US20200000718A1 - Solid Oral Pharmaceutical Compositions for Isoxazoline Compounds - Google Patents
Solid Oral Pharmaceutical Compositions for Isoxazoline Compounds Download PDFInfo
- Publication number
- US20200000718A1 US20200000718A1 US16/508,758 US201916508758A US2020000718A1 US 20200000718 A1 US20200000718 A1 US 20200000718A1 US 201916508758 A US201916508758 A US 201916508758A US 2020000718 A1 US2020000718 A1 US 2020000718A1
- Authority
- US
- United States
- Prior art keywords
- pharmaceutical composition
- solid oral
- oral pharmaceutical
- compound
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P33/10—Anthelmintics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
- A61P33/12—Schistosomicides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/14—Ectoparasiticides, e.g. scabicides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C37/00—Component parts, details, accessories or auxiliary operations, not covered by group B29C33/00 or B29C35/00
- B29C37/0003—Discharging moulded articles from the mould
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C43/00—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor
- B29C43/003—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor characterised by the choice of material
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
- B29L2031/00—Other particular articles
- B29L2031/753—Medical equipment; Accessories therefor
Definitions
- a number of parasites can infest or infect domestic animals especially also companion animals such as cats and dogs. These pests and parasites are of great nuisance to both the animals and their owners.
- Isoxazoline compounds are known in the art and these compounds and their use as antiparasitic are described, for example, in US patent application US 2007/0066617, and International Patent applications WO 2005/085216, WO 2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003075, WO 2009/080250, WO 2010/070068 and WO 2010/079077, the disclosures of which, as well as the references cited herein, are incorporated by reference.
- This class of compounds is known to possess excellent activity against ectoparasites, i.e. parasitic insect and acarids, such as ticks and fleas and endoparasites such as nematodes.
- isoxazoline compounds are carbamoyl benzamide phenyl isoxazoline (CBPI) compounds.
- CBPI carbamoyl benzamide phenyl isoxazoline
- a specific example of a CBPI compound is 4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN [864731-61-3])—USAN fluralaner.
- the CBPI compound fluralaner is disclosed in patent application WO 2005/085216.
- One known and convenient way of administering an ectoparasiticide compound to an animal is oral administration, e.g. as solid oral formulation such as tablets or soft chews that have a high bioavailability to allow the control of parasites with a low dosage of the ectoparasiticide compound orally administered to the animal.
- the current invention is directed to a solid oral pharmaceutical composition
- a solid oral pharmaceutical composition comprising an effective amount of at least one isoxazoline compound of the Formula (I)
- R 2 C 1 -C 3 -haloalkyl, preferably CF 3 or CF 2 Cl
- Q X—NR 3 R 4 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;
- X CH 2 , CH(CH 3 ), CH(CN), CO, CS,
- R 3 hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halome
- Z A hydrogen, halogen, cyano, halomethyl (CF 3 );
- R 4 hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; or R 3 and R 4 together form a substituent selected from the group consisting of:
- the solid oral pharmaceutical composition is a soft chewable veterinary pharmaceutical composition for oral administration.
- the solid carrier is microcrystalline cellulose.
- composition further comprises pamoic acid or a pharmaceutically acceptable salt thereof.
- the isoxazoline compound is fluralaner.
- the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N—[(Z)-(methoxyimino)methyl]-2-methyl-benzamide.
- the isoxazoline compound is afoxolaner.
- the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide.
- the isoxazoline compound is 5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide.
- the solid oral pharmaceutical composition comprises an additional pharmaceutically active compound.
- the additional pharmaceutically active compound is a macrocyclic lactone selected from the group of ivermectin, milbemycin, and moxidectin.
- the solid oral pharmaceutical composition comprises an isoxazoline compound of Formula (I) or a salt or solvate thereof, 2-pyrrolidone, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, sodium pamoate, magnesium stearate, aspartame, glycerol, soybean oil, and polyethylene glycol
- the solid oral pharmaceutical composition comprises an isoxazoline compound of Formula (I) or a salt or solvate thereof, dimethyl acetamide, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, sodium pamoate, magnesium stearate, aspartame, glycerol, soybean oil, and polyethylene glycol.
- Another aspect of the invention is a method of preparing a solid pharmaceutical composition comprising dissolving the isoxazoline compound as above in the solvent and then adsorbing the resulting solution on to the solid carrier excipient.
- the solid carrier is microcrystalline cellulose.
- the solvent is 2-pyrrolidone or dimethyl acetamide.
- Another aspect of the current invention is a method of controlling parasite infestation in an animal comprising administering to the animal a therapeutically effective amount of the composition as described above.
- Another aspect of the current invention is a solid oral pharmaceutical composition
- a solid oral pharmaceutical composition comprising an isoxazoline compound of Formula (I) or a salt or solvate thereof, and 2-pyrrolidone.
- the isoxazoline compound is fluralaner.
- the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N—[(Z)-(methoxyimino)methyl]-2-methyl-benzamide.
- the isoxazoline compound is afoxolaner.
- the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide.
- the isoxazoline compound is 5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide.
- the solid oral pharmaceutical composition is a soft chewable veterinary pharmaceutical composition for oral administration.
- Another aspect of the current invention is a method of controlling parasite infestation in an animal comprising administering to the animal a therapeutically effective amount of the composition as described above.
- FIG. 1 mean plasma concentration of the CPBI compound fluralaner administered orally to dogs.
- FIG. 2 mean plasma concentration of the isoxaoline compounds afoxolaner and -[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide administered orally to dogs.
- the present invention relates to the formulation of a solid oral dosage form (sometimes referred to as solid pharmaceutical composition or formulation) containing an isoxazoline compound of Formula (I) (as described below), that provides significantly improved bioavailability of such isoxazoline compound after administration to an animal.
- a solid oral dosage form sometimes referred to as solid pharmaceutical composition or formulation
- an isoxazoline compound of Formula (I) as described below
- the isoxazoline compound of Formula (I) is dissolved in a solvent. This drug solution is then adsorbed onto a solid carrier which is incorporated into a traditional solid oral dosage form. Utilizing pre-dissolved isoxazoline compounds of Formula (I) in the formulation significantly improves the bioavailability of the active drug substance compared to traditional solid oral dosage forms containing the active drug substance incorporated as a solid.
- DMAC dimethylacetamide
- This formulation approach provides unexpectedly significant improvement in bioavailability, enabling a significantly lower dosage required to achieve similar or superior pharmakokinetic profiles. Hence, similar blood levels can be achieved that lead to similar effectiveness to control parasites but with a reduced dosage of the isoxazoline compound.
- the solid oral dosage form according to the invention comprises an isoxazoline compound of the Formula (I)
- R 2 C 1 -C 3 -haloalkyl, preferably CF 3 or CF 2 Cl
- Q X—NR 3 R 4 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals Z A , Z B Z D ;
- X CH 2 , CH
- R 4 hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; or R 3 and R 4 together form a substituent selected from the group consisting of:
- Z A hydrogen, halogen, cyano, halomethyl (CF 3 ); or a salt or solvate thereof, a solid carrier and a solvent, wherein the solvent is selected from 2-pyrrolidone, dimethylacetamide or mixtures thereof.
- T is selected from
- T-1, T-3 and T-4 the radical Y is hydrogen, halogen, methyl, halomethyl, ethyl, haloethyl.
- R 3 , R 4 , X and Z A are as defined above.
- Preferred compounds of Formula (I) are:
- a more preferred compound has the Formula (II),
- R 1a , R 1b , R 1c are independently from each other hydrogen, Cl or CF 3 , preferably R 1a and R 1c are Cl or CF 3 and R 1b is hydrogen,
- Y is methyl, bromine, Cl, F, CN or C(S)NH 2 , and Q is as described above.
- R 3 is H and R 4 is —CH 2 —C(O)—NH—CH 2 —CF 3 , —CH 2 —C(O)—NH—CH 2 —CH 3 , —CH 2 —CH 2 —CF 3 or —CH 2 —CF 3 .
- the compound of Formula (I) is 4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3-USAN fluralaner).
- the compound of Formula (I) is (Z)-4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN 928789-76-8).
- the compound of Formula (I) is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide (CAS RN 1164267-94-0) that was disclosed in WO2009/0080250.
- the compound of Formula (I) is 4-[5-[3-Chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (CAS RN 1093861-60-9, USAN-afoxolaner) that was disclosed in WO2007/079162-.
- the compound of Formula (I) is 5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CAS RN 1231754-09-8) that was disclosed in WO2010/070068.
- Especially preferred compounds of Formula (II) are:
- Isoxazoline compounds are known in the art and these compounds and their use as parasiticide are described, for example, in US patent application No. US 2007/0066617, and International Patent applications WO 2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003075, WO2009/080250, WO 2010/070068, WO 2010/079077, WO 2011/075591 and WO 2011/124998, the disclosures of which, as well as the references cited herein, are incorporated by reference.
- This class of compounds is known to possess excellent activity against ectoparasites such as ticks and fleas.
- the isoxazoline compounds may exist in various isomeric forms.
- a reference to an isoxazoline compound always includes all possible isomeric forms of such compound.
- a compound structure that does not indicate a particular conformation is intended to encompass compositions of all the possible conformational isomers of the compound, as well as compositions comprising fewer than all the possible conformational isomers.
- the compound is a chiral compound. In some embodiments, the compound is a non-chiral compound.
- Isoxazoline compounds of Formula (I) can be prepared according to one or other of the processes described e.g. in Patent Applications US 2007/0066617, WO 2007/079162, WO 2009/002809, WO 2009/080250, WO 2010/070068, WO 2010/079077, 2011/075591 and WO 2011/124998 or any other process coming within the competence of a person skilled in the art who is an expert in chemical synthesis.
- a person skilled in the art is regarded as having at his disposal, inter alia, the entire contents of “Chemical Abstracts” and of the documents which are cited therein.
- formulations according to the invention are effective for long durations of time in the treatment of ectoparasites of mammals and, in particular, of fleas and ticks in small mammals such as dogs and cats.
- the amount of the isoxazoline compound of Formula (I) in the formulation may be in the range of 1-15% w/w. In an alternative embodiment the amount of such compound may be in the range of 2.0-7.5% w/w. The preferred range is 3.0-4.5% w/w.
- the composition comprises a solid carrier, e.g. microcrystalline cellulose, colloidal silicone dioxide, polyvinyl pyrrolidone or other solid carrier excipient with appropriate characteristic behaviours.
- a solid carrier e.g. microcrystalline cellulose, colloidal silicone dioxide, polyvinyl pyrrolidone or other solid carrier excipient with appropriate characteristic behaviours.
- the solid carrier is microcrystalline cellulose (10.0-50.0% w/w, preferred 15.0-25.0% w/w).
- one preferred solvent is a pyrrolidone solvent, especially 2-pyrrolidone.
- pyrrolidone solvents such as N-methylpyrrolidone can be used.
- dimethyl acetamide Another preferred solvent is dimethyl acetamide (DMAC).
- DMAC dimethyl acetamide
- Alternative solvents for use in the current invention dimethyl sulfoxide, dimethyl formamide, diethylene glycol monoethyl ether, ethyl lactate, ethylene monomethyl ether, glycofurol, N,N-diethyl-m-toluamide (DEET) or other solvent with suitable solubility for the compound of Formula (I). Solvent combinations may also be utilized in the formulation according to the invention. The preferred range of such other solvents is 2.0-35.0% w/w.
- the amount of the pyrrolidone solvent, especially 2-pyrrolidone in the formulation may be in the range of 2.5-30.0% w/w.
- the preferred range is 7.0-12.0% w/w.
- the preferred range of other dimethyl acetamide is 2.0-35.0% w/w.
- the solid oral dosage form is a soft chew.
- the solid oral dosage form is a conventional (hard) tablet.
- Such tablet can include a coating or can include excipients for extended release that are known in the art.
- granules for oral administration or capsules are employed.
- Soft chew or “Soft chewable veterinary pharmaceutical product” is intended to mean a product which is solid at room temperature and that is soft to chew and which is functionally chewy because the product has some plastic texture during the process of mastication in the mouth. Such soft chews have a softness that is similar to a cooked ground meat patty.
- the forming agent is important for the texture of the soft chew and the possibility to form single soft chews from the dough that stay intact and separate.
- Forming agents are agents providing texture to the soft chew product, like for example polyethylene glycol (PEG), microcrystalline wax, cetyl alcohol or polyvinylpyrrolidone (PVP).
- the forming agent is polyethylene glycol (PEG).
- PEG polyethylene glycol
- different molecular weight PEG may be utilized.
- PEG 8000 is utilized. However, the PEG chosen is a matter of choice and the molecular weight may be higher or lower than 8000, but preferably higher than 600. Alternatively PEG 3500 might be used.
- the forming agent comprises about 3.0% to about 35% w/w of the pharmaceutical composition. In an alternate embodiment, a forming agent comprises about 4.5% to about 30% w/w % of the pharmaceutical composition. In an alternate embodiment, a forming agent comprises about 10% to about 20% w/w of the pharmaceutical composition. In case the forming agent is polyvinylpyrrolidone e.g. 2, 4, 5, 6 or 9% w/w are present in the soft chew.
- a preferred formulation for the solid oral pharmaceutical composition includes:
- the amount of glycerol in the formulation may range from 0-12.0% with the preferred range of 0.5-10.0%.
- Soybean oil amounts may range from 5.0-25.0% with the preferred range of 10.0-22.0%. Desired ranges of the other excipients include sodium starch glycolate (2.0-15.0%), flavor (5-25%), sodium lauryl sulfate (0.05-5.0%), sodium pamoate (0.01-5.0%), aspartame (0.01-2.0%), and magnesium stearate (0.01-2.0%).
- the formulation according to the current invention conventionally further comprise physiologically acceptable formulation excipients known in the art e.g. as described in “Gennaro, Remington: The Science and Practice of Pharmacy” (20th Edition, 2000) incorporated by reference herein. All such ingredients, carriers and excipients must be substantially pharmaceutically or veterinary pure and non-toxic in the amounts employed and must be compatible with the pharmaceutically active ingredients.
- excipients that can be present in the formulation are e.g. one or more fillers, one or more flavours, or sugar components, surfactants, stabilizers, flow agents, disintegration agents, preservatives and/or lubricating agents.
- This invention is also directed to formulations as described above with combinations comprising more than one pharmaceutically active ingredient, e.g. in addition to the compound of Formula (I) another compound of Formula (I) or a pharmaceutically active ingredient with a different structure.
- Preferred combinations comprising active ingredients selected from the group consisting of isoxazoline compounds of Formula (I) or (II) and avermectins and milbemycins.
- the formulation, especially soft chew comprises a combination of an isoxazoline compound of Formula (I), especially fluralaner or afoxolaner, with ivermectin.
- the soft chew comprises a combination of an isoxazoline compound of Formula (I), especially fluralaner por afoxolaner, with milbemycin or with moxidectin.
- AGRs or IGRs insect or acarid growth regulators
- fenoxycarb e.g. fenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine, methoprene, pyriproxyfen etc.
- fenoxycarb e.g. fenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine, methoprene, pyriproxyfen etc.
- the inventors discovered that oral solid dosage forms of isoxazoline compounds of Formula (I) as described above, especially of fluralaner, afoxoloaner can be produced that result in a higher bioavailability of the isoxazoline compound after administration to animals.
- the isoxazoline compound of Formula (I) is first dissolved in a suitable solvent (e.g. 2-pyrol or DMAC) and then adhered to a solid carrier (e.g. microcrystalline cellulose).
- a suitable solvent e.g. 2-pyrol or DMAC
- a solid carrier e.g. microcrystalline cellulose
- a general method for preparing a solid oral dosage form, such as a soft chewable tablet formulation comprises the steps of:
- the tablets may be formed from the final bulk mass utilizing a forming machine.
- the tablets may be formed by other means known in the art.
- the tablets may be formed by hand.
- the product of the invention is intended for use for controlling a parasitic insect-, acarid and/or helminth, especially parasitic insect and/or acarid infestation.
- controlling a parasitic insect- and/or acarid infestation refers to preventing, reducing or eliminating an infestation by such parasites on animals preferably by killing the insects and/or acarids or nematode parasites within hours or days.
- parasitic insect- and acarid refers to ectoparasites e.g. insect and acarine pests that commonly infest or infect animals.
- ectoparasites include the egg, larval, pupal, nymphal and adult stages of lice, fleas, mosquitoes, mites, ticks, and biting or nuisance fly species. Especially important are fleas and ticks, especially their adult stages.
- invertebrate parasitic pests controlled by administering the solid oral formulation of this invention to an animal to be protected include ectoparasites (arthropods, acarines, etc) and endoparasites (helminths, e.g., nematodes, trematodes, cestodes, acanthocephalans, etc.).
- ectoparasites arthropods, acarines, etc
- endoparasites helminths, e.g., nematodes, trematodes, cestodes, acanthocephalans, etc.
- the formulations of this invention are effective against ectoparasites including: flies such as Haematobia (Lyperosia) irritans (horn fly), Stomoxys calcitrans (stable fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestica (house fly), Morellia simplex (sweat fly), Tabanus spp. (horse fly), Hypoderma bovis, Hypoderma lineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphora spp.
- flies such as Haematobia (Lyperosia) irritans (horn fly), Stomoxys calcitrans (stable fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies),
- cyanotis ear mites
- ticks such as Ixodes spp., Boophilus spp., Rhipicephalus spp., Amblyomma spp., Dermacentor spp., Hyalomma spp. and Haemaphysalis spp.
- fleas such as Ctenocephalides felis (cat flea) and Ctenocephalides canis (dog flea).
- the formulations according to the invention will contain an effective amount of the isoxazoline compounds of Formula (I) as defined above, meaning a non-toxic but sufficient amount to provide the desired control effect.
- an appropriate “effective” amount in any individual case. Such an amount will depend on the age, condition, weight and type of the target animal.
- the solid oral dosage forms may be formulated to contain an amount of the isoxazoline compound of Formula (I) that is adjusted to animals in a specific weight range.
- the animals may receive a dosage of the solid oral formulation according to the invention every 2, 3, 4, 5 or 6 months or receives a monthly, weekly or daily dosage.
- the treatment can, for example, be continuing or seasonal. The time period between treatments depends upon factors such as the parasite(s) being treated, the degree of infestation, the type of mammal or bird and the environment where it resides. It is well within the skill level of the practitioner to determine a specific administration period for a particular situation.
- the solid oral formulations of the present invention are especially suitable for combating parasites that infest mammals (including humans).
- Mammalian subjects include primates (e.g., monkeys), bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine (e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs), feline (e.g., house cats), camels, deer, donkeys, buffalos, antelopes, rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils, and hamsters).
- the animals to be protected are domesticated dogs (i.e. Canis lupus familiaris ) and domestic house cats (i.e. Felis catus ).
- the solid oral formulation of an isoxazoline of Formula (I) is administered to treat parasitoses of an animal (or make a medicament to treat parasitoses of an animal).
- parasitoses includes pathologic conditions and diseases associated with or caused by one or more ectoparasites directly, such as, for example, anemia and flea allergy dermatitis. It also includes pathologic conditions or diseases associated with caused by one or more vector-transmitted pathogens, such as, for example, Lyme disease, Ehrlichiosis (particularly Canine Ehrlichiosis), and Rocky Mountain spotted fever from vector ticks.
- This invention also relates to treatment methods wherein at least an ancillary goal of controlling ectoparasites in and/or on an animal is to control an ectoparasitic infestation in an environment that is occupied (periodically or continuously) by the animal.
- the animal is a companion animal (e.g., a cat or dog).
- the environment may be, for example, a house or other shelter; a room; a pen, a stall, or other confinement means; bedding; etc.
- kits that are, for example, suitable for use in performing the treatment methods described above.
- a kit will comprise an oral solid formulation according to the invention comprising a therapeutically effective amount of a isoxazoline of Formula (I), and an additional component(s).
- the additional component(s) may be, for example, one or more of the following: a diagnostic tool, instructions for administering the composition, an apparatus for administering the composition, a container comprising an excipient or other active ingredient to be mixed or administered in combination with the composition, or a memory aid (e.g., a stamp to adhere to a calendar to remind an animal owner of a time to administer a subsequent dose of the composition).
- w/w designates weight/weight
- w/v designates weight/volume
- mg/kg designates milligrams per kilogram of body weight.
- % w/w represents the percentage by weight of an ingredient in the recipe of the product.
- Dimethylacetamide is a good solvent for the active (A-1443) with a solubility of 791.5 mg/mL.
- DMAC Dimethylacetamide
- This formulation approach provides significant improvement in bioavailability, enabling a significantly lower dosage required to achieve similar to superior pharmacokinetic profiles.
- the objective of this study is to compare the blood plasma pharmacokinetic profile of three different isoxazoline compounds in two different chewable formulations after a single oral (PO) administration of in dogs.
- the following compounds were formulated according to the invention. Specifically, the isoxazoline compound was first dissolved in a solvent, i.e. 2-pyrrolidone. This drug solution was then adsorbed onto the solid carrier, i.e. microcrystalline cellulose, which was incorporated into a solid oral dosage form as described in the specification with excipients as described in Table 3.
- a solvent i.e. 2-pyrrolidone.
- This drug solution was then adsorbed onto the solid carrier, i.e. microcrystalline cellulose, which was incorporated into a solid oral dosage form as described in the specification with excipients as described in Table 3.
- Comparative example formulation ID No. 13-009, 13-011 and 13-013 contain the active drug substance incorporated as a solid that was manufactured as described in general in the specification without prior pre-dissolving the active ingredient and adsorption to the solid carrier.
- test compounds were administered orally to four beagle dogs per dose group for a total of twenty-four dogs.
- Each animal was administered the tablet or chew by placing it in the back of the oral cavity over the tongue to initiate swallowing.
- Individual blood samples (approximately 4.5 mL per sample) were taken via jugular venipuncture into sodium-citrate tubes from all dogs for drug analysis. Blood samples were collected at the following time points: pretreatment (within 2 h prior to dosing) and approximately 1, 2, 4, 6, 8, 24, 48, 72 hours after dosing ( ⁇ 15 min). A final blood sample was taken from each dog on Day 7 ( ⁇ 2 h after the time of dosing on Day 0).
- a solid pharmaceutical composition according to the invention with the following excipients was prepared.
- Excipient Composition (% w/w) Fluralaner 4.27% 2-pyrrolidone 10.19% microcrystalline cellulose 24.27% sodium starch glycolate 4.95% flavor 14.56% sodium lauryl sulfate 3.40% sodium pamoate 2.43% aspartame 0.49% magnesium stearate 0.49% glycerol 2.91% soybean oil 16.75% Polyethylene Glycol 8000 15.29%
- Dogs were randomly assigned to 4 treatment groups of 8 animals each, and one untreated control group of 8 animals.
- the dogs in the treatment groups were treated with the composition as described above on Day Zero as shown in Table 6:
- the dogs were infested on Day ⁇ 2 with approximately 50 adult unfed ticks ( R. sanguineus ) and on Day 28 and 56. Ticks were counted approximately 48 h post infestation and on Days 30 and 58 (approximately 48 hour after each post-treatment re-infestation) to evaluate the acaricidal activity in the treated groups.
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Abstract
Description
- A number of parasites can infest or infect domestic animals especially also companion animals such as cats and dogs. These pests and parasites are of great nuisance to both the animals and their owners.
- Isoxazoline compounds are known in the art and these compounds and their use as antiparasitic are described, for example, in US patent application US 2007/0066617, and International Patent applications WO 2005/085216, WO 2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003075, WO 2009/080250, WO 2010/070068 and WO 2010/079077, the disclosures of which, as well as the references cited herein, are incorporated by reference.
- This class of compounds is known to possess excellent activity against ectoparasites, i.e. parasitic insect and acarids, such as ticks and fleas and endoparasites such as nematodes.
- Examples of isoxazoline compounds are carbamoyl benzamide phenyl isoxazoline (CBPI) compounds. A specific example of a CBPI compound is 4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN [864731-61-3])—USAN fluralaner.
- The CBPI compound fluralaner is disclosed in patent application WO 2005/085216.
- As these isoxazoline compounds have been originally investigated for their use in the agricultural area it is necessary to identify specific formulations that allow their veterinary use, i.e. safe administration to control parasites in animals effectively.
- One known and convenient way of administering an ectoparasiticide compound to an animal is oral administration, e.g. as solid oral formulation such as tablets or soft chews that have a high bioavailability to allow the control of parasites with a low dosage of the ectoparasiticide compound orally administered to the animal.
- In one aspect the current invention is directed to a solid oral pharmaceutical composition comprising an effective amount of at least one isoxazoline compound of the Formula (I)
- wherein
R1=halogen, CF3, OCF3, CN,
n=integer from 0 to 3, preferably 1, 2 or 3,
R2=C1-C3-haloalkyl, preferably CF3 or CF2Cl,
T=5- or 6-membered ring, which is optionally substituted by one or more radicals Y,
Y=methyl, halomethyl, halogen, CN, NO2, NH2—C═S, or two adjacent radicals Y form together a chain, especially a three or four membered chain;
Q=X—NR3R4 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;
X=CH2, CH(CH3), CH(CN), CO, CS,
R3=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, - wherein ZA=hydrogen, halogen, cyano, halomethyl (CF3);
R4=hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl;
or R3 and R4 together form a substituent selected from the group consisting of: - or a salt or solvate thereof, a solid carrier and a solvent, wherein the solvent is selected from 2-pyrrolidone, dimethylacetamide or mixtures thereof.
- In a preferred embodiment the solid oral pharmaceutical composition is a soft chewable veterinary pharmaceutical composition for oral administration.
- In a preferred embodiment the solid carrier is microcrystalline cellulose.
- In one embodiment the composition further comprises pamoic acid or a pharmaceutically acceptable salt thereof.
- In one embodiment the isoxazoline compound is fluralaner.
- In one embodiment the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N—[(Z)-(methoxyimino)methyl]-2-methyl-benzamide.
- In one embodiment the isoxazoline compound is afoxolaner.
- In one embodiment the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide.
- In one embodiment the isoxazoline compound is 5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide.
- In one embodiment the solid oral pharmaceutical composition comprises an additional pharmaceutically active compound.
- In one embodiment the additional pharmaceutically active compound is a macrocyclic lactone selected from the group of ivermectin, milbemycin, and moxidectin.
- In one embodiment the solid oral pharmaceutical composition comprises an isoxazoline compound of Formula (I) or a salt or solvate thereof, 2-pyrrolidone, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, sodium pamoate, magnesium stearate, aspartame, glycerol, soybean oil, and polyethylene glycol
- In another embodiment the solid oral pharmaceutical composition comprises an isoxazoline compound of Formula (I) or a salt or solvate thereof, dimethyl acetamide, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, sodium pamoate, magnesium stearate, aspartame, glycerol, soybean oil, and polyethylene glycol.
- Another aspect of the invention is a method of preparing a solid pharmaceutical composition comprising dissolving the isoxazoline compound as above in the solvent and then adsorbing the resulting solution on to the solid carrier excipient.
- In one embodiment of this method the solid carrier is microcrystalline cellulose.
- In another embodiment of this method the solvent is 2-pyrrolidone or dimethyl acetamide.
- Another aspect of the current invention is a method of controlling parasite infestation in an animal comprising administering to the animal a therapeutically effective amount of the composition as described above.
- Another aspect of the current invention is a solid oral pharmaceutical composition comprising an isoxazoline compound of Formula (I) or a salt or solvate thereof, and 2-pyrrolidone.
- In one embodiment the isoxazoline compound is fluralaner.
- In one embodiment the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N—[(Z)-(methoxyimino)methyl]-2-methyl-benzamide.
- In one embodiment the isoxazoline compound is afoxolaner.
- In one embodiment the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide.
- In one embodiment the isoxazoline compound is 5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide.
- In one embodiment the solid oral pharmaceutical composition is a soft chewable veterinary pharmaceutical composition for oral administration.
- Another aspect of the current invention is a method of controlling parasite infestation in an animal comprising administering to the animal a therapeutically effective amount of the composition as described above.
-
FIG. 1 —mean plasma concentration of the CPBI compound fluralaner administered orally to dogs. -
FIG. 2 —mean plasma concentration of the isoxaoline compounds afoxolaner and -[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide administered orally to dogs. - The present invention relates to the formulation of a solid oral dosage form (sometimes referred to as solid pharmaceutical composition or formulation) containing an isoxazoline compound of Formula (I) (as described below), that provides significantly improved bioavailability of such isoxazoline compound after administration to an animal.
- Specifically, in this formulation the isoxazoline compound of Formula (I) is dissolved in a solvent. This drug solution is then adsorbed onto a solid carrier which is incorporated into a traditional solid oral dosage form. Utilizing pre-dissolved isoxazoline compounds of Formula (I) in the formulation significantly improves the bioavailability of the active drug substance compared to traditional solid oral dosage forms containing the active drug substance incorporated as a solid.
- As indicated in the example the inventors discovered, that with dimethylacetamide (DMAC) as solvent for isoxazoline compounds in a solid oral dosage form similar pharmacokinetic profiles were obtained when it was s dosed at a lower dose compared to dosage forms with the active incorporated in higher dosage as a solid.
- When 2-pyrrolidone (2-pyrol) was utilized as the solvent in the formulation, significantly higher plasma levels were observed compared to the control, even with the formulation comprising an isoxazoline compound dosed at a lower dose.
- This formulation approach provides unexpectedly significant improvement in bioavailability, enabling a significantly lower dosage required to achieve similar or superior pharmakokinetic profiles. Hence, similar blood levels can be achieved that lead to similar effectiveness to control parasites but with a reduced dosage of the isoxazoline compound.
- The solid oral dosage form according to the invention comprises an isoxazoline compound of the Formula (I)
- wherein
R1=halogen, CF3, OCF3, ON,
n=integer from 0 to 3, preferably 1, 2 or 3,
R2=C1-C3-haloalkyl, preferably CF3 or CF2Cl,
T=5- or 6-membered ring, which is optionally substituted by one or more radicals Y,
Y=methyl, halomethyl, halogen, CN, NO2, NH2—C═S, or two adjacent radicals Y form together a chain CH—CH═CH—CH, N—CH═CH—CH, CH—N═CH—CH, CH—CH═N—CH, or CH—CH═CH—N, HC═HC—CH, CH—CH═CH, CH═CH—N, N—CH═CH;
Q=X—NR3R4 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals ZA, ZB ZD;
X=CH2, CH(CH3), CH(CN), CO, CS,
R3=hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, - R4=hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; or
R3 and R4 together form a substituent selected from the group consisting of: - wherein ZA=hydrogen, halogen, cyano, halomethyl (CF3);
or a salt or solvate thereof, a solid carrier and a solvent, wherein the solvent is selected from 2-pyrrolidone, dimethylacetamide or mixtures thereof. - In one preferred embodiment in Formula (I) T is selected from
- wherein in T-1, T-3 and T-4 the radical Y is hydrogen, halogen, methyl, halomethyl, ethyl, haloethyl.
- In an preferred embodiment in Formula (I) Q is selected from
- Wherein R3, R4, X and ZA are as defined above.
- Preferred compounds of Formula (I) are:
-
(R1)n R2 R3 R4 T Y Q Z X 3-Cl, 5Cl CF3 CH2CF3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 CH2CH3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 CH2CH2OCH3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 CH2C(O)NHCH2CF3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 CH2C(O)NHCH2CH3 H T-2 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-2 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CH3 H T-2 — Q-1 — C(O) 3-CF3, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-2 — Q-1 — C(O) 3-CF3, 5-Cl CF3 CH2C(O)NHCH2CH3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 — T-2 — Q-6 ZB-7 3-Cl, 5Cl CF3 — — T-2 — Q-7 ZB-7 3-Cl, 5Cl CF3 — — T-2 — Q-5 ZB-7 3-Cl, 5Cl CF3 — — T-2 — Q-2 ZD-1 3-Cl, 5Cl CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-Cl, 5Cl CF3 CH2C(O)NHCH2CC H T-3 CH3 Q-1 — C(O) 3-Cl, 5Cl CF3 CH2C(O)NHCH2CN H T-3 CH3 Q-1 — C(O) 3-Cl, 5Cl CF3 CH2C(O)NHCH2CH3 H T-3 CH3 Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CH3 H T-3 CH3 Q-1 — C(O) 3-Cl, 4-Cl, CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 5-Cl 3-Cl, 4-Cl, CF3 CH2C(O)NHCH2CH3 H T-3 CH3 Q-1 — C(O) 5-Cl 3-Cl, 4-F, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-Cl, 4-F, 5-Cl CF3 CH2C(O)NHCH2CH3 H T-3 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-20 — Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CH3 H T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 CH3 T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CH3 CH3 T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CH3 H T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-21 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CH3 H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CH3 H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2CH2SCH3 H T-21 — Q-1 — C(O) 3-Cl, 4-Cl, CF3 C(O)CH3 H T-22 F Q-1 — CH2 5-Cl 3-Cl, 4-Cl, CF3 C(O)CH(CH3)2 H T-22 F Q-1 — CH2 5-Cl 3-Cl, 4-Cl, CF3 C(O)-cyclo-propyl H T-22 F Q-1 — CH2 5-Cl 3-Cl, 4-F, 5-Cl CF3 C(O)CH3 H T-22 F Q-1 — CH2 3-Cl, 4-Cl, CF3 C(O)CH2CH3 H T-22 F Q-1 — CH2 5-Cl 3-Cl, 4-F, 5-Cl CF3 C(O)CH3 H T-22 Cl Q-1 — CH2 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-1 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CH3 H T-1 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 R3-1 (Z) H T-1 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 R3-1 (E) H T-1 CH3 Q-1 — C(O) - Especially preferred compounds of Formula (I) are
-
(R1)n R2 R3 R4 T Y Q Z X 3-Cl, 5Cl CF3 CH2CF3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 CH2CH3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 CH2CH2OCH3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 CH2C(O)NHCH2CF3 H T-2 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-2 — Q-1 — C(O) 3-CF3, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 — T-2 — Q-6 ZB-7 3-Cl, 5Cl CF3 — — T-2 — Q-7 ZB-7 3-Cl, 5Cl CF3 — — T-2 — Q-5 ZB-7 3-Cl, 5Cl CF3 — — T-2 — Q-2 ZD-1 3-Cl, 5Cl CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-Cl, 5Cl CF3 CH2C(O)NHCH2CC H T-3 CH3 Q-1 — C(O) 3-Cl, 5Cl CF3 CH2C(O)NHCH2CN H T-3 CH3 Q-1 — C(O) 3-CF3,5-CF3 CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-Cl, 4-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-Cl, 4-F, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 CH T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2CH2SCH3 H T-21 — Q-1 — C(O) 3-Cl, 4-Cl, 5-Cl CF3 C(O)CH3 H T-22 F Q-1 — CH2 3-Cl, 4-Cl, 5-Cl CF3 C(O)CH(CH3)2 H T-22 F Q-1 — CH2 3-Cl, 4-Cl, 5-Cl CF3 C(O)-cyclo-propyl H T-22 F Q-1 — CH2 3-Cl, 4-F, 5-Cl CF3 C(O)CH3 H T-22 F Q-1 — CH2 3-Cl, 4-Cl, 5-Cl CF3 C(O)CH2CH3 H T-22 F Q-1 — CH2 3-Cl, 4-F, 5-Cl CF3 C(O)CH3 H T-22 Cl Q-1 — CH2 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-1 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 R3-1 (Z) H T-1 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 R3-1 (E) H T-1 CH3 Q-1 — C(O) - A more preferred compound has the Formula (II),
- R1a, R1b, R1c are independently from each other hydrogen, Cl or CF3, preferably R1a and R1c are Cl or CF3 and R1b is hydrogen,
-
- wherein Y is methyl, bromine, Cl, F, CN or C(S)NH2, and
Q is as described above. - In another preferred embodiment in R3 is H and R4 is —CH2—C(O)—NH—CH2—CF3, —CH2—C(O)—NH—CH2—CH3, —CH2—CH2—CF3 or —CH2—CF3.
- In one embodiment the compound of Formula (I) is 4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3-USAN fluralaner).
- In another embodiment the compound of Formula (I) is (Z)-4-[5-(3,5-Dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN 928789-76-8).
- In another embodiment the compound of Formula (I) is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide (CAS RN 1164267-94-0) that was disclosed in WO2009/0080250.
- In another embodiment the compound of Formula (I) is 4-[5-[3-Chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (CAS RN 1093861-60-9, USAN-afoxolaner) that was disclosed in WO2007/079162-.
- In another embodiment the compound of Formula (I) is 5-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CAS RN 1231754-09-8) that was disclosed in WO2010/070068.
- An especially preferred compound is
- Especially preferred compounds of Formula (II) are:
-
(R1)n R2 R3 R4 T Y Q Z X 3-Cl, 5Cl CF3 CH2CF3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 CH2C(O)NHCH2CF3 H T-2 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-2 — Q-1 — C(O) 3-CF3, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-2 — Q-1 — C(O) 3-Cl, 5Cl CF3 — T-2 — Q-6 ZB-7 3-Cl, 5Cl CF3 — — T-2 — Q-7 ZB-7 3-Cl, 5Cl CF3 — — T-2 — Q-5 ZB-7 3-Cl, 5Cl CF3 — — T-2 — Q-2 ZD-1 3-Cl, 5Cl CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-Cl, 4-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-Cl, 4-F, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-3 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 CH3 T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-20 — Q-1 — C(O) 3-CF3, 5-CF3 CF3 CH2C(O)NHCH2CF3 H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-21 — Q-1 — C(O) 3-Cl, 5-Cl CF3 CH2C(O)NHCH2CF3 H T-1 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 R3-1 (Z) H T-1 CH3 Q-1 — C(O) 3-Cl, 5-Cl CF3 R3-1 (E) H T-1 CH3 Q-1 — C(O) - Isoxazoline compounds are known in the art and these compounds and their use as parasiticide are described, for example, in US patent application No. US 2007/0066617, and International Patent applications WO 2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003075, WO2009/080250, WO 2010/070068, WO 2010/079077, WO 2011/075591 and WO 2011/124998, the disclosures of which, as well as the references cited herein, are incorporated by reference. This class of compounds is known to possess excellent activity against ectoparasites such as ticks and fleas.
- The isoxazoline compounds may exist in various isomeric forms. A reference to an isoxazoline compound always includes all possible isomeric forms of such compound. Unless otherwise stated, a compound structure that does not indicate a particular conformation is intended to encompass compositions of all the possible conformational isomers of the compound, as well as compositions comprising fewer than all the possible conformational isomers. In some embodiments, the compound is a chiral compound. In some embodiments, the compound is a non-chiral compound.
- Isoxazoline compounds of Formula (I) can be prepared according to one or other of the processes described e.g. in Patent Applications US 2007/0066617, WO 2007/079162, WO 2009/002809, WO 2009/080250, WO 2010/070068, WO 2010/079077, 2011/075591 and WO 2011/124998 or any other process coming within the competence of a person skilled in the art who is an expert in chemical synthesis. For the chemical preparation of the products of the invention, a person skilled in the art is regarded as having at his disposal, inter alia, the entire contents of “Chemical Abstracts” and of the documents which are cited therein.
- The formulations according to the invention are effective for long durations of time in the treatment of ectoparasites of mammals and, in particular, of fleas and ticks in small mammals such as dogs and cats.
- The amount of the isoxazoline compound of Formula (I) in the formulation may be in the range of 1-15% w/w. In an alternative embodiment the amount of such compound may be in the range of 2.0-7.5% w/w. The preferred range is 3.0-4.5% w/w.
- In one embodiment, the composition comprises a solid carrier, e.g. microcrystalline cellulose, colloidal silicone dioxide, polyvinyl pyrrolidone or other solid carrier excipient with appropriate characteristic behaviours.
- In one embodiment the solid carrier is microcrystalline cellulose (10.0-50.0% w/w, preferred 15.0-25.0% w/w).
- In the formulation according to the invention one preferred solvent is a pyrrolidone solvent, especially 2-pyrrolidone. Alternatively other pyrrolidone solvents such as N-methylpyrrolidone can be used.
- Another preferred solvent is dimethyl acetamide (DMAC). The preferred range of dimethyl acetamide (DMAC) is 2.0-35.0% w/w. Alternative solvents for use in the current invention dimethyl sulfoxide, dimethyl formamide, diethylene glycol monoethyl ether, ethyl lactate, ethylene monomethyl ether, glycofurol, N,N-diethyl-m-toluamide (DEET) or other solvent with suitable solubility for the compound of Formula (I). Solvent combinations may also be utilized in the formulation according to the invention. The preferred range of such other solvents is 2.0-35.0% w/w.
- The amount of the pyrrolidone solvent, especially 2-pyrrolidone in the formulation may be in the range of 2.5-30.0% w/w. The preferred range is 7.0-12.0% w/w. The preferred range of other dimethyl acetamide is 2.0-35.0% w/w.
- In one embodiment, the solid oral dosage form is a soft chew. In another embodiment, the solid oral dosage form is a conventional (hard) tablet. Such tablet can include a coating or can include excipients for extended release that are known in the art. In yet another embodiment, granules for oral administration or capsules are employed.
- “Soft chew” or “Soft chewable veterinary pharmaceutical product” is intended to mean a product which is solid at room temperature and that is soft to chew and which is functionally chewy because the product has some plastic texture during the process of mastication in the mouth. Such soft chews have a softness that is similar to a cooked ground meat patty.
- In soft chew formulations the forming agent is important for the texture of the soft chew and the possibility to form single soft chews from the dough that stay intact and separate. Forming agents are agents providing texture to the soft chew product, like for example polyethylene glycol (PEG), microcrystalline wax, cetyl alcohol or polyvinylpyrrolidone (PVP). In an embodiment, the forming agent is polyethylene glycol (PEG). Moreover, depending upon the desired consistency of the soft chew, different molecular weight PEG may be utilized. In an embodiment, PEG 8000 is utilized. However, the PEG chosen is a matter of choice and the molecular weight may be higher or lower than 8000, but preferably higher than 600. Alternatively
PEG 3500 might be used. - In an embodiment, the forming agent comprises about 3.0% to about 35% w/w of the pharmaceutical composition. In an alternate embodiment, a forming agent comprises about 4.5% to about 30% w/w % of the pharmaceutical composition. In an alternate embodiment, a forming agent comprises about 10% to about 20% w/w of the pharmaceutical composition. In case the forming agent is polyvinylpyrrolidone e.g. 2, 4, 5, 6 or 9% w/w are present in the soft chew.
- A preferred formulation for the solid oral pharmaceutical composition includes:
-
- 4.4% w/w compound of Formula (I), especially fluralaner
- 10.5% w/w 2-pyrrolidone
- 25.0% w/w microcrystalline cellulose
- 5.1% w/w sodium starch glycolate
- 15.0% w/w flavor
- 2.0% w/w sodium lauryl sulphate
- 2.5% w/w sodium pamoate
- 0.5% w/w aspartame
- 0.5% w/w magnesium stearate
- 1.5% w/w glycerol
- 17.25% w/w soybean oil
- 15.75% w/w PEG8000
- The amount of glycerol in the formulation may range from 0-12.0% with the preferred range of 0.5-10.0%. Soybean oil amounts may range from 5.0-25.0% with the preferred range of 10.0-22.0%. Desired ranges of the other excipients include sodium starch glycolate (2.0-15.0%), flavor (5-25%), sodium lauryl sulfate (0.05-5.0%), sodium pamoate (0.01-5.0%), aspartame (0.01-2.0%), and magnesium stearate (0.01-2.0%).
- The formulation according to the current invention conventionally further comprise physiologically acceptable formulation excipients known in the art e.g. as described in “Gennaro, Remington: The Science and Practice of Pharmacy” (20th Edition, 2000) incorporated by reference herein. All such ingredients, carriers and excipients must be substantially pharmaceutically or veterinary pure and non-toxic in the amounts employed and must be compatible with the pharmaceutically active ingredients.
- Additional excipients that can be present in the formulation are e.g. one or more fillers, one or more flavours, or sugar components, surfactants, stabilizers, flow agents, disintegration agents, preservatives and/or lubricating agents.
- This invention is also directed to formulations as described above with combinations comprising more than one pharmaceutically active ingredient, e.g. in addition to the compound of Formula (I) another compound of Formula (I) or a pharmaceutically active ingredient with a different structure.
- Preferred combinations comprising active ingredients selected from the group consisting of isoxazoline compounds of Formula (I) or (II) and avermectins and milbemycins. In one embodiment the formulation, especially soft chew comprises a combination of an isoxazoline compound of Formula (I), especially fluralaner or afoxolaner, with ivermectin. In another embodiment the soft chew comprises a combination of an isoxazoline compound of Formula (I), especially fluralaner por afoxolaner, with milbemycin or with moxidectin.
- Other combinations of the present invention can include insect or acarid growth regulators (AGRs or IGRs) such as e.g. fenoxycarb, lufenuron, diflubenzuron, novaluron, triflumuron, fluazuron, cyromazine, methoprene, pyriproxyfen etc., thereby providing both initial and sustained control of parasites (at all stages of insect development, including eggs) on the animal subject, as well as within the environment of the animal subject.
- The inventors discovered that oral solid dosage forms of isoxazoline compounds of Formula (I) as described above, especially of fluralaner, afoxoloaner can be produced that result in a higher bioavailability of the isoxazoline compound after administration to animals. In such methods the isoxazoline compound of Formula (I) is first dissolved in a suitable solvent (e.g. 2-pyrol or DMAC) and then adhered to a solid carrier (e.g. microcrystalline cellulose). Such process can be used in general for various solid oral dosage forms such as hard tablets, granules, capsules or soft chews (soft chewable tablets).
- A general method for preparing a solid oral dosage form, such as a soft chewable tablet formulation comprises the steps of:
-
- 1. Dissolve the isoxazoline compound (e.g. fluralaner or afoxolaner) in the solvent (e.g. 2-pyrrolidone) to form a solution.
- 2. Add the isoxazoline solution to the solid carrier (e.g. microcrystalline cellulose) and mix to form a first dry mixture.
- 3. Add all other dry excipients to the first dry mixture and mix to form a second dry mixture.
- 4. Add liquid ingredients, glycerol and soybean oil, to the second dry mixture. Mix to form wet mass.
- 5. Melt a wax (e.g. polyethylene glycol 8000) and add to the wet mass. Mix well to form the final bulk mass.
- 6. Form appropriately sized chewable tablets
- In an embodiment the tablets may be formed from the final bulk mass utilizing a forming machine. Alternatively, the tablets may be formed by other means known in the art. For example, the tablets may be formed by hand.
- Methods of Using the Solid Oral Pharmaceutical Compositions
- In one embodiment the product of the invention is intended for use for controlling a parasitic insect-, acarid and/or helminth, especially parasitic insect and/or acarid infestation. The term “controlling a parasitic insect- and/or acarid infestation” refers to preventing, reducing or eliminating an infestation by such parasites on animals preferably by killing the insects and/or acarids or nematode parasites within hours or days.
- The term “parasitic insect- and acarid” refers to ectoparasites e.g. insect and acarine pests that commonly infest or infect animals. Examples of such ectoparasites include the egg, larval, pupal, nymphal and adult stages of lice, fleas, mosquitoes, mites, ticks, and biting or nuisance fly species. Especially important are fleas and ticks, especially their adult stages.
- Examples of invertebrate parasitic pests controlled by administering the solid oral formulation of this invention to an animal to be protected include ectoparasites (arthropods, acarines, etc) and endoparasites (helminths, e.g., nematodes, trematodes, cestodes, acanthocephalans, etc.).
- In particular, the formulations of this invention are effective against ectoparasites including: flies such as Haematobia (Lyperosia) irritans (horn fly), Stomoxys calcitrans (stable fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies), Hydrotaea irritans (head fly), Musca autumnalis (face fly), Musca domestica (house fly), Morellia simplex (sweat fly), Tabanus spp. (horse fly), Hypoderma bovis, Hypoderma lineatum, Lucilia sericata, Lucilia cuprina (green blowfly), Calliphora spp. (blowfly), Protophormia spp., Oestrus ovis (nasal botfly), Culicoides spp. (midges), Hippobosca equine, Gastrophilus instestinalis, Gastrophilus haemorrhoidalis and Gastrophilus naslis; lice such as Bovicola (Damalinia) bovis, Bovicola equi, Haematopinus asini, Felicola subrostratus, Heterodoxus spiniger, Lignonathus setosus and Trichodectes canis; keds such as Melophagus ovinus; mites such as Psoroptes spp., Sarcoptes scabei, Chorioptes bovis, Demodex equi, Cheyletiella spp., Notoedres cati, Trombicula spp. and Otodectes cyanotis (ear mites); ticks such as Ixodes spp., Boophilus spp., Rhipicephalus spp., Amblyomma spp., Dermacentor spp., Hyalomma spp. and Haemaphysalis spp.; and fleas such as Ctenocephalides felis (cat flea) and Ctenocephalides canis (dog flea).
- In general, the formulations according to the invention will contain an effective amount of the isoxazoline compounds of Formula (I) as defined above, meaning a non-toxic but sufficient amount to provide the desired control effect. A person skilled in the art using routine experimentation may determine an appropriate “effective” amount in any individual case. Such an amount will depend on the age, condition, weight and type of the target animal.
- The solid oral dosage forms may be formulated to contain an amount of the isoxazoline compound of Formula (I) that is adjusted to animals in a specific weight range. The animals may receive a dosage of the solid oral formulation according to the invention every 2, 3, 4, 5 or 6 months or receives a monthly, weekly or daily dosage. The treatment can, for example, be continuing or seasonal. The time period between treatments depends upon factors such as the parasite(s) being treated, the degree of infestation, the type of mammal or bird and the environment where it resides. It is well within the skill level of the practitioner to determine a specific administration period for a particular situation.
- The solid oral formulations of the present invention are especially suitable for combating parasites that infest mammals (including humans). Mammalian subjects include primates (e.g., monkeys), bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine (e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs), feline (e.g., house cats), camels, deer, donkeys, buffalos, antelopes, rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils, and hamsters). Of particular note is the embodiment wherein the animals to be protected are domesticated dogs (i.e. Canis lupus familiaris) and domestic house cats (i.e. Felis catus).
- In some embodiments of this invention, the solid oral formulation of an isoxazoline of Formula (I) is administered to treat parasitoses of an animal (or make a medicament to treat parasitoses of an animal). The term “parasitoses” includes pathologic conditions and diseases associated with or caused by one or more ectoparasites directly, such as, for example, anemia and flea allergy dermatitis. It also includes pathologic conditions or diseases associated with caused by one or more vector-transmitted pathogens, such as, for example, Lyme disease, Ehrlichiosis (particularly Canine Ehrlichiosis), and Rocky Mountain spotted fever from vector ticks.
- This invention also relates to treatment methods wherein at least an ancillary goal of controlling ectoparasites in and/or on an animal is to control an ectoparasitic infestation in an environment that is occupied (periodically or continuously) by the animal. In some such embodiments, for example, the animal is a companion animal (e.g., a cat or dog). The environment may be, for example, a house or other shelter; a room; a pen, a stall, or other confinement means; bedding; etc.
- This invention also is directed to kits that are, for example, suitable for use in performing the treatment methods described above. In general, such a kit will comprise an oral solid formulation according to the invention comprising a therapeutically effective amount of a isoxazoline of Formula (I), and an additional component(s). The additional component(s) may be, for example, one or more of the following: a diagnostic tool, instructions for administering the composition, an apparatus for administering the composition, a container comprising an excipient or other active ingredient to be mixed or administered in combination with the composition, or a memory aid (e.g., a stamp to adhere to a calendar to remind an animal owner of a time to administer a subsequent dose of the composition).
- As used herein, the term “w/w” designates weight/weight, the term “w/v” designates weight/volume, and the term “mg/kg” designates milligrams per kilogram of body weight. As used herein, % w/w represents the percentage by weight of an ingredient in the recipe of the product.
- The invention having been fully described, its practice is illustrated by the examples provided below. The examples do not limit the scope of the invention, which is defined entirely by the appended claims.
- An embodiment for a direct compression tablet containing two active ingredients includes:
- 0.015% w/w ivermectin
2.5% w/w fluralaner
0.1% w/w citric acid - 4.5% w/w 2-pyrrolidone
50.0% w/w microcrystalline cellulose
33.735% w/w corn starch
8.0% w/w flavor
0.5% magnesium stearate
0.1% w/w aspartame
0.05% w/w red iron oxide - An embodiment for soft chewable tablets containing two active ingredients includes:
- 0.42% w/w moxidectin
1.67% w/w fluralaner
0.2% w/w citric acid
4.0% w/w 2-pyrol
10.0% w/w microcrystalline cellulose
3.0% w/w flavor
0.2% w/w aspartame - 30.51% w/w soy grits
4.0% w/w propylene glycol - 8.0% w/w cetyl alcohol
- 20.0% w/w sodium starch glycolate
- Additional embodiments for the soft chewable tablets include:
- 5.333% w/w fluralaner
9.0% w/w 2-pyrrolidone
11.0% w/w microcrystalline cellulose - 5.0% w/w sodium lauryl sulfate
10.0% w/w flavor
5.0% w/w sodium starch glycolate
16.667% soy grits - 7.25% w/w fluralaner
10.5% w/w 2-pyrrolidone
22.75% microcrystalline cellulose
2.0% colloidal silicone dioxide - 3.5% w/w sodium lauryl sulfate
15.0% w/w flavor
0.5% w/w aspartame
0.5% w/w magnesium stearate - 14.75% w/w soybean oil
- 7.5% w/w fluralaner
7.0% w/w dimethyl acetamide
23.5% microcrystalline cellulose
15.0% w/w flavor
7.5% w/w sodium starch glycolate
3.5% w/w sodium lauryl sulfate
2.0% w/w sodium pamoate
0.5% w/w magnesium stearate
0.5% w/w aspartame
7.0% w/w glycerol
10.0% w/w soybean oil - 4.4% w/w fluralaner
10.5% w/w 2-pyrrolidone
25.0% microcrystalline cellulose
15.0% w/w flavor
5.1% w/w sodium starch glycolate
3.5% w/w sodium lauryl sulfate
2.5% w/w sodium pamoate
0.5% w/w magnesium stearate
0.5% w/w aspartame
3.0% w/w glycerol
14.25% w/w soybean oil - Multiple formulations were evaluated for their impact on bioavailability of Fluralaner when formulated in a soft chewable tablet.
- The descriptions of selected formulations are listed below.
-
TABLE 1 Control 2-Pyrol DMAC Excipient Formulation Formulation Formulation fluralaner 13.64% 4.4% 7.5% 2-pyrrollidone 10.5% dimethylacetamide 7.0% Avicel PH102 25.0% 23.5% flavor 20.0% 15.0% 15.0% corn starch 16.06% sodium starch glycolate 5.1% 7.5% sucrose 7.0% sodium lauryl sulfate 2.0% 3.5% 3.5% sodium pamoate 2.0% 2.5% 2.0% magnesium stearate 0.75% 0.5% 0.5% aspartame 0.25% 0.5% 0.5% glycerol 7.5% 3.0% 7.0% soybean oil 12.3% 14.25% 10.0% Polyethylene Glycol 3350 18.5% Polyethylene Glycol 8000 15.75% 16.0% - Dimethylacetamide (DMAC) is a good solvent for the active (A-1443) with a solubility of 791.5 mg/mL. However, when utilized in this type of formulation approach, similar pharmacokinetic profiles were obtained compared to chewable tablets with the active incorporated as a solid (control). Given that the DMAC formulation was dosed at a lower dose (15 mg/kg compared to 25 mg/kg for the control), these results are improvements in dose adjusted pharmacokinetic measurements (Cmax and AUC) over the control (see Table 2 and
FIG. 1 ). - When 2-pyrrolidone (2-pyrol) was utilized as the solvent in the formulation (solubility 775.41 mg/mL), significantly higher plasma levels were observed compared to the control, even with the formulation dosed at a lower dose (15 mg/kg compared to 25 mg/kg for the control). Dose normalized pharmacokinetic measurements (Cmax and AUC) for the 2-pyrol formulation are more than double that of the DMAC formulation and more than triple that of the control (see Table 2 and
FIG. 1 ). These results were unexpected. - This formulation approach provides significant improvement in bioavailability, enabling a significantly lower dosage required to achieve similar to superior pharmacokinetic profiles.
-
TABLE 2 Control 2-Pyrol DMAC Pharmacokinetic Parameter Formulation Formulation Formulation T1/2 (days) 20.3 21.6 21.3 Tmax (hours) 40.8 55.2 48.8 Cmax (ng/mL) 2832 5973 2511 Dose (mg/kg) 25 15 15 Cmax/Dose (kg*ng/mL/mg) 113 398 167 AUC0-inf (h*ng/mL) 1501420 3562496 1531455 AUC0-inf/Dose 60057 237500 102097 (h*kg*ng/mL/mg) Bioavailability 27.8% 109.8% 47.2% - The objective of this study is to compare the blood plasma pharmacokinetic profile of three different isoxazoline compounds in two different chewable formulations after a single oral (PO) administration of in dogs.
- The following compounds were formulated according to the invention. Specifically, the isoxazoline compound was first dissolved in a solvent, i.e. 2-pyrrolidone. This drug solution was then adsorbed onto the solid carrier, i.e. microcrystalline cellulose, which was incorporated into a solid oral dosage form as described in the specification with excipients as described in Table 3. Comparative example formulation ID No. 13-009, 13-011 and 13-013 contain the active drug substance incorporated as a solid that was manufactured as described in general in the specification without prior pre-dissolving the active ingredient and adsorption to the solid carrier.
-
TABLE 3 Test formulations Excipient 13-009 13-010 13-011 13-012 13-013 13-014 Compound A 13.64% 4.27% Compound B 13.64% 4.27% Compound C 13.64% 4.27% 2-pyrrolidone 10.19% 10.19% 10.19% microcrystalline 24.27% 24.27% 24.27% cellulose sodium starch 4.95% 4.95% 4.95% glycolate flavor 20.0% 14.56% 20.0% 14.56% 20.0% 14.56% sucrose 7.0% 7.0% 7.0% corn starch 16.06% 16.06% 16.06% sodium lauryl 2.0% 3.4% 2.0% 3.4% 2.0% 3.4% sulfate sodium 2.0% 2.43% 2.0% 2.43% 2.0% 2.43% pamoate magnesium 0.75% 0.49% 0.75% 0.49% 0.75% 0.49% stearate aspartame 0.25% 0.49% 0.25% 0.49% 0.25% 0.49% glycerin 7.5% 2.91% 7.5% 2.91% 7.5% 2.91% soybean oil 12.3% 16.75% 12.3% 16.75% 12.3% 16.75% PEG 3350 18.5% 18.5% 18.5% PEG 8000 15.29% 15.29% 15.29% - The test compounds were administered orally to four beagle dogs per dose group for a total of twenty-four dogs.
-
-
TABLE 4 Study Design Treatment No. of Formulation Compoud Dose Formulation ID dogs ID ID (mg/kg) Type2,3 1 4 13-009 A 25 Control Chew 2 4 13-010 A 10 Alternate Chew 3 4 13-011 B 25 Control Chew 4 4 13-012 B 10 Alternate Chew 5 4 13-013 C 25 Control Chew 6 4 13-014 C 10 Alternate Chew 2Control Chew - compound is not dissolved when formulated into chew (comparative example). 3Alternate Chew - compound is dissolved when formulated into chew - Each animal was administered the tablet or chew by placing it in the back of the oral cavity over the tongue to initiate swallowing.
- Plasma was obtained from the collected blood samples and analyzed for concentrations of the test compounds. Individual blood samples (approximately 4.5 mL per sample) were taken via jugular venipuncture into sodium-citrate tubes from all dogs for drug analysis. Blood samples were collected at the following time points: pretreatment (within 2 h prior to dosing) and approximately 1, 2, 4, 6, 8, 24, 48, 72 hours after dosing (±15 min). A final blood sample was taken from each dog on Day 7 (±2 h after the time of dosing on Day 0).
- When 2-pyrrolidone (2-pyrol) was utilized as the solvent in the formulation (alternate chew), similar or even higher plasma levels were observed compared to the control chew, even with the formulation dosed at a lower dose (10 mg/kg compared to 25 mg/kg for the control)—see
FIG. 2 . - Pharmacokinetic analysis was performed on the plasma concentration data with the computer program Pharsight WinNonlin Enterprise, Version 4.0.1, or more recent update (Model 200: plasma data, extravascular input).
- Dose normalized pharmacokinetic measurements (Cmax and AUC) for the 2-pyrol formulation (alternate chew) are much higher, in some cases more than double to five times that of the control formulation (see Table 5).
- This formulation approach provides significant improvement in the bioavailability relative to the control formulation, enabling a significantly lower dosage required to achieve similar to superior pharmacokinetic profiles. These results were unexpected.
-
TABLE 5 Pharma- Dis- Dis- Dis- cokinetic Control solved Control solved Control solved Parameter Compound A Compound B Compound C Dose 25 10 25 10 25 10 (mg/kg) Tmax (h) 5.0 15.5 27.5 15.5 Cmax 19.2 17.1 4340 3213 1589 2538 (ng/mL) Cmax/ 0.768 1.71 174 321 63.5 254 Dose (kg * ng/ mL/mg) AUC(0−168h) ND ND 416522 334163 164332 326601 (h * ng/mL) AUC0−168h/ ND ND 16661 33416 6573 32660 Dose (h * kg * ng/mL/mg) - Efficacy Against Brown Dog Ticks (R. sanguineus) on Dogs
- A solid pharmaceutical composition according to the invention with the following excipients was prepared.
-
Excipient Composition (% w/w) Fluralaner 4.27% 2-pyrrolidone 10.19% microcrystalline cellulose 24.27% sodium starch glycolate 4.95% flavor 14.56% sodium lauryl sulfate 3.40% sodium pamoate 2.43% aspartame 0.49% magnesium stearate 0.49% glycerol 2.91% soybean oil 16.75% Polyethylene Glycol 8000 15.29% - Dogs were randomly assigned to 4 treatment groups of 8 animals each, and one untreated control group of 8 animals. The dogs in the treatment groups were treated with the composition as described above on Day Zero as shown in Table 6:
-
TABLE 6 Treatment Groups Group Treatment A Untreated control B 4.27% fluralaner chewable tablet 8 mg/kg bw C 4.27% fluralaner chewable tablet 10 mg/kg bwD 4.27% fluralaner chewable tablet 12 mg/kg bw E 4.27% fluralaner chewable tablet 20 mg/kg bw - The dogs were infested on Day −2 with approximately 50 adult unfed ticks (R. sanguineus) and on Day 28 and 56. Ticks were counted approximately 48 h post infestation and on
Days 30 and 58 (approximately 48 hour after each post-treatment re-infestation) to evaluate the acaricidal activity in the treated groups. - Table 7 shows the observed tick counts:
-
TABLE 7 Brown Dog Ticks (R. sanguineus) on dogs- Tick counts - Group Day 2 Day 30Day 58 A 21.25 23 25.9 B 0 0 0 C 0.125 0 0 D 0 0 1.13 E 0 0 0
Claims (18)
Priority Applications (3)
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US16/508,758 US20200000718A1 (en) | 2012-04-04 | 2019-07-11 | Solid Oral Pharmaceutical Compositions for Isoxazoline Compounds |
US17/189,939 US11712416B2 (en) | 2012-04-04 | 2021-03-02 | Solid oral pharmaceutical compositions for isoxazoline compounds |
US18/335,415 US20230320981A1 (en) | 2012-04-04 | 2023-06-15 | Solid oral pharmaceutical compositions for isoxazoline compounds |
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US201361782028P | 2013-03-14 | 2013-03-14 | |
PCT/EP2013/056992 WO2013150055A1 (en) | 2012-04-04 | 2013-04-03 | Solid oral pharmaceutical compositions for isoxazoline compounds |
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Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE112013000869T5 (en) | 2012-02-06 | 2014-10-16 | Merial Ltd. | Oral parasiticidal veterinary compositions comprising systemic agents, methods and uses thereof |
RU2765231C2 (en) | 2012-04-04 | 2022-01-26 | Интервет Интернэшнл Б.В. | Soft chewable pharmaceutical products |
US9532946B2 (en) | 2012-11-20 | 2017-01-03 | Intervet Inc. | Manufacturing of semi-plastic pharmaceutical dosage units |
HUE046067T2 (en) * | 2013-12-10 | 2020-02-28 | Intervet Int Bv | Antiparasitic use of isoxazoline compounds |
US10456358B2 (en) | 2013-12-20 | 2019-10-29 | Intervet Inc. | Isoxazoline compositions and use thereof in the prevention or treatment of parasite infestations in animals |
HUE055444T2 (en) * | 2013-12-20 | 2021-11-29 | Intervet Int Bv | Use of isoxazoline derivatives for the treatment or prevention of arthropod infestations in poultry |
US20170354593A1 (en) * | 2014-11-03 | 2017-12-14 | Zoetis Services Llc | Palatable chewable veterinary composition |
CN114681453A (en) | 2014-12-22 | 2022-07-01 | 英特维特国际股份有限公司 | Use of isoxazoline compounds for the treatment of demodex diseases |
UY36570A (en) | 2015-02-26 | 2016-10-31 | Merial Inc | INJECTABLE FORMULATIONS OF PROLONGED ACTION THAT INCLUDE AN ISOXAZOLINE ACTIVE AGENT, METHODS AND USES OF THE SAME |
UY37137A (en) | 2016-02-24 | 2017-09-29 | Merial Inc | ANTIPARASITARY COMPOUNDS OF ISOXAZOLINE, INJECTABLE FORMULATIONS OF PROLONGED ACTION THAT INCLUDE THEM, METHODS AND USES OF THE SAME |
WO2018039508A1 (en) | 2016-08-25 | 2018-03-01 | Merial, Inc. | Method for reducing unwanted effects in parasiticidal treatments |
EP3532041A4 (en) * | 2016-10-31 | 2020-06-24 | The Scripps Research Institute | Methods and compositions for preventing vector-borne disease transmission |
AU2018307726C1 (en) | 2017-07-26 | 2023-03-30 | Tgx Soft Chew, Llc | Starch-free soft chew for veterinary applications |
MX2021002606A (en) * | 2018-09-05 | 2021-05-12 | Zoetis Services Llc | Palatable antiparasitic formulations. |
AU2020316642A1 (en) * | 2019-07-22 | 2022-01-27 | Intervet International B.V. | Soft chewable veterinary dosage form |
WO2021122513A1 (en) * | 2019-12-16 | 2021-06-24 | Intervet International B.V. | Composition for lice control |
WO2022192623A1 (en) * | 2021-03-11 | 2022-09-15 | In The Bowl Animal Health, Inc. | Oral canine feed and methods for controlling flea infestations in a canine |
AU2022232440A1 (en) * | 2021-03-11 | 2023-09-21 | In The Bowl Animal Health, Inc. | Oral canine feed and methods for controlling tick infestations in a canine |
WO2022271937A2 (en) * | 2021-06-25 | 2022-12-29 | In The Bowl Animal Health, Inc. | Oral feline feed and methods for controlling flea infestations in a feline |
CN113476419A (en) * | 2021-08-17 | 2021-10-08 | 江苏恒丰强生物技术有限公司 | Flurana chewable tablet for pets and preparation method thereof |
CA3237113A1 (en) * | 2021-11-11 | 2023-05-19 | David Griffin | Soft chew |
WO2023198476A1 (en) | 2022-04-15 | 2023-10-19 | Krka, D.D., Novo Mesto | Soft chewable veterinary dosage form |
CN117122571A (en) * | 2022-05-20 | 2023-11-28 | 天津瑞普生物技术股份有限公司 | Oral medicinal preparation for resisting parasitic infection, and preparation method and application thereof |
FR3138315A1 (en) | 2022-07-27 | 2024-02-02 | Virbac | Product for veterinary use and process for its manufacture |
Family Cites Families (162)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB819681A (en) * | 1957-01-24 | 1959-09-09 | Wellcome Found | Improvements in and relating to quaternary ammonium compounds and the preparation thereof |
US3486186A (en) | 1967-05-08 | 1969-12-30 | Hollymatic Corp | Molding apparatus |
US3887964A (en) * | 1972-01-24 | 1975-06-10 | Formax Inc | Food patty molding machine |
US3952478A (en) | 1974-10-10 | 1976-04-27 | Formax, Inc. | Vacuum sheet applicator |
US4054967A (en) | 1975-10-20 | 1977-10-25 | Formax, Inc. | Food patty molding machine |
US4284652A (en) | 1977-01-24 | 1981-08-18 | The Quaker Oats Company | Matrix, product therewith, and process |
US4182003A (en) | 1978-02-28 | 1980-01-08 | Formax, Inc. | Food patty molding machine |
US4338702A (en) | 1979-03-29 | 1982-07-13 | Holly Harry H | Apparatus for making a ground food patty |
US4334339A (en) | 1980-05-12 | 1982-06-15 | Hollymatic Corporation | Mold device with movable compression insert |
US4356595A (en) | 1980-11-07 | 1982-11-02 | Formax, Inc. | Method and apparatus for molding food patties |
US4327076A (en) | 1980-11-17 | 1982-04-27 | Life Savers, Inc. | Compressed chewable antacid tablet and method for forming same |
US4343068A (en) | 1981-01-19 | 1982-08-10 | Holly James A | Method and apparatus for unidirectional formation of a plug-formed patty with cleanout feature |
US4372008A (en) | 1981-04-23 | 1983-02-08 | Formax, Inc. | Food patty molding machine with multi-orifice fill passage and stripper plate |
US4393085A (en) | 1981-08-13 | 1983-07-12 | General Foods Corporation | Enzyme digestion for a dog food of improved palatability |
IE53474B1 (en) | 1981-09-17 | 1988-11-23 | Warner Lambert Co | A chewable comestible product and process for its production |
CH657506A5 (en) | 1981-12-10 | 1986-09-15 | Hollymatic Ag | PORTIONING MACHINE FOR FILLING CAVES WITH DEFORMABLE MATERIAL AND USE THEREOF. |
US4535505A (en) | 1982-11-23 | 1985-08-20 | Holly Systems, Inc. | Method and apparatus for forming a patty to accommodate tissue fiber flow |
US4608731A (en) | 1983-01-11 | 1986-09-02 | Holly Systems, Inc. | Food patty with improved void structure, shape, and strength and method and apparatus for forming said patty |
US4609543A (en) | 1983-11-14 | 1986-09-02 | Nabisco Brands, Inc. | Soft homogeneous antacid tablet |
US4597135A (en) | 1984-02-21 | 1986-07-01 | Holly Systems, Inc. | Food patty forming method and apparatus employing two or more agitator bars |
DE3406497A1 (en) | 1984-02-23 | 1985-09-05 | Mueller Bernhard Willi Werner | HIGHLY DISPERSAL PHARMACEUTICAL MULTI-COMPONENT SYSTEMS AND METHOD FOR THEIR PRODUCTION |
US4768941A (en) | 1986-06-16 | 1988-09-06 | Hollymatic Corporation | Food patty and machine and method for making thereof |
US4697308A (en) | 1986-10-29 | 1987-10-06 | Formax, Inc. | Patty molding mechanism for whole fiber food product |
DE3636882C1 (en) | 1986-10-30 | 1988-05-19 | Schreiber Berthold | Device for the fine-bubble introduction of a gas into a liquid |
US4714620A (en) | 1986-12-12 | 1987-12-22 | Warner-Lambert Company | Soft, sugarless aerated confectionery composition |
US4780931A (en) | 1987-02-13 | 1988-11-01 | Marlen Research Corporation | Feeding device for patty forming machine |
US4821376A (en) | 1988-06-02 | 1989-04-18 | Formax, Inc. | Seal-off for food patty molding machine with multi-orifice fill passage and stripper plate |
US4997671A (en) | 1988-09-09 | 1991-03-05 | Nabisco Brands, Inc. | Chewy dog snacks |
US4872241A (en) | 1988-10-31 | 1989-10-10 | Formax, Inc. | Patty molding mechanism for fibrous food product |
US4935243A (en) | 1988-12-19 | 1990-06-19 | Pharmacaps, Inc. | Chewable, edible soft gelatin capsule |
US5021025A (en) | 1989-09-12 | 1991-06-04 | Wagner Richard C | Method and machine for making food patties |
US4975039A (en) | 1989-09-18 | 1990-12-04 | Dare Gary L | Food molding and portioning apparatus |
US4996743A (en) | 1990-01-29 | 1991-03-05 | Formax, Inc. | Mold plate drive linkage |
US5022888A (en) | 1990-05-03 | 1991-06-11 | Formax, Inc. | Co-forming apparatus for food patty molding machine |
US5262167A (en) | 1990-12-20 | 1993-11-16 | Basf Corporation | Edible, non-baked low moisture cholestyramine composition |
US5380535A (en) | 1991-05-28 | 1995-01-10 | Geyer; Robert P. | Chewable drug-delivery compositions and methods for preparing the same |
JP2575325B2 (en) | 1991-06-18 | 1997-01-22 | サクマ製菓株式会社 | candy |
US5439924A (en) | 1991-12-23 | 1995-08-08 | Virbac, Inc. | Systemic control of parasites |
TW376319B (en) | 1993-04-28 | 1999-12-11 | Janssen Pharmaceutica Nv | Pharmaceutical composition containing risperidone pamoate and having a long acting activity for treating psychoses induced by the release of dopamine |
BR9507637A (en) | 1994-05-20 | 1997-10-07 | Janssen Pharmaceutica Nv | Flubendazole chewable tablets for pets |
US5637313A (en) | 1994-12-16 | 1997-06-10 | Watson Laboratories, Inc. | Chewable dosage forms |
GB9508443D0 (en) | 1995-04-26 | 1995-06-14 | Gilbertson & Page | Biscuit for working racing or sporting dogs |
AUPN290395A0 (en) | 1995-05-10 | 1995-06-01 | Virbac (Australia) Pty Limited | Canine anthelmintic preparation |
US5578336A (en) | 1995-06-07 | 1996-11-26 | Monte; Woodrow C. | Confection carrier for vitamins, enzymes, phytochemicals and ailmentary vegetable compositions and method of making |
SK74396A3 (en) | 1995-06-13 | 1997-04-09 | American Home Prod | Organoleptically acceptable oral pharmaceutical compositions |
US5606889A (en) | 1995-09-19 | 1997-03-04 | G & H Technology, Inc. | Reusable initiator for use in triggering high-load actuators |
DE19628776A1 (en) | 1996-07-17 | 1998-01-22 | Bayer Ag | Oral granules of hexahydropyrazine derivatives |
US5730650A (en) | 1996-08-29 | 1998-03-24 | Progressive Technology Of Wisconsin, Inc. | Food patty molding machine |
US5655436A (en) | 1996-08-29 | 1997-08-12 | Progressive Technology Of Manitowoc, Inc. | Food patty molding machine |
US6093427A (en) | 1997-09-03 | 2000-07-25 | T.F.H.Publications, Inc. | Vegetable-based dog chew |
US6110521A (en) | 1996-10-25 | 2000-08-29 | T.F.H. Publications, Inc. | Wheat and casein dog chew with modifiable texture |
US6086940A (en) | 1996-10-25 | 2000-07-11 | T.F.H. Publications, Inc. | High starch content dog chew |
US5827565A (en) | 1996-10-25 | 1998-10-27 | T.F.H. Publications, Inc. | Process for making an edible dog chew |
US5753255A (en) | 1997-02-11 | 1998-05-19 | Chavkin; Leonard | Chewable molded tablet containing medicinally active substances |
US6723358B1 (en) | 1998-03-23 | 2004-04-20 | General Mills, Inc. | Encapsulation of components into edible products |
US6093441A (en) | 1998-07-15 | 2000-07-25 | Tfh Publications, Inc. | Heat modifiable peanut dog chew |
US6270790B1 (en) | 1998-08-18 | 2001-08-07 | Mxneil-Ppc, Inc. | Soft, convex shaped chewable tablets having reduced friability |
US6387381B2 (en) | 1998-09-24 | 2002-05-14 | Ez-Med Company | Semi-moist oral delivery system |
US6060078A (en) | 1998-09-28 | 2000-05-09 | Sae Han Pharm Co., Ltd. | Chewable tablet and process for preparation thereof |
CA2349700A1 (en) * | 1998-11-12 | 2000-05-18 | Merck & Co., Inc. | Therapeutic polymorphs of a gaba-a alpha-5 inverse agonist and pamoate formulations of the same |
US6159516A (en) | 1999-01-08 | 2000-12-12 | Tfh Publication, Inc. | Method of molding edible starch |
GB9902073D0 (en) | 1999-01-29 | 1999-03-24 | Nestle Sa | Chewy confectionery product |
US6500463B1 (en) | 1999-10-01 | 2002-12-31 | General Mills, Inc. | Encapsulation of sensitive components into a matrix to obtain discrete shelf-stable particles |
EP1103181A1 (en) * | 1999-11-25 | 2001-05-30 | Novartis AG | Combination of N-phenyl-N'-benzoyl urea derivatives and avermectine compounds for parasite control |
US6787342B2 (en) | 2000-02-16 | 2004-09-07 | Merial Limited | Paste formulations |
US6340672B1 (en) * | 2000-02-16 | 2002-01-22 | Phoenix Scientific, Inc. | Parasiticidal formulation and a method of making this formulation |
IT1317048B1 (en) | 2000-06-23 | 2003-05-26 | Sigma Tau Ind Farmaceuti | USE OF PAMOIC ACID OR ITS DERIVATIVE, OR ANALOGUE, FOR THE PREPARATION OF A MEDICATION FOR THE TREATMENT OF DISEASES |
DE10031044A1 (en) | 2000-06-26 | 2002-01-03 | Bayer Ag | Endoparasiticidal agents for voluntary oral ingestion by animals |
PL207109B1 (en) | 2001-01-31 | 2010-11-30 | Bayer Cropscience Ag | Herbicide-safener combination based on isoxozoline carboxylate safeners |
EP1247456A3 (en) | 2001-02-28 | 2003-12-10 | Pfizer Products Inc. | Palatable pharmaceutical compositions for companion animals |
GB0108485D0 (en) | 2001-04-04 | 2001-05-23 | Pfizer Ltd | Combination therapy |
US20040234580A1 (en) | 2001-10-05 | 2004-11-25 | Huber Gordon R. | Animal feeds including actives and methods of using the same |
KR101030735B1 (en) * | 2002-08-13 | 2011-04-26 | 인터벳 인터내셔널 비.브이. | Compositions and process for delivering an additive |
US20040037869A1 (en) * | 2002-08-16 | 2004-02-26 | Douglas Cleverly | Non-animal product containing veterinary formulations |
US20040151759A1 (en) | 2002-08-16 | 2004-08-05 | Douglas Cleverly | Non-animal product containing veterinary formulations |
GB0219639D0 (en) | 2002-08-22 | 2002-10-02 | Prestwick Scient Capital Inc | Novel piperidin-2,6-dione salts and their use for the treatment of stress-related affective disorders |
US20040234579A1 (en) | 2003-05-22 | 2004-11-25 | Mark D. Finke, Inc. | Dietary supplements and methods of preparing and administering dietary supplements |
TWI366442B (en) | 2003-07-30 | 2012-06-21 | Novartis Ag | Palatable ductile chewable veterinary composition |
AU2008201605B2 (en) | 2003-07-30 | 2010-04-29 | Novartis Ag | Palatable ductile chewable veterinary composition |
US6987111B2 (en) | 2003-08-06 | 2006-01-17 | Alkermes Controlled Therapeutics, Ii | Aripiprazole, olanzapine and haloperidol pamoate salts |
WO2005016356A1 (en) | 2003-08-08 | 2005-02-24 | The Hartz Mountain Corporation | Improved anthelmintic formulations |
US7396819B2 (en) | 2003-08-08 | 2008-07-08 | Virbac Corporation | Anthelmintic formulations |
UA79571C2 (en) * | 2003-12-04 | 2007-06-25 | Basf Ag | Metod for the protection of seeds from soil pests comprising |
PE20051096A1 (en) | 2004-02-04 | 2006-01-23 | Novartis Ag | SALT FORMS OF 4- (4-METHYLPIPERAZIN-1-ILMETHYL) -N- [4-METHYL-3- (4-PYRIDIN-3-IL) PYRIMIDIN-2-ILAMINO) PHENYL] -BENZAMIDE |
ES2526614T3 (en) | 2004-03-05 | 2015-01-13 | Nissan Chemical Industries, Ltd. | Isoxazoline-substituted benzamide compound and harmful organisms control agent |
EP1734954A4 (en) | 2004-04-07 | 2007-05-30 | Intervet Int Bv | Efficacious composition of a benzimidazole, an avermectin and praziquantel and related methods of use |
CA2562015A1 (en) † | 2004-04-09 | 2005-10-20 | Janssen Pharmaceutica Nv | Intermittent dosing regimens of apob secretion/mtp inhibitors for overweith and obese subjects |
US20050234119A1 (en) | 2004-04-16 | 2005-10-20 | Soll Mark D | Antiparasitical agents and methods for treating, preventing and controlling external parasites in animals |
DE102004034043A1 (en) * | 2004-07-13 | 2006-02-09 | Krka Tovarna Zdravil, D.D. | Solid pharmaceutical composition containing mirtazapine |
US7348027B2 (en) * | 2005-04-08 | 2008-03-25 | Bayer Healthcare Llc | Taste masked veterinary formulation |
US7838532B2 (en) * | 2005-05-18 | 2010-11-23 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
MX2007014422A (en) * | 2005-05-20 | 2008-02-11 | Pfizer Ltd | Synergistic combinations of non-steroidal antiinflammatory drugs with alpha-delta-ligands. |
AU2006285613B2 (en) | 2005-09-02 | 2011-11-17 | Nissan Chemical Corporation | Isoxazoline-substituted benzamide compound and harmful organism-controlling agent |
US7955632B2 (en) | 2005-12-07 | 2011-06-07 | Bayer B.V. | Process for manufacturing chewable dosage forms for drug delivery and products thereof |
US20070128251A1 (en) | 2005-12-07 | 2007-06-07 | Piedmont Pharmaceuticals, Inc. | Process for manufacturing chewable dosage forms for drug delivery and products thereof |
BRPI0620668A2 (en) | 2005-12-14 | 2011-11-22 | Du Pont | compound of formula 1, composition comprising compound, invertebrate pest control composition, spray composition, bait composition, trap device, invertebrate pest control methods, cockroach, ants or termites control method and protection method. seeds against invertebrate pests |
TW200803740A (en) | 2005-12-16 | 2008-01-16 | Du Pont | 5-aryl isoxazolines for controlling invertebrate pests |
TWI412322B (en) * | 2005-12-30 | 2013-10-21 | Du Pont | Isoxazolines for controlling invertebrate pests |
EP1997813B1 (en) | 2006-03-10 | 2010-05-05 | Nissan Chemical Industries, Ltd. | Substituted isoxazoline compound and pest control agent |
BRPI0710403A2 (en) | 2006-04-20 | 2011-08-09 | Du Pont | compound composition, control composition, spraying, bait, trap device, control methods, protection methods, treated seed, protective composition |
TWI342532B (en) * | 2006-07-10 | 2011-05-21 | Himax Tech Inc | Method for generating a gamma table |
JP2008044880A (en) * | 2006-08-15 | 2008-02-28 | Bayer Cropscience Ag | Insecticidal isooxazolines |
AU2007293068C1 (en) | 2006-09-07 | 2013-09-19 | Boehringer Ingelheim Animal Health USA Inc. | Soft chewable, tablet, and long-acting injectable veterinary antibiotic formulations |
CN101190223A (en) * | 2006-11-29 | 2008-06-04 | 天津市润拓生物技术有限公司 | Combantrin chewable tablets for dog or cat |
US20090281059A1 (en) | 2007-02-21 | 2009-11-12 | Robert Falotico | Coating for a medical device having an anti-thrombotic conjugate |
JP5206993B2 (en) | 2007-03-07 | 2013-06-12 | 日産化学工業株式会社 | Isoxazoline-substituted benzamide compounds and pest control agents |
KR20090130064A (en) | 2007-04-10 | 2009-12-17 | 바이엘 크롭사이언스 아게 | Insecticidal aryl isoxazoline derivatives |
JP2008260691A (en) * | 2007-04-10 | 2008-10-30 | Bayer Cropscience Ag | Insecticidal arylisoxazoline derivative |
WO2008136791A1 (en) | 2007-05-03 | 2008-11-13 | Merial Limited | Compositions comprising c-13 alkoxyether macrolide compounds and phenylpyrazole compounds |
NZ580357A (en) * | 2007-05-07 | 2011-06-30 | Jurox Pty Ltd | Chewable gelatinised protein dosage form and process |
ME03373B (en) | 2007-05-15 | 2020-01-20 | Merial Inc | Aryloazol-2-yl cyanoethylamino compounds, method of making and method of using thereof |
US20080293645A1 (en) | 2007-05-25 | 2008-11-27 | Schneider Lawrence F | Antiparasitic combination and method for treating domestic animals |
ES2445651T3 (en) | 2007-06-13 | 2014-03-04 | E. I. Du Pont De Nemours And Company | Isoxazoline insecticides |
TWI430995B (en) * | 2007-06-26 | 2014-03-21 | Du Pont | Naphthalene isoxazoline invertebrate pest control agents |
ES2666187T3 (en) | 2007-06-27 | 2018-05-03 | E. I. Du Pont De Nemours And Company | Pest control procedure in animals |
EP2172448A4 (en) | 2007-06-29 | 2012-01-11 | Nissan Chemical Ind Ltd | Substituted isoxazoline or enone oxime compound, and pest control agent |
ITCL20070039A1 (en) | 2007-07-10 | 2009-01-11 | Michele Neri | CONSTANT PRESSURE CYLINDER WITH EXTRUDED PROBOSCIDE TUBE AND DOSING VALVE, ATTACHED TO A STRUCTURE ON WHICH ROLLS, ACTIVATED BY A SOURCE OF CONTROLLED PRESSURE, USED IN PARTICULAR FOR THE EXTRUSION AND PROCESSING OF ALL PASTA: |
TWI556741B (en) * | 2007-08-17 | 2016-11-11 | 英特威特國際股份有限公司 | Isoxazoline compositions and their use as antiparasitics |
CN101801940B (en) | 2007-09-10 | 2013-04-10 | 日产化学工业株式会社 | Substituted isoxazoline compound and pest control agent |
HUE043897T2 (en) | 2007-09-25 | 2019-09-30 | Solubest Ltd | Compositions comprising lipophilic active compounds and method for their preparation |
JP5676262B2 (en) | 2007-10-03 | 2015-02-25 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニーE.I.Du Pont De Nemours And Company | Naphthalene isoxazoline compounds for the control of harmful invertebrates |
TWI411395B (en) * | 2007-12-24 | 2013-10-11 | Syngenta Participations Ag | Insecticidal compounds |
ES2582575T3 (en) | 2008-07-09 | 2016-09-13 | Nissan Chemical Industries, Ltd. | Process for the production of isoxazoline-substituted benzoic acid amide compound |
CN102088857A (en) * | 2008-07-09 | 2011-06-08 | 巴斯夫欧洲公司 | Pesticidal mixtures comprising isoxazoline compounds ii |
EP2306837B2 (en) * | 2008-07-09 | 2023-10-25 | Basf Se | Pesticidal active mixtures comprising isoxazoline compounds i |
JP2010026724A (en) * | 2008-07-17 | 2010-02-04 | Fujitsu Ltd | Web page providing apparatus, method for interlocking web page with ranking and program thereof |
NZ590756A (en) | 2008-09-04 | 2013-01-25 | Syngenta Participations Ag | Insecticidal compounds |
US9820977B2 (en) * | 2008-10-03 | 2017-11-21 | Bayer Healthcare Llc | Systemic treatment of blood-sucking and blood-consuming parasites by oral administration of a parasiticidal agent |
SI3050874T1 (en) | 2008-11-14 | 2019-04-30 | Merial Inc. | Enantiomerially enriched aryloazol-2-yl cyanoethylamino paraciticidal compounds |
US8450357B2 (en) | 2008-11-19 | 2013-05-28 | Merial Limited | Compositions comprising an aryl pyrazole and/or a formamidine, methods and uses thereof |
MX2011005726A (en) | 2008-12-04 | 2011-07-29 | Merial Ltd | Dimeric avermectin and milbemycin derivatives. |
EP2379544B1 (en) | 2008-12-18 | 2013-10-16 | Novartis AG | Isoxazolines derivatives and their use as pesticide |
ES2395704T3 (en) | 2008-12-19 | 2013-02-14 | Novartis Ag | Isoxazoline derivatives and their use as a pesticide |
CN102325759A (en) * | 2008-12-23 | 2012-01-18 | 巴斯夫欧洲公司 | Substituted amidine compounds for combating animal pests |
BRPI1007310A2 (en) | 2009-01-22 | 2015-08-25 | Syngenta Participations Ag | Insecticide Compounds. |
US20120030841A1 (en) | 2009-04-01 | 2012-02-02 | Basf Se | Isoxazoline compounds for combating invertebrate pests |
AU2010100349B4 (en) * | 2009-04-15 | 2012-03-29 | Jurox Pty Ltd | Anthelmintic formulation |
US9040583B2 (en) | 2009-07-22 | 2015-05-26 | Temple University-Of The Commonwealth System Of Higher Education | Treatment of disorders associated with G protein-coupled receptor 35 (GPR35) |
TWI487486B (en) * | 2009-12-01 | 2015-06-11 | Syngenta Participations Ag | Insecticidal compounds based on isoxazoline derivatives |
AP3106A (en) | 2009-12-17 | 2015-01-31 | Merial Ltd | Antiparisitic dihydroazole compounds and compositions comprising same |
JP2013518084A (en) | 2010-02-01 | 2013-05-20 | ビーエーエスエフ ソシエタス・ヨーロピア | Substituted ketonic isoxazoline compounds and derivatives for controlling pests |
US20130085064A1 (en) | 2010-02-25 | 2013-04-04 | Syngenta Crop Protection Llc | Pesticidal mixtures containing isoxazoline derivatives and insecticide or nematoicidal biological agent |
EP2556060A1 (en) | 2010-04-08 | 2013-02-13 | Ah Usa 42 Llc | Substituted 3,5- diphenyl-isoxazoline derivatives as insecticides and acaricides |
CN101919857B (en) * | 2010-05-05 | 2012-05-30 | 四川宝盛康药业有限公司 | Novel compound albendazole preparation, application thereof and preparation method thereof |
MY156670A (en) | 2010-05-27 | 2016-03-15 | Du Pont | Crystalline form of 4-[5-[3-chloro-5-(trifluoromethly)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-n-[2-oxo-2-[(2,2,2-trifluoroethyl) amino]ethyl]-1-naphthalenecarboxamide |
EP2579723A2 (en) | 2010-06-09 | 2013-04-17 | Syngenta Participations AG | Pesticidal mixtures comprising isoxazoline derivatives |
WO2011154434A2 (en) | 2010-06-09 | 2011-12-15 | Syngenta Participations Ag | Pesticidal mixtures including isoxazoline derivatives |
EP2579724A2 (en) | 2010-06-09 | 2013-04-17 | Syngenta Participations AG | Pesticidal mixtures including isoxazoline derivatives |
UY33403A (en) | 2010-06-17 | 2011-12-30 | Novartis Ag | ORGANIC COMPOUNDS WITH NEW ISOXAZOLINES, THEIR N-OXIDES, S-OXIDES AND SALTS |
DK178277B1 (en) | 2010-06-18 | 2015-10-26 | Novartis Tiergesundheit Ag | Diaryloxazoline compounds for the control of fish lice |
CA2804147A1 (en) | 2010-06-30 | 2012-01-05 | Upsher-Smith Laboratories, Inc. | Sustained release composition comprising an amine as active agent and a salt of a cyclic organic acid |
WO2012007426A1 (en) | 2010-07-13 | 2012-01-19 | Basf Se | Azoline substituted isoxazoline benzamide compounds for combating animal pests |
JP2012046486A (en) * | 2010-07-30 | 2012-03-08 | Sumitomo Chemical Co Ltd | Animal ectoparasite-controlling agent |
KR101508862B1 (en) | 2010-08-05 | 2015-04-07 | 조에티스 엘엘씨 | Isoxazoline derivatives as antiparasitic agents |
WO2012038851A1 (en) | 2010-09-24 | 2012-03-29 | Pfizer Inc. | Isoxazoline oximes as antiparasitic agents |
US9744127B2 (en) | 2010-10-12 | 2017-08-29 | Bayer Intellectual Property Gmbh | Non-starch based soft chewables |
RU2749733C2 (en) * | 2010-12-27 | 2021-06-16 | Интервет Интернэшнл Б.В. | Composition of isoxazoline for topical and external use |
DK2755473T3 (en) | 2011-09-12 | 2019-03-11 | Merial Inc | PARACITICIDE COMPOSITIONS CONTAINING AN ISOXAZOLINE ACTIVE SUBSTANCE, PROCEDURES AND APPLICATIONS THEREOF |
JP2014533735A (en) * | 2011-11-29 | 2014-12-15 | ノバルティス アーゲー | Use of aryl derivatives to control ectoparasites |
DE112013000869T5 (en) * | 2012-02-06 | 2014-10-16 | Merial Ltd. | Oral parasiticidal veterinary compositions comprising systemic agents, methods and uses thereof |
RU2765231C2 (en) * | 2012-04-04 | 2022-01-26 | Интервет Интернэшнл Б.В. | Soft chewable pharmaceutical products |
US9532946B2 (en) | 2012-11-20 | 2017-01-03 | Intervet Inc. | Manufacturing of semi-plastic pharmaceutical dosage units |
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