DE10233342A1 - 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);

Description

The invention relates to cholesterol-lowering Dietary fiber, especially carob fiber, and at least a cholesterol-lowering active ingredient. The invention further relates to a process for the preparation of such agents and 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 seen as 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. To this end, a number of approaches 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 (among others US 4,231,938 ; US 4,444,784 ; US 4,346,227 ), Inhibitors of bile acid absorption (among others US 5,998,400 ; US 6,277,831 ; US 6,221,897 ) or bile acid sequestrants (among others US 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 compound classes mentioned (inter alia WO 96/38047, WO 99/56558, US 6,087,353 ) to call. 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.

This contrasts with food components, who have shown several times that if they are taken in sufficiently significant the risk of cardiovascular disease, in particular also by lowering increased Can lower cholesterol levels. For fiber as typical food components, it is generally known that high dietary fiber compared to one Low fiber diet positive with a lower risk of cardiovascular disease (Jacobs et al. 1998; Am J Clin Nutr. 68: 248-257; Wolk et al. 1999; JAMA 2281: 1998-2004). 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 make a positive contribution to the reduction cardiovascular risk and increased Achieve cholesterol levels. So show a number of water soluble Dietary fiber, such as 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).

There are also water-insoluble carob fibers as food components, preferably those produced by a process according to EP-A-0 616780 , are known to significantly lower serum cholesterol levels, especially 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 towards "good cholesterol" and thus the risk of arteriosclerosis decreases.

The achievable effects are included the food components but clearly below those with therapeutic Active ingredients are achieved, and thus much lower than desirable. Even if one with fiber, especially with carob fiber, fortified diet thus contribute to the control of cholesterol levels can, in many cases, especially with very high cholesterol levels (total cholesterol> 300 mg / dl), for sustainable Lowering is not sufficient.

A synergistic, cholesterol-lowering Interaction between food components, especially fiber like carob fiber, and active ingredients are unknown. Within the group of food components, for example an antagonistic effect on soluble fiber from Locust bean gum with water-insoluble fibers of the locust bean meat (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. Furthermore are 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 work at the same or even improved effectiveness the administered amounts of each Reduce active ingredient and thus the possible side effects and reduce costs, particularly of long-term therapies.

This task is solved by cholesterol-lowering agents made from fiber, in particular carob fiber, 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 (psyllium), guar, carob seeds, Tragacanth, pectin, inulin, non-digestible oligosaccharides, carob pulp, linseed, Soybean fiber, soy bran, dextrins, arabinoxylans, arabinogalactans.

Preferred fibers in the sense of the invention are locust bean fibers, which are characterized by a high content of insoluble fibers but also polyphenols. The fiber is produced in such a way that the pulp freed from the locust bean seeds is separated from the water-soluble locust bean components in a continuous extraction process and the residue thus obtained is dried, ground and, if necessary, sieved. The method according to is particularly preferred EP-A-0 616 780 , 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 10-55%).

About the active ingredients in the sense of the invention counting cholesterol-lowering substances from the group of tripods, the bile acid absorption inhibitors and bile acid sequestrants, but also the group of phytosterols and vegetable stanols.

Statins include compounds such as lovastatin ( US 4,231,938 ), see 1 , Paravastatin ( US 4,346,227 ), Simvastatin ( US 4,444,784 ), see 2 , Fluvastatin ( US 5,354,772 ), Atorvastatin ( US 5,273,995 ) or cerivaststatin ( US 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 ( US 6,180,660 ) widely used.

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 process mediated by a receptor. These are in particular benzothiazepine derivatives ( US 5,998,400 . US 6,277,831 ), Benzothiepin-1,1-dioxide derivatives (US 6,221,897, WO 97/33882), in particular compounds according to Figures 3 and 4, which specifically block the bile acid reabsorption in the intestine, in particular in the ileum.

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 (examples: cholestyramine or colestipol). The two compounds mentioned are distinguished by a weaker Efficacy out as statins or inhibitors of bile acid absorption.

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 their natural or synthetic or isomeric derivatives. Vegetable stanols are hydrogenated Plant sterols understood, e.g. Campestanol, Sitostanol and the respective esters as well as vegetable extracts, mixtures and Food rich in vegetable stanols.

The agents according to the invention contain in addition the fiber, in particular the carob fiber, at least one or more active substances. About that beyond that cholesterol-lowering agents usual Additives such as solvents, fillers, excipients like methyl cellulose, sweetening carbohydrates and other sweeteners, Flavors, antioxidants, etc. included. The combination of fiber, especially carob fiber, and active ingredients can also be in shape can be administered by two different dosage forms. there offer themselves for Dietary fiber, especially carob fiber, common food applications such as baked goods, cereals, snack or fruit bars or powdered drinks on. About that is also the direct addition of fiber in food own production as well as use in typical food supplements Form (including tablets, coated tablets, capsules, sachets, granules, bars etc.) possible while the active ingredients are administered in a more typical manner (e.g. tablets, coated tablets, capsules, sachets, granules, etc.).

The agents according to the invention contain the active ingredients in amounts which are necessary for the therapeutic effect when administered 2 to 3 times a day. The locust bean component is also contained in the agents according to the invention in concentrations which bring about a significant reduction in cholesterol. The daily dose of carob fiber can be in the range of 1-25 g, usually 5- 15 g. It is used in these quantities 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 application concentrations can be reduced by up to 50-90% due to synergies. Possibly. Additives present can advantageously be added in concentrations of 1-90% by weight, in particular 10-60% by weight (based on the particular preparation form).

For the preparation of the agents according to the invention moves it’s best to get the amount of fiber you want, in particular carob fiber, and the active ingredient mixes with one another, spray dried, from 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 it has been found that the combined intake of fiber, especially carob fiber, and cholesterol-lowering active ingredients a much stronger one Lowering cholesterol results in the sum of the effects when administering the individual components. The surprising thing is that the additional Add fiber, especially carob fiber, to the Active substances the activity the active ingredients are not reduced by 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. They represent a major 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 one the fiber, especially the carob fiber, administer containing food or dietary supplement. For the Active ingredient come the usual Pharmaceutical dosage forms such as tablets, capsules, solutions for Intake as drops or to be dissolved powder preparation or granules in question. Suitable for this combination therapy as a fiber-containing, in particular carob fiber-containing Basically food any food in which the fiber is incorporated can, with limits arising from the properties of the food component as derived from the intended use. Particularly suitable would be accordingly Cereal-based foods such as baked goods, cereals, snack foods 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 explained by examples.

Example 1:

Determination of hypocholesterolemic Effect of carob fiber and statins in vivo

The hamster is considered a suitable animal model viewed to illustrate the present invention, even if the metabolic processes differ slightly in hamsters and humans. However, both show here Combination of tested substances on their own in humans a lowering effect on serum cholesterol levels in particular on the LDL cholesterol. The effect of a combined dose of Locust bean and a statin, here Lovastatin, in this model should therefore draw conclusions too for the Give people.

Male Syrian hamsters (100-120 g at the start of the study) received food enriched with 0.1% cholesterol. The test substances carob fiber, produced according to the method EP-A-0 616 780 , and the statin lovastatin were mixed into the feed individually or in combination. The hamsters were divided into groups of 6 animals and treated with the test substances over a period of 21 days. After anesthesia, blood was obtained for the determination of the serum cholesterol values. This Rum cholesterol levels were determined after obtaining the plasma from the whole blood using a commercially available enzyme test kit. The total cholesterol contents of the test groups determined in this way were compared to the results of a control group which received no test substances. The results were as follows:

Results:

Example 2:

Determination of hypocholesterolemic Effect of carob fiber and inhibitors of bile acid absorption in vivo

This experiment was carried out analogously to Example 1. The in 5 Diastereomeric 1,4-benzothiazepine-1,1-dioxide derivatives (BART) shown were mixed into the food of the hamsters instead of lovastatin. The concentration of the diastereomeric inhibitor of bile acid absorption was 30 mg / kg / day.

Results:

The possible combinations of the agents according to the invention are exemplified by the following combination preparations: Example 3: Powdered preparation (for one serving size) Lovastatin 10 mg Carob fiber 3 g Xanthan (stabilizer) 150 mg Vanillin 15 mg

Suspend the preparation in 150 ml of lukewarm milk and stir. Example 4: Chewable tablet Benzothiazepine derivative (according to Example 2) 100 mg Carob fiber 2 g sorbitol 1.4 g magnesium stearate 15 mg Acesulfame K 12 mg aspartame 12 mg chocolate flavor qs

The chewable tablets are more common Wise mixed and pressed.

Claims (16)

Cholesterol-lowering agent containing at least one Dietary fiber and at least one cholesterol-lowering active ingredient. Agent according to claim 1, characterized in that the dietary fiber is selected from one or more of the following substances: whole grain cereals, oat bran, β-glucan, rice bran, corn bran, barley, psyllium husk (psyllium), guar, locust bean seeds, tragacanth, pectin, inulin, non-digestible oligosaccharides, carob pulp or a product derived from carob pulp, linseed, soy fiber, soy bran, dextrins, arabinoxylans and arabinogalactans. Agent according to claim 2, characterized in that the fiber Carob pulp or one made from carob pulp won product is. Agent according to claim 3, characterized in that the fiber Carob fiber is. Agent according to claim 4, characterized in that the fiber insoluble in water is. Agent according to one of the claims 1 to 5 characterized in that the active ingredient is selected from one or more of the following substances: statins, inhibitors bile acid absorption, Gallensäurensequestrantien and phytosterols and vegetable stanols. Cholesterol-lowering combination preparation containing at least a fiber and at least one cholesterol-lowering active ingredient in separate dosage forms. Cholesterol-lowering combination preparation according to claim 7, characterized characterized that the fiber is a food. Cholesterol-lowering combination preparation according to claim 7 or 8, characterized in that the cholesterol-lowering active ingredient is a food or medicine. A process for producing an agent according to any one of claims 1 to 6, characterized in that one has 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 6 for the manufacture of a medicament. Use according to claim 11 for the manufacture of a cholesterol-lowering agent Drug. Use of a combination preparation according to claim 7 for Manufacture of a drug. Use according to claim 13 for the manufacture of a cholesterol-lowering agent Drug. Use of an agent according to any one of claims 1 to 6 for the manufacture of a medicament for the prophylaxis of hypercholesterolemia, hyperlipidemia or Arteriosclerosis. Use of a combination preparation according to claim 7 for Manufacture of a medicament for the prophylaxis of hypercholesterolemia, hyperlipidemia or Arteriosclerosis.