WO2023198476A1 - Soft chewable veterinary dosage form - Google Patents

Abstract

The invention relates to a soft chewable veterinary dosage form comprising (a) at least one active agent; (b) a humectant selected from sorbitol, preferably in combination with propylene glycol, liquid polyethylene glycol, glycerol or liquid paraffin; and at least one additional excipient selected from the group of (c) forming agent; (d) filler; (e) a liquid component; and (f) flavor.

Description

Soft chewable veterinary dosage form

[0001] Priority is claimed of Slovenian patent application no. SI P-202200055 that was filed on April 15, 2022.

[0002] The invention relates to a soft chewable veterinary dosage form comprising an active agent, preferably an antiparasitic agent, and sorbitol in combination with other humectants, and to a method for preparing said soft chewable veterinary dosage form.

[0003] For veterinary medicinal products compliance and convenience are critical to ensure the success of prevention, control, and treatment medication programs. There is a recognized need for highly palatable solid oral dosage forms for companion animals that are freely accepted from their feeding bowl or via the hand of the pet owner. Improving dosage forms to focus on the treatment regime, with convenience and compliance, represent a growing trend in companion animal formulations; this is especially true for medications administered for chronic conditions, such as parasitic infections, cardiovascular disease, pain, rheumatologic, dermatologic conditions.

[0004] According to the European Medicines Agency (EMA) palatability is defined as being acceptable to the mouth, "pleasant to the taste" or "acceptable to the taste" . When applied to veterinary medicinal products, this term suggests that the product is palatable enough to ensure voluntary uptake of the product from a feeding vessel, or via hand when offered as a treat by the animal owner. In this instance palatability involves taste, smell, and mouthfeel such as texture, size, or chewiness.

[0005] Chronic conditions are most often treated in domestic animals, especially companion animals such as cats and dogs. One known and convenient way of administering an active agent to an animal is oral administration, by way of solid oral dosage forms. Compared to the common compressed tablet, soft chewable veterinary dosage forms are reported to have several advantages. For example, they may have a higher palatability for the treated animal, preferable texture and taste over a tablet and additionally, they are better to chew and subsequently being more palatable.

[0006] In the prior art there are disclosed several compositions for soft chewable dosage forms.

[0007] WO 2004/014143 discloses soft chewable composition comprising a sugar component, a starch component, an oil component, an additive component and flavoring component. Further, the composition comprise emulsifier component glycerin (glycerol) or polyethylene glycol, which acts as a humectant or a forming agent. [0008] WO 2005/062782 discloses a chewable composition comprising at least one disintegrant; at least one non-animal product containing flavor or flavor derived from a non-animal source; at least one binder; at least one humectant; at least one granulating solvent, for example, water or an aqueous sorbitol solution.

[0009] WO 2005/013714 discloses palatable ductile chewable veterinary composition for oral administration which consists of an effective amount of one or more ingredients that are active against animal pests, pathogens or animal diseases; meat flavoring; partially gelatinized starch; a softener; and up to 9% water.

[0010] WO 2005/099692 discloses a soft chewable composition comprising a starch component, a sugar component, and an oil component. The starch component comprises about 5 percent to about 60 percent of the soft chew, the sugar component comprises about 5 percent to about 75 percent of the soft chew, and the oil component comprises about 1 percent to about 40 percent of the soft chew.

[0011] WO 2007/067582A2 discloses soft chewable veterinary compositions and a method for production thereof. The composition comprises a flavor, softening agents, lubricants, humectants or wetting agents, vegetable oils, bulking agents, binders and sweeteners.

[0012] WO 2013/150052 discloses a soft chewable pharmaceutical product comprising pamoic acid or pharmaceutically acceptable salt of pamoic acid.

[0013] WO 2013/119442 relates to oral veterinary compositions for combating ectoparasites and endoparasites in animals, comprising at least one systemically-acting active agent in combination with a pharmaceutically acceptable carrier.

[0014] WO 2022/049149 discloses a chewable veterinary composition comprising an active ingredient and carbonate compound, preferably a sodium bicarbonate.

[0015] As evident from the list of prior art documents above, soft chewable composition should comprise a flavor, a filler, such as starch, a humectant, such as glycerol, oils such as soybean oil, anticaking and wetting agents such as polyethylene glycol and sodium lauryl sulfate, binders or forming agents such as PVP and polyethylene oxide and starches. The prior art shows that variation in qualitative and quantitative contents of excipients in the compositions results in texture profile changes which may lead to poor hardness or brittleness, thereby causing the product not palatable or unsuitable to be further processed. For these reasons, there remains a need for alternative pharmaceutical compositions exhibiting a desired physical and chemical stability and at the same time providing for stable texture profile retaining plastic structure also at the long term storing conditions.

[0016] The soft chewable dosage forms of the prior art are not satisfactory in every respect and there is a demand for improved soft chewable dosage forms. [0017] When the hardness is too low, the dosage forms deform very easily and are not processable in the later stages of manufacture. Too low hardness also causes problems with handling. Hardness should be adequate without brittle deformation, as brittle texture can negatively affect palatability; a tablet that is crushed in the mouth has completely different sensory properties than one that is chewable. Thus, the soft chewable veterinary dosage forms should have a certain degree of hardness with plastic deformation.

[0018] The optimal texture of a soft chewable veterinary dosage form is one with a plastic deformation that does not have brittle deformation in the mouth and is still hard enough to maintain processability and handling. Soft chewable dosage form having desirable texture provide a force-time curve of the first compression having a certain shape: In case of plastic texture, the sample loses its shape during the test procedure, deforms plastically and does not fracture; no additional peaks besides the peak force (hardness) are observed. In contrast, in case of brittle texture, the sample fractures during the test and additional peaks occur - a fracture point occurs where the force-time curve has its first significant peak because the force falls off.

[0019] It is an object of the invention to provide soft chewable dosage forms that have advantages compared to the prior art. The soft chewable dosage forms should have satisfactory properties with respect to processing and handling but additionally need to have a desirable texture without brittle deformation.

[0020] This object has been achieved by the subject-matter of the patent claims.

[0021] It has been surprisingly found that sorbitol, especially in combination with propylene glycol, liquid polyethylene glycol, glycerol or liquid paraffin, provides soft chewable veterinary dosage forms with an improved texture profile.

[0022] Figure 1 shows typical force-time curve for samples prepared by Examples 10, 22 and 26 during the first compression (one cycle).

[0023] A first aspect of the invention relates to a soft chewable veterinary dosage form comprising or essentially consisting of

(a) at least one active agent; preferably fluralaner;

(b) one or more humectants comprising sorbitol; preferably in combination with propylene glycol, liquid polyethylene glycol, glycerol or liquid paraffin; and at least one additional excipient selected from the group of (c) forming agents; (d) fillers; (e) liquid components; (f) flavors; and (g) sweeteners.

[0024] In one embodiment the soft chewable veterinary composition of the invention comprises or essentially consist of

(a) at least one active agent; preferably fluralaner; (b) a combination (preferably mixture) of sorbitol with

(bi) propylene glycol; or

(b2) liquid polyethylene glycol; or

(bs) glycerol; or

(bi) liquid paraffin; and at least one additional excipient selected from the group of (c) forming agents; (d) fillers; (e) liquid components; (f) flavors; and (g) sweeteners.

[0025] The terms "soft chew", "soft chewable veterinary dosage form" or "soft chewable veterinary composition" can be used synonymously and mean a product that is solid at room temperature and that can be soft enough to be chewed. Further, the product can be functionally chewy because the product has a plastic texture during the process of mastication in the mouth.

[0026] In line with the invention, the terms "weight %" and "(w/w) %" can be used synonymously and designate weight/weight. As used herein, these terms represent the percentage by weight of an ingredient relative to the total weight of the composition or a dosage form.

[0027] Component (a) is at least one active agent. For the purpose of the specification, the term "active agent" refers to a "pharmacologically active agent" (drug, active pharmaceutical ingredient, API, etc.) or to a "food supplement" .

[0028] The at least one active agent (a) is administered orally in the soft chewable veterinary dosage form according to the invention, i.e. the soft chewable veterinary dosage form is an oral dosage form devoted for oral administration (peroral by swallowing).

[0029] In preferred embodiments of the invention, the soft chewable veterinary composition comprises at least one active agent (a) selected from the group consisting of (ai) antiparasitic agents, (a2) analgesic agents, (as) anti-inflammatory agents, (aft antipruritic agents, (as) anti-emetic agents, (ae) cardiovascular agents, (a?) antimicrobial agents, (as) food supplements, and combinations thereof.

[0030] Unless expressly stated otherwise, any at least one active agent (a) may be present in non-salt form or as a physiologically acceptable salt. Further, unless expressly stated otherwise, any at least one active agent (a) may be present in crystalline form, amorphous form, as a solvate or any polymorph.

[0031] In preferred embodiments of the invention, component (a) comprises or essentially consists of an antiparasitic agent (aft, preferably a systemic parasiticide, especially an insecticide and/or acaricide. A "systemic parasiticide" according to the invention can be referred to as an insecticide and/or acaricide or anthelmintic, which has an effect on the whole of the animal to be treated and not just on a single part of said animal. In preferred embodiments, component (a) comprises or essentially consists of an isoxa- zoline ectoparasiticide. In preferred embodiments, the insecticide and/or acaricide comprises an isoxazoline compound such as fluralaner, S-fluralaner, afoxolaner, S-afoxolaner, sarolaner, lotilaner, tigo- laner, optionally in combination with other active agents.

[0032] These isoxazoline ectoparasiticides are currently marketed under the trade names NexGard® (afoxolaner, Boehringer Ingelheim), Bravecto® (fluralaner, Merck), Simparica® (sarolaner, Zoetis), and Credelio® (lotilaner, Elanco), as well as combination drugs NexGard Spectra® (afoxolaner and milbemycin oxime, Boehringer Ingelheim), Bravecto Plus® (fluralaner and moxidectin, Merck), Simparica Trio® (sarolaner, moxidectin, and pyrantel, Zoetis), and Revolution Plus® (selamectin and sarolaner, Zoetis).

[0033] In preferred embodiments, component (a) comprises or essentially consists of an active agent selected from the group consisting of a macrocyclic lactone (e.g., moxidectin, ivermectin, selamectin, dimadectin, eprinomectin, abamectin, doramectin, emamectin, latidectin, lepimectin, milbemycin and milbemycin oxime), pyrantel, including the salt forms (e.g., pamoate, citrate, and tartrate), lufenuron, emodepside, oxfendazole, albendazole, triclabendazole, levamisole, closantel, clorsulon, praziquantel, and combinations thereof.

[0034] In preferred embodiments, component (a) comprises or essentially consists of a combination of

(i) an isoxazoline compound; and

(ii) at least one additional antiparasitic agent selected from the group consisting of a macrocyclic lactone (e.g., moxidectin, ivermectin, selamectin, dimadectin, eprinomectin, abamectin, doramectin, emamectin, latidectin, lepimectin, milbemycin, and milbemycin oxime), pyrantel, including the salt forms (e.g., pamoate, citrate, and tartrate), lufenuron, oxfendazole, albendazole, triclabendazole, levamisole, closantel, clorsulon, praziquantel, and combinations thereof.

[0035] In preferred embodiments, component (a) comprises or essentially consists of a combination of

(i) an isoxazoline compound; and

(ii) at least one additional antiparasitic agent selected from the group consisting of moxidectin, doramectin, ivermectin, abamectin, milbemycin, milbemycin oxime, pyrantel, including the salt forms (e.g., pamoate, citrate, and tartrate), levamisole, praziquantel, and combinations thereof.

[0036] In preferred embodiments, component (a) comprises or essentially consists of

(i) fluralaner, S-fluralaner, afoxolaner, S-afoxolaner, lotilaner or sarolaner; and

(ii) moxidectin.

[0037] In preferred embodiments, component (a) comprises or essentially consists of

(i) fluralaner, S-fluralaner, afoxolaner, S-afoxolaner, lotilaner or sarolaner; and

(ii) moxidectin; and

(iii) pyrantel. [0038] In preferred embodiments, component (a) comprises or essentially consists of

(i) fluralaner, S-fluralaner, afoxolaner, S-afoxolaner, lotilaner or sarolaner; and

(ii) milbemycin oxime.

[0039] In preferred embodiments, component (a) comprises or essentially consists of

(i) fluralaner, S-fluralaner, afoxolaner, S-afoxolaner, lotilaner or sarolaner; and

(ii) milbemycin oxime; and

(iii) pyrantel.

[0040] In preferred embodiments, component (a) comprises or essentially consists of an anti-inflammatory agent (as), preferably selected from the group consisting of

- aspirin, methyl salicylate, diflunisal amoxiprin, acetaminophen;

- arylalkanoic acids such as diclofenac and indomethacin;

- propionic acid derivatives (profens) such as ibuprofen, carprofen, naproxen and ketoprofen;

- N-ary lanthranlic acids (fenamic acid derivatives) such as mefanamic acid, meclofenamic acid and flufenamic acid;

- oxicams such as piroxicam, sudoxicam, isoxicam and meloxicam;

- coxibs such as celecoxib, robenacoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib;

- sulphonanilides such as nimesulide; and

- non-steroidal anti-inflammatory drugs that have both cyclo-oxygenase (II) and lipooxygenase inhibition properties such as tepoxalin and mixtures of two or more thereof.

[0041] The anti-inflammatory agent (as) is preferably meloxicam, piroxicam, carprofen, ibuprofen, ketoprofen, robenacoxib or mixtures thereof; more preferably robenacoxib or carprofen; and most preferably robenacoxib.

[0042] In preferred embodiments, the component (a) comprises or essentially consists of an anti -pruritic agent (as), preferably comprising oclacitinib.

[0043] In preferred embodiments, the component (a) comprises or essentially consists of an anti-emetic agent (as), preferably selected from maropitant, metoclopramide and ondansetron.

[0044] In preferred embodiments, the component (a) comprises or essentially consists of a cardiovascular agent (ae), preferably selected from the group of furosemide, torsemide, pimobendan, amlodipine, enalapril, benazepril, captopril, lisinopril, ramipril, spironolactone, propranolol, atenolol, esmolol, verapamil, diltiazem and digoxin.

[0045] In preferred embodiments, the component (a) comprises or essentially consists of an antimicrobial agent (a?), preferably selected from the group consisting of cefpodoxime proxetil, clavulanic acid, amoxicillin doxycycline hyclate, quinolones such as enrofloxacin, norfloxacin, pradofloxacin, mar- bofloxacin, cephalosporins (1st, 2nd, 3rd, and 4th generation), tetracyclines, penicillins, [3-lactams, macrolides and phenicols.

[0046] In preferred embodiments, the component (a) comprises or essentially consists of a food supplement (as), preferably selected from the group consisting of

- vitamins, such as B-complex vitamins, vitamin C, vitamin E, vitamin D;

- minerals such as calcium, selenium, zinc;

- glucosamine, chondroitin, hyaluronic acid;

- fatty acids/oils such as alpha linoleic acid, docosahexaenoic acid, eicosapantaenoic acid, arachidonic acid;

- aloe vera, milk thistle, probiotics, multivitamins, yeast, enzymes, herbs, garlic; and

- specific amino acids such as phenylalanine, tyrosine, tryptophan, 5 -hydroxytryptophan, leucine, isoleucine, valine, glutamine, L-camitine, L-theanine, lysine, taurine.

[0047] Preferably, the total content of the at least one active agent (a) in the dosage form is within the range of 0.1 to 30 w/w %, preferably 0.2 to 20 w/w %.

[0048] Component (b) comprises or essentially consists of one or more humectants selected from sorbitol, preferably in combination with propylene glycol or liquid polyethylene glycol or liquid paraffin or glycerol. Preferably, the humectant (b) comprises or essentially consists of a combination (preferably mixture) of sorbitol

(bl) with propylene glycol; or

(b2) with liquid polyethylene glycol (PEG); or

(b3) with liquid paraffin; or

(b4) with glycerol.

[0049] Sorbitol is preferably used in the form of solution, most preferably in the form of aqueous solution. The content of sorbitol in the solution, preferably aqueous solution, is preferably above 50 w/w %, preferably above 60 w/w %, most preferably within the range of 69.0 - 72.0 w/w %.

[0050] Liquid polyethylene glycol (PEG) is preferably used in grades of 200-600 (M_n), which are liquids under common ambient temperature conditions (20-23°C); preferably, PEG 300 and PEG 400 are used.

[0051] Liquid paraffin is a mixture of refined liquid saturated aliphatic (C14-C18) and cyclic hydrocarbons obtained from petroleum.

[0052] In preferred embodiments, the weight content of sorbitol is greater than the weight content of glycerol, liquid paraffin, liquid PEG, and propylene glycol, respectively. [0053] In other preferred embodiments, the weight content of sorbitol is lower than the weight content of glycerol, liquid paraffin, liquid PEG, and propylene glycol, respectively.

[0054] Sorbitol is preferably used in combination with glycerol or liquid paraffin or liquid PEG or propylene glycol, preferably in a weight ratio in the range of from 10: 1 to 1:10, preferably 7:1 to 1:7, more preferably 4:1 to 1:4.

[0055] Sorbitol solution is preferably used in combination with glycerol or liquid paraffin or liquid PEG or propylene glycol, preferably in a weight ratio in the range of from 10 : 1 to 1 : 10, preferably 5 : 1 to 1:5, more preferably 3: 1 to 1:3.

[0056] Preferably, the total content of the humectant (b) in the dosage form is within the range of 1 to 20 w/w %, preferably 3 to 15 w/w %.

[0057] In preferred embodiments, the dosage form comprises sorbitol at a content of 5.3±3.6 w/w %, preferably 5.3±1.8 w/w %; but preferably neither propylene glycol nor liquid polyethylene glycol, nor glycerol, nor liquid paraffin.

[0058] In other preferred embodiments, the dosage form comprises sorbitol at a content of 3.2±2.2 w/w %, preferably 3.2±1.2 w/w %, in combination with propylene glycol at a content of 3.0±2.0 w/w %, preferably 3.0±1.0 w/w %.

[0059] In other preferred embodiments, the dosage form comprises sorbitol at a content of 3 ,2±2.2 w/w %, preferably 3.2±1.2 w/w %, in combination with liquid polyethylene glycol at a content of 3.0±2.0 w/w %, preferably 3.0±1.0 w/w %.

[0060] In still other preferred embodiments, the dosage form comprises sorbitol at a content of 1. l±0.8 w/w %, preferably 1.1 ±0.4 w/w %, in combination with liquid polyethylene glycol at a content of 6.0±4.0 w/w %, preferably 6.0±2.0 w/w %.

[0061] In further preferred embodiments, the dosage form comprises sorbitol at a content of 3.2±2.2 w/w %, preferably 3.2±1.2 w/w %, in combination with glycerol at a content of 3.0±2.0 w/w %, preferably 3.0±1.0 w/w %.

[0062] In other preferred embodiments, the dosage form comprises sorbitol at a content of 2.1±1.4 w/w %, preferably 2.H0.7 w/w %, in combination with glycerol at a content of 4.5±3.0 w/w %, preferably 4.5±1.5 w/w %.

[0063] In still other preferred embodiments, the dosage form comprises sorbitol at a content of 1. l±0.8 w/w %, preferably 1.1±0.4 w/w %, in combination with glycerol at a content of 6.0±4.0 w/w %, preferably 6.0±2.0 w/w %.

[0064] Component (c) is a forming agent. [0065] Component (c) binds the components together and influences the soft and plastic texture of the soft chewable veterinary dosage form. Component (c) is important for the texture of the soft chewable dosage form, because it contributes to the structural integrity such that it stays intact and separate.

[0066] The forming agent (c) is preferably a solid under common ambient temperature conditions (20- 23°C). Preferably, a forming agent has a melting temperature within the range of 45°C to 100°C.

[0067] The forming agent (c) preferably comprises or essentially consists of a forming agent selected from polyethylene glycol (preferably solid polyethylene glycol), polypropylene glycol, polyethylene glycol-polypropylene glycol copolymer, microcrystalline wax, cetyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinylacetate copolymer, polysaccharides, hydroxypropyl methyl cellulose, poly(meth)acrylates, alkyl poly(meth)acrylates and combinations thereof.

[0068] In preferred embodiments, the forming agent (c) comprises or essentially consists of a forming agent selected from polyethylene glycol, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymer and combinations thereof.

[0069] In preferred embodiments, the forming agent (c) comprises or essentially consists of polyethylene glycol (PEG). Depending on the desired consistency of the soft chew, different molecular weight PEG may be utilized. Preferred are PEG components that are solid at room temperature and have a molecular weight higher than 600. Such PEGs preferably have a melting temperature between 30°C and 80°C, preferably between 35°C and 70°C, wherein the melting temperature is determined by means known to the skilled person.

[0070] In preferred embodiments, the forming agent (c) comprises or essentially consists of PEG 8000. The molecular weight of PEG 8000 may be higher or lower than 8000 g/mol, preferably between 6000 and 10000 g/mol.

[0071] In preferred embodiments, the forming agent (c) comprises or essentially consists of PEG 3350 or PEG 4000. The molecular weight of PEG 3350 or PEG 4000 may be higher or lower than 3350 g/mol, preferably between 2500 and 4500 g/mol, more preferred between 3000 and 4000 g/mol.

[0072] Preferably, the total content of the one or more forming agents (c) in the dosage form is within the range of 1 to 40 w/w %, preferably 10 to 30 w/w %.

[0073] Component (d) is a filler.

[0074] Filler can be an inorganic compound or an organic compound or a mixture thereof.

[0075] In preferred embodiments, the filler (d) comprises or essentially consists of a filler selected from starch such as com starch, tapioca starch, wheat starch or pea starch, sucrose, lactose, dextrin, dextrate, mannitol, isomalt, glucose, fructose, soy grits, soy protein fines, microcrystalline cellulose, silicified microcrystalline cellulose, silica, titan dioxide, kaolin, bentonite, calcium phosphate and combinations thereof.

[0076] Preferably, the fdler (d) comprises or essentially consists of sucrose and/or starch, such as com starch, tapioca starch, wheat starch or pea starch. Preferably, the fdler (d) comprises or essentially consists of a combination of sucrose

(ci) with com starch; or

(C2) with tapioca starch; or

(C3) with wheat starch; or

(C4) with pea starch.

[0077] Preferably, the total content of the one or more fdlers (d) in the dosage form is within the range of 5 to 60 w/w %, preferably 10 to 40 w/w %.

[0078] Component (e) is liquid.

[0079] A liquid component (e) is a component, which is in a liquid state under common ambient temperature conditions (20-23 °C).

[0080] In preferred embodiments, the liquid component (e) comprises or essentially consists of a solvent selected from an organic solvent such as dimethylacetamide, N methyl pyrrolidone, 2- pyrrolidone, diethylene glycol monoethyl ether, ethyl lactate, ethylene monomethyl ether, glycofurol or medium chain triglycerides sold under the trademark Miglyol, especially Miglyol 812 or 814, or vegetable oil, especially soybean oil, butylene glycol, hexylene glycol, glyceryl triacetate or combinations thereof.

[0081] In preferred embodiments, the liquid component (e) comprises or essentially consists of a solvent selected from medium chain triglycerides sold under the trademark Miglyol, vegetable oil, especially soybean oil.

[0082] Preferably, the total content of the one or more liquid components (e) in the dosage form is within the range of 2 to 30 w/w %, preferably 3 to 20 w/w %.

[0083] Component (f) is flavor.

[0084] In preferred embodiments, the flavor (f) comprises or essentially consists of a flavor selected from flavors of animal origin such as chicken flavor, pork flavor, beef flavor, ham flavor, fish flavor, vegetarian flavor, Chardex Hickory flavor or artificial flavor such as sweet apple & molasses flavor, braised beef flavor and combinations thereof. Preferably, the flavor (f) comprises or essentially consists of meat flavor of animal origin or artificial meat flavor. [0085] Preferably, the total content of the one or more flavors (f) in the dosage form is within the range of 5 to 60 w/w %, preferably 10 to 40 w/w %.

[0086] Component (g) is a sweetener.

[0087] In preferred embodiments, the sweetener (g) comprises or essentially consists of an artificial non-saccharide sweetener, preferably selected from acesulfame K, aspartame, cyclamate, saccharine, sucralose, thaumatin, neohesperidine, stevioglycoside, neotame, acesulfame aspartame salt, advantame, and combinations thereof. Aspartame is particularly preferred.

[0088] Preferably, the total content of the one or more sweeteners (g) in the dosage form is within the range of 0.1 to 5 w/w %, preferably 0.1 to 0.5 w/w %.

[0089] Optionally, the composition according to the invention comprises additionally at least one further excipient, which may be selected from surfactants, antioxidants, preservatives, stabilizers, lubricants, glidants and colorants.

[0090] Preferred surfactants may be nonionic or anionic.

[0091] Surfactants may be selected form, but not limited to, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, sorbitan esters including sorbitan monooleate (Span® 20), polyvinyl alcohol, polysorbates including polysorbate 20 and polysorbate 80, d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS), Vitamin E TPGS (D-a-Tocopheryl polyethylene glycol 1000 succinate), sodium lauryl sulfate (SLS), copolymers of ethylene oxide and propylene oxide (e.g. poloxamers such as Poloxamer 124, 188, 338, and 407, and LUTROL® F87 and the like), polyethylene glycol castor oil derivatives including polyoxyl 35 castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor® RH60); propylene glycol monolaurate (L AUROGLYCOL®); glyceride esters including glycerol capryl ate/caprate (CAPMUL® MCM), polyglycolized glycerides (GELUCIRE®, such as Gelucire® 44/14), PEG 300 caprylic/capric glycerides (Softigen® 767), PEG 400 caprylic/capric glycerides (Labrasol®), PEG 300 oleic glycerides (Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafd® M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxy stearates including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl 40 stearate (PEG 1750 monostearate), PEG3350, and the like.

[0092] Polyethylene glycol stearates (synonyms include macrogol stearates, polyoxylstearates, polyoxyethylene stearates, ethoxylated stearates; CAS No. 9004-99-3, 9005-08-7) are mixtures of mono- and distearate esters of mixed polyoxyethylene polymers.

[0093] Polyethylene glycol hydroxystearate is a mixture of mono- and diesters of hydroxystearic acid with polyethylene glycols. [0094] One polyethylene glycol hydroxystearate that may be used in the compositions is polyethylene glycol 12- hydroxy stearate.

[0095] The compositions may include the surfactant polyethylene glycol 15 12- hydroxystearate (Solutol® HS 15 from BASF), a mixture of mono- and diesters of 12- hydroxystearic acid with 15 moles of ethylene oxide.

[0096] The compositions may include polyoxyl 35 castor oil (Cremophor® EL) as a surfactant.

[0097] The compositions may include polyoxyl 40 hydrogenated castor oil (Cremophor® RH 40) or polyoxyl 60 hydrogenated castor oil (Cremophor® RH 60) as surfactants.

[0098] Surfactants may optionally be included in the compositions, in concentrations of about 0. 1 to 5 w/w %, preferably 0. 1 to 3 w/w %.

[0099] Antioxidants may be selected form, but are not limited to, Tenox® 2;Tenox® PG; Tenox® s-1; BHA (2-t-butyl-4-methoxyphenol); BHT (2,6-di-t-butyl-4- methylphenol); sodium metabisulfite reducing agents; antoxidant synergists such as tocopherols (alpha, beta, or delta-tocopherol, tocopherol esters, alpha-tocopherol acetate), alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, citric acid anhydrous and hydrous, edetic acid and its salts, lecithin, tartaric acid, ascorbic acid, ascrobyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfate, n-propyl gallate, monothioglycerol, resveratrol, quercetin, benzoic acid, dimethyl thiourea (DMTU), hesperetin, tetrahydrocurcumin, tetrahydrodemethoxycurcumin, and Trolox (N- acetylcysteine, 6-hydroxy-2, 5,7,8- tetramethylchroman-2-carboxylic acid). In a preferred embodiment, the antioxidant is BHA.

[0100] Antioxidants may optionally be included in the compositions, in concentrations of about 0.01 to about 2.0 w/w % based upon total weight of the soft chewable dosage form.

[0101] Preservatives may be selected form, but are not limited to, the parabens (methylparaben and/or propylparaben), benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thimerosal, ascorbic acid, calcium.

[0102] Preservatives may optionally be included in the compositions, in concentrations of about 0.01 to about 5.0 w/w%, preferably about 0.05 to about 1.0 w/w % based on total weight of the dosage form.

[0103] Stabilizers may be selected from, but are not limited to, magnesium stearate, citric acid, and sodium citrate.

[0104] pH stabilizers (also referred to as buffers) include, for example, acetic acid/acetate, malic acid/malate, citric acid/citrate, tartaric acid/tartrate, lactic acid/lactate, phosphoric acid/phosphate, glycine/glycimate, tris, glutamic acid/glutamates, sodium carbonate, glycerol formal, amino sugars (e.g., glucosamine, tromethamine, meglumine, and the like), glycol ethers, modified starches, for example hydroxypropyl starch phosphate; cellulose derivatives (e.g., hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, hydroxypropylmethyl cellulose acetyl succinate, carboxymethyl cellulose, and the like); and non-ionic triblock copolymers (e.g., Poloxamer- 101 , -108, -124, -188, - 215, -284, -338, -407, and the like).

[0105] Stabilizers may optionally be included in the compositions, in concentrations of about 0.01 to about 5.0 w/w %, preferably about 0.05 to about 1.0 w/w % based on total weight of the dosage form.

[0106] Lubricants may be selected from, but are not limited to, polyethylene glycols of various molecular weight ranges including PEG 3350 (Dow Chemical) and PEG 4000, com oil, mineral oil, hydrogenated vegetable oils (STEROTEX or LUBRITAB), peanut oil and/or castor oil.

[0107] In certain embodiments, the lubricant is a neutral oil comprising a medium chain triglyceride (MCT) or propylene glycol fatty acid esters including caprylic/capric triglycerides.

[0108] Non-limiting examples of neutral oils are known by the trademark MIGLYOL® including MIGLYOL® 810, MIGLYOL® 812, MIGLYOL® 818, MIGLYOL® 829 and MIGLYOL® 840.

[0109] further lubricants include vegetable oils termed long -chain triglycerides, magnesium stearate, stearic acid, and sodium stearyl fumarate.

[0110] Lubricants may optionally be included in the compositions, in concentrations of about 0.01 to about 5.0 w/w %, preferably about 0.05 to about 1.0 w/w % based on total weight of the dosage form.

[0111] Glidants may be selected from, but are not limited to, silicon dioxide (CARBOSIL) or silica gel (SYLOID), talc, starch, calcium, stearate, magnesium stearate, and aluminum magnesium silicate (NEUSILIN).

[0112] Glidants may optionally be included in the compositions, in concentrations of about 0.01 to about 2.0 w/w %, preferably about 0.05 to about 1.0 w/w % based on total

[0113] The content of the above mentioned components, (a), (b), (c), (d) and (e), in the dosage form according to the invention is as follows:

[0114] The soft chewable veterinary dosage form according to the invention may preferably comprise components (a), (b), (c), (d), (e) and (f) and optionally at least one of further excipients selected from surfactants, antioxidants, preservatives, stabilizers, lubricants, glidants and colorants.

[0115] The soft chewable veterinary dosage form according to the invention preferably comprises:

0. 1 to 30 w/w %, preferably 0.2 to 20 w/w %, of the at least one active agent (a);

1 to 20 w/w %, preferably 3 to 15 w/w %, of the humectant (b);

1 to 40 w/w %, preferably 10 to 30 w/w %, of the forming agent (c);

5 to 60 w/w %, preferably 10 to 40 w/w %, of the filler (d);

2 to 30 w/w %, preferably 3 to 20 w/w %, of the liquid component (e);

5 to 60 w/w %, preferably 10 to 40 w/w % of the flavor (f); optionally, 0.1 to 5 w/w %, preferably 0.1 to 0.5 w/w % of the sweetener (g); and 0-10 w/w % of the at least one further excipient.

[0116] The soft chewable veterinary dosage form according to the invention preferably comprises: 0. 1 to 30 w/w %, preferably 0.2 to 20 w/w %, of the at least one active agent (a);

1 to 20 w/w %, preferably 3 to 15 %, of the humectant (b), wherein the humectant is selected from:

- a combination (preferably mixture) of sorbitol with propylene glycol; or

- a combination (preferably mixture) of sorbitol with liquid polyethylene glycol (PEG); or

- a combination (preferably mixture) of sorbitol with liquid paraffin; or

- a combination (preferably mixture) of sorbitol with glycerol;

1 to 40 w/w %, preferably 10 to 30 %, of the forming agent (c);

5 to 60 w/w %, preferably 10 to 40 w/w %, of the filler (d);

2 to 30 w/w %, preferably 3 to 20 w/w %, of the liquid component (e);

5 to 60 w/w %, preferably 10 to 40 w/w % of the flavor (f);

0.1 to 5% w/w, preferably 0. 1 to 0.5 w/w % of the sweetener (g); and

0 to 10 w/w % of the at least one further excipient.

[0117] The soft chewable veterinary dosage form according to the invention preferably comprises: 0. 1 to 30 w/w %, preferably 0.2 to 20 w/w %, of the at least one active agent (a);

1 to 20 w/w %, preferably 3 to 15 %, of the humectant (b), wherein the humectant is selected from:

- a combination (preferably mixture) of sorbitol with propylene glycol; or

- a combination (preferably mixture) of sorbitol with liquid polyethylene glycol (PEG); or

- a combination (preferably mixture) of sorbitol with liquid paraffin; or

- a combination (preferably mixture) of sorbitol with glycerol;

1 to 40 w/w %, preferably 10 to 30 %, of the forming agent (c) which is selected from polyethylene glycols PEGs that are solid at room temperature and have a molecular weight higher than 600; 5 to 60 w/w %, preferably 10 to 40 w/w %, of the filler (d) which is selected from starch, such as com starch, tapioca starch, wheat starch or pea starch;

2 to 30 w/w %, preferably 5 to 20 w/w %, of the liquid component (e) which is selected from medium chain triglycerides and vegetable oil;

5 to 60 w/w %, preferably 10 to 40 w/w % of the flavor (f) which is preferably meat flavor; optionally, 0.1 to 5 w/w %, preferably 0.1 to 0.5 w/w %, of the sweetener (g) which is selected from aspartame; and

0 to 10 w/w % of the at least one further excipient.

[0118] Preferred embodiment A¹ to G⁸ to the dosage form according to the invention are compiled in the tables here below.

[0119] Embodiments A¹ to A⁸ relate to preferred dosage forms containing sorbitol but neither propylene glycol, nor liquid polyethylene glycol (PEG), nor glycerol, nor liquid paraffin.

[0120] Embodiments B¹ to B⁸ relate to preferred dosage forms containing sorbitol in combination with propylene glycol.

[0121] Embodiments C¹ to C⁸ and D¹ to D⁸ relate to preferred dosage forms containing sorbitol in combination with liquid polyethylene glycol (PEG).

[0122] Embodiments E¹ to E⁸ relate to preferred dosage forms containing sorbitol in combination with glycerol.

[0123] Embodiments F¹ to F⁸ and G¹ to G⁸ relate to preferred dosage forms containing sorbitol in combination with liquid paraffin:

[0124] A further aspect of the invention is a method for preparing a soft chewable veterinary dosage form according to the invention as described above, said method comprising the steps:

(i) blending the (a) at least one active agent with (b) humectant, (c) forming agent, (d) filler, (e) a liquid component and (f) flavor to obtain a dough,

(ii) forming the dough from step (i) to a soft chewable veterinary dosage form.

[0125] The order of addition of the components (a), (b), (c), (d), (e), (f) and optionally (g) for blending can be different.

[0126] Step (i) of forming the dough comprises blending (a) at least one active agent, (b) humectant, (c) forming agent, (d) filler, (e) liquid component, (f) flavor, and optionally (g) sweetener under optionally elevated temperature to obtain a dough can be carried out with methods known to the skilled person.

[0127] In preferred embodiments, step (i) comprises the following sub-steps:

(i-a) blending the at least one active agent (a), a filler (d) and a flavor (f);

(i-b) combining the mixture from step (i-a) with humectant(s) (b), forming agent (c), liquid component (e), and optionally sweetener (g) either individually or in the form of a mixture thereof; and

(i-c) blending the mixture together to obtain a dough, preferably a homogenous dough.

[0128] In another embodiment of the invention and/or embodiments thereof step (i) comprises the following sub-steps:

(i-a) blending the at least one active agent (a), a filler (d) and a flavor (f);

(i-b) preparing a mixture of humectant(s) (b), forming agent (c), liquid component (e), and optionally sweetener (g); and

(i-c) combining the mixtures from steps (i-a) and (i-b) together and blending the mixture to obtain the dough, preferably homogenous dough.

[0129] The forming agent (c) may be molten prior to combination with the mixture of step (i-a). Melting of the forming agent (c) is carried out at a temperature that is preferably in the range of the melting or glass transition temperature of the forming agent and a temperature that is higher than the melting or glass transition temperature of the forming agent, but preferably not more than about 30 higher than the melting or glass transition temperature of the forming agent.

[0130] In step (ii) a soft chewable veterinary dosage form is formed from the dough from step (i). This can be carried out by utilizing any soft chew-forming machine known in the art such as the MFT 0100 Molding Machine (Kruger & Salecker) or the Formax F6114 (Formax Corporation). [0131] Alternatively, the soft chewable veterinary dosage form may be formed by other means known in the art. For example, the soft chewable veterinary dosage form may be formed by extrusion, by hand or compressed into tablet dosage form.

[0132] Surprisingly, a dosage form according to the invention comprising at least the above-named combination of components possesses an extraordinary palatability with a texture that is particularly well accepted by animals, in particular by dogs and cats.

[0133] Another aspect of the invention relates to the soft chewable veterinary dosage form according to the invention as described above for use in the prevention or treatment of a disease, disorder or condition in cats or dogs.

[0134] The dosage form according to the invention exhibits a meat-like, semi solid, soft texture and can be chewed readily by animals such as dogs and cats while providing a pleasant mouthfeel to the animals. The term "semi-solid" as used herein refers to a texture, which holds its shape unless certain levels of pressure are applied. Hardness measurements performed with a texture analyzer (as further described below) also provide information on textural characteristics such as elastic behavior, plastic deformation and brittleness or lack of brittleness (see e.g. Szczesniak, A. S. (1963), Classification of textural characteristics, Journal of Food Science 28(4): 385-389).

[0135] The dosage form according to the invention exhibits a long shelf-life even if stored over extended periods of times, e.g. for longer than two months or for longer than three months or for longer than six months. In particular, the hardness of the dosage form remains substantially stable during storage for several months. Substantially stable herein means that the hardness of the formed body does not change by more than 50 %, preferably not by more than 30 %, most preferably not by more than 20 %, when comparing hardness measurements of the formed body after approximately one hour after formation with measurements of the dosage form after several months of storage, e.g. after 3 months or after 6 months. The skilled person knows how to perform such hardness measurements, which typically require a texture analyzer, e.g. a TA.XTplus, Stable Micro Systems Ltd., UK.

[0136] As evidenced by the examples and results of the texture analysis below, the optimal dosage forms are achieved when a combination (preferably mixture) of sorbitol with liquid PEG, or sorbitol with propylene glycol, or sorbitol with liquid paraffin, or sorbitol with glycerol is used. Comparative dosage forms comprising sorbitol or glycerol or liquid PEG or liquid paraffin as a single humectant do not provide a texture with adequate hardness, plasticity and chewability.

[0137] The optimal texture of the dosage form is one with a plastic deformation that does not break in the mouth and form a chalky mouthfeel and that is still hard enough to maintain processability and handling. Optimal hardness of the dosage form according to the invention is between 15 and 80 N as measured at room temperature at approximately 1 hour post formation i.e. the time needed for cooling the product to room temperature, preferably between 20 and 70 N. The texture profile is preferably determined by means of a Texture Analyzer by a method known to a skilled person (for preferred parameters, see experimental section).

[0138] The following examples further illustrate the invention but are not to be construed as limiting its scope:

[0139] Manufacturing process

[0140] Manufacturing process for preparing a soft chewable veterinary dosage form was carried out in two major steps: preparation of the dough and formation of soft chewable tablets.

[0141] Preparation of the dough comprised the following sub-steps:

[0142] Dry powdery ingredients (active agent, filler, meat flavor and others) were first sieved in case that agglomerates were presented in the materials. Afterwards they were placed in the mixing vessel of a laboratory-scale planetary mixer and mixed until the blend was visually practically homogeneous (dry powdery mixture).

[0143] The powdery PEG 3350 (forming agent) was mixed with other liquid ingredients (one or more humectants and other liquid components) and the mixture was heated until PEG 3350 was completely molten (heated liquid mixture).

[0144] The heated liquid mixture was then added to the dry powdery mixture while mixing under elevated temperature. The mixer was heated to the temperature inhibiting too fast precipitation of the PEG. The whole mixture was then mixed until it was homogeneous and could be separated from the wall - it resembled a "cookie dough-like" appearance. The temperature of the resulting dough was in the range between 40°C and 46°C.

[0145] Formation of soft chewable dosage forms comprised formation of soft chewable dosage form from the dough.

[0146] Assessment of Hardness and Brittleness

[0147] The hardness/brittleness of the formed bodies was measured by means of a texture analyzer (texture profile analysis); name of device: TA.XTplus, Stable Micro Systems Ltd., UK; software: »Exponent«; parameters: test mode: TPA; pre-test speed: 1.0 mm/s; test speed: 1.0 mm/s; post-test speed: 5.0 mm/s; target mode: strain (strain: 50 %); trigger force: 150 g; probe: P/35 (35 mm die cylinder aluminum; contact area: 962.11 mm²); sample shape: undefined; strain height: measured at runtime; stress area: 962.11 mm²; acquisition rate (PPS): 500; load cell: 50 kg; number of measurements: 3.

[0148] Texture Profile Analysis [0149] In The Texture Profile Analysis Method, a tension/compression tester TA.XTplus, Stable Micro Systems Ltd., UK, was used. A tester was outfitted with a 50 kg tension/compression load cell and 35 mm diameter cylinder aluminum probe with contact area of 962.11 mm². The probe, which was screwed to the load cell, was used as the upper member of the tension/compression, and the bottom member was the solid, flat base of the instrument (the sample plate).

[0150] The sample (chewable dosage form) was placed on the sample plate beneath the center of the raised probe. The parameters were set via the software »Exponent« as stated above, and then the measurement was started. When the measurement was started, the probe was moved downwards at a rate 1.0 mm/s (pre-test speed). As soon as the probe was in contact with the sample (the trigger was a force > 150 g), the monitoring of the force [N] in dependency to the time [s] and the position of the probe [mm] was started. The sample was compressed at the same rate (test speed 1.0 mm/s) until 50 % strain (50 % deformation in relation to the initial sample height) was reached and this was referred to as the »first compression«. Immediately, the probe returned to its initial position at 5.0 mm/s (post-test speed). As soon as the probe was in the starting position, the next cycle of the measurement started (this means that the measurement was performed two times, with the second measurement directly following the first measurement) using the same sample. The monitoring of force versus time was finished as soon as the probe reached the starting position after the second cycle.

[0151] In total, three samples were characterized as described above for each of the Examples given. For the evaluation of the measurement results, the preset TPA macro was applied.

[0152] The composition of the chewable tablets and results of the mechanical analysis are compiled in the tables here below:

*70% aqueous sorbitol solution was used; B = brittle; P = plastic; / = not determined

*70% aqueous sorbitol solution was used; B = brittle; P = plastic; / = not determined

*70% aqueous sorbitol solution was used; B = brittle; P = plastic; / = not determined

*70% aqueous sorbitol solution was used; B = brittle; P = plastic; / = not determined

[0153] Evaluation of the results:

[0154] The qualitative and quantitative composition of the dosage form affects processability, texture and handling. The dosage forms with very low hardness deform very quickly and are not processable in the later stages of the technological process, in addition, there are problems with handling. Experiments with adequate hardness should not have brittle deformation, as their brittle texture can affect palatability. A tablet that is crushed in the mouth has completely different sensory properties than one that is chewable.

[0155] The optimal texture of the dosage form is one with a plastic deformation that does not break in the mouth and is still hard enough to maintain processability and handling. Optimal hardness is between 15 and 80 N at room temperature at approximately 1 hour post formation i.e. the time needed for cooling the formed product to room temperature, preferably between 20 and 70 N. The hardness is determined by Texture Profde Analyzer.

[0156] The optimal texture of the dosage form is one with a plastic deformation that does not have brittle deformation in the mouth and is still hard enough to maintain processability and handling. The said texture can be described from the shape of the force-time curve of the first compression. In the case of plastic texture (the sample loses its shape during the test procedure, deforms plastically and does not fracture), no additional peaks besides the peak force (hardness) are observed on the plot. In the case of brittle deformation (when the tablet fractures during the test), additional peaks occurs - fracture point occurs where the plot has its first significant peak (where the force falls off) during the probe's first compression of the product.

[0157] The formulations of Examples 1, 3, 4, 6, 7 and 9 contained Macrogol 3350, whereas the formulations of the other Examples contained PEG 3350. Macrogol and PEG are synonyms of polyethylene glycol. Thus, while two different commercial polyethylene glycol products were employed, their properties were identical (or at least very similar) so that this should not have any significant influence on the experimental results.

[0158] The formulations of Examples 1, 2 and 3 contain sorbitol, but not in combination with any one of propylene glycol, liquid polyethylene glycol, glycerol or liquid paraffin. Texture is brittle with brittleness within the range of 41 to 51 N.

[0159] When the total content of humectants is kept constant (7.50 w/w %) but a portion of sorbitol is substituted with liquid paraffin (Examples 4 and 7), with liquid polyethylene glycol (Examples 10 and 13), or with propylene glycol (Examples 16, 17 and 18), the texture becomes plastic with satisfactory hardness within the range of from 23 to 36 N.

[0160] The formulations of comparative Examples 22 to 26 contain no sorbitol at all. The formulations of comparative Examples 22 to 24 contain glycerol. Texture is brittle with brittleness within the range of 48 to 80 N. The formulations of comparative Examples 25 and 26 contain liquid polyethylene glycol and liquid paraffin, respectively. Texture is plastic but harness is only within the range of 12 to 15 N.

[0161] It is evident from the Figure 1 that most promising Examples (e.g. Example 10) exhibit typical force-time curve with no additional peaks besides the "Hardness" . Similarly, Example 26 exhibits the curve of the plastic texture with no additional peaks, but the hardness is much lower than that of the Example 10. In case of Example 22, the sample fractures during the test and additional peaks occur - the first significant peak is a fracture point.

Claims

Patent claims

1. A soft chewable veterinary dosage form comprising or essentially consisting of

(a) at least one active agent; preferably fluralaner;

(b) one or more humectants comprising sorbitol; preferably in combination with propylene glycol, liquid polyethylene glycol, glycerol or liquid paraffin; and at least one additional excipient selected from the group of (c) forming agents; (d) fillers; (e) liquid components; and (f) flavors.

2. The dosage form according to claim 1, which in addition to components (a) and (b) comprises or essentially consists of

(c) one or more forming agents;

(d) one or more fillers;

(e) one or more liquid components;

(f) one or more flavors;

(g) optionally, one or more sweeteners; and optionally at least one further excipient selected from surfactants, antioxidants, preservatives, stabilizers, lubricants, glidants and colorants.

3. The dosage form according to any of the preceding claims, which comprises or essentially consists of:

0. 1 to 30 w/w %, preferably 0.2 to 20 w/w %, of the at least one active agent (a);

1 to 20 w/w %, preferably 3 to 15 w/w %, of the one or more humectants (b);

1 to 40 w/w %, preferably 10 to 30 w/w %, of the one or more forming agents (c);

5 to 60 w/w %, preferably 10 to 40 w/w %, of the one or more fillers (d);

2 to 30 w/w %, preferably 3 to 20 w/w %, of the one or more liquid components (e);

5 to 60 w/w %, preferably 10 to 40 w/w % of the one or more flavors (f); optionally, 0.1 to 5 w/w %, preferably 0.1 to 0.5 w/w % of the one or more sweeteners (g); and

0-10 w/w % of the at least one further excipient. The dosage form according to any of the preceding claims, wherein the at least one active agent (a) comprises or essentially consists of

(ai) one ore more antiparasitic agents; preferably selected from the group consisting of fluralaner, S-fluralaner, afoxolaner, S-afoxolaner, sarolaner, lotilaner, tigolaner, moxidectin, ivermectin, selamectin, dimadectin, eprinomectin, abamectin, doramectin, emamectin, latidectin, lepimectin, milbemycin, milbemycin oxime, pyrantel, lufenuron, emodepside, oxfendazole, albendazole, triclabendazole, levamisole, closantel, clorsulon, praziquantel, and combinations thereof;

(a2) one ore more analgesic agents;

(as) one ore more anti-inflammatory agents; preferably selected from the group consisting of aspirin, methyl salicylate, diflunisal amoxiprin, acetaminophen; arylalkanoic acids such as diclofenac and indomethacin; propionic acid derivatives (profens) such as ibuprofen, carprofen, naproxen and ketoprofen; N-arylanthranlic acids (fenamic acid derivatives) such as mefanamic acid, meclofenamic acid and flufenamic acid; oxicams such as piroxicam, sudoxicam, isoxicam and meloxicam; coxibs such as celecoxib, robenacoxib, rofecoxib, valdecoxib, parecoxib and etoricoxib; sulphonanilides such as nimesulide; and non-steroidal anti-inflammatory drugs that have both cyclo-oxygenase (II) and lipooxygenase inhibition properties such as tepoxalin; and combinations thereof; more preferably meloxicam, piroxicam, carprofen, ibuprofen, ketoprofen, robenacoxib or mixtures thereof; still more preferably robenacoxib or carprofen; and most preferably robenacoxib;

(a.0 one ore more antipruritic agents; preferably oclacitinib;

(as) one ore more anti-emetic agents; preferably selected from maropitant, metoclopramide and ondansetron;

(ae) one ore more cardiovascular agents; preferably selected from the group of furosemide, torsemide, pimobendan, amlodipine, enalapril, benazepril, captopril, lisinopril, ramipril, spironolactone, propranolol, atenolol, esmolol, verapamil, diltiazem and digoxin;

(a?) one ore more antimicrobial agents; preferably selected from the group consisting of cefpodoxime proxetil, clavulanic acid, amoxicillin doxycycline hyclate, quinolones such as enrofloxacin, norfloxacin, pradofloxacin, marbofloxacin, cephalosporins (1st, 2nd, 3rd, and 4th generation), tetracyclines, penicillins, P-lactams, macrolides and phenicols;

(as) one ore more food supplements; preferably selected from the group consisting of vitamins, such as B-complex vitamins, vitamin C, vitamin E, vitamin D; minerals such as calcium, selenium, zinc; glucosamine, chondroitin, hyaluronic acid; fatty acids/oils such as alpha linoleic acid, docosahexaenoic acid, eicosapantaenoic acid, arachidonic acid; aloe vera, milk thistle, probiotics, multivitamins, yeast, enzymes, herbs, garlic; and specific amino acids such as phenylalanine, tyrosine, tryptophan, 5 -hydroxytryptophan, leucine, isoleucine, valine, glutamine, L-camitine, L-theanine, lysine, taurine; or any combination thereof. The dosage form according to any of the preceding claims, wherein the at least one active agent (a) comprises or essentially consists of an antiparasitic agent (ai); preferably a systemic parasiticide; more preferably an insecticide and/or acaricide; still more preferably fluralaner, S-fluralaner, afoxolaner, S-afoxolaner, sarolaner, lotilaner, or tigolaner; most preferably fluralaner. The dosage form according to any of the preceding claims, wherein the at least one active agent (a) comprises or essentially consists of a combination of

(i) fluralaner, S-fluralaner, afoxolaner, S-afoxolaner, lotilaner or sarolaner; and

(ii) moxidectin; and

(iii) optionally, pyrantel. The dosage form according to any claims 1 to 5, wherein the at least one active agent (a) comprises or essentially consists of a combination of

(i) fluralaner, S-fluralaner, afoxolaner, S-afoxolaner, lotilaner or sarolaner; and

(ii) milbemycin oxime; and

(iii) optionally, pyrantel. The dosage form according to any of the preceding claims, wherein the total content of the at least one active agent (a) in the dosage form is within the range of 0. 1 to 30 w/w %, preferably 0.2 to 20 w/w %. The dosage form according to any of the preceding claims, wherein the humectant (b) comprises or essentially consists of a combination of sorbitol with propylene glycol. The dosage form according to any of the preceding claims, wherein the humectant (b) comprises or essentially consists of a combination of sorbitol with liquid polyethylene glycol; preferably wherein the liquid polyethylene glycol has a grade of 200-600; more preferably PEG 300 or PEG 400. The dosage form according to any of the preceding claims, wherein the humectant (b) comprises or essentially consists of a combination of sorbitol with glycerol. The dosage form according to any of the preceding claims, wherein the humectant (b) comprises or essentially consists of a combination of sorbitol with liquid paraffin; preferably wherein liquid paraffin is a mixture of refined liquid saturated aliphatic (C14-C18) and cyclic hydrocarbons obtained from petroleum. The dosage form according to any of the preceding claims, wherein the humectant (b) comprises or essentially consists of a combination of sorbitol with propylene glycol, liquid polyethylene glycol, glycerol or liquid paraffin and wherein the weight content of sorbitol is greater than the weight content of propylene glycol, liquid polyethylene glycol, glycerol, and liquid paraffin, respectively. The dosage form according to any of claims 1 to 12, wherein the humectant (b) comprises or essentially consists of a combination of sorbitol with propylene glycol, liquid polyethylene glycol, glycerol or liquid paraffin and wherein the weight content of sorbitol is lower than the weight content of propylene glycol, liquid polyethylene glycol, glycerol, and liquid paraffin, respectively. The dosage form according to any of the preceding claims, wherein the humectant (b) comprises or essentially consists of a combination of sorbitol with propylene glycol, liquid polyethylene glycol, glycerol or liquid paraffin, in a weight ratio in the range of from 10: 1 to 1: 10, preferably 7: 1 to 1:7, more preferably 4: 1 to 1:4. The dosage form according to any of the preceding claims, wherein sorbitol is present as a solution, preferably aqueous solution. The dosage form according to claim 16, wherein the content of sorbitol in the solution is at least 50 w/w %. The dosage form according to claim 16 or 17, wherein the humectant (b) comprises or essentially consists of a combination of sorbitol solution with propylene glycol, liquid polyethylene glycol, glycerol or liquid paraffin, in a weight ratio in the range of from 10: 1 to 1: 10, preferably 5: 1 to 1 : 5 , more preferably 3 : 1 to 1:3. The dosage form according to any of the preceding claims, wherein the total content of the humectant (b) in the dosage form is within the range of 1 to 20 w/w %, preferably 3 to 15 w/w %. The dosage form according to any of the preceding claims, which comprises sorbitol at a content of 5.3±3.6 w/w %, preferably 5.3±1.8 w/w %; but preferably neither propylene glycol nor liquid polyethylene glycol, nor glycerol, nor liquid paraffin. The dosage form according to any of claims 1 to 19, which comprises sorbitol at a content of 3.2±2.2 w/w %, preferably 3.2±1.2 w/w %, in combination with propylene glycol at a content of 3.0±2.0 w/w %, preferably 3.0±1.0 w/w %. The dosage form according to any of claims 1 to 19, which comprises sorbitol at a content of 3.2±2.2 w/w %, preferably 3.2±1.2 w/w %, in combination with liquid polyethylene glycol at a content of 3.0±2.0 w/w %, preferably 3.0±1.0 w/w %. The dosage form according to any of claims 1 to 19, which comprises sorbitol at a content of l.l±0.8 w/w %, preferably l.l±0.4 w/w %, in combination with liquid polyethylene glycol at a content of 6.0±4.0 w/w %, preferably 6.0±2.0 w/w %. The dosage form according to any of claims 1 to 19, which comprises sorbitol at a content of 3.2±2.2 w/w %, preferably 3.2±1.2 w/w %, in combination with glycerol at a content of 3.0±2.0 w/w %, preferably 3.0±1.0 w/w %. The dosage form according to any of claims 1 to 19, which comprises sorbitol at a content of 2.H1.4 w/w %, preferably 2.H0.7 w/w %, in combination with glycerol at a content of 4.5±3.0 w/w %, preferably 4.5±1.5 w/w %. The dosage form according to any of claims 1 to 19, which comprises sorbitol at a content of l.l±0.8 w/w %, preferably l.l±0.4 w/w %, in combination with glycerol at a content of 6.0±4.0 w/w %, preferably 6.0±2.0 w/w %. The dosage form according to any of the preceding claims, wherein the one or more forming agents (c) comprise or essentially consist of a forming agent selected from solid polyethylene glycol, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymer, microcrystalline wax, cetyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinylacetate copolymer, polysaccharides, hydroxypropyl methyl cellulose, poly(meth)acrylates, alkyl poly(meth)acrylates and combinations thereof. The dosage form according to any of the preceding claims, wherein the one or more forming agents (c) comprise or essentially consist of PEG having a number average molecular weight (Mn) within the range of from 6000 to 10000 g/mol. The dosage form according to any of the preceding claims, wherein the one or more forming agents (c) comprise or essentially consist of solid PEG having a number average molecular weight (Mn) within the range of from 3000 to 4000 g/mol. The dosage form according to any of the preceding claims, wherein the total content of the one or more forming agents (c) in the dosage form is within the range of 1 to 40 w/w %, preferably 10 to 30 w/w %. The dosage form according to any of the preceding claims, wherein the one or more fdlers (d) comprise or essentially consist of a fdler selected from starch, sucrose, lactose, dextrin, dextrate, mannitol, isomalt, glucose, fructose, soy grits, soy protein fines, microcrystalline cellulose, silicified microcrystalline cellulose, silica, titan dioxide, kaolin, bentonite, calcium phosphate and combinations thereof. The dosage form according to any of the preceding claims, wherein the one or more fillers (d) comprise or essentially consist of a starch; preferably selected from com starch, tapioca starch, wheat starch, and pea starch. The dosage form according to any of the preceding claims, wherein the one or more fillers (d) comprise or essentially consist of a combination of sucrose and starch; preferably selected from com starch, tapioca starch, wheat starch, and pea starch. The dosage form according to any of the preceding claims, wherein the total content of the one or more fillers (d) in the dosage form is within the range of 5 to 60 w/w %, preferably 10 to 40 w/w %. The dosage form according to any of the preceding claims, wherein the one or more liquid components (e) comprise or essentially consist of a solvent selected from dimethylacetamide, N methyl pyrrolidone, 2-pyrrolidone, diethylene glycol monoethyl ether, ethyl lactate, ethylene monomethyl ether, glycofurol, medium chain triglycerides, vegetable oil, butylene glycol, hexylene glycol, glyceryl triacetate, and combinations thereof. The dosage form according to any of the preceding claims, wherein the one or more liquid components (e) comprise or essentially consist of soybean oil. The dosage form according to any of the preceding claims, wherein the total content of the one or more liquid components (e) in the dosage form is within the range of 2 to 30 w/w %, preferably 3 to 20 w/w %. The dosage form according to any of the preceding claims, wherein the one or more flavors (f) comprise or essentially consist of a flavor selected from flavors of animal origin such as chicken flavor, pork flavor, beef flavor, ham flavor, or fish flavor; vegetarian flavors; Chardex Hickory flavor; artificial flavors such as sweet apple; molasses flavor; braised beef flavor; and combinations thereof. The dosage form according to any of the preceding claims, wherein the one or more flavors (f) comprise or essentially consist of meat flavor of animal origin or artificial meat flavor. The dosage form according to any of the preceding claims, wherein the total content of the one or more flavors (f) in the dosage form is within the range of 5 to 60 w/w %, preferably 10 to 40 w/w %. The dosage form according to any of the preceding claims, wherein the one or more sweeteners (g) comprise or essentially consist of an artificial non-saccharide sweetener; preferably selected from acesulfame K, aspartame, cyclamate, saccharine, sucralose, thaumatin, neohesperidine, ste- vioglycoside, neotame, acesulfame aspartame salt, and advantame; more preferably aspartame. The dosage form according to any of the preceding claims, wherein the total content of the one or more sweeteners (g) in the dosage form is within the range of 0. 1 to 5 w/w %, preferably 0. 1 to 0.5 w/w %. The dosage form according to any of the preceding claims, which comprises at least one further excipient selected from surfactants; preferably anionic surfactants; more preferably sodium lauryl sulfate. The dosage form according to any of the preceding claims, which comprises at least one further excipient selected from lubricants; preferably magnesium stearate. The dosage form according to any of the preceding claims, which has a texture with a plastic deformation that does not break upon chewing. The dosage form according to any of the preceding claims, which has a hardness of between 15 and 80 N, preferably between 20 and 70 N. A method for preparing a soft chewable veterinary dosage form according to any of preceding claims comprising the steps:

(i) blending the (a) at least one active agent with (b) humectant, (c) forming agent, (d) filler, (e) a liquid component and (f) flavor to obtain a dough; and

(ii) forming the dough from step (i) to a soft chewable veterinary dosage form. The method according to the claim 47, wherein the step (i) comprises the following sub-steps: (i-a) blending the at least one active agent (a), a filler (d) and a flavor (f);

(i-b) combining the mixture from step (i-a) with humectant(s) (b), forming agent (c) and liquid component (e), either individually or in the form of a mixture thereof; and

(i-c) blending the mixture together to obtain a dough, preferably a homogenous dough. The method according to the claim 47, wherein the step (i) comprises the following sub-steps: (i-a) blending the at least one active agent (a), a filler (d) and a flavor (f);

(i-b) preparing a mixture of humectant(s) (b), forming agent (c) and liquid component (e); and (i-c) combining the mixtures from steps (i-a) and (i-b) together and blending the mixture to obtain the dough, preferably homogenous dough.