RU2267319C2 - Pharmaceutical composition and method for treating chronic fatigue syndrome due to its application - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: the suggested pharmaceutical composition contains 2-ethylthiobenzimidasol hydrobromide at efficient quantity and a pharmaceutically acceptable carrier. Method for preventing and treating chronic fatigue syndrome should be fulfilled due to introducing the mentioned pharmaceutical composition at its daily dosage of 250-1500 mg for 5-20 d to provide the chance for repeating the course of therapy after an interval of 5 d or more. While treating chronic fatigue syndrome one should additionally apply cavinton, adenosine triphosphate, vitamins, cibazone, mesapam to realize the mentioned indication.

EFFECT: higher efficiency.

4 cl, 6 ex, 4 tbl

Description

The invention relates to medicine, in particular to pharmacology, in particular to pharmaceutical compositions for the treatment of multiple sclerosis, other neurodegenerative diseases, as well as chronic fatigue syndrome.

Multiple sclerosis is a demyelinating disease of the central nervous system of unknown etiology. Multiple sclerosis is characterized by disseminated demyelination of the axons of the brain in the periventricular regions and in corpus callosum. In the pathogenesis of multiple sclerosis, the leading role is played by autoimmune inflammation, manifested in the destruction of myelin by the type of delayed-type hypersensitivity, the mechanism of which is mediated by Th1 lymphocytes.

The appearance of foci of demyelination in the stem structures of the brain and vertebro-basilar insufficiency are the cause of vestibular disorders in multiple sclerosis, resulting from a deterioration in the rheological properties of blood, spasm of small and medium-sized vessels. Violations of vestibular function in the form of permanent or paroxysmal disorders are almost mandatory for multiple sclerosis. Vestibular dysfunction is usually manifested by symptoms of irritation - a feeling of dizziness, spontaneous nystagmus, impaired vestibulo-spinal reflexes, spinal functions and others.

Changes in the mental sphere have various clinical manifestations: asthenic syndrome, hysteroform reactions, obsessive disturbances, depression and euphoria, a kind of organic dementia. Depression occurs in 20-30% of patients, and in 2-3% there are suicidal attempts. The risk of suicide in patients with multiple sclerosis is significantly higher than in the population as a whole.

Etiotropic therapy for multiple sclerosis does not currently exist. Complex symptomatic therapy of the disease is aimed at preventing the destruction of brain tissue and suppressing autoimmune inflammation. Therapy includes corticosteroids, adrenocorticotropic hormone (ACTH), interferons, glatiramer acetate, in the acute stage of the disease, immunosuppressive therapy with cytostatics is prescribed.

However, the existing scheme for the treatment of multiple sclerosis has significant drawbacks. The applied medical and physical methods of therapy do not significantly reduce the severity of neurological manifestations, their rate of increase, or significantly increase the duration of remissions. With the help of these drugs, it is impossible to achieve the repair of defects associated with the destruction of myelin in the shells of axons, and, consequently, the patient's recovery.

Secondly, it is also not possible to improve the condition of patients and stop the loss of memory, attention and adequate thinking, as well as stopping the pyramidal symptoms: dizziness, loss of vision and other disorders. In addition, the drugs used do not eliminate the autoimmune component in the pathogenesis of multiple sclerosis and, therefore, are not able to break the vicious cycle of disease progression.

At the same time, corticosteroid therapy in increasing doses gives a number of side effects, manifested in the development of Itsenko-Cushing's syndrome, hypertension, exacerbation of peptic ulcer, hypertrichosis and other effects, and immunosuppressive therapy significantly increases the risk of developing infectious diseases.

It is known that chronic fatigue syndrome, which is currently regarded as an independent disease, is often found in multiple sclerosis. Usually, this syndrome manifests itself in the form of an inability to prolong or repeat the usual actions that are everyday for the patient and the need for frequent rest. Fatigue affects not only physical but also mental performance. Chronic fatigue significantly affects the quality of life of patients and even in the early stages of the disease limits their ability to work. It is believed that the immune system also takes part in the development of this syndrome, which is manifested, in particular, in increasing the content of pro-inflammatory cytokines in the blood serum of patients.

There is no specific treatment for chronic fatigue syndrome. At the same time, a sufficient number of means and methods of treatment are proposed, including the use of fasting, special diets, vitamin therapy, herbal medicine, nutraceuticals and biologically active additives (BAA), adaptogens, antidepressants, some tranquilizers, nootropic drugs, enterosorbents and other means.

However, all these methods and means of treating chronic fatigue syndrome are symptomatic and do not fully take into account the pathogenetic features of the development and course of the disease.

It is known the use of drugs based on benzimidazole derivatives to increase the mental and physical performance of persons in professional activities associated with increased physical activity, in case of asthenic conditions; in the complex therapy of craniocerebral trauma, in cases of cerebrovascular accident.

The use of 2-ethyl-mercaptobenzimidazole bromide is known as a psychotropic agent with an actoprotective psycho-energetic and antihypoxic effect (RU, 1251374, A1).

The use of hydrobromide and hydrochloride derivatives of 2-ethylthiobenzimidazole, which exhibit weak tranquilizing activity (RU, 2061686, C1), is also known in pharmaceutical compositions.

A drug is known that belongs to the group of actoprotectors that have a moderate psychostimulating effect, in which the active ingredient is 2-ethyl-mercaptobenzimidazole hydrobromide, used to treat systemic lupus erythematosus (RU, 2157684, C2). This compound, which has antihypoxic activity, is used in borderline psychiatric disorders when stimulation of mental and physical functions is indicated.

It is known to use 2-ethyl-mercaptobenzimidazole bromide in the treatment of patients with primary biliary cirrhosis as an immunomodulating agent that acts on the cellular component of immunity and helps increase the effectiveness of other drugs used in the treatment of cirrhosis (RU, 2188012, C2).

The use of actoprotectors containing the 2-ethylthiobenzimidazole hydrobromide monohydrate derivative as an active ingredient for the treatment of Duchenne-Becker myodystrophy is known (RU, 2173144, C2). It was noted that this derivative, due to structural similarities with purine bases, adenine and guanine enhances the synthesis of mitochondrial enzymes, increasing the energy potential of muscle tissue and stimulating redox processes. An increase in the energy potential of muscle tissue contributes to the activation of protein and enzyme synthesis, which leads to a decrease in the permeability of myocyte membranes, promotes muscle regeneration, and slows the myodystrophic process.

The use of a drug containing 2-ethylthiobenzimidazole hydrobromide monohydrate is known as a means of increasing the body's resistance to hypoxia and restoring performance when performing heavy physical exertion and when exposed to adverse factors, as well as to eliminate polypharmacy, to prevent occupational hearing loss (RU, 2017483, C1), the prevention of acute glaucoma attacks during geomagnetic storms (RU, 2019161, C1).

It is known to use 2-ethylthiobenzimidazole hydrobromide for the treatment of hypothalamic-pituitary insufficiency in women (RU, 2138263, C1) using the effect of increasing the resistance of the brain to asphyxia and circulatory hypoxia, which is manifested by a marked increase in cerebral circulation, improved oxygen supply to the brain, as well as the effect of inhibiting degradation energy functions of mitochondria of neuroglial cells.

The increased formation of mitochondrial enzymes and structural mitochondrial proteins provides an increase in energy production and maintains a high degree of conjugation of oxidation with phosphorylation.

Maintaining a high level of ATP synthesis with oxygen deficiency contributes to the pronounced antihypoxic and antiischemic activity of benzimidazole derivatives, while pharmaceutical compositions based on these compounds enhance the synthesis of antioxidant enzymes and have a pronounced antioxidant effect.

The purpose of the invention is to develop a medicinal product and method for the treatment of multiple sclerosis, other neurodegenerative diseases and chronic fatigue syndrome.

When creating the invention, the task was to find a drug that can have a combined psychotropic and immunotropic effect and thereby significantly reduce the pathological effects associated with the neurodegenerative consequences of myelin destruction in multiple sclerosis, pathological effects in other neurodegenerative diseases and chronic fatigue syndrome.

Analysis of the above data revealed common signs in the effectiveness of action on the central nervous and immune systems of drugs based on benzimidazole derivatives.

The problem was solved by the development of a pharmaceutical composition containing benzimidazole derivatives as an active ingredient, which have a pronounced psychostimulating and immunomodulating effect, as well as the development of methods for treating these diseases.

Studies of the biological activity of benzimidazole derivatives, confirming the effectiveness of the drug for the treatment of multiple sclerosis, other neurodegenerative diseases and chronic fatigue syndrome, were performed using 2-ethylthiobenzimidazole hydrobromide in the following experimental models.

Example 1. The effect of benzimidazole derivatives on neurochemical indices of neurodegeneration in rats caused by MPTP neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).

MPTP neurotoxin (Schneider & Kovelowski, 1990) was used as an experimental model of neurodegenerative pathology that causes persistent disorders of specific neurons, activation of membrane lipid peroxidation, membrane transport blockade, and intracellular metabolism of neurotransmitters. The experiments were performed on adult male Wistar rats.

This toxin was administered to rats intraperitoneally twice a day at a dose of 20 mg / kg, then the animals were decapitated, the striatum was removed from the brain, and the secretory ability of this brain structure, providing cognitive and motor activity, was studied under ex vivo perfusion of brain fragments according to a known method (Kereczen et al., 1984; Budygin et al., 1996). A group of experimental animals with a simulated neurodegenerative pathology was also injected with 2-ethylthiobenzimidazole hydrobromide (hereinafter EBIG) at a dose of 50 mg / kg ip.

As the studied parameters, we used the quantitative content of the neurotransmitter dopamine and its metabolite - dioxiphenylacetic acid (hereinafter DOPUK) in isolated fragments of the striatum of the brain of rats. The test results are presented in table. one.

From the results shown in Table 1, it is seen that a single injection of neurotoxin MPTP (group 2) inhibits the metabolism of the neurotransmitter dopamine, which is accompanied by a decrease in the concentration of DOPUK by 44% compared with the control. Administration of MPTP neurotoxin for 5 days (group 3) caused a decrease in dopamine neurotransmitter secretion to 33% compared to the control. The introduction of 2-ethylthiobenzimidazole hydrobromide at a dose of 50 mg / kg (group 4) restores the initial secretion of dopamine to 118%, which indicates its ability to compensate for these effects of neurotoxic brain damage.

Example 2. The effect of benzimidazole derivatives on the behavioral symptoms of neurodegeneration caused in rats by neurotoxin MPTP.

It is known that the destructive effect of MPTP neurotoxin on the secretory processes of the striatum of the brain at the level of the whole organism is manifested in the form of symptoms of oligokinesia, tremor and muscle rigidity. The change in these parameters was studied in experiments on Wistar rats, which were injected with neurotoxin MPTP (20 mg / kg) or neurotoxin MPTP (20 mg / kg) in combination with 2-ethylthiobenzimidazole hydrobromide (50 mg / kg), as described in example 1 .

As the studied parameters, the severity of oligokinesia was taken, which was assessed by the level of their motor activity in the open field test and muscle rigidity, which was evaluated in arbitrary units according to the known method (Voronina et al., 2000). The research results are presented in table. 2.

table 2 The effect of benzimidazole derivatives on the behavioral symptoms of neurodegeneration caused by MPTP neurotoxin and EBIG in rats Group number Substances used, their doses, administration regimen, number of animals n The severity of oligokinesia,% of control Muscular rigidity, in arbitrary units - points one Control, saline, n = 8 100 ± 12 0.3 2 MPTP (20 mg / kg, once a day for 5 days), n = 6 10 ± 4 * 1.0 * 3 MPTP (20 mg / kg, once a day for 5 days) + EBIG (50 mg / kg, once), n = 6 55 ± 6 #
(after 1 h) 0.3 #
(after 3 hours)

As can be seen from the table. 2, the introduction of a toxin within 5 days leads to a decrease in the motor activity of animals by 10 times and an increase in muscle rigidity by 3 times. A single injection of 2-ethylthiobenzimidazole hydrobromide at a dose of 50 mg / kg after 1 hour provides a partial restoration of mobility and complete disappearance of muscle rigidity, which indicates its ability to compensate for the behavioral symptoms of neurotoxic brain damage.

Example 3. The effect of benzimidazole derivatives on the symptoms of impaired attention and spatial orientation in mice caused by the excitatory amino acid l-glutamate in neurotoxic concentration.

As an experimental model of impaired attention and orientation in space resulting from neurodegenerative processes, we used a test of the research behavior of animals in a cruciform labyrinth (the method is described by Salimov, 1988; Salimov et al., 1995; Salimov et al., 1995). Studies were conducted on adult male C57BL mice.

Bilateral application to the frontal cortex of mice (coordinates: F - 2.0, L - 1.4, Н - 0.6) 5 μl 1.0 mM l-glutamate solution was used as a damaging factor. It is known that at this concentration, l-glutamate has a neurotoxic effect (Finkbeiner, Stevens, 1988; Crabbe, Dorsa, 1989; Meldrum, Garthwaite, 1990) and causes local death of about 95% of glutamate-sensitive neurons in the region within 1-2 hours applications, the restoration of which does not occur, at least during the next month. Testing was carried out a week after application. 2-ethylthiobenzimidazole hydrobromide was administered intraperitoneally at a dose of 50 mg / kg 30 minutes before testing. The test results are shown in table.3.

Table 3 The effect of benzimidazole derivatives on impaired motor activity and spatial orientation in mice Group number Test model, substance, mode of administration, dose, number of animals n Duration of the labyrinth examination up to the criterion of 12 transitions, s The number of transitions to the first full maze walk one Saline application (control), n = 25 224.3 ± 14 4.7 ± 0.2 2 Application of l-glutamate, once, n = 25 304.9 ± 33.3 *** 7.4 ± 0.6 *** 3 Application of l-glutamate in combination with EBIG (one week after l-glutamate, 50 mg / kg, once), n = 25 216.6 ± 12.1 ### 4.8 ± 0.2 ### Note: *** and ### mean a statistically significant difference from the effect of the introduction of physiological saline and neurotoxic application of l-glutamate, respectively.

From the table. Figure 3 shows that the neurotoxic application of l-glutamate caused pronounced impaired attention and orientation in space, which manifested itself in the form of an increase in the number of transitions until the first complete maze bypass. The application of l-glutamate also caused a slowdown in the research activity of mice, which manifested itself in the form of an increase in the duration of the labyrinth examination to the criterion of 12 transitions. A single injection of 2-ethylthiobenzimidazole hydrobromide at a dose of 50 mg / kg completely eliminated the indicated behavioral manifestations of the neurotoxic effect of l-glutamate.

Example 4. The effect of benzimidazole derivatives on the symptoms of chronic fatigue in mice caused by subchronic administration of the antipsychotic haloperidol.

As an experimental model of chronic fatigue syndrome, we used an estimate of the time of complex sensorimotor (research) activity in mice that received a subchronic course of haloperidol antipsychotic.

As measurements of the binding of labeled dopamine agonists show, daily administration of haloperidol for 2–3 weeks at doses higher than 0.5 mg / kg leads to an increase in the number of D2 dopamine receptors in the striatum (Joseph et al., 1983; Fleminger et al., 1983 ; Hitri et al., 1978) and in the adjacent nucleus (Seeger et al., 1982; Wolffgramm et al., 1990; Hitri et al., 1978), observed for at least 7 days after cancellation of haloperidol. Moreover, chronic difficulties of complex sensorimotor (research) activity are observed (Salimov et al., 2000).

Studies were conducted on adult male C57BL mice. Haloperidol at a dose of 1 mg / kg was administered intraperitoneally once a day for 12 days. The sensorimotor activity of mice in a cruciform labyrinth was studied according to the known method (Salimov, 1988; Salimov et al., 1995; Salimov et al., 1995) a day after the end of the subchronic administration of haloperidol antipsychotic. 2-ethylthiobenzimidazole hydrobromide (EBIG) was administered intraperitoneally at a dose of 50 mg / kg 30 minutes before the test. The test results are shown in table 4.

Table 4 The effect of benzimidazole derivatives on the violation of complex sensorimotor (research) activity caused by the subchronic administration of haloperidol and an EBIG derivative Group number Substances used, their doses, administration regimen, number of animals n Duration of the labyrinth examination up to the criterion of 12 transitions, s The number of transitions to the first full maze walk one The introduction of physiological saline (control), n = 25 248.5 ± 12.7 5.6 ± 0.3 2 The introduction of haloperidol (1 mg / kg, once a day for 12 days), n = 25 369.1 ± 39.2 *** 4.9 ± 0.2 3 Administration of haloperidol (1 mg / kg, once daily 256.6 ± 15.4 ### 5.1 ± 0.4 within 12 days) in combination with EBIG (a day after the course of haloperidol, once, 50 mg / kg), n = 25 Note: *** and ### mean a statistically significant difference from the effect of the introduction of saline and antipsychotic haloperidol, respectively.

From table 4 it is seen that the introduction of the antipsychotic haloperidol causes chronic difficulty (slowdown) of research activity, which manifested itself in the form of an increase in the time it took for the animals to make 12 transitions from sleeve to sleeve of the labyrinth. A single injection of 2-ethylthiobenzimidazole hydrobromide, performed a day after the last injection of haloperidol, completely eliminated these symptoms of difficulty in research activity.

The pharmaceutical composition according to the invention, containing a benzimidazole derivative as a biologically active ingredient, has been used under clinical conditions in the treatment of 10 patients with multiple sclerosis and 10 patients suffering from chronic fatigue syndrome.

Example 5. The use of 2-ethylthiobenzimidazole hydrobromide for the treatment of multiple sclerosis.

The pharmaceutical composition according to the invention, containing as a biologically active ingredient a benzimidazole derivative, for example 2-ethylthiobenzimidazole hydrobromide, can be used according to the invention for the prevention and treatment of multiple sclerosis and other neurodegenerative diseases in a daily dose of 500-1500 mg with a course of 20-25 days with the possibility of repeating the course of treatment after a two-week interval.

The proposed method of treatment was used in the treatment of multiple sclerosis in 10 patients with various clinical forms of the disease. As an example of the effectiveness and safety of treatment of multiple sclerosis with 2-ethylthiobenzimidazole hydrobromide, we provide an extract from the medical history.

Patient P. 47 years old (medical history No.201 / 46). Diagnosis: Multiple sclerosis, cerebrospinal form, relapsing-remitting form. 2 severity.

She fell ill in 1990, when there was a sharp weakness in the legs, numbness, visual impairment. Three months later, the functions fully recovered. In 1997, after physical exertion, weakness appeared in the hands, coordination of movements was disturbed, and vision deteriorated. It was treated with piracetam, pentoxifylline, multivitamins, symptoms slowly regressed. Last exacerbation since May 2003.

In the study of the nervous system: knee and Achilles reflexes are higher on the right, conductor type D9 hypersthesia, deep sensitivity of the lower extremities is disturbed, Barre symptom from both lower extremities, no abdominal reflexes, incoordination during PNP, instability in the Romberg position, positive Neri symptom , limitation of the volume of active movements in the cervical and lumbar spine, mainly rotational and lateroflexic.

On admission: blood test - Hb - 126 g / l, Er 4.4 10 ¹² l ^-1 , color indicator - 0.87; L - 7.5 · 10 l, of which: eosinophils - 1%, basophils - no, young forms - no, stab - 2%, segmented - 74%, lymphocytes - 16%, monocytes - 7%, ESR - 9, 0 mm / hour. Glucose level - 5.17 mmol / L, creatinine - 71.5 mmol / L, creatine - 20.5 μmol / L.

Urinalysis: color - yellow; transparency is incomplete; the reaction is acidic; protein - no; glucose - no; cylinders and epithelium of the kidneys are absent; erythrocytes - no; white blood cells 0-1 in the field of view; squamous epithelium - 0-1 in the field of view; bacteria in large numbers.

ECG: heart rate - 70 per min, sinus rhythm, blockade of the left anterior branch of the bundle of His, signs of left ventricular hypertrophy.

Echocardiography: mild aortic sclerosis, cardiac cavities are not dilated.

MRI of the brain: no pathological changes.

Treatment: piracetam, pentoxifylline, B vitamins, massage. The patient received 2-ethylthiobenzimidazole hydrobromide three times a day, 250 mg orally. Taking the drug lasted for three weeks.

Against the background of the therapy, clinical and MR tomography remission was achieved. The patient returned to normal clinical and immunological parameters. Objectively, the mental and physical condition improved, which was characterized by a decrease in the severity of the pathological symptoms of multiple sclerosis, an increase in the muscle strength of the lower extremities, an increase in the volume of physical activity, and an improvement in the coordination of movements. Significantly improved memory and speed of thought processes. Improved mood and sleep. The patient was discharged under the supervision of a local neurologist with a recommendation to continue treatment with ethylthiobenzimidazole on an outpatient basis.

In connection with the above mechanism of action of benzimidazole derivatives, for example 2-ethylthiobenzimidazole hydrobromide, on the central nervous system and the immune system of patients with multiple sclerosis, the pharmaceutical composition according to the invention can also be used to treat other neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, in a daily dose of 750 -1500 mg with a course of 20 days with the possibility of repeating the course of treatment after a two-week interval.

Example 6. The use of 2-ethylthiobenzimidazole hydrobromide for the treatment of chronic fatigue syndrome.

The pharmaceutical composition according to the invention, containing benzimidazole derivatives, for example 2-ethylthiobenzimidazole, as a biologically active substance, can be used according to the invention for treating chronic fatigue syndrome in a daily dose of 500-1000 mg in a course for 15-20 days with the possibility of repeating the course of treatment after a two-week interval.

Clinical studies of the effectiveness of the use of a pharmaceutical composition according to the invention, for example, containing 2-ethylthiobenzimidazole hydrobromide as an active ingredient, for the treatment of chronic fatigue syndrome (CFS) were carried out in a group of 10 patients. As an example of the effectiveness of the treatment of CFS by the method according to the invention, we provide an extract from the medical history.

Patient Ch. 29 years old (No. 2995/180) Diagnosis: Chronic fatigue syndrome. Neurasthenia with syncopal seizures.

Sick since 1993 after a traumatic situation in life. Complains of persistent headache, general weakness, weakness in the lower extremities, noise in the head, fatigue, irritability, tearfulness, fainting.

In the study of the nervous system it was established: deep reflexes are increased, D = S, animated by the functional type, tremor of the fingers of the upper extremities, incoordination when performing dynamic coordinating tests from two sides (functional).

Upon admission, a blood test: Hb - 130 g / l; Er - 4.5 10 l; color indicator - 0.86; Rt - 8%; L - 4.4 10 L, of which E - 6%, B - no, M - no, Yu - no, P - 6%, C - 47%, L - 37%, M - 4%; Tr - 270. ESR - 7 mm / hour. Blood coagulability - 10 min.

Glucose - 5.06 mmol / L, urea - 6.6 mmol / L, bilirubin - 16.5 mmol / L, protein - 59 g / L, cholesterol - 5.64 mmol / L, IPT - 87%.

Urinalysis: color - straw yellow, transparency - incomplete, density - 1010 g / l, reaction - acid, protein - no, glucose - no, cylinders, kidney epithelium - not found. Er - no, L - isolated in the field of view.

ECG - heart rate - 77 per min, the position of the electrical axis of the heart is normal, sinus rhythm.

EEG - mild diffuse changes in the bioelectric activity of the brain.

Treatment: Cavinton, ATP, vitamins, sibazon, mezapam, 2-ethylthiobenzimidazole hydrobromide, the patient received daily 750 mg orally for 15 days.

As a result of the therapy, a significant improvement in the general condition of the patient was achieved. Deep reflexes returned to normal, coordination improved significantly, tremor of the upper extremities disappeared. The frequency and intensity of headaches has decreased significantly. Improved mood, appetite, complaints of weakness are not presented. The patient was discharged with a recommendation to conduct a second course of therapy with 2-ethylthiobenzimidazole hydrobromide after a month on an outpatient basis.

Thus, from the above test results of the pharmaceutical composition according to the invention, in particular the biological activity of its active ingredient, benzimidazole derivatives, in particular 2-ethylthiobenzimidazole hydrobromide, in relation to disorders caused by multiple sclerosis, other neurodegenerative diseases and chronic fatigue syndrome, the following conclusion can be drawn.

The pharmaceutical composition according to the invention is an effective drug for the treatment of multiple sclerosis, other neurodegenerative diseases and chronic fatigue syndrome using methods of treating these diseases according to the invention.

The use of benzimidazole derivatives or their pharmacologically acceptable salts as active ingredients of the pharmaceutical composition allows the creation of pharmaceutical compositions of a wide range, in particular for neurology and immunopathology. Derivatives of benzimidazole have an effect on the central nervous and immune systems of warm-blooded animals, which, depending on the amount of the active ingredient in the drug, the dose, conditions and dosage regimen, can be chosen optimal.

The pharmaceutical composition according to the invention may, as an active ingredient, contain a composition of several active compounds, for example benzimidazole and nicotinic acid, which are well compatible and, depending on biological activity, can, for example, increase the effectiveness of a drug in the body.

Moreover, the pharmaceutical composition according to the invention may be a solution of the active ingredient in a pharmaceutically acceptable liquid carrier or solvent, for example in water, physiological saline, buffer solutions.

In addition, the pharmaceutical composition according to the invention may be a fine powder of the active ingredient, suitable for use in injection solutions, applications, in the preparation of other dosage forms.

Derivatives of benzimidazole according to the invention are readily soluble in water or in alcohol, physiological saline, buffer solutions or compatible with ingredients that increase their solubility.

Oral administration is usually the preferred route for administering drugs to the body, as this method is the most convenient and acceptable for the patient. The pharmaceutical compositions according to the invention can be made in the form of means for oral administration, for example tablets, granules, beads, powders, capsules, suspensions, emulsions. Moreover, the pharmaceutical composition may additionally contain means for increasing bioavailability, for example microcrystalline cellulose, or, for example, biologically active additives, which allows to reduce the content of biologically active ingredient in a single dose of the drug. Or, in addition, it can be made in the form of a spontaneously dispersible concentrate, which, when mixed with distilled water or an alcoholic solution, creates aqueous microemulsions, phase-stable, with increased penetration and distribution ability.

Rapid absorption of the active ingredient of the pharmaceutical composition according to the invention can be achieved by parenteral injection, which is traditional for clinical conditions, but less acceptable for self-medication. In this case, it is effective to deliver the drug to the body by rectal administration, using suppositories, enemas, soft gelatine capsules, suppositories, for example in the form of solid dosage forms with a suitable configuration, which either melt at body temperature or dissolve or disperse in a cavity coated mucous membrane.

Specialists in the field of medicine are aware that in order to improve the adsorption of biologically active substances having poor solubility in water or in any selective medium, the active ingredient of the pharmaceutical composition in the form of a highly saturated solution in solid form can be encapsulated in one or more plate membranes containing lipids for example, in liposomes, allowing the active ingredient to be delivered to a specific region.

According to the invention, in the pharmaceutical composition, the benzimidazole derivatives and their salts can be contained in a liposomal form, for example in a multiphase liposome drug delivery system, which is stable and can be easily diluted with water, in the state of the pharmaceutical composition from a diluted liquid state to a gel state, which is important for derivatives poorly soluble in the acidic environment of the gastrointestinal tract, and also expands the possibility of using higher doses of the active ingredient that when administered orally.

In addition, in a pharmaceutical composition according to the invention, the pharmaceutically acceptable carrier may be a composition containing pharmacologically active additives.

Moreover, according to the invention, pharmacologically active additives can be selected from the group of stabilizers, dispersants, flavors, emulsifiers, conductors, bioavailability enhancers, one of which may be a means to increase the solubility of sparingly soluble compounds, for example, dimethyl sulfoxide (DMSO) solvent.

In many diseases, it is advisable to use various methods of local effects on the pathological process, especially if there are contraindications to systemic therapy, for example, with impaired liver or kidney function, as well as other vital organs. One of the methods of local exposure is the use of external drugs containing analgesic, anti-inflammatory, immunomodulating or antiseptic drugs.

It is known that, based on the sensitivity of the skin, the likelihood of its irritation and transdermal absorption capacity (hygrocopy of the skin), it is desirable to maintain the pH of the pharmaceutical product for external use in the range of 4-8, more preferably in the range of 5-7. When the pH is too low (3.0 or less), high acidity causes severe skin irritation. When the pH is too high (9.0 or more), the transdermal absorption of the active ingredient decreases, skin irritation intensifies, and the drug turns yellow. The most optimal pH values for transdermal absorption are from 4 to 8.

To enhance the transdermal absorption (absorption) of the active ingredient in the pharmaceutical composition according to the invention, a so-called absorption enhancer, for example, organic bases, for example triethanolamine, crotamiton, medium chain fatty acid esters, 1-menthol, benzyl, may also be contained in effective amounts. alcohol and the like. The organic base facilitates the release of the active ingredient from the base, as it makes it more water soluble due to the formation of salts. The organic base acts as a regulator of the pH of the drug.

Alkaline compounds (potassium and sodium hydroxide, triethanolamine, diisopropanolamine, monoethanolamite and others) can also be used to adjust the pH of the drug.

Solutions of hydrochlorides, acetates, phosphates, hydrobromides, nitrates, sulfates and other organic salts of benzimidazole derivatives have a pH of 4-7, which creates good prospects for creating drugs for external use.

The pharmaceutical composition for external use may be a gel emulsion containing, as an active ingredient, a derivative, for example, 2-ethylthiobenzimidazole hydrobromide according to the invention, a hydrophilic polymer, an oily substance, a nonionic surfactant, an alkaline compound or an organic base as a pH regulator environment and water. Moreover, derivatives of 2-ethylthiobenzimidazole hydrobromide according to the invention are chemically compatible with these ingredients, do not cause allergic reactions and are well tolerated by patients.

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Claims (4)

1. A pharmaceutical composition for treating chronic fatigue syndrome, comprising a biologically active ingredient and a pharmaceutically acceptable carrier, characterized in that the biologically active ingredient contains 2-ethylthiobenzimidazole hydrobromide in an effective amount and a pharmaceutically acceptable liquid carrier. 2. The pharmaceutical composition according to claim 1, characterized in that the liquid carrier is selected from the group consisting of water, alcohol, physiological fluid, buffer solutions. 3. A method for the prevention and treatment of chronic fatigue syndrome by administering a drug, characterized in that the pharmaceutical composition according to claim 1 or 2 is administered in a daily dose of 250-1500 mg for 5-20 days with the possibility of repeating the course of treatment after a break of 5 or more days. 4. The method according to claim 3, characterized in that it additionally uses cavinton, adenosine triphosphate, vitamins, sibazon, mezapam.