Pharmaceutical composition for preventing and treating mental, behaviour and cognitive disorders

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and chemical-pharmaceutical industry, namely to neurology, and concerns new compositions containing memantine and melatonin. It is possible to implement the invention by preparing a solid dosage form, such as a tablet or capsule.

EFFECT: intensified effect of memantine when combined with melatonin.

10 cl, 5 ex

 

The invention relates to the field of medicine and pharmaceutical industry, in particular to the field of neurology, and relates to new compositions containing Memantine and Melatonin.

The background to the invention.

Memantine - potentsialzavisimye, the average affinity, noncompetitive antagonist of the NMDA receptor. Memantine blocks the effects of pathologically elevated levels of glutamate that may lead to dysfunction of neurons. Exerts neuroprotective, anti-spastic, anti-Parkinsonian actions. Inhibits glutamatergic neurotransmission and progression of neurodegenerative processes, has neyromoduliruyuschim action. Contributes to the normalization of mental activity, improves memory, increases ability to concentrate, correction of musculoskeletal disorders [Ditzler K. Efficacy and tolerability of memantine in patients with dementiasyndrome. A double-blind, placebocontrolledtrial. Arzneimittel-Forschung. 1991; 41:773-80]. In addition to their primary mechanism of action (effect on glutamatergic transmission) memantine has additional serotoninergicheskim effect (non-competitive antagonist NT receptors) and, possibly, its antidepressant effect due to this mechanism. Clinically antidepressant effect of memantine shown in a number of works on the model of major depression [Ferguson JM, Shingleton RN. An open-label, flexible-dose study of memantne in major depressive disorder. ClinNeuropharmacol 2007; 30 (3); 136-44].

After a single dose of memantine peak concentration in the brain is achieved after 1 h half-life of memantine is quite long and is about 100 hours for Such a long half-life suggests that this drug has the effect of accumulation during chronic administration. So, after a single dose of memantine concentration of dopamine remains unchanged, but long-term use concentration of dopamine in frontal areas of the cerebral cortex increases by more than 10 times. The longer applies memantine, the more increases the concentration of dopamine. Analysis of concentrations of metabolites of dopamine showed that the use of memantine is an increase in the release and synthesis of dopamine [Hesselink MB, DeBoer AG, Breimer DD et al. J NeuralTransm 1999; 106: 803-18].

From literature data it is known that the chronic administration of memantine affects the increase in the concentration of not only dopamine, and acetylcholine, as well as increasing the number of cerebral muscarinic receptors. Thus, it can be assumed that this drug has a complex mediated mediator effects on the neurons of the cortex of the frontal lobes and entorhinal cortex and its connections with the parietal-temporal lobe brain.

The second and the aspect of therapeutic activity of memantine - neuroprotective effect. This effect is a direct result of the blockade of NMDA receptors, closing ionotropic channels and, accordingly, stabilization of the cell membrane that protects cells from death. The neuroprotective effect of memantine was proven in models of cerebral ischemia in the experiment [Danysz W, Parsons CG, Mobius H-J et al. NeurotoxRes 2000; 2: 85-97]. Preventive administration of memantine reduced the area of ischemic penumbra, the severity of cerebral edema, and reduced the area of the ischemic focus. A similar result was obtained in other models of brain lesions. It is assumed that memantine may have a stimulating effect on the synthesis of a number of neurotrophic factors, in particular mezhoperatorskogo neurotrophic factors (brain-derived neurotrophic factor), which also leads to stabilization of neuronal membranes and protect cells from death.

It was shown that the use of antagonists of the NMDA receptor has a positive effect on cognitive function in patients with Parkinson's disease [Dumoulin IV eng. the honey. Journe. 2001; 9 (25): 1178-82, Litvinenko, I.V., M. Odinak, Ukr. neurol. and the psychiatrist. them. Saw. 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 U.S. patents NN 4122193; 4273774; 5061703. Memantine and other 1-aminoalkylsilane on what has proved useful in reducing various progressive neurodegenerative disorders such as dementia in patients with moderate and severe disease of Alzeihmer, Parkinson's disease, and muscle spasticity, which are disclosed in U.S. patents NN 5061703; 5614560 and 6034134.

Melatonin (N-acetyl-5-methoxytryptamine) - neuropeptide synthesized mainly by the pineal gland and has a number of unique properties in humans and mammals. Significant is the fact circadian (okolomatocnah) frequency generation in pinealocyte biologically active compounds. The synthesis of melatonin effectively occurs only after dark, and falls into a light phase of the day - a fact first shown R.Wurtman in 1960. Quite short light pulse power 0.1 to 1 lux)to suppress this process. In the daytime in the tissue of the gland, in contrast, accumulate serotonin. The daily rhythm in melatonin depends on NAT activity in the retina, which, in turn, depends on calcium ions, dopamine and gammaaminobutyric acid (GABA). With the help of melatonin, the pineal gland is involved in the organization of the daily periodismo and in the regulation of cyclic processes, mediating between the pacemaker mechanism of the suprachiasmatic nuclei (SHA) and peripheral organs. The epiphysis with SHA hypothalamus included in the system of so-called biological clock of the body, which play a key role in the mechanisms of accounts internal time" is aging [Arushanyan AB, 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 anti-tumor protection [Anisimov V.N., 1998, 2003]. Although the major source of melatonin circulating in the blood, is the epiphysis detected and paracrine synthesis of melatonin in almost all organs and tissues: thymus, gastrointestinal tract, gonads, connective tissue [Reiter R.J.; Raikhlin IM, kvetnoy I.M.; Huether G.].

Melatonin (N-acetyl-5-methoxytryptamine) is an indole compound produced by the pineal gland, retina, and intestines.

As the age of the epiphysis of people and animals, like the thymus, involucrum. Decreases the number of active secretory elements gland, pinealocytes, with the fall production of melatonin. About 45 years in the plasma contains only half the amount of hormone that is produced in adolescence. In the elderly and to vary the amplitude and dynamics of the circadian secretion of melatonin [Korkushko O.V., Khavinson V.H., Shatilo V.B. have been the Pineal gland: path correction during aging. SPb. Science - 2006. 204 C., Reiter R.J. The aging pineal gland and its physiological consequences // BioEssays - 1992. - V.14. - p.169-175, D.J. Skene, Swaab D.F. Melatonin rhythmicity: effect of age and Alzheimer's disease // Exp.Gerontol. - 2003. - V.38. - p.199-206]. In experiments on animals and monitoring therapy of elderly people, as in n is RME, and with various forms of cerebral pathologies, including cardiovascular in nature, melatonin improves the processes of memory, visual and auditory perception, concentration. These facts determined therapeutic possibilities of melatonin as a potential neuroprotective agent [Arushanyan AB Hormone of pineal melatonin is a new nootropic agent? // Expert. and the wedge. Pharmacol. - 2005. - T. - p.74-79, Arushanyan AB Epiphyseal hormone melatonin and neurological pathology // Rus. the honey. Journe. - 2006. - T. - s-1063].

In experiments on models of acute cerebral hemodynamics in animals: a total or focal ischemia due to occlusion of the arteries, photothrombosis melatonin has continuously provided a clear neuroprotective effect [Reiter R.J., Tan D.X, 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 model of a closed injury of the brain the hormone during the week accelerated normalization of animal behavior and regenerative processes in the hearth damage in the form of decreasing size with increasing plasma concentration of some antioxidants, including ascorbic acid [Beni S.M., Cohen R., Reiter R.J. et al. 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 R.G. Neuroprotection by melatonin in mice submitted to brain injury // Naunyn. Schmiedeberg'sArch Pharmacol. - 1998. V.358. - p.R32/]. Data obtained using objective imaging techniques (magnetic-adenokortsinoma), have shown that repeated administration to rats melatonin 2 times reduces ischemic brain edema [Torii K., Uneyama H., 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 the cerebral formations, such as the neocortex, hippocampus, striatum, with data, nuclear magnetic resonance imaging allows to detect a statistically significant protective effect epiphyseal hormone, where it was able to maintain the viability of a significant number of cellular elements. This significantly limited the severity of cerebral edema. Noted the fact that in the cerebral cortex swelling weakened stronger than in the striatum [Kondoh T., Uneyama N., Nishino H. 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., etal. Melatonin improves cerebral circulation security margin in rats // Am. J. Physiol. - 1998. - V.275. - p.H139-H134, Sinha K., Degaonkar M.N., Jagannathan N.R. 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 evolutionary included in the natural protection system of the brain from ischemic damage, as evidenced by the results of experiments on animals is, have a variety of ways, the extirpation of the epiphysis, long content in bright light, creating a hormone deficiency. Under such conditions was much pronounced foci of infarction of brain tissue in the simulation stroke by cortical photothrombosis or local occlusion of the middle cerebral artery. While injections of melatonin on the background, for example, the same apisaksirikul dostovernoi protection of cortical neurons from ischemia of razlichayuthikhsya [E. Kilic, Y. Ozdemir, H. Bolay Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia. // J. Cerebr. BloodFlowMetabol. - 1999. - V.19. - p.511-516].

A strong factor of oxidative stress in cerebral blood flow due to atherosclerosis, stroke, or traumatic brain injury is recognized pathological hyperactivity glutamic acid [Gusev E.I., V.I. Skvortsova Glutamic neurotransmission and calcium metabolism in normal and cerebral ischemia // Success Fiziol. Sciences. - 2002. - V.33 - P80-93]. The accumulation of glutamate in the synapses and the intercellular space leads to the launch of glutamate-calcium cascade. By excitation of N-methyl-D-aspartate (NMDA) glutamate receptors opens channels in neuronal membranes to calcium ions and intracellular accumulation of them in large quantities, which inevitably determines the damage of cellular structures. Melatoni is clearly inhibits glutamate neurotoxicity. As installed on the culture of isolated cortical neuronal damage in excess of glutamate or NMDA was significantly inhibited after the addition of the incubation environment of melatonin. This is to some extent due to its ability to bind calmodulin and to restrict the function of the NMDA receptor. And apisalome increased density of the latter with simultaneous strengthening of GENDER in different brain structures. Melatonin protects neurons from NO aggression, the excess of which can potentiate glutamate neurotoxicity [GuerreroJ.M., 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 supported. - p.24-31]. Melatonin, also normalizes the activity of the mitochondria [El-Abhar H.S., M. Shaalan, M. Barakat 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 hyperphosphorylated proteins and disruption of the cytoskeleton, and also restores the function tyrosinekinase receptor apparatus. Which is an important element of the system of phosphorylation and is involved in reparative processes of the nervous tissue through the involvement in it of neurotrophins [Olivieri G., Often U., Meier F. etal. Beta-amyloid modulates tyrosine kinase In receptor expression in SH SY SY neuroblastome cells: influenc of the antioxidant melatonin // Neurosci. - 2003. - V.120. - p.659-665]. Melatonin is probably stimulates neurogenesis in the adult nervous tissue. In the culture of stem cells revealed that they can Express melatoninbuy receptors, mainly of the 1st type. Adding thereto a solution of melatonin in low concentration provokes, among others, the induction of mRNA of one of the neurotrophins - glial growth factor (GDNF) [Niles L.P., Armstrong K.J., RinconCastro L.M. et al. 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]. Known patent documents, which revealed the use of Melatonin. RF patent №2268737 "a Method for the treatment of atopic dermatitis" by assigning Melatonin at a dose of 3 mg, at 21.00, 21 days course; RF patent №2428183 use of melatonin as adaptogene"; patent RF №2418586 "Method for correction of abnormalities in the reproductive organs by introducing melatonin"; patent RF №2394571 "Method of treatment of inflammatory bowel disease by introducing melatonin 40 minutes before sleep: RF patent №2336890 "Compositions comprising melatonin, glingobiloba and Biotin", discloses a composition for stimulating hair growth; RF patent №2294741 "A method for the treatment of patients with ischemic heart disease, administration of melatonin on the background of standard therapy; RF application No. 2008150624 (PCT application US 373.06.2007 20070521) "Treatment of depressive disorders; application R the No. 2009141713 (PCT application US 100.06.2008 20080411) "Protective composition from ischemia/reperfusion", where reference is made in combination melatonin; RF application No. 2009137472 "Tablet melatonin and methods of manufacture and application"containing melatonin in a dissolved state, associated with a pharmaceutically acceptable carrier; RF application No. 97113435 "Method of treatment of drug abuse".

Well-known medication for the treatment of dementia in the form of tablets, coated film-coated, containing memantine. Tablets contain the memantine hydrochloride 10 mg, excipients: colloidal silicon dioxide (Aerosil) 3 mg; calcium hydrogen phosphate dehydrate and 50.4 mg; croscarmellose sodium (Primerose) 3 mg; lactose monohydrate (milk sugar) 136 mg; magnesium stearate 1.6 mg; povidone 6 mg; shell: Select AQ-02003 6 mg, including: hypromellose (hypromellose) 3.6 mg; macrogol-6000 (polyethylene glycol 6000) 1.2 mg; titanium oxide a 1.2 mg(http://www.canonpharma.ru/EN/drugs/expert/doctors/neurology/memantinkanon/).

Known drug VITA-MELATONIN®, manufactured Kiev vitamin factory containing Melatonin 3 mg other ingredients: milk sugar, microcrystalline cellulose, potato starch, calcium stearate. The drug is intended for the prevention and treatment of disorders of circadian rhythm sleep-Wake" when you change time zones, manifested by fatigue; sleep disorders, including chronic insomnia functional origin is I, insomnia in the elderly (including those with concomitant hypertension and hypercholesterolemia); to improve mental and physical performance, and eliminate stress reactions and depression that has a seasonal character. High blood pressure and hypertension (stage I-II) in elderly patients (in complex therapy) (http://compendium.com.ua/info/67093).

As the closest analogue may be specified patent RU 2326660 C1, which concerns the manufacture of oral dosage forms of drugs with neuroprotective effect, in particular drug memantine modulator glutamatergic system used in the treatment of dementia, weakening of memory, cerebral and spinal spastic syndrome. The drug Memantine in the form of capsules, and it is included in a therapeutically effective amount of the composition fill these capsules weight, which is a mixture of powders or granules. Capsule weight further comprises excipients: physiologically neutral filler, and if necessary disintegrant and anti-friction substance.

The objective of the invention is the creation of solid dosage forms, where memantine and melatonin are in fixed combination with high therapeutic properties and reduced pobo the different effects.

The problem is solved with new preparative forms in which the content of active substances can reach very high values, about 90%, and even more, use the minimum number of auxiliary substances, which are affordable and which provide for cost-effective production in industrial scale. The present invention provides the ability to get these important technical results.

Thus, minimizing the number of auxiliary substances, exception use, but not exclusively, organic solvents, reducing the number of stages and reducing the time and cost of production creates preconditions to the invention.

The object of the invention is a pharmaceutical composition for the prevention and treatment of mental, behavioral, and cognitive disorders in the form of a solid dosage form containing memantine and melatonin as active principle and excipients comprising at least one diluent selected from lactose, starch, a derivative of starch, microcrystalline cellulose, sucrose, inverted from what you think of sugar, dextrose and dextrine at least one dezintegriruetsja agent selected from sodium carboxymethylcellulose, Croscarmellose, gelatinising starch, a binder selected from polyvinyl is rolidone, gelatin, cellulose derivatives, natural gums, glycols, sodium alginate, anti-friction agent is selected from stearic acid and/or its salts, colloidal silicon dioxide, talc, sodium benzoate, sodium acetate and sodium oleate in the following components in wt.%:

Memantineof 40.0 to 90.0
Melatonin2,0-5,0
thinnera 2.0 to 50.0
binder3,5-10,0
disintegrity agentthe 1.5-10.0
Antifriction agent0,2-3,0

To obtain the drug, in particular, the composition of Memantine with Melatonin mixed with a different accessory with getting a solid form of Memantine with Melatonin. In some embodiments, the implementation of the solid form is a tablet formulation, in other embodiments, the implementation of this capsule or powder for solution oral administration.

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

Also the invention includes the use of these compositions for the treatment of diseases and/or disorders in people in need, which includes oral administration of therapeutically effective amounts of the compositions of the present invention.

For the implementation of the present invention, but are not limited to, a composition, which includes Memantine and Melatonin does not contain magnesium silicate or talc. In some preferred embodiments of the described composition contains Memantine and Melatonin, one or more diluents, each independently selected from starch, monohydrate lactose or microcrystalline cellulose, one or more dezintegriruetsja substances, each independently selected from gelatinizing starch or carboxymethyl cellulose, binder and anti-friction agent representing a lubricating substance. In other preferred embodiments, the implementation of the binder is polyvinylpyrrolidone, and a lubricating substance is a stearate. In other variants, but not exceptional, the implementation of the invention, the diluent may be lactose (the form of the monohydrate), dezintegriraat substance can be crosscarmellose (as sodium salt), and the binder is a Povidone.

Pharmaceutically acceptable excipients are chosen to deliver a therapeutically effective dose amount of the Memantine and Melatonin in the conventional unit dosage form and to optimize the cost, ease, and stability of the production process. A necessary condition for the auxiliary substances are inert, chemical-physical compatibility with Memantine and Melatonin. Excipients used in solid dosage forms like tablets and capsules, may additionally include dyes and pigments, substances that mask the taste, flavors, sweeteners and adsorbents.

Thinners help to increase size pills with small amounts of active drug. The diluents include lactose, in the form of alpha-lactose or beta-lactose. Different types of lactose may consist of monohydrate lactose monohydrate, alpha-lactose, anhydrous alpha-lactose, anhydrous beta-lactose and agglomerated lactose. Other diluents may include sugars such as sucrose, investirovanie sugar, dextrose and dexterity. The preferred diluent is monohydrate lacquer is eskers. Another diluent may be microcrystalline cellulose, including micronized.

Diluents may include starch and derivatives of starch. Starches include natural starches derived from different grains and/or other agricultural crops. The starches may also include pre-starch and starch-modified glycolate sodium. Starch and derivatives of starch are also in it dezintegriruetsja substances. Many also act as diluents dezintegriruetsja substance and a binder, and these additional properties need to be considered in the technology of drug composition. Dezintegriruetsja substances added to destroy the tablets on the particles of the active pharmaceutical component and auxiliary, to facilitate dissolution and increase the bioavailability of a therapeutically active ingredients. Starch and starch derivatives, including sodium salt carboxymethylated ether of starch, such as starch, modified glycolate sodium, are used dezinfeciruyuhimi substances. Preferred, but not exclusive, dezintegriraat substance can be gelatinising starch. Other preferred dezintegriraat substance is carboxymethylcellulose sodium./p>

Binders are used as pharmaceutically acceptable auxiliary substances for the wet granulation to improve the concentration of therapeutically active substances, and other supporting ingredients in forming the granules. The binder is added to improve the fluidity of the powder and to improve compaction. Binders include cellulose derivatives such as microcrystalline cellulose, methylcellulose, carboxymethyl cellulose, hypromellose, hydroxyethylcellulose and hydroxypropylcellulose. Other binder ingredients selected from substances such as povidone, polyvinylpyrrolidone, gelatin, a natural gum, namely acacia, tragacanth, guar and pectin gum, starch paste, pre-gelatinising starch, polyethylene glycols, and sodium alginate. The preferred binder is polyvinylpyrrolidone, in particular, Povidone.

Antifriction agents are lubricating and sliding substances that are used in the manufacturing of solid dosage forms to inhibit bonding of tablets with technological surfaces and to reduce the buildup during the stages of pressing. Such substances include stearic acid, salts of stearic acid such as calcium stearate,magnesium stearate and stearyl fumarate sodium, talc, sodium benzoate, sodium acetate and sodium oleate. Choice for lubricants, but not exceptional, is magnesium stearate.

To improve yield, reduce friction between particles, use a lubricating substance in solid dosage forms. Lubricants are property and diluents and curing component.

In additional embodiments, the manufacture of the composition of Memantine and Melatonin content of the active principle is about 30-50% by weight of the combination. Preferably the composition comprises a diluent which is a monohydrate lactose, but not exclusively, a second diluent, which is a microcrystalline cellulose, but not exclusively, dezintegriruetsja substance, which is gelatinising starch, but not exclusively, the second dezintegriruetsja substance, which represents a carboxymethyl cellulose, but not exclusively, binder, which is polyvinylpyrrolidone, but not exclusively, and grease, which is a stearate, but not exclusively. In some other preferred embodiments, the implementation of the lactose monohydrate is about 25-40% by weight of the composition, microcrystalline cellulose is from about 5-15% gelatinising starch is about 5-10%, carboxymethylcellulose sodium is from about 1-5%, polyvinylpyrrolidone is from about 1-5%, and magnesium stearate is from about 0.2 to 2.0 percent.

In some of the most selected embodiments of the active principle is about 40,0% by weight of the composition, the lactose monohydrate is approximately 28.7 percent, microcrystalline cellulose is approximately 10.4%, starch is approximately 10.9%, carboxymethylcellulose is about 4.0%, polyvinylpyrrolidone is about 5.2% and magnesium stearate is about 0.8%.

In another embodiments, the implementation of Memantine and Melatonin is 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;

dezintegriruetsja substance, such as, for example, cross-linked carboxymethylcellulose sodium, preferably from about 2-10% by weight of the composition; a binder such as polyvinylpyrrolidone, preferably from about 2-10% by weight of the composition; and a lubricating substance, such as, for example, magnesium stearate, preferably about from 0.2 to 2.0% by weight of the composition.

In additional embodiments, the implementation of Memantine and Melatonin is approximately 80% by weight of the composition, the diluent is a monohydrate lacquer is eskers, which is from 8 to 15% by weight of the composition; dezintegriruetsja substance is a carboxymethyl cellulose, which ranges from 1 to 10% by weight of the composition; the binder is polyvinylpyrrolidone, which ranges from 1 to 10% by weight of the composition; and antifriction lubricating agent is a stearate, which is 0.2 to 2.0% by weight of the composition.

In some preferred embodiments, the implementation of the diluent is a monohydrate lactose, and it can be about 9.5 percent by weight of the composition, dezintegriruetsja substance represents croscarmelose, and it can be approximately 5% by weight of the composition, the binder is a Povidone, and it can be approximately 5% by weight of the composition, and a lubricating substance is a stearate, and it can be about 0.5% by weight of the composition.

In other embodiments, the implementation of Memantine and Melatonin is about 90% by weight of the composition. Preferably, but not exclusively, the composition comprises a diluent as lactose monohydrate, ranging from 3-10% by weight of the composition; dezintegriruetsja substance, for example carboxymethylcellulose, preferably from about 2-5% by weight of the composition; a binder, such as polyvinyle alidon, preferably from about 2-5% by weight of the composition; and a lubricating substance, such as magnesium stearate, preferably about from 0.2 to 2.0% by weight of the composition. In other preferred embodiments, the implementation of the diluent is a monohydrate lactose, and he may be about 3.5% by weight of the composition, dezintegriruetsja substance is croscamellose, and it can be about 3% by weight of the composition, the binder is a Povidone, and it can be about 3% by weight of the composition, and a lubricating substance is a stearate, and it can be approximately 1% by weight of the composition.

In another embodiment, the described invention provides for the contents of 50, 100, or 150 mg of Memantine and 3 mg, 5 mg or 10 mg of Melatonin, where Memantine/ Melatonin ranges from 45 to 90% by weight of the composition. In other embodiments of the Memantine with Melatonin is approximately from 60 to 90% or 70-80% of the composition. In another embodiment, these compositions contain one or more of starches, such as corn starch, lactose monohydrate, microcrystalline cellulose, gelatinising starch, carboxymethylcellulose; sodium salt carboxymethylated ether of starch, polyvinylpyrrolidone, hypromellose; magnesium stearate is; and mineral salt, such as talc. In an additional embodiment, these compositions contain lactose monohydrate, corn starch, carboxymethylcellulose sodium, polyvinylpyrrolidone, talc and magnesium stearate.

In the following embodiment, these compositions contain lactose monohydrate, microcrystalline cellulose, gelatinising starch, carboxymethylcellulose, polyvinylpyrrolidone and magnesium stearate. In another embodiment, these compositions contain lactose monohydrate, carboxymethylcellulose sodium, polyvinylpyrrolidone and magnesium stearate.

Preferably the standard dose of Memantine and Melatonin is in the form of a solid dosage form such as tablet or capsule, and more preferably represents a tablet. In particular, this tablet may include 30, 50, and/or preferably 100 mg of Memantine and 3, 5, 10 mg Melatonin pill weight 250 mg. In other variants of implementation, the tablet may contain up to 150 mg of Memantine and up to 5 mg Melatonin tablet 500 mg, 200 mg of Memantine and 10 mg of Melatonin per tablet 700 mg and 200 of Memantine and up to 20 mg of Melatonin per tablet 1000 mg

In the following variants of implementation, the tablet may contain 100 mg of Memantine and up to 5 mg of Melatonin per tablet 150 mg, 200 mg of Memantine and 10 mg Melatonin tablet is e, 250 mg,300 mg of Memantine and up to 5 mg Melatonin AB tablet 375 mg and 400 mg per tablet 500 mg

In other embodiments of this dosage form dosage form may contain 100 mg of Memantine and up to 3 mg of Melatonin per tablet 125 mg (+/-3 mg), 150 mg of Memantine and up to 5 mg of Melatonin per tablet 225 mg (+/-5 mg), 200 mg of Memantine and 10 mg of Melatonin per tablet 340 mg (+/-5 mg) and 250 mg of Memantine and 15 mg of Melatonin per tablet 450 mg of Memantine and 10 mg of Melatonin. The capsule can contain 25, 50 or 100 mg of Memantine and up to 3 mg Melatonin capsule 125 mg or 200 mg of Memantine and 10 mg of Melatonin per capsule 250 mg. Similarly, the capsule may also contain 100 mg of Memantine and up to 3 mg of Melatonin per capsule 115 mg or 200 mg of Memantine and 10 mg Melatonin capsule 230 mg.

In one of the embodiments the present invention provides a method of obtaining a solid dosage form of Memantine and Melatonin using a wet mixing of Memantine and Melatonin and excipients with water, drying and grinding of granulated mixture. In this embodiment, the final mixture is pressed into a pill. In other embodiments, the final mixture can complete kapsulirovaniem mixture.

The process of manufacturing tablets of this invention technologically represented as follows.

Charged to the reactor Memantine, Melatonin, lactose. In the resulting mixture is fed to a mixer where add others who g other carboxymethylcellulose, the starch in the ratio, taking into account the amount necessary for the preparation of a solution of starch paste and powder for dusting. Hydrate aqueous solution of polyvinylpyrrolidone. The composition of active substances and excipients is optimal for the implementation of this variant of the invention and allows you to get a quality tablet that meet the requirements of the Pharmacopoeia. After stirring the mass in the mixer and moistened with a solution of starch paste. Manage settings for strength and raspadaemost tablets, carried out by varying the concentration of starch paste. Then the tablet mass is discharged from the mixer, it is dried in a fluidized bed. Ready weight granularit through flow in a sieve with apertures of 1.2-2 mm, and loaded into the mixer, where you add a mixture of starch and calcium stearate and mix. The granulate serves for the preparation of tablet mass. The dry granules are loaded into the mixer, add calcium stearate and mix for 1-2 minutes. Powdered pill-weight unloaded from the reactor and serves on stage tableting. Tableting is performed on a rotary press using punches round shape.

Example 1. The composition of the tablets Memantine and Melatonin.

Substance mgWt.%
Memantine10040,00%
Melatonin52,00%
Lactose7028,00%
Microcrystalline cellulose24,759,90%
Starch26the 10.40%
Povidone12,5to 5.00%
Crosscarmellose9,753,90%
Calcium stearate20,80%
Total weight pills250100,00%

Example 2. The composition of the tablets Memantine and Melatonin.

SubstancemgWt.%
Memantine10083,332%
54,167%
Lactosethe 5.254,375%
Microcristalina cellulose1,251,042%
Starch2,251,875%
Povidone21,667%
Crosscarmellose2,251,875%
Calcium stearate21,667%
Total weight pills120100%

Example 3. Compounds with a high dose of Memantine and Melatonin.

SubstancemgWt.%mgWt.%
Memantine100,0089,83%200,0088,95%
Melatonin 3,002,69%10,004,45%
Lactose3,002,69%4,502,00%
Povidone2,001,80%4,121,83%
Crosscarmellose2,121,91%4,121,83%
Calcium stearate1,201,08%2,100,94%
Total weight pills111,32100%224,84100%

A possible implementation of the described invention by manufacturing in the form of finished medicines like capsules, preferably in hard gelatin capsules. Hard gelatin capsules can be manufactured by filling the long part of the capsules prepared mixture and kapsulirovaniem long part of the capsule machine. In this way the implementation of the offer is aemula invention implements a method of manufacture of the finished dosage form of Memantine with Melatonin. To produce this dry mixing Memantine Melatonin with auxiliary substances. In one embodiment, the mixer load sifted powders lactose, carboxymethylcellulose, Memantine and Melatonin, starch, carefully peremeshivayu the resulting mass add the sifted powder, colloidal silicon dioxide, mix, then add the sifted magnesium stearate. The resulting mixture was thoroughly stirred. The resulting mass transfer for encapsulation.

Example 4. The capsules of Memantine and Melatonin.

Substancemg%mg%
Memantine5040,13%10080,0%
Melatonin32,41%54,0%
Lactose59,547,75%a 9.257,4%
Povidoneof 5.754,62% 21,6%
Crosscarmelloseof 5.75br4.61%6,755,4%
Calcium stearate0,60,48%21,6%
Total weight capsules124,6100%125100%

It should be noted that the solid dosage forms can include, via the described invention, as tablets and capsules, but also tablets, lozenges, powders, starch capsules and the like.

Other aspects of the invention also describe the use of these compositions for the prevention and treatment of diseases or disorders in a mammal in need of such appointment, including the introduction of this mammal a therapeutically effective amount of the compositions according to the invention. In particular, these compositions are suitable for the prevention and treatment of mental, behavioral, and cognitive disorders.

Example 5. The study of pharmacological activity.

Examined 25 patients with mixed dementia, 12 patients with Bo what esnu Alzheimer's. The average age of patients was 70±3 years. Diagnosis of dementia was conducted in accordance with the criteria of dementia ICD-10 [international statistical classification of diseases and problems related to health. Tenth revision (ICD-10). Vol. 1 (part 1). Geneva: who, 1995; s, 510-1]. Severity of dementia was assessed by clinical scale for assessing the severity of dementia (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 she was 1.2±0.3 and in the group with Alzheimer's disease was 1.1±0,36. All patients were divided into two groups. The first group was administered memantine 50 mg 1 time a day. The second group was administered capsules according to example 4. Within six months, the patients performed a comprehensive neurological examination, including a brief assessment of mental status (MMSE), a test of visual and oral-aural memory scale dementia, test drawing hours (Clock Drawing Test), and test for attention - sample Schulte. Processing of the obtained results was performed using the statistical software package SPSS, version 10.0 g.

Results: After 1.5 mespace start taking the drug in patients of both groups showed a significant decrease in the severity of cognitive impairment. In the first group after 6 months cumulative score assessment of mental status increased by 1.5±0.3, and the visual is Amati - 0.5±0.2, a test drawing hours - about 0.2±0.1. sample Schulte decrease by 20.5±3,6, in the second group, respectively: 2,4±0,5, 0,8±0,2, 0,4±0,1, 36,2±4,5.

In the first group, 2 patients needed dose reduction, as observed increased intracranial pressure.

In the first group, a positive effect of treatment was observed in 25% of patients with Alzheimer's disease, 86% of 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%did not experience side effects. The rest of subjects observed effect stabilization of the condition.

So, clearly, there is a significant increase effect of memantine in combination with melatonin.

The materials, methods and examples are illustrative, and in no way should be interpreted as limiting the completeness and/or content of the invention. Only if technological, scientific and experimental data are well-known in this field of use of the described invention.

1. Pharmaceutical composition for prevention and treatment of mental, behavioral, and cognitive disorders in the form of a solid dosage form, characterized in that it includes memantine and chalk the onin war as the active agent and excipients, comprising at least one diluent selected from lactose, starch, a derivative of starch, microcrystalline cellulose, sucrose, inverted from what you think of sugar, dextrose and dextrine at least one dezintegriruetsja agent selected from sodium carboxymethylcellulose, croscarmellose, gelatinising starch, a binder selected from polyvinylpyrrolidone, gelatin, cellulose derivatives, natural gums, glycols, sodium alginate, anti-friction agent is selected from stearic acid and/or its salts, colloidal silicon dioxide, talc, sodium benzoate, sodium acetate and sodium oleate in the following, wt.%:

Memantineof 40.0 to 90.0
Melatonin2,0-5,0
Thinnera 2.0 to 50.0
Binder3,5-10,0
Disintegrity agent1,5-10,0
Antifriction agent0,2-3,0

2. The pharmaceutical composition according to claim 1, characterized in that it contains a combination of memantine and melatonin in the amount of 70-80% of the t weight of the composition.

3. The pharmaceutical composition according to claim 1, characterized in that it contains a combination of memantine and melatonin in the amount of 70-80% by weight of the composition, the diluent is lactose monohydrate in an amount of 3-20% by weight of the composition; as dezintegriruetsja agent is cross-linked carboxymethylcellulose sodium in the amount of 2-10% by weight of the composition; polyvinylpyrrolidone as a binder in the amount of 2-10% by weight of the composition; and as an antifriction agent - magnesium stearate in an amount of 0.2 to 2.0% by weight of the composition.

4. The pharmaceutical composition according to claim 1, characterized in that it contains a combination of memantine and melatonin in the amount of 60-90% by weight of the composition.

5. The pharmaceutical composition according to claim 1, characterized in that provided in tablet form.

6. The pharmaceutical composition according to claim 5, characterized in that comprises about 100 mg of memantine 5 mg of melatonin.

7. The pharmaceutical composition according to claim 5, comprising about 150 mg of memantine and 10 mg of melatonin.

8. The pharmaceutical composition according to claim 5, comprising about 30 mg of memantine and 3 mg of melatonin.

9. The pharmaceutical composition according to claim 1, characterized by what is presented in the form of hard capsules.

10. The pharmaceutical composition according to claim 1, characterized in that it contains, wt%:

Memantine89,83%
Melatonin2,69%
Lactose2,69%
Povidone1,80%
Crosscarmellose1,91%
Calcium stearate1,08%



 

Same patents:

FIELD: chemistry.

SUBSTANCE: described is an effective low-toxicity agent, which is methyl ether of 2-cyano-3,12-dioxo-18βH-olean-1(2),11(9)-dien-30-ic acid of formula (I): having anti-oxidant, anti-inflammatory, neuroprotective, hypolipidemic, hypocholesterolemic, hypoglycemic, hepatoprotective and immunosuppressive activity.

EFFECT: agent has low toxicity and is synthesised based on readily available plant material.

1 cl, 13 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

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18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted oxindole derivatives of formula (I) wherein X1 means -O-, -O-CH2-, -O-C(=O)-, -NR11-, -NR11-CH2- or -NR11-C(=O) -; X2 means a single bond, CO or CH2; X3 means N or CH; X4 means N or CH; A means phenylene or 6-merous heteroarylene with 1 or 2 nitrogen atoms as ring members with phenylene or heteroarylene being substituted by 1 or 2 residues R10; R1 and R3 independently mean hydrogen, C1-C3-alkyl, C1-C3-fluoroalkyl, C1-C3-alkoxy, C1-C3-fluoroalkoxy, halogen or CN; R2 means hydrogen or methoxy; at least one of residues R1, R2 and R3 mean hydrogen; R4 means hydrogen or C1-C4-alkyl; R5 means ethoxy, fluorinated ethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, or isopropoxy; R6 means hydrogen or methyl; R7 means hydrogen, I, Br, CI, F or CN; R8 means hydrogen, I, Br, CI, F or CN; R9 means C1-C3-alkyl or C1-C3-fluoroalkyl; R10 means C1-C3-alkyl, C1-C3-fluoroalkyl, C1-C3-alkoxy or C1-C3-fluoroalkoxy; R11 means hydrogen, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy or C1-C4-fluoroalkoxy; a means 0, 1 or 2; and m and n independently mean 1 or 2; as well as to pharmaceutically acceptable salts thereof. Furthermore, the invention refers to a pharmaceutical agent for treating and preventing the vasopressin-dependent diseases on the basis of the substituted oxindole derivatives, to the use of these compounds for preparing a drug, and moreover, to a method of treating the diseases.

EFFECT: there are prepared and described new compounds which may be effective in treating the vasopressin-dependent diseases.

38 cl, 82 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a composition for nicotinic immunonanotherapy containing synthetic nanocarriers having a polymeric surface conjugated with a variety of nicotine residues with the variety of the nicotinic residues on the nanocarrier form an immunogenic surface providing a low affinity, a high-avidity binding of the nicotinic residues to the surfaces of an antigen presenting cell (APC) compared with an antibody binding, and a pharmaceutically acceptable excipient. The invention provides the nanocarriers capable to stimulate an immune response in T-cells and/or B cells and to produce the antinicotin antibodies with the humoral and cellular response to be achieved in the absence of an exogenous adjuvant.

EFFECT: invention provides the absence of the non-specific response on an inflammation caused by an adjuvant.

17 cl, 37 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition the form of an oral suspension consisting of valsartan or a pharmaceutically acceptable salt thereof and at least one or two or more ingredients specified in glycerol or a syrup or a mixture thereof, a preserving agent, a buffer system, a suspending/stabilising agent and anti-foaming agent. The buffer system is specified in sodium citrate, potassium citrate, sodium bicarbonate, sodium dihydrophosphate and potassium dihydrophosphate, and maintains pH of the composition within the range of 3.0 to 5.0. Further, the present invention refers to using the pharmaceutical composition for preparing a drug.

EFFECT: orally administered valsartan suspension provides high bioavailability and reduced variability of response to the administered dose when administered to different subjects or one subject.

10 cl, 4 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted compounds of general formula I , in which n equals 1; R1 denotes H; F; Cl; Br or I; R2 denotes H; F; Cl; Br; I; -CF3; -CN; -NH2; -OH or -OR16; R3 denotes H; F; Cl; Br; I; -NH2; -NO2; -OH; -C(=O)-NH2; -C(=NH)-NH2; -NH-C(=O)-R13; -OR16; -C(=O)-NHR18; -C(=O)-R25 or a linear or branched, saturated of unsaturated, unsubstituted or at least mono-substituted aliphatic C1-10 radical, where said substitutes are independently selected from a group which includes F; -OH; -NH2; -NH(C1-5-alkyl) and -N(C1-5-alkyl)(C1-5-alkyl); R4 denotes H; F; Cl; Br, I or a linear or branched, saturated or unsaturated, unsubstituted aliphatic C1-10 radical; R5 denotes H; F; Cl; Br or I; R6 denotes H or a linear or branched, saturated or unsaturated, unsubstituted aliphatic C1-10 radical; R7 denotes hydrogen; R8 denotes -CF3; -O-CFH2; -O-CF2H; -CFH2; -CF2H or an unsubstituted or at least mono-substituted tert-butyl radical; T denotes C-R35; U denotes C-R36; V denotes N or C-R37; W denotes C-R38 and where values of R13, R16, R18, R25, R35, R36, R37 and R38 are as given in claim 1 of the invention. The invention also relates to methods of producing the compounds described above, a medicinal compound based on said compounds for treating vanilloid receptor mediated disorders or diseases, as well as use of compounds of formula I to produce a medicinal agent.

EFFECT: novel compounds used as vanilloid receptor ligands are obtained and described.

25 cl, 34 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine and aims at treating amnestic syndrome. A local anaesthesia is applied by infiltration of the tissues surrounding the external auditory canal with 0.5% novocaine along an anteromedial surface of the mastoid process bypassing the eardrum directly into the ear. The therapeutic effect is implemented by administering 1 g of streptomycin dissolved in 1 ml of physiological saline, intratympanic from one or both sides once a day every 2-3 days, with the manipulations performed 2 to 5 times per a course during 10-20 days. The transcranial exposure is generated by direct electric current at the intensity of 200-600 mA in the mid-temporal area of the head for 20-40 minutes daily for 8-10 days, repeated 2-3 times every 1-2 months. The electric exposure is generated by applying lead electrodes with each electrode having an area of 400-600 mm.

EFFECT: method enables improving associative cortex activity and improving the clinical effectiveness.

3 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a solid pharmaceutical composition for oral administration on the basis of taxane. The solid pharmaceutical composition for oral administration contains amorphous taxane, a hydrophilic carrier and a surfactant (sodium dodecylsulphate (SDS)), with specific weight proportions of taxane and the carrier with taxane, the carrier and the surfactant found in a solid dispersion. The use of the composition for preparing a drug for treating a neoplastic disease. A method for preparing the pharmaceutical composition.

EFFECT: pharmaceutical composition is characterised by higher solubility and higher dissolution rate of taxane.

16 cl, 21 dwg, 18 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical industry and deals with solid pharmaceutical composition, possessing high physical strength. Claimed invention also presents method of manufacturing solid pharmaceutical composition. Claimed pharmaceutical composition contains 7 varicoloured types of granules in form of capsule. Granules contain, wt %: nikotinamide 1-35; pyridoxine 0.1-8; calcium pantitenate 0.1-15, thiamin 0.1-30; tryptophan 1-30; tocoferol 0.5-5; ascorbic acid 0.1-50; 5-hydroxyanthranyl acid 0.01-10; Riboflavin 0.1-10; folic acid 0.1-6; cyanocobalomin 0.001-6; isoleucin 0.5-10; leucin 0.5-15; lysine 0.5-20; phenylalanine 0.1-5; threonine 0.1-5.0; valin 0.1-8.0; methionine 0.1-15; lactose 1-4.0; ergocalcioferol 1-95.0 and auxiliary substances for obtaining granules.

EFFECT: claimed composition possesses excellent properties of medication release and digectionin application composition possesses hepatoprotective hypolipidemic immunostimulating and normalising kidney activity action.

2 cl. 2 ex. 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for the correction of cerebrovascular disease accompanying cardiovascular diseases which contains the active ingredients presented by atorvastating or pharmaceutically acceptable salt thereof and nicergolin in the therapeutically effective amounts.

EFFECT: pharmaceutical composition is characterised by high stability and bioavailability.

8 cl, 8 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, and represents an oral dosage form in the form of capsule, containing: 1) pomalidomide in the amount of 0.1 to 3 wt % of total weight; 2) a binding agent or an excipient in the amount of 90 to 99 wt % of total weight wherein the binding agent or the excipient represent starch, mannitol or their mixture.

EFFECT: invention provides stability of the declared dosage form.

22 cl, 7 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and represents a pharmaceutical composition containing: {1S-[1α,2α,3β(1S*,2R*),5β]}-3-(7-{[2-(3;4-difluorophenyl)cyclopropyl]amino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl)-5-(2-hydroxyethoxy)cyclopentane-1,2-diol; an excipient representing mixed mannitol and dibasic calcium phosphate dihydrate; a binding agent representing hydroxypropyl cellulose; a disintegrant representing sodium starch glycolate; and one or more lubricating agents.

EFFECT: invention provides preparing the composition of the active compound possessing high stability and high bioavailability of the active agent.

12 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely a stable pharmaceutical composition of a water-soluble salt of vinorelbine. The composition contains approximately 56 wt % of a diluent, approximately 2.5 wt % of a binding agent, approximately 5 wt % of a disintegrant, approximately 0.25 wt % of a flow agent and approximately 0.5 wt % of a lubrication agent. The water-soluble salt of vinorelbine is preferentially vinorelbine ditartrate.

EFFECT: pharmaceutical composition is preferentially presented in the form of a gelatine capsule or a tablet.

5 cl, 6 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition applicable for oral administration contains an S1P receptor agonist and mannitol with the composition representing a solid dosage form. Mannitol has a particle specific surface area 1 to 7 m2/g, and the S1P receptor agonist is specified from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), its pharmaceutically acceptable salt and FTY720-phosphate.

EFFECT: compositions under the invention are characterised by a high level of distribution uniformity of said S1P receptor agonist, and applicable for oral administration in the solid dosage form, eg in the form of a tablet or a capsule.

14 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method for preparing a pharmaceutical composition consists in mixing an S1P receptor agonist - 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt with sugar alcohols; the mixture is milled and/or granulated, and then mixed with an oil agent. The method under invention is implemented on high-speed automated equipment and enables producing the compositions with high-level distribution uniformity of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

EFFECT: preparing the pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

15 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

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