3. Electronic Theses and Dissertations (ETDs)

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    A Multi-Unit, Polymer-Based, Prolonged-Release, Intrauterine Device for the Relief of the Genitourinary Syndrome of Menopause
    (University of the Witwatersrand, Johannesburg, 2024) Abdelgader, Ahmed Abdalla Bakheit; Govender, Mershen; Kumar, Pradeep; Choonara, Yahya E.
    The genitourinary syndrome of menopause (GSM) is a prevalent condition affecting millions of women globally, with a large number of drug delivery systems currently available for the treatment of this condition. A critical examination of these contemporary delivery modalities for addressing GSM underscores a recurring issue: therapeutic shortcomings frequently arise due to suboptimal patient adherence to prescribed regimens, a consequence attributed to the inefficacy and unsuitability of delivery systems employed. The current therapeutic strategies for GSM management additionally commonly involve oral or vaginal administration of estrogens, yet these methodologies are also affected by inherent limitations and the associated risk of endometrial hyperplasia. Thus, in an effort to address these GSM formulation challenges, an implantable, multi-unit, polymer-based, prolonged release platform (MUPP) has been designed, formulated and evaluated for the site-specific delivery of two hormonal drugs in a prolonged release manner, ultimately easing complicated treatment regimens, and improving patient compliance. The MUPP has been designed as two variants, each comprising three units: The first variant is a fully intrauterine device composed of an estradiol hemihydrate (E2) unit and a norethindrone acetate (NETA) unit, while the second variant is an advancement on the first variant and is composed of a NETA-loaded intrauterine unit and a E2-loaded intravaginal unit. These variants have been prepared to ascertain the effect of site-specific delivery of the active ingredients in both the uterine and vaginal cavities. In the fabrication of both variations an additional intrauterine indomethacin (IND)-loaded unit has been included to alleviate the pain and inflammation associated with the administration of intrauterine devices (IUDs). The MUPP employs a combination of polymer blends to tailor the drug release and weight loss profiles of the individual units. These polymeric blends, which comprises of polycaprolactone (PCL) and ethyl cellulose (EC), were employed to fabricate the E2- and NETA-loaded uterine units, as well as E2-loaded vaginal unit. Meanwhile, the unit loaded with IND employed a polymeric blend of PCL and polyethylene glycol (PEG). The intrauterine units were prepared as hollow cylindrical devices using a simple molding technique, while the intravaginal unit was prepared as a donut-shaped tablet through direct compression. The influence of the drug load and the ratio of each polymer on the key attributes of the intrauterine units were evaluated and thereafter these units were optimized using a design of experiments (DoE) methodology. In addition, the effect of polymer ratio in the polymer blend and the compression force on the E2- 3 loaded intravaginal unit characteristics was studied using a 22 factorial design. The incorporation of E2 aims to achieve adequate hormonal levels to effectively manage GSM symptoms, while NETA serves to alleviate the potential adverse effects due to estrogen monotherapy, such as endometrial hyperplasia. Additionally, through addressing the potential challenges associated with intrauterine device usage, pharmacologically effective concentrations of IND were included to enhance the therapeutic profile and potential acceptability of the MUPP. In both configuration variants, the in vitro drug release and weight loss profiles of NETA- and IND- loaded units were assessed in simulated uterine fluid (SUF, pH 7, 37°C), while the E2-loaded unit was assessed in SUF in the first configuration (variant) and in simulated vaginal fluid (SVF, pH 6 and 4.2, 37°C) in the second configuration. The prepared units were noted to erode gradually and released the drugs in a controlled sustained manner. The fabrication processes were also noted to be simple and reproducible. Furthermore, when regarding the critical attributes of the prepared units such as drug release and erosion patterns, it was found that through the selection of optimal formulation variables (employed polymers concentrations) and processing factors such as a compression force (for the intravaginal unit), there was the potential to fabricate a platform capable of sustaining the release of E2 and NETA for an extended period of time (variant one releasing E2 up to 22 weeks and NETA up to 19 weeks, with variant two further increasing the release of E2 up to 140 weeks), while also delivering IND for two weeks to alleviate the initial pain and inflammatory response due to IUD insertion. Furthermore, the implementation of the design of experiments emerges as a significant methodology, enabling the statistical elucidation of crucial experimental factor combinations and interactions that influence the characteristics of the fabricated units of the MUPP. The produced units furthermore exhibited heightened hardness and resistance to indentation. Moreover, the fabricated units demonstrate commendable cytocompatibility, both individually and when integrated as a unified platform. Overall, the MUPP presents a promising solution to address the challenges of current GSM treatment regimens, potentially revolutionizing drug delivery in the genitourinary tract by providing a versatile platform for the sustained and targeted delivery of multiple drugs in a site-specific manner.