Development and evaluation of novel intravaginal rings fabricated via hot-melt extrusion-based technologies as innovative microbicides
| dc.contributor.author | Chen, Yufei | |
| dc.contributor.examiningcommittee | Gu, Xiaochen (Pharmacy) Liu, Song (Biosystems Engineering) Haddadi, Azita (University of Saskatchewan) | en_US |
| dc.contributor.supervisor | Ho, Emmanuel (Pharmacy) | en_US |
| dc.date.accessioned | 2017-12-12T17:48:05Z | |
| dc.date.available | 2017-12-12T17:48:05Z | |
| dc.date.issued | 2014-10-09 | en_US |
| dc.degree.discipline | Pharmacy | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Recently, there has been an increasing interest of developing topically applied microbicides as novel women-oriented prevention strategies against sexually transmitted infections. Among the different drug delivery systems, drug-eluting intravaginal rings (IVRs) became an attractive option from a pharmacokinetic perspective as it can provide extended residence in the female genital tract (FGT) with controllable sustained release of active pharmaceutical ingredients (APIs) with high user acceptability and patient adherence. In the current thesis, I focused on the development and evaluation of different types of IVRs with emphasis on hot-melt extrusion-based technologies for fabrication including hot-melt extrusion (HME), hot-melt injection molding (HMIM), and fused deposition modeling (FDM) based three-dimensional (3D) printing. Matrix and reservoir type IVRs for sustained delivery of an anti-HIV and immunomodulatory compound, hydroxychloroquine (HCQ), were fabricated with HME and HMIM processes. Surface coating with either polyvinylpyrrolidone or poly(vinyl alcohol) dramatically reduced the burst release effect from matrix-type HCQ polyurethane (PU) IVRs while reservoir-type PU IVRs made from 35% water swellable hydrophilic PU exhibited nearly zero-order release profile of HCQ at the rate of 32.23 g/mL/day. Furthermore, we transformed the same reservoir IVR segments into a RFID-tagged rabbit vaginal implant and evaluated its in vivo release and efficacy to maintain a low baseline of local immune activity under acute exposure of nonoxynol-9 (N9). We developed a novel implantation procedure to non-invasively place the implant within the upper section of the rabbit vaginal cavity and its vaginal residence was more than 40 days with evident long-term biocompatibility even when in direct contact with rabbit vaginal epithelium. The HCQ delivered from the rabbit implant maintained therapeutic effective concentrations of HCQ in rabbit vaginal fluid during the study, attenuated N9-induced vaginal epithelium damage, reduced pro-inflammatory cytokine and chemokine production, and most appealingly, abolished the expression of local T lymphocyte activation markers. In an attempt to realize precise and tunable release of APIs under different categories, we introduced FDM 3D printing to produce reservoir PU IVR and IVR segments with precisely controlled rate-controlling membrane (RCM) thickness and porosity for API diffusion. By altering print patterns and interior fill densities, FDM 3D printing demonstrated to be an attractive fabrication technology to modulate the release of small chemotherapeutics, macromolecules, and PLGA nanoparticles. | en_US |
| dc.description.note | February 2018 | en_US |
| dc.identifier.citation | Chen, Y., et al., Development of polyether urethane intravaginal rings for the sustained delivery of hydroxychloroquine. Drug Des Devel Ther, 2014. 8: p. 1801-15. | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/32716 | |
| dc.language.iso | eng | en_US |
| dc.publisher | Drug Design, Development and Therapy | en_US |
| dc.rights | open access | en_US |
| dc.subject | Drug Delivery | en_US |
| dc.title | Development and evaluation of novel intravaginal rings fabricated via hot-melt extrusion-based technologies as innovative microbicides | en_US |
| dc.type | doctoral thesis | en_US |