WO1998040059A1 - Unsaturated fatty acid anhydrides for use in therapy - Google Patents

Unsaturated fatty acid anhydrides for use in therapy Download PDF

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Publication number
WO1998040059A1
WO1998040059A1 PCT/GB1998/000712 GB9800712W WO9840059A1 WO 1998040059 A1 WO1998040059 A1 WO 1998040059A1 GB 9800712 W GB9800712 W GB 9800712W WO 9840059 A1 WO9840059 A1 WO 9840059A1
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WIPO (PCT)
Prior art keywords
acid
fatty acids
gla
fatty acid
anhydride
Prior art date
Application number
PCT/GB1998/000712
Other languages
French (fr)
Inventor
David Frederick Horrobin
Mehar Singh Manku
Austin Mcmordie
Andrea Pitt
Paul Bradley
Philip Knowles
Original Assignee
Scotia Holdings Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Scotia Holdings Plc filed Critical Scotia Holdings Plc
Priority to AU64085/98A priority Critical patent/AU6408598A/en
Publication of WO1998040059A1 publication Critical patent/WO1998040059A1/en

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Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/03—Monocarboxylic acids

Definitions

  • the invention relates to presentation of fatty acids.
  • This invention particularly relates to the presentation of bioactive polyunsaturated fatty acids, including fatty acids which contain 16 - 26 carbon atoms and which have 2 to 6 double bonds in either the cis or trans configuration. It more particularly relates to fatty acids of 18 to 22 carbon atoms with 2 to 6 double bonds all in the cis configuration.
  • Such fatty acids include linoleic acid (18:2 n-6, LA), gamma-linolenic acid (18:3 n-6, GLA), dihomogamma-linolenic, acid (20:3 n-6, DGLA), arachidonic acid (20:4 n-6, AA), adrenic acid (22:4 n-6, AdrA), alpha-linolenic acid (18:3 n-3, ALA) stearidonic acid (18:4 n-3, SA), eicosapentaenoic acid (20:5 n-3, EPA), docosapentaenoic acid (22:5 n-3, DPA) and docosahexaenoic acid (22:6 n-3, DHA).
  • n-6 and n-3 series essential fatty acids are related as follows:-
  • the acids which in nature are of the all - cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. z,z-octadeca - 9,12 - dienoic acid or z,z,z,z,z,z - docosa- 4,7,10,13,16,19 - hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2 n-6 or 22:6 n-3, are convenient Initials, e.g.
  • EPA eicosapentaenoic acid
  • Other possible acids include columbinic acid or parinaric acid or conjugated linoleic acid or conjugated octadecatrienoic acid or alpha-eleostearic acid.
  • the fatty acid or derivative should be well tolerated when given orally or parenterally. This requirement rules out the free fatty acids themselves for most purposes since in other than carefully controlled quantities they cause gastrointestinal irritation when given orally or blood cell dissolution when given intravenously.
  • the fatty acid derivatives should be well absorbed and metabolised along normal metabolic pathways.
  • the invention therefore lies in compounds of the following acid anhydride structure, when for use in therapy in non-aqueous formulations, particularly for securing rapid uptake in the constituent fatty acids of the blood plasma and red cell lipids:-
  • R 1 is an acyl group derived from a bioactive unsaturated fatty acid particularly a C 16 - 26 preferably C ⁇ 8- 22 fatty acid with two to six cis or trans double bonds
  • R 2 is an acyl group as R 1 , the same or different.
  • the invention further lies in the compounds for use as nutritional supplements or food additives in non-aqueous formulations.
  • Particular fatty acids are as set out earlier herein and the acids may be provided in daily doses of 1 mg to 200 g, preferably 50 mg to 20 g and very preferably 300 mg to 5 g, except in cancers where the higher dose ranges may be required.
  • the preferred route of administration is oral, in gelatin or other capsules but other routes and formulations may be applied by those skilled in the art, provided the formulation is non-aqueous in the sense of protecting the anhydrides from hydrolysis by access of water before administration.
  • the individual fatty acids may be purified from natural animal, vegetable or microbial sources or may be chemically synthesised, all by methods known to those skilled in the art or to be developed hereafter. Synthesis of the claimed compounds requires the formation of an acid anhydride. Such chemistry may be achieved by any reasonable method of anhydride synthesis and especially:
  • N,N-d ⁇ sopropylethylamine was added dropwise to a mixture of z,z,z,z,z-eicosa-5, 8, 11,14,17- pentaenoyl chloride and z,z,z-octadeca-6,9, 12-trienoic acid in hexane at room temperature. After stirring overnight at room temperature under nitrogen, the mixture was filtered to remove N,N-d ⁇ sopropylethylammonium chloride.
  • suitable formulations are soft or hard gelatin capsules containing 50 to 1000 mg of anhydride (Examples 1 to 4), taken for example 2 capsules 3 times a day.
  • the biological efficacy of the anhydrides was illustrated as follows. Rats were put on a fat free diet to which was added 0.1% of GLA in six different forms, triglyceride-GLA (TriGLA); 1,3 propane diol GLA diester (DiGLA); 1,3 propane diol GLA monoester (GLA monester); ascorbyl-GLA; niacin-GLA, and the GLA-GLA anhydride. After two weeks blood samples were taken and the GLA derivatives ranked according to their ability to raise the levels of GLA itself and of its main metabolite, DGLA, in the phospholipids and cholesterol esters of plasma and the phospholipids of the red cell membrane.
  • TriGLA 1,3 propane diol GLA diester
  • GLA monester 1,3 propane diol GLA monoester
  • ascorbyl-GLA niacin-GLA
  • GLA-GLA anhydride After two weeks blood samples were taken and the GLA derivatives ranked
  • the GLA-GLA anhydride was the most effective compound in raising GLA levels. It was also the most effective compound in raising the levels of DGLA in all three fractions, showing that the GLA in the anhydride is not only the derivative which is most effectively absorbed but also the one which is most effectively metabolised to DGLA Similar but less extensive results were obtained with the EPA-EPA anhydride and the mixed GLA-EPA and GLA-DHA anhydrides.
  • the anhydrides are therefore an unexpectedly favourable way to administer one or two bioactive unsaturated fatty acids.

Abstract

Compounds of the following acid anhydride structure, when for use in therapy in non-aqueous formulations, particularly for securing rapid uptake in the constituent fatty acids of the blood plasma and red cell lipids: R?1- O - R2¿ where R1 is an acyl group derived from a bioactive unsaturated fatty acid particularly a C¿16-26? preferably C18-22 fatty acid with two to six cis or trans double bonds, and R?2¿ is an acyl group as R1, the same or different.

Description

UNSATURED FATTY ACID ANHYDRIDES FOR USE IN THE THERAPY
The invention relates to presentation of fatty acids.
This invention particularly relates to the presentation of bioactive polyunsaturated fatty acids, including fatty acids which contain 16 - 26 carbon atoms and which have 2 to 6 double bonds in either the cis or trans configuration. It more particularly relates to fatty acids of 18 to 22 carbon atoms with 2 to 6 double bonds all in the cis configuration. Such fatty acids include linoleic acid (18:2 n-6, LA), gamma-linolenic acid (18:3 n-6, GLA), dihomogamma-linolenic, acid (20:3 n-6, DGLA), arachidonic acid (20:4 n-6, AA), adrenic acid (22:4 n-6, AdrA), alpha-linolenic acid (18:3 n-3, ALA) stearidonic acid (18:4 n-3, SA), eicosapentaenoic acid (20:5 n-3, EPA), docosapentaenoic acid (22:5 n-3, DPA) and docosahexaenoic acid (22:6 n-3, DHA). These n-6 and n-3 series essential fatty acids are related as follows:-
TABLE 1 n - 6 EFA's n-3 EFA's
18:2n - 6 18:n - 3 (Linoleic acid, LA) (α-Linolenic acid, ALA)
4 delta - 6 - I desaturase
18:3n - 6 18:4n - 3 (γ - Linolenic acid GLA) (Stearidonic acid) i elongation 4-
20:3n - 6 20:4n - 3 (Dihomo - γ - linolenic acid, DGLA)
I delta - 5 - i desaturase
20:4n - 6 20:5n - 3
(Arachidonic acid, AA) (Eicosapentaenoic acid, EPA) i elongation 4
22:4n - 6 22:5n - 3 (Adrenic acid, AdrA) i delta - 4 - I desaturase
22:5n - 6 22:6n - 3 (Docosahexaenoic acid, DHA)
The acids, which in nature are of the all - cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. z,z-octadeca - 9,12 - dienoic acid or z,z,z,z,z,z - docosa- 4,7,10,13,16,19 - hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2 n-6 or 22:6 n-3, are convenient Initials, e.g. EPA, and shortened forms of the name e.g. eicosapentaenoic acid, are used as trivial names in some instances. Other possible acids include columbinic acid or parinaric acid or conjugated linoleic acid or conjugated octadecatrienoic acid or alpha-eleostearic acid.
These fatty acids have biological and therapeutic effects which in themselves are well documented in the literature and in many previous patent applications by the present applicants. When developing such fatty acids or their derivatives as agents for pharmaceutical use or for nutritional use either as nutritional supplements or as substances to be added to foodstuffs there are several important considerations:
1. The fatty acid or derivative should be well tolerated when given orally or parenterally. This requirement rules out the free fatty acids themselves for most purposes since in other than carefully controlled quantities they cause gastrointestinal irritation when given orally or blood cell dissolution when given intravenously.
2. The fatty acid derivatives should be well absorbed and metabolised along normal metabolic pathways.
3. In some situations two or three fatty acids with similar or different biological actions need to be incorporated into a single molecule. This is particularly important in pharmaceutical situations where it may be important simultaneously to provide two or three bioactives within a single chemical entity.
Recent filings from the applicants have described in detail various fatty acid derivatives that may be used with these ends in mind, and anhydrides are briefly mentioned in PCT/GB96/01053, published as WO96/34846. In the course of testing a range of fatty acid derivatives we have made the surprising observation that anhydrides are extremely well tolerated, absorbed and metabolised. Consistently the anhydrides perform better than other fatty acid derivatives in raising blood levels of the constituent fatty acids. These anhydrides are thus preferred derivatives for pharmaceutical use in particular, although they also have value as nutritional supplements in situations such as encapsulated products where water is excluded. On addition of water to these compounds they dissociate into free fatty acids. This may explain why they are so effective when taken by mouth since no digestive processes are required to allow them to be absorbed into the body.
The Invention
The invention therefore lies in compounds of the following acid anhydride structure, when for use in therapy in non-aqueous formulations, particularly for securing rapid uptake in the constituent fatty acids of the blood plasma and red cell lipids:-
R1 - O - R2
where R1 is an acyl group derived from a bioactive unsaturated fatty acid particularly a C 16-26 preferably Cι8-22 fatty acid with two to six cis or trans double bonds, and R2 is an acyl group as R1, the same or different.
The invention further lies in the compounds for use as nutritional supplements or food additives in non-aqueous formulations.
Particular fatty acids are as set out earlier herein and the acids may be provided in daily doses of 1 mg to 200 g, preferably 50 mg to 20 g and very preferably 300 mg to 5 g, except in cancers where the higher dose ranges may be required. The preferred route of administration is oral, in gelatin or other capsules but other routes and formulations may be applied by those skilled in the art, provided the formulation is non-aqueous in the sense of protecting the anhydrides from hydrolysis by access of water before administration.
Synthetic Routes
The individual fatty acids may be purified from natural animal, vegetable or microbial sources or may be chemically synthesised, all by methods known to those skilled in the art or to be developed hereafter. Synthesis of the claimed compounds requires the formation of an acid anhydride. Such chemistry may be achieved by any reasonable method of anhydride synthesis and especially:
(a) by reaction of a fatty acid with a dehydrating agent, e.g. 1,3-dicyclohexylcarbodiirnide or acetic anhydride, with or without an inert solvent, e.g. methylene chloride, at a temperature between -20°C and 200°C
(b) by reaction of an alkali metal or alkaline earth metal or silver salt of a fatty acid with a fatty acid chloride or other suitable activated fatty acid derivative with or without an inert solvent, e.g. methylene chloride, at a temperature between -20°C and 50°C.
(c) by reaction of a fatty acid and a fatty acid chloride with or without the presence of an organic tertiary base, e.g. pyridine and with or without an inert solvent, e.g. hexane, at a temperature between -20°C and 100°C.
(d) by reaction of a fatty acid chloride with an appropriate quantity of water in the presence of an organic tertiary base, e.g. pyridine, with or without a suitable inert solvent, e.g. hexane, at a temperature between -20°C and 50°C.
Preparative examples Example 1 z,z,z-octadeca-6,9, 12-trienoic anhydride (GLA anhydride)
A mixture of z,z,z-octadeca-6,9, 12-trienoic acid and 1,3-dicyclohexylcarbodiirnide (0.55 equiv.) in hexane was stirred overnight under nitrogen at room temperature. The reaction mixture was filtered to remove precipitated 1,3-dicyclohexylurea. The filtrate was stored overnight at -20°C to precipitate any residual 1,3-dicyclohexylurea which was again removed by filtration. Concentration under reduced pressure yielded z,z,z-octadeca-6,9, 12-trienoic anhydride as a pale yellow, free flowing oil. Infra red analysis indicated two peaks at 1820cm'1 and 1750 cm"1, consistent with an anhydride grouping. Example 2 z,z,z,z,z-eicosa-5,8,l 1,1 ,17-pentaenoic anhydride (EPA anhydride)
Reaction of z,z,z,z,z-eicosa-5,8,l 1,14,17-pentaenoic acid and 1,3-dicyclohexylcarbodiimide under the conditions given in Example 1 yielded z,z,z,z,z-eicosa-5,8,l 1,14,17-pentaenoic anhydride as a pale yellow, free flowing oil. Infra red analysis indicated two peaks at 1820 cm"1 and 1750 cm"1, consistent with an anhydride grouping.
Example 3 z,z,z,z,z-eicosa-5,8,ll,14,17-pentaenoic, z,z,z-octadeca-6,9, 12-trienoic mixed anhydride (GLA-EP A mixed anhydride)
N,N-dϋsopropylethylamine was added dropwise to a mixture of z,z,z,z,z-eicosa-5, 8, 11,14,17- pentaenoyl chloride and z,z,z-octadeca-6,9, 12-trienoic acid in hexane at room temperature. After stirring overnight at room temperature under nitrogen, the mixture was filtered to remove N,N-dϋsopropylethylammonium chloride. Concentration under reduced pressure yielded z,z,z,z,z-eicosa-5,8,l l,14,17-pentaenoic, z,z,z-octadeca-6,9, 12-trienoic mixed anhydride as a yellow, free flowing oil. Inra red analysis indicated two peaks at 1820 cm"1 and 1750 cm"1, consistent with an anhydride grouping.
Example 4 z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic, z,z,z-octadeca-6,9, 12-trienoic mixed anhydride (GLA-DHA mixed anhydride)
Reaction of z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoyl chloride and z,z,z-octadeca-6,9, 12- trienoic acid under the conditions given in Example 3 yielded z,z,z,z,z,z-docosa- 4,7,10,13,16,19-hexaenoic, z,z,z-octadeca-6, 9, 12-trienoic mixed anhydride as a yellow, free flowing oil. Infra red analysis indicated two peaks at 1820 cm"1 and 1750 cm"1, consistent with an anhydride grouping. Formulations
Among suitable formulations are soft or hard gelatin capsules containing 50 to 1000 mg of anhydride (Examples 1 to 4), taken for example 2 capsules 3 times a day.
Experimental
The biological efficacy of the anhydrides was illustrated as follows. Rats were put on a fat free diet to which was added 0.1% of GLA in six different forms, triglyceride-GLA (TriGLA); 1,3 propane diol GLA diester (DiGLA); 1,3 propane diol GLA monoester (GLA monester); ascorbyl-GLA; niacin-GLA, and the GLA-GLA anhydride. After two weeks blood samples were taken and the GLA derivatives ranked according to their ability to raise the levels of GLA itself and of its main metabolite, DGLA, in the phospholipids and cholesterol esters of plasma and the phospholipids of the red cell membrane. For all three GLA fractions, the GLA-GLA anhydride was the most effective compound in raising GLA levels. It was also the most effective compound in raising the levels of DGLA in all three fractions, showing that the GLA in the anhydride is not only the derivative which is most effectively absorbed but also the one which is most effectively metabolised to DGLA Similar but less extensive results were obtained with the EPA-EPA anhydride and the mixed GLA-EPA and GLA-DHA anhydrides. The anhydrides are therefore an unexpectedly favourable way to administer one or two bioactive unsaturated fatty acids.
Table 1. R-anking ** of the efficiency of various GLA derivatives in raising blood levels of GLA and DGLA when provided at 0.1% of rate diet. PPL plasma phospholipid: PCE plasma cholesterol ester: RPL red cell phospholipids.
GLA GLA GLA DGLA DGLA DGLA
PPL PCE RPL PPL PCE RPL
GLA-GLA anhydride 1 1 1 1 1 1
TriGLA 6 5 6 6 3 6
DiGLA 3 3 4 5 5 5
GLA monoester 2 2 5 3 4 4
Ascorbyl-GLA 5 6 2 2 2 3
Niacin-GLA 4 3 2 3 6 2
** Arbitrary 1 - 6 scale (1 most effective, 6 least effective)

Claims

1. Compounds of the following acid anhydride structure, when for use in therapy in non-aqueous formulations, particularly for securing rapid uptake in the constituent fatty acids of the blood plasma and red cell lipids :-
R1 - O - R2
where R1 is an acyl group derived from a bioactive unsaturated fatty acid particularly a C╬╣╬▓-26 preferably C╬╣g-22 fatty acid with two to six cis or trans double bonds, and R2 is an acyl group as R!, the same or different.
2. A compound according to claim 1, wherein the fatty acids are selected from the n-6 and n-3 series essential fatty acids and, columbinic acid, parinaric acid, conjugated linoleic acid, conjugated octadecatrienoic acid and alpha-eleostearic acid.
3. A compound according to claim 2, wherein the fatty acids are selected from linoleic acid, gamma-linolenic acid, dihomogamma-linolenic acid, arachidonic acid, adrenic acid, alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosapentaenoic acid n-3 and docosahexaenoic acid.
4 . Compounds as in claims 1 - 3 for use as nutritional supplements or food additives in non-aqueous formulations.
PCT/GB1998/000712 1997-03-12 1998-03-10 Unsaturated fatty acid anhydrides for use in therapy WO1998040059A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64085/98A AU6408598A (en) 1997-03-12 1998-03-10 Unsatured fatty acid anhydrides for use in the therapy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9705102.3A GB9705102D0 (en) 1997-03-12 1997-03-12 Presentation of fatty acids
GB9705102.3 1997-03-12

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AU (1) AU6408598A (en)
GB (2) GB9705102D0 (en)
JO (1) JO2013B1 (en)
WO (1) WO1998040059A1 (en)
ZA (1) ZA981668B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8809560B2 (en) 2011-05-17 2014-08-19 Board Of Trustees Of The University Of Arkansas Trans-, trans-conjugated linoleic acid compositions and use thereof
US9062276B2 (en) 2012-12-03 2015-06-23 Board Of Trustees Of The University Of Arkansas Conjugated linoleic acid rich vegetable oil production from linoleic rich oils by heterogeneous catalysis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19941609A1 (en) * 1999-09-01 2001-03-08 Inst Pflanzenbiochemie Ipb Fatty acid desaturase gene from plants

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JPS61129190A (en) * 1984-11-27 1986-06-17 Nippon Oil & Fats Co Ltd Polymerizable glycerophospholipid
US4668664A (en) * 1985-05-14 1987-05-26 L'oreal Bi- or tri-enic fatty esters of erythromycin A; pharmaceutical and cosmetic compositions containing them
EP0246540A2 (en) * 1986-05-20 1987-11-25 Paul Y. Wang Implant preparations for delivery of bioactive macromolecules
JPH0551355A (en) * 1991-11-21 1993-03-02 Sekimoto Hiroshi Polyene acid derivative
US5321145A (en) * 1990-10-31 1994-06-14 A. Nattermann & Cie. Gmbh Process of producing phosphatidylcholine derivatives

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Patent Citations (5)

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JPS61129190A (en) * 1984-11-27 1986-06-17 Nippon Oil & Fats Co Ltd Polymerizable glycerophospholipid
US4668664A (en) * 1985-05-14 1987-05-26 L'oreal Bi- or tri-enic fatty esters of erythromycin A; pharmaceutical and cosmetic compositions containing them
EP0246540A2 (en) * 1986-05-20 1987-11-25 Paul Y. Wang Implant preparations for delivery of bioactive macromolecules
US5321145A (en) * 1990-10-31 1994-06-14 A. Nattermann & Cie. Gmbh Process of producing phosphatidylcholine derivatives
JPH0551355A (en) * 1991-11-21 1993-03-02 Sekimoto Hiroshi Polyene acid derivative

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PATENT ABSTRACTS OF JAPAN vol. 017, no. 361 (C - 1080) 8 July 1993 (1993-07-08) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8809560B2 (en) 2011-05-17 2014-08-19 Board Of Trustees Of The University Of Arkansas Trans-, trans-conjugated linoleic acid compositions and use thereof
US9062276B2 (en) 2012-12-03 2015-06-23 Board Of Trustees Of The University Of Arkansas Conjugated linoleic acid rich vegetable oil production from linoleic rich oils by heterogeneous catalysis

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AR011456A1 (en) 2000-08-16
GB9805123D0 (en) 1998-05-06
JO2013B1 (en) 1999-05-15
GB2323031A (en) 1998-09-16
ZA981668B (en) 1998-09-11
AU6408598A (en) 1998-09-29
GB9705102D0 (en) 1997-04-30

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