Tocopherol-modified therapeutic drug compound formulations

Abstract

Tocopherol-modified therapeutic drug compounds; emulsion, microemulsion, and micelle formulations that include the compounds; methods for making the compounds and formulations; methods for administering the compounds and formulations; and methods for treating conditions using the compounds and formulations.

1 . An emulsion, comprising: 
 (a) an oil phase comprising 
 (i) a compound having the formula  
   (T-L) n (T) m D  
 wherein T is a lipophilic moiety;  
 L is a linker moiety;  
 D is a therapeutic drug moiety;  
 n=0, 1, 2, or 3;  
 m=0, 1, 2, or 3; and  
 m+n=1, 2, or 3;  
 wherein the n T-L moieties are covalently coupled to the therapeutic drug moiety through the linker moiety and the in lipophilic moieties are covalently coupled to the therapeutic drug moiety;  
 (ii) a lipophilic medium; and  
   (b) an aqueous phase.    
   
   
       2 . The emulsion of  claim 1 , wherein the therapeutic drug moiety is derived from a therapeutic drug compound having a solubility in water at room temperature less than about 500 μg/mL.  
   
   
       3 . The emulsion of  claim 1 , wherein the therapeutic drug moiety is at least one of paclitaxel, docetaxel, camptothecin, or derivatives thereof.  
   
   
       4 . The emulsion of  claim 1 , wherein the lipophilic moiety is a tocopherol.  
   
   
       5 . The emulsion of  claim 1 , wherein the linker moiety is a succinate.  
   
   
       6 . The emulsion of  claim 1 , wherein the lipophilic medium comprises tocopherol.  
   
   
       7 . A micelle formulation, comprising: 
 (a) a compound having the formula      (T-L) n (T) m D  wherein T is a lipophilic moiety;    L is a linker moiety;    D is a therapeutic drug moiety;    n=0, 1, 2, or 3;    m=0, 1, 2, or 3; and    m+n=1, 2, or 3;    wherein the n T-L moieties are covalently coupled to the therapeutic drug moiety through the linker moiety and the m lipophilic moieties are covalently coupled to the therapeutic drug moiety; and      (b) an aqueous phase.    
   
   
       8 . The formulation of  claim 7 , wherein the therapeutic drug moiety is derived from a therapeutic drug compound having a solubility in water at room temperature less than about 500 μg/mL.  
   
   
       9 . The formulation of  claim 7 , wherein the therapeutic drug moiety is at least one of paclitaxel, docetaxel, camptothecin, or derivatives thereof.  
   
   
       10 . The formulation of  claim 7 , wherein the lipophilic moiety is a tocopherol.  
   
   
       11 . The formulation of  claim 7 , wherein the linker moiety is a succinate.  
   
   
       12 . The emulsion of  claim 1 , wherein the therapeutic drug is butanedioic acid, (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl (4S)-4-ethyl-3,4,12,14-tetrahydro-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl ester.  
   
   
       13 . The emulsion of  claim 1 , wherein the therapeutic drug is butanedioic acid, (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl (4S)-4-ethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl ester.  
   
   
       14 . The emulsion of  claim 1 , wherein the therapeutic drug is butanedioic acid, (4S)-4,1-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl ester.  
   
   
       15 . The formulation of  claim 7 , wherein the therapeutic drug is butanedioic acid, (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl (4S)-4-ethyl-3,4,12,14-tetrahydro-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl ester.  
   
   
       16 . The formulation of  claim 7 , wherein the therapeutic drug is butanedioic acid, (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl (4S)-4-ethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl ester.  
   
   
       17 . The formulation of  claim 7 , wherein the therapeutic drug is butanedioic acid, (4S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl ester.  
   
   
       18 . An emulsion, comprising: 
 (a) an oil phase comprising 
 (i) a compound selected from the group consisting of 
 (A) butanedioic acid, (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl (4S)-4-ethyl-3,4,12,14-tetrahydro-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl ester,  
 (B) butanedioic acid, (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl (4S)-4-ethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl ester, and  
 (C) butanedioic acid, (4S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl ester, and  
 
 (ii) a lipophilic medium; and  
   (b) an aqueous phase.    
   
   
       19 . The emulsion of  claim 18 , wherein the compound is butanedioic acid, (4S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl ester.  
   
   
       20 . The emulsion of  claim 18 , wherein the lipophilic medium comprises a tocopherol.  
   
   
       21 . The emulsion of  claim 18 , wherein the lipophilic medium comprises α-tocopherol.  
   
   
       22 . The emulsion of  claim 18  further comprising a tocopherol polyethylene glycol derivative.  
   
   
       23 . The emulsion of  claim 22 , wherein the tocopherol polyethylene glycol derivative is present in the emulsion in an amount from about 1 to about 10 percent by weight based on the total weight of the emulsion.  
   
   
       24 . The emulsion of  claim 22 , wherein the tocopherol polyethylene glycol derivative is vitamin E succinate polyethylene glycol.  
   
   
       25 . The emulsion of  claim 18  further comprising a block copolymer of ethylene oxide and propylene oxide.  
   
   
       26 . The emulsion of  claim 18  further comprising polyethylene glycol.  
   
   
       27 . The emulsion of  claim 26 , wherein the polyethylene glycol is selected from the group consisting of polyethylene glycol-200, polyethylene glycol-300, and polyethylene glycol-400.  
   
   
       28 . The emulsion of  claim 18 , wherein the compound is present in the emulsion in an amount from about 0.005 to about 3.0 weight percent based on the total weight of the emulsion.  
   
   
       29 . The emulsion of  claim 18 , wherein the lipophilic medium is present in the emulsion in an amount from about 2 to about 20 weight percent based on the total weight of the emulsion.  
   
   
       30 . The emulsion of  claim 18 , wherein the aqueous phase comprises saline.  
   
   
       31 . The emulsion of  claim 18 , wherein the aqueous phase comprises buffered saline.  
   
   
       32 . The emulsion of  claim 18 , wherein the aqueous phase comprises citrate buffered saline or succinate buffered saline.  
   
   
       33 . A micelle formulation, comprising: 
 (a) a compound selected from the group consisting of 
 (i) butanedioic acid, (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl (4S)-4-ethyl-3,4,12,14-tetrahydro-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-4-yl ester,  
 (ii) butanedioic acid, (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl (4S)-4-ethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl ester, and  
 (iii) butanedioic acid, (4S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl ester; and  
   (b) an aqueous phase.    
   
   
       34 . The formulation of  claim 33 , wherein the compound is butanedioic acid, (4S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl (2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl ester.  
   
   
       35 . The formulation of  claim 33  further comprising a tocopherol polyethylene glycol derivative.  
   
   
       36 . The formulation of  claim 35 , wherein the tocopherol polyethylene glycol derivative is present in the emulsion in an amount from about 1 to about 10 percent weight based on the total weight of the emulsion.  
   
   
       37 . The formulation of  claim 35 , wherein the tocopherol polyethylene glycol derivative is vitamin E succinate polyethylene glycol.  
   
   
       38 . The formulation of  claim 33  further comprising a block copolymer of ethylene oxide and propylene oxide.  
   
   
       39 . The formulation of  claim 33  further comprising polyethylene glycol.  
   
   
       40 . The formulation of  claim 39 , wherein the polyethylene glycol is present in the emulsion in an amount from about 1 to about 10 percent weight based on the total weight of the emulsion  
   
   
       41 . The formulation of  claim 39 , wherein the polyethylene glycol is selected from the group consisting of polyethylene glycol-200, polyethylene glycol-300, and polyethylene glycol-400.  
   
   
       42 . The formulation of  claim 33 , wherein the compound is present in the emulsion in an amount from about 0.005 to about 3.0 weight percent based on the total weight of the emulsion.  
   
   
       43 . The formulation of  claim 33  further comprising a lower alkyl alcohol.  
   
   
       44 . The formulation of  claim 43 , wherein the lower alkyl alcohol is present in the emulsion in an amount from about 2 to about 15 percent weight based on the total weight of the emulsion  
   
   
       45 . The formulation of  claim 43 , wherein the lower alkyl alcohol is ethanol.  
   
   
       46 . The formulation of  claim 33 , wherein the aqueous phase comprises saline.  
   
   
       47 . The formulation of  claim 33 , wherein the aqueous phase comprises buffered saline.  
   
   
       48 . The formulation of  claim 33 , wherein the aqueous phase comprises citrate buffered saline or succinate buffered saline.