16 research outputs found
Enhanced Bioavailability and Reduced Variability of Dasatinib and Sorafenib with a Novel Amorphous Solid Dispersion Technology Platform
No full textDespite clinical advances with protein kinase inhibitors (PKIs), oral administration of many PKIs is associated with highly variable plasma exposure and a narrow therapeutic window. We developed a novel hybrid nanoparticle-amorphous solid dispersion (ASD) technology platform consisting of an amorphous PKI embedded in a polymer matrix. The technology was used to manufacture immediate-release formulations of 2 tyrosine kinase inhibitors (TKIs), dasatinib and sorafenib. Our primary objective was to improve the absorption properties and reduce the pharmacokinetic (PK) variability of each TKI. The PKs of XS004 (dasatinib-ASD, 100 mg tablet) and XS005 (sorafenib-ASD, 2 x 50 mg capsules) were compared with their crystalline formulated reference drugs (140 mg of dasatinib-reference and 200 mg of sorafenib-reference). The in vitro biopharmaceutics of dasatinib-ASD and XS005-granulate showed sustained increased solubility in the pH range 1.2-8.0 compared to their crystalline references. In vivo, XS004 was bioequivalent at a 30% lower dose and showed increased absorption and bioavailability, with 2.1-4.8 times lower intra- and intersubject variability compared to the reference. XS005 had an increased absorption and bioavailability of 45% and 2.2-2.8 times lower variability, respectively, but it was not bioequivalent at the investigated dose level. Taken together, the formulation platform is suited to generate improved PKI formulations with consistent bioavailability and a reduced pH-dependent absorption process
Severe Impact of Omeprazole Timing on pH-Sensitive Dasatinib Absorption : Unveiling Substantial Drug-Drug Interaction
No full textThe absorption and bioavailability of most tyrosine kinase inhibitors are affected by gastrointestinal pH as they are weak basic lipophilic drugs. Hence, concomitant use of acid reducing agents (ARAs) is frequently restricted. Particularly comedication of crystalline dasatinib (Sprycel) and proton-pump inhibitors (PPIs) should be avoided. Drug–drug interaction (DDI) studies with PPIs report approximately 40%-80% bioavailability reduction of dasatinib. Limitations in the design of these studies do not allow for assessing the near maximum DDI as timing of PPI dosing was either not reported or 22 h prior to dasatinib intake. We conducted a DDI study of crystalline dasatinib and omeprazole in healthy, fasted participants, investigating the impact of PPI comedication on dasatinib plasma exposure at a time point when the near maximum DDI effect is expected. Participants were administered omeprazole (day 2-5) to reach steady state. On day 6, a single dose of crystalline dasatinib was given. Crystalline dasatinib dosing alone on day 1 served as control (single dose). The dosing interval between omeprazole administration and crystalline dasatinib was 10 h (median [range: 9-10 h]). Dasatinib Cmax and AUC0-24 were reduced by 96% and 89% by omeprazole comedication. Cmax was 224.6 ± 104.7 ng/mL (mean ± SD) and 8.0 ± 4.5 ng/mL (P < .0001) and AUC0-24 was 797.6 ± 274.5 and 90.6 ± 38.1 h·ng/mL (P < .0001) without and with omeprazole. T1/2 was 5.7 ± 1.5 h (mean ± SD) with crystalline dasatinib dosing alone and could not be reliably calculated with comedication. To ensure optimal patient outcome, it is vital to investigate bioavailability of pH-sensitive drugs at the maximal DDI effect of ARAs to understand the worst-case influence for efficient clinical management
ChemInform Abstract: Serotonergic and Dopaminergic Activities of Rigidified (R)‐Aporphine Derivatives.
No full textCarbon Dioxide-Mediated Generation of Hybrid Nanoparticles for Improved Bioavailability of Protein Kinase Inhibitors
Get PDFA versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs). The 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. 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. Hybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration.</p
Design and Synthesis of Amide Isosteres of Phe-Gly: Potential Peptidomimetic Ligands for the Intestinal Oligopeptide Transporter PepT1
No full textAlkylation of Tricarbonylchromium-Stabilized Benzylic Anions of 3-(Dipropylamino)chroman
No full textTricarbonylchromium complexes of racemic and resolved 3-(dipropylamino)chromans were prepared.
Benzylic alkylation of the complexes provided access to 4-alkylated derivatives. Alkylations of the
endo complex gave only the expected trans products. Unexpectedly, the exo complex predominantly
(with methyl iodide) or almost exclusively (with allyl and benzyl bromide) produced the trans
derivatives. Steric effects and the nature of the electrophiles appear to direct the outcome of the
alkylations
ChemInform Abstract: Derivatives of (R)-1,11-Methyleneaporphine: Synthesis, Structure, and Interactions with G-Protein Coupled Receptors.
No full textMatrix effects in nilotinib formulations with pH-responsive polymer produced by carbon dioxide-mediated precipitation
No full textFactors determining the pH-controlled dissolution kinetics of nilotinib formulations with the pH-titrable polymer hydroxypropyl methylcellulose phthalate, obtained by carbon dioxide-mediated precipitation, were mechanistically examined in acid and neutral environment. The matrix effect, modulating the drug dissolution, was characterized with a battery of physicochemical methodologies, including ToF-SIMS for surface composition, SAXS/WAXS and modulated DSC for crystallization characterization, and simultaneous UV-imaging and Raman spectroscopy for monitoring the dissolution process in detail. The hybrid particle formulations investigated consisted of amorphous nilotinib embedded in a polymer matrix in single continuous phase, displaying extended retained amorphicity also under wet conditions. It was demonstrated by Raman and FTIR spectroscopy that the efficient drug dispersion and amorphization in the polymer matrix were mediated by hydrogen bonding between the drug and the phthalate groups on the polymer. Simultaneous Raman and UV-imaging studies of the effect of drug load on the swelling and dissolution of the polymer matrix revealed that high nilotinib load prevented matrix swelling on passage from acid to neutral pH, thereby preventing re-precipitation and re-crystallization of incorporated nilotinib. These findings provide a mechanistic foundation of formulation development of nilotinib and other protein kinase inhibitors, which are now witnessing an intense therapeutic and industrial attention due to the difficulty in formulating these compounds so that efficient oral bioavailability is reached.</p
