TW201300119A - Composition useful for the treatment of lipid metabolism disorders - Google Patents

Abstract

The present invention relates to a composition useful for the treatment of lipid metabolism disorders, comprising one or more of the following active ingredients: (a) 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 a natural extract containing policosanols; (e) resveratrol or a natural extract containing resveratrol; (f) Coenzyme Q10; and (g) at least one vitamin.

Description

Composition for treating disorders of lipid metabolism

The present invention relates to combinations of active ingredients and compositions containing the same for use in medical and nutritional applications for the preparation of a medicament or food additive 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 an active ingredient, (a) an extract of rice fermented by 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 a natural extract containing sugarcane; (e) resveratrol or a natural extract of resveratrol; (f) coenzyme Q10; and (g) at least one vitamin.

Cardiovascular diseases associated with abnormal lipid metabolism are very common in industrialized countries. For example, in Italy, these cardiovascular diseases account for more than 40% of the total mortality (Capocaccia R., Farchi G., Prati S. et al.: La mortalità in Italia nell'anno 1989. Rappcrto ISTISAN 1992/22) . Our understanding of the relationship between cholesterol and coronary heart disease stems from epidemiological studies conducted in the past few years. The conclusions of these studies indicate that the development of severe coronary atherosclerosis and coronary heart disease is closely related to serum cholesterol (McGill HCJr. et al.: The International Atherosclerosis Project. Lab. Invest. 18: 463-653) , 1968; Keys A.: Seven Countries: Death and Coronary Heart Disease. Harvard University Press, Cambridge, 1980).

Correcting eating habits through proper diet is always the first step taken in the case of hyperlipidemia. However, due to the generally poor tolerance of strict dietary discipline, the severity of hypercholesterolemia or hereditary resistance, satisfactory results are not always achieved.

In order for these patients to achieve the desired results, that is, the blood concentration of triglycerides and cholesterol is normalized, it is necessary to rely on pharmacological treatment. There are two types of hypolipidemic drugs: the most important are those who lower cholesterol and those who mainly lower triglycerides.

Cholesterol-lowering drugs include statins, probucol, and resins, including bentic esters, niacin, and fatty acids belonging to the omega-3 series.

Statins (lovastatin, simvastatin, pravastatin, fluvastatin, and the like) are inhibitors of hydroxy-methyl-pentamethylene-coenzyme A (HMG-CoA) reductase. By inhibiting this enzyme, statins can reduce liver synthesis of cholesterol (Lancet 1994; 334: 1383-1389). To compensate for the reduction in intracellular cholesterol, hepatocytes produce several receptors for LDL and VLDL lipoproteins, thus removing these lipoproteins from the blood.

Statins are drugs that are better tolerated than other anticholesterol agents, but they are not without drawbacks. The most common side effects of these drugs are gastrointestinal diseases, rashes and headaches.

It has been reported that although statins can cause a reduction in the number of deaths due to coronary heart disease, an increase in death due to other events (such as tumors or trauma) has been observed in patients treated (Davey-Smith G., Song F., Sheldon TA: Cholesterol lowering and mortality: the importance of considering initial level at risk. BMJ, 1993, 306: 1367-1373; Ravnshov U.: Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome. BMJ 1992, 305: 15-19). Experimental results in animals and humans have shown that in order to reduce the amount of cholesterol, pharmacological treatment with statins should be administered only to patients at high risk of coronary artery disease (JAMA, 1996; 275: 55-60).

Red yeast rice is a product of the growth yeast on the rice (Mycotoxin) and is used as a major dietary ingredient in some Asian countries. Red glutinous rice contains several compounds commonly known as monacolin, a substance known to inhibit cholesterol synthesis. Among them, "monacolin K" is a potent inhibitor of HMG-CoA reductase.

The American Journal of Clinical Nutrition, Vol. 69, No. 2, 231-236 (February 1999) describes the cholesterol lowering efficacy of red glutinous rice addition.

The efficacy of omega-3 fatty acids to reduce triglyceride and increase the amount of high density lipoprotein (HDL) is known.

Document BMJ. April 1, 2006, 332 (7544): 752-760 describes the use of omega-3 fatty acids for the treatment of cardiovascular diseases.

Sugarcane is a long-chain aliphatic alcohol. Examples of sugar cane are triacontanol, hexadecanol, hexadecanol, alkanol ecocontanol, tetracosyl alcohol, tridecyl alcohol and tetradecyl alcohol. The sugarcane may be in the form of an original or in the form of an extract containing its natural product, for example Wheat or rice embryo, waxy cuticle of sugar cane or ginkgo leaf. Sugarcane is widely used in the fields of medicine and nutrition.

Literature Nutr Rev. 2003 Nov, 61(11): 376-83 describes the use of sugarcane in the treatment of cardiovascular diseases.

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

Document Free Radic Res. 2000 Jul, 33(1): 105-14 describes the use of resveratrol to inhibit lipid peroxidation.

The use of coenzyme Q10 in humans is now well known and therefore need not be specifically stated, and Coenzyme Q10 is commercially available. Experts in this field can refer to the patent documents filed by the present applicant, in which coenzyme Q10 has been fully described.

Vitamin B ₆ is a water-soluble vitamin and is a member of the multivitamin B group widely used in medicine and nutrition. Several forms of vitamins are conventional, but pyridoxal phosphate (PLP) is an active form and is a cofactor for many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation. PLP is also required for the enzyme-catalyzed reaction that controls the release of glucose from glycogen.

Vitamin B _{12 (} also known as cobalamin) is a water-soluble vitamin that plays a key role in the normal functioning of the brain and nervous system and blood formation. Vitamin B ₁₂ is one of eight B vitamins. Vitamin B ₁₂ is usually involved in the metabolism of every cell in the body, especially affecting DNA synthesis and regulation, and also affects fatty acid synthesis and energy production. As the largest and most complex vitamin, vitamin B _{12 is} industrially produced only by bacterial fermentation.

Vitamin B ₁₂ is also widely used in the fields of medicine and nutrition.

L-carnitine is a quaternary ammonium compound biosynthesized from amino acid lysine and methionine. In living cells, in the process of breaking down lipids (fats) to produce metabolic energy, L-carnitine is required to carry fatty acids from the cytosol to the mitochondria.

US 4255449 reports that L-carnitine can be used to increase HDL cholesterol and to treat diseases that may be caused by high cholesterol levels.

WO 040916029 reports that L-carnitine can be used to treat cardiovascular diseases.

While other publications present show that the compounds of the invention are useful in the prevention and/or treatment of hypertriglyceridemia and hypercholesterolemia and related disease states, none of these publications mention or suggest compositions of the present invention. Unpredictable synergies that appear.

Brief description of the invention

It has been unexpectedly found that the synergistic use of the composition of the following substances as active ingredients is compared with the following active ingredients or the smallest combination of them, individual administration (the term synergistic use will be It is precisely defined in the text) to enhance the anti-cholesterol and anti-triglyceride blood effects: (a) extracts of rice fermented with Rhododendron chinense; (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 sugar cane or natural extract containing sugarcane; (e) resveratrol or natural resveratrol Extract; (f) Coenzyme Q10; and (g) at least one vitamin.

Accordingly, the subject matter of the present invention is a synergistic combination composition comprising as an active ingredient the following: (a) an extract of rice fermented with Rhodobacter sphaeroides; (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 sugar cane or natural extract containing sugarcane; (e) resveratrol or white a natural extract of resveratrol; (f) coenzyme Q10; and (g) at least one vitamin.

Another subject of the present invention is a synergistic composition comprising, as an active ingredient, (a) an extract of rice fermented with Rhodobacter sphaeroides; (b) at least one omega-3 fatty acid; c) L-carnitine or a salt thereof; (d) at least one sugar cane or natural extract containing sugarcane; (e) resveratrol or a natural extract containing resveratrol; (f) coenzyme Q10; and optionally (g) at least one vitamin.

Another subject of the present invention is a synergistic composition comprising as an active ingredient the following: (a) an extract of rice fermented with Rhodobacter sphaeroides, at a dose of from 1 mg to 3000 mg, preferably The dose is 10 mg to 2000 mg, the most preferred dose is 200 mg; (b) at least one omega-3 fatty acid at a dose of 1 mg to 2000 mg, preferably at a dose of 10 mg to 1000 mg, the most preferred dose being 600 mg; (c) L-carnitine or a salt thereof (as an internal salt) at a dose of 1 mg to 3000 mg, preferably at a dose of 10 mg to 1000 mg, most preferably at a dose of 100 mg; (d) at least A sugarcane or a natural extract containing sugarcane, at a dose of 0.1 mg to 1000 mg, preferably at a dose of 1 mg to 100 mg, most A preferred dose is 10 mg; (e) resveratrol or a natural extract containing resveratrol at a dose of 0.1 mg to 1000 mg, preferably a dose of 1 mg to 100 mg, most preferably a dose of 10 (f) Coenzyme Q10 at a dose of 0.1 mg to 1000 mg, preferably at a dose of 1 mg to 100 mg, most preferably at a dose of 10 mg; (g) vitamin B6 at a dose of 0.03 mg to 300 mg, A preferred dose is from 0.3 mg to 30 mg, most preferably a dose of 3 mg; and (h) a vitamin B12 at a dose of from 0.025 micrograms to 250 micrograms, a preferred dose of from 0.25 micrograms to 25 micrograms, most preferably a dose of 2.5 Microgram (mcg).

Another subject of the present invention is a synergistic composition comprising as an active ingredient the following: (a) an extract of 200 mg of Rhododendron sinensis, which contains 3 mg of mona. Kelin K; (b) 600 mg of fish oil containing 120 mg DHA and 165 mg EPA; (c) a dose of 147 mg of L-carnitine tartrate corresponding to 100 mg of L-carnitine internal salt; (d) A dose of 10 mg of sugar cane extract containing sugarcane; (e) a dose of 10 mg of resveratrol; (f) a dose of 10 mg of coenzyme Q10; (g) a dose of 3 mg of vitamin B6; and (h) a dose of 2.5 micrograms of vitamin B12.

Another subject of the present invention is the above composition as an anticholesterol and anti-glyceride blood agent and for increasing HDL cholesterol.

Another subject of the invention is a composition for preventing or treating altered lipid metabolism and complications thereof, wherein the complication is selected from the group consisting of cardiovascular disease, atherosclerotic disease, and/or embolic disease.

Another subject of the present invention is the above composition for the preparation of a medicament The drug is for preventing or treating altered lipid metabolism and its complications, wherein the complication is selected from the group consisting of cardiovascular disease, atherosclerotic disease, and/or embolic disease.

Another subject of the present invention is a composition for the preparation of a dietary supplement for preventing or treating altered lipid metabolism and complications thereof, wherein the complication is selected from the group consisting of cardiovascular diseases, Atherosclerotic disease and / or embolic disease.

Another subject of the invention is a method for increasing HDL cholesterol and lowering cholesterol and triglycerides comprising administering to a patient in need thereof an appropriate amount of the above composition.

Another subject of the invention is a method of preventing or treating altered lipid metabolism and complications thereof, wherein the complication is selected from the group consisting of a cardiovascular disease, an atherosclerotic disease, and/or an embolic disease, the method comprising The patient in need is given an appropriate amount of the above composition.

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

The salt of L-carnitine refers to any salt formed by L-carnitine with an acid which does not cause toxic effects or side effects.

Non-limiting examples of such salts are chloride, bromide, orotate, aspartate, acid aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, rich And the acidic fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pate, sulfate, Acidic sulfates, glucose phosphates, tartrates and acid tartrates, glycerol phosphates, Mucic acid salt, magnesium tartrate, 2-amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate and trifluoroacetate.

A list of pharmaceutically acceptable salts approved by the FDA is published in the publication Int. J. of Pharm. 33 (1986), 201-217.

Detailed description of the invention

The Rhodobacter sinensis used in the present invention is an extract of red rice (rice Oryza sativa) fermented by red yeast (Mycotoxin), which contains 1.5% monacolin K.

The omega-3 fatty acids of the invention may be esterified or salted. These fatty acids can be obtained synthetically or preferably from fish oil. In this regard, depending on the characteristics of the omega-3 fatty acid, various mixtures of omega-3 fatty acids can be used. Preferably, the omega-3 fatty acid is a long chain fatty acid (containing from 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 with an alcohol or alkalized, respectively, to form a pharmaceutically acceptable derivative. Separate omega-3 fatty acids or their esters or salts or mixtures thereof may be commercially available or may be prepared by conventional methods. These mixtures may in particular be formulated to a combination of the invention.

The sugar cane of the present invention is a long-chain aliphatic alcohol. Examples of sugar cane are triacontanol, hexadecanol, hexadecanol, alkanol ecocontanol, tetracosyl alcohol, tridecyl alcohol and tetradecyl alcohol. The sugar cane is present in its original form or in the form of an extract containing its natural product, such as wheat or rice embryos, waxy cuticles of sugar cane or ginkgo leaves.

The resveratrol of the present invention is a polyphenol molecule found in many plant species, including grapes and others. Polyphenols (including flavonoids, flavonols, catechins and terpenoids) are present in plant materials of the human diet, in which polyphenols act as antioxidants and protect plants from bacteria, fungi and Damage to ultraviolet radiation. Since resveratrol is present in wine, it has been postulated that resveratrol may be the cause of “French Paradox”, which is an epidemiological phenomenon: the French show a significantly lower incidence of cardiovascular disease Rate, although the French diet consumes higher fat than other people's diets.

The Rhodobacter sphaeroides, omega-3 fatty acids, sugarcane, resveratrol, coenzyme Q10, vitamin B6, vitamin B12 and L-carnitine of the present invention can be administered in a "synergistic manner". By "co-use" of the foregoing compounds means co-administration (ie, substantially simultaneous or sequential supplementation) of Rhodopseudomonas and at least one omega-3 fatty acid, at least one sugarcane, resveratrol, coenzyme Q10, vitamin B6 And vitamin B12 and L-carnitine, or indiscriminately administered as a composition of the aforementioned active ingredient in the form of a composition or mixture and optionally further comprising one or more pharmaceutically acceptable excipients or diluents.

The compositions of the invention are administered orally in any suitable form. Examples of administration forms are sachets, pills, vials, creams, gels or liposomes in liquid, semi-liquid or solid form.

The conventional compounds of the present invention are readily available from the genus Rhodotorula, omega-3 fatty acids, sugar cane, resveratrol, coenzyme Q10, vitamin B6, vitamin B12 and L-carnitine.

The composition of the present invention is familiar to practitioners in the medical field and has It consists of the active ingredients used. These active ingredients do not have the side effects of anti-lipemic agents (statins, probucol, resins and fibrates) which are well known in the art.

The above active ingredients are highly available because they have been sold on the market for a long time and have a product suitable for human body grades.

For any compound, the therapeutically effective dose can be estimated initially in a cell culture assay or in an animal (usually mouse or rat) model.

This animal model can also be used to determine the appropriate concentration range and route of administration. This information can then be used to determine the useful dose and route to the human body.

The precise effective dose to a human individual will depend on the severity of the condition, the general state of health of the individual, age, weight and sex, diet, time and frequency of administration, drug combination, response sensitivity, and tolerance to treatment. / answer.

This means that in addition to the synergistic effects demonstrated below, the dosages and ratios of the individual components can be determined by experts in the field by routine pre-clinical testing and clinical trials or by general considerations for modulation of the dietary product.

The compositions encompassed by the present invention are entirely conventional and are available by the general practice of the pharmaceutical industry. The compositions of the present invention comprise the active ingredient and at least one pharmaceutically acceptable carrier or excipient. Particularly useful may be adjuvants such as, for example, solubilizers, dispersing agents, suspending agents, and emulsifying agents. The general reference tool is the Remington's Pharmaceutical Sciences Handbook, the latest edition.

The invention is further illustrated by the following non-limiting examples.

Example 1. Reduction of serum lipid activity in db/db mice

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

The mice were housed in cages with a stainless steel lid-feed port and a sterilized and dust-free cushion. Animals were housed under light-dark cycles to maintain constant temperature and humidity. The parameters of the evaluation animal room were as follows: 22 ± 2 ° C temperature, 55 ± 10% relative humidity, about 15-20 filtered air replacement / hour, and a 12-hour day and night cycle of artificial light (7 am, 7 pm). Monitor environmental conditions.

Mice were grouped (10 mice per group) and orally administered (1 ml) twice a day (1 ml) of the compounds of the invention or a combination of them: - monacolin K 2 mg/kg (dissolved in water) );- fish oil 200 mg/kg (dissolved in ethanol); - hexadecanol 25 mg/kg (dissolved in ethanol); - resveratrol 5 mg/kg (dissolved in ethanol); - coenzyme Q10 50 mg /kg (dissolved in water); - Vitamin B6 0.3 mg/kg (dissolved in water); - Vitamin B12 0.25 mg/kg (dissolved in water); - L-carnitine 20 mg/kg (dissolved in water).

At the beginning of the treatment, the animal's body weight was examined and the animal's water and feed consumption was monitored as planned.

On day 18, plasma cholesterol, triglyceride and HDL cholesterol were assessed.

Blood samples were taken from the tail vein with the aid of a Jelco 22G catheter (Johnson and Johnson) at 7.3 hours after the last treatment and after post-absorptive conditions (fasting from 9 am to 4 pm).

The results obtained are shown in Tables 1 to 3 below.

Table 2 Plasma glycerol of male CD1 mice (10 mice per group) of a high cholesterol diet administered orally (2 times a day for 17 days; once every 18 days) by a compound of the invention or a combination or carrier thereof The amount of triester. Eight hours after the last treatment, blood was collected in the post-absorptive state (fasting from 9 am to 5 pm). Mean ± standard error. Student's t-test.

Table 3 Males on a high cholesterol diet administered orally (2 times a day for 17 days; once every 18 days) via a compound of the invention or a combination or carrier thereof

The above results clearly demonstrate the unpredictable synergy of the combinations of the present invention over a single component or a minimum combination thereof.

Some examples of the compositions of the present invention are described below.

Composition 1

Claims (15)

A composition comprising, as an active ingredient, (a) an extract of rice fermented with Rhodopseudomonas; (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 sugar cane or natural extract containing sugar cane; (e) resveratrol or natural extract containing resveratrol; (f) coenzyme Q10; and (g) at least one vitamin. The composition of claim 1, which comprises as an active ingredient the following substances: (a) an extract of rice fermented with Rhodobacter sphaeroides; (b) at least one omega-3 fatty acid; (c) L - carnitine or a salt thereof; (d) at least one sugar cane or natural extract containing sugar cane; (e) resveratrol or a natural extract containing resveratrol; (f) coenzyme Q10; Optionally (g) at least one vitamin. The composition of claim 1, which comprises as an active ingredient the following substances: (a) an extract of rice fermented with Rhodobacter sinensis at a dose of 1 mg to 3000 mg, preferably a dose of 10 From mg to 2000 mg, the most preferred dose is 200 mg; (b) at least one omega-3 fatty acid at a dose of from 1 mg to 2000 mg, preferably at a dose from 10 mg to 1000 mg, most preferably at a dose of 600 mg; (c) L-carnitine or a salt thereof as an internal salt at a dose of from 1 mg to 3000 mg, preferably at a dose of from 10 mg to 1000 mg, most preferably at a dose of 100 mg; (d) at least one sugar cane Or a natural extract containing sugarcane, at a dose of 0.1 mg to 1000 mg, preferably at a dose of 1 mg to 100 mg, most preferably at a dose of 10 mg; (e) resveratrol or resveratrol Natural The extract is at a dose of 0.1 mg to 1000 mg, preferably at a dose of 1 mg to 100 mg, and the most preferred dose is 10 mg; (f) Coenzyme Q10 at a dose of 0.1 mg to 1000 mg, preferably a dose of 1 From mg to 100 mg, the most preferred dose is 10 mg; (g) vitamin B6 at a dose of 0.03 mg to 300 mg, preferably at a dose of 0.3 mg to 30 mg, most preferably at a dose of 3 mg; and (h) Vitamin B12 is administered at a dose of from 0.025 micrograms to 250 micrograms, a preferred dose is from 0.25 micrograms to 25 micrograms, and the most preferred dose is 2.5 micrograms. The composition of claim 1, which comprises as an active ingredient the following: (a) an extract of 200 mg of Rhododendron sinensis, which contains 3 mg of monacolin K (b) a 600 mg fish oil containing 120 mg DHA and 165 mg EPA; (c) a 147 mg L-carnitine tartrate corresponding to 100 mg L-carnitine inner salt; (d) a dose of 10 mg of sugarcane extract containing sugar cane; (e) a dose of 10 mg of resveratrol; (f) a dose of 10 mg of coenzyme Q10; (g) a dose of 3 mg of vitamin B6; (h) Vitamin B12 at a dose of 2.5 μg. The composition of claim 1 is used as an anticholesterol and anti-triglyceride blood and is used to increase HDL cholesterol. The composition of claim 1 is for use in the prevention or treatment of altered lipid metabolism and its complications, wherein the complication is selected from the group consisting of cardiovascular disease, atherosclerotic disease, and/or embolic disease. For example, the composition of claim 1 is used as a medicine. The composition of claim 1 is used as a dietary supplement. The composition of claim 1 of the patent scope further comprises other vitamins, coenzymes, minerals and antioxidants or active ingredients which can be used for the treatment of lipid diseases. The composition of claim 1 further comprising at least one pharmaceutically acceptable carrier and/or excipient. The composition of claim 1 can be administered orally in the form of a liquid, semi-liquid or solid via a sachet, pill, vial, ointment, gel or liposome. The composition of claim 1, wherein the salt of L-carnitine is selected from the group consisting of chloride, bromide, orotate, aspartate, acid aspartate, acid citrate, lemon Magnesium, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, flutter Acid salt, acid pamoate, sulfate, acid sulfate, glucose phosphate, tartrate and acid tartrate, glycerol phosphate, mucic acid, magnesium tartrate, 2-amino-ethanesulfonate, 2-amine Magnesium-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate or trifluoroacetate. The composition of claim 1, wherein the sugarcane is selected from the group consisting of triacontanol, hexadecanol, hexadecanol, alkanol ecocontanol, tetracosyl alcohol, tridecanol or tetra Decalkanol. The composition of claim 1, wherein the sugar cane is in the form of an extract of a natural product selected from the group consisting of wheat germ and rice. Embryo, sugar cane or ginkgo leaves. A medicament for the manufacture of a medicament or kit for preventing or treating altered lipid metabolism and its complications, wherein the complication is selected from the group consisting of cardiovascular diseases, atherosclerotic diseases, and / or embolic disease.