WO2011055242A1

WO2011055242A1 - Composition comprising a nopal powder and red rice yeast

Info

Publication number: WO2011055242A1
Application number: PCT/IB2010/054258
Authority: WO
Inventors: Bernard Dewaghe
Original assignee: Valorimer
Priority date: 2009-11-03
Filing date: 2010-09-21
Publication date: 2011-05-12
Also published as: FR2951908B1; FR2951908A1

Abstract

The present invention relates to a composition comprising a nopal powder and red rice yeast, characterized in that the nopal powder is a powder of which the particle size is such that 37% of the particles have a size of between 104 μm and 515 μm, the rest of the particles having a size of less than 106 μm, and less than 60% of the particles have a size of less than 75 μm, and in that the red rice yeast is a yeast of which the statin concentration is at least 0.5% by weight relative to the total weight of the red rice yeast. In addition, the invention relates to a food supplement comprising this composition, to a method for obtaining this supplement or this composition and, finally, to the use of this supplement or of this composition for reducing the LDL-cholesterol level and the triglyceride level.

Description

COMPOSITION COMPRISING NOPAL POWDER AND RED RICE YEAST

The subject of the present invention is a composition comprising a nopal powder and red rice yeast, a dietary supplement comprising this composition and the use of this dietary supplement to lower the level of LDL-cholesterol and the level of triglycerides.

It relates more particularly to a composition and food supplements containing it for treating problems related to overeating, including hyperlipoprotémémie. Hyperlipoproteinemia is understood to mean the increase in the normal amount of lipids contained in the blood in the form of lipoproteins, especially LDL-cholesterol.

Cholesterol, a lipid of the sterol family, plays a central role in many biochemical processes. It is a hydrophobic compound that does not dissolve in the blood. It is transported by four types of lipoproteins:

• Low Density Lipoprotein (LDL) transports cholesterol from secretory sites to the cells of the body. Significant rates of

LDL-cholesterol usually leads to cholesterol deposition on the artery walls, which increases the risk of cardiovascular disease and is called "bad" cholesterol;

• High Density Lipoprotein (HDL) unloads arteries and extrahepatic tissues from cholesterol, and returns it to the liver where it is degraded; we then speak of "good" cholesterol;

• Chylo microns: these lipoproteins transport lipids (cholesterol) from the intestine to other tissues

• Very low density lipoproteins (or VLDL: Very Low Density Lipoprotein).

For a long time we have been trying to lower the level of "bad" LDL-cholesterol and, for this purpose, to treat the cholesterolemia of people susceptible to cardiovascular disease, is used a class of pharmaceuticals, known as statins. Statins act in particular by lowering the level of LDL-cholesterol in the blood. These are HMG-CoA reductase inhibitors. HMG-CoA reductase (or 3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGR, EC 1.1.1.88) is the enzyme that regulates the biosynthesis of cholesterol.

The class of statins includes atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin, among others.

Statins can be obtained by synthesis or be of natural origin. Among the statins widely used for their cholesterol-lowering effects, mention may be made in particular of lovastatin (monacolin K), which can be of synthetic origin or of natural origin and whose formula is:

(1S, 3R S, 8S, 8aK) -8- {2 - [(2R)

hexahydro-naphthalen-1-yl- (25) -2-methyl-butanoate.

Lovastatin is also widely used as a medicine to treat hypercholesterolemia. Originally, this drug was extracted from a yeast, Monascus ruber. Obtained synthetically they are a source of very high health costs and they give rise to side effects, especially in the neuromuscular sector, the myalgia that patients under treatment with synthetic statins worry the entire medical profession and sometimes arouse rejection in treated patients.

Red yeast rice is a food product widely used in many Asian countries and known to lower LDL cholesterol levels, which is considered to be a "bad cholesterol". The main statin found in red rice yeast, which is of natural origin, is lovastatin. The lovastatin content of red rice yeast, intended for the food industry, can vary from 0 to 0.58%.

Red rice yeast is a mushroom that grows on rice. This microorganism,

Monascus purpureus, produces a characteristic red pigment that gave its name to yeast. Yeast-based supplements that have been clinically proven in the past for their cholesterol-lowering effects are extracts made from a specific strain called Monascus purpureus Went.

In addition to statins, other lipid regulators are known, including the cladodes of certain cacti, which are quite widely used in food in South and Central America. These cladodes, as recalled in EP 1 377 183, which are generally appreciated from the standpoint of food for their water and carbohydrate intake, are also used as medicinal diuretic, laxative, antispasmodic or else for the treatment of fevers, ulcers or hyperglycemia.

It is stated in this EP 1 377 183, in particular, that Opuntia Ficus indica - commonly called nopal- grown in Mexico, is suitable for the treatment of obesity, hyperlipidemia or diabetes. It is also reported that studies in obese, diabetic and healthy subjects have shown that ingestion of cladodes of nopal for several days before the three main meals significantly reduces the obese and diabetic subjects' LDL-cholesterol levels, their triglyceride levels and their weight [cf. "Effects of nopal (Opuntia) on serum lipids, glycemia and body weight," Mexican Archives of Medical Research, Vol 14 No. 2, 1983]. It has also been found that this makes it possible to reduce the glycemia of diabetics and it has moreover been found that this produces a spread over time of the assimilation of sugars.

All these advantages make cladodes of the Opuntia Ficus indica cactus part of the therapeutic products prescribed in the case of diabetes, obesity, "bad cholesterol" or digestive disorders. One of the parameters for measuring the therapeutic effect of nopal is the ratio known as the "fixation ratio":

In this context, patent EP 1 377 183 describes a preparation having the property of fixing fats, based on cladodes of the cactaceae Opuntia Ficus indica of the edible type and at least partially non-assimilable, which cactaceae is in the form of a particle powder of which at least 70% by weight have a dimension less than ΙΟΟμιη, so pass the meshes of a sieve whose mesh width is ΙΟΟμιη. (which corresponds to a mesh size of 148 mesh Tyler). In fact, according to a preferred version, defined in this patent EP 1 377 183, at least 90% by weight of the cactaceae particles have a size less than 75μιη. In addition, the cactaceae particles are in the form of granules coated with an acid-resistant film, in particular gastro-resistant, and soluble in the intestinal medium, which involves a treatment of these particles in fluidized beds.

The dietary supplement described in this patent EP 1 377 183 contains as nopal source NeOpuntia ^® product, marketed by BIO Laboratories SERAE, consisting of a lipophilic powder containing nopal of which at least 70%> particles have a dimension less than ΙΟΟμιη (i.e. <155 mesh Tyler); in fact more than 90%> have a dimension less than 75μιη. It is specifically mentioned in this patent EP 1,377,183 (page 8, Table 5 in relation to the test 3 described therein) that "it can be concluded with certainty that the ability to fix the oil of a powder

of cactus is a decreasing function of the size (dimension) of particles »

However, the food supplement according to this European patent is not completely satisfactory as regards the results to which it leads. It has a very fine granulometry resulting in high grinding costs and requires expensive coating treatments of particles in a fluidized bed. In addition, the use of NeOpuntia ^® having a granulometry as fine gives rise to risks of passage of the intestinal barrier and therefore the passage in the blood of the said product, with the consequences that this implies for health.

It has also been sought to combine lipid regulators, in particular statins, with nopal powder in order to lower the rate of absorption of fat by the body and lower the level of LDL-cholesterol. A product of this type, which proposes to regulate cholesterol, is marketed under the name CHOL'Germ ^®. This product combines 4 active ingredients including nopal, in the form of the powder marketed by Bio Serae Laboratories under the name NeOpuntia ^® , described above, and red rice yeast (Monascus purpureus). This product is intended for use as a dietary supplement. The object of the present invention is to provide a novel composition having a beneficial effect on cholesterol levels and at least partially overcomes the aforementioned drawbacks.

The subject of the present invention is a composition comprising a nopal powder and red rice yeast, in which:

nopal powder is a powder whose particle size is such that 37% of the particles have a dimension of between 104 μm and 515 μm, the rest of the particles having a dimension of less than 106 μιη and less than 60% of the particles have a dimension smaller than 75μητ,

the yeast of red rice is a yeast whose concentration in statins is at least 0.5% by weight relative to the total weight of the red rice yeast, and

- Red yeast rice is a yeast whose concentration in statins is at least 0.5%> by weight relative to the total weight of the yeast of red rice.

The invention further relates to a dietary supplement comprising said composition and relates to the use of such a composition or said dietary supplement to inter alia lower LDL-cholesterol and triglyceride levels.

By "at least 60%" by weight of the nopal powder particles have a dimension between 104μιη and 90μητ "is meant that the powder particles are retained by a sieve whose mesh size is 104μητ, or 150 mesh Tyler .

According to one embodiment of the composition according to the invention, 28% of the nopal powder has a particle size of between 150μιη and 515μιη.

According to another embodiment of the composition according to the invention, the statin concentration of the red rice yeast is at least 1.5% by weight relative to the total weight of the red rice yeast.

According to yet another embodiment of the composition according to the invention, the concentration of statins in the yeast of red rice relative to the total weight of the yeast of the red rice entering the composition is between 1.25 and 3.20 %, preferably between 2.00% and 2.80%. and more particularly between 2.40 and 2.70%. In general, the biological effectiveness of the composition increases with the concentration of statins.

In another embodiment, the composition also contains Advantol ^® powder of a product marketed by SPI Pharma. It is a product that meets the FCC standards for products to be absorbed that contains about 65% polyol and has a particle size of between 60 and 140 mesh, ie between 350μιη and 1 12μιη. The composition may also contain one or more of the compounds selected from the group consisting of vitamin C, chromium chloride, magnesium stearate, pharmaceutical grade talc, flavors and excipients.

According to one embodiment of the invention, the composition contains, expressed in weight proportions relative to the total weight of the composition, 10% to 90% of nopal powder and 0.05% to 45% of yeast. of red rice. Preferably it contains 30%> to 70%> of nopal powder and 0.15%) to 35% o of red rice yeast.

According to another embodiment of the invention, in said composition, the weight ratio yeast of red rice / nopal powder is between 0.005 and 0.5, preferably between 0.01 and 0.25.

According to another embodiment of the invention, the dietary supplement

contains 500 to 1500mg of nopal and 30 to 70mg of red yeast rice and more preferably 800 to 1200mg of nopal and 40 to 60mg of red yeast rice.

According to another embodiment of the invention, the dietary supplement contains:

contains:

In general, in the context of the present invention, all red rice yeasts having a statin concentration of at least 0.5% can be used. By way of example, red yeast rice powder containing 1.5% lovastatin, supplied by the company Quimdis, may be used. However, other powders of red yeast rice can be used. The red rice yeast of the variety Monascus purpureus Went will preferably be used. Advantageously, the nopal powder is the powder of the cactus shoot of the variety Opuntia Ficus Indica. Preferably, a dehydrated powder is used, the moisture content of which is less than 6% by weight / total weight of the nopal powder, such as the nopal powder supplied inter alia by the company Quimdis.

As shown below, a surprising and unexpected synergistic action results from the combination of the nopal powder whose particles have a greater dimension than the particle size used according to the prior art (in particular in the CHOL'Germ ^® supplement). which uses the NeOpuntia ^® powder) and a red rice yeast more loaded with statins than the red rice yeast commonly used according to the prior art in this dietary supplement

The composition of the invention may include other active ingredients such as vitamin C or chromium chloride.

In addition, the composition of the invention may comprise aromas, for example red fruits or lemon. These compounds are not considered essential

for the therapeutic effect of the invention but may be added to make the composition more attractive to the patient or consumer.

Another object of the invention is a process for obtaining a food supplement according to the invention comprising mixing a nopal powder whose particle size is 37% greater than 104 μm, a yeast whose the concentration of statins is at least 1.25% by weight, and preferably 2.6% by weight relative to the total weight of the yeast of the red rice and, if appropriate, one or more compounds selected from the group comprising vitamin C, chromium chloride, red fruit aroma, lemon flavor, magnesium stearate and pharmaceutical grade talc.

A final subject of the invention is the use of a composition according to the invention or a dietary supplement according to the invention for lowering the level of LDL-cholesterol and the triglyceride level of patients at risk of suffering. hyperlipoprotemia, or to be used for dietary purposes.

Other characteristics and advantages of the invention will appear on reading the examples of preferred embodiment of the invention given by way of non-limiting examples. Example I

Prepared by conventional methods of preparation of tablets tablets of 2 grams which have the following composition TABLE 3

The red rice yeast obtained by a fermentation process is marketed by the Qimdis Company.

Its composition is shown in Table 4 below

TABLE 4

Tests were conducted on a population of 60 patients aged between 30 and 40 years old. This group of 60 patients was divided into three subgroups with 20 volunteers of both sexes with random selection. Patients had lipid abnormalities and poor lifestyle and dietary habits requiring therapeutic intervention. All three groups were comparable and homogeneous in age, sex, weight and height distributions.

The actual treatment was preceded by a teaching on the possibilities of correcting the errors of hygiene of life and nutrition, conditions which were followed and continued for 180 days. Then at the 180th day, corresponding to the day 0 of the treatment, the treatment began and continued for 3 months, that is until day 90.

It consisted of administering daily to the first group of 20 patients, 2 tablets of 2g of placebo (group 1), to the second group of 20 patients, 2 tablets of 2g having a composition according to the invention given in Table 3 below. above (group 2) and, in the third group of 20 patients, synthetic statins (group 3).

The results obtained (mg / l) for total cholesterol, triglycerides, total HDL and total LDL are given in Table 5 below:

This study confirmed the good tolerance and therapeutic efficacy of the complement whose composition is given in Table 5. Over a treatment period of 3 months, a decrease in LDL, a decrease in triglycerides, an increase in cholesterol are observed. HDL levels. These results are significant.

The results obtained on subjects treated with synthetic lovastatin are positive for LDL cholesterol but not significant for triglycerides and HDL cholesterol.

Daily consumption of two tablets having the composition given in Table 5 essentially reduced LDL cholesterol and triglyceride levels

Example II

The powder of NeOpuntia ^® , marketed by Laboratoires Bio Seriae, as described in patent EP 0104960 and as used in the product marketed in the food supplement CHOL'Germ ^® has the particle size indicated in Table 10 below.

As is apparent from this Table 10, the proportion of granules NeOpuntia ^®, which have a diameter less than 75 μιτι is 90%.

On the other hand, the particle size of the nopal implemented in accordance with the invention is as indicated in Table 11 below.

Nopal powder used in the context of the present invention is formed of larger particles than the particle size of the nopal powder sold under the name ^® NeOpuntia used for the same purposes according to the prior art . In fact, the invention relates to a composition based on nopal and red yeast rice which, surprisingly and unexpectedly, is more effective than those known to the prior art containing the NeOpuntia ^®. It aims in particular at a composition that is more effective and less expensive to prepare than that of the food supplement CHOL'Germ ^{® of} which more than 90% of the particles have a dimension less than ΙΟβμητ, in fact more than 90%> of the particles have a dimension less than 75μιτι . Not only in fact, it is possible to reduce the costs required by the grinding to obtain a granulometry for 90%) less than 75 μιτι but still, the costs are reduced because the dietary supplement according to the The invention does not require the coating of the particles with an acid-fast, particularly gastro-resistant, and soluble in the intestinal medium that the process requires. described in EP 1 377 183. In fact, the addition of Advantol, intended to contribute to the dissolution of the food supplement according to the invention during its administration, is carried out by mixing with the other compounds during the preparation of the supplement food according to the invention. This also contributes to reducing the costs of obtaining said supplement.

Example III

Used tablets of 2 grams, therefore having the same composition and granulometry than tablets of Example I above, and compared their properties with product of the tablets sold under the Chol'germ ^®.

Table 13 gives the tablet content of active ingredients for these two types of dietary supplements:

TABLE 13

In the following table are compared the yeasts of red rice according to the invention and the yeasts of red rice used in tablets of Chol'germ® according to the state of the art:

As indicated above, the content of statins (HMG-CoA reductase inhibitors) in the red yeast rice used according to the invention is 2.6% by weight relative to the total weight of the yeast of rice red, whereas in the red yeast rice used according to the state of the art (Chol'germ ^® ), it is 0.44% by weight relative to the total weight of the red rice yeast.

The red rice yeast used according to the invention therefore comprises six times more statians (HMG-CoA reductase inhibitors) than the red rice yeast commonly used according to the state of the art. The other main difference is the size of the nopal particles. The nopal powder used is the same as that indicated above in Table 11, that is to say that the particle size of the nopal powder used is 37% between 104μ and 515μιη. The nopal powder used to obtain the product ChoPgerm ^® is the nopal powder marketed under the name of NeOpuntia ^® . It is formed of particles whose size is 90% less than 75μητ. The particles of this powder are therefore much finer than the particles of the powder used in the composition according to the invention.

Example IV

Comparison of the therapeutic efficacy of a food supplement according to the invention and of the food supplement Chol'germ ^®

This comparison is made between the composition according to Example 1 (according to the invention) above and the product (according to the state of the art) marketed under the name Chol'germ ^® .

Chol'germ ^® tablets are 1.718g tablets and the advice of use is to chew, or absorb after dissolution in water, 4 tablets per day while the advice of use given for the food supplement according to the invention is 2 tablets of 2 g per day.

TABLE 15

Table 15 indicates the amount of each of the active ingredients absorbed daily according to the recommended daily doses and the contents of active ingredients contained in the tablets according to the invention and tablets of Chol'germ ^® .

As it is advisable to take daily 4 tablets of 1.718 g of the product marketed under the name Chol'germ ^® , which contains 48mg of red rice; the quantity of statin thus ingested daily is 48 mg x 4 x 0.44%, ie 0.845 mg, whereas according to the invention, it is advisable to take 2 tablets of 2 g daily, so that the quantity of statin so ingested daily is 48mg x 2 x 2.60%> that is 2.5mg.

The formula according to the invention is more effective than is the product according to the state of the art because the daily intake recommended to achieve a therapeutic effect is lower. Thanks to the synergetic interaction of the yeast of the red rice with the nopal of the invention, the same therapeutic effect is at least achieved with half of the active ingredients in relation to the amount employed in the case of the use of Chol ' germ® according to the state of the art.

However, the composition of Chol'germ® is not entirely satisfactory as regards the results achieved. It is especially necessary to administer a high proportion of active ingredients, 3.8 g NeOpuntia ^® and Red Yeast Rice 192mg, matching 0,84mg statins daily.

Surprisingly and unexpectedly, the combination of a nopal powder having a larger particle size than that of NeOpuntia ^® powder and a red rice yeast more loaded with statins than is the product marketed under the brand name CHOL'Germ ^® has been shown to have improved properties, particularly with regard to therapeutic efficacy, far superior to those obtained with CHOL'Germ ^® . This result is particularly surprising since, as indicated above (EP Patent 1,377,183), the binding ratio obtained increases when the mean particle size of the nopal powder decreases. Moreover, this patent recommends the use of a powder whose particle size is less than ΙΟΟμητ, in fact 90% less than 75μιη.

In fact, the amount of absorbed nopal implied by the daily doses of 1900mg are of nopal in the product according to the invention and 3800mg of NeOpuntia ^® in the product according to the prior art, which corresponds to twice of NeOpuntia ^® , whose particle size is less than ΙΟΟμητ, than nopal, whose particle size is 37% greater than 104μιη. However, it was found that the very small particle size of NeOpuntia ^® used in the dietary supplement CHOL'Germ ^® gives rise to the passage of a proportion of NeOpuntia ^® through the intestinal barrier and thus to passage into the blood powder NeOpuntia ^® , which consequently produces undesirable side effects.

This is further aggravated by the high amount of NeOpuntia ^® that has to be absorbed daily in order to lower LDL-cholesterol levels and diglyceride levels compared to the amount obtained by dietary supplement absorption. the invention.

In addition, surprisingly and unexpectedly, the statins of this red rice yeast in combination with a nopal powder having a particle size such that the particle size is 37%> greater than 104μιη are more effective than the statins of synthetic origin for the treatment of patients with hyperlipoproteinemia.

Moreover, also surprisingly and unexpectedly, the tolerance by the patients of the composition of the invention comprising statins of red yeast in combination with nopal powder having a larger particle size is better than is the one with which give rise to statins of synthetic origin. The combination of nopal and yeast red of the present invention creates - surprisingly - a synergistic effect which leads to therapeutic effects superior to those of the state of the art, particularly compared to the product marketed under the trademark CHOL'Germ ^® .

Of course, the present invention is not limited to the examples and to the embodiment described and shown, but it is capable of numerous variants accessible to those skilled in the art.

Example IV

Preparation of a stick.

The food supplement according to the present invention may be in the form of sticks. By way of example, a composition that can be used for a stick of 1. 128 g will be given.

The sticks are manufactured according to a conventional method, by introduction, mixing and filling the containers.

Example V

An N29 compound according to the invention having the following composition:

is compared as regards the lipid balance with the product marketed Chol'in brand having the following composition:

The comparative tests carried out concerned 20 patients for the product of Table 17 and 14 patients for the product called Chol'in.

The product N29 in this study gives rise to a decrease twice as much as ChoPin for cholesterol and 5 times higher for triglycerides. These differences are significant with p <0.0001.

With regard to HDL the increase observed with the product N29 is 5 times greater (p <0.0001) than with Chol'in.

For LDL, the results show a slightly larger decrease (p <0.0055) for Chol'in than for N29, (Figure 19 above).

These results clearly establish the best hypocholesterolemic and hypotriglycerilemic powers of N29 as well as a favorable effect on HDL compared to the results obtained with Chol'in which, it will be noted, has the same composition as Chol'germ ^® .

These are surprising and unexpected results that nothing has suggested and that testify to the patentability of the present invention.

Claims

1. Composition comprising a nopal powder and red rice yeast, characterized in that:

the nopal powder is a powder whose particle size is such that 37% of the particles have a dimension of between 104 μm and 515 μm, the rest of the particles having a dimension of less than 106 μιη, and less than 60% of the particles have a smaller dimension. at 75μιη,

the red yeast rice is a yeast whose statin concentration is at least 0.5% by weight relative to the total weight of the red rice yeast.

2. Composition according to claim 1, characterized in that 28% of the nopal powder has a particle size of between 150μιη and 515μιη.

3. Composition according to claim 1 or 2, characterized in that the statin concentration of the red rice yeast is at least 1.5% by weight relative to the total weight of the red rice yeast.

4. Composition according to any one of claims 1 to 3, characterized in that the concentration of statins in the yeast of red rice relative to the total weight of the yeast of the red rice entering the composition is between 1.25 and 3.20%, preferably between 2.00% and 2.80% and more particularly between 2.40 and 2.70%.

5. Composition according to any one of claims 1 to 4, characterized in that it also contains Advantol ^® powder a product marketed by the company SPI Pharma whose particle size is between 350 and 112μιη.

6. Composition according to any one of claims 1 to 5, characterized in that it further contains one or more compounds selected from the group comprising vitamin C, chromium chloride, magnesium stearate, pharmaceutical quality talc, flavors and excipients.

7. Composition according to any one of claims 1 to 6, characterized in that it contains, expressed in proportions by weight relative to the total weight of the composition, 10%) to 90%) of nopal powder and 0.05 % to 45% yeast red rice.

8. Composition according to claim 7, characterized in that it contains 30% to

70%) of nopal powder and 0.15% to 35% of red rice yeast.

9. Composition according to any one of claims 1 to 7, characterized in that the weight ratio yeast of red rice / nopal powder is between 0.005 and 0.5, preferably between 0.01 and 0.25.

Food supplement comprising a composition according to any one of claims 1 to 9.

11. Dietary supplement according to claim 10, characterized in that it contains 500-1500mg of nopal and 30-70mg of red rice yeast and more preferably 800-1200mg of nopal and 40-60mg of red rice yeast.

12. Dietary supplement according to claim 10 or 11, characterized in that it comprises

13. Dietary supplement according to claim 12, characterized

comprises

14. Use of a composition according to any one of claims 1 to 9 or a food supplement according to any one of claims 10 to 13 for lowering the level of LDL-cholesterol and the triglyceride level.