Study On The Controled Drug Release Of Water-soluble Drugs With The Carrier: Polymethacrylates

The aim of this paper is preparing the water-insoluble drug metformin hydrochloride (MH)-loaded microspheres and sustained-release matrix tablets , using polymethacrylates as the matrices. The microspheres and matrix tablets obtained were characterized by SEM, DSC and XRD and in vitro drug release was studied as well.Major work and the result of this paper are:1.Preparation of MH-loaded Eudragit○R RS PO(Eu RS) microspheres using W1/O/W2,W/O1/O2,S/O1/O2 double emulsion solvent evaporation method. Because MH was highly soluble in water, the entrapment efficiency of microspheres prepared by W/O/W double emulsion solvent evaporation method was very low. Increasing the polymer concentration and introducing NaCl into outer water phase resulted in no increase in the entrapment efficiency, and the maximal entrapment efficiency is about 5%.Consequently, W/O1/O2 double emulsion solvent evaporation method was utilized and similar results were observed, the droplets were apt to broke and most of MH was diffused into water phase might be responsible for these results. In order to avoid MH loss during the process of solvent evaporation, We investigated S/O1/O2 emulsion solvent evaporation method. the entrapment efficiency of microspheres prepared by S/O1/O2 emulsion solvent evaporation method was improved. Changing polymer /MH ratio,increasing the amount of acetone﹑Span-80 and magnesium stearate, the entrapment efficiency of microspheres was about 99% in these cases.The S/O1/O2 type microspheres showed a significant burst effect (about 50%),with 95% of the drug released within 2h of the test period.The initial burst was attributed to release of the drug from the surface regions of the microspheres.2.Based on W1/O/W2,W/O1/O2,S/O1/O2multiple emulsion solvent evaporation method, the protected oil phase introduced between MH and polymer sustained release layer. The protected oil phase covered on the surface of MH power which can slowdown the release medium infiltration, and solved a rapid burst release of the drug and low entrapment efficiency during prepareing water soluble drugs containing microspheres. The S/O1/O2/O3 type multiple emulsion solvent evaporation method has advantages as follow: Entrapment efficiency was achieved approximately 100%.The S/O1/O2/O3 type microspheres successfully prevented the leakage of water soluble drugs, and achieved evident drug retarding property in vivo. These results was attributed to the barrier effect of the vegetable oils phase which separated the MH power from the EtOH phase.3. In the same time, we considered decreasing the solubility of MH. Triacetyl-β-cyclodextrin (TA-β-CD),a hydrophobic CD derivative practically insoluble in water, were prepared to evaluate their suitability for the development of a sustained-release dosage form of the drug. MH was set into TA-β-CD molecular cavity as guest.This inlusion complex supermolecular system can decrease guest's solubility and soluable velocity. The MH/TA-β-CD products were selected as the best candidates for a suitable prolonged-release oral dosage form of MH. Equimolar MH/TA-β-CD solid compounds were obtained by different techniques, i.e. kneading, Co-evaporating and cosolvent lyophilization, in order to investigate and compare their effectiveness and influence on the physical chemical properties of the final products. Differential scanning calorimetry and X-ray power diffractometry were used for the solid-state characterization of the different MH/TA-β-CD systems, whereas their in vitro dissolution properties were determined according to the dispersed amount method. According to the results of solid-state studies, the ability of the different preparation methods to promote effective interactions between drug and CD varied in the order: cosolvent lyophilization> co-evaporating> kneading> physical mixture. The same effectiveness rank order was observed also in dissolution studies. In fact the time to dissolve 100% varied increased from 1 min,for pure drug, to 3,60,240 up to 420 min for physically-mixed, keaded, co-evaporated, cosolvent lyophilization products, respectively. The resultant ternary complex could be subsequently incorporated in hydrophobic matrix tablets to achieve zero-order drug release systems.