| Verapamil hydrochloride（VRP）is a ramification of papaverine.VRP is a calciumchannel blocker and is the preferred drug for the treatment of paroxysmal ventriculartachycardia.VRP is widely used for treatment of essential hypertension in clinical. Atthe present time, the clinical application of VRP are mainly oral administration andinjection, but oral administration is subjected to a highly first-pass effect, with a lowsystemic bioavailability（20%-35%）;Injection is reported to have a short plasmahalf-life, a high clearance rate,repeated administration and poor compliance, thesedefects are limiting the widely used in clinical. Therefore, it’s become a big problemfor the pharmaceutical workers, to develop a new dosage form and improve theclinical application of VRP.Objective:The present studies concern the preparation of VRP microemulsiongel,in order to overcome the first-pass effect of oral administration, short half-life andhigh clearance of injection administration, the administer drug through skin, to avoidfirst-pass effect of liver、increase the bioavailability of drug、maintain steady stateplasma concentration and improve patient compliance.Method:1To determine the UV absorption wavelength of VRP, by investigatingthe methods of standard curve,repeatability,stability, specificity and recovery, toensure to use HPLC to determine content.2By using the method of phase inversion emulsification method to preparedVRP microemulsion, using drop water method to draw the pseudo ternary phasediagram,to study the effect of each component to microemulsion formation. thepreliminary prescription and preparation technology of blank microemulsion andVRP microemulsion were determined. Prescription and process were optimized aswell as,the physical and chemical properties of microemulsion was investigated.3To determine the preparation method of VRP microemulsion gel,choose theappropriate carbomer substrate concentration.And to investigate the physical and chemical properties. By using in vitro rat skin to investigate in vitro transdermalmethod and percutaneous permeability.4By using HPLC to establish the analysis method of VRP microemulsion gel inrats,to study the pharmacokinetics and bioequivalence of VRP tablet and VRPmicroemulsion gel in rats.5Using Sprague-Dawley rats as model animal to conduct skin irritation test, todeterminate the skin irritation of blank gel and VRP microemulsion gel.Results:1The concentration of VRP ranged from2to256μg/mL had a goodlinear relation, A=24.298C－14.221,R2=0.9999.The recovery and precision of8,32,128μg/mL three concentrations conform the requirements of methodology.2The optimal prescription of VRP microemulsion: surfactant: tween80;cosurfactant: isopropyl alcohol (surfactant:cosurfactant=3:2);oil: IPM (oil phase:mixed surfactant=1:9);80%water,7.8%VRP. The appearance of VRP microemulsionwas showed that blue opalescence, translucent. The average particle size was68.55nm, PDI was0.193, zeta was-7.1mV, the microemulsion sizes were round orapproach round by transmission electron microscopy.3In vitro percutaneous penetration experiment results showed that: the in vitrotransdermal effect of VRP microemulsion gel was better than aqueous microemulsiongel. The enhancement ratio of VRP microemulsion gel was4.88. In vitro transdermalmodel fitting results showed that the in vitro percutaneous of VRP accorded withfirst-order kinetic model.4VRP intragastric administration and percutaneous administration wereconformed to first-order model, the weight were1/C/C. The AUC, Cmax andelimination half-life were111.10±16.99μg/mL/h、2.38±0.10μg/mL and31.33±6.14h;the AUC, Cmax and elimination half-life of commercially available VRP tablets were27.19±1.64μg/mL/h、4.43±0.27μg/mLand3.39±0.35h, and the relative bioavailabilityof VRP microemulsion was174.24%.5We had conducted skin irritation experiment to12rats according to the skinirritation safely evaluation standard, the experimental results showed that blank geland VRP microemulsion gel did not appear obvious swelling and erythema in the experiment process.Conclusion: The content, stability, specificity, repeatability, precision andrecovery measure results of VRP’s were up to the determination of requirements, inline with the requirements of methodology. The appearance of VRP microemulsionwas good, particle size also conformed to the requirements of the microemulsion, andthe stability was good; the appearance of VRP microemulsion gel was good, thepreparation was stable, and in vitro permeation effect was better than aqueoussolution gel. VRP microemulsion improved the bioavailability, prolonged the half-lifeand reduced the clearance rate, compared with oral preparations. The skin irritationexperiments results showed that VRP microemulsion had not obvious irritation to theskin. |
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