Methods for inhibiting preterm labor and uterine contractility disorders and preventing cervical ripening

Abstract

The invention relates to methods and pharmaceutical compositions for inhibiting or preventing preterm birth, inhibiting or delaying cervical ripening, inhibiting myometrial contractility and treating or inhibiting uterine contractility disorders. The methods comprise administering an effective amount of a composition comprising steroid hormones such as soluble progesterone.

Description

[0001]This application is a continuation-in-part of, and includes a claim of priority under 35 U.S.C. §120 to, International Application No. PCT / US2011 / 027788, filed on Mar. 9, 2011, which designated the U.S. and that International Application was published under PCT Article 21(2) in English. This application also includes a claim of priority under 35 U.S.C. §119(e) to U.S. Ser. No. 61 / 311,944 filed Mar. 9, 2010 and to U.S. Ser. No. 61 / 434,309 filed Jan. 19, 2011, the contents of all of which are herein incorporated by reference.FIELD OF INVENTION[0002]The invention relates to methods for inhibiting or preventing preterm birth, delaying cervical ripening, inhibiting myometrial contractility and treating uterine contractility disorders, in subjects in need thereof. The method comprises administering an effective amount of a steroid hormone such as progesterone or a pharmaceutical equivalent, analog, derivative or a salt thereof. The invention also relates to pharmaceutical compositio...

AI Technical Summary

Benefits of technology

[0098]As described herein, use of steroid hormones like progesterone (P4), when mixed with agents that render the steroid hormone soluble, inhibit uterine contractility and cervical ripening, prevent preterm labor and prevent miscarriages. Agents that render steroid hormones soluble include but are not limited to cyclodextrins, sesame oil, fish oil, corn oil, olive oil, coconut oil, krill oil, omega fatty acids, mineral oil, peppermint oil, flaxseed oil, vitamin E oil, argan oil, saline solution and / or glucose solution. Progesterone has a relatively short half life of about 30 minutes and therefore must be administered daily. Progesterone dissolved in saline solution (for example isotonic saline solution) or in glucose solution may be administered by subcutaneous injections, intravascularly (IV), vaginally, topically or by other routes not applicable for oily compositions of progesterone. Oily compositions of progesterone such as those dissolved in fish oil, omega fatty acid or peppermint oil may readily be used topically, vaginally, intramuscularly or via other routes of administration.

[0099]In non-pregnant women, progesterone (P4) when mixed with the aforementioned agents is useful for postmenopausal hormone replacement therapy with and without estrogen, prevention of amenorrhea and abnormal uterine bleeding due to hormonal imbalance and prevention of cancer fibroids. Soluble progesterone is particularly useful because it can be used in injections, intravenously, subcutaneously, parenterally, topically and / or nasally.

[0100]The following example is provided to better illustrate the claimed invention and is not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention.

[0101]As disclosed herein, the inventor evaluated cervical changes and delivery at term during pregnancy in rats after various progestin treatments. Pregnant rats were treated by various routes and vehicles with progesterone (P4), 17-alpha-hydroxyprogesterone caproate (17P), promegestone (R5020) and RU-486. Delivery time was determined and cervical ripening assessed in vivo by collagen light-induced fluorescence (LIF).

[0102]As further disclosed herein, the cervix is rigid in P4 injection, 17P and vaginal promegestone (R5020) groups versus controls. Vaginal P4 had no effect. RU-486 treatment softened the cervix during preterm delivery. Only subcutaneously P4, promegestone (R5020) (subcutaneously and vaginal) and topical P4 in sesame and fish oil inhibits delivery. Delivery was not changed by subcutaneously 17P, vaginal P4, oral P4 and topical P4 in Replens. These results demonstrate why many of the commonly used treatments for preterm labor are not efficacious.

Problems solved by technology

Preterm birth (less than 37 completed weeks of gestation) is one of the major problems and challenges in obstetrics.

Despite all efforts to reduce the number of preterm births the problem is continuing to escalate.

Additionally, the neonatal and long-term health care costs of preterm infants impose a considerable economic strain both on individual families and on healthcare costs (>$26.2 billion in 2005 in the USA).

However the biochemical mechanisms that are responsible for the remarkable changes in the cervix remain poorly understood.

Although progesterone has been known to be used for recurrent or high risk preterm labor (PTL), its current use is crystalline progesterone in micronized form, and used to treat preterm labor and uterine contractile disorders by the often inconvenient and less effective routes of vaginal, oral or IM.

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