Carbon Dioxide-Mediated Generation of Hybrid Nanoparticles for Improved Bioavailability of Protein Kinase Inhibitors

Abstract

PurposeA versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs).MethodsThe approach is based on nanoparticle precipitation by sub- or supercritical CO2 together with a matrix-forming polymer, incorporating surfactants either during or after nanoparticle formation. Notably, striking synergistic effects between hybrid PKI/polymer nanoparticles and surfactant added after particle formation is investigated.ResultsThe hybrid nanoparticles, consisting of amorphous PKI embedded in a polymer matrix (also after 12 months), display dramatically increased release rate of nilotinib in both simulated gastric fluid and simulated intestinal fluid, particularly when surfactants are present on the hybrid nanoparticle surface. Similar results indicated flexibility of the approach regarding polymer identity, drug load, and choice of surfactant. The translation of the increased dissolution rate found in vitro into improved GI absorption and bioavalilability in vivo was demonstrated for male beagle dogs, where a 730% increase in the AUC0–24h was observed compared to the benchmark formulation. Finally, the generality of the formulation approach taken was demonstrated for a range of PKIs.ConclusionsHybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-013-1191-4) contains supplementary material, which is available to authorized users.

Formulation, Characterization, and in Vivo Evaluation of Celecoxib-PVP Solid Dispersion Nanoparticles Using Supercritical Antisolvent Process

“…Yasuji et al reviewed particle design of poorly water-soluble APIs using supercritical fluid technologies [14]. Solid dispersion nanoparticles manufactured with hydrophilic polymers and surfactants using the SAS process significantly improved the solubility, dissolution, and oral bioavailability of poorly water-soluble APIs such as atorvastatin calcium, azithromycin, dutasteride, lercanidipine, nilotinib, valsartan, tadalafil and telmisartan [15,16,17,18,19,20,21,22,23].…”

Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective

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Understanding the Structural Differences between Spherical and Rod‐Shaped Human Insulin Nanoparticles Produced by Supercritical Fluids Precipitation

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“…[4][5][6][8][9][10]] Surprisingly, protein nanoparticles fabricated with supercritical fluids retain their biological activity and native structure upon redissolution in aqueous solution. [1,[4][5][6][8][9][10] Pyo reported that two shapes of insulin nanoparticles can be produced using the SEDS process from dimethyl sulfoxide (DMSO) and ethanol (EtOH) solutions without the use of additives. [5] DMSO and EtOH were used to assist the supercritical carbon dioxide extraction of water from the aqueous protein solution.…”