WO2010126857A1 - Combinaisons antiparasitaires de lactones macrocycliques et d'antibiotiques polyéther - Google Patents

Combinaisons antiparasitaires de lactones macrocycliques et d'antibiotiques polyéther Download PDF

Info

Publication number
WO2010126857A1
WO2010126857A1 PCT/US2010/032490 US2010032490W WO2010126857A1 WO 2010126857 A1 WO2010126857 A1 WO 2010126857A1 US 2010032490 W US2010032490 W US 2010032490W WO 2010126857 A1 WO2010126857 A1 WO 2010126857A1
Authority
WO
WIPO (PCT)
Prior art keywords
combination
macrocyclic lactone
polyether antibiotic
moxidectin
composition
Prior art date
Application number
PCT/US2010/032490
Other languages
English (en)
Inventor
Cecil Mark Eppler
Thomas Gerard Cullen
Daniel Howard Cohen
Zhenpeng Xi
Robert Alan Pollet
Original Assignee
Wyeth Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wyeth Llc filed Critical Wyeth Llc
Publication of WO2010126857A1 publication Critical patent/WO2010126857A1/fr

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents

Definitions

  • the present invention relates to parasiticidal compositions including at least two active agents, and in particular, to parasiticidal compositions in which the two active agents are a macrocyclic lactone and a polyether antibiotic.
  • Parasiticidal formulations are widely used in veterinary medicine to control parasite infestations in and on animals, particularly farm animals.
  • parasites There are numerous types of parasites known to infest animals. These parasites are typically characterized as ectoparasites (which live on the outside of an animal's body, such as fleas, ticks and lice) and endoparasites or helminthes (which live inside an animal's body, such as tape worms, flat worms and round worms).
  • anthelmintic drug classes used in the control of parasitic roundworms (nematodes) of small ruminants and horses include benzimidazoles, imidothiazoles-tetrahydropyrimidines, and avermectin-milbemycins.
  • benzimidazoles imidothiazoles-tetrahydropyrimidines
  • avermectin-milbemycins avermectin-milbemycins.
  • parasitic nematodes have developed drug resistance against these major anthelmintic classes.
  • Two new classes of anthelmintics have emerged recently: the cyclooctadepsipeptides and the oxindole alkaloid, paraherquamide.
  • Polyether antibiotics exhibit a broad range of biological, antibacterial, antifungal, antiviral, anticoccidal, antiparasitic, and insecticidal activities. Polyether antibiotics improve feed efficiency and growth performance in ruminant and monogastric animals. However, only the anticoccidial activity in poultry and cattle, and the effect on feed efficiency in ruminants such as cattle and sheep, are currently of commercial interest.
  • K-41 is one example of a polyether antibiotic. The manufacturing method and certain properties of K-41 are described in The Journal of Antibiotics 29, 10-14 (1976).
  • JP2000109495 discloses the use of K-41 as an anti-coccidial, anti-nematodal and antibacterial agent and its agrochemical uses are disclosed in JP2000063395.
  • EP0326417 discloses anti-coccidial derivatives of K-41.
  • K-41 is disclosed as an antimalarial agent in JP 2003335667 and in The Journal of Antibiotic (2002) 55(9) 832-834.
  • the present invention provides a veterinarily effective combination of at least two active agents.
  • the present invention further provides a synergistic combination of at least two active agents, wherein the interaction of the two active agents has a combined effect that is greater than the sum of their individual effects.
  • An advantage of synergism between two active agents is that lower doses of each active agent can be administered to achieve the same therapeutic effect, while reducing any side effects associated with either active agent.
  • Another advantage is that of enhancement of clinical utility. That is to say, since the combination of active agents according to the present invention shows a better parasiticidal effect than the individual active agents, it is more effective for the treatment of parasites.
  • the present invention also provides veterinary formulations that are useful for treating parasitic infections in animals, as well as other types of infections/infestations in animals, such as bacterial, viral, fungal, protozoan or insect infections/infestations.
  • the present invention provides a veterinarily effective combination comprising at least two active agents, one of which is a macrocyclic lactone and one of which is a polyether antibiotic or veterinarily acceptable salts or derivatives thereof. Further, the present invention provides a veterinary composition comprising: a macrocyclic lactone; a polyether antibiotic; and a veterinarily acceptable carrier.
  • the present invention further provides a method of treating or controlling a parasitic infection, the method comprising administering to an animal in need thereof an effective amount of a combination of a macrocyclic lactone and a polyether antibiotic.
  • the present invention relates to veterinarily effective combinations of at least two active agents, one of which is a macrocyclic lactone and one of which is a polyether antibiotic.
  • a macrocyclic lactone and one of which is a polyether antibiotic.
  • the invention relates to veterinary compositions including a combination of a macrocyclic lactone and a polyether antibiotic. Applicants have surprisingly discovered that these combinations of a polyether antibiotic and a macrocyclic lactone have a synergistic effect.
  • the term “synergy”, “synergism” and the like is intended to mean that the interaction of two or more agents produces a combined parasiticidal effect that is greater than predicted from the separate parasiticidal effects of the individual agents. Predictions may be based on the sum of the separate effects or use of a specialized mathematical formula (e.g., Colby equation [Colby, S. R. in Calculating Synergistic and Antagonistic Responses of Herbicide Combinations, Weeds, (1967), 15 (1 ), 20-22] ). Synergy may alternatively, or additionally, be defined as the process in which two or more agents work together to enhance the functions and effects of one another. It is to be understood that synergism may be obtained irrespective of whether the at least two active agents are administered simultaneously, separately or sequentially.
  • polyether antibiotic refers to a class of antibiotics characterized by multiple tetrahydrofuran and tetrahydropyran rings connected by aliphatic bridges, direct carbon-carbon linkages, or spiro linkages. Other features include a free carboxyl group, many lower alkyl groups, and a variety of functional oxygen groups. These structural features enable transport of cations across lipid membranes. Examples of polyether antibiotics include K-41 , monensin, maduramicin, lasalocid, salinomycin and narasin, among others. Brimble, M.A. in Polyether Antibiotics, Kirk-Othmer Encyclopedia of Chemical Technology, 5th Edition [2006], A. Seidel, Ed., John Wiley & Sons, Inc., Volume 20, pp. 119-148.
  • microcyclic lactone designates a pharmaceutical compound in the avermectin or milbemycin family of compounds including avermectins such as ivermectin, abamectin or doramectin, and milbemycins such as milbemycin D or moxidectin, or combinations thereof.
  • Suitable non-organic salts include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, malic, maleic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like.
  • vehicleinarily acceptable derivatives is intended to include salt derivatives and analogs of the compound(s).
  • vehicleinarily acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
  • the compounds of the present invention may be administered neat or in combination with conventional veterinary or pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances that may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
  • the active ingredients of this invention can be dissolved or suspended in a veterinarily or pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or veterinarily or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable veterinary additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo- regulators.
  • suitable veterinary additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo- regulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water, alcohols and their derivatives, and oils.
  • benzimidazole compound designates a veterinary compound of the benzimidazole chemical family such as thiabendazole, cambendazole, parbendazole, mebendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiophanate, febantel, netobimin, or thiabendazole.
  • w/v designates weight/volume
  • mg/kg designates milligrams per kilogram of body weight
  • compositions of the present invention include a combination of a macrocyclic lactone and a polyether antibiotic. It is desirable to administer the polyether compound in combination with a macrocyclic lactone to enhance the parasiticidal activity of the composition. Furthermore, it is desirable to combine a macrocyclic lactone with a polyether antibiotic in order to enhance the spectrum of activity.
  • polyether antibiotics are active against a broad range of organisms, including bacteria, fungi, viruses, coccidia (small protozoans), parasites and insects.
  • Macrocyclic lactones, such as moxidectin are highly active against round worms and arthropods, such as insects, ticks, and lice. Therefore, by combining a macrocyclic lactone with a polyether antibiotic, the spectrum of organisms to be controlled is broadened.
  • a veterinary composition wherein the active agents are macrocyclic lactone and a polyether antibiotic may be formulated as a parasiticidal composition wherein the active agents synergistically interact to provide enhanced anti- nematodal activity relative to either active agent alone.
  • the compositions are suitable for administration to a homeothermic animal.
  • the composition is effective against nematodes.
  • the composition is expected to provide efficacy against other organisms as well, such as, but not limited to, protozoans, bacteria, fungi and viruses.
  • Macrocyclic lactones suitable for use in the present invention include avermectins, milbemycins or combinations thereof.
  • Suitable avermectins for use in the present invention include ivermectin, abamectin and combinations thereof.
  • Suitable milbemycins for use in the present invention include, but are not limited to, moxidectin, doramectin, nemadectin, salts thereof and combinations thereof.
  • Polyether antibiotics suitable for use in the present invention include, but are not limited to, the following: K-41 , maduramicin, monensin, lasalocid, salinomycin, narasin and combinations thereof. Derivatives, including salts and analogs, of these polyether antibiotics may also be employed, alone or in combination.
  • the effective amounts of the macrocyclic lactone compound and the polyether antibiotics may vary according to the potency of the compounds, the method of application, the host animal, the target parasite, the degree of infestation, or the like.
  • amounts of about 0.01-15.0% w/v, preferably 0.05-10.0% w/v and more preferably, 0.5% w/v of a macrocyclic lactone, such as moxidectin, are suitable.
  • suitable amounts of the polyether antibiotic are, in general, amounts of about 1-10% w/v preferably 3-7% w/v.
  • the weight ratio of macrocyclic lactone to polyether antibiotic is about 0.001 - 0.05:1. In a preferred embodiment, the weight ratio of macrocyclic lactone to polyether antibiotic is about 0.01 - 0.03:1. In one preferred embodiment, the macrocyclic lactone is moxidectin and the polyether antibiotic is K-41.
  • the macrocyclic lactone is moxidectin and the polyether antibiotic is maduramicin.
  • the macrocyclic lactone is moxidectin and the polyether antibiotic is monensin.
  • the macrocyclic lactone is ivermectin and the polyether antibiotic is K-41.
  • the macrocyclic lactone is nemadectin and the polyether antibiotic is K-41. In yet another embodiment, the macrocyclic lactone is ivermectin and the polyether antibiotic is maduramicin.
  • the combination/composition of the present invention may further include other anthelmintics in addition to the macrocyclic lactone and the polyether antibiotic.
  • the compositions may include a benzimidazole compound or a salt thereof.
  • Benzimidazoles suitable for use in the composition include thiabendazole, cambendazole, parbendazole, mebendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiophanate, febantel, netobimin, thiabendazole, salts thereof, and combinations thereof.
  • the benzimidazole compound is oxibendazole, albendazole, fenbendazole, mebendazole, thiabendazole or a salt thereof or combination thereof.
  • the benzimidazole anthelmintic is thiabendazole or a salt thereof. Triclabendazole is highly effective against liver fluke at all stages of their life cycle.
  • a benzimidazole compound or a salt thereof may be present in the composition in an amount of about 10% to about 40% w/v. In general, amounts of about 15-25% w/v, of a benzimidazole compound, such as triclabendazole, are preferred.
  • closantel or an organic amine salt of closantel may be present in the composition.
  • Organic amine salts suitable for use in the present invention include, but are not limited to, alkanol amine salts such as ethanolamine, diethanolamine, methylpropanol amine, or the like; N-methyl glucamine, piperidine, piperazine, triethylamine, methyl amine, ⁇ -methylbenzyl amine, or the like.
  • alkanol amine salts such as ethanolamine, diethanolamine, methylpropanol amine, or the like
  • such salts are prepared by contacting closantel with a solution of the organic amine.
  • Organic amine salts are generally described, for instance, in U.S. Patent No. 4,005,218. In general, amounts of about
  • compositions of the present invention may include one or more anthelmintics belonging to the class of imidothiazoles-tetrahydropyrimidines, which are used in the control of parasitic nematodes.
  • Drugs belonging to this class include, for example, levamisole and pyrantel.
  • the composition of the present invention includes pyrantel, which is a tetrahydropyrimidine. Pyrantel may be present in the composition in an amount of about 0-15% %w/v.
  • the composition includes an imidothiazole, such as levamisole or tetramisole or a salt thereof.
  • suitable amounts of levamisole or tetramisole or a salt thereof are in the range of about 0-30% %w/v.
  • the composition includes praziquantel.
  • Praziquantel has high efficacy against cestode parasites.
  • Praziquantel may be present in the composition in an amount of about 2-20% w/v.
  • the compositions may include other classes of anthelmintics, such as cyclooctadepsipeptides or oxindole alkaloids.
  • the composition includes emodepside or paraherquamide.
  • compositions of the present invention may also contain other typical formulation excipients, such as surfactants, solvents, stabilizing agents or combinations thereof. Buffering agents or preservatives may also be included.
  • Surfactants may be included in the composition in amounts of about 0-30% w/v, preferably 0.01-20% w/v, and more preferably 0.1-15% w/v.
  • a surfactant may be selected from non-ionic, cationic, anionic or amphoteric surfactants. Nonionic surfactants may be preferable.
  • Surfactants suitable for use in the composition include, but are not limited to, one or more of the following: Cs-Cio alkylphenol ethoxylates (e.g., Teric N9, Teric N20, Teric N100); C 9 -Ci 7 alcohol ethoxylates (e.g., Teric 9A2, Teric 16A16); C 8 -C 2 O alkyl amine ethoxylates (e.g., Teric 13M15, Teric 18M20); castor oil ethoxylates (e.g., Cremophor EL, Acconon CA-5, Teric 380); lanolin alcohol ethoxylates (e.g., Polycol 5, Polycol 40); sorbitan fatty acid ester ethoxylates (e.g., Polysorbate 20, Polysorbate 60, Polysorbate 80); sorbitan fatty acid esters (e.g., sorbitan monoisostearate, sorbitan monostearate, Ho
  • Labrasol® (Gattefosse, Saint-Priest, France), which is composed mainly of PEG esters and glycerides with medium acyl chains.
  • Labrasol® is also known as PEG-8 caprylic/capric glycerides.
  • Another suitable surfactant is PEG-6 caprylic/capric glycerides.
  • Other surfactants suitable for use in the compositions are those such as polyethylene glycol monolaurate, polyethylene glycol dilaurate, polyethylene glycol monooleate, polyethylene glycol dioleate or glycerin polyethylene glycol coconut oil.
  • a stabilizing agent may be added to the composition.
  • Stabilizing agents may be present in the composition in amounts of about 0-5% w/v, and preferably 0-2% w/v.
  • Suitable stabilizing agents include, but are not limited to, C 1 - 12 alkyl gallate; d- 6 alkyl hydroxybenzoate or a salt thereof; benzyl hydroxytoluene; a quinone or a salt thereof; nordihydroguaiaretic acid; a tocopherol; dilauryl thiodipropionate; monothioglycerol; potassium metabisulfite; sodium formaldehyde sufoxylate; sodium thiosulfate; thioglycolic acid; thiourea; ascorbyl palmitate; cysteine or a salt thereof; ethoxyquin, isoascorbic acid; ethylene diamine tetra-acetic acid or a salt thereof; potassium bisulfate; sodium metabisul
  • the stabilizing agent is butylated hydroxytoluene (BHT).
  • Organic solvents may be present in the composition. Suitable organic solvents include, but are not limited to, glycols, glycol ethers, glycol ether acetate, Ci-Cs alkyl pyrrolidones, lactone solvents (e.g., butyrolactone, ⁇ -hexalactone), aliphatic hydrocarbons, aromatic hydrocarbons, and combinations thereof.
  • the preferred alilphatic hydrocarbons are those with a boiling point between 30 and 320 0 C, such as hexane, heptane and pentane.
  • the preferred aromatic hydrocarbons are those with a boiling point between 100 and 240 0 C, such as toluene and xylene.
  • the composition may further include excipients, which are commonly used in parasiticidal compositions including, but not limited to, dyes, perfumes, preservatives, viscosity modifiers, suspending agents, antifoam agents or combinations thereof.
  • excipients which are commonly used in parasiticidal compositions including, but not limited to, dyes, perfumes, preservatives, viscosity modifiers, suspending agents, antifoam agents or combinations thereof.
  • the veterinary composition provides easy administration and effective biovailability of the anthelmintic ingredients. Accordingly, the present invention provides a method of treating or controlling a parasitic infection, the method comprising administering to an animal in need thereof an effective amount of a combination of a macrocyclic lactone and a polyether antibiotic.
  • the macrocyclic lactone and the polyether antibiotic may be administered in a therapeutically effective amount simultaneously (such as individually at the same time, or together in a veterinary composition), and/or successively with one or more compounds of the present invention. In either case, the treatment regimen will provide beneficial effects of the synergistic combination of active agents in treating parasite infections/infestations.
  • the macrocyclic lactone and the polyether antibiotic are administered simultaneously.
  • the macrocyclic lactone and the polyether antibiotic are administered separately, such as sequentially.
  • the parasiticidal composition may be formulated as an oral composition, such as an oral drench, a gavage, a feed additive, such as a granule or grain capsule, a tablet, powder, pill, liquid suspension, emulsion or the like; a topical composition, such as a pour-on, spray, dip, spot-on, ointment, salve, patch or the like; an injectable composition, a suppository or implant, and the like.
  • an oral composition such as an oral drench, a gavage, a feed additive, such as a granule or grain capsule, a tablet, powder, pill, liquid suspension, emulsion or the like
  • a topical composition such as a pour-on, spray, dip, spot-on, ointment, salve, patch or the like
  • an injectable composition a suppository or implant, and the like.
  • Animals suitable for treatment in the method include: swine, cattle, sheep, horses, goats, camels, water buffalos, donkeys, fallow deer, reindeer, or the like, preferably swine, cattle, horses or sheep.
  • the method of this invention is useful for the treatment and control of endo- and/or ectoparasitic infections or infestations in an animal.
  • Infections and infestations that may be treated or controlled by the method of the invention include, but are not limited to, Helminthiases caused by helminthes, such as Ostertagia circumcincta,
  • Haemonchus contortus, Thchostrongylus colubriformis, or the like nematode infections caused by, for example, Haemonchus, Ostertagia, Cooperia, Oesphagostomum, Nematodirus, or the like; acarid infestations, such as biting lice, i.e., Damalinia ovis, Damalinia bovis, or the like; chorioptic, sarcoptic or demodectic mange caused by Chorioptes bovis, Sarcoptes scabiei and Demodex, respectively; Psoroptic mange caused by Psoroptes ovis; arthropod endo-parasites, such as cattle grubs; and the like.
  • nematode infections caused by, for example, Haemonchus, Ostertagia, Cooperia, Oesphagostomum, Nematodirus, or the like
  • acarid infestations such as biting lice, i
  • composition of the invention may be administered in dose rates of mg of active agent per kg of body weight of the host animal. Dose rates suitable for use in the method of invention will vary depending upon the mode of administration, the species and health of the host animal, the target parasite, the degree of infection or infestation, the breeding habitat, the potency of the additional parasiticidal compound, and the like.
  • the macrocyclic lactone and the polyether antibiotic are each administered in an amount of about 1 to about 100 mg/Kg.
  • the present invention also provides a process of preparing a veterinary composition.
  • the process includes combining a macrocyclic lactone and a polyether antibiotic with a carrier solvent.
  • said combining comprises dissolving the macrocyclic lactone in the solvent to form a macrocyclic lactone/solvent solution; and mixing the macrocyclic lactone/solvent solution with the polyether antibiotic to form the composition.
  • said combining comprises dissolving the polyether antibiotic in the solvent to form a polyether antibiotic/solvent solution; and mixing the polyether antibiotic/solvent solution with the macrocyclic lactone to form the composition.
  • Macrocyclic lactones suitable for use in the process include milbemycin D, avermectin, ivermectin, abamectin, doramectin, moxidectin, or combinations thereof, preferably moxidectin.
  • Polyether antibiotics suitable for use in the process include K-41 , maduramicin, monensin, lasalocid, salinomycin, narasin and combinations thereof.
  • the process further includes adding additional active agents to the composition, examples of which are the same as those described above.
  • compositions according to the present invention are to be used, or are to be prepared for use, in veterinary medicine, they may also contain additional carriers, stabilizing agents, buffering agents, preservatives or other excipients well know in the art.
  • Example 1 Method 1 -Method for In vitro testing of the efficacy of various macrolide:polvether combinations against nematodes
  • C. elegans is a non-parasitic soil-dwelling nematode. It has morphology and drug sensitivities similar to parasitic nematodes and is useful in early-stage evaluation of nematicidal compounds (see Simpkin, K. G and Coles, G. C. in The Use of Caenorhabditis Elegans for Anthelmintic Screening [1981] J. Chem. Tech. Biotechnol. Vol. 31 : pp.
  • Test compounds were dissolved in solvent and added (1 ⁇ l) to each well of a 96-well plate at the final concentrations indicated in Tables 2-7 below. Concentrations of the macrolide (when present) were varied by serially diluting macrolide stock solutions such that the doses of the macrolide decreased to 1/3 of the previous dose in each dilution step. A mixture of C. elegans in buffer is added to each well, such that worms of mixed stages (L1 , l_2, L3, l_4 and adults) are present in each well. In each experiment, the macrolide and polyether were each tested individually and in combination, with each condition being assayed in duplicate. Observations were made under a dissecting microscope.
  • a rating was based on the motility of the larvae and adults, using the rating system shown in Table 1 below.
  • the results obtained using the method of this example are presented in Tables 2-7 below for the specific macrolide:polyether combinations. A higher score indicates greater efficacy.
  • Example 2 Employing the method described in Example 1 , the efficacy of the lvermectin:K- 41 combination was evaluated. The results are presented in Table 2 below, where scores for each duplicate are shown separately.
  • Example A-In vitro testing of the efficacy of moxidectin:K-41 combination The method described in Example 1 was used to evaluate the efficacy of the moxidectin:K-41 combination. The results are presented in Table 4 below, where scores for each duplicate are shown separately.
  • Example 1 The method described in Example 1 was used to evaluate the efficacy of the moxidectin:monensin combination. The results are presented in Table 7 below, where scores for each duplicate are shown separately.
  • Example 7 Method for In vivo testing of the efficacy of various macrolide:polvether combinations against nematodes
  • Larvae of the parasite nematode strain T. colubriformis were obtained from fecal cultures of infected sheep. Animals were de-wormed prior to experimental infection and propagation of nematodes. Fecal material collection began on day 21 post-infection for T. colubriformis. Larvae were harvested, rinsed with deionized water and held in a refrigerator until use.
  • gerbils were euthanized and the small intestine of the gastrointestinal tract was removed and processed for enumeration of T. colubhformis. After mixing, the gut contents were transferred to a Petri dish and worms were enumerated under a microscope.
  • Example 7 The method described in Example 7 above was used to evaluate the efficacy of the nemadectin:K-41 combination against the nematode strain T. colubriformis.
  • Example 9 In vivo analysis of moxidectin:K-41 combination
  • the method described in Example 7 above was used to evaluate the efficacy of the moxidectin:K-41 combination against the nematode strain T. colubriformis. Representative results from an individual study are presented in Table 10 below.
  • the Expected % Effect is the % effect expected from the additive contribution of the individual components. If the Expected % Effect of the combination is lower than the experimentally observed effect of the combination, synergism has occurred.
  • Example 7 The method described in Example 7 above was used to evaluate the efficacy of the moxidectin:maduramicin combination against the nematode strain T. colubriformis. Representative results from an individual study are presented in Table 13 below. Table 13. Analysis of Moxidectin:Maduramicin Combination
  • Example 7 The method described in Example 7 above was used to evaluate the efficacy of the moxidectin:maduramicin combination against the nematode strain T. colubriformis. Representative results from an individual study are presented in Table 15 below.
  • Example 12- Comparative Evaluation of the Efficacy of moxidectin - K41 against Blowfly Larvae
  • filter paper discs were treated with an acetone solution of test compound and allowed to dry.
  • Bovine serum and newly emerged larvae of blowfly, Lucilia sericata were added to the treated filter paper. Mortality was assessed at 24h and 48h. When more than one evaluation was performed, the data were averaged.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des compositions vétérinaires comprenant une combinaison d'une lactone macrocyclique ; et un antibiotique polyéther. L'invention porte également sur un procédé de traitement ou de lutte contre une infection parasitaire dans un mammifère avec ces compositions vétérinaires.
PCT/US2010/032490 2009-04-28 2010-04-27 Combinaisons antiparasitaires de lactones macrocycliques et d'antibiotiques polyéther WO2010126857A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US17329909P 2009-04-28 2009-04-28
US61/173,299 2009-04-28

Publications (1)

Publication Number Publication Date
WO2010126857A1 true WO2010126857A1 (fr) 2010-11-04

Family

ID=42272644

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/032490 WO2010126857A1 (fr) 2009-04-28 2010-04-27 Combinaisons antiparasitaires de lactones macrocycliques et d'antibiotiques polyéther

Country Status (1)

Country Link
WO (1) WO2010126857A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103353530A (zh) * 2012-12-12 2013-10-16 河南省农业科学院 马杜霉素快速检测试纸条和试纸卡

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326417A2 (fr) * 1988-01-27 1989-08-02 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. Dérivés de l'antibiotique K-41, leur préparation et l'utilisation
WO2003033031A1 (fr) * 2001-10-19 2003-04-24 Eli Lilly And Company Forme posologique, dispositif et procedes de traitement
US20070128239A1 (en) * 2005-12-06 2007-06-07 Wyeth Benzimidazole non-aqueous compositions
WO2009018198A1 (fr) * 2007-07-31 2009-02-05 Wyeth Compositions topiques endoparasiticides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0326417A2 (fr) * 1988-01-27 1989-08-02 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. Dérivés de l'antibiotique K-41, leur préparation et l'utilisation
WO2003033031A1 (fr) * 2001-10-19 2003-04-24 Eli Lilly And Company Forme posologique, dispositif et procedes de traitement
US20070128239A1 (en) * 2005-12-06 2007-06-07 Wyeth Benzimidazole non-aqueous compositions
WO2009018198A1 (fr) * 2007-07-31 2009-02-05 Wyeth Compositions topiques endoparasiticides

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
COLBY, S. R.: "In Calculating Synergistic and Antagonistic Responses of Herbicide Combinations", WEEDS, vol. 15, no. 1, 1967, pages 20 - 22, XP001112961
COLBY, S. R: "Calculating Synergistic and Antagonistic Responses of Herbicide Combinations", WEEDS, vol. 15, no. 1, 1967, pages 20 - 22, XP001112961
PURVIS H T II ET AL: "Effects of ionophore feeding and anthelmintic administration on age and weight at puberty in spring-born beef heifers", JOURNAL OF ANIMAL SCIENCE, vol. 74, no. 4, 1996, pages 736 - 744, XP002590237, ISSN: 0021-8812 *
SIMPKIN, K.G; COLES, G.C.: "The Use of Caenorhabditis Elegans for Anthelmintic Screening", J. CHEM. TECH. BIOTECHNOL., vol. 31, 1981, pages 66 - 69
THE JOUMAL OF ANTIBIOTICS, vol. 29, 1976, pages 10 - 14
THE JOURNAL OF ANTIBIOTIC, vol. 55, no. 9, 2002, pages 832 - 834

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103353530A (zh) * 2012-12-12 2013-10-16 河南省农业科学院 马杜霉素快速检测试纸条和试纸卡

Similar Documents

Publication Publication Date Title
RU2660346C1 (ru) Паразитицидные пероральные ветеринарные композиции, включающие системно действующие активные агенты, способы и применение этих композиций и способов
AU2008272646B2 (en) Anthelmintic combination
EP2892347B1 (fr) Combinaisons antiparasitaires d'isoxazoline spirocyclique
JP5342239B2 (ja) ベンジイミダゾール非水性組成物
JP3862938B2 (ja) 駆虫性組成物
JP2006508108A (ja) 表面殺寄生生物処方物および処置方法
US10307405B2 (en) Stable veterinary combination formulations of macrocyclic lactones and imidazothiazoles
AU2006100661B4 (en) Topical formulation
WO2010126857A1 (fr) Combinaisons antiparasitaires de lactones macrocycliques et d'antibiotiques polyéther
AU2006100657C4 (en) Stabilised formulation
Rahman et al. Prospects and genesis of the versatile antiparasitic drug Ivermectin and its unsurpassed beneficial impact in Human and Veterinary Medicine.
AU2014332597A1 (en) Veterinary formulations and methods
US10765657B2 (en) Selamectin for treatment of sea lice infestations
AU2003258756B8 (en) Oleaginous oral antiparasitic compositions
US11773066B2 (en) Indazolylcyanoethylamino compound, compositions of same, method of making, and methods of using thereof
Banks Antiparasitic agents
AU2013204176B2 (en) Stable veterinary combination formulations of macrocyclic lactones and imidazothiazoles
AU2008201924A1 (en) Stabilised formulation
Islam et al. www. ijns. net
AU2009245870A1 (en) Combinations of an avermectin or milbemycin with 3-aryl-4-hydroxyfuranones
MXPA00006760A (en) Anthelmintic compositions containing combinations of avermectins or milbemycins with bis-aryl compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10715647

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10715647

Country of ref document: EP

Kind code of ref document: A1