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Combining in vitro dissolution/permeation with microdialysis sampling: Capabilities and limitations for biopharmaceutical assessments of supersaturating drug formulations.
Holzem, Florentin Lukas; Jensen, Iben Højgaard; Petrig Schaffland, Jeannine; Stillhart, Cordula; Brandl, Martin; Bauer-Brandl, Annette.
Afiliação
  • Holzem FL; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, Odense 5230, Denmark; Pharmaceutical R&D, F. Hoffmann-La Roche Ltd., Basel 4070, Switzerland.
  • Jensen IH; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, Odense 5230, Denmark.
  • Petrig Schaffland J; Roche Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel 4070, Switzerland.
  • Stillhart C; Pharmaceutical R&D, F. Hoffmann-La Roche Ltd., Basel 4070, Switzerland.
  • Brandl M; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, Odense 5230, Denmark.
  • Bauer-Brandl A; Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, Odense 5230, Denmark. Electronic address: annette.bauer@sdu.dk.
Eur J Pharm Sci ; 188: 106533, 2023 Sep 01.
Article em En | MEDLINE | ID: mdl-37480963
Many novel small drug molecules are poorly water-soluble and thus, enabling drug formulations may be required to ensure sufficient absorption upon oral administration. Biopharmaceutical assessment and absorption prediction of enabling formulations, however, remains challenging. Combined in vitro dissolution/permeation (D/P) assays have gained increasing interest since they may provide a more realistic formulation ranking based on the drug permeation profiles from different formulations as compared to conventional dissolution, which captures both readily permeable and not readily permeable fractions of "dissolved" drug. Moreover, the combined in vitro D/P assays allow to better predict intestinal supersaturation and precipitation processes as compared to simple dissolution setups due to the effect of an absorptive sink. Microdialysis on the other hand has proven useful to determine molecularly dissolved drug in colloidal dispersions, thus allowing for a deeper mechanistic insight into the mechanism of drug release from supersaturating formulations. Here, microdialysis sampling from the donor compartment was used in combination with the dissolution/permeation (D/P) tool PermeaLoop™ to study commercial supersaturating drug formulations of the poorly soluble and weakly basic drug Posaconazole (PCZ). An amorphous solid dispersion (ASD)-based tablet, as well as a crystalline suspension in acidified and neutral dilution medium, respectively, were tested. Microdialysis sampling allowed for differentiation between molecularly dissolved and micellar drug concentration, as expected, but, surprisingly, it was found that the presence of the microdialysis probe affected the precipitation behavior of a crystalline suspension within the two-stage D/P setup, simulating the oral administration of the acidified PCZ (Noxafil®) suspension: the extent and duration of supersaturation in the donor decreased significantly, which also affected permeation. Similarly, for the ASD-based tablet, a less pronounced supersaturation was observed during the first 120 min of the experiment. Hence, in this case, the formulation ranking and the prediction of intestinal supersaturation in the in vitro D/P assay became less predictive as compared to a conventional PermeaLoop™ study without microdialysis sampling. It was concluded that valuable mechanistic insights into the molecularly dissolved drug profiles over time can be obtained by microdialysis. However, since the presence of the probe may affect the degree of supersaturation and precipitation, a conventional D/P assay (without microdialysis sampling) is preferred for formulation ranking of supersaturating drug formulations.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Produtos Biológicos / Química Farmacêutica Idioma: En Revista: Eur J Pharm Sci Assunto da revista: FARMACIA / FARMACOLOGIA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Suíça País de publicação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Produtos Biológicos / Química Farmacêutica Idioma: En Revista: Eur J Pharm Sci Assunto da revista: FARMACIA / FARMACOLOGIA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Suíça País de publicação: Holanda