Composition comprising tigarana for controlling parases

Abstract

The present invention relates to a composition comprising tigorane and optionally an endoparasite-killing agent, to a method for the production thereof and to the use thereof as a medicament for controlling parasites.

Description

[0001] This application is a divisional application of the invention patent application with the application date of August 12, 2020, application number 202080057562.3, and invention name “Composition containing ticopterin for preventing and treating parasites”. Technical Field

[0002] The present invention relates to a composition comprising tigolaner and optionally an endoparasiticide, a process for its manufacture and its use as a medicament for combating parasites. Background Art

[0003] Preparations for controlling ectoparasites in pets, such as cats, can be applied as so-called spot-on preparations. Spot-on treatments can be packaged as individual doses of liquid and are typically applied by pouring the liquid onto the pet's back, for example, between the shoulders. From there, the active agent is absorbed into the pet's system and / or distributed on the pet's skin, where it can act accordingly.

[0004] WO 2008 / 080542 A2 discloses a composition for controlling parasites on animals, comprising fipronil, flucythrin, an aliphatic cyclic carbonate, and an aliphatic cyclic or acyclic polyether. WO 2005 / 105034 A1 relates to a composition of matter comprising: a) 0.1-60% by weight of an active pyrethroid compound; b) 7.5-30.0% by weight of dinotefuran and / or a dinotefuran analog; c) 27.5-62.5% by weight of an organic solvent from the group consisting of methylpyrrolidones, fatty alcohols and cyclic carbonates, aliphatic, cyclic or acyclic ethers, and mixtures thereof; d) 0-5% by weight of water; e) 0-0.5% by weight of a phenolic antioxidant; and g) 0-0.5% by weight of an organic acid.

[0005] Emodepside (cyclic [(R)-lactyl-N-methyl-L-leucyl-(R)-3-(p-morpholinophenyl)lactyl-N-methyl-L-leucyl-(R)-lactyl-N-methyl-L-leucyl-(R)-3-(p-morpholinophenyl)lactyl-N-methyl-L-leucyl] is an anthelmintic effective against a variety of gastrointestinal nematodes. Its molecular structure, described below, can be described as a cyclic octadepsipeptide, which is a depsipeptide in which one or more of its amide groups is replaced by a corresponding ester group. On an industrial scale, emodepside can be obtained by derivatization of the naturally occurring substance PF1022A, in which two hydrogen atoms are exchanged for a morpholine ring.

[0006]

[0007] WO 93 / 19053 A1 (EP 0 634 408 A1) discloses a compound having the following general formula and its pharmaceutically acceptable salts:

[0008]

[0009] wherein A is a benzyl group having one or more suitable substituents or a phenyl group which may have one or more suitable substituents, a is benzyl which may have one or more suitable substituents or phenyl which may have one or more suitable substituents, B and D are both lower alkyl, and C is hydrogen or lower alkyl.

[0010] EP 0 662 326 A2 relates to the use of praziquantel and epsiprantel for enhancing the endoparasiticidal activity of cyclic depsipeptides in endoparasiticidal compositions.

[0011] US2003 / 125244 A1 relates to a transdermal composition comprising a cyclic depsipeptide, its preparation and its use for controlling endoparasites. In the composition according to the present patent application, the active compound may also be present in a mixture with a synergist or other compound active against pathogenic endoparasites. Examples of such active compounds are L-2,3,5,6-tetrahydro-6-phenylimidazothiazole, benzimidazole carbamates such as febantel, in addition to pyrantel, praziquantel and ivermectin.

[0012] US 2008 / 255037 A1 relates to a composition for external application comprising emodepside and praziquantel or ezetyl and 1,2-isopropylidene glycerol, its preparation and its use for controlling endoparasites.

[0013] Praziquantel and escitalopram have the following structures:

[0014]

[0015] There are Available animal deworming products. These include A spot-on solution containing emodepside and praziquantel as active ingredients and butylated hydroxyanisole, isopropylidene glycerol and lactic acid as excipients.

[0016] Tigoranab (WHO Drug Information, Vol. 31, No. 2, 2017, p. 341) is a veterinary antiparasitic agent having the following structure:

[0017]

[0018] Tigoranab is described in Structure Ic-2, Table 3 of WO 2014 / 122083 A1. Tigoranab is also mentioned, for example, in Example 3 (page 39) of WO 2016 / 177619 A1. International patent applications related to the synthesis of such compounds are, for example, WO 2014 / 012975 A1, WO 2015 / 078846 A1, WO 2015 / 078847 A1, WO 2015 / 150302 A1, WO 2015 / 181139 A1, and WO 2016 / 026789 A1.

[0019] Due to the various requirements that modern pharmaceuticals have to meet, for example with regard to activity levels (e.g. plasma concentrations of active compounds), duration of action, spectrum of action, range of application, toxicity, combinations of active compounds, combinations with formulation auxiliaries, and due to the possible emergence of drug resistance, the development of novel drugs cannot be considered complete and there continues to be a great need for novel compositions that are superior to known compositions in at least some respects.

[0020] In order to enable pet owners to apply parasiticidal compounds in the simplest possible manner, it is also necessary to provide a composition that can be applied topically, which in the context of this application generally means application to the skin or coat of an animal.

[0021] Such compositions need to meet additional criteria, such as:

[0022] - efficacy (especially in the case of systemic action of the active compound)

[0023] - Target animal safety and user safety

[0024] - Well tolerated

[0025] - Convenience Summary of the Invention

[0026] The invention relates to a composition according to claim 1 and, in further embodiments, to a method according to claim 7 and to a use according to claim 8. Advantageous embodiments are subject matter of the dependent claims. They can be freely combined unless the context clearly indicates otherwise.

[0027] Therefore, one embodiment of the present invention is a composition comprising ticoranab and 1,2-isopropylidene glycerol. The composition may preferably comprise ticorana in an amount of ≥1% by weight to ≤15% by weight; according to a further preferred embodiment, the composition may contain ticorana in an amount of ≥1% by weight to ≤11% by weight or ≥7% by weight to ≤11% by weight or ≥1% by weight to ≤9.5% by weight or ≥7% by weight to ≤9.5% by weight. The composition optionally further comprises praziquantel, preferably praziquantel in a concentration of ≥1% by weight to ≤15% by weight (preferably ≥6% by weight to ≤9% by weight). In the composition according to the present invention containing ticoranab and solketal but not containing praziquantel, the amount of ticoranab is preferably <10% by weight, more preferably <9.5% by weight.

[0028] According to another embodiment, the present invention includes a composition comprising praziquantel, emodepside, and a solvent component, further comprising ticagrelor. These substances have the structures defined in the previous subsection. The composition according to this embodiment utilizes the ectoparasiticidal effect of ticagrelor to extend the endoparasiticidal effect of praziquantel and emodepside. Specifically, it can control tapeworms, flukes, nematodes, acanthocephalans, fleas, and ticks.

[0029] Unless otherwise indicated, the solvent component preferably comprises a solvent suitable for transdermal administration of the active pharmaceutical ingredient, such as DMSO, NMP, 2-pyrrolidone, dimethylacetamide (DMAc), glycerol formaldehyde (also known as glycerol formal), tetraethylene glycol, triethyl phosphate, propylene carbonate, or 1,2-isopropylidenediol (also known as glycerol acetone acetal).

[0030] By controlling pathogenic endoparasites, the aim is to reduce disease, mortality and performance impairment (for example in the production of meat, milk, wool, leather, eggs, honey, etc.), thereby making more economical and simpler animal husbandry possible through the use of the active compounds. Pathogenic endoparasites include tapeworms, flukes, nematodes and acanthocephalians:

[0031] Praziquantel is particularly effective against the following internal parasites:

[0032] From the order of the Pseudophyllidea, for example, Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp.;

[0033] From the order of the Cyclophyllidea, for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyras spp., Bertiella spp., Taenia spp. spp.), Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., and Diplopylidium spp.;

[0034] From the Monogenea, for example: Gyrodactylus spp., Dactylogyrus spp., Polystoma spp.;

[0035] From the Digenea, for example: Diplostomum spp., Posthodiplostomum spp., Schistosoma spp., Trichobilharzia spp., Omithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp.), Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp. spp.), Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp.), Heterophyes spp., and Metagonimus spp.

[0036] Amodeus is particularly effective against the following internal parasites:

[0037] From the order Enoplida, for example, Trichuris spp., Capillaria spp., Trichomosoides spp., Trichinella spp.;

[0038] From the order of the Rhabditia, for example: Micronema spp., Strongyloides spp., Aelurostrongylus spp., Troglostrongylus brevior;

[0039] From the order of the Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp. spp.), Uncinaria spp., and Bunostomum spp.;

[0040] Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp.), Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp. spp.), Amidostomum spp., Ollulanus spp.;

[0041] From the order Oxyurida, for example, Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.;

[0042] From the order Ascaridia, for example, Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.;

[0043] From the order of the Spirurida, for example, Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Drashia spp., Dracunculus spp.;

[0044] From the order of the Filariida, for example, Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp., Onchocerca spp.;

[0045] From the order of the Gigantorhynchida, for example: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

[0046] Pests targeted by Tigoranab include:

[0047] From the order of the Anoplura, for example, Haematopinus spp., Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp.;

[0048] From the order of the Mallophaga, for example, Trimenopon spp., Menopon spp., Eomena-canthus spp., Menacanthus spp., Trichodectes spp., Felicola spp., Damalina spp., Bovicola spp.;

[0049] From the order Diptera, suborder Brachycera, for example, Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp., Lucilia spp., Calliphora spp., Auchmeromyia spp., Cordylobia spp., Cochliomyia spp. spp.), Chrysomyia spp., Sarcophaga spp., Wohlfartia spp., Gasterophilus spp., Oesteromyia spp., Oedemagena spp., Hypo-derma spp., Oestrus spp., Rhinoestrus spp., Melophagus spp., and Hippobosca spp.;

[0050] From the order Diptera, suborder Nematocera, for example, Culex spp., Aedes spp., Anopheles spp., Culicoides spp., Phlebotomus spp., Simulium spp.

[0051] From the order of the Siphonaptera, for example, Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp., Pulex spp.

[0052] From the order of the Metastigmata, for example, Hyalomma spp., Rhipicephalus spp., Boophilus spp., Amblyomma spp., Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp.;

[0053] From the order of the Mesostigmata, for example, Dermanyssus spp., Omithonyssus spp., Pneumonyssus spp.

[0054] From the order of the Prostigmata, for example, Cheyletiella spp., Psorergates spp., Myobia spp., Demodex spp., Neotrombicula spp.;

[0055] From the order of the Astigmata, for example, Acarus spp., Myocoptes spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Neoknemidocoptes spp., Cytodites spp., Laminosioptes spp.

[0056] Special emphasis can be placed on the control of fleas (Siphonaptera, for example Ctenocephalides species, Coronatus species, Ceratophyllum species, Siphonaptera species), ticks (Hydralomys species, Rhipicephalus species, Boophilus species, Amblyomma species, Haemaphysalis species, Dermacentor species, Ixodes species, Acutus species, Ornithodoros species, Ototrichum species) and the above-mentioned Diptera (Ballista species, Protostomys species, Musca species, Odontocephalus species, Rottenia species, Haematobium species) , black horn fly species, stable fly species, toilet fly species, tsetse fly species, green fly species, calliphora species, fire fly species, tumor fly species, cone fly species, golden fly species, flesh fly species, flesh fly species, stomach fly species, Oesteromyia species, Oedemagena species, gadfly, lizard fly, nose lizard fly, tick fly, and louse fly).

[0057] In one embodiment of the composition, the solvent component comprises 1,2-isopropylidene glycerol and the water content of the composition is at most 5 wt%, preferably at most 3 wt%, more preferably at most 2 wt%, even more preferably at most 1.5 wt%, in particular at most 1 wt%.

[0058] In another embodiment of the composition, the solvent component comprises only 1,2-isopropylidene glycerol. It has been determined that the solubility of ticopyranab in solketal alone is in the range of approximately 9.5-9.9% w / w. Surprisingly, it has been found that in the presence of praziquantel, particularly 7.5% w / w to 8.5% w / w praziquantel, its solubility in solketal can be increased to greater than 10.5% w / w.

[0059] In another embodiment, the composition comprises:

[0060] ≥1 wt% to ≤15 wt% (preferably ≥6 wt% to ≤9 wt%) of praziquantel;

[0061] ≥1 wt% to ≤10 wt% (preferably ≥1.2 wt% to ≤3 wt%) of emodepside;

[0062] ≥1 wt% to ≤15 wt% (preferably ≥7 wt% to ≤11 wt%) of ticopragmat;

[0063] The weight percentages are based on the total weight of the composition.

[0064] Preferably, the composition comprises:

[0065] ≥1 wt% to ≤15 wt% (preferably ≥6 wt% to ≤9 wt%) of praziquantel;

[0066] ≥1 wt% to ≤10 wt% (preferably ≥1.2 wt% to ≤3 wt%) of emodepside;

[0067] ≥1 wt% to ≤15 wt% (preferably ≥7 wt% to ≤11 wt%) of ticopragmat

[0068] ≥0 wt% to ≤5 wt% (preferably ≥1 wt% to ≤3 wt%) of other components other than solvents;

[0069] The weight percentages are based on the total weight of the composition, and the balance to 100 weight % is composed of 1,2-isopropylidene glycerol as a solvent component.

[0070] In another embodiment, the composition further comprises an antioxidant. These antioxidants can protect praziquantel and / or emodepside from oxidation.

[0071] In another embodiment, the antioxidant is butylated hydroxyanisole (BHA) and / or butylated hydroxytoluene (BHT). Preferably, the composition of the present invention contains BHT. According to another preferred embodiment, the composition of the present invention contains BHA and BHT.

[0072] In another embodiment, the composition further comprises an acid. These acids are preferably carboxylic acids. They can act as stabilizers.

[0073] In another embodiment, the acid is lactic acid.

[0074] In another embodiment, the composition comprises:

[0075] ≥1 wt% to ≤15 wt% (preferably ≥6 wt% to ≤9 wt%) of praziquantel;

[0076] ≥1 wt% to ≤10 wt% (preferably ≥1.2 wt% to ≤3 wt%) of emodepside;

[0077] ≥1 wt% to ≤15 wt% (preferably ≥7 wt% to ≤11 wt%) of ticopragmat;

[0078] ≥0.01 wt. % to ≤1 wt. % (preferably ≥0.1 wt. % to ≤0.5 wt. %) of butylated hydroxyanisole (BHA) and / or butylated hydroxytoluene (BHT);

[0079] ≥1 wt. % to ≤5 wt. % (preferably ≥1.5 wt. % to ≤2.5 wt. %) of lactic acid;

[0080] The weight percentages are based on the total weight of the composition.

[0081] Preferably, the composition comprises:

[0082] ≥1 wt% to ≤15 wt% (preferably ≥6 wt% to ≤9 wt%) of praziquantel;

[0083] ≥1 wt% to ≤10 wt% (preferably ≥1.2 wt% to ≤3 wt%) of emodepside;

[0084] ≥1 wt% to ≤15 wt% (preferably ≥7 wt% to ≤11 wt%) of ticopragmat;

[0085] ≥0.01 wt. % to ≤1 wt. % (preferably ≥0.1 wt. % to ≤0.5 wt. %) of butylated hydroxyanisole (BHA) and / or butylated hydroxytoluene (BHT);

[0086] ≥1 wt. % to ≤5 wt. % (preferably ≥1.5 wt. % to ≤2.5 wt. %) of lactic acid;

[0087] The weight percentages are based on the total weight of the composition, and the balance to 100 weight % is composed of 1,2-isopropylidene glycerol as a solvent component.

[0088] The presence of lactic acid slightly reduces the solubility of ticopyranab in 1,2-isopropyl glycerol. Therefore, it is preferred to use a low concentration of lactic acid in the composition containing ticopyranab and 1,2-isopropyl glycerol, i.e.

[0089] ≥1 wt.-% to ≤3 wt.-% (preferably ≥1 wt.-% to ≤2.5 wt.-%) of lactic acid.

[0090] The present invention also relates to a method for producing a composition according to the invention, comprising dissolving one or more active ingredients and optionally other ingredients in a solvent component. According to one embodiment, the method comprises dissolving praziquantel, emodepside and ticagrelor in a solvent component.

[0091] The compositions are prepared by combining appropriate quantities of the components in a suitable container; preferably, the components are mixed until a clear solution is formed.

[0092] According to one embodiment, in a composition containing emodepside and ticopranas, emodepside may be added before ticopranas to promote the dissolution of ticopranas.

[0093] According to a further embodiment, in the composition comprising praziquantel, emodepside and ticopanab, praziquantel and emodepside may be added before ticopanab to promote the dissolution of ticopanab.

[0094] To accelerate the dissolution kinetics, the mixture can be heated and / or shear forces applied.

[0095] The preparation of the composition of the present invention can be carried out under an inert gas, preferably a dry inert gas, for example by blanketing with nitrogen or argon. "Dry" inert gas preferably means a gas containing less than 100 ppm (per volume) of water.

[0096] In general, it has been found to be advantageous to dose the compositions of the invention so that from about 1 mg to about 100 mg of the active compound in question is administered per kg body weight. Preferred are 1 to 20 mg, in particular 1 to 10 mg, of active compound per kg body weight in the case of emodepside; 5 to 50 mg, in particular 5 to 20 mg, of active compound per kg body weight in the case of praziquantel; and 5 to 30 mg, in particular 10 to 20 mg, of active compound per kg body weight in the case of ticagrelor.

[0097] Another aspect of the invention is a composition according to the invention for use as a medicament.

[0098] Without being bound by any theory, it is believed that ticagrelor acts primarily systemically, ie, it penetrates the skin and enters the blood circulation. Since emodepside and praziquantel act against internal parasites, they are also believed to act systemically.

[0099] Administration can be performed both prophylactically and therapeutically.

[0100] Preferably, the composition according to the invention is suitable for spot application, pour-on application, or spray application, wherein spray application can be carried out, for example, using a pump sprayer or an aerosol spray (pressurized spray). For certain indications, the formulation can also be used as an immersion solution after dilution with water; in this case, the formulation should contain an emulsifying additive.

[0101] Preferred forms of application are pump spray, flow coating and spot coating. Spot coating is very particularly preferred.

[0102] The present invention also comprises a composition according to the invention for use in treating and / or preventing parasitic infections in animals.

[0103] The animal is preferably a mammal, such as a cat, dog or ferret.

[0104] In one embodiment, the animal is a cat.

[0105] In another embodiment, the parasites are endoparasites and ectoparasites.

[0106] In another embodiment, the parasite is selected from the group consisting of:

[0107] The endoparasite is selected from the group consisting of Toxocara cati, Toxascaris leonina, Ancylostoma tubaeforme, Uncinaria stenocephala, Dipylidium caninum, Taenia taeniaeformis, Echinococcus multiocularis, Aelurostrongylus abstrusus, and Troglostrongylus spp.;

[0108] The ectoparasites are selected from the group consisting of Ctenocephalides species, Coronophles species, Cteratophyllus species, Fleas species, Hyalomma species, Rhipicephalus species, Boophilus species, Amblyomma species, Haemaphysalis species, Dermacentor species, Ixodes species, Acutus species, Ornithodoros species, Otodectes species, Otodectes cynotis, Notoedrescati,

[0109] and their combinations.

[0110] Tigoranab shows long-term efficacy. Therefore, the composition of the present invention can be administered to the host animal at intervals of 4 weeks or longer, preferably 8 weeks or longer, more preferably 10 weeks or longer, and especially 12 weeks or longer. DETAILED DESCRIPTION

[0111] Example

[0112] The present invention will be further described in the following examples, without wishing to be limited thereto. Solvent acetone acetal is 1,2-isopropylidene glycerol. All examples shown include solvent acetone acetal containing 0.3% BHA for general stability of the solvent.

[0113] The examples were prepared by mixing the ingredients using a blender. In compositions containing praziquantel and ticar, praziquantel was added first to facilitate dissolution of ticar. In compositions containing emodepside and ticar, it was preferred to add emodepside first to facilitate dissolution of ticar. In compositions containing praziquantel, emodepside, and ticar, it was preferred to add praziquantel and emodepside first to facilitate dissolution of ticar. All examples were homogeneous solutions.

[0114] Example 1:

[0115] Element %w / w Tigoranin 9.7 acetone glycerol acetal Add to 100.0

[0116] Example 2:

[0117] Element %w / w Tigoranin 10.7 Praziquantel 7.4 acetone glycerol acetal Add to 100.0

[0118] Example 3:

[0119] Element %w / w Tigoranin 11.0 Praziquantel 7.4 Amodeus 1.7 acetone glycerol acetal Add to 100.0

[0120] Example 4:

[0121]

[0122] Example 5:

[0123]

[0124] Example 6:

[0125]

[0126] Example 7:

[0127] Element %w / w Tigoranin 9 acetone glycerol acetal Add to 100.0

[0128] Example 8:

[0129] Element %w / w Tigoranin 9.5 acetone glycerol acetal Add to 100.0

[0130] Example 9:

[0131] Element %w / w Tigoranin 9 BHT 0.1 acetone glycerol acetal Add to 100.0

[0132] Example 10:

[0133] Element %w / w Tigoranin 9.5 BHT 0.1 acetone glycerol acetal Add to 100.0

[0134] Example 11:

[0135] Element %w / w Tigoranin 9 BHT 0.2 acetone glycerol acetal Add to 100.0

[0136] Example 12:

[0137] Element %w / w Tigoranin 9.5 BHT 0.2 acetone glycerol acetal Add to 100.0

[0138] Example 13:

[0139] Element %w / w Tigoranin 9 BHT 0.4 acetone glycerol acetal Add to 100.0

[0140] Example 14:

[0141] Element %w / w Tigoranin 9.5 BHT 0.4 acetone glycerol acetal Add to 100.0

[0142] Example 15:

[0143] Element %w / w Tigoranin 9 Praziquantel 7.94 Amodeus 1.984 BHT 0.4 acetone glycerol acetal Add to 100.0

[0144] Example 16:

[0145] Element %w / w Tigoranin 9 Praziquantel 7.94 Amodeus 1.984 BHT 0.2 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0146] Example 17:

[0147] Element %w / w Tigoranin 9 Praziquantel 7.54 Amodeus 1.885 BHT 0.2 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0148] Example 18:

[0149] Element %w / w Tigoranin 9 Praziquantel 7.54 Amodeus 1.885 BHT 0.4 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0150] Example 19:

[0151] Element %w / w Tigoranin 9 Praziquantel 7.54 Amodeus 1.885 BHT 0.1 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0152] Example 20:

[0153] Element %w / w Tigoranin 8.909 Praziquantel 7.409 Amodeus 1.864 BHT 0.4 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0154] Example 21:

[0155] Element %w / w Tigoranin 9.1 Praziquantel 7.94 Amodeus 1.98 BHT 0.4 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0156] Example 22:

[0157] Element %w / w Tigoranin 9.1 Praziquantel 7.94 Amodeus 1.98 BHT 0.2 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0158] Example 23:

[0159] Element %w / w Tigoranin 9.1 Praziquantel 7.94 Amodeus 1.98 BHT 0.1 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0160] Example 24:

[0161] Element %w / w Tigoranin 8.909 Praziquantel 7.409 Amodeus 1.864 BHT 0.2 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0162] Example 25:

[0163] Element %w / w Tigoranin 8.909 Praziquantel 7.409 Amodeus 1.864 BHT 0.1 lactic acid 2.0 acetone glycerol acetal Add to 100.0

[0164] Biological Examples

[0165] A. Summary of in vitro test results of Tigoranab as disclosed in WO2014 / 122083:

[0166] The test methods and results are described in WO2014 / 122083. The results of Tigoranab disclosed therein (Example 1c-2 in WO2014 / 122083) against parasites relevant to veterinary medicine are summarized as follows:

[0167] Hebrew flower tick (Amblyomma hebraeum): 100% efficacy at 100 ppm

[0168] Boophilus microplus - immersion test: 100% efficacy at 100 ppm Boophilus microplus - injection test: 100% efficacy at 20 μg / tick

[0169] Ctenocephalides felis - oral test: 100% efficacy at 100 ppm

[0170] Ctenocephalides - contact test: at 1μg / cm 2 100% effective

[0171] Lucilia cuprina: 100% effective at 100 ppm

[0172] Housefly (Musca domestica): 100% efficacy at 100 ppm

[0173] Rhipicephalus sanguineus - contact test: at 1 μg / cm 2 100% effective

[0174] Ixodes ricinus - contact test: at 1 pg / cm 2 100% effective

[0175] Hebrew flower tick - contact test: at 1 μg / cm 2 100% effective

[0176] B. Summary of the in vivo test results of Tigoranab in rats as disclosed in WO2014 / 122083:

[0177] The test methods and results are described in WO 2014 / 122083. The results of ticoplasma (Example 1c-2 in WO 2014 / 122083) against parasites relevant in the veterinary field are summarized below:

[0178] Dermacentor variabilis - Systemic in vivo activity against American dog tick nymphs on rats; at an application rate of 10 mg / kg, efficacy against tick nymphs on day 2 was >90%.

[0179] Ctenocephalides - Systemic in vivo activity against fleas on rats: >95% efficacy on day 2 and >90% efficacy on day 9 at an application rate of 10 mg / kg.

[0180] C. In vivo parasite studies: Efficacy of the spot-on formulation against Toxocara felis and Digenea canis infections in experimentally infected cats.

[0181] Prior to treatment, 16 cats were experimentally infected with Toxocara cati (larval eggs) and a feline strain of Digonomella canis (using infected Ctenocephalides fleas—oral and topical infection).

[0182] Fourteen cats with patent infections of both T. felis and D. caninum were enrolled in the study on day 1. The cats were divided into two groups, each consisting of 7 cats.

[0183] The spot-on study veterinary product (IVP) is a composition according to the present invention containing 10% ticagrelor, 7.94% praziquantel and 1.98% emodepside (w / v) in solution based on glycerol acetone. Cats in the IVP group (Group 2) were administered IVP on day 0 at a dose rate of 3.2 mg emodepside plus 12.7 mg praziquantel and 16 mg ticagrelor / kg BW (BW=body weight), which is equivalent to 0.16 mL of spot-on formulation / kg BW. The cats in Group 1 served as the negative control group. On day 10, the cats were euthanized and gastrointestinal worms were recovered at necropsy. The worms were identified and counted. Efficacy calculations were based on the number of worms recovered at necropsy in the IVP group compared to the negative control group. The following formula was used:

[0184] Efficacy (%) = 100 × (Mc-Mt) / Mc,

[0185] in

[0186] Mc = geometric mean number of worms / scolex in the negative control group (Group 1)

[0187] Mt = geometric mean number of worms / scolex in the IVP group (Group 2)

[0188] All cats in the control group contained Toxocara felis worms, while 5 cats contained Digonomus canis scolex.

[0189] 100% efficacy was achieved against both Toxocara cati and Digonomella canis in the IVP group.

[0190] No adverse events (AEs) occurred.

[0191] D. In vivo studies of ectoparasites: efficacy of spot-on formulations against experimental tick and flea infestations in cats.

[0192] Twelve cats were enrolled in the study on SD-4. On SD-1, cats were experimentally infested with Ixodes ricinus ticks, which were counted without removal on SD 0 (for group assignment) and removed and counted on SD 2 (for treatment efficacy). On SD 0, six cats were treated with an IVP application of 14 mg ticagrelor, 3 mg emodepside, and 12 mg praziquantel per kg body weight, applied as a single spot-on. Six cats served as untreated controls.

[0193] IVP contains 10% (m / V) ticoplasma, 8.58% (m / V) praziquantel and 2.14% (m / V) emodepside in solution on a solketal basis.

[0194] Cats were experimentally infested with ticks and fleas every two weeks. The efficacy of the IVP was determined by comparing tick and flea counts in the treated versus control groups. General health was observed daily.

[0195] Table 1: Study Design

[0196]

[0197] *Each cat was infested with 20 female and 20 male Ixodes ricinus ticks. **Each cat was infested with 100 Ctenocephalides fleas

[0198] Table 2: Efficacy against fleas and ticks based on arithmetic means

[0199]

[0200] Efficacy against fleas (≥99%) can be claimed on all study days up to SD 85.

[0201] Curative efficacy (≥90%) against ticks can be claimed on SD2, and preventive efficacy against ticks can be claimed on SD87.

[0202] IVP was very well tolerated in cats after a single topical treatment. During this study, there were no adverse events related to IVP treatment.

Claims

1. A pharmaceutical composition, characterized in that The composition comprises, based on the total weight of the composition, 6wt% to 9wt% of praziquantel, 1.2wt% to 3wt% of emodin, 7 wt% to 11 wt% of ticopragmat, and 1,2-Isopropylideneglycerol.

2. The composition according to claim 1, wherein The water content of the composition is at most 5% by weight.

3. The composition according to claim 1 or 2, further comprising an antioxidant.

4. The composition according to claim 3, wherein The antioxidant is butylated hydroxyanisole (BHA) and / or butylated hydroxytoluene (BHT).

5. The composition according to claim 1 or 2, further comprising an acid.

6. The composition according to claim 5, wherein The acid is lactic acid.

7. A method for producing the composition according to claim 1, comprising the step of dissolving praziquantel, emodepside and ticopyranat in 1,2-isopropyl glycerol.

8. Use of a composition according to one of claims 1 to 6 for the preparation of a medicament for the treatment and / or prevention of parasitic infections in animals.

9. The use according to claim 8, wherein The animals are cats and dogs.

10. The use according to claim 8, wherein The parasites are endoparasites and ectoparasites.

11. The use according to one of claims 8 to 10, wherein The parasite is selected from the group consisting of: The endoparasite is selected from the group consisting of: Toxocara cati, Toxascaris leonina, Ancylostoma tubaeforme, Uncinaria stenocephala, Dipylidium caninum, Taenia taeniaeformis, Echinococcus multiocularis, Aelurostrongylus abstrusus, and Troglostrongylus spp.; The ectoparasites are selected from the group consisting of Ctenocephalides species, Coronophles species, Ceratophyllus species, Fleas species, Hyalomma species, Rhipicephalus species, Boophilus species, Amblyomma species, Haemaphysalis species, Dermacentor species, Ixodes species, Acutus species, Ornithodoros species, Otodectes species, Otodectes cynotis, Notoedrescati, and their combinations.

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