AT9808U1 - VITAMIN AND MINERAL MATERIAL PREPARATION AND ITS USE FOR IMPROVING THE SEED QUALITY - Google Patents

Description

2 AT 009 808 U1

The invention relates to a combination preparation according to claim 1 and a method for producing a combination preparation for the treatment of impaired fertility in men according to claim 11.

Fertility treatment in couples with unfulfilled desire for children has become increasingly important in practical medicine in recent years. Infertility now affects one in six pairs of children. The cause of an unfulfilled desire to have a baby can be in the woman as well as in the man, whereby the factor man has become increasingly important in recent years. In contrast to women, who have a range of therapeutic options available, the options for improving the only and crucial factor, namely semen quality, are very limited in men.

Both the quality and quantity of male semen are influenced by numerous factors. Various environmental burdens (pollutants, heavy metals, etc.) burdening lifestyle factors (such as nicotine, alcohol, etc.) and changing living conditions (pronounced stress) burden today the seed development and motility, the appearance and the number of sperm. Seed production is a very complicated and biologically complex process that lasts for several weeks and is slightly negatively influenced. As part of the sperm cell maturation, the body needs special auxiliaries for the different stages of development. These include various amino acids, trace elements, vitamins and vitamin-like substances. Only with these special nutrients is the optimal condition for a normal and healthy sperm formation. Due to certain life circumstances and a wrong lifestyle, a lack of these substances can occur quickly and is usually not noticed by those affected. For this reason, a regular supply of these substances in sufficient quantity is indispensable.

Many individual substances important for the course of sperm maturation have already been scientifically studied and described. The effectiveness of each vital substance is well known.

The individual components and their modes of action are all known separately in this case. The following is an overview of the individual active ingredients: L-carnitine [6645-46-1]: L-carnitine is an endogenous substance that serves the sperm cells as an energy substrate. L-carnitine can improve sperm motility and sperm count. L-arginine [74-79-3]: L-arginine is an amino acid that is needed by the body in large quantities and has led to significant improvements in sperm count and sperm motility.

Coenzyme Q10 [303-98-0]: Ubiquinone coenzyme Q10 may improve fertility, increase sperm count, and improve sperm motility.

Vitamin E, especially a-tocopherol [59-02-9]: Vitamin E can improve sperm motility and promote the sperm cell's ability to unite with the egg.

Zinc: Zinc is a vital trace element and acts on the one hand as an antioxidant, i. As a substance that binds free radicals or prevents the formation of new cells, zinc also contributes to an increase in sperm cell density, an increase in fast-moving sperm, and an increase in the testosterone level that is important for sperm maturity when it participates in numerous biochemical processes in the body. 3 AT 009 808 U1

Folic Acid [75708-92-8]: Folic acid is essential for cell growth, cell division (blood formation) and nerve metabolism and is involved in the protection of the cardiovascular system. For a long time the positive effect of this vitamin on the seed quality has been known, extensively studied and recommended for support.

Glutathione [70-18-8] and Selenium: Glutathione and selenium are highly effective scavengers and can significantly improve sperm motility.

There are also known from the prior art some preparations for improving the sperm quality of the man, in which some of these drugs are combined.

Thus, for example, WO 02/003974 describes a preparation for improving the quality of semen, which is based on the combination of folic acid with zinc sulfate.

Furthermore, US Pat. No. 6,338,862 describes a preparation for rectifying erectile dysfunctions, which combines L-arginine, ginseng and various B group vitamins.

So far, however, it is still extremely difficult and many believe that it is impossible to achieve a significant improvement in fertility through drug treatment, even if it is often propagated and asserted.

The object of the invention is therefore to provide an effective preparation, inter alia, to improve the sperm quality of the man.

This object is solved by the features of claim 1.

The individual substances combined in the combination preparation and carefully selected have proven their effectiveness in improving the quality of semen and have already been tested.

Studies have shown the surprising effect of the new combination preparation, which far exceeds the sum of the expected individual effects and also far exceeds the efficacy of all previously available compositions. By administering the combination preparation according to the invention, it was possible to achieve a clear improvement in the quality of the semen right up to a completely normal spermiogram. Such treatment successes are not known to date and the surprising level of effectiveness is extremely advantageous for the patients concerned. All fertility parameters of the spermiogram, e.g. Density, motility and sperm morphology were significantly increased.

As the literature proves and was confirmed by comparative experiments, none of the individual substances could achieve comparable results, which makes it understandable that only the specific combination of the substances used leads to the desired success.

In this connection, special attention should be drawn to the advantageous effect of arginine and the synergistic effects brought about by arginine, as will be explained in detail later.

In the dependent claims advantageous developments of the invention are shown.

The advantageous features of claim 2 describe a particularly effective composition of the combination preparation. Such a composition optimizes the interactions of the individual substances with one another and additionally reinforces the synergy effects.

The features of claim 3 enhance the effect in addition, it is advantageous if the concentrations of claim 4 are met. Due to the high antioxidant capacity and the well-known role of free radicals in sperm maturation, the administration of alpha-lipoic acid with a poor spermiogram is very beneficial. This has also already been clinically tested successfully in an application study. It is also known that the alpha-lipoic acid raises the important glutathione level.

The features of claim 5 cause a further effect-enhancing effect, it being advantageous if the concentrations of claim 6 are met. N-acetylcysteine (NAC) is a very important substance for the production of sufficient glutathione. The advantageous and surprisingly strong synergistic interaction between glutathione, NAC and alpha-lipoic acid contributes to the further improvement of the semen quality.

In both animal and human studies, the administration of vitamin C according to the features of claims 7 and 8 proves to be extremely useful for improving the quality of semen. Vitamin C significantly reduces sperm oxidation in the testes, which is harmful for semen production, and thus leads to an improvement in sperm quality in terms of an increase in sperm cell density and an increase in testosterone levels.

The effect of the combination preparation can be further increased by the provision of further features according to claim 9.

In one study, 66 patients with poor sperm quality were studied. The administration of ginseng extract led to an increase in sperm cell concentration, mobility and increased testosterone levels. The addition of ginseng also yielded further combinatorial effects, in particular with regard to sperm motility.

Both in animal studies and in humans, the administration of vitamin B12 proved to be an excellent opportunity to significantly improve both sperm cell concentration and motility.

The dependence of spermiogenesis on thiamine is a new discovery. In animal experiments it was discovered that experimental subjects with a thiamine deficiency in comparison to the control group without deficiency have deficits in spermiogenesis and are therefore very limited fertility. In addition, one suspects a negative influence on the thiamine deficiency on the hormone balance. The addition of thiamine also showed surprising increases in activity over the known individual substance. The same applies to biotin.

A particularly advantageous example of a highly effective combination preparation, the effectiveness of which has also been demonstrably confirmed by clinical investigations, is described in the features of claim 10. This preparation consists of the named active ingredients, whereby the desired surprising effects are already advantageously established from the relatively small number of combined active ingredients.

Furthermore, it is an object of the invention to provide an advantageous use of the combination preparation for the preparation of a medicament.

This object is achieved by the features of claim 11, in which the combination preparation is used as an effective drug for improving the quality of semen or for the treatment of impaired fertility. In addition, the combination preparation for the treatment of subfertility of a male individual, in particular a human, for the treatment or optimization of borderline normozoospermia, for the treatment of asthenozoospermia, oligozoospermia, teratozoospermia, oligo-astheno-terato zoospermia, in particular OAT I, OAT II and / or OAT III, cryptozoospermia, parvisemy and / or to improve impaired capacity for capacitance.

In this connection, it is particularly advantageous to see the features of claim 12 above, whereby the effectiveness is increased.

By the features of claim 13, an effective dosage is given, which is compatible on the one hand for the body and on the other hand has the above effective effects.

Infertility now affects one in six pairs of children. In the meantime, it is beginning to understand the pathologies both at the biochemical and at the cellular level, which subsequently cause the production of defective sperm cells. ROS (reactive oxygen species) are reaction products that attack the lipids of the sperm cell membrane in the plasma and thereby initiate a peroxidation cascade. As a result, the spermatozoa lose the ability to move, the acrosome reaction and the fusion between sperm and egg is no longer possible. ROS impede mitochondrial function and negatively affect the synthesis of DNA, RNA, and the formation of proteins. At this point, two substances of the combination preparation are already used. L-carnitine and coenzyme Q10 act at the cellular level by being crucial in the energy metabolism of mitochondria in the cells. L-arginine, an important amino acid, is the basic building block for protein biosynthesis. Only a sufficient supply of these substances in the body guarantees the above-mentioned functions.

Arginine causes in the combination preparation according to the invention a sperm quality-enhancing and fertility-promoting effect in three ways. It primarily has an independent positive effect on sperm motility and sperm count. Secondly, the exceptionally strong effect of arginine on the regulation of nitric oxide causes an optimization of the metabolic milieu as a starting point for an improved effect of all other ingredients. Arginine thus has a beneficial effect on the effectiveness of the other components of the combination preparation. The potent reduction of the oxidative stress provides the functionally effective components of the preparation a significantly improved starting situation and thus significantly increases their effect on mobility and motility. This is a justification why the combination of the individual substances brings an improvement in the influence on motility and sperm count, which goes beyond the effect of the individual substances. Surprisingly, as shown in the own study cited, the effect improved such that nine normal spermiograms (29%) were obtained at the end of the study. The third mechanism of action of arginine is based on the marked improvement in sperm capacity, namely, the preparation and penetration of sperm into the egg.

This characteristic of L-arginine, in combination with the other ingredients, especially with vitamin E, zinc and glutathione, also explains the surprising development that six pregnancies could already be observed within the study and just after the end of the study.

Glutathione plays a significant role in the antioxidant defense of sperm epithelium, the epididymis and generally in the ejaculate. This highly effective antioxidant, especially in combination with selenium, is particularly good at maintaining the functionality of sperm cells. Both testes and epididymis, and thus spermatogenesis, rely on the defense mechanisms of the combination of glutathione and selenium. This is done, among others, by the enzymes superoxide dismutase (SOD) and glutathione peroxidase, which can prevent damaging lipid oxidation. The enzyme glutathione-S-transferase deactivates other foreign and polluting substances (environmental toxins).

These protective mechanisms described only work under certain conditions, to a limited extent and only in combination and with the support of other antioxidants.

This includes zinc, which is involved in almost all important biochemical processes of the body. In addition, it requires the combination of the antioxidant substances vitamin E, supplemented with folic acid from the vitamin B complex. These two vitamins play a major role in spermatogenesis and are indispensable in their combination.

Thus, the surprising effectiveness of this preparation in the synergistic Zu-io sammenwirkung of the individual substances.

In the tables below, an inventive combination preparation is described by way of example, which unfolds the advantageous effects. 15 Table 1

Ingredients Amount of active ingredients per capsule% by weight of total active ingredients (example) Recommended amount [mg] per day (range) Recommended amount [mg] per day (example) L-Carnitine 220 mg 46.5 100-5000 440 L-Arginine 125 mg 26.4 100-5000 250 Coenzyme Q10 7.5 mg 1.59 5-250 15 Vitamin E 60 mg 12.7 50-1000 120 Zinc 20 mg 4.23. 5-100 40 folic acid 0.4 mg 0.085 0.1 -1 0.8 glutathione 40 mg 8.46 10-1000 80 selenium 0.03 mg 0.0063 0.01 - 1 0.06 active ingredients total 472.93 mg 100.00% 35

Table 2

Ingredients per day absorbed amounts of active ingredients% by weight based on the total weight of the combined preparation incl. Fillers (example) per capsule L-carnitine 440 mg 25.9 L-arginine 250 mg 14.7 coenzyme Q10 15 mg 0.9 vitamin E 120 mg 7,1 zinc 40 mg 2,4 folic acid 800 pg 0,0471 glutathione 80 mg 4,7 selenium 60 pg 0,0035 sum of active ingredients 55,7506 remainder fillers (not active active) ca. 44,2 total 100 , 0000 7 AT 009 808 U1

In Table 1, the composition of a particularly effective and clinically confirmed in its effectiveness combination preparation is described in detail. The combination preparation is in capsule form, wherein present in the interior of the capsule, the active water-soluble and fat-soluble active ingredients as granules.

Thus, according to this example, 472.93 mg of active ingredients are contained in one capsule. According to Table 2, this corresponds to an amount of about 56% by weight, based on the total weight of the capsule contents. The remaining 44% are fillers, for example starch, which are advantageous for the technical processability of the granules. However, these technical fillers have no efficacy and no positive effects on the sperm quality and are accordingly no active ingredients in the sense of the above.

Table 1 further describes the percentage composition or the ratio of the active substances to each other in% by weight. Glutathione has a decisive influence on the effectiveness of the preparation, since the glutathione enhances and additionally boosts the combinatorial and synergistic effects.

Table 1 also shows the recommended daily doses in the last two columns and the recommended dose when taking two capsules per day.

The combination preparations according to the invention may in particular be preparations and / or compositions which are directed and / or suitable for oral administration to a mammalian male, including but not limited to pharmaceutical, dietetic or veterinary preparations or compositions and / or nutritional supplements. The combination preparation is thus suitable both for human food and for animal food.

The term " a source for " refers to a compound which is suitable for administration and, in particular, for oral administration to a mammalian male, and which, in such administrations, provides the subject with the desired substance and / or renders it bioavailable.

Thus, among " a source of a vitamin B, especially folic acid " to understand a substance which results in increased levels of folic acid in the body or in at least a part thereof, including but not limited to a biological fluid such as blood, plasma and / or seminal fluid. Sources of folic acid include, for example, folic acid and its salts, folate compounds, or optionally suitable analogs, precursors and / or metabolites of folic acid or folate compounds, or any suitable combination thereof. The source (s) of folic acid may be in suitably reduced or oxidized form, as will be understood by one of ordinary skill in the art. Some specific examples of suitable sources of folic acid include mono- or polyglutamate forms of folic acid, salts and / or esters of folic acid and / or methylated derivatives of folic acid, for example folinic acid or 5-methyltetrahydrofolic acid, or any suitable combination thereof. The reduced monoglutamate form can also be used.

The term " a source of zinc " refers to a compound which is suitable for administration, and in particular for oral administration to a mammalian male, and which, after administration, provides zinc to that individual and / or makes it biologically available, especially in the form of Zn 2+ ions. Suitable examples of such biologically available sources of zinc include biologically available zinc salts with inorganic anions such as chloride, carbonate and sulfate, but also zinc salts with organic anions such as lactate, gluconate, fructose phosphates, orotates, citrates, malates, pyruvates, etc. and zinc complexes with one organic molecule such as an amino acid, or a di- or tridentate compound or any suitable combination thereof. 8 AT 009 808 U1

The same applies to the other substances, which may also be present in any form, be it as an organic or inorganic salt or as a derivative, which makes the active ingredient bioavailable to the body. 5 The term "in effective amounts" means quantities that are deliberately and intentionally contained in therapeutically sufficient quantities. Minor impurities, especially those without therapeutic effect, are not included.

To study the beneficial and surprising effects, a study was carried out, io In this study, a total of 40 men with long-term desire for children and at least 2 pathological spermiograms were included in the anamnesis. These patients received the combined preparation according to the invention over a period of a total of 3 months. The daily dose was 2 capsules, which corresponds to an amount of active agents as shown in the last column of Table 1. After a period of use of 3 months, 15 was subjected to a control sperm. So far, 18 patients could be evaluated.

The study produced the following clear results:

The ejaculation volume in relation to the total collective increased on average from 53.1 ml 20 to 66.5 ml. This corresponds to a total increase of 13.4 ml and an average increase in the ejaculation volume of 0.74 ml per patient. An increase was noted in 14 out of 18 patients.

Total sperm density increased from 60.7 million / ml to 94.5 million / ml. The ent-25 speaks a difference of 33.8 million / ml. An increase in the sperm count was recorded in 15 out of 18 patients. On average, the number of sperm per milliliter has increased by 18.8 million for each patient. In several individual cases there was an increase in the sperm count of up to 620%. By taking the combined preparation, the number of significant fast-moving sperm cells increased from 17.1% to 34.5%. This could be more than doubled. Again, this improvement occurred in 15 out of 18 cases. Total mobility, ie fast and slow moving, increased from 62.2% to 88.7%. This corresponds to an increase in mobile sperm of almost 15% per subject. 35

The number of morphologically unremarkable sperm cells could be more than doubled in relation to the total collective. The increase was 103%.

Almost all study participants evaluated so far improved all 40 relevant parameters. In 7 out of 18, the pathologies that have existed for years in the spermiogram have normalized to such an extent that the diagnosis was now normozoospermia. To date, 3 pregnancies have been developed within the study.

The combined preparation should be taken twice daily in the form of one capsule with a little liquid before or at meal. The minimum duration of use is 3 months to optimize each stage of sperm development. However, the combined preparation can and should continue to be taken until the onset of pregnancy. 50 The combination preparation is present as encapsulated granules, wherein the capsule material of pure vegetable materials, especially cellulose, is made. Thus, the preparation is also particularly suitable for vegetarians.

Table 3 describes further optional active ingredients which additionally synergistically enhance the effects 55 if at least one of them is additionally used.

Claims (12)

9 AT 009 808 U1 Table 3 further recommended amount recommended amount possible [mg] [mg] Ingredients per day (range) per day (example) Vitamin C (ascorbic acid) 100-1000 500 Vitamin B12 (Metylcobalamin) 0.1-5 1 , 25 Vitamin Bt (thiamine) 10-500 100 Vitamin B7 (biotin) 0,5 -10 2,5 Ginseng 500 - 2000 1000 a-lipoic acid 100-1000 600 N-acetylcysteine 100 -1000 600 Claims: 1. Combination preparation for improvement the semen quality of a male individual comprising as active substances - L-carnitine, - coenzyme Q10, - at least one vitamin E, in particular a-tocopherol, - zinc and / or at least one zinc compound, in particular zinc sulfate or zinc chloride, - at least one vitamin B, in particular Folic acid, selenium and / or at least one selenium compound, glutathione and L-arginine or salts thereof. 2. Combination preparation according to claim 1, comprising - 25 to 65% by weight, in particular 35 to 60% by weight, preferably 42 to 55% by weight, L-carnitine, - 0.5 to 11% by weight, in particular 1 to 6% by weight, preferably 1.5 to 4% by weight, coenzyme Qio, 4 to 30% by weight, in particular 7 to 25% by weight, preferably 10 to 16% by weight, of a vitamin E, in particular α-tocopherol, 0.5 to 20% by weight, in particular 1 to 15% by weight, preferably 2 to 7% by weight, zinc and / or at least one zinc compound, - 0.01 to 1% by weight, in particular 0.05 to 0.3% by weight, preferably 0.07 to 0.15 % By weight, of a vitamin B, in particular folic acid, from 0.001 to 0.1% by weight, in particular from 0.002 to 0.03% by weight, preferably from 0.005 to 0.015% by weight, selenium and / or at least one selenium compound, from 1 to 25% by weight, in particular from 3 to 17% by weight, preferably from 6 to 13% by weight, glutathione, from 15 to 45% by weight, in particular from 20 to 35% by weight, preferably from 22 to 29% by weight, of L-arginine, or salts thereof, the percentages being on the total weight of all active Wirksu refer to punching. 3. Combination preparation according to claim 1 or 2, characterized in that in addition lipoic acid, in particular of α-lipoic acid, or salts thereof, is contained. 4. Combination preparation according to claim 3, characterized in that lipoic acid in an amount of 1 to 20% by weight, in particular 3 to 17% by weight, preferably 5 to 10% by weight, based on the total weight of all active substances. 10 AT 009 808 U1 5. Combination preparation according to one of claims 1 to 4, characterized in that in addition N-acetylcysteine (NAC) or salts thereof, is included. 6. Combination preparation according to claim 5, characterized in that N-acetylcysteine 5 (NAC) in an amount of 1 to 20% by weight, in particular 3 to 17% by weight, preferably 5 to 10% by weight, based on the total weight of all active substances is. 7. Combination preparation according to one of claims 1 to 6, characterized in that io additionally at least one further vitamin, in particular ascorbic acid, or salts thereof, is contained. 8. Combination preparation according to claim 7, characterized in that ascorbic acid in an amount of 4 to 30% by weight, in particular 7 to 25% by weight, preferably 10 to 15 16% by weight, based on the total weight of all active substances. 9. Combination preparation according to one of claims 1 to 8, characterized in that at least one further active ingredient selected from the group of ginseng, vitamin B12 or methylcobalamin, thiamine and / or biotin, is included. 20 10. Combination preparation according to one of claims 1 to 9, consisting of - about 46 - 47% by weight of L-carnitine - about 1.5-1.6% by weight of coenzyme Q10 - about 12-13% by weight of a vitamin E, in particular a-tocopherol 25 - about 4-5% by weight of zinc and / or at least one zinc compound - about 0.08-0.09% by weight of a vitamin B, in particular folic acid - about 0.006-0.007% by weight of selenium and / or at least one selenium compound - about 8 - 9 wt% glutathione - about 26 - 27 wt% L-arginine 30 wherein the percentages based on the total weight of all active substances be. 11. Use of L-carnitine, coenzyme Q10, at least one vitamin E, in particular a-tocopherol, zinc and / or at least one zinc compound, in particular zinc sulfate or zinc chloride, at least one vitamin B, in particular folic acid, selenium and / or at least one selenium compound , Glutathione, arginine and optionally lipoic acid, acetylcysteine or other active ingredients according to any one of claims 1 to 10 or salts thereof, for the preparation of a combination preparation according to any one of claims 1 to 10 for the treatment of impaired fertility or subfertility of a male individual, in particular of a human, for the treatment or optimization of a borderline normo zoospermie, for the treatment of asthenozoospermia, oligozoospermia, teratozoospermia, oligo-astheno-terato zoospermia, in particular OAT I, OAT II and / or OAT III, cryptozoospermia, parvisemy and / or to improve sperm quality and / or impaired capacity ness. 45 12. Use according to claim 11, which comprises at least one further vitamin, in particular ascorbic acid. 50 No drawing 55