EP0521906A1 - Therapeutic composition containing a phenol compound and propolis useful against lipidic capside viruses, especially the herpes viruses - Google Patents

Therapeutic composition containing a phenol compound and propolis useful against lipidic capside viruses, especially the herpes viruses

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Publication number
EP0521906A1
EP0521906A1 EP91906059A EP91906059A EP0521906A1 EP 0521906 A1 EP0521906 A1 EP 0521906A1 EP 91906059 A EP91906059 A EP 91906059A EP 91906059 A EP91906059 A EP 91906059A EP 0521906 A1 EP0521906 A1 EP 0521906A1
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EP
European Patent Office
Prior art keywords
phenol
propolis
component
group
acid
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP91906059A
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German (de)
French (fr)
Inventor
Robert Vachy
Maryvonne Amoros
Françoise SAUVAGER
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Fileco
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Fileco
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Publication date
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Publication of EP0521906A1 publication Critical patent/EP0521906A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A61K35/64—Insects, e.g. bees, wasps or fleas
    • A61K35/644—Beeswax; Propolis; Royal jelly; Honey
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • the present invention relates to a new therapeutic composition containing a phenol component and propolis.
  • This composition is useful as an antiviral means, in general, vis-à-vis the lipid-coated viruses (abbreviated: LCV), and, in particular, vis-à-vis the herpes virus and of their analogues which are part of the LCV set.
  • LCV lipid-coated viruses
  • propolis is a gummy substance that is recovered in hives. More specifically, it is a substance that bees collect on certain plants, in particular the scales of poplar and alder buds, collect and use to seal the cracks in the hives, fix the shelves and varnish the walls. In the field of beekeeping, propolis is known as the antibiotic or disinfectant means of the hive preventing the proliferation of bacteria and molds.
  • Crude propolis generally contains resins and balsamic substances (approximately 55-50% by weight), beeswax (approximately 30-35% by weight), ethereal oils (approximately 10% by weight) and pollens ( approximately 5% by weight), see in particular EP-A-0 061 508 (page 2, lines 1-28), EP- A-0 109 993 (page 1, lines 24-26) and EMSCHNEIDEWIND et al., Die Pharmazie 34, 103, (1979).
  • an anti composition viral comprising in combination a synergistic mixture of a phenol component and propolis.
  • This new technical solution is advantageous in that it makes it possible in particular to reduce the practical doses previously recommended in the antiviral indications of the phenol component and of propolis.
  • the therapeutic composition which is recommended according to the invention which comprises a phenol component and propolis. and which is useful as an antiviral means vis-à-vis LCV, is characterized in that it contains
  • the preparation method according to the invention consists in mixing the phenol component with propolis according to a phenol / propolis component weight ratio of 100/1 to 650/1.
  • BHT compound 2,6-di-t.-butylphenol of formula I below [the letters BHT historically come from the expression "butylated hydroxytoluene”]
  • EBV Epstein Barr virus
  • HG1 2,6-di-t.-butyl-paracresol (i.e. BHT of formula
  • HG4 2,6-di-t.-butyl-4-butylphenol (i.e. BHT of formula I where R is n-butyl)
  • HGt4 2,4,6-tri-t.-butylphenol (i.e. BHT of formula I where R is t.-butyl)
  • HGt5 2,6-di-t.-butyl-4- (2,2-dimethylpropyl) phenol
  • HG6 2,6-di-t.-butyl-4-hexylphenol (i.e. BHT of formula I where R is n-hexyl)
  • HGt8 2,6-di-t.-butyl-4- (1,1,3,3-tetramethylbutyl) - phenol [ie BHT of formula I where R is C (CH 3 ) 2 -CH 2 -C (CH 3 ) 3 ]
  • HSV 1 herpes simplex virus type 1
  • HSV 2 herpes simplex virus type 2
  • HSV 1 R herpes simplex virus type 1 resistant to
  • LCV lipid capsid virus
  • RT room temperature (15-20 ° C)
  • the phenol component (Cp) which intervenes according to the invention is a compound chosen from phenols and their mixtures.
  • the phenol component can be a mono- or polyhydroxyl compound comprising in its molecule at least one non-condensed benzene ring, at least two condensed benzene rings or at least three condensed benzene rings, one of these phenolic OH functions being able to be etherified, replaced by a carboxylic group or replaced by a CHO group.
  • Cp Among the compounds falling within the definition of Cp, mention may in particular be made of phenol, pyrocatechol, resorcinol, hydroquinone (or 1,4-benzenediol), 1,2,4-benzenetriol, pyrogallol (or 1,2,3-benzenetriol) , phloroglucinol (or 1,3,5-benzenetriol), gallic acid (or 3,4,5-trihydroxybenzoic acid), saligenol (or 2-hydroxybenzenemethanol), vamillin (or 4-hydroxy-3-methoxybenzaldehyde), vanillic alcohol ( or 4-hydroxy-3-methoxybenzenemethanol), vanillic acid (or 4-hydroxy-3-methoxybenzoic acid), vanillinemandelic acid (or 4-hydroxy-3-methoxymandelic acid), o-cresol, m-cresol, p-cresol, o-cresotic acid (or 2-hydroxy-3-methyl-benzoic acid), m-cresotic acid (or 2-hydroxy-4-
  • BHTs are 2,6-di-t.-butylphenols compounds corresponding to the formula:
  • R represents the hydrogen atom or a C 1 -C 12 alkyl group with a linear or branched hydrocarbon chain.
  • R represents the hydrogen atom or a C 1 -C 12 alkyl group with a linear or branched hydrocarbon chain.
  • R represents the hydrogen atom or a C 1 -C 12 alkyl group with a linear or branched hydrocarbon chain.
  • R represents the hydrogen atom or a C 1 -C 12 alkyl group with a linear or branched hydrocarbon chain.
  • formula I include 2,6-di-t.-butyl-paracresol (HG1), 2,6-di-t.-butyl-4-butylphenol (HG4), 2,6-di-t .-butyl-4-t.-butylphenol (HGt4), 2,6-di-t.-butyl-4- (2,2-dimethylpropyl) phenol (HGt5), 2,6-di-t.-butyl- 4-hexylphenol
  • Bzp are 2-benzylphenol compounds corresponding to the formula
  • X and Y independently of one another, each represent the hydrogen atom, an OH group, an OMe group or an OEt group, X and Y considered together may represent a 3,4-methylenedioxy residue,
  • A represents H or a residue CH 2 C 6 H 3 XY, in which X and Y are defined as indicated above, and
  • B represents the hydrogen atom or a C 1 -C 12 alkyl group with a linear or branched hydrocarbon chain.
  • the Cp compounds comprising an unsaturated aliphatic side chain such as for example 1-propenyl or 2-propenyl, are not used alone but in combination with at least one other Cp devoid of ethylenic or acetylenic unsaturation on a side chain. Indeed, Cp compounds having ethylenic or acetylenic unsaturation are liable to polymerize be under the action of light. It is therefore advantageous according to the invention to combine them with at least one other phenol having anti-UV properties to avoid any polymerization during storage.
  • the preferred phenol component according to the invention will be chosen from BpA, pyrogallol, pyrocatechol, carvacrol, BHT and their mixtures.
  • the most interesting Cp compounds according to the invention are BHT and especially HG1, HGt-4, HG4, HG6, HGt5 and HGt8.
  • the propolis component which is involved in the composition according to the invention will be a purified Prp, in particular a Prp soluble in water or in the usual organic solvents, obtained by treatment of the crude Prp with an alcohol, such as MeOH or EtOH, or a water-alcohol mixture.
  • an alcohol such as MeOH or EtOH
  • a water-alcohol mixture particularly suitable for this purpose are the Prp obtained according to the methods described in DE-A-1 037 651,
  • the therapeutic composition useful in the treatment of viral diseases caused by LCV will comprise the Cp / Prp mixture with an Rp of between 100/1 and 650/1, in combination with one or more excipients suitable for oral, injectable or local administration.
  • Such a composition will be particularly advantageous with regard to herpes and diseases similar to herpes. It has indeed been found that such a composition is particularly effective in the treatment of herpes simplex type 1 and type 2, in particular the diseases caused by the strains HSV 1 and HSV 1 R, which are transmissible by contact between mucous membranes, on the one hand, and diseases caused by the HSV 2 strains, which are sexually transmitted and include in particular venereal vegetations, on the other hand.
  • the antiviral composition according to the invention can be prepared according to a method known per se.
  • the process which is recommended consists in mixing the means Cp and the means Prp in an appropriate aqueous or oily physiological medium, at a temperature between RT and 75oC.
  • the best embodiment of the invention consists in using a composition of BHT and of Prp, where the BHT is 2,6-di-t.-butyl-paracresol (HG1), 2,4, 6-tri-t.-butyiphenol (HGt4), 2,6-di-t.-butyl-4- n-hexylphenol (HG6) or 2,6-di-t.-butyi-4- (1, 1,3,3-tetramethylbutyl) phenol (HGt8) with an Rp ratio of between 135/1 and 560/1.
  • BHT 2,6-di-t.-butyl-paracresol
  • HGt4 2,6-di-t.-butyl-4- n-hexylphenol
  • a new therapeutic use is recommended according to which a mixture comprising a phenol component and propolis is used in a weight ratio of phenol / propolis component of between 100/1 and 650/1, and better still between 135/1 and 560/1, for obtaining an antiviral medicament intended for use in human or veterinary therapy with respect to diseases caused by lipid-capsid viruses, in particular diseases caused by strains (i) HSV 1 , HSV 2 and HSV 1 R, and (ii) IV A , EBV and ZV.
  • a culture medium containing HG1 at concentrations of 50 or 25 mg / ml is used and solutions of Prp at decreasing concentrations of 0.363 mg / ml, 0.272 mg / ml, 180 mg / ml, 136 mg / ml and 0.090 mg / ml. Equal volumes of said culture medium and said solutions are incubated in the presence of HSVxR for 1 hour at 37 ° C. with shaking.
  • the infectious titers are determined in the usual way according to the so-called limit dilution method and compared to control samples of HSVxR virus, control samples of propolis and control samples of HG1 incubated under the same conditions (it has it was not necessary to prepare control samples of excipient since previous tests have demonstrated the absence of effect of the excipient on viruses, in particular HSV 1 R).
  • Y b infectious titre in the presence of HG1 / TV titre
  • Y ab infectious titer in the presence of Prp + HG1 / TV titer
  • Y c Y a x Y b .
  • a mixture of 59 g of white petrolatum, 2.99 g of sorbitan sesquioleate and 3 g of glycerol monooleate is brought to 70-75 ° C.
  • the heating is stopped when the mixture has become homogeneous and then added with stirring 5 g of HG6 then 0.01 g of propolis, 30 g of water are then added at a temperature less than or equal to 65oC and the stirring is continued until cooled at RT. Homogenize and obtain an ointment consisting of a water-in-oil emulsion, usable as eye drops.
  • the propolis used in examples 1-12 above is a purified propolis obtained by extraction with 80% EtOH [ie EtOH / H 2 O mixture in a weight ratio of approximately (8/2)], as indicated below. .
  • the raw Prp is deposited by the bees on perforated plastic grids mounted on frames arranged in the hives. These grids containing the raw Prp are removed from the hives and brought to -30 ° C. in a freezer so as to make the raw Prp brittle, which is then ground in a mortar.
  • the ground material is extracted with 80% EtOH, at a rate of 1 part by weight of crude Prp per 10 parts by volume of 80% EtOH, for 24 h, with stirring, at RT.
  • the insoluble residue is removed by filtration.
  • the filtrate which is collected is evaporated under reduced pressure and gives a dry extract of light brown color. Yield: 65% by weight, relative to the starting gross Prp.

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Abstract

La présente invention concerne une nouvelle composition thérapeutique comprenant un composant phénol et de la propolis et utile en tant que moyen antiviral vis-à-vis des virus à capside lipidique, caractérisée en ce qu'elle renferme (i) de 100 à 650 parties en poids de composant phénol pour (ii) une partie en poids de propolis. Cette nouvelle composition est particulièrement utile dans le traitement de l'herpès, notamment les maladies provoquées par les souches virales HSV1, HSV2 et HSV1R.The present invention relates to a new therapeutic composition comprising a phenol component and propolis and useful as an antiviral means vis-à-vis lipid-coated viruses, characterized in that it contains (i) from 100 to 650 parts in weight of phenol component for (ii) part by weight of propolis. This new composition is particularly useful in the treatment of herpes, in particular the diseases caused by the viral strains HSV1, HSV2 and HSV1R.

Description

COMPOSITION THERAPEUTIQUE CONTENANT UN COMPOSE PHENOL ET DE LA PROPOLIS UTILE CONTRE LES VIRUS A CAPSIDE LIPIDIQUE, NOTAMMENT LES VIRUS DE L'HERPES  THERAPEUTIC COMPOSITION CONTAINING A PHENOL COMPOUND AND A PROPOLIS USEFUL AGAINST LIPID CAPSIDE VIRUSES, ESPECIALLY HERPES VIRUSES
DOMAINE DE L'INVENTION FIELD OF THE INVENTION
La présente invention a trait à une nouvelle composition thérapeutique contenant un composant phénol et de la propolis. Cette composition est utile en tant que moyen antiviral, d'une manière générale, vis-à-vis des virus à capside lipidique (en abrégé : LCV), et, en particulier, vis-à-vis des virus de l'herpès et de leurs analogues qui font partie de l'ensemble des LCV.  The present invention relates to a new therapeutic composition containing a phenol component and propolis. This composition is useful as an antiviral means, in general, vis-à-vis the lipid-coated viruses (abbreviated: LCV), and, in particular, vis-à-vis the herpes virus and of their analogues which are part of the LCV set.
ART ANTERIEUR PRIOR ART
On sait que des phénols ont déjà été préconisés en thérapeutique en tant qu'agents anti-infectieux eu égard à leurs propriétés bactériostatiques ou mycostatiques.  It is known that phenols have already been recommended in therapy as anti-infective agents having regard to their bacteriostatic or mycostatic properties.
Parmi ces phénols, on sait en particulier du brevet français FR-B-2 507 891, de l'article de W.SNIPES et al., Sciences, 187, pages 64-65, (1975), et de l'article de W.SNIPES et al. intitulé "Hydrophobic Alcohols and Di-tert-butyl Phénols as Antiviral Agents" et publié dans l'ouvrage "Symposium on the Pharmacological Effects of Lipids", pages 63-73, The American Oil Chemists' Society, Champaign, Illinois (1978), que les BHT de formule I ciaprès, à savoir les 4-alkyl-2,6-di-t.-butyl-phénols où le groupe alkyl en position 4 comporte une chaîne hydrocarbonée linéaire de 1 à 12 atomes de carbone. entent des effets inhibiteurs et/ou virucides vis-à-vis des LCV et notamment des virus de l'herpès. Selon le second article de W.SNIPES et al. précité, on sait que l'activité antiherpétique est fonction de la nature du groupe 4- alkyle du BHT, et que pratiquement seul le BHT présentant en position 4 un reste n-butyle est actif vis-à-vis de HSV2. Among these phenols, we know in particular from French patent FR-B-2 507 891, from the article by W. SNIPES et al., Sciences, 187, pages 64-65, (1975), and from the article by W. SNIPES et al. entitled "Hydrophobic Alcohols and Di-tert-butyl Phenols as Antiviral Agents" and published in the book "Symposium on the Pharmacological Effects of Lipids ", pages 63-73, The American Oil Chemists' Society, Champaign, Illinois (1978), that the BHTs of formula I below, namely 4-alkyl-2,6-di-t.-butyl-phenols where the alkyl group in position 4 comprises a linear hydrocarbon chain of 1 to 12 carbon atoms. have inhibitory and / or virucidal effects vis-à-vis LCVs and in particular herpes viruses. According to the second article by W. SNIPES et al. above, we know that the antiherpetic activity is a function of the nature of the 4-alkyl group of BHT, and that practically only the BHT having in position 4 an n-butyl residue is active with respect to HSV 2 .
On sait par ailleurs que la propolis est une substance gommeuse que l'on récupère dans les ruches. Plus précisément, il s'agit d'une substance que les abeilles recueillent sur certaines plantes, notamment les écailles de bourgeon de peupliers et d'aunes, rassemblent et utilisent pour colmater les fissures des ruches, fixer les rayons et vernisser les parois. Dans le domaine de l'apiculture, la propolis est connue comme étant le moyen antibiotique ou désinfectant de la ruche empêchant la prolifération des bactéries et des moisissures.  We also know that propolis is a gummy substance that is recovered in hives. More specifically, it is a substance that bees collect on certain plants, in particular the scales of poplar and alder buds, collect and use to seal the cracks in the hives, fix the shelves and varnish the walls. In the field of beekeeping, propolis is known as the antibiotic or disinfectant means of the hive preventing the proliferation of bacteria and molds.
La propolis brute renferme généralement des résines et substances balsamiques (approximativement 55-50 % en poids), de la cire d'abeille (approximativement 30-35% en poids), des huiles éthérées (approximativement 10 % en poids) et des pollens (approximativement 5 % en poids), voir notamment EP-A-0 061 508 (page 2, lignes 1-28), EP- A-0 109 993 (page 1, lignes 24-26) et E.M.SCHNEIDEWIND et al., Die Pharmazie 34, 103, (1979). On connaît, notamment de EP-A-0 061 508 (page 3, lignes 6-7) et de EP-A-0 109 993 (page 2, lignes 3-8; page 10, lignes 7-11; et page 11, lignes 1-4) précités, d'une part, et de EP-A-0 310 757 (page 3, lignes 31-32), d'autre part, les propriétés antivirales de la propolis extraite des ruches et purifiée vis-à-vis des virus de l'herpès (notamment HSV1 et HSV2) et des virus de la grippe (notamment IVA). Crude propolis generally contains resins and balsamic substances (approximately 55-50% by weight), beeswax (approximately 30-35% by weight), ethereal oils (approximately 10% by weight) and pollens ( approximately 5% by weight), see in particular EP-A-0 061 508 (page 2, lines 1-28), EP- A-0 109 993 (page 1, lines 24-26) and EMSCHNEIDEWIND et al., Die Pharmazie 34, 103, (1979). We know, in particular from EP-A-0 061 508 (page 3, lines 6-7) and from EP-A-0 109 993 (page 2, lines 3-8; page 10, lines 7-11; and page 11 , lines 1-4) mentioned above, on the one hand, and from EP-A-0 310 757 (page 3, lines 31-32), on the other hand, the antiviral properties of propolis extracted from hives and purified vis- against herpes viruses (especially HSV 1 and HSV 2 ) and influenza viruses (especially IV A ).
On connait par ailleurs du résumé No 83-762896 de la banque de données DATABASE WPI/L de Derwent Publications Ltd, qui a trait au document RO-A-81 340, une technique du traitement des infections virales selon laquelle on administre (a) une solution alcoolique de propolis par une voie orale, et simultanément (b) badigeonne les zones localement affectées avec une composition alcoolique de propolis susceptible de contenir un composant phénol (dans le cas d'espèce, l'acide salicylique, en tant que moyen antiinflammatoire) et/ou des vitamines; et du résumé des Chemical Abstracts CA 103, 220838q, qui a trait au document RO-A-86 003, une composition antiherpès comprenant de la propolis (une partie en poids), du phénol (0,5 partie en poids) et du menthol (une partie en poids).  We also know from summary No 83-762896 of the DATABASE WPI / L database of Derwent Publications Ltd, which relates to document RO-A-81 340, a technique for the treatment of viral infections according to which (a) an alcoholic solution of propolis by the oral route, and simultaneously (b) brushes the locally affected areas with an alcoholic composition of propolis which may contain a phenol component (in this case, salicylic acid, as an anti-inflammatory means ) and / or vitamins; and from the summary of Chemical Abstracts CA 103, 220838q, which relates to document RO-A-86 003, an antiherpes composition comprising propolis (one part by weight), phenol (0.5 parts by weight) and menthol (part by weight).
Or, il se trouve que ces deux derniers documents ne décrivent ni ne suggèrent la composition synergétique de l'invention qui présente un rapport pondéral composant phénol/propolis se situant entre 100/1 et 650/1.  However, it turns out that these last two documents do not describe or suggest the synergistic composition of the invention which has a weight ratio of phenol / propolis component between 100/1 and 650/1.
BUT DE L'INVENTION PURPOSE OF THE INVENTION
Selon l'invention, on préconise une nouvelle solution technique qui fait appel à une composition anti virale comprenant en association un mélange synergique d'un composant phénol et de propolis. According to the invention, a new technical solution is recommended which uses an anti composition viral comprising in combination a synergistic mixture of a phenol component and propolis.
Cette nouvelle solution technique est avantageuse en ce sens qu'elle permet notamment de réduire les doses pratiques antérieurement recommandées dans les indications antivirales du composant phénol et de la propolis.  This new technical solution is advantageous in that it makes it possible in particular to reduce the practical doses previously recommended in the antiviral indications of the phenol component and of propolis.
Selon un autre aspect de l'invention, on propose un procédé pour la préparation de ladite composition. OBJET DE L'INVENTION  According to another aspect of the invention, there is provided a process for the preparation of said composition. OBJECT OF THE INVENTION
On vient de trouver de façon surprenante que des mélanges particuliers renfermant un composant phénol et de la propolis présentent des propriétés synergiques.  We have just surprisingly found that particular mixtures containing a phenol component and propolis have synergistic properties.
La composition thérapeutique que l'on préconise suivant l'invention, qui comprend un composant phénol et de la propolis. et qui est utile en tant que moyen antiviral vis-à-vis des LCV, est caractérisée en ce qu'elle renferme  The therapeutic composition which is recommended according to the invention, which comprises a phenol component and propolis. and which is useful as an antiviral means vis-à-vis LCV, is characterized in that it contains
(i) de 100 à 650 parties en poids de composant phénol pour  (i) from 100 to 650 parts by weight of phenol component for
(ii) une partie en poids de propoiis.  (ii) part by weight of propoiis.
Le procédé de préparation selon l'invention consiste à mélanger le composant phénol avec la propolis selon un rapport pondéral composant phénol/propolis de 100/1 à 650/1.  The preparation method according to the invention consists in mixing the phenol component with propolis according to a phenol / propolis component weight ratio of 100/1 to 650/1.
ABREVIATIONS ABBREVIATIONS
Par commodité, les abréviations suivantes ont été utilisées dans la présente description.  For convenience, the following abbreviations have been used in the present description.
BHT = composé 2,6-di-t.-butylphénol de formule I ciaprès [les lettres BHT proviennent historiquement de l'expression "Hydroxytoluène butylé"]BHT = compound 2,6-di-t.-butylphenol of formula I below [the letters BHT historically come from the expression "butylated hydroxytoluene"]
BpA = bisphénol A BpA = bisphenol A
BpB = bisphénol B Bzp = composé 2-benzylphénol de formule II ci-aprèsBpB = bisphenol B Bzp = 2-benzylphenol compound of formula II below
Cp = composant phénol Cp = phenol component
EBV = virus de Epstein Barr  EBV = Epstein Barr virus
Et = éthyle  Et = ethyl
EtO = éthoxy EtO = ethoxy
HG1 = 2,6-di-t.-butyl-paracrésol (i.e. BHT de formule  HG1 = 2,6-di-t.-butyl-paracresol (i.e. BHT of formula
I où R est méthyle)  I where R is methyl)
HG4 = 2,6-di-t.-butyl-4-butylphénol (i.e. BHT de formule I où R est n-butyle)  HG4 = 2,6-di-t.-butyl-4-butylphenol (i.e. BHT of formula I where R is n-butyl)
HGt4 = 2,4,6-tri-t.-butylphénol (i.e. BHT de formule I où R est t.-butyle) HGt4 = 2,4,6-tri-t.-butylphenol (i.e. BHT of formula I where R is t.-butyl)
HGt5 = 2,6-di-t.-butyl-4-(2,2-diméthylpropyl)phénol  HGt5 = 2,6-di-t.-butyl-4- (2,2-dimethylpropyl) phenol
[i.e. BHT de formule I où R est CH2C ( CE3 ) 3 ][ie BHT of formula I where R is CH 2 C (CE 3 ) 3 ]
HG6 = 2,6-di-t.-butyl-4-hexylphénol (i.e. BHT de formule I où R est n-hexyle) HG6 = 2,6-di-t.-butyl-4-hexylphenol (i.e. BHT of formula I where R is n-hexyl)
HGt8 = 2,6-di-t.-butyl-4-(1,1,3,3-tétraméthylbutyl)- phénol [i.e. BHT de formule I où R est C(CH3)2-CH2-C(CH3)3] HGt8 = 2,6-di-t.-butyl-4- (1,1,3,3-tetramethylbutyl) - phenol [ie BHT of formula I where R is C (CH 3 ) 2 -CH 2 -C (CH 3 ) 3 ]
HSV1 = virus herpès simplex de type 1 HSV 1 = herpes simplex virus type 1
HSV2 = virus herpès simplex de type 2 HSV 2 = herpes simplex virus type 2
HSV1R = virus herpès simplex de type 1 résistant à HSV 1 R = herpes simplex virus type 1 resistant to
l'acyclovir [substance antivirale de référence répondant à la formule développée de 2-amino- 1,9-dihydro-9-[(2-hydroxyéthoxy)méthyl]-6H purine-6-one]  acyclovir [reference antiviral substance corresponding to the structural formula of 2-amino-1,9-dihydro-9 - [(2-hydroxyethoxy) methyl] -6H purine-6-one]
IVA = virus de la grippe de type A IV A = influenza A virus
LCV = virus à capside lipidique  LCV = lipid capsid virus
Me = méthyle  Me = methyl
MeO = méthoxy  MeO = methoxy
Prp = propolis Prp = propolis
RP = rapport pondéral R P = weight ratio
RT = température ambiante ( 15-20°C) TV = titre infectieux de l'échantillon de virus ZV = virus de Zoster RT = room temperature (15-20 ° C) TV = infectious titer of the ZV virus sample = Zoster virus
DESCRIPTION DETAILLEE DE L'INVENTION DETAILED DESCRIPTION OF THE INVENTION
Comme indiqué plus haut, il est important du point de vue de la synergie que la composition thérapeutique selon l'invention comprenne le composant phénol (Cp) et la propolis (Prp) dans un rapport pondéral (Rp = Cp/Prp) compris entre 100/1 et 650/1 et avantageusement un Rp compris entre 135/1 et 560/1.  As indicated above, it is important from the point of view of synergy that the therapeutic composition according to the invention comprises the component phenol (Cp) and propolis (Prp) in a weight ratio (Rp = Cp / Prp) of between 100 / 1 and 650/1 and advantageously an Rp of between 135/1 and 560/1.
Le composant phénol (Cp) qui intervient selon l'invention est un composé choisi parmi les phénols et leurs mélanges. Le composant phénol peut être un composé mono- ou polyhydroxyle comprenant dans sa molécule au moins un cycle benzenique non condensé, au moins deux cycles benzéniques condensés ou au moins trois cycles benzéniques condensés, l'une de ces fonctions OH phénoliques pouvant être éthérifiée , remplacée par un groupe carboxylique ou remplacée par un groupe CHO.  The phenol component (Cp) which intervenes according to the invention is a compound chosen from phenols and their mixtures. The phenol component can be a mono- or polyhydroxyl compound comprising in its molecule at least one non-condensed benzene ring, at least two condensed benzene rings or at least three condensed benzene rings, one of these phenolic OH functions being able to be etherified, replaced by a carboxylic group or replaced by a CHO group.
Parmi les composés entrant dans la définition de Cp, on peut notamment mentionner les phénol, pyrocatéchol, résorcinol, hydroquinone (ou 1,4-benzènediol), 1,2,4-benzènetriol, pyrogallol (ou 1,2,3-benzènetriol), phloroglucinol (ou 1,3,5-benzènetriol), acide gallique (ou acide 3,4,5-trihydroxybenzoique), saligénol (ou 2- hydroxybenzèneméthanol),vamilline (ou 4-hydroxy-3-méthoxybenzaldéhyde), alcool vanillique (ou 4-hydroxy-3-méthoxybenzèneméthanol), acide vanillique (ou acide 4-hydroxy- 3-méthoxybenzoique), acide vanillinemandélique (ou acide 4-hydroxy-3-méthoxymandélique), o-crésol, m-crésol, p- crésol, acide o-crésotique (ou acide 2-hydroxy-3-méthyl- benzoique), acide m-crésotique (ou acide 2-hydroxy-4- méthylbenzoique), acide p-crésotique (ou acide 2-hydroxy- 5-méthylbenzoique), gaiacol (ou 2-méthoxyphénol), eugénol (ou 4-allylgaiacol), créosol (ou 2-méthoxy-4-méthylphénol), thymol (ou 2-isopropyl-5-méthylphénol), orcinol (ou 5-méthyl-1,3-benzènediol), p-anol [ou 4-(1-propényl)phénol], acide salicylique (ou acide 2-hydroxybenzoique), chavicol [ou 4-(2-propényl)phénol], carvacrol [ou 2- méthyl-5-(1-méthyléthyl)phénol ou encore isopropyl-o-crésol], 4-t.-butylphénol, butylparaben (ou 4-hydroxybenzoate de n-butyle), benzorésorcinol [ou (2,4-dihydroxyphényl)phénylméthanone], bisphénol A [ou 4,4'-(1-méthyléthy- lidène)bisphénol, en abrégé : BpA], bisphénol B [ou 4,4'- (1-méthylpropylidène)bisphénol, en abrégé : BpB], bis(2- hydroxy-4-méthoxyphényl)méthanone, 1-naphtol, 2-naphtol, anthranol (ou 9-anthracénol), anthrarobine (ou 1,2,10- anthracénetriol), anthraline fou 1,8-dihydroxv-9-(10H)- anthracénone], anthrarufine (ou 1,5-dihydroxy-9,10- anthracènedione) et leurs mélanges. Among the compounds falling within the definition of Cp, mention may in particular be made of phenol, pyrocatechol, resorcinol, hydroquinone (or 1,4-benzenediol), 1,2,4-benzenetriol, pyrogallol (or 1,2,3-benzenetriol) , phloroglucinol (or 1,3,5-benzenetriol), gallic acid (or 3,4,5-trihydroxybenzoic acid), saligenol (or 2-hydroxybenzenemethanol), vamillin (or 4-hydroxy-3-methoxybenzaldehyde), vanillic alcohol ( or 4-hydroxy-3-methoxybenzenemethanol), vanillic acid (or 4-hydroxy-3-methoxybenzoic acid), vanillinemandelic acid (or 4-hydroxy-3-methoxymandelic acid), o-cresol, m-cresol, p-cresol, o-cresotic acid (or 2-hydroxy-3-methyl-benzoic acid), m-cresotic acid (or 2-hydroxy-4-methylbenzoic acid), p-cresotic acid (or 2-hydroxy-5-methylbenzoic acid), gaiacol (or 2-methoxyphenol), eugenol (or 4-allylgaiacol), creosol (or 2-methoxy-4-methylphenol), thymol (or 2-isopropyl-5-methylphenol), orcinol (or 5-methyl-1,3-benzenediol), p-anol [or 4- (1-propenyl) phenol], salicylic acid (or 2-hydroxybenzoic acid), chavicol [or 4- (2-propenyl) phenol], carvacrol [or 2- methyl-5- (1-methylethyl) phenol or even isopropyl-o-cresol], 4-t.-butylphenol, butylparaben (or n-butyl 4-hydroxybenzoate), benzoresorcinol [or (2,4-dihydroxyphenyl) phenylmethanone], bisphenol A [or 4,4 '- (1 -methylethylenedene) bisphenol, abbreviated: BpA], bisphenol B [or 4,4'- (1-methylpropylidene) bisphenol, abbreviated: BpB], bis (2-hydroxy-4-methoxyphenyl) methanone, 1-naphthol , 2-naphthol, anthranol (or 9-anthracenol), anthrarobine (or 1,2,10- anthracenetriol), mad anthralin 1,8-dihydroxv-9- (10H) - anthracenone], anthrarufine (or 1,5-dihydroxy -9,10- anthracenedione) and their mixtures.
Parmi les Cp qui conviennent, on peut également mentionner les BHT et les Bzp de formules I et respectivement II.  Among the Cp which are suitable, mention may also be made of BHT and Bzp of formulas I and II respectively.
Les BHT sont des composés 2,6-di-t.-butylphénols répondant à la formule :  BHTs are 2,6-di-t.-butylphenols compounds corresponding to the formula:
(I) (I)
dans laquelle R représente l'atome d'hydrogène ou un groupe alkyle en C1-C12 à chaîne hydrocarbonée linéaire ou ramifiée. Sont notamment inclus dans la formule I, les 2,6-di-t.-butyl-paracrésol (HG1), 2,6-di-t.-butyl-4-butylphénol (HG4), 2,6-di-t.-butyl-4-t.-butylphénol (HGt4), 2,6-di-t.-butyl-4-(2,2-diméthylpropyl)phénol (HGt5), 2,6- di-t.-butyl-4-hexylphénol (HG6), 2,6-di-t.-butyl-4-(1,1, 3,3-tétraméthylbutyl)phénol (HGt8) et leurs mélanges. in which R represents the hydrogen atom or a C 1 -C 12 alkyl group with a linear or branched hydrocarbon chain. Included in particular in formula I are 2,6-di-t.-butyl-paracresol (HG1), 2,6-di-t.-butyl-4-butylphenol (HG4), 2,6-di-t .-butyl-4-t.-butylphenol (HGt4), 2,6-di-t.-butyl-4- (2,2-dimethylpropyl) phenol (HGt5), 2,6-di-t.-butyl- 4-hexylphenol (HG6), 2,6-di-t.-butyl-4- (1,1, 3,3-tetramethylbutyl) phenol (HGt8) and mixtures thereof.
Les Bzp sont des composés 2-benzylphénols répondant à la formule  Bzp are 2-benzylphenol compounds corresponding to the formula
dans laquelle in which
X et Y, indépendamment l'un de l'autre, représentent chacun l'atome d'hydrogène, un groupe OH, un groupe OMe ou un groupe OEt, X et Y considérés ensemble pouvant représenter un reste 3,4-méthylènedioxy,  X and Y, independently of one another, each represent the hydrogen atom, an OH group, an OMe group or an OEt group, X and Y considered together may represent a 3,4-methylenedioxy residue,
A représente H ou un reste CH2C6H3XY, dans lequel X et Y sont définis comme indiqué ci-dessus, et A represents H or a residue CH 2 C 6 H 3 XY, in which X and Y are defined as indicated above, and
B représente l'atome d'hydrogène ou un groupe alkyle en C1-C12 à chaîne hydrocarbonée linéaire ou ramifiée. B represents the hydrogen atom or a C 1 -C 12 alkyl group with a linear or branched hydrocarbon chain.
Les composés Cp comportant une chaîne latérale aliphatique insaturée, telle que par exemple 1-propényle ou 2-propényle, ne sont pas utilisés seuls mais en association avec au moins un autre Cp dépourvu d'insaturation éthylénique ou acétylénique sur une chaîne latérale. En effet, les composés Cp présentant une insaturation éthylénique ou acétylénique sont susceptibles de se polyméri ser sous l'action de la lumière. On a donc intérêt selon l'invention à les associer avec au moins un autre phénol ayant des propriétés anti-UV pour éviter toute polymérisation lors du stockage. The Cp compounds comprising an unsaturated aliphatic side chain, such as for example 1-propenyl or 2-propenyl, are not used alone but in combination with at least one other Cp devoid of ethylenic or acetylenic unsaturation on a side chain. Indeed, Cp compounds having ethylenic or acetylenic unsaturation are liable to polymerize be under the action of light. It is therefore advantageous according to the invention to combine them with at least one other phenol having anti-UV properties to avoid any polymerization during storage.
Le composant phénol préféré selon l'invention sera choisi parmi les BpA, pyrogallol, pyrocatéchol, carvacrol, BHT et leurs mélanges. Les composés Cp les plus intéressants selon l'invention sont les BHT et surtout HG1, HGt-4, HG4, HG6, HGt5 et HGt8.  The preferred phenol component according to the invention will be chosen from BpA, pyrogallol, pyrocatechol, carvacrol, BHT and their mixtures. The most interesting Cp compounds according to the invention are BHT and especially HG1, HGt-4, HG4, HG6, HGt5 and HGt8.
Le composant propolis qui intervient dans la composition selon l'invention sera une Prp purifiée, notamment une Prp soluble dans l'eau ou les solvants organiques usuels, obtenue par traitement de la Prp brute par un alcool, tel que MeOH ou EtOH, ou un mélange eaualcool. Conviennent notamment à cet effet, les Prp obtenues selon les procédés décrits dans DE-A-1 037 651, The propolis component which is involved in the composition according to the invention will be a purified Prp, in particular a Prp soluble in water or in the usual organic solvents, obtained by treatment of the crude Prp with an alcohol, such as MeOH or EtOH, or a water-alcohol mixture. Particularly suitable for this purpose are the Prp obtained according to the methods described in DE-A-1 037 651,
FR-A-2 256 764, FR-A-2 374 030, FR-A-2 594 336, EP-A-0 061 508, EP-A-0 109 993, EP-A-0 135 601 et EP-A-0 310 757, et se présentant sous la forme de poudres ou granules de couleur blanche ou brun-clair. FR-A-2 256 764, FR-A-2 374 030, FR-A-2 594 336, EP-A-0 061 508, EP-A-0 109 993, EP-A-0 135 601 and EP- A-0 310 757, and being in the form of powders or granules of white or light brown color.
La composition thérapeutique utile dans les traitements des maladies virales provoquées par les LCV comprendra le mélange Cp/Prp avec un Rp compris entre 100/1 et 650/1, en association avec un ou plusieurs excipients appropriés pour administration orale, injectable ou locale.  The therapeutic composition useful in the treatment of viral diseases caused by LCV will comprise the Cp / Prp mixture with an Rp of between 100/1 and 650/1, in combination with one or more excipients suitable for oral, injectable or local administration.
Une telle composition sera particulièrement avantageuse vis-à-vis de l'herpès et des maladies analogues à l'herpès. On a en effet trouvé qu'une telle composition était particulièrement efficace dans le traitement de l'herpès simplex de type 1 et de type 2, notamment les maladies provoquées par les souches HSV1 et HSV1R, qui sont transmissibles par contact entre muqueuses, d'une part, et les maladies provoquées par les souches HSV2, qui sont sexuellement transmissibles et comprennent notamment les végétations vénériennes, d'autre part. Such a composition will be particularly advantageous with regard to herpes and diseases similar to herpes. It has indeed been found that such a composition is particularly effective in the treatment of herpes simplex type 1 and type 2, in particular the diseases caused by the strains HSV 1 and HSV 1 R, which are transmissible by contact between mucous membranes, on the one hand, and diseases caused by the HSV 2 strains, which are sexually transmitted and include in particular venereal vegetations, on the other hand.
La composition antivirale selon l'invention peut être préparée selon une méthode connue en soi. Le procédé que l'on préconise consiste à mélanger le moyen Cp et le moyen Prp dans un milieu physiologique aqueux ou huileux approprié, à une température comprise entre RT et 75ºC. MEILLEUR MODE  The antiviral composition according to the invention can be prepared according to a method known per se. The process which is recommended consists in mixing the means Cp and the means Prp in an appropriate aqueous or oily physiological medium, at a temperature between RT and 75ºC. BEST FASHION
Le meilleur mode de mise en oeuvre de l'invention consiste à faire appel à une composition de BHT et de Prp, où le BHT est le 2,6-di-t.-butyl-paracrésol (HG1), le 2,4,6-tri-t.-butyiphénol (HGt4), le 2,6-di-t.-butyl-4- n-hexylphénol (HG6) ou le 2,6-di-t.-butyi-4-(1,1,3,3-tétraméthylbutyl)phénol (HGt8) avec un rapport Rp compris entre 135/1 et 560/1.  The best embodiment of the invention consists in using a composition of BHT and of Prp, where the BHT is 2,6-di-t.-butyl-paracresol (HG1), 2,4, 6-tri-t.-butyiphenol (HGt4), 2,6-di-t.-butyl-4- n-hexylphenol (HG6) or 2,6-di-t.-butyi-4- (1, 1,3,3-tetramethylbutyl) phenol (HGt8) with an Rp ratio of between 135/1 and 560/1.
Selon l'invention, on préconise une nouvelle utilisation thérapeutique suivant laquelle on utilise un mélange comprenant un composant phénol et de la propolis dans un rapport pondéral composant phénol/propolis compris entre 100/1 et 650/1, et mieux entre 135/1 et 560/1, pour l'obtention d'un médicament antiviral destiné à une utilisation en thérapeutique humaine ou vétérinaire vis-à-vis des maladies provoquées par les virus à capside lipidique, notamment les maladies provoquées par les souches (i) HSV1, HSV2 et HSV1R, et (ii) IVA, EBV et ZV. According to the invention, a new therapeutic use is recommended according to which a mixture comprising a phenol component and propolis is used in a weight ratio of phenol / propolis component of between 100/1 and 650/1, and better still between 135/1 and 560/1, for obtaining an antiviral medicament intended for use in human or veterinary therapy with respect to diseases caused by lipid-capsid viruses, in particular diseases caused by strains (i) HSV 1 , HSV 2 and HSV 1 R, and (ii) IV A , EBV and ZV.
D'autres avantages et caractéristiques de l'invention seront mieux compris à la lecture qui va suivre d'essais comparatifs et d'exemples de préparation. Bien entendu, l'ensemble de ces éléments n'est nullement limitatif mais est donné à titre d'illustration. EXEMPLE 1 - Essais comparatifs -Other advantages and characteristics of the invention will be better understood on reading which will follow comparative tests and examples of preparation. Of course, all of these elements are in no way limiting but are given by way of illustration. EXAMPLE 1 - Comparative tests -
On fait appel à un milieu de culture contenant HG1 aux concentrations de 50 ou 25 mg/ml et à des solutions de Prp à des concentrations décroissantes de 0,363 mg/ml, 0,272 mg/ml, 180 mg/ml, 136 mg/ml et 0,090 mg/ml. Des volumes égaux dudit milieu de culture et desdites solutions sont incubés en présence de HSVxR pendant 1h à 37ºC sous agitation. Après centrifugation, les titres infectieux sont déterminés de la manière habituelle selon la méthode dite des dilutions limites et comparés à des échantillons témoins de virus HSVxR, des échantillons témoins de propolis et des échantillons témoins de HG1 incubés dans les mêmes conditions (il n'a pas été nécessaire de préparer d'échantillons témoins d'excipient dès lors que des essais précédents ont démontré l'absence d'effet de l'excipient sur les virus, notamment HSV1R). A culture medium containing HG1 at concentrations of 50 or 25 mg / ml is used and solutions of Prp at decreasing concentrations of 0.363 mg / ml, 0.272 mg / ml, 180 mg / ml, 136 mg / ml and 0.090 mg / ml. Equal volumes of said culture medium and said solutions are incubated in the presence of HSVxR for 1 hour at 37 ° C. with shaking. After centrifugation, the infectious titers are determined in the usual way according to the so-called limit dilution method and compared to control samples of HSVxR virus, control samples of propolis and control samples of HG1 incubated under the same conditions (it has it was not necessary to prepare control samples of excipient since previous tests have demonstrated the absence of effect of the excipient on viruses, in particular HSV 1 R).
Pour mesurer précisément l'interaction de Cp et de Prp, on a utilisé la méthode décrite par R.F.SCHINAZI et al., Antimicrob. Agents Chemother., 22 (No 3), pages 499-507 (1982) et reprise par J.C. POTTAGE, ibidem 30, (No 2), pages 215-219, (1986), en tenant compte des définitions suivantes :  To precisely measure the interaction of Cp and Prp, the method described by R.F. SCHINAZI et al., Antimicrob, was used. Agents Chemother., 22 (No 3), pages 499-507 (1982) and repeated by J.C. POTTAGE, ibidem 30, (No 2), pages 215-219, (1986), taking into account the following definitions:
Ya = titre infectieux en présence de Prp/titre TV, Y a = infectious titer in the presence of Prp / TV titer,
Yb = titre infectieux en présence de HG1/titre TV, Y b = infectious titre in the presence of HG1 / TV titre,
Yab = titre infectieux en présence de Prp + HG1/titre TV, Yc = Ya x Yb. Y ab = infectious titer in the presence of Prp + HG1 / TV titer, Y c = Y a x Y b .
Si :  Yes :
1º) Yab < Yc , l'interaction est une synergie,1º) Y ab <Y c , the interaction is a synergy,
2º) Yab > Yc mais < au composé le plus actif seul, l'interaction est dans ce cas une réaction subadditive, 3º) Yab > au composé le moins actif seul, l'interaction est un antagonisme, et 2º) Y ab > Y c but <to the most active compound alone, the interaction is in this case a subadditive reaction, 3º) Y ab > to the least active compound alone, the interaction is an antagonism, and
4°) Yab > au composé le plus actif mais < au composé le moins actif, l'interaction est aiors dénommée interférence. 4 °) Y ab > to the most active compound but <to the least active compound, the interaction is therefore called interference.
Pour simplifier les calculs, les titres infectieux trouvés lors des essais des associations HGl/Prp et des essais témoins ont été exprimés par leur logarithme décimal. Les résultats obtenus ont été consignés dans le tableau I ci-après.  To simplify the calculations, the infectious titers found during tests of HGl / Prp associations and control tests were expressed by their decimal logarithm. The results obtained are reported in Table I below.
Les résultats du tableau I montrent que : The results of Table I show that:
- aux plus fortes concentrations utilisées (Prp 0,363 mg/ml et HG1 50 mg/ml), il n'est pas possible d'observer une interaction dès lors que à cette dose la propoiis seule est virucide, - at the highest concentrations used (Prp 0.363 mg / ml and HG1 50 mg / ml), it is not possible to observe an interaction since at this dose propoiis alone is virucidal,
- à la concentration en Prp de 0,272 mg/ml, on observe uniquement un effet d' interférence avec HG1,  - at the Prp concentration of 0.272 mg / ml, only an interference effect with HG1 is observed,
- en revanche, pour les faibles concentrations en Prp (0,090 à 0,180 mg/ml), il y a une synergie avec HG1 intervenant à la concentration de 25 ou 50 mg/ml.  - on the other hand, for low Prp concentrations (0.090 to 0.180 mg / ml), there is a synergy with HG1 intervening at the concentration of 25 or 50 mg / ml.
Dans le cas d'espèce, il y a synergie quand le rapport Rp = HG1/Prp est compris entre 135/1 et 560/1. In the present case, there is synergy when the ratio Rp = HG1 / Prp is between 135/1 and 560/1.
EXEMPLE 2 - Formulation -EXAMPLE 2 - Formulation -
On porte à 70-75°C un mélange de 59 g de vaseline blanche, de 2,99 g de sesquioléate de sorbitan et de 3 g de monooléate de glycerol. On cesse de chauffer quand le mélange est devenu homogène et ajoute ensuite sous agitation 5 g de HG6 puis 0,01 g de propolis, on ajoute alors 30 g d'eau à une température inférieure ou égale à 65ºC et poursuit l'agitation jusqu'à refroidissement à RT. On homogénéise et obtient une pommade constituée par une émulsion eau-dans-huile, utilisable comme collyre. EXEMPLE 3 - Formulation -A mixture of 59 g of white petrolatum, 2.99 g of sorbitan sesquioleate and 3 g of glycerol monooleate is brought to 70-75 ° C. The heating is stopped when the mixture has become homogeneous and then added with stirring 5 g of HG6 then 0.01 g of propolis, 30 g of water are then added at a temperature less than or equal to 65ºC and the stirring is continued until cooled at RT. Homogenize and obtain an ointment consisting of a water-in-oil emulsion, usable as eye drops. EXAMPLE 3 - Formulation -
On mélange à 70-75°C 56,98 g de vaseline blanche avec 3,5 g de sesquioléate de sorbitan, 3,5 g de monooléate de glycerol. Quand le mélange est devenu homogène, on cesse le chauffage et ajoute 7 g de HG1. On mélange à nouveau et ajoute sous agitation un mélange constitué de 0,02 g de propolis (Rp = 350/1) et de 30 g d'eau à une température inférieure à 70°C environ. On poursuit l'agitation jusqu'à refroidissement à RT, puis on homogénéise et obtient une pommade constituée par une émulsion eau-dans-huile, utilisable comme collyre. 56.98 g of white petrolatum are mixed at 70-75 ° C. with 3.5 g of sorbitan sesquioleate, 3.5 g of glycerol monooleate. When the mixture has become homogeneous, heating is stopped and 7 g of HG1 are added. The mixture is mixed again and a mixture consisting of 0.02 g of propolis (Rp = 350/1) and 30 g of water at a temperature below approximately 70 ° C. is added with stirring. Stirring is continued until cooling to RT, then homogenization is obtained and an ointment consisting of a water-in-oil emulsion, usable as eye drops.
EXEMPLE 4 - Formulation -EXAMPLE 4 - Formulation -
On mélange 4,66 g de stéarate de polyéthylèneglycol 1500 avec 13 g de monostéarate de glycerol, 3 g de monooléate de glycerol, 10,5 g d'oleate de décyle, 5,5 g de triglycéride caprique/caprylique et 5 g d'isostéarate de glycerol. On chauffe progressivement jusqu'à 70-75°C et on cesse le chauffage dès que le mélange est devenu homogène. On ajoute alors 8 g de HGt4 et agite lentement. On verse alors dans le mélange résultant 3 g de propylèneglycol, 0,3 g de citral, 0,04 g de Prp (Rp = 400/1) et 47 g d'eau. On agite le mélange résultant tout en le laissant se refroidir jusqu'à RT. Après passage dans un dispositif d'homogénéisation, on obtient une émulsion eau-dans-huile ayant la consistance d'une crème. EXEMPLES 5-12 - Formulations -4.66 g of polyethylene glycol 1500 stearate are mixed with 13 g of glycerol monostearate, 3 g of glycerol monooleate, 10.5 g of decyl oleate, 5.5 g of capric / caprylic triglyceride and 5 g of glycerol isostearate. It is gradually heated to 70-75 ° C and the heating is stopped as soon as the mixture has become homogeneous. 8 g of HGt4 are then added and the mixture is stirred slowly. 3 g of propylene glycol, 0.3 g of citral, 0.04 g of Prp (Rp = 400/1) and 47 g of water are then poured into the resulting mixture. The resulting mixture is stirred while allowing it to cool to RT. After passing through a homogenization device, a water-in-oil emulsion having the consistency of a cream is obtained. EXAMPLES 5-12 - Formulations -
En procédant comme indiqué à l'exemple 4, mais en remplaçant le composant phénol HGt4 par une quantité appropriée d'un autre phénol, on obtient les compositions suivantes dans lesquelles seul le composant phénol est mentionné et le rapport pondéral Rp = Cp/Prp est donné entre parenthèses. By proceeding as indicated in Example 4, but replacing the phenol component HGt4 by an appropriate amount of another phenol, the following compositions are obtained in which only the phenol component is mentioned and the weight ratio Rp = Cp / Prp is given in parentheses.
Ex 5 : bisphénol A (Rp = 250/1),  Ex 5: bisphenol A (Rp = 250/1),
EX 6 : pyrogallol (Rp = 270/1),  EX 6: pyrogallol (Rp = 270/1),
EX 7 : carvacrol (Rp = 300/1),  EX 7: carvacrol (Rp = 300/1),
Ex 8 : pyrocatéchol ( Rp = 270/1),  Ex 8: pyrocatechol (Rp = 270/1),
EX 9 : 2-(3,4-méthylènedioxybenzyl)-4-t.-butyl- phénol (Rp = 340/1),  EX 9: 2- (3,4-methylenedioxybenzyl) -4-t.-butylphenol (Rp = 340/1),
Ex 10 : 2-(3,4-dihydroxybenzyl)-4-(1,1,3,3-tétraméthylbutyl)phénol (Rp = 450/1), Ex 10: 2- (3,4-dihydroxybenzyl) -4- (1,1,3,3-tetramethylbutyl) phenol (Rp = 450/1),
Ex 11 : HGt8 (Rp = 420/1), Ex 11: HGt8 (Rp = 420/1),
Ex 12 : HGt5 (Rp = 190/1).  Ex 12: HGt5 (Rp = 190/1).
EXEMPLE 13 - Obtention de la propolis purifiée -EXAMPLE 13 Obtaining Purified Propolis
La propolis utilisée dans les exemples 1-12 cidessus, est une propolis purifiée obtenue par extraction avec EtOH à 80 % [i.e. mélange EtOH/H2O dans un rapport pondéral d'environ (8/2)], comme indiqué ci-après. The propolis used in examples 1-12 above is a purified propolis obtained by extraction with 80% EtOH [ie EtOH / H 2 O mixture in a weight ratio of approximately (8/2)], as indicated below. .
La Prp brute est déposée par les abeilles sur des grilles plastiques perforées montées sur des cadres disposés dans les ruches. Ces grilles contenant la Prp brute sont prélevées des ruches et amenées à -30°C dans un congélateur de façon à rendre la Prp brute cassante, que l'on broie ensuite au mortier. Le matériau broyé est extrait avec EtOH à 80 %, à raison de 1 partie en poids de Prp brute pour 10 parties en volume de EtOH à 80 %, pendant 24 h, sous agitation, à RT. Le résidu insoluble est écarté par filtration. Le filtrat que l'on recueille est évaporé sous pression réduite et donne un extrait sec de couleur brun-clair. Rendement : 65 % en poids, par rapport à la Prp brute de départ.  The raw Prp is deposited by the bees on perforated plastic grids mounted on frames arranged in the hives. These grids containing the raw Prp are removed from the hives and brought to -30 ° C. in a freezer so as to make the raw Prp brittle, which is then ground in a mortar. The ground material is extracted with 80% EtOH, at a rate of 1 part by weight of crude Prp per 10 parts by volume of 80% EtOH, for 24 h, with stirring, at RT. The insoluble residue is removed by filtration. The filtrate which is collected is evaporated under reduced pressure and gives a dry extract of light brown color. Yield: 65% by weight, relative to the starting gross Prp.

Claims

REVENDICATIONS
1. Composition thérapeutique comprenant un composant phénol et de la propolis et utile en tant que moyen antiviral vis-à-vis des virus à capside lipidique, caractérisée en ce qu'elle renferme 1. Therapeutic composition comprising a phenol component and propolis and useful as an antiviral means vis-à-vis lipid-coated viruses, characterized in that it contains
(i) de 100 à 650 parties en poids de composant phénol pour  (i) from 100 to 650 parts by weight of phenol component for
(ii) une partie en poids de propolis.  (ii) one part by weight of propolis.
2. Composition suivant la revendication 1, caractérisée en ce que le composant phénol est choisi parmi l'ensemble constitué par les phénol, pyrocatéchol, résorcinol, hydroquinone, 1,2,4-benzènetriol, pyrogallol, phloroglucinol, acide gallique, saligénol, vanilline, alcool vanillique, acide vanillique, acide vanillinemandélique, o-crésol, m-crésol, p-crésol, acide o-crésotique, acide m-crésotique , acide p-crésotique, gaiacol, eugénol, créosol, thymol, orcinol, p-anol, acide salicylique, chavicol, carvacrol, 4-t.-butylphénol, butylparaben, benzorésorcinol, bisphénol A ,bisphénol B, bis(2- hydroxy-4- méthoxyphényl)méthanone, 1-naphtol, 2-naphtol, anthranol, anthrarobine, anthraline, anthrarufine et leurs mélanges. 2. Composition according to Claim 1, characterized in that the phenol component is chosen from the group consisting of phenol, pyrocatechol, resorcinol, hydroquinone, 1,2,4-benzenetriol, pyrogallol, phloroglucinol, gallic acid, saligenol, vanillin , vanillic alcohol, vanillic acid, vanillinemandelic acid, o-cresol, m-cresol, p-cresol, o-cresotic acid, m-cresotic acid, p-cresotic acid, gaiacol, eugenol, creosol, thymol, orcinol, p-anol , salicylic acid, chavicol, carvacrol, 4-t.-butylphenol, butylparaben, benzoresorcinol, bisphenol A, bisphenol B, bis (2- hydroxy-4-methoxyphenyl) methanone, 1-naphthol, 2-naphthol, anthranol, anthrarobin, anthralin , anthrarufin and their mixtures.
3. Composition suivant la revendication 1, caractérisée en ce que le composant phénol est choisi parmi l'ensemble constitué par 3. Composition according to claim 1, characterized in that the phenol component is chosen from the group consisting of
(i) les 2,6-di-t.-butylphénols répondant à la formule : (i) 2,6-di-t.-butylphenols corresponding to the formula:
dans laquelle R représente l'atome d'hydrogène ou un groupe alkyle en C1-C12 à chaîne hydrocarbonée linéaire ou ramifiée, et in which R represents the hydrogen atom or a C 1 -C 12 alkyl group with a linear or branched hydrocarbon chain, and
(ii) leurs mélanges. (ii) their mixtures.
4. Composition suivant la revendication 1, caractérisée en ce que le composant phénol est choisi parmi l'ensemble constitué par 4. Composition according to claim 1, characterized in that the phenol component is chosen from the group consisting of
(i) les 2-benzylphénols répondant à la formule (i) 2-benzylphenols corresponding to the formula
dans laquelle in which
X et Y, indépendamment l'un de l'autre, représentent chacun l'atome d'hydrogène, un groupe OH, un groupe MeO ou un groupe EtO, X et Y considérés ensemble pouvant représenter un reste 3,4-méthylènedioxy,  X and Y, independently of each other, each represent the hydrogen atom, an OH group, a MeO group or an EtO group, X and Y considered together may represent a 3,4-methylenedioxy residue,
A représente H ou un reste CH2C6H3XY, dans lequel X et Y sont définis comme indiqué ci-dessus, et A represents H or a residue CH 2 C 6 H 3 XY, in which X and Y are defined as indicated above, and
B représente l'atome d'hydrogène ou un groupe alkyle en C1-C12 a chaîne hydrocarbonée linéaire ou ramifiée, et B represents the hydrogen atom or a C 1 -C 12 alkyl group with a linear or branched hydrocarbon chain, and
(ii) leurs mélanges. (ii) their mixtures.
5. Composition suivant la revendication 1, caractérisée en ce que le composant phénol est choisi parmi l'ensemble constitué par les composés 5. Composition according to Claim 1, characterized in that the phenol component is chosen from the group consisting of the compounds
(a) 2,6-di-t.-butyl-paracrésol,  (a) 2,6-di-t.-butyl-paracresol,
(b) 2,4,6-tri-t.-butylρhénol, (c) 2,6-di-t.-butyl-4-(2,2-diméthylpropyl)phénol, (d) 2,6-di-t.-butyl-4-n-hexyiphénol, (b) 2,4,6-tri-t.-butylρhenol, (c) 2,6-di-t.-butyl-4- (2,2-dimethylpropyl) phenol, (d) 2,6-di-t.-butyl-4-n-hexyiphenol,
(e) 2,6-di-t.-butyl-4-(1,1,3,3-tétraméthylbutyl)- phénol  (e) 2,6-di-t.-butyl-4- (1,1,3,3-tetramethylbutyl) - phenol
(f) bisphénol A,  (f) bisphenol A,
(g) pyrogallol,  (g) pyrogallol,
(h) pyrocatéchol,  (h) pyrocatechol,
(i) carvacrol, et  (i) carvacrol, and
(j) leurs mélanges.  (j) their mixtures.
6. Composition suivant la revendication 1, caractérisée en ce que le rapport pondéral composant phénol/propolis est compris entre 135/1 et 560/1. 6. Composition according to claim 1, characterized in that the weight ratio of phenol / propolis component is between 135/1 and 560/1.
7. Utilisation thérapeutique caractérisée en ce que l'on fait appel à un mélange comprenant un composant phénol et de la propolis dans un rapport pondéral composant phénol/propolis compris entre 100/1 et 650/1, pour l'obtention d'un médicament antiviral destiné à une utilisation en thérapeutique humaine ou vétérinaire vis- à-vis des maladies provoquées par les virus à capside lipidique. 7. Therapeutic use characterized in that a mixture comprising a phenol component and propolis is used in a phenol / propolis component weight ratio of between 100/1 and 650/1, for obtaining a medicament antiviral intended for use in human or veterinary therapy vis-à-vis diseases caused by lipid-capsid viruses.
8. Utilisation suivant la revendication 7, caractérisée en ce que le rapport pondéral composant phénol/propolis est compris entre 135/1 et 560/1. 8. Use according to claim 7, characterized in that the weight ratio of phenol / propolis component is between 135/1 and 560/1.
9. Utilisation suivant l'une quelconque des revendications 7 et 8, caractérisée en ce que ledit mélange composant phénol/propolis est destiné à une utilisation en thérapeutique vis-à-vis des maladies provoquées par les souches HSV1, HSV2 et HSV1R. 9. Use according to any one of claims 7 and 8, characterized in that said mixture of phenol / propolis component is intended for use in therapy with respect to diseases caused by the strains HSV 1 , HSV 2 and HSV 1 R.
10. Procédé pour la préparation d'une composition antivirale suivant la revendication 1, ledit procédé étant caractérisé en ce qu'il consiste à mélanger le composant phénol et la propolis dans un milieu physiolologique aqueux ou huileux approprié, à une température comprise entre 15 et 75°C, selon un rapport pondéral composant phénol/propolis de 100/1 à 650/1. 10. A process for the preparation of an antiviral composition according to claim 1, said process being characterized in that it consists in mixing the phenol component and propolis in an appropriate aqueous or oily physiological medium, at a temperature between 15 and 75 ° C, according to a phenol / propolis component weight ratio of 100/1 to 650/1.
EP91906059A 1990-03-12 1991-03-08 Therapeutic composition containing a phenol compound and propolis useful against lipidic capside viruses, especially the herpes viruses Ceased EP0521906A1 (en)

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FR909003093A FR2659234B1 (en) 1990-03-12 1990-03-12 THERAPEUTIC COMPOSITION CONTAINING A PHENOL COMPOUND AND PROPOLIS USEFUL AGAINST LIPID CAPSIDE VIRUSES, ESPECIALLY HERPES VIRUSES.
FR9003093 1990-03-12

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Publication number Priority date Publication date Assignee Title
FR2672799B1 (en) * 1991-02-20 1995-02-03 Fileco Sa 4-SUBSTITUTED COMPOUNDS OF 2,6-DI-T-BUTYLPHENOL AS ANTIPAPILLOMAVIRUS SUBSTANCES AND THEIR USE WITH CONDYLOMAS.
EP0557404B1 (en) * 1990-11-12 1996-05-15 Fileco ANTIVIRAL USE OF A 2,6-DI-t-BUTYLPHENOL COMPOUND SUBSTITUTED IN POSITION 4, PARTICULARLY IN RELATION TO HERPESVIRUSES AND PAPILLOMAVIRUSES
DE4230268A1 (en) * 1992-09-10 1994-03-17 Bayer Ag Preservatives for injection formulations
AU7229598A (en) * 1997-04-09 1998-10-30 Viron Corporation Antiviral composition containing oxidized inositol, sodium sulfite, pyrocatecholand copper sulfate
DE19813802A1 (en) * 1998-03-27 1999-11-11 Retro Tech Gmbh Anti-viral effects of propolis through inhibition of viral nucleic acid polymerases
DE19834053A1 (en) 1998-07-29 2000-03-30 Centeon Pharma Gmbh Methods and means for sanitizing contamination caused by viruses
WO2002062361A1 (en) * 2001-02-06 2002-08-15 Cherbuliez Theodore Antiviral composition containing propolis and essential oils
GB0115344D0 (en) * 2001-06-22 2001-08-15 Unilever Plc Cosmetic compositions
FR2835522B1 (en) * 2002-02-06 2006-04-07 Robert Vachy PREPARATION FOR OXIDATION-SENSITIVE COMPOUNDS AND PROCESS FOR PRODUCING THE SAME
WO2004064781A2 (en) * 2003-01-14 2004-08-05 Adam Heller Anti-inflammatory substituted phenols and elastomeric compositions for oral delivery of drugs
BRPI0609071A2 (en) * 2005-04-12 2010-11-16 Elan Pharma Int Ltd stable nanoparticulate cyclosporine composition, method for preparing a nanoparticulate cyclosporine, use of stable nanoparticulate cyclosporine composition, and controlled release composition
US7790203B2 (en) * 2005-12-13 2010-09-07 Lowder Tom R Composition and regimen for the treatment of herpes simplex virus, herpes zoster, and herpes genitalia epidermal herpetic lesions
WO2008000920A1 (en) * 2006-06-23 2008-01-03 Rdw Pharma D-glucopyranose 1-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoate] compound and its derivatives, preparation thereof and uses thereof
FR2933616B1 (en) * 2008-07-10 2011-08-19 Robert Vachy "COMPOSITIONS COMPRISING AN ASSOCIATION OF PROPOLIS AND A PHENOLIC DERIVATIVE AND THEIR BIOLOGICAL APPLICATIONS"
US20110052727A1 (en) * 2009-08-31 2011-03-03 Hanan Polansky Anti Influenza Nutritional Supplements
FR2962332B1 (en) * 2010-07-09 2012-08-31 Robert Vachy USE OF PROPOFOL FOR MANUFACTURING ANTIVIRAL DRUGS
FR2963736B1 (en) * 2010-08-10 2012-08-31 Robert Vachy THERAPEUTIC COMPOSITION COMPRISING GALVINOXYL DERIVATIVE AND PROPOLIS AND USE THEREOF FOR LIPID CAPSID VIRUSES, IN PARTICULAR HERPES VIRUSES
FR3058640B1 (en) * 2016-11-14 2020-06-19 Robert Vachy COMPOUNDS FOR THEIR USE IN THE TREATMENT OF INFLUENZA

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
ATE13976T1 (en) * 1981-03-27 1985-07-15 Rudolf Schanze PROCESSES FOR OBTAINING PRODUCTS CONTAINING PRODUCTS AND PRODUCTS CONTAINING PRODUCTS.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9113626A1 *

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US6153226A (en) 2000-11-28
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CN1056813A (en) 1991-12-11
AU7472191A (en) 1991-10-10

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