Τίτλος:
In Vivo Performance of Innovative Polyelectrolyte Matrices for Hot Melt Extrusion of Amorphous Drug Systems
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Hot melt extrusion of amorphous systems has become a pivotal technology to cope with challenges of poorly water-soluble drugs. Previous research showed that small molecular additives with targeted molecular interactions enabled introduction of a polyelectrolyte matrix into hot melt extrusion that would otherwise not be possible to process due to the unfavorable properties upon heating of the pure polymer. Carboxymethyl cellulose sodium (NaCMC) with lysine or alternatively meglumine led to modified polymeric matrices that showed adequate processability by hot melt extrusion and yielded stable amorphous formulations. The investigated formulations, including fenofibrate as a model drug, were characterized by attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimetry, and viscosity measurements after aqueous dispersion. Further biopharmaceutical assessment started with biorelevant nonsink dissolution testing followed by a pharmacokinetic in vivo study in rats. The in vitro assessment showed superiority of the lysine-containing formulation in the extent of in vitro supersaturation and overall drug release. In accordance with this, the in vivo study also demonstrated increased exposure of the amorphous formulations and in particular for the system containing lysine. In summary, the combination of polyelectrolytes with interacting additives presents a promising opportunity for the formulation of poorly water-soluble drugs. Copyright © 2020 American Chemical Society.
Συγγραφείς:
Ditzinger, F.
Wieland, R.
Statelova, M.
Vertzoni, M.
Holm, R.
Kuentz, M.
Περιοδικό:
Molecular Pharmaceutics
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
carboxymethylcellulose; fenofibrate; lysine; polyelectrolyte; drug; drug carrier; polyelectrolyte; polymer; water, animal experiment; aqueous solution; area under the curve; Article; attenuated total reflectance Fourier transform infrared spectroscopy; chemical phenomena; comparative study; controlled study; data analysis software; differential scanning calorimetry; dispersion; drug absorption; drug bioavailability; drug delivery system; drug formulation; drug mixture; drug release; drug solubility; drug stability; hot melt extrusion; in vitro study; in vivo study; intestine fluid; male; maximum concentration; molecular dynamics; molecular model; nonhuman; plasma concentration-time curve; priority journal; rat; Sprague Dawley rat; supersaturation; thermodynamics; ultra performance liquid chromatography; viscometry; viscosity; X ray powder diffraction; animal; chemistry; drug effect; heat; infrared spectroscopy; medicinal chemistry; procedures; solubility, Animals; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Drug Carriers; Drug Compounding; Drug Liberation; Drug Stability; Hot Melt Extrusion Technology; Hot Temperature; Male; Pharmaceutical Preparations; Polyelectrolytes; Polymers; Rats; Rats, Sprague-Dawley; Solubility; Spectroscopy, Fourier Transform Infrared; Water
DOI:
10.1021/acs.molpharmaceut.0c00485
