WO2009045123A1 - Médicament possédant un effet stimulant l'hématopoïèse et hépatoprotecteur - Google Patents

Médicament possédant un effet stimulant l'hématopoïèse et hépatoprotecteur Download PDF

Info

Publication number
WO2009045123A1
WO2009045123A1 PCT/RU2008/000252 RU2008000252W WO2009045123A1 WO 2009045123 A1 WO2009045123 A1 WO 2009045123A1 RU 2008000252 W RU2008000252 W RU 2008000252W WO 2009045123 A1 WO2009045123 A1 WO 2009045123A1
Authority
WO
WIPO (PCT)
Prior art keywords
csf
radiation
drug
stimulating
neupogen
Prior art date
Application number
PCT/RU2008/000252
Other languages
English (en)
Russian (ru)
Inventor
Andrey Vladimirovich Artamonov
Petr Ivanovich Rodionov
Eugeny Danilovich Goldberg
Alexander Mikhailovich Dygai
Vadim Vadimovich Zhdanov
Gleb Nikolaevich Zyuzkov
Petr Petrovich Rodionov
Alexey Vyacheslavovich Stepanov
Evgeniy Ivanovich Vereshchagin
Original Assignee
Company Limited 'concern O3'
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Company Limited 'concern O3' filed Critical Company Limited 'concern O3'
Publication of WO2009045123A1 publication Critical patent/WO2009045123A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the invention relates to medicine, in particular to pharmacology and drugs, and can be used in the treatment of diseases associated with bone marrow depression and liver cirrhosis ⁇ schreib at the initial stage of development.
  • G-CSF granulocyte colony stimulating factor
  • glucocorticoid hormones or antihistamines are used for desensitization (Sentyakova T.N. Systemic lupus erythematosus, Novosibirsk, 2003, p. 192).
  • these methods have certain disadvantages.
  • the use of glucocorticoid hormones is accompanied by immunosuppression and an increased risk of infectious complications.
  • this method cannot be implemented with prolonged use of protein preparations, for example, with diabetes.
  • the object of the invention is to develop a medicament based on a granulocyte colony stimulating factor that can be used not only for parenteral, but also for oral administration. At the same time, this drug should have 5 no toxic effects inherent in G-CSF.
  • the solution to this problem is achieved by immobilizing a therapeutically effective amount of G-CSF on a water-soluble polymer carrier under the action of ionizing radiation.
  • ionizing radiation you can use electron radiation (directed stream of accelerated electrons), gamma radiation, x-ray radiation, laser radiation and ultraviolet radiation.
  • Appropriate ionization equipment and techniques are described in the following publications (Gopshar A.M. apd Auslepdeg VL Imbilizoprotezes on water-solvepulmegpremeprechim.
  • the most preferred method of immobilization is the impact on the polymer carrier and biologically active compound by a directed stream of accelerated electrons.
  • the treatment is carried out by bremsstrahlung generated by an ILU-6 or ILU-10 accelerator with an electron energy of 2.5 MeB, an absorbed dose of 2 to 10 kGy, and a dose rate of 1.65 kGy / hour.
  • a water-soluble polymer polymers traditional for immobilizing biologically active compounds are used, in particular, polyethylene glycol (PEG), hydroxyethyl starch, polyvinylpyrrolidone, dextrans, isoprenols can be used. Most preferably, polyethylene glycol of molecular weight 400 to 4000 Da is used as the water-soluble polymer.
  • Immobilization can be carried out either in one stage, when a reaction medium containing both a biologically active molecule and a polymer is irradiated, or in two stages, when the polymer is first activated, and then the second stage is carried out immobilization itself.
  • G-CSF immobilized by the action of ionizing radiation on a water-soluble polymer carrier can be used either directly for oral administration, or in the form of a pharmaceutical composition containing a physiologically acceptable solvent, for example water, and optionally other pharmaceutically acceptable additives traditionally used in the composition of pharmaceutical compositions.
  • the therapeutically effective amount of recombinant human G-CSF is determined depending on the specific purpose of the proposed medicinal product, the method of its administration, the severity of the disease and the condition of the patient and can be subcutaneous or intravenous: in humans
  • Example 1 The present invention is illustrated by the following examples.
  • Example 1 The present invention is illustrated by the following examples.
  • Example 2 A 10% aqueous solution of polyethylene glycol with a molecular mass of 1.5 kDa was irradiated with a stream of accelerated electrons at a dose of 1.5 Mrad. G-CSF was added to the irradiated solution to a final concentration of 10 mg G-CSF in 1 ml of 10% polyethylene glycol. The mixture was stirred for 10 minutes and the final immobilized preparation was obtained in the form of a slightly opalescent solution. The yield of the finished product is 98%.
  • Example 2 A 10% aqueous solution of polyethylene glycol with a molecular mass of 1.5 kDa was irradiated with a stream of accelerated electrons at a dose of 1.5 Mrad. G-CSF was added to the irradiated solution to a final concentration of 10 mg G-CSF in 1 ml of 10% polyethylene glycol. The mixture was stirred for 10 minutes and the final immobilized preparation was obtained in the form of a slightly opalescent solution. The yield of the
  • a 10.0% aqueous solution of polyethylene oxide with a molecular weight of 0.4 kDa was irradiated with inhibitory gamma radiation at a dose of 1.0 Mrad.
  • G-CSF was added to the irradiated solution to a final concentration of 1 mg G-CSF in 1 ml of 10% polyethylene glycol. The mixture was stirred for 30 minutes and received the preparation of immobilized G-CSF in the form of a clear solution. The yield of the finished product is 97%.
  • mice were divided into 3 groups. Cyclophosphamide (CF) was administered to all animals at a dose of 170 mg / kg. Then, mice of the 1st group received 0 subcutaneous drug G-CSF Neupogen ("Hoffman-la Roche"), mice of the 2nd group - the drug proposed in the present invention (imG-CSF), subcutaneously, and animals of the 3rd groups - immG-CSF intragastrically. All preparations were administered at a dose of 100 ⁇ g / kg, starting from the day after the administration of cytostatic 5 for 5 days 1 time per day.
  • G-CSF Neupogen Hoffman-la Roche
  • imG-CSF subcutaneous drug proposed in the present invention
  • CFU-GM hematopoietic progenitor cells
  • cyclophosphamide increased the CFU-GM content in circulation by 3 times already on the 5th day of the experiment (this is a known effect of this cytostatic agent).
  • the use of the studied drugs enhanced the indicated effect of CF on the 5th day, moreover, reliably - of the standard preparation G-CSF and imG-CSF administered per os (Table 3).
  • results obtained indicate the presence of G-CSF immobilized according to the present invention with hemostatic activity both when it is administered subcutaneously and intragastrically, and the ability to cause stem cells to enter the blood, more pronounced when the drug is administered orally.
  • Example 4 We studied changes in the morphological and functional state of liver tissue under the influence of imG-CSF and Neupogen in a model of chronic toxic liver damage.
  • hepatitis was caused by intragastric administration of a 50% solution of CCl 4 (hepatotropic poison) in olive oil at a dose of 2 ml / kg for 3 weeks 2 times a week (6 times )
  • Rats of the 1st group for 5 days were subcutaneously injected with 100 ⁇ g / kg of Neupogen, dissolved in 0.5 ml of solvent. The first administration was carried out the day after the last administration of carbon tetrachloride. Animals of the 2nd group were intragastrically injected with imG-CSF at a dose of 100 ⁇ g / kg for 5 days. Animals of the control group were injected with the same scheme in an equivalent volume distilled water.
  • rat death was assessed, biochemical studies of serum levels of aspartate and alanine aminotransferases (AcAT, AlAT) on days 14 and 28 were performed, 5 as well as a morphological study of the liver on day 40 of the experiment.
  • the activity of serum enzymes was determined by conventional methods using a semi-automatic biochemical analyzer from Sormau and standard kits for it. Blood for the study was obtained from the femoral artery through a catheter. On histological ⁇ about liver preparations stained with hematoxylin and eosin, the number of cells of the infiltrate was determined using an Avtandilov ocular network containing 25 test points. In 20 fields of view, the number of cells reaching the test points of the grid was counted. The relative area of infiltration was calculated as the ratio
  • the area of connective tissue was determined using computer graphics processing. For this, on the standard area of the liver section (consecutive microphotographs of 10 fields of view made by a digital video camera 0 "Digital mivierrschreib", with the program for transferring the image to a computer company "Elekard", Tomsk), the area of the structures stained with picrofuxin was measured, and the percentage of the selected standard area was calculated .
  • the drug imG-CSF revealed a significant hepatoprotective activity comparable to that of the recombinant G-CSF (Neupogen) preparation. This drug had a pronounced anti-inflammatory and antisclerotic effect.
  • CFU-GM granulocyte-macrophage precursors

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un médicament possédant un effet stimulant l'hématopoïèse et hépatoprotecteur, comprenant un facteur granulocytaire stimulant les colonies, immobilisé sur un vecteur polymère hydrosoluble sous l'action d'un rayonnement ionisant. On peut utiliser en tant que vecteur polymère hydrosoluble du polyéthylène glycol ou de l'amidon hydroxyéthylé possédant un poids moléculaire de 400 à 4000 Da. La source de rayonnement ionisant est un rayonnement électronique, gamma, de rayons X, laser ou ultraviolet.
PCT/RU2008/000252 2007-10-05 2008-04-22 Médicament possédant un effet stimulant l'hématopoïèse et hépatoprotecteur WO2009045123A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2007137044/15A RU2007137044A (ru) 2007-10-05 2007-10-05 Лекарственное средство, обладающее гемопоэзстимулирующим и гепатопротекторным действием
RU2007137044 2007-10-05

Publications (1)

Publication Number Publication Date
WO2009045123A1 true WO2009045123A1 (fr) 2009-04-09

Family

ID=40526424

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2008/000252 WO2009045123A1 (fr) 2007-10-05 2008-04-22 Médicament possédant un effet stimulant l'hématopoïèse et hépatoprotecteur

Country Status (2)

Country Link
RU (1) RU2007137044A (fr)
WO (1) WO2009045123A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU94006023A (ru) * 1993-02-25 1996-04-20 Стерлинг Уинтроп Инк. (US) Физиологически активная композиция на основе лиофилизированных модифицированных полиалкилен оксидом комплексов белка и полипептида с циклодекстрином и способ ее получения
RU2213557C2 (ru) * 2001-12-26 2003-10-10 Закрытое акционерное общество "Аксис" Фармацевтическая композиция, обладающая тромболитическими, противовоспалительными и цитопротективными свойствами
WO2004087739A1 (fr) * 2003-04-03 2004-10-14 Hanmi Pharm. Co. Ltd. Complexe homodimere peg-polypeptide physiologiquement actif a demi-vie prolongee in vivo et procede de preparation dudit complexe
RU2243784C2 (ru) * 2003-02-25 2005-01-10 Козлов Владимир Александрович Способ лечения больных хроническим гепатитом
RU2297225C2 (ru) * 2002-04-05 2007-04-20 Еуро-Селтик С.А. Матрица, обеспечивающая пролонгированное, инвариантное и независимое высвобождение активных соединений

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU94006023A (ru) * 1993-02-25 1996-04-20 Стерлинг Уинтроп Инк. (US) Физиологически активная композиция на основе лиофилизированных модифицированных полиалкилен оксидом комплексов белка и полипептида с циклодекстрином и способ ее получения
RU2213557C2 (ru) * 2001-12-26 2003-10-10 Закрытое акционерное общество "Аксис" Фармацевтическая композиция, обладающая тромболитическими, противовоспалительными и цитопротективными свойствами
RU2297225C2 (ru) * 2002-04-05 2007-04-20 Еуро-Селтик С.А. Матрица, обеспечивающая пролонгированное, инвариантное и независимое высвобождение активных соединений
RU2243784C2 (ru) * 2003-02-25 2005-01-10 Козлов Владимир Александрович Способ лечения больных хроническим гепатитом
WO2004087739A1 (fr) * 2003-04-03 2004-10-14 Hanmi Pharm. Co. Ltd. Complexe homodimere peg-polypeptide physiologiquement actif a demi-vie prolongee in vivo et procede de preparation dudit complexe

Also Published As

Publication number Publication date
RU2007137044A (ru) 2009-04-10

Similar Documents

Publication Publication Date Title
US20010041190A1 (en) Method for pulmonary and oral delivery of pharmaceuticals
CN112386595A (zh) 一种治疗呼吸系统病毒性感染的药物组合物
RU2371195C2 (ru) Способ лечения вирусных инфекций
CN105920586A (zh) 干扰素的雾化吸入剂
WO2023241179A1 (fr) Utilisation d'acide asiatique dans la préparation d'un médicament pour le traitement de l'hépatite b
Galanello Iron chelation: new therapies
EP2241571A1 (fr) 6-méthoxy-2',3'-didésoxyguanosine stable, son procédé de préparation et composition pharmaceutique la contenant
KR101654959B1 (ko) 만성 폐색성 폐질환 개선제
WO2009045123A1 (fr) Médicament possédant un effet stimulant l'hématopoïèse et hépatoprotecteur
JP2009514898A (ja) ガリウムを使用する、肝臓の有害状態の処置および予防
CN105816857A (zh) 干扰素的水溶液制剂
US10729713B2 (en) Pharmaceutical composition for treating hepatitis, liver fibrosis, and liver cancer
EP1748783A2 (fr) Traitement ou prevention d'infections virales respiratoires au moyen de composes immunomodulateurs
Dygai et al. Hemostimulating effects of Erythropoietin immobilized by the Nanotechnology method of electron-beam synthesis
CN114377027A (zh) 白头翁皂苷B4在制备治疗或预防SARS-CoV-2的药物的用途
CN1201737C (zh) 千金藤素在制备抗sars病毒药物中的应用
CN111840512B (zh) 治疗软骨修复和/或骨关节炎的组合物
Pajus et al. Erythroderma after clodronate treatment.
WO1999021561A1 (fr) Methode de traitement de troubles de l'attention
JP3167763B2 (ja) 創傷治癒促進剤
CN115252626B (zh) 一种含糖皮质激素的药物组合物及其应用
WO2001070203A2 (fr) Agent de traitement de l'hepatite c
JP2003081877A (ja) 経口吸収改善剤およびこれを利用する医薬組成物
Hui et al. Agranulocytosis associated with cephalosporin.
Bowen et al. Cyclosporin induced colitis.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08753926

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08753926

Country of ref document: EP

Kind code of ref document: A1