INTRAVENOUS FORMULATIONS OF COENZYME Q10 (CoQ10) AND METHODS OF USE THEREOF

Abstract

Disclosed herein are formulations suitable for parenteral administration of certain hydrophobic active agents such as Coenzyme Q10. Methods of preparing the same and methods of treatment of oncological disorders using the same are also provided herein. The formulations comprise an aqueous solution; a hydrophobic active agent dispersed to form a colloidal nano-dispersion of particles; and at least one of a dispersion stabilizing agent and an opsonization reducer wherein the colloidal nano-dispersion of the active agent is dispersed into nano-dispersion particles having a mean size of less than 200-nm. Methods of preparing the parenteral formulations comprise dispersing the hydrophobic active agent by high pressure homogenization by (1) adding hydrophobic active agent to a 65° C. bath of water and mixing to form a hydrophobic active agent/water mixture; (2) adding a dispersion stabilizing agent to the hydrophobic active agent/water mixture and mix at 65° C. to form a hydrophobic active agent/water/stabilizer mixture; (3) adding an opsonization reducer to form a hydrophobic active agent/water/stabilizer/reducer mixture; (4) pre-heating a Microfluidizer to 65° C.; and (5) processing by mixing the hydrophobic active agent/water/stabilizer/reducer mixture in the Microfluidizer at 65° C. such that a hydrophobic active agent colloidal nano-dispersion having a mean particle size less than 200-nm is formed. Provided herein are also methods of treating oncological disorders by administering formulations described herein to a subject such that treatment or prevention of the oncological disorder occurs.

1 . A therapeutic formulation suitable for intravenous administration to a subject comprising:
 an aqueous solution;   a hydrophobic active agent dispersed to form a colloidal nano-dispersion of particles; and   at least one of a dispersion stabilizing agent and an opsonization reducer;   wherein the colloidal nano-dispersion of the active agent is dispersed into nano-dispersion particles having a mean size of less than 200-nm.   
     
     
         2 . The formulation of  claim 1 , wherein the dispersion stabilizing agent is selected the group consisting of pegylated castor oil, Cremphor EL, Cremophor RH 40, Pegylated vitamin E, Vitamin E TPGS, and Dimyristoylphosphatidyl choline (DMPC). 
     
     
         3 . (canceled) 
     
     
         4 . The formulation of  claim 1 , wherein the opsonization reducer is selected from the group consisting of poloxamer and poloxamines. 
     
     
         5 . (canceled) 
     
     
         6 . The formulation of  claim 1 , wherein the hydrophobic active agent is Coenzyme Q10 (CoQ10). 
     
     
         7 . (canceled) 
     
     
         8 . The formulation of  claim 1 , wherein the colloidal nano-dispersion is a suspension or an emulsion . 
     
     
         9 . (canceled) 
     
     
         10 . The formulation of  claim 1 , wherein the active agent of the colloidal nano-dispersion is in a crystalline form or is in super-cooled melt form. 
     
     
         11 . (canceled) 
     
     
         12 . The formulation of  claim 1 , wherein the formulation comprises CoQ 10, DMPC and poloxamer 188, and where the formulation has a weight-per-volume of the CoQ 10, DMPC and poloxamer 188 of 4%, 3% and 1.5%, respectively or has a weight-per-volume of the CoQ 10, DMPC and poloxamer 188 of 8%, 6% and 3%, respectively. 
     
     
         13 . (canceled) 
     
     
         14 . The formulation of  claim 1 , wherein the mean size of the nano-dispersion particles is between about 10-nm and about 200-nm, between about 10-nm and about 100-nm, between about 30-nm and about 80-nm, or between about 35-nm and about 40-nm. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . The formulation of  claim 1 , wherein the mean size of the nano-dispersion particles is less than about 45-nm. 
     
     
         19 . A therapeutic formulation suitable for intravenous administration to a subject comprising:
 an aqueous solution;   a hydrophobic active agent dispersed to form a colloidal nano-dispersion of particles; and   at least one of a dispersion stabilizing agent and an opsonization reducer;   wherein the colloidal nano-dispersion of the active agent is dispersed into liposomes having sizes of less than 200-nm.   
     
     
         20 . The formulation of  claim 19 , wherein the liposomes are unilamellar or wherein the liposomes are bi-layered multilamellar liposomes having an aqueous space between the bi-layers and a lipophilic space within the bi-layers. 
     
     
         21 . (canceled) 
     
     
         22 . The formulation of  claim 20 , wherein the hydrophobic active agent is entrapped within the lipophilic space of the bi-layers. 
     
     
         23 . The formulation of  claim 20 , wherein the multilamellar liposome further includes a hydrophilic agent entrapped in the aqueous space between the bi-layers. 
     
     
         24 - 34 . (canceled) 
     
     
         35 . A therapeutic formulation suitable for intravenous administration to a subject comprising:
 an aqueous solution;   a hydrophobic active agent dispersed to form a colloidal nano-dispersion of particles; and   DMPC;   wherein the colloidal nano-dispersion of the active agent is dispersed into nano-dispersion particles having a mean size of less than 200-nm.   
     
     
         36 - 49 . (canceled) 
     
     
         50 . A method of preparing the therapeutic formulation of  claim 1 , wherein the method comprises dispersing the hydrophobic active agent by high pressure homogenization by:
 adding hydrophobic active agent to a 65° C. bath of water and mixing to form a hydrophobic active agent/water mixture;   adding a dispersion stabilizing agent to the hydrophobic active agent/water mixture and mix at 65° C. to form a hydrophobic active agent/water/stabilizer mixture;   adding an opsonization reducer to form a hydrophobic active agent/water/stabilizer/reducer mixture;   pre-heating a Microfluidizer to 65° C.; and   processing by mixing the hydrophobic active agent/water/stabilizer/reducer mixture in the Microfluidizer at 65° C. such that a hydrophobic active agent colloidal nano-dispersion having a mean particle size less than 200-nm is formed.   
     
     
         51 - 64 . (canceled) 
     
     
         65 . The method of  claim 50 , further comprising the step of lyophilizing the colloidal nano-dispersion to crystallize the CoQ10 colloidal nano-dispersion particles. 
     
     
         66 - 68 . (canceled) 
     
     
         69 . A method of treating or preventing an oncological disorder in a subject, comprising:
 intravenously administering a therapeutic formulation as described in  claim 1  to the subject such that treatment or prevention of the oncological disorder occurs.   
     
     
         70 . (canceled) 
     
     
         71 . The method of  claim 69 , wherein the oncological disorder is an aggressive oncological disorder , a metastatic oncological disorder, or a non-aggressive oncological disorder. 
     
     
         72 - 75 . (canceled) 
     
     
         76 . A method for inhibiting tumor cell growth in a subject, comprising:
 intravenously administering a therapeutic formulation as described in  claim 1  to the subject, such that tumor cell growth is inhibited.   
     
     
         77 - 78 . (canceled)