HK1188933B - Composition useful for the treatment of lipid metabolism disorders - Google Patents

Description

Composition useful for treating lipid metabolism disorders

Technical Field

The present invention relates to a combination of active ingredients and to compositions containing the same for medical and nutritional use for the preparation of a medicament or dietary supplement useful for the prevention and/or treatment of disorders of lipid metabolism and their complications.

Specifically, the present invention relates to a composition comprising, as active ingredients: (a) an extract of rice fermented with Monascus purpureus (Monascus purpureus); (b) at least one omega-3 fatty acid; (c) l-carnitine or a salt thereof; and one or more of the following active ingredients: (d) at least one policosanol (policosanol) or a natural extract containing policosanol; (e) resveratrol or a natural extract containing resveratrol; (f) coenzyme Q10; and (g) at least one vitamin.

Background

Cardiovascular diseases associated with abnormal lipid metabolism are very common in industrialized countries. For example, in Italy they account for over 40% of the total mortality (Capocaccia R., Farchi G., Prati S. et al: La mortalit Initialia nell' annino 1989.Rapporto ISTISSAN 1992/22). Our knowledge about the relationship between cholesterol and coronary heart disease has been derived from epidemiological studies performed in the last few years. Conclusions drawn in these studies indicate that The development of severe Atherosclerosis and Coronary Heart disease is closely related to serum cholesterol levels (McGill H.C.Jr. et al: The International Atherosclerosis project Lab.Invest.18:463-653,1968; Keys A.: Seven counties: Death and Coronary Heart disease. Harvard University Press, Cambridge, 1980).

The correction of eating habits by proper diet is always the first measure to be taken in case of hyperlipidemia. However, satisfactory results are not always achieved due to general intolerance of strict dietary discipline, severity of hypercholesterolemia, or genotypic resistance.

In order to achieve the desired result in these patients, i.e. normalization of the blood levels of triglycerides and cholesterol, recourse must be had to pharmacological treatment. Hypolipidemic agents fall into 2 classes: those that reduce cholesterol most, and those that reduce triglycerides most.

The former group of drugs includes statins, probucol and resins, while the latter group includes fibrates, niacin and fatty acids belonging to the omega-3 series.

Statins (lovastatin, simvastatin, pravastatin, fluvastatin, etc.) are inhibitors of hydroxy-methyl-glutaryl-coenzyme a (HMG-CoA) reductase. By inhibiting this enzyme, they reduce cholesterol synthesis in the liver (Lancet 1994;334: 1383-1389). To compensate for the decrease in intracellular cholesterol, hepatocytes produce several receptors for LDL and VLDL lipoproteins, which are thereby removed from the bloodstream.

Statins are drugs that are better tolerated than other anti-cholesterolemic agents (anticholesterolemic agents), but are not without their drawbacks, the most frequent side effects these drugs cause are gastrointestinal disorders, rashes and headaches.

It has been reported that although statins lead to a reduction in the number of deaths caused by coronary heart disease, an increase in deaths caused by other events such as tumors or trauma has been observed in treated patients (Davey-Smith G., Song F., Sheldon T.A.: Cholesterol lower and mortalities: the opportunity of contracting initial level at least. BMJ,1993;306: 1367) 1373; Ravnhov U.: Cholesterol lower metals in coronary heart disease: frequency of coronary output. BMJ1992;305: 15-19). Results of experiments in animal and human subjects have suggested that pharmacological treatment with statins should only be administered to patients at high risk of coronary artery disease for a short period of time in order to reduce cholesterol levels (JAMA, 1996;275: 55-60).

Red yeast rice (Red yeast rice) is a product of yeast (monascus purpureus) grown on rice and is used as a dietary main ingredient in some asian countries. It contains several compounds, collectively known as monacolin, a substance known to inhibit cholesterol synthesis. Among them, "monacolin K" is a potent inhibitor of HMG-CoA reductase.

In the American Journal of Clinical Nutrition, Vol.69, No.2, 231-.

Triglyceride lowering effects of omega-3 fatty acids and their effects of raising High Density Lipoprotein (HDL) levels are known.

The use of omega-3 fatty acids for the treatment of cardiovascular diseases is described in BMJ.2006, month 4, day 1, 332 (7544), 752-760.

Policosanols are long chain aliphatic alcohols. Examples of policosanols are triacontanol, hexacosanol, ecoontanol, tetracosanol, dotriacontanol and forty-alkanol. The policosanols may be present as such or in the form of extracts from natural products containing it, such as wheat or rice embryos, the waxy cuticle of sugar cane or ginkgo biloba leaves. Policosanols are widely used in the medical and nutritional fields.

In Nutr Rev.2003Nov;61 (11): 376-83, the use of policosanol for the treatment of cardiovascular diseases is described.

Resveratrol (trans-3, 4', 5-trihydroxystilbene) is a polyphenol molecule found in many plant species, including grapes and others.

In Free Radic Res.2000Jul;33 (1): 105-14, the use of resveratrol for inhibiting lipid peroxidation is described.

The use of coenzyme Q10 in humans is now well known and therefore does not require special explanation and the substance is commercially available. The expert in the field can refer to the patent literature filed by the applicant, in which the substance is fully described.

Vitamin B6 is a water-soluble vitamin and is part of the B-complex vitamin family that is widely used in the medical and nutritional fields. Several forms of vitamins are known, but pyridoxal phosphate (PLP) is the active form and a cofactor for many amino acid metabolic reactions, including transamination, deamination and decarboxylation. PLP is also necessary for the enzymatic reaction that controls the release of glucose from glycogen.

Vitamin B12 (also known as cobalamin) is a water-soluble vitamin that plays a key role in the normal function and blood formation of the brain and nervous system. It is one of 8B vitamins. It is usually involved in the metabolism of every cell of the human body, in particular affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. As the largest and most structurally complex vitamin, it is produced industrially only by bacterial fermentative synthesis.

Vitamin B12 is also widely used in the medical and nutritional fields.

L-carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required to transport fatty acids from the cytosol into the mitochondria during the breakdown of lipids (fats) to produce metabolic energy.

In US4255449 it is reported that L-carnitine is useful for increasing HDL cholesterol and for the treatment of diseases which may be caused by high cholesterol levels.

In WO040916029, L-carnitine is reported to be useful for the treatment of cardiovascular diseases.

Although there are other publications available in which the compounds of the present invention are demonstrated to be useful in the prevention and/or treatment of hypertriglyceridemia and hypercholesterolemia and associated disease states, none of them suggest the unexpected synergistic effects exhibited by the compositions of the present invention.

Disclosure of Invention

It has now been found, surprisingly, that the synergistic use of a composition comprising as active ingredients the following substances, the term being defined precisely hereinafter, enables an enhanced effect on the anticholesterolemic and anti-triglyceridaemic effects to be achieved, compared with the separate, independent administration of the following active ingredients or their minimum combination: (a) an extract of rice fermented with monascus purpureus; (b) at least one omega-3 fatty acid; (c) l-carnitine or a salt thereof; and one or more of the following active ingredients: (d) at least one policosanol or natural extract containing policosanol; (e) resveratrol or a natural extract containing resveratrol; (f) coenzyme Q10; and (g) at least one vitamin.

Therefore, an object of the present invention is a synergistic combination composition comprising as active ingredients: (a) an extract of rice fermented with monascus purpureus; (b) at least one omega-3 fatty acid; (c) l-carnitine or a salt thereof; and one or more of the following active ingredients: (d) at least one policosanol or natural extract containing policosanol; (e) resveratrol or a natural extract containing resveratrol; (f) coenzyme Q10; and (g) at least one vitamin.

Another object of the present invention is a synergistic composition comprising as active ingredients: (a) an extract of rice fermented with monascus purpureus; (b) at least one omega-3 fatty acid; (c) l-carnitine or a salt thereof; (d) at least one policosanol or natural extract containing policosanol; (e) resveratrol or a natural extract containing resveratrol; (f) coenzyme Q10; and optionally (g) at least one vitamin.

Another object of the present invention is a synergistic composition comprising as active ingredients: (a) an extract of rice fermented with monascus purpureus in a dose of 1mg to 3000mg, preferably 10mg to 2000mg, most preferably 200 mg; (b) at least one omega-3 fatty acid in a dose of 1mg to 2000mg, preferably in a dose of 10mg to 1000mg, most preferably in a dose of 600 mg; (c) l-carnitine or a salt thereof (as an inner salt) in a dose of 1mg to 3000mg, preferably in a dose of 10mg to 1000mg, and most preferably in a dose of 100 mg; (d) at least one policosanol or natural extract containing policosanol in a dose of 0.1mg to 1000mg, preferably in a dose of 1mg to 100mg, most preferably in a dose of 10 mg; (e) resveratrol or a natural extract containing resveratrol in a dose of 0.1mg to 1000mg, preferably in a dose of 1mg to 100mg, most preferably in a dose of 10 mg; (f) coenzyme Q10 in a dose of 0.1mg to 1000mg, preferably in a dose of 1mg to 100mg, most preferably in a dose of 10 mg; (g) vitamin B6 in a dose of 0.03mg to 300mg, preferably in a dose of 0.3mg to 30mg, most preferably in a dose of 3 mg; and (h) vitamin B12 in a dose of 0.025 microgram to 250 microgram, preferably in a dose of 0.25 microgram to 25 microgram, most preferably in a dose of 2.5 microgram.

Another object of the present invention is a synergistic composition comprising as active ingredients: (a) an extract of rice fermented with monascus purpureus at a dose of 200mg, comprising 3mg monacolin K; (b) fish oil at a dose of 600mg, comprising 120mg DHA and 165mg EPA; (c) l-carnitine tartrate at a dose of 147mg, corresponding to 100mg of L-carnitine inner salt; (d) a sugar cane extract comprising policosanol at a dose of 10 mg; (e) resveratrol in a dose of 10 mg; (f) coenzyme Q10 at a dose of 10 mg; (g) vitamin B6 in an amount of 3 mg; and (h) vitamin B12 in a dose of 2.5 micrograms;

another object of the present invention is the above composition for use as an anti-cholesterolemia agent and an anti-triglyceridaemia agent, and for increasing HDL cholesterol.

Another object of the present invention is the above composition for use in the prevention or treatment of altered lipid metabolism and its complications, wherein the complications are selected from the group consisting of: cardiovascular, atherosclerotic and/or embolic diseases.

Another object of the present invention is a composition as defined above for the preparation of a medicament for the prevention or treatment of altered lipid metabolism and its complications, wherein said complications are selected from the group consisting of: cardiovascular, atherosclerotic and/or embolic diseases.

Another object of the present invention is a composition as defined above for the preparation of a dietary supplement for the prevention or treatment of altered lipid metabolism and its complications, wherein said complications are selected from the group consisting of: cardiovascular, atherosclerotic and/or embolic diseases.

Another object of the invention is a method for increasing HDL cholesterol and for decreasing cholesterol and triglycerides, comprising: administering to a patient in need thereof a suitable amount of the above composition.

Another object of the invention is a method for the prevention or treatment of altered lipid metabolism and its complications selected from cardiovascular, atherosclerotic and/or embolic diseases, comprising: administering to a patient in need thereof a suitable amount of the above composition.

The composition of the invention may additionally comprise: other vitamins, coenzymes, minerals and antioxidants; or other active ingredients useful for the treatment of lipid metabolism disorders.

The salt of L-carnitine means any salt of L-carnitine with an acid that does not produce toxic or side effects.

Non-limiting examples of such salts are: chloride, bromide, orotate, aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulfate, acid sulfate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucate, magnesium tartrate, 2-amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate and trifluoroacetate.

In the publication int.j.of pharm.33 (1986), 201-217, a list of FDA-approved pharmaceutically acceptable salts is given.

Detailed Description

The monascus purpureus used according to the present invention is an extract of red yeast rice (oryzasativa) fermented with red yeast (monascus purpureus) containing 1.5% monacolin K.

The omega-3 fatty acids according to the invention may form esters or salts. These fatty acids may be obtained synthetically or, preferably, from fish oils. In this case, it is possible to use various mixtures of omega-3 fatty acids, according to their characteristics. Preferably, the omega-3 fatty acid is a long chain fatty acid (20 to 22 carbon atoms). Most preferred are 5,8,11,14, 17-eicosapentaenoic acid (EPA) and cis 0,13,16, 19-docosahexaenoic acid (DHA). These omega-3 fatty acids may be esterified or salified with an alcohol or a base, respectively, to form pharmaceutically acceptable derivatives. The individual omega-3 fatty acids or their esters or salts or mixtures thereof may be obtained commercially or may be prepared by known methods. In particular, mixtures can be formulated for use in the combination according to the invention.

Policosanols according to the invention are long chain aliphatic alcohols. Examples of policosanols are triacontanol, hexacosanol, ecoontanol, tetracosanol, dotriacontanol and forty-alkanol. The policosanols may be present as such or in the form of extracts from natural products containing it, such as wheat or rice embryos, the waxy cuticle of sugar cane or ginkgo biloba leaves.

Resveratrol according to the invention is a polyphenol molecule found in many plant species, including grapes and others. Polyphenols (including flavonoids, flavonols, catechins and stilbenes) are present in plant material of human diet, where they act as antioxidants and protect plants from damage by bacteria, fungi and ultraviolet radiation. Since resveratrol is present in wine, it has been assumed that it may be the cause of "french contradictions", an epidemiological phenomenon: among these, the french population has a significantly lower incidence of cardiovascular disease, even though the french population consumes a higher amount of fat in the diet than other populations.

The monascus purpureus, omega-3 fatty acids, policosanol, resveratrol, coenzyme Q10, vitamin B6, vitamin B12 and L-carnitine according to the invention may be administered in a "synergistic manner". By "synergistic manner" of the foregoing compounds is meant co-administration (i.e., substantially concurrent or sequential supplementation) of monascus purpureus and at least one of the following: omega-3 fatty acids, at least one policosanol, resveratrol, coenzyme Q10, vitamin B6, vitamin B12 and L-carnitine, or, in combination and in a mixture, optionally additionally comprising one or more pharmaceutically acceptable excipients or diluents, a composition comprising the aforementioned active ingredients.

The compositions of the invention are administered orally in any suitable form. An example of a form of administration is: liquid, semi-liquid or solid form in sachets, pills, vials, pastes, gels or liposomes.

The monascus purpureus, omega-3 fatty acids, policosanol, resveratrol, coenzyme Q10, vitamin B6, vitamin B12 and L-carnitine according to the present invention are known compounds and are readily available from the market.

The composition according to the invention consists of active ingredients familiar to practitioners in the medical field and already in use. The active ingredient does not have the side effects of antilipemics (statins, probucol, resins and fibrates) known in the art.

Their availability is therefore very easy, since these are products which have been marketed for a long time at present and have a grade suitable for human administration.

For any compound, the therapeutically effective dose can be estimated initially in cell culture assays or in animal models (usually mouse or rat).

The animal model may also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful dosages and routes for administration in humans.

For human subjects, the exact effective dose depends on: the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, time and frequency of administration, drug combination, sensitivity to response to treatment and tolerance/response.

This means that, in addition to taking into account the synergistic effects demonstrated below, the dosages and ratios of the individual components can be determined by the expert in the field with conventional preclinical and clinical trials, or with the usual considerations regarding the formulation of dietetic products.

The compositions encompassed by the present invention are entirely conventional and can be obtained by methods of common practice in the pharmaceutical industry. The composition according to the invention comprises, together with the active ingredient, at least one pharmaceutically acceptable carrier or excipient. Particularly useful may be formulation adjuvants such as solubilizing, dispersing, suspending and emulsifying agents. The general reference tool is Remington's Pharmaceutical Sciences Handbook, latest edition.

The following non-limiting examples further illustrate the invention.

Example 1

Serum lipid lowering activity in db/db mice

Male CD1 mice were used that underwent a high cholesterol diet (DP/104, Altromin-Rieper) for about 25 days. A 7 day acclimation period was allowed before starting the high cholesterol diet.

Mice were housed in cages with stainless steel lids-feed and sterile and dust-free bedding. Animals were housed under light-dark cycle, keeping temperature and humidity constant. Parameters of the animal room were evaluated as follows: temperature 22 + -2 deg.C, relative humidity 55 + -10%, about 15-20 filtered air changes/hour, and a 12-hour day-night cycle for artificial lights (7 am, 7 pm). Environmental conditions are monitored.

Mice were grouped (10 mice per group) and treated orally with a compound of the invention or their combination (1 mL) daily, 2 times daily at the doses reported below:

at the beginning of the treatment, the animals were checked for body weight and monitored for water and feed consumption as planned.

On day 18, plasma cholesterol, triglycerides and HDL cholesterol were evaluated.

Blood samples were collected from the caudal vein with the aid of Jelco22G catheter (Johnson and Johnson) in post-absorption conditions (semi-fasting from 9 am to 4 pm) 7 and half hours after the last treatment.

The results obtained are reported in tables 1-3 below.

TABLE 1

Plasma total cholesterol levels of male CD1 mice (10 mice per group) undergoing a high cholesterol diet treated orally (2 times daily, 17 days; 1 time on day 18) with a compound of the invention or a combination thereof or a carrier. Blood was collected 8 hours after the last treatment, in the postabsorptive state (fasting from 9 am to 5 pm).

Mean ± standard error.

Student's t-test.

TABLE 2

Plasma triglyceride levels of male CD1 mice (10 mice per group) undergoing a high cholesterol diet treated orally (2 times daily, 17 days; 1 time on day 18) with a compound of the invention or a combination thereof or a carrier. Blood was collected 8 hours after the last treatment, in the postabsorptive state (fasting from 9 am to 5 pm).

Mean ± standard error.

Student's t-test.

TABLE 3

Plasma HDL-cholesterol levels of male CD1 mice (10 mice per group) undergoing a high cholesterol diet treated orally (2 times daily, 17 days; 1 time on day 18) with a compound of the invention or a combination thereof or a carrier. Blood was collected 8 hours after the last treatment, in the postabsorptive state (fasting from 9 am to 5 pm).

Mean ± standard error.

Student's t-test.

The results reported above clearly demonstrate the unexpected synergistic effect of the combination according to the invention compared to the single ingredients or their minimal combinations.

In the following, some examples of the compositions of the present invention are reported.

Composition 1

Claims (31)

1. A composition comprising as active ingredients: (a) an extract of rice fermented with monascus purpureus containing 1.5% monacolin K; (b) at least one omega-3 fatty acid; (c) l-carnitine or a salt thereof; and one or more of the following active ingredients: (d) at least one policosanol or natural extract containing policosanol; (e) resveratrol or a natural extract containing resveratrol; (f) coenzyme Q10; and (g) at least one vitamin.

2. The composition according to claim 1, comprising as active ingredients: (a) an extract of rice fermented with monascus purpureus; (b) at least one omega-3 fatty acid; (c) l-carnitine or a salt thereof; (d) at least one policosanol or natural extract containing policosanol; (e) resveratrol or a natural extract containing resveratrol; (f) coenzyme Q10; and optionally (g) at least one vitamin.

3. The composition according to claim 1, comprising as active ingredients: (a) an extract of rice fermented with monascus purpureus in an amount of 1mg to 3000 mg; (b) at least one omega-3 fatty acid in an amount of 1mg to 2000 mg; (c) l-carnitine or a salt thereof as an internal salt in a dose of 1mg to 3000 mg; (d) at least one policosanol or natural extract containing policosanol in a dose of 0.1mg to 1000 mg; (e) resveratrol or a natural extract containing resveratrol in an amount of 0.1mg to 1000 mg; (f) coenzyme Q10 in an amount of 0.1mg to 1000 mg; (g) vitamin B6 in an amount of 0.03mg to 300 mg; and (h) vitamin B12 in a dose of 0.025 μ g to 250 μ g.

4. The composition according to claim 3, wherein the extract of rice fermented with monascus purpureus is contained in an amount of 10mg to 2000 mg.

5. The composition according to claim 3, wherein the extract of rice fermented with monascus purpureus is contained in an amount of 200 mg.

6. The composition according to claim 3, wherein it comprises at least one omega-3 fatty acid in a dose ranging from 10mg to 1000 mg.

7. The composition according to claim 3, wherein it comprises at least one omega-3 fatty acid in a dose of 600 mg.

8. Composition according to claim 3, wherein it comprises as internal salt L-carnitine or a salt thereof in a dose ranging from 10mg to 1000 mg.

9. The composition according to claim 3, wherein it comprises L-carnitine or a salt thereof as an internal salt in a dose of 100 mg.

10. The composition according to claim 3, wherein it comprises at least one policosanol or natural extract containing policosanol in a dose ranging from 1mg to 100 mg.

11. The composition according to claim 3, wherein it comprises at least one policosanol or natural extract containing policosanol in a dose of 10 mg.

12. The composition according to claim 3, wherein it comprises resveratrol or a natural extract containing resveratrol in a dose of 1mg to 100 mg.

13. The composition according to claim 3, wherein it comprises resveratrol or a natural extract containing resveratrol in a dose of 10 mg.

14. The composition according to claim 3, wherein it comprises coenzyme Q10 in a dose ranging from 1mg to 100 mg.

15. The composition according to claim 3, wherein it comprises coenzyme Q10 in a dose of 10 mg.

16. The composition according to claim 3, wherein it comprises vitamin B6 in a dose ranging from 0.3mg to 30 mg.

17. The composition according to claim 3, wherein it comprises vitamin B6 in a dose of 3 mg.

18. The composition according to claim 3, wherein it comprises vitamin B12 in a dose ranging from 0.25 to 25 μ g.

19. The composition according to claim 3, wherein it comprises vitamin B12 in a dose of 2.5 μ g.

20. The composition according to claim 1, comprising as active ingredients: (a) an extract of rice fermented with monascus purpureus at a dose of 200mg, comprising 3mg monacolin K; (b) fish oil at a dose of 600mg, comprising 120mg DHA and 165mg EPA; (c) l-carnitine tartrate at a dose of 147mg, corresponding to 100mg of L-carnitine inner salt; (d) a sugar cane extract comprising policosanol at a dose of 10 mg; (e) resveratrol in a dose of 10 mg; (f) coenzyme Q10 at a dose of 10 mg; (g) vitamin B6 in an amount of 3 mg; and (h) vitamin B12 in a dose of 2.5 μ g.

21. The composition according to claim 1 for use as an anti-cholesterolemia and anti-triglyceridaemia agent, and for increasing HDL cholesterol.

22. The composition according to claim 1 for use in the prevention or treatment of altered lipid metabolism and complications thereof, wherein the complications are selected from the group consisting of: cardiovascular, atherosclerotic and/or embolic diseases.

23. The composition according to claim 1 for use as a medicament.

24. The composition according to claim 1 for use as a dietary supplement.

25. The composition according to claim 1, additionally comprising other vitamins, coenzymes, minerals and antioxidants or active ingredients useful for the treatment of lipid disorders.

26. The composition according to claim 1, further comprising at least one pharmaceutically acceptable carrier and/or excipient.

27. The composition of claim 1, which can be administered orally in liquid, semi-liquid or solid form in sachets, pills, vials, pastes, gels or liposomes.

28. The composition of claim 1, wherein the salt of L-carnitine is selected from the group consisting of: chloride, bromide, orotate, aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulfate, acid sulfate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, mucate, magnesium tartrate, 2-amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate and trifluoroacetate.

29. The composition of claim 1, wherein the policosanol is selected from the group consisting of: triacontanol, hexacosanol, ecocontanol, tetracosanol, dotriacontanol and forty-alkanol.

30. The composition of claim 1, wherein the policosanol is in the form of an extract from a natural product selected from the group consisting of: wheat germ, rice germ, sugar cane or ginkgo leaf.

31. Use of a composition according to any of the preceding claims for the preparation of a medicament for the prevention or treatment of altered lipid metabolism and its complications selected from cardiovascular, atherosclerotic and/or embolic diseases.