Pharmaceutical composition comprising memantine and citicoline

Abstract

The invention relates to a pharmaceutical composition having a neuromodulatory, anti-Parkinsonism, neuroprotective, and antispastic effect and intended for the treatment of cognitive disorders of vascular origin, and comprising memantine or its pharmaceutically acceptable salt and citicoline or its pharmaceutically acceptable salt, as well as a method of producing a dosage form based on the pharmaceutical composition. The therapeutic activity of citicoline or its pharmaceutically acceptable salt is increased because of a synergistic effect when citicoline or its pharmaceutically acceptable salt is used concomitantly with memantine or its pharmaceutically acceptable salt.

Description

[0001] A PHARMACEUTICAL COMPOSITION CONTAINING MEMANTINE AND CITICOLINE

[0002] SCOPE OF APPLICATION

[0003] The proposed inventions relate to the field of pharmaceuticals and concern pharmaceutical compositions and solid oral dosage forms that have a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, methods for producing such pharmaceutical compositions and solid oral dosage forms and the use of said pharmaceutical compositions and solid oral dosage forms for the treatment of cognitive impairment of vascular origin.

[0004] LEVEL OF TECHNOLOGY

[0005] In the modern pharmaceutical market, a relevant and increasingly popular area is the area associated with the development of various dosage forms used primarily for the treatment of cognitive impairment of vascular origin, namely, for improving memory, for the prevention and treatment of cerebral ischemia, for the treatment of nervous system disorders, 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 that slow down or inhibit glutamatergic neurotransmission and the progression of neurodegenerative processes.It is known that citicoline (cytidine diphosphate choline, cytidine-5'-diphosphocholine, CDP-choline, Neurocolin), or 5'-0- [hydroxy({hydroxy[2-(trimethylammonio)ethoxy]phosphoryl}oxy)phosphoryl]cytidine, a substance of formula (I) with nootropic action, a natural endogenous compound that is an intermediate metabolite in the synthesis of phosphatidylcholine, one of the main structural components of the cell membrane, is quite actively used as an active ingredient for the development of modern drugs for the prevention and treatment of the above-mentioned therapeutic disorders.

[0006] An invention is known [1] under Russian 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 an omega-3 fatty acid or an omega-6 fatty acid, (b) uridine, and (c) a choline salt. In particular embodiments of the invention [1], uridine is an acyl derivative of uridine, uridine phosphate, or cytidine-5'-diphosphocholine (CDP-choline). Furthermore, patent [1] describes a pharmaceutical composition for improving intelligence in a subject, which comprises: (a) a polyunsaturated fatty acid selected from an omega-3 fatty acid or an omega-6 fatty acid, (b) uridine, and (c) a choline salt, wherein in particular embodiments of the invention, uridine is an acyl derivative of uridine, uridine phosphate, or cytidine-5'-diphosphocholine (CDP-choline).

[0007] Also known is an invention disclosed in Russian Patent No. 2603470, published on 27.11.2016 [2], relating to a method for improving the learning ability or memory of a subject, comprising administering to the subject a pharmaceutical composition containing (a) an omega-3 fatty acid, an omega-6 fatty acid, or a combination thereof; (b) uridine, its acyl derivative, uridine phosphate, or cytidine 5-diphosphocholine (CDP-choline), and (c) choline, its metabolic precursor, or a choline salt. Clause 6 of the claims specifies that uridine is an acyl derivative of uridine, uridine phosphate, or cytidine-5'-diphosphocholine (CDP-choline).

[0008] Patent [2] also discloses a pharmaceutical composition for improving learning or memory in a subject, comprising (a) an omega-3 fatty acid, an omega-6 fatty acid, or a combination thereof; (b) uridine; and (c) a choline salt. In particular embodiments of the invention [3], uridine is an acyl derivative of uridine, uridine phosphate, or cytidine-5'-diphosphocholine (CDP-choline).

[0009] Analogues [1] and [2] describe pharmaceutical compositions that improve a subject's intelligence through the synergistic action of the components of the composition, including CDP-choline (citicoline), in increasing brain phospholipid concentrations, but do not affect the glutamatergic system. In contrast, the composition proposed in the present invention, unlike solutions [1] and [2], provides a therapeutic effect not only by increasing brain phospholipid concentrations, but also by modulating the glutamatergic system.

[0010] In addition, an invention is known under Russian Patent No. 2605339, published on 20.12.2016 [3], which describes a medicinal product based on amantadine sulfate for stopping glutamate-induced apoptosis and inhibiting NMDA receptors for the treatment of nervous system disorders, 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 auxiliary substance selected from the group including stabilizers, prolongators, buffering additives, solvents, fillers, preservatives, in the following ratio of components, wt.%:

[0011] Amantadine sulfate 0.001-0.25

[0012] Cytidine 5'-diphosphocholine 5.0-25.0 Excipient - up to 100.

[0013] The patent also describes the use of the said drug for stopping glutamate-induced apoptosis and inhibiting N-methyl-O-aspartate receptors for the treatment of nervous system disorders, the consequences of traumatic brain injury and ischemic and hemorrhagic stroke.

[0014] Analogue [3] describes a medicinal product for reversing glutamate-induced apoptosis and inhibiting NMDA receptors. The medicinal product according to analogue [3] does not affect the concentration of phospholipids in the brain and spinal cord. In contrast, the solution claimed in the present invention, unlike the medicinal product according to analogue [3], has an additional therapeutic effect by increasing the concentration of phospholipids in the brain and spinal cord.

[0015] The second active ingredient chosen within the framework of the present invention was memantine, or 3,5-dimethyl-1-adamantanamine, a non-competitive antagonist of glutamate NMDA receptors of formula (II), which has a neuromodulatory, antiparkinsonian, neuroprotective and antispasmodic effect, which inhibits glutamatergic neurotransmission and the progression of neurodegenerative processes.

[0016] 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 the Russian Federation Patent No. 2371173, published on October 27, 2009 [4], a method for treating Alzheimer's disease of varying severity, from mild to moderate, is known, which consists in 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 its pharmaceutically acceptable salt, according to [4], is administered at an initial dose of 5 mg per day with an increase of 5 mg per day every week to a final dose of 20 mg per day. Also known from the patent [4] is a method for treating Alzheimer's disease of mild to moderate severity in subjects who have previously been treated with an acetylcholinesterase inhibitor (AChEI), wherein the method consists in administering to a subject in need thereof an effective amount of memantine or a pharmaceutically acceptable salt thereof.[4] describes a method for 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).

[0017] An invention is known from Russian patent No. 2326660, published on June 20, 2008 [5], which describes 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 mixture of powders.

[0018] Also described in the patent [5]:

[0019] - an oral preparation in the form of a solid dosage form containing memantine as an active substance, characterized in that the dosage form is in the form of capsules, wherein memantine is included in a therapeutically effective amount in the composition of the mass filling these capsules, which is a granulate;

[0020] - a method for producing an oral preparation in the form of a solid dosage form containing memantine as an active substance, which consists in sifting, weighing and mixing powders of memantine and auxiliary substances - a disintegrant, an antifriction substance and a carrier - in the following ratios of components, by weight. %: memantine 0.5-10.0 disintegrant 0.2-40.0 antifriction substance 0.2-10.0 filler - the rest, after which the mass in the form of a mixture of powders is filled into capsules; - a method for producing an oral preparation 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 as auxiliary substances, wherein the powders of memantine and the filler or, if necessary, also the powders of the disintegrant and antifriction substance are sifted, weighed and mixed in the specified mass proportions, by weight.%: memantine 0.5-10.0 filler the rest or memantine 0.5-10.0 disintegrant 0.2-40.0 antifriction agent 0.2-10.0 filler the rest, then the mixture of powders is granulated by dry or wet granulation, after which the capsules are filled with the granulate.

[0021] Also known from the prior art is an invention according to Russian Federation Patent No. 2404750, published on 27.11.2010 [6], relating to a pharmaceutical composition containing memantine or its pharmaceutically acceptable salt, intended for use in the treatment of dementia, where said memantine or its pharmaceutically acceptable salt is present in a dosage form with prolonged release and is to be administered without the use of a regimen with an increase in dose, for a pharmaceutical composition containing memantine or its pharmaceutically acceptable salt and a prolonged release component for use in the treatment of dementia, where said treatment leads to a therapeutically effective constant concentration of memantine in the plasma within 20 days from the moment of administration of the composition to the patient, for a pharmaceutical composition in the form of a capsule containing memantine or its pharmaceutically acceptable salt, where said memantine or its pharmaceutically acceptable salt have a ratio of C max / C meanfrom about 2.5 to about 1 at least 6 hours after administration of the composition to the patient, to a pharmaceutical composition comprising an oral extended release preparation comprising: a) memantine and a polymer selected from hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose and polyethylene glycol; and b) a coating comprising an insoluble matrix polymer and a water-soluble substance.

[0022] The prior art also includes an invention according to Russian patent No. 2483715, published on 10.06.2013 [7], relating to an antiparkinsonian agent and to a solid, rapidly disintegrating dosage form containing said agent, wherein said dosage form contains memantine and / or memantine hydrochloride as an active substance and target additives, characterized in that said 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.

[0023] Analogues [5], [6], and [7] describe monodrugs of memantine or its pharmaceutically acceptable salt, memantine hydrochloride. However, the use of memantine or its pharmaceutically acceptable salt as a single therapeutic agent may in some cases be insufficient to achieve an effect across the full range of cognitive impairments associated with forms of dementia other than vascular dementia.

[0024] The prior art also includes an invention according to Russian patent 2390354, published on 27.05.2010 [8], which discloses a matrix-type composition with a delayed release, containing:

[0025] (1) donepezil hydrochloride and / or memantine hydrochloride;

[0026] (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

[0027] (3) a water-insoluble polymer that is at least one selected from the group consisting of ethyl cellulose, aminoalkyl methacrylate RS copolymer, and ethyl acrylate-methyl methacrylate copolymer.

[0028] The patent [8] also discloses a method for producing a matrix-type composition with a delayed release, comprising the steps of: mixing (1) donepezil hydrochloride and / or memantine hydrochloride; (2) an enteric polymer which is at least one selected from the group consisting of a methacrylic acid-ethyl acrylate copolymer, a 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 ethyl cellulose, an aminoalkyl methacrylate RS copolymer and an ethyl acrylate-methyl methacrylate copolymer and compression molding the mixture obtained in the mixing step.

[0029] According to patent [8], memantine hydrochloride is mentioned as a remedy for dementia due to Alzheimer's disease (see patent [8], p. 15 of the description, section "Best mode for carrying out the invention"). At the same time, other areas of application of memantine and its pharmaceutically acceptable salts are also 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).

[0030] When analyzing the market of drugs intended for the treatment of cognitive impairment of vascular origin, possessing neuromodulatory, antiparkinsonian, neuroprotective and antispastic action, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, it becomes obvious that there is a need to create a pharmaceutical composition and a dosage form based on it, ensuring an increase in the therapeutic activity of the declared quantitative and qualitative composition of ingredients (pharmaceutical composition), effective, when administered to a patient in need, for the treatment of cognitive impairment of vascular origin, and also possessing neuromodulatory, antiparkinsonian, neuroprotective and antispastic action, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes.

[0031] The technical results achieved by the claimed group of inventions include:

[0032] - an increase in the therapeutic activity of citicoline or its pharmaceutically acceptable salt due to the supertotal (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 prolonged action of the proposed pharmaceutical composition and dosage form;

[0033] - simplification of the treatment of cognitive impairments of vascular origin due to the use of the pharmaceutical composition and dosage form containing said composition proposed in the present invention;

[0034] - providing a pharmaceutical composition and dosage form of memantine or its pharmaceutically acceptable salt and citicoline or its pharmaceutically acceptable salt, free from side effects, and at the same time stable during manufacture and storage.

[0035] In addition, the technical results achieved by the claimed group of inventions include:

[0036] - increasing the therapeutic activity of the pharmaceutical composition and medicinal product intended for the treatment of cognitive impairment of the vascular 4 9origin, possessing neuromodulatory, antiparkinsonian, neuroprotective and antispastic action, 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 pharmaceutically acceptable salt and citicoline or its pharmaceutically acceptable salt, as well as due to the immediate onset of action of the said drug and subsequent effective and long-lasting action;

[0037] - simplification of the treatment regimen (correction, mitigation or slowing of development) of cognitive impairments of vascular origin,

[0038] - as well as simplification and reduction of the cost of manufacturing a dosage form and pharmaceutical composition intended for the treatment of cognitive impairment of vascular origin, possessing neuromodulatory, antiparkinsonian, neuroprotective and antispasmodic action, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes.

[0039] In addition, the technical result is an increase in the range of pharmaceutical compositions and dosage forms intended for the treatment of cognitive impairment of vascular origin and possessing neuromodulatory, antiparkinsonian, neuroprotective and antispastic effects, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes.

[0040] DISCLOSURE OF THE INVENTION

[0041] The technical results are achieved by the pharmaceutical composition proposed in the present invention, intended for the treatment of cognitive disorders of vascular origin, having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, comprising 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, manufactured on the basis of the above pharmaceutical composition, including as active ingredients memantine or its pharmaceutically acceptable salt 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, made in the form of a modified-release tablet, coated with a film coating.Also a technical result relating to simplification and. the cost price 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.

[0042] 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 contain auxiliary components, including a pharmaceutically acceptable filler, hydroxypropyl methylcellulose, colloidal silicon dioxide and a pharmaceutically acceptable lubricant.

[0043] In preferred (non-limiting) embodiments of the invention, the pharmaceutically acceptable filler 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, the pharmaceutically acceptable filler is microcrystalline cellulose.

[0044] Also, in preferred (non-limiting) embodiments of the invention, the pharmaceutically acceptable lubricant is a pharmaceutically acceptable salt of stearic acid, such as (but not limited to) magnesium stearate or calcium stearate. One skilled in the art will recognize that other pharmaceutically acceptable lubricants, including other pharmaceutically acceptable salts of stearic acid, may also be used.

[0045] According to 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 as a pharmaceutically acceptable salt of an inorganic acid, such as memantine hydrochloride, memantine hydrobromide, memantine sulfate, memantine hydrogen sulfate, and memantine dihydrogen sulfate, etc. In other (non-limiting) embodiments of the present invention, memantine can be used in the form of a pharmaceutically acceptable salt of an organic acid, such as memantine oxalate, memantine citrate, memantine succinate, memantine maleate, memantine fumarate, memantine malate, memantine tartrate, etc., or in the form of a sulfonate, such as (without limitation) 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.

[0046] Most preferably (without limitation), memantine according to the present invention is used in the form of memantine hydrochloride.

[0047] 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 particular (non-limiting) embodiments of the present invention, citicoline can also be used in the form of a pharmaceutically acceptable salt of an inorganic acid, such as hydrochloric or phosphoric acid, or in the form of a pharmaceutically acceptable salt of an organic acid, such as acetic, oxalic, tartaric, mandelic, etc. acids, as well as in the form of a pharmaceutically acceptable salt formed by free carboxyl groups with inorganic ions, including sodium, potassium, ammonium, calcium, iron hydroxides, as well as with organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine and

[0048] Etc. Most preferably (without limitation), citicoline according to the present invention is used in the form of the monosodium salt of citicoline (also referred to herein as citicoline monosodium).

[0049] According to the method proposed in the present invention, a lubricant, citicoline or a pharmaceutically acceptable salt thereof, memantine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable filler, hydroxypropyl methylcellulose, colloidal silicon dioxide, are sifted through a sieve with a mesh diameter of no more than 0.5 mm, then citicoline monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose are loaded into a mixer-granulator or a similar mixing device, mixed until a homogeneous state 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, the mixture is moistened with purified water, while the mixing speed should be in the range of 150-400 rpm, and the mixing time is no more than 5 minutes, after which the resulting granulate is subjected to drying in a fluidized bed with maintaining the following parameters: inlet air temperature of 45-65 ° C,residual moisture content of the granulate is 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 powdered with colloidal silicon dioxide for 3 to 5 minutes, then part of the hydroxypropyl methylcellulose is added to the mixture, mixed for another 8 to 10 minutes, then magnesium stearate is added and mixed for another 2-3 minutes. The resulting mixture for tableting is subjected to tableting on a rotary tablet press, using a pressing tool with a diameter of 10 to 15 mm, the tableting process is controlled by the following parameters: hardness - 150-290 N, friability - no more than 1.0%, height - no more than 7.0 mm, then a film coating I is applied to the resulting tablet cores, which is a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol; during the process of dissolving the film coating I, 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 periodic mixing, including in the coater drum, then a solution of film coating II is prepared from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide, after obtaining a solution of the film-forming agent, thus obtaining film coating II. Film coating II is applied to the tablets over film coating I under the same conditions as film coating I.

[0050] 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, conversely, 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.

[0051] In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is commercially available microcrystalline cellulose grade 101. 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, such as (without limitation) hypromellose type 2208 (K100M) or the like. Finally, in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200.

[0052] Technical results are also achieved in the present invention by the fact that a pharmaceutical composition is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of ingredients, effective for the treatment of cognitive impairment of vascular origin, possessing neuromodulatory, antiparkinsonian, neuroprotective and antispastic action, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, comprising 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. An illustrative quantitative and qualitative example of the composition of the pharmaceutical composition is presented in Table 1. Other illustrative examples of the quantitative and qualitative composition of the ingredients of the pharmaceutical composition are presented in Table 2. A person 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 the claims.

[0053] Table 1. Quantitative and qualitative composition of the ingredients of the pharmaceutical composition

[0054] In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose. One skilled in the art will appreciate that other grades of microcrystalline cellulose with similar characteristics may be used, such as grades 105, 102, 103, 302, 200, 50 M, 90 M, or similar microcrystalline cellulose.

[0055] Preferably (without limitation), the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with a molecular weight of 1,000,000. Most preferably (also without limitation), the hydroxypropyl methylcellulose is hypromellose type 2208 (K100M). One skilled in the art will understand that other types of hydroxypropyl methylcellulose having similar characteristics can also be used, for example, hypromellose type 2208 K100M DC, K200M or the like. Also, in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other types of colloidal silicon dioxide having similar characteristics can also be used, for example, colloidal silicon dioxide grade A 300, A 380, R 972 or the like.

[0056] Also in a preferred (non-limiting) embodiment of the invention,’ ' film-coating 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, film-coating I is made from the commercially available mixture "Opadry 03F180011 white". It is clear to a person skilled in the art that other commercially available mixtures for the production of film-coatings with similar characteristics can also be used for film-coating I, for example, Opadry based on hydroxypropyl methylcellulose, including other auxiliary components in its composition or similar, as well as Opadry II based on hydroxypropyl methylcellulose, including other auxiliary components in its composition or similar.

[0057] Also in a preferred (non-limiting) embodiment of the invention, the film shell II is made from a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

[0058] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". One skilled in the art will appreciate that other commercially available mixtures for the production of film coatings with similar characteristics can also be used for film coating II, for example, Opadry based on polyvinyl alcohol, including other auxiliary components or similar, as well as Opadry II based on hydroxypropyl methylcellulose, including other auxiliary components or similar.

[0059] Also, the above-mentioned technical results are achieved in the present invention by the fact that a pharmaceutical composition is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of ingredients, effective for the treatment of cognitive disorders of vascular origin, possessing a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, made in the form of a film-coated tablet and including 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.%:

[0060] Citicoline monosodium salt 65.95-69.95

[0061] Memantine hydrochloride 0.67-2.50

[0062] Microcrystalline cellulose 0.63-5.13

[0063] Hydroxypropyl methylcellulose

[0064] 17.23-17.80

[0065] Colloidal silicon dioxide 0.91-1.0 Magnesium stearate 0.91-1.0

[0066] Film shell I

[0067] 5.18-5.33

[0068] Film shell II

[0069] 2.85-3.2

[0070] In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is microcrystalline cellulose grade 101. 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 types of hydroxypropyl methylcellulose with similar characteristics can also be used.

[0071] Also, in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used.

[0072] Also in a preferred (non-limiting) embodiment of the invention, film coating I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide, and macrogol. In a most preferred (non-limiting) embodiment of the invention, film coating I is made from the commercially available mixture "Opadry 03F180011 white."

[0073] Also in a preferred (non-limiting) embodiment of the invention, the film shell II is made from a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

[0074] In the most preferred (non-limiting) embodiment of the invention, the film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple".

[0075] It will be clear to a person skilled in the art that other commercially available mixtures well known to a person skilled in the art can be used for both film coating I and film coating II.

[0076] Also, the above-mentioned technical results are achieved in the present invention by the fact that a pharmaceutical composition is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of ingredients, effective for the treatment of cognitive disorders of vascular origin, possessing a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of 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:

[0077] Citicoline or its pharmaceutically acceptable 450-550 salt

[0078] Memantine or its pharmaceutically acceptable 5-20 salt

[0079] Microcrystalline cellulose 5-35

[0080] Hydroxypropyl methylcellulose

[0081] 120.5-140.6

[0082] Colloidal silicon dioxide 6, 8-7.2 Magnesium stearate 6, 8-7.2

[0083] Film shell I

[0084] 36.4-41.5

[0085] Film shell II

[0086] 21.8-24.5

[0087] In a preferred (non-limiting) embodiment of the present invention, the pharmaceutically acceptable salt of citicoline is citicoline monosodium salt. Also, in a preferred (non-limiting) embodiment of the present invention, the pharmaceutically acceptable salt of memantine is memantine hydrochloride.

[0088] In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is microcrystalline cellulose grade 101. 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 types of hydroxypropyl methylcellulose with similar characteristics can also be used.

[0089] Also, in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used.

[0090] Also in a preferred (non-limiting) embodiment of the invention, film coating I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide, and macrogol. In a most preferred (non-limiting) embodiment of the invention, film coating I is made from the commercially available mixture "Opadry 03F180011 white."

[0091] Also in a preferred (non-limiting) embodiment of the invention, the film shell II is made from a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

[0092] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by those skilled in the art that other commercially available mixtures well known to those skilled in the art can be used for both film coating I and film coating II.

[0093] Table 2. Examples of quantitative and qualitative composition of ingredients of a pharmaceutical composition

[0094] In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

[0095] 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 types of hydroxypropyl methylcellulose with similar characteristics may also be used.

[0096] Also, in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used.

[0097] Also in a preferred (non-limiting) embodiment of the invention, film coating I is made of a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide, and macrogol. In a most preferred (non-limiting) embodiment of the invention, film coating I is made of the commercially available mixture "Opadry 03F180011 white." Also in a preferred (non-limiting) embodiment of the invention, film coating II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides, and titanium dioxide.

[0098] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by those skilled in the art that other commercially available mixtures well known to those skilled in the art may be used for both film coating I and film coating II.

[0099] The technical result is also achieved in that, based on the above pharmaceutical composition, an oral solid dosage form is proposed, providing an increase in the therapeutic activity of the quantitative and qualitative composition of ingredients, effective for the treatment of cognitive disorders of vascular origin, having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including as active ingredients from 5.00 to 20.00 mg of memantine or its pharmaceutically acceptable salt, such as memantine hydrochloride, and from 450 to 550 mg of citicoline or its pharmaceutically acceptable salt, such as citicoline monosodium salt, wherein said oral solid dosage form is made in the form of a modified-release tablet, coated with a film coating.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:.

[0100] Table 3. Quantitative and qualitative composition of the ingredients of the dosage form per 1 tablet:

[0101] Table 4. Examples of the quantitative and qualitative composition of the ingredients of the dosage form per 1 tablet:

[0102] In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

[0103] 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 types of hydroxypropyl methylcellulose with similar characteristics may also be used.

[0104] Also, in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used.

[0105] Also in a preferred (non-limiting) embodiment of the invention, film coating I is made of a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide, and macrogol. In a most preferred (non-limiting) embodiment of the invention, film coating I is made of the commercially available mixture "Opadry 03F180011 white." Also in a preferred (non-limiting) embodiment of the invention, film coating II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides, and titanium dioxide.

[0106] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by those skilled in the art that other commercially available mixtures well known to those skilled in the art may be used for both film coating I and film coating II.

[0107] Also, the technical results are achieved in the present invention by the fact that an oral solid dosage form is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of ingredients, effective for the treatment of cognitive disorders of vascular origin, possessing a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, including as active ingredients memantine or its pharmaceutically acceptable salt, 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, wherein the said oral solid dosage form is 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, May. %:

[0108] Citicoline or its pharmaceutically acceptable 65.95-69.95 salt

[0109] Memantine or its pharmaceutically acceptable 0.67-2.50 salt

[0110] Microcrystalline cellulose 0.63-5.13

[0111] Hydroxypropyl methylcellulose 17.23-17.80

[0112] Colloidal silicon dioxide 0.91-1.0 Magnesium stearate 0.91-1.0

[0113] Film shell I

[0114] 5.18-5.33

[0115] Film shell II

[0116] 2.85-3.2

[0117] In a 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.

[0118] Also in a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

[0119] 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 types of hydroxypropyl methylcellulose with similar characteristics may also be used.

[0120] Also, in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is grade A 200 colloidal silicon dioxide. One skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used. Also, in a preferred (non-limiting) embodiment of the invention, 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, film coating I is made of the commercially available mixture "Opadry 03F180011 white".

[0121] Also in a preferred (non-limiting) embodiment of the invention, the film shell II is made from a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

[0122] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by those skilled in the art that other commercially available mixtures well known to those skilled in the art may be used for both film coating I and film coating II.

[0123] Also, the technical results are achieved in the present invention by the fact that an oral solid dosage form is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of ingredients, effective for the treatment of cognitive disorders of vascular origin, possessing a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the 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, 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, mg:

[0124] Citicoline or its pharmaceutically acceptable 450-550 salt

[0125] Memantine 5-20 or its pharmaceutically acceptable salt Microcrystalline cellulose 5-35

[0126] Hydroxypropyl methylcellulose

[0127] 120.5-140.6

[0128] Colloidal silicon dioxide 6, 8-7.2 Magnesium stearate 6, 8-7.2

[0129] Film shell I

[0130] 36.4-41.5

[0131] Film shell II

[0132] 21.8-24.5

[0133] In a 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.

[0134] Also in a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

[0135] 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 understand that other types of hydroxypropyl methylcellulose with similar characteristics can also be used. Also in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used. Also in a preferred (non-limiting) embodiment of 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, film coating I is made from the commercially available mixture "Opadry 03F 180011 white". Also in a preferred (non-limiting) embodiment of the invention, film coating II is made from a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

[0136] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by those skilled in the art that other commercially available mixtures well known to those skilled in the art may be used for both film coating I and film coating II.

[0137] Table 4. Examples of the quantitative and qualitative composition of the ingredients of the dosage form per 1 tablet: In a preferred (non-limiting) embodiment of the invention, the microcrystalline cellulose is grade 101 microcrystalline cellulose.

[0138] 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 types of hydroxypropyl methylcellulose with similar characteristics may also be used.

[0139] Also, in a preferred (non-limiting) embodiment of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used.

[0140] Also in a preferred (non-limiting) embodiment of the invention, film coating 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, film coating I is made from a commercially available mixture of "Opadry 03F180011 white".

[0141] Also in a preferred (non-limiting) embodiment of the invention, the film shell II is made from a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

[0142] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by those skilled in the art that other commercially available mixtures well known to those skilled in the art may be used for both film coating I and film coating II.

[0143] The technical result relating to the simplification and reduction of the cost of a dosage form and a pharmaceutical composition intended for the treatment of cognitive disorders of vascular origin, having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, is also achieved in the present invention by the fact that a method for producing a dosage form based on a pharmaceutical composition is proposed, 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 mesh diameter of no more than 0.5 mm, then citicoline monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose are loaded into a mixer-granulator or a similar mixing device,mixed until smooth at a mixing speed of 160-240 rpm and a mixing time in the range from 2 to 10 minutes, then with constant stirring for no more than 5 minutes at a mixing speed of 150 to 400 rpm, moisten the mixture with purified water, after which the resulting granulate is dried in a fluidized bed while maintaining the following parameters: inlet air temperature of 45-65 ° C, residual moisture content of the granulate from 2.5 to 4.5%, then the resulting mixture is powdered with colloidal silicon dioxide, then the resulting mixture is tableted on a rotary tablet press using a pressing 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 on the obtained tablet cores are coated with a mixture of hydroxypropyl methylcellulose during the dissolution of the film coating,titanium dioxide and macrogol, the pharmaceutical substance memantine hydrochloride is added in portions 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 periodic mixing, including in the coater drum, then a film-coating solution is prepared from a mixture of 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 per 1 tablet is presented in Table 3. Preferred (non-limiting) examples of the quantitative and qualitative composition of the ingredients of the dosage form per 1 tablet are presented in Table 4:,

[0144] 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, having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, is also achieved by the fact that within the framework of the present invention a method for obtaining a dosage form based on a pharmaceutical composition is proposed that provides an increase in the therapeutic activity of the quantitative and qualitative composition of ingredients, effective for the treatment of cognitive disorders of vascular origin, and also having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative 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 citicoline or its pharmaceutically acceptable salt, microcrystalline cellulose and hydroxypropyl methylcellulose are loaded into a mixer-granulator or similar mixing device, mixed until a homogeneous state 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 purified water, while the mixing speed should be in the range of 150-400 rpm, and the mixing time is no more than 5 minutes, after which the resulting granulate is subjected to drying in a fluidized bed while maintaining the following parameters: inlet air temperature of 45-65 ° C, residual moisture content of the granulate from 2.5 to 4.5%,then the resulting mixture is powdered with colloidal silicon dioxide, then the resulting mixture is subjected to tableting on a rotary tablet press, using a pressing 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 coating is applied to the resulting tablet cores, in the process of dissolving the film coating of the mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol, the pharmaceutical substance memantine or its pharmaceutically acceptable salt 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 periodic mixing, including in the coater drum, then a film-forming solution for the film coating II is prepared from a mixture of polyvinyl alcohol, talc, macrogol, iron and titanium oxides dioxide,After obtaining the film-forming solution for film coating II, it is applied to the tablets under the same conditions as the previous coating, with the following quantitative and qualitative composition of the ingredients of the dosage form per 1 tablet, wt. %:,

[0145] Citicoline or its pharmaceutically acceptable 65.95-69.95 salt

[0146] Memantine or its pharmaceutically acceptable 0.67-2.50 salt

[0147] Microcrystalline cellulose 0.63-5.13

[0148] Hydroxypropyl methylcellulose

[0149] 17.23-17.80

[0150] Colloidal silicon dioxide 0.91-1.0 Magnesium stearate 0.91-1.0

[0151] Film shell I

[0152] 5.18-5.33

[0153] Film shell II 2.85-3.2

[0154] In a 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.

[0155] In a preferred (non-limiting) embodiment of the method according to the invention, the microcrystalline cellulose is microcrystalline cellulose grade 101.

[0156] Also, in a preferred (non-limiting) embodiment of the method 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 types of hydroxypropyl methylcellulose with similar characteristics can also be used.

[0157] 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. A person skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used.

[0158] Also, in a preferred (non-limiting) embodiment of the method of the invention, film coating I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide, and macrogol. In a most preferred (non-limiting) embodiment of the invention, film coating I is made from the commercially available mixture "Opadry 03F180011 white."

[0159] Also in a preferred (non-limiting) embodiment of the method according to the invention, the film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

[0160] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by those skilled in the art that other commercially available mixtures well known to those skilled in the art may be used for both film coating I and film coating II.

[0161] The technical result related to the simplification and reduction of the cost of a dosage form and a pharmaceutical composition intended for the treatment of cognitive disorders of vascular origin, having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, is also achieved by the fact that within the framework of the present invention a method is proposed 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 ingredients, effective for the treatment of cognitive disorders of vascular origin, and also having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes,comprising from 5 to 20 mg of memantine or its pharmaceutically acceptable salt, for example, memantine hydrochloride, and from 450 to 550 mg of citicoline or its pharmaceutically acceptable salt, for example, citicoline monosodium, wherein, 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 no more than 0.5 mm, then citicoline monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose are loaded into a mixer-granulator or similar mixing device, mixed 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, the mixture is moistened with purified water, while the mixing speed should be in the range of 150-400 rpm,and the mixing time is no more than 5 minutes, after which the resulting granulate is dried in a fluidized bed while maintaining the following parameters: inlet air temperature of 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 powdered with colloidal silicon dioxide for 3 to 5 minutes, then part of the hydroxypropyl methylcellulose is added to the mixture, mixed for another 8 to 10 minutes, then magnesium stearate is added and mixed for another 2-3 minutes. The resulting mixture for tableting is subjected to tableting on a rotary tablet press, using a pressing 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 coating is applied to the resulting core tablets, in the process of dissolving the film coating of the hydroxypropyl methylcellulose mixture,titanium dioxide and macrogol, the pharmaceutical substance memantine hydrochloride is added in portions 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 periodic mixing, including in the coater drum, then a film coating solution is prepared from a mixture of 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, with the following quantitative and qualitative composition of the ingredients of the dosage form per 1 tablet, mg:,

[0162] Citicoline or its pharmaceutically acceptable 450-550 salt

[0163] Memantine or its pharmaceutically acceptable 5-20 salt

[0164] Microcrystalline cellulose 5-35

[0165] Hydroxypropyl methylcellulose

[0166] 120.5-140.6

[0167] Colloidal silicon dioxide 6, 8-7,2 Magnesium stearate 6, 8-7, 2 Film coating I

[0168] 36.4-41.5

[0169] Film shell II

[0170] 21.8-24.5

[0171] In a 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.

[0172] In a preferred (non-limiting) embodiment of the method according to the invention, the microcrystalline cellulose is microcrystalline cellulose grade 101.

[0173] Also, in a preferred (non-limiting) embodiment of the method 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 types of hydroxypropyl methylcellulose with similar characteristics can also be used.

[0174] 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. A person skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used.

[0175] Also, in a preferred (non-limiting) embodiment of the method of the invention, film coating I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide, and macrogol. In a most preferred (non-limiting) embodiment of the invention, film coating I is made from the commercially available mixture "Opadry 03F180011 white."

[0176] Also in a preferred (non-limiting) embodiment of the method according to the invention, the film shell II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

[0177] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by those skilled in the art that other commercially available mixtures well known to those skilled in the art may be used for both film coating I and film coating II.

[0178] In addition, the technical results are also achieved in the present invention by the fact that a medicinal preparation in the form of a modified-release tablet is proposed, comprising citicoline or a pharmaceutically acceptable salt thereof and memantine or a pharmaceutically acceptable salt thereof as pharmaceutical substances, microcrystalline cellulose as a filler, hypromellose as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, a film coating as an insulating coating (Film coating I), a protective coating (Film coating II) and a carrier (Film coating 1a), with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, wt.%: In a 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.

[0179] Also in a preferred (non-limiting) embodiment of the medicinal product (modified release tablet) according to the invention, the microcrystalline cellulose is microcrystalline cellulose grade 101.

[0180] 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 types of hydroxypropyl methylcellulose with similar characteristics can also be used.

[0181] Also, in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) according to the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. A person skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used.

[0182] Also, in a preferred (non-limiting) embodiment of the medicinal product (modified-release tablet) of the invention, film coating I is made from a commercially available mixture of hydroxypropyl methylcellulose, titanium dioxide, and macrogol. In a most preferred (non-limiting) embodiment of the invention, film coating I is made from the commercially available mixture "Opadry 03F180011 white."

[0183] Also, in a preferred (non-limiting) embodiment of the medicinal product (modified-release tablet) 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 coating II is made of the commercially available mixture "Opadry II 85F 200062 purple". It will be clear to those skilled in the art that other commercially available mixtures well known to those skilled in the art can be used for both film coating I and film coating II.

[0184] In addition, the technical results of the present invention are also achieved by the fact that a medicinal product is proposed, made in the form of a modified-release tablet, comprising 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, a film coating as a coating and a carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, mg:

[0185]

[0186] 42

[0187] In a 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.

[0188] In a preferred (non-limiting) embodiment of the medicinal product (modified release tablet) according to the invention, the microcrystalline cellulose is microcrystalline cellulose grade 101.

[0189] 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 types of hydroxypropyl methylcellulose with similar characteristics can also be used.

[0190] Also, in a preferred (non-limiting) embodiment of the medicinal product (modified-release tablets) of the invention, the colloidal silicon dioxide is colloidal silicon dioxide grade A 200. One skilled in the art will understand that other types of colloidal silicon dioxide with similar characteristics can also be used. Also, in a preferred (non-limiting) embodiment of the medicinal product (modified-release tablets) of 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 coating I is made of the commercially available mixture "Opadry 03F180011 white".

[0191] Also in a preferred (non-limiting) embodiment of the medicinal product (modified release tablets) according to the invention, the film coating II is made of a commercially available mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

[0192] In the most preferred (non-limiting) embodiment of the invention, film coating II is made from the commercially available mixture "Opadry II 85F 200062 purple". It will be understood by those skilled in the art that other commercially available mixtures well known to those skilled in the art may be used for both film coating I and film coating II.

[0193] Table 5. Examples of the quantitative and qualitative composition of ingredients per 1 tablet, including memantine hydrochloride (equivalent to 5 mg of memantine base) and sodium citicoline (equivalent to 500 mg of citicoline base) as active ingredients.

[0194] In addition, the technical results of the present invention are also achieved by the fact that a medicinal preparation in the form of a modified-release tablet is proposed, comprising citicoline or a pharmaceutically acceptable salt thereof, for example, sodium citicoline, 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, a film coating as a coating and a carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, wt.%:

[0195] In addition, the technical results of the present invention are also achieved by the fact that a medicinal preparation in the form of a modified-release tablet is proposed, comprising citicoline or a pharmaceutically acceptable salt thereof, for example, sodium citicoline 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, a film coating as a coating and a carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, mg: Table 6. Examples of the quantitative and qualitative composition of ingredients per 1 tablet, including memantine in the amount of 10 mg and citicoline in the amount of 500 mg as active ingredients.

[0196] In addition, the technical results of the present invention are also achieved by the fact that a method is proposed for producing a medicinal product in the form of a modified-release tablet containing sodium citicoline and memantine hydrochloride as active ingredients, as well as microcrystalline cellulose as a filler, hypromellose as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, a film coating as a coating and carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, mg: characterized in that the said method includes: sifting the raw material, in which magnesium stearate is sifted manually through a 0.5 mm sieve, the residue on the sieve is rubbed manually, then sodium citicoline is sifted on a sifting machine, for example, on a CISA RP 200 N vibrating sieve through a 0.50 mm sieve, while 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 are sifted, 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 humectant solution, where purified water is used as a humectant solution, and the amount of purified water is calculated depending on the mass of the dry mixture at a mixture to water ratio of 3.4: 1, the process of preparing a mixture for tableting, in which sifted sodium citicoline, microcrystalline cellulose, for example, sifted 101 marking, and hypromellose, including type 2208, are loaded into a mixer-granulator, then the components are mixed until a homogeneous state is achieved under visual control, while the mixing parameters depend on the volume of the laboratory batch.

[0197] In particular,

[0198] Parameters for a laboratory batch of 500 tablets:

[0199] Bowl volume: 3.0 l.

[0200] Mixing speed: 200.0 rpm.

[0201] The mixing time is 120 sec, then the granulation process is carried out, during which, with constant mixing of the mixture in the mixer-granulator, a moisturizer solution is added, mixing is carried out until a fine crumbly granulate is formed (visual control), the granulation parameters depend on the volume of the laboratory series, including,

[0202] Parameters for a laboratory batch of 500 tablets:

[0203] Stirring speed: 200.0-350.0 rpm.

[0204] The mixing time is 60 sec, then the granulate is dried, where the granulate is dried in a drying cabinet (fluidized bed dryer), the parameters of the drying process depend on the equipment used and the volume of the laboratory series, including,

[0205] Parameters for a laboratory batch of 500 tablets: Inlet air temperature 50-65°C. Drying time 3-6 hours.

[0206] The residual moisture content of the granulate is from 2.5 to 4.5%, after which the granulate is calibrated, namely, the granulate is sieved, for example, on a CIS A RP 200 N vibrating sieve through a 1.0 mm (0.710 mm) sieve, and the residue is rubbed through a 1.0 mm (0.710 mm) sieve manually, then powdering is carried out, in which the granulate and sieved colloidal silicon dioxide are added to the mixer, mixing is carried out until a homogeneous state (visual control), the mixing parameters depend on the type of equipment and the volume of the laboratory series, including,

[0207] Parameters for a laboratory batch of 500 tablets:

[0208] Bowl volume: 3.0 l

[0209] The mixing time is 300 sec, and if there are colloidal silicon dioxide agglomerates, it is permissible to sift the mixture through a 1.0 mm sieve; the colloidal silicon dioxide agglomerates are rubbed through the sieve manually. Hypromellose, including type 2208, is added to the mixer, sifted, and mixing is continued until a homogeneous state is achieved (visual control). The mixing parameters depend on the type of equipment and the volume of the laboratory batch, including,

[0210] Parameters for a laboratory batch of 500 tablets:

[0211] Bowl volume: 3.0 l

[0212] Mixing time is 600 sec, sieved magnesium stearate is loaded into the mixer and the components are mixed until a homogeneous state is achieved (visual control), the mixing parameters depend on the type of equipment and the volume of the laboratory batch, including,

[0213] Parameters for a laboratory batch of 500 tablets:

[0214] Bowl volume: 3.0 l

[0215] The mixing time is from 120 to 180 sec, the mixture for tableting is unloaded into a marked container, a representative sample is taken for control, according to the specification, then the tableting process is carried out, which is carried out on a tablet press, for example (without limitation), Futorque X-1, the tableting process is carried out on a round pressing tool with a geometry of 12.00 mm, at the beginning of the process, the tablet press is adjusted to produce tablets with an average weight, including 700.0 mg.After setting the average tablet weight, adjust the tablet press for the remaining parameters: 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 the tablet press, carry out the tableting process until the tableting mixture is completely consumed, during the tableting process, at least once every 10 minutes, check: average tablet weight; tablet hardness.

[0216] During the tableting process, the tablets are collected in labeled containers; after the process is completed, the containers are closed, a representative selection of tablets is carried out to carry out an intermediate control according to the specification, then the film coating process of the tablets is carried out, which includes the preparation of ‘film suspension, namely, in the process of applying the film coating, an 18% film suspension is used, stirring of purified water is established so that a funnel is formed on the surface of the water, a dry film coating is gradually added, preventing the formation of agglomerates on the surface of the solution, then the stirring speed is reduced so that foaming does not occur, and the solution is left to stir for 45 minutes, then the coating is applied, which is carried out on a coater of a modular unit, for example, BOSCH Solidlab 1, before the coating process, the tablets are heated to 37-39 ° C with periodic mixing in the drum of the coater, upon reaching the temperature of the tablets, spraying of the film suspension begins, the coating 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 mass of tablets is reached, the process is stopped and the tablets are cooled to a temperature not exceeding 33 °C. After the process is completed, 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 including the pharmaceutical substance memantine hydrochloride is carried out, in the process of applying the film coating, a 15% film suspension is used, for example, such as Opadry 03F180011 or Opadry II 85F200062, stirring of purified water is established so that a funnel is formed on the surface of the water, the pharmaceutical substance memantine hydrochloride is added, sifted and mixed until completely dissolved under visual control, then the dry film coating is gradually added, preventing the formation of agglomerates on the surface of the solution, then the stirring speed is reduced 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 unit, which is carried out on the coater of the modular unit, including BOSCH Solidlab 1, before the coating process, heat the tablets to 37-39 ° C with periodic mixing in the coater drum; when the tablet temperature is reached, spraying of the film suspension begins. The coating 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 of the 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, the coated tablets are stored in closed containers,then the process of coating the tablets with the final shell is carried out, in the process of applying the film coating, an 18% film suspension is used, stirring of purified water is established so that a funnel is formed on the surface of the water, a dry film coating is gradually introduced, preventing the formation of agglomerates on the surface of the solution, then the stirring speed is reduced so that foaming does not occur, and the solution is left to stir for at least 45 minutes, the coating is applied on a coater of a modular unit, for example, BOSCH Solidlab 1, before the process of applying the coating, the tablets are heated to 35-45 ° C with periodic stirring in the drum of the coater, upon reaching the temperature of the tablets, spraying of the film suspension begins, the coating 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 process of applying the coating is carried out until the average weight of the tablets is obtained, including,747.00 mg / 772.00 mg, when the specified tablet weight is reached, the process is stopped and the tablets are cooled to a temperature not exceeding 33 °C, after the process is completed, 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, packaging of film-coated tablets is carried out by placing, for example, in a PVC / Alu blister on an automatic blister machine DPP260ki-2, blister cell forming parameters:,

[0217] Pressure - 6 bar;

[0218] Forming temperature - 110 - 120°C

[0219] Sealing parameters:

[0220] Sealing temperature - 130 - 140°C;

[0221] Pressure - 6 bar;

[0222] Speed ​​- 18 cycles / min;

[0223] The coolant temperature is 10°C, after which the blisters are checked for leaks using, for example, an Erweka VDT / S tester. The first and last blisters received are subject to mandatory leak testing.

[0224] A comparative study of the specific pharmacological activity of the pharmaceutical composition proposed in the present invention, in comparison with the monodrug citicoline, was conducted on a model of ischemic stroke in rats. For this purpose, based on the guidelines for conducting preclinical studies edited by A.N. Mironov [9], a model of global transient cerebral ischemia was chosen using ligation of the common carotid arteries. Long-term memory was assessed using the Morris water maze test (Morris R., "J Neurosci Methods", 1984, Vol. 11, No. 1. - P. 47-60

[0010] ).

[0225] Table. Effect of the studied drugs on long-term memory in rats in the Morris water maze test. Surprisingly, the addition of memantine, a known treatment for Alzheimer's-type cognitive impairment (dementia), to therapy resulted in significant neuroprotective and procognitive effects in the correction of cognitive impairment caused by a completely different cause, namely, ischemia. Treatment with the study drugs facilitated successful skill recall during the long-term memory assessment phase. A significant reduction in the latency period (LP) for finding the target sector (compared to untreated animals with the pathology) was observed in all groups receiving the pharmaceutical composition proposed in the present invention, regardless of the drug dose. In the groups receiving Citicoline or Memantine, a similar effect was observed only in the group receiving the drug at the maximum studied doses.

[0226] The above examples illustrate, but do not limit, the application of the compositions and methods of the claimed inventions. The developed pharmaceutical compositions, as well as the proposed dosage form, manufactured by the described method based on the proposed compositions, ensure the achievement of the technical results of the present invention: an increase in the therapeutic activity of citicoline or its pharmaceutically acceptable salt by ensuring its supertotal (synergistic) interaction with memantine or its pharmaceutically acceptable salt, as well as due to its immediate onset of action and subsequent effective and prolonged action;simplification of therapy for cognitive impairment of vascular origin, provision of medicinal forms of memantine or its pharmaceutically acceptable salt and citicoline or its pharmaceutically acceptable salt that are free of side effects, stable in production and stable during storage, provision of an accessible and inexpensive method for obtaining medicinal forms of memantine or its pharmaceutically acceptable salt and citicoline or its pharmaceutically acceptable salt.

[0227] The resulting dosage form ensures stability during storage and a virtual absence of side effects.

[0228] Thanks to the proposed inventions, which form the basis for the dosage forms produced using the specified method, it is possible to increase the therapeutic efficacy of the claimed composition by:

[0229] - a modified-release dosage form manufactured on the basis of a pharmaceutical composition,

[0230] - the effective period of action of the dosage form based on the declared composition,

[0231] - by simplifying the dosage form's action pattern. All presented inventions are industrially applicable, have undergone laboratory testing, are feasible for practical implementation, and will find wide application in the pharmaceutical industry. Specifically, the following have been confirmed:

[0232] - the use of the above pharmaceutical composition,

[0233] - use of the proposed dosage form,

[0234] - application of a method for producing the proposed dosage form based on a pharmaceutical composition. Each of the proposed inventions is industrially applicable in the pharmaceutical field, ensures the stability of the stated properties, and maintains stability for at least three years.

[0235] The use of the proposed inventions increases the range of dosage forms.

[0236] 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.

[0237] Thus, the desired technical result has been achieved, the proposed group of inventions, including a pharmaceutical composition having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, intended for the treatment of cognitive disorders 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 ingredients due to the immediate onset of action and due to the effective and long-term action of the composition of ingredients, for the treatment of cognitive disorders of vascular origin, having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes,

[0238] - a dosage form that, upon administration of the said pharmaceutical composition, simplifies the action pattern of the claimed qualitative and quantitative composition of ingredients for the treatment of cognitive impairment of vascular origin, and also has a neuromodulatory, antiparkinsonian, neuroprotective and antispasmodic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes,

[0239] - as well as a method for obtaining the said dosage form based on the proposed pharmaceutical composition, intended for obtaining tablets for the treatment of cognitive disorders of vascular origin, as well as having a neuromodulating, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes. In addition, the technical result is an increase in the range of dosage forms intended for the treatment of cognitive disorders of vascular origin, having a neuromodulating, antiparkinsonian, neuroprotective and antispastic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes.

[0240] The proposed group of inventions is industrially applicable and has been implemented in practice, as evidenced by the provided examples of the 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 a neuromodulatory, antiparkinsonian, neuroprotective and antispasmodic effect, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, and intended for the treatment of cognitive impairment of vascular origin.

[0241] SOURCES OF INFORMATION:

[0242] 1. Russian Federation patent for invention X°2429851 "COMPOSITIONS CONTAINING PUFA AND / OR URIDINE, AND METHODS OF USING THEM", patent holder: "MASSACHUSETTS INSTITUTE OF TECHNOLOGY" (US), published: 09.27.2011, IPC: A61K 31 / 685, A61P 25 / 28.

[0243] 2. Russian Federation patent for invention Xe2603470 "METHOD AND PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF ALZHEIMER'S DISEASE AND MEMORY DISORDERS, IMPAIRMENTS OR LOSS", patent holder: MASSACHUSETTS INSTITUTE OF TECHNOLOGY (US), published: 27.11.2016, IPC: A61K 31 / 685, A61P 25 / 28.

[0244] 3. Russian Federation Patent for invention X°2605339 "AGENT FOR STOPPING GLUTAMATE-INDUCED APOPTOSIS AND INHIBITING NMDA RECEPTORS, HAVING AN IMMUNOMODULATING EFFECT, FOR THE TREATMENT OF NERVOUS SYSTEM DISORDERS, CONSEQUENCES OF TRAUMATIC BRAIN INJURY AND ISCHEMIC AND HEMORRHAGIC STROKE", patent holder: EcoPharmPlus Closed Joint-Stock Company (RU), published: 20.12.2016, IPC: A61K 31 / 7068, A61K 31 / 13, A61K 47 / 48, A61P 9 / 10, A61P 25 / 00.

[0245] 4. Russian Federation patent for invention No. 2371173 "MEMANTINE FOR THE TREATMENT OF MILD AND MILD TO MODERATE ALZHEIMER'S DISEASE", patent holder: "MERZ PHARMA GMBH UND KO. KGAA" (DE), published:

[0246] 27.10.2009, IPC: A61K 31 / 13, A61P 25 / 28.

[0247] 5. Patent of the Russian Federation for invention No. X2326660 “ORAL DRUG MEMANTINE (VARIANTS) AND METHOD FOR ITS PRODUCTION (VARIANTS)”, patent holder: Closed Joint-Stock Company “Biological Research and Systems” (RU), published: 20.06.2008, IPC: A61K 31 / 13, A61K 9 / 48, A61P 25 / 28.

[0248] 6. Russian Federation Patent for invention X°2404750 “COMPOSITION CONTAINING A BASE OR COATING FOR SLOW-RELEASE AND AN NMDA RECEPTOR ANTAGONIST, A METHOD OF ADMINISTRATION OF SUCH NMDA ANTAGONIST TO A SUBJECT”, patent holder: “ADAMAS PHARMACEUTICALS, INC.” (US), published:

[0249] 27.11.2010, IPC: A61K 9 / 20, A61P 25 / 28. 7. Russian Federation patent for invention No. 2483715 "SOLID DOSAGE FORM OF MEMANTINE AND ITS SALTS", patent holder: Limited Liability Company "AKADEMPHARM" (RU), published: 10.06.2013, IPC: A61K 31 / 13, A61K 47 / 38, A61K 9 / 16, A61K 9 / 20, A61P 25 / 16. 8. Russian Federation patent for invention ° 2390354 "MATRIX-TYPE DRUG WITH

[0250] SUSTAINED-RELEASE DRUGS CONTAINING A BASIC DRUG OR ITS SALT, AND A METHOD FOR OBTAINING THEREFORE”, patent holder: “EASAI R&D MANAGEMENT CO., LTD.” (JP), published: 27.05.2010, IPC: A61K 47 / 32, A61K 9 / 26, A61K 31 / 445, A61J 3 / 10. 9. Guidelines for conducting preclinical studies of drugs. Part one / edited by A.N. Mironov - M .: “Grif i K”, 2012. - 944 p.

[0251] 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

CLAUSES OF THE INVENTION 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 or its pharmaceutically acceptable salt in the range of 5-20 mg and citicoline or its pharmaceutically acceptable salt in the range of 450-550 mg.

2. The pharmaceutical composition according to paragraph 1, characterized in that the pharmaceutically acceptable salt of memantine is memantine hydrochloride, and the pharmaceutically acceptable salt of citicoline is citicoline monosodium salt.

3. A pharmaceutical composition having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, 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 Colloidal silicon dioxide 0.91-1.0 Magnesium stearate 0.91-1.0 Film shell I 3:00-7:00 Film shell II 1.00-2.00 4. The pharmaceutical composition according to claim 3, characterized in that the film coating I is made from a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol.

5. The pharmaceutical composition according to claim 3, characterized in that the film coating II is made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

6. A pharmaceutical composition with neuromodulatory, antiparkinsonian, neuroprotective and antispastic action, 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 quantitative and qualitative composition pharmaceutical composition, mg: Citicoline monosodium salt 450-550 Memantine hydrochloride 5-20 Microcrystalline cellulose 5-35 G hydroxypropyl methylcellulose (molecular weight 1,000,000) 120.5-140.6 Colloidal silicon dioxide 6, 8-7.2 Magnesium stearate 6, 8-7.2 Film shell I 36.4-41.5 Film shell II 21.8-24.5 7. The pharmaceutical composition according to paragraph 5, characterized in that the film coating made from a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol.

8. The pharmaceutical composition according to claim 5, characterized in that the film coating II is made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

9. A solid oral dosage form having a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, comprising as active ingredients memantine or its pharmaceutically acceptable salt 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 said dosage form is made in the form of a modified-release tablet, film-coated.

10. A 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 progression neurodegenerative processes, which includes as active ingredients memantine hydrochloride in the range of 5.00-20.00 mg and citicoline monosodium salt in the range of 450-550 mg, characterized in that the said dosage form is made in the form of a modified-release film-coated tablet, with the following quantitative and qualitative composition of the ingredients per 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 Colloidal silicon dioxide 0.91-1.0 Magnesium stearate 0.91-1.0 Film shell I 5.18-5.33 Film shell II 2.85-3.2 11. A solid oral dosage form according to claim 10, characterized in that the film coating I is made from a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol.

12. A solid oral dosage form according to claim 10, characterized in that the film coating II is made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

13. A solid oral dosage form with a neuromodulatory, antiparkinsonian, neuroprotective and antispastic effect, intended for the treatment of cognitive impairment of vascular origin, slowing down and inhibiting glutamatergic neurotransmission and the progression of neurodegenerative processes, comprising as active ingredients memantine hydrochloride in the range of 5.00-20.00 mg and citicoline monosodium salt in the range of 450-550 mg, characterized in that said dosage form is made in the form of a modified-release film-coated tablet, with the following quantitative and qualitative composition of ingredients per 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 Colloidal silicon dioxide 6, 8-7, 2 Magnesium stearate 6, 8-7, 2 Film shell I 36.4-41.5 Film shell II 21.8-24.5 14. A solid oral dosage form according to claim 13, characterized in that the film coating I is made from a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol.

15. A solid oral dosage form according to claim 13, characterized in that the film coating II is made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

16. A method for producing a solid oral dosage form according to any one of paragraphs. 9-15, 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 citicoline monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose are loaded into a mixer-granulator or similar mixing device, mixed until homogeneous for a time of 2 to 10 minutes, at a mixing 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 granules, after which the resulting granules are dried in a fluidized bed while maintaining the following parameters: incoming air temperature of 45-65°C, residual moisture content of the granules from 2,5 to 4.5%, then the resulting mixture is powdered with colloidal silicon dioxide and magnesium stearate, then the resulting mixture is subjected to tableting on a rotary tablet press to obtain tablet cores, using a pressing tool with a diameter of 10 to 15 mm, while the tableting process is controlled by the following parameters: hardness - 150-290 N, friability - no more than 1.0%, height - no more than 7.0 mm, then a film coating I made of a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol is applied to the resulting tablet cores, while in the process of dissolving the film coating I, the pharmaceutical substance memantine hydrochloride is added in parts and mixed until a homogeneous suspension is formed, after which the resulting film coating I is applied to the tablet core at a temperature of the tablet core of 35-40 ° C and periodic stirring, then a solution of film coating II is prepared, made of a mixture of polyvinyl alcohol, talc, macrogol,iron oxides and titanium dioxide, and apply it to tablets under the same conditions as film coating I., 17. The method according to paragraph 16, characterized in that microcrystalline cellulose of grade 101 is used.

18. The method according to paragraph 16, characterized in that colloidal silicon dioxide grade A 200 is used.

19. The method according to paragraph 16, characterized in that the application of the film coating I to the tablet core is carried out in the coating drum.

20. A method for producing a dosage form based on a pharmaceutical composition characterized according to any of paragraphs 1-8, 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 citicoline monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose are loaded into a mixer-granulator or similar mixing device, mixed until homogeneous for a time of 2 to 10 minutes, at a mixing speed of 160-240 rpm, and 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 a granulate, after which the resulting granulate is dried in a fluidized bed while maintaining the following parameters: inlet air temperature of 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 powdered with colloidal silicon dioxide for 3 to 5 minutes, then a portion of hydroxypropyl methylcellulose is added to the mixture, mixed for another 8 to 10 minutes, then magnesium stearate is added and mixed for another 2-3 minutes, thus obtaining a mixture for tableting, then the said mixture is tableted on a rotary tablet press to obtain tablet cores, using a pressing 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 coating I is applied to the obtained tablet cores, during the process of dissolution of film coating I, the pharmaceutical substance memantine hydrochloride is added in portions and mixed until a homogeneous suspension is formed, after which the obtained film coating I is applied to the tablet core at a tablet core temperature of 35-40°C and periodic stirring, then a solution of film coating II is prepared, made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide, and applied to the tablets under the same conditions as film coating I, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, may. %: 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 Colloidal silicon dioxide 0.91-1.0 Magnesium stearate 0.91-1.0 Film shell I 5.18-5.33 Film shell II 2.85-3.2 21. The method according to paragraph 20, characterized in that the application of the film coating I to the tablet core is carried out in the coating drum.

22. The method according to paragraph 20, characterized in that grade 101 microcrystalline cellulose is used as microcrystalline cellulose.

23. The method according to paragraph 20, characterized in that colloidal silicon dioxide grade A 200 is used as colloidal silicon dioxide.

24. A method for producing a dosage form based on a pharmaceutical composition characterized according to any of paragraphs 1 to 8, 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 citicoline monosodium salt, microcrystalline cellulose and hydroxypropyl methylcellulose are loaded into a mixer-granulator or similar mixing device, mixed until homogeneous for a time of 2 to 10 minutes, at a mixing speed of 160-240 rpm, and then with constant stirring for no more than 5 minutes, at a mixing speed of 150-400 rpm.the mixture is moistened with purified water to obtain a granulate, after which the resulting granulate is dried under fluidized bed conditions while maintaining the following parameters: inlet air temperature of 45-65°C, residual moisture content of the granulate from 2.5 to 4.5%, the resulting granulate is sieved through a sieve with a mesh diameter of no more than 1.0 mm, then the resulting mixture is powdered with colloidal silicon dioxide for 3 to 5 minutes, then a portion of hydroxypropyl methylcellulose is added to the mixture, mixed for another 8 to 10 minutes, then magnesium stearate is added and mixed for another 2-3 minutes., thus obtaining a mixture for tableting, then the said mixture is subjected to tableting on a rotary tablet press to obtain tablet cores, using a pressing 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 coating I is applied to the obtained tablet cores, during the process of dissolving the film coating I, the pharmaceutical substance memantine hydrochloride is added in parts and mixed until a homogeneous suspension is formed, after which the obtained film coating I is applied at a tablet core temperature of 35-40 ° C and periodic stirring, then a solution of film coating II is prepared, made from a mixture of polyvinyl alcohol, talc, macrogol, oxides. iron and titanium dioxide, and apply it to tablets under the same conditions as film coating I, with the following quantitative and qualitative composition of the ingredients of the dosage form per 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 Colloidal silicon dioxide 6.8-7.2 Magnesium stearate 6, 8-7,2 Film shell I 36.4-41.5 Film shell II 21.8-24.5 25. The method according to paragraph 24, characterized in that grade 101 microcrystalline cellulose is used as microcrystalline cellulose.

26. The method according to claim 24, characterized in that colloidal silicon dioxide grade A 200 is used as colloidal silicon dioxide.

27. A medicinal product in the form of a modified-release tablet, comprising 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, a film coating as a coating and a carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form, calculated per 1 tablet, wt.%:

28. The medicinal product according to claim 27, characterized in that the film coating I is made from a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol.

29. The medicinal product according to claim 27, characterized in that the film coating II is made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

30. A medicinal product in the form of a modified-release tablet, which contains sodium citicoline 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, and a film coating as a coating and carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form per 1 tablet, mg:

31. The medicinal product according to claim 30, characterized in that the film coating I is made from a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol.

32. The medicinal product according to paragraph 30, characterized in that the film coating II is made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

33. A medicinal product in the form of a modified-release tablet, which contains sodium citicoline 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, a film coating as a coating and carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, wt. %:

34. The medicinal product according to paragraph 33, characterized in that the film coating I is made from a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol.

35. The medicinal product according to paragraph 33, characterized in that the film coating II is made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

36. A medicinal product in the form of a modified-release tablet, comprising sodium citicoline and memantine hydrochloride as a pharmaceutical substances, microcrystalline cellulose as a filler, hypromellose as a matrix agent, colloidal silicon dioxide as a glidant, magnesium stearate as a lubricant, film coating as a coating and carrier, with the following quantitative and qualitative composition of the ingredients of the dosage form in terms of 1 tablet, mg:

37. The medicinal product according to claim 36, characterized in that the film coating I is made from a mixture of hydroxypropyl methylcellulose, titanium dioxide and macrogol.

38. The medicinal product according to claim 36, characterized in that the film coating II is made from a mixture of polyvinyl alcohol, talc, macrogol, iron oxides and titanium dioxide.

39. Use of a pharmaceutical composition according to any of paragraphs 1-8 for the treatment of cognitive impairment of vascular origin.

40. Use of a solid oral dosage form according to any one of claims 9 to 15 for the treatment of cognitive impairment of vascular origin.

41. Use of the method according to any one of claims 16 to 26 for obtaining a dosage form for the treatment of cognitive impairment of vascular origin.