EA038052B1 - Combination comprising palmitoylethanolamide for treating chronic pain - Google Patents

Abstract

The invention relates to the field of medicine, pharmacology, namely to a combination of palmitoylethanolamide and a substance selected from the group comprising uridine monophosphate, taurine and vitamin E or pharmaceutically acceptable salts thereof. Such combination is used for pathogenetc and symptomatic treatment as monotherapy and as a part of complex therapy of chronic pain, diseases and syndromes of nervous system of different origin.

Description

The invention relates to medicine, pharmacology, namely to a combination of palmitoylethanolamide and at least one substance selected from the group consisting of uridine monophosphate, taurine and vitamin E, or their pharmaceutically acceptable salts. This combination is used for pathogenetic and symptomatic treatment in the form of monotherapy and as part of the complex therapy of chronic pain, diseases and syndromes of the nervous system of various origins, especially neuropathic pain after chemotherapy;

diabetic chronic neuropathic pain;

neuropathic pain in nerve compression syndrome (carpal tunnel syndrome, sciatica; lumbago, other dorsopathies, neuritis, neuralgia, pudendal neuralgia, postherpetic neuralgia, accompanied by chronic peripheral neuropathic pain);

post-stroke chronic neuropathic pain (endometriosis, dysmenorrhea, interstitial cystitis, vulvodynia, prostatitis, accompanied by chronic pelvic pain);

chronic pelvic pain syndrome;

phantom pain;

pain in the post-stroke period, diabetic migraine, accompanied by chronic central neuropathic pain;

pain in rheumatic diseases (rheumatoid arthritis, osteoarthritis and other degenerative dystrophic diseases of the joints);

diseases, syndromes accompanied by acute and chronic visceral pain (for example, in Crohn's disease, IBS);

fibromyalgia, multiple sclerosis, accompanied by pain syndrome associated with disorders in the peripheral and central links of the nociceptive and antinociceptive systems;

pain syndrome with influenza and other acute respiratory viral infections.

Pain is one of the most common complaints that doctors of various specialties deal with in their daily practice. The prevalence of pain syndromes in the primary care system ranges from 11 to 40% [Gureje O., Simon G.E., Van Korff M. A cross-national study of the course of persistent pain in primary care // Pain. 2001. Vol. 92. P. 195-200]. According to the WHO, in the developed countries of the world, pain in terms of the scale of its spread is quite comparable to a pandemic.

Separation of acute and chronic pain is essential for success in treatment. Acute pain is inextricably linked to the injury that caused it and is usually a symptom of a medical condition. It usually disappears when the damage is repaired and / or the healing period expires. Chronic pain continues for a long time even after the elimination of the cause that caused the acute pain, and often acquires the status of an independent disease. The International Association for the Study of Pain defines pain as pain that lasts beyond the normal healing period. The main difference between chronic pain and acute pain is not a time factor, but qualitatively different neurophysiological, biochemical, psychological and clinical relationships [Korzhavina VB, Danilov A.B. New opportunities and prospects for the treatment of pain syndromes // BC. 2010. S. 31].

All pain syndromes, depending on the cause and mechanism of their development, can be conditionally divided into three main groups: nociceptive, neuropathic and psychogenic. Nociceptive pain occurs due to the activation of nociceptors, free nerve endings, due to tissue damage (examples of such pain are postoperative pain, pain in trauma, angina in patients with coronary heart disease, epigastric pain in gastric ulcer, pain in patients with arthritis and myositis). Psychogenic pain syndromes are characterized by the presence of pain in patients that cannot be explained by any known somatic diseases or damage to the structures of the nervous system. The localization of this pain usually does not correspond to the anatomical features of tissues or areas of innervation, the lesion of which could be suspected as the cause of the pain.

Ultimate pain perception is the result of the interaction of the nociceptive and antinociceptive systems. The formation of pain in humans is mediated by the structures of the nociceptive system, which perceives, conducts and processes information about various stimuli. Descending inhibitory cerebrospinal control over the conduction of pain impulses is a function of the antinociceptive system. Under physiological conditions, the antinociceptive system provides optimal modulation of the perception of pain stimuli, protecting against pain and maintaining pain thresholds at a certain level. However, long-term damaging effects often lead to sensitization of the pain system (stable long-term depolarization of neurons), which gives rise to its pathophysiological changes [Pain syndromes in neurological practice / Ed. Corresponding Member RAMS A.M. Wayne. M .: MEDpress-inform, 2001].

In the mechanisms of development of sensitization of nociceptive neurons, several stages are distinguished: activation of AMPA receptors (a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) in response to short-term stimulation of pain afferents, then excitation of NMDA receptors (N- methyl Daspartate) glutamate when applied with repeated or prolonged damaging effects. This leads to the removal of magnesium ions that block NMDA receptor channels, resulting in

- 1 038052 dit intracellular entry of calcium ions. Under conditions of increased input of calcium into neurons, the early response genes c-fos, c-jun, jun B are expressed, which, by activating effector genes, change the cellular phenotype and form long-term hyperexcitability of neurons. Through such mechanisms, central sensitization can exist even after the initial initiating factors have been eliminated [Kukushkin M.L., Khitrov N.K. General pathology of pain. - M .: Medicine, 2004, 144 s].

Therefore, it is fundamentally important to timely and adequate treatment of acute pain syndrome in order to prevent the chronicity of the pathological condition [Barinov A.N. Comprehensive pain management. RMZh, 2007, vol. 15, no. 4, p. 215-220].

Among adults, the most common cause of chronic pain is dorsopathies: osteoarthritis of the lumbar and cervical spine - 65% of the general population, of which 16-55% have a neuropathic component of pain; carpal tunnel syndrome - 1-3.8% of the general population. In the world in patients with diabetes mellitus (DM), peripheral neuropathic pain is recorded in 35% of all patients with diabetes [Marcucci M., Germini F., et al. Efficacy of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain: study protocol for a series of N-of-1 randomized trials. Trials. 2016, 17: 369].

In Russia, about 500 thousand strokes are registered annually, and one of the complications of stroke is post-stroke pain syndrome, which develops in 2.7% of patients who have had a stroke [Mulla S.M., Wang L., et al. Management of Central Poststroke Pain: Systematic Review of Randomized Controlled Trials. Stroke. 2015, 46 (10): 2853-60].

Thus, chronic pain is a complex phenomenon, often representing an interconnected combination of various pain phenomena. As you know, muscle pain can be combined with pain of a neurogenic nature, and in the process of the development of the syndrome, a psychological component is added to it, which affects the perception of pain by a person.

One of the types of chronic pain - chronic neuropathic pain (NB) - is a consequence of direct damage or dysfunction of the somatosensory nervous system (central and / or peripheral) with an intact state of peripheral (painful, nociceptive) receptors (in the domestic literature, neuropathic pain arising from damage to central structures of the somatosensory nervous system, also called central pain).

Central neuropathic pain is associated with an imbalance in the nociceptive (pain) and antinociceptive (analgesic) systems due to disorganization and damage to antinociceptive structures, which leads to increased and chronicity of pain.

Thus, in nociceptive pain, peripheral pain receptors are damaged when all parts of the nervous system are intact, while in NB, on the contrary, some structures of the somatosensory nervous system are damaged when pain receptors are intact. Unlike nociceptive pain, which is an adequate physiological response to a painful stimulus or tissue damage, NB, as a rule, is not adequate to the nature, intensity or duration of the stimulus [A.B. Danilov Pharmacotherapy of neuropathic back pain Neurology / Rheumatology. Consilium meducum supplement, 2011, no. 1, p. 51-55].

The causes of damage to the peripheral somatosensory nervous system can be metabolic disorders, trauma, intoxication, infectious process, mechanical compression, vitamin deficiency. The most common peripheral NB in patients with painful diabetic polyneuropathy, postherpetic neuralgia, and chronic back pain. The causes of NB with damage to the structures of the central nervous system, leading to a deficiency of somatosensory sensitivity, are considered spinal cord and brain injuries, ischemic and hemorrhagic strokes, pain in Parkinson's disease, syringomyelia and demyelinating diseases (multiple sclerosis) and other diseases.

Pathological processes that lead to the reorganization of the nociceptive system take part in the development and maintenance of chronic pain, of which the processes associated with the formation of peripheral neuropathic pain are most studied:

the formation of ectopic (spontaneous) discharges by nerve fibers due to dysfunction of ion channels localized in their membrane;

the formation of new pathological synaptic connections of afferent axonal terminals in the posterior horn of the spinal cord - the so-called sprouting phenomenon, which leads to the erroneous perception of non-painful information as painful (clinical phenomenon of allodynia);

the formation of connections by sympathetic postganglionic fibers with afferent conductors of the somatosensory system, as a result of this, signals are exchanged between them, i.e. activation of sympathetic (non-painful) postganglionic fibers leads to the excitation of nociceptors (pain receptors) [Pain syndromes in neurological practice / Ed. Corresponding Member RAMS A.M. Wayne. M .: MEDpress-inform, 2001].

The clinical manifestations of chronic pain are characterized by a combination of negative and positive symptoms, reflecting damage to the somatosensory analyzer. Chronic pain can

- 2 038052 be constant or paroxysmal in the form of shooting, squeezing or burning pain, which is most often localized in the area of altered tactile, temperature and pain sensitivity. With incomplete, partial damage to peripheral nerves, plexuses or dorsal spinal roots, in most cases, there is an acute periodic paroxysmal pain, similar to an electrical discharge, lasting several seconds. In conditions of extensive or complete damage to the nerve conductors, pain in the denervated area is often permanent in the form of numbness, burning, and aches. Neurological examination usually makes it possible to detect changes in tactile, temperature and pain sensitivity in the form of dysesthesia, hyperpathy, and allodynia in the zone of pain in patients with chronic pain. Enhanced perception of ordinary stimuli, characterized by long-lasting unpleasant painful sensations after the cessation of irritation, is referred to as hyperpathy, and painful sensations arising in response to mild mechanical or thermal (i.e., in response to non-painful) irritation of the skin areas are defined as allodynia. A common symptom in patients with neuropathic pain syndromes is paresthesia in the form of spontaneously arising sensations of tingling, numbness, or creeping in the area of damage. In the clinical picture, patients with chronic pain may have trophic disorders of the skin, subcutaneous tissue, hair, nails, changes in muscle tone or local autonomic disorders in the form of tissue swelling, changes in dermographism, skin color and temperature [Baron R., Binder A. How neuropathic is sciatica? The mixed pain concept. Orthopade 2004; 33 (5): 568-75].

In the case of chronic pain, when the central pathophysiological mechanisms of pain are activated, it is necessary to use drugs that affect the formation of central sensitization:

the use of anticonvulsants (carbamazepine, lamotrigine, valproate), which inhibit the conduction of excitatory nerve impulses by blocking voltage-dependent sodium and calcium channels of peripheral nerves;

the use of blockers of the reuptake of norepinephrine and serotonin, which increase the concentration of these neurotransmitters in the nuclei of the reticular formation of the brain stem, from which descending inhibitory pathways emanate that affect the interneurons of the dorsal horn (fluoxetine, amitriptyline, sertraline, duloxetine, etc.);

the use of NMDA receptor antagonists that erase pain memory (ketamine, dextrametorphan);

electrical stimulation and other methods of physical stimulation (physiotherapy, acupuncture, percutaneous electroneurostimulation, massage, etc.), causing inhibition of nociceptive neurons of the posterior horn by activating enkephalinergic neurons [Barinov A.N. Comprehensive pain management. RMZh, 2007, vol. 15, no. 4, p. 215-220].

Since conventional pain relievers from the NSAID group are ineffective for chronic pain, it is not only pointless to use them to treat such patients, but also unsafe, since NSAIDs have a number of adverse side effects. Treatment of chronic pain is a significant challenge and should be comprehensive, including medications, psychotherapy and reflexology. The treatment algorithm should take into account the clinical characteristics of chronic pain, be simple, safe and effective. Usually, drugs are prescribed for a long time, and they should be taken strictly on schedule in an individually selected (titrated) dosage.

Currently, pharmacological research in the search for effective therapy for chronic pain is focused mainly on drugs with neurotropic action, such as the tricyclic antidepressants amitriptyline (tryptisol), doxepin (synequan), clomipramine (anafranil); selective serotonin reuptake inhibitors (SSRIs) SSRIs - fluoxetine, sertraline (zoloft), paroxetine (paxil), fluvoxamine (fevarin); muscle relaxants, which demonstrate higher efficiency than analgesics [Tabeeva G.R. Modern principles of fibromyalgia treatment. RMZh, 2011, v. 19, no. 15, p. 1-9]. For the treatment of chronic pain, agents are used that reduce the excitability of nerve cells and thus partially block, reduce the conduction of pain impulses along nerve fibers to the brain. These are anticonvulsants, antidepressants and other drugs.

This is due to the fact that the results of numerous studies have shown that chronic pain (regardless of the history of traumatic brain damage and other neurological diseases) negatively affects cognitive function. In addition, it is often accompanied by anxiety, depression, restriction of daily activity, which significantly reduces the quality of life of patients suffering from chronic pain [Severeijns R., Vlaeyen J.W., van den Hout M.A. et al. Pain catastrophizing predicts pain intensity, disability, and psychological distress independent of the level of physical impairment // Clin J. Pain. 2001. Vol. 17. P. 165-172].

The first place in the treatment of chronic pain associated with depression is occupied by antidepressants, which have not only an antidepressant, but also an analgesic effect itself (Mosolov S.N. Clinical use of modern antidepressants. SPb, 1995; 565).

- 3 038052

The effectiveness of antidepressants in the treatment of chronic pain syndromes reaches 75% [Fuller

R.W. Serotonin uptake inhibitor // Prog Drug Res 1995; 45: 167-204]. The efficacy of antidepressants is greater the more depression plays a role in chronic pain.

The mechanisms of the analgesic action of antidepressants are as follows:

an analgesic effect due to the reduction of depression (this mechanism is especially significant if the pain syndrome was a mask of depression, i.e. in primary depressions, however, in the case of depression secondary to pain, the reduction of depression always leads to a weakening of the pain syndrome);

analgesic effect due to potentiation of the action of both exogenous and endogenous analgesic substances, mainly opioid peptides;

analgesic effect due to the stimulation of antinociceptive descending, mainly serotonergic systems of the brain.

To obtain a sufficient analgesic and antidepressant effect, antidepressants must be prescribed in a sufficient clinical dose and for a long time.

For the treatment of pain, taking into account the neurochemical mechanisms of its development, the developers proposed various combinations of drugs.

For example, US patent 7534806 (publ. 05/19/2009) is known, describing the treatment of neuropathic pain and associated symptoms with a combination of ibudilast (3-isobutyryl-2isopropylpyrazolo [1,5-a] pyridine) and a second component such as gabapentin, memantine, morphine, cannabinoids, tramadol, duloxetine, tricyclic antidepressants.

Also known patent US 6251863 (publ. 06/26/2001), describing the treatment of neurodegenerative diseases accompanied by pain, using a combination of relaxin with estrogen or glucosamine.

Known patent US 6245802 (publ. 12.06.2001), describing a method for the treatment of pain, including the introduction to mammals of an anesthetic combination containing duloxetine and a non-steroidal anti-inflammatory drug (NSAID) or paracetamol. The pain may represent pain from the group consisting of neuropathic pain, diabetic neuropathy, fibromyalgia, pain associated with somatoform disorders, joint pain, cancer pain, neck pain, shoulder pain, back pain, headaches, migraines, herpes neuralgia, phantom limb pain, central pain, toothache, NSAIDs persistent pain, visceral pain, surgical pain, postoperative pain, bone pain trauma, pain during labor, pain from burns, postpartum pain, angina pain, pain associated with the genitourinary system, and nociceptive pain.

On the other hand, for example, anticonvulsants are very effective in treating neuropathic pain. Their anti-pain activity is associated with the mechanism of blocking the excessive release of glutamate into the presynaptic cleft - the transmitter of the pain impulse from one neuron to another. Among anticonvulsants, the most recognized drugs for the treatment of neuropathic pain are gabapentin and pregabalin [Dworkin R.H., O'Soppog A.V., Backonja Metal. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132: 23 7-51]. For example, gabapentin for chronic neuropathic pain is prescribed as monotherapy, starting with the lowest dose and then increasing it until the desired result is achieved. The appropriate dose for the patient depends on many factors: hereditary pain threshold, living and working conditions, general physical condition and emotional status of the patient. The duration of treatment depends on the patient's clinical response to therapy [Danilov AB, Davydov OS. Principles and algorithms for the treatment of neuropathic pain. RMZh, 2008, vol. 16, p. 11-16].

These drugs often have serious side effects, in some cases they can become addictive, lose their effectiveness in chronic use, therefore, there is currently a need for new highly effective and safe drugs for the treatment of chronic pain, suitable for long-term use.

Palmitoylethanolamide (PEA, PEA), an endocannabinoid that does not directly bind to cannabinoid receptors (has low affinity for CB1 and CB2 receptors), is an endogenous ligand for α-receptors activated by peroxisome proliferators (PPAR-α). PPAR-α receptor is a regulator of genes that control pain and inflammation, possibly through the shutdown of the nuclear signaling cascade of kB-factor [Hesselink J.M., Hekker T.A. Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series. J. Pain Res. 2012, 5: 437-42].

palmitoylethanolamide

Palmitoylethanolamide does not have a pronounced affinity for CB1 and CB2 receptors, but has an antinociceptive effect that can be attenuated by selective CB2 antagonists, but not selective CB1 receptor blockers [D.M. Lambert, F.G. Di Paolo, P. Sonveaux, et al., Analogues and homologues of N-palmitoyletanolamides, a putative endogenous CB (2) cannabinoid, as potential ligands for the cannabinoid receptors. Biochim. Biophys. Acta, 1440,266-274,1999]. Analyzing this phenomenon in different models of nociception using different methods of administration of the substance, as well as the interaction of PEA with anandamide, the researchers concluded that there are CB receptors in the body that do not belong to the type of vanilloid receptors [G. Griffin, S.R. Fernando, R.A. Ross, et al., Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. Eur. J. Pharmacol., 339, 53-61, 1997].

It has now been proven that the pathogenesis of the development of chronic pain involves the activation of not only nociceptive pathways, but also non-neuronal cells, such as mast cells, glial and microglial cells. Mast cells (their degranulation) play a key role in the development of hyperalgesia with nerve damage, dorsopathy, migraine, and chronic pelvic pain. PEA refers to endogenous substrates of the body, is synthesized on demand, locally accumulates in tissues in proportion to stress, degree of damage and pain [Ghafouri N. et al. Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neckshoulder pain correlate with pain intensity and sensitivity. Pain. 2013,154 (9): 1649-58]. In animal models, it has been proven that PEA inhibits the activity of mast cells and the production of pro-inflammatory mediators, reducing endoneural edema, thereby realizing anti-inflammatory and analgesic effects [Marcucci M., Germini F., et al. Efficacy of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain: study protocol for a series of N-of-1 randomized trials. Trials. 2016, 17: 369]. In animal models, the use of PEA caused a thickening of the myelin sheath, an increase in axonal diameter, as well as the number of nerve fibers, which can be regarded as a neuroprotective effect.

PEA is lipophilic, poorly soluble in water; bioavailability in humans is not well understood (since it is a natural component of the body), in animals, bioavailability is probably low; T _1/2 in rats is 12 minutes; It is rapidly hydrolyzed by the enzymes NAAA (N-acylethanolamine-hydrolyzing acid amidase) and FAAH (fatty acid amide hydrolase). Distribution in the brain is heterogeneous, with maximum accumulation in the hypothalamus. The efficacy of the two available forms of PEA, micronized and ultra-micronized, has not been compared in humans; open sources lack data on the superiority of one form over another [Gabrielsson et al. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Br. J. Clin. Parmacol. 2016, 82 (4): 932-42].

To increase the solubility of palmitoylethanolamide, the technology of particle size reduction (micronization and / or ultra-micronization) is used to increase the area of interaction with the solvent [Nokhodchi A. The effect of type and concentration of vehicles on the dissolution rate of a poorly soluble drug from liquisolid compacts // J. Pharm. Pharmauceut. Sci. 2005,8 (1): 18-25].

Micronized palmitoylethanolamide can have a particle size of, for example, 0.5-10 microns (Nestmann ER Safety of micronized palmitoylethanolamide (microPEA): lack of toxicity and genotoxic potential. Food Sci Nutr, 2016, 5 (2): 292-309), and the ultra-micronized palmitoylethanolamide can have a particle size of, for example, 0.8-6 microns (US 20150328173).

Uridine monophosphate (UMP, UMP) is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with uridine nucleoside. UMP consists of a phosphate group, a pentose sugar ribose, and a uracil nucleotide; therefore, is a ribonucleotide monophosphate. The study found that gerbils given a combination of uridine monophosphate, choline, and docosahexaenoic acid (DHA) significantly improved learning and memory performance in maze tests compared to animals that did not receive the supplements, implying an increase in cognitive function. [Holguin, S. et al. Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils. The FASEB Journal. 22 (11): 3938-3946, 2008]. It was found that damage to the nervous tissue is accompanied by an increase in the need for uridine and cytidine, and the intake of uridine monophosphate and cytidine monophosphate accelerates the regeneration of nerve tissue and increases the speed of nerve conduction.

O

OH he uridine monophosphate

Currently, cytidine monophosphate (CMP) and uridine monophosphate (UMP) are prescribed to patients for the treatment of neuromuscular disorders. In patients receiving CMF / UMP, there is a restoration of impaired neurological functions and pain relief.

The use of uridine for the treatment of diabetic peripheral neuropathy is known (Gallai V., Mazzotta G., Montesi S., Sarchielli P., Del Gatto F. Effects of uridine in the treatment of diabetic neuropathy: an electrophysiological study. Acta Neurol Scand. 1992 Jul; 86 (l): 3-7) and the use of uridine triphosphate in the complex therapy of compression neuropathy (Henrique Goldberg, Marco Antonio Mibielli, Carlos Pereira Nunes, Stephanie Wrobel Goldberg, Luiz Buchman, Spyros GE Mezitis, Helio Rzetelna, Lisa Oliveira, Mauro Geller, and Fernanda Wajnsztajn. A double-blind, randomized, comparative study of the use of a combination of uridine triphosphate trisodium, cytidine monophosphate disodium, and hydroxocobalamin, versus isolated treatment with hydroxocobalamin, in patients presenting with compressive neuralgias. J. Res. 2017 ; 10: 397-404). It is known that uridine monophosphate, diphosphate and triphosphate can interconvert in the body under the action of kinase and phosphatase enzymes. It is believed that uridine does not have a direct analgesic effect, and its mechanism of action in neuropathic pain may be associated with the regeneration of nerve tissue.

Taurine (2-aminoethanesulfonic acid) is a sulfonic acid formed in the body from the amino acid cysteine. Taurine is often referred to as a sulfur-containing amino acid, and there is no carboxyl group in the molecule. It is present in small amounts in tissues and bile of animals and humans. Used as a food supplement or as a medicine.

taurine

Taurine, when administered subconjunctivally, has a retinoprotective, anti-cataract, and metabolic effect. With systemic exposure, taurine has not only a metabolic effect, but also has a hepatoprotective effect, cardiotonic and hypotensive properties [Sagara, M., Murakami, S., Mizushima, S. et al. Taurine in 24-h Urine Samples Is Inversely Related to Cardiovascular Risks of Middle Aged Subjects in 50 Populations of the World.//Taurine. 2015. Vol. 9. P. 623636].

There is evidence that taurine promotes the formation of new cells in the hippocampus, a region of the brain associated with memory [Gebara, E., Udry, F., Sultan, S. et al. Taurine increases hippocampal neurogenesis in aging mice.//Stem cell research. 2015. Vol. 14 (3). P. 369-379]. It also promotes brain regeneration in closed head injuries. Possesses radioprotective properties.

Taurine plays an important role in lipid metabolism, helps to normalize the function of cell membranes, optimize energy and metabolic processes, and maintain the electrolyte composition of the cytoplasm due to the accumulation of potassium and calcium ions. In the brain, it acts as a neurotransmitter that inhibits synaptic transmission and has anticonvulsant activity. It normalizes the metabolism of eye tissues in diseases of a dystrophic nature.

Known antinociceptive activity of taurine in neuropathic pain, expressed in a decrease in allodynia in models of diabetic neuropathy and nerve compression in rats. It is believed that the effect of taurine may be due to the activation of glycine receptors of neurons [Terada T., Hara K., Haranishi Y., Sata T. Antinociceptive effect of intrathecal administration of taurine in rat models of neuropathic pain. Can. J. Anaesth. 2011, 58 (7): 630-637], or its protective effect against inhibitory neurons in the central nervous system from their excitotoxic damage [Belfer I., Davidson E., Ratner A., Beery E., Shir Y., Seltzer Z. Dietary supplementation with the inhibitory amino acid taurine suppresses autotomy in HA rats. Neuroreport. 1998,9 (13): 3103-3107]. The analgesic effect of taurine is also manifested when it is administered orally.

Vitamin E (vitamin E) is a group of natural compounds derived from tocol. The most important compounds are tocopherols and tocotrienols. Fat-soluble vitamin. It was first isolated in 1922, and in 1938 it was chemically synthesized.

Vitamin E is a versatile protector of cell membranes against oxidative damage. It occupies a position in the membrane that prevents the contact of oxygen with unsaturated membrane lipids (formation of hydrophobic complexes). This protects biomembranes from their peroxide destruction. The antioxidant properties of tocopherol are also due to the ability of the mobile hydroxyl of the chroman nucleus of its molecule to directly interact with free oxygen radicals (O ₂ ·, HO ·, HO ₂ ·), free radicals of unsaturated fatty acids (RO ·, RO ₂ ·) and fatty acid peroxides. The membrane stabilizing effect of the vitamin is also manifested in its ability to protect membrane proteins from SH-group oxidation. Its antioxidant effect also lies in the ability to protect double bonds in carotene and vitamin A molecules from oxidation. Vitamin E (together with ascorbate) promotes the inclusion of selenium in the active center of glutathione peroxidase, thereby activating the enzymatic antioxidant defense (glutathione peroxidase detoxifies lipid hydroperoxides).

Tocopherol is not only an antioxidant, but also an antihypoxant, which is explained by its ability to stabilize the mitochondrial membrane and conserve oxygen consumption by cells.

Vitamin E is known to have an analgesic effect in chronic pain and allodynia, and its effect is likely due to antioxidant properties, since reactive oxygen species play a critical role in the pathogenesis of neuropathic pain (Kim HK, Kim JH, Gao X., et al. Analgesic effect of vitamin E is mediated by reducing central sensitization in neuropathic pain. Pain. 2006 May; 122 (1-2): 53-62; Jun-Mo Park, Chae Kyung Kim, Hyung Chul Lee, et al. Antiallodynic effects of vitamin C and vitamin E in chronic post-ischemia pain rat model Korean J. Anesthesiol 2013 Nov; 65 (5): 442-448).

The present inventors have found that it is not previously known to use a combination of palmitoylethanolamide and at least one substance selected from the group consisting of uridine monophosphate, taurine and vitamin E for the treatment of chronic pain, and this combination provides an unexpected synergistic effect in the treatment of chronic pain ...

The following are definitions of terms that are used in the description of the present invention.

Medicinal product (preparation) - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments, etc. disease prevention, diagnostics, anesthesia, contraception, cosmetology and others.

Pharmaceutical composition means a composition comprising a new combination according to the present invention and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, dispensing agents, delivery devices such as preservatives, stabilizers, fillers, humectants, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavorings, antibacterial agents, fungicides, lubricants, delayed delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents such as sugars, sodium chloride and the like. The prolonged action of the composition can be provided by agents that delay the absorption of the active principle, for example, aluminum monostearate and gelatin, cellulose derivatives, for example, hydroxypropyl methylcellulose (HPMC). Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, as well as mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples and dispensing agents are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, silicon dioxide, and high molecular weight polyethylene glycol. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, as a mixture with traditional pharmaceutical carriers. Suitable unit forms of administration include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

Pharmaceutical compositions can include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, auxiliary agents and / or carriers used in the pharmaceutical field. The pharmaceutical composition, along with the active substances according to the present invention, or their pharmaceutically acceptable salts and derivatives, may include other active substances, including those with activity, provided that they do not cause undesirable effects.

If necessary, the use of the pharmaceutical composition of the present invention in clinical practice, it can be mixed with conventional pharmaceutical carriers.

The carriers used in the pharmaceutical compositions of the present invention are those used in the pharmaceutical field to produce common forms, including in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, flavoring agents are used. ; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

Dietary supplement means a composition of natural or identical to natural

- 7 038052 biologically active substances intended for direct intake or introduction into food products in order to enrich the diet with chemical or biologically active substances and their complexes.

Pharmaceutically acceptable salt means the relatively non-toxic organic and inorganic salts of acids and bases as claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation, or purification of compounds, or they can be specially prepared. In particular, base salts can be specially prepared starting from the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of the salts obtained in this way are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates, mesites malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (for a detailed description of the properties of such salts, see Berge SM, et al., Pharmaceutical Salts J. Pharm. Sci. 1977, 66: 1-19). Salts of the claimed acids can also be specially prepared by reacting a purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metallic salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be derived are sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which the salts of the claimed acids can be obtained, amines and amino acids are selected that are basic enough to form a stable salt and are suitable for medical use (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane, and the like. In addition, tetraalkylammonium hydroxides such as choline, tetramethylammonium, tetraethylammonium and the like can be used for salt formation. Basic amino acids - lysine, ornithine and arginine - can be used as amino acids.

More preferred pharmaceutically acceptable taurine salts and derivatives of the present invention are Li, K, Mg and Ca taurates, taurine adducts with L-carnitine and Oacetyl-L-carnitine, and N-acetyltaurine salts.

More preferred pharmaceutically acceptable salts of uridine monophosphate of the present invention are the sodium salt of uridine monophosphate, preferably the disodium salt of uridine monophosphate, its dihydrate.

Vitamin E of the present invention includes all of its pharmaceutically acceptable forms, isomers and derivatives having vitamin E activity, including tocopherols and tocotrienols such as α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β- tocotrienol, γ-tocotrienol, δ-tocotrienol, as well as their esters such as α-tocopheryl acetate, succinate, nicotinate and linoleate, and mixtures thereof.

The term treatment means any treatment of a disease or condition in a subject, including suppressing the development of the disease or condition, which means stopping or suppressing the development of clinical symptoms, and / or reducing the intensity of the symptoms of the disease or condition, which means regressing the clinical symptoms.

The term therapeutically effective amount means an amount of a combination of compounds of the present invention or any derivatives thereof that (1) treats or prevents a specific disease, condition or disorder, (2) reduces, improves, or eliminates one or more symptoms of a specific disease, condition or disorder, or (3) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

The term “pharmaceutically acceptable” means that a given substance or composition to which this term is applied must be chemically and / or toxicologically compatible with the other ingredients in the formulation and safe for the person being treated with this substance or composition.

The terms containing, contains means that the specified combinations, compositions and kits include the listed components, but do not exclude the inclusion of other components.

The term nutraceutically acceptable for the purposes of this application means that a given component can in principle be used in the manufacture of nutraceutical compositions, that it is safe for the consumer of the dietary supplement composition, and that it is compatible with other components of the dietary supplement composition.

The object of the present invention is to provide a new agent for the treatment of chronic pain, containing in effective amounts palmitoylethanolamide and at least one substance,

- 8 038052 selected from the group consisting of uridine monophosphate, taurine, vitamin E, or a pharmaceutically acceptable salt or derivative thereof.

The technical results of the present invention are to increase the effectiveness of the treatment of chronic pain due to the synergistic effect of active substances and, as a result, to reduce the required doses of active substances, reduce side effects and increase the safety of treatment;

expanding the arsenal of remedies for the treatment of chronic pain.

The task is achieved, and the technical result is achieved by creating a combination for the treatment of chronic pain, containing in effective amounts palmitoylethanolamide, which also includes at least one substance selected from the group including uridine monophosphate, taurine, vitamin E, or their pharmaceutically acceptable salts or their derivatives ...

According to preferred embodiments, the technical result is also achieved in that:

the active substances in the above combination are administered in daily dosages of palmitoylethanolamide 50-2500 mg / day;

uridine monophosphate 1 - 200 mg / day;

taurine 50 - 10,000 mg / day;

vitamin E 15 - 2000 IU / day;

the introduction of the above combination is carried out orally;

said combination is an oral tablet or a sublingual sachet; palmitoylethanolamide in said combination is in micronized or ultra-micronized form;

said combination further comprises a substance selected from the group consisting of carnitine, B vitamins, resveratrol, curcumin, benfotiamine, linoleic, linolenic acid, lipoic acid.

The task is also achieved, and the technical result is achieved by obtaining a pharmaceutical composition for the treatment of chronic pain, which contains in effective amounts the above-mentioned combination and at least one excipient and / or at least one pharmaceutically acceptable carrier.

According to preferred embodiments, the technical result is also achieved in that the active substances in the composition of the said composition are administered in daily dosages of palmitoylethanolamide 50 - 2500 mg / day;

uridine monophosphate 1 - 200 mg / day;

taurine 50 - 10,000 mg / day;

vitamin E 15 - 2000 IU / day;

the active substances in the said composition are included in the mass ratios of palmitoylethanolamide: uridine monophosphate from 1: 4 to 2500: 1;

palmitoylethanolamide: taurine 1: 200 to 500: 1;

palmitoylethanolamide: vitamin E from 1: 37 to 192: 1 the introduction of the above composition is carried out orally;

said composition is an oral tablet or sublingual sachet;

palmitoylethanolamide in said composition is in micronized or ultra micronized form;

said composition further comprises a substance selected from the group consisting of carnitine, B vitamins, resveratrol, curcumin, benfotiamine, linoleic, linolenic acid, lipoic acid.

The stated task is also achieved, and the technical result is achieved by creating a kit for the treatment of chronic pain, characterized in that said kit includes a pharmaceutical composition that contains palmitoylethanolamide in effective amounts and at least one excipient and / or at least one pharmaceutically acceptable carrier. The kit also includes at least one additional pharmaceutical composition containing in an effective amount at least one substance selected from the group consisting of uridine monophosphate, taurine, vitamin E or their pharmaceutically acceptable salts or derivatives, and, optionally, auxiliary substances and pharmaceutically acceptable medium. In addition, instructions for use are included in the kit.

The stated task is also achieved, and the technical result is achieved by using the said combination or the said pharmaceutical composition or the said set of co-9 038052 according to the present invention for the treatment of chronic pain.

According to preferred embodiments, the technical result is also achieved in that chronic pain is selected from the group including neuropathic pain after chemotherapy, diabetic chronic neuropathic pain, neuropathic pain in nerve compression syndrome, post-stroke chronic neuropathic pain, chronic pelvic pain syndrome, pain in rheumatic diseases, inflammatory diseases, fibromyalgia, phantom pain;

neuropathic pain in nerve compression syndrome is carpal tunnel syndrome, dorsopathy, or sciatica;

chronic pelvic pain syndrome is pain with vulvodynia, interstitial cystitis, endometriosis, menstrual pain;

pain in rheumatic diseases is pain in rheumatoid arthritis, osteoarthritis;

pain in inflammatory diseases is pain in Crohn's disease, irritable bowel syndrome, influenza;

active substances are administered in preferred daily dosages: palmitoylethanolamide 50 - 2500 mg / day;

uridine monophosphate 1 - 200 mg / day;

taurine 50 - 10,000 mg / day;

vitamin E 15 - 2000 IU / day;

The task is also achieved, and the technical result is achieved by creating a biologically active food supplement comprising palmitoylethanolamide, which also includes at least one substance selected from the group including uridine monophosphate, taurine, vitamin E or their nutraceutically acceptable salt or derivative.

According to preferred embodiments, the technical result is also achieved in that said additive is an oral tablet or a sublingual sachet;

palmitoylethanolamide in the additive is in a micronized or ultra-micronized state;

said additive further comprises a substance selected from the group consisting of carnitine, B vitamins, resveratrol, curcumin, benfotiamine, linoleic, linolenic acid, lipoic acid.

Drugs and pharmaceutical compositions can be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally, or topically). The clinical dosage of an agent containing a new combination of palmitoylethanolamide and at least one substance selected from the group consisting of uridine monophosphate, taurine and vitamin E, according to the present invention, in patients can be adjusted depending on the therapeutic efficacy and bioavailability of active ingredients in the body, their metabolic rate and excretion from the body, as well as depending on the age, sex and stage of the patient's disease, while the daily dose of palmitoylethanolamide in adults is usually 50-2500 mg per day, preferably 300-1200 mg per day, for example about 600-1200 mg per day ... The daily dose of taurine in adults may be 50-10000 mg per day, preferably 500-6000 mg per day, preferably 1500-3000 mg per day, for example about 2000 mg per day. The daily dose of uridine monophosphate in adults may be 1-1000 mg per day, preferably 1-500 mg per day, preferably 1-200 mg per day, for example about 150 mg per day. The daily dose of vitamin E in adults may be 15-2000 IU per day, preferably 1001000 IU per day, preferably 60-75 IU per day, for example about 30 IU per day. Therefore, during the preparation of the pharmaceutical composition of the drug according to the present invention in the form of dosage units, it is necessary to take into account the above effective dosage, while each dosage unit of the drug may contain one or more of the following substances: 25-2500 mg palmitoylethanolamide, 25-5000 mg taurine, 0 , 5-200 mg uridine monophosphate, 5-2000 IU of vitamin E. In accordance with the instructions of a doctor or pharmacist, these preparations can be taken several times during certain periods of time (preferably from one to six times).

The examples below illustrate but do not limit the invention.

Example 1. Model of pain syndrome caused by transection of the sciatic nerve (post-stroke chronic pain).

Chronic pain associated with peripheral nerve injury is characterized by an unpleasant, abnormal sensation (dysesthesia), increased response to pain stimuli (hyperalgesia), and pain in response to a stimulus that usually does not cause pain (allodynia). Axotomy, a complete transection of a peripheral nerve, is widely used as an experimental model for inducing peripheral neuropathy in rats [A. Muthuraman et al. Ameliorative effects of Ocimum sanctum in sciatic

- 10 038052 nerve transection-induced neuropathy in rats. J. Ethnopharmacol. 120 (l): 56-62, 2008]. Ecotomic neuropathy in experimental animals can be associated with complex regional pain syndrome (CRPS) in humans, which is common after fracture, knee arthroplasty and stroke [Daviet, J.C., et al. 2002. Clinical factors in the prognosis of complex regional pain syndrome type 1 after stroke: a prospective study. American Journal of Physical Medicine and Rehabilitation 81, 34-39].

In the experiments, adult Wistar rats with a body weight of 180-250 g were used. The rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour day and night cycle and a sufficient amount of water and food.

One hundred and ten (110) Wistar rats were randomly assigned to twenty-two (22) equal groups (N = 5), differing in the type of drug administered and the dosage. The formed groups of rats are briefly described in table. 1 below.

The study was conducted for 4 drugs (palmitoylethanolamide, uridine monophosphate, taurine, vitamin E), each of which was administered in 3 different doses, and for 3 combinations (palmitoylethanolamide and uridine monophosphate, palmitoylethanolamide and taurine, palmitoylethanolamide, each of which also vitamin E) three doses. A group of rats receiving vehicle only (placebo group) served as a control. Dosage information is given in table. 1. All drugs were administered orally 3 days after surgery and then once a day during the entire study period. All doses are per person.

Table 1

Study groups formed by types of drugs administered and dosages

(N = 5 rats in each group) Media only Palmitoylethanolamide, mg / day fifty 200 2500 Media only group number 1 (placebo) group number 2 group number 3 group No. 4 Uridine monophosphate, mg / day one group No. 5 group number 9 100 group number 6 group No. 10 200 group number 7 group number 8 Taurine, mg / day fifty group No. 11 group number 15 1000 group No. 12 group No. 16 10000 group number 13 group No. 14 Vitamin E, IU / day fifteen group number 17 group number 21 1000 group number 18 group number 22 2000 group No. 19 group number 20

Peripheral neuropathy was induced in rats by a complete sciatic nerve transaction (axotomy). The rats were anesthetized with sodium thiopental (35 mg / kg ip). The skin of the lateral surface of the left thigh was cut and the incision was made directly through the thigh muscle to expose the sciatic nerve. It was tightly ligated with silk in two places before trifurcation of the terminal branches (gastrocnemius, common peroneal and tibial nerves). The sciatic nerve was cut between ligatures about 5 mm in length in the left paw. No surgery was performed on the right thigh, and the intact right paw served as a control. Nociceptive thresholds were assessed on the 14th day after surgery (allodynia and hyperalgesia).

Mechanic-tactile allodynia. The animals were placed in an acrylic chamber (15x15x15 cm) raised above the ground with a wire mesh at the bottom. Before testing, the animals were left in the chamber for 5-10 minutes for adaptation. Next, the plantar surface of the animal's paw was stimulated with calibrated von Frey filaments (or threads) (BIOSEB, USA). The filaments were a set of 10 standard plastic filaments increasing in diameter. The stiffness of the filaments, expressed as the minimum force required to bend a hair, increased with this calibration logarithmically with absolute values from 0.6 to 26 g. s for each filament; the interval between successive applications of different filaments was 2 min). The tip of the thread touched the middle of the plantar surface of the paw with the effort required to bend the hair, and held the hair in this position for 6-8 s. A positive response was recorded if the animal abruptly jerked back its paw when touched. The sensitivity threshold was determined by the minimum pressure causing a reflex paw withdrawal response (4 times out of 6 applications).

Cold hyperalgesia. To assess cold hyperalgesia, a special hot / cold plate test chamber (Ugo Basile, Italy) was used in this study. The test was carried out in a chamber with acrylic walls 30 cm high on a 30x30 cm metal plate cooled to 0 ° C. Healthy animals are able to withstand this temperature for a long time,

- 11 038052 resting all the limbs on the chilled floor, while in case of nerve damage, the contact time of the limb with the cold plate is significantly reduced. To quantify this parameter, the time of keeping the limb on weight was recorded during 1 min of the animal's stay in the test chamber. Each animal was tested three times with an interval of 5 min between measurements; the obtained values were averaged.

For each study group (n = 5), the mean score obtained in the corresponding test and the standard error of the mean for each value were calculated. The significance of differences between the groups was assessed using the paired Student's t-test (at a significance level of p <0.05).

The results are shown in table. 2-4 below.

Table 2 Effect of palmitoylethanolamide and uridine monophosphate, used alone or in combination, ________ on the behavior of rats in a model of post-stroke chronic pain ________

A drug Dose, mg / day Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) severity of cold hyperalgesia, sec (mean ± standard error of the mean) Carrier - one 2.6 + 0.5 6.3 + 0.8 Palmitoyl- ethanolamide fifty 2 9.0 + 0.5 11.3 + 1.5 200 3 10.0 + 1.0 11.5 + 0.8 2500 4 11.0 + 1.1 12.7 + 2.2 uridine monophosphate one five 7.7 + 0.5 10.5 + 1.7 100 6 8.5 + 0.5 11.6 + 1.2 200 7 9.5 + 0.9 12.0 + 1.1 Palmitoylethanolamide + uridine monophosphate 2500 + 200 eight* 24.5 + 1.5 28.6 + 1.3 50+ 1 nine# 23.3 + 1.3 26.3 + 1.1 200 + 100 10 ^$ 23.5 + 1.5 27.0 + 1.5

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and uridine monophosphate (significance level p <0.05) for each dose level.

Table 3

Effect of palmitoylethanolamide and taurine, used alone or in combination, on the behavior of rats in a model of post-stroke chronic pain

A drug Dose, mg / day Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) severity of cold hyperalgesia, sec (mean ± standard error of the mean) Carrier - one 2.6 + 0.5 6.3 + 0.8 Palmitoyl- fifty 2 9.0 + 0.5 11.3 + 1.5 ethanolamide 200 3 10.0 + 1.0 11.5 + 0.8 2500 4 11.0 + 1.1 12.7 + 2.2 fifty AND 7.3 + 0.5 10.0 + 1.7 taurine 1000 12 7.5 + 0.5 10.6 + 1.2 10000 13 8.5 + 0.9 11.0 + 1.1 2500 + fourteen* 23.5 + 1.5 28.0 + 1.3 Palmitoyl- 10000 ethanolamide + 50 + 50 15 ^# 22.3 + 1.3 26.0 + 1.0 taurine 200 + 16 ^$ 22.5 + 1.5 27.1 + 1.5 1000

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and taurine (significance level p <0.05) for each dose level.

- 12 038052

Table 4

Effect of palmitoylethanolamide and vitamin E, alone or in combination, on the behavior of rats in a model of post-stroke chronic pain

A drug Dose, mg / day (IU / day for vitamin E) Group no. severity of mechanical allodynia, g (mean ± standard error middle) severity of cold hyperalgesia, sec (mean ± standard error of the mean) Carrier - one 2.6 + 0.5 6.3 + 0.8 Palmitoyl- ethanolamide fifty 2 9.0 + 0.5 11.3 + 1.5 200 3 10.0 + 1.0 11.5 + 0.8 2500 4 11.0 + 1.1 12.7 + 2.2 Vitamin E fifteen 17 6.3 + 0.5 9.0 + 1.7 1000 18 6.5 + 0.5 9.6 + 1.2 2000 nineteen 7.5 + 0.9 10.0 + 1.0 Palmitoylethanolamide + Vitamin E 2500 + 2000 twenty* 23.0 + 1.5 27.0 + 1.0 50 + 15 21 ^# 21.5 + 1.3 24.0 + 1.0 200 + 1000 22 ^$ 22.3 + 1.5 26.8 + 1.5

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and vitamin E (significance level p <0.05) for each dose level.

In groups receiving a combination of palmitoylethanolamide and uridine monophosphate, palmitoylethanolamide and taurine, palmitoylethanolamide and vitamin E, the rates of mechanical allodynia and cold hyperalgesia are significantly reduced, which indicates the effectiveness of their use for post-stroke chronic pain. But in addition to this, a synergistic effect of these combinations was also found at all tested dose levels.

Example 2. Model of pain syndrome caused by ligation of the spinal nerves.

The Spinal Nerve Neuropathic Pain (SNL) model has been widely used for various research work on the mechanisms of neuropathic pain, as well as for screening tests for the development of new analgesic drugs. This model was developed by tightly ligating one (L5) or two (L5 and L6) rat segmental spinal nerves. The operation results in long-term behavioral signs of mechanical allodynia, thermal hyperalgesia, cold allodynia, and persistent pain [Jin Mo Chung et al. Segmental Spinal Nerve Ligation Model of Neuropathic Pain. Methods in Molecular Medicine 99: 35-45, 2004].

The experiments used adult Spreg-Dawley rats weighing 250-300 g. The rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour day and night cycle and a sufficient amount of water and food.

One hundred and ten (110) Sprague-Dawley rats were randomly assigned to twenty-two (22) equal groups (N = 5), differing in the type of drug administered and dosage. The formed groups of rats are briefly described in table. one.

The study was conducted for 4 drugs (palmitoylethanolamide, uridine monophosphate, taurine, vitamin E), each of which was administered in 3 different doses, and for 3 combinations (palmitoylethanolamide and uridine monophosphate, palmitoylethanolamide and taurine, palmitoylethanolamide, each of which also vitamin E) three doses. A group of rats receiving vehicle only (placebo group) served as a control. Dosage information is given in table. 1. All drugs were administered orally 3 days after surgery and then once a day during the entire study period. All doses are per person.

The animals are anesthetized with an intraperitoneal injection of sodium pentobarbital and the hair on the back is trimmed. Each animal is then placed on the surgical platform in a prone position and the limbs are secured with adhesive tape. Under sterile conditions, a prolonged incision (about 3 cm in length and 5 mm on the sides of the midline) is made at the lower lumbar and sacral levels (from the tail of the L5 vertebra to the first sacral vertebra). The location of the incision is determined by the position of the L5 vertebra, which is located at the level of the rostral end of the iliac crest. Using small blunt-tipped scissors, the paraspinal muscles are exposed and removed from the L5 vertebra to the sacrum.

To assess pain behavior, a test with von Frey filaments (emergence of mechanical allodynia) was used on the 15th day after surgery. Testing was performed as described in Example 1 above, except that the filaments were applied only to the leg.

For each study group (n = 5), the mean score obtained in the corresponding test and the standard error of the mean for each value were calculated. The significance of differences between the groups was assessed using the paired Student's t-test (at a significance level of p <0.05).

The results are shown in table. 5-7 below.

Table 5

Effect of palmitoylethanolamide and uridine monophosphate, alone or in combination, on the behavior of rats with pain syndrome caused by ligation of the spinal nerves

A drug Dose, mg / day Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) carrier - one 3.0 + 0.5 Palmitoylethanolamide fifty 2 10.4 + 1.2 200 3 11.7 + 0.5 2500 4 12.1 ± 2.0 uridine monophosphate one five 8.0 + 1.0 100 6 9.5 + 0.5 200 7 9.6 + 1.0 Palmitoylethanolamide + uridine monophosphate 2500 + 200 eight* 27.5 + 1.5 50 + 1 nine# 24.8 + 1.5 200 + 100 10 ^$ 26.5 + 1.5

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and uridine monophosphate (significance level p <0.05) for each dose level.

Table 6

Effect of palmitoylethanolamide and taurine, alone or in combination, on the behavior of rats with pain syndrome caused by ligation of the spinal nerves

A drug Dose, mg / day Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) carrier - one 3.0 + 0.5 Palmitoyl- ethanolamide fifty 2 10.4 + 1.2 200 3 11.7 + 0.5 2500 4 12.1 ± 2.0 taurine fifty AND 7.5 ± 1.0 1000 12 8.8 ± 0.5 10000 13 9.2 ± 1.0 Palmitoyl- ethanolamide + taurine 2500 + 10000 fourteen* 26.5 ± 1.5 50 + 50 15 ^# 23.5 ± 1.5 200 + 1000 16 ^$ 25.1 ± 1.5

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and taurine (significance level p <0.05) for each dose level.

- 14 038052

Table 7

Effect of palmitoylethanolamide and vitamin E, alone or in combination, on the behavior of rats with pain syndrome caused by ligation of the spinal nerves

A drug Dose, mg / day (IU / day for vitamin E) Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) carrier - one 3.0 + 0.5 Palmitoyl- ethanolamide fifty 2 10.4 + 1.2 200 3 11.7 + 0.5 2500 4 12.1 ± 2.0 vitamin E fifteen 17 7.0 + 1.0 1000 18 8.0 + 0.5 2000 nineteen 8.4 + 1.0 Palmitoylethanolamide + vitamin E 2500 + 2000 twenty* 25.4 + 1.5 50 + 15 21 ^# 22.4 + 1.5 200 + 1000 22 ^$ 23.6 + 1.5

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and vitamin E (significance level p <0.05) for each dose level.

In the groups receiving the combination of palmitoylethanolamide and uridine monophosphate, palmitoylethanolamide and taurine, palmitoylethanolamide and vitamin E, the indicators of mechanical allodynia are significantly reduced, which indicates the effectiveness of their use for the treatment of pain syndrome caused by ligation of the spinal nerves. In addition, a synergistic effect of these combinations was also found at all tested dose levels.

Example 3. Model of diabetic neuropathic pain syndrome.

Diabetic neuropathy is a common complication of diabetes. This occurs in about 10-20% of diabetic patients or about 40-50% of patients with diabetic neuropathy [F. Gao, Z.M. Zheng. Animal Models of Diabetic Neuropathic Pain. Exp Clin Endocrinol Diabetes, 122: 100-106, 2014].

A streptozocin-induced diabetic rat has been put forward as a chronic pain model with signs of hyperalgesia and allodynia, which may reflect those seen in people with diabetes [S. Courteix et al. Study of the sensitivity of the diabetes-induced pain model in rats to a range of analgesics, Pain, 57: 153-160, 1994].

The experiments used adult Spreg-Dawley rats weighing 250-300 g. The rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour day and night cycle and a sufficient amount of water and food.

One hundred and ten (110) Sprague-Dawley rats were randomly assigned to twenty-two (22) equal groups (N = 5), differing in the type of drug administered and dosage. The formed groups of rats are briefly described in table. one.

The study was conducted for 4 drugs (palmitoylethanolamide, uridine monophosphate, taurine, vitamin E), each of which was administered in 3 different doses, and for 3 combinations (palmitoylethanolamide and uridine monophosphate, palmitoylethanolamide and taurine, palmitoylethanolamide, each of which also vitamin E) three doses. A group of rats receiving vehicle only (placebo group) served as a control. Dosage information is given in table. 1. All doses are per person.

The rats received a diabetic intraperitoneal injection of 75 mg / kg streptozocin (STZ) (Zanosar®, Upjohn) dissolved in distilled water. Four weeks later, diabetes was confirmed by measuring venous blood glucose levels with an Ames Dextrostix and a reflectance colorimeter (Ames Division, Miles Laboratories). Blood samples were obtained from the tail and only rats with final blood glucose levels greater than 14 mM were included in the study. The tests were performed 4 weeks after the induction of diabetes.

To assess pain behavior, a test with von Frey filaments (the occurrence of mechanical allodynia) was used. Testing was performed as described in Example 1 above, except that nociceptive thresholds, expressed in grams, were measured by applying increasing pressure to the left hind paw until vocalization was induced. When two stable vocalization thresholds were obtained, a drug or placebo was administered. Vocalization thresholds were then determined within 2 hours. The cutoff was 750 g.

- 15 038052

For each study group (n = 5), the mean score obtained in the corresponding test and the standard error of the mean for each value were calculated. The significance of differences between the groups was assessed using the paired Student's t-test (at a significance level of p <0.05).

The results are shown in table. 8-10 below.

Table 8 Effect of palmitoylethanolamide and uridine monophosphate, alone or in combination, on rat behavior in a diabetic neuropathy model

A drug Dose, mg / day Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) Time, min one fifteen 60 90 120 carrier - one 150 + 5 153 + 5 148 + 5 145 + 5 140 + 5 Palmitoyl- ethanolamide fifty 2 177 + 5 290 + 5 280 + 5 270 + 5 260 + 5 200 3 180 + 5 296 + 5 290 + 5 287 + 5 280 + 5 2500 4 184 + 5 320 + 5 315 + 5 308 + 5 290 + 5 uridine monophosphate one five 167 + 5 220 + 5 218 + 5 215 + 5 210 + 5 100 6 170 + 5 225 + 5 223 + 5 221 + 5 218 + 5 200 7 170 + 5 230 + 5 227 + 5 224 + 5 220 + 5 Palmitoylethanolamide + uridine monophosphate 2500 + 200 eight 189 + 5 574 + 5 * 570 + 5 * 568 + 5 * 565 + 5 * 50 + 1 nine 180 + 5 528 ± 5 ^# 525 ± 5 ^# 520 ± 5 ^# 526 ± 5 ^# 200 + 100 10 184 + 5 565 ± 5 ^$ 562 ± 5 ^$ 560 ± 5 ^$ 554 ± 5 ^$

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and uridine monophosphate (significance level p <0.05) for each dose level at the corresponding time point.

Table 9

Effect of palmitoylethanolamide and taurine, alone or in combination, on rat behavior in a diabetic neuropathy model

A drug Dose, mg / day Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) Time, min one fifteen 60 90 120 carrier - one 150 + 5 153 + 5 148 + 5 145 + 5 140 + 5 Palmitoyl- ethanolamide fifty 2 177 + 5 290 + 5 280 + 5 270 + 5 260 + 5 200 3 180 + 5 296 + 5 290 + 5 287 + 5 280 + 5 2500 4 184 + 5 320 + 5 315 + 5 308 + 5 290 + 5 taurine fifty AND 157 + 5 165 + 5 163 + 5 160 + 5 159 + 5 1000 12 160 + 5 168 + 5 165 + 5 162 + 5 160 + 5 10000 13 161 + 5 169 + 5 166 + 5 164 + 5 162 + 5 Palmitoylethanolamide + taurine 2500 + 10000 fourteen 188 + 5 534 + 5 * 530 + 5 * 527 + 5 * 525 + 5 * 50 + 50 fifteen 180 + 5 488 ± 5 ^# 485 ± 5 ^# 480 ± 5 ^# 475 ± 5 ^# 200 + 1000 sixteen 183 + 5 515 ± 5 ^$ 513 ± 5 ^$ 509 ± 5 ^$ 505 ± 5 ^$

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and taurine (significance level p <0.05) for each dose level at the corresponding time point.

- 16 038052

Table 10

Effect of palmitoylethanolamide and vitamin E, alone or in combination, on rat behavior in a diabetic neuropathy model

A drug Dose, mg / day (IU / day for vitamin E) Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) Time, min one fifteen 60 90 120 carrier - one 150 ± 5 153 ± 5 148 ± 5 145 ± 5 140 ± 5 Palmitoyl- ethanolamide fifty 2 177 ± 5 290 ± 5 280 ± 5 270 ± 5 260 ± 5 200 3 180 ± 5 296 ± 5 290 ± 5 287 ± 5 280 ± 5 2500 4 184 ± 5 320 ± 5 315 ± 5 308 ± 5 290 ± 5 Vitamin E fifteen 17 155 ± 5 158 ± 5 153 ± 5 150 ± 5 149 ± 5 1000 18 156 ± 5 160 ± 5 155 ± 5 152 ± 5 150 ± 5 2000 nineteen 157 ± 5 161 ± 5 156 ± 5 154 ± 5 152 ± 5 Palmitoylethanolamide + vitamin E 2500 + 2000 twenty 188 ± 5 520 ± 5 * 525 ± 5 * 520 ± 5 * 515 ± 5 * 50 + 15 21 180 ± 5 480 ± 5 ^# 475 ± 5 ^# 470 ± 5 ^# 472 ± 5 ^# 200 + 1000 22 183 ± 5 510 ± 5 ^$ 505 ± 5 ^$ 501 ± 5 ^$ 496 ± 5 ^$

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and vitamin E (significance level p <0.05) for each dose level at the corresponding time point.

In the groups receiving the combination of palmitoylethanolamide and uridine monophosphate, palmitoylethanolamide and taurine, palmitoylethanolamide and vitamin E, the indicators of mechanical allodynia are significantly reduced, which indicates the effectiveness of their use for the treatment of diabetic neuropathy. In addition, a statistically significant synergistic analgesic effect of the action of these combinations during the period of maximum action was also found at all tested dose levels.

Example 4. Model of chronic visceral hypersensitivity (chronic abdominal pain).

In all experiments, 13-week-old male C57 BL / 6 mice were used. One hundred and ten (110) mice were randomly assigned to twenty-two (22) equal groups (N = 5), differing in the type of drug administered and dosage. Formed groups of mice are similar to those described in table. 1. Colitis is induced by injecting 0.1 ml TNBS (trinitrobenzenesulfonate) (130 μg / ml in 30% EtOH) into the colon through a polyethylene catheter inserted 3 cm into the anus of isoflurane anesthetized mice. The mice are then housed individually and monitored daily for changes in body weight, appearance and behavior. Histological examination of the structure of the mucous membrane, cellular infiltrate, abscesses of intestinal crypts and goblet cells confirmed significant damage caused by the administration of TNBS on the 3rd day, to a large extent on the 7th day. High-threshold nociceptors of mice on the 28th day showed significant mechanical hypersensitivity, lower thresholds of mechanical activation, hyperalgesia and allodynia [de Araujo A.D. et al. Selenoether oxytocin analogs have analgesic properties in a mouse model of chronic abdominal pain. Nature Communications, 2014, 5: 3165].

To assess pain behavior, a test with von Frey filaments (the occurrence of mechanical allodynia) was used on the 28th day after TNBS administration. Testing was performed as described in Example 1 above, except that the filaments were applied to the abdominal cavity.

For each study group (n = 5), the mean score obtained in the corresponding test and the standard error of the mean for each value were calculated. The significance of differences between the groups was assessed using the paired Student's t-test (at a significance level of p <0.05).

The results are shown in table. 11-13 below.

- 17 038052

Table 11

Effect of palmitoylethanolamide and uridine monophosphate, alone or in combination, on __________ behavior in rats with chronic abdominal pain __________

A drug Dose, mg / day Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) Carrier - one 2.0 + 0.5 Palmitoylethanolamide fifty 2 8.0 + 0.5 200 3 9.0 + 1.0 2500 4 10.0 + 1.1 Uridine monophosphate one five 7.0 + 0.5 100 6 7.6 + 0.5 200 7 8.5 + 0.9 Palmitoylethanolamide + uridine monophosphate 2500 + 200 eight* 23.5 + 1.5 50 + 1 nine# 22.3 + 1.3 200 + 100 10 ^$ 22.5 + 1.5

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and uridine monophosphate (significance level p <0.05) for each dose level.

Table 12

The effect of palmitoylethanolamide and taurine used alone or in combination

*, #, $ - significant difference from the expected '(calculated) additive effect of the combination of palmitoylethanolamide and taurine (significance level p <0.05) for each dose level.

- 18 038052

Table 13

Effect of palmitoylethanolamide and vitamin E, alone or in combination, __________ on the behavior of rats with chronic abdominal pain __________

A drug Dose, mg / day (IU / day for vitamin E) Group no. severity of mechanical allodynia, g (mean ± standard error of the mean) Carrier - one 2.0 + 0.5 Palmitoyl- ethanolamide fifty 2 8.0 + 0.5 200 3 9.0 + 1.0 2500 4 10.0 + 1.1 Vitamin E fifteen 17 5.4 + 1.0 1000 18 6.0 + 1.0 2000 nineteen 6.9 + 1.0 Palmitoylethanolamide + vitamin E 2500 + 2000 twenty* 22.0 + 1.5 50 + 15 21 ^# 20.5 + 1.5 200 + 1000 22 ^$ 21.2 + 1.5

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and vitamin E (significance level p <0.05) for each dose level.

In the groups receiving the combination of palmitoylethanolamide and uridine monophosphate, palmitoylethanolamide and taurine, palmitoylethanolamide and vitamin E, the rates of mechanical allodynia are significantly reduced, which indicates the effectiveness of their use for the treatment of chronic abdominal pain. In addition, a synergistic effect of these combinations was also found at all tested dose levels.

Example 5. Model of adjuvant arthritis caused by the introduction of Freund's adjuvant.

The similarity of adjuvant arthritis in rats with human rheumatoid arthritis is the presence of edema of the extremities, degradation of cartilage, lymphocytic infiltration of the inflamed joint tissue, loss of their function, in addition, bone and periosteum resorption is noted. In animals, the spine, gastrointestinal tract, genitourinary tract, skin and eyes are also affected, which is similar to human spondyloarthropathies. The adjuvant arthritis model is T-cell-dependent and complement-independent. Induction of adjuvant arthritis is carried out by intradermal or subcutaneous administration of complete Freund's adjuvant (FFA). Freund adjuvant [lat. adjuvans (adjuvantis) assisting, facilitating] - one of the most common adjuvants, which contains killed mycobacterium tuberculosis suspended in the oil phase of an aqueous emulsion. Freund's adjuvant is a potent stimulator of nonspecific immune responses.

The adjuvant can be injected into the base of the tail or one of the pads of the paws, which allows the study of an acute inflammatory response at the injection site, as well as an immunological response that develops in about 5-9 days in the contralateral paw and various organs.

Hindpaw edema was monitored from the very first day up to 15 days or more, depending on the duration of the experiment. In the later stages of the disease (12 days and beyond), rats with adjuvant arthritis are often immobile due to the severity of the paw edema and require special care, including guaranteed access to water and food. When using the model for the purpose of developing preventive measures, therapeutic drugs are used from day zero, and if it is necessary to develop a treatment strategy, drugs are prescribed from the eighth day of creating the model [Gromyko MV, Gritsuk A.I. Experimental models of rheumatoid arthritis. Health and ecology problems. No. 2 (32), 2012, p. 115-118].

The experiment is carried out on 3-month-old male Wistar rats weighing 180-200 g, kept under standard vivarium conditions. One hundred and ten (110) Wistar rats were randomly assigned to twenty-two (22) equal groups (N = 5), differing in the type of drug administered and the dosage. The formed groups of rats are briefly described in table. one.

Adjuvant arthritis in rats is induced by subplantar injection of complete Freund's adjuvant (FFA) into the hind paw. Joint edema, which determines the severity of the development of the disease, after the introduction of PAF is measured with a caliper through the sagittal diameter in the tarsal joint. The joint edema index is calculated by the formula: x = a / b, where x = joint edema index, a = average value of the joint diameter of rats with adjuvant arthritis for the group, b = average value of the joint diameter for the group before the administration of the adjuvant. For intact animals, the joint edema index was taken as 1.

Treatment begins on the 5th day after the injection. Starting from 2 days after induction of adjuvant

- 19 038052 arthritis in animals, the development of progressive joint edema was observed, which reached its maximum on the 15-20th day (index 2.50 ± 0.10). To assess pain behavior, a test with von Frey filaments (the occurrence of mechanical allodynia) was used for 30 days after the administration of PAF and the development of adjuvant arthritis.

Testing was performed as described in Example 1 above, except that the filaments were applied to the injured joint of the hind paw into which the PAF was injected.

For each study group (n = 5), the mean score obtained in the corresponding test and the standard error of the mean for each value were calculated. The significance of differences between the groups was assessed using the paired Student's t-test (at a significance level of p <0.05).

The results are shown in table. 14-16 below.

Table 14 Effect of palmitoylethanolamide and uridine monophosphate, alone or in combination, _______________ on the behavior of rats in an adjuvant arthritis model _______________

A drug Dose, mg / day and Group a No. The severity of mechanical allodynia, g (mean ± standard error of the mean) Time, day five 10 fifteen twenty 25 thirty Carrier - one 2.0 + 0.5 1.8 + 0.5 1.5 + 0.5 1.0 + 0.5 1.1 + 0.5 1.2 + 0.5 Palmitoyl- ethanolamide fifty 2 7.7 + 1.0 7.5 + 1.0 7.2 + 1.0 7.1 + 1.0 7.5 + 1.0 7.6 + 1.0 200 3 8.5 + 1.0 8.2 + 1.0 8.0 + 1.0 7.8 + 1.0 8.0 + 1.0 8.3 + 1.0 2500 4 9.3 + 1.0 9.0 + 1.0 8.8 + 1.0 8.5 + 1.0 8.6 + 1.0 8.8 + 1.0 uridine monophosphate at one five 7.0 + 1.0 6.8 + 1.0 6.5 + 1.0 6.3 + 1.0 6.5 + 1.0 6.8 + 1.0 100 6 7.5 + 1.0 7.3 + 1.0 7.1 + 1.0 6.7 + 1.0 6.8 + 1.0 7.0 + 1.0 200 7 7.7 + 1.0 7.5 + 1.0 7.3 + 1.0 7.0 + 1.0 7.1 + 1.0 7.4 + 1.0 Palmitoylethanolamide + uridine monophosphate 2500 + 200 eight* 23.0 + 1.9 22.8 + 1.9 22.5 + 1.9 22.0 + 1.9 22.3 + 1.9 22.7 + 1.9 50 + 1 9 ^# 22.0 + 1.5 21.8 + 1.5 21.6 + 1.5 21.3 + 1.5 21.4 + 1.5 21.5 + 1.5 200 + 100 10 ^$ 22.3 + 1, one 22.1 + 1, one 21.9 + 1, one 21.7 + 1, 1 21.8 + 1, 1 22.0 + 1, one

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and uridine monophosphate (significance level p <0.05) for each dose level at the corresponding time point.

- 20 038052

Table 15

Effect of palmitoylethanolamide and taurine, alone or in combination, on the behavior of ___________________ rats in an adjuvant arthritis model ____________________

A drug Dose, mg / day Group no. severity of mechanical standard error of the mean) Time, days allodynia, g (mean ± five 10 fifteen twenty 25 thirty carrier - one 2.0 + 0.5 1.8 + 0.5 1.5 + 0.5 1.0 + 0.5 1.1 + 0.5 1.2 + 0.5 fifty 2 7.7 + 1.0 7.5 + 1.0 7.2 + 1.0 7.1 + 1.0 7.7 + 1.0 7.9 + 1.0 Palmitoyl- 200 3 8.5 + 1.0 8.2 + 1.0 8.0 + 1.0 7.8 + 1.0 8.0 + 1.0 8.4 + 1.0 ethanolamide 2500 4 9.3 + 1.0 9.0 + 1.0 8.8 + 1.0 8.5 + 1.0 8.6 + 1.0 8.8 + 1.0 fifty AND 6.9 + 1.5 6.7 + 1.5 6.6 + 1.5 6.2 + 1.5 6.3 + 1.5 6.4 + 1.5 taurine 1000 12 7.1 + 1.5 6.9 + 1.5 6.8 + 1.5 6.5 + 1.5 6.6 + 1.5 6.7 + 1.5 10000 13 7.4 + 1.5 7.2 + 1.5 7.0 + 1.5 7.1 + 1.5 7.2 + 1.5 7.3 + 1.5 2500 + fourteen* 22.5 + 1.8 22.3 + 1.8 22.1 + 1.8 21.8 + 1.8 21.9 + 1.8 22.0 + 1.8 Palmitoyl- 10000 ethanolamide 50 + 50 15 ^# 21.7 + 1.8 21.5 + 1.8 21.4 + 1.8 21.1 + 1.8 21.2 + 1.8 21.3 + 1.8 + taurine 200 + 16 ^$ 22.2 + 1.8 22.0 + 1.8 21.9 + 1.8 21.7 + 1.8 21.8 + 1.8 21.9 + 1.8 1000

*, #, $ - significant difference from the expected (calculated) 'additive effect of the combination of palmitoylethanolamide and taurine (significance level p <0.05) for each dose level at the corresponding time point.

Table 16 Effect of palmitoylethanolamide and vitamin E, alone or in combination, ___________ on the behavior of rats in an adjuvant arthritis model ______________

A drug Dose, mg / day (IU / day for vitamin E) Group no. The severity of mechanical allodynia, g (mean ± standard error of the mean) Time, day five 10 fifteen twenty 25 thirty Carrier - one 2.0 + 0.5 1.8 + 0.5 1.5 + 0.5 1.0 + 0.5 1.1 + 0.5 1.2 + 0.5 Palmitoyl- ethanolamide fifty 2 7.7 + 1.0 7.5 + 1.0 7.2 + 1.0 7.1 + 1.0 7.7 + 1.0 7.9 + 1.0 200 3 8.5 + 1.0 8.2 + 1.0 8.0 + 1.0 7.8 + 1.0 8.0 + 1.0 8.4 + 1.0 2500 4 9.3 + 1.0 9.0 + 1.0 8.8 + 1.0 8.5 + 1.0 8.6 + 1.0 8.8 + 1.0 Vitamin E fifteen 17 5.9 + 1.1 5.7 + 1.1 5.5 + 1.1 5.2 + 1.1 5.3 + 1.1 5.4 + 1.1 1000 18 6.3 + 1.1 6.1 + 1.1 5.8 + 1.1 5.6 + 1.1 5.7 + 1.1 5.9 + 1.1 2000 nineteen 6.5 + 1.2 6.3 + 1.2 6.1 + 1.2 5.9 + 1.2 6.0 + 1.2 6.1 + 1.2 Palmitoyl- ethanolamide 2500 + 2000 twenty* 22.0 + 1.5 21.8 + 1.5 21.6 + 1.5 21.4 + 1.5 21.5 + 1.5 21.6 + 1.5 + vitamin E 50 + 15 21 ^# 21.1 + 1.5 20.9 + 1.5 20.7 + 1.5 20.4 + 1.5 20.6 + 1.5 20.8 + 1.5 200 + 1000 22 ^$ 21.3 + 1.5 21.1 + 1.5 20.9 + 1.5 20.6 + 1.5 20.7 + 1.5 20.9 + 1.5

*, #, $ - significant difference from the expected (calculated) additive effect of the combination of palmitoylethanolamide and vitamin E (significance level p <0.05) for each dose level at the corresponding time point.

In groups receiving a combination of palmitoylethanolamide and uridine monophosphate, palmitoylethanolamide and taurine, palmitoylethanolamide and vitamin E, the indicators of mechanical allodynia are significantly reduced, which indicates the effectiveness of their use for the treatment of pain syndromes

- 21 038052 for adjuvant or rheumatoid arthritis. In addition, a statistically significant synergistic analgesic effect of the action of these combinations during the period of maximum action was also found at all tested dose levels.

Example 6. Obtaining a composition in the form of tablets.

To obtain a micronized form of palmitoylethanolamide, standard methods of mechanical or ultrasonic dispersion are used [Ultrasound. Little encyclopedia. Main ed. I.P. Golyamina. Ed. Soviet encyclopedia, Moscow, 1989, 399 pages].

1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc, 1000 mg of palmitoylethanolamide and 1000 mg of uridine monophosphate are mixed and pressed into a bar.

1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc, 1000 mg of palmitoylethanolamide and 4000 mg of taurine are mixed and pressed into a bar.

1600 mg of starch, 1600 mg of crushed lactose, 400 mg of talc, 1000 mg of palmitoylethanolamide and 500 mg of vitamin E are mixed and pressed into a bar.

The resulting bars are crushed into granules and sieved to collect 1416 mesh granules. The resulting granules are tableted into a suitable tablet form, each weighing 500 mg.

Example 7. Obtaining a composition in the form of capsules.

Thoroughly mix palmitoylethanolamide and uridine monophosphate in a 1: 1 ratio.

Thoroughly mix palmitoylethanolamide and taurine in a 1: 4 ratio.

Thoroughly mix palmitoylethanolamide and vitamin E in a 2: 1 ratio.

The resulting combinations are mixed with lactose powder in a 2: 1 ratio.

The resulting powder mixture is packaged in 300 mg gelatin capsules of a suitable size.

Example 8. Obtaining a composition in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection.

Mix 1000 mg of palmitoylethanolamide and 1000 mg of uridine monophosphate with 600 mg of chlorobutanol, 4 ml of propylene glycol and 200 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed.

1000 mg of palmitoylethanolamide and 4000 mg of taurine are mixed with 600 mg of chlorobutanol, 4 ml of propylene glycol and 200 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed.

1000 mg of palmitoylethanolamide and 500 mg of vitamin E are mixed with 600 mg of chlorobutanol, 4 ml of propylene glycol and 200 ml of injection water. The resulting solution is filtered and placed in 1 ml ampoules, which are sealed.

The invention can be used in medicine, pharmacology, as well as for the production of functionally active biologically active food supplements.

Claims (18)

CLAIM 1. A combination for the treatment of chronic pain containing palmitoylethanolamide, characterized in that said combination also includes a substance selected from the group consisting of uridine monophosphate, taurine, vitamin E or their pharmaceutically acceptable salts, where the active substances are contained in the following amounts: palmitoylethanolamide - 25-2500 mg; uridine monophosphate - 0.5-200 mg; taurine - 25-5000 mg; vitamin E - 5-2000 ME. 2. A combination according to claim 1, wherein said combination is an oral tablet or a sublingual sachet. 3. A combination according to claim 1, characterized in that the palmitoylethanolamide in said combination is in micronized or ultra-micronized form. 4. A combination according to claim 1, wherein said combination further comprises a substance selected from the group consisting of carnitine, B vitamins, resveratrol, curcumin, benfotiamine, linoleic, linolenic acids, lipoic acid. 5. Pharmaceutical composition for the treatment of chronic pain, characterized in that said composition contains a combination according to any one of claims 1 to 4 and at least one excipient and / or at least one pharmaceutically acceptable carrier, where the active substances are in the following mass ratios: palmitoylethanolamide: uridine monophosphate 1: 4 to 2500: 1; palmitoylethanolamide: taurine 1: 200 to 50: 1; palmitoylethanolamide: vitamin E from 1: 26.8 to 248.7: 1. 6. A composition according to claim 5, wherein said composition is an oral tablet or a sublingual sachet. - 22 038052 7. Composition according to claim 5, characterized in that the palmitoylethanolamide in said composition is in micronized or ultra-micronized form. 8. Composition according to claim 5, characterized in that said composition further comprises a substance selected from the group consisting of carnitine, B vitamins, resveratrol, curcumin, benfotiamine, linoleic, linolenic acids, lipoic acid. 9. A kit for the treatment of chronic pain, characterized in that said kit comprises a pharmaceutical composition containing palmitoylethanolamide and at least one excipient and / or at least one pharmaceutically acceptable carrier, at least one additional pharmaceutical composition containing a substance selected from the group consisting of uridine monophosphate, taurine, vitamin E or their pharmaceutically acceptable salts, and excipients and a pharmaceutically acceptable carrier, and instructions for use, where the active substances are contained in the following amounts: palmitoylethanolamide - 25-2500 mg; uridine monophosphate - 0.5-200 mg; taurine - 25-5000 mg; vitamin E - 5-2000 ME. 10. Use of a combination according to claim 1 for the treatment of chronic pain. 11. Use of a pharmaceutical composition according to claim 5 for the treatment of chronic pain. 12. Use of the kit according to claim 9 for the treatment of chronic pain. 13. Use according to claims 10-12, characterized in that the chronic pain is selected from the group consisting of neuropathic pain after chemotherapy, diabetic chronic neuropathic pain, neuropathic pain in nerve compression syndrome, which is carpal tunnel syndrome, dorsopathy or sciatica, post-stroke chronic neuropathic pain, chronic pelvic pain syndrome, which is pain in vulvodynia, interstitial cystitis, endometriosis, menstrual pain, pain in rheumatic diseases, which is pain in rheumatoid arthritis, osteoarthritis, inflammatory diseases, which is pain in Crohn's disease, irritable bowel syndrome, flu, fibromyalgia, phantom pain. 14. Use according to claims 10-12, characterized in that the active substances are administered in preferred daily dosages of palmitoylethanolamide - 50-2500 mg / day; uridine monophosphate - 1-200 mg / day; taurine - 50-10000 mg / day; vitamin E - 15-2000 IU / day 15. Biologically active food supplement, including palmitoylethanolamide, characterized in that said additive also includes a substance selected from the group consisting of uridine monophosphate, taurine, vitamin E or their nutraceutically acceptable salt, where the substances are contained in the following amounts: palmitoylethanolamide - 25-2500 mg; uridine monophosphate - 0.5-200 mg; taurine - 25-5000 mg; vitamin E - 5-2000 ME. 16. The biologically active food supplement according to claim 15, characterized in that said supplement is an oral tablet or a sublingual sachet. 17. The biologically active food supplement according to claim 15, characterized in that the palmitoylethanolamide in the supplement is in a micronized or ultra-micronized state. 18. The biologically active food supplement according to claim 15, wherein said supplement further comprises a substance selected from the group consisting of carnitine, B vitamins, resveratrol, curcumin, benfotiamine, linoleic, linolenic acids, lipoic acid.