EP0000133A1 - Pharmaceutical preparations containing sulfated polysaccharides or polymers and zinc ions for topical application in virus infections. - Google Patents

Pharmaceutical preparations containing sulfated polysaccharides or polymers and zinc ions for topical application in virus infections. Download PDF

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Publication number
EP0000133A1
EP0000133A1 EP78100133A EP78100133A EP0000133A1 EP 0000133 A1 EP0000133 A1 EP 0000133A1 EP 78100133 A EP78100133 A EP 78100133A EP 78100133 A EP78100133 A EP 78100133A EP 0000133 A1 EP0000133 A1 EP 0000133A1
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EP
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Prior art keywords
pharmaceutical preparations
zinc ions
preparations according
content
heparin
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EP78100133A
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German (de)
French (fr)
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EP0000133B1 (en
Inventor
Bohumir Dr. Lukas
Walter Wiesendanger
Karl Heinz Dr. Schmidt-Ruppin
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Novartis AG
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Ciba Geigy AG
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    • 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 topical use, in particular for the topical treatment of viral infections, which contain an antiviral combination of an acidic, sulfated polysaccharide or polymer, in particular heparin, and zinc ions, and the use of these preparations for the topical treatment of infections caused by herpes.
  • Viruses especially those caused by herpes virus hominis (HVH), e.g. of genital herpes and herpes dermatitis.
  • 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 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 ml of LY agaroverlay [Hanks' solution with 0.5% lactalbumin hydrolyzate and 0.01% yeastolate (yeast extract)] were added and then until the plaques were counted (96 hours) incubated at 35 ° C.
  • 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, 0.5% OXO-L-28 agar, without diethylaminoethyl dextran) were added to the infected cell cultures and these were counted at 35 until the plaques were counted (96 hours) ° C incubated.
  • LY agaroverlay with 5% sheep serum, 0.5% OXO-L-28 agar, without diethylaminoethyl dextran
  • Confluent monolayers of VERO cells were treated with F15 medium [Minimum Essential Medium (Eagle), Gibco Bio-Cult Ldt. Paisley, Scotland] washed and then with each 4 ml of the different concentrations of the preparations in F15 medium occupied.
  • F15 medium Minimum Essential Medium (Eagle), Gibco Bio-Cult Ldt. Paisley, Scotland
  • the cultures were infected after 60 minutes with 1000 PFU HVH2 / Ang. in 0.1 ml medium. After 20 hours of incubation at 35 ° C., the condition of the cells was assessed microscopically and the virus content of the cell lysates (cells with 1 ml of double-distilled water, frozen twice and thawed) was determined by titration for chicken embryo fibroblasts (plaque formation).
  • Virus replication is only moderate according to Table III of zinc sulfate in the highest concentration of 25 mcg / ml, but of heparin in the only concentration tested of 6 mcg / ml, corresponding to the highest in the other test series, due to the strong absorption inhibitory effect of heparin clearly inhibited; however, all tested combinations show an effect that is at least 10 times stronger than the individual components.
  • the therapeutic effect of the combination is not only stronger, but also occurs earlier than the effect of the individual components, moreover 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.
  • polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monostearate and / or especially polyoxyethylene sorbitan monolaurate or primarily poloyoxyethylene sorbitan monooleate.
  • 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 mostly have an aqueous-ethanolic or aqueous base, which among other things.
  • Polyalcohols e.g. Propylene glycol or glycerin and / or low polyethylene glycols, as humectants to reduce evaporation
  • optionally refatting substances such as fatty acid esters of low polyethylene glycols, i.e. lipophilic substances soluble in the aqueous-ethanol mixture, as a substitute 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, e.g. the polyoxyethylene sorbitan fatty acid esters already mentioned, such as polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monooleate, have also been added.
  • Creams are oil-in-water emulsions that contain more than 50% water.
  • the main oils used are fatty alcohols, e.g. lauryl, cetyl or stea ryl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristinate, wool wax or beeswax, and / or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil.
  • Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), and also polyoxyethylene fatty alcohol ethers or corresponding fatty acid emulsifiers, such as ionic emulsifiers or corresponding fatty acid emulsifiers of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetylic alcohol or stearyl alcohol.
  • corresponding nonionic emulsifiers for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters
  • Additives to the water phase include agents which reduce the drying out of the cream, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
  • polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
  • Ointments are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phases.
  • the fat phase primarily comes from hydrocarbons, e.g. Vaseline, paraffin oil and / or hard paraffins, which preferably contain suitable hydroxy compounds, such as fatty alcohols, or esters thereof, e.g. Cetyl alcohol or wool wax alcohols or wool wax.
  • 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, fragrances, etc.
  • Gels are in particular aqueous solutions of the active ingredient substances in which gel formers, preferably those from the group of cellulose ethers, such as methyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose, or of vegetable hydrocolloids, such as sodium alginate, tragacanth or acacia, are dispersed and swollen.
  • gel formers preferably those from the group of cellulose ethers, such as methyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose, or of vegetable hydrocolloids, such as sodium alginate, tragacanth or acacia
  • the gels preferably also contain humectants from the group of polyalcohols, such as propylene glycol, glycerol and / or low polyethylene glycols, and wetting agents, for example polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monostearate, monolaurate or monooleate, in concentrations of about 0.02 to 5% .
  • the gels contain conventional preservatives, for example 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. anti-inflammatory or anti-microbial, such as anti-bacterial, anti-fungal or also anti-viral substances, e.g. Contain flumethasone, neomycin, gentamycin, lactic acid or mikonazole.
  • the preparations according to the invention are produced in a manner known per se.
  • the present invention relates in particular to topically applicable antiviral preparations, the acid 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 or monooleate.
  • 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 in the form of the corresponding amounts of a dissociable zinc compound, e.g. 0.8-80 mg or 0.8-20 mg ZnSO 4 .7H 2 O, added.
  • Corresponding topically applicable preparations in particular gels and also tinctures, aqueous solutions, creams or ointments, contain, for example, 0.1 to 5 mg of an acidic sulfated polysaccharide or polymer, in particular 16 to 800 IU heparin, and 0.18 to per g or ml 18 mg of zinc ions, corresponding, for example, to about 0.8 to 80 mg of ZnSO 4 .7H 2 0, and optionally additionally 0.2 to 50 mg of polyoxyethylene sorbitan monolaurate and / or monooleate.
  • an antivirally effective amount of another acidic sulfated polysaccharide or polymer such as natural or partially degraded acidic sulfated polysaccharides, such as sulfated amylopectins; sulfated dextrans, sulfated polyglucoses or sulfated polypentoses, or of polyvinyl sulfates, such as the sodium salt of the calcium complex of the sulfation products of oxidatively degraded polygalacturonic acid methyl esters [active ingredient of HEMERAN (Geigy)].
  • another acidic sulfated polysaccharide or polymer such as natural or partially degraded acidic sulfated polysaccharides, such as sulfated amylopectins; sulfated dextrans, sulfated polyglucoses or sulfated polypentoses, or of polyvinyl sulfates, such as the sodium salt of the calcium
  • 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.
  • gels according to the invention are applied as early as possible, for example using a tube or applicator, 2-3 times a day, and for the treatment of herpes labialis several times a day on the diseased parts of the body until the symptoms have subsided or until they have healed.
  • Aqueous solutions according to the invention can be used, for example, to rinse diseased body cavities, in particular for the treatment of herpes gingivostomatitis, or for the treatment of herpes keratoconjunctivitis.
  • 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 slotted trademarks of ICI of America Inc., Stamford, Connecticut 06904.

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Abstract

Die Erfindung betrifft neue pharmazeutische Präparate zur topischen Behandlung von Infektionen durch Herpes-Viren, insbesondere solchen, die durch Herpes-Virus hominis verursacht wurden, z.B. von Herpes genitalis und Herpes dermatitis. Die Präparate enthalten als antivirale Wirkstoffe eine synergistische Kombination eines sauren, sulfatierten Polysaccharids oder Polymeren, insbesondere Heparin, mit Zinkionen, und gegebenenfalls einen zusätzlichen Gehalt an Polyoxyäthylensorbitan- monolaurat und/oder -monooleat in üblichen topisch anwendbaren Arzneimittelformen, wie Cremes, Salben, Tinkturen, wässrigen Lösungen und vor allem Gelen.The invention relates to new pharmaceutical preparations for the topical treatment of infections caused by herpes viruses, particularly those caused by herpes virus hominis, e.g. of genital herpes and herpes dermatitis. As antiviral active ingredients, the preparations contain a synergistic combination of an acidic, sulfated polysaccharide or polymer, in particular heparin, with zinc ions and, if appropriate, an additional content of polyoxyethylene sorbitan monolaurate and / or monooleate in customary topically applicable pharmaceutical forms, such as creams, ointments, tinctures, aqueous solutions and especially gels.

Description

Die Erfindung betrifft neue pharmazeutische Präparate zur topischen Anwendung, insbesondere zur topischen Behandlung von Virusinfektionen, die eine antiviral wirksame Kombination eines sauren, sulfatierten Polysaccharids oder Polymeren, insbesondere Heparin, und Zinkionen enthalten, und die Verwendung dieser Präparate zur topischen Behandlung von Infektionen durch Herpes-Viren, insbesondere solchen, die durch Herpes-Virus hominis (HVH) verursacht wurden, z.B. von Herpes genitalis und Herpes dermatitis.The invention relates to new pharmaceutical preparations for topical use, in particular for the topical treatment of viral infections, which contain an antiviral combination of an acidic, sulfated polysaccharide or polymer, in particular heparin, and zinc ions, and the use of these preparations for the topical treatment of infections caused by herpes. Viruses, especially those caused by herpes virus hominis (HVH), e.g. of genital herpes and herpes dermatitis.

Es wurde Uberraschenderweise gefunden, dass saure sulfatierte Polysaccharide oder Polymere, insbesondere Heparin, und Zinkionen zusammen eine starke antivirale Wir-' kung ausüben, welche die Summe der Wirkungen der Einzelkomponenten weit Ubertrifft. Die synergistische Wirkung der beiden Komponenten lässt sich in vitro, d.h. in Zellkulturen, z.B. auf Grund der Virus-Inaktivierung, der Hemmung der Plaquebildung und der Virus-Replikation nachweisen:Surprisingly, it was found that acidic sulfated polysaccharides or polymers, in particular heparin, and zinc ions together have a strong antiviral effect which far exceeds the sum of the effects of the individual components. The synergistic effect of the two components can be demonstrated in vitro, i.e. in cell cultures, e.g. due to virus inactivation, inhibition of plaque formation and virus replication:

1. Inaktivierung von Herpes-Virus hominis1. Inactivation of hominis herpes virus

Die Präparate wurden in bidestilliertem Wasser in abgestuften Konzentrationen gemischt, mit HVH2/Ang. beimpft und während 1 Stunde bei 35°C inkubiert. Die Bestimmung des Virusgehaltes in den Kontaktgemischen erfolgte auf HUhnerembryofibroblasten im Plaquetest. Die Proben wurden in Hanks'-Lösung + 0,05 % Albumin verdünnt auf Zellmonolayer von Hühnerembryofibroblasten gegeben. Nach 90 Minuten Virusabsorption wurden die Kulturen 2-mal gewaschen, mit 4 ml LY-Agaroverlay [Hanks'Lösung mit 0,5 % Lactalbuminhydrolysat und 0,01 % Yeastolate (Hefeextrakt)] versetzt und dann bis zur Zählung der Plaques (96 Stunden) bei 35°C inkubiert.

Figure imgb0001
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 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 ml of LY agaroverlay [Hanks' solution with 0.5% lactalbumin hydrolyzate and 0.01% yeastolate (yeast extract)] were added and then until the plaques were counted (96 hours) incubated at 35 ° C.
Figure imgb0001

2. Hemmung der Plaquebildung von HVH2/Ang. in Hühnerembryofibroblasten.2. Inhibition of plaque formation by HVH2 / Ang. in chicken embryo fibroblasts.

Die Zellmonolayer wurden mit 100 PFU HVH2/Ang. während 90 Minuten infiziert. Je 4 ml der in LY-Agaroverlay (mit 5 % Schafserum, 0,5 % OXO-L-28-Agar, ohne Diäthylaminoäthyldextran) inkorporierten Präparate wurden auf die infizierten Zellkulturen gegeben und diese bis zur Zählung der Plaques (96 Stunden) bei 35°C inkubiert.

Figure imgb0002
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, 0.5% OXO-L-28 agar, without diethylaminoethyl dextran) were added to the infected cell cultures and these were counted at 35 until the plaques were counted (96 hours) ° C incubated.
Figure imgb0002

3. Hemmung der Replikation von HVH2/Ang. in VERO-Zellen bei präinfektiösem Behandlungsbeginn .3. Inhibition of replication of HVH2 / Ang. in VERO cells at the start of pre-infectious treatment.

Konfluente Monolayer von VERO-Zellen wurde mit F15-Medium [Minimum Essential Medium (Eagle), Gibco Bio-Cult Ldt. Paisley, Schottland] gewaschen und dann mit je 4 ml der verschiedenen Konzentrationen der Präparate in F15 Medium belegt. Die Infektion der Kulturen erfolgte nach 60 Minuten mit 1000 PFU HVH2/Ang. in 0,1 ml Medium. Nach 20 Stunden Inkubation bei 35°C wurde der Zustand der Zellen mikroskopisch beurteilt und der Virusgehalt der Zell-Lysate (Zellen mit 1 ml bidestilliertem Wasser 2-mal tiefgefroren und getaut) durch Titration auf HUhnerembryofibroblasten (Plaquebildung) bestimmt.

Figure imgb0003
Confluent monolayers of VERO cells were treated with F15 medium [Minimum Essential Medium (Eagle), Gibco Bio-Cult Ldt. Paisley, Scotland] washed and then with each 4 ml of the different concentrations of the preparations in F15 medium occupied. The cultures were infected after 60 minutes with 1000 PFU HVH2 / Ang. in 0.1 ml medium. After 20 hours of incubation at 35 ° C., the condition of the cells was assessed microscopically and the virus content of the cell lysates (cells with 1 ml of double-distilled water, frozen twice and thawed) was determined by titration for chicken embryo fibroblasts (plaque formation).
Figure imgb0003

Schlussfolgerungen aus den Resultaten der drei VersuchsreihenConclusions from the results of the three test series

In den obigen Versuchsanordnungen ist die synergistische Wirkung der erfindungsgemässen Kombinationen von Zinksulfat und Heparin deutlich erkennbar'. Besonders bemerkenswert ist bei der Virus-Inaktivierung gemäss Tabelle I, dass jede Komponente allein in allen geprüften Konzentrationen praktisch unwirksam war, während die Kombination von je einem Drittel der Maximalkonzentration der einzelnen Komponenten den Virusgehalt der Hühnerembryofibroblasten bereits um 102 verminderte. Aus Tabelle II ergibt sich u.a., dass Heparin allein nur schwach wirksam ist, jedoch sowohl Heparin als auch Zinksulfat in der niedrigsten Konzentration zusammen mit jeder Konzentration der zweiten Komponente eine höhere Wirkung ergeben als die nächsthöhere Konzentration der zweiten Komponente allein. Mit der Kombination von 6 mcg/ml Zinksulfat und 3 mcg/ml Heparin wird bereits die Wirkung von 25 mgc/ml Zinksulfat allein, und mit je 6 mcg/ml Zinksulfat und Heparin wie auch mit 12 mcg/ml Zinksulfat und 3 mcg/ml Heparin nahezu die Wirkung der Kombination von 25 mcg/ml Zinksulfat und 6mcg/ml Heparin erreicht. Die Virus-Replikation wird gemäss Tabelle III von Zinksulfat in der höchsten Konzentration von 25 mcg/ml nur mässig, dagegen von Heparin in der einzigen geprüften Konzentration von 6 mcg/ml, entsprechend der höchsten in den andern Versuchsreihen, infolge der starken Absorptionshemmwirkung des Heparin deutlich gehemmt; alle geprüften Kombinationen zeigen indessen eine noch mindestens 10-mal stärkere Wirkung als die Einzelkomponenten.The synergistic effect of the combinations of zinc sulfate and heparin according to the invention can be clearly seen in the above test arrangements. It is particularly noteworthy for the virus inactivation according to Table I that each component alone was practically ineffective in all the concentrations tested, during the combination of a third of the maximum concentration of the individual components already reduced the virus content of the chicken embryo fibroblasts by 10 2 . Table II shows, inter alia, that heparin alone is only weakly effective, but both heparin and zinc sulfate in the lowest concentration together with each concentration of the second component give a higher activity than the next higher concentration of the second component alone. With the combination of 6 mc g / ml zinc sulfate and 3 mcg / ml heparin, the effect of 25 mgc / ml zinc sulfate alone becomes apparent, and with 6 mcg / ml zinc sulfate and heparin as well as with 12 mcg / ml zinc sulfate and 3 mcg / ml heparin almost achieved the effect of the combination of 25 mcg / ml zinc sulfate and 6mcg / ml heparin. Virus replication is only moderate according to Table III of zinc sulfate in the highest concentration of 25 mcg / ml, but of heparin in the only concentration tested of 6 mcg / ml, corresponding to the highest in the other test series, due to the strong absorption inhibitory effect of heparin clearly inhibited; however, all tested combinations show an effect that is at least 10 times stronger than the individual components.

Ebenfalls festgestellt werden kann der synergistische Effekt der erfindungsgemäss kombinierten Wirkstoffe und zugleich die überlegene therapeutische Wirkung der Kombination im Vergleich zu andern, topisch anwendbaren antiviralen Präparaten in vivo bei der durch Infektion mit HVH2/Ang.. verursachten.Herpes genitalis des Meerschweinchens bei 72 Stunden nach Infektion (Stadium deutlicher Symptome) beginnender Behandlung, wobei auf die von B. Lukas et al., Arch.Ges.Virusforsch.44, 153-155 (1974) und 49, 1-11 (1975) beschriebene Methodik hingewiesen wird. Die therapeutische Wirkung der Kombination ist nicht nur stärker, sondern tritt auch früher ein als die Wirkung der einzelnen Komponenten, überdies ist die Zahl .der Rezidive stark vermindert.The synergistic effect of the active compounds combined according to the invention and, at the same time, the superior therapeutic effect of the combination in comparison with other topically applicable antiviral preparations in vivo in the case of the genital herpes of guinea pigs after 72 hours after infection with HVH2 / ang Infection (stage of clear symptoms) of beginning treatment, whereby reference is made to the methodology described by B. Lukas et al., Arch. Ges.Virusforsch. 44, 153-155 (1974) and 49, 1-11 (1975). The therapeutic effect of the combination is not only stronger, but also occurs earlier than the effect of the individual components, moreover the number of recurrences is greatly reduced.

Die synergistische Wirkung der obengenannten Wirkstoffe wird noch verstärkt, wenn eine Präparategrundlage, insbesondere Gelgrundlage, verwendet wird, die einen oder mehrere Polyoxyäthylensorbitanfettsäureester, wie Polyoxyäthylensorbitan-monostearat und/oder vor allem Polyoxyäthylensorbitan-monolaurat oder in erster Linie Poloyoxyäthylensorbitan-monooleat, enthält.The synergistic effect of the above-mentioned active substances is further enhanced if a preparation base, in particular a gel base, is used 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.

Die erfindungsgemässen pharmazeutischen Präparate enthalten die oben definierten Wirkstoffe vorzugsweise in Kombination mit für die topische Applikation geeigneten pharmazeutischen Trägerstoffen. Als Formen von erfindungsgemässen Präparaten kommen insbesondere Tinkturen, Lösungen, Cremes, Salben und vor allem Gele in Betracht.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.

Tinkturen und Lösungen weisen meistens eine wässerig-äthanolische bzw. wässerige Grundlage auf, der u.a. Polyalkohole, wie z.B. Propylenglykol oder Glycerin und/oder niedrige Polyäthylenglykole, als Feuchthaltemittel zur Herabsetzung der Verdunstung, und gegebenenfalls rückfettende Substanzen, wie Fettsäureester von niedrigen Polyäthylenglykolen, d.h. im wässerig-äthanolischen Gemisch lösliche, lipophile Substanzen, als Ersatz für die der Haut mit dem Aethanol entzogenen Fettsubstanzen, und gegebenenfalls weitere Hilfs- und Zusatzstoffe, neben üblichen, wie den untengenannten, Konservierungsmitteln z.B. auch die bereits erwähnten Polyoxyäthylen- sorbitan-fettsäureester, wie Polyoxyäthylensorbitan-monolaurat oder Polyoxyäthylensorbitanmonooleat, zugegeben sind.Tinctures and solutions mostly have an aqueous-ethanolic or aqueous base, which among other things. Polyalcohols, e.g. Propylene glycol or glycerin and / or low polyethylene glycols, as humectants to reduce evaporation, and optionally refatting substances, such as fatty acid esters of low polyethylene glycols, i.e. lipophilic substances soluble in the aqueous-ethanol mixture, as a substitute 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, e.g. the polyoxyethylene sorbitan fatty acid esters already mentioned, such as polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monooleate, have also been added.

Cremes sind Oel-in-Wasser-Emulsionen, die mehr als 50 % Wasser aufweisen. Als ölige Grundlage verwendet man in erster Linie Fettalkohole, z.B. Lauryl-, Cetyl- oder Stearylalkohol, Fettsäuren, z.B. Palmitin- oder Stearinsäure, flüssige bis feste Wachse, z.B. Isopropylmyristinat, Wollwachs oder Bienenwachs, und/oder Kohlenwasserstoffe, z.B. Vaseline (Petrolatum) oder Paraffinöl. Als Emulgatoren kommen oberflächenaktive Substanzen mit vorwiegend hydrophilen Eigenschaften in Frage, wie entsprechende nichtionische Emulgatoren, z.B Fettsäureester von Polyalkoholen oder Aethylenoxidaddukte davon, wie Polyglycerinfettsäureester oder Polyoxyäthylen-sorbitan-fettsäureester (Tweens), ferner Polyoxyäthylenfettalkoholäther oder -fettsäureester, oder entsprechende ionische Emulgatoren, wie Alkalimetallsalze von Fettalkoholsulfaten, z.B. Natriumlaurylsulfat, Natriumcetylsulfat oder Natriumstearylsulfat, die man Üblicherweise in Gegenwart von Fettalkoholen, z.B. Cetylakohol oder Stearylalkohol, verwendet. Zusätze zur Wasserphase sind u.a. Mittel, welche die Austrocknung der Creme vermindern, z.B. Polyalkohole, wie Glycerin, Sorbit, Propylenglykol und/oder Polyäthylenglykole, ferner Konservierungsmittel, Riechstoffe, etc.Creams are oil-in-water emulsions that contain more than 50% water. The main oils used are fatty alcohols, e.g. lauryl, cetyl or stea ryl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristinate, wool wax or beeswax, and / or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), and also polyoxyethylene fatty alcohol ethers or corresponding fatty acid emulsifiers, such as ionic emulsifiers or corresponding fatty acid emulsifiers of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetylic alcohol or stearyl alcohol. Additives to the water phase include agents which reduce the drying out of the cream, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.

Salben sind Wasser-in-Oel-Emulsionen, die bis zu 70 %, vorzugsweise jedoch von etwa 20 % bis etwa 50 % Wasser oder wässrige Phasen enthalten. Als Fettphase kommen in erster Linie Kohlenwasserstoffe,z.B. Vaseline, Paraffinöl und/oder Hartparaffine in Frage, die zur Verbesserung des Wasserbindungsvermögens vorzugsweise geeignete Hydroxyverbindungen, wie Fettalkohole,oder Ester davon, z.B. Cetylalkohol oder Wollwachsalkohole, bzw..Wollwachs enthalten. Emulgatoren sind entsprechende lipophile Substanzen, wie Sorbitan-fettsäureester (Spans), z.B. Sorbitanoleat und/ oder Sorbitaniosostearat. Zusätze zur Wasserphase sind u.a. Feuchthaltungsmittel, wie Polyalkohole, z.B. Glycerin, Propylenglykol, Sorbit und/oder Polyäthylenglykol, sowie Konservierungsmittel, Riechstoffe, etc.Ointments are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phases. The fat phase primarily comes from hydrocarbons, e.g. Vaseline, paraffin oil and / or hard paraffins, which preferably contain suitable hydroxy compounds, such as fatty alcohols, or esters thereof, e.g. Cetyl alcohol or wool wax alcohols or wool wax. 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, fragrances, etc.

Gele sind insbesondere wässrige Lösungen der Wirkstoffe, in denen Gelbildner, vorzugsweise solche aus der Gruppe der Celluloseäther, wie z.B. Methylcellulose, Hydroxyäthylcellulose oder Carboxymethylcellulose, oder der pflanzlichen Hydrokolloide, wie Natrium-alginat, Traganth oder Gummi arabicum, dispergiert und ausgequollen sind. Weiter enthalten die Gele vorzugsweise ebenfalls Feuchthaltemittel aus der Gruppe der Polyalkohole, wie Propylenglykol, Glycerin und/oder niedrige Polyäthylenglykole, sowie Netzmittel, z.B. Polyoxyäthylensorbitan-fettsäureester, wie Polyoxyäthylensorbitanmonostearat,-monolaurat oder -monooleat in Konzentrationen von ca. 0,02 bis 5 %. Als weitere Zusatzstoffe enthalten die Gele übliche Konservierungsmittel, z.B. Benzylakohol, Phenäthylalkohol, Phenoxyäthanol, p-Hydroxybenzoesäureniederalkylester-wie der Methyl- und/oder Propylester, Sorbinsäure oder organische Quecksilberverbindungen, wie Merthiolat.Gels are in particular aqueous solutions of the active ingredient substances in which gel formers, preferably those from the group of cellulose ethers, such as methyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose, or of vegetable hydrocolloids, such as sodium alginate, tragacanth or acacia, are dispersed and swollen. The gels preferably also contain humectants from the group of polyalcohols, such as propylene glycol, glycerol and / or low polyethylene glycols, and wetting agents, for example polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monostearate, monolaurate or monooleate, in concentrations of about 0.02 to 5% . As additional additives, the gels contain conventional preservatives, for example 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.

Die erfindungsgemässen Präparate können - neben den üblichen Konservierungsmitteln - auch weitere biologisch, z.B. antiphlogistisch oder antimikrobiell, wie antibakteriell, antifungal oder ebenfalls anLiviral wirksame Stoffe, wie z.B. Flumethason, Neomycin, Gentamycin, Milchsäure oder Mikonazol enthalten. Die Herstellung der erfindungsgemässen Präparate erfolgt in an sich bekannter Weise.The preparations according to the invention can - in addition to the usual preservatives - also other biological, e.g. anti-inflammatory or anti-microbial, such as anti-bacterial, anti-fungal or also anti-viral substances, e.g. Contain flumethasone, neomycin, gentamycin, lactic acid or mikonazole. The preparations according to the invention are produced in a manner known per se.

Die vorliegende Erfindung betrifft insbesondere topisch anwendbare antivirale Präparate, die saure sulfatierte Polysaccharide oder Polymere, wie Heparin, und Zinkionen in einem Verhältnis von 1 mg zu 0,18 bis 18 mg, insbesondere von 1 mg zu 0,18 bis 4,5 mg, und gegebenenfalls Polyoxyäthylensorbitanmonolaurat und oder -monooleat enthalten. Für Heparin beziehen sich obige Mengenangaben auf solches mit 160 IE/mg, von anderem Heparin sind gleiche IE-Mengen einzusetzen. Die Zinkionen werden in Form der entsprechenden Mengen einer dissozierbaren Zinkverbindung, z.B. von 0,8-80 mg bzw. 0,8-20 mg ZnSO4.7H2O, zugeftigt. Entsprechende topisch anwendbare Präparate, insbesondere Gele, ferner auch Tinkturen, wässrige Lösungen, Cremen oder Salben, enthalten beispielsweise pro g oder ml 0,1 bis 5 mg eines sauren sulfatierten Polysaccharids oder Polymeren, insbesondere 16 bis 800 IE Heparin, und 0,18 bis 18 mg Zinkionen, entsprechend z.B. ca. 0,8 bis 80 mg ZnS04.7H20, und gegebenenfalls zusätzlich 0,2 bis 50 mg Polyoxyäthylensorbitan-monolaurat und/oder -monooleat. Besonders bevorzugt ist ein Gehalt von 80-320 IE Heparin, 0,45 bis 4,5 mg Zinkionen und gegebenenfalls zusätzlich 0,5 bis 10 mg Polyoxyäthylensorbitan-monolaurat und/oder -monooleat pro g oder ml.The present invention relates in particular to topically applicable antiviral preparations, the acid 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 or monooleate. For 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 in the form of the corresponding amounts of a dissociable zinc compound, e.g. 0.8-80 mg or 0.8-20 mg ZnSO 4 .7H 2 O, added. Corresponding topically applicable preparations, in particular gels and also tinctures, aqueous solutions, creams or ointments, contain, for example, 0.1 to 5 mg of an acidic sulfated polysaccharide or polymer, in particular 16 to 800 IU heparin, and 0.18 to per g or ml 18 mg of zinc ions, corresponding, for example, to about 0.8 to 80 mg of ZnSO 4 .7H 2 0, and optionally additionally 0.2 to 50 mg of polyoxyethylene sorbitan monolaurate and / or monooleate. A content of 80-320 IU heparin, 0.45 to 4.5 mg zinc ions and optionally additionally 0.5 to 10 mg polyoxyethylene sorbitan monolaurate and / or monooleate per g or ml is particularly preferred.

Anstelle des Heparins kann auch eine antiviral wirkungsgleiche Menge eines andern sauren sulfatierten Polysaccharids oder Polymeren, wie von natürlichen oder partiell abgebauten, sauren sulfatierten Polysacchariden, wie sulfatierten Amylopectinen; sulfatierten Dextranen, sulfatierten Polyglucosen oder sulfatierten Polypentosen, bzw. von Polyvinylsulfaten, wie beispielsweise das Natriumsalz des Calciumkomplexes der Sulfatationsprodukte von oxidativ abgebauten Polygalakturonsäure-methylestern [Wirkstoff von HEMERAN (Geigy)] verwendet werden. Die Zinkionen können, statt in Form von Zinksulfat, auch in Form einer andern dissozierbaren Zinkverbindung, wie z.B. Zinkchlorid, oder des Zinksalzes einer Säure.oder eines andern Stoffes von saurem Charakter und eigenen biologischen, z.B. antibakteriellen oder antiphlogistischen, Eigenschaften, wie z.B. Zink-sudoxicam (Zinksalz des 4-Hydroxy-2-methyl-N-(2-thiazolyl)-1,2-benzothiazin-3-carboxamid-1,1-dioxid) zugefügt werden.Instead of heparin, an antivirally effective amount of another acidic sulfated polysaccharide or polymer, such as natural or partially degraded acidic sulfated polysaccharides, such as sulfated amylopectins; sulfated dextrans, sulfated polyglucoses or sulfated polypentoses, or of polyvinyl sulfates, such as the sodium salt of the calcium complex of the sulfation products of oxidatively degraded polygalacturonic acid methyl esters [active ingredient of HEMERAN (Geigy)]. 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.

Die erfindungsgemässen Präparate eignen sich insbesondere zur Behandlung von Herpes genitalis, Herpes dermatitis und Herpes labialis. Zur Behandlung der beiden ersteren werden erfindungsgemässe Gele so frühzeitig als möglich z.B. mittels Tube oder Applikator 2-3 mal täglich, und zur Behandlung von Herpes labialis mehrmals täglich auf die erkrankten Körperstellen aufgetragen bis zum Abklingen der Symptome bzw. bis zur Abheilung. Erfindungsgemässe wässrige Lösungen können z.B. zum SpUlen von erkrankten Körperhöhlen, insbesondere zur Behandlung von Herpes gingivostomatitis, oder zur Behandlung von Herpes keratokon- junktivitis verwendet werden.The preparations according to the invention are particularly suitable for the treatment of genital herpes, herpes dermatitis and herpes labialis. To treat the two the former, gels according to the invention are applied as early as possible, for example using a tube or applicator, 2-3 times a day, and for the treatment of herpes labialis several times a day on the diseased parts of the body until the symptoms have subsided or until they have healed. Aqueous solutions according to the invention can be used, for example, to rinse diseased body cavities, in particular for the treatment of herpes gingivostomatitis, or for the treatment of herpes keratoconjunctivitis.

Das nachfolgende Beispiel beschreibt die Herstellung einer typischen Applikationsform; es soll jedoch den Umfang der Erfindung in keiner Weise beschränken.The following example describes the production of a typical application form; however, it is not intended to limit the scope of the invention in any way.

Beispielexample

Zur Herstellung von 10,0 Liter Gel vermischt man 200,0 g hochvisköse Natrium-carboxymethylcellulose und 50,0 g Polyoxyäthylensorbitan-monostearat (TWEEN 60) mit 1000 g Glycerin und 6,5 Liter Aqua conservans und lässt das Gemisch zu einem homogenen Schleim ausquellen. Dann wird eine Lösung von 1,6.106 internationalen Einheiten Heparin (z.B. 10,0 g Heparin Biofac), 100,0 g Zinksulfatheptahydrat und 10,0 g Polyoxyäthylensorbitan-monooleat (TWEEN 80) in 2.0 Liter Aqua conservans zugemischt. Schliesslich wird mit Aqua conservans auf 10,0 Liter ergänzt, sorgfältig gemischt und das erhaltene Gel in Tuben abgefüllt.To prepare 10.0 liters of gel, 200.0 g of highly viscous sodium carboxymethyl cellulose and 50.0 g of polyoxyethylene sorbitan monostearate (TWEEN 60) are mixed with 1000 g of glycerin and 6.5 liters of aqua conservans and the mixture is allowed to swell to form a homogeneous slime . Then a solution of 1.6.10 6 international units of heparin (for example 10.0 g of heparin Biofac), 100.0 g of zinc sulfate heptahydrate and 10.0 g of polyoxyethylene sorbitan monooleate (TWEEN 80) in 2.0 liters of aqua conservans is added. Finally, make up to 10.0 liters with aqua conservans, mix thoroughly and fill the gel into tubes.

Unter Aqua conservans wird eine wässrige Lösung von 0,07 % p-Hydroxy-benzoesäure-methylester (Methylparaben) und 0,03 % p-Hydroxybenzoesäure-propylester (Propylparaben) verstanden. TWEEN 60 und TWEEN 80 sind geschlitzte Markenbezeichnungen der ICI of America Inc., Stamford, Connecticut 06904.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 slotted trademarks of ICI of America Inc., Stamford, Connecticut 06904.

Anstelle von 100,0 g ZnS04.7H20 kann man auch 50,0 g verwenden und im übrigen gleich vorgehen wie oben angegeben.Instead of 100.0 g of ZnS0 4 .7H 2 0, 50.0 g can also be used and the rest of the procedure is the same as stated above.

Claims (13)

1. Pharmazeutische Präparate zur topischen Anwendung, gekennzeichnet durch einen Gehalt an einer antiviral wirksamen Kombination eines sauren, sulfatierten Polysaccharids oder Polymeren und Zinkionen.1. Pharmaceutical preparations for topical use, characterized by a content of an antivirally effective combination of an acidic, sulfated polysaccharide or polymer and zinc ions. 2. Pharmazeutische Präparate gemäss Anspruch 1 zur topischen Behandlung von Virusinfektionen.2. Pharmaceutical preparations according to claim 1 for the topical treatment of viral infections. 3. Pharmazeutische Präparate gemäss Anspruch 1 in der Form von Gelen, Cremes, Salben, Tinkturen oder wässerigen Lösungen.3. Pharmaceutical preparations according to claim 1 in the form of gels, creams, ointments, tinctures or aqueous solutions. 4. Pharmazeutische Präparate gemäss Anspruch 1, gekennzeichnet durch einen zusätzlichen Gehalt an Polyoxyäthylensorbitan-monolaurat und/oder -monooleat.4. Pharmaceutical preparations according to claim 1, characterized by an additional content of polyoxyethylene sorbitan monolaurate and / or monooleate. 5. Pharmazeutische Präparate gemäss Anspruch 1, gekennzeichnet durch einen Gehalt an sauren sulfatierten Polysacchariden oder Polymeren und Zinkionen in einem Mengenverhältnis von 1 mg zu 0,18 bis 18 mg.5. Pharmaceutical preparations according to claim 1, characterized by a content of acid sulfated polysaccharides or polymers and zinc ions in a ratio of 1 mg to 0.18 to 18 mg. 6. Pharmazeutische Präparate gemäss Anspruch 5, gekennzeichnet durch einen Gehalt in sauren sulfatierten Polysacchariden oder Polymeren und Zinkionen in einem Mengenverhältnis von 1 mg zu 0,18 bis 4,5 mg.6. Pharmaceutical preparations according to claim 5, characterized by a content in acid sulfated polysaccharides or polymers and zinc ions in a ratio of 1 mg to 0.18 to 4.5 mg. 7. Pharmazeutische Präparate gemäss.Anspruch 5, gekennzeichnet durch einen Gehalt an Heparin und Zinkionen in einem Verhältnis von 160 IE zu 0,18 bis 18 mg.7. Pharmaceutical preparations according to claim 5, characterized by a content of heparin and zinc ions in a ratio of 160 IU to 0.18 to 18 mg. 8. Pharmazeutische Präparate gemäss Anspruch 5, gekennzeichnet durch einen Gehalt, pro g oder ml, von 0,1 bis 5 mg eines sauren sulfatierten Polysaccharids oder Polymeren und 0,18 bis 18 mg Zinkionen.8. Pharmaceutical preparations according to claim 5, characterized by a content, per g or ml, of 0.1 to 5 mg of an acidic sulfated polysaccharide or polymer and 0.18 to 18 mg of zinc ions. 9. Pharmazeutische Präparate gemäss Anspruch 5, gekennzeichnet durch einen Gehalt, pro g oder ml, von 16 bis 800 IE Heparin und 0,18 bis 18 mg Zinkionen.9. Pharmaceutical preparations according to claim 5, characterized by a content, per g or ml, of 16 to 800 IU heparin and 0.18 to 18 mg zinc ions. 10. Pharmazeutische Präparate gemäss Ansprüchen 8 und 9, denen die Zinkionen in Form von 0,8-80 mg ZnS04. 7H20 als dissozierbare Zinkverbindung zugefügt sind.10. Pharmaceutical preparations according to claims 8 and 9, which the zinc ions in the form of 0.8-80 mg ZnS0 4th 7H 2 0 are added as a dissociable zinc compound. 11. Pharmazeutische Präparate gemäss Anspruch 8, gekennzeichnet durch einen Gehalt, pro g oder ml, von 80-320 IE Heparin und 0,45 bis 4,5 mg Zinkionen.11. Pharmaceutical preparations according to claim 8, characterized by a content, per g or ml, of 80-320 IU heparin and 0.45 to 4.5 mg zinc ions. 12. Pharmazeutische Präparate gemäss Ansprüchen 8 bis 11, gekennzeichnet durch einen zusätzlichen Gehalt, pro g oder ml, von 0,2 bis 50 mg Polyoxyäthylensorbitan- monolaurat und/oder -monooleat.12. Pharmaceutical preparations according to claims 8 to 11, characterized by an additional content, per gram or milliliter, from 0.2 to 50 mg of polyoxyethylene sorbitan - monolaurate and / or monooleate. 13. Pharmazeutische Präparate gemäss Ansprüchen 8 bis 11, gekennzeichnet durch einen zusätzlichen Gehalt, pro g oder ml, von 0,5 bis 10 mg Polyoxyäthylensorbitan- monolaurat und/oder -monooleat.13. Pharmaceutical preparations according to claims 8 to 11, characterized by an additional content, per g or ml, of 0.5 to 10 mg of polyoxyethylene sorbitan monolaurate and / or monooleate.
EP78100133A 1977-06-17 1978-06-09 Pharmaceutical preparations containing sulfated polysaccharides or polymers and zinc ions for topical application in virus infections. Expired EP0000133B1 (en)

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US4465666A (en) * 1977-06-17 1984-08-14 Ciba-Geigy Corporation New pharmaceutical preparations
EP0012115A1 (en) * 1978-12-04 1980-06-11 Ciba-Geigy Ag Pharmaceutical compositions for topical treatment of virus infections
EP0045282A2 (en) * 1980-07-30 1982-02-03 Ciba-Geigy Ag Antiherpes lipstick and its use in treating lips and other face parts attacked by herpes hominis
EP0045282A3 (en) * 1980-07-30 1982-09-08 Ciba-Geigy Ag Antiherpes lipstick and its use in treating lips and other face parts attacked by herpes hominis
EP0066283A1 (en) * 1981-06-02 1982-12-08 Eupan Corporation Eustatic composition for nonspecifically facilitating and amplifying the generalized homeostatic regulation and maintenance, compensation and repair in living organisms
GB2141929A (en) * 1983-06-16 1985-01-09 Victoria State Treatment of footrot
US4661354A (en) * 1984-06-21 1987-04-28 Finnerty Edmund F Topical treatment of herpes simplex with a zinc sulfate-camphor water solution
EP0506207A3 (en) * 1985-05-03 1993-03-03 Chemex Pharmaceuticals, Inc. Pharmaceutical vehicles for reducing transdermal flux
EP0506207A2 (en) * 1985-05-03 1992-09-30 CHEMEX PHARMACEUTICALS, Inc. Pharmaceutical vehicles for reducing transdermal flux
EP0314835A1 (en) * 1987-10-19 1989-05-10 Mostafa S. Fahim Composition and process for promoting epithelial regeneration
EP0402078A2 (en) * 1989-06-06 1990-12-12 Patrick Daniel Kelly Sexual lubricants containing zinc as an anti-viral agent
EP0402078A3 (en) * 1989-06-06 1991-07-31 Patrick Daniel Kelly Sexual lubricants containing zinc as an anti-viral agent
EP0497341A2 (en) * 1991-01-31 1992-08-05 FARMITALIA CARLO ERBA S.r.l. Synergistic composition comprising a fibroblast growth factor and a sulfated polysaccahride, for use as antiviral agent
EP0497341A3 (en) * 1991-01-31 1993-05-05 Farmitalia Carlo Erba S.R.L. Synergistic composition comprising a fibroblast growth factor and a sulfated polysaccahride, for use as antiviral agent
US5288704A (en) * 1991-01-31 1994-02-22 Farmitalia Carlo Erba S.R.L. Synergistic composition comprising a fibroblast growth factor and a sulfated polysaccharide, for use as antiviral agent
WO1998005341A1 (en) * 1996-08-06 1998-02-12 Medicarb Ab The use of heparin or heparan sulphate in combination with chitosan for the prevention or treatment of infections caused by herpes virus
US6207653B1 (en) 1996-08-06 2001-03-27 Medicarb Ab Use of heparin or heparan sulphate in combination with chitosan for the prevention or treatment of infections caused by herpes virus
EP2283805A1 (en) 2009-07-28 2011-02-16 Sirvis BV Compositions comprising a zinc containing compound dissolved in a hydrophobic phase
EP2316415A2 (en) 2009-07-28 2011-05-04 Sirvis Lip compositions comprising a zinc containing compound dissolved in a hydrophobic phase
ITMI20100816A1 (en) * 2010-05-07 2011-11-08 Advance Holdings Ltd PHARMACEUTICAL COMPOSITION TOPICAL COMPARING EPARIN
WO2011138262A1 (en) * 2010-05-07 2011-11-10 Advance Holdings Limited Topical pharmaceutical composition comprising heparin
CN102946862A (en) * 2010-05-07 2013-02-27 先进控股有限公司 Topical pharmaceutical composition comprising heparin
EA026568B1 (en) * 2010-05-07 2017-04-28 Лектио Фармаэнтвиклунгс-Унд Фервертунгс Гмбх Topical pharmaceutical composition comprising heparin

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Publication number Publication date
LU77562A1 (en) 1979-03-26
IT1105718B (en) 1985-11-04
IE781212L (en) 1978-12-17
AU3715378A (en) 1979-12-20
US4465666A (en) 1984-08-14
CA1116083A (en) 1982-01-12
DE2861070D1 (en) 1981-12-03
ZA783480B (en) 1979-07-25
EP0000133B1 (en) 1981-09-16
IT7849884A0 (en) 1978-06-15
AU522600B2 (en) 1982-06-17
NZ187598A (en) 1981-03-16
JPS6225126B2 (en) 1987-06-01
JPS548727A (en) 1979-01-23
IE47096B1 (en) 1983-12-14

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