AU2001235489A1 - Veterinary compositions for the treatment of parasitic diseases - Google Patents
Veterinary compositions for the treatment of parasitic diseasesInfo
- Publication number
- AU2001235489A1 AU2001235489A1 AU2001235489A AU2001235489A AU2001235489A1 AU 2001235489 A1 AU2001235489 A1 AU 2001235489A1 AU 2001235489 A AU2001235489 A AU 2001235489A AU 2001235489 A AU2001235489 A AU 2001235489A AU 2001235489 A1 AU2001235489 A1 AU 2001235489A1
- Authority
- AU
- Australia
- Prior art keywords
- composition
- composition according
- rafoxanide
- treatment
- weight
- 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
Links
- 239000000203 mixture Substances 0.000 title claims description 118
- 208000030852 Parasitic disease Diseases 0.000 title claims description 7
- NEMNPWINWMHUMR-UHFFFAOYSA-N rafoxanide Chemical compound OC1=C(I)C=C(I)C=C1C(=O)NC(C=C1Cl)=CC=C1OC1=CC=C(Cl)C=C1 NEMNPWINWMHUMR-UHFFFAOYSA-N 0.000 claims description 64
- 229950002980 rafoxanide Drugs 0.000 claims description 63
- 241001465754 Metazoa Species 0.000 claims description 31
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 20
- 229920000136 polysorbate Polymers 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 244000045947 parasite Species 0.000 claims description 16
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 claims description 14
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 claims description 14
- 229960002418 ivermectin Drugs 0.000 claims description 14
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 13
- 239000005660 Abamectin Substances 0.000 claims description 12
- 230000000507 anthelmentic effect Effects 0.000 claims description 12
- 229940074076 glycerol formal Drugs 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 241000283690 Bos taurus Species 0.000 claims description 9
- 241000244206 Nematoda Species 0.000 claims description 9
- 241001494479 Pecora Species 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 claims description 7
- 239000004094 surface-active agent Substances 0.000 claims description 7
- 241000283707 Capra Species 0.000 claims description 6
- 244000000013 helminth Species 0.000 claims description 6
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- -1 photostabilisers Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
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- 238000002360 preparation method Methods 0.000 claims description 3
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- 229940088594 vitamin Drugs 0.000 claims description 3
- 229930003231 vitamin Natural products 0.000 claims description 3
- 235000013343 vitamin Nutrition 0.000 claims description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 239000002562 thickening agent Substances 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims 2
- 208000031295 Animal disease Diseases 0.000 claims 1
- 206010061217 Infestation Diseases 0.000 description 18
- 241000242711 Fasciola hepatica Species 0.000 description 16
- 208000006275 fascioliasis Diseases 0.000 description 12
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 10
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- 230000037396 body weight Effects 0.000 description 9
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- 238000012360 testing method Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 241000204939 Fasciola gigantica Species 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000036470 plasma concentration Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
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- 230000000977 initiatory effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- 241001266304 Bunostomum phlebotomum Species 0.000 description 2
- 241000243992 Haemonchus placei Species 0.000 description 2
- 241000510960 Oesophagostomum Species 0.000 description 2
- 241000242541 Trematoda Species 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 210000000013 bile duct Anatomy 0.000 description 2
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- 239000003518 caustics Substances 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- HDDSHPAODJUKPD-UHFFFAOYSA-N fenbendazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1SC1=CC=CC=C1 HDDSHPAODJUKPD-UHFFFAOYSA-N 0.000 description 2
- 229960005473 fenbendazole Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000000232 gallbladder Anatomy 0.000 description 2
- 244000000050 gastrointestinal parasite Species 0.000 description 2
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- 229910052705 radium Inorganic materials 0.000 description 2
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 2
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- 239000003440 toxic substance Substances 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- DBDJCJKVEBFXHG-UHFFFAOYSA-N L-Oleandrose Natural products COC1CC(O)OC(C)C1O DBDJCJKVEBFXHG-UHFFFAOYSA-N 0.000 description 1
- 241000543819 Oestrus ovis Species 0.000 description 1
- DBDJCJKVEBFXHG-BNHYGAARSA-N Oleandrose Natural products O(C)[C@H]1[C@H](O)[C@H](C)O[C@H](O)C1 DBDJCJKVEBFXHG-BNHYGAARSA-N 0.000 description 1
- 241000243985 Onchocerca volvulus Species 0.000 description 1
- 241001674048 Phthiraptera Species 0.000 description 1
- 241000282849 Ruminantia Species 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
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- 239000000945 filler Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
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- 238000011081 inoculation Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000001418 larval effect Effects 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 201000002266 mite infestation Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000005645 nematicide Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 208000002042 onchocerciasis Diseases 0.000 description 1
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- 210000004767 rumen Anatomy 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
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Description
Title: Veterinary compositions for the treatment of parasitic diseases
Field of the invention:
The present invention concerns compositions comprising rafoxanide, the compositions being intended to be used in the veterinary field, and preferably for the treatment of parasitic diseases in farm and domestic animals, like the liver fluke or bot fly infestations.
Background of the invention:
Rafoxanide is the generic name of 3 ' -chloro-4 ' - (4- chlorophenoxy) -3, 5-di-iodosalicylanilide. Rafoxanide is sold, for example, by the company Pfizer Animal Health Inc., Zimbabwe, under the trade name Ranox®, or by the company Ventron, India.
It is known that rafoxanide is useful as an anthelmintic and fasciolicide agent and is active for the treatment of parasitic diseases affecting animals and caused by parasitic worms or nematodes infestations.
It is also known that rafoxanide is extremely water insoluble (see for example Nessel, GB patent 1 472 385), its solubility in water at 25°C being approximately 0.005% weight/volume .
Attempts to improve the solubilisation of rafoxanide by adding surface-active agents in the composition have been made. The results have shown that in a 1% surface-active agent composition, the solubility of rafoxanide is 0.14%.
This has the drawback that, when given orally, the absorption of rafoxanide by the body is low. As a consequence, its plasma concentration in the body is also low, and the majority of the active substance is unabsorbed and excreted in the faeces. For example, the absorption may be as low as 10% in non-gastric species, and only up to 50% or less in ruminants where the rumen aids in the absorption process .
As far as the anthelmintic activity is directly related to the plasma concentration of rafoxanide, to achieve a sufficient plasma concentration, a high dose of rafoxanide must be given to the subject to be treated, which is clearly economically disadvantageous.
Another solution would be to deliver the drug via injection, but here again, rafoxanide has been shown to be irritating and it is therefore not desirable to inject it as such.
In addition, rafoxanide is known to persist in the bloodstream of animals and to bind strongly to protein in the blood. This can lead to toxicity, which is clearly undesirable in the case of animals which are slaughtered for human consumption.
Several studies have been conducted to improve the absorption of rafoxanide by the body or its solubility in
a composition which would be acceptable for administration.
Nessel (GB Patent 1 472 385) describes an aqueous composition which contains rafoxanide, polyvinylpyrrolidone and a caustic agent like sodium hydroxide or the sodium salt of cholic acid, deoxycholic acid, stearic acid or isostearic acid. According to the author, the presence of polyvinylpyrrolidone and of the caustic agent in the composition enhances the solubility of the active agent to such an extent that an aqueous composition containing up to 7.5% of rafoxanide can be prepared.
However, polyvinylpyrrolidone is an expensive material and, as mentioned in Nessel, the molecular weight of the polyvinylpyrrolidone molecules varies widely within the range of about 10,000 to about 360,000. This causes a drawback in the use of polyvinylpyrrolidone since only biologically pure grades of polyvinylpyrrolidone exempts of pyrogens and other toxic materials and with a molecular weight of 3,000 to 50,000 should be used.
In a similar manner, Lo et al. (US Patent 4 128 632) describes an aqueous composition which contains a complex of rafoxanide and polyvinylpyrrolidone. The process for the preparation of the composition differs from the process of Nessel by the use of a specific solvent like acetone or glycerol formal, which can optionally be removed by evaporation. According to Lo et al., the advantage over Nessel is that the process is faster and less expensive since it does not require the expensive step of spray drying of the rafoxanide/polyvinylpyrrolidone complex formed in the solvent before its dissolution in water.
However, in addition to the drawbacks mentioned above for
the compositions of Nessel and which are due to the use of polyvinylpyrrolidone, the compositions of Lo et al. may also contain traces of acetone, which is a toxic chemical compound not desired in veterinary or pharmaceutical compositions.
It should also be noted that the processes of Nessel or Lo et al. both contain a step of heating the composition at a temperature higher than +40°C which, at an industrial level, is an expensive and inconvenient step.
In another reference, Burke (WO 95/16447) describes an anthelmintic composition for oral administration containing 4.5% rafoxanide and 3% of another insoluble nematocidal agent belonging to the benzimidazole derivatives, fenbendazole. The compositions are micronised compositions, i.e. in the form of a suspension of particles, and contain also several additional components such as xanthan gum, polyvinylpyrrolidone and a dispersing agent. The author reports that the composition shows an improved anthelmintic effect without undesirable toxic side effects. The improved effect is connected with an increased plasma concentration of fenbendazole, originated by the combined administration of both agents. However, no improvement of the absorption of rafoxanide is reported.
From the above examples, it can be concluded that there is still a need for a composition for the treatment of parasitic diseases in animals which is based on the active substance rafoxanide, which can be prepared in an easy way, which is sufficiently concentrated to permit satisfactory dosage forms and which, when administered parenterally, topically or orally, shows good absorption characteristics by the body.
Surprisingly, the inventor of the present invention has found that the efficacy of rafoxanide in the treatment of parasitic diseases in animals is improved when it is dissolved in a specific combination of solvents which is able to keep the active molecule in a micellar stable state in the composition even at high concentrations. Thus, the resulting composition is a non-aqueous micellar composition.
A stable composition in the meaning of the present invention is a composition wherein the compounds are present in a soluble form, i.e. there is for example no precipitate, the composition also remaining stable during storage.
The inventor of the present invention has also found that, if necessary, water can be added to the composition, to obtain an aqueous micellar composition.
The inventor of the present invention has also found that said compositions are particularly effective in the treatment of parasitic worms or nematodes infestations in animals, like for example the liver fluke in cattle, buffaloes, sheep and goats, the blood sucking nematodes infestations, and the larval stages of the nasal bot fly infestation in sheep and goats.
Thus, the main object of the present invention is to provide new anthelmintic and fasciolicide compositions.
Another object of the present invention is to provide these compositions as compositions which are stable upon storage.
Another object of the present invention is to provide these compositions as compositions which can be administered orally, topically or parenterally (e.g. by injection).
One of the advantages of the present invention is therefore that the composition can be prepared in an easy manner, i.e. by simply mixing the components together, and without the addition of expensive or toxic substances.
Another advantage of the present invention is that the compositions have good absorption characteristics when compared to the above mentioned known compositions of the prior art.
Further problems which can be solved by this invention with respect to known prior art compositions will become apparent to the reader of the following description.
Summary of the invention:
The present invention provides a solution to the aforementioned problems.
The aforementioned object is achieved by a micellar composition having the features defined in claim 1 and comprising as an essential active ingredient rafoxanide and a combination of solvents which act as a stabilizing and absorption-promoting agent, the combination being selected from a group consisting of specific combinations of a non- ionic surface active agent such as Tween® 80 with N- methylpyrrolidone (NMP) , 2-pyrrolidone , dimethylsulfoxide (DMSO) , or specific combinations thereof.
The aforementioned object is also achieved by the use of the micellar composition for the treatment of diseases, and most preferably diseases due to parasitic worms or nematodes infestations in animals like sheep, goats, buffalos or cattle.
Preferred embodiments of the invention, including the use of preferred concentrations, the addition of optional ingredients in the composition like for example glycerol formal, water, excipients, preservatives, vitamins, further stabilizing agents, carriers, antioxidants, photostabilizers, colorants, further absorption-promoting substances, or the use of the composition for the treatment of specific diseases in animal are defined in the dependent claims.
A combination of anthelmintic antibiotics selected from the group consisting of avermectins or their derivatives, such as avermectin and ivermectin, with the micellar composition comprising rafoxanide as defined in claim 1, and the use of this combination for the treatment of specific diseases in animal, are also defined in the dependent claims.
Unless otherwise specified, the percentages of ingredients used in the compositions are defined as weight per volume. The preferred concentrations or ranges of concentrations mentioned hereafter are concentrations which are more suitable to achieve the object of the present invention.
Description of preferred embodiments:
The micellar composition according to the present invention comprises as an essential active ingredient rafoxanide and
a combination of solvents which act as a stabilising and absorption-promoting agent.
The amount of rafoxanide in the composition is preferably between 2.5 and 25% weight/volume. Most preferably, the composition contains 12.5% weight/volume of rafoxanide.
The combination of solvents which act as a stabilising and absorption-promoting agent always comprise a non-ionic surface active agent such as Tween® 80 (commercial name of polyoxyethylene sorbitan monooleate) or Cremophor® (commercial name of polyoxyethylated castor oil) , which is necessary for the formation of the micelles, and at least a further solvent selected from N-methylpyrrolidone (NMP) , 2-pyrrolidone and dimethylsulfoxide (DMSO) .
Preferably, the combination of solvents is a combination of Tween® 80 with NMP, or Tween® 80 with 2-pyrrolidone, or Tween® 80 with NMP and 2-pyrrolidone, or Tween® 80 with DMSO and NMP and/or 2-pyrrolidone. These combinations may contain additionally glycerol formal, which acts as filler or cosolvent.
It should be noted that when DMSO and/or glycerol formal are the only solvents added in a composition containing rafoxanide and Tween® 80, a precipitate will form when the composition is kept at a low temperature. Therefore, it is recommended to always combine DMSO and /or glycerol formal with either NMP or 2-pyrrolidone.
The amount of Tween® 80 in the composition is preferably between 5% and 50% weight/volume.
The compositions may also comprise optionally other agents
like excipients, preservatives, vitamins, further stabilising agents, carriers, antioxidants, photostabilisers, colorants, further absorption-promoting substances, thickeners or any other agent or additive commonly used in veterinary or medical compositions which is for example useful for the stability of the composition or permits to improve the formulation for a specific way of administration without altering the anthelmintic or fasciolicide activity.
When necessary, the composition may be diluted with water, in order to obtain an aqueous micellar composition. Acetic acid should then be added in the composition to improve the stability and solubility of the components in the composition.
The composition may also comprise in addition an anthelmintic antibiotic selected from the group consisting of avermectins or their derivatives, such as for example avermectin or ivermectin.
Avermectins were isolated as compounds possessing anthelmintic activity from the culture broth of an actinomycete strain. Chemically, avermectins are oleandrose disaccharide derivatives of 16-membered pentacyclic lactones . The avermectin complex is a family of four closely related major components, Ala, A2a, Bla and B2a, and four minor components, Alb, A2b, Bib and B2b, which are lower homologues of the major components. Ivermectin, an hydrogenated product of the Bl component (22,23- dihydroavermectin Bl), is used as an important anthelmintic in veterinary fields and for the control of onchocerciasis in human.
When combining avermectin or ivermectin with rafoxanide in a composition in accordance with the present invention, the composition is especially indicated for the treatment of diseases caused by internal and external parasites affecting cattle, buffaloes, sheep and goats. Examples of internal parasites aimed at are adult and immature round worms, young (6 to 10 weeks old) and adult liver flukes, and tissue invading fly maggots such as larvae of cattle warble fly and sheep nostril fly. Examples of external parasites aimed at are parasites causing mange, ticks and lice.
The amount of avermectin or ivermectin in the composition is preferably between 0% and 15% weight/volume.
The preferred combination is a combination of rafoxanide with ivermectin. The best ratio between rafoxanide and ivermectin in the composition, or in other words the ratio that provides the best effect, can be easily determined via a routine experiment. In one embodiment, the composition preferably comprises 12% of rafoxanide and 0.8% of ivermectin.
Generally, the compositions are intended to be administered orally, topically or by injection and will be prepared in a suitable form. However, it should be noted that the form in which the compositions are administered depends upon the particular infection to be treated and may be adapted in order, for example, to deliver the agent closer to the site of infection. Thus, in the case of infections of a topical nature, a formulation for topical application may be prepared and topical application may be used.
The compositions are effective for the treatment of
diseases in animals, in particular the treatment of infestations by parasitic worms or nematodes in animals.
The parasitic worms or nematodes include, for example, worms or nematodes of the following types: Fasciola hepatica, Fasciola gigantica, Haemonchus placei, Bunostomum phlebotomum and Oesophagostomum radium.
In the case of a combination with avermectin or ivermectin, the compositions are, as already mentioned above, more specifically effective for the treatment of diseases caused by internal and external parasites affecting cattle, buffaloes, sheep and goats.
The posology and way of administration depend on the subject to be treated and the stage and severity of the infestation.
For example, for systemic treatment of cattle infested by liver fluke, the composition is administered by subcutaneous injection and rafoxanide is given at a single dose of 3 mg/kg body weight.
In the case of a composition comprising a combination of 12% rafoxanide with 0.8% ivermectin, the composition may, for example, also be administered by subcutaneous injection such that rafoxanide is given at a dose of 3 mg/kg body weight, and ivermectin is then given at a dose of 0.2 mg/kg body weight.
The invention will now be described in more detail with reference to the following examples.
Examples :
The amounts of ingredients are given in % of weight/volume. The volume is adjusted by addition of deionized water. The abbreviation q.s.p. means "quantity sufficient per".
Example 1:
A composition comprising:
Rafoxanide 2.5%
NMP 4%
Tween® 80 10% 2-pyrrolidone q.s.p. 100ml
Example 2 :
A composition comprising: Rafoxanide 2.5%
Tween® 80 8%
NMP q.s.p. 100ml
Example 3:
A composition comprising:
Rafoxanide 2.5%
2-pyrrolidone 30%
Tween® 80 10% DMSO 20%
NMP q.s.p. 100ml
Example 4 :
A composition comprising:
Rafoxanide 2.5%
2-pyrrolidone 20%
Tween® 80 8%
NMP 20%
Glycerol formal q.s.p 100ml
Example 5: A composition comprising:
Rafoxanide 12.5%
NMP 28%
Tween® 80 20%
Glycerol formal q.s.p. 100ml
Example 6 :
A composition comprising:
Rafoxanide 15% Tween® 80 40%
NMP q.s.p. 100ml
Example 7 : A composition comprising:
Rafoxanide 6.25%
Glycerol formal 40% Tween® 80 20%
NMP q.s.p. 100ml
Example 8:
A composition comprising:
Rafoxanide 12.5%
2-pyrrolidone 40% Tween® 80 10% Glycerol formal q.s.p. 100ml
Example 9:
A composition comprising:
Rafoxanide 2.5%
Acetic acid 10%
Tween® 80 10%
NMP 60%
Water q.s.p. 100ml
Example 10:
A composition comprising: Rafoxanide 12% Ivermectin 0.8% Tween® 80 40% NMP q.s.p. 100ml
The ingredients are mixed at room temperature and give a clear solution, which can be used for injections and is miscible with water in all proportions.
All the above exemplified compositions are stable upon storage at least for two years at room temperature (+25°C +/-2°C) .
The following examples illustrate the efficacy of the compositions of the present invention and their industrial applicability.
Evaluation of the efficacy of a composition in accordance with the present invention in the treatment of liver fluke infestation in cattle.
The aim of this study was to evaluate the effect of a treatment with a composition in accordance with the present invention (composition of Example 5) on liver fluke infestation in cattle, and to compare the efficacy of this treatment with the efficacy of a treatment with a 2.5% aqueous rafoxanide suspension.
Thus, the following experiment was carried out.
A group of calves infested experimentally or naturally with one or more liver flukes of the Fasciola hepatica or Fasciola gigantica type or with gastrointestinal parasites of the Haemonchus placei, Bunostomum phlebotomum or Oesophagostomum radium type, each of immature or adult type, was used in the experiment.
Prior to the initiation of the tests, all animals were confirmed to be positively infested by identification of eggs of the parasites in the faeces.
The animals were then separated into four groups, and treated as follows. Three groups were treated by a single subcutaneous injection of a composition in accordance with Example 5 of the present invention, and respectively at a dose of rafoxanide of 1, 2 or 3 mg/kg body weight. The last group was treated with a single dose of rafoxanide suspension at a dose of 7.5 mg/kg of body weight.
Eight days after the treatment, the animals were killed. In the case of the animals infested by Fasciola hepatica or Fasciola gigantica, the flukes were collected from the liver, gall bladder and bile duct and counted. In the case of the other infestations, the entire gastrointestinal content was examined for a counting of the number of parasites present.
In each case, the results of the tests were compared to the results obtained with infested animals which did not receive any treatment.
The results are summarised in the following Table I where the effect of the treatment is expressed as a percentage of reduction of the number of parasites.
Table I
As is clear from Table I, the treatment with a composition in accordance with Example 5 of the present invention is more effective in reducing the number of parasites associated with the infestation than the treatment using a suspension of rafoxanide in accordance with the prior art, and this even if a lower dose of rafoxanide is given to the animal .
Evaluation of the efficacy of a composition in accordance with the present invention in the treatment of liver fluke infestation in buffaloes.
The aim of this study was to evaluate the effect of a treatment with a composition in accordance with the present invention (composition of Example 5) on liver fluke infestation in buffaloes, and to compare the efficacy of this treatment with the efficacy of a treatment with a 2.5% aqueous rafoxanide suspension.
Thus, the following experiment was carried out.
A group of 15 buffaloes infested naturally with Fasciola gigantica was used in the experiment.
Prior to the initiation of the tests, all animals were confirmed to be positively infested by identification of eggs of the parasites in the faeces.
The animals were then separated into three groups each of five animals, and treated as follows. The first group was untreated and served as control. The second group was treated by a single subcutaneous injection of a composition in accordance with Example 5 of the present invention, at a dose of rafoxanide of 3 mg/kg body weight. The third group was treated with a single dose of rafoxanide suspension at a dose of 7.5 mg/kg of body weight.
Ten, eighteen and fifty days after the treatment, a counting of the number of parasites present in the faeces was effected.
The results are summarised in the following Table II
Table II
As is clear from Table II, the treatment with a composition in accordance with Example 5 of the present invention is more effective in reducing the number of parasites associated with the infestation than the treatment using a suspension of rafoxanide in accordance with the prior art, and this even if a lower dose of rafoxanide is given to the animal.
Evaluation of the efficacy of a composition in accordance with the present invention in the treatment of liver fluke infestation in sheep.
The aim of this study was to evaluate the effect of a treatment with a composition in accordance with the present invention (composition of Example 5) on liver fluke infestation in sheep, and to compare the efficacy of this treatment with the efficacy of a treatment with a 2.5% aqueous rafoxanide suspension.
Thus, the following experiment was carried out.
A group of sheep was infested with Fasciola hepatica by inoculation of 250 viable metacercariae/animal .
Prior to the initiation of the tests, all animals were confirmed to be positively infested by identification of eggs of the parasites in the faeces.
The animals were then separated into four groups, and treated as follows. Three group were treated by a single subcutaneous injection of a composition in accordance with
Example 5 of the present invention, and respectively at a dose of rafoxanide of 1, 2 or 3 mg/kg body weight. The last group was treated with a single dose of rafoxanide suspension at a dose of 7.5 mg/kg of body weight.
Seven days after the treatment, the animals were killed. The flukes were collected from the liver, gall-bladder and bile duct and counted.
In each case, the results of the tests were compared to the results obtained with infested animals which did not receive any treatment.
The results are summarised in the following Table III where the efficacy of the treatment is expressed as a percentage of reduction of the number of parasites.
Table III
As is clear from Table III, the treatment with a composition in accordance with Example 5 of the present invention is more effective in reducing the number of parasites associated with the infestation than the treatment using a suspension of rafoxanide in accordance with the prior art, and this even if a lower dose of rafoxanide is given to the animal.
The compositions according to the present invention can therefore be used as a treatment for animals infested by liver flukes or gastrointestinal parasites.
Although the present invention has been described with reference to several examples and embodiments of specific compositions and concentrations of ingredients, this is not to be considered as a limitation of the invention but merely illustrative thereof.
Specifically, other compounds like chemical derivatives of the active compounds cited herein could be used, as soon as the modification does not lead to a substantial loss of the activity of the compound.
Claims
1. A micellar composition for the treatment of parasitic diseases in animals, said composition comprising rafoxanide, a non-ionic surface active agent, and either N- methylpyrrolidone, or 2-pyrrolidone, or a combination of N- methylpyrrolidone with 2-pyrrolidone, or the combination of dimethylsulfoxide with N-methylpyrrolidone and/or 2- pyrrolidone .
2. A composition according to claim 1 wherein the non-ionic surface active agent is polyoxyethylene sorbitan monooleate (Tween® 80) .
3. A composition according to claim 1 or 2, which further comprises glycerol formal.
. A composition according to any one of claims 1 to
3 wherein the amount of rafoxanide is between 2.5% and 25% weight/volume.
5. A composition according to any one of claims 1 to
4 wherein the amount of rafoxanide is 12.5% weight/volume.
6. A composition according to any one of claims 1 to
5 wherein the amount of non-ionic surface-active agent is between 5 and 50% weight/volume.
7. A composition according to any one of claims 1 to 6, which further comprises water and acetic acid.
8. A composition according to any one of claims 1 to
7 which further comprises other agents like excipients, preservatives, vitamins, further stabilising agents, carriers, antioxidants, photostabilisers, colorants, further absorption-promoting substances, or thickeners.
9. A composition according to any one of claims 1 to 8, which further comprises an anthelmintic antibiotic selected from the group consisting of avermectins or their derivatives.
10. A composition according to claim 9 wherein the amount of avermectin or derivative thereof in the composition is preferably between 0% and 15% weight/volume.
11. A composition according to claim 9 wherein the anthelmintic antibiotic is ivermectin.
12. A composition according to claim 11, which comprises 12% of rafoxanide and 0.8% of ivermectin.
13. A composition according to any one of claims 1 to 12 for use as a medicament.
14. Use of a composition according to any one of claims 1 to 12 for the preparation of a medicament for the therapeutic treatment of animal diseases caused by parasitic worms or nematodes.
15. Use of a composition according to any one of claims 9 to 12 for the preparation of a medicament for the therapeutic treatment of internal or external diseases caused by parasites affecting cattle, buffaloes, sheep and goats .
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00104126.8 | 2000-02-29 | ||
| EP00104126A EP1129713A1 (en) | 2000-02-29 | 2000-02-29 | Veterinary compositions for the treatment of parasitic diseases |
| PCT/EP2001/002037 WO2001064222A1 (en) | 2000-02-29 | 2001-02-22 | Veterinary compositions for the treatment of parasitic diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2001235489A1 true AU2001235489A1 (en) | 2001-11-22 |
| AU2001235489B2 AU2001235489B2 (en) | 2004-11-18 |
Family
ID=8167975
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001235489A Ceased AU2001235489B2 (en) | 2000-02-29 | 2001-02-22 | Veterinary compositions for the treatment of parasitic diseases |
| AU3548901A Pending AU3548901A (en) | 2000-02-29 | 2001-02-22 | Veterinary compositions for the treatment of parasitic diseases |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU3548901A Pending AU3548901A (en) | 2000-02-29 | 2001-02-22 | Veterinary compositions for the treatment of parasitic diseases |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US6777448B2 (en) |
| EP (2) | EP1129713A1 (en) |
| CN (1) | CN1213756C (en) |
| AT (1) | ATE247970T1 (en) |
| AU (2) | AU2001235489B2 (en) |
| BR (1) | BR0108727A (en) |
| DE (1) | DE60100666T2 (en) |
| ES (1) | ES2206406T3 (en) |
| NZ (1) | NZ521533A (en) |
| TR (1) | TR200302027T4 (en) |
| WO (1) | WO2001064222A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2002952597A0 (en) * | 2002-11-11 | 2002-11-28 | Schering-Plough Pty. Limited | Topical parasiticide formulations and methods of treatment |
| KR20050103685A (en) * | 2004-04-27 | 2005-11-01 | 삼성전자주식회사 | Brightness enhancement film for liquid crystal display and manufacturing method thereof |
| GB0711957D0 (en) * | 2007-06-21 | 2007-08-01 | Syntopix Ltd | Formulations |
| DE102010051404B4 (en) | 2010-11-16 | 2017-08-31 | Marc de Cocq | Use of substituted salicylanilides for the treatment of fish |
| RU2569740C1 (en) * | 2014-05-20 | 2015-11-27 | Рамзия Тимергалеевна Маннапова | Method of correction of mineral metabolism of dictyocaulosis of sheep |
| CN104800158A (en) * | 2015-04-14 | 2015-07-29 | 四川美嘉龙生物科技有限公司 | Rafoxanide preparation and preparation method |
| AR116524A1 (en) * | 2018-10-04 | 2021-05-19 | Elanco Tiergesundheit Ag | HELMINTOS TREATMENT POTENTIAL |
| CN118986876A (en) * | 2024-08-09 | 2024-11-22 | 山东德州神牛药业有限公司 | Iodoethersalamine nanosuspension and preparation method and application thereof |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL184257C (en) * | 1974-06-19 | 1989-06-01 | Merck & Co Inc | PROCESS FOR PREPARING RAFOXANIDE PREPARATIONS. |
| US4128632A (en) * | 1978-02-13 | 1978-12-05 | Merck & Co., Inc. | Solubilization of Rafoxanide |
| AU527154B2 (en) * | 1978-12-15 | 1983-02-17 | Pitman-Moore Australia Limited | Composition and process |
| ZA842571B (en) * | 1983-04-07 | 1985-11-27 | Merck & Co Inc | Novel synergistic antiparasitic combinations |
| NZ208992A (en) * | 1983-08-12 | 1987-03-06 | Ici Australia Ltd | Endoparasiticidal compositions for topical administration,containing ether or glycol carboxylate ester |
| NZ209100A (en) * | 1983-08-22 | 1987-01-23 | Ici Australia Ltd | Topical compositions for control of endoparasites |
| EP0202568A1 (en) * | 1985-05-13 | 1986-11-26 | Syntex (U.S.A.) Inc. | Anthelmintic compositions |
| US5340804A (en) * | 1991-11-14 | 1994-08-23 | Eli Lilly And Company | 1,5-diphenyl-3-formazancarbonitril parasiticides |
| AU698431B2 (en) * | 1993-12-13 | 1998-10-29 | Michael Hilary Burke | Anthelmintic composition containing rafoxanide and fenbendazole |
| JP2002531540A (en) | 1998-12-10 | 2002-09-24 | バイエル アクチェンゲゼルシャフト | Method for producing a strobilurin intermediate |
-
2000
- 2000-02-29 EP EP00104126A patent/EP1129713A1/en not_active Withdrawn
-
2001
- 2001-02-22 ES ES01907553T patent/ES2206406T3/en not_active Expired - Lifetime
- 2001-02-22 CN CNB018057292A patent/CN1213756C/en not_active Expired - Fee Related
- 2001-02-22 TR TR2003/02027T patent/TR200302027T4/en unknown
- 2001-02-22 AU AU2001235489A patent/AU2001235489B2/en not_active Ceased
- 2001-02-22 WO PCT/EP2001/002037 patent/WO2001064222A1/en active IP Right Grant
- 2001-02-22 AU AU3548901A patent/AU3548901A/en active Pending
- 2001-02-22 EP EP01907553A patent/EP1259244B1/en not_active Expired - Lifetime
- 2001-02-22 US US10/220,393 patent/US6777448B2/en not_active Expired - Fee Related
- 2001-02-22 BR BR0108727-4A patent/BR0108727A/en not_active IP Right Cessation
- 2001-02-22 DE DE60100666T patent/DE60100666T2/en not_active Expired - Lifetime
- 2001-02-22 AT AT01907553T patent/ATE247970T1/en not_active IP Right Cessation
- 2001-02-22 NZ NZ521533A patent/NZ521533A/en not_active IP Right Cessation
-
2003
- 2003-06-17 US US10/464,415 patent/US20040072909A1/en not_active Abandoned
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