Film preparation having adhesiveness to inside of animal oral cavity

Abstract

The present invention provides a preparation for animals, with which it is possible to retain a drug in an oral cavity of an animal for a sufficient time or rapidly release a drug in an oral cavity of an animal. The present invention relates to a film preparation having adhesiveness to the inside of an oral cavity of an animal, the film preparation having at least one film layer containing a prophylactic or therapeutic agent for an animal disease and an easily-water-soluble polymer having high adhesiveness to a mucosal membrane.

Description

Film formulation adhesive to animal oral cavity

[0001] The present invention relates to a film preparation that is adhesive to the oral cavity of an animal.

[0002] Similar to humans, non-human animals such as dogs and cats are experiencing an increase in oral diseases such as gingivitis, periodontal disease, and dental caries, and preventive treatments are being implemented. Preventive treatment methods include toothpaste, application of ointments, and oral administration of supplements such as tablets and gels. Toothpastes designed to suppress bad breath caused by these oral diseases are also commercially available. A composition for the prevention and treatment of periodontal disease in dogs has also been reported (Patent Document 1). Furthermore, diseases similar to lifestyle-related diseases in humans are also increasing year by year in non-human animals such as dogs and cats.

[0003] Japanese Patent Application Laid-Open No. 2009-173558

[0004] However, when conventional veterinary drugs are administered by owners, they are mixed with feed or drink and administered in the form of tablets or gels, and their retention time in the oral cavity is short, and sufficient preventive and therapeutic effects, particularly for oral diseases, are not achieved. Furthermore, even when oral ointments are administered to animals, they are easily dissolved in saliva, etc., and sufficient effects are not achieved. Therefore, an object of the present invention is to provide an veterinary preparation that can retain the drug in the animal's oral cavity for a sufficient period of time or can quickly release the drug in the animal's oral cavity.

[0005] Therefore, the present inventors discovered that if a drug for animal use is encapsulated in a film preparation that can be adhered to the gums in the animal's oral cavity, a film preparation that can adhere to the gums in the animal's oral cavity for a long period of time and quickly release the drug can be obtained, and thus completed the present invention.

[0006] That is, the present invention provides the following inventions [1] to [8]. [1] An adhesive film preparation for animal oral cavity, having at least one film layer containing a preventive or therapeutic agent for an animal disease and a water-soluble polymer. [2] The film preparation of [1], wherein the water-soluble polymer is one or more selected from pullulan, starch, xanthan gum, sodium alginate, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymer, and hydroxyethylcellulose. [3] The film preparation of [1] or [2], wherein the adhesive film preparation for animal oral cavity has two or more film layers, the outermost film layer being a film layer containing a preventive or therapeutic agent for an animal disease and a water-soluble polymer or a film layer containing a water-soluble polymer. [4] The film preparation of any of [1] to [3], wherein the thickness is 50 to 1000 μm. [5] An animal oral cavity-adherent film preparation having at least one film layer containing a preventive or therapeutic agent for an animal disease and a highly mucosally-adherent, water-soluble polymer. [6] The film preparation of [5], which has two or more film layers, wherein the outermost film layer is a film layer containing a preventive or therapeutic agent for an animal disease and a highly mucosally-adherent, water-soluble polymer or a film layer containing a highly mucosally-adherent, water-soluble polymer. [7] The film preparation of [5] or [6], wherein the highly mucosally-adherent, water-soluble polymer is one or more selected from pullulan, polyvinylpyrrolidone, polyacrylic acid, and carboxyvinyl polymer. [8] The film preparation of any of [5] to [7], which has a thickness of 50 to 1000 μm.

[0007] The film preparation for adhesion to the oral cavity of animals of the present invention quickly adheres to the oral mucosa of non-human animals and quickly releases a preventive or therapeutic agent for animal diseases, allowing the agent to remain in the oral cavity for a long period of time, thereby reliably achieving preventive or therapeutic effects, particularly for oral diseases in animals. Furthermore, the film preparation for adhesion to the oral cavity of animals of the present invention is extremely thin and can be attached to the gums of animals, so the animal will not try to remove the film, allowing the drug to be released for a long period of time.

[0008] Shows the results of the periodontitis score evaluation. Shows the results of the halitosis sensory score. Shows the results of the evaluation for odor type A (putrid odor (sulfur compound-based: odor related to the degree of periodontal disease)). Shows the results of the evaluation for odor type B (slightly fishy odor (odor related to the amount of saliva secretion)). Shows the results of the evaluation using AuraStrip (thymol concentration in the mouth is used as an indicator). Shows the results of the evaluation using Adplit (N-benzoyl-DL-arginyl peptidase concentration in the mouth is used as an indicator).

[0009] Terms used in this specification are used in the sense commonly used in the art unless otherwise specified.

[0010] As used herein, "animal" refers to non-human animals, preferably non-human mammals kept by humans, including dogs, cats, hamsters, rabbits, degus, guinea pigs, chinchillas, pigs, cows, horses, and donkeys. As used herein, "oral cavity" refers to the space inside the mouth, specifically including the gums, jaw, palate, cheeks, oral mucosa, and salivary glands. As used herein, "adhesion" means that an object adheres to another object, and a film adhering to a mucosa indicates that the film remains attached for a certain period of time. As used herein, "film" refers to a thin film, and a film preparation refers to a preparation in the form of a thin film. The film thickness is preferably 50 to 1,000 μm, more preferably 70 to 500 μm, and even more preferably 100 to 400 μm.

[0011] As used herein, the term "easily water-soluble polymer" refers to a polymer that has the property that, when 1 g of the polymer is weighed out and immersed in 10 g of ion-exchanged water under an environment of 1 atmosphere and 23°C, 0.5 g or more of the immersed polymer dissolves in water after 24 hours. In the present invention, any edible polymer that is easily water-soluble can be suitably used. Specific examples include one or more selected from pullulan, starch, xanthan gum, sodium alginate, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymer, and hydroxyethylcellulose.

[0012] As used herein, the term "highly mucosally adhesive, water-soluble polymer" refers to a polymer among the water-soluble polymers described above that absorbs moisture from the mucosa to thicken and has high adhesiveness to the mucosa. That is, examples of the water-soluble polymers include polymers that have a high viscosity, and specifically, one or more selected from pullulan, polyvinylpyrrolidone, polyacrylic acid, and carboxyvinyl polymers are preferred.

[0013] In this specification, the term "prophylactic or therapeutic drug for animal diseases" refers to any drug capable of preventing or treating various animal diseases, including various oral care active ingredients and various disease preventive and therapeutic drugs.Here, animal diseases include the diseases of non-human animals, including oral diseases, digestive system diseases, liver diseases, kidney diseases, central nervous system diseases, circulatory system diseases such as heart and blood vessel diseases, and infectious diseases, but oral diseases are preferred.Oral diseases include gingivitis, periodontal disease, dental caries, stomatitis, etc.Oral care active ingredients include bacterial cells such as lactic acid bacteria and lactic acid bacteria (killed bacteria), protein-based active ingredients such as lactoferrin and lactoperoxidase; plant extracts such as bay laurel leaf extract, licorice-platycodon root complex extract, and licorice extract; sugar alcohols such as erythritol, sorbitol, and xylitol. Other examples include ingredients that improve the oral environment, such as eriodictyol-6-C-glucoside, epigallocatechin gallate, reduced coenzyme Q10, and green tea fluoride; anti-inflammatory ingredients, such as lysozyme chloride, glycyrrhizinic acid, glycyrrhetinic acid, sodium azulene sulfonate, purple root extract, meloxicam, aluminum aspirin, anhydrous caffeine, ascorbic acid, and tocopherol succinate; bactericidal ingredients, such as cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, dequalinium, isopropylmethylphenol, clavulanic acid, potassium clavulanate, and interferon α; and antibiotics, such as azithromycin, tetracycline hydrochloride, amoxicillin hydrate, clindamycin hydrochloride, minocycline, spiramycin, metronidazole, and pradofloxacin.

[0014] In addition to oral care active ingredients, the following ingredients are also listed: aspirin aluminum, anhydrous caffeine, meloxicam, robenacoxib, grapiprant, ketoprofen, zonisamide, mavacoxib, firocoxib, imepitoin, fluoxetine, carprofen and other neurological drugs; alacepril, temocapril hydrochloride, enalapril maleate, Mokuboito dried extract, telmisartan, pimobendan, benazepril hydrochloride, beraprost sodium, torasemide, allopurinol, amlodipine, candesartan, beraprost sodium and other circulatory and respiratory drugs; maropitant citrate monohydrate, berberine tannate, bismuth subnitrate, geranium herb dried extract, Chinese gallnut powder, Scopolia extract powder, ursodeoxycholic acid, Phellodendron bark powder, biodiastase, biotamylase, lipase, hydrolase, Gastrointestinal medications such as aluminum xinaphthoate, vomica extract, cinnamon powder, fennel powder, acrinol, tannic acid albumin, spore-forming lactic acid bacteria, pancreatin, betaine hydrochloride, sugar-containing pepsin, cellulase, saccharifying bacteria, mosapride citrate hydrate, aluminum silicate, and metoclopramide hydrochloride; liver disease and detoxification agents such as Kremezin; metabolic drugs such as cyclosporine, trilostane, oclacitinib maleate, osaterone acetate, levothyroxine sodium hydrate, and iron dextran; synthetic antibacterial agents such as enrofloxacin, marbofloxacin, ofloxacin, and orbifloxacin; prednisolone, clindamycin, erythromycin, gentamicin sulfate, betamethasone valerate, clotrimazole, amoxicillin hydrate, potassium clavulanate, and cefpodoxime Antibiotics such as proxetil, cephalexin, and tilmicosin; endoparasiticides such as ivermectin, piperazine citrate, santonin, bromfenofos, macri, camara, actinidia, pyrantel pamoate, melarsomine dihydrochloride, milbemycin oxime, praziquantel, selamectin, eprinomectin, dichlorphen, lufenunone, piperamine adipate, disophenol, emodepside, toltrazuril, flubendazole, febantel, and moxidectin;These include liver disease and detoxification agents such as aminoethylsulfonic acid, thiamine hydrochloride, pyridoxine hydrochloride, DL-methionine, thiamine nitrate, riboflavin sodium phosphate, spherical adsorptive charcoal, choline chloride, nicotinamide, taurine, and cyanocobalamin; vitamin preparations such as vitamin A, vitamin D3, thiamine nitrate, riboflavin, pyridoxine hydrochloride, cyanocobalamin, tocopherol acetate, aminoethylsulfonate, calcium pantothenate, nicotinic acid, and nicotinamide; anti-cancer agents such as interferon and toceranib phosphate; food ingredients with intestinal regulating properties such as lactic acid bacteria (such as Lactobacillus species, Lactococcus species, and Streptococcus species) and bifidobacteria (Bifidobacterium species); and food ingredients supporting kidney function such as calcium carbonate, chitosan, and phosphorus adsorbents.

[0015] One aspect of the present invention is a film preparation adherent to the oral cavity of an animal, which has at least one film layer containing a preventive or therapeutic agent for an animal disease and a water-soluble polymer. Hereinafter, the film layer containing the preventive or therapeutic agent for an animal disease may be simply referred to as a drug layer, and the film layer not containing the preventive or therapeutic agent for an animal disease may be simply referred to as a coating layer.

[0016] The film preparation of the present invention may be a single-layer preparation or a multi-layer preparation. That is, it may be a single-layer preparation in which all active ingredients are added to one layer, or a multi-layer preparation in which one layer is formed for each active ingredient and then laminated together to form a single sheet. Furthermore, it may be a combination of multiple film layers (film layers not containing a prophylactic or therapeutic agent for an animal disease) (coating layers) containing a water-soluble polymer and a drug layer. That is, the film preparation of the present invention may have at least one film layer containing a prophylactic or therapeutic agent for an animal disease and a water-soluble polymer, but it may also be a film preparation adhesive to the oral cavity of an animal having two or more film layers, the outermost film layer of which is a film layer containing a prophylactic or therapeutic agent for an animal disease and a water-soluble polymer, or a film layer containing a water-soluble polymer (a film layer not containing a prophylactic or therapeutic agent for an animal disease). More specifically, examples include (1) a film preparation having one to three film layers containing a preventive or therapeutic drug for an animal disease and a water-soluble polymer, and (2) a film preparation having one to three film layers containing a preventive or therapeutic drug for an animal disease and a water-soluble polymer, with a film layer containing a water-soluble polymer on one or both sides (a film layer not containing a preventive or therapeutic drug for an animal disease).

[0017] Furthermore, when a protein-based active ingredient is included among the multiple active ingredients, it is preferable to have a structure having two layers: a layer containing the protein-based active ingredient (drug layer I) and a layer containing the other active ingredient (drug layer II). This is to prevent the active ingredient from being denatured or inactivated due to the influence of the solvent used in the production or thermal load. The formulation may have a structure of (drug layer I) / (drug layer II) / (drug layer I) or (drug layer II) / (drug layer I) / (drug layer II). Furthermore, a more complex multilayer structure may be used. Furthermore, when the active ingredient has a bitter taste, a layer for masking the bitterness may be provided on both sides of the film or between each layer.

[0018] First, the "film layer containing a preventive or therapeutic agent for an animal disease and a water-soluble polymer" (drug layer) will be described. This film layer (drug layer) contains a preventive or therapeutic agent for an animal disease. Animal diseases include the systemic diseases described above, but oral diseases such as gingivitis, periodontal disease, dental caries, and stomatitis are preferred. In recent years, the dietary habits of pet animals have changed, resulting in an increase in oral diseases similar to those in humans, and the development of effective preventive and therapeutic agents for these oral diseases is desired. Furthermore, the incidence of lifestyle-related diseases in pet animals (hypertension, diabetes, heart disease, cerebrovascular disease, cirrhosis, chronic renal failure, cancer, etc.) is also increasing, and a convenient administration method for these diseases at home or at a veterinarian is also desired. The preventive or therapeutic agents for these animal diseases are preferably the oral care active ingredients described above, including bacterial cells such as lactic acid bacteria and lactic acid bacteria (killed bacteria), protein-based active ingredients such as lactoferrin and lactoperoxidase; plant extracts such as bay leaf extract, licorice-platycodon root complex extract, and licorice extract; and erythritol. Also preferred are ingredients that improve the oral environment, such as eriodictyol-6-C-glucoside, epigallocatechin gallate, reduced coenzyme Q10, and green tea fluoride; anti-inflammatory ingredients, such as lysozyme chloride, glycyrrhizinic acid, glycyrrhetinic acid, sodium azulene sulfonate, purple root extract, meloxicam, aluminum aspirin, anhydrous caffeine, ascorbic acid, and tocopherol succinate; bactericidal ingredients, such as cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, dequalinium, isopropylmethylphenol, clavulanic acid, potassium clavulanate, and interferon α; and antibiotics, such as azithromycin, tetracycline hydrochloride, amoxicillin hydrate, clindamycin hydrochloride, minocycline, spiramycin, metronidazole, and pradofloxacin.

[0019] The characteristics and preferred dosage of the oral care active ingredient are as follows. Lactic acid bacteria are generally known to be effective against periodontal disease bacteria, including Lactobacillus salivarius, Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus sporogenes, as well as Lactococcus Enterococcus faecalis. However, spore-forming lactic acid bacteria are preferred to enhance the stability of the final formulation. Raw material powders of lactic acid bacteria that are said to be effective against periodontal disease typically contain 300 to 400 billion lactic acid bacteria per gram. For dogs and cats weighing around 10 kg, preferably 8 kg to less than 15 kg, the recommended daily intake of lactic acid bacteria is 0.0001 mg to 200 mg, preferably 0.1 mg to 100 mg, and more preferably 1 mg to 50 mg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily dose is 0.00005 mg to 100 mg, preferably 0.05 mg to 50 mg, and more preferably 0.5 mg to 25 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily dose is 0.0002 mg to 400 mg, preferably 0.2 mg to 200 mg, and more preferably 2 mg to 100 mg.

[0020] When live lactic acid bacteria are used, the lactic acid bacteria are inactivated during the manufacturing process, storage environment, and storage over time.On the other hand, killed bacteria maintain their effectiveness while being highly stable during formulation and storage, making them easy to handle.In general, killed Lactobacillus crispatus bacteria are known, and their intake amount is 0.1 mg to 200 mg, preferably 1 mg to 100 mg, more preferably 3 mg to 50 mg per day for dogs and cats weighing around 10 kg, preferably 8 kg to 15 kg.Furthermore, for dogs and cats weighing around 5 kg, preferably less than 8 kg, the intake amount is 0.05 mg to 100 mg, preferably 0.5 mg to 50 mg, more preferably 1.5 mg to 25 mg per day.For dogs and cats weighing around 20 kg, preferably 15 kg or more, the intake amount is 0.2 mg to 400 mg, preferably 2 mg to 200 mg, more preferably 6 mg to 100 mg per day.

[0021] Lactoferrin is present in saliva, where it binds to bacteria and is digested or excreted along with the saliva. It is generally known that lactoferrin is present in saliva at a ratio of 9 to 24 parts per 100 parts of the total components. It is said that humans produce 1 to 1.5 liters of saliva per day, while a 20 kg dog produces as much as 3 liters. The circadian rhythm, which is a time period favoring the development of harmful bacteria in the oral cavity, shows a tendency for harmful bacteria to proliferate for approximately half of the day. Assuming an average 10:1 difference in component amounts between humans and dogs, a 20 kg dog would need approximately 15 mg. In other words, the recommended lactoferrin intake for dogs and cats weighing around 10 kg, preferably between 8 kg and less than 15 kg, is 1 mg to 100 mg per day, preferably between 2 mg to 50 mg, and more preferably between 3 mg and 25 mg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily dose is 0.5 mg to 50 mg, preferably 1 mg to 25 mg, and more preferably 2 mg to 12.5 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily dose is 2 mg to 200 mg, preferably 4 mg to 100 mg, and more preferably 8 mg to 50 mg.

[0022] Lactoperoxidase, like lactoferrin, is present in saliva and has strong bactericidal activity. It is generally known that lactoperoxidase is present in saliva at a ratio of 2:1, assuming the total amount of components in saliva is 100. It is said that the daily amount of saliva produced by humans is 1 to 1.5 liters, and that of a 20 kg dog is as high as 3 liters. The circadian rhythm, which is a time wave that favors the growth of harmful bacteria in the oral cavity, shows a tendency for the proliferation of harmful bacteria for approximately half of the day. Furthermore, assuming an average difference in the amount of components between humans and dogs of 10:1, a 20 kg dog's required amount is approximately 1 to 2 mg. In other words, the recommended intake amount of lactoperoxidase for dogs and cats weighing around 10 kg, preferably 8 kg to less than 15 kg, is 0.1 mg to 20 mg per day, preferably 0.2 mg to 10 mg, and more preferably 0.5 mg to 5 mg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily dose is 0.05 mg to 10 mg, preferably 0.1 mg to 5 mg, and more preferably 0.25 mg to 2.5 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily dose is 0.2 mg to 40 mg, preferably 0.4 mg to 20 mg, and more preferably 1 mg to 10 mg.

[0023] The bay laurel leaf extract can be extracted with water or hot water, alcoholic solvents, acetone, or other organic solvents, and then the filtrate is concentrated or dried, and can be used as a dried product, or as a crude or purified product. The recommended intake amount is 0.5 mg to 50 mg, preferably 1 mg to 30 mg, and more preferably 2 mg to 20 mg per day for dogs and cats weighing around 10 kg, preferably 8 kg to 15 kg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the recommended intake amount is 0.25 mg to 25 mg, preferably 0.5 mg to 15 mg, and more preferably 1 mg to 10 mg per day. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the recommended intake amount is 1 mg to 400 mg, preferably 2 mg to 200 mg, and more preferably 4 mg to 100 mg per day.

[0024] Licorice and Platycodon grandiflorum root complex extract can be used as a dried product, or a crude or purified product, obtained by extracting licorice root and platycodon grandiflorum root with water or hot water, alcoholic solvents, acetone, or other organic solvents, and then concentrating or drying the filtrate. The intake amount is 1 mg to 200 mg, preferably 2 mg to 100 mg, and more preferably 5 mg to 50 mg per day for dogs and cats weighing around 10 kg, preferably 8 kg to 15 kg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily intake is 0.5 mg to 100 mg, preferably 1 mg to 50 mg, and more preferably 2 mg to 25 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily intake is 2 mg to 400 mg, preferably 4 mg to 200 mg, and more preferably 10 mg to 100 mg.

[0025] Erythritol is a sugar known to inhibit plaque accumulation and promote the antibacterial activity of saliva in humans. Similar effects are expected in dogs. For dogs and cats weighing around 10 kg, preferably 8 to 15 kg, the daily dose is 0.01 mg to 800 mg, preferably 0.1 mg to 400 mg, and more preferably 1 mg to 200 mg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily dose is 0.005 mg to 400 mg, preferably 0.05 mg to 200 mg, and more preferably 0.5 mg to 100 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily dose is 0.02 mg to 1600 mg, preferably 0.2 mg to 800 mg, and more preferably 2 mg to 400 mg. Xylitol, the same sugar alcohol as erythritol, can also be used because it is known to inhibit the growth of periodontal disease bacteria and plaque accumulation in humans.

[0026] The water-soluble polymer may be any suitable water-soluble and edible polymer. Specific examples include one or more selected from pullulan, starch, xanthan gum, sodium alginate, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymers, and hydroxyethyl cellulose. Among these, due to their properties of rapid thickening and dissolution in mucous membranes and saliva, one or more selected from pullulan, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymers, and hydroxyethyl cellulose are more preferred, one or more selected from pullulan, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymers, and hydroxyethyl cellulose are even more preferred, and one or more selected from hydroxypropyl cellulose and hydroxypropyl methylcellulose are even more preferred. Hydroxypropyl cellulose is preferred in that the drug release rate can be changed by combining grades with different degrees of polymerization. Specific examples include HPC-SSL, HPC-SL, HPC-L, HPC-M, and HPC-H manufactured by Nippon Soda Co., Ltd. Hydroxypropyl methylcellulose is preferred in that the dissolution rate and drug release rate can be changed by changing the degree of substitution of methoxy groups and hydroxypropoxy groups. Specific examples include TC-5E, TC-5M, TC-5R, and TC-5S manufactured by Shin-Etsu Chemical Co., Ltd. Hydroxypropyl methylcellulose (HPMC) has lower hygroscopicity than hydroxypropyl cellulose (HPC). Therefore, when the film is multilayered, it is preferred that the main water-soluble polymer in the outer layer be hydroxypropyl methylcellulose.

[0027] From the viewpoints of the solubility of the drug-containing film layer and the retention of the drug, the water-soluble polymer is preferably contained in the drug-containing film layer in an amount of 20 to 70% by mass, more preferably 25 to 60% by mass.

[0028] In addition to the above-mentioned components, the drug layer may contain plasticizers, antioxidants, sweeteners, colorants, etc. "Plasticizer" refers to a substance that is compatible with water-soluble polymers and provides flexibility to the drug-containing film layer. Examples of plasticizers include polyethylene glycol, glycerin, propylene glycol, triacetin, triethyl citrate, castor oil, etc. Polyethylene glycol is preferred because it is available in grades with different average molecular weights and makes it easy to adjust the flexibility of the drug-containing film layer. The content of the plasticizer in the drug film layer is preferably within 20% by mass from the standpoint of handleability.

[0029] Examples of antioxidants include L-ascorbic acid stearate, ascorbic acid, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, vitamin E, tocopherol, and butylhydroxyanisole. Examples of sweeteners that can be used include aspartame, stevia, sucralose, glycyrrhizic acid and its salts, thaumatin, acesulfame potassium, and saccharin and its salts. Colorants can be added to the film formulation to enhance the distinctiveness of the formulation, to make it easier to check the state of the formulation while it is being applied to the gums, and to make the formulation less noticeable while it is being applied to the gums. Colorants are not particularly limited as long as they are commonly used in pharmaceuticals. Examples include tar-based dyes and their aluminum lakes as specified in Ministry of Health, Labor and Welfare Ordinance No. 30. Other examples include red ferric oxide and yellow red ferric oxide. Furthermore, opacifying agents such as titanium oxide, talc, zinc oxide, and magnesium oxide can be added to make the film formulation opaque. Furthermore, the colorant and opacifying agent may be added to the same layer. Furthermore, by combining a colored layer and an opacified layer and optimizing the layer structure of the preparation, it is possible to improve the distinguishability between the front and back of the film preparation and to improve the appearance.

[0030] Next, a film layer containing a water-soluble polymer (a film layer not containing a preventive or therapeutic drug for an animal disease) (coating layer) will be described. The coating layer is basically a film layer containing a water-soluble polymer, and the water-soluble polymer used is preferably the same as that blended in the drug layer. From the viewpoint of the solubility of the coating layer, the water-soluble polymer is preferably contained in the coating layer in an amount of 60 to 100% by mass, more preferably 80 to 100% by mass.

[0031] In addition to the water-soluble polymer, the coating layer may contain a compound that promotes solubility, such as a surfactant. To ensure that the coating layer quickly exhibits adhesiveness when the formulation comes into contact with the mucosal surface of the gums, it is recommended to add a solubility-promoting compound, such as a sugar alcohol, to accelerate dissolution of the coating layer. Specific examples include sorbitol, maltitol, xylitol, and mannitol. Among these, sorbitol is preferred because it not only promotes solubility but also imparts good plasticity to the formulation. To ensure that the coating layer quickly dissolves and exhibits adhesiveness, it is recommended to add a surfactant to ensure that the components of the mucosal surface (such as saliva) quickly mix with the coating layer surface. Examples of surfactants include sucrose fatty acid esters, sodium lauryl sulfate, glycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene hydrogenated castor oil. Sucrose fatty acid esters are more preferred in terms of their effect on the taste of the formulation and their potential for mucosal irritation.

[0032] The size and shape of the film formulation of the present invention are not particularly limited as long as they are easy to handle during administration and do not cause resistance from the animal to which they are administered. Examples include squares, squares with rounded corners, circles, and ellipses. The ratio of the short side (minor axis) to the long side (major axis) is preferably 1 to 5, more preferably 1 to 4, and even more preferably 1 to 3. To adjust the dosage, notches or perforations may be provided so that the size can be adjusted by cutting the film formulation. Possible notch shapes include "V" and "I" shapes. Alternatively, the user may cut the sheet-like product into individual film formulations to an appropriate size based on the animal's weight or other factors. The sheet may have a grid pattern (or a lattice pattern) printed on its surface using edible ink. For example, the film formulation is administered in a size of 1 sho per kg of animal weight.

[0033] The thickness of the preparation is preferably 50 to 1000 μm, more preferably 70 to 800 μm, and even more preferably 100 to 500 μm. Within this range, the preparation is easy to handle during administration and has good solubility after administration.

[0034] Another embodiment of the present invention is a film preparation adherent to the oral cavity of an animal, which has at least one film layer containing a preventive or therapeutic agent for an animal disease and a highly mucosally adhesive, water-soluble polymer.

[0035] The film preparation of the present invention may be a single-layer preparation or a multi-layer preparation. That is, it may be a single-layer preparation in which all active ingredients are added to one layer, or a multi-layer preparation in which a layer is formed for each active ingredient and then laminated together to form a single sheet. Furthermore, it may be a combination of multiple film layers (coating layers) containing a water-soluble polymer (film layers not containing a preventive or therapeutic agent for an animal disease) and drug layers. That is, the film preparation of the present invention may have at least one film layer containing a preventive or therapeutic agent for an animal disease and a highly mucosally-adhesive, water-soluble polymer. However, it may also be a film preparation adhesive to the oral cavity of an animal having two or more film layers, the outermost film layer of which is a film layer containing a preventive or therapeutic agent for an animal disease and a highly mucosally-adhesive, water-soluble polymer, or a film layer containing a highly mucosally-adhesive, water-soluble polymer (a film layer not containing a preventive or therapeutic agent for an animal disease). More specifically, examples include (1) film preparations having one to three film layers containing a preventive or therapeutic agent for an animal disease and a highly mucosally adherent, water-soluble polymer, and (2) film preparations having one to three film layers containing a preventive or therapeutic agent for an animal disease and a highly mucosally adherent, water-soluble polymer, and having a film layer having a highly mucosally adherent, water-soluble polymer on one or both sides thereof (a film layer not containing a preventive or therapeutic agent for an animal disease).

[0036] Furthermore, when a protein-based active ingredient is included among the multiple active ingredients, it is preferable to have a structure having two layers: a layer containing the protein-based active ingredient (drug layer I) and a layer containing the other active ingredient (drug layer II). This is to prevent the active ingredient from being denatured or inactivated due to the influence of the solvent used in the production or thermal load. The formulation may have a structure of (drug layer I) / (drug layer II) / (drug layer I) or (drug layer II) / (drug layer I) / (drug layer II). Furthermore, a more complex multilayer structure may be used. Furthermore, when the active ingredient has a bitter taste, a layer for masking the bitterness may be provided on both sides of the film or between each layer.

[0037] First, the "film layer containing a preventive or therapeutic agent for an animal disease and a highly mucosally adhesive, water-soluble polymer" (drug layer) will be described. This film layer contains a preventive or therapeutic agent for an animal disease. Animal diseases include the systemic diseases described above, but oral diseases such as gingivitis, periodontal disease, dental caries, and stomatitis are preferred. In recent years, changes in the eating habits of pet animals have led to an increase in oral diseases similar to those in humans, creating a demand for the development of effective preventive and therapeutic agents for these oral diseases. Furthermore, the incidence of lifestyle-related diseases in pet animals (e.g., hypertension, diabetes, heart disease, cerebrovascular disease, cirrhosis, chronic renal failure, and cancer) is also increasing, creating a demand for convenient administration methods for these diseases at home or at a veterinarian. The preventive or therapeutic agents for these animal diseases are preferably the oral care active ingredients described above, including bacterial cells such as lactic acid bacteria and lactic acid bacteria (killed bacteria), protein-based active ingredients such as lactoferrin and lactoperoxidase; plant extracts such as bay leaf extract, licorice-platycodon root complex extract, and licorice extract; and erythritol. Also preferred are ingredients that improve the oral environment, such as eriodictyol-6-C-glucoside, epigallocatechin gallate, reduced coenzyme Q10, and green tea fluoride; anti-inflammatory ingredients, such as lysozyme chloride, glycyrrhizinic acid, glycyrrhetinic acid, sodium azulene sulfonate, purple root extract, meloxicam, aluminum aspirin, anhydrous caffeine, ascorbic acid, and tocopherol succinate; bactericidal ingredients, such as cetylpyridinium chloride, benzethonium chloride, benzalkonium chloride, chlorhexidine hydrochloride, dequalinium, isopropylmethylphenol, clavulanic acid, potassium clavulanate, and interferon α; and antibiotics, such as azithromycin, tetracycline hydrochloride, amoxicillin hydrate, clindamycin hydrochloride, minocycline, spiramycin, metronidazole, and pradofloxacin.

[0038] The characteristics and preferred dosage of the oral care active ingredient are as follows. Lactic acid bacteria are generally known to be effective against periodontal disease bacteria, including Lactobacillus salivarius, Lactobacillus reuteri, Lactobacillus rhamnosus, and Lactobacillus sporogenes, as well as Lactococcus Enterococcus faecalis. However, spore-forming lactic acid bacteria are preferred to enhance the stability of the final formulation. Raw material powders of lactic acid bacteria that are said to be effective against periodontal disease typically contain 300 to 400 billion lactic acid bacteria per gram. For dogs and cats weighing around 10 kg, preferably 8 kg to less than 15 kg, the recommended daily intake of lactic acid bacteria is 0.0001 mg to 200 mg, preferably 0.1 mg to 100 mg, and more preferably 1 mg to 50 mg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily dose is 0.00005 mg to 100 mg, preferably 0.05 mg to 50 mg, and more preferably 0.5 mg to 25 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily dose is 0.0002 mg to 400 mg, preferably 0.2 mg to 200 mg, and more preferably 2 mg to 100 mg.

[0039] When live lactic acid bacteria are used, the lactic acid bacteria are inactivated during the manufacturing process, storage environment, and storage over time.On the other hand, killed bacteria maintain their effectiveness while being highly stable during formulation and storage, making them easy to handle.In general, killed Lactobacillus crispatus bacteria are known, and their intake amount is 0.1 mg to 200 mg, preferably 1 mg to 100 mg, more preferably 3 mg to 50 mg per day for dogs and cats weighing around 10 kg, preferably 8 kg to 15 kg.Furthermore, for dogs and cats weighing around 5 kg, preferably less than 8 kg, the intake amount is 0.05 mg to 100 mg, preferably 0.5 mg to 50 mg, more preferably 1.5 mg to 25 mg per day.For dogs and cats weighing around 20 kg, preferably 15 kg or more, the intake amount is 0.2 mg to 400 mg, preferably 2 mg to 200 mg, more preferably 6 mg to 100 mg per day.

[0040] Lactoferrin is present in saliva, where it binds to bacteria and is digested or excreted along with the saliva. It is generally known that lactoferrin is present in saliva at a ratio of 9 to 24 parts per 100 parts of the total components. It is said that humans produce 1 to 1.5 liters of saliva per day, while a 20 kg dog produces as much as 3 liters. The circadian rhythm, which is a time period favoring the development of harmful bacteria in the oral cavity, shows a tendency for harmful bacteria to proliferate for approximately half of the day. Assuming an average 10:1 difference in component amounts between humans and dogs, a 20 kg dog would need approximately 15 mg. In other words, the recommended lactoferrin intake for dogs and cats weighing around 10 kg, preferably between 8 kg and less than 15 kg, is 1 mg to 100 mg per day, preferably between 2 mg to 50 mg, and more preferably between 3 mg and 25 mg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily dose is 0.5 mg to 50 mg, preferably 1 mg to 25 mg, and more preferably 2 mg to 12.5 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily dose is 2 mg to 200 mg, preferably 4 mg to 100 mg, and more preferably 8 mg to 50 mg.

[0041] Lactoperoxidase, like lactoferrin, is present in saliva and has strong bactericidal activity. It is generally known that lactoperoxidase is present in saliva at a ratio of 2:1, assuming the total amount of components in saliva is 100. It is said that the daily amount of saliva produced by humans is 1 to 1.5 liters, and that of a 20 kg dog is as high as 3 liters. The circadian rhythm, which is a time wave that favors the growth of harmful bacteria in the oral cavity, shows a tendency for the proliferation of harmful bacteria for approximately half of the day. Furthermore, assuming an average difference in the amount of components between humans and dogs of 10:1, a 20 kg dog's required amount is approximately 1 to 2 mg. In other words, the recommended intake amount of lactoperoxidase for dogs and cats weighing around 10 kg, preferably 8 kg to less than 15 kg, is 0.1 mg to 20 mg per day, preferably 0.2 mg to 10 mg, and more preferably 0.5 mg to 5 mg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily dose is 0.05 mg to 10 mg, preferably 0.1 mg to 5 mg, and more preferably 0.25 mg to 2.5 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily dose is 0.2 mg to 40 mg, preferably 0.4 mg to 20 mg, and more preferably 1 mg to 10 mg.

[0042] The bay laurel leaf extract can be extracted with water or hot water, alcoholic solvents, acetone, or other organic solvents, and then the filtrate is concentrated or dried, and can be used as a dried product, or as a crude or purified product. The recommended intake amount is 0.5 mg to 100 mg, preferably 1 mg to 50 mg, and more preferably 2 mg to 25 mg per day for dogs and cats weighing around 10 kg, preferably 8 kg to 15 kg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the recommended intake amount is 0.25 mg to 50 mg, preferably 0.5 mg to 25 mg, and more preferably 1 mg to 12.5 mg per day. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the recommended intake amount is 1 mg to 200 mg, preferably 2 mg to 100 mg, and more preferably 4 mg to 50 mg per day.

[0043] Licorice and Platycodon grandiflorum root complex extract can be used as a dried product, or a crude or purified product, obtained by extracting licorice root and platycodon grandiflorum root with water or hot water, alcoholic solvents, acetone, or other organic solvents, and then concentrating or drying the filtrate. The intake amount is 1 mg to 200 mg, preferably 2 mg to 100 mg, and more preferably 5 mg to 50 mg per day for dogs and cats weighing around 10 kg, preferably 8 kg to 15 kg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily intake is 0.5 mg to 100 mg, preferably 1 mg to 50 mg, and more preferably 2 mg to 25 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily intake is 2 mg to 400 mg, preferably 4 mg to 200 mg, and more preferably 10 mg to 100 mg.

[0044] Erythritol is a sugar known to inhibit plaque accumulation and promote the antibacterial activity of saliva in humans. Similar effects are expected in dogs. For dogs and cats weighing around 10 kg, preferably 8 to 15 kg, the daily dose is 0.01 mg to 800 mg, preferably 0.1 mg to 400 mg, and more preferably 1 mg to 200 mg. For dogs and cats weighing around 5 kg, preferably less than 8 kg, the daily dose is 0.005 mg to 400 mg, preferably 0.05 mg to 200 mg, and more preferably 0.5 mg to 100 mg. For dogs and cats weighing around 20 kg, preferably 15 kg or more, the daily dose is 0.02 mg to 1600 mg, preferably 0.2 mg to 800 mg, and more preferably 2 mg to 400 mg. Xylitol, the same sugar alcohol as erythritol, can also be used because it is known to inhibit the growth of periodontal disease bacteria and plaque accumulation in humans.

[0045] As the highly mucosally adhesive, water-soluble polymer, among the aforementioned water-soluble polymers, preferred are polymers that absorb moisture from the mucosa to thicken and exhibit high adhesion to the mucosa. Specific examples include one or more selected from pullulan, starch, xanthan gum, sodium alginate, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyacrylic acid, carboxyvinyl polymers, and hydroxyethyl cellulose. Of these, one or more selected from polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyacrylic acid, and carboxyvinyl polymers are more preferred due to their rapid thickening and dissolution in the mucosa or saliva. Hydroxypropyl cellulose is preferred because the drug release rate can be varied by combining grades with different degrees of polymerization. Specific examples include HPC-SSL, HPC-SL, HPC-L, HPC-M, and HPC-H from Nippon Soda Co., Ltd. Hydroxypropyl methylcellulose is preferred because the dissolution rate and drug release rate can be adjusted by varying the degree of substitution of methoxy and hydroxypropoxy groups. Specific examples include TC-5E, TC-5M, TC-5R, and TC-5S from Shin-Etsu Chemical Co., Ltd. Hydroxypropyl methylcellulose (HPMC) has lower hygroscopicity than hydroxypropyl cellulose (HPC). Therefore, when the film is multilayered, it is preferable that the main water-soluble polymer in the outer layer is hydroxypropyl methylcellulose. To achieve sustained mucoadhesion, polyvinylpyrrolidone (PVP) is preferably used. Polyvinylpyrrolidone improves the bonding between the components of the film and has the effect of making the film less likely to crack. Specific examples include Kollidon K-30 and Kollidon K-90 from BASF. A combination of hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone (PVP) is preferred in terms of adjusting the adhesiveness of the film to the gums and the drug release rate. The adhesive strength and release properties can be adjusted by changing the grade of HPC and PVP and the mixing ratio of the two.PVP is preferably added in an amount of 15 to 80 parts by mass, more preferably 25 to 50 parts by mass, and even more preferably 30 to 40 parts by mass, per 100 parts by mass of HPC. If the amount of PVP is too small, sufficient adhesiveness may not be obtained. If the amount of PVP is too large, the formulation may soften over time, causing problems with handling during application.

[0046] From the viewpoints of the solubility of the drug-containing film layer, retention of the drug, etc., the highly mucosa-adherent water-soluble polymer is preferably contained in the drug-containing film layer in an amount of 10 to 90% by mass, more preferably 30 to 90% by mass, and even more preferably 45 to 80% by mass.

[0047] In addition to the above-mentioned components, the drug-containing film layer may contain plasticizers, antioxidants, sweeteners, colorants, etc. "Plasticizer" refers to a substance that is compatible with the highly mucoadhesive, water-soluble polymer and provides flexibility to the drug-containing film layer. Examples of plasticizers include polyethylene glycol, glycerin, propylene glycol, triacetin, triethyl citrate, castor oil, etc. Polyethylene glycol is preferred because it is available in grades with different average molecular weights and makes it easy to adjust the flexibility of the drug-containing film layer. The content of the plasticizer in the drug film layer is preferably within 20% by mass from the standpoint of handleability.

[0048] Examples of antioxidants include L-ascorbic acid stearate, ascorbic acid, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, vitamin E, tocopherol, and butylhydroxyanisole. Examples of sweeteners that can be used include aspartame, stevia, sucralose, glycyrrhizic acid and its salts, thaumatin, acesulfame potassium, and saccharin and its salts. Colorants can be added to the film formulation to enhance the distinctiveness of the formulation, to make it easier to check the state of the formulation while it is being applied to the gums, and to make the formulation less noticeable while it is being applied to the gums. Colorants are not particularly limited as long as they are commonly used in pharmaceuticals. Examples include tar-based dyes and their aluminum lakes as specified in Ministry of Health, Labor and Welfare Ordinance No. 30. Other examples include red ferric oxide and yellow red ferric oxide. Furthermore, opacifying agents such as titanium oxide, talc, zinc oxide, and magnesium oxide can be added to make the film formulation opaque. Furthermore, the colorant and opacifying agent may be added to the same layer. Furthermore, by combining a colored layer and an opacified layer and optimizing the layer structure of the preparation, it is possible to improve the distinguishability between the front and back of the film preparation and to improve the appearance.

[0049] Next, a film layer containing a highly mucosally adhesive, water-soluble polymer (a film layer not containing a preventive or therapeutic drug for animal diseases) (coating layer) will be described. The coating layer is basically a film layer containing a highly mucosally adhesive, water-soluble polymer. The highly mucosally adhesive, water-soluble polymer used is preferably the same as that blended in the drug layer. However, from the viewpoint of adhesion to the mucosal surface of the gums, polyvinylpyrrolidone, polyacrylic acid, carboxyvinyl polymer, and pullulan are preferred. Of these, pullulan is preferred because it quickly exerts adhesion upon contact with the mucosal surface of the gums. From the viewpoint of the mucosal adhesion and solubility of the coating layer, the highly mucosally adhesive, water-soluble polymer is preferably contained in the coating layer at 60 to 100% by mass, more preferably 80 to 100% by mass.

[0050] In addition to the highly mucosally adhesive, water-soluble polymer, the coating layer may contain a compound that promotes solubility, such as a surfactant. To ensure that the coating layer quickly exhibits adhesiveness when the formulation comes into contact with the mucosal surface of the gums, it is recommended to add a solubility-promoting compound, such as a sugar alcohol, to accelerate dissolution of the coating layer. Specific examples include sorbitol, maltitol, xylitol, and mannitol. Among these, sorbitol is preferred because it not only promotes solubility but also imparts good plasticity to the formulation. To ensure that the coating layer quickly dissolves and exhibits adhesiveness, it is recommended to add a surfactant to ensure that the coating layer surface quickly mixes with components on the mucosal surface (such as saliva). Examples of surfactants include sucrose fatty acid esters, sodium lauryl sulfate, glycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene hydrogenated castor oil. Sucrose fatty acid esters are more preferred in terms of their effect on the taste of the formulation and their potential for mucosal irritation.

[0051] The size and shape of the film formulation of the present invention are not particularly limited as long as they are easy to handle during administration and do not cause resistance from the animal to which they are administered. Examples include squares, squares with rounded corners, circles, and ellipses. The ratio of the short side (minor axis) to the long side (major axis) is preferably 1 to 5, more preferably 1 to 4, and even more preferably 1 to 3. To adjust the dosage, notches or perforations may be provided so that the size can be adjusted by cutting the film formulation. Possible notch shapes include "V" and "I" shapes. Alternatively, the user may cut the sheet-like product into individual film formulations to an appropriate size based on the animal's weight or other factors. The sheet may have a grid pattern (or a lattice pattern) printed on its surface using edible ink. For example, the film formulation is administered in a size of 1 sho per kg of animal weight.

[0052] The thickness of the preparation is preferably 50 to 1000 μm, more preferably 70 to 800 μm, and even more preferably 100 to 500 μm. Within this range, the preparation is easy to handle during administration and has good solubility after administration.

[0053] Next, the methods for producing both types of film preparations of the present invention will be described. Film preparations can be produced by known methods. For example, a film preparation with a three-layer structure of (A layer) / (B layer) / (A layer) can be produced by the following methods. Method 1: (1) The components of each of the A layer and B layer are dissolved in a predetermined solvent to obtain a layer A coating liquid and a layer B coating liquid (coating liquid preparation step). (2) The A layer coating liquid or the B layer coating liquid is uniformly coated on a plastic film and dried to form the A layer or the B layer (coating and drying step). (3) The B layer is laminated on the A layer obtained in the coating and drying step, the plastic film on the B layer side is peeled off, and then the A layer is laminated on the B layer (laminating step). Method 2: (1) The A layer coating liquid is uniformly coated on a plastic film and dried to form the A layer. (2) The B layer coating liquid is uniformly coated on the A layer and dried to form the B layer (laminating and drying step). (3) The laminated coated and dried products are laminated together so that the B layers are in contact with each other. Method 3: (1) The A layer coating liquid is evenly coated on the plastic film and then dried to form the A layer. (2) The B layer coating liquid is evenly coated on the A layer and then dried to form the B layer. (3) The A layer coating liquid is evenly coated on the B layer and then dried to form the A layer.

[0054] Method 1 is a method in which each layer formed separately by coating and drying is laminated together to form a desired formulation. Method 3 is a method in which the coating liquids for each layer are sequentially laminated and dried to form a desired formulation. Method 2 is a combination of Methods 1 and 3. Methods 1 to 3 can be combined taking into consideration the layer structure and thickness of the desired film formulation, the drying properties of the coating liquid, the heat load on the active ingredient, etc. When laminating layers together during the manufacturing process, it is preferable that the water-soluble polymer in one or both of the laminated layers contains hydroxypropyl cellulose (HPC). In the above method, when layers obtained from the same coating liquid are laminated together, they are counted as one layer. Furthermore, layers obtained by laminating and drying the same coating liquid are also counted as one layer. When multiple layers of the same composition are provided, for example, in a formulation with a (Layer A) / (Layer B) / (Layer A) structure, the thicknesses of Layer A may be the same or different.

[0055] Examples of the coating film (plastic film) include those made of polyethylene terephthalate (PET), polypropylene (PP), and polyethylene (PE). The surface of the plastic film is preferably silicone-treated or discharge corona-treated as needed. By performing such treatments, the coating liquid can be uniformly applied and the plastic film can be easily removed from the surface of each layer formed after drying. The plastic film is preferably made of polyethylene terephthalate (PET) because it generates less distortion during the coating and drying process. The solvent used to prepare the coating liquid is not particularly limited, as long as it can obtain a coating liquid in which the components of each layer are uniformly dissolved or dispersed and can be coated and dried uniformly. From the standpoints of ease of handling and toxicity, water, ethanol, and a mixture of water and ethanol are preferred.

[0056] When active ingredient is the protein active ingredient such as lactoferrin or lactoperoxidase, from the viewpoint of the solubility of protein active ingredient and avoiding the denaturation caused by ethanol, it is preferable to use the water that does not add ethanol.When it is necessary to add ethanol in order to improve the coating drying property during production or improve the antiseptic property of coating liquid, the ethanol concentration is preferably 15% or less, more preferably 10% or less.

[0057] Furthermore, when the active ingredient is a protein-based active ingredient, care must be taken to prevent denaturation or inactivation due to the heat load during coating and drying. Specifically, it is recommended that the protein-based active ingredient be added to a drug layer separate from other active ingredients. Furthermore, it is recommended that a low-viscosity grade water-soluble polymer be used in the drug layer containing the protein-based active ingredient. This reduces the amount of solvent in the coating solution, allowing for a thinner coating thickness, shorter drying time, and reduced heat load.

[0058] When the film preparation of the present invention is administered to the oral cavity, it disintegrates or dissolves in the saliva present in the oral cavity. Since the drug and the thickener, which is a base component, are present together, they easily adhere to the surface of the oral mucosa. On the other hand, when administered as a liquid preparation, the liquid preparation is easily diluted and flows in the oral cavity because it is composed of water-soluble substances. Therefore, higher medicinal efficacy is expected when administered as a film preparation rather than as a liquid preparation.

[0059] The film preparation of the present invention is preferably used by applying it to the oral mucosa of a non-human animal. As mentioned above, oral diseases such as periodontal disease, gingivitis, and dental caries have been increasing in pet animals such as dogs and cats in recent years, and a simple administration method for their prevention and treatment is desired. When the film preparation of the present invention is applied to the oral mucosa of these animals, particularly the gums, it quickly adheres to the mucosa, the film quickly dissolves, and the drug is released into the oral cavity, where it remains in the oral cavity for a long period of time, thereby preventing and treating oral diseases in animals. Furthermore, the film preparation of the present invention is preferably applied to the buccal side of the gums, which are difficult to reach with the tongue, etc. Therefore, the size of the film preparation of the present invention is preferably large enough to be applied to the gums.

[0060] The present invention will be described in more detail below with reference to examples, but is not limited to these examples. The preparations in Table 1 use highly mucosally adhesive, water-soluble polymers and are sometimes referred to as adhesive (AD) films or ADF types. The preparations in Table 2 use only water-soluble polymers and are sometimes referred to as fast-dissolving (OD) films or ODF types.

[0061] [Preparation manufacturing example]

[0062]

[0063] Films with a (coating layer) / (drug layer I) / (drug layer II) / (drug layer I) / (coating layer) structure were prepared using the following method. Table 1 shows the composition (%) of each layer: coating layer, drug layer I, and drug layer II. The components shown in Table 1 were added to an appropriate amount of water and stirred to prepare a coating layer coating solution. The components shown in Table 1 were added to an appropriate amount of water and stirred to prepare a drug layer I coating solution. The components shown in Table 1 were added to an appropriate amount of ethanol and stirred to prepare a drug layer II coating solution. Multilayer films with the desired configuration were obtained by combining Methods 1 to 3 described above. The films were then cut into the desired shape to obtain films. Each of the obtained films was packaged individually in an aluminum bag. The thickness (coating clearance) of each coating solution during application was adjusted so that the mass ratios of the coating layer, drug layer I, and drug layer II in one film were the values ​​shown in Table 1.

[0064]

[0065] Films with a (drug layer I) / (drug layer II) / (drug layer I) structure were prepared using the following method. Table 2 shows the composition (%) of each layer of drug layer I and drug layer II. Drug layer I coating solution: The components shown in Table 1 were added to an appropriate amount of water and stirred to prepare the drug layer I coating solution. Drug layer II coating solution: The components shown in Table 2 were added to an appropriate amount of ethanol and stirred to prepare the drug layer II coating solution. Multilayer films with the desired structure were obtained by applying Methods 1 to 3 described above. The films were then cut into the desired shape to obtain films. The obtained films were individually packaged in aluminum bags. The coating thickness (coating clearance) of each coating solution was adjusted so that the mass ratio of drug layer I to drug layer II in one film would be the value shown in Table 3.

[0066] [Animal Testing] (1) Test Formulations (Films) The following three types of film formulations were used: Adhesive (AD) film: The formulation of Example 1 was cut into an oval shape with a minor axis of 10.6 mm and a major axis of 21.2 mm. Formulation area: 1.77 cm 2 , Preparation mass: 43.60 mg Adhesive (AD) (small) film The preparation of Example 1 was cut into an oval shape with a minor axis of 7.5 mm and a major axis of 15 mm Preparation area: 0.88 cm 2 , Preparation mass: 21.80 mg Rapidly dissolving (OD) film The preparation of Example 3 was cut into a rectangle with a short side of 14 mm and a long side of 20 mm Preparation area: 2.8 cm 2 , formulation mass: 59.00 mg

[0067] (2) Experimental Animals Twelve dogs suffering from gingivitis / periodontal disease were used as test animals. The test animals were divided into an AD film group, an AD (small) film group, and an OD film group. The test animals were divided into groups based on gingivitis score evaluation, halitosis sensory test, and periodontal disease bacterial evaluation so that the degree of gingivitis / periodontal disease was the same in each group. (3) Gingivitis Score Evaluation The degree of gingivitis inflammation was evaluated according to the table below. Gingivitis score evaluation was performed on the gingival regions of the following teeth: Maxilla: third incisor, canine, second premolar, third premolar, fourth premolar, first molar; Mandible: canine, second premolar, third premolar, fourth premolar, first molar. In other words, evaluation was performed at 11 locations, and the total score for each location was used as the evaluation result. For example, if all locations received a score of 3, the evaluation result would be 33 (3 x 11). Evaluation was performed five times in total on Day 1, Day 5, Day 9, Day 16, and Day 29. Day 1 was the first day of the test, before the first administration. Day 29 was the day after the final administration (28th administration).

[0068]

[0069] The periodontitis score was evaluated using the color tones PI-3, PI-6, and PI-8 of the "New Color Card 199a" (Nippon Shikiken Jyo Co., Ltd.) as a reference. The evaluation results are shown in Figure 1. Figure 1 demonstrates that the film preparation of the present invention is effective in preventing and treating periodontitis.

[0070] (4) Bad breath sensory test The bad breath of the test animals was judged by four panelists. The judgment was made from the viewpoint of "odor strength" and "odor type" according to the scores in the table below. The judgment was made four times in total, on Day 1, Day 9, Day 16, and Day 29. Day 1 was the first day of the test, before the first administration. Day 29 was the day after the final administration (28th administration).

[0071]

[0072]

[0073] Specific test method For example, the bad breath evaluation for Day 1 of the AD group was compiled as follows. Panelist A rated the bad breath intensity of dog No. 1 as 2 and determined that the type of odor he perceived was B, so he checked "○" for bad breath intensity 2 and odor type B. Panelists B to D also made evaluations using the same procedure. Next, the judgment value for dog No. 1 was the average value of the four panelists for odor intensity, and the total of the check marks for each odor type. Dogs No. 2 to 4 were also judged in the same way (only the judgment value is listed). The final evaluation value for Day 1 of the AD group was the average of the judgment values ​​of each dog for odor intensity, and the total of the check marks for each odor type.

[0074]

[0075] The same evaluation method was used for each group, and the final evaluation results are shown in Figures 2 to 4. When the odor intensity was evaluated as 0 or 1, the type of odor was not checked. Figures 2 to 4 demonstrate that the film preparation of the present invention has an effect of preventing bad breath, particularly reducing odors caused by periodontal disease, increasing the natural odor caused by saliva, and improving the oral environment, such as the moist state of the oral cavity.

[0076] (5) Periodontal Bacteria Evaluation Periodontal bacteria were evaluated using two types of measurement kits: AuraStrip (DS Pharma Animal Health Co., Ltd.) and Adplit (Kyoritsu Seiyaku Co., Ltd.). Measurements were performed at four locations on the left and right upper and lower jaws, from the canine (C) to the fourth premolar (P4). The average concentration (score) of the four locations was used as the measurement result. AuraStrip is a commercially available measurement kit that measures the concentration of thiol, a metabolic product of oral anaerobic bacteria. Adplit is a commercially available kit that measures the concentration of N-benzoyl-DL-arginyl peptidase, an enzyme specifically produced by bacteria that cause periodontal disease in dogs. Both kits provide measurement results as a score of 0 to 5. The higher the score, the higher the concentration of the target component, i.e., the more severe the symptoms of gingivitis / periodontal disease. Assessment using AuraStrip was performed four times: on Day 1, Day 9, Day 16, and Day 29. Day 1 was the first day of the test, before the first administration. Day 29 was the day after the final administration (28th administration). Assessment using Adoprit was performed four times: on Day 1, Day 10, Day 17, and Day 30. Day 1 was the first day of the test, before the first administration. Day 30 was two days after the final administration (28th administration). The periodontal disease bacteria evaluation is shown in Figures 5 and 6. Figures 5 and 6 demonstrate that the film formulation of the present invention inhibits the growth of periodontal disease bacteria in the oral cavity. (6) Administration of Test Formulation - Administration of Food and Water The test animals were fed once a day between 9:00 and 11:00. Water was available ad libitum throughout the test. - Administration of Test Formulation The designated film formulation was applied between 13:00 and 14:00. Before application, it was confirmed that there was no remaining food in the mouth or cage. If present, it was removed. On days when gingivitis / periodontal disease status was assessed, the appropriate assessment was performed and then the film was applied.

[0077] (7) Evaluation of dissolution time - Experimental animals: 16 dogs were used as test animals. - Evaluation method: One of the following preparations was applied to the gums of the dogs: adhesive (AD) film, adhesive (AD) (small) film, or fast-dissolving (OD) film. 15 and 30 minutes after application, the presence or absence of the preparation was visually confirmed. Regardless of the size of the preparation, if the preparation could be visually confirmed, it was rated as "present," and if not, it was rated as "absent." If the evaluation at 15 minutes was "absent," the evaluation at 30 minutes was not carried out.

[0078]

[0079]

[0080] Regarding the degree of dissolution of the formulation, the ADF type dissolved within 15 to 30 minutes, while the ODF type dissolved within 15 minutes. The remaining percentage of the formulation after 15 minutes was 61.5% (8 ÷ 13) for the ADF type and 33.3% (1 ÷ 3) for the ODF type.

[0081] As can be seen in Figures 1 to 6, the ADF type tends to have a higher therapeutic effect. This is thought to be because the ADF type formulation remains in the oral cavity (above the gums) for a longer period of time, allowing the active ingredient to remain in the oral cavity for a longer period of time. However, brachycephalic dogs and cats have small gums, which may make it difficult to apply the formulation to the oral cavity. Furthermore, depending on the personality of each individual, if the formulation is present above the gums, the individual may try to remove the formulation with their tongue. In such cases, the ODF type, in which the formulation dissolves in a short time and the active ingredient remains on the gum surface in a viscous state, may provide a higher therapeutic effect.

Claims

1. A film preparation for adhesion in the oral cavity of an animal, which has at least one film layer containing a preventive or therapeutic drug for an animal disease and a water-soluble polymer that is highly adhesive to the mucosa.

2. A film preparation for application in the oral cavity of animals having two or more film layers, wherein the outermost film layer is a film layer containing a preventive or therapeutic drug for an animal disease and a water-soluble polymer that is highly adhesive to the mucosa, or a film layer having a water-soluble polymer that is highly adhesive to the mucosa, as described in claim 1.

3. The film preparation according to claim 1, wherein the highly mucosally adhesive water-soluble polymer is one or more selected from the group consisting of pullulan, polyvinylpyrrolidone, polyacrylic acid and carboxyvinyl polymer.

4. The film preparation according to any one of claims 1 to 3, which has a thickness of 50 to 1000 µm.

Images