Design And Evaluation Of Carvedilol SEDDS And SMEDDS

Carvedilol is a highly lipophilicβ-adrenoceptor blocking. It has a low solubility in gastrointestinal fluids and undergoes extensive first-pass metabolism in the liver, which leads to the low absolute oral bioavailability which is about 20% in humans. The objectives of our researches are to improve its bioavailability by self-emulsifying drug delivery system (SEDDS) and self-microemulsifying drug delivery system (SMEDDS) and to prepare a series of liquid, semi-solid and solid self-emulsifying and self-microemulsifying formulations that have different release characteristics. Based on the above work, we hope to do contributions to the development of SEDDS and SMEDDS.To prepare a SEDDS and SMEDDS and evaluate their in vitro properties, first of all, the HPLC analytic methods were established. The physical and chemical properties of carvedilol were investigated. The solubility of carvedilol in solutions increases with respect to the decrease of pH value because it is a weak base. It has the biggest solubility in 0.1 mol·L^-1HCl which is 102.9μg/mL. The logP increases with the pH value of the water phase, the logP in pH1.0, Ph5.8, pH6.8, pH7, pH7.4 were 2.57, 2.67, 3.51, 3.78, 4.08 respectively. The DSC results showed that carvedilol is stable under 200℃. The balance solubility of carvedilol in different oil phase, surfactant and cosurfactant were assayed. Ternary phase diagrams were constructed. The optimal SEDDS were obtained by comparing the self-emulsifying and self-microemulsifying domain and by the evaluation of the resultant emulsion's appearance. The optimal SEDDS was Labrafil M 1944CS, Tween 80, Transcutol P. The self-emulsifying time of self-emulsifying and self-microemulsifying formulations were investigated. When the surfactant content increase from 30% to 60%, the self-emulsifying time decreased firstly and then increased. The minimal self-emulsifying time which was 22s was found at the formulation that has 40% surfactant. The particle size distribution,ζ-potential and phase distribution of the resultant emulsion and microemulsion were studied. The diameter of the emulsion decreased with respect to the increase of surfactant content. Adding acid benzoic to formulations led to positively charged emulsions. Phase distribution is the results of pH value and the surfactant content. Drug distribution in water phase increased with respect to the decrease of pH value and the increase of surfactant content. Small amount of drug distributed into water phase (18.49%-25.87%) and oil phase (6.84%-29.79%), most of the drug distributed into interface (51.68%-67.29%). Direct dissolution test and bulk equilibrium reverse dialysis bag technique were used to evaluate the dissolution of drug from SEDDS and SMEDDS in media of different pH values. The results showed that the four formulations could release drug fast and completely. The dissolution rate increased with respect to the increase of surfactant content. The dissolution results of bulk equilibrium reverse dialysis bag technique showed that about 50% free drug was released at 30min. the dissolution rate increased with respect to the increase of pH values.To testify if the self-made SEDDS and SMEDDS could improve the bioavailability, the pharmacokinetic study of commercial available tablets, self-made SEDDS and SMEDDS in beagle dogs was carried out. The C_max of commercial available tablets, self-made SEDDS and SMEDDS were (510.15±156.20) ng·mL^-1,(2060.38±534.60) ng·mL^-1,(746.17±170.27) ng·mL^-1 respectively; t_max were (0.79±0.1) h,(1.00±0.00) h,(0.91±0.13) h respectively; AUC were (1755.79±409.75) ng·mL^-1·h,( 7264.29±1911.35) ng·mL^-1·h,(4182.47±798.68) ng·mL^-1·h respectively; the relative bioavailability of SEDDS and SMEDDS were (446±190) %, (249±74)% respectively; the results of variance analysis by using SPSS software showed that self-made SEDDS and SMEDDS could improve the bioavailability of carvedilol significantly.To investigate the tissue distribution of self-made SEDDS and SMEDDS, the tissue distribution of Luode tablet suspension, emulsions and microemulsions were investigated after oral administration to rats at a dose of 20mg. SEDDS could improve the drug distribution at heart, lung, hepatic, blood, lymph, decrease drug distribution at kidney (P＜0.05). SEDDS had no significant effect on the distribution at spleen and brain (P＞0.05). SMEDDS improve the drug distribution at heart, blood, lymph, decrease drug distribution at hepatic and kidney (P＜0.05). SMEDDS had no significant effect on the distribution at lung, brain and spleen (P＞0.05).To prepare a semi-solid self-microemulsifying capsule, the solubility of carvedilol in different semi-solid self-emulsifying materials was investigated. By study of ternary phase diagrams, the optimal semi-solid formulation was optimized that is Gelucire 44/14 was used as oil phase, Lutrol F68 was used as surfactant, Transcutol P was used as cosurfactant. Three different semi-solid self-microemulsifying formulations could all release drug fast and completely, and the cumulated release of three formulations were all above 90% at 30min. Zero-order equation, first-order equation, higuchi equation, ritger-peppas equation, weibull equation, Hixon-crowell were used to calculate drug release kinetics. The results showed that the drug release fitted Hixon-crowell equation most. The dissolution mechanism is erosion dependent. Differential Scanning Calorimeter (DSC), Infrared spectroscopy (IR), X-ray diffraction (XRD) methods were used to investigate the physical characterization of drug in semi-SMEDDS. The results showed that carvedilol was amorphous in dosage form.To prepare a novel self-emulsifying osmotic pump tablet (SEOPT), the following experiments were carded out. The release assay method by UV was established. By comparing the absorbing ability, silicon dioxide was used as the adsorbent. By assaying the disintegration time, citric acid and sodium hydrogen carbonate was used as disintegration substance. By comparing the similarity of profiles using f₂ factor method, the effects of the type of osmotic active agent, orifice size, coating weight gained on drug release were investigated. Based on the experiments, the SEOPT formulation was optimized, that is silicon dioxide was used as adsorbent, citric acid and sodium hydrogen carbonate was used as disintegration substance, mannitol was used as osmotic active agent, talc powder was used as lubricant. The coating solution was prepared by dissolving 27.0g cellulose acetate in 1000ml acetone and then adding 50 mL water solution with 10g PEG-400 dissolved in it. Then two orifice of 1.0mm were punched on two sides. In most release period, the drug was released at zero order, the cumulated release at 12h was 85%. The results of transmission electron microscope showed that self-made SEOPT could form regular and round emulsion particles. The volume diameter was 246nm, the surface diameter was 242nm.To investigate if the semi-SMEDDS and SEOPT could improve the bioavailability, the pharmacokinetics of Luode tablet, semi-SMEDDS and SEOPT was carried out. The C_max of Luode tablet, semi-solid SMEDDS and SEOPT were (1311.60±156.20)ng·mL^-1, (2006.38±633.26) ng·mL^-1,(640.23±162.79) ng·mL^-1; the t_max of Luode tablet, semi-SMEDDS and SEOPT were (2.83±0.61) h,(1.63±0.74) h,(4.50±1.22) h; the AUC of Luode tablet, semi-SMEDDS and SEOPT were (4063.36±822.30) ng·mL^-1·h,(6578.15±2508.09) ng·mL^-1·h,(6189. 68±1873. 58 ) ng·mL^-1·h. The relative bioavailability of semi-SMEDDS and SEOPT were (162±50) %, (152±33)%. The results of variance analysis by SPSS software showed that C_max of semi-SMEDDS increased significantly, C_max of SEOPT decreased significantly. Rank sum test showed that tmax of semi-SMEDDS move forward greatly and t_max of SEOPT move backward greatly. SPSS variance analysis results showed that semi-solid SMEDDS and SEOPT could improve the bioavailabitliy significantly. Semi-solid SMEDDS showed fast release characteristics and SEOPT showed sustained release characteristics. W-N method and L-R method both can be used to calculated in vitro and in vivo correlation well.