Veterinary soft chewable product and its manufacturing method

Abstract

A soft chewable product (1) for oral administration having at least one pair of score marks (5, 6), configured to favor division of the product into doses (1a, 1b), wherein the force required to divide the product (1) into doses (1a, 1b) along the at least one pair of score marks (5, 6) is 10 to 60 N, and the mass loss during division of the product (1) into doses (1a, 1b) is 0.5%.

Description

[Technical Field]

[0001] The present invention relates to products in soft chewable form, in particular soft chews that can be easily divided into multiple doses by the application of moderate manual force. The subject of the invention is more particularly such products for veterinary use, in particular for dogs and cats, and methods for their manufacture. [Background technology]

[0002] In the veterinary field, oral administration is the easiest and most convenient method of administration for animals, or at least for their owners. A wide variety of dosage forms have been developed for oral administration, including solid dosage forms, of which tablets are the most common.

[0003] Hard tablets and chewable tablets are manufactured from conventional powder, granule, or fine powder materials. Their dry, rough texture is often unappealing to many animals. Furthermore, hard tablets and chewable tablets tend to disintegrate in the oral cavity when chewed by an animal, and pieces of the tablet often fall out of the animal's mouth. This reduces dosage compliance.

[0004] In contrast, soft chewable products have a soft texture, a pleasant mouthfeel, a palate that is pleasing to the animal, and are generally readily accepted by the animal. Furthermore, soft chewable tablets differ significantly from hard or chewable tablets in that they are wettable and maintain sufficient cohesion when chewed by the animal, without disintegrating.

[0005] Soft chewable products are often unit doses of a consistent shape and weight containing the same amount of active ingredient, and are almost exclusively obtained by compressing, molding, or extruding a paste containing the active ingredient.

[0006] Because the amount of active ingredient to be administered can vary from patient to patient, particularly depending on the patient's weight, animal health product manufacturers have developed different sizes of products to target broader or narrower weight ranges. For example, a veterinary product may be sold in tablet form for dogs weighing 20 to 40 kg. Administering the tablet to a 20 kg dog may result in an overdose, which could lead to adverse reactions, while administering the same tablet to a 40 kg dog may result in an underdose, which could result in a compromised therapeutic effect.

[0007] However, offering products for narrower weight ranges is practically and economically limited, as it would require more manufacturing campaigns and more product forms for different dosage strengths of the same product.

[0008] The prior art describes products consisting of soft, divisible chewable compositions. Patent document 1 describes the possibility of providing a soft chew obtained by molding with a score, cross score or score marking on one side. Patent document 2 describes a "soft tablet" with score marking for dividing the tablet into up to four doses.

[0009] The prior art also describes providing score markings on opposite sides of hard tablets to facilitate division. However, soft chews and hard tablets differ significantly in their rheological properties: solid tablets are designed to be hard, brittle, and resistant to fracture, while soft chews are flexible (ductile), easily deformed, and have a plastic texture.

[0010] The phenomenon of a material breaking (or fracturing) into two or more pieces under stress is known to vary depending on whether the material is brittle or ductile. In brittle materials, such as tablets, fracture occurs through a mechanism known as brittle fracture. When stress is applied to a material, the material does not deform, and fracture occurs when the applied stress reaches its maximum yield strength (ultimate yield strength). Fracture results from the spontaneous and extremely rapid growth of unstable cracks. The fracture surface is typically smooth. Reducing the thickness of the tablet with a notch marking creates a predetermined weakness that reduces the ultimate yield strength, allowing cracks to form at lower stresses. Adding a second notch marking opposite the first creates a predetermined fracture path that guides the crack propagation. The fracture surface is essentially smooth, extending from one groove to the other.

[0011] In the case of ductile materials like soft chews, failure occurs through a mechanism known as ductile fracture; unlike brittle materials, the material deforms under stress, but does not fail when it reaches its ultimate yield strength. Fracture occurs when the material reaches its plastic limit. The material does not literally break, but rather tears apart by the formation of a stable crack that propagates, not spontaneously, but under the action of additional stress. The fracture surface is usually irregular due to the deformation the material underwent prior to failure. In ductile products like soft chews, notch markings can reduce the stress required for crack initiation, making them easier to separate, but once initiated, the crack will not propagate spontaneously. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] U.S. Patent Application Publication No. 2014 / 0141055 [Patent Document 2] U.S. Patent Application Publication No. 2020 / 0360290 Summary of the Invention [Problem to be solved by the invention]

[0013] The object of the present invention is to solve the problems associated with the divisibility of prior art soft chewable products by improving the accuracy of division and the precision of the dose obtained after division, while reducing the risk of contamination to the user with the active ingredients in the soft chew composition. [Means for solving the problem]

[0014] It has been discovered that by carefully selecting the rheological properties of the product and the placement of the score markings on the product, the soft chewable product can be more easily divided into doses.

[0015] The present invention therefore proposes a soft chewable product for oral administration comprising a pharmaceutical, veterinary or nutraceutical active substance, a humectant and a molding agent, the soft chewable product having a pair of opposing score markings on opposite faces of the product, the force required to separate the product into doses along the pair of score markings is preferably 10-60 N, and the mass loss during separation of the product into doses is less than 0.5%. Preferably, the combined depth of the two score markings exceeds 10% of the thickness of the product.

[0016] "Soft chewable product" refers to a dimensionally stable pharmaceutical unit dosage form that has a soft and elastic (ductile) texture. Soft chewable products have a higher moisture content than conventional tablets or chewable tablets. Unlike chewable or hard tablets, soft chewable products are deformable without breaking. In other words, they may be dropped and eventually deform without breaking. In the present invention, the soft chewable product is preferably a soft chew intended for animals such as dogs and cats.

[0017] The physical characteristics of the soft chewable product of the present invention, such as the configuration of the score markings, facilitate the simple application of moderate force to divide the product evenly along the score markings. The risk of contamination to the person dividing the product is also limited. Furthermore, by adjusting the number of score markings, the product can be divided into 2, 4, 6, 8, or any other fraction, with each divided piece containing a controlled amount of active ingredient.

[0018] To provide a soft chewable product that can be easily divided without mass loss, other characteristics such as the hardness and friability of the soft chew must also be considered, as these affect the texture of the soft chew and also affect the mass loss when the soft chew product is divided. The friability of a soft chew is an indicator of its tendency to easily crumble or disintegrate upon pressure or handling, and is a measure of the structural integrity and resistance to disintegration of the soft chew. A lower friability indicates a soft chew product that is less likely to break or disintegrate, while a higher friability indicates a soft chew that is more likely to disintegrate or disintegrate.

[0019] In other words, it is an object of the present invention to provide a soft chewable product that contains a defined and reproducible amount of a substance and that can be divided into two or more portions if necessary. Dividing the product allows for easy adjustment of the amount of substance to be administered depending on the dosage and / or the body weight of the recipient. A pair of notch markings configured to facilitate dose division of the product can demarcate portions of unequal size and weight of the product, or portions of the product of the same size and weight.

[0020] Because the entire product, any divided portion, or multiples of the divided portions can be administered, e.g., 1 / 8, 2 / 8, 3 / 8, 4 / 8, 5 / 8, 6 / 8, 7 / 8, or 8 / 8 for an 8-divisible product, the products of the present invention have the following advantages, among others: - The same product can be used to administer precise amounts of substance to subjects with significantly different weights. For example, if each dose of product contains the dose per 10 kg of subject weight, a 30 kg subject can be administered 3 / 8 of the product, and a 70 kg subject can be administered 7 / 8 of the product. This avoids over- or under-dosing. - If a dose requires multiple administrations, multiple doses of the same product can be administered sequentially. For example, if a product requires twice-daily administration, the product can be divided into two halves and each dose administered at a predetermined time of day. - The same product can be administered multiple times to subjects who have difficulty swallowing the product in one dose. For example, the product can be divided into smaller, easier-to-swallow doses for elderly or pediatric subjects. - The same product can be administered to multiple subjects simultaneously, such as in hospitals, clinics, veterinary clinics, etc., where multiple subjects receive the same treatment at the same time.

[0021] It is also noteworthy that the products of the present invention can increase the exchange surface area of ​​the undivided product due to the presence of one or more indentation markings, which can facilitate the diffusion of the composition within the body and thus enhance the therapeutic effect when the product is used undivided.

[0022] An additional benefit is that the same multi-dose product reduces the amount of packaging used - for example, if a product requires twice-daily dosing, the product can be packaged in one blister instead of two.

[0023] The features of the present invention can be implemented independently of one another or in all technically possible combinations, constituting a wide variety of variants of the invention. - The force required to separate the product along the notch marking is 20-55N; - The mass loss during division is less than 0.1% of the total mass of the product; - The notch marking has a V-shaped cross section, - at least one notch marking extends parallel to a larger dimension of the product; - the product is formed by extrusion, compression or molding; - at least one notch marking is provided with a cutting start; - the hardness of the product is 10 to 300N, preferably 10 to 150N, more preferably 30 to 80N; - the friability of the product is less than 1%, preferably less than 0.5%, more preferably less than 0.2%; - Each pair of opposing notch markings, independent of the other, has a depth of 1 / 20 to 4 / 10 of the thickness of the product; - the total depth of the two notch markings and pairs of notch markings is greater than 20%, preferably greater than 30%, more preferably greater than 40%, and in certain embodiments greater than 50%; - the two notch markings have the same depth, and the depth of each notch marking is 5-45%, preferably 10-45%, more preferably 25-35% of the thickness of the product; - the notch marking (called the primary notch marking) runs in particular parallel to the long edge of the product, - All notch markings run parallel to the longest edge of the product; - Alternatively, other notch markings (called additional notch markings) extend transversely to the longest edge of the product; - the notch marking or pairs of notch markings form a grid on the product surface; - The notch markings are configured to allow the product to be divided into 4, 6 or 8 doses; - the notch markings are configured to be divisible into identical doses; - the product has a cylindrical, oval, elongated, or rectangular and / or parallelepiped shape, - the product has a base and protrusions extending from the base and separated by notched markings; - the base has a substantially rectangular cross section; - The mass of the product is between 100mg and 20g; - the pharmaceutical, veterinary or nutraceutical active substance is homogeneously distributed throughout the product; - the product further comprises an excipient; - the product is intended for use as a medicinal product administered to a recipient, for human or veterinary use; - the product is intended to be administered multiple times, in particular for a single and identical treatment; - the product is intended to be administered at defined and / or regular intervals, each dose providing an amount of pharmaceutical, veterinary or nutraceutical active substance that is effective in the treated subject until the next administration; - The doses of the product are intended to be administered multiple times per day, multiple days per week, and / or multiple days per month, - the product is intended to be administered to elderly or pediatric recipients; - the product is intended to be administered to a non-human mammal, preferably a pet, - the product is intended to be administered to dogs or cats, preferably dogs;

[0024] The present invention also provides a method for producing such a molded soft chewable product.

[0025] Preferably, the method comprises the steps of: (a) obtaining a composition; (b) forming said composition to obtain a shaped soft chewable product.

[0026] According to a first embodiment, the shaping of the composition is carried out by compression or moulding, and at least one notch marking is cut out in step (b), in particular by means of a mould of suitable shape.

[0027] According to another embodiment, the shaping is carried out by extrusion and at least one notch marking is cut out in step (b) by means of a die of particular suitable shape.

[0028] The present invention will be better understood, and other objects, details, features and advantages will become apparent, from the following detailed description of at least one embodiment, in accordance with at least one embodiment of the invention described herein, which is purely illustrative and non-limiting, and which refers to the accompanying schematic drawings, in which: [Brief explanation of the drawings]

[0029] [Figure 1] 1 is a perspective view schematically illustrating a first embodiment of a product according to the present invention. [Figure 2] FIG. 2 is a perspective view schematically showing a second embodiment of the product according to the present invention. [Figure 3] FIG. 10 is a perspective view schematically showing a third embodiment of the product according to the present invention. [Figure 4] FIG. 2 is a side view schematically showing a first test performed on the product of FIG. 1. [Figure 5] FIG. 2 is a side view schematically showing a second test performed on the product of FIG. 1. [Figure 6] FIG. 1 shows a soft chew showing high friability after attempting to split it by hand. DETAILED DESCRIPTION OF THE INVENTION

[0030] In these figures, the same reference numbers indicate the same or similar elements.

[0031] The present invention relates to a soft chewable product 1 for oral administration, the soft chewable product 1 comprising a pharmaceutical, veterinary or nutraceutical active substance, a humectant, and a molding agent, the product 1 having at least one pair of opposing score markings 5, 6 on opposite faces 3a, 3b of the product, the score markings configured for dividing the product into doses 1a, 1b, wherein the combined depth of the pair of score markings 5, 6 exceeds 10% of the thickness of the product 1, and the mass loss during division of the product 1 into doses 1a, 1b is less than 0.5%.

[0032] As shown in Figures 1-3, the present invention provides a soft chewable product 1 for oral administration, which has at least one score marking 5, 6 configured to facilitate dividing the product into doses 1a, 1b, 1c, 1d.

[0033] Score markings 5 ​​and 6 indicate the state before separation. To separate product 1, a user can grasp two different areas of the product with the thumb and index finger of one hand. The user then separates the two halves along at least one score marking 5 and 6.

[0034] According to the present invention, to achieve controlled and uniform manual division of the product, the product has score markings 5, 6 configured such that the force required to divide the product along the score markings 5, 6 into doses is 10-60 N and the mass loss during division into doses is less than 0.5%. These characteristics ensure that each dose contains a controlled amount of substance. They also reduce the risk of contamination for the user.

[0035] The soft chewable products of the present invention are characterized by a flexible (ductile) texture, softness, and susceptibility to elastic deformation. The products of the present invention are also characterized by their texture, in particular in that the hardness of the products is preferably 10 to 300 N. Unlike solid tablets (e.g., chewable tablets and hard tablets), the products of the present invention are deformable without breaking.

[0036] Unlike tablets, soft chews are flexible and lack the structural integrity to divide cleanly, tending to deform and stretch rather than break cleanly.

[0037] Hardness corresponds to the force required to produce a given deformation in the product.

[0038] As shown in FIG. 4, in the present invention, hardness is measured using a texturometer, in particular a TA XT2i (Stable Micro Systems), at a temperature of 18 to 25° C. using a spherical probe with a diameter of 8 mm, with the following parameters: Test mode compression Pretest speed: 1.00 mm / sec Test speed: 1.00mm / sec Post-test speed: 10.00 mm / sec Target Mode Distance Distance: 2.00mm Trigger Type: Automatic (Force) Release force: 0.5N Measurement points per second: 25

[0039] These parameters are set, for example, directly in the texturometer software.

[0040] Briefly, the product 1 as a test sample was placed on a flat base / surface 10, and a spherical probe 12 was lowered onto the sample at a predetermined speed for a distance of 2 mm. The sample 1 was deformed by the probe 12, and the resistance corresponding to the force required to penetrate 2 mm was recorded. The measured resistance (N) corresponds to the hardness of the product. The test was performed on the sample 1 at a position away from the indentation markings 5 ​​and 6.

[0041] The product of the invention advantageously has a hardness of between 10 and 150N, preferably between 30 and 80N.

[0042] The composition of the products of the invention can vary widely. Suitable compositions for obtaining products with textural properties are described, for example, in WO 2005 / 013714, WO 2022 / 049149, WO 2021 / 180603, WO 2016 / 073347, WO 2009 / 064859, WO 2014 / 079825, WO 2007 / 067582 ... These are described in International Publication No. WO 2020 / 172232, International Publication No. WO 2021 / 013825, International Publication No. WO 2013 / 119442, International Publication No. WO 2013 / 150052, International Publication No. WO 2021 / 046296, International Publication No. WO 2019 / 021191, International Publication No. WO 2014 / 141223 and International Publication No. WO 2012 / 049156.

[0043] The soft chewable products of the present invention comprise a pharmaceutical, veterinary or nutraceutical active agent, a humectant and a bulking agent.

[0044] As used herein, the term "humectant" refers to a substance that has the effect of maintaining the softness of the soft chew during the shelf life of the product. Preferably, the humectant is selected from the group consisting of propylene glycol, glyceryl triacetate, vinyl alcohol, neoagarobiose, glycerol, sugar polyols such as sorbitol, xylitol, and maltitol, polymeric polyols such as polydextrose, caprylic / capric triglyceride, propylene glycol dicaprylate / dicaprate, medium-chain triglycerides sold under the trademark Miglyol®, particularly Miglyol 812 or 814, vegetable oils, or mixtures thereof.

[0045] As used herein, the term "former" refers to a substance that imparts texture to a soft chewable product.

[0046] Preferably, the molding agent is selected from the group consisting of polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, various grades of polyethylene glycol including PEG 3350, PEG 4000, PEG 6000 and PEG 8000, copolymers of vinylpyrrolidone and vinyl acetate, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymers (poloxamers), microcrystalline wax, cetyl alcohol, polysaccharides, hydroxypropyl methylcellulose, poly(meth)acrylates, alkyl poly(meth)acrylates and mixtures thereof.

[0047] Preferably, the soft chewable product further comprises a filler (or diluent).

[0048] As used herein, the term "filler" refers to a food product whose main component is starch and / or starch-like substances.

[0049] Preferably, the filler is selected from the group consisting of starch such as corn starch, rice starch or potato starch, sucrose, powdered sugar, lactose including anhydrous lactose, hydrated lactose, spray dried lactose, dextrin, decylates, mannitol, soy grits, soy protein fines, microcrystalline cellulose, silicided microcrystalline cellulose, calcium phosphate, crystalline maltose, maltodextrin and mixtures thereof. More preferably, the filler is selected from the group consisting of corn starch, lactose, microcrystalline cellulose, powdered sugar and mixtures thereof.

[0050] Preferably, the soft chewable product further comprises paratant.

[0051] As used herein, "paratant" refers to an inactive ingredient that encourages pets to ingest the veterinary dosage form of the present invention. The paratant of the present invention can be used in the form of a dry powdered paratant, a non-powdered paratant, or a system that combines the dry powdered paratant and the non-powdered paratant.

[0052] Paratants include chicken, turkey, beef, pork, lamb, fish, eggs, cheese, seafood, vegetables and vegetable ingredients, yeast (e.g., brewer's yeast), yeast extract, and mixtures thereof. Natural meat-derived paratants are derived from meat, meat products, organ meats, yeast extract, vegetable ingredients, and mixtures thereof. For example, oral veterinary compositions can use animal-derived foods such as dried or powdered meats and meat parts, such as beef, pork, chicken, turkey, fish, and lamb; organ meats, such as liver and kidney; animal-based flavorings, such as meat meal, bone meal, and ground bone; casein; milk (which can include dried milk, such as dried skim milk, and low-fat milk); yogurt; gelatin; cheese; and eggs (collectively, "animal-derived paratants"). Non-animal-derived palatants include essential oils, oleoresins, essences or extracts, protein hydrolysates, distillates, roasting, heating, or enzymatic degradation products, including flavor components derived from spices, fruits or fruit juices, vegetables or vegetable juices, edible yeasts (active and inactive), herbs, bark, buds, roots, leaves, or other edible parts of plants. The type and amount of palatant can be easily determined by one skilled in the art. More preferably, the palatant is selected from the group consisting of animal-derived palatants such as dried or powdered meat and meat parts, such as beef, pork, chicken, turkey, fish, and lamb; organ meats, such as liver and kidney; meat meal, bone meal, and ground bone; and non-animal-derived palatants, such as yeast, yeast extract, and glutamic acid. The most preferred palatants are chicken (or poultry) liver meal, yeast, yeast extract, and mixtures thereof.

[0053] In a preferred embodiment, the soft chewable product comprises: - pharmaceutical, veterinary or nutraceutical active substances, - a moisturizing agent selected from the group consisting of propylene glycol, glyceryl triacetate, vinyl alcohol, neoagarobiose, glycerol, sugar polyols such as sorbitol, xylitol and maltitol, polymeric polyols such as polydextrose, caprylic / capric triglyceride, propylene glycol dicaprylate / dicaprate, medium chain triglycerides sold under the trademark Miglyol, in particular Miglyol 812 or 814, vegetable oils, or mixtures thereof; - a molding agent selected from the group consisting of polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, various grades of polyethylene glycol including PEG 3350, PEG 4000, PEG 6000 and PEG 8000, copolymers of vinylpyrrolidone and vinyl acetate, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymers (poloxamers), microcrystalline wax, cetyl alcohol, polysaccharides, hydroxypropyl methylcellulose, poly(meth)acrylates, alkyl poly(meth)acrylates and mixtures thereof; a filler selected from the group consisting of starch such as corn starch, rice starch or potato starch, sucrose, powdered sugar, lactose including anhydrous lactose, hydrated lactose, spray dried lactose, dextrin, decylates, mannitol, soy grits, soy protein fines, microcrystalline cellulose, silicided microcrystalline cellulose, calcium phosphate, crystalline maltose, maltodextrin and mixtures thereof; - Paratants selected from the group consisting of animal-derived paratants such as dried or powdered meat and meat parts such as beef, pork, chicken, turkey, fish, lamb, etc., organ meats (liver, kidney, etc.), meat meal, bone meal and ground bone, or non-animal-derived paratants such as essential oils, oleoresins, essences or extracts, protein hydrolysates, distillates, products of roasting, heating or enzymatic degradation, containing flavoring ingredients derived from spices, fruits or fruit juices, vegetables or vegetable juices, edible yeasts (active and inactive), herbs, bark, buds, roots, leaves or other edible parts of plants, and mixtures thereof.

[0054] Of note, soft chewable products contain, based on total product weight: - 0.01 to 30%, preferably 0.1 to 20%, more preferably 5 to 15% of a pharmaceutical, veterinary or nutraceutical active substance, - 5 to 40%, preferably 10 to 30%, more preferably 10 to 20% of a humectant, preferably selected from the group consisting of propylene glycol, glyceryl triacetate, vinyl alcohol, neoagarobiose, glycerol, sugar polyols such as sorbitol, xylitol and maltitol, polymeric polyols such as polydextrose, caprylic / capric triglyceride, propylene glycol dicaprylate / dicaprate, medium chain triglycerides sold under the trademark Miglyol, in particular Miglyol 812 or 814, vegetable oils, or mixtures thereof, - 1 to 40%, preferably 1 to 20%, more preferably 10 to 20% of a molding agent, preferably selected from the group consisting of polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, various grades of polyethylene glycol including PEG 3350, PEG 4000, PEG 6000 and PEG 8000, copolymers of vinylpyrrolidone and vinyl acetate, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymers (poloxamers), microcrystalline wax, cetyl alcohol, polysaccharides, hydroxypropyl methylcellulose, poly(meth)acrylates, alkyl poly(meth)acrylates and mixtures thereof; - 10-60%, preferably 15-45%, more preferably 15-35% of a filler, preferably selected from the group consisting of starch such as corn starch, rice starch or potato starch, sucrose, powdered sugar, lactose including anhydrous lactose, hydrated lactose, spray dried lactose, dextrin, decylates, mannitol, soy grits, soy protein fines, microcrystalline cellulose, silicided microcrystalline cellulose, calcium phosphate, crystalline maltose, maltodextrin and mixtures thereof; - 10 to 50%, preferably 10 to 35%, more preferably 15 to 35% of palatants, preferably selected from the group consisting of animal-derived palatants such as dried or powdered meat and meat parts such as beef, pork, chicken, turkey, fish, lamb, etc., offal (liver, kidney, etc.), meat meal, bone meal and crushed bones, or non-animal-derived palatants such as essential oils, oleoresins, essences or extracts, protein hydrolysates, distillates, products of roasting, heating or enzymatic degradation, containing flavouring components derived from spices, fruits or fruit juices, vegetables or vegetable juices, edible yeasts (active and inactive), herbs, bark, buds, roots, leaves or other edible parts of plants, and mixtures thereof, more preferably chicken (or poultry) liver meal, yeast, yeast extract and mixtures thereof. - 0.1 to 20%, preferably 1 to 15%, more preferably 5 to 15% of a disintegrant selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose and mixtures thereof.

[0055] The soft chewable product may further comprise at least one additive selected from the group consisting of lubricants, glidants, surfactants, and colorants.

[0056] As a non-limiting example, a soft chewable product containing a pharmaceutical, veterinary or nutraceutical active substance of the present invention may contain the following ingredients by weight of the total product: - 1-20% of a molding agent, preferably selected from the group consisting of polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, various grades of polyethylene glycol, including PEG 3350, PEG 4000, PEG 6000 and PEG 8000, copolymers of vinylpyrrolidone and vinyl acetate, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymers (poloxamers), microcrystalline wax, cetyl alcohol, polysaccharides, hydroxypropyl methylcellulose, poly(meth)acrylates, alkyl poly(meth)acrylates and mixtures thereof, - 15 to 35% of fillers, such as microcrystalline cellulose, starch or a mixture of these two fillers, 10 to 20% of a humectant, such as polyethylene glycol, glycerol, or a mixture of these two humectants, - 15 to 35% of at least one palatability enhancer, such as poultry liver powder or non-animal-derived Paratant from Diana Petfood, - 5-15% of a disintegrant, such as croscarmellose sodium, - Additives selected from antioxidants, lubricants and fragrances as needed.

[0057] The configuration of the notch marking may vary so long as it allows the product to be divided into doses. For example, a product having two perpendicular notch markings on two opposite faces would not be considered to be configured to facilitate dose division.

[0058] Preferably, the notch markings are cut through the thickness of the product, which means the dimension perpendicular to the main lower or upper surface of the product in the case of an elongated, rectangular or parallelepiped shape, or the longest direction in the case of a cylindrical or elliptical shape. When referring to a fraction or part of the thickness in this invention, this refers to the thickness at the location where the pair of notch markings are cut out.

[0059] According to the invention, the product can be divided into two parts, for example, by applying a pulling force on both sides of at least one notch marking. If other notch markings are present, it is also possible to divide the product into smaller parts by pulling again along these, thereby obtaining a desired number of, for example, identical parts.

[0060] The force applied to separate the products of the present invention may be a pulling force (pulling the portions of the product away from each other, or pulling a single portion along the length of the score marking) or pressure (pressing one portion with a hand or finger and holding the other portion with the other hand).

[0061] As shown in Figure 5, in the present invention, a force of 10 to 60 N required to separate the product along at least one score marking means a force measured in particular using a TA XT2i (Stable Micro Systems) texturometer at a temperature of 18 to 25°C using a cylindrical probe with a diameter of 2 cm and the following parameters: Test mode compression Pretest speed: 1.00 mm / sec Test speed: 10.00mm / sec Post-test speed: 10.00 mm / sec Target Mode Distance Distance: 5.00mm Trigger Type: Automatic (Force) Release force: 0.5N

[0062] These parameters are set, for example, directly in the texturometer software.

[0063] Briefly, the first half of the product was fixed in the jaws 20, and the cylindrical probe 22 was positioned directly above (1 mm) the sample (product 1) and lowered a distance of 5 mm at a predetermined speed of 10 mm / sec.

[0064] A cylindrical probe 22 applies pressure to the second half of the product, pushing it down until it splits. The product is placed in the jaws 20 so that the test splits the sample along at least one of the notch markings 5, 6. The resistance exhibited by the sample (the force required to split the sample) is recorded. The measured resistance (expressed in N) corresponds to the splitting force.

[0065] Advantageously, the score markings on the product are configured so that the force required to divide the product into doses is between 20 and 55N, more advantageously between 24 and 52N.

[0066] Advantageously, the composition of the product and / or the score markings are configured such that the mass loss upon division is particularly strictly less than 0.4%, preferably less than 0.3%, more preferably less than 0.2% and even more preferably less than 0.1% of the total mass of the product.

[0067] The composition of the product according to the invention is provided to provide a friability of less than 0.5%, preferably less than 0.2%, as measured according to European Pharmacopoeia Chapter 2.9.7 (Friability of uncoated tablets), in order to minimize mass loss during division.

[0068] For example, notch markings can be provided with rounded, square, or rectangular cross sections so that the width of the notch marking is constant over its entire depth. Notch markings with U-shaped or V-shaped cross sections are particularly suitable.

[0069] When the notch marking has a V-shaped cross section as shown in Figures 1 to 3, the V-shaped cross section has an opening angle of 40° to 120°, preferably 60° to 100°, and more preferably 80°±5°. The V-shaped cross section is understood to lie along a cross-sectional plane perpendicular to the major dimension of the product.

[0070] According to a first embodiment (not shown), the product has a notch marking on a single surface of the product, preferably through the thickness of the product. In this configuration, the notch marking has a depth of more than 20% of the thickness of the product, advantageously more than 25%, and preferably more than 50%. The total depth of the notch marking is advantageously less than 90% of the thickness of the product. Beyond such a depth, the product may be too fragile and may separate into multiple doses without any intended separation during storage or when removing the product from the packaging.

[0071] According to a preferred embodiment of the present invention, as shown in Figures 1-3, the product has at least one pair of score markings 5, 6 facing each other on opposing sides 3, 4 of the product. In this configuration, the combined depth of the two score markings is preferably greater than 20%, more preferably greater than 30%, even more preferably greater than 40%, and in certain embodiments, greater than 50%. The combined depth of the score markings is less than 90% of the thickness of the product. Exceeding this depth may make the product too fragile and may result in separation into multiple doses without intended separation during storage or upon removal of the product from the packaging. Advantageously, the combined depth of the score markings 5, 6 or the pair of score markings is less than 70% of the thickness of the product.

[0072] In this configuration, the indentation markings 5, 6 facing each other may have the same depth or different depths.

[0073] According to one embodiment, each notch marking has a different depth from the opposing notch marking, said depth being in the range of 5% to 80%, with the total depth of the two notch markings 5, 6 being more than 10%, more than 20%, more preferably more than 30%, even more preferably more than 40%, and in a particular embodiment more than 50% and less than 90%, advantageously less than 70%.

[0074] According to another advantageous embodiment, corresponding to the embodiment shown, the indentation markings 5, 6 facing each other have the same depth, for example in the range of 5% to 45%, preferably 10% to 35%, more preferably 25% to 35%, the total depth of the two indentation markings being more than 10%, more than 20%, more preferably more than 30%, even more preferably more than 40%, and in a particular embodiment more than 50% and less than 90%, advantageously less than 70%.

[0075] When a product according to the invention is intended to be divided into two parts, the product may have a single notch marking cut into a single surface of the product, or a pair of notch markings 5, 6 facing each other on opposite faces 3, 4 of the product, as shown in Figure 1.

[0076] The notch marking or opposing notch markings may be cut through the thickness of the product to define two identical sections, as shown in Figure 1, or they may be two distinct sections.

[0077] The choice of the configuration of the opposing indentation markings depends on the desired division and dosage of the substance to be administered, particularly the dose of the active ingredient. For an active ingredient to be administered in two equal doses, the indentation marking or opposing indentation markings 5, 6 would be configured to separate two equal portions of the product. For an active ingredient to be administered in a first dose comprising 1 / 3 of the total active ingredient amount and a second dose comprising 2 / 3 of the total active ingredient amount, the opposing indentation markings would be configured to separate 1 / 3 and 2 / 3 of the product, respectively.

[0078] As shown in Figures 2 and 3, when a product according to the present invention is intended to be divided into more than two portions, the product has, in addition to the first notch marking or a pair of opposing notch markings, at least one other notch marking cut into a single surface of the product, or another pair of opposing notch markings on opposite sides of the product, as shown in Figures 2 and 3, which notch marking or pair of notch markings are configured to enable the product to be divided into multiple doses.

[0079] Each pair of indentation markings can be configured to allow the product to be divided into as many portions or doses as required.

[0080] As shown in the drawings, multiple pairs of indentation markings are cut into the same surface or surfaces of the product.

[0081] The pairs of notch markings may be cut in parallel as in FIG. 3 and / or transversely as in FIG.

[0082] The multiple pairs of notch markings can demarcate equal third doses of product as in Figure 3, or equal quarter doses as in Figure 2, or even different halves and quarters of product doses.

[0083] According to a first variant, the depth of the notch markings is the same for the same pair of notch markings and / or for all notch markings.

[0084] Alternatively, additional score markings or pairs of score markings can be provided at a different depth than the first score marking or first pair of score markings to facilitate dividing the product along either score marking. For example, a first score marking or pair of score markings can be provided that is deeper to divide the product into two halves, and other score markings or pairs of score markings that are shallower to divide each half into smaller portions.

[0085] The three-dimensional shape of the products according to the invention can be very diverse and can be structures of superposed cylinders, triangles, etc. Preferably, the products have the shape of an elongated cylinder, an oval, an ellipse, a parallelepiped or a rectangular parallelepiped.

[0086] In Figure 1, the product has the shape of two parallel cylinders, each corresponding to one of doses 1a, 1b, and connected to the other by a pair of notch markings 5, 6. In Figure 2, the product has a generally parallelepiped shape with small rounded sides, forming four rectangular doses connected by pairs of orthogonal notch markings 5, 6. In Figure 3, the product has the shape of three parallel cylinders, each corresponding to one of doses 1a, 1b, 1c, and connected to the other by a pair of notch markings 5, 6.

[0087] The products according to the invention advantageously have a mass of 100 mg to 20 g, in particular about 100 mg to about 10 g, more preferably 500 mg to 7 g. In an exemplary embodiment, the three products have masses of 700 mg, 3.5 g and 6.5 g.

[0088] The products according to the invention are intended for administration to any kind of patient, human and non-human, and preferably are intended for non-human mammals.

[0089] Molded soft chewable products according to the present invention can thus be formulated in the form of palatable bite-sized or soft chewable tablets.

[0090] The molded soft chewable products according to the invention are particularly suitable for administration to companion animals, especially dogs, cats and ferrets.

[0091] According to an advantageous embodiment, the molded soft chewable product is intended for patients who have difficulty swallowing large medications, such as the elderly or children.

[0092] The products according to the invention can be used for the administration of any kind of substance, in particular pharmaceutical active substances, veterinary active substances or nutritional supplements.

[0093] The products of the invention therefore contain at least one nutritional supplement or at least one pharmaceutically active substance, which is homogeneously distributed within the product.

[0094] In one embodiment, the active ingredient is a pharmaceutically active ingredient, in particular selected from an anesthetic, a corticosteroid, an NSAID, an antibiotic, an antiemetic, an antithyroid drug, an anthelmintic, an antiparasitic, an appetite stimulant, an antihistamine, an antipruritic, a histamine blocker, an antifungal, an antiprotozoal, an anthelmintic, an antidepressant or a steroid, or a combination of two or more thereof.

[0095] The NSAID may be selected from meloxicam, carprofen, naproxen, tolfenamic and meclofenamic acids, flunixin and indomethacin.

[0096] The anthelmintic drug is selected from macrocyclic lactones such as abamectin, moxidectin, avermectin, ivermectin, selamectin or sidectin, milbemycin; benzimidazoles such as mebendazole, fenbendazole, oxifendazole, albendazole, thiabendazole or carbendazole; imidazothiazoles such as levamisole or pyrantel; salicylanilides such as closantel or niclosamide; praziquantel or epsipantel.

[0097] Antibiotics include penicillins, aminopenicillins (e.g., amoxicillin, ampicillin, hetacillin), cephalosporins (e.g., cefovecin, cefuroxime, ceftiofur), quinolones (e.g., ciprofloxacin, enrofloxacin, difloxacin, orbifloxacin, marbofloxacin), chloramphenicols (e.g., chloramphenicol, thiamphenicol, florfenicol), tetracyclines (e.g., chlortetracycline, tetracycline), and thiamphenicol. cyclosporine, oxytetracycline, doxycycline, minocycline); macrolides (e.g., erythromycin, tylosin, trimicosin, clarithromycin, azithromycin, tulathromycin); lincosamides (e.g., lincomycin, clindamycin); aminoglycosides (e.g., gentamicin, amikacin, kanamycin, apramycin, tobramycin, neomycin, dihydrostreptomycin, paromomycin).

[0098] The antiemetic agent may be selected from maropitant and aprepitant.

[0099] Parasiticides may be selected from organochlorines, organophosphates, carbamates, amidines, pyrethrins and synthetic pyrethroids, benzoylureas, juvenile hormone analogues, macrocyclic lactones, neonicotinoids, phenylpyrazoles, spinosyns (e.g., spinosad), isoxazolines (e.g., fluralaner, afoxolaner, sarolaner, and lotilaner).

[0100] The antipruritic agent is a JAK-1 inhibitor, particularly selected from oclacitinib, momelotinib, tofacitinib, and ruxolitinib.

[0101] As used herein, the term "nutraceutical ingredient" refers to an ingredient intended to maintain or promote the health of a target animal. For example, a nutritional ingredient can provide a nutritional benefit to a target animal. Nutraceutical ingredients include, but are not limited to, vitamins, minerals, plant extracts, and combinations thereof.

[0102] Vitamins include, for example, vitamin A, vitamin E, vitamin B12, vitamin B3, d-pantothenic acid (vitamin B5), folic acid, vitamin B6, vitamin B1, vitamin D3, vitamin C, vitamin B2, and provitamins such as β-carotene and panthenol.

[0103] Minerals include potassium, sodium, manganese, zinc, iron, calcium, copper, cobalt, iodine, chlorine and selenium. Minerals may be in the form of suitable salts.

[0104] Other nutritional supplements that may be considered include antioxidants such as lecithin, phosphatidylserine, pycnogenol, ginkgo biloba extract, bacopa monnieri extract, huperzine A, omega-3 polyunsaturated fatty acids such as DHA and l-EPA; flavonoids or flavonoid-containing plant extracts such as blueberry or maqui berry, anthocyanins, flavan-3-ols, epigallocatechin gallate (ECGC) and proanthocyanidins, isoflavones (e.g., puerarin and genistein) and flavonols (e.g., rutin and troxerutin); cytochrome C, sodium glutamate, N-acetylcysteine, zinc methionine, biotin, L-carnitine, phytoceramides, prebiotics, probiotics, postbiotics, casein phosphopeptides, L-theanine or green tea extract, ashwagandha, and fish protein hydrolysate.

[0105] In certain embodiments, the nutritional supplement is selected from the group consisting of eggshell membrane, krill powder or krill oil, astaxanthin or a source of astaxanthin such as seaweed, yeast, salmon, trout, krill, shrimp, and crayfish, Boswellia serrata, hyaluronic acid or a salt thereof, and vitamin D3. Preferably, the nutritional supplement is a mixture of at least two, at least three, or at least four ingredients selected from the group consisting of eggshell membrane, krill powder, astaxanthin or a source thereof (seaweed, yeast, salmon, trout, krill powder or krill oil, shrimp, and crayfish), Boswellia serrata, hyaluronic acid or a salt thereof, and vitamin D3. More preferably, the nutritional supplement is a mixture of eggshell membrane, krill powder or krill oil, astaxanthin, Boswellia serrata, and hyaluronic acid or a salt thereof.

[0106] The pharmaceutical, veterinary or nutraceutical active may be present in the product in any amount necessary to achieve the desired therapeutic effect or health benefit. Advantageously, the pharmaceutical, veterinary or nutraceutical active is present at a level of 0.1 to 20%, preferably 1 to 10%, of the total mass of the product.

[0107] Of particular note are soft chewable products according to the present invention, wherein the active ingredient is meloxicam.

[0108] The present invention also provides a method for producing the above-described molded soft chewable product for oral administration.

[0109] The method may, for example, include the following steps: (a) obtaining a structure comprising a pharmaceutical, veterinary or nutraceutical active substance and an inactive ingredient such as an excipient; (b) shaping the composition to obtain the product.

[0110] The products according to the invention can be advantageously produced by extrusion, molding or compression of the composition.

[0111] Accordingly, the present invention relates to a method for producing a molded soft chewable product for oral administration, comprising a pharmaceutical, veterinary medicinal or nutraceutical active substance, a humectant and a molding agent, having a pair of score markings on opposite sides of the product facing each other and configured for dividing the product into doses, wherein the combined depth of the pair of score markings is more than 10% of the thickness of the product and the combined depth of the two score markings is less than 90% of the thickness of the product, and wherein the mass loss upon dividing the product (1) into doses (1a, 1b) is less than 0.5%.

[0112] More specifically, the method may include, for example, the following steps: a) preparing said composition by mixing a pharmaceutical, veterinary or nutraceutical active substance with a moisturizing agent and a bulking agent, and optionally with inactive ingredients such as excipients; c) molding, compressing or extruding the composition into a product under conditions, particularly temperature and pressure, suitable for obtaining a soft chewable product, wherein a pair of score markings is cut out by a mold during compression or molding, or by a die during extrusion.

[0113] In one embodiment, the present invention relates to a method for manufacturing a product as defined above, wherein the product is formed by extrusion of a composition and at least one indentation marking 5, 6 is cut into the product by a die in the extruder.

[0114] According to this embodiment, inactive ingredients such as pharmaceutical, veterinary, or nutraceutical active substances and excipients are added to the hopper of an extruder, preferably after a mixing step. The composition is then extruded through the extruder under conditions suitable to impart the desired structural characteristics, e.g., a hardness of 10-300 N and a friability of less than 1%, until it exits the extruder and is discharged from the extruder. At the extruder exit, a suitably shaped die forms a pair of notch markings 5, 6 in the extrudate.

[0115] The extrudate with at least one score marking cut therein is then cut transversely to the length of the extrudate to desired lengths, each resulting portion constituting a product according to the invention.

[0116] Preferably, the pair of score markings extends along the major dimension of the product, as this avoids excessively frequent cutting of the extrudate and improves mass uniformity between units of product.

[0117] The present invention therefore relates to a method for preparing a molded soft chewable product for oral administration as described above by extrusion, comprising the steps of: (a) obtaining in a mixer a composition comprising inactive ingredients such as pharmaceutical, veterinary or nutraceutical active substances, moisturizing agents and excipients, if necessary; (b) adding pharmaceutical, veterinary or nutraceutical active substances, humectants and inactive ingredients such as bulking agents, excipients, etc., to the hopper of an extruder to obtain said composition, or adding the composition previously obtained in step (a) to the hopper of an extruder; (c) extruding the composition under suitable conditions to obtain an extrudate; (d) cutting a pair of notch markings with an extruder die; (e) cutting the extrudate to obtain shaped soft chewable products for oral administration; (f) Packaging the product as required.

[0118] If the product has multiple notch markings or multiple notch marking pairs in parallel directions, these can be formed directly on the product using an appropriately shaped die, which will then be used to provide the desired number of notch markings or notch marking pairs on the product.

[0119] If the product has at least one notch marking or pair of notch markings (referred to as an additional notch marking) that is lateral to another notch marking or pair of notch markings (referred to as a first notch marking), an additional step is required to form the additional notch marking or pair of additional notch markings.

[0120] Said additional notch marking or pair of additional notch markings may be formed on the product by any means. According to one embodiment, the additional notch marking or pair of notch markings is formed on the product by molding or compression.

[0121] In this embodiment, the product obtained by extrusion may be processed in a tablet press, U.S. Patent Nos. 3,486,186, 3,887,964, 3,952,478, 4,054,967, 4,097,961, 4,182,003, 4,334,339, 4,338,702, 4,343,068, 4,356,595, 4,372,008, 4,535,505, 4,597,135, The product is then placed into an apparatus such as a Formax® Formax F6™ type molding machine as described in US Pat. Nos. 4,608,731, 4,622,717, 4,697,308, 4,768,941, 4,780,931, 4,818,446, 4,821,376, 4,872,241, 4,975,039, 4,996,743, 5,021,025, 5,022,888, 5,655,436, 5,980,228, or a machine as described in European Patent No. 2922526, whereupon the product is compressed or molded to form the additional notch marking or pair of notch markings.

[0122] The present invention therefore relates to a method for preparing a molded soft chewable product for oral administration as described above by extrusion, comprising the steps of: (a) obtaining in a mixer a composition comprising inactive ingredients such as pharmaceutical, veterinary or nutraceutical active substances, moisturizing agents and excipients, if necessary; (b) pouring inactive ingredients such as pharmaceutical, veterinary or nutraceutical active substances, moisturizing agents and molding agents, and optionally excipients, into the hopper of an extruder to obtain a composition, or pouring the composition previously obtained in step (a) into the hopper of an extruder; (c) extruding the composition and cutting a pair of notch markings through an extruder die; (d) cutting the extrudate; (e) forming an additional indentation marking or pair of indentation markings on the product, preferably by compression or molding, under conditions suitable to result in a soft chewable product; (f) Packaging the product as required.

[0123] In another embodiment, the present invention relates to a method of manufacturing a product as defined above, wherein the indentation marking is formed in the product by molding or compression without prior extrusion.

[0124] According to this embodiment, a mixture containing the active ingredient and the excipients of the composition is introduced into a mixer, and then the resulting (paste-like) composition is compressed in a tablet press, as described in U.S. Patents 3,486,186, 3,887,964, 3,952,478, 4,054,967, 4,097,961, 4,182,003, 4,334,339, 4,338,702, 4,343,068, 4,356,595, 4,372,008, 4,5 and compressing or molding the material in an apparatus such as a Formax F6™ type molding machine manufactured by Formax Corporation, as described in US Pat. Nos. 3,5505, 4,597,135, 4,608,731, 4,622,717, 4,697,308, 4,768,941, 4,780,931, 4,818,446, 4,821,376, 4,872,241, 4,975,039, 4,996,743, 5,021,025, 5,022,888, 5,655,436, or 5,980,228, or a machine described in European Patent No. 2,922,526, using an appropriately shaped mold to form the notch marking or pair of notch markings.

[0125] By using a suitable die or punch, this method allows for the production in one step of a product having a pair of notch markings and an additional notch marking or pair of additional notch markings, whatever the direction, particularly a direction parallel and / or transverse to the first notch marking or pair of notch markings.

[0126] The present invention therefore relates to a method for preparing a molded soft chewable product for oral administration as described above, comprising the steps of: (a) obtaining in a mixer a composition comprising inactive ingredients such as pharmaceutical, veterinary or nutraceutical active substances, moisturizing agents and excipients, if necessary; (b) adding pharmaceutical, veterinary or nutraceutical active substances, moisturizing agents and molding agents, and optionally inactive ingredients (excipients) to obtain a composition, or adding the composition obtained in step (a) to a container connected to a compression or molding machine; (c) compressing or molding the composition under suitable conditions to obtain a soft chewable product, wherein a mold cuts a pair of score markings into the product; (d) Packaging the product as required.

[0127] According to this embodiment, it is preferred to mix the pharmaceutical, veterinary or nutraceutical active agent, humectant and molding agent, and optionally inactive ingredients (excipients) in a mixer prior to the compression or molding step to ensure uniform distribution of the pharmaceutical, veterinary or nutraceutical active agent throughout the composition.

[0128] The present invention also particularly relates to a soft chewable product for oral administration as described above, which is used for pharmaceutical purposes.

[0129] According to an advantageous embodiment of the invention, the product is intended to be administered in the form of simultaneous doses to several patients and / or in the form of sequential doses to the same patient.

[0130] Most pharmaceutical, veterinary or nutritional active substances are administered according to a dose determined according to the patient's weight. The product according to the invention can be divided into portions, allowing the amount of active pharmaceutical ingredient to be precisely adjusted to the weight of the patient being treated.

[0131] In the present invention, a "dose" refers to a portion of a product that is capable of producing a desired therapeutic effect in a treated subject. Thus, the terms "portion" and "dose" are interchangeable herein.

[0132] Doses of effective pharmaceutical, veterinary or nutraceutical active substances correspond to those amounts generally known in the literature or recommended by practitioners, as determined by the skilled artisan using his general knowledge or by carrying out preliminary or clinical tests.

[0133] Advantageously, the present invention also relates to a product as described above and containing an active ingredient, in particular a veterinary drug intended for companion animals such as dogs, cats or ferrets, for pharmaceutical use as described below.

[0134] More generally, the present invention relates to a soft chewable product for oral administration, as described above, having a pair of score markings configured to facilitate dividing the product into doses, wherein the force required to divide the product into doses is preferably 10-60 N, and wherein the mass loss when dividing the product into doses is less than 0.5%, and wherein the product contains a pharmaceutical, veterinary or nutraceutical active substance and is used for pharmaceutical applications.

[0135] Advantageously, the dose of the product is intended to provide the subject with an effective amount of the pharmaceutical, veterinary or nutraceutical active substance until the next administration of the pharmaceutical, veterinary or nutraceutical active substance.

[0136] The amount of product can be adjusted to suit the weight of the patient being treated, reducing the risk of overdosing. Furthermore, because no mass loss occurs when the product is divided, the amount of product administered is precise and underdosing due to product division is not possible. For example, the same product can be used to administer the correct amount of active ingredient to patients with significantly different weights. For example, if each portion of the product contains an effective amount of active ingredient per 10 kg of body weight, a patient weighing 30 kg would receive 3 / 8 of the product, and a patient weighing 70 kg would receive 7 / 8. This avoids overdosing or underdosing patients.

[0137] According to one aspect of the invention, the product is intended to be administered in multiple doses at defined intervals, each dose providing an effective amount of the pharmaceutical, veterinary or nutraceutical active substance to the subject until the next dose is administered.

[0138] The same product may be administered in multiple doses consecutively if the dosing regimen requires multiple administrations. For example, if the product requires administration twice daily, the product may be cut in half and each dose taken at the indicated times of day.

[0139] Additionally, multiple consecutive doses of the same product can be administered when a patient has difficulty swallowing the entire product at once, such as elderly or pediatric patients. The ability to divide the product into smaller, easier-to-swallow doses ensures that the entire treatment is delivered without underdosing due to divided product.

[0140] Thus, the product is also intended to be administered in multiple doses to elderly or pediatric patients in a single treatment, if desired.

[0141] Preferably, the product is intended for companion animals, in particular dogs or cats. In one embodiment, the product comprises a nutraceutical active substance.

[0142] The present invention particularly relates to a soft chewable product as described above, which is used as a pharmaceutical product for sequential administration of effective doses of the product to an animal in need thereof.

[0143] In certain embodiments, the present invention relates to a soft chewable product as described above, for use in pharmaceutical applications where the product is divided into doses and each dose is administered at defined intervals.

[0144] By "defined intervals" is meant a time interval corresponding to the administration schedule of the drug. For example, the intervals can be a few hours (e.g., 4, 6, 12, or 24 hours), a few days (e.g., 2, 3, or 7 days), or a few weeks (e.g., 2, 3, or 4 weeks).

[0145] Preferably, the product is divided into two equal doses, with the second dose being administered within 24 hours of the first dose. In certain embodiments, the invention relates to a soft chewable product as described above, for use in pharmaceutical applications where the product is administered in two doses once daily.

[0146] The present invention also relates to a method of treating a disease state or condition in a patient, the method comprising the steps of: (1) providing a soft chewable product 1 comprising a pharmaceutical, veterinary or nutraceutical active agent, a humectant, and a molding agent, the product having a pair of opposing score markings 5, 6 on opposing sides 3a, 3b of the product; (2) dividing the soft chewable product 1 along the score markings into individual doses specifically adapted to the patient's weight; (3) Repeating the administration of the individual doses at predetermined intervals based on the recommended treatment regimen for the condition.

[0147] The present invention also relates to a method of treating a medical condition in a subject, the method comprising the step of administering to the subject a dose of a soft chewable product for oral administration, the soft chewable product comprising a pharmaceutical, veterinary or nutraceutical active substance, a humectant and a bulking agent, the product having a pair of score markings configured to facilitate division of the product into doses, wherein the force required to divide the product into doses is 10-60 Newtons, the mass loss upon dividing the product into doses is less than 0.5%, and the doses provide an effective amount of the pharmaceutical, veterinary or nutraceutical active substance to the subject until the next administration of the pharmaceutical, veterinary or nutraceutical active substance.

[0148] The present invention further relates to a method of treating a medical condition in a subject, the method comprising the step of sequentially administering to the subject multiple doses of a soft chewable oral product comprising a pharmaceutical, veterinary or nutraceutical active substance, a humectant and a bulking agent, the product having a pair of score markings configured to facilitate division of the product into doses, wherein the force required to divide the product into doses is 10-60 Newtons, and the mass loss during division of the product into doses is less than 0.5%, and each dose provides the subject with an effective amount of the pharmaceutical, veterinary or nutraceutical active substance until the next dose is administered.

[0149] The present invention further relates to the use of a soft chewable product for oral administration comprising a pharmaceutical, veterinary or nutraceutical active substance, a humectant and a bulking agent, the product having a pair of score markings configured to facilitate division of the product into doses, wherein the force required to divide the product into doses is between 10 and 60 N, and wherein the mass loss during division of the product into doses is less than 0.5%, for the manufacture of a medicament for treating a medical condition in a patient.

[0150] The invention further relates to a soft chewable product for oral administration comprising a pharmaceutical, veterinary or nutraceutical active substance, a humectant and a bulking agent, the product having a pair of score markings configured to facilitate division of the product into doses, wherein the force required to divide the product into doses is between 10 and 60 Newtons, and wherein the mass loss upon dividing the product into doses is less than 0.5%, when used in the manufacture of a medicinal product for the treatment of a medical condition, wherein the product is administered to a subject in multiple doses.

[0151] The invention further relates to a soft chewable product for oral administration comprising a pharmaceutical, veterinary or nutraceutical active substance, a humectant and a bulking agent, the product having a pair of score markings configured to facilitate division of the product into doses, wherein the force required to divide the product into doses is 10-60 Newtons, and wherein the mass loss during division of the product into doses is less than 0.5%, the soft chewable product being used in the manufacture of a medicament for treating a medical condition, the product being administered to a subject in multiple doses to provide an effective amount of the pharmaceutical, veterinary or nutraceutical active substance each day until the next dose is administered.

[0152] The present invention further relates to a treatment schedule in which the soft chewable product described above is administered in equal doses at regular intervals.

[0153] The present invention is particularly directed to a soft chewable product 1 for oral administration, comprising a pharmaceutical, veterinary or nutraceutical active substance, a humectant and a bulking agent, the product 1 having a pair of opposing score markings 5, 6 on opposite faces 3a, 3b of the product and configured for dividing the product into doses 1a, 1b, wherein the force required to divide the product 1 into doses 1a, 1b along the score markings 5, 6 is preferably 10-60 N, and wherein the mass loss during division of the product 1 into doses (1a, 1b) is less than 0.5%.

[0154] Preferably, the combined depth of the two indentation markings 5, 6 is more than 20%, preferably more than 30%, more preferably more than 40%, and in a particular embodiment more than 50% of the thickness of the product 1, and the combined depth of the two indentation markings 5, 6 is less than 90%, advantageously less than 70% of the thickness of the product 1. More preferably, the two indentation markings 5, 6 have the same depth, and the depth of each indentation marking 5, 6 is between 10% and 45%, preferably between 25% and 35%, of the thickness of the product 1.

[0155] In one embodiment, said notch markings (5, 6) comprise cutting primers.

[0156] Preferably, the product has a friability of less than 0.5%, more preferably less than 0.2%.

[0157] Preferably, the product comprises: - a pharmaceutical, veterinary or nutraceutical active substance, - a moisturizing agent selected from the group consisting of propylene glycol, glyceryl triacetate, vinyl alcohol, neoagarobiose, glycerol, sugar polyols such as sorbitol, xylitol and maltitol, polymeric polyols such as polydextrose, caprylic / capric triglyceride, propylene glycol dicaprylate / dicaprate, medium chain triglycerides sold under the trademark Miglyol, in particular Miglyol 812 or 814, vegetable oils, or mixtures thereof; - a molding agent selected from the group consisting of polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, various grades of polyethylene glycol including PEG 3350, PEG 4000, PEG 6000 and PEG 8000, copolymers of vinylpyrrolidone and vinyl acetate, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymers (poloxamers), microcrystalline wax, cetyl alcohol, polysaccharides, hydroxypropyl methylcellulose, poly(meth)acrylates, alkyl poly(meth)acrylates and mixtures thereof; Includes.

[0158] More preferably, the product is - a filler preferably selected from the group consisting of starch such as corn starch, rice starch or potato starch, sucrose, powdered sugar, lactose including anhydrous lactose, hydrated lactose, spray dried lactose, dextrin, decylates, mannitol, soy grits, soy protein fines, microcrystalline cellulose, silicided microcrystalline cellulose, calcium phosphate, crystalline maltose, maltodextrin and mixtures thereof; - Paratants, preferably selected from the group consisting of animal-derived paratants such as dried or powdered meat and meat parts such as beef, pork, chicken, turkey, fish, lamb, etc., organ meats (liver, kidney, etc.), meat meal, bone meal and crushed bones, or non-animal-derived paratants such as essential oils, oleoresins, essences or extracts, protein hydrolysates, distillates, products of roasting, heating or enzymatic degradation, containing flavouring components derived from spices, fruits or fruit juices, vegetables or vegetable juices, edible yeasts (active and inactive), herbs, bark, buds, roots, leaves or other edible parts of plants, and mixtures thereof; Further includes:

[0159] Preferably, the product further comprises an excipient.

[0160] Preferably, the product is for pharmaceutical use, human or veterinary use.

[0161] Preferably, the product is intended for geriatric or pediatric patients.

[0162] Preferably, the product is intended for dogs or cats, preferably dogs.

[0163] Preferably, the product is manufactured by extrusion.

[0164] Preferably, the product is prepared by the following steps: (a) obtaining in a mixer a composition comprising a pharmaceutical, veterinary or nutraceutical active substance, if necessary, and inactive ingredients such as excipients, (b) charging the pharmaceutical, veterinary or nutraceutical active substance and inactive ingredients such as excipients into the hopper of an extruder to obtain the composition, or charging the composition formed in step (a) into the hopper of an extruder; (c) extruding the composition under suitable conditions to obtain an extrudate; (d) cutting a pair of notch markings with an extruder die; (e) cutting the extrudate to obtain a shaped soft chewable product for oral administration; (f) optionally packaging the product. [Example]

[0165] <Evaluation of product characteristics according to the present invention> The tested products have the following composition (mass percentages relative to the total mass): Active ingredients approximately 3-5%; microcrystalline cellulose 4-6%; powdered sugar 4-6%; polyethylene glycol 3350 4-6%; native corn starch 15-25%; croscarmellose sodium 5-15%; paratant 25-35%; sodium chloride 0.1-5%; purified water 1-10%; glycerin 5-20%; soybean oil 1-10%; antioxidants and preservatives 0.001-1%.

[0166] Example 1.1 - Hardness of the product The hardness of the product was measured according to the method described above.

[0167] The average value measured is 65N.

[0168] Example 1.2 - Friability The friability of the products was determined according to European Pharmacopoeia Chapter 2.9.7 (Friability of uncoated tablets) using 12 divisible product halves. The results are shown in Table 1. Friability is expressed as mass loss (%).

[0169] [Table 1]

[0170] Example 1.3 - Dividability: Tensile Strength and Mass Loss The tensile strength was measured according to the method described above.

[0171] The test was carried out on samples of approximately 700 mg, approximately 3.5 g, and approximately 6.5 g each (six samples each). The results are shown in Table 2.

[0172] [Table 2]

[0173] After the splitting test, half of the product was reweighed to evaluate the mass loss after splitting, and the results are shown in Table 3.

[0174] [Table 3]

[0175] It can be seen that each sample tested has a specified value for the hardness of the product of the present invention. Furthermore, the presence of at least one score marking, in conjunction with the force required to split the product along the one or more score markings, according to the specified value for the product of the present invention, allows for splitting of the product with very low mass loss.

[0176] Example 1.4 - Comparison of a soft chew with a single notch marking and a soft chew with a pair of notch markings facing each other on opposite sides (3a, 3b) of the product The products were soft chews with a single indentation marking on one side of the product, or a pair of indentation markings facing each other on opposite sides of the product. The one or more indentation markings had the same depth, with a total depth of 20% of the thickness of the soft chew. The formulation of both types of soft chews was the same.

[0177] The purpose of this example was to evaluate the effect of introducing a second notch marking on the opposite side of the product, opposite the first notch marking.

[0178] Two parameters were evaluated: mass loss and precision of division. To do so, 30 soft chews of each type (with one notch marking or two notch markings) were weighed individually. These 30 soft chews were then manually divided along the notch markings by three different users (10 pieces per user). Each half of the soft chew was weighed and used for statistical evaluation.

[0179] There was no significant difference in mass loss between both types of soft chews, both of which were less than 0.01% of the total mass of the soft chew.

[0180] There was a significant difference in the mass of the divided soft chew halves, and the results are shown in the following table.

[0181] [Table 4]

[0182] It can be seen that the difference in mass between the halves is greater for the soft chew with one notch marking than for the soft chew with a pair of notches.

[0183] Thus, the presence of a pair of notch markings facilitates dividing the soft chew into two equal doses.

[0184] The % mass difference between doses was also statistically different, with a dose difference of 2±1.5% for soft chews with two notch markings and 5.9±3.5% for those with only one notch marking, indicating a higher risk of overdose or underdose when only one notch marking is present on the soft chew.

[0185] Example 1.5 - Comparison of soft chews with no opposing score markings on opposite sides of the product, varying in friability The products were soft chews of approximately 3.5g (hardness approximately 60N) with no score markings present and varying degrees of friability.

[0186] The purpose of this example was to evaluate the effect of soft chew friability on the ease and accuracy of division under real-world conditions. To this end, 20 soft chews of each type were individually weighed. These 20 soft chews were then manually divided by two different users (each user divided 10 pieces). During this test, it was quickly discovered that soft chews with high friability, although acceptable for use as a whole, were not acceptable for use as a dose.

[0187] In fact, in almost all cases, the soft chew either disintegrated in the user's hand upon finger pressure on the product or along the score markings when tearing the two doses, resulting in unacceptable mass loss and uneven division into doses. Figure 6 shows a soft chew with high friability after an attempt to manually separate it into two portions. As shown, the soft chew disintegrated upon division, resulting in multiple fragments. Therefore, the mass loss was unacceptable. In one example (photo on the right), the soft chew broke into three large fragments and other smaller fragments.

[0188] Therefore, the low friability of the soft chew aids in clean and uniform division of the soft chew.

Claims

1. A soft chewable product (1) for oral administration comprising a pharmaceutical, veterinary or nutritional active substance, a moisturizing agent and a forming agent, the product (1) presenting at least one pair of score marks (5, 6) facing each other on opposite faces (3a, 3b) of the product and configured to divide the product into doses (1a, 1b), the cumulative depth of the pair of score marks (5, 6) being greater than 10% of the thickness of the product (1), and the loss of mass when dividing the product (1) into doses (1a, 1b) being less than 0.5%.

2. 2. The soft chewable product (1) of claim 1, wherein the cumulative depth of the two score markings (5, 6) is more than 20%, preferably more than 30%, more preferably more than 40% of the thickness of the product (1), and the cumulative depth of the two score markings (5, 6) is less than 90%, preferably less than 70% of the thickness of the product (1).

3. 3. The soft chewable product (1) according to claim 2, wherein the two score marks (5, 6) have the same depth, and each of the score marks (5, 6) has a depth between 10% and 45%, preferably between 25% and 35%, of the thickness of the product (1).

4. A soft chewable product (1) according to any one of the preceding claims, having a friability of less than 0.5%, preferably less than 0.2%.

5. The humectant is selected from the group consisting of propylene glycol, glyceryl triacetate, vinyl alcohol, neoagarobiose, glycerin, sugar polyols such as sorbitol, xylitol and maltitol, polydextrose, caprylic / capric triglyceride, polymer polyols such as propylene glycol dicaprylate / dicaprylate, medium chain triglycerides sold under the trademark Miglyol, particularly Miglyol 812 or 814, vegetable oils, or mixtures thereof. The swellable agent is polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, PEG 3350, PEG 4000, PEG 6000, and PEG 8000, and copolymers of vinylpyrrolidone and vinyl acetate, polypropylene glycol, polyethylene glycol-polypropylene glycol copolymers (poloxamers), microcrystalline wax, cetyl alcohol, polysaccharides, hydroxypropyl methylcellulose, poly(meth)acrylates, alkyl poly(meth)acrylates, and mixtures thereof.

6. Fillers, preferably selected from the group consisting of starches such as corn starch, rice starch or potato starch, sucrose, confectioners' sugars, lactose including anhydrous lactose, hydrous lactose, spray dried lactose, dextrin, dextrates, mannitol, soybean granules, soy protein, microcrystalline cellulose, silicified microcrystalline cellulose, calcium phosphate, crystalline maltose, maltodextrin and mixtures thereof, are preferably used in animal product bases such as dried or powdered meat and meat parts, e.g., beef, pork, chicken, turkey, fish, and lamb.

6. The soft chewable product (1) according to claims 1 to 5, further comprising a savory agent selected from the group consisting of savory agents, organ meats such as liver and kidney, meat meal, bone meal, ground bone and non-animal product based palatants such as essential oils, oleoresins, essences or extracts, protein hydrolysates, distillates or any product of roasting, heating or enzymatic degradation containing flavor components derived from spices, fruits or fruit juices, vegetables or vegetable juices, edible yeasts (active and inactive), herbs, bark, buds, roots, leaves or any other edible part of a plant, and mixtures thereof.

7. A soft chewable product (1) according to any one of claims 1 to 6 for use as a medicine.

8. 8. A soft chewable product (1) for use according to claim 7, wherein said product is divided into doses for administering an appropriate amount of an active pharmaceutical, veterinary or nutritional supplement to a subject to be treated.

9. 8. The soft chewable product (1) for use according to claim 7, wherein an appropriate amount of an active pharmaceutical, veterinary or nutritional supplement is administered at predetermined intervals.

10. A soft chewable product (1) for use according to any one of claims 7 to 9, intended for dogs or cats, preferably dogs.

11. 11. A soft chewable product (1) for use according to claim 10, wherein said active substance is a nutritional supplement.

12. (a) a pharmaceutical, veterinary, or nutraceutical active agent and a humectant, preferably selected from the group consisting of sugar polyols such as propylene glycol, glyceryl triacetate, vinyl alcohol, neoagarobiose, glycerin, sorbitol, xylitol, and maltitol, polymer polyols such as polydextrose, caprylic / capric triglyceride, propylene glycol dicaprylate / dicaprylate, medium chain triglycerides, vegetable oils, or mixtures thereof, and preferably polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, PEG 3350, PEG 4000, PEG 6000, and PEG 7000. and (b) forming a composition to obtain a product having score markings.

13. 13. The method of claim 12, wherein the forming of the composition is performed by compression or molding, and the indentation markings (5, 6) are hollow in step (b).

14. 13. The method according to claim 12, wherein the shaping is performed by extrusion, and the notch markings (5, 6) are hollowed out in step (b) through a die having a shape suitable for hollowing out the notch markings.

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