Solid Dispersions in Medium-Insoluble Hydrogels for Enhancing the Solubility and Bioavailability of Poorly Soluble Drugs

Formulating poorly water-soluble drugs into Amorphous Solid Dispersions (ASDs) based on medium-insoluble hydrogels is an emerging approach showing promise for tackling solubility related oral bioavailability problems. However, critical parameters important to the design of these ASDs have not been fully elucidated. Thus, the first part of the present study examines design factors for ASDs based on Poly(2-Hydroxyethyl methacrylate) (PHEMA) hydrogel beads. Here, it is shown that one can obtain a more sustained supersaturation either through increasing the particle size of medium-insoluble hydrogels to reduce the rate of supersaturation generation or by lowering the total dose under non-sink dissolution conditions. The results of the second part demonstrate that the interplay of particle size, total dose and the swelling capacity is an essential aspect to be considered when tailoring the supersaturation generation from these ASDs. Generally, the higher the swelling capacity of the medium-insoluble carrier, the faster the rate of supersaturation generation, and the shorter the sustained supersaturation due to associated drug precipitation. Furthermore, a large drug partitioning effect between the polymer carrier and dissolution medium has been found to limit the extent of drug supersaturation buildup from these ASDs. The subsequent third part of the study highlights the benefit of defining the Sink Index (SI) as when one simply changes the volume of the dissolution medium or its scale; the resulting kinetic solubility profiles can still remain similar as long as SI is kept constant. It also reveals the difficulty in predicting in vivo performance due to the impact of changing the media buffer composition on the kinetic solubility profiles of amorphous pharmaceuticals. The results of the fourth and the last part of the study serve as a proof of concept exercise for the combined effects of supersaturation rate and dose approach in rats. Here, the head-to-head in vivo comparison of ASDs in water-insoluble and soluble carriers coupled with the Physiologically based Biopharmaceutics Modeling using GastroPlus® demonstrates that these test carriers can provide similar oral absorption enhancement. Further optimization of ASDs in water-insoluble carriers is still required before they can be employed as alternative strategies for bioavailability enhancement.

Department dc:contributor.department

Pharmaceutical Sciences

Year dc:date.issued

2020

Author dc:creator

• Schver, Giovanna

Advisor dc:contributor.advisor

• Lee, Ping I

• Amorphous Solid Dispersions
• Enabling Formulations
• In vivo Evaluation
• Kinetic Solubility
• Non-sink Dissolution
• Supersaturation

Statement dc:rights

• Attribution 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/121546

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/121546