RU2686334C2 - Rectal medicinal agent for correction of spermatogenesis disorders in male infertility - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine and represents a rectal drug for correction of spermatogenesis disorders in male infertility, containing water-soluble compounds of zinc and L-arginine and pharmaceutically acceptable carrier, presented in a form selected from a group comprising a solution or suspension enclosed in a rectal capsule or microclyster, as well as a foam, an ointment, a cream, a gel and a suppository, wherein the agent contains the following per mg therapeutic unit: L-arginine 50–250, zinc 10–50.EFFECT: use of the declared agent enables effective treatment of spermatogenesis disorders and sexual disorders, reduces viscosity of ejaculate, increases concentration of spermatozoa, increases their mobility and reduces degree of fragmentation of sperm cell DNA.5 cl, 4 tbl, 3 ex

Description

The invention relates to medicine, in particular to drugs, namely to drugs intended for rectal use. These tools can be used in the treatment of diseases of the male reproductive system, namely, disorders of spermatogenesis, such as increased DNA fragmentation of spermatozoa, teratozoospermia, asthenozoospermia, oligozoospermia, as well as sexual disorders, such as erectile dysfunction, premature ejaculation.

A known agent for the treatment of diseases of the prostate gland, comprising 7-60% wt. complex bioregulatory peptides of the prostate gland of cattle with a content of water-soluble peptides of at least 9% and 40-93% wt. chelate complex of zinc-arginine-glycine [RU 2430733, IPC А61K 35/55, 2011]. This tool can be used parenterally to treat diseases of the prostate gland, such as prostatitis, or enterally (rectally) in the form of rectal suppositories on a fat basis. It is noted that the addition of the zinc-arginine-glycine complex to the drug in 48.5% of cases led to an increase in libido compared with the use of suppositories that did not contain the chelate complex.

The disadvantage of the known means is that it contains bioregulatory peptides isolated from the prostate gland of cattle. Like any preparation of natural origin, it does not differ in the constancy of its composition and includes up to 90% of side substances released together with the target product, which can cause allergic and other undesirable reactions in a patient. In addition, impaired spermatogenesis is not always associated with prostatitis, and then the use of products containing bioregulatory peptides is impractical.

The closest in technical essence and the achieved effect to the claimed product is a dietary supplement (BAA) arginine-zinc "Vitamax" manufactured by "Paragon Laboratories", USA [vitamax.ru/product/arginine-cink; certificate of registration RU.77.99.11.003.E.014885.05.11 of 18.05.2011]. This supplement comprises a mixture of 500 mg of L-arginine and 4 mg of water soluble zinc salt in the form of zinc glycinate per therapeutic dose. The supplement is available in the form of capsules and is administered orally, one capsule during meals 1-2 times a day or 2 capsules 1 time a day. It is indicated that in addition to improving the vascular tone and metabolic reactions, arginine-zinc is indicated for violations of spermatogenesis, in particular with a decrease in sperm motility.

The disadvantage of this tool is that it is available for oral use. Oral medication has a number of contraindications for a certain category of people suffering from gastrointestinal diseases (heartburn, gastric ulcer, difficulty swallowing, atrophic gastritis, dyspeptic disorders, etc.). These problems are solved using the rectal method of administration. Moreover, the rectal route of administration may be preferable in view of the anatomical proximity of the site of administration (rectum) and the male reproductive organs. And, finally, with the rectal route of administration, the drug does not undergo metabolic destruction in the liver, due to which the concentration of the drug required to produce a therapeutic effect is achieved.

The result achieved in the claimed invention is to obtain a drug for the treatment of spermatogenesis disorders and sexual disorders, more effectively and quickly reaching the male reproductive organs.

This result is achieved by rectal drug correction of disorders of spermatogenesis in male infertility, containing water-soluble compounds of zinc and L-arginine and a pharmaceutically acceptable carrier, made in a form selected from the group comprising a solution or suspension enclosed in a rectal capsule or microclysmic, and foam, ointment , cream, gel and suppository, and the product contains in mg per therapeutic unit:

L-arginine 50-250 zinc 10-50

The rectal agent may include a mixture of L-arginine with a water-soluble zinc salt, such as zinc chloride or a glycine-zinc complex, or a chelate compound L-argininezinc, or a mixture of L-arginine-zinc with L-arginine; it is only necessary to maintain the arginine-zinc ratio mentioned above.

The rectal agent may also include, at a therapeutic dose, 10-100 mg of dimethyl sulfoxide (DMSO), 10-300 mg of coenzyme Q10, 30-300 μg of selenium in the form of sodium selenate, selenium methionine or selenoxanthene, and 0.1-4.5 g of L-carnitine.

An aqueous solution of the inventive mixture for rectal administration may contain sorbic acid and glycerin as a pharmaceutically acceptable carrier; such a solution can be used in a rectal capsule or in the form of microclysters.

The rectal suspension, also used with a capsule or microclyster, may include the following excipients (pharmaceutically acceptable carrier): disodium edetate dihydrate, sodium disulfite, sodium acetate trihydrate, carbomer (a group of polymers derived from acrylic acid), xanthan gum, sodium ethylamine acetate, potassium acetate , sodium benzoate, potassium disulfite, nitrogen gas, truck, sodium metabisulfite and sodium acetate.

Rectal foam, which can be produced in cylinders with a dosing device, contains propylene glycol, sodium disulfite, polysorbitol, disodium edetate, cetostearyl alcohol, and propellants as auxiliary substances.

Rectal ointment as auxiliary substances may include 2-octyldodecanol, castor oil, macrogol 4000 (polyethylene glycol with a molecular weight of 4000), carbomer, a stabilizer bronopol (2-bromo-2-nitropropane-1,3-diol), Lunacera-M emulsifiers and hostafat kw -340-N (triceteorate-4-phosphate), levomenthol, liquid and solid paraffin, lanolin, colloidal silicon dioxide, purcelinol, glycerides of fatty acids, sodium edetate, trolamine, petrolatum and water.

The rectal cream may include cetyl alcohol, macrogol, liquid paraffin, isopropyl palmitate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, stearic acid, sorbitol, sorbitan stearate, and disodium edetate.

The rectal gel may include carbomer, levomenthol, disodium edetate, triethanolamine, essential oils, sorbitol, isopropanol, softigen 767 (macrogol glycerol caprolocaprate), polysorbate, and water.

Rectal ointment, cream and gel can be produced in tubes with long tips or can be used with special syringes.

Rectal suppositories for the introduction of the claimed medicinal composition can be made on the basis of a water-soluble polymer - polyethylene glycol (PEG) with a molecular weight of 1500 and additionally contain DMSO.

Capsules for rectal use - one of the forms of delivery of powders, solutions, suspensions, etc. The shell of a rectal capsule can be made from a mixture of 64-70% gelatin and 30-36% glycerol and also contain methyl and propylparaben, titanium dioxide and water.

Microclysters for single use (rectioli, rectal pipettes) for the introduction of solutions or suspensions are an elastic cartridge with a volume of 3-5 ml, equipped with a tip and a protective cap.

To confirm the effectiveness of the rectal forms of the claimed medicinal composition, comparative studies of its rectal and non-rectal use, given in the examples, were conducted.

Example 1

Effect of arginine and zinc (AC) composition on plasma testosterone levels in a model of irritative prostatitis in rats.

It is known that inflammatory processes in the prostate gland cause blockade of testosterone biosynthesis in the testes [Tesakova S.V., Makarova M.N., Makarov V.G. et al. // Bulletin of the Volgograd Scientific Center of the Russian Academy of Medical Sciences. 2009. - №2. - pp. 35-39.]. Reducing the level of this sex hormone is one of the reasons for the deterioration of male reproductive and erectile functions.

The experiment was conducted on 24 outbred male rats. To simulate prostatitis, a 10% solution of DMSO with turpentine was rectally administered to animals. Modeling has led to the development of inflammation and a progressive decrease in plasma testosterone levels. Starting from the 21st day of the experiment, a statistically significant violation of the hormone synthesis was noted: testosterone levels decreased by 20-50% compared with the background. A decrease in testosterone production was observed throughout the experiment in rats from the control group.

Starting from 21 days, one experimental group of AC (0.27 mg / kg arginine and 0.1 mg / kg zinc) was administered rectally, while the other group was administered orally. For rectal administration, an atraumatic probe was used, and the suppositories were previously softened in a water bath to a gel state. For oral administration, an atraumatic probe was also used and the AC was administered as a solution. The results are presented in table 1.

Note: * - differences are significant compared with the background, p <0.05

** - the differences are significant compared with the control, p <0.05

As can be seen from table 1, the administration of AC prevented a decrease in plasma testosterone levels, and rectal administration was more effective than oral administration.

Example 2

The effectiveness of the composition of arginine and zinc (AC) in patients with impaired spermatogenesis.

The study of the effectiveness of the AC was performed in 30 men aged 25-45 years with impaired spermatogenesis against the background of chronic inflammation of the prostate.

Patients of the first group were given 1 suppository each, containing 100 mg of arginine and 37.6 mg of zinc, deep into the anus after a bowel movement or enema 1 time per day (in the evening). Patients of the second group were prescribed 1 capsule of AC containing the same concentrations of arginine and zinc as in the suppositories prescribed to the first group, orally once a day. The course of treatment was 10 days.

The efficacy of treatment was evaluated on the basis of changes in the erythrocyte sedimentation rate (ESR, inflammation index) and assessment of spermogram parameters (viscosity, concentration and motility of spermatozoa).

The definition of ESR is the most simple, but at the same time informative and generally accepted method, allowing to detect the presence of inflammatory process and assess its activity. The use of AC promoted a pronounced decrease in ESR, the value of which after the course of treatment was 21-26% compared with baseline in both groups. The dynamics of ESR before and after treatment are given in table 2.

* - differences are significant compared with the initial survey, p <0.05

Inflammatory diseases of the prostate gland worsen the quality of the ejaculate, reduce the number (concentration) of spermatozoa, increase the viscosity of the ejaculate, reduce the motility of spermatozoa. The above indicators were evaluated before and after treatment. The results are presented in table 3.

* - differences are significant compared with the initial survey, p <0.05

As can be seen from table 3, the initial weighted average viscosity of the ejaculate was increased and went beyond the upper limit (the norm is up to 2.0 mm). The treatment contributed to a significant decrease in the viscosity of seminal fluid to normal values.

The use of the drug also contributed to an increase in sperm concentration per unit volume of ejaculate compared with the results prior to treatment.

Sperm motility largely depends on the secretory activity and the functional state of the prostate gland. When assessing sperm motility, the percentage of progressively mobile forms of spermatozoa was estimated (with progressive movement, category A + B). During the analysis and comparative assessment of average indicators, it was found that the study drug leads to a significant increase in the number of progressively mobile forms of spermatozoa in patients after treatment.

Example 3

The effectiveness of the composition of arginine and zinc with selenium, carnitine and coenzyme Q10 (AC-SCC) in comparison with arginine-zinc (AC) in patients with impaired fertility.

A comparative study of the effectiveness of AC-SCC and AC was performed in 16 men aged 33-45 years with a diagnosis of idiopathic subfertility.

The patients were divided into 2 groups: the first received 1 suppository each, containing 100 μg of selenium, 1000 mg of carnitine, 100 mg of coenzyme Q10, 100 mg of arginine and 37.6 mg of zinc, while the patients of the second group received 1 suppository containing 100 mg arginine and 37.6 mg of zinc. Suppositories were administered rectally after a bowel movement or an enema 1 time per day (in the evening). The course of treatment was 8 weeks.

Treatment efficacy was determined by assessing the quality of the ejaculate (volume, viscosity), changes in sperm performance (sperm concentration, the number of progressively mobile forms of spermatozoa, sperm morphology and the presence of antisperm antibodies in the ejaculate), as well as the degree of fragmentation of sperm DNA.

The determination of the titer of antispermal antibodies of the classes IgA and IgG (ACAT) in the ejaculate was performed using the MAR (mixed antiglobulin reaction) test, which today is the main method of verifying the immunological form of male infertility.

The results are presented in table 4.

* - differences are significant compared with the initial survey, p <0.05

As follows from table 4, in all patients, the MAR test values before the start of treatment were elevated (> 10%). After 8 weeks of using both the AC-SSC and AC, a decrease in the number of spermatozoa coated with antisperm antibodies was observed. However, if the AC reduced the number of ASAT by about 2 times, then the AC-CCM - almost 3 times.

An important indicator, determined in the treatment of idiopathic forms of male infertility, is sperm DNA fragmentation. The greater the damage to DNA (> 15% of DNA breaks), the greater the likelihood of missed abortion (cessation of fetal development and death in the early pregnancy of a sexual partner - up to 13 weeks). The number of sperm DNA breaks was determined by flow cytofluorimetry. It was established that both drugs - AC and AC-HSC - had similar efficacy in reducing the degree of fragmentation of the DNA of spermatozoa.

Thus, the results of the study show that the rectal use of both drugs (AC-SCC and AC) was effective, leading to an improvement in the quality of sperm, spermogram indicators in patients with idiopathic subfertility, but the use of AC-SCC was somewhat more effective (for some indicators up to 30 %) than AC.

In general, these examples indicate a higher clinical efficacy of the AC in rectal use compared with oral administration.

Claims (6)

1. Rectal medicinal remedy for the correction of spermatogenesis disorders in male infertility, containing water-soluble compounds of zinc and L-arginine and a pharmaceutically acceptable carrier, made in a form selected from the group consisting of a solution or suspension enclosed in a rectal capsule or microclysmic, and foam, ointment, cream, gel and suppository, and the product contains in mg per therapeutic unit: L-arginine 50-250 zinc 10-50 2. The rectal medicinal product according to claim 1, characterized in that it additionally contains dimethyl sulfoxide in an amount of 10-100 mg per therapeutic dose. 3. The rectal drug under item 1, characterized in that it additionally contains coenzyme Q10 in an amount of 10-300 mg per therapeutic dose. 4. The rectal drug of claim. 1, characterized in that it further comprises selenium in an amount of 30-300 μg per therapeutic dose. 5. The rectal drug of claim. 1, characterized in that it additionally contains 0.1-4.5 g of L-carnitine per therapeutic dose.