RU2423981C2 - Pharmaceutical composition for treating parkinson's disease - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacology and pharmaceutics, and concerns a pharmaceutical composition containing a therapeutically effective amount of N-(2-adamantyl)-hexamethylenimine hydrochloride (hymatan) as an active ingredient, and excipients - starch, lactose, microcrystalline cellulose (MCC), aerosil, ludipress, twice-substituted calcium phosphate, polyvinylpyrrolidone, methylcellulose, carboxymethyl cellulose and its sodium salt, oxypropylcellulose, oxpropylmethylcellulose, mannitol, sorbite, stearic acid and/or its salts and other excipients. The composition is presented as solid dosage forms.

EFFECT: dosage forms easily release the active ingredient that enables its high bioavailability; the solid dosage forms provides a manifested antiparkinsonian action when administered in the patients suffering Parkinson's disease.

14 cl, 3 tbl, 10 ex

Description

The invention relates to medicine, in particular to pharmacology and pharmacy, and relates to a pharmaceutical composition for the treatment of Parkinson's disease containing N- (2-adamantyl) -hexamethyleneimine hydrochloride as an active ingredient (RF Patent No. 1825499, “N- (2-adamantyl hydrochloride) ) -hexamethyleneimine with anticaleptic activity ”, Seredenin SB and co-authors; BI No. 24, 1993).

According to the World Health Organization, the number of patients with Parkinson's disease is 3.7 million. Annually 305 thousand cases are recorded. Parkinson's disease is a chronic progressive neurodegenerative disease caused by the death of dopaminergic neurons and the resulting disturbances in other neurotransmitter systems, in particular activation of choline and glutamatergic neurotransmission. A common mechanism of neurotoxic effects is an unbalanced increase in the production of free radicals, one of the important sources of which is the oxidation of dopamine.

There are several groups of drugs used to treat a disease. The main and most common method is replacement therapy with drugs containing the dopamine precursor L-DOPA (L-3,4-dihydroxyphenylalanine). However, the possibilities of these drugs are limited by the occurring side effect and decreased effectiveness in the treatment process. In the pharmacotherapy of parkinsonism, anticholinergic and dopamine receptor agonists are also used, mainly selective action. Monoamine oxidase inhibitors (MAOs) and catecholamine-O-methyltransferases are used to increase the effectiveness of dopamine replacement therapy, MAO-B inhibitors have neuroprotective potential. Derivatives of adamantane, amantadine and memantine, which cause blockade of the glutamate receptors of the NMDA subtype and stimulate dopaminergic transmission, are also used in therapy. Antioxidants are included in the complex therapy of the disease. Currently, in the absence of data on the primary link in the pathogenesis of the disease and the interdependence of emerging biochemical disorders, the most promising development of new anti-Parkinsonian drugs that can affect several parts of the pathogenetic process.

In a pharmacological study of N- (2-adamantyl) -hexamethyleneimine hydrochloride, dubbed hematan, it was shown that the drug has a complex mechanism of action aimed at several components of the pathogenetic process in Parkinson's disease, weakens glutamate and serotonergic activity, and stimulates dopaminergic activity of brain structures , reduces the activity of MAO-B, has antioxidant properties (Waldman E.A. et al., Exper. and Clinical Pharmacol. - 1999. - No. 4, p. 3-7; Andyarzhanova E.A. et al., Ex perim. and clinical pharmacol. - 2001. - No. 6, pp. 13-17; Waldman E.A. et al., Experimental and clinical pharmacol. - 2003. - No. 5, p. 3-5). The ability of gimantan to eliminate oligokinesia, rigidity, and tremor in various experimental models is described (Waldman E.A. et al., Exper. And Clinical Pharmacol. - 1999. - No. 4, p. 3-7; Nerobkova L.N. et al. ., Experimental and Clinical Pharmacol. - 2000. - No. 3, p. 3-6). The spectrum of pharmacological effects established in the experiment made it possible to recommend N- (2-adamantyl) -hexamethyleneimine hydrochloride for clinical study as an anti-Parkinsonian drug.

The essence of the present invention is to create a pharmaceutical composition, the active substance of which is N- (2-adamantyl) -hexamethyleneimine hydrochloride, to develop, based on this composition, solid dosage forms for oral administration that have high bioavailability and meet all the requirements of the State Pharmacopoeia, as well as the use of solid dosage forms of the specified pharmaceutical composition in Parkinson's disease.

The pharmaceutical composition in solid form contains N- (2-adamantyl) hexamethyleneimine hydrochloride as an active ingredient in a therapeutically effective amount ranging from 0.01-0.10 g, and at least as auxiliary substances one selected from the group consisting of: starch, lactose, microcrystalline cellulose (MCC), aerosil, ludipress, calcium phosphate disubstituted, polyvinylpyrrolidone, methyl cellulose, carboxymethyl cellulose and its sodium salt, hydroxypropyl cellulose, hydroxypropylmethyl methylcellulose, mannitol, sorbitol, stearic acid and / or salts thereof and other adjuvants permitted for medical application.

The first variant of the pharmaceutical composition for the treatment of parkinsonism contains a therapeutically effective amount of the active substance and excipients, which include lactose, starch, microcrystalline cellulose, aerosil, calcium phosphate disubstituted, stearic acid and / or its salts in the following ratio of components, wt.% ( composition and ratio of components per tablet):

N- (2-Adamantyl) -hexamethyleneimine hydrochloride 5.0-45.0 Lactose 10.0-51.0 Microcrystalline cellulose 6.0-35.0 Stearic acid and / or its salts 1.0-1.3 Starch rest

Starch is preferably used potato and / or corn, and as the salt of stearic acid, mainly magnesium stearate. The pharmaceutical composition is made in solid form, mainly in the form of tablets or capsules containing 0.01-0.10 g of active ingredient. A tablet or capsule mass is obtained by wet granulation.

The second variant of the pharmaceutical composition based on N- (2-adamantyl) -hexamethyleneimine hydrochloride contains a therapeutically effective amount of the active substance and excipients, which are at least one selected from the group consisting of ludipress, lactose, microcrystalline cellulose, aerosil, stearin acid and / or its salts in the following ratio of components, wt.%:

N- (2-Adamantyl) -hexamethyleneimine hydrochloride 5.0-40.0 Stearic acid and / or its salts 1.0-1.5 Ludipress rest

The pharmaceutical composition is in solid form, preferably in the form of a tablet or capsule, containing 0.01-0.10 g of active ingredient. The mass for solid dosage forms, such as capsules, tablets, can be obtained from the compositions of the present invention by any suitable method, for example, wet granulation, direct mixing, etc.

The following examples illustrate variants of a pharmaceutical composition.

Example 1. Pre-weighed sieved 200.0 g of N- (2-adamantyl) hexamethyleneimine hydrochloride (41.67 wt.%), 140.0 g of lactose (29.17 wt.%) And 44.0 g of microcrystalline cellulose ( 9.17 wt.%) Are mixed in a mixer. Moisturize the mass with starch paste 8.0%. The moistened mass should not have interspersed from poor distribution of the humidifier and should clump well. The wetted mass is subjected to wet granulation. Wet granulate is dried in an oven for 2-3 hours at a temperature of 40 ± 5 ° C or at room temperature for 22-24 hours to a residual moisture content of 2-3%. The dried mass of granules is ground in a granulator with a pore size of 1.0-1.5 mm. The granulate is collected, the remainder of potato starch (82.4 g) is added. The mass of dry granulate dusted with stearic acid in an amount of 3.7 g (0.83 wt.%). The granules are compressed on a tablet press or encapsulated. Upon external examination, the surface of the tablets should be smooth and uniform, tablets and capsules should not crumble. The resulting tablets and capsules contain 0.05 g of active ingredient and meet the requirements of the State Pharmacopoeia (see table 1).

Example 2. Pre-weighed sieved 200.0 g of N- (2-adamantyl) hexamethyleneimine hydrochloride (41.67 wt.%), 140.0 g of lactose (29.17 wt.%) Are mixed in a mixer. Humidify the mass with starch paste 8.0%, adding it in parts. The wetted mass is subjected to wet granulation. Wet granulate is dried in an oven for 2-3 hours at a temperature of 40 ± 5 ° C or at room temperature for 22-24 hours to a residual moisture content of 2-3%. The dried mass of granules is ground in a granulator with a pore size of 1.0-1.5 mm. The granulate is collected, 44.0 g of microcrystalline cellulose (9.17 wt.%) And the remainder of potato starch (82.4 g) are added. The mass of dry granulate dusted with stearic acid in an amount of 3.7 g (0.83 wt.%). The granulate is compressed or encapsulated and tablets or capsules are obtained with an active substance content of 0.05 g. The obtained solid dosage forms meet the requirements of the State Pharmacopoeia (see table 1).

Example 3. Pre-weighed sieved 200.0 g of N- (2-adamantyl) -hexamethyleneimine hydrochloride (41.67 wt.%), 140.0 g of lactose (29.17 wt.%), 44.0 g of microcrystalline cellulose ( 9.17 wt.%) And potato starch (82.4 g) are thoroughly mixed, after which the mixture is moistened with purified water, then the moistened mass is granulated and dried to a residual moisture content of 2-3%. The dried granules are ground in a granulator. Dry granules are dusted with 0.8 g (1.0 wt.%) Of magnesium stearate. Get tablets or capsules with an active substance content of 0.05 g. The resulting solid dosage forms meet the requirements of the State Pharmacopoeia (see table 1).

Example 4. The preparation of solid dosage forms of N- (2-adamantyl) -hexamethyleneimine hydrochloride is carried out as in Example 1 based on 50.0 g (10.0 wt.%) Of the active substance, 220.0 g (44.0 wt.%) ) lactose, 50.0 g (10.0 wt.%) potato starch, 175.0 g (35.0 wt.%) microcrystalline cellulose and 5.0 g (1.0 wt.%) magnesium stearate. Get tablets or capsules with an active substance content of 0.01 g that meet all regulatory requirements (see table 1).

Example 5. The preparation of solid dosage forms of N- (2-adamantyl) -hexamethyleneimine hydrochloride is carried out as in Example 1 based on 100.0 g (20.0 wt.%) Of the active substance, 251.5 g (50.3 wt.%) ) lactose, 97.0 g (19.4 wt.%) potato starch, 45.0 g (9.0 wt.%) microcrystalline cellulose and 6.5 g (1.3 wt.%) magnesium stearate. Get tablets or capsules with an active substance content of 0.1 g that meet all regulatory requirements (see table 1).

Example 6. In a dry clean mixer, pre-sieved powders of N- (2-adamantyl) -hexamethyleneimine hydrochloride 10.0 g (10.0 wt.%), 89.0 g of ludipress and 1.0 g (1.0 wt. .%) magnesium stearate. The mass is mixed and pressed into tablets or encapsulated to obtain solid dosage forms with an active substance content of 0.01 g (see table 1).

Example 7. In a dry clean mixer, pre-sieved powders of N- (2-adamantyl) -hexamethyleneimine hydrochloride 20.0 g (20.0 wt.%), 79.0 g of ludipress and 1.0 g (1.0 wt. .%) magnesium stearate. The mass is mixed and pressed into tablets or placed in capsules with an active substance content of 0.02 g (see table 1).

Example 8. The preparation of solid dosage forms is carried out according to example 1, starting from 40.0 g (20.0 wt.%) Of N- (2-adamantyl) hexamethyleneimine hydrochloride, 158.0 g of ludipress and 2.0 (1, 0 wt.%) Magnesium stearate. Get tablets or capsules with an active substance content of 0.04 g that meet regulatory requirements (see table 1).

Example 9. The preparation of solid dosage forms is carried out according to example 1, starting from 60.0 g (30.0 wt.%) Of N- (2-adamantyl) hexamethyleneimine hydrochloride, 138.0 g of ludipress and 2.0 g (1 , 0 wt.%) Magnesium stearate. Get tablets or capsules with an active substance content of 0.06 g that meet regulatory requirements (see table 1).

Example 10. The preparation of solid dosage forms is carried out according to example 1 based on 100.0 g (30.0 wt.%) Of N- (2-adamantyl) hexamethyleneimine hydrochloride, 385.0 g of ludipress and 5.0 g (1, 0 wt.%) Magnesium stearate. Get tablets or capsules with an active substance content of 0.06 g that meet regulatory requirements (see table 1).

The use of a solid dosage form of N- (2-adamantyl) -hexamethyleneimine hydrochloride (gimantan) for the treatment of Parkinson's disease.

An open study of the effectiveness of N- (2-adamantyl) -hexamethyleneimine hydrochloride (gimantan) as a monotherapy of the initial stages of Parkinson's disease was carried out. At the first stage of the study, the drug dose was found to be the most effective with good tolerance, which was 25 mg per day with a single dose in the morning. In the second stage, 20 patients received hematan for 10 weeks as monotherapy. The criteria for inclusion of patients in the study were stage 1-2.5 of Parkinson's disease, the absence of previous treatment with antiparkinsonian drugs, the absence of severe dysfunctions of the main organs and systems. The duration of the disease ranged from 6 months to 1.5-3 years. The average age was 59 ± 11.3 years. To assess the effectiveness of treatment, the following scales were used: a unified rating scale for Parkinson's disease (UPDRS, Fahn S., Elton S., et al., 1987), global clinical exposure (CGI-I), a scale for assessing Hamilton anxiety. Safety assessment included: general examination of the patient, measurement of pulse and blood pressure, ECG, laboratory tests (hematology, biochemical blood counts, urinalysis). By the end of the course of hematan therapy, the percentage of improvement on the UPDRS scale was 15.5%. The analysis showed that the improvement was achieved both by improving the total score of section II of the scale - “daily activity” (by 43%), and due to section III - “movement disorders” (by 29%). The improvement on the CGI-I scale was detected in 15 (75%) patients, in 4 (18%) the absence of changes, in 1 patient the condition slightly worsened compared to the beginning of the study. Gimantan was effective against the main motor symptoms of Parkinson's disease - akinesia, rigidity, tremor. Against the background of taking gimantan, in parallel with the improvement of the motor sphere, the mood background improved, tearfulness, irritability decreased, and sleep was normalized. The average score on the Hamilton anxiety scale decreased from 17.6 ± 5.9 points to 12.6 ± 4.7 points (p <0.05). At a dose of 25 mg per day, hematan was well tolerated. In the first days of receiving hematan, 3 patients had slight dizziness and headaches, 1 patient - nausea, decreased appetite. These phenomena disappeared by the end of the first week. The results of the safety assessment of the hematan drug showed that the drug does not affect the biochemical parameters of blood, hematology, urine analysis. None of the patients had ECG deterioration during treatment with hematan. Thus, N- (2-adamantyl) -hexamethyleneimine hydrochloride (gimantan) at a dose of 25 mg per day can be effectively used for monotherapy of early and rigid forms of Parkinson's disease.

The following are examples illustrating the effectiveness of treatment with hematan.

Medical history 1.

Patient S., born in 1950. Diagnosis: Parkinson's disease, Rigid-rigid form, stage 2.5 on the Hoen-Yar scale.

Complaints when turning to trembling in the right hand, general stiffness when moving, feeling of “sticking” feet when walking, impaired handwriting (micrography), decreased mood.

Anamnesis: The patient considers herself ill for about 1.5 years, when she first noted tremors in her right hand. Over the next time, the symptoms increased: trembling of the right hand increased, general stiffness during movement increased, the handwriting changed, which became small, poorly legible when read, difficulty appeared when walking, the feet “stuck” when walking. A year later, he was diagnosed with Parkinson's disease, a rigidly rigid form. Before prescribing the drug Himantan, the patient received no anti-Parkinsonian therapy.

In neurological status at the time of the first treatment (examination): there is no meningeal and cerebral symptomatology. Cranial innervation is not broken. Easy hypomimia of the facial muscles. Speech is slow, understandable. There are no sensitive violations on the face. General bradykinesia. Muscle tone is increased in plastic type D> S, a symptom of a "gear" in the upper limbs D> S. Tremor of rest, constant, medium amplitude in the right hand. Medium-amplitude, unstable tremor of action in the right hand. When carrying out samples for pronation and supination, the right hand lags behind more, the right hand lags behind in the test for tapping with fingers and movement in the limbs. Tendon and periosteal reflexes are low D = S. In the Romberg position - it is stable. Coordination tests are performed with intention. The gait is slow, the soles of the feet “stick” when walking, acherokinesis. The patient has an anxious mood background, poor sleep, tearfulness, irritability (according to the Hamilton anxiety scale - 38 points, the Beck depression self-rating scale - 23 points).

The total score on the UPDRS scale was 31.5. The total score of section I is 1 point. The total score of section II (“daily activity”) is 9.5. The total score of Section III (“Motor Disorders”) - 21.5 points, (Table 2) for items 1) intellectual disabilities - 0, 2) mental disorders - 0, 3) depression - 1, 4) motivation / initiative - 0 , 20) rest tremor - 3, 21) action tremor - 1,5, 22) rigidity - 4, 23) test with tapping with fingers - 1,5, 24) hand movement - 1,5, 25) pronation / supination - 1.5 (table 2).

At the screening visit (before treatment with hematan) the patient underwent the following set of examinations: ECG, general blood and urine tests, biochemical blood tests (total protein, total bilirubin, ALT, blood glucose, alkaline phosphatase, creatinine). The results were within the age limits.

Gimantan was prescribed during the second visit, at a dose of 25 mg / day, once in the morning. The first change in well-being was noted by the end of the first week of receiving hematan, but a distinct dynamics was recorded after 2 weeks of taking the drug. By the third visit (the second week of taking the drug), the patient showed a decrease in stiffness of movements and tremor, which was confirmed by a decrease in the total score for UPDRS (see table 2). Improvement was achieved both by reducing the total score of section II of the scale - (7.5 points) “daily activity” (taking into account the patient’s subjective assessment of the dynamics of motor, autonomic symptoms, general activity), and due to section III (14 points) “movement disorders "(Reflecting changes in symptoms recorded directly by the doctor). The patient has decreased muscle tone, improved motility. The patient began to perform better tests on pronation-supination, movement of hands, tapping fingers. On a scale of "Global Clinical Impact - Improvement", the patient identified a good improvement (paragraph 2). By the fourth visit (the fourth week of taking the drug), a significant improvement was noted - the severity of general rigidity decreased, the patient became more mobile, noted improvement when walking (walking became easier since the feet “stuck” less). Tremor of action was not noted, resting tremor occurred periodically. The drug was well tolerated. At the fifth visit (fifth week of taking the drug), the patient's condition was regarded as stably good. By the sixth visit (the eighth week of taking the drug), the emotional mood background improved, which was reflected in a decrease in the total score on the Hamilton scale and Beck scale. In neurological status, a minimally pronounced low-amplitude, periodically occurring hand tremor remained at rest, which almost did not bother the patient. At the seventh visit (the ninth week of taking the drug), in comparison with the initial state of the patient, persistent good improvement was noted. On a scale of “Global Clinical Impact - Improvement”, the patient noted a very good improvement (1). On a scale of "Global Clinical Impact - Severity" mild manifestations of the disease (2). The Parkinson's stage of the Hoen-Yar scale decreased from 2.5 to 1 point. The eighth visit (the twelfth week of receiving hematan) - the patient is in good health, no side effects from taking the medicine have been identified. Sleep improved, the patient became easier to fall asleep, less likely to wake up at night. No tremor was detected. Tremor of rest is unstable, of small amplitude and severity, short in time. Muscle tone is low, in plastic type, somewhat more pronounced in the right hand. A very good improvement was noted compared with the start of treatment at the visit, the drug was canceled.

During the study, four times (at 1, 4, 6, 8 visits) laboratory parameters were evaluated (general blood test; biochemical blood test by indicators: total protein, total bilirubin, ALT, blood glucose, alkaline phosphatase, creatinine; general urine analysis). All the results obtained corresponded to the limits of age norms. ECG deterioration was not noted.

Medical history 2.

Patient B., 59 years old. Diagnosis: Parkinson's disease, akinetic-rigid form, stage 2 on the Hohen-Yar scale.

Complaints: stiffness in the right hand, inconsistent tremor in this hand, difficulty in moving in the left hand, general stiffness when walking and moving.

Medical history. In 2005, the patient noted stiffness when moving in her right hand. In 2006, stiffness began to build up in the right hand, later the patient felt stiffness in the left hand. The handwriting has changed (micrography). I began to notice a decrease in mood. Parkinson's was diagnosed in the winter of 2007. Over the past 3-4 months, an unstable rest tremor appeared in the right hand, and tremor also began to be noted during movement, especially when performing minor manipulations. I have not received any anti-Parkinsonian therapy.

In neurological status at the time of examination: meningial, cerebral symptoms were not noted. Cranial innervation is not broken. Easy hypomimia of the facial muscles. There are no sensitive violations on the face. General bradykinesia. Muscle tone plastic D> S. There was an increase in rigidity in the right hand, a symptom of the “gear”. Tendon and periosteal reflexes of moderate severity D = S. In the Romberg position - it is stable. Finger-nasal test performs with intention with both hands. Tremor of fingers of extended arms of medium amplitude. Tremor action in the right hand. Mild acherokinesis. The gait is slow, shuffling. When carrying out samples for pronation and supination, the right hand lags behind more, the right hand lags behind in the test for tapping with fingers and movement in the limbs.

The total score on the UPDRS scale was - 25.5. The total score of section I is 1 point. The total score of section II (“daily activity”) is 12 points. The total score of section III (“Motor impairment”) is 15.5 points, (see Table 3) for items 1) intellectual impairment - 0, 2) mental disorders - 0, 3) depression - 1, 4) motivation / initiative - 0, 20) rest tremor - 1,5, 21) action tremor - 1, 22) rigidity - 3, 23) test with tapping fingers - 1,5, 24) movement of the hands - 1,5, 25) pronation / supination - 1.5. On the Hamilton scale - 18 points. Beck scale (18 points) revealed depression.

At the screening visit (before treatment with hematan) the patient underwent the following set of examinations: ECG, general blood and urine tests, biochemical blood tests (total protein, total bilirubin, ALT, blood glucose, alkaline phosphatase, creatinine). The results were within the age limits.

The drug gimantan was prescribed during the second visit, at a dose of 25 mg / day, once. By the second week of taking the drug (third visit), there were no significant changes in well-being. There were no side effects. By the end of the fourth week of taking the drug (fourth visit), there was an improvement in the form of a decrease in resting tremor (the tremor became small in amplitude and less pronounced) and a slight decrease in tremor of action. Rigidity has decreased. Against the background of taking gimantan, the symptoms of the disease became less intense in severity. The marked decrease in stiffness of movements and tremor was confirmed by a decrease in the total score for UPDRS (15 points). Improvement was achieved both by reducing the total score of section II of the scale (3 points) “daily activity” (taking into account the patient’s subjective assessment of the dynamics of motor, autonomic symptoms, general activity), and due to section III (12 points) “movement disorders” (reflecting changes in symptoms recorded directly by the doctor). The patient has decreased muscle tone, improved motility. The patient began to perform better tests on pronation-supination, movement of hands, tapping fingers. On a scale of "Global Clinical Impact - Improvement" the patient identified a slight improvement (paragraph 3). Hamilton and Beck scores improved. Improved sleep sick. Side effects and negative dynamics in the patient’s health were not observed. In the fifth week of taking the drug (fifth visit), compared with the previous week, the patient's condition was regarded as consistently good. By the sixth visit (the eighth week of taking the drug), compared with previous visits, there was also a slight improvement. The severity of general rigidity decreased, the tremor of rest almost did not bother, the amplitude of the tremor at rest was minimal, the severity of the tremor of action remained at the same level (compared with the fifth visit). The indicators on the UPDRS scale improved (Table 3). The patient has become much more mobile. The emotional mood background has improved. Negative dynamics were not noted. At the seventh visit (ninth week of taking the drug), in comparison with the initial state of the patient, persistent good improvement was noted. The eighth visit (twelfth week of taking the drug) - the patient is in good health, side effects and negative dynamics from taking the medicine were not detected. The sleep improved significantly, the patient became easier to fall asleep, less likely to wake up at night. Regressed rest tremor, action tremor disappeared completely. The severity of general rigidity decreased, its minimal manifestations were noted in the left hand. Muscle tone is low, in plastic type, somewhat more pronounced in the right hand. Tendon and periosteal reflexes are low. In the Romberg position - it is stable. Coordination tests are performed confidently. A very good improvement was noted compared with the start of treatment. According to the Global Clinical Impact - Improvement scale, the patient noted very good improvement (1). On a scale of "Global clinical impact - severity" mild manifestations of the disease are noted. On the background of taking gimantan, indicators on scales improved (Hamilton, Beck, UPDRS). The rest tremor decreased significantly and almost did not bother the patient, the action tremor regressed completely. The effect of the drug on the state of muscle tone was noted, the severity of general rigidity decreased.

During the study four times (at 1, 4, 6, 8 visits) hemodynamic parameters were assessed (general blood count; blood biochemical analysis by indicators: total protein, total bilirubin, ALT, blood glucose, alkaline phosphatase, creatinine; general urine analysis). All the results obtained corresponded to the limits of age norms.

Table 1 Technological characteristics of the substance of N- (2-adamantyl) -hexamethyleneimine hydrochloride Indicator Indicator value Flowability, g / s 0 Bulk weight, g / cm ³ 0.475 ± 0.025 Compressibility, N 22.05 ± 2.5 Slope angle, ° 47.3 ± 1.3 Moisture content,% 0 Technological characteristics of a granular pharmaceutical composition for the treatment of Parkinson's disease Indicator Indicator value Flowability, g / s 10.1 ± 0.5 Bulk weight, g / cm ³ 0.46 ± 0.03 Compressibility, N 82.5 ± 9.5 Technological characteristics of the pharmaceutical composition for the treatment of Parkinson's disease using ludipress Indicator Indicator value Flowability, g / s 9.8 ± 0.4 Bulk weight, g / cm ³ 0.47 ± 0.05 Compressibility, N 81.8 ± 9.32 Characteristics of finished tablets of N- (2-adamantyl) -hexamethyleneimine hydrochloride obtained by wet granulation Indicator Indicator value Disintegration, min no more than 15 Compressive strength, H 53.77 ± 1.9 Abrasion resistance,% 98.3 ± 0.8 Characteristics of the finished tablets of N- (2-adamantyl) -hexamethyleneimine hydrochloride obtained by direct compression Indicator Indicator value Disintegration, min no more than 15 Compressive strength, N 48.81 ± 1.5 Abrasion resistance,% 99.7 ± 0.6

table 2 The dynamics of the symptoms of Parkinson's disease on the scales of UPDRS, Hamilton, Beck on the background of treatment with hematan (patient 1) Scales / Weeks 1 visit 1 2 visit 2 3 visit 3 4 visit 4 5 visit 5 8 visit 6 9 visit 7 12 visit 8 UPDRS 1) section, paragraph 1 (intellectual disabilities) 0 0 0 0 0 0 0 0 UPDRS 1) section, paragraph 2 (mental disorders) 0 0 0 0 0 0 0 0 UPDRS 1) section, paragraph 3 (depression) one one one 0 0 0 0 0 UPDRS 1) section, paragraph 4 (motivation) 0 0 0 0 0 0 0 0 TOTAL SCORE on the first section of UPDRS one one one 0 0 0 0 0 TOTAL UPDRS SECTION 2 SCORE 9.5 9.5 7.5 6 6 2 1.5 1.5 UPDRS 3) section, item 20 (rest tremor) 3 3 0.5 0 0 0.5 0.5 0.5 UPDRS 2) section, item 21 (action tremor) 1.5 1.5 one 0.5 0.5 0 0 0.5 UPDRS 3) section, clause 22 (rigidity) four four 1.5 2.5 2.5 2 2 0.5 UPDRS 3) section, item 23 (test with tapping fingers) 1.5 1.5 1.5 1.5 1.5 one one 0.5 UPDRS 3) section, paragraph 24 (hand movements) 1.5 1.5 1.5 1.5 1.5 0.5 0.5 0.5 UPDRS 3) section, item 25 (fast multidirectional movements of hands) 1.5 1.5 1.5 1.5 1.5 0.5 0.5 0 Total score 31.5 31.5 21.5 15.5 15.5 9 9 5.5 Hamilton Scale 38 38 - 32 thirty 21 21 13 Beck Scale 23 23 - 21 eighteen 8 8 6

Table 3 The dynamics of the symptoms of Parkinson's disease according to the UPDRS, Hamilton, Beck scales on the background of treatment with hematan (patient 2) scales 1 week
1 visit 2 weeks
2 visit 3 weeks
3 visit 4 weeks
4 visit 5 weeks
5 visit 8 weeks
6 visit 9 weeks
7 visit 12 weeks
8 visit UPDRS 1) section, paragraph 1 (intellectual disabilities) 0 0 0 0 0 0 0 0 UPDRS 1) section, paragraph 2 (mental disorders) 0 0 0 0 0 0 0 0 UPDRS 1) section, paragraph 3 (depression) l one 0 0 0 0 0 0 UPDRS 1) section, paragraph 4 (motivation) 0 0 0 0 0 0 0 0 TOTAL SCORE of the first UPDRS section one one 0 0 0 0 0 0 TOTAL SCORE of the second section of UPDRS 12 12 9 3 3 1.5 1.5 1.5 UPDRS 3) section, item 20 (rest tremor) 1.5 1.5 0.5 0.5 0.5 0.5 0.5 0 UPDRS 2) section, item 21 (action tremor) one one one 1.5 1.5 0.5 0.5 0 UPDRS 3) section, clause 22 (rigidity) 3 3 3 one one one 1.5 0.5 UPDRS 3) section, item 23 (test with tapping fingers) 1.5 1.5 1.5 one one 0.5 0.5 0 UPDRS 3) section, paragraph 24 (hand movements) 1.5 1.5 1.5 one one 0.5 0.5 0 UPDRS 3) section, item 25 (fast multidirectional movements of hands) 1.5 1.5 1.5 0.5 0.5 0.5 0.5 0 TOTAL SCORE of the third section of UPDRS 15.5 15.5 12 12 12 7 3 3 TOTAL SCORE on three sections of UPDRS 25.5 25.5 15.0 12 12 7 7 four S. Hamilton eighteen eighteen - fourteen fourteen fifteen 10 6 S. Beck eighteen eighteen - 6 6 12 12 5

Claims (12)

1. A pharmaceutical composition in the form of a solid dosage form for the treatment of Parkinson's disease, comprising, as an active substance, a therapeutically effective amount of N- (2-adamantyl) -hexamethyleneimine hydrochloride, and at least one selected from the group consisting of excipients starch, lactose, microcrystalline cellulose (MCC), ludipress, calcium phosphate disubstituted, polyvinylpyrrolidone, methyl cellulose, carboxymethyl cellulose or its sodium salt, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, mannitol, sorbitol and, if necessary, stearic acid, and / or its salts, and / or aerosil. 2. A pharmaceutical composition in the form of a solid dosage form for the treatment of Parkinson's disease, including N- (2-adamantyl) hexamethyleneimine hydrochloride as an active ingredient, and lactose, starch, microcrystalline cellulose, stearic acid, and / or its salt, and / or aerosil in the following ratio, wt.%:
N- (2-Adamantyl) -hexamethyleneimine hydrochloride 5.0-45.0 Lactose 10.0-51.0 Microcrystalline cellulose 6.0-35.0 Stearic acid and / or its salts 1.0-1.3 Aerosil 0.5-10.0 Starch Rest 3. The pharmaceutical composition according to claim 2, characterized in that it contains potato starch as starch. 4. The pharmaceutical composition according to claim 2, characterized in that the predominantly magnesium salt is used as the stearic acid salt. 5. The pharmaceutical composition according to claim 2, characterized in that it is made by wet granulation. 6. A pharmaceutical composition in the form of a solid dosage form for the treatment of Parkinson's disease, comprising N- (2-adamantyl) hexamethyleneimine hydrochloride as an active ingredient, and ludipress, stearic acid and / or its salt as excipients in the following ratio of components, wt.%:
N- (2-Adamantyl) -hexamethyleneimine hydrochloride 10,0-40,0 Stearic acid and / or its salt 1.0-1.5 Ludipress and / or MCC and / or lactose Rest 7. The pharmaceutical composition according to claim 6, characterized in that it further comprises aerosil. 8. The pharmaceutical composition according to claim 6, characterized in that the predominantly magnesium salt is used as the stearic acid salt. 9. The pharmaceutical composition according to claim 6, characterized in that it is made by direct compression. 10. A solid dosage form made from a pharmaceutical composition according to claim 2 or 6, with an active substance content of from 0.01 to 0.10 g. 11. Tablets made from the pharmaceutical composition according to claim 2 or 6, with an average weight of from 0.10 to 0.50 g. 12. The use of a solid dosage form made from the pharmaceutical composition according to claim 1, for the treatment of Parkinson's disease.