MXPA00000793A - Therapeutic and dietary compositions containing essential fatty acids and bioactive disulphides - Google Patents

Abstract

Compositions of GLA and/or other EFAs with TA or related compounds, and their use in therapy or nutrition or in preparation of compositions for therapy or nutrition, especially to improve cell membrane EFA concentration and/or (particularly in diabetic complications) impaired nerve function and blood flow.

Description

THERAPEUTIC AND DIETETIC COMPOSITIONS CONTAINING ESSENTIAL FATTY ACIDS AND BIOACTIVE SULFURES FIELD OF THE INVENTION The invention relates to therapeutic and dietetic compositions.

Fatty acids Gamma-linolenic acid (GLA), its immediate metabolite dihomogama-linolenic acid (DGLA) and, in certain circumstances, the metabolite of DGLA arachidonic acid (AA), have wide ranges of desirable biological effects as essential nutrients and as nutrients or therapeutic agents with specific preventive or therapeutic effects in various diseases, including those of the skin (such as eczema and psoriasis), those of metabolism (in particular diabetes and its complications, such as retinopathy, neuropathy, nephropathy and cardiovascular problems), those of inflammation and autoimmunity (such as rheumatoid arthritis, osteoarthritis, Sjogren's syndrome, systemic lupus, Crohn's disease, ulcerative colitis), those of the respiratory system (including asthma, pulmonary hypertension and pulmonary fibrosis), those of the psyche and the nervous system central (such as schizophrenia, Alzheimer's dementia and vascular or other types of pressure) and multiple sclerosis), those of the cardiovascular system (such as hypertension and coronary and peripheral arterial disease), those of the kidney (such as glomerulonephritis and other conditions A) ^^^^^ Eteta ^ Jl ^ fe ^^^ j ^ l inflammatory and autoimmune), those of the gastrointestinal system (such as esophagitis, gastritis, peptic ulcer, Crohn's disease, ulcerative colitis) and those of the endocrine system and its two target organs (such as benign breast disease and benign prostatic disease). Cancer and other precancerous conditions can respond to treatment with GLA and DGLA. It has also been discovered that GLA and DGLA are beneficial in diseases of animals and also in the care of diseased and normal skin where they improve the blood flow of the skin and the smoothness of the skin. Other essential fatty acids, of the n-3 series, notably stearidonic acid (SA), icosapentaenoic acid (EPA), docosapentaneoic acid (DPA) and docosahexaenoic acid (DHA), also have many desirable nutritional and therapeutic effects, and many of the Previous patents filed by the present applicants refer to the use of any series, or both, of essential fatty acids under various conditions, EPA 0 218 460, relating to the complications of diabetes which are an example. Both series of essential fatty acids are well known per se and their terminology and relationships are discussed below. s3Mg & ^ Kag | «! JKÉ« TABLE 1 EFA n-6 EFA n-3 18: 2n-6 18: n-3 (Linoleic acid, LA) (a-linolenic acid, ALA) 4 delta-6-desaturase i 18: 3n-6 18: 4n-3 ( GLA (linoleic acid) (stearidonic acid) i elongation i 20: 3n -6 20: 4n-3 (dihomo-α-linolenic acid, DGLA) delta-5-desaturase i 20: 4n-6 20: 5n-3 ( Acid 10 (Arachidonic acid, AA) icosapentaenoic, EPA) and elongation i 22: 4n - 6 22: 5n-3 (Adrenal acid, AdrA) delta-4-desaturase i 22: 5n-6 22: 6n-3 (Docosahexaenoic acid , DHA) Acids, which by nature are of completely cis configuration, are designated systematically as derivatives of the corresponding octadecanoic, icosanoic or docosanoic acids, for example z, z-octadeca-9,12-dienoic acid or oz, z , z, z, z, z, -docosa-4,7,10,13,16,17,19-hexaenoic, but they are Suitable are the numerical designations based on the number of carbon atoms, the number of unsaturation centers and the number of carbon atoms at the end of the chain where the unsaturation begins, such as, correspondingly, 18: 2 n-6 or 22: 6 n-3. Initials are used, for example EPA and abbreviated forms of the name, for example icosapentaenoic acid, as trivial names, in some cases. In addition, acids are known informally beyond the 6-desaturation step, as "6-desaturated" acids.

Disulfides Completely different types of chemical entity are a-lipoic acid, also known as thioctic acid (TA), and related compounds. In the body, the TA is converted to dihydrolipoic acid (DHL) during the formation of acetyl-CoA from pyruvic acid or the formation of succinyl-CoA from 0 a-oxoglucárico acid and during other oxidation-reduction reactions. It can re-convert DHL to TA with lipoic acid dehydrogenase, which requires the NAD cofactor. The TA and the DHL have been seen as equivalents, since they interconvert quickly in the body. The structures are: CH2 - CH2 - CH - CH2 - CH2 - CH2 - CH2 - COOH 5 S s Thioctic acid or a-lipoic acid (TA) with R, S and racemic forms and 0 CH2 - CH2 - CH - CH2 - CH2 - CH2 - CH2 - COOH S- H H Dihydrolipoic acid (DHL) ^ .. ^^. ^^ .- also with R, S and racemic forms. In the context of this application, thioctic acid means pure isomeric D- or S-alpha-lipoic acid, racemic alpha-lipoic acid or any mixture of the R and S isomers, and correspondingly for compounds related to thioctic acid, including the forms reduced. 5 TA and related free disulfide compounds, which are strongly lipophilic, are antioxidant agents capable of forming an oxidation-reduction pair in the body and have been found, for example, to be of therapeutic value in the management of diabetes complications, especially of diabetic neuropathy. It is believed that such complications are associated with excessive regimes of oxidation of lipids and proteins and the pair of oxidation-reduction TA / DHL has been seen so significant in the neutralization of many species of free radicals. In addition, it can "re-circulate" other important antioxidants, such as -tocopherol and scurvy, and produce an increase in intracellular glutathione. In addition to diabetic complications, there is evidence that TA can improve insulin sensitivity, thus being of value in pre-diabetic X syndrome and in obesity. The metabolites of TA with function similar to that of TA are tetranorlipoic acid (TALA), snorlipoic acid (BALA) and 8-hydroxy-bisnorlipoic acid (8BALA) with R and S isomers as with lipoic acid. 20 The antioxidant properties and the consequent previously proposed clinical applications of α-lipoic acid and its reduced form in diabetes and other conditions are discussed in the Handbook of Antioxidants (eds E Cadanas and L Packer, Marcel Dekkar, New York 1996), see chapter 18 p.

^ - KJ- Ig ^^^^^^^^^^, ^^^^^^^^^^^^! ^^^^^^^^^^^^^^^^^^^^^ ^^^^! 545-591, by Packer Will and Tritschler. In addition, the prior PCT patent application of Applicants GB 96/01053 (WO 96/34846) discloses fatty acid / antioxidant 1,3-propanediol derivatives and their use and conditions in which antioxidants are beneficial including cardiovascular diseases, cancer and inflammatory disorders. Some particular diesters exposed are GLA or DHA and lipoic acid. Related compounds, formally hydroxymethane derivatives, are set forth in the additional PCT specification of Applicants GB 96/01052 (WO 96/34855). In these applications, however, it is emphasized that compounds containing portions of the fatty acid and lipoic acid are used. There is no reference to the co-administration of fatty acids and lipoic acid as separate molecules or for particular purposes. In the patent of E.U.A. 5,043,328 Hoechst, lipoic acid is mentioned as an antioxidant, although in a context of prostaglandin metabolism, in gastrointestinal problems and dysfunctions of the skin and subdermal tissue.

BRIEF DESCRIPTION OF THE INVENTION The therapies available in the treatment and prevention of most of the conditions mentioned up to now, including diabetes, insulin resistance, syndrome X and diabetic complications such as neuropathy and retinopathy, are far from satisfactory. It is considered that it would be worthwhile to test the use of the two different previous procedures simultaneously, in relation to diabetic complications. HE ljgfc aß »^^^« ¡¡¡¡¡títa believes that GLA works mainly in microcirculation, while it is believed that TA / DHL works mainly in the oxidation mechanisms, but it seemed reasonable to see if the co-application of these agents could have at least additive effects. Indeed, surprising and unexpected synergism was observed in medicine of nerve conduction velocity and blood flow in the nerves, with the effect that the agents applied together was much greater than the sum of the effects of the two agents when they applied themselves. The results are shown in Figures 1 and 2. In diabetic animals, both nerve conduction and blood flow in the nerves are greatly influenced. Both can be completely normalized with the co-administration of amounts of GLA and TA that alone have little effect. The EPA's results and the synergistic effects with TA were completely unexpected and it was decided to investigate them further. Vitamin E, like TA, is a lipophilic antioxidant and is one that is generally considered to be physiologically more important than TA. However, when vitamin E was administered together with GLA in animals with diabetes, there was no improvement at all in the effect of GLA. Likewise, it has been shown in several clinical studies that the effects of GLA are not improved in conditions such as atopic eczema, chest pain, rheumatoid arthritis and cardiovascular disease, with the co-administration of vitamin E. There was therefore no reason at all to suspect the surprising increase in power that has been observed, which is not thought to be explained by the antioxidant effect. ^ mt? & a8, ^ In an effort to further examine the effect, terminal experiments in rats have been conducted on the effects of either GLA, EPA or DHA administration with or without vitamin E antioxidants, vitamin C or TA. Each fatty acid was added to the food at 0.1% by weight over a period of 2 5 weeks. The diet did not contain any other added material (control) or 0.1% by weight in vitamin E, vitamin C or TA. After two weeks, the animals were sacrificed and the levels of the fatty acids or their immediate metabolites were determined, in plasma phospholipids and in phospholipids of red cell membranes. Neither vitamin E nor vitamin C had effects on the levels in the fatty acids neither in the plasma nor the red cells. It can be understood therefore that there is no effect of the antioxidants per se on the metabolism of GLA, EPA or DHA in this situation. Likewise, there were no effects of TA on the plasma phospholipid fatty acid composition. In contrast, concentrations of the acids increased in each of the groups relevant fatty acids in the phospholipids of red cells, in 10-20%. This shows that TA has an effect hitherto unknown unsuspected in the incorporation of EFAs to cell membranes. This effect does not seem to be related to antioxidant activity. What is being demonstrated is that TA can improve the incorporation of EFAs into regular membrane phospholipids. This will have effects on membrane structure and the availability of EFAs for cell signaling systems and is likely to explain the energetic effects that have been observed on nerve function and blood flow in cells. «^,., .. ^« ite ^^ ^^. ^ I ^ .. nerves in diabetic animals. The effect is not general that is applicable to all EFAs and not only to GLA. The invention relates generally to GLA and / or other EFAs, to TA or related compounds, and to their use in therapy or nutrition or the preparation of compositions for therapy or nutrition. The conditions involved are set forth herein, but the invention is especially concerned with improving the concentration of EFA in the cell membrane and / or, particularly in diabetic communications, nerve function will deteriorate (e.g., condition velocity of the motor nerves) and flow blood Deteriorated blood flow can also be important in other diseases, especially heart disorders and peripheral circulation. The incorporation of deteriorated EPA into the membranes can be a major problem, under most of the listed conditions.

DETAILED DESCRIPTION OF THE INVENTION In particular, the invention provides: 1. Use in the preparation of a medicament for treatment to improve or maintain the concentration of EFA and cell membranes, with health or any of the conditions set forth herein, or use in such treatment itself, of an essential fatty acid, particularly one beyond the 6-desaturation step in the n-6 and n-3 metabolic pathways, and a bioactive disulfide, particularly TA or a related compound, including the use of a It is an active ingredient wherein, for co-administration with the other and each active ingredient, it is present as such or as a derivative that releases the active ingredient in the drug. 2. Use in the preparation of a medicament for therapy (including prophylaxis of impaired nerve fusion, for example conduction velocity in the motor nerves) or blood flow in any of the conditions set forth herein, but particularly in the neuropathy, retinopathy, diabetic neuropathy or other complications of diabetes, or the use of such therapy itself, of an essential fatty acid, particularly one beyond the passage of 6-desaturation in the metabolic pathways n-6 and n-3, and a biocompatible disulfide, particularly TA or a related compound, including the use of an active ingredient wherein, for co-administration with the other and each active ingredient, is present as such or as a derivative It releases the active ingredient in the body. 3. Use as above, comprising the active ingredients at least one of GLA, DGLA and AA, and / or SA EPA, DPA and DHA. 4. Use as above, the active ingredients comprising one or more of TA, TALA, BALA or 8-BALA, as such or in their respective reduced form. 5. Use as above, the active ingredients also comprising one or more other essential nutrients, particularly vitamins A, D and E; the B group vitamins such as riboflovin, pyridozidine, niacin or niacinamide; phonic acid; vitamin C; or zinc, chromium, magnesium or selenium assimilate. 6. Use as above, with fatty acid and disulfide being introduced for its administration from 1 mg to 100 g / day of each, preferably from 10 mg to 10 g / day, most preferably from 50 mg to 5 g / day, and in a weight ratio of from 1: 20 to 20: 1, more preferably from 1: 5 to 5: 1, most preferably from 1: 3 to 3: 1. 7. Use as above, in the context of the treatment regimen or the prevention of any of the conditions to which reference is made herein and in particular, but without restriction, in: a) diabetes and its complications, particularly diabetic retinopathy, all forms of insulin resistance and syndrome X, related conditions, such as obesity, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, macrovascular and diabetic peripheral arterial coronary disease, diabetic leg ulcers and diabetic impotence. b) disorders in which the blood flow reduced to any tissue is considerable, particularly insulin resistance, type II diabetes and peripheral coronary or cerebral vascular disease of any etiology. c) any inflammatory disorder, particularly rheumatoid arthritis, osteoarthritis and asthma. d) any psychiatric or central nervous system disorder, particularly schizophrenia, depression, ischemic dementias, Alzheimer's disease, other dementias, multiple scleroids, and attention deficit hyperactivity disorder. e) eczema and psoriasis. f) any respiratory disorder, particularly asthma, pulmonary hypertension and pulmonary fibrosis. g) any cardiovascular disorder, particularly hypertension, coronary or peripheral arterial disease or thrombotic disorder. h) Crohn's disease or ulcerative colitis. i) any endocrine disorder, particularly benign breast and prosthetic diseases. j) Any form of cancer or precancerous condition, including cachexia associated with cancer. k) Improvement of athletic performance, for example, by increasing blood flow in the muscles and the use of energy in humans or animals. As indicated above, the most effective EFAs are the 6-desaturated EFAs, particularly GLA AA, DGLA, SA, EPA, DPA or DHA, particularly in a dose range of 1 mg to 100 g, preferably 10 mg to 10 g most preferably from 50 mg to 5 g per day. Disulfides, such as TA, BALA, TAL and 8BALa or their reduced forms, can be used in similar dose ranges. The weight ratio of the EFA to the disulfide may be, for example, from 1: 20 to 20: 1, but is preferably from 1: 5 to 5: 1, more preferably from 1: 3 to 3: 1. Additionally, each of the EFAs and the disulfide can be used in any suitable combined chemical form that is pharmacologically acceptable and capable of raising the concentration of the EFA or the disulfide-related compound in the blood or other body tissues. Such prodrugs may include triglycerides, phospholipids, other glycerides, propanediol derivatives, germline diols and others known to those skilled in the art. Even EFA and disulfide can be combined in the same molecule, whose function is then to act as a prodrug for both EFA and disulfide. Some examples are 1,3-propanediol derivatives which are produced as set out in the PCT application GB 96/01053 (WO 96/34836) and germ-diol derivatives which are produced as set out in the PCT application GB 96 / 01052 (WO 96/34855). 10 The active ingredients can be presented together or separately, setting the instructions how they should be administered. When presented in a separate dosage form, the two can be supplied together in packages. They can be presented, for example, by the oral, enteric, parenteral, topical, rectal or vaginal routes, using formulations known to those skilled in the art. technique. Active ingredients can also be provided in nutritional supplements, medical foods, functional foods, concentrated nutrients or ordinary foods along with other essential nutrients, including minerals and vitamins such as vitamins A, B and E; Group B vitamins such as riboflavin, pyridoxine, niacin and nicotinamide; folic acid; vitamin C; or zinc, chromium, magnesium or selenium assimilated. Such nutrients can be provided in any suitable bioassimilable chemical form.

Experimental Initial experimental evidence was obtained by studying rats made diabetic by the administration of streptozotocin. In such animals, complications developed similar to human complications of diabetes 5 and are characterized by reduction in conduction velocity of impulses along the sciatic nerve and reduction in blood flow to the sciatic nerve. Reduced blood flow is particularly important and is likely to be many diabetes complications relevant, including retinopathy, nephropathy, macrovascular arterial heart disease and 10 peripheral arteries, impotence and altered legs. It may also be relevant to many of the other conditions in which essential fatty acids are useful treatments, including inflammatory disorders. Five groups of animals were tested and given streptozotocin (STZ). They were accepted in the study, only if they developed unequivocal elevation of blood glucose after STZ. Ten animals acted as normal controls. Ten animals were diabetic, but they were not treated. Eight animals were treated with TA only, 11 with GLA alone and 11 with TA and GLA combined. GLA was added to the feed to give an approximate dose of 20 mg / kg / day and TA was given by daily intraperitoneal injection at a dose of 20 mg / kg / day. Since fats are metabolized in relation to the surface area and since the surface area / volume ratio is much higher in a small animal than in a large one, these doses are very approximately equivalent to a dose of about 2-3 mg / kg / day in an adult human being. The animals were diabetic by injection of 45 mg / kg / STZ intraperitoneally. The rats were males of the Spregue Dawley strain and were 5 of 19 weeks of age at the time of the STZ injection. The animals were allowed to develop nervous deterioration for 6 weeks after the STZ and were then given treatment with either nothing or with GLA or TA, or both together, for 2 weeks. At the end of the 2 weeks, the animals were anesthetized and the conduction velocity in the motor nerves was measured in the perineal branch of the sciatic nerve. The blood flow in the sciatic nerve was also measured by hydrogen dissipation with microelectrode polarography. The figures were plotted for the conduction velocity in the motor nerves and the total blood flow in the nerves. Both GLA and TA alone produced only slight improvements of the conduction velocity in nerve 15 and blood flow to the nerves, but the improvements at these doses were far from restoration of normality. The estimated additive effects of the two compounds added together were also far from being normal restoring. However, and in contrast to an expected additive effect, the two compounds together effectively normalized both the conduction velocity in the nerves and the blood flow in the nerves. Based on previous studies of dose / response of GLA alone or ALA alone, the presence of GLA or TA seemed to amplify the effect of the other compound around 10 times. Contrast with the absence of the effect on driving in • HfíJMfTt - ** - ** - iillÉMii I l, IHII, IIÉIH | lÜMÍttÍBll I liailÍM I llílffilíl lillill nerves with only TA to which referred to in Packer et al (loc cit, pp 570-572...) . The foregoing illustrates the invention in terms of treatment, since the actual morbid conditions can be attacked with the administration of the compounds. In terms of the drugs and their preparation, the invention is illustrated in the following examples: EXAMPLES The following are examples of effective compositions in relation to the complications of diabetes, and other purposes, discussed. 1.- Soft or hard gelatin capsules, each containing 100 mg of TA, TALA, BALA or 8-BALA, as such or in their respective reduced form, having to use 100 mg of GLA, DGLA, AA, SA, EPA, DPA or DHA, in a dose of 1 to 4 capsules per day. 2. Capsules as in 1, but in which the daily dose of the active ingredients varies from 0 mg to 200 mg for the compound related to thioctic acid and from 20 mg to 200 mg for the fatty acid. 3. Capsules as in 1 or 2, but in which the fatty acid is provided as a derivative, namely an ethyl or other ester; a mono-, di- or triglyceride; a phospholipid; an amine or any other derivative that originates the biologically active fatty acid in the body. 4. - Capsules as in 1 or "8 ?, which contain a diester by an acid of a fatty acid selected from GLA, DGLA, AA, SA, EPA, DPA and DHA, and a residue of thioctic acid or one of the related compounds TALA , BALA or 8-BALA, as such or in their respective reduced form, the diester being 1-3, 5-propanediol prepared as described in Example 5 or 17 of WO 96/34846 or dihydroxymethane prepared as described in US Pat. example 4 of document 96/34855, reference to which specifications can be made 5.- Tablets or capsules each containing 50, 100 or 200 mg of TA, TALA, BALA or 8-BALA, as such or in their respective reduced form, 10 presented in the same package, for example in blister pack, as soft or hard gelatin capsules, each containing 50 mg, 100 mg or 200 mg of LA, DGLA, AA, SA, EPA, DPA or DHA , taken each dosage form with a dose of 1-4 units / day 6.- A nutritional supplement for use in humans hands or animals with diabetes or any other disease, which provides in each capsule 50 mg of TA, 100 mg of GLA or DGLA, 100 mg of DHA, 50 mg of ascorbic acid, the recommended daily allowance of the vitamins of group B and 300 mg of chromium like picolinate. 1. A functional food for use by people with diabetes or any other disease, which in addition to essential calories and nutrients provides in each serving 100 mg of GLA and 100 mg of TA, optionally also DGLA, AA, SA, EPA, DPA or DHA. 8. - A cosmetic or skin care preparation for eczema or psoriasis, in which 0.1% to 2.0% of TA and 0.1% to 10.0% of GLA or DGLA are incorporated into the emollient base. 9.- A food or drink for use by athletes or people in gymnastic training for any reason, including rehabilitation after an injury, heart disease or fulminating attack, which in each portion provides 50-200 mg of TA and 50-200 mg of GLA or DGLA, optionally with other essential nutrients and fatty acids. 10.- A food, drink or supplement for use by 10 horses or dogs, which provides 1-50 mg / kg / day of TA together with 1-50 mg / kg / day of GLA or DGLA, optionally with other essential nutrients and fatty acids. t-iil yfv & t. < _i, * * * * á "Yes-! ¿, ^^ t ^ Ma M¡a ^^ A. ^) - ^ 5feMfeJ¿afeMit - - '' t? g»? 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Claims (5)

NOVELTY PE THE INVENTION CLAIMS

1. - The use of an essential fatty acid, particularly one beyond the 6-desaturation step in metabolic pathways n-6 and n-3, in combination with a biocompatible disulfide, particularly TA or a related compound, for the preparation of a medicament, for the treatment or prevention of diabetes, insulin resistance or complications of diabetes, wherein each active ingredient is present as such or as a derivative that releases the active ingredient in the body.

2. The use according to claim 1, wherein the active ingredients comprise one or more of GLA, DGLA and AA, and / or SA, EPA, DPA and DHA.

3. The use according to claim 1 or 2, wherein the active ingredients comprise one or more of TA, TALA, BALA or 8-BALA, as such or in their respective reduced form.

4. The use according to claim 1, 2 or 3, wherein the active ingredients further comprise one or more other essential nutrients, particularly vitamin A; vitamin D; Vitamin E; Group B vitamin, particularly riboflavin, pyroxine, niacin or niacinamide; folic acid; vitamin C; or zinc, chromium, magnesium or selenium assimilated. ^ a ^^^ t? t ^ a

5. - The use according to claims 1, 2, 3 or 4, wherein said medicament comprising the fatty acid and the disulfide provides from 1 mg to 100 g / day of each to the body, particularly from 10 mg to 10 g / day, more particularly from 50 mg to 5 g / day and in a weight ratio of 1: 20 to 20: 1, particularly from 1: 5 to 5: 1, more particularly from 1: 3 to 3: 1.