ITRM20060203A1 - COMPOSITION BASED ON EXTRACTIVE PREPARATIONS OF OFFICINAL PLANTS AND EDULE FOR THE TREATMENT OF DISLIPIDEMIES - Google Patents

Description

Description of the patent for industrial invention entitled:

"COMPOSITION BASED ON EXTRACTIVE PREPARATIONS OF OFFICINAL AND EDULE PLANTS FOR THE TREATMENT OF DYSLIPIDEMIA"

Background of the invention

Dyslipidemias and, in particular, increased plasma cholesterol, increase the risk of cardiovascular diseases (arterial and atherosclerosis, myocardial infarction, stroke...). Polygenic (non-familial) hypercholesterolemia is the most common form of elevation of piasmatic total cholesterol (usually between 240 and 350 mg / dL) and can present as isolated or mixed dyslipidemia, if associated with an increase in triglyceridemia (usually within i 350 mg / dL). Total blood cholesterol levels above 200 mg / dl are considered, even if isolated, a relevant risk factor for coronary heart disease. The risk is not so much related to increases in the concentration of total cholesterol, but, in particular, to alterations of the different forms of cholesterol. In fact, persistently high LDL (low density lipoprotein) cholesterol levels are the cause of lipoprotein deposits on vascular endothelium over time with the formation of atherosclerotic plaques and low levels of HDL cholesterol (high density lipoproteins), not ensuring optimal transport of lipoproteins body to the liver for their elimination, favor their deposit on the vascular wall.

The correlations existing between the piasmatic concentrations of the various circulating forms of cholesterol and the cardiovascular risk are currently classified as follows.

Total cholesterol (CTI

<200 mg / dL low risk

200-239 mg / dL borderline high

> 240 mg / dL high risk

Cholesterol - LDL fLDL-CI

<100 mg / dL optimal level

Low borderline 100-129 mg / dL

130-159 mg / dL borderline high

160-189 mg / dL high risk

> 190 mg / dL very high risk

HDL cholesterol (HDL-C

<40 mg / dL high risk

40-59 mg / dL borderline

60 mg / dL risk protection

Isolated high levels of triglyceridemia do not represent an index of cardiovascular risk but are considered an indicator of lipoprotein problems that can contribute to the onset of heart disease. Various ranges of pathological values have been defined for triglycerides:

Triglycerides (TG)

<150 mg / dL normal

150-199 mg7dL borderline high

200-499 mg / dL high

> 500 mg / dL very high

The therapeutic decision in the case of dyslipidemias is however taken only after having typed them with sufficient certainty.

In particular, using defined algorithms, it is clinically ascertained whether the dyslipidemia is of the monogenic type (hypercholesterolemia, hypertriglyceridemia, combined familial hyperlipemia) or polygenic.

In the first case (familial dyslipidemia), therapy is always indicated regardless of the overall cardiovascular risk. In the second case (unfamiliar dyslipidemia), also in consideration of the multifactorial nature of coronary heart disease, Γ assessment of the absolute risk of developing coronary heart disease needs to be done by examining also the co-presence of other risk factors (age:> 45 for for men and> 55 for women; high blood pressure, diabetes, smoking, excess body weight, physical inactivity). After a qualitative and quantitative assessment of the individual risk factors, the patient can undergo therapeutic treatment and / or specific lifestyle changes (dietary regimen, physical activity).

Generally when relevant risk factors and not yet dangerous deviations from the reference intervals for non-circulating cholesterol are not ascertained, the patient is directed to lifestyle changes for a few months and only in case of failure of this intervention. , the possibility of directly establishing a therapy with antidyslipidemic drugs or of resorting to a waiting treatment with food supplements or functional foods associated with dietary regimen and physical activity is evaluated.

The drugs currently used in monotherapy and combined therapy of dyslipidemias belong to four categories:

Statins

Statins are the most prescribed drugs for lowering LDL cholesterol and their efficacy in reducing morbidity and mortality from coronary heart disease has been demonstrated in various longitudinal clinical trials. Statins act by blocking the synthesis of cholesterol in the liver by mediating Γ inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, they also cause overexpression of LDL receptors with consequent increase in the capture and elimination of LDL- C circulating. Statins induce decreases in TG and increases in HDL-C of little relevance. The activity of statins is generally evident 4-6 weeks after the start of oral treatment. Statins can impair liver function and present the risk especially if associated with certain drugs including some antidyslipidemics (fenofibrate, gemfibrozil clofibrate, niacin) of giving myopathies and rhabdomy. Lysis. In the face of such occurrences, therapy must be suspended.

Bundles

Fibrates (fenofibrate, gemfibrozil) are mainly used to reduce triglycerides. Combined with statins, they are used in the treatment of dyslipidemias but increase the risk of myopathies and rhabdomyolysis.

Resins

The resins (cholestyramine, coleselvelma and colestipol) sequester bile acids in the intestine and prevent their absorption. They are used to lower LDL-C, in monotherapy and combination therapy, in patients with low responsiveness to statins. They interfere with the intestinal absorption of numerous drugs including some antidyslipidemics (clofibrate, statins, niacin). They cause severe constipation.

Inhibitors of cholesterol absorption

The most representative drug of this relatively new category of antidyslipidemics is ezetimibe which inhibits the intestinal absorption of dietary cholesterol. Ezetimibe is used both alone and in combination with statins to lower LDL-C, although in these cases it can increase the risk of liver disease.

Vitamins

Vitamin B3 (niacin, niconitic acid) lowers LDL-C and triglycerides and raises HDL-C. It is used orally in high dosages (Γ-6 gr / day). However, its use is limited by the poor tolerability due, in particular, to the induction of intense skin vasodilation (flushing). There are controlled release products that have more attenuated flushing phenomena but are more hepatotoxic. Niacin is used in association with statins to increase the lowering of triglycerides and the increase of HDL-C in mixed dyslipidemias and hypertriglyceridemias. A combined lovastatin / niacin controlled-release product was developed to maximize the therapeutic benefits of the two drugs.

Having examined the state of the art relating to antidyslipidemic drugs and in particular their limited handling in terms of tolerability, toxicity and interactions with other drugs, including some belonging to the same category, the possibility of developing an innovative formulation was identified. The formulation classifiable as a food supplement is represented by a mixture of derivatives of officinal and edible plants appropriately selected and balanced in order to be overall effective in reducing LDL-cholesterol and triglycerides and in increasing HDL-cholesterol, with a mechanism multitargets. This formulation and therapeutic approach ensures efficacy at relatively low dosages of the various components with advantages of tolerability and reduced side effects compared to conventional antidyslipidemic drugs.

Description of the invention

The subject of the present invention is an oral solid composition containing plant extracts, vitamins and coenzyme Q-10, effective as an antidyslipidemic. The composition, which is preferably in the form of halved oral tablets, contains, as titrated and standardized preparations, dry extracts of Commiphora mukul gum resin and Cynara scolymus leaves, purified powders of fermented rice with Monascus ruber, of policosanols from rice bran wax and of Beta-sitosterol from Pinus pinaster. Also present in the composition are vitamins C, E, B6 and B3 and coenzyme Q-10.

Commiphora mukul (gugguD is a medicinal plant used in medicine as a lipid-lowering agent. It is also provided with antiplatelet activity. In particular, it reduces LDL cholesterol, triglycerides and increases HDL cholesterol. The pharmacologically active part of the plant is constituted by rubber resin and specifically from the steroisomers Z and E, of the sterol guggulsterone contained in its extract. Guggulsterones perform a lipid-lowering activity both by reducing intestinal absorption of cholesterol and by blocking the famesoid FX receptor responsible for regulating the conversion of cholesterol into bile acids by competitive antagonism.

Cynara scolymus is an edible plant particularly rich in flavonoids (heterosides of luteolol and apigenol), polyphenols (chlorogenic acid), sterols and organic acids. The extracts of the leaves find medical use for their cholesterol-lowering effect, resulting from the increase in the biliary excretion of cholesterol by induction of choleresis, and the inhibition of the hepatic synthesis of the enzyme (HMG-CoA) reductase.

The flavonoids contained in artichoke leaf extracts are also attributed antithrombotic and antiarherosclerotic properties resulting from their ability to increase the production of nitric oxide in the vascular endothelium by activating nitrogen oxide synthetase.

Red rice fermented with Monascus ruber is a product used for a long time in China in cooking and as a functional food with lipid-lowering activity effective in reducing cholesterol (total and LDL) and triglyceridemia and in increasing HDL cholesterol. These activities are attributable to the presence in the powder product of nine different statins (called levostatins or monacolins or mevinolins), sterol (beta-sitosterol, campesterol, stigmasterol) and isoflavones. The cholesterol-lowering effect is determined by the inhibition of hepatic (HMG-CoA) reductase with consequent blocking of cholesterol synthesis.

Policosanols are a mixture of long-chain alcohols isolated and purified from rice bran wax and represented by 66% octacosanols. Policosanols have been shown to be effective in significantly improving altered serum lipid profiles by reducing total and LDL cholesterol and increasing HDL cholesterol. These results are obtainable at dosages ranging from 5 to 20 mg / day. To reduce triglycerides it is necessary to bring the daily dose above 40 mg.

Beta-sitosterol is present together with other sterols in many plants and is structurally linked to cholesterol, but, compared to this, it is poorly absorbed in the intestine and has a greater hydrophobicity. These characteristics give beta-sitosterol greater affinity for the micelles from which it manages to displace cholesterol, reducing intestinal absorption. The result is a lowering of piasmatic LDL-cholesterol concentrations.

Vitamins C. E and CO- 10

The two vitamins and coenzyme CQ-10 have high antioxidant properties useful for counteracting various oxidative processes including lipid peroxidation which leads to the formation of oxidized LDL which is attributed an important role in the evolution of the atherosclerotic process.

Coenzyme Q-10 is also administered to renormalize decreases in its normal blood concentrations induced in the course of therapies with anticolesterolemics that act by inhibiting HMG-CoA reductase and block its synthesis, exposing to the risk of tissue depletion that can compromise cardiac function and muscular.

Vitamin B6

High blood levels of homocysteine are considered an independent risk factor in vascular diseases as they induce endothelial dysfunction by inhibiting endothelial nitric oxide synthetase and with it the bioavailability of nitric oxide at the level of the vessel walls. Vitamin B6 by lowering the blood levels of homocysteine prevents its harmful effects on the vessel walls.

Vitamin B3

Vitamin B3 in high doses enhances the antidyslipidemic action of statins by increasing HDL-cholesterol. At low dosages, it counteracts the damage inducible from situations of hyperhomocysteinemia at the level of the vascular endothelium.

In a particularly preferred embodiment, the invention refers to a composition in divisible tablet form containing 100 g, 10 g of Commiphora mukul dry rubber resin extract corresponding to 250 mg of guggulsterones Z and E, 14 g of Cynara scolymus dry extract of leaves corresponding to 700 mg of chlorogenic acid, 10 gr of Beta-sitosterol powder with 75% title corresponding to 750 mg of Beta-sitosterol, 1 gr of Polycosanol of rice bran wax powder corresponding to 600 mg of octacosanol, 20 gr of rice fermented red with Monascus ruber powder corresponding to 300 mg of mevinoline, 2.7 gr of vitamin B3, 18 gr of vitamin C, 6 gr of vitamin E acetate 50% title corresponding to 3 gr of vitamin E acetate, vitamin B6 title 87.5% 350 mg corresponding to 300 mg of vitamin B6. Excipients of quality and in quantities approved for pharmaceutical use. The composition according to the invention administered orally exerts an antidyslipemic effect by lowering LDL-cholesterol and triglyceride levels and raising HDL-cholesterol.

An optimal dosage schedule involves taking 1 tablet during the evening meal. Each tablet of 1 gr. contains 100 mg of Commiphora mukul dry extract, 140 mg of Cynara scolymus dry extract, 100 mg of Beta-sitosterol powder, 10 mg of Policosanol powder, 200 mg of Red Rice fermented powder with Monascus ruber, 27 mg. of Vitamin B3, 180 mg of Vitamin C, 30 mg of Vitamin E, 3 mg of Vitamin B6, 10 mg of Coenzyme Q-10 and excipients for a total of 170 mg.

The tablets can be produced following a conventional pharmaceutical technical protocol which provides, in sequence, the mixing of the components, the sieving, the wet granulation, the drying and the compression in a compressing machine suitably adjusted for the production of tablets of the desired weight and of adequate hardness.

The following example illustrates the invention in greater detail.

EXAMPLE

Clinical cases

10 healthy subjects, 5 male and 5 female, with an average age of 49 years had before being treated (Time 0) the lipid profile shown in Table I:

All subjects underwent oral treatment with the composition object of the present invention in the form of 1 g tablets each containing the following ingredients:

- Commiphora mukul dry extract, titrated and standardized, of rubber resin:

100 mg corresponding to 2.5 mg of guggulsterones Z and E.

- Cynara scolymus dry extract, titrated and standardized, of leaves: 140 mg corresponding to 7 mg of chlorogenic acid

- Beta-sitosterol 75 mg

- Policosanol powder, titrated and standardized, of rice bran wax: 10 mg corresponding to 6 mg of octacosanol

- Red rice fermented with Monascus ruber titrated and standardized powder:

200 mg corresponding to 3 mg of mevinoline

- Vitamin B3: 27 mg

- Vitamin C: 180 mg

- Vitamin E: 30 mg

- Vitamin B6: 3 mg

- Coenzyme Q- 10: 10 mg

The dosage adopted was one tablet per day taken during the evening meal.

After 6 weeks of treatment the average values of the blood parameters have undergone variations with respect to time 0 (Total cholesterol - 16%; LDL cholesterol - 18%; HDL cholesterol 16%; Triglycerides - 9%) such that they can be considered returned or close to return to the non-cardiovascular risk or normal range. Patients reported no significant side effects during treatment.

1) Oral solid composition containing dry extract of Commiphora mukul gum resin, dry extract of Cynara scolymus leaves, Beta-sitosterol powder, Polycosanol powder purified from rice bran wax, red rice powder fermented with Monascus ruber, vitamin B3 , vitamin C, vitamin E, vitamin B6 and coenzyme Q-10.

2) Composition according to claim 1 which is in form of divisible tablets

3) Composition according to claims 1 and 2 containing 10% by weight of Commiphora Mukul titrated and standardized dry extract of gum resin, 14% by weight of Cynara scolymus titrated and standardized dry extract of leaves, 10% by weight of titrated Beta-sitosterol powder and standardized, 1% by weight of policosanols from rice bran wax titrated and standardized powder, 20% by weight of red rice fermented with Monascus ruber titrated powder and

Claims (2)

The dosage adopted was one tablet per day taken during the evening meal. After 6 weeks of treatment the average values of the blood parameters have undergone variations with respect to time 0 (Total cholesterol - 16%; LDL cholesterol - 18%; HDL cholesterol 16%; Triglycerides - 9%) such that they can be considered returned or close to return to the non-cardiovascular risk or normal range. Patients reported no significant side effects during treatment. CLAIMS 1) Oral solid composition containing dry extract of Commiphora mukul gum resin, dry extract of Cynara scolymus leaves, Beta-sitosterol powder, Polycosanol powder purified from rice bran wax, red rice powder fermented with Monascus ruber, vitamin B3 , vitamin C, vitamin E, vitamin B6 and coenzyme Q-10. 2) Composition according to claim 1 which is in form of divisible tablets 3) Composition according to claims 1 and 2 containing 10% by weight of Commiphora Mukul titrated and standardized dry extract of gum resin, 14% by weight of Cynara scolymus titrated and standardized dry extract of leaves, 10% by weight of titrated Beta-sitosterol powder and standardized, 1% by weight of policosanols from rice bran wax titrated and standardized powder, 20% by weight of red rice fermented with Monascus ruber titrated and standardized powder, 2.7% by weight of vitamin B3, 18% by weight of vitamin C, 6% by weight of vitamin E, 0.35% by weight of vitamins B6 and 1% by weight of coenzyme Q-10. 4) Composition according to the preceding claims for use in the treatment of monogenic and polygenic dyslipidemias 5) Food supplement comprising a composition according to any one of the preceding claims.