EA031906B1 - Solid oral dosage form of mirtazapine and tizamidine for treating a pain disorder - Google Patents

Abstract

The invention relates to the field of psychopharmacology and neuropsychiatry, and in particular to means for the treatment of disorders associated with pain, more specifically to solid oral dosage form for the treatment of pain disorders containing 5-50 mg of mirtazapine and 0.5-6 mg of tizanidine at a ratio of mirtazapine and tizanidine, constituting from 20: 1 to 5: 1, and a pharmaceutically acceptable carrier. The solid oral dosage form of the invention makes it possible to increase the effectiveness of treatment by reducing the dosage of the agents in the composition, namely mirtazapine (INN) and tizanidine (INN) to achieve the desired therapeutic effect.

Description

The invention relates to medicine, namely to psychopharmacology, psychoneurology, in particular for the treatment of disorders associated with pain.

Pain, and in particular chronic pain, is a pain syndrome that, over an extended period of time, causes discomfort in a person. The length of this time interval is a relative value and does not allow us to specifically indicate the period when acute pain becomes chronic pain. Chronic pain is the end result of a number of physiological, psychological and even social processes. These biopsychosocial components of chronic pain interact and, moreover, affect each other.

According to Mathew Lefkowitz (MD Clinical Associate Professor of Anesthesiology State University of New York Health Science Center at Brooklyn), permanent nociceptive stimulation leads to neurophysiological responses, which in turn can trigger a chain of psychological reactions, and the resulting psychological changes can affect on the neurophysiological system of the body, accelerating or slowing down the conduct of nociceptive impulses. Social environmental factors, such as stress, attention and care from others, financial compensation for the costs of staying in the hospital, can significantly affect the level of pain intensity perceived by the patient. Stress and trauma clearly affect the perception of pain and can exacerbate pain.

Intense neuropathic pain can be a serious problem. Under normal conditions, damage to nerves that transmit a nociceptive signal leads to the fact that the signal does not pass further and pain is not perceived. But with damage to the sensory pathways, in many cases a paradoxical reaction occurs. Sensitivity to pain stimuli does not fall, on the contrary, spontaneous pains are noted. This is due to the fact that in a similar situation, damage causes deafferentation (interruption of the afferent innervation) of spinal neurons that conduct pain impulses, and in a certain way increases the activity of these neurons. Thus, the patient can feel pain in denervated areas. Usually, neuropathic pain is burning or stitching. Patients complain of strange sensations under the skin, as if something is torn, itchy, or there are pins and needles under the skin. Along with this, paresthesias and paroxysms of sharp electric shocks are noted. Patients often admit that the pain they feel is abnormal, pathological. Clinical examples of neuropathic pain include sympathetically supported pain (SPB), reflex sympatodystrophy (RSD), postherpetic neuralgia, phantom pains in the extremities and an avulsion of the brachial plexus.

The term sympathetically supported pain (SPB) refers to pain that is caused by impaired sympathetic efferent fibers. Reflex sympatodystrophy is a post-traumatic pain syndrome that is realized and maintained with the participation of the autonomic nervous system. However, in some cases, the history may indicate only minimal trauma or its complete absence, and damage to the nerve (causalgia) may not be.

In 90-95% of cases, STD is caused by trauma (for example, surgical trauma or injuries resulting from compression or rupture). Among other causes of the development of SPB syndrome, we note such as iatrogenic nerve damage (for example, a tight plaster cast); vein puncture or intramuscular injection; burns; infectious process; tooth extraction; or cerebrovascular accident.

Peripheral α-adrenergic activity in sympathetically supported pain syndrome. After certain types of injuries, the A1-adrenergic sensitivity of skin nociceptors increases, and at the same time, they begin to react more strongly to the activity of sympathetic efferent fibers. Sympathetic efferent impulse maintains the aforementioned skin nociceptors in a state of constant increased activity, and this leads to the fact that the central neurons that signal pain are in a state of permanent hypersensitivity. In this regard, the stimulation of mechanoreceptors with a low threshold of excitability leads to pain, which under normal conditions does not occur. Incoming nociceptive impulse from skin nociceptors, which is due to efferent sympathetic activity, maintains a state of central sensitization. When the impulse emanating from mechanoreceptors reaches the sensitized central neurons, pain occurs. In the later stages of SPB syndrome, nociceptors are in a state of sensitization even when the level of release of neurotransmitters in the sympathetic nervous system does not exceed normal values.

To date, the pathophysiology of sympatodystrophy remains unclear.

A special place among pain syndromes is visceralgia. The so-called pain in the pathological functioning of internal organs, the innervation of which is provided by the autonomic nervous system. It is known that central nervous apparatuses that conduct, analyze and suppress pain are common to the autonomic and somatic nervous systems. Probably these pains are provided by the disturbed functions of sympathetic efferent fibers, sympathetic pain (SPB). It should be emphasized that autonomic pain (vegetalgia) is not limited

- 1 031906 visceralgia and can be manifested by sympathetic syndromes on the face, limbs and trunk.

In many cases, patients with chronic pain syndrome become overly subordinate and dependent. They require more attention to themselves, feel seriously ill, begin to relax more and relieve themselves of responsibility for certain duties. This impedes the healing process and delays it. Additional characteristic signs of chronic pain syndrome (CHD): 1) the patient’s attention is constantly focused on pain, 2) constant complaints of pain, 3) dramatization of his pain sensations and a strong demonstration that he is sick (for example, grimacing, groaning, groaning, limping), 4) the use of a large number of different medicines, 5) the frequency of requests for medical care, 6) Munchausen’s syndrome, when they persistently prompt the doctor to do new research or interventions) and 7) family relationships are negative Live dynamics. Relatives of a patient with CHD also experience anxiety, depression, and fear.

For the treatment and prevention of pain syndromes, various drugs are used:

drugs affecting the synthesis of prostaglandins (non-narcotic analgesics, paracetamol, non-steroidal anti-inflammatory drugs - NSAIDs), which reduce the concentration of substance P (capsicum preparations for external use - capsaicin, capsins, etc.), local anesthetics, opiates, drugs that affect GABA -ergic structures (baclofen, sirdalud, gabapentin), anticonvulsants (carbamazepine, valproate, benzodiazepines, etc.), preparations - agonists of a2-adrenergic receptors, serum reuptake blockers otonin, for example amitriptyline, antidepressants.

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

Known combinations for treating headaches 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 (patent application RU 2002129356 A published on March 27, 2004). This solution has a narrow scope.

Known combination containing mirtazapine and zonisamide used in the treatment of disorders such as depression, schizophrenia, anxiety disorders associated with sleep disorders of the breath, insomnia, migraine, chronic head-on-head, hot flashes, lower back pain; neuropathic pain and functional somatic syndromes (PCT application WO 2006055854 A2, publ. 2006.05.26).

As the closest analogue, a combination containing α2 receptor agonists in a concentration effective to obtain a therapeutic effect and A2 adrenergic receptor antagonists in concentrations capable of effectively enhancing the therapeutic effect of a2 agonists of the receptor can be indicated (US 2008020076 A1, 2008.01.24 ) As a condition in which the introduction of such a combination is required, there may be pain, hypertension, glaucoma, nasal congestion, anxiety or withdrawal symptoms of opioids. Among a large number of agonists, tizanidine is mentioned, and among a number of antagonists, mirtazapine is mentioned. The task to be solved when creating this combination is to prevent side effects and tolerance to agonist therapy, such as sedation in clonidine, as well as dependence due to the use of ultra-low doses of the antagonist. There is no indication of the joint administration of a specific combination of mirtazapine and tizanidine with advantages for treating a specific condition - pain and the possibility of preventing side effects of antagonists when used in the form of solid oral forms in certain proportions.

The objective of the present invention is to develop a new, more effective means for the prevention and treatment of pain disorder, well tolerated by patients.

The problem is solved by creating a solid oral dosage form containing 5-50 mg of mirtazapine and 0.5-6 mg of tizanidine with a ratio of mirtazapine and tizanidine from 20: 1 to 5: 1, as well as a pharmaceutically acceptable inert carrier, and intended for the treatment or prevention of pain with psycho-organic, neurological, nociceptive, traumatic and other somatomorphic disorders.

Mirtazapine is disclosed in US Pat. No. 4,062,848. Known as a medicament for the treatment of depression and anxiety, it combines a good profile of side effects and a low risk of overdose with death. The dual mechanism of action of mirtazapine on 2 neurotransmitter systems defines it as a noradrenergic and specific serotonergic antidepressant NaSSA (T. De Boer et al., 1995). According to its action, mirtazapine is quite rapidly able to neutralize anxiety manifestations even in the first days of treatment. Available data suggest that mirtazapine is superior to placebo in the treatment of depression with anxiety and insomnia (J. Fawcett, R.L. Barkin, 1998). 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 rapidly reducing anxiety symptoms (H. Agren et al., 1998; D. Benkert et al., 1998; C. Kremer et al. , 1998). Mirtazapine has also been shown to be effective in treating post-traumatic stress disorder (K. Conner et al., 1998). More than half of the patients showed positive dynamics in terms of the reduction of the anxious component both during the interview with the doctor and during the self-test. Mirtazapine is effective in treating depression with generalized anxiety disorder. For example, an 8-week pilot study showed a marked decrease in depressive and anxiety symptoms. (P. Goodnick et al., 1997). A characteristic of mirtazapine is the fact that it does not inhibit cytochrome P-450.

With respect to mirtazapine, it is known that it has been investigated for anti-pain effects, Racemic intrathecal mirtazapine but not its enantiomers acts anti-neuropathic after chronic constriction injury in rats (Brain Res Bull. 2009 Apr 6; 79 (1): 63-8. Epub 2009 Jan 20), Mirtazapine decreases the pain feeling in healthy participants (Clin. J. Pain. 2008 Feb; 24 (2): 116-9), The effect of mirtazapine in patients with chronic pain and concomitant depression (Curr Med Res Opin. 2006 Feb; 22 (2): 257-64), Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain (Neuropharmacology. 2005 Feb; 48 (2): 252-63) , Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache (Neurology. 2004 May 25; 62 (10): 1706-11).

Tizanidine belongs to the group of drugs exhibiting muscle relaxant, central pharmacological effect. A2-adrenergic receptors excites mainly at the level of the spinal cord; reduces the release of exciting amino acids from intermediate neurons of the spinal cord, selectively suppresses the polysynaptic mechanisms responsible for muscle hypertonicity. It relaxes skeletal muscles in chronic spastic conditions of spinal and cerebral origin, eliminates acute painful muscle cramps and clonic convulsions. Reduces muscle resistance during passive movements, increases the strength of voluntary muscle contractions. Muscle relaxants reduce pathologically increased muscle tone. Due to this, pain decreases (rupture of the vicious circle pain-muscle spasm-pain), the volume of active movements increases. One of the drugs of choice is tizanidine, a muscle relaxant with antinociceptive action at a dose of 4-6 mg / day with a possible gradual increase to 12 mg / day. The effect is manifested in the first week of treatment. [Handbook of outpatient physician. Volume 1 / N 1/2001, V.V. Alekseev. Clinic of Nervous Diseases (headed by Prof. NN Yakhno) MMA named after THEM. Sechenov]. It is proved that the use of 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 recurrence of MFS. Tizanidine, along with muscle relaxant effect, has an analgesic effect.

Like other agonists, tizanidine has a sedative effect. However, while the purpose of the solution for the closest analogue is to eliminate the sedative effect of clonidine as a side effect, it was unexpectedly found that in the claimed combination this effect is not pronounced, but to such an extent that it provides additional advantages: it allows to achieve better tolerance in patients.

Documents WO 2009/092601 A1, 07/30/2009, WO 2006/082099 A1, 08/10/2006, RU 2461381 C2, 09/20/2012 by the company GRUNENTAL GmbH (DE) indicate that solid oral dosage forms may contain one active ingredient or several compounds selected from a huge variety of these drugs, including mirtazapine and tizanidine. However, in these sources there is no indication that it is a combination of mirtazapine and tizanidine in a single dosage form, in certain doses and ratios, that will achieve a greater therapeutic effect in conditions accompanied by pain. There are no indications of specific dosages of the active ingredients. In these sources, the aim of the invention is to increase the strength of the tablets for the controlled release of the active substance.

Moreover, the present invention provides oral preparations and methods of treating a mammal, in particular a person suffering from a pain syndrome and / or conditions / diseases accompanied by pain. In specific clinical situations of implementation, such methods involve the systemic administration of a composition for the treatment of acute and / or chronic pain.

Pain can 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, for fibromyalgia, somatotrophic disorders, arthralgia, oncology, neck pain, shoulder pain, back pain, headaches, 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 pain, including

- 3 031906 sunburn, urogenital pains, including cystitis, tonsillitis.

A feature of the present invention is that the combined use of specific drug agents of mirtazapine and tizanidine in certain dosages and ratios allows to achieve a greater therapeutic effect in conditions accompanied by pain.

Thus, the present invention, as described above, provides a solid oral dosage form containing in effective amounts mirtazapine and a muscle relaxant, tizanidine. In particular, the present invention provides a solid oral dosage form containing 5-50 mg of mirtazapine and 0.5-6 mg of muscle relaxant tizanidine with a ratio of mirtazapine and tizanidine of 20: 1-5: 1.

The present invention provides, according to the invention, an effective use in the prevention or treatment of preferably chronic pain.

The present invention also includes the treatment of an animal, for example a mammal, including a person suffering or suffering from a disease of pain and / or somatomorphic disorder.

Preferably, the pain disorder is a somatomorphic pain disorder.

A special case of the appointment is a pain disorder that is associated with inflammatory disorders, with spastic disorders, with arthritis, and with an autoimmune disease.

Another feature of the present invention is a method of reducing the amount of therapeutic agent required to create an analgesic effect, which includes treatment with a therapeutically effective amount of a combination according to the present invention.

The present invention also provides the use of mirtazapine in a medicament for simultaneous and / or sequential administration with the muscle relaxant tizanidine for the treatment and / or prevention of pain disorder. At the same time, muscle relaxant is used in the manufacture of a medicinal product for simultaneous or sequential administration with mirtazapine.

The introduction of muscle relaxant in combination with mirtazapine provides the possibility of reducing the dosage of the active substances used to achieve the same therapeutic effect. The dosage of active substances can be reduced by 25-90% or 35-75%, the most acceptable option is 5070%.

Reducing the required amount of active substances will depend on the need for clinical effect. The dose of mirtazapine used is the dose described below.

Patients treated with a combination of mirtazapine and tizanidine in certain amounts and ratios did not experience increasing weakness. In addition, patients tolerated therapy better than in the control group, where the active components were used separately.

The combination of mirtazapine and tizanidine for convenience may be presented in the form of a pharmaceutical composition in unit dosage form, such as a solid oral dosage form. A convenient solid oral dosage unit form contains active substances in amounts of mirtazapine 5-50 mg; tizanidine 0.5-6 mg with a ratio of 20: 1-5: 1.

The pharmaceutical compositions of the invention comprise a combination together with one or more pharmaceutically acceptable carriers or excipients suitable for the preparation of solid oral dosage forms.

The carrier (s) should be acceptable in the sense of compatibility with other ingredients of the composition and not harmful to the recipient. When the components of the combination are administered separately, each of them is generally presented as a pharmaceutical composition.

Currently, pharmaceutical compositions are more often prescribed to the patient in patient packs containing a full course of treatment in one pack, usually a blister pack.

Compositions suitable for oral administration can be presented in the form of dosage forms, such as tablets, troches, starch capsules, capsules, microcapsules, each of which contains a predetermined amount of the active ingredient in the form of powder or granules. The active ingredient may also be present as a bolus and may be contained within liposomes.

The possibility of carrying out the invention can be demonstrated by the following (not limiting the scope of the invention) examples.

Example 1. A tablet.

Mirtazapine - 20 mg.

Tizanidine - 1 mg.

Mannitolum - 225 mg.

Magnesium stearate - 5 mg.

Silicon dioxide - 1 mg.

Lactose - 48 mg.

Example 2. The use of animal models for the study of analgesic activity.

An animal model of chemically induced pain was used to determine the analgesic activity of various concentrations of the test combination.

- 4 031906

Formalin test on mice.

The combination of mirtazapine and tizanidine was administered orally to groups of ten male mice. A decrease in formalin-induced hind paw licking, fixed at five-minute intervals during the next period from 0 to 35 minutes after formalin injection, by 50% or more (> 50%) indicates significant analgesic activity. Statistical analysis was carried out using a one-way analysis, for which the Student criterion was used to compare the results obtained with mirtazapine and tizanidine with the results obtained in comparison with the control (glucose solution). The significance of P <0.05 was taken. The results are shown below.

Mirtazapine and tizanidine.

r / o - the oral route of administration (per os);

p / e - parenteral route of administration (parenteral).

A drug The method is entered Administered dose of mg Hind paw licking time (seconds) (Average ± SOS) Time (minutes) 0-5 5-10 10-15 15-20 20-25 25-30 30-35 The control r / o - 71.2 ± 3, 2 70.9 ± 0, 9 78.0 + 5, 7 79.4 ± 12 ,9 75.1 ± 19 , 2 41.2 ± 9, 6 14.5 ± 7 4 Mirtazapi n r / o 2,4 69.5 + 11 , 3 10.2 + 2, 8 64.1 + 1, 5 59.5 + 2, 8 42.5 + 9, 9 39.4 ± 8, 8 36.9 + 14 , 3 Tizanidine r / o 0.32 67.8 ± 9, 1 66.9 + 3. 7 67.5 ± 12 ,1 54.3 + 9. 7 45.5 ± 6, 8 45.0 + 11, 2 35.3 ± 1O, 4 Mirtazapi n + Tizanidine r / o 1.2 + 0.16 55.4 + 12, 1 47.3 + 13 ,5 43.7 + 1, 9 19.6 + 10 , 7 26.3 + 8, 1 24.6 + 9. 2 14.1 + 5, 9 Mirtazapi n + Tizanidine r / o 2.4 + 0.32 46.7 ± 2, 8 42.4 ± 13 ,8 29.4 ± 8, 1 34.9 ± 11 ,5 33.1 ± 15, 2 6.5 ± 9.2 19.3 ± 11 ,5 Mirtazapi n + Tizanidine r / o 3.6 + 0.48 45.2 + 17 ,4 41.9 ± 8, 4 40.1 + 12 ,5 25.2 ± 10 , 3 11.7 + 1, 9 27.2 ± 9, 4 18.7 + 6, 6 Ketorolac r / e thirty 26.8 ± 13 .2 10.1 + 2, 6 12.0 + 5. 4 22.1 * ± 2 0 15.4 * ± 1 .3 10.2 ± 6. 1 4.9 ± 2.7 * P <0.05 with respect to the control group receiving the glucose solution

The results indicate that oral administration of the combination of mirtazapine + tizanidine leads to analgesia after 15-20 minutes against the background of the introduction of a formalin sample. The reference drug Ketorolac causes a significant analgesic effect during the early (0-5 min) medium-delayed (15-25 min) and late phase after formalin injection, as expected.

It was also established that the use of a combination in the form of a solid dosage form orally with the claimed ratio of active components allows us to achieve the necessary half-life of tizanidine, which, unlike mirtazapine, which has been circulating for a long time in the blood, is usually rapidly excreted from the body.

In the practical application of the proposed solid oral dosage form, said dosage form may contain the active ingredients mirtazapine and tizanidine, taken in the above amounts and quantitative ratios, in a homogeneous mixture with an acceptable inert pharmaceutical carrier.

Claims (6)

CLAIM 1. A solid oral dosage form for the treatment of pain disorder, containing 5-50 mg of mirtazapine and 0.5-6 mg of tizanidine with a ratio of mirtazapine and tizanidine ranging from 20: 1 to 5: 1, and a pharmaceutically acceptable carrier. 2. The solid oral dosage form according to claim 1, characterized in that the pain disorder is a somatomorphic pain disorder. - 5,031,906 3. A solid oral dosage form is associated with inflammatory disorders. 4. A solid oral dosage form is associated with spastic disorders. 5. A solid oral dosage form is associated with arthritis. 6. A solid oral dosage form is associated with an autoimmune disease. claim 1, characterized in that the pain disorder claim 1, characterized in that the pain disorder claim 1, characterized in that pain disorder claim 1, characterized in that pain disorder