Ginkgo Biloba Extracts Self-emulsifying Drug Delivery Systems And Interactions Of Ginkgo Biloba Extracts-drugs

Ginkgo biloba extracts (GBE) have become a widely used herbal remedy for increasing cognitive function in elderly people in the USA, Europe, Japan and many other countries. The primary active components of GBE include 5-7% terpene lactones (ginkgolides and bilobalide) and 22-27% ginkgo flavonol glycosides (e.g., the flavones quercetin, kaempferol, and isorhamnetin). The dissolution and bioavailability of the primary active components from the oral solid preparations of different Ginkgo biloba brands were obviously different and irreproducible, due to the lower solubility of the active components. Self-emulsifying drug delivery systems (SEDDS) are homogeneous mixtures of oils, surfactants and cosolvent, which are emulsified in aqueous media under conditions of gentle stirring and digestive motility that would be encountered in the gastrointestinal tract. It was found that SEDDS could efficiently improve oral absorption of the sparingly soluble drugs by rapid self-emulsification and subsequently dispersion in the absorption sites. GBE needs long-term administering medicine to the patients, especially to elderly patients, for treatment and prevention cerebrovascular diseases. The interactions of GBE and other drugs may occur in all probability in the clinic. So the main purpose of the present study is to prepare SEDDS for improving oral absorption of GBE and to investigate the interactions of GBE and drugs. The results will provide theory bases for clinical administration and prevention of side effects.In the pre-formulation study, the solubility of GBE in 1,2-propanediol and glycerol was higher than other chose vehicles at 25℃. The methods of content and dissolution determination for the active components of GBE were developed and validated. The flavonol glycosides were determined after hydrolyzing by HPLC-UV for content and dissolution. The terpene lactones were determined by HPLC-ELSD and HPLC-ESI-MS for the contents and dissolutions, respectively. Pseudo-ternary phase diagrams were constructed to identify the efficient self-emulsifying region using Miglyol 812 and ethyl oleate as oils, 1, 2-propanediol as cosolvent, Tween 80 and T₅₀C₅₀(50ï¼…Tween 80-50ï¼…Cremophor EL35) as emulsifiers. For both systems, the self-enulsifying region was larger when ethyl oleate as oil than Miglyol 812. The mixed surfactant T₅₀C₅₀ increased the self-emulsifying region slightly comparing with Tween 80 at the same weight level. We investigated the effects of temperature, flow shape, pH and volume of media on the self-emulsifying efficiency. At last, the conditions of 37℃, low speed and diluting with 500-fold volume of the distilled water were used for evaluating the efficiency of self-emulsifying. GBE did not affect the self-emulsifying region, but prolonged self-emulsifying time and increased the droplet size comparing with the blank vehicles. Optimum formulation for in vitro dissolution and bioavailability assessment consisted of 45ï¼…T₅₀C₅₀, 45ï¼…ethyl oleate and 10ï¼…1, 2-propanediol. The content of GBE was fixed at 12.5ï¼…w/w of the vehicle. The in vitro dissolution rates of the active components of GBE from optimum SEDDS were faster than those of the GBE tablets. The dissolution of SEDDS at 20 rain was more than 90ï¼…, and the dissolution of tablet at 20 rain was less than 40ï¼…. The stability of GBE SEDDS was good in the accelerated test and under room temperature.A sensitive and selective method using HPLC-ESI-MS was developed for the quantification of bilobalide and ginkgolides in canine plasma. The lower limit of quantification (LLOQ) of the method was 2.5 ng/ml for ginkgolide B and 10.0 ng/ml for bilabolide, ginkgolide A and ginkgolide C. The accuracy of the method was within 15ï¼…of the actual values over a wide range of plasma concentrations. The intra-day and inter-day precision was better than 15ï¼…(R.S.D.). The plasma profiles of ginkgolides and bilobalide in dogs following oral administration of tablets and self-emulsifying formulation of GBE at a single dose of 800 mg (3BE were investigated. The short T_max values of SEDDS for all three tested components showed the fairly rapid onset compared to the conventional tablets. The marked differences were also observed for the C_max. The C_max of SEDDS increased 44.8ï¼…, 52.4ï¼…and 44.4ï¼…for bilobalide gikgolide A and B compared to the conventional tablets, respectively. And the AUC_0-10h of SEDDS was increased significantly comparing with the conventional tablets. The relative bioavailability of bilobalide, ginkgolide A and ginkgolide B was 162.1±42.5ï¼…, 154.6±65.3ï¼…and 155.8±26.8ï¼…, respectively. These data clearly demonstrate the utility of SEDDS in improving the rate and extent of oral absorption of GBE. The analysis variance, two-one sided tests and (1-2α) confidence interval analysis of main pharmacokinetic parameters showed that the absorptions of bilobalide, ginkgolide A and B for SEDDS and tablets were not bioequivalence.This study attempted to investigate the effect of GBE on the pharmacokinetics of theophylline, a cytochrome P450 (CYP) 1A2 substrate and an important therapeutic agent with narrow therapeutic window (5～20μg/ml) used for the treatment of asthma. GBE (10 or 100 mg/kg, p.o.) or water (control group) was given to rats (6 rats for each group) for 5 consecutive days and on the sixth day theophylline (10 mg/kg) was administered either orally or intravenously. The results showed that pretreatment of rats with GBE resulted in an increase in the total clearance of theophylline of about 30 percent (GBE 10 mg/kg, p＜0.05) and 70 percent (GBE 100 mg/kg, p＜0.01) compared with the control group after intravenous administration of theophylline (10 mg/kg). After pretreatment with GBE (100 mg/kg), the AUC_0-24h of theophylline was reduced by 40ï¼…following intravenous administration and by 38ï¼…following oral administration. These results demonstrated that GBE pretreatment increased CYP1A2 metabolic activity and the clearance of theophylline in rats.The aim of this study is to investigate the effects of GBE and the active components of GBE on the transport activity of P-glycoprotein (P-gp) in the rat small intestine. The efflux of P-gp substrates from rat everted sac in the absence or presence Of verapamil, GBE, rutin, quercetin or terpene lactones was measured. Fexofenadine and celiprolol were used as P-gp substrates. Verapamil and the quercetin inhibited the efflux from the intestine of the two drugs tested. GBE, rutin and terpene lactones did not affect the efflux of fexofenadine and celiprolol in the intestine.