Oral transmucosal compositions including aromatase inhibitors for low testosterone levels in men

Abstract

Formulations for oral transmucosal compositions that include aromatase inhibitors (AIs) in combination with transmucosal absorption enhancers are disclosed. Disclosed oral transmucosal compositions may be for immediate release or slow release, and may be administered to increase bloodstream testosterone levels and thereby reduce symptoms of testosterone deficiency. Disclosed oral transmucosal compositions may include liquid dosage forms, solid dosage forms, and chewing gums. Further dosage forms may include mucoadhesive thin strips, thin films, tablets, patches, and tapes, among others. Other dosage forms may be: mucoadhesive liquids such as gel-forming liquid; gel-forming; semisolids; and gel-forming powders, among other dosage forms that exhibit mucoadhesive properties, and provide oral transmucosal delivery of AIs. Disclosed oral transmucosal compositions may allow the delivery of AIs directly into the patient's bloodstream, thus providing high bioavailability of AIs; therefore, required dose may be lower. Additionally, adjustments of AIs dosages may be achieved when using disclosed oral transmucosal compositions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This Application is a 35 U.S.C. §371 National Stage Entry of PCT / US2015 / 041560, filed on Jul. 22, 2015 which claims priority to U.S. patent application Ser. No. 14 / 337,783, filed Jul. 22, 2014 entitled “Oral Transmucosal Compositions including Aromatase Inhibitors for Low Testosterone Levels in Men”, the entirety of which is incorporated herein by reference as if set forth herein in its entirety.BACKGROUND[0002]Field of the Disclosure[0003]The present disclosure relates generally to pharmaceutical compositions, and more particularly, to oral transmucosal compositions including a plurality of aromatase inhibitors for testosterone deficiency or high estradiol in men.[0004]Background Information[0005]Testosterone is the androgenic hormone primarily responsible for normal growth and development of male sex and reproductive organs, including the penis, testicles, scrotum, prostate, and seminal vesicles. It facilitates the development of second...

AI Technical Summary

Benefits of technology

[0020]In some embodiments, transmucosal absorption enhancers provide more efficient API skin and mucosal tissue penetration. In these embodiments, the transmucosal absorption enhancers allow lower API dosage requirements.

[0021]In some embodiments, oral transmucosal compositions allow the delivery of AIs directly into the patient's bloodstream bypassing the gastrointestinal tract and the hepatic metabolism. In these embodiments, bypassing the gastrointestinal tract and the hepatic metabolism results in a higher percentage of bioavailability of AIs to the patient. Further to these embodiments, adjustments of AIs dosages may be achieved when using the disclosed oral transmucosal compositions.

Problems solved by technology

Depending on age, insufficient testosterone production can lead to abnormalities in muscle and bone development, underdeveloped genitalia and diminished virility.

Oral therapy of testosterone lacks effectiveness because testosterone is metabolized extensively during the first passage of the liver before reaching the systemic blood circulation (i.e., the first-pass effect).

Intramuscular injections of testosterone esters are widely used, but local pain, tolerability, and the unphysiologically high levels of testosterone in the body during the first days / weeks after injection are severe drawbacks to this form of treatment.

Local pain is attributed to the large volumes of testosterone injected and the required help of health care professionals makes injections inconvenient and expensive.

These same drawbacks also apply to implanted pellets.

Unfortunately, transdermal compositions, excluding patches, currently prescribed for hypogonadal men include from 40 mg to 120 mg (dosed daily) of which only a low percentage is absorbed through the skin.

Another drawback is that a large part of the testosterone remains on the skin, with the potential risk of transferring the medication to the skin of another person when direct skin-to-skin contact is made.

Additionally, the non-absorbed portion of testosterone is lost to the surrounding environment making these formulations non-environmentally-friendly.

Additionally, a common side effect of transdermal compositions is local skin irritation.

Increased LH and FSH results in a subsequent increase in testicular stimulation and serum testosterone levels without the increase in estrogen levels, and thus could limit the likelihood of undesirable effects such as gynecomastia.

However, there are no AI products on the market for treatment of either testosterone deficiency or high estradiol in men.