Development Of Carvedilol Floating Tablets In Stomach And Its Pharmacokinetics And Relative Bioavailability Study In Beagle's Dogs

Objective:The objective of the study is to persuit the new idea, new technology and new method of designing and preparing oral controlled drug delivery via gastric retention based on principles of hydrodynamically balanced systems, so as to extend the retention time of the drug in stomach, to control the drug release rate, to enhance the drug absorption in stomach, and to improve drug bioavailability.Carvedilol , one of theβ-adrenergic receptor antagonists , has multiple pharmacological actions, and is an important cardiovascular medicine which are widely used in therapy of hypertension, congestive heart failure, angina pectoris and other ischemic disease, and have the advantages of definite effects on above disease, of lower rehospitalization and mortality, and of cardiac protection etc. But the defects of low bioavailability, great individual difference, and the frequent adverse effects such as headache, dizziness, fatigue etc. of carvedilol limit its clinical usefulness. So it is of great valuable to prepare the carvedilol floating drug delivery systems in stomach, so as to decrease the times of carvedilol administration, to enhance the drug bioavailability, to improve the individual difference of drug absorption due to different gastrointestinal tract physiological environment.Methods:Carvedilol floating tablets in stomach was designed based on principle of hydrodynamically balanced systems, and hydrophilic gel was chose as matrices. Single factor experiment was conducted to establish the influencing factors on the drug release. The formulation was optimized by orthogonal design. Carvedilol content of floating tablets and their in vitro release rate were tested by HPLC and UV assay methods respectively. The floatation of carvedilol floating tablets in release media was observed by naked eyes. In vitro release mechanism should be studied. A random, cross study in beagle's dogs was conducted to study the pharmacokinetics of carvedilol floating tablets, and the correlation between in vitro cumulative percent released (Ft) and in vivo absorption fraction (Fa) should be established.Results:1. The HPLC method of carvedilol content test has been established, and the methodology study showed that there's no impact of excipients on carvedilol assay under the established chromatography condition, the concentration of carvedilol was good linear with peak area (50μg/ml-400μg/ml, r=0.9999), the precision (RSD<1%) and recovery rate (>99%) of carvedilol in mobile test met the requirement of carvedilol assay.The UV method of carvedilol release rate test has been established, and the methodology study showed that there's no impact of excipients on carvedilol assay, the concentration of carvedilol was good linear with peak area( 1-8μg/ml, r=0.9999), the precision (RSD<1 %) and recovery rate (>99%) of carvedilol in release media met the requirement of carvedilol assay.2. Carvedilol floating tablets were bi-layer tablets that were consisted of immediate-releasing part and extended-releasing part, and HPMC K4M and E50 were chose as the gel matrices, glyceryl monostearate as light excipients, and NaHCO₃ as bubble-resulting excipient. It was showed that the total amount of HPMC had significant effects on in vitro drug release of carvedilol floating tablets, and the ratio of HPMC K4M/HPMC E50 had an influence on tablets' release. In addition, the amount of glyceryl monostearate, NaHCO₃ and the hardness of tablets also had different degree of impact on release rate and floatation of carvedilol floating tablets. Based on these found, orthogonal design was conducted to optimized the formulation, and finally the best formulation composition and preparation process of extended-releasing part was gained.3. It was showed that the drug release of carvedilol floating tablets either in the same batch or batch to batch were homogeneous, and it was showed that the process was stable and highly reproducible. Primarily stability study showed that carvedilol floating tablets were stable under the condition of high humidity (RH75%) and strong light, but were unstable under the high temperature and higy humidity (RH92.5%). The accelerated study showed that carvedilol floating tablets were stable for 3 months under the condition of 40℃, RH75%.4. It was showed that in vitro drug release of carvedilol floating tablets followed the Weibull distribution, and the 2-8h drug release of carvedilol floating tablets followed Higuchi square root equation. The drug release mechanism of this formulation was matrix diffusion and erosion.5. Pharmacokinetics study in beagle's dogs:The plasma drug concentration was tested by the method of HPLC. A random, cross study in beagle's dogs was conducted to study the pharmacokinetics of carvedilol floating tablets, and chose carvedilol tablets as reference drug.The pharmacokinetics parameters of carvedilol tablets and carvedilol floating tablets are as follows: T_1/2 was 3.58±0.56h and 9.99±3.16h, Cmax was 133.85±16.45ng/ml and 83.40±5.85ng/ml, Tmax was 2.083±0.801h and 7.333±1.033h, respectively.The result showed that carvedilol had apparent delayed Tmax and siginificant low Cmax compared to carvedilol tablets, and had longer drug concentration duration. It was concluded that the carvedilol floating tablets was floating and extended release in beagle's dog stomach.In vitro-in vivo correlation was studied and the result indicated that carvedilol floating tablets had a good in vitro-in vivo correlation (Fa=1.0999Ft-26.7256, r= 0.9629) .Conclusion:Carvedilol floating tablets have the characteristics of extended-release and longer retention time in stomach, and the preparation process is stable and suitable for industrial applications. It can be maintained floating and extended release over 8h in vitro. Animal pharmacokinetics study showed that carvedilol floating tablets have good in vivo floatation and extended release, and have good correlation between in vitro drug release and in vivo accumulated absorption percent rate. This new formulation can decrease administration times, prolong drug half-life and control the fluctuation of drug plasma concentration.This new formulation will have a promising market with its good compliance of patients and good therapy effects.