Improving semen quality

Abstract

A composition for use in a method of improving semen quality of a human male, said composition comprising at least one spermidine source, and optionally one or more further components and / or one or more carriers or excipients.

Description

Technical Field

[0001] The present invention relates to the field of food supplements and pharmaceutical preparations for improving the quality and quantity of semen in human males, thereby contributing to male fertility. Background Art

[0002] Male fertility depends largely on the number and condition of sperm, as well as the morphology and motility of semen.

[0003] One of the most common causes of male infertility is insufficient sperm production, specifically the inability to produce sufficient numbers of sperm. When there is no sperm production, this is called azoospermia, while when there is sperm production but at very low levels, this is diagnosed as oligospermia.

[0004] Semen analysis is indicated for the diagnosis of male infertility and for planning assisted insemination. The number of sperm in a single ejaculation, the volume of a single ejaculate, and the motility of the sperm are several factors that need to be considered in semen analysis. The spermogram test, also known as the spermiogram, is designed to evaluate the parameters of the semen. These parameters are established at both the macroscopic and microscopic levels. The macroscopic parameters are: appearance, liquefaction, viscosity, pH, volume, and color. The microscopic parameters are: the concentration and total number of spermatozoa, the motility and survival of spermatozoa, the sperm morphology, and the presence of any agglutination (antisperm antibodies). The World Health Organization has published a laboratory manual for the examination and processing of human semen (Cooper, TG (ed.) WHO laboratory manual for the examination and processing of human semen, WHO Press, Geneva, Switzerland, 2010), which establishes guidelines for these analyses and provides references and standards for normal semen. The guidelines were updated by the European Society of Human Reproduction and Embryology in 2002 (ESHRE Monographs, Volume 2002, Issue 2, 15 June 2002, Manual on Basic Semen Analysis). These values ​​are summarized in the Examples herein.

[0005] AT503219B1 (US2013295068A1) discloses vitamins and minerals in a combined preparation for improving semen quality.

[0006] Bauer et al. (Cell Cycle 2013;12:2,346–352) described spermidine, a naturally occurring polyamine, which promotes mating and fertilization efficiency in model organisms such as yeast or nematodes.

[0007] Lefevre et al. (Endocrine Reviews 2011, 32(5):694-712) reviewed the role of polyamines (eg, spermine, spermidine, and putrescine) in the reproductive landscape.

[0008] WO200040231A1 discloses a composition for enhancing male fertility and libido, comprising spermine and spermidine and selenium in amounts effective for enhancing fertility and libido.

[0009] CN107242550A discloses a nutritional formula for male infertility, comprising the following components and their weight proportions: 15-40 parts of protein, 2-8 parts of fat, 40-55 parts of carbohydrates, 5.8-8 parts of dietary fiber, 0.6-1.2 parts of macroelements, 0.01-0.04 parts of trace elements, 0.005-0.02 parts of fat-soluble vitamins, 0.008-0.2 parts of water-soluble vitamins, 0.05-1 parts of dietary essence, and medicinal and edible ingredients. 0.1-2 parts, 0.1-3 parts of natural plant compounds, and 0.005-5 parts of new resource foods; wherein the medicinal and edible components are selected from at least one of Poria cocos, raspberry, wolfberry, yam, jujube pit, oyster, and licorice; wherein the new resource food is selected from at least one of colostrum basic protein, γ-aminobutyric acid, chitosan oligosaccharides, Eucommia ulmoides male flowers, bamboo leaf flavonoids, casein phosphopeptide, oat β-glucan, yeast β-glucan, and milk mineral salts, maca powder, cactus fruit, and oligoxylose.

[0010] US2014155492A1 and CA3034941A1 disclose enhancing male or female fertility by affecting the levels of cortisol, dehydroepiandrosterone sulfate, testosterone, progesterone and estradiol in the human body. The composition comprises an effective amount of spermine and / or spermidine.

[0011] WO2022034234A1 discloses an oral product comprising spermidine and one or more polyphenols as antiviral active ingredients.

[0012] CH437994A discloses a preparation for supplementing vitamins for humans or animals.

[0013] US8663709B1 discloses a composition for male fertility treatment, specifically comprising Inca radish, carnitine, coenzyme Q10 and ginseng.

[0014] US2017252388A1 discloses a beverage comprising pomegranate juice, ginseng, maca root and L-arginine for enhancing sexual function of men and women.

[0015] New preparations and therapeutic agents are needed to improve semen quality in human males. Summary of the invention

[0016] The object of the present invention is to provide a novel method and formulation for administration to human male subjects to improve semen quality.

[0017] This object is solved by the subject matter of the claims and is further described herein.

[0018] Surprisingly, the quality of semen in human males can be improved by oral administration of a preparation comprising a composition containing a specific spermidine content, in particular spermidine from chlorella powder, buckwheat sprout powder or synthetic spermidine (also known as "chemical spermidine"). Sperm quality is particularly improved as determined in a spermatozoon diagram (seminogram), for example, by increasing quantitative parameters such as sperm concentration and total number, and / or by improving qualitative parameters such as sperm motility, sperm survival and sperm morphology, as determined by standard test methods (e.g. according to ESHRE Monographs).

[0019] According to the present invention, there is provided a composition for use in a method of improving semen quality in a human male, the composition comprising at least one source of spermidine, and optionally one or more further components and / or one or more carriers or excipients.

[0020] Specifically, the composition comprises 3-8 mg spermidine content, preferably 4-8 mg spermidine content.

[0021] In particular, at least one spermidine source is included in an amount to provide a spermidine content of 3-8 mg, preferably 4-8 mg.

[0022] According to a preferred aspect, spermidine is administered in an amount of at least about any of 3, 4, 5, 6, 7 or 8 mg. A particularly preferred amount is about 6 mg.

[0023] According to a preferred aspect, the amount of spermidine is provided in one or more doses per day, such as up to 5, 4, 3, 2 or 1 doses per day.

[0024] Specifically, the spermidine dosage (or specifically daily dosage) reaches 3-8mg, preferably 4-8mg. According to a preferred aspect, the spermidine dosage is at least about any one of 3, 4, 5, 6, 7 or 8mg. A particularly preferred dosage is about 6mg.

[0025] Specifically, the spermidine dosage (or specifically daily dosage) reaches 40-120 mg / kg body weight, preferably at least about any of 50, 60, 70, 80, 90, 100, 110 or 120 mg / kg body weight, more preferably about 85 mg / kg body weight.

[0026] According to a specific aspect, at least one spermidine source is a natural source, such as microalgae powder, buckwheat sprout powder or synthetic spermidine.

[0027] Specifically, the microalgae powder comprises dried microalgae (eg unicellular freshwater algae), in particular microalgae of the genus Chlorella (eg Chlorella), or a dried preparation of a microalgae part comprising spermidine.

[0028] In particular, Chlorella powder is used as a source of spermidine, wherein Chlorella is any of the following species, which are understood herein to be comprised in the genus Chlorella: Auxenochlorella protothecoides, Auxenochlorella pyrenoidosa, Chlorella sorokiniana, Chlorella vulgaris, Jaagichlorella luteoviridis, Heterochlorella luteoviridis, Parachlorella kessleri.

[0029] Specifically, the composition comprises chlorella powder in an amount containing 0.1%-0.3% spermidine, preferably about 0.15% spermidine.

[0030] Specifically, the amount of Chlorella powder is about 2000-6000 mg, preferably about 4000 mg, to provide a spermidine content of 3-8 mg, preferably 4-8 mg, preferably about 6 mg.

[0031] In particular, the at least one spermidine source is buckwheat sprout powder, preferably wherein the buckwheat sprout powder comprises 0.1%-1% spermidine, preferably about 0.5% spermidine.

[0032] Specifically, the amount of buckwheat sprout powder is about 800-1600 mg, preferably about 1200 mg, to provide a spermidine content of 3-8 mg, preferably 4-8 mg, preferably about 6 mg.

[0033] According to a specific aspect, one or more further components are selected from one or more of the following:

[0034] a) plant extracts or powders, preferably one or more selected from: red ginseng root extract, maca root powder, tribulus terrestris fruit extract, ginkgo leaf extract, tomato extract, chicory root extract;

[0035] b) at least one source of L-carnitine;

[0036] c) trace elements, preferably comprising one or both of zinc and selenium;

[0037] d) vitamins, preferably one or more selected from the group consisting of folic acid, vitamin B6, vitamin B12, vitamin C, vitamin D3, vitamin E;

[0038] e) Antioxidants, preferably including coenzyme Q 10 and N-acetylcysteine.

[0039] Specifically:

[0040] a) Plant extracts or powders including:

[0041] i. Red ginseng root extract, preferably 1000-2000 mg, preferably about 1500 mg;

[0042] ii. Maca root powder, preferably 1000-2000 mg, preferably about 1650 mg;

[0043] iii. Tribulus terrestris fruit extract, preferably 50-150 mg, preferably about 90 mg; and / or an amount thereof to provide a saponin content of 10-60 mg, preferably about 36 mg saponin content;

[0044] iv. Ginkgo biloba extract, preferably 10-100 mg, preferably about 52 mg, and / or an amount thereof to provide a flavonoid glycoside content of 5-20 mg, preferably about 12.5 mg flavonoid glycoside content; and

[0045] v. a tomato extract, preferably 100-200 mg, preferably about 150 mg, and / or an amount thereof to provide a lycopene content of 10-20 mg, preferably about 15 mg;

[0046] vi. chicory root extract, preferably 15-80 mg, preferably about 50 mg, and / or an amount thereof to provide an inulin content of 10-60 mg, preferably about 40 mg;

[0047] b) comprising at least one L-carnitine source in an amount providing a L-carnitine content of 500-1000 mg, preferably about 680 mg, preferably wherein the L-carnitine source is L-carnitine tartrate;

[0048] c) Trace elements include:

[0049] i. Zinc, preferably 10-50 mg, preferably about 28 mg, preferably in the form of zinc gluconate; and

[0050] ii. Selenium, preferably 10-100 μg, preferably about 55 μg, preferably in the form of sodium selenite or sodium selenite pentahydrate;

[0051] d) Vitamins include:

[0052] i. folic acid, preferably 500-1000 μg, preferably about 800 μg, preferably in the form of pteroylmonoglutamate;

[0053] ii. Vitamin B6, preferably 1-6 mg, preferably about 3.5 mg, preferably in the form of pyridoxine hydrochloride, pyridoxal or pyridoxamine;

[0054] iii. Vitamin B12, preferably 10-20 μg, preferably about 15 μg, preferably in the form of cyanocobalamin or cobalamin;

[0055] iv. Vitamin C, preferably 100-500 mg, preferably about 250 mg, preferably in the form of L-ascorbic acid;

[0056] v. Vitamin D3, preferably 10-20 μg, preferably about 15 μg, preferably in the form of cholecalciferol, calciferol, calcitriol or ergocalciferol; and

[0057] vi. Vitamin E, preferably 80-160 mg, preferably about 120 mg, preferably in the form of DL-α-tocopheryl acetate, α-tocopherol, tocopherol or tocotrienol;

[0058] e) Antioxidants include:

[0059] i. Coenzyme Q10, preferably 50-150 mg, preferably about 100 mg; and

[0060] ii N-acetylcysteine, preferably 100-300 mg, preferably about 200 mg.

[0061] Specifically, the amounts of the components of the compositions described herein are understood to be amounts administered in daily doses (or daily doses / amounts). The compositions can be provided in containers containing one or more daily doses, for example, to provide a dosage for a treatment period of at least one or more weeks, for example at least 1, 2, 3, 4, 5, 6, 7 or 8 weeks, or a treatment period of at least one or more months, for example at least 1, 2, 3, 4, 5 or 6 months.

[0062] According to a specific aspect, the composition further comprises:

[0063] a) one or more dietary carrier materials, preferably comprising one or both of fiber and carbohydrates; and / or

[0064] b) one or more auxiliary agents, preferably selected from the group consisting of sweeteners, food colorants, anti-caking agents and flavoring agents.

[0065] In particular, the dietary carrier substances and / or adjuvants are selected from those substances which are suitable for use in food products or food additives.

[0066] Preferred thickeners may be: guar gum or other natural thickeners.

[0067] Preferred sweeteners may be: stevia or other sweeteners.

[0068] Preferred food coloring agents may be carrot concentrate, blackcurrant concentrate and other fruit and vegetable based concentrates.

[0069] A preferred release agent may be silicon dioxide.

[0070] Preferred flavoring agents may be: DL-malic acid, citric acid and other natural flavors.

[0071] According to a specific aspect, the composition is used as a food supplement, a food product, a nutritional product, a dietary and nutritional composition, a beverage, a medicament, a medicinal food, a pharmaceutical composition or a food for special medical purposes.

[0072] According to a particular aspect, the composition is in the form of a solid or liquid composition for oral use, in particular for oral ingestion.

[0073] Specifically, the composition is in the form of a solid or liquid preparation for oral use, specifically an oral preparation. Specifically, the oral preparation contains 3-8 mg per dose, preferably about 6 mg spermidine per dose.

[0074] In particular, the composition is contained in an oral formulation. In particular, the formulation is a storage-stable and / or ready-to-use formulation.

[0075] According to a specific aspect, the composition or oral preparation is provided in the form of powder, granules, aqueous solution, suspension, capsule, tablet or pill.

[0076] According to a specific aspect, the semen quality is improved as determined by spermatogram, in particular according to one or more parameters of the semenatogram, including quantitative parameters (such as sperm concentration, total sperm count, motility or survival), and / or qualitative parameters (such as morphology). Preferably, one or more of sperm concentration, total sperm count, sperm motility, sperm survival and sperm morphology are improved.

[0077] Specifically, the semen quality is improved as determined by at least one quantitative analysis, preferably wherein the improvement is at least any one of 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times or 2 times.

[0078] The present invention further provides a food supplement or a food supplement product comprising:

[0079] a) a spermidine source in an amount providing 3-8 mg spermidine content, preferably 4-8 mg spermidine content, preferably about 6 mg spermidine content, preferably wherein the spermidine source is a natural source, preferably microalgae powder (e.g. chlorella powder), or buckwheat sprout powder, or wherein the spermidine source is synthetic spermidine;

[0080] b) Plant extracts or powders, including:

[0081] i. Red ginseng root extract, preferably 1000-2000 mg, preferably about 1500 mg;

[0082] ii. Maca root powder, preferably 1000-2000 mg, preferably about 1650 mg;

[0083] iii. Tribulus terrestris fruit extract, preferably 50-150 mg, preferably about 90 mg; and / or an amount thereof to provide a saponin content of 10-60 mg, preferably about 36 mg saponin content;

[0084] iv. Ginkgo biloba extract, preferably 10-100 mg, preferably about 52 mg, and / or an amount thereof to provide a flavonoid glycoside content of 5-20 mg, preferably about 12 mg flavonoid glycoside content; and

[0085] v. a tomato extract, preferably 100-200 mg, preferably about 150 mg, and / or an amount thereof to provide a lycopene content of 10-20 mg, preferably about 15 mg;

[0086] vi. chicory root extract, preferably 15-80 mg, preferably about 50 mg, and / or an amount thereof to provide an inulin content of 10-60 mg, preferably about 40 mg;

[0087] c) at least one L-carnitine source, preferably 500-1000 mg L-carnitine, preferably about 680 mg L-carnitine, preferably wherein the L-carnitine source is L-carnitine tartrate;

[0088] d) Trace elements, including:

[0089] i. Zinc, preferably 10-50 mg, preferably about 28 mg, preferably in the form of zinc gluconate; and

[0090] ii. Selenium, preferably 10-100 μg, preferably about 55 μg, preferably in the form of sodium selenite or sodium selenite pentahydrate;

[0091] e) Vitamins, including:

[0092] i. folic acid, preferably 500-1000 μg, preferably about 800 μg, preferably in the form of pteroylmonoglutamate;

[0093] ii. Vitamin B6, preferably 1-6 mg, preferably about 3.5 mg, preferably in the form of pyridoxine hydrochloride, pyridoxal or pyridoxamine;

[0094] iii. Vitamin B12, preferably 10-20 μg, preferably about 15 μg, preferably in the form of cyanocobalamin or cobalamin;

[0095] iv. Vitamin C, preferably 100-500 mg, preferably about 250 mg, preferably in the form of L-ascorbic acid;

[0096] v. Vitamin D3, preferably 10-20 μg, preferably about 15 μg, preferably in the form of cholecalciferol, calciferol, calcitriol or ergocalciferol; and

[0097] vi. Vitamin E, preferably 80-160 mg, preferably about 120 mg, preferably in the form of DL-α-tocopheryl acetate, α-tocopherol, tocopherol or tocotrienol;

[0098] f) Antioxidants, including:

[0099] i. Coenzyme Q10, preferably 50-150 mg, preferably about 100 mg; and

[0100] ii. N-acetylcysteine, preferably 100-300 mg, preferably about 200 mg.

[0101] In particular, such food supplements are used in the methods of treatment described further herein. DETAILED DESCRIPTION

[0102] Unless otherwise specified or defined, all terms used herein have their ordinary meanings in the art, and the meanings of the terms are clear to those skilled in the art. Specific terms used in the specification have the following meanings.

[0103] Unless otherwise stated, the term "about" as used herein refers to a value that is the same as a given value or a value that differs from a given value by + / -20%, or + / -10%, or + / -5%. The term "about" used for temperatures in °C typically refers to + / -1 °C.

[0104] In order to provide a more concise description, some quantitative expressions given herein are not qualified with the term "about". It should be understood that, whether or not the term "about" is explicitly used, each amount given herein refers to the actual given value, and also refers to the approximate value of the given value that can be reasonably inferred based on a person of ordinary skill in the art, including the approximate value of the given value due to experimental and / or measurement conditions.

[0105] As used herein, the terms "comprise," "contain," "have," and "include" may be used synonymously and should be understood as open definitions allowing for further members or components or elements. "Consisting" is considered the most closed definition, with no further elements constituting the defining feature. Thus, "comprising" is broader and encompasses the definition of "consisting."

[0106] The term "seminogram" is also referred to as "spermiogram" and is understood as follows: Spermiogram is a part of andrological research that includes the study of the physics, morphology and biochemistry of semen.

[0107] Semen quality is a measure of the ability of semen to accomplish fertilization. Therefore, it is a measure of the fertility of a male subject. Semen quality relates to both sperm count and sperm quality. Semen quality as described herein is specifically determined by the corresponding qualitative and quantitative parameters of spermatozoa graphics and semen analysis. Specifically, these parameters are one or more (or all) of the following: sperm concentration, sperm count, motility, morphology, volume, fructose level, and pH.

[0108] The term "sperm motility" as used herein refers to the ability of sperm to move forward. In this context, the term should be understood to also refer to the motility level, where the motility of sperm can be one of four different levels:

[0109] Grade A: Spermatozoa have progressive motility. These are the strongest, swimming quickly in a straight line.

[0110] Class B: (Non-Linear Vitality): These also move forward but tend to travel in a bending or twisting motion.

[0111] Class C: They have non-progressive dynamism because although they move their tails, they do not move forward.

[0112] Class D: These are non-motile and cannot move at all.

[0113] The term "Total Motile Sperm Count" (TMSC) or "Total motile spermatozoa" (TMS) as used herein refers to a combination of sperm number, motility and volume, measuring how many millions of sperm cells are motile in a single complete ejaculate.

[0114] The sperm profile of a normal semen analysis will usually include the results shown in Table 1, or at least the corresponding results for the following: sperm concentration, total sperm count, motility, and morphology.

[0115] Table 1: World Health Organization standards for normal semen analysis

[0116] standard parameter volume 2.0-5.0mL pH 7.2-7.8 Sperm concentration <![CDATA[≥20×10 6 / mL]]> Total sperm count <![CDATA[≥40×10 6 Sperm]]> vitality ≥50% forward travel or ≥25% rapid linear travel within 60 minutes of collection form ≥50% have normal morphology Survival rate ≥75% viable (ie, free of dye) leukocyte <![CDATA[≤1×10 6 / mL]]> Fructose (total) ≥13mol / single ejaculation

[0117] "Spermidine" as used herein is a polyamine of biological origin and a precursor of other polyamines (e.g., spermine). The term "spermidine" as used herein shall refer to any one or both of spermidine and / or spermidine salts. Spermidine is present in most organisms and plays a vital role in growth. The spermidine described herein can be used in the form of its pharmaceutically acceptable salts. These salts include, for example, salts containing inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, and boric acid), and salts containing organic acids (e.g., acetic acid, citric acid, tartaric acid, and glutaric acid). Therefore, the term "pharmaceutically acceptable salt" of spermidine refers to one or more of the above-mentioned salts, but is not limited thereto, and also includes other possible salts of spermidine.

[0118] Spermidine and / or its pharmaceutically acceptable salt can be obtained from a variety of sources, such as biological sources (including, for example, natural sources or biotechnology sources) and / or synthetic sources. Plants and microorganisms (such as yeast) are natural sources of spermidine and its pharmaceutically acceptable salt. Specifically, natural fruits, vegetables, beans and / or cereal-based foods can be used as the source of spermidine. Preferred sources are microalgae powder (such as dried chlorella) or buckwheat sprout powder. The results show that chlorella powder and buckwheat sprout powder have high concentrations of spermidine. Suitable other preferred sources can be malt or soybeans, and extracts of any of the aforementioned substances. As a substitute for biological sources, synthetic pharmaceutically acceptable salts of spermidine can be obtained by suitable synthetic methods. Pharmaceutically acceptable spermidine salts can be obtained from biologically derived or synthetic spermidine. Spermidine can also be produced by enzymatic methods, such as using spermidine synthetase to convert putrescine into spermidine.

[0119] In particular, spermidine is provided in an extract of a source material, or is provided in a solid source material, for example in powdered or granulated form.

[0120] One preferred source is microalgae powder, such as Chlorella powder (eg Chlorella vulgaris powder), or an extract thereof, particularly in the form of a dry preparation, provided as a solid powder or granules.

[0121] Another preferred source is buckwheat sprout powder (also known as buckwheat grass powder or buckwheat sprout seed powder) or an extract thereof, particularly in the form of a powder, provided as a solid powder or granules.

[0122] The results showed that the chlorella powder or buckwheat sprout powder had a high concentration of spermidine.

[0123] The concentration of spermidine in the Chlorella powder is typically 0.1% to 0.3% (w / w) spermidine, preferably at least or about 0.15% (w / w) spermidine.

[0124] One preferred source is chlorella powder, such as the commercially available "Algomed Chlorella Pulver" (Roquette KL tze GmbH & co. KG, KL tze, Germany).

[0125] The concentration of spermidine in the buckwheat sprout powder is generally 0.1% to 1% (w / w) spermidine, preferably at least or about 0.5% spermidine.

[0126] A preferred source is organic buckwheat sprout powder, such as commercially available (The CeuticsCompany GesmbH, Austria).

[0127] Biotechnologically derived spermidine and / or its pharmaceutically acceptable salts can also be obtained by other production methods, such as by recombinantly expressing the well-known expression system of the enzyme involved in the synthesis of spermidine, including spermidine synthetase (putrescine is converted into spermidine). These are also suitable as preferred sources.

[0128] Studies have determined that a daily intake of 12 mg of spermidine provided by plant extracts (e.g., wheat germ extract) is safe (U.S. Food and Drug Administration GRAS Notice No. 889 Spermidine-Rich Wheat Germ Extract). Such a spermidine intake level is far below the NOAEL (No Observed Adverse Effect Level) of spermidine 83 mg / kg body weight / day (470 mg per day for a 70 kg person) (Til et al., Food and Chemical Toxicology 1997, v. 35, p. 337-348).

[0129] As used herein, the term "plant extract" refers to a substance that has been obtained from a plant material. The plant extract can be prepared by treating any plant material with a suitable extractant to obtain an extract containing at least some of the components of the plant material from an aqueous solution or suspension of the plant material. The plant material treated with the extractant to provide the plant extract can be or can be derived from any part of a plant, such as leaves, bark, roots, flowers, seeds or fruits of the plant, preferably leaves, stems or flowers of the plant, or the skin of a fruit or any combination thereof.

[0130] Methods for preparing plant extracts are known to those skilled in the art. Specifically, plant extracts can be obtained by decoction, digestion, diafiltration, Soxhlet extraction, maceration or any other suitable extraction method known to those skilled in the art. Specifically, the plant extracts described herein are extracted using water or an aqueous solvent, specifically comprising or consisting of hot water or cold water.

[0131] In the preparation of a plant extract, the plant components extracted from the plant material will be at least partially dissolved or suspended in an extractant. After treating the plant material with the extractant, insoluble plant material may remain in the extractant, or insoluble plant material may be separated from the extractant. The insoluble plant material may be separated from the extractant according to any suitable method, such as decantation, filtration or centrifugation.

[0132] Specifically, insoluble plant material is separated from the extractant and the plant extract contains no insoluble components.

[0133] Specifically, the plant extract is an extract that does not contain an extractant. That is, preferably a plant extract is used from which the extractant has been substantially removed, for example to provide a dry or non-aqueous extract.

[0134] As used herein, the term "plant powder" refers to a substance obtainable or obtained from plant material by grinding and drying. Plant powders include any kind of powdered or granular plant material. The plant material processed to provide a plant powder can be or can be derived from any part of a plant, such as leaves, bark, roots, flowers, seeds or fruits of a plant, preferably leaves, stems or flowers of a plant, or the skin of a fruit or any combination thereof.

[0135] As used herein, the term "subject" or "individual" shall refer to a warm-blooded mammal, particularly a human (eg, an adult). A subject may be a patient, particularly a patient in need of treatment, such as prevention or treatment of a disease or disorder described herein.

[0136] The term "patient" includes a human subject who is receiving preventive or therapeutic treatment or is at risk of or diagnosed with a disease or condition that results in low semen quality, such as a drug-induced, environmentally induced, or age-related abnormality, or an abnormality affecting an organ or hormonal system. The corresponding condition or disease can be chronic or acute. When the subject contains one or more risk factors for male infertility, such as smoking, using (or abusing) alcohol, using certain illegal drugs, being obese, having certain past or present infections, being exposed to toxins, overheating of the testicles, having experienced testicular trauma, or when the likelihood of ovarian fertilization (e.g., IVF) should be increased, improved semen quality may also be indicated. Specifically, patients suffering from male infertility and / or low semen quality are treated as described herein, e.g., characterized by low amounts of one or more of sperm concentration, sperm count, or sperm motility, e.g., below normal, e.g., below the middle or lower end of the normal range, or even below any of 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the middle or lower end of the normal range.

[0137] The term "treatment" is meant to include both prophylactic and therapeutic treatment.

[0138] According to specific aspects described herein, spermidine is administered in an effective amount or a therapeutically effective amount.

[0139] As described herein, with respect to the effects on semen quality, the term "effective amount" shall refer to an amount or activity sufficient to produce a beneficial desired result when administered to a subject, and thus an effective amount or its synonyms depend on the context in which it is used. Specifically, an effective amount is understood to be a predetermined amount that has a proven effect on improving semen quality, such as normalizing spermatozoa profile, such as obtaining normal values ​​for spermatozoa profile.

[0140] Specifically, an effective amount of the compositions described herein is determined by an effective amount of spermidine contained in the composition.

[0141] As used herein, the term "therapeutically effective amount" refers to that amount of a compound or composition that will elicit a desired biological or medical response in a human male subject.

[0142] The regimen for treating a subject with an effective amount of the composition described herein can consist of a single application or administration, or a series of applications and administrations, respectively. For example, the composition can be used at least once a week, or at least once a day. However, in some cases, the composition can be used more frequently, such as 1-5 times a day. The composition described herein can be provided according to single dose or multiple dose use.

[0143] The length of the treatment period depends on a variety of factors, such as the severity of the disease or condition, acute or chronic disease, age of the patient, and the concentration of spermidine in the composition. It should also be understood that the effective dose for treatment may increase or decrease over the course of a particular treatment regimen. Treatment results and dosage changes may occur and become apparent through standard diagnostic assays known in the art.

[0144] Unit dose or multi-dose containers, such as sealed containers, can be used and can be stored in storage-stable packaging. The composition can be provided as a dry formulation composition, or include a liquid phase. Exemplary compositions can be provided as dry, such as freeze-dried (lyophilized) compositions, requiring only the addition of liquid (e.g., water) prior to use. Preferred unit dose formulations contain daily doses or unit daily sub-doses or multi-dose compositions.

[0145] The compositions described herein can be administered to an individual by various routes. The formulations and dosage forms for administering the compositions are preferably adapted according to the route of administration. A preferred formulation is an oral formulation. A preferred route of administration is oral administration.

[0146] As used herein, the term "oral formulation" refers to any composition or pharmaceutically acceptable formulation intended for oral use, particularly administration into the mouth of a subject.

[0147] Specifically, the composition is formulated into a solid dosage form (eg, capsule, granule, powder or tablet), or a liquid dosage form (eg, suspension, solution, gel).

[0148] Depending on the route of administration, the compositions described herein may include various carriers and / or excipients. The use of carriers and / or excipients for the composition types described herein or for pharmaceutically active substances is known in the art. Exemplary pharmaceutically acceptable carriers may be auxiliary substances and additives further described herein.

[0149] The tablet of the present invention can be made by compression or molding, optionally containing one or more additional ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), and / or a surfactant or dispersant.

[0150] Solid dosage forms of the composition can be prepared with coatings, such as enteric coatings and other coatings known in the art. It can also be formulated using, for example, different proportions of hypromellose (to provide a desired release profile), other polymer matrices, liposomes or microspheres to provide slow or controlled release of the active ingredient therein.

[0151] Liquid dosage forms for oral administration of compositions can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.Liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitol and mixtures thereof.In addition to inert diluents, oral compositions can also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, aromatics and preservatives.Suspensions can contain suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and mixtures thereof.

[0152] The compositions described herein may include one or more pharmaceutically acceptable carriers and / or excipients. The compositions may be formulated with conventional carriers and / or excipients, which will be selected according to conventional practice.

[0153] Preferred compositions are in a storage stable form, having a shelf life of at least one or two years.

[0154] One or more carriers suitable for the expected route of administration can be used.Said composition can, for example, comprise one or more edible carriers, such as carbohydrates (e.g., lactose, sucrose or starch), or can comprise sodium and calcium salts of cellulose alkanoate, stearic acid, talcum, magnesium stearate, magnesium oxide, phosphoric acid and sulfuric acid, gum arabic, gelatin, sodium alginate, polyvinyl pyrrolidone, polyvinyl alcohol, and optionally further made into tablets or capsules for conventional administration.Tablets can contain excipients, glidants, fillers, adhesives, disintegrants, lubricants, flavoring agents, etc.Isomaltose can be used to produce particles.

[0155] The composition can be dispersed or dissolved in saline solution, water, polyethylene glycol, propylene glycol, carboxymethylcellulose colloid solution, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum and / or various buffers. Liquid preparations can be solutions, emulsions or suspensions, and can include excipients such as suspending agents, solubilizing agents, surfactants, preservatives and chelating agents. Typical carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspending agents, typical suspension aids include methylcellulose, sodium carboxymethylcellulose, tragacanth gum and sodium alginate; typical wetting preparations include lecithin and polysorbate 80; typical preservatives include methyl paraben and sodium benzoate.

[0156] The oral compositions may also contain one or more ingredients such as sweetening, flavoring and coloring agents known in the art.

[0157] The carrier may also include a controlled release or time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax or other materials well known in the art.

[0158] The composition may also be coated by conventional methods, typically with a pH or time-dependent coating, so that the subject formulation is released in the gastrointestinal tract near the intended topical application, or released at different times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate, polyvinyl acetate phthalate, hypromellose phthalate, ethyl cellulose, wax, and shellac.

[0159] Other carriers, adjuvants and modes of administration are known in the pharmaceutical art.

[0160] The term "pharmaceutically acceptable" refers to ingredients other than active ingredients in a composition or formulation for medical or therapeutic use that are free of excessive toxicity, incompatibility, instability, irritation, allergic response, etc. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives, specifically saline, phosphate buffered saline, glucose, glycerol, ethanol, and the like.

[0161] The compositions provided herein can be produced or prepared by conventional methods known to those skilled in the art. Specifically, the compositions provided herein are produced by incorporating the components of the compositions described herein into a pharmaceutically acceptable formulation comprising a pharmaceutically acceptable carrier. Specifically, the compositions are produced by formulating the compositions described herein with a pharmaceutically acceptable carrier, preferably in a manner that allows them to be used as an oral formulation.

[0162] The embodiments described herein are explanations of the present invention, rather than limitations of the present invention. Without departing from the spirit and scope of the present invention, many modifications and changes may be made to the technology described and shown herein. Therefore, it should be understood that these embodiments are merely illustrative and do not limit the scope of the present invention.

[0163] Example

[0164] Example 1: Preparation of spermidine composition

[0165] The following ingredients were used as the dry components of a powder mix known as "Men's Fertility Powder" and were prepared for oral ingestion in a daily dose of 8 g.

[0166] Ingredients: Maca root powder, Red ginseng root extract, Buckwheat sprout powder (contains spermidine), L-carnitine tartrate, DL-alpha-tocopheryl acetate, Natural flavor, L-ascorbic acid, Acid: DL-malic acid, Zinc gluconate, N-acetyl-L-cysteine, Tomato extract (10% lycopene), Natural flavor, Coenzyme Q10, Tribulus terrestris fruit extract (40% saponins), Thickener: Guar gum, Acid: Citric acid, Natural flavor, Ginkgo biloba leaf extract (24% flavonoid glycosides), Inulin, (Chicory), Anti-caking agent: Silicon dioxide Coloring food (carrot concentrate, blackcurrant concentrate), Sweetener: Steviol glycosides from Stevia, Cyanocobalamin, Sodium selenite, Cholecalciferol, Pyridoxine hydrochloride, Pteroylmonoglutamic acid.

[0167] The characteristics of the composition are as follows:

[0168]

[0169] Example 2: Clinical Trial

[0170] Clinical trial: A 3-month study was conducted on 10 subjects. The trial evaluated the positive effects of the composition on sperm quality, as well as the safety associated with spermidine supplementation.

[0171] The purpose of this study is to observe the effects and side effects of the male fertility powder produced according to Example 1 on sperm quality.

[0172] This observational study aimed to analyze the improvement in sperm quality over 90 days after taking a new dietary supplement.

[0173] The study lasted for 3 months. At the beginning of the study, sperm analysis, blood tests and blood pressure measurements were performed. During the study, the men's fertility powder was taken once a day for 90 days.

[0174] Take 8 g and suspend in enough cold water (or juice) and mix to make a drink. After the 90-day treatment period, another spermatozoa map and blood test and blood pressure measurement are performed.

[0175] The blood test includes analysis of testosterone, prolactin, and follicle-stimulating hormone (FSH). All three are key hormones associated with sperm quality and male fertility.

[0176] According to ESHRE Monographs, the findings determined by standard analysis are presented in the corresponding spermatozoa monographs.

[0177] The data showed improvements in semen quality, specifically spermatozoa analysis. The highest improvements were related to the shape (morphology) of the sperm cells, according to the interim results.

[0178] Interim results from this proof-of-concept study showed that the product can improve semen quality (based on spermatozoa mapping). The study subjects included only infertile men who sought medical advice because they were desiring to have children. Therefore, a clear indicator that the product did improve semen quality was that at least 30% of the study subjects got their partners pregnant during the study period.

[0179] Sperm diagram:

[0180] Normal value WHO normal values** Sample volume** 1.5 ml and above Liquefaction time Within 30-60 minutes pH-value 7.2 to 8.0 leukocyte Less than 1 million / mL Special Values Concentrated / dense sperm per mL More than 20 / 15** million sperm per mL Sperm motility, in %: At least 40%** a. Rapid forward movement More than 25% b. Overall forward a+b exceeds 32%**(50%) c.Move slowly Less than 50% d.Still Less than 50% flexible a+b+c**at least 40% Sperm cell morphology / shape in % Spermatozoa with unclear shape >4%**(30%) **WHO fifth edition

[0181] Example 3: Preparation of a composition comprising Chlorella powder as a source of spermidine

[0182] The following ingredients were used as dry components of a powder mixture known as "Spermine PRO ANDUIXX" and were prepared for oral ingestion in a daily dose of 10.8 g.

[0183] Ingredients: Chlorella powder, Maca root powder, Red ginseng root extract, L-carnitine tartrate, Natural flavors, DL-alpha-tocopheryl acetate, L-ascorbic acid, Acid: DL-malic acid, Zinc gluconate, N-acetyl-L-cysteine, Tomato extract, Coenzyme Q10, Tribulus terrestris fruit extract, Thickener: Guar gum, Acid: Citric acid, Ginkgo biloba leaf extract, Inulin, Coloring food (Carrot concentrate, Blackcurrant concentrate), Anti-caking agent: Silicon dioxide, Sweetener: Steviol glycosides from Stevia, Cyanocobalamin, Sodium selenite, Cholecalciferol, Pyridoxine hydrochloride, Pteroylmonoglutamic acid.

[0184] The characteristics of the composition are as follows:

[0185]

[0186] *Nutrient Reference Value (NRV) in percentage according to VO(EU)1169 / 2011.

[0187] **No NRV available.

Claims

1. A composition for use in a method for improving semen quality in a human male, said composition comprising at least one source of spermidine, and optionally one or more further components and / or one or more carriers or excipients.

2. The composition according to claim 1, wherein the composition comprises 3-8 mg spermidine content, preferably about 6 mg spermidine content.

3. A composition for use according to claim 1 or 2, wherein the at least one spermidine source is a natural source, preferably chlorella powder or buckwheat sprout powder.

4. A composition according to claim 3, wherein a) the chlorella powder contains 0.1%-0.3% spermidine, preferably about 0.15% spermidine; b) wherein the buckwheat sprout powder comprises 0.1%-1% spermidine, preferably about 0.5% spermidine.

5. A composition for use according to any one of claims 1 to 4, wherein one or more further components are selected from one or more of the following: a) plant extracts or powders, preferably one or more selected from: red ginseng root extract, maca root powder, tribulus terrestris fruit extract, ginkgo leaf extract, tomato extract, chicory root extract; b) at least one source of L-carnitine; c) trace elements, preferably comprising one or both of zinc and selenium; d) vitamins, preferably one or more selected from the group consisting of folic acid, vitamin B6, vitamin B12, vitamin C, vitamin D3, and vitamin E; e) Antioxidants, preferably including coenzyme Q 10 and N-acetylcysteine.

6. A composition for use according to claim 5, wherein: a) The plant extract or powder comprises: i. Red ginseng root extract, preferably 1000-2000 mg, preferably about 1500 mg; ii. Maca root powder, preferably 1000-2000 mg, preferably about 1650 mg; iii. Tribulus terrestris fruit extract, preferably 50-150 mg, preferably about 90 mg; and / or an amount thereof to provide a saponin content of 10-60 mg, preferably about 36 mg saponin content; iv. Ginkgo biloba extract, preferably 10-100 mg, preferably about 52 mg, and / or an amount thereof to provide a flavonoid glycoside content of 5-20 mg, preferably about 12.5 mg flavonoid glycoside content; and v. tomato extract, preferably 100-200 mg, preferably about 150 mg, and / or an amount thereof to provide a lycopene content of 10-20 mg, preferably about 15 mg lycopene content; vi. chicory root extract, preferably 15-80 mg, preferably about 50 mg, and / or an amount thereof to provide an inulin content of 10-60 mg, preferably about 40 mg; b) comprising at least one L-carnitine source in an amount providing a L-carnitine content of 500-1000 mg, preferably about 680 mg, preferably wherein the L-carnitine source is L-carnitine tartrate; c) The trace elements include: i. Zinc, preferably 10-50 mg, preferably about 28 mg, preferably in the form of zinc gluconate; and ii. Selenium, preferably 10-100 μg, preferably about 55 μg, preferably in the form of sodium selenite or sodium selenite pentahydrate; d) The vitamins include: i. folic acid, preferably 500-1000 μg, preferably about 800 μg, preferably in the form of pteroylmonoglutamate; ii. Vitamin B6, preferably 1-6 mg, preferably about 3.5 mg, preferably in the form of pyridoxine hydrochloride, pyridoxal or pyridoxamine; iii. Vitamin B12, preferably 10-20 μg, preferably about 15 μg, preferably in the form of cyanocobalamin or cobalamin; iv. Vitamin C, preferably 100-500 mg, preferably about 250 mg, preferably in the form of L-ascorbic acid; v. Vitamin D3, preferably 10-20 μg, preferably about 15 μg, preferably in the form of cholecalciferol, calciferol, calcitriol or ergocalciferol; and vi. Vitamin E, preferably 80-160 mg, preferably about 120 mg, preferably in the form of DL-α-tocopheryl acetate, α-tocopherol, tocopherol or tocotrienol; e) The antioxidant comprises: i. Coenzyme Q10, preferably 50-150 mg, preferably about 100 mg; and ii. N-acetylcysteine, preferably 100-300 mg, preferably about 200 mg.

7. A composition for use according to any one of claims 1 to 6, wherein the composition further comprises: a) one or more dietary carrier materials, preferably comprising one or both of fiber and carbohydrates; and / or b) one or more auxiliary agents, preferably selected from the group consisting of sweeteners, food colorants, anti-caking agents and flavoring agents.

8. Composition for use according to any one of claims 1 to 7, wherein the composition is used as a food supplement, a food product, a nutritional product, a dietary and nutritional composition, a beverage, a medicament, a medicinal food, a pharmaceutical composition or a food for special medical purposes.

9. A composition for use according to any one of claims 1 to 8, wherein the composition is in the form of a solid or liquid composition for oral use.

10. A composition for use according to any one of claims 1 to 9, wherein the composition is provided in the form of a powder, granules, aqueous solution, suspension, capsule, tablet or pill.

11. A composition for use according to any one of claims 1 to 10, wherein The semen quality is improved as determined by spermatozoa profiling, preferably by improving one or more of: sperm concentration, total sperm count, sperm motility, sperm survival rate and sperm morphology.

12. A composition for use according to claim 11, wherein The semen quality is improved as determined by quantitative analysis, preferably wherein the improvement is at least 1.1 fold.

13. Food supplement products, including: a) a spermidine source in an amount providing 3-8 mg spermidine content, preferably 4-8 mg spermidine content, preferably about 6 mg spermidine content, preferably wherein the spermidine source is a natural source, preferably microalgae powder, such as chlorella powder, or buckwheat sprout powder, or the spermidine source is synthetic spermidine; b) Plant extracts or powders, including: i. Red ginseng root extract, preferably 1000-2000 mg, preferably about 1500 mg; ii. Maca root powder, preferably 1000-2000 mg, preferably about 1650 mg; iii. Tribulus terrestris fruit extract, preferably 50-150 mg, preferably about 90 mg; and / or an amount thereof to provide a saponin content of 10-60 mg, preferably about 36 mg saponin content; iv. Ginkgo biloba extract, preferably 10-100 mg, preferably about 52 mg, and / or an amount thereof to provide a flavonoid glycoside content of 5-20 mg, preferably about 12 mg flavonoid glycoside content; and v. tomato extract, preferably 100-200 mg, preferably about 150 mg, and / or an amount thereof to provide a lycopene content of 10-20 mg, preferably about 15 mg lycopene content; vi. chicory root extract, preferably 15-80 mg, preferably about 50 mg, and / or an amount thereof to provide an inulin content of 10-60 mg, preferably about 40 mg; c) at least one L-carnitine source, preferably providing 500-1000 mg L-carnitine, preferably about 680 mg L-carnitine, preferably wherein the L-carnitine source is L-carnitine tartrate; d) Trace elements, including: i. Zinc, preferably 10-50 mg, preferably about 28 mg, preferably in the form of zinc gluconate; and ii. Selenium, preferably 10-100 μg, preferably about 55 μg, preferably in the form of sodium selenite or sodium selenite pentahydrate; e) Vitamins, including: i. folic acid, preferably 500-1000 μg, preferably about 800 μg, preferably in the form of pteroylmonoglutamate; ii. Vitamin B6, preferably 1-6 mg, preferably about 3.5 mg, preferably in the form of pyridoxine hydrochloride, pyridoxal or pyridoxamine; iii. Vitamin B12, preferably 10-20 μg, preferably about 15 μg, preferably in the form of cyanocobalamin or cobalamin; iv. Vitamin C, preferably 100-500 mg, preferably about 250 mg, preferably in the form of L-ascorbic acid; v. Vitamin D3, preferably 10-20 μg, preferably about 15 μg, preferably in the form of cholecalciferol, calciferol, calcitriol or ergocalciferol; and vi. Vitamin E, preferably 80-160 mg, preferably about 120 mg, preferably in the form of DL-α-tocopheryl acetate, α-tocopherol, tocopherol or tocotrienol; f) Antioxidants, including: i. Coenzyme Q10, preferably 50-150 mg, preferably about 100 mg; and ii. N-acetylcysteine, preferably 100-300 mg, preferably about 200 mg.

Images