Design And Evaluation Of Self-Microemulsifying Drug Delivery Systems (SMEDDS) And Solid-SEDDS Containing Vinpocetine

Vinpocetine is the primary drug to improve the circulation of brain vessel.The dissolution and bioavailability of vinpocetine were obviously different and irreproducible, due to the lower solubility in gastrointestinal fluids which restricts its clinical application. The objectives of our researches are to improve its bioavailability by self-emulsifying drug delivery system（SEDDS） and self-microemulsifying drug delivery system （SMEDDS） and to prepare a series of liquid and solid self-emulsifying and self-microemulsifying formulations that have different release characteristics.The results proved to be valuable for the investigation and development of such dosage forms.To prepare a SEDDS and SMEDDS and evaluate their in vitro properties,first of all, the HPLC analytic methods were established.The physical and chemical properties of vinpocetine were investigated.The solubility of vinpocetine in solutions decreases with respect to the increase of pH value because it is a weak base（pKa=7.31）,but would not be significantly changed when pH>7.0.The logP increases quickly with the pH value of the water phase（pH2.0^pH8.0）,but would slowly changed in the range of pH 6.0-8.0. the logP in water was 3.13±0.10.The balance solubility of vinpocetine in different oil phase,surfactant and cosurfactant were assayed.Ternary phase diagrams were constructed.The optimal SMEDDS were obtained by comparing the self-emulsifying and self-microemulsifying domain and by the evaluation of the resultant emulsion’s appearance.The optimal SMEDDS was Ethyl Oleate,Solutol HS15,Transcutol P.The effects of oil,surfactant,cosurfactant,Km,and drug on vinpocetine SMEDDS were then investigated.D-optimal methodology was utilized to optimize the ratio of these vehicles.The Caco-2 cell line was used to investigate the cellular transport of vincepotine and vinpocetine SMEDDS.Under the experimental conditions,SMEDDS can significantly improve the drug cellular transport and absorption when comparing to the vinpocetine solution（P<0.05）.The Papp of SMEDDS is 1.290×10^-3,which is significantly higher than the control group,that is 0.5089×10^-3（P<0.05）.It is suggested that SMEDDS could significantly improve the cellular transportation of the drug,which will further increase the bioavailability of vinpocetine.To investigate the tissue distribution of self-made SMEDDS,the tissue distribution of Duolikang tablet suspension,microemulsions were investigated after oral administration to rats at a dose of 10mg/kg.SMEDDS could improve the drug distribution at spleen,lymph,blood,decrease drug distribution at kidney,liver which suggest that SMEDDS could reduce the drug accumulation in the liver and kidney.The brain distribution of SMEDDS vinpocetine is significantly higher than that of tablets, indicating that SMEDDS could improve the transport of drug through the BBB,as an aid to the therapy against brain vessel diseases.The liquid SEDDS were made into SEDDS pellets by extrusion/spheronisation technique by using Gum Acacia as adsorbent,microcrystalline cellulose as fillers and sodium chloride as osmotic active agent.The optimized SEDDS pellets was prepared: in which the self-emulsifying ingredient:Gum Acacia:MCC:NaCl ratio was 20:14:14: 2.The extrusion speed was 30rpm,the spheronisation speed was 800rpm,and the spheronisation time was 5min.The self-emulsifying time was between 20-30 min,and the mean droplet size and zeta-potential of the resultant emulsion were 317.1nm and -1.85mv,respectively.The dissolution behavior of vinpocetine from SEDDS pellets exhibited the independence of the kind of medium.Differential Scanning Calorimeter（DSC） was used to investigate the physical characterization of drug in solid SEDDS pellets.The results showed that vinpocetine was amorphous in dosage form.A pH-dependent gradient-release pellet system was investigated by using HPMC and various methacrylic acid copolymers aqueous systems as coater,respectively.For the pellets with a 30%Eudragit L30D55,Eudragit FS30D coating level,no VIN was delivered in 0.1mol/L HC1 medium within 3hours,but they would start release at pH6.5 and about pH7.6,respectively.The above three kinds of coating pellets were designed to start release drug in stomach,duodenum and jejunum or ileum,respectively.To investigate if the SMEDDS and SEDDS pellet could improve the bioavailability, the pharmacokinetics of Duolikang tablet,SMEDDS and SEDDS pellet was carried out. The C_max of Duolikang tablet,SMEDDS and SEDDS pellet were（110.340±8.715）, （110.614±l0.385）、（242.296±41.7）ng/mL;the t_max of Duolikang tablet,SMEDDS and SEDDS pellet were（1.667±0.258）,（2.167±0.258）、（2.083±0.376）h;the AUC_（0-t） of Duolikang tablet,SMEDDS and SEDDS pellet were（349.155±37.813）、（630.942±41.616）、（476.937±20.374）ng/mL·h.The results indicated the oral bioavailability of SMEDDS and SEDDS pellet were improved significantly.Compared with commercial tablet,the relative bioavailability of SMEDDS and SEDDS pellet were （174.2±17.3）%and（149.8±23.4 ）%,respectively.