Study On Ketoprofen Bioadhesive Gel Beads

Ketoprofen (KP) is an effective nonsteroidal antiinflammatory drug which has been widely used to treat analgesia and rheumatoid arthritis in clinical. Due to its bitter taste and gastro-intestinal side effects, the further development of its oral preparations and clinical applications was restricted greatly.Ketoprofen was selected as the model drug to prepare bioadhesive gel beads with dripping method. The aim of this study was to lower its side effects, prolong the drug’s action time and extend the drug’s retention time in intestine with mucoadhesion.Ultraviolet-visible spectrophotometry (UV) method was developed for in vitro assay of drug content in ketoprofen gel beads and used to study the release of drug from the formulations.The dripping method was selected to prepare the ketorofen-loaded calcium pectinate gel (CPG) beads. Applying entrapment efficiency and release profiles as main indexes, formulation factors and technology factors were investigated and optimized by the single factor test. Ketoprofen-loaded calcium pectinate gel-calcium alginate gel (CPG-CAG) beads and ketoprofen-loaded CAG beads were prepared by optimization formulation and technology. The characters of CPG beads were compared with CAG beads and CPG beads were selected as better preparation for further modifying.The dripping method was also chosen to prepare the ketorofen-loaded chitosan-coated CPG beads using one-step and two-step process, and the characters of chitosan-coated CPG beads were investigated. The release of ketoprofen from pectin beads could be retarded by coating with chitosan. Especially, the chitosan-coated CPG beads exhibited excellent mucoadhesive characters.The investigation on the drug release mechanisms indicated that drug release from CPG beads and chitosan-coated CPG beads accorded with non-Fick diffusion model. The drug released from the CAG and CAG-CPG beads followed the erosion mechanism. Results of stability studies on ketoprofen gel beads showed that the gel beads were stable when exposed to high temperature and light, but sensitive to high humidity. The accelerating test showed that the stability of the formulation was strengthened after packing.HPLC method was developed to quantify the drug plasma concentration of rabbits, and the studies of pharmacokinetics were performed after oral administration of two formulations. The pharmacokinetic parameters of bioadhesive gel beads and domestic tablets were as below:tmax were 7.833±0.516h and 1.833±1.169h, respectively. cmax were 3.725±1.907μg·mL-1 and 4.547±2.075μg·mL-1, respectively.t1/2 were 2.985±1.654h and1.742±0.700h, respectively; AUCo-t were 20.580±7.854 and 19.455±9.615μg·h·ml-1, respectively. Tmax was retarded and T1/2 was extended which indicated the sustained release characteristics of ketoprofen-loaded chitosan-coated CPG beads. The relative bioavailability of bioadhesive gel beads was 113.6±30.2% compared with domestic capsules. And the release of ketoprofen in HCL was lower than 10% which indicated that the beads could reduce the gastrointestinal adverse effects.In one word, the preparation of bioadhesive gel beads of ketoprofen was feasible, and could achieve the primal purpose to prolong the drug’s action time, decrease administration times and lower its side effects.