Off-Label use of Raloxifene hydrochloride in uterine fibroids: A novel insert-based formulation approach and IN-VIVO preclinical evaluation

Abstract

Most available uterine fibroids (UF) treatments are invasive and administered through either oral or parenteral routes. Raloxifene hydrochloride (RLH), a selective estrogen receptor modulator, is chosen as a drug of choice. Currently, it is used in the prevention and treatment of osteoporosis. However, RLH in recent clinical trials on UF shows a significant reduction in the size of UF; therefore, the present work is proposed to use RLH for its off-label use for the treatment of UF. This research aimed to formulate an RLH-loaded drug eluting insert (DEI) and study its uterine-targeting efficiency after intrauterine administration. Capsular-shaped biodegradable insert was prepared by melting method. PCL was selected as the rate-controlling polymer, while PEG 4000 and Vitamin ETPGS were selected as solubilizers. The insert was characterized using SEM, FTIR, XRD, and DSC and evaluated for mechanical strength, drug loading, in-vitro drug release, in-vivo evaluation, and histology studies. The results signify no interference between the drug and excipients in designing the RLH insert. The drug release showed up to 45–50% in 15 days with the desired degradation. In a healthy New Zealand white female rabbit, uterus fibroid was induced by Diethylstilbestrol. The uterus fibroid was confirmed by ultrasonography before the insertion of the implant surgically. The therapeutic effects of Raloxifene were evaluated based on detecting fibroid shrinkage at specific intervals and tissue histology at the end of the study. The Raloxifene-treated rabbits showed positive therapeutic results in comparison to placebo and untreated animals. Preclinical in vivo results show the biodegradation of DEI with a significant reduction in the size of UF. Uterine targeting of RLH-insert was successfully designed and evaluated for its off-label use in the treatment of UF through intrauterine targeting via. Vaginal route. Drug targeting to the site of action anticipates the dose reduction desired to elicit the therapeutic outcome and overcome the side effects of existing therapies.