WO2012126777A1 - Inhibition de l'activité de la neuraminidase - Google Patents

Inhibition de l'activité de la neuraminidase Download PDF

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Publication number
WO2012126777A1
WO2012126777A1 PCT/EP2012/054407 EP2012054407W WO2012126777A1 WO 2012126777 A1 WO2012126777 A1 WO 2012126777A1 EP 2012054407 W EP2012054407 W EP 2012054407W WO 2012126777 A1 WO2012126777 A1 WO 2012126777A1
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Prior art keywords
infection
pni
group
molecular weight
neuraminidase
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PCT/EP2012/054407
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English (en)
Inventor
Eva Prieschl-Grassauer
Andreas Grassauer
Andreas LEIBBRANDT
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Marinomed Biotechnologie Gmbh
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Publication of WO2012126777A1 publication Critical patent/WO2012126777A1/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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/731—Carrageenans
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61K9/0043—Nose

Definitions

  • the present invention is in the field of virology and relates to a method of inhibition of neuraminidase activity of viruses useful in the prophylactic or therapeutic treatment of viral infections.
  • neuraminidase Several virus families encode a surface glycoprotein that has neuraminidase activity. Among them, the orthomyxoviridae and paramyxoviridae are of particular interest since they comprise the influenza virus and parainfluenza virus species. While in case of influenza viruses the neuraminidase (NA) is expressed as a single NA protein on the viral surface of the influenza virus, in most other paramyxoviruses its structure and activity are encoded together with those of the hemagglutinating protein into a combined hemagglutinin- neuraminidase (HN) protein.
  • HN hemagglutinin- neuraminidase
  • the attachment protein binds to cellular sialic acid-containing receptors which receptors can be glycoproteins or glycolipids. Since the attachment protein also possesses neuraminidase activity it has been designated hemagglutinin-neuraminidase (HN).
  • HN hemagglutinin-neuraminidase
  • Fig. 1 graphical representation of the inhibition of H3N2 influenza virus
  • the untreated control (hatched bar) in section "C” is set to 100 %; the efficacy each of 0.5 nM oseltamivir and 0.5nM zanamivir without PNIs is represented in the control section C (white and grey bars next to hatched bar).
  • the data represent triplicates in the controls and quadruplets for all other measurements, lota carrageenan concentrations (abscissa) have been varied in a range of from 0.4 ⁇ g I ml to 40 vg / ml; the ordinate relates to the relative NA activity in % .
  • Fig. 2 Inhibition of influenza B virus neuraminidase activity by PNIs.
  • the graphical representation mirrors the relative percentage of NA- activity (ordinate) in comparison to the positive control (p) as determined by a NA-Star test.
  • PNIs tested comprised iota-carrageenan (black bars) and carboxy- methyl cellulose (white bars).
  • the untreated control (hatched bar) was set to 100 %; data represent triplicates in the control and quadruplets for all other measurements.
  • PNI concentrations (abscissa) have been varied in a range of from 0.4 £/g / ml to 40 vg / ml.
  • NA activity typically originates from an attachment protein presented by the virus at its outer surface, the attachment protein being either a neuraminidase (NA) or a combined neuraminidase plus hemagglutinin (HN) protein.
  • NA neuraminidase
  • HN hemagglutinin
  • NA neuraminidase and neuraminidase + hemagglutinin, unless otherwise stated or derivable from the context.
  • PNIs Polymeric Neuraminidase Inhibitors
  • suitable PNIs may be selected from the group consisting of iota-carrageenan, kappa-carrageenan, cellulose sulphate, high-molecular weight (HMW) fucoidan, low-molecular weight (LMW) fucoidan, and dextran sulphate.
  • the condition or disease to be prevented, treated or alleviated is selected primarily from the group consisting of acute bronchitis, chronic bronchitis, rhinitis, sinusitis, croup, acute bronchiolitis, pharyngitis, tonsillitis, laryngitis, tracheitis, asthma and pneumonia and including typical symptoms frequently accompanying said conditions or diseases such as fever, pain, dizziness, shivering, sweating, and dehydration.
  • the invention relates to a PNI for use as a medicament in the prophylactic or therapeutic treatment of a symptom, condition or disease caused by or associated with an influenza virus infection It also relates to said PNIs for such a use wherein the influenza virus infection is accompanied by a co-infection by a non-influenza respiratory virus, said respiratory virus typically selected among the group of rhinoviruses, coro- naviruses, and non-influenza paramyxoviruses.
  • the invention relates to a combined use of at least one PNI and at least one other, preferably non-polymeric, low-molecular weight (LMW) neuraminidase inhibitor for the aforementioned purposes, said other LMW neuraminidase inhibitor preferably selected from the group consisting of zanamivir, oseltamivir, peramivir and laninamivir.
  • LMW low-molecular weight
  • the invention relates to such a combined use, wherein medication is started 24 hours or more post infection.
  • the inven- tion also relates to such a combined use, wherein the administration of a physiologically active composition or medicament is started 48 hours or more post infection, the composition or medicament containing the at least one PNI component and the at least one other neuraminidase inhibitor component either separately, i.e. in two separate preparations to be applied simultaneously or consecutively, or mixed together in a single pharmaceutical composi- tion.
  • the present invention relates to PNIs together with at least one other, particularly non-polymeric, low molecular weight neuraminidase inhibitor for any such aforementioned use by way of a pharmaceutical composition or a kit of parts suitable for a combined prophylactic or therapeutic treatment of a said symptom, condition or disease caused by or associated with an infection by an influenza virus, optionally including a said co-infection by a non-influenza virus.
  • the present invention relates to a method of prophylactic or therapeutic intervention or treatment of a symptom, condition or disease caused by or associated with either or both of an infection by an influenza virus and an infection or co-infection by at least one other non-influenza respiratory virus, the respiratory virus typically selected from the group consisting of rhinovirus, coronavirus, and paramyxovirus, the method comprising administering to a human or non-human individual at risk of or suffering from a said infection or co-infection an anti-viral effective amount of a PNI in combination with an anti-viral effective amount of another, preferably non-polymeric low-molecular weight neuraminidase inhibitor.
  • the invention relates to such a method, wherein the other low-molecular weight neuraminidase inhibitor is selected from the group consisting of zanamivir, oseltamivir, peramivir and laninamivir.
  • the invention relates to such a method, wherein the administration of a PNI in combination with a said other LMW neuraminidase inhibitor is started 24 hours or more post infection.
  • the invention relates to such a method, wherein the administration of a PNI in combination with a said other LMW neuraminidase inhibitor is started 48 hours or more post infection.
  • dosage units of the antiviral-effective pharmaceutical compositions disclosed herein for either mono-drug-therapy or combined use dual-drug therapy may be administered by any suitable route, which includes but is not limited to oral, inhalative, intranasal or any combination of oral, inhalative and intranasal administration.
  • the invention relates to such a method, wherein the other, e.g. non-polymeric LMW neuraminidase inhibitor is provided as a liquid pharmaceutical composition and is administered orally, and the PNI compound is provided as a liquid solution and is administered intranasally, optionally by spraying.
  • the invention in another aspect relates to a pharmaceutical composition suitable for prophylactic or therapeutic application against influenza virus infection, comprising an antiviral effective amount of a PNI and an antiviral effective amount of another, particularly non-polymeric LMW neuraminidase inhibitor.
  • the intranasal administration of a liquid solution comprising an effective LMW neuraminidase inhibitor together with at least one PNI offers the possibility of a direct treatment of a human or non- human individual with a well-proven neuraminidase inhibitor such as zanamivir or the active metabolite of oseltamivir.
  • a well-proven neuraminidase inhibitor such as zanamivir or the active metabolite of oseltamivir.
  • co-administration of a PNI and a said other LMW NA inhibitor allows for reducing the dosage of said other LMW neuraminidase inhibitor as compared to the dosage otherwise (i.e. in the absence of a PNI) required to obtain anti- viral-effective systemic drug levels .
  • the invention relates to a pharmaceutical composition adapted as a nasal spray comprising a LMW neuraminidase inhibitor and at least one PNI in a combination preparation.
  • zanamivir In the case of zanamivir (ZA) no oral formulation is available at the moment resulting in poor sales of the medicament that currently needs to be inhaled. It was now surprisingly found that the inclusion of an anti-viral effective amount of zanamivir in a nasal spray formulation comprising one or more PNIs results in an enhancement of the local and systemic efficacy of zanamivir in addition to the anti-viral effect of the PNIs and thereby in a substantial and synergistic improvement of the overall anti-influenza therapeutic efficacy of the combination preparation.
  • the invention relates to a pharmaceutical composition, wherein the LMW neuraminidase inhibitor is oseltamivir, in particular osel- tamivir carboxylate (cOS).
  • the invention relates to a kit of parts suitable for prophylactic or therapeutic treatment of influenza virus infection, comprising a first container comprising an antiviral effective amount of at least one PNI together with a pharmaceutically acceptable carrier, and a second container comprising an antiviral effective amount of at least one other, preferably non-polymeric LMW neuraminidase inhibitor together with a pharmaceutically acceptable carrier, and preferably a package insert containing instructions for a combined use of said antiviral effective components in the prophylactic or therapeutic treatment of a human or non-human individual in need thereof or benefitting therefrom.
  • Effective dosage amounts of combinations of PNIs with said other LMW neuraminidase inhibitors in accordance with the present invention may vary within usual pharmaceutical dosage units of the known LMW NA-inhibitors. Suitable dosages of the LMW NA-inhibitors will therefore typically range from 0.01 - 10 mg/kg/d (e.g. in case of oseltamivir) or from 0.01 - 1 mg/kg/d (e.g. in case of zanamivir), while the dosages of the polymeric NA-inhibitor component may typically vary within a range of from 0.1 - 50 /vg/kg/d, preferably of from 2 - 35 /vg/kg/d and most preferred of from 8 - 25 /vg/kg/d.
  • the PNI doses are supplied intranasally or by inhalation typically of from 100- 400 ⁇ per application.
  • a combination product containing PNI at a concentration of 2400 yg/ml of a suitable liquid carrier is applied three times per day by spraying 1 40 ⁇ in each nostril. This corresponds to a daily dose of 201 6 vg/d or approximately 27 yg/kg/d of a 75kg average recipient.
  • Influenza viruses agglutinate chicken erythrocytes via direct binding to sialic acids on the surface of the red blood cells.
  • an NA-inhibitor such as Zanamivir.
  • the test was applied for the substances listed in Table 1 and similar results were obtained for comparable polymers not disclosed herein.
  • the PNIs according to the present invention exert NA inhibiting activity whereas comparative compounds such as heparan sulfate and carboxymethyl cellulose are inactive.
  • High molecular weight polymers having molecular weights at or above 100kDa show a stronger activity while monomeric sulphated sugars are completely inactive.
  • lota-Carrageenan showed the broadest NA inhibiting spectrum by inhibiting all subtypes tested.
  • Typical molecular weight values for LMW fractions of the PNIs suitable for the present invention are in a range of from around 5 kDa to 1 5 kDa, such as, for example, approximately 8 kDa for fucoidan or from about 6 to about 10 kDa for dextran sulfate.
  • Typical molecular weight values for the HMW fractions of the PNIs suitable for the present invention are in a range of from about 1 00 kDa to about 1 000 kDa, such as, for example, about 100 kDa for fucoidan and about 100 - 500 kDa for dextran sulfate.
  • NA Star Influenza Neuraminidase Inhibitor Resistance Detection Kit (Applied Biosystems #4374348) was applied as described by the manufacturer. In all cases zanamivir served as control inhibitor of the NA-activity and showed IC50 values of 3-10 nM as expected. All substances listed in Table 1 were tested for their ability to inhibit the NA of influenza viruses of the sub-types H 1 N 1 , H3N2, H3N8, H5N 1 , H7N7 and H7N3.
  • Example 3 Combined application of PNI and known LMW NA-inhibitors
  • NA Star test was applied to determine whether a combination of PNIs with known NA-inhibitors has a beneficial effect.
  • neuraminidase inhibitors oseltamivir and zanamivir
  • the application of iota-carrageenan alone resulted in a total reduction of NA-activity of > 50% at concentrations higher than 1 .27 ⁇ g/m ⁇ .
  • the addition of 0,5nM cOS or ZA resulted in an additional reduction of 20 - 30 % .
  • This result demonstrated that the combined use of a PNI and another, i .e. non-polymeric low molecular weight NA-inhibitor even at suboptimal concentrations of the respective inhibitors resulted in a significant increase of inhibitory activity of the combination preparation towards the viral NA.
  • Example 4 Inhibition of influenza B neuraminidase
  • the NA Star test was applied to test whether influenza B virus neuraminidase can be inhibited by PNIs. As shown in Figure 2 the NA of influenza B virus (B/Lee/40) was inhibited by PNIs in a dose dependent manner, lota-carra- geenan was the most effective polymer with an effective concentration ⁇ 4 yg/ml. This result demonstrates the broad neuraminidase inhibiting activity of the PNIs of the present invention.
  • Example 5 Inhibition of the NA activity of parainfluenzavirus type 3
  • the MUNANA WHO assay for NA-activity was applied for the determination of the inhibitory effect of PNIs towards parainfluenza virus. Briefly, a 2-fold MUNANA assay buffer (33g, MES Sigma M8250, 8 ml, 1 M CaCI2, 992 ml, pH 6.52) was used to obtain a reaction mixture with parainfluenzavirus type 3 ( > 10 6 TCID 50 ) and 4-methylumbelliferyl-alpha-D-N-acetylneuraminic acid (Sigma M8639) at a concentration of 300 ⁇ as the substrate.

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Abstract

La présente invention concerne de nouveaux inhibiteurs de neuraminidase pour utilisation comme médicament dans le traitement prophylactique ou thérapeutique d'un symptôme, d'un état pathologique ou d'une maladie provoqué(e) ou associé(e) à une infection ou une co-infection par un virus présentant une activité neuraminidase (NA), en particulier issu des familles des orthomyxovirus ou des paramyxovirus.
PCT/EP2012/054407 2011-03-18 2012-03-13 Inhibition de l'activité de la neuraminidase WO2012126777A1 (fr)

Applications Claiming Priority (2)

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US201161454090P 2011-03-18 2011-03-18
US61/454,090 2011-03-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017139854A1 (fr) * 2016-02-17 2017-08-24 Ent Technologies Pty Ltd Compositions et méthodes de traitement des troubles et des pathologies des sinus
EP3076983B1 (fr) 2013-12-03 2019-08-21 Gerolymatos International S.A. Compositions aqueuses ioniques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009027057A1 (fr) * 2007-08-24 2009-03-05 Marinomed Biotechnologie Gmbh Composition antivirale contenant un polysaccharide sulfaté
WO2011076367A2 (fr) * 2009-12-22 2011-06-30 Marinomed Biotechnologie Gmbh Composition antivirale synergique et utilisation associée

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009027057A1 (fr) * 2007-08-24 2009-03-05 Marinomed Biotechnologie Gmbh Composition antivirale contenant un polysaccharide sulfaté
WO2011076367A2 (fr) * 2009-12-22 2011-06-30 Marinomed Biotechnologie Gmbh Composition antivirale synergique et utilisation associée

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANTIVIR. THER., vol. 14, no. 7, 2009, pages 891 - 898
BURCH ET AL., LANCET INFECT DIS., vol. 9, no. 9, September 2009 (2009-09-01), pages 537 - 45
HAYASHI TOSHIMITSU: "Studies on evaluation of natural products for antiviral effects and their applications", YAKUGAKU ZASSHI, vol. 128, no. 1, January 2008 (2008-01-01), pages 61 - 79, XP009159151, ISSN: 0031-6903 *
LEIBBRANDT ANDREAS ET AL: "Iota-Carrageenan Is a Potent Inhibitor of Influenza A Virus Infection", PLOS ONE, vol. 5, no. 12, December 2010 (2010-12-01), XP009159153, ISSN: 1932-6203 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3076983B1 (fr) 2013-12-03 2019-08-21 Gerolymatos International S.A. Compositions aqueuses ioniques
US11672821B2 (en) 2013-12-03 2023-06-13 Gerolymatos International S.A. Methods for treating respiratory conditions using ionic aqueous polysaccharide compositions
WO2017139854A1 (fr) * 2016-02-17 2017-08-24 Ent Technologies Pty Ltd Compositions et méthodes de traitement des troubles et des pathologies des sinus
US11357791B2 (en) 2016-02-17 2022-06-14 Ent Technologies Pty Ltd Compositions and methods for the treatment of sinus disease and disorders

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