WO2018038623A1 - Améliorations apportées à des traitements de parasites - Google Patents

Améliorations apportées à des traitements de parasites Download PDF

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Publication number
WO2018038623A1
WO2018038623A1 PCT/NZ2017/050111 NZ2017050111W WO2018038623A1 WO 2018038623 A1 WO2018038623 A1 WO 2018038623A1 NZ 2017050111 W NZ2017050111 W NZ 2017050111W WO 2018038623 A1 WO2018038623 A1 WO 2018038623A1
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WIPO (PCT)
Prior art keywords
formulation
levamisole
compound
solvent
salt
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PCT/NZ2017/050111
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English (en)
Inventor
Karen Yeritsyan
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Donaghys Limited
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Publication of WO2018038623A1 publication Critical patent/WO2018038623A1/fr

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • Described herein are improvements in parasite treatments. More specifically, there are described formulations and methods of manufacture providing levamisole in a salt form, and an additional anthelmintic with a different class of activity, formulated using a solvent system to produce a topically applied formulation with all compounds in solution.
  • Anthelmintics are widely used to prevent and treat parasite infections or infestations in animals, particularly in farmed foraging animals such as sheep, cattle, dairy cows and deer to name a few examples.
  • Anthelmintics are challenging to formulate since they have quite varied physical and chemical properties.
  • Combining of anthelmintics from different families has become a more desirable and common practice since many parasites are developing resistance. Combinations of anthelmintics from different families, (and hence activities) means that treatments tend to be more effective at addressing parasite infection. Combinations do however increase formulation complexity since, a solvent system that works for one active may not be compatible with the solvent system used for another active.
  • the final formulation may be difficult to manufacture and require specific handling or processing parameters to achieve the end result. Further, the final formulation may present only a compromise between preferred end characteristics and active delivery - that compromise not necessarily meeting all objectives e.g. potentially irritating the skin and having other unwanted side effects.
  • Levamisole is a commonly used anthelmintic. Despite being water soluble and generally cheaper, levamisole salts are not widely used in topically applied veterinary art formulations as an active, the base form normally being used. The art describes considerable variability in levamisole salt uptake into the animal bloodstream from topical administration which is unwanted, typically due to slow dissolution, but sometimes also due to the solvent system used. In addition, the low/acidic pH of levamisole salt solutions presents formulating challenges particularly when other desired anthelmintics are added such as macrocyclic lactones that prefer alkaline solutions. By contrast to the above, the base form of levamisole is well transferred hence the base form has seen widespread adoption for topical treatments.
  • levamisole salt in suspension or emulsion for example along with a benzimidazole.
  • Suspensions and emulsions may be acceptable in oral drenches or injectables but are not as useful in topically applied formulations since they either do not transfer through the skin barrier or only transfer poorly. Solutions are general ly preferable for topical formulations.
  • Another work-around is the use of high amounts of solvent in order to achieve solubility. This is usually to the detriment of the formulation efficacy since a lower rate of active(s) is only possible. Further, high solvent concentrations tend to increase cost and potential handling issues particularly if the solvent is not biocompatible. A further disadvantage is that the solvents used may be hazardous and/or difficult, or sometimes dangerous, to handle and use. In addition, if substantial amounts of organic solvent are used, these solvents may often irritate the skin and therefore be less desirable for both animal and user.
  • Described herein are formulations and methods of manufacture providing levamisole in a salt form and an additional anthelmintic with a different class of activity formulated using a solvent system to produce a topically applied formulation with all compounds in solution.
  • the levamisole salt and at least one additional compound being dissolved in a solvent system comprising a plurality of solvents, to form a solution, wherein at least one of the solvents is an inorganic polar solvent.
  • a formulation comprising in solution a mixture of: a therapeutically effective amount of levamisole salt dissolved in at least one inorganic solvent; a therapeutically effective amount of at least one additional anthelmintic compound with a different class of activity to levamisole, the at least one additional anthelmintic compound being substantially lipophilic and being dissolved in at least one organic solvent.
  • a veterinary medicament formulated for topical administration to a non-human animal, the medicament comprising at least one of the formulations substantially as hereinbefore described.
  • a method of prevention and/or treatment of a parasite infection or infestation in a non-human animal comprising the steps of:
  • a formulation substantially as described above in the manufacture of a medicament for the treatment of internal and/or external parasites in or on an animal in need thereof.
  • a method of manufacturing a veterinary medicament comprising the steps of:
  • the additional anthelmintic solvent having a different spectrum of activity as levamisole and being substantially lipophilic;
  • formulations and methods of manufacture providing levamisole in a salt form and an additional anthelmintic with a different class of activity formulated using a solvent system to produce a topically applied formulation with all compounds in solution.
  • the term 'about' or 'approximately' and grammatical variations thereof mean a quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% to a reference quantity, level, degree, value, number, frequency, percentage, dimension, size, amount, weight or length.
  • substantially' or grammatical variations thereof refers to at least 50%, for example 75%, 85%, 95% or 98%.
  • 'therapeutically effective amount' or grammatical variations thereof refers to the amount or dosage of an active agent or agents sufficient to cause a desired level of anti-parasite prevention or treatment effect in an animal post administration of the active agent or agents.
  • 'topical' refers to administration on an external skin area of an animal.
  • hydrophilic' or grammatical variations thereof refers to a compound that is attracted to and tends to be dissolved in water, the compound having an HLB value greater than or equal to 10 using Griffin's Method.
  • 'lipophilic' or grammatical variations thereof refers to a compound that is attracted to and tends to be dissolved in fats, oils, lipids and non-polar solvents, the compound having an HLB value less than or equal to 7 using Griffin's Method.
  • solvent system refers to a plurality of solvents, the solvent comprising both inorganic and organic solvents.
  • solvent refers to a substance that dissolves a solute (typically an active compound in the context of this specification) to form a homogenous solution.
  • the levamisole salt and at least one additional compound being dissolved in a solvent system comprising a plurality of solvents, to form a solution, wherein at least one of the solvents is an inorganic polar solvent.
  • the levamisole salt and at least one additional compound being dissolved in a solvent system comprising a plurality of solvents, to form a solution, wherein at least one of the solvents is characterised by having: organic solvent function, penetrant function, and/or degreasing function.
  • a formulation comprising in solution a mixture of:
  • levamisole salt dissolved in at least one inorganic solvent
  • at least one additional anthelmintic compound with a different class of activity to levamisole, the at least one additional anthelmintic compound being substantially lipophilic and being dissolved in at least one organic solvent.
  • a veterinary medicament formulated for topical administration to a non-human animal, the medicament comprising at least one of the formulations substantially as hereinbefore described.
  • a method of prevention and/or treatment of a parasite infection or infestation in a non-human animal comprising the steps of:
  • a formulation substantially as described above in the manufacture of a medicament for the treatment of internal and/or external parasites in or on an animal in need thereof.
  • a method of manufacturing a veterinary medicament comprising the steps of:
  • the additional anthelmintic solvent having a different spectrum of activity as levamisole and being substantially lipophilic;
  • the levamisole salt is a levamisole HCI but other hydrophilic salt forms (e.g. phosphate, acetate, fluoride, sulphate forms) may also be used.
  • hydrophilic salt forms e.g. phosphate, acetate, fluoride, sulphate forms
  • the levamisole salt may be present in the formulation at a rate of approximately: 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30% by weight.
  • the levamisole salt may be present at a rate of approximately: 10 to 30% or 10 to 20% or 20 to 30% or 15 to 25% or 20 to 30% by weight. This level of concentration may be sufficient based on application rates of 1ml per 10 to 20kg animal live weight however these figures are provided by way of illustration only and may be increased or decreased depending on the dose volume desired and the level of efficacy needed (prevention or treatment for example where a higher dose may be desirable for treatment versus prevention).
  • the levamisole salt may be in powder form prior to production of the formulation and mixed with the inorganic polar solvent to provide the levamisole salt solution . This salt solution is then mixed with at least one additional solvent and active to form the formulation described herein.
  • the at least one additional anthelmintic compound may be a macrocyclic lactone compound.
  • the macrocyclic lactone compound or compounds may be selected from the group of avermectins or milbemycins. Examples of macrocyclic lactone compounds that may be used include for example: abamectin, ivermectin, moxidectin, eprinomectin, doramectin, selamectin, and combinations thereof.
  • Macrocyclic lactones have a potent, broad antiparasitic spectrum at low dose levels. They are active against many immature nematodes (including hypobiotic larvae) and arthropods.
  • the published literature contains reports of use to treat infections of >300 species of endo- and ectoparasites in a wide range of hosts. Moreover, a single therapeutic dose can persist in concentrations sufficient to be effective against new nematode infections for prolonged periods after treatment.
  • macrocyclic lactones are used as the at least one additional active, they may be present at a rate of approximately: 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1.0, or 1.1, or 1.2, or 1.3, or 1.4, or 1.5% by weight.
  • the additional active may be present at a rate of approximately: 0.5 to 1.5%, or 0.5 to 1.0%, or 1.0 to 1.5%, or 0.75 to 1.25% by weight. This level of concentration may be sufficient based on application rates of 1ml per 10 to 20kg animal live weight however these figures are provided by way of illustration only and may be increased or decreased depending on the dose volume desired and the level of efficacy needed (prevention or treatment for example where a higher dose may be desirable for treatment versus prevention).
  • the inorganic polar solvent noted above may be a substantially aqueous solution.
  • the inorganic polar solvent may be water.
  • the inorganic polar solvent may be present in the formulation at a rate of approximately: 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30, or 31, or 32, or 33, or 34, or 35, or 36, or 37, or 38, or 39, or 40, or 41, or 42, or 43, or 44, or 45, or 46, or 47, or 48, or 49, or 50% by weight.
  • the inorganic polar solvent may be present in the formulation at a rate of approximately: 15-50%, or 15-45%, or 20-35%, or 15-35%, or 35-50%, or 20-30%, or 15-25%, or 25-35% by weight.
  • levamisole salt is water soluble but traditionally only poorly transferred via the topical route of administration. Historically, it is used in base form for topical administration so as to provide greater transfer into the blood stream of an animal to which the levamisole base is administered. Salt forms of levamisole have largely only been used in drenches where emulsions and suspensions are acceptable. Topically applied formulations generally need to be solutions as different phases or suspended solids can be poorly transferred through the skin barrier.
  • biocompatible refers to the formulation as a whole or at least one compound or ideally most if not all of the compounds being:
  • the at least one additional solvent may be an organic solvent.
  • the at least one additional solvent may have solvent properties as well as other properties or functions selected from: humectant properties, penetrant properties, degreasing properties and combinations thereof.
  • the at least one organic solvent may be characterised by having: an organic solvent function; and a penetrant function; and a degreasing function.
  • the at least one additional solvent may be at least one sulfoxide.
  • the at least one additional solvent may be dimethyl sulfoxide (DMSO).
  • DMSO may be found particularly useful in this formulation for a variety of reasons.
  • DMSO is a naturally occurring compound presents in many vegetables, fruits, grains and animal products.
  • Therapeutic applications for DMSO began in 1963 when it was reported to penetrate through skin and produce analgesia, reducing pain and promoting tissue healing.
  • one of the most significant properties of DMSO is its low toxicity, another source describing DMSO as practically nontoxic. These properties may make DMSO a useful compound in the present formulations to introduce greater biocompatibility and safer use for both the animal to which the formulation is to be applied and for the operator/user.
  • DMSO also provides a combination of organic solvent, penetrant and degreasing properties.
  • the DMSO may be present in the formulation at a rate of approximately 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10% by weight.
  • the DMSO may be present in the formulation at a rate of approximately 1-10%, or 1-5%, or 5-10%, or 3-7% by weight.
  • the at least one additional solvent may be: at least one sugar alcohol, examples including sorbitol and glycerol although other sugar alcohols may also be used; isopropyl myristate; D-limonene; at least one aromatic solvent, (examples including benzene or naptha blends and derivatives, one commercially available product being marketed under the name A150 solvent); at least one water miscible solvent; and combinations thereof.
  • These compounds may all be useful candidates as organic solvents due to their having organic solvent and penetrant and/or degreasing and/or humectant properties making them advantageous for the formulations described herein.
  • the water miscible solvent may be present in the formulation to volume of total formulation.
  • a water miscible solvent may be at least one form of glycol ether.
  • the glycol ether may be diethylene glycol monobutyl ether although other glycol ethers may be used.
  • Glycol ethers may be useful as they have organic solvent, diluent and penetrant properties plus they act to bridge water and oil solutions and may prevent separation.
  • the compounds noted above are generally non-irritant compounds. Further, through use of one or more of these compounds, no special additional treatments or pre-treatments are required before or during administration of the formulations e.g. agitation prior to use or heating prior to use. The selection of biocompatible compounds also reduces handling risk for the person administering the formulation and avoids additional handling steps and/or special equipment.
  • the formulation may further comprise at least one additional active compound.
  • the additional active compound may for example comprise: at least one anthelmintic, at least one vitamin, at least one mineral, at least one antigen, at least one ectoparasiticide, and combinations thereof.
  • co-administration of the above formulation along with other actives may be useful in order to minimise labour and time needed to maintain the wellbeing and/or treat animals.
  • the at least one additional anthelmintic may be an anthelmintic with a further different spectrum of anti-parasite activity to levamisole and the additional anthelmintic e.g. a macrocyclic lactone already noted above.
  • the at least one additional anthelmintic may be selected from the benzimidazole family of compounds.
  • the at least one vitamin may be vitamin B12.
  • the at least one mineral may be selenium. Vitamin B12 and selenium are commonly supplemented vitamins and minerals to farmed animals, at least in New Zealand. Co-administration with other actives may be beneficial at least in terms of labour and handling requirements.
  • the at least one antigen may be a vaccine.
  • the at least one ectoparasiticide may be deltamethrin.
  • the rate at which the additional actives or actives are incorporated may be related to the concentration needed for that active to be therapeutically effective which varies dependent on active type. In the inventor's experience it is quite easy to adjust the solvent system and other compound amounts present to suit the addition of a further active or actives yet retain the stability and efficacy desired.
  • the formulation may comprise at least one additional non-active agent or carrier compound.
  • the at least one additional non-active agent may be at least one surfactant and/or wetting agent.
  • the at least one surfactant and/or wetting agent may be present in the formulation at a rate of approximately 0.1, or 0.2, or 0.3, or 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23, or 24, or 25, or 26, or 27, or 28, or 29, or 30% by weight.
  • the at least one surfactant and/or wetting agent may be present in the formulation at a rate of approximately 0.1-30%, or 0.1-1%, or 1- 10%, or 10-20%, or 20-30%, or 0.5 to 1.5%, or 5-15%, or 15-25% by weight.
  • the at least one surfactant and/or wetting agent may be at least one ionic or non-ionic surfactant.
  • the at least one surfactant and/or wetting agent may be polysorbate.
  • the polysorbate may be polysorbate 80.
  • the formulation may also comprise at least one preservative or antioxidant compound.
  • preservative or antioxidant compound may be butylated hydroxytoluene (BHT), this being a common preservative used in many anthelmintic containing formulations although other preservatives may also be used.
  • BHT butylated hydroxytoluene
  • the preservative if used, may be included at a rate of approximately: 0.5, or 0.6, or 0.7, or 0.8, or 0.9, or 1, or 1.1, or 1.2, or 1.3, or 1.4, or 1.5% by weight of the total formulation.
  • the preservative may be present at a rate of approximately 0.5-1.5%, or 0.5-1, or 1-1.5, or 0.8-1.2, or 0.9-1.1% by weight.
  • the rates described may be varied to suit the preservative used.
  • Stability refers to the various formulation components and compounds remaining in solution when stored for at least approximately 1, or 2, or 3, or 4 weeks, or at least 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12 months at ambient temperature and pressure and when subjected to UV light or sunlight.
  • the term 'ambient temperature' refers to diurnal outdoor temperatures that, depending on climate may range from -20 ° C-50 ° C, or -20 ° C-40 ° C, or -10 ° C- 40 ° C, or 0 ° C-40 ° C, or 0 ° C-35 ° C, or 0 ° C-30 ° C.
  • Stability further refers to the active compounds being present after storage at a rate substantially the same as that at manufacture. Stability also may refer to the formulation being able to withstand moisture, typically from humid ambient conditions and/or condensation.
  • the rate of active post storage in the formulation may remain at: 90, or 91, or 92, or 93, or 94, or 95, or 96, or 97, or 98, or 99% by weight of that present at manufacture when stored for at least 1, or 2, or 3 months.
  • the rate of active post storage in the formulation may remain above approximately: 90-99%, or 90-95%, or 95-99%, or 97-99% by weight of that present at manufacture.
  • a further unexpected outcome of the above described formulation was that the transfer of actives into the animal bloodstream post topical administration was fast enough to be comparable to other commercially available formulations (topical or oral) or, at least to a level that is still therapeutically effective.
  • levamisole salt this result was contrary to the art that generally shows a much slower - to the point of being un-commercial - rate of uptake into the animal bloodstream.
  • the rate of uptake post administration for the formulation described herein using levamisole salt was comparable (greater than approximately 70% by weight) of that observed for a levamisole base formulation.
  • the slower rate of uptake is one reason for commercialised formulations using levamisole base instead of levamisole salt.
  • the combination of compounds described in the formulation noted herein achieved results contrary to that taught by the art.
  • the rate of transfer of macrocyclic lactone to the animal bloodstream was also comparable to other commercially available formulations (topical or oral) or, at least to a level that is still therapeutically effective.
  • a problem with art formulations using anthelmintic combinations is that the combination may, as a result of the solvent system chosen, become too viscous to be administered topically or at least not used with some special pre-treatment handling step such as heating. Achieving a viscosity with Newtonian flow and shear properties that is also sufficiently low to be administered using art equipment e.g. a backpack tank and applicator gun, is essential to the commercial success of new products.
  • the formulation embodiments described herein all easily fall with maximum practical viscosity levels when subjected to extremes in temperature and storage time.
  • the formulations produced had substantially Newtonian flow and shear properties.
  • the formulation may have a viscosity of less than approximately: 6000cps, or 5500cps, or 5000cps, or 4500cps, or 4000cps, or 3500cps, or 3000cps, or 2500cps, or 2000cps.
  • the viscosity may be approximately equivalent to that measured for water at 20°C and atmospheric pressure.
  • levamisole the salt form in particular
  • macrocyclic lactones are more stable in alkaline conditions (pH up to 9).
  • the final formulation may have a pH of approximately: 4, or 4.5, or 5, or 5.5, or 6.
  • the pH may be from approximately: 4 to 6 or 4 to 5, or 5 to 6, or 4.5 to 5.5, or 4.5 to 6, or 4 to 5.5.
  • the above formulation is formulated for topical administration. That is, the formulation is applied to the skin and the actives pass through the skin barrier and into the blood stream.
  • topical administration That is, the formulation is applied to the skin and the actives pass through the skin barrier and into the blood stream.
  • the term 'topical' or grammatical variations thereof is used however, as may be appreciated, this encompasses other terms such as 'transdermal administration', 'pour-on' treatment and 'spot-on' treatment. Reference to one term or the other should not be seen as limiting.
  • topical administration can be challenging particularly for anthelmintic compounds where the skin barrier tends to repel such actives (especially those that are hydrophilic as skin oils tend to prevent movement across the skin barrier).
  • levamisole salts are often acidic and macrocyclic lactones are alkaline presenting considerable compatibility issues.
  • the formulation described herein unexpectedly delivers both of the actives to the animal at therapeutically effective levels, well above what the art would suggest is possible. It is the inventor's understanding that this outcome is a result of the selection of actives/agents used.
  • the above formulation need not be diluted or otherwise subjected to any preparatory steps before use. This may be of benefit to minimise labour and time needed during administration and is often a useful commercial success factor as well. Despite not requiring dilution, the formulation may be diluted at time of use as desired and reference to not diluting should not be seen as limiting.
  • the formulation described herein may be manufactured by mixing levamisole salt with the inorganic polar solvent to form a first solution and separately mixing the further anthelmintic active with the remaining solvent or solvents to form a second solution and then simple mixing the first and second solutions to form the formulation described with both anthelmintic agents dissolved in solution.
  • the first solution may be an inorganic solution and the second solution may be an organic solution.
  • the above formulation is intended for veterinary use to prevent or treat a parasite infection or infestation.
  • Parasite infection can be a key issue in farmed animals, particularly those that are grass fed and hence, anthelmintic treatments are commonly used in agriculture.
  • Anthelmintics are a group of anti-parasitic active compounds that expel parasitic worms (helminths) and other internal parasites from the body by either stunning or killing them without causing significant damage to the host animal. Due to resistance, formulations that contain more than one anthelmintic active may be beneficial particularly when the actives have differing spectrum of activity.
  • the animal to which the formulations are applied may be of various farmed livestock species including but not limited to those from the genus: bovine, ovine, cervine, porcine. Despite these examples, the formulation may be used for many other farmed animals e.g. Llamas, and may also be used for companion animals such as cats and dogs. Reference to farmed livestock should not be seen as limiting.
  • the formulations described herein are generally designed for use in topical treatments. That is, they are coated, painted, spot applied, poured, sprayed or otherwise administered to the skin of an animal in need thereof. Despite reference to topical administration, the formulations described could also be administered orally as a drench and via injection. Despite non-topical modes of administration being possible, they may not be as commercially valuable or viable as existing alterative art oral or injectable anthelmintic containing products. Topical treatments are however highly valued particularly where many animals require treatment since the mode of administration avoids the need for a trained user (e.g. a vet for injections) and minimises animal handling and therefore minimises trauma on the animal and reduces labour and time needed from the person applying the formulation.
  • a trained user e.g. a vet for injections
  • a possible formulation mix is described below showing the compounds used, their mode of action and the concentration of each compound in the formulation by weight. Note that the formulation described is formulated for administration topically to an animal at a rate of 1ml per 20kg animal live weight.
  • a possible formulation mix is described below showing the compounds used, their mode of action and the concentration of each compound in the formulation by weight. Note that the formulation described is formulated for administration topically to an animal at a rate of 1ml per 20kg animal live weight.
  • a possible formulation mix is described below showing the compounds used, their mode of action and the concentration of each compound in the formulation by weight. Note that the formulation described is formulated for administration topically to an animal at a rate of 1ml per 20kg animal live weight.
  • BHT Butylated hydroxytoluene
  • Vitamin B12 Additional active 0.04-0.05
  • a possible formulation mix is described below showing the compounds used, their mode of action and the concentration of each compound in the formulation by weight. Note that the formulation described is formulated for administration topically to an animal at a rate of 1ml per 20kg animal live weight.
  • BHT Butylated hydroxytoluene
  • a possible formulation mix is described below showing the compounds used, their mode of action and the concentration of each compound in the formulation by weight. Note that the formulation described is formulated for administration topically to an animal at a rate of 1ml per 20kg animal live weight and the formulation in this case has a further anthelmintic from the benzimidazole family in fine suspension with the dissolved levamisole salt and macrocyclic lactone.
  • Example 1 The stability of Formulation 1 in Example 1 was tested by storing samples of Formulation 1 at 4 ° C, 25 ° C and 40 ° C storage temperature conditions and testing the relative active concentrations on
  • Levamisole salt is dissolved in water to form a first liquid solution
  • Macrocyclic lactone and BHT are dissolved in an organic solvent, for example in DMSO, and then diethylene glycol ether is added to form a second liquid solution;
  • Surfactant and other compounds as desired may then be mixed in, agitation continuing until a homogenous clear solution is formed, in the inventor's experience being less than 5-10 minutes.
  • the final formulations are clear solutions with no observable particles suspended or otherwise in the solution.
  • the solution is flowing at ambient conditions within viscosity limits suitable for art pour on equipment.

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Abstract

L'invention concerne des formulations et des procédés de fabrication fournissant du lévamisole sous forme de sel avec un anthelminthique supplémentaire ayant une classe d'activité différente. La formulation utilise un système multi-solvant pour produire une formulation à application topique avec tous les composés en solution. Dans un aspect, l'invention concerne une formulation comprenant en solution un mélange d'une quantité thérapeutiquement efficace de sel de lévamisole dissous dans au moins un solvant inorganique; et une quantité thérapeutiquement efficace d'au moins un composé anthelminthique supplémentaire ayant une classe d'activité différente au lévamisole, ledit au moins un composé anthelminthique supplémentaire étant sensiblement lipophile et étant dissous dans au moins un solvant organique. L'invention concerne également un médicament vétérinaire associé et un procédé de traitement de parasites.
PCT/NZ2017/050111 2016-08-23 2017-08-17 Améliorations apportées à des traitements de parasites WO2018038623A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000074489A1 (fr) * 1999-06-04 2000-12-14 Nufarm Limited Compositions biocides stables
WO2004069242A1 (fr) * 2003-02-05 2004-08-19 Jurox Pty Ltd Composition anthelmintique
AU2006100661B4 (en) * 2006-05-15 2006-09-07 Wyeth Topical formulation
WO2010014015A1 (fr) * 2008-07-29 2010-02-04 Bomac Research Limited Procédé de fabrication de comprimé
WO2011143479A1 (fr) * 2010-05-12 2011-11-17 Merial Limited Formulations parasiticides injectables de lévamisole et de lactones macrocycliques
WO2013043064A1 (fr) * 2011-09-23 2013-03-28 Alleva Animal Health Limited Système d'administration d'anthelminthiques vétérinaires
AU2010101389B4 (en) * 2010-12-08 2013-07-18 Jurox Pty Ltd Anthelmintic formulation
WO2014098619A1 (fr) * 2012-12-18 2014-06-26 Donaghys Industries Limited Formulations antiparasitaires transdermiques
WO2015147655A1 (fr) * 2014-03-24 2015-10-01 Donaghys Limited Formulations anthelmintiques vétérinaires stables

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000074489A1 (fr) * 1999-06-04 2000-12-14 Nufarm Limited Compositions biocides stables
WO2004069242A1 (fr) * 2003-02-05 2004-08-19 Jurox Pty Ltd Composition anthelmintique
AU2006100661B4 (en) * 2006-05-15 2006-09-07 Wyeth Topical formulation
WO2010014015A1 (fr) * 2008-07-29 2010-02-04 Bomac Research Limited Procédé de fabrication de comprimé
WO2011143479A1 (fr) * 2010-05-12 2011-11-17 Merial Limited Formulations parasiticides injectables de lévamisole et de lactones macrocycliques
AU2010101389B4 (en) * 2010-12-08 2013-07-18 Jurox Pty Ltd Anthelmintic formulation
WO2013043064A1 (fr) * 2011-09-23 2013-03-28 Alleva Animal Health Limited Système d'administration d'anthelminthiques vétérinaires
WO2014098619A1 (fr) * 2012-12-18 2014-06-26 Donaghys Industries Limited Formulations antiparasitaires transdermiques
WO2015147655A1 (fr) * 2014-03-24 2015-10-01 Donaghys Limited Formulations anthelmintiques vétérinaires stables

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Product Safety Summary: Aromatic 100 Fluid; SolvessoTM 100 Fluid", EXXONMOBIL CHEMICAL, March 2016 (2016-03-01), XP055467484, Retrieved from the Internet <URL:https://www.exxonmobilchemical.com/Chem-English/Files/Resources/aromatic_100_product_safety_summarypdf.pdf> [retrieved on 20171005] *

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