GB2504061A - Omega-6 Enriched PUFA Phospholipids - Google Patents

Abstract

Pharmaceutical formulations comprise dihomo gamma linolenic acid (DGLA) or any appropriate metabolite or derivative e.g. 15-hydroxy-DGLA and krill oil (KO). They may be used for the treatment of a wide range of diseases and disorders. They may also be taken as a general nutritional supplement.

Description

Omega-6 Enriched Pufa Phospholipids The present invention provides pharmaceutical formulations containing dihomo gamma linolenic acid or any appropriate metabolite or derivative (hereinafter collectively referred to as DGLA) and krill oil (1(0).

DGLA may be replaced by one or more of its metabolites, for example iS-hydroxy DGLA, also known as 15-HETrE, or their derivatives. The ratio of 1(0 to DGLA is preferably between 1:1 and 20:1, and more preferably between 1:1 and 8:1.

The DGLA is preferably provided in a dose of between 100mg and 10,000 mg/day. The formulation may be a single preparation comprising i00-io,ooo mg DGLA. An alternative upper limit is 2,500mg OGLA.

Preferably, the formulations of the invention comprise 1-4 g 1(0 and 0.1-2.0 g DGLA. Still preferred amounts are 1.5-3 g 1(0 and 0.2-1 g DGLA.

The formulation may be a single daily dose preparation to give in one dose the above intakes, or maybe in convenient divided doses, for example, a daily dose formed of four soft gelatin or other capsules, each containing 500mg of 1(0 in an appropriate form and 150mg of DGLA in an appropriate form.

The compositions of the first aspect of the present invention are prepared by combining DGLA in biologically assimilable form in which the DGIA is at least 50% pure, preferably at least 90% pure, and krill oil (1(0) in any biologically assimilable form. Biologically assimilable forms of DGLA include the free acid, esters and other derivatives discussed herein. As used herein "DGLA" covers any such biologically assimilable form.

The DGIA may be produced synthetically from highly pure GLA. The starting materials must include one containing substantial amounts of the GLA, the precursor of DGLA. DGLA may be derived by elongating GLA by methods known in the art. Repurification separates out the DGLA.

iS-HETrE may be used in place of the OGLA, obtained from DGLA as discussed herein. Biologically assimilable forms of 15-HETrE include the free acid, esters and other derivatives discussed herein. As used herein "15-HETrE" covers any such biologically assimilable form.

Still preferably, the active ingredient of the formulations of the present invention consists essentially wholly of the KO and OGLA or OGLA metabolfte. In that case, less than 1% of any other omega-6 EFAs are present besides OGLA.

Flavourants or ernulsifiers 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 DGLA 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 DGLA into body tissues. Phospholipids containing DGLA maybe used in the present formulations when combined with KO, which is rich in phospholipids containing omega-3 fatty acids.

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 Alzheirner'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, including disease of the mouth and teeth, of the eyes or of the ears; infection with viruses, bacteria, fungi, protozoa or other organisms.

They may also be taken as a general nutritional supplement.

The present invention further provides a method of treatment or prevention of any of the aforesaid diseases or conditions, in particular cardiovascular disease, dyslipidemia and inflammatory diseases.

The treatment or preventative method is, for example, by the combined application of OGLA and <0 at the dosage regime of between 100mg and 10,000 mg/day DGLA and a ratio of KO to OGLA of between 1:1 and 20:1. A metabolite of DGLA, such as iS-HETrE, may be used instead of DGLA. The preferred range of KO to DGLA (or its metabolite) is between 1:1 and 8:1.

The present invention still further provides a method of treatment or prevention of any disease selected from: 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; any form of dyslipidaemia, any form of diabetes or any form of metabolic diseases; any form of derrnatological diseases; any form of kidney or urinary tract disease; any form of liver disease; any form of disease of the male or female reproductive system or related secondary sexual organs such as the breast or prostate gland; any form of cancer or for cancer cachexia; any disease of the head and neck including diseases of the mouth and teeth, of the eyes or of the ears; and any form of infection with viruses, bacteria, fungi, protozoa or other organisms by, for example, the combined application of KO and DGLA at the dosage regime of between 100mg and 10,000 mg/day KG and a ratio of KO to DCLA of between 1:1 and 20:1. A metabolite of OGLA may be used in place of DGL.A. The most preferred range of KO to OGLA (or a metabolite) is between 1:1 and 8:1.

Use of the formulations of the invention in the manufacture of a medicament for the treatment or prevention of any disease or disorder, including those mentioned above, is included in the present invention.

The specific therapeutic compositions proposed are ones which provide not less than 100mg and not more than 10,000 mg of KO/day combined with DGLA (or metabolite) in doses of between 100mg and 10,000 mg/day. An alternative upper limit is 5,000 mg/day of the combined composition. Particularly preferred amounts are 1-4 g per day KO combined with 0.1-2.0 g per day of DGLA (or metabolite). A still preferred composition comprises 1.5-3 g KO and 0,2-1 g OGLA (or metabolite), The present invention further provides a formulation, for example) in a one-a-day dose comprising 1.5-3 g <0 and 0.1-2.0 g DGLA or one of its metabolites. The DGLA or nietabolite and KO can be co-formulated as a single dosage unit or can be formulated as two to a plurality of dosage units for coordinated, combination or concomitant administration.

The ratio of KO to the omega-6 fatty acid is important because the high bioavailability of KO is likely to lead to the loss of DGLA from membranes. The loss of DGLA from cell membranes can lead to a diminution of beneficial metabolites such as the anti-inflammatory 15-HETrE and vasorelaxive prostaglandin This could be prevented by alternately using rnetabolites of DGLA in combination with Kb. The ratio of KG to DGLA should preferably be in the range between 20:1 and 1:1, and should still preferably be in the range of between 8:1 and 1:1, These combinations will ensure that the beneficial effects of KO are enhanced and maintained even at relatively high KO doses, because the provision of DGLA and its precursors will prevent UGLA depletion which may occur when too much KO is given alone.

During absorption from the gut and within the body, DGLA moieties are readily transformed intact from one chemical form to another. Simple esters such as ethyl or methyl esters are readily split by esterases and the freed fatty acids can then be bound by albumin or other binding or transport proteins or incorporated into complex lipids such as phospholipids, cholesterol ester or glycerides. The fatty acids in the present formulations can therefore be administered in any form such as glycerides, esters, free acids, salts, phospholipids amides or any other form which leads to their incorporation into the blood and cell membranes, Krill oil can be extracted from Antarctic krill such as Euphausia superb, a zooplankton crustacean rich in phospholipids carrying long-chain omega-3 PUFAs, mainly EPA and DHA. Krill oil also contains various potent antioxidants, including vitamins A and F, astaxanthin, and a novel flavonoid similar to 6,8-di-c-glucosylluteolin, but with two or more glucose molecules and one aglycone. Krill oil has a unique biomolecular profile of phospholipids naturally rich in omega-3 fatty acids and diverse antioxidants significantly different from the usual profile of fish oils. The association between phospholipids and long-chain omega-3 fatty acids highly facilitates the passage of fatty acid molecules through the intestinal wall, increasing bioavailability. Frequently though, high exposure to EPA can drive down levels of beneficial omega-S fatty acids such as DGLA and consequently its active metabolites.

The OGLA may be synthesized from gamma linolenic acid (GLA) derived from any appropriate source including plant seed oils and microbial oils from algae or fungi. DGLA is also available as a derivative of microbial and fungal oil. They may be used in the form of the natural oil, if that oil meets the required purity requirements of the starting material, or may be purified to give products containing 30%, 40%, 50%, 60%, 70%, 80%, 90% or more of the fatty acid. Particularly useful forms of OGLA include highly purified ethyl esters or highly pure free fatty acids. Synthetic routes to the fatty acids are known by one skilled in the art by starting with gamma linolenic acid, elongating the GLA (18:3n-6) by 2 carbons and optionally exposing DGIA (20:3 n-6) to lipoxygenase to yield iS-HETrE, Once the oils containing the individual fatty acids have been obtained, and purified as necessary, the starting materials may be blended to give the desirable ratios of KO to DGLA or a metabolite described above.

The blended fatty acid compositions may then be incorporated into any appropriate dosage form for oral, enteral, parenteral, rectal, vaginal, dermal or other route of administration. Soft or hard gelatin capsules, flavoured oil blends, emulsifiers or other liquid forms, and microencapsulate powders or other dry form vehicles are all appropriate ways of administering the products.

Example Formulations: (a) Soft or hard gelatin capsules each containing 500mg or 1000mg of a mix of 10 parts KO to? parts of DGLA ethyl ester; (b) As in (a) but where the DGLA ethyl esters are replaced with the fatty acids in any other appropriate bloassimilable form such as the free acid, tn-, di-or monoglyceride, other esters, salts such as the sodium, potassium or lithium salts, amides, phospholipids or any other appropriate derivatives; (c) As in (a) or (b) but where the DGLA or its metabolite is 50%, 60%, 70%, 80% 90% or >90% pure in combination with 1<0; (d) As in (a)-(c) but where the ratio of 1<0 to DGLA is anywhere in the range from 1:1 to 20:1; (e) As in (a)-(d) but where the material is in the form of a microencapsulated powder which can be used as a powder or compressed into tablets. Such powders may be prepared by a variety of technologies known to those skilled in the art; (f) As in (a)-(d) but where the formulation is a liquid or emulsion, appropriately flavoured for palatable oral administration; (g) As in (a)-(d) but where the material is formulated in to material appropriate for topical application such as a cream or ointment; (h) As in (a)-(g) but where the DGLA is replaced by one of metabolites such as 15-HETrE.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. the metabolic pathways of the two series of essential fatty acids.

Claims (4)

1. Claims 1. A pharmaceutical formulation comprising: i) dihomo gamma linolenic acid (DGLA) or any appropriate metabolite or derivative; and ii) krill oil (KO).
2. 2. A pharmaceutical formulation according to claim 1, wherein the DGLA metabolite is 15-hydroxy DGLA, or its derivative.
3. 3. A pharmaceutical formulation according to any preceding claim) wherein the ratio of krill oil to DGLA is between 1:1 and 20:1, preferably between 1:1 and 8:1.
4. 4. A pharmaceutical formulation according to claim 1, wherein the DGLA is at least 50% pure, preferably at least 90% pure. C')LU (0 r