Prophylactic / therapeutic agent for periodontal diseases

Abstract

The present invention addresses the problem of providing a prophylactic / therapeutic agent for periodontal diseases, which is highly safe, which can be taken continuously, and which has an excellent prophylactic / therapeutic effect on periodontal diseases.　A prophylactic / therapeutic agent for periodontal diseases, which solves the problem of the present invention, is characterized by containing a galactooligosaccharide as an active ingredient.

Description

Periodontal disease prevention and treatment

[0001] The present invention relates to an agent for preventing and treating periodontal disease.

[0002] In recent years, the number of pet companion animals, such as dogs and cats (18.5 million), has far exceeded the population of people under the age of 15 (approximately 16 million), and they have come to be regarded as members of the family in Japan, where the birthrate is declining and the population is aging. On the other hand, as the average lifespan has increased due to improvements in the environment in which they are kept and advances in medical technology, the risk of them contracting various diseases has also increased.

[0003] One such disease is periodontal disease, and it has been reported that approximately 80% of dogs over the age of two suffer from periodontal disease (Non-Patent Document 1). If proper care is not provided, symptoms of periodontal disease will progress with age, and in recent years, a link between periodontal disease and systemic diseases such as kidney disease and liver disease has been suggested. As companion animals live longer, preventing and improving periodontal disease is important not only for the health of the oral cavity but also for maintaining overall health.

[0004] Porphyromonas gulae (P. gulae) and Porphyromonas gingivalis (P. gingivalis) are known periodontal pathogens in companion animals. P. gulae is a Gram-negative anaerobic bacterium, and the formation of a biofilm by P. gulae contributes to the progression of periodontal disease symptoms. In dogs, in particular, the accumulation of dental calculus maintains an anaerobic subgingival environment, facilitating the formation of periodontal pockets, which subsequently leads to the destruction of periodontal tissues and even tooth mobility and loss. It has also been reported that FimA, the main component protein of the fimbriae involved in the attachment and colonization of P. gulae in the oral cavity, is classified into three genetic types in both dogs and cats, and the detected types are associated with the severity of periodontal disease and show high homology with each other (Non-Patent Document 2). It has also been suggested that P. gulae can be transmitted to humans via companion animals. These bacteria are also known to possess N-benzoyl-DL-arginyl peptidase activity. Other bacteria having this activity include Tannerella forsythia and Treponema denticola.

[0005] The standard treatment for periodontal disease in dogs is plaque removal under general anesthesia, while preventative measures include daily tooth brushing and periodic plaque removal under anesthesia. However, daily tooth brushing places a significant burden on owners, and plaque removal under general anesthesia involves anesthetic risks and is expensive. In response, various dental care products have been developed to make oral care easier. For example, Patent Document 1 discloses a dental gum based on the growth inhibitory effect of probiotic bacteria such as bifidobacteria on pathogenic bacteria such as Streptococcus mutans.

[0006] Registered Utility Model Publication No. 3216201

[0007] Niemiec.B., Gawor.J., Nemec.A., et al.: World Small Animal Veterinary Association Global Dental Guidelines. J. Small Anim.Pract.,2020.61(7)Naoki Iwashita, Ryota Nomura, et al.: Identification and molecular characterization of Porphyromonas gulae fimA types among cat isolates, Veterinary Microbiology, Volume 229, February 2019, Pages 100-109

[0008] An object of the present invention is to provide a preventive and therapeutic agent for periodontal disease that is highly safe, can be taken continuously, and has excellent preventive and therapeutic effects against periodontal disease.

[0009] As a result of extensive research to solve the above problems, the inventors discovered that ingesting galactooligosaccharides can suppress the growth or activity of periodontal disease bacteria, thereby providing excellent preventive and therapeutic effects against periodontal disease, and thus completed the present invention.

[0010] The present invention relates to a preventive and therapeutic agent for periodontal disease caused by bacteria having N-benzoyl-DL-arginyl peptidase activity, which contains galactooligosaccharide as an active ingredient.

[0011] The present invention also relates to a preventive and / or therapeutic agent for periodontal disease or a periodontal disease bacteria inhibitor for companion animals, which contains galactooligosaccharide as an active ingredient.

[0012] The present invention also provides a method for preventing and treating periodontal disease in companion animals, which comprises administering galactooligosaccharides to the companion animals.

[0013] The preventive and therapeutic agent for periodontal disease of the present invention is highly safe and can be taken on a daily basis, and by suppressing the growth or activity of periodontal disease bacteria, it can prevent and treat periodontal disease simply and effectively.

[0014] N-benzoyl-DL-arginyl peptidase activity (periodontal bacteria level) of dog plaque samples before and 8 weeks after galactooligosaccharide intake in Example 1 (mean ± standard deviation, n = 26, *: p < 0.05)

[0015] The preventive and therapeutic agent for periodontal disease of the present invention contains galactooligosaccharide as an active ingredient. Galactooligosaccharide is a general term for oligosaccharides containing at least one galactose residue in the molecule, and examples include sugars in which 2 to 9, preferably 3 to 4, monosaccharides are linked together. Galactooligosaccharides include those in which galactose is linked via β1-2, β1-3, β1-4, or β1-6 bonds, with β1-4 and β1-6 bonds being particularly preferred. More preferred galactooligosaccharides include β-1,4 galactosyllactose (Galβ1-4Galβ1-4Glc), β-1,6 galactosyllactose (Galβ1-6Galβ1-4Glc), and β-1,3 galactosyllactose (Galβ1-3Galβ1-4Glc). From the viewpoint of the effectiveness in preventing and treating periodontal disease, galactooligosaccharides containing β-1,4 galactosyllactose as the main component are more preferred, and for example, Oligomate 55N (manufactured by Yakult Pharmaceutical Co., Ltd., galactooligosaccharide content of 55% by mass and β-1,4 galactosyllactose content of 18.5% by mass in the solid content) can be used.

[0016] The preventive and therapeutic agent for periodontal disease of the present invention can achieve preventive and therapeutic effects against periodontal disease by suppressing the growth or activity of periodontal disease bacteria in the oral cavity. In the present invention, periodontal disease refers to an infection of periodontal tissues by periodontal disease bacteria, including gingivitis, periodontitis, and alveolar pyorrhea. Periodontal disease bacteria include bacteria having N-benzoyl-DL-arginyl peptidase activity, such as Porphyromonas gulae, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola. The preventive and therapeutic agent for periodontal disease of the present invention can be applied to humans and non-human mammals. Examples of non-human mammals include companion animals such as dogs, cats, rabbits, and hamsters, and livestock such as pigs and cows. Among these, companion animals are preferred, with dogs and cats being more preferred, and dogs being particularly preferred.

[0017] The form of the agent for preventing and treating periodontal disease of the present invention is not particularly limited, and may be in the form of a human medicine, food or drink, supplement, pet food, pet supplement, pet medicine, etc. As a pharmaceutical, galactooligosaccharide can be formulated as is or, if necessary, in combination with a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers include glucose, lactose, starch, mannitol, dextrin, fatty acid glycerides, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid esters, amino acids, gelatin, albumin, water, and physiological saline. Furthermore, conventional additives such as stabilizers, humectants, emulsifiers, binders, isotonicity agents, and excipients can be added as needed. The dosage form is not particularly limited, and examples include liquids, powders, granules, capsules, and tablets, and can be prepared according to conventional methods. The content of galactooligosaccharides in the preventive and therapeutic agent for periodontal disease of the present invention is not particularly limited, and is, for example, preferably 1 to 100% by mass, more preferably 5 to 70% by mass, and even more preferably 10 to 60% by mass.

[0018] The dose of the preventive and therapeutic agent for periodontal disease of the present invention is not particularly limited, but for example, the daily dose for a human adult is about 0.03 to 0.4 g per kg of body weight, preferably about 0.04 to 0.3 g, and particularly preferably about 0.1 to 0.25 g. Similar doses can also be used for mammals other than humans, such as companion animals.

[0019] When in the form of a food or drink, the galactooligosaccharide is used as is or, if necessary, mixed with known food additives and / or food materials and prepared according to a conventional method, and the form is not particularly limited, and examples thereof include starch-based foods such as bread, biscuits, pancakes, noodles, tablet candy, etc., confectioneries such as gum, candy, and Japanese sweets, meat foods such as ham and sausage, fish foods such as chikuwa and kamaboko, seafood foods, seasonings such as dressing, soy sauce, jam, furikake, etc., beverages such as tea, juice, soft drinks, and alcoholic beverages, etc. When in the form of a pet food or pet supplement, the galactooligosaccharide can be used as is or, if necessary, can be produced by appropriately mixing with raw materials used in known pet foods or pet supplements. Examples of such raw materials include meats such as beef, chicken, pork, etc., seafood such as bonito, mackerel, scallops, clams, etc., grains such as corn, barley, wheat, rye, etc., starches such as corn starch, wheat starch, rice starch, etc., dairy products such as butter and cheese, vitamins such as vitamins A, B1, B2, D, E, niacin, pantothenic acid, etc., minerals such as iron, calcium, sodium, potassium, etc., probiotics, etc. Furthermore, additives such as gelling agents, shape-retaining agents, pH adjusters, seasonings, preservatives, nutritional supplements, etc. may also be added.

[0020] Pet food or pet supplements can be prepared by mixing the above ingredients in a conventional manner and can be in any form, such as dry type, wet type, jerky, gum, granules, powder, drink, etc.

[0021] The present invention will be described in detail below by way of examples, but the present invention is not limited to these examples in any way.

[0022] Example 1: Dogs were administered galactooligosaccharides (GOS) to examine their effect on periodontal disease bacteria. A total of 26 dogs were studied, including 12 small dogs (<5 kg), 9 medium-sized dogs (5-10 kg), and 5 large dogs (>10 kg). The sex ratio was 9:17, with an average age of 8.88 years and an average weight of 7.76 kg. Oligomate 55N (galactooligosaccharide liquid sugar; Yakult Pharmaceutical Co., Ltd.) was administered at doses shown in Table 1 for 8 weeks. The prescribed amount of GOS was dispensed onto a spoon and administered orally or sprinkled on top of food. Statistical analysis was performed using the Wilcoxon signed-rank test. A p < 0.05 was considered significant.

[0023]

[0024] Plaque samples were collected from the gum-side surfaces of the maxillary canines or molars of dogs before and after 8 weeks of galactooligosaccharide ingestion. N-benzoyl-DL-arginyl peptidase activity, an enzyme specific to Porphyromonas gulae, was measured using an N-benzoyl-DL-arginyl peptidase activity measurement kit (ADplit®; Kyoritsu Seiyaku Co., Ltd.) according to the instructions in the package insert, and the periodontal disease bacteria level was evaluated on a 5-point scale. A higher value indicates higher enzyme activity. The results are shown in Figure 1. The score after 8 weeks of galactooligosaccharide ingestion (3.12) was significantly lower than the score before ingestion (3.58), confirming that galactooligosaccharide has an inhibitory effect on periodontal disease bacteria.

[0025] In addition, blood samples were taken before galactooligosaccharide intake, and 4 and 8 weeks after the end of intake, and blood biochemistry data such as total protein, albumin, total bilirubin, blood urea nitrogen, and creatinine were measured. No changes in the data that could be considered adverse events were observed, confirming that there were no safety issues.

[0026] The preventive and therapeutic agent for periodontal disease of the present invention is highly safe, can be taken continuously on a daily basis over a long period of time, and provides excellent preventive and therapeutic effects against periodontal disease in dogs, cats, etc., and can therefore be used as pet food for periodontal disease, pet supplements, etc.

Claims

1. A preventive and therapeutic agent for periodontal disease caused by bacteria having N-benzoyl-DL-arginyl peptidase activity, which contains galactooligosaccharide as an active ingredient.

2. The preventive and therapeutic agent for periodontal disease according to claim 1, wherein the bacterium having N-benzoyl-DL-arginyl peptidase activity is Porphyromanas gulae or Porphyromonas gingivalis.

3. A preventive and therapeutic agent for periodontal disease in companion animals, containing galactooligosaccharide as an active ingredient.

4. A periodontal disease bacteria inhibitor for companion animals, containing galactooligosaccharide as an active ingredient.

5. A method for preventing and treating periodontal disease in companion animals, which comprises administering galactooligosaccharides to the companion animals.

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