Design and Optimization of a Nanoparticulate Pore Former as a Multifunctional Coating Excipient for pH Transition-Independent Controlled Release of Weakly Basic Drugs for Oral Drug Delivery
Research output: Contribution to journal › Journal article › Research › peer-review
Documents
- Fulltext
Final published version, 4.01 MB, PDF document
Bioavailability of weakly basic drugs may be disrupted by dramatic pH changes or unexpected pH alterations in the gastrointestinal tract. Conventional organic acids or enteric coating polymers cannot address this problem adequately because they leach out or dissolve prematurely, especially during controlled release applications. Thus, a non-leachable, multifunctional terpolymer nanoparticle (TPN) made of cross-linked poly(methacrylic acid) (PMAA)-polysorbate 80-grafted-starch (PMAA-PS 80-g-St) was proposed to provide pH transition-independent release of a weakly basic drug, verapamil HCl (VER), by a rationally designed bilayer-coated controlled release bead formulation. The pH-responsive PMAA and cross-linker content in the TPN was first optimized to achieve the largest possible increase in medium uptake alongside the smallest decrease in drug release rate at pH 6.8, relative to pH 1.2. Such TPNs maintained an acidic microenvironmental pH (pHm) when loaded in ethylcellulose (EC) films, as measured using pH-indicating dyes. Further studies of formulations revealed that with the 1:2 VER:TPN ratio and 19% coating weight gain, bilayer-coated beads maintained a constant release rate over the pH transition and exhibited extended release up to 18 h. These results demonstrated that the multifunctional TPN as a pHm modifier and pH-dependent pore former could overcome the severe pH-dependent solubility of weakly basic drugs.
Original language | English |
---|---|
Article number | 547 |
Journal | Pharmaceutics |
Volume | 15 |
Issue number | 2 |
Number of pages | 21 |
ISSN | 1999-4923 |
DOIs | |
Publication status | Published - 2023 |
Bibliographical note
Funding Information:
This project is supported in part by the Natural Sciences and Engineering Research Council (NSERC) Discovery grant (RGPIN-2019-07204) and equipment grants (EQPEQ 374799-09, EQPEQ 440689-13) to X.W.; and the Mitacs Accelerate Internship to H.H.R.C. with Patheon by Thermo Fisher Scientific (IT08610).
Funding Information:
The authors would like to thank BASF, Colorcon, and Croda for providing samples of PVP, Surelease EC, and PS 80, respectively; and to thank David Dubins, for the use of the fluid bed coater in the Patheon Pharmaceutics Teaching Laboratory; and to thank the Departmental Scholarships and Hoffman-La Roche/Rosemarie Hager Graduate Fellowship to K.C., and to thank the Dean’s Fund for Ph.D. Scholarship to J.A.L.-P.; and to thank the stipendium from the government of Denmark to N.A.-M. ®
- bilayer-coated beads, controlled release, microenvironmental pH modifier, multifunctional terpolymer excipient, nanogel optimization, pH-independent release, pH-responsive nanoparticles, pore former, weakly basic drug
Research areas
ID: 339334341