Preparation Of Metoprolol Tartaric Acid Core-in-cup Tablets With Double-pulsatile Release

Objective: Pulsatile drug system is a newly-developed drug-delivering, developing with the chronopharmacology. After the lag-time, the drug of the system can reselase qucikly and entirly on the need of the disease, so the drug can prevent or cure the disease effectually and reduce the drug doseage,and degrate adverse effect.Research in man shows heart rate exist obvious hour rhythmic, which led to the break of angina pectoris also has the obvious hour rhythmic. Angina pectoris generally attack at 2 :00 3:00 and 6:00 7:00 in the morning. The tradition sustained release preparations may start to release when it is not need or the blood drug level is not enough when it is need. It may delay effective treatment opportunity. According to the characteristics, we can proudce a newly two-pulsed drug release system, which can ease the anginal pectoris attack, and also won't affect the angina. In this study, Metoprolol Tartaric Acid was the model drug, the drug was prepared to be double pulsed system. After screening the accessories of the prepartion, we selected the required accessories,and the drug can treat the angina pectoris.Methods: This system is made up three parts: water insoluble cup core-in-cup tablets with tri-layered tablet(two fast release layers with drug and one inhibitor layer), corrosion inhibitor layer.The screening of water insoluble cup: We chose ethylcellulose as cup stuff, which can make water did not penetrate and the two lag time satisfied the required. We investigated several factors that infulence the water on penetrating. The factors were different types ethylcllulose (10cp, 20cp, 45cp and 100cp), the hardness of different types ethylcllulose in the same conditions, the hardness of different grain sizes, water penetrating with different types ethylcllulose but same hardness.Preparation of core-in-cup tablets with tri-layered tablet: The operation of direct compression is simple and the fluidity of the drug and accessories is good, so we depressed 7mm core-in-cup tablets with tri-layered tablet by direct compression. The two outer layers are fast release layers with drug, the middel layer is corrosion inhibitor layer. The fast release layer are made up of disintegrant, diluent agent, adhesive. We investigated the factors of rescription and different release medium on the pulsed tablet release.The screening of preparation of inhibitor layer: We depressed the pulsed tablets by direct compression. The parameter, time-lag (Tlag) and cummulative release, was used to evaluate the influence of factors, such as the dose of adhesive, coherence to the cup, the tpye of corrosion materials. The orthogonal erperment was designed to the fomulation in which the dose of corrosion materials, the dose of corrosion inhibitor layer, the hardness of the pulsed tablet were taken as three influnence factors. The cummulative release was taken to be standard.The release test of Metoprolol Tartaric Acid core-in-cup tablets is acconding to pharmacopoeia of people's republic of china 2005 second edition appendix XC dissloution degrees of the third measurement device, the speed is 100r/min. The first 2h medium is HCl solutions(250ml) and last hoursmedium is pH5.8 phosphate butter(250ml), which can imitate the human situation.Samples were obtained at set time and detcted at 274 nm by UV spectrophotometer. We calculated the drug concentration according to standard curve.Stability test: The stability tests of Metoprolol Tartaric Acid core-in-cup tablets with double-pulsatile release were strong light, high humidity and high temperature, the standard of which were appearance of the tabet, drug content, lag timeand the accumulative release.Pharmacokinetic test in vivo: The Beagle dogs were taken as laboratory animals, which were devided into two groups in random. One group dogs were given common market Metoprolol Tartaric Acid, the other group dogs were given self-made Metoprolol Tartaric Acid core-in-cup tablets with double-pulsatile release, then taking blood sample at set time and analysising the data after handling the samples on some method. Crossover trial was done after elution time(two weeks). The concention of blood was analysising by HPLC with fluorescence detector. At last accounting on the pharmacokinetic parameters and relative bioavailability.Results: We have the optimization prescription of the core tablet after sing factor screening: 25mg Metoprolol Tartaric Acid, 14mg croscarmellose sodium, 3mg spray-dried lactose and 3mg microcrystalline cellulose,the hardness is 15 kg/mm2, the dose of inhibition layer is 70mg. We obtained the optimization prescription of the inhibition layer by orthogonal design was: 30% HPMC E5, 15% HPMC K15, 30%PVPP K30, 3% Gum Acacia, 10% spray-dried lactose, 12% microcrystalline cellulose, the hardness is 13 kg/mm2, the dose of inhibition layer is 120mg. The accessories of cup is ethyl cellulose with 45cp.The hardness of the core tablet and the doses of the disintegrating agent are influenceing on the acummulative release. With the increase of the disintegrating agent and the hardness, the accumlative release was worse. With the the dose of the HPMC K15 increase, the lag time was long, but the accummlative release become worse. With the increase of hardness of the tablet, the lag time become long, but the accummulative release become worse. The second lag time was decided by the dose of inhibition layer. The release medium and ionic strength have no influnence on the release.The release curve of Metoprolol Tartaric Acid core-in-cup tablets with double-pulsatile release showed that the two lag times are (4.5±0.079)h and(8±0.069)h, the two accumulative releases are (1.50±0.12)%/min and (2.4±0.37)%/min.The stability test showed that the tablet is not stabile in relative humidity of 75% and 92.5%. The lag time became short, but the content was not changed. The tablet was not changed in the 40℃after 10 days, and in 60℃ after 5 days, but the lag time became short in 60℃after 10 days. The strong light has no inffluence on the tablet fo 10 days.Pharmacokinetic test in vivo: Chromatographic chart indicates that the samples peak and impurities peak of the blood are separated properly. The liner is good in the concentration of 10¹300ng/ml, The standard curve equation is A = 0.2646 c + 3.2034 (r =0.9997). The Pharmacokinetic parameter of self-made Metoprolol Tartaric Acid core-in-cup tablets with double-pulsatile release and common market Metoprolol Tartaric Acid were as follow: two-pulsed drug released rapidly-disintegrate tablet capsule Timemax(h) 5±0.4082 1.157±0.3094 9.13±0.4787 C_max(ng·ml^-1) 958.78±133.74 747.52±431.95 1095.55±158.66 Tlag(h) 4.375±0.25 0.4546±0.04241 8.5±0.41 Ke(h^-1) 0.1924±0.04848 0.5164±0.1111 AUC(ng·h·ml^-1) 4875.043±806.95 3273.65±430.92Relative MT(%) 74.45±24.65 100.00Conclusion: The test in vivo and in vitro showed that inhibition layer prescription infflunced the lag time and the accmulative release. The self-made double pulsed tablet can achieve the two-pulsed release, which can require the need of treatment.