Construction And In Vivo/in Vitro Evaluation Of Clonidine Hydrochloride Oral Liquid Controlled Drug Release System

Clonidine hydrochloride?CH?is a central?₂ receptor agonist.It is recommended for the treatment of various types and degrees of hypertension.The patients whose course of the disease has developed to moderate to severe are especially suitable to take it.The oral dosage of clonidine hydrochloride is small and the the oral absorption is good.CH is one of the preferred drugs in the current sympathetic inhibition drugs.The existing domestic products on the market are mainly ordinary quick-release tablets,patches and so on.For the elderly and dysphagia,there are many shortcomings of solid preparations,such as dysphagia,accurate dose distribution,difficult to take flexible dosage according to the development of the disease;In addition,the routine dosage forms should be taken 2 or 3 times a day,the blood drug concentration fluctuates greatly,and the patients'medication compliance with the medication is poor.Although clonidine hydrochloride sustained-release tablets were approved by the FDA in 2010,but they have not been imported into China,and they are mainly used for the treatment of attention deficit hyperactivity disorder in children and adolescents.In recent years,there has been no liquid sustained-release dosage for the treatment of hypertension on the market at home and abroad.Therefore,it is urgent to develop a sustained-release oral liquid preparation,which can effectively improve the above problems.On this basis,in this project,with CH as the model drug and cation exchange resin as the drug carrier,liquid sustained-release suspension was prepared by using ion exchange technology and water-based coating technology.1.Preparation of drug resin complexDrug resin complex?CH-DRC?was prepared by the bath method,and the best preparation scheme were finalized as follows:under 25.0?±0.5?temperature conditions,250 mg Amberlite^?IRP69 cation resin was weighed and added into 50 mL CH solution with concentration of 5.0 mg·mL^-1,the drug loading time was 1 h.And the final CH-DRC drug loading?Q_??was0.87mg CH/1 mg Amberlite^?IRP69,the drug utilization?E?of CH was 86.53%.2.Study on CH-DRC binding mechanism and in vitro release behaviorThe binding mechanism of CH-DRC was analyzed by means of SEM,XRD,FTIR and DSC,and the results showed that the drug was bound to the resin by ion exchange reaction instead of simple physical adsorption.In this chapter,the effects of the volume,ion type,ion strength,temperature and rotational speed of the release medium on the in vitro release process of CH-DRC were investigated.In this study,900 mL 0.15 mol·L^-1 NaCl was used as the releasing medium to conduct in vitro release experiment at a speed of 50 r·m^-1 and a temperature of 37.0?±0.5?.3.Research on the coating process of CH-DRCBased on the bottom spray fluidized bed coating method,The CH coating microcapsule was prepared by using Surelease?aqueous dispersion suspension?as the coating material.The effects of coating process and coating prescription on the release of coating microcapsule in vitro were investigated by single factor investigation and orthogonal design optimization.The optimal coating prescription process was determined as follows:under the conditions of inlet air quantity40 m³·h^-1,inlet air temperature 50?and coating liquid injection rate 2 mL·min^-1,the solid content of the coating liquid was selected to be 12.5%,the coating level of the coating material was 45%from continuous coating to coating.After coating,the materials were further heat-treated and cured for 1.0h in the fluidization room.The drug release behavior of CH coated microcapsules was investigated,and the results showed that it was in line with the first-order kinetic model,i.e.the release was mainly controlled by membrane,supplemented by particle diffusion.4.Preparation of CH sustained-release suspensionWith the sedimentation volume ratio and re-dispersity as the indexes,the types and dosage of suspension were screened,and the optimal formulation process of self-made sustained-release suspension was determined.The content,drug leakage,sedimentation volume ratio,re-dispersity and in vitro release curve were used as the indexes to compare the stability test sample with the 0-day sample to investigate the stability of the self-made CH sustained release suspension.And the results showed that the stability of the self-made CH sustained-release suspension was good.5.In vivo pharmacokinetic study of CH sustained-release suspensionIn this part,the HPLC method for in vivo CH detection was constructed,and the methodology of the analytical method was investigated.The results all met the requirements of pharmacokinetic research in vivo.Rats were given ordinary CH tablets and CH sustained-release suspension by intragastric administration respectively.The concentration curve and the related pharmacokinetic parameters were investigated by the non-compartment model.The results showed that compared with CH tablets,the T_max of the CH sustained-release suspension was delayed from 2 h to 5 h,the C_max was reduced from 32.138?g·mL^-1 to 18.150?g·mL^-1,and the concentration curve was more gentle.It indicated that the CH sustained-release suspension could effectively reduce the blood drug concentration,prolong the drug action time.The sustained release effect of CH suspension was obvious.The AUC_0-24-24 of commercially available clonidine hydrochloride tablets was 123.337?g·h·mL^-1,and the AUC_0-24-24 of homemade CH sustained-release suspension was 137.703?g·h·mL^-1.The relative bioavailability of the clonidine hydrochloride suspension to commercially available clonidine hydrochloride tablets was 111.65%via calculations,which was in the range of80%¹25%.This meant that the results met the relevant requirements in the design principles of sustained-release and controlled-release preparations.The two dosage forms were bioequivalent.