Preparation And Characterization Of Nano-Micro Composite Particles Of Vinpocetine

Vinpocetine (VIN) is used as a cerebral vasodilator, which improves the utilization of oxygen by the cerebral cells and protects the brain cells against ischaemic anoxia. It is now widely used for the treatment of chronic cerebral vascular ischemia, acute stroke, senile cerebral dysfunction and Alzheimer's disease. However, VIN is a poorly water-soluble drug and has a remarkable first pass effect. Therefore, there is a need to enhance the dissolution rate and its oral bioavailability. In order to improve the bioavailability of water insoluble drugs, it is better to process the drug particles into nano-range.Nanomedicine possesses some potential advantages, such as smaller particle size, more active sites and better adsorption capacity. Therefore, the engineering and broadly application of pharmaceutical nanoparticles are the primary research fields. In this study, liquid precipitation method, including reactive precipitation process and anti-solvent re-crystallizationprocess was used to obtain composite particles of vinpocetine. In addition, we combinedliquid precipitation method with high pressure homogenization (HPH) method to prepare ultrafine particles of vinpocetine.In this study, reactive precipitation process combined with spray-drying method was employed to prepare small and uniform composite particles of vinpocetine. In the process, HCl aqueous solution was used to dissolvethe raw drug and hydroxypropylmethylcellulose(HPMC) was chosen as a stabilizer to inhibit the particle growth and control the particle morphology. Theeffects of HPMC concentration, acid/alkali volume ratios, precipitation temperature and stirring speed on theparticle size and morphology of VIN were investigated. The particle size exhibited a decrease tendency with the increase of HPMC concentration, and stirring speed, but increased with the improving of acid/alkali volume ratios and temperature. Under the condition that drug concentration was 10 mg/ml, HPMC was used as stabilizer (0.2 wt%), acid/alkali volume ratios was 1:10,system temperature was 5℃, stirring time 5 min and stirring speed was 10000 rpm,VIN nanoparticles with a mean sizeof 130 nm were successfully prepared in the slurry.Raw drug and the composite VIN particlesprepared via spray drying were characterized by XRD, FTIR, BET and DSC. The experimental results indicated thatthe composite VIN particles kept the same crystallization with the raw drug.More importantly, the dissolution rate of the compositeVIN particles was markedlyimproved owing to a decreased particle size and an enlarged specific surface area.Meanwhile, the method combined anti-solvent re-crystallization process with high pressure homogenization technology was employed to prepare ultrafine vinpocetine.The effects of experimental parameters, such as solvent and anti-solvent systems, surfactant types and concentrations, stirring time and operating parameters of high pressure homogenization on the morphology and size of vinpocetine particles were investigated in detail. The particles obtained under optimal conditions were characterized.The experimental results showed that the particles obtained from the systems of single solvent and water were at the micron scale and nonuniform. When the volume ratios of tetrahydrofuran (THF)to isopropanol(IPA) were 5, smaller and slender VIN particles were prepared. In addition, this morphology was of advantages in obtaining smaller and uniform particles via combining anti-solvent re-crystallization process with high pressure homogenization technology. In the co-solvent system, polyvinylpyrrolidone (PVP) was chosen as a proper stabilizer to inhibit the particle growth and control the particle morphology.When PVP was used as stabilizer (0.2 wt%), THF and IPA as co-solvent (5:1),drug concentration was 10 mg/ml, system temperature 20℃,volume ratio of co-solvent to water 1/10, stirring time 5 min, bar-shaped particles could be got in slurry.Then the slurry was homogenized under the pressure of 700 bar, and the particles were crushed into elliptic particles with the size of about 1μm after 15 cycles.The particle size exhibited a decrease tendency with the increase of homogenization cycles. However, after 15 cycles, the particle size reached a minimum.Raw drug and the ultrafine VIN particlesprepared via directly spray drying of the suspension, were characterized by XRD and FTIR. The results showed that the ultrafine VIN was crystal and the ultrafine VIN particles kept the same crystallization with the raw drug. In addition, the as-prepared VIN had the same molecular structure as raw drug.During the 45 min dissolution testing period, only 7.2% of raw VIN was dissolved, while about 60% of ultrafine VINpowder was released.