Therapeutic combinations of fatty acids

Details Therapeutic combinations of fatty acids Therapeutic combinations of fatty acids

2001-06-29

2002-11-12

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S558000

Reexamination Certificate

active

06479544

ABSTRACT:

There are two series of essential fatty acids (EFAs) in humans. They are termed “essential” because they cannot be synthesised de novo in mammals. Their metabolic pathways are shown in FIG.
1
. These fatty acids can be interconverted within a series, but the omega-6 (n-6) series cannot be converted to the omega-3 series nor can the omega-3 (n-3) series be converted to the omega-6 series in humans. The main EFAs in the diet are linoleic acid of the omega-6 series and alpha-linolenic acid of the omega-3 series. However, to fulfil most of their biological effects these “parent” EFAs must be metabolised to the other fatty acids shown in FIG.
1
. Each fatty acid probably has a specific role in the body. Particularly important in the n-6 series are dihomogammalinolenic acid (DGLA, 20:3n-6) and arachidonic acid (AA, 20:4n-6), while particularly important in the n-3 series are eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (22:6n-3). This patent specification particularly concerns combinations of AA and EPA.
AA is found as an important constituent of all cell membranes and particularly of cell membranes of nerve cells. It is an important component of many signal transduction systems which are activated by many different forms of cell stimulation. AA is usually found in cells in the form of phospholipids. Cell activation generates a range of active phospholipases which can release AA as the free acid. The free acid has many direct actions of its own in regulating protein kinases and other enzymes, in modulating movements of calcium and other ions, in activating receptors such as peroxisome proliferator activated receptors (PPARs), and in modulating gene function. Furthermore AA can be converted to an enormous range of even more active derivatives known by the general name of eicosanoids. These include prostaglandins, leukotrienes, thromboxanes, various types of hydroxy acids, lipoxins, hepoxilins and many other compounds. These substances are often involved in inflammatory and thrombotic reactions and are frequently regarded as harmful in their overall effects. This harmful image is illustrated by the fact that intravenous AA is frequently lethal because of its thrombotic effects, and by the fact that the steroids which are widely used, in particular for their anti-inflammatory effects, block the release of AA by phospholipases. Moreover, the class of drugs known as cyclo-oxygenase inhibitors, which include aspirin and many other well known compounds, known for their antithrombotic and anti-inflammatory effects, inhibit the conversion of AA to prostaglandins and thromboxanes.
This concept of the potential toxicity of AA has become well established. The expert organisation in the field, the International Society for the Study of Fatty Acids and Lipids (ISSFAL) in 1999 organised a workshop in association with the US National Institutes of Health. The remit of the workshop was to make recommendations concerning the human uses of EFAs. The participants, all leading experts in the field, had no doubts about the harmful effects of AA, and emphasised this in their final statement (AP Simopoulos et al, Essentiality of and recommended dietary intakes for omega-6 and omega-3 fatty acids, Nutrition and Metabolism 1999; 43:127-130). The ISSFAL newsletter reporting on this workshop stated that “after much discussion, consensus was reached on the importance of reducing the omega-6 polyunsaturated fatty acids (PUFAs) even as the omega-3 PUFAs are increased in the diet of adults and newborns for optimal brain and cardiovascular function. This is necessary to reduce adverse effects of arachidonic acid and its eicosanoid products”.
In contrast to this general view of AA toxicity, the experts of ISSFAL and NIH were keen to promote the value of the n-3 EFAs, particularly EPA and DHA for human health. The view was taken that EPA and DHA would replace AA in cell membrane phospholipids and also reduce AA synthesis from linoleic acid. The lowering of AA levels by EPA and/or DHA was expected to have widespread beneficial effects on human health.
The present invention results from recent surprising observations of the inventor which suggest that this view may be wrong. Contrary to the general expert opinion, it has now been found that AA is highly desirable rather than undesirable and it may be helpful to administer AA in association with EPA. The present invention provides this combination treatment.
The present invention provides pharmaceutical formulations containing eicosapentaenoic acid or any appropriate derivative (hereinafter collectively referred to as EPA) and arachidonic acid (AA), as set out in the claims attached hereto. AA may be replaced by one or more of its precursors, DGLA or GLA. The ratio of EPA to AA is preferably between 1:1 and 20:1.
The EPA is preferably provided in a dose of between 100 mg and 10,000 mg/day. The formulation may be a single preparation comprising 100-10,000 mg EPA. An alternative upper limit is 5,000 mg EPA. Preferably, the formulations of the invention comprise 1-4 g EPA and 0.1-2.0 g arachidonic acid (AA). Still preferred amounts are 1.5-3 g EPA and 0.2-1 g AA.
The formulation may be a single daily dose preparation to give in one dose the above intakes, or may be in convenient divided doses, for example, a daily dose formed of four soft gelatin or other capsules, each containing 500 mg of EPA in an appropriate form and 150 mg of AA in an appropriate form.
The compositions of the first aspect of the present invention are prepared by combining EPA in biologically assimilable form in which the EPA is at least 50% pure, preferably at least 90% pure, and arachidonic acid (AA) in any biologically assimilable form. The starting materials must include one containing substantial amounts of the EPA. The same can apply for the AA, which may be at least 30% pure, preferably at least 90% pure.
Still preferably, the active ingredient of the formulations of the present invention consists essentially wholly of the EPA and AA or AA precursor. In that case, no significant amounts of other EFAs are present.
Flavourants or emulsifiers may be included to make the preparation palatable. Other conventional additives, diluents and excipients may be present. The preparation for ingestion may be in the form of a capsule, a dry powder, a tablet, an oil, an emulsion or any other appropriate form. The capsules may be hard or soft gelatin capsules, agar capsules, or any other appropriate capsule.
The EPA is preferably composed of a triglyceride or ethyl ester which is 50% pure or purer, more preferably more than 90% pure. Other forms of the fatty acids which may be useful include the free acids, salts, esters of any type, amides, mono-, di- or triglycerides, phospholipids or any other form which can lead to the incorporation of EPA into body tissues. If phospholipids are considered, it is specifically excluded from the present invention that a phospholipid containing two different fatty acids, that is containing both EPA and AA (or AA precursor) is used. Phospholipids containing EPA may however be used in the present formulations when combined with phospholipids containing AA or AA precursor.
The formulations of the present invention may be used for the treatment of a wide range of diseases and disorders including:
any psychiatric, neurological or other central or peripheral nervous system disease—in particular schizophrenia, depression, bipolar disorder and degenerative disorders of the brain including Alzheimer's disease and other dementias and Parkinson's disease;
asthma and other respiratory diseases;
diseases of the gastrointestinal tract including inflammatory bowel diseases and irritable bowel syndrome;
inflammatory disease affecting any system;
cardiovascular disease;
dyslipidaemia, any form of diabetes or any form of metabolic diseases;
dermatological diseases;
kidney or urinary tract diseases;
liver diseases;
disease of the male or female reproductive organs such as the breast or the prostate gland;
cancer or cancer cachexia;
diseases of the head and neck, incl

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