Starch-free soft chews for veterinary applications

Abstract

The present invention relates to a starch-free soft chew formulation for oral delivery of at least one active ingredient to an animal, and a starch-free soft chew containing the formulation and at least one active ingredient. The starch-free soft chew comprises one or more active ingredients and excipients, such as bulking agents, flavoring agents, humectants, preservatives, antioxidants, and lubricants, but no added water. Furthermore, the present invention relates to a composition of starch-free non-aqueous excipients for use in a final dosage form of a soft chew for oral administration of at least one active ingredient to an animal. Methods for manufacturing the starch-free soft chew formulation and the starch-free soft chew are also provided.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 537,273, filed July 26, 2017, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates generally to soft chewing materials, and more particularly to starch-free soft chewing compositions and methods for preparing such compositions suitable for animal and veterinary applications. Background Technology

[0004] Chewable compositions suitable for oral delivery of pharmaceutical compounds and other agents are well known. Many pharmaceutical compounds that are otherwise unpalatable as a result of unacceptable tastes due to factors such as acidity, bitterness, a tingling or burning sensation in the throat, or lack of flavor can often be made palatable through suitable coatings, capsules, or flavorings. In a veterinary context, chewable compositions (with suitable flavorings if desired) are preferred because encouraging animals to swallow whole tablets or capsules can be challenging.

[0005] Currently, some chewable drug products on the market for animal use do not possess desirable physicochemical properties (e.g., they have high water content, a hard texture, slow disintegration, poor dissolution in physiologically relevant media, etc.). Older soft chewable drug products on the market for animal use exhibit poor in vitro disintegration and dissolution, failing to meet current U.S. Food and Drug Administration (FDA) regulations regarding in vitro dissolution. Only recently have regulatory agencies begun requiring the use of identifying in vitro dissolution methods to test the dissolution of drug products. Identifying dissolution methods should be able to detect changes in formulation, raw material properties, and process parameters during the manufacturing process of the drug product. Therefore, there is a need for a new soft chewable formulation that meets regulatory requirements for dissolution in physiologically relevant media.

[0006] Numerous patents exist relating to chewable compositions. For example, U.S. Patent No. 5,637,313 discloses a soft chewable dosage form comprising a matrix of hydrogenated starch hydrolysate, a water-soluble leavening agent, and a water-insoluble leavening agent. This patent also discloses a method for preparing the soft chewable dosage form, comprising the step of mixing the hydrogenated starch hydrolysate, the water-soluble leavening agent, and the water-insoluble leavening agent under high shear stress.

[0007] The importance of water for the stability of chewable oral delivery systems has been recognized. Controlling the water content in a product affects not only microbial rancidity but also chemical and physical stability. U.S. Patent No. 6,387,381 discloses a carrier formed from a matrix having suitable ratios of starch, sugar, fat, polyol, and water. This patent explains that controlling the water activity in the oral delivery system is its primary objective; it describes the ability to adjust the water activity of the product matrix upwards or downwards so that the water utilization in the finished product is not detrimental to the contained active ingredient, which may be a pharmaceutical, nutritional supplement, or vitamin-mineral complex.

[0008] U.S. Patent No. 7,955,632 discloses a delicious, edible, soft, chewable drug delivery vehicle for delivering pharmaceutically acceptable active ingredients, such as drugs, to animal or human subjects. The edible soft chew contains only food-grade or better inactive ingredients, including various starches, and preferably no animal-derived ingredients. The method for manufacturing the edible soft chew does not require the use of heat during the mixing of the active and inactive ingredients, and this disclosure claims to provide a stable concentration of the active ingredient and produce chewables with consistent weight and texture.

[0009] U.S. Patent No. 8,541,019 discloses a delicious, stretchable, chewable veterinary composition for oral administration. This composition is capable of killing endoparasites and ectoparasites and / or can be used to treat preventative or curative animal diseases, and can be used to treat any warm-blooded non-human animal, including herd animals such as horses, cattle, sheep, or poultry, and preferably pets such as dogs and cats. It essentially consists of an effective amount of one or more ingredients effective against animal pests, pathogens, or animal diseases, meat seasoning, partially gelatinized starch, a softener, and up to 9% water. According to the patent, if the mixture of excipients and active ingredients does not contain moisture, water should be added during the extrusion process to improve the flexibility of the chewable veterinary composition.

[0010] As noted above, although several patents discuss palatable chewable oral dosage forms for delivering drug ingredients to animals, there remains a need to produce animal soft chewables that meet current FDA requirements for dissolution testing, particularly the FDA's requirement to use identification dissolution methods to test drug products. Furthermore, existing chewable oral dosage forms for delivering drug ingredients to animals contain starch as an essential ingredient. Starch is a well-known pharmaceutical excipient with a high moisture content. The high level of moisture contained in starch makes it unsuitable for pharmaceutical formulations where the moisture content must be consistent, including formulations of moisture-sensitive drugs.

[0011] Therefore, although chewable compositions are known, improvements are desirable, especially regarding the stability of soft chewable products and the development of identification dissolution methods for testing them. Summary of the Invention

[0012] As described herein, the inventors seek to develop a palatable, soft-chewable oral dosage form for administering pharmaceuticals or nutritional supplements to animals that avoids some of the challenges of existing soft chewables. For example, the inventors seek to prepare a soft chewable that will meet FDA requirements for dissolution in physiologically relevant media. They also seek to develop a soft chewable with a low water content and that retains suitability for water-sensitive active ingredients. Therefore, an object of the present invention is to provide an improved soft-chewable composition and a method for preparing such a composition suitable for administering pharmaceuticals and other active ingredients to animals.

[0013] As discussed in more detail below, the inventors have developed a soft chewable oral dosage form that does not contain starch and does not require the addition of water to the process. With these characteristics, the inventors' soft chewable formulation is particularly suitable for moisture-sensitive pharmaceuticals.

[0014] According to one aspect of the invention, a soft chewable is provided, comprising one or more pharmaceutically active or nutritionally active ingredients and a plurality of excipients. The soft chewable does not contain added water and the plurality of excipients does not contain starch. The excipients may comprise fillers, flavoring agents or taste enhancers, humectants, solvents, softeners, preservatives, antioxidants, and lubricants. In one embodiment, the plurality of excipients comprises at least two dry or solid components and at least two wet or liquid components. In another embodiment, the solid components do not contain starch as an excipient, and the liquid components do not contain water as an excipient. In yet another embodiment, the solid components comprise at least dicalcium phosphate (e.g., anhydrous, monohydrated, or dihydrated) and microcrystalline cellulose, the liquid components comprise at least glycerol and medium-chain triglycerides, and the soft chewable does not contain added water, and the filler does not contain starch. In yet another embodiment, the plurality of excipients further comprises at least one flavoring agent. In still another embodiment, the plurality of excipients are pharmaceutical grade.

[0015] According to another aspect of the invention, a method for manufacturing soft chewables is provided. The method includes dry mixing multiple dry ingredients in a mixer; wet agglomerating a dough-like material by adding multiple liquid ingredients to the mixer; shaping the dough-like material into a strip; dividing the strip into soft chewable portions of predetermined lengths; and packaging the soft chewable portions. The dry ingredients do not contain starch as an excipient, and the liquid ingredients do not contain water as an excipient.

[0016] According to another aspect of the invention, a starch-free excipient composition is provided for a final dosage form of a soft chewable without making the use of starch or added water necessary. In one embodiment, the starch-free excipient composition comprises at least two solid components and at least two liquid components. In another embodiment, the solid components do not contain starch as an excipient, and the liquid components do not contain water as an excipient. In yet another embodiment, the solid components contain at least calcium hydrogen phosphate dihydrate and microcrystalline cellulose, the liquid components contain at least glycerol and medium-chain triglycerides, and starch or added water is not required. In yet another embodiment, the starch-free excipient composition is a carrier for the oral administration of a pharmaceutically active ingredient that is sensitive to moisture. In yet another embodiment, the starch-free excipient composition further comprises at least one flavoring agent. In still another embodiment, all excipients are pharmaceutical grade.

[0017] In another aspect, the present invention relates to a soft chewable material comprising a pharmaceutically active ingredient and a plurality of excipients. In some embodiments, the soft chewable material does not contain added water and the plurality of excipients does not contain starch.

[0018] In one embodiment, the various excipients in the soft chewable include fillers, flavoring agents, humectants, solvents, softeners, preservatives, antioxidants, and lubricants. Exemplary fillers include calcium dicalcium phosphate dihydrate (DiCal), microcrystalline cellulose (MCC), lactose, and any combination thereof. In one exemplary embodiment, the filler is 15%-90% w / w of dicalcium phosphate dihydrate in the soft chewable. Exemplary solvents include caprylic / capric triglycerides, medium-chain triglycerides (MCT), long-chain triglycerides (LCT), and any combination thereof. Exemplary softeners include magnesium stearate, stearic acid, sodium stearoyl fumarate, and any combination thereof.

[0019] In another embodiment, the multiple excipients may further comprise binders and / or disintegrants and / or surfactants. Exemplary binders comprise povidone, hydroxypropyl cellulose (HPC), hydroxymethyl cellulose (HPMC), and any combination thereof.

[0020] In one exemplary embodiment, the soft chewable contains: 15%-90% w / w dicalcium phosphate dihydrate; 5%-30% w / w flavoring; 5%-40% w / w microcrystalline cellulose; 0%-15% w / w croscarmellose sodium; 0%-5% w / w sodium stearoyl fumarate; 15%-50% w / w glycerol; 15%-50% w / w medium-chain triglycerides; 0%-5% w / w anhydrous citric acid; 0.01%-3% w / w potassium sorbate; and 0.01%-3% w / w DL-α-tocopherol acetate.

[0021] In another aspect, the present invention relates to a method for manufacturing the soft chewable by: (a) dry mixing multiple dry ingredients in a mixer; (b) wet agglomerating a dough-like material by adding multiple liquid ingredients to the mixer; (c) shaping the dough-like material into a strip; (d) dividing the strip into soft chewable portions of predetermined lengths; and (e) packaging the soft chewable portions.

[0022] In one embodiment of the method, the plurality of dry components comprises at least one pharmaceutically active ingredient. In another embodiment of the method, the plurality of liquid components comprises at least one pharmaceutically active ingredient.

[0023] In another embodiment of the method, the plurality of dry components includes at least one of fillers, flavoring agents, humectants, solvents, softeners, preservatives, antioxidants, and lubricants, and the plurality of liquid components includes at least one of fillers, flavoring agents, humectants, solvents, softeners, preservatives, antioxidants, and lubricants.

[0024] In one embodiment of the method, the mixer can be a low-shear mixer or a high-shear mixer. In another embodiment of the method, a portioning tool can be used for cutting.

[0025] In another aspect, the present invention relates to a starch-free soft chewable formulation for oral delivery of at least one active ingredient to animals. In some embodiments, the soft chewable formulation comprises a plurality of starch-free excipients. These starch-free excipients may comprise, for example, non-starch solid excipients and non-aqueous liquid excipients. Some embodiments comprise at least two non-starch solid excipients and at least two non-aqueous liquid excipients. In some embodiments, the soft chewable formulation is manufactured without the addition of water as an excipient.

[0026] Exemplary starch-free excipients used in this soft chewing formulation include, but are not limited to, at least one filler, humectant, solvent, softener, and lubricant. In some embodiments, the plurality of starch-free excipients includes at least two fillers. In some embodiments, the plurality of starch-free excipients further includes at least one of a flavoring agent, a binder, a disintegrant, and a surfactant.

[0027] In some embodiments of this soft chewing formulation, the at least two non-starch solid excipients comprise dicalcium phosphate and microcrystalline cellulose. In some embodiments, the at least two non-starch solid excipients comprise dicalcium phosphate, microcrystalline cellulose, and lactose (e.g., lactose monohydrate). Exemplary dicalcium phosphate suitable for this soft chewing formulation comprises, but is not limited to, hydrated dicalcium phosphate, such as dicalcium phosphate dihydrate. In some embodiments, the weight ratio of dicalcium phosphate to microcrystalline cellulose is about 1:1 to 4:1 or about 2:1 to 3:1.

[0028] In some embodiments of this soft chewing formulation, the at least two non-aqueous excipients comprise glycerol and triglycerides of a fatty acid having a carbon chain length of C6-C12. Exemplary fatty acid triglycerides suitable for this soft chewing formulation include, but are not limited to, caprylic / capric triglycerides and medium-chain triglycerides. In some embodiments, the weight ratio of glycerol to the triglyceride of the fatty acid is about 4:1 to 7:1 or about 5:1 to 6:1.

[0029] In some embodiments, the soft chewing formulation further comprises one or more of the following: croscarmellose sodium; magnesium stearate, stearic acid, or sodium stearoyl fumarate; citric acid (e.g., anhydrous citric acid); potassium sorbate; α-tocopherol (e.g., DL-α-tocopherol acetate); and povidone, hydroxypropyl cellulose, or hydroxymethyl cellulose.

[0030] In some embodiments of this soft chewable formulation, the multiple starch-free excipients comprise calcium hydrogen phosphate dihydrate, microcrystalline cellulose, glycerol, and medium-chain triglycerides. In some embodiments, the weight ratio of calcium hydrogen phosphate dihydrate to microcrystalline cellulose is about 2:1 to about 3:1. In some embodiments, the weight ratio of glycerol to medium-chain triglycerides is about 5:1 to 6:1.

[0031] In one embodiment, the soft chewing formulation comprises: calcium hydrogen phosphate dihydrate; microcrystalline cellulose; flavoring agent; croscarmellose sodium; glycerol; medium-chain triglycerides; and magnesium stearate or sodium stearoyl fumarate. By way of example, in some embodiments, the soft chewing formulation comprises calcium hydrogen phosphate dihydrate, microcrystalline cellulose, flavoring agent, croscarmellose sodium, glycerol, medium-chain triglycerides, and magnesium stearate in a weight ratio of about 25:8:30:5:25:5:2 or about 30:10:23:5:25:5:2. In some embodiments, the soft chewing formulation further comprises: anhydrous citric acid; potassium sorbate; and DL-α-tocopherol acetate.

[0032] In another aspect, the present invention also relates to a starch-free soft chewable for orally delivering at least one active ingredient to animals. The soft chewable comprises a starch-free soft chewable formulation (such as one described above) and at least one active ingredient. In some embodiments, the soft chewable formulation is manufactured without adding water as an excipient.

[0033] In some embodiments of this soft chewable, the at least one active ingredient comprises an active pharmaceutical ingredient, such as an antiparasitic drug (e.g., a darticide). Exemplary active pharmaceutical ingredients suitable for this soft chewable include, but are not limited to, milbemycin oxime, ivermectin, moxidectin, abamectin, selamectin, pyrantel (e.g., pyrantel pamoate), febantel, fenbendazole, oxibendazole, emodepside, piperazine, mebendazole, levamisole, praziquantel, and oxantel. In some exemplary embodiments, the active pharmaceutical ingredient is milbemycin oxime, praziquantel, ivermectin, or pyrantel. In some embodiments, the at least one active ingredient further comprises a second active pharmaceutical ingredient, such as an antiparasitic drug (e.g., a darticide). In some embodiments of the soft chewable, the at least one active ingredient comprises: milbemycin oxime or ivermectin; and praziquantel or pyrantel pamoate. For example, in some embodiments, the at least one active ingredient comprises milbemycin oxime and praziquantel. In some embodiments, the at least one active ingredient comprises ivermectin and pyrantel pamoate.

[0034] In some embodiments of this soft chewable, the at least one active ingredient is moisture-sensitive. By way of example, in some embodiments, the at least one active ingredient may comprise a moisture-sensitive active pharmaceutical ingredient, such as clavulanic acid, nitenpyram, milbemycin oxime, or ivermectin.

[0035] In some embodiments of this soft chewable, the at least one active ingredient comprises an active nutrient. Exemplary active nutrients used in this soft chewable include, but are not limited to, glucosamine, enzymes, fish oil, herbal ingredients, etc.

[0036] In one exemplary embodiment of the soft chewable, the soft chewable formulation comprises: 15%-90% w / w calcium hydrogen phosphate dihydrate; 5%-30% w / w flavoring; 5%-40% w / w microcrystalline cellulose; 0%-15% w / w croscarmellose sodium; 0%-5% w / w sodium stearoyl fumarate or magnesium stearate; 15%-50% w / w glycerol; 15%-50% w / w medium-chain triglycerides; 0%-5% w / w anhydrous citric acid; 0.01%-3% w / w potassium sorbate; and 0.01%-3% w / w DL-α-tocopherol acetate. In another exemplary embodiment of the soft chewable, the soft chewable formulation comprises: 10%-60% w / w calcium hydrogen phosphate dihydrate; 5%-35% w / w flavoring; 5%-40% w / w microcrystalline cellulose; 0%-15% w / w croscarmellose sodium; 0%-5% w / w sodium stearoyl fumarate or magnesium stearate; 15%-50% w / w glycerol; 2%-20% w / w medium-chain triglycerides; 0%-5% w / w anhydrous citric acid; 0.01%-3% w / w potassium sorbate; and 0.01%-3% w / w DL-α-tocopherol acetate.

[0037] In another aspect, the present invention relates to a composition of a starch-free, non-aqueous excipient for use in a final dosage form of a soft chewable for oral administration of at least one active ingredient to animals. The composition consists essentially of a non-starch solid excipient and a non-aqueous liquid excipient, and the starch-free, non-aqueous excipient comprises: dicalcium phosphate (e.g., hydrated dicalcium phosphate, such as dicalcium phosphate dihydrate); microcrystalline cellulose; glycerol; and triglycerides of fatty acids having a carbon chain length of C6-C12. In one embodiment, the weight ratio of dicalcium phosphate to microcrystalline cellulose is from about 1:1 to about 4:1 (e.g., from about 2:1 to about 3:1).

[0038] The triglycerides of exemplary fatty acids suitable for use in this composition include, but are not limited to, caprylic triglyceride, capric triglyceride, and mixtures thereof. In some embodiments, the triglyceride of the fatty acid is a medium-chain triglyceride. In some embodiments, the weight ratio of glycerol to the triglyceride of the fatty acid is about 4:1 to 7:1 (e.g., about 5:1 to 6:1).

[0039] In some embodiments of the composition, the starch-free non-aqueous excipient further comprises at least one of the following: a filler, such as lactose (e.g., lactose monohydrate); a flavoring agent; a disintegrant, such as croscarmellose sodium; a lubricant, such as magnesium stearate, stearic acid, sodium stearoyl fumarate; a preservative, such as citric acid, potassium sorbate; an antioxidant, such as citric acid (e.g., anhydrous citric acid), α-tocopherol (e.g., DL-α-tocopherol acetate); and a binder, such as povidone (e.g., povidone K30).

[0040] Exemplary active ingredients used in this composition include, but are not limited to, active pharmaceutical ingredients and active nutritional ingredients. For example, the at least one active ingredient may include an active pharmaceutical ingredient, such as an antiparasitic drug (e.g., a darticide). In some embodiments, the at least one active ingredient includes an active nutritional ingredient.

[0041] In another aspect, the present invention relates to a method for manufacturing a starch-free soft chewable for oral delivery of at least one active ingredient to an animal by: (a) dry-mixing at least two non-starch dry excipients in a mixer (e.g., a low-shear mixer or a high-shear mixer); and (b) mixing the dry excipients into a dough-like material by adding at least two non-aqueous liquid excipients to the mixer (e.g., by sequentially adding the at least two non-aqueous liquid excipients to the mixer). In some embodiments, the method includes at least one of the following additional steps: (c) shaping the dough-like material into a strip; (d) portioning the strip into soft chewable portions (e.g., using a portioning tool); and (e) packaging the soft chewable portions. In some embodiments, the method further includes the step of dry-mixing the at least one active ingredient with the starch-free dry excipients. In some embodiments, the method is carried out at ambient room temperature.

[0042] In some embodiments of the method, the at least two non-aqueous liquid excipients comprise a humectant (e.g., glycerol) and a solvent (e.g., medium-chain triglycerides). By way of example, and not limited to, the humectant may be added to the mixer first, and the solvent may be added to the mixer thereafter.

[0043] In some embodiments, the method further includes the step of mixing the at least one active ingredient with one of the non-aqueous liquid excipients. By way of example, and but not limited to, the at least one active ingredient may be mixed with the solvent.

[0044] Details of one or more embodiments are set forth in the description below. Other features and advantages will be apparent from this specification and the claims. Attached Figure Description

[0045] The features and advantages of the embodiments of this application will become apparent from the following detailed description and accompanying drawings: wherein:

[0046] Figure 1 This is a simplified flowchart illustrating an exemplary manufacturing method for preparing a soft chewable food according to one embodiment of the present invention;

[0047] Figure 2 It demonstrates the preparation of... Figure 1 A simplified flowchart of the process steps involved in the manufacturing of dry components;

[0048] Figure 3 This is a simplified flowchart illustrating an exemplary manufacturing method for preparing an embodiment of the soft chewable food described herein;

[0049] Figure 4 This is a graph showing the average dissolution rate of milbemycin oxime from 2.5 g portions of soft chewable A from Example 1, stored at 25ºC and 60% relative humidity (RH) for 6 months; and

[0050] Figure 5 This is a graph showing the average dissolution of praziquantel from 2.5 g portions of soft chewable A from Example 1, which was stored at 25ºC and 60% relative humidity (RH) for 6 months. Detailed Implementation

[0051] This invention discloses a composition or dosage form suitable for the oral delivery of one or more pharmaceutically active ingredients and other pharmaceutical agents, including nutritional supplements, which are particularly well-suited for treating companion animals such as dogs, cats, or other pets. More specifically, the inventors herein describe soft chewables as the final dosage form of a formulation of a veterinary drug or nutritional ingredient and excipients used in such soft chewables. Embodiments of soft chewables can enhance the stability and bioavailability of the pharmaceutically active ingredients contained therein, can exhibit structural integrity to retain an adequate amount of flavoring, and / or can maintain a soft and pliable texture over time. Embodiments of soft chewables can also inhibit microbial growth and exhibit improved shelf life. Furthermore, embodiments of the soft chewable formulations described herein perform well in dynamic dissolution tests of pharmaceutical products.

[0052] The main chemical reactions affecting drug stability are generally considered to be oxidation and hydrolysis. Oxidation involves the removal of electrons from molecules (or the addition of oxygen); oxidation reactions can be initiated by light, heat, or certain trace metals. Oxidative degradation can often be reduced to acceptable levels by storing susceptible drugs in the absence of light and oxygen, or by using antioxidants in formulations.

[0053] Hydrolysis is the reaction of a molecule with water, resulting in the breaking of chemical bonds within that molecule. Hydrolysis is a more common pathway for the breakdown of pharmaceutical products and is particularly problematic in formulations used in veterinary applications, where swallowable dosage forms (e.g., tablets or capsules) are not preferred. Unfortunately, many active pharmaceutical ingredients are sensitive to water because they contain readily hydrolyzable functional groups. Examples of such water-sensitive drugs include acetamiprid, milbemycin oxime, clavulanic acid, and ivermectin. Ivermectin, in particular, is highly sensitive to aqueous environments and undergoes degradation; therefore, it must be protected from moisture. Its chemical instability upon contact with water is strongly emphasized in US Standard 2016 / 0303151 A1.

[0054] The water content in pharmaceutical products can be quantified using Karl Fischer titration. It should generally be understood that the water content of a product includes both bound and unbound water. In addition to measuring the total water content using the Karl Fischer method, measuring water activity or the level of unbound water may be an effective method for assessing the impact of water on the safety and stability of a product. The level of water activity can also affect the texture properties of soft chewable products. While low water activity is desirable for safety and stability, it can lead to undesirable texture properties such as hardness, dryness, staleness, and toughness, especially in conventional soft chewables containing starch.

[0055] In the soft chewable formulations described herein, starch and water are not used as excipients, and water exists primarily as bound water. The levels of free or unbound water in the soft chewables are actually low. Therefore, the water content of the soft chewables generally remains consistent over time without significant fluctuations.

[0056] The excipient compositions described by the inventors support the stability and bioavailability of the dosage form. Furthermore, the soft chewables prepared according to the invention can be more easily designed into many different shapes and sizes, adopting the appearance of a palatable treat rather than a pharmaceutical pill.

[0057] Advantageously, the disclosed composition of functional ingredients produces a texture that remains soft and extensible over time. This makes in vitro dissolution methods with identifying properties a reliable quality control test.

[0058] A dissolution identification method is a method that distinguishes a pharmaceutical product manufactured under target conditions from one intentionally manufactured under meaningful variations. The phrase "meaningful variations" is used to indicate changes in formulation, raw material properties, and / or process parameters that may occur during the manufacture of a pharmaceutical product. Ideally, the identification method should be able to detect changes in formulation, raw material properties, and processing conditions (i.e., batch-to-batch variations or planned deviations). Therefore, dissolution testing should be able to indicate possible changes in product quality before affecting in vivo performance. One such change could be an increase in the hardness of a soft chewable formulation over time. The necessary dissolution method should be identificationally sufficient to detect these changes.

[0059] For products intended for use in developed country markets, it is essential to utilize identification dissolution methods in product evaluation for quality control testing or quality-by-design trials. Major regulatory agencies expect identification dissolution methods to be used for the quality control of pharmaceutical products, particularly oral solid dosage forms.

[0060] Many chewable pharmaceutical products on the market contain starch as an excipient. These products typically do not possess desirable physicochemical properties. They tend to have high moisture content and a hard texture, and exhibit slow disintegration and dissolution. These undesirable physicochemical properties are likely due to the presence of starch in the formulation. Starch is an excipient with high moisture content, which can readily absorb moisture in high humidity environments and lose moisture when exposed to dry environments. Fluctuations in moisture content within the chewable can alter its texture over time. These changes in the characteristics of soft chewables can, in turn, affect the product's bioavailability.

[0061] The soft chewables described in this article do not require starch or added water as excipients. They exhibit stable water content and low levels of water activity, and maintain texture extensibility over time, thus allowing for the use of identification dissolution methods to measure the release of active pharmaceutical ingredients and generate dissolution profiles for the soft chewables.

[0062] For various reasons, the embodiments of the present invention may be superior to the prior art. For example:

[0063] • The implementation of soft chewable formulations can demonstrate high stability and bioavailability and eliminate the need for the addition of starch and / or water.

[0064] • In some embodiments of soft chewable formulations, the water activity (i.e., the amount of free water) is sufficiently low. Low levels of free water are important in drug delivery systems because many active pharmaceutical ingredients are sensitive to moisture.

[0065] • Implementation plans for soft chewable formulations can achieve sufficient shelf life by reducing the opportunity for microbial growth.

[0066] • By providing a more uniform surface appearance and overall improved appearance, and also improving digestion in companion animals like dogs and cats, it avoids starch leading to higher quality soft chews, as these animals lack the essential enzymes for digesting starch.

[0067] • Soft chewable formulations can be more easily designed into many different shapes and sizes, appearing more like a delicious snack than a pill.

[0068] • Soft chewable formulations can maintain a soft and elastic texture over time.

[0069] • The implementation plan for soft chewable formulations allows for the use of in vitro dissolution methods with identification properties as reliable quality control tests.

[0070] • In some implementations, the entire process for preparing soft chewables can be carried out at ambient room temperature, which is particularly beneficial for heat-sensitive active ingredients.

[0071] • Producing soft chewable products of consistent quality across significantly different batch sizes facilitates easy manufacturing scaling.

[0072] Exemplary Implementation

[0073] In one aspect, the present invention relates to a starch-free soft chewable comprising one or more pharmaceutically active or nutritionally active ingredients and a plurality of excipients (e.g., pharmaceutical-grade excipients). The soft chewable is free of added water and the plurality of excipients are starch-free. Exemplary starch-free excipients used in the soft chewable may comprise fillers, flavoring agents or flavor enhancers, humectants, solvents, softeners, preservatives, antioxidants, and lubricants. In one embodiment, the plurality of excipients comprises at least two dry or solid components and at least two wet or liquid components. The solid components do not contain starch as an excipient, and the liquid components do not contain water as an excipient. In one exemplary embodiment, the solid components comprise at least dicalcium phosphate (e.g., anhydrous, monohydrated, or dihydrated) and microcrystalline cellulose, the liquid components comprise at least glycerol and medium-chain triglycerides, the soft chewable is free of added water, and the filler is starch-free. In some embodiments, the plurality of excipients further comprises at least one flavoring agent.

[0074] According to another aspect, the present invention relates to a method for manufacturing soft chewables. The method includes some or all of the following steps: dry-mixing multiple dry or solid components in a mixer; wet-mixing with multiple wet or liquid components to form a dough-like material; shaping the dough-like material into a strip; dividing the strip into soft chewable portions of predetermined lengths; and packaging the soft chewable portions. The dry components do not contain starch as an excipient, and the liquid components do not contain water as an excipient.

[0075] In another aspect, the present invention relates to a soft chewable substance comprising at least one active ingredient and multiple excipients. The active ingredient may be a pharmaceutical or nutritional agent that can be administered orally. The multiple excipients are a combination of non-starch solid excipients and non-aqueous liquid excipients. In some embodiments, the soft chewable substance comprises two active ingredients, which may be pharmaceutical or nutritional. In other embodiments, the soft chewable substance comprises more than two active ingredients, which may be pharmaceutical or nutritional. In still other embodiments, the multiple active ingredients are all pharmaceutical ingredients or all nutritional ingredients.

[0076] In some embodiments, the soft chewables described herein contain at least one active ingredient that is an antiparasitic agent. The antiparasitic agent may be an ether-based external parasiteicide or an internal parasiteicide, or both. In some embodiments, the soft chewables do not contain added water, the active ingredient is an external parasiteicide belonging to the isoxazoline class, and the various excipients do not contain starch. Exemplary external parasiteicides of the isoxazoline class include, for example, afoxolaner, fluralaner, sarolaner, lotelaner, etc. In other embodiments, the soft chewables do not contain added water, the active ingredient is an internal parasiteicide or anthelmintic belonging to the macrolide class, and the various excipients do not contain starch. Exemplary anthelmintics of the macrolide class include, for example, milbemycin oxime, moxifloxacin, ivermectin, avermectin, doramectin, irinotecan, silacloxacin, etc.

[0077] In some embodiments, the chewable substance contains two or more active ingredients; at least one is an external parasite control and at least one is an internal parasite control. In some embodiments, the active ingredients are a combination of isoxazoline and macrolide classes. In other embodiments, the chewable substance contains an active pharmaceutical ingredient that belongs to a class of chemicals excluding isoxazolines.

[0078] In one embodiment, the various excipients in the soft chewable include fillers, flavoring agents, humectants, solvents, softeners, preservatives, antioxidants, and lubricants. Exemplary fillers include, but are not limited to, calcium dicalcium phosphate dihydrate (DiCal or DCPD), microcrystalline cellulose, lactose, and any combination thereof. In one exemplary embodiment, the filler is dicalcium phosphate dihydrate, microcrystalline cellulose, or any combination thereof. Exemplary solvents include, but are not limited to, caprylic / capric triglycerides, medium-chain triglycerides, long-chain triglycerides, and any combination thereof. In one exemplary embodiment, the solvent is a medium-chain triglyceride or a mixture of caprylic and capric triglycerides. Exemplary softeners include, but are not limited to, magnesium stearate, stearic acid, sodium stearoyl fumarate, and any combination thereof.

[0079] The various excipients may further comprise binders and / or disintegrants and / or surfactants. Exemplary binders include, but are not limited to, povidone, hydroxypropyl cellulose (HPC), hydroxymethyl cellulose (HPMC), and any combination thereof.

[0080] In one exemplary embodiment, the soft chewable contains at least one active pharmaceutical ingredient and the following excipients: 10%-90% w / w dicalcium phosphate dihydrate; 5%-35% w / w flavoring; 5%-40% w / w microcrystalline cellulose; 0%-15% w / w croscarmellose sodium; 0%-5% w / w sodium stearoyl fumarate or magnesium stearate; 15%-50% w / w glycerol; 2%-50% w / w medium-chain triglycerides; 0%-5% w / w anhydrous citric acid; 0.01%-3% w / w potassium sorbate; and 0.01%-3% w / w DL-α-tocopherol acetate. In another exemplary embodiment, the soft chewable contains at least one active pharmaceutical ingredient and the following excipients: 15%-90% w / w dicalcium phosphate dihydrate; 5%-30% w / w flavoring; 5%-40% w / w microcrystalline cellulose; 0%-15% w / w croscarmellose sodium; 0%-5% w / w sodium stearoyl fumarate or magnesium stearate; 15%-50% w / w glycerol; 15%-50% w / w medium-chain triglycerides; 0%-5% w / w anhydrous citric acid; 0.01%-3% w / w potassium sorbate; and 0.01%-3% w / w DL-α-tocopherol acetate. In another exemplary embodiment, the soft chewable contains at least one active pharmaceutical ingredient and the following excipients: 10%-60% w / w dicalcium phosphate dihydrate; 5%-35% w / w flavoring; 5%-40% w / w microcrystalline cellulose; 0%-15% w / w croscarmellose sodium; 0%-5% w / w sodium stearoyl fumarate or magnesium stearate; 15%-50% w / w glycerol; 2%-20% w / w medium-chain triglycerides; 0%-5% w / w anhydrous citric acid; 0.01%-3% w / w potassium sorbate; and 0.01%-3% w / w DL-α-tocopherol acetate.

[0081] In another aspect, the present invention relates to a method for manufacturing a soft chewable material by: (a) dry-mixing multiple dry or solid components in a mixer (e.g., a low-shear mixer or a high-shear mixer); and (b) wet-mixing a dough-like material by adding multiple wet or liquid components to the mixer. The method may include one or more of the following additional steps: (c) shaping the dough-like material into a strip; (d) dividing the strip into soft chewable portions of predetermined lengths (e.g., using a portioning tool); and (e) packaging the soft chewable portions. In a preferred embodiment, the wet-mixing step includes the sub-steps of adding a humectant to the mixer, mixing the blend in the mixer, and then adding a solvent to the mixer. In one embodiment, the entire method is carried out at room temperature without heating or cooling.

[0082] In one embodiment of the method, the plurality of dry components comprises at least one active ingredient that is a pharmaceutical or nutrient. In another embodiment of the method, the plurality of liquid components comprises at least one active ingredient that is a pharmaceutical or nutrient. In yet another embodiment of the method, the active ingredient in powder form is mixed with or dissolved in a liquid excipient and then added to a mixer. In a further embodiment of the method, the plurality of dry components comprises at least one of a filler, flavoring agent, humectant, solvent, softener, preservative, antioxidant, and lubricant, and the plurality of liquid components comprises at least one of a filler, flavoring agent, humectant, solvent, softener, preservative, antioxidant, and lubricant.

[0083] According to another aspect of the invention, a starch-free excipient composition is provided for the final dosage form of a soft chewable without making the use of starch or added water necessary. In one embodiment, the starch-free excipient composition comprises at least two solid components and at least two liquid components. In an exemplary embodiment, the solid components do not contain starch as an excipient, and the liquid components do not contain water as an excipient. In some embodiments, the starch-free excipient composition is a carrier for oral administration of at least one water-sensitive active ingredient. In some embodiments, all excipients are pharmaceutical grade.

[0084] In yet another embodiment, the solid component comprises at least calcium hydrogen phosphate and microcrystalline cellulose, and the liquid component comprises at least glycerol and triglycerides of fatty acids having a carbon chain length of C6-C12, wherein starch or added water is not required. In some embodiments, the starch-free excipient composition is a carrier for oral administration of at least one moisture-sensitive active ingredient. In yet another embodiment, the starch-free excipient composition further comprises at least one flavoring agent. In yet another embodiment, all excipients are pharmaceutical grade.

[0085] Calcium hydrogen phosphate can be hydrated or anhydrous. In some embodiments, hydrated calcium hydrogen phosphate is used, and more preferably, calcium hydrogen phosphate dihydrate is used.

[0086] The triglycerides of fatty acids having a carbon chain length of C6-C12 can be triglycerides of any one of the C6-C12 fatty acids or any combination thereof. In some embodiments, caprylic / capric triglycerides or medium-chain triglycerides are used, and more preferably, medium-chain triglycerides.

[0087] By way of example, and not limited to, exemplary starch-free excipient formulations used in soft chewables as described herein comprise calcium hydrogen phosphate dihydrate and microcrystalline cellulose in a weight ratio of about 1:1 to 4:1 (e.g., about 2:1 to 3:1 or about 2.5:1 to 3:1). Glycerol and medium-chain triglycerides may be contained in a weight ratio of about 2:1 to 7:1 (e.g., about 4:1 to 7:1 or about 5:1 to 6:1).

[0088] As is well known, many active pharmaceutical ingredients (APIs) used to treat both humans and non-human animals are unpalatable and unsuitable for oral delivery unless accompanied by appropriate excipients. The starch-free excipient formulations described herein may further include flavorings. Exemplary embodiments of the compositions and dosage forms described herein may contain flavorings in an amount sufficient to mask the unpalatable taste of the API while inducing voluntary acceptance in animals, potentially eliminating the need for forced administration or veterinary intervention.

[0089] By way of example, based on the total weight of all excipients, the flavoring agent may be included in a weight ratio of about 0.1 to 0.35 (e.g., about 0.15 to 0.3 or about 0.2 to 0.25). The flavoring agent is preferably pharmaceutical grade. Exemplary flavoring agents include, but are not limited to, FlavorPal. TM (TetraGenX, Saint Laurent, Quebec, Canada) Desiccated Pork Liver Powder TM (Gurvey and Berry, Toronto, Ontario, Canada), Provesta ® 356 (Ohly Inc., Hamburg, Germany), Provesta ® 400 (Oly, Hamburg, Germany) and PC-0125 Artificial Powdered Beef Flavor TM (Pet Flavors Inc., Melbourne, Florida, USA). Includes FlavorPal TM The soft chewable of the present invention can demonstrate excellent voluntary acceptance in animals, thereby enhancing the animals' perception that the soft chewable is a palatable snack rather than a drug.

[0090] In one embodiment, the excipient composition for use in soft chewables comprises calcium hydrogen phosphate dihydrate, microcrystalline cellulose, glycerol, and medium-chain triglycerides, but does not contain starch or water as an excipient. This starch-free composition can provide a final dosage form of soft chewables with sufficient structural integrity, desired softness and extensibility, low water activity, and consistent water content. The starch-free carrier composition may further comprise at least one flavoring agent. Antioxidants (e.g., DL-α-tocopheryl acetate) may also be added to the composition.

[0091] Starch-free carrier compositions are particularly suitable for formulating moisture-sensitive active ingredients. Excipients such as dicalcium phosphate dihydrate, microcrystalline cellulose, glycerol, and medium-chain triglycerides typically exhibit good compatibility with most commercially available active pharmaceutical ingredients.

[0092] Excipient formulation

[0093] Embodiments of the present invention include excipient formulations for the final dosage form of soft chewables. Soft chewables refer to materials that are not brittle or easily broken, so that they do not immediately break apart when chewed by companion animals or pets.

[0094] Filler / Leaving Agent

[0095] According to an exemplary embodiment of the present invention, a soft chewing formulation comprises a filler or leavening agent. Exemplary compounds that can be used as fillers or leavening agents include hydrated or anhydrous dicalcium phosphate, microcrystalline cellulose (MCC), hydrated or anhydrous lactose, or combinations thereof. Preferably, dicalcium phosphate dihydrate (DiCal or DCPD), microcrystalline cellulose (MCC), lactose monohydrate, or any combination thereof can be used as fillers. However, starch is not used in the fillers used in embodiments of the present invention.

[0096] Although starch is frequently used as an excipient in many conventional oral solid dosage forms, its use as a filler is avoided in exemplary embodiments of the present invention. Starch has the chemical formula (C6H). 10 O5) n Where n = 300-1000. Many conventional fillers contain, and often even prefer, starch, which can be pregelatinized or non-pregelatinized. Furthermore, depending on the specific filler or leavening agent used and the presence of other starch-containing inputs, extrusion often induces starch gelatinization.

[0097] Although starch is commonly used in conventional soft chew formulations, it has certain adverse effects on the final dosage form of soft chews containing APIs. For example, starch has a high moisture content, which promotes water activity in the dosage form. High water activity, in turn, leads to decreased API stability (e.g., hydrolysis) and increased microbial activity, thereby compromising the efficacy of the API and the shelf life of the soft chew. Furthermore, companion animals like dogs and cats cannot easily digest starch. These animals are carnivores with short, simple digestive tracts and lack the essential enzymes required to digest starch, such as amylase. Therefore, the starch-free formulations of the present invention are more beneficial to these animals.

[0098] Embodiments of the present invention do not use or require starch. In embodiments of the present invention, pregelatinized starch or non-pregelatinized starch is not required as a filler ingredient. Advantageously, avoiding starch in the filler results in higher quality soft chewables. At least some of the exemplary soft chewables shown in embodiments of the present invention have a more uniform surface appearance and an overall improved appearance. Furthermore, starch has a high moisture content, and by not using starch, at least some embodiments of the present invention will have a much lower moisture content, which can accommodate moisture-sensitive APIs.

[0099] Conversely, embodiments of the present invention use dicalcium phosphate, MCC, lactose, or combinations thereof as fillers or leavening agents. Therefore, some embodiments of the present invention may use fillers containing dicalcium phosphate. Therefore, other embodiments of the present invention may use fillers containing MCC, and therefore, still other embodiments of the present invention may use fillers containing lactose. Some embodiments may use fillers containing both MCC and dicalcium phosphate, while other embodiments may use fillers containing both MCC and lactose, and still other embodiments may use fillers containing both lactose and dicalcium phosphate. Still other embodiments may use fillers containing all of MCC, dicalcium phosphate, and lactose. Exemplary lactose includes, but is not limited to, hydrated lactose, anhydrous lactose, and lactose monohydrate.

[0100] Microcrystalline cellulose (MCC) is widely used as a diluent and binder in pharmaceutical formulations and is generally considered a relatively non-toxic and non-irritating material. As a pharmaceutical excipient, MCC has been shown to tolerate a variety of APIs well. Microcrystalline cellulose is purified, partially depolymerized cellulose, which appears as a white, odorless, and tasteless crystalline powder composed of porous particles. Microcrystalline cellulose is commercially available in several different grades. These MCCs differ in their manufacturing methods, particle size, moisture content, flowability, and other physical properties. In exemplary embodiments, MCC may constitute about 5% to 40% by weight (“w / w”) of a soft chewable.

[0101] Calcium dicalcium phosphate is available in anhydrous or hydrated form. Its dihydrate has the chemical formula CaHPO4·2H2O and is widely used as a diluent in tablet formulations and as a calcium and phosphorus source in nutritional supplements. As a pharmaceutical excipient, calcium dicalcium phosphate dihydrate has been shown to tolerate a variety of APIs well. Because DiCal is abrasive, lubricants are typically used when used in pharmaceutical dosage forms, and lubricants are generally required for tableting. Calcium dicalcium phosphate dihydrate is non-hygroscopic and stable at temperatures close to room temperature. In other exemplary embodiments, calcium dicalcium phosphate dihydrate may constitute 15% to 90% ("w / w") of the soft chewable. DCPD can support the structural integrity of the soft chewable of the present invention through synergistic interaction with MCC.

[0102] Flavor

[0103] Many flavoring agents can be used in the exemplary compositions of embodiments of the present invention to improve the palatability of the dosage. The meat or beef seasonings used in the exemplary embodiments can be naturally derived or artificially formulated to have a meat or beef flavor.

[0104] Natural seasonings often consist of dried and ground or powdered meat, which can be obtained from domesticated carnivores, including livestock (such as cows or bulls, pigs, deer, sheep, and goats) and poultry (which may include turkeys, chickens, ducks, etc.).

[0105] Non-animal, typically plant-derived flavorings are also known in the art and can be used in embodiments of the invention. These may include peanuts, fruits, sweeteners, honey, sugar, maple syrup and fructose, parsley, celery, mint, spearmint, garlic, etc. In exemplary embodiments, the flavoring or flavor enhancer may comprise 5% to 30% w / w of the soft chewing material.

[0106] Preferably, the flavoring agent is pharmaceutical grade. Exemplary flavoring agents include, but are not limited to, FlavorPal. TM , Desiccated Pork Liver Powder TM Provesta ® 356, Provesta ® 400, and PC-0125Artificial Powdered Beef Flavor TM .

[0107] softener / moisturizer

[0108] At least some embodiments of the present invention utilize glycerin as a softener or humectant. Glycerin is a transparent, colorless, viscous organic compound with the molecular formula HOCH2CHOHCH2OH.

[0109] Moisturizers are known in the art, and many conventional soft chewables are known to use ammonium alginate, sodium lactate, sorbitol, glyceryl triacetate, xylitol, and glycerin. In a preferred embodiment of the invention, glycerin is used as a softener or moisturizer. Glycerin is also known to be antibacterial and bactericidal against certain bacterial species.

[0110] Water (not used)

[0111] Unlike many known and conventional formulations and methods, embodiments of the present invention do not introduce water into the soft chewing composition. Soft chewing articles are typically manufactured by mixing blends of ingredients and using an extruder.

[0112] U.S. Patent No. 6,387,381 emphasizes the importance of controlling water activity, or free water content, in oral delivery systems. Free water, or available water, in soft chewables promotes microbial growth and participates in and supports chemical and enzymatic reactions as well as rancidity processes, especially in the presence of flavorings containing nutrients. This amount of free water is known as water activity, and it is more important than total water content for the chemical and microbiological stability of the final product.

[0113] In conventional soft chewable formulations, the water introduced into the mixture typically must be pharmaceutical grade. In the soft chewable formulations described herein, no water is used as an excipient; the absence of water as an excipient avoids the need for expensive pharmaceutical-grade water and reduces the possibility of microbial growth or loss of efficacy of the active ingredient. The fact that no water or starch with a high moisture content is added to the formulation allows embodiments of the invention to accommodate moisture-sensitive APIs.

[0114] Advantageously, in embodiments of the invention, the processes and costs associated with maintaining pharmaceutical-grade water are avoided because water is not introduced into the mixture during manufacturing.

[0115] This contrasts sharply with some chewables known in the art, such as the aforementioned U.S. Patent No. 8,541,019, which discloses a delicious, stretchable, chewable veterinary composition containing up to 9% water.

[0116] Solvent / Other Liquids

[0117] Some embodiments of the present invention use solvents comprising caprylic / capric triglycerides or medium-chain triglycerides (MCTs), and vegetable oils referred to as long-chain triglycerides (LCTs). In exemplary embodiments, MCTs may comprise 15% to 50% w / w of the soft chewable. In other embodiments, the solvent may be triglycerides of fatty acids having a carbon chain length of C6-C12, including triglycerides of any one of C6-C12 fatty acids, triglycerides of any combination of C6-C12 fatty acids, caprylic / capric triglycerides, and medium-chain triglycerides (MCTs).

[0118] Medium-chain triglycerides, or MCTs, can be synthesized by esterifying glycerol with fatty acids of C8 or C10 carbon chain length. MCTs are commercially available as a mixture of glycerides of C8 (octanoic acid / caprylic acid) and C10 (decanoic acid / capric acid) fatty acids with small amounts (< 1% each time) of glycerides of C6 (hexanoic acid or caprylic acid) and C12 (laundric acid or lauric acid) fatty acids, as disclosed in WO2013126990 A1.

[0119] MCT possesses physical characteristics distinct from common animal fats or vegetable oils, including lower viscosity and higher solubility in alcohols. Although the fatty acids found in MCT are saturated like animal fats, MCT is a liquid at room temperature, similar to vegetable oils. WO 2013 / 126990 A1 states that MCT, when used as an excipient, can improve the solubility of active ingredients with poor water solubility. It should also be noted that MCT is generally known to be antimicrobial and antiviral.

[0120] MCT is a multifunctional excipient and, as noted below, can act as a lubricant. MCT can increase the processability of soft chewing formulations during extrusion, strip forming, etc., and can facilitate high-speed processing.

[0121] softener

[0122] Embodiments of the present invention also use softeners. Softeners are typically used to reduce the hardness of soft chew products by limiting density.

[0123] Pharmaceutically acceptable softeners are well known and may contain, for example, polysaccharides, vegetable or animal fats (such as cocoa butter, seed oil, palm oil, or coconut oil), or alcohols (such as glycerin). In an exemplary embodiment, glycerin may comprise 15% to 50% w / w of the soft chewable.

[0124] In a preferred embodiment of the present invention, the softener used is magnesium stearate (MgSt), having the chemical formula C 17 H 35 CO2H stearic acid and / or sodium stearoyl fumarate (C) are also used as lubricants. 22 H 39 NaO4).

[0125] adhesives

[0126] Exemplary embodiments of soft chewables may include an adhesive in the form of povidone, hydroxypropyl cellulose (HPC), hydroxymethyl cellulose (HPMC), or a combination thereof. In some embodiments of the invention, the use of an adhesive is optional.

[0127] Povidone has the chemical formula (C6H9NO). n The molecular weight ranges from 2,500 to 3,000,000. Besides its use as a binder, povidone can also act as a disintegrant, dissolving agent, and suspending agent. Povidone products are typically accompanied by a K number, which indicates the viscosity in solution, as well as the average molecular weight of the specific povidone (e.g., povidone K30).

[0128] In some embodiments, the adhesive may contain only povidone when present, while in other embodiments, the adhesive may contain only HPC; and in yet another embodiment, the adhesive may contain only HPMC. In some exemplary embodiments, the soft chewable may contain all three of povidone, hydroxypropyl cellulose (HPC), and carboxymethyl cellulose (HPMC).

[0129] surfactants

[0130] Exemplary embodiments of soft chewables may include surfactants. Surfactants, as surface-active agents, are sometimes also referred to as wetting agents, emulsifiers, or suspending agents, depending on their properties and uses. Surfactants reduce the surface tension or interfacial tension between two liquids or between a liquid and a solid. They are soluble in both organic solvents and water and are suitable for ingestion. However, in embodiments of the invention, the use of surfactants is optional.

[0131] Disintegrant

[0132] Exemplary embodiments of soft chewables may include a disintegrant. In an exemplary embodiment, the disintegrant may comprise up to 15% w / w of the soft chewable. Exemplary disintegrants known in the art include crospovidone, croscarmellose sodium, and cellulose. As noted above, povidone can also act as a disintegrant. In some embodiments of the invention, the use of a disintegrant is optional. In a specific exemplary embodiment, croscarmellose sodium may comprise up to 15% w / w of the soft chewable. The disintegrant is also used to modify the texture and can be used to modify drug release.

[0133] antioxidants

[0134] Exemplary embodiments of soft chewables may include antioxidants. Examples of antioxidants include α-tocopherol, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, sodium ascorbate, sodium metabisulfite, n-propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), and monothioglycerol. In exemplary embodiments, the antioxidant may comprise 0.01%-3% w / w of the soft chewable.

[0135] Other antioxidants may also include tocopherols (such as α, β, or δ-tocopherol), tocopherol esters, α-tocopherol acetate; alkyl gallate, butylated hydroxyanisole, butylated hydroxytoluene, anhydrous citric acid and hydrated citric acid, edema acid and its salts, lecithin, and tartaric acid. Other antioxidants are resveratrol, quercetin, benzoic acid, dimethylthiourea (DMTU), hesperidin, tetrahydrocurcumin, tetrahydrodemethoxycurcumin, and monothioglycerol. In specific embodiments, α-tocopherol or DL-α-tocopherol acetate may comprise 0.01%–3% w / w of the soft chewable.

[0136] preservative

[0137] Exemplary embodiments of soft chewables may include preservatives. Examples of preservatives include pharmaceutically acceptable and well-known preservative excipients such as benzoic acid, ascorbic acid, calcium propionate, potassium sorbate, hydrated citric acid, and anhydrous citric acid. In exemplary embodiments, potassium sorbate may comprise 0.01%-3% w / w of the soft chewable, and anhydrous citric acid may comprise up to 5% w / w of the soft chewable.

[0138] In some cases, some of the antioxidants mentioned above may also have the same effect as preservatives.

[0139] lubricant

[0140] Exemplary embodiments of soft chewables may include a lubricant. Examples of lubricants include caprylic / capric triglycerides or medium-chain triglycerides (MCTs), as well as vegetable oils known as long-chain triglycerides (LCTs), magnesium stearate (MgSt), stearic acid, sodium stearoyl fumarate, and combinations thereof. In exemplary embodiments, a lubricant such as sodium stearoyl fumarate may constitute up to 5% w / w of the soft chewable. Medium-chain triglycerides (MCTs) may constitute up to 15%-50% w / w of the soft chewable.

[0141] Lubricants (such as LCT, MCT, and MgSt, stearic acid, and sodium stearoyl fumarate) help lubricate machines for easier processing. Lubricant formulations also lubricate equipment, especially during strip forming. Additionally, lubricants can help mitigate the potential abrasive characteristics of other excipients, such as DiCal.

[0142] Active ingredients

[0143] Of course, the above-described ingredients or excipients in conjunction with exemplary embodiments of soft chewables can be used in combination with one or more suitable active ingredients, including active pharmaceutical ingredients (APIs) and active nutritional ingredients.

[0144] Active pharmaceutical ingredients are the biologically active components of pharmaceutical products, which can be subject to stricter legal control and regulation than other pharmaceutical ingredients. Active nutritional ingredients are the active components found in nutritional supplements.

[0145] The active ingredients applicable to the soft chewables described herein can be any medicine, nutritional supplement, etc., that can be administered orally. Examples include, but are not limited to, anti-infective agents such as antibiotics, antibacterial agents, antifungal agents, antiprotozoal agents, and antiviral agents; analgesics; antiparasitic agents such as external and internal parasite-killing agents (anthelmintics); hormones and their derivatives; anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, etc.; behavioral modifiers; vaccines; antacids; laxatives; anticonvulsants; sedatives; tranquilizers; antitussives; antihistamines; decongestants; expectorants; appetite stimulants and suppressants; minerals and vitamins; amino acids; fatty acids; glucosamine; enzymes; fish oil; herbal ingredients; and traditional medicines.

[0146] In veterinary medicine, antiparasitic and anti-infective drugs play a major role in the veterinary drug product market, with their combined share reaching nearly 50%. Anti-infective drugs particularly include antibiotics, antifungals, and antivirals. Exemplary antibiotics used in the soft chewables described herein include, but are not limited to, amoxicillin, cephalexin, clavulanic acid, enflufloxacin, and metronidazole. Antiparasitic drugs include antiparasitic agents against ectoparasites present on the body surface (external parasite killers) and antiparasitic agents against endoparasites present in the body (internal parasite killers). Exemplary external parasite killers used in the soft chewables described herein include, but are not limited to: (a) isoxazoline compounds, such as afolanar, fleranal, sarolaner, and lotelanar; and (b) neonicotinoid compounds, such as imidacloprid, acetamiprid, thiamethoxam, dinotefuran, acetamiprid, thiamethoxam, and thiamethoxam. Exemplary endoparasitic drugs (anthelmintics) used in the soft chewables described herein include, but are not limited to: (a) macrolides, such as avermectin insecticides (e.g., ivermectin, abamectin, doramectin, irinotecan, silachlor) and milbemycin (e.g., milbemycin oxime, moxichlor); and (b) other anthelmintics, such as pyrantel pamoate, febantel, fenbendazole, ocbendazole, ambroxol, piperazine, mebendazole, levamisole, praziquantel, and octetil. Anti-infective or antiparasitic APIs may be included in the soft chewables, alone or in combination with one or more other active ingredients.

[0147] Many APIs are moisture-sensitive. Exemplary moisture-sensitive active ingredients include clavulanic acid, acetamiprid, milbemycin oxime, and ivermectin. These compounds may become unstable upon contact with water, and aqueous environments should be avoided during the preparation of soft chewables and in the soft chewable formulations themselves.

[0148] In some embodiments, the API excludes isoxazoline compounds. In other embodiments, the API does not exclude isoxazoline compounds. In embodiments of the invention, any active pharmaceutical ingredient that can be used to treat companion animals may be included as the API.

[0149] Manufacturing method

[0150] Exemplary processes or methods for embodiments of the present invention for use in soft chewables will now be described. An exemplary method for manufacturing embodiments of the present invention for soft chewables involves mixing dry ingredients to form a mixture of uniform consistency. Liquid ingredients are added and the wet mixture is wet-aggregated, or the blend is mixed until a dough-like consistency is obtained. Strips of suitable length and shape are then formed from the wet dough using suitable machinery, and then portioned into desired formulation lengths having a final dosage weight. These are then packaged into suitable packages for presentation, storage, and / or transport.

[0151] Figure 1 The steps involved in an exemplary manufacturing method or process 100 for producing soft chewables are illustrated. As shown, method 100 begins with dry ingredients 208 to be mixed together in a mixer. The mixer can be a low-shear mixer or a high-shear mixer. For some embodiments, a low-shear mixer is preferred.

[0152] Please refer to later Figure 2 The pre-processing steps for preparing dry component 208 for use are described. In step 102, dry component 208 is added to a mixer and mixed together.

[0153] conduct Figure 1 Continue the dry mixing step 102 until a dry mixture of uniform consistency is obtained. Then, add the liquid component 114 to the mixer and continue mixing in the wet aggregation or wet mixing step 104. Here, glycerin may be added, followed by MCT. Continue the wet aggregation or wet mixing step 104 until a wet dough with the desired dough-like consistency is achieved.

[0154] The next step is strip forming step 106, which involves using a strip forming machine or extruder to form the wet agglomerate into a strip with a suitable processing length and shape, as defined by the machine tooling and process equipment. Advantageously, the formulation of the components in an earlier step provides lubrication for the equipment used, particularly during strip forming step 106.

[0155] In step 107, the strip produced by the strip forming step 106 is cured. In some embodiments, the curing step 107 may take up to 24 hours. In step 108, the strip formed in the previous strip forming step 106 is fractionated into desired formulation lengths to obtain a final dosage weight that varies with size and product density.

[0156] In step 109, the portions produced in step 108 are cured. In some embodiments, the curing of the portions in step 109 may take up to 72 hours. These portions are then packaged into the desired package presentation in step 110.

[0157] Figure 2 This is a simplified flowchart illustrating the method steps involved in preparing the dry components used in manufacturing method 100 as described above. Preparation method 200 begins by obtaining the raw dry components in step 202, which are then dispersed or sieved in step 204 through a desired sieve with a suitable opening diameter, or, as needed, through a combination of multiple sieves in steps 206 and 204. The suitable dry components 208 are then obtained, which can be fed into… Figure 1 The mixer in the process is used for dry mixing step 102.

[0158] Some of the excipients discussed above may be provided as part of dry component 208, while others may be provided as part of liquid component 114.

[0159] Figure 3 The steps involved in an exemplary manufacturing method or process 300 for manufacturing the soft chewables disclosed herein are shown.

[0160] Method 300 begins with the preparation of dry components. In a dispersing step 301, dry components 320 (such as flavoring agents, APIs, fillers (e.g., DCPD), and lubricants (e.g., magnesium stearate, sodium stearoyl fumarate, or any combination thereof) are dispersed or sieved through a 20-mesh sieve 330. In a grinding step 311, preservatives 321, such as potassium sorbate and anhydrous citric acid, are ground using a rotary impeller mill 331. The dispersed dry components 320 and the ground components 321, along with any remaining dry components that may not need to be prepared before mixing, such as a second filler (e.g., microcrystalline cellulose) and a disintegrant (e.g., croscarmellose sodium), are then loaded into a plow mixer 332. In a dry mixing step 302, the dry components are mixed in the plow mixer 332, which operates at approximately 100 rpm, for approximately 2 minutes.

[0161] The liquid component can be prepared before mixing with the dry component. If the soft chewable formulation incorporates a second API that requires precise dosing due to its high potency, the second API can first be dissolved in solvent 323, such as MCT oil, to prepare an excess solution of the second API and solvent. For this purpose, a propeller mixer and an appropriately sized container can be used. Alternatively, a humectant (e.g., glycerin) and an antioxidant (e.g., DL-α-tocopheryl acetate) 322 can be manually mixed together for approximately 1 minute using a scalpel.

[0162] In step 312, with the plow mixer 332 operating at approximately 100 rpm, liquid is added, wherein the glycerol / DL-α-tocopherol acetate mixture 322 is added to the blend for a period of approximately 2 minutes. After the full amount of glycerol / DL-α-tocopherol acetate 322 has been added, mixing step 303 is performed by further mixing the blend in the plow mixer 332 for approximately 1 minute. In step 313, with the plow mixer 332 operating at approximately 100 rpm, liquid is added, wherein a solvent 323 (e.g., MCT) or a second API and an excess solution of the solvent are then added to the mixture for a period of approximately 2 minutes.

[0163] For wet aggregation step 304, open plow mixer 332 and visually inspect any residue adhering to the walls and plow of the mixer. The residue can be scraped off the walls and plow and returned to the center of the mixer. Perform wet aggregation step 304 by mixing the blend at room temperature until the material achieves a dough-like consistency, for example, for approximately 17 minutes.

[0164] For the strip forming step 305, the wet agglomerate from the wet aggregation step 304 is discharged from the plow mixer 332 and loaded into the hopper of the strip forming machine or extruder 333. Strips of appropriate length (e.g., about 15") are formed at room temperature and placed on a parchment-lined tray. The strips are cured at room temperature for 18-24 hours. Then, in the cutting step 306, the strips are cut into segments of predetermined unit weight using a special tool 334 to provide the final dose weight of the one or more APIs. These segments are then cured at room temperature for a period of time (e.g., 72 hours) before being packaged in bulk.

[0165] The exemplary method of embodiments of the present invention can be carried out at ambient room temperature without any specific heating or cooling. This is particularly advantageous for heat-sensitive active ingredients.

[0166] Exemplary methods of embodiments of the present invention may include adding one or more pharmaceutically active ingredients and a group of excipients comprising at least one of fillers, flavoring agents, humectants, solvents, softeners, preservatives, antioxidants, and lubricants. Optionally, binders, disintegrants, and surfactants may also be added to the mixture of ingredients.

[0167] Prior to the wet aggregation step, the active ingredient in powder form can be mixed with one or more other dry or solid components (containing one or more dry excipients), while the active ingredient in liquid form can be mixed with one or more other liquid components (containing one or more liquid excipients). For example, the active ingredient, such as milbemycin oxime, praziquantel, or pyrantel pamoate, can be uniformly mixed with dry excipients such as potassium sorbate, citric acid, flavoring agents, croscarmellose sodium, microcrystalline cellulose, magnesium stearate, and sodium stearoyl fumarate. In some embodiments, the active ingredient in powder form can be processed together with one or more dry excipients to produce an intermediate mixture, which is then added to and mixed with other dry components. The one or more dry excipients that can be used to form the intermediate mixture may contain fillers (e.g., lactose) and / or binders (e.g., povidone). For example, milbemycin oxime can be processed together with lactose monohydrate and povidone K30 to form an intermediate mixture, which is then co-blended with other dry components.

[0168] In some embodiments, the active ingredient, in powder form, can be mixed with one or more liquid excipients to facilitate precise dosing of the active ingredient. For example, ivermectin is exceptionally potent, with effective dose levels being very low (in micrograms); therefore, accurate measurement of ivermectin is crucial during methods of manufacturing ivermectin-containing soft chewables. Although ivermectin is typically provided in powder form, it may be more beneficial to prepare and use an excess solution of ivermectin in a solvent such as caprylic / capric triglycerides or medium-chain triglycerides.

[0169] In some embodiments, the multiple dry ingredients may include at least one of the following: fillers, flavoring agents, humectants, solvents, softeners, preservatives, antioxidants, and lubricants.

[0170] In some embodiments, the multiple liquid components may include at least one of the following: fillers, flavoring agents, humectants, solvents, softeners, preservatives, antioxidants, and lubricants.

[0171] As noted earlier, embodiments of the present invention have several advantages, including producing soft chewables with a texture that remains soft and elastic over time. Furthermore, some embodiments of the exemplary soft chewables of the present invention enable in vitro dissolution methods with identifying properties to be used as reliable quality control tests.

[0172] This application can be better understood by referring to the following non-limiting embodiments provided as exemplary implementations of the invention. The following embodiments, set forth to aid in understanding the invention, should not be construed in any way as limiting the scope of the invention as defined by the claims that follow.

[0173] Example

[0174] Example 1 - Preparation of soft chewable A:

[0175] Milbemycin oxime / praziquantel (5.75 mg / 57 mg) soft chewable tablets

[0176] Table 1: Composition of soft chewable food A

[0177]

[0178] The excipients listed above are pharmaceutical grade and meet USP standards.

[0179] Add DL-α-tocopherol acetate to MCT oil and mix manually with a scalpel. Tumble together the dry ingredients: milbemycin oxime / povidone K30 / lactose monohydrate intermediate (prepared), praziquantel, DCPD, potassium sorbate (pre-ground using a mortar and pestle), anhydrous citric acid, flavoring agent, croscarmellose sodium, MCC, and magnesium stearate, and then break up or sieve through a 20-mesh sieve. Tumble the broken-up dry ingredients again for 2 minutes and then load into a low-shear mixer. While operating the mixer, add glycerin to the blend (addition time = 2 minutes). After adding all the glycerin, mix the blend for another 1 minute. Then, add the MCT oil / DL-α-tocopherol acetate solution to the mixture (addition time = 2 minutes). Mix the blend at room temperature until the material reaches a dough-like consistency (approximately 9 minutes). Then transfer the wet dough to a strip forming machine. Strips with a diameter of 11 mm and a length of approximately 25 cm were formed at room temperature. The strips were then cured at room temperature for 24 hours. The strips were then divided into segments of 2.5 g ± 0.13 g to provide the final dose weight of milbemycin oxime (5.75 mg) and praziquantel (57 mg). These segments were then cured at room temperature for 72 hours before being packaged in bulk.

[0180] The entire method described above is performed at ambient room temperature without the need for heating or cooling.

[0181] Example 2 - Dissolution curve of soft chewable product A:

[0182] Milbemycin oxime / praziquantel (5.75 mg / 57 mg) soft chewable tablets

[0183] Table 2: Dissolution curves of soft chewable product A

[0184]

[0185] Dissolution conditions: 0.5% SLS (sodium lauryl sulfate) in water, 1000 ml, 75 rpm, 37.0ºC ±0.5ºC

[0186] The soft chewables from Example 1 (soft chewables A, 2.5 g / chewable) were stored at 25ºC and 60% relative humidity (RH) for 6 months. Dissolution tests were performed at 0 and 6 months for each API (milbemycin oxime and praziquantel) under the conditions indicated above. Samples were taken at different time intervals to generate dissolution profiles at each given time point. The resulting dissolution profiles for milbemycin oxime and praziquantel are shown in Table 2 above, as well as those for each API. Figure 4 and Figure 5In the meantime, the dissolution profiles for each API remained rapid and consistent over a 6-month period, without significant changes.

[0187] Example 3 - Stability of soft chewable food A:

[0188] Milbemycin oxime / praziquantel (5.75 mg / 57 mg) soft chewable tablets

[0189] Table 3: Stability of soft chewable food A

[0190]

[0191] The pharmaceutical product was packaged in 150cc HDPE (high-density polyethylene) bottles (each containing 20 soft chewables) and stored at 25ºC / 60% RH. Moisture content, milbemycin oxime assay, and praziquantel assay of the soft chewables were tested over 6 months. As shown in Table 3, all test results remained stable over time.

[0192] Example 4 - Physical properties of soft chewable material A over time:

[0193] Milbemycin oxime / praziquantel (5.75 mg / 57 mg) soft chewable tablets

[0194] Table 4: Physical properties of soft chewable food A over time

[0195]

[0196] *Texture was measured as the peak force (in Newtons) required to push a 5.0 mm diameter sphere into a soft chewable material at a speed of 1.0 mm / sec to a depth of 2.0 mm.

[0197] The soft chewable material was allowed to solidify under ambient conditions over a period of 28 days. Disintegration and texture of the soft chewable material were measured on days 0, 1, 7, and 28 post-manufacturing. As shown in Table 4, the pharmaceutical product maintained its rapid disintegration time, and the soft chewable material remained soft and elastic over time.

[0198] Example 5 - Preparation of soft chewable substance B:

[0199] Ivermectin / Pyrantel thiamethoxam (68 µg / 57 mg) Soft Chewable

[0200] Table 5: Composition of Soft Chewable Food B

[0201]

[0202] The excipients listed above are pharmaceutical grade and meet USP standards.

[0203] First, dissolve ivermectin in MCT oil using a propeller mixer and an appropriately sized container. Weigh out an additional 10% of ivermectin and MCT oil to prepare a 10% ivermectin / MCT oil excess solution. Disperse or sieve the dry ingredients: pamoate, DCPD, potassium sorbate (pre-ground using a mortar and pestle), citric acid, flavoring agent, croscarmellose sodium, microcrystalline cellulose, and sodium stearoyl fumarate through a 20-mesh sieve. Tumble the dispersed dry ingredients together for 2 minutes and then transfer to the mixing bowl of a planetary mixer. Add DL-α-tocopherol acetate to the container containing glycerin and mix manually with a scalpel. While operating the mixer, add the glycerin / DL-α-tocopherol acetate emulsion to the blend (addition time = 2 minutes). After adding the full amount of glycerin / DL-α-tocopherol acetate, mix the blend for another 1 minute. Add the precise amount of ivermectin / MCT oil solution to the mixture (addition time = 2 minutes). The blend was mixed at room temperature until the material achieved a dough-like consistency (approximately 50 minutes). The wet dough was then transferred to a strip forming machine. Strips with a diameter of 11 mm and a length of approximately 25 cm were formed at room temperature. The strips were cured at room temperature for 24 hours. The strips were then portioned into segments of 2.5 g ± 0.13 g to provide the final dosage weight of ivermectin (68 µg) and pyrantel pamoate (57 mg). These portions were then cured at room temperature for 72 hours before being bulked.

[0204] The entire method described above is performed at ambient room temperature without the need for heating or cooling.

[0205] Example 6 - Dissolution curve of soft chewable product B:

[0206] Ivermectin / Pyrantel thiamethoxam (68 µg / 57 mg) Soft Chewable

[0207] Table 6: Dissolution curves of soft chewable product B

[0208]

[0209] Dissolution conditions: 4% SLS in water, 500 ml, 75 rpm, 37.0ºC ± 0.5ºC

[0210] The soft chewables from Example 5 (soft chewables B, 2.5 g / chewable) were stored at 25ºC and 60% relative humidity (RH) for 4 weeks. Dissolution tests were performed at 0 and 4 weeks for each API (ivermectin and pyrantel pamoate) under the conditions indicated above. Samples were taken at different time intervals to generate dissolution profiles at each given time point. As shown in Table 6 above, the dissolution profiles for each API remained rapid and consistent after the 4-week time period, without significant changes.

[0211] Example 7 - Stability of soft chewable food B:

[0212] Ivermectin / Pyrantel thiamethoxam (68 µg / 57 mg) Soft Chewable

[0213] Table 7: Stability of Soft Chewable Food B

[0214]

[0215] The pharmaceutical product was packaged in 60 cc HDPE bottles (each containing 15 soft chewables) and stored at 25ºC / 60% RH. Moisture content, ivermectin assay, and pyrantel thiamethoxam assay of the soft chewables were tested over 6 months. As shown in Table 7, all test results remained stable over time.

[0216] Example 8 - Physical properties of soft chewable material B over time:

[0217] Ivermectin / Pyrantel thiamethoxam (68 µg / 57 mg) Soft Chewable

[0218] Table 8: Physical properties of soft chewable food B over time

[0219]

[0220] *Texture was measured as the peak force (in Newtons) required to push a 5.0 mm diameter sphere into a soft chewable material at a speed of 1.0 mm / sec to a depth of 2.0 mm.

[0221] The soft chewable material was allowed to solidify under ambient conditions over a period of 28 days. Disintegration and texture of the soft chewable material were measured on days 0, 1, 7, and 28 post-manufacturing. As shown in Table 8, the pharmaceutical product maintained its rapid disintegration time, and the soft chewable material remained soft and elastic over time.

[0222] Example 9 - Preparation of soft chewable substance C:

[0223] Ivermectin / Pyrantel thiamethoxam (68 µg / 57 mg) Soft Chewable

[0224] Table 9: Composition of Soft Chewable C

[0225]

[0226] The excipients listed above are pharmaceutical grade and meet USP standards.

[0227] First, dissolve ivermectin in MCT oil using a propeller mixer and an appropriately sized container. Weigh out an additional 10% of ivermectin and MCT oil to prepare a 10% ivermectin / MCT oil excess solution. Then, use a rotary impeller mill (Comil) equipped with a 2A024R sieve. ® - Quadro Engineering Corp. (Waterloo, Ontario, Canada) grinds potassium sorbate and anhydrous citric acid. Dry ingredients, including flavoring agent, pyrantel pamoate, DCPD, and sodium stearoyl fumarate, are dispersed or sieved through a 20-mesh sieve. The ground potassium sorbate and anhydrous citric acid, along with the dispersed dry ingredients of microcrystalline cellulose and croscarmellose sodium, are loaded into a plow mixer and mixed at 100 rpm for 2 minutes. DL-α-tocopherol acetate is added to a container containing glycerin and manually mixed with a scalpel for 1 minute. While the plow mixer is operating at 100 rpm, the glycerin / DL-α-tocopherol acetate mixture is added to the blend (addition time = 2 minutes). After adding the full amount of glycerin / DL-α-tocopherol acetate, the blend is mixed for another 1 minute. While the plow mixer is operating at 100 rpm, a precise amount of ivermectin / MCT oil solution is added to the mixture (addition time = 2 minutes). Open the plow mixer and visually inspect any residue adhering to the mixer walls and plow. Scrape the residue off the mixer walls and plow and return it to the center of the mixer. Mix the blend at room temperature until the material reaches a dough-like consistency (approximately 17 minutes). Discharge the wet dough from the plow mixer and load it into a strip forming machine (Vemag Robot 500). TM The portioner is placed in the hopper of VEMAG Maschinenbau GmbH (Welden County, Germany). A strip of approximately 15” in length is formed at room temperature and placed on a parchment-lined tray. The strip is cured at room temperature for 18–24 hours. Then, using a special tool, the strip is cut into segments of 2.5 g ± 0.125 g to provide the final dosage weight of ivermectin (68 µg) and pyrantel pamoate (57 mg). These portions are then cured at room temperature for 72 hours (3 days) before being packaged in bulk.

[0228] The entire method described above was performed at ambient room temperature without the need for heating or cooling. Furthermore, the batch size was significantly increased (i.e., 50-fold) compared to the batch size used for the same formulation in Example 5.

[0229] Example 10 - Dissolution curve of soft chewable material C:

[0230] Ivermectin / Pyrantel thiamethoxam (68 µg / 57 mg) Soft Chewable

[0231] Table 10: Dissolution curves of soft chewable C

[0232]

[0233] Dissolution conditions: 4% SLS in water, 500 ml, 75 rpm, 37.0ºC ± 0.5ºC

[0234] The soft chewables of Example 9 (soft chewables C, 2.5 g / chewable) were stored at 25ºC and 60% relative humidity (RH) for 4 weeks. Dissolution tests were performed for each API (ivermectin and pyrantel pamoate) at day 3, day 3 + 2 weeks, and day 3 + 4 weeks under the conditions indicated above. Samples were taken at different time intervals to generate dissolution profiles at each given time point. As shown in Table 6 above, the dissolution profiles for each API remained rapid and consistent after the 4-week time period, without significant changes.

[0235] Example 12 - Physical properties of soft chewable material C over time:

[0236] Ivermectin / Pyrantel thiamethoxam (68 µg / 57 mg) Soft Chewable

[0237] Table 12: Physical properties of soft chewable material C over time

[0238]

[0239] *Texture was measured as the peak force (in Newtons) required to push a 1 / 4-inch diameter sphere into a soft chewable material to a depth of 2.0 mm at a speed of 1.0 mm / sec.

[0240] The soft chewable material was allowed to cure under ambient conditions over a period of 4 weeks. The texture of the soft chewable material was measured on day 3, day 3 + 2 weeks, and day 3 + 4 weeks after manufacturing. As shown in Table 12, the pharmaceutical product remained soft and elastic over time.

[0241] Example 13 - Preparation of soft chewable substance D:

[0242] Ivermectin / Pyrantel thiamethoxam (136 µg / 114 mg) Soft Chewable

[0243] Table 13: Composition of soft chewable food D

[0244]

[0245] The excipients listed above are pharmaceutical grade and meet USP standards.

[0246] First, dissolve ivermectin in MCT oil using a propeller mixer and an appropriately sized container. Weigh out an additional 10% of ivermectin and MCT oil to prepare a 10% ivermectin / MCT oil excess solution. Then, use a rotary impeller mill (Comil) equipped with a 2A024R sieve. ® Grind potassium sorbate and anhydrous citric acid. Disperse or sieve the dry ingredients of flavoring agent, dihydroxynaphthyl pyrantel, DCPD, and sodium stearoyl fumarate through a 20-mesh sieve. Load the ground potassium sorbate and anhydrous citric acid, dispersed dry ingredients of microcrystalline cellulose and croscarmellose sodium into a plow mixer and mix at 100 rpm for 2 minutes. Add DL-α-tocopherol acetate to the container containing glycerin and mix manually with a scalpel for 1 minute. While the plow mixer is operating at 100 rpm, add the glycerin / DL-α-tocopherol acetate mixture to the blend (addition time = 2 minutes). After adding the full amount of glycerin / DL-α-tocopherol acetate, mix the blend for another 1 minute. While the plow mixer is operating at 100 rpm, add the precise amount of ivermectin / MCT oil solution to the mixture (addition time = 2 minutes). Open the plow mixer and visually inspect for any residue adhering to the mixer walls and the plow. Scrape the residue off the walls and plow of the mixer and return it to the center of the mixer. Mix the blend at room temperature until the material reaches a dough-like consistency (approximately 15 minutes). Discharge the wet dough from the plow mixer and load it into a strip forming machine (Vemag Robot500). TM Place the portion into the hopper of the dispenser. Shape the strips into strips approximately 15” in length at room temperature and place them on a parchment-lined tray. Allow the strips to cure at room temperature for 18–24 hours. Then, using a special tool, cut the strips into segments of 5 g ± 0.25 g to provide the final dose weight of ivermectin (136 µg) and pyrantel pamoate (114 mg). Then, cure these portions at room temperature for 72 hours (3 days) before bulking.

[0247] The entire method described above was performed at ambient room temperature without the need for heating or cooling. Furthermore, the batch size was significantly increased (i.e., 50-fold) compared to the batch size used for the same formulation in Example 5.

[0248] Example 14 - Dissolution curve of soft chewable material D:

[0249] Ivermectin / Pyrantel thiamethoxam (136 µg / 114 mg) Soft Chewable

[0250] Table 14: Dissolution curves of soft chewable food D

[0251]

[0252] Dissolution conditions: 4% SLS in water, 1000 ml, 75 rpm, 37.0ºC ± 0.5ºC

[0253] The soft chewables of Example 13 (soft chewables D, 5 g / chewable) were stored at 25ºC and 60% relative humidity (RH) for 4 weeks. Dissolution tests were performed for each API (ivermectin and pyrantel pamoate) at day 3, day 3 + 2 weeks, and day 3 + 4 weeks under the conditions indicated above. Samples were taken at different time intervals to generate dissolution profiles at each given time point. As shown in Table 14 above, the dissolution profiles for each API remained rapid and consistent after the 4-week time period, without significant changes.

[0254] Example 15 - Stability of soft chewable material D:

[0255] Ivermectin / Pyrantel thiamethoxam (136 µg / 114 mg) Soft Chewable

[0256] Table 15: Stability of soft chewable food D

[0257]

[0258] Bulk pharmaceutical products were placed in 16" x 24" x 4" fibrous boxes lined with pseudo-parchment paper and stored under warehouse conditions. Each box contained approximately 4.5 kg of chewable material. Moisture content, average weight, ivermectin assay, and pyrantel thiamethoxam assay of the soft chewable material were tested over 3 months. As shown in Table 15, all test results remained stable over time.

[0259] Example 16 - Texture of soft chewable material D over time:

[0260] Ivermectin / Pyrantel thiamethoxam (136 µg / 114 mg) Soft Chewable

[0261] Table 16: Texture of Soft Chewable Food D over Time

[0262]

[0263] *Texture was measured as the peak force (in Newtons) required to push a 1 / 4-inch diameter sphere into a soft chewable material at a speed of 1.0 mm / sec to a depth of 2.0 mm.

[0264] The soft chewable material was allowed to cure under ambient conditions for a period of 4 weeks. The texture of the soft chewable material was measured on day 3, day 3 + 2 weeks, and day 3 + 4 weeks after manufacturing. As shown in Table 16, the soft chewable material remained soft and elastic over time.

[0265] Example 17 - Preparation of soft chewable substance E:

[0266] Ivermectin / Pyrantel thiamethoxam (272 µg / 227 mg) Soft Chewable

[0267] Table 17: Composition of Soft Chewable Food E

[0268]

[0269] The excipients listed above are pharmaceutical grade and meet USP standards.

[0270] First, dissolve ivermectin in MCT oil using a propeller mixer and an appropriately sized container. Weigh out an additional 10% of ivermectin and MCT oil to prepare a 10% ivermectin / MCT oil excess solution. Then, use a rotary impeller mill (Comil) equipped with a 2A024R sieve. ® Grind potassium sorbate and anhydrous citric acid. Disperse or sieve the dry ingredients of flavoring agent, dihydroxynaphthyl pyrantel, DCPD, and sodium stearoyl fumarate through a 20-mesh sieve. Load the ground potassium sorbate and anhydrous citric acid, dispersed dry ingredients of microcrystalline cellulose and croscarmellose sodium into a plow mixer and mix at 100 rpm for 2 minutes. Add DL-α-tocopherol acetate to the container containing glycerin and mix manually with a scalpel for 1 minute. While the plow mixer is operating at 100 rpm, add the glycerin / DL-α-tocopherol acetate mixture to the blend (addition time = 2 minutes). After adding the full amount of glycerin / DL-α-tocopherol acetate, mix the blend for another 1 minute. While the plow mixer is operating at 100 rpm, add the precise amount of ivermectin / MCT oil solution to the mixture (addition time = 2 minutes). Open the plow mixer and visually inspect for any residue adhering to the mixer walls and the plow. Scrape the residue off the walls and plow of the mixer and return it to the center of the mixer. Mix the blend at room temperature until the material reaches a dough-like consistency (approximately 15 minutes). Discharge the wet dough from the plow mixer and load it into a strip forming machine (Vemag Robot500). TMPlace the portion into the hopper of the dispenser. Shape the strips to approximately 15” in length at room temperature and place them on a parchment-lined tray. Allow the strips to cure at room temperature for 18–24 hours. Then, using a special tool, cut the strips into 10 g ± 0.5 g segments to provide the final dose weight of ivermectin (272 µg) and pyrantel pamoate (227 mg). Then, cure these segments at room temperature for 72 hours (3 days) before bulking.

[0271] The entire method described above was performed at ambient room temperature without the need for heating or cooling. Furthermore, the batch size was significantly increased (i.e., 50-fold) compared to the batch size used for the same formulation in Example 5.

[0272] Example 18 - Dissolution curve of soft chewable product E:

[0273] Ivermectin / Pyrantel thiamethoxam (272 µg / 227 mg) Soft Chewable

[0274] Table 18: Dissolution curves of soft chewable product E

[0275]

[0276] Dissolution conditions: 4% SLS in water, 2000 ml, 75 rpm, 37.0ºC ± 0.5ºC

[0277] The soft chewables of Example 17 (soft chewables E, 10 g / chewable) were stored at 25ºC and 60% relative humidity (RH) for 4 weeks. Dissolution tests were performed for each API (ivermectin and pyrantel pamoate) at day 3, day 3 + 2 weeks, and day 3 + 4 weeks under the conditions indicated above. Samples were taken at different time intervals to generate dissolution profiles at each given time point. As shown in Table 18 above, the dissolution profiles for each API remained rapid and consistent after the 4-week time period, without significant changes.

[0278] Example 19 - Texture of soft chewable food E over time:

[0279] Ivermectin / Pyrantel thiamethoxam (272 µg / 227 mg) Soft Chewable

[0280] Table 19: Texture of Soft Chewable Food E over Time

[0281]

[0282] *Texture was measured as the peak force (in Newtons) required to push a 1 / 4-inch diameter sphere into a soft chewable material at a speed of 1.0 mm / sec to a depth of 2.0 mm.

[0283] The soft chewable material was allowed to cure under ambient conditions for a period of 4 weeks. The texture of the soft chewable material was measured on day 3, day 3 + 2 weeks, and day 3 + 4 weeks after manufacturing. As shown in Table 19, the soft chewable material remained soft and elastic over time.

[0284] Example 20 - Microbiological examination of soft chewable food E:

[0285] Ivermectin / Pyrantel thiamethoxam (272 µg / 227 mg) Soft Chewable

[0286] Table 20: Microbiological examination of soft chewable food E

[0287]

[0288] According to the United States Pharmacopeia (USP) <61> and USP <62> The method described herein was used to test the microbiological levels of soft chewables. As shown in Table 20, the microbiological levels in the soft chewables were acceptable.

[0289] Example 21 - Preparation of soft chewable substance F:

[0290] Placebo soft chewable

[0291] Table 21: Composition of soft chewable food F

[0292]

[0293] The excipients listed above are pharmaceutical grade and meet USP standards.

[0294] The dry ingredients—flavoring agent, DCPD, MCC, croscarmellose sodium, and magnesium stearate—are dispersed or sieved through a 20-mesh sieve. The sieved dry ingredients are then tumbled and mixed for approximately 2 minutes. The mixed dry ingredients are then loaded into a low-shear planetary mixer (Globe SP8). TM – Globe Food Equipment Company, Dayton, Ohio, USA. While operating the mixer, add glycerin to the mixture (addition time = 2 minutes). After adding glycerin, add MCT oil to the mixture under continuous mixing (addition time = 2 minutes). Mix all components under ambient conditions until the material achieves a dough-like consistency (approximately 17 minutes). Then transfer the wet dough to a strip forming machine. Form strips approximately 25 cm in length under ambient conditions. Cure the strips at room temperature for 24 hours. Then divide the strips into segments of 10 g ± 0.5 g.

[0295] The entire method described above is performed at ambient room temperature without the need for heating or cooling.

[0296] Example 22 - Texture of soft chewable substance F:

[0297] Placebo soft chewable

[0298] Table 22: Texture of Soft Chewable Food F

[0299]

[0300] *Texture was measured as the peak force (in Newtons) required to push a 5.0 mm diameter sphere into a soft chewable material at a speed of 1.0 mm / sec to a depth of 2.0 mm.

[0301] The soft chewable material was allowed to cure under ambient conditions for 14 days. Disintegration and texture of the soft chewable material were measured on the day of manufacture (Day 0) and on Days 1, 7, and 14 after manufacture. As shown in Table 22, the soft chewable material maintained its rapid disintegration time and remained soft and elastic over time.

[0302] Example 23 - Preparation of soft chewable substance G:

[0303] Placebo soft chewable

[0304] Table 23: Composition of soft chewable food G

[0305]

[0306] The excipients listed above are pharmaceutical grade and meet USP standards.

[0307] The dry ingredients—flavoring agent, DCPD, MCC, croscarmellose sodium, and magnesium stearate—are dispersed or sieved through a 20-mesh sieve. The sieved dry ingredients are then tumbled and mixed for approximately 2 minutes. The mixed dry ingredients are then loaded into a low-shear planetary mixer (Globe SP8). TM – Universal Food Equipment, Dayton, Ohio, USA. While operating the mixer, add glycerin to the mixture (addition time = 2 minutes). After adding glycerin, add MCT oil to the mixture under continuous mixing (addition time = 2 minutes). Mix all components under ambient conditions until the material achieves a dough-like consistency (approximately 19 minutes). Then transfer the wet dough to a strip forming machine. Form strips approximately 25 cm in length under ambient conditions. Cure the strips at room temperature for 24 hours. Then divide the strips into segments of 10 g ± 0.5 g.

[0308] The entire method described above is performed at ambient room temperature without the need for heating or cooling.

[0309] Example 24 - Texture of soft chewable G:

[0310] Placebo soft chewable

[0311] Table 24: Texture of Soft Chewable Food G

[0312]

[0313] *Texture was measured as the peak force (in Newtons) required to push a 5.0 mm diameter sphere into a soft chewable material at a speed of 1.0 mm / sec to a depth of 2.0 mm.

[0314] The soft chewable material was allowed to cure under ambient conditions for 14 days. Disintegration and texture of the soft chewable material were measured on the day of manufacture (Day 0) and on Days 1, 7, and 14 after manufacture. As shown in Table 24, the soft chewable material maintained its rapid disintegration time and remained soft and elastic over time.

[0315] All publications, patents and patent applications are incorporated herein by reference in their entirety to the same extent as each individual publication, patent or patent application expressly and individually indicates that they are incorporated herein by reference in their entirety.

[0316] While certain embodiments have been shown and described herein, it will be apparent that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will become apparent to those skilled in the art without departing from these embodiments; it should be understood that various alternatives to the embodiments described herein may be employed in the practice of the compositions and methods described herein. Although the foregoing invention has been described in considerable detail for purposes of clarity and understanding, those skilled in the art will appreciate, upon reading this disclosure, that various changes in form and detail may be made without departing from the true scope of the invention as set forth in the appended claims.

Claims

1. A starch-free soft chewable formulation for the oral delivery of at least one active ingredient to animals, the formulation comprising a non-starch solid excipient, a non-aqueous liquid excipient, and at least one active ingredient. The non-starch solid excipient contains at least: 10% - 60% w / w dicalcium phosphate, and 5% -40% w / w microcrystalline cellulose, and The non-aqueous liquid excipient contains at least: 15% - 50% w / w glycerin, and 2% - 20% w / w triglycerides of fatty acids, wherein the triglycerides of these fatty acids are medium-chain triglycerides. in, The triglycerides of this fatty acid have a C6-C12 carbon chain length, and This formulation does not contain starch, nor does it contain water as an excipient or any added water.

2. The soft chewing formulation of claim 1, wherein the formulation further comprises a flavoring agent.

3. The soft chewing formulation of claim 1, wherein the formulation further comprises a binder.

4. The soft chewing formulation of claim 1, wherein the formulation further comprises a disintegrant.

5. The soft chewing formulation of claim 1, wherein the formulation further comprises a surfactant.

6. The soft chewing formulation of claim 1, wherein the dicalcium phosphate is hydrated.

7. The soft chewable formulation of claim 6, wherein the dicalcium phosphate is dicalcium phosphate dihydrate.

8. The soft chewing formulation of claim 1, wherein the non-starch solid excipient further comprises lactose.

9. The soft chewing formulation of claim 8, wherein the lactose is lactose monohydrate.

10. The soft chewing formulation according to any one of claims 1 and 6-9, wherein the weight ratio of dicalcium phosphate to microcrystalline cellulose is 1:1 to 4:

1.

11. The soft chewing formulation of claim 10, wherein the weight ratio of dicalcium phosphate to microcrystalline cellulose is 2:1 to 3:

1.

12. The soft chewing formulation of claim 1, wherein the weight ratio of glycerol to the triglyceride of the fatty acid is 4:1 to 7:

1.

13. The soft chewing formulation of claim 12, wherein the weight ratio of glycerol to the triglyceride of the fatty acid is 5:1 to 6:

1.

14. The soft chewing formulation according to any one of claims 1-13, comprising croscarmellose sodium.

15. The soft chewing formulation according to any one of claims 1-14, comprising magnesium stearate, stearic acid, or sodium stearoyl fumarate.

16. The soft chewing formulation according to any one of claims 1-15, comprising citric acid.

17. The soft chewing formulation of claim 16, wherein the citric acid is anhydrous citric acid.

18. The soft chewing formulation according to any one of claims 1-17, comprising potassium sorbate.

19. The soft chewable formulation according to any one of claims 1-18, comprising α-tocopherol.

20. The soft chewable formulation of claim 19, wherein the α-tocopherol is DL-α-tocopherol acetate.

21. The soft chewing formulation according to any one of claims 1-20, comprising povidone, hydroxypropyl cellulose or hydroxymethyl cellulose.

22. The soft chewing formulation of claim 7, wherein the weight ratio of dicalcium phosphate dihydrate to microcrystalline cellulose is 2:1 to 3:

1.

23. The soft chewable formulation of claim 22, wherein the weight ratio of glycerol to medium-chain triglycerides is 5:1 to 6:

1.

24. The soft chewing formulation of claim 2, wherein the formulation comprises 20%-30% w / w of flavoring.

25. The soft chewable formulation of claim 1, further comprising: Crosslinked carboxymethyl cellulose sodium; and Magnesium stearate or sodium stearoyl fumarate.

26. The soft chewing formulation of claim 25, comprising, by weight ratio of, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, flavoring, croscarmellose sodium, glycerol, medium-chain triglycerides and magnesium stearate in the form of calcium hydrogen phosphate dihydrate, microcrystalline cellulose, flavoring, croscarmellose sodium, glycerol, medium-chain triglycerides and magnesium stearate.

27. The soft chewing formulation of claim 25, comprising, by weight ratio of, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, flavoring, croscarmellose sodium, glycerol, medium-chain triglycerides and magnesium stearate in the form of calcium hydrogen phosphate dihydrate, microcrystalline cellulose, flavoring, croscarmellose sodium, glycerol, medium-chain triglycerides and magnesium stearate.

28. The soft chewable formulation according to any one of claims 25-27, further comprising: Anhydrous citric acid; Potassium sorbate; and DL-α-Tocopherol Acetate.

29. The soft chewing formulation according to any one of claims 1-28, wherein the formulation has a texture value of 11N or lower 4 weeks after preparation, wherein the texture value is measured as the peak force necessary to push a 5.0 mm diameter sphere into a soft chewing material having a depth of 2.0 mm at a speed of 1.0 mm / sec to a depth of 2.0 mm.

30. The soft chewable formulation of claim 29, wherein the at least one active ingredient comprises an active pharmaceutical ingredient.

31. The soft chewable formulation of claim 30, wherein the active pharmaceutical ingredient is an antiparasitic drug.

32. The soft chewable formulation of claim 31, wherein the active pharmaceutical ingredient is an anthelmintic.

33. The soft chewable formulation of claim 32, wherein the active pharmaceutical ingredient is milbemycin oxime, ivermectin, moxifloxacin, avermectin, silaquine, pyrantel, febantel, fenbendazole, octendaazole, amedas, piperazine, mebendazole, levamisole, praziquantel, or octendaazole.

34. The soft chewable formulation of claim 33, wherein the active pharmaceutical ingredient is milbemycin oxime, praziquantel, ivermectin, or pyrantel pamoate.

35. The soft chewable formulation according to any one of claims 30-34, wherein the at least one active ingredient further comprises a second active pharmaceutical ingredient.

36. The soft chewable formulation of claim 35, wherein the second active pharmaceutical ingredient is an antiparasitic drug.

37. The soft chewable formulation of claim 36, wherein the second active pharmaceutical ingredient is an anthelmintic.

38. The soft chewable formulation according to any one of claims 35-37, wherein the at least one active ingredient comprises: milbemycin oxime or ivermectin; and praziquantel or pyrimethamine.

39. The soft chewable formulation of claim 38, wherein the at least one active ingredient comprises milbemycin oxime and praziquantel.

40. The soft chewable formulation of claim 38, wherein the at least one active ingredient comprises ivermectin and pyrantel pamoate.

41. The soft chewable formulation of claim 40, wherein the pyrantel is bis(hydroxynaphthyl)pyrantel.

42. The soft chewable formulation of claim 29, wherein the at least one active ingredient is moisture-sensitive.

43. The soft chewable formulation of claim 42, wherein the at least one active ingredient comprises clavulanic acid, acetamiprid, milbemycin oxime, or ivermectin.

44. The soft chewable formulation of claim 32, wherein the active pharmaceutical ingredient is moisture-sensitive.

45. The soft chewable formulation of claim 44, wherein the active pharmaceutical ingredient is milbemycin oxime or ivermectin.

46. ​​The soft chewable formulation of claim 29, wherein the at least one active ingredient comprises an active nutrient.

47. The soft chewable formulation of claim 46, wherein the active nutrient is glucosamine, an enzyme, fish oil, or a herbal ingredient.

48. The soft chewing formulation according to any one of claims 1-23, comprising: 24.585%-30% w / w of calcium hydrogen phosphate dihydrate; 20%-30% w / w of flavoring agent; 8%-10% w / w of microcrystalline cellulose; 0%-15% w / w of croscarmellose sodium; 0%-5% w / w of sodium stearoyl fumarate or magnesium stearate; 25%-28% w / w of glycerol; 4.575%-5% w / w of medium-chain triglycerides; 0%-5% w / w of anhydrous citric acid; 0.01%-3% w / w of potassium sorbate; and 0.01%-3% w / w of DL-α-tocopherol acetate.

49. The soft chewing formulation according to any one of claims 1-23, comprising: 24.585%, 25%, 29% or 30% w / w of calcium hydrogen phosphate dihydrate; 20%, 23% or 30% w / w of flavoring; 8%, 9.66% or 10% w / w of microcrystalline cellulose; 0%-15% w / w of croscarmellose sodium; 0%-5% w / w of sodium stearoyl fumarate or magnesium stearate; 25%, 26% or 28% w / w of glycerol; 4.575% or 5% w / w of medium-chain triglycerides; 0%-5% w / w of anhydrous citric acid; 0.01%-3% w / w of potassium sorbate; and 0.01%-3% w / w of DL-α-tocopherol acetate.

50. A starch-free, non-aqueous composition for use in a final oral dosage form in animals, said composition comprising essentially a non-starch solid excipient, a non-aqueous liquid excipient, and at least one active ingredient, said starch-free, non-aqueous composition comprising: 10% - 60% w / w dicalcium phosphate; 5% -40% w / w microcrystalline cellulose; condiment; 15% - 50% w / w glycerin; and 2% - 20% w / w triglycerides of fatty acids with a carbon chain length of C6-C12, wherein the triglycerides of these fatty acids are medium-chain triglycerides. in, The composition does not contain starch, nor does it contain water as an excipient or added water.

51. The composition of claim 50, wherein the dicalcium phosphate is hydrated dicalcium phosphate.

52. The composition of claim 51, wherein the dicalcium phosphate is dicalcium phosphate dihydrate.

53. The composition according to any one of claims 50-52, wherein the weight ratio of dicalcium phosphate to microcrystalline cellulose is 1:1 to 4:

1.

54. The composition according to any one of claims 50-52, wherein the weight ratio of dicalcium phosphate to microcrystalline cellulose is 2:1 to 3:

1.

55. The composition according to any one of claims 50-54, wherein the weight ratio of glycerol to the triglyceride of the fatty acid is 4:1 to 7:

1.

56. The composition according to any one of claims 50-54, wherein the weight ratio of glycerol to the triglyceride of the fatty acid is 5:1 to 6:

1.

57. The composition of any one of claims 50-56, wherein the starch-free, non-aqueous composition further comprises a filler.

58. The composition of claim 57, wherein the filler is lactose.

59. The composition of claim 58, wherein the lactose is lactose monohydrate.

60. The composition of any one of claims 50-59, wherein the starch-free, non-aqueous composition further comprises a flavoring agent.

61. The composition of any one of claims 50-60, wherein the starch-free non-aqueous composition further comprises a disintegrant.

62. The composition of claim 61, wherein the disintegrant is croscarmellose sodium.

63. The composition of any one of claims 50-62, wherein the starch-free, non-aqueous composition further comprises a lubricant.

64. The composition of claim 63, wherein the lubricant is magnesium stearate, stearic acid, or sodium stearoyl fumarate.

65. The composition of any one of claims 50-64, wherein the starch-free, non-aqueous composition further comprises a preservative.

66. The composition of claim 65, wherein the preservative is citric acid or potassium sorbate.

67. The composition of any one of claims 50-66, wherein the starch-free non-aqueous composition further comprises an antioxidant.

68. The composition of claim 67, wherein the antioxidant is citric acid or α-tocopherol.

69. The composition of claim 66 or 68, wherein the citric acid is anhydrous citric acid.

70. The composition of claim 68, wherein the α-tocopherol is DL-α-tocopherol acetate.

71. The composition of any one of claims 50-70, wherein the starch-free, non-aqueous composition further comprises a binder.

72. The composition of claim 71, wherein the adhesive is polyvinylpyrrolidone.

73. The composition of claim 72, wherein the povidone is povidone K30.

74. The composition of any one of claims 50-73, wherein the at least one active ingredient comprises at least one active pharmaceutical ingredient or at least one active nutrient ingredient.

75. The composition of any one of claims 50-74, wherein the at least one active ingredient comprises an active pharmaceutical ingredient.

76. The composition of claim 75, wherein the active pharmaceutical ingredient is an antiparasitic drug.

77. The composition of claim 76, wherein the active pharmaceutical ingredient is an anthelmintic.

78. The composition of any one of claims 50-74, wherein the at least one active ingredient comprises an active nutrient.

79. A method for manufacturing a starch-free soft chewable for orally delivering at least one active ingredient to an animal, the method comprising the steps of: a) Dry-mix at least two non-starch solid excipients in a mixer, the non-starch solid excipients comprising 10%-60% w / w dicalcium phosphate and 5%-40% w / w microcrystalline cellulose; and b) By adding at least two non-aqueous liquid excipients to the mixer, the at least two non-starch solid excipients are mixed into a dough-like material, the non-aqueous liquid excipients comprising 15%-50% w / w glycerol and 2%-20% w / w triglycerides of fatty acids, the triglycerides of fatty acids being medium-chain triglycerides having a C6-C12 carbon chain length. This does not include the step of adding starch or water. Prior to step b), the at least one active ingredient is premixed with the at least two non-starch solid excipients or the at least two non-aqueous liquid excipients.

80. The method of claim 79, further comprising the following steps: c) Shape the dough-like material into a strip.

81. The method of claim 80, further comprising the following steps: d) Divide the strip into soft chewable portions.

82. The method of claim 81, further comprising the following steps: e) Package the soft chewable portion.

83. The method according to any one of claims 79-82, wherein, Prior to step b), the at least one active ingredient is premixed with the non-starch solid excipient.

84. The method of any one of claims 79-83, wherein step b) is carried out by adding the at least two non-aqueous liquid excipients sequentially to the mixer.

85. The method of claim 79, wherein glycerol is used as a humectant and medium-chain triglycerides are used as a solvent.

86. The method of claim 85, wherein the humectant is first added to the mixer and the solvent is subsequently added to the mixer.

87. The method according to any one of claims 79-86, wherein, Prior to step b), the at least one active ingredient is premixed with one of the non-aqueous liquid excipients.

88. The method of claim 85 or 86, wherein the at least one active ingredient is mixed with the solvent.

89. The method of claim 79, wherein the mixer is a low-shear mixer.

90. The method of claim 79, wherein the mixer is a high-shear mixer.

91. The method of claim 81, wherein a partitioning tool is used for the partitioning step.

92. The method of any one of claims 79-91, wherein the method is performed at ambient room temperature.

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