Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-01-11
2002-05-28
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
Reexamination Certificate
active
06395778
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to a process for making an enriched mixture of esters of polyunsaturated fatty acids from a natural source containing a high concentration of glycerides (particularly triglycerides) which comprise one or more polyunsaturated fatty acid residues. In a particularly preferred embodiment, this invention is directed to making an enriched mixture of esters of polyunsaturated fatty acids (particularly esters of docosahexaenoic acid) from an oil obtained from the marine algae identified as Schizochytrium sp.
BACKGROUND OF THE INVENTION
Many polyunsaturated fatty acids are known to have therapeutic and nutritional benefits. One such fatty acid is docosahexaenoic acid (“DHA”). DHA is a 22-carbon, naturally occurring, unbranched fatty acid comprising 6 carbon-carbon double bonds (with the biologically active form containing all cis carbon-carbon double bonds). DHA and many of its derivatives (e.g., esters comprising a DHA residue, particularly the ethyl ester of DHA and triglycerides containing one or more DHA residues) have been used, for example, to treat cardiovascular and inflammatory diseases. They also have been added to infant milk to promote the development of brain and retina functions. Use of DHA esters (as opposed to the free DHA fatty acid) is often particularly advantageous because such esters (especially the ethyl ester and triglycerides) tend to have a palatable taste and tend to be easily absorbed by animal digestive systems.
Sources of DHA and derivatives thereof include marine animal oils, fish oils (e.g., menhaden oil, salmon oil, mackerel oil, cod oil, herring oil, sardine oil, capelin oil, and tuna oil), marine algae (e.g., Schizochytrium sp.), and human milk. Such sources, however, normally contain a substantial amount of saturated fatty acid residues (often as residues of triglyceride molecules) which dilute the concentration of DHA residues in the oil. It is therefore advantageous to reduce the concentration of undesirable saturated fatty acid residues in the oil while increasing the concentration of DHA or a derivative(s) thereof.
Numerous methods have been used alone or in combination to isolate (or at least concentrate) and recover specific fatty acids and their derivatives from various naturally occurring sources. These processes include fractional crystallization at low temperatures, molecular distillation, urea adduct crystallization, extraction with metal salt solutions, super critical fluid fractionation on countercurrent columns, and high performance liquid chromatography.
In W. W. Christie,
Lipid Analysis
, pp. 147-49 (Pergamon Press, 1976), a method is disclosed generally for using urea to separate methyl esters of saturated fatty acids from a mixture which also contains methyl esters of polyunsaturated fatty acids. According to Christie, when urea is permitted to crystallize in the presence of various long-chain aliphatic compounds, it forms hexagonal crystals which incorporate the aliphatic compounds (a urea crystal which incorporates an aliphatic compound is sometimes referred to as a “urea complex”), thereby allowing the aliphatic compounds to be easily separated from the solution via filtration. Christie states generally that methyl esters of saturated fatty acids form urea complexes more readily than methyl esters of unsaturated fatty acids having the same length, and that methyl esters of unsaturated fatty acids having trans double bonds form urea complexes more readily than methyl esters of analogous fatty acids having cis double bonds. Christie also reports using urea crystallization to concentrate methyl esters of polyunsaturated fatty acids from a mixture containing methyl esters of polyunsaturated fatty acids and methyl esters of saturated fatty acids.
Another reference directed to separating methyl esters of fatty acids using urea crystallization is T. Nakahara, T. Yokochi, T. Higashihara, S. Tanaka, T. Yaguchi, & D. Honda, “Production of Docosahexaenoic and Docosapentaenoic Acids by Schizochytrium sp. Isolated from Yap Islands,”
JAOCS
, vol. 73, no. 11, pp. 1421-26 (1996). Nakahara et al. report making a mixture of methyl esters of fatty acids by washing and drying Schizochytrium sp. cells, and then methyl-esterifying the cells directly with methanol in the presence of 10% HCl. Nakahara et al. report that 34.9% of the resulting methyl esters contained DHA residues, and 8.7% contained DPA residues. To concentrate these polyunsaturated fatty acid methyl esters, Nakahara et al. report adding methanol and urea to the mixture, heating the mixture to 60° C. to dissolve the urea, and then cooling the mixture to 10° C. to crystallize the urea. Nakahara et al. report that they were able to recover 73.3% of the DHA methyl esters and 17.7% of the DPA methyl esters using this method.
The growing use of polyunsaturated fatty acids (particularly DHA) and esters thereof in medical and nutritional applications has created a further need for a cost-effective and reliable process that may be used to prepare a composition comprising an enriched concentration of polyunsaturated fatty acid compounds (and a minimal concentration of saturated fatty acid compounds) from sources (particularly naturally occurring sources) of glycerides having at least one polyunsaturated fatty acid residue.
SUMMARY OF THE INVENTION
This invention provides for a novel and useful process for making an enriched composition comprising polyunsaturated fatty acid compounds (particularly compounds containing a DHA residue). This process is particularly advantageous because it provides a method for enrichment of polyunsaturated fatty acid esters (e.g., methyl and ethyl esters) despite the fact that: (1) the compounds involved here are highly complex molecules (e.g., they contain carbon chains having from 3 to 21 carbon atoms and up to 6 double bonds), and (2) there often is only a subtle difference in structure between polyunsaturated fatty acid compounds and many saturated fatty acid compounds.
Briefly, therefore, this invention is directed to a process for making a mixture comprising a polyunsaturated fatty acid ester having the Formula (V):
In one embodiment, the process comprises transesterifying an oil from Schizochytrium sp. with an alcohol in the presence of a base to form a saturated fatty acid ester and the polyunsaturated fatty acid ester (these fatty acid esters are formed from the alcohol and fatty acid residues of at least one glyceride in the oil). Urea is subsequently dissolved in a medium comprising the fatty acid esters to form a medium comprising the fatty acid esters and dissolved urea. This medium is then cooled or concentrated to form (a) a precipitate comprising urea crystals and at least a portion of the saturated fatty acid ester, which is trapped within the urea crystals; and (b) a liquid fraction comprising at least most of the polyunsaturated fatty acid ester. Afterward, the precipitate is separated from the liquid fraction. Here, the alcohol is R
3
—OH, R
3
is a hydrocarbyl or a substituted hydrocarbyl, and R
4
is a straight chain hydrocarbyl comprising 21 carbon atoms and at least 2 carbon-carbon double bonds.
In another embodiment, the process comprises transesterifying an oil from Schizochytrium sp. with an alcohol in the presence of an acid to form a saturated fatty acid ester and the polyunsaturated fatty acid ester (these fatty acid esters are formed from the alcohol and fatty acid residues of at least one glyceride in the oil). Urea is subsequently dissolved in a medium comprising the fatty acid esters to form a medium comprising the fatty acid esters and dissolved urea. This medium, in turn, is cooled to a temperature of no less than about 15° C. to form (a) a precipitate comprising urea crystals and at least a portion of the saturated fatty acid ester, which is trapped within the urea crystals; and (b) a liquid fraction comprising at least most of the polyunsaturated fatty acid ester. Afterward, the precipitate is separated from the liquid fraction. Here, the alcohol is R
3
—OH, R
3
is a hyd
Henley III Raymond
OmegaTech Inc.
Sheridan & Ross P.C.
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