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

• Published in: Pharmaceutical research Vol. 31; no. 3; pp. 694 - 705
• Main Authors: Jesson, Gérald, Brisander, Magnus, Andersson, Per, Demirbüker, Mustafa, Derand, Helene, Lennernäs, Hans, Malmsten, Martin
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.03.2014; Springer Nature B.V
• Subjects: Administration, Oral; Animals; Bioavailability; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Carbon dioxide; Carbon Dioxide - chemistry; Dogs; Drug Carriers - chemistry; hybrid; Hybridization; Inhibitor drugs; Intestinal Absorption; Kinases; Male; Medical Law; nanoparticle; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Pharmaceutical sciences; Pharmacology/Toxicology; Pharmacy; Polymers - chemistry; protein kinase inhibitor; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Research Paper; Solubility; Surface-Active Agents - chemistry; carbon dioxide; nanoparticle; protein kinase inhibitor; hybrid; bioavailability
• ISSN: 0724-8741; 1573-904X; 1573-904X
• DOI: 10.1007/s11095-013-1191-4

ABSTRACT Purpose A versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs). Methods The approach is based on nanoparticle precipitation by sub- or supercritical CO 2 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. Results The 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 AUC 0–24h was observed compared to the benchmark formulation. Finally, the generality of the formulation approach taken was demonstrated for a range of PKIs. Conclusions Hybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration.