Preparation Of Carteolol Hydrochloride Matrix Sustained-release Pellets And Pharmacokinetic Study In Beagle Dogs

Sustained-release pellets not only have many advantages of pellets, such as improving the bioavailability, reducing or eliminating gastrointestinal irritant caused by irritant drugs, and the transport in the gastrointestinal tract is unaffected by food conveying rhythms and so on, but also can control the rate of drug release, provide stable drug concentration in the blood, reduce the side effects, reduce the frequency of administration and improve the compliance of patients. The carteolol hydrochloride matrix sustained-release pellets were prepared with the method of extrusion-spheronization based on the study of carteolol hydrochloride basic physical and chemical properties.The quality standard, stability, pharmacokinetic in Beagle dogs and other aspects were studied according to the "Chemical registration requirements of the classification and reporting information" of "Drug Registration"of State Food and Drug Administration’s document of No.28, 2007, for accumulating the data of carteolol hydrochloride matrix sustained-release pellets registration.The first part. The preformulation study of carteolol hydrochloride matrix sustained release pellets. The equilibrium solubility of carteolol hydrochloride in water,0.1 mol·L-1 HCl and phosphate buffer solution with different pH values (5,5.8,6.8,7.4) were determined, the oil/water partition coefficients and the stability in these medium were also determined. The results showed that carteolol hydrochloride had the maximum aqueous solubility in water, oil/water partition coefficient did not show obvious regularity with pH value changing, the solution in different medium were stable. HPLC method of determination of carteolol hydrochloride raw material and related substances were established, and the methodology was investigated.The second part. The prescription and preparation study of carteolol hydrochloride matrix sustained release pellets. First, the amounts of microcrystalline cellulose (MCC), different proportion between ethyl cellulose (EC) and stearic acid (SA) and the amounts of sodium carboxymethyl cellulose (CMC-Na) were screened through single factor experiment, and then, the reasonable proportion of material in prescription was optimized by orthogonal test. Extrusion speed, spheronization speed and spheronization time were investigated with micromeritic properties of pellets (particle size distribution, surface morphology, roundness and friability) as reference parameters, the drug release of carteolol hydrochloride matrix sustained-pellets in vitro were evaluated.The optimization of prescription was definited:carteolol hydrochloride 5.5 g, MCC 6.0 g, SA 26.3 g, EC 21.0 g, CMC-Na 1.2 g, the optimization of technology:speed of extrusion:45 r·min-1 speed of spheronization:750 r·min-1, time of spheronization:6 min. Drug release characteristics:the release time was over 12 h, the drug release behavior consistent with a first-order kinetic equation, the process of drug was drug diffusion and frame erosion at the same time.The third part. The quality standard study of carteolol hydrochloride matrix sustained release pellets. The character, identification, release in vitro, content and the related substances of carteolol hydrochloride sustained release pellets were researched. RP-HPLC method for content and related substances determination in carteolol hydrochloride matrix sustained-release pellets was established. The separation was performed on a VP-ODSC18 column (4.6 mm×150 mm,5μm), the mobile phase consisted of 0.067% dibasic sodium phosphate-acetonitrile (87:13 V/V) and the flow rate was 1.0 mL-min-1. The detection wavelength was 251 nm and the column temperature was 30℃. Result showed that related substances and degraded substances were completely separated from carteolol hydrochloride, the linear range of determination was 2μg-mL-1-40μg-mL-1 with the correlation coefficient of 0.9997. The average recovery was 101.2%, RSD was 0.36%(n=9) and the LOD was 0.4 ng-mL-1, LOQ was 1.6 ng-mL-1. The RP-HPLC method is simple, accurate, rapid, sensitive and suitable for the determination of the content and related substances in carteolol hydrochloride matrix sustained-release pellets. The release in vitro of the three batches of carteolol hydrochloride matrix sustained-release pellets complied with the relevant requirements.The fourth part. The stability study of carteolol hydrochloride matrix sustained release pellets.The strong illumination test, accelerated test and long term test were researched on the matrix sustained-release pellets. The results showed that the pellets were sensitive to light, so they should be stored away from light.The pellets were stable in the condition of accelerated test and long term test conditions.The fifth part. The pharmacokinetic study of carteolol hydrochloride matrix sustained release pellets in Beagle dogs. The pharmacokinetic characteristics in Beagle dogs of carteolol hydrochloride matrix sustained-release pellets were studied with the carteolol hydrochloride common tablets from Japan as the reference preparation. The data of drug concentration in blood was analyzed by Winnonlin pharmacokinetics intelligent analysis software, the pharmacokinetics parameter and relative bioavailability were calculated,AUCo-24 and Cmax of test preparation and reference preparation were analyzed by the SPSS software. The result showed that the AUCo-24 of test and reference preparation were 1779.45 ng/mL·h and 1311.96 ng/mL-h, Cmax were 265.07 ng-mL-1 and 292.19 ng-mL-1, Tmax were 3.00 h and 1.00 h, the relative bioavailability of carteolol hydrochloride matrix sustained-release pellets was 135.63% calculated as AUCo-24.The time over effective blood drug concentration of carteolol hydrochloride matrix sustained release pellets in Beagle dogs was 1.5 time compared with carteolol hydrochloride common tablets, setting 20 ng-mL-1 as the minimum effective blood drug concentration of carteolol hydrochloride.