Hot Melt Extrusion Technology Preparation Of Biphenyl Double Ester Solid Dispersions

Purpose of this article was to apply hot-melt extrusion in preparing solid dispersion (SD) of water insoluble drug bifendate (DDB) and investigate the improvement of dissolution and bioavailability in beagle dogs.HPLC and UV methods were established to determine the DDB concentration in vitro. PH=1.2 HCl solution was selected as the dissolution medium, and the method was also established. S-630, Eudragit EPO, PEG6000 were selected as the hot-melt carriers with good compatibility and thermal stability after calculating of the solubility parameter and TGA test.SDs were first prepared with the three carriers at the same drug content level 20%, and the dissolution test were processed together with crude drug and commercial dripping pills as the references. Comparing to the references, the drug dissolution were greatly improvement in SDs. Drug release percents of the physical mixtures with the same drug content were insufficient 1%。The dissolution improvement effects of the SDs prepared through hot-melt extrusion with different drug contents as well as different operating temperatures were investigated in all the three carriers. The dissolution characteristics were:Drug dissolution rate degraded from 35% to 15% as the drug contents increased from 2 to 36% in DDB-PEG6000 systems. Drug dissolution was obviously better in the SD prepared at 180℃then at 60℃,100℃,140℃, and there was nearly no difference between the latter three operating temperatures. It was a binary partial solid solution. The dissolution of the drug was more than 90%, when the drug contents no more than 10% in DDB-S-630 systems, which was degraded to 20% as the drug contents increased to 30%. When the operating temperature below the drug melt-point 180℃, drug wasn’t well-distributed in the carrier.Dissolution rate didn’t decrease as the drug increase from 5% to 40%, but it decreased as the temperature fell below 180℃. But the foreign substance increased as the temperature raised, high temperature was prone to the drug degradation. And it was the case of DDB-Eudrdgit EPO system.The stability DDB-S-630 and DDB-Eudragit EPO systems were investigated. Appearance, drug content and dissolution were used to examine the physicochemical properties of the SDs during the storage period. The result was that DDB-Eudragit EPO system was more stable than DDB-S-630 system, and so was the case high drug content to low in both systems.DDB-Eudragit EPO system (drug content 20%) was selected with better stability for post-processing. Taken lastose as filler,10% starch paste as binder, wet granule method was used to prepare tablet containing DDB SD. DSC and X-ray power diffraction analysis disclosed that there was no crystalline bifendate in the tablet, dissolution of the drug from the tablet was above 90%.HPLC method was established to determine DDB concentration in beagle plasma. Taking commercial dripping pills as the reference, the bioavailability of T1(DDB-S-630 system drug content 10%) and T2 (DDB-Eudragit EPO system drug content 20%) were investigated, and relative bioavailability was 87.8±51.8%å'Œ110±62%.