17-hydroxyprogesterone ester-containing oral compositions and related methods

Abstract

The present invention provides for bioavailable oral dosage forms containing esters of 17-hydroxyprogesterone as well as related methods. The oral dosage forms can be formulated for pregnancy support and can include a therapeutically effective amount of an ester of 17-hydroxyprogesterone and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutically acceptable oral dosage form for pregnancy support is provided. The pharmaceutically acceptable oral dosage can include a therapeutically effective amount of an ester of 17-hydroxyprogesterone and a pharmaceutically acceptable carrier. The oral dosage form can, when measured using a USP Type-II dissolution apparatus in 900 mL of deionized water with 0.5 (w / v) of sodium lauryl sulfate at 50 RPM at 37° C., release at least 20 wt % of the dose of the ester of 17-hydroxyprogesterone after 60 minutes, or in the alternative release at least 20 wt % more after 60 minutes than an equivalently dosed oral dosage form without the carrier.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a continuation of U.S. patent application Ser. No. 15 / 190,109, filed Jun. 22, 2016, which claims the benefit of U.S. Provisional Application No. 62 / 183,031 filed Jun. 22, 2015 and U.S. Provisional Application No. 62 / 295,951 filed Feb. 16, 2016, each of which is incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention relates to 17-hydroxyprogesterone ester containing compositions, oral dosage forms thereof, and associated methods. Accordingly, this invention involves the fields of chemistry, pharmaceutical sciences, medicine and other health sciences.BACKGROUND OF THE INVENTION[0003]17-alpha hydroxyprogesterone (alternatively hereinafter referred to as 17-hydroxyprogesterone or “17HP”) is a C-21 endogenous steroid hormone produced during the syntheses of glucocorticoids and sex steroids. Like progesterone, 17HP is a natural progestagen. It has been isolated from both adrenal glands...

AI Technical Summary

Benefits of technology

[0009]It has now been surprisingly found that esters of 17HP can be effectively delivered orally to mammals. The pharmaceutical oral compositions and dosage forms of the present inventions can provide effective bioavailability of an ester of 17HP. Further, the compositions and / or dosage forms disclosed herein provide effective release enhancement for 17 HP esters. We have also surprisingly found that an ester of 17HP can be formulated into oral compositions and oral dosage forms thereof with higher percent w / w loading of the ester. For example, we have found that when one or more solubilizing agents such as for example, benzyl alcohol, benzyl benzoate etc., is incorporated in the composition, a significant amount (i.e. greater than 12% w / w) of the ester of 17HP can be solubilized in the composition or dosage form. The increased drug loading in the compositions and dosage forms of the current inventions, can provide avid advantages including but not limited to reduced size or volume of the unit dosage (i.e., tablet, capsule, syrup, elixir, beverage, etc.), reduced number of dosage units to be taken per single administration, improved patient compliance etc., because patients typically can take fewer number of dosage units per day in order to get a sufficient dose to provide the desired efficacy. In a separate aspect, it was also surprisingly found that an effective bioavailability of the ester of 17HP can be provided by the compositions of the current inventions which when dispersed in an aqueous medium, provide clear or colloidal to hazy or unclear dispersions having partially or fully solubilized drug in the dispersions.

[0010]It was also found that the compositions of current invention facilitate production of solid dosage forms such as tablets, caplets, granules, beads, particulates etc., which can solve the drawbacks of having the 17HP ester in a liquid solution form in the dosage unit. This eliminates a number of undesirable inconveniences, such as specialized manufacturing process and / or equipment, poor chemical and / or physical stability of the ester typical to liquid solutions due to the nature of the ester or solvents used, and so-on.

Problems solved by technology

PTB is the primary cause of neonatal morbidity and mortality.

PTB related time and costs in intensive care are a major health, social and economic issue with an average cost of PTB delivery amounting to up to 10× that of normal delivery.

This therapy regimen could result increasing the patient's distress and / or anxiety in addition to increasing the repeated travel risks for the patient and fetus.

The injection therapy's interferences with the personal and family activities and disruption in professional life are also a major disadvantage.

In addition, adverse events associated with injection of 17-hydroxyprogesterone caproate (e.g. Makena®) at once weekly intervals (every 7 days) the injection site reactions (˜45%) such as urticaria, pruritis, swelling, nodule formation and pain at the site of injection have been reported as significant.

Due to its extremely low water solubility and a potential to be susceptible for first pass hepatic inactivation oral delivery of long chain esters of 17HP has remained a challenge.

This could be likely due to very poor or no oral bioavailability of 17 HPC.

Although much desired, to date the development of an orally active composition of long chain ester of hydroxyl progesterone remains a significant unmet need.

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