SE448604B - PHARMACEUTICAL PREPARATION CONTAINING HEPARIN, DEXTRANSULPHATE OR POLYVINYL SULPHATE AND ZINCION - Google Patents
PHARMACEUTICAL PREPARATION CONTAINING HEPARIN, DEXTRANSULPHATE OR POLYVINYL SULPHATE AND ZINCIONInfo
- Publication number
- SE448604B SE448604B SE7909952A SE7909952A SE448604B SE 448604 B SE448604 B SE 448604B SE 7909952 A SE7909952 A SE 7909952A SE 7909952 A SE7909952 A SE 7909952A SE 448604 B SE448604 B SE 448604B
- Authority
- SE
- Sweden
- Prior art keywords
- pharmaceutical preparations
- preparations according
- pharmaceutically acceptable
- heparin
- content
- Prior art date
Links
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 title claims description 19
- 229920000669 heparin Polymers 0.000 title claims description 18
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 title claims description 17
- 229960002897 heparin Drugs 0.000 title claims description 17
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 title claims description 12
- 229910021653 sulphate ion Inorganic materials 0.000 title claims description 9
- 229920002554 vinyl polymer Polymers 0.000 title claims description 8
- 150000003839 salts Chemical class 0.000 claims description 23
- 239000000499 gel Substances 0.000 claims description 19
- -1 polyoxyethylene Polymers 0.000 claims description 15
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 12
- 229920000053 polysorbate 80 Polymers 0.000 claims description 12
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 9
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 8
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 8
- 229920002307 Dextran Polymers 0.000 claims description 7
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- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000006071 cream Substances 0.000 claims description 5
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 239000002674 ointment Substances 0.000 claims description 4
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- OHJKXVLJWUPWQG-PNRHKHKDSA-N Heparinsodiumsalt Chemical compound O[C@@H]1[C@@H](NS(O)(=O)=O)[C@@H](O)O[C@H](COS(O)(=O)=O)[C@H]1O[C@H]1[C@H](OS(O)(=O)=O)[C@@H](O)[C@H](O)[C@H](C(O)=O)O1 OHJKXVLJWUPWQG-PNRHKHKDSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 13
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- 239000011686 zinc sulphate Substances 0.000 description 11
- 235000009529 zinc sulphate Nutrition 0.000 description 11
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- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
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- RZLVQBNCHSJZPX-UHFFFAOYSA-L zinc sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Zn+2].[O-]S([O-])(=O)=O RZLVQBNCHSJZPX-UHFFFAOYSA-L 0.000 description 4
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 3
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
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- 206010067152 Oral herpes Diseases 0.000 description 2
- 239000005662 Paraffin oil Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
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- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
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- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
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- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940057429 sorbitan isostearate Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 229950004959 sorbitan oleate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 229950005175 sudoxicam Drugs 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 235000013904 zinc acetate Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011746 zinc citrate Substances 0.000 description 1
- 235000006076 zinc citrate Nutrition 0.000 description 1
- 229940068475 zinc citrate Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- 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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- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Oncology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Description
448 604 i plaquetest. Proverna utspäddes i Hanks'-lösning + 0,05 % albu- min satta på cellenkelskíkt av hönsembryofibroblasterna. Efter 90 min virusabsorptíon tvättades kulturerna två gånger, försattes med 4 ml "LY~Agaroverlay" {Hanks'-lösning med 0,5 % laktalbumin- hydrolysat och 0,01 % "Yeastolate" (jästextrakt)} och inkuberades därpå vid 3500 tills räkning av plaques (efter 96 h) genomfördes. 448 604 and plaque test. The samples were diluted in Hanks' solution + 0.05% albumin applied to the cell layer of the chicken embryo fibroblasts. After 90 minutes of virus absorption, the cultures were washed twice, added with 4 ml of "LY-Agaroverlay" {Hanks' solution with 0.5% lactalbumin hydrolyzate and 0.01% "Yeastolate" (yeast extract)} and then incubated at 3500 until counting. of plaques (after 96 hours) was performed.
Tabell Ia Preparat, ng/ml: ZHSO4 Heparín-natríumsalt* .7 H20 O . 33 100 0 5,10 aï 5,04 5,00 33 4,89 4,76 4,95 100 4,76 2,60 2,62 300 4,68 <1,00 <1,00 a) Virushalt: Värdena betecknar log 10 av antalet PFU/ml ("Plaque formíng Units/pro ml"). i: 160 IE/mg (från Bíofac AS, Köpenhamn, Danmark) Tabell Ib Polysulfat-salt Koncentratíon i ZnSO4-7H20 ug/ml Koncentratíon í ng/ml 0 11 ' 33 100 Inte: 1 0 6,06 a) 5,33 4,06 4,65 Kaliumsalt av 11 5,34 3,20 2,84 2,50 polyvinylsulfat.Table Ia Preparation, ng / ml: ZHSO4 Heparin sodium salt * .7 H 2 O. 33 100 0 5.10 aï 5.04 5.00 33 4.89 4.76 4.95 100 4.76 2.60 2.62 300 4.68 <1.00 <1.00 a) Virus content: The values denotes log 10 of the number of PFU / ml ("Plaque Forming Units / pro ml"). i: 160 IU / mg (from Bíofac AS, Copenhagen, Denmark) Table Ib Polysulphate salt Concentration in ZnSO4-7H20 ug / ml Concentration in ng / ml 0 11 '33 100 Inte: 1 0 6.06 a) 5.33 4.06 4.65 Potassium salt of 11 5.34 3.20 2.84 2.50 polyvinyl sulfate.
Molekylvikt 33 5,27 _2,95 2,39 2,27 ca 8-104 100 4,78 2,74 2,30 2,17 Natríumsalt av 11 5,39 4,72 4,63 3,74 dextransulfat.Molecular weight 33 5.27 _2.95 2.39 2.27 about 8-104 100 4.78 2.74 2.30 2.17 Sodium salt of 11 5.39 4.72 4.63 3.74 dextran sulfate.
Molekylvikt 33 5,22 4,05 3,32 2,69 ca 5-105 100 4,61 3,14 2,39 2,54 Natriumsalt av 11 5,49 4,54 4,30 3,69 dextransulfat.Molecular weight 33 5.22 4.05 3.32 2.69 about 5-105 100 4.61 3.14 2.39 2.54 Sodium salt of 11 5.49 4.54 4.30 3.69 dextran sulfate.
Molekylvíkt 33 5,30 4,05 3,62 3,02 ca 2-106 100 4.67 3,43 2,95 2,90 a) Jämför tabell Ia. 10 448 604 2. Hämning av plaquebildning av "HVH2/Ang." i höns- embryofíbroblaster Cellenkelskikt inficierades med 100 PFU "HVH2/Ang." under 90 min. Varje gång 4 ml av de i "LY-Agaroverlay" (med S % fâr- serum, 0,5 % "OXO-L-28-Agar", utan dietylaminoetyldextranj inkor- porerade preparaten sattes på de ínfícíerade cellkulturerna och dessa ínkuberades vid 3500 tills räkning av plaques (efter 96 h] genomfördes.Molecular weight 33 5.30 4.05 3.62 3.02 about 2-106 100 4.67 3.43 2.95 2.90 a) Compare table Ia. 10 448 604 2. Inhibition of plaque formation by "HVH2 / Ang." in chicken embryo fibroblasts Cell layer was infected with 100 PFU "HVH2 / Ang." under 90 min. Each time 4 ml of the preparations incorporated in "LY-Agaroverlay" (with S% feed serum, 0.5% "OXO-L-28-Agar", without diethylaminoethyldextran) were applied to the infected cell cultures and incubated at 3500 until counting of plaques (after 96 hours] was performed.
Tabell Ila Preparat, ng/ml: ZnSO4.7H2O Heparin-natriumsalt* 0 1,5 3 6 0 100 a) sz s? 76 2-3 b) 2~3 2-3 1-2 3 104 65 57 42 1-3 1~2 0,5-1 0,5 6 64 31 11 2 l-Z 0,5-1 0,5 0,5 12 43 8 Z 0,5-1 0,5 0,5 0,5 25 15 5 2 1 0,5 0,5 0,5 0,5 a) Genomsnittligt plaquetal från S skålar för varje koncentra- tion i % av kontrolltestens plaquetal. b) Plaquestorlek ø i mm (ca). * 160 IE/mg ("Biofac"). 10 15 448 604 4 Tabell Ilb Polysulfat-salt Koncentra- ZnSO4.7H2O tion i K . . /ml oncentration 1 Hg lig/ml 0 3 6 12 24 :mer o maa) 100 92 s? 66 Kaliumsalt av polyvinyl- _ 1,5 100 89 87 69 57 â:lšató4Molekylv1kt 3 88 75 59 48 9 6 43 33 7 5 1 Natríumsalt av dextran- 1,5 102 103 96 81 34 sulfat.Table 11a Preparation, ng / ml: ZnSO4.7H2O Heparin sodium salt * 0 1.5 3 6 0 100 a) sz s? 76 2-3 b) 2 ~ 3 2-3 1-2 3 104 65 57 42 1-3 1 ~ 2 0,5-1 0,5 6 64 31 11 2 lZ 0,5-1 0,5 0, 5 12 43 8 Z 0.5-1 0.5 0.5 0.5 25 15 5 2 1 0.5 0.5 0.5 0.5 a) Average plaque count from S bowls for each concentration in% of the plaque number of the control test. b) Plaque size ø in mm (approx.). * 160 IU / mg ("Biofac"). 10 15 448 604 4 Table IIb Polysulfate Salt Concentra- ZnSO4.7H2O tion in K. . / ml oncentration 1 Hg lig / ml 0 3 6 12 24: mer o maa) 100 92 s? 66 Potassium salt of polyvinyl- _ 1,5 100 89 87 69 57 â: lšató4Molecular weight1 88 75 59 48 9 6 43 33 7 5 1 Sodium salt of dextran- 1,5 102 103 96 81 34 sulphate.
Molekylvikt ca 5-105 ä gå ïâ 7š 61 g Natríumsalt av 1,5 96 96 94 75 52 dextransulfat.Molecular weight approx. 5-105 ä go ïâ 7š 61 g Sodium salt of 1.5 96 96 94 75 52 dextran sulphate.
Moiekyivikt ca 2-106 ä gå 128 1? Ög 5% a) Jämför tabell IIa. Genomsnittliga plaquetal från 6 skålar för varje koncentration. Med antalet plaques avtar även deras diameter från ca 2-3 mm i kontrolltesten till <0,5 mm i testerna med den mest verksamma kombinationen, 3. Hämning av replikation av "HVH2/Ang." i "VBRO"-celler vid påbörjande av preinfektiös behandling Konfluenta enkelskikt av "VERO"-celler tvättades med "F15-Medium" {"Minimum Essential Medium (Eag1e)", Gibco Bio. Cult Ltd. Paísley, Skottlandl och belades sedan med varje gäng 4 ml av de olika koncentrationerna av preparaten i "F15-Medium". In- fektionen av kulturerna skedde efter 60 min med 1000 PFU "HVH/Ang." i 0,1 ml medium. Efter ínkubation 20 h vid 35°C be- dömdes cellernas tillstånd mikroskopiskt och vírushalten hos cell- lysaten (celler med 1 ml bidestillerat vatten tvâ gånger djupfrys~ ta och upptinade) bestämdes genom titratíon på hönsembryofibro- blaster (plaquebíldning). 10 15 20 25 448 604 5 Tabell III Preparat, ng/ml Natrium- ZnSO .7H O Heparin salt* 4 Z 0 6 o 4,581) 1,84 6 3,59 <1,00 12 3,32 <1,00 25 2,82 <1,00 1) Log 10 PFU/ml cell-lysat * 160 IE/mg ("Biofac").Moiekyivikt ca 2-106 ä gå 128 1? Eye 5% a) Compare Table IIa. Average plaque count from 6 bowls for each concentration. With the number of plaques, their diameter also decreases from about 2-3 mm in the control test to <0.5 mm in the tests with the most effective combination, 3. Inhibition of replication of "HVH2 / Ang." in "VBRO" cells at the beginning of pre-infectious treatment Confluent single layers of "VERO" cells were washed with "F15-Medium" {"Minimum Essential Medium (Eag1e)", Gibco Bio. Cult Ltd. Paísley, Scotlandl and then coated with each batch 4 ml of the various concentrations of the preparations in "F15-Medium". The cultures were infected after 60 min with 1000 PFU "HVH / Ang." in 0.1 ml of medium. After incubation for 20 hours at 35 ° C, the condition of the cells was assessed microscopically and the virus content of the cell lysates (cells with 1 ml of bidistilled water twice frozen and thawed) was determined by titration on chicken embryo fibroblasts (plaque formation). 10 15 20 25 448 604 5 Table III Preparation, ng / ml Sodium ZnSO .7H O Heparin salt * 4 Z 0 6 o 4,581) 1.84 6 3.59 <1.00 12 3.32 <1.00 25 2.82 <1.00 1) Log 10 PFU / ml cell lysate * 160 IU / mg ("Biofac").
Konklusioner dragna ur resultaten av de tre undersökníngsserierna Av ovan anförda undersökningsresultat framgår tydligt syner- gismen hos kombinationerna enligt uppfinningen av zínksulfat (ZnS04.7H20) och heparin-natriumsalt enligt tabellerna Ia, Ila och III. en enligt tabell Ia. varvid varje komponent enbart för sig i alla Speciellt anmärkningsvärd är därvid virus-inaktivering- provade koncentrationer var praktiskt taget overksam, medan kombination av varje gång en tredjedel av maximalkoncentrationen av de enskilda komponenterna redan förminskade virushalten hos hönsembryofibroblasterna med 102. Av tabell Ila framgår bl.a. att heparin-natriumsalt enbart endast har en svag verkan, men att emellertid såväl heparin-natriumsalt som även zinksulfat i den lägsta koncentrationen tillsammans med varje koncentration av den andra komponenten visar en högre verkan än den nästhögsta Med en kombination av 6 ng/ml zinksulfat och 3 pg/ml heparin-natrium- koncentrationen av den andra komponenten enbart för sig. salt erhålles redan samma verkan som med 25 pg/ml zinksulfat en- bart, och med 6 ug/ml zinksulfat och 6 ng/ml heparin-natriumsalt liksom även med 12 pg/ml zinksulfat och 3 ng/ml heparin-natrium- salt nästan samma verkan som med en kombination av 25 ng/ml zink- sulfat och 6 ng/ml heparin-natríumsalt. Virus-replikationen är enligt tabell III medelst zinksulfat i den högsta koncentrationen på 25 ng/ml endast måttlig, men är med heparin i den enda prova- de koncentrationen på 6 ng/ml, motsvarande de högsta i de andra undersökningssericrna, på grund av den starka absorptionshämman- 10 15 2D 25 30 448 604 de verkan hos heparin-natriumsaltet tydligt hämmad; alla provade kombinationer visar emellertid en åtminstone 10-faldígt kraftiga- re verkan än de enskilda komponenterna.Conclusions drawn from the results of the three series of tests The above test results clearly show the synergism of the combinations according to the invention of zinc sulphate (ZnSO 4 .7H 2 O) and heparin-sodium salt according to Tables Ia, IIa and III. one according to Table Ia. In particular, virus-inactivation-tested concentrations were practically ineffective, while combining each time one third of the maximum concentration of the individual components already reduced the virus content of the chicken embryo fibroblasts by 102. Table IIa shows, among other things. a. that heparin-sodium salt has only a weak effect, but that nevertheless both heparin-sodium salt and also zinc sulphate in the lowest concentration together with each concentration of the second component shows a higher effect than the next highest With a combination of 6 ng / ml zinc sulphate and 3 pg / ml the heparin-sodium concentration of the second component alone. salt already has the same effect as with 25 pg / ml zinc sulphate alone, and with 6 ug / ml zinc sulphate and 6 ng / ml heparin sodium salt as well as with 12 pg / ml zinc sulphate and 3 ng / ml heparin sodium salt almost the same effect as with a combination of 25 ng / ml zinc sulphate and 6 ng / ml heparin sodium salt. Virus replication is only moderate according to Table III by means of zinc sulphate at the highest concentration of 25 ng / ml, but is with heparin in the only tested concentration of 6 ng / ml, corresponding to the highest in the other study series, due to the strong absorption inhibitors clearly inhibit the action of the heparin sodium salt; however, all tested combinations show an effect at least 10 times stronger than the individual components.
Av de i tabellerna Ib och Ilb angivna resultaten framgår även en synergism vid kombinationen zinksulfat med natriumsalter- na av två dextransulfater med olika molekylvikter ävensom med ka- liumsaltet av polyvinylsulfat. Speciellt anmärkningsvärda är re- sultaten i form av virus-inaktiveringen enligt tabell I, genom att komponenterna enbart för sig i den högsta koncentrationen av 100 ug/ml förminskade vírushalten med endast ca 101°5, dvs. lika eller mindre kraftigt än kombinationen av vardera en niondel av maximalkoncentrationen av de enskilda komponenterna och att där- emot kombinationen av vardera en tredjedel av maximalkoncentra- tionen av de enskilda komponenterna förminskade virushalten be- 2'5 till 103,5. Av tabell 11b framgår, att verkan av polysulfat-salter, vilka för sig allena tydligt kraftigare, dvs. med ca 10 t.o.m. i den högsta koncentrationen av 6 pg/ml icke visade någon stark effekt, betydligt ökade genom tillsatsen av zinksulfat i koncentrationer av 6 ng/ml och 12 ug/ml, vilka för sig allena är overksamma resp. nästan overksamma. 4. Verkan vid genom infektion med "HVH2/Ang." förorsakad herpes genitalis hos marsvin av honkön Synergismen kan jämväl fastställas hos de enligt uppfin- ningen kombinerade verksamma ämnena in vivo vid genom infektion med "HVH2/Ang." förorsakad herpes genitalis hos marsvin av hon- kön vid 72 h efter intravaginal infektion (stadium med tydliga symptom) påbörjad behandling enligt av B. Lukas o. medarb., Arch.The results given in Tables Ib and IIb also show a synergism in the combination of zinc sulphate with the sodium salts of two dextran sulphates with different molecular weights as well as with the potassium salt of polyvinyl sulphate. Of particular note are the results in the form of virus inactivation according to Table I, in that the components alone in the highest concentration of 100 μg / ml reduced the virus content by only about 101 ° 5, ie. equal or less strongly than the combination of each one-ninth of the maximum concentration of the individual components and that on the other hand the combination of each one-third of the maximum concentration of the individual components reduced the virus content by 2'5 to 103.5. Table 11b shows that the effect of polysulphate salts, which alone are clearly stronger, ie. with about 10 t.o.m. at the highest concentration of 6 pg / ml did not show any strong effect, significantly increased by the addition of zinc sulphate in concentrations of 6 ng / ml and 12 ug / ml, which alone are ineffective respectively. almost inactive. 4. Effect on by infection with "HVH2 / Ang." Synergism can also be determined in the active substances combined according to the invention in vivo by infection with "HVH2 / Ang." caused genital herpes in female guinea pigs at 72 hours after intravaginal infection (stage with clear symptoms) started treatment according to B. Lukas et al., Arch.
Ges. Virusforsch. Ai, 153-155 (1974) o. íg, 1-11 (1975) beskri- ven metodik. Resultaten av motsvarande dubbelblindförsök har an- givits i följande tabell IV. f; 10 15 20 448 604 7 Tabell IV' Preparat Verkan på lokala symptom b) Nr H Z a) % djur med % symptom- Para- Exitus IU % n mera än 66 % fria djur lys % regression dag 4 dag 4 7 9 11 9 11 14 18 25 1. - F) 108 o o s 6 z 3 5 915 39 24 2 - -d) 35 0 11 17 37 14 25 40 48 51 23 11 3 32 - 8 0 O 25 37 0 12 25 37 62 0 4 160- - 7 36 0 11 39 61 30 30 41 58 66 3 5 - 0,5 10 0 0 10 10 0 10 30 50 70 20 0 6 - 1,0 18 0 5 5 17 0 17 28 33 33 11 5 7 32 0,5 10 10 10 30 40 0 10 50 40 40 20 0 8 32 1,0 10 0 0 30 20 20 20 30 50 80 0 0 9 160 0,5 19 0 5 84 94 53 72 94 94 94 10 5 10 160 1,0 46 6 37 63 87 43 74 78 87 90 4 0 H = heparin-natriumsalt, 160 IU/mg ("Biofac") Z = ZnSO4.7H20. a) Djurantal >10 är totalantal försöksdjur av flera försök med varje gång 8 eller 10 djur. b) Dag 0 är dagen för påbörjad behandling 72 h efter infektionen.Ges. Virus research. Ai, 153-155 (1974) et al., 1-11 (1975) described methodology. The results of the corresponding double-blind experiments have been given in the following Table IV. f; 10 15 20 448 604 7 Table IV 'Preparation Effect on local symptoms b) No. HZ a)% animals with% symptoms- Para- Exitus IU% n more than 66% free animals lys% regression day 4 day 4 7 9 11 9 11 14 18 25 1. - F) 108 oos 6 z 3 5 915 39 24 2 - -d) 35 0 11 17 37 14 25 40 48 51 23 11 3 32 - 8 0 O 25 37 0 12 25 37 62 0 4 160 - - 7 36 0 11 39 61 30 30 41 58 66 3 5 - 0,5 10 0 0 10 10 0 10 30 50 70 20 0 6 - 1,0 18 0 5 5 17 0 17 28 33 33 11 5 7 32 0.5 10 10 10 30 40 0 10 50 40 40 20 0 8 32 1.0 10 0 0 30 20 20 20 30 50 80 0 0 9 160 0.5 19 0 5 84 94 53 72 94 94 94 10 5 10 160 1.0 46 6 37 63 87 43 74 78 87 90 4 0 H = heparin sodium salt, 160 IU / mg ("Biofac") Z = ZnSO4.7H2O. a) Number of animals> 10 is the total number of experimental animals of several experiments with 8 or 10 animals each time. b) Day 0 is the day of starting treatment 72 hours after the infection.
Behandlingen utgjordes av intravaginal applikation av 0,1 ml av det för provning avsedda preparatet två gånger dagligen under 5 på varandra följande dagar. c) Inficierade kontrolldjur som icke erhöll någon behandling. d) Infiçierade kontrolldjur, som behandlades med den i alla pre- parat använda gel-basen, som innehöll 0,1 % polyoxietylen- sorbitan-monooleat.The treatment consisted of intravaginal application of 0.1 ml of the test preparation twice daily for 5 consecutive days. (c) Infected control animals which did not receive any treatment. d) Infected control animals, which were treated with the gel base used in all preparations, which contained 0.1% polyoxyethylene sorbitan monooleate.
Resultaten av de jämförande undersökningarna visar, att administrering av enbart heparin-natriumsalt eller zinkjoner som verksamt ämne med en lämplig gel-bas endast måttligt förstärker den gynnsamma verkan hos den sistnämnda, enär efter behandling med enbart ett av de anförda verksamma ämnena vid undersöknings- periodens slut högst 70 % av försöksdjuren är symptomfria medan efter behandling med enbart gel-basen redan ca 50 % av försöks- djuren är symptomfria. I motsats härtill resulterade den kombi- nerade administreringen av zinkjoner och heparin-natriumsalt i 10 15 20 35 40 448 604 s koncentrationsomrâdet enligt uppfinningen i ett nästan full- ständigt botande av det experimentella sjukdomstillständet, i det att vid undersökningsperiodens slut 18 av 19 resp. 42 av 46 för- söksdjur, dvs. minst 90 % var symptomfria. Dessutom blir även det vid enbart administrering av heparin-natriumsalt fastställba- ra tidiga insättandet av en kurativ verkan efter administrering av kombinationen ännu väsentligt kraftigare synligt, medan verkan efter administrering av enbart zinkjoner först sätter in vid en f sen tidpunkt.The results of the comparative studies show that the administration of only heparin sodium salt or zinc ions as active substance with a suitable gel base only moderately enhances the beneficial effect of the latter, since after treatment with only one of the active substances mentioned during the study period end no more than 70% of the experimental animals are asymptomatic, while after treatment with the gel base alone, about 50% of the experimental animals are asymptomatic. In contrast, the combined administration of zinc ions and heparin sodium salt in the concentration range of the invention resulted in an almost complete cure of the experimental disease state, in that at the end of the study period 18 of 19 and 19, respectively. 42 of 46 experimental animals, ie. at least 90% were asymptomatic. In addition, even with the administration of heparin-sodium salt alone, the early onset of a curative effect after administration of the combination becomes even more pronounced, while the effect after administration of zinc ions alone only becomes apparent at a later time.
De ovan anförda verksamma ämnenas synergism förstärkes dess- utom, när en preparat-bas, i synnerhet en gel-bas, användes, som innehåller en eller flera polyoxietylensorbitan-fettsyraestrar, såsom polyoxietylensorbitan-monostearat och/eller framför allt polyoxietylensorbitan-monolaurat eller i första hand polyoxiety- lensorbitan-monooleat.In addition, the synergism of the above active substances is enhanced when 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 in particular polyoxyethylene sorbitan monolaurate or in the first hand polyoxyethylene lens sorbitan monooleate.
De farmaceutiska preparaten enligt uppfinningen innehåller de ovan definierade verksamma ämnena företrädesvis i kombination med för topisk applikation lämpade farmaceutiska bärarmaterial.The pharmaceutical preparations according to the invention contain the active ingredients defined above, preferably in combination with pharmaceutical carrier materials suitable for topical application.
Som former för preparat enligt uppfinningen ifrågakommer i syn- nerhet tinkturer, lösningar, krämer, salvor och framför allt geler.As forms of preparation according to the invention, tinctures, solutions, creams, ointments and, above all, gels are particularly relevant.
Tinkturer och lösningar uppvisar för det mesta en vatten- haltig-etanolisk resp. vattenhaltig bas, som är försatt med b1.a. polyalkoholer, såsom propylenglykol eller glycerol och/el- ler lågmolekylära polyetylenglykoler, som fuktbevarande medel för nedsättning av avdunstningen, och eventuellt återfettning åstadkommande substanser, såsom fettsyraestrar av lågmolekylära polyetylenglykoler, dvs. i vattenhaltig-etanolisk blandning lös- liga, lipofila substanser, som ersättning för från huden med etanolen extraherade fettsubstanser, och eventuellt ytterligare hjälp- och tillsatsämnen, förutom sedvanliga, såsom nedan anför- da, konserveringsmcdel t.ex. även redan anförda polyoxietylen- sorbítan-fettsyraestrar, såsom polyoxietylensorbítan-monolaurat eller polyoxietylensorbitan-monooleat.Tinctures and solutions mostly show an aqueous-ethanolic resp. aqueous base, which is provided with b1.a. polyalcohols, such as propylene glycol or glycerol and / or low molecular weight polyethylene glycols, as humectants to reduce evaporation, and optionally re-greasing substances, such as fatty acid esters of low molecular weight polyethylene glycols, i.e. in aqueous-ethanolic mixture soluble, lipophilic substances, as a substitute for fatty substances extracted from the skin with ethanol, and possibly additional auxiliaries and additives, in addition to customary, as stated below, preservatives e.g. also already mentioned polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monooleate.
Krämer är olja-i-vatten-emulsioner, som innehåller mera än g 50 % vatten. t.ex. lauryl-, cetyl- eller stearylalkohol, fettsyror, t.ex. pal- Som olje-bas användes i första hand fettalkoholer, mitin- eller stearinsyra, flytande till fasta vaxer, t.ex. iso- propylmyristinat, ullvax eller bivax, och/eller kolväten, t.ex. vasclin ("petrolatum") eller paraffinolja. Som emulgatorer 10 15 20 25 30 35 40 448 604 ifrågakommer ytaktiva substanser med företrädesvis hydrofila egen- skaper, såsom motsvarande nonjonaktiva emulgatorer, t.ex. fettsy- raestrar av polyalkoholer eller etylenoxidaddukter därav, såsom polyglycerolfettsyraestrar eller polyoxietylensorbitan-fettsyra- estrar ("Tweens"), vidare polyoxietylenfettalkoholetrar eller -fettsyraestrar, eller motsvarande jonaktiva emulgatorer, såsom alkalimetallsalter av fettalkoholsulfater, t.ex. natriumlauryl- sulfat, natriumcetylsulfat eller natríumstearylsulfat, som vanli- gen användes i närvaro av fettalkoholer, t.ex. cetylalkohol eller stearylalkohol. Tillsatser till vattenfasen är bl.a. medel vilka minskar uttorkningen av krämen, t.ex. polyalkoholer, såsom gly~ cerol, sorbitol, propylenglykol och/eller polyetylenglykoler, vi- dare konserveringsmedel, luktämnen etc.Creams are oil-in-water emulsions, which contain more than g 50% water. for example lauryl, cetyl or stearyl alcohol, fatty acids, e.g. pal- As an oil base, fatty alcohols, mitic or stearic acid, liquid to solid waxes, e.g. isopropyl myristinate, wool wax or beeswax, and / or hydrocarbons, e.g. vasclin ("petrolatum") or paraffin oil. As emulsifiers, surfactants with preferably 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"), further polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal alkaloids; sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are commonly used in the presence of fatty alcohols, e.g. cetyl alcohol or stearyl alcohol. Additives to the water phase include agents which reduce the dehydration of the cream, e.g. polyalcohols, such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, further preservatives, odorants, etc.
Salvor är vatten-i-olja-emulsioner, vilka innehåller upp till 70 %, företrädesvis dock från ca 20 % till ca 50 % vatten eller vattenhaltig fas. Som fettfas ifrågakommer i första hand kolväten, t.ex. vaseliner, paraffinolja och/eller hårdparaffiner, vilka för förbättring av vattenhållningsförmågan innehåller före- trädesvis tjänliga hydroxiföreningar, såsom fettalkoholer, eller estrar därav, t;ex. cetylalkohol eller ullvaxalkoholer, resp. ullvax. sorbitan-fettsyraestrar ("Spans"), t.ex. sorbitanoleat och/eller sorbitanisostearat. Tillsatser till vattenfaser är bl.a. medel för bevarande av fukthalten, såsom polyalkoholer, t.ex. glycerol, Emulgatorer är motsvarande lipofila substanser, såsom Opropylenglykol, sorbitol och/eller polyetylenglykol, ävensom kon- serveringsmedel, luktämnen etc.Ointments are water-in-oil emulsions which contain up to 70%, but preferably from about 20% to about 50% water or aqueous phase. As the fat phase, hydrocarbons are primarily in question, e.g. Vaseline, paraffin oil and / or hard paraffins, which for the improvement of water holding capacity preferably contain useful hydroxy compounds, such as fatty alcohols, or esters thereof, e.g. cetyl alcohol or wool wax alcohols, resp. wool wax. sorbitan fatty acid esters ("Spans"), e.g. sorbitan oleate and / or sorbitan isostearate. Additives to water phases include moisture retention agents, such as polyalcohols, e.g. glycerol, Emulsifiers are corresponding lipophilic substances, such as Opropylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, odorants, etc.
Geler är i synnerhet vattenhaltiga lösningar av de verksam- ma ämnena, i vilka díspergerats och svällts gelbildare, företrä- desvis sådana ur gruppen cellulosaetrar, såsom metylcellulosa, hydroxiotylccllulosa eller karboxímetylccllulosa, eller ur grup- pen vegetabiliska hydrokolloider, såsom natrium-alginat, dragant eller gummi arabicum. Dessutom innehåller gelerna företrädesvis medel för bibehållande av vattenhållningsförmâgan ur gruppen poly-, alkoholer, såsom propylenglykol, glycerol och/eller lågmolekylära polyetylenglykoler, ävensom vätmedel, t.ex. polyoxíetylensorbitan- fettsyraestrar, såsom polyoxietylensorbitan-monostearat, -mono- laurat eller -monoolcat i koncentratíoner av ca 0,02-5 %. Som ytterligare tillsatsämnen innehåller gelerna sedvanliga konser- veringsmedel, t.ex. bensylalkohol, fenetylalkohol, fenoxietanol, p-hydroxibensoesyralågalkylestrar såsom metyl- och/eller propyl- 10 15 20 25 30 35 40 448 604 10 ester, sorbinsyra eller organiska kvicksilverföreningar, såsom mertiolat.Gels are in particular aqueous solutions of the active substances in which gel formers are dispersed and swollen, preferably those from the group of cellulose ethers, such as methylcellulose, hydroxiotylcellulose or carboxymethylcellulose, or from the group of vegetable hydrocolloids, such as sodium alginate, traction alginate, gummi arabicum. In addition, the gels preferably contain water-retaining agents from the group of poly-, alcohols, such as propylene glycol, glycerol and / or low molecular weight polyethylene glycols, as well as wetting agents, e.g. polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monostearate, monolaurate or monoolcate in concentrations of about 0.02-5%. As additional additives, the gels contain customary preservatives, e.g. benzyl alcohol, phenethyl alcohol, phenoxyethanol, p-hydroxybenzoic acid lower alkyl esters such as methyl and / or propyl esters, sorbic acid or organic mercury compounds such as merthiolate.
Preparaten enligt uppfinningen kan, förutom sedvanliga konserveringsmedel, även innehålla ytterligare biologiskt, t.ex. ,antíflogístískt eller antimikrobiellt, såsom antibakteriellt, antifungalt eller jämväl antivíralt verksamma ämnen, såsom "Flumethason", neomycin, gentamycin, mjölksyra eller "Mikonazol".The compositions according to the invention may, in addition to customary preservatives, also contain additional biological, e.g. , antiflogistic or antimicrobial, such as antibacterial, antifungal or even antivirally active substances, such as "Flumethasone", neomycin, gentamycin, lactic acid or "Miconazole".
Framställningen av preparaten enligt uppfinningen sker på i och för sig känt sätt.The preparations according to the invention are prepared in a manner known per se.
Föreliggande uppfinning avser i synnerhet topiskt använd- bara antivirala preparat, vilka innehåller farmaceutískt godtag- bara salter av sura sulfaterade polysackarider eller sura sulfa- terade polymerer, såsom heparin, och zinkjoner i ett förhållande av 1 mg till 0,18-18 mg, i synnerhet 1 mg till 0,18-4,5 mg, och eventuellt polyoxietylensorbítan-monolaurat och/eller -monooleat.In particular, the present invention relates to topically useful antiviral compositions which contain pharmaceutically acceptable salts of acid sulfated polysaccharides or acid sulfated polymers, such as heparin, and zinc ions in a ratio of 1 mg to 0.18-18 mg, in in particular 1 mg to 0.18-4.5 mg, and optionally polyoxyethylene sorbitan monolaurate and / or monooleate.
För heparin-salter hänför sig ovan angivna mängduppgifter till sådana med 160 IE/mg, och för salter av annat heparin bör samma IE-mängder insättas. Zínkjonerna tillsättes i form av motsva- rande mängder av en dissocierbar zinkförening, t.ex. 0,8-80 mg resp. 0,8-20 mg ZnS04.7H2O. Motsvarande topiskt användbara pre- parat, i synnerhet geler, och vidare även tinkturer, vattenhal- tiga lösningar, krämer eller salvor, innehåller exempelvis per g eller ml 0,1-5 mg i synnerhet 0,25-3 mg av ett farmaceutiskt god- tagbart salt av en sur sulfaterad polysackarid eller sur sulfa- terad polymer, exempelvis 16-800 IE, i synnerhet 40-480 IE av ett motsvarande salt av heparin, och 0,18-18 mg zinkjoner, mot- svarande t.ex. ca 0,8-80 mg ZnSO4.7H20 och eventuellt dessutom 0,2-50 mg polyoxíetylensorbitan-monolaurat och/eller -monooleat.For heparin salts, the above amounts refer to those of 160 IU / mg, and for salts of other heparin, the same IU amounts should be used. The zinc ions are added in the form of corresponding amounts of a dissociable zinc compound, e.g. 0.8-80 mg resp. 0.8-20 mg ZnSO 4 .7H 2 O. Correspondingly topically useful preparations, in particular gels, and furthermore tinctures, aqueous solutions, creams or ointments, contain, for example, per g or ml 0.1-5 mg, in particular 0.25-3 mg of a pharmaceutical preparation. absorbable salt of an acid sulphated polysaccharide or acid sulphated polymer, for example 16-800 IU, in particular 40-480 IU of a corresponding salt of heparin, and 0.18-18 mg of zinc ions, corresponding to e.g. about 0.8-80 mg of ZnSO4.7H2 O and optionally in addition 0.2-50 mg of polyoxyethylene sorbitan monolaurate and / or monooleate.
Speciellt föredragna är en halt av 80-320 IE av ett farmaceutískt godtagbart salt av heparin, 0,45-4,5 mg zinkjoner och eventuellt dessutom 0,5-10 mg polyoxietylensorbitan~monolaurat och/eller -monooleat per g eller ml.Particularly preferred are a content of 80-320 IU of a pharmaceutically acceptable salt of heparin, 0.45-4.5 mg of zinc ions and optionally in addition 0.5-10 mg of polyoxyethylene sorbitan monolaurate and / or monooleate per g or ml.
I stället för ett farmaceutiskt godtagbart salt av heparin kan även en antiviralt med avseende på verkan lika mängd av ett motsvarande salt av en annan sur sulfuterad polysackaríd eller sur sulfaterad polymer, såsom en av i det följande anförd südan, i synnerhet dextransulfat resp. polyvinylsulfat användas, varvid en halt av, per g eller ml, 0,25-2 mg är speciellt att föredraga.Instead of a pharmaceutically acceptable salt of heparin, an antiviral with respect to the action of an equivalent salt of another acid sulphuted polysaccharide or acid sulphated polymer, such as one of the following sude, in particular dextran sulphate resp. polyvinyl sulfate may be used, with a content of, per g or ml, 0.25-2 mg being especially preferred.
Med sura sulfaterade polysackarider avses sådana, i vilka envärda svavelsyrarester -S02-OH är bundna-vid syreatomer ochlel- *J 10 15 20 25 30 35 40 448 604 11 ler, såsom fallet är vid heparin, vid kväveatomer. Sådana sura sulfaterade polysackaríder kan vara av naturligt ursprung, såsom heparin, kondroitinsulfat (kondroitinsvavelsyra) eller karragen, eller framställda genom sulfatering av naturliga eller partiellt nedbrutna polysackarider, såsom sulfaterade amylopektiner, sul- faterade dextraner, sulfaterade polyglukoser eller sulfaterade polypentoser. Dessa ämnen användes i form av sina farmaceutiskt godtagbara salter, såsom kalium- eller i synnerhet natriumsalter.By acidic sulphated polysaccharides is meant those in which monovalent sulfuric acid residues -SO 2 -OH are attached to oxygen atoms and, as is the case with heparin, to nitrogen atoms. Such acid sulfated polysaccharides may be of natural origin, such as heparin, chondroitin sulfate (chondroitin sulfuric acid) or carrageenan, or prepared by sulfation of natural or partially degraded polysaccharides, such as sulfated amylopectins, sulfated dextrans, sulfated polyglucose or sulfated polyglucoses. These substances are used in the form of their pharmaceutically acceptable salts, such as potassium or in particular sodium salts.
Som sådana må anföras natriumsaltet av heparin som vanlig handels- form av det senare, vidare kalium- och magnesiumsalt av heparin och natriumsalter av sulfaterade dextraner med olika molekylvik- ter, t.ex. 4,8.104, 5.105 eller 2.106. rer är sulfateringsprodukter av hydroxigrupper innehållande poly- Sura sulfaterade polyme- merer, såsom sura sulfaterade polyvinylalkoholer (polyvinylsulfa- ter) med olika molekylvikter, vilka i sin tur användes i form av farmaceutiskt godtagbara salter, såsom natrium- eller framför allt kaliumsalter. Allmänt är såsom farmaceutiskt godtagbara salter natrium- och kaliumsalter av speciell betydelse.As such, the sodium salt of heparin may be mentioned as a common commercial form of the latter, furthermore potassium and magnesium salts of heparin and sodium salts of sulphated dextrans with different molecular weights, e.g. 4, 8,104, 5,105 or 2,106. Acid sulphated polymers, such as acid sulphated polyvinyl alcohols (polyvinyl sulphates) with different molecular weights, which in turn are used in the form of pharmaceutically acceptable salts, such as sodium or especially potassium salts. In general, as pharmaceutically acceptable salts, sodium and potassium salts are of particular importance.
Zinkjonerna kan, i stället för i form av zinksulfat, även tillsättas i form av en annan dissocierbar zinkförening, såsom zinkklorid, zinkacetat eller zinkcitrat, eller som zinksalt av en syra eller av ett annat ämne av sur karaktär och egna biolo- giska t.ex. antibakteriella eller antiflogistiska egenskaper, såsom zink-sudoxicam (zinksalt av 4-hydroxi-Z-metyl-N-(2-tiazo- lyl)-1,Z-bensotiazin-3-karboxamid-1,1-dioxid). Härvid är det icke nödvändigt, att de tillförda zinksalterna i det använda bärarmediet är fullständigt dissocienfle utan det är tillräck- ligt, att en inom ramen för de ovan angivna koncentrationsupp- gifterna liggande halt av zinkjoner föreligger tillsammans med icke-dissocierat salt.The zinc ions can, instead of in the form of zinc sulphate, also be added in the form of another dissociable zinc compound, such as zinc chloride, zinc acetate or zinc citrate, or as zinc salt of an acid or of another substance of an acidic nature and own biological e.g. . antibacterial or antiphlogistic properties, such as zinc-sudoxicam (zinc salt of 4-hydroxy-Z-methyl-N- (2-thiazolyl) -1,2-benzothiazine-3-carboxamide-1,1-dioxide). In this case, it is not necessary that the zinc salts added in the carrier medium used are completely dissociated, but it is sufficient that a content of zinc ions within the concentration data given above is present together with non-dissociated salt.
Preparaten enligt uppfinningen lämpar sig i synnerhet för behandling av herpes genitalis, herpes dermatitis och herpes labialis. För behandling av båda de förstnämnda anbringas geler enligt uppfinningen så tidigt som möjligt, t.ex. medelst tub eller applikator, 2-3 gånger dagligen, och för behandling av herpes labialis flera gånger dagligen på de sjuka kroppsställena tills symptomen avklingat resp. till läkning. Vattenhaltiga lösningar kan t.ex. användas för sköljning av insjuknade kropps- hålor, t.ex. för behandling av herpes gingivostomatitis, eller för behandling av herpes keratokonjuktivitis. 15 25 30 40 443 604 12 'Följande exempel beskriver framställning av några typiska applikationsformer, givetvis utan att därigenom uppfinningens omfång på något sätt inskränkes.The compositions according to the invention are particularly suitable for the treatment of genital herpes, herpes dermatitis and labial herpes. For the treatment of both the former, gels according to the invention are applied as early as possible, e.g. by means of a tube or applicator, 2-3 times daily, and for the treatment of herpes labialis several times daily in the diseased places of the body until the symptoms subside resp. for healing. Aqueous solutions can e.g. be used for rinsing diseased body cavities, e.g. for the treatment of herpes gingivostomatitis, or for the treatment of herpes keratoconjunctivitis. The following examples describe the preparation of some typical application forms, of course without thereby limiting the scope of the invention in any way.
Exempel 1. För framställning av 10,0 liter gel blandas 200,0 g högviskös natrium-karboxímetylcellulosa och 50,0 g polyoxiety- lensorbítanmonostearat ("Tween 60") med 1000 g glycerol och 6,5 liter "Aqua conservans" och blandningens får svälla till ett homogent slem. Därpå tillsättes en lösning av 1,6.106 IE hepa- rin-natriumsalt (t.ex. 10,0 g "Heparin Bíofac"), 50,0 g zinksul- fat-heptahydrat och 10,0 g polyoxietylensorbitan-monooleat ("Tween 80") i 2 liter "Aqua conservans". Slutligen uppfylles med "Aqua conservans" till 10 liter, blandas omsorgsfullt och den erhållna gelen fylles på tuber.Example 1. To prepare 10.0 liters of gel, 200.0 g of highly viscous sodium carboxymethylcellulose and 50.0 g of polyoxyethylene sorbitan monostearate ("Tween 60") are mixed with 1000 g of glycerol and 6.5 liters of "Aqua conservans" and the mixture of sheep swell to a homogeneous mucus. Then a solution of 1.6,106 IU of heparin sodium salt (eg 10.0 g of "Heparin Biofac"), 50.0 g of zinc sulphate heptahydrate and 10.0 g of polyoxyethylene sorbitan monooleate ("Tween 80") is added. ") in 2 liters" Aqua conservans ". Finally, fill with "Aqua conservans" to 10 liters, mix thoroughly and fill the resulting gel into tubes.
Med "Aqua conservans" avses en vattenhaltig lösning av 0,07 % p-hydroxibensoesyra-metylester ("Metylparaben") och 0,0§ % p-hydroxibensoesyra-propylester ("Propylparaben"). "Tween 60ïÉ'" och "Tween 80 ~ " är skyddade varumärkesbeteckningar för ovan an- förda föreningar från ICI of America Inc., Stamford, Connecticut 06904.By "Aqua conservans" is meant an aqueous solution of 0.07% p-hydroxybenzoic acid methyl ester ("Methylparaben") and 0.0§% p-hydroxybenzoic acid propyl ester ("Propylparaben"). "Tween 60" and "Tween 80" are trademarked trademarks of the above compounds from ICI of America Inc., Stamford, Connecticut 06904.
I stället för 50,0 g ZnS04.7HzO kan även 100,0 g användas och för övrigt följes ovan anförda förfaringssätt.Instead of 50.0 g of ZnSO 4 .7H 2 O, 100.0 g can also be used and otherwise follow the above procedures.
Exempel 2. Analogt med exempel 1 framställes en gel med använd- ning av 5,0 g natriumsalt av dextransulfat med en molekylvikt av ca 4,8.104 í stället för heparin.Example 2. In analogy to Example 1, a gel is prepared using 5.0 g of sodium salt of dextran sulfate having a molecular weight of about 4.8.104 instead of heparin.
Exempel 3. Analogt med exempel 1 framställes en gel med använd- ning av 2,5 g natriumsalt av dextransulfat med en molekylvikt av ca 2.106 i stället för heparin.Example 3. In analogy to Example 1, a gel is prepared using 2.5 g of sodium salt of dextran sulfate having a molecular weight of about 2,106 instead of heparin.
Exempel 4. Analogt med exempel 1 framställes en gel med använd- ning av 2,5 g kaliumsalt av polyvinylsulfat med en molekylvikt av ca 8.104 i stället för heparin.Example 4. In analogy to Example 1, a gel is prepared using 2.5 g of potassium salt of polyvinyl sulfate having a molecular weight of about 8,104 instead of heparin.
Exempel 5. För framställning av 10,0 liter gel blandas 200,0 g högviskös natrium-karboximetylcellulosa och 50,0 g polyoxietylen- sorbitan-monostearat ("Tween 60", jämför exempel 1) med 1000 g glycerol och 6,5 liter "Aqua conservans" och blandningen får svälla till ett homogent slem. Därpå tillblandas en lösning av 5,0 g natriumsalt av dextransulfat med en molekylvikt av ca 5.105, 50,0 g zinksulfatheptahydrat och 10,0 g polyoxietylensor- bitan-monooleat ("Tween 80", jämför exempel 1) i 2,0 liter "Aqua_ conservans" (jämför exempel 1). Slutligen uppfylles med "Aqua conservans" till 10,0 liter, blandas omsorgsfullt och den erhåll- na gelen fylles på tuber. a) F! naExample 5. To prepare 10.0 liters of gel, 200.0 g of highly viscous sodium carboxymethylcellulose and 50.0 g of polyoxyethylene sorbitan monostearate ("Tween 60", compare Example 1) are mixed with 1000 g of glycerol and 6.5 liters. Aqua conservans "and the mixture is allowed to swell to a homogeneous mucus. Then a solution of 5.0 g of sodium salt of dextran sulfate with a molecular weight of about 5,105, 50.0 g of zinc sulfate heptahydrate and 10.0 g of polyoxyethylene sorbitan monooleate ("Tween 80", compare Example 1) in 2.0 liters is mixed. Aqua_conservancy "(compare Example 1). Finally, fill with "Aqua conservans" to 10.0 liters, mix thoroughly and fill the resulting gel into tubes. a) F! na
Claims (12)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CH1236078 | 1978-12-04 |
Publications (2)
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| SE7909952L SE7909952L (en) | 1980-06-05 |
| SE448604B true SE448604B (en) | 1987-03-09 |
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| SE7909952A SE448604B (en) | 1978-12-04 | 1979-12-03 | PHARMACEUTICAL PREPARATION CONTAINING HEPARIN, DEXTRANSULPHATE OR POLYVINYL SULPHATE AND ZINCION |
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| EP (1) | EP0012115A1 (en) |
| JP (1) | JPS5579321A (en) |
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| IT (1) | IT1164070B (en) |
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| NZ (1) | NZ192294A (en) |
| SE (1) | SE448604B (en) |
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| GB2080682B (en) * | 1980-07-30 | 1984-03-28 | Ciba Geigy Ag | Antiherpetically active lipstick |
| DE3273138D1 (en) * | 1981-06-02 | 1986-10-16 | Eupan Corp | Eustatic composition for nonspecifically facilitating and amplifying the generalized homeostatic regulation and maintenance, compensation and repair in living organisms |
| AU556817B2 (en) * | 1982-02-03 | 1986-11-20 | Efamol Limited | Topical application of a lithium salt and dihomo-alpha- linolenic acid |
| GB2141929B (en) * | 1983-06-16 | 1986-12-17 | 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 |
| US4895727A (en) * | 1985-05-03 | 1990-01-23 | Chemex Pharmaceuticals, Inc. | Pharmaceutical vehicles for exhancing penetration and retention in the skin |
| EP0240098A3 (en) * | 1986-04-04 | 1989-05-10 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Oligo and polysaccharides for the treatment of diseases caused by retroviruses |
| ATE129254T1 (en) * | 1987-03-19 | 1995-11-15 | Arthropharm Pty Ltd | ANTI-INFLAMMATORY AGENTS AND COMPOSITIONS. |
| EP0285357A3 (en) * | 1987-03-31 | 1989-10-25 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Control of retroviruses |
| AU620218B2 (en) * | 1989-02-10 | 1992-02-13 | Taiho Pharmaceutical Co., Ltd. | Anti-hiv drug |
| EP0402078A3 (en) * | 1989-06-06 | 1991-07-31 | Patrick Daniel Kelly | Sexual 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 |
| DE4200499A1 (en) * | 1992-01-10 | 1993-07-15 | Bode Chemie Gmbh & Co | DISINFECTANT |
| JP2571190Y2 (en) * | 1992-10-31 | 1998-05-13 | 株式会社ミヨシ | Hydraulic circuits such as power shovels |
| GB9521805D0 (en) * | 1995-10-25 | 1996-01-03 | Cortecs Ltd | Solubilisation methods |
| US6475526B1 (en) * | 2001-06-05 | 2002-11-05 | Jeffrey B. Smith | Zinc containing compositions for anti-viral use |
| US7968122B2 (en) | 2003-12-10 | 2011-06-28 | Adventrx Pharmaceuticals, Inc. | Anti-viral pharmaceutical compositions |
| EP2283805A1 (en) | 2009-07-28 | 2011-02-16 | Sirvis BV | Compositions comprising a zinc containing compound dissolved in a hydrophobic phase |
| WO2012136218A1 (en) * | 2011-04-04 | 2012-10-11 | Coloplast A/S | An adhesive patch |
| EP3791884A1 (en) | 2019-09-16 | 2021-03-17 | Oskar Bunz | Combination of heparin and magnesium salt for the treatment of viral infections |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LU77562A1 (en) * | 1977-06-17 | 1979-03-26 | Ciba Geigy Ag | METHOD FOR PRODUCING NEW PHARMACEUTICAL PREPARATIONS |
| JPS6225126A (en) * | 1985-07-25 | 1987-02-03 | Matsushita Electric Works Ltd | Addition-type imide resin prepolymer, prepreg and laminated board |
-
1979
- 1979-11-28 EP EP79810167A patent/EP0012115A1/en not_active Withdrawn
- 1979-11-30 CA CA000340999A patent/CA1146859A/en not_active Expired
- 1979-11-30 IT IT50953/79A patent/IT1164070B/en active
- 1979-12-03 AU AU53379/79A patent/AU531882B2/en not_active Ceased
- 1979-12-03 LU LU81944A patent/LU81944A1/en unknown
- 1979-12-03 NZ NZ192294A patent/NZ192294A/en unknown
- 1979-12-03 ZA ZA00796549A patent/ZA796549B/en unknown
- 1979-12-03 SE SE7909952A patent/SE448604B/en not_active IP Right Cessation
- 1979-12-04 JP JP15645879A patent/JPS5579321A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| NZ192294A (en) | 1982-05-31 |
| LU81944A1 (en) | 1980-07-01 |
| IT7950953A0 (en) | 1979-11-30 |
| JPS5579321A (en) | 1980-06-14 |
| AU5337979A (en) | 1980-06-12 |
| ZA796549B (en) | 1980-11-26 |
| IT1164070B (en) | 1987-04-08 |
| JPS6348849B2 (en) | 1988-09-30 |
| AU531882B2 (en) | 1983-09-08 |
| EP0012115A1 (en) | 1980-06-11 |
| SE7909952L (en) | 1980-06-05 |
| CA1146859A (en) | 1983-05-24 |
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