Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2000-05-12
2002-08-27
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C554S213000
Reexamination Certificate
active
06441206
ABSTRACT:
The present invention concerns dietary fat compositions in accordance with patent claims 1 and 2, and food products in accordance with patent claim 6.
The invention also concerns plant stanol derivatives in accordance with patent claim 15, plant sterol and/or plant stanol dicarboxylic acid derivatives in accordance with patent claim 21, amino acid derivatives in accordance with patent claim 22, citric acid derivatives in accordance with patent claim 23, tartaric acid derivatives in accordance with patent claim 24, and plant sterol and/or plant stanol 3 (R)hydroxybutyric acid esters and their derivatives or salts in accordance with patent claim 25.
The method here described also concerns a method to make phytostanol esters in accordance with patent claim 26.
Plant sterols or phytosterols refer to the sterols appearing in the plant kingdom which closely resemble cholesterol in terms of structure. They are, like cholesterol in mammals, a certain structural component of external and internal membranes and thus essential constituents for the living functions of cells. Isolated plant sterols often appear in poorly soluble, crystalline form. The phytosterols appearing in nature are intrinsically fat solutions, however. Chemically, natural sterols are C
26
. . . C
30
alcohols, which have an aliphatic side chain in the C-17 position.
Cholesterol (5-cholestene-3-&bgr;-ol) and its hydrogenated form cholestanol ((3&bgr;, 5&agr;) cholestane-3-ol) are found mainly in humans and animals. The sterols found in the animals, plants and mushrooms of marine organisms and sea-weeds form a wide variety of oxidation, double bond, methyl group substitution and C-17 side-group structures. The a configuration of the C-5 position when a hydrogen atom is linked to it is common to the natural sterols. A small number of plant stanols are also found in plants, the isolation of which is not economically profitable. Using a catalyst, phytosterols isolated in commercial applications can be hydrogenated into corresponding stanols.
Many phytosterols (independent of origin) are closely reminiscent of cholesterol in structure. The most well-known and the most studied are e.g. &bgr;-sitosterol (24&bgr;-ethyl-&Dgr;
5
-cholestene (S24(&bgr;)-ethyl-&Dgr;
5
-cholestene-3&bgr;-ol). The sterol that is characteristic of yeast and mushrooms is ergosterol (&bgr;24-methyl-22,23-dehydro-&Dgr;
5
, &Dgr;
7
-cholestadien-3&bgr;-ol=5,7,22-ergostatrien-3&bgr;-ol; provitamin D). The anticholesteric nature of the two first-mentioned phytosterols is generally known. It is possible that other sterols suited for this purpose can be found in nature, in addition to the &bgr;-sitosterol.
Plant sterols form part of our natural nourishment. The sources of plant sterols in our diet include plant oils and the margarines made from them, while phytosterols can also be found in grain products, soy beans and rice. The regular daily diet includes 0.2-0.3 g of plant sterols.
A certain physiologically important group of compounds is formed by relatives of the sterols, the cholic acids whose role in the food digestion organs is to act as a “biological soap”, as an emulsifying agent of fat and as an absorption aid. Human bile contains several cholic acids conjugated with glycine and taurine (2-aminoethanesulphonic acid); glycine conjugates are those which mostly appear.
The effect preventing the cholesterol absorption of the &bgr;-sitosterol is assumed to be based on its ability to displace the cholesterol molecule in cholic acid/fat micelle. (Ikeda et al. 1989, J. Nutr. Sci. Vitaminol. 35:361-369). Many pieces of research into plant sterols have also shown that crystalline phytosterols do not dissolve very effectively in the micelle phase and therefore are not able to effectively prevent the absorption of cholesterol from the digestive tract. When water is present, solubility of phytosterols in plant oils is restricted to 2% at room temperature and to 3% at body temperature.
According to the observations of Heineman et al. 1991 (Eur. J. Clinic. Pharmacol. 40 Suppl. 1, p. 50-63), plant sterols inhibit cholesterol absorption only in fat-soluble form. A saturated form of &bgr;-sitosterol, &bgr;-sitostanol, inhibited cholesterol absorption in an infusion test substantially more effectively than the corresponding sterol (83% vs 50%). In general, the plant sterols are absorbed into the blood circulation poorly and the stanols not at all. Normally, the concentration of plant sterols in serum is {fraction (1/300)}
th
part of the serum cholesterol level. In addition, according to the observations of Miettinen et al. (U.S. Pat. No. 5,502,045), an increase in sitostanol concentration in nutrition also lowers the measured &bgr;-sitosterol and campesterol concentration of the blood serum.
According to the observations of Mattson et al. (1977, J. Nutr. 107:1139-1146), it is probable that the molecules that really prevent cholesterol absorption are free phytosterol molecules which are hydrolytically released from their esters. This argument is supported by the fact that the cholesterol absorption lowering effect of the phytosterols does not depend on the length of the carbon chain of the fatty acid. Molar quantities of the fatty acid esters such as acetate, decanoate and oleate are equally as effective. In addition, the dicarboxylic acid esters such as phytosterol hemisuccinate lower the cholesterol content of blood as effectively as the phytosterol monocarboxyl acid esters.
The previously known methods to take advantage of the hydrophilic derivatives of &bgr;-sitosterol in food are based on a particular compound's glycosides obtainable from nature, e.g. the &bgr;-sitosteryl-&bgr;-D-glucoside. The carrier in the aqueous solution is, for example, lecithin, while the solvent may be isopropanol and the additive isopropylmyristate. In addition, the sterols' glycoside derivatives are bonded from the alcohol solution and/or emulsion to the starch (DE publication 2113215).
GB patent publication 938 937 describes a synthetic chemical, water-soluble phytosterol hemisuccinate-polyethyleneglycol condensate which has proved, in animal tests, to be effective in lowering blood cholesterol concentrations. The publication does not, however, state an opinion on the compound's hydrolytic decomposition in the system, or whether this kind of derivative is absorbed into the blood circulation or not. The compound is planned for use as a component of various juices, soups and soft drinks. It is clear, however, that the widespread use of the compound in food will be limited by the ethyleneglycol-based polyether component it contains and which is foreign to the human body.
Herting and Harris (1960, Fed. Proc. 19:18) have reported on a water-soluble soy sterol-2-carbamate glutaric acid K
+
—salt which has been proved to lower blood cholesterol concentrations. Carbamates can be made by e.g. a reaction between chloroformates and primary amines. The carbamine acids are unstable and break up, releasing amine and carbon dioxide. The salts of carbamine acids are much more stable, however. As the chemical environment of food varies greatly, one can justifiably assume that there will be significant restrictions to the use of the compound. The publication does not indicate whether the presented compound is planned at all for use in foods.
A rise in the blood cholesterol levels is among the more important risk factors, along with smoking and higher blood pressure, in the spread of cardiac and vascular diseases. U.S. Pat. No. 5,502,045 describes the production of &bgr;-sitostanol fatty acid esters and their addition to food, especially as a part of edible fats in margarine, for example. The research carried out by Miettinen et al. 1995 (New Engl. J. Med. 333: 1308-1312) observed a decrease in the total serum cholesterol when the daily supply of plant sterol of the test individuals had stabilised at the 2-3 g level. The test used a saturated form of plant stanol, sitostanol, whose fat solubility had been increased by the esterification process. The tendency of the plant st
Anttila Erkki
Heikkilä Elina
Lindeman Anneli
Mikkonen Hannu
Birch & Stewart Kolasch & Birch, LLP
Carr Deborah D.
Raisio Benecol Ltd.
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