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

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, more particularly, the present application relates to a new use of optical isomer composition of phenylpropionic acid analogues in treating or preventing metabolic disorders. BACKGROUND

[0002] Metabolic disorders are pathological, uncoordinated state of supply and demand imbalance of the body's digestion, absorption, excretion of substances, which can be manifested as a disorder of a substance or multiple substances. Different metabolic state disorders will cause different diseases, for example, glucose metabolism disorder causes diabetes, lipid metabolism disorder causes hyperlipidemia, and uric acid metabolism disorder causes 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 excessive accumulation of fat in the liver, which is the most typical feature of NAFLD affecting adults and children. Although liver steatosis usually appears as a benign condition with no obvious 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, it is of great significance to develop new drugs for treating metabolic disorders.

[0003] Zaltoprofen is a phenylpropionic acid non-steroidal anti-inflammatory drug, which is used for treating chronic rheumatoid arthritis, osteoarthritis, lumbago, periarthritis of shoulder joint, cervical shoulder wrist syndrome, and postoperative, post-traumatic and post-extraction anti-inflammatory analgesia. SUMMARY

[0004] The present application provides a new use of optical isomer composition of phenylpropionic acid analogues for treating or preventing metabolic disorders, in particular for preventing or treating uric acid and blood glucose and lipid related metabolic disorders.

[0005] One aspect of the present application provides use of zaltoprofen or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing metabolic disorders, wherein the medicament comprises a mixture of S-type optical isomer and R-type optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the weight ratio of the S-type optical isomer and the R-type optical isomer is 1:(0.1-10), for example, it can be 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:1 or any value therebetween.

[0007] In some embodiments, the weight ratio of the S-type optical isomer and the R-type optical isomer is 1:(1-9), more preferably 1:(3-9), and further preferably 1:(5-7). In some specific embodiments, the weight ratio of the S-type optical isomer and the R-type optical isomer is 1:6.

[0008] In some embodiments, the metabolic disorder comprises at least one of uric acid metabolism disorder, blood sugar 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 abnormality, 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 abnormality, neurodegenerative disease, or Alzheimer's disease.

[0010] 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.

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

[0012] In some embodiments, the dosage form of the drug 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.

[0013] In some embodiments, the administration route of the drug comprises oral administration, injection administration, intravenous drip administration, sublingual administration, spray inhalation, or rectal administration.

[0014] Yet another aspect of the present application provides a method of reducing uric acid, blood sugar, and / or blood 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, wherein the drug comprises a mixture of an S-type optical isomer and an R-type optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the weight ratio of the S-type optical isomer and the R-type optical isomer is 1:(0.1-10), for example, can be 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:1 or any value between them.

[0016] In some embodiments, the weight ratio of the S-type optical isomer and the R-type optical isomer is 1:(1-9), preferably 1:(1-9), more preferably 1:(3-9), further preferably 1:(5-7). In some specific embodiments, the weight ratio of the S-type optical isomer and the R-type optical isomer is 1:6.

[0017] Yet another aspect of the present application provides a method for preventing or treating a metabolic disorder, the method comprising administering to a subject in need thereof an effective amount of zaltoprofen or a pharmaceutically acceptable salt thereof, wherein the drug comprises a mixture of the S-type optical isomer and the R-type optical isomer of zaltoprofen or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the weight ratio of the S-type optical isomer and the R-type optical isomer is 1:(0.1-10), for example, can be 1:0.1, 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:1 or any value between them.

[0019] In some embodiments, the weight ratio of the S-type optical isomer and the R-type optical isomer is 1:(1-9), preferably 1:(1-9), more preferably 1:(3-9), further preferably 1:(5-7). In some specific embodiments, the weight ratio of the S-type optical isomer and the R-type optical isomer is 1:6.

[0020] In some embodiments, the metabolic disorder comprises at least one of a uric acid metabolism disorder, a blood sugar metabolism disorder, or a blood lipid metabolism disorder.

[0021] 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, 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.

[0022] In some embodiments, the metabolic disorder comprises at least one of acute hyperuricemia, chronic hyperuricemia, uric acid-induced gouty arthritis, glycolipid metabolic disorder accompanying chronic hyperuricemia model, or type 2 diabetes.

[0023] In some embodiments, the method comprises administering to a subject in need thereof a dosage of 0.01-100 mg / kg, preferably a dosage of 0.1-30 mg / kg, further preferably a dosage of 0.5-20 mg / kg of zaltoprofen or a pharmaceutically acceptable salt thereof.

[0024] The present application has found that zaltoprofen has uric acid-lowering effect on hyperuricemia and anti-inflammatory effect on uric acid-induced gouty arthritis, and that zaltoprofen has blood glucose-lowering and blood lipid-lowering effects on glycolipid metabolic disorder accompanying hyperuricemia and type 2 diabetes, and that different optical isomer forms of zaltoprofen have different effects on different metabolic disorders. Further, the present application has found that different proportions of racemic zaltoprofen and optical isomers have different effects on uric acid-lowering, blood glucose-lowering and blood lipid-lowering, and anti-gout effects, and that a specific range of proportions has better effects, 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

[0025] Figure 1 Effects of different proportions of JKT optical isomers on serum uric acid concentration-time curves of hyperuricemia model mice induced by hypoxanthine (N=8, M±SD) are shown.

[0026] Figure 2 Effects of different proportions of JKT optical isomers on the area under the serum uric acid concentration-time curve (AUC) of hyperuricemia model mice induced by hypoxanthine (N=8, M±SD) are shown.

[0027] Figure 3 Inhibition rates of different proportions of JKT optical isomers on the area under the serum uric acid concentration-time curve (AUC) of hyperuricemia model mice induced by hypoxanthine (N=8, M±SD) are shown (calculated according to the mean values of each group).

[0028] Figure 4 Effects of different proportions of JKT optical isomers on serum uric acid concentration of chronic hyperuricemia model mice induced by hypoxanthine + potassium oxonate (N=8, M±SD) are shown, where A shows the RS group and the 9R1S group, B shows the 6R1S group and the 3R1S group, and C shows the 1R3S group, the 1R6S group, and the 1R9S group; **P<0.01, compared with the normal group; # P<0.05, ##P<0.01, compared with the model group.

[0029] Figure 5 The inhibition rate of serum uric acid in the mouse chronic hyperuricemia model induced by hypoxanthine + potassium oxonate is shown for different compatible proportions of JKT optical isomers (N=8, M±SD).

[0030] Figure 6 The effect of different compatible proportions of JKT optical isomers on the serum uric acid concentration in the 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.

[0031] Figure 7 The effect of different compatible proportions of JKT optical isomers on the glucose-timing curve of glucose tolerance in the mouse chronic hyperuricemia model induced by hypoxanthine + potassium oxonate is shown (N=8, M±SD), where A is the RS group and B is the 6R1S group; *P<0.05, **P<0.01, compared with the normal group; # P<0.05, ## P<0.01, compared with the model group.

[0032] Figure 8 The effect of different compatible proportions of JKT optical isomers on the area under the curve (AUC) of the glucose-timing curve of glucose tolerance in the mouse chronic hyperuricemia model induced by hypoxanthine + potassium oxonate is shown (N=8, M±SD); **P<0.01, compared with the normal group; # P<0.05, ## P<0.01, compared with the model group.

[0033] Figure 9 The effect of different compatible proportions of JKT optical isomers on the blood lipid levels in the mouse chronic hyperuricemia model induced by hypoxanthine + potassium oxonate is shown (N=8, M±SD), where A is triglyceride (TG) and B is total cholesterol (TC).

[0034] Figure 10 The effect of different compatible proportions of JKT optical isomers on gouty arthritis in rats induced by sodium urate is shown (N=8, M±SD), where A shows the RS group and the 9R1S group, B shows the 6R1S group and the 3R1S group, and C shows the 1R3S group, the 1R6S group, and the 1R9S group; # P<0.05, ## P<0.01, compared with the model group.

[0035] Figure 11 The effect of different compatible proportions of JKT optical isomers on body weight (g) is shown (N=8, M±SD). N=8), where A is the RS group and B is the 6R1S group; *P<0.05, **P<0.01 compared with the normal group.

[0036] Figure 12 The effect of different compatibility ratios of JKT optical isomers on blood glucose levels (mmol / L) is shown N=8); **P<0.01 compared with the normal group. # P<0.05, ## P<0.01 compared with the model group.

[0037] Figure 13 The effect of different compatibility ratios of JKT optical isomers on serum triglycerides (mmol / L) is shown N=8); **P<0.01 compared with the normal group. # P<0.05, ## P<0.01 compared with the model group.

[0038] Figure 14 The effect of different compatibility ratios of JKT optical isomers on serum cholesterol (mmol / L) is shown N=8); *P<0.05, **P<0.01 compared with the normal group. # P<0.05, ## P<0.01 compared with the model group.

[0039] Figure 15 The effect of different compatibility ratios of JKT optical isomers on the glucose tolerance blood glucose-time curve (N=8, M±SD) is shown, where A is the RS group and B is the 6R1S-JKT group; **P<0.01 compared with the normal group. # P<0.05, ## P<0.01 compared with the model group.

[0040] Figure 16 The effect of different compatibility ratios of JKT 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. DETAILED DESCRIPTION

[0041] In order to make the objectives, technical solutions, and advantages of the present application clearer, the following further describes the present application in conjunction with embodiments. The specific embodiments described herein are intended for the purpose of explanation only and are not intended to constitute any limitation of the present application. Further, in the following description, descriptions of well-known structures and techniques are omitted to avoid unnecessarily obscuring the concept of the present disclosure. Such structures and techniques are described in many publications.

[0042] Definitions

[0043] 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. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in this specification, the words "comprises", "comprising", "includes", "including", "has", "having" or the like are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0044] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. 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.

[0045] As used herein, the term "about" means ±20% of the number it directly precedes. In some embodiments, the term "about" means ±10% of the number it directly precedes. In some embodiments, the term "about" means ±5% of the number it directly precedes.

[0046] As used herein, the term "metabolic disorder" means a metabolic abnormality caused by a disease in the body or caused by a congenital defect of the body. In the present application, the metabolic disorder includes, but is not limited to, a uric acid metabolic disorder, a sugar metabolic disorder, a lipid metabolic disorder, and the like. In some specific embodiments, the metabolic disorder includes hyperuricemia, gout, diabetes, metabolic syndrome, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperinsulinemia, lipoprotein abnormality, 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.

[0047] Zaltoprofen (10,11-dihydro-α-methyl-10-oxodibenz[b,f]thi-epine-2-acetic acid, Zaltoprofen) has the following structure shown in Formula (I). Zaltoprofen is a potent non-steroidal anti-inflammatory analgesic of the propionic acid class. Zaltoprofen is a racemate, containing both the S optical isomer (S-) and the R optical isomer (R-). In this document, the code for Zaltoprofen is JKT, the racemic form is denoted as RS-JKT, the S optical isomer is denoted as S-JKT, and the R optical isomer is denoted as R-JKT.

[0048]

[0049] The term "treatment" as used herein includes an action that occurs while a subject has a particular disease, disorder, or condition, and that 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 action that occurs before a subject has a particular disease, disorder, or condition ("prophylactic treatment").

[0050] 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.

[0051] 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 not deleterious to the recipient thereof. 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; other non-toxic compatible 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, according to the judgment of the formulator, and can be in the form of either a lyophilized powder or a liquid solution.

[0052] The term "subject" as used herein includes, but is not limited to, a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) and / or a non-human animal, e.g., a mammal such as a primate (e.g., a cynomolgus monkey, a rhesus monkey), a bovine, a porcine, a equine, an ovine, a caprine, a rodent, a feline, and / or a canine. 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.

[0053] The term "effective amount" as used herein refers to an amount that is 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.

[0054] The term "therapeutically effective amount" as used herein refers to an amount that is sufficient to provide a therapeutic benefit in the course of treating 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 course of treating 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 symptoms, or enhances the therapeutic efficacy of another therapeutic agent.

[0055] An effective amount of a drug of the application will generally be in the range of 0.01 mg to 100 mg of the drug per kilogram of patient body weight per day, preferably 0.1 mg to 30 mg of the drug per kilogram of patient body weight per day, and further preferably 0.5 mg to 20 mg of the drug per kilogram of patient body weight per day, in single or divided doses. Typically, a drug of the application can be administered to a patient in need thereof at a daily dose range of about 0.1 mg / kg to about 30 mg / kg per patient, preferably 0.5 mg / kg to 20 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 per patient per day. The administration can be once or multiple times per day, per week (or at intervals of days), 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 weeks, e.g., 4-10 weeks. Alternatively, the drug can be administered daily for a period of days (e.g., 2-10 days), followed by a period of days (e.g., 1-30 days) without administration of the drug, with the cycle being repeated indefinitely or for a given number of times, e.g., 4-10 cycles. For example, a drug of the application can be administered daily for 5 days, followed by 9 days of rest, followed by 5 days of daily administration, followed by 9 days of rest, and so on, with the cycle being repeated indefinitely or for 4-10 times. It is also possible to administer a drug provided herein chronically ("chronic administration"). Chronic administration refers to administration of a 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 over a long period of time, e.g., within a therapeutic window.

[0056] 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.

[0057] Generally, an effective amount of a pharmaceutical provided herein will be administered. The amount of the pharmaceutical actually to be administered will vary depending, e.g., on the condition being treated, the chosen route of administration, the actual pharmaceutical being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0058] When used to prevent a condition described herein, a pharmaceutical 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 include, generally, those who have a family history of the condition, or those who, through genetic testing or screening, are determined to be particularly susceptible to developing the condition.

[0059] The pharmaceuticals 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, among others.

[0060] For example, in some embodiments, the pharmaceutical can be administered as a bolus, e.g., to raise the concentration of the pharmaceutical in the blood to an effective level. The bolus dosage depends on the target systemic level of the active ingredient through the body, e.g., a bolus dosage intramuscularly or subcutaneously releases the active ingredient slowly, while a bolus delivered directly to the vein, e.g., by IV drip, can deliver more rapidly, such that the concentration of the active ingredient in the blood rises quickly to an effective level. In other embodiments, the pharmaceutical can be administered as a continuous infusion, e.g., 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 dosage of the pharmaceutical can be administered first, followed by a continuous infusion.

[0061] For example, in other embodiments, oral pharmaceuticals can take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the pharmaceutical is presented in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable for unitary dosing to human patients and other mammals, each unit containing a predetermined quantity of active material, i.e., the pharmaceutical, 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 will generally comprise a smaller component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), the remainder being various carriers or excipients and processing aids useful in forming the desired dosing form.

[0062] Liquid forms suitable for oral administration can include a suitable aqueous or nonaqueous carrier and a buffering agent, suspending agent, and dispersing agent, colorant, flavorant, and the like. Solid forms can include, for example, any of the following components, or pharmaceuticals of 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.

[0063] Injectable forms are typically based upon injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As previously described, in such dosage forms the active drug is typically a minor component, often about 0.05 to 10% by weight, with the remainder being the injectable excipient or the like.

[0064] Transdermal dosage forms are typically formulated to contain active ingredients that are released into the body of the recipient having a transdermal delivery system. A transdermal patch contains a reservoir made of a polymer film that is impregnated with drug. The drug permeates the polymer film and is released into the body of the recipient. Transdermal patches are typically formulated to provide a continuous or discontinuous release of drug into the body of the recipient. Transdermal patches are typically formulated to provide a continuous release of drug into the body of the recipient for a certain period of time, such as about 12 to 48 hours. Transdermal patches are typically formulated to provide a discontinuous release of drug into the body of the recipient, such as about 1 to 5 days.

[0065] The pharmaceuticals of the present application can also be administered by a transdermal device. Thus, transdermal administration can be achieved using a reservoir or porous matrix-type patch, or a variety of solid matrix self-stick patches.

[0066] Examples and figures are provided below to assist in the understanding of the present application. It is understood that the examples and figures are intended to be illustrative only and that no limitations are intended thereby. Actual scope of the present application is set forth in the claims that follow. It is understood that any modifications and alterations might be made therein without departing from the spirit of the present application.

[0067] Examples

[0068] Experimental Materials

[0069] 1. Test Drug

[0070] Racemic JKT (RS-JKT, wherein R-JKT:S-JKT = 1:1), 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 Jikeway Biomedical Technology Co., Ltd.

[0071] R-JKT and S-JKT were mixed according to weight to form 6 different proportion samples, including: 9R1S (R-JKT:S-JKT = 9:1), 6R1S (R-JKT:S-JKT = 6:1), 3R1S (R-JKT:S-JKT = 3:1), 1R3S (R-JKT:S-JKT = 1:3), 1R6S (R-JKT:S-JKT = 1:6), 1R9S (R-JKT:S-JKT = 1:9).

[0072] Febuxostat tablets (Fengdingning), 40 mg x 14 tablets, Hangzhou Zhuyangxin Pharmaceutical Co., Ltd.

[0073] Rosiglitazone tablets (Aineng): 4 mg*7 tablets*2 boards, Chengdu Hengrui Pharmaceutical Co., Ltd.

[0074] The test drugs were all ground with 0.3% sodium carboxymethyl cellulose to prepare a suspension of the corresponding concentration for intragastric administration.

[0075] 2. Animals and feeding

[0076] (1) Species, source

[0077] Male Kunming mice, SPF level, weighing 18-22 g, purchased from Henan Skrbio Biotechnology Co., Ltd., production license number: SCXK(Yu)2020-0005.

[0078] Male SD rats, SPF level, weighing 180-220 g, purchased from Hangzhou Medical College Experimental Animal Center, production license number: SCXK(Zhe)2019-0002.

[0079] C57 mice, SPF level, male, 5-6 weeks old, purchased from Shanghai Family Planning Science Institute Experimental Animal Operation Department, license number: SCXK(Su)2018-0006.

[0080] (4) KM male mice 48, SPF level, weighing 18-22 g, purchased from Henan Skrbio Biotechnology Co., Ltd., production license number: SCXK(Yu)2020-0005.

[0081] (2) Feeding conditions

[0082] Male Kunming mice and male SD rats were bred in the animal center of China Pharmaceutical University (Animal Use License No: SYXK(Su)2021-0011). The feeding laboratory temperature was 24±2℃; relative humidity 40%-70%; air exchange per hour: 10-15 times / hour; light cycle: 12(day) / 12(night) hours, no more than 5 per cage. The feed was full-value granular feed for mice, purchased from Jiangsu Cooperation Pharmaceutical Biological Engineering Co., Ltd., which met the quality standards of GB14924.1-2010 "General Quality Standards for Experimental Animal Compound Feed".

[0083] C57 mice were all bred in a clean animal room (Animal Use License No: SYXK(Su)2021-0011), with a laboratory temperature of 24±2℃, relative humidity of 60%-80%, air exchange per hour of 10-15 times / hour, and a light cycle of 12h(day) / 12h(night). No more than 5 per cage. The feed was full-value basic granular feed for mice.

[0084] High-fat feed (80% basic feed, 15% lard, 4% milk powder, 1% cholesterol).

[0085] Drinking water: purified water.

[0086] 3. Main instruments

[0087] Multifunctional ultrapure water system, Unique-R20, Unique-R20 Water Purification Technology Co., Ltd.; Multifunctional high-speed 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; Microbenchtop high-speed centrifuge, Thermo Scientific 21R; KD-160 electronic scale, Dongguan Bailida Health Equipment Co., Ltd.; 3-18k low-temperature centrifuge, SIGMA, USA; Vortex, Scientific Industries VORTEX-2GENIE.

[0088] 4. Main reagents

[0089] Potassium oxonate, Beijing Solabio Technology Co., Ltd. (P9770); Hypoxanthine, Shanghai Aladdin Bio-Chem Technology Co., Ltd. (H301755); Sodium urate (S30775), Shanghai Yuan Ye Biological Technology Co., Ltd.; Streptozotocin (STZ), A610130, Genview Biotech Co., Ltd.; Sodium carboxymethylcellulose, Xilong Scientific Co., Ltd.

[0090] Uric acid (UA) test kit (colorimetric method), Nanjing Jiancheng Biological Engineering Institute (C012-1); Glucose (GLU) assay kit (glucose oxidase method), triglyceride (TG) test kit, total cholesterol (TC) test kit, all purchased from Nanjing Jiancheng Biological Engineering Institute.

[0091] Example 1. Effects of different compatibility ratios of JKT optical isomers on acute hyperuricemia induced by hypoxanthine in mice

[0092] 1.1 Animal grouping

[0093] After the mice were adapted to feeding for 1 week, they were randomly divided into 9 groups according to body weight, 8 mice in each group, respectively:

[0094] (1) Model group

[0095] (2) Positive drug febuxostat (10 mg / kg)

[0096] (3) RS-JKT (10 mg / kg)

[0097] (4) 9R1S-JKT (10 mg / kg)

[0098] (5) 6R1S-JKT (10 mg / kg)

[0099] (6) 3R1S-JKT (10 mg / kg)

[0100] (7) 1R3S-JKT (10 mg / kg)

[0101] (8) 1R6S-JKT (10 mg / kg)

[0102] (9) 1R9S-JKT (10 mg / kg)

[0103] 1.2 Model establishment and drug administration

[0104] Overnight fasted mice (without water deprivation) were given corresponding doses of test drugs by gavage, with a drug volume of 10 mL / kg, and the model group was given the same volume of 0.3% sodium carboxymethylcellulose solution. After 30 min of gavage administration, acute hyperuricemia animal models were established by a single intraperitoneal injection of hypoxanthine 1 g / kg, with an injection volume of 10 mL / kg.

[0105] Blood samples were collected from the orbital sinus of all mice before and 0.5, 1, 2 and 6 hours after hypoxanthine injection. 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 uric acid concentration in the serum of each group was detected using a uric acid kit.

[0106] 1.3 Detection Indicators

[0107] Serum uric acid levels in each group were measured at different time points using reagent kits. Uric acid concentration-time curves were plotted based on the changes in uric acid levels over time, and the area under the curve (AUC) for each group was calculated. The inhibition rate (%) of each drug against hyperuricemia was calculated using the mean AUC of each group.

[0108] The inhibition rate of the drug on hyperuricemia (%) = (AUC) 模型组 -AUC 药物组 ) / AUC 模型组 ×100%.

[0109] 1.4 Data Processing and Statistical Methods

[0110] 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.

[0111] 1.5 Results

[0112] like Figure 1 As shown, the baseline serum uric acid levels of mice in each group were similar. In the model group, after intraperitoneal injection of hypoxanthine, serum uric acid levels rose rapidly, reaching a peak at 1 hour, and then began to decline, returning to near the baseline level 6 hours after modeling. Compared with the model group, each tested drug could inhibit the increase in serum uric acid induced by hypoxanthine to varying degrees, resulting in a lower serum uric acid concentration-time curve.

[0113] The area under the serum uric acid concentration-time curve (AUC) for each group is as follows: Figure 2 As shown in the figure, all tested drugs can reduce the AUC value of model mice; the results of AUC inhibition rates in each group are as follows. Figure 3 As shown, based on AUC inhibition rate, the uric acid-lowering effects of the same dose of test substance are as follows: 6R1S>3R1S>RS>9R1S>1R3S>1R6S>1R9S.

[0114] Example 2. Effects of different ratios of JKT optical isomers on chronic hyperuricemia induced by hypoxanthine + potassium oxonate in mice.

[0115] 2.1 Model Establishment

[0116] Mice were purchased and acclimated for 1 week. The chronic hyperuricemia animal model was established by gavage with 300 mg / kg hypoxanthine combined with intraperitoneal injection of 300 mg / kg potassium oxonate. The normal group was given gavage combined with intraperitoneal injection of the corresponding volume of normal saline as a control. After two weeks of modeling, the blood uric acid level of the normal group and the model group was detected. Mice with uric acid higher than 30% of the mean value of the normal group were selected from the model group and randomly grouped according to the uric acid level.

[0117] 2.2 Grouping and administration

[0118] The blood uric acid of the model mice was elevated, and the mice were divided into the following 10 groups, 8 mice in each group:

[0119] (1) Normal group

[0120] (2) Model group

[0121] (3) Positive drug febuxostat (10 mg / kg)

[0122] (4) RS-JKT (10 mg / kg)

[0123] (5) 9R1S-JKT (10 mg / kg)

[0124] (6) 6R1S-JKT (10 mg / kg)

[0125] (7) 3R1S-JKT (10 mg / kg)

[0126] (8) 1R3S-JKT (10 mg / kg)

[0127] (9) 1R6S-JKT (10 mg / kg)

[0128] (10) 1R9S-JKT (10 mg / kg)

[0129] Each group was given gavage once a day, continuously for 3 weeks, with a dosage of 10 mL / kg, and the normal group and the model group were given gavage with the same volume of 0.3% carboxymethylcellulose sodium.

[0130] 2.3 Detection index

[0131] At 1, 2, and 3 weeks of administration, overnight fasting mice (without water restriction) were taken, and blood samples were taken from the eye orbit 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 by using a uric acid kit.

[0132] 2.4 Data processing and statistical method

[0133] Data are expressed as mean ± standard deviation (M ± SD), and ANOVA analysis was performed using GraphPad Prism 6 software to investigate the significance between groups, with P < 0.05 as the significant standard.

[0134] 2.5 Results

[0135] The serum uric acid concentration results of each group are shown in Figure 4 A- Figure 4 C. During the 3-week administration period, the serum uric acid level of the model group mice remained stable and was significantly higher than that of the normal group (P < 0.01). After 1 week of administration, each test drug can significantly reduce the serum uric acid concentration of the model mice, and the uric acid reduction rate further increases with the extension of the administration time.

[0136] The inhibition rate of hyperuricemia was calculated according to the uric acid concentration of each group at 1, 2, and 3 weeks of administration [=(model group uric acid concentration-drug group uric acid concentration) / model group uric acid concentration x 100%], and the results are shown in Figure 5 It can be seen that the uric acid reduction effect under the same dose is in the order of 6R1S > 3R1S > RS > 9R1S > 1R3S > 1R6S > 1R9S, which is consistent with the results of the acute model.

[0137] Example 3. Effect of different compatibility ratios of JKT optical isomers on the improvement of glycolipid metabolism disorder accompanied by chronic hyperuricemia model

[0138] 3.1 Model establishment

[0139] The mice were purchased and adaptively fed for 1 week, and a chronic hyperuricemia animal model was established by gavage with hypoxanthine 300 mg / kg combined with intraperitoneal injection of oxonicate potassium 300 mg / kg. The normal group was given gavage combined with intraperitoneal injection of the corresponding volume of normal saline as a control. After two weeks of modeling, the blood uric acid level of the normal group and the model group was detected. From the model group, mice with uric acid higher than the mean value of the normal group by 30% were selected and randomly grouped according to the uric acid level.

[0140] 3.2 Grouping and administration

[0141] The normal and blood uric acid elevated model successful mice were divided into the following 8 groups, 8 mice in each group:

[0142] (1) Normal group

[0143] (2) Model group

[0144] (3) Positive drug febuxostat (10 mg / kg)

[0145] (4) Positive drug rosiglitazone (10 mg / kg)

[0146] (5) RS-JKT high dose (10 mg / kg)

[0147] (6) RS-JKT low dose (5 mg / kg)

[0148] (7) 6R1S-JKT high dose (10 mg / kg)

[0149] (8) 6R1S-JKT low dose (5 mg / kg)

[0150] Each group was administered once daily by gavage for 3 consecutive weeks, with a dosage volume of 10 ml / kg, and the normal and model groups were administered with an equal volume of 0.3% sodium carboxymethyl cellulose by gavage.

[0151] 3.3 Detection index

[0152] (1) Uric acid detection

[0153] Before and 3 weeks after administration, overnight fasted mice (without water restriction) were taken, and blood samples were taken from the orbit 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.

[0154] (2) Blood glucose, blood lipid and glucose tolerance detection

[0155] On the third week of administration, overnight fasted mice (without water restriction) were taken, and blood samples were taken from the orbit before administration on the same day as the base blood sample (0 h); then, the mice in each group were injected intraperitoneally with glucose 2.0 g / kg, and blood samples were taken from the orbit at 0.5, 1 and 2 h after glucose injection. After standing for 1 h, the serum was separated by centrifugation at 3500 rpm for 15 min. The base blood sample was detected for GLU, TC and TG levels using a kit, and the remaining three blood samples were detected for GLU levels. The blood glucose levels at the four time points were plotted into a glucose tolerance curve, the area under the curve (AUC) was calculated, and comparisons were made between groups.

[0156] 3.4 Data processing and statistical method

[0157] The data are expressed as mean ± standard deviation (M ± SD), and ANOVA analysis was performed using GraphPad Prism 6 software to investigate the significance, with P < 0.05 as the significant standard.

[0158] 3.5 Results

[0159] (1) Effect on serum uric acid level

[0160] The serum uric acid level results of each group are shown in Table 1. After 3 weeks of administration, the febuxostat and JKT test groups can significantly reduce the serum uric acid concentration of model mice, among which 6R1S-JKT has a better effect, while rosiglitazone has no obvious improvement on the serum uric acid concentration of model mice. Figure 6 ​

[0161] (2) Effects on fasting blood glucose and glucose tolerance

[0162] The glucose tolerance blood glucose-time curves of each group are shown in Figure 7 A- Figure 7 B, and the area under the glucose tolerance blood glucose-time curve (AUC) is shown in Figure 8 Compared with normal mice, the fasting blood glucose and the area under the glucose tolerance curve of the hyperuricemia model mice were significantly increased, indicating that the hyperuricemia model also had glucose and lipid metabolism disorders. Compared with the model group, febuxostat had no significant effect on fasting blood glucose and the area under the glucose tolerance curve, while rosiglitazone significantly reduced the fasting blood glucose and the area under the glucose tolerance curve of the model mice. JKT of each test group also significantly improved the fasting blood glucose and the area under the glucose tolerance curve of the model mice, among which 6R1S-JKT had a relatively stronger effect.

[0163] (3) Effects on blood lipid levels

[0164] The results of the blood lipid triglyceride (TG) and total cholesterol (TC) levels of each group are shown in Figure 9 A-9B. Compared with normal mice, the fasting triglyceride levels (TC) of the hyperuricemia model mice were increased, and the total cholesterol (TC) levels showed no significant change. Compared with the model group, JKT of each test drug reduced the triglyceride levels of the model mice, among which 6R1S-JKT had a relatively stronger effect, and the total cholesterol (TC) levels showed no significant effect.

[0165] Example 4. Effects of different compatibility ratios of optical isomers of JKT on gouty arthritis in rats induced by sodium urate

[0166] 4.1 Animal grouping

[0167] After being purchased and raised for one week, the SD rats were randomly divided into the following 9 groups according to body weight, with 8 rats in each group:

[0168] (1) Model group

[0169] (2) Positive drug febuxostat (10 mg / kg)

[0170] (3) RS-JKT (10 mg / kg)

[0171] (4) 9R1S-JKT (10 mg / kg)

[0172] (5) 6R1S-JKT (10 mg / kg)

[0173] (6) 3R1S-JKT (10 mg / kg)

[0174] (7) 1R3S-JKT (10 mg / kg)

[0175] (8) 1R6S-JKT (10 mg / kg)

[0176] (9) 1R9S-JKT (10 mg / kg)

[0177] 4.2 Model establishment

[0178] The overnight fasted rats were given the test drugs by gavage, and the volume of each drug was 20 mL / kg. The model group was given the same volume of 0.3% sodium carboxymethyl cellulose by gavage. Thirty minutes after gavage, the right ankle joint of the right hind limb of the rat was disinfected with iodophor. A 1 mL syringe was inserted into the ankle joint cavity at an angle of 45 degrees between the right ankle joint of the right hind limb and the tibia. Each rat was injected with 0.2 mL of sodium urate suspension (25 mg / mL). The syringe was pulled out, and a cotton swab was pressed for a few seconds to prevent the drug solution from leaking out.

[0179] 4.3 Detection index

[0180] The volume of the rat hind foot was determined by the drainage method. The volume was determined once after the injection of sodium urate, which was used as the baseline volume. The volume of the rat hind foot was then determined at 0.5, 1, 2, 4, and 6 hours after the inflammation was induced to observe the peak time and the regression time of the swelling. The swelling degree at each time point was calculated to evaluate the anti-inflammatory effect. The calculation formula is as follows:

[0181] Swelling degree (mL) = (measured volume - baseline volume)

[0182] 4.4 Data processing and statistical method

[0183] The data are expressed as mean ± standard deviation (M ± SD). The ANOVA analysis was performed by GraphPad Prism 6 software to investigate the significance. P < 0.05 was used as the significance criterion.

[0184] 4.5 Results

[0185] The results are shown in Figure 10 A- Figure 10 C. The injection of sodium urate into the ankle joint can cause significant swelling of the rat hind foot, which reaches the peak at about 4 hours. The different proportions of JKT optical isomers have a significant inhibitory effect on the swelling degree of gouty arthritis in rats caused by sodium urate. Under the same dose, the inhibitory effect of each test drug on sodium urate-induced arthritis is in the order of 6R1S > 3R1S > RS > 9R1S > 1R3S > 1R6S ≈ 1R9S. Non-busilast has no effect on joint swelling.

[0186] Example 5. Improvement effect of JKT optical isomers with different proportions on type 2 diabetes mellitus mouse model

[0187] 5.1 Model establishment

[0188] Except for the normal control group, the rest of the mice were fed with high-fat feed. After 3 weeks of feeding, intraperitoneal injection of streptozotocin (STZ 40 mg / kg) was performed, 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 (blood glucose substandard mice, additional injection of STZ 40 mg / kg). During the treatment period, the model mice continued to be fed with high-fat feed.

[0189] 5.2 Grouping and administration

[0190] Take the blood glucose elevated model mice and divide them into the following 6 groups, 8 in each group:

[0191] (1) Model group

[0192] (2) Positive drug rosiglitazone (10 mg / kg)

[0193] (3) RS-JKT high dose (10 mg / kg)

[0194] (4) RS-JKT low dose (5 mg / kg)

[0195] (5) 6R1S-JKT high dose (10 mg / kg)

[0196] (6) 6R1S-JKT low dose (5 mg / kg)

[0197] Another 8 normal mice were set as a control group. Each group was administered once a day by gavage, continuously for 4 weeks, with a dosage of 10 ml / kg, and the normal and model groups were administered with the same volume of 0.3% sodium carboxymethyl cellulose by gavage.

[0198] 5.3 Index determination

[0199] (1) General condition

[0200] Observe the fur color, manner, spirit, etc., and record the animal death situation.

[0201] (2) Body weight

[0202] Weigh the body weight once a week to observe the body weight change.

[0203] (3) Fasting blood glucose and blood lipids

[0204] After 2 and 4 weeks of administration, blood was collected from the orbit, and serum was separated to detect the levels of serum glucose, total cholesterol, and triglyceride.

[0205] (4) Glucose tolerance test

[0206] Five days before the end of the experiment, the mice were fasted for 12 h, not water-restricted, injected with glucose (2.0 g / kg) tolerance test, capillary orbital blood was taken, centrifuged at 3500 r / min for 10 min to separate the serum, and the blood glucose values before injection and 0.5, 1, 2 h after injection of each group of animals were determined using a glucose kit to draw a glucose tolerance curve to calculate the area under the curve (AUC).

[0207] 5.4 Results

[0208] (1) General condition

[0209] The appearance and behavior of the mice in the normal group were normal during the experiment, and there were no obvious changes in food intake, water intake, and defecation. The spontaneous activity of the mice in the model group decreased during the experiment, the fur was dirty, and most of the animals showed symptoms of polydipsia, polyphagia, and polyuria. There was no death in each group of animals during the experiment.

[0210] (2) Body weight

[0211] The results of the body weight of each group are shown in Figure 11 A- Figure 11 B. The body weight of the mice in the normal group increased normally during the experiment, and the body weight of the mice in the model group did not increase during the experiment, which was consistent with the symptoms of weight loss in diabetes. The JKT test drugs had no obvious effect on the body weight of the model mice.

[0212] (3) Fasting blood glucose and blood lipids

[0213] The results of the blood glucose level of each group are shown in Figure 12 A- Figure 12 B. Compared with the normal group, the fasting blood glucose level of the model group was significantly increased during the experiment, and the fasting blood glucose of the JKT test drugs was significantly lower than that of the model group after 4 weeks of intervention, among which 6R1S-JKT had a relatively stronger effect.

[0214] The results of the serum triglyceride level 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 model mice was significantly reduced after 4 weeks of intervention of the JKT test drugs RS-JKT and 6R1S-JKT.

[0215] The results of the serum cholesterol level 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 model mice was significantly reduced after 4 weeks of intervention of the JKT test drugs RS-JKT and 6R1S-JKT.

[0216] (4) Glucose tolerance test

[0217] The results of the glucose tolerance level of each group are shown in Figure 15 A- Figure 15The results of the area under the curve (AUC) of the glucose tolerance test of each group are shown in FIG. 6B. Figure 16 Compared with the normal group, the blood glucose level of the diabetes model group was significantly increased after oral glucose, and the area under the curve of the glucose tolerance test was significantly increased, indicating impaired glucose tolerance. Each of the JKT test samples significantly improved the glucose tolerance curve of the diabetic mice, with 6R1S-JKT being particularly effective.

[0218] As can be seen from the above examples, in the acute hyperuricemia model induced by hypoxanthine in mice, JKT optical isomers with different proportions 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 optical isomers with different proportions have a potential inhibitory effect on uric acid production, and the uric acid-lowering effect of the same dose of test substances in order is: 6R1S > 3R1S > RS > 9R1S > 1R3S > 1R6S > 1R9S.

[0219] In the chronic hyperuricemia model of mice induced by hypoxanthine combined with potassium oxonate, JKT optical isomers with different proportions 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, and the uric acid-lowering effect of the same dose in order is: 6R1S > 3R1S > RS > 9R1S > 1R3S > 1R6S > 1R9S. In this model, although the chronic uric acid-lowering effect of febuxostat is still stronger than that of JKT optical isomers with different proportions, the difference in drug efficacy intensity is significantly reduced compared with the acute model, especially the uric acid-lowering amplitude of 6R1S-JKT is close to that of febuxostat at the same dose.

[0220] In the model of glucose and lipid metabolism disorder accompanied by chronic hyperuricemia induced by hypoxanthine combined with potassium oxonate, 6R1S-JKT and RS-JKT can significantly improve the fasting blood glucose and the area under the curve of the glucose tolerance test of mice, and can also reduce the fasting triglyceride level of mice, with 6R1S-JKT being relatively strong.

[0221] JKT optical isomers with different proportions 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 in order is: 6R1S > 3R1S > RS > 9R1S > 1R3S > 1R6S ≈ 1R9S.

[0222] In the high-fat diet combined with streptozotocin induced type 2 diabetes model, S-JKT and 6R1S-JKT have no obvious effect on the body weight of mice. RS-JKT and 6R1S-JKT can significantly reduce the fasting blood glucose level. RS-JKT and 6R1S-JKT can significantly reduce the serum triglyceride level and serum cholesterol level of model mice; and can significantly improve the glucose tolerance curve of diabetic mice.

[0223] As can be seen from the above, for acute and chronic hyperuricemia models, JKT optical isomers with different proportions have obvious effects of reducing uric acid, and for uric acid sodium induced gouty arthritis in rats, they also have different degrees of anti-inflammatory and detumescence effects, and for the glucose and lipid metabolism disorder accompanying chronic hyperuricemia model, they have obvious effects of reducing blood sugar, and for high-fat diet combined with streptozotocin induced type 2 diabetes, they have obvious effects of reducing blood sugar and blood lipid. Overall, 6R1S is the best proportion in the experiment, and its pharmacodynamic effect is stronger than that of the racemate (RS), and it has significant application value in the treatment of metabolic disorder diseases such as hyperuricemia, gout, glucose and lipid metabolism disorder and diabetes.

[0224] The technical scheme of the present application is not limited to the restriction of the above specific embodiments, and any technical transformation made according to the technical scheme of the present application falls within the protection scope of the present application.

Claims

1. Use of zaltoprofen or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of metabolic disorder, wherein, The drug includes a mixture of S-type optical isomer and R-type optical isomer of zaltoprofen or pharmaceutically acceptable salt thereof, the metabolic disorder includes uric acid metabolic disorder, and the uric acid metabolic disorder includes at least one of acute hyperuricemia, chronic hyperuricemia, gouty arthritis caused by uric acid or glycolipid metabolic disorder accompanying chronic hyperuricemia model.

2. Use according to claim 1, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1: (0.1-10).

3. Use according to claim 1, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1: (1-9).

4. Use according to claim 1, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1: (3-9).

5. Use according to claim 1, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1: (5-7).

6. Use according to claim 1, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1:

6.

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

8. Use according to any one of claims 1 to 7, characterized in that, The drug further includes a pharmaceutically acceptable carrier.

9. Use according to claim 8, characterized in that, The dosage form of the drug includes tablets, capsules, granules, oral solutions, water injections, powder injections, sprays, suppositories or dripping pills.

10. Use according to claim 8, characterized in that, The dosage form of the drug is a freeze-dried powder injection.

11. Use according to any one of claims 1 to 7, characterized in that, The administration route of the drug includes oral administration, injection administration, intravenous drip administration, sublingual administration, spray inhalation or rectal administration.

12. Use of zaltoprofen or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing uric acid level in a subject, wherein, The zaltoprofen or pharmaceutically acceptable salt thereof includes a mixture of S-type optical isomer and R-type optical isomer of zaltoprofen or pharmaceutically acceptable salt thereof.

13. Use according to claim 12, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1: (0.1-10).

14. Use according to claim 12, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1: (1-9).

15. Use according to claim 12, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1: (3-9).

16. Use according to claim 12, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1: (5-7).

17. Use according to claim 12, characterized in that, The weight ratio of the S-type optical isomer and the R-type optical isomer is 1:

6.

18. Use according to any one of claims 12-17, characterized in that, The use includes administering 0.01-100 mg / kg dosage of zaltoprofen or pharmaceutically acceptable salt thereof to a subject in need.

19. Use according to claim 18, characterized in that, The use includes administering 0.1-50 mg / kg dosage of zaltoprofen or pharmaceutically acceptable salt thereof to a subject in need.

20. Use according to claim 18, characterized in that, The use includes administering 0.5-30 mg / kg dosage of zaltoprofen or pharmaceutically acceptable salt thereof to a subject in need.

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