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WO2021112724A1 - Combinaison de mirtazapine et de tizanidine utilisée en case de troubles douloureux - Google Patents

Combinaison de mirtazapine et de tizanidine utilisée en case de troubles douloureux Download PDF

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Publication number
WO2021112724A1
WO2021112724A1 PCT/RU2020/050357 RU2020050357W WO2021112724A1 WO 2021112724 A1 WO2021112724 A1 WO 2021112724A1 RU 2020050357 W RU2020050357 W RU 2020050357W WO 2021112724 A1 WO2021112724 A1 WO 2021112724A1
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Prior art keywords
tizanidine
mirtazapine
pharmaceutical composition
cellulose
daily dosage
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English (en)
Russian (ru)
Inventor
Аллан Герович БЕНИАШВИЛИ
Маргарита Алексеевна МОРОЗОВА
Максим Эдуардович ЗАПОЛЬСКИЙ
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Valenta Intellect LLC
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Valenta Intellect LLC
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Priority to KR1020227022618A priority Critical patent/KR20220110259A/ko
Priority to TNP/2022/000140A priority patent/TN2022000140A1/en
Priority to BR112022010718A priority patent/BR112022010718A2/pt
Priority to IL293562A priority patent/IL293562A/en
Priority to MX2022006581A priority patent/MX2022006581A/es
Priority to CN202080083655.3A priority patent/CN114761017B/zh
Publication of WO2021112724A1 publication Critical patent/WO2021112724A1/fr
Priority to SA522432821A priority patent/SA522432821B1/ar
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to the chemical-pharmaceutical industry and medicine and concerns a new use of a pharmaceutical combination comprising mirtazapine and tizanidine, or their pharmaceutically acceptable salts, for the treatment of pain disorders, characterized in that the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine is from 6 to 24 mg, as well as 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.
  • prostaglandins non-narcotic analgesics, paracetamol, non-steroidal anti-inflammatory drugs - H11VP
  • - serotonin reuptake blockers for example, amitriptyline
  • zonisamide used in the treatment of disorders such as depression, schizophrenia, anxiety disorders, sleep-related breathing disorders, insomnia, migraine, chronic HDN, hot flashes, back pain; neuropathic pain and functional somatic syndromes [8].
  • 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.
  • zonisamide is characterized by various adverse events, including a transient increase in the level of liver enzymes, weight change, hematological disorders, neurological / psychiatric disorders such as insomnia, agitation and irritability, adverse events from the urinary and cardiovascular system [3], which is 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 a-adrenergic receptors in the central nervous system and enhances the central noradrenergic and serotonergic transmission of nerve impulses. In this case, an increase in serotonergic transmission is realized only through serotonin 5-HT 1 receptors, since mirtazapine blocks serotonin b-HT 1 and 5-HT 3 receptors.
  • mirtazapine both enantiomers of mirtazapine have antidepressant activity, the S (+) enantiomer, blocking the ag-adreno- and serotonin 5-HT 2 receptors, and the R (-) enantiomer, blocking the serotonin 5-HT 3 receptors.
  • the sedative properties of mirtazapine are due to its antagonistic activity towards H1-histamine receptors. Mirtazapine practically does not have M-anticholinergic activity and, in therapeutic doses, has limited effect (eg, orthostatic hypotension) on the cardiovascular system.
  • Mirtazapine is disclosed in US patent [4].
  • the dual mechanism of action of mirtazapine on 2 neurotransmitter systems defines it as a noradrenergic and specific serotonergic antidepressant.
  • mirtazapine is quite quickly able to neutralize 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 a significant (p ⁇ 0.05) reduction in anxiety symptoms at 1, 2, 4, 6 weeks of the study, as well as at the end of treatment compared with placebo.
  • a number of comparative studies demonstrate that mirtazapine is superior to other antidepressants, such as citalopram, fluoxetine, paroxetine, in terms of the rapid reduction of anxiety symptoms [5].
  • Mirtazapine has also been shown to be effective in the treatment of PTSD. More than half of the patients showed positive dynamics in terms of the reduction of the anxiety component, both when questioned by a doctor 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 marked reduction in depressive and anxiety symptoms. Another feature of mirtazapine is the fact that it does not inhibit cytochrome P-450 [6].
  • mirtazapine it is known that it has been investigated for anti-pain effects, and can be used in the treatment of chronic neuropathic pain conditions, tension-type headaches and other pain conditions [7-11].
  • pain syndromes muscle spasm develops 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.
  • Characteristics of pain in painful muscle spasm is local in nature within the spasmodic muscle; provoked by irritation of the affected muscle; when probing muscle fibers, intense pain is determined; the tone is increased.
  • the main features of pain in degenerative-dystrophic lesions or myofascial pain syndrome reflected or regional pain, which is always far from the spasmodic muscle; on palpation of a painful muscle, the pain increases significantly; a sharp diffuse muscle spasm with inclusions of areas of compaction, which play the role of a trigger, when these zones are pressed, very intense pain develops both in the muscle and at a distance [12].
  • 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 the connective tissue.
  • Tizanidine is a centrally acting muscle relaxant. By stimulating presynaptic alpha2 receptors, it inhibits the release of excitatory amino acids that stimulate 1M-methyl-O-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 In addition to muscle relaxant properties, tizanidine also has a central moderate analgesic effect.
  • NMDA receptors 1M-methyl-O-aspartate receptors
  • Tizanidine relaxes skeletal muscles in chronic spastic conditions of spinal and cerebral origin, eliminates acute painful muscle spasms and clonic cramps. 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 “pain-muscle spasm-pain”), increases the volume of active movements.
  • 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, reducing the recurrence of myofascial pain syndrome (MFS).
  • MFS myofascial pain syndrome
  • a known combination contains alpha-2 receptor agonists in a concentration effective to obtain a therapeutic effect, and alpha-2 adrenergic receptor antagonists in concentrations capable of effectively enhancing the therapeutic effect of alpha-2 receptor agonists [14].
  • alpha-2 receptor agonists in a concentration effective to obtain a therapeutic effect
  • alpha-2 adrenergic receptor antagonists in concentrations capable of effectively enhancing the therapeutic effect of alpha-2 receptor agonists [14].
  • As a condition in which the introduction of such a combination is required there may be pain, hypertension, glaucoma. Solves the problem of potentiating the analgesic effect of agonists About NY - adrenergic receptors and reduce their adverse side effects by combining agonists al-adrenoceptor antagonists of al-adrenergic receptors.
  • mirtazapine and tizanidine are indicated in the application only as one of a large number of fundamentally possible antagonists and antagonists of al-adrenergic receptors, therefore this document does not push the specialist to the preference of using it mirtazapine and tizanidine as an antagonist and agonist of al-adrenergic receptors, respectively, and does not give the specialist reason to believe that when choosing mirtazapine as an antagonist of al-adrenergic receptors and tizanidine as an agonist of n-adrenergic receptors, a super-total (synergistic) effect can be achieved.
  • an al-adrenergic receptor agonist As preferred examples of the combination of an al-adrenergic receptor agonist and ultra-low doses of an al-adrenergic receptor antagonist, specific examples are given, including an al-adrenergic receptor antagonist and an al-adrenergic receptor agonist, taken in a quantitative ratio of 1: 1000, 1: 10000, 1: 100000 or 1: 1,000,000 ...
  • 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 5-50 mg of mirtazapine; tizanidine 0.5-6 mg at a ratio of 20: 1-5: 1 and a pharmaceutically acceptable carrier [15].
  • the analog provides an effective agent 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 20 mg mirtazapine and 1 mg tizanidine (in a ratio of 20: 1). At the same time, the specified source does not disclose in what doses this combination should be taken.
  • the present inventors unexpectedly found that the use of a pharmaceutical combination or pharmaceutical composition comprising mirtazapine and tizanidine, or their pharmaceutically acceptable salts, when the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine - from 6 to 24 mg, in a ratio of 2.5: 1, respectively, leads to the most effective treatment of pain disorders associated with painful muscle spasms or skeletal muscle spasticity, reduces the acute toxicity of the components of the combination used and their addictiveness , helps to improve the quality of life in patients with persistent pain syndrome, reduce pain and depressive conditions accompanying the sensation of pain.
  • the invention also provides an expansion of the arsenal of drugs with a combined (muscle relaxant and analgesic) effect.
  • the objective of the present invention is to provide a drug with increased efficacy for the treatment and / or prevention of pain disorders, including pain disorders associated with painful muscle spasms or skeletal muscle spasticity, which has a combined (muscle relaxant and analgesic) effect, an increased safety profile and tolerance.
  • the problem is solved, and the technical result is achieved by using a pharmaceutical combination or pharmaceutical composition containing mirtazapine and tizanidine or their pharmaceutically acceptable salts for the treatment of pain disorders, characterized in that the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine is from 6 to 24 mg, in a ratio of 2.5: 1, respectively.
  • the specified technical result is also achieved in that:
  • the daily dosage of mirtazapine is 15 to 45 mg, and tizanidine is from 6 to
  • the daily dosage of mirtazapine is 15 to 30 mg, and tizanidine is from 6 to
  • the daily dosage of mirtazapine is 60 mg, and tizanidine is 24 mg;
  • the daily dosage of mirtazapine is 45 mg, and tizanidine is 18 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
  • - solid dosage form for oral administration contains at least one excipient
  • - solid dosage form for oral administration is a tablet
  • the tablet is a two-layer tablet
  • bilayer tablet is a prolonged-release tablet
  • a bilayer tablet comprises a layer containing mirtazapine or a pharmaceutically acceptable salt thereof, and a layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which tizanidine is slowly released;
  • the layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which the tizanidine is released slowly includes a polymeric release retardant, and the polymeric tizanidine release retardant is a hydrophilic polymeric release retardant;
  • a hydrophilic polymer retarder for the release of tizanidine can be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, a copolymer of ammonium methacrylate, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or hydroxypropyl hydroxypropyl methyl cellulose, carboxymethyl cellulose, cellulose acetate or phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate succinate or ethyl cellulose succinate;
  • mirtazapine is immediately released from the layer containing mirtazapine;
  • the sustained release tizanidine layer contains 6 mg of tizanidine and the immediate release mirtazapine layer contains 15 mg of mirtazapine;
  • the pharmaceutically acceptable salt of tizanidine is tizanidine hydrochloride
  • a layer containing tizanidine, from which tizanidine is released slowly additionally includes a lubricant;
  • the layer containing tizanidine contains tizanidine hydrochloride in an amount of 0.5-30 wt%, a hydrophilic polymer 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, filler, baking powder and lubricant;
  • the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt%, a filler in an amount of 70-95 wt%, a disintegrant in an amount of 1-10 wt% and a lubricant in an amount of 0.5-5 wt%;
  • the lubricant in the layer with mirtazapine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl 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 baking powder 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 arabic 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 mirtazapine contains mirtazapine and auxiliary components in the following ratios,% May: 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,% May: 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;
  • - pain disorder is painful muscle spasm or skeletal muscle spasticity
  • - diseases of the spine are cervical or lumbar syndromes
  • a neurological disease selected from the group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, the consequences of cerebrovascular accidents and cerebral palsy.
  • 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 a pharmaceutically acceptable carrier for use at 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.
  • pharmaceutically acceptable excipients The selection of specific excipients is carried out depending on the intended route of administration and dosage form, as known to the person skilled in the art. Suitable pharmaceutical carriers, excipients and their formulations are described, for example, in Remington: The Science and Practice of Pharmacy 1995, edited by E.W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania.
  • Pharmaceutically acceptable excipients can be selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliaries and distribution agents, delivery vehicles such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavorings, antibacterial agents, fungicides, lubricants, sustained delivery regulators, the choice and ratio of which depends on the nature of the active substances, route of administration and dosage.
  • delivery vehicles such as preservatives, stabilizers, fillers, grinders, humectants, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavorings, antibacterial agents, fungicides, lubricants, sustained delivery regulators, the choice and ratio of which depends on the nature of the active substances, route of administration and dosage.
  • suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances. Protection against the action of microorganisms can be provided by a variety of antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid, and the like.
  • the composition may also include isotonic agents such as sugars, sodium chloride and the like.
  • the prolonged action of the composition can be provided by agents slowing down the absorption of the active principle, for example, such as aluminum monostearate, gelatin, cellulose derivatives or a hydrophilic polymer release retardant, which is polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, acrylic acid polymer or its ethers, cellulose derivatives or mixtures thereof, copolymer of ammonium methacrylate, hydroxypropyl methylcellulose, methyl-, ethyl- or propylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, cellulose acetate or phthalate cellulose
  • the disintegrants can 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 can be selected from carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, gum arabic, and mixtures thereof.
  • suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, as well as mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • fillers are lactose, sucrose, glucose, sodium citrate, calcium carbonate, calcium phosphates, microcrystalline cellulose, mannitol, starch, silicic acid and the like.
  • grinders and dispensers are starch, alginic acid and its salts, silicates.
  • 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 administration form, as a mixture with traditional pharmaceutical carriers.
  • Suitable unit forms of administration include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules.
  • the active agent is mixed with at least one of the following: (a) one or more inert excipients (or carriers) such as dibasic calcium phosphate; (B) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (d) humectants such as glycerin; (e) disintegrants such as agar-agar, calcium carbonate, potato, corn or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (f) dissolution retardants such as paraffin or hydrophilic polymeric release retardants; (g) absorption accelerators such as quaternary ammonium compounds
  • the specified 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 the use of mirtazapine is from 15 to 30 mg, and tizanidine is from 6 to 12 mg;
  • the daily dosage for the use of mirtazapine is from 30 to 60 mg, and tizanidine is from 12 to 24 mg;
  • the daily dosage for the use of mirtazapine is 60 mg, and tizanidine -
  • the daily dosage for the use of mirtazapine is 45 mg, and tizanidine -
  • the daily dosage for the use of mirtazapine is 30 mg, and tizanidine -
  • the daily dosage for the use of mirtazapine is 15 mg, and tizanidine is 6 mg;
  • composition is made in the form of a solid dosage form for oral administration
  • - solid dosage form for oral administration is a tablet
  • the tablet is a two-layer tablet
  • bilayer 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 layer containing tizanidine, from which the tizanidine is released slowly includes tizanidine, or a pharmaceutically acceptable salt thereof, and a polymeric release retardant, which is a hydrophilic polymeric release retardant;
  • a layer containing tizanidine, from which tizanidine is released slowly additionally includes a lubricant;
  • the layer containing tizanidine contains tizanidine hydrochloride in an amount of 0.5-30 wt%, a hydrophilic polymer 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 salt
  • a hydrophilic polymer retarder for the release of tizanidine can be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, a copolymer of ammonium methacrylate, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose or hydroxypropyl hydroxypropyl ethyl cellulose, carboxymethyl cellulose, cellulose acetate or phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate succinate, ethyl cellulose 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, filler, baking powder and lubricant;
  • the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt%, a filler in an amount of 70-95 wt%, a disintegrant in an amount of 1-10 wt% and a lubricant in an amount of 0.5-5 wt%;
  • the lubricant in the layer with mirtazapine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof;
  • the filler is selected from mannitol, sorbitol, isomalt, microcrystalline cellulose, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid and mixtures thereof;
  • the baking powder 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;
  • composition additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, gum arabic 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 silicon colloidal 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 sustained release tizanidine layer contains 6 mg of tizanidine
  • the layer with mirtazapine contains mirtazapine and auxiliary components in the following ratios,% May: 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,% May: 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 immediate release mirtazapine layer contains 15 mg of mirtazapine
  • composition is intended for administration 1-4 times a day;
  • composition is intended for administration 1-3 times a day;
  • composition is intended for administration 1-2 times a day;
  • composition is intended for administration 2-4 times a day;
  • the 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 mirtazapine contains mirtazapine and auxiliary components in the following ratios,% May: 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 layer with mirtazapine is obtained by wet granulation.
  • - pain disorder is painful muscle spasm or skeletal muscle spasticity
  • - diseases of the spine are cervical or lumbar syndromes
  • a neurological disease selected from the group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, the consequences of cerebrovascular accidents and cerebral palsy.
  • the task is also achieved, 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 from 15 to 60 mg as free base per day and tizanidine 6 to 24 mg as free base per day.
  • the specified technical result is also achieved in that:
  • the daily dosage of mirtazapine is 15 to 45 mg, and tizanidine is from 6 to
  • the daily dosage of mirtazapine is 15 to 30 mg, and tizanidine is from 6 to
  • 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
  • - solid dosage form for oral administration contains at least one excipient
  • - solid dosage form for oral administration is a tablet
  • the tablet is a two-layer tablet
  • bilayer 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 sustained release tizanidine 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 salt
  • a layer containing tizanidine, from which tizanidine is released slowly additionally includes a lubricant;
  • the layer containing tizanidine contains tizanidine hydrochloride in an amount of 0.5-30 wt%, a hydrophilic polymer 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, filler, baking powder and lubricant.
  • the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt%, a filler in an amount of 70-95 wt%, a disintegrant in an amount of 1-10 wt% and a lubricant in an amount of 0.5-5 wt%;
  • the lubricant in the layer with mirtazapine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof;
  • the filler is selected from mannitol, sorbitol, isomalt, microcrystalline cellulose, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid and mixtures thereof;
  • the baking powder is selected from crospovidone, sodium carboxymethylcellulose, agar-agar, calcium carbonate, potato, corn or tapioca starch, alginic acid, complex silicates, sodium carbonate and mixtures thereof;
  • said combination additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, gum arabic 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 silicon colloidal 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 mirtazapine contains mirtazapine and auxiliary components in the following ratios,% May: 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,% May: 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;
  • - pain disorder is painful muscle spasm or skeletal muscle spasticity
  • - diseases of the spine are cervical or lumbar syndromes
  • a neurological disease selected from the group including multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, the consequences of cerebrovascular accidents and cerebral palsy.
  • a method for treating pain disorder which includes the use of said pharmaceutical combination, including mirtazapine and tizanidine, or their pharmaceutically acceptable salts, for the treatment of pain disorders, characterized in that that the daily dosage of mirtazapine is from 15 to 60 mg, and tizanidine is from 6 to 24 mg, or the administration to a subject in need of treatment of said pharmaceutical composition for the treatment of pain disorders, comprising a combination of mirtazapine and tizanidine or their pharmaceutically acceptable salts in a weight ratio of mirtazapine to tizanidine in terms of free bases 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 aforementioned 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
  • Clinical dosage of a pharmaceutical combination comprising mirtazapine and tizanidine, or their pharmaceutically acceptable salts, for the treatment of pain disorders, or a pharmaceutical composition for the treatment of pain disorders, comprising a combination of mirtazapine and tizanidine, or their pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier according to the present invention, in patients can be adjusted depending on the therapeutic efficacy 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, sex and stage of the patient's disease. As directed by your doctor or pharmacist, these medications can be taken several times over specific periods of time (preferably one to four times).
  • the pain can be a polymorphic disorder.
  • the term "pain” refers to all types of pain, including acute and persistent pain.
  • the term denotes chronic pain, but is not limited to: 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, toothache, visceral pain, during surgical procedures, postoperative pain, osteogenic pain, burn pains, including sunburn, urogenital pains, including cystitis, tonsillitis.
  • Medical product - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of finished forms intended for the restoration, correction or change of 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 , delivery devices such as preservatives, stabilizers, fillers, humectants, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavors, antibacterial agents, fungicides, delayed 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 acids and bases disclosed in the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or they can be obtained specially. In particular, base salts can be specially prepared starting from the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • Examples of the salts obtained in this way are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates, mesites malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like (a detailed description of the properties of such salts is given in [16]).
  • Salts of the claimed acids can also be specially prepared by reacting a purified acid with a suitable base, whereby salts can be synthesized metals and amines.
  • Metallic salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts.
  • Suitable inorganic bases from which metal salts can be derived are sodium hydroxide, carbonate, bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
  • organic bases from which the salts of the claimed acids can be obtained amines and amino acids are selected that are basic enough to form a stable salt and are suitable for medical use (in particular, they must have low toxicity).
  • Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane, and the like.
  • tetraalkylammonium hydroxides such as choline, tetramethylammonium, tetraethyl ammonium and the like can be used for salt formation.
  • Basic amino acids - lysine, ornithine and arginine - can be used as amino acids.
  • terapéuticaally effective amount means an amount of an 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 particular disease, condition, or disorder described herein.
  • pharmaceutically acceptable means that the substance or composition to which this term is applied must be chemically and / or toxicologically compatible with the other ingredients in the formulation and safe for the person being treated with this substance, or composition.
  • the subject of the present invention is a pharmaceutical composition for the treatment of pain disorders, comprising mirtazapine and tizanidine, or pharmaceutically acceptable salts with a weight ratio of mirtazapine to tizanidine based on free bases of 2.5 to 1 and at least one pharmaceutically acceptable carrier containing from 15 to 60 mg of mirtazapine and from 6 to 24 mg of tizanidine.
  • composition characterized in that the pharmaceutically acceptable tizanidine salt is a hydrochloride salt.
  • composition comprising 15 to 45 mg of mirtazapine and 6 to 18 mg of tizanidine.
  • composition comprising 15 to 30 mg of mirtazapine and 6 to 12 mg of tizanidine.
  • 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 comprising 60 mg of mirtazapine and 24 mg of tizanidine.
  • More preferred is a pharmaceutical composition comprising 45 mg of mirtazapine and 18 mg of tizanidine.
  • More preferred is a pharmaceutical composition comprising 30 mg of mirtazapine and 12 mg of tizanidine.
  • composition characterized in that it contains 15 mg of mirtazapine and 6 mg of tizanidine.
  • composition characterized in that it contains at least one excipient.
  • More preferred is a pharmaceutical composition characterized in that the pain disorder is 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 diseases of the spine are cervical or lumbar syndromes.
  • More preferred is a pharmaceutical composition characterized in that the painful muscle spasm is associated with surgery.
  • composition characterized in that skeletal muscle spasticity is associated with neurological disease.
  • a pharmaceutical composition characterized in that the neurological disease is selected from the group consisting of multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, the consequences of cerebrovascular accident and cerebral palsy.
  • the subject of the present invention is also a pharmaceutical combination for the treatment of pain disorders, comprising mirtazapine and tizanidine or their pharmaceutically acceptable salts in a weight ratio of mirtazapine to tizanidine 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 of tizanidine.
  • More preferred is a pharmaceutical combination wherein the pharmaceutically acceptable tizanidine salt is a hydrochloride salt.
  • More preferred is a pharmaceutical combination characterized in that it contains 15 to 45 mg of mirtazapine and 6 to 18 mg of tizanidine.
  • More preferred is a pharmaceutical combination characterized in that it contains 15 to 30 mg of mirtazapine and 6 to 12 mg of tizanidine.
  • 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 wherein the pain disorder is 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 diseases of the spine 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 neurological disease.
  • the neurological disease is selected from the group consisting of multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, the consequences of cerebrovascular accident and cerebral palsy.
  • the subject of the present invention is a medicament for the treatment of pain disorders comprising a pharmaceutical composition according to the present invention or a pharmaceutical combination according to the present invention and at least one excipient.
  • 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, hydroxypropylethyl cellulose, carbixmethyl 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, calcium phosphates, carbonic acid, carbonic acid 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.
  • cellulose derivatives or mixtures thereof such as methyl,
  • More preferred is a medicament characterized in that the daily dosage for mirtazapine is 15 to 45 mg and the daily dosage for tizanidine is 6 to 18 mg.
  • More preferred is a medicament characterized in that the daily dosage for mirtazapine is 15 to 30 mg and the daily dosage for tizanidine is 6 to 12 mg.
  • More preferred is a medicament 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.
  • More preferred is a medicament 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.
  • a medicament 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. More preferred is a medicament 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 preferred is a medicament 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.
  • More preferred is a medicament characterized in that it is in the form of a solid dosage form for oral administration.
  • More preferred is a medicament characterized in that the solid dosage form for oral administration is a tablet.
  • a medicament characterized in that the tablet is a bilayer tablet.
  • More preferred is a medicament characterized in that the tablet is an extended release tablet.
  • the bilayer tablet comprises a layer containing mirtazapine and a layer containing tizanidine, from which the tizanidine is slowly released.
  • the tizanidine-containing layer from which the tizanidine is released slowly comprises tizanidine, or a pharmaceutically acceptable salt thereof, a filler, a disintegrant and a polymer release retardant that is a hydrophilic polymer release retardant.
  • a medicament characterized in that the tizanidine-containing layer from which the tizanidine is released slowly further comprises a lubricant.
  • the layer containing tizanidine contains tizanidine hydrochloride in an amount of 0.5-30 wt%, a hydrophilic polymer retardant in an amount of 0.5-99 wt% and a lubricant in an amount of 0.5 -2.5 wt%.
  • the hydrophilic polymeric tizanidine release retardant can be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, copolymer of ammonium methacrylate, hydroxypropyl methylcellulose, methyl-, ethyl- or propylcellulose, hydroxyethyl cellulose cellulose, hydroxypropyl cellulose or hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate succinate, ethyl cellulose succinate or mixtures thereof.
  • 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.
  • the mirtazapine layer contains mirtazapine, a filler, a disintegrant and a lubricant.
  • the layer with mirtazapine contains mirtazapine in an amount of 5-35 wt%, a filler in an amount of 70-95 wt%, a disintegrant in an amount of 1-10 wt% and a lubricant in an amount of 0.5 -5 wt%.
  • the lubricant in the layer with mirtazapine is selected from stearic acid and its salts, such as calcium and magnesium stearate, talc, colloidal silicon dioxide, sodium stearyl fumarate and mixtures thereof.
  • the filler is selected from mannitol, sorbitol, isomalt, microcrystalline cellulose, starch, calcium phosphates, calcium carbonate, lactose, sucrose, glucose, silicic acid, and mixtures thereof.
  • a medicament characterized in that the disintegrant is selected from crospovidone, sodium carboxymethylcellulose, agar-agar, calcium carbonate, potato, corn, pea or tapioca starch, alginic acid, complex silicates, sodium carbonate, and mixtures thereof. More preferred is a drug characterized in that it additionally contains a binder selected from carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, gum arabic 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.
  • tizanidine layer is obtained by direct compression.
  • the sustained release tizanidine layer contains 6 mg of 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.
  • More preferred is a drug characterized in that the layer with mirtazapine is obtained by wet granulation.
  • More preferred is a medicament characterized in that the immediate release layer of mirtazapine contains 15 mg of mirtazapine.
  • More preferred is a medicament characterized in that the pain disorder is 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 preferred is a medicament characterized in that the diseases of the spine are cervical or lumbar syndromes.
  • More preferred is a medicament characterized in that the painful muscle spasm is associated with surgery.
  • More preferred is a medicament characterized in that skeletal muscle spasticity is associated with neurological disease.
  • the neurological disease is selected from the group consisting of multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, the consequences of cerebrovascular accidents and cerebral palsy.
  • 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 medicament 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.
  • the daily dosage of mirtazapine is 15 to 45 mg and that of tizanidine is 6 to 18 mg.
  • the daily dosage of mirtazapine is 15 to 30 mg and that of tizanidine is 6 to 12 mg.
  • the daily dosage of mirtazapine is from 30 to 45 mg, and tizanidine is from 12 to 18 mg.
  • the daily dosage of mirtazapine is 60 mg and that of tizanidine is 24 mg.
  • More preferable is the use, characterized in that the daily dosage of mirtazapine is 45 mg, and tizanidine is 18 mg.
  • More preferable is the use, characterized in that the daily dosage of mirtazapine is 30 mg, and tizanidine is 12 mg.
  • the daily dosage of mirtazapine is 15 mg and that of tizanidine is 6 mg.
  • the pain disorder is painful muscle spasm or skeletal muscle spasticity.
  • More preferred is an application characterized in that painful muscle spasm is associated with static and functional diseases of the spine.
  • the use characterized in that the diseases of the spine are cervical or lumbar syndromes. More preferred is the use in which the painful muscle spasm is associated with surgery.
  • skeletal muscle spasticity is associated with neurological disease.
  • the neurological disease is selected from the group consisting of multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, the consequences of cerebrovascular accidents and cerebral palsy.
  • compositions, pharmaceutical combination or medicament is intended to be administered 1-4 times a day.
  • compositions, pharmaceutical combination or medicament is intended to be administered 1-3 times a day.
  • compositions, pharmaceutical combination or medicament is intended to be administered 1-2 times a day.
  • compositions, pharmaceutical combination or medicament is intended to be administered 2-4 times a day.
  • More preferable is the use, characterized in that the said drug 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 oral dosage form is a tablet.
  • the tablet is a bilayer tablet. More preferred is the use characterized in that the bilayer tablet is an extended release tablet.
  • the bilayer tablet comprises a layer containing mirtazapine or a pharmaceutically acceptable salt thereof and a layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which the tizanidine is slowly released.
  • the layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which the tizanidine is released slowly includes a polymer release retardant, and the polymer tizanidine release retardant is a hydrophilic polymer release retardant.
  • the hydrophilic polymer retarder for the release of tizanidine can be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, acrylic acid polymer or its esters, cellulose derivatives or mixtures thereof, copolymer of ammonium methacrylate, hydroxypropyl methylcellulose ethyl or propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, carboxymethyl cellulose, cellulose acetate or phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate succinate or ethyl cellulose succinate.
  • mirtazapine is immediately released from the layer containing the mirtazapine.
  • the sustained release tizanidine layer contains 6 mg of tizanidine and the immediate release mirtazapine layer contains 15 mg of mirtazapine.
  • tizanidine salt 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 - 40.28; ammonium methacrylate copolymer - 54.165; colloidal silicon dioxide - 0.635.
  • tizanidine layer is obtained by direct compression.
  • 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 layer with mirtazapine is obtained by wet granulation.
  • the subject of the present invention is a method of treating a pain disorder, characterized in that it comprises the aforementioned use according to the present invention or the 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 medicament according to the present invention.
  • More preferred is a method of treatment characterized in that the pain disorder is painful muscle spasm or skeletal muscle spasticity.
  • More preferred is a method of treatment characterized in that painful muscle spasm is associated with static and functional diseases of the spine. More preferred is a method of treatment characterized in that the diseases of the spine are cervical or lumbar syndromes.
  • More preferred is a method of treatment characterized in that the painful muscle spasm is associated with surgery.
  • More preferred is a method of treatment characterized in that skeletal muscle spasticity is associated with neurological disease.
  • the neurological disease is selected from the group consisting of multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, the consequences of cerebrovascular accidents and cerebral palsy.
  • compositions, pharmaceutical combination or medicament is intended to be administered 1-4 times a day.
  • compositions, pharmaceutical combination or medicament is intended to be administered 1-3 times a day.
  • compositions, pharmaceutical combination or medicament is intended to be administered 1-2 times a day.
  • More preferred is a method of treatment characterized in that said pharmaceutical composition, pharmaceutical combination or medicament is intended to be administered 2-4 times a day.
  • More preferable is a method of treatment, characterized in that said drug 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. More preferred is a method of treatment characterized in that the tablet is a bilayer tablet.
  • bilayer tablet is an extended release tablet.
  • the bilayer tablet comprises a layer containing mirtazapine or a pharmaceutically acceptable salt thereof, and a layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which the tizanidine is slowly released.
  • the layer containing tizanidine or a pharmaceutically acceptable salt thereof, from which the tizanidine is released slowly comprises a polymeric release retardant, and the polymeric tizanidine release retardant is a hydrophilic polymeric release retardant.
  • the hydrophilic polymer retarder for the release of tizanidine can be polyvinyl alcohol, polyvinylpyrrolidone, polyethylene oxide, carbomers, alginates, a polymer of acrylic acid or its esters, cellulose derivatives or mixtures thereof, copolymer of ammonium methacrylate, hydroxypropylmethyl , ethyl or propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose, carboxymethyl cellulose, cellulose acetate or phthalate, hydroxypropyl methyl cellulose phthalate, cellulose acetate succinate or ethyl cellulose succinate.
  • mirtazapine is immediately released from the layer containing mirtazapine.
  • the sustained release tizanidine layer contains 6 mg of tizanidine and the immediate release mirtazapine layer contains 15 mg of mirtazapine.
  • tizanidine hydrochloride More preferred is a method of treatment characterized in that the pharmaceutically acceptable tizanidine salt is tizanidine hydrochloride. More preferable is a method of treatment, 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.
  • tizanidine hydrochloride in terms of tizanidine
  • More preferable is the method of treatment, characterized in that the layer with tizanidine is obtained by direct compression.
  • 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 a method of treatment characterized in that the layer with mirtazapine is obtained by wet granulation.
  • Example 1 Evaluation of the efficacy of a combination of mirtazapine and tizanidine for the treatment of pain syndrome associated with static and functional diseases of the spine.
  • Rats 98 adult male Sprague-Dawley rats with a body weight of 250-330 grams were used in the experiments. The rats were housed five rats each in temperature-controlled boxes (with an average temperature of 21 ° C) with a 12-hour day and night cycle and with sufficient water and food.
  • Surgical operation The rats were anesthetized with isoflurane (Sigma, USA). The skin on the lateral surface of the rat's thigh was cut and then an incision was made in the biceps femoris muscle to open access to 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 tied with silk threads and cut distally from the ligation site, leaving a nerve stump 2 + 4 mm in size. Muscles and skin were sutured separately.
  • Drugs administered and doses The study was carried out for 4 types of drugs (mirtazapine, tizanidine, mirtazapine + tizanidine in a ratio of 2.5: 1 according to the present invention and mirtazapine + tizanidine in a ratio of 5: 1 (closest analogue)), which were administered orally after 10 days after surgery and 30 minutes before the conduct of behavioral tests in the indicated doses and combinations:
  • Mirtazapine 15 mg / day (group N ° 1), 30 mg / day (group N ° 2), 45 mg / day (group N "3), 60 mg / day (group N" 4);
  • Tizanidine 6 mg / day (group N "5), 12 mg / day (group N” 6), 18 mg / day (group o 7), 24 mg / day (group N "8); Mirtazapine + tizanidine in a ratio of 2.5: 1 according to the present invention: mirtazapine, 15 mg / day + tizanidine, 6 mg / day (group N ° 9), mirtazapine, 30 mg / day + tizanidine, 12 mg / day (group N ° 10), mirtazapine, 45 mg / day + tizanidine, 18 mg / day (group No. 11), mirtazapine, 60 mg / day tizanidine, 24 mg / day (group No. 12);
  • a group of rats receiving vehicle only (group No. 14, placebo) served as a control. All doses are per person.
  • Behavioral tests The severity of pain in different groups of animals was assessed using two tests, recording the development of cold or mechanical allodynia. The animals were tested on the 10th day after the operation, 30 minutes after the administration of the study drugs.
  • 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 touched the middle of the plantar surface of the paw with the force necessary to bend the hair, and held the hair in this position for 6-8 seconds.
  • a positive response was recorded if the animal abruptly jerked back its paw when touched.
  • the sensitivity threshold was determined by the minimum pressure causing a reflex paw withdrawal response (4 times out of 6 applications).
  • Cold allodynia To assess cold allodynia, a special hot / cold plate test chamber (Ugo Basile, Italy) was used in this study. The test was carried out in a chamber with acrylic walls 30 cm high on a cooled up to 0 ° C on a metal plate 30x30 cm in size. Healthy animals are able to withstand this temperature for a long time, resting all limbs on the cooled floor, while with nerve damage, the contact time of the limb with the cold plate is significantly reduced. To quantify this parameter, the time of keeping the limb on weight was recorded during 1 minute of the animal's stay in the test chamber. The test was performed on the 10th day after the operation; each animal was tested three times with an interval of 5 minutes between measurements; the obtained values were averaged. The values obtained were used to calculate the average score obtained in the corresponding test and the standard error of the mean for each value for each group used in the study. Differences between groups were considered statistically significant at a significance level of p ⁇ 0.05.
  • Table 1 The effect of mirtazapine and tizanidine, used alone or in combination, on the behavior of rats with pain syndrome mimicking static and functional diseases of the spine.
  • Rats 98 adult male Sprague-Dawley rats with a body weight of 250-300 grams were used in the experiments. The rats were housed five rats each in temperature-controlled boxes (with an average temperature of 21 ° C) with a 12-hour day and night cycle and with sufficient water and food.
  • Surgical operation The rats were anesthetized with isoflurane (Sigma, USA). The plantar part of the hind paw was treated with a 10% povidone-iodine solution. Next, using a razor blade, a 1 cm longitudinal incision was made through the skin and fascia starting 0.5 cm below the proximal end of the heel towards the toes. The plantar muscle was lifted and also cut longitudinally. The muscle attachment sites remained intact. The wound was covered with 2 mattress sutures using nylon threads and a needle. The wound was treated with a mixture of antibiotics. After the operation, the animals recovered in their cages. The sutures were removed under anesthesia approximately 30 hours after surgery. The wounds usually healed in 5-6 days.
  • Drugs to be administered and doses The study was carried out for 4 types of drugs (mirtazapine, tizanidine, mirtazapine + tizanidine in a 2.5: 1 ratio according to the present invention and mirtazapine + tizanidine in a 5: 1 ratio (closest analogue)), which were administered orally after 3 days after surgery and 30 minutes before the conduct of behavioral tests in 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 per person.
  • Behavioral tests The von Frey filament test (occurrence of mechanical allodynia) was used to assess pain behavior. Testing was performed as described in Example 1 above, except that the filaments were applied only to the injured paw. Differences between groups were considered statistically significant at a significance level of p ⁇ 0.05.
  • Example 3 Evaluation of the efficacy of a combination of mirtazapine and tizanidine for the treatment of skeletal muscle spasticity in neurological diseases.
  • Rats 98 adult male Sprague-Dawley rats with a body weight of 250-330 grams were used in the experiments. The rats were housed five rats each in temperature-controlled boxes (with an average temperature of 21 ° C) with a 12-hour day and night cycle and with sufficient water and food.
  • Drugs administered and doses the study was carried out for 4 types of drugs (mirtazapine, tizanidine, mirtazapine + tizanidine in the ratio of 2.5: 1 according to the present invention and mirtazapine + tizanidine in the ratio 5: 1 (closest analogue)), which were administered orally at the indicated doses and the combinations according to Example 1.
  • a group of rats receiving vehicle alone (group No. 14, placebo) served as a control. All doses are 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 on the dorsal side of the spine was cut, and laminectomy was performed at the L2 level of the lumbar vertebra. A properly sized hook was placed under the spinal cord, which was completely cut with scissors, avoiding damage to the veins and arteries. The soft tissue layers were tightly sutured to the spinal cord.
  • Tail Spasticity Assessment The rats were placed in a Plexiglass cylinder so that the tail was sticking out and could move freely in the vertical direction.
  • the tail was manually stimulated as follows: the base of the tail was clamped with the left hand, and with the right hand, holding the tail between the thumb and forefinger, quickly passed along the tail from the base to the tip, tightly adhering to it, and releasing the tail at the end of the movement. The procedure was repeated three times. This achieved a longitudinal straightening of the tail.
  • the response to this stimulation was twisting of the tail with its retraction under the body of the rat (or in the dorsal direction in rats with more severe injuries).
  • the scale described below was used to assess tail spasticity.
  • 0-1 point very weak or insignificant twisting of the tail tip in response to stretching (at an angle less than 90 °, lasting only a few seconds), weak or absent muscle tone, no clonus, no response to light touch of skin or hair.
  • 2-3 points severe spasm (bending) of the tail in response to stretching stimulation, the tip is bent at an angle of 180-360 °, lasting 3-10 seconds. Repetitive twisting and cloning of the tail last more than 10 minutes, hypertonicity, high sensitivity to light touch.
  • the degree of tail spasticity in animals receiving a combination of mirtazapine and tizanidine was the least pronounced, which indicates the possibility of using this combination for the treatment of skeletal muscle spasticity in neurological diseases.
  • the experiment also found a synergistic effect of the combination of mirtazapine and tizanidine, which statistically significantly exceeds the therapeutic effect of the closest analogue.
  • the effect of the closest analogue is the additive effect of mirtazapine and tizanidine in similar dosages.
  • Example 4 Obtaining an immediate release layer containing mirtazapine.
  • Example 5 Preparation of a sustained release layer containing tizanidine. Several release control agents at various concentrations were tested to prepare a once-daily dosage form of tizanidine. Three different batches of tizanidine 6 mg tablets were prepared in three different compositions shown in Table 5.
  • collidon represents spray-dried mixture of polymers of polyvinyl acetate and polyvinylpyrrolidone in a ratio of 8: 2), and copolymers of ammonium methacrylate.
  • HPMC Hydroxypropyl methylcellulose
  • the production process was identical for all batches and consisted of the following stages. First, the starting materials were sieved through a stainless steel sieve with a mesh size of 0.610 mm and mixed for 5 minutes by hand without adding stearic acid. After premixing, stearic acid was added to the mixture and mixed by hand for 5 minutes. The tablets were made on a rotary tablet press. All tablets were made with the same weight (180 mg ⁇ 5%) and with the same hardness (15 ⁇ 3 kgf) in order to evaluate the effect of the polymer on drug release: with the same surface area exposed to the environment dissolution profile, the release profiles are influenced exclusively by different polymer concentrations and the formation of the matrix itself. Table 5. Qualitative and quantitative composition of the mixtures for the tizanidine layer.
  • Example 6 Preparation of a bilayer tablet containing mirtazapine and tizanidine in effective amounts.
  • Example 4 Consistent with the promising results obtained in Example 4 for a wet granulation process to produce a layer of mirtazapine, batch 2 was selected for 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 a layer of mirtazapine and a batch of tizanidine made according to Example 5 (batch 3).
  • the aim 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 composed as follows: 150 mg immediate release layer containing 15 mg of mirtazapine; sustained release layer 180 mg containing 6 mg of tizanidine.
  • bilayer tablet The development of a bilayer tablet was based on the results obtained in Examples 4 and 5. Two-layer tablets were prepared using a rotary tablet press equipped with ten flat punches with a diameter of 9 mm. The final composition is shown in Table 6. The technological characteristics of the bilayer tablet are shown in Table 7.
  • Example 7 Study of the effect of the drug mirtazapine + tizanidine according to the present invention on mechanical allodynia in rats in a model of neuropathic pain caused by ligation of the spinal nerve.
  • the model of neuropathic pain caused by spinal nerve ligation has been widely used for various research work on the mechanisms of neuropathic pain, as well as for screening tests for the development of new analgesic drugs.
  • the ligation is performed by tight ligation of one (L5) or two (L5 and L6) segmental spinal nerves in a rat.
  • the operation results in long-term behavioral signs of mechanical allodynia, thermal hyperalgesia, cold allodynia, and persistent pain [25].
  • the experiments used adult rats of the Sprague-Dawley line with a body weight of 250-300 grams.
  • the rats were kept in temperature-controlled boxes (21 ° C) with a 12-hour day and night cycle and a sufficient amount of water and food.
  • the mean lethal doses for the investigated drugs were established, mg / kg: mirtazapine 324.0; tizanidine 230.9; mirtazapine + tizanidine, 15 + 6 mg 465.3.
  • the hypothetical median lethal dose (LD50 type) for the combined drug (calculated on the basis of the assumption of the additive interaction of the components) was:
  • the additivity principle is used in general toxicology as an initial hypothesis for the combined action of several toxic agents. It is assumed that the predicted effect of the 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 Finney [26].
  • the ratio LD5o (hyp) / LD5o (fact) is equal to or less than 0.57, i.e. it is possible to reduce the toxicity of the components in combination.
  • the LD50 (hyp) / LD50 (fact) ratio is equal to or more than 1.75, i.e. an increase in the toxicity of the components in combination is possible.
  • the obtained value equal to 0.54 may indicate a tendency towards toxicological interaction by the type of antagonism, that is, a possible decrease in the toxicity of the components in combination.
  • the tested drug in terms of acute toxicity, can be attributed to the 3rd class of moderately toxic substances according to the classification of Hodge and Sterner [27] and to the III class of moderately hazardous compounds according to GOST 12.1.007-76 [28].
  • the invention can be used in medicine, pharmacology, chemical and pharmaceutical industry.
  • Fawcett J., Barkin RL "A meta-analysis of eight randomized, double-blind, controlled clinical trials of mirtazapine for the treatment of patients with major depression and symptoms of anxiety" // Journal of Clinical Psychiatry, V. 59 , No. 3, 1998, P. 123-127;
  • Bomholt SF Mikkelsen JD, Blackbum-Munro G .: "Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain" // Neuropharmacology, V. 48, Xa 2, 2005 P. 252-263;

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Abstract

L'invention se rapporte au domaine de l'industrie chimique et pharmaceutique et de la médecine, et concerne une nouvelle composition pharmaceutique comprenant de la mirtazapine et de la tizanidine, ou leurs sels pharmaceutiquement acceptables, afin de traiter des troubles douloureux, laquelle est caractérisée en ce que la quantité de mirtazapine varie de 15 à 60 mg, celle de tizanidine de 6 à 24 mg, pour un rapport en poids entre la mirtazapine et la tizanidine de 2,5 pour 1 en termes de bases libres. L'invention concerne également une composition pharmaceutique, un agent médicamenteux, leur utilisation et un procédé de traitement de troubles douloureux.
PCT/RU2020/050357 2019-12-02 2020-12-01 Combinaison de mirtazapine et de tizanidine utilisée en case de troubles douloureux Ceased WO2021112724A1 (fr)

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KR1020227022618A KR20220110259A (ko) 2019-12-02 2020-12-01 통증 질환에 사용하기 위한 미르타자핀 및 티자니딘 배합물
TNP/2022/000140A TN2022000140A1 (en) 2019-12-02 2020-12-01 Mirtazapine and tizanidine combination for use in pain disorders
BR112022010718A BR112022010718A2 (pt) 2019-12-02 2020-12-01 Combinação de mirtazapina e tizanidina para uso em transtornos de dor
IL293562A IL293562A (en) 2019-12-02 2020-12-01 Mirtazapine and tizanidine combination for use in pain disorders
MX2022006581A MX2022006581A (es) 2019-12-02 2020-12-01 Combinacion de mirtazapina y tizanidina para su uso en trastornos del dolor.
CN202080083655.3A CN114761017B (zh) 2019-12-02 2020-12-01 用于疼痛疾患的米氮平和替扎尼定组合
SA522432821A SA522432821B1 (ar) 2019-12-02 2022-06-01 توليفة من ميرتازابين وتيزانيدين للاستخدام في اضطرابات الألم

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008009141A1 (fr) * 2006-07-21 2008-01-24 Queen's University At Kingston Procédés et thérapies permettant de potentialiser l'action thérapeutique d'un agoniste du récepteur adrénergique alpha-2 et inhiber et/ou inverser la tolérance aux agonistes du récepteur adrénergique alpha-2
WO2009092601A1 (fr) * 2008-01-25 2009-07-30 Grünenthal GmbH Forme posologique pharmaceutique
WO2010080580A2 (fr) * 2008-12-19 2010-07-15 Aaipharma Servcies Corp. Formulations pharmaceutiques à libération prolongée
WO2014148951A1 (fr) * 2013-03-22 2014-09-25 Общество С Ограниченной Ответственностью "Валента-Интеллект" Nouvelle combinaisons thérapeutiques de mirtazapine destinées à s'utiliser en cas de troubles douloureux

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CN101318020B (zh) * 2007-06-06 2011-09-28 四川科瑞德制药有限公司 抗焦虑或/和抗抑郁的药物组合物及用途
US20130116215A1 (en) * 2011-10-28 2013-05-09 Mireia Coma Combination therapies for treating neurological disorders

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008009141A1 (fr) * 2006-07-21 2008-01-24 Queen's University At Kingston Procédés et thérapies permettant de potentialiser l'action thérapeutique d'un agoniste du récepteur adrénergique alpha-2 et inhiber et/ou inverser la tolérance aux agonistes du récepteur adrénergique alpha-2
WO2009092601A1 (fr) * 2008-01-25 2009-07-30 Grünenthal GmbH Forme posologique pharmaceutique
WO2010080580A2 (fr) * 2008-12-19 2010-07-15 Aaipharma Servcies Corp. Formulations pharmaceutiques à libération prolongée
WO2014148951A1 (fr) * 2013-03-22 2014-09-25 Общество С Ограниченной Ответственностью "Валента-Интеллект" Nouvelle combinaisons thérapeutiques de mirtazapine destinées à s'utiliser en cas de troubles douloureux

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