High-strength testosterone undecanoate compositions

• US 9,205,057 B2
• Filed: 04/20/2015
• Issued: 12/08/2015
• Est. Priority Date: 11/30/2010
• Status: Active Grant

• Current Assignee: Lipocine Inc.
• Original Assignee: Lipocine Inc.
• Inventors: Giliyar, Chandrashekar, Chickmath, Basawaraj, Nachiappan, Chidambaram, Patel, Mahesh V., Venkateshwaran, Srinivansan
• Primary Examiner(s): Haghighatian, Mina
• Application Number:
  US14/691,229
• Publication Number:
  US 20150224059A1
• Time in Patent Office: 232 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4875 Compounds of unknown constitution, e.g. material from plants or animals oils, fats, waxes, shellac A61K9/4858
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: G01N 33/743 Steroid hormones

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.

Claims

1. A method for replacement therapy in a male having a condition associated with a deficiency or absence of endogenous testosterone said method comprising:

(a) Orally administering to said male a daily dosing regimen of a pharmaceutical composition comprising about 14 weight % (wt %) to about 35 wt % testosterone undecanoate and a carrier, that provides from about 360 mg to about 480 mg of testosterone undecanoate to said male per day;

(b) Determining the serum level of testosterone of said male during the daily dosing regimen at from 1-8 hours after single dose administration of said pharmaceutical composition at steady state; and

(c) Orally administering a maintenance daily dosing regimen of a pharmaceutical composition comprising about 14 wt % to about 35 wt % testosterone undecanoate and a carrier, that provides within plus or minus 40% of from about 360 mg to about 480 mg of testosterone undecanoate to said male based on the serum testosterone level determined in step (b),

to provide a serum testosterone Cave in said male in the range of from about 300-1100 ng/dL.

2. The method of claim 1 said carrier comprising a solubilizer and a dispersant.

3. The method of claim 1 said carrier comprising a monoglyceride, diglyceride or both.

4. The method of claim 1 said carrier comprising oleic acid.

5. The method of claim 1 said carrier comprising a polyoxyethylene hydrogenated vegetable oil.

6. The method of claim 1 said carrier comprising tocopherol.

7. The method of claim 1 said daily dosing regimen or maintenance daily dosing regimen comprises twice daily dosing with said pharmaceutical composition.

8. The method of claim 1 said orally administering comprises administration of the pharmaceutical composition with a meal.

9. The method of claim 1 said carrier comprising a solubilizer in an amount of from about 50 wt % to about 86 wt % of the pharmaceutical composition.

10. The method of claim 1 said pharmaceutical composition having at least 5% of said testosterone undecanoate not dissolved and at least 33% dissolved in said carrier.

21. The method of claim 1, said carrier comprising a triglyceride, a sterol derivative, an ionic hydrophilic surfactant, a non-ionic hydrophilic surfactant, an alcohol or a combination thereof.

24. The method of claim 1, when used with a group of males provides a mean serum testosterone concentration in the range of about 350 ng/dL to 800 ng/dL.

11. A method for replacement therapy in a male having a condition associated with a deficiency or absence of endogenous testosterone said method comprising:

(a) Orally administering to said male a daily dosing regimen of a pharmaceutical composition comprising about 14 wt % to about 35 wt % testosterone undecanoate and a carrier to provide from about 350 mg testosterone undecanoate to about 650 mg testosterone undecanoate to said male per day;

(b) determining the serum level of testosterone of said male during the daily dosing regimen at a single time point from 1-8 hours after single dose administration of said pharmaceutical composition at steady state, C_t; and

(c) orally administering a maintenance daily dosing regimen of a pharmaceutical composition comprising about 14 wt % to about 35 wt % testosterone undecanoate and a carrier, that provides within plus or minus 40% of from about 350 mg to about 650 mg of testosterone undecanoate to said male based on the serum testosterone level determined in step (b),

said carrier comprising a monoglyceride, a diglyceride, a fatty acid, a polyoxyethylene hydrogenated vegetable oil or a combination thereof,

to provide a serum testosterone Cave in said male in the range of from about 300-1100 ng/dL.

12. The method of claim 11 said carrier comprising a solubilizer and a dispersant.

13. The method of claim 11 said carrier comprising a monoglyceride, diglyceride or both.

14. The method of claim 11 said carrier comprising oleic acid.

15. The method of claim 11 said carrier comprising a polyoxyethylene hydrogenated vegetable oil.

16. The method of claim 11 said carrier comprising tocopherol.

17. The method of claim 11 said daily dosing regimen or maintenance daily dosing regimen comprises twice daily dosing with said pharmaceutical composition.

18. The method of claim 11 said orally administering comprises administration of the pharmaceutical composition with a meal.

19. The method of claim 11 said pharmaceutical composition having at least 5% of said testosterone undecanoate not dissolved and at least 33% dissolved in said carrier.

22. The method of claim 11, said carrier comprising a triglyceride, a sterol derivative, an ionic hydrophilic surfactant, a non-ionic hydrophilic surfactant, an alcohol or a combination thereof.

25. The method of claim 11, when used with a group of males provides a mean serum testosterone concentration in the range of about 350 ng/dL to 800 ng/dL.

20. A method for replacement therapy in a male having a condition associated with a deficiency or absence of endogenous testosterone said method comprising:

(a) Orally administering to said male subject a daily dosing regimen of a pharmaceutical composition comprising about 14% to about 35% testosterone undecanoate and a carrier to provide from about 360 mg testosterone undecanoate to about 480 mg testosterone undecanoate to said male per day;

(b) determining the serum level of testosterone of said male during the daily dosing regimen at a single time point from 1-8 hours after single dose administration of said pharmaceutical composition at steady state, C_t; and

(c) orally administering a maintenance daily dosing regimen of a pharmaceutical composition comprising about 14% to about 35% testosterone undecanoate and a carrier, that provides within plus or minus 40% of from about 360 mg to about 480 mg of testosterone undecanoate to said male subject based on the serum testosterone level determined in step (b),

said carrier comprising a monoglyceride, a diglyceride, a polyoxyethylene hydrogenated vegetable oil or a combination thereof and said pharmaceutical composition having at least 5% of said testosterone undecanoate not dissolved and at least 33% dissolved in said carrier,

to provide a serum testosterone Cave in said male in the range of from about 300-1100 ng/dL.

23. The method of claim 20, said carrier further comprising a fatty acid.

26. The method of claim 20, when used with a group of males provides a mean serum testosterone concentration in the range of about 350 ng/dL to 800 ng/dL.