Abstract
Solid dispersions are a useful approach to improve the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). The aim of this study was to improve the physicochemical properties and bioavailability of a poorly water-soluble aprepitant by preparation of solid dispersions. The solid dispersions were characterized by dissolution, FTIR, XRPD, DSC, SEM and pharmacokinetic studies in rats. The dissolution rate of the aprepitant was significantly increased by solid dispersions, and XRD, DSC, and SEM analysis indicated that the aprepitant existed in an amorphous form within the solid dispersions. The result of dissolution study showed that the dissolution rate of SDs was nearly five-fold faster than aprepitant. FTIR spectrometry suggested the presence of intermolecular hydrogen bonds between the aprepitant and polymer. Pharmacokinetic studies in rats indicated that the degree drug absorption was comparable with that of Emend®. Aprepitant exists in an amorphous state in solid dispersions and the solid dispersions can markedly improve the dissolution and oral bioavailability of the aprepitant. The AUC0–t of the SDs was 2.4-fold that of the aprepitant. In addition, the method and its associated techniques are very easy to carry out.
Highlights
Substance P is the most abundant neurokinin in the mammalian CNS and a potent modulator of neuroimmunoregulation [1,2]
As we expected, an apparent trend was observed between the Soluplus® ratios and the dissolution rate of aprepitant
The dissolution rate of aprepitant was significantly increased by solid dispersion technology
Summary
Substance P is the most abundant neurokinin in the mammalian CNS and a potent modulator of neuroimmunoregulation [1,2]. Aprepitant is a selective high affinity antagonist of human substance. P/neurokinin 1 (NK1) receptors and has little or no affinity for serotonin (5-HT3), dopamine and corticosteroid receptors, which are the targets of existing therapies for chemotherapy-induced nausea and vomiting as well as postoperative nausea and vomiting [3,4,5]. Aprepitant is a basic compound with a pKa value of 9.7 within the pH range 2 to 12. The free base aqueous solubility (3–7 μg/mL) is very low over the pH range 2–10. The compound has a logP value of 4.8 at pH 7.0 [6,7]. The currently marketed formulation of aprepitant (Emend®) is based on nanoparticle technology in which its solubility is increased using drug nanoparticles. The complex nature of nanoparticle technology in terms of processing and effort required necessitate exploration of alternate technologies for solubility enhancement [9,10]
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