RU2546300C1 - Composition having action on central nervous system and using it - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: composition has an action of the central nervous system; it is presented in the form of a solution, contains glycine, glycerol, a preserving agent and water. The invention also concerns a therapeutic agent and a biologically active addition based on the above composition.

EFFECT: group of inventions provides high bioavailability as the composition is presented in the liquid and ease of dosing.

12 cl, 2 tbl, 3 ex

Description

The group of inventions relates to medicine, pharmacology and the food industry and can be used for the prevention and / or treatment of disorders of the nervous system.

Correction of disorders of the functioning of the nervous system has always been considered one of the most difficult and urgent tasks, which is associated with the complexity of the functional organization of the nervous system and the relative lack of knowledge about the causes and mechanisms of development of these disorders. In this regard, it is relevant to constantly search and put into practice various means: food, dietary supplements, new drugs for the prevention, correction and treatment of disorders of the nervous system.

It is known that substances that have a specific positive effect on the activity of the central nervous system (CNS) are called nootropics. Such preparations are known as Piracetam, Phenotropil, Akatinol (Memantine), various derivatives of GABA - Pantogam / Pantocalcin, Phenibut, Baclofen. The described agents have a pronounced therapeutic effect. But at the same time they have side effects associated with highly effective substances that limit the widespread use in everyday practice by patients who need the prevention and treatment of such diseases, especially pediatrics and gerontology. Therefore, the search and development of new effective and safe medicines and biologically active additives 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.

One of the substances that have a positive effect on the activity of the central nervous system and at the same time characterized by a low level of side effects is glycine. According to modern data, glycine is widely used in neuropsychiatric clinical practice. It appears that its pharmacological activity is due to the following properties:

- improvement of mental performance, memory;

- increasing attention, improving the learning process;

- normalization of the psychoemotional and neurological state;

- Normalization of the nervous system during hyper-excitation, overwork and intoxication;

- the presence of a nootropic effect;

- anti-stress effect, not accompanied by a sedative effect;

- detoxifying effect in chemical intoxications.

It should also be noted some other features of glycine, allowing its use not only as a medicine, but also as a biologically active additive:

- lack of contraindications and side effects;

- lack of age restrictions at admission;

- a wide range of dosages;

- the possibility of combination with other biologically active additives and drugs.

These features of glycine allow its use in pediatric or gerontological practice as a therapeutic and prophylactic agent.

It should be noted that the problem of the pathology of the nervous system in young children, which often leads subsequently to the maladaptation of the child in the social environment, and in severe cases to its disability, is especially relevant. Therefore, it seems appropriate to use glycine in young children (for example, from 1 year old), since many lesions of the central nervous system observed in adults are a consequence of perinatal pathology, complications of maternal pregnancy and childbirth, which an adult may not later know about. Therefore, it is obvious that glycine can be prescribed to children of younger age groups, in particular, to improve the child’s sleep, normalize metabolic processes and relieve emotional stress.

However, the currently used preparative forms of glycine do not allow its use in young children, since, on the one hand, in the recommended doses, they do not provide a therapeutically significant amount of glycine, on the other hand, they are simply not intended for such a reception and do not take into account physiological aspects of taking drugs in children.

In particular, it should be noted that the main form of glycine administration is sublingual administration. It is characterized by the prolonged presence of the tablet in the oral cavity (from 10 to 30 minutes), which can lead to its involuntary ingestion, getting into the respiratory passages. These problems are especially relevant when using the drug in young children. All this often leads to non-compliance with the dosage and even to refusal to take medication.

In fact, the same problems are present in relation to the elderly and patients suffering from disorders of swallowing reflexes or pathologies that violate salivation.

The following forms and compositions containing glycine are currently known:

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." The inventive tool containing amino acid glycine or its pharmaceutically acceptable salt in an amount of 0.1-0.2 mg per dose and an acceptable carrier, in the form of tablets used sublingually. The inventive antistress drug, stress-protective and nootropic action is used in children and adults with impaired attention, memory, decreased mental activity, with neurosis, neurosis-like conditions, residual effects of traumatic brain injury, mental retardation, deviant behavior, alcoholism, and neuropsychiatric Mental stress and coronary artery disease.

However, as we have already indicated, sublingual administration is characterized by prolonged exposure of the tablet to the oral cavity (from 10 to 30 minutes), which can lead to its involuntary ingestion and into the respiratory passages. These problems are especially relevant when using the drug in young children, the elderly and patients suffering from disorders of swallowing reflexes or pathologies that violate salivation. All this often leads to non-compliance with the dosage and even to refusal to take medication.

RF patent No. 2464013 "The combination in the form of an orodispersible form with a therapeutic effect on the excitatory and inhibitory functions of the nervous system (options)" suggests the use of glycine as part of a combined orodispersible form. Thanks to the use of effective excipients, the effect is achieved that the tablet is dispersed in the oral cavity in 2-3 minutes. This significantly reduces the above risks when taking, but does not completely eliminate them.

RF patent No. 2462243 "Means for the removal of a hangover syndrome" describes a tool containing glycine and octohedral smectite or saponite in the form of a powder or tablets dispersible in water. This tool differs from the above in that it must be dispersed in water before use. However, then the resulting suspension is taken orally, which significantly reduces the bioavailability of glycine. Also, due to the content of sorbents, this agent cannot be used for a long period of time.

Known RF patent No. 2322240 "A drug with nootropic activity (options)", in which dimephosphon is used as the active component in the syrup, and in addition glycine. Here, glycine is used in a concentration of 2-5%, which in the recommended doses of the syrup does not provide a therapeutically significant amount of glycine.

Closest to our proposed group of inventions is a “Pharmaceutical composition of prolonged action based on glycine and a method for its preparation”, which describes a method for producing nanoforms of glycine prolonged action, which can be used to obtain dosage forms in the form of tablets, powders, injection solutions (patent RF №2457835). However, the proposed method for converting the substance of glycine is complex, requires the use of a large number of auxiliary substances, including such dangerous ones as acetone, chloroform.

Thus, our task was to create a composition based on glycine, which would be convenient for use, including in pediatric and geriatric practices. Also, this composition would be characterized by high bioavailability and ease of dosing.

The technical result of the proposed group of inventions is the creation of a composition based on glycine, which would be convenient for use, including in children’s (children from 1 year old) and geriatric practices (in the elderly and patients suffering from swallowing reflex disorders or pathologies that violate salivation) . Also, this composition is characterized by high bioavailability due to its performance in liquid form and ease of dosing.

Therefore, in order to increase the patient's convenience, ease of administration and ensure the fastest possible absorption of the active substance in the oral cavity, we offer a composition developed by us, where the composition is an alcohol-free solution containing its composition, wt.%:

Glycine - 5-25

Glycerin - 1-25

Preservative - 0.001-2

Water - the rest

The composition in its composition may additionally contain corrective substances: sweeteners, flavoring agents, flavorings, thickeners.

The composition may be in the form of a solution for oral administration or a spray used orally.

As sweeteners, it may contain the following substances, at least selected from the group: saccharin, aspartame, sucrose, fructose, lactose, dextrose, mannitol, sorbitol, xylitol, glucose, maltodextrins in wt.%, From 5 to 50.

As a flavoring composition may contain menthol, and / or vanillin, and / or food flavorings, and / or essential oils in wt.%, From 0.001 to 0.1.

As a preservative, it may contain the following substances: sorbic acid and / or its salts, and / or benzoic acid and / or its salts, and / or methyl parahydroxybenzoate, and / or propyl parahydroxybenzoate, and / or benzalkonium chloride, and / or imidourea, and / or cetalkonium and / or cetylpyridinium.

As part of the flavor, the composition may contain the following acids: citric, and / or succinic, and / or malic, and / or tartaric acid in wt.%, From 0.01 to 5.

In its composition, the composition as thickeners may contain vinylpyrrolidone polymers in wt.%, From 0.1 to 20.

The composition can be obtained in the following way.

Purified water is loaded into a suitable vessel with a stirrer, heated to + 60ºC. The stirrer is turned on and glycerin, preservative and glycine are added. It is mixed until the components are completely dissolved, cooled, filtered and poured into vials. Corrective substances can be added to the composition: sweeteners, flavoring agents, flavorings, preservatives, thickeners.

The composition may be used as a dietary supplement or as a medicine; in the form of a solution or spray for oral administration, convenient for use, including in pediatric and geriatric practices.

The proposed ratio of active substance and excipients found experimentally is optimal for obtaining a stable solution.

The proposed solution has a pleasant taste. The selected concentration of glycine provides a convenient dosage of the drug both in the form of drops (from 3 to 10 drops), and in the form of a spray (from 1 to 5 injections). The use of a solution in the form of a spray provides a uniform finely dispersed solution throughout the oral mucosa, which contributes to the rapid absorption of glycine from the oral cavity.

Obtaining the composition and, accordingly, the drug or biological additives can be carried out, for example, by the following methods.

Example 1. Purified water (79.008 g) is loaded into a suitable vessel with a stirrer, heated to +60 C. The stirrer is turned on and glycerin (5 g), preservative (benzalkonium chloride or other acceptable salt) (0.002 g) and glycine (15 g) are added. ) It is mixed until the components are completely dissolved, cooled, filtered, poured into bottles and sealed.

Example 2. Purified water (59.009 g) is loaded into a suitable vessel with a stirrer, heated to +60 C. The stirrer is turned on and glycerin (5 g), a preservative (benzalkonium chloride or other acceptable salt) (0.001 g), sucrose (25 g) are added. ), citric acid (5 g) and glycine (15 g). It is mixed until the components are completely dissolved, cooled, filtered, poured into bottles and sealed.

Example 3. Purified water (74.008 g) was loaded into a suitable vessel with a stirrer, heated to +60 C. Then glycerin (5 g), preservative (benzalkonium chloride or other acceptable salt) (0.002 g) and glycine (10 g) were added. Stirred until the components are completely dissolved, cooled to 25 C. Turn on the stirrer and add low molecular weight polyvinylpyrrolidone (10 g). Stir until polyvinylpyrrolidone is completely dissolved. Then the solution is filtered, poured into vials and sealed.

Use the resulting composition as follows.

The use of glycine in the form of drops or spray as a dietary supplement:

Children older than 3 years of 4 pressures (spraying in the mouth) 3 times a day immediately after eating. 1 injection (0.17 ml of solution) contains 25 mg of glycine.

Adults 8 clicks (spray in the mouth) 3 times a day immediately after eating.

Duration of admission is 1 month. Reception is recommended to be repeated 3-4 times a year.

Use of glycine in the form of drops or spray as a recommended medicine:

Children under 3 years of age, 2 clicks (spraying in the oral cavity) 3 times a day.

Duration of administration is 7-14 days, then 2 clicks (spraying in the oral cavity) for 7-10 days.

Children older than 3 years and adults 4 clicks (spraying in the oral cavity) 3 times a day.

Duration of admission is 7-14 days. Reception can be increased up to 30 days. If necessary, the course is repeated after 30 days.

In case of sleep disturbance 20 minutes before bedtime or immediately before bedtime, 2-4 clicks, depending on age.

1 injection (0.17 ml of solution) contains 25 mg of glycine.

If necessary, courses are repeated 4-6 times a year.

An example confirming the equivalence of the biological effect of the developed form of liquid glycine with a known tablet preparation containing glycine.

To confirm that glycine in liquid form provides biological action equivalence, as well as the required level of bioavailability, comparative preclinical studies of the proposed liquid form in the form of drops and spray and the well-known drug in the form of tablets manufactured by MNPK Biotiki LLC were presented. Below are the results of animal tests in the context of modeling mnestic disorders.

The basic model for assessing the effect of substances on the formation and reproduction of a commemorative trace in normal conditions and in the conditions of its experimental violation is the technique of the conditioned passive avoidance reflex (passive avoidance reaction). The main advantages of this method are the speed of reflex production (learning from one sample) and the possibility of differentiated effects on different phases of memory.

The method is based on the inhibition of congenital activity or acquired skills, leading to negative consequences for the body. In conditions of passive avoidance, the animal learns to avoid harmful factors by suppressing certain forms of behavior, in this study - to avoid the preferred dark space.

The experiments were performed on outbred white male rats with an average weight of 160 g.

In animal experiments used the same dose of drugs. Since with a single injection of spray 25 mg of glycine gets into the oral cavity of a rat weighing 160 g, this will be 150 mg per kg of mass. Therefore, a lower dose of spray is not possible. This dose per glycine was used for other dosage forms, so that animals received equally effective doses of the compared drugs.

Before developing passive avoidance reaction, the experimental animals were administered the studied drugs at a dose of 150 mg / kg for 10 days.

The control animals were injected with distilled water in a volume of 0.2 ml per animal.

On day 11, rats underwent passive avoidance reaction in an installation, the triggering stimulus of which was the animal in a brightly lit space. The rat was placed in the bright compartment of a two-section chamber. After the rat went into the dark compartment, irreparable pain was immediately applied with five consecutive stimuli of alternating current (1 mA, each lasting 1 second with an interval of 2 seconds).

Amnesia of passive avoidance reaction was caused by intraperitoneal administration of 1.5 mg / kg scopolamine 30 minutes before training.

Electroconvulsive shock was applied through electrodes placed on the cornea of the eyes (15-20 mA, 200-500 ms) 60 minutes before training.

During testing (re-placement in the illuminated compartment after 24 hours in order to determine the preservation of passive avoidance reaction), the animals were monitored for 180 seconds, the latent period of the rat's transition to the dark part of the chamber, the time spent in the light and dark compartments, and the number of animals that did not enter were recorded into the dark compartment (number of trained animals). At the same time, groups without amnesia modeling and with amnesia were tested.

The results of the effect of the studied drugs on the effect on passive avoidance reaction are presented in Tables 1 and 2.

Considering the data presented in Table 1 and ", it can be noted that all compared means by themselves, when applied on a course, improve the mnestic functions of the central nervous system of animals in a similar way.

Glycine in the form of drops and spray and the preparation “Glycine tablets” equally opposed the effects of scopolamine and MESH, which was expressed by an increase in the latent transition time, a decrease in the time spent in the dark compartment and an increase in the number of animals that did not enter the dark compartment (trained animals).

Thus, we have developed a composition based on glycine, which is convenient for use, including in children’s (children from 1 year old) and geriatric practices (in the elderly and patients suffering from swallowing reflex disorders or pathologies that violate salivation). Also, this composition is characterized by high bioavailability, due to its performance in the form of a liquid form and ease of dosage.

Table 1 The effect of the compared drugs on passive avoidance reaction of rats without modeling amnesia (M ± m) Experimental groups Indicators Latent period of transition reaction, s The time spent in the light chamber, s Stay in a dark chamber, s The number of trained animals (% of the whole group) The control 80 ± 5 79 ± 5 24.5 ± 2.5 5 (50) Glycine spray 138 ± 9 * 118 ± 7 * 5.0 ± 0.5 * 10 (100) Glycine drops 129 ± 4 * 116 ± 6 * 5.5 ± 1.5 * 10 (100) Glycine tablets 142 ± 11 * 123 ± 14 * 4.5 ± 0.5 * 10 (100) * - significant differences from control animals at p <0.05

table 2 The effect of the compared drugs on passive avoidance reaction of rats with modeling amnesia (M ± m) Experimental groups Indicators Latent period of transition reaction, s The time spent in the light chamber, s Stay in a dark chamber, s The number of trained animals (% of the whole group) Control + scopolamine 41 ± 4 38 ± 5 82.5 ± 7.5 1 (10) Control + MESH 38 ± 2 54 ± 6 97.5 ± 6.5 0 (0) Glycine Spray + Scopolamine 132 ± 9 * 113 ± 4 * 9.0 ± 0.5 * 8 (80) Glycine Spray + MESH 125 ± 7 * 114 ± 8 * 8.5 ± 0.5 * 8 (80) Glycine drops + scopolamine 133 ± 5 * 111 ± 4 * 9.5 ± 0.5 * 8 (80) Glycine drops + MESH 127 ± 6 * 113 ± 5 * 8.0 ± 0.5 * 8 (80) Glycine tablets + scopolamine 125 ± 6 * 111 ± 10 * 10.5 ± 0.5 * 8 (80) Glycine tablets + MESH 129 ± 9 * 114 ± 12 * 9.0 ± 0.5 * 8 (80) * - significant differences from control animals at p <0.05

Claims (12)

1. A composition having an effect on the central nervous system, in the form of a solution, containing in its composition, wt.%:
Glycine 5-25 Glycerol 1-25 Preservative 0.001-2 Water rest 2. The composition according to claim 1, characterized in that it additionally contains the following substances, at least selected from the group: sweeteners, flavoring agents, flavorings, thickeners. 3. The composition according to claim 2, characterized in that as sweeteners contains the following substances, at least selected from the group: saccharin, aspartame, sucrose, fructose, lactose, dextrose, mannitol, sorbitol, xylitol, glucose, maltodextrins in wt. %, from 5 to 50. 4. The composition according to claim 2, characterized in that, as a flavoring agent, it contains the following substances, at least: menthol, and / or vanillin, and / or food flavorings, and / or essential oils in wt.%, From 0.001 to 0.1. 5. The composition according to claim 2, characterized in that the preservative contains the following substances, at least: sorbic acid and / or its salts, and / or benzoic acid and / or its salts, and / or methyl parahydroxybenzoate, and / or propyl parahydroxybenzoate and / or benzalkonium chloride and / or imidourea and / or cetalkonium and / or cetylpyridinium. 6. The composition according to claim 2, characterized in that in its composition as a flavoring agent of taste it contains at least the following acids: citric, and / or succinic, and / or malic, and / or tartaric in wt.%, From 0, 01 to 5. 7. The composition according to claim 2, characterized in that it contains thickeners: vinylpyrrolidone polymers in wt.%, From 0.1 to 20. 8. The composition according to claims 1 to 7, characterized in that it is used in the form of a solution, spray, drops, aerosol. 9. The use of the composition according to claims 1-8 as a therapeutic and / or prophylactic agent for the correction of the central nervous system. 10. The use of the composition according to claims 1-8 in the manufacture of a medicinal product or a biological active additive intended for the correction of the central nervous system. 11. A drug for the prevention and / or treatment of diseases of the central nervous system, including the composition according to claims 1-8. 12. A dietary supplement designed to correct the activity of the central nervous system, including the composition according to claims 1-8.