EA045187B1 - COMPOSITIONS TO IMPROVE SEXUAL FUNCTION - Google Patents

Description

Technical field of the invention

The present invention relates to compositions containing L-arginine and L-citrulline in certain proportions, and their use. In particular, the present invention relates to the use of such compositions to enhance sexual function in a sexually healthy person as needed.

BACKGROUND OF THE INVENTION

Sexuality is a complex interplay of many aspects, including anatomical, physiological, psychological, developmental, cultural, and relationship factors. They all contribute to varying degrees to an individual's sexuality at any given time, also developing and changing throughout the life cycle.

Certain sexual disorders and dysfunctions such as erectile dysfunction (ED), sexual arousal disorder, hypoactive sexual desire disorder (HSD), sexual aversion disorder (SAD), orgasmic disorder (anorgasmia), premature ejaculation, dyspareunia, vaginismus or sexual dissatisfaction ( nonspecific) have a negative impact on natural, healthy sexuality and can be caused by both physiological factors (for example, insufficient hormone levels, diabetes, cardiovascular disease or age) and psychological factors. The lack of required amounts of sex hormones is a major factor affecting sexual motivation in both men and women. Such hormones include androgens (eg, testosterone), estrogens (eg, estradiol), progestogens (eg, progesterone), oxytocin, and vasopressin. In women, estrogen deficiency can lead to sexual dysfunction, primarily causing vaginal atrophy and dyspareunia. These symptoms can be treated with systemic or local estrogen therapy. In contrast, androgen deficiency appears to be most strongly associated with decreased sexual desire. A growing body of evidence indicates that androgen administration may be beneficial in such situations.

Penile erection is controlled by the body through two different mechanisms: reflex erection, which is achieved through direct stimulation, and psychogenic erection, which is achieved through erotic or emotional stimuli. The former uses the peripheral nerves and lower parts of the spinal cord, while the latter uses the limbic system of the brain. In both cases, an intact nervous system is required for a successful and complete erection. Direct stimulation of the nervous system in the penile shaft results in the secretion of nitric oxide (NO). This second messenger causes relaxation of the smooth muscles of the corpora cavernosa (the main erectile tissue of the penis) and, as a result, erection of the penis. Nitric oxide functions by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase, and increasing intracellular levels of cyclic guanosine monophosphate (cGMP). cGMP, in turn, relaxes the vascular smooth muscle in the blood vessels, leading to vasodilation and increased blood flow necessary to maintain erectile function. The current first-line therapeutic class for ED is phosphodiesterase type 5 inhibitors (PDE-5 inhibitors), which prevent the metabolism of cGMP, prolonging the action of this second messenger on vascular smooth muscle. Increasing blood flow to the tissue of the female genital organs is also beneficial for improving sexual well-being. However, PDE5 inhibitors such as sildenafil (Viagra®) do not increase blood circulation to genital tissue in women as significantly as they do in men.

Another way to increase blood flow in the female or male reproductive organs is to increase the production of nitric oxide, which in turn triggers the release of cGMP. While sildenafil and related substances lead to a sustained increase in blood volume in the male or female genital organs by blocking the enzymatic breakdown of vasodilating cGMP, nitric oxide leads to a similar increase in blood volume by increasing the production of cGMP.

Nitric oxide (NO) is endogenously biosynthesized from L-arginine, oxygen and NADPH by various enzymes called nitric oxide synthase (NOS). NOS enzymes convert L-arginine into L-citrulline and NO, using O2 as the final oxidant. Thus, NO production is dependent on sufficient availability of L-arginine as a substrate. In some publications (for example, Urol Int. 1999; 63 (4): 220-3/ J Sex Marital Ther. 2003 May-Jun; 29(3): 207-13/ Int J Impot Res. 2008 Mar-Apr; 20 (2): 173-80. Epub 2007 Aug 16.) shows the beneficial effect of administering L-arginine to a person suffering from ED. L-arginine can also be synthesized endogenously from L-citrulline through the sequential action of two enzymes, argininosuccinate synthetase and argininosuccinate lyase. Both of these enzymes play important roles in the urea cycle. Some publications (eg, Urology. 2011 Jan; 77(1): 119-22) show beneficial effects of L-citrulline administration to patients suffering from ED, although it is less effective than administration of PDE-5 inhibitors. L-citrulline exhibits higher bioavailability than L-arginine, mainly due to less susceptibility to first-pass metabolism compared to L-arginine.

Several attempts to develop compositions for use in the treatment of sexual dysfunction

- 1 045187 or disorders by stimulation of NO production have been disclosed in the prior art. By way of example, EP 2585088 discloses compositions consisting of a source of L-arginine, proanthocyanidins from a plant extract and rose hips and/or Quercus robur extract. These compositions are intended for continuous treatment with a daily dosing regimen for the treatment of sexual disorders and/or dysfunction.

US 2004/062680 A1 discloses compositions containing arginine and proanthocyanidins to achieve sexual well-being and reproductive vascular health. Good sexual health or sexual performance is improved over time by introducing a source of proanthocyanidins and a source of arginine every day. The L-arginine source may be an L-arginine salt or an L-arginine peptide such as arginine aspartate. Over time, sufficient amounts of nitric oxide are released to improve sexual well-being or sexual performance.

EP 2585088 B1 and WO 11161655 A1 describe compositions for enhancing the sexual performance or well-being of both sexes, containing a source of proanthocyanidins, a source of arginine and rose hips and/or extracts thereof, or Quercus robur and/or extracts thereof, administered in a dose of 5 mg per day up to 2000 mg per day. A composition called Prelox Lady® is described, containing 20 mg of Pycnogenol®, 200 mg of L-arginine, 200 mg of L-citrulline and 50 mg of rose hip extract. This composition is intended for long-term treatment of sexually dysfunctional women.

WO 2017040421 A1 describes a composition containing approximately 5-1000 mg of L-arginine and L-citrulline or combinations thereof. Preferably, L-arginine and L-citrulline are present in the composition in a weight range of 1:1 to 5:1, and the amount of each of L-arginine and L-citrulline is 1-80% by weight of the composition. The composition is disclosed for use in the treatment of erectile dysfunction and premature ejaculation.

CN 103263018 A describes a functional drink containing per 1000 ml 4 g of L-arginine, 0.4 g of L-citrullic acid, 60 mg of vitamin C, 12 mg of vitamin E, 0.2 mg of folic acid, 30 mg of beta-carotene, 30 mg alpha lipoic acid and 300 mg taurine.

CN 104382892 A describes the daily consumption of a composition containing 4-6 g L-arginine, 200-1000 mg L-citrulline, 300-500 mg vitamin C and 20-30 mg beta-carotene.

US 9572848 B1 describes a slow release composition containing 2000-4000 mg L-arginine, 1000-2000 mg L-citrulline, 1000-2000 mg L-carnitine, 10-40 mg zinc and 100-400 mg magnesium. The composition is intended for long-term (at least 30 days) administration for the treatment of sexual arousal disorder in women, orgasmic disorder and hypoactive sexual desire disorder in women or erectile dysfunction in men.

US 2016/0038458 A1 describes the treatment of erectile dysfunction using a combination of mechanical and chemical treatments. The recommended chemical treatment is a continuous treatment consisting of a dose of 3000-6000 mg arginine and 3000 mg citrulline every day, given in 2 doses, for example, one in the morning and one in the evening.

However, the disadvantages of the above-described treatments with daily dosing schedules are the side effects experienced and the need for continuous dosing of the drug. In addition, compositions whose effects are derived from plant extracts contain complex mixtures of compounds, some of which may not be beneficial to human health. Such compositions inevitably vary in dosage of active ingredients due to differences between plant lots and/or species. In addition, the prior art compositions mentioned above are mainly directed towards erectile dysfunction as an alternative to a prescription drug such as sildenafil (Viagra®). Thus, there is a need for improvement to further develop new compounds and compositions for the treatment of ED or, more importantly, other sexual disorders or dysfunctions.

However, more importantly, there is a need for compositions to enhance the sexual experience of healthy human subjects on an as-needed (intermittent dosing) basis. Healthy subjects (i.e., those not suffering from sexual disorder or dysfunction) also have varying degrees of sexual functioning (eg, physical attraction, desire, or sexual fantasies), and many such subjects desire improvements over normal conditions. Historically, such improvements have been achieved through the use of compounds and compositions called aphrodisiacs or love drugs, which are substances or compositions that increase libido when consumed. Aphrodisiacs are different from substances that are intended to treat secondary sexual dysfunctions, such as erectile dysfunction.

Thus, there is still a need in the art to improve the sexual function of normally sexually functioning subjects. Normally functioning subjects do not want to be treated with drugs. In particular, normally functioning subjects do not want to be constantly (eg, every day) treated or influenced by aphrodisiacs and/or drugs (eg, due to side effects). Investigator

- 2 045187 but, there is a need for compositions for use on an as-needed basis (i.e. a need for compositions that are effective for a short period of time (0.5-4 hours) after a single dose), i.e. to enhance sexual impressions before planned sexual activity.

In particular, there is a need in the art to improve sexual function in normally functioning female subjects. In addition, there is a need in the art for compositions that increase libido (eg, psychological parameters such as sexual arousal) when consumed.

Moreover, there is a need in the art for compositions that increase libido while enhancing physiological function, such as erectile and orgasmic function.

In particular, there is a need in the art for such compounds and compositions that act on female subjects.

The present invention avoids some of the disadvantages of prior art compositions for the treatment of sexual disorders and dysfunctions. More importantly, the present invention solves the problem of providing a composition for use as needed as an aphrodisiac in a healthy subject characterized by normal sexual functioning.

Definitions

In the context of the present invention, an aqueous solution is understood to mean any solution in which at least 90% (v/v) of the solvent is water. Thus, the aqueous solution may also contain other co-solvents such as EtOH or glycerol. In a preferred embodiment, the aqueous solution contains water as the only solvent.

In the context of the present invention, treatment should be understood in the broadest sense. Thus, the term treatment is also intended to include the relief or reduction in intensity of any symptoms (physiological or psychological) caused by sexual disorder or dysfunction.

In the context of the present invention, the term unit dose should be understood as a single dose containing an amount of active ingredients that is sufficiently large to achieve the desired therapeutic response before sexual activity. Thus, the single dose is not intended for continuous treatment (eg, as a daily maintenance dose), but rather represents a single loading dose required before sexual activity.

In the context of the present invention, the term sexual disorder or dysfunction has its usual meaning in the art and may include, without limitation, endothelial dysfunction, erectile dysfunction, sexual arousal disorder, hypoactive sexual desire disorder (HSDD), sexual aversion disorder (SAD), orgasmic disorder ( anorgasmia), premature ejaculation, dyspareunia, vaginismus and/or sexual dissatisfaction (nonspecific). Sexual disorder or dysfunction has a negative impact on sexual function or sexual experience.

In the context of the present invention, the term sexually healthy human subject has its usual meaning in the art and refers to subjects having normal sexual function, i.e. subjects who do not suffer from a diagnosed (eg, self-diagnosed) sexual disorder or dysfunction.

In the context of the present invention, the term sexual function has its usual meaning in the art. Thus, sexual function refers to how the body responds at various stages of the sexual response cycle. The human sexual response cycle is a four-stage pattern of physiological responses to sexual stimulation (mental or physiological), which in order of occurrence are the arousal phase, the plateau phase, the orgasmic phase, and the resolution phase.

Sexual experience is closely related to an individual's sexual function. In the context of the present invention, improved sexual function and improved sexual experience can be equated and used interchangeably. Thus, in the context of the present invention, improved sexual function and/or experience may refer to an improvement in any physiological or psychological conditions, stimuli or characteristics present during any sex-related activity in a human subject, as well as an overall improvement in well-being or pleasure during sexual activity. Improvement in sexual function/experience can be assessed using the Sexual Arousal Scale, Lubrication Scale, Orgasm Scale, Emotional Satisfaction Scale, Penetrative Discomfort Scale, Global Intercourse Rating Scale, Erection Hardness Scale, Penile Sensitivity Scale, and/or IELT Scale. .

In the context of the present invention, the term sexual arousal has its usual meaning in the art and refers to the psychological state of a person before engaging in sexual activities. The arousal phase (also known as the sexual arousal phase or initial arousal phase) is the first stage of the human sexual response cycle, which

- 3 045187 which occurs as a result of physical or psychological erotic stimuli, such as kissing, petting or viewing erotic images, which lead to sexual arousal.

In the context of the present invention, the term orgasmic function has its usual meaning in the art and refers to the ability of a human subject to achieve a state of climax of sexual activity. Orgasm occurs during the orgasmic phase and is the end of the plateau phase of the sexual response cycle.

In the context of the present invention, the term IELT has its usual meaning in the art and refers to the latency time of intravaginal ejaculation. IELT represents the time it takes a man to ejaculate during vaginal penetration.

Proanthocyanidins have a common meaning in the art and are a class of polyphenols found in various plants. Chemically, they are oligomeric flavonoids. Proanthocyanidins include the subgroups procyanidins, prodelphinidins and propelargonidins. Proanthocyanidins are homogeneous or heterogeneous polymers consisting of monomer units of catechin or epicatechin and their esters with gallic acid, which are connected by either 4-8 or 4-6 bonds, and therefore there are a large number of isomers of proanthocyanidins. Typically, proanthocyanidin oligomers have a chain length of 2-12 monomer units. Proanthocyanidins can be synthesized or extracted from plant material. Non-limiting examples of sources of proanthocyanidins from plant material include grape seeds, grape skins, pine bark, ginkgo leaves, peanuts, cocoa beans, tamarind, raspberries, currants (black), peanuts, almonds, apple, cranberries, blueberries, tea leaves. Preferably, the source of proanthocyanidin, consisting of a plant extract, is selected from pine bark extract, grape seed extract or apple extract, peanut skins, walnuts, pomegranates, raspberries, currants (black), blueberries, almonds, tea, hawthorn or cocoa, or a combination thereof. Proanthocyanidins can be extracted by any conventional method, such as, for example, solvent extraction or supercritical fluid extraction with CO ₂ . In addition, the compounds can be purified to any desired degree of purity using conventional means and methods in the art, such as solvent extraction, affinity chromatography (normal phase or reverse phase), precipitation or crystallization. A commercial source containing proanthocyanidins exists under the trade name Pycnogenol®. This product is an extract of French maritime pine bark and can be used as a source of the proanthocyanidins of the present invention.

Brief description of the invention

The present invention relates to compositions containing specific ratios and dosages of L-arginine and L-citrulline or a physiologically acceptable salt or hydrate of any of them, and, in particular, such compositions additionally containing a source of proanthocyanidins. More specifically, the present invention relates primarily to the use of such compositions to improve sexual function or sexual experience in a healthy subject having normal sexual function. Secondly, the present invention relates to the use of such a composition as a medicament for the treatment of a sexual disorder or dysfunction such as ED. The inventors of the present invention have discovered that compositions containing a combination of the active ingredients L-arginine and L-citrulline in certain ratios and in certain doses provide compositions that demonstrate high synergistic effects in normal healthy human subjects, in particular women, compared to specific compounds individually, as well as in other ratios and quantities of active ingredients.

In particular, it was found that the minimum amount of L-arginine to provide the required effect was greater than 4.0 g, and that the corresponding minimum amount of L-citrulline was at least 1.0 g. Regarding the maximum amount of active ingredients, it was observed that The safe level for oral L-arginine is 20 g per day, and that even higher levels have been tested in short-term studies without serious side effects. At levels above 20 g per day, some side effects were observed, most commonly diarrhea. Corresponding acceptable levels were observed with oral administration of L-citrulline.

The additional presence of a source of proanthocyanidins was found to significantly improve results. Thus, these compositions can be used not only to treat a sexual disorder or dysfunction, but also to improve sexual function in a healthy subject characterized by normal sexual functioning. In addition, a significant advantage is that these compositions do not require a daily dosing frequency, but require only a single dose before sexual activity.

Thus, the present invention generally relates to a method of improving sexual condition or well-being or increasing sexual activity in a healthy (sexually) human subject of both sexes, comprising administering to the subject in need of improving sexual condition or well-being or increasing sexual activity, a composition of the present invention.

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In particular, the method of the present invention relates to a method of improving sexual condition or well-being or increasing sexual activity of a healthy (sexually) human subject of both sexes, comprising administering to the subject in need of improving sexual condition or well-being or increasing sexual activity, a composition containing L-arginine and L-citrulline or a physiologically acceptable salt or hydrate of any of them, wherein the content of L-arginine or its physiologically acceptable salt or hydrate is at least 4.0 g, and the content of L-citrulline or its physiologically acceptable salt or hydrate is at least 1. 0 g. Preferably the composition also contains one or more proanthocyanidins. Preferably, the composition is in unit dosage form and the content of L-citrulline or a physiologically acceptable salt or hydrate thereof is in the range of 1.0-3.0 g.

More preferably, the molar ratio of L-arginine:L-citrulline is in the range of 2.0:10.0.

Thus, the present invention relates to a method of improving sexual condition or well-being or increasing sexual activity of a healthy (sexually) human subject of both sexes, comprising administering to the subject in need of improving sexual condition or well-being or increasing sexual activity, a composition containing L-arginine and L-citrulline or a physiologically acceptable salt or hydrate of any of them, wherein L-arginine and L-citrulline are present in the composition, respectively, in a weight ratio of 2.0:1 to 10.0:1, preferably in the range of 2.2:1 to 5 ,8:1, and where the L-arginine content is at least 4.0 g, for example in the range of 4.0-20 g, preferably in the range of 4.0-12.0 g, more preferably in the range of 4.0 -8.0 g, and the content of L-citrulline or its physiologically acceptable salt or hydrate is at least 1.0 g, for example in the range of 1.0-5.0 g, for example in the range of 1.0-3, 0 g, preferably 1.2-2.1 g.

In a preferred aspect, the compositions contain a third component, wherein said third component contains an effective amount of a source of proanthocyanidins, preferably present in an amount of at least 5 mg.

Preferably, the composition is administered as needed (not continuously) in a single dose.

More preferably, the composition is administered as needed as a functional drink or as a composition intended to provide a functional drink, in a volume of 20-500 ml, more preferably 100-400 ml, more preferably 150-300 ml, most preferably 200-250 ml.

Detailed Description of the Invention

The present invention relates to compositions that are useful for improving the general well-being of a person during and/or prior to sexual activity. Thus, the compositions are intended for use as needed prior to planned sexual activity to achieve an unusual sexual experience or to relieve symptoms caused by sexual dysfunction or dysfunction. In other words, the compositions are suitable as an aphrodisiac or love medicine that increases libido (ie, sexual desire) in a human subject when consumed. Thus, one embodiment of the present invention relates to the use of the composition as an aphrodisiac. Another embodiment of the present invention relates to a method of improving sexuality and/or sexual functioning in a healthy human subject. The improved well-being achieved by the compositions of the present invention may involve a combination of both physiological and psychological effects due to the complexity of human sexuality. In one case, the composition is intended to enhance sexual arousal, emotional satisfaction, overall quality of sexual intercourse, or any combination thereof, in both men and women. In another case, the composition is intended to reduce sensitivity of the penis to avoid premature ejaculation in men. In yet another application, the composition is intended to increase vaginal lubrication, reduce discomfort during penetration, and increase the chance of achieving climax during sexual activity in women.

Amount of L-arginine, L-citrulline and proanthocyanidin source.

In a preferred aspect of the present invention, the present invention relates to a single dose composition containing L-arginine and L-citrulline in a weight ratio of from 2.0:1 to 10.0:1, wherein L-arginine is present in a single dose in an amount greater than 4 g, for example at least 5.0 g, for example at least 6.0 g, for example in the range of 4.0-20 g, preferably in the range of 5.0-20.0 g, for example in the range of 6 .0-20 g, preferably in the range of 4.0-12.0 g, preferably in the range of 5.0-12.0 g, for example in the range of 6.0-12 g, more preferably in the range of 4.0-10 .0 g, even more preferably 5.0-10.0 g, for example in the range of 6.0-10 g, for example 5.0-8.0 g, most preferably 5.5-7 g, even more preferably about 6 g, and the content of Lcitrulline or its physiologically acceptable salt or hydrate is at least 1.0 g, preferably at least 1.5 g, for example in the range of 1.0-5.0 g, for example in the range of 1 0-3.0 g, even more preferably 1.0-2.1 g, for example 1.5-2.1 g, more preferably 1.2-2.1 g.

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Preferably, the ratio between L-arginine and L-citrulline is as disclosed below.

Preferably, the compositions of the present invention contain a source of proanthocyanidin. The amount required is limited because proanthocyanidin is believed to be a catalyst.

The compositions of the present invention may be formulated as a solid or powder composition for direct consumption.

However, the single dose compositions of the present invention are preferably formulated as a functional beverage or, alternatively, formulated for mixing with a liquid composition for consumption, wherein the volume of said liquid composition is less than 500 ml. As required, the maximum total volume of standard functional beverage dosage forms is approximately 500 mL. Large volumes cannot be consumed as needed without affecting the purpose of the compositions of the present invention. Thus, preferably the composition is intended to be administered as needed as a functional drink or, alternatively, is provided as a composition intended to provide a functional drink, wherein the final volume of said functional drink is 20-500 ml, more preferably 50-400 ml , more preferably 100-300 ml, more preferably 150-250 ml.

A preferred liquid for mixing with the composition of the present invention is fruit juice, particularly orange juice. Orange juice was found to mask the flavor of the composition better than other juices. If fruit juice is used, caffeine is preferably added to the composition.

Another preferred liquid for mixing with the composition of the present invention are conventional soft drinks, particularly lemonade.

Ratio of L-arginine and L-citrulline.

The present inventors have discovered that L-arginine and L-citrulline in certain ratios provide synergistic effects compared to the individual compounds alone.

Thus, in a first aspect, the present invention relates to compositions containing L-arginine and L-citrulline or a physiologically acceptable salt or hydrate of either of them in certain proportions. Therefore, these compositions are suitable for improving human sexual function. Without being limited by theory, these compositions may help improve sexual function, for example, by increasing NO production in situ. The present inventors have found that the ratio of L-arginine to L-citrulline in the composition plays a significant role in improving sexual function in men and women, and that L-arginine should be in excess relative to L-citrulline. Thus, an embodiment of the present invention provides compositions wherein the molar ratio of L-arginine:L-citrulline is in the range of 2.0:1 to 10.0:1, e.g., 2.0:1 to 9.0:1, e.g. from 2.2:1 to 5.8:1, for example from 2.4:1 to 5.6:1, for example from 2.6:1 to 5.4:1, for example from 2.8: 1 to 5.2:1, e.g. 3:1 to 5.0:1, e.g. 3.2:1 to 4.8:1, e.g. 3.4:1 to 4.6:1 , preferably from 3.6:1 to 4.4:1, more preferably from 3.8:1 to 4.2:1, more preferably 4:1. The molar ratio of excess L-arginine compared to L-citrulline is important to achieve the synergistic effects of the compositions of the present invention.

The compositions of the present invention can be formulated by conventional methods known to one skilled in the art. In a preferred embodiment, the composition is a powder mixture suitable for dissolution and consumption prior to sexual activity. In a preferred embodiment, the powder mixture may be dissolved in a beverage, such as a soft drink. In another preferred embodiment of the present invention, the composition is formulated as an aqueous solution, which is intended for consumption as needed prior to sexual activity.

In one embodiment of the present invention, the L-arginine content of the powder composition is typically in the range of 53-75% w/w, such as 55-73% w/w, such as 56-72% w/w. eg 57-71% w/w, eg 58-70% w/w, eg 59-69% w/w, eg 60-68% w/w, preferably 61-67% w/w, more preferably 62-66% w/w, even more preferably 63-65% w/w, most preferably 64% w/w.

In one embodiment of the present invention, the content of L-citrulline in the powder composition is typically in the range of 8-25% w/w, 10-22% w/w, 12-20% w/w, e.g. .5-19.5% w/w, e.g. 13-19% w/w, e.g. 13.5-18.5% w/w, e.g. 1418% w/w. , preferably 14.5-17.5% w/w, more preferably 15-17% w/w, even more preferably 15.5-16.5% w/w, most preferably 16% w/w /weight.

Other Ingredients.

In addition to the main ingredients L-arginine and L-citrulline, the present inventors have discovered that additional additives such as D-alpha tocopherol, L-ascorbic acid, alpha

- 6 045187 lipoic acid, folic acid, calcium and, in particular, one or more proanthocyanidins improve the effect of the composition (eg improve sexual function in an individual). Thus, in one embodiment of the present invention, the composition contains L-arginine, L-citrulline and D-alpha tocopherol or a physiologically acceptable salt or hydrate thereof. In an alternative embodiment of the present invention, the composition contains L-arginine, L-citrulline and at least one proanthocyanidin.

In a more preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alpha tocopherol and proanthocyanidin (the preferred source of proanthocyanidins is Pycnogenol®). In a more preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alpha tocopherol, one or more proanthocyanidins and L-ascorbic acid. In an even more preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alphatocopherol, one or more proanthocyanidins, L-ascorbic acid and alpha-lipoic acid. In an even more preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alpha tocopherol, one or more proanthocyanidins, L-ascorbic acid, alpha lipoic acid and folic acid. In the most preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alphatocopherol, one or more proanthocyanidins, L-ascorbic acid, alpha-lipoic acid, folic acid and calcium.

The present inventors have discovered that proanthocyanidins are important for the activation of the compositions of the present invention containing L-arginine and L-citrulline in certain ratios. The inventors of the present invention have also discovered that in terms of function, proanthocyanidins appear to function as catalysts and, therefore, the amount of proanthocyanidins can be significantly reduced compared to other ingredients. The one or more proanthocyanidins are preferably supplied in the compositions as a plant extract, preferably as a natural plant extract derived from the bark of the maritime pine tree, which grows along the coast of southwestern France (and, for example, sold under the trade name Pycnogenol®. If the proanthocyanidins are supplied in form of Pycnogenol®, the preferred amount of Pycnogenol® in powder compositions is preferably 6.9-101% w/w, for example 7.1-99% w/w, for example 7.3-97% w/w. /wt., for example, 7.5-95% w/w, for example, 7.793% w/w, preferably 7.9-91% w/w, more preferably 8.1-89% wt. ./wt., even more preferably 8.3-87% wt./wt., more preferably 10-80% wt./wt. powder compositions.

The content of D-alpha tocopherol in the powder composition is usually in the range of 0.8-2.4% w/w, for example 0.9-2.3% w/w, for example 1.0-2 .2% w/w, e.g. 1.1-2.1% w/w, e.g. 1.2-2.0% w/w, preferably 1.3-1.9% w/w, more preferably 1.4-1.8% w/w, even more preferably 1.5-1.6% w/w, more preferably 1.4% w/w powder compositions .

The content of L-ascorbic acid in the powder composition is usually in the range of 3.7-6.9% w/w, for example 3.9-6.7% w/w, for example 4.1-6. 5% w/w, e.g. 4.3-6.3% w/w, e.g. 4.5-6.1% w/w, preferably 4.7-5.9% w/w ./wt., more preferably 4.95.7% wt./wt., even more preferably 5.1-5.5% wt./wt., more preferably 5.3% wt./wt. powder compositions.

The content of alpha lipoic acid in the powder composition is usually in the range of 0.3-1.8% w/w, for example 0.3-1.7% w/w, for example 0.4-1. 6% w/w, e.g. 0.5-1.5% w/w, e.g. 0.6-1.4% w/w, preferably 0.7-1.3% w/w ./wt., more preferably 0.81.2% wt./wt., even more preferably 0.9-1.1% wt./wt., most preferably 1% wt./wt. powder compositions.

The folic acid content of the powder composition is typically in the range of 0.01-0.07% w/w, for example 0.015-0.065% w/w, for example 0.02-0.06% w/w ., preferably 0.025-0.055% w/w, more preferably 0.03-0.05% w/w, even more preferably 0.0350.045% w/w, most preferably 0.04% weight/weight of powdered compositions.

The calcium content of the powder composition is typically in the range of 5.7-8.1% w/w, e.g. 5.9-7.9% w/w, e.g. 6.1-7.7% w/w ./wt., preferably 6.3-7.5% wt./wt., more preferably 6.5-7.3% wt./wt., even more preferably 6.7-7.1% wt./ wt., most preferably 6.9% w/w powdered compositions.

In addition, the inventors of the present invention have discovered that these compositions do not require daily administration, since it is sufficient to administer a single dose before sexual activity.

A single dose of the compositions for use as needed.

The present inventors have discovered that the compositions of the present invention can be administered to healthy human subjects in single dose formulations (at relatively low

- 7 045187 doses), which avoids the disadvantages of continuous treatment while providing the benefits of achieving improved sexuality on demand.

In addition, the present inventors have found that the same composition has comparable beneficial effects in improving sexual function in both sexes.

Thus, in a preferred embodiment of the present invention, the composition is presented in a single dose dosage form. A single dose may be in the form of a solid powder suitable for dissolving a premixed beverage for direct consumption. A single dose is intended to be an appropriate as-needed dose that is taken before sexual activity to achieve a better sexual experience or to relieve any symptoms caused by sexual dysfunction or dysfunction.

Thus, the composition does not need to be taken according to a predetermined dosing schedule (i.e. at predetermined time intervals) to maintain a certain concentration of the active substance in the blood plasma, which is usual for almost any medical treatment, i.e. it is not intended for continuous treatment. In other words, a given human subject can tailor consumption depending on his individual desire for sexual activity and desire for unusual sexual experiences (as needed). Thus, in a preferred embodiment of the present invention, the compositions are intended for use in healthy human subjects who do not suffer from any sexual disorder or dysfunction (ie, as an aphrodisiac). In another embodiment of the present invention, the compositions are for use in treating a human subject suffering from a diagnosed or self-diagnosed sexual dysfunction or disorder. Even in the latter case, if the composition is used in the treatment of sexual dysfunction or disorder, one dose before sexual activity may be sufficient, i.e. continuous treatment is not required.

Accordingly, in one embodiment of the present invention, a single dose contains L-arginine and L-citrulline or their physiologically acceptable salts or hydrates in a (combined) amount in the range of 6-14 g, for example, 6.2-13.0 g, for example, 6.4-12 g, for example 6.6-11 g, for example 6.8-10.0 g, for example 7.0-9.0 g, for example 7.2-8.0 g, preferably 7.5 g (as free amino acids). One skilled in the art will appreciate that amounts may vary depending on the source of L-arginine and/or L-citrulline (eg, salt and/or solvate). Thus, it is well known to one skilled in the art that amounts (eg, L-arginine) can be expressed in moles, and amounts (g) are calculated in terms of the amount of salt and/or solvate with a higher molecular weight.

In one embodiment of the present invention, the single dose comprises L-arginine or a physiologically acceptable salt or hydrate thereof present in the single dose in an amount greater than 4 g, such as at least 5.0 g, such as at least 5.0 g , for example in the range of 4.0-20 g, preferably in the range of 5.0-20.0 g, for example in the range of 6.0-20 g, preferably in the range of 4.0-12.0 g, preferably in the range 5.0-12.0 g, for example in the range of 6.0-12 g, more preferably 4.0-10.0 g, for example 4.4-9.5 g, for example 4.6-9, 0 g, for example 4.8-8.0 g, even more preferably 5.0-10.0 g, preferably 5.0-7.0 g, more preferably 5.2-6.8 g, even more preferably 5.4-6.6 g, 5.6-6.4 g, 5.8-6.2 g, preferably in the range of 6.0-10 g, for example 5.0-8.0 g, more preferably 5 .5-7 g, even more preferably about 6 g, more preferably 6.0 g (34.4 mmol, free amino acid). The present inventors found that 6.0 g of L-Arginine was most effective, and that in some cases side effects (eg, abdominal pain) occurred when exceeding 10 g. In addition, higher amounts of L-arginine impaired the organoleptic properties of a single dose.

In one embodiment of the present invention, a single dose contains L-citrulline or a physiologically acceptable salt or hydrate thereof in the range of 0.5-3.0 g, for example 0.5-2.9 g, preferably 0.5-2.8 g , more preferably 0.5-2.7 g, for example 0.7-2.0 g, preferably 0.9-2.0 g, more preferably 1.1-2.0 g, even more preferably 1.3 -2.0 g, most preferably 1.5-2.0 g. The present inventors found that single dose efficacy was not further improved by L-citrulline in amounts above 2.0 g (ie, plateau efficacy). In addition, the present inventors found that higher efficacy and activity of the composition were obtained when both L-arginine and L-citrulline were present. Specifically, the formulation was most effective when the amount of L-arginine was four times the amount of L-citrulline (i.e., a 4:1 ratio). The present inventors also found that the effect lasted longer and that a synergistic effect was obtained when both L-citrulline and L-arginine were present in the composition or single dose.

In one embodiment of the present invention, the single dose used contains L-arginine and L-citrulline or a physiologically acceptable salt or hydrate of any of them, where L-arginine or a physiologically acceptable salt or hydrate thereof is in the range of 4-10 g, for example,

- 8 045187

4.4-9.5 g, for example 4.6-9.0 g, for example 4.8-8.0 g, preferably 5.0-7.0 g, more preferably 5.26.8 g, even more preferably 5.4-6.6 g, 5.6-6.4 g, 5.8-6.2 g, most preferably 6.0 g, and Lcitrulline or a physiologically acceptable salt or hydrate thereof is in the range of 0 .5-3.0 g, for example 0.5-2.9 g, preferably 0.5-2.8 g, more preferably 0.5-2.7 g, for example 0.7-2.0 g , preferably 0.9-2.0 g, more preferably 1.1-2.0 g, even more preferably 1.3-2.0 g, most preferably 1.5-2.0 g.

In one embodiment of the present invention, a single dose contains D-alphatocopherol or a physiologically acceptable salt or hydrate thereof in the range of 85-185 mg, e.g. 90-180 mg, e.g. 95-175 mg, e.g. 100-170 mg, e.g. 105-165 mg, for example 110-160 mg, for example 115-155 mg, preferably 120-150 mg, more preferably 125-145 mg, even more preferably 130-140 mg, most preferably 133 mg.

In another embodiment of the present invention, a single dose contains L-arginine, L-citrulline and D-alpha tocopherol or a physiologically acceptable salt or hydrate of any of them, wherein the content of L-arginine or a physiologically acceptable salt or hydrate thereof is in the range of 410 g, for example 4.4-9.5 g, for example 4.6-9.0 g, for example 4.8-8.0 g, preferably 5.0-7.0 g, more preferably 5.2-6 .8 g, even more preferably 5.4-6.6 g, 5.6-6.4 g, 5.8-6.2 g, most preferably 6.0 g, content of L-citrulline or a physiologically acceptable salt thereof or hydrate is in the range of 0.5-3.0 g, for example 0.5-2.9 g, preferably 0.5-2.8 g, more preferably 0.5-2.7 g, for example 0. 7-2.0 g, preferably 0.9-2.0 g, more preferably 1.1-2.0 g, even more preferably 1.3-2.0 g, most preferably 1.5 g, and content D -alpha-tocopherol or its physiologically acceptable salt or hydrate is in the range of 85-185 mg, for example 90-180 mg, for example 95-175 mg, for example 100-170 mg, for example 105-165 mg, for example 110 -160 mg, for example 115-155 mg, preferably 120-150 mg, more preferably 125-145 mg, even more preferably 130-140 mg, most preferably 133 mg.

In an embodiment of the present invention, the single dose contains one or more proanthocyanidins, preferably present as part of a plant extract, preferably as a natural plant extract derived from the bark of the maritime pine tree, which grows along the coast of southwestern France (and, for example, sold under the trade name called Pycnogenol®). One or more proanthocyanidins in a single dose are present in the range of 5-220 mg, for example 10-220 mg, for example 15-210 mg, for example 20-200 mg, for example 25-190 mg, for example 30-180 mg, for example 35-170 mg, for example 40-160 mg, preferably 50-140 mg, more preferably 60-120 mg, even more preferably 70-100 mg, most preferably 80 mg.

In a preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline and one or more proanthocyanidins, wherein the content of L-arginine or a physiologically acceptable salt or hydrate thereof is in the range of 4-10 g, for example 4.4-9. 5 g, for example 4.6-9.0 g, for example 4.8-8.0 g, preferably 5.0-7.0 g, more preferably 5.2-6.8 g, even more preferably 5 .4-6.6 g, 5.6-6.4 g, 5.8-6.2 g, most preferably 6.0 g, the content of L-citrulline or its physiologically acceptable salt or hydrate is in the range of 0.5 -3.0 g, for example 0.5-2.9 g, preferably 0.5-2.8 g, more preferably 0.5-2.7 g, 0.5-2.0 g, for example 0 .7-2.0 g, preferably 0.9-2.0 g, more preferably 1.1-2.0 g, even more preferably 1.3-2.0 g, most preferably 1.5 g, and content proanthocyanidins is in the range of 10-220 mg, for example 15-210 mg, for example 20-200 mg, for example 25-190 mg, for example 30-180 mg, for example 35-170 mg, for example 40-160 mg, preferably 50-140 mg, more preferably 60-120 mg, even more preferably 70-100 mg, most preferably 80 mg.

In another preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alpha tocopherol and one or more proanthocyanidins, where the content of L-arginine or its physiologically acceptable salt or hydrate is in the range of 4-10 g, for example , 4.4-9.5 g, for example 4.6-9.0 g, for example 4.8-8.0 g, preferably 5.0-7.0 g, more preferably 5.2-6, 8 g, even more preferably 5.4-6.6 g, 5.6-6.4 g, 5.8-6.2 g, most preferably 6.0 g, content of L-citrulline or a physiologically acceptable salt thereof or hydrate is in the range of 0.5-3.0 g, for example 0.5-2.9 g, preferably 0.5-2.8 g, more preferably 0.5-2.7 g, for example 0.72 .0 g, preferably 0.9-2.0 g, more preferably 1.1-2.0 g, even more preferably 1.3-2.0 g, most preferably 1.5-2.0 g, content D -alpha-tocopherol or its physiologically acceptable salt or hydrate is in the range of 85-185 mg, for example 90-180 mg, for example 95-175 mg, for example 100-170 mg, for example 105-165 mg, for example 110 -160 mg, for example 115-155 mg, preferably 120-150 mg, more preferably 125-145 mg, even more preferably 130-140 mg, most preferably 133 mg, and one or more proanthocyanidins are present in the range of 10-220 mg, for example 15-210 mg, for example 20-200 mg, for example 25-190 mg, for example 30-180 mg, for example 35-170 mg, for example 40-160 mg, preferably 50-140 mg, more preferably 60 -120 mg, even more preferably 70-100 mg, most preferably 80 mg.

In one embodiment of the present invention, a single dose contains L-ascorbic acid or a physiologically acceptable salt or hydrate thereof in the range of 300-700 mg, per

- 9 045187 example, 320-680 mg, for example 340-660 mg, for example 360-640 mg, for example 380-620 mg, for example 400-600 mg, for example 420-580 mg, preferably 440-560 mg, more preferably 460-540 mg, even more preferably 480-520 mg, most preferably 500 mg.

In a more preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alpha tocopherol, L-ascorbic acid and one or more proanthocyanidins, wherein the content of L-arginine or a physiologically acceptable salt or hydrate thereof is in the range of 4 -10 g, for example 4.4-9.5 g, for example 4.6-9.0 g, for example 4.8-8.0 g, preferably 5.0-7.0 g, more preferably 5 ,2-6.8 g, even more preferably 5.4-6.6 g, 5.6-6.4 g, 5.8-6.2 g, most preferably 6.0 g, L-citrulline content or its physiologically acceptable salt or hydrate is in the range of 0.5-3.0 g, for example 0.5-2.9 g, preferably 0.5-2.8 g, more preferably 0.5-2.7 g, for example 0.7-2.0 g, preferably 0.9-2.0 g, more preferably 1.1-2.0 g, even more preferably 1.3-2.0 g, most preferably 1.5- 2.0 g, the content of D-alpha tocopherol or its physiologically acceptable salt or hydrate is in the range of 85-185 mg, for example 90-180 mg, for example 95-175 mg, for example 100-170 mg, for example 105 -165 mg, for example 110-160 mg, for example 115-155 mg, preferably 120-150 mg, more preferably 125-145 mg, even more preferably 130-140 mg, most preferably 133 mg, L-ascorbic acid content or its physiologically acceptable salt or hydrate is in the range of 300-700 mg, for example 320-680 mg, for example 340-660 mg, for example 360-640 mg, for example 380-620 mg, for example 400-600 mg, for example , 420-580 mg, preferably 440-560 mg, more preferably 460-540 mg, even more preferably 480-520 mg, most preferably 500 mg, and one or more proanthocyanidins are present in the range of 10-220 mg, for example 15-210 mg, for example 20-200 mg, for example 25-190 mg, for example 30-180 mg, for example 35-170 mg, for example 40-160 mg, preferably 50-140 mg, more preferably 60-120 mg, even more preferably 70-100 mg, most preferably 80 mg.

In one embodiment of the present invention, a single dose contains alpha lipoic acid or a physiologically acceptable salt or hydrate thereof in the range of 5-15 mg, for example 5.5-14.5 mg, for example 6-14 mg, for example 6.5-13 .5 mg, for example 7-13 mg, for example 7.5-12.5 mg, for example 8-12 mg, preferably 8.5-11.5 mg, more preferably 9-11 mg, even more preferably 9 .5-10.5 mg, most preferably 10 mg.

In an even more preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alpha tocopherol, L-ascorbic acid, alpha lipoic acid and one or more proanthocyanidins, wherein the content of L-arginine or a physiologically acceptable salt thereof or hydrate is in the range of 4-10 g, for example 4.4-9.5 g, for example 4.6-9.0 g, for example 4.8-8.0 g, preferably 5.0-7, 0 g, more preferably 5.2-6.8 g, even more preferably 5.4-6.6 g, 5.6-6.4 g, 5.8-6.2 g, most preferably 6.0 g , the content of L-citrulline or its physiologically acceptable salt or hydrate is in the range of 0.5-3.0 g, for example 0.5-2.9 g, preferably 0.52.8 g, more preferably 0.5-2 .7 g, for example 0.7-2.0 g, preferably 0.9-2.0 g, more preferably 1.1-2.0 g, even more preferably 1.3-2.0 g, more preferably 1.5-2.0 g, the content of α-tocopherol or its physiologically acceptable salt or hydrate is in the range of 85-185 mg, for example 90-180 mg, for example 95-175 mg, for example 100-170 mg, for example , 105-165 mg, for example 110-160 mg, for example 115-155 mg, preferably 120-150 mg, more preferably 125-145 mg, even more preferably 130-140 mg, most preferably 133 mg, L-ascorbic acid content acid or a physiologically acceptable salt or hydrate thereof is in the range of 300-700 mg, for example 320-680 mg, for example 340-660 mg, for example 360-640 mg, for example 380-620 mg, for example 400-600 mg e.g. 420-580 mg, preferably 440-560 mg, more preferably 460-540 mg, even more preferably 480-520 mg, most preferably 500 mg, the content of alpha-lipoic acid or its physiologically acceptable salt or hydrate is in the range of 5 -15 mg, e.g. 5.5-14.5 mg, e.g. 6-14 mg, e.g. 6.5-13.5 mg, e.g. 7-13 mg, e.g. 7.5-12.5 mg for example, 8-12 mg, preferably 8.5-11.5 mg, more preferably 9-11 mg, even more preferably 9.5-10.5 mg, most preferably 10 mg, and the content of one or more proanthocyanidins is range 10-220 mg, for example 15-210 mg, for example 20-200 mg, for example 25-190 mg, for example 30-180 mg, for example 35-170 mg, for example 40-160 mg, preferably 50 -140 mg, more preferably 60-120 mg, even more preferably 70-100 mg, most preferably 80 mg.

In one embodiment of the present invention, a single dose contains folic acid or a physiologically acceptable salt or hydrate thereof in the range of 200-600 μg, for example, 220-580 μg, for example, 240-560 μg, for example, 260-540 μg, for example, 280-520 μg eg 300-500 µg, eg 320-480 µg, preferably 340-460 µg, more preferably 360-440 µg, even more preferably 380-420 µg, most preferably 400 µg. Folic acid can be replaced by folinic acid or its salts, such as calcium folinate.

In an even more preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alpha tocopherol, L-ascorbic acid, alpha lipoic acid, folic acid and one or more proanthocyanidins, wherein the content of L-arginine or its physiologically acceptable salt or hydrate is in the range of 4-10 g, e.g. 4.4-9.5 g, e.g.

- 10 045187

4.6-9.0 g, for example 4.8-8.0 g, preferably 5.0-7.0 g, more preferably 5.2-6.8 g, even more preferably 5.4-6, 6 g, 5.6-6.4 g, 5.8-6.2 g, most preferably 6.0 g, the content of L-citrulline or its physiologically acceptable salt or hydrate is in the range of 0.5-2.0 g for example 0.7-1.9 g, preferably 0.9-1.8 g, more preferably 1.1-1.7 g, even more preferably 1.3-1.6 g, most preferably 1.5 d, the content of D-alpha tocopherol or its physiologically acceptable salt or hydrate is in the range of 85-185 mg, for example 90-180 mg, for example 95-175 mg, for example 100-170 mg, for example 105-165 mg, for example , 110-160 mg, for example 115-155 mg, preferably 120-150 mg, more preferably 125-145 mg, even more preferably 130-140 mg, most preferably 133 mg, content of L-ascorbic acid or its physiologically acceptable salt or hydrate is in the range of 300-700 mg, for example 320-680 mg, for example 340-660 mg, for example 360-640 mg, for example 380-620 mg, for example 400-600 mg, for example 420-580 mg , preferably 440-560 mg, more preferably 460-540 mg, even more preferably 480-520 mg, most preferably 500 mg, the content of alpha-lipoic acid or its physiologically acceptable salt or hydrate is in the range of 5-15 mg, for example, 5 .5-14.5 mg, for example 6-14 mg, for example 6.5-13.5 mg, for example 7-13 mg, for example 7.5-12.5 mg, for example 8-12 mg , preferably 8.5-11.5 mg, more preferably 9-11 mg, even more preferably 9.5-10.5 mg, most preferably 10 mg, the content of folic acid or its physiologically acceptable salt or hydrate is in the range of 200- 600 µg, for example 220580 µg, for example 240-560 µg, for example 260-540 µg, for example 280-520 µg, for example 300-500 µg, for example 320-480 µg, preferably 340-460 µg, more preferably 360-440 μg, even more preferably 380-420 μg, most preferably 400 μg, and the content of one or more proanthocyanidins is in the range of 10-220 mg, for example 15-210 mg, for example 20-200 mg, for example 25 -190 mg, for example 30-180 mg, for example 35-170 mg, for example 40-160 mg, preferably 50-140 mg, more preferably 60-120 mg, even more preferably 70-100 mg, most preferably 80 mg .

In one embodiment of the present invention, a single dose contains calcium in the range of 20-100 mg, for example 25-95 mg, for example 30-90 mg, for example 35-85 mg, for example 40-80 mg, preferably 45-75 mg , more preferably 50-70 mg, even more preferably 55-65 mg, most preferably 60 mg.

In an even more preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alpha tocopherol, L-ascorbic acid, alpha lipoic acid, folic acid, calcium and one or more proanthocyanidins, wherein the L-arginine content is or a physiologically acceptable salt or hydrate thereof is in the range of 4-10 g, for example 4.4-9.5 g, for example 4.6-9.0 g, for example 4.8-8.0 g, preferably 5 0-7.0 g, more preferably 5.2-6.8 g, even more preferably 5.4-6.6 g, 5.6-6.4 g, 5.8-6.2 g, most preferably 6.0 g, the content of Lcitrulline or its physiologically acceptable salt or hydrate is in the range of 0.5-2.0 g, for example 0.7-1.9 g, preferably 0.9-1.8 g, more preferably 1.1-1.7 g, even more preferably 1.3-1.6 g, most preferably 1.5 g, the content of D-alpha tocopherol or its physiologically acceptable salt or hydrate is in the range of 85-185 mg, for example , 90-180 mg, for example 95-175 mg, for example 100-170 mg, for example 105-165 mg, for example 110-160 mg, for example 115-155 mg, preferably 120-150 mg, more preferably 125 -145 mg, even more preferably 130-140 mg, most preferably 133 mg, the content of L-ascorbic acid or its physiologically acceptable salt or hydrate is in the range of 300-700 mg, for example 320-680 mg, for example 340-660 mg , for example, 360-640 mg, for example, 380-620 mg, for example, 400-600 mg, for example, 420-580 mg, preferably 440-560 mg, more preferably 460-540 mg, even more preferably 480-520 mg, most preferably 500 mg, the content of alpha lipoic acid or its physiologically acceptable salt or hydrate is in the range of 5-15 mg, for example 5.5-14.5 mg, for example 6-14 mg, for example 6.5-13 .5 mg, for example 7-13 mg, for example 7.5-12.5 mg, for example 8-12 mg, preferably 8.5-11.5 mg, more preferably 9-11 mg, even more preferably 9 .5-10.5 mg, most preferably 10 mg, the content of folic acid or its physiologically acceptable salt or hydrate is in the range of 200-600 μg, for example 220-580 μg, for example 240-560 μg, for example 260-540 μg, for example, 280-520 µg, for example 300-500 µg, for example 320-480 µg, preferably 340-460 µg, more preferably 360-440 µg, even more preferably 380-420 µg, most preferably 400 µg, calcium content is in the range of 20-100 mg, for example 25-95 mg, for example 30-90 mg, for example 35-85 mg, for example 40-80 mg, preferably 45-75 mg, more preferably 50-70 mg, even more preferably 55-65 mg, most preferably 60 mg, and the content of one or more proanthocyanidins is in the range of 10-220 mg, for example 15-210 mg, for example 20-200 mg, for example 25-190 mg, for example 30- 180 mg, for example 35-170 mg, for example 40-160 mg, preferably 50-140 mg, more preferably 60-120 mg, even more preferably 70-100 mg, most preferably 80 mg.

In another embodiment, the single dose preferably contains caffeine or a physiologically acceptable salt or hydrate thereof in the range of 20-180 mg, e.g. 30-170 mg, e.g. 40-160 mg, e.g. 50-150 mg, e.g. 60-140 mg, preferably 70-130 mg, more preferably 80-120 mg, even more preferably 90-110 mg, most preferably 100 mg. As an alter

- 11 045187 natives, compositions can be mixed with caffeine-containing soft drinks before use.

In the most preferred embodiment of the present invention, the single dose contains L-arginine, L-citrulline, D-alpha tocopherol, L-ascorbic acid, alpha lipoic acid, folic acid, calcium, caffeine and one or more proanthocyanidins, wherein the content of L-arginine or its physiologically acceptable salt or hydrate is in the range of 4-10 g, for example 4.4-9.5 g, for example 4.6-9.0 g, for example 4.8-8.0 g, preferably 5. 0-7.0 g, more preferably 5.26.8 g, even more preferably 5.4-6.6 g, 5.6-6.4 g, 5.8-6.2 g, most preferably 6. 0 g, the content of L-citrulline or its physiologically acceptable salt or hydrate is in the range of 0.5-3.0 g, for example 0.5-2.9 g, preferably 0.5-2.8 g, more preferably 0 .5-2.7 g, for example 0.7-2.0 g, preferably 0.9-2.0 g, more preferably 1.1-2.0 g, even more preferably 1.3-2.0 g, most preferably 1.5-2.0 g, the content of D-alpha tocopherol or its physiologically acceptable salt or hydrate is in the range of 85-185 mg, for example 90-180 mg, for example 95-175 mg, for example 100-170 mg, for example 105-165 mg, for example 110-160 mg, for example 115-155 mg, preferably 120-150 mg, more preferably 125-145 mg, even more preferably 130-140 mg, most preferably 133 mg, the content of L-ascorbic acid or its physiologically acceptable salt or hydrate is in the range of 300-700 mg, for example 320-680 mg, for example 340-660 mg, for example 360-640 mg, for example 380-620 mg, for example, 400-600 mg, for example, 420-580 mg, preferably 440-560 mg, more preferably 460-540 mg, even more preferably 480-520 mg, most preferably 500 mg, content of alpha-lipoic acid or its physiologically acceptable salt or hydrate is in the range of 5-15 mg, for example 5.5-14.5 mg, for example 6-14 mg, for example 6.5-13.5 mg, for example 7-13 mg, for example 7, 5-12.5 mg, for example 8-12 mg, preferably 8.5-11.5 mg, more preferably 9-11 mg, even more preferably 9.5-10.5 mg, most preferably 10 mg, folate content acid or its physiologically acceptable salt or hydrate is in the range of 200-600 µg, for example 220-580 µg, for example 240-560 µg, for example 260-540 µg, for example 280-520 µg, for example 300-500 µg, for example , 320-480 µg, preferably 340-460 µg, more preferably 360-440 µg, even more preferably 380-420 µg, most preferably 400 µg, calcium content is in the range of 20-100 mg, for example 25-95 mg, for example , 30-90 mg, for example 35-85 mg, for example 40-80 mg, preferably 45-75 mg, more preferably 50-70 mg, even more preferably 55-65 mg, most preferably 60 mg, caffeine content or its physiologically acceptable salt or hydrate is in the range of 20-180 mg, for example 30-170 mg, for example 40-160 mg, for example 50-150 mg, for example 60-140 mg, preferably 70-130 mg, more preferably 80 -120 mg, even more preferably 90-110 mg, most preferably 100 mg, and the content of one or more proanthocyanidins is in the range of 10-220 mg, for example 15-210 mg, for example 20-200 mg, for example 25-190 mg, for example 30-180 mg, for example 35-170 mg, for example 40-160 mg, preferably 50-140 mg, more preferably 60-120 mg, even more preferably 70-100 mg, most preferably 80 mg.

In another embodiment, the single dose preferably contains taurine or a physiologically acceptable salt or hydrate thereof in the range of 200-1800 mg, for example 300-1700 mg, for example 400-1600 mg, for example 500-1500 mg, for example 600-1400 mg , preferably 700-1300 mg, more preferably 800-1200 mg, even more preferably 900-1100 mg, most preferably 1000 mg. Alternatively, the single dose may be mixed with caffeinated soft drinks prior to use.

In one embodiment of the present invention, where the unit dose is a powder composition for dissolution in a soft drink, the powder composition may contain less and/or smaller amounts of an ingredient already present in the soft drink. In these cases, a soft drink may provide the required amount of, for example, caffeine or taurine.

One skilled in the art will appreciate that the amount of any of the mentioned ingredients in the above single dose may vary depending on the molecular weight of the source of the ingredient (eg, salt and/or solvate).

Other optional ingredients.

In addition to the active ingredients mentioned above, the compositions may further contain additional ingredients to improve the organoleptic properties and/or shelf life of the composition, such as flavoring agents, natural flavoring agents, acidity regulators and/or preservatives. Suitable flavoring agents, natural flavoring agents, acidity regulators and/or preservatives, and concentrations necessary to achieve the desired organoleptic properties and shelf life are well known to those skilled in the art.

Thus, in one embodiment of the present invention, the composition or unit dose further contains one or more flavoring agents. Suitable flavoring agents may include, without limitation, geranyl acetate, methyl acetate, methyl propionate, methyl butyrate, ethyl butyrate, isoamyl acetate, pentyl butyrate, octyl butyrate, pentyl pentanoate, octyl acetate, benzyl acetate, methyl anthra

- 12 045187 nilate, geraniol, nerolidol, limonene, menthol, vanillin. Suitable natural flavors may include, but are not limited to, isoamyl acetate (banana), benzaldehyde (cherry), ethyl propionate, methyl anthranilate (grape), limonene (orange), ethyl decadienoate (pear), allyl hexanoate (pineapple), ethyl vanillin (vanilla), methyl salicylate (wintergreen), manzanate (apple), mango, lemon, lime.

The pH value of the aqueous solution of the present invention can be adjusted to the desired value in order to obtain the desired balance between organoleptic properties and shelf life of the compositions. The pH value can be adjusted by adding acids or bases (i.e. acidity regulators) to achieve the desired pH value. As such, any physiologically acceptable base or acid can be used to adjust the pH. Suitable acidity regulators may include, but are not limited to, carbon dioxide (CO2), hydrogen carbonate ( _H2CO3 ), sulfuric acid ( _H2SO4 ), hydrochloric acid ( _HCl ), acetic acid (CH3COOH), fumaric acid, lactic acid, citric acid, malic acid acid, glucono-delta-lactone, sodium bicarbonate (NaHCO ₃ ), potassium acetate, sodium acetate, ammonium acetate (NH ₄ CH ₃ COO), calcium acetate (Ca(CH ₃ COO)2), ammonium adipate ((NH ₄ ) ₂ (C ₄ H ₈ (COO) ₂ )), calcium gluconate, Epsom salts (magnesium sulfate), sodium aluminum phosphate, sodium hydroacetate, sodium succinate, trisodium citrate.

Liquid compositions typically have a pH value in the range of 1-7, for example 1.5-5.0, preferably 2.0-4.0, more preferably 2.5-3.5. In a preferred embodiment, the acidity regulator is selected from citric acid and/or trisodium citrate. Often the pH in liquid formulations is maintained using a buffer solution containing any of the above pH adjusters. Depending on the final pH value and buffer capacity, the desired suitable buffer system can be selected. Buffers have a common meaning in the art and have the ability to neutralize the addition of both strong acids and strong bases. Typical preparation of buffers involves dissolving one compound and adjusting the pH with a strong acid or base. Typical buffers used in the context of the present invention include, but are not limited to, carbonate-based buffers (H ₂ CO ₃ /HCO ₃ '/CO ₃ ² '), acetic acid/acetate-based buffers (CH3COOH/ ^CH3COO- ), citric acid-based buffers acid/citrate (C3H ₅ O(COOH) ₃ /C ₃ H ₅ O(COO) ₃ ^3- ), phosphate buffers (H3PO4/H2PO47HPO4 ² 7PO4 ^3- ) and/or tartaric acid/tartrate buffers (HOOC (CHOH) ₂ COOH/h0oC(CHOH) ₂ COO7OOC(CHOH) ₂ COO ^- ).

Suitable antimicrobial agents may include, but are not limited to, sorbic acid (E200), sodium sorbate (E201), potassium sorbate (E202), benzoic acid (E210), sodium benzoate (E211), potassium benzoate (E212), calcium benzoate (E213), ethyl -4-hydroxybenzoate (E214), sodium salt of ethyl 4-hydroxybenzoate (E215), propyl-4-hydroxybenzoate (E216), sodium salt of propyl-4-hydroxybenzoate (E217), methyl 4-hydroxybenzoate (E218), sodium salt of methyl- 4-hydroxybenzoate (E219), sulfur dioxide (E220), sodium sulfite (E221), sodium hydrosulfite (E222), sodium metabisulfite (E223), potassium metabisulfite (E224), potassium sulfite (E225), calcium sulfite (E226), hydrosulfite calcium (E227), potassium nitrite (E249), sodium nitrite (E250), sodium nitrate (E251), potassium nitrate (E252), lactic acid (E270), propionic acid (E280), sodium propionate (E281), calcium propionate ( E282), potassium propionate (E283) or mixtures thereof. In a preferred embodiment, the antimicrobial agent is potassium sorbate (E202) and/or sodium benzoate (E211).

Suitable antioxidants may include, but are not limited to, ascorbic acid (E300), sodium ascorbate (E301), calcium ascorbate (E302), ascorbyl palmitate (E304(i)), ascorbyl stearate (E304(ii)), propyl gallate (E310), octyl gallate (E311), dodecyl gallate (E312), butylated hydroxyanisole (E320), butylated hydroxytoluene (E321) or mixtures thereof. In a preferred embodiment, the antioxidant is calcium ascorbate (E302). The compositions of the present invention may further contain one or more ingredients selected from the group consisting of taurine, caffeine, calcium, or a suitable salt or hydrate of any of these. In the most preferred embodiment of the present invention, the unit dose is a powder composition that is dissolved in a commercial beverage such that no additional ingredients other than the active ingredients are required in the unit dose.

A wide range of physiologically acceptable salts are well known to those skilled in the art. The present invention contemplates the inclusion of any physiologically acceptable salt. As simple, non-limiting examples, cations typically present in suitable salts are selected from alkali metal or alkaline earth metal ions or combinations thereof. Thus, suitable acid salts can be formed by treating the acid with a suitable base (eg NaOH). These salts may include lithium salt (Li⁺), sodium salt (Na⁺), potassium salt (K⁺), magnesium salt (Mg²⁺) or calcium salt (Ca²⁺) with acid or any combination thereof. In addition, suitable base salts can be formed by treating the base with a suitable acid (eg, HCl). These salts may include chloride (Cl^-) salt, bromide (Br^-) salt, iodide (G) salt, acetate (CH3COO^-) salt, tosylate (CH3C6H4SO2^-) salt, tartrate (C4H₅O₆7C₄H₄O₆ ²’) salt, sulfate (HSO4^-/SO4^2-) salt, succinate ((CH2)2(COO)2^2-) salt, phosphate (H2PO4^-/HPO4^2-/PO4^3-) salt, nitrate (NO3^-) salt, mesylate (CH3SO₃ ^-) salt, maleate (-O2CCH=CHCOO /HO2CCH=CHCOO^-) salt, malate salt, citrate salt with base, or any combination thereof.

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Application of compositions.

As described above, the present inventors have discovered that the compositions of the present invention can be administered to healthy human subjects in single dose formulations (at relatively low doses), thereby avoiding the disadvantages of continuous treatment while providing the benefits of achieving improved sexuality on demand.

Thus, in a particularly preferred embodiment, the present invention provides a composition or unit dose according to the first aspect above for use in improving the sexual function of a sexually healthy human subject. In particular, the compositions are intended to be administered as needed (not continuously). In addition, the compositions are intended for use in enhancing the sexual function of a sexually healthy woman. In addition, the compositions are intended for use in improving the sexual function of a sexually healthy male. Moreover, the compositions are intended for use in improving sexual function in sexually healthy subjects of both sexes simultaneously.

The present inventors have found that the composition of the present invention improves sexual function in sexually functioning heterosexual men and women, as well as in sexually functioning homosexual women.

In the examples below, the following parameters were tested:

a) assessment of sexual arousal (male and female),

b) emotional satisfaction (man and woman),

c) assessment of sexual intercourse in general (male and female),

d) erection hardness (men only),

e) assessment of decreased sensitivity of the penis (male),

f) IELT score (male),

g) assessment of lubrication release (female),

h) orgasm assessment (female),

i) assessment of discomfort during penetration (female) (example 1 only).

Sexual arousal.

This assessment is a measurement of sexual desire before and during sexual activity. Sexual arousal is a feeling that includes both physical and psychological aspects of sexual arousal. It may include warm or tingling sensations in the genitals, lubrication (wetness), or muscle contractions. A number of physiological reactions arise in the body and in the mind as preparation for sexual intercourse and continue during it. Male arousal will lead to an erection, and the body reacts to female arousal by swelling tissues related to sexual intercourse, such as the nipples, vulva, clitoris, vaginal walls, and secreting vaginal lubrication. Psychological stimuli and physical stimuli such as touch, as well as internal fluctuations in hormone levels, can influence sexual arousal. In example 1, sexual arousal was rated on a scale from 1 to 5, where 1 is very low, 2 is low, 3 is moderate, 4 is high and 5 is very high.

In example 2, the assessment was carried out as follows: 0 - absent, 1 - very low, 2 - normal, 3 - moderately higher than normal, 4 - high, 5 - very high.

Emotional satisfaction.

This assessment is a measurement of the level of emotional intimacy between partners during and after sexual activity. Emotional satisfaction is an important part of relationships and feelings of sexual health and functioning. In Example 1, emotional satisfaction was rated on a scale from 1 to 5, where 1 was moderately dissatisfied, 2 was equally satisfied and dissatisfied, 3 was moderately satisfied, 4 was very satisfied, and 5 was extremely satisfied.

In example 2, the assessment was carried out as follows: 0 - very dissatisfied, 1 - dissatisfied, 2 - normally satisfied, 3 - more than normal satisfied, 4 - very satisfied, 5 - extremely satisfied.

Assessment of sexual intercourse in general.

This score is a measure of the overall assessment of a single sexual experience. In Example 1, overall sexual intercourse was rated on a scale of 1 to 5, where 1 was moderately dissatisfied, 2 was equally satisfied and dissatisfied, 3 was moderately satisfied, 4 was very satisfied, and 5 was extremely satisfied.

In example 2, the assessment was carried out as follows: 0 - very dissatisfied, 1 - dissatisfied, 2 - normally satisfied, 3 - more than normal satisfied, 4 - very satisfied, 5 - extremely satisfied.

Erection Hardness (EHS) (men only).

In Example 1, this assessment is a measurement of the overall hardness of the penis before penetration. Erection hardness was rated on a scale from 1 to 5, where 1 - the penis was larger but not hard, 2 - the penis was hard but not hard enough for penetration, 3 - sex

- 14 045187 howl the penis was hard enough for penetration but not completely hard, 4 - the penis was very hard and rigid, and 5 - the penis was completely hard and completely rigid.

In example 2, the assessment was carried out as follows: 0 - the penis did not increase, 1 - the penis was larger, but was not hard, 2 - the penis was hard, as in the normal state, 3 the penis was harder than in the normal state 4 - the penis was much harder than normal, 5 - the penis was much harder than normal and for a much longer period of time.

Assessment of decreased sensitivity of the penis (men only).

This assessment is a measurement of penile sensitivity during sexual activity. In example 1, the decrease in sensitivity was assessed on a scale from 1 to 5, where 1 - the skin of the glans penis was slightly more sensitive, 2 - the skin of the glans penis was characterized by normal sensitivity, 3 - the skin of the glans penis was characterized by slightly less sensitivity, 4 - the skin of the glans penis the penis was characterized by a moderate decrease in sensitivity, and 5 - the skin of the glans penis was characterized by a clear decrease in sensitivity. In example 2, the assessment was carried out as follows: 0 - the skin of the glans penis was very sensitive, 1 - the skin of the glans penis was slightly more sensitive, 2 the skin of the glans penis was characterized by normal sensitivity, 3 - the skin of the glans penis was characterized by slightly less sensitivity, 4 - the skin of the glans penis was characterized by a clear decrease in sensitivity, 5 - the skin of the glans penis was characterized by a pronounced decrease in sensitivity.

IELT score (men only).

Intravaginal ejaculation latency time (IELT) is the time it takes a man to ejaculate during vaginal penetration. IELT is known to vary not only from person to person, but also from time to time for the same man and tends to decline with age. Research has demonstrated that average IELT decreases with age (ages 18–30: 6.5 min; ages 31–50: 5.4 min; ages over 51: 4.3 min).

The male participants in Examples 1 and 2 recorded IELT during the studies. Assessing lubrication (women only).

This assessment evaluates how difficult/easy it was to achieve lubrication (wetness) during sexual activity or intercourse. In Example 1, lubrication release was rated on a scale of 1 to 5, where 1 is very difficult, 2 is difficult, 3 is normal, 4 is easy, and 5 is very easy.

In example 2, the rating was carried out as follows: 0 - extremely difficult or impossible, 1 very difficult, 2 - normal, 3 - easier than normal, 4 - very easy, 5 - very easy (really moisturizing).

Orgasm assessment (women only).

This assessment assesses a woman's level of orgasm (climax) during sexual activity. In Example 1, orgasm was rated on a scale from 1 to 5, where 1 was difficult to achieve orgasm, 2 was normal, 3 was easy to achieve orgasm, 4 was very easy to achieve orgasm, and 5 was multiple orgasms.

In example 2, the assessment was carried out as follows: 0 - no orgasm, 1 - difficult to achieve orgasm, 2 - normal, 3 - easy to achieve orgasm, 4 - very easy to achieve orgasm, 5 - multiple orgasms.

Assessing discomfort during penetration (women only, example 1 only).

This assessment assesses the level of discomfort or pain women have during or after vaginal penetration. In example 1, discomfort was rated on a scale from 1 to 5, where 1 is high, 2 is moderate, 3 is low, 4 is very low and 5 is absent.

As can be seen in the examples, the compositions were tested on heterosexual couples and homosexual female couples. Notably, the compositions showed highly significant effects in homosexual women, thereby documenting effects in women (without any involvement of a male subject). Thus, in one embodiment of the present invention, the human subject is a woman. In another embodiment of the present invention, the human subject is a heterosexual woman. In yet another embodiment, the human subject is a homosexual woman. Sexual function usually declines with age due to hormonal changes. Thus, in yet another embodiment, the compositions are for use in improving sexual function in a postmenopausal woman. In one embodiment of the present invention, the human subject is a heterosexual male. They did not even test whether the same beneficial effects of the compositions could be expected in homosexual men. Thus, in yet another embodiment of the present invention, the subject is a homosexual man. The composition was effective in heterosexual couples (ie, both men and women) when administered at the same dosage amount (ie, as a single dose). Thus, another advantage of the present invention is that it is a single dose that is suitable for both men and women.

Without being limited by theory, the composition may work in part by increasing NO production

- 15 045187 in situ. Thus, in one embodiment of the present invention, the composition or unit dose according to the first aspect can be used in improving genital blood flow.

The single dose of the present invention is intended to be used as a unit dose. However, a single dose is intended for a sexually healthy subject with a body weight of 50-75 kg. To obtain maximum effect in sexually dysfunctional subjects, as well as in subjects with higher body weights, it is likely necessary to increase doses.

However, in certain cases, more than one single dose may be required to achieve the desired response. Thus, in one embodiment of the present invention, one or more single doses are administered as needed prior to sexual activity. Alternatively, one or more single doses may be administered concomitantly with other known treatments for sexual disorders or dysfunctions. Thus, the composition or unit dose can be combined with one or more other active ingredients. In one embodiment of the present invention, the additional active pharmaceutical ingredient is selected from the group consisting of PDE5 inhibitors, androgens, estrogens and/or progesterones.

The inventors of the present invention have found that a single dose must be administered at a certain period of time before sexual activity to achieve the best clinical result. It is important to note that the single dose compositions of the present invention were found to provide an effect as early as 30 minutes after consumption, and the maximum effect was found to be achieved after only 1-1.5 hours. The effect was found to decline slowly within 24 hours after consumption. Thus, in one embodiment, the composition or single dose is consumed 0.5-12.0 hours before sexual activity, e.g., 0.5-5.5 hours before sexual activity, e.g., 1.0-5 hours, preferably 1.0-4.5 hours, more preferably 1.0-4.0 hours, most preferably 1.0-3.5 hours, for example 1.0-3.0 hours before sexual activity.

Medical use.

A second aspect of the present invention relates to a composition or unit dose according to the first aspect for use as a medicament.

One skilled in the art will appreciate that dosages will likely need to be increased to obtain maximum effect in sexually dysfunctional subjects. Significant increases in dosage (more than twice the as-needed doses described above) may be accompanied by a side effect (primarily stomach problems) that has a negative effect on the subject's sexual functioning as well as the subject's sexual partner. However, adherence to the dosing regimens described herein will provide significant benefits also for sexually dysfunctional subjects.

Thus, more specifically, the second aspect relates to a pharmaceutical composition or unit dose in accordance with the first aspect for use in treating a sexual performance disorder or dysfunction in a human subject.

In a preferred embodiment of the present invention, the disease, disorder or dysfunction associated with sexual activity is selected from endothelial dysfunction, erectile dysfunction, sexual arousal disorder, hypoactive sexual desire disorder (HSDD), sexual aversion disorder (SAD), orgasmic disorder (anorgasmia) , premature ejaculation, dyspareunia, vaginismus and/or sexual dissatisfaction (non-specific).

Aspects of the Present Invention.

1. A composition containing L-arginine and L-citrulline or a physiologically acceptable salt or hydrate of any of them, where the molar ratio of L-arginine:L-citrulline is in the range from 2.2:1 to 10.0:1, preferably from 2.2:1 to 5.8:1, even more preferably 3:1 to 5:1.

2. The composition according to the above aspect 1, where the composition contains one or more proanthocyanidins.

3. A composition according to any of the above aspects, wherein the composition is in a single dose dosage form, and wherein the content of L-arginine or a physiologically acceptable salt or hydrate thereof is at least 4.0 g, for example in the range of 4.0 -10.0 g, preferably 4.0-8.0 g.

4. A composition according to any of the above aspects 1-3, wherein the content of L-arginine or a physiologically acceptable salt or hydrate thereof is at least 4.0 g, for example in the range of 4.0-10.0 g, and the content of L- citrulline or a physiologically acceptable salt or hydrate thereof is at least 1.0 g, for example preferably in the range of 1.0-3.0 g.

5. A composition or unit dose according to any of the above aspects for use in improving sexual function in a sexually healthy human subject.

6. A composition or single dose for use in accordance with the above aspect 5 for use in increasing sexual arousal in a sexually healthy human subject.

7. A composition or unit dose for use in accordance with any of the above aspect 5 or the above aspect 6, where the human subject is a woman.

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8. A composition or single dose for use in accordance with the above aspect 7 for use in enhancing orgasmic function in a sexually healthy female subject.

9. A composition or unit dose for use in accordance with any of the above aspect 5 or the above aspect 6, wherein the human subject is male.

10. A composition or single dose for use in accordance with the above aspect 9 for use in improving IELT in a sexually healthy male subject.

11. A single dose for use in accordance with the above aspects 5-10, where one or more single doses are administered 0.5-5.5 hours before sexual activity, for example, 1.0-5 hours, preferably 1.0- 4.5 hours, more preferably 1.0-4.0 hours, most preferably 1.0-3.5 hours, for example, 1.0-3.0 hours before sexual activity.

12. Use of a pharmaceutical composition or single dose in accordance with any of the above aspects 1-4 to improve sexuality and/or sexual function of a healthy human subject for a period of time of up to 6 hours.

13. A method of improving sexuality and/or sexual function of a healthy human subject over a period of time of up to 6 hours, comprising the steps of administering to the subject one or more single doses in accordance with any of the above aspects 1-4.

14. A pharmaceutical composition or unit dose according to any of the above aspects 1-4 for use as a medicinal product.

15. A pharmaceutical composition or a single dose in accordance with any of the above aspects for use in the treatment of a sexual disorder or dysfunction in a human subject, where the sexual disorder or dysfunction is selected from the group consisting of endothelial dysfunction, erectile dysfunction, impotence, sexual arousal disorder, hypoactive sexual desire disorder (HSDD), sexual aversion disorder (SAD), orgasmic disorder (anorgasmia), premature ejaculation, dyspareunia, vaginismus and/or sexual dissatisfaction (non-specific).

The following figures and examples are presented below to illustrate the present invention. They are intended to be illustrative and should not be construed as limiting in any way.

Examples

General.

Organization of clinical trials.

In Example 1 below, a double-blind, placebo-controlled clinical trial of the composition of the present invention was conducted. Two treatment groups were formed, consisting of 10 heterosexual couples and 10 homosexual couples (women). Each couple in each treatment group received six sets of bottles (labeled A-F) containing either the active powder mixture (3 sets of bottles) or the placebo mixture (3 sets of bottles) and instructions for obtaining the test drink. The color, taste and smell of the test and placebo drinks were almost identical. Couples were asked to choose two bottles with the same label for consumption before sexual activity and then rate the sexual act.

The treatment bottles contained 12 grams of a powdered mixture containing 500 mg vitamin C (as calcium ascorbic acid), 200 IU vitamin E (as D-alphatocopheryl acetate), 400 mcg folic acid, 60 mg calcium, 10 mg alpha lipoic acid, 6 g L-arginine, 1.5 g L-citrulline, 1000 mg L-taurine, 100 mg caffeine and 80 mg Pycnogenol®, with the remainder of the composition being sugar.

Placebo bottles contained 12 grams of a powdered mixture containing 500 mg vitamin C (as calcium ascorbic acid), 200 IU vitamin E (as D-alpha tocopheryl acetate), 400 mcg folic acid, 60 mg calcium, 10 mg alpha lipoic acid, 0.5 g L-arginine, 1000 mg L-taurine and 100 mg caffeine, with the remainder of the composition being sugar.

The appearance of the test mixtures and placebo mixtures was identical. L-arginine is characterized by an undesirable taste and odor. Due to the presence of a small amount of L-arginine in the placebo composition, the taste and odor of the test mixtures and the placebo mixtures were (almost) identical and indistinguishable after mixing with the corresponding soft drink.

In Example 2 below, a double-blind clinical trial was conducted on the composition of the present invention and reference compositions containing varying amounts of active ingredients. Three treatment groups were formed, consisting of 2 heterosexual couples and 2 homosexual couples (women). Each couple in each treatment group tested 3 different compositions. All couples received six sets of vials containing either the active powder formula (all couples received 2 sets of vials labeled A) or the reference/treatment formula (each couple received 2*2 sets of reference/treatment vials labeled B-G respectively), and instructions for obtaining the test drink. The color, taste and smell of the test drinks and the reference drinks were identical. Couples were asked to choose two bottles with the same label for consumption before sexual activity and then rate the sexual act.

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Treatment bottles labeled A contained 6 g L-arginine, 1.5 g L-citrulline and 80 mg Pycnogenol®, as well as a supplement mixture containing: 500 mg Vitamin C (as calcium ascorbic acid), 200 IU Vitamin E (as D-alpha tocopheryl acetate), 400 mcg folic acid, 60 mg calcium, 10 mg alpha lipoic acid, 1000 mg L-taurine and 100 mg caffeine.

Reference bottles labeled B contained 6 g L-arginine, 1.5 g L-citrulline, and a supplement blend containing: 500 mg vitamin C (as calcium salt of ascorbic acid), 200 IU vitamin E (as D-alpha -tocopheryl acetate), 400 mcg folic acid, 60 mg calcium, 10 mg alpha lipoic acid, 1000 mg L-taurine and 100 mg caffeine. These compositions lacked the source of proanthocyanidins Pycnogenol® compared to vials A.

Label C reference bottles contained 6 g L-arginine and 80 mg Pycnogenol®, plus a supplement mixture containing: 500 mg Vitamin C (as calcium ascorbic acid), 200 IU Vitamin E (as D-alpha tocopheryl acetate) , 400 mcg folic acid, 60 mg calcium, 10 mg alpha lipoic acid, 1000 mg L-taurine and 100 mg caffeine. These compositions lacked citrulline compared to vials A.

Treatment vials (compositions of the present invention) labeled D contained 6 g L-arginine, 2.0 g L-citrulline and 80 mg Pycnogenol®, as well as a supplement mixture containing: 500 mg Vitamin C (as calcium salt ascorbic acid), 200 IU vitamin E (as D-alphatocopheryl acetate), 400 mcg folic acid, 60 mg calcium, 10 mg alpha lipoic acid, 1000 mg L-taurine and 100 mg caffeine. These formulations contained slightly higher amounts of citrulline compared to vials A.

Reference bottles labeled E contained 7.5 g of L-citrulline and 80 mg of Pycnogenol®, as well as a supplement mixture containing: 500 mg of vitamin C (as calcium salt of ascorbic acid), 200 IU of vitamin E (as D-alpha- tocopheryl acetate), 400 mcg folic acid, 60 mg calcium, 10 mg alpha lipoic acid, 1000 mg L-taurine and 100 mg caffeine. These compositions contained a total amount of citrulline that was identical to the total amount of arginine + citrulline in the A bottles.

Reference bottles labeled F contained 3 g L-arginine, 1.5 g L-citrulline and 80 mg Pycnogenol®, as well as a supplement mixture containing: 500 mg vitamin C (as calcium salt of ascorbic acid), 200 IU vitamin E ( as D-alpha tocopheryl acetate), 400 micrograms (mcg) of folic acid, 60 mg calcium, 10 mg alpha lipoic acid, 1000 mg L-taurine and 100 mg caffeine. These compositions contained a reduced amount of arginine compared to vials A.

Reference bottles labeled G contained 3 g L-arginine, 3.5 g L-citrulline and 80 mg Pycnogenol®, as well as a supplement mixture containing: 500 mg vitamin C (as calcium salt of ascorbic acid), 200 IU vitamin E ( as D-alpha tocopheryl acetate), 400 micrograms (mcg) of folic acid, 60 mg calcium, 10 mg alpha lipoic acid, 1000 mg L-taurine and 100 mg caffeine. These compositions contained reduced amounts of arginine. These compositions contained a reduced amount of arginine and an increased amount of citrulline. The total amount of citrulline + arginine, which was identical to the total amount of arginine + citrulline in bottles A with different arginine:citrulline ratios.

The color, taste and smell of bottles A-G were almost identical.

Homosexual and heterosexual women were asked to rate sexual arousal, rate lubrication, rate orgasm, rate emotional satisfaction, and rate overall sexual performance on a general scale of 1 to 5 (Sample 1) or 0 to 5 (Sample 2).

Heterosexual men were asked to rate sexual arousal, rate emotional satisfaction, rate sexual intercourse in general, rate erection hardness, rate decrease in penile sensation on a scale of 1 to 5 (Sample 1) or 0 to 5 (Sample 2), and complete an IELT assessment.

The study was carried out under the supervision of a physician (researcher), who was not informed about the identity of the set of bottles or the contents of the tested mixtures. Testing was conducted with confidentiality for both the participants and the researcher.

Pairs received the instructions listed below.

Instructions.

1) Schedule a sexual intercourse test/event.

Schedule a sexual intercourse event. Initiate the test procedure only if you have reasonable grounds to believe that other conditions are favorable for sexual arousal.

Choose 2 bottles with the same label. You can choose any label.

2) Obtaining the test drink.

Immediately before consumption, add a soft drink (lemonade) to the test bottles (approx. 250 ml) and mix with the dry powder by gently shaking the test bottle until all the dry powder is dissolved (this may take a few minutes. It is important that the material is completely dissolved in the test bottle). bottle) to obtain the test drink. Pay attention to the label of the bottle, as well as the time and date of consumption of the tested drink in the attached questionnaire.

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3) Consumption of the test drink.

Drink one test drink per subject at least 1 hour, preferably 2-3 hours and no more than 5 hours before the planned sexual intercourse event. Please consume the test beverage at least one hour before consuming a low-fat meal or, alternatively, at least two hours after consuming a low-fat meal.

4) Sexual intercourse.

Perform sexual intercourse at least 1 hour, preferably 2-3 hours and no more than 5 hours after consuming the test drink.

5) Questionnaire.

After sexual intercourse (preferably immediately after sexual intercourse), please answer the questions in the questionnaire by filling out the attached data registration form.

6) Repeat the procedure.

Repeat the above procedure 6 times (until all vials are consumed). Each sexual event should be separated by at least two days without sexual activity. Please answer the questionnaire after each sexual encounter.

All subjects tested identified their sexual functioning as normal (no sexual dysfunction) prior to the study.

Example 1a. Results for heterosexual men.

In Example 1, a paired t test was used to compare the mean scores of the treatment groups (heterosexual men, heterosexual women, or homosexual women) with the placebo groups (heterosexual men, heterosexual women, or homosexual women).

Paired t-test. Is there a difference between the placebo group and the treatment group according to the various assessments?

Null hypothesis μ _D = 0.

Alternative hypothesis μ _D > 0.

Significance level α = 0.05, t = 1.833 with α = 0.05 and degrees of freedom = 9.

D t =----— _ s _D /Vn where D and S _D ² are given as follows:

and Di=Xi-Yi.

Assessing sexual arousal.

Conclusion: The results show an average improvement of 1.43 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests Χ-Υ 1 (MJ) 3.00 5.00 2.00 2 (DL) 3.00 5.00 2.00 3 (JR) 3.00 3.00 0.00 4 (AM) 3.67 5.00 1.33 5 (TM) 3.00 5.00 2.00 6 (MS) 2.67 5.00 2.33 7 (NE) 3.67 5.00 1.33 8 (RH) 3.00 3.00 0.00 9 (TR) 3.67 5.00 1.33 10 (MW) 3.00 5.00 2.00 SUM (X-Y) 14.3 D (average difference) 1.43 1.14 t-value 2.98 t-value > 1.833 Significant difference

Assessment of emotional satisfaction.

Conclusion: The average improvement is 1.00 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests X-Y 1 (MJ) 3.00 4.00 1.00 2 (DL) 3.00 4.00 1.00 3 (JR) 2.00 3.00 1.00 4 (AM) 3.33 4.00 0.67 5 (TM) 2.67 4.00 1.33 6 (MS) 2.33 4.00 1.67 7 (NE) 3.00 4.00 1.00 8 (RH) 2.67 3.00 0.33 9 (TR) 3.00 4.00 1.00 10 (MW) 3.00 4.00 1.00 SUM (X-Y) 10.0 D (average difference) 1.00 _sD 0.60 t-value 5.37 t-value > 1.833 Significant difference

Assessment of sexual intercourse in general.

Conclusion: The results show an average improvement of 1.00 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests Χ-Υ 1 (MJ) 3.00 4.00 1.00 2(DL) 3.00 4.00 1.00 3 (JR) 2.00 3.00 1.00 4 (AM) 3.33 4.00 0.67 5 (TM) 2.67 4.00 1.33 6 (MS) 2.33 4.00 1.67 7 (NE) 3.00 4.00 1.00 8 (RH) 2.67 3.00 0.33 9 (TR) 3.00 4.00 1.00 10 (MW) 3.00 4.00 1.00 SUM (X-Y) 10.0 D (average difference) 1.00 ^S D 0.59 t-value 5.37 t-value > 1.833 Significant difference

Evaluating erection hardness.

Conclusion: The results show an average improvement of 0.73 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score (X) Average of 3 tests Χ-Υ 1 (MJ) 3.00 4.00 1.00 2 (DL) 3.00 4.00 1.00 3 (JR) 3.00 3.00 0.00 4 (AM) 3.33 4.00 0.67 5 (TM) 3.00 4.00 1.00 6 (MS) 3.00 4.00 1.00 7 (NE) 3.33 4.00 0.67 8 (RH) 3.00 3.00 0.00 9 (TR) 3.33 4.00 0.67 10 (MW) 3.00 4.33 0.67 SUM (X-Y) 7.34 D (average difference) 0.73 _sD 0.63 t-value 3.37 t-value > 1.833 Significant difference

Assessment of decreased sensitivity of the penis.

Conclusion: The results show an average improvement of 1.83 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests Χ-Υ 1 (MJ) 2.00 4.00 2.00 2(DL) 1.67 4.00 2.33 3(JR) 1.00 1.00 0.00 4 (AM) 2.00 4.00 2.00 5 (TM) 1.67 4.00 2.33 6 (MS) 1.00 4.00 3.00 7 (NE) 2.33 4.00 1.67 8 (RH) 1.33 2.00 0.67 9 (TR) 2.67 4.00 1.33 10 (MW) 1.00 4.00 3.00 SUM (X-Y) 18.3 D (average difference) 1.83 _sD 1.39 t-value 4.16 t-value > 1.833 Significant difference

IELT Score.

IELT is known to vary not only from person to person, but also from time to time for the same man and tends to decline with age. Studies have demonstrated that average IELT decreases with age (18-30: 6.5 minutes, 31-50: 5.4 minutes, over 51: 4.3 minutes). The average IELT for all participants was 5.4 minutes. Some medications, such as selective serotonin reuptake inhibitors (SSRIs), affect IELT.

Conclusion: the tested composition shows an average improvement of 236.8 s, which is statistically significant (P < 0.05).

Detailed results.______________________________________________________________

Individual Placebo (sec) (Υ) Average of 3 tests Heal (sec) (X) Average of 3 tests Χ-Υ 1 (MJ) 387 784 397

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2 (DL) 373 775 402 3 (JR) 367 361 -6 4 (AM) 484 728 244 5 (TM) 345 680 335 6 (MS) 339 686 347 7 (NE) 447 693 246 8 (RH) 289 299 10 9 (TR) 381 579 198 10 (MW) 386 581 195 SUM (X-Y) 2368 D (average difference) 236.8 _sD 170.8 t-value 4.38 t-value > 1.833 Significant difference

Example 1b. Results for heterosexual women.

Assessing sexual arousal.

Sexual arousal (also sexual desire) is the arousal of sexual desire during or in anticipation of sexual activity. A number of physiological reactions arise in the body and in the mind as preparation for sexual intercourse and continue during it. Male arousal will lead to an erection, and the body reacts to female arousal by swelling tissues related to sexual intercourse, such as the nipples, vulva, clitoris, vaginal walls, and secreting vaginal lubrication. Psychological stimuli and physical stimuli such as touch, as well as internal fluctuations in hormone levels, can influence sexual arousal.

Sexual arousal has several stages and may not lead to any actual sexual activity other than psychological arousal and accompanying physiological changes. With sufficient sexual stimulation, sexual arousal in humans culminates in orgasm. This can also be achieved for arousal as such, even in the absence of orgasm.

Conclusion: The results show an average improvement of 1.3 points (on a scale of 1 to 5), which is statistically significant (P < 0.05). 2 women (LR and HN) (=80%) were considered non-responders. KA is defined as the average value for the responder.

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Detailed results

Individual Placebo score (Y) Average of 3 tests Treatment Score (X) Average of 3 tests Χ-Υ 1(LP) 3.00 5.00 2.00 2 (IM) 3.67 5.00 1.33 3 (SR) 3.00 5.00 2.00 4 (BL) 3.33 5.00 1.67 5 (DS) 3.33 5.00 1.67 6 (KA) 2.00 2.67 0.67 7 (MR) 2.67 5.00 2.33 8 (TC) 3.67 5.00 1.33 9(LR) 3.00 3.00 0.00 10 (HN) 1.00 1.00 0.00 SUM (X-Y) 13.0 D (average difference) 1.30 _sD 0.55 t-value 7.48 t-value > 1.833 Significant difference

Evaluation of lubricant release.

Conclusion: The results show an average improvement of 1.3 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests X-Y 1(LP) 3.00 5.00 2.00 2 (IM) 3.67 5.00 1.33 3 (SR) 3.00 5.00 2.00

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4(BL) 3.33 5.00 1.67 5(DS) 3.33 5.00 1.67 6 (KA) 2.33 3.00 0.67 7 (MR) 2.67 5.00 2.33 8 (TS) 3.67 5.00 1.33 9(LR) 2.33 3.00 0.67 10 (HN) 1.00 1.00 0.00 SUM (X-Y) 13.7 D (average difference) 1.37 $D 0.56 t-value 7.68 t-value > 1.833 Significant difference

Orgasm assessment.

Conclusion: The results show an average improvement of 1.6 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests Χ-Υ 1(LP) 2.00 4.67 2.67 2 (IM) 2.67 5.00 2.33 3 (SR) 2.00 4.00 2.00 4 (BL) 2.67 5.00 2.33 5 (DS) 2.00 4.00 2.00 6 (KA) 1.33 2.00 0.67 7 (MR) 1.67 4.00 2.33 8 (TC) 2.67 4.00 1.33 9(LR) 1.33 2.00 0.67 10 (HN) 1.00 1.00 0.00 SUM (X-Y) 16.3 D (average difference) 1.63 _sD 0.69 t-value 7.50 t-value > 1.833 Significant difference

Assessment of emotional satisfaction.

Conclusion: The results show an average improvement of 0.9 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests Χ-Υ 1(LP) 3.00 4.00 1.00 2 (IM) 3.33 4.00 0.67 3 (SR) 3.00 4.00 1.00 4 (BL) 3.00 4.00 1.00 5 (DS) 2.67 4.00 1.33 6 (KA) 2.33 3.00 0.67 7 (MR) 2.67 4.00 1.33 8 (TC) 3.00 4.00 1.00 9(LR) 2.33 3.00 0.67 10 (HN) 1.00 2.00 1.00 SUM (X-Y) 9.67 D (average difference) 0.97 ^S D 0.46 t-value 6.67 t-value > 1.833 Significant difference

Assessing discomfort during penetration.

Conclusion: The results show an average improvement of 0.9 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests Χ-Υ 1(LP) 4.00 5.00 1.00 2 (IM) 4.33 5.00 0.67 3(SR) 4.00 5.00 1.00 4 (BL) 3.67 5.00 1.33 5 (DS) 3.67 5.00 1.33 6 (KA) 3.33 4.00 0.67 7 (MR) 3.67 5.00 1.33 8 (TC) 4.00 5.00 1.00 9(LR) 3.00 4.00 1.00 10 (HN) 2.00 2.00 0.00 SUM (X-Y) 9.33 D (average difference) 0.93 S _D 0.42 t-value 6.94 t-value > 1.833 Significant difference

Assessment of sexual intercourse in general.

Conclusion: The results show an average improvement of 0.9 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests Χ-Υ 1(LP) 3.00 4.00 1.00 2 (IM) 3.00 4.00 1.00 3 (SR) 3.00 4.00 1.00 4 (BL) 3.00 4.00 1.00 5 (DS) 2.67 4.00 1.33 6 (KA) 2.33 3.00 0.67 7 (MR) 2.67 4.00 1.33 8 (TC) 3.00 4.00 1.00 9(LR) 2.33 3.00 0.67 10 (HN) 1.00 2.00 1.00 SUM (X-Y) 10.00 D (average difference) 1.0 _sD 0.44 t-value 7.12 t-value > 1.833 Significant difference

Example 1c. Results for homosexual women.

Assessing sexual arousal.

Conclusion: The results show an average improvement of 1.6 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

Detailed results.__________________________________________________________

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests X-Y 1(KL) 3.67 5.00 1.33 2 (LN) 3.00 5.00 2.00 3 (CF) 2.00 5.00 3.00

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4 (EM) 3.00 5.00 2.00 5 (JS) 3.00 3.00 0.00 6 (FW) 2.67 5.00 2.33 7 (MV) 3.00 3.00 0.00 8 (EP) 3.67 5.00 1.33 9 (AS) 3.00 5.00 2.00 10 (VT) 3.00 5.00 2.00 SUM (X-Y) 16.0 D (average difference) 1.60 _sD 1.33 t-value 3.78 t-value > 1.833 Significant difference

Evaluation of lubricant release.

Conclusion: The results show an average improvement of 1.5 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

Detailed results.__________________________________________________________

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests X-Y 1(KL) 3.67 5.00 1.33

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2 (LN) 3.00 5.00 2.00 3 (CF) 2.33 5.00 2.67 4 (EM) 3.00 5.00 2.00 5 (JS) 3.00 3.00 0.00 6 (FW) 2.67 5.00 2.33 7 (MV) 3.67 3.00 -0.67 8 (EP) 3.67 5.00 1.33 9 (AS) 3.00 5.00 2.00 10 (VT) 3.00 5.00 2.00 SUM (X-Y) 15.0 D (average difference) 1.50 _sD 1.40 t-value 3.39 t-value > 1.833 Significant difference

Orgasm assessment.

Conclusion: The results show an average improvement of 1.9 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Treatment Score(X) Χ-Υ Average of 3 tests Average of 3 tests 1(KL) 2.67 4.00 1.33 2 (LN) 3.00 5.00 2.00 3(CF) 1.33 4.00 2.67 4 (EM) 2.00 5.00 3.00 5 (JS) 2.00 2.00 0.00 6 (FW) 2.00 4.00 2.00 7 (MB) 2.00 2.00 0.00 8 (EP) 2.67 5.00 2.33 9 (AS) 2.00 4.00 2.00 10 (VT) 2.00 4.67 2.67 SUM (X-Y) 18.0 D (average difference) 1.80 _sD 1.51 t-value 3.78 t-value > 1.833 Significant difference

Assessment of emotional satisfaction.

Conclusion: The results show an average improvement of 1.1 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests Χ-Υ 1(KL) 3.33 4.00 0.67 2 (LN) 3.00 4.00 1.00 3 (CF) 2.33 4.00 1.67 4 (EM) 3.00 4.00 1.00 5 (JS) 2.33 3.00 0.67 6 (FW) 2.33 4.00 1.67 7 (MB) 3.00 4.00 1.00 8 (EP) 3.00 4.00 1.00 9 (AS) 2.33 4.00 1.67 10 (VT) 3.00 4.00 1.00 SUM (X-Y) I,4 D (average difference) 1.14 _sD 0.74 t-value 4.88 t-value > 1.833 Significant difference

Assessing discomfort during penetration.

Conclusion: The results show an average improvement of 1.0 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score(X) Average of 3 tests Χ-Υ 1(KL) 3.67 5.00 1.33 2 (LN) 4.00 5.00 1.00 3 (CF) 3.33 5.00 1.67 4 (EM) 4.00 5.00 1.00 5 (JS) 4.00 4.00 0.00 6 (FW) 3.33 5.00 1.67 7 (MB) 4.00 4.00 0.00 8 (EP) 4.33 5.00 0.67 9 (AS) 3.00 5.00 2.00 10 (VT) 4.00 5.00 1.00 SUM (X-Y) 10.3 D (average difference) 1.03 ^S D 0.95 t-value 3.43 t-value > 1.833 Significant difference

Assessment of sexual intercourse in general.

Conclusion: The results show an average improvement of 1.1 points (on a scale of 1 to 5), which is statistically significant (P < 0.05).

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Detailed results.

Individual Placebo score (Y) Average of 3 tests Treatment Score (X) Average of 3 tests Χ-Υ 1(KL) 2.67 4.00 1.33 2 (LN) 2.00 4.00 2.00 3 (CF) 2.33 4.00 1.67 4 (EM) 3.00 4.00 1.00 5 (JS) 3.00 3.00 0.00 6 (FW) 2.33 4.00 1.67 7 (MB) 3.00 3.00 0.00 8 (EP) 3.33 4.00 0.67 9 (AS) 2.67 4.00 1.33 10 (VT) 3.00 4.00 1.00 SUM (X-Y) 10.7 D (average difference) 1.07 _sD 0.87 t-value 3.86 t-value > 1.833 Significant difference

General observations after example 1.

All participants responded positively to the test formulation, and the effect of the test formulation was statistically significantly different from placebo. Approximately 80% of test subjects responded significantly to the test treatment, while approx. 20% of test subjects experienced only minor improvements. These latter participants, although showing a small positive response, were classified as functional non-responders (men (2/10), women (5/20)).

Example 2. Comparison of compositions.

Composition A.

Responders to treatment.

On average approx. 80% of the test subjects in Example 2 responded significantly to treatment with Test Formulation A, while 20% showed only minor improvements. None of the subjects showed a decrease in sexual impressions. These results confirm the conclusions from Example 1. Non-responders to treatment with Formula A also did not respond to treatment with all other formulations.

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Effect.

Responders to treatment Non-responders to treatment % those who responded for treatment Men 5.0 1.0 83% Women (all) 14.0 4.0 78% Heterosexual women 4.0 2.0 67% Homosexual women 19.0 5.0 79%

Without taking into account non-responders, the effect of composition A was very pronounced, as can be seen in the tables below, where the numbers represent the average questionnaire scores for treatment responders.

Men who responded to treatment Composition A Normal Sexual arousal 4.9 2.0 Erection hardness 5.0 2.0 Decreased sensitivity penis 4.8 2.0 Emotional satisfaction 4.6 2.0 Sexual intercourse in general 4.8 2.0 average rating 4.8 2.0 IELT 707.6 (sec) (The average IELT for placebo was 392 in Example 1 tests)

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Heterosexual women who responded to treatment Composition A Normal Sexual arousal 5.0 2.0 Lubricant release 4.8 2.0 Orgasm 4.2 2.0 Emotional satisfaction 4.7 2.0 Sexual intercourse in general 4.7 2.0 average rating 4.7 2.0 Homosexual women who responded to treatment Composition A Normal Sexual arousal 4.9 2.0 Lubricant release 4.8 2.0 Orgasm 4.6 2.0 Emotional satisfaction 4.9 2.0 Sexual intercourse in general 4.8 2.0 average rating 4.8 2.0

Composition (formula) A compared to other compositions.

Comparison of formulations average rating Men Women (all) Heterosexual women Composition A 4.8 4.9 4.8 4.7 Comp. IN 3.8 4.0 3.7 3.6 Comp. WITH 3.1 z, z 3.1 3.3 Comp. D 4.7 4.9 4.7 4.5 Comp. E h,o h,o h,o h,o Comp. F 2.9 h,o 2.9 h,o Comp. G 2.9 2.9 3.0 3.0

In the case of responders, the result demonstrates that all formulations are significantly better than normal levels, i.e. that all formulations are effective. However, formulas A and D are better than formula B, and formulas B are better than formulas C, E, F and G.

Comparison of Formula A with Formulas E, F and G demonstrates that the presence of significant amounts of arginine (at least 4.0 g) is advantageous and that the effect thus obtained cannot be replaced by increasing amounts of citrulline.

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Comparison of Formula A with Formula C demonstrates that the presence of citrulline (at least 1.0 g) is preferred and that the effect thus obtained cannot be replaced by increasing amounts of arginine.

Comparison of Formula A with Formula B demonstrates that the presence of proanthocyanidins is highly advantageous.

Comparison of Formula A with Formula D demonstrates that increasing the amount of citrulline (to at least 2.0 g) does not lead to a significantly better effect.

Taken together, these results demonstrate that the presence of both arginine and citrulline in effective formulations is preferred, with arginine present in excess relative to citrulline; arginine should preferably be present in an amount of at least 4 g, preferably 6 g; citrulline should preferably be present in an amount of at least 1 g, preferably 1.5 g; preferably proanthocyanidins should be present (the amount of which can be reduced since this ingredient is considered necessary only as a catalyst).

Primary data.

The tables below show the results of the test in example 2 (in parentheses the number of the tested couple, gender, initials, gender of the partner are shown). Test subject (1, M, BG, F), therefore of test pair 1, male, initials BG, and his partner is female).

Test couple (1, M, BG, F) A A IN IN E E N N Assessing sexual arousal 5 5 4 4 3 3 2 2 IELT (sec.) 688 701 612 619 402 415 Erection hardness 5 5 4 4 3 3 2 2 Decline penile sensitivity 5 5 4 4 3 3 2 2 Emotional satisfaction 5 5 4 4 3 3 2 2 Sexual intercourse in 5 5 4 4 3 3 2 2

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(7, F, NS, F) Sexual assessment 5 5 4 4 3 3 2 2 excitement Allocation Evaluation lubricants 5 5 4 4 3 3 2 2 Orgasm rating 5 5 3 3 3 3 2 2 Emotional satisfaction 5 5 4 4 4 3 2 2 Sexual intercourse in in general 5 5 3 4 3 3 2 2 (8, F, AN, F) Assessing sexual arousal 5 5 5 4 2 3 2 2 Allocation Evaluation lubricants 5 5 4 3 3 3 2 2 Orgasm rating 5 4 3 4 3 3 2 2 Emotional satisfaction 5 5 4 3 2 3 2 2 Sexual intercourse in in general 5 5 4 4 3 3 2 2 (8, F, CW, F) Assessing sexual arousal 4 5 4 4 3 3 2 2 Allocation Evaluation 5 5 3 4 3 3 2 2 lubricants Orgasm rating 4 4 4 3 3 3 2 2 Emotional satisfaction 4 5 4 4 3 3 2 2 Sexual intercourse in in general 4 5 4 4 3 3 2 2

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Test couple (3, M, AS, F) A A WITH WITH F F N N Assessing sexual arousal 5 5 4 4 3 3 2 2 IELT (sec.) 766 759 492 504 436 424 Erection hardness 5 5 4 4 3 3 2 2 Decline penile sensitivity 5 5 3 4 3 3 2 2 Emotional satisfaction 5 5 3 4 3 3 2 2

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Sexual intercourse in in general 5 5 3 3 3 3 2 2 (3, F, SG, M)) Assessing sexual arousal 5 5 3 4 3 3 2 2 Allocation Evaluation lubricants 4 5 4 4 3 3 2 2 Orgasm rating 4 5 3 3 3 3 2 2 Emotional satisfaction 5 5 3 3 3 3 2 2 Sexual intercourse in in general 5 5 3 3 3 3 2 2 (4, M, MN, F) Assessing sexual arousal 5 5 3 3 3 3 2 2 IELT (sec.) 709 728 457 444 405 426 Erection hardness 5 5 3 3 3 3 2 2 Decline penile sensitivity 4 5 3 3 3 3 2 2 Emotional satisfaction 4 4 3 3 3 3 2 2

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(9, F, MK, F) Assessing sexual arousal 5 5 3 3 3 3 2 2 Allocation Evaluation lubricants 5 5 3 2 3 3 2 2 Orgasm rating 5 5 3 3 3 3 2 2 Emotional satisfaction 5 4 2 3 3 2 2 2 Sexual intercourse in in general 4 4 2 3 3 2 2 2 (10, F, JW, F) Assessing sexual arousal 4 5 3 3 3 3 2 2 Allocation Evaluation lubricants 5 5 3 4 2 3 2 2 Orgasm rating 5 5 3 3 3 2 2 2 Emotional satisfaction 5 5 3 4 3 3 2 2 Sexual intercourse in in general 5 5 3 3 3 3 2 2 (10, F, TC, F) Grade 5 5 3 4 4 3 2 2 sexual arousal Allocation Evaluation lubricants 5 5 3 3 3 3 2 2 Orgasm rating 4 5 2 3 3 3 2 2 Emotional satisfaction 5 5 3 4 3 3 2 2 Sexual intercourse in in general 5 5 3 3 3 3 2 2

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Test couple (5, M, JC, F) A A D D G G Ν Ν Assessing sexual arousal 5 4 5 5 3 3 2 2 IELT (sec.) 685 681 694 699 451 443 Erection hardness 5 5 5 5 3 3 2 2 Decline penile sensitivity 5 5 5 5 2 3 2 2 Emotional satisfaction 5 5 5 5 3 3 2 2 Sexual intercourse in in general 5 5 5 5 3 3 2 2 (5, F, ML, M)) Assessing sexual arousal 4 5 5 4 3 3 2 2 Allocation Evaluation lubricants 4 5 5 4 3 3 2 2 Orgasm rating 4 5 4 4 β 3 2 2 Emotional satisfaction 4 5 5 5 3 3 2 2 Sexual intercourse in 4 5 5 4 3 3 2 2

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A paired t-test was calculated.

The present inventors interpret pD = 0 to indicate that the average improvement for the two formulations is the same, and pD > 0 to indicate that the average response to the INXO formulation is greater than to the comparison formulation.

Null hypothesis test But: pD = pD, ₀ is based on the relationship _t _ p - Up _ S _D / Vn where D and SD ² are given as follows:

and Di= Xi-Yi for i = 1, 2, 3..., n.

1. Null hypothesis: p _D = 0, alternative hypothesis: p D > 0.

2. Level of significance: α.

3. Criterion: reject the null hypothesis if t is greater than the value of ta for v degrees of freedom (n-1).

Comparison of formulation A with formulation B (Inxo with formulation without pycnogenol).

The average score of INXO and Formulation B was calculated based on individual scores on the Sexual Arousal Scale, Emotional Satisfaction Scale, Overall Sexual Activity Scale, Erection Hardness Scale, and Penile Sensitivity Scale for Men, and the average score based on individual scores on the Sexual Intercourse Scale. arousal scale, emotional satisfaction scale, overall sexual intercourse scale, lubrication scale, discomfort during penetration scale and orgasm scale for women.

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Detailed results.

Individual average rating Composition A (Xi) average rating Composition B (Yi) Xi-Yi 1(BG) 5.0 4.0 to 2 (HG) 4.8 3.8 1.0 3 (DA) 2.0 2.0 0 4 (SH) 4.4 z, z 1.1 5 (EV) 4.8 3.8 ι,ο 6 (NS) 5.0 3.7 1.3 7 (AH) 4.9 3.8 1.1 8 (CW) 4.5 3.8 0.7 SUM (X-Y) 7.2 D (average difference) 0.9 _sD 0.4 t-value 6.4 t-value > 3.449, for α = 0.005 and 7 degrees of freedom. Null hypothesis rejected Conclusion: Significant difference. Composition A is better than composition B with a probability of 99.5%. The chance that a Type I error has occurred and that Formulation A is no better than Formulation B is 0.5%.

Comparison of formulation A with formulation C (Inxo with formulation with 7.5 g arginine).

The average score for INXO and Formulation C was calculated based on individual scores on the Sexual Arousal Scale, Emotional Satisfaction Scale, Overall Intercourse Scale, Erection Hardness Scale, and Penile Sensitivity Scale for Men, and the average score based on individual scale scores. sexual arousal scale, emotional satisfaction scale, overall sexual intercourse scale, lubrication scale, discomfort during penetration scale and orgasm scale for women.

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Detailed results.

Comparison of formulation A with formulation D (Inxo with formulation with additional citrulline).

The average score for INXO and Formulation D was calculated based on individual scores on the Sexual Arousal Scale, Emotional Satisfaction Scale, Overall Intercourse Rating Scale, Erection Hardness Scale, and Penile Sensitivity Scale for Men, and the average score based on individual scale scores. sexual arousal scale, emotional satisfaction scale, overall sexual intercourse scale, lubrication scale, discomfort during penetration scale and orgasm scale for women.

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Detailed results.

Individual average rating Composition D (Xi) average rating Composition A (Yi) Xi-Yi 1(JC) 5.0 4.9 0.1 2 (ML) 4.5 4.5 0 3 (CH) 4.9 4.7 0.2 4 (SN) 2.7 2.2 0.5 5 (CJ) 4.7 4.6 ο,ι 6 (MD) 4.9 4.8 ο,ι 7(LP) 4.6 4.8 -0.2 8 (VH) 2.5 2.5 0 SUM (X-Y) 0.8 D (average difference) ο,ι _sD 0.2 t-value 1.41 t-value > 1.415, for α = 0.10 and 7 degrees of freedom. The null hypothesis cannot be rejected. Conclusion: The difference is insignificant. The present inventors cannot conclude with 90% certainty that Formulation D is better than Formulation A.

Comparison of composition A with composition E (Inxo with composition with 7.5 g of citrulline).

The average score for INXO and Composition E was calculated based on individual scores on the Sexual Arousal Scale, Emotional Satisfaction Scale, Overall Sexual Activity Scale, Erection Hardness Scale, and Penile Sensitivity Scale for Men, and the average score based on individual scores on the Sexual Intercourse Scale. arousal scale, emotional satisfaction scale, overall sexual intercourse scale, lubrication scale, discomfort during penetration scale and orgasm scale for women.

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Detailed results.

Individual average rating Composition A (Xi) average rating Composition E (Xi) Xi-Yi 1 (BG) 5.0 h,o 2 2 (HG) 4.8 h,o 1.8 3 (DA) 2.0 2.0 0 4 (SH) 4.4 h,o 1.4 5 (EV) 4.8 3.1 1.7 6 (NS) 4.8 3.1 1.7 7 (AH) 4.8 2.8 2 8 (CW) 4.4 h,o 1.4 SUM (X-Y) 12 D (average difference) 1.5 ^S D 0.65 t-value 6.5 t-value > 3.499, for α = 0.005 and 7 degrees of freedom. The null hypothesis is rejected. Conclusion: Significant difference. Composition A is better than composition E with a probability of 99.5%. The probability that a Type I error has occurred and that formulation A is no better than formulation E is 0.5%.

Comparison of formulation A with formulation F (Inxo with low arginine formulation).

The average score of INXO and Composition F was calculated based on individual scores on the Sexual Arousal Scale, Emotional Satisfaction Scale, Overall Intercourse Scale, Erection Hardness Scale, and Penile Sensitivity Scale for Men, and the average score based on individual scale scores. sexual arousal scale, emotional satisfaction scale, overall sexual intercourse scale, lubrication scale, discomfort during penetration scale and orgasm scale for women.

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Detailed results.

Individual average rating Composition A (Xi) average rating Composition F (Xi) Xi-Yi 1 (AS) 5.0 h,o 2.0 2 (SG) 4.8 h,o 1.8 3 (ΜΗ) 4.5 h,o 1.5 4 (ΝΜ) 2.3 2.0 o, s 5 (Sun) 2.2 2.0 0.2 6(ΜΚ) 4.6 2.8 1.8 7 (JW) 4.9 2.8 2.1 8 (TS) 4.9 3.1 1.8 SUM (X-Y) 11.5 D (average difference) 1.4 _sD 0.8 t-value 5.4 t-value > 3.499, for a = 0.005 and 7 degrees of freedom. The null hypothesis is rejected. Conclusion: Significant difference. Composition A is better than composition F with a probability of 99.5%. The probability that a Type I error has occurred and that Formulation A is no better than Formulation F is 0.5%.

Comparison of composition A with composition G (Ιηχο with a composition with more citrulline and less arginine).

The average score of INXO and Composition G was calculated based on individual scores on the Sexual Arousal Scale, Emotional Satisfaction Scale, Overall Sexual Activity Scale, Erection Hardness Scale, and Penile Sensitivity Scale for Men, and the average score based on individual scores on the Sexual Intercourse Scale. arousal scale, emotional satisfaction scale, overall sexual intercourse scale, lubrication scale, discomfort during penetration scale and orgasm scale for women.

Claims (7)

Detailed results. Individual average rating Composition A (Xi) average rating Composition G (Xi) Xi-Yi 1(JQ 4.9 2.9 2.0 2 (ML) 4.5 h,o 1.5 3 (CH) 4.7 h,o 1.7 4 (SN) 2.2 2.0 0.2 5 (CJ) 4.6 2.7 1.9 6 (MD) 4.8 3.0 1.8 7(LP) 4.8 3.1 1.7 8 (VH) 2.5 2.0 0.5 SUM (X-Y) from D (mean difference) 1.41 s _D 0.68 t-value 5.9 t-value > 3.499, for a = 0.005 and 7 degrees of freedom. The null hypothesis is rejected. Conclusion: Significant difference. Composition A is better than composition G with a probability of 99.5%. The probability that a Type I error has occurred and that the composition is 0.5%. And no better than composition G, CLAIM 1. Use 0.5-5.5 hours before sexual activity, as necessary, of a composition or single dose containing L-arginine and L-citrulline or a physiologically acceptable salt or hydrate of any of them, where the content of L-arginine or its physiologically acceptable salt or hydrate is at least 4.0 g and the content of L-citrulline or its physiologically acceptable salt or hydrate is at least 1.0 g, where the molar ratio of L-arginine:L-citrulline is in the range of 2.0:1 up to 10.0:1, to improve sexual function in a sexually healthy human subject over a period of up to 6 hours. 2. Use according to claim 1 to increase sexual arousal in a sexually healthy human subject. 3. Use according to any one of claims 1 or 2, wherein the human subject is a woman. 4. Use according to claim 3 to improve orgasmic function in a sexually healthy female subject. 5. Use according to any one of claims 1 or 2, wherein the human subject is male. - 57 045187 6. Use of claim 5 to improve intravaginal ejaculation latency time (IELT) in a sexually healthy male subject. 7. Use according to any one of claims 1 to 6, wherein the composition or single dose is administered over 1.0-5 hours, preferably 1.0-4.5 hours, more preferably 1.0-4.0 hours, most preferably 1 ,0-3.5 hours, for example 1.0-3.0 hours before sexual activity. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2