Use of citrulline and combination compound for improving male fertility

Summary

The invention relates to a combination preparation for improving the quantity and quality of sperm, comprising at least one antioxidant, containing citrulline and / or omega-3 fatty acids and citrulline for the treatment of oligozoospermia, asthenozoospermia and / or teratozoospermia.

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-1 The invention relates to a combination preparation for improving the quantity and quality of sperm, comprising at least one antioxidant or at least one of the active ingredients C vitamins, E vitamins, zinc, selenium, acetylcysteine, L-carnitine, glutathione, lycopene, ubiquinone-10- Component of their use, as well as cttrullin to improve sperm quality.

More and more couples find it difficult to have their dream child. In industrialized countries such as Germany and the USA, one in ten couples are unintentionally childless and the trend is rising. Impaired fertility can have many causes. The increasing age of couples who want to have children can play a role, as can environmental pollution, reduced sperm quality, impaired egg cells, an unhealthy lifestyle and others. So-called “lifestyle factors” are also a decisive factor. One of the prerequisites for fertility in men and women is an adequate supply of certain micronutrients, energy substrates and vitamins. A sufficient supply of vitamins and certain nutrients is increasingly difficult in our time Jeider. With increased stress in everyday life, poor food quality and unhealthy nutrition, the human organism is often inadequately supplied. As a result, the body is under constant stress and this is particularly true where the cells are most sensitive in the area of ​​the egg and sperm cells. The male sperm become sluggish, egg cells “miss” their ovulation and thus fertility can suffer from malnutrition. It has already been proven in several studies how much the right diet contributes to fulfilling the desire to have children.

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While the woman is already born with the egg cells, the man's sperm are reproduced for a lifetime. In every second unintentionally childless couple, the man is causally involved and in every third case the cause lies solely with the man. In the last few decades the quality of male fertility has declined continuously. One of the most common reasons for male infertility is limited sperm quality in the sense of oligozoospermia (too few sperm cells), asthenozoospermia (too poorly mobile sperm cells) or teratozoospermia (too many shape-changed sperm cells). It is not uncommon to find all three restrictions even in one and the same patient (OAT syndrome). In addition to a decreasing sperm count, the integrity of the DNA transported in the sperm also plays an important role in fulfilling the desire to have children. A major cause of DNA damage in sperm is oxidative stress. In the last ten years, oxidative stress has therefore become the focus of interest as a trigger for infertility (Agarwal, 2004). Oxidative stress is the damage to cells, tissues or even organs caused by increased amounts of so-called reactive oxygen species (ROS) (Möller et al, 1996; Sharma and Agarwal, 1996; Saleh et al, 2003). If the amount of reactive oxygen species exceeds the capacity of the body's own antioxidant defense mechanisms, the above-mentioned oxidative stress (OS) occurs. 30-80% of all infertile men have an increased amount of ROS in the seminalpiasm (Agarwal, 2004). 2009 could Varghese et al. also show a strong correlation between asthenospermia and reduced antioxidants in the seminal fluid. Damage to normal sperm occurs particularly in men who produce excessive amounts of reactive oxygen species (Aitken et al., 1998, Alvarez et al., 2002, Saleh et aL, 2002, Agarwal et al., 2003). Sperm are particularly susceptible to attack by ROS because they do not have their own cytoplasmic defense and repair mechanisms (Donnelly et al, 1999; Saleh and Agarwal, 2002). In addition, they have a plasma membrane with a particularly large number of polyunsaturated fatty acids. These are good points of attack for ROS. (Agarwal et al, 1994; Kobayashi et al, 2001; Zalata et al, 2004). Antioxidants ingested with foodN2011 / 15300

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Βάθη, represent an important part of the human antioxidative protection system - especially in the area of ​​spermiogenesis. Fruits and vegetables are a main source of the various antioxidants, but can withstand today's increasing loads and the resulting increased oxidative stress, even with a balanced diet can hardly be supplied in the required amount. To make matters worse, men in particular often do not eat particularly consciously and healthily. According to a survey of male patients in reproductive medicine treatment, the majority of men believe that they are very well nourished, even if they say they did not eat more than one to a maximum of two servings of fruit and vegetables per day. The 5 servings of fruit and vegetables recommended by the health authorities of many countries, however, hardly reaches a man (Wogatzky et al, the day before the 4th International Congress of the Jordanian Society for Fertility and Genetics, April 20-22, 2011). In a Spanish study from 2009 it was shown that men who consumed few antioxidants with their diet had an average of poorer semen quality {Mendiola et al, 2009).

For example, the applicant's Fertilovit * M preparation is known. Fertllovit * M contains a combination of vitamins and other vital substances that support the sperm in their maturation and additionally protect against oxidative stress around the clock with antioxidants in depot form. Fertilovit® M for men improves the quality of semen through its specific composition of endogenous substances.

The object of the present invention is therefore to provide an active ingredient or a combination preparation which further improves the sperm quality of men and increases the sperm quantity

The object of the invention is achieved independently by a combination preparation comprising at least one antioxidant and citrulline and / or omega-3 fatty acids or comprising at least one of the active ingredients C vitamins, E vitamins, zinc, selenium, acetylcysteine, L-camitine, glutathione, lycopene, ubiquinoneΝ2Ώ11 / 15300

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-41 Q component, which contains at least citrulline and / or omega-3 fatty acids and is dissolved independently by citrulline to treat a restricted sperm analysis. Citrulline has a very good bioavailability, which means that the organism uses the polyamines spermine and spermidine, which in high Concentration in the sperm fluid occurrence, as well as the protamines, which are necessary for the packaging of the sperm DNA and stabilize the DNA, can produce in sufficient quantities. Omega-3 fatty acids have a positive effect on the fusion of egg and sperm cells, as well as the prostaglandin and steroid hormone metabolism. In many patients (around 70%) the routine administration of additional antioxidants in the combination preparation significantly improves the sperm quality. On the other hand, the patients who do not benefit from such a measure do not have to fear any negative side effects.

C vitamins in the combination preparation interrupt the radical chain reaction and thus neutralize hydroxyl, hyperoxide and hydrogen dioxide radicals. C vitamins act as the main antioxidant in the seminal plasma of fertile men, where the concentration is ten times higher than in the blood plasma. Most of the time, only a small amount is found in the semen of sterile men.

E-Vrtamines are localized in the cell membrane and here very effectively interrupt the radical chain reaction and thus primarily neutralize H2O₂, OH and O2-. In this way they protect the cell membrane from oxidation. It has proven to be particularly advantageous that sperm motility is improved in 60% of patients with asthenozoospermia.

The selenium of the combination preparation can improve the sperm motility, viability and morphology of the sperm in OAT patients. In addition, the sperm DNA is protected from oxidative stress by promoting the protamine packaging of the DNA and selenium also has an antioxidant effect as a component of glutathione peroxidase. Selenium also works synergistically with vitamin E.

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Zinc is an essential part of spermatocytes. If the body does not have enough zinc available for sperm production, this is significantly reduced. The motility of the sperm cells also decreases because zinc helps bind the seed head to the seed tail. The additional zinc in the combination preparation results in an improved spermiogram in infertile men. The combination of zinc with folic acid leads to a 74% increase in sperm count. In addition, treatment over a period of 3 months leads to a significant improvement in astenozoospermia. Zinc, which is involved in almost all biochemical processes in the body, supports the effect of the combination preparation according to the invention.

L-camitine of the combination preparation acts as a receptor molecule for activated fatty acids in the cytosol and in the mitochondria (in interaction with acetyl-CoA) and is an important energy substrate for the spermatozoa. Carnitines are also antioxidants that lower the amount of reactive oxygen species by removing excess intracellular acetyl-CoA. Otherwise this increases the ROS production by the mitochondria. L-camitine also improves sperm motility. Camitin, more precisely L-camitin, plays an essential role in the energy metabolism of animal cells.

By adding glutathione to the combination preparation, the mobility of sperm is significantly increased. Glutathione also reduces DNA damage from ROS. The tripeptide glutathione (cysteine, glutamate, glycine) is the most common antioxidant in the human body. It protects lipids, proteins and nucleic acids from oxidative stress. Glutathione is found in high concentrations in almost old cells and is one of the most important substances in the body that act as an antioxidant. At the same time it is a reserve for cysteine. in combination with vitamin E and selenium, it forms glutathione peroxidase. Administering glutathione as a dietary supplement alone does not always lead to the desired success, however, since oral administration only leads to a moderate increase in the glutathione circulating in the body. However, the oral administration of N-acetylcysteine ​​of the combination preparation, an important precursor molecule of glutathione, can effectively increase the glutathione content in cells. Orally administered □ cm

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6th acetylcysteine ​​over a period of 3 months leads to a significant increase in the total antioxidative capacity in the plasma. This goes hand in hand with lower viscosity and thus with improved seed mobility.

Lycopene, also called lycopene or leukopene, is one of the antioxidants and is considered a radical scavenger, ie it can render certain reactive molecules in the human body harmless. Lycopene is a carotenoid with very good antioxidant and anti-inflammatory properties. Due to these anti-inflammatory properties, when added to the combination preparation, it reduces the seminal new production of ROS by leukocytes.

The addition of the ubiquinone-10 component (coenzyme Q10) in the combination preparation leads to an increase in the amount of sperm and an improvement in mobility. Coenzyme Q10 (CoQ10) is required by the body, among other things, for energy production in the mitochondria, so it is mainly found in the middle of sperm. But it also has antioxidant properties by recycling vitamin E and preventing its pro-oxidative activity. The tissue concentration of coenzyme Q10 decreases with increasing atter, which means that this decrease can be compensated for by the combination product. By administering the combination preparation with oral CoQ-10 to infertile male subjects, the fertilization rate is significantly increased. CoQ-10 also prevents the formation of H.₂O₂ in the seminal fluid.

Folic acid supports the protamine packaging of the sperm DNA. A diet low in folic acid in men increases the number of sperm with chromosomal aberrations. Men who consume plenty of folic acid through their diet or vitamin supplements are significantly less likely to have sperm with a disomy of the X chromosome (Klinefelter) or chromosome 21 (Down's syndrome) or a nullosomy of the X chromosome (Turner). After considering other factors such as age, alcohol consumption and comorbidity, men with the highest folic acid intake (722-1150 pg / d) have 20-30 percent fewer sperm with aneupliody in the ejaculate than men with the lowest folic acid intake. For every 100 pg of folic acid, the risk drops by 3.6 percent. Furthermore, FolN2011 / 15300 nc promotes 1 1 in 1 1cm

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-7 acid also the homocysteine ​​metabolism, which counteracts hyperhomocysteinemia and thus has an additional beneficial effect on spermiogenesis.

The combination preparation improves the membrane structure of the sperm by means of high-quality omega-3 fatty acids, which is particularly important for the fusion of sperm cells and egg cells during the actual fertilization, because a balanced membrane structure of the cells plays an important role for the healthy sperm function. Incapable of childbearing men have a lower proportion of polyunsaturated fatty acids than fertile men, and in particular a lower proportion of omega-3 fatty acids. This goes hand in hand with reduced sperm count, mobility and structure of the sperm. An intake of omega-3 fatty acids can counteract these problems. A positive side effect is the protective effect of omega-3 fatty acids for the prostate and the cardiovascular system. The membrane is largely made up of fats. Changes in nutritional conditions have demonstrably changed the relative proportions of different fatty acids in cell membranes in recent years. In particular, the essential polyunsaturated omega-3 fatty acids are relatively insufficiently available. This has an influence on processes such as the fusion of egg and sperm cells, as well as the prostaglandin and steroid hormone metabolism. While saturated and monounsaturated fats have been shown to have a detrimental effect on sperm quality, both omega-6 and omega-3 fatty acids are very good for sperm quality. The ratio of omega-3 fatty acids to omega-6 fatty acids is also important.

The combination preparation can also contain citrulline. Citrulline is used by the body for the synthesis of arginine. An important property of arginine is that it is, in turn, a precursor of the neurotransmitter nitric oxide (NO). The enzyme nitric oxide synthase catalyzes the conversion of the amino acid arginine into the endothelium derived reiaxing factor (EDRF) - another name for nitric oxide. This diffuses into the muscle layers of the vessels or of the corpus cavemosum. There, by activating the enzyme guanyiate cyclase, it leads to an increased release of cyclic guanosine monoN2011 / 15300

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-8 phosphate (cGMP). The increase in cGMP causes the smooth muscles to relax and thus a decrease in vascular tone. The gaseous NO thus triggers relaxation in the heart muscle and smooth vascular muscles.

By releasing nitric oxide, the amino acid L-arginine improves blood flow and oxygen supply to the coronary and peripheral blood vessels, inhibits the formation of clots in platelets and lowers blood pressure. This mechanism can also increase the erectile function of the limb.

Arginine is also necessary for normal spermatogenesis. The body uses arginine to produce the polyamines spermine and spermidine, which are found in high concentrations in the sperm fluid, as well as the protamines, which are necessary for the packaging of the sperm DNA and stabilize the DNA.

In infertile men, the combination preparation leads to an increase in the amount and mobility of sperm cells after just 6 to 8 weeks. However, arginine has the disadvantage that it does not have an optimal bioavailability chain when administered orally. The amino acid L-citrulline is an important precursor for the production of arginine in the body but, in contrast to arginine, is absorbed much better enterally. It therefore has a very good bioavailability. Taken orally, LCitrulline is absorbed into the bloodstream through the intestines and converted into LArginine by the body. Studies have shown that citrulline supplementation can raise arginine levels more effectively than taking the same dose of arginine directly. Since the body converts citrulline into arginine with a delay, citrulline acts as a retention time lengthener and increases the arginine level in the blood over a longer period of time. The organism benefits from a noticeably longer arginine effect. The use of citrulline for the production of a combination preparation comprising at least antioxidants to improve the quality of the sperm also proves to be advantageous.

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A ratio of eicosapentaenoic acid to docosahexaenoic acid of 3 to 2 is also favorable, because it can increase the number of sperm and improve the mobility and structure of the sperm.

By selecting the amounts of the active ingredients C vitamins in amounts of 1 to 20% by weight, in particular 5 to 15% by weight, preferably 6 to 10% by weight, EVrtamines in amounts of 1 to 20 cow. %, in particular 5 to 15% by weight, preferably 6 to 10% by weight, B9 vitamins in amounts of 0.005 to 2% by weight, in particular 0.009 to 1% by weight, preferably 0.01 to 0.1 % By weight, zinc in amounts of 0.5 to 5% by weight, in particular 0.8 to 3.5% by weight, preferably 1.2 to 2.5% by weight, selenium in amounts of 0.001 up to 1% by weight, in particular 0.004 to 0.5% by weight, preferably 0.006 to 0.1% by weight, acetylcysteine ​​in amounts of 0.5 to 10% by weight, in particular 1 to 6% by weight, preferably 2.5 to 4.5% by weight, Camitin in amounts of 3 to 30% by weight, in particular 5 to 25% by weight, preferably 10 to 23% by weight, glutathione in amounts of 0.5 to 15% by weight, in particular 1 to 10% by weight. -%, preferably 3 to 6% by weight, lycopene in amounts of 0.05 to 3% by weight, in particular 0.08 to 1% by weight, preferably 0.2 to 0.1% by weight, and a ubiquinone-10 component in amounts of 0.05 to 10% by weight, in particular 0.1 to 5% by weight, preferably 0.8 to 3% by weight, and omega-3 fatty acids in amounts of 5 up to 50% by weight, in particular 10 to 40% by weight, preferably 20 to 35% by weight, and / or citrulline in amounts of 5 to 40% by weight, in particular 8 to 30% by weight, preferably 12 to 20% by weight , based on the total weight of the therapeutically active ingredients of the combination preparation, the above-described positive effects of the individual active ingredients are put in an optimal ratio to one another and thus the sperm quality and number are increased most effectively.

By adding B6 vitamins and B12 vitamins in the combination preparation, the vascular function is supported by lowering the homocysteic acid levels and thus a sufficient production of sperm and spermatogenesis is supported.

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Copper is a component of many enzymes (metalloenzymes) and is therefore a vital trace element and can therefore also support optimal sperm production.

The sperm quality is also improved by the great antioxidant potential of the other carotenoids.

The addition of copper in amounts of 0.001 to 1% by weight, in particular 0.003 to 0.5% by weight, preferably 0.05 to 0.1% by weight, B6 vitamins in amounts of 0 has also proven to be advantageous , 05 to 3% by weight, in particular 0.08 to 1% by weight, preferably 0.2 to 0.1% by weight, B12 vitamins in amounts of 0.001 to 1% by weight, in particular 0.003 to 0, 5% by weight, preferably 0.05 to 0.1% by weight, other carotenoids such as ß-carotene, α-carotene, ß-cryptoxanthin, lutein and zeaxanthin in amounts of 0.05 to 3% by weight , in particular 0.08 to 1% by weight, preferably 0.2 to 0.1% by weight, based on the total weight of the therapeutically active ingredients of the combination preparation, because the advantageous effects described above have a cumulative effect on the development of the sperm . The described composition of the combination preparation optimizes the interaction of the individual substances with one another and additionally increases the synergy effects. In addition, a balanced interaction with the other substances can be achieved.

The combination preparation can be used both as a drug or a balanced diet and as a dietary supplement, which ensures that the user has at least one clinical trial for approval as a medicinal product or a balanced diet, and a simple one for approval as a dietary supplement and if necessary, discrete access to the specimen is given

It has also proven advantageous to use citrus for the treatment of oligozoospermia, asthenozoospermia and / or teratozoospermia. Citrulline proves to be advantageous to administer in daily doses of 100 mg to 1000 mg, in particular 150 mg to 500 mg, preferably 200 mg to 300 mg, which ensures that an adequate level of citrulline is present in the organism and

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-11 thus normal spermatogenesis can take place. This promotes a large amount of sperm and good sperm motility.

Citrulline is contained in amounts of 2 to 50% by weight, in particular 5 to 35% by weight, preferably 10 to 20% by weight, based on the total weight of the therapeutically active ingredients of the combination preparation, whereby on the one hand a sufficient effect of citrulline but on the other hand there is also no risk of overdosing. The selected weight fraction also ensures good processability in the manufacture of the combination preparation.

The invention describes citrulline for use in a therapeutic method for treating a restricted semen analysis. The combination with antioxidants is particularly beneficial. For the purposes of the invention, an antioxidant is a chemical compound which specifically prevents undesired oxidation of other substances. Antioxidants are of great physiological importance due to their effect as radical scavengers. They inactivate reactive oxygen species (ROS) in the organism, the occurrence of which in excess leads to oxidative stress. Oxidative stress is thought to be partly responsible for the process of attenuation and impairment of fertility and is also linked to the development of a number of diseases.

The invention further describes citrulline for use in a method for producing a combination preparation for the treatment of a restricted spermiogram. The effects of the various active ingredients in the combination product have already been described in advance. The combination preparation proves to be particularly advantageous for the treatment of a restricted sperm analysis in oligozoospermia, asthenozoospermia and / or teratozoospermia due to the targeted selection of the active ingredients in the appropriate amounts. A combination of C vitamins, E vitamins, zinc, selenium, acetylcysteine, L-camrtine, glutathione, lycopene, (jbiquinon-10 component with citrulline and / or omega-3 fatty acids) is particularly advantageous.

The preferred omega-3 fatty acids are eicosapentaenoic acid (EPA) and

Docosahexaenoic acid (DHA) is used. But it can also be α-linolenic acid (ALA)

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can be used as omega-3 fatty acids in the combination preparation. Fish oil is preferably used for the production of the combination preparation, 18% being DHA and 12% being EPA. Omega-3 fatty acids of both animal and vegetable origin can be used.

The combination preparation according to the invention is specially designed for the needs of the male organism when trying to have children. It can be a dietary supplement, a dietetic food for special medical purposes (supplementary balanced diet), or a medicinal product.

Furthermore, the combination preparation according to the invention shows a specially adapted mixture of antioxidants, partly in depot form, and other nutrients and minerals that are important for the reproductive cells. For example, vitamin C is added as a sustained release form. The prior art describes preparations for the delayed release of active ingredients. For example, vitamin C can be coated with hydroxypropyl methyl cellulose. Thus, optimal care is available to the man. Of course, other methods known from the prior art for the time-delayed release of vitamin C can also be used.

The mechanisms of action of the individual substances in the combination preparation according to the invention are complex. In addition to the supply of nutrients and enzyme induction, an essential mechanism of action is the targeted reduction of oxygen radicals.

The combination of active ingredients in the combination preparation according to the invention, which are matched to one another, has shown in studies that there is a significant improvement in their fertility in men.

The mechanisms described above work preferentially in combination of the active ingredients and through the support of several antioxidants.

Due to the synergistic effect of the individual active ingredients in the selected quantity ranges, the effectiveness with regard to sperm quality and quantity of the combination preparation according to the invention can be achieved.

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The use of citrulline, optionally in combination with at least one antioxidant or omega-3 fatty acids with at least one antioxidant, as well as the combination preparation according to the invention, is preferably recommended for oral administration. The preparation can be used both as a human and veterinary product.

The table below shows the quantity ranges of the recommended daily dose of the individual active ingredients relevant to the invention. The combination preparation according to the invention is preferably taken as two capsules per day. However, the amount of active ingredient can be chosen so that only one capsule per day is required to achieve the recommended dosage.

<td>Active ingredient</td><td>recommended amount range in mg per day</td>

<td>vitamin C</td><td> 50 -200</td>

<td>Vitamin E.</td><td> 10-120</td>

<td>Folic acid</td><td> 0,1-0,7</td>

<td>zinc</td><td> 5-50</td>

<td>selenium</td><td> 0,02-0,2</td>

<td>Acetylcysteine</td><td> 10-100</td>

<td>Camitin</td><td> 10-500</td>

<td>Glutathione</td><td> 10-100</td>

<td>Lycopene</td><td> 1-15</td>

<td>Ubiquinone-10 component</td><td> 1 -50</td>

<td>Omega 3-</td><td> 100-1000</td>

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<td>Fatty acids</td><td></td>

<td>Citruilin</td><td> 1-600</td>

<td>copper</td><td> 0,05-10</td>

<td>Vitamin B12</td><td> 0,01 -1</td>

<td>Vitamin B6</td><td> 1-10</td>

<td>Carotenoids</td><td> 0,1-10</td>

It also contains excipients, such as auxiliaries, fillers, carriers, binders, etc., which are necessary for the technical processability of the combination preparation according to the invention. However, these excipients have no therapeutic efficacy and no positive effects on the sperm and are accordingly not therapeutically active ingredients within the meaning of the invention.

In the following, exemplary embodiments of the composition of the therapeutically active ingredients are given in mg per daily dose of the combination preparation according to the invention which achieves the advantageous effects.

<td>Active ingredient</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 5</td><td> 6</td><td> 7</td><td> 8</td><td> 9</td><td> 10</td>

<td>vitamin C</td><td></td><td> 50</td><td> 120</td><td> 150</td><td> 100</td><td> 180</td><td> 200</td><td> 100</td><td> 80</td><td> 100</td>

<td>Vitamin E.</td><td></td><td> 10</td><td> 20</td><td> 50</td><td> 100</td><td> 100</td><td> 120</td><td> 100</td><td> 60</td><td> 80</td>

<td>Folic acid</td><td></td><td> 0,1</td><td> 0,3</td><td> 0,3</td><td> 0,5</td><td> 0,6</td><td> 0,7</td><td> 0,5</td><td> 0,4</td><td> 0,5</td>

<td>zinc</td><td></td><td> 5</td><td> 10</td><td> 15</td><td> 25</td><td> 40</td><td> 50</td><td> 25</td><td> 30</td><td> 10</td>

<td>selenium</td><td> *</td><td> 0,02</td><td> 0,05</td><td> 0,07</td><td> 0,1</td><td> 0,1</td><td> 0,2</td><td> 0,1</td><td> 0,09</td><td> 0,15</td>

<td>Acetylcysteine</td><td> •</td><td> 10</td><td> 40</td><td> 30</td><td> 50</td><td> 90</td><td> 100</td><td> 50</td><td> 80</td><td> 80</td>

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<td>Carnitine</td><td> -</td><td> 10</td><td> 100</td><td> 200</td><td> 300</td><td> 400</td><td> 500</td><td> 300</td><td> 250</td><td> 350</td>

<td>Glutathione</td><td></td><td> 10</td><td> 20</td><td> 25</td><td> 50</td><td> 80</td><td> 100</td><td> 50</td><td> 90</td><td> 70</td>

<td>Lycopene</td><td> -</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 2,5</td><td> 15</td><td> 4</td><td> 13</td><td> 10</td>

<td>Ubiquinone-10 component</td><td></td><td> 1</td><td> 3</td><td> 10</td><td> 15</td><td> 15</td><td> 50</td><td> 15</td><td> 30</td><td> 40</td>

<td>Omega 3- Fatty acids</td><td></td><td> 100</td><td> 200</td><td> 400</td><td> 500</td><td> 350</td><td> 1000</td><td> 500</td><td> 700</td><td> 900</td>

<td>Citruliine</td><td> 500</td><td> 100</td><td> 300</td><td> 800</td><td> 300</td><td> 600</td><td> 600</td><td> 200</td><td> 60</td><td> 10</td>

<td>copper</td><td></td><td></td><td></td><td></td><td></td><td> 0,5</td><td></td><td> 1</td><td></td><td></td>

<td>Vitamin B12</td><td></td><td></td><td> 0,05</td><td></td><td> •</td><td> 0,01</td><td></td><td> 0,09</td><td></td><td></td>

<td>Vitamin B6</td><td></td><td></td><td></td><td></td><td></td><td> 1</td><td></td><td> 3</td><td> 2</td><td> •</td>

<td>Carotenoids</td><td></td><td></td><td></td><td> 5</td><td> •</td><td> 5</td><td></td><td> 3</td><td></td><td> 3</td>

<td>Filling and Carriers</td><td>z</td><td> ✓</td><td>z</td><td>z</td><td>z</td><td>Z</td><td>z</td><td>Z</td><td>z</td><td>z</td>

Tests have shown that embodiment 5 is particularly effective. With a composition according to exemplary embodiment 5, the spermiogram is improved and the fertilization rate is increased by approximately 20%. In general, it has been shown that the preparation according to the invention significantly improves the quantity and quality of sperm in over 70% of men.

In the table below, the compositions of the active ingredients are described by way of example in absolute numbers of two combination preparations according to the invention which develop the advantageous effects.

N2011 / 16300 p

οο / ηΎοηιι icok

Mr m; ni

15:23:22 26-07-2011 /27

<td>Active ingredient</td><td>Amount in mg per daily dose</td><td>Wt%</td><td>Amount in mg per daily dose</td><td>Weight%</td>

<td>vitamin C</td><td> 100</td><td> 7,43715603</td><td> 100</td><td> 7,39814602</td>

<td>Vitamin E.</td><td> 100</td><td> 7,43715603</td><td> 100</td><td> 7,39814602</td>

<td>Folic acid (vitamin B9)</td><td> 0,5</td><td> 0,03718578</td><td> 0,5</td><td> 0,03699073</td>

<td>zinc</td><td> 25</td><td> 1,85928901</td><td> 25</td><td> 1,84953651</td>

<td>selenium</td><td> 0,1</td><td> 0,00743716</td><td> 0,1</td><td> 0,00739815</td>

<td>Acetylcysteine</td><td> 50</td><td> 3,71857802</td><td> 50</td><td> 3,69907301</td>

<td>Camitin</td><td> 300</td><td> 22,3114681</td><td> 300</td><td> 22,1944381</td>

<td>Glutathione</td><td> 50</td><td> 3,71857802</td><td> 50</td><td> 3,69907301</td>

<td>Lycopene</td><td> 4</td><td> 0,29748624</td><td> 4</td><td> 0,29592584</td>

<td>Ubtquinon-10 component</td><td> 15</td><td> 1,1155734</td><td> 15</td><td> 1,1097219</td>

<td>Omega-3 fatty acids</td><td> 500</td><td> 37,1857802</td><td> 500</td><td> 36,9907301</td>

<td>Citrulline</td><td> 300</td><td> 14,8743121</td><td> 300</td><td> 14,796292</td>

<td>copper</td><td> *</td><td> 0</td><td> 3</td><td> 0,22194438</td>

<td>Vitamin B12</td><td></td><td> 0</td><td> 0,09</td><td> 0,00665833</td>

<td>Vitamin B6</td><td> •</td><td> 0</td><td> 1</td><td> 0,07398146</td>

<td>Carotenoids</td><td></td><td> 0</td><td> 3</td><td> 0,22194438</td>

In a preferred embodiment variant, the combination preparation according to the invention consists of L-camitine, L-ascorbic acid, D-alpha-tocopheryl acetate, folic acid, silicon dioxide, calcium carbonate, N-acetyl-L-cysteine, glutathione, corn starch 26/07/2011 15:25

No .: R501

P.020/027

15:23:54 26-07-2011 /27

<img file="AT511776A1_D0004.tif" />

-17ke, zinc oxide, coenzyme Q10, lycopene, vegetable oils, pteroyl-L-glutamate, sodium selenite, fish oil and citrulline. The capsule shell is preferably made of cellulose, but can also be of a different type. The vegetable oils come from the fact that the raw material lycopene is fat-soluble and is offered dissolved in them. Instead of sodium selenite, the organic variant of L-selenomethionine can also be used. Corn starch is a carrier of the otherwise oily vitamin E.

The positive effect of cttruliin and the combination preparation according to the invention can be used both in preparation for a natural pregnancy and in preparation for insemination, in vitro fertilization and intracytoplasmic sperm injection.

The combination preparation according to the invention should be taken orally twice a day in the form of a capsule. The recommended minimum duration is 3 months.

All information on value ranges in the present description are to be understood as including any and all sub-areas thereof, e.g. the information 1 to 10 is to be understood in such a way that all sub-areas, starting from the lower limit 1 and the upper limit 10, are also included , ie all subranges begin with a lower limit of 1 or greater and end at an upper limit of 10 or less, for example 1 to 1.7, or 3.2 to

8.1 or 5.5 to 10.

The exemplary embodiments show possible design variants of the combination preparation, whereby it should be noted at this point that the invention is not restricted to the specially shown design variants thereof. Rather, various combinations of the individual design variants with one another are also possible and this possibility of variation is within the ability of a person skilled in the art based on the teaching of technical action through the present invention. All conceivable design variants that are possible by combining individual details of the design variant described are therefore also included in the scope of protection.

N2011 / 15300

hl r

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22/27

<img file="AT511776A1_D0005.tif" />

The task on which the independent inventive solutions are based can be found in the description.

M2011 / 15300

M ccm

P Π99 / Π97

15:24:55 26-07-2011 /27 ··»* ·«·* ·