Composition and method for oral delivery of androgen prodrugs

Abstract

Provided oral testosterone undecanoate compositions can be administered to hypogonadal males with a meal without the fat content of the meal substantially effecting bioavailability.

What is claimed is: 
     
         1 . A method for replacement therapy in a male for a condition associated with a deficiency or absence of endogenous testosterone, said method comprising: orally administering to a male having a condition associated with a deficiency or absence of endogenous testosterone, with a meal, a pharmaceutical composition comprising from about 50 mg to about 300 mg of testosterone undecanoate and a pharmaceutically acceptable carrier said pharmaceutical acceptable carrier being selected to provide bioequivalent amounts of serum testosterone, testosterone undecanoate, dihydrotestosterone, or dihydrotestosterone undecanoate levels to said male when administered with (1) meals containing standard fat as compared to low fat and high fat, (2) meals containing low fat as compared to high fat, or both (1) and (2). 
     
     
         2 . The method of  claim 1 , wherein said pharmaceutical composition has about 75 mg, about 112.5 mg, about 150 mg, about 225 mg, or 300 mg of testosterone undecanoate. 
     
     
         3 . The method of  claim 1 , wherein said pharmaceutically acceptable carrier selected to provide bioequivalent amounts of serum testosterone levels to said male for meals containing low, standard fat and high fat. 
     
     
         4 . The method of  claim 1 , wherein said method provides a serum testosterone Cavg in the range of 300 ng/dL to 1100 ng/dL. 
     
     
         5 . The method of  claim 1 , wherein said administering occurs twice-a-day. 
     
     
         6 . The method of  claim 1 , wherein said method comprises administering from 285 mg to about 625 mg of testosterone undecanoate per day. 
     
     
         7 . The method of  claim 1 , wherein said composition comprises a lipophilic additive. 
     
     
         8 . The method of  claim 1 , wherein said composition comprises a hydrophilic additive. 
     
     
         9 . The method of  claim 1 , wherein said pharmaceutical composition (1) is pharmaceutically equivalent to an oral pharmaceutical composition having about 75 mg or about 112.5 mg of testosterone undecanoate at about 15 wt % loading, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40, and about 6 wt % PEG 8000 or (2) has about 75 mg or about 112.5 mg of testosterone undecanoate at about 15 wt % loading, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40, and about 6 wt % PEG 8000. 
     
     
         10 . The method of  claim 1 , wherein said method comprises administering the pharmaceutical composition as 2, 3, 4, 5, 6, 7, or 8 unit dosage forms per day. 
     
     
         11 . A method for replacement therapy in a male for conditions associated with a deficiency or absence of endogenous testosterone, said method comprising: orally administering to a male having a condition associated with a deficiency or absence of endogenous testosterone, with a meal having about 10 wt % to 50 wt % fat, a pharmaceutical composition comprising from about 50 mg to about 300 mg of testosterone undecanoate and a pharmaceutically acceptable carrier said pharmaceutical acceptable carrier being selected to provide bioequivalent amounts of serum testosterone, testosterone undecanoate, dihydrotestosterone, or dihydrotestosterone undecanoate levels to said male when administered with meals containing (1) standard fat as compared to low fat and high fat, (2) low fat to high fat, or (3) a combination thereof. 
     
     
         12 . The method of  claim 11 , wherein said pharmaceutical composition (1) is pharmaceutically equivalent to an oral pharmaceutical composition having about 75 mg or about 112.5 mg of testosterone undecanoate at about 15 wt % loading, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40, and about 6 wt % PEG 8000 or (2) has about 75 mg or about 112.5 mg of testosterone undecanoate at about 15 wt % loading, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40, and about 6 wt % PEG 8000. 
     
     
         13 . The method of  claim 11 , wherein said method provides a serum testosterone Cavg in the range of 300 ng/dL to 1100 ng/dL. 
     
     
         14 . The method of  claim 11 , wherein said method comprises administering from 285 mg to about 625 mg of testosterone undecanoate per day. 
     
     
         15 . The method of  claim 11 , said administering occurs twice-a-day. 
     
     
         16 . A pharmaceutical composition for oral administration comprising testosterone undecanoate and a pharmaceutical acceptable carrier said pharmaceutical composition providing bioequivalent amounts of serum testosterone undecanoate, testosterone, dihydrotestosterone, dihydrotestosterone undecanoate or a combination thereof to a male for a condition associated with a deficiency or absence of endogenous testosterone when administered with a meal (1) containing medium fat as compared to high fat or low fat or (2) containing low, standard and high fat. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein said pharmaceutical composition is pharmaceutically equivalent to an oral pharmaceutical composition having about 75 mg or about 112.5 mg of testosterone undecanoate at 15 wt % loading, 63 wt % Maisine 35-1, 16 wt % Cremophor RH 40, and 6 wt % PEG 8000. 
     
     
         18 . The pharmaceutical composition of  claim 16 , further comprising a monoglyceride, a diglyceride or a combination thereof in amount of greater than about 10 wt % and has less than about 50 wt % triglyceride. 
     
     
         19 . A pharmaceutical composition for oral administration that is hypogonadal male serum testosterone bioequivalent to a formulation comprising 15 wt % testosterone undecanoate, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40, and about 6 wt % polyethylene glycol 8000 under medium fat as compared to low fat and high fat with the proviso that the formulation does not comprise about 15 wt % testosterone undecanoate, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40, and about 6 wt % polyethylene glycol 8000. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein said pharmaceutical composition is pharmaceutically equivalent to an oral pharmaceutical composition having about 75 mg or about 112.5 mg of testosterone undecanoate at 15 wt % loading, 63 wt % Maisine 35-1, 16 wt % Cremophor RH 40, and 6 wt % PEG 8000. 
     
     
         21 . The pharmaceutical composition of  claim 19 , further comprising a monoglyceride, a diglyceride or a combination thereof in amount of greater than 10 wt % and has less than 50 wt % triglyceride. 
     
     
         22 . A pharmaceutical composition for oral administration for replacement therapy in a male for a condition associated with a deficiency or absence of endogenous testosterone comprising testosterone undecanoate and a pharmaceutical acceptable carrier said pharmaceutical composition indicated to be taken (1) “WITH A MEAL”, (2) “WITH MEAL, BUT NOT ON EMPTY STOMACH”, (3) “WITH FAT CONTAINING FOOD” not specifying fat content, (4) “WITH MEAL, BUT NOT LOW FAT”, (5) “WITH MEAL, BUT NOT HIGH FAT”, or (6) “WITH STANDARD OR NORMAL MEAL”. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein said pharmaceutical composition is indicated to be taken “WITH A MEAL”. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein said pharmaceutical composition is indicated to be taken “WITH MEAL, BUT NOT ON EMPTY STOMACH”. 
     
     
         25 . The pharmaceutical composition of  claim 22 , wherein said pharmaceutical composition is indicated to be taken “WITH FAT CONTAINING FOOD” not specifying fat content. 
     
     
         26 . The pharmaceutical composition of  claim 22 , wherein said pharmaceutical composition is indicated to be taken “WITH MEAL, BUT NOT LOW FAT”. 
     
     
         27 . The pharmaceutical composition of  claim 22 , wherein said pharmaceutical composition is indicated to be taken “WITH STANDARD OR NORMAL MEAL” 
     
     
         28 . The pharmaceutical composition of  claim 22 , wherein said pharmaceutical composition is indicated to be taken “WITH MEAL, BUT NOT HIGH FAT”. 
     
     
         29 . The method of any one of  claim 1 , further comprising a dose titration of testosterone undecanoate. 
     
     
         30 . The method of any one of  claim 1 , wherein the meal has at least 10% of the calories present as fat. 
     
     
         31 . The method of any one of  claim 1 , wherein the meal has at least 15% or about 15% of the calories present as fat. 
     
     
         32 . The pharmaceutical composition of  claim 16 , indicated to be taken with a meal having at least 10% of the calories present as fat. 
     
     
         33 . The pharmaceutical composition of  claim 16 , indicated to be taken with a meal having at least 15% or about 15% of the calories present as fat. 
     
     
         34 . The pharmaceutical composition of  claim 16 , indicated to be taken with a meal having at least 10 grams or about 10 grams of fat. 
     
     
         35 . The pharmaceutical composition of  claim 16 , indicated to be taken with a meal having at least 15 grams or about 15 grams of fat. 
     
     
         36 . An oral dosage form in a container, comprising:
 a container having a label; and   an oral dosage form contained within the container, said oral dosage form comprising testosterone undecanoate and a pharmaceutically acceptable carrier, wherein the label indicates that the oral dosage is to be taken (1) “WITH A MEAL”, (2) “WITH MEAL, BUT NOT ON EMPTY STOMACH”, (3) “WITH FAT CONTAINING FOOD” not specifying fat content, (4) “WITH MEAL, BUT NOT LOW FAT”, (5) “WITH MEAL, BUT NOT HIGH FAT”, or (6) “WITH STANDARD OR NORMAL MEAL”.   
     
     
         37 . The oral dosage form of  claim 36 , wherein the container is selected from a bottle, a pouch, or a blister package. 
     
     
         38 . The oral dosage form of  claim 36 , wherein the pharmaceutically acceptable carrier includes a lipophilic additive, a hydrophilic additive, a solidifying agent or a combination thereof. 
     
     
         39 . The oral dosage form of  claim 36 , wherein the label indicates that the oral dosage form is to be taken with a meal having at least 10% of the calories present as fat. 
     
     
         40 . The oral dosage form of  claim 36 , wherein the label indicates that the oral dosage form is to be taken with a meal having at least 15% or about 15% of the calories present as fat. 
     
     
         41 . The oral dosage form of  claim 36 , wherein the label indicates that the oral dosage form is to be taken with a meal having at least 10 grams or about 10 grams of fat. 
     
     
         42 . The oral dosage form of  claim 36 , wherein the label indicates that the oral dosage form is to be taken with a meal having at least 15 grams or about 15 grams of fat.