Construction And In Vivo/In Vitro Evaluation Of Verapamil Hydrochloride Pulsed Sustained-Release Drug Delivery System

As a cardiovascular and cerebrovascular disease,hypertension has chronological rhythm.Verapamil hydrochloride（VH）is a commonly used clinical drug for hypertensiong,has the pharmacokinetic characteristics of short biological half-life and obvious hepatic first-pass effect.It requires multiple administrations to maintain the therapeutic concentration,resulting in problems such as blood drug concentration fluctuations,drug metabolism and excretion,which cause limitations in its clinical application.Traditional preparations can no longer meet the needs of clinical treatment.According to the recommendation of the US Food and Drug Administration,once-daily sustained and controlled-release preparations should be selected for the treatment of hypertension.To combine the characteristics of pulsatile and sustained-release administration and overcome the defects of single-dose administration of osmotic pump formulations,VH was prepared as an oral liquid pulse sustained release formulation in this paper.Amberlite^?IRP69cation exchange resin,a commonly used excipient for oral liquid preparations,has the defects of low drug loading and low drug utilization rate when applied to VH.In this paper,by preparing a porous sodium polystyrene sulfonate cation exchange resin,the problems of low exchange capacity and low specific surface area of the IRP69 resin were solved.The VH pulse sustained-release suspension was prepared by using the self-made porous cation exchange resin as the sustained-release carrier and EUDRAGIT L100 as the enteric coating material.It can be mainly divided into the following five aspects:1.Synthesis and characterization of porous cation exchange resinsIn this chapter,polystyrene-divinylbenzene（PS-DVB）gel microspheres were prepared by copolymerization of porogen and monomer,PS-DVB porous microspheres were prepared by Soxhlet extraction,and sulfonated PS-DVB porous microspheres were prepared by sulfonation reaction,and finally the porous cation exchange resin was prepared by basic titration.The synthesis process route was optimized with the microsphere morphology,pore structure and drug loading as indicators.The structure of the self-made resin was characterized by IR,SEM,XRD,high-performance automatic mercury porosimeter and other instruments.The results show that the median particle size of the self-made porous resin is 130μm,containing micropores,mesopores and macropores,and the pore size distribution is ranging from 1nm to 120μm.Compared with the IRP69 resin,the Na content and K exchange capacity are increased by about 1.5 times,and the BET analysis showed that the specific surface area was increased by 2.6 times Quality inspection according to the standards of USP and the EP related to sodium polystyrene sulfonate pharmaceutical excipient standards.Results show that the exchange capacity of the self-made porous cation exchange resin has been greatly improved,and solubility,chemical identification and other indicators meet the Pharmacopoeia quality standards.2.Preparation of drug-resin complexesIn this paper,ultraviolet spectroscopy（UV）method was used to establish an in vitro analytical method for verapamil hydrochloride,and the methodological content of the method was verified.Taking the time required for drug loading to reach equilibrium and the drug loading amount as indicators,the effects of VH concentration,drug-resin ratio,temperature and drug loading time on the drug loading behavior of resin were investigated.The optimal preparation process of VRC is as follows:drug loading temperature is 37±0.5℃,VH:resin=1:1,VH concentration is 5mg/m L,drug loading Q_∞is 0.73 mg·mg^-1,and drug utilization rate E is74.19%,which are about 2.2 times higher than IRP69 resins.3.Binding mechanism of drug and resin and evaluation of VRC release in vitroIn this paper,the apparent properties and structure of VRC were characterized by FTIR,SEM,XRD and DSC,and the binding mechanism between VH and resin was determined to be ion exchange.The in vitro drug release behavior of VRC under different conditions was investigated by the control variable method,and evaluated by the （?）₂similarity factor method.The in vitro drug release conditions were established as follows:the VRC was placed in a dissolution medium of 900 m L 0.15 mol/L Na Cl at a temperature of 37.0℃±0.5℃,the rotation speed was 50 r/min,and the cumulative release rate was 86%.The in vitro release behavior shows that VRC has a sustained release effect and achieves the intended purpose of administration4.Research on VRC coating formulation and preparation of pulse sustained-release suspensionIn this chapter,the problem of sudden release of resin in the medium is solved by impregnation treatment.The enteric-coated microcapsules are prepared by the emulsification-solvent evaporation method.EUDRAGIT L100 was used as the enteric coating material,methanol-acetone（1:5,v/v）is the inner oil phase,liquid paraffin is the outer oil phase,Span 80 is an emulsifier for coating,and the acetone is evaporated to obtain light yellow,granular verapamil hydrochloride-coated microcapsules（VRC-CM）.The particle size D₅₀of VRC-CM is 169μm,and the drug content is 28.84%,which meets the requirements of suspension preparation.Taking sedimentation volume ratio and redispersibility as evaluation indexes,the preparation process of VH pulse sustained-release suspension was designed.In order to eliminate the interference of the excipients in the suspension formulation on the determination of the content,the HPLC in vitro analysis methodology for VH was established through the specificity,precision and stability investigations.Investigate the appearance properties,drug content,release degree and other indicators of VH pulse sustained-release suspension.The results showed that the self-made suspension had good dispersion and stability,and the in vitro release had obvious pulse sustained-release effect.5.In vivo pharmacokinetic study of VH pulse sustained-release suspension in ratsIn this chapter,an HPLC method for in vivo analysis of verapamil hydrochloride was established,and diltiazem hydrochloride was used as the internal standard to investigate the specificity,precision,stability and recovery rate.SD rats were selected as animal models,and the pharmacokinetics of commercially available VH conventional tablets and self-made suspensions were investigated by single-dose intragastric administration and blood sampling from the inferior venous plexus.The compartment model was determined by DAS2.0 software,and the pharmacokinetic parameters were calculated by BAPP algorithmand.The T_maxof the commercially available VH conventional tablet and the homemade VH pulse sustained-release suspension were 2 h and 5 h,the t_1/2was 1.407 h and 4.191 h,and the peak plasma concentration C_maxwas 2.231μg·m L^-1and 1.100μg·m L^-1,AUC_0-24(μg·h·m L^-1)were 5.144 and 5.512,respectively.The relative bioavailability of the self-made suspension and the reference preparation is 107.03%,there was a significant difference in C_maxand t_1/2calculated by TTest,and there was no significant difference in AUC_0-24.Taking relative bioavailability and AUC_0-24as evaluation indexes,it shows that the home-made suspension is equivalent to the commercially available tablet bioavailability...