CA1146859A - Pharmaceutical preparations containing zinc - Google Patents
Pharmaceutical preparations containing zincInfo
- Publication number
- CA1146859A CA1146859A CA000340999A CA340999A CA1146859A CA 1146859 A CA1146859 A CA 1146859A CA 000340999 A CA000340999 A CA 000340999A CA 340999 A CA340999 A CA 340999A CA 1146859 A CA1146859 A CA 1146859A
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical preparation
- preparation according
- acceptable salt
- pharmaceutically acceptable
- zinc ions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
Abstract
New Pharmaceutical preparations containing zinc.
Abstract of the Disclosure The invention relates to new pharmaceutical preparations containing zinc for topical administration in the treatment of in-fections caused by herpes viruses, especially those which have been caused by herpes virus hominis, for example of herpes genitalis and herpes dermatitis. The preparations contain as antiviral agent an effective antiviral combination of a pharmaceutically acceptable salt of an acid sulphated polysaccharide or acid sulphated polymer, and zinc ions, and may further contain polyoxyethylene sorbitan mono-laurate and/or -monooleate. They are usual types of preparations for topical administration such as creams, ointments, tinctures, aqueous solutions and, especially, gels.
Abstract of the Disclosure The invention relates to new pharmaceutical preparations containing zinc for topical administration in the treatment of in-fections caused by herpes viruses, especially those which have been caused by herpes virus hominis, for example of herpes genitalis and herpes dermatitis. The preparations contain as antiviral agent an effective antiviral combination of a pharmaceutically acceptable salt of an acid sulphated polysaccharide or acid sulphated polymer, and zinc ions, and may further contain polyoxyethylene sorbitan mono-laurate and/or -monooleate. They are usual types of preparations for topical administration such as creams, ointments, tinctures, aqueous solutions and, especially, gels.
Description
New pharmaceutical preparations containing zinc The invention relates to new pharmaceutical preparations containing zinc for topical administration, especially for the topical treatment of virus infections, which contain an effective antiviral combination of a pharmaceutically acceptable salt of an acid sulphated polysaccharide or acid sulphated polymer, and zinc ions. These pre-parations can be used especially for the topical treatment of in-fections caused by herpes virus hominis (HVH), for example of herpes genitalis and herpes dermatitis.
The surprising discovery has been made that salts of acid sulphated poly~ccharides or of acid sulphated polymers, and zinc ions together exert a strong antiviral action which far exceed8 the sum of the action of each of the individual components. The synergistic action of both components can be ascertained in vitro, i.e. in cell cultures, for example on thebasis of the virus inactivation, of the inhibition of plaque formation and of the virus replication.
1 Inactivation of herpes virus hominis The preparations, mixed in bidistilled water in graduated concentrations, were inoculated with HVH2/Ang. and incubated for 1 hour at 35C. The determination of the virus content in the contact mixtures was made on chicken embryo fibroblasts in the plaque test.
The samples, diluted in Hank's solution with 0.05% of albumin, were added to cell monolayers of chicken embryo fibroblasts. After 90 minutes virus absorptîon, the cultures were washed twice, treated with 4 ml of LY-agar overlay [Hankst solution with 0.5% of lactalbumin hydrolysate and 0.01~ of yeastolate (yeast extract)] and then incu-bated at 35 C until the plaques were counted (36 hours).
The surprising discovery has been made that salts of acid sulphated poly~ccharides or of acid sulphated polymers, and zinc ions together exert a strong antiviral action which far exceed8 the sum of the action of each of the individual components. The synergistic action of both components can be ascertained in vitro, i.e. in cell cultures, for example on thebasis of the virus inactivation, of the inhibition of plaque formation and of the virus replication.
1 Inactivation of herpes virus hominis The preparations, mixed in bidistilled water in graduated concentrations, were inoculated with HVH2/Ang. and incubated for 1 hour at 35C. The determination of the virus content in the contact mixtures was made on chicken embryo fibroblasts in the plaque test.
The samples, diluted in Hank's solution with 0.05% of albumin, were added to cell monolayers of chicken embryo fibroblasts. After 90 minutes virus absorptîon, the cultures were washed twice, treated with 4 ml of LY-agar overlay [Hankst solution with 0.5% of lactalbumin hydrolysate and 0.01~ of yeastolate (yeast extract)] and then incu-bated at 35 C until the plaques were counted (36 hours).
- 2 -Table Ia Preparations, mcgAml :
ZnS04 heparin(sodium salt)*
0 5.10 a) 5.o4 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 are log 10 of the number of PFU (plaque fonming units) per ml.
* 160 IU/mg (Biofac AS, Copenhage~, DeNmark) Table Ib Poly~ulphate salt Concen- ZnS0 ~7H 0 tratlon conc~ntration in ln mcg/ml mcg/~l . 0 11 33 lO0 none 0 6,06 a)5.33 4,98 4.65 Potassium salt 11 5.34 3,20 2.84 2,50 ~ulphate 33 5,27 2,95 2,39 2,27 mol. wel~ht 100 4,78 2.74 2.30 2.17 about 8~10 Sodium salt of 11 5.39 4.72 4.63 3,74 dextran sulphate 33 5 22 4.05 3.32 2,69 of mol. weight of 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 sulphate 33 5.30 4.05 3.62 3.02 of mol. weight 6 100 4.67 3.43 2.95 2.90 of about 2-l0 a) Cp. Table Ia.
1~4613S9 2. Inhibition of the plaque formation of HVH2/Ang. in chicken embryo fibroblasts The cell monolayers were infectet with 100 PFU of HVH VAng.
over the course of 90 minutes. 4 ml of each of the preparations in-corporated in LY-agar overlay (with 5% of sheep serum, 0.5% of OX0-L-28-agar, without diethylaminoethyl dextrane) were atted to the in-fectet cell cultures, which were incubatet at 35~C until the plaques were countet (96 hours).
Table IIa Preparations, mcg/ml :
ZnS04.7H20 ___ _ (sodi~= s: lt)* _ 0 100 a) 82 8776 2-3 b) 2-3 2-3 1-2 ~: _
ZnS04 heparin(sodium salt)*
0 5.10 a) 5.o4 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 are log 10 of the number of PFU (plaque fonming units) per ml.
* 160 IU/mg (Biofac AS, Copenhage~, DeNmark) Table Ib Poly~ulphate salt Concen- ZnS0 ~7H 0 tratlon conc~ntration in ln mcg/ml mcg/~l . 0 11 33 lO0 none 0 6,06 a)5.33 4,98 4.65 Potassium salt 11 5.34 3,20 2.84 2,50 ~ulphate 33 5,27 2,95 2,39 2,27 mol. wel~ht 100 4,78 2.74 2.30 2.17 about 8~10 Sodium salt of 11 5.39 4.72 4.63 3,74 dextran sulphate 33 5 22 4.05 3.32 2,69 of mol. weight of 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 sulphate 33 5.30 4.05 3.62 3.02 of mol. weight 6 100 4.67 3.43 2.95 2.90 of about 2-l0 a) Cp. Table Ia.
1~4613S9 2. Inhibition of the plaque formation of HVH2/Ang. in chicken embryo fibroblasts The cell monolayers were infectet with 100 PFU of HVH VAng.
over the course of 90 minutes. 4 ml of each of the preparations in-corporated in LY-agar overlay (with 5% of sheep serum, 0.5% of OX0-L-28-agar, without diethylaminoethyl dextrane) were atted to the in-fectet cell cultures, which were incubatet at 35~C until the plaques were countet (96 hours).
Table IIa Preparations, mcg/ml :
ZnS04.7H20 ___ _ (sodi~= s: lt)* _ 0 100 a) 82 8776 2-3 b) 2-3 2-3 1-2 ~: _
3 104 65 57 42 1-3 1-2 0.5-1 0 5 __ _ 1-2 0.5-1 0.5 0.5 12 43 0.5 2 2 o.55 o.55 2 1 _ a) Average number of plaques of 3 dishes for each concentration in per cent of the number of plaques in the control test.
b) tiameter of plaques in mm (approx.) * 160 IU/mg (Biofac)~*
** Trade Mark ~146859 Table IIa ___ olysulphate salt Concen- 4 2 tration concentration ln ln mcg/ml . mcg/ml 0 ~ 6 12 24 .
none 0 lOOa) 100 98 57 66 Potass~um salt 1.5 100 89 87 69 57 sulphate 3 88 75 59 48 9 mol. welght 6 43 33 7 5 of about 8~104 .
Sodlum salt of 1.5 102 103 96 81 34 dextran sulphate 3 75 84 77 61 9 of mol. weight of about 5~105 6 52 18 5 1 0 Sodium salt of 1.5 96 96 94 75 52 dextran sulphate 3 92 100 76 61 32 of mol. welght of about 2~106 6 24 19 11 5 a) Cp.Table IIa.
In accordance with the number of the plaques, the diameter of the plaques decreased also from 2 to 3 mm in the control test to < 0.5 mm in the tests with the most active combinations.
3. Inhibition of the replication of H ~ . in VERO cells on pre-infective commencement of treatment . . .
Confluent monolayers of VERO cells were washed with F15-medium [Minimum Essential Medium (Eagle), Gibco Bio-Cult Ltd., Paisley, Scotland], and then covered with 4 ml of each of ~he different concentrations of the preparations in F15 medium. The cul-tures were infected after 60 minutes with 1000 PFU of HVH2/Ang.in 0.1 ml of medium. After an incubation of 20 hours at 35C, the state of the cells was assessed microscopically and the virus content of the cell lysates (cells with 1 ml of bidistilled water, deep frozen twice and thawed) tetermined by titration on chicken embryo fibro-blasts (evaluation of the plaque formation).
Table III
Preparations, mcg/ml : heparin (sodium salt)*
b) tiameter of plaques in mm (approx.) * 160 IU/mg (Biofac)~*
** Trade Mark ~146859 Table IIa ___ olysulphate salt Concen- 4 2 tration concentration ln ln mcg/ml . mcg/ml 0 ~ 6 12 24 .
none 0 lOOa) 100 98 57 66 Potass~um salt 1.5 100 89 87 69 57 sulphate 3 88 75 59 48 9 mol. welght 6 43 33 7 5 of about 8~104 .
Sodlum salt of 1.5 102 103 96 81 34 dextran sulphate 3 75 84 77 61 9 of mol. weight of about 5~105 6 52 18 5 1 0 Sodium salt of 1.5 96 96 94 75 52 dextran sulphate 3 92 100 76 61 32 of mol. welght of about 2~106 6 24 19 11 5 a) Cp.Table IIa.
In accordance with the number of the plaques, the diameter of the plaques decreased also from 2 to 3 mm in the control test to < 0.5 mm in the tests with the most active combinations.
3. Inhibition of the replication of H ~ . in VERO cells on pre-infective commencement of treatment . . .
Confluent monolayers of VERO cells were washed with F15-medium [Minimum Essential Medium (Eagle), Gibco Bio-Cult Ltd., Paisley, Scotland], and then covered with 4 ml of each of ~he different concentrations of the preparations in F15 medium. The cul-tures were infected after 60 minutes with 1000 PFU of HVH2/Ang.in 0.1 ml of medium. After an incubation of 20 hours at 35C, the state of the cells was assessed microscopically and the virus content of the cell lysates (cells with 1 ml of bidistilled water, deep frozen twice and thawed) tetermined by titration on chicken embryo fibro-blasts (evaluation of the plaque formation).
Table III
Preparations, mcg/ml : heparin (sodium salt)*
4- 2 0 6 0 4,58 1)1.84 6 3.59 < 1.00 12 3.32 < 1.00 2.82 1.00 1) Log 10 PFU/ml cell lysate * 160 IU/mg (Biofac) Conclusions trawn from the results of the three series of tests In the above experimental procedures, the synergistic action of the combinations of zinc sulphate (ZnS04.7H20) and heparin sodium salt of the present invention is evident from the results given in Tables Ia, IIa and III. Especially noteworthy in the virus inactivation according to Table Ia is the fact that each component by itself in all tested concentration2 was virtually inactive, whereas the combination of one third of the maximum concentration of each of the individual components reduced the virus content of the chicken embryo fibroblasts by 10 . Table IIa shows, inter alia, that heparin sodium salt by itself has only a weak action, but both heparin sodium salt and zinc sulphate in the lowest concentration, together with each concentration of the second component, have a stronger action than the next highe~t concentration of the second component by it-self. The action of 25 mcg/ml of zinc sulphate by itself is achieved with the combination of 6 mcg/ml of zinc sulphate ant 3 mcg/ml of heparin sotium salt, ant the action of the combination of 25 mcg/ml of zinc sulphate and 6 mcg/ml of heparin sodium salt is almost achieved with 6 mcg/ml of zinc sulphate ant 6 mcg/ml of heparin sodium salt ant also with 12 mcg/ml of zinc sulphate and 3 mcg/ml of heparin sodium salt. Table III shows that the virus replication is only derately inhibited by zinc sulphate in the highest concentration of 25 mcg/ml, but, on account of the s~rong absorption inhibiting action of heparin sodium salt, is clearly inhibited by heparin in the single tested concentration of 6 mcg/ml, corresponding to the highest concentration in the other test series. All tested combinations, how-ever, exhibit an action at least 10 times stronger than that of the single components.
From the test results given in Tables Ib and IIb, the synergistic action of the combinations of zinc sulphate (ZnS04.7H20) with the sodium salts of two textran sulphates of tifferent lecular weight ant with the potassium salt of polyvinyl sulfate accorting to the present invention is also evitent. ~specially noteworthy in the results of the virus inactivation accorting to Table Ib is the fact that each component by itself in the highest tested concentra-tion of 100 mcg/ml reduced the virus content of the chicken embryo fibroblasts by about 101-5, i.e. to the same extent as or less than the combinations of one ninth of the maximum concentrations of the intividual components, and that the combination~ of one thirt of the maximum concentrations of each of the intividual component~ reduced the virus content by about 10 to 10 5.
From Table IIb it can be seen that the effect of the polysulphate salts which by themselves do not show strong activity even in the highest concentration of 6 mcg/ml, is much increased , .
~46859 by the addition of zinc sulphate in the concentrations of 6 and 12 mcg/ml which by themselves are inactive or almost inactive.
4. Activity against herpes genitalis caused by intravaginal infection with HVH2/An~.in emale guinea pigs.
It is also possible to determine the synergistic effect of the combined active substances in vivo, in the treatment ~ommencing 72 hours after infection (stage of clear symptoms), of female guinea pig8 with herpes genitalis caused by intravaginal infection with HVH2~Ang., according to the method described by B. Lukas et al., Arch.
Ges. Virusforsch. 44, 153-155 (1974) and 49, 1-11 (1975). The results of corresponding double blind tests are given in the following table IV, ~146859 Table IV
Effect on local symptoms b) ~. :
Preparation ~ Animals with % Animals free Para Ex-No. H Z a) regression of symptoms lysi itus IU/g ~ ~66% at day at day _ 4 7 911- 9 1114 18 25 _ 1 ~ _ _c 108 0 0 3 6 2 3 5 9 15 39 24 2 _ _d 35 011 1737 14 2540 48 Sl 23 11 3 32 _ 8 0 0 2537 0 1225 37 62 0 0 g 160 _ 36 011 3961 30 3041 58 66 8 3 _ 0.5 10 0 0 1010 0 1030 50 70 20 0 6 _ 1.0 18 0 5 517 0 1728 33 33 11 5 7 32 0.5 10 10 1030 40 010 50 40 40 20 0 8 32 1.0 10 0 0 3020 20 2030 50 80 0 0 9 160 0.5 19 0 5 8494 53 729~ 94 94 10 5 10160 1.0 4~ 637 6387 43 7478 87 90 4 0 H = H y in scdium salt, 160 IU/mg (Biofac) Z ZnS04 7H2 a) Numbers of animals~ 10 are total numbers of test animals of several tests wlth groups of 8 or 10 anlmals b) Day 0 ls day of start of treatment 72 hours after ln-fection. The treatment consists in intravaginal admini-stratlon of 0.1 ml of the preparation to be tested twlce per day for 5 subsequent days c) Control animals recelving no treatment d) Control animals treated with gei base used for all preparationsand containing 0.1 % polyoxyethylene sor-bitan monooleate.
From the test results given in Tables Ib and IIb, the synergistic action of the combinations of zinc sulphate (ZnS04.7H20) with the sodium salts of two textran sulphates of tifferent lecular weight ant with the potassium salt of polyvinyl sulfate accorting to the present invention is also evitent. ~specially noteworthy in the results of the virus inactivation accorting to Table Ib is the fact that each component by itself in the highest tested concentra-tion of 100 mcg/ml reduced the virus content of the chicken embryo fibroblasts by about 101-5, i.e. to the same extent as or less than the combinations of one ninth of the maximum concentrations of the intividual components, and that the combination~ of one thirt of the maximum concentrations of each of the intividual component~ reduced the virus content by about 10 to 10 5.
From Table IIb it can be seen that the effect of the polysulphate salts which by themselves do not show strong activity even in the highest concentration of 6 mcg/ml, is much increased , .
~46859 by the addition of zinc sulphate in the concentrations of 6 and 12 mcg/ml which by themselves are inactive or almost inactive.
4. Activity against herpes genitalis caused by intravaginal infection with HVH2/An~.in emale guinea pigs.
It is also possible to determine the synergistic effect of the combined active substances in vivo, in the treatment ~ommencing 72 hours after infection (stage of clear symptoms), of female guinea pig8 with herpes genitalis caused by intravaginal infection with HVH2~Ang., according to the method described by B. Lukas et al., Arch.
Ges. Virusforsch. 44, 153-155 (1974) and 49, 1-11 (1975). The results of corresponding double blind tests are given in the following table IV, ~146859 Table IV
Effect on local symptoms b) ~. :
Preparation ~ Animals with % Animals free Para Ex-No. H Z a) regression of symptoms lysi itus IU/g ~ ~66% at day at day _ 4 7 911- 9 1114 18 25 _ 1 ~ _ _c 108 0 0 3 6 2 3 5 9 15 39 24 2 _ _d 35 011 1737 14 2540 48 Sl 23 11 3 32 _ 8 0 0 2537 0 1225 37 62 0 0 g 160 _ 36 011 3961 30 3041 58 66 8 3 _ 0.5 10 0 0 1010 0 1030 50 70 20 0 6 _ 1.0 18 0 5 517 0 1728 33 33 11 5 7 32 0.5 10 10 1030 40 010 50 40 40 20 0 8 32 1.0 10 0 0 3020 20 2030 50 80 0 0 9 160 0.5 19 0 5 8494 53 729~ 94 94 10 5 10160 1.0 4~ 637 6387 43 7478 87 90 4 0 H = H y in scdium salt, 160 IU/mg (Biofac) Z ZnS04 7H2 a) Numbers of animals~ 10 are total numbers of test animals of several tests wlth groups of 8 or 10 anlmals b) Day 0 ls day of start of treatment 72 hours after ln-fection. The treatment consists in intravaginal admini-stratlon of 0.1 ml of the preparation to be tested twlce per day for 5 subsequent days c) Control animals recelving no treatment d) Control animals treated with gei base used for all preparationsand containing 0.1 % polyoxyethylene sor-bitan monooleate.
5~
The results of the comparative tests show that administration of either heparin sodium salt or zinc ions alone as active ingredient in a suitable gel base gives rise to only a moderate increase of the beneficial effect of ~he gel base alone, as is demonstrated by the fact that, at most, about 70~ of the test animals are free of symptoms at the end of the test period when already about 50~ of the animals treated with the gel base are free of symptoms. In contradistinction thereto, the combined administration of zinc ions and heparin sodium salt within the range of concentration according to the invention re-sults in al st a complete cure of the experimental disease, with 18 out of 19, or 42 out of 46, test animals respectively, i.e. at least 90%, being free of symptoms at the end of the test period. Moreover, the early onset of the curative action perceptible after administration of the higher dosage of heparin sodium salt alone is also markedly en-hanced after administration of the combination, although after the administration of zinc ions alone the onset of the action i8 slow.
The synergistic action of the above active substances is further increased by using a preparation base, especially a gel base, which contains one or re polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monostearate and/or, in particular, polyoxyethylene sorbitan nolaurate, or st preferably, polyoxy-ethylene sorbitan nooleate.
The pharmaceutical preparations of the present invention con-tain the above defined active substances preferably in combination with pharmaceutical adjuvants suitable for topical application. Suit-able formulations of preparations of the invention are in particular tinctures, solutions, creams, ointments and, especially, gels.
Tinctures and solutions generally have an aqueous ethanolic base to which are added, inter alia, polyalcohols, for example propylene glycol or glycerin, and/or lower polyethylene glycols, 1146~59 as humectants for reducing water loss, and fat-restoring substances, such as fatty acid esters of lower polyethylene glycols, i.e. lipo-philic substances which are soluble in the aqueous-ethanolic mixture as substitute for fatty substances which are taken from the ~kin with the ethanol, and, if necessary, other assistants and adjuvants, in addition to conventional preservatives, such as those mentioned herein-below, for example also the polyoxyethylene sorbitan fatty acid esters already mentioned, such as polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monooleate.
Creams are oil-in-water emulsions which contain more than 50% of water. Fatty alcohols are chiefly used as oleaginous base, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to ~olid waxes, for example iso-propyl myristinate, wool wax or bees-wax, and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with primarily hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerin fatty acids or polyoxyethylene sorbitan fatty acid esters (Tweens); polyoxyethylene fatty alcohol ethers or esters;
or corre~ponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are customarily u~ed in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the water phase include agents which reduce water loss through evaporation, for example polyalcohols, such as glycerin, sorbitol propylene glycol and/or polyethylene glycols, as well as preservatives, perfumes etc.
Ointments are water-in-oil emul~ion~ which contain up to 70%, preferably however about 20% to about 50%, of water or aqueous phase. The oleaginous phase comprises chiefly hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which 11~6~59 contain preferably hydroxy compounds suitable for improving the water-absorption, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans~, for example sorbitan oleate and/or sorbitan isostearate. Additives to the water phase include humectants, such as polyalcohols, for example glycerin, propylene glycol, sorbitol and/
or polyethylene glycol, and preservatives, perfumes etc.
~ Gels are in particular aqueous solutions of the active sub-stances in which gel formers, preferably those of the group of cellulose ethers, for example methyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose, or of the vegetable hydrocolloids, such as sodium alginate, tragacanth or gum arabic, are disperset and swelled. The gels preferably also contain in addition humectants from the group of the polyalcohols, such as propylene glycol, glycerin and~or lower polyethylene glycols, as well as wetting agents, for example polyoxyethylene sorbitan fatty acid esters, such as polyoxy-ethylene sorbitan monostearate, monolaurate or monooleate, in con-centrations of about 0.02 to 5%. As further adjuvants, the gels con-tain conventional preservatives, for exsmple benzyl alcohol, phen-ethyl alcohol, phenoxyethanol, lower alkyl esters of p-hydroxy-benzoic acid such as the methyl and~or propyl esters, sorbic acid or organic mercury compounds such as merthiolate.
In addition to containing the conventional preservatives, the preparations of the present invention can also contain further biological, for example antiphlogistic or antimicrobial, such as anti-bacterial, antifungal or also antiviral, active substances, for e~ample flumethasone, neomycin, gentamycin, lactic scid or mikonazole.
The preparations of the invention are formulated in a manner which is in itself known.
* Trade ~lark ~1~685~
The antiviral preparations for topical administration applica-tion according to the present invention contain a pharmaceutically acceptable salt of an acid sulphated polysaccharide or acid sulphated polymer, such as a corresponding salt of heparin, and zinc ions, in a ratio of 1 mg to 0.18 up to 18 mg, especially of 1 mg to 0.18 up to 4.5 mg, and optionally in addition at least one surface active agent selected from polyoxyethylene sorbitan monolaurate and polyoxyethylene sorbitan monooleate. For salts of heparin, the above amounts refer to that having 160 IU/mg; equal IU amounts of salts of other heparin will be used. The zinc ions are added in the fo-;m of the corresponding amounts of a dissociable zinc compound, for example of 0.8 to 80 mg9 or 0.8 to 20 mg respectively of ZnS04.7H20. Corresponding preparations for topical application, especially gels, and also tinctures, aqueous solutions, creams or ointments, contain for example, per gram or millilitre, 0.1 to 5 mg, in particular 0.25 to 3 mg of a pharmaceuti-cally acceptable salt of an acid sulphated polysaccharide or acid su]fated polymer, corresponding to 16 to 800 IU, in partic~lar to 40 to 480 IU of a corresponding salt of heparin, and 0.18 to 18 mg of zinc ions, corresponding for example to about 0.8 to 80 mg of ZnS04.7H20, and optionally in addition 0.2 to 50 mg of st least one surface active agent selected from polyoxyethylene sorbitan mono-laurate and polyoxyethylene sorbitan monooleate.
A content of 80 to 320 IV of a pharmaceutically acceptable salt of heparin, 0.45 to 4.5 mg of zinc ions and optionally in addi-tion 0.5 to 10 mg of at least one surface active agent selected from polyoxyethylene sorbitan monolaurate and/or polyoxyethylene sorbitan monooleate, per gram or millilitre, is particularly preferred.
Instead of a pharmaceutically acceptable salt of heparin, it is also possible to use an equally effective antiviral amount of a corresponding salt of another acid sulphated polysaccharide or of an acid sulphated polymer, e.g. of one of those mentioned below, in particular a corresponding salt of dextran sulphate or polyvinyl sulphate respectively. A content of 0.25 to 2.0 mg, per gram or ml, is particularly preferred.
11~68S9 By acid sulphated polysaccharides are understood poly-saccharides wherein monovalent sulphuric acid radicals -S02-OH are linked with oxygen atoms ant/or, if present, as in the case of heparin, nitrogen atoms. Such acid sulphated polysaccharides may be of natural origin, such as heparin, chondroitin sulphate (chondroitinsulphuric acid) or carregheenan,or may be obtained by sulphation of natural or partially degraded polysaccharides, such as sulphated amylopectins, sulphated dextrans, sulphated polyglucoses or sulphated polypentoses.
These polysulphates are used in the form of suitable pharmaceutically acceptable salts, such as e.g. potassium and especially sodium salts.
Special reference is made in this regard to the sodium salt of heparin as the commonly used commercial form of heparin, also the potassium salt ant the magnesium salt of heparin, the sodium salts of dextran sulphates of various molecular weightB. Acid sulphated poly-mers are sulphation protucts of polymers containing hytroxy groups, such as e.g. acid sulphated polyvinyl alcohols (polyvinyl sulphates), of various molecular weights, ~hich againare used in the form of a pharmaceutically acceptable salt, such as the sotium or, above all, the potassium salts. Quite generally the sotium ant potassium salts are of special importance.
Instead of being added in the form of zinc sulphate, the zinc ions can also be added in the form of another dissociable zinc com-pount, for example zinc chloride, zinc acetate or zinc citrate, or of the zinc salt of an acid or another substance of acidic character and having its own biological, for example antibacterial or anti-phlogistic, properties, for example zinc sudoxicam (zinc salt of 4-hydroxy-2-methyl-N-(2-thiazolyl)-1,2-benzothiazine-3-carboxamide-l,l-dioxide). It is not necessary, that the zinc salt used be com pletely dissociated in the carrier-medium; it suffices if an amount of zinc ions with;n the range of concentration given above is present together with the untissociated salt.
~14685~
The preparations of the present invention are especially suit-able for the treatment of herpes genitalis, herpes dermatitis and herpes labialis. For treating the first two infections, gels formulated according to the invention are applied as early as po~sible, for example from a tube or dispenser, 2 to 3 times daily, and for treating herpes labialis, are applied several times daily to the infected parts of the body until the symptoms disappear and the infection heals. Aqueous solutions formulated according to the inven-tion can be used for example for washing infected body cavities, especially for treatin8 herpes gingivostomatitis or herpes kerato-conjunctivitis.
The following Examples describe the manufacture of typical formulations, without implying any re~triction of the scope of the invention.
1146~3S~
Example l: To prepare 10 litres of gel, 200 g of highly viscous sodium carboxymethyl cellulose and 50 g of polyoxyethylene sorbitan mono-stearate (T'~EEN 60)*are mixed with 1000 g of glycerin and 6.5 litres of aqua conservans and the mixture is allowed to swell to a homo-geneous mucilage. Then a solution of 1.6-106 international units of sodium salt of heparin (e.g. 10 g of heparin Biofac), 50.0 g of zinc sulphate heptahydrate and 10 g of polyoxyethylene sorbitan monooleate (TWEEN 80)*in 2 litres of aqua conservans is added. Finally, the mix-ture is bulked to 10 litres with aqua conservans, carefully mixed and tubes are filled with the resulting gel.
By aqua conservans is meant an aqueous solution of 0.07% of p-hytroxybenzoic acid methyl ester (methyl paraben) and 0.03% of p-hytroxybenzoic acid propyl ester (propyl paraben). TWEEN 60 and TWEEN 80*are registered trademarks of ICI of America Inc., Stamford, Connecticut 06904.
Instead of u~ing 50.0 g of ZnS04.7H20, it is also possible to use 100.0 g and to repeat the above procedure.
Example 2: The procedure of Example 1 i9 repeated, using instead of heparin 5.0 g of the sodium salt of dextran sulphate of a lecular weight of about 4.8-104.
Example 3: The procedure of Example 1 i9 repeated, using instead of heparin 2.5 g of the sodium salt of dextran sulphate of the molecular weight of about 2~106.
ExamDle 4: The procedure of Example 1 is repeated, using instead of heparin 2.5 g of the potassium salt of polyvinyl sulphate of a mole-cular weight of abou~ 8-10 .
* Trade ~lar~
,~
:1146859 Example 5: To prepare 10 litres of gel, 200 g of highly viscous sodium carboxymethyl cellulose and 50 g of polyoxyethylene sorbitan mono-stearate (TWEEN 60, cp. Example l)are mixed with 1000 g of glycerin and 6.5 litres of aqua conservans (cp. Example 1) and the mixture is allowed to swell to a homogeneous mucilage. Then a solution of 5.0 g of sodium salt of dextran sulphate of a molecular weight of about 5.105, 50.0 g of zinc sulphate heptahydrate and 10 g of polyoxy-ethylene sorbitan nooleate (TWEEN 80, cp. Example l) in 2 litres of aqua conservans is added. Finally, the mixture is bulked to 10 litres with aqua conservans, carefully mixed and tubes are filled with the resulting gel.
The results of the comparative tests show that administration of either heparin sodium salt or zinc ions alone as active ingredient in a suitable gel base gives rise to only a moderate increase of the beneficial effect of ~he gel base alone, as is demonstrated by the fact that, at most, about 70~ of the test animals are free of symptoms at the end of the test period when already about 50~ of the animals treated with the gel base are free of symptoms. In contradistinction thereto, the combined administration of zinc ions and heparin sodium salt within the range of concentration according to the invention re-sults in al st a complete cure of the experimental disease, with 18 out of 19, or 42 out of 46, test animals respectively, i.e. at least 90%, being free of symptoms at the end of the test period. Moreover, the early onset of the curative action perceptible after administration of the higher dosage of heparin sodium salt alone is also markedly en-hanced after administration of the combination, although after the administration of zinc ions alone the onset of the action i8 slow.
The synergistic action of the above active substances is further increased by using a preparation base, especially a gel base, which contains one or re polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monostearate and/or, in particular, polyoxyethylene sorbitan nolaurate, or st preferably, polyoxy-ethylene sorbitan nooleate.
The pharmaceutical preparations of the present invention con-tain the above defined active substances preferably in combination with pharmaceutical adjuvants suitable for topical application. Suit-able formulations of preparations of the invention are in particular tinctures, solutions, creams, ointments and, especially, gels.
Tinctures and solutions generally have an aqueous ethanolic base to which are added, inter alia, polyalcohols, for example propylene glycol or glycerin, and/or lower polyethylene glycols, 1146~59 as humectants for reducing water loss, and fat-restoring substances, such as fatty acid esters of lower polyethylene glycols, i.e. lipo-philic substances which are soluble in the aqueous-ethanolic mixture as substitute for fatty substances which are taken from the ~kin with the ethanol, and, if necessary, other assistants and adjuvants, in addition to conventional preservatives, such as those mentioned herein-below, for example also the polyoxyethylene sorbitan fatty acid esters already mentioned, such as polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monooleate.
Creams are oil-in-water emulsions which contain more than 50% of water. Fatty alcohols are chiefly used as oleaginous base, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to ~olid waxes, for example iso-propyl myristinate, wool wax or bees-wax, and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with primarily hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerin fatty acids or polyoxyethylene sorbitan fatty acid esters (Tweens); polyoxyethylene fatty alcohol ethers or esters;
or corre~ponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are customarily u~ed in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the water phase include agents which reduce water loss through evaporation, for example polyalcohols, such as glycerin, sorbitol propylene glycol and/or polyethylene glycols, as well as preservatives, perfumes etc.
Ointments are water-in-oil emul~ion~ which contain up to 70%, preferably however about 20% to about 50%, of water or aqueous phase. The oleaginous phase comprises chiefly hydrocarbons, for example petroleum jelly, paraffin oil and/or hard paraffins, which 11~6~59 contain preferably hydroxy compounds suitable for improving the water-absorption, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans~, for example sorbitan oleate and/or sorbitan isostearate. Additives to the water phase include humectants, such as polyalcohols, for example glycerin, propylene glycol, sorbitol and/
or polyethylene glycol, and preservatives, perfumes etc.
~ Gels are in particular aqueous solutions of the active sub-stances in which gel formers, preferably those of the group of cellulose ethers, for example methyl cellulose, hydroxyethyl cellulose or carboxymethyl cellulose, or of the vegetable hydrocolloids, such as sodium alginate, tragacanth or gum arabic, are disperset and swelled. The gels preferably also contain in addition humectants from the group of the polyalcohols, such as propylene glycol, glycerin and~or lower polyethylene glycols, as well as wetting agents, for example polyoxyethylene sorbitan fatty acid esters, such as polyoxy-ethylene sorbitan monostearate, monolaurate or monooleate, in con-centrations of about 0.02 to 5%. As further adjuvants, the gels con-tain conventional preservatives, for exsmple benzyl alcohol, phen-ethyl alcohol, phenoxyethanol, lower alkyl esters of p-hydroxy-benzoic acid such as the methyl and~or propyl esters, sorbic acid or organic mercury compounds such as merthiolate.
In addition to containing the conventional preservatives, the preparations of the present invention can also contain further biological, for example antiphlogistic or antimicrobial, such as anti-bacterial, antifungal or also antiviral, active substances, for e~ample flumethasone, neomycin, gentamycin, lactic scid or mikonazole.
The preparations of the invention are formulated in a manner which is in itself known.
* Trade ~lark ~1~685~
The antiviral preparations for topical administration applica-tion according to the present invention contain a pharmaceutically acceptable salt of an acid sulphated polysaccharide or acid sulphated polymer, such as a corresponding salt of heparin, and zinc ions, in a ratio of 1 mg to 0.18 up to 18 mg, especially of 1 mg to 0.18 up to 4.5 mg, and optionally in addition at least one surface active agent selected from polyoxyethylene sorbitan monolaurate and polyoxyethylene sorbitan monooleate. For salts of heparin, the above amounts refer to that having 160 IU/mg; equal IU amounts of salts of other heparin will be used. The zinc ions are added in the fo-;m of the corresponding amounts of a dissociable zinc compound, for example of 0.8 to 80 mg9 or 0.8 to 20 mg respectively of ZnS04.7H20. Corresponding preparations for topical application, especially gels, and also tinctures, aqueous solutions, creams or ointments, contain for example, per gram or millilitre, 0.1 to 5 mg, in particular 0.25 to 3 mg of a pharmaceuti-cally acceptable salt of an acid sulphated polysaccharide or acid su]fated polymer, corresponding to 16 to 800 IU, in partic~lar to 40 to 480 IU of a corresponding salt of heparin, and 0.18 to 18 mg of zinc ions, corresponding for example to about 0.8 to 80 mg of ZnS04.7H20, and optionally in addition 0.2 to 50 mg of st least one surface active agent selected from polyoxyethylene sorbitan mono-laurate and polyoxyethylene sorbitan monooleate.
A content of 80 to 320 IV of a pharmaceutically acceptable salt of heparin, 0.45 to 4.5 mg of zinc ions and optionally in addi-tion 0.5 to 10 mg of at least one surface active agent selected from polyoxyethylene sorbitan monolaurate and/or polyoxyethylene sorbitan monooleate, per gram or millilitre, is particularly preferred.
Instead of a pharmaceutically acceptable salt of heparin, it is also possible to use an equally effective antiviral amount of a corresponding salt of another acid sulphated polysaccharide or of an acid sulphated polymer, e.g. of one of those mentioned below, in particular a corresponding salt of dextran sulphate or polyvinyl sulphate respectively. A content of 0.25 to 2.0 mg, per gram or ml, is particularly preferred.
11~68S9 By acid sulphated polysaccharides are understood poly-saccharides wherein monovalent sulphuric acid radicals -S02-OH are linked with oxygen atoms ant/or, if present, as in the case of heparin, nitrogen atoms. Such acid sulphated polysaccharides may be of natural origin, such as heparin, chondroitin sulphate (chondroitinsulphuric acid) or carregheenan,or may be obtained by sulphation of natural or partially degraded polysaccharides, such as sulphated amylopectins, sulphated dextrans, sulphated polyglucoses or sulphated polypentoses.
These polysulphates are used in the form of suitable pharmaceutically acceptable salts, such as e.g. potassium and especially sodium salts.
Special reference is made in this regard to the sodium salt of heparin as the commonly used commercial form of heparin, also the potassium salt ant the magnesium salt of heparin, the sodium salts of dextran sulphates of various molecular weightB. Acid sulphated poly-mers are sulphation protucts of polymers containing hytroxy groups, such as e.g. acid sulphated polyvinyl alcohols (polyvinyl sulphates), of various molecular weights, ~hich againare used in the form of a pharmaceutically acceptable salt, such as the sotium or, above all, the potassium salts. Quite generally the sotium ant potassium salts are of special importance.
Instead of being added in the form of zinc sulphate, the zinc ions can also be added in the form of another dissociable zinc com-pount, for example zinc chloride, zinc acetate or zinc citrate, or of the zinc salt of an acid or another substance of acidic character and having its own biological, for example antibacterial or anti-phlogistic, properties, for example zinc sudoxicam (zinc salt of 4-hydroxy-2-methyl-N-(2-thiazolyl)-1,2-benzothiazine-3-carboxamide-l,l-dioxide). It is not necessary, that the zinc salt used be com pletely dissociated in the carrier-medium; it suffices if an amount of zinc ions with;n the range of concentration given above is present together with the untissociated salt.
~14685~
The preparations of the present invention are especially suit-able for the treatment of herpes genitalis, herpes dermatitis and herpes labialis. For treating the first two infections, gels formulated according to the invention are applied as early as po~sible, for example from a tube or dispenser, 2 to 3 times daily, and for treating herpes labialis, are applied several times daily to the infected parts of the body until the symptoms disappear and the infection heals. Aqueous solutions formulated according to the inven-tion can be used for example for washing infected body cavities, especially for treatin8 herpes gingivostomatitis or herpes kerato-conjunctivitis.
The following Examples describe the manufacture of typical formulations, without implying any re~triction of the scope of the invention.
1146~3S~
Example l: To prepare 10 litres of gel, 200 g of highly viscous sodium carboxymethyl cellulose and 50 g of polyoxyethylene sorbitan mono-stearate (T'~EEN 60)*are mixed with 1000 g of glycerin and 6.5 litres of aqua conservans and the mixture is allowed to swell to a homo-geneous mucilage. Then a solution of 1.6-106 international units of sodium salt of heparin (e.g. 10 g of heparin Biofac), 50.0 g of zinc sulphate heptahydrate and 10 g of polyoxyethylene sorbitan monooleate (TWEEN 80)*in 2 litres of aqua conservans is added. Finally, the mix-ture is bulked to 10 litres with aqua conservans, carefully mixed and tubes are filled with the resulting gel.
By aqua conservans is meant an aqueous solution of 0.07% of p-hytroxybenzoic acid methyl ester (methyl paraben) and 0.03% of p-hytroxybenzoic acid propyl ester (propyl paraben). TWEEN 60 and TWEEN 80*are registered trademarks of ICI of America Inc., Stamford, Connecticut 06904.
Instead of u~ing 50.0 g of ZnS04.7H20, it is also possible to use 100.0 g and to repeat the above procedure.
Example 2: The procedure of Example 1 i9 repeated, using instead of heparin 5.0 g of the sodium salt of dextran sulphate of a lecular weight of about 4.8-104.
Example 3: The procedure of Example 1 i9 repeated, using instead of heparin 2.5 g of the sodium salt of dextran sulphate of the molecular weight of about 2~106.
ExamDle 4: The procedure of Example 1 is repeated, using instead of heparin 2.5 g of the potassium salt of polyvinyl sulphate of a mole-cular weight of abou~ 8-10 .
* Trade ~lar~
,~
:1146859 Example 5: To prepare 10 litres of gel, 200 g of highly viscous sodium carboxymethyl cellulose and 50 g of polyoxyethylene sorbitan mono-stearate (TWEEN 60, cp. Example l)are mixed with 1000 g of glycerin and 6.5 litres of aqua conservans (cp. Example 1) and the mixture is allowed to swell to a homogeneous mucilage. Then a solution of 5.0 g of sodium salt of dextran sulphate of a molecular weight of about 5.105, 50.0 g of zinc sulphate heptahydrate and 10 g of polyoxy-ethylene sorbitan nooleate (TWEEN 80, cp. Example l) in 2 litres of aqua conservans is added. Finally, the mixture is bulked to 10 litres with aqua conservans, carefully mixed and tubes are filled with the resulting gel.
Claims (21)
1. Pharmaceutical preparation containing zinc for topical ad-ministration which contains an effective antiviral combination of a pharmaceutically acceptable salt of an acid sulphated polysaccharide or acid sulphated polymer and zinc ions in a ratio of 1 mg to 0.18 up to 18 mg.
2. Pharmaceutical preparation according to claim 1 in the form of a gel, cream, ointment, tincture or aqueous solution.
3. Pharmaceutical preparation according to claim 1 which additionally contains at least one surface active agent selected from polyoxyethylene sorbitan monolaurate and polyoxyethylene sorbitan monooleate.
4. Pharmaceutical preparation according to claim 1 which contains a pharmaceutically acceptable salt of an acid sulphated poly-saccharide or acid sulphated polymer and zinc ions in a ratio of 1 mg to 0.18 mg up to 4.5 mg.
5. Pharmaceutical preparation according to claim 1 which con-tains a pharmaceutically acceptable salt of heparin and zinc ions in a ratio of 160 IU up to 0.18 to 18 mg.
6. Pharmaceutical preparation according to claim 1 which con-tains, per gram or millilitre, 0.1 to 5 mg of a pharmaceutically acceptable salt of an acid sulphated polysaccharide or acid sul-phated polymer and 0.18 to 18 mg of zinc ions.
7. Pharmaceutical preparation according to claim 1 which contains, per gram or millilitre, 0.25 to 3 mg of a pharmaceuti-cally acceptable salt of an acid sulphated polysaccharide or acid sulphated polymer and 0.18 to 18 mg of zinc ions.
8. Pharmaceutical preparation according to claim 1 which con-tains, per gram or millilitre, 16 to 800 IU of a pharmaceutically acceptable salt of heparin and 0.18 to 18 mg of zinc ions.
9. Pharmaceutical preparation according to claim 8 which con-tains, per gram or millilitre, 40 to 480 IU of a pharmaceutically acceptable salt of heparin and 0.18 to 18 mg of zinc ions.
10. Pharmaceutical preparation according to claim 8 which contains 80 to 320 IU of a pharmaceutically acceptable salt of heparin, and 0.45 to 4.5 mg of zinc ions.
11. Pharmaceutical preparation according to any one of claims 5, 9 and 10, which contains the sodium salt of heparin as its pharmaceutically acceptable salt.
12. Pharmaceutical preparation according to claim 1 which con-tains, per gram or millilitre, 0.1 to 5.0 mg of a pharmaceutically acceptable salt of dextran sulphate and 0.18 to 18 mg of zinc ions.
13. Pharmaceutical preparation according to claim 12 which con-tains, per gram or millilitre, 0.25 to 3.0 mg of a pharmaceutically acceptable salt of dextran sulphate and 0.18 to 18 mg of zinc ions.
14. Pharmaceutical preparation according to claim 12 which con-tains, per gram or millilitre, 0.25 to 2.0 mg of a pharmaceutically acceptable salt of dextran sulphate and 0.45 to 4.5 mg of zinc ions.
15. Pharmaceutical preparation according to claim 1 which con-tains, per gram or millilitre, 0.1 to 5.0 mg of a pharmaceutically acceptable salt of polyvinyl sulphate and 0.18 to 18 mg of zinc ions.
16. Pharmaceutical preparation according to claim 15 which con-tains, per gram or millilitre, 0.25 to 3.0 mg of a pharmaceutically acceptable salt of polyvinyl sulphate and 0.18 to 18 mg of zinc ions.
17. Pharmaceutical preparation according to claim 15 which con-tains, per gram or millilitre, 0.25 to 2.0 mg of a pharmaceutically acceptable salt of polyvinyl sulphate and 0.45 to 4.5 mg of zinc ions.
18. Pharmaceutical preparation according to any one of claims 1, 4 and 6, which contains sodium or potassium salt as pharmaceutically acceptable salt of an acid sulphated polysaccharide or acid sulphated polymer.
19. Pharmaceutical preparation according to any one of claims 1, 4 and 6 to which the zinc ions are added in the form of ZnSO4.7H2O
as dissociable zinc compound.
as dissociable zinc compound.
20. Pharmaceutical preparation according to any one of claims 1, 4 and 6 which additionally contains, per gram or millilitre, 0.2 to 50 mg of a surface active agent selected from polyoxyethylene sorbi-tan monolaurate and polyoxyethylene sorbitan monooleate.
21. Pharmaceutical preparation according to any one of claims 1, 4 and 6 which additionally contains, per gram or millilitre, 0.5 to 10 mg of a surface active agent selected from polyoxyethylene sorbitan monolaurate and polyoxyethylene sorbitan monooleate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1236078 | 1978-12-04 | ||
| CH12360/78-6 | 1978-12-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1146859A true CA1146859A (en) | 1983-05-24 |
Family
ID=4382297
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000340999A Expired CA1146859A (en) | 1978-12-04 | 1979-11-30 | Pharmaceutical preparations containing zinc |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0012115A1 (en) |
| JP (1) | JPS5579321A (en) |
| AU (1) | AU531882B2 (en) |
| CA (1) | CA1146859A (en) |
| IT (1) | IT1164070B (en) |
| LU (1) | LU81944A1 (en) |
| NZ (1) | NZ192294A (en) |
| SE (1) | SE448604B (en) |
| ZA (1) | ZA796549B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4840941A (en) * | 1986-04-04 | 1989-06-20 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Method for inhibiting infection of human T-cells |
| US5100879A (en) * | 1987-03-31 | 1992-03-31 | K.K. Ueno Seiyaku Oyo Kenkyujo | Method of topically cleansing the human body |
| US5624675A (en) * | 1989-06-06 | 1997-04-29 | Kelly; Patrick D. | Genital lubricants containing zinc salts to reduce risk of HIV infection |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| AU556817B2 (en) * | 1982-02-03 | 1986-11-20 | Efamol Limited | Topical application of a lithium salt and dihomo-alpha- linolenic acid |
| NZ208536A (en) * | 1983-06-16 | 1986-11-12 | Victoria State | Footrot composition containing zinc salt and thioacid |
| 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 |
| ATE129254T1 (en) * | 1987-03-19 | 1995-11-15 | Arthropharm Pty Ltd | ANTI-INFLAMMATORY AGENTS AND COMPOSITIONS. |
| DE69023708T2 (en) * | 1989-02-10 | 1996-06-27 | Taiho Pharmaceutical Co Ltd | ANTI-HIV MEDICINE. |
| EP0402078A3 (en) * | 1989-06-06 | 1991-07-31 | Patrick Daniel Kelly | Sexual lubricants containing zinc as an anti-viral agent |
| 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 |
| JP6139506B2 (en) * | 2011-04-04 | 2017-05-31 | コロプラスト アクティーゼルスカブ | 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 NZ NZ192294A patent/NZ192294A/en unknown
- 1979-12-03 SE SE7909952A patent/SE448604B/en not_active IP Right Cessation
- 1979-12-03 LU LU81944A patent/LU81944A1/en unknown
- 1979-12-03 ZA ZA00796549A patent/ZA796549B/en unknown
- 1979-12-03 AU AU53379/79A patent/AU531882B2/en not_active Ceased
- 1979-12-04 JP JP15645879A patent/JPS5579321A/en active Granted
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4840941A (en) * | 1986-04-04 | 1989-06-20 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Method for inhibiting infection of human T-cells |
| US5100879A (en) * | 1987-03-31 | 1992-03-31 | K.K. Ueno Seiyaku Oyo Kenkyujo | Method of topically cleansing the human body |
| US5624675A (en) * | 1989-06-06 | 1997-04-29 | Kelly; Patrick D. | Genital lubricants containing zinc salts to reduce risk of HIV infection |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1164070B (en) | 1987-04-08 |
| LU81944A1 (en) | 1980-07-01 |
| AU531882B2 (en) | 1983-09-08 |
| SE448604B (en) | 1987-03-09 |
| JPS5579321A (en) | 1980-06-14 |
| NZ192294A (en) | 1982-05-31 |
| JPS6348849B2 (en) | 1988-09-30 |
| AU5337979A (en) | 1980-06-12 |
| EP0012115A1 (en) | 1980-06-11 |
| ZA796549B (en) | 1980-11-26 |
| SE7909952L (en) | 1980-06-05 |
| IT7950953A0 (en) | 1979-11-30 |
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