WO2015060746A1 - Combination for treating and/or preventing manifestations of psychiatric, cognitive, behavioral and neurological disorders in the case of organic diseases of the central nervous system having various origins - Google Patents

Abstract

The invention relates to the field of pharmacology and applied medicine, and specifically to the combined application of medicinal preparations which have a neurotrophic effect and which reduce manifestations of psychiatric, behavioral and cognitive disorders in the case of organic damage to the central nervous system having various origins, and also in the presence of manifestations of amyloid intoxication. The pharmaceutical combination contains therapeutically-effective amounts of melatonin and memantine.

Description

 A combination for the treatment and / or prevention of manifestations of mental, cognitive, behavioral and neurological disorders in organic diseases of the central nervous system of various origins

Technical field

The invention relates to the field of pharmacology and practical medicine, namely to the combined use of drugs with a neurotropic effect, facilitating the manifestation of mental, behavioral, cognitive disorders in organic damage to the central nervous system of various origins, as well as with manifestations of amyloid intoxication.

State of the art

It is known ["Endogenous-organic mental illness" - A. Tiganov (ed.)] that psycho-organic disorders occur, for example, against the background of a slowly progressing clinically “strokeless” course of the disease, neurodegenerative diseases, toxic brain damage, brain metabolic damage, brain damage due to the use of psychoactive substances or any other exogenous symptomatic diseases of the central nervous system or as a result of acute cerebrovascular accident.

 For example, the share of the psycho-organic syndrome, which does not reach the degree of dementia, of vascular origin, accounts for 25% of the diagnosed cases of mental pathology in people older than 60 who have turned to a general clinic [Mikhailova N. M., 1996]. In such patients, psycho-organic disorders with torpid phenomena, delayed psychomotor reactions, mild dysmnesthetic disorders, attention disorders can largely be determined and meet the criteria for “mild cognitive impairment” (ICD-10, heading F06.7 “Mild cognitive impairment”).

The presence of an organic psychosyndrome in vascular diseases of the brain is usually indicated when the observed personality changes indicate a more or less pronounced decrease in its level (loss of more subtle and differentiated personal attitudes and behaviors, disinhibition traits of lower drives, etc.). In addition, dysmnestic disorders, orientation inaccuracies (“violation of the internal clock”), a decrease in the productivity of mental activity, criticism and level of judgments, impoverishment and impoverishment of ideas, a decrease in the volume and clarity of perception are found. During hypertensive crises, individual psychotic manifestations, rudimentary, are possible hallucinosis - regarded as transient mental disorders that disappear with a decrease in blood pressure.

 From the list of disorders included in the organic psychosyndrome, the proximity, if not identity, of these conditions with mildly expressed, at the initial stage of their development, symptoms of dementia follows.

The severity of the problem of mental disorders, in particular, of vascular origin, is largely determined by widespread prevalence. In persons over 45 years of age with a history of: hypertension and cerebral arteriosclerosis (Kushakovsky M.S., 1995; Gogin E.E., 1997; Vilensky B.S., 1999; Volkov VS, Pozdnyakov Yu.M. , 1999; Myakotnykh BC et al., 1999; Kuzmenko V.M., 2001; Skvortsova V.I. et al., 2006; Kaplan NM, Lieberman E, 1994; Glassman AH, 1997; Hypertension control, 1997; Gross- Magnat G, 2000; Martin GM, 2000, etc.). These data confirm the significant role of these forms of pathology, as the cause of mental disorders at this age. It was established that in this case, there are signs of organic changes that do not, however, reach the degree of unfolded dementia (Gavrilova SI et al., 1995; Medvedev A.V., 1999; WHO Task Force, 1989; Hachinski V., 1994; Murphy E., Alexopoulos G., 1995, and others). Such a combination is the concept of "psycho-organic syndrome" (Sternberg E.Ya., 1983; Tiganov AS, 1983, 1999; Piven B.N., 1996; Vandysh-Bubko V.V., 2003; Gerts HJ., Anowski S., 1983; Reisberg B., 1986; Schmage N. et al., 1989; Yanagihara T., 1991; Holmes C, et al., 1999; Holland AJ, 2000; Wesnes KA, Harrison JE, 2003, et al.). At the same time, in this condition, a typical combination of cognitive impairment with other psychopathological manifestations, mainly nonpsychotic ones, was noted (Lebedev B.A., 1988; Mikhailova N.M., 1996; Popov Yu.V., Vid V.D., 1997 ; Chelysheva I. A, 1997; Mikhailova N.M., Ladova A.Yu., 1999; Piven B.N. et al., 2006; Finkel SI, 1996; Kurz A., 1998; Lyketsos CG et al, 1999 , and etc.).

The manifestation of manifestations of a psycho-organic syndrome, for example of vascular origin, for the most part, takes place in adulthood, the elderly and senile age (according to the WHO classification) / Melnik EM, 1990; Tibilova A.U., 1991, and others. Which makes it necessary to consider appropriate therapeutic approaches in the context of the general principles of treatment of the corresponding disorders. In this regard, it is important to note that a decrease in the compensatory capabilities in elderly patients contributes to their increased sensitivity to psycho-traumatic and somato-biological effects, which can impede the implementation of the treatment process and reduce its effectiveness (Tibilova A.U., 1990; Tibilova A.U., Melnik E.M., 1993; Finch E., irkwood T., 2000, and others). Over the age of 45 years, similar effects are noted often enough. These include the loss of loved ones with the formation of a situation of loneliness, retirement, reduced physical capabilities, the "accumulation" of chronic somatic diseases (Shakhmatov NF, 1996; Anisimov VN, Soloviev MV, 1999; Shabalin V. N., 1999; Victor K., 1987; Eisendrath SJ, 1992; Murphy E.A., 1994; Arking R, 1998, and others). Moreover, some variants of somatic pathology not only have a direct biological effect on the mental state, but also include a powerful psycho-traumatic factor, since they are regarded by patients as a threat to their physical health and life itself (Krylov V.I. et al., 1985; Neznanov N.G. , 1985; Gnezdilov A.V., 2002, and others).

 Since there is a tendency to increase the life span (the so-called life expectancy), improve medical care, increase the information load and others, including stressful situations, the urgency of the problem of the psycho-organic syndrome is growing.

A separate problem is the rational conduct of pharmacotherapy, taking into account the age of the patients. In this regard, along with the importance of observing the general principles of the use of drugs in therapy, the treatment of patients of late age with specialized means for the correction of both age-related changes and cognitive functions has significant features. Moreover expanding the range of new generation drugs should largely solve the problem of safe psychopharmacotherapy of these age groups.

 The main clinical manifestation of the psycho-organic syndrome, along with a disorder of memory, attention, asthenia, is a specific disorder of the sleep-wake cycle, with a decrease in the level of wakefulness during the day and a disturbance in night sleep. Such a rhythm disorder is a factor both independently impairing the functioning of the patient, and exacerbating other symptoms of the disease.

There is evidence that in the acute and long-term effects of sports head injury (TBI), axon damage causes both regenerative and degenerative reactions in brain tissue and repeated tremors can initiate a long-term neurodegenerative process, causing the so-called boxing dementia or chronic traumatic encephalopathy (CTE). Chronic traumatic encephalopathy is in many ways similar to other neurodegenerative diseases, such as Alzheimer's disease, in particular with regard to the metabolism and aggregation of tau, amyloid beta and TDP-43 (TAR-DNA binding protein) [Neuron. 2012 Dec 6; 76 (5): 886-99. doi: 10.1016 / j.neuron.2012.11.021. The neuropathology and neurobiology of traumatic brain injury. Blennow K, Hardy J, Zetterberg H.]. It is known that in patients with hyperproduction of beta-amyloid, stabilization of the state was facilitated by the use of NSAIDs, in particular indomethacin (Rogers J et al., Clinical trial of indomethacin in Alzheimer's disease Neurology, 1993 Aug; 43 (8): 1609-11).

 The role of cyclooxygenase-1 in beta-amyloid-induced neuroinflammation was also studied, and attempts were made to use COX inhibitors (cyclooxygenase) as protectors for the development of Alzheimer's disease (A role for cyclooxygenase-1 in beta-amyloid-induced neuroinflammation, Eduardo Candelario-Jalario-Jalario-Jalario-Jalario Vol 1, No. 4, pp 350-353).

 In neurodegenerative processes, as well as in cerebral ischemia, an important pathogenetic role is played by hyperactivation of the glutaminergic system. Therefore, the researchers suggested the use of NMDA receptor antagonists to treat mild cognitive impairment.

Despite the numerous studies confirming the usefulness of the use of drugs in the clinical practice of managing patients with organic CNS lesions of various origins, attempts to develop more effective means and methods of treating patients with similar disorders in connection with the growth of diseases accompanied by a whole complex of disorders. AT in particular, attempts have been made to create drug combinations.

 Known patents: EA 007632 "The combination of NMDA antagonist and acetylcholinesterase inhibitors for the treatment of Alzheimer's disease"; EA 008863 "Combination therapy using derivatives of 1-aminocyclohexane and acetylcholinesterase inhibitors"; EA 009668 "IFN-beta alone or in combination with other drugs for the treatment of Alzheimer's disease and disorders associated with dementia"; EA 010430 "The combination of an NMDA receptor antagonist and a selective serotonin reuptake inhibitor for the treatment of depression and other mental disorders." However, these combinations are effective in specific CNS pathologies.

Memantine is a voltage-dependent, medium affinity, non-competitive antagonist of NMDA receptors. Memantine blocks the effects of pathologically elevated levels of glutamate, which can lead to neuronal dysfunction. It has a neuroprotective, antispastic, antiparkinsonian effect. It inhibits glutamatergic neurotransmission and the progression of neurodegenerative processes, has a neuromodulating effect. It contributes to the normalization of mental activity, improves memory, increases the ability to concentrate, correct motor disorders [Ditzler K. Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial. Arzneimittel-Forschung. 1991; 41: 773-80.]. In addition to the main mechanism of action (effect on glutamatergic transmission), memantine has an additional serotonergic effect

(noncompetitive antagonist of 5NTZ receptors) and, possibly, its antidepressant effect is due to this very mechanism. Clinically, the antidepressant effect of memantine has been shown in a number of studies on a major depression model [Ferguson JM, Shingleton P N. An open-label, flexible-dose study of memantine in major depressive disorder. Clin. Neuropharmacol 2007; 30 (3); 136-44.].

With a single administration of memantine, a peak in its concentration in the brain is reached after 1 h. The half-life of memantine is quite long and is about 100 hours. Such a long half-life suggests that this drug has an accumulating effect in chronic use. So, with a single administration of memantine, the concentration of dopamine remains unchanged, but with prolonged use, the concentration of dopamine in the front parts of the brain increases 10 times or more. The longer memantine is used, the greater the concentration of dopamine. An analysis of the concentration of dopamine metabolites showed that the use of memantine results in an increase not only in the release but also in the synthesis of dopamine [Hesselink MB, De Boer AG, Breimer DD et al. J Neural Transm 1999; 106: 803-18.].

 From the literature it is known that chronic administration of memantine affects an increase in the concentration of not only dopamine, but also acetylcholine, and also contributes to an increase in the number of muscarinic cerebral receptors. Thus, we can assume that this drug has a complex mediated mediating effect both on neurons of the frontal cortex and on the entorhinal cortex and its connection with the parietal-temporal parts of the brain.

The second aspect of the therapeutic activity of memantine is a neuroprotective effect. This effect is a direct result of blockade of NMDA receptors, closure of ionotrophic channels and, accordingly, stabilization of the cell membrane, which protects cells from death. The neuroprotective effect of memantine has been proven in a model of cerebral ischemia in an experiment [Danysz W, Parsons CG, Mobius HJ etal. NeurotoxRes 2000; 2: 85-97.]. The preventive administration of memantine reduced the area of ischemic penumbra, the severity of cerebral edema, and also reduced the area of the focus of ischemia. A similar result was obtained on other models of brain damage. It is assumed that memantine can have a stimulating effect on the synthesis of a number of neurotrophic factors, in particular, brain-specific neurotrophic factor (brain-derived neurotrophic factor), which also leads to stabilization of the neuronal membrane and protect the cell from death.

 It was shown that the use of NMDA receptor antagonists has a positive effect on the cognitive functions of patients with Parkinson’s disease [Damulin I.V. Rus honey. journal 2001; 9 (25): 1178-82., Litvinenko I.V., Odinak M.M. Zhurn. nevrol. and psychiatrist them. S.S. Korsakova. 2004; 4: 76-81.].

 Memantine (1-amino-3,5-dimethyl adamantane) is an analogue of 1-amino-cyclohexane. The formula is disclosed, for example, in US patents NN 4,122, 193; 4.273, 774; 5,061, 703. Memantine and other 1-aminoalkylcyclohexanes have been shown to be useful in reducing various progressive neurodegenerative disorders, such as dementia in patients with moderate to severe Alzheimer's disease, Parkinson's disease, and muscle spasticity as disclosed in US Pat. Nos. 5,061,703; 5.614, 560 and 6.034, 134.

The use of memantine as a neuroprotective agent for amyloid intoxication is also known (Hidalgo JJM, Alvarez XA, Cacabelos R, Quack G. Neuroprotection by memantine against neurodegeneration induced by beta-amyloid (1-40). Brain Research, 2002, v.958, 210- 221). Melatonin (N-acetyl-5-methoxytryptamine) is a neuropeptide that is synthesized mainly by the pineal gland and has a number of unique properties on the human body and mammals. Meaningful is the fact of circadian (circadian) periodicity of the production of biologically active compounds in pinealocytes. The synthesis of melatonin effectively occurs only with the onset of darkness and falls into the light phase of the day - a fact first shown by R. Wurtman in 1960. A short light pulse (0.1-1 lux) is enough to suppress this process. In the afternoon, serotonin accumulates in the gland tissue. The daily rhythm of melatonin production depends on the activity of NAT in the retina, which, in turn, depends on calcium ions, dopamine and gamaaminobutyric acid (GABA). With the help of melatonin, the pineal gland participates in the organization of daily periodism and in the regulation of cyclic processes, acting as a mediator between the pacemaker mechanism of suprachiasmatic nuclei (SCN) and peripheral organs. The pineal gland along with the SCN of the hypothalamus is included in the system of the so-called biological clock of the body, which plays a key role in the mechanisms of “counting internal time” and aging [Arushanyan EB, 2005; Anisimov V.N., 2007]. The main functions of the pineal gland in the body are: regulation of circadian and seasonal rhythms; regulation of reproductive function; antioxidant protection and antitumor protection [Anisimov VN, 1998, 2003]. Although the main source of melatonin circulating in the blood is the pineal gland, paracrine synthesis of melatonin has been found in almost all organs and tissues: thymus, gastrointestinal intestinal tract, gonads, connective tissue [Reiter RJ; Raikhlin I.M., Kvetnoy I.M .; Huether G.].

 With age, the pineal gland of humans and animals, like the thymus, involves. The number of active secretory elements of the gland, pinealocytes decreases, with a decrease in the production of melatonin. By about 45 years old, plasma contains only half the amount of the hormone that is produced in youth. In older people, the amplitude and dynamics of daily secretion of melatonin also change [Korkushko OV, Khavinson V.Kh., Shatilo VB. Pineal gland: correction pathways during aging. SPb. Science - 2006.204 s, Reiter RJ. The aging pineal gland and its physiological consequences // BioEssays - 1992. - V.14. - p. 169-

175., Skene D.J., Swaab D.F. Melatonin rhythmicity: effect of age and Alzheimer disease // Exp. Gerontol. - 2003. - V.38. - p. 199-

206.1. In animal experiments and monitoring the treatment of the elderly, both normal and in various forms of cerebral pathology, including vascular nature, melatonin improves the processes of memory, visual and auditory perception, and concentration. These facts determine the healing potential of melatonin as a potential nootropic agent [Arushanyan EB Epiphysis hormone melatonin - a new nootropic agent? // Expert. and wedge, pharmacol. - 2005. - T. 68. - p. 74-79., Arushanyan E.B. Epiphyseal hormone melatonin and neurological pathology // Rus. honey. journal - 2006. - T.14. - p. 1057-1063.]. In experiments on models of acute disturbance of cerebral hemodynamics in animals: total or focal ischemia due to occlusion of arteries, melatonin photothrombosis invariably exerted a clear neuroprotective effect [Reiter RJ, Tan DX, Leon J. etal. When melatonin gets of your nerves: its beneficial actions in experimental models of stroke // Exp. Biol. Med. - 2005. - V.230. - p.104-117.]. In mice using a model of closed brain injury, the use of the hormone during the week accelerated the normalization of animal behavior and recovery processes in the lesion in the form of a decrease in its size with an increase in the plasma content of a number of antioxidants, including ascorbic acid [Beni SM, Kohen R., Reiter RJ etal. Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation ofNF-kB and AP-1 // FASEB J. - 2004. - V.18. - p. 149-151., Mesenge C, Verrecchia C, Boulu RG Neuroprotection by melatonin in mice submitted to brain injury // Naunyn. Schmiedeberg's Arch. Pharmacol - 1998. V.358. - p.R32 /]. The data obtained using objective imaging methods (magnetic nuclear resonance) showed that repeated administration of rats melatonin in 2 times reduces the volume of ischemic cerebral edema [Torii K., Uneyama N., Nishino N. Melatonin suppresses cerebral edema caused by middle cerebral artery occlusion / reperfusion in rats assessed by magnetic resonance imaging. // J.PinealRes. - 2004. - V.36. - p. 18-24.]. Accounting morphometric characteristics of neurons of various cerebral formations such as: neocortex, hippocampus, striatum, with data from magnetic nuclear resonance imaging allows you to identify the statistically significant protective effect of the epiphyseal hormone, where it was possible to maintain the viability of a significant number of cellular elements. At the same time, the severity of cerebral edema was significantly limited. It was noted that in the cerebral cortex, edema weakened more than in the striatum [Kondoh T., Uneyama N., Nishino N. Melatonin reduces cerebral edema formation caused by transient for ebrainis chemiak in rats // LifeSci. -. 2002. - V.72. - p. 583-590., Regriny O., Delagrange P., Scalbert E. et al. Melatonin improves cerebral circulation security margin in rats // Am. J. Physiol. - 1998. - V.275. - p.H139-H134., Sinha K., Degaonkar MN, Jagannathan NR Effect of melatonin on ischemia / reperfusion injury induced by middle cerebral artery occlusion in rats // Eur. J. Pharmacol. - 2002. - V.428. - p.185-192.]. There is an assumption that melatonin is evolutionarily included in the natural system of protecting the brain from ischemic damage, as evidenced by the results of experiments on animals in which, by different methods, extirpation of the pineal gland, prolonged maintenance in bright light, created a hormone deficiency. Under such conditions, a very pronounced foci of cerebral infarction appeared when modeling stroke by cortical photothrombosis or local occlusion of the median cerebral artery. While injections of melatonin against the background of an epiphysectomy led to reliable protection of cortical neurons from ischemia of various etiologies [Kilic E., Ozdemir Y., Bolay N. Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia. // J. Cerebr. BloodFlowMetabol. - 1999. - V.19. - p.511-516.].

Pathological hyperactivity of glutamic acid [Gusev E.I., Skvortsova V.I., is recognized as a pronounced factor of oxidative stress in cases of cerebrovascular accident due to atherosclerosis, stroke or traumatic brain injury). Glutamate neurotransmission and calcium metabolism in normal and cerebral ischemia // Uspekhi fiziol. sciences. - 2002. - T.ZZ - p. 80-93.]. The accumulation of glutamate in the synapses and intercellular space leads to the triggering of the glutamate-calcium cascade. By excitation of M-methyl-E-aspartate (NMDA) receptors, glutamate severs channels in neuronal membranes for calcium ions and their intracellular accumulation in large quantities, which inevitably determines damage to cellular structures. Melatonin clearly inhibits glutamate neurotoxicity. As was established on a culture of isolated cortical neurons, their damage with an excess of glutamate or NMDA was noticeably inhibited after melatonin was added to the incubation medium. This happens to a certain extent due to his the ability to bind calmodulin and limit the function of NMDA receptors. Epiphysectomy led to an increase in the density of the latter with a simultaneous increase in lipid peroxidation in various brain formations. Melatonin protects neurons from NO aggression, an excess of which can potentiate glutamate neurotoxicity [Guerrero JM, ReiterRJ., OrtizG. etal. Melatonin prevents increases in neuronal nitric oxide and cyclic GMP production after transient brain ischemia and reperfusion in the Mangolian gerbil // J. Pineal Res. - 1997. - V.23. - p.24-31.]. Melatonin also normalizes mitochondrial activity [El-Abhar HS, Shaalan M., Barakat M. et al. Effect of melatonin and nifedipine on some antioxidant enzymes and different energy fuels in the blood and brain of global ischemic rats // J. Pineal Res. - 2002. - V.33. - p.87-94.], not only limits due to hypoxia, defects in mitochondrial function, and protein hyperphosphorylation and disorganization of the cytoskeleton, and also restores the function of the tyrosine kinase receptor apparatus. Which is an important element of the phosphorylation system and participates in the reparative processes of the nervous tissue due to the involvement of neurotrophins in it [Olivieri G., Often U., Meier F. etal. Beta- amyloid modulates tyrosine kinase B receptor expression in SH SY SY neuroblastome cells: influence of the antioxidant melatonin // Neurosci. - 2003. - V.120. - p.659-665.]. Melatonin probably also stimulates neurogenesis in adult neural tissue. stem cell culture revealed that they can express melatonin receptors, mainly of the 1st type. The addition of a low concentration of melatonin solution to them provokes, among other things, the induction of mRNA of one of the neurotrophins - glial growth factor (GDNF) [Niles LP, Armstrong. J., RinconCastro LM etal. Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT 1 receptors with neuronal and glial markers // BMC Neurosci. - 2004. - V.5. - p.41-50.].

 From the presented prior art, therefore, it is known the use of memantine or melatonin in the treatment of a number of diseases of the central nervous system. However, clinically the effects of these drugs with monotherapy of moderate cognitive impairment (RBM) are negligible.

Disclosure of invention

The objective of the present invention is the creation of a more effective combination to eliminate disorders in patients with brain pathologies, for the prevention, correction and therapy of manifestations of mental, cognitive, behavioral and neurological disorders in organic diseases of the central nervous system of various origins and amyloid intoxication. Including in cases of moderate cognitive impairment, difficult to correct. This problem is solved by the use of a combination containing melatonin and memantine in therapeutically effective amounts, as well as the development of their formulations.

 This combination is prescribed to a mammal, including humans.

 For the treatment and / or prevention of manifestations of mental, cognitive, behavioral and neurological disorders in organic diseases of the central nervous system of various origins, therapeutically effective amounts are preferably 0.01 to 50 mg for melatonin and 0.01 to 100 mg for memantine. For amyloid intoxication in cases of RBM, cognitive decline in vascular lesions and post-traumatic conditions, therapeutically effective amounts are preferably 5 to 300 mg memantine and 3 to 10 mg melatonin. If necessary, the content in dosage forms can be increased for Melatonin up to 700 mg and Memantine up to 200 mg.

 The combination can be applied from 1 to 5 times a day.

The combination may be presented in the form of a tablet, including sublingual forms, capsules, modified-release dosage forms, injection forms, suppositories, powder for the preparation of a drink, drops, including drops in the nose, transdermal, buccal, aerosol form. Pharmaceutically acceptable excipients are selected to ensure the delivery of a therapeutically effective single dose amount of Memantine and Melatonin in a unit dosage form and to optimize the cost, ease and stability of the manufacturing process. A prerequisite for excipients is inertness, chemical and physical compatibility with Memantine and Melatonin. Excipients used in solid dosage forms, such as tablets and capsules, may further include colorants and pigments, taste masking agents, flavors, sweeteners and adsorbents.

 Diluents help to increase tablet size with a small amount of active drug substance. Diluents include lactose, in forms - alpha-lactose or beta-lactose. Different types of lactose may consist of lactose monohydrate, alpha-lactose monohydrate, anhydrous alpha-lactose, anhydrous beta-lactose and agglomerated lactose. Other diluents may include sugars such as sucrose, invert sugar, dextrose, and dextrates.

A more preferred diluent is lactose monohydrate. Another diluent may be microcrystalline cellulose, including micronized. Diluents can include starch and starch derivatives. Starches include natural starches obtained from various cereals and / or other crops. Starches may also include pre-starch and sodium glycolate modified starch. Starches and starch derivatives also carry the property of disintegrants. Many diluents also act as disintegrants and binders, and these additional properties should be taken into account when manufacturing a pharmaceutical composition. Disintegrants are added to break down the tablets into particles of the active pharmaceutical component and auxiliary, to facilitate dissolution and increase the bioavailability of therapeutically active ingredients. Starch and starch derivatives, including the sodium salt of starch carboxymethyl ester such as starch modified with sodium glycolate, are disintegrants used.

Gelatinized starch may be a preferred, but not exclusive, disintegrant. Another preferred disintegrant is sodium carboxymethyl cellulose. Binders are used as auxiliary pharmaceutically acceptable substances for wet granulation to increase the concentration of therapeutically active substances and other auxiliary ingredients in the forming granules. A binder is added to improve the fluidity of the powder and to improve compression. Binders include cellulose derivatives such as microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Other binders are selected from substances such as povidone, polyvinylpyrrolidone, gelatin, natural gum, namely acacia, tragacanth, guar and pectin resin, starch paste, pregelatinized starch, polyethylene glycols and sodium alginate.

Antifriction agents are lubricants and lubricants that are used in the manufacture of solid dosage forms in order to prevent the tablets from sticking to technological surfaces and to reduce sticking during the pressing stages. Such substances include stearic acid, salts of stearic acid, for example calcium stearate, magnesium stearate and sodium stearyl fumarate, talc, sodium benzoate, sodium acetate and sodium oleate. Dosage forms for rectal administration may be solutions or suspensions, or they may be prepared in the form of suppositories containing the active substances in a mixture with a neutral fat base, or gelatin rectal capsules containing the active substances in a mixture with vegetable oil or liquid paraffin.

 Solutions for parenteral administration by injection can be obtained in the form of an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substances, preferably in a concentration of from about 0.5% to about 2% by weight. These solutions may also contain stabilizers and / or buffering agents and can be conveniently prepared in ampoules with various dosage units.

 One option includes the use of combinations to treat a disease and / or disorder in people in need thereof, which includes oral administration of a therapeutically effective amount of the present invention.

The combination of active ingredients is included in the pharmaceutical composition for oral administration, which is preferably in the form of a solid dosage form containing memantine and melatonin in and excipients, including at least one diluent selected from lactose, starch, a starch derivative, microcrystalline cellulose, sucrose, invert sugar, dextrose and dextrate, at least one disintegrating agent selected from sodium carboxymethyl cellulose, Croscarmellose, gelatinized starch, a binder selected from polyvinylpyrrolidene, celomeric gum, polyamide, acetone, sodium, an antifriction agent selected from stearic acid and / or its salts, colloidal silicon dioxide, talc, sodium benzoate, sodium acetate and sodium oleate p and the following component in wt.%:

 Memantine 40.0-90.0

 Melatonin 2.0-5.0

 Thinner 2.0-50.0

 Binder 3.5-10.0

 Disintegrating agent 1, 5-10.0

 Anti-friction agent 0.2-3.0

 To obtain the drug, in particular, the composition of Memantine with Melatonin is mixed with various auxiliary products to obtain a solid form of Memantine with Melatonin.

An additional aspect of the present invention includes a method for the preparation of the claimed composition. This method involves obtaining a solid dosage form of the claimed composition, preferably by wet mixing of the active ingredients and excipients with water, and with further drying and grinding of the granular mixture.

 In some of the most selected embodiments, the active principle is about 40.0% by weight of the composition, lactose monohydrate is about 28.7%, microcrystalline cellulose is about 10.4%, starch is about 10.9%, carboxymethyl cellulose is about 4.0 %, polyvinylpyrrolidone is about 5.2% and magnesium stearate is about 0.8%.

 In still other embodiments, Memantine and Melatonin comprise from about 70-80% by weight of the composition. Preferably, the composition comprises a diluent, such as lactose monohydrate, preferably from about 3-20% by weight of the composition; a disintegrant, such as, for example, cross-linked sodium carboxymethyl cellulose, preferably from about 2-10% by weight of the composition; a binder such as, for example, polyvinylpyrrolidone, preferably from about 2-10% by weight of the composition; and a lubricant, such as magnesium stearate, preferably from about 0.2 to 2.0% by weight of the composition.

In additional embodiments, the implementation of Memantine and Melatonin is about 80% by weight of the composition, the diluent is lactose monohydrate, which is from 8 to 15% by weight of the composition; disintegrant is carboxymethyl cellulose, which is from 1 to 10% by weight of the composition; the binder is polyvinylpyrrolidone, which is from 1 to 10% by weight of the composition; and the anti-friction lubricant is magnesium stearate, which is 0.2 to 2.0% by weight of the composition.

 In some more preferred embodiments, the diluent is lactose monohydrate and it can be about 9.5% by weight of the composition, the disintegrant is croscarmellose and it can be about 5% by weight of the composition, the binder is povidone, and it may comprise approximately 5% by weight of the composition, and the lubricant is magnesium stearate, and it may comprise approximately 0.5% by weight of the composition.

In other embodiments, the implementation of Memantine and Melatonium is from about 90% by weight of the composition. Preferably, but not exclusively, the composition comprises a diluent, such as lactose monohydrate, in the range of 3-10% by weight of the composition; a disintegrant, for example, carboxymethyl cellulose, preferably from about 2-5% by weight of the composition; a binder, such as polyvinylpyrrolidone, preferably from about 2-5% by weight of the composition; and a lubricant, for example magnesium stearate, preferably from about 0.2-2.0% by weight of the composition. In other more preferred embodiments, the diluent is lactose monohydrate and it can be about 3.5% by weight of the composition, the disintegrant is croscamelose and it can be about 3% by weight of the composition, the binder is povidone and it may comprise about 3% by weight of the composition, and the lubricant is magnesium stearate, and it may comprise about 1% by weight of the composition.

In another embodiment of the described invention provides a content of 50, 100 or 150 mg of Memantine and 3 mg, 5 mg or 10 mg of Melatonin, where Memantini / Melatonin comprise from 45 to 90% by weight of the composition. In other embodiments, Memantine with Melatonin comprises from about 60 to 90% or 70-80%) of the composition. In another embodiment, these compositions comprise one or more of starches, such as corn starch, lactose monohydrate, microcrystalline cellulose, gelatinized starch, carboxymethyl cellulose; sodium salt of carboxymethyl starch ether; polyvinylpyrrolidone; hydroxypropyl methylcellulose; magnesium stearate; and a mineral salt such as talc. In a further embodiment, these compositions comprise lactose monohydrate, corn starch, sodium carboxymethyl cellulose, polyvinylpyrrolidone, talc and magnesium stearate.

 In a further embodiment, these compositions comprise lactose monohydrate, microcrystalline cellulose, gelatinized starch, carboxymethyl cellulose, polyvinylpyrrolidone and magnesium stearate. In another embodiment, these compositions comprise lactose monohydrate, sodium carboxymethyl cellulose, polyvinyl pyrrolidone and magnesium stearate.

Brief Description of the Drawings FIG. 1 shows the design of the experiments in Example 1 on the study of substances for functional and morphological disorders caused by the introduction of the beta-amyloid peptide into the lateral ventricle of the mouse brain.

 In FIG. 2 presents a diagram of the experiment in Example 1 on the study of episodic memory in the test of recognition of a new object in mice

FIG. 3 depicts a representative black and white micrograph of a superimage of a section of a brain passing through the dorsal hippocampus. The arrow indicates the route of administration of the beta-amyloid peptide. Rectangles indicate CA1, SAZ of the hippocampus and the area of the sensory-motor cortex. FIG. 4 depicts the effect of test substances on memory impairment in mice caused by amyloid beta in a new object recognition test. Presents the average values of the preference index of the new object.

FIG. 5 depicts representative black and white micrographs of the CA1 hippocampus region in control (A) and after administration of amyloid beta into the lateral ventricle of the brain (B). Micrographs B and D show the effect of the combination of memantine 5 mg / kg + melatonin 3 mg / kg (B), memantine 10 mg / kg + melatonin 6 mg / kg (G) on neurodegeneration caused by the introduction of beta-amyloid. Microphotographs were taken at x200 magnification. The arrow, by way of illustration, shows pycnotic cells stained with hematoxylin-eosin.

FIG. 6 depicts representative black and white micrographs of the SAZ hippocampus region in control (A) and after administration of amyloid beta into the lateral ventricle of the brain (B). Micrographs B and D show the effect of the combination of memantine 5 mg / kg + melatonin 3 mg / kg (B), memantine 10 mg / kg + melatonin 6 mg / kg (G) on neurodegeneration caused by the introduction of beta-amyloid. Microphotographs were taken at x200 magnification. The arrow, as an illustration, shows pycnotic cells stained with hematoxylin-eosin.

FIG. 7 shows representative black and white microphotographs of the sensory motor region of the cortex mouse brain in control (A) and after the introduction of beta-amyloid into the lateral ventricle of the brain (B. Micrographs B and D show the effect of the combination of memantine 5 mg / kg + melatonin 3 mg / kg (B), memantine 10 mg / kg + melatonin 6 mg / kg (G) for neurodegeneration caused by the introduction of beta-amyloid. Microphotographs were taken at a magnification of x200. The arrow, as an illustration, shows pycnotic cells stained with hematoxylin-eosin.

The best example of carrying out the invention

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

Example 1. The study of activity against amyloid intoxication of the claimed combination

 The study was conducted in two directions:

 1) Study of the effect of the combination of memantine + melatonin in comparison with memantine on impaired motor activity and episodic memory caused by the introduction of the beta-amyloid peptide into the lateral ventricle of the mouse brain;

2) Studying the effect of the combination of memantine + melatonin in comparison with memantine on neurodegeneration caused by the introduction of the beta-amyloid peptide into the lateral ventricle of the mouse brain. The study was conducted at the Institute of Pharmacology of the University of Tartu at the Biomedical Center of the University of Tartu, ul. Ravila 19, 51014 Tartu, Estonia.

 Research methods

 All experiments were carried out in accordance with the principles of working with laboratory animals (Principles of Animal Care, Directive 86/609 / EEC) according to the Helsinki Declaration. The purchase of animals and the conduct of experiments were made on the basis of an appropriate license from the Ethics Committee (Ministry of Agriculture of the Republic of Estonia). All animal caregivers and experimenters have personal licenses to conduct animal experiments. During the experiments, every effort was made to minimize the number of animals and their suffering.

All experiments were performed on male mice of the C57BL / 6 line. Animals were purchased from Harlan (England). The average age of the animals at the time of arrival at the vivarium of the Biomedical Center of the University of Tartu was 5.5 (40 mice) and 6 weeks (20 mice). Upon arrival, animals were quarantined for 2 weeks at the vivarium of the Biomedical Center of the University of Tartu. After which the animals were transferred to the vivarium of the Institute of Pharmacology (room number 3028). Animals were kept in plastic cages (5 mice per cage) measuring 25 cm x 45 cm x 12 cm (WxDxH) without restriction in food and water with a 12-hour light cycle (the light turns on automatically at 8.00). Cells with animals were in special climatic containers (Scanbur, Denmark). The containers are equipped with HEPA filters for air purification and have 24-hour monitoring of humidity and air temperature. Relative humidity in containers is maintained within 50 ± 2%, temperature 22 + 1 ° С. Access to animals is allowed only to personnel who have the appropriate license. Cell cleaning and provision of food and water are carried out once a day. Animal feed: granulated R70 (Lactamin, Stockholm, Sweden). Animals were kept in climatic containers for 1 week before the start of the experiments. Thus, the age of the animals at the beginning of the experiments was 8.5–9 weeks. The body weight of mice at the beginning of the experiments was 25.8 ± 0.30 g (n = 60). Before the start of the experiments, animals were divided into 6 groups (Table 1), 10 animals each, using a randomization program.

 Test setup and administration of test substances

The experimental setup is shown in FIG. 1. Table 1 shows the scheme of administration of substances. The first administration of the test substances was carried out 24 hours after the injection of amyloid beta into the lateral ventricle of the mouse brain. Substances were administered within 8 days (once a day), at the same time from 9.00 to 11.00 hours. All solutions the test substances were prepared every day immediately before administration and after their preparation were encoded by the leader and transmitted in encoded form to the experimenter. On the 6th and 7th day of the introduction of the test substances with animals, behavioral experiments were carried out (see Figure 1).

 Memantine was presented in the form of salt (memantine hydrochloride), molecular weight = 215.8, batch number 8061 1. There is a quality certificate. All doses of memantine were calculated on salt. Melatonin: molecular weight 232.278, batch number 20110915. There is a quality certificate.

 Table 1.

Groups of animals (n = 10) and the scheme of administration of the studied substances

 Nfi groups Doses of the studied Concentration and volume Concentration and volume of animal substances beta-amyloid, solutions of the test administered in substances introduced into the lateral ventricle inside

 1 Control Sterile water (3 μl) Control solution 0.1 ml / 10 g body weight

2 Control for the test 48 picogr / 3 μl Control solution of 0.1 substances ml / 10 g body weight

3 Memantine 5 mg / kg 48 picogr / 3 μl Memantine solution (0.5 mg / ml), 0.1 ml / 10 g body weight

 4 Memantine 10 mg / kg 48 picogr / 3 μl Memantine solution (1 mg / ml), 0.1 ml / 10 g body weight

 5 Memantine 5 mg / kg + 48 picogres / 3 μl A solution of memantine (0.5 melatonin 3 mg / kg mg / ml) and melatonin (0.3 mg / ml), 0.1 ml / 10 g body weight

6 Memantine 10 mg / kg + 48 picogr / 3 μl Memantine solution (1 melatonin 6 mg / kg mg / ml) + melatonin (0.6 mg / ml), 0.1 ml / 10 g body weight Preparation of solutions of test substances

 1) A solution of memantine hydrochloride (0.5 mg / ml) + melatonin (0.3 mg / ml)

 5 mg of memantine HCL was dissolved in 9 ml of water. Separately, 3 mg of melatonin was weighed, placed in a mortar and 2 drops of Tween-80 emulsifier were added, triturated until a homogeneous mass was formed, adding 1 ml of water in portions. The resulting emulsion was mixed with a solution of memantine (9 ml). Before administration, the emulsion was vigorously shaken on a shaker. The resulting emulsion was administered in a volume of 0.1 ml per 10 g of mouse body weight, which corresponds to doses of memantine 5 mg / kg and melatonin 3 mg / kg.

 2) A solution of memantine hydrochloride (1 mg / ml) + melatonin (0.6 mg / ml)

 10 mg of memantine HCL was dissolved in 9 ml of water. Separately, 6 mg of melatonin was weighed, placed in a mortar and 2 drops of Tween-80 emulsifier were added, triturated until a homogeneous mass was formed, adding 1 ml of water in portions. The resulting emulsion was mixed with a solution of memantine (9 ml). Before administration, the emulsion was vigorously shaken on a shaker. The resulting emulsion was administered in a volume of 0.1 ml per 10 g of mouse body weight, which corresponds to doses of memantine 10 mg / kg and melatonin 6 mg / kg.

3) A solution of memantine hydrochloride 0.5 mg / ml 5 mg of HCL memantine was dissolved in 10 ml of water, to which 2 drops of Tween-80 emulsifier were added and mixed with vigorous shaking using a shaker. The resulting emulsion was administered in a volume of 0.1 ml per 10 g of mouse body weight, which corresponds to a dose of 5 mg / kg.

 4) Solution of memantine hydrochloride 1 mg / ml

 10 mg of memantine hydrochloride was dissolved in 10 ml of water, 2 drops of Tween-80 emulsifier was added and mixed with vigorous shaking using a shaker. The resulting emulsion was administered in a volume of 0.1 ml per 10 g of body weight of the mouse, which corresponds to a dose of 10 mg / kg

 5) Control solution

 To 10 ml of water was added 2 drops of Tween-80 emulsifier and mixed with vigorous shaking using a shaker. The resulting emulsion was introduced in a volume of 0.1 ml per 10 g of mouse body weight.

 Solutions 1-5 were introduced into the stomach using a metal probe for mice (FTSS-20S-38) from Salomon Scientific (USA).

6) A solution of the beta-amyloid peptide (48 picograms / 3 μl) The peptide fragment of the beta-amyloid corresponding to the amino acid sequence of human beta-amyloid (25-35) was obtained from Tocris (England) (Batch No: 6, molecular weight: 1060.27, there is a certificate of quality).

1 mg of the peptide substance was dissolved in 1 ml of sterile water and placed in a sterile incubator at a temperature 37 ° C for 96 hours for peptide aggregation (oligomeric form). Immediately before use, the solution was diluted with sterile water to a peptide concentration of 16 nM and introduced into the left lateral ventricle of the mouse brain in the amount of 48 picograms in a volume of 3 microliters.

7) Control for amyloid beta

 Sterile water in a volume of 3 microliters was injected into the left lateral ventricle of the mouse brain.

 The introduction of the beta-amyloid peptide into the lateral ventricle of the mouse brain.

The introduction of amyloid beta into the lateral ventricle of the mouse brain was performed under general anesthesia. For anesthesia, a mixture of hypnorm (Hypnorm, VetaPharma; Lot P736 / 001; contains 0.315 mg of fentanyl and 10 mg of fluanisone in 1 ml), dormicum (Dormicum, Roche; Lot: F1038F71, 5 mg / ml) and water in a ratio of 1: 1 was used : 2. The mixture was administered ip in a volume of 0.1 ml per 10 g of body weight. 2-3 minutes after administration of the anesthetic, the animals developed a surgical stage of anesthesia, after which the animal was fixed in a David Kopf stereotactic apparatus (Leica Microsystems, Germany). An incision was made on the skull of the mouse, the bone surface was cleaned and bregma was found. The coordinates for introducing amyloid beta into the lateral ventricle were found using a Computer-assisted Stereotaxic system using the parameters of the mouse brain atlas (The Mouse Brain, in Stereotaxic Coordinates, KBJ Franklin and G. Paxinos, 2012). The coordinates for the introduction of amyloid beta with respect to Bregma were as follows: forward - 0.5 mm, laterally - 1 mm, ventrally - 2 mm.

 A hole was drilled in the skull using boron and a needle was inserted into the left lateral ventricle of the brain, connected to a programmable micropump (Syringe pump SP101 IZ, Gentaur, Germany), supplying a solution of beta-amyloid. A solution of the substance was injected at a speed of 0.75 μl / min and after the end of the infusion, the needle remained in the brain for 1 min. The control group received an infusion of sterile water in a volume of 3 μl. After this, the wound was treated with an antiseptic solution, sutured and animals were placed on a heated table until the anesthesia was completely exited.

 Surgical operation caused the death of four mice, one animal in groups intended for the introduction of the studied substances. Thus, the animal groups to which memantine or memantine + melatonin was to be administered consisted of 9 mice.

 Determination of motor activity and episodic memory in a model for recognizing a new object in mice On the 6th day of the experiment, 1 hour after the administration of the test substances, the animals were taken into behavioral experiments to study cognitive functions.

To evaluate cognitive functions, a recognition test of a new object was used. This test is widely used. to assess episodic memory in animals and its violation is characteristic of Alzheimer's patients. The test is based on the fact that healthy animals examine a new object much more time than the old one.

 The experience consisted of three phases: the addictive phase, the training phase and the retention phase.

1) Addictive phase

 During this phase, the mice were individually placed in a wooden box measuring 50 cm x 50 cm x 50 cm (length x width x height), located in an experimental room dimly lit by incandescent lamps, with a constant light of 60 lux. The box floor was divided into 16 identical squares with a side length of 12.5 cm. The animal was in the box for 5 minutes and the experimenter recorded the number of crossed squares. This indicator, in the future, was used to assess the motor activity of mice. After 5 minutes, the animal was removed from the box and the floor of the box was rubbed with a 5% ethanol solution to eliminate odor.

2) Training phase

2 hours after the end of the addictive phase, the training phase was conducted. For this, the animal was again placed in the center of the box on the floor of which two identical objects were installed. The objects were two wooden cubes located in opposite corners of the box (Fig. 2). The animal was given the opportunity to examine objects for 5 minutes, and at the same time, the time during which the animal examined each of the objects was recorded. These data are necessary to assess the degree of motivation and research activity of animals. After each animal, the box floor was wiped with a 5% ethanol solution. At the end of the experiment, the animal was placed in a home cage. 3) Retention phase

 24 hours after the training phase, the test substances were administered to the mice (seventh injection) and 1 hour after the administration of the substances, the animals were again placed in the study box, in which one object was replaced with a new object of a different shape and color (Fig. 3) .

 The animal was again given the opportunity to explore the old and new objects for five minutes and the time of investigation of each object was recorded by the experimenter.

 The research preference coefficient of a new object was presented as the ratio of the time of research of a new object in relation to the total time of research of the old and new objects according to the formula (Tnov x100) / (Tst + Tnov), where Tst and Tnov are the time of investigation of the old and new objects.

Preparation of histological preparations and determination of cell death 24 hours after the end of the behavioral tests, the animals were tested for the last time and, 1 hour after the introduction, the mice were injected with an anesthetic solution of chloral hydrate (350 mg / kg, ip). Within 5 minutes, the animals developed deep anesthesia. Upon reaching anesthesia, the animals were fixed, the chest was opened and a perfusion needle was inserted into the left ventricle of the heart. At the same time, the right atrium was opened and transcardial perfusion of the circulatory system was performed, first with physiological saline (0.9% NaCl), then 4%) with paraformaldehyde in 0.1 M phosphate buffer. Perfusion was carried out using a peristaltic pump Biorad Econo Pump (Biorad, Sweden). At the end of perfusion, the brain was removed and placed for 24 hours in a 4% solution of paraformaldehyde (postfixation).

Sagittal sections of the brain (40 μm thick) passing through the dorsal hippocampus were prepared using a vibrating microtome (Leica, Germany). Slices were placed on plates (one slice per well) filled with 0.1 M phosphate buffer and stored at 4 ° C (shelf life 3-4 days). For each animal, 4 sections were selected passing through the dorsal hippocampus. For this, all slices from each animal were distributed into a series of 6 slices each. For each animal, the selection of sections was carried out based on the Cavalieri principle: first, a section was randomly selected from the first series and then from each subsequent series was taken slice with the same serial number.

 Staining was performed on free-floating sections in a 24-seater plate. Sections were washed in 0.1 M phosphate buffer, then incubated in a solution of 0.025% trypsin (Sigma, USA) and 0.1% CaC in phosphate buffer for 10 min. After washing the sections in phosphate buffer, 0.25% Triton x-100 solution (Sigma, USA) was added to them and the sections were incubated for 1 hour. After that, the sections were washed again and a hematoxylin-eosin solution was added to them for 2 minutes, after which the sections were washed with running water and immersed for 5 seconds in an alcoholic solution of hydrochloric acid (1% HC1 in 70% ethanol) and washed again with water. Stained sections were placed on glass slides, filled with Vectashild medium (Vector Laboratories, USA) and covered with coverslips.

Analysis of cell death was carried out using a BX51 microscope (Olympus, Japan). The microscope is equipped with a DFC495 video camera (Leica, Germany). The microscope is controlled by NewCAST software from Visiopharm (Denmark). First, under the small magnification, using the UPlan ARC 4x / 0.16 lens and using the Newcast program, a super image was constructed on which the structures of interest to us were determined (Fig. 3) and the program recorded the coordinates of the structures in which a determination of the number of pyknotic cells should be carried out.

Then, using an LCAch 20x / 0.40 PhC oo / 1 objective, pycnotic cells were analyzed and counted in the structures CA1 and CAS of the hippocampus and sensorimotor region of the cortex. Pycnotic cells were defined as cells containing condensed hyperchromic nuclei, nuclear fragments, and condensed cytoplasm. Counting was carried out in each square, as shown in FIG. 5, 6, 7. The square area was set by the NewCast program and, depending on the size of the structure and cell density, it varied in the range of 0.1-0.5 mm ² . For each animal, the number of pycnotic cells and the area on which they were determined on four selected sections were summed up and the average density of pycnotic cells per 1 mm ² section was calculated and calculated. The obtained mean densities of pycnotic cells in the CA1, SAH areas of the hippocampus and the sensorimotor region of the cortex for each animal were subsequently used for statistical analysis.

 Statistical analysis

For each group of mice, the mean values (M) were calculated ± the standard error of the mean (t). Further, the data were analyzed using the Student's τ-test (control and beta-amyloid), one-way analysis of variance, followed by the retrospective Bonferroni criterion (action of the studied substances, dose effect). In a comparative assessment of the action of combinations of substances, two-way analysis of variance was used. Differences between groups were considered significant at p <0.05. Statistical data processing was performed using statistical software GraphPad PRISM-5 (USA).

 Study results and discussion of results

Justification of the choice of doses of memantine and melatonin for research

 In clinical practice, a therapeutic daily dose of memantine of 20 mg / day provides a plasma concentration level of 0.5-1 μmol / liter of plasma (12). In rodents (mice), corresponding memantine concentrations (1 μmol / liter of plasma) were observed after administration of memantine at a dose of 30 mg / kg / day (9). Since the aim of the study was to analyze whether melatonin can enhance the action of memantine, in the study, memantine was used in doses lower than those that give the maximum therapeutic plasma concentrations. In this study, doses of memantine 5 and 10 mg / kg were used, and, accordingly, the concentrations of memantine in these doses should be lower than the maximum therapeutic (1 μmol / liter of plasma).

Doses of melatonin were selected from the ratio of memantine: melatonin = 5: 3. Thus, the studied doses of the combination of memantine + melatonin were 5 + 3 mg / kg and 10 + 6 mg / kg. Separately, taken for comparison, memantine was studied at doses of 5 and 10 mg / kg. Characterization of the animal population used in the experiments

 In this study, to analyze the homogeneity of the animal population, body mass indices were used (Table 2). As can be seen from table 2, the groups of animals did not differ in body weight (analysis of variance: F5.59 = 0.93; p = 0.47; the differences are not statistically significant). This indicates that, according to this indicator, a homogeneous group of animals was used in the experiments.

 The influence of the studied substances on motor activity and the level of research motivation in mice after the introduction of amyloid beta into the lateral ventricle of the brain.

Data on the effect of the studied substances on the motor activity in the addictive phase and the level of research motivation in the training phase are shown in Table 2. As can be seen from Table 2, 6 days after the introduction of amyloid beta into the lateral ventricle of the brain, the animals showed increased motor activity compared to with a control group of mice. Repeated administration of memantine at doses of 5 and 10 mg / kg did not affect the increased locomotor activity. The introduction of a combination of substances memantine + melatonin in doses of 5 + 3 mg / kg and 10 + 6 mg / kg reduced motor activity to a control level. One-way analysis of variance showed a significant effect of the combination of substances (F2.27 = 16.97; p <0.0001), and the Bonferroni test showed a highly reliable effect of both combinations: memantine 5 mg / kg + melatonin 3 mg / kg (p <0.01 ) and memantine 10 mg / kg + melatonin 6 mg / kg (p <0.01).

 When assessing the motivational behavior of animals, after the introduction of beta amyloid and the studied substances, no statistically significant differences were detected (Table 2).

 Numerous studies indicate that in patients with Alheimer's disease circadian rhythms are disturbed, and during the night phase they have psychomotor activation. Since mice have reverse rhythms, and their sleep phase coincides with daytime, the calming effect of the memantine + melatonin combination on hyperactivity of mice in the daytime indicates the restoration of normal circadian rhythms, which may have therapeutic value in patients with Alzheimer's disease.

Body weight, locomotor activity (number of sectors crossed) in the addictive phase and the time of study of objects (level of motivation) in the training phase in mice after administration of beta amyloid and test substances. Average values presented standard errors of the mean (M + t) for groups of 9-10 animals. ## p <0.0001 compared to control; ** p <0.01 compared with beta-amyloid.

 Table 2.

The influence of the studied substances on memory impairment in mice caused by the introduction of beta-amyloid in the test of recognition of a new object

 The results of a study of the effect of the test substances on episodic memory impairment in mice caused by intracerebral administration of beta-amyloid are presented in Table 3 and in FIG. four.

Animals of the control group showed a pronounced preference in the study of a new object: the index of preference in the control group was 87.8 D2.3%. 7 days after the injection of beta amyloid into the lateral ventricle of the brain in mice, a decrease in the preference index of the new object to 49.7 P 14% was observed. Statistical analysis showed a highly reliable (p <0.0001, Student t-test) difference compared with the control group. A decrease in the preference index indicates memory impairment in mice after administration of beta-amyloid. Memantine and memantine in combination with melatonin increased the preference index, which indicates an improvement in memory impaired by the introduction of beta-amyloid. For a statistical analysis of the action of the studied substances, one-way analysis of variance was used, where a group with the introduction of beta-amyloid was used as a control. An analysis of the action of memantine revealed an improvement in memory (F2.27 = 34.23; ρΟ, ΟΟΟΙ), and this action of memantine was manifested in both doses of 5 mg / kg (p <0.01) and 10 mg / kg (p <0.01 ) Studying the effect of the combination of memantine + melatonin revealed a more significant improving effect on memory: F2.27 = 71.90; p <0.0001, and the Bonferroni test revealed a highly reliable effect of both combinations of memantine 5 mg / kg + melatonin 3 mg / kg (p <0.01) and memantine 10 mg / kg + melatonin 6 mg / kg (p <0.01 )

The influence of the test substances on the memory impairment in mice caused by beta-amyloid in the recognition test of a new object is shown in Table 3. The average values of the preference index of the new object are presented, the standard errors of the mean (M + t) for groups of 9-10 animals. Table 3.

The next step in the statistical analysis was to compare whether the combination of memantine + melatonin is different from the action of memantine in terms of anti-amnestic effect. For comparison, two-way analysis of variance was used, where one factor was “substance” and another factor was “dose” (Table 4). The analysis showed a strong influence of the factor “substance” (F 1.32 = 17.72; p = 0.0002) and the absence of the influence of the factor “dose” (F 1, 32 = 1, 837; p = 0.18), as well as lack of interaction "substance" x "dose" (F 1, 32 = 0.04; p = 0.8). From the analysis, it follows that the antiamnestic effect of the combination of memantine + melatonin significantly exceeds the antiamnestic effect of memantine on the model of amnesia in mice caused by the introduction of beta-amyloid, in the test of recognition of a new object. In addition, the improving effect on memory impairment caused by beta-amyloid was already evident in doses of the combination of memantine 5 mg / kg + melatonin 3 mg / kg.

 A matrix for comparing the antiamnestic effect of the combination of memantine + melatonin with the effect of memantine on memory impairment in mice caused by beta-amyloid in the test for recognition of a new object. Table 4 shows the average values of the index of preference for a new object ± standard errors of the mean per group of 9 animals.

Table 4.

The influence of the studied substances on the death of neurons caused by the introduction of beta-amyloid.

Data on the effect of the studied substances on the death of neurons in the CA1, SAH areas of the hippocampus and the sensorimotor region of the cortex after administration of beta-amyloid are presented in Table 5. As can be seen from the table, single pycnotic cells were detected in the brains of mice of the control group in all the studied structures. which, apparently, is associated with mechanical damage to brain tissue when a control solution is introduced into the lateral ventricle. The introduction of amyloid beta caused a significant death of neurons in all the studied brain structures: CA1, HAZ of the hippocampus and the area of the sensory-motor cortex. Statistical analysis showed a highly reliable (p <0.0001;Student's t-test) action of beta-amyloid, compared with the control in all studied structures (Table 5). The introduction of memantine reduced cell death, and a one-way analysis of variance revealed a significant effect of the substance: the analysis of variance for the CA1 region was (F2.27 = 9.42; p <0.001). Subsequent analysis using the Bonferroni test showed a significant effect of a dose of memantine at 10 mg / kg (p <0.01) and did not reveal a significant effect of memantine at a dose of 5 mg / kg. The effect of the melatonin + memantine combination on neuronal death caused by the administration of amyloid beta in the CA1 region is shown in FIG. 5. The results of statistical analysis are shown in Table 5. The combination of memantine + melatonin significantly reduced the density of pycnotic cells in the CA1 region of the hippocampus (F2.27 = 14.13; ρΟ, ΟΟΟΙ), and this effect was manifested after the introduction of combinations of memantine 5 mg / kg + melatonin 3 mg / kg (p <0.001) and memantine 10 mg / kg + melatonin 6 mg / kg (p <0.001).

The introduction of memantine also reduced cell death in the SAZ region, and one-way analysis of variance revealed a significant effect of the substance: the analysis of variance for the SAZ region was (F2.27 = 20.84; ρΟ, ΟΟΟΙ). Subsequent analysis using the Bonferroni test showed a significant effect of memantine doses of 5 mg / kg (p <0.001) and 10 mg / kg (pO.0001) (Table 5). The effect of the combination melatonin + memantine on neuronal death caused by the introduction of amyloid beta into the hippocampal SAZ region is shown in FIG. 6.

 The results of the statistical analysis are shown in Table 5. The combination of memantine + melatonin significantly reduced the density of pycnotic cells in the SAZ region of the hippocampus (F2.27 = 34.45; ρΟ, ΟΟΟΙ), and this effect was manifested after the introduction of combinations of memantine 5 mg / kg + melatonin 3 mg / kg (p <0.001) and memantine 10 mg / kg + melatonin 6 mg / kg (p <0.001).

 Memantine also significantly reduced the density of pycnotic cells in the sensory-motor cortex (F2.27 = 48.08; p <0.0001), both doses of 5 mg / kg and 10 mg / kg had a significant effect (Table 5). The combination of memantine + melatonin also significantly reduced the density of pycnotic cells in the sensory-motor region of the cortex (F2.27 = 34.45; p <0.0001), and this effect was manifested after doses of the combination of memantine 5 mg / kg + melatonin 3 mg / kg (p <0.001) and memantine 10 mg / kg + melatonin 6 mg / kg (p <0.001) (Fig. 7, Table 5).

The effect of the test substance on the density of pycnotic cells in the brain of mice after the introduction of beta-amyloid into the lateral ventricle of the brain. The average density values (N / mm) + standard error of the mean (M + t) per group of 9-10 mice. ## p <0.001 (Student's t-test) compared with the control, ** p <0.01; *** p <0.0001 compared with the group receiving beta-amyloid.

Table 5.

The next step in the statistical analysis was to compare the effect of the combination of memantine + melatonin and memantine on neuronal death in the CA1 and SAZ areas of the hippocampus and in the sensory-motor region of the cerebral cortex of mice after administration of beta-amyloid. For these purposes, we used two-way analysis of variance based on matrix Table 6. A matrix for comparing the effects of the combination of memantine + melatonin with memantine on neuronal death caused by beta-amyloid in mice. The table shows the average density (N / mm2) of pycnotic cells in the CA1, SAH areas of the hippocampus and the sensory-motor region of the cerebral cortex of mice + standard errors of the mean value for a group of 9 animals.

 Table 6.

For the CA1 region, two-way analysis of variance revealed a significant effect of the factor “substance” (F 1.32 = 7.77; p <0.01), a significant effect of the factor “dose” (F1, 32 = 5.53; p <0, 05) and the lack of interaction between the factors “substance” and “dose” (F 1.32 = 3, 38; p = 0.07).

For the SAZ area, two-way analysis of variance did not reveal a significant effect of the “substance” factor (f 1.32 = 2.09; p = 0.15), showed a significant influence of the “dose” factor (F 1.32 = 5.46; p = 0.03) and the absence of a reliable interaction between the factors “substance” and “dose” "(Fl, 32 = 0.63; p = 0.4).

 For the sensory-motor region of the cortex, two-way analysis of variance revealed a significant effect of the factor “substance” (Fl, 32 = 13.35; p = 0.0009), a significant effect of the factor “dose” (F 1, 32 = 44, 17; p = 0.0001) and a reliable interaction between the factors “substance” and “dose” (Fl, 32 = 16.66; p = 0.0003).

 Thus, based on the statistical analysis, it can be concluded that the combination of memantine + melatonin has a more pronounced neuroprotective effect than separately administered memantine in neurodegeneration caused by beta-amyloid in the CA1 region of the hippocampus and sensory-motor region of the cerebral cortex of mice.

Example 2. Pharmacological interaction

 To confirm the synergy of effects, several experiments were performed on animal models.

 For this, the active substances Melatonin 3 mg / Memantine 10 mg were taken; Melatonin 5 mg / Memantine 20 mg;

Melatonin 10 mg / Memantine 20 mg, and the dosages recommended for humans, adapted for mice, were translated according to the formula “(active substance / 70 (compare human weight)) x7”. For this, these compositions were dissolved in 5 ml of a solution and, in accordance with the above formula, were administered to animals intraperitoneally, once a day, for 5 days.

 The effect of the compositions on learning and memory factors was studied on white nonlinear male mice weighing 20 +/- 4 g. Using the conditional passive avoidance reaction (passive avoidance reaction) of electroconvulsive shock (ESH) (Ya. Buresh et al., 1991; K.M. Dumayev et al., 1995).

 An electroconvulsive shock (ESH) was used as an amnesic effect, electric current parameters: 50 Hz, 50 mA, 0.3 s, which were applied to mice with the help of clips in the form of clips fixed on the ears, transpineally, immediately after learning of passive avoidance reaction (“Manual on experimental (preclinical) study of new pharmacological substances ”, 2000). In animals of the control group, a pseudoelectroconvulsive shock was caused: pinneal electrodes were applied to apply ESH without applying an electric current. Testing of mice for the preservation of passive avoidance reaction was carried out at certain intervals after ECS.

The passive avoidance reaction test is the main model for assessing the effect of substances on the formation and reproduction of short-term memory in normal and in the conditions of its violation, artificial amnesia. And passive avoidance reaction is the most informative of the methods used today to assess the effectiveness of substances with the effect on the central nervous system of mammals ("Guide to experimental (preclinical) study of new pharmacological substances ”, 2000). The passive avoidance reaction (conditioned reflex of passive avoidance in a dark, light chamber) in mice was performed on the basis of electrodermal reinforcement according to the method of Cumin et al. (1982) taking into account the recommendations of Mondadori et al. (1990). The mouse installation of Lafayette Instrument Co., USA was a black chamber with an electrode floor and a white plastic platform, which was placed on the floor in the center of the chamber. Mice, one at a time, were placed on a plastic platform. Animals descend / jump from the platform onto the electrode floor, where they receive an electric shock, the so-called punishment. Electric current was supplied, the field as the animal rested with all four paws. The natural reaction of the animal is to return to a dead or safe platform. After several minutes of training, on average about 5 minutes, passive avoidance reaction was developed in mice and they remained on a safe platform. Tests for memorizing passive avoidance reaction were carried out at successive intervals after an amnesic effect. In the case when the animal lowered the axis / jumped about onto the platform for 1 min, he noted retrograde amnesia of the passive avoidance skill. The study of the compositions was carried out in comparison with Melatonin 5 mg (monopoly) and Memantine 10 mg (monopoly), in accordance with the above formula for adaptation to animal models.

 Table 7.

Thus, in most mice, ECS caused retrograde amnesia of passive avoidance skill; in 80% of animals (p <0.001), amnesia of acquired skills was observed after 24 hours. Melatonin and Memantine altered the amnestic effect. Compositions containing Memantine and Melatonin significantly (p <0.05) weakened the amnestic effect. Moreover, the severity of the action of the studied compositions was superior to both Melatonin and Memantine separately. The influence of the studied composition on amnesia in mice caused by electroconvulsive shock (ESH)

 5

 Table 8.

 Significance of differences compared with the control + false ESF group of rats at p <0.05 (Student t-test;%)

** Reliability of differences compared with the control group + 10 ESS at p <0.05 (Student t-test;%) Also, the antiamnestic effect of the studied compositions on the model of amnesia caused by scopolamine was studied on white nonlinear male mice weighing 20-24 g using development of passive avoidance reaction in animals according to the method described above. The scopolamine amnesia model - this m-anticholinergic blocker (scopolamine) was reproduced by administering to mice i.v. at a dose of 1 mg / kg immediately after learning passive avoidance reaction ("Manual on experimental (preclinical) study of new pharmacological substances", 2000). The test compositions indicated were dissolved in 5 ml. solution and in accordance with the above formula, was administered to animals intraperitoneally, once a day, for 5 days.

 Table 9.

Therapeutic agent Total number of mice, (dose) and ESH the number of trained passive avoidance mouse (%)

 Isotonic solution of NaCl 1 1 90.9

 (the control)

 Scopolamine (1 mg / kg) 12 58.3

 Melatonin 5 mg + scopolamine 1 1 66.7

 Memantine 10 mg + scopolamine 10 70

 Melatonin 3 mg / Memantine 10 12 75

 mg + scopolamine

 Melatonin 5 mg / Memantine 20 1 1 72.7

 mg + scopolamine

 Melatonin 10 mg / Memantine 20 11 81, 8

mg + scopolamine The effect of the studied composition on amnesia in mice caused by scopolamine

 Table 10.

 5

Scopolamine provoked retrograde amnesia of the skill in a significant part of animals in 90% of the animals, p <0.001 - after 24 h, passive avoidance reaction amnesia was observed. The single use of Melatonin and Memantine was not significant, but affected the amnesia of the acquired skills.

 Compositions containing Melatonin + Memantine significantly weakened the amnestic effect by 1.5 times to varying degrees of variation. Compositions Containing

Melatonin + Memantine exceeded the effects of monoprotein Melatonin + Memantine and prevented the development of amnesia of passive avoidance reaction.

Anti-amnestic effect of the studied compositions on the model of amnesia induced by swimming mice in cold water with the rotation of the wheel to exhaustion. The studies were conducted on white nonlinear male mice weighing 20-24 g using the development of passive avoidance reaction in animals, as in previous studies. The animal, one at a time, was placed in a water-filled container the size of a spinning wheel. Swimming mice in cold water with the simultaneous rotation of the wheel to exhaustion was performed after learning passive avoidance reaction. The safety of passive avoidance reaction was checked at periodic intervals. As a false simulation of swimming mice in cold water, the animal was placed in a cage with a bed of wet cold cotton. The test substances and isotonic sodium chloride solution (control) were carried out in comparison with Melatonin 5 mg (monopoly) and Memantine 10 mg (monopoly), in accordance with the above the formula for adapting to animal models in / b the introduction to the training of mice, once a day, for 5 days.

The influence of the studied compositions on the amnestic effect caused by swimming mice in cold water with the simultaneous rotation of the wheel to exhaustion

Table 1 1.

Table 12.

Passport Reproduction Group

 animal day after 3 days after 7 days after 10 days after learning training learning training latent latent latent latent latency time quality time quality time of entry into rats, entry into rats, entry into rats, entry into rats, dark, not dark, not dark, not dark, not a camera, with an input camera, with an input camera, with an input camera, from those entering them into their dark dark dark dark camera, camera, camera, camera,

%%%%

1 2 3 4 5 6 7 8 9

RR NaCI 152, 90 150, 70 147. 60 145, 60 ionotonic + 2 ± 13.2 3 ± Н4 2 123.5 2 + 18.5 imitation

swimming in

cold water

(the control)

 RR NaCI 69.4 36.3 72.5 45.4 74.1 54.5 75.1 54.5 isotonic

 + swimming ± 27.2 ± 12.9 ± 18.3 ± 12.7 mice in

cold

water with

simultaneous

rotation

wheels up

exhaustion

 elatonin 5 mg + 109, 61, 5 105.4 46.1 104.6 38.5 100.9 30.7 swimming mice 3 + 9.8 ± 13.5 ± 15.1 ± 17.4 in cold

water with

simultaneous

rotation

wheels up

exhaustion

 emantine 10 mg + 111.3 41.6 115.9 50 117.4 66.6 118.0 66.6 swimming mice ± 22.3 ± 16.5 ± 28.1 ± 23.3 in olodnoe

water with

simultaneous

rotation

wheels up

exhaustion Continuation of Table 12.

The influence of the studied compositions on passive avoidance reaction of animals in the conditions of the open field technique after acute

 5 normobaric hypoxic hypoxia with hypercapnia

Table 13.

Group of animals Horizontal- Vertical Examination of motor movement

 1 2 4 4

 1st day after surgery

NaCI solution isotonic + false 14.9 + 5.2 6.2 + 2.1 4.3 + 1.3 hypoxia (control) Continuation of Table 13.

1 2 4 4

NaCI solution isotonic + hypoxia 6.1 ± 3.1 3.0 + 1, 2 1, 5 + 0.9

Melatonin 5 mg + hypoxia 6.9 ± 2.3 3.2 + 1, 2 1, 7 + 0.6

Memantine 10 mg + hypoxia 7.1 + 2.7 3.7 ± 1.9 2.1 ± 1, 1

Melatonin 3 mg / Memantine 10 mg + 8.5 + 1, 9 4.6 + 3.1 1, 3 + 2.4 hypoxia

 Melatonin 5 mg / Memantine 20 mg + 8.7 ± 2.1 4.3 + 2.8 2.3 + 2.4 hypoxia

 Melatonin 10 mg / Memantine 20 mg + 8.4 + 1.5 4.2 ± 2.7 2.0 + 1.6 hypoxia

 3rd day after surgery

 NaCI solution isotonic + false 14.1 + 1.6 5.7 + 2.1 2.8 + 1, 2 hypoxia (control)

 NaCl solution isotonic + hypoxia 5.9 ± 1, 8 3.1 + 1.2 1, 3 + 1.0

Melatonin 5 mg + hypoxia 8.2 + 1, 4 * 3.5 + 0.9 1, 9 + 0.8

Memantine 10 mg + hypoxia 8.9 + 4.9 3.3 ± 1, 2 2.5 ± 1, 1

Melatonin 3 mg / Memantine 10 mg + 11.7 + 3.1 4.2 +1.7 2.5 ± 0.9 hypoxia

 Melatonin 5 mg / Memantine 20 mg + 12.1 ± 2.5 4.4 + 1, 5 2.9 + 1.3 hypoxia

 Melatonin 10 mg / Memantine 20 mg + 11.9 ± 3.2 4.5 +2.1 2.1 +1.4 hypoxia

 7th day after surgery

 NaCI solution isotonic + false 13.5 + 1, 9 5.1 + 2.1 3.4 ± 2.5 hypoxia (control)

 NaCI solution isotonic + hypoxia 7.0 + 1, 6 2.9 + 2.4 1, 9 + 1.3

Melatonin 5 mg + hypoxia 8.3 ± 2.8 3.2 + 1.3 2.4 + 0.5

Memantine 10 mg + hypoxia 9.6 ± 3.4 3.7 + 1, 8 3.0 + 2.7

Melatonin 3 mg / Memantine 10 mg + 14.2 + 2.6 ** 5.1 ± 3.1 3.2 ± 1.4 hypoxia

 Melatonin 5 mg / Memantine 20 mg + 16.1 + 1.6 ** 5.3 + 2.2 3.8 + 1.7 ** hypoxia

Melatonin 10 mg / Memantine 20 mg + 14.7 + 2.6 5.3 ± 3.5 2.7 ± 2.4 hypoxia Continuation of Table 13.

 * Significance of differences compared with a group of animals with false hypoxia at p <0.05 (Student's t-test)

** Reliability of differences compared with hypoxia at p <0.05 (Student t-test)

 Thus, the new combination shows high efficiency, expressed in facilitating the manifestation of mental, behavioral, cognitive disorders in organic lesions of the central nervous system of various origins.

Example 3. Clinical Trials

25 patients with mixed dementia and 12 patients with Alzheimer's disease were examined. The average age of patients was 70 ± 3 years. Diagnosis of dementia was carried out in accordance with the criteria for dementia ICD-10 [International Statistical Classification of Diseases and Health Problems. Tenth revision (ICD- 10). Tl (part 1). Geneva: WHO, 1995; p. 315, 510-1]. The severity of dementia was assessed using the Clinical Dementia Rating Scale (CDR) [Hughes CP, Berg L, Danziger WL et al. A new clinical scale for the staging of dementia. Brit J Psychiatry 1982; 140: 566-72]. In the group of patients with mixed dementia, it was 1.2 ± 0.3, and in the group with Alzheimer's disease 1.1 ± 0.36. All patients were divided into two groups. The first group was prescribed memantine 50 mg 1 time per day. The second group was prescribed capsules according to Example 4. For six months, patients underwent a comprehensive neurological study, including a brief assessment of mental status (MMSE), a test for visual and auditory-speech memory of the dementia scale, a clock drawing test (Clock Drawing Test), and a test for attention - Schulte test. Processing of the results was carried out using the statistical software package SPSS, version 10.0.

Results: After 1, 5 months. after taking the drug in patients of both groups, a significant decrease in the severity of cognitive impairment was noted. In the first group, after 6 months, the overall mental status score increased by 1.5 ± 0.3, visual memory - by 0.5 ± 0.2, the clock drawing test - 0.2 ± 0.1. Schulte test decrease - by 20.5 ± 3.6, in the second group, respectively: by 2.4 + 0.5, 0.8 ± 0.2, 0.4 + 0.1, 36.2 ± 4.5 . In the first group, in 2 patients there was a need to reduce the dose, since an increase in intracranial pressure was observed.

 In the first group, a positive effect of therapy was observed in 25% of patients with Alzheimer's disease, 86% in patients with mixed dementia. In the second group, a positive effect was observed in patients with Alzheimer's disease 40%, in patients with mixed dementia - 92%, no pronounced side effects were observed. The remaining subjects experienced the effect of stabilization of the state.

 Thus, a significant increase in the effect of memantine is clearly seen when combined with melatonin.

Example 4. Formulations

 Composition of tablets Memantine and Melatonin

 Table 14.

Substance mg wt.%

 Memantine 100 40.00%

Melatonin 5 2.00%

Lactose 70 28.00%

Microcrystalline cellulose 24.75 9.90%

Starch 26 10.40%

Povidone 12.5 5.00%

Croscarmellose 9.75 3.90%

Calcium Stearate 2 0.80%

Total tablet weight 250 100.00% Table 15.

 Table 16.

High-dose formulations of memantine and melatonin

Table 17.

Composition of Memantine and Melatonin Capsules

Substance mg% mg%

Memantine 50 40.13% 100 80.0%

Melatonin 3 2.41% 5 4.0%

Lactose 59.5 47.75% 9.25 7.4%

Povidone 5.75 4.62% 2 1.6%

Croscarmellose 5.75 4.61% 6.75 5.4%

Calcium stearate 0.6 0.48% 2 1.6%

Total capsule weight 124.6 100% 125 100% Industrial applicability

The combination can be indicated in medical conditions that are accompanied by clinical manifestations of organic psychosyndrome (and its most significant component - dementia): Alzheimer's disease, vascular (multi-infarction) dementia, alcoholism, intracranial volume processes - tumors, subdural hematomas and brain abscesses, anoxia, cranial brain injury, normotensive hydrocephalus, Parkinson's disease, Huntington's chorea, progressive supranuclear palsy, Peak's disease, amyotrophic lateral sclera h, spinocerebellar degeneration, ophthalmoplegia in combination with metachromatic leukodystrophy (adult form), Gellerwarden-Spatz disease, hash psychosis, advanced stages, infections, Creutzfeldt-Jakob disease, viral encephalitis, progressive multifocal leukocytic leukemic leukemia, meningitis; Deficit states, Gaye-Wernicke-Korsakov syndrome - thiamine deficiency, vitamin B 12 deficiency, folic acid deficiency, vitamin B3 deficiency, pellagra; Metabolic disorders, dialysis dementia, hypo- and hyperfunction of the thyroid gland, severe renal failure, Cushing's syndrome, liver failure, diseases parathyroid glands, systemic lupus erythematosus and other collagen diseases accompanied by cerebral vasculitis, multiple sclerosis, Whipple's disease.

Claims

CLAIM

1. A pharmaceutical combination for the treatment and / or correction and / or prevention of manifestations of mental, cognitive, behavioral and neurological disorders in organic diseases of the central nervous system of various origins, manifestations of amyloid intoxication, characterized in that it contains melatonin and memantine in therapeutically effective amounts.

2. The pharmaceutical combination according to claim 1, characterized in that for the treatment and / or prevention of manifestations of mental, cognitive, behavioral and neurological disorders in organic diseases of the central nervous system of various origins, it contains Melatonin in an amount of from 0.01 mg to 50 mg and Memantine amount from 0.01 to 100 mg.

3. The pharmaceutical combination according to claim 1, characterized in that for the treatment, prevention or correction of manifestations of amyloid intoxication, it contains from 5 to 300 mg of memantine and from 3 to 10 mg of melatonin.

4. The pharmaceutical combination according to any one of claims 1 to 3, characterized in that it is intended for administration to a mammal, including humans.

5. The pharmaceutical combination according to any one of claims 1 to 3, characterized in that the composition is presented in the form of: tablets, including sublingual forms, capsules, modified-release dosage forms, injectable form, suppository, beverage preparation powder, drops, including nasal drops, transdermal, buccal, aerosol forms.

6. A pharmaceutical composition for treating and / or correcting and / or preventing manifestations of mental, cognitive, behavioral and neurological disorders in organic diseases of the central nervous system of various origins, manifestations of amyloid intoxication, characterized in that it contains Melatonin and Memantine in an effective amount as an active principle and excipients.

7. The pharmaceutical composition according to claim 6, characterized in that it is made in the form of a solid dosage form for oral administration containing, as auxiliary substances, at least one diluent selected from lactose, starch, a derivative starch, microcrystalline cellulose, sucrose, invert sugar, dextrose and dextrate, at least one disintegrating agent selected from sodium carboxymethyl cellulose, Croscarmellose, gelatinized starch, a binder selected from polyvinylpyrrolidene alginate, cellulose gum, gelatin , an antifriction agent selected from stearic acid and / or its salts, colloidal silicon dioxide, talc, sodium benzoate, sodium acetate and sodium oleate in the following the content of the components in wt.%:

 Memantine 40.0-90.0

 Melatonin 2.0-5.0

 diluent 2.0-50.0

 binder 3.5-10.0

 disintegrating agent 1.5-10.0

 Anti-friction agent 0.2-3.0

8. The use of the combination of Melatonin and Memantine according to any one of claims 1 to 5 for the preparation of a drug for the treatment and / or correction and / or prevention of manifestations of mental, cognitive, behavioral and neurological disorders in organic diseases of the central nervous system of various origins, manifestations of amyloid intoxication.

9. The use of claim 8, where the manifestation of amyloid intoxication is observed in cases of cognitive decline in vascular lesions and post-traumatic conditions.