RU2701720C1 - Combinations of palmitoylethanolamide for treating chronic pain - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, pharmacology, namely to a combination for treating chronic pain. For this purpose, the combination contains in effective amounts palmitoylethanolamide, characterized by that said combination also includes at least one substance selected from a group comprising uridine monophosphate, taurine, vitamin E, or their pharmaceutically acceptable salts, where the active substances in the said combination are contained in the following amounts: palmitoylethanolamide 50–2,500 mg; uridine monophosphate 1–200 mg; taurine 50–10,000 mg; vitamin E 15–2,000 IU. Invention also relates to a pharmaceutical composition for treating chronic pain, which contains an effective amount of a combination according to any of claims 1–4 and at least one auxiliary substance and/or at least one pharmaceutically acceptable carrier, where the active substances in the composition are in weight ratios: palmitoyle ethanol : uridine monophosphate from 1:4 to 2,500:1; palmitoylethanolamide : taurine from 1:200 to 50:1; palmitoylethanolamide : vitamin E ranges from 1:36.4 to 248.7:1. Invention relates to a kit for treating chronic pain comprising a pharmaceutical composition according to claim 5 and an instruction for use, wherein the active ingredients in the pharmaceutical composition are contained in the following amounts: palmitoylethanolamide 50–2,500 mg; uridine monophosphate 1–200 mg; taurine 50–10,000 mg; vitamin E 15–2,000 IU.

EFFECT: invention provides higher clinical effectiveness in chronic pain ensured by synergetic effect of active substances and, as a result, reduced required doses of active substances, reduced side effects and higher safety of treatment, as well as extended range of products for chronic pain management.

9 cl, 16 tbl, 8 ex

Description

The invention relates to medicine, pharmacology, and in particular 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, particularly preferably:

- neuropathic pain after chemotherapy;

- diabetic chronic neuropathic pain;

- neuropathic pain with nerve compression syndrome (carpal tunnel syndrome, sciatica; lumbago, other dorsopathies, neuritis, neuralgia, pudental 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 joint diseases);

- diseases, syndromes accompanied by acute and chronic visceral pain (for example, with Crohn’s disease, IBS);

- fibromyalgia, multiple sclerosis, accompanied by pain associated with disorders in the peripheral and central link of the nociceptive and antinociceptive system;

- 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 everyday practice. The prevalence of pain in primary care varies 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 WHO, in developed countries, the pain in terms of its spread is quite comparable to a pandemic.

To achieve success in treatment, it is important to distinguish between acute and chronic pain. Acute pain is inextricably linked to the damage that caused it and is usually a symptom of a disease. It usually disappears when the damage is repaired and / or the healing period expires. Chronic pain continues for a long time even after the cause of acute pain has been eliminated, and often acquires the status of an independent disease. The International Association for the Study of Pain defines it as "pain that continues beyond the normal healing period." The main difference between chronic and acute pain is not a temporary factor, but qualitatively different neurophysiological, biochemical, psychological and clinical relationships [Korzhavina VB, Danilov AB New opportunities and prospects for the treatment of pain syndromes // breast cancer. 2010. S. 31].

All pain syndromes, depending on the cause and the mechanism of their development, can be divided into three main groups: nociceptive, neuropathic and psychogenic. Nociceptive pain occurs due to activation of nociceptors, free nerve endings, due to tissue damage (examples of such pain are postoperative pain, pain with trauma, angina pectoris in patients with coronary heart disease, epigastric pain with peptic ulcer, pain in patients with arthritis and myositis). Psychogenic pain syndromes are characterized by the presence in patients of pain 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 the tissues or areas of innervation, the defeat of which could be suspected as the cause of the pain.

The ultimate perception of pain is the result

interactions of nociceptive and antinociceptive systems. The formation of pain in a person is mediated by the structures of the nociceptive system, which carries out the perception, conduct and processing of information about various stimuli. The downward inhibitory cerebrospinal control 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. tsp - correspondent RAMS A.M. Wayne. M .: MEDpress-inform, 2001].

Several stages are distinguished in the mechanisms of sensitization of nociceptive neurons: activation of AMPA receptors (α-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 D-aspartate) glutamate when repeated or prolonged damaging effect is applied. This leads to the removal of magnesium ions blocking the NMDA receptor channels, resulting in intracellular entry of calcium ions. Under conditions of increased calcium intake in neurons, the expression of c-fos, c-jun, jun B early response genes occurs, which, by activating effector genes, change the cellular phenotype and form long-term neuronal hyper-excitability. Through such mechanisms, central sensitization can exist even after the initial initiating factors are eliminated [Kukushkin M.L., Khitrov N.K. General pathology of pain. - M .: Medicine, 2004. - 144 s].

Therefore, the timely and adequate treatment of acute pain syndrome with the aim of preventing the chronicity of the pathological condition is fundamentally important [Barinov AN Comprehensive treatment of pain. BC, 2007, Volume 15, No. 4, p. 215-220].

Among adults, the most common cause of chronic pain is dorsopathy: 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 total population. In the world in patients with diabetes mellitus (DM), peripheral neuropathic is registered 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].

About 500 thousand strokes are registered annually in Russia, and one of the complications of a stroke is post-stroke pain, which develops in 2.7% of stroke patients [Mulla SM, Wang L, et all. 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 it is an interconnected combination of various pain phenomena. As you know, muscle pains can be combined with pains of a neurogenic nature, and in the process of developing the syndrome, the psychological component also joins it, which affects the person’s perception of pain.

One of the types of chronic pain - chronic neuropathic pain (NB) - is a result of direct damage or dysfunction of the somatosensory nervous system (central and / or peripheral) in the intact state of peripheral (pain, nociceptive) receptors (in the domestic literature, neuropathic pain resulting from central lesions structures

somatosensory nervous system, also called "central pain").

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

Thus, with nociceptive pain, there is a lesion of peripheral pain receptors with intactness of all parts of the nervous system, and with NB, on the contrary, there is a lesion of any structures of the somatosensory nervous system with intactness of pain receptors. In contrast to nociceptive pain, which is an adequate physiological response to a pain stimulus or tissue damage, NB, as a rule, is not adequate to the nature, intensity or duration of exposure to the stimulus [A.B. Danilov "Pharmacotherapy of neuropathic back pain" Neurology / Rheumatology. Application consilium meducum, 2011, No. 1, p. 51-55].

The causes of damage to the peripheral somatosensory nervous system can be metabolic disorders, trauma, intoxication, the infectious process, mechanical compression, vitamin deficiencies. 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 injuries of the spinal cord and brain, ischemic and hemorrhagic strokes, pain in Parkinson's disease, syringomyelia and demyelinating diseases (multiple sclerosis) and other diseases.

Pathological processes involved in 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 the 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 (a clinical phenomenon of allodynia);

the formation of connections by sympathetic postganglionic fibers with afferent conductors of the somatosensory system, as a result of which there is an exchange of signals between them, that is, activation of sympathetic (“non-pain”) postganglionic fibers leads to the excitation of nociceptors (pain receptors) [Pain syndromes in neurological practice / Ed. tsp - correspondent 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 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 the peripheral nerves, plexuses or dorsal spinal roots, in most cases there is an acute periodic paroxysmal pain, similar to an electric discharge, lasting several seconds. In conditions of extensive or complete damage to the nerve conductors, pain in the denervated area is more often permanent in the form of numbness, burning, and aches. A neurological examination usually allows you to detect changes in tactile, temperature and pain sensitivity in the form of dysesthesia, hyperpathy, and allodynia in the area of pain in patients with chronic pain. The increased perception of ordinary stimuli, characterized by long lasting unpleasant painful sensations after the cessation of irritation, is referred to as hyperpathy, and pain sensations arising in response to mild mechanical or temperature (that is, in response to non-painful) irritation of the skin areas is defined as allodynia. A frequent symptom in patients with neuropathic pain syndromes is paresthesia in the form of spontaneous sensations of tingling, numbness or crawling ants 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, color and skin temperature [Baron R., Binder A. How neuropathic is sciatica? The mixed pain concept. Orthopade 2004; 33 (5): 568 - 75].

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

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

- the use of reuptake blockers 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 affecting the interneurons of the horn come from (fluoxetine, amitriptyline, sertraline, duloxetine, etc.);

- the use of antagonists of NMDA receptors, "erasing" pain memory (ketamine, dextramethorphan);

- electrical stimulation and other methods of physical stimulation (physiotherapy, acupuncture, percutaneous electroneurostimulation, massage, etc.) that cause inhibition of nociceptive neurons of the horn by activating enkephalinergic neurons [Barinov AN Comprehensive treatment of pain. BC, 2007, Volume 15, No. 4, p. 215-220].

Since conventional painkillers from the NSAID group are not effective in chronic pain, it is not only senseless to use them for treating such patients, but NSAIDs also have a number of adverse side effects. Treatment of chronic pain is a significant difficulty and should be comprehensive, including medications, methods of 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 according to the schedule in an individually selected (titrated) dosage.

Currently, pharmacological research in the field of the search for effective treatment of chronic pain is focused mainly on drugs with neurotropic effects, such as tricyclic antidepressants amitriptyline (tryptisol), doxepin (synequan), clomipramine (anafranil); selective serotonin reuptake inhibitors (SSRIs) SSRIs - fluoxetine, sertraline (zoloft), paroxetine (paxil), fluvoxamine (fevarin); muscle relaxants that demonstrate higher efficacy than analgesics [Tabeeva GR Modern principles of treatment of fibromyalgia. BC, 2011, Volume 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 conduct 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) adversely affects cognitive function. In addition, it is often accompanied by anxiety, depression, limited 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 antidepressant, but also an analgesic effect (Mosolov S.N. Clinical use of modern antidepressants. St. Petersburg, 1995; 565).

The effectiveness of antidepressants in the treatment of chronic pain syndromes reaches 75% [Fuller RW. Serotonin uptake inhibitor // Prog Drug Res 1995; 45: 167-204]. The effectiveness of antidepressants is higher, the greater the role played by depression in chronic pain.

The mechanisms of analgesic action of antidepressants are as follows. - analgesic effect in connection with the reduction of depression (this mechanism is especially significant if the pain syndrome was a mask of depression, i.e., with primary depressions, however, and with depressions secondary to pain, reduction of depression always leads to a weakening of the pain syndrome);

- analgesic effect in connection with the potentiation of the action of both exogenous and endogenous analgesic substances, mainly opioid peptides;

- analgesic effect in connection with the stimulation of antinociceptive descending mainly serotonergic systems of the brain.

To obtain a sufficient analgesic and antidepressant effect, antidepressants should 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, the patent US 7534806 (publ. 19.05.2009) is known, which describes the treatment of neuropathic pain and related symptoms with a combination of ibudilast (3-isobutyryl-2-isopropylpyrazolo [1,5-a] pyridine) and a second component, such as gabapentin, memantine, morphine, cannabioids, 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 of treating pain, comprising administering to mammals an analgesic 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, pain in the neck, shoulder, back, headaches, migraine, herpes neuralgia, phantom limb pain, central pain, toothache, NSAID-resistant pain, visceral pain, surgical pain, postoperative pain, bone pain trauma, pain during childbirth, pain resulting from burns, postpartum pain, angina pain, pain related to the genitourinary system topic, 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 excess release of glutamate into the presynaptic cleft - a transmitter of 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 'Connor A.V., Backonja Metal. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007; 132: 23 7-51]. For example, gabapentin in chronic neuropathic pain is prescribed as monotherapy, starting with the minimum dose, followed by its increase to achieve the desired result. The dose appropriate for the patient depends on many factors: a hereditarily determined threshold of pain sensitivity, living and working conditions, the general physical condition and emotional status of the patient. The duration of treatment depends on the clinical response of the patient to therapy [Danilov A.V., Davydov O.S. Principles and algorithms for the treatment of neuropathic pain. BC, 2008, T. 16, p. 11-16].

These drugs often have serious side effects, in some cases they can be addictive, lose their effectiveness in chronic use, therefore, there remains a need for new highly effective and safe treatments for chronic pain, suitable for long-term use.

Palmitoylethanolamide (PEA), an endocannabinoid that does not directly bind to cannabinoid receptors (has low affinity for CB1 and CB2 receptors), is an endogenous ligand for peroxisome proliferator activated alpha receptors (PPAR alpha). The PPAR alpha receptor is a regulator of genes that control pain and inflammation, possibly by turning off the KappaB factor nuclear signaling cascade [Hesselink JM., Hekker TA. 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 does not have a pronounced affinity for CB1 and CB2 receptors, but causes an antinociceptive effect, which 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 on different nociception models using various methods of substance administration, as well as the interaction of PEA with anandamide, the researchers concluded that there are CB receptors in the body that are not of the type of vanilloid receptor [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].

Currently, it has been proven that in the pathogenesis of the development of chronic pain lies 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 in 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 neck-shoulder pain correlate with pain intensity and sensitivity. Pain. 2013, 154 (9): 1649-58]. In animal models, PEA has been shown to inhibit mast cell activity and pro-inflammatory mediator production, 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 the axonal diameter, as well as the amount of nerve fiber, which can be regarded as a neuroprotective effect.

PEA lipophilen, 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 min; rapidly hydrolyzed by the enzymes NAAA (N-acylethanolamine-hydrolyzing acid amidase) and FAAH (fatty acid amide hydrolase). The distribution in the brain is heterogeneous, with maximum accumulation in the hypothalamus. A comparison of the efficacy of the two available forms of PEA, micronized and ultramikronized, in humans has not been carried out; 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, particle size reduction technology (micronization and / or ultramikronization) 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 may 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), a ultra-micronized palmitoylethanolamide may have a particle size of, for example, 0.8-6 microns (US20150328173).

Uridine monophosphate (UMP, UMP) is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with a urosine nucleoside. UMP consists of a phosphate group, pentose ribose sugar and uracil nucleotide; therefore, is a ribonucleotide monophosphate. The study found that gerbils treated with a combination of uridine monophosphate, choline, and docosahexaenoic acid (DHA) had significantly improved learning and memory characteristics in labyrinth tests compared to animals that did not receive these 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, while taking uridine monophosphate and cytidine monophosphate accelerates the regeneration of nerve tissue and increases the speed of nerve conduction.

Currently, cytidine monophosphate (CMF) and uridine monophosphate (UMF) are prescribed to patients for the treatment of neuromuscular disorders. In patients receiving CMF / UMF, impaired neurological functions are restored and pain is relieved.

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 (1) : 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 Wernaj. 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 Pain Res. 2017; 10: 397- 404). It is known that monophosphate, diphosphate and uridine triphosphate in the body can interconvert under the influence of kinase and phosphatase enzymes. It is believed that uridine does not have a direct analgesic effect, and its mechanism of action for 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 called a sulfur-containing amino acid, with no carboxyl group in the molecule. In small amounts is present in the tissues and bile of animals and humans. Used as a dietary supplement or as a medicine.

taurine

With subconjunctival administration, taurine has a retinoprotective, anti-cataract, and also metabolic effect. With systemic exposure, taurine not only has 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. 623-636].

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 with closed head injuries. It has radioprotective properties.

Taurine plays an important role in lipid metabolism, helps to normalize the function of cell membranes, optimizes energy and metabolic processes, preserves 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 causes the normalization of ocular tissue metabolism in diseases of a dystrophic nature.

The antinociceptive activity of taurine in neuropathic pain is known, which is expressed in the reduction of allodynia in models of diabetic neuropathy and nerve compression in rats. It is believed that the taurine effect may be due to activation of glycine neuron receptors [Terada T, Naga 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 against excitotoxic damage [Belfer I, Davidson E, Ratner A, Beery E, Shir Y, Seltzer Z. Dietary supplementation with the inhibitory amino acids 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 of tocol derivatives. The most important compounds are tocopherols and tocotrienols. Fat soluble vitamin. It was first isolated in 1922, and in 1938 was synthesized chemically.

Vitamin E is a universal protector of cell membranes against oxidative damage. It occupies a position in the membrane that prevents the contact of oxygen with unsaturated lipids of the membranes (the formation of hydrophobic complexes). This protects the biomembranes from their peroxide degradation. The antioxidant properties of tocopherol are also due to the ability of the mobile hydroxyl of the chromane 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 manifested and in its ability to protect against oxidation of the SH-group of membrane proteins. 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 an enzymatic antioxidant defense (glutathione peroxidase neutralizes lipid hydroperoxides).

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

Vitamin E is known to have an analgesic effect in chronic pain and allodynia, and its effect is probably due to antioxidant properties, since reactive oxygen species play a critical role in the pathogenesis of neuropathic pain (Kim NK, 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 authors of the present invention 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 allows you to achieve 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 and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and other things.

"Pharmaceutical composition" means a composition comprising a new combination of 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 means, means of delivery, such as preservatives, stabilizers, fillers, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, lubricants, prolonged 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, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be achieved using agents that slow down 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, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples and distribution 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. The pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

Pharmaceutical compositions may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the active substances of the present invention, or their pharmaceutically acceptable salts and derivatives, may include other active substances, including those having 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 traditional pharmaceutical carriers.

Carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to produce common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, flavoring agents taste; 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 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 the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds, or obtained on purpose. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates, mesylates malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (Detailed description of the properties of such salts is given in 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 the purified acid with a suitable base, and metal and amine salts can be synthesized. Metal 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 obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases from which salts of the claimed acids can be obtained, amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should 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, for example, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. As amino acids, the main amino acids can be used - lysine, ornithine and arginine.

More preferred pharmaceutically acceptable salts and derivatives of taurine of the present invention are taurates Li, K, Md and Ca, adducts of taurine with L-carnitine and O-acetyl-L-carnitine, as well as salts of N-acetyl taurine.

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

Vitamin E of the present invention includes all pharmaceutically acceptable forms, isomers and derivatives thereof having vitamin E activity, including tocopherols and tocotrienols such as alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta tocotrienol, gamma-tocotrienol, delta-tocotrienol, and their esters, such as alpha-tocopheryl acetate, succinate, nicotinate and linolate, as well as mixtures thereof.

The term “treatment” means any treatment for a disease or condition in a subject, including suppressing the development of a disease or condition, which means pausing or suppressing the development of clinical symptoms, and / or reducing the intensity of the symptoms of the disease or condition, which means regression of clinical symptoms.

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

The term "pharmaceutically acceptable" means that the substance or composition to which this term is applied must be compatible, in terms of chemistry and / or toxicology, with the other ingredients that make up the drug, and is safe for anyone who is being treated with this substance or composition.

The terms "comprising", "contains" means that these 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 this 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.

An 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 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:

- increasing the effectiveness of the treatment of chronic pain due to the synergistic effect of the active substances, and, as a result, reducing the required doses of active substances, reducing side effects and increasing the safety of treatment;

- expansion of the arsenal of funds for the treatment of chronic pain. The task is carried out, and the technical result

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 consisting of uridine monophosphate, taurine, vitamin E, or pharmaceutically acceptable salts or derivatives thereof.

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

- active substances in the composition of the above combination are administered in daily dosages:

palmitoylethanolamide 50-2500 mg / day; uridine monophosphate 1-200 mg / day;

taurine 50-10000 mg / day;

vitamin e 15-2000 IU / day;

- the introduction of the said combination is administered orally;

- said combination is an oral tablet or sublingual sachet;

- palmitoylethanolamide in said combination is in micronized or ultra-micronized form;

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

The task is also carried out, and the technical result is achieved by obtaining a pharmaceutical composition for the treatment of chronic pain, which contains in effective amounts the aforementioned 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:

- active substances in the composition of the composition are administered in daily dosages:

palmitoylethanolamide 50-2500 mg / day; uridine monophosphate 1-200 mg / day;

taurine 50-10000 mg / day;

vitamin e 15-2000 IU / day;

- active substances in the composition of the composition are included in mass ratios:

palmitoylethanolamide: uridine monophosphate from 1: 4 to 2500: 1;

palmitoylethanolamide: taurine from 1: 200 to 500: 1;

palmitoylethanolamide: Vitamin E 1:37 to 192: 1

- the introduction of the 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 includes a substance selected from the group consisting of carnitine, B vitamins, resveratrol, curcumin, benfotiamine, linoleic, linolenic acid, lipoic acid.

The task is also carried out, and the technical result is achieved by creating a kit for the treatment of chronic pain, characterized in that the kit includes a pharmaceutical composition that contains in effective amounts palmitoylethanolamide 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 of 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 a pharmaceutically acceptable carrier. In addition, the kit includes instructions for use.

The task is also carried out, and the technical result is achieved by using said combination or said pharmaceutical composition or said kit according to the present invention for treating chronic pain.

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

- chronic pain is selected from the group comprising neuropathic pain after chemotherapy, diabetic chronic neuropathic pain, neuropathic pain with nerve compression syndrome, post-stroke chronic neuropathic pain, chronic pelvic pain syndrome, pain with rheumatic diseases, inflammatory diseases, fibromyalgia, phantom pain;

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

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

- pain with rheumatic diseases is pain with rheumatoid arthritis, osteoarthritis;

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

- active substances are administered in preferred daily dosages:

palmitoylethanolamide 50-2500 mg / day; uridine monophosphate 1-200 mg / day;

taurine 50-10000 mg / day;

vitamin e 15-2000 IU / day;

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

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

- said additive is an oral tablet or sublingual sachet;

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

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

Medicines and pharmaceutical compositions may be administered orally or parenterally (e.g., 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 of the present invention in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, speed their metabolism and excretion from the body, as well as depending on the age, gender and stage of the patient’s disease, while the daily dose of palmitoylethanolamide in adults is usually It is 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 can 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 can 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 can be 15-2000 ME per day, preferably 100-1000 ME per day, preferably 60-75 ME per day, for example, about 30 ME per day. Therefore, when preparing the pharmaceutical composition of the medicine of the present invention in the form of dosage units, the above effective dosage must be taken into account, 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 of uridine monophosphate, 5-2000 IU of vitamin E. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The following examples illustrate but do not limit the invention.

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

Chronic pain associated with damage to the peripheral nerve is characterized by an unpleasant abnormal sensation (dysesthesia), an 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 the 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 nerve transection-induced neuropathy in rats. J Ethnopharmacol., 120 (1): 56-62, 2008]. Ecotomic neuropathy in experimental animals can be correlated with complex regional pain syndrome (CRPS) in humans, which is common after a fracture, arthroplasty of the knee joint 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, 34-3 9].

The experiments used adult Wistar rats having a body weight of 180-250 grams. Rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour cycle of day and night and plenty of water and food.

One hundred and ten (110) Wistar rats were randomly assigned to twenty-two (22) equal in group composition (N = 5), differing in the type of drug administered and the dosage. 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 and vitamin E each), three doses. The control was a group of rats receiving only the vehicle (placebo group). Information on dosages is shown in table 1. All drugs were administered orally 3 days after surgery and then once a day for the duration of the study. All doses are calculated per person.

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

Mechano-tactile allodynia. The animals were placed in an acrylic chamber (15 × 15 × 15 cm) raised above the ground with a wire mesh at the bottom. Before testing, animals were left in the chamber for 5-10 minutes to adapt. Further, the plantar surface of the animal's paws was stimulated by calibrated von Frey filaments (or filaments) (BIOSEB, USA). The filaments were a set of 10 standard plastic threads, increasing in diameter. The stiffness of the threads, expressed as the minimum force required to bend the hair, increased with this calibration logarithmically with absolute values from 0.6 grams to 26 grams. In each rat, the sensitivity threshold was determined in turn on each paw in three repetitions (a total of 6 applications with an interval of 10 seconds for each filament; the interval between sequential application of different filaments was 2 minutes). The tip of the thread touched the middle of the plantar surface of the paw with the force necessary to bend the hair, and held the hair in this position for 6-8 seconds. A positive response was recorded if the animal abruptly pulled back its paw while touching. The sensitivity threshold was determined by the minimum pressure that causes the reflex reaction of the paw withdrawal (4 times out of 6 applications).

Cold hyperalgesia. To evaluate 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 30 × 30 cm metal plate cooled to 0 ° C. Healthy animals are able to withstand this temperature for a long time, resting all limbs on a chilled floor, whereas when a nerve is damaged, the limb contact time with a cold plate is greatly reduced. To quantify this parameter, the retention time of the limb on weight for 1 minute of the animal in the test chamber was recorded. Each animal was tested three times with an interval of 5 minutes between measurements; the obtained values were averaged.

For each study group (n = 5), the average 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 evaluated using paired t-student test (at a significance level of p <0.05).

The results are shown in tables 2-4 below.

*, # s - 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.

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

*, #, s - a 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, indicators 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 the action of these combinations at all tested dose levels was also found.

Example 2. A model of pain caused by ligation of the spinal nerves.

The Neuropathic Spinal Nerve Pain (SNL) model has been widely used for various research projects on the mechanisms of neuropathic pain, as well as for screening tests to develop new analgesic drugs. This model was developed by tight ligation of one (L5) or two (L5 and L6) segmented spinal nerves in a rat. The operation leads to prolonged behavioral signs of mechanical allodynia, thermal hyperalgesia, cold allodynia, and constant 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 rats of the Spreg-Dowley line, having a body weight of 250-300 grams. Rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour cycle of day and night and plenty of water and food.

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

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 and vitamin E), each of which was also administered. The control was a group of rats receiving only the vehicle (placebo group). Information on dosages is shown in table 1. All drugs were administered orally 3 days after surgery and then once a day for the entire duration of the study. All doses are calculated per person.

Animals are anesthetized with an intraperitoneal injection of sodium pentobarbital and their back hair is trimmed. Each animal is then placed on a surgical platform in a prone position, and the limbs are fixed with adhesive tape. Under sterile conditions, a long 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 caudal part of the L5 vertebra to the first sacral vertebra). The localization of the incision is determined by the position of the vertebra L5, which is located at the level of the rostral end of the iliac crest. Using small blunt-tip scissors, the paraspinal muscles are secreted and removed from the level of the L5 vertebra to the sacrum.

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

For each study group (n = 5), the average 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 evaluated using paired t-student test (at a significance level of p <0.05).

The results are shown in tables 5-7 below.

*, #, s - a 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.

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

*, #, s - a 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, indicators of mechanical allodynia are significantly reduced, which indicates the effectiveness of their use for the treatment of pain caused by ligation of the spinal nerves. In addition, a synergistic effect of the action of these combinations at all tested dose levels was also found.

Example 3. A model of diabetic neuropathic pain syndrome.

Diabetic neuropathy is a common complication of diabetes. This occurs in approximately 10–20% of patients with diabetes, or in approximately 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 model of chronic pain with signs of hyperalgesia and allodynia, which may reflect the signs observed in people with diabetes [C. 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 rats of the Spreg-Dowley line, having a body weight of 250-300 grams. Rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour cycle of day and night and plenty of water and food.

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

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 and vitamin E), each of which was also administered. The control was a group of rats receiving only the vehicle (placebo group). Information on dosages is given in table 1. All doses are given in terms of per person.

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 glucose levels in the blood of a venous vein using an Ames Dextrostix and a reflectivity colorimeter (Ames Division, Miles Laboratories). Blood samples were obtained from the tail, and only rats with a final blood glucose level of more than 14 mM were included in the study. Tests were performed 4 weeks after the induction of diabetes.

To assess the pain behavior, a von Frey filament test was used (the occurrence of mechanical allodynia). Testing was performed as described in Example 1 above, except that the nociceptive thresholds, expressed in grams, were measured by applying increasing pressure to the left hind paw until vocalization was induced. When two stable thresholds for vocalization were obtained, a drug or placebo was administered. Vocalization thresholds were then determined for 2 hours. The cutoff was 7 50 g.

For each study group (n = 5), the average 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 evaluated using paired t-student test (at a significance level of p <0.05).

The results are shown in tables 8-10 below.

*, #, s - a 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.

*, #, s - a 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.

* # s - a 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, 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 effect was found at all tested dose levels.

Example 4. A model of chronic visceral hypersensitivity (chronic pain in the abdominal cavity).

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

To assess the pain behavior, a von Frey filament test (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 average 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 evaluated using paired t-student test (at a significance level of p <0.05).

The results are shown in tables 11-13 below.

* # s - a 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, on the behavior of rats with chronic abdominal pain.

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

*, #, s - a 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, indicators 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 the action of these combinations at all tested dose levels was also found.

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

The similarity of adjuvant rat arthritis with human rheumatoid arthritis is the presence of edema of the extremities, cartilage degradation, lymphocytic infiltration of the inflamed tissue of the joints, the loss of their function, in addition, bone and periosteum resorption is noted. Animals also suffer from the spine, gastrointestinal tract, genitourinary tract, skin and eyes, which is similar to human spondyloarthropathy. The adjuvant arthritis model is T cell dependent and complement independent. Induction of adjuvant arthritis is carried out by intradermal or subcutaneous administration of Freund's complete adjuvant (PAF). Freund adjuvant [lat. adjuvans (adjuvantis) - Helping, Contributing] - one of the most common adjuvants that contains dead tuberculous mycobacteria suspended in the oil phase of an aqueous emulsion. Freund's adjuvant is a potent stimulator of non-specific immune responses.

An adjuvant can be introduced into the base of the tail or into one of the paw pads, which allows us to study the acute inflammatory reaction at the injection site, as well as the immunological reaction, which develops after about 5-9 days in the contralateral paw and various organs.

Swelling of the hind paw is controlled from the very first day to 15 or more, depending on the duration of the experiment. In the later stages of the disease (day 12 and beyond), rats with adjuvant arthritis are often immobile due to the severity of paw edema and require special care, including guaranteed access to water and food. When using the model in order to develop 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 model creation [Gromyko MV, Gritsuk A.I. Experimental models of rheumatoid arthritis. Health and environmental issues. No. 2 (32), 2012, p. 115-118].

The experiment was carried out on 3-month-old male Wistar rats weighing 180-200 g contained in standard vivarium conditions. One hundred and ten (110) Wistar rats were randomly assigned to twenty-two (22) equal in group composition (N = 5), differing in the type of drug administered and the dosage. Formed groups of rats are briefly described in table 1.

Adjuvant arthritis in rats is induced by subplant implantation of Freund's complete adjuvant (PAF) into the hind paw. Joint swelling, which determines the severity of the development of the disease, after the administration of PAF is measured using a caliper through the sagittal diameter in the region of the tarsal joint. The index of joint edema is calculated by the formula: x = a / b, where x = index of joint edema, 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 administration of the adjuvant. For intact animals, the index of joint edema was taken as 1.

Treatment begins on the 5th day after the injection. Starting from 2 days after the induction of adjuvant arthritis in animals, the development of progressive joint edema was observed, which reached a maximum on the 15-20th day (index 2.50 ± 0.10). To assess pain behavior, a von Frey filament test (the occurrence of mechanical allodynia) was used for 30 days after the administration of PAP 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 PAF was inserted.

For each study group (n = 5), the average 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 evaluated using paired t-student test (at a significance level of p <0.05).

The results are shown in tables 14-16 below.

*, #, s - a 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.

*, #, s - a 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.

*, #, s - a 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 pain syndromes with adjuvant or rheumatoid arthritis. In addition, a statistically significant synergistic analgesic effect of the action of these combinations during the period of maximum effect was found at all tested dose levels.

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

To obtain the micronized form of palmitoylethanolamide using standard methods of mechanical or ultrasonic dispersion [Ultrasound. Little Encyclopedia. Main ed. I.P. Golyamina. Ed. “Soviet Encyclopedia”, Moscow, 1989, 399 pp.]

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 block.

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 block.

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 block.

The resulting bars are crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 500 mg each.

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

Palmitoylethanolamide and uridine monophosphate are thoroughly mixed in a ratio of 1: 1.

Palmitoylethanolamide and taurine are thoroughly mixed in a ratio of 1: 4.

Palmitoylethanolamide and vitamin E are thoroughly mixed in a 2: 1 ratio.

The resulting combinations are mixed with lactose powder in a ratio of 2: 1. The resulting powder mixture is packaged in 300 mg in a suitable size gelatin capsule.

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

1000 mg of palmitoylethanolamide and 1000 mg of uridine monophosphate 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 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 additives.

Claims (12)

1. A combination for the treatment of chronic pain, containing effective amounts of palmitoylethanolamide, characterized in that said combination also includes at least one substance selected from the group consisting of uridine monophosphate, taurine, vitamin E, or pharmaceutically acceptable salts thereof, wherein the active substances are the composition of the mentioned combinations are contained in the following amounts: palmitoylethanolamide 50-2500 mg uridine monophosphate                 1-200 mg taurine                       50-10000 mg vitamin e                       15-2000 IU 2. The combination according to claim 1, characterized in that the said combination is an oral tablet or a sublingual sachet. 3. The combination according to claim 1, characterized in that palmitoylethanolamide in said combination is in micronized or ultramikronized form. 4. The combination according to claim 1, characterized in that said combination further includes a substance selected from the group consisting of carnitine, B vitamins, resveratrol, curcumin, benfotiamine, linoleic, linolenic acid, lipoic acid. 5. A pharmaceutical composition for treating chronic pain, characterized in that said composition comprises in effective amounts a combination according to any one of claims. 1-4 and at least one excipient and / or at least one pharmaceutically acceptable carrier, where the active substances in the composition of the composition are included in mass ratios: palmitoylethanolamide: uridine monophosphate from 1: 4 to 2500: 1 palmitoylethanolamide: taurine                         from 1: 200 to 50: 1 palmitoylethanolamide: vitamin E       from 1: 36.4 to 248.7: 1 6. The composition according to claim 5, characterized in that the said composition is an oral tablet or a sublingual sachet. 7. The composition according to claim 5, characterized in that the palmitoylethanolamide in said composition is in micronized or ultramikronized form. 8. The 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 acid, lipoic acid. 9. A kit for the treatment of chronic pain, containing the pharmaceutical composition according to claim 5 and instructions for use, where the active substances in the pharmaceutical composition are contained in the following amounts: palmitoylethanolamide 50-2500 mg uridine monophosphate                 1-200 mg taurine                       50-10000 mg vitamin e                       15-2000 IU