Amorphous solid dispersions of carvedilol along with pH‐modifiers improved pharmacokinetic properties under hypochlorhydoria

Abstract

Carvedilol (CAR) belongs to biopharmaceutics classification system class-II drugs, with poor aqueous solubility and pH-dependent solubility. The present study aimed to develop a novel amorphous solid dispersion (ASD) of CAR with acidic counter ions for pH modifications in microenvironment to improve the pharmacokinetic properties under hypochlorhydric conditions. CAR-ASD was prepared by freeze-drying in combination with counter ions and hydroxypropyl cellulose, and their physicochemical properties including dissolution behavior, storage stability, and photostability were characterized. Pharmacokinetic studies were carried out after oral administration of CAR samples in both normal and omeprazole-treated (30 mg/kg, p.o.) rats as a hypochlorhydria model. Among the tested six counter ions, citric acid (CA) was found to be a preferable pH-modifier of CAR with respect to the dissolution profile and photostability (both potency and colorimetric evaluation). In CAR-ASD formulation with 50% loading of CA (CAR-ASD/CA50), amorphization of CAR was observed during the preparation process. After the oral administration of crystalline CAR in rats under hypochlorhydric condition, there was a 34.4% reduction in the systemic exposure of CAR compared with that in normal rats. However, orally-dosed CAR-ASD/CA50 resulted in limited alterations of pharmacokinetic behavior between normal and omeprazole-treated rats. From these findings, addition of CA as pH-modifier in CAR-ASD might provide consistent pharmacokinetic behavior of CAR even under hypochlorhydric conditions.

Impact of drying on dissolution behavior of carvedilol-loaded sustained release solid dispersion: development and characterization

“…According to DSC thermograms ( Figure 3 B), a melting endotherm was observed at ca. 119 °C for crystalline CAR ( Figure 3 B–I), corresponding to the melting point of CAR [ 6 ]. In contrast, there was a decrease of the endothermic peak in SRSD-CAR/RVD and SRSD-CAR/FD at the melting point of crystalline CAR ( Figure 3 B).…”

“…Carvedilol (CAR) is a nonselective, α1 and β1, β2 adrenergic receptor antagonist that has emerged as a promising drug moiety for cardiovascular disease, showing a significant improvement in patients suffering from chronic cardiac insufficiency [ 2 , 6 ]. It is a weakly basic drug with a pKa value 6.8 and practically insoluble in water (4.4 μg/mL) [ 7 ].…”

“…Therefore, poor solubility and short biological half-life limit its clinical application as multiple dosing required to maintain optimum plasma concentration. Considering these drawbacks, different strategies have been implemented to enhance the dissolution characteristics of CAR [ 2 , 6 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Enhancement of the Dissolution Rate of Indomethacin by Solid Dispersions in Low-substituted Hydroxypropyl Cellulose

“…Low-substituted hydroxypropylcellulose (L-HPC) [20] and sodium dodecyl sulphate (SDS) [21] have been used by several researchers as carriers to obtain solid dispersions of poorly soluble drugs. L-HPC, as an inert carrier, has properties as a disintegrant [22] , and also improves the wettability and dispersibility of solid dispersions, which may influence the drug's dissolution behaviour [23][24][25] . SDS is an anionic surfactant that enhances drug wetting [21] .…”