High-strength testosterone undecanoate compositions

Abstract

The present disclosure is drawn to pharmaceutical compositions and oral dosage capsules containing testosterone undecanoate, as well as related methods. The capsule includes a capsule shell and a capsule fill. The capsule fill can include a solubilizer and about 14 wt % to about 35 wt % testosterone undecanoate based on the total capsule fill. The oral dosage capsule is such that when a single oral administration to a male subject of one or more capsules with a total testosterone undecanoate daily dose of about 350 mg to about 650 mg it provides a ratio of serum testosterone C max to serum testosterone C ave of about 2.7 or less. In yet another embodiment, a method for providing a serum concentration of testosterone within a target serum testosterone concentration C ave range for a male subject is provided.

1 . A pharmaceutical capsule for oral delivery, comprising:
 a capsule shell   a capsule fill, comprising
 a solubilizer; and 
 about 14 wt % to about 35 wt % testosterone undecanoate based on the total capsule fill; 
   wherein a single oral administration to a male subject of one or more capsules with a total testosterone undecanoate daily dose of about 350 mg to about 650 mg provides a ratio of serum testosterone C max  to serum testosterone C ave  of about 2.7 or less.   
     
     
         2 . The pharmaceutical capsule of  claim 1 , wherein upon a single dose administration of the capsule provides a dose-normalized serum testosterone C max  of about 3×10 −6  dL −1  or higher. 
     
     
         3 . The pharmaceutical capsule of  claim 1 , wherein upon a single dose administration of the capsule provides a dose-normalized serum testosterone C ave  of about 1.9×10 −6  dL −1  or higher. 
     
     
         4 . The pharmaceutical capsule of  claim 1 , wherein the capsule is a hard capsule with having a fill volume of about 0.3 mL to about 1.1 mL. 
     
     
         5 . The pharmaceutical capsule of  claim 1 , wherein the testosterone undecanoate comprises about 14 wt % to about 18 wt % of the total capsule fill. 
     
     
         6 . The pharmaceutical capsule of  claim 1 , wherein the solubilizer is selected from the group consisting of C 8  to C 22  fatty acid glycerides, C 8  to C 22  fatty acids, omega fatty acids, and mixtures thereof. 
     
     
         7 . The pharmaceutical capsule of  claim 6 , wherein the C 8  to C 22  fatty acid glyceride comprises at least about 40 wt % as monoglycerides. 
     
     
         8 . The pharmaceutical capsule of  claim 6 , wherein the C 8  to C 22  fatty acid glycerides are selected from the group consisting of monoglycerides of linoleic acid, diglycerides of linoleic acid, monoglycerides of oleic acid, diglycerides of oleic acid, and combinations thereof. 
     
     
         9 . The pharmaceutical capsule of  claim 6 , wherein the C 8 -C 22  fatty acid glycerides are selected from the group consisting of monoglycerides of capric acid, diglycerides of capric acid, monoglycerides of caprylic acid, diglycerides of caprylic acid, and combinations thereof. 
     
     
         10 . The pharmaceutical capsule of  claim 6 , wherein the C 8  to C 22  fatty acid glycerides are derived from sources selected from the group consisting of maize oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, coconut oil, palm kernel oil, castor oil, and mixtures thereof. 
     
     
         11 . The pharmaceutical capsule of  claim 1 , wherein the solubilizer comprises about 50 wt % to about 86 wt % of the capsule fill. 
     
     
         12 . The pharmaceutical capsule of  claim 1 , wherein the capsule fill further includes a dispersant. 
     
     
         13 . The pharmaceutical capsule of  claim 12 , wherein the dispersant includes a lipophilic surfactant selected from the group consisting of propylene glycol mono caprylate, propylene glycol oleate, propylene glycol monostearate, propylene glycol monolaurate, propylene glycol monooleate, propylene glycol dicaprylate/dicaprate, sorbitan monooleate, PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, and combinations thereof. 
     
     
         14 . The pharmaceutical capsule of  claim 12 , wherein the dispersant includes a hydrophilic surfactant. 
     
     
         15 . The pharmaceutical capsule of  claim 14 , wherein the hydrophilic surfactant is present in an amount such that it does not appreciably solubilize the testosterone undecanoate in the capsule fill. 
     
     
         16 . The pharmaceutical capsule of  claim 13 , wherein the capsule fill includes a lipophilic component and a hydrophilic surfactant. 
     
     
         17 . The pharmaceutical capsule of  claim 1 , wherein the capsule fill further comprises a solidifying agent selected from the group consisting of: polyethylene glycols, sorbitol, gelatin, stearic acid, cetyl alcohol, cetosterayl alcohol, paraffin wax, polyvinyl alcohol, glyceryl stearates, glyceryl distearate, glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate, waxes, hydrogenated castor oil, hydrogenated vegetable oil, bees wax, microcrystalline wax, sterols, phytosterols, cholesterol, and mixtures thereof. 
     
     
         18 . The pharmaceutical capsule of  claim 17 , wherein the solidifying agent comprises about 3 wt % to about 15 wt % of the total capsule fill. 
     
     
         19 . The pharmaceutical capsule of  claim 1 , wherein upon administration of one or more capsules daily to each subject in a group of at least 24 hypogonadal males for a period of at least 84 days, the capsule provides a serum testosterone C avg  of 300 ng/dL to 1100 ng/dL in at least 75% of the hypogonadal males in the group, and at least one of the following:
 a) a serum testosterone C max  of less than 1500 ng/dL in at least 85% of the hypogonadal males in the group;   b) a serum testosterone C max  of about 1800 ng/dL to about 2500 ng/dL in 5% or less of the hypogonadal males in the group; or   c) a serum testosterone C max  greater than 2500 ng/dL in about 1% or less of the hypogonadal males in the group.   
     
     
         20 . The pharmaceutical capsule of  claim 19 , wherein the administration over the at least 84 days can be divided into two dosing regimens including an initial regimen in which an daily dose of the initial regimen is administered and a maintenance regimen in which a maintenance daily dose is administered. 
     
     
         21 . The pharmaceutical capsule of  claim 20 , wherein the daily dose of the maintenance regimen of testosterone undecanoate is about 45% to about 155% of the initial daily dose. 
     
     
         22 . The pharmaceutical capsule of  claim 20 , wherein the amount of the daily dose of the maintenance regimen is based on at least one testosterone undecanoate dose titration metric derived from the measurement of the serum testosterone concentration on at least one titration node day. 
     
     
         23 . The pharmaceutical capsule of  claim 22 , wherein the testosterone undecanoate dose titration can be such that:
 i) if at time (t) of 1 to less than 3 hours following administration the serum testosterone concentration is less than 2.0 ng/mL there is an increase is dose and if the serum testosterone concentration is more than 9.4 there is a decrease in dose;   ii) if at time (t) of 3 to less than 8 hours following administration the serum testosterone concentration is less than 4.1 ng/mL there is an increase is dose and if the serum testosterone concentration is more than 18.1 there is a decrease in dose;   iii) if at time (t) of 8 to less than 12 hours following administration the serum testosterone concentration is less than 3.0 ng/mL there is an increase is dose and if the serum testosterone concentration is more than 7.8 there is a decrease in dose; or   iv) if at time (t) of 12 to less than 14 hours following administration the serum testosterone concentration is less than 1.4 ng/mL there is an increase is dose and if the serum testosterone concentration is more than 2.9 there is a decrease in dose.   
     
     
         24 . The pharmaceutical capsule of  claim 1 , wherein the capsule fill is substantially free of ionizable fatty acids 
     
     
         25 . The pharmaceutical capsule of  claim 1 , wherein at least 5 wt % of the testosterone undecanoate in the capsule fill is present in undissolved form. 
     
     
         26 . The pharmaceutical capsule of  claim 1 , wherein the capsule fill includes 25 wt % or less total triglycerides. 
     
     
         27 . The pharmaceutical capsule of  claim 1 , wherein the capsule fill is substantially free of oleic acid. 
     
     
         28 . The pharmaceutical capsule of  claim 1 , wherein the male subject is a hypogonadal male subject. 
     
     
         29 . A method for providing a serum concentration of testosterone within a target serum testosterone concentration C ave  range for a male subject, comprising the steps of,
 1) orally administering to the male subject an initial regimen including a daily dose of a testosterone undecanoate-containing composition, wherein the testosterone undecanoate comprises about 14 wt % to about 35 wt % of the testosterone undecanoate-containing composition and wherein the daily dose provides about 350 mg to about 650 mg of testosterone undecanoate to the male subject;   2) determining a dose titration metric based on a measurement of serum testosterone concentration for the male subject on at least one titration node day within the initial regimen; and   3) orally administering to the male subject a maintenance regimen including a daily dose of testosterone undecanoate-containing composition, wherein the testosterone undecanoate-containing composition comprises about 14 wt % to about 35 wt % of the testosterone undecanoate-containing composition and wherein the maintenance regimen provides an daily dose of testosterone undecanoate to the subject based on the titration metric determined on the at least one titration node day of the initial regimen sufficient to provide a serum testosterone plasma concentration within the target range   wherein the method provides a steady state ratio of serum testosterone C max  to C ave  of 2.7 or less.   
     
     
         30 . The method of  claim 29 , further comprising the steps of:
 4) determining a dose titration metric based on a measurement of serum testosterone concentration for the male subject on at least one titration node day within the maintenance regimen;   5) orally administering to the male subject a second maintenance regimen including a daily dose of testosterone undecanoate-containing composition, wherein the testosterone undecanoate-containing composition comprises about 14 wt % to about 35 wt % of the testosterone undecanoate-containing composition and wherein the second maintenance regimen provides an daily dose of testosterone undecanoate to the subject based on the titration metric determined on the at least one titration node day of the maintenance regimen sufficient to provide a serum testosterone plasma concentration within the target range; and optionally   6) repeating steps 4 and 5, if needed.   
     
     
         31 . The method of  claim 29 , wherein the daily dose administered in the initial regimen is the same dosage amount as the daily dose administered in the maintenance regimen. 
     
     
         32 . The method of  claim 29 , wherein the titration node day is any single day from day 15 to day 84 following the start of the initial regimen. 
     
     
         33 . The method of  claim 29 , wherein the testosterone undecanoate dose titration can be such that:
 i) if at time (t) of 1 to less than 3 hours following administration the serum testosterone concentration is less than 2.0 ng/mL there is an increase is dose and if the serum testosterone concentration is more than 9.4 there is a decrease in dose;   ii) if at time (t) of 3 to less than 8 hours following administration the serum testosterone concentration is less than 4.1 ng/mL there is an increase is dose and if the serum testosterone concentration is more than 18.1 there is a decrease in dose;   iii) if at time (t) of 8 to less than 12 hours following administration the serum testosterone concentration is less than 3.0 ng/mL there is an increase is dose and if the serum testosterone concentration is more than 7.8 there is a decrease in dose; or   v) if at time (t) of 12 to less than 14 hours following administration the serum testosterone concentration is less than 1.4 ng/mL there is an increase is dose and if the serum testosterone concentration is more than 2.9 there is a decrease in dose.   
     
     
         34 . The method of  claim 29 , wherein the daily dose of the maintenance regimen provides an amount of testosterone undecanoate that is about 45% to about 155% of that of the initial daily dose. 
     
     
         35 . The method of  claim 29 , wherein the target serum testosterone C ave  range is about 300 ng/dL to 1100 ng/dL and is achieved on or after day 84 following the start of the initial regimen. 
     
     
         36 . The method of  claim 29 , wherein the daily dose during the initial and maintenance regimens includes twice-a-day administration of the testosterone undecanoate-containing composition in conjunction with meals. 
     
     
         37 . The method of  claim 29 , wherein the method provides a serum testosterone C avg  in the range of 300 ng/dL to 1100 ng/dL in 75% or more of hypogonadal males after 84 days from the start of the initial regimen based on a minimum group size of 24 hypogonadal males. 
     
     
         38 . The method of  claim 29 , wherein the method provides a serum testosterone C max  of 1500 ng/dL or less in less than or equal to 85% of hypogonadal males after 84 days from the start of the initial regimen based on a minimum group size of 24 hypogonadal males. 
     
     
         39 . The method of  claim 29 , wherein the method provides a serum testosterone C max  in the range of 1800 ng/dL to 2500 ng/dL in about 5% or less of hypogonadal males after 84 days from the start of the initial regimen based on a minimum group size of 24 hypogonadal males. 
     
     
         40 . The method of  claim 29 , wherein the method provides a serum testosterone C max  of 2500 ng/dL in about 1% or less of hypogonadal males after 84 days from the start of the initial regimen based on a minimum group size of 24 hypogonadal males. 
     
     
         41 . The method of  claim 29 , wherein testosterone undecanoate comprises about 14 wt % to about 18 wt % of the testosterone undecanoate-containing composition. 
     
     
         42 . The method of  claim 29 , wherein the male subject is a hypogonadal male.