Pharmaceutical composition for preventing or treating obesity in canines comprising enavogliflozin

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating obesity in canines, comprising enavogliflozin as an active ingredient. The composition reduces the body condition score, weight, fat thickness, body fat percentage, chest circumference and waist circumference of obese dogs, and is also effective in improving serological indices, and is therefore useful for preventing or treating obesity in canines.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for preventing or treating obesity in canines, comprising enavogliflozin. [Background technology]

[0002] As the number of people raising pet dogs increases, the variety and abundance of food such as feed and treats has increased. However, this can lead to overeating and poor eating habits in pet dogs, which can lead to overweight and obesity in pet dogs.

[0003] Obesity in pet dogs induces comorbidities such as metabolic disorders, endocrine disorders, orthopedic disorders, cardiopulmonary diseases, urogenital disorders, and tumors (J Nutr. 2006 Jul;136(7 Suppl):1940S-1946S.), and also accelerates aging and shortens lifespan. For example, moderate obesity is known to shorten life expectancy by almost 2 years in Labrador retrievers (J Am Vet Med Assoc. 2002 May 1;220(9):1315-20.). Therefore, to live a long and healthy life with your pet dog, you must actively manage your pet dog's obesity.

[0004] Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antihyperglycemic drugs that suppress blood glucose elevation by decreasing glucose reabsorption in the proximal nephron and increasing glucose excretion through a mechanism independent of insulin. Summary of the Invention [Problem to be solved by the invention]

[0005] In order to develop a therapeutic agent for obesity in obese dogs, the present inventors administered enavogliflozin to obese dogs and confirmed that enavogliflozin is highly effective in reducing the body condition score, body weight, fat thickness, body fat percentage, chest circumference and waist circumference in obese dogs, thereby completing the present invention.

[0006] Therefore, an object of the present invention is to provide a pharmaceutical composition for preventing or treating obesity in canines, which contains enavogliflozin as an active ingredient. [Means for solving the problem]

[0007] Obesity in humans as well as in canines such as pet dogs induces comorbidities such as metabolic disorders, endocrine disorders, osteoarthritis, patellar luxation, intervertebral disk disease, cardiopulmonary disease and tumors.

[0008] The degree of obesity in pet dogs can be determined based on the body condition score (BCS), which can be divided into 5 or 9 stages. On the 5-stage scale, stage 3 and on the 9-stage scale, stages 4 to 5 indicate a normal body shape. On the 9-stage scale, stages 6 to 7 indicate mild obesity, stage 8 indicates moderate obesity, and stage 9 indicates severe obesity. Detailed evaluation criteria are presented in Table 1 and Figure 1 in the Examples.

[0009] As confirmed in the following Examples, enavogliflozin demonstrated the effect of reducing indicators such as body condition score in obese dogs using body condition score as a criterion.

[0010] Therefore, the present invention provides a pharmaceutical composition for preventing or treating obesity in canines, which contains enavogliflozin as an active ingredient.

[0011] A representative example of the canine family is a dog. In addition to dogs, other canine family animals include foxes, wolves, coyotes, jackals, dholes, and raccoon dogs.

[0012] The term "prevention" as used herein means any action that inhibits or delays the onset of obesity by administering a pharmaceutical composition according to the present invention.

[0013] The term "treatment" as used herein means any action that reverses or beneficially alters obesity by administration of the pharmaceutical composition according to the present invention. More specifically, the treatment can be judged by the presence or absence of improvement in an index selected from the group consisting of body condition score, body weight, fat thickness, body fat percentage, chest circumference, waist circumference and resting energy requirement.

[0014] In one embodiment of the present invention, the canine may have a body condition score of 6 or 7 or more. As described above, a body condition score of 6 or more on a 9-point scale corresponds to mild obesity.

[0015] The dose of enavogliflozin that can be used for the prevention or treatment of obesity in canines is not particularly limited, and can be appropriately adjusted depending on the severity of obesity, body weight, age, sex, and the presence or absence of other comorbid diseases of the canines to which the drug is to be administered.

[0016] In the following examples, the present inventors orally administered enavogliflozin at doses of 0.2, 0.5, or 1 mg / kg to obese dogs for 8 weeks, and confirmed that the indices selected from the group consisting of body condition score, body weight, fat thickness, body fat percentage, chest circumference, waist circumference, and resting energy requirement were reduced (FIG. 4, Tables 2 and 3).

[0017] In particular, when enavogliflozin was administered to healthy dogs at high, medium, and low doses for 13 or 39 weeks, respectively, body weight was reduced in a dose-dependent manner (Figures 2 and 3), whereas in obese dogs, enavogliflozin had the most excellent anti-obesity effect when administered at a dose of 0.2 mg / kg (Figure 4, Tables 2 to 5).

[0018] Therefore, without being limited thereto, in one specific example of the present invention, the enavogliflozin can be administered at a dose of 0.01 to 1 mg / kg once a day, preferably 0.05 to 0.7 mg / kg once a day, and more specifically, 0.1 to 0.4 mg / kg once a day.

[0019] When the enavogliflozin is administered at a dose of 0.01 to 1 mg / kg once a day, it can be administered at a dose of 0.2, 0.5 or 1.0 mg / kg once a day, when the enavogliflozin is administered at a dose of 0.05 to 0.7 mg / kg once a day, it can be administered at a dose of 0.2 or 0.5 mg / kg, and when the enavogliflozin is administered at a dose of 0.1 to 0.4 mg / kg once a day, it can be administered at a dose of 0.2 mg / kg.

[0020] The administration period of enavogliflozin can be appropriately adjusted by a clinician based on the preventive or therapeutic effect of enavogliflozin on canine obesity. Although not limited thereto, a pharmaceutical composition containing enavogliflozin as an active ingredient can be administered for a minimum of 8 weeks for the prevention or treatment of obesity in canine animals.

[0021] In addition, administration of the pharmaceutical composition reduces fasting blood glucose, serum insulin concentration, and indicators selected from the group consisting of gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine phosphokinase (CPK), blood urea nitrogen (BUN), creatinine (CRE), and C-reactive protein (CRP) in obese dogs. This means that enavogliflozin not only has an anti-obesity effect, but can also improve hyperglycemia, dyslipidemia, and fatty liver, providing great benefits in the treatment of obesity.

[0022] Therefore, the canine animal to which the pharmaceutical composition needs to be administered may, in addition to obesity, also suffer from a metabolic disease selected from the group consisting of hyperglycemia, dyslipidemia, and fatty liver, but is not limited thereto.

[0023] The method of administration of the pharmaceutical composition containing enavogliflozin according to the present invention is not limited thereto, but can be administered orally or parenterally according to the intended method.The preparation for oral administration can be selected in various forms, such as syrup, tablet, capsule, cream and lozenge.Syrup preparations generally contain a suspension or solution of the compound or its salt in a liquid carrier, such as ethanol, peanut oil, olive oil, glycerin or water, optionally containing a flavoring or coloring agent.

[0024] When the composition is prepared in tablet form, any one of the pharmaceutical carriers generally used for preparing solid preparations can be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is prepared in capsule form, any one of the common encapsulation procedures can be used, for example, the above-mentioned carriers can be used in hard gelatin capsule shells. The composition is prepared in soft gelatin shell capsule form. Any one of the pharmaceutical compositions generally used for dispersion or suspension can be prepared using aqueous gums, cellulose, silicates or oils. Preparations for intramuscular or subcutaneous administration can be selected in liquid form, for example, solutions, suspensions and emulsions containing aqueous solvents, such as water, saline and Ringer's solution, or lipophilic solvents, such as fatty oils, sesame oil, corn oil and synthetic fatty acid esters.

[0025] The present invention also provides a method for treating obesity in a canine, comprising administering a pharmaceutical composition containing enavogliflozin as an active ingredient to a canine in need of treatment.

[0026] Any terms or elements mentioned in the method for treating obesity that are also mentioned in the description of the composition for preventing or treating obesity in canines are used with the same meaning in the description of the claimed composition for preventing or treating obesity in canines. Effect of the Invention

[0027] The pharmaceutical composition for preventing or treating obesity in canines of the present invention, which contains enavogliflozin as an active ingredient, reduces body condition score, body weight, fat thickness, body fat percentage, chest circumference and waist circumference in obese dogs, and is also excellent in improving serological indices, and therefore can be usefully used for preventing or treating obesity in canines. [Brief description of the drawings]

[0028] [Figure 1] This shows the body shape of pet dogs based on their body condition score. [Figure 2a] The results show that healthy male dogs were given different doses of enavogliflozin for 13 weeks and the changes in body weight were observed. [Figure 2b] The results show that healthy female dogs were given different doses of enavogliflozin for 13 weeks and the changes in body weight were observed. [Figure 3a] The results show that healthy male dogs were given different doses of enavogliflozin for 39 weeks and the changes in body weight were observed. [Figure 3b] The results show that healthy female dogs were given different doses of enavogliflozin for 39 weeks and the changes in body weight were observed. [Figure 4a] The results were obtained by administering different doses of enavogliflozin to obese dogs and observing the change in body condition score. [Figure 4b] The results were obtained by administering different doses of enavogliflozin to obese dogs and observing changes in body weight. [Figure 4c] The study examined changes in body fat when different doses of enavogliflozin were administered to obese dogs. [Figure 4d]The results were obtained by administering different doses of enavogliflozin to obese dogs and observing changes in fat thickness. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Hereinafter, one or more specific examples will be described in more detail based on examples. However, these examples are merely for illustrative purposes and the scope of the present invention is not limited to these examples.

[0030] Experimental Method

[0031] 1.Non-clinical toxicity studies

[0032] Four 6-month-old normal female and four male beagle dogs were administered enavogliflozin at doses of 0 (control group, gelatin capsule), 1, 3, and 6 mg / kg / day for 13 weeks, and changes in body weight were observed. Enavogliflozin was filled into gelatin capsules and administered daily at the above doses.

[0033] In addition, 4 normal female and 4 male beagle dogs aged 6 months were administered enavogliflozin at doses of 0 (control group, gelatin capsule), 0.3, 1, and 3 mg / kg / day for 39 weeks, and changes in body weight were observed.

[0034] 2. Clinical Trial Animal Selection, Grouping and Monitoring

[0035] Naturally obese but otherwise healthy adult dogs, regardless of breed, sex and altered status, were selected and prior parental consent was obtained for participation in the clinical trial.

[0036] All dogs were screened for obesity based on the results of physical examination, including body weight and body condition score (BCS, 9 levels in total, Figure 1 and Table 1). The BCS used for screening dogs was 9 levels in total, and dogs with a BCS of 6 or more were selected. Detailed criteria are shown in Table 1 and Figure 1.

[0037] [Table 1]

[0038] The selected dogs were generally healthy without underlying diseases such as liver, cardiac and / or renal abnormalities, and to ensure individual feeding, only one dog per household was analyzed.

[0039] Dogs were excluded if they had been used for reproductive purposes or had received long-acting steroids, medications affecting endocrine status (e.g., lipid-improving, cholesterol-lowering, antidiabetic medications), or medications affecting body weight or energy expenditure (e.g., phenobarbital) within 30 days prior to the start of the study.

[0040] A total of 20 dogs were selected and divided into 4 groups with 5 dogs in each group: normal obese control group (OC), enavogliflozin 0.2, enavogliflozin 0.5 and enavogliflozin 1 groups. The control group was fed with normal chow, and the enavogliflozin groups were fed with normal chow supplemented with enavogliflozin at doses of 0.2, 0.5 or 1 mg / kg, respectively. Enavogliflozin was orally administered as a chow supplement once daily for 8 weeks.

[0041] The breeds of dogs that participated in the clinical trials were: Shetland Sheepdog (5 / 20), Maltese (3 / 20), Pompitz (2 / 20), Bichon Frise (1 / 20), Border Collie (1 / 20), Cocker Spaniel (1 / 20), Japanese Spitz (1 / 20), Labrador Retriever (1 / 20), Poodle (1 / 20), Shih Tzu (1 / 20), Wire Fox Terrier (1 / 20), Yorkshire Terrier (1 / 20) and mixed breed (1 / 20).

[0042] Of the 20 dogs, 10 were male and all neutered, 10 were female and 7 were neutered. Age range was between 3 and 11 years, with a mean age of 7.15 years. Of the 20 dogs, 9 were under 6 years old, 8 were between 7 and 9 years old, and 3 were over 10 years old.

[0043] All dogs participating in the clinical trial were examined by a veterinarian once a week until the end of the study.

[0044] 3. Measurement of body weight, chest circumference, waist circumference and resting energy requirement

[0045] Body weight (BW), chest circumference, and waist circumference were measured immediately before the first intake of enavogliflozin-supplemented food, and then every 2 weeks for 10 weeks. Chest circumference and waist circumference were measured four times at the thickest part of the chest and at the thinnest part between the chest and hind legs, respectively, to obtain the average circumference. Resting energy requirement (RER) was calculated using Equation 1 in the reference (Brooks et al., Journal of the American Animal Hospital Association 50, 1-11. (2014)).

[0046] [Formula 1] RER(kcal / day)=70×(initial body weight) 0.75

[0047] 4. Measurement of Fat Thickness and Body Fat

[0048] Fat thickness was evaluated by measuring the perpendicular distance from the T10 spinal process to the skin using radiographs (Titan 2000 X-ray system, COMED Medical Systems Co., Ltd., Seoul, Korea) taken on the first day of enavogliflozin administration and 4, 8, and 10 weeks after administration. Body fat was measured with a body fat measuring device once every 2 weeks for a total of 10 weeks after the start of enavogliflozin administration.

[0049] 5. Blood, serum and urine tests

[0050] Hematological tests were performed the day before the first administration of enavogliflozin and then every 2 weeks for 10 weeks. A portion of the blood collected on the day of the test was stored in a CBC tube containing the anticoagulant EDTA-2K, and the red blood cell (RBC) count, hematocrit (Hct), hemoglobin concentration (Hb), white blood cell (WBC) count, and platelet (PLT) count were measured using an automated hematology analyzer (ADVIA 2120i TM The results were evaluated at Siemens Healthcare Diagnostics, Vienna, Austria.

[0051] Biochemical analysis was performed as follows: A portion of the blood collected on the day of the test was transferred to a vacuum tube containing a coagulation activator, left at room temperature for 15–20 min to solidify, and then centrifuged at 3000 rpm to obtain serum. Serum biochemical parameters were evaluated using a Hitachi 7180 instrument (Hitachi, Tokyo, Japan). The biochemical indices evaluated were aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine phosphokinase (CPK), total bilirubin (TBIL), glucose (GLU), total cholesterol (TC), triglycerides (TG), total protein (TP), albumin (ALB), gamma-glutamyl transpeptidase (GGT), blood urea nitrogen (BUN), creatinine (CRE), inorganic phosphorus (IP), calcium (Ca), and C-reactive protein (CRP).

[0052] Serum insulin concentrations were measured using the Quantikine Canine Insulin ELISA Kit (catalog number: DINS00, R&D Systems, Minneapolis, MN, USA) according to the manufacturer's protocol at weeks 2, 4, 6, 8, and 10 after the start of enavogliflozin treatment. Urinary biochemical parameters were assessed using urine test strips at weeks 2, 4, 6, and 10 after the start of enavogliflozin treatment, and urinary glucose (GLU) excretion was measured using UriSCAN Strip® (YD Diagnostics Corp., Yongin, Korea).

[0053] 6.Statistical analysis

[0054] Prism 5.03 software (GraphPad Software Inc., San Diego, CA, USA) was used for statistical analysis of data. Test results were expressed as mean ± standard error of the mean (SEM). Statistical methods used were paired Student's t-test or Wilcoxon matched pairs test, and the significance level was set at p < 0.05.

[0055] Experimental Results

[0056] 1.Non-clinical toxicity studies

[0057] Repeated oral administration of enavogliflozin for 13 weeks resulted in a decrease in body weight compared to the control group. Specifically, body weight was decreased by 17.7%, 16%, and 29.9% in male beagle dogs at doses of 1, 3, and 6 mg / kg / day, respectively (Fig. 2a), and by 19.6%, 18.5%, and 33.2% in female beagle dogs, respectively, with the decrease in body weight being dose-dependent (Fig. 2b).

[0058] When enavogliflozin was administered orally for 39 weeks, male beagle dogs at doses of 1, 3, and 6 mg / kg / day lost 9.1%, 12.7%, and 21.0%, respectively (Figure 3a), and female beagle dogs lost 7.6%, 11.8%, and 11.3%, respectively (Figure 3b).

[0059] 2. Changes in BCS, weight, body fat, fat thickness, chest circumference and waist circumference

[0060] The effects of enavogliflozin administration on BCS, body weight, body fat mass, fat thickness, chest and waist circumferences in obese dogs were evaluated.

[0061] The BCS of the enavogliflozin 0.2 group (DWP0.2) was significantly lower than that of the control group (OC) at 4, 8, and 10 weeks after the start of treatment (p<0.05), and the BCS of the enavogliflozin 0.5 group (DWP0.5) also decreased throughout the entire study period. The BCS of the enavogliflozin 1 group (DWP1.0) increased slightly compared to the control group (OC), but was lower than that of the control group (OC) at the end of the study (Figure 4a).

[0062] Body weight in the enavogliflozin 0.2 group was significantly lower than the control group (OC) from 4 weeks after the start of treatment to the end of the study (p<0.05), and body weight change was also the lowest of all groups. A similar weight loss occurred in the enavogliflozin 0.5 group, where body weight decreased at weeks 2 and 4 of the study and then slowly increased (Figure 4b). Body fat percentage was not significantly different in all groups, but was lowest in the enavogliflozin 0.2 group (Figure 4c). Fat thickness decreased in all treatment groups, and such changes were significant at weeks 8 and 10 in the enavogliflozin 0.2 group (Figure 4d). Chest and waist circumferences decreased in all enavogliflozin treatment groups (Table 2). Changes in chest and waist circumferences are listed in Table 2 below.

[0063] [Table 2]

[0064] 3. Changes in food intake and resting energy requirement

[0065] At 10 weeks of enavogliflozin treatment, the feed intake was 101.35±2.56% in the control group (OC), 166.59±4.72% in the enavogliflozin 0.2 group, 98.47±1.44% in the enavogliflozin 0.5 group, and 123.15±2.45% in the enavogliflozin 1.0 group compared with the initial feed intake. During the 10-week experimental period, the feed intake was significantly increased (p<0.001) in the enavogliflozin 0.2 and enavogliflozin 1 groups and decreased in the enavogliflozin 0.5 group compared with the control group (OC) (Table 3).

[0066] Analysis of resting energy requirement (RER) at 4 and 8 weeks after the start of enavogliflozin treatment revealed that RER was significantly lower in the enavogliflozin 0.2 group compared with the control group (OC) (p<0.05; Table 3).

[0067] The changes in food intake and resting energy requirement of each experimental group during the clinical trial are shown in Table 3. The results are shown as mean ± standard deviation, and * indicates significant results at p<0.05 level compared to the control group (OC).

[0068] [Table 3]

[0069] 4. Blood and serum biochemical indicators

[0070] During the 10-week study period, there were no significant differences in hematological indices between the treatment groups, except for the platelet (PLT) count. The platelet (PLT) count in the enavogliflozin 1 group was significantly lower than that in the control group (OC) (p<0.05), and serum total cholesterol (TC) and triglyceride (TG) concentrations in the enavogliflozin 0.2 group were lower than those in the control group (OC) (Table 4).

[0071] Fasting glucose and serum insulin concentrations were reduced in all treatment groups compared to the control group (OC), but glucose (GLU) concentrations were significantly lower than the control group (OC) only in the enavogliflozin 1 group, and insulin concentrations were significantly lower than the control group (OC) only in the enavogliflozin 0.5 group (Table 4).

[0072] The serum triglyceride (TG) concentrations in the enavogliflozin 0.2, 0.5, and 1 groups were 142.00±95.55, 133.86±70.19, and 282.60±419.03 mg / dL, respectively, and were significantly lower than those in the control group (361.60±622.34 mg / dL). In addition, the serum gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine phosphokinase (CPK), and C-reactive protein (CRP) concentrations were significantly decreased in the enavogliflozin 0.2 group compared with the control group (OC) (Table 4).

[0073] In Table 4, the results are shown as the mean ± standard deviation, and * indicates results that were significant at p<0.05 level in the post hoc test by one-way ANOVA compared to the control group (OC).

[0074] [Table 4]

[0075] Urinary glucose (GLU) excretion was greater in the enavogliflozin groups, especially in the enavogliflozin 0.2 group (Table 5).

[0076] [Table 5]

[0077] 5. Conclusion

[0078] Treatment with enavogliflozin for 8 weeks reduced BCS, body weight, percentage of body fat, fat thickness, and chest and waist circumferences in obese dogs, with the most effective results occurring when the diet was supplemented with enavogliflozin at a concentration of 0.2 mg / kg.

[0079] In addition, the enavogliflozin group showed reduced blood glucose concentrations, increased urinary glucose excretion, and reduced serum total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine phosphokinase (CPK), blood urea nitrogen (BUN), and creatinine (CRE), all of which are elevated in obese individuals. Increased total cholesterol (TC) and triglyceride (TG) concentrations are indicative of dyslipidemia, while increased blood urea nitrogen (BUN) and creatinine (CRE) concentrations can be seen in renal impairment. Increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine phosphokinase (CPK) concentrations are indicative of fatty liver.

[0080] Therefore, it is clear that enavogliflozin improves the condition of obese dogs and has the effect of improving hyperglycemia, dyslipidemia, and fatty liver.

Claims

1. A pharmaceutical composition for preventing or treating obesity in canines, comprising enavogliflozin as an active ingredient.

2. The pharmaceutical composition for preventing or treating obesity in a canine according to claim 1 , wherein the canine has a body condition score (BCS) of 6 or more.

3. The pharmaceutical composition for preventing or treating obesity in a canine according to claim 1 , wherein the canine has a body condition score (BCS) of 7 or more.

4. The pharmaceutical composition for preventing or treating obesity in canines according to claim 1, wherein the enavogliflozin is administered at a dose of 0.01 to 1 mg / kg once a day.

5. The pharmaceutical composition for preventing or treating obesity in canines according to claim 1, wherein the enavogliflozin is administered at a dose of 0.05 to 0.7 mg / kg once a day.

6. The pharmaceutical composition for preventing or treating obesity in canines according to claim 1, wherein the enavogliflozin is administered at a dose of 0.1 to 0.4 mg / kg once a day.

7. 2. The pharmaceutical composition for preventing or treating obesity in canines according to claim 1, wherein the pharmaceutical composition is administered for a minimum of 8 weeks.

8. The pharmaceutical composition for preventing or treating obesity in canines as described in claim 1, wherein the pharmaceutical composition improves one or more indicators selected from the group consisting of body condition score, body weight, fat thickness, body fat percentage, chest circumference, waist circumference and resting energy requirement.

9. 2. The pharmaceutical composition for preventing or treating obesity in canines according to claim 1, wherein the pharmaceutical composition reduces one or more indicators selected from the group consisting of fasting blood glucose, serum insulin concentration, gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatine phosphokinase (CPK) and C-reactive protein (CRP).

10. The pharmaceutical composition for preventing or treating obesity in canines according to claim 1 , wherein the pharmaceutical composition is administered orally or parenterally.

11. The pharmaceutical composition for preventing or treating obesity in a canine according to claim 1 , wherein the canine suffers from a metabolic disease selected from the group consisting of hyperglycemia, dyslipidemia and fatty liver.

12. 13. A method for treating obesity in a canine animal, comprising administering to the canine animal in need of treatment the pharmaceutical composition of claim 1.

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