| Carbinoxamine Maleate(CAM) is an antihistamine drugs with mild sedation effects, which is used to treat seasonal and perennial allergic rhinitis of children clinically.The amount of chemical agents is exceed than 3500 kinds at present in China, however, the percentage of pediatric formulations is less than 10% and child-specific medicines are fewer than 100 species. The lack of drug and appropriate dosage form suitable for children is a big short board for the pharmaceutical industry development. In view of the above situation, this paper carried out the research of the preparation of oral liquid controlled release formulations suitable for children with CAM as a model drug. This paper is divided into five parts as follows.Part I Preparation of CAM-resin complexesA full wavelength scan on CAM solution is conduced in this part. The wavelength of maximum absorption of the CAM is determined. The in vitro assay method different media is established. The effects of temperature, concentration, resin type and other factors on bath method were studied. The kinetics of drug-loading shows that the process of drug-loading by bath method belongs to first order kinetics.The effects of drug concentration, flow rate and temperature on the process of drug loading by column method were studied and the results showed that with high concentration and high flow rate, the drug-loading speed increased, and the breakthrough point appeared early; Bath method of preparing CAM resin is adopted through a comparative analysis. The optimum technological conditions were as follows: 100 mL CAM solution with concentration of 3mg·mL-1;300 mg Amberlite?IRP69; drug-loading at temperature(37.0℃±0.5℃);the equilibration time was 3hours.Part II The bonding mechanism of CAM-resin and the in vitro releaseThe combination of CAM and resin was proved a kind of chemical combi nation by SEM, XRD, IR and DSC tests; The effects of temperature, rotational speed, medium ion concentration, medium volume, and the counter ion type o n the drug release behavior were investigated; The release of CAM resin wasfound to be controlled by particle diffusion process. Diffusion rate was accele rated with the increase of temperature, speed, ionic strength of the medium an d the medium volume. Release behavior is also changed with the type of coun ter-ions accordingly.Part III Research on CAM-resin coating technology and prescriptionThe industrial thought of coating was designed by combining the reaction kettle and emulsion solvent evaporation process. Stirring speed, reaction temperature and vacuum degree on the resin microcapsules release was investigated. According to the result of the single factor investigation, the coating conditions were as follows:rotational speed 200 rpm, curing temperature 35℃, vacuum degree 0.01 Mpa. The effect of the coating formulation on release in vitro was studied under optimum coating process. Orthogonal design was utilized to obtain the optimum coating formulation which were as the follows:the mass ratio of coating material of RS100 and RL100 was 1:1; the amount of coating materials was 16% weight of CAM resin,the dosage of plasticizer was 5% of the coating material. The prepared resin microcapsules, which with uniform size and good controlled release, had a good reproducibility. The drug release of CAM was in accordance with the first order kinetics, and the drug diffusion was mainly controlled by membrane.Part IV Preparation of CAM sustained-release suspensionThe particle size, Wettability and Wet density of the microcapsule, as well as the density, viscosity and rheological properties of the diffrent kind of suspending agent were determined.Taking sedimentation volume ratio and redispersibility as the indicator, the suspending agent, filling agent and wetting agent were screened, the type and amount of chelating agent, flavoring agent and preservatives were determined at the same time. The in vitro release and stability of sustained-release microcapsule suspension were investigated, which show that the suspending medium does not influence the drug release. In the stability test, the characteristics, clarity,redispersibility, drug content and leakage of the ample were examined, which indicates that carbinoxamine maleate sustained-release suspension has a good stability.Part V Study on in vivo pharmacokinetics of CAM sustained-release suspensionIn this chapter, SD rats were used as model animal and the in vivo analysis of CAM was established and the specificity, intra- and inter-day precision, recovery rate and stability of in vivo analysis met with the requirements. With self-made suspension being the test preparation and CAM solution being the reference preparation, the concentration of CAM in blood plasma was measured by HPLC method and the non-compartment model was used to obtain the pharmacokinetic parameters of two preparations and evaluate the relative bioavailability. Pharmacokinetics showed that the Cmax of CAM solution and self-made suspension were 1885.78 ng·mL-1and1206.51 ng·mL-1,The time peak of drug concentrations(Tmax) were 3 h and 6 h and t1/2were 13.16 h and 17.40 h, which showed that CAM suspensions could reduce peak plasma concentration, prolong the Tmax, and make the drug release more gently. The AUC0-24 of CAM solution and sustained suspension were 16589.58 ng·h·mL-1and15172.09 ng·h·mL-1.The relative bioavailability of sustained-release suspension was91.46% compared with the CAM solution. |
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