Design And Evaluation Of Carvedilol Nanosuspension Drug Delivery System

Over the past decades, nanosuspensions have been widely used to tackle problems associated with poor solubility and low bioavailability. However, the acceleration of dissolution rate will give rise to pronounced fluctuations in plasma concentration. This is definitely harmful to patients with specific disease such as hypertension. So it is meaningful to combine extended drug delivery system and nanosuspension technology. The newly developed system can not be only used to improve oral bioavailability but also to control the drug release rate. Carvedilol (CAR) was selected as a model drug, CAR nanosuspension was prepared firstly to improve the solubility and bioavailability of the drug. Then the nanosuspension powder was made into osmotic pump capsule to avoid the weaknesses of existing technologies.Firstly, the equilibrium solubility of CAR in different pH value buffer solution and different organic solvent were determined, respectively. The results proved that CAR is a weak base, and the solubility of the drug in water was influenced significantly by pH value. It is soluble in acetone, DMSO and DMF.CAR nanosuspension was prepared using alpha-tocopherol succinate (VES) and SDS as stabilizer by anti-solvent precipitation-ultrasonication technique. Response surface methodology (RSM) based on central composite design (CCD) was utilized to evaluate the formulation factors that affect the particle size of nanosuspensions. The effects of the process parameters on particle size of the nanosuspensions were also investigated by single factor investigation. Then the nanosuspension was solidificated by freeze-drying. The optimized formulation showed a mean size of 212 ± 12 nm and a zeta potential of -42 ± 3 mV. The nanosuspension was flaky shaped. Powder X-ray diffraction and differential scanning calorimetry analysis confirmed that the nanoparticles were in the amorphous state and the crystalline state was not affected by ultrasonification. Fourier transform infrared analysis demonstrated that the reaction between CAR and VES is probably due to hydrogen bonding.The dissolution rate of the nanosuspensions was markedly enhanced by reducing the size.And there was no obvious difference in dissolution rate before and after drying. The nano suspension was physically stable at 25? for 1 week, which allows it to be further processing such as drying.With CAR conventional tablets as the reference, the pharmacokinetics study on CAR nanosuspension was carried out using Wistar rats. The Cmax and AUC0-36 values of nanosuspensions were approximately 3.3-fold and 2.9-fold greater than that of the commercial tablets, respectively. Tmax was shorten from 2.6 h to 0.85 h. The results demonstrated that CAR oral bioavailability in rat of was enhanced by nanosuspension. The absorption mechanisms and kinetics study of CAR nanosuspension in different segments of intestine was performed by rat single-pass intestinal perfusion technique.The results showed that the concentration and pH value of CAR solution had no obvious effect on drug absorption in jejunum, which indicated the mechanism of the intestinal absorption of CAR was transferred to cell via passive diffusion. CAR could be well absorbed at all segments of intestine in rats especially in jejunum and ileum. Compared to CAR solution, the effective permeabilities of CAR were improved by 1.38?1.12?1.42 and 1.29-fold in the duodenum,jejunum, ileum and colon, respectively,by microsuspension. As for nanosuspension,the Peff value was improved by 1.74?1.42?1.89 and 1.82-fold in the above segments of intestine. The two preparation could improve the intestinal absorption of CAR from the intestinal lumen. The smaller the particle size the more obvious enhancement of drug absorption was observed. Histological evaluation of the perfused segments showed no major effects on the intestinal morphology, which proved that the commercial tablets and the nanosuspension possess good biocompatibility.To reduce the fluctuations in plasma concentration, a novel nanosuspension osmotic pump capsule was prepared. First, the shells of the CA semipermeable capsule were prepared by perfusion method. The formulation and preparation factors which affect the shape of the capsules were investigated. Central composite design-response surface methodology was used to investigate the influence of factors, i.e., Plasdone S-630 content, Mannitol content and PEG 400 content on the responses including ultimate cumulative release and correlation coefficient of drug release profile. A second-order polynomial equation was fitted to the data, and the actual response values are in good accordance with the predicted ones. The optimized formulation displays a complete drug delivery and zero-order release rate. The powder flowability was suitable for capsule filling and the drug release profile was not affected by pH value of the dissolution media.The bioavailability study in Beagle dogs was carried out to compare three test preparations and the reference preparation. Compared to the commercial tablet, the relative bioavailability of the nanosuspension capsule, microsuspension capsule and the nanosuspension osmotic pump capsule was (224.3±40.0)%?(164.2±37.0)% and(203.5±46.4)%, respectively. The Cmax values of of the above preparations were approximately 2.32-fold and 1.57-fold and 0.72 of that of the commercial tablets, respectively.The Tmax value was obviously reduced by the nano or microsuspension and increased by the osmotic pump. The nano and microsuspension showed fast release characteristics and the nanosuspension osmotic pump showed sustained release characteristics. The three preparations were all not bioequivalent with the reference product. The nanosuspension osmotic pump showed a good in vitro and in vivo correlation.