Study On The Preparation Of Albendazole Solid Dispersion And Its Pharmacokinetics In Dogs

Albendazole(ABZ) is a benzimidazole antiparasitic agent. ABZ falls into the BSC classⅡcategory as has high permeability and low solubility. Because of its low aqueous solubility, it is poorly and erratically absorbed following oral administration, limiting the administration routes.To enhance the dissolution of ABZ, this paper adopts the solid dispersion technology, preparation of albendazole solid dispersions. Solids dispersions(SD), which are defined as molecular mixtures of poor water-soluble drugs and hydrophilic carriers, have been proposed as alternative for improvement of dissolution rate of this kind of drugs. Because SD can reduction of particle size and change the crystal structure. Then, to determine the bioavailability of albendazole through pharmacokinetic experimentThis paper established a method of UV to determine the in vitro release of ABZ solid dispersion. Then with PEG4000, PEG6000, P188 for single carrier, respectively, by using the melting method and solvent- melting of albendazole prepared by solid dispersions, by in vitro dissolution test, select the best method of preparation of single carrier. Using the melting method according to PEG6000 and P188 at the proportion of 1:1, 1:2, 1:4, 1:8, 2:1,4:1, 8:1, preparation of albendazole solid dispersions, albendazole and carrier for 1:5, by in vitro dissolution test screening the best proportion. Then according to the proportion of albendazole and carrier of 1:1, 1:3, 1:4,1:5, and the preparation of solid dispersions, by in vitro dissolution test, screening the best dosage of joint carrier. Finally, do the phase identification.The results showed that when PEG6000 and P188 at the ratio of 1:2, the dissolution rate of solid dispersion can reach 89.23%. When the proportion of albendazole and joint carrier is 1:3, the dissolution rate of solid dispersion can reach 94.17%, compared with physical mixture and pure drug can significantly improve its dissolution. Phase solubility study indicated that the solubility of ABZ almost linearly increased as the concentration of PEG6000, P188 and its combination respectively, and the co-carrier had shown higher solubility. Fourier transform infrared(FTIR)spectroscopy showed the stability of ABZ and the absence of a well-defined ABZ-PEG6000-P188 interaction. X-ray diffraction(XRD) studies revealed the amorphous state of ABZ in SDs with PEG6000 and P188 which was further confirmed from scanning electron microscopy(SEM)studies. In vitro dissolution studies showed a significant enhance in dissolution rate when PEG6000 and P188 were used in combination at the ratio of 1:2.In this study, the pharmacokinetics and bioavailability of ABZ solid dispersion in dogs werestudied comparing with tablets. The establishment of a high performance liquid chromatography tandem mass spectrometry method for determining dog plasma concentration of albendazole and its metabolic products. Plasma samples by using the method of liquid-liquid extraction processing with dichloromethane, and the internal standard phenacetin were resolved in a C18 column using the mobile phase acetonitrile-water acidified with 0.1% acetic acid. Positive electro spray ionization was employed as the ionization source. Through the methodology validation of this method is simple and feasible. The detection limits of 0.5 ng/m L, 1 ng/m L and 1 ng/m L for ABZ,ABZSO, and ABZSO2;The quantification limits of 1 ng/m L, 2.5 ng/m L and 2.5 ng/m L.In the pharmacokinetics tests, The AUC(0-∞) of ABZ、ABZSO、ABZSO2 in solid dispersion were(424.48±35.17) 、(6699.03±889.18) 、(3469.42 ±649.39) μg/L*h, The AUC(0-∞) of ABZ 、ABZSO 、 ABZSO2 in commercial tablet were(188.66 ±33.43) 、(3536.07 ±630.62) 、(1049.55±172.15) μg/L*h. The relative bioavailability of ABZ solid dispersion tablets were ABZ: 225.00%,ABZSO: 189.45%, ABZSO2:330.56%. Therefore albendazole solid dispersion can significantly improve its bioavailability in vivo, which holds the promise of becoming a new preparation for clinical in the future.To sum up, the optimum preparation technique of albendazole solid dispersion are as follow:PEG6000:P188=1:2, ABZ: carrier=1:3 and using the melting method. The solid dispersion can significantly enhance the dissolution rate. In vivo test, the preparation of solid dispersion can significantly improve its bioavailability.