RU2810575C1 - Pharmaceutical composition, including memantine and citicoline, and also a dosage form based on specified pharmaceutical composition, including memantine and citicoline, method of its obtaining and use of dosage form based on pharmaceutical ceutic composition, including memantine and citicoline - Google Patents

Abstract

FIELD: medicine; neurology.

SUBSTANCE: group of inventions discloses a pharmaceutical composition with neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, is intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including memantine hydrochloride in the range values of 5–20 mg and citicoline monosodium salt in the range of 450–550 mg, with the following ratio of the quantitative and qualitative composition of the ingredients of the pharmaceutical composition, wt.%: 65.95–69.95 of citicoline monosodium salt; 0.67–2.50 of memantine hydrochloride; 0.63–5.13 of microcrystalline cellulose; 17.23–17.80 of hydroxypropyl methylcellulose (molecular weight 1,000,000); 0.91–1.0 of colloidal silicon dioxide; 0.91–1.0 of magnesium stearate; 3.00–7.00 of film shell I; 1.00–2.00 (options) of film shell II. Also the following is disclosed: solid oral dosage forms (options), methods of preparing a solid oral dosage form (options), medicinal products in the form of a modified-release tablet (options), use of a solid oral dosage form, and the use of a method.

EFFECT: increase in the therapeutic activity of citicoline, simplification of the treatment of cognitive disorders of vascular origin, reduction of side effects and the stability of dosage forms during manufacture and their stability during storage.

45 cl, 8 tbl

Description

APPLICATION AREA

The proposed inventions relate to the field of pharmaceuticals and relate to pharmaceutical compositions and solid oral dosage forms that have neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, methods for obtaining such pharmaceutical compositions and solid oral dosage forms and the use of these pharmaceuticals compositions and solid oral dosage forms for the treatment of cognitive disorders of vascular origin.

BACKGROUND OF THE ART

In the modern pharmaceutical market, a relevant and increasingly popular area is the development of various dosage forms used primarily for the treatment of cognitive impairment of vascular origin, namely, to improve memory, for the prevention and treatment of cerebral ischemia, for the treatment of nervous system disorders. system, the consequences of traumatic brain injury and ischemic and hemorrhagic stroke, for the prevention or treatment of diabetic neuropathy, as well as for the treatment of all types of dementia, including Alzheimer's disease, from mild to moderate severity, drugs with neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, which slow down or inhibit glutamatergic neurotransmission and the progression of neurodegenerative processes.

It is known that a substance such as citicoline (cytidine-diphosphate-choline, cytidine-5′-diphosphocholine, CDP-choline, Neurocoline), or 5 '-O-[hydroxy({hydroxy[2-(trimethylammonio)ethoxy]phosphoryl}oxy)phosphoryl]cytidine, is a substance of formula (I) with a nootropic effect, a natural endogenous compound that is an intermediate metabolite in the synthesis of phosphatidylcholine - one of the main structural components of the cell membrane.

(I)

The invention is known [1] under RF patent No. 2429851, published on September 27, 2011, which describes a method for improving intelligence in a subject, which consists of administering to said subject a pharmaceutical composition containing (a) a polyunsaturated fatty acid selected from omega-3 fatty acid or omega -6 fatty acid, (b) uridine and (c) choline salt. In particular embodiments of the invention [1], uridine is an acyl derivative of uridine, uridine phosphate or cytidine-5′-diphosphocholine (CDP-choline). In addition, the patent [1] describes a pharmaceutical composition for improving intelligence in a subject, which contains: (a) a polyunsaturated fatty acid selected from an omega-3 fatty acid or an omega-6 fatty acid, (b) uridine, and (c) a salt choline, wherein in particular embodiments of the invention, uridine is an acyl derivative of uridine, uridine phosphate or cytidine-5′-diphosphocholine (CDP-choline).

The invention is also known, disclosed in RF patent No. 2603470, published on November 27, 2016 [2], relating to a method for improving the learning ability or memory of an object, including administering to the object a pharmaceutical composition containing (a) omega-3 fatty acid, omega-6 fatty acid or their combinations; (b) uridine, its acyl derivative, uridine phosphate or cytidine 5-diphosphocholine (CDP-choline); and (c) choline, its metabolic precursor or choline salt. Moreover, in paragraph 6 of the claims it is specified that uridine is an acyl derivative of uridine, uridine phosphate or cytidine-5′-diphosphocholine (CDP-choline).

The patent [2] also discloses a pharmaceutical composition for improving learning or memory in a subject, containing (a) an omega-3 fatty acid, an omega-6 fatty acid, or a combination thereof; (b) uridine and (c) choline salt. In particular embodiments of the invention [3], uridine is an acyl derivative of uridine, uridine phosphate or cytidine-5′-diphosphocholine (CDP-choline).

Analogs [1] and [2] describe pharmaceutical compositions that provide improvement in intelligence in a subject due to the synergistic effect of the components of the composition, including CDP-choline (citicoline), in relation to increasing the concentration of brain phospholipids, but do not affect the glutamatergic system. On the contrary, the composition proposed in the present invention, in contrast to solutions [1] and [2], provides a therapeutic effect not only by increasing the concentration of brain phospholipids, but also by modulating the effect on the glutamatergic system.

In addition, there is an invention under RF patent No. 2605339, published on December 20, 2016 [3], which describes a drug based on amantadine sulfate for stopping glutamate-induced apoptosis and inhibiting NMDA receptors for the treatment of nervous system disorders and the consequences of traumatic brain injury and ischemic and hemorrhagic stroke, characterized in that it contains as an active substance a therapeutically effective amount of amantadine sulfate and cytidine 5′-diphosphocholine, as well as at least one excipient selected from the group including stabilizers, prolongators, buffering additives , solvents, fillers, preservatives, in the following ratio of components, wt.%:

Amantadine sulfate 0.001-0.25

Cytidine 5′-diphosphocholine 5.0-25.0

Excipient – up to 100.

The patent also describes the use of this drug for reversing glutamate-induced apoptosis and inhibiting N-methyl-D-aspartate receptors for the treatment of nervous system disorders, the consequences of traumatic brain injury and ischemic and hemorrhagic stroke.

Analogue [3] describes a drug for stopping glutamate-induced apoptosis and inhibiting NMDA receptors. The drug according to the analogue [3] does not affect the concentration of phospholipids in the brain and spinal cord. On the contrary, the solution claimed in the present invention, in contrast to the drug according to the analogue [3], has an additional therapeutic effect by increasing the concentration of phospholipids in the brain and spinal cord.

Memantine, or 3,5-dimethyl-1-adamantanamine, a non-competitive antagonist of glutamate NMDA receptors of formula (II), which has neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, which inhibits glutamatergic neurotransmission, was selected as the second active substance within the framework of the present invention. and progression of neurodegenerative processes.

(II)

Memantine (II) can also be used in the form of a pharmaceutically acceptable salt, for example, in the form of memantine hydrochloride (hydrochloride salt). Thus, from RF patent No. 2371173, published on October 27, 2009 [4], a method of treating Alzheimer’s disease of varying severity is known, from mild to moderate, consisting of administering to a subject in need thereof an effective amount of memantine or a pharmaceutically acceptable salt thereof, such as a hydrochloride salt, wherein memantine or a pharmaceutically acceptable salt thereof, according to [4], is administered at an initial dose of 5 mg per day, increasing by 5 mg per day every week to a final dose of 20 mg per day. Also disclosed in the patent [4] is a method for treating mild to moderate Alzheimer's disease in subjects who have previously been treated with an acetylcholinesterase inhibitor (AChEI), wherein the method comprises administering to the subject in need thereof an effective amount of memantine or a pharmaceutically acceptable salt thereof. [4] describes a method of treating only one form of dementia (Alzheimer’s disease) using memantine or its pharmaceutically acceptable salt, but does not imply the use of memantine or its pharmaceutically acceptable salt for the treatment of other forms of dementia (in particular, vascular, as in the claimed solution) .

The invention is known according to RF patent No. 2326660, published on June 20, 2008 [5], which describes an oral drug in the form of a solid dosage form containing memantine as an active substance, characterized in that the dosage form is capsules, and memantine is included in a therapeutically effective quantity in the composition of the mass filling these capsules, which is a mixture of powders.

Also described in the patent [5] are:

- an oral preparation in the form of a solid dosage form containing memantine as an active substance, characterized in that the dosage form is capsules, and memantine is included in a therapeutically effective amount in the composition of the mass filling these capsules, which is a granulate;

- a method for producing an oral drug in the form of a solid dosage form containing memantine as an active substance, which consists in the fact that the powders of memantine and excipients - a disintegrant, an antifriction substance and a carrier - are sifted, weighed and mixed in the ratio of components, wt. %:

memantine 0.5-10.0 disintegrant 0.2-40.0 antifriction agent 0.2-10.0 filler rest,

after which the mass in the form of a mixture of powders is filled into capsules;

- a method for producing an oral drug in the form of a solid dosage form containing memantine as an active substance, which consists in using a filler and, if necessary, a disintegrant and an antifriction substance, powders of memantine and filler or, in the case of if necessary, the powders of the disintegrant and antifriction substance are also sifted, weighed and mixed in the indicated mass proportions, wt. %:

memantine 0.5-10.0 filler rest

or

memantine 0.5-10.0 disintegrant 0.2-40.0 antifriction agent 0.2-10.0 filler rest,

the powder mixture is then granulated using dry or wet granulation methods, after which the granulate is filled into capsules.

Also known from the prior art is an invention according to RF patent No. 2404750, published on November 27, 2010 [6], relating to a pharmaceutical composition containing memantine or a pharmaceutically acceptable salt thereof, intended for use in the treatment of dementia, where said memantine or a pharmaceutically acceptable salt thereof is present in extended-release dosage form and to be administered without the use of a dose escalation regimen, a pharmaceutical composition containing memantine or a pharmaceutically acceptable salt and extended-release component thereof for use in the treatment of dementia, wherein said treatment results in a therapeutically effective sustained plasma concentration of memantine within 20 days from the date of administration of the composition to the patient, for a pharmaceutical composition in capsule form containing memantine or a pharmaceutically acceptable salt thereof, wherein said memantine or a pharmaceutically acceptable salt thereof has a C _max /C _mean ratio of from about 2.5 to about 1 at least 6 h after administration of the composition to the patient, into a pharmaceutical composition containing an oral extended-release preparation, including:

a) memantine and a polymer selected from hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose and polyethylene glycol; And

b) a coating containing an insoluble matrix polymer and a water-soluble substance.

The invention is also known from the prior art according to RF patent No. 2483715, published on June 10, 2013 [7], relating to an antiparkinsonian agent and a solid, rapidly disintegrating dosage form containing the said agent, where the said dosage form contains memantine and/or as an active ingredient memantine hydrochloride and target additives, characterized in that the specified dosage form contains cellulose II as target additives in the following ratio of ingredients, wt.%:

memantine and/or memantine hydrochloride 5-10 cellulose II 90-95.

Analogs [5], [6] and [7] describe monopreparations of memantine or its pharmaceutically acceptable salt – memantine hydrochloride. At the same time, the use of memantine or its pharmaceutically acceptable salt as the only therapeutic agent in some cases may not be enough to provide an effect in all the variety of cognitive impairments caused by forms of dementia other than vascular.

The invention is also known from the prior art according to RF patent No. 2390354, published on May 27, 2010 [8], which discloses a matrix-type composition with a slow release containing:

(1) donepezil hydrochloride and/or memantine hydrochloride;

(2) an enteric polymer that is at least one selected from the group consisting of methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; And

(3) a water-insoluble polymer which is at least one selected from the group consisting of ethylcellulose, aminoalkyl methacrylate copolymer RS and ethyl acrylate-methyl methacrylate copolymer.

The patent [8] also discloses a method for producing a sustained release matrix composition, comprising the steps of:

mixing (1) donepezil hydrochloride and/or memantine hydrochloride; (2) an enteric polymer that is at least one selected from the group consisting of methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; and (3) a water-insoluble polymer which is at least one selected from the group consisting of ethylcellulose, aminoalkyl methacrylate copolymer RS and ethyl acrylate-methyl methacrylate copolymer and compression molding of the mixture obtained in the mixing step.

According to the patent [8], memantine hydrochloride is mentioned as an agent used for dementia due to Alzheimer's disease (see patent [8], page 15 of the description, section "Best mode of carrying out the invention"). At the same time, other areas of application of memantine and its pharmaceutically acceptable salts are known, in particular, vascular dementia (Cerebrovascular disease, cognitive impairment and dementia. – in: Cerebrovascular disease and dementia (Second edition) / Edited by J. O'Brien , D. Ames, L. Gustafson et al. London: Martin Dunitz, 2004).

When analyzing the market for drugs intended for the treatment of cognitive disorders of vascular origin, which have neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, it becomes obvious the need to create a pharmaceutical composition and dosage form based on it, providing increased therapeutic activity the declared quantitative and qualitative composition of the ingredients (pharmaceutical composition), effective, when administered to a patient in need, for the treatment of cognitive disorders of vascular origin, as well as having neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes.

The technical results achieved by the claimed group of inventions include:

- increasing the therapeutic activity of citicoline or its pharmaceutically acceptable salt due to the super-total (synergistic) effect when using citicoline or its pharmaceutically acceptable salt together with memantine or its pharmaceutically acceptable salt, as well as due to the immediate onset of action and subsequent effective and long-lasting action of the proposed pharmaceutical composition and dosage form;

- simplifying the treatment of cognitive impairment of vascular origin through the use of the pharmaceutical composition and dosage form proposed in the present invention containing the said composition;

- providing a pharmaceutical composition and dosage form of memantine or a pharmaceutically acceptable salt thereof and citicoline or a pharmaceutically acceptable salt thereof, free from side effects, and at the same time stable in manufacture and stable in storage.

In addition, the technical results achieved by the claimed group of inventions include:

- increasing the therapeutic activity of a pharmaceutical composition and medicinal product intended for the treatment of cognitive disorders of vascular origin, having neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, due to the synergistic effect achieved through the combined use of memantine or its a pharmaceutically acceptable salt and citicoline or a pharmaceutically acceptable salt thereof, as well as due to the immediate onset of action of the said medicinal product and subsequent effective and long-lasting action;

- simplification of the treatment regimen (correction, mitigation or slowdown of development) of cognitive disorders of vascular origin,

- as well as simplifying and reducing the cost of manufacturing a dosage form and pharmaceutical composition intended for the treatment of cognitive disorders of vascular origin, which has neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes.

In addition, the technical result is an increase in the range of pharmaceutical compositions and dosage forms intended for the treatment of cognitive disorders of vascular origin and having neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes.

DISCLOSURE OF INVENTION

Technical results are achieved by the pharmaceutical composition proposed in the present invention, intended for the treatment of cognitive disorders of vascular origin, which has neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including from 5.00 to 20.00 mg of memantine or its pharmaceutically acceptable salt and from 450 to 550 mg of citicoline or its pharmaceutically acceptable salt, as well as the oral solid dosage form proposed in the present invention, made on the basis of the above pharmaceutical composition, including memantine or its pharmaceutically acceptable salt as active ingredients in an amount of 5 .00 to 20.00 mg and citicoline or a pharmaceutically acceptable salt thereof in an amount of 450 to 550 mg, in the form of a film-coated modified-release tablet. Also, the technical result related to simplification and reduction of the cost of the dosage form is achieved by the method proposed in the present invention for producing an oral solid dosage form made on the basis of the above pharmaceutical composition .

The pharmaceutical composition and dosage form proposed in the present invention, in addition to memantine or a pharmaceutically acceptable salt thereof and citicoline or a pharmaceutically acceptable salt thereof, also contains auxiliary components, including a pharmaceutically acceptable excipient, hydroxypropyl methylcellulose, colloidal silicon dioxide and a pharmaceutically acceptable lubricant.

In preferred (non-limiting) embodiments of the invention, the pharmaceutically acceptable excipient is selected from microcrystalline cellulose, starch, glucose, sucrose, lactose, basic magnesium carbonate, gelatin, methylcellulose, sodium carboxymethylcellulose, calcium carbonate, glycine, dextrin, sorbitol and mannitol. In the most preferred embodiment of the invention, the pharmaceutically acceptable excipient is microcrystalline cellulose.

Also in preferred (non-limiting) embodiments of the invention, the pharmaceutically acceptable lubricant is a pharmaceutically acceptable salt of stearic acid, such as (without limitation), magnesium stearate or calcium stearate. One skilled in the art will appreciate that other pharmaceutically acceptable lubricant may be used, including other pharmaceutically acceptable stearic acid salt.

In accordance with the present invention, memantine can be used as a base or as a pharmaceutically acceptable salt. In particular (non-limiting) embodiments of the present invention, memantine can also be used in the form of a pharmaceutically acceptable inorganic acid salt, for example, in the form of memantine hydrochloride, memantine hydrobromide, memantine sulfate, memantine hydrogen sulfate and memantine dihydrogen sulfate, and the like. In other (non-limiting) embodiments of the present invention, memantine may be used as a pharmaceutically acceptable organic acid salt, such as memantine oxalate, memantine citrate, memantine succinate, memantine maleate, memantine fumarate, memantine malate, memantine tartrate, and the like. , either as a sulfonate, such as (but not limited to) memantine methanesulfonate (mesylate), memantine benzenesulfonate (besylate), or memantine toluenesulfonate (tosylate). In other particular (non-limiting) embodiments of the present invention, memantine can also be used in the form of memantine hydroiodide, memantine perchlorate, memantine acetate, memantine propionate, memantine glycolate, memantine lactate, memantine pyruvate, memantine malonate, memantine benzoate, memantine carbonate, memantine cinnamate, memantine mandelate, memantine ethanesulfonate, memantine hydroxyethanesulfonate, memantine p-toluenesulfonate, memantine cyclohexanesulfamate, memantine salicylate, memantine p-aminosalicylate, memantine 2-phenoxybenzoate or memantine 2-acetoxybenzoate.

Most preferably (without limitation), memantine in accordance with the present invention is used in the form of memantine hydrochloride.

In turn, in accordance with the present invention, citicoline can be used in the form of a base or in the form of a pharmaceutically acceptable salt. In certain non-limiting embodiments of the present invention, citicoline may also be administered as a pharmaceutically acceptable salt of an inorganic acid, such as hydrochloric or phosphoric acid, or as a pharmaceutically acceptable salt of an organic acid, such as acetic, oxalic, tartaric, mandelic, etc. P. acids, as well as in the form of a pharmaceutically acceptable salt formed by free carboxy groups with inorganic ions, including sodium, potassium, ammonium, calcium ions, iron hydroxides, as well as with organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine and etc.

Most preferably (without limitation), citicoline in accordance with the present invention is used in the form of citicoline monosodium salt (also referred to herein as citicoline monosodium).

According to the method proposed in the present invention, the lubricant, citicoline or its pharmaceutically acceptable salt, memantine or its pharmaceutically acceptable salt, pharmaceutically acceptable filler, hydroxypropyl methylcellulose, colloidal silicon dioxide, are sifted through a sieve with a mesh diameter of not more than 0.5 mm, then loaded into a mixer - a granulator or similar mixing device for citicoline monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose, mix until homogeneous at a mixing speed of 160-240 rpm, and a mixing time in the range from 2 to 10 minutes, then with constant stirring of the mixture, moisten the mixture with purified water, in this case, the mixing speed should be in the range of 150-400 rpm, and the mixing time should not exceed 5 minutes, after which the resulting granulate is dried under fluidized bed conditions while maintaining the following parameters: incoming air temperature 45-65 ° C, residual humidity granulate from 2.5 to 4.5%, the resulting granulate is sifted through a sieve with a mesh diameter of no more than 1.0 mm, then the resulting mixture is dusted with colloidal silicon dioxide for 3 to 5 minutes, then part of the hydroxypropyl methylcellulose is added to the mixture, stirred some more from 8 to 10 minutes, then add magnesium stearate and mix for another 2-3 minutes. The resulting mixture for tableting is subjected to tabletting on a rotary tablet press, using a press tool with a diameter of 10 to 15 mm, the tableting process is controlled by the following parameters: hardness - 150- 290 N, abrasion - no more than 1.0%, height - no more than 7.0 mm, then film shell I, which is a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol, is applied to the resulting tablet cores; in the process of dissolving the film shell I, the pharmaceutical substance memantine hydrochloride is added in parts and mixed until a homogeneous suspension is formed, after which the resulting shell is applied at a tablet core temperature of 35-40 ° C and periodic stirring, including in a coater drum, then a film solution is prepared shell II from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide, after obtaining a film-forming solution, thus obtaining film shell II. Film coating II is applied to the tablets over film coating I under the same conditions as film coating I.

In certain preferred (non-limiting) embodiments of the invention, film coating I and/or film coating II may also contain active ingredients selected from memantine or a pharmaceutically acceptable salt thereof and citicoline or a pharmaceutically acceptable salt thereof. In the most preferred embodiment of the invention, film coating I contains a pharmaceutically acceptable salt of memantine, for example, memantine hydrochloride, while film coating II contains a pharmaceutically acceptable salt of citicoline, for example, citicoline monosodium salt. In another preferred embodiment of the invention, film coating I, on the contrary, contains a pharmaceutically acceptable salt of citicoline, for example, citicoline monosodium salt, while film coating II contains a pharmaceutically acceptable salt of memantine, for example, memantine hydrochloride.

In a preferred (non-limiting) embodiment of the invention, microcrystalline cellulose is commercially available microcrystalline cellulose grade 101. Also in a preferred (non-limiting) embodiment of the invention, hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da, for example (without limitation), hypromellose type 2208 ( K100M) or similar. Finally, in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200.

Technical results are also achieved in the present invention in that a pharmaceutical composition is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of the ingredients, effective for the treatment of cognitive disorders of vascular origin, has a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slows down and inhibits glutamatergic neurotransmission and the progression of neurodegenerative diseases. processes comprising from 5 to 20 mg of memantine or a pharmaceutically acceptable salt thereof and from 450 to 550 mg of citicoline or a pharmaceutically acceptable salt thereof. An illustrative quantitative and qualitative example of the composition of a pharmaceutical composition is presented in Table 1. Other illustrative examples of the quantitative and qualitative composition of the ingredients of a pharmaceutical composition are presented in Table 2. One skilled in the art will understand that these examples are illustrative (non-limiting) and are provided for the purpose of illustrating the present invention, and not to limit the scope of claims.

Table 1. Quantitative and qualitative composition of the ingredients of the pharmaceutical composition

Name of components Content in % Content in mg Citicoline monosodium salt 65.95-69.95 450-550 Memantine hydrochloride 0.67-2.50 5-20 Microcrystalline cellulose 0.63-5.13 5-35 Hydroxypropyl methylcellulose 17.23-17.80 120.5-140.6 Silicon dioxide colloidal 0.91-1.0 6.8-7.2 Magnesium stearate 0.91-1.0 6.8-7.2 Film casing I 5.18-5.33 36.4-41.5 Film casing II 2.85-3.2 21.8-24.5

In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is microcrystalline cellulose grade 101. One skilled in the art will understand that other varieties of microcrystalline cellulose having similar characteristics can be used, for example, microcrystalline cellulose grades 105, 102, 103, 302 , 200, 50 M, 90 M or similar.

Preferably, without limitation, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000. Most preferably, without limitation, the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used, for example hypromellose type 2208 K100M DC, K200M or the like

Also, in a preferred (non-limiting) embodiment of the invention, colloidal silica is colloidal silica grade A 200. One skilled in the art will understand that other varieties of colloidal silica having similar characteristics can be used, for example colloidal silica grade A 300, A 380, R 972 or similar.

Also in a preferred (non-limiting) embodiment of the invention, film shell I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white". One skilled in the art will understand that other commercially available film coating mixtures having similar characteristics can be used for Film Shell I, for example, Opadry based on hydroxypropyl methylcellulose, including other auxiliary components or the like, and Opadry II based on hydroxypropyl methylcellulose, including other auxiliary components or similar.

Also in a preferred (non-limiting) embodiment of the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". One skilled in the art will understand that other commercially available film casing mixtures having similar characteristics can be used for Film Shell II, for example, Opadry based on polyvinyl alcohol, including other auxiliary components or the like, and Opadry II based on hydroxypropyl methylcellulose, including other auxiliary components or similar.

Also, the above technical results are achieved in the present invention in that a pharmaceutical composition is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of the ingredients, effective for the treatment of cognitive disorders of vascular origin, has a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slows down and inhibits glutamatergic neurotransmission and progression neurodegenerative processes, made in the form of a film-coated tablet and containing from 5 to 20 mg of memantine hydrochloride and from 450 to 550 mg of citicoline monosodium salt, as well as excipients, including microcrystalline cellulose, hydroxypropyl methylcellulose with a molecular weight of 1,000,000, colloidal silicon dioxide and magnesium stearate, with the following ratio of the quantitative and qualitative composition of the ingredients of the pharmaceutical composition, wt.%:

Citicoline monosodium salt 65.95-69.95 Memantine hydrochloride 0.67-2.50 Microcrystalline cellulose 0.63-5.13 Hydroxypropyl methylcellulose 17.23-17.80 Silicon dioxide colloidal 0.91-1.0 Magnesium stearate 0.91-1.0 Film casing I 5.18-5.33 Film casing II 2.85-3.2

In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, the colloidal silica is colloidal silica grade A 200. One skilled in the art will appreciate that other grades of colloidal silica having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, film shell I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple".

One skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

Also, the above technical results are achieved in the present invention in that a pharmaceutical composition is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of the ingredients, effective for the treatment of cognitive disorders of vascular origin, has a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slows down and inhibits glutamatergic neurotransmission and progression neurodegenerative processes, including from 5 to 20 mg of memantine or its pharmaceutically acceptable salt, and from 450 to 550 mg of citicoline or its pharmaceutically acceptable salt, with the following ratio of the quantitative and qualitative composition of the ingredients of the pharmaceutical composition, mg:

Citicoline or a pharmaceutically acceptable salt thereof 450-550 Memantine or a pharmaceutically acceptable salt thereof 5-20 Microcrystalline cellulose 5-35 Hydroxypropyl methylcellulose 120.5-140.6 Silicon dioxide colloidal 6.8-7.2 Magnesium stearate 6.8-7.2 Film casing I 36.4-41.5 Film casing II 21.8-24.5

In the most preferred (non-limiting) embodiment of this invention, the pharmaceutically acceptable salt of citicoline is citicoline monosodium salt. Also in the most preferred (non-limiting) embodiment of this invention, the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, the colloidal silica is colloidal silica grade A 200. One skilled in the art will appreciate that other grades of colloidal silica having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, film shell I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". One skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

Table 2. Examples of quantitative and qualitative composition of ingredients of a pharmaceutical composition

Name of components Content in % Content in mg Citicoline monosodium salt 65.95-67.68-69.95 450-500-550 Memantine hydrochloride 0.67-1.30-2.50 5-10-20 Microcrystalline cellulose 0.63-3.95-5.13 5-30-35 Hydroxypropyl methylcellulose 17.23-17.66-17.80 120.5-133.00-140.6 Silicon dioxide colloidal 0.90-0.94-1.0 6.8-7.0-7.2 Magnesium stearate 0.90-0.94-1.0 6.8-7.0-7.2 Film casing I 5.18-5.25-5.33 36.4-40-41.5 Film casing II 2.85-3.0-3.2 21.8-22-24.5

In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, the colloidal silica is colloidal silica grade A 200. One skilled in the art will appreciate that other grades of colloidal silica having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, film shell I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". However, one skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

The technical result is also achieved by the fact that, based on the above pharmaceutical composition, an oral solid dosage form is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of the ingredients, effective for the treatment of cognitive impairment of vascular origin, has a neuromodulating, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and progression of neurodegenerative processes, comprising as active ingredients from 5.00 to 20.00 mg of memantine or a pharmaceutically acceptable salt thereof, such as memantine hydrochloride, and from 450 to 550 mg of citicoline or a pharmaceutically acceptable salt thereof, such as citicoline monosodium salt , wherein said oral solid dosage form is in the form of a film-coated modified-release tablet. The quantitative and qualitative composition of the ingredients of the specified dosage form (in terms of 1 tablet) is presented in Table 3. Non-limiting (illustrative) examples of the quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet are presented in Table 4:

Table 3. Quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet:

Name of components Content in % Content in mg Citicoline monosodium salt 65.95-69.95 450-550 Memantine hydrochloride 0.67-2.50 5-20 Microcrystalline cellulose 0.63-5.13 5-35 Hydroxypropyl methylcellulose (molecular weight 1,000,000) 17.23-17.80 120.5-140.6 Silicon dioxide colloidal 0.91-1.0 6.8-7.2 Magnesium stearate 0.91-1.0 6.8-7.2 Film casing I 5.18-5.33 36.4-41.5 Film casing II 2.85-3.2 21.8-24.5 Total weight of coated tablet 682.3-772.0-791.0

Table 4. Examples of the quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet:

Name of components Content in % Content in mg Citicoline monosodium salt 65.95-67.68-69.95 450-500-550 Memantine hydrochloride 0.67-1.30-1.90 5-10-15 Microcrystalline cellulose 0.63-3.95-5.13 5-30-35 Hydroxypropyl methylcellulose 17.23-17.66-17.80 120.5-133.00-140.6 Silicon dioxide colloidal 0.90-0.94-1.0 6.8-7.0-7.2 Magnesium stearate 0.90-0.94-1.0 6.8-7.0-7.2 Film casing I 5.18-5.25-5.33 36.4-40-41.5 Film casing II 2.85-3.0-3.2 21.8-22-24.5 Total weight of coated tablet 682.3-772.0-791.0

In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, the colloidal silica is colloidal silica grade A 200. One skilled in the art will appreciate that other grades of colloidal silica having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, film shell I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". However, one skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

Also, technical results are achieved in the present invention in that an oral solid dosage form is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of the ingredients, effective for the treatment of cognitive disorders of vascular origin, has a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slows down and inhibits glutamatergic neurotransmission and progression of neurodegenerative processes, comprising as active ingredients memantine or a pharmaceutically acceptable salt thereof, in an amount from 5.00 to 20.00 mg, and citicoline or a pharmaceutically acceptable salt thereof, in an amount from 450 to 550 mg, with said oral solid dosage form made in the form of a modified-release tablet, film-coated, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, wt. %:

Citicoline or a pharmaceutically acceptable salt thereof 65.95-69.95 Memantine or a pharmaceutically acceptable salt thereof 0.67-2.50 Microcrystalline cellulose 0.63-5.13 Hydroxypropyl methylcellulose 17.23-17.80 Silicon dioxide colloidal 0.91-1.0 Magnesium stearate 0.91-1.0 Film casing I 5.18-5.33 Film casing II 2.85-3.2

In the most preferred (non-limiting) embodiment of the present invention, the pharmaceutically acceptable salt of citicoline is citicoline monosodium salt, and the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

Also in a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, the colloidal silica is colloidal silica grade A 200. One skilled in the art will appreciate that other grades of colloidal silica having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, film shell I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". However, one skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

Also, technical results are achieved in the present invention in that an oral solid dosage form is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of the ingredients, effective for the treatment of cognitive disorders of vascular origin, has a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slows down and inhibits glutamatergic neurotransmission and progression of neurodegenerative processes, including as active ingredients memantine or its pharmaceutically acceptable salt, for example, memantine hydrochloride, in an amount of 5.00 to 20.00 mg and citicoline or its pharmaceutically acceptable salt, in an amount of 450 to 550 mg, performed in in the form of a modified-release film-coated tablet, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, mg:

Citicoline or a pharmaceutically acceptable salt thereof 450-550 Memantine
or a pharmaceutically acceptable salt thereof 5-20 Microcrystalline cellulose 5-35 Hydroxypropyl methylcellulose 120.5-140.6 Silicon dioxide colloidal 6.8-7.2 Magnesium stearate 6.8-7.2 Film casing I 36.4-41.5 Film casing II 21.8-24.5

In the most preferred (non-limiting) embodiment of the present invention, the pharmaceutically acceptable salt of citicoline is citicoline monosodium salt, and the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

Also in a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, the colloidal silica is colloidal silica grade A 200. One skilled in the art will appreciate that other grades of colloidal silica having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, film shell I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". However, one skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

Table 4. Examples of the quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet:

Name of components Content in % Content in mg Citicoline monosodium salt 65.95-67.68-69.95 450-500-550 Memantine hydrochloride 0.67-1.30-1.90 5-10-15 Microcrystalline cellulose 0.63-3.95-5.13 5-30-35 Hydroxypropyl methylcellulose 17.23-17.66-17.80 120.5-133.00-140.6 Silicon dioxide colloidal 0.90-0.94-1.0 6.8-7.0-7.2 Magnesium stearate 0.90-0.94-1.0 6.8-7.0-7.2 Film casing I 5.18-5.25-5.33 36.4-40-41.5 Film casing II 2.85-3.0-3.2 21.8-22-24.5 Total weight of coated tablet 682.3-772.0-791.0

In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, the colloidal silica is colloidal silica grade A 200. One skilled in the art will appreciate that other grades of colloidal silica having similar characteristics may be used.

Also in a preferred (non-limiting) embodiment of the invention, film shell I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by one skilled in the art that for both film shell I and film shell II, other commercially available mixtures well known to one skilled in the art can be used.

The technical result related to the simplification and reduction of the cost of the dosage form and pharmaceutical composition intended for the treatment of cognitive disorders of vascular origin, which has neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, is also achieved in the present invention by that a method has been proposed for producing a dosage form based on a pharmaceutical composition, in which magnesium stearate, citicoline monosodium salt, memantine hydrochloride, microcrystalline cellulose, including grade 101, hydroxypropyl methylcellulose, colloidal silicon dioxide, including grade A 200, are sifted through a sieve with a cell diameter of no more than 0.5 mm, then load citicoline monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose into a mixer-granulator or similar mixing device, mix until homogeneous at a mixing speed of 160-240 rpm, and a mixing time in the range of 2 up to 10 minutes, then with constant stirring for no more than 5 minutes at a stirring speed ranging from 150 to 400 rpm, the mixture is moistened with purified water, after which the resulting granulate is dried under fluidized bed conditions while maintaining the following parameters: temperature incoming air 45-65°C, residual humidity of the granulate from 2.5 to 4.5%, then the resulting mixture is dusted with colloidal silicon dioxide, then the resulting mixture is tableted on a rotary tablet press using a press tool with a diameter of 10 to 15 mm, The tabletting process is controlled by the following parameters: hardness - 150-250 N, abrasion - no more than 1.0%, height - no more than 7.0 mm, then a shell is applied to the resulting tablet cores, in the process of dissolving the film shell of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol, the pharmaceutical substance memantine hydrochloride is added in parts and mixed until a homogeneous suspension is formed, after which the resulting coating is applied at a tablet core temperature of 35-40 ° C and periodically stirred, including in a coater drum, then a film coating solution is prepared from the mixture polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide, after obtaining a film-forming solution, it is applied to the tablets under the same conditions as the previous coating. The preferred quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet is presented in Table 3. Preferred (non-limiting) examples of the quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet are presented in Table 4:

The technical result related to the simplification and reduction of the cost of the dosage form and pharmaceutical composition intended for the treatment of cognitive disorders of vascular origin, which has neuromodulating, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, is also achieved by the fact that within The present invention proposes a method for obtaining a dosage form based on a pharmaceutical composition that provides an increase in the therapeutic activity of the quantitative and qualitative composition of the ingredients, effective for the treatment of cognitive disorders of vascular origin, and also has a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative diseases processes according to which magnesium stearate, citicoline or its pharmaceutically acceptable salt, memantine or its pharmaceutically acceptable salt, microcrystalline cellulose, hydroxypropyl methylcellulose, colloidal silicon dioxide, are sifted through a sieve with a mesh diameter of no more than 0.5 mm, then loaded into a mixer granulator or similar mixing device, citicoline or its pharmaceutically acceptable salt, microcrystalline cellulose and hydroxypropyl methylcellulose, mix until homogeneous at a mixing speed of 160-240 rpm, and a mixing time in the range of 2 to 10 minutes, then with constant stirring of the mixture, moisten the mixture with water purified, while the mixing speed should be in the range of 150-400 rpm, and the mixing time should not exceed 5 minutes, after which the resulting granulate is dried under fluidized bed conditions while maintaining the following parameters: incoming air temperature 45-65°C , the residual moisture content of the granulate is from 2.5 to 4.5%, then the resulting mixture is dusted with colloidal silicon dioxide, then the resulting mixture is tableted on a rotary tablet press using a press tool with a diameter of 10 to 15 mm, the tableting process is controlled by the following parameters: hardness - 150-250 N, abrasion - no more than 1.0%, height - no more than 7.0 mm, then a shell is applied to the resulting core tablets, while the film shell of the mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol is dissolved, the pharmaceutical substance is added in parts memantine or its pharmaceutically acceptable salt and stirred until a homogeneous suspension is formed, after which the resulting shell is applied at a tablet core temperature of 35-40°C and periodic stirring, including in a coater drum, then a film-forming agent solution for film shell II is prepared from the mixture polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide, after obtaining a film-forming solution for film shell II, it is applied to tablets under the same conditions as the previous coating, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, wt. %:

Citicoline or a pharmaceutically acceptable salt thereof 65.95-69.95 Memantine or a pharmaceutically acceptable salt thereof 0.67-2.50 Microcrystalline cellulose 0.63-5.13 Hydroxypropyl methylcellulose 17.23-17.80 Silicon dioxide colloidal 0.91-1.0 Magnesium stearate 0.91-1.0 Film casing I 5.18-5.33 Film casing II 2.85-3.2

In the most preferred (non-limiting) embodiment of the present invention, the pharmaceutically acceptable salt of citicoline is citicoline monosodium salt, and the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

In a preferred (non-limiting) embodiment of the method according to the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the method according to the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also, in a preferred (non-limiting) embodiment of the method according to the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other varieties of colloidal silicon dioxide having similar characteristics can be used.

Also in a preferred (non-limiting) embodiment of the method according to the invention, the film shell I is made of a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the method according to the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". However, one skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

The technical result related to the simplification and reduction of the cost of the dosage form and pharmaceutical composition intended for the treatment of cognitive disorders of vascular origin, which has neuromodulating, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, is also achieved by the fact that within The present invention proposes a method for obtaining a dosage form based on a pharmaceutical composition that provides an increase in the therapeutic activity of the quantitative and qualitative composition of the ingredients, effective for the treatment of cognitive disorders of vascular origin, and also has a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative diseases processes comprising from 5 to 20 mg of memantine or a pharmaceutically acceptable salt thereof, for example, memantine hydrochloride, and from 450 to 550 mg of citicoline or a pharmaceutically acceptable salt thereof, for example, citicoline monosodium, and, according to the specified method, magnesium stearate, citicoline or its pharmaceutically acceptable salt, memantine or its pharmaceutically acceptable salt, microcrystalline cellulose, hydroxypropyl methylcellulose and colloidal silicon dioxide are sifted through a sieve with a mesh diameter of not more than 0.5 mm, then citicoline monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose are loaded into a granulator mixer or similar mixing device , mix until homogeneous at a mixing speed of 160-240 rpm, and a mixing time in the range from 2 to 10 minutes, then, with constant stirring of the mixture, moisten the mixture with purified water, while the mixing speed should be in the range of 150-400 rpm min, and the mixing time is no more than 5 minutes, after which the resulting granulate is dried under fluidized bed conditions while maintaining the following parameters: incoming air temperature 45-65 ° C, residual moisture content of the granulate from 2.5 to 4.5%, the resulting granulate sift through a sieve with a mesh diameter of no more than 1.0 mm, then the resulting mixture is dusted with colloidal silicon dioxide for 3 to 5 minutes, then part of the hydroxypropyl methylcellulose is added to the mixture, stirred for another 8 to 10 minutes, then magnesium stearate is added and stirred some more 2-3 min. The resulting mixture for tableting is subjected to tabletting on a rotary tablet press, using a press tool with a diameter of 10 to 15 mm, the tableting process is controlled by the following parameters: hardness - 150-290 N, abrasion - no more than 1.0%, height - no more than 7 ,0 mm, then a shell is applied to the resulting core tablets, while the film shell of the mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol is dissolving, the pharmaceutical substance memantine hydrochloride is added in parts and mixed until a homogeneous suspension is formed, after which the resulting shell is applied at a tablet core temperature of 35- 40°C and periodic stirring, including in a coater drum, then a film coating solution is prepared from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide, after obtaining the film-forming solution, it is applied to the tablets under the same conditions as previous coating, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, mg:

Citicoline or a pharmaceutically acceptable salt thereof 450-550 Memantine or a pharmaceutically acceptable salt thereof 5-20 Microcrystalline cellulose 5-35 Hydroxypropyl methylcellulose 120.5-140.6 Silicon dioxide colloidal 6.8-7.2 Magnesium stearate 6.8-7.2 Film casing I 36.4-41.5 Film casing II 21.8-24.5

In the most preferred (non-limiting) embodiment of the present invention, the pharmaceutically acceptable salt of citicoline is citicoline monosodium salt, and the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

In a preferred (non-limiting) embodiment of the method according to the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the method according to the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also, in a preferred (non-limiting) embodiment of the method according to the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other varieties of colloidal silicon dioxide having similar characteristics can be used.

Also in a preferred (non-limiting) embodiment of the method according to the invention, the film shell I is made of a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from a commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the method according to the invention, film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". However, one skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

In addition, technical results are achieved in the present invention by also providing a medicinal product in the form of a modified-release tablet, including citicoline or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof as pharmaceutical substances, microcrystalline cellulose as a filler, hypromellose in as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, film coating, as an insulating coating (Film coating I), protective (Film coating II) and carrier (Film coating Ia), with the following quantitative and qualitative composition ingredients of the dosage form in terms of 1 tablet, wt.%:

Pharmaceutically acceptable citicoline salt (equivalent to citicoline base) 69.95
(66.93) Microcrystalline cellulose 4.08 Hypromellose 17.80 Silicon dioxide colloidal 0.94 Magnesium stearate 0.94 Film casing I 1.34 Pharmaceutically acceptable memantine salt 0.67 Film casing Ia 2.68 Film casing II 1.61

In the most preferred (non-limiting) embodiment of the present invention, the pharmaceutically acceptable salt of citicoline is citicoline monosodium salt, and the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

Also in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) of the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also, in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) according to the invention, colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other varieties of colloidal silicon dioxide can be used, having similar characteristics.

Also in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) according to the invention, the film coating I is made of a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) according to the invention, film coating II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". However, one skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

In addition, the technical results of the present invention are also achieved by providing a medicinal product in the form of a modified-release tablet, including citicoline or a pharmaceutically acceptable salt thereof, for example, citicoline monosodium, and memantine or a pharmaceutically acceptable salt thereof, for example, memantine hydrochloride, as active ingredients, microcrystalline cellulose as a filler, hypromellose as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, film shell, as a shell and carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of for 1 tablet, mg:

Pharmaceutically acceptable citicoline salt (equivalent to citicoline base) 522.50
(500.00) Microcrystalline cellulose 30.50 Hypromellose 133.00 Silicon dioxide colloidal 7.00 Magnesium stearate 7.00 Film casing I 10.00 Pharmaceutically acceptable memantine salt 5.00 Film casing Ia 20.00 Film casing II 12.00

In the most preferred (non-limiting) embodiment of the present invention, the pharmaceutically acceptable salt of citicoline is citicoline monosodium salt, and the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

In a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

Also in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) of the invention, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000 Da. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will appreciate that other varieties of hydroxypropyl methylcellulose having similar characteristics may be used.

Also, in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) according to the invention, colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other varieties of colloidal silicon dioxide can be used, having similar characteristics.

Also in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) according to the invention, the film coating I is made of a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. In the most preferred (non-limiting) embodiment of the invention, the film shell I is made from the commercially available mixture "Opadry 03F180011 white".

Also in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) according to the invention, film coating II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

In the most preferred (non-limiting) embodiment of the invention, film shell II is made from the commercially available mixture "Opadry II 85F 200062 purple". However, one skilled in the art will understand that other commercially available mixtures well known to one skilled in the art can be used for both film shell I and film shell II.

Table 5. Examples of the quantitative and qualitative composition of ingredients in terms of 1 tablet, including memantine hydrochloride (equivalent to 5 mg of memantine base) and citicoline sodium (equivalent to 500 mg of citicoline base) as active ingredients.

Name of components Content in % Content in mg/table Purpose Citicoline sodium (equivalent to citicoline base) 69.95 522.50
(500.00) Pharmaceutical substance Microcrystalline cellulose 101 4.08 30.50 Filler Hypromellose type 2208 (K100M) 17.80 133.00 Matrix agent Colloidal silicon dioxide A 200 0.94 7.00 Glidant Magnesium stearate 0.94 7.00 Lubricant Total weight of the tablet core 700.00 - Film coating Opadry 03F180011 white (Hypromellose, Titanium dioxide, Macrogol) 1.34 10.00 Shell Total weight of coated tablet 710.00 - Memantine hydrochloride 0.67 5.00 Pharmaceutical substance Film casing I (Opadry 03F180011 white) 2.68 20.00 Shell/Media Total weight of coated tablet 735.00 - Film casing II (Opadry II 85F200062
Purple) 1.61 12.00 Shell Total weight of coated tablet 747.00 -

In addition, the technical results of the present invention are also achieved by providing a medicinal product in the form of a modified release tablet, comprising citicoline or a pharmaceutically acceptable salt thereof, for example citicoline sodium, and memantine or a pharmaceutically acceptable salt thereof, for example memantine hydrochloride, as active ingredients, microcrystalline cellulose as a filler, hypromellose as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, film shell, as a shell and carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, wt.%:

Citicoline sodium (equivalent to citicoline base) 67.68
(64.77) Microcrystalline cellulose 101 3.95 Hypromellose type 2208 (K100M) 17.23 Colloidal silicon dioxide A 200 0.91 Magnesium stearate 0.91 Film casing Ia (Opadry 03F180011 white) 1.30 Memantine hydrochloride 1.30 Film casing Ib (Opadry 03F180011 white) 5.18 Film casing II (Opadry II 85F200062
Purple) 1.55

In addition, the technical results of the present invention are also achieved by providing a medicinal product in the form of a modified-release tablet, including citicoline or a pharmaceutically acceptable salt thereof, for example, citicoline sodium and memantine or a pharmaceutically acceptable salt thereof, for example, memantine hydrochloride, as active agents. substances, microcrystalline cellulose as a filler, hypromellose as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, film shell, as a shell and carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet , mg:

Citicoline sodium (equivalent to citicoline base) 522.50
(500.00) Microcrystalline cellulose 101 30.50 Hypromellose type 2208 (K100M) 133.00 Colloidal silicon dioxide A 200 7.00 Magnesium stearate 7.00 Film coating Opadry 03F180011 white (Hypromellose, Titanium dioxide, Macrogol) 10.00 Memantine hydrochloride 10.00 Film shell Opadry 03F180011 white (Hypromellose, Titanium dioxide, Macrogol) 40.00 Film casing Opadry II 85F200062
Purple (Polyvinyl alcohol, Titanium dioxide, Macrogol, Talc, Iron oxide red, Iron oxide black) 12.00

Table 6. Examples of the quantitative and qualitative composition of ingredients in terms of 1 tablet, including memantine in an amount of 10 mg and citicoline in an amount of 500 mg as active ingredients.

Name of components Content in % Content in mg/table Purpose Citicoline sodium (equivalent to citicoline base) 67.68 522.50
(500.00) Pharmaceutical substance Microcrystalline cellulose 101 3.95 30.50 Filler Hypromellose type 2208 (K100M) 17.23 133.00 Matrix agent Colloidal silicon dioxide A 200 0.91 7.00 Glidant Magnesium stearate 0.91 7.00 Lubricant Total weight of the tablet core 700.00 - Film shell Opadry 03F180011 white (Hypromellose, Titanium dioxide, Macrogol) 1.30 10.00 Shell Total weight of coated tablet 710.00 - Memantine hydrochloride 1.30 10.00 Pharmaceutical substance Film shell Opadry 03F180011 white (Hypromellose, Titanium dioxide, Macrogol) 5.18 40.00 Shell/Media Total weight of coated tablet 760.00 - Film casing Opadry II 85F200062
Purple (Polyvinyl alcohol, Titanium dioxide, Macrogol, Talc, Iron oxide red, Iron oxide black) 1.55 12.00 Shell Total weight of coated tablet 772.00 -

In addition, the technical results of the present invention are also achieved by the fact that a method is proposed for producing a drug in the form of a modified-release tablet containing citicoline sodium and memantine hydrochloride as active ingredients, as well as microcrystalline cellulose as a filler, hypromellose as a matrix agent, silicon colloidal dioxide as a glidant, magnesium stearate as a lubricant, film coating as a shell and carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, mg:

Citicoline sodium (equivalent to citicoline base) 522.50
(500.00) Microcrystalline cellulose 101 30.50 Hypromellose type 2208 (K100M) 133.00 Colloidal silicon dioxide A 200 7.00 Magnesium stearate 7.00 Film shell Opadry 03F180011 white (Hypromellose, Titanium dioxide, Macrogol) 10.00 Memantine hydrochloride 5.00-10.00 Film coating Opadry 03F180011 white (Hypromellose, Titanium dioxide, Macrogol) 20.00-40.00 Film casing Opadry II 85F200062
Purple (Polyvinyl alcohol, Titanium dioxide, Macrogol, Talc, Iron oxide red, Iron oxide black) 12.00

characterized in that said method includes:

sifting of raw materials, in which magnesium stearate is sifted manually through a 0.5 mm sieve, the residue on the sieve is wiped manually, then sodium citicoline is sieved using a screening installation, for example, on a vibrating sieve CISA RP 200 N through a 0.50 mm sieve, while , as memantine hydrochloride is sifted, for example, on a CISA RP 200 N vibrating sieve through a 0.075 mm sieve, microcrystalline cellulose 101, hypromellose K100M, colloidal silicon dioxide is sieved, for example, on a CISA RP 200 N vibrating sieve through a 0.5 mm sieve.

weighing of raw materials, in which each type of raw material is weighed into separate clean containers, labeled and transferred to the next stages,

the process of preparing a humidifier solution, where purified water is used as a humidifier solution, and the amount of purified water is calculated depending on the mass of the dry mixture with a mixture to water ratio of 3.4: 1,

the process of preparing a mixture for tableting, in which sifted citicoline sodium, microcrystalline cellulose, for example, sifted marking 101, and hypromellose, including type 2208, are loaded into a mixer-granulator, then the components are mixed until homogeneous under visual control, while the parameters mixing depends on the volume of the laboratory batch.

In particular,

Parameters for laboratory batch of 500 tablets:

Bowl volume – 3.0 l.

Mixing speed – 200.0 rpm.

Mixing time – 120 s,

Next, the granulation process is carried out, in which, with constant stirring of the mixture in a mixer-granulator, a humidifier solution is added, stirring is carried out until a fine crumbly granulate is formed (visual control), granulation parameters depend on the volume of the laboratory batch, including,

Parameters for laboratory batch of 500 tablets:

Mixing speed – 200.0-350.0 rpm.

Mixing time – 60 s,

Then the granulate is dried, where the granulate is dried in a drying cabinet (fluid bed dryer), the drying process parameters depend on the equipment used and the volume of the laboratory batch, including,

Parameters for laboratory batch of 500 tablets:

Inlet air temperature 50-65°C. Drying time 3-6 hours Residual moisture of granulate from 2.5 to 4.5%,

after which the granulate is calibrated, namely, the granulate is sifted, for example, on a CISA RP 200 N vibrating sieve through a 1.0 mm (0.710 mm) sieve, and the residues are rubbed through a 1.0 mm (0.710 mm) sieve manually,

Next, dusting is carried out, during which granulate and sifted colloidal silicon dioxide are added to the mixer, mixing is carried out until homogeneous (visual control), mixing parameters depend on the type of equipment and the volume of the laboratory batch, including,

Parameters for laboratory batch of 500 tablets:

Bowl volume – 3.0 l

Mixing time – 300 s,

moreover, in the presence of agglomerates of colloidal silicon dioxide, it is allowed to sift the mixture through a 1.0 mm sieve; agglomerates of colloidal silicon dioxide are rubbed through the sieve manually. Hypromellose, including type 2208, sifted, is added to the mixer and mixing continues until smooth (control visual), mixing parameters depend on the type of equipment and the volume of the laboratory batch, including

Parameters for laboratory batch of 500 tablets:

Bowl volume – 3.0 l

Mixing time – 600 s,

sifted magnesium stearate is loaded into the mixer and the components are mixed until homogeneous (visual control), mixing parameters depend on the type of equipment and the volume of the laboratory batch, including

Parameters for laboratory batch of 500 tablets:

Bowl volume – 3.0 l

Mixing time – from 120 to 180 s,

The tabletting mixture is discharged into a labeled container, a representative sample is taken for inspection according to the specification, then the tabletting process is carried out, which is carried out on a tablet press, for example (but not limited to), Futorque X-1, the tableting process is carried out on a round press tool with with a geometry of 12.00 mm, at the beginning of the process the tablet press is configured to produce tablets with an average weight, including 700.0 mg.

After setting the average weight of the tablets, adjust the tablet press according to other indicators:

hardness – 200-290 N;

abrasion – no more than 1.0%;

height – no more than 6.0 mm;

deviations from the average weight of 20 tablets - deviations from the average weight of individual tablets should not exceed 5%,

after setting up the tablet press, carry out the tableting process until the mixture for tableting is completely consumed; during the tableting process, at least once every 10 minutes, the following is monitored:

average weight of tablets;

tablet hardness.

During the tableting process, tablets are collected into labeled containers; after the end of the process, the containers are closed, a representative selection of tablets is carried out for intermediate control according to the specification, then the process of coating the tablets with a film coating is carried out, which includes the preparation of a film suspension, namely, in the process of applying the film coating, an 18% film suspension is used, mixing of purified water is established to form a funnel on the surface of the water, gradually add a dry film shell, preventing the formation of agglomerates on the surface of the solution, then reduce the mixing speed so that foaming does not occur, and leave the solution to mix for 45 minutes, then apply the shell, which is carried out on a coater modular installation, for example, BOSCH Solidlab 1, before the coating process, the tablets are heated to 37-39 ° C with periodic stirring in the coater drum, when the temperature of the tablets is reached, spraying of the film suspension begins, the application process is carried out at a product temperature of 35-40 ° C, during the process, the appearance of the tablets and the weight gain of the coating are controlled, the coating process is carried out until the average weight of the tablets is obtained, including 710.00 mg, when the specified weight of the tablets is reached, the process is stopped and the tablets are cooled to a temperature not exceeding 33 ° C., after completion process, the containers are closed, then a representative selection of tablets is carried out for intermediate control, the coated tablets are stored in closed containers, after which the process of coating the tablets with a coating is carried out, including the pharmaceutical substance memantine hydrochloride; in the process of applying the film coating, they use, among other things, 15% film suspension, for example, such as Opadry 03F180011 or Opadry II 85F200062, mix the purified water so that a funnel is formed on the surface of the water, add the pharmaceutical substance memantine hydrochloride, sifted and mix until completely dissolved under visual control, then gradually add the dry film the shell, preventing the formation of agglomerates on the surface of the solution, then reduce the mixing speed so that foaming does not occur, and leave the solution to mix for 45 minutes, then carry out the film coating process on the coater of the modular installation, which is carried out on the coater of the modular installation, including, BOSCH Solidlab 1, before the coating process, the tablets are heated to 37-39 ° C with periodic stirring in the coater drum; Once the temperature of the tablets is reached, spraying of the film suspension begins. The application process is carried out at a product temperature of 35-40°C, during the process the appearance of the tablets and the weight gain of the coating are controlled, the coating process is carried out until the average weight of the tablets is obtained, including 735.00 mg/760.00 mg, when the specified weight is reached tablets, the process is stopped and the tablets are cooled to a temperature not exceeding 33 ° C., after the end of the process, the containers are closed, a representative selection of tablets is carried out for intermediate control, the coated tablets are stored in closed containers, then the process of coating the tablets with the final shell is carried out, in In the process of applying a film shell, use an 18% film suspension, set the mixing of purified water so that a funnel is formed on the surface of the water, gradually add a dry film shell, preventing the formation of agglomerates on the surface of the solution, then reduce the mixing speed so that foaming does not occur, and leave the solution is mixed for at least 45 minutes, the coating is applied on a coater of a modular installation, for example, BOSCH Solidlab 1, before the coating process, the tablets are heated to 35-45 ° C with periodic stirring in the coater drum, when the temperature of the tablets is reached, spraying begins film suspension, the application process is carried out at a product temperature of 35-40°C, during the process the appearance of the tablets and the weight gain of the shell are controlled, the coating process is carried out until the average weight of the tablets is obtained, including 747.00 mg/772.00 mg, at When the specified mass of tablets is reached, the process is stopped and the tablets are cooled to a temperature not exceeding 33 ° C, after the end of the process the containers are closed, a representative selection of tablets is carried out for intermediate control, according to the specification, film-coated tablets are stored in closed containers, a package of tablets, coated with a film shell, is carried out by placing, for example, in a PVC/Alu blister on an automatic blister machine DPP260ki-2, parameters for forming blister cells:

Pressure – 6 bar;

Forming temperature – 110 - 120°С

Sealing parameters:

Sealing temperature – 130 - 140°C;

Pressure – 6 bar;

Speed – 18 cycles/min;

Coolant temperature - 10°C,

after which the blisters are checked for tightness using, for example, an Erweka VDT/S tester; the first and last blisters received are subject to mandatory tightness testing.

A comparative study of the specific pharmacological activity of the pharmaceutical composition proposed in the present invention in comparison with the monodrug citicoline was carried out on a model of ischemic stroke in rats. To do this, based on the guidelines for conducting preclinical studies edited by A.N. Mironov [9], a model of global transient cerebral ischemia using ligation of the common carotid arteries was chosen. Long-term memory was assessed using the Morris water maze test (Morris R., "J Neurosci Methods" , 1984, Vol. 11, No. 1. - P. 47-60 [10]).

Table. The effect of the studied drugs on long-term memory in rats in the Morris water maze test.

A drug Dose, mg/kg (citicoline + memantine) Latent period of platform location, s The claimed composition (citicoline + memantine) 100+2 8.7±2.3 500+10 7.9±1.5 1000+20 6.1±1.5 Citicoline 100+0 20.4±7.6 500+0 13.6±3.5 1000+0 10.4±3.5 Memantine 0+2 27.1±7.8 0+10 14.6±5.2 0+20 9.2±1.2

It turned out unexpectedly that the addition of memantine, which has a known prior art indication for the treatment of cognitive impairment (dementia) of the Alzheimer's type, to therapy, led to pronounced neuroprotective and procognitive effects in the correction of cognitive impairment caused by a completely different cause, namely ischemia. Treatment with the study drugs contributed to the successful reproduction of the skill at the stage of assessing long-term memory. A significant decrease in the latent period (LP) for finding the target sector (compared to animals with pathology without treatment) was noted in all groups receiving the pharmaceutical composition proposed in the present invention, regardless of the dose of the drug. In the groups receiving Citicoline or Memantine, a similar effect was observed only in the group receiving the drug at the maximum doses tested

The above examples illustrate, but do not limit the use of the specified compositions and methods of the claimed inventions.

The developed compositions of pharmaceutical compositions, as well as the proposed dosage form, manufactured in the described manner on the basis of the proposed compositions, ensure the achievement of the technical results of the present invention: increasing the therapeutic activity of citicoline or its pharmaceutically acceptable salt by ensuring its super-total (synergistic) interaction with memantine or its pharmaceutically acceptable salt, as well as due to its instant onset of action and subsequent effective and long-lasting action; simplifying the treatment of cognitive impairment of vascular origin, providing side-effect-free, stable upon receipt and storage-stable dosage forms of memantine or a pharmaceutically acceptable salt thereof and citicoline or a pharmaceutically acceptable salt thereof, providing an accessible and inexpensive method for obtaining dosage forms of memantine or a pharmaceutically acceptable salt thereof, and citicoline or a pharmaceutically acceptable salt thereof.

The resulting dosage form ensures stability, storage stability and a virtual absence of side effects.

Thanks to the proposed inventions, which formed the basis for dosage forms manufactured according to this method, it is possible to increase the therapeutic effectiveness of the claimed composition by:

- modified release dosage form made on the basis of a pharmaceutical composition,

- effective period of action of the dosage form based on the declared composition,

- by simplifying the scheme of action of the dosage form used. All presented inventions are industrially applicable, have passed laboratory tests, are practically implementable and will find wide application in the pharmaceutical industry, namely, it is confirmed:

- use of the above pharmaceutical composition,

- use of the proposed dosage form,

- application of a method for obtaining the proposed dosage form based on a pharmaceutical composition.

Each of the proposed inventions is industrially applicable in the field of pharmaceuticals, ensures the stability of the declared properties, and maintains the stability of properties for a period of at least 3 years.

The use of the proposed inventions increases the range of dosage forms.

In addition, the proposed method for obtaining a dosage form ensures the stability of the properties of the dosage form, maintaining the stability of properties for a period of at least 3 years.

Thus, the desired technical result has been achieved - the proposed group of inventions, including a pharmaceutical composition with neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes,

- a pharmaceutical composition that provides an increase in the therapeutic activity of the declared quantitative and qualitative composition of the ingredients due to the immediate onset of action and due to the effective and long-lasting action of the composition of the ingredients, for the treatment of cognitive disorders of vascular origin, which has a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and progression of neurodegenerative processes,

- a dosage form through which, with the introduction of the specified pharmaceutical composition, it is ensured that the scheme of action of the claimed qualitative and quantitative composition of ingredients for the treatment of cognitive disorders of vascular origin is simplified, and also has a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative diseases processes,

- as well as a method for obtaining the specified dosage form based on the proposed pharmaceutical composition, intended for the production of tablets for the treatment of cognitive disorders of vascular origin, as well as having neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes,

In addition, the technical result is an increase in the assortment of dosage forms intended for the treatment of cognitive disorders of vascular origin, which have neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes.

The proposed group of inventions is industrially applicable, implemented in practice, as evidenced by the provided examples of implementation of the group of inventions, which will find wide application in pharmaceuticals, both in Russia and abroad for pharmaceutical compositions and dosage forms that have neuromodulatory, antiparkinsonian, neuroprotective and antispastic action that slows down and inhibits glutamatergic neurotransmission and the progression of neurodegenerative processes, and intended for the treatment of cognitive disorders of vascular origin.

INFORMATION SOURCES:

1. RF patent for invention No. 2429851 “COMPOSITIONS CONTAINING PUFA AND/OR URIDINE AND METHODS OF THEIR APPLICATION”, patent holder: “MASSACHUSETTS INSTITUTE OF TECHNOLOGY” (US), published: 09/27/2011, IPC: A61K 31/685, A61P 25/28.

2. RF patent for invention No. 2603470 “METHOD AND PHARMACEUTICAL COMPOSITION FOR TREATING ALZHEIMER’S DISEASE AND DISORDERS, DISORDERS OR MEMORY LOSS”, patent holder: “MASSACHUSETTS INSTITUTE OF TECHNOLOGY” (US), published: 11/27/2016, M PC: A61K 31/685 , A61P 25/28.

3. RF patent for invention No. 2605339 “A DRUG FOR RELIEF OF GLUTAMATE-INDUCED APOPTOSIS AND INHIBITION OF NMDA RECEPTORS, HAVING AN IMMUNOMODULATING EFFECT, FOR THE TREATMENT OF NERVOUS SYSTEM DISORDERS, CONSEQUENCES OF CRANIOBRAIN OVY TRAUMA AND ISCHEMIC AND HEMORRHAGIC STROKE", patent holder: Closed Joint Stock Company " EcoPharmPlus" (RU), published: 12/20/2016, IPC: A61K 31/7068, A61K 31/13, A61K 47/48, A61P 9/10, A61P 25/00.

4. RF patent for invention No. 2371173 “MEMANTINE FOR THE TREATMENT OF ALZHEIMER’S DISEASE OF MILD AND MILD TO MODERATE SEVERITY”, patent holder: “MERZ PHARMA GMBH UND CO. KGAA” (DE), published: 10/27/2009, IPC: A61K 31/ 13, A61P 25/28.

5. RF patent for invention No. 2326660 “ORAL MEDICINE MEMANTINE (OPTIONS) AND METHOD FOR ITS OBTAINING (OPTIONS)”, patent holder: Closed Joint Stock Company “Biological Research and Systems” (RU), published: 06.20.2008, IPC: A61K 31 /13, A61K 9/48, A61P 25/28.

6. The RF patent for invention No. 240475 “A composition containing the basis or coating for slow release and the NMDA receptor antagonist, the method of introducing such a NMDA antagonist to the subject”, the patent holder: “Adamas Pharmasyutics, Inc.” (US), published: 11/27/2010, IPC: A61K 9/20, A61P 25/28.

7. RF patent for invention No. 2483715 “SOLID DOSAGE FORM OF MEMANTINE AND ITS SALTS”, patent holder: Limited Liability Company "ACADEMFARM" (RU), published: 06/10/2013, IPC: A61K 31/13, A61K 47/38, A61K 9/16, A61K 9/20, A61P 25/16.

8. RF patent for invention No. 2390354 “MATRIX TYPE DRUG WITH DELAYED RELEASE, CONTAINING THE BASIC MEDICINE OR ITS SALT, AND THE METHOD FOR ITS PRODUCTION”, patent holder: "EISAY AR & D MANAGEMENT CO., LTD." (JP), published: 05/27/2010, IPC: A61K 47/32, A61K 9/26, A61K 31/445, A61J 3/10.

9. Guidelines for conducting preclinical studies of drugs. Part one / ed. A.N. Mironova ‒ M.: "Grif and K", 2012. ‒ 944 p.

10. Morris R. Developments of a water-maze procedure for studying spatial learning in the rat // J Neurosci Methods. ‒ 1984. ‒ Vol. 11, No. 1. ‒ P. 47-60.

Claims (44)

1. A pharmaceutical composition with neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including memantine hydrochloride in the range of 5-20 mg and citicoline monosodium salt in the range of 450 -550 mg with the following ratio of the quantitative and qualitative composition of the ingredients of the pharmaceutical composition, wt.%: Citicoline monosodium salt 65.95-69.95 Memantine hydrochloride 0.67-2.50 Microcrystalline cellulose 0.63-5.13 Hydroxypropyl methylcellulose (molecular weight 1,000,000) 17.23-17.80 Silicon dioxide colloidal 0.91-1.0 Magnesium stearate 0.91-1.0 Film casing I 3.00-7.00 Film casing II 1.00-2.00 2. Pharmaceutical composition according to claim 1, characterized in that the film shell I is made of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. 3. Pharmaceutical composition according to claim 1, characterized in that film shell II is made of a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide. 4. A pharmaceutical composition with neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including memantine hydrochloride in the range of 5-20 mg and citicoline monosodium salt in the range of values 450-550 mg with the following ratio of the quantitative and qualitative composition of the ingredients of the pharmaceutical composition, mg: Citicoline monosodium salt 450-550 Memantine hydrochloride 5-20 Microcrystalline cellulose 5-35 Hydroxypropyl methylcellulose (molecular weight 1,000,000) 120.5-140.6 Silicon dioxide colloidal 6.8-7.2 Magnesium stearate 6.8-7.2 Film casing I 36.4-41.5 Film casing II 21.8-24.5 5. Pharmaceutical composition according to claim 3, characterized in that the film shell I is made of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. 6. Pharmaceutical composition according to claim 3, characterized in that the film shell II is made of a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide. 7. Solid oral dosage form with neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including memantine or its pharmaceutically acceptable salt as active ingredients in the range of 5 ,00-20.00 mg and citicoline or its pharmaceutically acceptable salt in the range of 450-550 mg, characterized in that the specified dosage form is in the form of a modified-release film-coated tablet. 8. Solid oral dosage form with neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including memantine hydrochloride as active ingredients in the range of 5.00-20 ,00 mg and citicoline monosodium salt in the range of 450-550 mg, characterized in that the specified dosage form is made in the form of a modified-release tablet, film-coated, with the following quantitative and qualitative composition of ingredients in terms of 1 tablet, wt.%: Citicoline monosodium salt 65.95-69.95 Memantine hydrochloride 0.67-2.50 Microcrystalline cellulose 0.63-5.13 Hydroxypropyl methylcellulose (molecular weight 1,000,000) 17.23-17.80 Silicon dioxide colloidal 0.91-1.0 Magnesium stearate 0.91-1.0 Film casing I 5.18-5.33 Film casing II 2.85-3.2 9. Solid oral dosage form according to claim 8, characterized in that the film shell I is made of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. 10. Solid oral dosage form according to claim 8, characterized in that film shell II is made of a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide. 11. Solid oral dosage form with neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including memantine hydrochloride as active ingredients in the range of 5.00-20 ,00 mg and citicoline monosodium salt in the range of 450-550 mg, characterized in that the specified dosage form is made in the form of a modified-release tablet, film-coated, with the following quantitative and qualitative composition of ingredients in terms of 1 tablet, mg: Citicoline monosodium salt 450-550 Memantine hydrochloride 5-20 Microcrystalline cellulose 5-35 Hydroxypropyl methylcellulose (molecular weight 1,000,000) 120.5-140.6 Silicon dioxide colloidal 6.8-7.2 Magnesium stearate 6.8-7.2 Film casing I 36.4-41.5 Film casing II 21.8-24.5 12. Solid oral dosage form according to claim 11, characterized in that the film shell I is made of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. 13. Solid oral dosage form according to claim 11, characterized in that film shell II is made of a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide. 14. A method for producing a solid oral dosage form according to any one of paragraphs. 7-13, characterized in that magnesium stearate, citicoline monosodium salt, memantine hydrochloride, microcrystalline cellulose, hydroxypropyl methylcellulose, colloidal silicon dioxide are sifted through a sieve with a mesh diameter of no more than 0.5 mm, then loaded into a mixer-granulator or similar citicoline mixing device monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose are mixed until homogeneous for a period of time ranging from 2 to 10 minutes, at a stirring speed of 160-240 rpm, then with constant stirring of the mixture for no more than 5 minutes, at a stirring speed of 150 -400 rpm, the mixture is moistened with purified water to obtain granulate, after which the resulting granulate is dried under fluidized bed conditions while maintaining the following parameters: incoming air temperature 45-65°C, residual moisture content of the granulate from 2.5 to 4.5% , then the resulting mixture is dusted with colloidal silicon dioxide and magnesium stearate, then the resulting mixture is subjected to tabletting on a rotary tablet press to obtain tablet cores, using a press tool with a diameter of 10 to 15 mm, while the tableting process is controlled by the following parameters: hardness - 150- 290 N, abrasion - no more than 1.0%, height - no more than 7.0 mm, then film shell I is applied to the resulting tablet cores, made from a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol, while in the process of dissolving the film shell I is added the pharmaceutical substance of memantine hydrochloride in parts and mixed until a homogeneous suspension is formed, after which the resulting film shell I is applied to the tablet core at a tablet core temperature of 35-40°C and periodic stirring, then a solution of film shell II made from a mixture of polyvinyl alcohol and talc is prepared , macrogol, iron oxides and titanium dioxide, and apply it to tablets under the same conditions as film coating I. 15. The method according to claim 14, characterized in that microcrystalline cellulose grade 101 is used. 16. The method according to claim 14, characterized in that colloidal silicon dioxide grade A 200 is used. 17. The method according to claim 14, characterized in that the film shell I is applied to the tablet core in a coater drum. 18. A method for obtaining a dosage form based on a pharmaceutical composition characterized according to any one of paragraphs. 1-6, characterized in that magnesium stearate, citicoline monosodium salt, memantine hydrochloride, microcrystalline cellulose, hydroxypropyl methylcellulose, colloidal silicon dioxide are sifted through a sieve with a mesh diameter of no more than 0.5 mm, then loaded into a mixer-granulator or similar citicoline mixing device monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose, are mixed until homogeneous for a time of 2 to 10 minutes, at a stirring speed of 160-240 rpm, and then with constant stirring of the mixture for no more than 5 minutes, at a stirring speed 150-400 rpm, the mixture is moistened with purified water to obtain granulate, after which the resulting granulate is dried under fluidized bed conditions while maintaining the following parameters: incoming air temperature 45-65°C, residual moisture content of the granulate from 2.5 to 4.5% , the resulting granulate is sifted through a sieve with a mesh diameter of no more than 1.0 mm, then the resulting mixture is dusted with colloidal silicon dioxide for 3 to 5 minutes, then part of the hydroxypropyl methylcellulose is added to the mixture, stirred for another 8 to 10 minutes, then magnesium stearate is added and stirred for another 2-3 minutes, thus obtaining a mixture for tableting, then the said mixture is subjected to tabletting on a rotary tablet press to obtain tablet cores, using a press tool with a diameter of 10 to 15 mm, while the tableting process is controlled by the following parameters: hardness - 150-290 N, abrasion - no more than 1.0%, height - no more than 7.0 mm, then a film shell I is applied to the resulting core tablets, while the film shell I is dissolving, the pharmaceutical substance memantine hydrochloride is added in parts and mixed until formation of a homogeneous suspension, after which the resulting film shell I is applied to the tablet core at a tablet core temperature of 35-40°C and periodic stirring, then a solution of film shell II is prepared, made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide , and apply it to the tablets under the same conditions as the film coating I. 19. The method according to claim 18, characterized in that the film shell I is applied to the tablet core in a coater drum. 20. The method according to claim 18, characterized in that microcrystalline cellulose grade 101 is used as microcrystalline cellulose. 21. The method according to claim 18, characterized in that colloidal silicon dioxide grade A 200 is used as colloidal silicon dioxide. 22. A drug in the form of a tablet with a modified release, which has neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including citicoline monosodium salt and memantine hydrochloride as active ingredients , microcrystalline cellulose - as a filler, hypromellose - as a matrix agent, colloidal silicon dioxide - as a glidant, magnesium stearate as a lubricant, film shell as a shell and carrier with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet , wt.%: 23. The drug according to claim 22, characterized in that the film shell I is made of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. 24. The medicinal product according to claim 22, characterized in that the film shell II is made of a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide. 25. A drug in the form of a tablet with a modified release, which has neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including citicoline sodium and memantine hydrochloride as active ingredients, microcrystalline cellulose as a filler, hypromellose as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, film shell as a shell and carrier with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, mg: 26. The drug according to claim 25, characterized in that the film shell I is made of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. 27. The medicinal product according to claim 25, characterized in that the film shell II is made of a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide. 28. A drug in the form of a tablet with a modified release, which has neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including citicoline sodium and memantine hydrochloride as active ingredients, microcrystalline cellulose - as a filler, hypromellose - as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, film shell as a shell and carrier with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, wt .%: 29. The drug according to claim 28, characterized in that the film shell I is made of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. 30. The drug according to claim 28, characterized in that the film shell II is made of a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide. 31. A drug in the form of a tablet with a modified release, having neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including citicoline sodium and memantine hydrochloride as a pharmaceutical substance, microcrystalline cellulose as a filler, hypromellose as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, film shell as a shell and carrier with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, mg: 32. The drug according to claim 31, characterized in that the film shell I is made of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol. 33. The medicinal product according to claim 31, characterized in that the film shell II is made of a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide. 34. The use of a solid oral dosage form according to any one of paragraphs. 7-13 for the treatment of cognitive impairment of vascular origin. 35. Application of the method according to any one of paragraphs. 14-21 to obtain a dosage form for the treatment of cognitive impairment of vascular origin.