Mirtazapine and tizanidine combination for use in pain disorders

Abstract

The invention relates to the chemical and pharmaceutical industry and medicine and concerns a novel pharmaceutical composition comprising mirtazapine and tizanidine or pharmaceutically acceptable salts thereof, for treating pain disorders, said composition being characterized in that the mirtazapine content ranges from 15 to 60 mg and the tizanidine content ranges from 6 to 24 mg, wherein the mass ratio of mirtazapine to tizanidine as free bases is 2.5:1. The invention also relates to a pharmaceutical combination, a therapeutic drug, to the use thereof and to a method for treating a pain disorder.

Description

[0001] COMBINATION OF MIRTAZAPINE AND TIZANIDINE FOR USE IN

[0002] PAIN DISORDERS

[0003] The invention relates to the chemical-pharmaceutical industry and medicine and concerns a new use of a pharmaceutical combination including mirtazapine and tizanidine, or their pharmaceutically acceptable salts, for the treatment of pain disorders, characterized in that the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine is from 6 to 24 mg, as well as to a pharmaceutical composition including a combination of mirtazapine and tizanidine and at least one pharmaceutically acceptable carrier, and a method for treating a pain disorder.

[0004] Pain is one of the most common complaints that doctors of various specialties deal with in their daily practice.

[0005] Various medications are used to treat and prevent pain syndromes:

[0006] - drugs that affect the synthesis of prostaglandins (non-narcotic analgesics, paracetamol, non-steroidal anti-inflammatory drugs - H11VP)

[0007] - providing a reduction in the concentration of substance P (capsicum preparations for external use - capsaicin, capsin, etc.);

[0008] - local anesthetics;

[0009] - opiates;

[0010] - drugs that affect GABA-ergic structures (baclofen, sirdalud, gabapentin);

[0011] - anticonvulsants (carbamazepine, valproates, benzodiazepines, etc.);

[0012] - drugs - alpha-adrenergic receptor agonists;

[0013] - serotonin reuptake blockers, for example, amitriptyline;

[0014] - antidepressants.

[0015] To develop more effective methods for pain relief and prevention, attempts are being made to combine various groups of drugs. However, few such combinations have been found to date. This is due, in particular, to the development of various side effects with combined use. Combinations for the treatment of headaches are known, containing paracetamol or a nonsteroidal anti-inflammatory drug (NSAID), or a pharmaceutically acceptable salt or solvate thereof, and mirtazapine or a pharmaceutically acceptable salt or solvate thereof, optionally in combination with one or more pharmaceutically acceptable carriers [1]. This solution has a narrow field of application, namely, it is intended for the treatment of headaches.

[0016] A combination containing mirtazapine and zonisamide is known, used in the treatment of disorders such as depression, schizophrenia, anxiety disorders, sleep-related breathing disorders, insomnia, migraine, chronic tension-type headaches, hot flashes, low back pain; neuropathic pain and functional somatic syndromes [8]. In this case, the combination of zonisamide with mirtazapine is used to reduce one or more side effects of mirtazapine, such as excessive daytime sleepiness, sedation and weight gain.

[0017] However, zonisamide is associated with various adverse events including transient increases in liver enzymes, weight changes, hematological disturbances, neurological / psychiatric disturbances such as insomnia, agitation and irritability, urinary and cardiovascular adverse events [3], which are unlikely to be acceptable in the treatment of pain disorders associated with painful muscle spasms or spasticity of skeletal muscles.

[0018] Mirtazapine is a tetracyclic antidepressant with a predominantly sedative effect. It is an antagonist of presynaptic a-adrenergic receptors in the central nervous system and enhances central noradrenergic and serotonergic transmission of nerve impulses. However, the enhancement of serotonergic transmission is realized only through serotonin 5-HT1 receptors, since mirtazapine blocks serotonin 6-HT2 and 5-HT3 receptors. Both enantiomers of mirtazapine are believed to have antidepressant activity: the S(+) enantiomer, blocking a-adrenergic and serotonin 5-HT2 receptors, and the R(-) enantiomer, blocking serotonin 5-HT3 receptors. Mirtazapine's sedative properties are due to its antagonist activity at histamine H1 receptors. Mirtazapine has virtually no M-anticholinergic activity and, in therapeutic doses, has a limited effect (e.g., orthostatic hypotension) on the cardiovascular system.

[0019] Mirtazapine

[0020] Mirtazapine is disclosed in a US patent [4]. Mirtazapine's dual mechanism of action on two neurotransmitter systems defines it as a noradrenergic and specific serotonergic antidepressant. Mirtazapine is capable of rapidly neutralizing anxiety symptoms, even in the first days of treatment. Available data suggest that mirtazapine is superior to placebo in the treatment of depression with anxiety and insomnia. Patients receiving mirtazapine had a significant (p<0.05) reduction in anxiety symptoms at 1, 2, 4, 6 weeks of the study, as well as at the end of treatment compared to placebo. A number of comparative studies demonstrate that mirtazapine is superior to other antidepressants, such as citalopram, fluoxetine, and paroxetine, in terms of rapid reduction of anxiety symptoms [5].

[0021] Mirtazapine has also proven effective in the treatment of post-traumatic stress disorder. More than half of patients demonstrated positive dynamics in terms of anxiety reduction, both in the physician interview and in self-tests. Mirtazapine is effective in the treatment of depression with generalized anxiety disorder. For example, an 8-week pilot study demonstrated a significant reduction in depressive and anxiety symptoms. Another unique feature of mirtazapine is that it does not inhibit cytochrome P-450 [6].

[0022] Regarding mirtazapine, it is known that it has been studied for its pain-relieving effects and can be used in the treatment of chronic neuropathic pain conditions, tension-type headaches and other pain conditions [7-11]. In pain syndromes, muscle spasms develop in two fundamentally different groups of diseases: neurological diseases; degenerative-dystrophic lesions of the joints and spine - osteochondrosis, spondylosis, spondyloarthrosis, arthrosis of the joints of the extremities.

[0023] The two pathologies mentioned above are fundamentally different from each other. In diseases of the nervous system, painful muscle spasms or tonic tension of muscle fibers develop when a painful stimulus is applied.

[0024] Characteristics of pain during painful muscle spasms: localized within the spasmodic muscle; provoked by irritation of the affected muscle; intense pain is detected when palpating the muscle fibers; tone is increased.

[0025] The main characteristics of pain in degenerative-dystrophic lesions or myofascial pain syndrome are: referred or regional pain, which is always located far from the spasmodic muscle; upon palpation of the painful muscle, the pain significantly increases; a sharp diffuse muscle spasm with the inclusion of areas of compaction, which act as a trigger; when pressing on these areas, very intense pain develops both in the muscle and at a distance

[0012] .

[0026] There are muscle relaxants that act exclusively on the first or second groups of diseases, for example, only on diseases of the nervous system, or systemic diseases of connective tissue.

[0027] Tizanidine is a centrally acting muscle relaxant. By stimulating presynaptic alpha2 receptors, it inhibits the release of excitatory amino acids, which stimulate NMDA receptors. This suppresses postsynaptic excitatory transmission at the level of spinal cord interneurons. Since this mechanism is responsible for excessive muscle tone, its suppression reduces muscle tone. In addition to its muscle relaxant properties, tizanidine also exerts a moderate central analgesic effect.

[0028] Tizanidine

[0029] Tizanidine relaxes skeletal muscles in chronic spastic conditions of spinal and cerebral origin, eliminating acute painful muscle spasms and clonic seizures. It reduces muscle resistance during passive movements and increases the strength of voluntary muscle contractions.

[0030] Muscle relaxants reduce abnormally elevated muscle tone. This reduces pain (breaking the vicious cycle of "pain-muscle spasm-pain") and increases range of motion. Tizanidine is used at a dose of 4-6 mg / day, with a possible gradual increase to 12 mg / day. The effect is evident within the first week of treatment

[0013] . Using a muscle relaxant helps relieve the muscle of not only active but also latent trigger points, improving the long-term prognosis by reducing the recurrence of myofascial pain syndrome (MPS).

[0031] A combination is known containing alpha-2 receptor agonists in a concentration effective to achieve a therapeutic effect, and alpha-2 adrenergic receptor antagonists in concentrations capable of effectively enhancing the therapeutic effect of alpha-2 receptor agonists

[0014] . Conditions requiring the administration of such a combination may include pain, hypertension, and glaucoma. The problem of potentiating the analgesic effect of O agonists is being solved. Й- adrenergic receptors and the reduction of their undesirable side effects by combining α-adrenergic receptor agonists with α-adrenergic receptor antagonists. At the same time, mirtazapine and tizanidine are listed in the application as only some of a large number of fundamentally possible α-adrenergic receptor antagonists and antagonists; therefore, this document does not lead the specialist to the preference of using mirtazapine and tizanidine as α-adrenergic receptor antagonists and agonists, respectively, and does not give the specialist grounds to believe that a supra-summary (synergistic) analgesic effect can be achieved by selecting mirtazapine as the α-adrenergic receptor antagonist and tizanidine as the α-adrenergic receptor agonist. In contrast, the in vivo results reported in this source support the analgesic properties of only the combination of clonidine and atipemazole (Example 3).The objective of this combination is to prevent side effects and tolerance to aladrenergic agonist therapy, such as the sedative effect of clonidine, as well as dependence, through the use of ultra-low doses of an aladrenergic antagonist. Specific examples of preferred combinations of an aladrenergic agonist and ultra-low doses of an aladrenergic antagonist include an aladrenergic antagonist and an aladrenergic agonist taken in a quantitative ratio of 1:1000, 1:10,000, 1:100,000, or 1:1,000,000.

[0032] The closest analogue of the present invention is a pharmaceutical combination for the treatment of pain disorders in the form of a solid dosage form for oral administration, characterized in that it contains mirtazapine 5-50 mg; tizanidine 0.5-6 mg in a ratio of 20:1-5:1 and a pharmaceutically acceptable carrier

[0015] . The analogue ensures the creation of an effective means for the prevention and treatment of pain disorders, well tolerated by patients. A pharmaceutical combination in the form of a tablet containing mirtazapine 20 mg and tizanidine 1 mg (in a ratio of 20:1) is indicated. However, the specified source does not disclose the doses in which this combination should be taken.The present invention unexpectedly demonstrates the possibility of achieving a synergistic effect when using mirtazapine in combination with tizanidine, taken in a different quantitative ratio, namely 2.5:1, which exceeds the effect achieved with the ratio of mirtazapine to tizanidine according to the prototype.

[0033] Having proceeded to preclinical and clinical studies, the inventors of the present invention unexpectedly discovered that the use of a pharmaceutical combination or pharmaceutical composition comprising mirtazapine and tizanidine, or their pharmaceutically acceptable salts, where the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine - from 6 to 24 mg, in a ratio of 2.5:1, respectively, leads to the most effective treatment of pain disorders associated with painful muscle spasms or spasticity of skeletal muscles, reduces the acute toxicity of the components of the used combination and their addictiveness, helps to improve the quality of life in patients with persistent pain syndrome, reduces pain sensations and depressive states accompanying the sensation of pain. The invention also provides an expansion of the arsenal of drugs with a combined (muscle relaxant and analgesic) effect.

[0034] The objective of the present invention is to create a medicinal product with increased efficacy for the treatment and / or prevention of pain disorders, including those associated with painful muscle spasms or spasticity of skeletal muscles, possessing a combined (muscle relaxant and analgesic) effect and an improved safety and tolerability profile. Technical results:

[0035] - synergistic effect when using mirtazapine in combination with tizanidine;

[0036] - increased safety and portability;

[0037] - expansion of the arsenal of drugs with combined (muscle relaxant and analgesic) action;

[0038] - improving the quality of life in patients with persistent pain syndrome.

[0039] The stated problem is solved, and the technical result is achieved by using a pharmaceutical combination or pharmaceutical composition including mirtazapine and tizanidine or their pharmaceutically acceptable salts, for the treatment of pain disorders, characterized in that the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine is from 6 to 24 mg, in a ratio of 2.5:1, respectively.

[0040] According to preferred embodiments, the said technical result is also achieved by the fact that:

[0041] - the daily dosage of mirtazapine is from 15 to 45 mg, and tizanidine - from 6 to

[0042] 18 mg;

[0043] - the daily dosage of mirtazapine is from 15 to 30 mg, and tizanidine - from 6 to

[0044] 12 mg; - the daily dosage of mirtazapine is from 30 to 45 mg, and tizanidine - from 12 to

[0045] 18 mg;

[0046] - the mass ratio of mirtazapine to tizanidine is 2.5 to 1;

[0047] - the daily dosage of mirtazapine is 60 mg, and tizanidine is 24 mg;

[0048] - the daily dosage of mirtazapine is 45 mg, and tizanidine is 18 mg;

[0049] - the daily dosage of mirtazapine is 30 mg, and tizanidine is 12 mg;

[0050] - the daily dosage of mirtazapine is 15 mg, and tizanidine is 6 mg;

[0051] - the pharmaceutical combination is made in the form of a solid dosage form for oral administration;

[0052] - a solid dosage form for oral administration contains at least one excipient;

[0053] - a solid dosage form for oral administration is a tablet;

[0054] - the tablet is a two-layer tablet;

[0055] - a two-layer tablet is a prolonged-release tablet;

[0056] - a bilayer tablet comprises a layer containing mirtazapine or its pharmaceutically acceptable salt, and a layer containing tizanidine or its pharmaceutically acceptable salt, from which tizanidine is released in a delayed manner;

[0057] - a layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which tizanidine is released in a delayed manner, includes a polymeric release retardant, and the polymeric release retardant of tizanidine is a hydrophilic polymeric release retardant;

[0058] - the hydrophilic polymeric tizanidine release retardant may be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, ammonium methacrylate copolymer, hydroxypropyl methylcellulose, methyl-, ethyl- or propylcellulose, hydroxyethylcellulose hydroxypropylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, cellulose acetate or phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate succinate or ethylcellulose succinate;

[0059] - mirtazapine is immediately released from the mirtazapine-containing layer; - the tizanidine sustained-release layer contains 6 mg tizanidine, and the mirtazapine immediate-release layer contains 15 mg mirtazapine;

[0060] - the pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride;

[0061] - a layer containing tizanidine, from which tizanidine is released in a slow manner, additionally includes a lubricant;

[0062] - the tizanidine-containing layer contains tizanidine hydrochloride in an amount of 0.5-30 wt.%, a hydrophilic polymer release retardant in an amount of 0.5-99 wt.% and a lubricant in an amount of 0.5-2.5 wt.%;

[0063] - the lubricant in the layer with tizanidine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof;

[0064] - the mirtazapine layer contains mirtazapine, filler, disintegrant and lubricant;

[0065] - the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt.%, a filler in an amount of 70-95 wt.%, a disintegrant in an amount of 1-10 wt.% and a lubricant in an amount of 0.5-5 wt.%;

[0066] - the lubricant in the layer with mirtazapine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumart and mixtures thereof;

[0067] - the filler is selected from mannitol, sorbitol, isomalt, microcrystalline cellulose, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid and mixtures thereof;

[0068] - the disintegrant is selected from crospovidone, sodium carboxymethylcellulose, agar-agar, calcium carbonate, potato, corn, pea or tapioca starch, alginic acid, complex silicates, sodium carbonate and mixtures thereof; the combination additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, acacia and mixtures thereof in an amount of 0.5-5 wt.%;

[0069] - the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 0.5-30; stearic acid - 0.5-2.0; hydroxypropyl methylcellulose - 30.0-50.0; ammonium methacrylate copolymer - 40.0-75.0; colloidal silicon dioxide - 0.5-2.0.

[0070] - the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 3.81; stearic acid - 1.11; hydroxypropyl methylcellulose (K100M) - 40.28; ammonium methacrylate copolymer, type A - 20.835; ammonium methacrylate copolymer, type B - 33.33; colloidal silicon dioxide (aerosil 200) - 0.635.

[0071] - the layer with tizanidine was obtained by direct pressing;

[0072] - the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 1.0-35.0; mannitol - 20.0-40.0; microcrystalline cellulose - 40.0-60.0; polyvinylpyrrolidone - 0.5-5.0; crospovidone - 0.5-5.0; colloidal silicon dioxide - 0.5-2.5; magnesium stearate - 0.5-2.5;

[0073] - the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine (micronized) - 10.0; mannitol - 33.13; microcrystalline cellulose - 51.34; polyvinylpyrrolidone (K30) - 1.0; crospovidone - 3.0; colloidal silicon dioxide (aerosil 200) - 0.53; magnesium stearate - 1.0;

[0074] - the layer with mirtazapine was obtained by wet granulation;

[0075] - pain disorder is a painful muscle spasm or spasticity of skeletal muscles;

[0076] - painful muscle spasm associated with static and functional diseases of the spine;

[0077] - diseases of the spine are cervical or lumbar syndromes;

[0078] - painful muscle spasm associated with surgery;

[0079] - spasticity of skeletal muscles is associated with neurological disease;

[0080] - a neurological disease selected from a group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents and cerebral palsy.

[0081] The stated task is also accomplished, and the technical result is achieved by obtaining a pharmaceutical composition for the treatment of pain disorders, including a combination of mirtazapine and tizanidine or their pharmaceutically acceptable salts at a mass ratio of mirtazapine to tizanidine in terms of free bases of 2.5 to 1 and at least one pharmaceutically acceptable carrier, intended for use in a daily dosage of mirtazapine from 15 to 60 mg, and tizanidine from 6 to 24 mg.

[0082] A pharmaceutical composition for the treatment of pain disorders, including a combination of mirtazapine and tizanidine, may include pharmaceutically acceptable excipients. Specific excipients are selected based on the intended route of administration and dosage form, as is known to those skilled in the art. Suitable pharmaceutical carriers, excipients, and their formulations are described, for example, in Remington: The Science and Practice of Pharmacy 1995, edited by E.W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania.

[0083] Pharmaceutically acceptable excipients may be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, auxiliary and distributing agents, delivery vehicles, such as preservatives, stabilizers, fillers, disintegrants, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavorings, aromatizers, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the selection and ratio of which depend on the nature of the active substance, the route of administration and dosage. Examples of suspending agents include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances.Protection against microorganisms can be provided by a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and similar compounds. The composition may also include isotonic agents, such as sugars, sodium chloride, and the like.Prolonged action of the composition can be ensured by means of agents that slow down the absorption of the active ingredient, such as, for example, aluminum monostearate, gelatin, cellulose derivatives or a hydrophilic polymeric release retardant, which is polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, ammonium methacrylate copolymer, hydroxypropyl methylcellulose, methyl-, ethyl- or propylcellulose, hydroxyethylcellulose hydroxypropylcellulose, hydroxypropyl ethylcellulose, carboxymethylcellulose, cellulose acetate or phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate succinate, ethylcellulose succinate or mixtures thereof.Disintegrating agents may be selected from crospovidone, sodium carboxymethylcellulose, agar-agar, calcium carbonate, potato, corn, pea or tapioca starch, alginic acid, complex silicates, sodium carbonate and mixtures thereof. Binders may be selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, acacia and mixtures thereof. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, sucrose, glucose, sodium citrate, calcium carbonate, calcium phosphates, microcrystalline cellulose, mannitol, starch, silicic acid and the like. Examples of grinding and distributing agents are starch, alginic acid and its salts, silicates.Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, sodium lauryl sulfate, talc, high molecular weight polyethyleneglycol, colloidal silicon dioxide, sodium stearyl fumarate, and mixtures thereof. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical, or rectal administration of the active ingredient, alone or in combination with another active ingredient, can be administered to animals and humans in a standard administration form, mixed with traditional pharmaceutical carriers. Suitable unit dosage forms include oral dosage forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal dosage forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular dosage forms and rectal dosage forms.

[0084] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is mixed with at least one of the following: (a) one or more inert excipients (or carriers), such as dibasic calcium phosphate; (b) fillers or diluents, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such as glycerol; (e) disintegrating agents, such as agar-agar, calcium carbonate, potato, corn, or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) dissolution retarders such as paraffin or hydrophilic polymeric release retarders; (g) absorption accelerators such as quaternary ammonium compounds;(h) wetting agents such as cetyl alcohol and glyceryl monostearate; (i) adsorbents such as kaolin and bentonite; and (j) lubricating agents such as talc, calcium stearate, magnesium stearate, stearic acid, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage forms may also contain buffering agents.

[0085] According to preferred embodiments, the said technical result is also achieved by the fact that:

[0086] - the daily dosage for mirtazapine is from 15 to 45 mg, and the daily dosage for tizanidine is from 6 to 18 mg;

[0087] - the daily dosage for mirtazapine is from 15 to 30 mg, and for tizanidine - from 6 to 12 mg;

[0088] - the daily dosage for mirtazapine is from 30 to 60 mg, and for tizanidine - from 12 to 24 mg;

[0089] - the daily dosage for mirtazapine is 60 mg, and for tizanidine -

[0090] 24 mg;

[0091] - the daily dosage for mirtazapine is 45 mg, and for tizanidine -

[0092] 18 mg;

[0093] - the daily dosage for mirtazapine is 30 mg, and for tizanidine -

[0094] 12 mg;

[0095] - the daily dosage for mirtazapine is 15 mg, and for tizanidine 6 mg;

[0096] - the said composition is made in the form of a solid dosage form for oral administration;

[0097] - a solid dosage form for oral administration is a tablet;

[0098] - the tablet is a two-layer tablet;

[0099] - a two-layer tablet is a prolonged-release tablet;

[0100] - a bilayer tablet comprising a layer containing mirtazapine and a layer containing tizanidine, from which tizanidine is released in a slow-release manner;

[0101] - a layer containing tizanidine, from which tizanidine is released in a slow manner, comprises tizanidine, or a pharmaceutically acceptable salt thereof, and a polymeric release delay agent, which is a hydrophilic polymeric release delay agent; - a layer containing tizanidine, from which tizanidine is released in a slow manner, further comprises a lubricant;

[0102] - the tizanidine-containing layer contains tizanidine hydrochloride in an amount of 0.5-30 wt.%, a hydrophilic polymer release retardant in an amount of 0.5-99 wt.% and a lubricant in an amount of 0.5-2.5 wt.%;

[0103] - the pharmaceutically acceptable salt of tizanidine is the hydrochloride;

[0104] - the hydrophilic polymeric tizanidine release retardant may be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, ammonium methacrylate copolymer, hydroxypropyl methylcellulose, methyl-, ethyl- or propylcellulose, hydroxyethylcellulose hydroxypropylcellulose, hydroxypropyl ethylcellulose, carboxymethylcellulose, cellulose acetate or phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate succinate, ethylcellulose succinate or mixtures thereof;

[0105] - the lubricant in the layer with tizanidine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof;

[0106] - mirtazapine is immediately released from the mirtazapine-containing layer;

[0107] - the mirtazapine layer contains mirtazapine, filler, disintegrant and lubricant;

[0108] - the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt.%, a filler in an amount of 70-95 wt.%, a disintegrant in an amount of 1-10 wt.% and a lubricant in an amount of 0.5-5 wt.%;

[0109] - the lubricant in the layer with mirtazapine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof;

[0110] - the filler is selected from mannitol, sorbitol, isomalt, microcrystalline cellulose, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid and mixtures thereof; - the leavening agent is selected from crospovidone, sodium carboxymethylcellulose, agar-agar, calcium carbonate, potato, corn, pea or tapioca starch, alginic acid, complex silicates, sodium carbonate and mixtures thereof;

[0111] - the said composition additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, acacia and mixtures thereof in an amount of 0.5-5 wt.%;

[0112] - the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 0.5-30; stearic acid - 0.5-2.0; hydroxypropyl methylcellulose - 30.0-50.0; ammonium methacrylate copolymer - 40.0-75.0 colloidal silicon dioxide - 0.5-2.0;

[0113] - the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 3.81; stearic acid - 1.11; hydroxypropyl methylcellulose - 40.28; ammonium methacrylate copolymer - 54.165; colloidal silicon dioxide - 0.635.

[0114] - the layer with tizanidine was obtained by direct pressing;

[0115] - the sustained release tizanidine layer contains 6 mg tizanidine;

[0116] - the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 1.0-35.0; mannitol - 20.0-40.0; microcrystalline cellulose - 40.0-60.0; polyvinylpyrrolidone - 0.5-5.0; crospovidone - 0.5-5.0; colloidal silicon dioxide - 0.5-2.5; magnesium stearate - 0.5-2.5; - the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 10.0; mannitol - 33.13; microcrystalline cellulose - 51.34; polyvinylpyrrolidone - 1.0; crospovidone - 3.0; colloidal silicon dioxide - 0.53; magnesium stearate - 1.0;

[0117] - the layer with mirtazapine was obtained by wet granulation;

[0118] - the immediate release mirtazapine layer contains 15 mg mirtazapine;

[0119] - the mentioned composition is intended for administration 1-4 times a day;

[0120] - the mentioned composition is intended for administration 1-3 times a day;

[0121] - the mentioned composition is intended for administration 1-2 times a day;

[0122] - the mentioned composition is intended for administration 2-4 times a day;

[0123] - the pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride;

[0124] - the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 3.81; stearic acid - 1.11; hydroxypropyl methylcellulose (K100M) - 40.28; ammonium methacrylate copolymer, type A - 20.835; ammonium methacrylate copolymer, type B - 33.33; colloidal silicon dioxide (Aerosil 200) - 0.635;

[0125] - the layer with tizanidine was obtained by direct pressing;

[0126] - the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine (micronized) - 10.0; mannitol - 33.13; microcrystalline cellulose - 51.34; polyvinylpyrrolidone (K30) - 1.0; crospovidone - 3.0; colloidal silicon dioxide (aerosil 200) - 0.53; magnesium stearate - 1.0;

[0127] - the layer with mirtazapine was obtained by wet granulation.

[0128] - pain disorder is a painful muscle spasm or spasticity of skeletal muscles;

[0129] - painful muscle spasm associated with static and functional diseases of the spine;

[0130] - diseases of the spine are cervical or lumbar syndromes;

[0131] - painful muscle spasm associated with surgery;

[0132] - spasticity of skeletal muscles is associated with a neurological disease;

[0133] - a neurological disease selected from a group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents and cerebral palsy.

[0134] The stated task is also accomplished, and the technical result is achieved by obtaining a pharmaceutical combination of mirtazapine and tizanidine or their pharmaceutically acceptable salts with a mass ratio of mirtazapine to tizanidine in terms of free bases of 2.5 to 1 for the treatment of pain disorders, characterized in that mirtazapine is used in a dose of 15 to 60 mg in terms of free base per day, and tizanidine - from 6 to 24 mg in terms of free base per day.

[0135] According to preferred embodiments, the said technical result is also achieved by the fact that:

[0136] - the daily dosage of mirtazapine is from 15 to 45 mg, and tizanidine - from 6 to

[0137] 18 mg;

[0138] - the daily dosage of mirtazapine is from 15 to 30 mg, and tizanidine - from 6 to

[0139] 12 mg;

[0140] - the daily dosage of mirtazapine is 45 mg, and tizanidine is 18 mg; - the daily dosage of mirtazapine is 60 mg, and tizanidine is 24 mg;

[0141] - the daily dosage of mirtazapine is 30 mg, and tizanidine is 12 mg;

[0142] - the daily dosage of mirtazapine is 15 mg, and tizanidine is 6 mg;

[0143] - the pharmaceutical combination is made in the form of a solid dosage form for oral administration;

[0144] - a solid dosage form for oral administration contains at least one excipient;

[0145] - a solid dosage form for oral administration is a tablet;

[0146] - the tablet is a two-layer tablet;

[0147] - a two-layer tablet is a prolonged-release tablet;

[0148] - a bilayer tablet comprising a layer containing mirtazapine and a layer containing tizanidine, from which tizanidine is released in a slow-release manner;

[0149] - mirtazapine is immediately released from the mirtazapine-containing layer;

[0150] - the tizanidine sustained release layer contains 6 mg tizanidine, and the mirtazapine immediate release layer contains 15 mg mirtazapine;

[0151] - the pharmaceutically acceptable salt of tizanidine is the hydrochloride;

[0152] - a layer containing tizanidine, from which tizanidine is released in a slow manner, additionally includes a lubricant;

[0153] - the tizanidine-containing layer contains tizanidine hydrochloride in an amount of 0.5-30 wt.%, a hydrophilic polymer release retardant in an amount of 0.5-99 wt.% and a lubricant in an amount of 0.5-2.5 wt.%;

[0154] - the lubricant in the layer with tizanidine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof;

[0155] - the mirtazapine layer contains mirtazapine, filler, disintegrant and lubricant.

[0156] - the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt.%, a filler in an amount of 70-95 wt.%, a disintegrant in an amount of 1-10 wt.% and a lubricant in an amount of 0.5-5 wt.%; - the lubricant in the layer with mirtazapine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof;

[0157] - the filler is selected from mannitol, sorbitol, isomalt, microcrystalline cellulose, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid and mixtures thereof;

[0158] - the disintegrating agent is selected from crospovidone, sodium carboxymethylcellulose, agar-agar, calcium carbonate, potato, corn or tapioca starch, alginic acid, complex silicates, sodium carbonate and mixtures thereof;

[0159] - the said combination additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, acacia and mixtures thereof in an amount of 0.5-5 wt.%;

[0160] - the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 0.5-30; stearic acid - 0.5-2.0; hydroxypropyl methylcellulose - 30.0-50.0; ammonium methacrylate copolymer - 40.0-75.0 colloidal silicon dioxide - 0.5-2.0;

[0161] - the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 3.81; stearic acid - 1.11; hydroxypropyl methylcellulose (K100M) - 40.28; ammonium methacrylate copolymer, type A - 20.835; ammonium methacrylate copolymer, type B - 33.33; colloidal silicon dioxide (aerosil 200) - 0.635;

[0162] - the layer with tizanidine was obtained by direct pressing;

[0163] - the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 1.0-35.0; mannitol - 20.0-40.0; microcrystalline cellulose - 40.0-60.0; polyvinylpyrrolidone - 0.5-5.0; crospovidone - 0.5-5.0; colloidal silicon dioxide - 0.5-2.5; magnesium stearate - 0.5-2.5;

[0164] - the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine (micronized) - 10.0; mannitol - 33.13; microcrystalline cellulose - 51.34; polyvinylpyrrolidone (K30) - 1.0; crospovidone - 3.0; colloidal silicon dioxide (aerosil 200) - 0.53; magnesium stearate - 1.0;

[0165] - the layer with mirtazapine was obtained by wet granulation;

[0166] - pain disorder is a painful muscle spasm or spasticity of skeletal muscles;

[0167] - painful muscle spasm associated with static and functional diseases of the spine;

[0168] - diseases of the spine are cervical or lumbar syndromes;

[0169] - painful muscle spasm associated with surgery;

[0170] - spasticity of skeletal muscles is associated with neurological disease;

[0171] - a neurological disease selected from a group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents and cerebral palsy.

[0172] The stated task is also accomplished and the technical result is achieved by a method for treating a pain disorder, which includes using the said pharmaceutical combination, including mirtazapine and tizanidine, or pharmaceutically acceptable salts thereof, for treating pain disorders, characterized in that the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine - from 6 to 24 mg, or administering to a subject in need of treatment, the said pharmaceutical composition for treating pain disorders, including a combination of mirtazapine and tizanidine or pharmaceutically acceptable salts thereof at a weight ratio of mirtazapine to tizanidine in terms of free bases of 2.5 to 1 and at least one pharmaceutically acceptable carrier, intended for use in a daily dosage of mirtazapine from 15 to 60 mg, and tizanidine from 6 to 24 mg,or the said pharmaceutical combination of mirtazapine and tizanidine or their pharmaceutically acceptable salts with a mass ratio of mirtazapine to tizanidine in terms of free bases of 2.5 to 1 for the treatment of pain disorders, characterized in that mirtazapine is used in a dose of 15 to 60 mg in terms of free base per day, and tizanidine - from 6 to 24 mg in terms of free base per day.

[0173] The clinical dosage of a pharmaceutical combination comprising mirtazapine and tizanidine, or pharmaceutically acceptable salts thereof, for the treatment of pain disorders, or a pharmaceutical composition for the treatment of pain disorders comprising a combination of mirtazapine and tizanidine, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier according to the present invention, in patients may be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, the rate of their metabolism and elimination from the body, as well as depending on the age, gender, and stage of the patient's disease. According to the instructions of a physician or pharmacist, these drugs can be taken several times over certain intervals (preferably from one to four times).

[0174] Below are definitions of terms used in the description of the present invention.

[0175] Pain may be a polymorphic disorder. According to the present invention, the term "pain" denotes all types of pain, including acute and persistent pain. Preferably, but not limited to, the term denotes chronic pain, without limitation, in: fibromyalgia, somatotrophic disorders, arthralgia, cancer, neck pain, shoulder pain, back pain, headache, tension headache, migraine, diabetic neuropathy, herpetic neuralgia, phantom limb pain, pain of central genesis, toothache, visceral pain, pain during surgical manipulations, postoperative pain, osteogenic pain, burn pain, including sunburn, urogenital pain, including cystitis, tonsillitis.

[0176] "Medicine (drug)" - a substance (or mixture of substances in the form of a pharmaceutical composition) in finished forms, intended to restore, correct or change physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology, etc.

[0177] "Pharmaceutical composition" means a composition comprising mirtazapine and tizanidine or their pharmaceutically acceptable salts in an effective amount and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, excipients, delivery vehicles such as preservatives, stabilizers, fillers, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavorings, aromatizers, antibacterial agents, fungicides, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage.

[0178] "Pharmaceutically acceptable salt" means relatively non-toxic organic and inorganic salts of the acids and bases claimed in the present invention. These salts can be prepared in situ during the synthesis, isolation or purification of the compounds or prepared specially. In particular, salts of bases can be prepared specially starting from 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, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (a detailed description of the properties of such salts is given in

[0016] ).Salts of the claimed acids can also be specifically prepared by reacting the purified acid with a suitable base, which can synthesize metal and amine salts. Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium, and aluminum salts, with sodium and potassium salts being the most desirable. Suitable inorganic bases from which metal salts can be obtained include sodium hydroxide, carbonate, bicarbonate, and hydride; potassium hydroxide and bicarbonate; potassium carbonate, lithium hydroxide, calcium hydroxide, magnesium hydroxide, and zinc hydroxide. Amines and amino acids are selected as organic bases from which salts of the claimed acids can be obtained, possessing sufficient basicity to form a stable salt and suitable for medicinal 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. Tetraalkylammonium hydroxides, such as choline, tetramethylammonium, tetraethylammonium, and the like, can also be used for salt formation. Essential amino acids—lysine, ornithine, and arginine—can be used as amino acids.

[0179] The term "therapeutically effective amount" means an amount of active substance that (1) treats or prevents a specified disease, condition, or disorder, (2) reduces, improves, or eliminates one or more symptoms of a specified disease, condition, or disorder, or (3) prevents or delays the onset of one or more symptoms of a specified disease, condition, or disorder as described herein.

[0180] The term "pharmaceutically acceptable" means that the substance or composition to which the term applies must be chemically and / or toxicologically compatible with the other ingredients of the drug and safe for the person being treated with the substance or composition.

[0181] The terms "comprising" and "contains" mean that the specified combinations, compositions and kits include the listed components, but do not exclude the inclusion of other components.

[0182] The subject of the present invention is a pharmaceutical composition for the treatment of pain disorders, comprising mirtazapine and tizanidine or their pharmaceutically acceptable salts in a weight ratio of mirtazapine to tizanidine, calculated as free bases, of 2.5 to 1 and at least one pharmaceutically acceptable carrier, containing from 15 to 60 mg of mirtazapine and from 6 to 24 mg of tizanidine.

[0183] More preferred is a pharmaceutical composition characterized in that the pharmaceutically acceptable salt of tizanidine is hydrochloride.

[0184] More preferred is a pharmaceutical composition characterized in that it contains from 15 to 45 mg of mirtazapine and from 6 to 18 mg of tizanidine.

[0185] More preferred is a pharmaceutical composition characterized in that it contains from 15 to 30 mg of mirtazapine and from 6 to 12 mg of tizanidine.

[0186] More preferred is a pharmaceutical composition characterized in that it contains from 30 to 45 mg of mirtazapine and from 12 to 18 mg of tizanidine.

[0187] More preferred is a pharmaceutical composition characterized in that it contains 60 mg of mirtazapine and 24 mg of tizanidine.

[0188] More preferred is a pharmaceutical composition characterized in that it contains 45 mg of mirtazapine and 18 mg of tizanidine.

[0189] More preferred is a pharmaceutical composition characterized in that it contains 30 mg of mirtazapine and 12 mg of tizanidine.

[0190] More preferred is a pharmaceutical composition characterized in that it contains 15 mg of mirtazapine and 6 mg of tizanidine.

[0191] More preferred is a pharmaceutical composition characterized in that it contains at least one excipient.

[0192] More preferred is a pharmaceutical composition characterized in that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles.

[0193] A more preferred pharmaceutical composition is one characterized by the fact that painful muscle spasm is associated with static and functional spinal disorders. A more preferred pharmaceutical composition is one characterized by the fact that the spinal disorders are cervical or lumbar syndromes.

[0194] More preferred is a pharmaceutical composition characterized by the fact that painful muscle spasm is associated with surgical intervention.

[0195] More preferred is a pharmaceutical composition characterized by the fact that skeletal muscle spasticity is associated with a neurological disease.

[0196] More preferred is a pharmaceutical composition characterized in that the neurological disease is selected from a group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accident and cerebral palsy.

[0197] Also the subject of the present invention is a pharmaceutical combination for the treatment of pain disorders, comprising mirtazapine and tizanidine or their pharmaceutically acceptable salts in a weight ratio of mirtazapine to tizanidine, calculated as free bases, of 2.5 to 1 and at least one pharmaceutically acceptable carrier, containing from 15 to 60 mg of mirtazapine and from 6 to 24 mg of tizanidine.

[0198] More preferred is a pharmaceutical combination characterized in that the pharmaceutically acceptable salt of tizanidine is hydrochloride.

[0199] More preferred is a pharmaceutical combination characterized by containing from 15 to 45 mg of mirtazapine and from 6 to 18 mg of tizanidine.

[0200] More preferred is a pharmaceutical combination characterized by containing from 15 to 30 mg of mirtazapine and from 6 to 12 mg of tizanidine.

[0201] A more preferred pharmaceutical combination is one containing 30 to 45 mg of mirtazapine and 12 to 18 mg of tizanidine. A more preferred pharmaceutical combination is one containing 60 mg of mirtazapine and 24 mg of tizanidine.

[0202] More preferred is a pharmaceutical combination characterized by containing 45 mg of mirtazapine and 18 mg of tizanidine.

[0203] More preferred is a pharmaceutical combination characterized by containing 30 mg of mirtazapine and 12 mg of tizanidine.

[0204] More preferred is a pharmaceutical combination characterized by containing 15 mg of mirtazapine and 6 mg of tizanidine.

[0205] More preferred is a pharmaceutical combination characterized by containing at least one auxiliary substance.

[0206] More preferred is a pharmaceutical combination characterized by the fact that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles.

[0207] More preferable is a pharmaceutical combination characterized by the fact that painful muscle spasm is associated with static and functional diseases of the spine.

[0208] More preferable is a pharmaceutical combination characterized by the fact that the spinal diseases are cervical or lumbar syndromes.

[0209] More preferable is a pharmaceutical combination characterized by the fact that painful muscle spasm is associated with surgical intervention.

[0210] More preferable is a pharmaceutical combination characterized by the fact that skeletal muscle spasticity is associated with a neurological disease.

[0211] More preferred is a pharmaceutical combination characterized in that the neurological disease is selected from the group consisting of multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accident, and cerebral palsy. The subject of the present invention is also a medicament for the treatment of pain disorders, comprising a pharmaceutical composition according to the present invention or a pharmaceutical combination according to the present invention and at least one excipient.

[0212] More preferred is a medicinal product characterized in that at least one auxiliary substance is selected from the group consisting of cellulose derivatives or mixtures thereof, such as methyl, ethyl or propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, carboxymethyl cellulose, cellulose acetate or phthalate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate succinate, ethyl cellulose succinate and microcrystalline cellulose, ammonium methacrylate copolymer, colloidal silicon dioxide, mannitol, sorbitol, isomalt, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid, polyvinylpyrrolidone, crospovidone, polyvinyl alcohol, polyethylene oxide, carbomers, alginates, acrylic acid polymer or its esters, stearic acid and its salts such as calcium and magnesium stearate, talc, sodium stearyl fumarate.

[0213] More preferable is a medicinal product characterized by the fact that the daily dosage for the use of mirtazapine is from 15 to 45 mg, and the daily dosage for the use of tizanidine is from 6 to 18 mg.

[0214] More preferable is a medicinal product characterized by the fact that the daily dosage for the use of mirtazapine is from 15 to 30 mg, and the daily dosage for the use of tizanidine is from 6 to 12 mg.

[0215] More preferable is a medicinal product characterized by the fact that the daily dosage for the use of mirtazapine is from 30 to 60 mg, and the daily dosage for the use of tizanidine is from 12 to 24 mg.

[0216] A more preferable drug is one in which the daily dosage for mirtazapine is 60 mg and the daily dosage for tizanidine is 24 mg.

[0217] A more preferred drug is one characterized by a daily dosage of 45 mg for mirtazapine and 18 mg for tizanidine. A more preferred drug is one characterized by a daily dosage of 30 mg for mirtazapine and 12 mg for tizanidine.

[0218] More preferable is a drug characterized by the fact that the daily dosage for mirtazapine is 15 mg, and the daily dosage for tizanidine is 6 mg.

[0219] More preferable is a medicinal product characterized by the fact that it is made in the form of a solid dosage form for oral administration.

[0220] More preferable is a medicinal product characterized in that the solid dosage form for oral administration is a tablet.

[0221] More preferable is a drug characterized by the fact that the tablet is a two-layer tablet.

[0222] More preferable is a medicinal product characterized by the fact that the tablet is an extended-release tablet.

[0223] More preferred is a medicinal product characterized in that the bilayer tablet comprises a layer containing mirtazapine and a layer containing tizanidine, from which tizanidine is released in a delayed manner.

[0224] More preferred is a medicinal product characterized in that the tizanidine-containing layer from which tizanidine is released in a delayed manner comprises tizanidine or a pharmaceutically acceptable salt thereof, a filler, a disintegrant, and a polymeric release retardant, which is a hydrophilic polymeric release retardant.

[0225] More preferred is a medicinal product characterized in that the layer containing tizanidine, from which tizanidine is released in a slow manner, additionally includes a lubricant.

[0226] More preferred is a medicinal product characterized in that the tizanidine-containing layer contains tizanidine hydrochloride in an amount of 0.5-30 wt.%, a hydrophilic polymeric release retardant in an amount of 0.5-99 wt.%, and a lubricant in an amount of 0.5-2.5 wt.%.

[0227] More preferred is a medicinal product characterized in that the hydrophilic polymeric tizanidine release retardant can be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, ammonium methacrylate copolymer, hydroxypropyl methylcellulose, methyl-, ethyl- or propylcellulose, hydroxyethylcellulose hydroxypropylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, cellulose acetate or phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate succinate, ethylcellulose succinate or mixtures thereof.

[0228] More preferred is a medicinal product characterized in that the lubricant in the layer with tizanidine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof.

[0229] More preferred is a drug characterized by the fact that mirtazapine is immediately released from the layer containing mirtazapine

[0230] More preferable is a medicinal product characterized in that the mirtazapine layer contains mirtazapine, a filler, a disintegrant and a lubricant.

[0231] More preferable is a medicinal product characterized in that the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt.%, a filler in an amount of 70-95 wt.%, a disintegrant in an amount of 1-10 wt.% and a lubricant in an amount of 0.5-5 wt.%.

[0232] More preferable is a medicinal product characterized in that the lubricant in the layer with mirtazapine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof.

[0233] More preferable is a medicinal product characterized in that the filler is selected from mannitol, sorbitol, isomalt, microcrystalline cellulose, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid and mixtures thereof.

[0234] More preferred is a medicinal product characterized in that the disintegrant is selected from crospovidone, sodium carboxymethylcellulose, agar-agar, calcium carbonate, potato, corn, pea or tapioca starch, alginic acid, complex silicates, sodium carbonate and mixtures thereof. More preferred is a medicinal product characterized in that it additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, acacia and mixtures thereof in an amount of 0.5-5 wt.%,

[0235] More preferable is a medicinal product characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 0.5-30; stearic acid - 0.5-2.0; hydroxypropyl methylcellulose - 30.0-50.0; ammonium methacrylate copolymer - 40.0-75.0; colloidal silicon dioxide - 0.5-2.0.

[0236] More preferable is a medicinal product characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 3.81; stearic acid - 1.11; hydroxypropyl methylcellulose - 40.28; ammonium methacrylate copolymer - 54.165; colloidal silicon dioxide - 0.635.

[0237] More preferable is a medicinal product characterized by the fact that the layer with tizanidine is obtained by direct pressing.

[0238] More preferred is a medicinal product characterized in that the sustained-release tizanidine layer contains 6 mg of tizanidine.

[0239] More preferable is a medicinal product characterized in that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 1.0-35.0; mannitol - 20.0-40.0; microcrystalline cellulose - 40.0-60.0; polyvinylpyrrolidone - 0.5-5.0; crospovidone - 0.5-5.0; colloidal silicon dioxide - 0.5-2.5; magnesium stearate - 0.5-2.5.

[0240] More preferable is a medicinal product characterized in that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 10.0; mannitol - 33.13; microcrystalline cellulose - 51.34; polyvinylpyrrolidone - 1.0; crospovidone - 3.0; colloidal silicon dioxide - 0.53; magnesium stearate - 1.0.

[0241] More preferable is a medicinal product characterized by the fact that the layer with mirtazapine is obtained by wet granulation.

[0242] More preferred is a medicinal product characterized in that the immediate-release mirtazapine layer contains 15 mg of mirtazapine.

[0243] More preferable is a drug characterized by the fact that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles.

[0244] More preferable is a drug characterized by the fact that painful muscle spasm is associated with static and functional diseases of the spine.

[0245] More preferable is a drug characterized by the fact that the spinal diseases are cervical or lumbar syndromes.

[0246] A more preferred drug is one characterized by the fact that painful muscle spasm is associated with surgical intervention.

[0247] More preferable is a drug characterized by the fact that spasticity of skeletal muscles is associated with a neurological disease.

[0248] More preferable is a medicinal product characterized by the fact that the neurological disease is selected from a group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents and cerebral palsy.

[0249] Also, the subject of the present invention is the use of a pharmaceutical composition according to the present invention, a pharmaceutical combination according to the present invention or a medicinal product according to the present invention for the treatment of pain disorders, characterized in that the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine is from 6 to 24 mg, in a ratio of 2.5 to 1.

[0250] More preferred is the use characterized by the fact that the daily dosage of mirtazapine is from 15 to 45 mg, and tizanidine is from 6 to 18 mg.

[0251] More preferred is the use characterized by the fact that the daily dosage of mirtazapine is from 15 to 30 mg, and tizanidine is from 6 to 12 mg.

[0252] More preferred is the use characterized by the fact that the daily dosage of mirtazapine is from 30 to 45 mg, and tizanidine is from 12 to 18 mg.

[0253] A more preferred application is one in which the daily dosage of mirtazapine is 60 mg and that of tizanidine is 24 mg.

[0254] A more preferred application is one in which the daily dosage of mirtazapine is 45 mg and that of tizanidine is 18 mg.

[0255] A more preferred application is one in which the daily dosage of mirtazapine is 30 mg and that of tizanidine is 12 mg.

[0256] A more preferred application is one in which the daily dosage of mirtazapine is 15 mg and that of tizanidine is 6 mg.

[0257] More preferred is the application where the pain disorder is characterized by painful muscle spasm or spasticity of skeletal muscles.

[0258] More preferable is the application characterized by the fact that painful muscle spasm is associated with static and functional diseases of the spine.

[0259] More preferable is the use characterized by the fact that the spinal diseases are cervical or lumbar syndromes. More preferable is the use characterized by the painful muscle spasm associated with surgical intervention.

[0260] More preferable is the application characterized by the fact that spasticity of skeletal muscles is associated with a neurological disease.

[0261] More preferred is the use characterized by the fact that the neurological disease is selected from the group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents and cerebral palsy.

[0262] More preferred is the use characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-4 times per day.

[0263] More preferred is the use characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-3 times a day.

[0264] More preferred is the use characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-2 times per day.

[0265] More preferred is the use characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 2-4 times a day.

[0266] More preferred is the use characterized in that the said medicinal product is made in the form of a solid dosage form for oral administration.

[0267] More preferred is the use characterized in that the solid dosage form for oral administration contains at least one excipient.

[0268] More preferred is the use characterized in that the solid dosage form for oral administration is a tablet.

[0269] A more preferred formulation is one in which the tablet is a bilayer tablet. A more preferred formulation is one in which the bilayer tablet is an extended-release tablet.

[0270] More preferred is a use characterized in that the bilayer tablet comprises a layer containing mirtazapine or a pharmaceutically acceptable salt thereof, and a layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which tizanidine is released in a delayed manner.

[0271] More preferred is a use characterized in that the layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which tizanidine is released in a delayed manner, includes a polymeric release retardant, and the polymeric release retardant of tizanidine is a hydrophilic polymeric release retardant.

[0272] More preferred is the use characterized in that the hydrophilic polymeric tizanidine release retardant can be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, ammonium methacrylate copolymer, hydroxypropyl methylcellulose, methyl-, ethyl- or propylcellulose, hydroxyethylcellulose hydroxypropylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, cellulose acetate or phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate succinate or ethylcellulose succinate.

[0273] More preferred is the application in which mirtazapine is immediately released from the mirtazapine-containing layer.

[0274] More preferred is a use characterized in that the sustained-release tizanidine layer contains 6 mg tizanidine and the immediate-release mirtazapine layer contains 15 mg mirtazapine.

[0275] More preferred is the use characterized in that the pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride.

[0276] More preferable is the use characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 3.81; stearic acid - 1.11; hydroxypropyl methylcellulose - 40.28; ammonium methacrylate copolymer - 54.165; colloidal silicon dioxide - 0.635.

[0277] More preferred is the application in which the tizanidine layer is obtained by direct pressing.

[0278] More preferable is the use characterized by the fact that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 10.0; mannitol - 33.13; microcrystalline cellulose - 51.34; polyvinylpyrrolidone - 1.0; crospovidone - 3.0; colloidal silicon dioxide - 0.53; magnesium stearate - 1.0.

[0279] More preferred is the application in which the mirtazapine layer is obtained by wet granulation.

[0280] Also, the subject of the present invention is a method for treating a pain disorder, characterized in that it includes the said use according to the present invention or administration to a subject in need thereof of a pharmaceutical composition according to the present invention, a pharmaceutical combination according to the present invention or a medicinal product according to the present invention.

[0281] A more preferred treatment method is one in which the pain disorder is characterized by painful muscle spasm or spasticity of skeletal muscles.

[0282] A more preferable treatment method is one in which the painful muscle spasm is associated with static and functional spinal disorders. A more preferable treatment method is one in which the spinal disorders are cervical or lumbar syndromes.

[0283] A more preferable treatment method is one in which the painful muscle spasm is associated with surgical intervention.

[0284] A more preferable treatment method is one in which skeletal muscle spasticity is associated with a neurological disorder.

[0285] A more preferable treatment method is one in which the neurological disease is selected from a group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents and cerebral palsy.

[0286] More preferred is a method of treatment characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-4 times per day.

[0287] More preferred is a method of treatment characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-3 times a day.

[0288] More preferred is a method of treatment characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-2 times per day.

[0289] More preferred is a method of treatment characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 2-4 times a day.

[0290] More preferable is a method of treatment characterized in that the said medicinal product is made in the form of a solid dosage form for oral administration.

[0291] More preferred is a method of treatment characterized in that the solid dosage form for oral administration contains at least one excipient.

[0292] A preferred method of treatment is one in which the solid oral dosage form is a tablet. A preferred method of treatment is one in which the tablet is a bilayer tablet.

[0293] A more preferred method of treatment is one in which the bilayer tablet is a prolonged-release tablet.

[0294] More preferred is a method of treatment characterized in that the bilayer tablet comprises a layer containing mirtazapine or a pharmaceutically acceptable salt thereof, and a layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which tizanidine is released in a delayed manner.

[0295] More preferred is a method of treatment characterized in that the layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which tizanidine is released in a delayed manner, includes a polymeric release retardant, and the polymeric release retardant of tizanidine is a hydrophilic polymeric release retardant.

[0296] More preferred is a method of treatment characterized in that the hydrophilic polymeric tizanidine release retardant can be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, ammonium methacrylate copolymer, hydroxypropyl methylcellulose, methyl-, ethyl- or propylcellulose, hydroxyethylcellulose hydroxypropylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, cellulose acetate or phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate succinate or ethylcellulose succinate.

[0297] A more preferred method of treatment is one in which mirtazapine is immediately released from the mirtazapine-containing layer.

[0298] More preferred is a treatment method characterized in that the sustained-release tizanidine layer contains 6 mg of tizanidine and the immediate-release mirtazapine layer contains 15 mg of mirtazapine.

[0299] More preferred is a method of treatment characterized in that the pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride. More preferred is a method of treatment characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 3.81; stearic acid - 1.11; hydroxypropyl methylcellulose - 40.28; ammonium methacrylate copolymer - 54.165; colloidal silicon dioxide - 0.635.

[0300] A more preferable method of treatment is one in which the tizanidine layer is obtained by direct pressing.

[0301] More preferable is the method of treatment characterized by the fact that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 10.0; mannitol - 33.13; microcrystalline cellulose - 51.34; polyvinylpyrrolidone - 1.0; crospovidone - 3.0; colloidal silicon dioxide - 0.53; magnesium stearate - 1.0.

[0302] A more preferred method of treatment is one in which the mirtazapine layer is obtained by wet granulation.

[0303] The following are examples of the invention, which illustrate but do not cover all possible embodiments of the invention and do not limit the invention.

[0304] Example 1. Evaluation of the efficacy of a combination of mirtazapine and tizanidine for the treatment of pain syndrome associated with static and functional diseases of the spine.

[0305] To evaluate the effectiveness of drugs for the treatment of pain syndrome associated with static and functional diseases of the spine (for example, cervical and lumbar syndromes), a model of transection of two of the three branches of the sciatic nerve in rats was chosen [17-19].

[0306] Rats: Ninety-eight adult male Sprague-Dawley rats weighing 250-330 grams were used in the experiments. Rats were housed five at a time in temperature-controlled boxes (averaging 21°C) with a 12-hour light / dark cycle and with ample food and water.

[0307] Description of the model: 10 days after nerve transection surgery in rats, which simulated a functional or static spinal disease, against the background of the resulting pain syndrome, the effectiveness of test drugs for the treatment of this pain syndrome was studied in rats.

[0308] Surgical Procedure: Rats were anesthetized with isoflurane (Sigma, USA). The skin on the lateral thigh was incised, followed by an incision in the biceps femoris muscle to expose the sciatic nerve and its three terminal branches: the sural, common peroneal, and tibial nerves. Only the tibial and common peroneal nerves were axotomized and ligated, leaving the sural nerve intact. These nerves were ligated with silk sutures and transected distally from the ligation site, leaving a nerve stump measuring 2 mm ± 4 mm. The muscles and skin were sutured separately.

[0309] Formation of study groups: rats were randomly divided into 14 equal groups (7 individuals in each), differing in the type of drug administered and its dosage.

[0310] Drugs and doses administered: The study was conducted for 4 types of drugs (mirtazapine, tizanidine, mirtazapine + tizanidine in a ratio of 2.5:1 according to the present invention and mirtazapine + tizanidine in a ratio of 5:1 (the closest analogue)), which were administered orally 10 days after surgery and 30 minutes before the behavioral tests in the indicated doses and combinations:

[0311] Mirtazapine: 15 mg / day (group N° 1), 30 mg / day (group N° 2), 45 mg / day (group N° 3), 60 mg / day (group N° 4);

[0312] Tizanidine: 6 mg / day (group N° 5), 12 mg / day (group N° 6), 18 mg / day (group N° 7), 24 mg / day (group N° 8); Mirtazapine + tizanidine in a ratio of 2.5: 1 according to the present invention: mirtazapine, 15 mg / day + tizanidine, 6 mg / day (group N° 9), mirtazapine, 30 mg / day + tizanidine, 12 mg / day (group N° 10), mirtazapine, 45 mg / day + tizanidine, 18 mg / day (group N° 11), mirtazapine, 60 mg / day tizanidine, 24 mg / day (group N° 12);

[0313] Mirtazapine + tizanidine in a ratio of 5:1 (closest analogue): mirtazapine, 30 mg / day + tizanidine, 6 mg / day (group N° 13).

[0314] The control group consisted of rats receiving only the vehicle (group No. 14, placebo). All doses are given in human equivalents.

[0315] Behavioral tests: Pain severity in different animal groups was assessed using two tests measuring the development of cold or mechanical allodynia. Animals were tested 10 days postoperatively, 30 minutes after administration of the study drugs.

[0316] Mechanical allodynia. Animals were placed in an acrylic chamber (15 x 15 x 15 cm) elevated above the ground with a wire mesh bottom. Before testing, animals were left in the chamber for 5-10 minutes to acclimate. The plantar surface of the animal's paw was then stimulated with calibrated von Frey filaments (or threads) (BIOSEB, USA). The filaments consisted of a set of 10 standard plastic threads of increasing diameter. The stiffness of the threads, expressed as the minimum force required to bend a hair, increased logarithmically with this calibration, with absolute values ​​ranging from 0.6 grams to 26 grams. For each rat, the sensitivity threshold was determined on each paw in turn, in triplicate (a total of six applications with a 10-second interval for each filament; the interval between successive applications of different filaments was 2 minutes).The tip of the thread was touched to the center of the plantar surface of the paw with a force sufficient to bend the hair, and the hair was held in this position for 6-8 seconds. A positive response was recorded if the animal abruptly withdrew its paw during the touch. The sensitivity threshold was determined by the minimum pressure eliciting a paw withdrawal reflex (4 times out of 6 applications).

[0317] Cold allodynia. To assess cold allodynia in this study, a special hot / cold plate test chamber (Ugo Basile, Italy) was used. The test was conducted in a chamber with 30 cm high acrylic walls on a 30 x 30 cm metal plate cooled to 0°C. Healthy animals are able to withstand this temperature for an extended period, resting all their limbs on the cooled floor, whereas with nerve injury, the time of limb contact with the cold plate is significantly reduced. To quantify this parameter, the time the animal could maintain limb balance for 1 minute in the test chamber was recorded. The test was conducted on the 10th day after surgery; each animal was tested three times with a 5-minute interval between measurements; the obtained values ​​were averaged.The obtained values ​​were used to calculate the mean score obtained in the corresponding test and the standard error of the mean for each value for each group used in the study. Differences between groups were considered statistically significant at a significance level of p < 0.05.

[0318] Results: The results obtained are shown in Table 1 below.

[0319] Table 1. Effect of mirtazapine and tizanidine, administered alone or in combination, on the behavior of rats with pain syndrome simulating static and functional spinal diseases.

[0320] * reliable difference in the effectiveness of the combination of mirtazapine + tizanidine in a ratio of 2.5:1 according to the present invention from the closest analogue (mirtazapine + tizanidine in a ratio of 5:1) in the treatment of pain syndrome in rats (significance level p<0.05).

[0321] Conclusion: In groups receiving the mirtazapine and tizanidine combination according to the present invention at a ratio of 2.5:1, mechanical and cold allodynia were significantly reduced, demonstrating its effectiveness in the treatment of functional and static spinal disorders. Furthermore, a synergistic effect of this combination was also observed across all tested doses, statistically significantly exceeding the therapeutic effect of the closest analogue. Furthermore, as shown in the table, the effect of the closest analogue is additive to that of mirtazapine and tizanidine at similar doses. Example 2. Evaluation of the efficacy of the mirtazapine and tizanidine combination for the treatment of post-injury and post-surgical pain.Testing the effectiveness of drugs for the treatment of pain syndrome after injuries and surgeries (for example, for intervertebral disc herniation or osteoarthritis of the hip joint) was carried out on a model of postoperative pain in rats formed by cutting the foot of the hind paw through the skin, fascia and muscles [20-21].

[0322] Rats: Ninety-eight adult male Sprague-Dawley rats weighing 250-300 grams were used in the experiments. Rats were housed five at a time in temperature-controlled boxes (averaging 21°C) with a 12-hour light / dark cycle and with ample food and water.

[0323] Description of the model: 3 days after the operation of cutting the hind paw, which resulted in pain syndrome in rats, the effectiveness of taking test drugs for the treatment of this pain syndrome was studied.

[0324] Surgery: Rats were anesthetized with isoflurane (Sigma, USA). The plantar surface of the hind paw was treated with a 10% povidone-iodine solution. Next, a 1-cm longitudinal incision was made through the skin and fascia using a blade, starting 0.5 cm below the proximal end of the heel in the direction of the toes. The plantaris muscle was elevated and also incised longitudinally. The muscle attachments were left intact. Two mattress sutures were applied to the wound using nylon threads and a needle. The wound was treated with an antibiotic mixture. After surgery, the animals recovered in their cages. Sutures were removed under anesthesia approximately 30 hours after surgery. Wounds typically healed within 5-6 days.

[0325] Formation of study groups: rats were randomly divided into 14 equal groups (7 individuals in each), differing in the type of drug administered and its dosage.

[0326] Drugs and doses administered: The study was conducted with 4 types of drugs (mirtazapine, tizanidine, mirtazapine + tizanidine in a ratio of 2.5:1 according to the present invention, and mirtazapine + tizanidine in a ratio of 5:1 (the closest analogue)), which were administered orally 3 days after surgery and 30 minutes before the behavioral tests at the doses and combinations indicated in Example 1. The control group of rats received only the vehicle (group No. 14, placebo). All doses are expressed in terms of humans. Behavioral tests: The von Frey filament test (the occurrence of mechanical allodynia) was used to evaluate pain behavior. Testing was performed as described in Example 1 above, except that the filaments were applied only to the injured paw. Differences between groups were considered statistically significant at a significance level of p < 0.05.

[0327] The results are shown in Table 2 below.

[0328] Table 2. Effect of mirtazapine and tizanidine, administered alone or in combination, on the behavior of rats with pain syndrome after surgery.

[0329] * reliable difference in the effectiveness of the combination of mirtazapine + tizanidine in a ratio of 2.5:1 according to the present invention from the closest analogue (mirtazapine + tizanidine in a ratio of 5:1) in the treatment of pain syndrome in rats (significance level p<0.05).

[0330] Conclusions: In the groups receiving the combination of mirtazapine and tizanidine, mechanical allodynia was significantly reduced, demonstrating the effectiveness of this combination for the treatment of post-surgical pain. The experiment also revealed a synergistic effect of the combination of mirtazapine and tizanidine, which was statistically significantly superior to the therapeutic effect of the closest analogue. Furthermore, as shown in the table, the effect of the closest analogue is additive to that of mirtazapine and tizanidine at similar doses.

[0331] Example 3. Evaluation of the efficacy of the combination of mirtazapine and tizanidine for the treatment of skeletal muscle spasticity in neurological diseases.

[0332] The effectiveness of drugs for the treatment of skeletal muscle spasticity in neurological diseases (for example, multiple sclerosis, chronic myelopathy, degenerative diseases) was studied in a model of transection of the sacral spinal cord of a rat (formation of tail muscle spasticity) [22-24].

[0333] Rats: Ninety-eight adult male Sprague-Dawley rats weighing 250-330 grams were used in the experiments. Rats were housed five at a time in temperature-controlled boxes (averaging 21°C) with a 12-hour light / dark cycle and with ample food and water.

[0334] Model description: On the 15th day after sacral spinal cord transection, tail spasticity was assessed in awake animals using electrical stimulation. Study group formation: Rats were randomly assigned to 14 equal-sized groups (7 animals each), each differing in the type of drug administered and its dosage.

[0335] Drugs and doses administered: The study was conducted with 4 types of drugs (mirtazapine, tizanidine, mirtazapine + tizanidine in a ratio of 2.5:1 according to the present invention and mirtazapine + tizanidine in a ratio of 5:1 (closest analogue)), which were administered orally at the indicated doses and combinations according to Example 1. The control group of rats received only the vehicle (group No. 14, placebo). All doses are given in human terms.

[0336] Surgical procedure: experimental transection of the sacral spinal cord was performed at the S2 level under general anesthesia (isoflurane, Sigma, USA) under sterile conditions [22-24]. Briefly, soft tissues on the dorsal side of the spine were incised, and a laminectomy was performed at the L2 lumbar vertebra. A hook of appropriate size was inserted under the spinal cord, which was completely transected with scissors, avoiding damage to the veins and arteries. The soft tissue layers were tightly sutured to the spinal cord.

[0337] Tail spasticity assessment: Rats were placed in a Plexiglas cylinder with their tails exposed and free to move vertically. The tail was manually stimulated as follows: the base of the tail was clamped with the left hand, and with the right hand, holding the tail between the thumb and index finger, the tail was quickly moved from base to tip, maintaining firm contact, and releasing the tail upon completion of the movement. This procedure was repeated three times. This achieved longitudinal tail straightening. The response to this stimulation was tail curling, with its retraction under the rat's body (or dorsal in rats with more severe injuries). The scale described below was used to assess tail spasticity.

[0338] Score 0-1: Very slight or negligible twisting of the tip of the tail in response to stretch (less than 90°, lasting only a few seconds), little or no muscle tone, no clonus, no response to light touch on the skin or fur. Score 2-3: Severe spasm (flexion) of the tail in response to stretch stimulation, with the tip curled at 180-360°, lasting 3-10 seconds. Repetitive twisting and clonus of the tail lasting more than 10 minutes, hypertonicity, high sensitivity to light touch. Score 4-5: Similar to the previous score, but with more frequent repetitive tail flexions and bending, often resulting in an S-shape, with the proximal portion of the tail curled under the rat and the distal portion curled in the opposite direction; more pronounced clonus, hypertonicity, and side-to-side movements.

[0339] Each rat was assigned a score on the tail spasticity scale, which was then averaged within each group. Differences between groups were considered statistically significant at a significance level of p < 0.05.

[0340] Results: The results obtained are shown in Table 3 below.

[0341] Table 3. Effect of mirtazapine and tizanidine, administered alone or in combination, on the behavior of rats experiencing pain due to skeletal muscle spasticity. in a ratio of 2.5:1 according to the present invention from the closest analogue (mirtazapine + tizanidine in a ratio of 5:1) in the treatment of pain syndrome in rats (significance level p<0.05).

[0342] Conclusions: Tail spasticity was the weakest in animals receiving the combination of mirtazapine and tizanidine, suggesting the potential for this combination to treat skeletal muscle spasticity in neurological disorders. The experiment also revealed a synergistic effect of the mirtazapine and tizanidine combination, which was statistically significantly superior to the therapeutic effect of the closest analogue. Furthermore, as shown in the table, the effect of the closest analogue is additive to that of mirtazapine and tizanidine at similar doses. Example 4. Preparation of an immediate-release layer containing mirtazapine.

[0343] Preliminary testing has shown that the best results can be obtained using the wet granulation technique.

[0344] The samples were manufactured according to the following steps:

[0345] • Weigh and calibrate mirtazapine and excipients through sieves; · Mix mirtazapine, mannitol and microcrystalline cellulose;

[0346] • Granulate using polyvinylpyrrolidone K30 (PUR K30); • Mix the granulate with crospovidone, silica and vegetable magnesium stearate.

[0347] During the preparation of granules, good results were obtained in batch 2 (Table 4).

[0348] Table 4. Qualitative and quantitative composition of the mixture for the mirtazapine layer.

[0349] Example 5. Preparation of a sustained-release coating containing tizanidine. To produce a once-daily, extended-release formulation of tizanidine, several release-controlling agents were tested at various concentrations. Three different batches of 6 mg tizanidine tablets were prepared in the three different formulations shown in Table 5.

[0350] Hydroxypropyl methylcellulose, ethylcellulose, kollidone (a spray-dried mixture of polyvinyl acetate and polyvinylpyrrolidone polymers in a ratio of 8:2), and ammonium methacrylate copolymers were used as release-controlling agents in systems with a hydrophilic matrix (hydrophilic polymer release retardant).

[0351] Hydroxypropyl methylcellulose (HPMC) is often used in controlled-release formulations. In this case, grade K100M was used. High-molecular-weight HPMCs are highly versatile release modulating agents; they are non-ionic polymers and work well with soluble and insoluble drugs at both high and low dosage levels.

[0352] The manufacturing process was identical for all batches and consisted of the following steps. First, the starting materials were sieved through a 0.610 mm stainless steel sieve and mixed manually for 5 minutes without adding stearic acid. After pre-mixing, stearic acid was added to the mixture and mixed manually for 5 minutes. Tablets were manufactured on a rotary tablet press. All tablets were manufactured with the same tablet weight (180 mg ± 5%) and the same tablet strength (15 ± 3 kgf) to evaluate the effect of the polymer on drug release: for the same surface area exposed to the dissolution medium, release profiles are influenced solely by varying polymer concentrations and matrix formation. Table 5. Qualitative and quantitative composition of tizanidine layer mixtures.

[0353]

[0354] However, the authors failed to achieve acceptable release characteristics and technological parameters of the mixture when using hydrophobic release retardants.

[0355] The results demonstrated that hydrophilic polymeric release retardants can be used to obtain a tizanidine-sustained release layer, with the most effective drug release retardant property being demonstrated by a mixture of ammonium methacrylate and HPMC copolymers (batch 3).

[0356] Example 6. Preparation of a bilayer tablet containing mirtazapine and tizanidine in effective amounts.

[0357] Based on the promising results obtained in Example 4 for the wet granulation process for the production of the mirtazapine layer, Batch 2 was selected to produce a preclinical batch of the bilayer tablet.

[0358] Batch 2 showed good processing properties, therefore a batch of bilayer tablets was prepared using this granulate for the mirtazapine layer and a batch of tizanidine prepared according to Example 5 (batch 3).

[0359] The aim of this work is to obtain a combination oral dosage form in the form of a 330 mg bilayer tablet containing two selected active substances and composed as follows: an immediate release layer of 150 mg containing 15 mg mirtazapine; a sustained release layer of 180 mg containing 6 mg tizanidine.

[0360] The development of a bilayer tablet was based on the results obtained in Examples 4 and 5. The bilayer tablets were prepared using a rotary tablet press equipped with ten flat punches with a diameter of 9 mm. The final composition is presented in Table 6. The technological characteristics of the bilayer tablet are presented in Table 7.

[0361] Table 6. Qualitative and quantitative composition of the layers of a bilayer tablet.

[0362] Table 7. Technological characteristics of the two-layer tablet.

[0363] Example 7. Study of the effect of the drug mirtazapine+tizanidine according to the present invention on mechanical allodynia in rats in a model of neuropathic pain caused by ligation of the spinal nerve.

[0364] The spinal nerve ligation (SNL) model of neuropathic pain has been widely used for various research studies on the mechanisms of neuropathic pain, as well as for screening tests for the development of new analgesic drugs. SNL is performed by tightly ligating one (L5) or two (L5 and L6) segmental spinal nerves in rats. The procedure results in long-lasting behavioral signs of mechanical allodynia, thermal hyperalgesia, cold allodynia, and persistent pain

[0025] .

[0365] Adult Sprague-Dawley rats weighing 250-300 grams were used in the experiments. The rats were kept in temperature-controlled cages (21°C) with a 12-hour light / dark cycle and were provided with ample food and water.

[0366] Fifty Sprague-Dawley rats were randomly assigned to five equal groups (N=10) differing in drug type: vehicle (placebo), mirtazapine 15 mg, tizanidine 6 mg, mirtazapine + tizanidine preparation according to the present invention, prolonged-release tablets, 15 mg + 6 mg (in a ratio of 2.5:1), and the comparator drug mirtazapine + tizanidine in a ratio of 5:1, 30 mg + 6 mg (the closest analogue). All drugs were administered orally 3 days after surgery and then once daily for the duration of the study. All doses are expressed as human doses. Animals were anesthetized with an intraperitoneal injection of sodium pentobarbital and the dorsal hair was clipped. Each animal was then placed on the surgical platform in a prone position, and the limbs were fixed with adhesive tape.Under sterile conditions, an incision (approximately 3 cm long and 5 mm lateral to the midline) was made at the lower lumbar and sacral levels (from the caudal aspect of the L5 vertebra to the first sacral vertebra). The location of the incision was 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 were isolated and removed from the level of the L5 vertebra to the sacrum.

[0367] To assess pain behavior, a von Frey filament test (mechanical allodynia) was used on days 1, 5, 10, and 15 postoperatively. For each rat, the sensitivity threshold was determined on each paw in turn, in triplicate (a total of 6 applications with a 10-second interval for each filament; the interval between successive applications of different filaments was 2 minutes). The tip of the filament was touched to the middle of the plantar surface of the paw with the force required to bend the hair, and the hair was held in this position for 6-8 seconds. A positive response was recorded if the animal sharply withdrew its paw during the touch. The sensitivity threshold was determined by the minimum pressure evoking a reflexive paw withdrawal reaction (4 times out of 6 applications).

[0368] For each study group (n=10), the mean score obtained in the corresponding test and the standard error of the mean for each value were calculated. Differences between groups were considered statistically significant at a significance level of p<0.05.

[0369] The results obtained are shown in Table 8 below.

[0370] Table 8. Effect of mirtazapine + tizanidine, prolonged-release tablets, 15 mg + 6 mg (in a ratio of 2.5:1) on the behavior of rats with pain syndrome caused by ligation of spinal nerves.

[0371] * reliable difference in the effectiveness of the combination of mirtazapine + tizanidine in a ratio of 2.5:1 according to the present invention from the closest analogue (mirtazapine + tizanidine in a ratio of 5:1) in the treatment of pain syndrome in rats (significance level p<0.05).

[0372] In the group receiving the combination of mirtazapine and tizanidine 15 mg + 6 mg (in a 2.5:1 ratio), mechanical allodynia indices were significantly reduced, demonstrating their effectiveness in treating pain caused by spinal nerve ligation (a model of post-stroke chronic pain). The experiment also revealed a synergistic effect of the combination of mirtazapine and tizanidine, which statistically significantly exceeded the therapeutic effect of the closest analogue. Furthermore, as shown in the table, the effect of the closest analogue is additive to that of mirtazapine and tizanidine at similar doses. Example 8. Acute toxicity studies.

[0373] Acute toxicity studies of mirtazapine + tizanidine extended-release tablets 15 mg + 6 mg were conducted in comparison with the monodrugs tizanidine modified-release capsules 6 mg and mirtazapine film-coated tablets 30 mg in outbred rats of both sexes with intragastric administration (fractional daily administration).

[0374] According to the conducted toxicometry data, the median lethal doses for the studied drugs (LD50) were established, mg / kg: mirtazapine 324.0; tizanidine 230.9; mirtazapine + tizanidine, 15 + 6 mg 465.3.

[0375] To determine the nature of the interaction using the acute toxicity parameters of the fixed combination, the Finney additivity equation

[0026] was used.

[0376] The hypothetical median lethal dose (LD50 type) for the combination drug (calculated based on the assumption of an additive interaction of the components) was:

[0377] 1 / LD50 type = 6 / (21*324.0) + 15 / (21*230.9) = 0.003975, respectively LD50 type = 251.5 mg / kg (based on the sum of active substances).

[0378] The ratio of the hypothetical (calculated) LD50 type to the experimentally obtained LD50 combination was: 251.5 / 465.3 = 0.54

[0379] The principle of additivity is used in general toxicology as a starting hypothesis for the combined action of several toxic agents. It is assumed that the predicted effect of a fixed combination is the sum of the effects of the individual components of the combination. The additivity equation underlies analytical techniques for determining the nature of interactions using the acute toxicity parameters of fixed combinations according to Finney

[0026] .

[0380] Depending on the ratio of the hypothetical LD50 value of the combination, calculated based on the LD50 values ​​of the individual components, to the actual, experimentally determined LD50 value of the combination, one of three conclusions is drawn: 1) No toxicological interaction. The LD50(hypo) / LD50(actual) ratio is equal to or close to 1. The toxicity of the components in the combination may be additive, i.e., it corresponds to the primary hypothesis of additive synergy.

[0381] 2) Toxicological interactions of the antagonist type. The LD5o(hypo) / LD5o(act) ratio is equal to or less than 0.57, i.e., a decrease in the toxicity of the components in combination is possible.

[0382] 3) Toxicological interactions by potentiation. The LD5o(hypo) / LD5o(act) ratio is equal to or greater than 1.75, i.e., increased toxicity of the components in combination is possible.

[0383] In the study conducted in rats, the obtained value of 0.54 may indicate a tendency towards toxicological interaction of the antagonist type, that is, a possible decrease in the toxicity of the components in combination.

[0384] Based on acute toxicity indicators, the tested drug, as well as the comparison drugs, can be classified as class 3 moderately toxic substances according to the Hodge and Sterner classification

[0027] and class III moderately hazardous compounds according to GOST 12.1.007-76

[0028] .

[0385] The invention can be used in medicine, pharmacology, and the chemical and pharmaceutical industry.

[0386] Bibliography

[0387] 1. Application RU 2002129356, 27.03.2004;

[0388] 2. Application WO 2006055854, 05 / 26 / 2006;

[0389] 3. Lu Y., Xiao Z., Yu W., Xiao F., Xiao Z., Hu Y., Chen Y., Wang X.: «Efficacy and safety of adjunctive zonisamide in adult patients with refractory partial-onset epilepsy: a randomized, double-blind, placebo-controlled trial» / / Clinical Drug Investigation, V. 31, N° 4, 2011, P. 221-229;

[0390] 4. Патент US JVfe 4062848, 13.12.1977;

[0391] 5. Fawcett J., Barkin R.L.: «А meta-analysis of eight randomized, double-blind, controlled clinical trials of mirtazapine for the treatment of patients with major depression and symptoms of anxiety» / / Journal of Clinical Psychiatry, V. 59, N° 3, 1998, P. 123-127;

[0392] 6. Goodnick P.J., Jimenez I., Kumar A.: «Sertraline in diabetic neuropathy: preliminary results» / / Annals of Clinical Psychiatry, V. 9, N° 4, 1997, P. 255-257; 7. Muth-Selbach U., Hermanns H., Driehsen C., Lipfert P., Freynhagen R.: «Racemic intrathecal mirtazapine but not its enantiomers acts anti-neuropathic afterchronic constriction injury in rats» / / Brain Research Bulletin, V. 79, Xa 1, 2009, P. 63-68;

[0393] 8. Arnold P., Vuadens P., Kuntzer T., Gobelet C., Deriaz O.: «Mirtazapine decreases the pain feeling in healthy participants» / / The Clinical Journal of Pain, V. 24, Xa 2, 2008, P. 116- 119;

[0394] 9. Freynhagen R., Muth-Selbach U., Lipfert P., Stevens M.F., Zacharowski K., Tolle T.R., von Giesen H.J.: «The effect of mirtazapine in patients with chronic pain and concomitant depression» / / Current Medical Research and Opinion, V. 22, Xa 2, 2006, P. 257-264;

[0395] 10. Bomholt SF, Mikkelsen JD, Blackbum-Munro G.: “Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain” / / Neuropharmacology, V. 48, Xa 2, 2005, P. 252-263;

[0396] 11. Bendtsen L., Jensen R.: “Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache” / / Neurology, V. 62, Xa 10, 2004, P. 1706-1711;

[0397] 12. Travell J.G., Simons D.G.: “Myofascial pain”. In 2 Volumes / / Medicine, Volume 1, 1989, 256 p.;

[0398] 13. Alekseev V. V.: “Handbook of a polyclinic doctor” / / Consilium medicum, T. 1, Ha 1, 2001;

[0399] 14. Application US Xa 2008020076, 01 / 24 / 2008;

[0400] 15. Patent of the Russian Federation Ha 2509560, 20.03.2014;

[0401] 16. Berge SM, Bighley LD, Monkhouse DC: “Pharmaceutical Salts” / / Journal of Pharmaceutical Sciences, V. 66, Xa 1, 1977, P. 1-19;

[0402] 17. Bennett G.J., Xie Y.K.: «А peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man» / / Pain, V. 33, Xa 1, 1988, P. 87-107;

[0403] 18. Decosterd I., Woolf C.J.: «Spared nerve injury: an animal model of persistent peripheral neuropathic pain» / / Pain, V. 87, Xa 2, 2000, P. 149-158;

[0404] 19. Kim S.H., Chung J.M.: «An experimental-model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat» / / Pain, V. 50, Xa 3, 1992, P. 355-363;

[0405] 20. Brennan T.J., Vandermeulen E.P., Gebhart G.F.: «Characterization of a rat model of incisional pain» / / Pain, V. 64, Xa 3, 1996, P. 493-501; 21. Pogatzki E.M., Niemeier J.S., Brennan T.J.: «Persistent secondary hyperalgesia after gastrocnemius incision in the rat» / / European Journal of Pain, V. 6, N° 4, 2002, P. 295-305;

[0406] 22. Bennett D.J., Sanelli L., Cooke C.L., Harvey P.J., Gorassini M.A.: «Spastic long- lasting reflexes in the awake rat after sacral spinal cord injury» / / Journal of Neurophysiology, V. 91, No 5, 2004, P. 2247-2258;

[0407] 23. Li Y., Gorassini M.A., Bennett D.J.: «Role of persistent sodium and calcium currents in motoneuron firing and spasticity in chronic spinal rats» / / Journal of Neurophysiology, V. 91, No 2, 2004, P. 767-783;

[0408] 24. Li X., Murray K., Harvey P.J., Ballou E.W., Bennett D.J.: «Serotonin facilitates a persistent calcium current in motoneurons of rats with and without chronic spinal cord injury» / /

[0409] Journal of Neurophysiology, V. 97, N° 2, 2007, P. 1236-1246;

[0410] 25. Chung J.M., Kim H.K., Chung K.: «Segmental Spinal Nerve Ligation Model of Neuropathic Pain» / / Methods in Molecular Medicine, V. 99, 2004, P. 35-45;

[0411] 26. “Probit analysis: A statistical treatment of the sigmoid response curves” / / by Linney DG, 2nd ed., Cambridge University Press, 1952, P.131-140;

[0412] 27. “Clinical Toxicology of Commercial Products” / / Acute Poisoning, Ed. IV, by Hodge HC Gosselin RE, Smith RP, Baltimore, 1976, P. 427;

[0413] 28. EOCT 12.1.007-76. "Occupational safety standards system. Harmful substances. Classification and general safety requirements."

Claims

CLAUSES OF THE INVENTION 1. A pharmaceutical composition for the treatment of pain disorders, comprising mirtazapine and tizanidine or their pharmaceutically acceptable salts in a weight ratio of mirtazapine to tizanidine, calculated as free bases, of 2.5 to 1 and at least one pharmaceutically acceptable carrier, containing from 15 to 60 mg of mirtazapine and from 6 to 24 mg of tizanidine.

2. A pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable salt of tizanidine is hydrochloride.

3. The pharmaceutical composition according to paragraphs 1-2, characterized in that it contains from 15 to 45 mg of mirtazapine and from 6 to 18 mg of tizanidine.

4. The pharmaceutical composition according to paragraphs 1-3, characterized in that it contains from 15 to 30 mg of mirtazapine and from 6 to 12 mg of tizanidine.

5. The pharmaceutical composition according to paragraphs 1-3, characterized in that it contains from 30 to 45 mg of mirtazapine and from 12 to 18 mg of tizanidine.

6. The pharmaceutical composition according to paragraphs 1-2, characterized in that it contains 60 mg of mirtazapine and 24 mg of tizanidine.

7. The pharmaceutical composition according to paragraphs 1-2, characterized in that it contains 45 mg of mirtazapine and 18 mg of tizanidine.

8. The pharmaceutical composition according to paragraphs 1-2, characterized in that it contains 30 mg of mirtazapine and 12 mg of tizanidine.

9. The pharmaceutical composition according to paragraphs 1-2, characterized in that it contains 15 mg of mirtazapine and 6 mg of tizanidine.

10. A pharmaceutical composition according to paragraphs 1-9, characterized in that it contains at least one auxiliary substance.

11. A pharmaceutical composition according to items 1-10, characterized in that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles.

12. The pharmaceutical composition according to claim 11, characterized in that painful muscle spasm is associated with static and functional diseases of the spine.

13. A pharmaceutical composition according to claim 12, characterized in that the spinal diseases are cervical or lumbar syndromes.

14. The pharmaceutical composition according to paragraphs 11-12, characterized in that the painful muscle spasm is associated with surgical intervention.

15. The pharmaceutical composition according to paragraph 11, characterized in that the spasticity of skeletal muscles is associated with a neurological disease.

16. The pharmaceutical composition according to claim 15, characterized in that the neurological disease is selected from the group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accident and cerebral palsy.

17. A pharmaceutical combination for the treatment of pain disorders, comprising mirtazapine and tizanidine or their pharmaceutically acceptable salts in a weight ratio of mirtazapine to tizanidine, calculated as free bases, of 2.5 to 1 and at least one pharmaceutically acceptable carrier, containing from 15 to 60 mg of mirtazapine and from 6 to 24 mg of tizanidine.

18. The pharmaceutical combination according to claim 17, characterized in that the pharmaceutically acceptable salt of tizanidine is hydrochloride.

19. The pharmaceutical combination according to items 17-18, characterized in that it contains from 15 to 45 mg of mirtazapine and from 6 to 18 mg of tizanidine.

20. The pharmaceutical combination according to items 17-19, characterized in that it contains from 15 to 30 mg of mirtazapine and from 6 to 12 mg of tizanidine.

21. The pharmaceutical combination according to items 17-19, characterized in that it contains from 30 to 45 mg of mirtazapine and from 12 to 18 mg of tizanidine.

22. Pharmaceutical combination according to items 17-18, characterized in that it contains 60 mg of mirtazapine and 24 mg of tizanidine.

23. Pharmaceutical combination according to items 17-18, characterized in that it contains 45 mg of mirtazapine and 18 mg of tizanidine.

24. Pharmaceutical combination according to items 17-18, characterized in that it contains 30 mg of mirtazapine and 12 mg of tizanidine.

25. The pharmaceutical combination according to items 17-18, characterized in that it contains 15 mg of mirtazapine and 6 mg of tizanidine.

26. A pharmaceutical combination according to paragraphs 17-25, characterized in that it contains at least one auxiliary substance.

27. The pharmaceutical combination according to items 17-26, characterized in that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles.

28. Pharmaceutical combination according to I. 27, characterized by the fact that painful muscle spasm is associated with static and functional diseases of the spine.

29. Pharmaceutical combination according to item 28, characterized by the fact that the spinal diseases are cervical or lumbar syndromes.

30. Pharmaceutical combination according to items 27-29, characterized by the fact that painful muscle spasm is associated with surgical intervention.

31. Pharmaceutical combination according to I. 27, characterized by the fact that spasticity of skeletal muscles is associated with a neurological disease.

32. The pharmaceutical combination according to claim 31, characterized in that the neurological disease is selected from the group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accident and cerebral palsy.

33. A medicinal product for the treatment of pain disorders, comprising a pharmaceutical composition according to items 1-16 or a pharmaceutical combination according to items 17-32 and at least one auxiliary substance.

34. The medicinal product according to item 33, characterized in that at least one auxiliary substance is selected from the group consisting of cellulose derivatives or mixtures thereof, such as methyl, ethyl or propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, carboxymethyl cellulose, cellulose acetate or phthalate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate succinate, ethyl cellulose succinate and microcrystalline cellulose, ammonium methacrylate copolymer, colloidal silicon dioxide, mannitol, sorbitol, isomalt, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid, polyvinylpyrrolidone, crospovidone, polyvinyl alcohol, polyethylene oxide, carbomers, alginates, acrylic acid polymer or its esters, stearic acid and its salts such as calcium and magnesium stearate, talc, sodium stearyl fumarate.

35. The medicinal product according to items 33-34, characterized in that the daily dosage for mirtazapine is from 15 to 45 mg, and the daily dosage for tizanidine is from 6 to 18 mg.

36. The medicinal product according to items 33-35, characterized in that the daily dosage for mirtazapine is from 15 to 30 mg, and the daily dosage for tizanidine is from 6 to 12 mg.

37. The medicinal product according to I. 33-34, characterized in that the daily dosage for the use of mirtazapine is from 30 to 60 mg, and the daily dosage for the use of tizanidine is from 12 to 24 mg.

38. The medicinal product according to items 33, 37, characterized in that the daily dosage for mirtazapine is 60 mg, and the daily dosage for tizanidine is 24 mg.

39. The medicinal product according to items 33-35, characterized in that the daily dosage for mirtazapine is 45 mg, and the daily dosage for tizanidine is 18 mg.

40. The medicinal product according to items 33-37, characterized in that the daily dosage for mirtazapine is 30 mg, and the daily dosage for tizanidine is 12 mg.

41. The medicinal product according to items 33-36, characterized in that the daily dosage for mirtazapine is 15 mg, and the daily dosage for tizanidine is 6 mg.

42. A medicinal product according to paragraphs 33-41, characterized in that it is made in the form of a solid medicinal form for oral administration.

43. The medicinal product according to item 42, characterized in that the solid dosage form for oral administration is a tablet.

44. The medicinal product according to paragraph 43, characterized in that the tablet is a two-layer tablet.

45. The medicinal product according to paragraphs 43-44, characterized in that the tablet is an extended-release tablet.

46. The medicinal product according to paragraphs 44-45, characterized in that the bilayer tablet includes a layer containing mirtazapine and a layer containing tizanidine, from which tizanidine is released in a delayed manner.

47. The medicinal product according to claim 46, characterized in that the layer containing tizanidine, from which tizanidine is released in a delayed manner, includes tizanidine, or a pharmaceutically acceptable salt thereof, a filler, a disintegrant, and a polymeric release retardant, which is a hydrophilic polymeric release retardant.

48. The medicinal product according to paragraphs 46-47, characterized in that the layer containing tizanidine, from which tizanidine is released in a slow manner, additionally includes a lubricant.

49. The medicinal product according to paragraphs 46-48, characterized in that the layer containing tizanidine contains tizanidine hydrochloride in an amount of 0.5-30 wt.%, a hydrophilic polymeric release retardant in an amount of 0.5-99 wt.% and a lubricant in an amount of 0.5-2.5 wt.%.

50. The medicinal product according to paragraphs 47-49, characterized in that the hydrophilic polymeric tizanidine release retardant can be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, ammonium methacrylate copolymer, hydroxypropyl methylcellulose, methyl-, ethyl- or propylcellulose, hydroxyethylcellulose hydroxypropylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, cellulose acetate or phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate succinate, ethylcellulose succinate or mixtures thereof.

51. The medicinal product according to paragraphs 48-50, characterized in that the lubricant in the layer with tizanidine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearate or fulvaline, and mixtures thereof.

52. The medicinal product according to paragraphs 46-51, characterized in that mirtazapine is immediately released from the layer containing mirtazapine 53. The medicinal product according to paragraphs 46-52, characterized in that the layer with mirtazapine contains mirtazapine, a filler, a disintegrant and a lubricant.

54. The medicinal product according to paragraphs 46-53, characterized in that the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt.%, a filler in an amount of 70-95 wt.%, a disintegrant in an amount of 1-10 wt.%, and a lubricant in an amount of 0.5-5 wt.%.

55. The medicinal product according to paragraphs 46-54, characterized in that the lubricant in the layer with mirtazapine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearate or fulvaline, and mixtures thereof.

56. The medicinal product according to paragraphs 46-55, characterized in that the filler is selected from mannitol, sorbitol, isomalt, microcrystalline cellulose, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid and mixtures thereof.

57. The medicinal product according to paragraphs 46-56, characterized in that the disintegrant is selected from crospovidone, sodium carboxymethylcellulose, agar-agar, calcium carbonate, potato, corn, pea or tapioca starch, alginic acid, complex silicates, sodium carbonate and mixtures thereof.

58. The medicinal product according to paragraphs 46-57, characterized in that it additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, acacia and mixtures thereof in an amount of 0.5-5 wt.%, 59. The medicinal product according to item 46, characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 0.5-30; stearic acid - 0.5-2.0; hydroxypropyl methylcellulose - 30.0-50.0; ammonium methacrylate copolymer - 40.0-75.0 colloidal silicon dioxide - 0.5-2.

0.

60. The medicinal product according to item 46, characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, % by weight: tizanidine hydrochloride (in terms of tizanidine) - 3.81; stearic acid - 1.11; hydroxypropyl methylcellulose - 40.28; ammonium methacrylate copolymer - 54.165; colloidal silicon dioxide - 0.

635.

61. The medicinal product according to paragraph 46-60, characterized in that the layer with tizanidine is obtained by direct pressing.

62. The medicinal product according to item 46, characterized in that the slow-release tizanidine layer contains 6 mg of tizanidine.

63. The medicinal product according to claim 46, characterized in that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 1.0-35.0; mannitol - 20.0-40.0; microcrystalline cellulose - 40.0-60.0; polyvinylpyrrolidone - 0.5-5.0; crospovidone - 0.5-5.0; colloidal silicon dioxide - 0.5-2.5; magnesium stearate - 0.5-2.

5.

64. The medicinal product according to I. 46, characterized in that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, % by weight: mirtazapine - 10.0; mannitol - 33.13; microcrystalline cellulose - 51.34; polyvinylpyrrolidone - 1.0; crospovidone - 3.0; colloidal silicon dioxide - 0.53; magnesium stearate - 1.

0.

65. A medicinal product according to paragraphs 46-64, characterized in that the layer with mirtazapine is obtained by wet granulation.

66. The medicinal product according to claim 46, characterized in that the immediate release mirtazapine layer contains 15 mg of mirtazapine.

67. The medicinal product according to paragraphs 33-66, characterized in that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles.

68. The medicinal product according to paragraph 67, characterized in that painful muscle spasm is associated with static and functional diseases of the spine.

69. The medicinal product according to paragraph 68, characterized in that the spinal diseases are cervical or lumbar syndromes.

70. A medicinal product according to paragraph 67-68, characterized in that the painful muscle spasm is associated with surgical intervention.

71. The medicinal product according to paragraph 67, characterized in that spasticity of skeletal muscles is associated with a neurological disease.

72. The medicinal product according to claim 71, characterized in that the neurological disease is selected from the group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents and cerebral palsy.

73. The use of a pharmaceutical composition according to any one of claims 1-16, a pharmaceutical combination according to any one of claims 17-32, or a medicinal product according to any one of claims 33-72, for the treatment of pain disorders, characterized in that the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine is from 6 to 24 mg, in a ratio of 2.5 to 1.

74. Use according to paragraph 73, characterized in that the daily dosage of mirtazapine is from 15 to 45 mg, and tizanidine is from 6 to 18 mg.

75. Use according to paragraph 73, characterized in that the daily dosage of mirtazapine is from 15 to 30 mg, and tizanidine is from 6 to 12 mg.

76. Use according to paragraph 73, characterized in that the daily dosage of mirtazapine is from 30 to 45 mg, and tizanidine is from 12 to 18 mg.

77. Use according to I. 73, characterized in that the daily dosage of mirtazapine is 60 mg, and tizanidine is 24 mg.

78. Use according to paragraph 1, characterized in that the daily dosage of mirtazapine is 45 mg, and tizanidine is 18 mg.

79. Use according to I. 73, characterized in that the daily dosage of mirtazapine is 30 mg, and tizanidine is 12 mg.

80. Use according to I. 73, characterized in that the daily dosage of mirtazapine is 15 mg, and tizanidine is 6 mg.

81. Use according to paragraphs 73-80, characterized by the fact that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles.

82. Application according to I. 81, characterized by the fact that painful muscle spasm is associated with static and functional diseases of the spine.

83. Application according to I. 82, characterized by the fact that the spinal diseases are cervical or lumbar syndromes.

84. Use according to paragraphs 81-82, characterized by the fact that painful muscle spasm is associated with surgical intervention.

85. Application according to I. 81, characterized by the fact that spasticity of skeletal muscles is associated with a neurological disease.

86. Use according to item 85, characterized in that the neurological disease is selected from a group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents, and cerebral palsy.

87. Use according to paragraphs 73-86, characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-4 times per day.

88. Use according to paragraphs 73-87, characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-3 times per day.

89. Use according to paragraphs 73-88, characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-2 times a day.

90. Use according to paragraphs 73-87, characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 2-4 times a day.

91. A method for treating a pain disorder, characterized in that it includes the use according to any of claims 73-90 or the administration to a subject in need thereof of a pharmaceutical composition according to any of claims 1-16, a pharmaceutical combination according to any of claims 17-32, or a medicinal product according to any of claims 33-72.

92. The method of treatment according to Article 91, characterized by the fact that the pain disorder is a painful muscle spasm or spasticity of the skeletal muscles.

93. The treatment method according to I. 92, characterized by the fact that painful muscle spasm is associated with static and functional diseases of the spine.

94. The treatment method according to I. 93, characterized by the fact that the spinal diseases are cervical or lumbar syndromes.

95. The method of treatment according to paragraphs 92-93, characterized in that the painful muscle spasm is associated with surgical intervention.

96. The method of treatment according to I. 92, characterized by the fact that spasticity of skeletal muscles is associated with a neurological disease.

97. The method of treatment according to paragraph 96, characterized in that the neurological disease is selected from the group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, consequences of cerebrovascular accidents and cerebral palsy.

98. The method of treatment according to paragraphs 91-97, characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-4 times per day.

99. The method of treatment according to paragraphs 91-98, characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-3 times a day.

100. The method of treatment according to paragraphs 91-99, characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 1-2 times per day.

101. The method of treatment according to paragraphs 91-98, characterized in that the said pharmaceutical composition, pharmaceutical combination or medicinal product is intended for administration 2-4 times a day.