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

Yazeed Hm Aljimaee, Abdel-Rahim M El-Helw, Osama Aa Ahmed, Khalid M El-Say, Yazeed Hm Aljimaee, Abdel-Rahim M El-Helw, Osama Aa Ahmed, Khalid M El-Say

Abstract

Background: Carvedilol (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).

Methods: Compatibility 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.

Results: The 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/cm(2)), 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.

Conclusion: The optimized CVD-ODTs showed improved oral absorption of CVD and a subsequent acceleration of clinical effect, which is favored for hypertensive and cardiac patients.

Keywords: Box-Behnken design; bioavailability; hydroxypropyl-β-cyclodextrin; oral absorption.

Figures

Figure 1
Figure 1
Solubility of CVD in solid dispersion and complexes with different polymers in different ratios. Values in the figure indicate highest and lowest solubility of binary complex compared with the raw CVD value. Notes: Solid dispersion polymers used were PVP K30 and PVP K90 with average molecular weights of 44,000, and 360,000, respectively. CVD was complexed with α, β, γ, and HP-β CD. Abbreviations: PVP, polyvinyl pyrrolidone; HP, hydroxylpropyl; CD, cyclodextrin; CVD, carvedilol.
Figure 2
Figure 2
Differential scanning calorimetry thermograms of carvedilol and various binary systems. Abbreviations: HP, hydroxylpropyl; CD, cyclodextrin.
Figure 3
Figure 3
Fourier transform infrared spectra of carvedilol alone, with HP-β-CD as a complex, and as binary mixtures with Explotab, camphor, Avicel, and mannitol. Abbreviations: HP, hydroxylpropyl; CD, cyclodextrin.
Figure 4
Figure 4
In vitro release profiles for CVD-ODT formulations prepared according to a Box-Behnken design. As a result of overlapping, error bars are omitted for clarity. Abbreviations: CVD, carvedilol; ODT, orodispersible tablet.
Figure 5
Figure 5
Standardized Pareto charts and main effect plots for Y1, Y2 and Y3. Abbreviations: Y1, hardness of the prepared tablets; Y2, disintegration time; Y3, cumulative amount of drug released after one hour.
Figure 6
Figure 6
Estimated response surfaces with contour plots showing the effects of X1, X2, and X3 on the dependent variables (Y1–Y3) Abbreviations: X1, percentage of Explotab; X2, percentage of camphor; X3, percentage of Avicel; Y1, hardness of the prepared tablets; Y2, disintegration time; Y3, cumulative amount of drug released after one hour.
Figure 7
Figure 7
Mean plasma concentration-time profiles for CVD and pharmacokinetic parameters (inset) after oral administration of a single dose (2.5 mg/kg) of the marketed tablet and the CVD-ODT formulations. Notes: Data represent the mean value ± standard deviation (n=6). Abbreviations: CVD, carvedilol; ODT, orodispersible tablet; AUC, area under the time–concentration curve; Cmax, maximum plasma concentration; Kel, elimination rate constant; MRT, mean residence time; SMV, simvastatin; t1/2, half-life; Tmax, time to reach Cmax.

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