GB2222080A

GB2222080A - Nutritional compositions comprising polyunsaturated fatty acid salts

Info

Publication number: GB2222080A
Application number: GB8829443A
Authority: GB
Inventors: David Horrobin
Original assignee: Efamol Holdings PLC
Current assignee: Efamol Holdings PLC
Priority date: 1988-08-15
Filing date: 1988-12-16
Publication date: 1990-02-28
Also published as: GB8829443D0

Abstract

There are provided pharmaceutical and nutritional compositions containing sodium or potassium salts of C18-22 polyunsaturated fatty acids. The compositions may be used in the treatment of conditions responsive to polyunsaturated fatty acid therapy, in parenteral alimentation or in food supplements. The compositions may further include a lithium salt of C18-22 polyunsaturated fatty acids.

Description

Compositions The present invention relates to pharmaceutical and nutritional compositions, in particular to such compositions containing sodium or potassium salts of polyunsaturated fatty acids, to the use of such sodium or potassium salts in the preparation of pharmaceutical and nutritional compositions, and to therapeutic treatments of the human or non-human body with such salts.

The essential fatty acids are essential nutrients which must be provided in the diet because they cannot be manufactured by the body. The main dietary essential fatty acids are linoleic and aiphalinolenic acids but to be fully utilised the essential fatty acids must be metabolised along the n-3 or n-6 pathways, of which alphalinolenic and linoleic acids are the respective starting points and of which gamma-linolenic, dihomogamma-linolenic, arachidonic and eicosapentaenoic acids are the major biologically active metabolites.

In patients who are receiving no food or only insufficient food by the normal oral route, such as patients who have been, or are to be subjected to surgery, for example, the essential fatty acids must be provided by enteral or parenteral feedinq.

On enteral administration, however, the fatty materials may not be fully absorbed bv patients having fat malabsorption. Such malabsorption is particularly likely to occur with patients with defective pancreatic or hepatic functions, with certain intestinal diseases or with cystic fibrosis.

In such patients conventional oral and enteral routes may not provide an adequate intake of essential fatty acids which may thus have to be administered as parenteral nutritional supplements.

Due to their lipid nature however, the essential fatty acids cannot be incorporated into a single parenterally administrable aqueous composition capable of meeting a patient's entire nutritional requirements, and are generally administered in the form of lipid emulsions usually containing triglycerides and/or phospholipids and linoleic acid with or without alphalinolenic acid. Some specialist emulsions, especially for use in pediatrics, may also contain 6-desaturated fatty acids such as the n-6 essential fatty acid gamma-linolenic acid and the n-3 essential fatty acid eicospentaenoic acid since the possibility exists that patients may be unable to convert enough of their dietary essential fatty acids to their metabolites.

Such liquid emulsions are not readily compatible with conventional aqueous fluids for parenteral nutrition, administration of liquid emulsions is not clear of side effects and there is particular concern regarding possible effects on the lungs, especially of infants.

Typical essential fatty acid emulsions for parenteral nutrition are for example the Intralipid products of Kabivitrum Ltd.

Thus, as a result of these problems, essential fatty acids are usually administered intravenously only to patients on long-term parenteral nutrition therapy, where omission of fatty acids over prolonged periods of time could not be tolerated, and to patients exhibiting lipid malabsorption; patients on short term parenteral nutrition, for example awaiting, during, and Just after surgery, or other procedures which may temporarily prevent oral nutrition, are rarely, if ever, administered essential fatty acids.

However, where the patient is receiving only parenteral alimentation, essential fatty acid deficiency may develop rapidly for at least three reasons: (1) no essential fatty acids are being taken in orally, (2) the parenteral solutions tend to block mobilization of lipids from body stores, so reducing the ability to make use of the body's own content of essential fatty acids, and (3) the high glucose intake in particular tends to inhibit 6-desaturation of the essential fatty acids linoleic acid and alpha-linolenic acid.

6-desaturation within the body is required if these essential fatty acids are to exert their full nutritional effects.

Since essential fatty acids are required for normal wound healing, for response to infections, for normal bowel movements and for resistance to thrombosis, it is possible that even a short term deficiency of essential fatty acids could have many adverse effects, particularly in patients subject to surgery.

Thus, there exists a need for an improved method for the parenteral, particularly intravenous, administration of the essential fatty acids. In particular it would be highly desirable to have available water soluble forms of the essential fatty acids, which could be formulated into conventional parenteral solutions, or into forms for addition to conventional parenteral nutrition solutions. Additionally, such water-soluble forms could be used for the preparation of oral administration compositions for use with patients suffering from fat malabsorption.

Furthermore, it is now recognised that polyunsaturated fatty acids have many physiological activities and have'been used in or proposed for the treatment of conditions such as for example atopic disorders (including eczema, asthma and allergic rhinitis), disorders associated with atopy, (including Crohn's disease, ulcerative colitis, otitis media and nephrotic syndrome), benign disease of the breast and prostate glands, premenstrual breast disease (cyclical mastalgia), breast, prostatic or other cancers, diabetes and the complications of diabetes (including nephropathy, neuropathy, retinopathy and microvascular and macrovascular cardiovascular complications), alcoholism and the complications of alcoholism, psychiatric disorders including schizophrenia, depression and tardive dyskinesia, conditions associated with elevated blood cholesterol and/or triglyceride levels, with elevated blood pressure, with an increased risk of development of thrombotic disorders, with an increased risk of development of coronary heart diseases, with ulcers in the stomach, duodenum or any other part of the gastrointestinal tract, with reflux oesophagitis or irritable bowel syndrome, and with rheumatoid arthritis, osteoarthritis or other diseases associated with inflammation, damage to connective tissue or disordered immune function such as Sjogren's syndrome, Raynaud's syndrome, systemic lupus erythematosus, polyarteritis nodosa, primary biliary cirrhosis, and multiple schlerosis, and diseases of the kidneys including acute and chronic glomerulonephritis, nephrotic syndrome, and diabetic nephropathy.

Thus the availability of water-soluble forms of the essential fatty acids would facilitate preparation of pharmaceutical compositions, and other therapeutic agents for use in the treatment or prevention of essential fatty acid deficiency and conditions associated therewith, such as those mentioned above.

The use of water-soluble lithium salts of the polyunsaturated fatty acids has already been proposed in EP-A-289204 for the preparation of enteral and parenteral compositions for the administration of lithium and/or polyunsaturated fatty acids.

Also, conjoint administration of lithium salts and of polyunsaturated fatty acids has been proposed for the treatment of disorders believed to be associated with prostaglandin imbalance and in EP-A-234733 orally administrable capsules containing lithium gammalinolenate and/or lithium eicosapentaenoate for use in the treatment of Alzheimer's disease are proposed. There was however no suggestion that any particular benefit in terms either of drug delivery or of therapeutic efficacy might arise from the use of polyunsaturated fatty acid salts and indeed there was no suggestion that administration of such salts may have any therapeutic effect beyond that expected for conjoint administration of a lithium salt and of a polyunsaturated fatty acid.Furthermore, as discussed below, the major benefit of such use is not achieved on oral adminstration unless the salts are administered in a manner which delays release until after the stomach is passed.

The use of lithium salts to administer fattv acids presents problems however, since lithium ions themselves have potent pharmacological activity and can be toxic at higher doses; indeed it is stated in Martindale, The Extra Pharmacopoeia, 28th Edition (1982) 1538 that the margin between the therapeutic and the toxic concentration of lithium is narrow, and that therefore lithium should only be administered under close medical supervision.

We have now found, that although the sodium and potassium salts of polyunsaturated fatty acids, unlike the lithium salts, are not crystalline solids at ambient temperature, they are also highly soluble in water and other polar solvents such as alcohol.

This property facilitates preparation of compositions containing the essential fatty acids and thus the salts can be used to promote polyunsaturated fatty acid uptake following administration. Furthermore the potential toxicity of lithium ions can be avoided.

In particular, the relatively poor water solubility of the conventionally administered polyunsaturated fatty acids presents problems when attempting to ensure an even distribution of the fatty acid through both the intravascular and extravascular compartments of the extracellular fluid or when attempting to administer polyunsaturated fatty acids enter alloy (especially in patients with lipid malabsorption) or parenterally, and particular intravenously, or when administering polyunsaturated fatty acids topically in a cosmetically acceptable aqueous base, and these problems may be reduced by adminstering the acid as its water-soluble sodium or potassium salt.

Thus, in one aspect the present invention provides a pharmaceutical composition comprising one or more sodium or potassium salts of a C18-22 polyunsaturated fatty acid having at least two unsaturated carboncarbon bonds, together with at least one physiologically acceptable carrier or excipient material.

Particularly conveniently, the composition may comprise essential fatty acids as sodium salts alone, potassium salts alone, or a mixture of sodium and potassium salts, in each case optionally in combination with lithium salts.

Preferred compositions include aaueous solutions for parenteral nutrition, sterile aqueous solutions to be added to intravenous fluids at the time of setting up intravenous infusions, oral or enteral administration compositions for use with patients suffering from lipid malabsorption, and compositions for treating essential fatty acid deficiency and combatting conditions responsive to therapy with C18-22 polyunsaturated fatty acids (C18-22 PUFAs) Thus, in another aspect the invention also provides the use of a sodium and/or potassium salt of a C18~22 PUFA (Na (C18-22 PUFA); K (C18-22 PUFA)) for the manufacture of an enteral or parenteral alimentat ion solution.

In a further aspect the invention provides the use of a Na or K (C18-22 PUFA) for the manufacture of a therapeutic agent for the treatment of essential fatty acid deficiency and conditions responsive to C18-22 PUFA therapy.

Particularly preferably the therapeutic agent may be used in parenteral nutrition or in the treatment of conditions selected from: essential fatty acid deficiency and conditions associated therewith; inflammatory and immunological disorders (including rheumatoid arthritis, osteoarthritis, atopic dermatitis and other forms of dermatitis, psoriasis, Crohn's disease and ulcerative colitis); psychiatric disorders (including manic-depressive pyschosis, schizophrenia and alcoholism); disorders associated with smooth muscle spasm (including asthma, ulcerative colitis and dysmenorrhoea); diabetes and the renal, neurological, retinal and cardiovascular complications of diabetes; cancers (including breast, prostatic and other cancers); and cardiovascular disorders (including elevated blood pressure, elevated blood levels of triglycerides, of total cholesterol or of LDL cholesterol, and thrombotic disorders).

In a still further aspect, the invention provides a method of preventing essential fatty acid deficiency in humans or animals, said method comprising adminstering an effective amount of a C18 22 PUFA sodium and/or potassium salt.

In a yet further aspect, the invention provides a method of treatment of the human or animal body to combat conditions responsive to C18-22 PUFA therapy, said method comprising administering to said body an effective amount of a C18-22 PUFA sodium and/or potassium salt.

In the above-mentioned methods and uses, the sodium or potassium salts may be administered in conjunction with lithium (C18-22 PUFA) salts.

When adminstered orally into the stomach, the acidic pH of the stomach contents may cause dissociation of the (C 18-22 PUFA) salts and thus for oral admini stration according to the invention the (C18-22 PUFA) salts are most preferably presented in a manner adapted to minimize dissociation in the stomach, e.g. by provision with an enteric, i.e. gastric juice resistant, coating or casing or by administration by tube, e.g. as a solution, directly into the intestines.

Suitable enteric coated compositions thus include capsules or tablets provided with an enteric coating of an acrylate (such as the enteric Eudragit coating materials produced by Röhm GmbH), cellulose acetate phthalate or other appropriate material which serves to delay active suvstance release until the composition reaches the intestines.

The Na or K (C18-22 PUFA) in the compositions of the invention is preferably the salt of an acid which has 2 - 6 carbon-carbon double bonds and suitable Na and K (C18-22 PUFA)s include the sodium and potassium salts of linoleic acid, alpha-linolenic acid, gammalinolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, 22:5n-6, 18:4n-3, 20:4n-3, eicospentaenoic acid, 22:5n-3, docosahexaenoic (22:6n-3) acid, and mixtures of two or more such salts. Sodium and potassium salts of n-3 and n-6 C18-22 PUFAs, especially 6-desaturated PUFAs are particularly preferred and where the pharmaceutical compositions of the invention are for use as nutritional compositions or as nutritional supplements, it is preferred that they contain at least one sodium or potassium salt of a C18-22 PUFA in the n-3 series (e.g. 18:3n-3 (alpha-linolenic acid), 18:4 n-3, 20:4 n-3, 20:5n-3, 22:5 n-3 and 22:6n-3) and at least one sodium or potassium salt of a C1822 PUFA in the n-6 series (e.g. 18:2 n-6 (linolenic acid), 18:3n-6 (gamma-linolenic acid), 20:3n-6 (dihomogammalinolenic acid), 20:4n6 (arachidonic acid), 22:4n-6 (adrenicacid) and 22:5n-6). Compositions containing sodium and potassium gamma-linolenate salts are especially preferred.

The nature of the carrier material or excipient in the compositions of the invention will of course depend on the end use to which the composition is to be put.

The compositions of the invention may conveniently comprise the Na and K (C18-22 PUFA)s optionally in combination with a Li (C18-22 PUFA) incorporated into a solid, liquid or aqueous carrier medium and the pharmaceutical compositions may be in forms suitable for topical, enteral, oral, rectal, vaginal, or parenteral (e.g. intravenous, subcutaneous, intramuscular or intravascular) administration to the human or animal body. The compositions, method and uses of the present invention are however especially suited to the oral, parenteral and topical and especially oral and intravenous, administration of Na or K (C18-22 PUFA) salts, optionally in combination with Li(C1822PUFA) salts.

For topical administration, the composition will preferably be in a form adapted for regular application in substantially similar quantities and thus the sodium and/or potassium salts, optionally in combination with lithium salts, may conveniently be incorporated into gels, creams, ointments and the like. Such compositions may suitably contain a further liphophilic component, e.g. a lipid or lipid solvent.

For oral or rectal administation, the pharmaceutical compositions of the invention may be formulated using conventional pharmaceutical carriers and excipients, e.g. in the form of tablets, coated tablets, syrups, suppositories, capsules, powders, suspensions, emulsions, sprays, etc. As discussed above, since the (C18 22PUFA) salts may dissociate at the normal pH of the stomach contents, oral administration forms will particularly preferably have the (C18 22PUFA) salt provided with an enteric coating to delay release of the (C1822 PUFA) salt until it has passed through the stomach. Thus enteric coated capsules or tablets are especially preferred. Solutions or suspensions for administration by enteral tube or for rectal administration are also preferred.

For injection, the pharmaceutical compositions of the invention are preferably formulated as sterile solutions, emulsions or suspensions, e.g. in water for injections, or in solutions in a lipid or lipid solvent, again preferably also including further lipophilic components. To enhance further the targeting of the compostions onto lipid-rich zones of the body, the (C18-22 PEFA) salts may optionally have a carrier in liposome, artificial chylomicron or micelle form.

The pharmaceutical compositions of the invention are preferably provided in a form suitable for parenteral, more preferably intravenous, administration.

Such parenterally administered Na and/or K (C18 22 PUFA)s, optionally in combination with Li (C1822PUFA)s, may be used as a means of supplying the essential fatty acids in parenteral alimentation or to prevent or treat essential fatty acid deficiency, and accordingly the pharmaceutical compostions of the invention may be administered either as a source of essential fatty acids or as a complete nutrition composition. Thus the compositions are preferably formulated as aqueous solutions for parenteral alimentation, or as aqueous solutions made up into sterile vials to be added to intravenous fluids at the time of setting up intravenous infusions.Such solutions are preferably stored under an inert atmosphere, e.g. in nitrogen flushed vials, buffered to a pH in the range 8.5 to 9.0, e.g with a physiologically acceptable acid such as citric acid. Moreover, such solutions preferably contain an antioxidant, e.g.

a fatty acid derivative of ascorbic acid such as ascorbyl palmitate, a tocopherol (e.g. gamma tocopherol or a mixed tocopherol) or butylated hydroxy toluene.

In a preferred embodiment, the pharmaceutical composition of the invention is in the form of a parenteral alimentation solution comprising at least one sodium or potassium salt of a 6-desaturated fatty acid from the n-6 series such as gammalinolenic or dihomogammalinolenic acid, and at least one sodium or potassium salt of a fatty acid from the n-3 series such as eicosapentaenoic acid or docosahexaenoic acid, optionally further comprising at least one lithium salt of said fatty acids.

In a further preferred embodiment, the composition additionally comprises at least one further nutritional component selected from: vitamins, essential minerals and calorie sources.

The essential fatty acid supply required to prevent essential fatty acid deficiency is probably within the range 0.1-10% of total daily calorie intake, especially 0.5-3% (or 1-5% during periods of metabolic stress such as rapid growth, pregnancy, lactation or injury). This is equivalent to approximately 2-11 g of Na or K salts of the essential fatty acids per day. In the case of orally or parenterally administrable compositions, the compositions are preferably administered at a daily or one-off dosage of the essential fatty salt of 1 to 100,000 mg, especially 1-50000 mg, preferably 100-10,000 mg, conveniently in dosage units of 50, 100, 250, 500 or 1,000 mg. For topical administration, concentrations of the essential fatty acid salts may conveniently be 0.001 to 50%, for example from 0.01 to 30%; preferably 0.1 to 5%, by weight.

In another preferred embodiment, the composition may take the form of a nutritional supplement.

Such nutritional suppplements, which most preferably are sterile, may be in a form adapted for enteral, parenteral or topical administration, but most preferably will be in a form adapted for oral ingestion. Liquid preparations made with sterile or deinonized water are particularly preferred. However, in another preferred embodiment the nutritional supplement may take the form of a dietary supplement, such as a foodstuff. The nutritional supplement may alternatively be in a conventional pharmaceutical dosage form adapted for administration to the gastrointestinal tract.

The present invention will now be illustrated further by the following non-limiting Examples in which all percentages, ratios and parts are by weight unless otherwise specified.

Examples 1 to 10 Nutritional solution supplements Nutritional solution supplements, for addition to parenteral or enteral nutrition solutions are prepared by dissolving the following materials in water for injections, optionally containing ethanol as up to 50% of the solvent. The solutions are optionally buffered to pH 8.5 to 9.0 and optionally further contain an antioxidant. The supplement solutions are sterile filled into dark glass ampoules which are flushed with and sealed under nitrogen.

Alternatively, similar amounts of the materials could be added to ready-prepared solutions for enteral nutrition or for parenteral nutrition, containing for example saline (0.9%), and glucose (5%).

Example No. 1 2 3 4 5 6 7 8 9 10 Sodium linoleate 500 200 250 250 150 300 500 300 300 Sodium gamma linolenate 100 100 100 200 100 100 Sodium dihomogamma- 100 100 -linolenate Sodium arachidonate 100 100 100 100 100 Sodium alphalinolenate 250 250 100 100 Sodium eicosapentaenoate 100 Sodium docosahexaenoate 100 Potassium linoleate 500 200 250 200 200 300 300 Potassium gamma linolenate 100 Potassium dihomogamma -linolenate 100 100 Potassium arachidonate 100 Potassium alphalinolenate 250 150 100 250 100 100 Potassium eicosapentaenoate 100 100 100 100 50 50 Potassium docosahexaenoate 100 100 100 100 50 50 Lithium linoleate 200 250 200 200 Lithium gamma inolenate 250 100 150 Lithium dihomogamma -linolenate 100 50 100 Lithium arachidonate 50 50 Lithium alphalinolenate 100 150 Lithium eicosapentaenoate 100 100 100 50 Lithium docosahexaenoate 100 100 100 50

Claims

CLAIMS: 1. A pharmaceutical composition comprising one or more sodium or potassium salts of a Cl822 polyunsaturated fatty acid having at least two unsaturated carbon-carbon bonds, together with at least one physiologically acceptable carrier or excipient material.
2. A composition as claimed in claim 1, further comprising one or more lithium salts of a C1822 polyunsaturated fatty acid having at least two unsaturated carbon-carbon bonds.
3. A composition as claimed in claim 1 or claim 2 adapted for oral administration and wherein said fatty acid salt is provided with a gastric juice resistant release delaying coating.
4. A composition as claimed in claim 1 or claim 2 in a form adapted for topical administration.
5. A composition as claimed in claim 1 or claim 2 in a form adapted for parenteral administration.
6. A composition as claimed in any one of claims 1 to 5 comprising said sodium or potassium salt in solution, suspension or emulsion in a physiologically acceptable sterile liquid.
7. A composition as claimed in claim 6 being an aqueous parenteral nutrition solution.
8. A composition as claimed in claim 6 being a aqueous solution adapted for addition to conventional parenteral and enteral nutritional compositions.
9. A composition as claimed in any one of claims 6 to 8 being a composition comprising at least one sodium or potassium salt of a n-3 C1822 polyunsaturated fatty acid and at least one sodium or potassium salt of a n-6 C1822 polyunsaturated fatty acid.
10. A composition as claimed in any one of claims 6 to 9 further comprising an antioxidant.
11. A composition as claimed in any one of claims 6 to 10 being a parenteral nutrition solution comprising in aqueous solution said sodium or potassium salt and at least one further nutritional component selected from vitamins, essential minerals and calorie sources.
12. A composition as claimed in any one of claims 1 to 6 in the form of a nutritional supplement.
13. A composition as claimed in anyone of claims 1 to 12 in the form of dosage units containing essential fatty acid salts sufficient to supply 0.1 to 10.0% of the total daily calorie consumption.
14. Use of a sodium and/or potassium salt of a C1822 polyunsaturated fatty acid for the manufacture of an enteral or parenteral alimentation solution.
15. Use of a sodium and/or potassium salt of a C1822 polyunsaturated fatty acid for the manufacture of a therapeutic agent for use in the treatment of essential fatty acid deficiency and/or conditions responsive to C1822 polyunsaturated fatty acid therapy.