Pharmaceutical composition and method for treating hypogonadism

Abstract

A pharmaceutical composition useful for treating hypogonadism is disclosed. The composition comprises an androgenic or anabolic steroid, a C1-C4 alcohol, a penetration enhancer such as isopropyl myristate, and water. Also disclosed is a method for treating hypogonadism utilizing the composition.

1 . A hydroalcoholic gel pharmaceutical composition, comprising: 
 (a) about 0.1% to about 10% testosterone weight to weight of the composition;    (b) an alcohol;    (c) a penetration enhancer; and    (d) a gelling agent;    wherein upon administration of the pharmaceutical composition to skin of a male subject, the testosterone is absorbed into bloodstream of the subject at a rate and duration that maintains a circulating serum concentration of the testosterone greater than about 400 ng testosterone per dl serum during a time period beginning about 2 hours after administration and ending about 24 hours after administration.    
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the serum testosterone concentration is maintained between about 400 ng testosterone per dl serum to about 105 ng testosterone per dl serum.  
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein for each about 0.1 gram per day administration of the composition to the skin, an increase of at least about 5 ng/dl in serum testosterone concentration results in the subject.  
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the composition is a dosage form of approximately 0.1 g, 2.5 g, 5 g, 7.5 g, or 10 g.  
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the dose is approximately a 5 g dose delivering about 50 mg to about 100 mg of testosterone to the skin.  
     
     
         6 . The pharmaceutical composition of  claim 4 , wherein the dose is approximately 7.5 g dose delivering about 50 mg to about 100 mg of testosterone to the skin.  
     
     
         7 . The pharmaceutical composition of  claim 4 , wherein the dose is approximately a 10 g dose delivering 50 mg to about 100 mg of testosterone to the skin.  
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein maximum serum testosterone concentration in the subject is reached about 16 hours after administration of the composition on day one of administration.  
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the subject is a male human.  
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the serum testosterone concentration in the subject is at least 490 ng/dl to about 860 ng/dl after at least about 30 days of daily administration.  
     
     
         11 . The pharmaceutical composition of  claim 9 , wherein upon administration of the composition to the skin of the subject after at least about 30 days of daily administration, the testosterone absorbs into the bloodstream of the subject at a rate and duration that maintains a serum dihydrotestosterone concentration in the subject greater than about 54 ng/dl.  
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein a ratio of serum dihydrotestosterone concentration to serum testosterone concentration of greater than about 0.23 is achieved in the subject after at least about 30 days of daily administration.  
     
     
         13 . The pharmaceutical composition of  claim 9 , wherein upon administration of the pharmaceutical composition to the skin of the subject after at least about 30 days of daily administration, the testosterone absorbs into the bloodstream of the subject at a rate and duration that maintains a total serum androgen concentration in the subject greater than about 372 ng/dl.  
     
     
         14 . The pharmaceutical composition of  claim 9 , wherein upon administration of the composition to the skin of the subject after at least about 30 days of daily administration, the testosterone absorbs into the bloodstream of the subject at a rate and duration that maintains a serum estradiol concentration in the subject greater than about 28 pg/ml.  
     
     
         15 . The pharmaceutical composition of  claim 9 , wherein upon administration of the composition to the skin of the subject after at least about 30 days of daily administration, the testosterone absorbs into the bloodstream of the subject at a rate and duration that maintains a serum follicle stimulating hormone concentration in the subject less than about 11 mIU/ml.  
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the serum follicle stimulating hormone concentration in the subject is less than about 3.7 mIU/ml after at least about 30 days of daily administration.  
     
     
         17 . The pharmaceutical composition of  claim 15 , wherein the serum follicle stimulating hormone concentration is within or below the normal range after at least about 30 days of daily administration.  
     
     
         18 . The pharmaceutical composition of  claim 9 , wherein upon administration of the composition to the skin of the subject after at least about 30 days of daily administration, the testosterone absorbs into the bloodstream of the subject at a rate and duration that maintains a serum luteinizing hormone concentration within normal range of an adult male.  
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the normal range is less than about 6.8 mIU/ml serum luteinizing hormone after at least about 30 days of daily administration.  
     
     
         20 . The pharmaceutical composition of  claim 9 , wherein upon administration of the pharmaceutical composition to the skin of the subject after at least about 30 days of daily administration, the testosterone has an accumulation ratio in the subject greater than about 1.5.  
     
     
         21 . The pharmaceutical composition of  claim 9 , wherein upon administration of the pharmaceutical composition to the skin of the subject after at least about 30 days of daily administration the testosterone has a net AUC0-24 in the subject greater than 220 nmol*h/l.  
     
     
         22 . The pharmaceutical composition of  claim 1 , wherein the testosterone comprises an enantiomer, a racemic mixture, a derivative, a base, or a salt thereof.  
     
     
         23 . The pharmaceutical composition of  claim 1 , wherein the composition is a dosage form containing about 1.0 gram to about 10 grams of the composition.  
     
     
         24 . The pharmaceutical composition of  claim 1 , wherein the composition is a dosage form containing about 2.5 grams to about 7.5 grams of the composition.  
     
     
         25 . The pharmaceutical composition of  claim 1 , wherein the composition is a dosage form containing about 2.5 grams to about 5.0 grams of the composition.  
     
     
         26 . The pharmaceutical composition of  claim 1 , wherein the composition comprises about 0.5% to about 5% (w/w) testosterone.  
     
     
         27 . The pharmaceutical composition of  claim 1 , wherein the composition comprises about 1% (w/w) testosterone.  
     
     
         28 . The pharmaceutical composition of  claim 1 , wherein the permeation enhancer comprises isopropyl myristate in an amount of about 0.25% to about 2.5% (w/w) of the composition.  
     
     
         29 . The pharmaceutical composition of  claim 1 , wherein the composition comprises isopropyl myristate in an amount of about 0.5% (w/w) of the composition.  
     
     
         30 . The pharmaceutical composition of  claim 1 , wherein the gelling agent is polyacrylic acid.  
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the composition comprises about 0.9% (w/w) polyacrylic acid.  
     
     
         32 . The pharmaceutical composition of  claim 1 , wherein the composition comprises about 40% to about 90% (w/w) alcohol.  
     
     
         33 . A method of treating hypogonadism in a male subject in need thereof, comprising administering a pharmaceutical composition to skin of the subject in a pharmacologically effective amount to treat the hypogonadism, wherein the composition comprises: 
 (a) about 0.1% to about 10% testosterone weight to weight of the composition;    (b) an alcohol;    (c) a penetration enhancer; and    (d) a gelling agent;    wherein the testosterone is absorbed into bloodstream of the subject at a rate and duration that maintains a circulating serum concentration of the testosterone greater than about 400 ng testosterone per dl serum during a time period beginning about 2 hours after administration and ending about 24 hours after administration.    
     
     
         34 . The method of  claim 33 , wherein the composition is administered daily for at least about 7 days.  
     
     
         35 . The method of  claim 33 , wherein the composition is administered daily for at least 30 days.  
     
     
         36 . The method of  claim 33 , wherein the composition is administered daily for at least about 180 days.  
     
     
         37 . The method of  claim 33 , wherein the administration of the composition exhibits dose proportionality.  
     
     
         38 . The method of  claim 33 , wherein the testosterone comprises an enantiomer, racemic mixture, a derivative, a base, or a salt thereof.  
     
     
         39 . The method of  claim 33 , wherein the subject is a male human.  
     
     
         40 . The method of  claim 39 , wherein the serum testosterone concentration is maintained between about 400 ng testosterone per dl serum to about 1050 ng testosterone per dl serum.  
     
     
         41 . The method of  claim 39 , wherein after at least about 30 days of daily administration serum testosterone concentration in the subject is at least about 490 ng/dl to about 860 ng/dl.  
     
     
         42 . The method of  claim 39 , wherein after at least about 30 days of daily administration serum dihydrotestosterone concentration in the subject is greater than about 54 ng/dl.  
     
     
         43 . The method of  claim 39 , wherein after at least about 30 days of daily administration a ratio of serum dihydrotestosterone concentration to serum testosterone concentration of greater than about 0.23 is achieved in the subject.  
     
     
         44 . The method of  claim 39 , wherein after at least about 30 days of daily administration total serum androgen concentration in the subject is greater than about 372 ng/dl.  
     
     
         45 . The method of  claim 39 , wherein after at least about 30 days of daily administration serum estradiol concentration in the subject is greater than about 28 pg/ml.  
     
     
         46 . The method of  claim 39 , wherein the subject has primary hypogonadism prior to administration.  
     
     
         47 . The method of  claim 46 , wherein after at least about 30 days of daily administration serum follicle stimulating hormone concentration in the subject is less than about 11 mIU/ml.  
     
     
         48 . The method of  claim 39 , wherein the subject has secondary hypogonadism prior to administration.  
     
     
         49 . The method of  claim 48 , wherein after at least about 30 days of daily administration serum follicle stimulating hormone concentration in the subject is less than about 3.7 mIU/ml.  
     
     
         50 . The method of  claim 39 , wherein the subject has a pretreatment serum follicle stimulating hormone concentration greater than a normal range of a normal subject.  
     
     
         51 . The method of  claim 50 , wherein after at least about 30 days of daily administration the serum follicle stimulating hormone concentration is within or below the normal range.  
     
     
         52 . The method of  claim 39 , wherein the subject has a pretreatment serum luteinizing hormone concentration greater than a normal range of a subject having primary hypogonadism.  
     
     
         53 . The method of  claim 52 , wherein after at least about 30 days of daily administration serum luteinizing hormone concentration is within the normal range.  
     
     
         54 . The method of  claim 53 , wherein after at least about 30 days of daily administration the serum luteinizing hormone concentration is less than about 6.8 mIU/ml.  
     
     
         55 . The method of  claim 39 , wherein after at least about 30 days of daily administration the testosterone has an accumulation ratio in the subject greater than about 1.5.  
     
     
         56 . The method of  claim 39 , wherein after at least about 30 days of daily administration the testosterone has a net ACU0-24 in the subject greater than 220 nmol*h/l.  
     
     
         57 . The method of  claim 33 , wherein for each about 0.1 gram per day administration of the composition to the skin, an increase of at least about 5 ng/dl in serum testosterone concentration results in the subject.  
     
     
         58 . The method of  claim 33 , wherein the composition is provided to the subject for daily administration in a dose of approximately 0.1 g, 2.5 g, 5 g, 7.5 g, or 10 g.  
     
     
         59 . The method of  claim 58 , wherein the dose is approximately a 5 g dose delivering about 50 mg to about 100 mg of testosterone to the skin.  
     
     
         60 . The method of  claim 58 , wherein the dose is approximately a 7.5 mg dose delivering about 50 mg to about 100 mg of testosterone to the skin.  
     
     
         61 . The method of  claim 58 , wherein the dose is approximately a 10 g dose delivering 50 mg to about 100 mg of testosterone to the skin.  
     
     
         62 . The method of  claim 58 , wherein the composition is provided to the subject in one or more packets.  
     
     
         63 . The method of  claim 33 , wherein maximum serum testosterone concentration in the subject is reached about 16 hours after administration of the composition on day one of administration.  
     
     
         64 . The method of  claim 33 , wherein the composition is a dosage form containing about 1.0 gram to about 10 grams of the composition.  
     
     
         65 . The method of  claim 33 , wherein the composition is a dosage form containing about 2.5 grams to about 7.5 grams of the composition.  
     
     
         66 . The method of  claim 33 , wherein the composition is a dosage form containing about 2.5 grams to about 5.0 grams of the composition.  
     
     
         67 . The method of  claim 33 , wherein the composition comprises about 0.5% to about 5% (w/w) testosterone.  
     
     
         68 . The method of  claim 33 , wherein the composition comprises about 1% (w/w) testosterone.  
     
     
         69 . The method of  claim 33 , wherein the penetration enhancer comprises isopropyl myristate in an amount of about 0.25% to about 2.5% (w/w) of the composition.  
     
     
         70 . The method of  claim 69 , wherein the composition comprises about 0.5 (w/w) isopropyl myristate.  
     
     
         71 . The method of  claim 33 , wherein the gelling agent is polyacrylic acid.  
     
     
         72 . The method of  claim 71 , wherein the composition comprises about 0.9% (w/w) polyacrylic acid.  
     
     
         73 . The method of  claim 33 , wherein the composition comprises about 40% to about 90% alcohol.