. The molecular weight of chitosan can affect the release characteristics ofdrugs from chitosan. Thus, chitosan with different molecular weights are used toprepare microspheres to find a kind of chitosan with optimal molecular weight. Withthe method of alcohol acid degradation, four kinds of different chitosan with samedeacetylation degree and different molecular weight are prepared. These chitosan areused respectively to prepare chitosan microspheres loaded ibuprofen byemulsion-chemical crosslinking method. The characterizations of the microspheresare examined by size analysis, swelling ratio, drug-loading efficiency,drug-encapsulation efficiency, and drug release behavior. The chitosan microspheresare also studied in terms of scanning electron microscopy (SEM) and fouriertransform infrared (FTIR) spectroscopy. As result, the mean particle sizes of chitosanmicrospheres with different molecular weights are increasing with the increase ofchitosan molecular weight. On the contrary, the swelling ratios of chitosanmicrospheres with different molecular weights are decreasing with the increase ofchitosan molecular weight. In addition, ibuprofen release rate from chitosanmicrospheres is slower with the increasing of chitosan molecular weight. The resultsfound that the microspheres prepared with240KDa chitosan have higherdrug-loading efficiency, higher encapsulation efficiency, and better drug releaseeffect.In order to overcome the low solubility, short half-life and gastrointestinal irritationof ibuprofen caused by the sudden release of some medicine, the SD-loaded chitosanmicrospheres are prepared by using240KDa chitosan. The results of in vitro releasestudy indicate that the solubility of ibuprofen is improved, and the microspheres cancontrol the release of ibuprofen in a certain extent.In summary, the SD is prepared with appropriate cosolvents and thecharacterizations of the SD are studied. The anti-inflammatory effects of SD-based tablets are also evaluated using the mouse ear edema test with xylene in this study.Four kinds of different chitosan microspheres are prepared with emulsion-chemicalcrosslinking method, and the240kDa of chitosan is chosen to prepare SD-loadedchitosan microspheres. The results indicated that the SD-loaded chitosanmicrospheres would apply extensively to overcome poorly water-soluble, shorthalf-life, gastrointestinal stimulation of some drugs. |
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