EA045581B1 - COMBINATION OF MIRTAZAPINE AND TIZANIDINE FOR USE IN PAIN DISORDERS - Google Patents

Description

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 from 6 up to 24 mg, as well as a pharmaceutical composition comprising a combination of mirtazapine and tizanidine and at least one pharmaceutically acceptable carrier, and a method for treating a pain disorder.

Pain is one of the most common complaints that doctors of various specialties deal with in everyday practice.

Various drugs are used to treat and prevent pain syndromes:

drugs that affect the synthesis of prostaglandins (non-narcotic analgesics, paracetamol, non-steroidal anti-inflammatory drugs - NSAIDs) that reduce the concentration of substance P (capsicum preparations for external use - capsaicin, capsin, etc.);

local anesthetics;

opiates;

drugs that affect GABAergic structures (baclofen, sirdalud, gabapentin);

anticonvulsants (carbamazepine, valproate, benzodiazepines, etc.);

drugs - alpha2-adrenergic receptor agonists;

serotonin reuptake blockers, such as amitriptyline;

antidepressants.

To develop more effective methods for eliminating and preventing pain, attempts are being made to combine different groups of drugs. However, currently few such combinations have been found. This is due in particular to the development of various side effects with combined exposure.

Combinations for the treatment of headache are known containing paracetamol or a non-steroidal 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 scope of application, namely, it is intended for the treatment of headaches.

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 of the side effects of mirtazapine, such as excessive daytime sleepiness, sedation and weight gain.

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

Mirtazapine is a tetracyclic antidepressant with a predominantly sedative effect. It is an antagonist of presynaptic _α2 -adrenergic receptors in the central nervous system and enhances central noradrenergic and serotonergic transmission of nerve impulses. In this case, the enhancement of serotonergic transmission is realized only through serotonin 5-HT ₁ receptors, since mirtazapine blocks serotonin 5-HT2 and 5-HT ₃ receptors. Both enantiomers of mirtazapine are believed to have antidepressant activity, the S(+) enantiomer by blocking _α2- adrenergic and serotonin 5- _HT2 receptors, and the R(-) enantiomer by blocking serotonin 5- _HT3 receptors. The sedative properties of mirtazapine are due to its antagonistic activity at H1 histamine receptors. Mirtazapine has virtually no M-anticholinergic activity and in therapeutic doses has a limited effect (for example, orthostatic hypotension) on the cardiovascular system.

Mirtazapine is disclosed in a US patent [4]. The dual mechanism of action of mirtazapine on 2 neurotransmitter systems defines it as noradrenergic and specific serotonergic

- 1 045581 Chinese antidepressant. In terms of its action, mirtazapine can quite quickly neutralize the manifestations of anxiety, even in the first days of treatment. Available evidence suggests that mirtazapine is superior to placebo in the treatment of depression with anxiety and insomnia. Patients treated with mirtazapine had significant (p<0.05) reductions in anxiety symptoms at study weeks 1, 2, 4, 6, and at the end of treatment compared with 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].

Mirtazapine has also been effective in the treatment of post-traumatic stress disorder. More than half of the patients showed positive dynamics in terms of reduction of the anxiety component both during the doctor’s survey and during self-testing. Mirtazapine is effective in the treatment of depression with generalized anxiety disorder. For example, an 8-week pilot study showed a significant reduction in depressive and anxiety symptoms. Another feature of mirtazapine is the fact that it does not inhibit cytochrome P-450 [6].

Mirtazapine is known to have been studied for its anti-pain effects and may be used in the treatment of chronic neuropathic pain conditions, tension 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.

The two pathologies listed above are fundamentally different from each other. In diseases of the nervous system, painful muscle spasms or tonic tension of muscle fibers develop when painful stimulation is applied.

The characteristics of pain during painful muscle spasms are local in nature within the spasmed muscle;

provoked by irritation of the affected muscle;

when palpating the muscle fibers, intense pain is determined;

the tone is increased.

The main features of pain in degenerative-dystrophic lesions or myofascial pain syndrome:

referred or regional pain, which is always far from the spasmed muscle;

when palpating the painful muscle, the pain increases significantly;

a sharp diffuse muscle spasm with inclusions of areas of compaction that play the role of a trigger; when these areas are pressed, very intense pain develops both in the muscle and at a distance [12].

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

Tizanidine is a centrally acting muscle relaxant. By stimulating presynaptic alpha2 receptors, it inhibits the release of excitatory amino acids that stimulate N-methyl-D-aspartate receptors (NMDA receptors). As a result, postsynaptic transmission of excitation is suppressed at the level of intermediate neurons of the spinal cord. Since it is this mechanism that is responsible for excess muscle tone, when it is suppressed, muscle tone decreases. In addition to muscle relaxant properties, tizanidine also has a moderate central analgesic effect.

Tizanidine

Tizanidine relaxes skeletal muscles in chronic spastic conditions of spinal and cerebral origin, eliminates acute painful muscle spasms and clonic convulsions. Reduces muscle resistance during passive movements, increases the strength of voluntary muscle contractions.

Muscle relaxants reduce pathologically increased muscle tone. Thanks to this, pain decreases (breaking the vicious circle of pain-muscle spasm-pain), and the range of active movements increases. Tizanidine is used at a dose of 4-6 mg/day with a possible gradual increase to 12 mg/day. The effect appears in the first week of treatment [13]. The use of a muscle relaxant allows you to rid the muscle not only of active, but also of latent trigger points, i.e. improves long-term prognosis by reducing the recurrence of myofascial pain syndrome (MPS).

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A combination is known that contains alpha-2 receptor agonists in a concentration effective to obtain a therapeutic effect, and alpha-2 adrenergic receptor antagonists in concentrations that can effectively enhance the therapeutic effect of alpha-2 receptor agonists [14]. Conditions that require administration of such a combination may include pain, hypertension, or glaucoma. The problem of potentiating the analgesic effect of _α2- adrenergic receptor agonists and reducing their undesirable side effects is solved by combining _α2- adrenergic receptor agonists with _α2- adrenergic receptor antagonists. At the same time, mirtazapine and tizanidine are indicated in the application only as one of a large number of fundamentally possible antagonists and antagonists of _α2- adrenergic receptors, therefore this document does not lead the specialist to prefer the use of mirtazapine and tizanidine as an antagonist and agonist of _α2- adrenergic receptors, respectively , and does not give the specialist any reason to believe that by choosing mirtazapine as an _α2- adrenergic receptor antagonist and tizanidine as an _α2- adrenergic receptor agonist, a super-total (synergistic) analgesic effect can be achieved. On the contrary, the results of in vivo studies presented in this source confirm the presence of analgesic properties only in the combination of clonidine and atipemazole (example 3). The goal of this combination is to prevent side effects and tolerance to _α2 adrenergic agonist therapy, such as the sedative effect of clonidine, as well as dependence through the use of ultra-low doses of _α2 adrenergic antagonist. As preferred examples of the combination of an α ₂ -adrenergic receptor agonist and ultra-low doses of an α ₂ -adrenergic receptor antagonist, specific examples are given, including an α ₂ -adrenergic receptor antagonist and an _{α 2} -adrenergic receptor agonist, taken in a quantitative ratio of 1:1000, 1:10000, 1:100000 or 1:1000000.

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 at a ratio of 20:1-5:1 and a pharmaceutically acceptable carrier [15]. The analogue provides the creation of an effective means for the prevention and treatment of a pain disorder that is well tolerated by patients. A pharmaceutical combination is indicated in the form of a tablet containing mirtazapine 20 mg and tizanidine 1 mg (in a ratio of 20:1). However, the specified source does not disclose in what doses this combination should be taken. Within the framework of the present invention, it is unexpectedly shown that it is possible to achieve 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.

Proceeding to preclinical and clinical studies, the present inventors unexpectedly discovered that the use of a pharmaceutical combination or pharmaceutical composition comprising mirtazapine and tizanidine, or pharmaceutically acceptable salts thereof, when 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, 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 improve the quality of life in patients with persistent pain syndrome, reduction of pain and depressive states accompanying the sensation of pain. The invention also provides an expansion of the arsenal of drugs that have a combined (muscle relaxant and analgesic) effect.

The objective of the present invention is to create a drug with increased effectiveness for the treatment and/or prevention of pain disorders, including pain disorders associated with painful muscle spasms or spasticity of skeletal muscles, having a combined (muscle relaxant and analgesic) effect, an increased safety and tolerability profile .

Technical results:

synergistic effect when using mirtazapine in combination with tizanidine;

increasing safety, tolerability;

expansion of the arsenal of drugs with a combined (muscle relaxant and analgesic) effect;

improving the quality of life in patients with persistent pain syndrome. The 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 from 6 to 24 mg, in a ratio of 2.5:1, respectively.

According to preferred embodiments, this technical result is also achieved by the fact that the daily dosage of mirtazapine is from 15 to 45 mg, and of tizanidine from 6 to 18 mg;

the daily dosage of mirtazapine is from 15 to 30 mg, and tizanidine is from 6 to 12 mg;

- 3 045581 the daily dosage of mirtazapine is from 30 to 45 mg, and tizanidine is from 12 to 18 mg;

the mass ratio of mirtazapine to tizanidine is 2.5 to 1;

the daily dosage of mirtazapine is 60 mg, and tizanidine 24 mg;

the daily dosage of mirtazapine is 45 mg, and tizanidine 18 mg;

the daily dosage of mirtazapine is 30 mg, and tizanidine 12 mg;

the daily dosage of mirtazapine is 15 mg, and tizanidine 6 mg;

the pharmaceutical combination is made in the form of a solid dosage form for oral administration;

the solid dosage form for oral administration contains at least one excipient;

the solid dosage form for oral administration is a tablet;

the tablet is a two-layer tablet;

a two-layer tablet is a prolonged-release tablet;

a bilayer tablet includes a layer containing mirtazapine or a pharmaceutically acceptable salt thereof and a layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which the tizanidine is released slowly;

a layer containing tizanidine or a pharmaceutically acceptable salt thereof from which tizanidine is released in a sustained manner includes a polymeric release retarder, and the polymeric release retarder of tizanidine is a hydrophilic polymeric release retarder;

The hydrophilic polymeric tizanidine release retardant may be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, 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, hydroxypropyl methylcellulose phthalate, cellulose acetate succinate or ethylcellulose succinate;

mirtazapine is immediately released from the layer containing mirtazapine;

the tizanidine sustained release layer contains 6 mg of tizanidine and the immediate release mirtazapine layer contains 15 mg of mirtazapine;

a pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride;

a layer containing tizanidine, from which tizanidine is released slowly, further comprising a lubricant;

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.%;

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;

the mirtazapine layer contains mirtazapine, a bulking agent, a disintegrant and a lubricant;

the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt.%, a filler in an amount of 7095 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 fumart and mixtures thereof;

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

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, gum acacia and mixtures thereof in an amount of 0.5-5 wt.%;

the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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.

the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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.

The tizanidine layer was obtained by direct pressing;

the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, wt.%: mirtazapine - 1.0-35.0; mannitol - 20.0-40.0; microcrystalline cellulose - 40.0-60.0;

- 4 045581 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, wt.%: 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;

the mirtazapine layer was obtained by wet granulation;

the pain disorder is a painful muscle spasm or skeletal muscle spasticity;

painful muscle spasm is associated with static and functional diseases of the spine;

spinal diseases are cervical or lumbar syndromes;

painful muscle spasm associated with surgery;

skeletal muscle spasticity is associated with neurological disease;

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.

The stated task is also carried out, 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 with a mass ratio of mirtazapine to tizanidine in terms of free bases of 2.5 to 1 and at least one pharmaceutically acceptable a carrier intended for use in a daily dosage of mirtazapine from 15 to 60 mg, and tizanidine from 6 to 24 mg.

A pharmaceutical composition for the treatment of pain disorders comprising a combination of mirtazapine and tizanidine may include pharmaceutically acceptable excipients. The selection of specific excipients is carried out depending on the intended route of administration and dosage form, as is known to a person skilled in the art. Suitable pharmaceutical carriers, excipients and their compositions 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.

Pharmaceutically acceptable excipients may be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary and dispensing agents, delivery agents such as preservatives, stabilizers, excipients, disintegrators, humectants, emulsifiers, suspending agents, thickeners, sweeteners, flavorings, flavors, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature of the active substance, route of administration and dosage. Examples of suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid and the like. The composition may also include isotonic agents, for example sugars, sodium chloride and the like. Prolonged action of the composition can be achieved using agents that retard the absorption of the active principle, for example, such as aluminum monostearate, gelatin, cellulose derivatives or a hydrophilic polymeric release retardant, which is polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, acrylic acid polymer 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. Disintegrants 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, gum acacia and mixtures thereof. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohols, as well as mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of fillers are lactose, sucrose, glucose, sodium citrate, calcium carbonate, calcium phosphates, microcrystalline cellulose, mannitol, starch, silicic acid and the like. Examples of grinders and distributing agents are starch, alginic acid and its salts, and silicates. Examples of lubricants are magnesium stearate, calcium stearate, stearic acid, sodium lauryl sulfate, talc, as well as high molecular weight polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof. A pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of an active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard form of administration, as a mixture with traditional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

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 than one inert excipient (or carrier), 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 gum acacia; (d) humectants such as glycerin; (e) disintegrants such as agar-agar, calcium carbonate, potato, corn or tapioca starch, alginic acid, some complex silicates and sodium carbonate; (f) dissolution retardants such as paraffin or hydrophilic polymeric release retardants; (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) lubricants such as talc, calcium stearate, magnesium stearate, stearic acid, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets and pills, dosage forms may also contain buffering agents.

According to preferred embodiments, this technical result is also achieved in 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;

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

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

the daily dosage for mirtazapine is 60 mg, and tizanidine 24 mg;

the daily dosage for mirtazapine is 45 mg, and tizanidine 8 mg;

the daily dosage for mirtazapine is 30 mg, and tizanidine 2 mg;

the daily dosage for mirtazapine is 15 mg, and tizanidine 6 mg;

the mentioned composition is made in the form of a solid dosage form for oral administration;

the solid dosage form for oral administration is a tablet;

the tablet is a two-layer tablet;

a two-layer tablet is a prolonged-release tablet;

a bilayer tablet includes a layer containing mirtazapine and a layer containing tizanidine, from which tizanidine is released slowly;

the tizanidine containing layer from which the tizanidine is released in a sustained manner includes tizanidine, or a pharmaceutically acceptable salt thereof, and a polymeric release retarder, which is a hydrophilic polymeric release retarder;

a layer containing tizanidine, from which tizanidine is released slowly, further comprising a lubricant;

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.%;

the pharmaceutically acceptable salt of tizanidine is the hydrochloride;

The hydrophilic polymeric tizanidine release retardant may be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, 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, hydroxypropyl methylcellulose phthalate, cellulose acetate succinate, ethylcellulose succinate or mixtures thereof;

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;

mirtazapine is immediately released from the layer containing mirtazapine;

the mirtazapine layer contains mirtazapine, a bulking agent, a disintegrant and a lubricant;

the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt.%, a filler in an amount of 70-6045581 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;

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

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

the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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;

the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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;

the layer with tizanidine was obtained by direct pressing;

tizanidine sustained release layer contains 6 mg tizanidine;

the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, wt.%: 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, wt.%: 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;

the mirtazapine layer was obtained by wet granulation;

immediate release mirtazapine layer contains 15 mg mirtazapine;

said composition is intended for administration 1-4 times a day;

the said composition is intended for administration 1-3 times a day;

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

said composition is intended for administration 2-4 times a day;

a pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride;

the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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;

the layer with tizanidine was obtained by direct pressing;

the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, wt.%: mirtazapine (micronized) - 10.0; mannitol - 33.13; microcrystalline cellulose - 51.34; polyvinylpyrrolidone (PZO) - 1.0; crospovidone - 3.0; colloidal silicon dioxide (Aerosil 200) - 0.53; magnesium stearate - 1.0;

The mirtazapine layer was obtained by wet granulation.

the pain disorder is a painful muscle spasm or skeletal muscle spasticity;

painful muscle spasm is associated with static and functional diseases of the spine;

spinal diseases are cervical or lumbar syndromes;

painful muscle spasm associated with surgery;

skeletal muscle spasticity is associated with neurological disease;

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.

The stated task is also carried out, 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 free base per day, and tizanidine 6 to 24 mg free base per day.

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According to preferred embodiments, the specified technical result is also achieved by the fact that:

the daily dosage of mirtazapine is from 15 to 45 mg, and tizanidine is from 6 to 18 mg;

the daily dosage of mirtazapine is from 15 to 30 mg, and tizanidine is from 6 to 12 mg;

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;

the daily dosage of mirtazapine is 30 mg, and tizanidine is 12 mg;

the daily dosage of mirtazapine is 15 mg, and tizanidine is 6 mg;

the pharmaceutical combination is made in the form of a solid dosage form for oral administration;

the solid dosage form for oral administration contains at least one excipient;

the solid dosage form for oral administration is a tablet;

the tablet is a two-layer tablet;

a two-layer tablet is a prolonged-release tablet;

a bilayer tablet includes a layer containing mirtazapine and a layer containing tizanidine, from which tizanidine is released slowly;

mirtazapine is immediately released from the layer containing mirtazapine;

the tizanidine sustained release layer contains 6 mg of tizanidine and the immediate release mirtazapine layer contains 15 mg of mirtazapine;

the pharmaceutically acceptable salt of tizanidine is the hydrochloride;

a layer containing tizanidine, from which tizanidine is released slowly, further comprising a lubricant;

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.%;

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;

The mirtazapine layer contains mirtazapine, a bulking agent, a disintegrant and a lubricant.

the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt.%, a filler in an amount of 7095 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;

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

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

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

the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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;

the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt %: 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;

the layer with tizanidine was obtained by direct pressing;

the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, wt.%: 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, wt.%: 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;

the mirtazapine layer was obtained by wet granulation;

the pain disorder is a painful muscle spasm or skeletal muscle spasticity;

- 8 045581 painful muscle spasms are associated with static and functional diseases of the spine;

spinal diseases are cervical or lumbar syndromes;

painful muscle spasm associated with surgery;

skeletal muscle spasticity is associated with a neurological disease;

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.

The stated task is also carried out, and the technical result is achieved by a method for treating a pain disorder, which includes the use of the mentioned 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 - from 6 to 24 mg, or administering to a subject in need of treatment, the mentioned pharmaceutical composition for the treatment of 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 mentioned pharmaceutical combination of mirtazapine and tizanidine or their pharmaceutically acceptable salts at a mass ratio of mirtazapine to tizanidine in terms of free bases 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 day.

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, including a combination of mirtazapine and tizanidine, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier of of the present invention, in patients can be adjusted depending on the therapeutic effectiveness and bioavailability of the active ingredients in the body, the rate of their metabolism and excretion from the body, as well as depending on the age, gender and stage of the patient's disease. As directed by your doctor or pharmacist, these medications may be taken several times over a period of time (preferably one to four times).

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

Pain may be a polymorphic disorder. In accordance with the present invention, the term pain refers to all types of pain, including acute and persistent pain. Preferably, but not limited to, the term refers to chronic pain, without limitation, fibromyalgia, somatotrophic disorders, arthralgia, cancer, neck pain, shoulder pain, back pain, headache, tension headache, migraine, diabetic neuropathy, herpetic neuralgia, phantom pain in amputated limbs, pain of central origin, dental pain, visceral pain, during surgical manipulations, postoperative pain, osteogenic pain, burn pain, including sunburn, urogenital pain, including cystitis, tonsillitis.

Medicine (drug) - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of 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 and other things.

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

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

- 9 045581 salts are given in [16]). Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, whereby metal and amine salts can be synthesized. Metallic salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts. Suitable inorganic bases from which metal salts can be prepared include sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. The organic bases from which salts of the claimed acids can be obtained are amines and amino acids that are sufficiently basic to form a stable salt and suitable for use for medical purposes (in particular, they must have low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane and the like. In addition, tetraalkylammonium hydroxides, such as choline, tetramethylammonium, tetraethylammonium and the like, can be used for salt formation. The basic amino acids that can be used as amino acids are lysine, ornithine and arginine.

The term therapeutically effective amount means an amount of active substance that (1) treats or prevents a specific disease, condition or disorder, (2) reduces, improves or eliminates one or more symptoms of a specific disease, condition or disorder, or (3) prevents or delays the onset of one or more symptoms of a specific disease, condition or disorder set forth herein.

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

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

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 with a mass ratio of mirtazapine to tizanidine in terms of free bases of 2.5 to 1 and at least one pharmaceutically acceptable carrier, containing from 15 to 60 mg mirtazapine and 6 to 24 mg tizanidine.

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

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.

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.

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.

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

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

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

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

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

More preferred is a pharmaceutical composition characterized in that the pain disorder is a painful muscle spasm or skeletal muscle spasticity.

More preferred is a pharmaceutical composition characterized in that painful muscle spasm is associated with static and functional diseases of the spine.

More preferred is a pharmaceutical composition characterized in that the spinal diseases are cervical or lumbar syndromes.

More preferred is a pharmaceutical composition characterized in that the painful muscle spasm is associated with surgery.

More preferred is a pharmaceutical composition characterized in that skeletal muscle spasticity is associated with a neurological disease.

More preferred is a pharmaceutical composition 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.

Also the subject of the present invention is a pharmaceutical combination for the treatment of pain disorders, including 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 and at least one pharmaceutically acceptable carrier containing from 15 to 60 mg mirtazapine and 6 to 24 mg tizanidine.

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

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

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

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

More preferred is a pharmaceutical combination characterized in that it contains 60 mg of mirtazapine and 24 mg of tizanidine.

More preferred is a pharmaceutical combination characterized in that it contains 45 mg of mirtazapine and 18 mg of tizanidine.

More preferred is a pharmaceutical combination characterized in that it contains 30 mg of mirtazapine and 12 mg of tizanidine.

More preferred is a pharmaceutical combination characterized in that it contains 15 mg of mirtazapine and 6 mg of tizanidine.

More preferred is a pharmaceutical combination characterized in that it contains at least one excipient.

More preferred is a pharmaceutical combination characterized in that the pain disorder is a painful muscle spasm or skeletal muscle spasticity.

More preferred is a pharmaceutical combination characterized in that painful muscle spasm is associated with static and functional diseases of the spine.

More preferred is a pharmaceutical combination characterized in that the spinal diseases are cervical or lumbar syndromes.

More preferred is a pharmaceutical combination characterized in that the painful muscle spasm is associated with surgery.

More preferred is a pharmaceutical combination characterized in that skeletal muscle spasticity is associated with a neurological disease.

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 accidents and cerebral palsy.

Also, the subject of the present invention is a medicament for the treatment of pain disorders, including a pharmaceutical composition according to the present invention or a pharmaceutical combination according to the present invention and at least one excipient.

More preferred is a medicinal product characterized in that at least one excipient 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, carbioxymethyl cellulose, cellulose acetate or phthalate , hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate succinate, ethylcellulose succinate and microcrystalline cellulose, ammonium methacrylate copolymer, colloidal silicon dioxide, mannitol, sorbitol, isomalt, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid, polyvinylpyrrolidone, k rospovidone, polyvinyl alcohol, polyethylene oxide, carbomers, alginates, polymer of acrylic acid or its esters, stearic acid and its salts, such as calcium and magnesium stearate, talc, sodium stearyl fumarate.

More preferably, a drug is characterized in 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.

More preferable is a drug characterized in 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.

More preferable is a drug 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

- 11 045581 tizanidine is from 12 to 24 mg.

More preferably, a drug is characterized in that the daily dosage for mirtazapine is 60 mg and the daily dosage for tizanidine is 24 mg.

More preferably, a drug is characterized in that the daily dosage for mirtazapine is 45 mg and the daily dosage for tizanidine is 18 mg.

More preferably, a drug is characterized in that the daily dosage for the use of mirtazapine is 30 mg, and the daily dosage for the use of tizanidine is 12 mg.

More preferably, a drug is characterized in that the daily dosage for mirtazapine is 15 mg and the daily dosage for tizanidine is 6 mg.

More preferred is a medicinal product characterized in that it is in the form of a solid dosage form for oral administration.

More preferable is a drug characterized in that the solid dosage form for oral administration is a tablet.

More preferable is a drug characterized in that the tablet is a two-layer tablet.

More preferable is a drug characterized in that the tablet is a sustained release tablet.

More preferred is a drug characterized in that the bilayer tablet includes a layer containing mirtazapine and a layer containing tizanidine, from which the tizanidine is released slowly.

More preferably, the drug is characterized in that the tizanidine containing layer from which the tizanidine is sustained released includes tizanidine, or a pharmaceutically acceptable salt thereof, an excipient, a disintegrant and a polymeric release retardant, which is a hydrophilic polymeric release retarder.

More preferred is a drug characterized in that the tizanidine-containing layer from which the tizanidine is released slowly further includes a lubricant.

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.%.

More preferred is a drug characterized in that the hydrophilic polymeric tizanidine release retardant may be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, 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.

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

More preferred is a drug characterized in that mirtazapine is immediately released from the mirtazapine-containing layer

More preferred is a drug characterized in that the mirtazapine layer contains mirtazapine, an excipient, a disintegrant and a lubricant.

More preferred is a medicinal product characterized in that the mirtazapine layer 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.%.

More preferred is a drug 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.

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

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 preferable is a medicinal product characterized in that it additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, gum acacia and mixtures thereof in an amount of 0.5-5 wt.%,

More preferable is a medicinal product characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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.

More preferable is a medicinal product characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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.

More preferable is a drug characterized in that the tizanidine layer is obtained by direct compression.

More preferred is a drug characterized in that the tizanidine sustained release layer contains 6 mg of tizanidine.

More preferable is a medicinal product characterized in that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, wt.%: 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.

More preferable is a medicinal product characterized in that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, wt.%: 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.

More preferable is a drug characterized in that the mirtazapine layer is obtained by wet granulation.

More preferred is a drug characterized in that the immediate release mirtazapine layer contains 15 mg of mirtazapine.

More preferred is a drug characterized in that the pain disorder is a painful muscle spasm or skeletal muscle spasticity.

More preferred is a drug characterized in that painful muscle spasm is associated with static and functional diseases of the spine.

More preferable is a drug characterized in that the spinal diseases are cervical or lumbar syndromes.

More preferred is a drug characterized in that the painful muscle spasm is associated with surgery.

More preferred is a drug characterized in that skeletal muscle spasticity is associated with a neurological disease.

More preferred is a medicinal product 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 accidents and cerebral palsy.

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 , with a ratio of 2.5 to 1.

More preferred is the use characterized in that the daily dosage of mirtazapine is from 15 to 45 mg, and tizanidine from 6 to 18 mg.

More preferred is the use characterized in that the daily dosage of mirtazapine is from 15 to 30 mg, and tizanidine from 6 to 12 mg.

More preferred is the use characterized in that the daily dosage of mirtazapine is from 30 to 45 mg, and tizanidine from 12 to 18 mg.

A more preferred use is that the daily dosage of mirtazapine is 60 mg and tizanidine is 24 mg.

A more preferred use is that the daily dosage of mirtazapine is 45 mg and tizanidine is 18 mg.

A more preferred use is that the daily dosage of mirtazapine is 30 mg and tizanidine is 12 mg.

- 13 045581

A more preferred use is that the daily dosage of mirtazapine is 15 mg and tizanidine is 6 mg.

More preferred is a use wherein the pain disorder is a painful muscle spasm or skeletal muscle spasticity.

More preferred is an application characterized by the fact that painful muscle spasm is associated with static and functional diseases of the spine.

More preferred is an application characterized in that the spinal diseases are cervical or lumbar syndromes.

More preferred is an application characterized in that the painful muscle spasm is associated with surgery.

More preferred is an application characterized in that skeletal muscle spasticity is associated with a neurological disease.

More preferred is an application 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 accidents and cerebral palsy.

More preferred is a use characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-4 times a day.

More preferred is a use characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-3 times a day.

More preferred is a use characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-2 times a day.

More preferred is a use characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 2-4 times a day.

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

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

More preferably, the use is characterized in that the solid dosage form for oral administration is a tablet.

More preferred is an application characterized in that the tablet is a two-layer tablet.

More preferred is a use characterized in that the bilayer tablet is a sustained release tablet.

More preferred is a use characterized in that the bilayer tablet includes a layer containing mirtazapine or a pharmaceutically acceptable salt thereof and a layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which the tizanidine is released in a sustained manner.

More preferably, the application is characterized in that the layer containing tizanidine or a pharmaceutically acceptable salt thereof from which tizanidine is released in a sustained manner includes a polymeric release retarder, and the polymeric release retarder of tizanidine is a hydrophilic polymeric release retarder.

More preferably, the hydrophilic polymeric tizanidine release retardant may be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, 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.

More preferred is a use characterized in that the mirtazapine is immediately released from the mirtazapine-containing layer.

More preferably, the tizanidine sustained release layer contains 6 mg of tizanidine and the immediate release mirtazapine layer contains 15 mg of mirtazapine.

More preferred is the use wherein the pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride.

More preferred is the application, characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%:

- 14 045581 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.

More preferred is an application characterized in that the tizanidine layer is obtained by direct compression.

More preferable is the application, characterized in that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, wt.%: 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.

More preferred is an application characterized in that the mirtazapine layer is obtained by wet granulation.

Also subject to the present invention is a method for treating a pain disorder, characterized in that it includes 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 drug according to the present invention.

More preferably, a treatment method is characterized in that the pain disorder is a painful muscle spasm or skeletal muscle spasticity.

More preferable is a treatment method characterized by the fact that painful muscle spasm is associated with static and functional diseases of the spine.

More preferable is a treatment method characterized in that the spinal diseases are cervical or lumbar syndromes.

More preferably, a treatment method is characterized in that the painful muscle spasm is associated with surgery.

More preferably, a method of treatment is characterized in that skeletal muscle spasticity is associated with a neurological disease.

More preferred is a method of treatment 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.

More preferred is a method of treatment, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-4 times a day.

More preferred is a method of treatment, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-3 times a day.

More preferred is a method of treatment, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-2 times a day.

More preferred is a method of treatment, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 2-4 times a day.

More preferred is a treatment method characterized in that said medicinal product is in the form of a solid dosage form for oral administration.

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

More preferred is a treatment method characterized in that the solid dosage form for oral administration is a tablet.

More preferable is a treatment method characterized in that the tablet is a two-layer tablet.

More preferred is a method of treatment characterized in that the two-layer tablet is a sustained-release tablet.

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

More preferably, a treatment method is characterized in that the layer containing tizanidine or a pharmaceutically acceptable salt thereof from which tizanidine is released in a sustained manner includes a polymeric release retarder, and the polymeric release retarder of tizanidine is a hydrophilic polymeric release retarder.

More preferably, the treatment method is characterized in that the hydrophilic polymeric tizanidine release retardant may be polyvinyl alcohol,

- 15 045581 polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, 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, hydroxypropyl methylcellulose phthalate, cellulose acetate succinate, or ethylcellulose succinate.

More preferred is a treatment method characterized in that mirtazapine is immediately released from the mirtazapine-containing layer.

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.

More preferred is a treatment method wherein the pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride.

More preferable is a treatment method characterized by the fact that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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.

More preferable is a treatment method characterized in that the tizanidine layer is obtained by direct compression.

More preferable is a treatment method characterized by the fact that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, wt.%: 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.

More preferable is a treatment method characterized in that the mirtazapine layer is obtained by wet granulation.

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

Example 1. Evaluation of the effectiveness of the combination of mirtazapine and tizanidine for the treatment of pain associated with static and functional diseases of the spine

To evaluate the effectiveness of drugs for the treatment of pain 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].

Rats: 98 adult male Sprague-Dawley rats weighing 250-330 grams were used in the experiments. Rats were housed in groups of five in temperature-controlled cages (average temperature 21°C) on a 12-hour light/dark cycle and with sufficient water and food.

Description of the model: 10 days after the operation of nerve transection in rats, during which a functional or static disease of the spine was simulated against the background of a pain syndrome, the effectiveness of taking the tested drugs for the treatment of this pain syndrome was studied in rats.

Surgery:

Rats were anesthetized with isoflurane (Sigma, USA). The skin on the lateral thigh of the rat was incised and a further incision was made on the biceps femoris muscle to expose the sciatic nerve and its three terminal branches: the gastrocnemius, common peroneal and tibial nerves. Only the tibial and common peroneal nerves were axotomized and ligated, while the sural nerve remained intact. These nerves were ligated with silk threads and cut distal to the ligation site, leaving a nerve stump measuring 2±4 mm. The muscles and skin were sutured separately.

Formation of study groups: rats were randomly distributed into 14 equal groups (7 animals each), differing in the type of drug administered and its dosage.

Drugs Administered and Doses: The study was conducted on 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 after 10 days after surgery and 30 minutes before behavioral tests in the indicated doses and combinations:

Mirtazapine: 15 mg/day (group No. 1), 30 mg/day (group No. 2), 45 mg/day (group No. 3), 60 mg/day (group No. 4);

Tizanidine: 6 mg/day (group No. 5), 12 mg/day (group No. 6), 18 mg/day (group No. 7), 24 mg/day (group No. 8);

Mirtazapine + tizanidine in a ratio of 2.5:1 according to the present invention: mirtazapine, 15 mg/day + tizanidine, 6 mg/day (group No. 9), mirtazapine, 30 mg/day + tizanidine, 12 mg/day (group No. 10 ), mirtazapine, 45 mg/day + tizanidine, 18 mg/day (group No. 11), mirtazapine, 60 mg/day tizanidine, 24 mg/day (group No. 12);

Mirtazapine + tizanidine in a 5:1 ratio (closest analogue): mirtazapine, 30 mg/day + tizanidine, 6 mg/day (group No. 13).

The control group was a group of rats receiving only vehicle (group No. 14, placebo). All doses are given per person.

Behavioral tests:

The severity of pain in different groups of animals was assessed using two tests that recorded the development of cold or mechanical allodynia. Animals were tested on day 10 after surgery, 30 minutes after administration of the study drugs.

Mechanical allodynia

Animals were placed in an acrylic chamber (15x15x15 cm) raised above the ground with a wire mesh at the bottom. Before testing, the animals were left in the chamber for 5-10 minutes to adapt. Next, the plantar surface of the animal’s paw was stimulated with calibrated von Frey filaments (or threads) (BIOSEB, USA). The filaments were a set of 10 standard plastic threads, increasing in diameter. The stiffness of the threads, expressed as the minimum force required to bend the hair, increased with such calibration logarithmically with absolute values from 0.6 to 26 g. For each rat, the sensitivity threshold was determined in turn on each paw in three repetitions (a total of 6 applications with an interval of 10 s for each filament; the interval between successive application of different filaments was 2 min). The tip of the thread was touched to the middle of the plantar surface of the paw with the force necessary 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 touch. The sensitivity threshold was determined by the minimum pressure that causes a reflex reaction of withdrawing the paw (4 times out of 6 applications).

Cold allodynia

To evaluate cold allodynia, a special test chamber with a hot/cold plate (Ugo Basile, Italy) was used in this study. The test was carried out in a chamber with acrylic walls 30 cm high on a metal plate measuring 30x30 cm cooled to 0°C. Healthy animals are able to withstand this temperature for a long time, resting all limbs on a cooled floor, whereas in case of nerve damage, the time of contact of the limb with the cold plate is significantly reduced. To quantify this parameter, the time the limb was held on weight was recorded during the 1 minute stay of the animal in the test chamber. The test was performed on the 10th day after surgery; each animal was tested three times with an interval of 5 min between measurements; the obtained values were averaged. The resulting values were used to calculate the mean score obtained on 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.

Results: the results obtained are shown in table. 1 below.

Table 1. Effect of mirtazapine and tizanidine, used individually or in combination, on the behavior of rats with pain syndrome simulating static and functional diseases of the spine

A drug Dose, mg/day Group no. pronounced mechanical allodynia, g (mean ± standard error of the mean) pronounced cold allodynia, sec (average + standard error of the mean) carrier - 14, placebo 2.5+0.3 6.1+0.3 Mirtazap in 15 1 7.8+0.4 10.9+0.5 thirty 2 8.1+0.3 11.2+0.7 45 3 8.9+0.3 12.1+0.6 60 4 9.6+0.4 12.9+0.7 tizanidi n 6 5 10.4+0.3 13.3+0.5 12 6 11.2+0.4 14.6+0.7 18 7 12.3+0.5 15.2+0.8

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24 8 13.6+0.5 16.1+0.7 mirtazap in + tizanidine (in a ratio of 2.5: 1) 15+6 9* 21.2+0.6 27.6+0.7 30+1 2 10* 23.9+0.6 28.9+0.8 45+1 8 eleven* 25.2+0.5 30.7+0.8 60+2 4 12* 27.1+0.5 31.8+0.6 closest analogue (mirtazapine + tizanidine in ratio 5: 1) 30+6 13 19.7+0.5 26.5+0.6

* significant 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).

Conclusion:

In groups receiving a combination of mirtazapine and tizanidine according to the present invention in a ratio of 2.5:1, the indicators of mechanical and cold allodynia were significantly reduced, which indicates the effectiveness of their use for the treatment of functional and static diseases of the spine. But in addition to this, a synergistic effect of this combination was also discovered in all tested doses, which was statistically significantly superior to the therapeutic effect of the closest analogue. Moreover, as follows from the table, the effect of the closest analogue is an additive effect of mirtazapine and tizanidine in similar dosages.

Example 2. Evaluation of the effectiveness of the combination of mirtazapine and tizanidine for the treatment of pain after injury and surgery

Testing the effectiveness of drugs for the treatment of pain after injury and surgery (for example, for a herniated disc 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, made through the skin, fascia and muscles [20 -21].

Rats: 98 adult male Sprague-Dawley rats weighing 250-300 g were used in the experiments. Rats were kept in groups of five in temperature-controlled boxes (with an average temperature of 21°C) with a 12-hour day-dark cycle and sufficient amount of water and food.

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

Surgery:

Rats were anesthetized with isoflurane (Sigma, USA). The plantar part of the hind paw was treated with a 10% povidone-iodine solution. Next, a 1 cm longitudinal incision was made using a blade through the skin and fascia, starting 0.5 cm below the proximal end of the heel in the direction of the toes. The plantaris muscle was elevated and also cut longitudinally. The muscle attachment sites remained intact. Two mattress sutures were placed on the wound using nylon threads and a needle. The wound was treated with a mixture of antibiotics. After the operation, the animals recovered in their cages. Sutures were removed under anesthesia approximately 30 hours after surgery. The wounds healed, as a rule, after 5-6 days.

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

Drugs administered and dosages: The study was conducted on 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 after 3 days after surgery and 30 minutes before behavioral tests in the indicated doses and combinations according to example 1. The control group was a group of rats receiving only the vehicle (group No. 14, placebo). All doses are given per person.

Behavioral tests: to assess pain behavior, the von Frey filament test was used (the occurrence of mechanical allodynia). 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.

The results are shown in table. 2 below.

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Table 2. Effect of mirtazapine and tizanidine, used alone or in combination, on the behavior of rats with pain after surgery

A drug Dose, mg/day Group No. severity of mechanical allodynia, grams (mean ± standard error of the mean) carrier - 14, placebo 4.8+0.2 mirtazapine 15 1 9.2+0.6 thirty 2 10.6+0.4 45 3 11.4+0.5 60 4 12.6±0.3 tizanidine 6 5 11.2+0.6 12 6 12.3+0.5 18 7 13.2+0.4 24 8 14.4+0.6 mirtazapine + tizanidine (in ratio 2.5:1) 15+6 9* 23.3+0.7 30+12 10* 24.9+0.6 45+18 eleven* 26.7+0.7 60+24 12* 29.1+0.7 nearest analogue (mirtazapine + 30+6 13 22.4+0.6 tizanidine in ratio 5:1)

* significant 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 in rats (significance level p < 0.05).

Conclusions:

In groups receiving a combination of mirtazapine and tizanidine, the rate of mechanical allodynia was significantly reduced, indicating the effectiveness of their use for the treatment of pain after surgery. The experiment also revealed a synergistic effect of the combination of mirtazapine and tizanidine, which is statistically significantly superior to the therapeutic effect of the closest analogue. Moreover, as follows from the table, the effect of the closest analogue is an additive effect of mirtazapine and tizanidine in similar dosages.

Example 3. Evaluation of the effectiveness of the combination of mirtazapine and tizanidine for the treatment of skeletal muscle spasticity in neurological diseases

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 rat sacral spinal cord transection model (formation of tail muscle spasticity) [22-24].

Rats: 98 adult male Sprague-Dawley rats weighing 250-330 g were used in the experiments. Rats were kept in groups of five in temperature-controlled boxes (with an average temperature of 21°C) with a 12-hour day-dark cycle and adequate amount of water and food.

Description of the model: on the 15th day after surgery to transect the sacral spinal cord, tail spasticity was assessed in awake animals during electrical stimulation.

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

Drugs Administered and Doses: The study was conducted on 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 was a group of rats receiving only the vehicle (group No. 14, placebo). All doses are given per person.

Surgical operation: experimental transection of the sacral spinal cord was performed at the S2 level under anesthesia (isoflurane, Sigma, USA) under sterile conditions [22-24]. Briefly, the soft tissue was cut on the dorsal side of the spine and a laminectomy was performed at the L2 level.

- 19 045581 lumbar vertebra. A hook selected to size was placed under the spinal cord, which was completely cut with scissors, avoiding damage to the veins and arteries. Layers of soft tissue were tightly sutured to the spinal cord.

Tail spasticity assessment: Rats were placed in a plexiglass cylinder with the tail protruding and free to move in a vertical direction. The tail was stimulated manually as follows: the base of the tail was pinched with the left hand, and with the right hand, holding the tail between the thumb and forefinger, quickly moved along the tail from the base to the tip, tightly fitting it, and releasing the tail at the end of the movement. The procedure was repeated three times. This achieved longitudinal straightening of the tail. The response to such stimulation was to curl the tail and move it under the rat's body (or dorsally in rats with more severe injuries). The scale described below was used to assess tail spasticity.

Score 0-1: very slight or insignificant curling of the tail tip in response to stretch (less than 90°, lasting only a few seconds), little or no muscle tone, no clonus, no response to light touch of skin or fur.

2-3 points: strong spasm (flexion) of the tail in response to stretching stimulation, the tip is bent at an angle of 180-360°, lasting 3-10 seconds. Repeated curling and clonus of the tail lasting more than 10 minutes, hypertonicity, high sensitivity to light touch.

4-5 points: Similar to the previous score, but more repeated bending and flexing of the tail, resulting in the tail often taking on an S-shape, with the proximal portion of the tail curling under the rat and the distal portion in the opposite direction; more pronounced clonus, hypertonicity and side-to-side movements.

For each rat, a score was given on the tail spasticity scale, which was then averaged within one group. Differences between groups were considered statistically significant at a significance level of p<0.05.

Results: the results obtained are shown in table. 3 below.

Table 3. Effects of mirtazapine and tizanidine, given alone or in combination, on the behavior of rats experiencing pain due to skeletal muscle spasticity

A drug Dose, mg/day Group No. Average spasticity score + standard error of the mean carrier - 14, placebo 4.8+0.2 mirtazapine 15 1 3.4+0.2 thirty 2 3.1+0.3 45 3 2.8+0.2 60 4 2.4+0.2 tizanidine 6 5 2.5+0.1 12 6 2.2+0.2 18 7 1.9+0.1 24 8 1.6+0.1 15+6 9* 1.0+0.1* Mirtazapine + tizanidine (in a ratio of 2.5: 1) 30+12 10* 0.9+0.2* 45+18 eleven* 0.8+0.2* 60+24 12* 0.7+0.1* nearest analogue (mirtazapine + tizanidine in ratio 5:1) 30+6 13 1.3+0.1

* significant 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).

Conclusions:

The degree of tail spasticity in animals receiving a combination of mirtazapine and tizanidine was least pronounced, indicating the possibility of using this combination for

- 20 045581 treatment of spasticity of skeletal muscles in neurological diseases. The experiment also revealed a synergistic effect of the combination of mirtazapine and tizanidine, which is statistically significantly superior to the therapeutic effect of the closest analogue. Moreover, as follows from the table, the effect of the closest analogue is an additive effect of mirtazapine and tizanidine in similar dosages.

Example 4 Preparation of an immediate release layer containing mirtazapine. Preliminary testing has shown that the best results can be obtained using the wet granulation technique

The samples were manufactured according to the following steps:

Weigh and calibrate mirtazapine and excipients through sieves;

Mix mirtazapine, mannitol and microcrystalline cellulose;

Granulate using polyvinylpyrrolidone K30 (PVP K30);

The granulate is mixed with crospovidone, silica and vegetable magnesium stearate.

During the preparation of the granulate, good results were obtained in batch 2 (Table 4).

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

Components, mg/layer The consignment 1 2 Mirtazapine (micronized) 15.00 15.00 Mannitol 50.00 49.70 Microcrystalline cellulose (PH 101) 77.50 77.00 Polyvinylpyrrolidone (PVP) 0.70 1.50 Crospovidone 4.50 4.50 Silicon dioxide colloidal (Aerosil 200) 0.80 0.80 Vegetable magnesium stearate 1.50 1.50 Total 150 150

Example 5 Preparation of Sustained Release Layer Containing Tizanidine

To obtain a long-acting (once daily) formulation of tizanidine, several release control agents were tested at various concentrations. Three different batches of tizanidine 6 mg tablets were prepared in the form of three different compositions shown in Table. 5.

Hydroxypropyl methylcellulose and ethylcellulose were used as release control agents in hydrophilic matrix systems (hydrophilic polymer release retardant). Kollidon (a spray-dried mixture of polyvinyl acetate and polyvinylpyrrolidone polymers in a ratio of 8:2) and ammonium methacrylate copolymers.

Hydroxypropyl methylcellulose (HPMC) is very often used for controlled release formulations. In this case, the K1OOM brand was used. High molecular weight HPMCs are highly versatile release modulators that are nonionic polymers and work well with soluble and insoluble drugs at high and low dosage levels.

The production process was identical for all batches and consisted of the following steps.

First, the starting materials were sieved through a stainless steel sieve with a mesh size of 0.610 mm and mixed manually for 5 min without adding stearic acid. After premixing, stearic acid was added to the mixture and mixed by hand for 5 min. Tablets were produced on a rotary tablet press.

All tablets were manufactured with the same weight (180 mg + 5%) and the same strength (15 ± 3 kgf) to evaluate the effect of the polymer on drug release: with the same surface area exposed to the environment dissolution, the release profiles are influenced solely by different polymer concentrations and the formation of the matrix itself.

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Table 5. Qualitative and quantitative composition of mixtures for the tizanidine layer

Components, mg/layer The consignment 1 2 3 Tizanidine hydrochloride 6.86 6.86 6.86 Stearic acid 2.00 2.00 2.00 Hydroxypropyl methylcellulose (K100M) 0 75.0 0 75.0 0 70.0 Ethylcellulose - 0 95.0 - Polyvinyl acetate/polyvinylpyrrolido n (Kollidon SR) 0 95.0 - - Ammonium methacrylate copolymer, type A (Eudragit RL) - - 0 40.0 Ammonium methacrylate copolymer, type B (Eudragit RS) - - 0 60.0 Colloidal silicon dioxide (Aerosil 200) 1.14 1.14 1.14 Total 180 180 180

However, the authors were unable to achieve acceptable release characteristics and technological parameters of the mixture when using hydrophobic release retarders.

The results demonstrated that it was possible to use hydrophilic polymeric release retardants to formulate a tizanidine sustained release layer, with a mixture of ammonium methacrylate and HPMC copolymers having the most effective drug release retardant properties (Lot 3).

Example 6. Preparation of a two-layer tablet containing mirtazapine and tizanidine in effective amounts

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

Batch 2 showed good processing properties, for this reason 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).

The purpose of this work is to obtain a combined oral dosage form in the form of a 330 mg bilayer tablet containing two selected active ingredients and formulated as follows:

150 mg immediate release layer containing 15 mg mirtazapine;

180 mg sustained release layer containing 6 mg tizanidine.

The development of the bilayer tablet was based on the results obtained in Examples 4 and 5.

Double-layer tablets were prepared using a rotary tablet press equipped with ten 9 mm diameter flat punches. The final composition is presented in table. 6. Technological characteristics of a two-layer tablet are given in table. 7.

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Table 6. Qualitative and quantitative composition of the layers of a two-layer tablet

Components Weight, mg/layer Mass ratio, % Immediate Release Layer Composition Mirtazapine (micronized) 15.00 10.00 Mannitol 49.70 33.13 Microcrystalline cellulose (PH 101) 77.00 51.34 Polyvinylpyrrolidone (PVP) 1.50 1.00 Crospovidone 4.50 3.00 Colloidal silicon dioxide (Aerosil 200) 0.80 0.53 Vegetable magnesium stearate 1.50 1.0 Total per layer: 150 100 Composition of the sustained release layer Tizanidine hydrochloride 6.86 3.81 Stearic acid 2.00 1.11 G hydroxypropyl methylcellulose (K100M) 70.00 40.28 Ammonium methacrylate copolymer, type A (Eudragit RL) 40.00 20,835 Ammonium methacrylate copolymer, type B (Eudragit RS) 60.00 33.33 Colloidal silicon dioxide (Aerosil 200) Total per layer: 1.14 180 0.635 100

Table 7. Technological characteristics of a two-layer tablet

Characteristic TFR15012 Average weight, mg 333.0 ± 1.9 Thickness, mm 4.792 + 0.0091 Hardness, kgf 9.31+0.33 Abrasion, % 0.27

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

The spinal nerve ligation (SNL) model of neuropathic pain has been widely used for various research works on the mechanisms of neuropathic pain as well as screening tests for the development of new analgesic drugs. Ligation is performed by tightly ligating one (L5) or two (L5 and L6) segmental spinal nerves in the rat. Surgery results in long-term behavioral symptoms of mechanical allodynia, heat hyperalgesia, cold allodynia, and persistent pain [25].

Adult Sprague-Dawley rats weighing 250-300 grams were used in the experiments. Rats were housed in temperature-controlled boxes (temperature 21°C) with a 12-hour light/dark cycle and adequate amounts of water and food.

Fifty Sprague-Dawley rats were randomly assigned to five equal groups (N=10) differing in the type of drug administered: vehicle (placebo), mirtazapine 15 mg, tizanidine 6 mg, mirtazapine + tizanidine according to the present invention, extended-release tablets , 15 mg + 6 mg (in a ratio of 2.5: 1), and the reference 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 a day throughout the study. All doses are given in terms of per person.

Animals were anesthetized with an intraperitoneal injection of sodium pentobarbital and their dorsal hair was clipped. Each animal was then placed on the surgical platform in a supine position while

- 23 045581 limbs were fixed with adhesive tape. Under sterile conditions, an incision (about 3 cm in length and 5 mm on each side of the midline) was made at the lower lumbar and sacral levels (from the caudal part of the L5 vertebra to the first sacral vertebra). The location of the incision is determined by the position of the vertebra

L5, which is located at the level of the rostral end of the iliac crest. Using small, blunt-tipped scissors, the paraspinal muscles were isolated and removed from the L5 vertebral level to the sacrum.

To assess pain behavior, the von Frey filament test (the occurrence of mechanical allodynia) was used on the 1st, 5th, 10th and 15th day after surgery. For each rat, the sensitivity threshold was determined in turn on each paw in three repetitions (a total of 6 applications with an interval of 10 seconds for each filament; the interval between successive applications of different filaments was 2 minutes). The tip of the thread was touched to the middle of the plantar surface of the paw with the force necessary 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 touch. The sensitivity threshold was determined by the minimum pressure that causes a reflex reaction of withdrawing the paw (4 times out of 6 applications).

For each study group (n=10), the mean score obtained on 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.

The results obtained are shown in table. 8 below.

Table 8. Effect of the drug mirtazapine + tizanidine, extended-release tablets, 15 mg + 6 mg (ratio 2.5:1) on the behavior of rats with pain syndrome caused by

spinal nerve ligation T Preparation Before per, mg/day Severity of mechanical allodynia, grams (mean ± standard error of the mean), per day 1st 5th 10th 15th carrier - 2 2.0+0, 3 2.5+0, 4 2.8+0, 3 3.9+0, pin myrtaza 15 2 7.0+0, 4 8.0+0, 5 9.3+0, 0.4 11.4+ in tizanide 6 0.3 10.2+ 0.5 11.4+ 0.3 13.7+ 0.5 16.2+ mirtaza pin + tizanidine (in a ratio of 2.5: 1) + 6* 15 0.5 19.5+ 0.5 21.8+ 0.4 25.6+ 0.3 30.2+ closest analogue (mirtazapine + tizanidine in a ratio of 5: 1) + 6 thirty 0.5 18.3± 0.6 20.7± 0.4 24.5± 0.4 29.1±

* significant 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).

In the group receiving the combination of mirtazapine and tizanidine 15 mg + 6 mg (in a ratio of 2.5:1), mechanical allodynia was significantly reduced, indicating the effectiveness of their use for pain caused by spinal nerve ligation (post-stroke chronic pain model). The experiment also revealed a synergistic effect of the combination of mirtazapine and tizanidine, which is statistically significantly superior to the therapeutic effect of the closest analogue. Moreover, as follows from the table, the effect of the closest analogue is an additive effect of mirtazapine and tizanidine in similar dosages.

Example 8 Acute Toxicity Studies

Acute toxicity studies of the drug mirtazapine + tizanidine, extended-release tablets, 15 mg + 6 mg, were carried out in comparison with single drugs tizanidine, modified-release capsules, 6 mg and mirtazapine, film-coated tablets, 30 mg, in out-24 045581 deliriums rats of both sexes with intragastric administration (fractional daily administration).

According to the toxicometry data, the average lethal doses for the studied drugs (LD ₅₀ ), mg/kg were established:

mirtazapine 324.0;

tizanidine 230.9;

mirtazapine + tizanidine, 15 + 6 mg 465.3.

Phinney's additivity equation was used to determine the nature of the interaction using acute toxicity parameters of a fixed combination [26].

The hypothetical mean lethal dose (LD ₅₀ hyp) for the combination drug (calculated based on the assumption of additive interaction of the components) was:

1/LD50 hyp = 6/ (21*324.0) + 15 /(21*230.9) = 0.003975, respectively

LD ₅₀ gip = 251.5 mg/kg (based on the sum of active ingredients).

The ratio of the hypothetical (calculated) LD ₅₀ hyp to the experimentally obtained LD ₅₀ combination was: 251.5/465.3 = 0.54

The principle of additivity is used in general toxicology as the initial hypothesis of 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 the interaction using the acute toxicity parameters of fixed combinations according to Phinney [26].

Depending on the ratio of the hypothetical _LD50 value of the combination, calculated on the basis of the LD50 of the individual components, and the actual, experimentally determined LD50 value of the combination, one of three conclusions is drawn:

1) No toxicological interaction.

The ratio of LD ₅₀ (hyp)/LD ₅₀ (actual) is equal to or close to 1. The toxicity of the components in combination can be additive, i.e. consistent with the primary hypothesis of additive synergy.

2) Toxicological interaction according to the type of antagonism.

The ratio LD50(hyp)/LD50(fact) is equal to or less than 0.57, i.e. it is possible to reduce the toxicity of the components in combination.

3) Toxicological interaction according to the type of potentiation.

The ratio of LD ₅₀ (hyp)/LD ₅₀ (actual) is equal to or more than 1.75, i.e. it is possible to increase the toxicity of the components in combination.

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

In terms of acute toxicity, the tested drug, as well as the reference drugs, can be classified as class 3 moderately toxic substances according to the Hodge and Sterner classification [27] and class III moderately hazardous compounds according to GOST 12.1.007-76 [28].

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

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Claims (101)

1. A pharmaceutical composition for the treatment of pain disorders, including 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 and at least one pharmaceutically acceptable carrier, containing from 15 to 60 mg of mirtazapine and 6 to 24 mg tizanidine. 2. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable salt of tizanidine is a hydrochloride. 3. Pharmaceutical composition according to claims 1, 2, characterized in that it contains from 15 to 45 mg of mirtazapine and from 6 to 18 mg of tizanidine. 4. Pharmaceutical composition according to claims 1-3, characterized in that it contains from 15 to 30 mg of mirtazapine and from 6 to 12 mg of tizanidine. 5. Pharmaceutical composition according to claims 1-3, characterized in that it contains from 30 to 45 mg of mirtazapine and from 12 to 18 mg of tizanidine. 6. Pharmaceutical composition according to claims 1, 2, characterized in that it contains 60 mg of mirtazapine and 24 mg of tizanidine. 7. Pharmaceutical composition according to claims 1, 2, characterized in that it contains 45 mg of mirtazapine and 18 mg of tizanidine. 8. Pharmaceutical composition according to claims 1, 2, characterized in that it contains 30 mg of mirtazapine and 12 mg of tizanidine. 9. Pharmaceutical composition according to claims 1, 2, characterized in that it contains 15 mg of mirtazapine and 6 mg of tizanidine. - 26 045581 10. Pharmaceutical composition according to claims 1 to 9, characterized in that it contains at least one excipient. 11. Pharmaceutical composition according to claims 1 to 10, characterized in that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles. 12. Pharmaceutical composition according to claim 11, characterized in that painful muscle spasm is associated with static and functional diseases of the spine. 13. Pharmaceutical composition according to claim 12, characterized in that the spinal diseases are cervical or lumbar syndromes. 14. Pharmaceutical composition according to claims 11, 12, characterized in that the painful muscle spasm is associated with surgical intervention. 15. The pharmaceutical composition according to claim 11, characterized in that skeletal muscle spasticity 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 accidents and cerebral palsy. 17. Pharmaceutical combination for the treatment of pain disorders, including 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 and at least one pharmaceutically acceptable carrier, containing from 15 to 60 mg of mirtazapine and 6 to 24 mg tizanidine. 18. The pharmaceutical combination according to claim 17, characterized in that the pharmaceutically acceptable salt of tizanidine is a hydrochloride. 19. Pharmaceutical combination according to claims 17, 18, characterized in that it contains from 15 to 45 mg of mirtazapine and from 6 to 18 mg of tizanidine. 20. Pharmaceutical combination according to claims 17-19, characterized in that it contains from 15 to 30 mg of mirtazapine and from 6 to 12 mg of tizanidine. 21. Pharmaceutical combination according to claims 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 claims 17, 18, characterized in that it contains 60 mg of mirtazapine and 24 mg of tizanidine. 23. Pharmaceutical combination according to claims 17, - 18, characterized in that it contains 45 mg of mirtazapine and 18 mg of tizanidine. 24. Pharmaceutical combination according to claims 17-18, characterized in that it contains 30 mg of mirtazapine and 12 mg of tizanidine. 25. Pharmaceutical combination according to claims 17-18, characterized in that it contains 15 mg of mirtazapine and 6 mg of tizanidine. 26. Pharmaceutical combination according to claims 17-25, characterized in that it contains at least one excipient. 27. Pharmaceutical combination according to claims 17 to 26, characterized in that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles. 28. Pharmaceutical combination according to claim 27, characterized in that painful muscle spasm is associated with static and functional diseases of the spine. 29. The pharmaceutical combination according to claim 28, characterized in that the spinal diseases are cervical or lumbar syndromes. 30. Pharmaceutical combination according to claims 27-29, characterized in that painful muscle spasm is associated with surgery. 31. The pharmaceutical combination according to claim 27, characterized in that skeletal muscle spasticity 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 accidents and cerebral palsy. 33. A medicinal product for the treatment of pain disorders, comprising a pharmaceutical composition according to claims 1-16 or a pharmaceutical combination according to claims 17-32 and at least one excipient. 34. The medicinal product according to claim 33, characterized in that at least one excipient is selected from the group consisting of cellulose derivatives or mixtures thereof, such as methyl-, ethyl- or propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylethylcellulose, carbioxymethylcellulose, celluloses acetate or phthalate, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate succinate, ethylcellulose succinate and microcrystalline cellulose, ammonium methacrylate copolymer, colloidal silica, mannitol, sorbitol, isomalt, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose - 27 045581 zy, silicic acid, polyvinylpyrrolidone, crospovidone, polyvinyl alcohol, polyethylene oxide, carbomers, alginates, polymer of acrylic acid or its esters, stearic acid and its salts, such as calcium and magnesium stearate, talc, sodium stearyl fumarate. 35. The medicinal product according to claims 33, 34, characterized in 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. 36. The medicinal product according to claims 33-35, characterized in 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. 37. The medicinal product according to claims 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 claims 33, 37, characterized in that the daily dosage for the use of mirtazapine is 60 mg, and the daily dosage for the use of tizanidine is 24 mg. 39. The medicinal product according to claims 33-35, characterized in that the daily dosage for the use of mirtazapine is 45 mg, and the daily dosage for the use of tizanidine is 18 mg. 40. The medicinal product according to claims 33-37, characterized in that the daily dosage for the use of mirtazapine is 30 mg, and the daily dosage for the use of tizanidine is 12 mg. 41. The medicinal product according to claims 33-36, characterized in that the daily dosage for the use of mirtazapine is 15 mg, and the daily dosage for the use of tizanidine is 6 mg. 42. The medicinal product according to claims 33-41, characterized in that it is made in the form of a solid dosage form for oral administration. 43. The medicinal product according to claim 42, characterized in that the solid dosage form for oral administration is a tablet. 44. The medicinal product according to claim 43, characterized in that the tablet is a two-layer tablet. 45. The medicinal product according to claims 43-44, characterized in that the tablet is a prolonged-release tablet. 46. The medicinal product according to claims 44-45, characterized in that the two-layer tablet includes a layer containing mirtazapine and a layer containing tizanidine, from which tizanidine is released slowly. 47. The medicinal product according to claim 46, characterized in that the tizanidine-containing layer from which the tizanidine is released in a sustained manner comprises tizanidine, or a pharmaceutically acceptable salt thereof, a filler, a disintegrant and a polymeric release retardant, which is a hydrophilic polymeric release retarder. 48. The medicinal product according to claims 46, 47, characterized in that the tizanidine-containing layer, from which the tizanidine is released slowly, further includes a lubricant. 49. The medicinal product according to claims 46-48, characterized in that the layer containing tizanidine 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.%. 50. The medicinal product according to claims 47-49, characterized in that the hydrophilic polymer 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 claims 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 stearyl fumarate and mixtures thereof. 52. The medicinal product according to claims 46-51, characterized in that mirtazapine is immediately released from the mirtazapine-containing layer. 53. The medicinal product according to claims 46-52, characterized in that the mirtazapine layer contains mirtazapine, a filler, a disintegrant and a lubricant. 54. A medicinal product according to claims 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 claims 46-54, characterized in that the lubricant in the layer with myrtase- - 28 045581 pinom is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof. 56. A medicinal product according to claims 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 claims 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 claims 46-57, characterized in that it additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, gum acacia and mixtures thereof in an amount of 0.5-5 wt.%, 59. The medicinal product according to claim 46, characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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 - 0.52.0. 60. The medicinal product according to claim 46, characterized in that the layer with tizanidine contains tizanidine hydrochloride and auxiliary components in the following ratios, wt.%: 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. Medicine according to claims 46-60, characterized in that the layer with tizanidine is obtained by direct pressing. 62. The drug according to claim 46, characterized in that the tizanidine sustained release 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, wt.%: 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 claim 46, characterized in that the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios, wt.%: 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. Medicine according to claims 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. A medicinal product according to claims 33 to 66, characterized in that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles. 68. The medicinal product according to claim 67, characterized in that painful muscle spasm is associated with static and functional diseases of the spine. 69. The medicinal product according to claim 68, characterized in that the spinal diseases are cervical or lumbar syndromes. 70. The medicinal product according to claims 67, 68, characterized in that the painful muscle spasm is associated with surgical intervention. 71. The medicinal product according to claim 67, characterized in that skeletal muscle spasticity 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 to 16, a pharmaceutical combination - 29 045581 tion according to any one of claims 17 to 32 or a medicinal product according to any one of claims 33 to 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 , with a ratio of 2.5 to 1. 74. Use according to claim 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 claim 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 claim 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 claim 73, characterized in that the daily dosage of mirtazapine is 60 mg and tizanidine is 24 mg. 78. Use according to claim 1, characterized in that the daily dosage of mirtazapine is 45 mg, and tizanidine is 18 mg. 79. Use according to claim 73, characterized in that the daily dosage of mirtazapine is 30 mg and tizanidine is 12 mg. 80. Use according to claim 73, characterized in that the daily dosage of mirtazapine is 15 mg and tizanidine is 6 mg. 81. Use according to claims 73-80, characterized in that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles. 82. Use according to claim 81, characterized in that painful muscle spasm is associated with static and functional diseases of the spine. 83. Use according to claim 82, characterized in that the spinal diseases are cervical or lumbar syndromes. 84. Use according to claims 81, 82, characterized in that the painful muscle spasm is associated with surgery. 85. Use according to claim 81, characterized in that skeletal muscle spasticity is associated with a neurological disease. 86. Use according to claim 85, 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. 87. Use according to claims 73-86, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-4 times a day. 88. Use according to claims 73-87, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-3 times a day. 89. Use according to claims 73-88, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-2 times a day. 90. Use according to claims 73-87, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 2-4 times a day. 91. A method of treating a pain disorder, characterized in that it includes the use of any one of claims 73 to 90 or the administration to a subject in need thereof of a pharmaceutical composition of any of claims 1 to 16, a pharmaceutical combination of any of claims 17 to 32 or a medicinal product according to any one of paragraphs 33-72. 92. The method of treatment according to claim 91, characterized in that the pain disorder is a painful muscle spasm or spasticity of skeletal muscles. 93. The method of treatment according to claim 92, characterized in that the painful muscle spasm is associated with static and functional diseases of the spine. 94. The method of treatment according to claim 93, characterized in that the spinal diseases are cervical or lumbar syndromes. 95. The method of treatment according to claims 92, 93, characterized in that the painful muscle spasm is associated with surgical intervention. 96. The method of treatment according to claim 92, characterized in that skeletal muscle spasticity is associated with a neurological disease. 97. The method of treatment according to claim 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 claims 91-97, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-4 times a day. - 30 045581 99. The method of treatment according to claims 91-98, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-3 times a day. 100. The method of treatment according to claims 91-99, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 1-2 times a day. 101. The method of treatment according to claims 91-98, characterized in that said pharmaceutical composition, pharmaceutical combination or drug is intended for administration 2-4 times a day.