DE10303900A1 - Synergistic cholesterol lowering composition, useful as medicament or food or feed additive, comprising dietary fiber component and ahypocholesterolemic agent, e.g. statin - Google Patents

Abstract

A cholesterol lowering composition (A) comprises at least one dietary fiber component (I) and at least one hypocholesterolemic agent (II), provided that either: (i) (II) is other than an aryl-substituted propanolamine derivative or 1,4-benzothiepin-1,1-dioxide derivative; or (ii) the daily dose of (I) is 1-50 g. A cholesterol lowering composition (A) comprises at least one dietary fiber component (I) and at least one hypocholesterolemic agent (II), provided that either: (i) (II) is other than an aryl-substituted propanolamine derivative or 1,4-benzothiepin-1,1-dioxide derivative; or (ii) the daily dose of (I) is 1-50 g. Independent claims are included for: (a) a cholesterol lowering combination preparation comprising (I) and (II) in separate dosage forms (where proviso (i) or (ii) applies); (b) the preparation of (A) by mixing (I) and (II); ACTIVITY : Antilipemic; antiarteriosclerotic. Hamsters fed a diet enriched with 0.35% cholesterol were treated for 28 days with 2.5% carob fiber (Ia) and/or 1.5 mg % simvastatin (IIa) (both added to feed). The final cholesterol levels in blood serum were 7.65 mM in untreated controls, 7.17 mM (6% reduction) after treatment with (Ia) alone, 6.50 mM (15% reduction) after treatment with (IIa) alone and 5.73 mM (25% reduction, compared with a predicted value of 19%) after treatment with a combination of (Ia) and (IIa). MECHANISM OF ACTION : None given in the source material.

Description

The invention relates to a combination of active ingredients containing at least one levan to lower cholesterol and at least one cholesterol-lowering active ingredient. Farther The invention relates to a method for producing such active substance combinations as well as their use.

In the context of an unbalanced diet, an excessive content of blood lipid values, in particular 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 needed in the case of significantly elevated cholesterol levels, especially LDL cholesterol and elevated blood lipid levels. To this end, a number of possible solutions 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 e.g. US-A-4,231,938 ; US-A-4,444,784 ; US-A-4,346,227 ), Inhibitors of bile acid absorption (see e.g. US-A-5,998,400 ; US-A-6,277,831 ; US-A-6,221,897 ) or bile acid sequestrants (see e.g. 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. This is primarily the cholesterol-lowering effect of a group of plant sterols, in particular phytosterols, phytostanols and the esters of the compound classes mentioned (see, for example, WO-A-96/38047, WO-A-99/56558, US-A-6,087,353 ) to call. However, the latter in particular are not suitable for consumption for all population groups (eg 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.

This contrasts with food components, who have shown several times that if they are taken in sufficiently significantly reduce the risk of cardiovascular disease can, especially by lowering high cholesterol. It It is generally known that a high fiber diet in Compared to a low-risk, low-fiber diet associated with cardiovascular disease. In addition to whole grain cereals (Wheat, oats, barley, rye, but also cereal bran such as oat bran, Rice bran, wheat bran, soy bran etc.), which are generally high in fiber are, can other fibers also contribute to reducing the cardiovascular risk and increased Cholesterol levels. So show a number of water soluble Dietary fiber, such as B. β-glucan (from oats or barley), psyllium, pectin or guar gum a lowering Effect on blood cholesterol levels (Brown et al. 1999; Am. J. Clin. Nutr. 69: 30-42).

They are still considered food components Levane known to selectively reduce serum cholesterol, i.e. without lowering of triglycerol or glucose levels in the serum significantly can (Yamamoto et al. 1999, J. Nutr. Biochem. 10, 13-18, and Yamamoto et al. 2000, Hydrocolloids Part 2, Fundamentals and Application in Food, Biology and Medicine, Elsevier, 2000, 399-404).

The achievable effects are included all of these food components but clearly below those with therapeutic agents can be achieved, and thus much lower as desirable. Even if one is enriched with fiber, especially with levans Diet one Contribute to the control of cholesterol levels and blood lipid levels it can afford in many cases, especially in the case of very high cholesterol levels (total cholesterol> 300 mg / dl), for sustainable lowering unsatisfactory.

A cholesterol-lowering interaction between food components, especially fiber such as Levans, and cholesterol-lowering agents are not known. Certainly not a synergy. Within the group of food components is even an antagonistic effect of the water-soluble Dietary fiber, e.g. of locust bean gum, with water-insoluble Fibers of the carob meat have been described (Peres-Olleros et al. 1999; J. Sci. Food Agric. 79, 173-178).

The purely pharmacological cholesterol lowerers have the disadvantage that to achieve the therapy goals in part significant concentrations must be used. Unwanted, some life-threatening side effects occur, also in combination with other therapeutic agents. Combination therapies to increase the Efficacy with various cholesterol-lowering agents or other therapeutic agents such as for cardiovascular diseases are more dangerous due to various Contraindications are not always usable. So show z. B. Combinations of fibrates with statins an increased risk of myopathy syndromes, which are even fatal in the case of combinations of cerivastatin with gemfibrozil could.

There are also saturation effects Known which cause increased intake of the active ingredient only minor additional Reductions in cholesterol levels can be achieved. Another The disadvantage is the high costs associated with long-term therapy mostly very expensive pharmacological cholesterol lowering occur.

From the vegetable sources isolated cholesterol counters (e.g. phytosterols) there are quantity limits, to unwanted Avoid side effects.

It therefore still exists Need for cholesterol-lowering drugs that are the same or even better Efficacy the administered amounts of the respective active ingredient reduce and thus the possible side effects and Reduce costs, especially of long-term therapies.

This task is solved by Providing a combination of active ingredients to lower cholesterol, containing at least one fiber, in particular a Levan, and at least one cholesterol-lowering active ingredient.

Among fibers in the sense of the invention become components of the plant cells and / or isolated natural or understand carbohydrates obtained through technological processes, those that cannot be absorbed by the human enzyme system in the small intestine Components are dismantled. But you can partially or completely by of the colon flora are fermented. The fiber can for example can be selected from one or more of the following substances: Whole grain cereals (wheat, oats, barley, rye), oat bran (β-glucan), rice bran, Corn bran, barley, psyllium husk, guar, locust bean seeds, Tragacanth, pectin, non-digestible oligosaccharides, carob pulp, Linseed, soy fiber, soy bran, dextrins, arabinoxylans, Arabinogalactans, resistant starches and β-polyfructans.

Preferred fiber in the sense of the invention is levan, a β-2,6-polyfructan which, depending on the extraction or production, can have additional β-2,1-fructofuranosyl bonds and molecular weights (M _w ) between 10 ³ and 10 ⁷ . The dietary fiber can, for example, be produced in such a way that sucrose is converted to levan in a biocatalytic reaction with the aid of an enzyme of the catalytic activity of a levan sucrase and then filtered, washed and dried. Levan sucrase can be used alone or together with other glycosyltransferases to produce branched levans. The method according to WO 99/40217 or WO 00/31287 is preferred. Control of the production process is particularly preferred in such a way that particularly long-chain levanes with high molar masses> 5 · 10 ⁵ are produced. The preparations obtained in this way have a pronounced hypocholesterolemic effect and can be used to fortify foods.

Among cholesterol-lowering agents in the sense of the invention are understood as active ingredients that have an elevated cholesterol level (> 200 mg / dl), in particular LDL cholesterol levels> 130 mg / dl. These are characterized by the fact that they specifically determine Affect metabolic processes and thereby secondary to one Lowering LDL cholesterol and total cholesterol (usually between 10 and 55%).

About the active ingredients in the sense of the invention counting cholesterol-lowering substances from the group of statins, the bile acid absorption inhibitors and bile acid sequestrants, Cholesterol absorption inhibitors, fibrates, nicotinic acid derivatives, but also the group of phytosterols and vegetable stanols as well cholesterol-lowering herbal extracts.

Compounds such as lovastatin [s. Formula 1 below] (e.g. US-A-4,231,938 ), Paravastatin (e.g. US-A-4,346,227 ), Simvastatin [s. Formula 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 used to lower cholesterol as medicines and for therapy (e.g. US-A-6,180,660 ) widely used.

Formel 3: Benzothiepin-Derivate (mit R = C₆H₄NHZR₃; R¹,R⁴,R⁵ = Me, Et, Pr, Bu; R² = N, OH, NH₂, Amino(alkyl); R³ = Zuckerrest; Z = -(C=O)_n-(C₀-C₁₆)-Alkyl-, -(C=O)_n-(C₀-C₁₆)-Alkyl-NH-, -(C=O)_n-(C₀-C₁₆)-Alkyl-O-, -(C=O)_n-(C₀-C₁₆)-Alkyl-(C=O)_m oder eine kovalente Bindung; n = 0 oder 1; m = 0 oder 1, sowie deren Salze)

Formel 4: Benzothiazepin-Derivate (mit R¹ = Me, Et, Pr, Bu; R² = N, OH; R³ = Zuckerrest; Z = -(C=O)_n-(C₀-C₁₆)-Alkyl-, -(C=O)_n-(C₀-C₁₆)-Alkyl-NH-, -(C=O)_n-(C₀-C₁₆)-Alkyl-O-, -(C=O)_n-(C₀-C₁₆)-Alkyl-(C=O)_m, oder eine kovalente Bindung; n = 0 oder 1; m = 0 oder 1, sowie deren Salze)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 (e.g. US-A-5,998,400 . US-A-6,277,831 ), Benzothiepin-1,1-dioxide derivatives (e.g. US-A-6,221,897 , WO-A-97/33882), in particular compounds according to formulas 3 and 4 below, which specifically block the absorption of bile acid in the intestine, in particular in the ileum.

Formula 3: Benzothiepin derivatives (with R = C ₆ H ₄ NHZR ₃ ; R ¹ , R ⁴ , R ⁵ = Me, Et, Pr, Bu; R ² = N, OH, NH ₂ , amino (alkyl); 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)

Formula 4: Benzothiazepine derivatives (with R ¹ = Me, Et, Pr, Bu; R ² = N, 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 work in the Gut as polymeric ion exchange resins specific to bile acids however also cholesterol and lead to a reinforced one Excretion of the substances mentioned. This group of active ingredients includes Cholestyramine, colestipol or colesevlam hydrochloride. The two Compounds mentioned are characterized by a significantly weaker effectiveness from as statins or inhibitors of bile acid absorption.

Cholesterol absorption inhibitors are active substances that mediate the receptor-mediated transport of Inhibit cholesterol and thus cholesterol excretion increase, ultimately resulting in a moderate decrease in serum cholesterol leads. These include especially hydroxy-substituted azetidinone cholesterol absorption inhibitors from the group 1- (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 pharmacologically active 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 slight improvement in HDL cholesterol levels. Serum triglycerides become stronger through fibrates affected.

Nicotinic acid derivatives in the sense of the invention are natural or synthetically produced nicotinic acid, its esters or synthetic Derivatives such as Niceritrol, Nicofuranose, β-Pyridylcarbinol or Acipimox. This Substance group has a moderate effect on total and LDL cholesterol, with improved HDL cholesterol levels at the same time.

Taking phytosterols in the sense of 4-Demethylsterine, 4-Monomethylsterine and 4,4-Dimethylsterine become invention and the respective esters, as well as vegetable extracts, mixtures and understood foods rich in phytosterols. These include β-sitosterol, campesterol, Stigmatosterol, brassicasterol, desmosterol, chalinosterol, poriferasterol, Clionasterol and all of its natural or synthetic or isomeric derivatives. Among vegetable stanols are hydrogenated plant sterols, e.g. campestanol, Sitostanol and the respective esters as well as vegetable extracts, Mixtures and foods rich in vegetable stanols.

Another herbal extract with cholesterol-lowering Close effect et al Artichoke extracts and extracts from garlic and guglipid guggulipid with a. 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 in addition the fiber, in particular the Levan, at least one cholesterol-lowering Active ingredient. About that can out the cholesterol-lowering agents are common additives like solvents, fillers, excipients like methyl cellulose, sweetening carbohydrates and other sweeteners, Contain flavors, antioxidants and preservatives. The combination of fiber, especially Levan, and at least one active ingredient can also be in the form of two or more different dosage forms be administered. Thereby lend themselves to the fiber, in particular the levan, common Food applications such as baked goods, cereals, snack or Fruit bars or powdered drinks on. About that In addition, the direct addition of fiber, in particular des Levans, in food produced in-house as well as an application in typical food supplements Form (including tablets, coated tablets, hard or soft capsules, sachets, Granules, bars, etc.) possible, while the active ingredients are administered in a more typical drug manner tablets, dragees, hard or soft capsules, sachets, granules etc.).

The agents according to the invention contain the active ingredients in amounts to achieve with 2-4 times daily administration of the therapeutic effect are required.

The levan component is in the agents according to the invention Contained in concentrations that significantly lower cholesterol cause. The daily dose of Levan can range from 1 to 25 g, usually from 5 to 15 g.

It is combined in these quantities with the usual ones Doses of the active ingredients are used if a particularly extensive one Reduction in cholesterol is sought. For the so far for single use necessary concentrations of active substances can the use concentrations be reduced by up to 50 to 90% due to synergies. The any additives that may be present expedient in concentrations from 1 to 90% by weight, in particular from 10 to 60% by weight, (based to the respective preparation form) are added.

The inclusion of the agents according to the invention can be done at a specific time of day or via the Distributed throughout the day, the proportions of active ingredient and fiber, especially Levan, when taking smaller doses the above conditions equivalent.

For the preparation of the agents according to the invention can preferably be carried out in such a way that the desired amounts of fiber, especially on Levan, and the active ingredient are mixed together, spray dried be from the solvent freed, agglomerated and / or instantized. Furthermore, everyone can common food technology but also Gallic manufacturing processes such as pressing, kneading or coating.

When administered together according to the present Invention became surprising found that the combined intake of fiber, in particular of Levan, and cholesterol-lowering active ingredients to a significantly stronger Lowering cholesterol leads to the sum of the effects when administering the individual components. Particularly surprising is that the additional Add fiber, especially Levan, to the active ingredients the activity does not degrade active substances through non-specific interference, but that the observed effects are clearly above the effects achievable with single administration of both substances go out.

The agents according to the invention thus allow a therapeutically often desirable, more Lower cholesterol than previously achieved or effects at a comparable level as before, but with lower amounts of active ingredient.

In particular, undesirable side effects, which often occur when cholesterol-lowering agents are administered, diminished or entirely be avoided. The active ingredient combination according to the invention provides a significant advance in drug therapy hypercholesterolemia or hyperlipidemia represents.

The agents according to the invention are expedient in a suitable, most effective quantity ratio coordinated, preparation used. For this come z. B. powder or tableted Preparations for dissolution but also chewable tablets in question. These preparations can also be others Ingredients (additives) to improve resolution such as soluble Carriers, Tablet disintegrants such as Starch, cellulose, bentonite, pectin or peroxides and carbonates in combination with organic acids, and general dyes, 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 contain flavorings to improve acceptance.

The agents according to the invention can, however also separately in the form of a pharmaceutical preparation of the active ingredient and in the form of one containing the fiber, in particular the Levan Food or nutritional supplement administer. For the active ingredient comes the usual Pharmaceutical dosage forms such as tablets, capsules, solutions for Intake as drops or to be dissolved powdery Preparation or granules in question. With this combination therapy is suitable as a food containing fiber, in particular levan in principle any food into which the fiber, especially the Levan, can be incorporated, with limits arising from the properties the food component as from the intended use result. Would be particularly suitable accordingly cereal-based foods such as baked goods, cereals, Snack and fruit bars, desserts, special diet preparations such as drinks and especially powder drinks based on milk, fruit concentrates or powders, carbohydrates or sugar alcohols. When it comes to phytosterols and plant stanols about that also fatty foods in question such as Vegetable spreads, Dressings and dairy products.

The invention is described below an example closer explained.

example

Powdered preparation (for one serving size) Lovastatin (MSD Sharp and Dome GmbH, D-85540 Haar) 10 mg Levan .... 3 g Xanthan (stabilizer) 150 mg vanillin 15 mg

The preparation in 150 ml of lukewarm milk by stirring suspend and drink.

Claims (15)

Cholesterol-lowering agent containing at least a fiber and at least one cholesterol-lowering active ingredient. Agent according to claim 1, characterized in that the fiber selected is from a group containing whole grain cereals, oat bran, β-glucan, rice bran, Corn bran, barley, psyllium husk, guar, locust bean seeds, Tragacanth, pectin, non-digestible oligosaccharides, carob pulp or a product made from carob pulp, linseed, Soybean fiber, soy bran, dextrins, arabinoxylans, arabinogalactans, resistant starch and β-polyfructans or mixtures of these. Agent according to claim 1, characterized in that the fiber is a levan or a branched levan. Agent according to one or more of claims 1 to 3, characterized in that the active ingredient is selected from one or more of the following substances: statins, inhibitors bile acid absorption, Cholesterol absorption inhibitors, fibrates, nicotinic acid derivatives, Gallensäurensequestrantien, Phytosterols, vegetable stanols and cholesterol-lowering vegetable Extracts. Containing cholesterol-lowering combination preparation at least one fiber and at least one cholesterol-lowering Active ingredient in separate dosage forms. Combined cholesterol-lowering preparation after Claim 5, wherein the fiber contained in a food is. Combined cholesterol-lowering preparation after Claim 5 or 6, wherein the active ingredient in a food or is contained in a medicinal product. Process for producing an agent according to a of claims 1 to 4, characterized in that you have at least one fiber and mixed together at least one cholesterol-lowering active ingredient. Use of an agent according to any one of claims 1 to 4 for manufacturing a drug. Use according to claim 9 for producing a cholesterol lowering drug. Use according to claim 9 for producing a Medicament for the prophylaxis of hypercholesterolemia, hyperlipidemia or Arteriosclerosis. Use of a combination preparation according to one of claims 5 to 7 for manufacturing a drug. Use according to claim 12 for producing a cholesterol lowering drug. Use according to claim 12 for producing a Medicament for the prophylaxis of hypercholesterolemia, hyperlipidemia or Arteriosclerosis. Use of an agent according to any one of claims 1 to 4 for making "pet food "as" heart food "for pets.