RU2461374C1 - Biologially active agent having effect on general metabolic, excitatory and inhibitory nerve function and intellectual mnestic cerebral functions (versions) - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely new orodispersible forms of biologically active agents having an effect on general metabolic, excitatory and inhibitory nerve functions, intellectual mnestic cerebral functions. The biologically active agents contain glycine, vitamin B₆ or its pharmaceutically acceptable salt and excipients which enable preparing the agent in the form of an orodispersible tablet.

EFFECT: composition may be used in various fields of therapy and prevention, particularly psychoneurology, and having an optimising effect on physiological and functional nerve activity in various borderline and pathological neural states; the agent is safe.

9 cl, 4 tbl, 4 ex

Description

The invention relates to pharmaceuticals and medicine, namely the use of a composition of glycine and vitamin pyridoxine (vitamin B ₆ ) in psychoneurology, which has an optimizing effect on the physiological and functional activity of the nervous system, in particular for various borderline and pathological conditions of nervous activity, while this composition is safe to use.

It is known that substances that affect the activity of the central nervous system (CNS) are called nootropics. A large number of nootropic drugs are used in the treatment of patients with impaired central nervous system function. They are "Piracetam", various derivatives of GABA - "Pantogam" ™ / "Pantocalcin" ™, "Phenibut", "Baclofen." Separately from the derivatives of GABA, "Fenotropil" ™, "Akatinol (Memantine ™)" are separated. The described agents have a pronounced therapeutic effect. But at the same time, there are side effects associated with highly effective substances that limit the widespread use in everyday practice by patients who need such treatment, and by clinicians who could prescribe such drugs without fear of serious side effects. Caffeine and some vitamins can also be considered nootropic: B ₆ , B ₁₅ , B _C and B ₁₂ . Therefore, the search and development of new effective and safe medicines that have a positive effect on the physiological and functional activity of the central nervous system, as well as on the memory functions of the brain, are currently relevant.

Glycine is the only amino acid of all proteins that does not have an asymmetric carbon atom in its molecule. However, it is metabolically linked to the chemical components of the body to a greater extent than any other amino acid.

The diagram shows that glycine in some syntheses plays an irreplaceable role, in particular in the formation of proteins, purine nucleotides, hemhemoglobin, paired bile acids, creatine, glutathione, etc.

Glycine is a natural activator of inhibitory neurotransmitter systems, including those with acute cerebral ischemia [Gusev E.I., Skvortsova V.I. Cerebral ischemia. - M .: Medicine, 2001 .-- 328 p. Astakhov A. Glitsied KMP: is it just amino acid that is versatile against stress? // Faces of Ukraine. - 2004. - No. 1. - S. 35-36].

Amino acid - glycine serves as a mediator in some cases of postsynaptic inhibition in the spinal cord. A specific antagonist of glycine is strychnine.

It is believed that glycine exhibits neurotransmitter properties at the level of the spinal cord, medulla oblongata, and bridge. It is released mainly from segmental interneurons and propriospinal systems and inhibiting motoneurons by axo-dendritic and axo-axonal contacts [Curtis D.R., Hosli L. 1968, Hammerstad J.F., Murray J.E. 1971, Hopkin J., Neal M.J. 1971, Osborne R.H., Bradford H.F. 1973]. The role of glycine as a inhibitory neurotransmitter in almost all parts of the central nervous system was also investigated. In the brain, a high density of glycine receptors was found not only in the trunk structures, but also in the cerebral cortex, striatum, hypothalamic nuclei, and conductors from the frontal cortex to the hypothalamus and cerebellum. It was concluded that GABA and glycine are equivalent neurotransmitters that provide protective inhibition in the central nervous system, the role of which increases under conditions of increased glutamate release [Fagg G.E., Foster A.S. 1983, Mayor F., Valdivieso F. 1991].

Along with the neurotransmitter glycine also has a general metabolic effect, binds low molecular weight toxic products (aldehydes, ketones), which are formed in large quantities during ischemia [Lavretskaya E.F. 1985, Meister A. 1957, Williams R. 1963]. In an experiment in rats with focal forebrain ischemia, the administration of glycine at a dose of 20 mg / kg (during the first 2 hours after surgery and then 1 time per day for 9 days) was accompanied by a significant increase in the concentration of glycine in the brain tissue (in the striatum - by 63 %, in the parietal cortex - by 45%), significantly increased the GABA turnover rate both in the ischemic zone and in the surrounding tissue compared with the control group of animals [Davalos A., Naveiro J. 1996]. Against the background of glycine use, a significant decrease in the concentrations of oxidative stress products in the ischemic zone was noted, which was accompanied by a quick normalization of behavior and conditioned reflexes in rats [Raevsky KS, Romanova G.A. 1997, Romanova G.A., Kudrin V.S. 1995].

Studies note the depriving effect of glycine on somato-sympathetic (vasomotor) reflexes, a pronounced "specific" inhibitory effect on the activity of neurons in the reticular formation [Gokin AP, Pavlasek Yu. Influence of stem microinjections of glycine and strychnine on start * reflexes in rats. // II All-Union Conference on Neuroscience: Abstracts. Dokl., 1988. - S.179-180], as well as the effect on the functional state of the sympathoadrenal system, due to its intervention in the processes of adrenergic mediation [Godovalova L.A., Kovalev G.V. The effect of glycine on the peripheral mechanisms of regulation of autonomic functions. // Fiziol. journal - 1983. - T.29, No. 4. - S. 492-496].

According to the literature, the successful use of the glycine amino acid for the treatment of patients with acute cerebrovascular accident brought the first serious confirmation of the proposed hypothesis [Gusev E.I., Skvortsova V.I. Neuroprotective therapy in the acute period of cerebral ischemic stroke. Clinical Herald. 2, p. 6 1995]. There is an application for a copyright certificate for this application 4120032 from 06.25.86.

There is a therapeutic effect of glycine in cerebellar lesions. The mechanism of action of glycine is the regulation of calcium metabolism by enhanced release of active phosphoinositides. For example, when using glycine for treatment in the form of a solution in the amount of 3-6 g per day for 30-50 days. There was a decrease in ataxia and other clinical signs of cerebellar damage, recorded by the end of the first week from the start of treatment, in parallel, an increase in the number of metabolites of the phosphoinositide cycle was noted [Khokhlov A.P., Savchenko Yu.N. Myelinopathies and demyelinating diseases].

Glycine has a nootropic, sedative, stress-protective, protistress and detoxification effect. The anti-stress effect of glycine is realized due to the interaction of amino acids with glycineergic reception, which activates the inhibition processes. Possessing the property of α ₁ -adrenolytic, glycine protects the cell from the excessive influence of catecholamines, a sharp increase in the content of which, as a rule, accompanies stress. The sedative effect of the drug is to weaken psychoemotional reactions, and their manifestations in response to an excessive stimulus become more adequate: irritability, aggressiveness, conflict are reduced, behavior becomes "more reasonable". Activates the braking processes. After a three-week intake of glycine twice a day, an increase in the speed of thought processes is recorded (Journal of Human Physiology (2001).

Glycine affects the process of falling asleep, deepens sleep [Shank R.P., Aprison M.N. The metabolism in vivo of glycine and serine in eight areas of the rat central nervous system. // J. Neurochem. - 1970. - Vol.17, No. 10. - P.1461-1475]. The positive effect of glycine on higher nervous activity is manifested by increased attention, a positive effect on the learning process, on the increase in the speed of computer operations and physiological reactions. The detoxifying effect of glycine is mainly manifested in relation to phenol. Interacting with phenol, the drug forms an absolutely non-toxic compound - hippuric acid. It is able to protect a nerve cell by acting on the myelin sheath of a neuron. Glycine is included in the synthesis of lecithin, which is one of the main components of phospholipids. The antitoxic effect of glycine is also manifested in relation to drugs. This applies especially to all groups of psychotropic drugs, the use of which contributes to a sharp decrease in the content of this amino acid in the nervous tissue.

The analysis of literature data confirms the beneficial effect of glycine on adaptation processes when changing motor modes, which is manifested in a decrease in the degree of metabolic dyshomeostasis [Gostkina I.P. The effect of demanol, glycine and glutamic acid on the parameters of homeostasis when changing motor modes: Author's abstract. dis ... cand. honey. Sciences: 14.00.25 / Mord. Gos. University of them. N.P. Ogareva. - Saransk, 1998. - 17 pp.], The positive effect of the drug on the bioelectric activity of the myocardium, which is probably due to its corrective effect on lipid peroxidation and electrolyte metabolism [Skorobogatova L.N. The effect of demanol, glycine and glutamic acid on bioelectric myocardial instability: Abstract. dis. ... cand. honey. Sciences: 14.00.25 / Mord. Gos. University of them. N.P. Ogareva. - Saransk, 1998. - 16 p.]. When glycine is used, there is a change in the qualitative composition of the substances of the average molecular pool, their quantitative content, the redistribution of substances of low and medium molecular weight in the blood, which can be considered as an option for optimal correction of metabolic processes [Zubatkina OV, Malakhova M.Ya. Changes in the molecular weight pool of substances when taking glycine. // Efferent therapy. - 2000. - T. 6, No. 1. - S. 63-65]. The metabolic properties of glycine contribute to the strengthening of recovery processes, and also positively affect the synthesis of collagen, inhibit the speed and time of physiological aging. As a natural metabolite of the body, glycine exhibits the properties of an energetic direct-acting antihypoxant, reducing the degree of hypoxic damage to the respiratory chain. The ability of glycine to inhibit the activation of adrenergic and pituitary-adrenal systems is associated with an antistress effect on the heart due to a decrease in alterative myocardial changes under stress [Malyshev VV, Oshchepkova OM, Seminsky I.Zh., Nefedova TV, Morozova T.P. Limiting lipid hyperoxidation and preventing stress damage to the heart by glycine derivatives. // Experiment. and clinic. pharmacology. - 1996. - No. 5. - S.23-25]. There is work on the action of glycine in the development of a neuropathic pain syndrome, in which it is shown that the drug does not affect the onset of pain, but has a therapeutic effect in pain [Danilova EI, Grafova VN, Reshetnyak V.K. . The role of the ketamine and glycine NMDA receptor blocker and stimulator in the development of neuropathic pain syndrome. // Experiment. and clinic. pharmacology. - 1997. - No. 4. - S.10-13].

In the literature there is information about the use of the neuroprotective effect of glycine in the acute period of ischemic stroke, while the authors indicate the need for fairly large doses of the drug (1-2 g / day) from the first hours of the development of stroke and within 5 days [Komissarova I.A. A new medicine against stress. // Terra medica. - 1996. - No. 2. - S.33-36]. Which indicates a large therapeutic breadth of use, and this fact is a confirmation of the safety of the drug. Glycine is also effective in children with a hyperreflex form of neurogenic bladder dysfunction [Artyukhina S.V. The effectiveness of the use of amino acids in children with neurogenic bladder dysfunction: Abstract. dis. ... cand. honey. Sciences: 14.00.09, 14.00.35 // Scientific research institute of pediatrics scientific. Center for Children's Health RAMS, Center for Urination Pathology. - M., 2000. - 22 pp.], In the treatment of ataxia and tremor in multiple sclerosis, for the relief of pain with trigeminal neuralgia, with damage to the facial muscles and peripheral polyneuropathies [Savchenko Yu.N. Multiple sclerosis: Importance of metabolic disorders and aspects of the pathogenet. treatment: Abstract. dis. (Doctor of Medical Sciences: 14.00.13 / I Moscow. Medical Institute named after IM Sechenov. - M., 1990. - 36 p.], for the prevention and treatment of conditions of alcohol intoxication [ Komissarova IA A new medicine against stress. // Terra medica. - 1996. - No. 2. - P.33 - 36], in the treatment of menopausal syndrome in combination with hormone replacement therapy [Dreval A.V., Marchenkova L.A. ., Tishenina R.S. et al. Combination of hormone replacement therapy with natural metabolite preparations (glycine and limontar) in the treatment of menopausal syndrome. // Problems of Endocrinology. - 1999. - V. 45, No. 4. - P.19-24 ]. Marked by therapeutic effect in relation to regression of skin manifestations in patients with psoriasis who received complex treatment with glycine [Dracheva MA Effect of amino acid preparations of glycine and limontara on the clinic and the course of psoriasis: Author's abstract. Cand. Sc. of Medical Sciences: 14.00.11 / Russian Medical Academy of Postgraduate Education - M., 1998. - 16 pp.]. The inclusion of glycine in the complex therapy of newborns with intrauterine hypotrophy is pathogenetically justified [Tsvirenko SN Pathogenetic rationale for the use of glycine in the rehabilitation of newborns with intrauterine hypotrophy at the second stage of nursing: Abstract. dis. (Candidate of Medical Sciences: 14.00.09 / Institute of Pediatrics, Obstetrics and Gynecology, Academy of Medical Sciences of Ukraine. - Kiev, 1995. - 20 p.].

It is also known that glycine helps in the treatment of decreased pituitary function. And since glycine supplies the body with creatine (a necessary element for the functioning of muscle cells), it has also proven effective in treating progressive muscular dystrophy.

Glycine is also used to treat hypoglycemia. Glycine stimulates the release of glucagon, which mobilizes glycogen, which is then released in the form of glucose into the blood. It is also effective in treating stomach acid. It is also used to treat certain types of acidosis (high blood acidity). Acidosis can be caused by an imbalance of leucine, which leads to the appearance of an unpleasant odor in the body and mouth (this condition was previously treated only by limiting leucine in the diet).

Glycine is actively involved in providing oxygen to the cell division process. It is an important component in the production of hormones involved in the functioning of the immune system. Glycine is the starting material for the synthesis of other amino acids, as well as an amino group donor in the synthesis of hemoglobin and other substances. Glycine is involved in the synthesis of connective tissues; in the anabolic phase, the need for this amino acid increases. A lack of glycine causes a violation of the structure of connective tissue. Increased glycine intake inhibits protein breakdown. Glycine is necessary for the synthesis of immunoglobulins and antibodies. The lack of this amino acid leads to a decrease in energy levels in the body.

Another important element of the functioning of the nervous system - vitamin "B ₆ " unites a group of compounds - pyridoxine, pyridoxal and pyridoxamine. They are derivatives of pyridine. Pyridoxol (another name is "pyridoxine") (2-methyl-3-hydroxy-4,5-di-hydroxymethylpyridyl) is a white crystalline substance, readily soluble in water and alcohol. Pyridoxol is stable against acids and alkalis (for example, 5 N. concentration), but is easily destroyed under the influence of light at pH 6.8.

2-Methyl-3-hydroxy-4,5-di- (hydroxymethyl) pyridine hydrochloride

The activity of vitamin B6 is possessed by a group of compounds derived from pyridine (pyridoxine (pyridoxol), pyridoxal and pyridoxamine), united under the general name "pyridoxine".

In tissues, all three forms of the vitamin are actively converted into coenzyme - pyridoxalphosphate (PF), a substrate for the production of energy from amino acids, and therefore is considered as a vitamin involved in obtaining energy for intracellular metabolism.

Derivatives of pyridoxyl (pyridoxine) - pyridoxal and pyridoxamine - are involved in the exchange of amino acids. Phosphorylated pyridoxal is involved in the transamination reaction - the transfer of an amino group from an amino acid to a keto acid.

Pyridoxine:

- Participates, especially in protein metabolism, the construction of enzymes that ensure the functioning of various enzymatic systems. Vitamin B ₆ (pyridoxine) is involved in fat metabolism.

- Participates in the functioning of the central nervous system.

- Necessary for the normal synthesis of nucleic acids (tryptophan, glycine, serine, glutamine and sulfur-containing).

- Necessary for the synthesis of antibodies, i.e. to maintain immunity, as well as for the formation of red blood cells.

- Relieves night muscle cramps, spasms of the calf muscles, numbness of the hands, has a therapeutic effect in some forms of neuritis of the extremities.

- Factor of assimilation of cyancobalamin (vitamin B ₁₂ ).

- Participates in the formation of magnesium compounds in the body [S. Ryss, “Hypovitaminosis and vitamin deficiency disease (C and group B)”].

In therapeutic practice, vitamin B ₆ is used very widely. The use of pyridoxine in combination reduces pain well, normalizes reflex reactions, and eliminates sensitivity disorders. Therefore, with pain syndromes, doctors often resort to the use of vitamins of this group in combination with other drugs [Bromm K, Herrmann WM, Schulz N. Do the B-vitamins exhibit antinociceptive efficacy in men? Results of a placebo-controlled repeated-measures double-blind study. Neuropsychobiology. 1995; 31 (3): 156-65; Eckert M, Schejbal P. Therapy of neuropathies with a vitamin B combination. Symptomatic treatment of painful diseases of the peripheral nervous system with a combination preparation of thiamine, pyridoxine and cyanocobalamin. Fortschr Med. 1992 Oct 20; 110 (29): 544-8 .; Jurna I. Analgesic and analgesia-potentiating action of B vitamins. Schmerz. 1998 Apr 20; 12 (2): 136-41].

In an experimental study of the biological effects of a combination of vitamins B ₁ , B ₆ and B ₁₂ for pain, inhibition of pain, the so-called nociceptive responses caused by formaldehyde. Moreover, these responses do not change after the administration of naloxone (a competitive antagonist of opioid receptors; an antidote to narcotic analgesics). This means that pain inhibition is not realized through opioid receptors. It is suggested that the antinociceptive (analgesic) effect of the combined vitamin complex may be due to inhibition of synthesis and / or blocking the action of inflammatory mediators [Franca DS, Souza AL, Almeida KR, Dolabella SS, Martinelli C, Coelho MM. In vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice. Eur J Pharmacol. 2001 Jun 15; 421 (3): 157-64].

Many studies emphasize that both combinatorial and separate use of vitamin B ₆ has an analgesic effect. It has been shown that in the complex use of vitamin B ₆ , with other representatives of group “B”, the action of norepinephrine and serotonin, the main antinociceptive (analgesic) neurotransmitters, is enhanced. Also, the experiment revealed the suppression of nociceptive (analgesic) responses not only in the horn, but also in the optic tubercle [Jurna I, Carlsson KN, Komen W, Bonke D. Acute effects of vitamin B6 and fixed combinations of vitamin B1, B6 and B12 on nociceptive activity evoked in the rat thalamus: dose-response relationship and combinations with morphine and paracetamol .: Klin Wochenschr. 1990 Jan 19; 68 (2): 129-35].

Patents are known that describe the use of glycine in various conditions.

RF patent No. 2025124 "Antistress, stress-protective, nootropic agent, a method for the prevention and treatment of stress conditions and a method of increasing mental performance", contains the amino acid glycine or its pharmaceutically acceptable salt in an amount of 0.1-0.2 mg per dose and an acceptable carrier, use sublingually in a dose of 1-2 mg / kg of weight 2-3 times a day for 14-30 days.

RF patent No. 2082398 "Method for the treatment of acute period of ischemic stroke", using the pharmaceutical preparation glycine, during the first five days of the disease, sublingually administered in tablet form 1 time per day at a dose of 1.0 g.

RF patent No. 2335926 "Food vitamin and mineral supplement", the supplement contains N-acetyl-L-glutamic acid, pyridoxine hydrochloride (vitamin B ₆ ), glycine (aminoacetic acid), zinc acetate dihydrate or zinc citrate, riboxin, nicotinamide, taurine and succinic acid in a certain ratio, which has an increased hepatoprotective and cardioprotective effect.

Patent No. 2254858 “A tool with hepatoprotective and anti-encephalopathic properties to reduce intoxication, prevention and removal of alcohol intoxication and hangover syndrome”, in addition to components based on succinic, fumaric, glutamic acids contains at least one vitamin of group “B”, may additionally contain plant extracts or mixtures thereof, L-carnitine, glycine, L-arginine, taurine and / or a mixture thereof, methylsulfonylmethane, dihydroquercytin, dimethyl sulfoxide or a mixture thereof, nicotinamide or nicotine oic acid or a mixture thereof, and energizer sweetener.

RF patent No. 2131244 "Solid dosage form", includes a porous mesh structure of a matrix material that is rapidly dispersible in water, made from a solution containing from 0.1 to 15 wt.% Of the matrix forming agent, the agent is selected from the group consisting of gelatin, pectin protein of soybean fiber and mixtures thereof and includes one or more amino acids containing from 2 to 12 carbon atoms, a form obtained by lyophilization of the specified solution of a matrix agent, a quantitative ratio of gelatin, pectin, protein of soybean fiber or mixtures thereof and amines Islota is in the range from 10: 1 to 1: 5. The amino acid is glycine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine, the improved dosage form disperses in water in less than 10 seconds and has high strength.

Vitamin B _{6 is} also widely distributed in various medicines and is described in numerous patents.

RF patent No. 2361602 "Dietary supplement for the prevention and treatment of vegetative-vascular dystonia and a method for its preparation", contains oil extract, dried water extract from the root with rhizomes of Valerian officinalis, root with rhizomes of elecampane high, thyme creeping grass, common oregano grass and sand immortelle flowers, taken in the ratio, h: 0.8-1.2: 0.8-1.2: 0.8-1.2: 0.8-1.2: 0.8-1.2 accordingly, linseed oil, thiamine hydrochloride, riboflavin and pyridoxine hydrochloride, a dietary supplement is effective for pro ilaktiki and treatment of vascular dystonia hypotonic and hypertonic type, restores the basic indicators cardiohemodynamics in acute alcoholic poisoning and ensures the safety and efficacy of vitamins of group "B" for a long time.

RF patent No. 2165759 "Means for the treatment of alcohol intoxication", the proposed tool contains picamilon, lipoic acid, pyridoxine hydrochloride and panthenol or calcium pantothenate and can be used in the form of ampoules or tablets, is effective for stopping the symptoms of acute alcohol intoxication, as well as for treatment alcohol and drug addiction.

RF patent No. 20066224 "Membrane-stabilizing and antioxidant drug" RIKAVIT "", containing as active ingredients, g: riboxin 0.1; glutamic acid 0.1; ascorbic acid 0.02; nicotinamide 0.01; riboflavin 0.002; pyridoxine 0.002; potassium chloride 0.05, can be used both as monotherapy and in complex treatment, in particular in the treatment of cardiovascular diseases in general therapeutic and geriatric practice.

RF patent No. 2287327 "Means for the treatment or prevention of atherosclerosis", contains pyridoxine hydrochloride (vitamin B ₆ ), cyanocobalamin (vitamin B ₁₂ ), folic acid (vitamin B _C ), characterized in that it is made in the form of a tablet, designed to normalize myocardial conditions in coronary heart disease.

RF patent No. 2153880 "General strengthening action for the prevention and treatment of diseases of the cardiovascular system", biologically active general strengthening means contains potassium succinate in combination with magnesium succinate in the ratio: 1: (0.25-4) and additionally contains B vitamins , for example pyridoxine hydrochloride (vitamin B ₆ ), excipients in a certain ratio of components.

The drug Biotredin® R No. 003744/01 is registered in the Russian Federation. In terms of pharmacological properties, it is described: “Biotredin® is a regulator of tissue metabolism, increases mental performance, has a therapeutic effect in alcohol withdrawal conditions, and reduces the craving for alcohol.

L-threonine in the presence of pyridoxine (vitamin B ₆ ) breaks down into the amino acid glycine and acetaldehyde (acetic acid), which stimulate inhibition processes and at the same time redox reactions, respiration and ATP synthesis in cells .... " This drug is indicated for alcoholism. “The drug makes it possible to get acetaldehyde into the cell, bypassing the oral (" alcohol ") path. In the body, biotretin decomposes with the formation of acetaldehyde. The drug is most effective for affective forms of pathological craving for alcohol (subdepressive mood swings in the form of depression, mild sadness, indefinite discomfort, irritability, but without a sense of anxiety), and provoking a pathological craving for alcohol with hunger. The drug is less active in stopping a situationally driven craving for alcohol. ”(Medicines in the clinic of alcoholism and drug addiction. (A guide for doctors) edited by A.Yu. Magalif. - M., 1999. - 111 (121) p.). But it must be said that threonine, an essential amino acid, is part of many proteins (pepsin, gliadin, fibrin, etc.). In the body, threonine is deaminated with the formation of 2-oxo-butyric acid with the participation of pyridoxalphosphate. Under the action of aldolase, threonine is reversibly split into acetaldehyde and glycine. The reaction is as follows: L-THREONINE = GLYCINE + ACETALDEHYDE, but this reaction is not catalyzed by pyridoxalphosphate, but by another enzyme, threoninaldolase (http: //humbio.m/humbio/Biochem/reactions/00051939.htm). Thus, vitamin B _{6 is} not involved as a catalyst for the conversion of threonine to glycine and this reaction is reversible, i.e. the conversion of threonine to glycine and acetaldehyde is not guaranteed.

Glycine Forte Evalar® tablets are known for use as dietary supplements, including those with increased mental and emotional stress. Each tablet "Glycine Forte Evalar" contains glycine 300 mg, vitamins. The tablet is kept in the mouth until completely resorbed. Duration of admission is 1 month. BAA SoGR No. 77.99.11.3. U.9888.10.09 from 10.22.2009 (http://www.evalar.ru/ru/consumer/production/parameter/?id_4=98).

However, in practice it has been noted that with increased dosages of glycine, if used, the incidence of nausea and vomiting increases.

In addition, such a method of administration as resorption is not always convenient and even undesirable, especially for children and the elderly. As you know, for the most part, children do not differ in the necessary patience and can swallow a sublingual tablet without waiting for it to completely dissolve, which, of course, complicates the action of a drug intended for sublingual (sublingual) use.

In addition, old people and children have poor swallowing ability, and therefore the sublingual (sublingual) method of using the known drug for them is also difficult. The same argument can be made for the use of the sublingual method of use by paralyzed patients.

For these categories of patients, fast-dispersing dosage forms are being developed.

It was found that fast-dispersing dosage forms induce pre-gastric absorption of the active components, thus, the absorption of active substances from the part of the digestive tract that is located before the stomach occurs. By "pre-gastric absorption" is meant the absorption of active substances through the mucous membrane of the cheeks, sublingual (sublingual region), oropharyngeal (oropharyngeal region) and the mucous membrane of the esophagus. Therapeutically active agents absorbed by such delivery are, for the most part, delivered directly to the systemic circulation, bypassing the primary passage through the liver.

As the closest analogue, RF patent 2253442 may be indicated, which discloses a buccal (buccal) composition having a nootropic, antiepileptic, sedative, anti-stress, normalizing metabolic processes in the body action, containing aminoacetic acid and a pharmaceutical carrier, consisting of a mixture of sorbitol and sodium salt, crosslinked carboxymethyl cellulose in a weight ratio of 1: 1 to 1: 3 in combination with an additive selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymers, stearic acid, ol stearic acid or mixtures thereof. To improve the organoleptic properties of the pharmaceutical composition, it is proposed to introduce sweeteners and flavorings into the composition. The dosage form has a disintegration of 2-3.5 minutes.

This solution does not disclose the possibility of introducing pyridoxine into the composition. For specialists, it is obvious that bioavailability does not have a direct linear dependence on disintegration or solubility and only an improvement in these parameters is not enough to ensure the effective action of the active principle and, especially, the combination of biologically active components.

Thus, it is relevant to create a dosage form of the drug having a very short time of complete disintegration in the patient’s oral cavity, convenient for administration and providing high bioavailability of the combined active principle.

Currently, a new direction in pharmaceutical practice has become such a form as an “orodispersible tablet” or orally disintegrating tablet (ODT). The term meets the following definition: "A tablet that, when placed in the mouth before swallowing, quickly disperses in it" (Pharmeuropa, Volume 10, No. 4, December 1998, p. 547).

A feature of the orodispersible form is that when it is taken there is no need to drink it with water, dissolve or chew. It breaks down in the presence of a small amount of saliva, preferably in less than one minute or longer, if the features of the therapeutically active substance require it.

Such forms can be obtained in two ways: degradable forms: obtained most often by lyophilization, these very porous forms contain soluble excipients, the dissolution of which leads to the destruction of the structure; decaying forms: they are obtained by pressing, while the mechanism involved in the destruction of these forms in the mouth is provided by the disintegrating substances contained in them.

The effective action of glycine through the receptor zones has been established, which significantly expands its therapeutic capabilities. 10 minutes after applying tritium-labeled glycine to the conjunctiva of the eyeball, intranasally, to the mucous membrane of the cheek by scintillation spectrometry, its increased consumption was recorded in different brain structures and cerebrospinal fluid [Badalyan L.O., Skvortsov I.A. 1986, Raevsky K.S., Romanova G.A. 1997].

The application of glycine to the conjunctiva of the eyeball is accompanied by an increase in its concentration to a maximum in the initial 30 minutes in the visual cross and after 2 hours in the visual zone of the cortex [Badalyan L.O., Skvortsov I.A. 1986].

It is highly desirable from a clinical point of view to propose a composition that would be simple for administration and convenient for use by the patient, thereby reducing the need for monitoring the administration, and which would bypass the metabolism upon initial exposure to the liver.

Thus, the delivery of glycine in combination with vitamin B ₆ through the receptor zones, which is the oral cavity (sublingual zone), in a dosage form convenient for the patient, therapeutically more effective, is a very urgent task.

This problem is solved by a new orodispersible form of a biologically active agent that affects the general metabolic, excitatory and inhibitory functions of the nervous system, the intellectual-mnestic functions of the brain, including glycine (aminoacetic acid), vitamin B ₆ or its pharmaceutically acceptable salt and excipients that allow to make the tool in the form of tablets, in the following ratio of components, wt.%:

Glycine 16.50-33.17 Vitamin B ₆ or a pharmaceutically acceptable salt 1.65-2.49 Flavoring 1.99-3.96 Aspartame 0.50-0.99 Stearic acid or its pharmaceutically acceptable salt 0.50-0.99 Lactose 49.09-60.73 Starch 12.27-15.18

Another embodiment of the invention is a biologically active agent that affects the general metabolic, excitatory and inhibitory functions of the nervous system, intellectual-mnestic functions of the brain, in which the magnesium salt is additionally introduced. The tool contains magnesium in the form of a salt, which is a lactate, carbonate, sulfate, in the following ratios, wt.%:

Glycine 12.41-33.33 Vitamin B ₆ or its pharmaceutically acceptable salt 1.24-2.50 Magnesium salt 24.81-33.33 Flavoring 2.00-2.98 Aspartame 0.50-0.74 Stearic acid or its pharmaceutically acceptable salt 0.50-0.74 Lactose 45.66-49.33 Starch 11.41-12.33

A biologically active agent can be dispersed in the oral cavity in less than three minutes.

Another embodiment of the invention is a biologically active agent that affects the general metabolic, excitatory and inhibitory functions of the nervous system, intellectual and mental functions of the brain, including the active substance glycine (aminoacetic acid), a vitamin B6 group or its pharmaceutically acceptable salt and excipients, which allow you to make a tablet form, in the following ratio of components, wt.%:

Glycine 16.50-33.17 Vitamin B ₆ or its pharmaceutically acceptable salt 1.65-2.49 Flavoring 1.99-3.96 Aspartame 0.50-0.99 Stearic acid or its pharmaceutically acceptable salt 0.50-0.99 A mixture of mannitol, crospovidone, polyvinyl acetate and povidone 49.09-60.73 Starch 12.27-15.18

provided that the mixture of mannitol, crospovidone, polyvinyl acetate and povidone contains components with the following content in wt.%:

Mannitol 84-92 Crospovidone 4-6 Polyvinyl acetate 3,5-6 Povidone 0.25-0.6

Most preferably, the vitamin B _{6 is} in the form of pyridoxal (the active form of vitamin B ₆ ) or pyridoxalaphosphate. Pyridoxine hydrochloride may also be an example of a pharmaceutically acceptable salt.

With a view to the possible implementation of a fast-dispersing dosage form, it is possible to change the degree of its adsorption by coating with a colloidal film or by coating said active components in a coating in the form of a dragee. The film coating can be carried out using various substances that allow you to neutralize and / or change the taste. These substances are known as cellulose polymers, namely ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate, cellulose acetate phthalate, as well as various mixtures thereof, polymethacrylates, cellulose polymer mixtures and other polymers such as polyvinyl pyrrolidone, for example, ®, with all of the described polymers and / or mixtures thereof can be used together with polyethylene glycol. Coating with a colloidal film can be carried out by methods, for example, as a method in a layer of liquefied air, a turbine method, microencapsulation, coacervation, extrusion giving a spherical shape.

Also used as a technology for coating the active substance is the manufacture of dragees. This technology is implemented using sugars or polyols, which, if necessary, are mixed with film-forming polymeric substances.

So, in this invention, the active components are mixed with excipients containing starch and lactose in the form of granules.

The proportion of lactose (glucose) / starch in granules is in the range of 95 / 5-80 / 20, but most preferably 80/20 to 50/50.

The methods by which it is possible to obtain granules are different. For example, it can be cumulative drying. In accordance with this method, granules are obtained by mixing lactose and starch and spraying them.

The composition of the described granules in solid form in accordance with the described invention may vary depending on the dosage of the incoming active components. Typically, these granules comprise from 20 to 96%, preferably from 40 to 90% by weight of the specified solid form.

It is possible to add additional flavors, lubricants, colorants, sweeteners to the prepared mixture.

In a preferred embodiment of the described invention, the mixture may include one or more sweeteners to optimize the organoleptic and stabilize the mechanical properties of the mixture. In this case, the amount of sweetener is selected in such a way as not to violate the fast-dispersing characteristics of the tablets.

Sweeteners are selected from the group of sugars, such as dextrose, maltose, fructose. Maltodextrins or polyhydric alcohols such as mannitol, sorbitol, maltitol, xylitol, erythritol, and lactitol can be sweeteners. The use of sugar or a polyhydric alcohol most suitable for direct compression is desirable. A more preferred option is polyhydric alcohol.

The best results were shown by the addition of direct compression mannitol with a content of from 10 to 30%, preferably from 15 to 25% by weight.

It is possible to include additional substances, such as organic acid, carbonate base, in order to obtain tablets with the effect of hissing in the oral cavity. Thus, the time that subjectively a person expects before the tablet begins to disintegrate, can be perceived as a sensation of the tablet disintegrating in the mouth and the therapeutic effect beginning.

In order to realize this effect, about 5% by weight of such an acid-base pair is used, for example citric acid - sodium bicarbonate. They are added to the reactor, where there is a mixture consisting of glycine, vitamin B ₆ , lactose / starch in granules, a sweetener from the group: maltose, dextrose, sucrose or mannitol from the group of polyhydric alcohols. The prepared mixture is then formed by compaction, for example, by direct compression in a tablet press.

The solid forms obtained by this technology are highly dispersible in the oral cavity, regardless of the hardness or density of the resulting tablet. The use of a mixture of lactose and starch both in the form of granules and in other forms provides a quick release of the active components.

Solid forms of the glycine and vitamin B ₆ compositions according to the present invention can also be used as a nutritional supplement, such as nutraceuticals.

The possibility of carrying out the invention can be demonstrated (but not limited to) by the following examples.

Example 1. Preparation of biologically active agents (option 1)

Glycine, B6 vitamin, lactose and aspartame are loaded into the reactor. The resulting mixture is transferred to a mixer and lactose, potato starch and flavor are added in a ratio, wt.%: Glycine 16.50-33.17, vitamin B ₆ or its hydrochloride, in particular pyridoxalphosphate, 1.65-2.49, lactose 49.09-60.73, starch 12.27-15.18, taking into account the amount necessary for the preparation of a 3-10% solution of starch paste and powder for dusting, flavoring 1.99-3.96 and aspartame 0.50- 0.99.

The proposed composition of active and auxiliary substances is optimal and provides high-quality tablets with a fast dispersing effect in the oral cavity and therapeutic effect of active substances. Preliminary granulation of a mixture of lactose and starch is possible.

After thorough mixing, the mass in the mixer is moistened with a starch paste solution.

It is possible to regulate the strength and disintegration of the tablet by changing the concentration of starch paste. Thus, a decrease in paste concentration below 3% leads to a decrease in tablet strength, and an increase in starch concentration over 10% leads to an increase in tablet disintegration time.

After the tablet mass is discharged from the mixer, it is dried in a fluidized bed.

The resulting mass is granulated by feeding through a 1.2-2 mm sieve and loaded into a mixer, where a mixture of starch and stearic acid or a pharmaceutically acceptable salt thereof, for example calcium stearate or magnesium stearate, is added and mixed.

The resulting mixture was analyzed by HPLC. Upon receipt of positive results pass to the stage of tabletting.

Tableting is carried out on the press using biconvex punches with a diameter of 16 mm (semi-deep sphere) with a bevel and the ability to print the logo on one side.

The proposed ranges of ratios of the ingredients are optimal and allow you to get an effective drug in the form of tablets with orodispersed properties and meets the requirements of the pharmacopeia in all respects and is stable during storage.

Examples of specific formulations, wt.%.

Example 1A Example 1B Example 1C Glycine Glycine Glycine 16.50 21.52 33.17 Pyridoxine Pyridoxal Pyridoxine hydrochloride 2.0 hydrochloride 2.49 1.65 Flavoring Peppermint flavoring Flavoring "orange" pepper "orange" 3.96 1.99 1.99 Aspartame Aspartame Aspartame 0.99 0.50 0.5 Calcium Stearate 0.99 Stearic acid Magnesium Stearate 0.50 0.99 Lactose Lactose Lactose 59.89 60.73 49.09 Starch 15.18 Starch 12.27 Starch 13.1

Example 2. Preparation of biologically active agents (option 3). A mixture of mannitol, crospovidone, polyvinyl acetate and povidone was also used as an auxiliary substance to achieve the orodispersed tablet form, with the following content in wt.%:

Mannitol 87,4-92 Crospovidone 4-6 Polyvinyl acetate 3,5-6 Povidone 0.25-0.6

The use of this mixture also allowed to achieve controlled disintegration of the tablets in the oral cavity. In this case, the tablets disintegrated in less than a minute.

The pharmaceutical composition is prepared as follows: glycine, a vitamin B of group ₆ or its hydrochloride, a mixture of mannitol, crospovidone and polyvinyl acetate, aspartame and flavor are loaded into the reactor.

The resulting mixture is transferred to a blender, adding starch in the ratio, wt.%: Glycine 16.50-33.17, vitamin B ₆ or its hydrochloride 1.65-2.49, a mixture of mannitol, crospovidone, polyvinyl acetate and povidone 49.09 -60.73, starch 12.27-15.18, taking into account the amount necessary for the preparation of a solution of starch paste and powder for dusting, flavoring 1.99-3.96 and aspartame 0.50-0.99.

The proposed composition of active and auxiliary substances is optimal and provides high-quality tablets with fast dispersing effect in the oral cavity and therapeutic effect of active substances.

After thorough mixing in a blender, the mass is moistened with a starch paste solution.

It is possible to regulate the strength and disintegration of the tablet by changing the concentration of starch paste.

After the tablet mass is discharged from the mixer, it is dried in a fluidized bed.

The resulting mass is granulated by feeding through a 1.2-2 mm sieve and loaded into a mixer, where a mixture of starch and stearic acid or a pharmaceutically acceptable salt thereof is added and mixed.

The resulting mixture was analyzed by HPLC. Upon receipt of positive results pass to the stage of tabletting.

Tableting is carried out on the press using biconvex punches with a diameter of 16 mm (semi-deep sphere) with a bevel and the ability to print with a logo on one side.

The proposed ranges of ratios of the ingredients are optimal and allow you to get an effective drug in the form of tablets for sublingual use with orodispersed properties and meets the requirements of the pharmacopeia in all respects and is stable during storage.

Examples of specific formulations, wt.%

Example 2A Example 2B Example 2C Glycine Glycine Glycine 16.50 33.17 29.6 Pyridoxal Pyridoxine Pyridoxine hydrochloride hydrochloride 1.65 2.49 1.65 Anise Flavor 3.96 Peppermint flavor 1.99 Peppermint flavor 2.99 Aspartame 0.50 Aspartame 0.50 Aspartame 0.99 Magnesium Stearate 0.99 Calcium Stearate 0.50 Calcium Stearate 0.50 A mixture of mannitol (90%), crospovidone (6%) and polyvinyl acetate (3.75%) povidone (0.25%) 60.38 A mixture of mannitol (87.4%), crospovidone (6%) and polyvinyl acetate (6%) povidone (0.6%) 49.92 A mixture of mannitol (92%), crospovidone (4%) and polyvinyl acetate (3.75%) povidone (0.25%) 49.09 Starch 15.18 Starch 12.27 Starch 15.18

Example 3

The effectiveness of this combination is characterized by the following studies.

Cognitive-mnestic functions were evaluated in the experience of passive avoidance, the so-called (so-called) conditional reflex of passive avoidance (passive avoidance reaction). The experiment room consisted of two compartments: dark with an electrified grating floor and illuminated, the compartments are separated by a movable lid. The experiment consisted of several stages.

Addictive - the rat was placed in a lighted chamber with its back to the dark compartment, the so-called "Starting position". The animal quickly found the entrance to the dark compartment and ran across the dark compartment. The period of movement into the dark compartment was measured using a stopwatch. Then the rat again, after 10 seconds, was moved to the lit compartment. The actions were repeated for 3 times every 30 minutes.

Training - during the last movement into the dark compartment, a non-fatal electric shock was applied to the bars of the cells of this compartment for 1 s. After that, the rat was transferred to a lit adjacent compartment.

The drug obtained in example 1B was crushed, diluted in 10 ml of distilled water. After that, 0.2-0.3 ml of the prepared solution was pipetted into the oral cavity of the rat, which corresponded to the approximately recommended dosage of Glycine 2-3 mg / kg and vitamin B ₆ (pyridoxine hydrochloride) 0.1-0.15 mg, 30 minutes before the start of training.

Reproduction - after 24 hours, the rat was re-placed in the illuminated compartment and the latent period of entry into the dark compartment was recorded. The experiment was terminated under the condition that the rat passed into the dark compartment or did not pass within 3 minutes.

As a control, 2 groups were used: the 1st group was administered “Fentropil” ®, the 2nd group - physiological saline.

Table 1 A drug Number of animals Experiment Stages Training Play Latent period of transition to the dark compartment, s, m ± Latent period of transition to the dark compartment, s, m ± Glycine 27.81 ± 12.79 139.73 ± 29.81 Glycine / Vitamin B ₆ 7 38.14 ± 7.12 161.8 ± 21.75 Phenotropil 6 43.81 ± 11.37 178.0 ± 7.67 The control 6 14.15 ± 11.24 117.63 ± 21.21

The results of cognitive-mnestic indicators are shown in table 1.

In the analysis of the preservation of passive avoidance reaction in rats 24 hours after training, 100% reproduction of passive avoidance reaction in animals with the administration of phenotropil was observed.

In groups where the test combination was administered to rats, passive avoidance reaction was also observed, and the latent period of transition to the dark compartment did not differ significantly from the latent period of transition to the dark compartment of animals using Phenotropil, although it was inferior in absolute values to the effectiveness of Phenotropil.

The general motor activity was evaluated by the following characteristics - tentatively research activity, the emotional state of the animals, carried out in the installation of "open field".

The rat was placed in a square located in the center. In animals, the number of individual behavioral acts was evaluated over 5 minutes. The following behavioral indicators of rats were calculated:

- Vertical motor activity (VDA) - shows the orientation and research behavior of animals.

- Horizontal motor activity (GDA) - shows the total motor activity of rats.

The emotional state of rats was evaluated by the following indicators:

- Fading reactions, p.

- Grooming reactions, p.

- Sniffing reactions, p.

The solution of the drug according to the above example and dosage was injected into the oral cavity of the rat, 30 minutes before the start of the tests.

When determining the probability of differences in the average of groups, the Student t-test was used. The differences were considered significant at a significance level of p <0.05.

table 2 A drug Number of animals WDA ± m GDA ± m T _sec r-tion fading, ± m T _sec grooming, ± m T _sec sniffing reaction, ± m 5.01 ± 3.1 51.5 ± 13.83 138.38 ± 38.51 18.13 ± 11.27 34.13 ± 7.81 Glycine 6 Glycine / Vitamin B ₆ 7 2.89 ± 2.51 * 43.31 ± 18.11 181.34 ± 31.59 * 14.15 ± 9.82 * 31.09 ± 7.47 * Phenotropil 6 1.71 ± 0.94 * 38.76 ± 12.96 * 191.09 ± 27.17 * 7.83 ± 5.52 * 25.99 ± 9.41 The control 6 8.94 ± 2.78 75.37 ± 10.38 52.0 ± 18.06 44.81 ± 6.89 46.94 ± 9.80 * - significant difference from control, p <0.05; ** - significant difference from Phenotropil, p <0.05.

The results identified during the experiment "Open field", allowing to evaluate the behavior of animals, are presented in table 2.

Under the condition of an open field, the duration of the grooming reaction, which is an expression of the restless state of the animal in an unusual “open field” environment, is clearly reflected in the control group. A decrease in the duration of the grooming reaction indicates a pronounced anxiolytic effect of the drug and is most evident in the groups: “Phenotropil” and the studied combinations.

Groups of experimental animals that took the test composition showed an “open field” experiment in comparison with the control group, higher indicators of horizontal activity (in the center and on the periphery), vertical activity (number of racks), which characterizes a positive adaptive level of tentative research activity . The grooming results showed, in comparison with the control group, a decrease in the level of anxiety and anxiety, which also indicates a positive effect on the emotional status of rats from the studied groups.

Studies on the effect on behavioral reactions in rats indicate that the effect of the developed combinations is effective and, in some cases, comparable to the pharmacological effect of the reference drug Phenotropil.

Example 4

1. Preparation of tablet mass for a biologically active agent (option 2)

Getting the mixture No. 1

Sifted pyridoxine hydrochloride is loaded into the mixer, lactose and starch are charged, and mixed thoroughly.

Sifted glycine is loaded into the mixer, the mixture is stirred, magnesium carbonate is introduced, mixed, aspartame is added, and mixed thoroughly.

Getting the mixture No. 2

Sifted sorbitol is loaded into the mixer for dry mixing, the flavor (for example, sifted mint) is mixed. The mixer is stopped and mixture No. 1 is added and mixed thoroughly.

The resulting mixture No. 2 was dusted with magnesium sieved stearate, mixed.

The tablet mass is discharged from the mixer and dried.

The resulting mass is granulated by feeding through a 1.2-2 mm sieve and loaded into a mixer, where a starch mixture is added.

The resulting mixture is passed to the tableting step.

Tableting is carried out on the press using biconvex punches with a diameter of 16 mm (semi-deep sphere) with a bevel and the ability to print with a logo on one side.

The tablets should be white round biconvex with the inscription on one side of the GR, with solid edges, a smooth and uniform surface.

Tablets should have sufficient strength under mechanical stress. The fracture strength of the tablet is 320-430 N.

During tabletting, the average weight of tablets is checked every 15-20 minutes, appearance (after setting the press, they are checked: strength, tablet height and disintegration). The data are shown in table 3.

Table 3 A drug Number of animals Experiment Stages Training Play Latent period of transition to the dark compartment, m ± Latent period of transition to the dark compartment, m ± Glycine 6 27.81 ± 12.79 139.73 ± 29.81 Glycine / Vitamin B ₆ 7 38.14 ± 7.12 161.8 ± 21.75 Glycine / Vitamin B ₆ / Mg 6 39.21 ± 8.05 162.3 ± 34.63 Phenotropil 6 46.81 ± 11.37 178.0 ± 7.67 The control 6 14.15 ± 11.24 117.63 ± 21.21

A comparative analysis of the results, cognitive and mnemonic functions of rats, indicates that during training, there is a significant difference in the latent period of transition to the dark compartment of the chamber in comparison with the control in groups using Phenotropil ™ and the studied combinations. Under the conditions of reproducing passive avoidance reaction in the studied groups of animals, the latent time of entry into the dark compartment increased in comparison with these indicators in the test "training". "Phenotropil" ™ showed an antiamnestic effect, statistically significantly increasing the latent time of transition to the dark chamber in comparison with the control. In the study group of rats against the background of the introduction of the studied combinations, the latent time of transition to the dark compartment during reproduction was close to the values of the group of animals that were injected with “Phenotropil” ™. But it should be noted that the studied combinations have less side effects, in contrast to the more selective nootropic drug.

As can be seen from the experimental data, the addition of Mg salt did not lead to statistically significant differences from the main test combination, but the absolute values were slightly higher in the “test” test and had no significant differences in the “reproduction” test.

In order to determine the effect of glycine dosages and to determine the comparative effect of vitamin B ₆ in the form of pyridoxine hydrochloride and in the phosophorelated form, the experiments shown in the table were performed, previously undetected data were found regarding the combined effect of glycine and pyridoxalphosphate.

Titration of dosages of Glycine upward began from 200 mg. And it came to 600 mg, calculated on the weight of the mouse. It was not possible to introduce more using the sublingual delivery model without violating the purity of the experiment.

During the experiment, paradoxical reactions were found in those groups of animals that were injected with glycine in dosages exceeding 200 mg, calculated on mice. So, in these groups there was a pronounced inhibition of animal behavior, which exceeded the observation time from 4 hours. In this case, the external behavior of animals was characterized by lethargy, inactivity, lack of response to external stimuli (touch, bright light). Only after 7 hours the animals gradually came to their senses, began to respond to external stimuli. It was noted that at high dosages of glycine more than 200 mg (in terms of mouse) in groups where the combination (example 2A) of glycine contained pyridoxal-5′-phosphate (a form of vitamin B ₆ ), the time out of the inhibited state was shorter. Mice exited this state after 5.5 hours. Perhaps this is due to the fact that it is pyridoxalphosphate, in the presence of acetaldehyde, that can convert glycine to threonine.

At a dosage starting from 500 mg (in terms of mouse), the animals showed a different paradoxical reaction - extreme excitement, animals rushed to the walls of the cage, tried to gnaw with their teeth, rushed about the cage, looked extremely excited. And also calmed down after 5 hours. Again, in the group with the inclusion of pyridoxalphosphate to glycine, the time to return to normal behavior came earlier, after 3.5-4 hours. Which is also probably related to the more active form of vitamin B ₆ .

Thus, we suddenly found that the addition of pyridoxalphosate as an active form of vitamin B ₆ unexpectedly increases the effectiveness of glycine, and more actively than pyridoxine. It was further noted that the addition of pyridoxalphosphate allows the excess glycine in the body to be converted to another amino acid, thereby reducing the side effect of a high dose of glycine.

It should also be noted that a high glycine content causes a change in the acidity of the blood (acidemia) and urine, as well as bile. These changes can lead to the risk of stone formation in the biliary and urinary tract.

Then, an extended group of combinations was tested for general motor activity in the “open field” experiment according to the following characteristics: tentatively research activity, emotional state of animals.

When determining the probability of differences in the average of groups, the Student t-test was used. The differences were considered significant at a significance level of p <0.05 (see table 4).

Table 4 A drug Number of animals WDA ± m GDA ± m T _sec fading reaction, ± m T _sec grooming, ± m T _sec sniffing reaction, ± m Glycine 6 5.01 ± 3.1 51.5 ± 3.83 138.38 ± 38.51 18.13 ± 11.27 34.13 ± 7.81 Glycine / Vitamin B ₆ 7 2.89 ± 2.51 * 43.31 ± 18.11 181.34 ± 31.59 * 14.15 ± 9.82 * 31.09 ± 7.47 * Glycine / Vitamin B ₆ / Mg 7 2.6 ± 7.49 * 43.01 ± 21.71 180.45 ± 44.79 13.85 ± 10.01 31.0 ± 3.97 Phenotropil 6 1.71 ± 0.94 * 38.76 ± 12.96 * 191.09 ± 27.17 * 7.83 ± 5.52 * 25.99 ± 09.41 The control 6 8.94 ± 2.78 75.37 ± 10.38 52.0 ± 18.06 44.81 ± 6.89 46.94 ± 9.80 * - significant difference from control, p <0.05; ** - significant difference from Phenotropil, p <0.05.

In the “open field” test, the studied groups showed higher indicators of horizontal activity, in the center and on the periphery, of vertical activity in the number of racks - this shows a positive effect, against the background of taking the studied combination and extended combinations, on orientation and research activities. The grooming results showed a significant decrease in the level of anxiety, animal anxiety - this also indicates a positive effect on the emotional status of the studied groups of rats.

The use of pyridoxalphosphate has advantages previously undetected. The differences are that it has a quick therapeutic effect, probably in comparison with the form of vitamin B ₆ . The use is justified in cases where there is a violation of the phosphorylation of pyridoxine. In such a situation, it is likely that the form of vitamin B ₆ cannot be absorbed and exert its therapeutic effect. Preparations containing the form of vitamin B ₆ in the form of pyridoxalphosphate are available outside the Russian Federation under the names: "Aderomine", "Aderoxal""Codecarboxylase""Pyridoxal", in the Russian Federation there is, but is not available for sale, the preparation "Pyridoxalphosphate", of the company "MIR- PHARM "tablets 0.01 g or 0.02 g, coated, 50 tablets in a jar. Reg. No. 78/122/8 of 05.21.04. Indications for use are similar, as for pyridoxine, including conditions that are resistant to the latter. In the literature there is evidence of the high effectiveness of pyridoxalphosphate in various skin diseases such as urticaria, eczema, neurodermatitis, psoriasis.

The results obtained - a study of passive avoidance reaction and in the "open field" demonstrate that the effect of experimental combinations has a therapeutic effect when compared with the control group and is inferior in therapeutic effect to the reference drug "Fenotropil" ™.

LD _{50 of the} studied combination was determined on mice in a group of 10 animals and rats, a group of 10 animals. It was found that with intragastric (using a probe) introduction of LD ₅₀ is in the range (for glycine) of more than 3000 mg / kg of animal weight. Thus, the studied combination can be attributed to a non-toxic group.

A pathomorphological study of the internal organs of animals after repeated intragastric administration of the inventive preparation for 60 days in doses up to 200 mg / kg of animal weight did not reveal their morphological and pathological changes.

Thus, the proposed composition in an orally dispersible form can be successfully used to normalize the physiological and functional activity of the central nervous system, intellectual and mnestic functions of the brain. They are characterized by stability during storage, have a pleasant taste, which simplifies their use in clinical practice.

The claimed variants of the biologically active agent also provide a number of additional advantages (technical results) that can be obtained by adding vitamin B ₆ to glycine in a rapidly dispersible form:

- destabilizing property,

- correction of PMS syndrome (premenstrual syndrome),

- a decrease in the formation of oxalates, most often the basis of kidney stones 5,

- effectiveness for acne, seborrheic dermatitis,

- the conversion of estradiol (one of the forms of estrogen) into estriol (another, the least dangerous form of this hormone), due to which you can also use the combination in the treatment of hormone-dependent diseases in women, such as uterine fibroma, endometriosis, fibrocystic mastopathy, etc.

Claims (9)

1. A biologically active agent that affects the general metabolic, excitatory and inhibitory functions of the nervous system, intellectual and mental functions of the brain, characterized in that it includes glycine (aminoacetic acid), a vitamin B ₆ or its pharmaceutically acceptable salt and excipients that allow to make the product in the form of an orodispersible tablet, in the following ratio of components, wt.%:
Glycine 16.50-33.17 Vitamin B ₆ or its pharmaceutically acceptable salt 1.65-2.49 Flavoring 1.99-3.96 Aspartame 0.50-0.99 Stearic acid or its pharmaceutically acceptable salt 0.50-0.99 Lactose 49.09-60.73 Starch 12.27-15.18, 2. The biologically active agent according to claim 1, characterized in that it can be dispersed in the oral cavity in less than three minutes. 3. The biologically active agent according to claim 1, characterized in that said active substance is coated by film formation. 4. The biologically active agent according to claim 1, characterized in that the vitamin of group B ₆ is in the form of pyridoxal. 5. The biologically active agent according to claim 1, characterized in that it contains a mixture of lactose and starch in the form of granules. 6. A biologically active agent that affects the general metabolic, excitatory and inhibitory functions of the nervous system, intellectual and mental functions of the brain, characterized in that it includes glycine (aminoacetic acid), a vitamin B ₆ or its pharmaceutically acceptable salt, magnesium in the form of a salt, representing lactate, carbonate, sulfate, and excipients that allow you to make the tool in the form of an orodispersible tablet, in the following ratio, wt.%:
Glycine 12.41-33.33 Vitamin B ₆ or its pharmaceutically acceptable salt 1.24-2.50 Magnesium salt 24.81-33.33 Flavoring 2.00-2.98 Aspartame 0.50 Stearic acid or its pharmaceutically acceptable salt 0.50-0.74 Lactose 45.66-49.33 Starch 11.41-12.33 7. The biologically active agent according to claim 6, characterized in that the vitamin of group B ₆ is in the form of pyridoxal. 8. A biologically active agent that affects the general metabolic, excitatory and inhibitory functions of the nervous system, intellectual and mnestic functions of the brain, characterized in that it includes glycine (aminoacetic acid), a vitamin B ₆ or its pharmaceutically acceptable salt and excipients that allow to make the product in the form of an orodispersible tablet, in the following ratio of components, wt.%:
Glycine 16.50-33.17 Vitamin B ₆ or a pharmaceutically acceptable salt 1.65-2.49 Flavoring 1.99-3.96 Aspartame 0.50-0.99 Stearic acid or its pharmaceutically acceptable salt 0.50-0.99 A mixture of mannitol, crospovidone, polyvinyl acetate and povidone 49.09-60.73 Starch 12.27-15.18,
provided that the mixture of mannitol, crospovidone, polyvinyl acetate and povidone contains components in the following content, wt.%:
Mannitol 87,4-92 Crospovidone 4-6 Polyvinyl acetate 3,5-6 Povidone 0.25-0.6 9. The biologically active agent according to claim 8, characterized in that the vitamin of group B ₆ is in the form of pyridoxal.