Soft chewable formulation for administration to animals

Abstract

The present invention relates to a shaped body for administration to animals and a method for producing a shaped body for administration to animals. The shaped body is particularly useful for the oral administration of pharmaceutically active substances to animals. The shaped body for administration to animals comprises one or more pharmaceutically active substances, one or more flavoring agents, one or more binders, one or more gel-forming agents, one or more fillers, water, and glycerol.

Description

[Technical Field]

[0001] The present invention relates to a shaped body for administration to animals and to a method for producing a shaped body for administration to animals, which is particularly useful for the oral administration of pharmaceutically active substances to animals. [Background technology]

[0002] Pet acceptance of medicines is primarily determined by their smell and taste (Thombre, AG, 2004, Advanced Drug Delivery Reviews 56 (10), 1399-1413). Thus, for example, the use of flavorings can increase acceptance by over 90% for bitter medications (Ahmed, I. and Kasraian, K. 2002, Advanced Drug Delivery Reviews 54 (6), 871-882). Cats prefer the taste of fish, while dogs prefer the taste of beef, pork, and lamb (Houpt, KA and Smith, SL 1981, Canadian Veterinary Journal 22 (4), 77-85). Despite being rich in flavorings and flavoring agents (Rose et al. 2008, US7348027) and in some cases animal by-products (Cleverly et al. 2004, WO2004016252), animal drugs are rejected because they are clearly distinguishable from feed. Oral formulations are generally harder or have a different morphology than traditional animal feeds.

[0003] The mouthfeel of a chewable drug product is largely determined by the resulting mouth sensation (Thombre, AG, 2004, Advanced Drug Delivery Reviews 56(10), 1399-1413). To create a pleasant mouthfeel, the texture of the drug product is tailored to the patient's preferences. In dogs, soft structures are significantly preferred (Rose et al., 2008, US7348027) over hard, brittle structures such as those in DE69937780 (Damon et al., 2008).

[0004] Previously developed chewing agents were based on flavored starch extrudates. These chewing agents are intended to be mixed with the animal feed and are not available to the animal (Isele 2008, AU2008201605B2; Kalbe 2008, EP1296655B1). Due to the high proportion of flavoring, palatability is very good, but this is not guaranteed throughout the shelf life. Starch-containing chewing agents harden over time, resulting in a perceived more brittle mouthfeel (Keetels, CJAM et al. 1996, Food Hydrocolloids 10(3), 343-353).

[0005] A further disadvantage of starch-containing chewables is that they cannot be embedded with thermolabile active compounds, which also applies to chewables made from sugar mixtures heated under high pressure (Han, YD and Park, JB 2002, US 6,444,218; Han, YD and Park, JB 2002, US 6,440,450).

[0006] The retrogradation of starch-containing products leads to the re-release of previously bound water, resulting in significant changes in the physical structure (Farhat et al. 2001, Starch / Starke 53(9), 431-436) and therefore in the elasticity of the extrudates (Vandeputte et al. 2003. Journal of Cereal Science, 38(19, 61-68). To circumvent these problems, highly complex formulations have been developed which, in addition to starch, contain vegetable oils, sugars and further additives (Huron, S. 2004, WO2004 / 014143 A1; Paulsen et al. 2011, US7955632B2). However, the addition of oils to improve the mouthfeel can cause problems during further processing of the chews. For example, adhesion to tableting tools or molding machines has been reported (Carrillo, B. and (Freehauf, K. 2013, WO2013068371A1). Furthermore, as the oil separates from the rest of the formulation during storage, these chews also harden and harden over time, resulting in a chalky mouthfeel. Hydrophobic active pharmaceutical ingredients (APIs) may also accumulate in the oil phase, which can negatively impact the drug delivery process of these chews.

[0007] Other starch-free chews have been developed in an attempt to prepare chews with a more consistent consistency and appeal (Gao et al. 2010, US20100291245; Hamann, HJ and Kanikanti, V.-R. 2012, WO2012049156A1). However, due to their high hardness, the texture of these chews cannot be tailored to dogs' palatability. The texture is brittle and crumbly. Furthermore, Gao's chew preparation requires a drying process of several hours until the chew reaches the desired moisture content.

[0008] US2008 / 0075759A1 describes a method for producing a chewable dosage form for drug delivery to an animal or human subject, and the resulting product. The disclosed process avoids extrusion and the associated high temperatures, but requires a separate wet mixing and molding step for the production of the chewable. WO2014 / 141223A1 relates to a chewable formulation for delivering a pharmaceutically active agent to an animal target. The chewable formulation, which can be formed by extrusion, is substantially free of unbound water and requires the addition of lipids or fats during the manufacturing process. Another highly palatable soft chewable animal composition for oral administration to animals is disclosed in WO2016 / 073347A1. However, the method for producing this soft chewable composition requires passing the extrudate through an air-conditioning chamber having a specific temperature range or air-drying the extrudate. WO2017 / 194415A1 discloses a method for producing a compact for administration to animals. However, the chewable tablets obtained by this method lack the necessary mechanical stability and tend to disintegrate during handling. Furthermore, the water activity (aw) did not comply with the range specified in USP 39,1112 (United States Pharmacopeia). [Prior art documents] [Patent documents]

[0009] [Patent Document 1] Rose et al. 2008, US7348027 [Patent Document 2] Cleverly et al.2004, W02004016252 [Patent Document 3] Isele 2008, AU2008201605B2 [Patent Document 4] Kalbe 2008, EP1296655B1 [Patent Document 5] Han, YDand Park, JB2002, US6444218 [Patent Document 6] Han, YDand Park, JB2002, US6440450

Patent document 7

Patent document 8

Patent Document 9

Patent document 10

Patent document 11

Patent document 12

Patent document 13

Patent document 14

Patent document 15

Non-licensed literature

[0010] [Non-licensed document 1] Thombre,AG,2004,Advanced Drug Delivery Reviews 56(10),1399-1413 [Non-licensed document 2] Ahmed,I.and Kasraian,K.2002,Advanced Drug Delivery Reviews 54(6),871-882 [Non-licensed document 3] Houpt,KAand Smith,SL1981,Canadian Veterinary Journal 22(4),77-85

Non-licensed Document 4

[0011] Object of the invention Against this background, the object of the present invention was to provide a shaped body for administration to animals, in particular dogs, in particular for administering a pharmaceutically active substance, which avoids or ameliorates one or more of the above-mentioned drawbacks of the prior art. Likewise, a further object was to provide an improved method for producing such a shaped body. In particular, the object of the present invention was to provide a chewable pharmaceutical product (hereinafter also referred to as chewable or soft chewable) that stands out from known products in particular by one or more of the following properties:

[0012] 1) High palatability should be achieved by a chewable pharmaceutical product that has a pleasant taste and texture profile that is well accepted by dogs, ensured by the following properties: a. There is virtually no breakage of the chewing agent under constant force loading; b. Sufficient elasticity and plasticity under a certain force load; c. The dog must chew it approximately as many times as a piece of meat sausage (at least three times on average).

[0013] 2) Chewable medicines should have a pleasant mouthfeel. They should not have a chalky or brittle feel when chewed.

[0014] 3) The disintegration time of the chewable pharmaceutical product must be 1 hour or less.

[0015] 4) The water activity of the chewable pharmaceutical product must be low enough to prevent the growth of microorganisms in the compact.

[0016] 5) The storage time should have a negligible effect on the properties of the drug product. a. The disintegration time must remain within 1 hour; b. The emission characteristics must not deteriorate; c. The product formed by the method of the present invention must retain its elasticity and be chewy.

[0017] 6) The manufacturing method must meet at least most of the following requirements: a.It is robust, b. preferably continuously processed; c. Short processing time, d. No adhesion to processed parts; e. No curing required; f. Can be performed at temperatures below 80°C.

[0018] Some or all of these objects can be achieved by the molded articles described in claims 1 and 13 and the method for producing a molded article described in claim 14.

[0019] Preferred embodiments of the invention are set out in the dependent claims and are described below. [Means for solving the problem]

[0020] The present invention provides a. one or more pharmaceutically active substances; b. One or more flavoring agents; c. one or more binders; d. one or more gel-forming agents; e. 1 or more fillers; f. water, and Glycerol The present invention relates to a molded article for administration to an animal, comprising: [Brief explanation of the drawings]

[0021] [Figure 1] FIG. 1 is a diagram showing hardness profiles of Examples 1 to 5, n=3±standard deviation. [Figure 2] FIG. 1 shows water activity plots for Examples 1 to 5, n=1. [Figure 3] FIG. 1 shows the disintegration times shown for Examples 1 to 5, n=3 or n=6±standard deviation. [Figure 4] FIG. 1 shows hardness profiles for gel-like croscarmellose-glycerol-water mixtures that differ in glycerol content in the liquid phase (see Table 6 in Example 7), cutoff <30 min, n=3±standard deviation. [Figure 5] FIG. 1 shows the hardness change of the sample of Example 1 over the measurement time (2 cycles). [Figure 6] FIG. 1 is a diagram showing hardness profiles for Examples 6 to 8, n=3±standard deviation. DETAILED DESCRIPTION OF THE INVENTION

[0022] Surprisingly, shaped bodies containing at least the above-mentioned combination of ingredients have exceptional palatability, with a texture that is particularly well-accepted by animals, particularly dogs and cats. The shaped bodies of the present invention exhibit a meat-like, semi-solid, and soft texture, allowing animals, such as dogs and cats, to easily chew them while providing a pleasant mouthfeel. As used herein, the term "semi-solid" refers to a texture that retains its shape unless a certain level of pressure is applied. Hardness measurements performed using a texture analyzer (described further below) also provide information on textural properties such as elastic behavior, plastic deformation, and brittleness or lack of brittleness (e.g., Szczesniak, A.S. (1963), Classification of textural characteristics, Journal of Food Science 28(4):385-389).

[0023] In addition to the excellent textural properties of the molded body of the present invention, all of its components are well distributed in the body, providing a uniform delivery of the contained pharmaceutical active substance in the animal. Furthermore, the molded body of the present invention has a pleasant aroma and is easy for the owner to handle.

[0024] The molded bodies of the present invention exhibit a long shelf life even when stored for a long period of time, for example, for more than 2 months, more than 3 months, or more than 6 months. In particular, the hardness of the molded bodies of the present invention remains substantially stable during storage for several months. As used herein, "substantially stable" means that the hardness of the molded body does not change by more than 50%, preferably does not change by more than 30%, and most preferably does not change by more than 20%, when the hardness measurement of the molded body 1 week after preparation is compared with the measurement of the molded body after several months of storage, for example, after 3 or 6 months. Those skilled in the art know how to perform such hardness measurements, which typically require a texture analyzer, such as TA.XTplus, Stable Micro Systems Ltd., UK. This is an important advantage of the molded bodies of the present invention over prior art chewable bodies that are primarily based on starch.

[0025] The disintegration time of the compacts of the present invention is 1 hour or less, preferably 45 minutes or less, and most preferably 30 minutes or less. The disintegration time of the compacts of the present invention can be determined by Method A of the European Pharmacopoeia (Ph.Eur.) 10.2. It has been found that the disintegration time of the compacts of the present invention remains substantially the same even after storage for up to 3 months, preferably up to 6 months, and more preferably up to 12 months.

[0026] The molded articles of the present invention can be used to efficiently and comfortably deliver a vast number of different pharmaceutically active substances to animals, particularly dogs and cats.

[0027] Without being bound by any particular scientific theory, it is believed that the interaction between one or more gel-forming agents, water, and glycerol provides the basic network structure of the molded body of the present invention, which is responsible for the molded body's exceptional properties. The gel-forming agent, water, and glycerol in the molded body of the present invention form a gel-like structure into which the other components of the body are integrated with the aid of one or more binders. As a result, the molded body of the present invention has a homogeneous and stable structure that remains largely unchanged even over long storage periods. As used herein, the term "glycerol" refers to anhydrous glycerol.

[0028] Surprisingly, it has been found that components typically used as disintegrants for tablet disintegration have optimal gel-forming properties and therefore function as gel-forming agents in the compacts of the present invention.This is probably because the disintegrants used as gel-forming agents in the compacts of the present invention rapidly swell when they come into contact with water, which is believed to be the mechanism by which these disintegrants impart their disintegrating effect.This swelling ability is believed to be the main reason why the compacts of the present invention exhibit good gel-forming properties.

[0029] The molded articles of the present invention can be produced by the manufacturing method of the present invention, which exhibits high throughput rates, short residence times, and high robustness.

[0030] For the purposes of the present invention, a shaped body is to be understood as an object obtained by cutting a strand obtained by a molding process, preferably by extrusion. The shaped body preferably has a smooth surface without cracks visible to the naked eye or irregularities that can be felt by hand. The weight of the shaped body is typically in the range of 0.1 g to 20 g, preferably 0.5 g to 10 g, and most preferably 1 g to 5 g.

[0031] The shaped bodies according to the invention are intended for administration to animals and can be employed in the breeding of livestock and agricultural animals, breeding animals, zoo animals, laboratory animals, research animals and pet animals, particularly mammals.

[0032] Agricultural and breeding animals include, for example, mammals such as cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such as mink, chinchillas, raccoons, and also birds such as chickens, geese, turkeys, ducks, pigeons, and ostriches. Preferred examples of agricultural animals are cattle, sheep, pigs, and chickens.

[0033] Experimental and research animals include dogs, cats, rabbits, and rodents such as mice, rats, guinea pigs, and golden hamsters.

[0034] Pets include dogs, cats, horses, rabbits, rodents such as golden hamsters, guinea pigs, and mice, as well as reptiles, amphibians, and birds kept at home or in zoos. Administration to cats and dogs is particularly preferred.

[0035] Since the shaped bodies according to the present invention are orally administered to animals and are usually chewed during administration, the terms "chewable" or "chewables" are used in combination with or alone as the term "shaped body" when referring to the shaped bodies according to the present invention. The shaped bodies are also referred to as "soft" if they have a soft consistency compared to prior art solid pharmaceuticals for animals that are orally administered, allowing them to be swallowed without chewing or with only slight chewing, and providing an animal to which they are administered with a meat-like mouthfeel. Thus, the terms "shaped body", "chewable body", "chewable" or "chewables" and "soft chewable body" can all be used interchangeably in the context of this application, which is for the purpose of the present invention, which is a soft chewable body for administration to animals.

[0036] For the purposes of this invention, extrusion or the extrusion process is to be understood as a mixing and / or forming process utilizing an extruder that continuously squeezes a highly viscous material from a solid under pressure through a forming orifice, also called a die, matrix or nozzle. The resulting body, having a cross section corresponding to the orifice and theoretically any length, is therefore called an extrudate.

[0037] According to the present invention, the mixing of solid powder components can be carried out after the solid components are charged into the extruder through an input opening, such as a funnel. Additional components of the extrusion mixture, including liquids, can be introduced into the extruder through this or other input openings at different locations before, during, or after the solid components are loaded into the extruder through the input opening. Homogenization and plasticization during transport through the multi-stage screws in the extruder can be carried out with heating or cooling until the material is finally drawn through a forming die at the head of the extruder.

[0038] For purposes of the present invention, the term extruder includes single-screw, twin-screw and multi-screw extruders, planetary roller extruders and cascade extruders, but is not limited to these extruder variants.

[0039] The shaped article of the present invention contains water, which is important for the texture and disintegration properties of the shaped article. According to a preferred embodiment of the shaped article of the present invention, the water content of the shaped article is in the range of 0.5 to 20 wt%, preferably 0.75 to 18 wt%, more preferably 1.0 to 15 wt%, even more preferably 1.5 to 13 wt%, and most preferably 1.75 to 11.5 wt%, based on the total weight of the shaped article. According to another preferred embodiment of the shaped article of the present invention, the water content is in the range of more than 2 wt%, particularly more than 4.5 wt%, preferably more than 4.8 wt%, more preferably more than 5.0 wt%, and most preferably more than 6.1 wt%, based on the total weight of the shaped article. In particular, the water content of the shaped article is in the range of 4.5 to 20 wt%, preferably 4.8 to 18 wt%, more preferably 5.0 to 15 wt%, even more preferably 5.5 to 13 wt%, and most preferably 6.1 to 11.5 wt%, based on the total weight of the shaped article. It has been found that compacts having such a preferred moisture content exhibit an extended shelf life and provide a particularly stable yet soft texture for the compacts. Furthermore, compacts having the preferred moisture content exhibit excellent workability and can be easily processed through an extrusion process. The water activity (aw) of the compacts is preferably 0.6 or less, more preferably in the range of 0.10 to 0.6, particularly preferably in the range of 0.20 to 0.58, and most preferably in the range of 0.30 to 0.55. When the water activity of the compacts is within such a preferred range, the compacts exhibit particularly long shelf life. The present inventors have found that microbial growth in the compacts is inhibited at such a low level of water activity.

[0040] The ranges given herein for each component of the shaped body of the present invention can be combined with any range given for another component of the shaped body, in particular, ranges of the same "palatability level" are compatible for different components of the shaped body.

[0041] Water activity (aw) is the partial vapor pressure of water in a compact divided by the partial vapor pressure of pure water at the same temperature. This relationship is expressed by the following equation:

[0042]

number

[0043] The aw value of the molded body given for this preferred embodiment of the invention refers to the aw measured at 22° C. A resistance-type electrolyte hygrometer, a capacitance-type hygrometer, or a dew-point hygrometer can be used to measure aw.

[0044] The water activity of the compact is determined not only by the water content but also by the types of gel-forming agents, additional liquids, and excipients used in the production of the compact of the soft chewable tablet. Maintaining the value of the water activity aw within the range specified in this specification prevents the growth of microorganisms and improves the shelf life of the compact.

[0045] The molded body of the present invention further comprises one or more binders. Preferably, one binder is used. The one or more binders may be selected from the group consisting of polyvinylpyrrolidone, croscarmellose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, pectin, pullulan, carrageenan, xanthan gum, alginic acid, and agar. It has been found that the texture and disintegration properties of the molded body are particularly favorable when the one or more binders comprise or consist of polyvinylpyrrolidone. When polyvinylpyrrolidone is used as a binder, one or more pharmaceutically active substances, one or more flavoring agents, and possible additives are particularly well dispersed in the gel network of the molded body.

[0046] Polyvinylpyrrolidone (PVP, povidone) is a commercially available hydrophilic polymer suitable for use in solid pharmaceutical formulations. Various PVPs are commercially available. PVPs with relatively low molecular weights are typically used as binders for tablets. PVPs swell and erode in aqueous solutions. The release kinetics of the drugs of the present invention can be varied within a defined range by using PVPs with different molecular weights.

[0047] The polyvinylpyrrolidone or polyvinylpyrrolidone derivative employed is preferably soluble in water, and in this case, the polyvinylpyrrolidone or polyvinylpyrrolidone derivative is preferably substantially linear and not cross-linked.

[0048] Generally, any type of polyvinylpyrrolidone can be used as a binder for the molded body. According to a preferred embodiment, the molded body comprises polyvinylpyrrolidone having a weight-average molecular weight Mw of 1,000 to 500,000 g / mol, particularly 1,200 to 300,000 g / mol, 1,500 to 100,000 g / mol, or 2,000 to 90,000 g / mol. Polyvinylpyrrolidone with such weight-average molecular weights has been found to be particularly suitable for integrating different components of the molded body into a gel-like structure. Polyvinylpyrrolidone with a weight-average molecular weight greater than 500,000 g / mol can result in molded bodies with a more brittle and less flexible general structure due to the hardening effect that can occur with polyvinylpyrrolidone of such very high molecular weights. In contrast, polyvinylpyrrolidone with a weight-average molecular weight less than 1,000 g / mol exhibits less than ideal binding effect of the components into a gel-like structure.

[0049] According to a preferred embodiment of the present invention, the molded body comprises polyvinylpyrrolidone having a K value of 17-90, preferably 17-60, most preferably 25-50.

[0050] The K value of polyvinylpyrrolidone or polyvinylpyrrolidone derivatives is related to viscosity and molecular weight and can be determined by methods known to those skilled in the art. In case of doubt, data on K values ​​from the Ph.Eur. are used. One possible way to calculate the K value is to use the Fikentscher K value. If the measurement conditions regarding solvent, polymer concentration in the solution, and temperature are constant, the Fikentscher K value depends only on the molecular weight of the polymer. The Fikentscher K value is calculated as follows:

[0051]

number

[0052] According to one embodiment of the present invention, the molded body can contain only one type of polyvinylpyrrolidone, which can be produced particularly inexpensively while exhibiting good texture and disintegration properties.

[0053] According to another embodiment of the present invention, the one or more binders comprise or consist of at least two different types of polyvinylpyrrolidone. According to a particularly preferred embodiment, the one or more binders comprise or consist of at least two types of polyvinylpyrrolidone having different weight-average molecular weights. When the molded article comprises two or more types of polyvinylpyrrolidone with different weight-average molecular weights as binders, the different types of polyvinylpyrrolidone can provide a molded article with properties that can be fine-tuned according to the specific components used and the specific intended use.

[0054] A certain type of polyvinylpyrrolidone is herein understood to be a polyvinylpyrrolidone having a specific weight-average molecular weight, specific rheological properties such as viscosity, and / or specific mechanical properties that differ from at least one other type of polyvinylpyrrolidone. Thus, different types of polyvinylpyrrolidone within the meaning of the present invention may differ with respect to their weight-average molecular weight, rheological properties such as viscosity, and / or mechanical properties. For example, one type of polyvinylpyrrolidone could be defined by having a weight-average molecular weight of 2,000 to 6,000 g / mol, while another different type of polyvinylpyrrolidone may have a weight-average molecular weight of 20,000 to 50,000 g / mol.

[0055] According to a preferred embodiment of the present invention, the weight content of polyvinylpyrrolidone in the molded article is in the range of 0.2 to 20.0 wt.%, preferably 0.3 to 10.0 wt.%, more preferably 0.4 to 9.0 wt.%, and most preferably 0.5 to 7.5 wt.%, based on the total weight of the molded article. At such a weight content of polyvinylpyrrolidone, the molded article of the present invention exhibits particularly good texture properties while all components are well dispersed within the body. If the weight content of polyvinylpyrrolidone exceeds 20 wt.%, there is a risk that the molded article will lose its desired properties.

[0056] If the content of polyvinylpyrrolidone is less than 0.2% by weight, it may be difficult to obtain a completely homogeneous molded product in which all components are well dispersed.

[0057] Further details regarding the above polyvinylpyrrolidone, polyvinylpyrrolidone derivatives and specific mixtures can be found in the following book: V. Biihler, "Kollidon, Polyvinylpyrrolidone for the pharmaceutical industry", 9th revised edition, BASF Pharma Ingredients, Germany, 2008.

[0058] The compacts of the present invention contain one or more gel-forming agents. The gel-forming agents used in the compacts of the present invention are typically used as disintegrants in solid tablets. Generally, different types of gel-forming agents can be used in the compacts, preferably one or more gel-forming agents selected from the group consisting of croscarmellose, low-substituted carboxymethylcellulose, low-substituted hydroxypropylcellulose, crospovidone, and cross-linked carboxymethyl starch. Experimental studies have shown that when the one or more gel-forming agents comprise or consist of croscarmellose, particularly robust and soft compacts are obtained. The croscarmellose referred to herein is also known as cross-linked carboxymethylcellulose. It has been recognized that croscarmellose is particularly suitable for combining with water and glycerol to form a soft yet robust network structure, into which different flavoring agents, pharmaceutical active substances, and optional additives can be incorporated. Compacts in which the one or more gel-forming agents comprise or consist of croscarmellose have a particularly long shelf life and exhibit good disintegration properties.

[0059] It is particularly preferred that croscarmellose is the only gel-forming agent in the compact, as this allows particularly homogeneous compacts to be obtained.

[0060] In a preferred embodiment according to the present invention, the molded body does not contain gelatin.

[0061] In principle, the gel-forming agent used in the molded body of the present invention can also be used as a binder. Preferably, the one or more binders and the one or more gel-forming agents differ from each other in at least one agent. Particularly preferably, the molded body of the present invention uses a combination of croscarmellose as the gel-forming agent and polyvinylpyrrolidone as the binder. Thus, in this embodiment of the molded body of the present invention, the gel-forming agent comprises or consists of croscarmellose, and the binder comprises or consists of polyvinylpyrrolidone. Another preferred combination of the molded body of the present invention is to use crospovidone as the gel-forming agent and hydroxypropyl cellulose as the binder. Therefore, in this embodiment of the molded body of the present invention, the gel-forming agent comprises or consists of crospovidone, and the binder comprises or consists of hydroxypropyl cellulose.

[0062] In another preferred embodiment of the present invention, the molded body of the present invention is substantially free of starch and / or starch derivatives. In another preferred embodiment, the molded body of the present invention is substantially free of starch and / or starch derivatives. The substantial absence of starch and / or starch derivatives in the molded body ensures that the hardness of the molded body remains particularly stable over long storage periods.

[0063] Croscarmellose is a salt, preferably the sodium salt, of crosslinked, partially O-(carboxymethylated) cellulose. Croscarmellose is known to those skilled in the art. The degree of substitution of the cellulose structure, i.e., the number of hydroxyl groups per glucopyranose monomer unit replaced with carboxymethyl groups, can vary widely. A typical degree of substitution can be preferably 0.5 to 0.9 carboxymethyl groups per glucopyranose unit, and particularly about 0.7 carboxymethyl groups per glucopyranose unit. Croscarmellose can be prepared by first soaking crude cellulose in sodium hydroxide and then reacting the cellulose with sodium monochloroacetate to form sodium carboxymethylcellulose. The excess sodium monochloroacetate then slowly hydrolyzes to glycolic acid, which catalyzes crosslinking to form croscarmellose sodium. Other crosslinking techniques are also possible.

[0064] It is believed that the pleasant mouthfeel of the molded body of the present invention can be largely attributed to the gel-like structure provided by the network of one or more gel-forming agents in which glycerol and water are integrated. The quality of the gel-like structure is particularly determined by the relative ratio of these components. The molded body has a particularly stable and robust network structure when the weight ratio of one or more gel-forming agents to the total weight of water and glycerol in the molded body is in the range of 1:2 to 1:20, preferably 1:3 to 1:15, more preferably 1:5 to 1:10, and most preferably 1:6 to 1:8. At such a weight ratio of one or more gel-forming agents to the total weight of water and glycerol, the gel structure is believed to have an optimal ratio of solid to liquid components to provide a particularly robust network structure. If the weight ratio of one or more gel-forming agents to the total weight of water and glycerol in the molded body exceeds 1:2, the texture of the molded body may become brittle and its flexibility may decrease. If the weight ratio of the one or more gel-forming agents to the total weight of water and glycerol is less than 1:20, there is a risk that all components of the shaped body will not be evenly distributed within the shaped body.

[0065] According to another preferred embodiment of the present invention, the weight content of one or more gel-forming agents in the shaped body is in the range of 0.5 to 30% by weight, preferably 1 to 25% by weight, more preferably 2 to 20% by weight, even more preferably 3 to 17% by weight, and most preferably 5 to 15% by weight, based on the total weight of the shaped body. With such a content of one or more gel-forming agents, the shaped body exhibits particularly favorable textural properties and a particularly long shelf life.

[0066] According to a particularly preferred embodiment, the weight ratio of the one or more gel formers to the total weight of water and glycerol in the shaped body is in the range of 1:2 to 1:20, preferably 1:3 to 1:15, more preferably 1:5 to 1:10, and most preferably 1:6 to 1:8, while the weight content of the one or more gel formers in the shaped body is 0.5 to 30 wt. %, preferably 1 to 25 wt. %, more preferably 2 to 20 wt. %, even more preferably 3 to 17 wt. %, and most preferably 5 to 15 wt. %, based on the total weight of the shaped body.

[0067] The molded body of the present invention contains glycerol and water. Surprisingly, when glycerol alone is used, particularly when croscarmellose is used as a gel former, the one or more gel formers are unable to form a proper network structure. However, when a mixture of glycerol and water is used in a molded body together with one or more gel formers, particularly croscarmellose, a soft and robust gel-like structure is obtained. The ratio of glycerol to water in the molded body of the present invention can vary over a wide range. Molded bodies having a water-to-glycerol weight ratio of 5:95 to 35:65, preferably 10:90 to 30:70, and most preferably 15:85 to 25:75, exhibit particularly high structural integrity of the gel-like structure. If the water-to-glycerol weight ratio is less than 5:95, the structural integrity of the gel-like structure of the molded body may be impaired. However, if the water-to-glycerol weight ratio exceeds 35:65, the chewability of the molded body may be adversely affected.

[0068] The molded body of the present invention has a soft yet firm structure. It is particularly suitable for administration to animals if the molded body has a hardness of 1.5 to 10 N, particularly 2.0 to 8 N, and preferably 2.5 to 7 N. According to the present invention, hardness is defined as the maximum force at 25% deformation ("strain") of the sample. Methods for measuring the hardness of molded bodies are known to those skilled in the art. For example, hardness can be measured using a TA.TXplus system from Stable Micro Systems Ltd., UK. In this case, the molded body is compressed under defined conditions, and the force required to achieve a certain deformation of the molded body is calculated using suitable software, such as "Exponent" software.

[0069] The molded body of the present invention comprises one or more pharmaceutically active substances. Preferably, at least one of the one or more pharmaceutically active substances a) is selected from the group of orally administrable systemically active veterinary drugs, such as antiparasitic drugs, in particular insecticides, acaricides, anthelmintics, and antibacterial agents. Thus, according to the present invention, the pharmaceutically active substances that can be contained in the molded body of the present invention are basically all possible active compounds that are commonly administered orally to animals.

[0070] Active compounds include, for example, antibacterial active compounds, such as antiviral active compounds, antibiotic active compounds and those acting against protozoa such as coccidia, as well as, for example, anti-inflammatory active compounds and psychotropic active compounds, and also proton pump inhibitors, and particularly preferably active compounds acting against parasites (ectoparasites and / or endoparasites), such as acaricides, insecticides and anthelmintic active compounds.

[0071] In a preferred embodiment, the pharmaceutical active substance(s) a) are antimicrobial substances or antibiotics, preferably for the treatment of bacterial diseases.

[0072] In another preferred embodiment, the pharmaceutically active substance(s) a) is an antiparasitic agent.

[0073] In another preferred embodiment, the pharmaceutically active substance(s) a) are compounds active against coccidia.

[0074] In a particularly preferred embodiment, the antiparasitic agent is an ectoparasiticide, in particular an arthropodicide, ie an insecticide or acaricide, or an endoparasiticide, in particular an anthelmintic.

[0075] In a very particularly preferred embodiment, the antiparasitic agent is an insecticide, acaricide or anthelmintic.

[0076] Examples of suitable active compounds are those of the known classes: acaricides, such as macrocyclic abamectin, doramectin, eprinomectin, ivermectin, milbemectin, nikkomycin, selamectin, tetranactin and thuringiensin; bridged diphenyl acaricides, such as azobenzene, benzoximate, benzyl benzoate, bromopropylate, chlorbenesid, chlorphenetole, chlorfenson, chlorfensulfide, chlorobenzilate, chloropropylate, dicofol, diphenylsulfone, dofenapine, fenson, furan; Entrifanil, Fluorobenside, Proclonol, Tetradifon and Tetrasulf; Carbamate acaricides such as Benomyl, Carbanolate, Carbaryl, Carbofuran, Fenothiocarb, Methiocarb, Metolcarb, Promacil and Propoxur; Oxime carbamate acaricides such as Aldicarb, Butocarboxim, Oxamyl, Thiocarboxim and Thiofanox; Dinitrophenol acaricides such as Binapacryl, Zinex, Zinobuton, Dinocap, Dinocap-4, Dinocap-6, Dinocton, Dinope formamidine acaricides such as amitraz, chlordimeform, chloromebuform, formetanate and formparanate; mite growth regulators such as clofentezine, dofenapine, fluazuron, flubenzimine, flucycloxuron, flufenoxuron and hexythiazox; organochlorine acaricides such as bromocyclen, camphechlor, dienochlor and endosulfan; pyrazole acaricides such as acetoprole, fipronil and its analogues and derivatives, tetracycline acaricides such as tetracycline, ... Bufenpyrad, pyriprole and vaniliprole; pyrethroid insecticides, for example, pyrethroid ester insecticides such as acrinathrin, bifenthrin, cyhalothrin, cypermethrin, α-cypermethrin, fenpropathrin, fenvalerate, flucythrinate, flumethrin, fluvalinate, taufluvalinate and permethrin, pyrethroid ether acaricides such as halfenprox; quinoxaline acaricides such as quinomethionate and thioquinox; sulfite acaricides such as propargite;Tetronic acid acaricides, such as spirodiclofen; and non-specified class acaricides, such as acequinocyl, amidoflumet, arsenic oxide, chlormethiuron, closantel, crotamiton, diafenthiuron, dichlofluanid, disulfiram, fenazaflor, fenazaquin, fenpiroximate, fluacrypyrim, fluenethyl, mesulfen, MNAF, nifluridide, pyridaben, pyrimidifen, sulfiram, sulfuramide, sulfur, and triatene;

[0077] Insecticides can belong to various chemical classes, such as, for example, chlorinated hydrocarbons, organophosphates, carbamates, pyrethroids, formamidines, borates, phenylpyrazoles, and macrocyclic lactones. Known insecticides include imidacloprid, fenthion, fipronil, allethrin, resmethrin, fenvalerate, permethrin, malathion, and their derivatives. According to one embodiment, insecticides of the neonicotinoid class are preferred, such as acetamiprid, clothianidin, dinotefuran, imidacloprid (see above), nitenpyram, thiacloprid, and thiamethoxam. Frequently used growth-regulating active compounds (insect growth regulators, IGRs) are, for example, active ingredients such as benzoylphenylureas, such as diflubenzuron, lufenuron, noviflumuron, hexaflumuron, triflumuron and teflubenzuron, or fenoxycarb, pyriproxyfen, methoprene, kinoprene, hydroprene, cyromazine, buprofezin, pymetrozine and its derivatives.

[0078] Anthelmintics may be endoparasiticides or endotectocides, and include the following known groups: macrocyclic lactones, benzimidazoles, probenzimidazoles, imidazothiazoles, tetrahydropyrimidines, organophosphates, piperazines, salicylanilides and cyclic depsipeptides (see below).

[0079] Preferred anthelmintics include broad-spectrum macrocyclic lactones such as avermectins, milbemycins, and their derivatives, such as ivermectin, doramectin, moxidectin, selamectin, emamectin, eprinomectin, milbemectin, abamectin, milbemycin oxime, nemadectin, and their derivatives. Benzimidazoles, benzimidazole carbamates, and probenzimidazoles include active compounds such as thiabendazole, mebendazole, fenbendazole, oxifendazole, oxibendazole, albendazole, luxabendazole, netobimin, perbendazole, flubendazole, cyclobendazole, febantel, thiophanate, and their derivatives. Imidazothiazoles include active compounds such as tetramisole, levamisole, and their derivatives. Tetrahydropyrimidines include active compounds such as morantel, pyrantel, and their derivatives. Organophosphates include active compounds such as dichlorvos, haloxone, trichlorfon, and their derivatives. Salicylanilides include active compounds such as closantel, tribromsalan, dibromsalan, oxyclozanide, clioxanide, lafoxanide, brothianide, bromoxanide, and their derivatives. Cyclic depsipeptides include compounds with 6 to 30 ring atoms, composed of amino acids and hydroxycarboxylic acids as ring structural units.

[0080] Examples of antibacterial compounds include various penicillins, tetracyclines, sulfonamides, cephalosporins, cephamycin, aminoglucosides, trimethoprim, dimetridazole, erythromycin, framycetin, fluazolidone, various pleuromutilins such as tiamulin and valnemulin, various macrolides, streptomycin, clopidol, salinomycin, monensin, halofuginone, narasin, robenidine, quinolones, and the like. Specific examples of fluoroquinolones include benofloxacin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, perfloxacin, temafloxacin, tosufloxacin, sarafloxacin, and sparfloxacin. A further example of an antibacterial fluoroquinolone that can be used in animals is pradofloxacin. Specific examples of other quinolones include pipemidic acid and nalidixic acid.

[0081] In addition to the above-mentioned pharmaceutically active compounds, it is also possible to have, for example, vitamins and minerals as constituents.

[0082] The active ingredient is preferably a depsipeptide, for example selected from the group consisting of PF1022A and emodepside.

[0083] Preferred antibacterial fluoroquinolones are, in particular, enrofloxacin or pradofloxacin.

[0084] In a further preferred embodiment, the shaped body according to the invention comprises an active ingredient selected from febantel, pyrantel (typically in the form of a salt, preferably embonate) and praziquantel, or a two-drug combination consisting of said active ingredients. Even more preferably, febantel, pyrantel embonate and praziquantel are used as a three-drug combination in the shaped body according to the invention.

[0085] The active compounds can also be used - if appropriate - in the form of their salts with pharmaceutically acceptable acids or bases, or as solvates, more particularly hydrates, of the active compounds or their salts.

[0086] Prodrugs of the active compounds may also be used.

[0087] In a preferred embodiment, the solid active compound used as component a) has an average particle size D(50) of 100 nm to 50 pm, preferably 100 nm to 10 pm. In the context of the present invention, D(50) is understood as the volumetric particle size distribution at which 50% of all particles have a size (diameter) equal to or less than this value. The particle sizes indicated here were determined by laser diffraction using a Malvern Mastersizer 2000 instrument (Hydro 2000G dispersion unit) in the Fraunhofer diffraction evaluation mode, since the refractive index of the active compound particles is unknown. Here, an appropriate amount of sample is pre-dispersed in 2 to 3 mL of a dispersion medium (low-viscosity paraffin) while stirring. This dispersion is then placed in the dispersion unit of the instrument and measured. Depending on the settings, the evaluation software reports the particle size as the D(50), D(10), D(90), etc.

[0088] According to the present invention, the shaped body contains at least one active compound in a pharmaceutically effective amount, where "a pharmaceutically effective amount" refers to a non-toxic amount of active compound capable of producing the desired effect. The amount of active compound employed depends on the active compound, the animal to be treated, and the nature, severity, and stage of the disease.

[0089] In a preferred embodiment of the present invention, the shaped body of the present invention comprises one or more flavoring agents, preferably meat flavoring agents. Meat flavoring agents refer to additives of synthetic or animal origin, or a mixture of the two, that impart a meat-like odor and / or taste to the shaped body of the present invention. Particularly preferred are meat flavoring agents of purely animal origin. These are prepared, for example, from beef, chicken, fish, animal skin, or animal liver. Even more preferred are dried liver powders, for example, from cows, sheep, poultry, or pigs, with very particular preference from poultry or pigs.

[0090] The molded body of the present invention can contain a filler, which can reduce costs and further improve the texture properties of the molded body. According to a preferred embodiment of the present invention, the molded body contains one or more fillers selected from lactose, cellulose, lignosulfonates, and sparingly soluble inorganic salts. According to the present invention, a sparingly soluble salt is a salt having a solubility of less than 1 g in 100 g of water at 20°C. Dicalcium phosphate is particularly preferred as a sparingly soluble inorganic salt, and this expression within the meaning of the present invention includes both anhydrous dicalcium phosphate and dicalcium phosphate dihydrate.

[0091] In another preferred embodiment according to the invention, the one or more fillers contained by the compact are selected from lignosulfonates, in particular calcium lignosulfonate, sodium lignosulfonate, magnesium lignosulfonate, potassium lignosulfonate or mixtures thereof. When lignosulfonates are used as the one or more fillers contained by the compact, the amount is preferably kept to 8% by weight or less, in particular 5% by weight or less, and most preferably 3% by weight or less, based on the total weight of the compact.

[0092] In an alternative preferred embodiment according to the invention, the one or more fillers contained by the shaped body are selected from solid sugar alcohols and inorganic calcium, magnesium, sodium or potassium salts.

[0093] In another alternative preferred embodiment according to the invention, the one or more fillers contained by the shaped body are selected from solid sugar alcohols, lignosulfonates, and inorganic calcium, magnesium, sodium or potassium salts.

[0094] In a particularly preferred embodiment of the method, the sugar alcohol used as a filler is selected from the group consisting of compounds of the following formula:

[0095] [ka] wherein n>3 and <5, preferably n=3 or 4.

[0096] In a very particularly preferred embodiment of the method, the sugar alcohol used as filler is mannitol, xylitol or sorbitol.

[0097] According to a preferred embodiment, the shaped body of the invention comprises one or more fillers selected from the group consisting of lactose, cellulose, sparingly soluble inorganic salts, in particular dicalcium phosphate, solid sugar alcohols, in particular mannitol, xylitol or sorbitol, and inorganic calcium, magnesium, sodium or potassium salts.

[0098] According to an alternative preferred embodiment, the shaped body of the invention comprises one or more fillers selected from the group of lignosulfonates and solid sugar alcohols, in particular calcium lignosulfonate, sodium lignosulfonate, magnesium lignosulfonate, potassium lignosulfonate, mannitol, xylitol, sorbitol or mixtures thereof.

[0099] In a preferred embodiment of the present invention, the shaped body comprises one or more surfactants. Preferred surfactants are nonionic amphiphiles. It has been found that the shaped body according to the present invention, comprising one or more surfactants, preferably nonionic amphiphiles, exhibits particularly good bioavailability of pharmaceutical active substances.

[0100] According to the present invention, a nonionic amphiphile is a compound that has both hydrophilic, i.e., water-loving or polar, and lipophilic, i.e., fat-loving or non-polar, properties. In contrast to cationic, anionic, or zwitterionic amphiphiles, nonionic amphiphiles do not contain charged groups. Typically, nonionic amphiphile compounds are characterized by an uncharged hydrophilic head group. Examples of nonionic amphiphiles according to the present invention include, but are not limited to, detergents containing polyoxyethylene chains as the hydrophilic moiety. Examples include esters of fatty acids and / or glycerol containing polyoxyethylene chains, such as stearoyl polyoxyl-32 glyceride (Gelucire® 50 / 13, Gattefosse) or polyethylene glycol monostearate (Gelucire® 48 / 16, Gattefosse).

[0101] In a preferred embodiment of the present invention, the content of one or more surfactants, particularly nonionic surfactants, in the soft chewable shaped body is in the range of 0.1 to 15 wt. %, preferably 0.5 to 10 wt. %, more preferably 1 to 5 wt. %, and most preferably 2 to 4 wt. Here, the surfactant content in wt. % is defined as the quotient of the mass of all surfactants contained in the shaped body and the total mass of the shaped body multiplied by 100. Shaped bodies having such a surfactant content exhibit particularly good bioavailability of one or more pharmaceutically active substances while maintaining a particularly pleasant mouthfeel for animals. If the content of one or more surfactants in the shaped body exceeds 15 wt. %, it may be difficult to meet the requirements for optimal hardness and texture integrity of the shaped body. In a preferred embodiment of the present invention, the one or more surfactants, preferably nonionic amphiphiles, have a hydrophilic-lipophilic balance (HLB) in the range of 6 to 20, particularly in the range of 8 to 18 or 9 to 11. Such surfactants have been found to be particularly suitable for providing improved bioavailability whilst the compact retains excellent textural properties.

[0102] In the sense of the present invention, the HLB of a surfactant is a measure of how hydrophilic or lipophilic the surfactant is, and is determined by calculation according to the Griffin method. The HLB is calculated according to the following formula:

[0103]

number

[0104] The molded body of the present invention can contain different components in various amounts. According to a preferred embodiment, the molded body comprises: 1 to 25% by weight of one or more pharmaceutically active substances a), 1 to 25% by weight of one or more flavoring agents b), 1 to 20 wt. % of one or more binders c), 0.5 to 30 wt. % of one or more gel formers d), 0 to 50 wt. % of one or more fillers e), 2 to 30% by weight of water (f), 5 to 65% by weight of glycerol g), 0-20% by weight of one or more auxiliary additives, such as formulation aids, lubricants, disintegrants, surfactants, moisturizers and preservatives; Here, the percentages add up to a total of 100% by weight. When the shaped bodies contain the aforementioned components in these amounts, the shaped bodies have a particularly pleasant mouthfeel and a long shelf life.

[0105] According to another embodiment, the shaped body essentially consists of 0.1-25% by weight of one or more pharmaceutically active substances (a), 1-25% by weight of one or more flavoring agents (b), 1-20% by weight of one or more binders (c), 0.5-30% by weight of one or more gel-forming agents (d), 0-50% by weight of one or more fillers (e), 2-30% by weight of water (f), and 5-65% by weight of glycerol (g), where "essentially consisting of" means that the shaped body consists of at least 80% by weight, preferably at least 85% by weight, more preferably at least 90% by weight, or at least 97% by weight, or at least 98% by weight, or at least 99% by weight of the aforementioned components. The remaining 20% ​​by weight (or 15% by weight, or 10% by weight, or 3% by weight, or 2% by weight, or 1% by weight) can be auxiliary additives such as formulation aids, lubricants, disintegrants, surfactants, humectants, and preservatives. The gel-forming agent used in the shaped bodies of the present invention may have disintegrant properties (as explained above), but the composition may optionally contain an additional disintegrant depending on the particular properties desired. When an additional disintegrant is present as an auxiliary additive, it is typically present in an amount of 5 to 15% by weight, preferably 8 to 12% by weight, and most preferably 5 to 10% by weight.

[0106] According to a further embodiment, the compact of the invention does not contain a further disintegrant as a co-additive, in which case the co-additive is present in an amount of 0-10 wt%, or 0-3 wt%, or 0-2 wt%, or 0-1 wt%, or 1-10 wt%, or 1-3 wt%, or 1-2 wt%, and components a) to g) constitute at least 90 wt%, or at least 97 wt%, or at least 98 wt%, or at least 99 wt% of the compact.

[0107] According to another embodiment, the shaped body consists of 0.1-25% by weight of one or more pharmaceutically active substances a), 1-25% by weight of one or more flavorings b), 1-20% by weight of one or more binders c), 0.5-30% by weight of one or more gel-forming agents d), 2-30% by weight of water f) and 5-65% by weight of glycerol g).

[0108] The present invention further relates to the shaped bodies according to the invention for use in controlling parasites in non-human animals, in particular in dogs and / or cats.

[0109] In the field of animal health, i.e., veterinary medicine, the soft chew molding according to the present invention can be used against animal parasites, particularly ectoparasites or endoparasites.The term endoparasites includes in particular helminths and protozoa such as coccidia.Ectoparasites are typically and preferably arthropods, in particular insects and acarids.

[0110] In the field of veterinary medicine, the soft chew shaped bodies according to the invention are suitable for controlling parasites encountered in animal husbandry and husbandry of farm, breeding, zoo, laboratory, research and pet animals.

[0111] By using the active compounds according to the invention to control animal parasites, morbidity, mortality and loss of performance (meat, milk, wool, hides, eggs, honey, etc.) can be reduced and / or prevented, making animal rearing more economical and simpler and improving animal welfare.

[0112] In the field of animal health, the term "control" or "controlling" means that an active compound is able to effectively prevent the development of the target parasite in an animal infected with the parasite to a harmless extent. More precisely, "controlling" in this specification means that an active compound is able to kill, inhibit the growth of, or inhibit the proliferation of the target parasite. All definitions and embodiments described with respect to the molded bodies of the present invention also apply to molded bodies for use in controlling parasites in non-human animals.

[0113] The present invention further relates to a method for producing the molded article of the present invention.

[0114] The method of the present invention comprises the following steps: a) At least the following ingredients: a. one or more pharmaceutically active substances; b. One or more flavoring agents; c. one or more binders; d. one or more gel-forming agents; e. 1 or more fillers; f. optionally providing one or more auxiliary additives such as formulation aids, lubricants, surfactants, wetting agents, and preservatives; b) mixing the ingredients of step a) with glycerol and water to prepare a swelling mixture; c) forming a shaped body by extruding the swollen mixture prepared in step b); Includes stages.

[0115] The method of the present invention can reliably and efficiently produce molded articles at a high throughput rate. Furthermore, the method of the present invention can be carried out continuously, allowing the molded articles of the present invention to be produced quickly and at low cost.

[0116] The components of step a) are provided as solids and / or liquids. In a preferred embodiment, the components of step a) are provided as solids, preferably powders. When at least one of the components of step a) is provided as a liquid, the liquid typically comprises water apart from the components of step a).

[0117] In step b) of the method of the present invention, a swelling mixture is prepared. As used herein, the term "swelling mixture" refers to a mixture of component a), water, and glycerol that has been in contact for a period of time (the "swelling time," which is the total time from initial contact of component a) with water and / or glycerol to the formation of a body), preferably for at least 10 seconds, more preferably at least 30 seconds, and even more preferably at least 60 seconds. According to one embodiment, the swelling time is between 0.5 and 10 minutes, preferably between 1 and 6 minutes.

[0118] In one embodiment, the swelling mixture is prepared by providing a pre-mixture comprising the components of step a) and mixing the pre-mixture with water and glycerol or with a pre-mixture of water and glycerol.

[0119] It is also possible to prepare the swelling mixture of step b) by providing a pre-swelling mixture comprising water, glycerol and at least one (but not all) of the components of step a) and mixing the remaining components of step a) with said pre-swelling mixture. The remaining components of step a) that are mixed into the pre-swelling mixture can be in solid form, preferably powder, or in liquid form, optionally containing additional water and / or glycerol.

[0120] Depending on which solid pharmaceutical active substance is used to form the pre-swelling or swelling mixture, the pharmaceutical active substance may be at least partially dissolved in the mixture of water and glycerol contained therein.Experimental studies have shown that the pharmaceutical active substance praziquantel has high solubility in the mixture of water and glycerol.Without being bound by any particular scientific theory, it is believed that dissolution of the pharmaceutical active substance increases its bioavailability.

[0121] The pre-mixture comprising the components of step a), the pre-swelling mixture comprising water, glycerol and at least one (but not all) of the components of step a) and / or the swelling mixture of step b) are preferably obtained by mixing in a mixer, kneader or extruder. Most preferably, an extruder is used to obtain the pre-mixture comprising the components of step a), the pre-swelling mixture comprising water, glycerol and at least one (but not all) of the components of step a) and / or the swelling mixture of step b).

[0122] The feeding rate of the solid, preferably the powder, for preparing the swelling mixture of step b) is typically carried out using a powder feeder, and the feeding rate of the liquid for preparing the swelling mixture of step b) is typically carried out using a pump, preferably a dosing pump.

[0123] The shaped bodies of the present invention are formed by extrusion of the swollen mixture obtained in step b) The extruded swollen mixture leaving the extruder nozzle is typically cut into pieces.

[0124] Preferably, process step(s) b) and / or c) are carried out in an extruder, most preferably in one extruder. In a preferred embodiment, the entire process of the present invention is an extrusion process. In this way, the process can be carried out continuously, which allows for particularly high throughput rates and process efficiencies.

[0125] According to a preferred embodiment, the temperature during steps b) and / or c) is in the range of 10° C. to 80° C., preferably 15° C. to 70° C., most preferably 20° C. to 60° C. By carrying out steps b) and / or c) at these temperatures, a particularly homogeneous mixture can be obtained.

[0126] All definitions and embodiments described with respect to the shaped body of the present invention also apply to the method for producing the shaped body of the present invention.

[0127] The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. [Example]

[0128] All components for the preparation of the molded bodies of the present invention were purchased from commercial sources with sufficient purity and used without further purification unless otherwise noted. The pharmaceutical active substances used were praziquantel ((RS)-2-(cyclohexylcarbonyl)-2,3,4,6,7,11b-hexahydro-1H-pyrazino[2,1-a]isoquinolin-4-one), hydrochlorothiazide (6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide), and carprofen ((RS)-2-(6-chloro-9H-carbazol-2-yl)propanoic acid). Pig liver powder was used as the flavoring agent. Kollidon® 30 (polyvinylpyrrolidone; K value 30) from BASF SE was used as the binder. The gel-forming agent used was Ac-Di-Sol® SD-711 croscarmellose sodium (cross-linked sodium carboxymethylcellulose). The bulking agent used was Pearlitol® 160C (mannitol, average particle size 160 pm). The surfactants used were Gelucire® 48 / 16 and 50 / 13.

[0129] Manufacturing method In the manufacturing method of the examples, all solid ingredients were thoroughly mixed in a drum mixer, passed through a 0.5 mm mesh twice, and then fed into a gravimetric dossier feeder (K-CL-24-KT 20, K-Tron, Niederlenz, Switzerland) of a twin-screw extruder (Thermo Pharma HME 16, Thermo Fisher Scientific, Larlsruhe, Germany). The total screw length was 64 cm (= 40 D). The extruder settings and screw configurations used in the examples and comparative examples are summarized below.

[0130] torso : Torso Zone 1 Zone Configuration : Zone 1 - Powder Feed Zone 2 - Pre-swelling liquid supply (water) Zone 6 - Swelling liquid supply (anhydrous glycerol)

[0131] Screw Configuration : [Table 1] F = Flat kneading disc S = sharp kneading disc DF = Distributed Flow Element FE = Conveying element KB = kneading block

[0132] [Table 2]

[0133] Screw Length :640mm(=40D) Screw Diameter :16mm(=1D) Extrusion Parameters : Body temperature: 40°C (excluding zone 1 and die: unheated) Screw speed: 100 rpm Powder supply amount: 10g / min

[0134] First, the screw was wetted by adding water to Zone 2 at a rate of 1.81 g / min until the entire screw was wet and liquid was emerging from the nozzle. The powder mixture was then pumped via a dossier into Zone 1 of the extruder at a rate of 10 g / min. Anhydrous glycerol was then added to Zone 6 of the extruder at a rate of 8 g / min, and the mixture was homogeneously mixed. After waiting for several minutes (approximately 10 minutes), a soft, homogeneous, brown, moist mass was extruded through a 10 x 5 mm slit die / nozzle. The entire barrel, except for Zone 1 and the nozzle, was heated and maintained at 40°C. The screw was rotated at 100 rpm. The output from the extruder was 19.81 g / min.

[0135] Example 1 To produce the compacts, a mixture containing the components listed in Table 1 was first prepared in a mixing drum and then added to a gravimetric dossier feeder (K-CL-24-KT 20, K-Tron, Niederlenz, Switzerland) of a twin-screw extruder (Thermo Pharma HME 16, Thermo Fisher Scientific, Karlsruhe, Germany). The total screw length of the extruder was 64 cm (=40D).

[0136] Table 1: Ingredients of the solid mixture; amounts in wt. % based on the total weight of the solid mixture [Table 3]

[0137] Next, the solid mixture in Table 1 was fed into Zone 1 of the extruder using a gravimetric dossier feeder. The solid mixture was fed into the extruder at a rate of 10 g / min. Water was added to Zone 2 of the extruder using a pump at a rate of 1.81 g / min. The water and solid mixture were thoroughly mixed in Zones 2-5 of the extruder. Next, anhydrous glycerol was added to this mixture at a rate of 8.0 g / min in Zone 6 of the extruder. After waiting for several minutes (approximately 10 minutes), a soft, homogeneous, brown, moist mass was extruded through a 10 x 5 mm (width x height) slit die / nozzle. The extruder screw was rotated at a speed of 100 rpm.

[0138] The temperature profile of the different zones of the extruder during the extrusion process is shown in Table 2.

[0139] Table 2: Temperature profile during extrusion process of Example 1 [Table 4]

[0140] Examples 2 and 3 In Examples 2 and 3, molded bodies were produced in the same manner as in Example 1, with some changes made to the composition of the solid mixture. A portion of the polyvinylpyrrolidone (Kollidon® 30) was replaced with Gelucire, which has a different HLB value. The compositions of the solid mixtures in Examples 2 and 3 are shown in Table 3.

[0141] Table 3: Ingredients of the solid mixtures of Examples 2 and 3; amounts in weight % based on the total weight of the solid mixture [Table 5]

[0142] The temperature profile of the different zones of the extruder during the extrusion process is shown in Table 4.

[0143] Table 4: Temperature profile during the extrusion process of Examples 2 and 3 [Table 6]

[0144] Examples 4 and 5 In Examples 4 and 5, molded bodies were produced in the same manner as in Example 1. However, praziquantel was replaced by hydrochlorothiazide (Example 4) or carprofen (Example 5). Furthermore, the same active ingredient amounts as for praziquantel in Example 1 were used.

[0145] Examples 6, 7 and 8: In Examples 6, 7, and 8, compacts were prepared in the same manner as in Example 1, with slight changes in the composition of the solid mixture. Different amounts of magnesium lignosulfonate were added to the powder mixture. The compositions of the solid mixtures in Examples 6 to 8 are shown in Table 5.

[0146] Table 5: Ingredients of the solid mixtures of Examples 6 to 8; amounts in % by weight based on the total weight of the solid mixture [Table 7]

[0147] The hardness, disintegration properties and water activity of the extrusion molded products obtained in Examples 1 to 5, and the hardness of the extrusion molded products obtained in Examples 6 to 8 were measured by the following methods.

[0148] 1) Measurement of the hardness of the compact using a texture analyzer Device name: TA.XTplus, Stable Micro Systems Ltd., UK Software: "Exponenf"-Software Measuring device: aluminum stamp (round), diameter 0.5 cm ("indenter").

[0149] Parameters: Sample size: Approximately 3 cm in length, the width and height of the sample are determined by the nozzle of the extruder. Starting position: 15 mm above the sample plate Test mode: Compression test Test target: 25% deformation ("strain") Pre-test speed: 3.0 mm / s Test speed: 1.0 mm / s Post-test speed: 1.0 mm / s Number of cycles: 2 test cycles Trigger force: 0.049N (equivalent to 1g).

[0150] evaluation: Number of measurements: 3 "Quick calculation" Positive Peak Force Negative Peak Force

[0151] procedure: At the start of the test, the extrudate was placed on the sample plate so that it was at the center of the aluminum stamp. The parameters were set as described above using the software, and the measurement was started.

[0152] Simultaneously with the start of the measurement, the gauge screwed onto the pressure cell was moved downward at 3 mm / s (pre-test speed). As soon as the gauge came into contact with the sample (trigger force > 0.049 N), monitoring of the force (N) began, which depended on the time (seconds) and the position (mm) of the aluminum stamp. The aluminum stamp penetrated the sample to the depth required to achieve a 25% deformation relative to the initial sample height. Penetration by the stamp occurred at a speed of 1.0 mm / s (test speed). Once 25% deformation was achieved, the stamp was returned to its initial position at a speed of 1.0 mm / s (post-test speed) until it reached its initial height of 15 mm. As soon as the stamp reached its starting position, the next measurement cycle was initiated using the same sample (here, two cycles means that hardness measurements were performed twice, with the second measurement being performed immediately after the first).

[0153] When the stamp penetrated the sample in the first cycle, time-dependent monitoring of the force that had to be applied to deform the sample began (X-axis is time, Y-axis is force). Force versus time monitoring ended from the second cycle onwards, when the aluminum stamp reached the starting position.

[0154] A total of three samples were characterized as described above for each example provided.

[0155] The software's "Quick calculation" function was used to evaluate the measurement results. Here, the evaluation parameters "positive peak force" and "negative peak force" were activated, and the measurement results were analyzed by the software. As a result, the positive and negative forces of each cycle were provided separately as average values ​​with standard deviations as output by the software.

[0156] After each measurement, the sample plate and aluminum stamp were cleaned with paper tissue and, if necessary, with ethanol (aqueous solution, 70%).

[0157] The hardness profile over the measurement time provides some information about the textural properties of the sample (see, for example, Szczesniak, AS (1963), Classification of textural characteristics, Journal of Food Science 28(4): 385-389). For example, the profile of Example 1 in Figure 5 shows that the sample is elastic with slight plastic deformation (the second cycle peak is lower than the first peak). Also, from the shape of the peaks, it can be concluded that this sample is not brittle.

[0158] 2) Measurement of the disintegration behavior of the sample Device name: PTZ AUTO 1EZ, Pharma Test Apparatebau AG, Germany Sample holder: 6-position "Type A" disintegration basket (corresponding to 2.9.1, Ph. Eur. 10, 2, Test A - Regular-sized tablets and capsules)

[0159] Parameters: Sample Preparation: Samples were cut into approximately 1.3 cm pieces representing 25 mg of API (single dose) per chew. Temperature setting: 38℃ (±1℃) Test volume: 900mL Threshold: 600 Mode: Automatic Endpoint Detection

[0160] procedure: First, the sample was cut into 1.3 cm long pieces. Next, each cut sample was placed in a digestion tube and weighted with a digestion disk for automatic endpoint detection. To begin the measurement, the PTZ AUTO 1EZ was started and the temperature was regulated to 38°C using an internal heating unit. Once the operating temperature was reached, the measurement was initiated. The end of the measurement was indicated when the sample disintegrated and each disk individually operated to stop the disintegration time. The measured disintegration time was obtained from the instrument output.

[0161] 3) Measurement of water activity (aw) using the Rotronic HC2-A W-USB water activity measuring head: Device name: HC2-AW-USB measuring head, Rotronic Messgeraete GmbH, Germany Software: HW4-Software Sample container: PS-14 (Rotronic) Sample cup: WP-40 (Rotronic) Target parameters of measurement: Constancy of temperature and water activity (deviation: temperature: 0.02°C, water activity: 0.0002) Sample preparation: To avoid misinterpretation of the measurements, samples were stored in sealed aluminum blisters at the measurement temperature for at least 12 hours and then transferred to a sample container approximately 1 hour before the start of the measurements.

[0162] evaluation: Number of measurements: 1 (continuous) Measurement method: Direct measurement of water activity (as relative equilibrium moisture)

[0163] procedure: Because water activity is strongly temperature-dependent, each sample was measured directly after production or stored in a sealed aluminum blister under measurement conditions for at least 12 hours. The extrusions were filled into a PS-14 sample container so that the bottom was covered with the extrusions up to the edge. The sample container was then closed.

[0164] To begin the measurement, the HW-4 software was started. The cap covering the sample container was removed and the bottom of the sample container was placed in the WP-40 sample cup. This was done at a pace that prevented any changes in the moisture equilibrium on the sample, which could have skewed the measurement. The HC2-AW-USB measurement head was attached to the sample cup.

[0165] The target parameters for the measurement were set by the software and the measurement was started. The measurement continued until the temperature and water activity did not change beyond the tolerance limits mentioned above. The end of the measurement was indicated by the software and the measured water activity value was obtained from the software output.

[0166] Example 7 In Example 7, ternary croscarmellose-glycerol-water mixtures were prepared. For this purpose, liquid glycerol-water premixes were prepared in different ratios and stirred with a spatula until a homogeneous suspension was produced. The ratios used for the water and glycerol liquid premixes are summarized in Table 6.

[0167] Table 6: Water and glycerol premixes used [Table 8]

[0168] To obtain a gel-like structure, 1 g of croscarmellose sodium was weighed into a snap-top glass. 7 g of a premix of water and glycerol was transferred directly onto the powder using a syringe. The resulting suspension was stirred with a spatula for at least 10 seconds to obtain a homogeneous-looking mixture, after which the evolving gel was analyzed for hardness.

[0169] A texture analyzer (TA.XTplus, Stable Micro Systems) equipped with a 5 kg pressure cell and a 0.5 cm aluminum punch as an indenter was used. The maximum positive force applied to the sample at 25% strain was defined as hardness [N]. The hardness of each gel was recorded after a given storage time. Initially, the system was too soft to measure. Therefore, the first 30 min of recording was cut.

[0170] result The results of the examples are shown in FIGS.

[0171] 1 shows the hardness profiles for Examples 1 to 5, n=3±standard deviation. For all Examples, the hardness of the analyzed samples remained nearly unchanged over the analysis period.

[0172] 2 shows water activity plots for Examples 1 to 5, n=1. For all Examples, the water activity of the analyzed samples remained nearly unchanged over the analysis period.

[0173] 3 shows the disintegration times shown for Examples 1-5, n=3 or n=6 ± standard deviation. For all Examples, the disintegration times of the analyzed samples were measured to be less than 20 minutes.

[0174] FIG. 4 shows hardness profiles for gel-like croscarmellose-glycerol-water mixtures that differ in glycerol content in the liquid phase (see Table 6 in Example 7), cutoff <30 min, n=3±standard deviation.

[0175] FIG. 5 shows the hardness change (2 cycles) of the sample of Example 1 over the measurement time.

[0176] 6 shows the hardness profiles for Examples 6-8, n=3±standard deviation. For all Examples, the hardness of the analyzed samples remained nearly unchanged over the analysis period.

Claims

1. a. one or more pharmaceutically active substances; b. one or more flavoring agents; c. one or more binders; d. one or more gel-forming agents; e. one or more fillers; f. Water, and g. glycerol, wherein the weight ratio of the gel-forming agent d) to the total weight of the water f) and glycerol g) in the molded body is in the range of 1:2 to 1:20; and wherein the weight ratio of water (f) to glycerol (g) in the molded body is 15:85 to 25:75; A shaped body for administration to animals.

2. 2. The molded body according to claim 1, wherein the weight content of the gel-forming agent d) in the molded body is in the range of 0.5 to 30% by weight based on the total weight of the molded body.

3. 2. The molded body according to claim 1, wherein the weight content of the gel-forming agent d) in the molded body is in the range of 1 to 25% by weight based on the total weight of the molded body.

4. 2. The molded body according to claim 1, wherein the weight content of the gel-forming agent d) in the molded body is in the range of 2 to 20% by weight based on the total weight of the molded body.

5. 2. The molded body according to claim 1, wherein the weight content of the gel-forming agent d) in the molded body is in the range of 3 to 17% by weight based on the total weight of the molded body.

6. 2. The molded body according to claim 1, wherein the weight content of the gel-forming agent d) in the molded body is in the range of 5 to 15 wt. % based on the total weight of the molded body.

7. The molded body according to any one of claims 1 to 6, wherein the weight ratio of the gel-forming agent d) to the total weight of water f) and glycerol g) in the molded body is in the range of 1:3 to 1:

15.

8. The molded body according to any one of claims 1 to 6, wherein the weight ratio of the gel-forming agent d) to the total weight of water f) and glycerol g) in the molded body is in the range of 1:5 to 1:

10.

9. The molded body according to any one of claims 1 to 6, wherein the weight ratio of the gel-forming agent d) to the total weight of water f) and glycerol g) in the molded body is in the range of 1:6 to 1:

8.

10. 10. The shaped body according to claim 1, wherein the one or more gel-forming agents d) are selected from the group consisting of croscarmellose, low-substituted carboxymethylcellulose, low-substituted hydroxypropylcellulose, crospovidone and cross-linked sodium carboxymethyl starch.

11. a. The moisture content of the compact is in the range of 0.5 to 20 wt. % based on the total weight of the compact; and / or b. The water activity (aw) value is 0.60 or less; The molded article according to any one of claims 1 to 10.

12. The molded body of claim 11, wherein the moisture content of the molded body is in the range of 0.75 to 18 wt % based on the total weight of the molded body.

13. The molded body according to claim 11, wherein the moisture content of the molded body is in the range of 1.0 to 15 wt % based on the total weight of the molded body.

14. The molded body of claim 11, wherein the moisture content of the molded body is in the range of 1.5 to 13 wt % based on the total weight of the molded body.

15. a. The moisture content of the molded body is in the range of 1.75 to 11.5 wt % based on the total weight of the molded body; The molded article according to claim 11.

16. The molded article according to claim 11, wherein the water activity aw value is in the range of 0.20 to 0.

58.

17. The molded article according to claim 11, wherein the water activity aw value is in the range of 0.30 to 0.

55.

18. The molded body according to any one of claims 1 to 17, wherein the one or more binders c) are selected from the group consisting of polyvinylpyrrolidone, croscarmellose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, pectin, pullulan, carrageenan, xanthan gum, alginic acid and agar.

19. 19. The shaped body according to any one of claims 1 to 18, wherein the gel-forming agent d) comprises or consists of croscarmellose and the binder c) comprises or consists of polyvinylpyrrolidone.

20. 20. The molded body according to any one of claims 1 to 19, wherein at least one of the one or more pharmaceutically active substances a) is selected from the group of orally administrable systemically active veterinary drugs.

21. 21. The molded body according to any one of claims 1 to 20, wherein the one or more flavorings b) are selected from the group of natural or artificial meat, poultry, fish and seafood flavorings.

22. 21. The molded body according to any one of claims 1 to 20, wherein the one or more flavouring agents b) are selected from the group of dried meat, poultry and fish powders.

23. The molded body according to any one of claims 1 to 20, wherein the one or more flavoring agents b) are selected from the group of pork liver powders.

24. The shaped body according to any one of claims 1 to 13, wherein the one or more fillers e) are selected from the group consisting of lactose, cellulose, sparingly soluble inorganic salts, solid sugar alcohols, and inorganic calcium, magnesium, sodium or potassium salts.

25. 25. The molded body according to claim 24, wherein the sparingly soluble inorganic salt is dicalcium phosphate and the solid sugar alcohol is mannitol, xylitol or sorbitol.

26. 0.1 to 25% by weight of one or more pharmaceutically active substances a), 1 to 25% by weight of one or more flavoring agents b), 1 to 20 wt. % of one or more binders c), 0.5 to 30 wt. % of one or more gel formers d), 0 to 50 wt. % of one or more fillers e), 2 to 30% by weight of water f), 5 to 65% by weight of glycerol g), 0-20% by weight of one or more auxiliary additives, where these percentages are added to total 100% by weight; The molded article according to any one of claims 1 to 25.

27. 27. The molded body according to claim 26, wherein the one or more auxiliary additives are selected from the group consisting of formulation aids, lubricants, disintegrants, surfactants, moisturizers and preservatives.

28. A shaped body according to any one of claims 1 to 27 for use in controlling parasites in non-human animals.

29. A shaped body according to any one of claims 1 to 27 for use in controlling parasites in dogs and / or cats.

30. The following steps: a) at least the following ingredients: a. one or more pharmaceutically active substances; b. one or more flavoring agents; c. one or more binders; d. one or more gel-forming agents; e. one or more fillers; b) preparing a swelling mixture by mixing the ingredients of step a), glycerol, and water; c) forming a shaped body by extruding the swollen mixture prepared in step b); The steps include: wherein the weight ratio of the gel-forming agent d) to the total weight of the water f) and glycerol g) in the molded body is in the range of 1:2 to 1:20; and wherein the weight ratio of water (f) to glycerol (g) in the molded body is 15:85 to 25:75; A method for producing the molded article according to any one of claims 1 to 26.

31. 31. The method of claim 30, further comprising providing one or more auxiliary additives in step a).

32. 32. The method of claim 31, wherein the one or more auxiliary additives are selected from the group consisting of formulation aids, lubricants, disintegrants, surfactants, humectants, and preservatives.

33. 33. The method of any one of claims 30 to 32, wherein steps b) and / or c) are carried out in an extruder.

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