Fabrication of Carvedilol Nanosuspensions Through the Anti-Solvent Precipitation–Ultrasonication Method for the Improvement of Dissolution Rate and Oral Bioavailability

Abstract

Abstract. The present study aims to prepare carvedilol (CAR) nanosuspensions using the anti-solvent precipitation-ultrasonication technique to improve its dissolution rate and oral bioavailability. Alphatocopherol succinate (VES) was first used as a co-stabilizer to enhance the stability of the nanosuspensions. The effects of the process parameters on particle size of the nanosuspensions were investigated. The optimal values of the precipitation temperature, power inputs, and the time length of ultrasonication were selected as 10°C, 400 W, and 15 min, respectively. Response surface methodology based on central composite design was utilized to evaluate the formulation factors that affect the size of nanosuspensions, i.e., the concentration of CAR and VES in the organic solution, and the level of sodium dodecyl sulfate in the antisolvent phase, respectively. The optimized formulation showed a mean size of 212±12 nm and a zeta potential of −42±3 mV. Scanning electron microscopy revealed that the nanosuspensions were flaky-shaped. Powder Xray diffraction and differential scanning calorimetry analysis confirmed that the nanoparticles were in the amorphous state. Fourier transform infrared analysis demonstrated that the reaction between CAR and VES is probably due to hydrogen bonding. The nanosuspension was physically stable at 25°C for 1 week, which allows it to be further processing such as drying. The dissolution rate of the nanosuspensions was markedly enhanced by reducing the size. The in vivo test demonstrated that the C max and AUC 0-36 values of nanosuspensions were approximately 3.3-and 2.9-fold greater than that of the commercial tablets, respectively.

Preparation, optimization, and in vitro simulated inhalation delivery of carvedilol nanoparticles loaded on a coarse carrier intended for pulmonary administration

“…This was carried out using USP II dissolution apparatus (Hanson Research Corp., Chatsworth, CA, USA) containing 900 mL Sorenson's phosphate buffer pH 6.8 as dissolution medium at 37°C and stirred at 50 rpm. 37 Dissolution samples were withdrawn at 5,10,15,20,30,45,60, and 90 minutes, with replacement of an equal volume of dissolution medium. The samples were filtered and analyzed using an UV spectrophotometer as mentioned earlier.…”

“…CAR is classified as biopharmaceutics classification system class II drug with low solubility and high permeability. 20 It is also subjected to a significant degree of first-pass metabolism. Hence, the absolute bioavailability of CAR has been estimated to be 24%.…”

“…20 Briefly, CAR was dissolved completely in methanol to prepare the organic phase. The antisolvent phase was prepared by dispersing the stabilizers (Pluronic F127, Pluronic F68, and Pluronic P123) each combined with SDC (costabilizer) at 1:1 weight ratio in distilled water.…”

Effect of particle size on oral absorption of carvedilol nanosuspensions: in vitro and in vivo evaluation

“…The HPLC conditions for carvedilol analysis and plasma sample preparation method conformed to the former research studies. 26 …”

Transformation of eutectic emulsion to nanosuspension fabricating with solvent evaporation and ultrasonication technique

“…9 The particle size of the nanosuspension decreased as the power input and ultrasonication time were increased. 10 During solvent removal from the emulsion, drug crystallization occurs in the internal phase droplets, but it is also possible for nucleation to occur within the aqueous phase. However, the crystallization tends to favor a formation of nuclei in the oil phase.…”