Intravaginal Drug Delivery Systems to Treat the Genitourinary Syndrome of Menopause: Towards the Design of Safe and Efficacious Estrogen-loaded Prototypes.

Estrogens locally delivered to the vagina by tablets, capsules, rings, pessaries, and creams are the most common and highly recommended platforms to treat the genitourinary syndrome of menopause (GSM). Estradiol, an essential estrogen, is routinely administered alone, or in combination with progestins, to effectively alleviate the symptoms associated with moderate to severe menopause when non-pharmacological interventions are not indicated. Since the risk and side effects of estradiol use depends on the administered amount and duration of use, the lowest effective dose of estradiol is recommended when long-term treatment is required. Although there is a wealth of data and literature comparing vaginally administered estrogen-containing products, there is a lack of information revealing the effect of the delivery system used and formulation constituent's attributes on the efficacy, safety, and patient acceptability of these dosage forms. This review therefore aims to classify and compare various designs of commercially available and non-commercial vaginal 17β-estradiol formulations and analyze their performance in terms of systemic absorption, efficacy, safety, and patient satisfaction and acceptance. The vaginal estrogenic platforms included in this review are the currently marketed and investigational 17β-estradiol tablets, softgel capsules, creams, and rings for the treatment of GSM, based on their different design specifications, estradiol loads, and materials used in their preparation. Additionally, the mechanisms of the effects of estradiol on GSM have been discussed, as well as their potential impact on treatment efficacy and patient compliance.