10 research outputs found
Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions
ABSTRACT: Purpose: Development of a method to assess the drug/polymer miscibility and stability of solid dispersions using a melt-based mixing method. Methods: Amorphous fractured films are prepared and characterized with Raman Microscopy in combination with Atomic Force Microscopy to discriminate between homogenously and heterogeneously mixed drug/polymer combinations. The homogenous combinations are analyzed further for physical stability under stress conditions, such as increased humidity or temperature. Results: Combinations that have the potential to form a molecular disperse mixture are identified. Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time. De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations. Conclusions: The presented results demonstrate that drug/polymer miscibility and stability of solid dispersions, with many mechanistic details, can be analyzed with Atomic Force Microscopy. The assay allows to identify well-miscible and stable combinations within hours or a few day
Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions
PURPOSE: Development of a method to assess the drug/polymer miscibility and stability of solid dispersions using a melt-based mixing method. METHODS: Amorphous fractured films are prepared and characterized with Raman Microscopy in combination with Atomic Force Microscopy to discriminate between homogenously and heterogeneously mixed drug/polymer combinations. The homogenous combinations are analyzed further for physical stability under stress conditions, such as increased humidity or temperature. RESULTS: Combinations that have the potential to form a molecular disperse mixture are identified. Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time. De-mixing is quantified by phase separation analysis, and the drug/polymer combinations are ranked to identify the most stable combinations. CONCLUSIONS: The presented results demonstrate that drug/polymer miscibility and stability of solid dispersions, with many mechanistic details, can be analyzed with Atomic Force Microscopy. The assay allows to identify well-miscible and stable combinations within hours or a few days
Acquired C1 Inhibitor (Cl -INH) Deficiency Type 11 Replacement Therapy with C1-INH and Analysis of Patients' C1-INH and Anti-Cl -INH Autoantibodies
Abstract The response of two patients with autoantibody-mediated Clinhibitor (Cl-INH
P-glycoprotein and surfactants: effect on intestinal talinolol absorption
BACKGROUND AND OBJECTIVE: Surfactants used in pharmaceutical formulations can modulate drug absorption by multiple mechanisms including inhibition of intestinal P-glycoprotein (P-gp). Our objective was to analyze the effect of 2 surfactants with different affinity for P-gp in vitro on the intestinal absorption and bioavailability of the P-gp substrate talinolol in humans. METHODS: In vitro, the influence of surfactants on talinolol permeability was studied in Caco-2 cells. In vivo, an open-label 3-way crossover study with 9 healthy male volunteers was performed. Subjects were intubated with a 1-lumen nasogastrointestinal tube. The study solution, containing either talinolol (50 mg), talinolol and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) (0.04%), or talinolol and Poloxamer 188 (0.8%), was administered through the tube. RESULTS: TPGS, but not Poloxamer 188, inhibited the P-gp-mediated talinolol transport in Caco-2 cells. In healthy volunteers TPGS increased the area under the plasma concentration-time curve with extrapolation to infinity (AUC 0-infinity ) of talinolol by 39% (90% confidence interval, 1.10-1.75) and the maximum plasma concentration (C max) by 100% (90% confidence interval, 1.39-2.88). Poloxamer 188 did not significantly alter the AUC 0-infinity or C max of talinolol. CONCLUSIONS: This in vivo intraduodenal perfusion study showed that low concentrations of TPGS, close to the concentrations that showed P-gp inhibition in vitro, significantly increased the bioavailability of talinolol. The study design excluded modulation of solubility by TPGS and unspecific surfactant-related effects. The latter was supported by the absence of modulation of the talinolol pharmacokinetics by Poloxamer 188, which does not modulate P-gp. Therefore we consider intestinal P-gp inhibition by TPGS as the major underlying mechanism for the increase in talinolol bioavailability
A Systematic Study of Molecular Interactions of Anionic Drugs with a Dimethylaminoethyl Methacrylate Copolymer Regarding Solubility Enhancement
The methacrylate-copolymer Eudragit
EPO (EPO) has raised interest
in solubility enhancement of anionic drugs. Effects on aqueous drug
solubility at rather low polymer concentrations are barely known despite
their importance upon dissolution and dilution of oral dosage forms.
We provide evidence for substantial enhancement (factor 4–230)
of aqueous solubility of poorly water-soluble anionic drugs induced
by low (0.1–5% (w/w)) concentration of EPO for a panel of seven
acidic crystalline drugs. Diffusion data (determined by <sup>1</sup>H nuclear magnetic resonance spectroscopy) indicate that the solubility
increasing effect monitored by quantitative ultraperformance liquid
chromatography was caused primarily by molecular API polymer interactions
in the bulk liquid phase. Residual solid API remained unaltered as
tested by X-ray powder diffraction. The solubility enhancement (SE)
revealed a significant rank correlation (<i>r</i><sub>Spearman</sub> = −0.83) with rDiff<sub>API</sub>, where SE and rDiff<sub>API</sub> are defined ratios of solubility and diffusion coefficient
in the presence and absence of EPO. SE decreased in the order of indomethacin,
mefenamic acid, warfarin, piroxicam, furosemide, bezafibrate, and
tolbutamide. The solubilizing effect was attributed to both ionic
and hydrophobic interactions between drugs and EPO. The excellent
solubilizing properties of EPO are highly promising for pharmaceutical
development, and the data set provides first steps toward an understanding
of drug–excipient interaction mechanisms