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WO2021241898A1 - Formulation vétérinaire de film à désintégration orale destinée au traitement ou à la prévention de maladies infectieuses parasitaires chez l'animal - Google Patents

Formulation vétérinaire de film à désintégration orale destinée au traitement ou à la prévention de maladies infectieuses parasitaires chez l'animal Download PDF

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WO2021241898A1
WO2021241898A1 PCT/KR2021/005334 KR2021005334W WO2021241898A1 WO 2021241898 A1 WO2021241898 A1 WO 2021241898A1 KR 2021005334 W KR2021005334 W KR 2021005334W WO 2021241898 A1 WO2021241898 A1 WO 2021241898A1
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Prior art keywords
film
present
veterinary
orally
oral
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English (en)
Korean (ko)
Inventor
한정석
이수경
김준기
고은정
정용운
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Kyongbo Pharmco ltd
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Kyongbo Pharmco ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics

Definitions

  • 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.
  • endoparasitic infections including, for example, helminthosis, which is most frequently caused by a group of parasitic worms described as nematodes or roundworms.
  • 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.
  • heartworms 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.
  • 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
  • adult insecticides eg melarsomin dihydrochloride
  • 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).
  • 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.
  • 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
  • the oral intake of the therapeutic agent is very excellent
  • the present invention has been completed.
  • 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.
  • 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.
  • 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.
  • the oral disintegrating film may have a thickness of 0.05mm to 0.3mm and a size of 1cm 2 to 15cm 2 .
  • the orally disintegrating film may further include an edible polymer.
  • 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.
  • the edible polymer may have a viscosity of 1.0 ⁇ 20 mPa ⁇ s at 20 °C.
  • 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.
  • 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.
  • 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.
  • FIG. 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.
  • FIG. 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.
  • HPC-M viscosity 150-400 mPa ⁇ s at 20° C., 2 mass% aqueous solution conditions
  • FIG. 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.
  • FIG. 4 is a photograph of the drug-containing orally disintegrating film of the present invention prepared in various sizes.
  • FIG. 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.
  • FIG. 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.
  • FIG. 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.
  • FIG. 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).
  • FIG. 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).
  • 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.
  • ODF oral dispersible film
  • the film formulation according to the present invention has the advantage that it can be taken without water.
  • drug refers to a pharmacologically active substance that provides a therapeutic effect, and includes the meaning of “active ingredient” or “therapeutic agent”.
  • 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.
  • 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.
  • animal used in the present invention includes, but is not limited to, a cat or a dog.
  • 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.
  • treatment refers 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).
  • prevention 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.
  • these terms also encompass preventing recurrence of infection or invasion or symptoms associated therewith.
  • pharmaceutically acceptable 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.
  • the term “about” or “approximately” means within 20%, preferably within 10%, more preferably within 5% of a given value or range.
  • the compound (drug) of the present invention 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.
  • 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.
  • 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.
  • a sufficiently basic compound such as an amine
  • suitable acid such as an amine
  • Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of carboxylic acids can also be prepared.
  • 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.
  • the orally disintegrating film according to the present invention may contain a drug in an effective amount from as little as 30 ⁇ g to as much as 500 mg.
  • 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 .
  • the oral disintegrating film of the present invention which forms the thickness and size range
  • a dosage rate of about 99.9% or more is shown, and drug delivery efficiency is maximized.
  • Example 3 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).
  • Example 4 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).
  • Example 5 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 °C, 75% RH) and severe conditions (60 °C) 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.
  • 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,
  • 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).
  • 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
  • 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.
  • Example 1 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 °C, 2 mass% aqueous solution, viscosity 0 mPa s at 20 ° C.
  • 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
  • the viscosity was 2 to 20 mPa ⁇ s at 20°C and 2% by mass aqueous solution conditions
  • HPC-SSL, HPC-SL, HPC-L, HPC-LM, fullulane an edible polymer 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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
  • HPC-L Viscosity of 2% by mass aqueous solution at 20°C 6.0-10.0 mPa ⁇ s, average molecular weight about 140,000
  • 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
  • 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
  • HPC-M Viscosity of 2 mass % aqueous solution at 20°C 150-400 mPa ⁇ s, average molecular weight about 700,000
  • D-mannitol (ROQUETTE, trade name Pearlitol 200SD): Viscosity of 2% by mass aqueous solution at 20° C. 0 mPa ⁇ s
  • an orally disintegrating film was prepared by varying the viscosity of the edible polymer.
  • hydroxypropyl cellulose HPC-SSL, HPC-SL, HPC-L, HPC-LM, HPC-LMM, HPC-M
  • 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.
  • HPC-SSL hydroxypropyl cellulose
  • 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.
  • HPC-SL hydroxypropyl cellulose
  • 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 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.
  • glycerin 3.44 g, polysorbate 80 0.4 g, and simethicone oil 0.2 g were added, followed by stirring to disperse.
  • 1.0 g of milbemycin oxime was added and stirred again to completely disperse.
  • 0.12 g of xanthan gum, 0.12 g of sucralose, and 7.2 g of titanium dioxide was added to the dispersed solution, the mixture was stirred again.
  • HPC-LM hydroxypropyl cellulose
  • 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.
  • HPC-LMM hydroxypropyl cellulose
  • 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 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 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.
  • HPC-M hydroxypropyl cellulose
  • 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 ⁇ 1-1> 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 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 - - - - - - - HPC-LMM (21-50 m
  • Disintegration time of oral disintegrating film by viscosity of edible polymer 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
  • 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.
  • HPC-SL hydroxypropyl cellulose
  • 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.
  • 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.
  • HPC-SL hydroxypropyl cellulose
  • 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.
  • Example ⁇ 3-1> Example ⁇ 3-2>
  • Example ⁇ 3-3> Example ⁇ 3-4>
  • Example ⁇ 3-5> Example ⁇ 3-6>
  • 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.
  • Example ⁇ 3-1> Example ⁇ 3-2>
  • Example ⁇ 3-3> Example ⁇ 3-4>
  • Example ⁇ 3-5> Example ⁇ 3-6>
  • Example ⁇ 3-8> Example ⁇ 3-9> film size 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
  • Each film sealed in an aluminum pouch was placed in a stability chamber at 60°C (manufacturer Vision Scientific, VS-1203PFC-L) and in a stability chamber at 40°C, 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.
  • Example ⁇ 3-1> Example ⁇ 3-2>
  • Orally disintegrating films were prepared by different types of raw materials.
  • HPC-SL hydroxypropyl cellulose
  • 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.
  • HPC-SL hydroxypropyl cellulose
  • 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.
  • HPC-SL hydroxypropyl cellulose
  • 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.
  • HPC-SL hydroxypropyl cellulose
  • 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.
  • HPC-SL hydroxypropyl cellulose
  • 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.
  • HPC-SL hydroxypropyl cellulose
  • 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.
  • HPC-SL hydroxypropyl cellulose
  • 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 ⁇ 4-1> Example ⁇ 4-2>

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à un médicament vétérinaire et, plus précisément, à une formulation vétérinaire de film à désintégration orale apte à traiter ou à prévenir une infection ou une infestation de parasites internes/externes chez l'animal. La formulation vétérinaire de film à désintégration orale apte à traiter ou prévenir efficacement l'infection ou l'infestation d'animaux par des parasites selon la présente invention est très efficace en termes d'ingestion orale de l'agent thérapeutique lorsqu'elle est fixée à la langue, au palais, sous la langue ou à la cavité buccale d'un petit chien. En particulier, un film à désintégration orale selon la présente invention présente des avantages en ce que, dans des plages d'épaisseur et de taille spécifiques, il est facile à fixer et à donner, une séparation efficace est possible, la commodité d'administration et l'efficacité d'administration de médicament peuvent être maximisées, et la stabilité au stockage est excellente. De plus, grâce à l'inclusion d'un polymère comestible ayant une viscosité spécifique, le film à désintégration orale selon la présente invention a des propriétés physiques (aspect et séparation) appropriées en tant que film, et a un temps de désintégration rapide inférieur à trois minutes.
PCT/KR2021/005334 2020-05-26 2021-04-27 Formulation vétérinaire de film à désintégration orale destinée au traitement ou à la prévention de maladies infectieuses parasitaires chez l'animal Ceased WO2021241898A1 (fr)

Applications Claiming Priority (4)

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KR20200062897 2020-05-26
KR10-2020-0062897 2020-05-26
KR10-2021-0052453 2021-04-22
KR1020210052453A KR102659363B1 (ko) 2020-05-26 2021-04-22 동물에서의 기생충 감염 질환을 치료 또는 예방하기 위한 수의학적 구강붕해필름 제제

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12304903B2 (en) 2020-07-24 2025-05-20 Elanco Us Inc. Process for making an isoxazoline compound and intermediate thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050136096A1 (en) * 2003-08-22 2005-06-23 Davidson R. S. Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
KR20120102585A (ko) * 2009-10-30 2012-09-18 아이엑스 바이오파마 피티이 리미티드 신속 용해 고체 투약 제형
KR101790666B1 (ko) * 2017-06-27 2017-10-26 (주)조안엠앤에스 애완동물용 구강용해필름
CN109172547A (zh) * 2018-11-07 2019-01-11 四川卫萌生物科技有限公司 一种宠物用自微乳化口腔速溶膜剂及其制备方法
WO2020014431A1 (fr) * 2018-07-11 2020-01-16 Cure Pharmaceutical Matrice de film oral à désintégration rapide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050136096A1 (en) * 2003-08-22 2005-06-23 Davidson R. S. Edible films for administration of medicaments to animals, methods for their manufacture and methods for their use for the treatment of animals
KR20120102585A (ko) * 2009-10-30 2012-09-18 아이엑스 바이오파마 피티이 리미티드 신속 용해 고체 투약 제형
KR101790666B1 (ko) * 2017-06-27 2017-10-26 (주)조안엠앤에스 애완동물용 구강용해필름
WO2020014431A1 (fr) * 2018-07-11 2020-01-16 Cure Pharmaceutical Matrice de film oral à désintégration rapide
CN109172547A (zh) * 2018-11-07 2019-01-11 四川卫萌生物科技有限公司 一种宠物用自微乳化口腔速溶膜剂及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12304903B2 (en) 2020-07-24 2025-05-20 Elanco Us Inc. Process for making an isoxazoline compound and intermediate thereof

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