WO2023214687A1 - Composition including macrolide antibiotic as active ingredient for prevention or treatment of respiratory diseases in canines - Google Patents

Composition including macrolide antibiotic as active ingredient for prevention or treatment of respiratory diseases in canines Download PDF

Info

Publication number
WO2023214687A1
WO2023214687A1 PCT/KR2023/003904 KR2023003904W WO2023214687A1 WO 2023214687 A1 WO2023214687 A1 WO 2023214687A1 KR 2023003904 W KR2023003904 W KR 2023003904W WO 2023214687 A1 WO2023214687 A1 WO 2023214687A1
Authority
WO
WIPO (PCT)
Prior art keywords
respiratory diseases
administration
preventing
canines
present
Prior art date
Application number
PCT/KR2023/003904
Other languages
French (fr)
Korean (ko)
Inventor
조진만
김지희
Original Assignee
녹십자수의약품 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 녹십자수의약품 주식회사 filed Critical 녹십자수의약품 주식회사
Publication of WO2023214687A1 publication Critical patent/WO2023214687A1/en

Links

Images

Classifications

    • 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
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to a composition for preventing or treating respiratory diseases in canine animals containing a macrolide antibiotic as an active ingredient.
  • Kennel cough, or infectious bronchitis is an acute, contagious respiratory infection in dogs primarily characterized by coughing.
  • Canine bronchitis is considered one of the most prevalent canine contagious respiratory diseases worldwide, and can reach endemic levels when dogs are housed in high-density environments such as kennels. Most outbreaks are due to direct dog-to-dog contact or aerosolization of respiratory secretions.
  • Clinical signs are caused by infection of the epithelium of the upper and lower respiratory tract from either bacterial or viral agents, and B. bronchiseptica is known as one of the main causative agents.
  • Bordetella bronchiseptica is a Gram-negative bacterium that colonizes the respiratory tract of dogs and causes disease. Bordetella bronchiseptica makes dogs susceptible to the effects of other respiratory pathogens and often coexists with them.
  • the present inventors have made intensive research efforts to develop a safe and effective treatment for canine respiratory diseases caused by Bordetella bronchiseptica , especially bronchopneumonia.
  • the present inventors found that when Tulathromycin, a macrolide antibiotic, was injected subcutaneously, the clinical symptoms of bacterial respiratory disease (bronchopneumonia) caused by Bordetella bronchiseptica were significantly improved. By doing so, the present invention was completed.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating respiratory diseases in canine animals.
  • Another object of the present invention is to provide an injectable agent for preventing or treating respiratory diseases in canine animals.
  • Another object of the present invention is to provide a feed composition for preventing or improving respiratory diseases in canine animals.
  • Another object of the present invention is to provide a method for treating respiratory diseases in canine animals.
  • the present invention provides a pharmaceutical composition for preventing or treating respiratory diseases in canine animals containing macrolide antibiotics as an active ingredient.
  • the macrolide antibiotics contain a macrocyclic lactone ring and are therefore called macrolide antibiotics.
  • any macrolide antibiotic can be used, for example, Tulasro. It may be one or more selected from the group consisting of tulathromycin, erythromycin, clarithromycin, azithromycin, tyrosine, tilmicosin, josamycin, kitasamycin, and spiramycin, but is not limited thereto.
  • the macrolide antibiotic is tulathromycin (CAS No. 217500-96-4) (C 41 H 79 N 3 O 12 ).
  • the respiratory disease of canine animals of the present invention may include without limitation general infectious diseases caused by the respiratory tract known in the art, and may preferably be characterized as being caused by pathogens.
  • the respiratory disease may include any respiratory disease as long as the composition of the present invention can achieve the purpose.
  • the respiratory disease is caused by Bordetella bronchiseptica , Actinobacillus pleuropneumoniae , Pasteurella multocida , Haemophilus parasuis ( It may be a respiratory disease caused by infection with a pathogen selected from the group consisting of Haemophilus parasuis and Mycoplasma hyopneumoniae , most preferably Bordetella bronchiseptica , but not limited thereto. No.
  • the above respiratory diseases include kennel cough, bronchopneumonia, respiratory inflammatory lung disease, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, lower respiratory tract infection, acute and chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, and emphysema.
  • pulmonary tuberculosis sequelae, acute respiratory distress syndrome, and pulmonary fibrosis preferably canine bronchitis (kennel cough), but is not limited thereto.
  • canine refers to an omnivorous animal such as a dog, wolf, fox, coyote, jackal, or dung beetle, and refers to a bipedal animal that walks on its toes, and as long as it achieves the purpose of the present invention, it is known in the art All known canine animals may be included.
  • the canids are largely divided into the dog family and the fox family.
  • the dog family includes dogs, maned wolves, striped jackals, black-backed jackals, dingoes, red wolves, Ethiopian wolves, Indian wolves, coyotes, golden jackals, crab-eating foxes, wild dogs, jackals, African wild dogs, small-eared dogs, Falkland wolves, Includes Andean fox, Darwin's fox, Argentine gray fox, Pampas fox, Peruvian desert fox, and white fox.
  • the fox family includes the Arctic fox, red fox, swift fox, kit fox, Cossack fox, Cape fox, black-tailed sand fox, Bengal fox, Vietnamese sand fox, Blandford fox, white-tailed sand fox, Fennec fox, gray fox, and island fox. , Cozumel fox, big-eared fox, and raccoon dog.
  • the subject of the canine animal is not limited thereto, but the canine animal in the present invention preferably includes a dog, for example, a purebred and/or mixed breed companion. dog, show dog, working dog, herding dog, hunting dog, guard dog, police dog, racing dog and/or laboratory It also includes dogs such as laboratory dogs, especially breeding dogs.
  • a dog for example, a purebred and/or mixed breed companion. dog, show dog, working dog, herding dog, hunting dog, guard dog, police dog, racing dog and/or laboratory It also includes dogs such as laboratory dogs, especially breeding dogs.
  • composition of the present invention can be used to treat or prevent respiratory disease in any breed of dog.
  • composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-mentioned ingredients for administration.
  • Pharmaceutically acceptable carriers may be saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these ingredients.
  • antioxidants such as antioxidants, solubilizers, pH adjusters, solvents, buffers, and bacteriostatic agents can be added as needed.
  • injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
  • compositions can be manufactured by conventional methods used for formulation in the art or by methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA, and can be formulated into various preparations depending on each disease or ingredient. It can be.
  • the composition includes Monothioglycerin, Anhydrous Citric Acid, Hydrochloric Acid, Propylene Glycol, Sodium Hydroxide, and Water for Injection. It additionally includes one or more types selected from the group consisting of injection.
  • the pharmaceutical composition of the present invention can be administered through any general administration route as long as it can reach the target tissue.
  • it can be administered parenterally or orally depending on the desired method, but is not limited thereto, and is preferably administered parenterally.
  • the parenteral administration may include any parenteral administration route as long as the composition of the present invention can achieve the purpose, for example, subcutaneous administration, intraperitoneal administration, intravenous administration, intramuscular administration, It may be one or more types selected from the group consisting of endothelial administration, intranasal administration, intrapulmonary administration, intrarectal administration, and intrathecal administration, and preferably, subcutaneous administration, but is not limited thereto.
  • composition according to the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level refers to the type and severity of the disease in the target livestock species, canine. , can be determined based on factors including the activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the field of medicine.
  • the composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.
  • the effective amount of the composition according to the present invention may vary depending on the age, sex, and weight of the target canine animal, and is generally 0.001 to 150 mg per kg of body weight, preferably 0.01 to 100 mg, more preferably. 0.1 to 10 mg, most preferably 2.5 mg, can be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity, gender, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.
  • the composition containing tulathromycin as an active ingredient of the present invention not only removes the causative bacteria of infection in dogs infected with dog respiratory disease, but can simultaneously exhibit a therapeutic effect, alleviating and treating clinical symptoms caused by bacterial infection. This can produce effects such as improvement of clinical symptoms, reduction of residual bacteria in infected tissues, and improvement of histopathological findings.
  • the present invention provides macrolide antibiotics (preferably tulathromycin), monothioglycerin (KVP), citric acid (Anhydrous Citric Acid, KVP), hydrochloric acid (KVP), Hydrochloric Acid (KVP), Propylene Glycol (KVP), Sodium Hydroxide (KVP), and Water for injection (KP).
  • macrolide antibiotics preferably tulathromycin
  • monothioglycerin KVP
  • citric acid Anhydrous Citric Acid, KVP
  • hydrochloric acid We provide injections for preventing or treating respiratory diseases in canine animals, including Hydrochloric Acid (KVP), Propylene Glycol (KVP), Sodium Hydroxide (KVP), and Water for injection (KP).
  • the injectable agent of the present invention can be formulated in various forms to achieve the purpose of treating respiratory diseases in dogs, but is most preferably formulated in an injectable form.
  • an injectable formulation it can be water for injection in the form of a transparent, colorless to light yellow liquid, and it is preferably prepared according to the injectable formulation method in the general rules for formulation of veterinary drug compendia.
  • the present invention provides a feed composition for preventing or improving respiratory diseases in canine animals containing macrolide antibiotics, preferably tulasromycin, as an active ingredient.
  • macrolide antibiotics preferably tulasromycin
  • the active ingredient, tulasromycin can be prepared in the same way as in the pharmaceutical composition.
  • tulathromycin of the present invention exhibits an antibacterial effect, it can be included in a feed composition as a growth promoter for animals or livestock.
  • the term “improvement” means any action that reduces at least the severity of a parameter, such as a symptom, related to the condition being treated.
  • the feed composition of the present invention can be used by adding the active ingredient directly to the feed or with other foods or food ingredients, and can be used appropriately according to conventional methods.
  • the mixing amount of the active ingredient can be appropriately determined depending on the purpose of use.
  • the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw materials.
  • the amount may be below the above range.
  • the feed composition of the present invention has no particular restrictions on other ingredients other than containing the above-mentioned effective ingredients as essential ingredients in the indicated proportions, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage.
  • natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)
  • synthetic flavoring agents sacharin, aspartame, etc.
  • the ratio of the natural carbohydrates can be appropriately determined by the selection of a person skilled in the art.
  • the feed composition of the present invention contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and It may contain its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients can be used independently or in combination. The proportions of these additives can also be appropriately selected by those skilled in the art.
  • the feed composition according to the present invention may include various feed additives.
  • the term "feed additive” refers to a substance added to feed for the purpose of various effects such as supplementing nutrients and preventing weight loss, improving digestibility of fiber in feed, improving milk quality, preventing reproductive disorders and improving conception rate, and preventing high temperature stress in the summer. says
  • the feed additive of the present invention corresponds to supplementary feed under the Feed Management Act, and includes mineral preparations such as sodium bicarbonate (sodium bicarbonate), bentonite, magnesium oxide, and complex minerals, and trace minerals such as zinc, copper, cobalt, and selenium.
  • vitamin preparations such as kerotene, vitamin E, vitamins A, D, E, nicotinic acid, and vitamin B complex
  • protective amino acid preparations such as methionine and lysic acid
  • protective fatty acid preparations such as fatty acid calcium salts
  • probiotics lactic acid bacteria
  • yeast culture Water live bacteria such as mold fermentation products, yeast, etc. may be additionally included.
  • the feed composition according to the present invention is not particularly limited and can be applied to any animal as long as it is intended to increase overall muscle strength and promote growth due to improved antibacterial efficacy, but is preferably canine.
  • the dosage of the feed composition according to the present invention will depend on a number of factors such as the species, size, weight, and age of the animal. In principle, typical dosages may range from 0.001 to 10 g per animal/day, but are not limited to this.
  • the present invention provides a method of treating respiratory diseases comprising administering a composition containing macrolide antibiotics, preferably tulasromycin, to a canine animal. do.
  • a composition containing macrolide antibiotics preferably tulasromycin
  • the above treatment method is administered at a rate of 0.1 ml of a drug containing tulasromycin (2.5 mg per 1 kg of body weight) 5 times a day, preferably 3 times a day, more preferably once a day, 3 to 7, 3 It may be administered for up to 5 days, but is not limited thereto.
  • Tulasromycin may be administered at 0.1 mg/kg to 10 mg/kg, preferably 1 to 5 mg/kg, and more preferably 2.5 mg/kg once a day.
  • complex treatment effects can be obtained in dogs, including improvement of clinical symptoms, reduction of residual bacteria in tissues, and improvement of histopathological findings.
  • the method of the present invention includes a composition containing tulasromycin, a macrolide antibiotic described above, as an active ingredient, duplicate content is omitted to avoid excessive complexity of the specification.
  • composition containing tulasromycin, a macrolide antibiotic of the present invention not only has an antibacterial effect in removing the causative bacteria infected with respiratory diseases in canine animals, but can also exhibit a therapeutic effect at the same time, so it can exhibit a therapeutic effect at the same time. It can be useful in preventing or treating diseases. Therefore, the present invention can expand the range of options for antibiotic treatment in animal hospitals and contribute to the domestic veterinary drug manufacturing industry and the companion animal drug industry.
  • Figures 1A to 1D show MBC results (strain name/concentration ( ⁇ g/ml)) for the strains used.
  • Figure 2 shows a graph of feed intake and body weight change in the control drug administration group (Ampicillin administration group) and the test drug administration group of the present invention (tulathromycin administration group).
  • Figure 3 shows the daily clinical index of the control drug administration group and the test drug administration group after Bordetella bronchiceptica challenge in the clinical efficacy test of the test drug of the present invention.
  • Figure 4 shows a graph of changes in general hematology (WBC) and serum chemistry in the control drug administration group (Ampicillin administration group) and the test drug administration group of the present invention (tulathromycin group). *p ⁇ 0.5 indicates that the clinical efficacy of the test drug administration group has statistical validity compared to the control drug administration group.
  • Figure 5 shows the results of an autopsy in which two animals, one each, died on the 3rd and 4th days in the control drug administration group after challenge vaccination.
  • A A large amount of pleural fluid was confirmed.
  • B When the trachea was incised, the inner wall was confirmed to be highly congested and filled with foamy inflammatory secretions.
  • C The inner wall of the bronchus was also confirmed to be hyperemic and foamy. Sexual inflammatory secretions were observed,
  • D Pulmonary hemorrhage and congestion were observed with the naked eye.
  • Figure 6 shows the results of histopathological examination after autopsy of two animals that died after challenge vaccination.
  • A Pulmonary hemorrhage observed (100 times)
  • B Bronchiopneumonia observed (400 times)
  • C Perivascular inflammatory infiltration observed (100 times)
  • D Hemosiderin and Atrophy of the white pulp was observed (100 times).
  • Figure 7 shows the results of liver and lung histopathological examination after autopsy of two animals that died after challenge vaccination.
  • A Coagulative necrosis of hepatocytes (400 times)
  • B Bronchial pneumonia (100 times).
  • Figure 8 shows dogs that participated in the outdoor clinical efficacy test. These were representative breeds commonly seen in Korea, and the main symptoms were chronic coughing and nasal discharge.
  • Figure 9 shows the chest radiography image results. All patients showed a diffuse bronchial pattern (red circle) and an interstitial pattern (blue circle). In particular, in (C) the affected dog, the epileptic pattern appears more dominant, and in (D) the affected dog, the bronchial pattern and epileptic pattern (green circles) are prominent.
  • Figure 10 shows the chest radiography results of dogs in the test drug administration group. These are the chest radiographs before (A) and after (B) treatment of the control drug administration group, and the chest radiographs before (C) and after treatment (D) of the tulathromycin administration group.
  • Figure 11 shows the chest radiograph results before and after administration of the control drug administration group.
  • Patient A was patient number 3.
  • the anterior and posterior lobes of the lung showed a mixture of interstitial and bronchial patterns.
  • After administration of the drug (B) clinical symptoms improved to some extent, and chest radiograph findings also improved to some extent.
  • Patient C was patient number 6.
  • the interstitial pattern was particularly evident in the anterior lung lobe, but after administration of the control drug (D), clinical symptoms and chest radiographs showed improvement.
  • Figure 12 shows the chest radiograph results before and after administration of the test drug administration group.
  • Patient A is patient number 1 before administration of the test drug, and shows a bronchial pattern in the anterior and posterior lobes of the lung. After administration of the test drug (B), it can be seen that the bronchial pattern has significantly improved.
  • Case C was patient number 4 before administration of the test drug, and severe bronchial and interstitial patterns were observed in the anterior and posterior lobes of the lung. After administration of the test drug (D), it was confirmed that there was a clear improvement in the chest radiograph.
  • the present inventors prepared a formulation containing tulasromycin, a macrolide antibiotic, with the composition shown in Table 1 per 1 mL, and used it in subsequent experiments.
  • the ingredients in Table 1 refer to the amounts contained in 1 ml of this agent.
  • the present inventors administered the tulasromycin of Example 1 per 1 kg of body weight to a healthy 2-3 month old dog (Beagle dog weighing 5-6 kg), as shown in Table 2. After subcutaneously injecting 0.1ml (2.5mg/kg bw/day as tulathromycin) or 0.3ml once, the condition was observed and statistically processed.
  • the above statistical processing uses the SPSS program, and when comparing two groups, student t-test is performed, when comparing three groups, one-way ANOVA (one-way analysis of variance) analysis is performed, and a post-hoc test is performed by Tukey analysis. (post hoc Tukey's multiple-comparison tests).
  • the tulathromycin of the present invention is a safe drug that does not cause side effects on the organ functions of an individual even when treated in high doses and does not have a harmful effect on overall health.
  • the present inventors used field isolate Bordetella bronchiseptica B1 (isolated in Seoul area for 20 years) and field isolate Bordetella bronchiseptica as test strains.
  • Minimum inhibition concentration is the lowest concentration of an antibiotic at which bacterial growth is completely inhibited and corresponds to the highest concentration at which bacteria do not grow.
  • Minimum bactericidal concentration is the minimum bactericidal concentration (MBC) that completely inhibits bacterial growth. This is the lowest concentration of killed antibiotics, and corresponds to the highest concentration at which bacteria did not grow after inoculating a bacterial solution with a higher concentration, including the MIC concentration, onto Muller-Hinton agar and culturing it at 35°C for 16 to 20 hours.
  • the extract was diluted and dispensed at 200 ⁇ l each into a 96 well plate.
  • the test concentration of the extract was 0, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256 ⁇ g/ml, placed in a 96 well plate, and inoculated with the prepared bacterial inoculum of McFarland 0.5 (1 x 10 8 CFU/ml) was diluted 10 times and 5 ⁇ l was inoculated into each well.
  • the final concentration of the inoculum is approximately 5 x 10 5 CFU/ml.
  • the 96 well plate inoculated with bacteria was cultured at 35°C for 16 to 20 hours.
  • the MIC for the 9 test strains was observed to be 1-16 ⁇ g/ml and the MBC was observed to be 2-32 ⁇ g/ml.
  • Staphylococcus aureus ATCC 29213 had an MIC of 8 ⁇ g/ml, falling within the QC range of 2-8 ⁇ g/ml.
  • the present inventors administered 10 mL ( 4.3
  • the recommended doses of the control drug (ampicillin) and the test drug (tulathromycin) were injected subcutaneously according to the dosage per kg of body weight (Table 11), and changes in clinical symptoms and blood tests were observed for 14 days.
  • both the control drug administration group (5 animals) and the test drug administration group (5 animals) underwent respiratory anesthesia and underwent bronchoscopy to collect samples and nasal swab through bronchoalveolar lavage (BAL). ) was carried out, and at the same time, bacterial culture was inoculated.
  • the challenge inoculum was 10 mL and the concentration was set to 4.3 x 10 10 CFU/mL and used for inoculation.
  • Acepromazien acepromazien 0.015 mg/kg, IM
  • butorphanol butorphanol 0.2 mg/kg, IV
  • ketamine ketamine 2 mg/kg, IV
  • propofol diluted in a 1:3 ratio with physiological saline
  • propofol dilution diluted in a 1:3 ratio with physiological saline
  • tracheal endoscopy was performed after sufficient oxygen was supplied for at least 10 minutes.
  • Aminophylline (15 mg/kg, IV) was administered 10 minutes before the scope was inserted to sufficiently dilate the bronchial tubes.
  • the present inventors subcutaneously injected the recommended amounts of the control drug and test drug per kg of body weight into the control drug (ampicillin) and test drug (tulathromycin) groups for naturally occurring inflammatory respiratory diseases in dogs, and treated clinical symptoms for 14 days. and changes in blood tests were observed.
  • control drug ampicillin
  • test drug tulathromycin
  • the degree of improvement in clinical symptoms was evaluated by assigning scores for each clinical symptom item before and 7 and 14 days after administration of the control and test drugs (Table 19). All 24 pet dogs visited the veterinary hospital and underwent examination. Overall, the clinical symptoms of the control drug administration group (Table 20) and the test drug administration group (Table 21) were significantly improved when they visited the hospital for treatment on the 7th day.
  • test drug was injected subcutaneously once, while the control drug was injected subcutaneously once daily, so the blood CK value in the control drug administration group was maintained at a higher value than the test drug administration group (Table 22).
  • the WBC count was statistically significantly lower on days 7 and 14 compared to day 0 (p ⁇ 0.05).
  • Chest X-ray examination is the most useful imaging method for diagnosing respiratory diseases and is especially effective in diagnosing bronchopneumonia, so it was performed along with physical examination and hematological examination of the patients. All patients had various degrees of interstitial pattern and bronchial pattern. (Bronchial pattern) lungs field was seen ( Figure 9).
  • the epileptic pattern is a common pattern in older dogs and can also occur in cases of severe respiratory disease.
  • the bronchial pattern is a typical chest radiograph change that occurs when there is a respiratory disease.
  • the present invention not only confirmed the antibacterial effect against Bordetella bronchiseptica, which is known to be the cause of infectious bronchopneumonia in dogs, in order to confirm the therapeutic effect of an injection containing tulathromycin as an active ingredient on respiratory diseases in dogs. , safety was confirmed by administering the clinically recommended dose and three times the dose to experimental dogs.
  • tulathromycin injection was administered to evaluate the bacterial removal effect and clinical efficacy, and the treatment effect was confirmed by administering the test drug to naturally occurring patients who visited the hospital with respiratory disease.
  • Tulathromycin of the present invention is an effective and safe drug for the treatment of dogs suffering from bacterial respiratory infections.
  • Tulathromycin of the present invention was found to be effective in treating dogs suffering from bacterial respiratory infections. It was confirmed that the antibacterial effect was excellent, and when experimental dogs were inoculated with field strains of Bordetella bronchiseptica and then administered tulathromycin of the present invention, clinical symptoms were observed. It was confirmed that it not only suppressed, but also improved.
  • subcutaneous treatment with tulasromycin at a dose of 2.5 mg per kg of body weight per day proves to be an effective treatment for respiratory diseases caused by Bordetella bronchiseptica infection.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Dermatology (AREA)

Abstract

The present invention relates to a composition including a macrolide antibiotic, preferably tulathromycin, as an active ingredient for the prevention or treatment of respiratory diseases in canines. The composition including the macrolide antibiotic of the present invention not only exhibits antibacterial effects by eliminating the causative bacteria of the respiratory diseases in canines, but also can demonstrate therapeutic effects. Hence, the composition can be advantageously used for the prevention or treatment of various respiratory diseases in various canines. Therefore, the present invention can broaden the range of choices in antibiotic treatment in veterinary clinics and contribute to the domestic animal pharmaceutical manufacturing industry and the pet medicine industry.

Description

마크로라이드 계열 항생제를 유효성분으로 포함하는 개과 동물의 호흡기 질환의 예방 또는 치료용 조성물Composition for preventing or treating respiratory diseases in canine animals containing a macrolide antibiotic as an active ingredient
본 발명은 마크로라이드 계열 항생제를 유효성분으로 포함하는 개과 동물의 호흡기 질환의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating respiratory diseases in canine animals containing a macrolide antibiotic as an active ingredient.
켄넬 코프(kennel cough) 또는 전염성 기관지염은 주로 기침에 의해 특징되는 개의 급성, 전염성 호흡기 감염이다. 개 기관지염은 전세계적으로 가장 널리 퍼진 개의 전염성 호흡기 질병들 중 하나로 여겨지고, 발병하면 개들이 사육장과 같은 고밀집 개체 환경에 수용시에 풍토병 수준에 이를 수 있다. 대부분의 발병은 호흡기 분비물이 직접적인 1:1(dog-to-dog) 접촉에 의하거나 분무주입(aerosolization)에 기인한 것이다. 임상 징후는 상기도 및 하기도의 상피에 박테리아 및 바이러스 병원체(viral agent)들 중 하나로부터의 감염에 의해 유발되며, 주원인체 중 하나로 보르데텔라 브론키셉티카(B. bronchiseptica)가 알려져 있다. Kennel cough, or infectious bronchitis, is an acute, contagious respiratory infection in dogs primarily characterized by coughing. Canine bronchitis is considered one of the most prevalent canine contagious respiratory diseases worldwide, and can reach endemic levels when dogs are housed in high-density environments such as kennels. Most outbreaks are due to direct dog-to-dog contact or aerosolization of respiratory secretions. Clinical signs are caused by infection of the epithelium of the upper and lower respiratory tract from either bacterial or viral agents, and B. bronchiseptica is known as one of the main causative agents.
보르데텔라 브론키셉티카는 개의 호흡기관에서 콜로니화하여 질환을 야기하는 그람 음성 세균이다. 보르데텔라 브론키셉티카는 개가 다른 호흡기 병원체의 영향에 취약하게 하고 종종 이들과 공존한다. Bordetella bronchiseptica is a Gram-negative bacterium that colonizes the respiratory tract of dogs and causes disease. Bordetella bronchiseptica makes dogs susceptible to the effects of other respiratory pathogens and often coexists with them.
현재, 보르데텔라 브론키셉티카에 의해 야기된 기관지염의 치료를 위해 노비백(Nobivac: 등록상표), 브론키-쉴드(Bronchi-Shield: 등록상표), 브론카이신(Bronchicine: 등록상표) CAe, 뱅가드(Vanguard: 등록상표) B, 유니백(Univac) 2, 레콤비텍(Recombitek: 등록상표) KC2, 나라뮨(Naramune: 상표)-2 및 케넬-젝(Kennel-Jec: 상표) 2를 포함하는 다수의 백신들이 개발되어 사용중이다.Currently, Nobivac (registered trademark), Bronchi-Shield (registered trademark), Bronchicine (registered trademark) CAe, Includes Vanguard (registered trademark) B, Univac 2, Recombitek (registered trademark) KC2, Naramune (trademark)-2 and Kennel-Jec (trademark) 2 Many vaccines have been developed and are in use.
그러나, 기존 상업용 백신들의 대다수는 번거롭고 위험한 비강내 투여뿐만 아니라, 유해한 부작용, 예컨대, 화상 및 자극을 야기할 수 있는 항원보강제(adjuvant)의 첨가를 필요로 한다. 서브유닛(subunit) 백신, 예컨대, 보르데텔라 브론키셉티카의 p68단백질(퍼택틴)의 사용을 수반하는 백신이 연구되었지만 지금까지 불충분한 면역원성, 반응성 및/또는 제제 안정성으로 인해 임의의 상업용 개 백신에 포함되지 않았다.However, the majority of existing commercial vaccines require cumbersome and dangerous intranasal administration, as well as the addition of adjuvants, which can cause harmful side effects such as burning and irritation. Subunit vaccines, such as those involving the use of the p68 protein (pertactin) of Bordetella bronchiseptica, have been studied, but have so far not been approved for use in any commercial dog due to insufficient immunogenicity, reactivity and/or formulation stability. Not included in the vaccine.
따라서, 유해한 부작용 또는 조합 백신 중의 다른 항원과의 간섭 없이, 개에게 안전하게 비경구 투여될 수 있어 수의사에게 위험을 야기하지 않으면서 보르데텔라 브론키셉티카로 인해 발생한 호흡기 질환에 대한 탁월한 효과를 제공하는 치료제에 대한 개발이 요구되고 있다.Therefore, a treatment that can be safely administered parenterally to dogs, without harmful side effects or interference with other antigens in the combination vaccine, providing excellent effectiveness against respiratory diseases caused by Bordetella bronchiseptica without posing a risk to veterinarians. development is required.
이러한 상황 하에서, 본 발명자들은, 안전하고 효과적인 보르데텔라 브론키셉티카(Bordetella bronchiseptica) 유발성 개 호흡기 질환, 특히 기관지 폐렴에 대한 치료제를 개발하기 위하여 예의 연구노력하였다. 그 결과, 본 발명자들은 마크로라이드 계열의 항생제인 툴라스로마이신(Tulathromycin)을 피하 주사했을 때, 보르데텔라 브론키셉티카에 의해 유발되는 세균성 호흡기 질환(기관지 폐렴)의 임상 증상들이 현저하게 개선됨을 규명함으로써, 본 발명을 완성하였다.Under these circumstances, the present inventors have made intensive research efforts to develop a safe and effective treatment for canine respiratory diseases caused by Bordetella bronchiseptica , especially bronchopneumonia. As a result, the present inventors found that when Tulathromycin, a macrolide antibiotic, was injected subcutaneously, the clinical symptoms of bacterial respiratory disease (bronchopneumonia) caused by Bordetella bronchiseptica were significantly improved. By doing so, the present invention was completed.
따라서, 본 발명의 일 목적은 개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물을 제공하는 데 있다.Therefore, an object of the present invention is to provide a pharmaceutical composition for preventing or treating respiratory diseases in canine animals.
또한, 본 발명의 다른 목적은 개과 동물의 호흡기 질환 예방 또는 치료용 주사제를 제공하는 데 있다.In addition, another object of the present invention is to provide an injectable agent for preventing or treating respiratory diseases in canine animals.
또한, 본 발명의 또 다른 목적은 개과 동물의 호흡기 질환 예방 또는 개선용 사료 조성물을 제공하는 데 있다.In addition, another object of the present invention is to provide a feed composition for preventing or improving respiratory diseases in canine animals.
또한, 본 발명의 또 다른 목적은 개과 동물의 호흡기 질환 치료 방법을 제공하는 데 있다.Additionally, another object of the present invention is to provide a method for treating respiratory diseases in canine animals.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명 및 청구범위에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become clearer from the following detailed description and claims.
본 명세서에서 사용한 용어는 단지 설명을 목적으로 사용된 것으로, 한정하려는 의도로 해석되어서는 안된다. 단수의 표현은 문맥상 명백하게 다르게 뜻하지 않는 한, 복수의 표현을 포함한다. 본 명세서에서, "포함하다" 또는 "가지다" 등의 용어는 명세서 상에 기재된 특징, 숫자, 단계, 동작, 구성요소, 부품 또는 이들을 조합한 것이 존재함을 지정하려는 것이지, 하나 또는 그 이상의 다른 특징들이나 숫자, 단계, 동작, 구성요소, 부품 또는 이들을 조합한 것들의 존재 또는 부가 가능성을 미리 배제하지 않는 것으로 이해되어야 한다.The terms used herein are for descriptive purposes only and should not be construed as limiting. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, terms such as “comprise” or “have” are intended to designate the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, but are not intended to indicate the presence of one or more other features. It should be understood that this does not exclude in advance the possibility of the existence or addition of elements, numbers, steps, operations, components, parts, or combinations thereof.
또한, 다르게 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 실시예가 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 가지고 있다. 일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥 상 가지는 의미와 일치하는 의미를 가지는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다.Additionally, unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as generally understood by a person of ordinary skill in the technical field to which the embodiments pertain. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related technology, and unless explicitly defined in the present application, should not be interpreted in an ideal or excessively formal sense. No.
이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일 양태에 따르면, 본 발명은 마크로라이드 계열 항생제(Macrolide Antibiotics)을 유효성분으로 포함하는 개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물을 제공한다.According to one aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating respiratory diseases in canine animals containing macrolide antibiotics as an active ingredient.
상기 마크로라이드 계열 항생제는 마크로사이클릭락톤 환을 포함하고 있어 마크로라이드계 항생제로 불리며, 본 발명의 조성물이 목적을 달성할 수 있는 한, 임의의 마크로라이드 계열 항생제도 이용할 수 있으며, 예컨대, 툴라스로마이신(tulathromycin), 에리트로마이신, 클라리트로마이신, 아지트로마이신, 타이로신, 틸미코신, 조사마이신, 키타사마이신 및 스피라마이신으로 이루어진 군으로부터 선택된 1 종 이상일 수 있으나, 이에 한정되지 않는다.The macrolide antibiotics contain a macrocyclic lactone ring and are therefore called macrolide antibiotics. As long as the composition of the present invention can achieve the purpose, any macrolide antibiotic can be used, for example, Tulasro. It may be one or more selected from the group consisting of tulathromycin, erythromycin, clarithromycin, azithromycin, tyrosine, tilmicosin, josamycin, kitasamycin, and spiramycin, but is not limited thereto.
본 발명의 바람직한 구현예에 따르면, 상기 마크로라이드 계열 항생제는 툴라스로마이신(tulathromycin)(CAS No. 217500-96-4)(C41H79N3O12)이다.According to a preferred embodiment of the present invention, the macrolide antibiotic is tulathromycin (CAS No. 217500-96-4) (C 41 H 79 N 3 O 12 ).
본 발명의 개과 동물의 호흡기 질환은 당 분야에 알려진 호흡기에 유발되는 일반적인 감염성 질환을 제한없이 포함할 수 있으며, 바람직하게는 병원균에 의한 것임을 특징으로 할 수 있다.The respiratory disease of canine animals of the present invention may include without limitation general infectious diseases caused by the respiratory tract known in the art, and may preferably be characterized as being caused by pathogens.
상기 호흡기 질환은, 본 발명의 조성물이 목적을 달성할 수 있는 한, 임의의 호흡기 질환을 포함할 수 있다. 바람직하게는, 상기 호흡기 질환은 보르데텔라 브론키셉티카(Bordetella bronchiseptica), 액티노바실러스 플루로뉴모니애(Actinobacillus pleuropneumoniae), 파스튜렐라 멀토시다(Pasteurella multocida), 헤모필러스 파라수이스(Haemophilus parasuis) 및 마이코플라즈마 하이오뉴모니애(Mycoplasma hyopneumoniae)로 이루어진 군으로부터 선택된 병원균의 감염으로 유발된 호흡기 질환일 수 있으며, 가장 바람직하게는 보르데텔라 브론키셉티카(Bordetella bronchiseptica)이나, 이에 한정되지 않는다.The respiratory disease may include any respiratory disease as long as the composition of the present invention can achieve the purpose. Preferably, the respiratory disease is caused by Bordetella bronchiseptica , Actinobacillus pleuropneumoniae , Pasteurella multocida , Haemophilus parasuis ( It may be a respiratory disease caused by infection with a pathogen selected from the group consisting of Haemophilus parasuis and Mycoplasma hyopneumoniae , most preferably Bordetella bronchiseptica , but not limited thereto. No.
또한, 상기 호흡기 질환은 개 기관지염(kennel cough), 기관지 폐렴, 호흡기 염증성 폐 질환, 만성 폐쇄성 폐 질환, 부비강염, 알레르기성 비염, 하기도 감염증, 급만성기관지염, 폐기종, 폐렴, 기관지 천식, 기관지 확장증, 폐기종, 폐결핵 후유증, 급성 호흡 궁박증후군 및 폐섬유증으로 이루어진 군으로부터 선택되는 1종 이상이며, 바람직하게는 개 기관지염(kennel cough)이나, 이에 한정되지 않는다.In addition, the above respiratory diseases include kennel cough, bronchopneumonia, respiratory inflammatory lung disease, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, lower respiratory tract infection, acute and chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, and emphysema. , pulmonary tuberculosis sequelae, acute respiratory distress syndrome, and pulmonary fibrosis, preferably canine bronchitis (kennel cough), but is not limited thereto.
본 명세서에서 사용되는 "개과 동물(canine)"은 개, 늑대, 여우, 코요테, 자칼, 승냥이 등의 잡식성 동물로서, 발가락으로 걷는 지행동물을 의미하며, 본 발명의 목적을 달성하는 한, 당업계에 공지된 개과 동물은 모두 포함할 수 있다.As used herein, “canine” refers to an omnivorous animal such as a dog, wolf, fox, coyote, jackal, or dung beetle, and refers to a bipedal animal that walks on its toes, and as long as it achieves the purpose of the present invention, it is known in the art All known canine animals may be included.
상기 개과동물은 크게 개족과 여우족으로 나뉜다. 개족은 개, 갈기늑대, 가로무늬자칼, 검은 등자칼, 딩고, 붉은늑대, 에티오피아늑대, 인도늑대, 코요태, 황금자칼, 게잡이여우속, 들개속, 승냥이, 아프리카들개, 작은귀개, 포클랜드늑대, 안데스여우, 다윈여우, 아르헨티나회색여우, 팜파스여우, 페루사막여우, 흰여우 등을 포함한다.The canids are largely divided into the dog family and the fox family. The dog family includes dogs, maned wolves, striped jackals, black-backed jackals, dingoes, red wolves, Ethiopian wolves, Indian wolves, coyotes, golden jackals, crab-eating foxes, wild dogs, jackals, African wild dogs, small-eared dogs, Falkland wolves, Includes Andean fox, Darwin's fox, Argentine gray fox, Pampas fox, Peruvian desert fox, and white fox.
여우족은 북극여우, 붉은여우, 스위프트여우, 키트여우, 코사크여우, 케이프여우, 검은꼬리모래여우, 벵골여우, 티베트모래여우, 블랜포드여우, 흰꼬리모래여우, 페넥여우, 회색여우, 섬여우, 코즈멜여우, 큰귀여우 및 너구리 등을 포함한다.The fox family includes the Arctic fox, red fox, swift fox, kit fox, Cossack fox, Cape fox, black-tailed sand fox, Bengal fox, Tibetan sand fox, Blandford fox, white-tailed sand fox, Fennec fox, gray fox, and island fox. , Cozumel fox, big-eared fox, and raccoon dog.
본 발명의 조성물이 효과를 발휘하는 한, 상기 개과 동물의 대상은 이에 제한되지 않으나, 본 발명에서 개과 동물은, 바람직하게는, 개를 포함하며, 예를 들어, 순종 및/또는 잡종 반려견(companion dog), 쇼견(show dog), 사역견(working dog), 목양견(herding dog), 수렵견(hunting dog), 호위견(guard dog), 경찰견(police dog), 경주견(racing dog) 및/또는 실험견(laboratory dog)과 같은 개들, 특히 사육견도 포함한다.As long as the composition of the present invention is effective, the subject of the canine animal is not limited thereto, but the canine animal in the present invention preferably includes a dog, for example, a purebred and/or mixed breed companion. dog, show dog, working dog, herding dog, hunting dog, guard dog, police dog, racing dog and/or laboratory It also includes dogs such as laboratory dogs, especially breeding dogs.
또한, 용어 "개과 동물"는 개과에 속하는 다양한 종을 제한없이 포함할 수 있으므로, 본 발명의 조성물은 개의 어느 품종에서도 호흡기 질환을 치료하거나 예방하기 위해 사용될 수 있다.Additionally, since the term “canine” can include various species belonging to the canine family without limitation, the composition of the present invention can be used to treat or prevent respiratory disease in any breed of dog.
또한, 본 발명의 약학적 조성물은 투여를 위해서 상기한 성분 이외에 추가로 약학적으로 허용가능한 담체를 1종 이상 포함하여 제조할 수 있다. In addition, the pharmaceutical composition of the present invention may be prepared by including one or more pharmaceutically acceptable carriers in addition to the above-mentioned ingredients for administration.
약학적으로 허용가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있다.Pharmaceutically acceptable carriers may be saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and a mixture of one or more of these ingredients.
또한, 필요에 따라 항산화제, 용해보조제, pH 조절제, 용매, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. Additionally, other common additives such as antioxidants, solubilizers, pH adjusters, solvents, buffers, and bacteriostatic agents can be added as needed.
또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.
이들 제제는 당 분야에서 제제화에 사용되는 통상의 방법 또는 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA에 개시되어 있는 방법으로 제조될 수 있으며 각 질환에 따라 또는 성분에 따라 다양한 제제로 제제화될 수 있다.These preparations can be manufactured by conventional methods used for formulation in the art or by methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA, and can be formulated into various preparations depending on each disease or ingredient. It can be.
본 발명의 일 실시예에서는, 상기 조성물은 모노티오글리세린 (Monothioglycerin), 시트르산 (Anhydrous Citric Acid), 염산 (Hydrochloric Acid), 프로필렌글리콜 (Propylene Glycol), 수산화나트륨 (Sodium Hydroxide) 및 주사용수 (Water for injection)로 이루어진 군으로부터 선택된 1종 이상을 추가적으로 포함한다.In one embodiment of the present invention, the composition includes Monothioglycerin, Anhydrous Citric Acid, Hydrochloric Acid, Propylene Glycol, Sodium Hydroxide, and Water for Injection. It additionally includes one or more types selected from the group consisting of injection.
본 발명의 약학 조성물은 목적 조직에 도달할 수 있는 한 어떠한 일반적인 투여 경로를 통하여 투여될 수 있다.The pharmaceutical composition of the present invention can be administered through any general administration route as long as it can reach the target tissue.
즉, 목적하는 방법에 따라 비경구 또는 경구 투여될 수 있으며, 이에 제한되지 않으나 바람직하게는 비경구 투여된다.That is, it can be administered parenterally or orally depending on the desired method, but is not limited thereto, and is preferably administered parenterally.
상기 비경구 투여는, 본 발명의 조성물이 목적을 달성할 수 있는 한, 임의의 비경구 투여 경로를 포함할 수 있고, 예를 들어, 피하 투여, 복강내 투여, 정맥내 투여, 근육내 투여, 내피 투여, 비강내 투여, 폐내투여, 직장내 투여, 경막내 투여로 이루어진 군으로부터 선택된 1 종 이상이고, 바람직하게는, 피하 투여일 수 있으나, 이에 한정되지 않는다.The parenteral administration may include any parenteral administration route as long as the composition of the present invention can achieve the purpose, for example, subcutaneous administration, intraperitoneal administration, intravenous administration, intramuscular administration, It may be one or more types selected from the group consisting of endothelial administration, intranasal administration, intrapulmonary administration, intrarectal administration, and intrathecal administration, and preferably, subcutaneous administration, but is not limited thereto.
또한, 본 발명에 따른 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 대상 축종인 개과 동물의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 따른 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.Additionally, the composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level refers to the type and severity of the disease in the target livestock species, canine. , can be determined based on factors including the activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the field of medicine. The composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.
구체적으로, 본 발명에 따른 조성물의 유효량은 대상 개과 동물의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 1 kg 당 0.001 내지 150 mg, 바람직하게는 0.01 내지 100 mg, 더욱 바람직하게는 0.1 내지 10mg, 가장 바람직하게는 2.5 mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the composition according to the present invention may vary depending on the age, sex, and weight of the target canine animal, and is generally 0.001 to 150 mg per kg of body weight, preferably 0.01 to 100 mg, more preferably. 0.1 to 10 mg, most preferably 2.5 mg, can be administered daily or every other day, or divided into 1 to 3 times a day. However, since it may increase or decrease depending on the route of administration, severity, gender, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.
따라서, 본 발명의 툴라스로마이신(tulathromycin)을 유효성분으로 포함하는 조성물은, 개 호흡기 질환에 감염된 개의 감염 원인균을 제거할 뿐만 아니라 동시에 치료 효과를 나타낼 수 있고, 세균 감염에 따른 임상 증상 완화 및 치료함으로써 임상 증상의 개선, 감염 조직 내 잔류 세균의 감소, 병리조직학적 소견의 개선과 같은 효과를 나타낼 수 있다.Therefore, the composition containing tulathromycin as an active ingredient of the present invention not only removes the causative bacteria of infection in dogs infected with dog respiratory disease, but can simultaneously exhibit a therapeutic effect, alleviating and treating clinical symptoms caused by bacterial infection. This can produce effects such as improvement of clinical symptoms, reduction of residual bacteria in infected tissues, and improvement of histopathological findings.
또한, 본 발명의 다른 양태에 따르면, 본 발명은 마크로라이드 계열 항생제(Macrolide Antibiotics)(바람직하게는 툴라스로마이신), 모노티오글리세린 (Monothioglycerin, KVP), 시트르산 (Anhydrous Citric Acid, KVP), 염산 (Hydrochloric Acid, KVP), 프로필렌글리콜 (Propylene Glycol, KVP), 수산화나트륨 (Sodium Hydroxide, KVP) 및 주사용수 (Water for injection, KP)을 포함하는 개과 동물의 호흡기 질환 예방 또는 치료용 주사제를 제공한다.In addition, according to another aspect of the present invention, the present invention provides macrolide antibiotics (preferably tulathromycin), monothioglycerin (KVP), citric acid (Anhydrous Citric Acid, KVP), hydrochloric acid ( We provide injections for preventing or treating respiratory diseases in canine animals, including Hydrochloric Acid (KVP), Propylene Glycol (KVP), Sodium Hydroxide (KVP), and Water for injection (KP).
상기 본 발명의 주사제는 개에서 호흡기 질환을 치료하는 목적을 달성하기 위해서 다양한 형태로 제형화 될 수 있으나, 가장 바람직하게는 주사제형으로 제형화될 수 있다. 주사제형으로 제형화되는 경우 이는 투명한 무색 내지 연한 황색의 액체의 형태를 갖는 주사용수가 될 수 있으며, 이는 동물용 의약품 공정서 제제총칙 중 주사제 제법에 따라 제조되는 것이 바람직하다.The injectable agent of the present invention can be formulated in various forms to achieve the purpose of treating respiratory diseases in dogs, but is most preferably formulated in an injectable form. When formulated as an injectable formulation, it can be water for injection in the form of a transparent, colorless to light yellow liquid, and it is preferably prepared according to the injectable formulation method in the general rules for formulation of veterinary drug compendia.
또한, 본 발명의 또 다른 양태에 따르면, 본 발명은 마크로라이드 계열 항생제(Macrolide Antibiotics), 바람직하게는 툴라스로마이신을 유효성분으로 포함하는 개과 동물의 호흡기 질환 예방 또는 개선용 사료 조성물을 제공한다.In addition, according to another aspect of the present invention, the present invention provides a feed composition for preventing or improving respiratory diseases in canine animals containing macrolide antibiotics, preferably tulasromycin, as an active ingredient.
상기 유효성분인 툴라스로마이신은 상기 약학 조성물의 경우와 동일하게 준비될 수 있다.The active ingredient, tulasromycin, can be prepared in the same way as in the pharmaceutical composition.
본 발명의 툴라스로마이신은 항균 효과를 나타내므로 동물이나 가축의 성장 촉진제로서 사료 조성물에 포함될 수 있다.Since tulathromycin of the present invention exhibits an antibacterial effect, it can be included in a feed composition as a growth promoter for animals or livestock.
본 발명에서 사용되는 용어, "개선"이란, 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term “improvement” means any action that reduces at least the severity of a parameter, such as a symptom, related to the condition being treated.
본 발명의 사료 조성물은 유효성분을 사료에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합량은 그의 사용 목적에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조시에 본 발명의 조성물은 원료에 대하여 15 중량%이하, 바람직하게는 10 중량% 이하의 양으로 첨가된다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있다.The feed composition of the present invention can be used by adding the active ingredient directly to the feed or with other foods or food ingredients, and can be used appropriately according to conventional methods. The mixing amount of the active ingredient can be appropriately determined depending on the purpose of use. Generally, when producing food or beverages, the composition of the present invention is added in an amount of 15% by weight or less, preferably 10% by weight or less, based on the raw materials. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be below the above range.
본 발명의 사료 조성물은 지시된 비율로 필수 성분으로서 상기 유효성분을 함유하는 것 외에 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 수크로오스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 당업자의 선택에 의해 적절하게 결정될 수 있다.The feed composition of the present invention has no particular restrictions on other ingredients other than containing the above-mentioned effective ingredients as essential ingredients in the indicated proportions, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose, etc.; Disaccharides such as maltose, sucrose, etc.; and polysaccharides, such as common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrates can be appropriately determined by the selection of a person skilled in the art.
상기 외에 본 발명의 사료 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율 또한 당업자에 의해 적절히 선택될 수 있다.In addition to the above, the feed composition of the present invention contains various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and It may contain its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients can be used independently or in combination. The proportions of these additives can also be appropriately selected by those skilled in the art.
본 발명에 따른 사료 조성물은 다양한 사료 첨가제를 포함할 수 있다.The feed composition according to the present invention may include various feed additives.
본 발명에서 용어 "사료 첨가제" 란 영양소 보충 및 체중감소 예방, 사료 내 섬유소의 소화 이용성 증진, 유질개선, 번식장애 예방 및 수태율 향상, 하절기 고온 스트레스 예방 등 다양한 효과를 목적으로 사료에 첨가하는 물질을 말한다. 본 발명의 사료첨가제는 사료관리법상의 보조사료에 해당하며, 탄산수소나트륨(중조), 벤토나이트 (bentonite), 산화마그네슘, 복합광물질 등의 광물질제제, 아연, 구리, 코발트, 셀레늄 등의 미량 광물질인 미네랄제제, 케로틴, 비타민 E, 비타민 A, D, E, 니코틴산, 비타민 B 복합체 등의 비타민제, 메티오닌, 리이산 등의 보호아미노산제, 지방산 칼슘염 등의 보호지방산제, 생균제(유산균제), 효모배양물, 곰팡이 발효물 등의 생균, 효모제 등이 추가로 포함될 수 있다.In the present invention, the term "feed additive" refers to a substance added to feed for the purpose of various effects such as supplementing nutrients and preventing weight loss, improving digestibility of fiber in feed, improving milk quality, preventing reproductive disorders and improving conception rate, and preventing high temperature stress in the summer. says The feed additive of the present invention corresponds to supplementary feed under the Feed Management Act, and includes mineral preparations such as sodium bicarbonate (sodium bicarbonate), bentonite, magnesium oxide, and complex minerals, and trace minerals such as zinc, copper, cobalt, and selenium. Preparations, vitamin preparations such as kerotene, vitamin E, vitamins A, D, E, nicotinic acid, and vitamin B complex, protective amino acid preparations such as methionine and lysic acid, protective fatty acid preparations such as fatty acid calcium salts, probiotics (lactic acid bacteria), yeast culture Water, live bacteria such as mold fermentation products, yeast, etc. may be additionally included.
본 발명에 따른 사료 조성물은 항균 효능의 향상으로 인하여 전체적인 근력 증가 효과 및 성장 촉진을 목적으로 하는 개체이면 특별히 한정되지 않고, 어떠한 것이든 적용 가능하나, 바람직하게는, 개과 동물이다.The feed composition according to the present invention is not particularly limited and can be applied to any animal as long as it is intended to increase overall muscle strength and promote growth due to improved antibacterial efficacy, but is preferably canine.
본 발명에 따른 사료 조성물의 복용량은 동물의 종(species), 크기(size), 무게(weight), 나이(age)와 같은 다수의 요인들에 좌우될 것이다. 원칙적으로, 전형적인 복용량은 동물/일 당 0.001 내지 10 g의 범위일 수 있으나, 이에 한정되지 않는다.The dosage of the feed composition according to the present invention will depend on a number of factors such as the species, size, weight, and age of the animal. In principle, typical dosages may range from 0.001 to 10 g per animal/day, but are not limited to this.
또한, 본 발명의 또 다른 양태에 따르면, 본 발명은 마크로라이드 계열 항생제(Macrolide Antibiotics), 바람직하게는 툴라스로마이신을 포함하는 조성물을 개과 동물에게 투여하는 단계를 포함하는 호흡기 질환의 치료 방법을 제공한다.In addition, according to another aspect of the present invention, the present invention provides a method of treating respiratory diseases comprising administering a composition containing macrolide antibiotics, preferably tulasromycin, to a canine animal. do.
상기 치료 방법에 따르면, 보르데텔라 브론키셉티카(Bordetella bronchiseptica)에 의해 유발된 호흡기 질환, 특히, 기관지 폐렴을 효과적으로 치료할 수 있다.According to the above treatment method, respiratory diseases caused by Bordetella bronchiseptica , especially bronchopneumonia, can be effectively treated.
상기 치료방법은 툴라스로마이신(체중 1kg 당 2.5mg)을 포함하는 약제 0.1ml 의 비율로 1일 5회, 바람직하게는 1일 3회, 더욱 바람직하게는 1일 1회로, 3 내지 7, 3 내지 5일 동안 투여하여 이루어질 수 있으나, 이에 제한되는 것은 아니다.The above treatment method is administered at a rate of 0.1 ml of a drug containing tulasromycin (2.5 mg per 1 kg of body weight) 5 times a day, preferably 3 times a day, more preferably once a day, 3 to 7, 3 It may be administered for up to 5 days, but is not limited thereto.
투여되는 툴라스로마이신은 0.1mg/kg 내지 10mg/kg로 투여될 수 있으며, 바람직하게는 1 내지 5mg/kg, 더욱 바람직하게는 2.5mg/kg으로 1일 1회 투여될 수 있다.Tulasromycin may be administered at 0.1 mg/kg to 10 mg/kg, preferably 1 to 5 mg/kg, and more preferably 2.5 mg/kg once a day.
본 발명의 치료방법에 의하면 개에서 임상 증상의 개선, 조직 내 잔류 세균의 감소 및 병리조직학적 소견의 개선 등 복합적인 치료 효과가 도출될 수 있다.According to the treatment method of the present invention, complex treatment effects can be obtained in dogs, including improvement of clinical symptoms, reduction of residual bacteria in tissues, and improvement of histopathological findings.
본 발명의 방법은 상술한 마크로라이드 계열 항생제(Macrolide Antibiotics)인 툴라스로마이신을 포함하는 조성물을 유효성분으로 포함하므로, 중복된 내용은 본 명세서의 과도한 복잡성을 피하기 위하여 그 기재를 생략한다.Since the method of the present invention includes a composition containing tulasromycin, a macrolide antibiotic described above, as an active ingredient, duplicate content is omitted to avoid excessive complexity of the specification.
본 발명의 마크로라이드 계열 항생제(Macrolide Antibiotics)인 툴라스로마이신을 포함하는 조성물은 개과 동물의 호흡기 질환에 감염된 원인균을 제거하는 항균 효과를 나타낼 뿐만 아니라 동시에 치료 효과를 나타낼 수 있으므로, 각종 개과 동물의 호흡기 질환의 예방 또는 치료에 유용하게 사용할 수 있다. 따라서, 본 발명은 동물병원에서 항생제 치료시 선택의 폭을 넓히고 국내 동물용의약품 제조업과 반려동물용 의약품산업에 기여할 수 있다.The composition containing tulasromycin, a macrolide antibiotic of the present invention, not only has an antibacterial effect in removing the causative bacteria infected with respiratory diseases in canine animals, but can also exhibit a therapeutic effect at the same time, so it can exhibit a therapeutic effect at the same time. It can be useful in preventing or treating diseases. Therefore, the present invention can expand the range of options for antibiotic treatment in animal hospitals and contribute to the domestic veterinary drug manufacturing industry and the companion animal drug industry.
도 1a 내지 1d는 사용된 균주들에 대한 MBC 결과(균주명/농도(μg/ml))를 보여준다. Figures 1A to 1D show MBC results (strain name/concentration (μg/ml)) for the strains used.
도 2는 대조약물 투여군(Ampicillin 투여군)과 본 발명의 시험약물 투여군(툴라스로마이신 투여군)의 사료 섭취량 및 체중변화 그래프를 보여준다.Figure 2 shows a graph of feed intake and body weight change in the control drug administration group (Ampicillin administration group) and the test drug administration group of the present invention (tulathromycin administration group).
도 3은 본 발명의 시험약물의 임상효능 시험에서 Bordetella bronchiceptica 공격접종 후의 대조약물 투여군과 시험약물 투여군의 일별 임상지수를 보여준다.Figure 3 shows the daily clinical index of the control drug administration group and the test drug administration group after Bordetella bronchiceptica challenge in the clinical efficacy test of the test drug of the present invention.
*, ** p < 0.5, p < 0.01 표시는 시험약물 투여군의 임상효능이 대조약물 투여군에 비해 매우 통계적 유효성이 있음을 의미한다. 상기 그래프에서는 대조약물 투여군에서 발생한 2마리의 폐사한 개체들의 값을 넣지 않고 남은 3마리의 값을 반영하였다.*, ** p < 0.5, p < 0.01 indicates that the clinical efficacy of the test drug administration group has greater statistical validity compared to the control drug administration group. In the above graph, the values of the two animals that died in the control drug administration group were not included, but the values of the remaining three animals were reflected.
도 4는 대조약물 투여군(Ampicillin 투여군)과 본 발명의 시험약물 투여군(툴라스로마이신군)의 일반혈액학 검사(WBC)와 혈청화학적 검사(Serum Chemistry) 변화 그래프를 보여준다. *p < 0.5 표시는 시험약물 투여군의 임상효능이 대조약물 투여군에 비해 통계적 유효성이 있음을 의미한다.Figure 4 shows a graph of changes in general hematology (WBC) and serum chemistry in the control drug administration group (Ampicillin administration group) and the test drug administration group of the present invention (tulathromycin group). *p < 0.5 indicates that the clinical efficacy of the test drug administration group has statistical validity compared to the control drug administration group.
도 5는 공격접종 후 대조약물 투약군에서 3일째와 4일째에 각각 1마리씩 두 2마리가 폐사하여 부검을 실시한 결과를 보여준다. (A) 다량의 흉수를 확인됨, (B) 기관(Trachea)을 절개했을 때 내벽은 충혈이 심했고 포말성의 염증성 분비물이 가득 찬 것을 확인함, (C) 기관지(Bronchus)에서도 내벽의 충혈과 포말성의 염증성 분비물들이 관찰됨, (D) 폐의 육안소견으로 폐출혈과 충혈이 관찰됨.Figure 5 shows the results of an autopsy in which two animals, one each, died on the 3rd and 4th days in the control drug administration group after challenge vaccination. (A) A large amount of pleural fluid was confirmed. (B) When the trachea was incised, the inner wall was confirmed to be highly congested and filled with foamy inflammatory secretions. (C) The inner wall of the bronchus was also confirmed to be hyperemic and foamy. Sexual inflammatory secretions were observed, (D) Pulmonary hemorrhage and congestion were observed with the naked eye.
도 6은 공격접종 후 폐사한 2마리의 부검 후 조직병리학적 검사 결과를 보여준다. (A) 폐출혈 소견이 관찰됨 (100배), (B) 기관지 폐렴 소견이 관찰됨 (400배), (C) 혈관주변 염증 침윤 소견이 관찰됨 (100배), (D) 비장에서는 hemosiderin과 white pulp의 위축 소견이 관찰됨(100배).Figure 6 shows the results of histopathological examination after autopsy of two animals that died after challenge vaccination. (A) Pulmonary hemorrhage observed (100 times), (B) Bronchiopneumonia observed (400 times), (C) Perivascular inflammatory infiltration observed (100 times), (D) Hemosiderin and Atrophy of the white pulp was observed (100 times).
도 7은 공격접종 후 폐사한 2마리의 부검 후 간과 폐 조직병리학적 검사 결과를 보여준다. (A) 간세포의 응고 괴사 소견 (400배), (B) 기관지성 폐렴 소견 (100배).Figure 7 shows the results of liver and lung histopathological examination after autopsy of two animals that died after challenge vaccination. (A) Coagulative necrosis of hepatocytes (400 times), (B) Bronchial pneumonia (100 times).
도 8은 야외임상효능 시험에 참여한 반려견들을 보여준다. 국내에서 흔하게 볼 수 있는 대표적인 품종들이었고 만성적인 기침(Coughing)과 콧물(Nasal discharge)을 주증으로 내원하였다.Figure 8 shows dogs that participated in the outdoor clinical efficacy test. These were representative breeds commonly seen in Korea, and the main symptoms were chronic coughing and nasal discharge.
도 9는 흉부방사선 검사 영상 결과를 보여준다. 모든 환견들은 전반적인 기관지패턴(diffuse bronchial pattern; 빨간색 동그라미)과 간질패턴(interstitial pattern; 파란색 동그라미) 양상을 보였다. 특히, (C) 환견은 간질패턴이 더 우세하고 나타나고 (D) 환견은 기관지패턴과 간질패턴(초록색 동그라미)이 두드러지게 나타난다.Figure 9 shows the chest radiography image results. All patients showed a diffuse bronchial pattern (red circle) and an interstitial pattern (blue circle). In particular, in (C) the affected dog, the epileptic pattern appears more dominant, and in (D) the affected dog, the bronchial pattern and epileptic pattern (green circles) are prominent.
도 10은 시험약물 투여군의 환견들의 흉부방사선 영상 결과를 보여준다. 대조약물 투여군의 치료전(A)과 치료후(B) 흉부방사선 사진과 툴라스로마이신 투여군의 치료전(C)과 치료후(D) 흉부방사선 사진이다. Figure 10 shows the chest radiography results of dogs in the test drug administration group. These are the chest radiographs before (A) and after (B) treatment of the control drug administration group, and the chest radiographs before (C) and after treatment (D) of the tulathromycin administration group.
도 11은 대조약물 투여군의 투여 전후 흉부방사선 결과를 보여준다. A는 3번 환견으로 대조약물 투여전 폐전엽과 후엽에 간질패턴과 기관지패턴이 섞인 형태의 양상을 보였으며 약물 투약 후(B)에 임상증상은 어느 정도 개선되었으며 흉부방사선 소견도 일부 개선되었다. C는 6번 환견으로 대조약물 투여전 폐전엽에 특히 간질패턴이 확연히 나타났으나 대조약물 투약 후(D)에 임상증상과 함께 흉부방사선 소견도 개선되는 양상을 보였다.Figure 11 shows the chest radiograph results before and after administration of the control drug administration group. Patient A was patient number 3. Before administration of the control drug, the anterior and posterior lobes of the lung showed a mixture of interstitial and bronchial patterns. After administration of the drug (B), clinical symptoms improved to some extent, and chest radiograph findings also improved to some extent. Patient C was patient number 6. Before administration of the control drug, the interstitial pattern was particularly evident in the anterior lung lobe, but after administration of the control drug (D), clinical symptoms and chest radiographs showed improvement.
도 12는 시험약물 투여군의 투여 전후 흉부방사선 결과를 보여준다. A는 시험약물 투약 전 1번 환견으로 폐전엽과 후엽에 기관지 패턴의 양상을 보이고 있고 시험약물 투약 후(B)에는 기관지 패턴이 상당히 개선된 것을 확인할 수 있다. C는 시험약물 투약 전 4번 환견으로 폐전엽과 후엽에 심한 기관지 패턴과 간질 패턴이 관찰되고 있으며 시험약물 투약 후(D)에는 흉부방사선 상 뚜렷한 개선이 있음을 확인하였다.Figure 12 shows the chest radiograph results before and after administration of the test drug administration group. Patient A is patient number 1 before administration of the test drug, and shows a bronchial pattern in the anterior and posterior lobes of the lung. After administration of the test drug (B), it can be seen that the bronchial pattern has significantly improved. Case C was patient number 4 before administration of the test drug, and severe bronchial and interstitial patterns were observed in the anterior and posterior lobes of the lung. After administration of the test drug (D), it was confirmed that there was a clear improvement in the chest radiograph.
이하, 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the examples are only for illustrating the present invention in more detail, and it is understood by those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. It will be self-evident.
실시예 1. 제제Example 1. Formulation
본 발명자들은 마크로라이드 계열 항생제(Macrolide Antibiotics)인 툴라스로마이신을 포함하는 제제를 1mL 당 하기 표 1과 같은 조성으로 제조하고, 이후 실험에 사용하였다.The present inventors prepared a formulation containing tulasromycin, a macrolide antibiotic, with the composition shown in Table 1 per 1 mL, and used it in subsequent experiments.
[표 1][Table 1]
Figure PCTKR2023003904-appb-img-000001
Figure PCTKR2023003904-appb-img-000001
상기 표 1의 성분은 본제 1ml 중 포함되는 양을 의미한다.The ingredients in Table 1 refer to the amounts contained in 1 ml of this agent.
실시예 2. 안전성 확인Example 2. Safety confirmation
본 발명자들은 툴라스로마이신(tulathromycin)의 안전성을 확인하기 위하여, 표 2와 같이, 건강한 2-3월령의 개(체중 5-6kg 비글견)에게 체중 1kg당 상기 실시예 1의 툴라스로마이신을 포함하는 제제 0.1ml(툴라스로마이신으로서 2.5mg/kg bw/day) 또는 0.3ml을 1회 피하 주사한 후 상태를 관찰하여 통계처리하였다.In order to confirm the safety of tulathromycin, the present inventors administered the tulasromycin of Example 1 per 1 kg of body weight to a healthy 2-3 month old dog (Beagle dog weighing 5-6 kg), as shown in Table 2. After subcutaneously injecting 0.1ml (2.5mg/kg bw/day as tulathromycin) or 0.3ml once, the condition was observed and statistically processed.
상기 통계처리는 SPSS 프로그램을 이용하여, 두 군간 비교 시 student t-test를, 세 군 비교 시 One-way ANOVA (one-way analysis of variance) 분석을 실시하고, Tukey 분석에 의해 사후검정을 실시한다 (post hoc Tukey's multiple-comparison tests).The above statistical processing uses the SPSS program, and when comparing two groups, student t-test is performed, when comparing three groups, one-way ANOVA (one-way analysis of variance) analysis is performed, and a post-hoc test is performed by Tukey analysis. (post hoc Tukey's multiple-comparison tests).
[표 2][Table 2]
Figure PCTKR2023003904-appb-img-000002
Figure PCTKR2023003904-appb-img-000002
그 결과, 하기 표 3 내지 8에 각각 나타낸 바와 같이, 투여전 및 투여후 14일에 체중. 사료섭취량, 음수량, 임상증상, 혈액학적 검사 및 요검사를 측정하고 비교했을 때, 임상권장 용량 및 3배 용량을 주사한 경우 모두 특이한 임상증상, 간독성, 신장독성, 폐사 및 유의한 변화(감소)가 관찰되지 않았다.As a result, as shown in Tables 3 to 8 below, body weight before and 14 days after administration. When measuring and comparing feed intake, water volume, clinical symptoms, hematological tests, and urinalysis, when the clinically recommended dose and 3 times the dose were injected, there were unusual clinical symptoms, hepatotoxicity, nephrotoxicity, death, and significant changes (reduction). was not observed.
이는, 본 발명의 툴라스로마이신은 고용량으로 처리하더라도 개체의 장기 기능에 부작용을 주지 않으며, 전반적인 건강에 유해한 영향을 미치지 않는 안전한 약물임을 보여준다.This shows that the tulathromycin of the present invention is a safe drug that does not cause side effects on the organ functions of an individual even when treated in high doses and does not have a harmful effect on overall health.
[표 3][Table 3]
Figure PCTKR2023003904-appb-img-000003
Figure PCTKR2023003904-appb-img-000003
[표 4][Table 4]
Figure PCTKR2023003904-appb-img-000004
Figure PCTKR2023003904-appb-img-000004
[표 5][Table 5]
Figure PCTKR2023003904-appb-img-000005
Figure PCTKR2023003904-appb-img-000005
[표 6][Table 6]
Figure PCTKR2023003904-appb-img-000006
Figure PCTKR2023003904-appb-img-000006
[표 7][Table 7]
Figure PCTKR2023003904-appb-img-000007
Figure PCTKR2023003904-appb-img-000007
[표 8][Table 8]
Figure PCTKR2023003904-appb-img-000008
Figure PCTKR2023003904-appb-img-000008
실시예 3. 공격접종 및 자연발생 시 임상 효능 확인Example 3. Confirmation of clinical efficacy during challenge vaccination and natural occurrence
본 발명자들은 본 발명의 툴라스로마이신(tulathromycin)을 유효성분으로 포함하는 주사제의 실제 개 호흡기 질병 원인체인 보르데텔라 브론키셉티카(Bordetella bronchiseptica)에 대한 치료 효능을 확인하기 위하여, 하기 표 9에 나타낸 바와 같이, 실험을 실시한 후 관찰하였다.In order to confirm the therapeutic efficacy of the injection containing tulathromycin as an active ingredient of the present invention against Bordetella bronchiseptica , the actual cause of respiratory disease in dogs, the present inventors used the results shown in Table 9 below. As shown, the experiment was conducted and then observed.
[표 9][Table 9]
Figure PCTKR2023003904-appb-img-000009
Figure PCTKR2023003904-appb-img-000009
3-1. In vitro MIC 시험3-1. In vitro MIC test
본 발명자들은 본 발명의 툴라스로마이신의 최소억제농도(MIC) 및 최소살균농도(MBC)를 확인하기 위하여, 시험 균주로 야외분리균주 Bordetella bronchiseptica B1 (20년 서울 지역 분리), 야외분리균주 Bordetella bronchiseptica B2 (20년 서울 지역 분리), 야외분리균주 Bordetella bronchiseptica B3 (20년 서울 지역 분리), 야외분리균주 Bordetella bronchiseptica B4 (20년 서울 지역 분리), 야외분리균주 Bordetella bronchiseptica C10-2 (19년 강원 지역 분리), 야외분리균주 Bordetella bronchiseptica E4-1 (19년 경상 지역 분리), 야외분리균주 Bordetella bronchiseptica S24-1 (19년 전북 지역 분리), 표준균주 Escherichia coli ATCC 25922 및 표준균주 Staphylococcus aureus ATCC 29213을 이용하였다.In order to confirm the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the tulasromycin of the present invention, the present inventors used field isolate Bordetella bronchiseptica B1 (isolated in Seoul area for 20 years) and field isolate Bordetella bronchiseptica as test strains. B2 (isolated in Seoul area for 20 years), outdoor isolate Bordetella bronchiseptica B3 (isolated in Seoul area for 20 years), outdoor isolate Bordetella bronchiseptica B4 (isolated in Seoul area for 20 years), outdoor isolate Bordetella bronchiseptica C10-2 (isolated in Gangwon area for 19 years) isolation), field isolate Bordetella bronchiseptica E4-1 (isolated in Gyeongsang region in 2019), field isolate Bordetella bronchiseptica S24-1 (isolated in Jeonbuk region in 2019), standard strain Escherichia coli ATCC 25922, and standard strain Staphylococcus aureus ATCC 29213. did.
최소억제농도 (MIC, minimum inhibition concentration)는 세균의 증식이 완전히 억제되는 항생제의 최저농도로서, 균이 성장하지 않은 가장 높은 농도에 해당하며, 최소살균농도 (MBC, minimum bactericidal concentration)는 세균이 완전히 사멸한 항생제의 최저농도로서, MIC 농도를 포함하여 그보다 높은 농도의 균액을 Muller-Hinton agar에 접종하고 35℃에서 16~20시간 배양한 후 균이 성장하지 않은 가장 높은 농도에 해당한다.Minimum inhibition concentration (MIC) is the lowest concentration of an antibiotic at which bacterial growth is completely inhibited and corresponds to the highest concentration at which bacteria do not grow. Minimum bactericidal concentration (MBC) is the minimum bactericidal concentration (MBC) that completely inhibits bacterial growth. This is the lowest concentration of killed antibiotics, and corresponds to the highest concentration at which bacteria did not grow after inoculating a bacterial solution with a higher concentration, including the MIC concentration, onto Muller-Hinton agar and culturing it at 35°C for 16 to 20 hours.
실험 방법은, 간략하게는 다음과 같다: The experimental method is briefly as follows:
1) 접종액 준비1) Preparation of inoculum
9종의 시험 균주를 McFarland 0.5 (1 x 108 CFU/ml)의 표준 탁도로 맞춘 균액을 준비하였다. 모든 시험에 사용되는 배지는 Muller-Hinton broth을 이용하였다.Nine test strains were prepared in a bacterial solution adjusted to a standard turbidity of McFarland 0.5 (1 x 10 8 CFU/ml). The medium used in all tests was Muller-Hinton broth.
2) 액체배지에 균의 접종2) Inoculation of bacteria into liquid medium
추출액을 희석하여 96 well plate에 200 μl씩 분주하였다. 추출액의 시험 농도는 0, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256 μg/ml로 96 well plate에 넣고, 준비된 McFarland 0.5의 균 접종액 (1 x 108 CFU/ml)을 10배 희석하여 각 well에 5 μl씩 접종하였다. 접종균의 최종 농도는 약 5 x 105 CFU/ml 이다.The extract was diluted and dispensed at 200 μl each into a 96 well plate. The test concentration of the extract was 0, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256 μg/ml, placed in a 96 well plate, and inoculated with the prepared bacterial inoculum of McFarland 0.5 (1 x 10 8 CFU/ml) was diluted 10 times and 5 μl was inoculated into each well. The final concentration of the inoculum is approximately 5 x 10 5 CFU/ml.
3) 배양3) Cultivation
균이 접종된 96 well plate는 35℃에서 16~20시간 배양하였다. The 96 well plate inoculated with bacteria was cultured at 35°C for 16 to 20 hours.
그 결과, 하기 표 10 및 도 1a 내지 1d에 나타낸 바와 같이, 시험균주 9종에 대한 MIC는 1-16 μg/ml, MBC는 2-32 μg/ml로 관찰되었다. Staphylococcus aureus ATCC 29213의 MIC 8 μg/ml로 QC range 2-8 μg/ml에 포함되었다. As a result, as shown in Table 10 below and Figures 1a to 1d, the MIC for the 9 test strains was observed to be 1-16 μg/ml and the MBC was observed to be 2-32 μg/ml. Staphylococcus aureus ATCC 29213 had an MIC of 8 μg/ml, falling within the QC range of 2-8 μg/ml.
즉, CLSI VET01-A4 standard에 따르면 Bordetella bronchiseptica의 툴라스로마이신에 대한 내성은 MIC ≥ 64, 중간감수성 MIC = 32, 감수성 MIC ≤ 16이다. 이는 본 실시예에 사용된 모든 Bordetella bronchiseptica 야외분리주는 툴라스로마이신에 감수성을 나타낸다는 것을 보여준다.That is, according to the CLSI VET01-A4 standard, the resistance of Bordetella bronchiseptica to tulasromycin is MIC ≥ 64, intermediate susceptibility MIC = 32, and susceptibility MIC ≤ 16. This shows that all Bordetella bronchiseptica field isolates used in this example are susceptible to tulathromycin.
[표 10][Table 10]
Figure PCTKR2023003904-appb-img-000010
Figure PCTKR2023003904-appb-img-000010
3-2. 공격접종시 임상효능 시험3-2. Clinical efficacy test during challenge vaccination
본 발명자들은 개 호흡기 질병의 원인체인 Bordetella bronchiceptica 10 mL (4.3 x 1010 CFU/mL)을 2개월령 비글견(체중 5~6 kg) 10마리에 2일 간격으로 2회 기관내 공격접종한 후, 각각 대조약물(암피실린)과 시험약물(툴라스로마이신) 권장용량을 체중 kg당 용법에 맞게 피하주사하고(표 11) 14일간 임상증상과 혈액검사상의 변화를 관찰하였다. The present inventors administered 10 mL ( 4.3 The recommended doses of the control drug (ampicillin) and the test drug (tulathromycin) were injected subcutaneously according to the dosage per kg of body weight (Table 11), and changes in clinical symptoms and blood tests were observed for 14 days.
보다 상세하게는 다음과 같다:In more detail:
Bordetella bronchiceptica Bordetella bronchiceptica 공격접종Attack vaccination
대조약물 투여군(5마리)와 시험약물 투여군(5마리)은 모두 순화기간이 끝난 뒤 호흡마취를 하여 기관내시경(Bronchoscopy)을 실시하여 기관폐포세척(BAL)을 통해 샘플 채취와 비강채취(nasal swab)를 진행하였으며, 동시에 세균배양액을 공격접종하였다. 공격접종액은 10 mL이고 농도는 4.3 x 1010 CFU/mL으로 맞추어 접종에 사용하였다.After the acclimatization period, both the control drug administration group (5 animals) and the test drug administration group (5 animals) underwent respiratory anesthesia and underwent bronchoscopy to collect samples and nasal swab through bronchoalveolar lavage (BAL). ) was carried out, and at the same time, bacterial culture was inoculated. The challenge inoculum was 10 mL and the concentration was set to 4.3 x 10 10 CFU/mL and used for inoculation.
마취시 전처치(premedication)로 아세프로마진(acepromazien 0.015 mg/kg, IM), 부토파놀(butorphanol 0.2 mg/kg, IV), 케타민(ketamine 2 mg/kg, IV)를 사용하였으며, 도입(induction) 약물로는 프로포폴(propofol 2 mg/kg, IV)을 사용하였고 유지(maintenance) 약물로는 프로포폴(propofol) 희석액(생리식염수와 1:3 비율로 희석)을 0.2 mg/kg/min의 속도로 사용하였다. 마취 도입(induction) 전에는 최소한 10분 이상 산소를 충분히 공급한 뒤 기관내시경을 진행하였다. 스코프를 삽입하기 10분 전에 아미노필린(aminophyline 15 mg/kg, IV)를 투여하여 기관지를 충분히 확장시켰다.Acepromazien (acepromazien 0.015 mg/kg, IM), butorphanol (butorphanol 0.2 mg/kg, IV), and ketamine (ketamine 2 mg/kg, IV) were used as premedication during anesthesia. ) As a drug, propofol (2 mg/kg, IV) was used, and as a maintenance drug, propofol dilution (diluted in a 1:3 ratio with physiological saline) was administered at a rate of 0.2 mg/kg/min. used. Before anesthesia induction, tracheal endoscopy was performed after sufficient oxygen was supplied for at least 10 minutes. Aminophylline (15 mg/kg, IV) was administered 10 minutes before the scope was inserted to sufficiently dilate the bronchial tubes.
이러한 기관내시경을 통한 세균접종 시술은 2일에 거쳐 2회씩 반복하였으며 기관내시경 시술이 끝난 후 실험견들은 대략 20~30분 내에 회복하였다.This bacterial inoculation procedure through a tracheal endoscope was repeated twice over two days, and after the tracheal endoscopy procedure was completed, the experimental dogs recovered within approximately 20 to 30 minutes.
[표 11][Table 11]
Figure PCTKR2023003904-appb-img-000011
Figure PCTKR2023003904-appb-img-000011
일반상태Normal state
(1) 체중변화(1) Weight change
공격접종과 함께 대조약물과 시험약물을 투여하기 전, 투여한 후 1일, 3일, 7일, 14일에 각각 체중을 측정한 결과 1일까지는 약한 체중 감소가 관찰되었고 7일째에는 완만한 체중의 증가를 보였으며 14일까지는 일반적인 속도로 체중이 증가한 것을 확인하였다(표 12, 도 2).As a result of measuring body weight on the 1st, 3rd, 7th, and 14th days before and after administration of the control drug and test drug along with the challenge vaccination, a slight weight loss was observed up to day 1, and a moderate weight loss on day 7. showed an increase, and it was confirmed that body weight increased at a normal rate until day 14 (Table 12, Figure 2).
[표 12][Table 12]
Figure PCTKR2023003904-appb-img-000012
Figure PCTKR2023003904-appb-img-000012
(2) 사료 섭취량(2) Feed intake
공격접종과 함께 대조약물과 시험약물을 투여하기 전, 투여한 후 매일 1일 1회 사료 섭취량을 측정한 결과 1일째에는 약한 사료 섭취량 감소가 관찰되었고 7일째까지는 완만한 사료 섭취율 증가를 보였고 그 이후 14일까지는 일반적인 사료 섭취량을 보였다(표 13, 도 2). As a result of measuring feed intake once a day before and after administering the control and test drugs along with the challenge vaccination, a slight decrease in feed intake was observed on day 1, and a gradual increase in feed intake was observed until day 7, and thereafter. Normal feed intake was observed until day 14 (Table 13, Figure 2).
[표 13][Table 13]
Figure PCTKR2023003904-appb-img-000013
Figure PCTKR2023003904-appb-img-000013
(3) 음수량(3) Negative amount
공격접종과 함께 대조약물과 시험약물을 투여하기 전, 투여한 후 매일 1일 1회 음수량을 측정한 결과 1일째에는 약한 음수량 감소가 관찰되었고 7일째까지는 완만한 사료 섭취율 증가를 보였고 이후 14일까지는 일반적인 음수량의 증가를 보였다(표 14).As a result of measuring the amount of drinking water once a day before and after administering the control drug and test drug along with the challenge vaccination, a slight decrease in the amount of drinking water was observed on the 1st day, and a gradual increase in the feed intake rate was observed until the 7th day, and then until the 14th day. There was an increase in general drinking water volume (Table 14).
[표 14] [Table 14]
Figure PCTKR2023003904-appb-img-000014
Figure PCTKR2023003904-appb-img-000014
임상증상 clinical symptoms
공격접종과 함께 대조약물과 시험약물을 투여하기 전, 투여한 후 외관, 행동이상, 직장 체온, 호흡수, 호흡양상, 기침 횟수, 기침양상, 콧물 분비량, 콧물양상, 피부, 피모, 폐사 여부 등의 호흡기 질환 임상증상을 확인하기 위하여 시험기간 동안 매일 1회 이상 일정한 시간에 관찰하였다. 대조약물 투여군에서는 공격접종 후 각각 3일째와 4일째에 시험견의 폐사가 발생하였다. Appearance, behavioral abnormalities, rectal temperature, respiratory rate, breathing pattern, coughing frequency, coughing pattern, amount of nasal discharge, nasal discharge pattern, skin, coat, presence of death, etc. before and after administration of control drug and test drug along with challenge vaccination. In order to check clinical symptoms of respiratory disease, observations were made at a certain time at least once a day during the test period. In the control drug administration group, test dogs died on the 3rd and 4th days after challenge vaccination, respectively.
공격접종 후 2~3일째에 대조약물 투여군과 시험약물 투여군은 행동 둔화, 호흡수 증가, 기침 등과 같은 임상증상들이 관찰되었다. 공격접종 후 7~8일째에 시험약물 투여군의 임상증상 개선 정도가 현저히 나타났다(표 15, 도 3). On the 2nd to 3rd day after the challenge vaccination, clinical symptoms such as slowed behavior, increased respiratory rate, and cough were observed in the control drug administration group and the test drug administration group. On the 7th to 8th day after challenge vaccination, there was a significant improvement in clinical symptoms in the test drug administration group (Table 15, Figure 3).
[표 15] [Table 15]
Figure PCTKR2023003904-appb-img-000015
Figure PCTKR2023003904-appb-img-000015
혈액학적 검사hematological tests
세균 공격접종을 한 후 대조약물과 시험약물을 투여하기 전, 투여한 후 1일, 3일, 7일, 14일에 각각 일반혈액학(Complete Blood Count) 검사와 혈청화학적 검사 (Serum Chemistry)를 실시하여 세균 제거 효과와 부작용의 여부를 확인하였다. After bacterial attack vaccination, a complete blood count test and serum chemistry test are conducted before and on the 1st, 3rd, 7th, and 14th days after administration of the control drug and test drug, respectively. The effect of removing bacteria and the presence of side effects were confirmed.
혈중 백혈구(WBC) 수치는 시험약물 투여군에서 7일 이후 정상 범위로 내려간 것을 확인하였다. 혈청화학적 검사에서는 시험약물 투여군의 ALP와 ALT가 통계적으로 유의하게 감소한 것을 확인하였으며 간과 신장에 부작용은 없는 것으로 확인되었다(도 4, 표 16). It was confirmed that the blood white blood cell (WBC) count fell to the normal range after 7 days in the test drug administration group. In the serum chemical test, it was confirmed that ALP and ALT in the test drug administration group were statistically significantly reduced, and there were no side effects on the liver and kidneys (Figure 4, Table 16).
[표 16] [Table 16]
Figure PCTKR2023003904-appb-img-000016
Figure PCTKR2023003904-appb-img-000016
비강 내 균수 변화 Changes in bacterial count in the nasal cavity
B. bronchiceptica를 기관내 접종한 후 각 개체별로 비강채취(nasal swab)를 통해 비강 내 존재하는 총 균수를 조사하였다. B. bronchiceptica 균 접종 후 1일째에 대조약물 투여군과 시험약물 투여군에서 각각 4.6±0.92x104CFU/mL, 5.56±1.78x104CFU/mL이 검출되었다. 세균 접종 후 3일째에 각각 비강 내에 존재하는 세균수가 가장 많이 증가했으며 7일째에는 다소 감소하였으며 시험이 종료한 14일째에는 대조약물 투여군과 시험약물 투여군 모두에서 비강 내에서 세균이 검출되지 않았다(표 17). After intratracheal inoculation with B. bronchiceptica , the total number of bacteria present in the nasal cavity was examined through nasal swab for each individual. On day 1 after B. bronchiceptica inoculation, 4.6±0.92x10 4 CFU/mL and 5.56±1.78x10 4 CFU/mL were detected in the control drug administration group and test drug administration group, respectively. The number of bacteria present in the nasal cavity increased the most on the 3rd day after bacterial inoculation, decreased slightly on the 7th day, and on the 14th day after the test was completed, no bacteria were detected in the nasal cavity in both the control drug administration group and the test drug administration group (Table 17) ).
[표 17] [Table 17]
Figure PCTKR2023003904-appb-img-000017
Figure PCTKR2023003904-appb-img-000017
부검 소견Autopsy findings
임상효능시험 기간 중 대조약물 투여군에서 2마리가 폐사가 발생하여 즉시 부검을 실시하여 육안 병변을 확인하였다. 부검 결과 2마리 모두에서 흉수가 관찰되었으며 폐는 충혈이 되어 있었다. 기관(Trachea)과 기관지에는 포말성의 점액성 액체가 관찰되어 기관지폐렴 소견으로 확인되었다(도 5). During the clinical efficacy test period, two animals in the control drug administration group died, and an autopsy was immediately performed to confirm gross lesions. As a result of the autopsy, pleural effusion was observed in both animals and the lungs were congested. Foamy mucous fluid was observed in the trachea and bronchi, confirming the finding of bronchopneumonia (Figure 5).
조직병리학적 소견Histopathological findings
대조약물 투여군에서 폐사한 실험견 2마리를 부검한 후 병변이 관찰된 부위를 채취하여 10% 중성 포르말린에 고정한 후 조직 염색하여 관찰하였다. 조직검사 상에서는 폐렴 소견과 세균집락이 관찰되었다. 또한 간에서는 응고괴사 소견이 관찰되었으며 심장 및 신장과 같은 주요한 장기들은 이상 소견이 관찰되지 않았으나 비장은 위축되어 있었으며 조직병리학적 검사상에서 hemosiderin과 white pulp가 위축된 소견을 보였다(도 6 및 도 7).After autopsy of two experimental dogs that died in the control drug administration group, the area where the lesion was observed was collected, fixed in 10% neutral formalin, and tissue stained for observation. On biopsy, pneumonia and bacterial colonies were observed. In addition, coagulative necrosis was observed in the liver, and no abnormalities were observed in major organs such as the heart and kidneys, but the spleen was atrophied, and histopathological examination showed atrophy of hemosiderin and white pulp (Figures 6 and 7). .
3-3. 야외 임상(자연발생) 효능 시험3-3. Outdoor clinical (naturally occurring) efficacy test
본 발명자들은 개에서 자연적으로 발생하는 염증성 호흡기 질병에 대조약물(암피실린) 투여군과 시험약물(툴라스로마이신) 투여군에 체중 kg당 각각 대조약물과 시험약물 권장량을 용법에 맞게 피하주사하고 14일간 임상증상과 혈액검사상의 변화를 관찰하였다. The present inventors subcutaneously injected the recommended amounts of the control drug and test drug per kg of body weight into the control drug (ampicillin) and test drug (tulathromycin) groups for naturally occurring inflammatory respiratory diseases in dogs, and treated clinical symptoms for 14 days. and changes in blood tests were observed.
보다 상세하게는 다음과 같다:In more detail:
시험약물의 호흡기 질환에 대한 야외임상효능 평가를 위해 기침(Coughing), 호흡곤란, 콧물 등과 같은 호흡기 질병에 의한 임상증상을 가지고 내원하여 진단을 통해 호흡기 질병으로 판명된 총 24마리의 반려견들을 대상으로 임상시험을 실시하였다(표 18, 도 8).To evaluate the field clinical efficacy of the test drug against respiratory diseases, a total of 24 dogs that visited the hospital with clinical symptoms of respiratory diseases such as coughing, difficulty breathing, and runny nose and were diagnosed with respiratory diseases were tested. A clinical trial was conducted (Table 18, Figure 8).
[표 18] [Table 18]
Figure PCTKR2023003904-appb-img-000018
Figure PCTKR2023003904-appb-img-000018
임상증상 clinical symptoms
대조약물과 시험약물 투여 전, 투여 후 7, 14일에 임상증상 항목별 점수(score)를 부여하여 임상증상의 개선 정도를 평가하였다(표 19). 24마리의 모든 반려견 환축은 동물병원에 내원하여 검사를 진행하였다. 대조약물 투여군(표 20)과 시험약물 투여군(표 21)은 전반적으로 7일째 내원하여 진료를 했을 때 임상증상들이 많이 개선되었다.The degree of improvement in clinical symptoms was evaluated by assigning scores for each clinical symptom item before and 7 and 14 days after administration of the control and test drugs (Table 19). All 24 pet dogs visited the veterinary hospital and underwent examination. Overall, the clinical symptoms of the control drug administration group (Table 20) and the test drug administration group (Table 21) were significantly improved when they visited the hospital for treatment on the 7th day.
[표 19] [Table 19]
Figure PCTKR2023003904-appb-img-000019
Figure PCTKR2023003904-appb-img-000019
[표 20] [Table 20]
Figure PCTKR2023003904-appb-img-000020
Figure PCTKR2023003904-appb-img-000020
[표 21] [Table 21]
Figure PCTKR2023003904-appb-img-000021
Figure PCTKR2023003904-appb-img-000021
혈액학적 검사 hematological tests
모든 환견들은 다양한 정도의 백혈구증가증(Leukocytosis)을 보였으나 적혈구와 혈소판 수치는 정상적인 범위에 분포하였다. 대조약물과 시험약물은 7일 후 모두 백혈구 감소 효과를 나타냈으나 시험약물 투여군이 대조약물 투여군에 비해 빠르게 백혈구증가증이 개선되었다. 시험약물은 1회 피하주사 하는 반면에 대조약물은 매일 1회씩 피하주사 하였으므로 대조약물 투여군에서 혈중 CK값이 시험약물 투여군에 비해 높은 값을 유지하였다(표 22). All patients showed varying degrees of leukocytosis, but red blood cell and platelet counts were within the normal range. Both the control drug and the test drug showed a white blood cell reduction effect after 7 days, but the leukocytosis in the test drug administration group improved more quickly than the control drug administration group. The test drug was injected subcutaneously once, while the control drug was injected subcutaneously once daily, so the blood CK value in the control drug administration group was maintained at a higher value than the test drug administration group (Table 22).
시험약물 투여군에서 WBC 수치가 0일째와 비교했을 때 7일째와 14일째에 통계적으로 유의성 있게 낮아졌다 (p<0.05).In the test drug administration group, the WBC count was statistically significantly lower on days 7 and 14 compared to day 0 (p<0.05).
[표 22][Table 22]
Figure PCTKR2023003904-appb-img-000022
Figure PCTKR2023003904-appb-img-000022
흉부방사선 검사 chest radiography
흉부방사선 검사는 호흡기 질병의 진단에 가장 유용한 영상진단법으로 특히, 기관지 폐렴의 진단에 효과적이므로 환견들의 신체검사, 혈액학적 검사와 함께 실시하였으며 모든 환견들은 다양한 정도의 간질패턴(Interstitial pattern)과 기관지패턴(Bronchial pattern)의 폐야(Lungs field)를 보였다(도 9). Chest X-ray examination is the most useful imaging method for diagnosing respiratory diseases and is especially effective in diagnosing bronchopneumonia, so it was performed along with physical examination and hematological examination of the patients. All patients had various degrees of interstitial pattern and bronchial pattern. (Bronchial pattern) lungs field was seen (Figure 9).
간질패턴은 노령의 반려견에서 흔하게 발생하는 패턴이고 호흡기 질병의 정도가 심한 경우에도 나타날 수 있다. 기관지패턴의 경우는 호흡기 질병이 있는 경우 나타나는 대표적인 흉부방사선 상의 변화이다. The epileptic pattern is a common pattern in older dogs and can also occur in cases of severe respiratory disease. The bronchial pattern is a typical chest radiograph change that occurs when there is a respiratory disease.
약물 투여 후 도 10 내지 12의 결과, 툴라스로마이신(Tulathromycin) 시험약물 투여군에서 환견들의 흉부방사선 영상도 뚜렷한 개선을 보여 치료 효과를 확인하였다.As shown in Figures 10 to 12 after drug administration, the chest radiographs of patients in the Tulatromycin test drug administration group also showed a clear improvement, confirming the treatment effect.
종합하면, 본 발명에서는 툴라스로마이신(Tulathromycin)을 유효성분으로 하는 주사제의 개에서 호흡기 질병에 대한 치료효과를 확인하고자 개 전염성 기관지 폐렴의 원인체로 알려져 있는 Bordetella bronchiseptica에 대하여 항균효과를 확인했을 뿐만 아니라, 실험견에서 임상권장용량 및 3배용량을 투여하여 안전성을 확인하였다. In summary, the present invention not only confirmed the antibacterial effect against Bordetella bronchiseptica, which is known to be the cause of infectious bronchopneumonia in dogs, in order to confirm the therapeutic effect of an injection containing tulathromycin as an active ingredient on respiratory diseases in dogs. , safety was confirmed by administering the clinically recommended dose and three times the dose to experimental dogs.
또한, 실험견에서 Bordetella bronchiseptica를 공격접종 후 툴라스로마이신 주사제를 투여하여 균 제거 효과 및 임상효능을 평가하고, 호흡기 질환으로 내원한 자연발생환자를 대상으로 시험약물을 투여하여 치료 효과를 확인하였다.In addition, after inoculating experimental dogs with Bordetella bronchiseptica , tulathromycin injection was administered to evaluate the bacterial removal effect and clinical efficacy, and the treatment effect was confirmed by administering the test drug to naturally occurring patients who visited the hospital with respiratory disease.
B. bronchiseptica 시험균주에 대한 툴라스로마이신의 MIC 및 MBC 값을 확인한 결과, 임상적 균억제 및 살균 효과가 확인되었다. As a result of checking the MIC and MBC values of tulasromycin for the B. bronchiseptica test strain, clinical bacterial inhibition and bactericidal effects were confirmed.
툴라스로마이신의 반려견에서 안전성을 확인한 결과 임상적 용량의 3배량을 주사한 경우에도 특이한 임상증상(주사 부위 부작용 포함), 간독성, 신장독성 및 폐사 등이 관찰되지 않아 안전한 약물로 확인되었다. As a result of confirming the safety of tulasromycin in dogs, no unusual clinical symptoms (including side effects at the injection site), hepatotoxicity, nephrotoxicity, or death were observed even when three times the clinical dose was injected, confirming that it is a safe drug.
실험견에 기관지 내시경을 통해 Bordetella bronchiseptica 를 접종하고 시험약물인 툴라스로마이신을 주사한 결과, 툴라스로마이신이 접종균을 제거함으로써 임상증상 발현의 억제 및 개선되는 효과를 확인하였다.Experimental dogs were inoculated with Bordetella bronchiseptica through a bronchoscope and injected with the test drug, tulasromycin. As a result, it was confirmed that tulasromycin was effective in suppressing and improving clinical symptoms by eliminating the inoculum.
자연 발생으로 내원한 반려견의 호흡기질병에서 적절한 검사를 위해 진단을 한 후 툴라스로마이신 주사제를 권장량 투약하였을 때 7일 사이에 임상증상의 개선효과가 나타나는 것을 확인하였다.After diagnosing a naturally occurring respiratory disease in a pet dog for an appropriate examination, it was confirmed that when the recommended dose of tulasromycin injection was administered, an improvement in clinical symptoms occurred within 7 days.
결론적으로, 본 발명의 툴라스로마이신(Tulathromycin)은 세균성 호흡기 감염증에 이환된 반려견의 치료에 유효하고 안전한 약물로서, 인 비트로 상에서 MIC 및 MBC 실험을 실시했을 때, 본 발명의 툴라스로마이신(tulathromycin)의 항균 효과가 뛰어남을 확인할 수 있었고, 실험견에 보르데텔라 브론키셉티카(Bordetella bronchiseptica) 야외균주를 공격접종한 후, 본 발명의 툴라스로마이신(tulathromycin)을 투여했을 때, 임상증상의 발현을 억제시킬 뿐만 아니라, 개선시키는 것을 확인하였다.In conclusion, Tulathromycin of the present invention is an effective and safe drug for the treatment of dogs suffering from bacterial respiratory infections. When MIC and MBC experiments were performed in vitro, Tulathromycin of the present invention was found to be effective in treating dogs suffering from bacterial respiratory infections. It was confirmed that the antibacterial effect was excellent, and when experimental dogs were inoculated with field strains of Bordetella bronchiseptica and then administered tulathromycin of the present invention, clinical symptoms were observed. It was confirmed that it not only suppressed, but also improved.
또한, 자연발생한 반려견에서 호흡기 질병으로 진단된 경우, 툴라스로마이신(tulathromycin) 권장량을 투여하였을 때에도 임상증상이 개선되는 것을 확인하였다.In addition, when a respiratory disease was diagnosed in a naturally occurring pet dog, clinical symptoms were confirmed to improve even when the recommended dose of tulathromycin was administered.
따라서, 1일 체중 1kg 당 2.5 mg의 투여량의 툴라스로마이신 피하 치료는 보르데텔라 브론키셉티카 (Bordetella bronchiseptica) 감염에 의한 호흡기 질환에 효과적인 치료제임을 입증한다.Therefore, subcutaneous treatment with tulasromycin at a dose of 2.5 mg per kg of body weight per day proves to be an effective treatment for respiratory diseases caused by Bordetella bronchiseptica infection.
이상으로, 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.As above, specific parts of the present invention have been described in detail, and those skilled in the art will understand that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. It will be obvious. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (14)

  1. 마크로라이드 계열 항생제(Macrolide Antibiotics)를 유효성분으로 포함하는, 개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating respiratory diseases in canine animals, comprising macrolide antibiotics as an active ingredient.
  2. 제1항에 있어서,According to paragraph 1,
    상기 마크로라이드 계열 항생제는 툴라스로마이신(tulathromycin), 에리트로마이신, 클라리트로마이신, 아지트로마이신, 타이로신, 틸미코신, 조사마이신, 키타사마이신 및 스피라마이신으로 이루어진 군으로부터 선택된 1 종 이상인 것을 특징으로 하는, The macrolide antibiotic is characterized in that it is at least one selected from the group consisting of tulathromycin, erythromycin, clarithromycin, azithromycin, tyrosin, tilmicosin, josamycin, kitasamycin, and spiramycin. doing,
    개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물.Pharmaceutical composition for preventing or treating respiratory diseases in canines.
  3. 제1항에 있어서,According to paragraph 1,
    상기 호흡기 질환은 보르데텔라 브론키셉티카(Bordetella bronchiseptica), 액티노바실러스 플루로뉴모니애(Actinobacillus pleuropneumoniae), 파스튜렐라 멀토시다(Pasteurella multocida), 헤모필러스 파라수이스(Haemophilus parasuis) 및 마이코플라즈마 하이오뉴모니애(Mycoplasma hyopneumoniae)로 이루어진 군으로부터 선택된 병원균의 감염으로 유발된 호흡기 질환인 것을 특징으로 하는,The respiratory diseases include Bordetella bronchiseptica , Actinobacillus pleuropneumoniae , Pasteurella multocida , Haemophilus parasuis , and Characterized in that it is a respiratory disease caused by infection with a pathogen selected from the group consisting of Mycoplasma hyopneumoniae ,
    개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물.Pharmaceutical composition for preventing or treating respiratory diseases in canines.
  4. 제1항에 있어서,According to paragraph 1,
    상기 호흡기 질환은 개 기관지염(kennel cough), 기관지 폐렴, 호흡기 염증성 폐 질환, 만성 폐쇄성 폐 질환, 부비강염, 알레르기성 비염, 하기도 감염증, 급만성기관지염, 폐기종, 폐렴, 기관지 천식, 기관지 확장증, 폐기종, 폐결핵 후유증, 급성 호흡 궁박증후군 및 폐섬유증으로 이루어진 군으로부터 선택되는 1종 이상인 것을 특징으로 하는,The above respiratory diseases include kennel cough, bronchopneumonia, respiratory inflammatory lung disease, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, lower respiratory tract infection, acute and chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, emphysema, and pulmonary tuberculosis. Characterized by one or more types selected from the group consisting of sequelae, acute respiratory distress syndrome and pulmonary fibrosis,
    개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물.Pharmaceutical composition for preventing or treating respiratory diseases in canines.
  5. 제1항에 있어서,According to paragraph 1,
    상기 조성물은 비경구 또는 경구 투여용인 것을 특징으로 하는,The composition is for parenteral or oral administration,
    개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물.Pharmaceutical composition for preventing or treating respiratory diseases in canines.
  6. 제5항에 있어서,According to clause 5,
    상기 비경구 투여는 피하 투여, 복강내 투여, 정맥내 투여, 근육내 투여, 내피 투여, 비강내 투여, 폐내투여, 직장내 투여, 경막내 투여로 이루어진 군으로부터 선택된 1 종 이상인 것을 특징으로 하는, The parenteral administration is characterized in that it is one or more selected from the group consisting of subcutaneous administration, intraperitoneal administration, intravenous administration, intramuscular administration, endothelial administration, intranasal administration, intrapulmonary administration, intrarectal administration, and intrathecal administration.
    개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물.Pharmaceutical composition for preventing or treating respiratory diseases in canines.
  7. 제6항에 있어서,According to clause 6,
    상기 투여는 0.1mg/kg 내지 10mg/kg으로 투여되는 것을 특징으로 하는, The administration is characterized in that it is administered at 0.1 mg/kg to 10 mg/kg,
    개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물.Pharmaceutical composition for preventing or treating respiratory diseases in canines.
  8. 제1항에 있어서,According to paragraph 1,
    상기 조성물은 모노티오글리세린 (Monothioglycerin), 시트르산 (Anhydrous Citric Acid), 염산 (Hydrochloric Acid), 프로필렌글리콜 (Propylene Glycol), 수산화나트륨 (Sodium Hydroxide) 및 주사용수 (Water for injection)로 이루어진 군으로부터 선택된 1종 이상을 추가적으로 포함하는 것을 특징으로 하는, The composition is one selected from the group consisting of Monothioglycerin, Anhydrous Citric Acid, Hydrochloric Acid, Propylene Glycol, Sodium Hydroxide, and Water for injection. Characterized in that it additionally includes more than one species,
    개과 동물의 호흡기 질환 예방 또는 치료용 약학적 조성물.Pharmaceutical composition for preventing or treating respiratory diseases in canines.
  9. 마크로라이드 계열 항생제(Macrolide Antibiotics), 모노티오글리세린 (Monothioglycerin, KVP), 시트르산 (Anhydrous Citric Acid, KVP), 염산 (Hydrochloric Acid, KVP), 프로필렌글리콜 (Propylene Glycol, KVP), 수산화나트륨 (Sodium Hydroxide, KVP) 및 주사용수 (Water for injection, KP)을 포함하는, 개과 동물의 호흡기 질환 예방 또는 치료용 주사제.Macrolide Antibiotics, Monothioglycerin (KVP), Anhydrous Citric Acid (KVP), Hydrochloric Acid (KVP), Propylene Glycol (KVP), Sodium Hydroxide, Injections for preventing or treating respiratory diseases in canine animals, including KVP) and water for injection (KP).
  10. 제9항에 있어서,According to clause 9,
    상기 마크로라이드 계열 항생제는 툴라스로마이신(tulathromycin)인 것을 특징으로 하는,The macrolide antibiotic is tulathromycin,
    개과 동물의 호흡기 질환 예방 또는 치료용 주사제.Injectable medication for preventing or treating respiratory diseases in canine animals.
  11. 마크로라이드 계열 항생제(Macrolide Antibiotics)를 유효성분으로 포함하는, 개과 동물의 호흡기 질환 예방 또는 개선용 사료 조성물.A feed composition for preventing or improving respiratory disease in canine animals, comprising macrolide antibiotics as an active ingredient.
  12. 제11항에 있어서,According to clause 11,
    상기 마크로라이드 계열 항생제는 툴라스로마이신(tulathromycin)인 것을 특징으로 하는, The macrolide antibiotic is tulathromycin,
    개과 동물의 호흡기 질환 예방 또는 개선용 사료 조성물.A feed composition for preventing or improving respiratory diseases in canine animals.
  13. 마크로라이드 계열 항생제(Macrolide Antibiotics)를 포함하는 조성물을 개과 동물에게 투여하는 단계를 포함하는, 개과 동물의 호흡기 질환 치료 방법.A method of treating respiratory disease in a canine animal, comprising administering a composition containing macrolide antibiotics to the canine animal.
  14. 제13항에 있어서,According to clause 13,
    상기 마크로라이드 계열 항생제는 툴라스로마이신(tulathromycin)인 것을 특징으로 하는, The macrolide antibiotic is tulathromycin,
    개과 동물의 호흡기 질환 치료 방법.Methods for treating respiratory diseases in canines.
PCT/KR2023/003904 2022-05-03 2023-03-23 Composition including macrolide antibiotic as active ingredient for prevention or treatment of respiratory diseases in canines WO2023214687A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2022-0054660 2022-05-03
KR1020220054660A KR20230155155A (en) 2022-05-03 2022-05-03 Composition for Preventing or Treating Canine Respiratory Diseases Comprising Macrolide Antibiotics

Publications (1)

Publication Number Publication Date
WO2023214687A1 true WO2023214687A1 (en) 2023-11-09

Family

ID=88646593

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2023/003904 WO2023214687A1 (en) 2022-05-03 2023-03-23 Composition including macrolide antibiotic as active ingredient for prevention or treatment of respiratory diseases in canines

Country Status (2)

Country Link
KR (1) KR20230155155A (en)
WO (1) WO2023214687A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000052444A (en) * 1999-01-29 2000-08-25 실버스타인 아써 에이. Azithromycin combination for emesis control in dogs
US20040023899A1 (en) * 2001-10-19 2004-02-05 Murthy Yerramilli V.S.N. Methods for the controlled delivery of pharmacologically active compounds
WO2015067959A1 (en) * 2013-11-08 2015-05-14 Norbrook Laboratories Limited Tulathromycin and nonsteroidal anti-inflammatory drug compositions
US20170304450A1 (en) * 2014-09-09 2017-10-26 Ceva Sante Animale Parenteral compositions and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000052444A (en) * 1999-01-29 2000-08-25 실버스타인 아써 에이. Azithromycin combination for emesis control in dogs
US20040023899A1 (en) * 2001-10-19 2004-02-05 Murthy Yerramilli V.S.N. Methods for the controlled delivery of pharmacologically active compounds
WO2015067959A1 (en) * 2013-11-08 2015-05-14 Norbrook Laboratories Limited Tulathromycin and nonsteroidal anti-inflammatory drug compositions
US20170304450A1 (en) * 2014-09-09 2017-10-26 Ceva Sante Animale Parenteral compositions and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "CVMP assessment report for Increxxa (EMEA/V/C/005305/0000) INN: tulathromycin", EUROPEAN MEDICINES AGENCY. EMA/457503/2020, 16 July 2020 (2020-07-16), XP093106058, Retrieved from the Internet <URL:https://www.ema.europa.eu/en/documents/assessment-report/increxxa-epar-public-assessment-report_en.pdf> [retrieved on 20231127] *

Also Published As

Publication number Publication date
KR20230155155A (en) 2023-11-10

Similar Documents

Publication Publication Date Title
WO2010074388A1 (en) Novel bacteriophage and antibacterial compositions including the same
JP5872700B2 (en) Novel bacteriophage and antimicrobial composition containing the same
WO2015160089A1 (en) Novel bacteriophage, and composition containing same
WO2014133290A1 (en) Novel bacteriophage and antibacterial composition comprising the same
WO2014133289A1 (en) Novel bacteriophage and antibacterial composition comprising the same
WO2015156509A1 (en) Novel bacteriophage and composition containing same
WO2015160166A1 (en) Novel bacteriophage and composition comprising same
WO2014133301A1 (en) Novel bacteriophage and antibacterial composition comprising the same
WO2015160165A1 (en) Novel bacteriophage and composition comprising same
WO2011049327A2 (en) A skin external composition comprising a salt and sugar as active ingredients for preventing and treating vaginosis and the use thereof
WO2019231220A1 (en) Use of 2,3,5-substituted thiophene compound to prevent, ameliorate, or treat breast cancers
WO2022071718A1 (en) Novel bacteriophage opt-sc01 specific to staphylococcus bacteria and antibacterial composition comprising same
WO2019225953A2 (en) Composition comprising nut pine tree by-product extract and having effect of controlling helicobacter pyrori
WO2023214687A1 (en) Composition including macrolide antibiotic as active ingredient for prevention or treatment of respiratory diseases in canines
KR20210053637A (en) Probiotic yeast Kluyveromyces marxianus A5 from kefir and uses thereof
RU2197237C2 (en) Method for treating animal diseases induced by bacteria (variants) and method for manufacturing a medicinal product
WO2015160164A1 (en) Novel bacteriophage and composition comprising same
WO2022065914A1 (en) Anticoccidial composition comprising ginkgo leaves and use thereof
WO2015065059A1 (en) Composition for preventing or treating fish viral hemorrhagic septicemia comprising ecklonia cava extract
KR20090005287A (en) Composition for treatment and prophylaxis of diseases and infections of poultry
US11491135B2 (en) Medical use of tectorigenin in treatment of chicken necrotic enteritis
WO2021080388A1 (en) Composition for preventing or treating porcine epidemic diarrhea virus infection, comprising complex containing curcuminoid-based compound and licorice extract or fraction thereof
CN113476431A (en) Application of cyclotrione derivative in preparation of animal medicine
JPH06217708A (en) Remidy for gram-positive bacteria causing disease of aquatic organisms
KR102489659B1 (en) Composition of antimicrobial complex for animal comprising amphenicols and aminoglycosides

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23799570

Country of ref document: EP

Kind code of ref document: A1