Pharmacology, pharmacogenomics, drug discovery and design, drug therapy
Background: Nabumetone (NAB) is a poorly soluble nonsteroidal anti-inflammatory prodrug
(BCS class II drug) whose solubility is significantly improved by complexation with
cyclodextrins (CDs). Methods: The solid complexes, in a 1:1 molar ratio, were prepared
by mechanochemical activation by grinding, using β-cyclodextrin (β-CD) and its derivatives,
hydroxypropyl- and sulfobutylether-β-cyclodextrin (HP-β-CD and SBE-β-CD). The complexation
was confirmed by differential scanning calorimetry (DSC), powder X-ray diffraction
(PXRD), and attenuated total reflectance Fourier-transformed infrared spectroscopy
(ATR–FTIR). Obtained products were further characterized regarding their solubility,
in vitro dissolution, permeability and chemical stability. Results: Co-grinding with
HP-β-CD and SBE-β-CD yielded products that showed in vitro dissolution profiles in
hydrochloric acid medium (pH 1.2) that were substantially different from that of pure
NAB, yielding dissolution efficiency enhancements of 34.86 ± 1.64 and 58.30 ± 0.28
times, respectively, for the optimized products. Their in vitro dissolution and gastrointestinal
permeability were also studied in a low-volume environment at pH 6.8, corresponding
to the intestinal environment. Both β-CD derivatives increased NAB dissolution rate
and NAB mass transport across the biomimetic membrane. The effect of β-CD derivatives
on NAB chemical stability was studied under the stress conditions by the developed
and validated UHPLC–DAD–HRMS method. In acidic conditions, pure and complexed NAB
was prone to hydrolytic degradation, yielding one degradation product—pharmacologically
inactive NAB metabolite. However, under the oxidative conditions at elevated temperatures,
10 NAB degradation products were identified from co-ground samples. All systems were
stable during photo- and long-term stability studies. Conclusions: NAB complexes with
HP-β-CD and SBE-β-CD are promising candidates for pharmaceutical product development.
