Application of rotigotine microspheres in preparation of medicine for preventing and treating rheumatoid arthritis

Abstract

The invention discloses an application of rotigotine microspheres in preparation of medicines for preventing or treating rheumatic arthritis, the rotigotine microspheres can directly act on joint parts, joint synovial hyperplasia, joint injury and bone erosion are effectively reduced, and the curative effect of the rotigotine microspheres is improved. The rotigotine microspheres can be independently used or matched with other known medicines, compounds or carriers to be prepared into various forms of medicaments or pharmaceutical compositions for prevention or treatment, and the dopamine receptor can be continuously excited for 4-8 weeks by injecting once during administration, so that the'on-off 'phenomenon caused by fluctuation of blood concentration is remarkably improved, and the bioavailability of the rotigotine microspheres is improved. Therefore, the curative effect can be effectively improved, and the compliance of a patient is greatly improved.

Description

Technical Field

[0001] The present invention relates to the field of drugs, and particularly to the application of rotigotine microspheres in the preparation of drugs for preventing and treating rheumatoid arthritis, belonging to the field of pharmaceutical technology. Background Art

[0002] Rotigotine is a kind of non-ergoline dopamine receptor agonist, with the chemical formula C 19 H 25 NOS, and the molecular weight is 315.47. Rotigotine can act on dopamine, among which it has the highest affinity and the strongest agonist effect on DRD3, relatively weaker affinities for DRD2, DRD4 and DRD5, and the weakest affinity for DRD1. Rotigotine microspheres are suitable for the treatment of idiopathic Parkinson's disease, and are administered by intramuscular injection once a week. Its anti-Parkinson's disease effect is achieved by activating DRD1, DRD2 and DRD3. Compared with non-continuous administration of rotigotine, continuous administration of rotigotine induces less dyskinesia.

[0003] Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disease, belonging to extravascular immune diseases. There are many aggregates of immunoglobulins in the synovial fluid and pleural effusion of patients, but few in the serum. However, there are many autoantibodies in the serum. The immunoglobulins in the synovium are produced locally and contain a large amount of IgG-type rheumatoid factor. Under special conditions, rheumatoid arthritis may develop into systemic vasculitis, and severe patients may even be life-threatening.

[0004] The main clinical treatment methods for RA include drug treatment, surgical treatment, physical treatment and alternative therapies. Usually, combination drug use is adopted, using non-steroidal anti-inflammatory painkillers and hormonal drugs. Long-term use of hormonal drugs will produce side effects such as osteoporosis. Non-steroidal drugs usually inhibit the synthesis of prostaglandins and the production of pain-causing substances, and their side effects include adverse reactions in the gastrointestinal, urinary and cardiovascular systems. Other drugs such as plant drugs represented by tripterygium glycosides, biological agents and targeted drugs are also the key drugs for the treatment of RA this year, and all have varying degrees of toxic side effects.

[0005] Currently, no drug that can provide long-term sustained release for preventing or treating rheumatoid arthritis has been found, so as to improve the compliance of patients and reduce the toxicity of drug use. Summary of the Invention

[0006] The present invention has for the first time discovered the application of rotigotine microspheres in the preparation of drugs for preventing or treating rheumatoid arthritis, providing a new treatment plan for the treatment of multiple sclerosis.

[0007] The present invention provides, on the one hand, the use of rotigotine microspheres in the preparation of a medicament for preventing and / or treating rheumatoid arthritis.

[0008] Furthermore, the rotigotine microspheres are for preventing rheumatoid arthritis or treating acute-phase rheumatoid arthritis.

[0009] Furthermore, the rotigotine microspheres can significantly weaken joint damage, and / or; reduce bone erosion, and / or; reduce synovial hyperplasia of joints, and / or, delay the acute onset of rheumatoid arthritis.

[0010] Furthermore, the medicament for preventing or treating rheumatoid arthritis is the use of the rotigotine microspheres in the preparation of a medicament for preventing or treating rheumatoid arthritis induced by early overactivation of the immune system.

[0011] Furthermore, when the rotigotine microspheres are used in the preparation of a medicament for preventing and / or treating rheumatoid arthritis, they can significantly reduce TNF-α while increasing IL-10.

[0012] Furthermore, according to the use described in claim 1, the medicament for preventing or treating rheumatoid arthritis is an injection, and can be administered by subcutaneous injection or intramuscular injection.

[0013] Furthermore, the rotigotine microspheres are administered once every 4 to 8 weeks.

[0014] Furthermore, the dosage of the rotigotine microspheres is 14 mg / kg to 28 mg / kg.

[0015] Furthermore, the rotigotine microspheres can be used alone, or compounded with other drugs, compounds, carriers into a pharmaceutical composition.

[0016] Furthermore, the pharmaceutical composition contains an effective therapeutic amount of rotigotine microspheres.

[0017] Advantages of the present invention:

[0018] 1. The present invention has for the first time discovered the application of rotigotine microspheres in the preparation of a medicament for preventing and / or treating rheumatoid arthritis. The rotigotine microspheres can directly act on the joint site, effectively reducing synovial hyperplasia of joints, joint damage and bone erosion.

[0019] 2. The rotigotine microspheres described in the present invention can, by injection, continuously activate dopamine receptors for 4 to 8 weeks after one injection, significantly improving the "on-off" phenomenon caused by blood drug concentration fluctuations, thereby effectively improving the curative effect and also greatly improving the compliance of patients.

[0020] 3. The rotigotine microspheres of the present invention can regulate DRD2 and DRD1 to control rheumatoid arthritis.

[0021] 4. The rotigotine microspheres can be used alone or in combination with other known drugs, compounds or carriers to prepare various forms of medicaments or pharmaceutical compositions for prevention or treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 Body weights of rats in each group at different times after immunization (A) and body weights of rats in each group on the 35th day (n = 5).

[0023] Figure 2 Joint index scores of rats in each group at different times after immunization (A) and on the 35th day (B) (n = 5).

[0024] Figure 3 Thickness of the right posterior toes of rats in each group at different times after immunization (A) and on the 35th day (B) (n = 5).

[0025] Figure 4 On the 30th day, X-ray analysis of the toes of CIA rats treated with different regimens, including the left lateral view of the toes of CIA rats (A), the right lateral view of the toes of CIA rats (B), the bone erosion score (C) and the joint space stenosis rate (D) of each group of CIA rats. The red arrow indicates bone erosion damage, and the blue arrow indicates soft tissue swelling.

[0026] Figure 5 Effect of LARM on the joint pathology of CIA rats, (A) joint HE staining (100×, 200×); (B) joint pathology score (n = 3).

[0027] Figure 6 Effect of LARM on the joint cartilage injury of CIA rats. (A) Joint safranin O fast green staining (100×, 200×); (B) joint cartilage injury score (n = 3).

[0028] Figure 7 Effect of LARM on plasma IL-10 (A) and TNF-α (B) in CIA rats. DETAILED DESCRIPTION OF THE INVENTION

[0029] The methods and techniques of the present invention are generally carried out according to the traditional methods known in the art, unless otherwise specified. The nomenclatures related to biology, pharmacology, and medical and pharmaceutical chemistry described herein, as well as the experimental methods and techniques, are known and commonly used in the art.

[0030] Unless otherwise specified, the scientific and technical terms used herein shall have the meanings commonly understood by those of ordinary skill in the art. However, the following terms have the following definitions:

[0031] Term

[0032] The term "therapeutically effective dose" refers to any amount of a drug that, when used alone or in combination with another therapeutic agent, promotes the regression of a disease, which is manifested by a decrease in the severity of the disease symptoms, an increase in the frequency and duration of the disease-free period, or the prevention of a disorder or disability caused by the disease. The "therapeutically effective dose" of the drug of the present invention also includes a "preventively effective dose", which is any amount of a drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or suffering from a recurrence of the disease, inhibits the occurrence or recurrence of the disease.

[0033] As will be apparent to those skilled in the art, the effective in vivo dosage and the specific mode of administration will vary depending on the species, body weight and age of the mammal being treated, the specific compound used, and the specific purpose for which these compounds are used. Those skilled in the art can determine the effective dosage level (i.e., the dosage level necessary to achieve the desired effect) according to conventional pharmacological methods. Generally, the clinical application of the product in humans starts at a lower dosage level and the dosage level is then continuously increased until the desired effect is achieved. Alternatively, the useful dosage and route of administration of the composition identified by this method can be established by acceptable in vitro studies using existing pharmacological methods.

[0034] To better understand the content of the present invention, the content of the present invention will be further described below in conjunction with specific implementation methods, but the protected content of the present invention is not limited to the following examples.

[0035] Experimental materials and reagents

[0036] Experimental animals: Female SD rats, 6 - 8 weeks old, weighing 160 - 180 g, were purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd., and the certificate number was SCXK(Lu)20230002. Breeding conditions: Room temperature, alternating light and dark, and the experiment was started after 3 days of adaptive breeding.

[0037] Experimental drug: Rotigotine microspheres, from Shandong Luye Pharmaceutical Co., Ltd.

[0038] Experimental reagents and consumables:

[0039] 0.9% sodium chloride solution, 2% pentobarbital sodium, isoflurane, methotrexate, rotigotine;

[0040] Rat TNF-α kit, rat IL-10 kit, absolute ethanol, paraformaldehyde, PBS buffer, bovine type II collagen, Incomplete Freund's Adjuvant (IFA), Tween 20, red blood cell lysate;

[0041] Three-way valve, screw-thread syringe, straight-tip surgical scissors, sterile centrifuge tube, disposable sampling trough.

[0042] Experimental instruments: AL 204 electronic balance, vortex mixer, centrifuge, electronic balance, incubator, ice maker, Forma 902 vertical ultra-low temperature refrigerator, pipette and others.

[0043] All experimental materials and reagents are commercially available.

[0044] Abbreviations:

[0045] Rotigotine microspheres: LARM

[0046] Sodium Carboxymethylcellulose: Sodium Carboxymethylcellulose, CMC-Na

[0047] Phosphate Buffered Saline: PBS

[0048] Bovine type II collagen: Bovin type II collagen, CII

[0049] Incomplete Freund's Adjuvant: IFA

[0050] Preparation of the solution in Example 1

[0051] 1. Preparation of bovine type II collagen solution

[0052] Slowly add 0.05 M acetic acid solution to the freeze-dried powder of bovine type II collagen, adjust the final concentration to 2 mg / mL, place it at 4°C and shake slowly overnight, and use it after complete dissolution.

[0053] 2. Preparation of CII / IFA emulsion

[0054] Use two 5 mL syringes to separately draw 2 mg / mL CII solution and 5 mg / mL IFA solution. Push the CII solution into the mother liquor of IFA in an ice bath environment. After repeatedly pushing the solution until the syringe piston can be easily pushed, drop the emulsion into water. If the liquid droplets form solid lumps on the water surface without spreading, the preparation is successful.

[0055] 3. Preparation of LARM suspension

[0056] Add 1% CMC-Na to LARM to make a 2.8 mg / mL LARM suspension.

[0057] Animal grouping and membrane formation in Example 2

[0058] Standard determination:

[0059] According to the animal screening requirements, determine the animal screening evaluation criteria table (Table 1).

[0060] Table 1 Animal Screening Evaluation Criteria Table

[0061] Score Meaning 0 points No redness or swelling, normal joint movement 1 point Mild redness or swelling, slightly limited joint movement 2 points Moderate redness or swelling, significantly limited joint movement 3 points Severe redness or swelling, joint stiffness or partial ankylosis 4 points Severe swelling with joint deformity, completely immobile

[0062] Animal membrane formation:

[0063] Select female SD rats at the SPF level, 6 - 8 weeks old, with no redness or swelling in the limbs of each rat and normal joint movement of each ankle joint. Inject 150 μL of normal saline subcutaneously at the root of the tail of 5 rats as the blank control group (Control), number the remaining rats in sequence, and perform modeling by injecting 150 μL of CII / IFA emulsion subcutaneously at the root of the tail. After modeling, observe the joint status of the rats daily, and exclude the rats with joint swelling within one week. Seven days later, inject 100 μL of normal saline or CII / IFA emulsion subcutaneously at a point 1 cm proximal to the first injection point at the root of the rat's tail to complete the booster immunization, which is recorded as day 0 at this time.

[0064] Animal grouping:

[0065] On the 1st day and the 5th day, weigh the rats and record the joint index scores. On the 5th day, select 25 animals with a joint score of 1 point and randomly divide them into 5 groups, namely the model group (Model), the LARM 14 mg / kg group (LARM-L), the LARM 28 mg / kg group (LARM-H), the methotrexate 2 mg / kg group (MTX), and the rotigotine 1 mg / kg group (ROT), with 5 animals in each group. Start drug administration, with an oral administration volume of 1 mL / 100 g and a subcutaneous or intramuscular injection volume of 0.5 mL / 100 g. Rats in the Control group and the Model group were intramuscularly injected with 1% CMC-Na, subcutaneously injected with normal saline containing 1% DMSO, and gavaged with 0.5% CMC-Na; rats in the LARM-L and LARM-H groups were intramuscularly injected with the corresponding concentration of LARM suspension, subcutaneously injected with normal saline containing 1% DMSO, and gavaged with 0.5% CMC-Na; rats in the MTX group were gavaged with 2 mg / kg of methotrexate, subcutaneously injected with normal saline containing 1% DMSO, and intramuscularly injected with 1% CMC-Na; rats in the ROT group were subcutaneously injected with 1 mg / kg of rotigotine, intramuscularly injected with 1% CMC-Na, and gavaged with 0.5% CMC-Na. Intramuscular injection is administered once every four weeks, subcutaneous injection is administered once a day, and gavage is administered once a week.

[0066] Example 3 Monitoring of Rat Joint Index

[0067] The joints of the rats were evaluated at the same time every 5 days. The joint evaluation criteria are shown in Table 1. Meanwhile, the body weights of the rats were recorded until the samples were taken after the 35-day evaluation.

[0068] The changes in body weight were as Figure 1 shown. Compared with the Control group, the body weight of the rats in the Model group was significantly reduced and the weight gain rate was significantly slowed down. The rats in the Model group showed compensatory weight gain on D25, indicating the transition of arthritis from the acute phase to the chronic phase. Compared with the Model group, the body weights of the rats in the MTX group, LARM-L group, and LARM-H group were significantly increased, and the body weight of the rats in the ROT group had an upward trend. The body weight of the rats in the MTX group showed a biphasic response and significantly recovered after D30. The LARM-H group showed a continuous weight gain effect starting from D10. Compared with the LARM-L group, the weight gain advantage brought by the high dose was statistically significant starting from D25 (p < 0.05).

[0069] The joint index scores were as Figure 2 shown. The Model group reached the peak on D25. The MTX group significantly inhibited the progression of inflammation starting from D20; the ROT group showed a certain protective trend but no statistical difference was observed.

[0070] Combining the joint index scores and the results of body weight changes, it was found that compared with ROT, the protective effect of LARM on CIA in rats was significantly enhanced.

[0071] Example 4 Measurement of the toe thickness of rats

[0072] The toe thickness was measured every 5 days starting from 5 days. The measurement claw was perpendicular to the long axis of the foot. The caliper was closed until it touched the skin without squeezing and deforming the tissue. As Figure 3 shown.

[0073] In the early stage of the progression of CIA, MTX had an inhibitory effect on the toe thickness, but there was no significant improvement in the joint score, indicating that it was effective in inhibiting edema but had limited protection against bone and joint damage; after LARM intervention, the effect of inhibiting the toe swelling of rats and improving the joint score of rats was better than that of the MTX group, indicating that it could inhibit the inflammatory edema and joint destruction induced by early immune overactivation; no significant protective effect was observed on the joint index score and toe swelling using ROT.

[0074] According to the research results of Example 3 and Example 4, administering LARM in the early stage of immunity could delay the acute inflammation peak period of CIA and significantly weaken the intensity of joint damage and functional destruction; after ROT intervention, the disease manifestation of the rats had a certain remission trend, but there was no statistical difference.

[0075] Example 5 X-ray examination of the joints of rats

[0076] On the 30th day, rats in each group were induced to general anesthesia by intraperitoneal injection of sodium pentobarbital, and X-ray photography was used to detect bone destruction in the toes of rats. As Figure 4 shown.

[0077] Through X-ray imaging examination, it was found that in the Control group, the articular surface was smooth, the bone cortex was continuous, the joint space was clear, and there was no bone erosion or osteophyte formation; in the Model group, the soft tissue swelling was severe, and moth-eaten bone destruction could be seen at the distal ends of the metatarsal bones and phalanges, the bone cortex was discontinuous, a large number of osteophytes were formed on the phalanges, the joint space was narrow, and the local space disappeared; in the MTX group, the soft tissue swelling was improved, the erosion area of the metatarsal bones was reduced by about 40% compared with the Model group, the joint space of the phalanges was partially restored, but there were still small osteophytes formed; in the LARM-L group, the soft tissue swelling was still obvious, the bone erosion was reduced compared with the Model group, and the bone erosion of the metatarsal bones led to the discontinuity of the bone cortex and the narrowing of the joint space; in the LARM-H group, there was a significant protective effect, the soft tissue swelling of the bone was significantly reduced, the bone erosion area was reduced by more than 70%, the bone cortex was continuous, and the articular surface was close to smooth; in the ROT group, the soft tissue swelling was relatively severe, and there was no statistical difference in the overall bone erosion compared with the Model group, only the local bone erosion of the metatarsal bones had slight improvement.

[0078] It was proved that early administration of LARM in the immune period had a significant protective effect on bone erosion and joint destruction in CIA rats.

[0079] Example 6 Detection of inflammatory cytokines in rat plasma

[0080] On the 35th day, blood was taken from the inner canthus of the rat's eye with a glass capillary tube rinsed with 0.1% sodium heparin into an anticoagulant EP tube. After blood collection, the EP tube was gently inverted immediately to mix evenly, centrifuged at 3000×g for 10 minutes at room temperature, the upper plasma was separated, aliquoted into pre-cooled EP tubes, and stored at -80°C to avoid repeated freezing and thawing. Subsequently, it was used to detect inflammatory cytokines such as IL-10, IL-4, TNF-α, and IL-1β. The detection process of the commercial Elisa kit was used for the detection of cytokines. At a wavelength of 450 nm, the OD value of each well was directly measured using an enzyme-labeled instrument.

[0081] As Figure 5As shown, compared with the Control group, the plasma IL-10 level in the Model group of rats was significantly reduced by about 50%, and the TNF-α level was significantly increased; compared with the Model group, the expression of TNF-α in the MTX group, LARM-L group, and LARM-H group was significantly reduced, while there were obvious differences in the content of IL-10. After LARM intervention, the expression of IL-10 was significantly increased, while in the rats treated with MTX, there was no significant difference in the expression of IL-10; the content of IL-10 and TNF-α in the ROT group of rats was improved compared with the Model group, but there were no statistical differences. In summary, LARM can significantly increase the expression of peripheral blood IL-10 in CIA rats, while ROT did not show a similar effect.

[0082] Example 7 Extraction of Bone Marrow Mononuclear Cells

[0083] After euthanizing the rats described in Example 6, take their hind limbs, remove the skin and muscle, soak them in 75% ethanol for 2 min, and then soak all the bones in a petri dish filled with sterile PBS. Take the bone marrow cell solution, sieve it through a 40 μm cell sieve, transfer it to a 15 mL centrifuge tube, centrifuge at 2000 rpm for 10 min, discard the supernatant, resuspend the cell pellet with 3 mL of erythrocyte lysate for a cell reaction of 5 min, add PBS to 8 mL to terminate the reaction, centrifuge at 2000 rpm for 10 minutes, discard the supernatant, add 2 mL of new pre-cooled PBS to resuspend the cells, so that the cell concentration is 10 - 20 million / mL, aliquot and place at 4°C for flow cytometry detection for standby.

[0084] Example 8 Histopathological Detection of Rat Joint Tissues

[0085] Take the rat joint tissues described in Example 7. After decalcifying, dehydrating, embedding, and sectioning the rat knee joint tissues, perform HE staining of the ankle joint, safranin O-fast green staining of the rat ankle joint, and mounting. Through HE staining, observe the sections and use ImageJ software to score synovial hyperplasia, inflammatory cell infiltration, and bone destruction.

[0086] Through safranin O-fast green staining, score the cartilage integrity respectively according to the continuity of the tangent layer, the arrangement of chondrocytes, and the degree of calcified layer destruction. The scoring criteria follow the OARSI rules. After scoring the tibial and talar sides respectively, calculate the sum to evaluate the degree of cartilage destruction and bone erosion.

[0087] According to the HE staining results, as Figure 6As shown, the synovial structure of the Control group was intact, the synovial cells were arranged in a single layer, without inflammatory infiltration or pannus formation, and the thickness of the cartilage layer was uniform and continuous. In the Model group, there was necrosis of the synovium and inflammatory hyperplasia of the surrounding joint capsule, necrotic substances and inflammatory exudates were seen in the joint cavity, and pannus invasion occurred; the LARM-H group and the MTX group showed significant curative effects, with reduced synovial hyperplasia and decreased density of inflammatory cell infiltration; in the LARM-L group, synovial hyperplasia was reduced, and a small amount of necrotic substances and inflammatory cell exudates were seen in the joint cavity; although the overall score of the ROT group was somewhat alleviated, the improvement of various tissue lesions was not significant. Therefore, early administration of LARM can significantly reduce synovial hyperplasia and inflammatory infiltration of the joints.

[0088] The results of safranin O-fast green staining were as Figure 7 shown. The content of chondroitin sulfate in the cartilage of the Model group was significantly decreased compared with that of the Control group, and the tidemark of the cartilage was disrupted, and the cartilage matrix was severely degraded and damaged; fast green staining further confirmed that the arrangement of collagen fibers in the Model group was disordered, and there was local destruction of the subchondral bone on the tibial side. After drug intervention, there was mild loss of the cartilage matrix in the MTX group and the LARM-H group, but the cartilage arrangement was relatively intact, the directionality of the arrangement of collagen fibers was restored, and no obvious bone erosion was seen; in the LARM-L group, there was loss of the articular cartilage matrix, the cartilage was discontinuous, the arrangement of bone collagen fibers was disordered, and the injury of the subchondral bone was improved; although the ROT group showed partial recovery of bone destruction, the cartilage matrix was severely lost until the tidemark was discontinuous, and the overall severity of the injury was not different from that of the Model group. Comprehensive analysis of the above results suggests that LARM intervention can significantly improve the injury of articular cartilage and the degree of subchondral bone destruction in CIA rats, while the repair ability of ROT for cartilage and bone is limited.

[0089] The data of this study were presented in the form of mean ± standard deviation (mean ± SD). Statistical analysis was completed using IBM SPSS v.21.0. The drawing work was achieved through Graph Pad Prism. When comparing between groups, normality test and homogeneity of variance test were first carried out to judge whether the data met the prerequisite conditions for analysis of variance. If the data met the requirements, one-way analysis of variance (One-Way ANOVA) or t-test was used for statistical comparison between groups. In this study, * indicated p < 0.05, ** indicated p < 0.01, and *** indicated p < 0.001.

[0090] In summary, rotigotine microspheres can be used in the preparation of drugs for preventing or treating rheumatoid arthritis. Rotigotine microspheres can be used alone, or compounded with other drugs, compounds, and carriers into a pharmaceutical composition. During use, the drug contains an effective therapeutic amount of rotigotine microspheres. The rotigotine microspheres can be prepared into various forms of medicaments such as oral preparations and injections for use.

[0091] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the embodiments, for those of ordinary skill in the art, it is still possible to modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions required to be protected by the present invention.

Claims

1. Use of rotigotine microspheres in the preparation of a medicament for preventing or treating rheumatoid arthritis.

2. The use according to claim 1, characterized in that, The medicament for preventing or treating rheumatoid arthritis is for preventing rheumatoid arthritis or treating acute-phase rheumatoid arthritis.

3. The use according to claim 1, wherein The medicament for preventing or treating rheumatoid arthritis is the use of the rotigotine microspheres in a medicament for preventing or treating rheumatoid arthritis induced by early immune overactivation.

4. The use according to claim 1, wherein The use is as follows: 1) Weakening joint damage, and / or; 2) Reducing bone erosion, and / or; 3) Reducing joint synovial hyperplasia, and / or 4) Delaying the acute onset of rheumatoid arthritis.

5. The use according to claim 1, characterized in that, The use is to increase IL-10 while reducing TNF-α.

6. The use according to claim 1, wherein The medicament for preventing or treating rheumatoid arthritis is an injection.

7. The use according to claim 6, characterized in that, The rotigotine microspheres are administered once every 4 to 8 weeks by subcutaneous injection or intramuscular injection.

8. The use according to claim 7, wherein, The dosage of the rotigotine microspheres is 14 mg / kg to 28 mg / kg.

9. The use according to claim 1, characterized in that, The rotigotine microspheres can be used alone or compounded with other drugs, compounds, carriers into a pharmaceutical composition.

10. The use according to claim 1, wherein The medicament contains an effective therapeutic amount of rotigotine microspheres.

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