Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same

Abstract

A drug delivery system for oral administration of hydrophobic drugs with enhanced and extended absorption and improved pharmacokinetics is provided. In one embodiment, formulations comprising testosterone and testosterone esters, e.g., testosterone palmitate, are disclosed. Methods of treating a hormone deficiency or effecting male contraception with the inventive formulations are also provided.

1 . A pharmaceutical composition comprising testosterone palmitate (TP) and two or more lipid components at least the first of which comprises a hydrophilic surfactant and at least the second of which comprises a lipophilic surfactant that provides for the controlled release of TP, said lipid components together providing for the solubilization of TP. 
     
     
         2 . The pharmaceutical composition of  claim 1  which comprises at least three lipid components at least the first of which comprises a hydrophilic surfactant, at least the second of which comprises a lipophilic surfactant that provides for the controlled release of TP and at least the third of which comprises a lipophilic surfactant that further provides for the solubilization of TP. 
     
     
         3 . The pharmaceutical composition of  claim 2  which further comprises a second lipid-soluble therapeutic agent. 
     
     
         4 . The pharmaceutical composition of  claim 1  in which the at least first lipid component exhibits an HLB of 10 to 45. 
     
     
         5 . The pharmaceutical composition of  claim 2  in which the at least second lipid component is a glyceryl palmitate, stearate, palmitostearate and blends thereof. 
     
     
         6 . The pharmaceutical composition of  claim 1  in which the at least second lipid component exhibits an HLB of less than 10. 
     
     
         7 . The pharmaceutical composition of  claim 2  in which the at least second lipid component is a fatty acid; a glyceryl palmitostearate; a semi-synthetic glyceride; a monoglyceride or a diglyceride of fatty acids; an acetic ester, succinic ester, lactic ester, citric ester or tartaric ester of a monoglyceride or diglyceride of fatty acids; a polyglycerol ester of a fatty acid; or an acid and ester ethoxylate. 
     
     
         8 . The pharmaceutical composition of  claim 2  in which the at least third lipid component is selected from the group consisting of caprylic, capric, lauric, myristic, palmitic, oleic acid, stearic acid, their esters, or combinations thereof. 
     
     
         9 . The pharmaceutical composition of  claim 2  in which the at least third lipid component comprises a transesterified glyceride of a vegetable oil. 
     
     
         10 . The pharmaceutical composition of  claim 1  in which the at least first lipid component is selected from the group consisting of a polyoxythylene glycerol fatty acid ester, a sorbitan fatty acid ester, a tocopherol ester, an ester of ascorbic acid, or combinations thereof. 
     
     
         11 . The pharmaceutical composition of  claim 1  in which the at least first lipid component is a castor oil ethoxylate or a hydrogenated castor oil ethoxylate, and combinations thereof. 
     
     
         12 . The pharmaceutical composition of  claim 1  in which the first lipid component is a polyoxyethylene sorbitan fatty acid ester; an α-tocopherol-polyethylene glycol-1000-succinate (TPGS), ascorbyl-6-palmitate, polyoxyethylene/polyoxypropylene block copolymer; or a combination thereof. 
     
     
         13 . The pharmaceutical composition of  claim 1  which comprises from about 5 to about 20 percent by weight of testosterone palmitate. 
     
     
         14 . The pharmaceutical composition of  claim 1  further comprising one or more cosolvents. 
     
     
         15 . The pharmaceutical composition of  claim 14  comprising a cosolvent selected from the group consisting of ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate or polyethylene glycol with an average molecular weight from about 200 to about 10,000, diethylene glycol monoethyl ether, and combinations thereof. 
     
     
         16 . The pharmaceutical composition of  claim 3  in which said lipid-soluble hydrophobic drug comprises a synthetic progestin. 
     
     
         17 . The pharmaceutical composition of  claim 3  in which said lipid-soluble hydrophobic drug comprises an inhibitor of type-I and/or type II 5α-reductase. 
     
     
         18 . A method of preventing or alleviating the symptoms of testosterone deficiency in a mammalian subject comprising administering to the mammalian subject an effective amount of testosterone palmitate (TP) solubilized in two or more lipid components, such that the administration of said solubilized TP raises the mammalian subject's steady state serum level of testosterone to within those levels found in mammalian subjects having no testosterone deficiency and providing at least some relief from such symptoms. 
     
     
         19 . The method of  claim 18  in which the TP is solubilized in at least three lipid components. 
     
     
         20 . The method of  claim 18  in which the solubilized TP is administered orally. 
     
     
         21 . The method of  claim 18  in which the mammalian subject is a human male or human female. 
     
     
         22 . The method of  claim 21  in which the human male's steady state serum level of testosterone is raised to fall within a range of about 300 ng/dl to about 1100 ng/dl. 
     
     
         23 . The method of  claim 18  which further comprises administering an amount of a synthetic progestin sufficient to substantially inhibit gonadotropin release in said mammalian subject. 
     
     
         24 . A method of delivering steady-state serum levels of testosterone effective to provide at least some relief from symptoms of testosterone deficiency comprising solubilizing testosterone palmitate (TP) in two or more lipid components at least the first of which comprises a hydrophilic surfactant and at least the second of which comprises a lipophilic surfactant that provides for the controlled release of TP and administering an effective amount of the solubilized TP to a subject suffering from the symptoms of testosterone deficiency. 
     
     
         25 . The method of  claim 24  which comprises solubilizing TP in at least three lipid components at least the first of which comprises a hydrophilic surfactant, at least the second of which comprises a lipophilic surfactant that provides for the controlled release of TP and at least the third of which comprises a lipophilic surfactant that further provides for the solubilization of TP. 
     
     
         26 . The method of  claim 24  in which the steady-state serum levels of testosterone fall between about 300 ng/dl to about 1100 ng/dl. 
     
     
         27 . A method of providing extended release of testosterone in vivo comprising solubilizing testosterone palmitate (TP) in a lipid mixture comprising two or more lipid components at least the first of which comprises a hydrophilic surfactant and at least the second of which comprises a lipophilic surfactant having a melting point of greater than about 30° C. 
     
     
         28 . A pharmaceutical composition comprising testosterone palmitate (TP) and two or more lipid components at least the first of which comprises a hydrophilic surfactant and at least the second of which comprises a lipophilic surfactant, in which the at least first hydrophilic component or the at least second lipophilic component provides for the controlled release of TP, and said lipid components together provide for the solubilization of TP. 
     
     
         29 . The pharmaceutical composition of  claim 28 , in which the each of the two or more lipid components provide controlled release of TP. 
     
     
         30 . The pharmaceutical composition of  claim 28  in which the at least first hydrophilic component provides for the controlled release of TP. 
     
     
         31 . A method of inhibiting the hydrolysis of and ester of testosterone in a mammal comprising co-administering to said mammal along with a medium or long chain fatty acid ester of testosterone an effective inhibitory amount of a medium or long chain fatty acid ester. 
     
     
         32 . The method of  claim 31  in which the medium or long chain ester of testosterone is selected from the group consisting of testosterone palmitate, testosterone stearare, testosterone myristate, testosterone laurate, testosterone caprate, testosterone decanoate, testosterone octanoate, testosterone caprylate, testosterone pelargonate, testosterone undecanate, testosterone tridecanoate and testosterone pentadecanoate. 
     
     
         33 . The method of  claim 31  in which the medium or long chain fatty acid moiety of the ester and the testosterone ester are the same. 
     
     
         34 . The method of  claim 31  in which the medium or long chain fatty acid ester is a palmitate. 
     
     
         35 . The method of  claim 31  in which the palmitate is ascorbyl palmitate.