RU2814110C1 - Anxiolytic, sedative and anti-stress medicinal product and method of its obtaining - Google Patents

Abstract

FIELD: chemical; pharmaceutical industry and medicine; neurology.

SUBSTANCE: anxiolytic, sedative and anti-stress agent is proposed in the form of a tablet oral form, containing as an active principle a combination of alimemazine tartrate and ethylmethylhydroxypyridine succinate, as excipients microcrystalline cellulose, povidone K25, croscarmellose sodium, talc and magnesium stearate at a certain content of components.

EFFECT: anxiolytic, sedative and anti-stress medicinal product and a method of its obtaining.

2 cl, 3 ex, 3 tbl

Description

The invention relates to the field of chemical-pharmaceutical industry and medicine, and concerns the field of neurology.

One of the current problems of interest to both neurologists and psychiatrists is psychovegetative disorders. They are often defined as “vegetative-vascular dystonia syndrome,” although it is not identified as a separate nosology in the International Classification of Diseases 10 and is discussed only in domestic medicine.

From a practical point of view, these disorders are most often understood as psychogenically caused multisystem autonomic disorders that arise as a result of disruption of the activity of the structures of the central nervous system (CNS) (upper parts of the brain stem, hypothalamus, limbic system) under the influence of stress factors. Accordingly, therapy should be complex (etiotropic, pathogenetic, symptomatic).

Pathogenetic therapy is aimed at various parts of the development mechanism of the main process: adherence to a rational daily regimen, psychotherapy, acupuncture, x-ray and physiotherapy (physical therapy, electrosleep, nasal electrophoresis, transcerebral ionogalvanization, balneological treatment). Patients are prescribed drugs of central and peripheral action that reduce sympathetic tone, usually chlorpromazine, reserpine, phentolamine, tropafen, dihydroergotamine, pyrroxane, inderal, etc. To lower blood pressure, drugs that act on vascular smooth muscle are prescribed: papaverine, dibazol , no-spa, nicotinic acid. To reduce parasympathetic tone, antichodinesterase substances, cholinomimetics, and potassium preparations are used. To increase sympathetic tone, mezatone, ephedrine, isadrine, monoamine oxidase blockers (iprazide, nialamide, nuredal, psychostimulants (phenamine, caffeine), calcium preparations; methionine, ascorbic and glutamic acids are prescribed. For parasympathicotonia, anticholinergics are prescribed (butyroxane, amizil, metamisil, atropine, cyclodol), ganglioblockers (benzohexonium, pentamin, pachycarpine, gangleron). Antihistamines are effective for the treatment of vegetative-vascular dystonia: diphenhydramine, pipolphen, histaglobulin. In recent years, tranquilizers (elenium, seduxen, frenolone, phenibut) have been widely used for the treatment of vegetative-vascular disorders. in adults and children, the authors explain it by its effect on the limbic system.

Thus, to date, extensive experience has been accumulated in the treatment of psychovegetative disorders. However, despite the diverse arsenal of medications, the search for new, more effective vegetotropic drugs continues.

The result of attempts to optimize the pharmacotherapy of neurological diseases of this kind was the creation of combination drugs containing two or less often more components with different mechanisms of action, which have different effects on the pathogenesis and clinical manifestations of specific forms of pathology.

A combination agent is known for the treatment of disorders that are characterized by mood disorders, psychomotor dysfunction and autonomic symptoms, containing an atypical antipsychotic and a second therapeutic agent selected from the group consisting of GABA modulators, anticonvulsants and benzodiazepines, both in the form of one or several combinations . In particular, a composition is disclosed prepared by combining ziprasidone with a GABA modulator that is either (a) gabapentin, (b) pregabalin, or (c) lamotrigine in a pharmaceutically acceptable carrier (WO 2004100992 A2). The known combination, although it has an effect on psychogenically caused autonomic disorders, was developed mainly for the treatment of schizophrenia.

There is a known drug that can be used for acute and chronic disorders of cerebral circulation and their consequences, discirculatory encephalopathy, vegetative-vascular dystonia, psychosomatic diseases, neurotic and neurosis-like disorders with the manifestation of anxiety, fear, emotional stress, memory and attention disorders, impaired mental performance, mental and neurological diseases in the elderly, containing a combination of active ingredients from a pharmaceutically acceptable salt of 2-ethyl-6-methyl-3-pyridin-3-ol (EMP) and taurine. Tablets containing EMP hydrochloride and taurine are prepared by separately sieving EMP hydrochloride, taurine, microcrystalline cellulose and potato starch through sieves with aperture size of 0.15 mm, mixing, moistening, granulating the mass, passing through a granulator with aperture size of 1.0 mm, drying, dry granulation, passing through a granulator with a hole size of 1.0 mm, dusting with magnesium stearate, pressing (RU 2493841 C1).

The known combination does not have a significant vegetotropic effect.

Thus, the objective of the present invention is to obtain oral forms with a combined fixed active principle, which is highly effective in the treatment of psychovegetative disorders, and at the same time is stable.

The problem is solved by obtaining a new anxiolytic, sedative and anti-stress drug in the form of a tablet oral form containing a combination of Alimemazine tartrate and Ethylmethylhydroxypyridine succinate (EMHPS) as the active principle.

Alimemazine tartrate (trade name “Teraligen”, etc.) is an antipsychotic. Alimemazine tartrate also exhibits antihistamine effect, antispasmodic, dopamine-blocking, and alpha-adrenergic blocking properties. The literature describes the use of drugs containing alimemazine tartrate as an active substance for the treatment of psychiatric diseases [Fernandez-Zoila A. Alimemazine tartrate in ambulatory psychiatric practice, Sem Hop, 1961, 20; 37, 1355-1357]; the use of this drug for the treatment of sleep disorders has been studied [Simonoff E.A., Stores G. Controlled trial of trimeprazine tartrate for night waking, Arch Dis Child, 1987, 62(3), 253-257. DOI: 10.1136/adc.62.3.2538].

For severe psychoses, the drug is relatively ineffective; acts primarily as a mild sedative and anti-anxiety agent. It is used mainly for psychosomatic manifestations that develop due to vascular traumatic, somatogenic, infectious dysfunctions of the central nervous system and for neurovegetative disorders. Alimemazine has a pronounced effect in the treatment of insomnia and provides a sedative effect. The drug has a vegetotropic effect (D.F. Ibragimov, Alimemazine in medical practice, JOURNAL OF NEUROLOGY AND PSYCHIATRY, 9, 2008).

Alimemazine tartrate is produced and prescribed mainly in tablets, for example, under the trade name Teraligen®.

However, despite less pronounced side effects compared to phenothiazine, of which it is a derivative, manifestations of drowsiness, lethargy, fatigue, and irritability are possible. And, in addition, with prolonged use, the effect may decrease and require increasing doses.

The present invention unexpectedly made it possible not only to increase the vegetotropic effect and stabilize it, but also to reduce the side effects of alimemazine.

Ethylmethylhydroxypyridine succinate (EMHPS) is a drug from the 3-hydroxypyridine group, which has a wide range of applications in medical practice. EMGPS has antihypoxic, membrane protective, nootropic, anticonvulsant, anxiolytic effects, and increases the body's resistance to stress. Increases the body's resistance to the effects of major damaging factors in oxygen-dependent pathological conditions (shock, hypoxia and ischemia, cerebrovascular accident, intoxication with alcohol and antipsychotics). Improves cerebral metabolism and blood supply to the brain, microcirculation and rheological properties of blood, platelet aggregation. Stabilizes the membrane structures of blood cells (erythrocytes and platelets) during hemolysis. It has a hypolipidemic effect, reduces the level of total cholesterol and LDL. Reduces enzymatic toxemia and endogenous intoxication in acute pancreatitis.

EMGPS is registered as a medicinal product in the Russian Federation in the form of dosage forms for parenteral use (solutions) and oral administration (tablets, capsules).

Since this drug has a complex effect and has a high degree of safety, there are often attempts to include it in complex therapy for the treatment of various diseases. However, as a rule, such therapy involves administering the drug first in parenteral form, and only then switching to the oral form. In this case, additional active substances are taken mainly in a separate dosage form. We have selected a combination that avoids these disadvantages.

The present invention relates to a combined anxiolytic, sedative and anti-stress agent in the form of a tablet containing the following components, mg:

Alimemazine tartrate 5.0-10.0 Ethylmethylhydroxypyridine succinate 150.0-300.0 Microcrystalline cellulose 80.0-120.0 Povidone K25 20.0-30.0 Croscarmellose sodium 15.0-20.0 Talc 5.0-6.0 Magnesium stearate 3.0-5.0

The invention also concerns a method for obtaining the specified product, which consists in mixing alimemazine tartrate and half of microcrystalline cellulose, adding ethylmethylhydroxypyridine succinate and the remaining amount of microcrystalline cellulose to the resulting mixture, stirring for 10-15 minutes at a stirrer speed of 60 rpm, then for another 1-2 minutes at a rotation speed of 1500 rpm, wet granulation is carried out using a 10% aqueous solution of povidone K25, the resulting wet granulate is mixed and dried in a fluidized bed dryer at a temperature of 40-45 ° C, controlling the content during the drying process moisture in the granulate is from 1.0 to 2.0%, then the granulate is calibrated, the sifted granulate is dusted with croscarmellose sodium, talc and magnesium stearate, followed by pressing. Preferably, dusting is carried out in a mixer with stirring for 10-15 minutes, at a rotation speed of 6 to 8 rpm.

If necessary, but not necessarily, a water-soluble film coating can be applied. In particular, polyvinyl alcohol can be used, which is a water-soluble polymer whose properties are independent of pH and guarantee that the disintegration time of the tablet is maintained regardless of the thickness of the coating. For example, a ready-made composition based on low molecular weight polyvinyl alcohol under the trade name Opadry II from Colorcon (USA) can be used. Or, to improve the appearance of the tablets, protect them from mechanical damage, and from exposure to air moisture, another film coating can be applied, for example, a polyvinylpyrrolidone shell, which is applied in the form of 20-30% solutions in 50-90% ethyl or isopropyl alcohol, followed by drying to remove organic solvent.

The invention can be illustrated by the following examples.

Example 1.

The composition of the tablet is presented in Table 1.

In a separate container, mix the calculated amount of alimemazine tartrate and part of microcrystalline cellulose. A weighed amount of ethylmethylhydroxypyridine succinate, a mixture of alimemazine tartrate and parts of microcrystalline cellulose, that is, the remaining amount of microcrystalline cellulose. The components are mixed for 15 minutes at a stirrer speed of 60 rpm, then turn on the chopper and stir the mixture for another 2 minutes at a chopper speed of 1500 rpm. Then the calculated amount of the prepared granulating liquid (10% aqueous solution of povidone) is loaded into the mixer, the mixture is stirred for 2 minutes, the stirrer speed is 30 rpm. After mixing the components and moistening the mixture, the resulting mass is pressed through the cells of the granulator using a sieve with a hole diameter of 2 mm. Then the wet granulate is dried in a fluidized bed at a temperature of 40-45°C, controlling the moisture content in the granulate to 1.0% during the drying process. Next, the dried granulate is loaded into a calibrator-granulator and crushed to a uniform particle size using a sieve with a hole diameter of 2.0 mm. The sifted granulate is dusted with croscarmellose sodium, talc and magnesium stearate. The process is carried out in a mixer, mixing time is 15 minutes, cone rotation speed is from 6 to 8 rpm. The finished mixture is pressed using a tablet press. Obtain biconvex tablets with a score of white or almost white color. Upon external examination, the surface of the tablets is smooth and uniform; the tablets must have high abrasion resistance. The average tablet weight is 410 mg.

Example 2.

Pharmacological activity.

The properties were studied on white outbred male rats weighing 180-220 g, which were divided into groups. 30 minutes before testing, one group was injected with saline or water (control), two other groups were given comparison drugs, and another group was given a test group. The study was carried out in experimental tests-models of acute stress - “open field”; models of chronic stress - forced long-term isolation in cells.

The results of the study are presented in Tables 2 (acute stress) and 3 (chronic stress).

Dosing regimen in the experiment:

Open field test. The rat was placed in the center of the chamber with its tail facing the experimenter and its behavior was observed for 3 minutes. The test recorded the following indicators: the latent period of exit from the center of the field, the number of crossed squares on the periphery, the number of crossed brightly lit squares, the number of vertical stands - wall and free, the number of looks into holes, the number of urinations and defecations, the number of acts of short-term grooming (caring for yourself). At the end of the specified time (3 minutes), the animal was returned to the cage.

The results obtained were compared using the nonparametric Mann-Whitney test. To visually present the results, conventional units (%) were used.

In group 2, compared to group 1, the level of research activity increased by 120.1%, in group 3 - by 206.2%, in group 4 - 238%), respectively. Compared to the control, in group 3 the indicators of horizontal motor activity and defecation were reduced by 58.0 and 46.2%, respectively, which indicates the manifestation of sedative properties, in group 2 - practically no changes, in group 4 - indicators of horizontal motor activity and defecation by 56.3 and 51.4%, respectively. The results obtained indicate a decrease in anxiety, which is regarded as a manifestation of anxiolytic properties.

Analysis of the results of studies under conditions of chronic stress revealed significant changes in the behavioral reactions of the control group of animals (high emotional reactivity, reduced orienting-exploratory reactions) and involution of the thymus and spleen, as well as hypotrophy of the adrenal glands. In the case of the experimental groups, such changes were not observed. Thus, in Wistar rats in a model of chronic immobilization stress lasting 21 days, it was shown that the combination of EMGPS and alimemazine exhibits anxiolytic activity and has the maximum effect (relative to the group of animals with chronic stress without treatment).

When conducting preliminary studies on volunteers (42 people in total) who took the declared combination of EMGPS + alimemazine tartrate 2 times a day, the main effects were identified, which were enhanced when using this combination of drugs: anti-stress, sedative, anxiolytic and treatment of sleep disorders. However, the two effects (anxiolytic and treatment of sleep disorders) are due to different mechanisms of action, which likely led to the fact that the combination of these drugs was more effective than using them separately.

As a result of therapy, which lasted 1.6-2 months, a very low percentage of side effects was observed (less than 7% of subjects).

There is no special term associated with the vegetative-stabilizing effect of drugs in the PASS and PharmaExpert dictionary of types of biological activity, however, it is known that for vegetative-vascular dystonia, anxiolytics, sleep normalizers and sedative drugs are used. Therefore, the combination of EMGPS + alimemazine tartrate can be considered as having a vegetative-stabilizing effect and can be recommended as promising for the treatment of vegetative-vascular dystonia.

Example 3.

Assessment of storage stability.

Stability data were determined under accelerated test conditions (40±2)°C and relative humidity (75±5)%.

Determination of impurities was carried out by HPLC. A buffer solution pH 3.5.1.5 g of sodium heptane sulfonate is placed in a 1000 ml volumetric flask, dissolved in 950 ml of water, 4.2 ml of triethylamine is added, and mixed. Adjust the pH of the buffer solution to 3.5 with concentrated phosphoric acid and make up to the mark with water.

Test solution. 50 mg of the mixture (crushed tablet according to example 1) is placed in a 50 ml flask, water is added and the volume is adjusted to the mark.

Reference solution. Place 1.0 ml of the test solution in a 100 ml volumetric flask and adjust the volume of the solution to the mark with water. Transfer 2.0 ml of the resulting solution into a 10 ml volumetric flask and adjust the volume of the solution to the mark with water.

Solutions of standard samples. About 50 mg (exactly weighed) of a standard sample of alimemazine tartrate is placed in a 50 ml volumetric flask, dissolved in water and the volume of the solution is adjusted to the mark with water. 50 mg (exactly weighed) of a standard sample of ethylmethylhydroxypyridine succinate is placed in a 50 ml volumetric flask, dissolved with stirring in water, after which the volume of the solution is adjusted to the mark with the same solvent, and filtered.

The content of impurities was determined chromatographically.

Mobile phase A: buffer solution pH 3.5.

Mobile phase B: acetonitrile.

Detector: UV, 297 nm.

Chromatography mode: gradient

The content of impurities before and after storage was determined by chromatography. The content of a single impurity was no more than 0.2%, the total content of all impurities at the end of storage did not exceed 0.5%.

Thus, we have developed an effective remedy for psychovegetative disorders, with fewer side effects, made in the form of a stable solid form, convenient for use by different age groups of patients.

Claims (3)

1. An anxiolytic, sedative and anti-stress agent in the form of a tablet oral form, characterized by the fact that it contains as an active principle a combination of alimemazine tartrate and ethylmethylhydroxypyridine succinate, as excipients microcrystalline cellulose, povidone K25, croscarmellose sodium, talc and magnesium stearate with the following content components, mg: alimemazine tartrate 5.0-10.0 ethylmethylhydroxypyridine succinate 200.0-300.0 microcrystalline cellulose 80.0-120.0 Povidone K25 20.0-30.0 croscarmellose sodium 15.0-20.0 talc 5.0-6.0 magnesium stearate 3.0-5.0 2. A method for producing an anxiolytic, sedative and anti-stress agent in the form of a tablet oral form according to claim 1, characterized by mixing alimemazine tartrate and half of microcrystalline cellulose, adding ethylmethylhydroxypyridine succinate and the remaining amount of microcrystalline cellulose to the resulting mixture, stirring for 10-15 minutes at a stirrer speed of 60 rpm, then another 1-2 minutes at a speed of 1500 rpm, wet granulation is carried out using a 10% aqueous solution of povidone K25, the resulting wet granulate is mixed and dried in a fluidized bed dryer at a temperature of 40 -45°C, controlling the moisture content in the granulate from 1.0 to 2.0% during the drying process, then the granulate is calibrated, the sifted granulate is dusted with croscarmellose sodium, talc and magnesium stearate, followed by pressing.