Development and optimization of carvedilol orodispersible tablets: enhancement of pharmacokinetic parameters in rabbits

Abstract

BackgroundCarvedilol (CVD) is used for the treatment of essential hypertension, heart failure, and systolic dysfunction after myocardial infarction. Due to its lower aqueous solubility and extensive first-pass metabolism, the absolute bioavailability of CVD does not exceed 30%. To overcome these drawbacks, the objective of this work was to improve the solubility and onset of action of CVD through complexation with hydroxypropyl-β-cyclodextrin and formulation of the prepared complex as orodispersible tablets (ODTs).MethodsCompatibility among CVD and all tablet excipients using differential scanning calorimetry and Fourier transform infrared spectroscopy, complexation of CVD with different polymers, and determination of the solubility of CVD in the prepared complexes were first determined. A Box-Behnken design (BBD) was used to study the effect of tablet formulation variables on the characteristics of the prepared tablets and to optimize preparation conditions. According to BBD design, 15 formulations of CVD-ODTs were prepared by direct compression and then evaluated for their quality attributes. The relative pharmacokinetic parameters of the optimized CVD-ODTs were compared with those of the marketed CVD tablet. A single dose, equivalent to 2.5 mg/kg CVD, was administered orally to New Zealand white rabbits using a double-blind, randomized, crossover design.ResultsThe solubility of CVD was improved from 7.32 to 22.92 mg/mL after complexation with hydroxypropyl-β-cyclodextrin at a molar ratio of 1:2 (CVD to cyclodextrin). The formulated CVD-ODTs showed satisfactory results concerning tablet hardness (5.35 kg/cm2), disintegration time (18 seconds), and maximum amount of CVD released (99.72%). The pharmacokinetic data for the optimized CVD-ODT showed a significant (P<0.05) increase in maximum plasma concentration from 363.667 to 496.4 ng/mL, and a shortening of the time taken to reach maximum plasma concentration to 2 hours in comparison with the marketed tablet.ConclusionThe optimized CVD-ODTs showed improved oral absorption of CVD and a subsequent acceleration of clinical effect, which is favored for hypertensive and cardiac patients.

Optimization of carvedilol solid lipid nanoparticles: An approach to control the release and enhance the oral bioavailability on rabbits

“…The blood samples (0.5 ml) were withdrawn from the marginal ear vein at predetermined time points (0, 0.5, 1, 2, 4, 6, 8, 12, and 24 h) after oral administration of the test/reference formulations. Afterward, the samples were centrifuged at 3,500 rpm for 5 min and then the obtained plasma samples were stored at −20°C until assay using the previously reported modified HPLC method [ 29 , 31 ].…”

Development of an Electrospun Patch Platform Technology for the Delivery of Carvedilol in the Oral Mucosa

“…The peaks at 2923 and 2835 cm −1 can be assigned to the C-H stretching and the peaks at 1502 and 1589 cm −1 were assigned to the C=C stretching bond in the aromatic ring (dashed line pointed in Figure 3 ). The vibration of C–N is observed at 1454 cm −1 , whilst the vibration associated with the phenyl group ring C–C is in the range of 1403–1256 cm −1 [ 18 , 35 , 36 ].…”