GB2150024A - Anthelmintic compositions - Google Patents
Anthelmintic compositions Download PDFInfo
- Publication number
- GB2150024A GB2150024A GB08429264A GB8429264A GB2150024A GB 2150024 A GB2150024 A GB 2150024A GB 08429264 A GB08429264 A GB 08429264A GB 8429264 A GB8429264 A GB 8429264A GB 2150024 A GB2150024 A GB 2150024A
- Authority
- GB
- United Kingdom
- Prior art keywords
- levamisole
- glycofurol
- salt
- nitroxynil
- dimethyl isosorbide
- 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.)
- Granted
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Tropical Medicine & Parasitology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The compositions contain the nitroxynil salt of levamisole in solution in a solvent comprising dimethyl isosorbide, glycofurol or a mixture thereof, and contain up to 40% w/v of the nitroxynil salt. The compositions can be administered orally, parenterally or in a pour-on form.
Description
SPECIFICATION
New anthelmintic compositions
This invention relates to new formulations of an organic salt having anthelmintic properties, to processes for the preparation of such formulations and to their use in combatting helminthiasis.
Levamisole (L-2, 3,5, 6-tetrahydro-6-phenylimidazo-[2, 1 -b]-thiazole), which is widely-used to control intestinal nematodes and lungworm in warm-blooded animals, and nitroxynil (4cyano-2-iodo-6-nitrophenol or 4-hydroxy-3iodo-5-nitrobenzonitrile), which is widely-used to control trematode and certain nematode parasites in warm-blooded animals, form a salt, hereinafter referred to as the nitroxynil salt of levamisole, which is as to be expected from the known basic nature of levamisole which is generally provided and used in the form of its hydrochloride or dihydrogen phosphate salts, and the known acid nature of nitroxynil, which is commercially available in the form of an aqueous solution of the eglumine (N-ethyl-D-glucamine) salt of nitroxynil.
The nitroxynil salt of levamisole combines the activity of levamisole against nematodes, for example Haemonchus contortus, Ostertagia spp., Trichostrongylus spp., e.g. Trichostrongylus axei, Cooperia spp., e.g. Cooperia oncophora, Nernatodirus spp., e.g. Nematodirus fillicolis, Oesaphagostomum spp., e.g. Oesa phagostomum venulosum, Strongyloides spp., e.g. Strongyloides papillosus, Bunostomum spp., e.g. Bunostomum trigonocephalum,
Chabertia spp., e.g. Chabertia ovina, Trichuris spp., e.g. Trichuris ovis, and Dictyocaulus spp., e.g.Dictyocaulus filaria and Dictyocaulus viviparus, and the activity of nitroxynil against trematodes, for example Fasciola hepatica and Fasciola gigantica, and certain nematodes, e.g. Haemonchus contortus, Bunostomum spp, Oesaphagostomum spp, and Parafilaria bovicola. The nitroxynil salt of levamisole may be used to kill internal helminth, e.g. nematode and trematode, parasites of warm-blooded animals, for example cattle, sheep, pigs, goats, horses and dogs. The dosage used depends upon the nature of the helminths, the animal being treated and the route of administration but the administration of a single dose of the nitroxynil salt of levamisole at dosage levels of from 10 to 30 milligrams, and usually about 1 8 milligrams of the salt per kilogram of animal body weight, generally gives satisfactory control of the parasites.Administration may be parenteral, i.e. by intravenous, intramuscular or subcutaneous injection, oral, e.g. in an oral dosage form such as tablet, bolus, capsule or drench, as an additive to feed, or dermally by a 'pour-on' dosage form, administration of an effective dose in a single unit dose, more especially a single parenteral unit dose, being preferred.
The nitroxynil salt of levamisole may be prepared by the reaction of stoichiometric quantities of nitroxynil and levamisole in water or an inert organic solvent, e.g. ethanol, or by the reaction in water of stoichiometric quantities of water-soluble salt of nitroxynil, for example the sodium, meglumine (N-methyl-Dglucamine) or eglumine salt and a watersoluble salt of levamisole, for example the hydrochloride or dihydrogen phosphate salt.
The aforesaid salts of nitroxynil and levamisole are commercially available or may be readily prepared by known methods from nitroxynil and levamisole, which are themselves commercially available or may be prepared by known methods. (By the term 'known methods' as used in the present specification is meant methods heretofore used or described in the chemical literature). The following procedures illustrates the preparation of the nitroxynil salt of levamisole:
Procedure
A solution of the eglumine salt of nitroxynil (63.059; 0.125 moles) in water (100ml) was added slowly, with stirring at ambient temperature, to a solution of levamisole hydrochloride (29.12g; 0.125 moles) in water (100my).
After completion of the addition, the precipitate which formed was removed by filtration, washed with water and dried in vacuo, to give the nitroxynil salt of levamisole (60.2g), m.p.
1 29 C, in the form of yellow needles.
For parenteral administration to animals, it is desirable to provide a sterile solution suitable for injection which contains an amount of the nitroxynil salt of levamisole in a pharmaceutically acceptable solvent enabling the desired dose to be administered in a single unit dose and which is well tolerated by the animal. Desirably, such solutions would contain from 5 to 70% w/v (weight/volume), and particularly from 5 to 40% w/v, of the nitroxynil salt of levamisole.
The nitroxynil salt of levamisole is only sparingly soluble in water and suspensions of the salt have been found to be poorly tolerated by parenteral administration to animals, even when additives expected to reduce local intolerance are included in the suspensions.
Suitable solvents to give solutions of the nitroxynil salt of levamisole which have been mentioned are pharmaceutically-acceptable alcohols, e.g. benzyl alcohol and tetrahydrofurfuryl alcohol, ketones, esters, e.g. ethyl lactate, amides, e.g. N-(2-hydroethyl)lactamide, sulphoxides, e.g. dimethylsulphoxide, sulphones, e.g. sulpholane, cyclic ether derivatives, formals, e.g. glycerol formal, hydrocarbons, perfluorinated hydrocarbons, e.g. perfluorodecalin, glycols and glycol derivatives, e.g.
ethylene glycol, propylene glycol, ethylene glycol mono- and di-alkyl ethers, propylene glycol mono- and di-alkyl ethers, poly-propy lene glycols, polyethylene glycols, for example polyethylene glycols having an average molecular weight in the range of from 100 to 600, polypropylene glycol mono- and di-alkyl ethers, polyethylene glycol mono- and di-alkyl ethers, for example diethylene glycol dimethyl ether, pyrrolidones, for example N-methylpyrrolidone and poly-(N-vinylpyrrolidone), silicone oils, for example polymethylsiloxane, aprotic solvents, for example dimethylformamide, dimethylacetamide and tetramethylurea, and mixtures of such solvents.
As indicated above, it is desirable to be able to prepare solutions of the nitroxynil salt of levamisole which contain from 5 to 40% w/v of the salt, which are well-tolerated on parenteral administration to the animal and which use solvents which are othewise accepted as being suitable for use as the diluent or carrier in a pharmaceutical composition. In practice, it has been found that these criteria are difficult to achieve.For example, although the nitroxynil salt of levamisole is highly soluble in neat benyl alcohol, the latter is biologically active, being used at concentrations up to 2% volume/volume as a preservative in liquid pharmaceutical compositions and the use of high concentrations of benzyl alcohol in such compositions is unacceptable and solutions in dimethylsulphoxide and mixtures of N-methylpyrrolidone and polyethylene-glycol 400 have been found to be poorly tolerated on parenteral administration to animals. Accordingly, there remains a need for solutions of nitroxynil salt of levamisole which meet the aforesaid criteria.
As a result of research and experimentation, it has been found that solutions of the nitroxynil salt of levamisole which meet these criteria, i.e. which can contain up to 40% w/v of the salt, are well-tolerated on parenteral administration to animals and which utilize a solvent which is otherwise accepted as being suitable for use as the diluent or carrier in a liquid pharmaceutical composition can be prepared using dimethyl isosorbide or glycofurol or a mixture of dimethyl isosorbide and glycofurol as the sole diluent or carrier or in admixture with a co-solvent or co-solvents.
The present invention accordingly provides novel pharmaceutical formulations comprising the nitroxynil salt of levamisole in solution in a solvent comprising dimethyl isosorbide and/or glycofurol, and containing up to 40% w/v of the nitroxynil salt of levamisole. The lower limit of the nitroxynil salt of levamisole content of the compositions according to the present invention is not critical, the salt content being selected such that the required amount of the nitroxynil salt of levamisole is contained in a volume of solution appropriate to the intended purposes. In practice, it is preferred that the nitroxynil salt of levamisole content of the solution is at least 5% w/v, although, as already indicated, lower concentrations may, if desired, be used.
As used in the present specification in respect of solutions according to the present invention, the term 'nitroxynil salt of levamisole' is to be understood to embrace not only the salt formed between nitroxynil and levamisole but also an association of nitroxynil and levamisole in equimolar proportions.
Dimethyl isosorbide or glycofurol or mixtures thereof may be used alone as carrier or diluent in pharmaceutical compositions according to the present invention, but if desired one or more co-solvents, for example water, butyrolactone and alcohols, for example, ethanol, glycols, e.g. ethylene glycol propylene glycol, polyethylene glycols and polypropylene glycols, glycerol, tetrahydrofurfuryl alcohol and benzyl alcohol, or mixtures thereof may be included. Preferably, the proportion of dimethyl isosorbide or glycofurol or mixtures of dimethyl isosorbide and glycofurol in the solvent should not be less than 25% by volume.
When mixtures of dimethyl isosorbide and glycofurol are used as the sole diluent or carrier or in association with co-solvents, the ratio of dimethyl isosorbide to glycofurol in the mixture used as the sole diluent or carrier and the ratio of dimethyl isosorbide to glycolfurol in the dimethyl isosorbide-glycofurol component of dilents or carriers which comprise, in addition, one or more co-solvents can vary widely, for example from 1 00:1 to 1:100 by volume. Suitable solvents include 80:20% v/v (volume/volume) mixtures of dimethyl isosorbide and water and 1:1:1 v/v mixtures of dimethyl isosorbide, glycofurol and water.
The pharmaceutical formulations according to the present invention may be used to administer the nitroxynil salt of levamisole to kill internal helminth, e.g. nematode and trematode, parasites of warm-blooded animals, e.g. cattle, sheep, pigs, goats, horses and dogs, at the dosages and for the purposes herein before described for the nitroxynil salt of levamisole, by parenteral administration, i.e. by intravenous, intramuscular or subcutaneous administration, by oral administration as a drench or dermally as a 'pour-on' dosage form, administration of an effective dose of the nitroxynil salt of levamisole in a single unit dose of the pharmaceutical formulation according to the present invention, more especially a single parenteral unit dose, being preferred. Accordingly, there are provided as a preferred feature of the present invention, novel pharmaceutical compositions comprising sterile solutions of the nitroxynil salt of levamisole in dimethyl isosorbide or glycofurol or mixtures of dimethyl isosorbide and glycofurol alone or in admixture with a co-solvent or cosolvents as hereinbefore described, containing up to 40% w/v, and preferably at least 5% w/v, of the nitroxynil salt of levamisole, wherein, when a co-solvent or co-solvents is present, the proportion of dimethyl isosorbide or glycofurol or mixture thereof in the solvent is preferably at least 25% by volume. As will be appreciated, when administered orally as a drench or dermally by a 'pour-on' dosage form, the pharmaceutical formulations according to the present invention need not be sterile, but sterile formulations may, if desired, be used for these purposes.
The novel pharmacutical formulations according to the present invention may be prepared by dissolving the nitroxynil salt of levamisole in dimethyl isosorbide or glycofurol or mixture thereof alone or in admixture with a co-solvent or co-solvents as herein before described, or by dissolving stoichiometric amounts of levamisole or a salt thereof, e.g.
the hydrochloride or dihydrogen phsophate, and nitroxynil or a salt thereof, e.g. the eglumine, meglumine or sodium salt, in dimethyl isosorbide or glycofurol or mixture thereof alone or in admixture with a co-solvent or cosolvents as hereinbefore described. These dissolutions of the nitroxynil salt of levamisole or levamisole and nitroxynil or salts thereof may be carried out at ambient temperature or with gentle heating, e.g. to 60 to 70"C and with agitation. The solution thus obtained may then, if desired, be sterilised, for example, by passage through a suitable bacteria-proof filter to give the preferred sterile pharmaceutical compositions according to the present invention suitable for parenteral administration, which are then placed and sealed under sterile conditions in sterile single unit dose or multidose containers.
Bases, for example organic bases, e.g. eglumine, or inorganic bases, e.g. sodium hydroxide, may, if required, be included in the pharmaceutical compositions according to the present invention to obtain complete dissolution of the nitroxynil salt of levamisole in mixtures of dimethyl isosorbide and/or glycofurol and co-solvents in which the salt is only sparingly soluble, e.g. water, which contains significant proportions of the co-solvent(s) and from which precipitation would otherwise occur.
If desired, biological preservatives, e.g. up to 2% v/v of benzyl alcohol, additives to improve chemical and physical stability on storage, and additives to reduce localised tissue reaction on injection, may be incorporated into the pharmaceutical compositions according to the present invention.
Dimethyl isosorbide is offered by ICI
Americas Inc. and Atlas Chemicals Industries (UK) Ltd.
Glycofurol is offered by Lusochimica S.p.a.,
Italy.
The following non-limitative examples illustrate the present invention.
EXAMPLE 1
A clear 20% w/v solution of the nitroxynil salt of levamisole was obtained by dissolving nitroxynil (11.79) and levamisole (8.3g) with stirring at ambient temperature in dimethyl isosorbide (100ml) until dissolution of solid material was complete.
The solution thus obtained was sterilised by passage through a bacteria-proof filter and divided and sealed under sterile conditions into sterile ampoules in quantities such as to give a suitable unit dose for parenteral administration. Sterile solutions similarly prepared may, if desired, be placed and sealed under sterile conditions in sterile multi-dose containers from which suitable unit doses for parenteral administration may be withdrawn for use as required.
EXAMPLE 2
A clear 20% w/v solution of the nitroxynil salt of levamisole in a 80:20% v/v mixture of dimethyl isosorbide and water was obtained by adding nitroxynil (11 .7g) and levamisole (8.39), with stirring to a mixture of dimethyl isosorbide (80ml) and water (20ml) and stirring the suspension thus obtained at 40"C until dissolution of solid material was complete.
The solution thus obtained was sterilised by passage through a bacteria-proof filter and divided and sealed under sterile conditions into sterile ampoules in quantities such as to give a suitable unit dose for parenteral administration. Sterile solutions similarly prepared may, if desired, be placed and sealed under sterile conditions in sterile multi-dose containers from which suitable unit doses for parenteral administration may be withdrawn for use as required.
EXAMPLE 3
The nitroxynil salt of levamisole (209) and eglumine (8.49) were added, with stirring at 40"C, to a mixture of dimethyl isosorbide (33ml), glycofurol (33ml), water (32ml) and benzyl alcohol (2ml) and stirring at 40"C was continued until dissolution was complete.
The clear 20% w/v solution of the nitroxynil salt of levamisole in a 33:33:32:2% v/v mixture of dimethyl isosorbide, glycofurol, water and benzyl alcohol thus obtained was sterilised by passage through a bacteria-proof filter and divided and sealed under sterile conditions into sterile ampoules in quantities such as to give a suitable unit dose for parenteral administration. Sterile solutions similarly prepared may, if desired, be placed and sealed under sterile conditions in sterile multi-dose containers from which suitable unit doses for parenteral administration may be withdrawn for use as required.
EXAMPLE 4
The nitroxynil salt of levamisole (209) was added, with stirring at 60"C, to a mixture of glycofurol (60ml) and benzyl alcohol (1.5ml) and the volume made up to 1 OOml with glycofurol with stirring at 60"C until dissolution was complete.
The clear 20% w/v solution of the nitroxynil salt of levamisole in a 98.5:1.5 v/v mixture of glycofurol and benzyl alcohol thus obtained was sterilised by passage through a
bacteria-proof filter and divided and sealed under sterile conditions into sterile ampoules in quantities such as to give a suitable unit dose for parenteral administration. Sterile solutions similarly prepared may, if desired, be placed and sealed under sterile conditions in sterile multi-dose containers from which suitable unit doses for parenteral administration may be withdrawn for use as required.
Claims (16)
1. A pharmaceutical composition which comprises the nitroxynil salt of levamisole in solution in a solvent comprising dimethyl isosorbide and/or glycofurol, and containing up to 40% w/v of the nitroxynil salt of levamisole.
2. A composition according to claim 1 which comprises at least 5% w/v of the nitroxynil salt of levamisole.
3. A composition according to claim 1 or 2 which comprises one or more co-solvents.
4. A composition according to claim 3 in which the co-solvents are selected from water, butyrolactone and alcohols.
5. A composition according to claim 3 or 4 in which the proportion of dimethyl isosorbide or glycofurol or mixture of dimethyl isosorbide and glycofurol in the solvent is not less than 25% by volume.
6. A composition according to any one of the preceding claims wherein the solvent comprises dimethyl isosorbide and glycofurol in a ratio of dimethyl isosorbide and glycofurol in a from 100:1 to 1:100 by volume.
7. A composition according to any one of the preceding claims in which the solvent is a mixture of dimethyl isosorbide and glycofurol in a ratio of 80:20 v/v.
8. A composition according to any one of claims 1 to 6 in which the solvent is a mixture of dimethyl isosorbide, glycofurol and water in a ratio of 1:1:1 v/v.
9. A composition according to any one of the preceding claims in a form suitable for parenteral or oral administration, or for dermal administration as a pour-on dosage form.
10. A sterile pharmaceutical composition which comprises the nitroxynil salt of levamisole in a solvent comprising dimethyl isosorbide or glycofurol or a mixture of dimethyl isosorbide and glycofurol alone or in admixture with a co-solvent or co-solvents, and containing up to 40% w/v of the nitroxynil salt of levamisole.
11. A composition according to claim 10 which comprises at least 5% w/v of the nitroxynil salt of levamisole.
12. A composition according to claim 10 or 11 wherein, when one or more co-solvents is present the proportion of dimethyl isosorbide or glycofurol or mixture thereof in the solvent is at least 25% v/v.
1 3. A composition according to any one of the preceding claims which comprises a base to obtain complete dissolution of the nitroxynil salt of the levamisole in a solvent comprising dimethyl isosorbide and/or glycofurol and a co-solvent in which the salt is only sparing soluble.
1 4. A composition according to any one of the preceding claims in unit dosage form.
15. A composition according to claim 14 for parenteral administration.
16. A pharmaceutical composition according to claim 1 substantially as herein before described in any one of Examples 1, 2, 3 and 4.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB838331037A GB8331037D0 (en) | 1983-11-21 | 1983-11-21 | Compositions of matter |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8429264D0 GB8429264D0 (en) | 1984-12-27 |
| GB2150024A true GB2150024A (en) | 1985-06-26 |
| GB2150024B GB2150024B (en) | 1987-02-04 |
Family
ID=10552109
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB838331037A Pending GB8331037D0 (en) | 1983-11-21 | 1983-11-21 | Compositions of matter |
| GB08429264A Expired GB2150024B (en) | 1983-11-21 | 1984-11-20 | Anthelmintic compositions |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB838331037A Pending GB8331037D0 (en) | 1983-11-21 | 1983-11-21 | Compositions of matter |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS60123419A (en) |
| AU (1) | AU3564984A (en) |
| BE (1) | BE901095A (en) |
| CA (1) | CA1236402A (en) |
| CH (1) | CH662273A5 (en) |
| DE (1) | DE3442402A1 (en) |
| DK (1) | DK548884A (en) |
| ES (1) | ES537825A0 (en) |
| FR (1) | FR2555047B1 (en) |
| GB (2) | GB8331037D0 (en) |
| HU (1) | HU196307B (en) |
| IT (1) | IT1177262B (en) |
| NL (1) | NL8403528A (en) |
| NZ (1) | NZ210247A (en) |
| ZA (1) | ZA849008B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0147883A2 (en) * | 1983-12-21 | 1985-07-10 | Janssen Pharmaceutica N.V. | Aqueous non-aggressive anthelmintic pour-on formulations |
| EP0202568A1 (en) * | 1985-05-13 | 1986-11-26 | Syntex (U.S.A.) Inc. | Anthelmintic compositions |
| WO1989004179A1 (en) * | 1987-11-03 | 1989-05-18 | Also Laboratori S.A.S. | Pharmaceutical formulations for transdermal administration |
| WO2007068073A2 (en) | 2005-12-16 | 2007-06-21 | Ouro Fino Participações E Empreendimentos S/A | Veterinarian composition comprising an organic salt of levamisole in combination with at least one avermectine and/or milbemycine |
| WO2011054068A1 (en) * | 2009-11-05 | 2011-05-12 | Ouro Fino Participações E Empreendimentos S/A | Pharmaceutical combinations, pharmaceutical compositions, medicament and method for the treatment of animals |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100500648C (en) * | 2006-12-29 | 2009-06-17 | 浙江工业大学 | A kind of synthetic method of nitrophenol nitrile |
| US20130274302A1 (en) * | 2010-12-27 | 2013-10-17 | Stefan Fuchs | Topical localized isoxazoline formulation comprising glycofurol |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4082881A (en) * | 1976-12-23 | 1978-04-04 | E. R. Squibb & Sons, Inc. | Topical and other type pharmaceutical formulations containing isosorbide carrier |
| AU527154B2 (en) * | 1978-12-15 | 1983-02-17 | Pitman-Moore Australia Limited | Composition and process |
| DE3163536D1 (en) * | 1980-11-20 | 1984-06-14 | Beecham Group Plc | Pharmaceutical compositions containing two beta-lactam derivatives |
| NZ202422A (en) * | 1981-11-25 | 1985-02-28 | Ici Australia Ltd | D, l-and l-2,3,5,6-tetrahydro-6-phenylimidazo(2,1-b)thiazolium 4-cyano-2-iodo-6-nitrophenoxide and veterinary compositions |
-
1983
- 1983-11-21 GB GB838331037A patent/GB8331037D0/en active Pending
-
1984
- 1984-11-19 ZA ZA849008A patent/ZA849008B/en unknown
- 1984-11-19 DK DK548884A patent/DK548884A/en not_active Application Discontinuation
- 1984-11-19 NZ NZ210247A patent/NZ210247A/en unknown
- 1984-11-19 JP JP59242550A patent/JPS60123419A/en active Pending
- 1984-11-19 AU AU35649/84A patent/AU3564984A/en not_active Abandoned
- 1984-11-20 IT IT23660/84A patent/IT1177262B/en active
- 1984-11-20 CA CA000468249A patent/CA1236402A/en not_active Expired
- 1984-11-20 FR FR8417647A patent/FR2555047B1/en not_active Expired
- 1984-11-20 HU HU844307A patent/HU196307B/en unknown
- 1984-11-20 NL NL8403528A patent/NL8403528A/en not_active Application Discontinuation
- 1984-11-20 GB GB08429264A patent/GB2150024B/en not_active Expired
- 1984-11-20 DE DE19843442402 patent/DE3442402A1/en not_active Withdrawn
- 1984-11-20 BE BE0/214033A patent/BE901095A/en not_active IP Right Cessation
- 1984-11-21 CH CH5562/84A patent/CH662273A5/en not_active IP Right Cessation
- 1984-11-21 ES ES537825A patent/ES537825A0/en active Granted
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0147883A2 (en) * | 1983-12-21 | 1985-07-10 | Janssen Pharmaceutica N.V. | Aqueous non-aggressive anthelmintic pour-on formulations |
| EP0147883A3 (en) * | 1983-12-21 | 1986-12-30 | Janssen Pharmaceutica N.V. | Aqueous non-aggressive anthelmintic pour-on formulations |
| EP0202568A1 (en) * | 1985-05-13 | 1986-11-26 | Syntex (U.S.A.) Inc. | Anthelmintic compositions |
| WO1989004179A1 (en) * | 1987-11-03 | 1989-05-18 | Also Laboratori S.A.S. | Pharmaceutical formulations for transdermal administration |
| WO2007068073A2 (en) | 2005-12-16 | 2007-06-21 | Ouro Fino Participações E Empreendimentos S/A | Veterinarian composition comprising an organic salt of levamisole in combination with at least one avermectine and/or milbemycine |
| WO2007068073A3 (en) * | 2005-12-16 | 2007-08-16 | Ouro Fino Participacoes E Empr | Veterinarian composition comprising an organic salt of levamisole in combination with at least one avermectine and/or milbemycine |
| US8227427B2 (en) | 2005-12-16 | 2012-07-24 | NPA—Nucleo de Pesquisas Aplicadas Ltda. | Veterinarian composition comprising an organic salt of levamisole in combination with at least one avermectin and/or milbemycin |
| WO2011054068A1 (en) * | 2009-11-05 | 2011-05-12 | Ouro Fino Participações E Empreendimentos S/A | Pharmaceutical combinations, pharmaceutical compositions, medicament and method for the treatment of animals |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA849008B (en) | 1985-07-31 |
| IT8423660A0 (en) | 1984-11-20 |
| ES8600933A1 (en) | 1985-10-16 |
| IT8423660A1 (en) | 1986-05-20 |
| DK548884A (en) | 1985-05-22 |
| IT1177262B (en) | 1987-08-26 |
| BE901095A (en) | 1985-05-20 |
| NZ210247A (en) | 1988-01-08 |
| GB8331037D0 (en) | 1983-12-29 |
| DE3442402A1 (en) | 1985-05-30 |
| FR2555047B1 (en) | 1987-04-17 |
| GB8429264D0 (en) | 1984-12-27 |
| FR2555047A1 (en) | 1985-05-24 |
| AU3564984A (en) | 1985-05-30 |
| ES537825A0 (en) | 1985-10-16 |
| HU196307B (en) | 1988-11-28 |
| GB2150024B (en) | 1987-02-04 |
| CA1236402A (en) | 1988-05-10 |
| JPS60123419A (en) | 1985-07-02 |
| DK548884D0 (en) | 1984-11-19 |
| HUT35955A (en) | 1985-08-28 |
| NL8403528A (en) | 1985-06-17 |
| CH662273A5 (en) | 1987-09-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |