Study On Preparation Of Solid Dispersion And Micro - Skeleton Sustained - Release Tablets By Hot - Melt Extrusion

In view of the current situation of pharmaceutical technology, gingkolides was developed new drug delivery systems by using a novel pharmaceutical technology for its biopharmaceutical properties of poor solubility, good permeability and short half-life. This study is going to prepare solid dispersions in different formulations via hot-melt extrusion of Ginkgo biloba extracts; Then X-ray diffraction, differential scanning calorimeter, Fourier transform-infrared spectroscopy are used to study the drug disperse state in carrier matrix. We studied the dissolution profiles of total flavonoids (TFs) by HPLC-UV and total terpene lactones (TTLs) by HPLC-ELSD, respectively. Ultra-performance liquid chromatography tandam mass spectrometry with electrospray ionization (ESI) source was used for determination of seven bioactive compounds in rat plasma. The novel solid dispersion of GBE prepared using hot-melt extrusion can increase the dissolution rate and bioavailability of TFs and TTLs. Then we prepared Mini-matrices in different formulations via hot-melt extrusion. And we study the influences of drug loding, the content of release modifier, the length and diameter on the release profiles of Mini-matrices. Moreover, the spatial distribution of the active pharmaceutical ingredients (API) of mini-matrices is determined by NIR-CI. Hot melt extrusion technology was used to prepare solid dispersions of ginkgo biloba extract and Mini-matrices has the potential to get practical application, the technology used in the preparation of new dosage forms of Chinese medicine extracts has the profound significance. Intruduce in detail as following:1. Formulation development and characterization of solid dispersionsThe aim of this study was to improve the dissolution rate and oral bioavailability of Gingkgo biloba extract (GBE) through preparing G. biloba extract solid dispersions (GBE-SD) via hot-melt extrusion (HME). Firstly we prepared the GBE-SD based on Kollidon(?) VA64/Kolliphor(?) RH40 (85:15) spray dried powder. Then physicochemical properties were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR), the results indicated that GBE dispersed in carrier matrix very well.2. The dissolution profiles of solid dispersionsSubsequently, we studied the dissolution profile of total flavonoids (TFs) by HPLC-UV and total terpene lactones (TTLs) by HPLC-ELSD, respectively. The dissolution percentage of TFs and TTLs were improved within 120 min.3. Pharmacokinetic characteristics and bioavailability of solid dispersionsA rapid, reliable, sensitive method was developed using ultra-performance liquid chromatography-mass spectrometry with electrospray ionization (ESI) source for determination of seven bioactive compounds in rat plasma. The method simultaneously detects bilobalide (BB), ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC), quercetin (QCT), kaempferol (KMF) and isorhamnetin (ISR) for pharmacokinetic study. The analytes and internal standard (IS) were extracted from rat plasma by acetidin. Chromatographic separation was achieved on a Acquity BEH C18 column (2.1 mm×100 mm,1.7 μm) with a mobile phase was acetonitrile (A) and water-0.1% formic acid (B) at a flow rate of 0.4 mL/min. A tandem mass spectrometric detection was conducted using multiple reaction monitoring (MRM) and operating in the negative ionization mode. The calibration curve ranges were 5-500,5-500,2.5-250,1-100,1-100,1-100 and 1-100 ng/mL for bilobalide (BB), ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC), quercetin (QCT), kaempferol (KMF) and isorhamnetin (ISR), respectively. Themean recovery of the analytes ranged from 68.11% to 84.42%. The intra- and inter-day precisions were in the range of 2.33-9.86% and the accuracies were between 87.67% and 108.37%. The method was further and implemented to a pharmacokinetic study of G.biloba tablets (GBTs) successfully. The pharmacokinetic parameters of seven compounds after were analyzed using a non-compartment model.Plasma concentrations of the seven compounds were detected up to 48 h after administration, and the pharmacokinetic parameters of the seven compounds were in agreement with previous studies. We studied the pharmacokinetic characteristics and bioavailability in rats by UPLC-MS/MS. The results showed that the Cmax and AUC0-INF of bilobalide (BB), ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC), quercetin (QCT), kaempferol (KMF) and isorhamnetin (ISR) in rats were increased remarkably after oral administration of GBE-SD comparing with oral administration of GBE. These results suggest that solid dispersion prepared by HME could serve as a promising formulation approach to enhance the dissolution rate and oral bioavailability of GBE.4. Formulation development and characterization of sustained release Mini-matricesKollidon(?) SR as a drug carrier and Ginkgo biloba total lactones, were studied by hot-melt extrusion. Powder mixtures containing Kollidon SR were extruded using a twin-screw extruder at temperatures 90℃ for Ginkgo biloba total lactones. The results of X-ray diffraction analysis showed that remained Ginkgo biloba total lactones in an amorphous or dissolved state in the extrudates containing drug up to 5%.5. The release profiles of Mini-matricesThe increasing amounts of Ginkgo biloba total lactones in the hot-melt extrudates resulted in the increase in the drugrelease rates. By adding of Klucel(?) LF as a water-soluble additiveto the hot-melt extruded matrices, an increase in Ginkgo biloba total lactones release rates was obtained. Adjust the diameter and length of Mini-matrices, can increase flexibility the release profiles.6. The spatial distribution homogeneity of API of sustained release Mini-matricesIn this study, the spatial distribution of the active pharmaceutical ingredients (API) of mini-matrices is determined and the spatial distribution has been obtained. In addition, the same NIR-CI allowed its surface distribution to be quantified. Images were processed to extract the target data and calibration models constructed using BACRA method. The distribution of active pharmaceutical ingredients (API) distributed homogeneous in Mini-matrices.