Emulsion formulations

Abstract

A SEDDS or SMEDDS or SNEDDS formulation for drug delivery of a lipophilic therapeutic agent, providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of the therapeutic agent by formulation with a lipophilic surfactant, a hydrophilic surfactant, one or more solubilizers and, optionally, digestible oils, resulting in higher bioavailability of the therapeutic agent administered to a subject in need of such therapeutic agent. Also described are pharmaceutical compositions containing the formulations and methods of making and methods of using the formulations and pharmaceutical compositions. Formulations of the disclosure can be constituted to minimize the synthesis of dihydrotestosterone when the therapeutic agent includes testosterone or testosterone esters.

1 . A pharmaceutical composition comprising:
 a) from 2.5 to 37.5% by weight of solubilized testosterone undecanoate; and   b) from 2 to 65% by weight of one or more phytosterol esters,   
       wherein the composition is a self-emulsifying oral formulation. 
     
     
         2 . The pharmaceutical composition of  claim 1 , comprising from about 5% to about 37.5% by weight of one or more phytosterol esters. 
     
     
         3 . The pharmaceutical composition of  claim 2 , comprising from about 10% to about 37.5% by weight of one or more phytosterol esters. 
     
     
         4 . The pharmaceutical composition of  claim 3 , comprising from about 10% to about 25% by weight of one or more phytosterol esters. 
     
     
         5 . The pharmaceutical composition of  claim 1 , comprising:
 a) from 2.5 to 37.5% by weight of solubilized testosterone undecanoate;   b) from 5 to 37.5% by weight of a hydrophilic surfactant;   c) from 15 to 65% by weight of a lipophilic surfactant;   d) from 5 to 37.5% by weight of one or more phytosterol esters;   e) from 0 to 15% by weight of a solubilizer; and   f) from 0 to 15% by weight of a digestible oil,   
       wherein the composition is a self-emulsifying oral formulation. 
     
     
         6 . The pharmaceutical composition of  claim 5 , comprising from 10 to 37.5% by weight of solubilized testosterone undecanoate. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the hydrophilic surfactant is selected from polyoxyethylene sorbitan fatty acid esters, hydrogenated castor oil ethoxylates, PEG mono- and di-esters of palmitic and stearic acids, fatty acid ethoxylates, and combinations thereof. 
     
     
         8 . The pharmaceutical composition of  claim 6 , wherein the lipophilic surfactant is a fatty acid selected from octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. 
     
     
         9 . The pharmaceutical composition of  claim 6 , wherein the solubilizer comprises dl-alpha-tocopherol. 
     
     
         10 . The pharmaceutical composition of  claim 6 , wherein the digestible oil is a vegetable oil selected from soybean oil, safflower seed oil, corn oil, olive oil, castor oil, cottonseed oil,  arachis  oil, sunflower seed oil, coconut oil, palm oil, rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil, almond oil, borage oil, peppermint oil and apricot kernel oil. 
     
     
         11 . The pharmaceutical composition of  claim 1 , comprising:
 a) from 10 to 25% by weight of solubilized testosterone undecanoate;   b) from 10 to 37.5% by weight of hydrogenated castor oil ethoxylate;   c) from 10 to 60% by weight of a hydrophobic surfactant;   d) from 5 to 37.5% by weight of one or more phytosterol esters; and   e) 0-10% by weight of dl-alpha-tocopherol,   
       wherein the composition is a self-emulsifying oral formulation. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the hydrogenated castor oil ethoxylate is selected from Cremophor RH40 and Cremophor EL-35. 
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein the hydrophobic surfactant is selected from Maisine 35-1, oleic acid, Imwitor 742, Lauroglycol 90, and combinations thereof. 
     
     
         14 . The pharmaceutical composition of  claim 1 , comprising:
 a) from 10 to 25% by weight of solubilized testosterone undecanoate;   b) from 5 to 20% by weight of hydrogenated castor oil ethoxylate;   c) from 10 to 45% by weight of a hydrophobic surfactant;   d) from 5 to 45% by weight of one or more phytosterol esters; and   e) from 0 to 5% by weight of dl-alpha-tocopherol,   
       wherein the composition is a self-emulsifying oral formulation. 
     
     
         15 . The pharmaceutical composition of  claim 14 , comprising:
 a) from 15 to 20% by weight of solubilized testosterone undecanoate;   b) from 10 to 20% by weight of hydrogenated castor oil ethoxylate;   c) from 35 to 45% by weight of a hydrophobic surfactant;   d) from 20 to 30% by weight of one or more phytosterol esters; and   e) from 0 to 5% by weight of dl-alpha-tocopherol,   
       wherein the composition is a self-emulsifying oral formulation. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the hydrogenated castor oil ethoxylate is selected from Cremophor RH40 and Cremophor EL-35. 
     
     
         17 . The pharmaceutical composition of  claim 15 , wherein the hydrophobic surfactant is selected from Maisine 35-1, oleic acid, Imwitor 742, Lauroglycol 90, and combinations thereof. 
     
     
         18 . The pharmaceutical composition of  claim 15 , comprising:
 a) about 18.2% by weight of solubilized testosterone undecanoate;   b) about 15.0% by weight of Cremophor RH40;   c) about 39.9% by weight of Lauroglycol 90;   d) about 25.0% by weight of one or more phytosterol esters; and   e) about 2.0% by weight of dl-alpha-tocopherol,   
       wherein the composition is a self-emulsifying oral formulation. 
     
     
         19 . A method of treating testosterone deficiency in a subject in need thereof, said method comprising administering to the subject a pharmaceutical composition of  claim 1  in an amount effective to treat the testosterone deficiency. 
     
     
         20 . The method of  claim 19 , wherein said subject is a hypogonadal male. 
     
     
         21 . A method of treating androgen deficiency in a subject in need thereof, said method comprising administering to the subject a pharmaceutical composition of  claim 1  in an amount effective to treat the androgen deficiency. 
     
     
         22 . The method of  claim 21 , wherein said subject is a postmenopausal woman, menopausal woman, sexually dysfunctional woman, andropausal man, hypogonadal man, erectile dysfunctional man, or hypogonadal adolescent boy.