| Pentoxyverine Citrate is a non-dependent central antitussive,used for cough caused by upper respiratory tract infection and whooping cough clinically.Antitussive effect is about 1/3 of codeine without addiction,accompanied by mild atropine and local anesthesia.The effect on children is better than that of adults.Bromine hydrochloride is suitable for a variety of bronchitis,bronchial asthma,emphysema,bronchiectasis and other sticky sputum not easy to cough up,the effect of BH is particularly good on white sputum.The dosage form for children is less than one-tenth of the total in domestic.The number of cough and expectorant drugs specifically for children is limited.In view of the increasing incidence of respiratory diseases,Pentoxyverine Citrate and Bromine Hydrochloride were taken as model drugs to prepare compound sustained-release suspensions for children.Part ? Preparation of PC/BH resin complexesThe in vitro assay method was established in this part.The precision,stability and recovery of the analytical methods were investigated and the results were in accordance with the requirements.The equilibrium solubility and oil-water partition coefficient of PC and BH were investigated.The p H solubility curve of BH was determined.The effects of resin type,concentration of drug,temperature and other factors on bath method were studied.The optimum technological conditions of PC were as follows: 200 m L PC solution with concentration of 3 mg·m L-1,500 mg Amberlite? IRP 69,drug-loading at(25.0 °C±0.5 °C),the equilibration time was 2.5hours.The optimum technological conditions of BH were as follows: 200 m L BH solution with concentration of 0.4 mg·m L-1,80 mg Amberlite? IRP 69,drug-loading at(25.0°C±0.5°C),the equilibration time was 3 hours.The kinetics and thermodynamics of drug loading by bath method on PC and BH belonged to first order kinetics.The preparation of the drug resin is an endothermic reaction.Part ? The bonding mechanism of PC/BH resin and the in vitro releaseThe combination of drug and resin was proved by chemical combination rather than a simple physical adsorption using SEM,DSC and XRD detection method.Theeffects of temperature,medium volume,stirring speed,ion concentration,and the type of counter ion on the drug release behavior were investigated using f2 similarity factor analysis.The release mechanism was investigated by Viswanathan equation.The results showed that the release process of PC and BH resinates were controlled by particle diffusion.Part ? Research on PC/BH resin coating technology and prescriptionPC and BH drug-resinates microcapsules were prepared using fluidized bed coating method with ethyl cellulose as coating material,ethanol as solvent.The effects of fluidizing air volume,coating temperature,coating speed on the drug release were studied using single factor.The optimum coating process was determined.The type and concentration of coating material,ratio of resin to EC,plasticizer amount on the drug release were investigated.The obvious sustained release effect of PC and BH microcapsules were prepared with orthogonal design to optimize the prescription.The coating prescription of PC was: the concentration of ethyl cellulose was 5.5%,the ratio of resin to coating material was 6:1,and the amount of plasticizer was 14% of EC.BH coating prescription was: the concentration of the ethyl cellulose was 4%,ratio of resin to coating material was 7:1,and the amount of plasticizer was8% of coating material.The morphology,density,particle size,content and drug release were investigated.The results showed that the sustained release effect and reproducibility of microcapsules were good.The release behavior of PC and BH sustained release microcapsules was in accordance with the first order kinetics,and the drug diffusion was mainly controlled by membrane,supplemented by particle.Part ? Preparation of PC/BH sustained release suspensionIn this chapter,the related properties of microcapsules and suspending agents were determined,and the suspending agents were determined by taking sediment volume ratio and redispersibility as indicator.The xanthan gum was used as suspending agent.The effects of temperature,p H,heat treatment time on the viscosity of xanthan gum were investigated.The filler and wetting agent were screened.The optimized prescription was as follows: sucrose 1.0 g,xanthan gum 0.8 g,propylene glycol 1.0 m L diluted with water to 100 m L.The sediment volume ratio was 0.99 and redispersibility was good.The release behavior and stability of PC and BH sustained release suspensions in vitro were investigated.The results showed that the overall release of the suspension was similar to microcapsules of PC and BH,f2 factor is greater than 70.No release interference was observed between PC and BH.The characteristics,redispersibility,sediment volume ratio,drug release,drug content and drug leakage were examined in the stability test,which indicating the stability of the suspension was good.Part ? Study on in vivo pharmacokinetics of PC/BH sustained-release suspensionThe in vivo analysis of PC and BH were established in SD rats.Specificity,stability,precision,extraction recovery rate and method recovery were analyzed.The results showed that all the requirements were in accordance with the requirements.The appropriate dose of PC/BH compound sustained release suspension and ordinary tablets were given respectively.The concentration curve and related parameters of the drug after administration were studied.And the relative bioavailability of the two were evaluated.From the pharmacokinetic parameters,the Cmax of PC ordinary tablets and sustained-release suspension were 659.134 and 403.660 ng·m L-1 respectively,and Tmax were 2 h and 6 h,t1/2 were 2.841 h and 4.024 h.AUC0-24 were 4180.703ng·h·m L-1 and 3975.431 ng·h·m L-1 respectively.The Cmax of BH ordinary tablets and sustained-release suspension were 462.648 and 322.104 ng·m L-1 respectively,Tmax were 1 h and 4 h,t1/2were 4.251 h and 8.222 h,AUC0-24 were 3518.678 ng·h·m L-1 and3325.089 ng·h·m L-1 respectively,indicating that PC/BH suspension can reduce the peak plasma concentration,prolong Tmax.The relative bioavailability of PC and BH compound sustained-release suspensions to ordinary tablets was 95.09% and 94.50%. |
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