Physical characteristics and properties of estradiol softgel vaginal inserts

Abstract

Objective: TX-004HR is a low-dose estradiol (E2) softgel vaginal insert designed to be rapidly dissolving and mucoadhesive. This report describes the physical attributes and pharmacokinetic parameters of the softgel vaginal insert evaluated for the treatment of moderate to severe dyspareunia due to menopausal vulvar and vaginal atrophy. Methods: In vitro dissolution studies with 25-μg E2 inserts were performed and media samples were analyzed for E2 by high-performance liquid chromatography. Effects of body position on E2 bioavailability were assessed in a phase 1, randomized trial of the 25-μg softgel capsule versus a reference product in which women remained supine after dosing (n = 16), and in a substudy (n = 16) in which women were ambulatory or seated after dosing. Estradiol C max, AUC0-24, and t max were measured by high-performance liquid chromatography-tandem mass spectroscopy. A phase 2, randomized study (n = 50) of 10-μg E2 versus placebo inserts assessed timing of capsule disintegration at days 1 and 15. Results: In vitro testing detected more than 80% of E2 in the dissolution medium by 15 minutes (first time point measured). In the phase 1 studies, baseline-corrected E2 plasma levels were not significantly different regardless of supine versus ambulatory/seated position after dosing: C max, 24.1 versus 34.3 pg/mL; AUC0-24, 77.6 versus 93.7 h · pg/mL; and t max, 2.1 versus 1.9 hours, respectively. In the phase 2 study, no remnants of the softgel capsule were found at day 1 (6 hours) after dosing and day 15. Vaginal discharge was minimal (1/48 women; 2.1%). Conclusions: The presented data support rapid dissolution of the softgel capsule and similar E2 pharmacokinetic parameters regardless of body position after dosing.

Estradiol softgel inserts for the treatment of VVA symptoms: an expert opinion

“…Overall, the results indicated lower systemic exposure with the E2 softgel vaginal insert than with the vaginal tablet comparator (Figure 3; Table 2) [31]. A follow up of this PK study also demonstrated that there were no body position effects (supine vs ambulatory/seated) on the E2 bioavailability with the TX-004 HR inserts [15]. Finally, the PK parameters for TX-004 HR were evaluated in a substudy of the REJOICE trial [32].…”

“…The E2 softgel vaginal insert (TX-004 HR, Imvexxy® [estradiol vaginal inserts]; TherapeuticsMD, Boca Raton, FL) is approved by the FDA at dosages of 4 μg and 10 μg for the treatment of moderate to severe dyspareunia, a symptom of VVA due to menopause [14]. The E2 vaginal inserts are small, light-pink, tear-shaped softgel capsules, which are inserted manually without the use of an applicator in the lower part of the vagina [15]. The outer capsule shell is composed of gelatin polymers to impart mucoadhesive properties and aid in the retention of the capsule in the vagina while allowing fast dissolution and quick release of the medication in the vagina, and complete dissolution by 6 hours after insertion [15].…”

Application of Sol–Gels for Treatment of Gynaecological Conditions—Physiological Perspectives and Emerging Concepts in Intravaginal Drug Delivery

“…From a patient perspective, such polymers have also assisted in addressing the practical challenges of semi-solid dosage forms, such as leakage [ 37 ]. Mucoadhesive polymers used in soft gelatin capsules of oestradiol provided flexibility of drug positioning, faster dissolution, and higher satisfaction among 85% women, compared to women using conventional vaginal inserts and cream formulations of oestradiol [ 138 ].…”