Study On Bioavailability Of Osthole With Cyclodextrin Inclusion And Its Mechanism

The osthole,a coumarin compound,extractes from the Umbelliferae Cnidium monnieri(L.)Cuss.dry ripe fruit Cnidium.In recent years,studies have shown that the osthole can inhibit cardiac antiarrhythmic,dilate blood vessels,promote learning memory,Invigorant ph-armacological,and have obvious effects on the nervous system.cardiovascular system,imm-une system,endocrine system,and so on.Our previous study has shown that the bioavaila-bility of osthole is low.Cyclodextrins,a class of white crystalline compound,found in 1891 by Viliers,are a class by amylose Bacillus produce cyclodextrin glycosyltransferase enzy-me to generate a series of oligosaccharides collectively,by D-glucopyranosyl unit in theα-1,4 glycosidic bond combined mutually chair conformation of the cyclic material,typica-lly containing from 6 to 12 Glucopyranose unit.have an inner hydrophobic and the outer hydrophilic of the hollow truncated cone structure,a variety of organic molecular inclusi-on in the cavity optionally.Common use of significance of α-β-,γ-cyclodextrin,β-cyclodex-trin is the most commonly used.Scholars has developed a variety of β-cyclodextrin deriv-atives in recent years,such as methyl-p-cyclodextrin,hydroxypropyl-β-cyclodextrin.Extensive literature reported that β-cyclodextrin inclused drug can increase its solubility,stability,bi-oavailability,etc.But its not been reported to the mechanism of improvi-ng bioavailability of the drug.In this experiment used three different cyclodextrins(β-cyclodextrin,methyl-β-cyclodextrin,hydroxypropyl-β-cyclodextrin)inclusion Osthole,compared different cyclodextrin cooperation with the impact of bioavailability and absorbed of osthole,preliminary study inclusion affect the bioavailability and absorption mechanism.Saturated aqueous solution prepared by three different inclusion complexes of cyclo-dextrin incluse osthole,by L9(34)orthogonal table design experiments to investigate the in-clusion time,inclusion temperature and cyclodextrin dosage affect largely factors on the r-esult of the inclusion of the three inclusion rate.Which the best inclusion process for P-cyclodextrin inclusion osthole is that inclusion temperature is 40 ℃,inclusion time is 5 h,cyclodextrin dosage molar ratio is 1:1;the best inclusion process for Hydroxypropyl-β-cy-clodextrin inclusion osthole is that inclusion temperature is 50 ℃.the inclusion time is 2 h,cyclodextrin dosage with osthole molar ratio is 3:1;Methyl-β-cyclodextrin inclusion proc-ess is that inclusion temperature is 50 ℃,inclusion time is 3 h and the cyclodextrin dos-age molar ratio is 3:1.The results showed that the(3-cyclodextrin inclusion osthole the o-ptimum mixing temperature is 40 ℃.the optimum temperature for the methyl-β-cyclodext-rin,hydroxypropyl-β-cyclodextrin inclusion is 50 ℃,least amount of β-cyclodextrin inclus-ion has the longest inclusion time.Hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextr-in h-ave an amount larger,the inclusion rate of three different cyclodextrin inclusion osth-ole a-re also differences.The inclusion rate of hydroxypropyl-β-cyclodextrin and methyl-β-cyclo-dextrin inclusion osthole is higher than β-cyclodextrin inclusion.The formation of inclusion complex of osthole was confirmed by SEM,IR and DSC,compared several different inclusion complex to determine the quality of the inclusion c-omplex of osthole.Three characterization methods results show that new images is appear-ed of osthole and three cyclodextrin,is not a simple physical mixing.Determination of t-he solubility prove three cyclodextrin can increase the solubility osthole.Hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin inclusion complex solubility is higher than the sol-ubility of P-cyclodextrin inclusion.The reason may be due to the introduction of hydroxy-propyl and methyl groups destroyed stabilize the hydrogen bonding interactions within th-e β-cyclodextrin molecule,so these two cyclodextrin solubility in water is better than theβ-cyclodextrin.Experiments with in vivo pharmacokinetic model were compared osthole bioavailabil-ity by three cyclodextrin inclusion.The results show that β-cyclodextrin inclusion can slo-w down osthole vivo elimination phase(ie CL),increase in AUC and MRT,The osthole oral bioavailability can significantly increase inclusion by β-cyclodextrin;Hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin cyclodextrin inclusion can reduce osthole Tmax an d CL,significant increase in Cmax and AUC,inclusion can increase the osthole oral absorp-tion,slow down the osthole elimination,thereby increasing its bioavailability;bioavailability of Osthole inclusion by three different cyclodextrin is that:Osthole-β-cyclodextrin inclusi-on complex>Osthole-methyl-β-cyclodextrin inclusion complex>Osthole-hydroxypropyl-β-cy-clode-xtrin inclusion complex>osthole.The everted intestinal sac is used to research of absorption and mechanism of ostho?le by different cyclodextrin inclusion.Experimental results show that the amount of ostho-1e monomer drug absorption is(1.558±0.108)μg,β-cyclodextrin inclusion complex uptake is(2.172±0.121)μg,hydroxypropyl-β-cyclodextrin inclusion complex uptake is(2.067±0.130)μg,methyl-p-cyclodextrin inclusion complex uptake is(2.140±0.153).g at 120 min.Th-ree cyclodextrin inclusion can increase osthole total amount of permeable membrane,have a highly significant difference(P<0.01),which descripted that cyclodextrin inclusion can increase Osthol the permeable membrane ability promote Osthol vivo absorption,thereby increasing Osthol bioavailability.Different cyclodextrin have different ability of promoting osthole absorption,which the absorption by β-cyclodextrin inclusion in promoting is stro-ngest.hydroxypropyl-β-cyclodextrin inclusion role in promoting is the weakest.Stirring the gut sacs experiments(study does not flow to absorb the impact of the unstire water la-yer and mucosal mucus layer osthole)results show that:Stir around the osthole penetrati-on were(1.558±0.108)μg、(2.422±0.313)μg;through the film amount of β-cyclodextrin(2.172±0.121)μg,(2.609±0.211)μg,hydroxypropyl-β-cyclodextrin inclusion complex thro-ugh the film amount(2.067±0.130)μg,(2.416±0.350)μg;through the film amount of me-thyl-β-cyclodextrin inclusion complex(2.140±0.153)μg(2.497±0.248)μg.By comparing t-he data,the results indicate that the unstire water layer is the absorption barrier of osthol-e.Cyclodextrins can promote absorption of osthole through this barrier into the body,and different cyclodextrin have different ability of promoting osthole absorption,the order of the three cyclodextrin promote osthole body absorbed:Osthole-β-cyclodextrin inclusion co-mplex>Osthole-methyl-β-cyclodextrin inclusion complex>Osthole-hydroxypropyl-β-cyclode-xtrin inclusion complex>osthole.The results of this experimental study shows that three different cyclodextrin can in-crease the bioavailability of osthole.Its reasons in addition to increasing the solubility of osthole to make the osthole more evenly distributed in the gastrointestinal fluid and can also promote osthole absorption,Promote absorption of the mechanism is due to a cyclod-extrin inclusion can to promote Osthole through the mucosal layer of the un-stire water layer in the outside of the intestinal wall cells,and better close make Osthole molecules to be absorbed by the intestinal wall cells.This topic investigated the absorption mechanism by valgus intestinal sac model and improved model based on valgus intestinal sac.The cyclodextrin promote drug through t-he flow of the unstire water layer,elaborated reasonable applications of cyclodextrin,a no-vel pharmaceutical excipients.