WO2012001668A1 - Compositions pour lutter contre les poux de mer et leur utilisation - Google Patents
Compositions pour lutter contre les poux de mer et leur utilisation Download PDFInfo
- Publication number
- WO2012001668A1 WO2012001668A1 PCT/IB2011/052922 IB2011052922W WO2012001668A1 WO 2012001668 A1 WO2012001668 A1 WO 2012001668A1 IB 2011052922 W IB2011052922 W IB 2011052922W WO 2012001668 A1 WO2012001668 A1 WO 2012001668A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- thymol
- sea lice
- carvacrol
- fish
- composition
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 210
- 241001674048 Phthiraptera Species 0.000 title claims abstract description 181
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 claims abstract description 210
- 241000251468 Actinopterygii Species 0.000 claims abstract description 130
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- 229960000790 thymol Drugs 0.000 claims abstract description 105
- 238000011282 treatment Methods 0.000 claims abstract description 90
- RECUKUPTGUEGMW-UHFFFAOYSA-N carvacrol Chemical compound CC(C)C1=CC=C(C)C(O)=C1 RECUKUPTGUEGMW-UHFFFAOYSA-N 0.000 claims abstract description 72
- HHTWOMMSBMNRKP-UHFFFAOYSA-N carvacrol Natural products CC(=C)C1=CC=C(C)C(O)=C1 HHTWOMMSBMNRKP-UHFFFAOYSA-N 0.000 claims abstract description 72
- 235000007746 carvacrol Nutrition 0.000 claims abstract description 72
- WYXXLXHHWYNKJF-UHFFFAOYSA-N isocarvacrol Natural products CC(C)C1=CC=C(O)C(C)=C1 WYXXLXHHWYNKJF-UHFFFAOYSA-N 0.000 claims abstract description 72
- 229940002612 prodrug Drugs 0.000 claims abstract description 70
- 239000000651 prodrug Substances 0.000 claims abstract description 70
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- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 4
- WFMIUXMJJBBOGJ-UHFFFAOYSA-N Thymyl acetate Chemical compound CC(C)C1=CC=C(C)C=C1OC(C)=O WFMIUXMJJBBOGJ-UHFFFAOYSA-N 0.000 claims description 4
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- WRIVMPQKUQTSFV-UHFFFAOYSA-N (5-methyl-2-propan-2-ylphenyl) butanoate Chemical compound CCCC(=O)OC1=CC(C)=CC=C1C(C)C WRIVMPQKUQTSFV-UHFFFAOYSA-N 0.000 claims description 2
- RIJOKQDIPZLLFF-UHFFFAOYSA-N (5-methyl-2-propan-2-ylphenyl) pentanoate Chemical compound CCCCC(=O)OC1=CC(C)=CC=C1C(C)C RIJOKQDIPZLLFF-UHFFFAOYSA-N 0.000 claims description 2
- PRPGMVZMFLIBQK-UHFFFAOYSA-N (5-methyl-2-propan-2-ylphenyl) propanoate Chemical compound CCC(=O)OC1=CC(C)=CC=C1C(C)C PRPGMVZMFLIBQK-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- IWDCLRJOBJJRNH-UHFFFAOYSA-N p-cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 1
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- 239000000419 plant extract Substances 0.000 description 1
- 235000021118 plant-derived protein Nutrition 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000012254 powdered material Substances 0.000 description 1
- 229960002957 praziquantel Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229960005134 pyrantel Drugs 0.000 description 1
- YSAUAVHXTIETRK-AATRIKPKSA-N pyrantel Chemical compound CN1CCCN=C1\C=C\C1=CC=CS1 YSAUAVHXTIETRK-AATRIKPKSA-N 0.000 description 1
- HYJYGLGUBUDSLJ-UHFFFAOYSA-N pyrethrin Natural products CCC(=O)OC1CC(=C)C2CC3OC3(C)C2C2OC(=O)C(=C)C12 HYJYGLGUBUDSLJ-UHFFFAOYSA-N 0.000 description 1
- VJFUPGQZSXIULQ-XIGJTORUSA-N pyrethrin II Chemical compound CC1(C)[C@H](/C=C(\C)C(=O)OC)[C@H]1C(=O)O[C@@H]1C(C)=C(C\C=C/C=C)C(=O)C1 VJFUPGQZSXIULQ-XIGJTORUSA-N 0.000 description 1
- 239000002728 pyrethroid Substances 0.000 description 1
- 229940124551 recombinant vaccine Drugs 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000004455 soybean meal Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- UHEPJGULSIKKTP-UHFFFAOYSA-N sulcatone Chemical compound CC(C)=CCCC(C)=O UHEPJGULSIKKTP-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000001585 thymus vulgaris Substances 0.000 description 1
- 229960000898 toltrazuril Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 229910052723 transition metal Inorganic materials 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000012711 vitamin K3 Nutrition 0.000 description 1
- 239000011652 vitamin K3 Substances 0.000 description 1
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- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K40/00—Shaping or working-up of animal feeding-stuffs
- A23K40/20—Shaping or working-up of animal feeding-stuffs by moulding, e.g. making cakes or briquettes
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/111—Aromatic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K40/00—Shaping or working-up of animal feeding-stuffs
- A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to compositions for treatment and prevention of sea copepods including Lepeophtheirus sp. and Caligus sp., referred to as sea lice, in aquaculture.
- the invention concerns new compositions comprising cyclic monoterpenoid phenols selected from thymol and carvacrol or prodrugs thereof for treatment and prevention of sea lice infections or infestations in fish.
- Another aspect of the invention relates to the use of at least one cyclic
- monoterpenoid phenol selected from thymol and carvacrol or a prodrug thereof in the preparation of a composition for treatment of sea copepods, especially sea lice infection in fish. infestations with marine copepods such as phylum arthropoda, subphylum crustacean, and subclass copepoda are difficult to avoid within net-pen based production, and is a serious issue within the aquaculture industry worldwide. The significance of the issue varies from region to region.
- sea lice can affect the growth, fecundity, and survival of their hosts because their feeding may cause lesions leading to osmotic problems and secondary infections and, if untreated they can reach a level that is highly detrimental to the fish.
- Both wild and farmed salmonids can act as hosts to sea lice.
- Sea lice can move through the waters and can transfer from farmed fish to wild fish and vice versa. T he possible interaction and cross- infestations of the parasite between farmed and wild fish is causing much concern.
- the aim for the aquaculture industry is to ensure that sea lice from fish farming facilities do not have any negative effect on the wild fish populations.
- the class as such is hereinafter called: sea lice.
- the economic impacts of sea lice investigations have been reviewed. Johnson et, al., (2004) concluded that the average annual cost of sea lice infestations in aquaculture (globally) exceeds US$ 100 mill. Sea lice infestations in Chile have been reported to represent a total loss of US$ 222 mill in 2007 (Bustos, 2007). The cost of sea lice infestations in Norway in 2007 was about 10% compared to the Chile 2007 figures (US$ 23.5 mill).
- treatment of sea lice on farmed fish includes biological treatment (wrasse, cleaner fish), pharmaceutical treatment (oral treatment and bath treatments) and additive in-feed compounds.
- biological treatment cotton, cleaner fish
- pharmaceutical treatment oral treatment and bath treatments
- additive in-feed compounds The various treatments might be combined.
- Antiparasitic agents have been used to combat infestations since the early 1980's, and organophosphates were used from early 1980 until development of resistance in the mid 1990's. From that time, the synthetic pyrethroids cypermethrin, deltamethrin, and the avermectin emamectin almost completely replaced the organophosphates for treatment of sea lice. Lately, however, several treatment failures with these pyrethroids and emamectin have been reported, and reduced sensitivity has been detected. The strategies for pest management today rely on very few anti-parasitic agents.
- Hydrogen peroxide is used to remove sea lice from fish.
- the large volumes of hydrogen peroxide needed and the limited therapeutic activity and toxicity for the fish do not make this an ideal method. Hydrogen peroxide does not kill the lice, so the lice might re-attack the fish.
- WO2007025694 (Novartis) describes use of oxazole derivatives alone or in combination with a vaccine component for controlling fish parasites, in particular sea lice.
- WO2008/145074 (Centro de Ingenieria Genetica Y Biotechnologia) describes a vaccine to control ectoparasite infections including those known as sea lice in fish.
- WO2007/039599 (Intervet International) describes a sea lice vaccine.
- WO2007/146359 (Diversa Corp.) describes a sea lice antigen vaccine.
- WO02/054873 (Biocontrol) describes microbiological agents derived from protozoan, bacterium and virus for treating or prevention sea lice infestations.
- US6,982,285 (Novartis) describes compositions of known benzoylurea compounds for controlling fish parasites including sea lice.
- US6,538,031 (Novartis) describes methods of controlling sea lice infections in fish comprising administering benzoylurea compounds.
- US2002/0045600 (Schwarzman) describes topical skin treatment for sea lice, insect bites and irritation with focus on papain.
- WO00/57704 (Campina Melkunie) describes a method of controlling lice comprising
- N0312056 (Alpharma) relates to compositions comprising a combination of an antiparasite compound and an antigen. The document focuses on Crustacia including salmon lice and on benzoylurea derivatives, hexaflumuron and others. US6, 054,454 (Novartis) describes a method of controlling fish parasites including sea lice using
- compositions comprising cyclic guanidine derivatives.
- EP0894434 (Grampian Pharmaceutical) describes treatment of immature phases of sea lice infestation. The document focuses on cypermethrin, high-cis-cypermethrin, lambda-cyhalothrin and deltamethrin.
- GB2286756 (Binnie) relates to lure for sea lice.
- WO92/16106 (Peter Hand Animal Health) relates to use of pyrethroid pesticide for treatment of lice infestation. The document focuses on cypermethrin and alphacypermethrin.
- EP0407343 (Novartis) describes use of azamethiphos to control sea lice.
- NO305681 (Bayer) describes use of nicotinergic agonists or antagonists for treatment of fish parasites including sea lice.
- WO2009/010755 (Nettforsk) describes a method of combating sea lice; first treatment with a carbamate, then treatment with pyreothroid or pyrethrin.
- US2008/003233 (National Research Canada) relates to recombinant vaccines against sea lice.
- GB2388544 (University of Aberdeen) relates to methods to control sea lice using isophorone or 6-methyl-5-heptene-2-one.
- WOO 1/07047 (Forskningsparken i As) relates to use of compounds having juvenile hormone activity for controlling crustacean infestation, such as sea lice infestations, in aquatic animals.
- WO98/24304 (Andorsen) relates to a method and device for removing parasites, especially salmon lice, from fish.
- WO2009/063044 (PHARMAQ) relates to use of vitamin K3 for treatment of fish suffering from parasite infestation including sea lice.
- EP 1208751 (Nippon Suisan Kaisha) provides a naturally occurring physiologically active substance being an essential oil containing one or more components selected from eugenol, cineol, citronellal, menthol and linalyl acetate for use against fish parasites, including Caligus.
- sea lice still represent a challenge for the aquaculture industry and for wild salmonids. Even though numerous treatments are available, no 100% reliable methods have been established. In addition, reduced sensitivity to sea lice treatments has been recorded in areas subjected to frequent use. Cross-resistance may also occur between related compounds. Where there is evidence of resistance to a particular treatment, care should be taken to avoid use of related compounds. The potential for resistance can be reduced by following correct treatment procedures, administering the full recommended dose and by alternating use of different treatment methods where possible. Hence, to avoid resistance development it is necessary that several different groups of effective compounds are available for treatment of sea lice infestations.
- benzimidazoles (fenbendazole, mebendazole, albendazole, flubendazole, etc.) being antihelmintics but without any effect on lice.
- Pyrantel is another antihelminitcs (antinematodal thiophene) without effect on lice.
- Antiprotozoal agents such as toltrazuril and diclazuril (coccidiostats) are also without effect on lice. The same is true for apelitrazin having effect on intestine protozoa, but without effect on lice.
- Only a very limited number of the available pesticides have shown good efficacy against fish parasites like sea lice. These include the pyrethroids such as
- Parasites in fish are a natural occurrence and common.
- Parasitic disorders include among others infections with Gyrodactylus salaris and Ichthyophthirius multifiliis, cryptocaryon, velvet disease, Brooklynella hostilis, Hole in the head, Glugea,
- Ceratomyxa shasta Ceratomyxa shasta, Kudoa thyrsites, Tetracapsuloides bryosalmonae, Cymothoa exigua, leeches, nematode, flukes, Platyhelminthes, carp lice and salmon lice.
- Parasites in fish thus constituting a large, non-homogeneous group, may be grouped into two categories; those which live inside (endoparasites) and those which live on the outside (ectoparasites) on the skin of their host. Even though the sea lice is an ectoparasite which lives on the skin of the fish, the various chemicals widely used to control ectoparasites do not automatically have any effect in treatment of sea lice.
- Arthropods constitute a group that has considerable genetic diversity. Approximately 40% of the genes of Lepeophtheirus salmonis share no homology with genes from other known Arthropods. The remaining genes demonstrate larger genetic distance between Salmon louse and other known Arthropods, than between human and fish (Eichner et al. (2008) Salmon louse (Lepeophtheirus salmonis) transcriptomes during post moltin maturation and egg production, revealed using EST-sequencing and microarray analysis. BMC Genomics, 9: 126).
- Arthropoda has a common ancestor that existed 725 ( ⁇ 46) million years ago (Pisani et al. (2004) The colonization of land by animals: molecular phylogeny and divergence times among arthropods. BMC Biology. 2: 1). This ancestor has given rise to animals that occupy most habitats on earth and has resulted in the occurrence of several subphyla that share few similarities in their way of living.
- An evolutionary events occurred 666 ( ⁇ 58) million years ago when one branch of Arthropods (subphylum Hexapoda, including insects) colonized land, while the other branch (subphylum Crustacea) were left in an aquatic environment.
- the colonization of land required the development of a new respiratory system and the hexapods developed a tubular system, trachea.
- Salmon louse and other fish lice have neither gills nor trachea. Moving from water to land has also resulted in metabolic differences, for example in the metabolism of nitrogen. This exemplifies how the large genetic distance between hexapods and crustaceans can result in fundamental phenotypic differences.
- ectoparasites depends on the habitat of the parasite and tolerance for the active substance.
- Parasitic insects can be treated with chemical compounds, e.g., applied locally as a cream, or spread over the whole organism to be protected. Often, these are used prophylactic to prevent new infestations.
- Treatment of aquatic animals against parasitic copepods often focuses on removing already established infestations (Karlsbakk et al, supra).
- Aquatic animals, typically fish are usually treated by administrating the active substance by bath, orally, or by injection. Due to the nature of water, the whole body- surface of the fish, including sensitive organs such as gills and eyes, could come into contact with the substance, especially during bath-treatments. It is therefore a larger risk for harming the host when ecto -parasitic treatments are given to aquatic animals compared to terrestrial host-parasite systems (Karlsbakk et al. supra).
- Differences in tolerance between species can be due to varying ability of the compound to disturb vital mechanisms in the cell biology of the organism.
- the way the compound is taken up in the organism can, however, be equally important in contributing to different tolerances.
- An example of this is the use of organo- phosphates to inactivate sea lice. These compounds antagonize the enzyme acetylcholine esterase. Although this enzyme is active in all life stages of the Salmon louse, the parasite show no sensitivity towards organophosphates in some larval stages (Chalimus) (Karlsbakk et al. supra). These compounds are therefore not suitable to treat chalimus-stages of the parasite.
- thymol and carvacrol or prodrugs thereof are useful for treating and preventing sea lice infections including sea lice and salmon lice infections in fish by administration of said compounds.
- the chemical formulas of thymol and carvacrol are shown below.
- Thymol is present in thyme oil and other volatile oils, but can also be obtained by chemical synthesis. Thymol is not a pharmaceutical product as such, but it is used as a pharmaceutical additive in a dermal drug product due to its antioxidant properties. Furthermore, thymol has antiseptic, antibacterial and antifungal properties.
- Carvacrol is like thymol a phenolic monoterpene.
- the compound is present in Origanum vulgare, but can also be prepared synthetically.
- Carvacrol is among others known to have antibacterial properties.
- JP11060421 suggests thymol and carvacrol among others as active components in insect pest-controlling agents.
- JP2006306777 discloses a parasitism reducing agent for parasites on cultured warm water fishes and a fish feed composition.
- the parasitism reducing agent comprises one or more kinds selected from caffeine, eugenol, carvacrol, thymol, paracresol, citronellal, anisaldehyde, cinnamaldehyde and a coixenolide as an active ingredient.
- the document does not mention treatment of fish infected with sea lice.
- JP2007131611 relates to antihelmintic compositions comprising natural plant extracts containing among others thymol, carvacrol, citral, etc.
- WO08/048963 discloses natural compositions for killing ectoparasites on companion animals.
- the compositions include plant essential oils comprising among others carvacrol, carveol and thymol.
- WO00/21364 discloses a composition comprising an active ingredient being among others for example thymol and carvacrol to repel or kill insects, fungi, nematodes and bacteria.
- US2003/0036530 describes pesticidal compositions comprising at least one plant essential oil compound being among others for example thymol, carveol and carvacrol for control of human body louse.
- WO02/058469 describes a pesticidal composition comprising at least one organic phenolic compound chosen from thymol or carvacol and at least one salt comprising a transition metal, to eradicate, repel or prevent infestations of pests, such as insects, mites, ova, fungus, or parasites.
- US2007/0009616 discloses a pesticidal composition comprising at least one essential oil compound being among others for example thymol or carvacrol for control of insects or arachnid pests.
- WO2009/038599 discloses a pest-control composition comprising a synergistic combination of at least two ingredients which among others can be thymol/thyme oil.
- the target pest can be an insect, arthropod, worm, parasitic organism, fungus, bacterium or a plant.
- US6,322,825 relates to compositions containing thymol and carvacrol for treatment of gastrointestinal infections in human and veterinary medical field.
- Thymol has been described as one of several components in paw herbal shampoo for removal of head lice (CM. McCage et al. in Phytomedicine, 9, 743-748 (2002), the activity of essential oil comprising terpenoid alcohols and phenols against human lice is further described (C:M: Priestley et al. in Fitorick,77, 303-309 (2006).
- C:M: Priestley et al. in Fitorick,77, 303-309 (2006) The effect on human lice has been disputed: A monograph on thymol and Thyme claims that treatment of human lice is one out of very many indications that can be listed under "historical or theoretical indications which lack sufficient evidence. (E. Basch et al. in J. Herbal Pharmacotherapy, 4, 49-67.
- thymol Pediculus humanus capitis
- sea lice which are crustaceas
- the head louse is an insect.
- thymol may be considered relatively environmentally safe when used as a pesticide there have been reports of thymol having moderately toxic effects on fish. In light of the reports of toxic effects of thymol on fish, a man skilled in the art could not have expected thymol to be active against sea lice infestations without negatively effecting the fish.
- the present invention relates to new compositions for treatment and/or prevention of sea lice infections in fish in aquaculture.
- These anti-sea lice compositions comprise an effective amount of at least one cyclic monoterpenoid phenol or a prodrug thereof for treatment and prevention of sea lice infections.
- a further aspect of the present invention relates to use of at least one cyclic monoterpenoid phenol or a prodrug thereof in the preparation of a pharmaceutical or nutraceutical composition for treatment or prophylactic treatment of fish to combat sea lice infections.
- the present invention provides anti-sea lice composition comprising an effective amount of at least one cyclic monoterpenoid phenol selected from thymol and carvacrol or a prodrug thereof.
- the present invention provides a pharmaceutical or nutraceutical composition comprising an effective amount of at least one cyclic monoterpenoid phenol selected from thymol and carvacrol or a prodrug thereof for treatment of fish infected by sea lice.
- the present invention provides a pharmaceutical or nutraceutical composition comprising at least one of thymol and carvacrol or a prodrug thereof for treatment of fish infected by sea lice.
- the present invention provides anti-sea lice composition comprising an effective amount of at least one of thymol and carvacrol, or a prodrug thereof.
- the present invention provides an anti-sea lice composition comprising at least one of thymol and carvacrol.
- the present invention provides a pharmaceutical or nutraceutical composition comprising an effective amount of at least one cyclic monoterpenoid phenol or a prodrug thereof for treatment of fish infected by sea lice where said cyclic monoterpenoid phenol is thymol, or a prodrug thereof.
- the present invention provides an anti-sea lice composition comprising an effective amount of thymol, or a prodrug thereof.
- the present invention provides an anti-sea lice composition comprising an effective amount of thymol.
- the present invention provides a pharmaceutical or nutraceutical composition comprising an effective amount of at least one cyclic monoterpenoid phenol or a prodrug thereof for treatment of fish infected by sea lice where said cyclic monoterpenoid phenol is carvacrol, or a prodrug thereof.
- the present invention provides an anti-sea lice composition comprising an effective amount of carvacrol, or a prodrug thereof.
- the present invention provides an anti-sea lice composition comprising an effective amount of carvacrol.
- the anti-sea lice composition according to the present invention might comprise a mixture of the two cyclic monoterpenoid phenols thymol and carvacrol or prodrugs thereof.
- anti-sea lice composition is to be understood as a composition useful to treat or prevent fish from being infested with sea lice.
- effective amount is to be understood as the amount sufficient to combat sea lice infections in fish without affecting the fish negatively and will depend on the type of composition, e.g. whether it is a feed composition, bath composition etc. as well as the nature and activity of the active ingredient applied. Without being limited, an effective amount is considered to be in the range from 0.1 to 99% w/w, preferably from 0.1 to 95% w/w of the active component.
- Monoterpenes are terpenes consisting of two isoprene units and the term
- “monoterpenoid” is to be understood as a modified monoterpene, wherein methyl groups have been moved or removed, or oxygen atoms added.
- the cyclic monoterpenoid phenols are phenolic monoterpenoids being monocyclic and aromatic.
- the above mentioned monoterpenoids can be extracted from naturally occurring plants, oils, etc., but will preferably be provided by synthesis and are available from various sources and suppliers.
- a prodrug is to be understood as a cyclic monoterpenoid phenol (drug) that is administered in an inactive or significantly less active form, i.e. an inactive or significantly less active cyclic monoterpenoid phenol.
- the prodrug is metabolized or transformed in vivo in the fish into an active metabolite.
- a prodrug of a cyclic monoterpenoid phenol will typically be such a compound wherein the alcohol function has been modified to, for example, an ether, ester or anhydride function.
- Inactive monoterpenoid esters can be prepared from the corresponding cyclic monoterpenoid phenol and an acid or acid derivative using standard methods in synthetic organic chemistry.
- Such methods include various active acid derivatives such as for example acid chlorides and acid anhydrides, various coupling agents like for example carbodiimides and carbonyldiimidazole and simple acid catalyst coupling.
- Some preferred cyclic monoterpenoid phenol esters to be used in compositions according to the present invention are typically: thymol formiate, thymol acetate, thymol propionate, thymol butyrate, thymol valerate and other thymol esters with straight or branched, substituted or un-substituted aliphatic acids (C3 to C20), thymol benzoate and other thymol esters of substituted aromatic acids; carvacrol formiate, carvacrol acetate, carvacrol propionate, carvacrol butyrate, carvacrol valerate and other carvacrol esters with straight or branched, substituted or un- substituted aliphatic acids (C3 to C20), carvacrol benzoate and other carvac
- a potential composition according to the present invention might for example comprise of one or more cyclic monoterpenoid phenols or prodrugs thereof in a composition comprising protein 37%, lipid 32%, carbohydrate 18%, ash 6%) and water 7%.
- the active component can be dissolved and added to the feed in a defined concentration.
- a potential composition according to the present invention might comprise the active component formulated as a ready-to-use formulation which can be mixed with any commercial available fish feed.
- anti-sea lice compositions according to the present invention can be any anti-sea lice compositions according to the present invention.
- compositions according to the present invention is oral dosing.
- the dosing is preferably in the form of a feed comprising an effective amount of the at least one cyclic monoterpenoid phenol selected from thymol and carvarol or a prodrug thereof.
- the invention provides an oral pharmaceutical or nutraceutical composition comprising at least one cyclic monoterpenoid phenol selected from thymol and carvacrol or a prodrug thereof for treatment of fish infected by sea lice.
- the present invention provides an oral anti-sea lice composition comprising an effective amount of at least one of thymol and carvacrol or a prodrug thereof.
- the present invention provides an oral anti-sea lice composition comprising an effective amount of at least one of thymol and carvacrol.
- the invention provides an oral pharmaceutical or nutraceutical composition comprising at least one cyclic monoterpenoid phenol, or prodrug thereof, for treatment of fish infected by sea lice where said cyclic monoterpenoid phenol is thymol, or a prodrug thereof.
- the present invention provides an oral anti-sea lice composition comprising an effective amount of thymol, or a prodrug thereof.
- the present invention provides an oral anti-sea lice composition comprising an effective amount of thymol.
- the invention provides an oral pharmaceutical or nutraceutical composition comprising at least one cyclic monoterpenoid phenol, or prodrug thereof, for treatment of fish infected by sea lice where said cyclic monoterpenoid phenol is carvacrol, or a prodrug thereof. Accordingly, the present invention provides an oral anti-sea lice composition comprising an effective amount of carvacrol, or a prodrug thereof. In another embodiment the present invention provides an oral anti-sea lice composition comprising an effective amount of carvacrol.
- compositions according to the present invention is injection.
- the compositions for injection will preferably be in the form of a solution, a powder to be dissolved or dispersed before injection, etc.
- the invention provides an injection pharmaceutical or nutraceutical composition comprising at least one cyclic monoterpenoid phenol selected from thymol and carvacrol or a prodrug thereof for treatment of fish infected by sea lice.
- the present invention provides an injectable anti- sea lice composition comprising an effective amount of at least one cyclic monoterpenoid phenol selected from thymol and carvacrol, or a prodrug thereof.
- the present invention provides an injectable anti-sea lice composition comprising an effective amount of at least one of thymol and carvacrol.
- the invention provides an injection pharmaceutical or nutraceutical composition comprising at least one cyclic monoterpenoid phenol, or prodrug thereof, for treatment of fish infected by sea lice where said cyclic monoterpenoid phenol is thymol, or a prodrug thereof.
- the present invention provides an injectable anti-sea lice composition comprising an effective amount of thymol, or a prodrug thereof.
- the present invention provides an injectable anti-sea lice composition comprising an effective amount of thymol.
- the invention provides an injection pharmaceutical or nutraceutical composition comprising at least one cyclic monoterpenoid phenol, or prodrug thereof, for treatment of fish infected by sea lice where said cyclic monoterpenoid phenol is carvacrol, or a prodrug thereof. Accordingly, the present invention provides an injectable anti-sea lice composition comprising an effective amount of carvacrol, or a prodrug thereof. In another embodiment the present invention provides an injectable anti-sea lice composition comprising an effective amount of carvacrol.
- compositions according to the present invention is bath treatment in the form of an undiluted or diluted solution
- the invention provides a bath pharmaceutical or nutraceutical composition comprising at least one cyclic monoterpenoid phenol selected form thymol and carvacrol, or a prodrug thereof for treatment of fish infected by sea lice.
- the present invention provides a bath anti-sea lice composition comprising an effective amount of at least one cyclic monoterpenoid phenol selected from thymol and carvacrol, or a prodrug thereof.
- the present invention provides a bath anti-sea lice composition comprising an effective amount of at least one of thymol and carvacrol.
- the invention provides a bath pharmaceutical or
- nutraceutical composition comprising at least one cyclic monoterpenoid phenol, or prodrug thereof, for treatment of fish infected by sea lice where said cyclic monoterpenoid phenol is thymol, or a prodrug thereof.
- the present invention provides a bath anti-sea lice composition comprising an effective amount of thymol, or a prodrug thereof.
- nutraceutical composition comprising at least one cyclic monoterpenoid phenol, or prodrug thereof, for treatment of fish infected by sea lice where said cyclic monoterpenoid phenol is carvacrol, or a prodrug thereof.
- the present invention provides a bath anti-sea lice composition comprising an effective amount of carvacrol, or a prodrug thereof.
- the present invention relates to compositions which can be used in different methods for treatment of fish infected by sea lice.
- Particular useful amounts of the cyclic monoterpenoid phenol compounds or of the mixture of cyclic monoterpenoid phenol compounds are as defined below in relation to the formulations of the invention.
- compositions of the present invention comprise at least one cyclic monoterpenoid phenol selected from thymol and carvacrol or a prodrug thereof, thus including one or more cyclic monoterpenoid phenols and/or prodrugs, for example one, two or three cyclic monoterpenoid phenols or prodrugs thereof in the same composition.
- compositions of the present invention comprise only one cyclic monoterpenoid phenol compound.
- cyclic monoterpenoid phenol compound includes both cyclic monoterpenoid phenols and prodrugs thereof.
- compositions according to the present invention might in addition to the cyclic monoterpenoid phenol compound(s) also comprise one or more additional, active compounds such as antiviral, anti-bacterial, antifungal agents or pesticides.
- the anti-sea lice composition according to the present invention can be formulated to be in the form of a concentrate, solution, suspension, powder, granulate, capsule, pellet, tablet or effervescent tablet.
- One aspect of the present invention relates to a concentrate of the cyclic
- the concentration of the cyclic monoterpenoid phenol compound or the mixture of such active components in the concentrate may vary from 5% by weight to 95% by weight depending on the mixture of active component and excipients or the mixture of active components and excipients.
- the concentrate can be in the form of a solid powder, a granulate, a tablet or a capsule or in the form of an aqueous or non-aqueous solution or suspension.
- the concentrate can be diluted before use.
- Taste is an important factor in the development of dosage forms for oral consumption.
- the methods most commonly involved for achieving taste masking include various chemical and physical methods.
- Flavour enhancers have been found to show effective taste masking abilities. Coating using for example a suitable polymer is an excellent method for masking undesirable taste. Use of ion exchange resins to achieve taste coverage has been documented as well. Inclusion complex formation with cyclodextrins is also a technique used for taste masking. Other techniques include solubility- limiting methods, incorporation of active substances in vesicles and liposomes, and chemical modification. The solubility limiting method can be applied to a number of substances whose taste profiles are dependent on aqueous solubility. Also when it comes to fish farming taste masking might influence the ingestion of feed. Accordingly, the anti-sea lice compositions according to the present invention might further comprise a taste masking component.
- the concentration of the cyclic monoterpenoid phenol compound(s) is/are typically from 0.001 % by weight to 5 % by weight, but the exact concentrations and amounts depends on the type of formulation.
- Oral dosage forms may comprise either of the cyclic monoterpenoid phenol compounds or the mixture of said compounds in combination with conventional aquatic feed ingredients.
- the oral dosage forms comprise cyclic monoterpenoid phenol compounds or the mixture of said compounds in combination with one or more components selected from the group consisting of: A carbohydrate source, a protein source, a lipid source, ash and water.
- the protein source may constitute from 25-50% (w/w) of said
- the carbohydrate source may constitute from 10-25%) (w/w) of the composition, such as from 10-22%> (w/w), 10- 20% (w/w), 10-18% (w/w), 10-15% (w/w), 12-25% (w/w), 15-25% (w/w), or 17- 25%) (w/w).
- the lipid source may constitute from 15-40%) (w/w) of the composition, such as from 15-35% (w/w), 15-30% (w/w), 15-28% (w/w), 15-25% (w/w), 18-40% (w/w), 20-40% (w/w), 22-40% (w/w), 25-40% (w/w), 27-40% (w/w).
- Typical protein sources may be fish or blood meal or plant proteins from soybean or other plants.
- Typical carbohydrate sources may be corn wheat or soybean meal.
- Typical lipid sources may be fish oil or plant oils from soybean, rapeseed, saffiower or others.
- the cyclic monoterpenoid phenol compounds or the mixture of said compounds may either be used as a dry powder or solubilized in an appropriate oil.
- dry feed pellets suitable for fish may first be coated with a small amount of oil to make them
- the cyclic monoterpenoid phenol compounds or the mixture of said compounds is applied to the feed pellets without prior coating of the pellet with oil.
- the cyclic monoterpenoid phenol compounds or the mixture of said compounds is preferably micronized prior to coating.
- the feed pellets may be coated with oil, for instance to increase palatability.
- the cyclic monoterpenoid phenol compounds or the mixture of said compounds are solubilized directly in oil, and coated directly on the dry feed pellets.
- carvacrol is diluted in oil and coated directly on dry feed pellets.
- the cyclic monoterpenoid phenol compounds or the mixture of said compounds is mixed together with the fish feed ingredients prior to formation of the fish feed pellets.
- the aim is to administrate either of the cyclic monoterpenoid phenol compounds or the mixture of said compounds in a dosage of 30-600 mg/kg fish/day for 7 days.
- a salmon eats 15-20 g feed per kg body weight per day.
- the feed should contain 40-600 mg of said compound or mixture of compounds, corresponding to of 0.2-3% w/w of the total feed.
- more narrow dosages are desirable, such as for instance a dosage of 30-400 mg/kg fish/day, such as a dosage of 30-400 mg/kg fish/day, a dosage of 50-200 mg/kg fish/day or such as a dosage of 80-120 mg/kg fish/day.
- the dosage forms based on conventional aquatic feed ingredients comprises the said cyclic mo no terpenoid phenol compounds or said mixture of cyclic monoterpenoid phenol compounds in amounts ranging from 0.2% - 2% w/w of total feed, such as from 0.2% - 1.5%, from 0.2% - 1%, from 0.2% - 0.9%, from 0.2% - 0.8%, from 0.2% - 0.7%, from 0.2% - 0.6%, from 0.3% - 3% w/w of total feed, such as from 0.3% - 2%, from 0.3% - 1.5%, from 0.3% - 1%, from 0.3% - 0.9%, from 0.3% - 0.8%, from 0.3% - 0,7%, from 0.3% - 0.6%, from 0.4 - 3%, from 0.4 - 2%, from 0.4% - 1.5%, from 0.4 - 1%, w/w, from 0.4% - 0.9%, from 0.4% - 0.8%, from 0.4% - 0.7%, from 0.4% - 0.7%, from 0.
- the compound or mixture of compounds is preferably solubilized in an appropriate solvent, for instance alcohol or oil or another polar or unpolar solubilizer.
- an appropriate solvent for instance alcohol or oil or another polar or unpolar solubilizer.
- useful solubilizers include etanol, DMSO and oils for example mineral oil and plant oils.
- the cyclic monoterpenoid phenol compounds or the mixture of said compounds is preferably administered in amounts of 20 mg/kg fish - lOOmg/kg fish, In order to arrive at such dosages a formulation is provided, preferably comprising 20-100 mg/ml of the cyclic monoterpenoid phenol compounds or the mixture of said compounds.
- the formulation may comprise 30-100 mg/ml, 40-100 mg/ml, 50-100 mg/ml, 20-80 mg/ml, 20-60 mg/ml, 30-80 mg/ml, or 30-60 mg/ml of the cyclic monoterpenoid phenol compounds or the mixture of said compounds.
- the compound or mixture of compounds is first solubilized, and may be formulated in an appropriate system with one or more relevant emulsifiers, for instance selected from the group consisting of alkylphenyl phosphate esters, EO/PO block copolymers, alkylphenol ethoxylates, castor oil ethoxylates, dodecylbenzene sulphonate salts, alkyl sulfonates, alkylphenylethoxylate phosphate esters.
- one or more relevant emulsifiers for instance selected from the group consisting of alkylphenyl phosphate esters, EO/PO block copolymers, alkylphenol ethoxylates, castor oil ethoxylates, dodecylbenzene sulphonate salts, alkyl sulfonates, alkylphenylethoxylate phosphate esters.
- the one or more emulsifiers are present in amounts corresponding to 5-40% w/w, such as from 5-30% w/w, 5-25% w/w, 5-15% w/w, 10-14% w/w, 10-35% w/w, 10- 30%% w/w, 10-25% w/w, 15-40% w/w, 15-30% w/w or such as from 20-40% w/w.
- the cyclic monoterpenoid phenol compounds or the mixture of said compounds are present in said concentrated solution at concentrations of lOg/liter - lOOOg/liter, such as from lOOg/liter - lOOOg/liter, 200g/liter - lOOOg/liter, 400g/liter - lOOOg/liter, lOg/liter - 800g/liter, lOg/liter - 600g/liter, lOg/liter - 400g/liter, 1 OOg/liter - 800g/liter, 200g/liter - 800/liter, or from 200g/liter - 600/liter.
- the effective bath dosage is preferably from 40-300 ppm (0.04-0.3 g/liter), such as from 60-300 ppm, 80-300 ppm, 100-300 ppm, 40-200 ppm, 40-100 ppm, 60-250 ppm, or from 60-200 ppm.
- a tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted into a solid. A polymer coating is often applied to control the release rate of the active component or to make it more resistant to the environment. Tablets are simple and convenient to use.
- One preferred tablet composition is an effervescent tablet that might be added and dissolved in water to prepare the bath before bath treatment.
- Excipients to be used in concentrate compositions according to the present invention include all pharmaceutically and nutraceutically acceptable ingredients being compatible with the active ingredients, including ingredients used in food and feed.
- Typical such ingredients include for example: physiologically acceptable solvents or solvent mixtures like for example water, lower alcohols, esters and triglycerides, carbohydrates including mono-, di -, oligio- and poly-saccharides, proteins, diluents, binders, disintegrants, lubricants, glidants and in many cases, colorants.
- excipients include sugar alcohols preferably sorbitol, xylitol, mannitol, isomalt, maltitol, inositol or lactol or mixtures of two or more of these sugar alcohols.
- Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight. The most commonly used lubricants are magnesium stearate, stearic acid, hydrogenated oil, and sodium stearyl fumarate.
- Tablets often contain diluents, such as lactose, which are added to increase the bulk weight of the blend resulting in a practical size for compression. This is often necessary where the dose of the drug is relatively small.
- diluents include for example dicalcium phosphate, calcium sulphate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and other sugars.
- the cellulose can preferably be microcrystalline cellulose (Avicel®).
- Binders are agents which impart cohesive qualities to the powdered material.
- binders include starch, gelatine, sugars such as sucrose, glucose, dextrose, and lactose, natural and synthetic gums, carboxymethylcellulose, methylcellulose, polyvinyl pyrrolidone, ethylcellulose and waxes.
- Disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration.
- Typical disintegrants include starch derivatives, crospovidone, croscaramelose and salts of carboxymethylcellulose.
- Some binders, such as starch and cellulose, are also excellent disintegrants.
- excipients include high compressibility to allow strong tablets to be made at low compression forces, good flow properties that can improve the flow of other excipients in the formula and cohesiveness (to prevent tablet from crumbling during processing, shipping and handling).
- Effervescent tablet is a tablet intended to be dissolved or dispersed in water before administration. It generally contains in addition to active components, mixture of acids/acid salts (citric, tartaric, malic acid or any other suitable acid or acid anhydride) and carbonate and hydrogen carbonates (sodium, potassium or any other suitable alkali metal carbonate or hydrogen carbonate) which release carbon dioxide when mixed with water.
- a concentrated solid material composition might be in the form of a powder, in the form of crystalline materials, in the form of granulates, in the form of pellets or in the form of any mixture of powder, crystals, granulates and pellets.
- the solid material might dissolve when diluted or may not be dissolved when diluted before use. These solid compositions might comprise excipients.
- the solid material can be produced using state of the art technology well known for a man skilled in the art.
- the active component or the concentrated solid material composition can be incorporated into fish feed. There are numerous recipes for making fish feeds.
- Incorporation of the active component(s) or the concentrated solid material composition in fish feed includes using state of the art technology well known for a man skilled in the art.
- a concentrated liquid composition can be an aqueous or non-aqueous solution or suspension.
- Fish oil is typically used in non-aqueous preparations.
- a further aspect of the present invention provides methods for the manufacture of compositions and formulations as defined above.
- these methods include steps of providing one or more cyclic monoterpenoid phenol compounds as defined above with any of the ingredients defined above in relation to the various dosage forms defined above, e.g. the concentrates, solutions, suspensions, powders, granulates, capsules, pellets, tablets or effervescent tablets defined above.
- the invention provides a method for the manufacture of an anti-sea lice composition as defined above, comprising the steps of:
- the invention provides a method for manufacturing an anti- sea lice composition according to the invention, comprising the steps of:
- Another aspect of the present invention relates to the use of the above mentioned compounds and compositions.
- the invention relates to use of at least one cyclic monoterpenoid phenol or a prodrug thereof in the preparation of a composition for treatment or prevention of sea lice infection in fish.
- the invention relates to use of at least one cyclic monoterpenoid phenol selected from thymol and carvacrol or a prodrug thereof in the preparation of a composition for controlling sea lice, such as Lepeophtheirus sp. and Caligus sp.
- Said compositions can be pharmaceutical or nutraceutical compositions depending on the desired form of administration.
- the present invention relates to compositions comprising at least one cyclic monoterpenoid phenol selected from thymol and carvacrol or a prodrug thereof for use in the treatment or prevention of sea lice infection in fish.
- the present invention relates to use of at least one cyclic monoterpenoid phenol, or a prodrug thereof wherein said cyclic monoterpenoid phenol is thymol, or a prodrug thereof in the preparation of a composition for treatment of sea lice infection in fish.
- Said composition might, as mentioned above, be a pharmaceutical or nutraceutical composition.
- the present invention relates to compositions comprising at least one cyclic monoterpenoid phenol, or a prodrug thereof wherein said cyclic monoterpenoid phenol is thymol, or a prodrug thereof for use in the treatment or prevention of sea lice infection in fish.
- the present invention relates to use of at least one cyclic monoterpenoid phenol, or a prodrug thereof wherein said cyclic monoterpenoid phenol is carvacrol, or a prodrug thereof in the preparation of a composition for treatment of sea lice infection in fish.
- Said composition might, as mentioned above, be a pharmaceutical or nutraceutical composition.
- the present invention relates to compositions comprising at least one cyclic monoterpenoid phenol, or a prodrug thereof wherein said cyclic monoterpenoid phenol is carvacrol, or a prodrug thereof for use in the treatment or prevention of sea lice infection in fish. Any sea lice infection in fish might be treated using the compositions according to the present invention.
- Preferred sea lice to be treated according to the present invention are sea lice and salmon lice, in particular Lepeophtherius sp. and Caligus sp.
- the compositions might be any of the above mentioned compositions, i.e., compositions suitable as oral compositions, bath compositions as well as
- compositions for injection are provided.
- the treatment time and dose varies over a wide range.
- the dosage of the cyclic monoterpenoid phenol compounds or said mixture of cyclic monoterpenoid phenol compounds is as as defined above in relation to the formulations according to the invention.
- Example 1 Solution comprising thymol for injection or dilution before bath treatment
- composition Active component (thymol) 500 mg
- the active component (thymol, Sigma- Aldrich, lot 80070) was dissolved in part of the solvent whilst stirring and then made up to the desired volume of 50 ml.
- Example 2 Bath treatment of preadult/adult sea lice with thymol
- Live means normal behavior, fast swimming if touched.
- Inactivated means abnormal behavior. The swimming is slow, sometimes in circles, problems with sucking to the wall of the dish. Even more inactivated or dead are also classified as inactivated.
- Formulations for bath treatment comprising thymol were prepared by diluting the composition according to Example 1 in seawater to the desired concentrations.
- Sea lice Lepeophtheirus salmonis, preadults and adults
- the effect of different formulations was tested by exposing the sea lice to different concentrations of the formulation for 30 minutes. The response was evaluated 24 h post end of exposure. The results are summarized in Table 2.
- Table 2 Effect of thymol on sea lice
- Motile Lice moved normally after tapping of exposure chamber and were able to adhere to the exposure chamber. Lice placed on their backs were able to return to the upright position.
- Immotile Lice were still or unable to self-propel after tapping the exposure chamber. Lice were not able to adhere to the walls of the exposure chamber. Lice placed on their backs were not able to return to the upright position.
- Formulations for bath treatment comprising thymol were prepared by diluting the composition according to Example 1 in seawater to the desired concentrations. 20 copepodites were counted into each exposure chamber and exposed for 60 minutes to each test regime. Exposed and control lice were transferred to clean seawater for observation for 24 hours after ended exposure before registration of results. Effect of treatment was assessed by evaluating motility of the copepodites. The results are summarized in Table 3. Table 3 Effect of thymol on copepodites
- Motile Lice moved normally after tapping of exposure chamber and were able to adhere to the exposure chamber. Lice placed on their backs were able to return to the upright position.
- Immotile Lice were still or unable to self-propel after tapping the exposure chamber. Lice were not able to adhere to the walls of the exposure chamber. Lice placed on their backs were not able to return to the upright position.
- Thymol has a very good effect on copepodites at 50ppm, 75ppm and lOOppm. There was some effect at 25ppm and lOppm. LC50 was calculated to 27 ppm (95%> confidence).
- Example 5 Solution comprising carvacrol for injection or dilution before bath treatment
- Formulations for bath treatment comprising carvacrol were prepared by diluting the composition according to Example 5 in seawater to the desired concentrations.
- Motile Lice moved normally after tapping of exposure chamber and were able to adhere to the exposure chamber. Lice placed on their backs were able to return to the upright position.
- Immotile Lice were still or unable to self-propel after tapping the exposure chamber. Lice were not able to adhere to the walls of the exposure chamber. Lice placed on their backs were not able to return to the upright position.
- Example 7 Fish feed comprising thymol for oral treatment
- composition of fish feed is Composition of fish feed:
- the active component thymol (Sigma- Aldrich, lot 80070), was dissolved in fish oil and added to the feed in a concentration of 20 g/kg fish feed using state of the art technology well known for a man skilled in the art.
- composition comprising thymol according to Example 7 was fed to Rainbow trout and Atlantic salmon with Caligus at a concentration of lOOmg thymol/kg fish for seven days.
- the number of Caligus attached per fish was recorder before feeding with thymol- feed and 15 days after start of feeding. The results are shown in Table 5.
- Example 9 Solution comprising thymol for injection or dilution before bath treatment
- the active component (thymol, Sigma Aldrich, lot 80070) was dissolved in the defined volume of a mixture of ethyl alcohol 90% and Tween 80 whilst stirring.
- Example 10 Treatment of trout by injection of thymol
- Thymol was dissolved in ethanol and injected into Rainbow trout of approximately 2.2kg with approximately 25 preadult/adult Caligus attached. The number of attached Caligus was assessed 72 hours after injection. The results are shown in Table 6.
- Example 11 Powder comprising a taste masking component and thymol in a concentrated solid material composition for oral treatment
- the active component, thymol was mixed with ascorbic acid using state of the art technology well known for a man skilled in the art.
- the mixture was then dissolved in vegetable oil and mixed with fish feed (pellets) by using state of the art technology well known for a man skilled in the art.
- Example 12 Oral treatment with thymol of fish infected with sea lice
- the formulation in Example 11 was used to treat fish infected with sea lice.
- the formulation was administered orally.
- Treatment concentration was 50 mg of the mixture containing thymol and ascorbic acid/kg fish per day for a period of 7 days.
- the mortality rate was determined by counting the dead parasites.
- the formulation of Example 11 showed good activity in this test. The number of sea lice decreased by 80-90% after 15 days.
- Example 11 The formulation of Example 11 was used to treat fish infected with sea lice. The formulation was administered orally. Treatment concentration was 100 mg of the mixture containing thymol and ascorbic acid /kg fish per day for a period of 7 days. The mortality rate was determined by counting the dead parasites. The formulation of Example 11 showed good activity in this test. The number of sea lice decreased by 75-95% after 15 days.
- Ester prodrugs of thymol are mixed with adjuvants using state of the art technology well known to a man skilled in the art.
- the release of the thymol may occur prior to, during or after absorption or in the specific target tissue.
- Example 15 Effervescent dosage form comprising thymol
- the active component is mixed thoroughly with for example calcium carbonate and sodium hydrogen carbonate and formulated as a tablet.
- the skilled man knows the type of excipients appropriate for effervescent tablet formulation.
- Trial fish are smoltified and adapted to sea water well in advance of trial start.
- the fish are transferred into tanks and challenged with L. salmonis copepodids. After 7 days when the salmon lice have reached to the chalimus 1 stage, 40 fish are randomly extracted from the challenge tanks and transferred to each replicate test tank. The fish are observed in the new tanks until appetite is considered to be adequate to start the trial.
- Trial fish are weaned onto feed that is compatible with the prospective trial feed during acclimatisation.
- the trial is conducted with 3 diets: Control diet without cyclic monoterpenoid phenol, diet containing 0,67% (w/w) thymol, and diet containing 0,67% (w/w) carvacrol.
- Each of the 3 trial diets are given in duplicate tanks in a 3 x 2 design.
- Control diets are given at a rate of 2.0% per unit fish biomass per day for 7 subsequent days, followed by another 7 subsequent days of feeding of test diets.
- the fish receive lOOmg/kg cyclic monoterpenoid phenol per fish/day for 7-10 days.
- Differences in amounts of motile stages of salmon louse before and after feeding of test diets in the respective trial groups are assessed by sampling and counting lice before start feeding of test diets, and 1 , 2 and 3 weeks after last day of feeding of test diets. Assessment on the effect of water transmission is performed 3 weeks after the last day of feeding of test diets. After feeding of test diets fish are fed commercial standard feed until end of trial.
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Abstract
La présente invention concerne des compositions pour traiter et prévenir une infestation des poissons par les poux de mer. En particulier, l'invention concerne de nouvelles compositions contenant des phénols monoterpénoïdes cycliques choisis parmi le thymol, le carvacrol et leurs promédicaments, pour traiter et prévenir les infections ou les infestations des poissons par les poux de mer. En outre, la présente invention concerne l'utilisation d'au moins un phénol monoterpénoïde cyclique choisi parmi le thymol, le carvacrol et leurs promédicaments, dans la préparation d'une composition destinée à traiter une infection des poissons par les poux de mer.
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