Classifications

• • C—CHEMISTRY; METALLURGY
  • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
  • C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
  • C11C3/00—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom
  • C11C3/04—Fats, oils, or fatty acids by chemical modification of fats, oils, or fatty acids obtained therefrom by esterification of fats or fatty oils
  • C11C3/10—Ester interchange
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
  • A23L33/12—Fatty acids or derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids

Definitions

• This invention refers to wax esters enriched in l ⁇ )-3 unsaturated fatty acids, to the procedure to obtain them, to their peculiar biochemical behaviour which enables them to be used as drug and food additives, and to formulations which contain them for both pharmaceutical and dietetic-alimentary purposes.
• wax usually means a wide class of lipids, which are characterized more according to their physical feature than according to their chemical structure. Generally, a material is classified as a wax when it looks like honeycomb material.
• waxes are particular carboxylic esters (wax esters). Namely, they are esters of long chain aliphatic acids (fatty acids) with long chain aliphatic alcohols. Both acids and alcohols can be either saturated or unsaturated.
• Wax esters are esters of long chain aliphatic acids (fatty acids) with long chain aliphatic alcohols. Both acids and alcohols can be either saturated or unsaturated.
• the starting material to be used in the preparation of products herein described is a mixture of esters enriched in ⁇ J-3 unsaturated fatty acids.
• This mixture is usually obtained by current industrial procedures from natural sources such as fish oil, containing a relatively high amount of polyunsaturated «A)-3 fatty acids, such as EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid).
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• fish oil triglycerides are split by treatment with low boiling alcohols in the presence of a catalyst. After removing glycerol, esters thus obtained are further enriched in tC-3 unsaturated fatty acids by some techniques, such as distillation and urea fractionation.
• Methyl and ethyl esters enriched in EPA and DHA, along with natural or synthetical triglycerides, and free fatty acids, also enriched in EPA and DHA, have been the forms so far available for material enriched in ii -3 polyunsaturated acid, to be used as both pharmaceuticals and food integrators.
• Oxidation by-products even at a low content, render the main material stenching, irritant and disgusting, so that this cannot be easily handled and utilized.
• wax esters enriched in -3 polyunsaturated fatty acids are much more readily absorbed and metabolized than wax esters naturally encountered, characterized by a low contents in ⁇ -3 fatty acids.
• Products herein described are solid waxy materials, so that oxidation is limited to the only surface layer.
• This invention concerns therefore also the use of wax esters herein described in the preparation of drugs which can conveniently used in the aforementioned pathologies, as well as in the preparation of dietetic and alimentary formulations.
• R" methyl, ethyl, or a low boiling alcohol residue
• R' residue of an alcohol contained in natural wax esters.
• R EPA and DHA residues are preferred.
• R methyl and ethyl are preferred.
• residues of saturated alcohols are preferred, with a number of carbon atoms ranging from 12 and 40.
• Another preferred alcohol is oleyl alcohol.
• the reaction is performed starting from nearly stoichiometric amount of the reactant ⁇ , and it is catalyzed by bases, according to procedures usually adopted for transesterifications.
• the product is obtained with the highest yield when low boiling alcohol R"OH is removed as a reaction product by distillation under reduced pressure.
• reaction mixture is treated with hot water containing small amounts of an acid, preferably citric acid, in order to quench and remove the catalyst, along with small traces of soap formed during the reaction. Further addition of hot water separates the wax ester as a melted liquid phase, which is allowed to separate and to solidify.
• an acid preferably citric acid
• Wax esters described by this invention can be recrystallize in small white needle-shaped crystals.
• the content of t ⁇ -3 unsaturated fatty acids in the final wax ester is the same as in the starting mixture of esters, as shown by the analysis of the acidic moiety obtained by hydrolysis of wax esters.
• Transesterification reaction is the best suited procedure in order to obtain wax esters highly enriched in polyunsaturated fatty acids, but also other reactions can give the same products, starting both from esters enriched in polyunsaturated acids and from free fatty acids obtained by hydrolizing these esters. Some of these reactions can be mentioned, such as direct esterification of free fatty acids with alcohols, treatment of alcohols with reactive derivatives of acids, such as anhydrides, chlorides, isopropenyl esters, and so on, interesterification of either methyl or ethyl esters of fatty acids with either acetic or propionic esters of long chain alcohols.
• Wax esters herein described are more stable toward air oxidation than the starting esters, as shown by the parallel determination of peroxide number, made at increasing times, of a sample of ethyl ester enriched in EPA and DHA and of the corresponding wax ester, v/hen both samples were allowed to stand in an open vessel. After one week of exposure to air, peroxide number was increased from five to seven times more in the case of ethyl esters than in the case of wax esters; values were corrected on the basis of the actual weight of polyunsaturated fatty acid in the molecular formula of ethyl esters and of wax esters.
• wax esters described by this invention As to absorption and biotransformation of wax esters described by this invention, it has been found that these compounds are well absorbed and that they are actually metabolized, contrary to what described in the case of natural wax esters, which are not enriched in polyunsaturated fatty acids.
• Digestibility of the products described by this invention was tested in in vi tro experiments. After digestion with pancreas lipase, the hydrolysis of wax esters was monitored on the basis of formation of both the alcoholic and the acidic moieties.
• jojoba oil was used, which is a natural oil containing an acid moiety where monounsaturated fatty acid are in the majority, and an alcoholic moiety containing prevailingly saturated chains. Thin layer chromatographic analysis clearly showed that wax esters enriched in C -3 unsaturated fatty acids were nearly completely hydrolyzed into their constituents already after 5 hours, whereas jojoba oil was nearly unreacted.
• Table 2 shows that plasma triglycerides are raised, in comparison with untreated animals, at both times after the treatment.
• Table 3 clearly shows that the plasma of treated animals was noticeably enriched in EPA and DHA 6 hours after the treatment, in comparison with untreated animals. No effect is visible after 16 hours from the treatment, probably because the rapid metabolism of lipids.
• wax esters can be sprayed in melted form and injected into cold water, where droplets of the product solidify in the form of small spheres with a prefixed radium. The procedure can be performed with water treated with salt and natural fragrances, in order to obtain synthetic caviar.
• wax esters can be absorbed onto a solid matrix (flour, bran, granules, and so on) in order to obtain foods enriched in Cj -3 unsaturated fatty acids .
• products described by this invention can be formulated using conventional excipients and techniques, such as described in
• this invention concerns also dietetic and pharmaceutical formulations containing wax esters enriched in CAJ-3 unsaturated fatty acids which can be obtained according to the procedures herein described.
• the stirred mixture darkened, as ethanol started boiling at ca. 80 °C. A temperature of 120 °C was maintained for half an hour. During this time, ethanol evolution almost ceased.
• the mixture was then cooled at 40°C, then the vacuum was removed by filling the flask with nitrogen.
• the liquid mixture was poured into a 1% aqueous solution of citric acid (200 ml) stirred under nitrogen at room temperature. Stirring was continued for five minutes at room temperature, then the mixture, still stirred, was cooled down to 5°C, whereby crystallization occurred.
• the solid material was filtered under vacuum, washed with water on the filter, and recrystallized from 400 ml of acetone. After cooling the mixture at -10 °C for one hour, the whitish crystalline product was filtered under vacuum and dried under reduced pressure overnight at room temperature. Yield: 42.5 gr (89%). The product gives a clean spot in
• Example 4 25 gr of ethyl ester (the same as in Example 1) were reacted with 16.2 gr of 1-tetradecanol (molecular weight 214). Reaction conditions were the same as for example 1. After pouring the mixture into acidic water, the oily phase was washed twice at 45"C with 100 ml of water. After separation, the oily phase was then dried under reduced pressure. Yield: 35 gr
• Example 5 33 gr of the same ethyl ester of example 1
• Example 1 with 24 gr of 1 hexadecanol (cetyl alcohol).
• Example 7 The same preparation described in Example 2 was repeated. Crystallization from acetone was omitted, but the raw product obtained after separation of the melted wax from hot water was washed again by the same procedure. A product was obtained, having the same melting point and the same purity as the one described in Example 2. The yield was raised to 96%.
• Examples 1--7 All samples (Examples 1-7) were subjected to hydrolysis according to the conditions described for the analysis of natural wax esters (Linskens, H.J.and Jackson, I .J. , Essential Oils and Waxes, Springier Verlag, Berlin (1991)), followed by the proper work up and analysis of the composition of the free fatty acid moiety. Analyses showed the same EPA and DHA content in the wax esters as in the esters utilized as a starting material .
• Example 8 Digestibility test. The effect of pancreas lipase on wax esters has been verified according to the method by Neumann (U.Neumann, P.Kaspar, and J.Ziegenborn, "Methods in Enzymatic Analysis", Berg ayer

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• General Chemical & Material Sciences (AREA)
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• Wood Science & Technology (AREA)
• Veterinary Medicine (AREA)
• Mycology (AREA)
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• Food Science & Technology (AREA)
• Polymers & Plastics (AREA)
• Fats And Perfumes (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)

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Citations (4)

• 1997
  • 1997-06-11 IT IT97MI001369A patent/IT1292126B1/it active IP Right Grant
• 1998
  • 1998-06-09 AT AT98932141T patent/ATE228556T1/de active
  • 1998-06-09 DK DK98932141T patent/DK0991741T3/da active
  • 1998-06-09 AU AU82148/98A patent/AU740719B2/en not_active Ceased
  • 1998-06-09 US US09/445,419 patent/US6274751B1/en not_active Expired - Lifetime
  • 1998-06-09 EP EP98932141A patent/EP0991741B1/en not_active Expired - Lifetime
  • 1998-06-09 CA CA002293367A patent/CA2293367C/en not_active Expired - Fee Related
  • 1998-06-09 NZ NZ501690A patent/NZ501690A/en not_active IP Right Cessation
  • 1998-06-09 WO PCT/EP1998/003466 patent/WO1998056883A1/en active IP Right Grant
  • 1998-06-09 DE DE69809743T patent/DE69809743T2/de not_active Expired - Lifetime
• 1999
  • 1999-12-09 NO NO19996074A patent/NO312163B1/no not_active IP Right Cessation

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