Application of tazeostat in preparation of medicine for preventing and / or treating rheumatoid arthritis

Abstract

The invention relates to application of tazeostat or pharmaceutically acceptable salt thereof in preparation of medicines for preventing and / or treating rheumatoid arthritis and / or diseases caused by rheumatoid arthritis. It is found for the first time and proved through experiments that the tazeostat or the pharmaceutically acceptable salt thereof can obviously reduce joint swelling, joint morphological change, bone erosion and other symptoms of rheumatoid arthritis and shows a remarkable treatment effect on rheumatoid arthritis, and the treatment effect of the tazeostat or the pharmaceutically acceptable salt thereof is obviously superior to that of drugs in the prior art. In addition, the inventor also finds that the tazeostat and the methotrexate have an obvious synergistic interaction effect in the aspect of treating the rheumatoid arthritis. In view of the above, the tazeostat is expected to become a candidate therapeutic drug for rheumatoid arthritis or related diseases thereof, and has great clinical application prospects and values.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to the use of tazemetostat or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating rheumatoid arthritis. BACKGROUND

[0002] Rheumatoid arthritis (RA) is a common and high-incidence autoimmune disease, which is mainly characterized by inflammatory synovial hyperplasia and erosion of cartilage and subchondral bone. Patients often show chronic joint swelling, stiffness and pain, and the lesions often involve the small joints of the hands and feet. The current core of RA treatment is to maximize the delay of disease progression and reduce joint damage, so as to improve the motor function of patients and improve their quality of life. The currently used therapeutic drugs in clinical practice are mainly divided into four categories: non-steroidal anti-inflammatory drugs, glucocorticoids, disease-modifying antirheumatic drugs and biological agents.

[0003] Tazemetostat (its English name is Tazemetostat, and its chemical name is (4-(cyclopropanecarbonyl)-N-((3,4-dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)methyl)-1-methyl-1H-pyrazole-3-carboxamide)) is a representative high-efficiency and high-selectivity EZH2 methyltransferase activity inhibitor, and its chemical molecular formula is C 34 H 44 N4O4, and its CAS number is 1403254-99-8. The mechanism of action of this compound is clear, which specifically competes with the SAM binding site of EZH2, directly inhibits the methyltransferase activity of EZH2, reduces the production of H3K27me3, thereby relieving the silencing of downstream tumor suppressor genes, and finally inhibits the proliferation and survival of tumor cells.

[0004] At present, the application of tazemetostat is mainly reported in the field of cancer treatment. Tazemetostat has been approved for marketing, and its approved indications include: treating metastatic or locally advanced epithelioid sarcoma (adult and ≥16 years old pediatric patients) who are not suitable for radical resection, treating adult relapsed / refractory follicular lymphoma who have received at least 2 treatment regimens and are positive for EZH2 mutation, and treating adult relapsed / refractory follicular lymphoma who have no satisfactory alternative treatment options. SUMMARY

[0005] Object of the invention

[0006] In view of the needs or defects in the prior art, the purpose of the present application is to provide the use of tasocitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating rheumatoid arthritis; in addition, the present application also provides the use of tasocitinib or a pharmaceutically acceptable salt thereof in combination with methotrexate in the preparation of a medicament for preventing and / or treating rheumatoid arthritis, and a pharmaceutical combination for preventing and / or treating rheumatoid arthritis comprising both.

[0007] Solution

[0008] To achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0009] In a first aspect, the present application provides the use of tasocitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating rheumatoid arthritis and / or a condition caused by rheumatoid arthritis.

[0010] In an implementable embodiment, the rheumatoid arthritis is active rheumatoid arthritis.

[0011] In an implementable embodiment, the treatment of rheumatoid arthritis includes alleviating, relieving and / or improving the symptoms of rheumatoid arthritis.

[0012] Preferably, the symptoms of rheumatoid arthritis are selected from the group consisting of joint swelling, pain, bone destruction and / or reduced bone density.

[0013] In an implementable embodiment, the condition caused by rheumatoid arthritis is selected from the group consisting of chronic progressive polyarthritis, synovial tissue hyperplasia, inflammatory cell joint infiltration or joint cartilage damage.

[0014] In the medicament, the tasocitinib or the pharmaceutically acceptable salt thereof can be used as the only active ingredient or as one of the active ingredients.

[0015] In an implementable embodiment, the medicament further comprises a pharmaceutically acceptable carrier and / or excipient.

[0016] In an implementable embodiment, the subject is a mammal, preferably a human.

[0017] In a second aspect, the present application provides the use of tasocitinib or a pharmaceutically acceptable salt thereof in combination with methotrexate in the preparation of a medicament for preventing and / or treating rheumatoid arthritis and / or a condition caused by rheumatoid arthritis.

[0018] In a third aspect, the present application provides a pharmaceutical combination for preventing and / or treating rheumatoid arthritis, the pharmaceutical combination comprising:

[0019] tasocitinib or a pharmaceutically acceptable salt thereof; and,

[0020] Methotrexate.

[0021] In feasible embodiments, the taselisib or pharmaceutically acceptable salt thereof and the methotrexate are provided in different formulations and administered separately to the subject.

[0022] As preferred, the taselisib or pharmaceutically acceptable salt thereof is formulated into a local administration dosage form;

[0023] Further preferably, the local administration dosage form is selected from the group consisting of a local injection administration dosage form, a local implant administration dosage form and / or a transdermal administration dosage form.

[0024] As preferred, the methotrexate is formulated into an oral administration dosage form;

[0025] Further preferably, the oral administration dosage form is selected from the group consisting of a tablet, a pill, a granule, a capsule and / or an oral liquid.

[0026] In a fourth aspect, the present application provides a method for preventing and / or treating rheumatoid arthritis and / or a condition caused by rheumatoid arthritis, the method comprising: administering to a subject in need thereof a prophylactically and / or therapeutically effective amount of:

[0027] (1) taselisib or a pharmaceutically acceptable salt thereof; or,

[0028] (2) a combination of taselisib or a pharmaceutically acceptable salt thereof and methotrexate.

[0029] In feasible embodiments, the rheumatoid arthritis is active rheumatoid arthritis.

[0030] In feasible embodiments, the treatment of rheumatoid arthritis comprises alleviating, relieving and / or improving symptoms of rheumatoid arthritis.

[0031] Preferably, the symptoms of rheumatoid arthritis are selected from the group consisting of joint swelling, pain, bone destruction and / or reduced bone density.

[0032] In feasible embodiments, the condition caused by rheumatoid arthritis is selected from the group consisting of chronic progressive polyarthritis, synovial tissue proliferation, inflammatory cell joint infiltration or joint cartilage damage.

[0033] For the above item (1), feasibly, the taselisib or pharmaceutically acceptable salt thereof can be used as the only active ingredient or as one of the active ingredients; and feasibly, the medicament further comprises a pharmaceutically acceptable carrier and / or excipient.

[0034] For the above item (2), the tasocitinib or the pharmaceutically acceptable salt thereof and the methotrexate can be provided in different formulations and administered to the subject separately.

[0035] Preferably, the tasocitinib or the pharmaceutically acceptable salt thereof is formulated into a local administration dosage form; more preferably, the local administration dosage form is selected from the group consisting of a local injection administration dosage form, a local implant administration dosage form and / or a transdermal administration dosage form.

[0036] Preferably, the methotrexate is formulated into an oral administration dosage form; more preferably, the oral administration dosage form is selected from the group consisting of a tablet, a pill, a granule, a capsule and / or an oral solution.

[0037] In an available embodiment, the subject is a mammal, preferably a human.

[0038] The term "effective amount" refers to an amount or dose of an effective ingredient administered to a subject, either singly or in multiple, to provide an intended effect to the subject to be prevented or treated. The effective amount can be determined by a diagnostician who is a person skilled in the art according to known techniques and observations in similar cases. In determining the effective amount or dose of the administered effective ingredient, the diagnostician involved should consider various factors, including but not limited to: the species of the mammal; the volume, age and general health; the specific disease involved; the degree or severity of the disease involved; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability properties of the formulation administered; the selected dosage regimen; the use of concomitant medication; and other relevant circumstances.

[0039] Advantages

[0040] The present application provides the use of tasocitinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating rheumatoid arthritis and / or a condition caused by rheumatoid arthritis, the use of tasocitinib or a pharmaceutically acceptable salt thereof in combination with methotrexate in the preparation of a medicament for preventing and / or treating rheumatoid arthritis and / or a condition caused by rheumatoid arthritis, and a pharmaceutical combination for preventing and / or treating rheumatoid arthritis comprising tasocitinib or a pharmaceutically acceptable salt thereof and methotrexate.

[0041] The inventors have proved by experiments that tasocitinib can significantly reduce the symptoms of joint swelling, joint morphological changes, bone erosion and the like of rheumatoid arthritis, showing a significant therapeutic effect on rheumatoid arthritis, and the therapeutic effect is significantly better than that of the prior art drugs. Moreover, when tasocitinib is used in combination with methotrexate for treating rheumatoid arthritis, it has a significant synergistic effect, and the effect is significantly higher than that of the two drugs used alone.

[0042] In addition, safety is one of the key considerations for drug application. The present application has found that, in the process of treating rheumatoid arthritis rats with tasocitinib, tasocitinib does not cause obvious side effects to any internal organs of the rats, which fully indicates that tasocitinib has good safety in the body.

[0043] In summary, in view of the excellent effect and outstanding safety of tasocitinib and the combination of tasocitinib and methotrexate in the treatment of rheumatoid arthritis, tasocitinib has great potential and broad application prospects as a drug for treating rheumatoid arthritis, and is a promising candidate drug. BRIEF DESCRIPTION OF DRAWINGS

[0044] One or more embodiments are illustrated by way of example in the figures that constitute a part of this specification, which are illustrative only and not restrictive of the embodiments. The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any implementation described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations.

[0045] Figure 1 The foot photos of the rats in each experimental group in Example 1 are shown; the group is shown on the top of the figure, and the days after administration are shown on the left of the figure.

[0046] Figure 2 The measurement results of the foot swelling degree of the rats in each experimental group in Example 1 are shown; wherein, the A, B, and C figures respectively show the changes of the foot width, the foot thickness, and the ankle medial-lateral width of the rats in each group, the D, E, and F figures respectively show the statistical columnar charts of the measurement values of the foot width, the foot thickness, and the ankle medial-lateral width of the rats in each group after four administrations (30 days after the first injection of the modeling agent), the G, H, and I figures respectively show the statistical columnar charts of the measurement values of the foot width, the foot thickness, and the ankle medial-lateral width of the rats in each group after eight administrations (40 days after the first injection of the modeling agent); wherein, * indicates P < 0.05 between the two groups compared, ** indicates P < 0.01 between the two groups compared, *** indicates P < 0.001 between the two groups compared, and **** indicates P < 0.0001 between the two groups compared.

[0047] Figure 3 The Micro-CT observation results of the feet of the rats in each experimental group in Example 1 are shown; wherein, the upper figure is a side view, and the lower figure is a top view.

[0048] Figure 4 The drug safety evaluation results of Example 2 are shown; wherein, the A figure is the body weight change curve of the rats in each group during the administration, the B figure is the blood biochemical results of the rats in each group after the administration, and the C figure is the H&E staining results of the liver and kidney sections of the rats in each group after the administration.

[0049] In the above figures, "PBS" represents the PBS group, "TAZ" represents the tazarotene treatment group, "MTX" represents the methotrexate treatment group, and "normal" represents the normal healthy control group. DETAILED DESCRIPTION

[0050] In order to make the objects, technical solutions and advantages of the present application clearer, the technical solutions of the present application will be described clearly and completely below in conjunction with embodiments. Obviously, the described embodiments are only part of, rather than all of, the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without any creative work fall within the protection scope of the present application.

[0051] In addition, in order to better illustrate the present application, numerous specific details are given in the specific embodiments below. Those skilled in the art should understand that the present application can be implemented without some specific details. In some embodiments, the raw materials, elements, methods, means and the like that are well known to those skilled in the art are not described in detail, so as to highlight the main idea of the present application.

[0052] Unless otherwise explicitly indicated, in the entire specification and claims, the term "comprise" or its variants such as "contain" or "include" and the like will be understood to include the stated elements or components, without excluding other elements or components.

[0053] The present application will be further described in detail by the following examples.

[0054] In the following examples, the materials, animals, reagents and the like used, if not specifically stated, can be obtained through commercial channels.

[0055] Example 1: Therapeutic effect of tazarotene on rheumatoid arthritis rats

[0056] In this example, Wistar female rats of about 6 weeks old and weighing 150-170 g were used to construct a rheumatoid arthritis rat model, collagen-induced arthritis (CIA rat model), by collagen induction method, and the therapeutic effect of tazarotene on CIA rats was explored.

[0057] Collagen-induced arthritis (CIA) is an experimental autoimmune disease that can be induced in susceptible strains of rodents (rats and mice) and non-human primates by immunization with type II collagen (CII), a major component of articular cartilage. Following immunization, these animals develop an autoimmune-mediated polyarthritis that shares many clinical, histological and immunological features with the human autoimmune disease rheumatoid arthritis. Like rheumatoid arthritis, susceptibility to CIA in rodents is associated with class II molecules of the major histocompatibility complex (MHC). The immune response to CII is characterized by the stimulation of collagen-specific T cells and the production of high titers of specific antibodies directed against both the immunogen (xenogenic CII) and the self-antigen (mouse or rat CII). Histologically, the CIA model in mice and rats is characterized by severe synovitis that precisely parallels the clinical onset of arthritis. Within days of onset, pannus-like tissue is evident on the cartilage and subchondral bone, and subsequently the affected joints slowly heal with fibrosis and ankylosis. Because of the important similarities between CIA and rheumatoid arthritis, this experimental animal model of autoimmune arthritis is a widely studied and accepted animal model of RA.

[0058] Wistar female rats used in this example were purchased from Vantian Li Hua, and taselisib used was purchased from Selleck Chemicals, with the item number S7128.

[0059] (I) Preparation of the injection solution of taselisib and the solution of methotrexate (as a control)

[0060] To prepare the taselisib injection, first dissolve the taselisib drug powder in DMSO to prepare a taselisib stock solution with a concentration of 10 mM; before use, take a certain amount of the taselisib stock solution and dilute it 100 times with PBS to prepare a working solution with a concentration of 100 μM, which is the taselisib injection used for pharmacodynamic studies in RA rats.

[0061] To prepare the methotrexate solution, first dissolve the methotrexate drug powder in DMSO to prepare a methotrexate stock solution with a concentration of 10 mg / mL; before use, take a certain amount of the methotrexate stock solution and dilute it to a concentration of 0.1 mg / mL with 0.5% carboxymethylcellulose sodium (CMC-Na) solution, which is the methotrexate solution used for pharmacodynamic studies in RA rats.

[0062] (II) Construction of a rat model of rheumatoid arthritis

[0063] The specific method for constructing the RA rat model by collagen induction is as follows:

[0064] First, the preparation of the modeling emulsion, 1 volume (up to 2.5 mL) of incomplete adjuvant was added to the syringe, and then an equal volume of collagen solution (0.05 M acetic acid dissolved bovine type 2 collagen solution, the final concentration was 2 mg / mL) was added, and the emulsion was stirred at low speed during the dropwise addition. Continue to mix the emulsion in an ice bath until a stable emulsion is formed (about 30000 rpm / 2-3 min). After the emulsion is prepared, 0.2 mL (collagen: 200 μg) of the emulsion is taken, and the needle is inserted 2 cm from the base of the rat tail, with the tip of the needle inserted 0.5 cm from the base of the tail. The needle is inserted subcutaneously and each injection is thoroughly wiped to prevent the emulsion from coming out. The needle is inserted obliquely upward parallel to the direction of the mouse tail. The booster immunization was performed 7 days after the initial immunization. The booster immunization used collagen-incomplete adjuvant and was injected at 3 cm from the base of the tail, with the tip of the needle inserted subcutaneously 1.5 cm from the base of the tail, and 0.1 mL of the emulsion was injected. After the initial immunization, the rat joint score was recorded every 3 days to determine the success of the modeling.

[0065] Arthritis index scoring criteria:

[0066] 0 points: no signs of redness and swelling

[0067] 1 point: redness and mild swelling limited to the midfoot (tarsal) or ankle joint.

[0068] 2 points: redness and mild swelling extending from the ankle to the midfoot.

[0069] 3 points: redness and moderate swelling extending from the ankle to the metatarsal joint.

[0070] 4 points: redness and severe swelling of the ankle, foot, and toes.

[0071] The score was mainly based on clinical manifestations (0-4 points listed above), and the scores of the four limbs of each rat were added together. The total arthritis index score was significantly higher than that of the control group (generally more than 4 points was considered to be sick), and the success of the modeling was determined by observing bone erosion and joint structure destruction through X-ray observation, and observing typical RA pathological features such as synovitis, pannus, and bone destruction through histopathological examination.

[0072] (III) Effect of taselisib on rats with rheumatoid arthritis

[0073] The experimental groups and the treatment methods of each group are as follows:

[0074] 1) Tazarotene treatment group (i.e., "TAZ" group in the figure): The rat rheumatoid arthritis model was constructed according to the method described in (2) above, and the rheumatoid arthritis model rats were administered by injecting the prepared tazarotene injection into the ankle joint cavity, specifically, 50 μL of tazarotene injection with a concentration of 100 μM was given to each foot once every three days, for a total of 8 times.

[0075] 2) Methotrexate treatment group (i.e., the “MTX” group in the figure, as a positive drug control): a rat rheumatoid arthritis model was constructed according to the method described in (2) above. The rats with rheumatoid arthritis were given the above-prepared methotrexate solution by gavage according to the administration method reported in the prior art and optimized in advance (i.e., 0.5 mg / kg of methotrexate each time, once every three days, for a total of 8 times).

[0076] 3) PBS group (as model control): The rat rheumatoid arthritis model was constructed according to the method described in (2) above. The rats with rheumatoid arthritis model were injected with PBS solution through the ankle joint cavity. Specifically, 50 μL of PBS solution was given to each foot every three days for a total of 8 times.

[0077] 4) Normal healthy group (i.e., the “normal” group in the figure, as a normal control): healthy rats that did not undergo modeling treatment.

[0078] (IV) Monitoring of the state of the rats and evaluation of the drug efficacy

[0079] (1) Appearance inspection:

[0080] Observe whether there are any abnormalities in the diet and excretion of rats in each group after drug administration, and observe whether the range of motion of the rat joints, fur color, gloss and length are normal.

[0081] (2) Weight monitoring:

[0082] The weight of rats in each group was measured every three days.

[0083] (3) Measurement of swelling in the soles and ankles:

[0084] The width and thickness of the hind paws and the thickness of the inner and outer sides of the ankles of rats in each group were measured using vernier calipers. At the same time, the degree of swelling of arthritis in rats was scored (the scoring criteria are described above), and photos were taken for recording.

[0085] The results are as follows:

[0086] 1. Rats in the tazestat treatment group had greater joint mobility than those in the PBS and MTX groups. Diet, excretion, and other aspects were normal. Body weight was measured every three days, showing an increasing trend in each group. The PBS group had the lightest overall weight, while the healthy group had the heaviest overall weight. The tazestat and MTX groups had similar body weights. (See details...) Figure 4 .

[0087] 2. Photographs of the paws of rats in each group are shown below. Figure 1 As shown. By Figure 1It can be seen that the paw of the model control group (i.e., the "PBS" group) rat is obviously swollen compared with the normal healthy rat (i.e., the "normal" group), which indicates that the above model construction is successful; after treatment with talazoparib or the positive control drug methotrexate, the swelling degree of the paw of the rheumatoid arthritis rat gradually decreases, which indicates that: talazoparib and the positive control drug methotrexate both have a therapeutic effect on rheumatoid arthritis; and the swelling reduction degree of the talazoparib treatment group is better than that of the methotrexate group, which indicates that: the therapeutic effect of talazoparib on rheumatoid arthritis of rats is better than that of the prior art drug methotrexate.

[0088] 3. The changes of the paw width, the paw thickness and the ankle medial-lateral width of the rats in each group are shown in the A, B and C graphs of FIG. 1, respectively; the measured values of the paw width, the paw thickness and the ankle medial-lateral width of the rats in each group after four times of administration (30 days after the first injection of the modeling agent) are shown in the D, E and F graphs of FIG. 2, respectively; the measured values of the paw width, the paw thickness and the ankle medial-lateral width of the rats in each group after eight times of administration (40 days after the first injection of the modeling agent) are shown in the G, H and I graphs of FIG. 3, respectively. Figure 2 Figure 2 Figure 2

[0089] From the A-I graphs of FIG. 1, it can be seen that: Figure 2

[0090] (1) Compared with the normal healthy rat (i.e., the "normal" group), the paw width, the paw thickness and the ankle medial-lateral width of the model control group (i.e., the "PBS" group) rat are obviously increased, which indicates that: the above model construction is successful.

[0091] (2) At the time of four times of administration, compared with the model control group (i.e., the "PBS" group), the paw width (P<0.0001), the paw thickness (P<0.0001) and the ankle medial-lateral width (P<0.0001) of the talazoparib treatment group (i.e., the "TAZ" group) rat are obviously reduced; this indicates that talazoparib can obviously reduce the joint swelling and other arthritic symptoms of rheumatoid arthritis, thereby showing an obvious therapeutic effect on rheumatoid arthritis;

[0092] and compared with the positive drug control - the methotrexate treatment group (i.e., the "MTX" group), the paw width (P<0.001), the paw thickness (P<0.01) and the ankle medial-lateral width (P<0.01) of the talazoparib treatment group (i.e., the "TAZ" group) rat are also obviously reduced; this indicates that the therapeutic effect of talazoparib on rheumatoid arthritis of rats is obviously better than that of the prior art drug - methotrexate.

[0093] ​​​​(3) After eight administrations, the width, thickness and lateral width of the foot of rats in the tazestat treatment group were still significantly smaller than those in the PBS group and the MTX group. This indicates that tazestat has a good therapeutic effect on rat rheumatoid arthritis in the long-term treatment regimen.

[0094] Figure 2 The results reflected are Figure 1 Consistent results showed that tazestat effectively reduced paw swelling in rats with rheumatoid arthritis, and its effect on reducing paw swelling was significantly better than that of the existing drug methotrexate. This indicates that tazestat has a significantly better therapeutic effect on rheumatoid arthritis than the existing drug methotrexate.

[0095] (V) Rat dissection, tissue sampling, and Micro-CT observation

[0096] After administration of the drug, rats were anesthetized by intraperitoneal injection, followed by blood collection from the abdominal aorta. After blood collection, the rats were euthanized under excessive anesthesia. The liver, spleen, kidneys, and other organs, as well as the rat's paws and ankles, were collected and cryopreserved.

[0097] Micro-CT scans were used to observe and photograph the rat toes and ankles to assess the degree of bone destruction. Differences in inflammation among groups were evaluated in terms of bone erosion, joint space, and bone destruction.

[0098] The results are as follows Figure 3 As shown, this is the Micro-CT observation result of the rat paws in each group after sampling.

[0099] from Figure 3 As can be seen, compared with the normal healthy group, the PBS group rats showed obvious morphological changes in their joints, rough bone surfaces, and severe bone erosion, which again demonstrates that the above model construction was successful. After treatment with tazestat or the positive control drug methotrexate, the morphological changes and bone erosion of the rat ankle joints were significantly reduced. This indicates that tazestat or the positive control drug methotrexate can significantly alleviate the symptoms of rheumatoid arthritis such as joint morphological changes and bone destruction, thus showing a significant therapeutic effect on rheumatoid arthritis. Furthermore, the reduction in ankle joint morphological changes and bone erosion in the tazestat treatment group was significantly better than that in the methotrexate group, indicating that the therapeutic effect of tazestat on rheumatoid arthritis in rats is superior to that of the existing drug methotrexate.

[0100] The above results indicate that tazestat can effectively reduce ankle joint morphological changes and bone erosion in a rat model of rheumatoid arthritis, and its effect is significantly better than that of the existing drug methotrexate. This demonstrates that tazestat has a significantly better therapeutic effect on rheumatoid arthritis than the existing drug methotrexate.

[0101] It is worth noting that the tazestat treatment described above uses a local injection at the ankle, which can be expected to significantly reduce its impact on the systemic system. In contrast, methotrexate, a drug currently available, is administered via gavage. After absorption through the gastrointestinal tract, the drug is widely distributed throughout the body, potentially causing a wider range of systemic effects. This demonstrates the advantage of tazestat over methotrexate in treating rheumatoid arthritis.

[0102] Example 2: Safety assessment of tazestat in a rat model of rheumatoid arthritis

[0103] In this embodiment, the safety of tazestatin in a rat model of rheumatoid arthritis was evaluated based on rats from each experimental group in Example 1.

[0104] Specifically, following the first administration, the weight of rats in each group was measured every three days. After the administration was completed, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea (UREA), and creatinine (CREA) in the blood of each group of rats were measured to evaluate the safety of ankle-injected tazestat for the treatment of rheumatoid arthritis. Liver and kidney samples were fixed in neutral formalin and stained with H&E to evaluate the safety of intra-articular tazestat for liver and kidney renal use.

[0105] The results are as follows Figure 4 As shown.

[0106] Figure 4 Figure A shows the changes in body weight of rats in each group during the drug administration period. As can be seen from the figure, compared with normal rats, the body weight of rats in the model control group and each treatment group was lower than that of the normal control group. This may be due to the influence of the rheumatoid arthritis model. However, their body weight growth trend was similar to that of the normal healthy group. That is, the body weight of rats in each group showed an upward trend throughout the treatment period.

[0107] Figure 4 Figure B shows the blood biochemical results of rats in each group after the drug administration was completed. As can be seen from the figure, there were no significant differences in the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), and urea (UREA) in the serum of rats in all groups.

[0108] Figure 4Figure C shows the H&E staining results of liver and kidney sections of rats in each group after drug administration; as can be seen from the figure, no obvious damage was observed in the liver and kidney tissues of rats in each group.

[0109] The above results confirm that intra-articular injection of tazestat in the ankle joint has a good safety profile for the treatment of rheumatoid arthritis.

[0110] In addition, the inventors evaluated the therapeutic effect of the combination of tazestat and methotrexate on rheumatoid arthritis; preliminary experimental results showed that the therapeutic effect of the combination of tazestat and methotrexate was significantly improved compared with monotherapy, indicating that tazestat and methotrexate have a synergistic effect in the treatment of rheumatoid arthritis.

[0111] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of tazestar or a pharmaceutically acceptable salt thereof in the preparation of medicines for the prevention and / or treatment of rheumatoid arthritis and / or conditions caused by rheumatoid arthritis.

2. The use according to claim 1, characterized in that, The rheumatoid arthritis mentioned is active rheumatoid arthritis.

3. The use according to any one of claims 1-2, characterized in that, The treatment of rheumatoid arthritis includes reducing, alleviating, and / or improving the symptoms of rheumatoid arthritis; Preferably, the symptoms of rheumatoid arthritis are selected from: joint swelling, pain, bone destruction and / or decreased bone density.

4. The use according to any one of claims 1-3, characterized in that, The symptoms caused by rheumatoid arthritis are selected from: chronic progressive polyarthritis, synovial tissue hyperplasia, inflammatory cell infiltration of the joint, or articular cartilage damage.

5. The use according to any one of claims 1-4, characterized in that, In the drug, tazocine or a pharmaceutically acceptable salt thereof is the sole active ingredient or one of the active ingredients; And / or, the drug may also include a pharmaceutically acceptable carrier and / or excipient.

6. Use of tazestat or a pharmaceutically acceptable salt thereof in combination with methotrexate in the preparation of a medicine for the prevention and / or treatment of rheumatoid arthritis and / or conditions caused by rheumatoid arthritis.

7. A pharmaceutical combination for the prevention and / or treatment of rheumatoid arthritis, characterized in that, The drug combination includes: Tazestat or its pharmaceutically acceptable salts; and, Methotrexate.

8. The pharmaceutical combination according to claim 7, characterized in that, The tazolidinone or its pharmaceutically acceptable salts are provided in different formulations and administered separately to the subjects.

9. The pharmaceutical combination according to claim 8, characterized in that, The tazelstat or its pharmaceutically acceptable salts are formulated into topical dosage forms; Preferably, the local drug delivery dosage form is selected from: local injection dosage form, local implantation dosage form and / or transdermal dosage form.

10. The pharmaceutical combination according to claim 8 or 9, characterized in that, The methotrexate was formulated into an oral dosage form; Preferably, the oral dosage form is selected from: tablets, pills, granules, capsules and / or oral liquids.

Images