Design and in vitro/in vivo evaluation of a compound estradiol-progesterone patch for the treatment of menopausal syndrome

Transdermal estradiol patches have been widely used for the prevention and treatment of ovarian insufficiency. However, they should not be used alone and must be combined with adequate progestin therapy for a full course to provide sufficient endometrial protection. This study aimed to develop a compound estradiol-progesterone transdermal patch by incorporating progesterone into the estradiol patch to reduce the number of medications administered, and to evaluate its feasibility and efficacy. Key excipients in the patch, including pressure-sensitive adhesive, permeation enhancers, and plasticizers, were screened and optimized. The optimal patch formulation was selected based on evaluation criteria including adhesion, cumulative release rate, cumulative permeation, and appearance. Subsequently, a menopausal rat model was established to conduct single-dose pharmacokinetic studies and multiple-dose pharmacodynamic evaluations, comparing results with a commercial estradiol patch and progesterone injection. Results demonstrated that the prepared patches exhibited good conformability and adhesion. The cumulative release rate of E2 over 72 hours was 94.58%, with a cumulative permeation rate of 154.56 μg·cm^-2 over 24 hours. These results are comparable to those of commercially available estradiol patches, which exhibit a 72-hour cumulative release rate of 90.02% and a 24-hour cumulative permeation rate of 148.69 μg·cm^-2. P4 exhibited a 72-hour cumulative release rate of 92.45% and a 24-hour cumulative permeation rate of 104.92 μg·cm^-2, achieving the clinically effective dose threshold. The time to peak concentration and residence time for a single application were longer than those of ESTRANA® Tapes and progesterone injection. Compared with the model group, the combined administration group showed a significantly increased uterine coefficient without the abnormal endometrial thickening observed after using estradiol patches alone. This patch achieves synchronized delivery of estrogen and progesterone, meeting the clinical demand for long-acting hormone therapy.