An integrated drug delivery device for the localized treatment of the genitourinary syndrome of menopause

The Genitourinary Syndrome of Menopause (GSM) affects millions of women worldwide, with current treatment regimens associated with frequent dosing, inconsistent release profiles, and systemic adverse effects, leading to a decreased patient acceptability. Patient acceptability is pivotal in ensuring adherence and therapeutic outcomes and is defined by the European Medicines Agency as "an overall ability of the patient and caregiver to use a medicinal product as intended" with the International Conference on Harmonization Pharmaceutical Development Guideline (Q8 (R2)) further stating "in all cases, the product should be designed to meet patients' needs and the intended product performance". Accordingly, this study focuses on the development of a multi-unit, polymer-based, intravaginal-intrauterine platform (MUPP) for targeted and controlled hormone delivery with the aim of GSM treatment. The platform comprises of a doughnut-shaped intravaginal device (DVDS) releasing estradiol hemihydrate (E2) and an intrauterine cylindrical unit (NLPM) delivering norethindrone acetate (NETA). An experimental design was implemented to optimize the DVDS formulation. The optimized device was characterized in vitro, assembled with NLPM, and evaluated for their drug release, ex vivo permeation, and cytocompatibility, using NIH/3T3 cells and a 3D-engineered uterine-vaginal cellular model (EUVM). Results showed that the optimal DVDS and NLPM displayed cumulative releases of 5.84 ± 0.24 % (E2) 38.00 ± 1.60 % (NETA) after 4 weeks, with maximum drug flux values (peak permeation rates) of 0.18 ± 0.05 mg⋅cm^-2⋅h^-1 and 0.01 ± 0.03 mg⋅cm^-2⋅h^-1, respectively. Moreover, cytocompatibility analyses showed an average cell viability exceeding the ISO 10993-5 minimum threshold of 70 % after 3 days, rising to above 80 % by Day 7 in both 2D and 3D models, thereby confirming the non-cytotoxic nature of the platform. In conclusion, the MUPP presents a promising and patient-friendly approach to addressing the current challenges of GSM therapy.