β-Casein is a 24 kDa natural protein that has an open conformation and almost no folded or secondary structure, and thus is classified as an intrinsically unstructured protein. At neutral pH, β-casein has an amphiphilic character. Therefore, in contrast to most unstructured proteins that remain monomeric in solution, β-casein self-assembles into well-defined core-shell micelles. We recently developed these micelles as potential carriers for oral administration of poorly water-soluble pharmaceuticals, using celecoxib as a model drug. Herein we present deep and precise insight into the physicochemical characteristics of the protein-drug formulation, both in bulk solution and in dry form, emphasizing drug conformation, packing properties and aggregation state. In addition, the formulation is extensively studied in terms of structure and morphology, protein/drug interactions and physical stability. Particularly, NMR measurements indicated strong drug-protein interactions and noncrystalline drug conformation, which is expected to improve drug solubility and bioavailability. Small-angle X-ray scattering (SAXS) and cryogenic transmission electron microscopy (cryo-TEM) were combined for nanostructural characterization, proving that drug-protein interactions lead to well-defined spheroidal micelles that become puffier and denser upon drug loading. Dynamice light scattering (DLS), turbidity measurements, and visual observations complemented the analysis for determining formulation structure, interactions, and stability. Additionally, it was shown that the loaded micelles retain their properties through freeze-drying and rehydration, providing long-term physical and chemical stability. Altogether, the formulation seems greatly promising for oral drug delivery.
Beta-casein (bCN) micelles were developed as a platform for improved oral bioavailability (BA) of poorly water-soluble drugs. Here we demonstrate a proof-ofconcept using the NSAID celecoxib (Cx) loaded into bCN micelles (Cx/bCN). In a crossover pharmacokinetic (PK) study in pigs (n = 4), dosed intraduodenally with either the commercial Cx formulation Celebra ® or Cx/bCN, the C max obtained after administration of Cx/bCN was 2.3-fold higher and the T max was 1.57-fold faster, leading to a 1.76-fold increase in the BA of Cx, compared to the Celebra ® formulation. It is suggested that this BA enhancement was caused by improvement of Cx solubility in intestinal fluids by bCN micelles, which maintained their Cx cargo in an amorphous state.
The physico-chemical characterization of novel celecoxib-loaded beta-casein micelles (Cx/bCN) was recently described and its superiority in enhancing celecoxib bioavailability after intraduodenal administration to pigs was demonstrated. Here, using solution differential scanning calorimetry (DSC) combined with analysis of size distribution by DLS, zeta potential and changes in composition we demonstrate that the above superiority may be related to the thermotropic behavior of these micelles under physiological conditions. DSC of Cx/bCN reveals a characteristic irreversible exotherm upon heating, having its temperature of maximal change in heat capacity (T
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