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Preterm birth (PTB) is a significant global problem, but few therapeutic options exist. Vaginal progesterone supplementation has been demonstrated to reduce PTB rates in women with a sonographic short cervix, yet there has been little investigation into the most effective dose or delivery form. Further, vaginal products like progesterone gel often contain excipients that cause local toxicity, irritation, and leakage. Here, we describe the development and characterization of a mucoinert vaginal progesterone nanosuspension formulation for improved drug delivery to the female reproductive tract. We compare the pharmacokinetics and pharmacodynamics to the clinical comparator progesterone gel in pregnant mice and demonstrate increased vaginal absorption and biodistribution via the uterine first-pass effect. Importantly, the unique plasma progesterone double peak observed in humans, reflecting recirculation from the uterus, was also observed in pregnant mice with vaginal dosing. We adapted a mouse model of progesterone withdrawal that was previously believed to be incompatible with testing the efficacy of exogenous progestins, and are first to demonstrate efficacy in preventing preterm birth with vaginal progesterone in this model. Further, improved vaginal progesterone delivery by the nanosuspension led to increased efficacy in PTB prevention. Further, we identified histological and transcriptional evidence of cervical and uterine toxicity with a single vaginal administration of the clinical gel that are absent after dosing with the mucoinert nanosuspension formulation. We demonstrate that a progesterone formulation that is designed for improved vaginal progesterone absorption and vaginal biocompatibility could be more effective for PTB prevention.
This article was published in the following journal.
Name: Journal of controlled release : official journal of the Controlled Release Society
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A derivative of CHLORAL HYDRATE that was used as a sedative but has been replaced by safer and more effective drugs. Its most common use is as a general anesthetic in animal experiments.
A muscarinic antagonist structurally related to ATROPINE but often considered safer and more effective for inhalation use. It is used for various bronchial disorders, in rhinitis, and as an antiarrhythmic.
Specific proteins found in or on cells of progesterone target tissues that specifically combine with progesterone. The cytosol progesterone-receptor complex then associates with the nucleic acids to initiate protein synthesis. There are two kinds of progesterone receptors, A and B. Both are induced by estrogen and have short half-lives.
The major progestational steroid that is secreted primarily by the CORPUS LUTEUM and the PLACENTA. Progesterone acts on the UTERUS, the MAMMARY GLANDS and the BRAIN. It is required in EMBRYO IMPLANTATION; PREGNANCY maintenance, and the development of mammary tissue for MILK production. Progesterone, converted from PREGNENOLONE, also serves as an intermediate in the biosynthesis of GONADAL STEROID HORMONES and adrenal CORTICOSTEROIDS.
Steroidal compounds related to PROGESTERONE, the major mammalian progestational hormone. Progesterone congeners include important progesterone precursors in the biosynthetic pathways, metabolites, derivatives, and synthetic steroids with progestational activities.
Women's Health - key topics include breast cancer, pregnancy, menopause, stroke Follow and track Women's Health News on BioPortfolio: Women's Health News RSS Women'...
<!--LGfEGNT2Lhm-->Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. <!--LGfEGNT2Lhm-->Drug delivery technologies are <!--LGfEGNT2Lhm-->patent pr...
Obstetrics and gynaecology
Fertility Menopause Obstetrics & Gynaecology Osteoporosis Women's Health Obstetrics and gynaecology comprises the care of the pregnant woman, her unborn child and the management of diseases specific to women. Most consultant...