Water-soluble compositions of bioactive lipophilic compounds

Abstract

Water-soluble compositions comprising a lipophilic compound and a solubilizing agent of the general formula: {X—OOC—[(CH 2 ) n —COO] m } p —Y  (I) wherein: X is a residue of a hydrophobic moiety, Y is a residue of a hydrophilic moiety, p is 1 or 2, m is 0 or 1, and n is an integer greater than or equal to 0 are disclosed. The lipophilic compound is preferably selected from the group consisting of water-insoluble ubiquinones, ubiquinols, vitamins, provitamins, polyene macrolide antibiotics, and mixtures thereof. The hydrophobic moiety is preferably a sterol or a tocopherol and the hydrophilic moiety is preferably a polyalkylene glycol. In some embodiments, the sterol is cholesterol or sitosterol, the tocopherol is α-(+)-tocopherol, the polyalkylene glycol is a polyethylene glycol or its methyl monoether having an average molecular weight between 400 and 1000, p is equal to 1 or 2, m is equal to 0 or 1 and n is an integer between 2 and 18.

1 . A method for the treatment of a fungal infection in humans or warm-blooded animals in need of such treatment, comprising administering to such human or warm-blooded animal, a therapeutically effective amount of a water-soluble composition, comprising a solubilizing agent selected from the group consisting of polyoxyethanyl-sitosterol sebacate, polyoxyethanyl-cholesteryl sebacate and polyoxyethanyl-α-tocopheryl sebacate, and a macrolide polyene antibiotic, formulated in a weight ratio of solubilizing agent to antibiotic of 2:1 to 4:1, in conjunction with a pharmaceutically effective carrier or excipient.  
     
     
         2 . A method according to  claim 1 , wherein the antibiotic is selected from the group consisting of amphotericin B and nystatin.  
     
     
         3 . A method according to  claim 1 , wherein the antibiotic is amphotericin B, and wherein the weight ratio of solubilizing agent to antibiotic is 3:1 to 4:1 w/w.  
     
     
         4 . A method according to  claim 1 , wherein the antibiotic is nystatin, and wherein the weight ratio of solubilizing agent to antibiotic is 2:1 to 4:1 w/w.  
     
     
         5 . A water-soluble composition, comprising a solubilizing agent selected from the group consisting of polyoxyethanyl-sitosterol sebacate, polyoxyethanyl-cholesteryl sebacate and polyoxyethanyl-α-tocopheryl sebacate, and a macrolide polyene antibiotic, formulated in a weight ratio of solubilizing agent to antibiotic of 2:1 to 4:1.  
     
     
         6 . A composition according to  claim 5 , wherein the antibiotic is selected from the group consisting of amphotericin B and nystatin.  
     
     
         7 . A composition according to  claim 5 , wherein the antibiotic is amphotericin B, and wherein the weight ratio of solubilizing agent to antibiotic is 3:1 to 4:1 w/w.  
     
     
         8 . A composition according to  claim 5 , wherein the antibiotic is nystatin, and wherein the weight ratio of solubilizing agent to antibiotic is 2:1 to 4:1 w/w.  
     
     
         9 . A composition according to  claim 7 , wherein the solubilizing agent is polyoxyethanyl-sitosterol sebacate.  
     
     
         10 . A composition according to  claim 7 , wherein the solubilizing agent is polyoxyethanyl-cholesteryl sebacate.  
     
     
         11 . A composition according to  claim 7 , wherein the solubilizing agent is polyoxyethanyl-α-tocopheryl sebacate.  
     
     
         12 . A composition according to  claim 8 , wherein the solubilizing agent is polyoxyethanyl-sitosterol sebacate.  
     
     
         13 . A composition according to  claim 8 , wherein the solubilizing agent is polyoxyethanyl-cholesteryl sebacate.  
     
     
         14 . A composition according to  claim 8 , wherein the solubilizing agent is polyoxyethanyl-α-tocopheryl sebacate.  
     
     
         15 . A method for preparing a water soluble composition according to  claim 5 , which method comprises the steps of, 
 (e) dissolving the antibiotic and the solubilizing agent in a water-miscible organic solvent, in a weight ratio of solubilizing agent to antibiotic of 2:1 to 4:1,    (f) removing from the solution the organic solvent to achieve a desired concentration of the water soluble composition,    (g) dissolving the composition in water, and    (h) drying.    
     
     
         16 . A method according to  claim 15 , wherein the antibiotic is amphotericin B, and wherein the weight ratio of solubilizing agent to antibiotic is 3:1 to 4:1 w/w.  
     
     
         17 . A method according to  claim 15 , wherein the antibiotic is nystatin, and wherein the weight ratio of solubilizing agent to antibiotic is 2:1 to 4:1 w/w.  
     
     
         18 . A method according to  claim 15 , wherein the solvent is methanol/acetic acid 3:1 v/v.  
     
     
         19 . A method for delivery of α-tocopherol to humans or warm-blooded animals in need thereof, comprising administering to such human or warm-blooded animal, an effective amount of a water-soluble form of vitamin E.  
     
     
         20 . A method according to  claim 19 , wherein the water-soluble form of vitamin E is polyoxyethanyl-α-tocopheryl sebacate.  
     
     
         21 . A water-soluble composition, comprising a solubilizing agent selected from the group consisting of polyoxyethanyl-sitosterol sebacate, polyoxyethanyl-cholesteryl sebacate and polyoxyethanyl-α-tocopheryl sebacate, and a compound having a high content of polyunsaturated fatty acids.  
     
     
         22 . A composition according to  claim 21 , wherein the compound is an oil, and wherein the solubilizing agent and oil are formulated in a weight ratio of solubilizing agent to oil of 2:1 to 3:1.  
     
     
         23 . A composition according to  claim 22  wherein the oil is selected from the group consists of flaxseed oil and fish oil.  
     
     
         24 . A water-soluble composition comprising a solubilizing agent selected from the group consisting of polyoxyethanyl-sitosterol sebacate, polyoxyethanyl-cholesteryl sebacate and polyoxyethanyl-α-tocopheryl sebacate, and a bioactive lipophilic compound selected from the group consisting of a terpene and a terpenoid.  
     
     
         25 . A composition according to  claim 24 , wherein the solubilizing agent and bioactive compound are formulated in a weight ratio of solubilizing agent to bioactive compound of 3:1 to 4:1.  
     
     
         26 . A composition according to  claim 25 , wherein the bioactive lipophilic compound is selected from the group consisting of squalene, geranoil, farnesol, β-carotene, astaxanthin, canthaxanthin, zeaxanthin, cryptoxanthin, lutein and lycopene.  
     
     
         27 . A composition according to  claim 25 , comprising polyoxyethanyl-α-tocopheryl sebacate and squalene, in a weight ratio of polyoxyethanyl-α-tocopheryl sebacate to squalene of 3:1.  
     
     
         28 . A composition according to  claim 25 , comprising polyoxyethanyl-α-tocopheryl sebacate and astaxanthin, in a weight ratio of polyoxyethanyl-α-tocopheryl sebacate to astaxanthin of 4:1.  
     
     
         29 . A method for preparing a water-soluble composition according to  claim 28 , comprising: 
 a) dissolving solubilizing agent and astaxanthin in a water-miscible organic solvent, in a weight ratio of solubilizing agent to astaxanthin of 4:1 to form a mixture;    b) diluting the mixture with water to form an aqueous solution;    c) concentrating the aqueous solution to remove the organic solvent and excess of water;    
     
     
         30 . A method according to  claim 29 , wherein step c) is effected by evaporation under reduced pressure.  
     
     
         31 . A water-soluble composition, comprising polyoxyethanyl-α-tocopheryl sebacate and α-tocopheryl acetate, formulated in a ratio of 2:1 to 5.5:1 w/w.  
     
     
         32 . A composition according to  claim 31 , comprising PCS-400 and α-tocopheryl acetate, formulated in a ratio of PCS-400 to α-tocopheryl acetate of 2:1 to 4.5:1 w/w.  
     
     
         33 . A composition according to  claim 31 , comprising PCS-600 and α-tocopheryl acetate, formulated in a ratio of PCS-600 to 1-tocopheryl acetate of 5.5:1 w/w.  
     
     
         34 . A water-soluble composition, comprising a solubilizing agent selected from the group consisting of polyoxyethanyl-α-tocopheryl sebacate and polyoxyethanyl tocotrienyl sebacate, and a tocotrienol, formulated in a ratio of solubilizing agent to tocotrienol of about 5.5:1 w/w.  
     
     
         34 . A composition according to  claim 34 , wherein the solubilizing agent is PTS-600.  
     
     
         35 . A composition according to  claim 34 , wherein the solubilizing agent is PtrienS-600.  
     
     
         36 . A water-soluble composition, comprising a solubilizing agent selected from the group consisting of polyoxyethanyl-α-tocopheryl sebacate and polyoxyethanyl tocotrienyl sebacate, and coenzyme Q 10 , formulated in a ratio of solubilizing agent to coenzyme Q 10  of 2.5:1 to 3.5:1 w/w.  
     
     
         37 . A composition according to  claim 36 , wherein the solubilizing agent is PTS-400, and wherein the ratio of PCS-400 to coenzyme Q 10  is 2.5:1 w/w.  
     
     
         38 . A composition according to  claim 36 , wherein the solubilizing agent is PtrienS600, and wherein the ratio of PtrienS-600 to coenzyme Q 10  is 3.5:1 w/w. 
 2.5:1 w/w.    
     
     
         39 . A water-soluble composition comprising a bioactive lipophilic compound and a solubilizing agent of the general formula  
         {X—OOC—[(CH 2 ) n —COO] m } p —Y  wherein: 
 p is 1 or 2,  
 m is 0 or 1, and  
 n is an integer in the range O≦n≦18  
 X is a residue of a hydrophobic moiety is selected from the group consisting of cholesterol, 7-dehydrocholesterol, campesterol, sitosterol, ergosterol, stigmasterol, and α-, β-, γ-, and Δ-tocopherols and derivatives thereof Y is a residue of a hydrophilic is moiety, selected from the group consisting of polyalcohols, polyethers, polyanions, polycations, polyphosphoric acids, polyamines, polysaccharides, polyhydroxy compounds, polylysines, and derivatives thereof provided that:  
 when p and m are equal to 1 and the hydrophobic moiety is (+)-α-tocopherol, n is not equal to 2.  
   
     
     
         40 . A composition according to  claim 43 , wherein the bioactive lipophilic compound is selected from the group consisting of ubiquinones, ubiquinols, vitamins, provitamins, polyene macrolide antibiotics, and mixtures thereof, provided that: 
 when the bioactive lipophilic compound is ubiquinone and the hydrophobic moiety is cholesterol, n is not equal to 8.    
     
     
         41 . A composition according to  claim 39 , where the hydropholic moiety is PEG-400.  
     
     
         42 . A method for making polyoxyethanyl tocotrienyl sebacate, comprising 
 a) dissolving a tocotrienol and triethyl amine in a water-miscible organic solvent,    b) reacting the solution with sebacoyl chloride, and    c) reacting with a polyethylene glycol.    
     
     
         43 . A water-soluble composition comprising a bioactive lipophilic compound and a solubilizing agent of the general formula  
         {X—OOC—[(CH 2 ) n —COO] m } p —Y  wherein: 
 p is 1 or 2,  
 m is 0 or 1, and  
 n is an integer in the range O≦n≦18  
 X is a residue of a hydrophobic moiety is selected from the group consisting of cholesterol, 7-dehydrocholesterol, campesterol, sitosterol, ergosterol, stigmasterol, and α-, β-, γ, and Δ-tocopherols and derivatives thereof Y is a residue of a hydrophilic is moiety, selected from the group consisting of polyalcohols, polyethers, polyanions, polycations, polyphosphoric acids, polyamines, polysaccharides, polyhydroxy compounds, polylysines, and derivatives thereof provided that:  
 when p and m are equal to 1 and the hydrophobic moiety is (+)-α-tocopherol, n is not equal to 2, and when the hydrophobic moiety is campesterol, sitosterol or stigmasterol, n is greater than 6.