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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• Health & Medical Sciences (AREA)
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• Public Health (AREA)
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• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Insects & Arthropods (AREA)
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• 1990
  • 1990-03-12 FR FR909003093A patent/FR2659234B1/fr not_active Expired - Fee Related
• 1991
  • 1991-03-08 US US07/930,411 patent/US6153226A/en not_active Expired - Lifetime
  • 1991-03-08 AU AU74721/91A patent/AU7472191A/en not_active Abandoned
  • 1991-03-08 ZA ZA911718A patent/ZA911718B/xx unknown
  • 1991-03-08 EP EP91906059A patent/EP0521906A1/de not_active Ceased
  • 1991-03-08 WO PCT/FR1991/000186 patent/WO1991013626A1/fr not_active Application Discontinuation
  • 1991-03-11 IE IE079591A patent/IE910795A1/en unknown
  • 1991-03-11 CN CN91102224A patent/CN1056813A/zh active Pending

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