Isoxazoline complex and composition thereof

Abstract

A pharmaceutical composition comprising an isoxazoline compound complexed with a cyclodextrin (such as hydroxypropylcyclodextrin) and combined with a polyol in a dry (anhydrous) composition. The composition can be a mixture of isomers, an enriched mixture of a specific enantiomer, or a single enantiomer.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compositions containing isoxazoline compounds for use in animals or poultry. Background Art

[0002] Fluralaner is available in several commercial forms and has the chemical formula 4-[5(RS)-5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-1,2-oxazol-3-yl]-N-[2-oxo-2-[(2,2,2-trifluoroethylamino)ethyl]-oxy-benzamide. Fluralaner inhibits gamma-aminobutyric acid (GABA)-gated chloride channels (GABA receptors) and L-glutamate-gated chloride channels (GluCl).

[0003] Fluerana and Afoxolaner belong to a class of compounds known as isoxazolines (a class of five-membered heterocyclic compounds with one oxygen and one nitrogen atom adjacent to each other). Fluerana is a hydrophobic compound that has been shown to be degraded by water in various compositions within about 48 hours at room temperature. Therefore, any commercial composition with a long shelf life must be essentially anhydrous, its components must not interact negatively with fluerana or other isoxazolines, and must not be inherently hygroscopic in the corresponding packaging.

[0004] Flurana is available in anhydrous hard chewable tablets for dogs and acetone-based transdermal drops for dogs and cats, either alone or in combination with macrolides. In the prior art, various organic solvents, such as diacetoacetamide, n-methylpyrrolidone or pyrrolidone, have been used to enhance the absorption of flurana in chewable tablets for dogs.

[0005] Water in the drinking water supply of a piggery or animal enclosure is subject to laminar flow through pipes and coils and to so-called "tangential" forces which affect the flow rate. In such a complex piping system, there is a significant risk of drug separation or precipitation when using water-insoluble compounds. The effectiveness of a drug throughout the drinking water supply depends largely on the quality of the composition (and its stability in the drinking water supply) and the taste of the formulation.

[0006] A suitable composition should ensure maximum availability of the active ingredient and ensure that there is no or minimal separation and precipitation of the active substance in the drinking water supply system. It is further desirable to achieve a precise and uniform distribution of the active ingredient in the drinking water and to ensure the stability of the active ingredient in the composition itself and after dilution to the target concentration in the medicinal drinking water. Such a pharmaceutical composition is contemplated in the present invention, which does not contain any organic solvent.

[0007] There is a need for a delivery system for flurellan which would provide improved water solubility, stability and taste and could be used in a single form in a variety of compositions, whether oral, injectable or transdermal for cats, dogs, poultry and pigs. Ideally, flurellan should be synergistically combined with other components such as macrolides or complexes thereof. Summary of the invention

[0008] Surprisingly, it was found that the combination of flurana, a trifluoro compound, in a hydroxypropyl beta-cyclodextrin complex in dry form with anhydrous poly powder (Poly 80 adsorbed onto hydroxypropyl beta-cyclodextrin (HPBCD)) had a water solubility of 20 to 30 mg / ml. (where "mg" is milligram and "ml" is "millimeter"), where the water solubility of the complex itself was less than 20 mg / ml. In a first experiment, 1% flurana was added in water at 0.5 mg / kg (where "kg" is kilogram) in poultry, and it was found that the solubility of the flurana complex with poly powder was unexpectedly enhanced. Further tests were then conducted, as described in the detailed description below.

[0009] Similar trifluoro compounds, such as tecovir, exhibited fairly high solubility (>10 mg / ml) when complexed with HPBCD, but showed no increase in solubility when their complexes were combined with polysorbate 80. In fact, over the temperature range of 4C to 40C (where "C" is "degrees Celsius"), the solubility of the tecovir complex decreased when combined with polysorbate 80, but at 4C, polysorbate 80 only slightly increased the solubility of the complex.

[0010] Over the temperature range, solubility decreased after the addition of polysorbate 80 compared to the tecovir complex alone. We surprisingly found that combining the flurellanine HPBCD complex with an anhydrous polysorbate 80 powder with a long shelf life significantly improved the solubility of the complex over the temperature range of 4C to 40C, where the solubility of the complex itself was less than 20mg / ml flurellanine. However, when combined with the poly powder, the solubility was improved from 20mg / ml to 30mg / ml, dissolution was immediate, and the anhydrous powder mixture had a long shelf life stability.

[0011] Thus, the combination powder can be prepared in all desired forms, such as anhydrous, soft chews, anhydrous hard chews and aqueous solutions (for use in metered water systems or as granules for inclusion in feeds or as powders for feed mixes), even in a form ready for injection.

[0012] Thus, the composition has many advantages over the prior art, including long shelf life, improved taste masking of the isoxazoline component, instant dissolution, and a synergistic combination with a macrolide complex for combined treatment of dogs, cats, pigs, and other livestock animals.

[0013] The present invention contemplates combinations with macrolides or preferably cyclodextrin complexes thereof to extend shelf life and enhance absorption, as well as triple combinations with drugs such as pyrantel or praziquantel, and many other drugs currently used in livestock farming, for the treatment of internal and external parasites. More advantageously, in embodiments of the disclosed technology, the use of polypowders with flurellanine complexes can be combined with various other cyclodextrin complexes, resulting in greater absorption and / or solubilization of drugs used to target internal or external parasites in livestock animals.

[0014] In a method for treating animal parasitic infections using an anhydrous pharmaceutical composition that is stable in storage, an isoxazoline cyclodextrin complex having a maximum solubility of less than 20 mg / ml in water is combined with a polypowder (e.g., polysorbate adsorbed to 2-hydroxypropyl beta-cyclodextrin in anhydrous form). Before being combined with isoxazoline, the polypowder has a shelf life of at least 2 years. The polypowder is combined with the isoxazoline cyclodextrin complex to obtain a solubility of 20 mg to 30 mg / ml isoxazoline in water and to form a dry anhydrous drug with a shelf life of at least 2 years. The drug can be administered through water or feed taken orally by animals and has a medicinal effect.

[0015] From another aspect, an oral drug for treating parasitic infections in animals and suitable for safe ingestion by animals, the drug having a polysorbate adsorbed onto 2-hydroxypropyl-β-cyclodextrin in an anhydrous form, and having a shelf life of at least 2 years. Thus, a storage-stable anhydrous pharmaceutical composition is produced, which has a combination of an isoxazoline cyclodextrin complex, and a maximum solubility in water of 20 mg / ml to 30 mg / ml isoxazoline, wherein the combination of the isoxazoline cyclodextrin complex and the adsorbed polysorbate forms a dry anhydrous drug with a shelf life of at least 2 years.

[0016] The poly powder can be any polysorbate adsorbed onto cyclodextrin under anhydrous conditions. The isoxazoline cyclodextrin complex can be a flurellanine cyclodextrin complex, administered at 0.5 mg / kg of body weight of the poultry to be treated in water or feed. The flurellanine cyclodextrin complex can be administered twice over a period of 7 to 14 days. In some embodiments of the disclosed technology, the mixture of isoxazoline complex and poly powder is a mixture of flurellanine complex and poly powder, administered in a hard or soft anhydrous chewable tablet in felines or canines at a rate of 2 to 4 mg / kg per month.

[0017] In some embodiments of the disclosed technology, the isoxazoline complexes and polypowder mixtures synergistically combine with cyclodextrin complexes of macrolides to increase the solubility and bioavailability of the drug and improve the taste parameters of the drug.

[0018] In some embodiments of the disclosed technology, pyrantel pamoate is combined with a drug, wherein the combination provides a broad spectrum antiparasitic effect in a water-free, storage-stable chewable form.Isoxazoline can be alternatively or additionally complexed with cyclodextrin in a stoichiometric ratio of 1:1 or 1:2.

[0019] The isoxazoline cyclodextrin complex can be a cyclodextrin complex of flurellane, which has a limited water solubility of less than 20 mg / ml, which can be enhanced by combining with polysorbate polypowder. In some embodiments, the water solubility of the cyclodextrin complex of flurellane combined with polysorbate polypowder is increased from 20 mg / ml to 30 mg / ml in water.

[0020] The animal receiving the drug may be a feline, canine, bovine or porcine animal. The animal parasitic infection may be a tick infection or a louse infection, and the animal may have an infection that is one or both of an internal parasite and an external parasite. The animal parasitic infection may be a tick infection of one of the spiky mites or the avian mites. DETAILED DESCRIPTION

[0021] The present invention relates to the use of a pharmaceutical composition comprising an isoxazoline compound complexed with a cyclodextrin (such as hydroxypropyl cyclodextrin) and combined with a polypowder in a dry (anhydrous) composition. The composition can be a mixture of isomers, an enriched mixture of a specific enantiomer, or a single enantiomer.

[0022] The isoxazoline compounds used in the present invention can be described by the following formula (hereinafter referred to as "formula"):

[0023]

[0024] R 1 = halogen, CF3, OCF3, CN,

[0025] N = an integer from 0 to 3, preferably 1, 2 or 3,

[0026] R 2 =C1-C3-halogenated, preferably CF3 or CF2Cl,

[0027] T = 5- or 6-membered ring, optionally substituted by one or more free radicals Y,

[0028] Y = methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or two adjacent free radicals Y together form a chain, mainly a ternary or quaternary chain;

[0029] Q=X-NR 3 R 4 or a 5-membered N-heteroaryl ring, optionally substituted with one or more free radicals;

[0030] X=CH2, CH(CH3), CH(CN), CO, CS,

[0031] R 3 =halogen(N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, halogenethylaminocarbonylcyclopropyl.

[0032]

[0033]

[0034]

[0035]

[0036]

[0037] Where Z A =Hydrogen, halogen, cyano, halomethyl (CF3

[0038] R 4 = hydrogen, ethyl, methoxymethyl, halogenmethoxymethyl, ethoxymethyl, halogenethoxymethyl, propyloxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propylaminocarbonylmethyl, halogenethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl or halogenethylaminocarbonylethyl;

[0039] or R 3 and R 4 together form a substituent selected from the group consisting of:

[0040]

[0041] In the cyclodextrin complex, hydroxypropyl-β-cyclodextrin can be mixed with polysorbate, and the complex is adsorbed on HPBCD to form a drug, which is applied by dissolving in drinking water to prevent or treat animal parasite invasion. This drug is anhydrous and has a long shelf life in a dry form, and can be put into animal drinking water or feed. Therefore, treatment or prevention of animal parasite invasion can be achieved. When put into feed, microparticle form can be used. In other embodiments, hard chewing drug therapeutics (hard when gently kneaded) or soft chewing drug therapeutics (squeezed together when gently kneaded) for cats or dogs can be used.

[0042] Furthermore, it has been found that the composition can be used to prepare a medicinal water which is stable over a period of time to allow distribution to feed animals (not less than 24 hours) and which can be evenly distributed in the system to ensure that an effective amount of the isoxazoline compound is introduced to the animals through the drinking water supply system.

[0043] In the above formula, T can be selected from:

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] Wherein, in T-1, T-3 and T-4, the free radical Y is hydrogen, halogen, methyl, halomethyl, ethyl, halogenethyl. In the above formula, Q can be selected from:

[0053]

[0054]

[0055]

[0056] Where R 3 , R 4 , X and Z A With the above values.

[0057] Z b =

[0058]

[0059]

[0060]

[0061]

[0062] The isoxazoline compounds used in the present invention have the following molecular formula:

[0063] (R one) n R 2 R 3 R four TYQZX3-Cl、5ClCF3CH2CF3HT-2-Q-1-C(O)3-Cl、5ClCF3CH2CH3HT-2-Q-1-C(O)3-Cl、5ClCF3CH2CH2OCH3HT-2-Q-1-C(O)3-Cl、5ClCF3CH2C(O)NHCH2CF3HT-2-Q-1-C(O)3-Cl、5ClCF3CH2C(O)NHCH2CH3HT-2-Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CF3HT-2-Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CH3HT-2-Q-1-C(O)3-CF3、5-ClCF3CH2C(O)NHCH2CF3HT-2-Q-1-C(O)3-CF3、5-ClCF3CH2C(O)NHCH2CH3HT-2-Q-1-C(O)3-Cl、5ClCF3-T-2-Q-6Z B -73-Cl、5ClCF3-T-2-Q-7Z B -73-Cl、5ClCF3-T-2-Q-5Z B -73-Cl、5ClCF3-T-2-Q-2Z D-13-Cl、5ClCF3CH2C(O)NHCH2CF3HT-3CH3Q-1-C(O)3-Cl、5ClCF3CH2C(O)NHCH2CCHT-3CH3Q-1-C(O)3-Cl、5ClCF3CH2C(O)NHCH2CNHT-3CH3Q-1-C(O)3-Cl、5ClCF3CH2C(O)NHCH2CH3HT-3CH3Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CF3HT-3CH3Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CH3HT-3CH3Q-1-C(O)3-Cl、4-Cl,5-ClCF3CH2C(O)NHCH2CF3HT-3CH3Q-1-C(O)3-Cl、4-Cl,5-ClCF3CH2C(O)NHCH2CH3HT-3CH3Q-1-C(O)3-Cl、4-F,5-ClCF3CH2C(O)NHCH2CF3HT-3CH3Q-1-C(O)3-Cl、4-F,5-ClCF3CH2C(O)NHCH2CH3HT-3CH3Q-1-C(O)3-Cl、5-ClCF3CH2C(O)NHCH2CF3HT-20-Q-1-C(O)3-Cl、5-ClCF3CH2C(O)NHCH2CH3HT-20-Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CF3CH3T-20-Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CH3CH3T-20-Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CF3HT-20-Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CH3HT-20-Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CF3HT-21-Q-1-C(O)3-CF3、5-CF3CF3CH2C(O)NHCH2CH3HT-21-Q-1-C(O)3-Cl、5-ClCF3CH2C(O)NHCH2CF3HT-21-Q-1-C(O)3-Cl、5-ClCF3CH2C(O)NHCH2CH3HT-21-Q-1-C(O)3-Cl、5-ClCF3CH2CH2SCH3HT-21-Q-1-C(O)3-Cl、4-Cl,5-ClCF3C(O)CH3HT-22FQ-1-CH23-Cl、4-Cl,5-ClCF3C(O)CH(CH3)2HT-22FQ-1-CH23-Cl、4-Cl,5-ClCF3C(O)-cyclopropylHT-22FQ-1-CH23-Cl, 4-F,5-ClCF3C(O)CH3HT-22FQ-1-CH23-Cl, 4-Cl,5-ClCF3C(O)CH2CH3HT-22FQ-1-CH23-Cl, 4-F,5-ClCF3C(O)CH3HT-22Cl Q-1-CH23-Cl, 5-ClCF3CH2C(O)NHCH2 CF3HT-1CH3Q-1-C(O)3-Cl, 5-ClCF3CH2C(O)NHCH2CH3HT-1CH3Q-1-C(O)3-Cl, 5-ClCF3R 3-1(Z)HT-1CH3Q-1-C(O)3-Cl, 5-ClCF3R 3-1(E)HT-1CH3Q-1-C(O),

[0064] The isoxazoline compounds used in the present invention include:

[0065] (R one ) n R 2 R 3 R four TYQZX3-Cl, 5ClCF3CH2CF3HT-2-Q-1-C(O)3-Cl, 5ClCF3CH2CH3HT-2-Q-1-C(O)3-Cl, 5ClCF3CH2CH2OCH3HT-2-Q-1-C(O)3-Cl, 5ClCF3CH2C(O)NHCH2CF3HT-2-Q-1-C(O)3-CF3, 5-CF3CF3CH2C(O)NHCH2CF3HT-2-Q-1-C(O)3-CF3, 5-ClCF3CH2C(O)NHCH2CF3 HT-2-Q-1-C(O)3-Cl、5ClCF3-T-2-Q-6Z B -73-Cl, 5ClCF3-T-2-Q-7Z B -73-Cl, 5ClCF3-T-2-Q-5Z B -73-Cl, 5ClCF3-T-2-Q-2Z D-13-Cl, 5ClCF3CH2C(O)NHCH2CF3HT-3CH3Q-1-C(O)3-Cl, 5ClCF3CH2C(O)NHCH2CCHT-3CH3Q-1-C(O)3-Cl, 5ClCF3CH2C(O)NHCH2CN HT-3CH3Q-1-C(O)3-CF3, 5-CF3CF3CH2C(O)NHCH2CF3HT-3CH3Q-1-C(O)3-Cl, 4-Cl,5-Cl CF3CH2C(O)NHCH2CF3HT-3CH3Q-1-C(O)3-Cl、4-F,5-ClCF3CH2C(O)NHCH2CF3HT-3CH3Q-1-C(O)3-Cl、5-ClCF3CH2C(O)NHCH2CF3HT-20-Q-1-C(O)3-CF3、5-CF3CF3CH2C(O) NHCH2CF3CH3T-20-Q-1-C(O)3-CF3, 5-CF3CF3CH2C(O)NHCH2CF3HT-20-Q-1-C(O)3-CF3, 5-CF3CF3CH2C(O)NHCH2CF3HT-21-Q-1-C(O)3-Cl, 5-ClCF3CH2C(O)NHCH2CF3HT-21 -Q-1-C(O)3-Cl,5-ClCF3CH2CH2SCH3HT-21-Q-1-C(O)3-Cl,4-Cl,5-ClCF3C(O)CH3HT-22FQ-1-CH23-Cl,4-Cl,5-ClCF3C(O)CH(CH3)2HT-22FQ-1-CH23-Cl,4-Cl,5-ClCF3C (O)-CyclopropylHT-22FQ-1-CH23-Cl,4-F,5-ClCF3C(O)CH3HT-22FQ-1-CH23-Cl,4-Cl,5-ClC F3C(O)CH2CH3HT-22FQ-1-CH23-Cl, 4-F,5-ClCF3C(O)CH3HT-22ClQ-1-CH23-Cl, 5-Cl CF3CH2C(O)NHCH2CF3HT-1CH3Q-1-C(O)3-Cl, 5-ClCF3R 3-1(Z)HT-1CH3Q-1-C(O)3-Cl, 5-ClCF3R 3 -1(E)HT-1CH3Q-1-C(O)

[0066] Another isoxazoline compound used in the present invention is a second formula (hereinafter referred to as "the second formula"):

[0067]

[0068] in

[0069] R 1a , R 1b , R 1c Each independently represents hydrogen, Cl or CF3, preferably R 1a and R 1c Represents Cl or CF3, R 1b Represents hydrogen,

[0070] T stands for

[0071]

[0072]

[0073] in

[0074] Y is methyl, bromine, Cl, F, CN or C(S)NH2, and

[0075] Q is as above.

[0076] In another embodiment, in the second formula, R 3 For H, R 4 It is -CH2-C(O)-NH-CH2-CF3, -CH2-C(O)-NH-CH2-CH3, -CH2-CH2-CF3 or -CH2-CF3.

[0077] In some embodiments of the disclosed invention, the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoroethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3-USAN, flurella).

[0078] In some embodiments, the isoxazoline compound is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN 928789-76-8).

[0079] In some embodiments, the isoxazoline compound is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thiophen-3-yl)benzamide (CAS RN 1164267-94-0), which is disclosed in application WO2009 / 0080250.

[0080] In some embodiments, the isoxazoline compound 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-naphthamide (CAS RN 1093861-60-9, USAN, Afolan), which is disclosed in WO 2007 / 079162.

[0081] In some embodiments, the isoxazoline compound is 1-[5′-[(5S)-5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]spiro[azetidine-3,1′(3′H)-isobenzofuran]-1-yl]-2-(methylsulfonyl)ethanone, Sarolaner (CAS RN 1398609-39-6).

[0082]

[0083] In some embodiments, the isoxazoline compound is 5-((5S)-4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl)-3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-2-thiophenecarboxamide, Lotilaner (INN, CAS RN 1369852-71-0).

[0084]

[0085] In some embodiments, 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 (CAS RN 1231754-09-8), which is disclosed in WO 2010 / 070068.

[0086] For example, a racemic mixture can be used for equal amounts of enantiomers of any isoxazoline compound as described above. In addition, the method of the present invention includes an isoxazoline compound enriched as the enantiomer of the first formula compared to the racemic mixture. The substantially pure enantiomer of the isoxazoline compound can also be used for the method described in the present invention.

[0087] In enantiomeric enrichment, one enantiomer is present in excess over the other, and the degree of enrichment can be determined by expressing the enantiomeric excess ("ee"), which is defined as (2x-1)-100%, where x is the mole fraction of the major enantiomer in the mixture (e.g., ee 20% corresponds to a 60:40 ratio of enantiomers). Compositions useful in the present invention have an enantiomeric excess of at least 50% in some embodiments, and at least 75% in a subset of such embodiments. In other cases, an enantiomeric excess of 90%-94% of the more active isomer is achieved. Of particular note are enantiomerically pure embodiments of the more active isomer.

[0088] The isoxazoline compounds described above may contain additional chiral centers. The process of the present invention encompasses racemic mixtures as well as stereochemically enriched and substantially pure forms at these additional chiral centers.

[0089] As described above, in an embodiment of the present invention, after diluting the dry powder in water, the isoxazoline compound is present in an amount of about 0.001 mg / ml to about 30 mg / ml. The combination of the mixture of isoxazoline and flurellana in the cyclodextrin complex and the polypowder as a dry mixture can immediately (in less than one minute) form a concentrated solution of 20 mg / ml to 30 mg / ml of the isoxazoline compound dissolved in water, which can be directly distributed as a solution to the animal or poultry to be treated. If necessary, the solution can be further diluted.

[0090] The compositions according to the invention have particularly advantageous properties, such as long-term stability after storage (two years or more), good mouthfeel characteristics and the absence of precipitation of the isoxazoline compound after dilution of the composition in water or ingestion of the isoxazoline in the form of a chewable tablet or powder.

[0091] Polysorbate surfactants (such as sorbitan esters or poly(hydroxy-1,2-ethylenediyl) derivatives) are water-soluble nonionic surfactants that contain or consist of esters and alkoxy acid esters. Esters are derived from hexols, alkylene oxides, and fatty acids by adding polyoxyethylene chains to hydroxysorbitol and hexitol anhydrides (hexosanes and hexose esters) (obtained from sorbitol) and then esterifying with common fatty acids such as lauric acid, palmitic acid, stearic acid, and oleic acid.

[0092] In one embodiment, the polysorbate surfactant is selected from one or more of Tween 20, Tween 40, Tween 60 and Tween 80, also known as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80 in the pharmaceutical industry. Polysorbate 20 (polyoxyethylated sorbitan monolaurate) is a laurate; polysorbate 60 (polyoxyethylated sorbitan monostearate) is a mixture of stearate and palmitate; polysorbate 80 (polyoxyethylated sorbitan monooleate) is an oleate. Such polysorbate surfactants are commercially available and / or can be obtained by methods known in the art. These polysorbates are adsorbed onto hydroxypropyl beta-cyclodextrin under anhydrous conditions to form a polypowder, which is dry mixed with the isoxazoline cyclodextrin complex to form a highly water-soluble dry mixture.

[0093] In some embodiments, the polysorbate surfactant is polysorbate 80 (polyoxyethylene sorbitan monooleate, Tween 80), which has the chemical name polyoxyethylene (20) sorbitan monooleate and is adsorbed onto 2-hydroxypropyl β-cyclodextrin as a water-free flowable compressible powder with a long shelf life.

[0094] Some embodiments use preservatives, such as benzyl alcohol, butyl paraben sodium salt, methyl paraben sodium salt, propyl paraben sodium salt and mixtures thereof. However, in view of the shelf life of the drug being greater than two years, the preservatives in these embodiments are generally unnecessary. Some embodiments may use antioxidants, such as butylated hydrogen anisole, butylated hydrogen toluene, tocopherol and its derivatives such as alpha-tocopherol polyethylene glycol succinate and mixtures thereof. However, in view of the shelf life of the drug being greater than two years, the antioxidants in these embodiments are generally unnecessary.

[0095] The term "treating" or "treat" or "treatment" is defined as "the application or administration of a composition of the invention to an animal having a parasitic infestation to eliminate the parasite or to reduce the number of parasites infecting one or more animals."

[0096] The parasites eliminated or reduced may be ovicidal, larvicidal, adult stage or a combination thereof. This effect may be manifested directly, i.e. killing the parasite immediately or after a period of time, e.g. when molting occurs, or destroying the parasite's eggs, or indirectly, e.g. by reducing the number of eggs laid and / or the hatching rate.

[0097] "Prevention" or "prevention" is defined as "preventing a future occurrence that would otherwise occur", and in the present invention, new infections of animals by parasites can be prevented by killing the adult worms and / or any developmental / larval stages that can infect the host either before infection of the host or immediately after infection by protected parasites. This prevention can be achieved by reducing the number of eggs laid and / or the hatching rate.

[0098] The term "effective amount" is defined as the dose or amount of an isoxazoline compound required to partially reduce or decrease the number of parasites in an animal and / or the animal's environment (e.g., a house / structure), and / or to completely or partially inhibit the development of a parasitic infection in an animal. In embodiments of the invention, the effective amount is determined by observing or detecting the number of parasites on the animal or in the animal's environment (e.g., using a trap) before and after the introduction of the isoxazoline compound, which is introduced through the drinking water or on / in the feed. For example, the goal may be to reduce the number of parasites by 5% to essentially 100% after the first treatment, which can be measured by capturing and / or counting and / or making an educated approximation of the number of parasites in a given location.

[0099] Parasite invasion can be an invasion of parasites on the body surface or inside the body. In one embodiment, the parasite invasion to be prevented or treated is an invasion of parasites on the body surface. Specific examples of parasites on the body surface include, but are not limited to fleas (cat fleas, Ctenocephalides species, etc.), ticks (Rhipicephalus species, Ixodes species, Dermacentor species, Flower tick species, Blood tick species, Boophilus species, etc.) and mites (Demodex type, Sarcoptes species, Otomites species, Chelicerus species, Dermatospinus species, Avian spiny mite species, etc.), lice (Hairy lice species, Cat lice species, Gnathid species, etc.), mosquitoes (Aedes species, Culex species, Anopheles species, etc.) and flies (Horn fly species, including Horn flies, House flies species; Schistosoma fly species, including Stable flies, Skin flies species, Triatomine flies species, etc.).

[0100] The isoxazoline compositions are useful for treating or preventing parasitic infections in animals such as pigs, cattle, horses, goats, sheep, dogs, cats, poultry, and fish.

[0101] Isoxazoline drugs can be administered by systemic administration. "Systemic administration" is defined as "introduced in a place at least partially away from the target parasite's life". After systemic administration, at least part of the compound reaches the target parasite through the blood, other biological fluids (lymph) and / or tissues (such as skin or adipose tissue) of the recipient animal. In many cases, the parasite swallows up this compound together with the blood, other body fluids and / or tissues of the animal recipient. Systemic administration can be carried out in a variety of forms, such as oral, injection or topical administration. When parenteral administration is performed, it can be intramuscular, intravenous or subcutaneous injection. In some embodiments, the drug is orally administered in liquid form, such as by inserting a portion of it into a syringe in the animal's mouth. Alternatively, oral administration can be implemented by the feed or drinking water of the recipient animal. When applied in drinking water, this may be to prevent or treat the invasion of parasitic arthropods.

[0102] In one embodiment, the pharmaceutical compositions are useful for treating or preventing parasite infestations in animals, particularly farm animals (eg, cattle, poultry, and pigs), by administering an isoxazoline compound, such as flurellan, through the drinking water system.

[0103] The final concentration of the isoxazoline compound in the medicinal drinking water depends on the effective amount, the animal's weight, the amount of water the animal drinks, and the treatment time. In general, the effective amount per kilogram of body weight of the treated animal depends on the type of parasitic infection. In one embodiment, the concentration of the isoxazoline compound in the cyclodextrin complex mixed with the polypowder in the treated water is 0.002 mg / ml to 0.2 mg / ml.

[0104] For some isoxazoline compounds containing flurellana, the concentration in the medicinal drinking water is calculated to provide a target amount of flurellana per unit body weight (MT) of the poultry to be treated, ranging from about 0.1 mg to about 2 mg of flurellana per kilogram of body weight, for example, more specifically, 0.5 mg / kg of body weight per day. The compound in that amount is placed in the drinking water that is normally consumed by the poultry to be treated during a treatment period of 2 to 24 hours, preferably 4 to 8 hours. The pharmaceutical composition can be used for one animal or a group of animals at the same time, such as poultry (chickens, turkeys, etc.) and pigs, or for such animals in one room (cage) or farm during the treatment period through the medicinal drinking water. Chickens raised on an industrial scale, such as laying hens, chickens or repair chickens, breeding chickens, broilers and breeding birds, etc., can all be treated in this way. Other types of poultry, such as turkeys, geese, ducks, pigeons, quails or pheasants can also be treated with these compounds.

[0105] The frequency of using the pharmaceutical composition for treatment by medicinal drinking water depends on the parasite (and its biological life cycle) to be treated or prevented and the production cycle of the host animal to be treated. The pharmaceutical composition of the present invention is applied once or twice at least by medicinal drinking water in the production cycle of the treated animal host (for example, the egg-laying period with respect to laying hens). By introducing the pharmaceutical composition with medicinal water having this effect, it is possible to achieve a higher efficacy of resisting parasites, because the parasites in different life cycle stages can be affected. Under this introduction scheme, the parasite colony can be reduced to the level that only causes minimum damage and minimum production loss to animals.

[0106] For some parasites, not all stages of the parasite can be affected by a single administration of the pharmaceutical composition via the medicinal drinking water, as some stages of the parasite either do not feed the animal or feed in other ways. A second dose of the pharmaceutical composition is introduced via the medicinal drinking water, during which parasites that develop from non-susceptible stages (following the life cycle of the parasite), or parasites that develop from difficult-to-affect parasite stages, such as parasites that mature from juvenile parasite stages (e.g., eggs, nymphs, or pupae) may be affected. In the case of treating poultry, the pharmaceutical composition may be administered once or twice during the production cycle via the medicinal drinking water or feed at intervals of approximately or exactly 7 or 14 days (depending on the life cycle of the parasite and the production cycle of the host animal).

[0107] In one embodiment, the pharmaceutical composition is administered via medicinal drinking water to treat or prevent tick infestations. Some ticks migrate from birds, rodents, food, plants, and house dust and can infest and harass animals and humans. There are many types of mites, including Ornithonyssus sylviarum, Dermanyssus gallinae, Demodex folliculorum, scab mites, or itch mites (Scabies species, Chelicerus species, Demodex species). Tick infestations caused by poultry mites may be a Dermestes mite (such as Dermanyssus gallinae) and / or an avian mite, particularly Ornithonyssus sylviarum.

[0108] In one embodiment, according to the present invention, the pharmaceutical composition administered through treated drinking water or feed controls the various stages of parasitic arthropods present in the poultry environment as described above. The various stages of parasitic arthropods can be all life cycle stages known to those skilled in the art, i.e., the larval stage (developmental / larval stage) and the adult stage.

[0109] In one embodiment, according to the present invention, the pharmaceutical composition administered via the medicinal drinking water or feed is used to combat arthropods in poultry, especially broiler chickens, which arthropods do not normally infect poultry directly but cause damage to the poultry, such as dark eyebrows.

[0110] In the above solvent-free composite product, two groups of six laying hens were given a dose of 0.5 mg / kg of flurella in the purified water of the chicken feed. The prior art, called "Exzolt", contains 10 mg of flurella per milliliter of solution for use in the drinking water of chickens and contains alpha-tocopherol, diethylene glycol monoethyl ether and polysorbate 80.

[0111]

[0112] Faster onset of action is seen by Tmax. Lower absorption variability and lower egg retention can also be seen. In a highly water-soluble powder formulation, the combination of flurellana with anhydrous polypowder (anhydrous polysorbate 80 / HPBCD, e.g., a 1:5 ratio) can produce a fast-absorbing, premium product.

Claims

1. A method for preparing a storage-stable anhydrous pharmaceutical composition, comprising the following steps: Combining an isoxazoline cyclodextrin complex with a polypowder, wherein the isoxazoline is flurella, and the maximum solubility of the isoxazoline cyclodextrin complex in water is less than 20 mg / ml flurella; the polypowder is a polysorbate adsorbed onto 2-hydroxypropyl beta-cyclodextrin in an anhydrous form, and the shelf life of the polypowder is at least 2 years; and the solubility of the anhydrous pharmaceutical composition in water is 20 mg / ml to 30 mg / ml flurella; The isoxazoline cyclodextrin complex and the adsorbed polypowder are combined to form a dry anhydrous drug with a shelf life of at least 2 years; wherein the drug can be administered through water or feed ingested orally by an animal and has a medicinal effect.

2. Use of a storage-stable anhydrous pharmaceutical composition in the preparation of a medicament for treating parasitic infections in animals, wherein the anhydrous pharmaceutical composition comprises: An isoxazoline-cyclodextrin complex, wherein the cyclodextrin is 2-hydroxypropyl β-cyclodextrin and the isoxazoline is flurellanine; the solubility of the isoxazoline-cyclodextrin complex in water is lower than 20 mg / ml flurellanine; and Polypowder comprising polysorbate adsorbed onto 2-hydroxypropyl beta-cyclodextrin in anhydrous form.

3. The use according to claim 2, wherein The drug is administered in the water or feed at 0.5 mg of flurellana per kg of animal body weight, wherein the animal is poultry.

4. The use according to claim 2, wherein The drug is administered twice over a period of 7 to 14 days.

5. The use according to claim 2, wherein The drug is administered in a hard or soft anhydrous chewable dosage form at a rate of 2 mg to 4 mg of flurellana per kg of animal body weight per month, the animal being a feline or a canine.

6. The use according to claim 2, wherein: The medicament comprises a combination of the anhydrous pharmaceutical composition and a cyclodextrin complex of a macrolide.

7. The use according to claim 2, wherein the medicament further comprises pyrantel pamoate, wherein the medicament provides a broad-spectrum antiparasitic effect in a water-free, storage-stable chewable form.

8. The use according to claim 2, wherein The water solubility of the anhydrous pharmaceutical composition in water is 20 mg / ml to 30 mg / ml of flurellan.

9. The use according to claim 2, wherein: The animal is a bovine or a porcine animal.

10. The use according to claim 2, wherein: The animal parasitic infection includes tick infection or lice infection, and the infection is an internal parasite infection or an external parasite infection.

11. The use according to claim 2, wherein: The animal parasitic infection is a tick infection with one of the species Dermatosauria or Oryctolagus avium.

12. An oral medicament for treating parasitic infections in animals and suitable for safe ingestion by animals, comprising: Polysorbate adsorbed onto 2-hydroxypropyl beta-cyclodextrin in anhydrous form and having a shelf life of at least 2 years; An isoxazoline cyclodextrin complex, wherein the isoxazoline is flurellanil; The combination of the isoxazoline cyclodextrin complex and the polypowder forms a dry anhydrous drug with a shelf life of at least 2 years, and the water solubility of the composition of the isoxazoline cyclodextrin complex and the polypowder in water is 20 mg / ml to 30 mg / ml of flurella.

13. The medicament according to claim 12, wherein the medicament is administered in a ratio of 2 mg to 4 mg of flurellana per kg of animal body weight per month in a hard or soft anhydrous chewable tablet to treat parasitic infections in the animal, which is a feline or canine.

14. The drug according to claim 12, wherein the drug comprises a combination of the isoxazoline cyclodextrin complex and the polypowder and a cyclodextrin complex of a macrolide.

15. The medicament of claim 12, wherein the medicament further comprises pyrantel pamoate, wherein the medicament provides a broad spectrum antiparasitic effect in a water-free, storage-stable chewable form.

16. The drug according to claim 12, wherein The isoxazoline and the cyclodextrin are compounded in a stoichiometric ratio of 1:1 or 1:

2.

17. The drug according to claim 12, wherein The animal parasitic infection includes tick infection or lice infection, and the infection is an external parasitic infection.

18. The drug according to claim 12, wherein The infection includes a tick infestation or a lice infestation, or the infection is an internal parasite or an external parasite infection.

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