WO2020085952A1 - Forme pharmaceutique pour le traiement de la grippe et de maladies respiratoires aiguës - Google Patents

Forme pharmaceutique pour le traiement de la grippe et de maladies respiratoires aiguës Download PDF

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WO2020085952A1
WO2020085952A1 PCT/RU2019/050194 RU2019050194W WO2020085952A1 WO 2020085952 A1 WO2020085952 A1 WO 2020085952A1 RU 2019050194 W RU2019050194 W RU 2019050194W WO 2020085952 A1 WO2020085952 A1 WO 2020085952A1
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dosage form
acid
form according
imidazol
ethanamide
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PCT/RU2019/050194
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English (en)
Russian (ru)
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Антон Петрович ПЕРЕВЕРЗЕВ
Наталья Александровна ГОЛУБЕВА
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Общество С Ограниченной Ответственностью "Валента-Интеллект"
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Priority to EA202191124A priority Critical patent/EA202191124A1/ru
Publication of WO2020085952A1 publication Critical patent/WO2020085952A1/fr

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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
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the invention relates to the pharmaceutical industry and medicine and relates to a new liquid dosage form for the treatment and prevention of influenza and SARS, containing 2- (imidazol-4-yl) -ethanamide pentand new 1.5 acid in an effective amount and excipients.
  • ARVI Acute respiratory viral infections
  • a group of infectious diseases of viral etiology characterized by damage to the respiratory tract, mainly the upper sections, and a common clinical symptoms.
  • the successes achieved by medicine in the field of infectious pathology have contributed to the development and improvement of methods for the prevention and treatment of diseases, but ARVI continues to be a serious public health problem for most countries of the world due to the extremely high incidence rate, usually in the form of seasonal epidemics.
  • SARS satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica satutica, pulmonary fibros, etc.).
  • ARVI - polyetiological diseases Currently, more than 200 pathogens are known, but rhinoviruses (30-50%) and influenza viruses (5-15%), causing a high outbreak in the autumn and winter, are much less likely to cause adenoviruses, parainfluenza viruses, and respiratory infections. syncytial virus [Selkova EP Prevention and treatment of acute respiratory viral infections. The use of amixin. Manual for doctors. M., 2004].
  • influenza A and B viruses causing annual epidemics, the economic damage from which amounts to billions of US dollars.
  • Russia the annual total economic damage from influenza is estimated by experts in the amount of up to 40 billion rubles.
  • Numerous studies have shown a consistent relationship between influenza and acute myocardial infarction [Kuznetsova O.Yu., Pleshanova Zh.V. The place of modern combination drugs in the treatment of acute respiratory viral infections in outpatient practice. Consilium medicum, 2012, 3: 74-83].
  • the disease is characterized, as a rule, by an acute onset and a severe course: high (40 ° C or more) temperature and prolonged fever with symptoms of intoxication - headache, insomnia, pain in the muscles and joints, meningeal symptoms.
  • One of the adverse currents is the fulminant form, i.e. rapid development of hemorrhagic toxic pulmonary edema and death from respiratory and cardiovascular failure [Int. J. Tuberc. Lung dis. // 2007 - V.11. - N7. - S.710-721].
  • a viral infection predisposes to the development of complications, the most common of which are otitis media (most often in children), sinusitis (in adults), exacerbation of chronic bronchitis / COPD or bronchial asthma.
  • SARS of non-influenza etiology is more often characterized by a milder short course. This is due to the fact that rhinoviruses primarily affect the epithelium of the upper respiratory tract, while influenza viruses have a tropism for the epithelium of the lower respiratory tract and can cause the development of acute tracheobronchitis, bronchiolitis. Pneumonia is a rare complication of rhinovirus infection, but develops in 5-30% of patients with influenza A and 10% of patients with influenza B [A. Zaitsev. Directions of pharmacotherapy and prevention of acute respiratory viral infections. Rus Honey. Jury, 2009, 17 (23): 1525].
  • Live vaccines are administered intranasally, the traditional route of administration of inactivated vaccines is subcutaneous or intramuscular.
  • inactivated vaccines are recommended for mass influenza prophylaxis.
  • the most important requirement for the vaccines used is the antigenic composition of the influenza virus strains that are relevant in this epidemiological season [A. Zaitsev. Directions of pharmacotherapy and prevention of acute respiratory viral infections. Rus Honey. Jury, 2009, 17 (23): 1525].
  • Treatment and prevention of antiviral drugs is indicated in the following cases [Zaitsev A.A. Directions of pharmacotherapy and prevention of acute respiratory viral infections. Rus Honey. Journal, 2009, 17 (23): 1525]: 1) as an addition to late vaccination in people at risk in the first 2 weeks after vaccination (for the period of antibody production); 2) for children who are vaccinated for the first time: the administration of drugs is indicated within 6 weeks after the first vaccination (the final production of antibodies ends by 2 weeks after the second vaccination); 3) for persons with immunodeficiency who may give an insufficient immune response to vaccination; 4) for persons for whom vaccination is contraindicated (for example, with allergic reactions to chicken protein); 5) in elderly people for whom the vaccination efficiency is reduced and reaches 50-70%, as an addition to vaccination; 6) for unvaccinated persons who are in contact with sick relatives and neighbors; 7) when there is a threat of a pandemic; 8) if the antigenic composition of the vaccine used does not correspond to the epidemic situation.
  • influenza A virus Given that it is impossible to predict the antigenic structure of the future epidemic (pandemic) influenza A virus, the early construction of effective influenza vaccines is difficult, therefore it is important to have chemotherapeutic agents in the arsenal of prevention and treatment of diseases caused by highly pathogenic virus strains.
  • Means that have a direct effect on the influenza virus are used for emergency treatment and prevention of influenza.
  • M2-channel blockers are active against influenza A.
  • amantadine and rimantadine which are antiviral against influenza virus strains, have been widely used and are still used [Am. J. Med. - 1997. - V.102 (FOR) - N17. - P. 55-60], [Watts J. “Asian nations step up action to curb spread of avian influenza” // Lancet. - 2004. - V.363 - N9406. - P.373].
  • the antiviral drug rimantadine has spread. It is used for the treatment and prevention of infection caused by type A influenza viruses.
  • rimantadine as a representative of the adamantane group has limitations in its use. At high doses, side effects from the central nervous system occur, in particular, the drug can cause convulsive effects. It also has an adverse effect on the liver and kidneys, which makes it unlikely to be used in people with diseases of these organs.
  • rimantadine should not be long (for prevention, it is recommended to use 50 mg once a day for 10-15 days). It is important that, against the background of other antiviral agents, rimantadine is most economically advantageous.
  • influenza A and B virus neuraminidase inhibitors are widely used - oseltamivir phosphate (oseltamivir) and zanamivir (zanamivir), which, when combined with the hydrophobic portion of the active portion of the influenza virus neuraminidase, block the ability of the latter to cleave sialic acid residues from the surface of the infected cell, thereby suppressing the exit from it of newly formed virions.
  • Neuraminidase inhibitors act on influenza A and B viruses.
  • Oseltamivir is available in capsule form. Preventive use is allowed from the age of 12: 75 mg daily 1 time per day for at least 10 days. The drug has a safety profile acceptable for prescription, the observed adverse events (headaches, nausea, diarrhea, and others) most often do not require its cancellation. Zanamivir is available only in inhaled form, therefore it is not used for prevention.
  • influenza A virus subtype H5N1 has acquired resistance to oseltamivir by replacing one amino acid in neuraminidase (H274Y and N294S)
  • H274Y and N294S Hui-Ling Y., Ilyshina NA, Salomon R. et al.
  • Neuraminidase inhibitor-resistant recombinant A / Vietnam / l203 / 04 (H5N1) influenza vimses retain their replication efficiency and pathogenicity in vitro and vivo // J. Virol. - 2007.
  • interferon preparations for the treatment and prevention of viral infections.
  • IFN interferon preparations
  • PFH-b PFH-b
  • IFN-t IFN-t
  • IFN-co type II interferons
  • type III interferons which include IFN- l.
  • IFN-a has the most pronounced antiviral effect [Ershov F.I., Kiselev O.I.
  • pentanedio-1,5-acid 2- (imidazol-4-yl) -ethanamide or a pharmaceutically acceptable salt thereof is known for the treatment and / or prevention of highly pathogenic infectious diseases such as highly pathogenic influenza A caused by viruses having a pathogenicity index of more than 1.2 and severe acute respiratory syndrome (SARS) due to type IV coronavirus [EA020283, 10/30/2014].
  • highly pathogenic infectious diseases such as highly pathogenic influenza A caused by viruses having a pathogenicity index of more than 1.2 and severe acute respiratory syndrome (SARS) due to type IV coronavirus [EA020283, 10/30/2014].
  • 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid for the treatment of hepatitis C.
  • This agent can also be administered in combination with pegylated interferon and ribavirin.
  • the pharmaceutical composition of 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid for the treatment of viral hepatitis C which has a pronounced antiviral effect and is effective in the treatment of viral hepatitis C, which can significantly reduce the frequency of side effects of antiviral therapy [RF Patent N ° 2496512, 10.27.2013].
  • pentanedio-1,5-acid 2- (imidazol-4-yl) ethanamide or its pharmaceutically acceptable salts is also known to prevent or treat diseases caused by (+) RNA viruses belonging to the genus enteroviruses or the genus of flaviviruses, [WO2014035297 , 08/29/2013].
  • 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid is widely used in medicine as a means for the treatment and prevention of influenza A and B and other acute respiratory viral infections ( adenovirus infection, parainfluenza, respiratory syncytial infection) and was registered as a medicine under the trade name Ingavirin®.
  • the well-known drug Ingavirin® is presented in capsule form.
  • compositions of 2- (imidazol-4-yl) - pentanedio-1,5 acid ethanamide in solid dosage form in the form of tablets or capsules having virusotropic and immunogenic activity, characterized in that it includes 2- (as an active principle) imidazol-4-yl) -ethanamide pentanedio-1,5 acid, as excipients, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide (Aerosil 300) and calcium stearate [RF Patent N ° 2546002, 01.20.2014. , WO2015108440, July 23, 2015].
  • Rhinosinusitis is an inflammation of the mucous membrane of the nasal cavity and paranasal sinuses (ONI), the problem of which is currently one of the most urgent in otorhinolaryngology (Fokkens WJ, Lund VJ, Mullol J. et ak, European Position Paper on Rhinosinusitis and Nasal Polyps, Rhinology, 2007; 45; 20: 1-139).
  • liquid dosage forms of 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid or 1- [2- (1H-imidazol-4-yl) ethyl] piperidin-2,6- are not known from the prior art. dione, as well as their combined use in one dosage form for the treatment and prevention of influenza and SARS.
  • Liquid dosage forms including syrups, make up a significant part of the range of pharmacies. Their widespread use is due to a number of advantages over other dosage forms:
  • this dosage form is simple and convenient to use
  • liquid dosage forms it is possible to mask the unpleasant taste and smell of drugs, as well as the possibility of accurate dosing in a wide range of doses, which is especially important in children's practice. But at the same time, there are also disadvantages, the main of which are instability during storage and susceptibility to microbiological contamination, as well as the fact that not all biologically active substances are effective in such a dosage form.
  • the present invention is the creation of a new stable and suitable for use in pharmaceutical dosage form of 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid, which provides high antiviral activity, an optimal rate of onset of therapeutic effect and increased ease of use , as well as expanding the arsenal of drugs with antiviral effects.
  • liquid dosage form for oral administration for the treatment and prevention of influenza and SARS, containing 2- (imidazol-4-yl) pentanedio-1,5 acid ethanamide or its pharmaceutically acceptable salt in an effective amount and auxiliary substances. More preferred is a liquid dosage form, wherein the pH of the liquid dosage form is 3-8, more preferably 4-8, even more preferably 5-8, even more preferably 5-7, even more preferably 6-7 even more preferably 6, 3-6, 7, most preferably 6.5.
  • liquid dosage form characterized in that the mass ratio of 2- (imidazol-4-yl) ethanamide pentand new-1,5 acid or its pharmaceutically acceptable salt to 1- [2- (1H-imidazol-4-yl) ethyl] piperidin-2,6-dione or a pharmaceutically acceptable salt thereof is from 10000: 1 to 1: 2, preferably from 10000: 1 to 20: 1, even more preferably from 10000: 1 to 200: 1, even more preferably from 10000: 1 to 2000: 1, even more preferably from 10000: 1 to 1000: 1.
  • liquid dosage form characterized in that 1- [2- (1H-imidazol-4-yl) ethyl] piperidin-2,6-dione or a pharmaceutically acceptable salt thereof is contained in an amount of not more than 50 wt.% Of the content 2- (imidazol-4-yl) pentanedio-1,5 acid ethanamide, preferably not more than 10 wt.%, Even more preferably not more than 5 wt.%, Even more preferably not more than 1 wt.%, Even more preferably not more than 0.2 wt.%, even more preferably, 0.1-0.01 wt.%.
  • liquid dosage form characterized in that it further comprises an acid.
  • the acid may be an organic or inorganic acid.
  • Inorganic acid can be selected from the group comprising hydrochloric, phosphoric and sulfuric. More preferred is a liquid dosage form, wherein the acid is an organic acid.
  • liquid dosage form wherein the organic acid is selected from the group consisting of malic, ascorbic, citric, acetic, succinic, tartaric, fumaric, lactic, aspartic, glutaric, glutamic, sorbic acids.
  • liquid dosage form characterized in that the excipients are selected from a stabilizer, preservative, thickener, sweetener, flavoring and water.
  • liquid dosage form wherein the stabilizer is gum, chitosan, fatty acids and their salts, glycerin, propylene glycol and tragacanth.
  • liquid dosage form wherein the preservative is selected from the group consisting of benzyl alcohol, urotropin, ethylenediaminetetraacetic acid, benzoic acid, sorbic acid, parabens, alkyl pyridinium, benzetonium and their pharmaceutically acceptable salts.
  • liquid dosage form wherein the thickener is selected from the group consisting of gums, pectin, alginic acid, gum arabic, agar-agar, methyl cellulose, carboxymethyl cellulose and their pharmaceutically acceptable salts.
  • sweetener is selected from the group consisting of maltitol, isomalt, sucralose, glucose, sucrose, fructose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotam, lactitol and their pharmaceutically acceptable salts.
  • a liquid dosage form characterized in that the flavoring is raspberry, strawberry, orange, berry, apricot, pear, melon, mango, lemonade or plum flavor both in dry and in liquid form. More preferred is a liquid dosage form, characterized in that the concentration of 2- (imidazol-4-yl) -ethanamide pentand-1.5 acid is from 1 to 50 mg / ml, preferably from 5 to 30 mg / ml, 5 to 25 mg / ml, 5 to 10 mg / ml, even more preferably 6 mg / ml.
  • a liquid dosage form characterized in that the excipients are contained in an amount, g: maltitol liquid 20.0-50.0;
  • the subject of the present invention is also a method for the treatment or prophylaxis of influenza and SARS, according to which a liquid dosage form of the present invention is administered to a subject orally.
  • the subject of the present invention is the use of 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid in the form of a liquid dosage form for the treatment or prevention of influenza and SARS.
  • Medical product (preparation) a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of ready-made 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, diagnosis, anesthesia, contraception , cosmetology and other things.
  • “Pharmaceutical composition” means a composition comprising in pentanedio-1,5 acid 2- (imidazol-4-yl) ethanamide or a pharmaceutically acceptable salt thereof 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 vehicles such as preservatives, stabilizers, emulsifiers, suspending agents agents, thickeners, sweeteners, perfumes, flavors, antibacterial agents, fungicides, the choice and ratio of which depends on the nature and method of administration and dosage. Protection against the action of microorganisms can be provided using a variety of antibacterial and antifungal agents.
  • the composition may also include isotonic agents, for example, sugars, sodium chloride and the like.
  • 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).
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate
  • stabilizers are gums (e.g., xanthan, gellan, konjac), fatty acids and their salts, pectin and tragacanth.
  • preservatives are benzyl alcohol, urotropine, ethylenediaminetetraacetic acid, benzoic acid, parabens, alkyl pyridinium, benzetonium and their pharmaceutically acceptable salts.
  • thickeners are glycerin, alginic acid, gum arabic, glucose, sucrose, fructose, agar-agar, methyl cellulose and their pharmaceutically acceptable salts.
  • sweeteners are maltitol, isomaltitol, sucralose, saccharin, cyclamate, aspartame, sorbitol, xylitol, stevioside, mannitol, acesulfame, neotam, lactitol and their pharmaceutically acceptable salts.
  • dispensing agents are starch, alginic acid and its salts.
  • a pharmaceutical composition for oral, topical 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 dosage forms include oral forms such as oral solutions or suspensions, syrups, sublingual, buccal and topical forms.
  • compositions may include pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field.
  • the pharmaceutical composition along with the active substance of the present invention or its pharmaceutically acceptable salt may include other active substances, including those with activity, provided that they do not cause undesirable effects.
  • Carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, for example, disintegrants, solvents, diluents, stabilizers, suspending agents, flavoring agents, antiseptic agents are used in oral 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 (Detailed description of the properties of such salts is 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).
  • amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris (hydroxymethyl) aminomethane and the like.
  • tetraalkylammonium hydroxides for example, such as 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.
  • terapéuticaally effective amount means an amount of an active substance that (1) treats or prevents a particular disease, condition or disorder, (2) alleviates, improves or eliminates one or more symptoms of 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 those who are being treated with this substance or composition.
  • syrup in the present invention means any liquid dosage form, solution or elixir intended for oral administration, preferably, but not necessarily, containing a thickening agent, including active and auxiliary substances.
  • the syrup may have opalescence or be a heterogeneous dispersed system (most often a suspension). Additional liquid dosage forms for oral administration may be oral solutions.
  • Example 1 Obtaining a syrup containing 2- (imidazol-4-yl) -ethanamide pentand new - 1, 5 acid.
  • Powders of 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid, as well as solid auxiliary substances (sodium methyl parahydroxybenzoate, xanthan gum) were sieved through a sieve with a mesh size of 250 ⁇ m.
  • Sifted powders, as well as liquid excipients (glycerin, liquid maltitol), as well as purified water, were weighed in accordance with the calculation on calibrated attorney scales in individual marked containers.
  • Citric acid monohydrate was sieved through a sieve with a mesh size of 800 ⁇ m.
  • Purified citric acid was added purified water to prepare a 20.0% aqueous citric acid solution.
  • the resulting solution was filtered through a metal sieve with a hole size of 200 ⁇ m into a clean, individually labeled container.
  • Glycerin was placed in a manufacturing vessel. Using an overhead stirrer without heating, sifted xanthan gum was added in portions to the glycerol while stirring. Stirring was continued with increasing speed of the stirrer at room temperature from 20 to 45 minutes.
  • the intermediate was transferred to the stage of obtaining the filtered solution using a filter with a pore size of not more than 1.2 ⁇ m in a sealed production vessel.
  • Example 2 The study of the effect of pH of syrup on the stability of the finished dosage form during storage.
  • the stability of the syrup was evaluated by the content of the active substance 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid at 4 different pH values by accelerated aging.
  • the method of "accelerated aging” is to withstand the test drug at temperatures and humidity exceeding the temperature and humidity of its storage during handling.
  • elevated temperatures as a rule, physicochemical processes occurring in medicines are accelerated, leading to undesirable quality changes over time.
  • the period of time during which controlled quality indicators of the drug are kept within acceptable limits is artificially reduced in comparison with the shelf life at storage temperature. This can significantly reduce the time required to establish the expiration date.
  • the inverse problem i.e. set the storage temperature that provides any specified shelf life.
  • Shelf life (C) at storage temperature (/ hr ) is associated with the experimental shelf life (Ce) at elevated experimental storage temperature (/ e ) by the following relationship:
  • the temperature coefficient of the chemical reaction rate (A) is taken equal to 2.5.
  • the above dependence is based on the Vant-Hoff rule on a 2-4-fold increase in the rates of chemical reactions with increasing temperature by
  • the value of the correspondence coefficient (K), depending on the selected temperature interval (t 3 -t x p ), equal to 30 ° ⁇ , is 15.6.
  • the experimental storage period for a selected shelf life of 3 years is 71 days.
  • Example 3 Obtaining syrups with different pH and concentrations of the active substance.
  • syrup formulations prepared according to the present invention are shown in Tables 3-30.
  • HPLC The compositions show high stability.
  • Example 4 Obtaining syrups of various composition.
  • syrup formulations prepared according to the present invention are shown in Table 31.
  • compositions shown in Table 3 show high stability, which indicates that the stability of the liquid dosage form of 2- (imidazol-4-yl) -ethanamide pentane povoy-1,5 acid is mainly due to the pH value and not to the composition of specific excipients, which are strongly varied in chemical nature for the compositions shown in Table 3.
  • Example 5 Obtaining a syrup containing 2- (imidazol-4-yl) - pentanedio-1,5 acid ethanamide and 1- [2- (1H-imidazol-4-yl) ethyl] piperidin-2,6-dione.
  • compositions of syrups containing together 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid and 1- [2- (1H-imidazol-4-yl) ethyl] piperidin-2,6-dione were obtained analogously to the procedure from Example 1, with the difference that after the stage dissolving 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid, the calculated amount of sieved 1- [2- (1H-imidazol-4-yl) ethyl] piperidin-2,6-dione was visually introduced into the reactor portionwise controlling the dissolution of the latter (see Table 32).
  • Example 6 The study of the influence of pH of syrup on the stability of the finished dosage form containing 2- (imidazol-4-yl) -ethanamide pentanedio-1,5 acid and 1- [2- (1H-imidazol-4-yl) ethyl] piperidine 2,6-dion, during storage.
  • the stability of the syrup was evaluated by the content of the histamine contamination at 5 different pH values by accelerated aging according to Example 2.
  • the histamine content was determined by HPLC using a standard solution of histamine dihydrochloride.
  • the invention can be used in medicine, pharmacology, chemical and pharmaceutical industry.

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Abstract

L'invention concerne l'industrie chimique et pharmaceutique et la médecine humaine et porte sur une nouvelle forme pharmaceutique pour administration orale visant le traitement et la prévention de la grippe et des maladies respiratoires aiguës contenant le 2-(imidazol-4-yl)-éthanamide de l'acide pendadiéenique1,5 en quantités efficaces et des produits accessoires.
PCT/RU2019/050194 2018-10-23 2019-10-22 Forme pharmaceutique pour le traiement de la grippe et de maladies respiratoires aiguës WO2020085952A1 (fr)

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RU2546002C1 (ru) * 2014-01-20 2015-04-10 Общество с ограниченной ответственностью ООО "ВАЛЕНТА-ИНТЕЛЛЕКТ" Фармацевтическая композиция в форме таблетки и способ ее получения
RU2562773C2 (ru) * 2013-04-12 2015-09-10 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Производные глутаримидов, их применение, фармацевтическая композиция на их основе, способы их получения
WO2016073947A1 (fr) * 2014-11-07 2016-05-12 Kineta, Inc. Composés anti-viraux, compositions pharmaceutiques et méthodes d'utilisation de ces derniers
RU2611383C2 (ru) * 2013-05-13 2017-02-21 Закрытое Акционерное Общество "Вертекс" Комбинированный препарат для устранения симптомов и лечения острых респираторных вирусных инфекций и гриппа

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RU2562773C2 (ru) * 2013-04-12 2015-09-10 Общество С Ограниченной Ответственностью "Фарминтерпрайсез" Производные глутаримидов, их применение, фармацевтическая композиция на их основе, способы их получения
RU2611383C2 (ru) * 2013-05-13 2017-02-21 Закрытое Акционерное Общество "Вертекс" Комбинированный препарат для устранения симптомов и лечения острых респираторных вирусных инфекций и гриппа
RU2546002C1 (ru) * 2014-01-20 2015-04-10 Общество с ограниченной ответственностью ООО "ВАЛЕНТА-ИНТЕЛЛЕКТ" Фармацевтическая композиция в форме таблетки и способ ее получения
WO2016073947A1 (fr) * 2014-11-07 2016-05-12 Kineta, Inc. Composés anti-viraux, compositions pharmaceutiques et méthodes d'utilisation de ces derniers

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RU2018137368A3 (fr) 2020-04-23
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RU2737086C2 (ru) 2020-11-24

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