EP0000133B1 - 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 PDFInfo
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- 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
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- zinc ions
- pharmaceutical preparation
- heparin
- preparation according
- zinc
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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
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- 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
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- 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
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- 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
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- 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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Description
Die Erfindung betrifft neue pharmazeutische Präparate zur topischen Behandlung von Virusinfektionen, die eine antiviral wirksame Kombination eines sulfatierten Polysaccharids oder Polymeren, insbesondere Heparin, und Zinkionen in Form von dissoziierbaren Zinkverbindungen enthalten.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.
F. Lebel und Gy. Hadhazy berichteten in Acta Microbiol. Acad. Sci. Hung. 13(3) 197-203 (1966) [Chem. Abstr. 66, 45191 (1987)] über Versuche betreffend die hemmende Wirkung von exogenem Heparin auf das Wachstum von verschiedenen Stämmen von Herpes simplex-Virus an Kaninchen. Das Wachstum von 5 von 6 geprüften Stämmen und die Entwicklung von Hautläsionen wurde durch kutane Injektion von 1,2 mg Heparin 1 bis 18 Stunden vor der Infektion durch die zu prüfenden Stämme gehemmt.F. Lebel and Gy. Hadhazy reported in Acta Microbiol. Acad. Sci. Hung. 13 (3) 197-203 (1966) [Chem. Abstr. 66, 45191 (1987)] on experiments relating to the inhibitory effect of exogenous heparin on the growth of various strains of herpes simplex virus in rabbits. The growth of 5 out of 6 strains tested and the development of skin lesions were inhibited by cutaneous injection of 1.2 mg heparin 1 to 18 hours before infection by the strains to be tested.
Es wurde nun überraschenderweise gefunden, dass sulfatierte Polysaccharide oder Polymere, insbesondere Heparin, und Zinkionen in Form von dissoziierbaren Zinkverbindungen zusammen eine starke antivirale Wirkung ausüben, welche die Summe der Wirkungen der Einzelkomponenten weit übertrifft. 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:It has now surprisingly been found that sulfated polysaccharides or polymers, in particular heparin, and zinc ions in the form of dissociable zinc compounds 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:
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 Hühnerembryofibroblasten 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 m LY-Agaroverlay [HanksLösung mit 0,5% Lactalbuminhydrolysat und 0,01% Yeastolate (Hefeextrakt)J versetzt und dann bis zur Zählung der Plaques (96 Stunden) bei 35°C inkubiert.
Die Zellmonolayer wurden mit 100 PFU HVH2/Ang. während 90 Minuten infiziert. Je 4 ml der in LY-Agaroverlay (mit 5% Schafserum und 0,5% OXO-L-28-Agar, einem gereinigten Agar der Oxoid Ltd., Wade Road, Basingstoke, England, ohne Diäthylaminoäthyldextran) inkorporierten Präparate wurden auf die infizierten Zellkulturen gegeben und diese bis zur Zählung der Plaques (96 Stunden) bei 35°C inkubiert.
Konfluente Monolayer von VERO-Zellen (Affennierenzellen, Cell Repository No. CGL 81 der American Type Culture Collection) wurde mit F15-Medium (Minimum Essential Medium nach Eagle von der Gibco Biocult Ltd., 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 Zelle mikroskopisch beurteilt und der Virusgehalt der Zell-Lysate (Zellen mit 1 ml bindestilliertem Wasser 2-mal tiefgefroren und getaut) durch Titration auf Hühnerembryofibroblasten (Plaquebildung) bestimmt.
In den obigen Versuchsanordnungen ist die synergistische Wirkung der erfindungsgemässen Kombination von Heparin und Zinksulfat 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 Konponenten den Virusgehalt der Hühnerembryrofibroplasten bereits um 102 verminderte. Aus Tabelle II ergibt sich u:a., dass Heparin allein nur schwach wirksam ist, jedoch sowohl Heparin als auch Zinksulfat-heptahydrat 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 6.10-6 g/ml Zinksulfat-heptahydrat und 3.10-8 g/ml Heparin wird bereits die Wirkung von 25.10-6 ml Zinksulfat-heptahydrat allein, und mit je 6.10-6 g/ml Zinksulfat-heptahydrat und Heparin wie auch mit 12.10-6 g/ml Zinksulfatheptahydrat und 3.10-6 g/ml Heparin nahezu die Wirkung der Kombination von 25.10-6 g/ml Zinksulfat-heptahydrat und 6.10-6 g/ml Heparin erreicht. Die Virus-Replikation wird gemäss Tabelle III von Zinksulfat in der höchsten Konzentration von 25.10-6 g/ml nur mässig, dagegen von Heparin in der einzigen geprüften Konzentration von 6.10-6 g/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 combination of heparin and zinc sulfate according to the invention can be clearly seen in the above test arrangements. It is particularly noteworthy with the virus inactivation according to Table I that each component alone was practically ineffective in all the concentrations tested, while the combination of one third of the maximum concentration of the individual components already reduced the virus content of the chicken embryrofibroplastes by 10 2 . From Table II it follows, inter alia, that heparin alone is only weakly effective, but both heparin and zinc sulfate heptahydrate in the lowest concentration together with each concentration of the second component give a greater effect than the next higher concentration of the second component alone. With the combination of 6.10 -6 g / ml of zinc sulfate heptahydrate and 3.10- 8 g / ml heparin, the effect of 25.10 -6 ml is already zinc sulfate heptahydrate alone, and each 6.10 -6 g / ml of zinc sulfate heptahydrate and heparin as virtually achieved with 12.10- 6 g / ml of zinc sulfate heptahydrate and 3.10 -6 g / ml heparin, the effect of the combination of 25.10 -6 g / ml of zinc sulfate heptahydrate and 6.10- 6 g / ml heparin. 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.
Ebenfalls festgestellt weraen kann der synergistische Effekt der erfindungsgemäss kombinierten Wirkstoffe und zugleich die überlegene therapeutische Wirkung der Kombination im Vergleich zu andem, 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 infection with HVH2 / Ang. caused genital herpes in guinea pigs at 72 hours after infection (stage of clear symptoms) of treatment beginning, with the results of 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, it also occurs earlier than the effect of the individual components, and the number of recurrences is greatly reduced.
Die synergistische Wirkung der obengenannten Wirkstoffe wird noch verstärkt, wenn eine Präparate-grundlage, insbesondere Gelgrundlage, verwendet wird, die einen oder mehrere Polyoxy- äthlensorbitanfettsäureester, 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. contains.
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 Polyoxyäthylensorbitan-fettsäureester, wie Polyoxyäthylensorbitan-monolaurat oder Polyoxyäthylensorbitanmonooleat, zugegeben sind.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. 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.
Cremes sind Oel-in-Wasser-Emulsioneri, 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 Emulgätoren kommen oberflächenaktive Substanzen mit vorwiegend hydrophilen Eigenschaften in Frage, wie entsprechende nichtionische Emulgatoren, z.B. Fettsäureester von Polyalkoholen oder Aethylenoxidaddukte davon, wie Polyglycerinfettsäureester oder Polyoxyathylen-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 und Riechstoffe.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. 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.
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 zue 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 und Riechstoffe.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.
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 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. The 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.
Die erfindungsgemässen Präparate können - neben den üblichen Konservierungsmitteln - auch weitere biologisch, z.B. antiphlogistisch oder antimikrobiell, wie antibakteriell, antifungal oder ebenfalls antiviral 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. antiphlogistic or antimicrobial, such as antibacterial, antifungal or also antiviral substances, such as 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 topisch anwendbare antivirale Präparate, die 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 ZnS04.7H20, zugefügt. 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 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 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. 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 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. 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 sulfatierten Polysaccharids oder Polymeren, wie von natürlichen oder partiell abgebauten, sulfatierten Polysacchariden, wie sulfatierten Amylopectinen, sulfatierten Dextranen, sulfatierten Polyglucosen oder sulfatierten Polypentosen, bzw. von Polyvinylsulfaten, wie beispielsweise das Natriumsatz 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 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)]. 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.The preparations according to the invention are particularly suitable for the treatment of genital herpes, herpes dermatitis and herpes labialis.
Das nachfolgende Beispiel beschreibt die Herstellung einer typischen Applikationsform.The following example describes the production of a typical form of application.
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 geschützte 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 registered 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 (9)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LU77562 | 1977-06-17 | ||
| LU77562A LU77562A1 (en) | 1977-06-17 | 1977-06-17 | METHOD FOR PRODUCING NEW PHARMACEUTICAL PREPARATIONS |
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| Publication Number | Publication Date |
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| EP0000133A1 EP0000133A1 (en) | 1979-01-10 |
| EP0000133B1 true EP0000133B1 (en) | 1981-09-16 |
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| EP78100133A Expired EP0000133B1 (en) | 1977-06-17 | 1978-06-09 | Pharmaceutical preparations containing sulfated polysaccharides or polymers and zinc ions for topical application in virus infections. |
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| US (1) | US4465666A (en) |
| EP (1) | EP0000133B1 (en) |
| JP (1) | JPS548727A (en) |
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| CA (1) | CA1116083A (en) |
| DE (1) | DE2861070D1 (en) |
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| IT (1) | IT1105718B (en) |
| LU (1) | LU77562A1 (en) |
| NZ (1) | NZ187598A (en) |
| ZA (1) | ZA783480B (en) |
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| LU77562A1 (en) * | 1977-06-17 | 1979-03-26 | Ciba Geigy Ag | METHOD FOR PRODUCING NEW PHARMACEUTICAL PREPARATIONS |
| EP0012115A1 (en) * | 1978-12-04 | 1980-06-11 | Ciba-Geigy Ag | Pharmaceutical compositions for topical treatment of virus infections |
| GB2080682B (en) * | 1980-07-30 | 1984-03-28 | Ciba Geigy Ag | Antiherpetically active lipstick |
| EP0066283B1 (en) * | 1981-06-02 | 1986-09-10 | Eupan Corporation | Eustatic composition for nonspecifically facilitating and amplifying the generalized homeostatic regulation and maintenance, compensation and repair in living organisms |
| NZ208536A (en) * | 1983-06-16 | 1986-11-12 | Victoria State | Footrot composition containing zinc salt and thioacid |
| CA1291034C (en) * | 1987-10-19 | 1991-10-22 | Mostafa S. Fahim | Composition for promoting epithelial regeneration |
| US4661354A (en) * | 1984-06-21 | 1987-04-28 | Finnerty Edmund F | Topical treatment of herpes simplex with a zinc sulfate-camphor water solution |
| US4895727A (en) * | 1985-05-03 | 1990-01-23 | Chemex Pharmaceuticals, Inc. | Pharmaceutical vehicles for exhancing penetration and retention in the skin |
| WO1987002246A1 (en) * | 1985-10-21 | 1987-04-23 | William Sergio | Method for reducing the risk or probability of infection from the aids virus (htlv-iii/lav/arv) |
| US5668116A (en) * | 1987-03-19 | 1997-09-16 | Anthropharm Pty. Limited | Anti-inflammatory compounds and compositions |
| DE3864188D1 (en) * | 1987-05-20 | 1991-09-19 | Ueno Seiyaku Oyo Kenkyujo Kk | CONDOM. |
| US5159069A (en) * | 1988-12-20 | 1992-10-27 | Yamanouchi Pharmaceutical Co., Ltd. | Sulfated tannins and their salts |
| WO1990009181A1 (en) * | 1989-02-10 | 1990-08-23 | Taiho Pharmaceutical Co., Ltd. | Anti-hiv drug |
| US5208031A (en) * | 1989-06-06 | 1993-05-04 | Kelly Patrick D | Sexual lubricants containing zinc as an anti-viral agent |
| US5599551A (en) * | 1989-06-06 | 1997-02-04 | Kelly; Patrick D. | Genital lubricants containing zinc as an anti-viral agent |
| US5624675A (en) * | 1989-06-06 | 1997-04-29 | Kelly; Patrick D. | Genital lubricants containing zinc salts to reduce risk of HIV infection |
| US5482053A (en) * | 1989-06-06 | 1996-01-09 | Kelly; Patrick D. | Condom 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 |
| US5545673A (en) * | 1989-06-06 | 1996-08-13 | Kelly; Patrick D. | Method for reducing risk of infection by sexually transmitted viruses |
| US5785054A (en) * | 1989-06-06 | 1998-07-28 | Kelly; Patrick D. | Genital lubricant with zinc salt, labelled as anti-viral agent |
| AU1052492A (en) * | 1991-01-31 | 1992-08-06 | Farmitalia Carlo Erba S.R.L. | Synergistic composition comprising a fibroblast growth factor and a sulfated polylsaccharide, for use as antiviral agent |
| US5605938A (en) * | 1991-05-31 | 1997-02-25 | Gliatech, Inc. | Methods and compositions for inhibition of cell invasion and fibrosis using dextran sulfate |
| US5705178A (en) * | 1991-05-31 | 1998-01-06 | Gliatech, Inc. | Methods and compositions based on inhibition of cell invasion and fibrosis by anionic polymers |
| US5980477A (en) * | 1991-07-29 | 1999-11-09 | Patrick Kelly | Genital lubricants with zinc salts as anti-viral additives |
| US6321750B1 (en) * | 1993-05-03 | 2001-11-27 | Patrick D. Kelly | Condom lubricants with zinc salts as anti-viral additives |
| US5662919A (en) * | 1994-11-21 | 1997-09-02 | Alcon Laboratories, Inc. | Sulfated polyvinyl alcohol polymers to stabilize pharmaceutical drug compounds |
| US5837266A (en) * | 1996-04-30 | 1998-11-17 | Hydromer, Inc. | Composition, barrier film, and method for preventing contact dermatitis |
| SE507028C2 (en) * | 1996-08-06 | 1998-03-16 | Medicarb Ab | New medical use |
| EP0948347A4 (en) * | 1997-07-16 | 2000-08-30 | Sophie Chen | Antiviral and antitumor agents |
| US6187768B1 (en) | 1999-06-01 | 2001-02-13 | Becton, Dickinson And Company | Kit for flushing medical devices and method of preparation |
| US6558710B1 (en) | 1999-06-14 | 2003-05-06 | Helen Rebecca Godfrey | Topical zinc compositions and methods of use |
| US6977248B1 (en) * | 1999-08-25 | 2005-12-20 | Massachusetts Institute Of Technology | Pharmaceutical preparations for the inhibition of herpes simplex virus 1 entry |
| US6475526B1 (en) | 2001-06-05 | 2002-11-05 | Jeffrey B. Smith | Zinc containing compositions for anti-viral use |
| US20080274209A1 (en) * | 2002-11-04 | 2008-11-06 | Integritas Pharma, Inc. | Methods of treating inflammation |
| US6855341B2 (en) * | 2002-11-04 | 2005-02-15 | Jeffrey B. Smith | Anti-viral compositions and methods of making and using the anti-viral compositions |
| US7968122B2 (en) * | 2003-12-10 | 2011-06-28 | Adventrx Pharmaceuticals, Inc. | Anti-viral pharmaceutical compositions |
| US20060147559A1 (en) * | 2005-01-06 | 2006-07-06 | National Research Laboratories, Ltd. | Methods for Altering the Mineral Content of Foods |
| AU2006337161B2 (en) | 2006-02-03 | 2012-06-07 | Obagi Cosmeceuticals Llc | Anti-aging treatment using copper and zinc compositions |
| US7897800B2 (en) | 2006-02-03 | 2011-03-01 | Jr Chem, Llc | Chemical compositions and methods of making them |
| US7687650B2 (en) | 2006-02-03 | 2010-03-30 | Jr Chem, Llc | Chemical compositions and methods of making them |
| US7867522B2 (en) | 2006-09-28 | 2011-01-11 | Jr Chem, Llc | Method of wound/burn healing using copper-zinc compositions |
| US8273791B2 (en) | 2008-01-04 | 2012-09-25 | Jr Chem, Llc | Compositions, kits and regimens for the treatment of skin, especially décolletage |
| WO2010085753A1 (en) | 2009-01-23 | 2010-07-29 | Jr Chem, Llc | Rosacea treatments and kits for performing them |
| EP2283805A1 (en) | 2009-07-28 | 2011-02-16 | Sirvis BV | Compositions comprising a zinc containing compound dissolved in a hydrophobic phase |
| IT1400232B1 (en) * | 2010-05-07 | 2013-05-24 | Advance Holdings Ltd | PHARMACEUTICAL COMPOSITION TOPICAL COMPARING EPARIN |
| US8952057B2 (en) | 2011-01-11 | 2015-02-10 | Jr Chem, Llc | Compositions for anorectal use and methods for treating anorectal disorders |
| DE102011077393A1 (en) * | 2011-06-10 | 2012-12-13 | Johannes Reinmüller | Antiinfective agent |
| EP3551175A1 (en) | 2016-12-11 | 2019-10-16 | Seanergy Dermatology Ltd. | Compositions comprising sulfated polysaccharides |
| CN110041124A (en) * | 2019-04-23 | 2019-07-23 | 浙江工业大学 | A kind of dedicated zinc-rich nutrient liquid of rice and its method for producing rice rich in zinc |
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|---|---|---|---|---|
| DE2715711A1 (en) * | 1977-04-07 | 1978-10-19 | Robugen Gmbh | Topical compsn. for viral infections of skin and mucosa - contains heavy metal salt, esp. zinc sulphate, and opt. anti:metabolic virustatics |
| LU77562A1 (en) * | 1977-06-17 | 1979-03-26 | Ciba Geigy Ag | METHOD FOR PRODUCING NEW PHARMACEUTICAL PREPARATIONS |
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- 1977-06-17 LU LU77562A patent/LU77562A1/en unknown
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1978
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| EP0000133A1 (en) | 1979-01-10 |
| IT7849884A0 (en) | 1978-06-15 |
| AU3715378A (en) | 1979-12-20 |
| DE2861070D1 (en) | 1981-12-03 |
| AU522600B2 (en) | 1982-06-17 |
| IT1105718B (en) | 1985-11-04 |
| LU77562A1 (en) | 1979-03-26 |
| NZ187598A (en) | 1981-03-16 |
| JPS548727A (en) | 1979-01-23 |
| IE781212L (en) | 1978-12-17 |
| IE47096B1 (en) | 1983-12-14 |
| JPS6225126B2 (en) | 1987-06-01 |
| CA1116083A (en) | 1982-01-12 |
| US4465666A (en) | 1984-08-14 |
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