WO2021241898A1 - Veterinary orally-disintegrating-film formulation for treating or preventing parasitic infectious diseases in animals - Google Patents

Abstract

The present invention relates to a veterinary medicine and, specifically, to a veterinary orally-disintegrating-film formulation capable of treating or preventing infection or invasion of internal/external parasites in animals. The veterinary orally-disintegrating-film formulation capable of effectively treating or preventing the infection or invasion of animals by parasites, according to the present invention, is highly effective in terms of the oral ingestion of the therapeutic agent when attached to the tongue, the roof of the mouth, sublingually, or to the buccal cavity of a small dog. Particularly, an orally disintegrating film of the present invention has advantages in that, within specific thickness and size ranges, it is easy to attach and supply, effective separation is possible, the convenience of administration and drug delivery efficiency can be maximized, and storage stability is excellent. In addition, by including an edible polymer having specific viscosity, the orally disintegrating film of the present invention has suitable physical properties (appearance and separation) as a film, and has a rapid disintegration time of within three minutes.

Description

Veterinary oral disintegrating film formulation for treating or preventing parasitic infections in animals

The present invention relates to veterinary pharmaceuticals, and more particularly, to a veterinary orally disintegrating film formulation capable of treating or preventing infection or invasion of internal/external parasites in animals.

Animals, such as mammals and birds, are often susceptible to parasitic infestation. These parasites can be ectoparasites such as insects, and endoparasites such as heartworms and worms. Animals and humans also suffer from endoparasitic infections, including, for example, helminthosis, which is most frequently caused by a group of parasitic worms described as nematodes or roundworms. These parasites cause serious economic losses in pigs, sheep, horses, and cattle, as well as affect livestock animals and poultry. Other parasites that occur in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Parasites, including Toxocara, Toxascaris, Trichiris, Enterobius, found in the blood or other tissues and organs, for example, filamentous worms and extra-intestinal stage strong gilloids, toxocara and trichinella.

A type of internal parasites seriously harm the mammals di Leah immi pillars and teeth (Dirofilaria immitis), which is also known as heartworm. The most common hosts are dogs and cats, but other mammals such as ferrets and raccoons can also be infected. After going through several life stages, heartworms become adults and infect the pulmonary artery of the host mammal. Heartworm requires the mosquito as an intermediate step to complete its life cycle. The period between the initial infection, when a dog is bitten by a mosquito, and the maturation of the worm to an adult living in the heart takes 6 to 7 months in dogs and is known as the “latent phase”. L3 larvae migrate to the tip of the mosquito's mouth part (lips) during blood intake of the mosquito, leave the mosquito, and deposit on the dog's skin, where they then migrate into the host through the bite wound. Most L3 larvae molt into quaternary larvae (L4) in the canine subcutaneous tissue within 1-3 days after infection. Thereafter, they migrate to the muscles of the chest and abdomen, and molt to stage 5 (L5, immature adult), 45-60 days after infection. Between 75 and 120 days post infection, these immature heartworms then enter the bloodstream and are carried through the heart to reside in the pulmonary artery. Around 7 months after infection, D. immitis adults reach a mature state and reproduce sexually in the pulmonary artery and right ventricle. Adult males are approximately 15 cm long, females are approximately 25 cm long, and their average lifespan as adults is calculated to be approximately 5 years. After mating, the female worm releases larvae (or L1) known as microheartworms into circulation. Microheartworms circulate in the bloodstream for two years, waiting for the next phase of their life cycle in the digestive tract of bloodsucking mosquitoes. When ingested by mosquitoes, microheartworms undergo a series of molting into an infectious tertiary larval stage, which then migrates to the mosquito's salivary glands, where they wait to infect another host.

Heartworm infection is a serious and life-threatening disease. Heartworm infection in dogs is preventable and prophylactic treatment is a priority in heartworm endemic areas. Treatment of adult heartworm infection with adult insecticides (eg melarsomin dihydrochloride) is expensive and can cause serious adverse side effects, and thus prevention by monthly administration of drugs that interfere with larval development. I am widely used The goal of heartworm prophylaxis in dogs is to kill the tertiary larvae (L3), as well as the young and maturing quaternary larvae (L4), when they are deposited by mosquitoes and first enter the dog, so that the D. It was to stop the infection caused by the Teeth. Macrocyclic lactone (ML) can be used monthly in uninfected dogs to inhibit reproduction in adult worms and eliminate microheartworm, thereby reducing transmission and progressively causing depletion of adult worms (Veterinary Parasitology) 2005 Oct 24 133(2-3) 197-206).

On the other hand, the parasite therapeutic agent as described above may be administered to the animal through various routes. Examples include oral ingestion, topical application or parenteral administration. The particular route chosen by the expert will depend on factors such as the physicochemical properties of the drug or therapeutic agent, the condition of the host, and economic requirements. In certain instances, it is convenient and effective to orally administer a veterinary drug by placing the therapeutic agent in a solid or liquid matrix suitable for oral delivery. Tablets or chewable tablets are used as oral dosage forms.

However, conventionally marketed therapeutic agents in tablet or chewable formulations often provide an unpleasant taste, smell or texture, which causes animals to reject the composition. Rejection of the drug is frequent, making oral intake of the treatment difficult.

Accordingly, the present inventor has developed a parasite treatment agent in the form of an oral disintegrating film to solve the above problems, and when attaching such an oral disintegrating film formulation to the tongue, roof of the mouth, sublingual or buccal of small dogs By confirming that the oral intake of the therapeutic agent is very excellent, the present invention has been completed. In particular, when the orally disintegrating film of the present invention is manufactured to a specific thickness and size, it is easy to attach and feed, peel can be effectively made, convenience in administration and drug delivery efficiency can be maximized, and excellent storage stability. Confirmed. In addition, when the oral disintegrating film of the present invention was prepared using an edible polymer having a viscosity in a specific range, it was first identified that it has suitable film properties (properties and peeling) and has a fast disintegration time.

Accordingly, it is an object of the present invention to provide a veterinary orally disintegrating film formulation that can effectively treat or prevent parasitic infection or invasion in animals.

In order to achieve the above object,

The present invention provides a veterinary orally disintegrating film formulation for treating or preventing parasitic infection or infestation in animals, comprising one or more drugs selected from the drug groups listed in the following table as an active ingredient.

In one embodiment of the present invention, the oral disintegrating film may have a thickness of 0.05mm to 0.3mm and a size of 1cm ² to 15cm ² .

In one embodiment of the present invention, the orally disintegrating film may further include an edible polymer.

In one embodiment of the present invention, the edible polymer is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, carboxymethyl cellulose potassium, carboxymethyl It may be selected from the group consisting of cellulose and fullulane.

In one embodiment of the present invention, the edible polymer may have a viscosity of 1.0 ~ 20 mPa·s at 20 ℃.

In one embodiment of the present invention, the animal may be a dog or a cat.

The veterinary orally disintegrating film formulation, which can effectively treat or prevent parasitic infection or invasion in animals according to the present invention, is very effective for oral ingestion of the therapeutic agent when it is attached to the tongue, roof of the mouth, sublingual or buccal of small dogs. It has an excellent effect. In particular, the orally disintegrating film of the present invention has the advantages of easy attachment and application, effective peeling, in a specific thickness and size range, can be made effective in dosing, convenience and drug delivery efficiency can be maximized, and excellent storage stability. . In addition, the constituent disintegration film of the present invention has suitable film properties (properties and peeling) by including an edible polymer having a specific viscosity, and has a fast disintegration time of less than 3 minutes.

1 is a photograph showing film peeling from the base film paper of the drug-containing orally disintegrating film of the present invention using D-mannitol (0 mPa·s in 20° C., 2 mass% aqueous solution conditions) as an edible polymer.

2 is a photograph showing the properties of the drug-containing orally disintegrating film of the present invention using hydroxypropyl cellulose HPC-M (viscosity 150-400 mPa·s at 20° C., 2 mass% aqueous solution conditions) as an edible polymer.

3 is a photograph evaluating the disintegration time of the drug-containing oral disintegrating film of the present invention prepared by varying the viscosity of the edible polymer.

4 is a photograph of the drug-containing orally disintegrating film of the present invention prepared in various sizes.

5 is a photograph of a test subject beagle dog for measuring the dosing compliance of the drug-containing orally disintegrating film of the present invention prepared in various sizes.

6 is a photograph of attaching a film to the roof of the mouth of a beagle dog in order to measure the dosing compliance of the drug-containing oral disintegrating film of the present invention having a size of 2x3cm.

7 is a photograph showing film peeling from the base film paper of the drug-containing orally disintegrating film of the present invention having a thickness of 0.03mm.

8 is a photograph showing the stability of the drug-containing oral disintegrating film of the present invention having a thickness of 0.45mm at 60° C. and storage for 4 weeks (cured, broken).

9 is a photograph showing the stability of the drug-containing oral disintegrating film of the present invention having a thickness of 0.05 mm at 40° C., 75% RH, and storage for 4 weeks (it cannot be peeled off because it is pressed into an alu pouch).

Terms used in the present invention shall have their conventional meanings in the art unless otherwise specified.

The term “oral dispersible film” used in the present invention is also called an oral dispersible film (ODF), a strip, an orally dissolving film, etc., and is used in the oral cavity. It can be taken by dissolving or finely dispersing it. These films are usually placed on the tongue to dissolve, but may be administered by attaching them to the roof of the mouth, sublingual, buccal, and the like. The film formulation according to the present invention has the advantage that it can be taken without water.

It should be noted that terms used herein, such as "consisting of," "consisting of," "consisting of," and the like, may have the meanings assigned to them in patent law; For example, they can mean "comprises", "including", "comprising", and the like.

As used herein, the term “drug” refers to a pharmacologically active substance that provides a therapeutic effect, and includes the meaning of “active ingredient” or “therapeutic agent”.

The use of the term “a” or “an” as used in the present invention is used to describe the elements and components of the present invention. This is merely for convenience and to give a general meaning of the present invention. This description is to be construed as including one or at least one, and the simple also includes the plural unless it is clear that it is meant otherwise.

As used herein, the term “sequentially” or “sequentially” refers to separate administration of each drug in a sequential manner in any order, for example at intervals or intervals of minutes, hours, days or weeks, and where appropriate The drug may be administered in regular repeating cycles. Where sequential administration is present, a delay in administering one of the drugs should not lose the benefit of, for example, an efficient effect of the combination of drugs. In all cases of “sequential” administration, the routes of administration may be the same or different.

As used herein, the term “simultaneous” or “simultaneously” refers to administration of at least two drugs to a mammal at the same time. In all cases of “simultaneous” administration, the routes of administration may be the same or different.

The term “animal” used in the present invention includes, but is not limited to, a cat or a dog.

As used herein, the term “effective amount” refers to a concentration of a drug in the composition sufficient to elicit a desired biological response to the target parasite(s) after administration of the composition to an animal, which is known in the art and/or It is measured by the method described in the Examples of the present invention. In some embodiments, an “effective amount” of a drug in the composition can provide an efficacy of at least 80%, or at least 85%, when compared to an untreated control. More typically, an “effective amount” of the drug will provide at least 90%, at least 93%, at least 95%, or at least 97% efficacy against the target parasite. In certain embodiments, the term “effective amount” can provide efficacy as high as 100%, including the prevention of heartworm disease caused by resistant strains of D.

As used herein, the terms “treatment”, “treating”, etc., unless otherwise specified, refer to removing or ameliorating a parasitic infection, infestation or pathology. It also includes reference to reducing the frequency or duration of symptoms of a parasitic infection, as well as "control" (eg, killing, repelling, deporting, neutralizing, eliminating, alleviating, minimizing and eradicating).

In the present invention, the term “prevention” or “prophylactic” or “prophylactic therapy”, “prevention” or “protecting against” means preventing infection or infestation of parasites from occurring, or caused by parasitic infection. It includes preventing the development of, defending against, or protecting from the development of a disease, these terms also preventing the onset of a disorder or condition, or symptoms associated with a disorder or condition, before suffering from said infection or infestation, depending on the condition of the animal includes doing For example, by administering the composition of the present invention to an animal to kill tertiary larvae, as well as young and maturing quaternary larvae so that they do not mature into adult worms, thereby preventing diseases caused by parasitic infection. Accordingly, these terms may refer to administration of a composition of the present invention to an animal that is not suffering from infection or infestation at the time of administration.

As used herein, these terms also encompass preventing recurrence of infection or invasion or symptoms associated therewith.

The term "pharmaceutically acceptable" as used in the present invention means that it is suitable for use in contact with animal cells without excessive toxicity, irritation, allergic response, etc. within the scope of reasonable judgment in veterinary medicine, and has a reasonable benefit / It means that it is commensurate with the hazard ratio.

As used herein, the term “about” or “approximately” means within 20%, preferably within 10%, more preferably within 5% of a given value or range.

When the compound (drug) of the present invention is basic or acidic enough to form a stable non-toxic acid or base salt, the compound (drug) of the present invention may be in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the art. In particular, examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids that form physiologically acceptable anions, for example tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, alpha-ketoglutarate, and alpha-glycerophosphate. Suitable inorganic salts may also be formed, including sulfate, nitrate, bicarbonate and carbonate salts.

Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable anion. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids can also be prepared.

In one embodiment, the present invention is a veterinary orally disintegrating film preparation for treating or preventing parasitic infection or invasion in animals, comprising one or more drugs selected from the drug groups listed in the table below as an active ingredient. can

The orally disintegrating film according to the present invention may contain a drug in an effective amount from as little as 30 μg to as much as 500 mg.

In addition, the drug may be included in an amount of 1 to 50% by weight based on 100% by weight of the oral disintegrating film formulation of the present invention.

Orally disintegrating film according to the present invention may have a thickness of 0.05mm to 0.3mm and a size of 1cm ² to 15cm ² .

In the case of applying the oral disintegrating film of the present invention, which forms the thickness and size range, in small dogs and medium-sized dogs, a dosage rate of about 99.9% or more is shown, and drug delivery efficiency is maximized.

In the following <Experimental Example 3> of the present invention, disintegration time and dose compliance of oral disintegrating films having various sizes were evaluated, and as a result, when the size of the oral disintegrating film was 0.5x1cm (0.5cm ² ), the size of the film was It is very small, so it is difficult to attach and pay when feeding (adherence is poor), ^{and in the case of the film size of 6x8cm (48cm 2} ), it was confirmed that the film was very large and could not be attached to the roof of the mouth of medium-sized dogs (not payable). In addition, in the case of the film having a size of 5x6cm (30cm ² ), it was confirmed that the disintegration time in the oral cavity was 5 minutes or more, which was not suitable as an immediate-release oral disintegration film (see Table 5). Accordingly, as a result of comprehensively evaluating disintegration time and dosing compliance, ^{it was confirmed through an experiment that when the size of the film was formed in the range of 1 cm 2} to 15 cm ² , the convenience of dosing and drug delivery efficiency could be maximized.

In addition, in the following <Experimental Example 4> of the present invention, the physical properties and disintegration time of the oral disintegrating films having various thicknesses were evaluated. It was not possible to proceed (not peelable), and in the case of a film of 0.35 mm or larger, disintegration time was found to be 8 minutes or more, confirming that it was not suitable as an oral disintegrating film for pets. On the other hand, in the case of an oral disintegrating film prepared to a thickness of 0.05 mm to 0.30 mm, peeling from the base film paper was good, and the disintegration time was from a minimum of 9 seconds to a maximum of about 5 minutes, showing an appropriate disintegration rate (see Table 6). Accordingly, as a result of comprehensively evaluating the physical properties and disintegration time of the film, it was confirmed through experiments that the film thickness formed in the range of 0.05 mm to 0.30 mm enables the production of a film with good physical properties while maximizing drug delivery efficiency. did

In addition, in the following <Experimental Example 5> of the present invention, the storage stability of the oral disintegrating films having various thicknesses was evaluated, and as a result, storage for 2 weeks under accelerated conditions (40 ℃, 75% RH) and severe conditions (60 ℃) After that, there was no specific change in properties in the film with a thickness of 0.30 mm or less, but in the case of a film with a thickness of 0.45 mm, it was cured and hardened or cracked. In addition, as a result of checking the stability of properties after storage for 4 weeks under accelerated conditions, there was no change in properties in films with a thickness of 0.08 mm or more. As a result of the tensile strength test of films other than the film having a problem in properties, it was confirmed that there was no abnormality in the stability depending on the moisture and temperature of the film under the conditions set by measuring at least 3N/cm2 (see Table 7). Accordingly, as a result of comprehensively evaluating the physical properties of the film over time under accelerated conditions (40°C, 75% RH) and harsh conditions (60°C), storage stability is that the thickness of the film is formed in the range of 0.08 mm to 0.3 mm. This excellence was confirmed through an experiment.

In addition, when the thickness of the oral disintegrating film of the present invention is less than 0.05mm, the loading efficiency of the drug is lowered, and there is a problem that it cannot carry a pharmaceutically effective amount for treating or preventing parasitic infection or invasion, When the disintegration film thickness exceeds 0.3mm, the time until the oral disintegration film is in contact with the mouth and ingested is prolonged, causing leakage into saliva during taking, which has a problem with taking (results not shown).

Therefore, in the case of the orally disintegrating film according to the present invention, it ^{is easy to attach and feed at a thickness of 0.05mm to 0.3mm and a size of 1cm 2} to 15cm ² , and peeling can be made effectively, and the convenience of administration and drug delivery efficiency can be maximized. and excellent storage stability was confirmed through an objective experiment.

The oral disintegrating film of the present invention may further include an edible polymer in addition to the drug.

The edible polymer is a polymer that forms an orally disintegrating film, which means a film former, and is an edible (edible) polymer.

The edible polymer is, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, carboxymethyl cellulose potassium, carboxymethyl cellulose, fullulan , starch, modified starch (pregelatinized starch, etc.), gelatin, pectin, sodium alginate, maltodextrin, polymerized rosin, methylcellulose, crystalline cellulose, colicott, Eudragit, polyethylene oxide, polyvinyl pyrrolidone, It may be selected from the group consisting of polyvinyl alcohol, hyaluronic acid, hyaluronic acid derivatives, chitosan, chitosan derivatives, xanthan gum and carrageenan. These polymer|macromolecules may be used independently and may be used in combination of 2 or more type. The polymer may be included in an amount of 20 to 80% by weight based on 100% by weight of the oral disintegrating film formulation of the present invention.

In one embodiment of the present invention, the edible polymer may have a viscosity in the range of 1.0 to 30 mPa·s at 20° C., preferably in the range of 1.0 to 20 mPa·s.

In the following <Experimental Example 1> of the present invention, the physical properties of the oral disintegrating film according to the viscosity of the edible polymer were evaluated, and as a result, D-mannitol (20 ℃, 2 mass% aqueous solution, viscosity 0 mPa s at 20 ° C. ), it was found that film peeling was not performed properly from the base film paper, and when using hydroxypropyl cellulose HPC-M (viscosity 150-400 mPa s at 20°C, 2 mass% aqueous solution conditions) as an edible polymer When a large amount of purified water is used, separation of the preparation solution and purified water occurs during drying on the base film paper, so that only the surface of the film is dried and the purified water inside is trapped. It was confirmed that the material exceeding 150 mPa·s was not suitable for the preparation of an orally disintegrating film (see FIGS. 1 and 2).

In addition, in the following <Experimental Example 2> of the present invention, the disintegration time of the oral disintegrating film was evaluated according to the viscosity of the edible polymer, and as a result, the viscosity was 2 to 20 mPa·s at 20°C and 2% by mass aqueous solution conditions In the case of an oral disintegrating film using an edible polymer (HPC-SSL, HPC-SL, HPC-L, HPC-LM, fullulane) having , it was confirmed that, when using a viscosity of 21-50 mPa·s) in a 2% by mass aqueous solution condition, the disintegration time was significantly increased, and thus it was not suitable as an immediate-release orally disintegrating film (see Table 2).

Accordingly, the constituent disintegration film of the present invention has suitable physical properties (properties and peeling) by including an edible polymer having a viscosity in the range of 1.0 to 20 mPa·s at 20° C., and a fast disintegration time within 3 minutes It was confirmed through an objective experiment.

In addition, the oral disintegrating film of the present invention contains at least one plasticizer, a sweetener, a flavoring agent, a salivary secretion stimulant, a surfactant, a colorant, an antioxidant, an anti-foaming agent, and other excipients, if necessary, together with an edible polymer. can be formed by

The plasticizer is a material used to impart flexibility and elasticity to the orally disintegrating film, for example, acetyl triethyl citrate, polyethylene glycol, propylene glycol, glycerin, citrate ester, triacetin and triethyl citrate, etc. It can be selected from the group consisting of. These plasticizers may be used independently and may be used in combination of 2 or more type. The plasticizer may be included in an amount of 0.1 to 50% by weight based on 100% by weight of the oral disintegrating film formulation of the present invention.

The sweetener is a substance that makes it easier to take by adding it to an unpleasant taste, for example, sucralose, stevia, maltitol, isomaltooligosaccharide, sorbitol, xylitol, polyol, mannitol, sucrose, dextrose, fructose, ali Tam, neotame, saccharin and salts thereof, aspartame, glycyrrhizin, stebitene, acesulfame K, sodium saccharide and cyclomate may be selected from the group consisting of. The said sweetener may be used independently and may be used in combination of 2 or more type. The sweetener may be included in an amount of 0.1 to 50% by weight based on 100% by weight of the oral disintegrating film formulation of the present invention.

The flavoring agent is a substance imparting flavor, for example, beef flavor, natural flavoring (guarana, orange, lemon, peppermint, cinnamon, menthol, peppermint oil, winter green mint, clove, butterscotch, maple, apricot, peach flavor , cherry flavor, anise, strawberry flavor, vanillin, citrus flavor, licorice flavor, root beer flavor, gardenia, raspberry flavor, walnut flavor, chocolate flavor, etc.) and synthetic flavor. The flavoring agent or taste-blocking agent may be used alone or in combination of two or more. The flavoring agent may be included in an amount of 0.01 to 20% by weight based on 100% by weight of the oral disintegrating film formulation of the present invention.

The salivary stimulating agent may be selected from the group consisting of citric acid, citrate, lactic acid, malic acid, ascorbic acid, tartaric acid and tartrate. These salivary stimulating agents may be used alone or in combination of two or more. The salivary stimulating agent may be included in an amount of 1 to 15% by weight based on 100% by weight of the oral disintegrating film formulation of the present invention.

The surfactant may be selected from the group consisting of poloxamer, sodium lauryl sulfate, benzethonium chloride, polyoxyethylene fatty acid ester, polysorbate, and sorbitan ester. The said surfactant may be used independently and may be used in combination of 2 or more type. The surfactant may be included in an amount of 0.1 to 5% by weight based on 100% by weight of the oral disintegrating film formulation of the present invention.

The pigment may be selected from the group consisting of natural and synthetic pigments including red iron oxide, titanium oxide, titanium dioxide, silicon dioxide, and zinc oxide. The said pigment|dye may be used independently and may be used in combination of 2 or more type. The pigment may be included in an amount of 0.001 to 5% by weight based on 100% by weight of the oral disintegrating film formulation of the present invention.

The antioxidant may be selected from the group consisting of sodium hydrogen sulfite, methyl paraben, propyl paraben, sodium benzoate, benzalkonium chloride and benzethonium chloride. The said antioxidant may be used independently and may be used in combination of 2 or more type. The antioxidant may be included in an amount of 0.01 to 2% by weight based on 100% by weight of the oral disintegrating film formulation of the present invention.

The anti-foaming agent refers to a formulation capable of removing bubbles generated during liquid preparation, for example, simethicone and the like may be used.

The oral disintegrating film of the present invention is effective in treating or preventing parasitic infection or infestation in small animals such as dogs or cats.

Another embodiment of the present invention is a method for treating or preventing a parasitic infection in an animal, comprising the step of orally administering the orally disintegrating film to the animal.

The oral administration may be carried out by attaching it to the tongue, roof of the mouth, sublingual or buccal of the animal.

In order to increase the therapeutic or preventive effect of parasitic infections in the method, the oral disintegrating film of the present invention may be administered in a sequential manner at intervals of minutes, hours, days or weeks, or, the oral disintegrating film of the present invention It may be administered together with the conventionally known anthelmintic agents simultaneously or sequentially with the oral administration of

Hereinafter, the present invention will be described in more detail by way of Examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited to these examples.

<Example>

material preparation

1) HPC-SSL (Nippon Soda Co., Ltd.): Viscosity of 2% by mass aqueous solution at 20°C 2.0-2.9 mPa·s, average molecular weight about 40,000

2) HPC-SL (Nippon Soda Co., Ltd.): Viscosity of 2% by mass aqueous solution at 20°C 3.0-5.9 mPa·s, average molecular weight about 100,000

3) HPC-L (Nippon Soda Co., Ltd.): Viscosity of 2% by mass aqueous solution at 20°C 6.0-10.0 mPa·s, average molecular weight about 140,000

4) HPC-LM (Nippon Soda Co., Ltd.): Viscosity of 2% by mass aqueous solution at 20°C of 11-20 mPa·s, average molecular weight of about 180,000

5) HPC-LMM (Nippon Soda Co., Ltd.): Viscosity of 2% by mass aqueous solution at 20°C of 21-50 mPa·s, average molecular weight of about 280,000

6) HPC-M (Nippon Soda Co., Ltd.): Viscosity of 2 mass % aqueous solution at 20°C 150-400 mPa·s, average molecular weight about 700,000

7) Flurane (Shandong Kangnaxin Biotechnology Co., Ltd.): Viscosity of 2% by mass aqueous solution at 20° C. 5.0-7.0 mPa·s

8) D-mannitol (ROQUETTE, trade name Pearlitol 200SD): Viscosity of 2% by mass aqueous solution at 20° C. 0 mPa·s

<Example 1>

Oral disintegration film production by edible polymer viscosity

In this experiment, an orally disintegrating film was prepared by varying the viscosity of the edible polymer. In order to impart various viscosities, hydroxypropyl cellulose (HPC-SSL, HPC-SL, HPC-L, HPC-LM, HPC-LMM, HPC-M) and fullulane having different viscosities for each example were used, and the following The process was carried out. The equipment used for manufacturing was an IKA homogenizer (T25 digital ULTRA TURRAX®) and was performed at 4,000 rpm.

Example <1-1>

80 g of purified water was placed in a preparation container, glycerin 3.44 g, polysorbate 80 0.4 g, and simethicone oil 0.2 g were added, followed by stirring to disperse. Into the dispersed solution, 1.0 g of milbemycin oxime (Hubei Honch Pharmaceutical Co., Ltd. China) was added and stirred again to disperse completely. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SSL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution is poured on the base film paper (Youngtech G&P, SC38), cast with a film applicator (1117, SI), dried at a high temperature of 80° C. or higher, and separated from the base film paper (peeled) to obtain milbemycin oxime. A contained film was obtained.

Example <1-2>

Put 90 g of purified water in a preparation container, add 3.44 g of glycerin, 0.4 g of polysorbate 80, and 0.2 g of simethicone oil, followed by stirring to disperse. Into the dispersed solution, 1.0 g of milbemycin oxime was added and stirred again to completely disperse. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <1-3>

105 g of purified water was placed in a preparation container, glycerin 3.44 g, polysorbate 80 0.4 g, and simethicone oil 0.2 g were added, followed by stirring to disperse. Into the dispersed solution, 1.0 g of milbemycin oxime was added and stirred again to completely disperse. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-L, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <1-4>

155 g of purified water was placed in a preparation container, glycerin 3.44 g, polysorbate 80 0.4 g, and simethicone oil 0.2 g were added, followed by stirring to disperse. Into the dispersed solution, 1.0 g of milbemycin oxime was added and stirred again to completely disperse. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-LM, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <1-5>

Put 180 g of purified water in a preparation container, add 3.44 g of glycerin, 0.4 g of polysorbate 80, and 0.2 g of simethicone oil, followed by stirring to disperse. Into the dispersed solution, 1.0 g of milbemycin oxime was added and stirred again to completely disperse. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-LMM, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <1-6>

85 g of purified water was placed in a preparation container, glycerin 3.44 g, polysorbate 80 0.4 g, and simethicone oil 0.2 g were added, followed by stirring to disperse. Into the dispersed solution, 1.0 g of milbemycin oxime was added and stirred again to completely disperse. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of flurane (Shandong kangnaxin), the mixture was stirred until a homogeneous solution was obtained, and then degassed under reduced pressure to be used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

<Comparative Example 1>

Comparative Example <1-1>

80 g of purified water was placed in a preparation container, glycerin 3.44 g, polysorbate 80 0.4 g, and simethicone oil 0.2 g were added, followed by stirring to disperse. Into the dispersed solution, 1.0 g of milbemycin oxime was added and stirred again to completely disperse. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of D-mannitol (Pearlitol 200SD, ROQUETTE), the mixture was stirred until a homogeneous solution was obtained, and then degassed under reduced pressure to be used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Comparative Example <1-2>

590 g of purified water was placed in a preparation container, glycerin 3.44 g, polysorbate 80 0.4 g, and simethicone oil 0.2 g were added, followed by stirring to disperse. Into the dispersed solution, 1.0 g of milbemycin oxime was added and stirred again to completely disperse. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-M, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

The components used for preparing the film of the present invention and their weights are shown in Table 1 below.

Components used to prepare the film of the present invention and their weight (mg/sheet)

ingredient	Example <1-1>	Example <1-2>	Example <1-3>	Example <1-4>	Example <1-5>	Example <1-6>	Comparative Example <1-1>	Comparative Example <1-2>	content (mass%)
Milbemycinoxime	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
HPC-SSL (2.0-2.9mPa s)	68.8	-	-	-	-	-	-	-	68.8
HPC-SL (3.0-5.9 mPa s)	-	68.8	-	-	-	-	-	-
HPC-L (6.0-10.0 mPa s)	-	-	68.8	-	-	-	-	-
HPC-LM (11-20 mPa s)	-	-	-	68.8	-	-	-	-
HPC-LMM (21-50 mPa s)	-	-	-	-	68.8	-	-	-
fullulan (5.0-7.0 mPa s)	-	-	-	-	-	68.8	-	-
D-mannitol (0 mPa s)	-	-	-	-	-	-	68.8	-
HPC-M (150-400mPa s)	-	-	-	-	-	-	-	68.8
glycerin	8.6	8.6	8.6	8.6	8.6	8.6	8.6	8.6	8.6
Polysorbate 80	One	One	One	One	One	One	One	One	One
Simethicone Oil	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
xanthan gum	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3
sucralose	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3	0.3
titanium dioxide	18	18	18	18	18	18	18	18	18
Sum	100	100	100	100	100	100	100	100	100
Purified water	80	90	105	155	180	85	80	590

<Experimental Example 1>

Properties of Oral Disintegration Films by Edible Polymer Viscosity

In this experiment, in order to confirm the physical properties of the orally disintegrating film prepared by varying the viscosity of the edible polymer prepared in <Example 1> and <Comparative Example 1>, the properties and peeling of the orally disintegrating film were investigated. .

In order to confirm the peeling from the base film paper, the properties after drying of the orally disintegrating film prepared by <Example 1> and <Comparative Example 1> were evaluated.

As a result, as shown in FIG. 1, in the case of Comparative Example <1-1> using D-mannitol (viscosity 0 mPa·s at 20° C. and 2 mass% aqueous solution conditions) as the edible polymer, film peeling from the base film paper was It was confirmed that it was not done properly. In addition, as shown in FIG. 2, in the case of Comparative Example <1-2> using hydroxypropyl cellulose HPC-M (viscosity 150-400 mPa·s at 20°C and 2 mass% aqueous solution conditions) as the edible polymer, a large amount of purified water was used, and separation of the prepared solution and purified water occurred during drying on the base film paper, so that only the surface of the film was dried and the purified water inside was trapped.

Through these results, it was confirmed that a material having no viscosity as an edible polymer or having a viscosity exceeding 150 mPa·s is not suitable for the preparation of an orally disintegrating film.

<Experimental Example 2>

Disintegration time of oral disintegrating film by viscosity of edible polymer

In this experiment, in order to predict the disintegration rate in the oral cavity after taking the oral disintegrating film for each viscosity of the edible polymer, the oral cavity prepared by varying the viscosity of the edible polymer prepared through <Example 1> and <Comparative Example 1> The disintegration time of the disintegration film was confirmed.

After floating the oral disintegrating films prepared in <Example 1> and <Comparative Example 1> on a glass Petri dish containing 20 ml of purified water, respectively, the glass was placed on a shaker (manufacturer DLAB, SK-O180-Pro) The time taken for the film to disintegrate was measured while raising the Petri dish and stirring at 200 rpm.

Disintegration time of oral disintegrating film by viscosity of edible polymer

Example	Example <1-1>	Example <1-2>	Example <1-3>	Example <1-4>	Example <1-5>	Example <1-6>
disintegration time	1 minute 00 seconds 24	1 minute 21 seconds 33	1 minute 57 seconds 80	2 minutes 21 seconds 58	8 minutes 35 seconds 19	1 minute 24 seconds 55

As a result, as shown in Table 2, edible polymers (HPC-SSL, HPC-SL, HPC-L, HPC-LM, In the case of an orally disintegrating film (Example 1-4) using an orally disintegrating film (Example 1-4), it disintegrates within 3 minutes, whereas HPC-LMM (viscosity 21-50 mPa·s at 20°C, 2% by mass aqueous solution condition) was used as an edible polymer. In this case, it was confirmed that the disintegration time was significantly increased, making it unsuitable as an immediate-release oral disintegrating film.

<Example 2>

Manufacture by size of oral disintegrating film

In this experiment, an orally disintegrating film was prepared by varying the size of the orally disintegrating film.

270 g of purified water was put in a preparation container, 10.32 g of glycerin, 1.2 g of polysorbate 80, and 0.6 g of simethicone oil were added and dispersed by stirring. 3.0 g of milbemycin oxime was added to the dispersed solution and stirred again to disperse completely. After the addition of 0.36 g of xanthan gum, 0.36 g of sucralose, and 21.6 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80° C. or higher to obtain a film having a thickness of 0.12 mm, and then the size of the film was 0.5x1cm, 1x1cm, 1.5, respectively. It was cut into sizes of x2cm, 2x3cm, 3x5cm, 5x6cm, and 6x8cm, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Oral disintegrating film by size

Example	Example <2-1>	Example <2-2>	Example <2-3>	Example <2-4>	Example <2-5>	Example <2-6>	Example <2-7>
film size	0.5x1cm	1x1cm	1.5x2cm	2x3cm	3x5cm	5x6cm	6x8cm
film thickness	0.12mm	0.12mm	0.12mm	0.12mm	0.12mm	0.12mm	0.12mm

<Example 3>

Manufacture by thickness of oral disintegrating film

In this experiment, an orally disintegrating film was prepared by varying the thickness of the orally disintegrating film.

270 g of purified water was put in a preparation container, 10.32 g of glycerin, 1.2 g of polysorbate 80, and 0.6 g of simethicone oil were added and dispersed by stirring. 3.0 g of milbemycin oxime was added to the dispersed solution and stirred again to disperse completely. After the addition of 0.36 g of xanthan gum, 0.36 g of sucralose, and 21.6 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution is poured on the base film paper, and the film thickness after drying is 0.03mm, 0.05mm, 0.08mm, 0.12mm, 0.20mm, 0.25mm, 0.30mm, 0.35mm, and a film applicator so that it can be secured to 0.45mm (1117, SI), dried at a high temperature of 80° C. or higher, cut to the same size of 2x3 cm, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Oral disintegrating film by thickness

Example	Example <3-1>	Example <3-2>	Example <3-3>	Example <3-4>	Example <3-5>	Example <3-6>	Example <3-7>	Example <3-8>	Example <3-9>
film size	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm
film thickness	0.03mm	0.05mm	0.08mm	0.12mm	0.20mm	0.25mm	0.30mm	0.35mm	0.45mm

<Experimental Example 3>

Disintegration time and dosage compliance according to the size of the oral disintegrating film

In this experiment, in order to check the disintegration rate and dosing compliance in the oral cavity after taking according to the size of the oral disintegrating film, 7 number of beagle test dogs were requested to KPC, a non-clinical testing agency, and the above < After the oral disintegration film prepared in Example 2> was attached to the roof of the mouth, the dose compliance and the disintegration time in the oral cavity were measured.

At this time, the degree of dosing compliance was shown as follows.

+++++: very good

++++: good

+++: Moderate

++: bad

+: no pay

Disintegration time and dosage compliance according to the size of the oral disintegrating film

Example	Example <2-1>	Example <2-2>	Example <2-3>	Example <2-4>	Example <2-5>	Example <2-6>	Example <2-7>
film size	0.5x1cm	1x1cm	1.5x2cm	2x3cm	3x5cm	5x6cm	6x8cm
film thickness	0.12mm	0.12mm	0.12mm	0.12mm	0.12mm	0.12mm	0.12mm
disintegration time	30 seconds	1 minute 15 seconds	2 minutes 00 seconds	3 minutes 15 seconds	5 minutes 00 seconds	7 minutes 45 seconds	no pay
Dosage compliance	+++	++++	+++++	+++++	++++	+++	+

As a result, as shown in Table 5, when the size of the film was 0.5x1cm, the size of the film was very small, so it was difficult to attach and feed when feeding. It was impossible. On the other hand, in the case of the film size of 5x6cm, it was confirmed that the disintegration time in the oral cavity was 5 minutes or more, which was not suitable as an immediate-release oral disintegration film.

<Experimental Example 4>

Disintegration time according to the thickness of the oral disintegrating film

In this experiment, in order to predict the disintegration rate in the oral cavity after taking according to the thickness of the oral disintegrating film, the disintegration time of the oral disintegrating film prepared through <Example 3> was confirmed.

Orally disintegrating films of 0.03mm, 0.05mm, 0.08mm, 0.12mm, 0.20mm, 0.25mm, 0.30mm, 0.35mm, and 0.45mm thickness were floated on a glass Petri dish containing 20 ml of purified water, respectively, A glass Petri dish was placed on a shaker (manufacturer DLAB, SK-O180-Pro) and stirred at 200 rpm to measure the time it takes for the film to disintegrate.

Disintegration time according to the thickness of the oral disintegrating film

Example	Example <3-1>	Example <3-2>	Example <3-3>	Example <3-4>	Example <3-5>	Example <3-6>	Example <3-7>	Example <3-8>	Example <3-9>
film size	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm
film thickness	0.03mm	0.05mm	0.08mm	0.12mm	0.20mm	0.25mm	0.30mm	0.35mm	0.45mm
disintegration time	No peeling	9 seconds	27 seconds	1 minute 14 seconds	2 minutes 49 seconds	4 minutes 43 seconds	5 minutes 10 seconds	8 minutes 11 seconds	15 minutes 35 seconds

As a result, as shown in Table 6, in the case of a film prepared with a thickness of 0.03 mm, the test could not be carried out because it was impossible to peel from the base film paper, and in the case of an orally disintegrating film having a thickness of 0.05 mm to 0.30 mm, it disintegrated. The time showed an appropriate disintegration rate from a minimum of 9 seconds to a maximum of around 5 minutes. On the other hand, in the case of a film of 0.35 mm or more, it was confirmed that the disintegration time was 8 minutes or more, which was not suitable as an oral disintegrating film for pets.

<Experimental Example 5>

Storage stability according to the thickness of the orally disintegrating film

In this experiment, in order to evaluate the stability according to the thickness of the orally disintegrating film, the change in properties and tensile strength of the orally disintegrating film prepared in Example 3 was measured.

Each film sealed in an aluminum pouch was placed in a stability chamber at 60℃ (manufacturer Vision Scientific, VS-1203PFC-L) and in a stability chamber at 40℃, 75% RH (manufacturer CARON, 7000-50-2). The properties and tensile strength of the film were checked by storage for one week or four weeks. For the tensile strength test, the tensile strength (tensile strength=max load value(N)/sample area(cm ² )) value is obtained while slowly pulling the material property tester (manufacturer LLOYD, LS-1) at a test speed of 200 mm/min.

Changes in properties and tensile strength according to the thickness of the orally disintegrating film

Example		Example <3-1>	Example <3-2>	Example <3-3>	Example <3-4>	Example <3-5>	Example <3-6>	Example <3-7>	Example <3-8>
film size		2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm	2x3cm
film thickness		0.05mm	0.08mm	0.12mm	0.20mm	0.25mm	0.30mm	0.35mm	0.45mm
2 weeks	60℃	Good	Good	Good	Good	Good	Good	Hardening	hardened, cracked
	40℃, 75% RH	Good	Good	Good	Good	Good	Good	Good	Good
	Tensile strength (N/cm 2 )	3.61	4.94	5.57	7.07	9.94	15.68	16.77	21.42
4 weeks	60℃	Good	Good	Good	Good	Good	Good	Hardening	hardened, cracked
	40℃, 75% RH	No peeling	Good	Good	Good	Good	Good	Good	Good
	Tensile strength (N/cm 2 )	-	5.32	5.34	7.84	8.68	15.11	17.37	21.85

As a result, as shown in Table 7, there was no specific change in properties in the film with a thickness of 0.30 mm or less after storage for 2 weeks under accelerated conditions (40 ° C, 75% RH) and severe conditions (60 ° C), but at a thickness of 0.45 mm In the case of the film, it was hardened and cracked. As a result of checking the stability of properties after storage for 4 weeks under accelerated conditions, there was no change in properties in films with a thickness of 0.08 mm or more, but films with a thickness of 0.05 mm were stuck inside the aluminum wrapping paper and could not be peeled off. As a result of the tensile strength test of films other than the film having a problem in properties, it was confirmed that there was no abnormality in the stability depending on the moisture and temperature of the film under the set conditions by measuring at least 3N/cm2.

<Example 4>

Oral disintegration film manufacturing for each API

Orally disintegrating films were prepared by different types of raw materials.

Example <4-1>

Put 90 g of purified water in a preparation container, add 3.44 g of glycerin, 0.4 g of polysorbate 80, and 0.2 g of simethicone oil, followed by stirring to disperse. 1.0 g of apoxolane was added to the dispersed solution and stirred again to disperse completely. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <4-2>

Put 90 g of purified water in a preparation container, add 3.44 g of glycerin, 0.4 g of polysorbate 80, and 0.2 g of simethicone oil, followed by stirring to disperse. In the dispersed solution, 1.0 g of milbemycin oxime and 1.0 g of apoxolane were added and stirred again to disperse completely. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <4-3>

Put 90 g of purified water in a preparation container, add 3.44 g of glycerin, 0.4 g of polysorbate 80, and 0.2 g of simethicone oil, followed by stirring to disperse. 1.0 g of praziquantel was added to the dispersed solution, and stirred again to disperse completely. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <4-4>

Put 90 g of purified water in a preparation container, add 3.44 g of glycerin, 0.4 g of polysorbate 80, and 0.2 g of simethicone oil, followed by stirring to disperse. 1.0 g of Seroleiner was added to the dispersed solution and stirred again to disperse completely. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <4-5>

Put 90 g of purified water in a preparation container, add 3.44 g of glycerin, 0.4 g of polysorbate 80, and 0.2 g of simethicone oil, followed by stirring to disperse. 1.0 g of ivermectin was added to the dispersed solution and stirred again to disperse completely. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <4-6>

Put 90 g of purified water in a preparation container, add 3.44 g of glycerin, 0.4 g of polysorbate 80, and 0.2 g of simethicone oil, followed by stirring to disperse. 1.0 g of pyrantel pamoate was added to the dispersed solution and stirred again to completely disperse. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Example <4-7>

Put 90 g of purified water in a preparation container, add 3.44 g of glycerin, 0.4 g of polysorbate 80, and 0.2 g of simethicone oil, followed by stirring to disperse. To the dispersed solution, 1.0 g of milbemycin oxime and 1.0 g of pyrantel pamoate were added and stirred again to disperse completely. After the addition of 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide to the dispersed solution, the mixture was stirred again.

Finally, after adding 27.52 g of hydroxypropyl cellulose (HPC-SL, NISSO), the mixture was stirred until it became a homogeneous solution, degassed under reduced pressure, and used as a film preparation solution.

The prepared film preparation solution was poured on the base film paper, cast with a film applicator (1117, SI), dried at a high temperature of 80 ° C. or higher, and separated (peeled) from the base film paper to obtain a film containing milbemycin oxime.

Drug substance and ingredients used in the production of the film of the present invention, and their weight (mg/sheet)

ingredient	Example <4-1>	Example <4-2>	Example <4-3>	Example <4-4>	Example <4-5>	Example <4-6>	Example <4-7>
Milbemycinoxime	-	2.5	-	-	-	-	2.5
Apoxollaner	2.5	2.5	-	-	-	-	-
Praziquantel	-	-	2.5	-	-	-	-
Seroleiner	-	-	-	2.5	-	-	-
ivermectin	-	-	-	-	2.5	-	-
Pyrantel pamoate	-	-	-	-	-	2.5	2.5
HPC-SL (3.0-5.9mPa s)	68.8	68.8	68.8	68.8	68.8	68.8	68.8
glycerin	8.6	8.6	8.6	8.6	8.6	8.6	8.6
Polysorbate 80	One	One	One	One	One	One	One
Simethicone Oil	0.5	0.5	0.5	0.5	0.5	0.5	0.5
xanthan gum	0.3	0.3	0.3	0.3	0.3	0.3	0.3
sucralose	0.3	0.3	0.3	0.3	0.3	0.3	0.3
titanium dioxide	18	18	18	18	18	18	18
Sum	100	102.5	100	100	100	100	102.5
Purified water	90	90	90	90	90	90	90

So far, the present invention has been looked at with respect to preferred embodiments thereof. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in modified forms without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.

Claims (6)

1. A veterinary orally disintegrating film formulation for treating or preventing parasitic infection or invasion in animals, comprising as an active ingredient at least one drug selected from the group of drugs listed in the table below.

   
2. According to claim 1,

   The oral disintegrating film is a veterinary orally disintegrating film formulation, characterized in that the thickness of 0.05mm ~ 0.3mm and the size of 1cm ² ~ 15cm ^{2 .}
3. According to claim 1,

   The oral disintegrating film is a veterinary orally disintegrating film formulation, characterized in that it further comprises an edible polymer.
4. 4. The method of claim 3,

   The edible polymer is selected from the group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, carboxymethyl cellulose potassium, carboxymethyl cellulose, and fullulan Veterinary oral disintegrating film formulation, characterized in that.
5. 4. The method of claim 3,

   The edible polymer is a veterinary orally disintegrating film formulation, characterized in that it has a viscosity of 1.0 ~ 20 mPa · s at 20 ℃.
6. According to claim 1,

   The animal is a veterinary orally disintegrating film formulation, characterized in that the dog or cat.

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