WO2015012780A1 - Médicament à effet cérébroprotecteur - Google Patents

Médicament à effet cérébroprotecteur Download PDF

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Publication number
WO2015012780A1
WO2015012780A1 PCT/UA2013/000128 UA2013000128W WO2015012780A1 WO 2015012780 A1 WO2015012780 A1 WO 2015012780A1 UA 2013000128 W UA2013000128 W UA 2013000128W WO 2015012780 A1 WO2015012780 A1 WO 2015012780A1
Authority
WO
WIPO (PCT)
Prior art keywords
mexidol
meldonium
cerebroprotective
drug
excipients
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/UA2013/000128
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English (en)
Russian (ru)
Inventor
Глеб Владимирович ЗАГОРИЙ
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Individual
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Individual
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Filing date
Publication date
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Publication of WO2015012780A1 publication Critical patent/WO2015012780A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/08—Solutions
    • 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
    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention relates to medicine and the pharmaceutical industry, in particular for the creation, production and use of drugs with cerebroprotective effects, namely for the treatment of vascular diseases, as agents that improve metabolism and improve cerebral circulation.
  • ischemic vascular diseases have become epidemic in recent decades and they are the leading cause of death in many economically developed countries. Ukraine is no exception, where these diseases account for up to 60% of total mortality. It should also be noted that of all the individual risk factors for complications, the most powerful effect on life expectancy is arterial hypertension (AH), which is closely associated with various types of brain strokes (hemorrhagic, ischemic). In connection with the search for new directions of influence on various links in the pathogenesis of ischemic brain damage, as well as to expand the understanding of the mechanisms of action of already known drugs, Mexidol (3-hydroxy-6-methyl-2-ethylpyridine succinate) is proposed, which is an inhibitor of free radical processes ( antioxidant).
  • AH arterial hypertension
  • Mexidol 3-hydroxy-6-methyl-2-ethylpyridine succinate
  • Mexidol is proposed for the treatment of acute cerebrovascular accidents, dyscirculatory encephalopathy, vegetative-vascular dystonia, atherosclerotic dysfunctions of the brain, for the relief of withdrawal symptoms in alcoholism and drug addiction, but there are a number of disadvantages, namely:
  • Mexidol should be used mainly in the form of a solution for injection, which does not contain pharmaceutically acceptable, but in general ballast substances, which are several times higher than the content of the main active substance, thereby reducing the effectiveness of treatment; I would also like the drug to be effective against related diseases that occur during physical and mental overloads, cerebrovascular diseases in cerebrovascular diseases, with retinal hemorrhage, and eyeball diseases,
  • angina pectoris angina pectoris
  • acute myocardial infarction in case of chronic ischemic heart disease, in strokes that are not specified as hemorrhage or heart attack, in pain in the region of the heart, in the period of recovery after surgery, as well as in limiting activity caused by reduced ability to work and other
  • the disadvantages of the prototype should include the fact that the qualitative and quantitative composition of the components does not provide a sufficiently high level and a wide range of specific activity for diseases that are indicated in the shortcomings of the above patent and does not reduce the presence of side effects and contraindications, namely it does not provide normalization of energy metabolism , reducing the accumulation of harmful metabolites, in particular, activated forms of unoxidized fatty acids (patent RU 2205640 C1).
  • SUBSTITUTE SHEET (RULE 26)
  • the basis of the invention is the task of creating a drug of cereproprotective action for the treatment of vascular diseases that improves metabolism and cerebral circulation and is an effective tool in the treatment of diseases and human conditions, such as physical and mental stress, cerebrovascular diseases in cerebrovascular diseases, with retinal hemorrhage, with diseases of the eyeball, with strokes not specified as hemorrhage or heart attack, during the recovery period after surgery interventions, as well as limiting activities caused by reduced ability to work, etc., by selecting a qualitative and quantitative composition of components that would ensure a sufficiently high level and a wide range of specific activity, reduce or eliminate the presence of side effects and contraindications, expand the range of indications .
  • meldonium is added in the following ratio of components, g:
  • Mexidol - 10 - 50 Meldonium - 80 - 200 excipients - the rest is up to 1 liter.
  • Meldonium-Meldonium (a structural synthetic analogue of gamma-butyrobetaine - the precursor of carnitine) inhibits the enzyme gamma-butyrobetaine hydroxylase, reduces the synthesis of carnitine and the transport of long chain fatty acids through cell membranes, and prevents the accumulation of activated forms of undeoxidized fatty acids in cells (in
  • SUBSTITUTE SHEET (RULE 26) including acylcarnitine, which blocks the delivery of ATP to the organelles of the cell), improves metabolic processes.
  • IHD angina pectoris, myocardial infarction
  • chronic heart failure cardialgia against the background of dishormonal myocardial dystrophy, acute and chronic cerebrovascular disorders (stroke, cerebrovascular insufficiency); withdrawal syndrome in chronic alcoholism (in combination with specific therapy); in ophthalmology - with hemophthalmia and retinal hemorrhage of various etiologies; thrombosis of the central retinal vein and its branches; retinopathies of various etiologies
  • Mexidol is an inhibitor of free radical processes (/ antioxidant / drug that prevents lipid peroxidation of cell membranes), but also has a more pronounced antihypoxic (increasing resistance
  • Mexidol has a wide spectrum of biological activity. It is effective in different types of hypoxia (with insufficient supply of tissue with oxygen or a violation of its absorption). Increases the body's resistance to oxygen-related pathological
  • SUBSTITUTE SHEET (RULE 26) conditions (shock, cerebrovascular accident, etc.), improves mnemonic functions (memory processes), reduces the toxic effects of alcohol, etc.
  • Mexidol is proposed for the treatment of acute cerebrovascular accidents, dyscirculatory encephalopathy (a brain disease caused by chronic cerebrovascular accident), vascular dystonia (impaired vascular tone due to dysfunction of the autonomic nervous system), atherosclerotic dysfunctions of the brain, for relief of withdrawal symptoms ( arising from a sudden cessation of drug use or alcohol), with alcoholism and addiction, with other conditions accompanied by tissue hypoxia.
  • dyscirculatory encephalopathy a brain disease caused by chronic cerebrovascular accident
  • vascular dystonia impaired vascular tone due to dysfunction of the autonomic nervous system
  • atherosclerotic dysfunctions of the brain for relief of withdrawal symptoms ( arising from a sudden cessation of drug use or alcohol), with alcoholism and addiction, with other conditions accompanied by tissue hypoxia.
  • Combined drugs combine metabolic and vasoactive properties, which allows to achieve a better effect in a shorter time and reduce the dose of active substances compared with their separate use.
  • the technical result obtained by carrying out the invention is to achieve a high level and a wide range of cerebroprotective activity in a combination of two active substances, with a synergistic effect, which allows to reduce the dose of the active substance and thus reduce side effects and contraindications.
  • a cerebroprotective drug for the treatment of vascular diseases that improves metabolism and cerebral circulation can be used to treat patients with acute and chronic cerebrovascular disorders (stroke, cerebrovascular insufficiency).
  • SUBSTITUTE SHEET (RULE 26) Store in a dark place at a temperature of no higher than 25 ° C.
  • the inventive drug has a ratio of components, g: Mexidol - 50
  • the inventive drug has a ratio of components, g: Mexidol - 12.5
  • Water is loaded into the reactor, cooled to (20 + 5) ° C. Add stabilizer, mix. Mexidol is added and mixed. Meldonium is added, mixed.
  • the inventive drug has a ratio of components, g: Mexidol - 50
  • Water is loaded into the reactor, cooled to (20 ⁇ 5) ° C. Add stabilizer, mix. Mexidol is added and mixed. Meldonium is added, mixed.
  • SUBSTITUTE SHEET (RULE 26) Store in a dark place at a temperature of no higher than 25 ° C.
  • the inventive drug has a ratio of components, g: Mexidol - 10
  • the qualitative and quantitative composition of the claimed agent fully fulfills the task of the invention to create a highly effective agent for the treatment of vascular diseases, which also improves metabolism and cerebral circulation.
  • meldonium improves metabolism, suppresses gamma-butyrobetaine hydroxynases, inhibits the synthesis of carnitine and the transport of long-chain fatty acids through cell membranes, and prevents the accumulation of activated forms of unoxidized fatty acids in the cells - derivatives of acylcarnitine and acylcoenzyme A.
  • Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) is a derivative of 3-hydroxypyridine, in chemical structure it is an analogue of pyridoxine, the phosphorylated form of which has neurotropic, antioxidant and energizing effects.
  • the drug easily penetrates the blood-brain barrier. In the liver, its rapid phosphorylation occurs, where active metabolites are formed and its deposition is noted.
  • Mexidol is able to potentiate the effects of other neuropsychotropic drugs - tranquilizers, antipsychotics, antidepressants, sleeping pills and anticonvulsants.
  • the combined drug in the selected prescription (meldonium 100 mg / ml + mexidol 12.5 mg / ml) at a dose of 100 mg / kg meldonium (12.5 mg / kg - mexidol) provides the maximum cerebroprotective effect on the effect of oxidative prooxidant status in brain tissue - the content of lipid hydroperoxides and the activity of glutathione peroxidase.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Hospice & Palliative Care (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Psychiatry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne la médecine et l'industrie chimico-pharmaceutique, notamment la mise au point, la fabrication et l'utilisation de médicaments cérébroprotecteurs utilisés pour améliorer la circulation sanguine cérébrale. Le médicament contient, en g: Mexidol 10-50; Meldonium 80-200; des substances auxiliaires jusqu'à 1 l. Le résultat technique consiste à assurer un degré élevé et une gamme étendue d'action cérébroprotectrice et, en même temps, à réduire ou éliminer les effets secondaires et les contre-indications.
PCT/UA2013/000128 2013-07-22 2013-11-05 Médicament à effet cérébroprotecteur Ceased WO2015012780A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
UA2013009189 2013-07-22
UAA201309189 2013-07-22

Publications (1)

Publication Number Publication Date
WO2015012780A1 true WO2015012780A1 (fr) 2015-01-29

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Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/UA2013/000128 Ceased WO2015012780A1 (fr) 2013-07-22 2013-11-05 Médicament à effet cérébroprotecteur
PCT/UA2014/000076 Ceased WO2015023244A1 (fr) 2013-07-22 2014-07-22 Agent médicamenteux ayant une action de protection cérébrale

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/UA2014/000076 Ceased WO2015023244A1 (fr) 2013-07-22 2014-07-22 Agent médicamenteux ayant une action de protection cérébrale

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WO (2) WO2015012780A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12290510B2 (en) 2019-02-07 2025-05-06 Riesner Verwaltungs Gmbh Polyvalent derivatives of emoxypine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2440132C2 (ru) * 2006-12-27 2012-01-20 Закрытое акционерное общество "Синтез пептидов" Композиция, обладающая нейропротективной, антиамнестической, противогипоксической и противоишемической активностью

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2145855C1 (ru) * 1999-05-26 2000-02-27 Смирнов Леонид Дмитриевич Анксиолитическое, противоалкогольное, церебропротекторное лекарственное средство
LV14268B (lv) * 2009-06-25 2011-03-20 Grindeks, A/S Meldonija sukcinātu saturoši medicīniskie produkti
RU2485953C1 (ru) * 2012-04-12 2013-06-27 Общество с ограниченной ответственностью "Научно-внедренческий центр Агроветзащита" Комплекс 3-(2,2,2-триметилгидразиний) пропионат-2-этил-6-метил-3-гидроксипиридина дисукцинат, обладающий антигипоксическим и адаптогенным действием, и способ его получения

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2440132C2 (ru) * 2006-12-27 2012-01-20 Закрытое акционерное общество "Синтез пептидов" Композиция, обладающая нейропротективной, антиамнестической, противогипоксической и противоишемической активностью

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Instruktsiia po meditsinskomu primeneniiu preparata Meksidol", 14 March 2008 (2008-03-14), Retrieved from the Internet <URL:http://grls.rosminzdrav.ru/Instrlmg.aspx?idReg=I1707&t=251710cc-b5cd-4238-97d0-a71Zs9152101&is01d=1> *
"Instruktsiia po meditsinskomu primeneniiu preparata Meldonii-ESKOM", 22 December 2009 (2009-12-22), Retrieved from the Internet <URL:http://grls.rosminzdrav.ru/InstrlmgMZ.aspx?isNew=I&idReg=9547&page=I&is01d=I&t=b2df06f8-99ac-4b76-9210-2c383fcbflaf> *
"Sovremennye vozmozhnosti lecheniia sedrechno-sosudistykh zabolevanii", INFORMATSIONNOE IZDANIE AO ''GRINDEKS'' DLYA VRACHEI, FARMATSEVTOV I SPETSIALISTOV, ZH2(8, 2012, pages 4, 6 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12290510B2 (en) 2019-02-07 2025-05-06 Riesner Verwaltungs Gmbh Polyvalent derivatives of emoxypine

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Publication number Publication date
WO2015023244A9 (fr) 2015-04-23
WO2015023244A1 (fr) 2015-02-19

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