Development Of The Aspirin And Dipyridamole Floating Tablets In Stomach And Its Pharmacokinetics And Reltive Bioavailability Study

Objective: To develop a aspirin and dipyridamole (AD) floating tablets in stomach. An orthogonal design (OD) was used to optimize the formulation and technology. A HPLC method was established for the determination of the content the sustained release rate of the tablets and the content of SA , the floatation of the tablets in vitro was watched directly. We also studied on the pharmacokinetics, relative bioavailability and in vitro-in vivo correlation of the aspirin and dipyridamole floating tablets in stomach.Methods: HPMC_K4m and HPMC _E50 was chosen as the hydrophilic gel matrix materials, CaCO₃ as the floating excipients, polymeric methaerylates No.â…¡ as the light excipients. The core tablets were prepared by wet method , the yellow micro-coated was used to coat them. Based on the single tests, the quantity of HPMC _K4m - HPMC _E50 and CaCO₃ and the size of the hardness of the tablets were chosen as four important factors that affected the drug release characteristics, three levels were chosen. We used the orthogonal design U (12⁵) to arrange 12 kinds of the tests to optimize the formulation and technology. After the ideal formulation and technology was assured, we measured their release characteristics in vitro. The release content , k_z linear correlation coefficient of Higuchi equation , r, t_1/2 were measured . In vivo pharmacokinetics and relative bioavailability of AD floating tablets was studied on in dogs with A normal tablet and D sustained capsule used as reference preparation based on a random-cross experiment design . In vivo-in vitro correlation was also evaluated.Results: In vitro release tests indicated that the quantity of HPMC ?4m â– > HPMC E5o and CaCCb and the size of the hardness of the tablets had great effect on release characteristics. Increase of the quantity of HPMC K4m -> HPMC eso and the size of hardness of the tablets or decrease of the quantity of CaCC>3 would cause a decrease of the drug release content , in an appropriate range of them , the tablets were floated well. But their effects on Higuchi equation or Peppas equation correlation coefficient were relatively complex. The orthogonal design was used to optimize the formulation and technology. The ideal formulation optimized by the orthogonal design was A 12.5g> D lOOg, HPMC K4m 10g> HPMC E5020g , CaCO3 10g, PolymericmethaerylatesNo.il 3(^ talc 2g, hardness 5⁸kg. The linear relationships between the factors and the release parameters were represented well and faithful. In vitro drug release tests of AD floating tablets prepared according to the ideal formulation optimized by the orthogonal design showed that the release equation of D.- Q =50.428t1/2 -22.596 , r= 0.9992, t50=2.07h;the release equation of A: Q = 50.078t1/2 -22.253, r=0.997, t50=2.08h;the floating tablets in vitro was floated and sustained for 6 hours in 0. lmol/L HCL.The characteristics of A n D plasma concentration-time curve fitted to one-compartment model after a single oral dose of A 25mg and D 200rrrg. The pharmacokinetics parameters of the AD foating tablets > A normal tablets and D sustained capsules were as follows: SA: Tmax were (4.7 + 0.5) and (2.3 + 0. 5) h, Cmax were (4. 7±0. 6) and (6.4 + 0.5) u g/mL, t,/2 were (3.9 + 0.9)and(3.9 + 0.6)h,AUC0- were (42.0 + 6.1) and (44.4 + 4.6)(u g/mL).h , MRTwere (7.8 + 0.4) and (6.3 ±0.9) h respectively;D: Tmax were (2.17 + 0.16) and (2.21+0.15) h, Cmax were (2.67 + 0.27) and (2.63 + 0.29) ug/mL , ti/2were (4.7 + 0.7) and (4.9 + 0.6) h, AUC0- were (23.46 + 4.25) and (24.72 + 3.88) (p g/mL).h a, MRT were (7.7 + 0.8) and (8.4 + 1.2) h respectively.In vitro-in vivo correlation was studied on with the in vivo absorption percent calculated by Loo-Riegelman method. The result indicated that AD floating tablets had a good In vitro-in vivo correlation.Conclusin: In vitro release characteristics of A, D of AD floating tablets fitted to Higuchi equation, the floating tablets in vitro was floated and sustained for 6 hours in O.lmol/L HCL. In vivo study indicated that the characteristics of A^ D plasma concentration-time curve fitted to one-compartment model. Compared to A> D normal tablets , the plasma concentration fluctuation degree was lower after multi-dose administration of AD floating tablets. AD floating tablets had a good In vitro-in vivo correlation , thus we can predict in vivo absorption percent of A> D based on in vitro release rate.The orthogonal design is quite useful for optimizing pharmaceutical formvilations and technology when the factors and the times of the test are more.