Stabilized formulations of fatty acids

Abstract

Disclosed herein are stabilized powder and aqueous formulations comprising a substantially water insoluble lipophilic bioactive compound and a micelle-forming surfactant. In one embodiment, the formulation further comprises a water soluble reducing agent, and/or a water insoluble reducing agent, and/or a metal chelator, and/or a metal bisulfite reducing agent, or combinations thereof, wherein the formulation remains substantially clear and stable when stored at or below room temperature for a period of at least 6 months or at least 12 months; and methods for preparing these formulations.

What is claimed is: 
     
         1 .- 28 . (canceled) 
     
     
         29 . A stable, water soluble formulation comprising:
 a) an omega-fatty acid;   b) one or more solubilizing agents selected from the group consisting of Poloxamer 188, PEG-8-glyceryl capylate/caprate (Labrasol), PEG-32-glyceryl laurate (Gelucire 44/14), PEG-32-glyceryl palmitostearate (Gelucire 50/13); Polysorbate 85, Polyglyceryl-6-dioleate (Caprol MPGO), Sorbitan monooleate (Span 80), Capmul MCM, Maisine 35-1, Glyceryl monooleate, Glyceryl monolinoleate, PEG-6-glyceryl oleate (Labrafil M 1944 CS), PEG-6-glyceryl linoleate (Labrafil M 2125 CS), Propylene glycol monocaprylate (Capmul PG-8 or Capryol 90), Propylene glycol monolaurate (Capmul PG-12 or Lauroglycol 90), Polyglyceryl-3 dioleate (Plurol Oleique CC497), Polyglyceryl-3 diisostearate (Plurol Diisostearique), Lecithin, and a solubilizing agent of the Formula (I):
   Y 1 -[L 1 ] a Z  (I)
 
   wherein:   a is 0 and 1;   L 1  is a linker moiety that covalently links the hydrophobic moiety Z and the hydrophilic moiety Y 1 ;   Y 1  is a linear or branched hydrophilic moiety comprising at least one polymeric moiety independently selected from poly(alkylene oxides) and polyalcohols; and   Z is a hydrophobic moiety;   or mixtures thereof; and   c) a metal chelator and one or more than one additive selected from the group consisting of a metal chelator, a water soluble reducing agent, a water soluble antioxidant, a water-insoluble reducing agent, a bisulfite salt, a meta-bisulfite salt or mixtures thereof;   wherein the formulation is prepared by initially heating a mixture of the omega-fatty acid, the solubilizing agent, a metal chelator and one or more additives above 95° C., followed by cooling; and   wherein the formulation remains substantially clear and stable for a period of at least 6 months when stored at or below room temperature.   
     
     
         30 . The water soluble formulation of  claim 29 , wherein the solubilizing agent is TPGS (polyoxyethanyl-a-tocopheryl succinate) or TPGS-1000 (D-alpha-tocopheryl polyethylene glycol 1000 succinate), wherein the tocopheryl is the natural tocopherol isomer or the unnatural tocopherol isomer. 
     
     
         31 . The water soluble formulation of  claim 29 , wherein the omega-fatty acid is selected from the group consisting of omega-3 fatty acid, omega-6 fatty acid, omega-9 fatty acid, omega-12 fatty acid, the glyceride esters of the omega-fatty acids, and the non-glyceride esters of the omega-fatty acids, and mixtures thereof. 
     
     
         32 . The water soluble formulation of  claim 29 , wherein the omega-fatty acid is selected from the group consisting of α-linolenic acid (ALA), stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, docosahexaenoic acid (DHA), linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma-linolenic acid, arachidonic acid, docosadienoic acid, adrenic acid, docosapentaenoic acid, oleic acid, eicosenoic acid, mead acid, erucic acid and nervonic acid, and combinations thereof. 
     
     
         33 . The water soluble formulation of  claim 29 , wherein the water-soluble or water-insoluble reducing agent and the water soluble antioxidant is selected from the group consisting of L-ascorbic acid-6-palmitate, vitamin C and its salts alpha, beta, gamma, and delta tocopherol or mixtures of tocopherol, and alpha, beta, gamma, and delta-tocotrienols or mixtures thereof. 
     
     
         34 . The water soluble formulation of  claim 29 , wherein the metal chelator is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), disodium EDTA and calcium disodium EDTA and mixtures thereof. 
     
     
         35 . The water soluble formulation of  claim 29 , wherein the bisulfite is sodium bisulfite, potassium bisulfite, sodium metabisulfite or potassium metabisulfite. 
     
     
         36 . The water soluble formulation of  claim 29 , wherein the formulation, when dissolved in water, provides a solution with a clarity range of about 1,000 to 20 NTU. 
     
     
         37 . The water soluble formulation of  claim 29 , wherein the formulation, when dissolved in water, provides a solution that remains clear and stable toward degradation when stored at or below room temperature for a period of at least 6 months. 
     
     
         38 . The water soluble formulation of  claim 29 , wherein the ratio of the solubilizing agent to omega-3 fatty acids is less than or equal to 2:1 to 0.5 to 1. 
     
     
         39 . The stable water soluble formulation of  claim 29 , further comprising HI-CAP 100 (modified food starch derived from waxy maize), Emcap Starch (emulsifying starches), TICAMULSION FC (TIC GUMS, modified gum arabic) and Spray gum F (gum acacia with Maltrin-100 (maltodextrin)). 
     
     
         40 . A stable, water soluble formulation comprising:
 a) an omega-fatty acid;   b) a solubilizing agent selected from the group consisting of a solubilizing agent of the Formula (I):
   Y 1 -[L 1 ] a -Z  (I)
 
   wherein:   a is 0 and 1;   L 1  is a linker moiety that covalently links the hydrophobic moiety Z and the hydrophilic moiety Y 1 ;   Y 1  is a linear or branched hydrophilic moiety comprising at least one polymeric moiety independently selected from poly(alkylene oxides) and polyalcohols; and   Z is a hydrophobic moiety; and   c) a metal chelator and one or more than one additive selected from the group consisting of a metal chelator, a water soluble reducing agent, a water soluble antioxidant, a water-insoluble reducing agent, a bisulfite salt, a meta-bisulfite salt or mixtures thereof;   wherein the formulation is prepared by initially heating a mixture of the omega-fatty acid, the solubilizing agent, a metal chelator and one or more additives above 95° C., followed by cooling; and   wherein the formulation remains substantially clear and stable for a period of at least 6 months when stored at or below room temperature.   
     
     
         41 . The water soluble formulation of  claim 40 , wherein the solubilizing agent is TPGS (polyoxyethanyl-a-tocopheryl succinate) or TPGS-1000 (D-alpha-tocopheryl polyethylene glycol 1000 succinate), wherein the tocopheryl is the natural tocopherol isomer or the unnatural tocopherol isomer. 
     
     
         42 . The water soluble formulation of  claim 40 , wherein the omega-fatty acid is selected from the group consisting of omega-3 fatty acid, omega-6 fatty acid, omega-9 fatty acid, omega-12 fatty acid, the glyceride esters of the omega-fatty acids, and the non-glyceride esters of the omega-fatty acids, and mixtures thereof.