EA041149B1 - LIQUID ORAL DOSAGE WITH NOOTROPIC ACTIVITY - Google Patents

Description

The invention relates to the chemical-pharmaceutical industry and medicine and concerns a new liquid dosage form for oral administration with nootropic activity, containing as an active ingredient hopantenic acid or its pharmaceutically acceptable salt in a therapeutically effective amount, paraben or its pharmaceutically acceptable salt and excipients.

Hopantenic ((R)-4-(2,4-dihydroxy-3,3-dimethyl-1-oxobutyl) aminobutanoic) acid is characterized by the structural formula (I).

Hopantenic acid and its calcium salt, hereinafter also referred to as calcium hopantenate, are known as a broad-spectrum nootropic agent affecting the gamma-aminobutyric acid (GABA, GABA) system. In accordance with the terminology proposed in 1972 by the Belgian pharmacologist Corneliu E. Giurgea [Corneliu E. Giurgea (1972). [Pharmacology of integrative activity of the brain. Attempt at nootropic concept in psychopharmacology] (Vers une pharmacologie de l'active integrative du cerveau: Tentative du concept nootrope en psychopharmacologie). // Actual Pharmacol (Paris) (in French). 25: 115-56], nootropic drugs (nootropics) are drugs designed to have a specific effect on higher mental functions, including those that can stimulate mental activity, activate cognitive functions, improve memory and increase learning ability. Among the most important features of nootropics that are important for a neurologist, it should be noted the ability of nootropics to stimulate metabolic processes in brain tissues, facilitate the restoration of brain tissue after damage of various origins, and also increase the resistance of nerve cells to adverse factors [Mosolov S.N. Modern trends in the development of psychopharmacology. // Journal of Neurology and Psychiatry. S.S. Korsakova, 1998, No. 5, pp. 12-19]. The use of nootropic drugs is especially important in pediatric psychoneurology, where indications for the use of nootropics, in general, are mental and speech developmental delay, mental retardation, the consequences of perinatal CNS damage, cerebral palsy, attention deficit disorder, as well as a number of other diseases and disorders of the central nervous system, such as stuttering, hyperkinesis, urination disorders, etc.

Hopantenic acid and its calcium salt were developed in the 1970s [protocol No. 24 of the Pharmaceutical Committee of the USSR Ministry of Health of 11/11/1977]. Currently, preparations of the calcium salt of hopantenic acid (calcium hopantenate) are produced in the form of a tablet dosage form, which is used for mental retardation, with a decrease in intellectual-mnestic productivity with arteriosclerotic changes in cerebral vessels, with initial forms of senile dementia, with mental and speech development delay , cerebrosthenic syndrome; for the correction of side effects of antipsychotics, including neuroleptic extrapyramidal syndrome; with epilepsy (as part of complex therapy), residual manifestations of traumatic or toxic encephalopathy, residual manifestations of neuroinfection, with post-vaccination encephalitis, craniocerebral trauma, cerebral organic insufficiency in patients with schizophrenia (as part of complex therapy), hyperkinesis, urination disorders (enuresis, daytime urinary incontinence, pollakiuria, imperative urge, etc.). Hopantenic acid combines nootropic, antihypoxic and anticonvulsant effects, and is also successfully used to treat children with CNS diseases in the presence of convulsive syndrome.

Calcium hopantenate (R(D)-4-[(2,4-dihydroxy-3,3-dimethylbutyryl)amino]calcium butyrate (2:1)) is a highly effective nootropic drug, which is the highest homologue

R(D)(+)-pantothenic acid, in which beta-alanine is replaced by GABA. The mechanism of action is due to the direct effect of calcium hopantenate on the GABAB receptor. Due to the presence of the pantoyl radical in the hopantenic acid molecule, hopantenic acid and calcium hopantenate are able to penetrate the blood-brain barrier and have a pronounced effect on the functional activity of the brain. The spectrum of action of calcium hopantenate is associated with the presence of GABA in its structure. Calcium hopantenate also has an activating effect on the synthesis of acetylcholine. In addition, calcium hopantenate has a nootropic and anticonvulsant effect, increases the resistance of the brain to hypoxia and the effects of toxic substances, stimulates anabolic processes in neurons, combines a moderate sedative effect with a mild stimulating effect, reduces motor excitability, activates mental and physical performance. In addition, hopantenic acid and calcium hopantenate improve GABA metabolism in chronic alcohol intoxication and after ethanol withdrawal. Hopantenic acid and calcium hopantenate are able to inhibit acetylation reactions involved in the mechanisms of inactivation of novocaine and sulfonamides, thereby prolonging the action of the latter. Also, calcium hopantenate causes inhibition of the pathologically increased cystic reflex and detrusor tone [Avakumov V.M., Kovler M.A. Pan- 1 041149 togam. Prospect CBNTI // M., 1980, 20 s; Maslova O.I. Tactics of rehabilitation of children with mental retardation. // Russian Medical Journal, 2000, No. 8 (18), pp. 746-748]. Calcium hopantenate is rapidly absorbed from the gastrointestinal tract, penetrates well through the blood-brain barrier, is not metabolized and is excreted unchanged within 48 hours: 67.5% of the accepted dose of calcium hopantenate is excreted by the kidneys, and 28.5% is excreted with faeces [Register of medicinal products]. funds of Russia Encyclopedia of medicines. // M., 2004, pp. 675-676].

It has been shown that calcium hopantenate has a nootropic and anticonvulsant effect, increases the resistance of the brain to hypoxia and the effects of toxic substances, stimulates anabolic processes in neurons, combines a moderate sedative effect with a mild stimulating effect, reduces motor excitability, activates mental and physical performance [Badalyan O.L. ., Burd S.G., Savenkov A.A., Tertyshnik O.Yu., Yutskova E.V. Possibilities of using pantogam in the practice of a neurologist // Farmateka, 2006. No. 0(2). Special issue: Psychiatry, neurology, pp. 52-56].

Neuropsychiatric diseases in children remain one of the most important problems in pediatrics. The nootropic concept has become the largest contribution to the development of psychopharmacology. In recent decades, a significant number of nootropic agents have been created that are used to treat and correct intellectual-mnestic disorders, developmental dysfunctions [Varpakhovskaya I.P. The state of production and development of nootropic drugs abroad and in Russia. // Remedium, 2002, No. 7, S. 3-8].

Mental retardation (MPD) is a state bordering on mental retardation, characterized by a slowdown in the rate of mental ontogenesis. Until now, the clear boundaries of this pathology have not been defined, since they depend on social criteria, in particular, on the requirements imposed by society on the abilities of the child. There is no consensus on the age up to which this diagnosis is valid. Mistakes in the timely diagnosis of mental retardation lead to the choice of an inadequate training program and the emergence of school maladaptation, against which deviant behavior may develop in the future [Vostroknutov N.V. School maladjustment: key problems of diagnostics and rehabilitation. School maladaptation: Emotional and stress disorders in children and adolescents. M., 1995. S. 8-11].

Neurometabolic (nootropic) drugs are traditionally used to treat mental retardation. In particular, calcium hopantenate is widely used in the treatment of children with mental retardation. The use of calcium hopantenate in children of younger preschool age contributes to the acceleration of mental development by not only improving intellectual prerequisites, but also by stimulating the actual analytic-synthetic and psychomotor activity [Sukhotina N.K., Kryzhanovskaya I.L., Konovalova V.V., Kupriyanova T. A. Experience in the use of nootropics in borderline mental disorders in children // Psychiatry and psychopharmacotherapy, 2004. No. 6. P. 298-301].

A nootropic drug based on GABA (aminolon) is known, which has a pronounced effect on the functional activity of the central nervous system, however, poor penetration of GABA through the blood-brain barrier makes it difficult to use aminolon in the clinic for the treatment of central disorders [V.M. Kopelevich. Advances in Chemistry, 48 (7), 1979, pp. 1273-1296].

Piracetam is known, the first drug from the class of nootropics, created in 1964 by the aforementioned pharmacologist Corneliu E. Giurgea. Currently, piracetam is used in violation of learning and memory processes, cognitive functions both in healthy individuals and, in particular, impaired in various diseases [T.A. Voronina, S.B. Seredinin, Experimental and Clinical Pharmacology, 61 (4), 1998, pp. 3-8].

The disadvantage of piracetam is some limitations in its use: the drug is not used for young children (under 8 years old). In addition, piracetam is contraindicated in a number of diseases, in particular in Huntington's chorea.

Known pharmaceutical composition with nootropic action [RF patent No. 2145213, 10.02.2000, IPC: A61K 9/20, A61K 31/197], made in the form of a coated tablet, where the tablet core contains gamma-aminobutyric acid as an active substance , sugar and lubricants - as auxiliary substances, and the shell consists of basic magnesium carbonate, wheat flour and sugar in the following ratio of ingredients, wt.%: core: gamma-aminobutyric acid - 84-94; sugar - 5-15; lubricants - 0.8-1; shell: basic magnesium carbonate - 10-50; wheat flour - 10-30; sugar - 40-80.

However, the use of the tablet according to the patent of the Russian Federation No. 2145213, especially in children, faces problems associated with the complexity of dosing the drug, since with a daily dose of the drug from 0.75 to 3 g (dose for children), children have to take from 3 to 12 tablets per day depending on age and diagnosis. Since the drug is taken by children from 2 months to 15 years, then, given the medical indications of the drug, it can be difficult to administer the right dose to younger children, and sometimes older ones. This is further complicated by the fact that the remedy itself has a bitter taste.

Known nootropic drug Pantocalcin® in tablet form, containing as an active substance a pharmaceutically acceptable salt of hopantenic acid (calcium hopantenate) in an amount of 0.25 g or 0.5 g, as well as excipients, including magnesium hydroxycarbonate, calcium stearate, talc, starch potato [Register of Medicinal Products of Russia: Encyclopedia of Medicines 2 041149]. Annual collection // [prepared. V. V. Abramov and others; ch. ed. G. L. Vyshkovsky] - Moscow, LLC

RLS-2003, 2003, pp. 638-639].

This drug is characterized by the same disadvantages as for tablets of gamma-aminobutyric acid according to the patent of the Russian Federation No. 2145213.

These disadvantages can be overcome by creating liquid dosage forms, preferably oral solutions.

Liquid dosage forms, including oral solutions, make up a significant part of the pharmacy assortment. Their widespread use is due to a number of advantages over other dosage forms:

in their composition, it is possible to reduce the irritating effect of certain medicinal substances;

liquid dosage forms are simple and convenient to use;

when using liquid dosage forms, it is possible to mask the unpleasant taste and smell of medicinal substances; in addition, the use of liquid dosage forms simplifies the task of dosing the drug (in a wide range of doses), which is especially important in pediatrics.

At the same time, liquid dosage forms of nootropics known from the prior art also have disadvantages, the main of which are storage instability and susceptibility to microbiological contamination, as well as the fact that not all biologically active substances are effective in such a dosage form.

Nootropic preparations containing hopantenic and succinic acid as active substances, intended for the correction of intellectual-mnestic functions in children and made in the form of a liquid dosage form - syrup on sucrose, sorbitol and chitosan, have been developed and investigated [A. I. Slivkin et al. Development of a syrup-like dosage form of nootropic action. VSU VESTNIK, SERIES: CHEMISTRY. BIOLOGY. PHARMACIA, 2013, No. 1, p. 200-206. Accessible via the Internet; URL: http://www.vestnik.vsu.ru/pdf/chembio/2013/01/2013-01-34.pdfl. However, chitosan, which is part of this drug, is an expensive component, which negatively affects the cost of this drug.

In addition, it has been shown that at neutral pH values, chitosans have limited solubility, therefore, to increase the solubility of chitosan, additional modification of chitosan molecules with ion-exchange groups, as well as its depolymerization, is desirable [Colten H., Berth G., Dautzenberg H. Hydrodynamic studies on chitosans in aqueous solutions. // Carbohydrate Polymers, 2001, V.45, pp. 373-383]. These factors, in turn, further complicate the production technology of the drug described in the work of A.I. Slivkin and co-authors, and increase its cost. It has also been shown in the literature that chitosans, when taken orally, prevent the absorption of mineral salts and vitamin E [Deuchi K., Kanauchi O., Shizukuishi M., Kobayashi E. // Biosci Biotechnol Biochem, 1995 Jul; volume 59, issue 7, pp. 1211-1216].

These factors also limit the therapeutic potential of the nootropic preparation of hopantenic and succinic acids, described in the work of A.I. Slivkin and co-authors.

Known liquid dosage form of the calcium salt of hopantenic acid, which has nootropic activity, containing a therapeutically effective amount of calcium salt of hopantenic acid and excipients, characterized in that it is a drop and as excipients contains benzoic acid, sodium saccharinate, orange flavor, hydrochloric acid 1M, Trilon B, with the following ratio of components, wt.%:

Calcium salt of hopantenic acid 21.0-41.0

Benzoic acid 0.08-0.15 sodium saccharinate 0.08-0.15 Orange flavor 0.08-0.15 Hydrochloric acid 1M 30.0-39.0 Trilon B 0.1-0.35 Purified water The rest up to 100%,

and its use for the treatment of neurological and cognitive disorders of various etiologies [RF patent No. 2542419, 20.02.2015, IPC: A61K 9/08, A61K 31/195, A61K 47/02, A61K 47/12, A61R 25/28].

The disadvantages of this composition include a relatively high content of the active substance (more than 20%), which, again, prevents its use in pediatrics.

The closest analogue of the claimed invention is a nootropic agent containing the calcium salt of hopantenic acid and excipients, characterized in that it is a syrup and contains glycerin, sorbitol, citric acid, aspartame, aromatic essence, sodium benzoate as excipients in the following ratio of components , wt.%:

- 3 041149

hopantenic acid calcium salt 5-20 Glycerol 25-35 Sorbitol 10-20 Lemon acid 0.20-0.25 aspartame 0.02-0.08 Essence aromatic 0.05-0.15 sodium benzoate 0.05-0.15 Water rest

[RF patent No. 2177783, 01/10/2002, IPC: A61K 9/08, A61K 31/197, A61R 25/28].

The disadvantages of nootropic drugs according to the patents of the Russian Federation No. 2542419 and 2177783 include the use of benzoic acid and sodium benzoate as a preservative, which are prohibited for children of the age category for which the drug is intended, and at the same time are not effective as a preservative in the pH range, in in which the liquid dosage form of the calcium salt of hopantenic acid is stable. It should also be noted that most of the compositions (5 compositions out of 6) obtained and studied in the above work by A.I. Slivkin et al., also contains sodium benzoate, which is prohibited for use in pediatrics, as a preservative.

The disadvantages of known dosage forms, in addition, are bitter taste, limited shelf life, the presence of aspartame, often causing allergies after half the shelf life, the presence of adverse reactions such as headaches, insomnia [Mashkovsky M.D. Medicines: 16th edition. - M.: Medicine, 2010. 1216 s].

The UK Food Standards Agency conducted a study in 2007 on the effect of sodium benzoate on hyperactivity in children. The combination of this preservative with certain dyes has been shown to cause behavioral disturbances in the child. It is believed that it can cause attention deficit hyperactivity disorder in children. Exceeding the allowable concentration of benzoic acid and sodium benzoate in children caused irritability, headache, vomiting, and in more severe cases, dysfunction of the renal tubules. Symptoms resolved rapidly after discontinuation of benzoic acid [Martindale-The Complete Reference Drug. ^36th edition, London: Pharmaceutical Press, 2009]. Many food companies are looking for an alternative to sodium benzoate and intend to phase out its use in the near future. At the same time, the disadvantages inherent in sodium benzoate are deprived of parabens.

The objective of the present invention is to create a new, safer and more technologically advanced liquid dosage form of hopantenic acid or its pharmaceutically acceptable salt, which makes it possible to use it in children, while having acceptable organoleptic properties that facilitate its intake by children, as well as expanding the arsenal of drugs , which have nootropic activity and are acceptable for use in the practice of pediatricians.

The technical results of the invention include the provision of a safe and convenient for use in pediatric psychoneurology, long-term storage stability (retaining chemical and microbiological purity) dosage form of hopantenic acid or its pharmaceutically acceptable salt, simplification of the manufacturing technology of the dosage form, as well as expanding the arsenal of nootropic drugs, convenient to use and suitable for use in pediatrics, while not containing components prohibited for use in pediatrics.

Within the framework of the present invention, it has surprisingly been found that by using safer preservatives such as parabens, sufficient microbiological purity of the liquid dosage form of hopantenic acid can be ensured. Also within the framework of the present invention, the authors were able to choose other parameters of the composition, which provide the greatest stability of the liquid dosage form of hopantenic acid, such as the pH range. These technical solutions can be used in the finished liquid dosage form according to the invention both separately and together.

In the framework of the present invention, it was unexpectedly found that the task is solved, and the technical result is achieved by creating a new liquid dosage form (pharmaceutical composition) for oral administration, having nootropic activity, containing hopantenic acid or its pharmaceutically acceptable salt as an active ingredient in a therapeutically effective quantity, paraben (parahydroxybenzoate) or a pharmaceutically acceptable salt thereof and excipients. Said liquid dosage form of hopantenic acid or a pharmaceutically acceptable salt thereof is thus an object of the present invention.

However, for the purposes of the present invention, the term "pharmaceutical composition" means a composition comprising hopantenic acid or a pharmaceutically acceptable salt thereof in an effective amount, a paraben or a pharmaceutically acceptable salt thereof, and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, excipients, agents

- 4 041149 delivery agents, such as preservatives, stabilizers, fillers, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, flavors, flavorings, antibacterial agents, fungicides, delayed delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Non-limiting (illustrative) examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, as well as mixtures of these substances. Protection against the action of microorganisms can be provided using a variety of antibacterial and antifungal agents, such as sorbic acid, parabens (methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, heptylparaben and mixtures thereof) and the like. Non-limiting (illustrative) examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and mixtures thereof. Non-limiting (illustrative) examples of stabilizers are gums (eg, xanthan, gellan, konjac), fatty acids and their salts, pectin and tragacanth. Non-limiting (illustrative) examples of preservatives are parabens, benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, alkylpyridinium, benzethonium and their pharmaceutically acceptable salts. Non-limiting (illustrative) examples of thickeners are glycerol, alginic acid, gum arabic, glucose, sucrose, fructose, agar-agar, methylcellulose, carboxymethylcellulose, and their pharmaceutically acceptable salts. Non-limiting (illustrative) examples of sweeteners are maltitol, isomaltitol, sucralose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol, glucose, sucrose, fructose, saccharin and their pharmaceutically acceptable salts. A pharmaceutical composition for oral administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard form of administration, as a mixture with conventional pharmaceutical carriers. Suitable unit administration forms include liquid oral forms, such as, but not limited to, oral solutions or suspensions, oral spray solutions, or syrups. Pharmaceutical compositions may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, auxiliary agents and/or carriers used in the pharmaceutical field. The pharmaceutical composition, along with the active substance of the present invention or its pharmaceutically acceptable salt, may include other active substances, including those with activity, provided that they do not cause undesirable effects. If necessary, the use of the pharmaceutical composition of the present invention in clinical practice, it can be mixed with traditional pharmaceutical carriers. The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, for example, in oral forms, solvents, diluents, stabilizers, suspending agents, flavoring agents, antiseptic agents are used.

In turn, the term medicinal product (preparation) for the purposes of the present invention means a substance or a mixture of substances in the form of ready-made forms, intended for the restoration, correction or change of physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology, etc.

Also, for the purposes of the present invention, the terms "comprises" mean that said combinations, compositions, and kits include the components listed, but do not exclude the inclusion of other components.

For the purposes of the present invention, the term pharmaceutically acceptable means that the substance or composition to which the term is applied must be chemically and/or toxicologically compatible with the other ingredients in the formulation and safe for the person being treated with it. substance or composition.

In particular, the term pharmaceutically acceptable salt for the purposes of the present invention means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation, or purification of compounds, or obtained specially. In particular, base salts can be prepared specifically from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like. A detailed description of the properties of such salts is given in Berge S.M., et al., Pharmaceutical Salts // Journal of Pharmaceutical Sciences, 1977, 66: 1-19, incorporated herein by reference. Salts of the claimed acids can also be specifically prepared by reacting a purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are calcium, sodium and potassium salts. Suitable inorganic

- 5 041149 bases from which metal salts can be obtained are sodium hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that have sufficient basicity to form a stable salt and are suitable for medical use (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane, and the like. In addition, tetraalkylammonium hydroxides such as choline, tetramethylammonium, tetraethylammonium and the like can be used for salt formation. As amino acids, the basic amino acids lysine, ornithine and arginine can be used.

In addition, for the purposes of the present invention, the term therapeutically effective amount means an amount of an active substance that treats or prevents a particular disease, condition or disorder, or reduces, improves or eliminates one or more symptoms of a particular disease, condition or disorder, or prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as set forth herein.

In the most preferred non-limiting embodiments of the present invention, the dosage form is characterized in that the paraben is selected from methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, heptylparaben, and mixtures thereof.

In the most preferred non-limiting embodiment of the present invention, the dosage form is characterized in that the paraben is methylparaben.

Also in the most preferred non-limiting embodiments of the present invention, the dosage form is characterized in that the excipients are selected from the group consisting of a thickener, pH adjuster, sweetener, flavor and water.

Also in the most preferred non-limiting embodiments of the invention, the dosage form is characterized in that the thickener is selected from the group including glycerol, gums, pectin, alginic acid, gum arabic, agar-agar, methylcellulose, carboxymethylcellulose and their pharmaceutically acceptable salts.

In the most preferred non-limiting embodiment of the present invention, the dosage form is characterized in that the thickener is glycerol.

More preferred is a dosage form characterized in that the sweetener is selected from the group consisting of maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and their pharmaceutically acceptable salts.

More preferred is a dosage form characterized in that the sweetener is sucralose.

More preferred is a dosage form wherein the flavor is selected from the group consisting of raspberry, strawberry, apricot, pear, melon, mango, lemonade and plum flavor.

More preferred is a dosage form characterized in that the flavor is strawberry flavor.

More preferred is a dosage form characterized in that it contains a pharmaceutically acceptable acid as a pH regulator.

More preferred is a dosage form wherein the pharmaceutically acceptable acid is a pharmaceutically acceptable organic acid.

More preferred is the dosage form, characterized in that the pharmaceutically acceptable organic acid is selected from the group including malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids.

In alternative preferred embodiments of the present invention, the dosage form is characterized in that it contains a crystalline hydrate of a pharmaceutically acceptable organic acid. In private (non-limiting) embodiments of the invention, the crystalline hydrate of a pharmaceutically acceptable organic acid may be a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate or decahydrate of a pharmaceutically acceptable organic acid. In the most preferred embodiment of the present invention, the dosage form is characterized in that the pharmaceutically acceptable organic acid crystalline hydrate is citric acid monohydrate.

More preferred is the dosage form, characterized in that the pharmaceutically acceptable salt of hopantenic acid is a calcium salt of hopantenic acid (calcium hopantenate).

More preferred is a dosage form characterized in that it is

- 6 041149 oral solution. In alternative preferred embodiments of the present invention, the dosage form may be a syrup. Moreover, for the purposes of the present invention, the term syrup means any liquid dosage form, solution or elixir intended for oral administration, preferably, but not necessarily, containing a thickener, including active and excipients. Depending on the composition and physico-chemical properties of the active and auxiliary substances, the syrup may have opalescence or be a heterogeneous dispersed system (most often, a suspension).

In other alternative embodiments of the present invention, the dosage form may be an oral spray solution or oral suspension.

More preferred is a dosage form, characterized in that it contains hopantenic acid or its pharmaceutically acceptable salt, for example calcium hopantenate, in an amount of 520 wt.%.

More preferred is a dosage form, characterized in that it contains paraben in the amount of 0.1-0.5 wt.%.

More preferred is a dosage form, characterized in that it includes the following ratio of components, g/100 ml:

hopantenic acid calcium salt glycerin sucralose methyl parahydroxybenzoate (methylparaben) citric acid flavor monohydrate purified water

15,000;

19.152;

0.175;

0.164;

0.077;

0.131;

up to 100 ml.

In the second embodiment of the present invention, the task is also solved, and the technical results are achieved by creating a liquid dosage form for oral administration with nootropic activity, containing as an active ingredient hopantenic acid or its pharmaceutically acceptable salt in a therapeutically effective amount and excipients, characterized in that that the pH of the liquid dosage form is greater than 5.0 but not greater than 7.0. The specified liquid dosage form of hopantenic acid or its pharmaceutically acceptable salt is also one of the objects of the present invention.

More preferred is the dosage form according to the second embodiment, characterized in that the pH of the liquid dosage form is from 6.0 to 7.0.

More preferred is the dosage form according to the second embodiment, characterized in that the pH of the liquid dosage form is from 6.2 to 6.6.

More preferred is the dosage form according to the second embodiment, characterized in that the excipients are selected from the group consisting of a thickener, a pH adjuster, a preservative, a sweetener, a flavor and water.

More preferred is the dosage form according to the second embodiment, characterized in that the thickener is selected from the group consisting of glycerol, gums, pectin, alginic acid, gum arabic, agar-agar, methylcellulose, carboxymethylcellulose and their pharmaceutically acceptable salts.

More preferred is the dosage form according to the second embodiment, characterized in that the thickener is glycerol.

More preferred is the dosage form according to the second embodiment, characterized in that the sweetener is selected from the group consisting of maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and their pharmaceutically acceptable salts.

More preferred is the dosage form according to the second embodiment, characterized in that the sweetener is sucralose.

More preferred is the dosage form according to the second embodiment, characterized in that it contains a pharmaceutically acceptable acid or its crystalline hydrate (eg, monohydrate, dihydrate, trihydrate, etc.) as a pH adjuster.

More preferred is the dosage form according to the second embodiment, characterized in that it contains an acid as a pH adjuster, which is a pharmaceutically acceptable organic acid or its crystalline hydrate (eg, monohydrate, dihydrate, trihydrate, etc.).

More preferred is the dosage form according to the second embodiment, characterized in that the pharmaceutically acceptable organic acid is selected from the group consisting of malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic and sorbic acids.

More preferred is the dosage form according to the second embodiment, characterized in that the crystalline hydrate of the pharmaceutically acceptable organic acid is citric acid monohydrate.

- 7 041149

More preferred is the dosage form according to the second embodiment, wherein the pharmaceutically acceptable salt of hopantenic acid is the calcium salt of hopantenic acid.

More preferred is the dosage form according to the second embodiment, characterized in that it is an oral solution.

More preferred is the dosage form according to the second embodiment, characterized in that it contains hopantenic acid or a pharmaceutically acceptable salt thereof in an amount of 5-20% by weight.

More preferred is the dosage form according to the second embodiment, characterized in that it contains paraben as a preservative in an amount of 0.1-0.5 wt.%, for example (without limitation), such as methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, heptylparaben, or a mixture thereof.

Another object of the present invention is the use of a liquid dosage form according to the invention for the treatment of neurological and cognitive disorders of various etiologies. In the framework of the present invention, neurological and cognitive disorders, without limitation, include mental retardation, mental and speech retardation, cerebrosthenic syndrome, epilepsy, residual manifestations of a neuroinfection, post-vaccination encephalitis, craniocerebral trauma, cerebral organic insufficiency, schizophrenia, hyperkinesis, urination disorders and side effects of antipsychotics, in particular neuroleptic extrapyramidal syndrome. In addition, neurological and cognitive impairments include cognitive impairments not explicitly stated herein, and neurological impairments in which the patient experiences cognitive decline. This also includes cognitive impairment and neurological impairment accompanied by a decrease in cognitive function, which will be discovered later.

The following are examples of the invention, which illustrate the invention, but do not cover all possible options for its implementation and do not limit the invention. A person skilled in the art understands that other particular embodiments of the invention are also possible, including other liquid dosage forms of hopantenic acid or its pharmaceutically acceptable salt in accordance with the present invention, not described in these examples, for example, syrups, oral spray solutions, suspensions for oral administration, etc.

Example 1. Obtaining a liquid dosage form of the calcium salt of hopantenic acid.

Powders of methyl parahydroxybenzoate and sucralose were sieved through a sieve with a mesh size of 250 μm. Sieved powders, as well as liquid excipients (glycerin), as well as purified water in accordance with the calculation, were weighed on calibrated verified scales into individual marked containers.

Citric acid monohydrate was sieved through a sieve with a mesh size of 800 μm. Purified water was added to the sifted citric acid to prepare a 20.0% aqueous solution of citric acid. The resulting solution was filtered through a metal sieve with a hole size of 200 μm into a clean individual labeled container.

Glycerin was placed in a production container. With the help of an overhead stirrer without heating, with stirring, purified water was added in portions to glycerol, the stirring device was turned on, and sieved methyl parahydroxybenzoate was added in portions, visually controlling its dissolution.

Upon completion of the dissolution of methyl parahydroxybenzoate, the calcium salt of hopantenic acid was added in portions from the process vessel to the reactor, visually controlling the dissolution.

After the dissolution of the calcium salt of hopantenic acid, weighed sucralose was added in portions to the reactor.

Then, a filtered 20% aqueous solution of citric acid and flavor were added to the reactor.

After adding all the components, the stirrer speed was reduced and the solution was allowed to stand for 1 to 3 hours, after which the pH of each composition was adjusted to values of 4, 5, 6.4, 7, and 8 by adding a 20% aqueous solution of citric acid or sodium hydroxide.

At the end of the exposure time of the unfiltered solution, the intermediate was transferred to the stage of obtaining a filtered solution using a filter with a pore size of not more than 1.2 μm in a sealed production container.

Filling was carried out in vials. The drug was dosed by volume. The volume of the filling dose was controlled by weight for compliance with the requirements of the State Pharmacopoeia of the Russian Federation XIII edition (SP XIII) (OFS.1.4.2.0007.15). For this, scales were used. The drug vials were sealed.

According to this method received the compositions shown in table. 1.

- 8 041149

Table 1. Preparation of oral solutions containing calcium salt of hopantenic acid as the active substance

Name Composition per 100 ml filtered solution Composition 1 Composition 2 Composition 3 g per 100 ml vial g per 100 ml vial g per 100 ml vial Hopantenic acid calcium salt 5,000 15,000 20,000 Glycerol 25,500 19.152 15,500 Sucralose 0.150 0.175 0.275 Methyl parahydroxybenzoate 0.100 0.164 0.500 Citric acid monohydrate 0.125 0.131 0.135 flavoring 0.067 0.077 0.087 Purified water up to 100 ml up to 100 ml up to 100 ml

Example 2. Study of the stability of the finished dosage form of the calcium salt of hopantenic acid during storage.

The stability of the oral solution was evaluated by the content of the active substance in a long-term stability test.

All samples were stored in glass or plastic vials in a climate chamber at 25°C. The content of the active substance was determined by HPLC using standards.

Statistical processing of the results of the study is carried out using the statistical package SPSS Statistics 19.0.

It has been found that the new liquid dosage form of the present invention remains the most stable and chemically pure at pH values from 5.0 to 7.0. With an increase in pH, the solution remains chemically pure only for 12 months, then the content of hopantenic acid decreases by almost 20%, which determines the choice of pH values for the finished dosage form of the present invention to achieve the highest storage stability (see Table 2).

Table 2. Evaluation of the stability of the obtained dosage forms by the accelerated aging method

storage time at 25°С, months The amount of active substance found according to HPLC data in % of the theoretical content in solution at various pH values 4.0 5.0 6.4 7.0 8.0 0 100 100 100 100 100 6 96.4 99.5 99.7 99.3 96.5 9 95.2 99.2 99.4 99.0 94.1 12 94.5 98.7 99.0 98.4 92.8 18 93.0 98.2 98.7 97.9 89.2 24 92.5 97.8 98.3 97.3 85.7 36 90.8 97.0 97.9 96.5 80.0

Example 3. Study of the microbiological purity of the finished dosage form (solution for oral administration) of the calcium salt of hopantenic acid.

One of the requirements for the standardization of liquid oral dosage forms is a stable state of microbial presence in the dosage form for a specified shelf life in the process of acceptable standards. There are certain requirements for the microbiological purity of syrups:

the total number of mushrooms - no more than 100 in 1.0 g or 1.0 ml;

the total number of aerobic bacteria - no more than 1000 in 1.0 g or 10 ml; absence of Escherichia coli in 1.0 g or 1.0 ml.

Comparative control of the effect of methylparaben on microbiological purity was carried out for all formulations in accordance with SP XIII OFS 1.2.4.0002.15. Compound 4 was used as a reference formulation, similar to formulation 2, but containing sodium benzoate instead of methylparaben. The pH of the composition was adjusted to 6.4 by adding 20% aqueous citric acid.

Tests were carried out with samples newly prepared according to the developed methods (see Table 1), as well as after 6, 12, 24 months of their storage according to a known method (Pantyukhin A.V. Rheology and surface phenomena in pharmaceutical technology // A.V. Pantyukhin - Saratov: Saratov State Technical University, 2010. 124 p. Statistical processing of the results of the study is carried out using the statistical package SPSS Statistics 19.0. The results obtained are presented in table. 3.

-

Claims (26)

Table 3. Assessment of the microbiological purity of the obtained dosage forms. Compound The number of aerobic bacteria in 10 ml of the sample (± 10) after a time, months. 0 6 12 24 Composition 1 190 270 390 600 Composition 2 160 250 360 570 Composition 3 150 240 350 550 Composition 4 230 320 440 730 The obtained experimental data indicate that all samples of the developed liquid dosage form (solution for oral administration) of the calcium salt of hopantenic acid, created in the framework of the present invention, meet the requirements of regulatory documentation for microbiological purity throughout the entire storage period. The analysis of the obtained results shows that the total number of aerobic bacteria in 10 ml of samples from the developed dosage forms is below the acceptable standards (Escherichia coli is completely absent). Thus, within the framework of the present invention, it has surprisingly been shown that the replacement of the sodium benzoate used as a preservative according to the closest analogue with the parabens used in accordance with the present invention does not impair the microbiological purity of the finished liquid dosage form of hopantenic acid or its pharmaceutically acceptable salt. The invention can be used in the chemical and pharmaceutical industry, as well as in medicine and pharmacology, including for the treatment of neurological and cognitive disorders of various etiologies, in particular (without limitation), in complex therapy for mental retardation, mental retardation and speech development , cerebrasthenic syndrome, for the correction of side effects of antipsychotics, including neuroleptic extrapyramidal syndrome, with epilepsy, residual manifestations of neuroinfection, post-vaccination encephalitis, traumatic brain injury, cerebral organic insufficiency in patients with schizophrenia, hyperkinesis, urination disorders, as well as in children with diseases of the central nervous system in the presence of convulsive syndrome. CLAIM 1. Liquid dosage form for oral administration, having nootropic activity, containing as an active ingredient the calcium salt of hopantenic acid in a therapeutically effective amount, paraben and excipients, while the pH of the liquid dosage form is 5.0-7.0. 2. The dosage form according to claim 1, characterized in that the paraben is selected from the group consisting of methylparaben, propylparaben, ethylparaben, butylparaben, isobutylparaben, isopropylparaben, benzylparaben, heptylparaben and mixtures thereof. 3. Dosage form according to claim 2, characterized in that the paraben is methylparaben. 4. Dosage form according to claim 1, characterized in that the excipients are selected from the group consisting of a thickener, pH regulator, sweetener, flavor and water. 5. Dosage form according to claim 4, characterized in that the thickener is selected from the group consisting of glycerol, gums, pectin, alginic acid, gum arabic, agar-agar, methylcellulose, carboxymethylcellulose and their pharmaceutically acceptable salts. 6. Dosage form according to claim 5, characterized in that the thickener is glycerin. 7. Dosage form according to claim 4, characterized in that the sweetener is selected from the group including maltitol, isomaltitol, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotame, lactitol and their pharmaceutically acceptable salts. 8. Dosage form according to claim 7, characterized in that the sweetener is sucralose. 9. Dosage form according to claim 4, characterized in that the flavor is selected from the group including raspberry, strawberry, apricot, pear, melon, mango, lemonade and plum flavors. 10. Dosage form according to claim 9, characterized in that the flavor is a strawberry flavor. 11. The dosage form according to claim 4, characterized in that it contains a pharmaceutically acceptable acid as a pH regulator. 12. A dosage form according to claim 11, wherein the pharmaceutically acceptable acid is a pharmaceutically acceptable organic acid. 13. Dosage form according to claim 12, characterized in that the pharmaceutically acceptable organic acid is selected from the group consisting of malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids, as well as crystalline hydrates the indicated acids. 14. The dosage form according to claim 4, characterized in that it contains a crystalline hydrate of a pharmaceutically acceptable acid as a pH regulator. - 10 041149 15. Dosage form according to and. 14, characterized in that it contains a crystalline hydrate of a pharmaceutically acceptable organic acid as a pH regulator, wherein the pharmaceutically acceptable organic acid is selected from the group including malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids. 16. The dosage form according to claim 15, characterized in that the crystalline hydrate of the pharmaceutically acceptable organic acid is citric acid monohydrate. 17. Dosage form according to claim 1, characterized in that it is a syrup. 18. Dosage form according to claim 1, characterized in that it is a solution for oral administration. 19. Dosage form according to claim 1, characterized in that it is a suspension for oral administration. 20. Dosage form according to claim 1, characterized in that it is a solution for spraying in the oral cavity. 21. Dosage form according to claim 1, characterized in that it contains hopantenic acid or its pharmaceutically acceptable salt in an amount of 5-20 wt.%. 22. Dosage form according to claim 1, characterized in that it contains paraben in the amount of 0.1-0.5 wt.%. 23. Dosage form according to any one of claims 1-22, characterized in that it includes the following ratio of components, g/100 ml: calcium salt of hopantenic acid - 15,000; glycerin - 19.152; sucralose - 0.175; methyl parahydroxybenzoate - 0.164; flavor - 0.077; citric acid monohydrate - 0.131; purified water - up to 100 ml. 24. Dosage form according to claim 1, characterized in that the pH of the liquid dosage form is 6.2-6.6. 25. The use of a liquid dosage form according to any one of claims 1 to 24 for the treatment of neurological and cognitive disorders of various etiologies. 26. Use according to claim 25, where neurological and cognitive impairments are selected from mental retardation, mental and speech developmental delay, cerebrosthenic syndrome, side effects of antipsychotics, including neuroleptic extrapyramidal syndrome, epilepsy, residual manifestations of a neuroinfection, post-vaccination encephalitis, craniocerebral trauma, cerebral organic insufficiency in patients with schizophrenia, hyperkinesis, urination disorders, as well as CNS diseases in children with convulsive syndrome. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 -