No donor and dithiolane-containing compositions and their application for improvement of sexual function

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmacology and represents peroral composition, including L-arginine and R-α-lipoic acid in effective amount, where L-arginine is present in molar excess with respect to amount of R-α-lipoic acid present in composition.

EFFECT: invention ensures improvement or treatment of sexual disorders, both in males and females, without risk of side effects.

18 cl, 7 ex

The present invention relates to solid compositions containing the compound, which improves the availability of nitric oxide (NO), NO donor or precursor biosynthesis of nitric oxide or is a direct or indirect agonist NO, and the preferred compound is arginine in combination with dithiolane, preferably in combination with α-lipoic acid as the preferred compounds, and their use to improve sexual function. The composition of the invention contain NO donor or his predecessor in abundance in the calculation of the molar number of components. Compositions are also designed to improve sexual function. First of all, the present invention relates to the use of dithiolane in combination with the NO donor or its precursor for obtaining a medicinal product intended for the treatment of sexual dysfunction.

Sexual function is a major biological and social factors in adult life. She contributes in all spheres of human activity and is associated with the control of individual reproduction. Sexual function compensates for external exposure and stress. Completeness or positive experience in sexual life thus have a positive impact on the functions of other organs and mo is ut in General to improve health. Most people perceive a full sex life, as a determining factor for a positive quality of life.

Sexual health and sexual function may be impaired for various reasons. Perhaps the lack of libido or damage to sexual function. Sexual function in men and women in most cases is different. However, modern methods of treatment or improvement of methods of treatment currently mainly aimed at improving erectile dysfunction in men (ED) and limited to the specified destination.

Since an erection requires a precise sequence of events, ED happens if you violate any of these events. The sequence includes nerve impulse in the brain, spinal cord and the area around the penis and response in muscles, fibrous tissues, veins and arteries in and in the area of the cavernous bodies of the penis.

The most common cause of ED is damage to the nerves, arteries, smooth muscles, and fibrous tissues resulting diseases. A number of diseases, such as diabetes, kidney disease, chronic alcoholism, multiple sclerosis, atherosclerosis, vascular disease and neurological diseases that cause physical erectile dysfunction. ED is observed in 35-50% of men with diabetes.

In addition to the, damage to the nerves and arteries near the penis with surgery (radical operations on prostate and bladder cancer) cause ED. Damage to the penis, spinal cord, prostate, bladder and pelvis leads to the ED in connection with damage to the nerves, smooth muscles, arteries, and fibrous tissues within and in the area of the cavernous bodies of the penis.

In addition, many well-known drugs, such as, for example, medicines for blood pressure, antihistamines, antidepressants, tranquilizers, substances that reduce appetite, and cimetidine (an anti-ulcer drug), as side effects can cause ED.

Experts believe that such physiological factors as stress, anxiety, guilt, depression, low self-esteem and fear of sexual impotence also cause ED. Men whose ED is caused by physical reasons, in most cases experienced the same type of physiological reactions (stress, anxiety, guilt, depression).

Other possible causes are Smoking, which affects blood flow in veins and arteries, and hormonal abnormalities, such as lack of testosterone.

In the clinic ED assessed using the international index erectile the Noah function (International Index of Erectile Function, on a scale IIEF). The scale includes 5 ratings erectile function from 1 (never occurs) to 5 (always). 21-25 points mean lack of erectile function, 16-20 points indicate a low level of erectile function, 11-15 points indicate moderate levels of erectile function and 5-10 points indicate a high level of erectile function.

Female sexual function is assessed using the index of female sexual function (Femal Sexual Function IFSF), on a 9-point scale according to the questionnaire survey. IFSF is more comprehensive assessment of sexual function in comparison with IIEF. The evaluation parameters include discomfort during intercourse, dryness in the vagina, the number of attempted sexual relations, a degree of sexual desire, satisfaction with sexual life and relationship, the feeling of the clitoris and the quality of orgasm.

A common method for the treatment of ED include the use of inhibitors phophodiesterase type 5 (PDE5-I), for example, solifenacin, vardenafil and tadalafil. The mechanism of action is that PDE5-I does not induce an erection, but only enhances it. Such means have an effect only in the case of sexual arousal, as by themselves do not induce sexual arousal. With this type of action of PDE5-I cannot be used for heart or vascular diseases. the first of all these drugs can have severe side effects when used together with nitrate drugs. They can also be used in combination with sexual stimulants types of NO donors (e.g., alkyl nitrate and alkyl nitrites).

Other drugs varied type of action, but with some degree constraints are apomorphine and yohimbine. As a local drug use prostaglandin E1 (alprostadil), which causes an erection when injected into the penis. However, this method of treatment is not appropriate for all patients.

The above medicines contribute to the erection or stimulate it. None of these drugs does not affect any other signs or symptoms of sexual function, primarily the lack of libido or premature ejaculation, and they do not apply to women. Such medicines are not valid even in the case of psychogenic ED.

For decades, α-lipoic acid are used as drugs, food additives and in the form of pharmaceutical compositions. It is used in the form of a racemic mixture, in the form of one enantiomer or mixture of enantiomers (DE 4035442 A1). Also use modified derivatives of lipoic acid (for example, the restored dithiol, lipoamide and their derivatives as described in patent US 6387945 B2, β-lipoic acid, mutellibova acid, bis - and teenolivia acid is one thiosulfonate, sulfonylmethane, desultory, sulfonic acid and other derivatives described in patent EP 089126 A1, derivatives of esters of a-lipoic acid and glycerol, esters, amides and salts and other derivatives. Also use salts and metabolites. For all of these modifications use redox balance, the reactive dithiolane with redox potential -0,325 C. Thus, the remainder dithiolane restores all intracellular redox system and re-used (recycled) in enzymatic and not enzymatic systems in the presence of redox equivalents NADH and NADPH. All molecular derivatives dithiolane exhibit different pharmacodynamic properties depending on the specified mechanism. However, chemical modification affects the metabolism, distribution and the rate of turnover in the redox of recyclization.

Preparations include tablets, capsules, ampoules for injection, solutions and drugs intended for percutaneous, subcutaneous and rectal administration, and formulations for inhalation, separately and in combinations. The described compositions with quick release, controlled release and delayed release. According to the literature dealing with the major data connection is used to treat various conditions and diseases, such as, for example, diabetic neuropathy, liver disease, mushroom poisoning, poisoning by heavy metals, radiation disease, diabetes, hyperlipidemia, skin diseases, migraine, etc. In the treatment of Alzheimer's disease and other conditions used in combination with acetylcholinesterase inhibitors.

In case of temporary fatigue use arginine to normalize cholesterol low density after long-term consumption. It was later suggested its use for the treatment of ED because it is the precursor of NO synthesis. Assume that NO enhances the blood circulation in the penis and thereby improves erectile tension. This action, however, has not yet been confirmed in the clinic. However, for the treatment of ED propose to combine the NO donors or agonists NO, like arginine, with PDE5 inhibitors.

One of the modulators of vascular relaxation is nitric oxide (NO), the so-called endothelial relaxing factor. Based on General assumptions, suppose that all of the antioxidants, as well as dithiolane type α-lipoic acid, have a positive impact on the availability of nitric oxide (NO). When the in vitro experiment one of the reactive oxygen-containing agents, anion superoxide interacts with NO to form peroxynitrite (Du and others). The antioxidant type α-lipoic acid absorbs oxygen free radicals and thereby increases the bioavailability of NO. However, according to other experiments in cellular systems specified the proposed mechanism a significant increase in the bioavailability of NO is not confirmed. In article Liang and Akaike described that α-lipoic acid inhibits NO synthesis in hepatocytes induced by cytokines, the production of NO is reduced in the presence of thiols, including α-lipoic acid (Tabatabaie and others), and reduced production of NO in the proinflammatory stimulation (Guo and others). In conclusion, it was found that the thiols, including α-lipoic acid reduce synthase activity of nitric oxide (NOS). In connection with the proposed derivatives of α-lipoic acid for use as inhibitors of NO-synthase (US patents 6605637, US 2004/00190084 A1). In addition, there were other proposed synthase inhibitors of nitric oxide and of NO synthesis, like arginine, in combination with thiols, including α-lipoic acid (WO 03/028714 A2, WO 00/59448), in connection with a similar mechanism of pharmacological action.

In conclusion, it should be noted that currently there is no rational explanation for the stimulatory effect of α-lipoic acid and dithiolane on the bioavailability of NO in vivo. In contrast, in the prior art it is known inhibitory effect. In this regard, so far not described the use of a mixture of arginine and α-lipoic acid or both components in the comp who stood to improve conditions associated with ED, and there are no data on the additive or synergistic action of both components on the bioavailability of NO. Described only one try to share both compounds in the case of ED to reduce the arginine-dependent side effects (formation of free radicals of oxygen) with the introduction of antioxidan together with carnitine and coenzyme Q₁₀(WO 03/032751).

First of all, are not described in literature joint introduction of arginine and α-lipoic acid to improve overall sexual functions, including functions that are not dependent on nitric oxide. On the contrary, it is proposed to use a combination of antioxidants including α-lipoic acid, only to absorb oxygen radicals formed during the introduction of arginine, as described in the application WO 03/028714, to prevent the arginine-dependent side effects such as pulmonary toxicity.

In the application WO 03/032751 A1 describes a joint use of a salt of carnitine and zinc chloride in a mixture with a solid preparation containing a mixture of arginine, coenzyme Q₁₀and α-lipoic acid in a ratio of 1-3 g, 80-100 mg 20-50 mg, in the treatment of sexual disorders in men (sperm motility and erectile dysfunction). Q₁₀and α-lipoic acid is added to reduce the side effects arginine (free radical formation), and needle improving the pharmacodynamic actions or increase the pharmacodynamic action.

In EP 1273295 A1 describes a combination of ozonized oils with α-lipoic acid and arginine, in which the maximum content of arginine is 25 wt.%. In EP 947194 B1 describes a mixture of arginine with α-lipoic acid, forming a solid salt. The formation of salts of α-lipoic acid and basic amino acids is also described for liquid compositions for injection and infusion DE 3840076 A1. Some patents, such as US 5281722, are related to the release of the enantiomers of α-lipoic acid from a racemic mixture. The formation of a solid salt of R(+)-α-lipoic acid and arginine are described only in equimolar ratio. In DE 4317646 described mixture of α-lipoic acid with alkaline compounds, including arginine, however, the composition of α-lipoic acid is present in excess.

None of these compositions are not suitable for the treatment of sexual dysfunction, since all of these compositions do not contain the combination of components in an appropriate amount and in a desired ratio. To obtain the composition of the desired destination, you cannot use the above recommendations. The described compositions are not suitable for oral administration in liquid form.

Thus, have not proposed a single method for improving or treating sexual dysfunction in both men and women, without the risk of severe side effects. Therefore, at present things is there is an acute need in the composition, you can enter without any risk of severe side effects, and such a composition can be introduced in the form of dietary supplements to improve sexual function in both men and women, as well as drugs for treatment of sexual dysfunction. The composition is preferably in a simple way, most preferably oral way and even more preferable to take liquid with a pleasant taste. This ensures a high degree of consent of the patients course of treatment, especially in older patients. First of all, for the specified group, usually taking other medicines you should avoid the introduction of the above medicines (such inhibitors PDE) for improving sexual function due to the possible negative interaction between two or more medicines.

It has been unexpectedly found that the above problems can be excluded when it is used to improve sexual function composition comprising a combination of a NO donor or his predecessor with arginine as the preferred connection, in combination with dithiolane, with α-lipoic acid as the preferred connection. The compositions of the present invention contain NO donor or his predecessor in molar is the excess in respect of dithiolane. In one embodiment of the present invention the molar amount of arginine exceeds the number of α-lipoic acid 2.1-40, preferably 4-20 times. Compositions suitable for effective treatment of the signs and symptoms of sexual dysfunction.

In one embodiment, the present invention proposes the use of dithiolane in combination with the NO donor or its precursor for obtaining a medicinal product intended for the treatment of sexual dysfunction.

NO donors or precursors or agonists are, for example, endothelin, cytokines, bradykinin, calreticulin, bidabadi, phenolphthalein, organic nitrates and nitrites, including volatile drugs alkylnitrates etc. also Used α-adrenergic blockers such as phentolamine, papaverine and prostaglandin. One of the preferred compounds is arginine. Compounds dithiolane of the present invention are, for example, α-lipoic acid, β-lipoic acid, dihydrolipoic acid, lipoamide, bis - and teenolivia acid, mutellibova acid, 7,8-mitigatedby acid, 7,8-diciannove acid and many others (see US 6387945 B2, EP 089126 A1), and you can also use the preferred precursors, prodrugs of α-lipoic acid and functional agonists glutathione.

Such compositions by us is oedema invention include two components, arginine and α-lipoic acid, provided that NO donor or his predecessor (in this case, arginine) are present in excess, based on the molar amount of dithiolane α-lipoic acid, and the preferred interval quantities of compounds present in the composition ranges from 200 mg to 15 g of arginine and from 25 mg to 1.2 g of α-lipoic acid. The preferred content of arginine ranges from 500 mg to 10 g, and α-lipoic acid from 55 mg to 800 mg, most preferably the content of arginine ranges from 3.5 g to 5 g, and α-lipoic acid 100 mg to 600 mg For the introduction of a specific patient, the total amount of the two compounds and their relative ratio is chosen in accordance with the necessity with regard to pharmacokinetic and pharmacodynamic differences, the patient's condition and the simultaneous use of medicines and nutritional supplements.

Mainly the composition of the present invention include at least the NO donor or his predecessor (inducer of nitric oxide) and ditiolan. The NO donor is preferably a natural amino acid arginine as a precursor of NO synthesis, and ditiolan, natural cofactor α-lipoic acid. More preferably use natural L-form of arginine and natural R(+)-enantiomer of α-lipoic acid. According to the present invention two connection NO donor or resistant" and "ditiolan", may be present in separate compositions, so as to improve sexual function requires the introduction of a combination of the two compounds. New application of the present invention includes an introduction in the form of two separate compositions, and this introduction is preferred in those cases that require individual selection of doses of the two components of compositions for a particular patient.

In a preferred embodiment of the invention the composition of the invention administered orally by the way. Preferred is the introduction of one time per day., but in some specific cases it is preferable to divide the daily dose into several doses.

Usually due to low content dithiolane in composition compared to the NO donor or his predecessor, primarily arginine, in the song you want to add pharmaceutically acceptable salt component and an organic or inorganic acid. Such salts must first add in the liquid compositions, since both compounds, arginine and α-lipoic acid, are characterized by extremely low solubility. Salt should be used to achieve the desired concentration of active components primarily in liquid formulations. However, the same requirements apply to solid oral compositions, if you want to complete and aprosodia dissolution in the intestine. When receiving arginine salts preferably used in such organic acids like aspartic acid, glutamic acid, pyruvic acid, benzoic acid, lactic acid, citric acid, malonic acid, tartaric acid or polyanion, or carboxylic acid. Preferably the acid to obtain the salt of arginine use a stronger acid than α-lipoic acid (PK_and5,3), for example, ascorbic acid, malonic acid, citric acid, etc. Thus, the use of liquid compositions is preferred since it is easy to obtain a solution with a higher desired concentration of active compounds. Extremely unpleasant taste of α-lipoic acid usually limits its oral administration in liquid form, however, the proposed compositions oral administration of the liquid composition becomes possible. This refers also to solid compositions, preferably intended for oral administration, since the solubility of salts of active ingredients increases after injection. The advantage of the compositions of the present invention also lies in the fact that the taste of the compositions is improved by adding a small excess of acid compared to the amount required to compensate alkaline argini the and. However, in terms of stability, compositions with higher content of α-lipoic acid (about 100 mg or more) must contain a slight excess of alkaline components. This excess is provided by adding arginine or preferably another alkaline component, preferably with a higher PK_bsuch as ethanolamine or tromethamine, or organic alkaline compounds.

To obtain the solid dispersible forms, you can use a solid matrix or polyanionic dispersible colloidal gel matrix. In another embodiment, use is also dispersible colloidal Sol to obtain a liquid form. The composition of the invention can be obtained in the form of dosage forms with controlled release. To obtain a standard dosage forms using pharmaceutically acceptable excipients.

In addition to these two components, described in this context, add a suitable connection, such as, for example, vitamins and minerals, intermediate metabolites, carbohydrates, lipids, fatty acids, alcohols, amino acids and peptides pharmaceutical or pharmacological or nutritional purpose or connection to improve the taste or smell.

For solid oral dosage forms total mass of one form is in the range of masses which provide the t easy swallowing. Thus you can enter multiple dosage forms at the same time or several times per day. The total daily dose can easily administered in a single dosage form with a tonic drink or effervescent composition which is dissolved in water before administration. Solid dosage form is dissolved before swallowing and it preferably should disintegrate in the mouth.

The introduction of liquid compositions is facilitated by adding sweeteners, flavorings and dyes. Preferably one dose contained in one standard dosage form. More preferably, both of the compound (donor NO and ditiolan) are contained in one standard dosage form in a fixed ratio. By pre-packaging the possibility of individual dosages of the composition in the distribution of medicines. The liquid composition may contain, for example, 10 g of R(+)-α-lipoic acid as a compound dithiolane, 300 g of arginine as a NO donor, 199,5 g aspartic acid as additional anion for the formation of salts. Compounds are dissolved under stirring in a mixture with 2% sucrose solution in a mixture of water-ethanol, 95:5 wt./wt. in total volume of 5 l, sterile for injection and filtered through a membrane filter with a diameter of 0.2 μm. Portions of 50 ml spill in petlemiewly in aseptic conditions.

In some cases, it is necessary that the two compounds were related to each other not ion, and chemical communication. For this purpose, both the active component connected through functional spacer that links the two components through their reactive residue, for example, amide linkages, ether, thioester or ester bonds.

In the invention are also pharmaceutical or food packaging containing one or more of the respective dosage forms according to the invention. The pack contains instructions for use, which indicates a government Agency or regulatory authority or engaged in the production, distribution, storage and use of pharmaceutical, biological and food products. The package also contains information on the content and composition of packaging on stability, routes of administration, dosing, injection and the appointment of a medicinal product. This information is presented in the insert statement or printed on the package.

With the introduction of the compositions of the present invention for the first time there has been improvement of erectile function with compounds of natural origin and in most cases the normalization function. The combination of donor and NO dithiolane in the specified quantity and the ratio effectivnes cases of ED, even when high doses of arginine or α-lipoic acid does not have a therapeutic effect. Therefore the effect of the proposed combination on ED is synergistic and not associated with a decrease in arginine-dependent side effects caused by thiol. It has been unexpectedly found that the effectiveness of the composition is observed not only in the case of physical ED, but in the case of diagnosed psychogenic ED, and also if there are signs and symptoms of sexual dysfunction, with the exception of ED, such as low libido or reduced ability to orgasm or her absence, reduction or absence of salivation, decrease or absence of erection of the clitoris and excitability and decrease labeling and vaginal filling. It is important to note that the contribution of arginine into effect on sexual function based, as you know, the metabolism of NO. Therefore, any potential combined effect of the limited physical ED. As noted above, it has been unexpectedly found that the effect of the combination of the donor and NO dithiolane not limited to NO-dependent pharmacological properties. The obtained results allow to overcome prejudice in the prior art. It can be assumed that although the present invention is not limited to this assumption that the interactive effect of composition on izopet the tion is partially dependent on the actions of metabolism of nitric oxide. This assumption is supported by data that indicate that not only improves erectile function, and sexual function as a whole, including libido in both men and women. Although the mechanism of the observed clinical action songs not yet fully installed, the positive effect seems to be associated with the specified ratio of the two compounds, which are preferably arginine and α-lipoic acid, and arginine is present in excess.

It should be noted that the composition according to the invention is effective in the treatment for ED, which is not amenable to treatment with PDE5 inhibitors.

In the present invention primarily include:

the composition containing the NO donor or his predecessor and ditiolan in which NO donor or its precursor are present in excess in molar ratio, the above composition in which NO donor or its precursor is arginine, and dithiolane is derived α-lipoic acid,

the above composition in which a derivative of α-lipoic acid is α-lipoic acid,

the above composition, which optionally add the acid, preferably pharmaceutically acceptable acid, such as L-aspartic acid, L-glutamic acid, pyruvic acid, Moloch the I acid, benzoic acid, malonic acid, citric acid, ascorbic acid and the like,

the above composition in which derivatives of α-lipoic acid and/or arginine is used in the form of salts, esters and ethers, amides and other chemical derivatives, and derivative gain due to the formation of chemical bonds or conjugates,

the above composition, which is used in the form of medicines, dietetic foods, food supplements, nutraceuticals or food,

the above composition in liquid form, containing additional anion for the formation of salts in contrast to α-lipoic acid as a counterion for the NO donor or its precursor, which is preferably arginine,

the above composition in liquid form for oral administration, contains additional anion for the formation of salts in contrast to α-lipoic acid as a counterion for the NO donor or its precursor, which is preferably arginine,

the above composition in solid form, containing additional anion for the formation of salts in contrast to α-lipoic acid as a counterion for the NO donor or its precursor, which is preferably arginine,

packaging dosage forms containing the above whom is ositio in solid or liquid form,

packaging dosage forms containing two separate dosage forms which, when the joint introduction of a form described in this context the composition, and in one of the dosage forms you can add additional anion for the formation of a salt,

the application described in this context, the composition for improving sexual function,

the application described in this context, the composition for improving sexual function in men,

the application described in this context, the composition for improving sexual function in women, the use described in this context composition, in which sexual dysfunction is ED,

the application described in this context composition, in which sexual dysfunction is psychogenic ED,

the application described in this context composition, in which sexual dysfunction is physical ED,

the application described in this context composition, in which sexual dysfunction is the loss of libido in men,

the application described in this context composition, in which sexual dysfunction is the loss of libido in women

the application described in this context composition, in which sexual dysfunction is substantiated physical cause,

the application described in this context com is osili, in which sexual dysfunction is justified psychogenic cause,

the application described in this context composition, in which sexual dysfunction is frigidity, inability to achieve orgasm, unacceptably short sexual act in connection with premature ejaculation, no salivation, decrease or absence of clitoral erection or excitability and decrease labeling or vaginal filling

the application described in this context composition for obtaining a medicinal product intended for the treatment of sexual dysfunction,

use for the treatment of the above condition, in which sexual dysfunction is ED,

use for the treatment of the above condition, in which sexual dysfunction is the loss of libido in men or women,

use for the treatment of the above condition, in which sexual dysfunction is caused by physical cause,

use for the treatment of the above condition, in which sexual dysfunction is frigidity,

use for the treatment of the above conditions, which leads to frigidity inability to reach orgasm, use for the treatment of the above condition, in which sexual dysfunction is justified psychogenic cause,

p is the changes to ensure the above condition in men,

use for the treatment of the above condition in women,

use for the treatment of the above condition, in which sexual dysfunction is premature ejaculation,

use for the treatment of the above conditions, in which premature ejaculation leads to unacceptably short sex

used as described above, in which α-lipoic acid and arginine or related compounds administered orally or parenterally in a solid or liquid form,

used as described above, in which α-lipoic acid is used in the form of enantiomer (R(+) or S(-)) or in the form of mixtures of enantiomers, including racemic mixture

used as described above, in which arginine is used in the form of L - or D-isomer or mixtures thereof,

used as described above, in which the dose of the drug that is usually used for the primary treatment of ED, can be reduced, and the main drug is a PDE5 inhibitor, power the speed of blood flow, the erection stimulator, means for hormone replacement therapy

the application described in this context composition for obtaining a medicinal product intended for the treatment of sexual dysfunction, while simultaneously reducing the dose of the drug for the treatment of ED, which reduces poboc the second action, which occurs during primary treatment,

the use of a composition or both components together, as described, in this context, in addition to the main treatment alkyl nitrate, such as volatile alkyl nitrate or other sexual stimulants.

Examples of pharmaceutical compositions

In the following examples 1-4 describe the typical composition of the present invention. Upon receipt of the songs recommended to dissolve salts of lipoic acid or arginine instead of the free acids or bases, especially in the case of natural forms. Excess arginine provides stability and acceptable taste. Water should be sterilized and degassing preferably at 10°C. the type Antioxidants ascorbic acid is used to increase the stability and improve the taste. The add flavorings to mask the residual odor. Complex carbohydrates synthetic or biological origin used for masking an unpleasant taste.

The following examples are provided only to describe individual cases and do not limit the scope of the present invention.

Example 1

the composition is packaged in bottles made of polyethylene terephthalate PET (200 ml), and

stored at 4°C.

Example 2

the composition is Packed in bottles of polyethylene is of terephtalate PET (200 ml), and

stored at 4°C.

Example 3

the composition is packaged in bottles made of polyethylene terephthalate PET (200 ml), and

stored at 4°C.

Example 4

the composition is Packed in 5 bags or processed in 5 effervescent tablets.

Clinical trials

Example 1

Male 37 years experienced within 3 months of worsening dysfunction (decrease in voltage of the penis) and a slight decrease in libido. His condition by IIEF is 9 points. The results of all biochemical analyses and hormones are normal. Doppler echography vessels of the penis is normal. Reaction to shock dose sildenatil is positive, which eliminates the development of organic pathology ED. Introduction sildenatil causes severe facial flushing and discomfort to the patient. After the examination diagnosed with psychogenic ED. Oral administration of 600 mg of α-lipoic acid does not affect the scoring IIEF. 30 minutes before intercourse were introduced 5 g of arginine and 600 mg of α-lipoic acid. After treatment have a normal erection. Assessment in the IIEF scores increased from 9 to 21 points.

Example 2

Male 23 years experienced within one week of deterioration of an erection (started sexual life at the age of 18, regularly performs sexual intercourse twice a week). 3 months later he changed his sexual partner. During the first intercourse with a new partner he experienced sverkhvozbuzhdeniyu. Since the erection deteriorated, and IIEF score dropped to 8 points. Biochemical and hormonelamictal are normal. Diagnosed with psychogenic ED and symptoms of lack of expectations. By oral administration of 4 g of arginine IIEF score is not changed. With the introduction of 1 g of arginine and 600 mg of α-lipoic acid for 30 minutes before sexual intercourse is also not observed any improvement. After increasing the dose to 4 grams of arginine, and 300 mg of α-lipoic acid improved erections. Score IIEF increased from 8 to 12 points. The patient subsequently reduced daily dose of up to 1 g of arginine and 100 mg of α-lipoic acid. Sometimes when needed before sexual intercourse it takes an extra dose of 4 grams of arginine +300 mg α-lipoic acid.

Example 3

Male 35 years experiencing deterioration erection for 7 years. Intercourse carries out only in a certain position. In addition, experiencing premature ejaculation and libido remains not the same level. Score on a scale of IIEF was 11 points. Diagnosed physical ED and premature ejaculation. The patient was administered 600 mg of α-lipoic acid in the form of a single dose of 2 grams of arginine in the form of 4 single doses per day. Improved erections, and the duration of sexual intercourse increased from 1-2 minutes to 7 minutes IIEF Score varies from 11 to 15 points. Then 4 single dose was replaced with a single dose of 10 g of arginine together with α-lipoic acid.

Example 4

Male 44 years (Manager of the firm who suffered mental the cue stress) experienced a decrease in erectile dysfunction and decreased libido in the past 13 years. Morning the reaction persists. Frequency of sex decreased from 3 times a week to 3 times a month. Diagnosed with psychogenic ED and Manager syndrome. With the introduction of a single dose of 200 mg of α-lipoic acid changes are not observed, while increasing the dose to 600 mg of improvement of the patient's condition. However, with the introduction of 200 mg of α-lipoic acid together with 5 g of arginine, there is complete normalization of erection. The IIEF score improved from 9 to 24 points. As a long course of treatment the daily dose of arginine was reduced to 2 g without changing the dose of α-lipoic acid.

Example 5

Male 37 years there has been a deterioration of erection and premature ejaculation. After the introduction sildenatil and vardenafil improved erections, however, there is still a premature ejaculation. Diagnosed with psychogenic ED and premature ejaculation. In addition to the specified primary treatment of the patient were introduced 10 g of arginine, and the patient's condition has not changed. However, the introduction of 200 mg lipoic acid together with 10 g of arginine leads to an improvement, i.e. a higher score IIEF from 8 to 20 points. The duration of sexual intercourse increased from 1 to 4 minutes

Example 6

Female 32 years experienced loss of libido after the birth of their first child. Sexual intercourse is often accompanied by pain due to the decrease salivation She feels no orgasm, because completely absent libido. Within two years she and her husband regularly consulted with the sexologist. The woman took arginine in a daily dose of 3 g, and then increased the dosage to 10 g, and the condition has not changed. Then additionally injected α-lipoic acid, starting with a dose of 100 mg per day. and the dose was increased by 100 mg per week. After administration of 300 mg of α-lipoic acid was observed first impression libido. For some time it is administered jointly 300 g of α-lipoic acid and 5 g arginine, and she has regularly observed the sensation of orgasm, a ISFS increases to 10 points. Relationship with my husband has improved and visits to the sexologist terminated.

Example 7

55 year old man is able to engage in intercourse only after intranasal administration of isoamylamine for 5 years. However, sexual intercourse is still unsatisfactory due to the unpredictable erections and premature ejaculation. Diagnosed physical ED and premature ejaculation. After administration of 10 g of arginine +600 mg α-lipoic acid normal duration of sexual intercourse increased from 2 min to 5 min, and the dose of amylnitrite can be reduced. With continued introduction of arginine +α-lipoic acid dose combinations was reduced to 5 g +300 mg. Introduction of isoamylamine canceled.

None of these examples was not observed Autry is atelinae action with the introduction of components of the combination. Cardiovascular disorders were observed. For short term treatment used oral liquid dosage forms, and for long-term treatment used both liquid and solid dosage forms.

The combination is effective in the treatment of the signs and symptoms of ED, but the application is not limited to the physical (organic) ED. Other signs of sexual function and libido improve in both men and women. In conclusion, it should be noted that with the introduction of combinations of the observed therapeutic effect, which includes an action mediated by nitric oxide, but is not limited dependent nitric oxide pharmacological action.

1. Oral composition comprising L-arginine and R-α-lipoic acid in an effective amount, where L-arginine is present in a molar excess relative to the number of R-α-lipoic acid, which is present in the composition.

2. The composition according to claim 1, which is obtained in the form of effervescent drug and/or Packed in bags.

3. The composition according to claim 1, in which the molar excess relative to the number of R-α-lipoic acid is from 2.1 to 50 times.

4. The composition according to claim 1, in which an excess of L-arginine in relation to R-α-lipoic acid is compensated by the addition of the anionic component of the salt.

5. The composition according to claim 4, where the added anionic components is Tom salt is an organic acid.

6. The composition according to claim 5, where the organic acid is selected from the group comprising aspartic acid, glutamic acid, pyruvic acid, benzoic acid, lactic acid, citric acid, malonic acid, tartaric acid.

7. The composition according to claim 1, in which the content of L-arginine ranges from 200 mg to 15 g, and the content of R-α-lipoic acid is from 25 to 1200 mg

8. The composition according to claim 1, in which the content of L-arginine ranges from 500 mg to 10 g, and the content of R-α-lipoic acid is from 55 to 1200 mg.

9. The composition according to claim 1, which is obtained in the form of a solid substance.

10. The use of a composition according to any one of the preceding paragraphs to improve sexual function in men and women.

11. The use of claim 10, in which sexual dysfunction is erectile dysfunction.

12. The use of claim 10, in which sexual dysfunction is the loss of libido in men or women.

13. The use of claim 10, in which sexual dysfunction is caused by physical and/or psychogenic causes.

14. The use of claim 10, in which^:sexual dysfunction is frigidity, inability to experience orgasm or delayed orgasm, deterioration of genital sensitivity, premature ejaculation, unacceptably short duration of sexual intercourse, no salivation, snizeni is or absence of erection of the clitoris or excitability and decrease labeling or vaginal filling.