EP0000133B1 - Préparations pharmaceutiques contenant des polysaccharides on polymères sulfatés et des ions de zinc pour l'application topique dans les infections virales. - Google Patents

Préparations pharmaceutiques contenant des polysaccharides on polymères sulfatés et des ions de zinc pour l'application topique dans les infections virales. Download PDF

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Publication number
EP0000133B1
EP0000133B1 EP78100133A EP78100133A EP0000133B1 EP 0000133 B1 EP0000133 B1 EP 0000133B1 EP 78100133 A EP78100133 A EP 78100133A EP 78100133 A EP78100133 A EP 78100133A EP 0000133 B1 EP0000133 B1 EP 0000133B1
Authority
EP
European Patent Office
Prior art keywords
zinc ions
pharmaceutical preparation
heparin
preparation according
zinc
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.)
Expired
Application number
EP78100133A
Other languages
German (de)
English (en)
Other versions
EP0000133A1 (fr
Inventor
Bohumir Dr. Lukas
Walter Wiesendanger
Karl Heinz Dr. Schmidt-Ruppin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Ciba Geigy AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ciba Geigy AG filed Critical Ciba Geigy AG
Publication of EP0000133A1 publication Critical patent/EP0000133A1/fr
Application granted granted Critical
Publication of EP0000133B1 publication Critical patent/EP0000133B1/fr
Expired legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • 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
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the invention relates to new pharmaceutical preparations for the topical treatment of viral infections, which contain an antiviral combination of a sulfated polysaccharide or polymer, in particular heparin, and zinc ions in the form of dissociable zinc compounds.
  • the preparations were mixed in bidistilled water in graduated concentrations, with HVH2 / Ang. inoculated and incubated at 35 ° C for 1 hour.
  • the virus content in the contact mixtures was determined on chicken embryo fibroblasts in a plaque test.
  • the samples were diluted in Hanks' solution + 0.05% albumin onto cell monolayers of chicken embryo fibroblasts. After 90 minutes of virus absorption, the cultures were washed twice, 4 M LY agaroverlay [Hanks solution with 0.5% lactalbumin hydrolyzate and 0.01% yeastolate (yeast extract) J were added and then at 35 until the plaques were counted (96 hours) ° C incubated.
  • the cell monolayers were treated with 100 PFU HVH2 / Ang. infected for 90 minutes.
  • 4 ml each of the preparations incorporated in LY agaroverlay (with 5% sheep serum and 0.5% OXO-L-28 agar, a purified agar from Oxoid Ltd., Wade Road, Basingstoke, England, without diethylaminoethyl dextran) were infected on the infected Cell cultures were given and incubated at 35 ° C. until the plaques were counted (96 hours).
  • VERO cells monkey kidney cells, Cell Repository No. CGL 81 from the American Type Culture Collection
  • F15 medium Eagle's minimum essential medium from Gibco Biocult Ltd., Paisley, Scotland
  • the cultures were infected after 60 minutes with 1000 PFU HVH2 / Ang. in 0.1 ml medium.
  • the condition of the cell was assessed microscopically and the virus content of the cell lysates (cells with 1 ml of distilled water, frozen twice and thawed) was determined by titration on chicken embryo fibroblasts (plaque formation).
  • Virus replication is moderate according to Table III of zinc sulfate in the highest concentration of 25.10 -6 g / ml, but of heparin in the only concentration tested of 6.10 -6 g / ml, corresponding to the highest in the other test series, as a result of strong absorption inhibitory effect of heparin significantly inhibited; however, all tested combinations show an effect that is at least 10 times stronger than that of the individual components.
  • the therapeutic effect of the combination is not only stronger, it also occurs earlier than the effect of the individual components, and the number of recurrences is greatly reduced.
  • a preparation base in particular a gel base, which contains one or more polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monostearate and / or especially polyoxyethylene sorbitan monolaurate or primarily poloyoxyethylene sorbitan monooleate. contains.
  • the pharmaceutical preparations according to the invention preferably contain the active substances defined above in combination with pharmaceutical carriers suitable for topical application. Tinctures, solutions, creams, ointments and especially gels are particularly suitable as forms of preparations according to the invention.
  • Tinctures and solutions usually have an aqueous-ethanolic or aqueous base, which, among other things, contains polyalcohols, such as propylene glycol or glycerol and / or low polyethylene glycols, as humectants to reduce evaporation and, if necessary, lipid-replenishing substances.
  • polyalcohols such as propylene glycol or glycerol and / or low polyethylene glycols, as humectants to reduce evaporation and, if necessary, lipid-replenishing substances.
  • fatty acid esters of low polyethylene glycols such as fatty acid esters of low polyethylene glycols, ie lipophilic substances soluble in the aqueous / ethanol mixture, as a replacement for the fatty substances extracted from the skin with the ethanol, and optionally other auxiliaries and additives, in addition to conventional preservatives such as those mentioned below, for example those already mentioned Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monooleate are added.
  • Creams are oil-in-water emulsions that contain more than 50% water.
  • Fatty alcohols e.g. Lauryl, cetyl or stearyl alcohol, fatty acids e.g. Palmitic or stearic acid, liquid to solid waxes, e.g. Isopropyl myristinate, wool wax or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffin oil.
  • Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, e.g.
  • Fatty acid esters of polyalcohols or ethylene oxide adducts thereof such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), furthermore polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, e.g. Sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are commonly used in the presence of fatty alcohols, e.g. Cetyla alcohol or stearyl alcohol used.
  • fatty alcohols e.g. Cetyla alcohol or stearyl alcohol used.
  • Additions to the water phase include Agents which reduce the drying out of the cream, e.g. Polyalcohols, such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives and fragrances.
  • Polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives and fragrances.
  • Ointments are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phases.
  • the fatty phase is primarily hydrocarbons, e.g. Vaseline, paraffin oil and / or hard paraffins in question, the preferred to improve the water-binding capacity suitable hydroxy compounds, such as fatty alcohols, or esters thereof, e.g. Cetyl alcohol or wool wax alcohols or wool wax included.
  • Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (spans), e.g. Sorbitan oleate and / or sorbitan anostearate.
  • Additions to the water phase include Humectants such as polyalcohols e.g. Glycerin, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives and fragrances.
  • Gels are in particular aqueous solutions of the active ingredients in which gel formers, preferably those from the group of cellulose ethers, such as e.g. Methyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose, or the vegetable hydrocolloids, such as sodium alginate, tragacanth or acacia, are dispersed and swollen.
  • gels preferably also contain humectants from the group of polyalcohols, such as propylene glycol, glycerol and / or low polyethylene glycols, and also wetting agents, e.g.
  • Polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monostearate, monolaurate or monooleate in concentrations of approximately 0.02 to 5%.
  • the gels contain other preservatives as additional additives, e.g. Benzyl alcohol, phenethyl alcohol, phenoxyethanol, p-hydroxybenzoic acid lower alkyl esters such as the methyl and / or propyl ester, sorbic acid or organic mercury compounds such as merthiolate.
  • the preparations according to the invention can - in addition to the usual preservatives - also other biological, e.g. antiphlogistic or antimicrobial, such as antibacterial, antifungal or also antiviral substances, such as Contain flumethasone, neomycin, gentamycin, lactic acid or mikonazole.
  • antiphlogistic or antimicrobial such as antibacterial, antifungal or also antiviral substances, such as Contain flumethasone, neomycin, gentamycin, lactic acid or mikonazole.
  • the present invention relates to topically applicable antiviral preparations, the sulfated polysaccharides or polymers, such as heparin, and zinc ions in a ratio of 1 mg to 0.18 to 18 mg, in particular 1 mg to 0.18 to 4.5 mg, and optionally Contain polyoxyethylene sorbitan monolaurate and monooleate.
  • heparin the quantities given above relate to those with 160 IU / mg; the same IU quantities should be used for other heparin.
  • the zinc ions are added in the form of the corresponding amounts of a dissociable zinc compound, for example 0.8-80 mg or 0.8-20 mg ZnS0 4 .7H 2 0.
  • Corresponding topically applicable preparations in particular gels, also tinctures, aqueous solutions, creams or ointments, contain, for example, 0.1 to 5 mg of a sulfated polysaccharide or polymer, in particular 16 to 800 IU heparin, and 0.18 to 18 per g or ml mg zinc ions, corresponding, for example, about 0.8 to 80 mg ZnS0 4 .7H 2 0, and optionally additionally 0.2 to 50 mg polyoxyethylene sorbitan monolaurate and / or monooleate.
  • an antivirally effective amount of another sulfated polysaccharide or polymer such as natural or partially degraded, sulfated polysaccharides, such as sulfated amylopectins, sulfated dextrans, sulfated polyglucoses or sulfated polypentoses, or of polyvinyl sulfates, such as, for example, sodium complex, such as the complex of sodium, can be used of the sulfation products of oxidatively degraded polygalacturonic acid methyl esters [active ingredient of HEMERAN (Geigy)].
  • sulfated polysaccharide or polymer such as natural or partially degraded, sulfated polysaccharides, such as sulfated amylopectins, sulfated dextrans, sulfated polyglucoses or sulfated polypentoses, or of polyvinyl sulfates, such as, for example
  • the zinc ions can, instead of in the form of zinc sulfate, also in the form of another dissociable zinc compound, e.g. Zinc chloride, or the zinc salt of an acid or other substance of acidic character and of its own biological, e.g. antibacterial or anti-inflammatory properties, such as e.g. Zinc sudoxicam (zinc salt of 4 - hydroxy - 2 - methyl - N - (2 - thiazolyl) - 1,2 - benzothiazine - 3 - carboxamide - 1,1 - dioxide) can be added.
  • Zinc sudoxicam zinc salt of 4 - hydroxy - 2 - methyl - N - (2 - thiazolyl) - 1,2 - benzothiazine - 3 - carboxamide - 1,1 - dioxide
  • the preparations according to the invention are particularly suitable for the treatment of genital herpes, herpes dermatitis and herpes labialis.
  • Aqua conservans is understood to mean an aqueous solution of 0.07% p-hydroxybenzoic acid methyl ester (methyl paraben) and 0.03% p-hydroxybenzoic acid propyl ester (propyl paraben).
  • TWEEN 60 and TWEEN 80 are registered trademarks of ICI of America Inc., Stamford, Connecticut 06904.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Inorganic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Biotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Claims (9)

1. Compositions pharmaceutiques pour le traitement topique des infections à virus, caractérisées en ce qu'elles contiennent une combinaison antivirale active d'un polysaccharide ou polymère sulfaté et d'ions zinc sous la forme de composés dissociables du zinc.
2. Compositions pharmaceutiques selon la revendication 1, caractérisées en ce qu'elles contiennent en outre du monolaurate et/ou du monooléate de sorbitanne polyoxyéthyléné.
3. Compositions pharmaceutiques selon la revendication 1, caractérisées en ce qu'elles contiennent des polysaccharides ou polymères sulfatés et des ions zinc dans des proportions relatives de 1 mg pour 0,18 à 18 mg.
4. Compositions pharmaceutiques selon la revendication 3, caractérisées en ce qu'elles contiennent de l'héparine et des ions zinc dans des proportions relatives de 160 UI pour 0,18 à 18 mg.
5. Compositions pharmaceutiques selon la revendication 1, caractérisées en ce qu'elles contiennent, par g ou ml, de 0,1 à 5 mg d'un polysaccharide ou polymère sulfaté et de 0,18 à 18 mg d'ions zinc.
6. Compositions pharmaceutiques selon la revendication 1, caractérisées en ce qu'elles contiennent, par g ou ml, de 16 à 800 UI d'héparine et de 0,18 à 18 mg d'ions zinc.
7. Compositions pharmaceutiques selon les revendications 5 et 6, dans lesquelles les ions zinc ont été introduits sous la forme de 0,8 à 80 mg de ZnS04.7H20 en tant que composé dissociable du zinc.
8. Compositions pharmaceutiques selon la revendication 6, caractérisées en ce qu'elles contiennent, par g ou ml, de 80 à 320 UI d'un sel acceptable pour l'usage pharmaceutique de l'héparine et de 0,45 à 4,5 mg d'ions zinc.
9. Compositions pharmaceutiques selon les revendications 5 à 8, caractérisées en ce qu'elles contiennent en outre, par g ou ml, de 0,5 à 10 mg de monolaurate ou de monooléate de sorbitanne polyoxyéthyléné..
EP78100133A 1977-06-17 1978-06-09 Préparations pharmaceutiques contenant des polysaccharides on polymères sulfatés et des ions de zinc pour l'application topique dans les infections virales. Expired EP0000133B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
LU77562 1977-06-17
LU77562A LU77562A1 (de) 1977-06-17 1977-06-17 Verfahren zur herstellung von neuen pharmazeutischen praeparaten

Publications (2)

Publication Number Publication Date
EP0000133A1 EP0000133A1 (fr) 1979-01-10
EP0000133B1 true EP0000133B1 (fr) 1981-09-16

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ID=19728615

Family Applications (1)

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EP78100133A Expired EP0000133B1 (fr) 1977-06-17 1978-06-09 Préparations pharmaceutiques contenant des polysaccharides on polymères sulfatés et des ions de zinc pour l'application topique dans les infections virales.

Country Status (11)

Country Link
US (1) US4465666A (fr)
EP (1) EP0000133B1 (fr)
JP (1) JPS548727A (fr)
AU (1) AU522600B2 (fr)
CA (1) CA1116083A (fr)
DE (1) DE2861070D1 (fr)
IE (1) IE47096B1 (fr)
IT (1) IT1105718B (fr)
LU (1) LU77562A1 (fr)
NZ (1) NZ187598A (fr)
ZA (1) ZA783480B (fr)

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LU77562A1 (de) * 1977-06-17 1979-03-26 Ciba Geigy Ag Verfahren zur herstellung von neuen pharmazeutischen praeparaten
EP0012115A1 (fr) * 1978-12-04 1980-06-11 Ciba-Geigy Ag Préparations pharmaceutiques pour le traitement topique d'infections virales
GB2080682B (en) * 1980-07-30 1984-03-28 Ciba Geigy Ag Antiherpetically active lipstick
EP0066283B1 (fr) * 1981-06-02 1986-09-10 Eupan Corporation Composition eustatique pour faciliter et amplifier de façon non-spécifique la régulation généralisée homéostatique et la conservation, la compensation et la régénération dans les organismes vivants
NZ208536A (en) * 1983-06-16 1986-11-12 Victoria State Footrot composition containing zinc salt and thioacid
CA1291034C (fr) * 1987-10-19 1991-10-22 Mostafa S. Fahim Composition favorisant la regeneration de l'epithelium
US4661354A (en) * 1984-06-21 1987-04-28 Finnerty Edmund F Topical treatment of herpes simplex with a zinc sulfate-camphor water solution
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EP0243352A1 (fr) * 1985-10-21 1987-11-04 SERGIO, William Procede pour reduire le risque ou la probabilite d'infections par le virus du sida (htlv-iii/lav/arv)
US5668116A (en) * 1987-03-19 1997-09-16 Anthropharm Pty. Limited Anti-inflammatory compounds and compositions
EP0292220B1 (fr) * 1987-05-20 1991-08-14 Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo Préservatif masculin
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EP0402078A3 (fr) * 1989-06-06 1991-07-31 Patrick Daniel Kelly Lubrifiant sexuel contenant du zinc comme agent antiviral
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CN110041124A (zh) * 2019-04-23 2019-07-23 浙江工业大学 一种水稻专用富锌营养液及其用于生产富锌大米的方法

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LU77562A1 (de) * 1977-06-17 1979-03-26 Ciba Geigy Ag Verfahren zur herstellung von neuen pharmazeutischen praeparaten

Also Published As

Publication number Publication date
IT7849884A0 (it) 1978-06-15
JPS6225126B2 (fr) 1987-06-01
ZA783480B (en) 1979-07-25
NZ187598A (en) 1981-03-16
AU3715378A (en) 1979-12-20
IE47096B1 (en) 1983-12-14
IE781212L (en) 1978-12-17
AU522600B2 (en) 1982-06-17
DE2861070D1 (en) 1981-12-03
US4465666A (en) 1984-08-14
EP0000133A1 (fr) 1979-01-10
LU77562A1 (de) 1979-03-26
IT1105718B (it) 1985-11-04
CA1116083A (fr) 1982-01-12
JPS548727A (en) 1979-01-23

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