Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profile of lipophilic drugs by sterols

Abstract

A formulation for drug delivery, providing enhanced modulation of solubility, stability, absorption, metabolism, and/or pharmacokinetic profile of a lipophilic therapeutic agent by formulation with sterols and/or sterol esters, resulting in higher bioavailability of a therapeutic agent administered to a subject in need of such therapeutic agent. The formulation contains a therapeutic agent and a sterol or sterol ester, and can, optionally, further contain a solubilizer and/or an enhancing 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 formulation for increased biological absorption of one or more therapeutic agents, the formulation comprising:
 a) at least one lipophilic, poorly water soluble therapeutic agent; and   b) a phytosterol or phytosterol ester,   wherein the phytosterol or phytosterol ester provides enhanced biological absorption of the at least one therapeutic agent, as compared to the absorption of the therapeutic agent without the phytosterol or phytosterol ester.   
     
     
         2 . The formulation of  claim 1 , wherein the at least one therapeutic agent is selected from the group consisting of: testosterone, testosterone esters, and combinations thereof. 
     
     
         3 . The formulation of  claim 2 , wherein the testosterone ester comprises testosterone undecanoate. 
     
     
         4 . The formulation of  claim 1 , wherein the therapeutic agent is present in an amount selected from about 25 mg testosterone equivalent to about 300 mg testosterone equivalent for administration to a male subject and from about 2.5 mg testosterone equivalent to about 30 mg testosterone equivalent for administration to a female subject. 
     
     
         5 . The formulation of  claim 1 , wherein the therapeutic agent is present in an amount sufficient to achieve a serum testosterone level of about 300 ng/dL to about 1100 ng/dL in a male subject or about 30 ng/dL to about 110 ng/dL in a female subject. 
     
     
         6 . The formulation of  claim 1 , wherein the phytosterol or phytosterol ester is present in an amount of about 2% to about 45% by weight of the formulation. 
     
     
         7 . The formulation of  claim 1 , further comprising a non-sterol solubilizing agent effective for solubilization of the therapeutic agent. 
     
     
         8 . The formulation of  claim 7 , wherein the non-sterol solubilizing agent is present in an amount of about 10% to about 90% by weight of the formulation. 
     
     
         9 . The formulation of  claim 7 , wherein the non-sterol solubilizing agent is selected from the group consisting of: lipids, surfactants, and mixtures thereof. 
     
     
         10 . The formulation of  claim 7 , further comprising an enhancing agent effective to improve at least one of biological absorption and metabolic stability of the therapeutic agent. 
     
     
         11 . The formulation of  claim 10 , wherein the enhancing agent comprises Polyoxyl 40 Hydrogenated Castor Oil and Polysorbate 80 in a ratio selected from the group consisting of from (i) about 1:10 to about 10:1 and (ii) about 1:2 to about 2:1. 
     
     
         12 . The formulation of  claim 1 , wherein the biological absorption is intestinal lymphatic absorption of testosterone undecanoate. 
     
     
         13 . A method of enhancing solubility of one or more poorly soluble therapeutic agents, the method comprising combining:
 a) a phytosterol or phytosterol ester;   b) a non-sterol solubilizing agent; and   c) at least one lipophilic, poorly water soluble therapeutic agents,   in a composition, wherein the composition is effective to enhance solubility of the at least one therapeutic agent, as compared to the solubility of the therapeutic agent in the absence of a) a phytosterol or phytosterol ester and b) a non-sterol solubilizing agent.   
     
     
         14 . The method of  claim 13 , wherein the at least one therapeutic agent is selected from the group consisting of: testosterone, testosterone esters, and combinations thereof. 
     
     
         15 . The method of  claim 14 , wherein the testosterone ester comprises testosterone undecanoate. 
     
     
         16 . The method of  claim 13 , wherein the non-sterol solubilizing agent is selected from the group consisting of: lipids, surfactants, and mixtures thereof. 
     
     
         17 . The method of  claim 13 , further comprising an enhancing agent effective to improve at least one of biological absorption and metabolic stability of the therapeutic agent. 
     
     
         18 . The method of  claim 17 , wherein the enhancing agent comprises Polyoxyl 40 Hydrogenated Castor Oil and Polysorbate 80 in a ratio selected from the group consisting of from (i) about 1:10 to about 10:1 and (ii) about 1:2 to about 2:1. 
     
     
         19 . The method of  claim 17 , wherein the biological absorption is intestinal lymphatic absorption of testosterone undecanoate. 
     
     
         20 . A method of enhancing biological absorption or metabolic stability of one or more poorly soluble therapeutic agents, the method comprising administering:
 a) a phytosterol or phytosterol ester;   b) a non-sterol solubilizing agent;   c) an enhancing agent; and   d) at least one lipophilic, poorly water soluble therapeutic agent   in a composition, wherein the composition is effective to enhance biological absorption or metabolic stability of at least one therapeutic agent, as compared to correspondingly administered therapeutic agent in the absence of a) a phytosterol or phytosterol ester, b) a non-sterol solubilizing agent and c) an enhancing agent.   
     
     
         21 . The method of  claim 20 , wherein the at least one therapeutic agent is selected from the group consisting of: testosterone, testosterone esters, and combinations thereof. 
     
     
         22 . The method of  claim 21 , wherein the testosterone ester comprises testosterone undecanoate. 
     
     
         23 . The method of  claim 20 , wherein the non-sterol solubilizing agent is selected from the group consisting of: lipids, surfactants, and mixtures thereof. 
     
     
         24 . The method of  claim 20 , wherein the enhancing agent comprises Polyoxyl 40 Hydrogenated Castor Oil and Polysorbate 80 in a ratio selected from the group consisting of from (i) about 1:10 to about 10:1 and (ii) about 1:2 to about 2:1. 
     
     
         25 . The method of  claim 20 , wherein the biological absorption is intestinal lymphatic absorption of testosterone undecanoate. 
     
     
         26 . A method of treating a condition, comprising administering:
 a) at least one lipophilic, poorly water soluble therapeutic agent;   b) a phytosterol or phytosterol ester;   c) a non-sterol solubilizing agent effective for solubilization of the at least one therapeutic agent; and   d) an enhancing agent effective to improve the biological absorption and/or metabolic stability of the at least one therapeutic agent.   
     
     
         27 . The method of  claim 26 , wherein the at least one therapeutic agent is selected from the group consisting of: testosterone, testosterone esters, and combinations thereof. 
     
     
         28 . The method of  claim 27 , wherein the testosterone ester comprises testosterone undecanoate. 
     
     
         29 . The method of  claim 26 , wherein the non-sterol solubilizing agent is selected from the group consisting of: lipids, surfactants, and mixtures thereof. 
     
     
         30 . The method of  claim 26 , wherein administration comprises any of: a), b), c) and d) administered at different times; a), b), c) and d) administered at the same time; a), b), c) and d) administered as a single composition; and a), b), c) and d) administered as one or more compositions. 
     
     
         31 . The method of  claim 26 , wherein the administration is selected from oral, parenteral, intramuscular, transdermal, nasal, sublingual, buccal and subcutaneous administration. 
     
     
         32 . The method of  claim 26 , wherein the biological absorption is intestinal lymphatic absorption of testosterone undecanoate. 
     
     
         33 . The method of  claim 26 , wherein the condition comprises testosterone deficiency. 
     
     
         34 . The method of  claim 33 , where the condition is erectile dysfunction and the one or more therapeutic agents is selected from the group consisting of: testosterone, testosterone esters, PDE V inhibitors, and combinations thereof. 
     
     
         35 . The method of  claim 34 , wherein the PDE V inhibitor comprises tadalafil. 
     
     
         36 . A method for maintaining or controlling physiological levels of testosterone and DHT in a subject in need of testosterone replacement, the method comprising administering:
 a) one or more therapeutic agents selected from the group consisting of testosterone, testosterone esters, and combinations thereof, in a formulation selected from immediate release, sustained release, and combinations thereof;   b) a phytosterol or phytosterol ester;   c) a non-sterol solubilizing agent effective for solubilization of the testosterone or testosterone ester; and   d) an enhancing agent effective to improve the biological absorption and/or metabolic stability of the one or more therapeutic agents;   
       wherein the method is effective to deliver the one or more therapeutic agents to the subject to achieve in the subject a testosterone level of about 300 ng/dL to about 1100 ng/dL and a DHT level of about 30 ng/dL to about 300 ng/dL. 
     
     
         37 . The method of  claim 36 , wherein the administration is oral. 
     
     
         38 . The method of  claim 36 , wherein the testosterone ester comprises testosterone undecanoate. 
     
     
         39 . The method of  claim 36 , wherein the non-sterol solubilizing agent is selected from the group consisting of: lipids, surfactants, and mixtures thereof. 
     
     
         40 . The method of  claim 36 , wherein the enhancing agent comprises Polyoxyl 40 Hydrogenated Castor Oil and Polysorbate 80 in a ratio selected from the group consisting of from (i) about 1:10 to about 10:1 and (ii) about 1:2 to about 2:1. 
     
     
         41 . The method of  claim 36 , wherein the biological absorption is intestinal lymphatic absorption of testosterone undecanoate.