RU2464013C1 - Combination in oral dispersible form with therapeutic action on activating and inhibitory functions of nervous system (versions) - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely applying a composition of glycine and phenazepam, in psychoneurology, and having therapeutic action on physiological and functional activity of the nervous system in various borderline and pathological conditions of the nervous activity while being safe for application. The combinations in the oral dispersible form having therapeutic action on activating and inhibitory functions of the nervous system contain bromdihydrochlorphenylbenzodiazepine, glycine (aminoacetic acid) and pyridoxine, as well as acceptable excipients.

EFFECT: combinations provide the fast onset of the therapeutic effect and reduced and/or relieved side effects, particularly CNS depression.

7 cl, 4 ex, 5 tbl

Description

The invention relates to pharmaceuticals and medicine, namely the use of a composition of glycine and phenazepam in psychoneurology, and which has a therapeutic effect on the physiological and functional activity of the nervous system in various borderline and pathological states of nervous activity, while it is safe to use.

Substances that affect the activity of the central nervous system are called nootropics. A large number of nootropic drugs that are used to treat patients in order to correct impaired CNS function. Such as: "Piracetam", derivatives of GABA - "Pantogam" ™ / "Pantocalcin" ™; Phenibut “Baclofen”, Separately from the derivatives of GABA, “Phenotropil” ™, “Akatinol (Memantin ™)”, “Phenazepam” are separated. The described agents have a therapeutic effect. And, as a rule, they have side effects associated with highly effective substances that limit the widespread use in everyday practice by patients who need such therapy and doctors who could prescribe such drugs, without fear of serious side effects. Caffeine and vitamins: B6, B15, BC and B12 can also indirectly be considered as nootropic agents. Therefore, the search and development of new effective and safe combinations of drugs that have a positive effect on the central nervous system, including higher brain activity, is currently relevant.

Glycine is the only amino acid in proteins that lacks an asymmetric carbon atom in its molecule. Metabolic glycine is associated with 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, hemoglobin heme, 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].

Glycine acts as a mediator in some cases of postsynaptic inhibition in the spinal cord. A specific antagonist of glycine is strychnine.

Glycine also has a general metabolic effect with neurotransmitter functions, it 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 limited forebrain ischemia, the administration of glycine at a dose of 20 mg / kg for the first 2 hours after surgery and 1 time per day for 9 days was accompanied by a significant increase in the concentration of glycine in the brain tissue. So, in the striatum by 63%, in the parietal cortex by 45%. Increased GABA metabolism both in the ischemic zone and in the surrounding tissue, compared with the control group of animals [Davalos A., Naveiro J. 1996]. When glycine was used, a significant decrease in the concentration of oxidative stress products in the ischemic zone was recorded, this led to the normalization of behavior and conditioned reflexes in rats [Raevsky KS, Romanova G.A. 1997, Romanova G.A., Kudrin V.S. 1995].

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]. 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. GABA and glycine are probably 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].

Studies note that the depressing mechanism of glycine on somatosympathetic reflexes has a pronounced selective inhibitory effect on the functional activity of neurons of the reticular formation [Gokin AP, Pavlasek Yu. Influence of stem microinjections of glycine and strychnine on startreflexes in rats // II All-Union Conference on Neurons: . Dokl., 1988. - S. 179-180]. It affects the functional state of the sympathoadrenal system by influencing the processes of adrenergic mediation [Godovalova L.A., Kovalev G.V. The effect of glycine on peripheral mechanisms of regulation of autonomic functions // Fiziol. journal - 1983. - T.29, No. 4. - S. 492-496].

According to published data, the use of the glycine amino acid for the treatment of patients with acute cerebrovascular accident has a therapeutic effect [Gusev E.I., Skvortsova V.I. Neuroprotective therapy in the acute period of cerebral ischemic stroke. Clinical Herald. 2, p. 6, 1995]. What is registered by the application for copyright certificate 4120032 from 06.25.86.

Glycine has an effect on cerebellar lesions. The mechanism of action of glycine is realized by regulating 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, lasting 30-50 days [Khokhlov A.P., Savchenko Yu.N. Myelinopathies and demyelinating diseases] it was noted:

- a decrease in ataxia and other clinical signs of cerebellar damage was recorded by the end of the first week from the start of treatment,

- An increase in the number of metabolites of the phosphoinositide cycle was noted in the blood.

Glycine has a nootropic, sedative, anti-stress, stress-protective and detoxifying effect. The anti-stress effect of glycine is realized due to the interaction of amino acids with glycineergic receptors, which activates the inhibition processes. Possessing the property of α1-adrenolytic, glycine prevents the excessive effect of catecholamines on the cell, an increase in the content of which, as a rule, accompanies stress. The sedative effect of the drug is realized through the weakening of psychoemotional reactions: irritability, aggressive behavior are reduced, the likelihood of conflict situations is reduced, behavior becomes “adequate” to external circumstances. Glycine activates inhibition processes. After a three-week intake of glycine twice a day, an increase in the speed of thought processes is noted (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 effect of glycine on higher nervous activity is manifested by increased attention, improves the learning process, affects the increase in the speed of computer operations and physiological reactions. The detoxifying effect of glycine relates more to phenol. Reacting with phenol, the drug forms a non-toxic compound - hippuric acid. The antitoxic effect of glycine is also present in relation to drugs. In particular, this applies 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. Glycine is also able to protect a nerve cell by acting on the myelin sheath of a neuron. Since glycine is included in the synthesis of lecithin, which is one of the main components of phospholipids.

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 medium 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 affects the synthesis of collagen, interferes with 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. There is the ability of glycine to inhibit the activation of adrenergic and pituitary-adrenal systems. It is probably associated with an antistress effect on the heart muscle due to a decrease in alterative changes in the myocardium under stress [Malyshev VV, Oshchepkova OM, Seminsky I.Zh., Nefedova TV, Morozova TP Limitation of lipid hyperoxidation and prevention of stress damage to the heart by glycine derivatives // Exper. and clinic. pharmacology. - 1996. - No. 5. - S.23-25]. There is an article on the action of glycine in the development of a neuropathic pain syndrome - glycine does not affect the onset of pain and has a therapeutic effect in pain [Danilova EI, Grafova VN, Reshetnyak VK The role of the ketamine and glycine NMDA receptor blocker and stimulator in the development of neuropathic pain syndrome // Exper. 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. The authors at the same time indicate the importance of using high doses of the drug (1-2 g / day) from the first hours of stroke, within 5 days [I. Komissarova New medicine against stress // Terra medica. - 1996. - No. 2. - S.33-36]. This shows the therapeutic breadth of use, with confirmation of the safety of the drug. Glycine has an effect 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 p.]. It can be used for the prevention and treatment of alcohol intoxication [Komissarova I.A. New medicine against stress // Terra medica. - 1996. - No. 2. - S.33-36], in the treatment of ataxia and tremor in the case of multiple sclerosis, for the relief of pain in the case of 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. ... Dr. honey. Sciences: 14.00.13 / I Mosk. honey. Institute of them. I.M.Sechenova. - M., 1990. - 36 s]. Since glycine supplies the body with creatine as an essential element for the functioning of muscle cells, glycine is very effective in treating progressive muscular dystrophy.

Glycine has an effect in the treatment of decreased pituitary function. Treatment of menopausal syndrome in combination with hormone replacement therapy [Dreval A.V., Marchenkova L.A., Tishenina R.S. and etc]. The combination of hormone replacement therapy with natural metabolite preparations (glycine and limontar) in the treatment of menopausal syndrome // Probl. endocrinology. - 1999. - T. 45, No. 4. - S.19-24]. The use of glycine in the complex therapy of newborns with intrauterine hypotrophy is pathogenetically substantiated [Tsvirenko SN] The pathogenetic substantiation of the purpose of glycine in the rehabilitation of newborns with intrauterine hypotrophy at the second stage of nursing: Abstract. dis. Cand. honey. Sciences: 14.00.09. Institute of Pediatrics, Obstetrics and Gynecology, Academy of Medical Sciences of Ukraine. - Kiev, 1995, - 20 s].

Glycine is actively involved in providing oxygen to the cell division process. Participates as an important component in the production of regulatory substances involved in the immune system. Glycine is the starting material for the synthesis of other amino acids. Glycine is an amino group donor in the synthesis of hemoglobin and a number of other substances. Glycine is involved in the synthesis of connective tissues. In the situation of the anabolic phase - the need for glycine - the amino acid increases. Increased glycine intake inhibits protein catabolism. Glycine is an indispensable component in the synthesis of immunoglobulins and antibodies.

Numerous patents are known regarding the use of glycine in various conditions.

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

In the patent of the Russian Federation No. 2171673 "Pharmaceutical composition and method for its preparation" the disintegration of this dosage form is at least 10 and no more than 30 minutes.

RF patent No. 2025124 "Antistress, stress-protective, nootropic agent, a method for the prevention and treatment of stressful conditions and a way to increase mental performance."

Patent No. 2335926 “Food vitamin-mineral supplement”, the supplement contains, in addition to glycine (aminoacetic acid) N-acetyl-L-glutamic acid, pyridoxine hydrochloride (vitamin B6), zinc acetate dihydrate or zinc citrate, riboxin, nicotinamide, tauric acid and amber in a ratio with hepatoprotective and cardioprotective action.

RF patent No. 2322240 "A drug with nootropic activity (options)", a tool in the form of an aqueous solution, additionally containing glycine.

Patent No. RF 2253442 "Shielding (buccal) pharmaceutical composition comprising aminoacetic acid." The known composition has a nootropic, antiepileptic, sedative, anti-stress, normalizing metabolic processes in the body and contains aminoacetic acid and a pharmaceutical carrier, consisting of a mixture of sorbitol and sodium salt of cross-linked carboxymethyl cellulose in a mass ratio of from 1: 1 to 1: 3 in combination with an additive, selected from the group consisting of vinylpyrrolidone-vinyl acetate copolymers, stearic acid, a stearic acid salt, or mixtures thereof.

An important element in the functioning of the nervous system is vitamin B6.

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 the production of 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 B6 (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 B12).

In therapeutic practice, vitamin B6 is used very widely. For example, for pain and inflammation. It has been shown that in the complex use of vitamin B6 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 KH, 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].

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 geriartic practice.

RF patent No. 2287327 "Means for the treatment or prevention of atherosclerosis", contains pyridoxine hydrochloride (vitamin B6), cyanocobalamin (vitamin B12), folic acid (vitamin Bc), characterized in that it is made in the form of a tablet, designed to normalize the state of the myocardium with coronary heart disease.

The combination of vitamin B6 with antiepileptic, or neuroprotective, or nootropic drugs can reduce the risk of epileptic disorders (application WO 2005016228).

In neurological practice, compounds of the benzodiazepine group are also widely used.

The original domestic compound of this group is bromodihydrochlorophenylbenzodiazepine, better known as Phenazepam®, the chemical name is C ₁₅ H ₁₀ BrClN ₂ O 7-bromo-5- (2-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepin-2 -it. The general structure of phenazepam is described by the formula.

Bromo dihydrochlorophenylbenzodiazepine in terms of the severity of the therapeutic effect of tranquilizing and anxiolytic effects is superior to other tranquilizers. Also has an anticonvulsant, muscle relaxant and hypnotic effect. In the case of joint use together with sleeping pills and drugs, there is a mutual strengthening of the effect on the central nervous system. Bromo dihydrochlorophenylbenzodiazepine is used for neurotic, neurosis-like, psychopathic and psychopathic conditions. These conditions may be accompanied by anxiety, fear, increased irritability, emotional lability. The drug is used for obsessive states, phobias, hypochondriac syndromes, in particular, resistant to the action of tranquilizers. Used for psychogenic psychoses, panic reactions, etc., as it relieves anxiety and fear. Bromo dihydrochlorophenylbenzodiazepine is comparable in comparison with some antipsychotics in sedative effect and mainly in anti-anxiety effect. Bromo dihydrochlorophenylbenzodiazepine is prescribed as part of combination therapy for the relief of alcohol withdrawal. Apply as an anticonvulsant and sleeping pill. Use bromodihydrochlorophenylbenzodiazepine and with premedication in preparation for surgical operations.

After oral administration, it is well absorbed from the digestive tract, T _max - 1-2 hours. It is metabolized in the liver. T _1/2 - 6-10 hours. It is excreted mainly by the kidneys in the form of metabolites (Vidal Handbook, 2009, p. B-1341).

The following patents are known for compositions containing bromodihydrochlorophenylbenzodiazepine:

- RF patent No. 2271197, describes a method for the treatment of hypertension;

- RF patent No. 2239441, describes a method for the treatment of patients with neurotic and somatoform disorders;

- RF patent No. 2224521, describes a solid dosage form of a tranquilizing effect containing bromodihydrochlorophenylbenzodiazepine (Phenazepam®) and a method for its manufacture as an active agent.

RF patent No. 2183121, describes a dosage form containing bromodihydrochlorophenylbenzodiazepine (Phenazepam®) in the form of a tablet as an active agent and a method for its preparation.

It is highly desirable from a clinical point of view to propose a combination of phenazepam, which would be easy to administer and convenient for use by a patient with disorders of the nervous system, thereby reducing the need to monitor the administration, and which would bypass the metabolism upon initial exposure to the liver .

As the closest analogue, US Pat. No. 4,229,447 may be indicated regarding intraoral (buccal and sublingual) methods and compositions for administering benzodiazepines. The tablets quickly disintegrate - within no more than 2 minutes and the active principle is rapidly absorbed.

A disadvantage of the known solution is that for benzodiazepines used as an active principle (as well as for phenazepam), side effects are characteristic, and especially after administration and in particular after 6-8 hours, and especially after sleep, such as dizziness, headache, drowsiness, muscle weakness, impaired memory, concentration of attention, coordination of movements, paradoxical agitation, ataxia.

The objective of the invention is to create a drug combination that combines the preservation of the therapeutic effect of incoming active components and the reduction and / or elimination of side effects, in particular CNS depression.

The problem is solved by new variants of combined formulations in the form of an orodispersible dosage form.

Such forms are currently a new direction in pharmaceutical practice. They are usually referred to 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, it is not necessary 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.

The first option is a combination in the form of an orodispersible form, with a therapeutic effect on the excitatory and inhibitory functions of the nervous system, containing bromodihydrochlorophenylbenzodiazepine, glycine (aminoacetic acid) and excipients, in the ratio of components, wt.%:

Bromo dihydrochlorophenylbenzodiazepine 0.017-0.02 Glycine 16.78-34.01 Flavoring 2.04-4.03 Aspartame 0.51-1.01 Stearic acid or its pharmaceutically acceptable salts 0.51-1.01 Lactose 50.33-61.73 Starch 12.58-15.43

Another embodiment of the invention is a combination in the form of an orodispersible form, with a therapeutic effect on the excitatory and inhibitory functions of the nervous system, containing bromodihydrochloro phenylbenzodiazepine, glycine (aminoacetic acid), vitamin B6 or its pharmaceutically acceptable salt and excipients in the following ratios, wt.% :

Bromo dihydrochlorophenylbenzodiazepine 0.014-0.01 Glycine 14.37-29.07 Vitamin group "B6" or its pharmaceutically acceptable salt 14.37-14.53 Flavoring 1.74-3.45 Aspartame 0.44-0.86 Stearic acid or its pharmaceutically acceptable salts 0.44-0.86 Lactose 43.02-52.87 Starch 10.75-13.22

Another embodiment of the invention is a combination in the form of an orodispersible form, with a therapeutic effect on the excitatory and inhibitory functions of the nervous system, containing bromodihydrochlorophenylbenzodiazepine, glycine (aminoacetic acid), vitamin B6 or its pharmaceutically acceptable salt and excipients in the ratio of components, wt.% :

Glycine 16.50-33.17 Vitamin B6 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

A biologically active agent can be dispersed in the oral cavity in less than less than three minutes, preferably less than 2 minutes.

In order to vary the release from the fast-dispersing dosage form, it is possible to change the degree of adsorption of the active substances by coating the colloidal film or coating said active components. 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, mixtures of cellulose polymers and other polymers such as polyvinyl, such as, for example, "Kollidon" ®, with all of the described polymers and / or mixtures thereof can be used together with polyethylene glycol. Coating with a colloidal film may 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.

The technology of dragee production is also used as a technology for coating an active substance. This technology is implemented using sugars or polyols, which, if necessary, are mixed with film-forming polymeric substances.

If the active ingredients are combined with excipients, such as starch and lactose, the latter can be presented both in the form of a dry mixture, and in the form of granules.

Additionally, glucose may be added.

Pellets can be prepared in various ways. This may be a cumulative drying. In this method, granules are obtained by mixing lactose and starch and spraying them.

The composition of the granules in solid form in accordance with the invention is dependent on the dose of the active substance. Basically, the granules comprise from 20 to 96%, preferably from 40 to 90% by weight of the specified solid form.

If there is no possibility of preparing granules, then it is possible to use the mixture not only in the form of granules, but also in the form of a simple mixture. Flavors, colorants, lubricants, sweeteners, if necessary, are added to the prepared mixture.

The amount of sweetener should not violate the dispersibility of the form.

Sweeteners are selected from the group of sugars: maltose, dextrose, fructose. Maltodextrins or polyhydric alcohols can also be sweeteners: mannitol, maltitol, sorbitol, erythritol, xylitol, lactitol. It is preferable to use sugars or polyols most suitable for direct compression. The best option is polyhydric alcohol.

Good results for direct compression mannitol are added to the prepared mixture with a content of 10 to 30%, most preferably 15 to 25% by weight.

It is also justified that the inclusion of substances such as organic acid, carbonate base, in order to obtain a dosage form with the effect of "hissing" in the oral cavity. This gives a subjective feeling of disintegration of the tablet in the mouth and the beginning of the therapeutic effect immediately before the destruction of the tablet.

To achieve this effect, about 5% by weight of such an acid-base pair is used, for example citric acid - sodium bicarbonate, is added to the reactor, where the mixture consisting of bromodihydrochlorophenylbenzodiazepine, glycine, lactose with starch in granules, a sweetener (maltose, dextrose, sucrose) or beckons) 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 with this technology have a pronounced dispersion in the oral cavity, which does not depend on the hardness or density of the tablet. Because the use of a mixture of lactose and starch in the form of granules, and not only in a mixture in the form of granules, allows to achieve rapid release of the active components. In addition, while waiting for a quick relief of symptoms, the placebo effect increases.

As already noted in the disclosure of the prior art, there are rapidly dispersible forms of glycine. It should also be noted that it is known that phenazepam, like some other benzodiazepines, can be used in a form suitable for sublingual use, which is more convenient if the patient cannot swallow tablets or takes the drug on a full stomach, which slows down absorption. (Guidelines for Psychopharmacotherapy, George Arana, Gerald Rosenbaum, 2001, p. 135).

However, in the same source it is noted that, depending on the combination of substances, the generic forms may not be absorbed sublingually. Thus, the difficulty in creating the claimed new compositions was to combine the two known drugs in such a way as to maintain their high bioavailability. This was achieved by the choice of form and composition of excipients.

The possibility of carrying out the invention can be demonstrated by the following examples.

Example 1

Bromo dihydrochlorophenylbenzodiazepine and glycine are charged to the reactor.

The resulting mixture is transferred to the mixer and sequentially adding lactose, potato starch, aspartame, stearic acid or a pharmaceutically acceptable salt thereof, for example magnesium or calcium stearate, and the latter is introduced flavoring in the ratio, wt.%:

bromodihydrochlorophenylbenzodiazepine 0.017-0.02 glycine 16.78-34.01 flavoring 2.04-4.03 lactose 50.33-61.73 starch 12.48-15.43 stearic acid or its salt 0.51-1.01 aspartame 0.51-1.01

The recipe also takes into account the amount required for the preparation of starch paste and powder for dusting.

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

The tablet mass is discharged from the mixer and dried in a fluidized bed. After that, the tablet mass is passed through a sieve with holes of 1.2-2 mm and loaded into the mixer, with the addition of a dusting mixture of starch and stearic acid or its salt, mixed thoroughly, then granulated. The resulting mixture was checked by HPLC. In the case of positive results pass to the stage of tabletting.

Tableting is carried out on the press, on flat or biconvex punches with a diameter of 16 mm with a bevel and the ability to print with a logo on one side.

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

Examples of specific formulations are shown in table 1.

Table 1 Example 1A Example 1B Example 1C Glycine 16.78 Glycine 21.66 Glycine 34.01 Bromo dihydrochlorophenyl Bromo dihydrochlorophenyl Bromo dihydrochlorophenyl benzodiazepine benzodiazepine benzodiazepine 0.02 0.02 0.017 Flavoring Flavoring from Flavoring "orange" peppermint "orange" 4.03 2.99 2.04 Aspartame 1.01 Aspartame 0.51 Aspartame 0.513 Stearic acid 1.01 Stearic acid 0.99 Stearic acid 0.51 Lactose 61.73 Lactose 60.73 Lactose 50.33 Starch 15.43 Starch 13.1 Starch 12.58

Example 2

A mixture of mannitol, crospovidone, polyvinyl acetate and povidone was also used as an auxiliary substance to achieve the orodispersed form of the tablet in the following content, wt.%:

mannitol 87.4-92.0 crospovidone 4-6 polyvinyl acetate 3,5-6,0 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 — bromide dihydrochlorophenyl benzodiazepine, glycine, a vitamin B6 group or a pharmaceutically acceptable salt thereof, for example, hydrochloride, a mixture of mannitol, crospovidone, povidone 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.%: Bromodihydrochlorophenyl benzodiazepine 0.02-0.017, glycine 16.50-33.17, vitamin B6 or its pharmaceutically acceptable salt 1.65-2.49, mannitol mixture , 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 are shown in table 2.

table 2 Example 2A Example 2B Example 2C Glycine 16.50 Glycine 33.17 Glycine 29.6 Bromo dihydrochlorophenyl benzodiazepine 0.02 Bromo dihydrochlorophenyl benzodiazepine 0.017 Bromo dihydrochlorophenyl benzodiazepine 0.02 Pyridoxal hydrochloride 2.49 Pyridoxine hydrochloride 1.65 Pyridoxine 1.65 Anise Flavor 3.96 Peppermint flavor 1.99 Peppermint flavor 2.97 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%), polyvinyl acetate (3.75%) and povidone (0.25% ") 60.73 A mixture of mannitol (87.4%), crospovidone (6%), polyvinyl acetate (6%) and povidone (0.6%) 49.903 A mixture of mannitol (92%),
crospovidone (4%),
polyvinyl acetate (3.75%) and
povidone (0.25%) 49.09 Starch 15.16 Starch 12.27 Starch 15.18

Example 3

Preparation of tablet mass.

Bromo dihydrochlorophenylbenzodiazepine, a vitamin of group "B6" or a pharmaceutically acceptable salt thereof, for example pyridoxine hydrochloride, sieved, are mixed into a drum-type mixer, mixed for 10 minutes. Next, lactose and starch in the form of granules are loaded one after another, mixed thoroughly. Sifted glycine is loaded into a drum-type mixer, the mixture is stirred for 3 minutes. The mixer is stopped. Add aspartame, mix for 20 minutes.

In the mixer for dry mixing, so-called a blender is loaded with a sweetener, for example sifted sorbitol (optional), a flavor (such as sifted mint), is mixed for 5 minutes. The contents of the mixture described above are added to the blender and mixed thoroughly for 15 minutes.

In a blender, the mixture was dusted with stearic acid or its pharmaceutically acceptable salt, stirred for 5 minutes.

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

Then the mass is granulated, passing through a sieve with holes of 1.2-2 mm and loaded into the mixer, and a mixture of starch and stearate for dusting is added.

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 flat or biconvex punches with a diameter of 16 mm (semi-deep sphere) with a bevel and the ability to print the logo on one side.

Resorption tablets should be white round flat or biconvex with the inscription on one side, with solid edges, a smooth and uniform surface.

Tablets 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).

Table 3 Formulation Examples Example 3A Example 3B Example 3C Glycine 24.63 Glycine 29.07 Glycine 14.37 Bromo dihydrochlorophenyl benzodiazepine 0.01 Bromo dihydrochlorophenyl benzodiazepine 0.01 Bromo dihydrochlorophenyl
benzodiazepine 0.014 Pyridoxal hydrochloride 14.37 Pyridoxine Hydrochloride 14.53 Pyridoxine 4.53 Anise flavor 3.45 Peppermint flavoring 1.74 Mint flavoring 3.45 Aspartame 0.86 Aspartame 0.44 Aspartame 0.86 Magnesium Stearate 0.44 Stearic acid 0.44 Calcium Stearate 0.86 Lactose 43.02 Lactose 43.02 Lactose 52.87 Starch 13.22 Starch 10.75 Starch 13.05

Example 4

We studied the antistress effect of the combination by creating a multifactorial extreme situation in rats - deprivation of the paradoxical phase of sleep, novelty of the situation, immobilization, isolation.

The deprivation of the paradoxical phase of sleep was carried out in a pool of water, on a platform with a diameter of 6-6.5 cm, protruding 2 cm above the water level, on which animals could sit freely. 7-day deprivation of the paradoxical phase of sleep, causes a pronounced violation of the structure of sleep and leads to behavioral disorders. After 7 days, the animals recorded the behavior in the test "open field" and memory impairment for the reproduction of passive avoidance reaction. The control group without stress was performed according to the same indicators. The rats were administered the combination of Example 1B.

Finding animals in extreme conditions for 7 days leads to significant changes in behavior and memory.

The effect of the combinations on the orientational research behavior of rats in an open field after Juve stress after 7-day stress is shown in Table 4.

Table 4 Impact General motor
activity Stress-free control 29.1 ± 3.2 Stress control 41.4 ± 2.3 Bromo dihydrochlorophenylbenzodiazepine 31.4 ± 3.5 Glycine 39.9 ± 5.2 Bromo dihydrochlorophenylbenzodiazepine / Glycine 30.7 ± 1.9 Bromo dihydrochlorophenylbenzodiazepine / Glycine / Pyridoxine 30.2 ± 4.1

Under the influence of the studied combinations, a decrease in the orientational-research behavior was noted, and the indices were comparable with those of rats without stress.

Cognitive-mnestic was evaluated in the experience of passive avoidance, the so-called conditioned 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 the illuminated 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.

The effects of combinations with amnesia of passive avoidance reaction, with stress according to Juve, are shown in table 5.

Table 5 Impact Latent time of the first call, s Time in the dark compartment, s Learning Control 105.3 ± 9.8 7.8 ± 0.8 Amnesia Control 47.4 ± 8.2 54.3 ± 2.2 Bromo dihydrochlorophenylbenzodiazepine 56.9 ± 4.8 44.5 ± 7.5 Glycine 69.5 ± 10.6 61.5 ± 5.6 Bromo dihydrochlorophenylbenzodiazepine / Glycine 87.2 ± 3.9 36.9 ± 8.9 Bromo dihydrochlorophenylbenzodiazepine / Glycine / Pyridoxine (Example 2C) 86.8 ± 1.6 37.3 ± 7.9

The studied combinations have a pronounced normalizing effect on the orientational research behavior of animals after severe stress, i.e. combinations have a directed antistress effect. It should be noted that the combination with the addition of Pyridoxine did not have significant advantages over the combination without Pyridoxine, although they did not differ significantly.

General motor activity.

The evaluation was carried out according to the following data:

- indicative research activity of the emotional state of animals was carried out in the installation of "open field". The rat was placed in a square centered 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). The orientation and exploratory behavior of animals was evaluated;

- horizontal motor activity (GDA). The overall motor activity of rats was evaluated.

The emotional state of rats was evaluated by the following indicators: fading reactions, sec; grooming reactions, sec; sniffing reactions, sec.

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

To determine the likelihood of differences in the mean values in the groups, Student t-test was used. The differences were considered significant at a significance level of p <0.05.

The groups of experimental animals to which the studied combinations were administered showed in the experiment “open field”, high rates of horizontal activity (in the center and on the periphery), vertical activity (number of racks), in comparison with the control group. This indicates a good adaptability of the research activity. Grooming data indicate a positive effect on the emotional status of rats from the studied groups, a decrease in the level of anxiety, anxiety in comparison with the control group.

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

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

A pathomorphological study of the internal organs of animals after repeated intragastric administration of the claimed drugs for 60 days in doses up to 150 mg / kg of the animal's weight did not reveal their morphological and pathological changes.

Thus, the proposed composition in orodispersible 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.

Claims (7)

1. The combination in the form of an orodispersible form with a therapeutic effect on the excitatory and inhibitory functions of the nervous system, characterized in that it contains bromodihydrochlorophenylbenzodiazepine, glycine (aminoacetic acid) and excipients in the ratio of components, wt.%:
Bromo dihydrochlorophenylbenzodiazepine 0.017-0.02 Glycine 16.78-34.01 Flavoring 2.04-4.03 Aspartame 0.51-1.01 Stearic acid or its pharmaceutically acceptable salts 0.51-1.01 Lactose 50.33-61.73 Starch 12.58-15.43 2. The combination in the form of an orodispersible form with a therapeutic effect on the excitatory and inhibitory functions of the nervous system, characterized in that it contains bromodihydrochlorophenylbenzodiazepine, glycine (aminoacetic acid), vitamin B6 or its pharmaceutically acceptable salt and excipients in the following ratios, wt. .%:
Bromo dihydrochlorophenylbenzodiazepine 0.014-0.01 Glycine 14.37-29.07 Vitamin group "B6" or its pharmaceutically acceptable salt 14.37-14.53 Flavoring 1.74-3.45 Aspartame 0.44-0.86 Stearic acid or its pharmaceutically acceptable salts 0.44-0.86 Lactose 43.02-52.87 Starch 10.75-13.22 3. The combination according to claim 1, characterized in that it contains a mixture of lactose and starch in the form of granules. 4. The combination according to claim 2, characterized in that it contains a mixture of lactose and starch in the form of granules. 5. The combination according to claim 1, characterized in that said active substance is coated by film formation. 6. The combination according to claim 2, characterized in that said active substance is coated by film formation. 7. The combination in the form of an orodispersible form with a therapeutic effect on the excitatory and inhibitory functions of the nervous system, containing bromodihydrochlorophenylbenzodiazepine, glycine (aminoacetic acid), vitamin B6 or its pharmaceutically acceptable salt and excipients in the ratio of components, wt.%:
Bromo dihydrochlorophenylbenzodiazepine 0.017-0.02 Glycine 16.50-33.17 Vitamin B6 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