WO2019182474A1 - Combinaison de buspirone utilisée pour traiter l'étourdissement - Google Patents

Combinaison de buspirone utilisée pour traiter l'étourdissement Download PDF

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WO2019182474A1
WO2019182474A1 PCT/RU2019/000057 RU2019000057W WO2019182474A1 WO 2019182474 A1 WO2019182474 A1 WO 2019182474A1 RU 2019000057 W RU2019000057 W RU 2019000057W WO 2019182474 A1 WO2019182474 A1 WO 2019182474A1
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buspirone
dizziness
piracetam
vestibular
betahistine
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Russian (ru)
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Максим Валерьевич ЗАМЕРГРАД
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Общество с ограниченной ответственностью "ВАЛЕНТА ИНТЕЛЛЕКТ"
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Definitions

  • the present invention relates to the field of medicine and pharmacology, in particular to new combinations of buspirone with at least one substance selected from the group consisting of betahistine and piracetam, for the treatment of vestibular and bribery dizziness.
  • Dizziness is often a debilitating condition that causes a feeling of loss of balance and illusory impressions from the movement of the body or the environment of the patient.
  • the causes of dizziness can be otogenic (as in the case of Meniere's syndrome), i.e. associated with an imbalance of the otovestibular apparatus and the labyrinth, toxic (for example, caused by drugs or alcohol), psychogenic, neurological, associated with blood circulation, tumors or vision (diplopia).
  • the treatment for dizziness obviously depends on its etiology, but currently symptomatic treatment is based on drugs such as dimenhydrinate, promethazine, and meclosin.
  • Dizziness is observed in 17-30% of adults in the general population. Distinguish vestibular dizziness (systemic dizziness, vertigo) and brides dizziness (non-systemic dizziness).
  • Vestibular dizziness in the broad sense may be due to organic changes in the central and peripheral structures of the vestibular apparatus.
  • Vestibular dizziness about 24% of cases of dizziness (3-10% of adults in the general population) - is associated with damage to the peripheral (structure of the inner ear) or central (core and CNS pathways) link of the vestibular apparatus.
  • Comorbidity of vestibular and mental (anxiety, depression) disorders is about 50%. Vertigo is more likely to be detected in women and people with migraines. The presence of vertigo can cause the secondary development of anxiety disorders.
  • agents such as gentamicin (Meniere's disease) may be used; carbamazepine (vestibular paroxysm); acetazolamide, 4-aminopyridine (episodic ataxia type 2).
  • Symptomatic treatment of dizziness is aimed at stopping the manifestations of vestibular dysfunction.
  • the main drugs are vestibulosuppressors and antiemetics: dimenhydrinate, metoclopramide, phenothiazines (fluorophenazine, thiethylperazine, thioridazine, promazine), benzodiazepine tranquilizers (nozepam, diazepam, hydazepam). Due to vomiting, these drugs are administered intramuscularly or in the form of suppositories. The duration of their use is dictated by the severity of dizziness. Usually it is limited to 3 days, since these drugs inhibit vestibular compensation.
  • Non-vestibular (not associated with an organic lesion of the vestibular analyzer) dizziness - about 76% of dizziness cases - may be due to various diseases of the nervous system, manifested by instability (polyneuropathy, cerebellar ataxia, frontal dysbasia), cardiovascular disorders (fainting, orthostatic hypotension), but most often has a functional nature (persistent postural perceptual dizziness, previously - chronic subjective dizziness, phobic postural dizziness).
  • Functional dizziness occurs as a result of a violation of the interaction between the vestibular, visual and somatosensory systems, which normally together provide spatial orientation. Dizziness can also be caused by physiological stimulation of normally functioning sensory systems or a mismatch between the information received from various sensory systems (motion sickness in a car, altitude dizziness and visually caused dizziness). Another example of functional dizziness is dizziness, which occurs due to too active movement of the head in zero gravity.
  • Dizziness which develops in connection with psychological factors, is also defined as functional dizziness, as opposed to organic, arising from structural changes in organs.
  • functional disorders are often preceded by organic ones, which increase the functional vulnerability of the organ in stressful situations.
  • the concept of somatoform disorders adopted in modern international classifications, provides for their diagnosis based on persistent complaints of patients in the absence of pathogenetically caused changes in organs. Essentially this concept is devoid of any significant psychopathological content [Veltishchev D.Yu., Seravina O.F. // Psychiatry, N ° 4 (55), 2010].
  • a functional disorder is a state of health in which a normal physiological process is disturbed, but the pathology of any organ is not detected during the study. This contrasts with a structural disorder (in which it may be found that an organ is functioning abnormally) or a psychosomatic disorder (in which the symptoms are caused by a psychological or mental illness).
  • a structural disorder in which it may be found that an organ is functioning abnormally
  • a psychosomatic disorder in which the symptoms are caused by a psychological or mental illness.
  • functional dizziness is not a mental illness [Dieterich M., Staab J.P., Brandt T. Functional (psychogenic) dizziness // Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468], i.e. not caused by primary psychiatric pathology, such as anxiety disorder or depression, and also not caused by structural changes in the central nervous system.
  • Functional vestibular disorders include, in particular, the following diseases, described in detail in the neuro-otological literature: persistent postural perceptual dizziness, postural phobic instability, and chronic subjective dizziness. None of these disorders has a pathognomonic symptom or manifestation, but all of them have key features that indicate their presence, regardless of whether the patient has other diseases [Dieterich M., Staab JP, Brandt T. Functional (psychogenic) dizziness // Handbook of Clinical Neurology, Vol. 139, Chapter 37, 2016, pp. 447-468].
  • Ataxia is a neurological condition, manifested by a lack of coordination of movements, including gait disorders. Ataxia is a non-specific clinical manifestation involving dysfunction of parts of the nervous system that coordinate movement, such as the cerebellum. Ataxia can be limited to one side of the body.
  • An example of a disease manifested by ataxia is Friedreich's disease.
  • EA familial periodic ataxia or hereditary paroxysmal cerebellar ataxia
  • EA-2 episodic ataxia type 2
  • EA-1 and EA-2 were identified as an opiate channel.
  • EA-1 is due to various heterozygous point missense mutations in the gene of the voltage-dependent potassium channel delayed rectification (KCNAl / Kvl.l) in chromosome 12pl 3, while EA-2 is caused by mutations in the alpha 1 subunit of the cerebral calcium channel P / Q subunit CACNL1A4 localized on chromosome 19p, which is significantly expressed in the cerebellum [Brandt T., Strupp M. Episodic ataxia type 1 and 2 (familial periodic ataxia / vertigo) Audiol. Neurootol. 1997; 2 (6): 373-83].
  • Treatment of episodic ataxia includes rehabilitation measures (special exercises to adapt the vestibular apparatus) and pharmacotherapy aimed at stopping the symptoms and achieving vestibular compensation.
  • acetazolamide has been suggested that the mechanism of action of acetazolamide is to reduce the pH, which prevents the penetration of ions through open calcium channels. Acetazolamide can stabilize channels that cannot be effectively inactivated. Acetazolamide may not work in cases where the mutation affects the pore region of calcium channels, eliminating the stabilizing effect of H + ions. 4-AR is a potassium channel blocker, and it is usually used when acetazolamide does not give a therapeutic effect [Yue Q, Jen JC, Nelson SF, Baloh RW. Progressive ataxia due to a missense mutation in a calcium channel gene. Am J. Hum. Gen, 1997 61 (5): 1078-87].
  • the drugs of choice for vestibular dizziness are vasoactive (cinnarizine, cinnarizine and piracetam), H ! antihistamines (dimenhydrinate) and vestibulotropic (betahistine) drugs.
  • Dimenhydrinate is characterized by a sedative effect and may have a negative effect on the processes of central vestibular compensation (from a clinical point of view, it is advisable to use a short course of 3 days, mainly to stop dizziness, nausea and vomiting in acute vestibulopathies).
  • Buspirone (and its pharmaceutically acceptable salt hydrochloride) is a partial 5-HT1A receptor agonist, which was launched more than 20 years ago by Bristol-Myers Squibb for the oral treatment of anxiety disorders with or without accompanying depression. In 1990, buspirone was launched by the company in collaboration with Menarini to treat generalized anxiety disorder (GAD).
  • GAD generalized anxiety disorder
  • NCI National Cancer Institute
  • NINDS National Institute of Neurological Disorders and Stroke
  • NINDS National Institute of Neurological Disorders and Stroke
  • NIDA National Institute for Drug Abuse Control
  • NIDA National Institute for Drug Abuse Control
  • Buspirone is an atypical anxiolytic that is highly effective against generalized anxiety disorder [Apter JT, Allen LA. Buspirone: future directions. J Clin Psychopharmacol. 1999; 19 (1): 86-93; Flint AJ. Generalized anxiety disorder in elderly patients: epidemiology, diagnosis and treatment options. Drugs Aging. 2005; 22 (2): 101-14; Gale CK, Millichamp J. Generalized anxiety disorder in children and adolescents. BMJ Clin Evid. 2016; 2016. pii: 1002; Goa KL, Ward A. Buspirone. A preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs 1986 Aug; 32 (2): 114-29]. Partial 5-HT1A receptor agonist and 02 receptor antagonist [Loane C, Politis M.
  • Buspirone what is it all about? // Brain Res. 2012; 1461: 111-8; Newman-Tancredi A, Gavaudan S, Conte C, Chaput C, Touzard M, Verriele L, Audinot V, Millan MJ. Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S] GTPgammaS binding study. Eur J Pharmacol. 1998; 355 (2-3): 245-56; Tunnicliff G. Molecular basis of buspirone's anxiolytic action. Pharmacol Toxicol. 1991; 69 (3): 149-56], buspirone, apparently, does not slow down the processes of vestibular compensation.
  • Buspirone differs from typical benzo-diazepine anxiolytics in that it does not have an anticonvulsant or muscle relaxant effect. With its use, there is also no known sedative effect, which is associated with more typical anxiolytics.
  • In vitro buspirone showed high affinity for serotonin receptors (5-HT1A). The drug has no significant affinity for benzodiazepine receptors and does not affect binding to GABA receptors in vitro or in vivo when tested in preclinical models. It exhibits a moderate affinity for dopamine D2 receptors in the brain.
  • buspirone Unlike benzodiazepines, the probable anxiolytic mechanism of action of buspirone remains unclear due to conflicting anxiolytic effects in the clinic and in studies using animal models [Bauer MS, Wisniewski SR, Marangell LB, Chessick CA, Allen MH, Dennehy EB, Miklowitz DJ , Thase ME, Sachs GS. Are antidepressants associated with new-onset suicidality in bipolar disorder? A prospective study of participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). J. Clin Psychiatry. 2006; 67 (1): 48-55].
  • buspirone The anxiogenic effect of buspirone is of great clinical significance due to the fact that an exacerbation may be observed at the initial stage of chronic treatment with buspirone, which requires careful monitoring of the treatment regimen [Chignon JM, Lepine JP. Panic and hypertension associated with single dose of buspirone. Lancet. 1989; 2 (8653): 46-7; Liegghio NE, Yeragani VK, Moore NC. Buspirone-induced jitteriness in three patients with panic disorder and one patient with generalized anxiety disorder. J Clin Psychiatry. 1988; 49 (4): 165-166; Newton RE, Marunycz JD, Alderdice MT, Napoliello MJ. Review of the side-effect profile of buspirone. Am J Med., 1986; 80 (3B): 17-21].
  • Buspirone acts as a complete agonist of 5-HT1A autoreceptors located on the surface of suture nucleus dendritic neurons, reducing the excitation of 5-HT neurons and thereby reducing the release of serotonin in this structure, and thereby activating other brain structures. This mechanism is believed to be partially responsible for the anxiolytic effect of buspirone [Carli M, Prontera C, Samanin R.
  • buspirone also has the activity of a postsynaptic 5-HT1A receptor agonist, thereby reducing neuronal excitation.
  • These opposite effects can cause the biphasic anxiety-modulating effect of buspirone [Sillar CT1, Simmers AJ. Presynaptic inhibition of primary afferent transmitter release by 5-hydroxytryptamine at a mechanosensory synapse in the vertebrate spinal cord. J Neurosci. 1994; 14 (5 Pt 1): 2636-47; McNaughton N, Panickar KS, Logan B. The pituitary-adrenal axis and the different behavioral effects of buspirone and chlordiazepoxide. Pharmacol Biochem Behav.
  • buspirone for palliative treatment of neurosis, in which symptoms of anxiety are manifested, is known from the prior art (US 4182763, January 8, 1980); with hyperactivity, attention deficit (EP 0497314, 03/01/1989); for the treatment of drug addiction and dependence (US 5185329, 02/03/1993); for the treatment of anxiety disorders (WO 2005049041, 02/02/2005; US 7678363, 03/16/2010); psychiatric disorders (US 7678363, March 16, 2010); depression (WO 2007144080, 12/21/2007); neurological disorders (WO 2008083204, 07/10/2008).
  • buspirone or its derivatives for the treatment of pathological conditions associated with immune responses is known (EP0690715, 05.28.2003); for the treatment of disorders of sexual function and reproduction (US 8052982, 08/08/2011) and sexual dysfunction (US 4640921, 02/03/1987); for the treatment of sleep-related respiratory diseases (WO 2000006163, 02.10.2000).
  • buspirone for the treatment of glaucoma (US 7763619, 07/27/2010), pain, neuropathy (US 6511982, 01/28/2003), pruritus (WO 2004084900, 10/07/2004), for the treatment, prevention or alleviation of motor disorders such as Parkinson's disease is known.
  • dyskinesia US 9186359, 11/17/2015
  • Parkinson's disease WO 2015127558, AND
  • Betagistin an NZ-antagonist and weak agonist of H1-histamine receptors, enhances cochlear blood flow, affects the activity of vestibular neurons, changes the production of endolymph in the labyrinth, and therefore the effects of the drug can be expected mainly with dizziness against the background of lesions of the peripheral link of the vestibular analyzer.
  • Piracetam is a nootropic drug, one of the main representatives of this group of drugs, it remains one of the most important in it. It is chemically a pyrrolidone derivative.
  • Piracetam binds to the polar heads of phospholipids and forms mobile complexes of piracetam-phospholipid. As a result, the two-layer structure of the cell membrane and its stability are restored, which in turn leads to the restoration of the three-dimensional structure of membrane and transmembrane proteins and the restoration of their function.
  • piracetam facilitates various types of synaptic transmission, exerting a predominant effect on the density and activity of postsynaptic receptors (data obtained in animal studies). Improves connections between the hemispheres of the brain and synaptic conduction in neocortical structures, improves cerebral blood flow. It has an effect on the central nervous system in various ways: modifies neurotransmission in the brain, improves metabolic conditions conducive to neuronal plasticity, improves microcirculation, affecting the rheological characteristics of the blood. With cerebral dysfunction, it increases concentration and improves cognitive functions, including learning ability, memory, attention and consciousness, mental performance without sedating or psychostimulating effect.
  • piracetam is accompanied by significant changes in the EEG (increased a- and b-activity, decreased d-activity). It helps to restore cognitive abilities after various cerebral injuries due to hypoxia, intoxication or electroconvulsive therapy, with encephalopathic disorders, memory disorders, intellectual deficiency, etc., can be used to reduce the manifestations of hypoxia and cerebral ischemia in acute viral neuroinfections [Niss A.I., Umansky K.G. et al. On the effectiveness of piracetam treatment of acute viral neuroinfections. // Journal. neuropathol. and a psychiatrist. - 1985. 2. S. 189-195].
  • Piracetam is also used for diseases of the nervous system, accompanied by a decrease in intellectual-mnestic functions and disorders of the emotional-volitional sphere.
  • piracetam is used in patients with neurotic and astenoadynamic depressive states of various origins with a predominance of clinical signs of adynamia, asthenic and senesto-hypochondriacal disorders, phenomena of idiopathic inhibition, as well as sluggish apathic defective states in patients with schizophrenia, psycho-organic syndromes of various etiologies, senile and atrophic processes, in the complex therapy of various mental diseases.
  • Piracetam can also be used as an adjuvant in the treatment of patients with depressive states that cannot be treated with antidepressants, as well as with poor tolerance of antipsychotics and other psychotropic drugs in order to eliminate or prevent somatovegetative, neurological and psychological complications caused by them.
  • the therapeutic properties of piracetam are determined by its ability to enhance the integrative activity of the brain and intellectual activity, promote memory consolidation, improve learning processes, restore and stabilize brain functions, including in the elderly and senile [L. Pimenov, S. A. Kalinina ., Churshin A.D. Clinical and hemodynamic efficacy of piracetam (nootropil) in patients with coronary heart disease in the elderly and senile at the outpatient stage of rehabilitation. // Cardiol. - 1992. N ° 5. S. 35-38].
  • Piracetam is also used to relieve withdrawal, pre-lirious and delirious conditions in cases of alcoholism and drug addiction, as well as in cases of acute poisoning with alcohol, morphine, barbiturates, etc.
  • the use of piracetam in the complex of drugs for the relief of acute phenomena of alcohol withdrawal reduces the severity of cerebral vascular disorders, reduces dizziness, a feeling of apathy, drowsiness [Entin G. M. Treatment of alcoholism. - M .: Medicine, 1990].
  • piracetam is prescribed to reduce the phenomena of asthenia, intellectual-mental and other disorders of mental activity.
  • Piracetam is characterized by very low toxicity, LD50 for rats is 10.6 g / kg when administered intravenously [AN Gouliaev, A Senning Piracetam and other structurally related nootropics // Brain Research. Brain Research Reviews. - 1994. N ° 19 (2). C. 180-222].
  • piracetam reduced erythrocyte adhesion to vascular endothelium and stimulated the production of prostacyclins in the endothelium. Animal studies have shown that piracetam inhibits vascular spasm and is antagonistic to the action of various vasospastic substances.
  • the number of patients with dizziness decreased from 3265 to 960 (an improvement of 70.6%), with a decrease in motivation - from 3803 to 1185 (68.8%), with severe fatigue - from 4255 to 1474 (65.4%), with depression - from 2238 to 830 (62.9%), with a decrease in concentration of attention - from 4676 to 1759 (62.4%), with a decrease in adaptation - from 1566 to 623 (60.2%), with tinnitus - from 2064 to 888 (57%), with a decrease in perception - from 4518 to 2086 (53.8%), with sleep disturbance - from 3024 to 1690 (44.1%).
  • the drug tolerance was rated as very good: only 339 (6.6%) patients had minor side effects - sleep disturbances, gastrointestinal upsets, agitation, headaches.
  • Piracetam treatment was carried out for 90 days in various dosages: patients under 60 took 2 capsules 3 times a day (2400 mg / day), patients over 60 took a drinking solution of 1 g three times a day (3 g / day) . Patients were examined before starting therapy, on the 45th and 90th day of treatment.
  • Medical product - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations intended to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology.
  • “Pharmaceutical composition” means a composition comprising a combination according to the invention and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, dispersants, delivery vehicles, such as preservatives, stabilizers, fillers, disintegrants, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, perfumes, flavors, antibacterials tal agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on their nature, method of administration of the composition and dosage.
  • suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be achieved using a variety of antibacterial and antifungal agents, for example, such as parabens, chlorobutanol, sorbic acid and the like.
  • the composition may also include isotonic agents, for example, sugars, sodium chloride and the like. The prolonged action of the composition can be provided with the help of agents, slowing down the absorption of the active principle, for example, such as aluminum monostearate and gelatin.
  • Suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate).
  • excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
  • disintegrating and dispersing agents are starch, alginic acid and its salts, silicates.
  • lubricants are magnesium and calcium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
  • the pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers.
  • Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • “Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of the compounds, or obtained on purpose. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates, mesylates malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like, preferably hydrochlorides and maleates (Detailed description of properties such salts are given in Berge SM, et al., “Pharmaceutical Salts” // J.
  • Salts of the claimed acids can also be specially prepared by reacting the purified acid with a suitable base, and metal and amine salts can be synthesized.
  • Metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum salts, the most desirable of which are sodium and potassium salts.
  • Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, sodium bicarbonate and hydride, potassium hydroxide and bicarbonate, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide.
  • amines and amino acids are selected that are sufficiently basic to form a stable salt and are suitable for medical use (in particular, they should have low toxicity).
  • Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like.
  • tetraalkylammonium hydroxides, choline, tetramethylammonium, tetraethylammonium and the like can be used for salt formation.
  • amino acids the main amino acids can be used - lysine, ornithine and arginine.
  • the pharmaceutically acceptable salt of buspirone is buspirone hydrochloride; preferred pharmaceutically acceptable salts of betahistine are dihydrochloride, maleate, mesylate, betahistine dimesilate.
  • treatment means any treatment for a disease or condition in a subject, including 1) suppressing the development of a disease or condition, which means stopping or suppressing the development of clinical symptoms, and / or 2) reducing the intensity of the symptoms of the disease or condition, which means regression of clinical symptoms.
  • terapéuticaally effective amount means an amount of a combination of the compounds of the present invention or any derivatives thereof that (1) treats or prevents a particular disease, condition or disorder, (2) alleviates, improves or eliminates one or more symptoms a particular disease, condition or disorder, or (3) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder set forth herein.
  • pharmaceutically acceptable means that the substance or composition to which this term is applied must be compatible, in terms of chemistry and / or toxicology, with the other ingredients that make up the drug, and is safe for anyone who is being treated with this substance or composition, in applicable doses.
  • buspirone in combination with at least one substance selected from the group consisting of betahistine and piracetam, gives an unexpected synergistic effect in the treatment of vestibular and bribery dizziness.
  • the task is carried out, and the technical result is achieved by obtaining a combination for the treatment of vestibular and brides dizziness, containing in effective amounts (a) buspirone and (b) at least one substance selected from the group comprising betahistine and piracetam, or their pharmaceutically acceptable salts .
  • the specified technical result is also achieved by the fact that:
  • a pharmaceutical composition for the treatment of vestibular and brides dizziness containing in effective amounts a combination of (a) buspirone and (b) a substance selected from the group comprising betahistine and piracetam, or their pharmaceutically acceptable salts, and at least one excipient and / or at least one pharmaceutically acceptable carrier.
  • the specified technical result is also achieved by the fact that:
  • betahistine from 1: 288 to 6.25: 1;
  • buspirone piracetam from 1: 1200 to 1: 2.
  • a kit for the treatment of vestibular and brides dizziness containing instructions for use and a pharmaceutical composition containing in an effective amount of buspirone or its pharmaceutically acceptable salt, at least one excipient and / or at least one a pharmaceutically acceptable carrier and a pharmaceutical composition comprising in an effective amount of at least one substance selected from uppy consisting of betahistine and piracetam, or its pharmaceutically acceptable salt, at least one excipient and / or at least one pharmaceutically acceptable carrier.
  • the subject of the present invention is also the use of a combination of either a pharmaceutical composition or a kit of the present invention for the treatment of vestibular and bridy dizziness.
  • the task is also carried out, and the technical result is achieved by using the aforementioned combination or the said pharmaceutical composition, or the said kit for the treatment of vestibular and bridy dizziness.
  • the specified technical result is also achieved by the fact that:
  • the combination, composition or kit of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally).
  • the clinical dosage of the agent of the present invention in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients, their metabolic rate and excretion from the body, as well as on the age, gender and stage of the patient’s disease, with a daily dose in adults usually of 5 - 100 mg of buspirone, 16 - 1500 mg of betahistine and 200 - 6000 mg of piracetam.
  • each dosage unit of the drug containing 5-100 mg buspirone and 16- 1500 mg of betahistine and / or 200 to 6000 mg of piracetam.
  • these drugs can be taken several times during certain periods of time (preferably from one to six times).
  • Example 1 Evaluation of the effectiveness of drugs with vestibular dizziness.
  • Symptoms similar to those of vestibular dizziness are observed in rats that have lost vestibular function as a result of unilateral labyrinectomy.
  • the loss of vestibular function in this case is not complete and irreversible: normally, vestibular compensation begins to occur over time.
  • Rats In the experiments, adult Spreg-Dawley rats were used, having a body weight of 370-400 grams. Rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour cycle of day and night and plenty of water and food.
  • Dosage and administration The study was carried out for 3 drugs (buspirone, betahistine, piracetam), each of which was administered in 3 different doses, and for 2 combinations (buspirone + betagistin, buspirone + piracetam), each of which was also administered in three doses.
  • the control was a group of rats receiving only the vehicle (placebo group).
  • Dosage information is given in table 1 below. All drugs were administered intravenously (in the tail vein) 30 minutes before surgery and then once a day for the entire duration of the study. All doses are calculated per person.
  • Results In general, the functional state of the animals, recorded in the first week after surgery, was better in the groups receiving any drug, compared with the placebo group, which was administered only the carrier. The groups receiving the combination of drugs on the 5th and 7th day showed the highest recovery rates, significantly different from the mono-administration and placebo groups. Moreover, the observed effect was super-additive at each concentration level.
  • Example 2 Evaluation of the effectiveness of drugs in reducing brides dizziness.
  • Non-vestibular dizziness can be modeled for rodents under rotation for a predetermined period of time.
  • Rats the study involved adult Sprague-Dawley rats having a body weight of 350-370 grams. Rats were kept in temperature-controlled boxes (with a temperature of 21 ° C) with a 12-hour cycle of day and night and plenty of water and food.
  • Dosage and administration The study was carried out for 3 drugs (buspirone, betahistine, piracetam), each of which was administered in 3 different doses, and for 2 combinations (buspirone + betagistin, buspirone + piracetam), each of which was also administered in three doses.
  • the control was a group of rats receiving only the vehicle (placebo group).
  • Dosage information is given in table 1 above. All drugs were administered intravenously (in the tail vein) daily for a week before the start of testing. All doses are calculated per person.
  • the test is based on maintaining equilibrium with rats on a narrow bar raised above the ground (width 3 cm, length 1 m). Preliminarily, for 2 minutes, the rats were rotated at a speed of 50 rpm in a closed compartment, after which they were moved to a narrow bar, brightly lit at the start, and the animals were monitored for 120 seconds. In this format, the experiment was repeated three times with an interval of 30 minutes.
  • Example 3 Obtaining a drug in the form of tablets. 1600 mg of starch, 1600 mg of ground lactose, 400 mg of talc are mixed with a combination of 64 mg of buspirone and 936 mg of betahistine or a combination of 20 mg of buspirone and 980 mg of piracetam and pressed into a block. The resulting bar is crushed into granules and sieved through sieves, collecting granules with a size of 14-16 mesh. The granules obtained are tabletted into a suitable tablet form weighing 500 mg each.
  • Example 4 Obtaining a drug in the form of capsules. A combination of 64 mg of buspirone and 936 mg of betahistine or a combination of 20 mg of buspirone and 980 mg of piracetam and lactose powder in a ratio of 2: 1 are thoroughly mixed. The resulting powder mixture is packed into 300 mg gelatin capsules in a suitable size.
  • Example 5 Obtaining a medicinal product in the form of injection compositions for intramuscular, intraperitoneal or subcutaneous injection.
  • a combination of 32 mg of buspirone and 468 mg of betahistine or a combination of 10 mg of buspirone and 490 mg of piracetam are mixed with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water.
  • the resulting solution is filtered and placed in 1 ml ampoules, which are sealed.
  • the invention can be used in medicine, pharmacology.

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Abstract

L'invention concerne le domaine de la médecine humaine et de la pharmacologie et plus particulièrement de nouvelles combinaisons de buspirone avec au moins une substance sélectionné dans le groupe comprenant la bétahistine, le pyracétame, pour le traitement d'un étourdissement vestibulaire ou non vestibulaire.
PCT/RU2019/000057 2018-03-20 2019-01-31 Combinaison de buspirone utilisée pour traiter l'étourdissement WO2019182474A1 (fr)

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RU2018109757A RU2682966C1 (ru) 2018-03-20 2018-03-20 Комбинации буспирона для лечения головокружения
RU2018109757 2018-03-20

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2481861C2 (ru) * 2008-01-24 2013-05-20 Вектура Деливери Дивайсиз Лимитед Ингалятор
WO2017192407A1 (fr) * 2016-05-02 2017-11-09 Roman Bielski Microcapsules pour l'administration contrôlée d'un principe actif pharmaceutique
EP2774991B1 (fr) * 2013-03-06 2017-12-06 Life Science Inkubator Betriebs GmbH & Co. KG Système d'administration de médicament destiné à être utilisé dans le traitement ou le diagnostic de troubles neurologiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2481861C2 (ru) * 2008-01-24 2013-05-20 Вектура Деливери Дивайсиз Лимитед Ингалятор
EP2774991B1 (fr) * 2013-03-06 2017-12-06 Life Science Inkubator Betriebs GmbH & Co. KG Système d'administration de médicament destiné à être utilisé dans le traitement ou le diagnostic de troubles neurologiques
WO2017192407A1 (fr) * 2016-05-02 2017-11-09 Roman Bielski Microcapsules pour l'administration contrôlée d'un principe actif pharmaceutique

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