Study On Transdermal Drug Delivery Systems Of Rivastigmine

Rivastigmine is one of the most common drugs for the treatment of Alzheimer’s disease and moderate or mild dementia that related to Parkinson’s disease. The curative effect of rivastigmine is definite, but oral administration may cause gastrointestinal side effects. Rivastigmine is suitable for transdermal drug delivery, because the oral dose is small, half-life is short, and bioavailability is only36%. Rivastigmine transdermal patch is already on the market, but the preparation process is complicated, the production cost is expensive, and use of patch may lead to skin irritation. To overcome the disadvantages of patch, transdermal metered-dose spray film (MDSF) of rivastigmine was studied. Ultrasound was used to increase the transdermal delivery of rivastigmine, and the promoting effect to rivastigmine and rivastigmine tartrate was investigated.The physicochemical properties are the main factors that influence skin transdermal flux. Prediction of the skin transdermal flux by the physicochemical properties and molecular structure parameters could be helpful to the design of transdermal drug delivery system. Although some mathematical models had been estabilished for the prediction of skin permeability, the prediction results were not ideal. Molecular weight, amount of hydrogen donor, amount of hydrogen acceptor, partition coefficient, topological polar surface area, molar volume, melting point of47compounds from articles were selected as input parameters, transdermal fluxes of compounds were selected as output parameter. BP neural network was established using Matlab software. The prediction ability was compared with other7mathematical models. The result indicated that BP neutral network predicted transdermal permeability preferably, the computed results were better than the other7mathematical models. These models were used to predict human skin transdermal flux (logJmax) of rivastigmine.In vitro transdermal experiment is necessary for developing transdermal drug delivery system. The choice of skin has great influence on the significance of experimental result. To investigate the percutaneous permeability of rivastigmine and rivastigmine tartrate, through different animal skins in vitro, mouse, rat, rabbit, miniature pig and sucking pig were selected as experimental animals. Epidermis structures of fixed detersile abdominal skins were observed by transmission election microscopy (TEM). The transdermal experiments in vitro were carried on modified Franz diffusion cells.20%PEG400physiological saline solution was used as receiving media. The concentrations of drug in receiving fluid were determined by RP-HPLC. The steady transdermal flux and cumulative permeation quantities in24h were calculated. The relative transdermal fluxes of rivastigmine through different animal skins was miniature pig:porket:rabbit:rat: mouse=1:0.83:1.47:2.01:2.55. The relative transdermal fluxes of rivastigmine tartrate through different animal skins was miniature pig:porket:rat:rabbit: mouse=1:0.13:1.30:1.71:8.31. The permeation coefficients of rivastigmine through different animal skins were34-to695-fold higher than rivastigmine tartrate. The result indicated that great differences of transdermal permeability were existed among different animals. These differences were also related with properties of drugs. There was directive significance of the study results for the choice of appropriate animal skins.Metered-dose spray film (MDSF) of rivastigmine was investigated. Polymer dissolution rate, solvent properties, spray ability and film-forming properties were used as indexes for selecting the suitable polymer. Polymer methyl acrylic acid-acrylate copolymer A, B, C were suitable for preparing MDSF. The influences of polymer type, plasticizer and penetration enhancer on percutaneous permeability of rivastigmine were investigated by in vitro transdermal experiments. MDSF prepared by methyl acrylic acid-acrylate copolymer A had the biggest transdermal flux of rivastigmine. The plasticizer triethyl citrate, the penetration enhancer isopropyl myristate, menthol, N-methylpyrrolidinone, azone, oleic acid all decreased the transdermal flux. The best formulation was screened out.To evaluate the relative bioavailability of MDSF, a method of determination of rivastigmine in rat plasma using HPLC with UV detection was established. This method was suitable for the determination of rivastigmine in plasma sample, because the pretreatment of sample was simple and the specificity, precision and recovery were all excellent. The relative bioavailability of MDSF was investigated using rat as model.2.4mg rivastigmine tartrate was administrated orally as control.100μL of spray liquid contain1.5mg rivastigmine was given on the detersile abdomen of rats. Blood level of rivastigmine was determined at the setting times, and AUC was caculated. The relative bioavailability of MDSF was567%. The results indicated that MDSF can be taken as a new transdemal delivery systerm of rivastigmine..The penetration enhancements of low frequency ultrasound to rivastigmine and rivastigmine tartrate were investigated. The saturated solution of rivastigmine and2%rivastigmine tartrate-water solution were prepared.20%PEG400solution was used as receiving fluid. The promotion effect of20kHz ultrasoun was evaluated by in vitro transdermal experiment. The enhancing effect of ultrasound to rivastigmine salt was better than rivastigmine under the same condition. The enhance rate of transdermal fluxes were raised from9.15fold to84.79fold, when the working time was fixed as a constant and the intensity of ultrasound was raised from6W to33W. The enhance rate of transdermal fluxes were raised from9.15fold to42.85fold, when the the intensity was fixed as a constant and the working time of ultrasound raised from3min to30min. The result indicated that ultrasound could enhance the transdermal delivery of water-soluble drug.In order to evaluate the effect of practical application of phonophoresis, ultrasonic couplaint incorporating rivastigmine salt was prepared. The influence of ultrasound to the percutaneous permeability of rivastigmine ultrasonic couplaint was investigated in vitro. The ultrasound power was fixed as4W and ultrasonic time was set for10s in every40s. When the accumulate ultrasonic time was2.5min, the transdermal flux and24h accumulative penetration amount increased to3fold of the control. Compared to the control group, the relative bioavailability of phonophoresis group was295%. This research provided initial dates for phonophoresis.