Studies On Nano-matrix Solid Oral Drug Delivery System For Water Insoluble Drug-fenofibrate

BCS type ? drug have the characters of low solubility and high membrane permeability,thus,solubility and dissolution rate,as well as the contact area and time between drug and gastrointestinal wall,become the key factors that impact its efficacy.Based on this,we designed a new type of solid nano-matrix drug delivery system(NMDDS)with drug highly dispersed in a molecule or amorphous state in a mixture of pH-sensitive polymer and silica with nanostructures.In our research,fenofibrate,which belongs to BCS type II,was chosen as model drug.Nano-porous silica Sylysia~?and non-porous silica Aerosil?were used as nano-matrix material and meantime a kind of polymer was also included to prepare the NMDDS.Through the test of supersaturation stabilizing effect of different polymers,Eudragit?displayed better stabilizing effect than PVP and HPMC.So we chose the pH sensitive Eudragit~?(Eudragit~?L 100-55?Eudragit~?L 100?Eudragit~?S 100)as the polymer carrier in the NMDDS.The nano-porous silica was highly dispersed in the ethanol solution of drug and Eudragit~?,the solvent was evaporated under the vacuum decompression condition and finally obtained the NMDDS with the drug and polymer dispersed within the aperture and/or on the surface of the nano-matrix.The drug dissolution was increased and finally the high bioavailability was obtained.Then,9 NMDDS were prepared,which were designed by an L9(34)orthogonal design.The dissolution and pharmacokinetic behavior in rats were studied.The AUC was set as evaluation index to analyze the impact factor for drug absorption.The dissolution experiment indicated that the drug dissolution was increased as the amount of carrier raised.The range analysis of AUC of 9 different NMDDS showed that the ratio of silica to drug was the most important factor,the type of silica was the second,the ratio of Eudragit?to drug was three,and the type of Eudragit?was the last.The optimal NMDDS was F:S350:EL100-55= 1:3:3.According to this,in the following studies for formulation screening,we fixed the carrier to drug ratio at 3:3:1,changing one type of carrier only in one test to investigate the dissolution and pharmacokinetic behavior.Meanwhile,we also study the formulation with only one type of carrier.The drug dissolution under surpersaturation condition and sink condition were conducted in acidic solution first and then in basic medium.The results indicated that in the surpersaturation condition the NMDDS displayed pH sensitive character,however,in the sink condition,the NMDDS didn't show any pH sensitive character,which maybe affected by the surfactant SDS.Finally,the 0.3%SDS-PBS solution with the pH at 7.4 was chosen as the main release medium to study the release behavior of various formulations.The release rate of NMDDS was much faster than the crude fenofibrate and the commercial product Lipanthly?.The type of Eudragit~?had little effect on drug release.The release of NMDDS made of Aerosil?200 was slower than that of Sylysia?350.The NMDDS made by the combination of Eudragit~?L100-55 and Sylysia?350 showed the best release.The NMDDS made by ordered meso-porous silica has slower release rate than the non-ordered porous silica.The NMDDS made by only Eudragit?or Sylysia?350 has slower release rate than the NMDDS made of the combination of the two.The crystalline rate of FNB in the NMDDS after adding water was slowed down by Eudragit~?,and this result proved the good supersaturation stabilizing effect of Eudragit~?.We compared the oral bioavailability of the optimal NMDDS,crude drug and SMEDDS.The results showed that the NMDDS can significantly increase the oral bioavailability of FNB,and the AUC and Cmax was 5.4 and 5.9 times of that of the crude fenofibrate,2.6 and 1.9 times that of the commercial products,respectively.The bioavailability was equal to the SMEDDS,which was regarded as the best formulation in the oral absortion.In order to validate the optimal formulation,we designed other formulations to investigate the oral bioavailability,including different types of Eudragit or silica and the combination of the two or the sole using one of them.When using only Eudragit or silica as the carrier,the ratio of FNB and carrier was set at 1:6.The NMDDS made of only EL100-55 has similar pharmacokinetic behavior as the optimal NMDDS,except larger SD between rats.The oral bioavailability of NMDDS made of only EL 100 or ES100 decreased a lot.Significant decrease of Cmax was also found in NMDDS made of only silica,either with porous Sylysia or non-porous,and the Aerosil NMDDS was lower than the Sylysia NMDDS.The results showed the necessity of the combination of the two carriers.The ratio of FNB:Silica:Eudragit was set at 1:3:3,changing only one type of carrier at one test.When the Eudragit type was fixed as EL 100-55,we investigated the difference among A200,S350 and S550.Results showed that the bioavailability of the two porous materials was basically the same,and the NMDDS with non-porous material A200 was much lower than the optimal NMDDS.When the silica type was fixed as S350,we investigated the difference among EL100-55,EL 100 and ES100 as the polymer carrier.Results showed that the type of Eudragit has certain effect on bioavailability compared.Howerver,the EL 100-55,which displayed best supersaturation effect,also has better oral bioavailability than the EL 100 and ES100.The NMDDS with EL 100 and ES100 had no obvious difference.We also compared the oral bioavailability of NMDDS made by the SCF method and the rotary evaporation method,and no obvious improvement was found by the SCF method,so finally we chose the much easier rotary evaporation method as the preparation method.The optimal NMDDS was stored in normal condition for one year,and the drug release and pharmcokinetc behavior were investigated.It was clear that no obvious change in both aspescts.XRD and DSC analysis showed that after one year storage,there was still no crystallation of FNB.Though the SEM and TEM results combined with the BET analysis,we could find that the diameter of Sylysia?350 was much bigger than Aerosil?200,and there are porous structure in the Sylysia?350.The pore size obtained by BET analysis was 20 nm in Sylysia350 and 10 nm in Aerosil?200.In the NMDDS,we could see that the pore number was much lower than the Sylysia?350 which indicates that the pores in the Sylysia?350 maybe occupied by drug moleculars or covered by polymer.The results of XRD and DSC analysis were basically the same.The FNB showed strong crystallization and disappeared in the NMDDS and the amorphous state can be maintained for at least one year.With the combination of Sylysia?350 and Eudragit~?L100-55?the crystallization of NMDDS with different drug to carrier ratio was investigated.With the increase of carrier to drug ratio,the crystallization disappeared gradually,and fully disappeared at 1:3:3.When using only Sylysia?350 or Eudragit~?L100-55 as carriers,the drug crystallization disappeared at 1:4 for Sylysia?350 and at 1:2 for Eudragit~?L100-55,which indicated that the better crystal inhibition ability of Eudragit.The caco-2 cell model was set up to investigate the cell uptake and membrane FNB transport of the NMDDS.The results were in accordance with the in vitro drug dissolution and pharmacokinetic study.The optimal drug uptake and transport were also found in the optimal formulation of NMDDS.