RU2727506C1 - Agent for treating erectile dysfunction - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: invention relates to medicine and pharmaceutics and represents an agent for treating erectile dysfunction, containing as active substance 9-phenyl-simm-octahydroselenoxantene in amount of 5–20 wt. % and excipients, wherein agent can be made in form of capsules or tablets.EFFECT: technical result consists in treating erectile dysfunction by means of the invention, which does not exhibit side effects in patients with accompanying somatic pathologies.3 cl, 6 dwg, 1 tbl, 6 ex

Description

Technology area

The invention relates to medicine, in particular urology, and can be used to create an agent for the treatment of erectile dysfunction (ED), containing 9-phenyl-sym-octahydroselenoxanthene (selenoxanthene).

State of the art

Recently, erectile dysfunction has become increasingly important. About 150 million men worldwide suffer from erectile dysfunction (ED), and this number could double in the next 25 years. The widespread prevalence of ED is associated not only with age, but also with an increase in morbidity, the use of drugs that cause sexual dysfunction, stress and the presence of bad habits (smoking, alcohol consumption). Therefore, the prevalence of ED as a whole is a reflection of social health indicators [1]. Epidemiological data on the prevalence of ED in Russia are limited by the results of a study, according to which the incidence in the Central Federal District is 26.9% of surveyed men aged 20 to 75 years, inclusive [2]. The first line of therapy is type 5 phosphodiesterase inhibitors (IFDE-5) [3]. Despite the high efficiency of PDE-5 inhibitors, there remains a large proportion of patients in whom therapy with these drugs is ineffective or contraindicated due to the concomitant intake of nitrates [4]. In addition, co-administration with antihypertensive drugs is fraught with episodes of orthostatic hypotension, and is contraindicated with α-blockers. Due to the fact that ED often develops against the background of concomitant pathology, these circumstances determine the relevance of the search and development of new drugs for the treatment of ED.

Other approaches to the treatment of ED are also known, in particular, the use of selenium-containing drugs in complex therapy. So, in the application US2002182585 (08.01.2002) describes the use of a composition containing EDTA, cystine, selenium, vitamin C, vitamin E and zinc, for vascular disorders, which in turn cause erectile dysfunction in some cases.

In the patent CN104799271 (01/26/2014) an agent for improving erection is described, including 10-35 g of vegetable protein, 12-58.8 g of vegetable fat, 3.5-15 g of dietary fiber, 0.0018-0.0026 g of zinc and 0.000003-0.0000015 g of selenium.

However, these methods provide a complex effect on the body, and improving erection when using them is one of a number of achieved effects. In addition, from the use of these methods does not follow the effect on erectile dysfunction, since the effect is made up of many factors and many compounds that act together, i.e. treatment of the specified disease is determined by low-specific factors.

At the same time, the selenium-containing substance selenoxanthene is known from the prior art, which is used in the treatment of various diseases.

Selenoxanthene is a biologically active substance containing selenium 9-phenyl-sym-octahydroselenoxanthene (9-phenyl-symmetric-octahydroselenoxanthene, C19H22Se, molecular weight: 329.37 amu). This compound has antioxidant, bactericidal, radioprotective, antitumor, sedative, antispasmodic, analgesic, hypnotic effects and is used to prevent selenium deficiency in humans and animals, normalize thyroid function, increase the activity of antioxidant enzymes, and normalize the functions of the reproductive system. In particular, as an example of the normalizing effect of selenoxanthene on the functioning of the reproductive system, one can cite a method for correcting spermatogenesis in animals under conditions of chronic intoxication with natural gas (patent RU 2480221 C1, 28.02.2012), which reveals the possibility of selenoxanthene to improve the reproductive potential of males, due to the positive influence on spermogram indicators. However, this work does not cover the therapy of ED in humans (ICD-10 codes: N48.4 and F52) and does not take into account possible conditions or diseases associated with this pathology (for example, asthenozoospermia).

Thus, the technical problem and the problem solved with the claimed invention is the creation of an agent for the treatment of erectile dysfunction, which contains in its composition. 9-phenyl-sym-octahydroselenoxanthene /

Disclosure of the essence of the invention .

Our studies on animal models have shown the effect of 9-phenyl-sym-octahydroselenoxanthene on erectile function, which makes it possible to use it as part of a drug for the treatment of ED, including those associated with somatic causes.

Based on the foregoing, we propose an agent for the treatment of erectile dysfunction, containing in its composition as an active substance 9-phenyl-sym-octahydroselenoxanthene in an amount of 5-20 wt% and excipients.

In a particular case, the pharmaceutical composition is made in the form of capsules or tablets.

In a particular case, as excipients are used for tablets: MCC 65-77 wt%, calcium carbonate 4-5 wt%, calcium stearate 1.5-2.5 wt%, talc 2.5-3.5 wt%, silicon dioxide 4.5-5 wt%;

for capsules: MCC 60-75 wt%, calcium carbonate 3.5-4.5 wt%, calcium stearate 2-3 wt%, talc 3-3.5 wt%, silicon dioxide 7.5-9 wt%.

The technical result of the claimed invention is to obtain an agent that eliminates erectile dysfunction in men, and does not exhibit side effects in patients with concomitant somatic pathologies. The proposed agent can be a good alternative to PDE-5 inhibitors, since it does not have pronounced side effects, and its effect is "cumulative" in nature.

Brief description of the drawings .

Table 1. The results of measuring the peak pressure in the cavernous sinus during electrical stimulation of the cavernous nerve in the model of bilateral ligation of the internal iliac artery in rats, where * is the significance level of p <0.05 (when compared with the control group).

- группа 1,

- группа 2.Figure 1. Peak intracavernous pressure (ICP) during electrical stimulation of the cavernous nerve in a model of bilateral ligation of the internal iliac artery in rats, where

- group 1,

- group 2.

Figure 2. Ratio of CDI / BP (ratio of intracavernous pressure / mean arterial pressure) at different doses of 9-phenyl-sym-octahydroselenoxanthene in a model of 2-week cavernous nerve injury in rats, where

Figure 3. Total CDI exposure (AUC) at different dosages of 9-phenyl-sym-octahydroselenoxanthene in a model of 2-week cavernous nerve injury in rats, where

Figure 4. Dynamics of fibrosis (%) at different dosages of 9-phenyl-sym-octahydroselenoxanthene in a model of 2-week cavernous nerve injury in rats, where

Figure 5. Comparison of the activity of 9-phenyl-sym-octahydroselenoxanthene and Impaza in relation to peak CDI in a rat model of hyperlipidemia, where

Figure 6. NO-synthase activity of penile tissue homogenate (L-arginine / citrulline conversion in pmol / min / mg) in the model of "passive smoking" in rats (comparison of 9-phenyl-sym-octahydroselenoxanthene and Impaza preparation), where

Implementation of the invention.

Below are examples of implementation of the invention in particular cases of implementation.

Example 1. Obtaining 9-phenyl-sym-octahydroselenoxanthene.

To obtain 9-phenyl-sym-octahydroselenoxanthene, 12.5 g of 9- (o-hydroxyphenyl) -octahydro-10-oxoxanthene were taken and placed in a three-necked flask with a magnetic stirrer and gas supply. Then added 30 ml of a mixture of acetic acid: acetic anhydride (4: 1). With stirring, the reaction mixture was purged with nitrogen for 30 minutes, then the nitrogen flow was stopped and hydrogen selenide was passed into the reaction mixture. 30 minutes after the start of the passage of hydrogen selenide, 1.0 ml of concentrated hydrochloric acid was added twice to the reaction mixture at intervals of 1 hour. The rate of transmission of hydrogen selenide was 2-3 bubbles per second. The total time of passage of hydrogen selenide was 6 hours, after which the reaction mixture was purged with nitrogen for 40 minutes. Then the reaction mixture was placed in a refrigerator, and after a day the precipitate formed was filtered, washed with acetic acid and alcohol. The product yield was 11.5 g.

Example 2. Preparation of an agent containing 9-phenyl-sym-octahydroselenoxanthene.

Empirically, it has been found that the most preferred (although not limiting the scope of claims in accordance with the present invention) method for preparing a dosage form (tablet or capsule) of 9-phenyl-sym-octahydroselenoxanthene includes:

The sifted microcrystalline cellulose powder is stirred for 2 minutes, powder of 9-phenyl-sym-octahydroselenoxanthene and calcium carbonate is added, the mixture is thoroughly mixed for 4 minutes, then calcium stearate powder is added and stirred for 3 minutes, sifted powders of talc and silicon dioxide are added and again mixed for 2 ÷ 4 minutes, the resulting mixture is tableted by direct compression of a solid dosage form, or the mixed mixture is enclosed in capsules.

Composition of the dosage form 9-phenyl-simm-octahydroselenoxanthene in the form of tablets

9-phenyl-sym-octahydroselenoxanthene 20 mg MCC 70 mg calcium carbonate 5 mg calcium stearate 2 mg talc 3 mg silicon dioxide 5 mg

or

9-phenyl-sym-octahydroselenoxanthene 6 mg MCC 70 mg calcium carbonate 5 mg calcium stearate 2 mg talc 3 mg silicon dioxide 5 mg

Composition of the dosage form of 9-phenyl-simm-octahydroselenoxanthene in the form of capsules

9-phenyl-sym-octahydroselenoxanthene 10 mg MCC 80 mg calcium carbonate 5 mg calcium stearate 3 mg talc 4 mg silicon dioxide 10 mg

or

9-phenyl-sym-octahydroselenoxanthene 25 mg MCC 80 mg calcium carbonate 5 mg calcium stearate 3 mg talc 4 mg silicon dioxide 10 mg

Below are the results of experiments confirming the effectiveness of 9-phenyl-sym-octahydroselenoxanthene in relation to erectile function. The studies cited in these examples were designed and performed in accordance with current publications concerning the development of animal models for the study of ED.

It is important to note that many patients without a doctor-verified diagnosis and appropriate examination take over-the-counter drugs on their own, the most common of which is Impaza. Therefore, additional studies were carried out comparing the effectiveness of 9-phenyl-sym-octahydroselenoxanthene and the drug Impaza, the results of which are highlighted in examples 5 and 6.

Example 3. Study of the pharmacological activity of 9-phenyl-sym-octahydroselenoxanthene in rats on the model of ligation of the internal iliac artery.

Materials and methods . One of the most common causes of erectile dysfunction is arterial insufficiency of the corpora cavernosa. Atherosclerosis or traumatic arterial occlusion due to a decrease in blood flow and blood filling of the corpus cavernosum affects the severity of erection. Such vascular risk factors include hypertension, hyperlipidemia, smoking, diabetes mellitus and pelvic irradiation [5, 6, 7, 8]. Vasculogenic erectile dysfunction is the most common type in clinical practice. The experiment was based on the model described in [8].

The study involved 40 male rats aged 3 months. weighing 350-400 g. The animals were anesthetized by an intraperitoneal injection of 35 mg / kg pentobarbital after preliminary inhalation with methoxyflurane. After a midline laparotomy under a microscope, ligatures were applied bilaterally to the internal iliac arteries of 40 rats. Others (control group, n = 10) underwent only revision. An additional incision in the lower leg area provided a 23G catheter to monitor intracavernous pressure (ICP) during electrical stimulation of the cavernous nerve. Additional ligatures were applied to achieve a lack of dynamics (increase) in the ICD during electrical stimulation. The wound was sutured and the animals were monitored after 1, 2 and 6 weeks.

For electrical stimulation, bipolar platinum electrodes were used. The positive electrode was placed 2-3 mm proximally to the negative one on the nerve fiber, the voltage was 1.5 V, the frequency was 20 Hz, the pulse duration was 0.2 ms, and the total duration of the procedure was 50 s.

Before the start of the experiment, the animals were randomly divided into two groups: 1) control - only revision of the abdominal cavity; 2) 9-phenyl-sym-octahydroselenoxanthene, 1 mg / kg * day. Animals received all preparations orally (through an intragastric tube) for 6 weeks, then the animals were euthanized, and the penile tissues were examined under a microscope after immunohistochemical staining.

From the data presented in tab. 1, it can be seen that 9-phenyl-sym-octahydroselenoxanthene showed an advantage over placebo in terms of CDI recovery.

Example 4. Study of the effect of 9-phenyl-sym-octahydroselenoxanthene on ED in a model of 2-week damage to the cavernous nerve (CN). Search for optimal dosages.

The following study was performed to establish the most effective dosage. The model of damage to the cavernous nerve in rats was chosen as a model, which demonstrated its advantages in the work [9].

The studied dosages of 9-phenyl-sym-octahydroselenoxanthene were as follows: 0.1; 0.5 and 1.0 and 10 mg / kg. Additional cohorts were the control group (without traumatization) and the control group with CN injury, which received placebo.

Rats 8-10 weeks of age, a total of 120 rats were divided into 6 cohorts (n = 20 in each), 10 rats in each cohort were subjected to ICD study and subsequent euthanasia on the 14th day of the experiment, and the other 10 rats - on 30 day of the experiment.

9-phenyl-simm-octahydroselenoxanthene was administered via an intragastric tube (orally) in the form of a pre-ground pharmaceutical composition (Example 2).

The pharmacological activity of the compounds was assessed according to the following criteria: 1) the ratio of the CDI to the mean blood pressure; 2) ICD exposure; and 3) the proportion of fibrosis.

The animals were anesthetized with ketamine / xylazine (100 + 10 mg / kg) administered intraperitoneally. Access to the prostate was performed by a midline laparotomy. The cavernous nerve and the greater pelvic ganglion are located behind and lateral to the prostate. Bilateral nerve trauma was performed with Dumont # 5 forceps, which clamped the cavernous nerve 2-3 mm distal to the greater pelvic ganglion. The nerve was clamped with forceps 3 times for 15 s each time, resulting in a standardization of the level of trauma. In the control group, the cavernous nerve was not traumatized, and the wound was simply sutured. In 14 and 30 days after the operation, the indicators of erectile function were measured and euthanasia was performed, followed by histological examination. Blood pressure was measured using a 25G catheter placed in the lower leg and connected to a heparinized (250 U / ml) polyethylene tube inserted for ICD measurement. An electrical stimulator was placed in the area of the cavernous nerve injury. Electric impulses were produced with a frequency of 20 Hz and a duration of 0.5 ms each with a total duration of 30 s. and a voltage of 8 volts.

For normalization to the value of mean arterial pressure (BP), the ratio between the maximum CDI level and the average blood pressure measured at the peak of the erectile response was calculated. Total ICD exposure was calculated as the area under the erectile curve (AUC; mmHg x sec) from initiation of cavernous nerve stimulation until the ICD returned to baseline. The erectile response was measured 14 and 30 days after trauma to the cavernous nerve. Weight was also monitored. Then the animals were euthanized, and the penile tissues were removed for histological examination.

It is interesting to note that increasing the dosage of 9-phenyl-sym-octahydroselenoxanthene up to 10 mg / kg did not improve the efficacy indicators (the ratio “ICD / BP” and the total exposure of the ICD), but even, although statistically insignificant, decreased. The maximum efficiency was observed at a dosage of 1 mg / kg (Fig. 2 and 3).

After bilateral injury of the cavernous nerve, fibrosis induction was observed in all groups. At the same time, in the group receiving 9-phenyl-sym-octahydroselenoxanthene, a lesser severity of the fibrotic process was revealed. The area of smooth muscle fibers did not change after injury. The ratio of collagen and smooth muscle elements was determined visually on transverse sections in Masson's trichrome stain. The ratio of collagen to smooth muscle was assessed as the proportion of fibrosis.

After injury, within 14 and 30 days, there was a significant increase in the proportion of fibrosis compared with the control group. (p-value <0.05). However, fibrotic changes were reversible, and under the action of 9-phenyl-sym-octahydroselenoxanthene, it was significantly significant at doses of 0.5 mg / kg and 1.0 mg / kg (Fig. 4).

Example 5. Comparison of the efficacy of 9-phenyl-sym-octahydroselenoxanthene and Impaza in the model of ED associated with hyperlipidemia.

Hyperlipidemia is associated with endothelial dysfunction and is a common cause of ED. Moreover, the risk of developing ED is directly proportional to the level of cholesterol and low-density lipoproteins in the blood [10, 11]. Hyperlipidemia, manifested at the cellular level by a decrease in the production of nitric oxide (NO) and acting as a neurogenic and vasculogenic factor, can be successfully used to model ED [12].

The study involved 3-month-old white male Wistar rats, a total of 40 individuals. The animals were divided into 4 groups: 1) control, which received a normal diet; 2) a control who received a diet high in fat, but did not receive therapy; 3) active control who received Impaza (at a dose of 0.3 mg / kg * day); 4) the group receiving 9-phenyl-sym-octahydroselenoxanthene at a dose of 1 mg / kg * day. The animals received the compared preparations 5 months after feeding for 28 days (4 weeks).

9-phenyl-simm-octahydroselenoxanthene was administered once a day by means of an intragastric tube; the animals received Impaza with water: 1 tablet of 3 mg was dissolved in 1000 ml of water, so that taking into account the volume of fluid consumed 20 ± 3 ml / animal * day, each the animal received 0.3 mg / kg of the active substance of the Impaza drug per day, which corresponds to the therapeutic dose of a person (≈3 mg).

Hyperlipidemia was modeled on a high fat diet that the animals received for 5 months (diet consisted of 2% cholesterol and 10% pork fat). Further, some animals received 9-phenyl-sym-octahydroselenoxanthene (group 4), others received Impaza (group 3), and finally the animals from group 2 did not receive any therapy. Control group No. 1 received a normal diet throughout the experiment. 28 days after receiving the study drugs, all rats were anesthetized with an intraperitoneal injection of ketamine (100 mg / kg) and midazolam (5 mg / kg). An inferior median laparotomy was performed and the cavernous nerve was bilaterally isolated.

ICD was measured with electrical stimulation for 50 sec. The penis was freed from the overlying skin and the cavernous sinus was catheterized with a hyparinized 25G catheter for CDI monitoring. The cavernous nerves were stimulated with an electrical impulse lasting 50 seconds, a frequency of 20 Hz and 1.5 mA. The ICD response was recorded using the LabView 6.0.2 software (USA). Maximum (peak) values were used for analysis. After performing the functional tests, systemic blood pressure was measured by art catheterization. Mean arterial pressure was calculated using the formula mean arterial pressure = (2/3 diastolic blood pressure + 1/3 systolic blood pressure). Next, a blood sample was obtained to perform a biochemical blood test for testosterone levels. We also performed the determination of the content of neuronal NO-synthase (nNOS) in the dorsal nerve by immunohistochemical method.

It was found that hyperlipidemia significantly reduces the number of nNOS positive fibers, and the intake of both 9-phenyl-sym-octahydroselenoxanthene and the drug Impaza had a positive effect, increasing their number. At the same time, no differences were found between the drugs. Mean arterial pressure did not differ between groups. Testosterone levels were also comparable in the compared treatment groups and, moreover, this level did not differ significantly from the control groups. However, CDI monitoring data showed a clear and statistically significant advantage of 9-phenyl-sym-octahydroselenoxanthene over Impaza (Fig. 5).

Example 6. Comparison of the effectiveness of 9-phenyl-sym-octahydroselenoxanthene and Impaza on the activity of NO-synthase in the model of passive exposure of cigarette smoke (model of "passive smoking").

For the study, a model was used as a basis, which showed its adequacy in [13]. Smoking is known to be a risk factor for ED. It was also found that exposure to cigarette smoke damages the NO-dependent mechanism of erection, reducing the content of nitric oxide synthase (NOS) in the tissues of the penis, and these changes are associated with changes in systemic blood pressure. Also in the study [13], some stimulating effect of exposure to tobacco smoke on the CDI was shown, therefore, in our experiment, it was decided to investigate only the activity of NO-synthase of the penile tissues, since this indicator will reflect the long-term effect of smoking on erectile function. The activity of NO-synthase was determined by assessing the arginine-citrulline conversion and expressed in pmol / min per 1 mg of protein cytosol, for which [3H] -labeled arginine was used.

The study included 4 groups of male rats, 6 animals each. All animals were 5 months old. Group 1 - untouched control (no exposure to tobacco smoke), 2nd - control of the "passive smoking" model (animals were exposed to smoke), 3rd group also received 9-phenyl-sym-octahydroselenoxanthene at a dose of 1.0 mg / kg for 4 weeks, and the 4th group received Impaza for 4 weeks at a dose of 0.3 mg / kg.

Selenoxanthen was administered once a day by means of an intragastric tube; the animals received Impaza with water: 1 tablet of 3 mg was dissolved in 1000 ml of water, so that taking into account the volume of fluid consumed 20 ± 3 ml / animal * day, each animal received 0.3 mg / kg of the active ingredient of the drug Impaza.

To simulate secondhand smoke, rats were kept in plastic containers measuring 25 × 60 × 20 cm, which were constantly receiving cigarette smoke. The exposure to cigarette smoke continued for 1 hour daily for 8 weeks.

Penis tissues were homogenized and dissected in 0.32 M sucrose / 20 mM Hepes (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) pH 7.2 / 0.5 mM EDTA / 1 mM DTT (dithiothreitol), as well as inhibitors proteases (3 μM leupeptin, 1 mM PMSF (phenylmethylsulfonyl fluoride), 1 μM pepstatin A). The microsomal fraction was isolated by centrifugation at 12500 g for 60 min. Then the fraction was filtered through Dowex AG5OWX-8 medium (Na +, Sigma Aldrich, USA) to remove endogenous arginine, and aliquots (3 pcs.) Were further incubated for 45 min at 37 ° C in the presence of [3H] -labeled L-arginine (2 μCi / ml), 100 μM L-arginine, 0.45 mM Ca2 +, 2 mM NADPH, in the presence and absence of L-NAME (L-nitro-N-arginine methyl ester) (2 mM). After elimination of [3H] -labeled L-arginine, the amount of [3H] -labeled citrulline was calculated, by which the NO-synthase activity was determined. All values were corrected for the level of radioactivity during incubation of blank samples.

The results showed that exposure to cigarette smoke significantly reduced the activity of NO synthase in penile tissues. Selenoxanthene to a greater extent than the Impaza drug and statistically significantly increased its activity (p-value <0.05) (Fig. 6).

Conclusion and conclusions

The present invention presents the results of studying the efficacy of 9-phenyl-sym-octahydroselenoxanthene for the treatment of ED, obtained in traumatic (neurogenic), vascular, metabolic models, as well as in a physical stress model - a "passive smoking" model. Thus, the effect of 9-phenyl-sym-octahydroselenoxanthene was studied taking into account all the main etiological causes of ED and taking into account all the most common pathophysiological mechanisms of this disease.

It is possible that the good efficacy of 9-phenyl-sym-octahydroselenoxanthene in the therapy of ED, shown in the above models, is associated with the antioxidant properties of this substance. At the same time, taking into account the multifaceted action of selenium derivatives in the body, one cannot exclude the presence of other mechanisms of activity that are more specific for ED.

It is known that IFDE-5 is indicated as the drug of choice for ED. However, these recommendations are limited to the organic component in the etiology of the disease. In other clinical cases, with less pronounced clinical symptoms, in particular with the psychogenic component of ED (stress, smoking, etc.), patients most often take other drugs, for example, the drug Impaza (homeopathic remedy, affinity purified antibodies to endothelial NO synthase ), medicinal products of natural origin or symptomatic medications. For this most frequent category of patients, the use of 9-phenyl-sym-octahydroselenoxanthene seems to be more reasonable, since it implies the absence of pronounced side effects.

The mechanism of realization of the activity of 9-phenyl-sym-octahydroselenoxanthene, which differs from IFD-5, and the presence of antioxidant properties in it, can explain the better indicators of CDI.

With regard to ED-effective dosages of 9-phenyl-sym-octahydroselenoxanthene, good results were obtained for a dose of 1.0 mg / kg in rats, which corresponds to a daily human dose of about 10 mg / day. The daily dose can be divided into 2 doses. Therefore, for the treatment of ED, it is advisable to take into consideration the dosage forms of 9-phenyl-sym-octahydroselenoxanthene with dosages of 5 and 10 mg. At the same time, it is known that therapeutically effective doses for humans do not always correspond to the equivalent doses obtained when recalculated from animal models. Obviously, the refinement of dosages and dosage regimen when taken by patients with erectile dysfunction will be carried out in the course of clinical development, according to the results of which the content of 9-phenyl-sym-octahydroselenoxanthene in the composition of the agent can be adjusted.

List of references

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Claims (4)

1. An agent for the treatment of erectile dysfunction, containing in its composition as an active substance 9-phenyl-sym-octahydroselenoxanthene in an amount of 5-20 wt.% And auxiliary substances. 2. The agent according to claim 1, which is made in the form of capsules or tablets. 3. The agent according to claim 2, characterized in that the following are used as auxiliary substances for tablets: MCC 65-77 wt.%, Calcium carbonate 4-5 wt.%, Calcium stearate 1.5-2.5 wt.%, talc 2.5-3.5 wt%, silicon dioxide 4.5-5 wt%; for capsules: MCC 60-75 wt%, calcium carbonate 3.5-4.5 wt%, calcium stearate 2-3 wt%, talc 3-3.5 wt%, silicon dioxide 7.5-9 wt%.

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