WO2020005111A1 - Méthodes pour traiter et prévenir les complications liées à une perméabilité plus élevée de l'intestin - Google Patents

Méthodes pour traiter et prévenir les complications liées à une perméabilité plus élevée de l'intestin Download PDF

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Publication number
WO2020005111A1
WO2020005111A1 PCT/RU2019/000461 RU2019000461W WO2020005111A1 WO 2020005111 A1 WO2020005111 A1 WO 2020005111A1 RU 2019000461 W RU2019000461 W RU 2019000461W WO 2020005111 A1 WO2020005111 A1 WO 2020005111A1
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polymer complex
antibiotic
copolymer
azithromycin
acrylamido
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Russian (ru)
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Виктор Вениаминович ТЕЦ
Георгий Викторович ТЕЦ
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the invention relates to chemistry and pharmacology, in particular, to polymer complexes of macrolide antibiotic.
  • the inventive substance is the product of the interaction of a macrolide antibiotic with a copolymer of acrylamide with 2-acrylamido-2-methylpropanesulfonic acid.
  • This substance is intended for use in medical practice for the treatment and prevention of complications associated with chemotherapy and radiotherapy, conditions associated with increased intestinal permeability, as well as for similar purposes in veterinary medicine.
  • This substance can be used both individually and in the form of its pharmacologically acceptable salts, complexes, as well as in combination with other drugs and complexes.
  • Patent RU2635558 describes sulfonated polymers with their own antiviral activity against the influenza virus H3N2, H1N1, which are copolymers of 2-acrylamido-2-methylpropanesulfonic acid of molecular weight
  • MM 40000-70000.
  • RU2623877 describes a polymer complex of rifampicin with reduced toxicity and high anti-tuberculosis activity, obtained by complexing rifampicin with poly-2-acrylamido-2-methylpropanesulfonic acid with a molecular weight of 20,000-4,000 with a polymer: antibiotic weight ratio of 1, 9-4.0 .
  • the patent 2394618 describes a polymer complex of arbidol with poly-2-acrylamido-2-methylpropanesulfonic acid with a molecular weight of 19000-31000 with an antibiotic content in the complex of 26.4 - 32.1% of the mass.
  • macrolide antibiotics including erythromycin, midecamycin, oleandomycin, spiramycin, josamycin, clarithromycin, azithromycin, roxithromycin, are currently the most popular in therapy.
  • Antibiotics of the macrolide group have a wide spectrum of antimicrobial activity.
  • the activity of these drugs is primarily directed against such harmful microorganisms as streptococci and staphylococci. They are also able to effectively destroy parasitic microorganisms: chlamydia, mycoplasmas, legionella.
  • Antibiotics from the macrolide group are one of the safest types of antibacterial agents. They have a relatively low toxicity, do not have a pronounced effect on the body's immune system and are well tolerated by patients. Compared to antibiotics of other groups, macrolides are less likely to cause allergic reactions. Currently, they are widely used in the treatment of infectious diseases in newborns, children and pregnant patients.
  • Azithromycin has the best tolerance among macrolide antibiotics, the main indications for use of which are infections of the oropharynx and nasopharynx, respiratory and urinary systems.
  • Azithromycin is a compound: 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A [United States Patent # 4,512,982, 1985].
  • the mechanism of action of azithromycin is based on the fact that this substance inhibits protein synthesis in bacteria.
  • diseases with an unclear etiology are a huge problem in modern therapy, for which no clear explanation of their origin has yet been received, they include various diseases and conditions that are not similar, in particular, alcoholic cirrhosis of the liver, schizophrenia, cancer intoxication, headache, hypertensive crises, etc.
  • microbiota bacterial DNA was discovered by the authors of the present invention in the blood of people with the following pathologies: complications arising from chemo- and radiotherapy; cancer cachexia; diabetes; hangover syndrome; bipolar disorder and schizophrenia; hypercholesterolemia; Alzheimer's disease; acute respiratory distress syndrome; oncological diseases, including colon cancer; infertility; primary biliary cirrhosis; primary sclerosing cholangitis; violation of heart rhythm and conduction; psoriasis; atopic dermatitis; ankylosing spondylitis; systemic lupus erythematosus; scleroderma; autoimmune thyroiditis; gout; senile dementia; acute liver failure, acute renal failure; aviation toxic syndrome; headache; age-related skin changes; unstable angina
  • macrolide antibiotics including azithromycin
  • they are characterized by rapid absorption from the intestine, as a result of which their effect on the intestinal microbiota is mild.
  • the objective of the invention is to obtain a new chemical compound with high antimicrobial activity with reduced toxicity, which is also implemented in the human intestine, and is able to bind to cytokines of inflammation and prevents the development of toxic conditions of chemotherapy, x-ray therapy and conditions associated with increased intestinal permeability.
  • a new antimicrobial substance which is a polymer complex of a macrolide antibiotic with a high molecular weight copolymer of acrylamide with 2-acrylamido-2-methylpropanesulfonic acid of the general formula:
  • the specified polymer complex contains from about 9% of the mass, to about 44% of the mass of the antibiotic.
  • the macrolide antibiotic is selected from the group consisting of erythromycin, clarithromycin, roxithromycin, oleandomycin, dirithromycin, azithromycin, spiramycin, midecamycin, josamycin.
  • the present invention relates to a polymer complex of azithromycin with a high molecular weight copolymer of acrylamide with 2-acrylamido-2-methylpropanesulfonic acid of the formula (1):
  • the specified polymer complex contains from about 9% to about 44% by weight of an antibiotic.
  • the present invention provides a method for producing a macrolide antibiotic polymer complex.
  • the specified method involves the interaction of an antibiotic with a copolymer of acrylamide with 2-acrylamido-2-methylpropanesulfonic acid containing from 20.1 mol% to 30.9 mol. % sulfo groups, with MM 33000-160000, and the mass ratio of antibiotic to polymer is from 0.1: 1 to 0.8: 1.
  • a polymer complex of a macrolide antibiotic for the treatment or prevention of conditions associated with increased permeability of the intestine, as well as complications after chemotherapy and radiotherapy.
  • the present invention provides the use of a macrolide antibiotic polymer complex for the manufacture of a medicament for the treatment or prevention of conditions associated with increased intestinal permeability, as well as complications after chemotherapy and radiotherapy.
  • the present invention provides a method for treating or preventing conditions associated with increased intestinal permeability, as well as complications after chemotherapy and radiotherapy, comprising administering to a subject in need of such treatment a pharmaceutically effective amount of a macrolide antibiotic polymer complex.
  • the antibiotic polymer complex is for oral administration.
  • the polymer complex is in the form of capsules.
  • Figure 1 shows the change in the concentration of IL -1 alpha in the culture of monocytes when using the polymer complex of azithromycin and copolymer AA with 2-AAMPSC in comparison with azithromycin.
  • Figure 2 shows the change in the concentration of IL-6 alpha in the culture of monocytes when using the polymer complex of azithromycin and copolymer AA with 2-AAMPSC in comparison with azithromycin.
  • FIG. 3 shows a change in the concentration of IL-10 alpha in monocyte culture when using the polymer complex of azithromycin and copolymer AA with 2-AAMPSC in comparison with azithromycin.
  • Figure 4 shows the effect of the polymer complex of azithromycin and copolymer AA with 2-AAMPSK on the number of copies of bacterial DNA in the blood serum of mice receiving chemotherapy. The following notation was used:
  • the present invention provides a novel antimicrobial agent, which is a macrolide polymer complex an antibiotic with a copolymer of acrylamide with 2-acrylamido-2-methylpropanesulfonic acid of the general formula:
  • the specified polymer complex contains from about 9% of the mass to about 44% of the mass of the antibiotic, preferably from about 13% of the mass. up to about 43% of the mass. antibiotic, more preferably, from about 17% of the mass to 41% of the mass, antibiotic, even more
  • the mass of the antibiotic preferably, from about 20% of the mass to about 39% of the mass of the antibiotic, even more preferably from about 23% of the mass to about 37% of the mass of the antibiotic and most preferably from about 23% of the mass. up to 33% of the mass of the antibiotic.
  • the macrolide antibiotic is selected from the group consisting of erythromycin, clarithromycin, roxithromycin,
  • the present invention relates to a polymer complex of azithromycin with a high molecular weight copolymer of acrylamide with 2-acrylamido-2-methylpropanesulfonic acid of the formula (1):
  • the specified polymer complex contains from about 9% of the mass, to about 44% of the mass of the antibiotic, preferably from about 13% of the mass to about 43% of the mass.
  • antibiotic more preferably, from about 17% of the mass, to 41% of the mass, antibiotic, even more preferably, from about 20% of the mass, to about 39% of the mass of the antibiotic, even more preferably, from about 23% of the mass, to about 37% of the mass , antibiotic, and most preferably, from about 23% of the mass. up to 33% of the mass, antibiotic.
  • the present invention provides a method for producing a macrolide antibiotic polymer complex.
  • the specified method involves the interaction of an antibiotic with a copolymer of acrylamide with 2-acrylamido-2-methylpropanesulfonic acid containing from 20.1 mol% to 30.9 mol. % sulfo groups, with MM 33000-160000, and the mass ratio of antibiotic to polymer is from 0.1: 1 to 0.8: 1.
  • the present invention provides a method for producing a polymer complex of azithromycin, comprising reacting azithromycin with a copolymer of acrylamide with 2-acrylamido-2-methylpropanesulfonic acid containing from 20.1 mol% to 30.9 mol. % sulfo groups, with MM 33000-160000, and the mass ratio of the antibiotic azithromycin to the polymer is from 0, 1: 1 to 0.8: 1
  • the mass ratio of antibiotic to polymer is from 0.15: 1 to 0.75: 1, more preferably from 0.2: 1 to 0.7: 1, even more preferably from 0.25: 1 to 0 , 65: 1, even more preferably from 0.3: 1 to 0.6: 1, and most preferably from 0.3: 1 to 0.5: 1.
  • a polymer complex of a macrolide antibiotic for the treatment or prevention of conditions associated with increased permeability of the intestine, as well as complications after chemotherapy and radiotherapy.
  • the present invention provides the use of a polymer complex of azithromycin for the treatment or prevention of conditions associated with increased intestinal permeability, as well as complications after chemo and radiotherapy
  • the present invention provides the use of a macrolide antibiotic polymer complex for the manufacture of a medicament for the treatment or prophylaxis of conditions associated with increased intestinal permeability, as well as complications after chemotherapy and radiotherapy.
  • the present invention provides the use of a polymer complex of azithromycin for the manufacture of a medicament for the treatment or prophylaxis of conditions associated with increased intestinal permeability, as well as complications after chemotherapy and radiotherapy.
  • the present invention provides a method for treating or preventing conditions associated with increased intestinal permeability, as well as complications after chemotherapy and radiotherapy, comprising administering to a subject in need of such treatment a pharmaceutically effective amount of a macrolide antibiotic polymer complex.
  • the present invention provides a method for treating or preventing conditions associated with increased intestinal permeability, as well as complications after chemotherapy and radiotherapy, comprising administering to a subject in need of such treatment a pharmaceutically effective amount of the azithromycin polymer complex.
  • the effective amount of the polymer complex of the antibiotic for administration can be easily determined by a specialist in the field of technology or a physician based on certain parameters, such as age, weight, severity of the disease, etc.
  • said effective amount is from about 1 mg / kg to about 50 mg / kg, preferably from about 3 mg / kg to about 40 mg / kg, more preferably from about 6 mg / kg to about 30 mg / kg and most preferably from about 12 mg / kg to about 25 mg / kg.
  • the antibiotic polymer complex is for oral administration.
  • the polymer complex of a macrolide antibiotic, including azithromycin is presented in the form of powder, capsules, tablets, granules, sachets, lozenges for resorption.
  • the polymer complex is in the form of capsules.
  • the invention is illustrated by the following examples of the synthesis of intermediate substances, examples of the synthesis of the claimed substance, tables of yields and characteristics of the target substances, experiments on the study of biological properties and tables of experimental results to determine the biological properties of the claimed substances.
  • Example 1 In a round-bottomed two-tube flask with a capacity of 250 ml, equipped with a stirrer and reflux condenser, 10 g of acrylamide (AA), 12.5 g of 2-acrylamido-2-methylpropanesulfonic acid (2-AAMPSK), 0.9 g of initiator 2 were introduced , 2'-azo-bisisobutyronitrile, 50 ml of ethanol, 50 ml of 2-propanol. The flask was placed in a water bath at a temperature of (65 ⁇ 1) ° C, and the stirrer was turned on, the reaction mixture was stirred for 6 hours, then the flask was cooled and 150 ml of diethyl ether was added to it.
  • AA acrylamide
  • 2-AAMPSK 2-acrylamido-2-methylpropanesulfonic acid
  • the precipitated polymer was collected on a filter and dried in a vacuum dryer to constant weight.
  • Polymers are isolated from an aqueous solution by sublimation of a frozen solvent at 10-20 Pa and 30 ° C.
  • the molecular weight of the polymer complex is determined by the molecular weight of the carrier polymer.
  • the molecular weight of the starting carrier copolymers was determined by the viscometric method.
  • Example 2 The synthesis of copolymers of complexing agents using a mixture of alcohols.
  • Example 4 3 g of a copolymer of AA with 2-AAMPSC obtained in example 1 was dissolved with stirring in 200 ml of distilled water and 1.41 g of azithromycin was added. The mass ratio of antibiotic to polymer was 0.47: 1. The reaction solution was stirred for 2 hours at room temperature, then filtered and the filtrate was freeze dried. Received 4.26 g (96.6%) of a water-soluble polymer complex of azithromycin containing May 32. % antibiotic.
  • Example 5 The experiment was carried out under the conditions of example 4, using the copolymer AA with 2-AAMPSC obtained in example 2, with a mass ratio of antibiotic: polymer equal to 0.33: 1. Received 4.23 g (95.9%) of the polymer complex azithromycin containing May 25th. % antibiotic.
  • Example 6 The experiment was carried out under the conditions of example 4 using a copolymer of AA with 2-AAMPSC obtained in example 3, with a mass ratio of antibiotic: polymer equal to 0.39: 1. 4.25 g (96.4%) of the azithromycin polymer complex containing May 28 are obtained. % antibiotic.
  • Example 6 The effect of the polymer complex of azithromycin and copolymer AA with 2-AAMPSK on the production of IL by monocyte cell culture.
  • Monocytes were isolated from whole blood of volunteers by centrifugation in a density gradient of ficoll. To determine the level of monocyte production of IL-1 alpha, IL-6, IL-10, we used the Human IL-la ELISA Kit, Human IL-6 ELISA Kit II, Human IL-10 ELISA Kit II (PharMingen). LPS of bacteria was used as an agent stimulating the production of interlykin by monocytes.
  • Example 7 Comparison of the antibacterial activity of the polymer complex of Azithromycin and copolymer AA with 2-AAMPSK and Azithromycin Table 1. Comparison of the antibacterial activity of the polymer complex
  • Example 8 The effect of the polymer complex of Azithromycin and copolymer AA with 2-AAMPSK on the development of complications of chemotherapy.
  • Example 9 The effect of the polymer complex of azithromycin and copolymer AA with 2 ⁇ AAMPSC on the survival of mice using chemotherapeutic agents.
  • azithromycin and a copolymer of AA with 2-AAMPSC effectively increases the survival of mice and reduces the toxicity of the anticancer drugs Doxorubicin and Xeloda.
  • Example 10 The effect of the polymer complex of azithromycin and copolymer AA with 2-AAMPSK on the number of copies of bacterial DNA in the blood serum of mice receiving chemotherapy.
  • Probe 5 -FAM- AAC7 AC5TGCTCC ACCGCT -BHQ 1-3 (nt 948 to 937).
  • azithromycin and copolymer AA with 2-AAMPSK (1 mg / kg) reduces the amount of bacterial DNA to 10 3 microorganisms per 1 ml, and when using the polymer complex
  • azithromycin and copolymer AA with 2-AAMPSC 3 mg / kg
  • this figure is 10 2 microorganisms per 1 ml.
  • the highest efficiency was demonstrated by the polymer complex of azithromycin and copolymer AA with 2-AAMPSC (25 mg / kg), using which the amount of bacterial DNA in patients is 10 2 - 10 1 microorganisms.
  • Example 11 The effect of the polymer complex of azithromycin and copolymer AA with 2-AAMPSK on the intestinal permeability of mice receiving chemotherapy. It is known that with chemotherapy, there is a syndrome of increased intestinal permeability (leaky gut syndrome, “leaky gut”). This leads to additional
  • Intestinal permeability was measured using a lactulose-mannitol test.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Engineering & Computer Science (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Communicable Diseases (AREA)
  • Genetics & Genomics (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne la chimie et la pharmacologie et concrètement des complexes polymères d'un antibiotique macrolidique. La présente invention concerne un produit d'interaction entre l'antibiotique macrolidique avec un copolymère d'acrylamide avec l'acide 2-acrylamido-2-méthylpronanesulfonique. L'invention concerne un médicament possédant une activité antibactérienne capable d'agir longuement dans l'intestin et lier les cytokines. Ce médicament permet d'empêcher efficacement la propagation de bactéries et de leurs toxines provenant de l'estomac et empêche la formation d'états pathologiques liés à l'activité de composants du système immunitaire. En outre, l'invention porte sur un complexe polymère d'azithromycine avec un copolymère d'acrylamide avec de l'acide 2-acrylamido-2-méthylpronanesulfonique, ayant la formule générale suivante.
PCT/RU2019/000461 2018-06-25 2019-06-25 Méthodes pour traiter et prévenir les complications liées à une perméabilité plus élevée de l'intestin Ceased WO2020005111A1 (fr)

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RU2018122994A RU2692469C1 (ru) 2018-06-25 2018-06-25 Лекарственное средство для лечения и предупреждения возникновения осложнений, связанных с химиотерапией и рентгенотерапией, а также состояний, связанных с повышенной проницаемостью кишки
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024133192A1 (fr) 2022-12-20 2024-06-27 Avantium Knowledge Centre B.V. Processus de production d'un (co)polymère de polyester biodégradable

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WO1997016174A1 (fr) * 1995-11-01 1997-05-09 Abbott Laboratories Procede de granulation aqueuse de la clarithromycine
US20090269392A1 (en) * 2008-04-29 2009-10-29 Ocugenics, LLC Drug Delivery System And Methods Of Use
US9044508B2 (en) * 2013-03-15 2015-06-02 Insite Vision Corporation Concentrated aqueous azalide formulations
RU2623877C1 (ru) * 2016-08-04 2017-06-29 Федеральное государственное бюджетное учреждение науки Институт высокомолекулярных соединений Российской академии наук Способ получения полимерных комплексов рифампицина с пониженной токсичностью и высокой противотуберкулёзной активностью
RU2635558C2 (ru) * 2016-04-06 2017-11-14 Федеральное государственное бюджетное учреждение науки Институт высокомолекулярных соединений Российской академии наук Сульфосодержащие полимеры с собственной противовирусной активностью

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WO1997016174A1 (fr) * 1995-11-01 1997-05-09 Abbott Laboratories Procede de granulation aqueuse de la clarithromycine
US20090269392A1 (en) * 2008-04-29 2009-10-29 Ocugenics, LLC Drug Delivery System And Methods Of Use
US9044508B2 (en) * 2013-03-15 2015-06-02 Insite Vision Corporation Concentrated aqueous azalide formulations
RU2635558C2 (ru) * 2016-04-06 2017-11-14 Федеральное государственное бюджетное учреждение науки Институт высокомолекулярных соединений Российской академии наук Сульфосодержащие полимеры с собственной противовирусной активностью
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024133192A1 (fr) 2022-12-20 2024-06-27 Avantium Knowledge Centre B.V. Processus de production d'un (co)polymère de polyester biodégradable

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