title: Reversibly pH-responsive polyurethane membranes for on-demand intravaginal drug delivery.
abstract: To provide better protection for women against sexually transmitted infections, on-demand intravaginal drug delivery was attempted by synthesizing reversibly pH-sensitive polyether-polyurethane copolymers using poly(ethylene glycol) (PEG) and 1,4-bis(2-hydroxyethyl)piperazine (HEP). Chemical structure and thermo-characteristics of the synthesized polyurethanes were confirmed by attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR),1H-nuclear magnetic resonance (1H-NMR), and melting point testing. Membranes were cast by solvent evaporation method using the prepared pH-sensitive polyurethanes. The impact of varying pH on membrane swelling and surface morphology was evaluated via swelling ratio change and scanning electron microscopy (SEM). The prepared pH-responsive membranes showed two times higher swelling ratio at pH 4 than pH 7 and pH-triggered switchable surface morphology change. The anionic anti-inflammatory drug diclofenac sodium (NaDF) was used as a model compound for release studies. The prepared pH-responsive polyurethane membranes allowed continuous NaDF release for 24h and around 20% release of total NaDF within 3h at pH 7 but little-to-no drug release at pH 4.5. NaDF permeation across the prepared membranes demonstrated a reversible pH-responsiveness. The pH-responsive polyurethane membranes did not show any noticeable negative impact on vaginal epithelial cell viability or induction of pro-inflammatory cytokine production compared to controls. Overall, the non-cytotoxic HEP-based pH-responsive polyurethane demonstrated its potential to be used in membrane-based implants such as intravaginal rings to achieve on-demand "on-and-off" intravaginal drug delivery.
  
  
  
  A reversible and sharp switch between "off" and "on" drug release is achieved for the first time through new pH-sensitive polyurethane membranes, which can serve as window membranes in reservoir-type intravaginal rings for on-demand drug delivery to prevent sexually transmitted infections (STIs). Close to zero drug release occurs at the normal vaginal pH (4.5) for minimal side effects. Drug release is only triggered by elevation of pH to 7 during heterosexual intercourse. The reversibly sharp and fast "on-and-off" switch arises from the creative incorporation of a pH-sensitive monomer in the soft segment of polyurethane. This polyurethane biomaterial holds great potential to better protect women who are generally at higher risk and are more vulnerable to STIs.
authors.affiliation: Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Seungil
authors.initials: S
authors.lastname: Kim
authors.affiliation: Laboratory for Drug Delivery and Biomaterials, College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, Manitoba, Canada; Laboratory for Drug Delivery and Biomaterials, College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: Emmanuel_ho@umanitoba.ca.
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Ho
authors.affiliation: Biomedical Engineering, Faculty of Engineering, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Biosystems Engineering, Faculty of Agricultural and Food Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, Manitoba, Canada. Electronic address: Song.Liu@umanitoba.ca.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
mesh_terms: D000282:Administration, Intravaginal; D004008:Diclofenac / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008855:Microscopy, Electron, Scanning; D010539:Permeability; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry; D011140:Polyurethanes / Q000138:chemical synthesis / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D017550:Spectroscopy, Fourier Transform Infrared; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D010879:Piperazines; D011140:Polyurethanes; D004008:Diclofenac; D011092:Polyethylene Glycols
keywords: Intravaginal drug delivery; Reversibly pH-responsive; pH-sensitive polyurethane; pH-triggered on-demand drug release