| Objective: The solid dispersion(SD)of rutin with high bioavailability was prepared with colloidal silicon dioxide(CSD)as carriers(Ru-CSD-SD),colloidal silicon dioxide is hydrophilic and porous.The Ru-CSD-SD sustained-release tablets with high bioavailability was prepared by direct compression method with hydroxypropyl methycellulose(HPMC)as skeleton material.With the cumulative release of drug in the dissolution medium as index,using the single factor investigation,to optimized the formulation by central composite design-response surface methodology.The releases in vitro of Ru-CSD-SD and sustained-release tablet were determined by ultraviolet(UV)spectrophotometry.Relative bioavailability of oral Ru-CSD-SD and sustained-release tablet were determined by high performance liquid chromatography(HPLC).Methods:(1)Preparation of rutin colloidal silicon dioxide solid dispersions(Ru-CSD-SD).The releases in vitro of Ru-CSD-SD was determined by UV,The effects of different colloidal silicon dioxide,the ratio of drug and carriers,three methods of preparation(spray drying,solvent evaporation,grinding methods)on the in vitro release of Ru-CSD-SD.The equilibrium solubility of Ru-CSD-SD was determined;the solid dispersion was identified by differential scanning calorimetry(DSC)and X-ray diffraction(XRD).(2)Study on bioavailability of Ru-CSD-SD.Pharmacokinetics of the tested Ru-CSD-SD was studied in single oral dose of it,saled rutin tablet as reference preparation.The bioavailability in vivo of Ru-CSD-SD were determined by HPLC,The pharmacokinetic parameters were calculated by DAS 2.0,two kinds of pharmacokinetic characteristics were compared,and evaluate in vivo bioavailability of Ru-CSD-SD.(3)Preparation of Ru-CSD-SD sustained-release tablets.The releases in vitro of Ru-CSD-SD sustained-release tablets were determined by UV,The effects of specifications and dosage of HPMC,filler,dosage of microcrystalline cellulose(MCC)and lactose on the in vitro release of Ru-CSD-SD sustained-release tablet were investigated.The dosage of HPMC,MCC and lactose were chosen as the three factors on the basis of the single-factor tests.The three factors were analyzed with the formulation by central composite design-response surface methodology and optimal formulation was obtained.(4)Study on bioavailability of Ru-CSD-SD sustained-release tablet.Pharmacokinetics of the tested Ru-CSD-SD sustained-release tablets were studied in single oral dose of it,saled rutin tablet as reference preparation.The bioavailability in vivo of Ru-CSD-SD sustained-release tablets were determined by HPLC,The pharmacokinetic parameters were calculated by DAS 2.0,two kinds of pharmacokinetic characteristics were compared,and evaluate in vivo bioavailability of Ru-CSD-SD sustained-release tablet.Results:(1)The regression equation for rutin in distilled water was A=30.18 C-0.0218,r2=0.9993;The regression equation for rutin in p H 1.0 was A=26.66 C+0.0010,r2=0.9999;The regression equation for rutin in p H 6.8 was A=20.78 C+0.0216,r2=0.9990.The linear relationship was good ranges from 0.010 mg/m L to 0.030 mg/m L.(2)Colloidal silicon dioxide AEROPERL?300 pharma(CSD 300)was used as carrier,the ratio of drug(rutin)and carrier(CSD 300)were 1:2,and the SD prepared by solvent evaporation was better in vitro.The equilibrium solubility of rutin and Ru-CSD-SD were 72.69 mg/L?198.73 mg/L in 37?.After preparation of Ru-CSD-SD,the equilibrium solubility of rutin increased 2.7 times.(3)The linear regression equation for rutin in vivo was A/AS=0.012 C+0.0539,r2=0.9998.The linear relationship of rutin in plasma samples was good ranges from 0.05 ?g/m L to 20.00 ?g/m L.The low limit of quantitative(LLOQ)was 0.05 ?g/m L.(4)The main pharmacokinetics parameters of reference preparation and self-designed Ru-CSD-SD were as follows: Cmax(?g/m L)were 6.69±0.62 and 103.45±4.62,Tmax(h)were 1.50±0.08 and 0.49±0.02,t1/2(h)were 1.08±0.17 and 10.90±1.45,AUC0-t(?g·h/m L)were 13.83±0.92 and 143.09±0.22,AUC0-?(?g·h/m L)were 13.97±0.63 and 170.41±6.42,MRT0-?(h)were 2.51±0.12 and 11.56±0.10.The Cmax of Ru-CSD-SD was 15.46 times of ordinary tablets.The AUC0~? of Ru-CSD-SD was 12.20 times of ordinary tablets.(5)HPMC K15 M was used as skeleton material,lactose was used as filler,the dosage of HPMC was 36% of excipients,the dosage of MCC was 6% of excipients,the dosage of lactose was 46% of excipients,the dosage of chitosan was 12% of excipients.The cumulative dissolution of Ru-CSD-SD sustained-release tablet was(26.15±0.56)% in 2 h,(57.56±2.57)% in 6 h,(83.89±4.13)% in 12 h.(6)The main pharmacokinetics parameters of reference preparation and self-designed Ru-CSD-SD sustained-release tablet were as follows: Cmax(?g/m L)were 6.69±0.62 and 16.46±0.29,Tmax(h)were 1.50±0.08 and 7.97±0.93,t1/2(h)were 1.08±0.17 and 2.95±0.10,AUC0-t(?g·h/m L)were 13.83±0.92 and 91.12±0.12,AUC0-?(?g·h/m L)were 13.97±0.63 and 118.31±0.73,MRT0-?(h)were 2.51±0.12 and 9.50±0.43.The Cmax of Ru-CSD-SD sustained-release tablet was 2.46 times of ordinary tablets.The AUC0~? of Ru-CSD-SD sustained-release tablet was 8.47 times of ordinary tablets.Conclusion:(1)UV spectrophotometry was accurate,reliable,easy to operate and reproducible,it can be used for analysis of rutin in vitro.(2)The Ru-CSD-SD can increase the solubility and dissolution rate of rutin,the preparation method is simple and feasible.(3)HPLC was good separation,high sensitivity and speed,it can be used for analysis of rutin in vivo.(4)The Ru-CSD-SD can increase the oral bioavailability of rutin.Laid the foundation for the following preparation of sustained-release tablet.(5)The Ru-CSD-SD sustained-release tablet was prepared and the in vitro drug release conformed to the requirements.(6)The Ru-CSD-SD sustained-release tablet can significantly increase the oral bioavailability of rutin and prolong action time. |
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