FIELD OF THE INVENTION

The present invention relates to the field of compositions for treatment of infertility. DESCRIPTION OF THE PRIOR ART

Pathologies are known that can jeopardise the reproductive capacities of human beings, whether male or female, and which, therefore can cause problems of infertility.

In the field of traditional medicine, various drugs are at present known for treating infertility, some of which are however characterised by significant side effects and/or high costs. With the purpose of minimising side effects the food supplement industry has conducted tests on compositions comprising natural substances known for their use in treating infertility. Patent application B02006A 000544, belonging to the same Applicant, for example, describes a composition for treatment of infertility which comprises, as main ingredients: lepidium meyenii walp (also known as maca); manganese; vitamin E; selenium; zinc. The composition can further comprise, as optional components, including L-arginine and folic acid. Unfortunately, owing to the tendency to commence attempts at conception at a mature age, and the increase of factors leading to infertility, there has emerged a need for a composition, to which minimal or no side effects can be associated, which is effective in the treatment of infertility, both male and female.

SUMMARY OF THE INVENTION

An aim of the present invention is to provide a composition for treatment of infertility that is very effective in improving the reproductive capacity of human beings, whether in males or females, which at the same time has extremely limited or nil side effects. A further aim of the present invention is to provide a composition which is easy to administer to a patient.

The above aims are attained according to the contents of the independent claims. The characteristics of the invention will be evidenced in the following in which preferred but not exclusive compositions and relative use are described. The best modes for administering the composition include, for example, daily consumption of a suitable daily dose for a period comprised between 3 and 8 months. As can be observed from experimental data reported herein, the effects of taking the composition according to the invention are already measurable from the third month of the treatment.

The proposed composition, usable for treating infertility, is able to increase the reproductive ability of human beings, both male and female, while at the same time not presenting significant side effects. In this matter, the effects were tested on various indicators of male and female fertility, i.e: sperm fragmentation; sperm count; on sperm motility; on ovarian volume and on follicle diameter.

It has emerged that the composition of the invention, when administered to male individuals, carries out a synergic effect among its components which leads to an unexpected and significant increase in the number, sperm integrity, vitality and motility. In particular, the Applicant posits that the contemporary presence, in the composition, of: selenium; zinc; coenzyme Q10; alpha-lipoic acid; and melatonin has a synergic effect in significantly increasing protection from attack by free radicals towards the cell membranes including those of the sperm, so that sperm DNA fragmentation, among the most important causes of infertility in man, is prevented.

The composition of the invention, when administered to individuals of the female gender, enables regulation of the menstrual cycle and the hormone levels, as well as improving the efficiency of the corpus luteum. In particular a surprising and unexpected effect on the ovarian volume and the follicle diameter was observed. Further, the Applicant has verified that administering the composition of the invention leads to an increase in the level of glutathione or GSH in the organism, GSH is synthesised internally of the cells and is a natural tripeptide, i.e. constituted by three amino acids: glutamic acid, cysteine and glycine. This particular chemical composition gives the glutathione a high capacity to oxidise or reduce, thus protecting the protein and the other compounds that can be oxidised by the harmful action of free radicals. Glutathione is part of the composition of a group of enzymes having antioxidant properties, called glutathione peroxidase. Glutathione is considered the most powerful antioxidant present in the human organism. In cells in a good state of health, the ratio between “reduced” glutathione and “oxidised” Glutathione should be 9:1. A diminution thereof is considered an indicator of oxidative stress. Oral administration of glutathione is poorly effective as the presence, in the intestine, of known enzymes, such as Gamma-glutamyl transferase, hydrolyses the glutathione assumed and thus drastically reduces the bio-availability thereof. Further, the bio-availability of the glutathione is also compromised by the cellular sequestration exerted by the enterocytes of the intestinal mucosa. It is therefore very important for the composition of the invention to be able to raise the glutathione levels in the organism in order to reduce the oxidation and ageing of the cells of the reproductive apparatus. The Applicant believes that among the various components of the composition, the ones that are especially responsible for the increase in the level of glutathione are the following: coenzyme Q10; vitamin E; vitamin C and alpha-lipoic acid.

To this can be added that the composition does not have side effects, is easy to administer to a patient, as it can be obtained, for example, in powder form, in tablets, etc. The composition is preferably a food supplement, in water-soluble powder or granule form, or can be suspended in water, packed in sachets as this facilitates assumption of a daily dose in a single step.

The composition comprises: lepidium meyenii walp; a pharmaceutically acceptable salt of manganese; vitamin E; a pharmaceutically acceptable salt of selenium a pharmaceutically acceptable salt of zinc and is characterised in that it further comprises the following components: alpha-lipoic acid, coenzyme Q10, melatonin and vitamin C. The composition for use in treatment of male or female infertility falls within the object of the present invention.

In all the described embodiments of the present composition, the pharmaceutically acceptable selenium and zinc salts can be gluconates and/or orotates, more preferably gluconates.

The composition preferably further comprises at least an additional component selected from the group consisting of d-aspartic acid, folic acid, L-arginine, L- citrulline, acetyl-L-carnitine, myo-inositol, and an omega 3 fatty acid and mixtures thereof.

In a preferred aspect of the invention, the proposed composition also comprises myo-inositol. It is known that lack of myo-inositol is correlated to a reduced sperm count. The presence of myo-inositol leads to various unexpected synergic effects in increasing the number and mobility of the sperm, in the regularisation of the maturation of the follicles and in the improvement in the efficiency of the endometrium, with a consequent increase in the probability of pregnancy.

Particular preferred are the compositions of the invention that comprise, as well as myo-inositol, also folic acid and an omega 3 fatty acid, in particular if it is docosahexaenoic acid (DHA). This is because the use of the compositions leads to: an unexpected improvement in the physical maturation of the Graafian follicles, of the normalisation of the secretion of oestrogens; of the reinforcement of the endometrium; of the production of some Prostaglandins (PgF2-alpha). It follows that if the risk of abortion is minimised, the contractions of the smooth muscles of the genital tracts used in ejaculation are made more powerful (facilitating the rise of the sperm through the tract up to the place of fecundation) and the contractions of the uterine smooth muscles are also made more powerful, during the step of follicular dehiscence, i.e. in the freeing of the oocyte from the mature follicle, which oocyte thus can rise up the tube to reach the place of its fecundation.

The composition of the invention advantageously comprises both d-aspartic acid, and folic acid, and L-arginine, and L-citrulline, and acetyl-L-carnitine, and myo inositol, and an omega 3 fatty acid, preferably DHA (docosahexaenoic).

In a preferred aspect of the invention, the ratio by weight on weight between the quantity present of alpha-lipoic acid and the quantity present of lepidium meyenii walp is comprised between 0.04 and 0.06, and preferably is 0.05; and/or the ratio by weight on weight between the quantity present of melatonin and the quantity present of lepidium meyenii walp is comprised between 0.0004 and 0.0006 and preferably is 0.0005; and/or the ratio by weight on weight between the quantity present of vitamin C and the quantity present of lepidium meyenii walp is comprised between 0.23 and 0.27, preferably between 0,024 and 0.26 and more preferably is 0.25; and/or the ratio by weight on weight between the quantity present of coenzyme Q-10 and the quantity present of lepidium meyenii walp is comprised between 0.035 and 0.065, preferably between 0.04 and 0.06 and more preferably is 0.05; and/or the ratio by weight on weight between the quantity present of vitamin E and the quantity present of lepidium meyenii walp is comprised between 0.010 and 0.020, and preferably is 0,015; and/or the ratio by weight on weight between the quantity present of manganese and the quantity present of lepidium meyenii walp is comprised between 0.002 and 0.003, and preferably is 0.0025; and/or the ratio by weight on weight between the quantity present of zinc and the quantity present of lepidium meyenii walp is comprised between 0.003 and 0.0045, and preferably is 0.0035; and/or the ratio by weight on weight between the quantity present of selenium and the quantity present of lepidium meyenii walp is comprised between 0.000020 and 0.000021 , and preferably is 0.00002075.

Each ratio preferably between the quantity of: manganese; vitamin E; selenium, zinc, alpha-lipoic acid, coenzyme Q10, melatonin or vitamin C and the quantity present of lepidium meyenii walp is within the mentioned ranges.

It is clear that the quantities of zinc, manganese and selenium are calculated as weight equivalent of the relative metal, which in the composition is present in the form of pharmaceutically acceptable salt.

In a further preferred aspect of the invention in the composition, the ratio by weight on weight between the quantity present of d-aspartic acid and the quantity present of lepidium meyenii walp is comprised between 0.120 and 0.130, and preferably is 0.0125; and/or the ratio by weight on weight between the quantity present of folic acid and the quantity present of lepidium meyenii walp is comprised between 0.00008 and 0.00012, preferably is 0.00010; and/or the ratio by weight on weight between the quantity present of L-arginine and the quantity present of lepidium meyenii walp is comprised between 0.05 and 0.07, and preferably is 0.006; and/or the ratio by weight on weight between the quantity present of L-citrulline and the quantity present of lepidium meyenii walp is comprised between 0.2 and 0.4, and preferably is 0.3; and/or the ratio by weight on weight between the quantity present of acetyl-L-carnitine and the quantity present of lepidium meyenii walp is comprised between 0.065 and 0.085, and preferably is 0.075; and/or the ratio by weight on weight between the quantity present of myo-inositolo, and the quantity present of lepidium meyenii walp is comprised between 0.04 and 0.06 and preferably is 0.05; and/or the ratio by weight on weight between the quantity present of omega 3 fatty acid and the quantity present of lepidium meyenii walp is comprised between 0.04 and 0.06, and preferably is 0.05.

Preferably, each ratio preferably between the quantity of d-aspartic acid, folic acid, L-arginine, L-citrulline, acetyl-L-carnitine, myo-inositol, an omega 3 fatty acid, preferably docosahexaenoic acid, and the quantity present of lepidium meyenii walp is within the mentioned ranges.

The composition of the invention, comprising folic acid, myo-inositol and an omega 3 fatty acid is particularly indicated for use in treatment of female infertility. In this composition, the ratios between the quantities of each component present and the quantity of lepidium meyenii walp present are preferably within the above- mentioned relative values.

The composition of the invention, comprising d-aspartic acid, folic acid, L-arginine, L-citrulline, acetyl-L-carnitine, myo-inositol and an omega 3 fatty acid, preferably docosahexaenoic acid, is particularly indicated for use in treatment of male infertility. In this composition, the ratios between the quantities of each component present and the quantity of lepidium meyenii walp present are preferably within the above-mentioned relative values.

An advantageous embodiment of the composition of the invention comprises at least acetyl-L-carnitine, as synergically with some other essential components of the composition, the energy will increase in the form of ATP, in the gonad cells. Further, this embodiment of the composition is surprisingly effective in misalignment of the uterus, which is very frequent and which leads to a high probability that the embryo-uterus implant will fail.

When the composition of the invention comprises both acetyl-L-carnitine and L- citrulline, it is unexpectedly effective in reducing erectile dysfunction.

In a preferred aspect of the invention, omega 3 fatty acid, which is a polyunsaturated acid, is preferably of vegetable origin as in this way the composition can be destined also to vegetarians, vegans and Muslims. A particularly preferred example of omega 3 fatty acid is selected from the group constituted by hexadecatrienoic acid (HTA); octadecatrienoic acid (ALA) (also known as alpha-linolenic acid); octadecatrienoic acid (SDA) (also known as stearidonic acid); eicosatrienoic acid (ETE); eicosatetraenoic acid (ETA) (also known as juniperonic acid); eicosapentaenoic acid (EPA); (also known as timnodonic acid); eicosapentaenoic acid (HPA); docosapentaenoic acid (DPA) (also known as clupanodonic acid); docosahexaenoic acid (DHA) (also known as cervonic acid); tetracosapentaenoic acid; tetracosanoic acid, also known as nisinic acid) and mixtures thereof. The most preferred among the foregoing is a omega 3 fatty acid selected from the group consisting in: hexadecatrienoic acid (HTA); octadecatrienoic acid (SDA); eicosatrienoic acid (ETE); eicosatetraenoic acid (ETA); eicosapentaenoic acid (HPA); eicosapentaenoic acid (HPA); docosapentaenoic acid (DPA); tetracosapentaenoic acid; tetracosanoic acid and mixtures thereof. These mixtures preferably comprise docosahexaenoic acid (DHA). According to a more preferred aspect of the invention, the omega 3 fatty acid is docosahexaenoic acid (DHA) as it has a greater synergic effect with the other components of the composition, and preferably is of vegetable origin. It is further preferable for the docosahexaenoic acid (DHA) to be extracted from algae, as this is of vegetable origin and is easy and cheap to obtain.

EXPERIMENTAL DATA

In all the tests carried out, and reported in the following, different groups of volunteers were administered, daily and continuously for three months, one only of the following compositions A, B, C or D in the relative daily quantities as indicated in the respective tables.

PREPARATIONS TESTED

Table 1 -4 includes the compositions and the relative quantity of composition administered daily.

Table 1

Table 2

Table 3

Table 4

As can be observed, compositions A and B are constituted by the same components, although in different quantities, while the compositions of invention C and D comprise these components, present in compositions A and B, in the same quantities as in composition B.

1) DNA FRAGMENTATION

The tests relative to DNA fragmentation in sperm were carried out in the following way. First, the initial fragmentation of each participant in the test was measured. The test participants were classified in relation to the initial fragmentation of the sperm DNA by applying the following table:

Table 5

The participants of categories 2, 3 and 4 were divided into four groups, each of which was continuously and daily administered for three months with a different composition A, B, C and D in the daily administering quantities as indicated in respective tables 1 -4. After three months of continuous use the sperm fragmentation of each participant was verified. Then, for each tested composition and for each category 2, 3 and 4, the diminution percentages of the number of cases were calculated. In the following, for each composition these percentages will be reported.

Composition A: - diminution of fragmentation in 12% of cases in category 2 (borderline)

- diminution of fragmentation in 41 % of cases in category 3 (reduced integrity)

- diminution of fragmentation in 52% of cases in category 4 (greatly reduced integrity)

Composition B:

- diminution of fragmentation in 12% of cases in category 2 (borderline)

- diminution of fragmentation in 44% of cases in category 3 (reduced integrity)

- diminution of fragmentation in 54% of cases in category 4 (greatly reduced integrity)

Composition C:

- diminution of fragmentation in 17% of cases in category 2 (borderline)

- diminution of fragmentation in 45% of cases in category 3 (reduced integrity)

- diminution of fragmentation in 61% of cases in category 4 (greatly reduced integrity)

Composition D:

- diminution of fragmentation in 22% of cases in category (borderline)

- diminution of fragmentation in 47% of cases in category (reduced integrity)

- diminution of fragmentation in 65% of cases in category (greatly reduced integrity)

2) SPERM COUNT

The tests relative to sperm count were carried out in the following way. First, the sperm count of each participant in the test was measured. The participants were divided into four groups, each of which was continuously administered for three months with a different composition A, B, C or D. After three months of continuous use the sperm count of each participant was measured. In the following, for each composition tested, the percentages of participants having a sperm count of greater than 25 mil/ml (% sperm count greater than 25 mil/ml) are reported.

Table 6

3) SPERM MOTILITY

The tests relative to sperm motility were carried out in the following way. First the sperm motility of each test participant was measured and an initial percentage was calculated of participants having at least 50% of sperm that moved in an hour. The participants were divided into four groups, each of which was continuously administered for three months with a different composition A, B, C and D.

After three months of continuous use the sperm motility of each participant was measured and the final percentage of participants having at least 50% of sperm that moved in an hour was calculated. In the following, for each composition tested, the percentages of participants having a sperm motility of greater than 25 mil/ml (% SPERM MOTILITY < 50 % 1 h).

Table 7

4) OVARIAN VOLUME

The tests relative to ovarian volume were carried out in the following way. First, the ovarian volume of each participant in the test was measured and an initial calculation was made of the participants having an ovarian volume of lower than 16.02 cc which is a typical reference value for evaluation of female infertility. The participants were divided into four groups, each of which was continuously administered for three months with a different composition A, B, C or D.

After three months of continuous use the ovarian volume of each participant was measured and a final percentage was calculated of the participants having an ovarian volume of lower than 16.02 cubic centimetres. In the following, for each composition tested, the initial and final percentages of participants having an ovarian volume of greater than or equal to 16.02 cc (% having an ovarian volume < o % 16.02) are reported.

Table 8

5) FOLLICLE DIAMETER

The tests relative to follicle diameter were carried out in the following way. First, the ovarian volume of each participant in the test was measured and a final percentage was calculated of the participants having a follicle diameter of greater than or equal to 20-24 mm which is a typical reference value for evaluation of female infertility. The participants were divided into four groups, each of which was continuously administered for three months with a different composition A, B, C or D. After three months of continuous use the follicle diameter of each participant was measured and a final percentage was calculated of the participants having a follicle diameter of greater than or equal to 20-24 mm. In the following, for each composition tested, the percentages were reported of participants having an ovarian volume of greater than or equal to 16.02 cc (% follicle diameter = o > a 20- 24 mm).

Table 9

From the data relative to the tests carried out it is clear that compositions C and D, according to the invention, offer high effectiveness in the treatment of infertility, both male and female, as they bring a greater and positive variation to the parameters usually evaluated for this infertility, i.e. the sperm fragmentation, the sperm count, the sperm motility, the ovarian volume and the follicle diameter.

We note that the presence of optional components, i.e. d-aspartic acid, folic acid, L-arginine, L-citrulline, acetyl-L-carnitine, myo-inositol and an omega 3 fatty acid (preferably docosahexaenoic acid), in particular when all present, increases the effectiveness of the composition of the invention. In this matter the results obtained with composition D and those relative to composition C were compared. The foregoing has been described by way of non-limiting example, for which reason any eventual variants of a practical-applicational nature are understood to fall within the protective scope of the invention as described in the foregoing and as claimed herein below.