United States Patent:  6,045,826

Assignee:  National Research Council of Canada (Ottawa, CA)

Filed:  April 2, 1999

Water-soluble compositions comprising a lipophilic compound and a solubilizing agent of the general formula: {X--OOC--[(CH₂)_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 preferred embodiments, the sterol is cholesterol or sitosterol, the tocopherol is a-(+)-tocopherol, the polyalkylene glycol is a polyethylene glycol or its methyl monoether having an average molecular weight between 600 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.

SUMMARY OF THE INVENTION

According to one aspect, the present invention provides a water-soluble composition comprising a lipophilic compound and a solubilizing agent of the general formula:

{X--OOC--[(CH₂)_n --COO]_m }--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.

The lipophilic compound is preferably selected from the group consisting of 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 preferred embodiments, the sterol is cholesterol or sitosterol, the tocopherol is a-(+)-tocopherol, the polyalkylene glycol is a polyethylene glycol or its methyl monoether having an average molecular weight between 600 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.

According to another aspect, the invention provides a method of preparation and purification of a water-soluble composition comprising a solubilizing agent of the general formula (I), in the presence or in the absence of an auxiliary organic solvent. The solubilization is achieved by dissolving a water-insoluble lipophilic compound and a solubilizing agent in a water-miscible organic solvent, diluting the solution with water, and removing the organic solvent and optionally a part of water under reduced pressure. Alternatively, a lipophilic compound and solubilizing agent can be admixed directly in a predetermined molar ratio and heated to a temperature higher than the their respective melting points, to form a water-soluble composition in the form of a clear melt, which can be then diluted with an aqueous solution to a desired concentration. The water-soluble composition may be additionally purified by dissolving it in a small amount of water, heating the solution until the composition separates as a clear liquid phase, and removing the separated composition from the solution while keeping the temperature of the solution substantially unchanged.

According to still another aspect, the invention provides pharmaceutical or cosmetic formulations comprising a water-soluble composition of a lipophilic compound and a solubilizing agent of formula (I).

According to yet another aspect, the invention provides novel solubilizing agents of formula (I) and methods of their preparation and purification.

Claim 1 of 45 Claims

1. A water-soluble composition comprising a bioactive lipophilic compound and a solubilizing agent of the formula

{X--OOC--[(CH₂)_n --COO]_m }_p --Y

wherein: x is a residue of a hydrophobic moiety, selected from the group consisting of sterols, tocopherols, and derivatives thereof,

y is a residue of a hydrophilic moiety, selected from the group consisting of polyethers, polyalcohols, and derivatives thereof,

p is 1 or 2,

m is 0 or 1, and

n is an integer in the range 0.ltoreq.n.ltoreq.18,

provided that:

when p and m are equal to 1 and the hydrophobic moiety is cholesterol, n is greater than 4 and not equal to 8, and

when p and m are equal to 1, and the hydrophobic moiety is (+)-.alpha.-tocopherol, n is not equal to 2.

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