Use of phenylpropionic acid analogs in the treatment or prevention of metabolic disorders

Abstract

Provided is a novel use of phenylpropionic acid analogs in the treatment and / or prevention of metabolic disorders.

Description

Use of phenylpropionic acid analogs in treating or preventing metabolic disorders Technical Field

[0001] The present invention belongs to the field of medicine, and more specifically, relates to a novel use of phenylpropionic acid analogs in treating or preventing metabolic disorders. Background Art

[0002] Metabolic disturbances are pathological, uncoordinated imbalances in the body's digestion, absorption, and excretion of substances, resulting in a disordered supply and demand. These disorders can manifest as disturbances in one or more substances. Different metabolic disorders can lead to different diseases, such as diabetes caused by disturbances in glucose metabolism, hyperlipidemia caused by disturbances in lipid metabolism, and gout caused by disturbances in uric acid metabolism. Metabolic syndrome significantly increases the risk of type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). In insulin resistance, elevated hepatic glucose production and lipoprotein secretion contribute to the pathogenesis of hyperglycemia and hyperlipidemia. Obesity is also associated with the accumulation of excess fat in the liver, which is the most characteristic feature of NAFLD, affecting both adults and children. Although hepatic steatosis typically presents as a benign condition with no apparent adverse effects on liver function, progressive liver damage, inflammation, and fibrosis are observed in 20%-30% of NAFLD patients with non-alcoholic steatohepatitis (NASH). NASH is emerging as a major risk factor for end-stage liver disease. Therefore, the development of new drugs for the treatment of metabolic disorders is of great significance.

[0003] Zaltoprofen is a phenylpropionic acid nonsteroidal anti-inflammatory drug used to treat chronic rheumatoid arthritis, osteoarthritis, low back pain, periarthritis of the shoulder, cervical-shoulder-wrist syndrome, and anti-inflammatory analgesia after surgery, trauma, and tooth extraction.

[0004] Summary of the Invention

[0005] The present invention provides a novel use of a phenylpropionic acid analogue zaltoprofen for treating or preventing metabolic disorders, in particular for treating or preventing metabolic disorders related to uric acid and blood glucose and blood lipids.

[0006] One aspect of the present invention provides use of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing metabolic disorders.

[0007] In some embodiments, the zaltoprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemate, an S optical isomer, or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the metabolic disorder comprises at least one of uric acid metabolism disorder, blood glucose metabolism disorder, or blood lipid metabolism disorder.

[0009] In some embodiments, the metabolic disorder comprises at least one of hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein aberrations, liver inflammation, adipose tissue inflammation, fatty liver disease, non-alcoholic fatty liver disease, hypercholesterolemia, coronary heart disease, congestive heart failure, stroke, peripheral vascular disease, atherosclerosis, arteriosclerosis, obesity, nephrolithiasis, kidney disease, diabetic retinopathy, insulin resistance, hyperinsulinemia, hypertension, hepatic steatosis, fatty liver, non-alcoholic fatty liver disease, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormalities, neurodegenerative diseases, or Alzheimer's disease.

[0010] In some embodiments, the metabolic disorder includes at least one of acute hyperuricemia, chronic hyperuricemia, uric acid-induced gouty arthritis, glycolipid metabolism disorder associated with chronic hyperuricemia model, or type 2 diabetes.

[0011] In some embodiments, the drug can reduce at least one of blood uric acid, blood sugar, glucose tolerance, cholesterol and triglycerides.

[0012] Another aspect of the present invention provides use of a racemate or R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing uric acid metabolism disorders.

[0013] In some embodiments, the uric acid metabolism disorder includes acute hyperuricemia, chronic hyperuricemia, etc.

[0014] Another aspect of the present invention provides use of a racemate or S optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing blood glucose metabolism disorders and / or blood lipid metabolism disorders.

[0015] In some embodiments, the blood glucose metabolism disorder and / or blood lipid metabolism disorder includes glucose and lipid metabolism disorder associated with chronic hyperuricemia model, diabetes, etc.

[0016] In some embodiments, the dosage form of the drug includes tablets, capsules, granules, oral solutions, aqueous injections, powder injections, lyophilized powder injections, sprays, suppositories, or pills.

[0017] In some embodiments, the administration route of the drug includes oral administration, injection, intravenous drip, sublingual administration, spray inhalation or rectal administration.

[0018] Another aspect of the present invention provides a method for reducing uric acid, blood glucose and / or blood lipid levels in a subject, comprising administering an effective amount of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0019] In some embodiments, the zaltoprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemate, an S optical isomer, or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the method comprises administering to a subject in need thereof an effective amount of a racemate or R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof for reducing uric acid levels in the subject.

[0021] In some embodiments, the method comprises administering to a subject in need thereof an effective amount of a racemate or S optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof for lowering the subject's blood glucose and / or blood lipid levels.

[0022] Yet another aspect of the present invention provides a method for preventing or treating metabolic disorders, comprising administering an effective amount of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0023] In some embodiments, the zaltoprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemate, an S optical isomer, or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the metabolic disorder comprises at least one of uric acid metabolism disorder, blood glucose metabolism disorder, or blood lipid metabolism disorder.

[0025] In some embodiments, the metabolic disorder comprises at least one of hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein aberrations, liver inflammation, adipose tissue inflammation, fatty liver disease, non-alcoholic fatty liver disease, hypercholesterolemia, coronary heart disease, congestive heart failure, stroke, peripheral vascular disease, atherosclerosis, arteriosclerosis, obesity, nephrolithiasis, kidney disease, diabetic retinopathy, insulin resistance, hyperinsulinemia, hypertension, hepatic steatosis, fatty liver, non-alcoholic fatty liver disease, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormalities, neurodegenerative diseases, or Alzheimer's disease.

[0026] In some embodiments, the metabolic disorder includes at least one of acute hyperuricemia, chronic hyperuricemia, uric acid-induced gouty arthritis, glycolipid metabolism disorder associated with chronic hyperuricemia model, or type 2 diabetes.

[0027] In some embodiments, the method comprises administering zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof at a dose of 0.01-100 mg / kg, preferably 0.1-50 mg / kg, and more preferably 0.5-30 mg / kg.

[0028] The present invention creatively discovered zaltoprofen's uric acid-lowering effects on hyperuricemia and its anti-inflammatory effects on uric acid-induced gouty arthritis. It also discovered zaltoprofen's hypoglycemic and hypolipidemic effects on hyperuricemia-associated glucose and lipid metabolism disorders and type 2 diabetes. The present invention further discovered that different optical isomers of zaltoprofen have different effects on different metabolic disorders, providing significant clinical value for its prevention and treatment of metabolic disorders such as hyperuricemia, gout, and diabetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG1 shows the effects of JKT and its optical isomers on serum uric acid concentration in a hypoxanthine-induced hyperuricemia model in mice (N=8, M±SD).

[0030] Figure 2 shows the effects of JKT and its optical isomers on the area under the serum uric acid concentration-time curve (AUC) in hypoxanthine-induced hyperuricemia mouse model (N=8, M±SD); **P<0.01, compared with the model group.

[0031] FIG3 shows the inhibition rate of JKT and its optical isomers on the area under the serum uric acid concentration-time curve (AUC) of hypoxanthine-induced hyperuricemia model in mice (calculated based on the mean value of each group).

[0032] Figure 4 shows the effects of JKT and its optical isomers on serum uric acid concentration in a mouse model of chronic hyperuricemia induced by hypoxanthine and potassium oxonate (N=8, M±SD), where A is the RS-JKT group, B is the R-JKT group, and C is the S-JKT group; **P<0.01, compared with the normal group; # P<0.05, ## P<0.01, compared with the model group.

[0033] FIG5 shows the inhibition rate of JKT and its optical isomers on serum uric acid in a chronic hyperuricemia model of mice induced by hypoxanthine+potassium oxonate (calculated based on the mean value of each group).

[0034] FIG6 shows the effects of JKT and its optical isomers on serum uric acid concentration in a mouse model of chronic hyperuricemia induced by hypoxanthine and potassium oxonate (N=8, M±SD); **P<0.01, compared with the normal group; ## P<0.01, compared with the model group.

[0035] Figure 7 shows the effects of JKT and its optical isomers on the glucose tolerance-time curve in the hypoxanthine + potassium oxonate-induced chronic hyperuricemia model in mice (N=8, M±SD), where A is the RS-JKT group, B is the R-JKT group, and C is the S-JKT group; *P<0.05, **P<0.01, compared with the normal group; # P<0.05, ## P<0.01, compared with the model group.

[0036] Figure 8 shows the effects of JKT and its optical isomers on the area under the glucose-time curve (AUC) of glucose tolerance in a chronic hyperuricemia model of mice induced by hypoxanthine + potassium oxonate (N=8, M±SD); **P<0.01, compared with the normal group; #P<0.05, ##P<0.01, compared with the model group.

[0037] Figure 9 shows the effects of JKT and its optical isomers on blood lipid levels in a chronic hyperuricemia model of mice induced by hypoxanthine + potassium oxonate (N=8, M±SD), where A is triglyceride (TG) and B is total cholesterol (TC).

[0038] Figure 10 shows the effects of JKT and its optical isomers on gouty arthritis in rats induced by sodium urate (N=8, M±SD), where A is the RS-JKT group, B is the R-JKT group, and C is the S-JKT group; #P<0.05, ##P<0.01, compared with the model group.

[0039] Figure 11 shows the effects of JKT and its optical isomers on body weight (g) ( N=8), A is the RS-JKT group, B is the R-JKT group, and C is the S-JKT group; *P<0.05, **P<0.01, compared with the normal group.

[0040] Figure 12 shows the effect on blood glucose level (mmol / L) N=8), where A is the RS-JKT group, B is the R-JKT group, and C is the S-JKT group; **P<0.01, compared with the normal group; # P<0.05, ## P<0.01, compared with the model group.

[0041] Figure 13 shows the effect on serum triglycerides (mmol / L) ( N=8); **P<0.01, compared with the normal group; # P<0.05, ## P<0.01, compared with the model group.

[0042] Figure 14 shows the effect on serum cholesterol (mmol / L) ( N=8); *P<0.05, **P<0.01, compared with the normal group; # P<0.05, ## P<0.01, compared with the model group.

[0043] Figure 15 shows the effects of JKT and its optical isomers on the blood glucose-time curve of glucose tolerance (N=8, M±SD), where A is the RS-JKT group, B is the R-JKT group, and C is the S-JKT group; **P<0.01, compared with the normal group; #P<0.05, ##P<0.01, compared with the model group.

[0044] FIG16 shows the effects of JKT and its optical isomers on the area under the glucose tolerance-time curve (AUC) (N=8, M±SD); **P<0.01, compared with the normal group; #P<0.05, ##P<0.01, compared with the model group.

[0045] FIG17 shows the serum uric acid levels (mg / L) at different time points after a single administration (N=8, M±SD); *P<0.05, **P<0.01, compared with the model group. DETAILED DESCRIPTION

[0046] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0047] definition

[0048] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of interpreting this specification, the following definitions will be used, and where appropriate, terms used in the singular will also include the plural form, and vice versa.

[0049] Unless the context clearly dictates otherwise, as used herein, the expressions "a" and "an" include plural references. For example, reference to "a cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art, and so forth.

[0050] As used herein, the term "about" refers to a range of ±20% of the value that follows. In some embodiments, the term "about" refers to a range of ±10% of the value that follows. In some embodiments, the term "about" refers to a range of ±5% of the value that follows.

[0051] As used herein, the term "metabolic disorder" refers to metabolic abnormalities caused by diseases in the body or by congenital defects of the body. In the present invention, metabolic disorders include, but are not limited to, uric acid metabolism disorders, glucose metabolism disorders, lipid metabolism disorders, etc. In some embodiments, metabolic disorders include hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein aberrations, liver inflammation, adipose tissue inflammation, fatty liver disease, non-alcoholic fatty liver disease, hypercholesterolemia, coronary heart disease, congestive heart failure, stroke, peripheral vascular disease, atherosclerosis, arteriosclerosis, obesity, nephrolithiasis, kidney disease, diabetic retinopathy, insulin resistance, hyperinsulinemia, hypertension, hepatic steatosis, fatty liver, non-alcoholic fatty liver disease, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormalities, neurodegenerative diseases, or Alzheimer's disease.

[0052] Zaltoprofen (10,11-dihydro-α-methyl-10-oxo-dibenzo[b,f-thio]-2-acetic acid, Zaltoprofen) has the structure shown in the following formula (I). Zaltoprofen is a potent nonsteroidal analgesic and anti-inflammatory drug of the phenylpropionic acid class. Zaltoprofen is a racemate containing two optical isomers: the S optical isomer (S-) and the R optical isomer (R-). Herein, the code name for zaltoprofen is JKT, and its racemic form is represented by RS-JKT, the S optical isomer is represented by S-JKT, and the R optical isomer is represented by R-JKT.

[0053] As used herein, the term "treating" includes actions that occur while a subject has a particular disease, disorder or condition that reduces the severity of, or delays or slows the development of, the disease, disorder or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder or condition ("prophylactic treatment").

[0054] As used herein, the term "pharmaceutically acceptable" means that the carrier, diluent, and / or excipient used in the pharmaceutical must be compatible with the other ingredients of the formulation and not deleterious to the recipient.

[0055] As used herein, the term "pharmaceutically acceptable carrier" refers to any form of non-toxic, inert solid, semi-solid, diluent, encapsulating material, or formulation adjuvant. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; malt; gelatin and other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate; as well as colorants; release agents; coating agents; sweeteners; flavorings and fragrances; preservatives, and antioxidants, which may also be used in the pharmaceutical at the discretion of the formulator.

[0056] As used herein, the term "subject" includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0057] As used herein, the term "effective amount" refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those skilled in the art, the effective amount of the drug of the present invention may vary depending on factors such as the biological target, the pharmacokinetics of the drug, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount encompasses both a therapeutically effective amount and a prophylactically effective amount.

[0058] As used herein, the term "therapeutically effective amount" is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a drug refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effects of other therapeutic agents.

[0059] The effective amount of the drug of the present invention is generally administered in a single or multiple dose at an average daily dose of 0.01 mg to 100 mg of drug / kg patient body weight, preferably 0.1 mg to 50 mg of drug / kg patient body weight, and more preferably 0.5 mg to 30 mg of drug / kg patient body weight. Generally, the drug of the present invention can be administered to a patient in need of such treatment at a daily dose ranging from about 0.1 mg / kg to about 50 mg / kg per patient, preferably 0.5 mg / kg to 30 mg / kg. For example, the daily dose per patient can be about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2.5 mg / kg, about 5 mg / kg, about 7.5 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg. Can be administered once or multiple times every day, every week (or at intervals of several days) or with an intermittent schedule.For example, can be on a weekly basis (for example every Monday), every day give described medicine once or multiple times, erratically or continue for several weeks, for example 4-10 weeks.Or, can be administered every day for several days (for example 2-10 days), then a few days (for example 1-30 days) do not administer described medicine, erratically repeat this cycle or repeat given number of times, for example 4-10 cycles.For example, medicine of the present invention can be administered every day for 5 days, then interrupted for 9 days, then administered every day for 5 days, then interrupted for 9 days, and so on, erratically repeat this cycle or repeat 4-10 times altogether.Can also be administered medicine provided herein (" long-term administration ") for a long time.Long-term administration refers to administering medicine for a long time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years etc., or can continue to administer indefinitely, for example, the rest of the life of experimenter.In some embodiments, long-term administration is intended to provide the constant level of described medicine in blood for a long time, for example, in therapeutic window.

[0060] As used herein, the term "prophylactically effective amount" is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a drug refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0061] Typically, an effective amount of the drug provided herein is administered. The amount of the drug actually administered can be determined by a physician based on the relevant circumstances, including the condition being treated, the route of administration selected, the drug actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0062] When used to prevent the conditions described herein, the drugs provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0063] The drugs provided by the present invention can be administered by many routes, including but not limited to oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, administration by implant or other modes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration or infusion techniques, etc.

[0064] For example, in some embodiments, the drug can be administered by bolus, for example, in order to increase the concentration of the drug in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient by the body, for example, an intramuscular or subcutaneous bolus dose slowly releases the active ingredient, while a bolus delivered directly to a vein (for example, by IV intravenous drip) can be delivered more quickly, so that the concentration of the active ingredient in the blood is quickly increased to an effective level. In other embodiments, the drug can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide a steady-state concentration of the active ingredient in the subject's body. In addition, in other embodiments, the drug can be first given in a bolus dose, followed by a continuous infusion.

[0065] For example, in other embodiments, oral medications can be in the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate accurate dosing, the medication is provided in unit dosage form. The term "unit dosage form" refers to a physical discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined amount of active substances and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes for liquid dosage forms, or pills, tablets, capsules, etc. in the case of solid dosage forms. In this dosage form, the medication is typically a smaller component (about 0.1 to about 50 weight %, or preferably about 1 to about 40 weight %), with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0066] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous carrier and a buffer, suspending and dispersing agents, coloring agents, flavoring agents, etc. Solid forms may include, for example, any of the following components, or drugs of similar nature: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, sodium starch glycolate, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavorings, such as mint, methyl salicylate, or orange flavor; stabilizers, such as tartaric acid, aspartic acid, glutamic acid, etc.

[0067] Injectable dosage forms are typically based on sterile saline or phosphate buffered saline for injection, or other injectable excipients known in the art. As previously mentioned, in such dosage forms, the active drug is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0068] Typically, transdermal dosage forms are formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream together with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components that enhance the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.

[0069] The medicaments of the present invention may also be administered via transdermal devices. Thus, transdermal administration may be achieved using patches of the reservoir or porous membrane type, or various solid matrices.

[0070] The following examples and accompanying drawings are provided to facilitate understanding of the present invention. However, it should be understood that these examples and accompanying drawings are intended to illustrate the present invention only and are not intended to limit the present invention in any way. The actual scope of protection of the present invention is set forth in the claims. It should be understood that any modifications and variations may be made without departing from the spirit of the present invention.

[0071] Example

[0072] Experimental Materials

[0073] 1. Test drug

[0074] Racemic JKT (RS-JKT), purity: 99.3%; JKT S-type optical isomer (S-JKT), purity: 99.4%; JKT R-type optical isomer (R-JKT), purity: 99.1%, all provided by Hefei Jinke Biopharmaceutical Technology Co., Ltd.

[0075] Febuxostat tablets (Fengdingning), 40 mg × 14 tablets, Hangzhou Zhu Yangxin Pharmaceutical Co., Ltd.

[0076] Rosiglitazone tablets (Aineng): 4mg*7 tablets*2 plates, Chengdu Hengrui Pharmaceutical Co., Ltd.

[0077] Aspirin, S17061-100 g, was purchased from Shanghai Yuanye Biotechnology Co., Ltd.

[0078] Ibuprofen, S31057-5g, was purchased from Shanghai Yuanye Biotechnology Co., Ltd.

[0079] Diclofenac sodium, H10960217, was purchased from China National Pharmaceutical Group.

[0080] Acetaminophen, H20010394, was purchased from Shanghai Johnson & Johnson Pharmaceutical Co., Ltd.

[0081] The tested drugs were ground into suspensions of corresponding concentrations using 0.3% sodium carboxymethyl cellulose for oral administration.

[0082] 2. Animals and husbandry

[0083] (1) Species and origin

[0084] Male Kunming mice, SPF grade, weighing 18–22 g, were purchased from Henan Sikebes Biotechnology Co., Ltd. with a production license number of SCXK (Yu) 2020-0005.

[0085] Male SD rats, SPF grade, weighing 180–220 g, were purchased from the Experimental Animal Center of Hangzhou Medical College with a production license number of SCXK (Zhejiang) 2019-0002.

[0086] C57 mice, SPF grade, male, 5 - 6 weeks old, purchased from the Experimental Animal Business Department of Shanghai Institute of Planned Parenthood Research, license number: SCXK(Su)2018 - 0006.

[0087] (4) 48 male KM mice, SPF grade, weighing 18 - 22 g, purchased from Henan Sk贝斯 Biotechnology Co., Ltd., production license number: SCXK(Yu)2020 - 0005.

[0088] (2) Feeding conditions

[0089] Male Kunming mice and male SD rats were housed in the Animal Center of China Pharmaceutical University (animal use license number: SYXK(Su)2021 - 0011). The temperature in the feeding laboratory was 24 ± 2°C; the relative humidity was 40% - 70%; the number of air exchanges per hour was 10 - 15 times / hour; the light cycle was 12 (day) / 12 (night) hours, and no more than 5 animals were kept in each cage. The feed was a complete pellet feed for mice, purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd., and its quality met the General Quality Standard for Experimental Animal Compound Feed (GB14924.1 - 2010).

[0090] C57 mice were all housed in a clean - grade animal room (animal use license number: SYXK(Su)2021 - 0011). The laboratory temperature was 24 ± 2°C, the relative humidity was 60% - 80%, the number of air exchanges per hour was 10 - 15 times / h, and the light cycle was 12 h (day) / 12 h (night). No more than 5 animals were kept in each cage. The feed was a complete basic pellet feed for mice.

[0091] High - fat diet (80% basal diet, 15% lard, 4% milk powder, 1% cholesterol).

[0092] Drinking water: Purified water was provided.

[0093] 3. Main instruments

[0094] Multifunctional ultrapure water system, Unique-R20, Ruisijie Water Purification Technology Co., Ltd.; multipurpose high-efficiency centrifuge, BECKMAN COULTER 369003 / Avanti JE; electronic analytical balance, BSA124S-CW, Sartorius Scientific Instrument Co., Ltd.; electric constant temperature blast drying oven, CIMO DHG-9140A, Shanghai Yiheng Scientific Instrument Co., Ltd.; Varioskan™ LUX multifunctional microplate reader, Thermo Scientific; 4 / -20°C low-temperature freezer, BCD-551EPCX, Hefei Meiling Co., Ltd.; microtabletop high-speed centrifuge, Thermo Scientific 21R; KD-160 electronic scale, Dongguan Bailida Health Equipment Co., Ltd.; 3-18k low-temperature centrifuge, SIGMA, USA; vortexer, VORTEX-2GENIE, Scientific Industries.

[0095] 4. Main Reagents

[0096] Potassium oxonate, Beijing Solebow Technology Co., Ltd. (P9770); hypoxanthine, Shanghai Aladdin Biochemical Technology Co., Ltd. (H301755); sodium urate (S30775), Shanghai Yuanye Biotechnology Co., Ltd.; streptozotocin (STZ), A610130, Sangon Biotech (Shanghai) Co., Ltd.; sodium carboxymethyl cellulose, Xilong Science Co., Ltd.

[0097] Uric acid (UA) test kit (colorimetric method), Nanjing Jiancheng Bioengineering Institute (C012-1), glucose (GLU) determination kit (glucose oxidase method), triglyceride (TG) detection kit, and total cholesterol (TC) detection kit were all purchased from Nanjing Jiancheng Bioengineering Institute.

[0098] Example 1. Effects of Zaltoprofen (JKT) and its optical isomers on hypoxanthine-induced acute hyperuricemia in mice

[0099] 1.1 Animal grouping

[0100] After the mice were acclimated to the feeding for one week, they were randomly divided into 8 groups according to their body weight, with 8 mice in each group, namely:

[0101] (1) Model group

[0102] (2) Positive drug Febuxostat (10 mg / kg)

[0103] (3) RS-JKT high dose (20 mg / kg)

[0104] (4) RS-JKT low dose (10 mg / kg)

[0105] (5) High dose of R-JKT (20 mg / kg)

[0106] (6) Low dose of R-JKT (10 mg / kg)

[0107] (7) S-JKT high dose (20 mg / kg)

[0108] (8) S-JKT low dose (10 mg / kg)

[0109] 1.2 Model establishment and drug administration

[0110] Overnight fasted mice (without water deprivation) were gavaged with the corresponding dose of the test drug at a volume of 10 mL / kg. The model group received the same volume of 0.3% sodium carboxymethylcellulose solution. Thirty minutes after gavage, each group received a single intraperitoneal injection of 1 g / kg hypoxanthine at a volume of 10 mL / kg to establish an acute hyperuricemia model.

[0111] All mice were given orbital blood before hypoxanthine injection and 0.5, 1, 2, and 6 hours after injection. The blood samples were allowed to stand for 1 hour and then centrifuged at 3500 rpm for 15 minutes to separate the serum. The uric acid concentration in the serum of each group was detected using a uric acid kit.

[0112] 1.3 Detection indicators

[0113] The serum uric acid (SUA) levels of each group at different time points were detected using a kit. The uric acid concentration-time curve was drawn based on the temporal changes in uric acid levels, and the area under the curve (AUC) of the uric acid concentration-time curve of each group was calculated. The inhibition rate (%) of each drug on hyperuricemia was calculated based on the mean AUC of each group.

[0114] The inhibition rate of drug on hyperuricemia (%) = (AUC 模型组 -AUC 药物组 ) / AUC 模型组 ×100%.

[0115] 1.4 Data processing and statistical methods

[0116] The data were expressed as mean ± standard deviation (M ± SD). The inter-group comparisons were analyzed by ANOVA using GraphPad Prism 6 software, with P < 0.05 as the significance standard.

[0117] 1.5 Results

[0118] As shown in Figure 1, baseline serum uric acid levels were similar in all groups of mice. Following intraperitoneal injection of hypoxanthine in the model group, serum uric acid levels increased rapidly, reaching a peak value 1 hour later, then began to decline, essentially returning to pre-modeling baseline values ​​6 hours after modeling. Compared with the model group, each test drug inhibited the hypoxanthine-induced increase in serum uric acid levels in mice to varying degrees, resulting in a lowered serum uric acid concentration-time curve.

[0119] The area under the serum uric acid concentration-time curve (AUC) of each group is shown in Figure 2. It can be seen that each test drug can significantly reduce the AUC value of the model mice; the results of the AUC inhibition rate of each group are shown in Figure 3. It can be seen that according to the AUC inhibition rate, the uric acid-lowering effect of the test substances at the same dose is in the order of R-JKT>RS-JKT>S-JKT.

[0120] Example 2. Effects of JKT and its optical isomers on chronic hyperuricemia in mice induced by hypoxanthine + potassium oxonate

[0121] 2.1 Model establishment

[0122] Mice were acclimated and housed for one week. A chronic hyperuricemia model was established by oral administration of 300 mg / kg hypoxanthine combined with intraperitoneal injection of 300 mg / kg potassium oxonate. A control group received oral administration combined with intraperitoneal injection of a corresponding volume of saline as a control. Two weeks after modeling, serum uric acid levels were measured in both the control and model groups. Mice from the model group with uric acid levels 30% higher than the mean of the control group were randomly divided into groups based on uric acid levels.

[0123] 2.2 Grouping and Dosing

[0124] Mice with successful serum uric acid elevation models were divided into the following 9 groups, with 8 mice in each group:

[0125] (1) Normal group

[0126] (2) Model group

[0127] (3) Positive drug Febuxostat (10 mg / kg)

[0128] (4) RS-JKT high dose (10 mg / kg)

[0129] (5) RS-JKT low dose (5 mg / kg)

[0130] (6) R-JKT high dose (10 mg / kg)

[0131] (7) R-JKT low dose (5 mg / kg)

[0132] (8) S-JKT high dose (10 mg / kg)

[0133] (9) S-JKT low dose (5 mg / kg)

[0134] Each group was given the drug by gavage once a day for 3 consecutive weeks with a dosage of 10 mL / kg. The normal group and the model group were given the same volume of 0.3% sodium carboxymethyl cellulose by gavage.

[0135] 2.3 Detection indicators

[0136] At 1, 2, and 3 weeks after administration, mice were fasted overnight (without water deprivation) and blood was collected from their orbits before administration on the same day. The blood samples were allowed to stand for 1 hour and then centrifuged at 3500 rpm for 15 minutes to separate the serum. The uric acid concentration in the fasting serum of each group was detected using a uric acid kit.

[0137] 2.4 Data processing and statistical methods

[0138] The data were expressed as mean ± standard deviation (M ± SD). The inter-group comparisons were analyzed by ANOVA using GraphPad Prism 6 software, with P < 0.05 as the significance standard.

[0139] 2.5 Results

[0140] The results of serum uric acid concentrations in each group are shown in Figures 4A-4C. During the 3-week dosing period, serum uric acid levels in the model group remained stable and significantly higher than those in the normal group (P < 0.01). After 1 week of dosing, each test drug significantly reduced serum uric acid concentrations in the model mice, and the magnitude of the reduction increased further with prolonged dosing.

[0141] The inhibition rate of hyperuricemia was calculated based on the uric acid concentrations of each group at 1, 2, and 3 weeks after administration [= (uric acid concentration in model group - uric acid concentration in drug group) / uric acid concentration in model group × 100%]. The results are shown in Figure 5. It can be seen that the intensity of the uric acid-lowering effect of the same dose is: R-JKT > RS-JKT > S-JKT, which is consistent with the efficacy results of the acute model.

[0142] Example 3. Effects of JKT and its optical isomers on improving glucose and lipid metabolism disorders associated with chronic hyperuricemia model

[0143] 3.1 Model establishment

[0144] Mice were acclimated and housed for one week. A chronic hyperuricemia model was established by oral administration of 300 mg / kg hypoxanthine combined with intraperitoneal injection of 300 mg / kg potassium oxonate. A control group received oral administration combined with intraperitoneal injection of a corresponding volume of saline as a control. Two weeks after modeling, serum uric acid levels were measured in both the control and model groups. Mice from the model group with uric acid levels 30% higher than the mean of the control group were randomly divided into groups based on uric acid levels.

[0145] 3.2 Grouping and Dosing

[0146] Normal mice and mice with elevated serum uric acid levels were divided into the following 10 groups, with 8 mice in each group:

[0147] (1) Normal group

[0148] (2) Model group

[0149] (3) Positive drug Febuxostat (10 mg / kg)

[0150] (4) Positive drug rosiglitazone (10 mg / kg)

[0151] (5) RS-JKT high dose (10 mg / kg)

[0152] (6) RS-JKT low dose (5 mg / kg)

[0153] (7) R-JKT high dose (10 mg / kg)

[0154] (8) Low dose of R-JKT (5 mg / kg)

[0155] (9) S-JKT high dose (10 mg / kg)

[0156] (10) S-JKT low dose (5 mg / kg)

[0157] Each group was given the drug by gavage once a day for 3 consecutive weeks with a dosage of 10 ml / kg. The normal group and the model group were given the same volume of 0.3% sodium carboxymethyl cellulose by gavage.

[0158] 3.3 Detection indicators

[0159] (1) Uric acid test

[0160] Before administration and 3 weeks after administration, mice were fasted overnight (without water deprivation) and blood was collected from their orbits before administration on the same day. The blood samples were allowed to stand for 1 hour and then centrifuged at 3500 rpm for 15 minutes to separate the serum. The uric acid concentration in the fasting serum of each group was detected using a uric acid kit.

[0161] (2) Blood sugar, blood lipid and glucose tolerance testing

[0162] During the third week of dosing, mice were fasted overnight (without water withdrawal) and blood was collected from their orbits before dosing on the same day as a baseline blood sample (0 h). Subsequently, mice in each group were intraperitoneally injected with 2.0 g / kg of glucose. Blood was collected from their orbits 0.5, 1, and 2 h after glucose injection. The blood samples were allowed to rest for 1 h and then centrifuged at 3500 rpm for 15 min to separate serum. Glucose, TC, and triglyceride levels were measured using a kit in the baseline blood sample. Glucose levels were measured at the remaining three time points. Glucose tolerance curves were plotted using blood glucose levels at the four time points, and the area under the curve (AUC) was calculated and compared between groups.

[0163] 3.4 Data processing and statistical methods

[0164] The data were expressed as mean ± standard deviation (M ± SD). The inter-group comparisons were analyzed by ANOVA using GraphPad Prism 6 software, with P < 0.05 as the significance standard.

[0165] 3.5 Results

[0166] (1) Effect on serum uric acid levels

[0167] The results of serum uric acid levels in each group are shown in Figure 6. After 3 weeks of administration, both the febuxostat and JKT test groups could significantly reduce the serum uric acid concentration in the model mice, while rosiglitazone had no significant effect on the serum uric acid concentration in the model mice.

[0168] (2) Effects on fasting blood glucose and glucose tolerance

[0169] The glucose tolerance-time curves for each group are shown in Figures 7A-7C, and the area under the glucose tolerance-time curve (AUC) is shown in Figure 8. Compared with normal mice, the fasting blood glucose and area under the glucose tolerance curve (AUC) of the hyperuricemia model mice were significantly increased, indicating that this hyperuricemia model also exhibited lipid metabolism disorders. Compared with the model group, febuxostat had no significant effect on fasting blood glucose and the AUC of the glucose tolerance curve, while rosiglitazone significantly reduced both fasting blood glucose and the AUC of the model mice. All JKT test groups also showed significant improvements in fasting blood glucose and the AUC of the model mice.

[0170] (3) Impact on blood lipid levels

[0171] Figures 9A-9B show the results of triglyceride (TG) and total cholesterol (TC) levels in each group. Compared with normal mice, fasting triglyceride (TC) levels in hyperuricemia model mice were elevated, while total cholesterol (TC) levels remained unchanged. Compared with the model group, each test drug reduced triglyceride levels in the model mice, while total cholesterol (TC) levels were not significantly affected.

[0172] Example 4. Effects of JKT and its optical isomers on gouty arthritis in rats induced by sodium urate

[0173] 4.1 Animal grouping

[0174] After being purchased and raised for one week, SD rats were randomly divided into the following 8 groups according to body weight, with 8 rats in each group:

[0175] (1) Model group

[0176] (2) Positive drug Febuxostat (10 mg / kg)

[0177] (3) RS-JKT high dose (10 mg / kg)

[0178] (4) RS-JKT low dose (5 mg / kg)

[0179] (5) High dose of R-JKT (10 mg / kg)

[0180] (6) Low dose of R-JKT (5 mg / kg)

[0181] (7) S-JKT high dose (10 mg / kg)

[0182] (8) S-JKT low dose (5 mg / kg)

[0183] 4.2 Model establishment

[0184] Overnight fasted rats were gavaged with the test drug at a volume of 20 mL / kg. The model group received the same volume of 0.3% sodium carboxymethylcellulose. Thirty minutes after gavage, the right hind ankle joint of the rat was disinfected with iodine. A 1 mL syringe was inserted into the ankle joint cavity from the outside of the right ankle joint of the right hind foot at a 45-degree angle to the tibia. 0.2 mL of sodium urate suspension (25 mg / mL) was injected into each rat. The syringe was removed and applied with a cotton swab for several seconds to prevent leakage.

[0185] 4.3 Detection indicators

[0186] The hind paw volume of rats was measured using the water displacement method. The baseline volume was measured once immediately after sodium urate injection. Subsequently, the hind paw volume of rats was measured 0.5, 1, 2, 4, and 6 hours after inflammation. The time to peak swelling and resolution was observed, and the degree of swelling at each time point was calculated to evaluate the anti-inflammatory effect. The calculation formula is as follows:

[0187] Swelling (mL) = (measured volume - basal volume)

[0188] 4.4 Data processing and statistical methods

[0189] The data were expressed as mean ± standard deviation (M ± SD). The inter-group comparisons were analyzed by ANOVA using GraphPad Prism 6 software, with P < 0.05 as the significance standard.

[0190] 4.5 Results

[0191] The results, as shown in Figures 10A-10C, show that injection of sodium urate into the ankle joint caused significant swelling in the rat hindfoot, reaching a peak around 4 hours. JKT and its optical isomers significantly inhibited the swelling of rats with gouty arthritis induced by sodium urate, while febuxostat had no effect on joint swelling. At the same dose, the inhibitory effects of the tested drugs on sodium urate-induced arthritis were as follows: S-JKT ≈ RS-JKT > R-JKT.

[0192] Example 5. Improvement effect of JKT and its optical isomers on type 2 diabetes mouse model

[0193] 5.1 Model establishment

[0194] All mice, except the normal control group, were fed a high-fat diet. After three weeks of feeding, streptozotocin (STZ 40 mg / kg) was injected intraperitoneally. Fasting blood glucose was measured 72 hours after STZ injection, and mice with blood glucose >11 mmol / L were designated as type 2 diabetes for testing. (Mice with blood glucose levels below the target were given an additional injection of STZ 40 mg / kg.) During the treatment period, model mice continued to be fed a high-fat diet.

[0195] 5.2 Grouping and Dosing

[0196] Mice with successful hyperglycemia model were divided into the following 8 groups, with 8 mice in each group:

[0197] (1) Model group

[0198] (2) Positive drug rosiglitazone (10 mg / kg)

[0199] (3) RS-JKT high dose (10 mg / kg)

[0200] (4) RS-JKT low dose (5 mg / kg)

[0201] (5) High dose of R-JKT (10 mg / kg)

[0202] (6) Low dose of R-JKT (5 mg / kg)

[0203] (7) S-JKT high dose (10 mg / kg)

[0204] (8) S-JKT low dose (5 mg / kg)

[0205] Eight normal mice were set up as the control group. Each group was given the drug by gavage once a day for 4 consecutive weeks, with a dosage of 10 ml / kg. The normal group and the model group were given the same volume of 0.3% sodium carboxymethyl cellulose by gavage.

[0206] 5.3 Index determination

[0207] (1) General condition

[0208] Observe the coat color, demeanor, spirit, etc., and record the animal's death.

[0209] (2)Weight

[0210] Weigh yourself once a week and observe weight changes.

[0211] (3) Fasting blood sugar and blood lipids

[0212] After 2 and 4 weeks of administration, blood was collected from the orbital cavity and serum was separated to measure serum glucose, total cholesterol, and triglyceride levels.

[0213] (4) Glucose tolerance test

[0214] Five days before the end of the experiment, mice were fasted for 12 h but not water, and then injected with glucose (2.0 g / kg) for a tolerance test. Blood was collected by capillary orbital tube, and the serum was separated by centrifugation at 3500 rpm for 10 min. The blood glucose levels of each group of animals were measured using a glucose kit before glucose injection and 0.5, 1, and 2 h after injection. The glucose tolerance curve was drawn and the area under the curve (AUC) was calculated.

[0215] 5.4 Results

[0216] (1) General condition

[0217] Mice in the normal group showed normal appearance and behavior during the experiment, with no significant changes in food intake, water consumption, or defecation. Mice in the model group showed decreased spontaneous activity, matted fur, and most exhibited polydipsia, polyphagia, and polyuria. No mortality occurred in any of the groups during the experiment.

[0218] (2)Weight

[0219] The body weight results for each group are shown in Figures 11A-11C. The normal group mice showed normal weight gain during the experiment, while the model group showed no weight gain, consistent with the weight loss symptoms associated with diabetes. The test drugs did not significantly affect the body weight of the model mice.

[0220] (3) Fasting blood sugar and blood lipids

[0221] The blood glucose level results for each group are shown in Figures 12A-12C. Compared with the normal group, the fasting blood glucose level in the model group increased significantly during the trial. The fasting blood glucose levels of RS-JKT and S-JKT samples after 4 weeks of intervention were significantly lower than those of the model group. R-JKT showed a trend toward lowering blood glucose, but the improvement was not significant.

[0222] The results of serum triglyceride levels in each group are shown in Figure 13. Compared with the normal group, the serum triglyceride level in the model group was significantly increased. Four weeks of RS-JKT intervention significantly reduced the serum triglyceride level in the model mice. S-JKT and R-JKT showed a trend of reducing serum triglyceride, but the improvement was not significant.

[0223] The results of serum cholesterol levels in each group are shown in Figure 14. Compared with the normal group, the postprandial serum cholesterol level in the model group was significantly increased. Four weeks of RS-JKT intervention significantly reduced the serum cholesterol level of the model mice. S-JKT and R-JKT showed a trend of lowering serum cholesterol, but the improvement was not significant.

[0224] (4) Glucose tolerance test

[0225] The results of glucose tolerance levels for each group are shown in Figures 15A-15C, and the results of the area under the glucose-time curve (AUC) for glucose tolerance are shown in Figure 16. Compared with the normal group, the diabetic model group showed a significant increase in blood glucose levels and an increase in the area under the glucose tolerance curve after oral glucose administration, indicating impaired glucose tolerance. Samples RS-JKT, S-JKT, and R-JKT all significantly improved the glucose tolerance curve of diabetic mice, with RS-JKT having a particularly pronounced improvement.

[0226] From the above examples, it can be found that in the hypoxanthine-induced acute hyperuricemia model in mice, JKT and its optical isomers can inhibit the increase in serum uric acid in mice caused by hypoxanthine to varying degrees, resulting in a decrease in the serum uric acid concentration-time curve. This result suggests that JKT and its optical isomers have a potential inhibitory effect on uric acid production. The uric acid-lowering effect of the same dose of the test substances is as follows: febuxostat > R-JKT > RS-JKT > S-JKT. In this model, the acute uric acid-lowering effect of febuxostat is significantly stronger than that of JKT and its optical isomers.

[0227] In a mouse model of chronic hyperuricemia induced by hypoxanthine combined with potassium oxonate, JKT and its optical isomers significantly reduced serum uric acid concentrations, and the magnitude of the reduction increased with prolonged administration. At the same dose, the order of uric acid-lowering efficacy was: febuxostat > R-JKT > RS-JKT > S-JKT. In this model, although febuxostat's chronic uric acid-lowering effect was still stronger than that of JKT and its optical isomers, the difference in efficacy was significantly narrowed compared to the acute model, with R-JKT's uric acid-lowering effect approaching that of febuxostat at the same dose.

[0228] In a model of chronic hyperuricemia accompanied by glucose and lipid metabolism disorders induced by hypoxanthine combined with potassium oxalate, JKT and its optical isomers significantly improved fasting blood glucose and the area under the glucose tolerance curve in mice, with RS-JKT having a relatively stronger effect. JKT and its optical isomers also reduced fasting triglyceride levels in mice.

[0229] JKT and its optical isomers significantly inhibited the swelling of rats with gouty arthritis induced by sodium urate, while febuxostat had no effect on joint swelling. At the same dose, the inhibitory effect of each test drug on sodium urate-induced arthritis was in the order of S-JKT ≈ RS-JKT > R-JKT.

[0230] In a high-fat diet combined with streptozotocin-induced type 2 diabetes model, JKT and its optical isomers had no significant effect on mouse body weight. JKT and its optical isomers significantly reduced fasting blood glucose levels in mice. RS-JKT and S-JKT significantly reduced fasting blood glucose levels; R-JKT showed a trend toward lowering blood glucose, but the improvement was not significant. JKT and its optical isomers reduced serum triglyceride levels in mice. RS-JKT significantly reduced serum triglyceride levels in model mice; S-JKT and R-JKT showed a trend toward lowering serum triglyceride levels, but the improvement was not significant. JKT and its optical isomers significantly reduced serum cholesterol levels in mice; RS-JKT significantly reduced serum cholesterol levels in mice; S-JKT and R-JKT showed a trend toward lowering serum cholesterol, but the improvement was not significant. RS-JKT, S-JKT, and R-JKT all significantly improved the glucose tolerance curve of diabetic mice, with RS-JKT showing a particularly significant improvement.

[0231] In summary, JKT and its optical isomers demonstrate significant uric acid-lowering effects in both acute and chronic hyperuricemia models. They also exhibit significant anti-inflammatory and detumescent effects in rats with gouty arthritis induced by sodium urate. They also demonstrate significant hypoglycemic effects in the chronic hyperuricemia model associated with glucose and lipid metabolism disorders, and in type 2 diabetes induced by a high-fat diet combined with streptozotocin. Zaltoprofen, a nonsteroidal anti-inflammatory analgesic drug with many years of clinical use, has been creatively discovered to have significant therapeutic value in the treatment of metabolic disorders such as hyperuricemia, gout, glucose and lipid metabolism disorders, and diabetes.

[0232] Example 6 Comparison of the pharmacodynamics of five nonsteroidal anti-inflammatory drugs against hyperuricemia

[0233] 6.1 Mouse grouping and drug treatment

[0234] Male KM mice were housed in a barrier-grade room with a 12-hour light-dark cycle and had free access to a standard diet and clean drinking water. The animal room temperature was maintained at 25 ± 2°C, and the relative humidity was maintained between 30% and 70%. After acclimation, the mice were randomly divided into six groups (8 mice each) according to body weight: the model control group, the RS-JKT group, the aspirin group, the ibuprofen group, the diclofenac sodium group, and the acetaminophen group, for a total of 48 mice. The model group and all treatment groups were fed a standard diet. On the day of the acute experiment, an acute hyperuricemia mouse model was established in each group with an intraperitoneal injection of 1 g / kg hypoxanthine (10 ml / kg). Hypoxanthine and each nonsteroidal anti-inflammatory drug were suspended in a 0.5% CMC-Na solution. The dosage of each nonsteroidal anti-inflammatory drug was converted based on the clinical adult dosage. Details are shown in Table 1 below.

[0235] Table 1 Dosage settings for different nonsteroidal anti-inflammatory drugs

[0236] 6.2 Pharmacological efficacy of single-dose administration of different nonsteroidal anti-inflammatory drugs in acute hyperuricemia

[0237] Mice were acclimated for 5 days and fasted for 12 hours. Fasting blood samples were collected via capillary orbital blood sampling. Following this, each group was gavaged with the corresponding test drug (RS-JKT 20 mg / kg, aspirin 250 mg / kg, ibuprofen 150 mg / kg, diclofenac sodium 20 mg / kg, and acetaminophen 250 mg / kg). The model group was gavaged with normal saline (10 ml / kg). Thirty minutes after gavage, each group received an intraperitoneal injection of 10 ml / kg hypoxanthine solution. Capillary orbital blood samples were collected 30, 60, 120, and 360 minutes after the hypoxanthine injection. After stabilization, the blood samples were centrifuged at 3500 rpm for 15 minutes to obtain serum, which was then assayed for uric acid levels according to the uric acid assay kit instructions.

[0238] Effects of a single administration of different nonsteroidal anti-inflammatory drugs on serum uric acid levels in mice with acute hyperuricemia

[0239] The results are shown in Figure 17. The blood uric acid level in the model group reached a peak at 60 minutes after hypoxanthine injection. The effects of the five tested non-steroidal anti-inflammatory drugs on the serum uric acid levels of model mice showed significant differences. Compared with the model group, RS-JKT significantly reduced the blood uric acid levels at 1 and 2 hours after modeling (P < 0.05, P < 0.01), showing a significant inhibitory effect on uric acid production. Ibuprofen, diclofenac sodium, and acetaminophen had an increasing or decreasing effect on blood uric acid levels at different times, but the changes were small and the effects were not obvious. The blood uric acid levels in the aspirin group were higher than those in the model group at each time point after modeling, with statistically significant differences at 2 and 6 hours (P < 0.05, P < 0.01), indicating that aspirin has a clear effect of increasing blood uric acid.

[0240] These results suggest that, although both are NSAIDs with similar anti-inflammatory and analgesic mechanisms, RS-JKT exhibits a significant uric acid-lowering effect, whereas other NSAIDs, such as ibuprofen, diclofenac sodium, acetaminophen, and aspirin, do not. This result suggests that RS-JKT's uric acid-lowering effect may not be dependent on the pharmacological pathways of its NSAID counterparts, but rather on a novel mechanism of action.

[0241] The technical solution of the present invention is not limited to the above-mentioned specific embodiments. Any technical variations made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. Use of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing metabolic disorders.

2. The use according to claim 1, characterized in that The zaltoprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemate, an S optical isomer or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.

3. The use according to claim 1, characterized in that The metabolic disorder includes at least one of uric acid metabolism disorder, blood sugar metabolism disorder or blood lipid metabolism disorder.

4. The use according to claim 1, characterized in that The metabolic disorder comprises at least one of hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein aberration, liver inflammation, adipose tissue inflammation, fatty liver disease, non-alcoholic fatty liver disease, hypercholesterolemia, coronary heart disease, congestive heart failure, stroke, peripheral vascular disease, atherosclerosis, arteriosclerosis, obesity, nephrolithiasis, kidney disease, diabetic retinopathy, insulin resistance, hyperinsulinemia, hypertension, hepatic steatosis, fatty liver, non-alcoholic fatty liver disease, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormalities, neurodegenerative diseases or Alzheimer's disease; Preferably, the metabolic disorder includes at least one of acute hyperuricemia, chronic hyperuricemia, gouty arthritis caused by uric acid, glucose and lipid metabolism disorder associated with chronic hyperuricemia model, or type 2 diabetes.

5. The use according to claim 1, characterized in that: The medicine can reduce at least one of blood uric acid, blood sugar, glucose tolerance, cholesterol and triglyceride.

6. Use of a racemate or R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing uric acid metabolism disorders.

7. Use of a racemate or S optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing blood sugar metabolism disorders and / or blood lipid metabolism disorders.

8. The method according to any one of claims 1 to 7, characterized in that The drug also includes a pharmaceutically acceptable carrier, Preferably, the dosage form of the drug includes tablets, capsules, granules, oral solutions, aqueous injections, powder injections, lyophilized powder injections, sprays, suppositories or pills.

9. The method according to any one of claims 1 to 7, characterized in that The administration routes of the drug include oral administration, injection, intravenous drip, sublingual administration, spray inhalation or rectal administration.

10. A method for reducing uric acid, blood glucose and / or blood lipid levels in a subject, the method comprising administering an effective amount of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof.

11. The method according to claim 10, characterized in that The zaltoprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemate, an S optical isomer or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof, Preferably, the method comprises administering to a subject in need thereof an effective amount of a racemate or R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof for reducing the subject's uric acid level; Preferably, the method comprises administering an effective amount of a racemate or S optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof for lowering blood glucose and / or blood lipid levels in the subject.

12. A method for preventing or treating a metabolic disorder, the method comprising administering an effective amount of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof.

13. The method according to claim 12, characterized in that The zaltoprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemate, an S optical isomer or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.

14. The method according to claim 12, characterized in that The metabolic disorder includes at least one of uric acid metabolism disorder, blood sugar metabolism disorder or blood lipid metabolism disorder; Preferably, the metabolic disorder comprises at least one of hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein aberration, liver inflammation, adipose tissue inflammation, fatty liver disease, non-alcoholic fatty liver disease, hypercholesterolemia, coronary heart disease, congestive heart failure, stroke, peripheral vascular disease, atherosclerosis, arteriosclerosis, obesity, nephrolithiasis, kidney disease, diabetic retinopathy, insulin resistance, hyperinsulinemia, hypertension, hepatic steatosis, fatty liver, non-alcoholic fatty liver disease, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormalities, neurodegenerative diseases or Alzheimer's disease; More preferably, the metabolic disorder includes at least one of acute hyperuricemia, chronic hyperuricemia, gouty arthritis caused by uric acid, glucose and lipid metabolism disorder associated with chronic hyperuricemia model, or type 2 diabetes.

15. The method according to any one of claims 10 to 14, characterized in that The method comprises administering zaltoprofen or a pharmaceutically acceptable salt thereof at a dose of 0.01-100 mg / kg, preferably 0.1-50 mg / kg, and more preferably 0.5-30 mg / kg to a subject in need thereof.

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