| Levodopa?LD?is the most important drug for treating Parkinson's disease.Levodopa enters the brain and produce dopamine?DA?with the dopa decarboxylase.Benzhydrazine hydrochloride?BDH?is a common dopa decarboxylase inhibitor,which can inhibit the decarboxylation of levodopa in the peripheral central nervous system,reducing the dosage of levodopa,increasing its bioavailability and reducing side effects.At present,there are tablets and capsules of levodopa compound preparations in the market,the liquid dosage forms have not yet been seen.Solid preparations have many disadvantages,such as inconvenient to divide dose,poor taste and unsuitable for patients with dysphagia.The liquid preparations can overcome these disadvantages.In this study,levodopa and benserazide hydrochloride was used as the model to study the sustained-release suspension,the process was divided into the following steps:Part I Preparation of LD/BDH-resin complexesLevodopa/benserazide hydrochloride drug resin complex was prepared and the condition of preparation process was studied.The levodopa drug resin complex was prepared by column method and the preparation conditions were as follows:a dynamic exchange column with a cross-sectional area of 4 cm2,a flow rate of 1mL·min-1 and a temperature of 37.0°C±0.5°C,the drug loading time was 2.5 h,the levodopa solution was 1 mg·m L-1 and the drug loading rate of the resin was 0.508.The benserazide hydrochloride drug resin was prepared by bath method and the preparation conditions were as follows:100 mg of Amberlite?IRP69 was added to100 m L of benserazide hydrochloride solution(dissolved in 0.01 mol·L-1HCl solution)at a concentration of 0.7 mg·m L-1.The temperature was 25.0°C±0.5°C and the drug loading time was 2h.The final drug loading rate was 0.601 and the drug utilization rate was 85.9%.Part II Characterization analysis and the in vitro release of LD/BDH-resinThe in vitro release mechanism and the bonding form of LD/BDH drug resin complex were studied.By examining and comparing the DSC,SEM and IR spectra of the blank resin and the two drugs,it was proved that the drug and the resin were combined chemically rather than the general physical mixture.The release of BDH and LD in different media conditions were investigated.900 mL 0.4 mol·L-1 KH2PO4was used as the dissolution medium in this study,the temperature was 37°C and the speed was 50 rpm,under these conditions,both levodopa and benserazide hydrochloride can be released completely.The investigation of the release mechanism showed that the release of the drug from the resin was dominated by particle diffusion.Part III Preparation of LD/BDH microcapsulesThe drug resin microcapsules was prepared by emulsion-solvent evaporation and the formulation process was screened.The final formulation for levodopa-resinates coating was as follows:Eudragit?RL100 was used as the coating material,the amount of the coating materia was equivalent to 15%of the drug resin mass,and the concentration of the coating materials was 1%,the amount of plasticizer was 18%of the amount of coating material,the preparation temperature was 35°C and the coating time was 4 hours.The benserazide hydrochloride coating formulation was:Eudragit?RS100:RL100=1:1 was used as the coating material,the amount was 18%of the resin mass,the concentration of coating materials was 1%and the plasticizer dosage was 20%of material usage.The preparation temperature was 35°C and the coating time was 4.5 h.The release mechanism of the drug-resin microcapsules was investigated.The release process accords with the first-order kinetics,and the release of the drug from the resin microcapsules was dominated by the membrane diffusion rather than particle diffusionPart IV Preparation of LD/BDH sustained-release suspensionSustained-release suspension was prepared with drug-resin microcapsules and the basic characteristics of suspended particles were determined by measuring the particle size and wettability.Then,the sedimentation volume ratio and redispersibility were used to select the suspending agent,filler,and wetting agent in the prescription.Finally,the sustained release suspension satisfying the requirements was prepared.Part V The pharmacokinetic study of LD/BDH sustained-release suspensionHPLC-UV analysis method for plasma samples of levodopa and benserazid e hydrochloride that meet in vivo analysis requirements was established.The in vivo pharmacokinetic parameters of LD/BDH tablet and LD/BDH sustained-rel ease suspensions were investigated.The Cmax of the two dosage forms of levod opa was 13.479?g·m L-1 and 5.837?g·m L-1,respectively.The Tmax was 0.75h and 3h,respectively.The Cmax of BDH was 3.698 and 1.816?g·m L-1,resp ectively.The Tmax was 1.25h and 4h.The AUC0-24 concentrations of LD in ord inary tablets and sustained-release suspensions were 32.053 mg·L-1·h and 31.003mg·L-1·h,respectively.The relative bioavailability of LD in the sustained relea se suspensions to the tablets was 96.71%.The AUC0-24 concentrations of BDH in ordinary tablets and in the sustained-release suspension was 12.209 mg·L-1·h and 11.091 mg·L-1·h,respectively.The relative bioavailability of BDH in the s ustained-release suspension to the tablets was 90.84%. |
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