Abstract
Naringenin, a flavonoid compound which exists abundantly in Citrus fruits, is proven to possess excellent antitussive and expectorant effects. However, the clinical applications of naringenin are restricted by its poor solubility and low local concentration by oral administration. The aim of the present study is to prepare a naringenin-hydroxypropyl-β-cyclodextrin (naringenin-HPβCD) inclusion as an inhalation solution for pulmonary delivery. The naringenin-HPβCD inclusion was characterized by phase solubility study, XRD, differential scanning calorimetry (DSC), proton nuclear magnetic resonance (1HNMR), and two-dimensional rotating frame Overhauser effect spectroscopy (2D ROESY). The in vitro permeability of the inclusion was evaluated on Calu-3 cells and the pharmacokinetic profile of pulmonary delivery was investigated in Sprague-Dawley (SD) rats. Based on the linear model of phase solubility study, the relationship between naringenin and HPβCD was identified as AL type with a 1:1 stoichiometry. XRD, DSC, and NMR studies indicated that the entire naringenin molecule is encapsulated into the cavity of HPβCD. HPβCD could increase the concentration of naringenin in the epithelium-lining fluid (ELF) of Calu-3 cells and act as a sustained release system for naringenin. The pharmacokinetic profile of naringenin-HPβCD inclusion showed rapid response and higher local concentration by pulmonary delivery. In conclusion, pulmonary delivery of naringenin-HPβCD inclusion is a promising formulation strategy, which could provide a new possibility for the clinical application of naringenin.
Highlights
Naringenin (5,7,40 -trihydroxyflavanone, Figure 1a) is a flavanone found abundantly in Citrus fruits, such as grapefruits, oranges and pummelos, and it is the active ingredient of many Chinese herbal medicines [1]
The solubility of naringenin increased linearly (37 to 273 times) as a function of HPβCD concentration over the studied concentration range, which could be classified as AL type according to Higuchi and Connors [21]
The stability constant Ks is introduced to present the solubilizing efficiency of cyclodextrins for a drug, and the complexation efficiency is used to describe the ratio between cyclodextrin inclusions and free cyclodextrins [25]
Summary
Naringenin (5,7,40 -trihydroxyflavanone, Figure 1a) is a flavanone found abundantly in Citrus fruits, such as grapefruits, oranges and pummelos, and it is the active ingredient of many Chinese herbal medicines [1]. A large number of formulation strategies were employed to solve these problems, including inclusion complexes, self-nanoemulsifying drug delivery system, solid dispersions, and nanoparticles [1,2,12,13,14,15]. These formulations were designed for oral administration, which has limited improvement of bioavailability due to the first pass effect, and tissue distribution study showed that most naringenin was concentrated in the gastrointestinal tract, while a little naringenin could reach the lungs [16,17,18]. To achieve better therapeutic efficiency for respiratory diseases, it is necessary to develop a new delivery route for naringenin
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