WO2008035998A1 - Formulation médicinale destinée à inhiber la propagation du virus de l'immunodéficience humaine - Google Patents

Formulation médicinale destinée à inhiber la propagation du virus de l'immunodéficience humaine Download PDF

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Publication number
WO2008035998A1
WO2008035998A1 PCT/RU2006/000573 RU2006000573W WO2008035998A1 WO 2008035998 A1 WO2008035998 A1 WO 2008035998A1 RU 2006000573 W RU2006000573 W RU 2006000573W WO 2008035998 A1 WO2008035998 A1 WO 2008035998A1
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WO
WIPO (PCT)
Prior art keywords
glycyrrhizic acid
human immunodeficiency
immunodeficiency virus
sodium carbonate
trinicotinates
Prior art date
Application number
PCT/RU2006/000573
Other languages
English (en)
Russian (ru)
Inventor
Andrei Georgievich Pokrovsky
Genrikh Aleksandrovich Tolstikov
Nariman Faridovich Salakhutdinov
Original Assignee
Obschestvo S Ogranichennoy Otvetstvennostyu 'sibfarmakon'
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 Obschestvo S Ogranichennoy Otvetstvennostyu 'sibfarmakon' filed Critical Obschestvo S Ogranichennoy Otvetstvennostyu 'sibfarmakon'
Publication of WO2008035998A1 publication Critical patent/WO2008035998A1/fr

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Classifications

    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the invention relates to pharmaceutical compositions based on derivatives of glycyrrhizic acid, which can significantly increase the bioavailability of the compounds and can be used in medicine, virology, pharmacology, for example, as an inhibitor of the reproduction of the human immunodeficiency virus.
  • glycyrrhizic acid is the main ingredient in the extract of the roots of licorice (Glusurrhiza glabra) and Ural licorice (Gl. Uralepsis), has high biological activity and is a highly effective tool in the treatment of various diseases. So, it is used in the treatment of viral hepatitis, is included in the list of drugs 15 (which has about 50 items) that suppress the reproduction of human immunodeficiency virus in vitro.
  • the named acid has an antiviral, anti-inflammatory, antipruritic and immunomodulatory effect, acts on different types of DNA and RNA viruses of the vitro and ip vivos (Varicella zoster; Nepres simrlex 1 and 2 types;
  • various types of human papillomavirus interrupts the replication of viruses in the early stages, causes the virion to exit the capsid, thereby preventing its penetration into the cells, which is associated with selective dose-dependent inhibition of phosphorylating kinase P.
  • ⁇ r Glycyrrhizic acid interacts with the structures of the virus (possibly with proteins), changing various phases of the virus cycle, which is accompanied by irreversible inactivation of viral particles that are in a free state outside the cells, blocks the introduction of active viral particles into the cell, and violates the ability of the virus to induce synthesis
  • glycyrrhizic acid as well as the acid itself, have high biological activity.
  • glycyrrhizic acid derivatives are known that exhibit properties useful for the treatment of various diseases, which indicates the high potential of these substances for use in medicine, pharmacology, and biology.
  • the closest technical solution is a derivative of glycyrrhizic acid - a glycopeptide of glycyrrhizic acid with anti-AIDS activity (RU, 2024546, publ.
  • One of the most important characteristics for candidates for antiviral drugs is not only the antiviral activity of the compound, but its bioavailability, i.e. the ability to be absorbed by the body. Many derivatives of glycyrrhizic acid, including the prototype compound, have poor solubility in water, and hence insufficient bioavailability when introduced into the body.
  • the technical result of the invention is the development of such a medicinal composition that provides increased bioavailability of a biologically active component - a derivative of glycyrrhizic acid, for example, glycirrhizic acid di- and trinicotinates.
  • the specified technical result is achieved by the fact that in the medicinal composition for inhibiting the reproduction of the human immunodeficiency virus, including derivatives of glycyrrhizic acid, according to the invention, it additionally contains sodium carbonate, and as derivatives of glycyrrhizic acid it contains di - and / or three glycyrrhizic acid nicotinates having general formula:
  • R - e either H, and two and / or three of these R are
  • the mass ratio of di - and / or three nicotinates of glycyrrhizic acid and sodium carbonate is in the range from 3: 1 to 1: 3.
  • the solubility of the di - and / or three nicotinates of glycyrrhizic acid is significantly reduced, and with a decrease in the ratio of the components less than 1: 3, the stability and biological activity of the drug composition decreases.
  • the compounds of di - and / or trinicotinates of glycyrrhizic acid are an inhibitor of the reproduction of the human immunodeficiency virus, for which the application is filed (RU, 2006108329/04, filing date 03/17/2006).
  • nicotinic acid is dissolved in an organic aprotic solvent by heating the reaction mixture to form a suspension, to which phosphorus pentachloride is also added while heating, then the suspension is cooled.
  • Glycyrrhizic acid is added to the cooled suspension and then heated again.
  • ice and concentrated hydrochloric acid are added to it until a slightly acidic reaction.
  • Glycyrrhizic acid di- and trinicotinates precipitate as a mixture of them. If necessary, dinicotinates can be separated from trinicotinates and are thus isolated separately.
  • Studies of the toxicity of glycyrrhizic acid di- and trinicotinates showed that they are non-toxic and can be used in medicine, pharmacology and biology
  • glycyrrhizic acid di- and tri-nicotinates are water-insoluble and, as a result, their bioavailability is low when Heros is administered.
  • mice received a drug substance at a dose of 7.8 mg / kg once intragastrically or intravenously. Whole blood was used as biological material to evaluate pharmacokinetic parameters.
  • Example 1 The study of the stability of di- and trinicotinato glycyrrhizic acid with the addition of various amounts of sodium carbonate.
  • Example 2 A study of the bioavailability of various ratios of sodium carbonate and di- and trinicotinates of glycyrrhizic acid.
  • the claimed optimal pharmaceutical composition provides a more than 6-fold increase in the bioavailability of the compound.
  • this composition does not worsen the anti-HIV activity of di - and trinicotinates of glycyrrhizic acid.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des formulations médicinales à base de dérivés d'acide glycyrrhizique, qui permet d'augmenter sensiblement la biodisponibilité de compositions et peut s'utiliser en médecine, en virologie ou en pharmacologie, par exemple, en qualité d'inhibiteur de propagation du virus de l'immunodéficience humaine. L'invention permet d'assurer une plus grande biodisponibilité du composant bioactif, un dérivé d'acide glycyrrhizique, par exemple, de di- et de trinicotinates d'acide glycyrrhizique. La formulation médicinale destinée à l'inhibition de propagation du virus de l'immunodéficience humaine comprend du carbonate de sodium et des dérivés d'acide glycyrrhizique, plus précisément des di- et des trinicotinates d'acide glycyrrhizique possédant la formule commune suivante (Formule I) dans laquelle R est (Formule II) ou H, deux et/ou trois des R étant (Formule III). Le rapport massique dans le di- et/ou trinicotinates d'acide glycyrrhizique et de carbonate de sodium est compris entre 3:1 et 1:3.
PCT/RU2006/000573 2006-09-18 2006-11-02 Formulation médicinale destinée à inhiber la propagation du virus de l'immunodéficience humaine WO2008035998A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2006133168/15A RU2365374C2 (ru) 2006-09-18 2006-09-18 Лекарственный состав для ингибирования репродукции вируса иммунодефицита человека
RU2006133168 2006-09-18

Publications (1)

Publication Number Publication Date
WO2008035998A1 true WO2008035998A1 (fr) 2008-03-27

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2006/000573 WO2008035998A1 (fr) 2006-09-18 2006-11-02 Formulation médicinale destinée à inhiber la propagation du virus de l'immunodéficience humaine

Country Status (2)

Country Link
RU (1) RU2365374C2 (fr)
WO (1) WO2008035998A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1625882A1 (ru) * 1988-10-04 1991-02-07 Институт химии Башкирского научного центра Уральского отделения АН СССР Способ получени гликопептидов глицирризиновой кислоты
RU2024546C1 (ru) * 1991-03-04 1994-12-15 Институт органической химии УНЦ РАН ГЛИКОПЕПТИД β-ГЛИЦИРРИЗИНОВОЙ КИСЛОТЫ С ДИБУТИЛОВЫМ ЭФИРОМ L-ГЛУТАМИНОВОЙ КИСЛОТЫ, ПРОЯВЛЯЮЩИЙ АНТИ-СПИД-АКТИВНОСТЬ
RU2004111994A (ru) * 2004-04-20 2005-10-10 Государственный научный центр вирусологии и биотехнологии "Вектор" (ГНЦ ВБ "Вектор") (RU) Синергическая композиция для ингибирования вич

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1625882A1 (ru) * 1988-10-04 1991-02-07 Институт химии Башкирского научного центра Уральского отделения АН СССР Способ получени гликопептидов глицирризиновой кислоты
RU2024546C1 (ru) * 1991-03-04 1994-12-15 Институт органической химии УНЦ РАН ГЛИКОПЕПТИД β-ГЛИЦИРРИЗИНОВОЙ КИСЛОТЫ С ДИБУТИЛОВЫМ ЭФИРОМ L-ГЛУТАМИНОВОЙ КИСЛОТЫ, ПРОЯВЛЯЮЩИЙ АНТИ-СПИД-АКТИВНОСТЬ
RU2004111994A (ru) * 2004-04-20 2005-10-10 Государственный научный центр вирусологии и биотехнологии "Вектор" (ГНЦ ВБ "Вектор") (RU) Синергическая композиция для ингибирования вич

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BIOORG. KHIM., vol. 15, no. 3, 1989, pages 392 - 398 *
DATABASE MEDLINE [online] HOEVER G. ET AL.: "Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus", Database accession no. (15715493) *
DATABASE MEDLINE [online] TOLSTIKOV G.A. ET AL.: "Transformation of glycyrrhizic acid. Synthesis of glycopeptides of glycycyrrhizic acid monomethyl ether, having anti-inflammatory and immunostimulating action", Database accession no. (2742620) *
J. MED. CHEM., vol. 48, no. 4, 2005, pages 1256 - 1259 *
PROKROVSKY A.G. ET AL.: "Sintep proizvodnykh triterpenov i issledovanie ikh protivovirusnoi i immunostimulirujuschei aktivnosti", KHIMIYA V INTERESAKH USTOICHIVOGO RAZVTIYA, vol. 9, 2001, pages 485 - 491 *

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Publication number Publication date
RU2006133168A (ru) 2008-03-27
RU2365374C2 (ru) 2009-08-27

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