Preparation And Pharmacokinetics Of Lorcaserin Hydrochloride Osmotic Pump Controlled-release Tablets

Objective:Long-term and constant-release chlorcarseline hydrochloride osmotic pump controlled-release tablets were prepared,and the drug release mechanism in vitro was investigated,and the pharmacokinetic characteristics and correlation between in vivo and in vitro of Beagle dogs were studied.Methods:1).By establishing a highly effective method for determining the content of lorcaserin hydrochloride,and examining its solubility in different media and oil-water partition coefficients,the intestinal absorption of lorcaserin hydrochloride in different intestinal segments and different concentrations was investigated in rats.2).By establishing a high-efficiency method for measuring the release of lorcaserin hydrochloride in vitro,and optimizing it by single-factor and orthogonal experiments,the best formulation of lorcaserin hydrochloride osmotic pump controlled-release tablets was determined,and it’s in vitro release mechanism and Quality requirements related to controlled release preparations.3).The LC-MS/MS method was used to determine the pharmacokinetic parameters of chlorcaserin hydrochloride osmotic pump controlled-release tablets in Beagle dogs.The pharmacokinetic parameters of lorcaserin hydrochloride osmotic pump controlled-release tablets and lorcaserin hydrochloride immediate-release tablets in Beagle dogs were compared.To investigate the bioavailability,bioequivalence and in vitro and in vivo correlation of lorcaserin hydrochloride osmotic pump controlled release tablets in Beagle dogs.Results:1).The saturated solubility of lorcaserin hydrochloride is 0.54 g/m L in water,the oil-water partition coefficient is 2.46（37℃）,and the medium concentration of lorcaserin hydrochloride（6.0 mg/L）K_aare 2.06±0.17,1.81±0.036,1.62±0.13,1.30±0.067 min^-1(×10^-1),in the duodenum and jejunum,Ileum,colon,respectively.The different concentrations（1.0,6.0,24 mg/L）of lorcaserin hydrochloride in the jejunum were 0.16±0.014,0.18±0.0036,and 0.16±0.0079 min^-1.The results showed that lorcaserin hydrochloride is highly soluble,highly permeable drugs,namely BCS class I drugs,are well absorbed in each intestinal segment and are best absorbed in the duodenum.The absorption method is passive diffusion.2).The prescription of lorcaserin hydrochloride osmotic pump controlled release tablets were as follows（one piece）:lorcaserin hydrochloride 20.8 mg;mannitol 100 mg,microcrystalline cellulose 125 mg,stearase 5 mg.CA 3%,PEG 4000 10%,DBP10%Acetone 500 m L.Aperture 0.8 mm,Weight gain 3%.The prepared lorcaserin hydrochloride osmotic pump controlled-release tablets can be released at a constant rate in vitro and sustained for 16 hours with a cumulative release rate of 95.69%,and exhibit good zero-order release in vitro（r=0.997）.3).UPLC-MS/MS was established to determine the concentration of lorcaserin hydrochloride in the plasma of Beagle dogs.The lorcaserin hydrochloride has a linear relationship（r=0.9992）in the range of 1 to 500 ng/m L,and the immediate release tablets in comparison,the relative bioavailability of lorcaserin hydrochloride osmotic pump controlled-release tablets in Beagle dogs is 99.27%,which is bioequivalent（80.15%,101.22%）;lorcaserin hydrochloride osmotic pump controlled-release tablets are absorbed in vivo The regression equation of percentage（F_a）to in vitro release（F）is:F_a=0.682F-2.459（r=0.9916）.In vitro release and in vivo absorption have a good correlation between in vivo and in vitro.Conclusion:The self-made lorcaserin hydrochloride osmotic pump controlled-release tablets meet the release requirements of controlled-release preparations（r>0.95）.The cumulative release rate can reach 95.69%within 16 hours,and the relative bioavailability in Beagle dogs is 99.27%,Equivalent and good correlation in vivo and in vivo.