EP1581240A1

EP1581240A1 - Cholesterol-reducing agent containing an n-3 fatty acid

Info

Publication number: EP1581240A1
Application number: EP03789380A
Authority: EP
Inventors: Bernd Haber; Stephan Hausmanns; Matthias RÜSING
Original assignee: Nutrinova Nutrition Specialties and Food Ingredients GmbH
Current assignee: Lonza AG
Priority date: 2002-12-24
Filing date: 2003-12-22
Publication date: 2005-10-05
Also published as: JP2006514040A; US20070166413A1; DE10261067A1; WO2004058281A1; AU2003293967A1

Abstract

The invention relates to a cholesterol-reducing active substance combination containing at least one cholesterol-reducing carob product, particularly water-insoluble carob fibers, at least one n-3 fatty acid and at least one cholesterol-reducing active substance. The invention also relates to a method for producing active substance combinations of this type and to the use thereof.

Description

Cholesterol-lowering agent containing an n-3 fatty acid

The invention relates to an active ingredient combination for lowering the cholesterol level, comprising at least one cholesterol-lowering carob product, in particular carob fiber, at least one n-3 fatty acid and at least one cholesterol-lowering active ingredient. The invention further relates to a process for the preparation of such combinations of active substances and their use.

In the context of an unbalanced diet, an excessive content of blood lipid values, in particular of blood cholesterol values, is evident in broad sections of the population. A cholesterol level above 200 mg / dl, especially LDL cholesterol levels above 130 mg / dl, is considered to be one of the main risk factors for cardiovascular diseases. Therefore, therapeutic treatment is urgently required in the event of significantly increased cholesterol levels, in particular LDL cholesterol, and increased blood lipid levels. Various approaches to this have been described so far. In addition to the mostly poorly effective change in lifestyle and diet, a number of special active ingredients have been developed that intervene in different ways in the absorption and metabolism of cholesterol. These include pharmacologically active substances such as statins (see, for example, US Pat. No. 4,231,938; US Pat. No. 4,444,784; US Pat. No. 4,346,227), inhibitors of bile acid absorption (see, for example, US Pat. No. 5,998,400; US -A-6,277,831; US-A-6,221, 897) or bile acid sequestrants (see for example US-A-4,027,009). All of these active ingredients must be taken under medical prescription and control.

The active ingredients can also include cholesterol-lowering agents isolated from plant sources. The cholesterol-lowering effect of a group of plant sterols, in particular phytosterols, phytostanols and the esters of the classes of compounds mentioned (cf. WO-A-96/38047, WO-A-99/56558, US-A-6,087,353) should be mentioned here in particular. However, the latter in particular are not suitable for consumption for all population groups (e.g. exclusion for pregnant women or small children) and are often restricted in their use. Other natural cholesterol-lowering agents also include extracts from other plant sources, such as. B. Artichoke extracts, tocotrienol-rich extracts, garlic or guglipid extracts.

In contrast, there are food components that have repeatedly shown that if they are ingested sufficiently, they can significantly reduce the risk of cardiovascular diseases, especially by lowering high cholesterol levels. It is well known that a high fiber diet is associated with a lower risk of cardiovascular disease compared to a low fiber diet. In addition to wholegrain cereals (wheat, oats, barley, rye, but also cereal bran such as oat bran, rice bran, wheat bran, soy bran, etc.), which is generally high in fiber, other fibers can also contribute to reducing cardiovascular risk and increasing cholesterol levels. So show a number of water-soluble fiber such. B. ß-glucan (from oats or barley), psyllium, pectin or guar gum have a lowering effect on blood cholesterol (Brown et al. 1999; Am. J. Clin. Nutr. 69: 30-42).

Water-insoluble carob fibers are also known as food components, for example those produced by a process according to EP-A-0616780, which can significantly lower serum cholesterol values, in particular LDL cholesterol (Zunft et al. 2001, Adv. In Ther. 18: 230 -36). The HDL value remains constant, so that the important LDL / HDL ratio shifts to "good cholesterol" and thus the risk of arteriosclerosis decreases. The clear effect of this insoluble, non-viscous preparation was all the more surprising since such cholesterol reductions generally only occur with viscous, soluble fiber.

Other food components that can significantly reduce the risk of cardiovascular diseases include n-3 fatty acids. It is known that the supply of n-3 fatty acids is poor in most industrialized nations. In contrast, the total fat content in the diet and the intake of saturated fatty acids and n-6 fatty acids are too high. This is due to a change in the composition of our food, which has mainly taken place in the past approx. 150 years and which varies with the appearance whose chronic (civilization) diseases, especially cardiovascular diseases - the main cause of death in industrialized nations - is correlated. A large number of studies have meanwhile shown that by specifically increasing the intake of n-3 fatty acids, in particular AII-cis-5,8,11, 14,17-eicosapentaenoic acid (EPA) and Allcis-4,7, 10,13,16,19-docosahexaenoic acid (DHA), the cardiovascular risk can be significantly reduced [GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'lnfarto miocardico), Dietary supplementation with n-3 polyunsaturated fatty acids and Vitamin E after myocardial infarction: results of the GISSI-pevenzione trial. Lancet. 1999; 354: 447-455; Burr et al. Effects of changes in fat, fish, and fiber intake on death and myocardial reinfarction: diet and reinfarction trial (DART), The Lancet, 1989, 757-761]. Accordingly, many different organizations (WHO, FAO, AHA, ISSFAL, British Nutrition Foundation and many others) recommend significantly increasing the intake of n-3 fatty acids. Depending on the recommendation, there is a supply gap of at least 0.5 to 1.5 g of n-3 fatty acids. Most of the recommendations refer to the intake of n-3 fatty acids (especially DHA and EPA) through the regular consumption (at least twice a week) of fatty sea fish. The positive effects of reducing cardiovascular risk from n-3 fatty acids are often not clear in detail, but are mainly associated with positive effects on some of the main risk factors for cardiovascular diseases such as arteriosclerosis, hypertension, plasma triglyceride levels, arrhythmias and heart rate variability. Interestingly, the n-3 fatty acids appear to have little or no impact on another of the main risk factors, cholesterol levels. At most, a slight shift in the LDL / HDL ratio to "good cholesterol" is discussed (Gylling and Miettinen, Curr Control Trials Cardiovasc Med 2001, 123-128).

The achievable effects for all these food components are, however, significantly lower than those that can be achieved with therapeutic agents, and thus far lower than desirable. Even if a diet enriched with fiber, in particular with carob fiber, can help to control cholesterol levels and blood lipid levels, it is in many cases, especially in very high cholesterol levels (total cholesterol> 300 mg / dl), not sufficient for sustained lowering. Likewise, a diet enriched with n-3 fatty acids, especially with all-cis-9,12,15-octadecatrienoic acid (ALA), EPA and DHA, can make a valuable contribution to the general reduction of cardiovascular risk and improvement of general health, but in In many cases, especially when there is an increased risk of cardiovascular disease (e.g. after a heart attack), this alone is not sufficient.

A cholesterol-lowering interaction between carob products, n-3 fatty acids and cholesterol-lowering active substances is not known. However, there are indications that viscous fibers such as pectin with n-3 fatty acids can have a synergistic effect in lowering cholesterol (V. Bartz 2002, Nutrition & Medicine 17, 149-150). Since carob products, especially carob fiber, are not viscous, a cholesterol-lowering interaction is not obvious, and certainly not a synergistic one. For example, even an antagonistic effect of the water-insoluble fibers of the carob pulp with the viscous fiber locust bean gum has been described (Peres-Olleros et al. 1999; J. Sei. Food Agric. 79, 173-178). Also showed e.g. B. an additional daily administration of 56 g of oat bran to therapy with nicotinic acid does not further lower the LDL cholesterol (Keenan J.M. et al .: J. Farn. Pract. 34 (1992), 313-319).

The purely pharmacological cholesterol lowerers have the disadvantage that in order to achieve the therapy goals, in some cases considerable concentrations have to be used. Undesirable, sometimes life-threatening side effects can occur, even in combination with other therapeutic agents. Combination therapies to increase the effectiveness with various cholesterol-lowering agents or other therapeutic agents such as B. for cardiovascular diseases are not always usable due to various dangerous contraindications. So show z. B. combinations of fibrates with statins an increased risk of myopathy syndromes, which could even be fatal in the case of combinations of cerivastatin with gemfibrozil. In addition, saturation effects are known which have the effect that only slight additional reductions in the cholesterol level are achieved with an increased absorption of the active substance. Another disadvantage is the high cost of long-term therapy with the mostly very expensive pharmacological cholesterol-lowering agents.

There are quantity limits for the cholesterol-lowering agents (e.g. phytosterols) isolated from plant sources in order to avoid undesirable side effects.

There is therefore still a need for cholesterol-lowering agents which, with the same or even improved efficacy, reduce the amounts administered of the respective active ingredient and thus reduce the side effects and costs which may be present, in particular of long-term therapies.

This object is achieved by providing an active ingredient combination for lowering the cholesterol level, containing at least one carob product, in particular carob fiber, with a high content of fiber, at least one n-3 fatty acid, and at least one cholesterol-lowering active ingredient. When the active compound combination according to the invention is applied, in addition to the previously described effect of lowering total cholesterol, the ratio of HDL and LDL to the "good" HDL cholesterol shifts.

Furthermore, this synergistic reduction of the cholesterol level by the active ingredient combination according to the invention is advantageously supplemented by the known positive influence of n-3 fatty acids on the cardiovascular system (see above).

Regardless of the positive effects on cardiovascular health already described, an additional positive effect on health is achieved by the dietetic foods according to the invention by means of an increased supply of n-3 fatty acids. The DHA which is preferably used according to the invention plays a special role here. Furthermore, the active ingredient combination according to the invention can be processed. Balance the body's intake of essential n-3 fatty acids, which experience has shown after fiber administration and in particular as an undesirable side reaction when medication is used to treat high cholesterol levels with statins.

Therapy with the active ingredient combination according to the invention thus has a beneficial effect on health beyond the actual cardiovascular health.

Locust bean products in the sense of the invention are the locust bean fruit itself and components obtained therefrom. For the purposes of the invention, locust bean fibers, which have a high total fiber content, determined according to AOAC method 985.29, of at least 30% by weight, preferably at least 60% by weight, particularly preferably at least 80% by weight, are preferably used. in relation to the dry matter). Their water-insoluble fiber content, determined according to AOAC method 991.42, is at least 25% by weight, preferably at least 50% by weight, particularly preferably at least 70% by weight.

For the production of the carob fiber product, it is particularly necessary to separate the water-soluble carob components from the pulp freed from the carob seeds and to heat them for (partial) denaturation of the condensed tannins. Other process steps include washing and separating steps, drying, grinding and, if necessary, screening. Fiber lengths of <250 μm, preferably <150 μm, in particular <100 μm, are obtained. The methods according to EP-A-0 616 780 and according to the unpublished PCT / EP03 / 08636 are particularly preferred. The preparations obtained in this way have a pronounced hypocholesterolemic and moderate triglyceride-lowering effect and can be used to fortify foods.

N-3 fatty acids (omega-3 fatty acid, ω-3 fatty acids) in the sense of the invention include polyunsaturated long-chain fatty acids (polyunsaturated fatty acids, PUFAs) with a chain length> C1 with at least two double bonds understood, wherein the first of the at least two or more double bonds, starting from the alkyl end, is constituted between the carbon atoms C3 and C4 (see Table 1). The n-3 fatty acids can be present as free fatty acids, esters, triglycerides, phospholipids, glycolipids, sphingolipids, waxes or sterol esters or by chemical or biocatalytic transesterification of the triglycerides, for. B. with the help of suitable enzymes (lipases) in the form of their monohydric alcohol esters. All of these substances and products which contain these substances in concentrations of at least 15 area% of TFA (see below) are summarized below under the terms n-3 fatty acid or n-3 active ingredients, the terms are used synonymously.

Table 1: n-3 fatty acids

For the purposes of the invention, preference is given to using an n-3 active substance with an n-3 fatty acid content of at least 20 area% of TFA (area% refer to the AOCS Official Method Ce 1 b-89; TFA = Total Fatty Acid). A content of at least 30 area% of TFA is particularly preferred, in particular of at least 40 area% of TFA and very particularly preferably of at least 60 area% of TFA.

Mixtures of the various are also preferred for the purposes of the invention n-3 active ingredients, preferably of at least 2 of the n-3 active ingredients DHA, EPA and ALA and particularly preferably a mixture of the n-3 active ingredients DHA and EPA. The use of EPA or DHA as the main constituent of the n-3 active ingredient is very particularly preferred, in particular the use of DHA as the only n-3 active ingredient.

A suitable source for one of the above. Mixture of EPA and DHA are fish oils. A suitable source of ALA are vegetable oils, especially linseed oil or hemp oil and the like. a.

N-3 active ingredients which are isolated from microorganisms are particularly preferred. Preferred microorganisms are organisms of the Stramenopiles (or Labyrinthulomycota), particularly preferably of the order Thraustochytriales (Thraustchytriidea), in particular of the genera Schizochytrium, Thraustochytrium and Ulkenia, and also dinoflagellates (Dinophyta), preferably Crypthecohninium are preferably suitable for the production of DHA with a concentration of at least 20 area% of TFA, preferably of at least 30 area% of TFA and particularly preferably of at least 40 area% of TFA DHA. With regard to the production of n-3 fatty acids, reference is made in particular to the following publications: WO-A-91/07498, WO-A-91/11918, WO-A-96/33263 and WO-A-98/03671 ,

Additional sources for EPA and / or DHA are e.g. B. also microalgae such as Euglena (JP-A 60-196157), Nannochloropsis, Phaeodactylum and others (Tonon et al., Long chain polyunsaturated fatty acid production and partitioning to triacylglycerols in four microalgae. Phytochemistry 2002, 15-24), but also Bacteria, preferably z. B. Shewanella, Vibrio or Moritella (Cho and Mo, Screening and characterization of eicosapentaenoic acid-producing marine bacteria, Biotechnology Letters 1999, 215-218; JP-A-2000/245442; JP-A-63-216490, JP-A -2001 / 309797).

Another possible source of n-3 fatty acids is represented by transgenic organisms, preferably microorganisms and plants. Furthermore, n-3 active ingredients can be used in the sense of the invention, which are derived from oils as described above (e.g. fish oils, vegetable oils or oils from microorganisms) by various methods known to the person skilled in the art (e.g. chromatography, absorption or adsorption processes) , Winterization etc.) are cleaned up or concentrated on.

Cholesterol-lowering active substances in the sense of the invention are understood to be active substances which can lower an elevated cholesterol level (> 200 mg / dl), in particular LDL cholesterol levels> 130 mg / dl. These are characterized by the fact that they specifically influence certain metabolic processes and thus lead to a secondary reduction in LDL cholesterol and total cholesterol (usually between 10-55%).

The active substances in the context of the invention include cholesterol-lowering substances from the group of statins, bile acid absorption inhibitors and bile acid sequestrants, cholesterol absorption inhibitors, fibrates, nicotinic acid derivatives, but also the group of phytosterols and plant levels and cholesterol-lowering plant extracts.

Compounds such as lovastatin [s. Fig. 1 below] (e.g. US-A-4,231,938), Paravastatin (e.g. US-A-4,346,227), Simvastatin [s. Fig. 2 below] (e.g. US-A 4,444,784), fluvastatin (e.g. US-A-5,354,772), atorvastatin (e.g. US-A-5,273,995) or cerivaststatin (e.g. US A-5, 177,080) understood that act specifically by inhibiting cholesterol synthesis (HMG CoA reductase inhibitors) in the liver. These active substances have been described several times and are widely used for lowering cholesterol as medicaments and for therapy (for example US-A-6, 180,660).

Fig. 1: Lovastatin Fig. 2: Simvastatin

Inhibitors of bile acid absorption in the sense of the invention are understood to mean substances which prevent the reuptake of bile acids in the intestine / ileum via a receptor-mediated process. These are in particular benzothiazepine derivatives (for example US Pat. No. 5,998,400, US Pat. No. 6,277,831), benzothiepin-1,1-dioxide derivatives (for example US Pat. No. 6,221,897, WO-A- 97/33882), in particular compounds according to Figures 3 and 4 below, which specifically block the bile acid reabsorption in the intestine, in particular in the ileum.

Fig. 3: Benzothiepin derivatives (with R = C ₆ H ₄ NHZR ₃ ; R ¹ , R ⁴ , R ⁵ = Me, Et, Pr, Bu; R ² = H, OH, NH ₂ , amino (alkyl); R ³ = sugar residue; Z = - (C = O) _n - (C ₀ -C _1β ) -alk l-. - (C = O) _n - (C ₀ -C ₁₆ ) -alkyl-NH-, - (C = O) _n - ( C ₀ -C ₁₆ ) - alkyl-O-, - (C = O) _n - (C ₀ -C ₁₆ ) alkyl- (C = O) _m or a covalent bond; n = 0 or 1; m = 0 or 1, and their salts)

Fig. 4: Benzothiazepine derivatives

(with R ¹ = Me, Et, Pr, Bu; R ² = H, OH; R ³ = sugar residue; Z = - (C = O) _n - (C ₀ -C ₁₆ ) -alkyl-, - (C = O) _n - (C ₀ -C ₁₆ ) alkyl-NH-, - (C = O) _n - (C ₀ -C ₁₆ ) -alkyl-O-, - (C = O) _n - (C ₀ - C ₁₆ ) -alkyl- (C = O) _m or a covalent bond; n = 0 or 1; m = 0 or 1, and their salts)

Bile acid sequestrants act as polymeric ion exchange resins in the intestine, specifically on bile acids, but also on cholesterol, and lead to an increased excretion of the substances mentioned. This group of active ingredients includes a. Cholestyramine, colestipol or colesevlam hydrochloride. The two compounds mentioned are distinguished by a significantly weaker activity than statins or inhibitors of bile acid absorption.

Cholesterol absorption inhibitors are active substances that inhibit the receptor-mediated transport of cholesterol in the intestine and thus increase the excretion of cholesterol, which ultimately leads to a moderate decrease in serum cholesterol levels. These include, in particular, hydroxy-substituted ones Group 1 Azetidinone Cholesterol Absorption Inhibitors - (4-fluorophenyl) -3 (R) - [3 (S) - (4-fluorophenyl) -3-hydroxypropyl)] - 4 (S) -4-hydroxyphenyl) -2-azetidinone ) and 1 - (4-fluorophenyl) -3 (R) - [3 (R) - (4-fluorophenyl) -3-hydroxypropyl)] - 4 (S) -4-hydroxyphenyl) -2-azetidinone) and their pharmacological effective salts or substituted β-lactam cholesterol absorption inhibitors (e.g. WO-A-95/35277, WO-A-02/058733, WO-A-02/50060).

The group of fibrates includes a. Clofibrate, etophylline clofibrate, bezafibrate, ciprofibrate, clinofibrate, binifibrate, lifibrol, fenofibrate, gemfibrozil or etofibrate. Depending on the clinical picture, fibrates have a moderate lowering effect on LDL cholesterol with a slight improvement in HDL cholesterol values. Serum triglyderides are more affected by fibrates.

Nicotinic acid derivatives in the sense of the invention are natural or synthetically produced nicotinic acid, its esters or synthetic derivatives such as, for. B. niceritrol, nicofuranose, ß-pyridylcarbinol or acipimox. This group of substances has a moderate effect on total and LDL cholesterol with improved HDL cholesterol levels.

Phytosterols in the sense of the invention are understood to mean 4-demethylsterols, 4-monomethyl sterols and 4,4-dimethyl sterols and the respective esters as well as plant extracts, mixtures and foods rich in phytosterols. These include ß-sitosterol, campesterol, stigmatosterol, brassicasterol, desmosterol, chalinosterol, poriferasterol, clionasterol and all their natural or synthetic or isomeric derivatives. Vegetable stanols are understood to mean hydrogenated plant sterols such as, for example, B. Campestanol, Sitostanol and the respective esters as well as vegetable extracts, mixtures and foods rich in vegetable stanols.

Other herbal extracts with a cholesterol-lowering effect include artichoke extracts and extracts from garlic and guggulipid. They have long been used as natural remedies and show moderate effectiveness on total and LDL cholesterol levels. The agents according to the invention contain a carob product, in particular carob fiber, at least one cholesterol-lowering active ingredient and at least one n-3 fatty acid. In addition, the cholesterol-lowering agents can contain conventional additives such as solvents, fillers, carriers such as methyl cellulose, sweetening carbohydrates and other sweeteners, flavors, antioxidants and preservatives. The combination of a carob product, in particular carob fiber, with at least one n-3 fatty acid and at least one active ingredient can also be administered in the form of two or more different dosage forms. Common food applications such as baked goods, cereals, snack or fruit bars or powdered beverages are suitable for the carob products, in particular the carob fiber, and for the n-3 fatty acids. In addition, the direct addition of the carob product, in particular the carob fiber, and the n-3 fatty acids in foodstuffs produced in-house as well as use in the form of food supplements typical (e.g. tablets, dragees, hard or soft capsules, sachets, granules, bars, etc .) possible, while the active ingredients are administered rather in the manner typical of medicines (including tablets, coated tablets, hard or soft capsules, sachets, granules, etc.).

The dietetic foods according to the invention contain the food components in amounts which are required for administration 2 to 4 times a day to achieve the therapeutic effect.

The carob product or the carob fiber component is contained in the products according to the invention in concentrations which bring about a significant cholesterol reduction or influence the HDLΛDL ratio in a positive manner. The daily dose of carob fiber can be in the range of 1-25 g, usually 5-15 g.

The n-3 fatty acids are contained in the products according to the invention in concentrations which, in synergy with the carob products described above, bring about a significant reduction in cholesterol and the HDL / LDL ratio in a positive manner

Influence wise. The daily dose of n-3 fatty acids can be in the range of 50 mg to 10 g, usually from 100 mg to 5 g and preferably from 200 mg to 2 g.

Locust bean product, in particular locust bean fiber, and n-3 fatty acids are used in these amounts in combination with the daily doses of the active ingredients if a particularly extensive reduction in the cholesterol level is desired. For the concentrations of active ingredients previously required for individual use, the use concentrations can be reduced by up to 50-90% due to synergies. The additives which may be present can advantageously be added in concentrations of 1-90% by weight, in particular 10-60% by weight (based on the particular preparation form).

The active ingredient combination according to the invention can be taken up at a specific time of day or distributed over the day, the quantitative ratios of active ingredient, locust bean product, in particular locust bean fiber, and n-3 fatty acid corresponding to the above-mentioned ratios when ingesting smaller doses.

To produce the agents according to the invention, the procedure can preferably be such that the desired amounts of carob product, in particular carob fiber, n-3 fatty acids and active ingredient are mixed with one another, spray-dried, freed from the solvent, agglomerated and / or instantized. Furthermore, all common food technology, but also Gallic manufacturing processes such as pressing, kneading or coating can be used. The n-3 fatty acids can be added to the mixture in pure form or encapsulated or microencapsulated, it being possible to use all methods familiar to the person skilled in the art such as coacervation, spray drying or fluidized bed drying for the encapsulation or microencapsulation. Inclusion in liposomes or micelles is also possible.

Furthermore, the n-3 fatty acids can be added to the mixture in a form which provides a continuous (retarding) release of the fatty acids in the body allowed. Suitable processes for producing these slow release formulations are, for example, coating processes or the use of suitable capsule matrices in the (micro) encapsulation.

Furthermore, the carob product, in particular the carob fiber, can itself be used as a carrier or matrix for the n-3 fatty acids.

When administered together in accordance with the present invention, it was found that the combined intake of locust bean products, in particular locust bean fiber, n-3 fatty acids and cholesterol-lowering active ingredients, leads to a significantly greater reduction in the cholesterol level than the sum of the effects when the individual components are administered. It is surprising that the addition of locust bean products, in particular locust bean fiber, and n-3 fatty acids to the active ingredients does not reduce the activity of the active ingredients through non-specific interference, but that the effects observed go far beyond those achievable with individual administration of the three groups of substances ,

The agents according to the invention thus make it possible to achieve a therapeutically often desirable, stronger lowering of the cholesterol level than previously or to achieve effects in a comparable amount as before, but with lower amounts of active ingredient. In particular, undesirable side effects, which frequently occur during the administration of cholesterol-lowering active ingredients, can thus be reduced or avoided entirely. The combination of active substances according to the invention thus represents a significant advance in drug therapy for hypercholesterolemia or hyperlipidemia.

The active compound combinations according to the invention are expediently used in a suitable preparation which is coordinated with the most effective quantitative ratios. For this come z. B. powder or tablet preparations for dissolution, but also chewable tablets in question. These preparations can also contain other ingredients (additives) to improve resolution such as soluble Carriers, tablet disintegrants such. B. Starch, cellulose, bentonite, pectin or peroxides and carbonates in combination with organic acids and in general colorants, sweeteners such as sucrose, glucose, fructose and other carbohydrates, sugar alcohols such as. As sorbitol, xylitol, maltitol and isomalt or sweeteners such as. B. acesulfame-K, cyclamate, saccharin, sucralose or aspartame and in particular flavorings to improve acceptance.

However, the agents according to the invention can also be administered separately in the form of a pharmaceutical preparation of the active ingredient and in the form of a food or food supplement containing the carob product, in particular carob fiber, and the n-3 fatty acids. In particular, the carob product, in particular the carob fiber, can be used as a carrier of the n-3 fatty acids. Furthermore, the separate administration of two foods or nutritional supplements is possible, one food or nutritional supplement containing the carob product and the other containing the n-3 fatty acid (s). The common pharmaceutical dosage forms such as tablets, capsules, solutions for ingestion as drops or powdered preparation or granules to be dissolved are suitable for the active ingredient. With this combination therapy, any food into which the carob product and the n-3 fatty acid can be incorporated is basically suitable as a food, with limits arising from the properties of the food component and the intended use. Accordingly, cereal-based foods such as baked goods, cereals, snack bars and fruit bars, desserts, special diet preparations such as beverages and in particular powdered drinks based on milk, fruit concentrates or powders, carbohydrates or sugar alcohols would be particularly suitable. With phytosterols and plant stanols, fatty foods such as B. vegetable spreads, dressings and dairy products.

The invention is explained below using an example. example

Powdered preparation (for one serving size)

Lovastatin (MSD Sharp and Dome GmbH, D-85540 Haar) 10 mg carob fiber (Caromax ^® , Nutrinova, Frankfurt) 3 g

DHA-rich algae oil (DHA content 43 area% of TFA; Nutrinova, Frankfurt) 150 mg xanthan (stabilizer) 150 mg

Vanillin 15 mg

Suspend the preparation in 150 ml of lukewarm milk and stir.

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Claims

claims

1) Cholesterol-lowering agent containing at least one carob product, at least one n-3 fatty acid and at least one cholesterol-lowering active ingredient.

2) Agent according to claim 1, characterized in that the carob product is carob pulp or a product obtained from carob pulp.

3) Agent according to claim 1, characterized in that the carob product is carob fiber.

4) Agent according to claim 3, characterized in that the carob fiber is insoluble in water.

5) Agent according to one of claims 1 to 4, characterized in that the n-3 fatty acid is a polyunsaturated fatty acid with a chain length> C12 with at least two double bonds or its ester, triglyceride, phospholipid, glycolipid, sphingolipid, wax or is sterol ester.

6) Agent according to claim 5, wherein the first of the at least two double bonds, starting from the alkyl end, is constituted between the carbon atoms C ₃ and C ₄ .

7) Composition according to claim 5 or 6, characterized in that the n-3 fatty acid is selected from one or more of the following substances: all-cis-9,12,15-octadecatrienoic acid (ALA), AII-cis-6, 9,12,15-octadecatetraenoic acid, all-cis-11, 14,17-eicosatrienoic acid, AII-cis-8,11, 14,17-eicosatetraenoic acid, all-cis- 5,8,11, 14, 17-eicosapentaenoic acid ( EPA), AII-cis-13,16,19-docosatrienoic acid,

AII-cis-7,10,13,16,19-docosapentaenoic acid (DPA) and AII-cis-4,7,10,13,16,19-docosahexaenoic acid (DHA). 8) Agent according to claim 7, characterized in that the n-3 fatty acid is all-cis-4,7,10,13,16,19-docosahexaenoic acid (DHA).

9) Agent according to one of claims 5 to 8, characterized in that the n-3 fatty acid is not derivatized.

10) Agent according to one of claims 1 to 9, characterized in that the active ingredient is selected from one or more of the following substances: statins, inhibitors of bile acid absorption, cholesterol absorption inhibitors, fibrates, nicotinic acid derivatives, bile acid sequestrants, phytosterols, vegetable stanols and cholesterol-lowering vegetable extracts.

11) Cholesterol-lowering combination preparation containing at least one carob product, at least one n-3 fatty acid and at least one cholesterol-lowering active ingredient in separate dosage forms.

12) Cholesterol-lowering combination preparation according to claim 11, wherein the carob product and the n-3 fatty acid are contained in a food.

13) Cholesterol-lowering combination preparation according to claim 11, wherein the active ingredient is contained in a food or a pharmaceutical.

14) Process for the preparation of an agent according to any one of claims 1 to 9, characterized in that at least one carob product and at least one n-3 fatty acid and at least one cholesterol-lowering active ingredient are mixed together.

15) Use of an agent according to one of claims 1 to 9 as a medicament.

16) Use according to claim 12 as a cholesterol-lowering drug. 17) Use according to claim 12 for the prophylaxis of hypercholesterolemia, hyperlipidemia or arteriosclerosis.

18) Use according to claim 12 for the positive shift of the HDLJLDL ratio.

19) Use of an agent according to one of claims 1 to 9 for the additional supply with n-3 fatty acids.

20) Use of an agent according to one of claims 1 to 9 for the production of "pet food" as "heart food" for pets.

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