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

Abstract

The present invention provides new uses of phenylpropionic acid analogs in the treatment and / or prevention of metabolic disorders.

Description

Technical Field

[0001] This invention belongs to the field of medicine, and more specifically, this invention relates to novel uses of phenylpropionic acid analogs in the treatment or prevention of metabolic disorders. Background Technology

[0002] Metabolic disorders are pathological imbalances in the body's digestion, absorption, and excretion of substances, resulting in a disharmony between supply and demand. These disorders can manifest as disturbances in one or more substances. Different metabolic states can lead to different diseases; for example, glucose metabolism disorders cause diabetes, lipid metabolism disorders cause hyperlipidemia, and uric acid metabolism disorders cause gout. 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 typical feature of NAFLD affecting adults and children. Although hepatic steatosis often appears as a benign condition without significant 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 becoming a major risk factor for end-stage liver disease. Therefore, developing 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, cervicobrachial syndrome, and postoperative, post-traumatic, and post-tooth extraction anti-inflammatory and analgesic conditions. Summary of the Invention

[0004] This invention provides a novel use of the phenylpropionic acid analogue zaltobuprofen for the treatment or prevention of metabolic disorders, particularly for the treatment or prevention of metabolic disorders related to uric acid, blood glucose, and blood lipids.

[0005] One aspect of the present invention provides the use of zaltopibuprofen or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the treatment and / or prevention of metabolic disorders.

[0006] In some embodiments, the zaltobuprofen or a pharmaceutically acceptable salt thereof includes at least one of a racemic mixture, an S-type optical isomer, or an R-type optical isomer of zaltobuprofen or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the metabolic disorder includes at least one of uric acid metabolism disorder, glucose metabolism disorder, or lipid metabolism disorder.

[0008] In some embodiments, the metabolic disorder comprises at least one of hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein disorder, 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 disease, or Alzheimer's disease.

[0009] In some embodiments, the metabolic disorder comprises at least one of acute hyperuricemia, chronic hyperuricemia, uric acid-induced gouty arthritis, glucose and lipid metabolism disorder accompanying chronic hyperuricemia model, or type 2 diabetes.

[0010] In some embodiments, the drug can reduce at least one of blood uric acid, blood glucose, glucose tolerance, cholesterol, and triglyceride.

[0011] Another aspect of the present application provides use of a racemic or R-type optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a uric acid metabolism disorder.

[0012] In some embodiments, the uric acid metabolism disorder comprises at least one of acute hyperuricemia, chronic hyperuricemia, etc.

[0013] Still another aspect of the present application provides use of a racemic or S-type optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing a glucose metabolism disorder and / or a lipid metabolism disorder.

[0014] In some embodiments, the glucose metabolism disorder and / or the lipid metabolism disorder comprises at least one of glucose and lipid metabolism disorder accompanying chronic hyperuricemia model, diabetes, etc.

[0015] In some embodiments, the dosage form of the medicament comprises a tablet, a capsule, a granule, an oral solution, an aqueous injection, a powder injection, a lyophilized powder injection, a spray, a suppository, or a dripping pill.

[0016] In some embodiments, the administration route of the medicament comprises oral administration, injection administration, intravenous drip administration, sublingual administration, spray inhalation, or rectal administration.

[0017] Still another aspect of the present application provides a method of reducing uric acid, blood glucose, and / or lipid levels in a subject, the method comprising administering to a subject in need thereof an effective amount of zaltoprofen or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the zaltoprofen or the pharmaceutically acceptable salt thereof comprises at least one of a racemate, an S optical isomer, or an R optical isomer of zaltoprofen or the pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the method comprises administering to a subject in need thereof an effective amount of a racemate or an R optical isomer of zaltoprofen or the pharmaceutically acceptable salt thereof for reducing uric acid level in the subject.

[0020] In some embodiments, the method comprises administering to a subject in need thereof an effective amount of a racemate or an S optical isomer of zaltoprofen or the pharmaceutically acceptable salt thereof for reducing blood glucose and / or blood lipid level in the subject.

[0021] In some embodiments, the method comprises administering to a subject in need thereof an effective amount of a racemate or an R optical isomer of zaltoprofen or the pharmaceutically acceptable salt thereof for reducing uric acid level in the subject.

[0022] In some embodiments, the zaltoprofen or the pharmaceutically acceptable salt thereof comprises at least one of a racemate, an S optical isomer, or an R optical isomer of zaltoprofen or the pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the metabolic disorder comprises at least one of a uric acid metabolic disorder, a blood glucose metabolic disorder, or a blood lipid metabolic disorder.

[0024] In some embodiments, the metabolic disorder comprises at least one of hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein disorder, 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 steatohepatitis, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormality, neurodegenerative disease, or Alzheimer's disease.

[0025] In some embodiments, the metabolic disorder comprises at least one of acute hyperuricemia, chronic hyperuricemia, gouty arthritis caused by uric acid, glucose and lipid metabolic disorder accompanying a chronic hyperuricemia model, or type 2 diabetes.

[0026] In some embodiments, the method comprises administering to a subject in need thereof a dose of 0.01-100 mg / kg, preferably a dose of 0.1-50 mg / kg, further preferably a dose of 0.5-30 mg / kg of zaltoprofen or a pharmaceutically acceptable salt thereof.

[0027] The present application has found that zaltoprofen has a uric acid-lowering effect on hyperuricemia and an anti-inflammatory effect on gouty arthritis caused by uric acid. It has also found that zaltoprofen has a blood glucose-lowering and blood lipid-lowering effect on glucose and lipid metabolism disorders and type 2 diabetes accompanying hyperuricemia. The present application has further found that different optical isomer forms of zaltoprofen have different effects on different metabolic disorders, which provides important value for the clinical application of zaltoprofen in the prevention and treatment of metabolic disorder-related diseases such as hyperuricemia, gout, and diabetes. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 The effect of JKT and its optical isomers on serum uric acid concentration in a mouse hyperuricemia model induced by hypoxanthine is shown (N=8, M±SD).

[0029] Figure 2 The effect of JKT and its optical isomers on the area under the serum uric acid concentration-time curve (AUC) in a mouse hyperuricemia model induced by hypoxanthine is shown (N=8, M±SD); **P<0.01, compared with the model group.

[0030] Figure 3 The inhibition rate of JKT and its optical isomers on the area under the serum uric acid concentration-time curve (AUC) in a mouse hyperuricemia model induced by hypoxanthine is shown (calculated according to the mean value of each group).

[0031] Figure 4 The effect of JKT and its optical isomers on serum uric acid concentration in a mouse chronic hyperuricemia model induced by hypoxanthine+potassium oxonate is shown (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.

[0032] Figure 5 The inhibition rate of JKT and its optical isomers on serum uric acid in a mouse chronic hyperuricemia model induced by hypoxanthine+potassium oxonate is shown (calculated according to the mean value of each group).

[0033] Figure 6 The effect of JKT and its optical isomers on serum uric acid concentration in a mouse chronic hyperuricemia model induced by hypoxanthine+potassium oxonate is shown (N=8, M±SD); **P<0.01, compared with the normal group;## P<0.01, compared with the model group.

[0034] Figure 7 The effects of JKT and its optical isomers on glucose-time curves in a mouse model of chronic hyperuricemia induced by hypoxanthine + potassium oxonate were shown (N = 8, M ± SD), where A was the RS-JKT group, B was the R-JKT group, and C was 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.

[0035] Figure 8 The effects of JKT and its optical isomers on the area under the glucose-time curve (AUC) of a mouse model of chronic hyperuricemia induced by hypoxanthine and potassium oxonate were shown (N=8, M±SD); **P<0.01, compared with the normal group; #P<0.05, ##P<0.01, compared with the model group.

[0036] Figure 9 The effects of JKT and its optical isomers on blood lipid levels in a mouse model of chronic hyperuricemia induced by hypoxanthine + potassium oxonate were shown (N = 8, M ± SD), where A represents triglycerides (TG) and B represents total cholesterol (TC).

[0037] Figure 10 The effects of JKT and its optical isomers on sodium urate-induced gouty arthritis in rats were shown (N=8, M±SD), where A was the RS-JKT group, B was the R-JKT group, and C was the S-JKT group; #P<0.05, ##P<0.01, compared with the model group.

[0038] Figure 11 The effect of JKT and its optical isomers on body weight (g) is shown. N = 8), 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.

[0039] Figure 12 The effect on blood glucose levels (mmol / L) was shown. 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.

[0040] Figure 13 The effect on serum triglycerides (mmol / L) was shown. N=8); *P<0.05, **P<0.01, compared with normal group; # P<0.05, ## P<0.01, compared with model group.

[0041] Figure 14 The effect on serum cholesterol (mmol / L) is shown N=8); *P<0.05, **P<0.01, compared with normal group; # P<0.05, ## P<0.01, compared with model group.

[0042] Figure 15 The effect of JKT and its optical isomers on the glucose tolerance blood glucose-time curve (N=8, M±SD) is shown, 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.

[0043] Figure 16 The effect of JKT and its optical isomers on the area under the glucose tolerance blood glucose-time curve (AUC) (N=8, M±SD) is shown; **P<0.01, compared with the normal group; #P<0.05, ##P<0.01, compared with the model group.

[0044] Figure 17 The serum uric acid content (mg / L) at different time points after single administration is shown (N=8, M±SD); *P<0.05, **P<0.01, compared with the model group. DETAILED DESCRIPTION

[0045] In order to make the objects, technical solutions, and advantages of the present application clearer, the present application will be further described in detail below with reference to examples. The specific examples described herein are only used to explain the present application and do not constitute any limitation on the present application. In addition, in the following description, the description of well-known structures and technologies is omitted to avoid unnecessary confusion of the concept of the present disclosure. Such structures and technologies are also described in many publications.

[0046] Definitions

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. For purposes of interpreting this specification, the following definitions will apply and, where appropriate, terms used in the singular form will also include the plural form and vice versa.

[0048] As used herein, the terms "a" and "one" include plural referents unless the context clearly dictates otherwise. For example, reference to "a cell" includes a plurality of such cells, as well as equivalents thereof known to those skilled in the art, and so forth.

[0049] As used herein, the term "about" means ±20% of the number that it precedes. In some embodiments, the term "about" means ±10% of the number that it precedes. In some embodiments, the term "about" means ±5% of the number that it precedes.

[0050] As used herein, the term "metabolic disorder" means a metabolic abnormality caused by a disease in the body or by a congenital defect of the body. In the present application, the metabolic disorder includes, but is not limited to, a disorder of uric acid metabolism, a disorder of sugar metabolism, a disorder of lipid metabolism, and the like. In some specific embodiments, the metabolic disorder includes hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein disorder, 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, kidney stone disease, kidney disease, diabetic retinopathy, insulin resistance, hyperinsulinemia, hypertension, hepatic steatosis, fatty liver, non-alcoholic fatty liver disease, polycystic ovary syndrome, acanthosis nigricans, endocrine abnormality, neurodegenerative disease, or Alzheimer's disease, and the like.

[0051] Zaltoprofen (10, 11-dihydro-α-methyl-10-oxo-dibenz[b, f]thioxepine-2-acetic acid, Zaltoprofen) has the following structure shown in Formula (I). Zaltoprofen is a potent phenylpropionic acid non-steroidal analgesic anti-inflammatory drug. Zaltoprofen is a racemate, containing both S-type optical isomer (S-) and R-type optical isomer (R-). In this document, the code of Zaltoprofen is JKT, the racemate form of Zaltoprofen is represented as RS-JKT, the S-type optical isomer is represented as S-JKT, and the R-type optical isomer is represented as R-JKT.

[0052]

[0053] As used herein, the term "treatment" includes an effect on a subject that is afflicted with a particular disease, disorder or condition, which effect reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also includes an effect on a subject prior to the onset of a particular disease, disorder or condition ("prophylactic treatment").

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

[0055] The term "pharmaceutically acceptable carrier" as used herein means any form of a non-toxic, inert, solid, semi-solid, diluent, encapsulation material, or formulation auxiliary of whatever class, which is compatible with the other ingredients of the formulation. 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; malt; gelatin; talc; lubricants such as sodium lauryl sulfate and magnesium stearate; and coloring agents; releasing agents; coating agents; sweetening, flavoring and perfuming agents; preservatives and antioxidants can also be present in the compositions, in amounts that are compatible with a given formulation.

[0056] The term "subject" as used herein 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 elderly adults)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), bovines, porcines, equines, ovines, caprines, rodents, felines, and / or canines. 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] The term "effective amount" as used herein means an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of a drug of the application can vary depending on, for example, 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 includes both a therapeutically effective amount and a prophylactically effective amount.

[0058] The term "therapeutically effective amount" as used herein means an amount that is 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 means that 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 encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0059] An effective amount of the drug of the present application will generally be in the range of 0.01 mg to 100 mg of the drug per kg of patient body weight per average daily dose, preferably 0.1 mg to 50 mg of the drug per kg of patient body weight per average daily dose, and further preferably 0.5 mg to 30 mg of the drug per kg of patient body weight per average daily dose, in single or divided doses. Generally, the drug of the present application can be administered to such a patient in need of such treatment in the range of about 0.1 mg / kg to about 50 mg / kg per day of each patient, preferably 0.5 mg / kg to 30 mg / kg. For example, the daily dose 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 per day of each patient. The administration can be one or more times per day, per week (or days apart), or on an intermittent schedule. For example, the drug can be administered one or more times per day on a daily basis (e.g., on a Monday), for an indefinite or for a period of several weeks, e.g., 4-10 weeks. Alternatively, the drug can be administered daily for a period of several days (e.g., 2-10 days), followed by a period of non-administration of the drug for several days (e.g., 1-30 days), with the cycle repeated indefinitely or for a given number of times, e.g., 4-10 cycles. For example, the drug of the present application can be administered daily for a period of 5 days, followed by a period of non-administration for 9 days, followed by a period of daily administration for 5 days, followed by a period of non-administration for 9 days, and so on, with the cycle repeated indefinitely or for 4-10 times. It is also possible to administer the drugs provided herein on a chronic basis (“chronic administration”). Chronic administration refers to administration of the drug over a long period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can continue indefinitely, e.g., for the remainder of the subject’s life. In some embodiments, chronic administration is intended to provide a constant level of the drug in the blood, e.g., within a therapeutic window, over a long period of time.

[0060] The term "prophylactically effective amount" as used herein 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 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, which provides a prophylactic benefit in the process of preventing a disease, disorder or condition. The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or enhances the prophylactic effect of other prophylactic agents.

[0061] Generally, an effective amount of a drug provided herein is administered. The amount of a drug actually to be administered can be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual drug 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 a condition described herein, a drug provided herein is administered to a subject at risk of developing the condition, typically on the advice and under the supervision of a doctor, at a dosage level as described above. Subjects at risk of developing a particular condition generally include those having a family history of the condition, or those determined to be particularly susceptible to developing the condition, for example, through genetic testing or screening.

[0063] A drug provided herein can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, administration by inhalation, topical administration, rectal administration, nasal administration, buccal administration, administration via an implant, or other means of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration, or infusion techniques.

[0064] For example, in some embodiments, a drug can be administered as a bolus, for example, to raise 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 through the body, for example, a bolus dose intramuscularly or subcutaneously releases the active ingredient slowly, while a bolus delivered directly to the vein (for example, by IV drip) can deliver more quickly, such that the concentration of the active ingredient in the blood rises quickly to an effective level. In other embodiments, a drug can be administered as a continuous infusion, for example, by IV drip, to provide a steady state concentration of the active ingredient in the body of the subject. In still other embodiments, a bolus dose of a drug can be administered first, followed by a continuous infusion.

[0065] For example, in other embodiments, the oral pharmaceutical can take the form of a bulk liquid solution or suspension, or a bulk powder. More commonly, however, the pharmaceutical is presented in unit dosage form to facilitate accurate dosing. The term "unit dosage form" means physically discrete units suitable for unitary dosing to human patients and other mammals, each unit containing a predetermined quantity of active material, in an amount suitable for producing the desired therapeutic effect, in association with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampules of liquid forms, or syringes, or, in the case of solid dosage forms, pills, tablets, capsules, etc. In such dosage forms, the pharmaceutical is typically the minor component, from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight, with the rest being various carriers, excipients and processing aids helpful for forming the desired dosing form.

[0066] Liquid forms suitable for oral administration can include a suitable aqueous or nonaqueous carrier and a buffer, a suspending agent, and a dispensing agent, a coloring agent, a flavoring agent, and the like. Solid forms can include, for example, any of the following ingredients, or pharmaceutical agents of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring; a stabilizer such as tartaric acid, aspartic acid, glutamic acid, and the like.

[0067] Injectable forms are typically based upon injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As before, in such dosage forms, the active pharmaceutical is typically the minor component, often from about 0.05 to 10% by weight, with the remainder being the injectable excipient and the like.

[0068] Transdermal dosage forms are typically formulated to contain active ingredients in a topical ointment or cream. When formulated in an ointment, the active ingredient typically is combined with a petrolatum or water miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are known in the art and typically include additional components to enhance penetration of the active ingredient or formulation through the skin. All such known transdermal formulations and components are contemplated to be within the scope of the present application.

[0069] The pharmaceuticals of the present application can also be administered by transdermal devices. Thus, transdermal administration can be achieved using a reservoir or porous matrix-type patch, or a variety of solid matrix self-stick patches.

[0070] The following examples and drawings are provided to aid in the understanding of the present application. It should be understood, however, that the examples and drawings are set forth only for the purpose of illustration and that the actual scope of the present application is set forth in the claims. Any modification and change can be made without departing from the spirit of the present application.

[0071] Examples

[0072] Experimental materials

[0073] 1. Test drugs

[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 Biomedicine Technology Co., Ltd.

[0075] Febuxostat tablets (Fengdingning), 40 mg x 14 tablets, Hangzhou Zhuyangxin Pharmaceutical Co., Ltd.

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

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

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

[0079] Diclofenac sodium, H10960217, purchased from China Pharmaceutical University Pharmaceutical.

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

[0081] The test drugs were all ground with 0.3% sodium carboxymethyl cellulose to prepare a suspension of the corresponding concentration for intragastric administration.

[0082] 2. Animals and feeding

[0083] (1) Species, source

[0084] Male Kunming mice, SPF level, body weight 18-22g, purchased from Henan Skb Bioscience Co., Ltd., production license number: SCXK(YU)2020-0005.

[0085] Male SD rats, SPF level, body weight 180-220g, purchased from Hangzhou Medical College Experimental Animal Center, production license number: SCXK(ZHE)2019-0002.

[0086] C57 mice, SPF level, male, 5-6 weeks old, purchased from Shanghai Bikaike Wings Biotechnology Co., Ltd., license number: SCXK(Su)2018-0006.

[0087] (4) KM male mice, 48, SPF level, body weight 18-22 g, purchased from Henan Skbess Biotechnology Co., Ltd., production license number: SCXK(Yu)2020-0005.

[0088] (2) Feeding conditions

[0089] Male Kunming mice and male SD rats were raised in the animal center of China Pharmaceutical University (animal use license number: SYXK(Su)2021-0011). The feeding laboratory temperature was 24±2℃; the relative humidity was 40%-70%; the air exchange frequency per hour was 10-15 times / hour; the light cycle was 12(day) / 12(night) hours, and no more than 5 per cage. The feed was full-value granular feed for mice, purchased from Jiangsu Cooperation Pharmaceutical Biological Engineering Co., Ltd., and its quality met the GB14924.1-2010 "General Quality Standard for Experimental Animal Compound Feed".

[0090] C57 mice were raised in a clean level animal room (animal use license number: SYXK(Su)2021-0011), the laboratory temperature was 24±2℃, the relative humidity was 60%-80%, the air exchange frequency per hour was 10-15 times / hour, and the light cycle was 12h(day) / 12h(night). No more than 5 per cage. The feed was full-value basic granular feed for mice.

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

[0092] Drinking water: purified water.

[0093] 3. Main instruments

[0094] Multifunctional ultrapure water system, Unique-R20, Unique-R Water Purification Technology Co., Ltd.; Multifunctional high-efficiency centrifuge, BECKMAN COULTER 369003 / Avanti J-E; Electronic analytical balance, Sartorius Scientific Instruments Co., Ltd. BSA124S-CW; Electric heating constant temperature blast drying oven, Shanghai Yiheng Scientific Instruments Co., Ltd. CIMO DHG-9140A; Varioskan TM LUX multifunctional microplate reader, Thermo Scientific; 4 / -20℃ low temperature freezer, Hefei Midea Co., Ltd. BCD-551EPCX; Microscale table top high speed centrifuge, Thermo Scientific 21R; KD-160 electronic scale, Dongguan Bailida Health Equipment Co., Ltd.; 3-18k low temperature centrifuge, SIGMA, USA; Vortex instrument, Scientific Industries VORTEX-2GENIE.

[0095] 4. Main reagents

[0096] Potassium oxonate, Beijing Solabio Technology Co., Ltd. (P9770); Hypoxanthine, Shanghai Aladdin Biochemical Technology Co., Ltd. (H301755); Sodium urate (S30775), Shanghai Yuan Ye Biological Technology Co., Ltd.; Streptozotocin (STZ), A610130, GenScript Biotech (Shanghai) Co., Ltd.; Sodium carboxymethylcellulose, Xilong Scientific Co., Ltd.

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

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

[0099] 1.1 Animal grouping

[0100] After the mice were adapted to feeding for 1 week, they were randomly divided into 8 groups according to body weight, 8 mice in each group, respectively:

[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) R-JKT high dose (20 mg / kg)

[0106] (6) R-JKT low dose (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] The overnight fasted mice (without water restriction) were respectively given corresponding doses of test drugs by gavage, and the volume of each drug administration was 10 mL / kg. The model group was given the same volume of 0.3% sodium carboxymethyl cellulose solution by gavage. After 30 min of gavage administration, the acute hyperuricemia animal model was established by a single intraperitoneal injection of 1 g / kg of hypoxanthine, and the injection volume was 10 mL / kg.

[0111] All mice were taken blood from the orbit before and after hypoxanthine injection at 0.5, 1, 2, and 6 h. After standing for 1 h, the serum was separated by centrifugation at 3500 rpm for 15 min, and the uric acid concentration in the serum of each group was detected by using a uric acid kit.

[0112] 1.3 Detection index

[0113] The serum uric acid (SUA) level at different time points of each group was detected by using a kit, and the uric acid concentration-time curve was drawn according to the time change of the uric acid level, 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 according to the mean value of AUC of each group

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

[0115] 1.4 Data processing and statistical method

[0116] The data were expressed as mean ± standard deviation (M ± SD), and the significant difference between groups was analyzed by ANOVA using GraphPad Prism 6 software, and P < 0.05 was taken as the significant standard.

[0117] 1.5 Results

[0118] As Figure 1As shown, the serum uric acid levels of the mice in each group were close to the base level. After intraperitoneal injection of hypoxanthine, the serum uric acid levels of the mice in the model group rapidly increased, reached a peak at 1 h, and then began to decrease, and basically returned to the base level before modeling at 6 h after modeling. Compared with the model group, each of the test drugs inhibited the increase of serum uric acid in mice caused by hypoxanthine to different extents, and lowered the serum uric acid concentration-time curve.

[0119] The area under the serum uric acid concentration-time curve (AUC) of each group is shown in Table 2. Figure 2 As shown in Table 2, each of the test drugs can significantly reduce the AUC value of the model mice; the results of the AUC inhibition rate of each group are shown in Table 3. Figure 3 As shown in Table 3, according to the AUC inhibition rate, the uric acid-lowering effect of the test drugs 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] The mice were purchased and acclimated for 1 week, and then a chronic hyperuricemia animal model was established by intragastrically administering hypoxanthine 300 mg / kg combined with intraperitoneal injection of potassium oxonate 300 mg / kg. The normal group was administered with the corresponding volume of physiological saline by gavage combined with intraperitoneal injection as a control. After two weeks of modeling, the blood uric acid levels of the normal group and the model group were detected. From the model group, mice with uric acid levels 30% higher than the mean value of the normal group were selected and randomly grouped according to the uric acid levels.

[0123] 2.2 Grouping and administration

[0124] The mice with elevated blood uric acid were divided into the following 9 groups, 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 (5mg / kg)

[0134] Each group was administered the drug once daily by gavage for 3 consecutive weeks, with a drug volume of 10 mL / kg. The normal group and the model group were administered an equal volume of 0.3% sodium carboxymethyl cellulose by gavage.

[0135] 2.3 Detection Indicators

[0136] At 1, 2, and 3 weeks after administration, mice that had been fasted overnight (but with access to water) were collected. Blood was collected from the orbital sinus on the day of administration. After the blood samples were allowed to stand for 1 hour, they were centrifuged at 3500 rpm for 15 minutes to separate the serum. The concentration of uric acid in the fasting serum of each group was detected using a uric acid kit.

[0137] 2.4 Data Processing and Statistical Methods

[0138] Data are expressed as mean ± standard deviation (M ± SD). ANOVA analysis was performed using GraphPad Prism 6 software to examine significance between groups, with P < 0.05 as the significance criterion.

[0139] 2.5 Results

[0140] The serum uric acid concentration results for each group are as follows: Figure 4 As shown in A-4C. During the 3-week administration period, the serum uric acid level in the model group mice remained stable and significantly higher than that in the normal group (P < 0.01). One week after administration, all the tested drugs significantly reduced the serum uric acid concentration in the model mice, and the uric acid reduction further increased with the extension of administration time.

[0141] The inhibition rate of hyperuricemia was calculated based on the uric acid concentrations of each group at 1, 2, and 3 weeks of drug administration [=(model group uric acid concentration - drug group uric acid concentration) / model group uric acid concentration × 100%], and the results are as follows: Figure 5 As shown, the uric acid-lowering effects of the same dose are in the following order: 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 in a model of chronic hyperuricemia.

[0143] 3.1 Model Establishment

[0144] Mice were purchased and acclimatized for one week. A chronic hyperuricemia animal model was established by gavage administration of hypoxanthine 300 mg / kg combined with intraperitoneal injection of potassium oxonate 300 mg / kg. The normal control group was administered gavage combined with intraperitoneal injection of the corresponding volume of physiological saline. Two weeks after modeling, serum uric acid levels were measured in both the normal and model groups. Mice with uric acid levels 30% higher than the mean in the normal group were selected from the model group and randomly assigned to other groups according to their uric acid levels.

[0145] 3.2 Grouping and administration

[0146] Normal and hyperuricemic model mice were taken and divided into the following 10 groups, 8 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) R-JKT low dose (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 administered once a day by gavage for 3 consecutive weeks, with a volume of 10 ml / kg, and the normal and model groups were administered with the same volume of 0.3% sodium carboxymethyl cellulose by gavage.

[0158] 3.3 Detection index

[0159] (1) Uric acid detection

[0160] Before administration and 3 weeks after administration, overnight fasted mice (without water restriction) were taken, and blood samples were taken from the eye sockets before administration on the same day. After standing for 1 h, the serum was separated by centrifugation at 3500 rpm for 15 min, and the uric acid concentration in the fasting serum of each group was detected using a uric acid kit.

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

[0162] During the third week of drug administration, mice that had been fasted overnight (but with access to water) had blood collected from their orbits before drug administration to serve as baseline blood samples (0h). Subsequently, each group of mice was intraperitoneally injected with glucose (2.0 g / kg), and orbital blood samples were collected at 0.5, 1, and 2 hours after glucose injection. After standing for 1 hour, the blood samples were centrifuged at 3500 rpm for 15 min to separate serum. GLU, TC, and TG levels were measured in the baseline blood samples using a kit, and GLU levels were measured in the blood samples at the remaining three time points. Glucose tolerance curves were plotted at the four time points, the area under the curve (AUC) was calculated, and comparisons were made between the groups.

[0163] 3.4 Data Processing and Statistical Methods

[0164] Data are expressed as mean ± standard deviation (M ± SD). ANOVA analysis was performed using GraphPad Prism 6 software to examine significance between groups, with P < 0.05 as the significance criterion.

[0165] 3.5 Results

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

[0167] Serum uric acid levels in each group are as follows: Figure 6 As shown, after 3 weeks of administration, febuxostat and JKT significantly reduced serum uric acid concentration in model mice, while rosiglitazone did not show a significant effect on improving serum uric acid concentration in model mice.

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

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

[0170] (3) Effects on blood lipid levels

[0171] The results of triglyceride (TG) and total cholesterol (TC) levels in each group are as follows: Figure 9The results are shown in Figure A-9B. Compared with normal mice, the fasting triglyceride level (TC) of the hyperuricemia model mice increased, and the total cholesterol (TC) level did not change significantly. Compared with the model mice, each of the test drugs reduced the triglyceride level of the model mice, and the total cholesterol (TC) level did not change significantly.

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

[0173] 4.1 Animal grouping

[0174] After being purchased, the SD rats were randomly divided into the following 8 groups according to body weight, 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) R-JKT high dose (10 mg / kg)

[0180] (6) R-JKT low dose (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] The rats were fasted overnight and then administered with the test drugs by gavage, the administration volume was 20 mL / kg, and the model group was administered with the same volume of 0.3% sodium carboxymethyl cellulose. Thirty minutes after the administration of the test drugs, the right hind ankle joint of the rat was disinfected with iodophor, a 1 mL syringe was inserted into the ankle joint cavity at an angle of 45 degrees from the right ankle joint of the right hind leg and the tibia, 0.2 mL (25 mg / mL) of sodium urate suspension was injected into each ankle joint, the syringe was pulled out, and a cotton swab was pressed for a few seconds to prevent the drug solution from leaking out.

[0185] 4.3 Detection index

[0186] The rat hind foot volume was determined by the drainage method. The volume was determined once immediately after the injection of sodium urate as the baseline, and then the volume of the rat hind foot was determined at 0.5, 1, 2, 4, and 6 h after the inflammation was induced to observe the peak time and the subsidence time of the swelling, and the swelling degree at each time point was calculated to evaluate the anti-inflammatory effect. The calculation formula is as follows:

[0187] Swelling (mL) = (Measured volume - Baseline volume)

[0188] 4.4 Data processing and statistical method

[0189] Data were expressed as mean ± standard deviation (M ± SD), and the significance was analyzed by ANOVA using GraphPad Prism 6 software, and P < 0.05 was considered as the significant standard.

[0190] 4.5 Results

[0191] The results are shown in Table 4.4, and Table 4.5. Figure 10 As shown in Table 4.4 and Table 4.5, ankle injection of sodium urate can cause significant swelling of the hind paw of rats, reaching a peak at about 4 h. JKT and its optical isomers have a significant inhibitory effect on the swelling of gouty arthritis caused by sodium urate in rats, while non-steroidal anti-inflammatory drugs have no effect on joint swelling. Under the same dose, the inhibitory effect of each test drug on sodium urate-induced arthritis is in the order of S-JKT ≈ RS-JKT > R-JKT.

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

[0193] 5.1 Model establishment

[0194] Except for the normal control group, the rest of the mice were fed with high-fat feed. After 3 weeks of feeding, streptozotocin (STZ 40 mg / kg) was injected intraperitoneally, and 72 h after STZ injection, fasting blood glucose was measured. Mice with blood glucose > 11 mmol / L were selected as type 2 diabetes for testing (mice with blood glucose not meeting the standard were given additional STZ injection of 40 mg / kg). During the drug treatment period, the model mice continued to be fed with high-fat feed.

[0195] 5.2 Grouping and administration

[0196] The blood glucose increased model mice were divided into the following 8 groups, 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) R-JKT high dose (10 mg / kg)

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

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

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

[0205] Eight normal mice were used as a control group. Each group was administered the drug once daily by gavage for 4 weeks at a volume of 10 ml / kg. The normal group and the model group were administered an equal volume of 0.3% sodium carboxymethyl cellulose by gavage.

[0206] 5.3 Index Measurement

[0207] (1) General situation

[0208] Observe the animal's coat color, expression, and mental state, and record any deaths.

[0209] (2)Weight

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

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

[0212] Two and four weeks after administration, blood was collected from the orbital cavity, and serum was separated to detect 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 hours but allowed free access to water. They were then injected with glucose (2.0 g / kg) for a glucose tolerance test. Blood was collected from the orbital capillary, centrifuged at 3500 rpm for 10 min to separate serum. Blood glucose levels were measured in each group of animals before and 0.5, 1 and 2 hours after glucose injection using a glucose kit. The area under the glucose tolerance curve (AUC) was calculated.

[0215] 5.4 Results

[0216] (1) General situation

[0217] Mice in the normal control group showed normal appearance and behavior during the experiment, with no significant changes in feeding, drinking, or defecation. Mice in the model group exhibited reduced spontaneous activity, dirty and disheveled fur, and most showed symptoms of polydipsia, polyphagia, and polyuria. No animals died during the experiment.

[0218] (2)Weight

[0219] The weight results for each group are as follows: Figure 11 As shown in A-11C. The normal control group mice showed normal weight gain during the experiment, while the model group showed no weight gain, consistent with weight loss symptoms in diabetic mice. The test drugs had no significant effect on the weight of the model mice in any of the groups.

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

[0221] The blood glucose level results of each group are shown in Figure 12 A-12C. Compared with the normal group, the fasting blood glucose level of the model group was significantly increased during the test period, and the fasting blood glucose level of the sample RS-JKT and S-JKT was significantly lower than that of the model group after 4 weeks of intervention; R-JKT had a trend of reducing blood glucose, but the improvement was not significant.

[0222] The serum triglyceride level results of each group are shown in Figure 13 Compared with the normal group, the serum triglyceride level of the model group was significantly increased, and the serum triglyceride level of the sample RS-JKT was significantly reduced after 4 weeks of intervention; S-JKT and R-JKT had a trend of reducing serum triglyceride, but the improvement was not significant.

[0223] The serum cholesterol level results of each group are shown in Figure 14 Compared with the normal group, the postprandial serum cholesterol level of the model group was significantly increased, and the serum cholesterol level of the sample RS-JKT was significantly reduced after 4 weeks of intervention; S-JKT and R-JKT had a trend of reducing serum cholesterol, but the improvement was not significant.

[0224] (4) Glucose tolerance test

[0225] The results of the glucose tolerance level of each group are shown in Figure 15 A-15C, and the results of the area under the blood glucose-time curve (AUC) are shown in Figure 16 Compared with the normal group, the blood glucose level after oral glucose of the diabetic model group was significantly increased, and the area under the glucose tolerance curve was significantly increased, showing impaired glucose tolerance; the samples RS-JKT, S-JKT and R-JKT could significantly improve the glucose tolerance curve of diabetic mice, and the improvement of RS-JKT was particularly obvious.

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

[0227] In the chronic hyperuricemia model of mice induced by allopurinol combined with potassium oxonate, JKT and its optical isomers can significantly reduce the serum uric acid concentration of model mice, and the uric acid-lowering amplitude further increases with the extension of the administration time. The uric acid-lowering effect of the same dose is in the order of: febuxostat > R-JKT > RS-JKT > S-JKT. In this model, although the chronic uric acid-lowering effect of febuxostat is still stronger than that of JKT and its optical isomers, the difference in the intensity of the drug effect is significantly reduced compared with the acute model, and especially the uric acid-lowering amplitude of R-JKT is close to that of febuxostat at the same dose.

[0228] In the model of glucose and lipid metabolism disorder accompanied by chronic hyperuricemia induced by allopurinol combined with potassium oxonate, JKT and its optical isomers can significantly improve the fasting blood glucose and the area under the curve of the glucose tolerance curve of mice, and RS-JKT has a relatively strong effect. JKT and its optical isomers can reduce the fasting triglyceride level of mice.

[0229] JKT and its optical isomers have a significant inhibitory effect on the swelling degree of gouty arthritis in rats induced by sodium urate, while febuxostat has no effect on joint swelling. At the same dose, the inhibitory effect of each test drug on arthritis induced by sodium urate is in the order of: S-JKT ≈ RS-JKT > R-JKT.

[0230] In the type 2 diabetes model induced by high-fat feed combined with streptozotocin, JKT and its optical isomers have no significant effect on the body weight of mice. JKT and its optical isomers can significantly reduce the fasting blood glucose level of mice, and RS-JKT and S-JKT can significantly reduce the fasting blood glucose level. R-JKT has a tendency to reduce blood glucose, but the improvement is not significant. JKT and its optical isomers can reduce the serum triglyceride level of mice, and RS-JKT can significantly reduce the serum triglyceride level of model mice. S-JKT and R-JKT have a tendency to reduce serum triglyceride, but the improvement is not significant. JKT and its optical isomers can significantly reduce the serum cholesterol level of mice, and RS-JKT can significantly reduce the serum cholesterol level of mice. S-JKT and R-JKT have a tendency to reduce serum cholesterol, but the improvement is not significant. RS-JKT, S-JKT and R-JKT can significantly improve the glucose tolerance curve of diabetic mice, and RS-JKT has a particularly obvious effect.

[0231] In summary, JKT and its optical isomer have obvious effects of reducing uric acid for acute and chronic hyperuricemia models, have obvious anti-inflammatory and detumescence effects for gouty arthritis induced by sodium urate in rats, have obvious effects of reducing blood sugar for the accompanying glucose and lipid metabolism disorder of chronic hyperuricemia model, have obvious effects of reducing blood sugar and blood lipid for type 2 diabetes induced by high-fat feed combined with streptozotocin. Zaltoprofen has been used in clinical use as a non-steroidal anti-inflammatory analgesic for many years, and the present application creatively finds that it also has remarkable use value in the treatment of hyperuricemia, gout, glucose and lipid metabolism disorder and diabetes and other metabolic disorder diseases.

[0232] Example 6 Pharmacodynamics comparison of five non-steroidal anti-inflammatory drugs against hyperuricemia

[0233] 6.1 Grouping and administration of mice

[0234] The KM male mice were bred in a barrier level room with a 12-hour light-dark cycle, and freely obtained standard diet and clean drinking water. The temperature of the animal room was controlled at 25±2℃, and the relative humidity was controlled at 30-70%. After adaptation, the mice were randomly grouped according to the body weight, and a total of 6 groups, 8 mice in each group, were prepared, i.e. model control group, RS-JKT group, aspirin group, ibuprofen group, diclofenac sodium group and acetaminophen group, a total of 48 mice. The model group and each administration group were fed with ordinary feed. On the day of acute experiment, the acute hyperuricemia mouse model was established by intraperitoneal injection of hypoxanthine 1g / kg, and the injection volume was 10ml / kg. The hypoxanthine and each non-steroidal test drug were suspended and dispersed in 0.5% CMC-Na solution. The doses of each non-steroidal anti-inflammatory drug were calculated by reference to the clinical adult drug dose, and the details are shown in Table 1 below.

[0235] Table 1 Dose setting of different non-steroidal anti-inflammatory drugs

[0236]

[0237]

[0238] 6.2 Pharmacodynamic experiment of single administration of different non-steroidal anti-inflammatory drugs under acute hyperuricemia

[0239] The mice were acclimated for 5 days, and after fasting for 12 h, the fasting blood samples were obtained by capillary orbital blood sampling. After the fasting blood samples were collected, the corresponding test drugs (RS-JKT-20 mg / kg, aspirin-250 mg / kg, ibuprofen-150 mg / kg, diclofenac sodium-20 mg / kg, acetaminophen-250 mg / kg) were administered by gavage to each group, and the model group was administered with normal saline by gavage, and the gavage volume was 10 ml / kg. After gavage for 30 min, the hypoxanthine solution was injected intraperitoneally, and the injection volume was 10 ml / kg. Capillary orbital blood sampling was performed at 30, 60, 120 and 360 min after the intraperitoneal injection of the hypoxanthine solution in each group. After the blood samples were allowed to stand, centrifugation was performed at 3500 rpm for 15 min to obtain serum, and the blood uric acid level was detected according to the uric acid kit instructions.

[0240] 6.3. Influence of single administration of different non-steroidal anti-inflammatory drugs on the change of blood uric acid level in acute hyperuricemia mice

[0241] The results are shown in Table 1. Figure 17 As shown in Table 1, the blood uric acid level of the model group reached a peak at 60 min after injection of hypoxanthine. The effects of the five tested non-steroidal anti-inflammatory drugs on the serum uric acid level of the model mice showed great differences. Compared with the model group, RS-JKT can significantly reduce the blood uric acid level 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 have a small change in the blood uric acid level at different times, and the effect is not obvious. The blood uric acid level of the aspirin group at each time point after modeling is higher than that of the model group, and there is a statistically significant difference at 2 and 6 hours (P<0.05, P<0.01), indicating that aspirin has a clear effect of increasing blood uric acid.

[0242] As can be seen, although they are non-steroidal anti-inflammatory drugs with similar anti-inflammatory and analgesic mechanisms, RS-JKT has a significant uric acid-lowering effect, while ibuprofen, diclofenac sodium, acetaminophen and aspirin do not have a uric acid-lowering effect. This result suggests that the uric acid-lowering effect of RS-JKT may not depend on the pharmacological pathway of non-steroidal anti-inflammatory drugs, but on a new pharmacological mechanism.

[0243] The technical solutions of the present application are not limited to the above specific embodiments, and any technical variations made according to the technical solutions of the present application fall within the protection scope of the present application.

Claims

1. Use of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of metabolic disorders, including uric acid metabolic disorders, including at least one of acute hyperuricemia, chronic hyperuricemia, uric acid-induced gouty arthritis, or a glycolipid metabolic disorder accompanying a chronic hyperuricemia model.

2. 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. Use according to claim 1, characterized in that, The medicament can reduce at least one of blood uric acid, blood sugar, sugar tolerance, cholesterol, and triglyceride.

4. Use of a racemate or an R optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of uric acid metabolic disorders, including at least one of acute hyperuricemia, chronic hyperuricemia, uric acid-induced gouty arthritis, or a glycolipid metabolic disorder accompanying a chronic hyperuricemia model.

5. Use according to any one of claims 1 to 4, characterized in that, The medicament further includes a pharmaceutically acceptable carrier.

6. Use according to claim 5, characterized in that, The dosage form of the medicament includes a tablet, a capsule, a granule, an oral solution, an aqueous injection, a powder injection, a spray, a suppository, or a dripping pill.

7. Use according to claim 5, characterized in that, The dosage form of the medicament is a freeze-dried powder injection.

8. Use according to any one of claims 1 to 4, characterized in that, The administration route of the medicament includes oral administration, injection administration, intravenous drip administration, sublingual administration, spray inhalation, or rectal administration.

9. Use of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing uric acid levels in a subject.

10. Use according to claim 9, 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.

11. Use according to claim 9 or 10, characterized in that, The use includes administration of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof at a dose of 0.01-100 mg / kg.

12. Use according to claim 9 or 10, characterized in that, The use includes administration of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof at a dose of 0.1-50 mg / kg.

13. Use according to claim 9 or 10, characterized in that, The use includes administration of zaltoprofen or a pharmaceutically acceptable salt thereof to a subject in need thereof at a dose of 0.5-30 mg / kg.

Images