KR20230012860A - Compositions for co-administration of sphingosylphosphorylcholine and fingolimod, and the method for the prevention, improvement, or treatment of arthritis using the same - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for combined administration for the prevention, improvement, and/or treatment of arthritis, including rheumatoid arthritis. As a result of confirming the effect of the combined administration of sphingosylphosphorylcholine and fingolimod on the treatment of rheumatoid arthritis, the present inventors found that: lymphocyte activation is shown when the above two drugs are administered together compared to when administered individually; the swelling of the soles and joints is suppressed; the enlargement of the spleen and lymph nodes is improved; immunomodulation in inflamed tissues is shown; inflammatory cytokines and immune cells are suppressed; and the increase in anti-inflammatory cytokines was induced more effectively. Accordingly, a superior rheumatoid arthritis treatment effect has been achieved. Therefore, the combined use of sphingosylphosphorylcholine and fingolimod, according to the present invention, is expected to be utilized in a variety of fields in the prevention and treatment of arthritis, especially rheumatoid arthritis.

Description

Compositions for co-administration of sphingosylphosphorylcholine and fingolimod, and the method for the prevention, improvement, or treatment of arthritis using the same}

The present invention relates to a composition for preventing, improving, or treating arthritis, preferably rheumatoid arthritis.

Arthritis is a disease in which damage or inflammation occurs due to various causes in joints, where bones meet, and is accompanied by symptoms such as pain, heat, and swelling. Arthritis is divided into several types depending on the site of occurrence and cause, and is largely classified into osteoarthritis (degenerative arthritis) and rheumatoid arthritis.

Rheumatoid arthritis is a chronic inflammatory disease associated with chronic inflammation of the joints. Often, the inflammation spreads to tissues around the joint and other organs. In general, rheumatoid arthritis is a progressive disease that can lead to joint destruction and dysfunction, and joint inflammation associated with rheumatoid arthritis causes joint swelling, pain, stiffness, and redness. Joint inflammation associated with rheumatoid arthritis can also occur in the tissues around the joint (tendons, ligaments, muscles). In some patients with rheumatoid arthritis, chronic inflammation destroys cartilage, bone, and ligaments, leading to joint deformities. Damage to the joints may occur early in the disease and may be progressive. Progressive damage to the joint does not necessarily correlate with the degree of pain, stiffness, or swelling in the joint.

Various clinical treatment methods for rheumatoid arthritis have been developed, which are divided into general conservative treatment, drug treatment, and surgical treatment. In general, treatment of rheumatoid arthritis aims to return to normal life by suppressing pain and inflammation and minimizing functional loss of joints because the disease causes joint pain, joint deformation, and loss of function due to chronic arthritis.

Among the currently used treatment methods for rheumatoid arthritis, anti-TNF-α drugs are typically used as drug therapies. It is known to cause adverse reactions in the digestive system, musculoskeletal system, kidney and endocrine system as side effects.

Therefore, there is an urgent need to discover new therapeutic agents for more effective prevention or treatment of arthritis, including rheumatoid arthritis.

Republic of Korea Patent Registration No. 10-1355440

The present invention was made to solve the above problems, and the present inventors confirmed the therapeutic effect of rheumatoid arthritis according to the combined administration of sphingosylphosphorylcholine (SPC) and fingolimod (FTY720), Compared to the single administration of the above two drugs, the inhibition of swelling of the soles and joints, inhibition of the enlargement (hypertrophy) of the spleen and lymphoid tissue, inhibition of inflammatory cytokines in the blood and increase of anti-inflammatory cytokines are more effectively promoted when administered in combination. It was confirmed that a more excellent treatment effect for rheumatoid arthritis was achieved by being, and the present invention was completed.

Accordingly, an object of the present invention is sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; And to provide a pharmaceutical composition for concomitant administration for the prevention or treatment of arthritis, containing fingolimod or a pharmaceutically acceptable salt thereof as an active ingredient.

However, the technical problem to be achieved by the present invention is not limited to the above-mentioned problems, and other problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.

The present invention relates to sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for concomitant administration for preventing or treating arthritis, comprising Fingolimod or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the pharmaceutical composition for concomitant administration includes sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; and fingolimod or a pharmaceutically acceptable salt thereof may be in the form of a mixture, but is not limited thereto.

In another embodiment of the present invention, the pharmaceutical composition for concomitant administration includes sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; Alternatively, fingolimod or a pharmaceutically acceptable salt thereof may be formulated and administered simultaneously (simultaneously) or sequentially (sequentially), but is not limited thereto.

In another embodiment of the present invention, the arthritis may be at least one selected from the group consisting of rheumatoid arthritis, osteoarthritis, degenerative arthritis, and polyarthritis, but is not limited thereto.

In another embodiment of the present invention, the pharmaceutical composition may satisfy one or more of the following characteristics, but is not limited thereto;

(a) promote activation of regulatory T cells;

(b) inhibits the activation of T helper 17 cells; or

(c) Inhibits activation of T helper 1 cells.

In another embodiment of the present invention, the pharmaceutical composition may inhibit at least one selected from the group consisting of edema, enlargement of the spleen, enlargement of the lymph node, and inflammation in the joint, but is not limited thereto.

In another embodiment of the present invention, the pharmaceutical composition may satisfy one or more of the following characteristics, but is not limited thereto:

(a) reducing the level of inflammatory cytokines in the blood; or

(b) increase the level of anti-inflammatory cytokines in the blood.

In another embodiment of the present invention, the inflammatory cytokine is one or more selected from the group consisting of TNF-α, IL-6, IL-1β, IFN-γ, and IL-17a; The anti-inflammatory cytokine may be IL-10, but is not limited thereto.

In addition, the present invention provides a method for preventing or treating arthritis, comprising administering the pharmaceutical composition for concomitant administration according to the present invention to a subject in need thereof. Alternatively, the present invention relates to sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; and jointly administering fingolimod or a pharmaceutically acceptable salt thereof to a subject in need thereof, providing a method for preventing or treating arthritis.

In addition, the present invention relates to sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof for the preparation of a drug for preventing or treating arthritis; and the use of fingolimod or a pharmaceutically acceptable salt thereof. Preferably, the drug may be a drug for concomitant administration.

In addition, the present invention relates to sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; And it provides a use for preventing or treating arthritis of a composition for concomitant administration comprising fingolimod or a pharmaceutically acceptable salt thereof.

The present invention relates to a pharmaceutical composition for combined administration for the prevention, improvement, and/or treatment of arthritis, including rheumatoid arthritis, and the present inventors are concerned with the therapeutic effect of rheumatoid arthritis according to the combined administration of sphingosylphosphorylcholine and fingolimod As a result of confirming, lymphocyte activation when the two drugs were administered in combination compared to each alone; Inhibition of swelling of the soles and joints; improvement of enlargement of spleen and lymph nodes; immunomodulation in inflamed tissue; inhibition of inflammatory cytokines and immune cells; And it was confirmed that the increase in anti-inflammatory cytokines was more effectively induced to achieve a more excellent treatment effect for rheumatoid arthritis. Therefore, the combined use of sphingosylphosphorylcholine and phingolimod according to the present invention is expected to be variously utilized in the field of preventing and treating arthritis, particularly rheumatoid arthritis.

1 shows the result of confirming the degree of activation of CD4 ⁺ T lymphocytes according to single or combined administration of SPC and FTY720 by flow cytometry.
Figure 2 shows the results of quantitatively analyzing the degree of CD4 ⁺ T lymphocyte activation according to single or combined administration of SPC and FTY720 (*P<0.05, **P<0.01, ***P<0.001, *** *P<0.0001, same hereafter).
Figure 3 shows the results of observation of changes in the onset of rheumatoid arthritis over time after single or combined administration of SPC and FTY720 in a CIA animal model.
Figure 4 shows the results of photographing paw edema after single or combined administration of SPC and FTY720 in a CIA animal model.
5 shows the results of measuring paw thickness to confirm the degree of paw edema after single or combined administration of SPC and FTY720 in a CIA animal model.
Figure 6 shows the results of confirming the size of the spleen, inguinal lymph node, and popliteal lymph node after single or combined administration of SPC and FTY720 to the CIA animal model.
Figure 7 shows the result of confirming the CD4 ⁺ T lymphocyte ratio in the inflamed tissue after single or combined administration of SPC and FTY720 to the CIA animal model by flow cytometry.
Figure 8 shows the results of quantitatively analyzing the ratio of regulatory T cells in inflamed tissue after single or combined administration of SPC and FTY720 to the CIA animal model.
Figure 9 shows the results of quantitatively analyzing the number of CD4 ⁺ T lymphocytes in inflamed tissues after single or combined administration of SPC and FTY720 in a CIA animal model.
10 shows the result of confirming the ratio of T 17 _lymphocytes in the gateway lymph node by flow cytometry after single or combined administration of SPC and FTY720 in a CIA animal model.
FIG. 11 shows the results of quantitatively analyzing the ratio of TH 17 lymphocytes in the gateway lymph node after single or combined administration of SPC and _FTY720 in a CIA animal model.
12 shows the result of confirming the ratio of T _H 1 lymphocytes in the gateway lymph node by flow cytometry after single or combined administration of SPC and FTY720 in a CIA animal model.
13 shows the results of quantitatively analyzing the ratio of T _H 1 lymphocytes in the gateway lymph node after single or combined administration of SPC and FTY720 in a CIA animal model.
Figure 14 shows the results of confirming the change of inflammation-inducing cytokines and anti-inflammatory cytokines in peripheral blood after single or combined administration of SPC and FTY720 to the CIA animal model by ELISA.

The present inventors confirmed the treatment effect of rheumatoid arthritis according to the combined administration of sphingosylphosphorylcholine (SPC) and Fingolimod (FTY720). It was confirmed that an effective rheumatoid arthritis therapeutic effect was achieved, and the present invention was completed.

Specifically, in one embodiment of the present invention, as a result of combined treatment with SPC and FTY720 while inducing activation of CD4 ⁺ cells isolated from the spleen of mice, regulatory T cells (regulatory T cells) by combined administration compared to single administration of each drug. ), it was confirmed that the activation effect was more excellent, that is, the immunomodulatory effect was more excellent (see Example 1).

In another embodiment of the present invention, as a result of observing the rheumatoid arthritis incidence index after co-administering SPC and FTY720 to a rheumatoid arthritis animal model, it was confirmed that the rheumatoid arthritis incidence index was significantly lowered when the combination was administered compared to the case of single administration of each drug (see Example 2).

In another embodiment of the present invention, as a result of observing the edema state of the feet after co-administration of SPC and FTY720 to an animal model with arthritis, it was confirmed that the edema of the feet was significantly improved when the combined administration compared to the case of administering each drug alone ( see Example 3).

In another embodiment of the present invention, as a result of confirming the effect of improving the enlargement (hypertrophy) of the spleen and lymph nodes after the combined administration of SPC and FTY720 to an animal model with arthritis, the spleen and lymph nodes were improved when the spleen and lymph nodes were administered in combination compared to when each drug was administered alone. It was confirmed that enlargement was remarkably suppressed (see Example 4).

In another embodiment of the present invention, after the joint administration of SPC and FTY720 to an animal model with arthritis, the degree of infiltration of immune cells into inflamed tissue was compared, and the result of the combined administration of the two drugs showed that CD4 ⁺ lymphocytes infiltrated into the inflamed tissue. It was confirmed that an excessive immune response was prevented by a decrease in T cells, and a more effective immune regulation function could be achieved by increasing regulatory T cells (see Example 5).

In another embodiment of the present invention, after the joint administration of SPC and FTY720 to an animal model of arthritis, the ratio of T 17 cells, which are autoimmune-induced T _lymphocytes , was observed. It was confirmed that the excessive increase of T _H 17 cells was effectively inhibited (see Example 6).

In another embodiment of the present invention, after the joint administration of SPC and FTY720 to an animal model of arthritis, the ratio of T 1 cells, which are autoimmune-induced T _lymphocytes , in the lymph node was observed. It was confirmed that the increase of T _H 1 cells was effectively inhibited when the treatment was performed (see Example 7).

In another embodiment of the present invention, as a result of observing the levels of inflammatory and anti-inflammatory cytokines in peripheral blood after co-administration of SPC and FTY720 to an animal model with arthritis, inflammatory cytokines in the blood when each drug was administered in combination compared to when each drug was administered alone It was confirmed that the level of caine further decreased and the level of anti-inflammatory cytokine further increased (see Example 8).

Hereinafter, the present invention will be described in detail.

The present invention relates to sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for concomitant administration for the prevention or treatment of arthritis, comprising fingolimod or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the "sphingosylphosphorylcholine (SPC)" refers to a bioactive sphingolipid in plasma metabolized from hydrolysis of cell membrane sphingolipid. Sphingosylphosphorylcholine is known as a ligand of endothelial differentiation gene receptor 3 (EDG3), and in particular induces the release of Ca ²⁺ from intracellular stores through the IP3-independent pathway. As it is known to do, it functions to mediate signal transduction inside and outside the cell. Sphingosylphosphorylcholine according to the present invention may be represented by Formula 1 below, but is not limited thereto.

[Formula 1]

In the present invention, "Fingolimod; FTY720" is an oral drug mainly used for the treatment of multiple sclerosis, and binds to the sphingosine 1-phosphate receptor to It suppresses inflammation by reducing the number of lymphocytes in the peripheral blood by blocking the drainage of lymphocytes from the lymph nodes. However, excessive use or long-term use of pingolimod can cause side effects such as headache, diarrhea, back pain, and cough, and in serious cases, liver disease, increased risk of infectious diseases, macular edema, increased blood pressure, leukoencephalopathy ( It is known to cause diseases such as leukoencephalopathy) and cancer. The fingolimod according to the present invention may be represented by Formula 2 below, but is not limited thereto.

[Formula 2]

The composition according to the present invention may also include a pharmaceutically acceptable salt of sphingosylphosphorylcholine; and/or a pharmaceutically acceptable salt of pingolimod as an active ingredient. As used herein, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.

Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Acid addition salts can be prepared by conventional methods, for example, by dissolving a compound in an aqueous solution of excess acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can also be prepared by heating equimolar amounts of the compound and an acid or alcohol in water and then evaporating the mixture to dryness, or suction filtering the precipitated salt.

Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. An alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable for pharmaceutical purposes to prepare a sodium, potassium or calcium salt, and the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof in the composition of the present invention; And the content of fingolimod or a pharmaceutically acceptable salt thereof can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc., for example, 0.0001 to 99.9% by weight, or 0.001 to 0.001% by weight based on the total weight of the composition. It may be 50% by weight, but is not limited thereto. The content ratio is a value based on the dry amount after removing the solvent.

Preferably, the weight ratio (w/w %) of sphingosylphosphorylcholine and fingolimod contained in the pharmaceutical composition according to the present invention is SPC:FTY720 = 0.1 to 10:1, 0.5 to 10:1, 1 to 10:1, 0.1 to 8:1, 0.1 to 6:1, 0.1 to 5:1, 0.1 to 4:1, 0.1 to 3:1, 0.1 to 2:1, 0.1 to 1.5:1, 0.5 to 5:1 1, 0.5 to 4:1, 0.5 to 3:1, 0.5 to 2:1, 0.5 to 1.5:1, 0.8 to 5:1, 0.8 to 4:1, 0.8 to 3:1, 0.8 to 2:1, 0.8 to 1.5:1, 0.8 to 1.3:1, or 1 to 1.3:1, but is not limited thereto.

The pharmaceutical composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. The excipient may be, for example, one or more selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, an adsorbent, a moisturizer, a film-coating material, and a controlled release additive.

The pharmaceutical compositions according to the present invention are powders, granules, sustained-release granules, enteric granules, solutions, eye drops, elsilic agents, emulsions, suspensions, spirits, troches, perfumes, and limonadese, respectively, according to conventional methods. , tablets, sustained-release tablets, enteric tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric capsules, pills, tinctures, soft extracts, dry extracts, fluid extracts, injections, capsules, perfusate, It can be formulated and used in the form of external preparations such as warning agents, lotions, pasta agents, sprays, inhalants, patches, sterile injection solutions, or aerosols, and the external agents are creams, gels, patches, sprays, ointments, and warning agents. , lotion, liniment, pasta, or cataplasma may have formulations such as the like.

Carriers, excipients and diluents that may be included in the pharmaceutical composition according to the present invention include lactose, dextrose, sucrose, oligosaccharide, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

Corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, di-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, phosphoric acid as additives for tablets, powders, granules, capsules, pills, and troches according to the present invention Calcium monohydrogen, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropylmethyl Excipients such as cellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, Primogel; Gelatin, gum arabic, ethanol, agar powder, cellulose phthalate acetate, carboxymethyl cellulose, calcium carboxymethyl cellulose, glucose, purified water, sodium caseinate, glycerin, stearic acid, sodium carboxymethyl cellulose, sodium methyl cellulose, methyl cellulose, microcrystalline cellulose, dextrin Binders such as hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, purified shellac, starch arc, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone may be used, Hydroxypropyl Methyl Cellulose, Corn Starch, Agar Powder, Methyl Cellulose, Bentonite, Hydroxypropyl Starch, Sodium Carboxymethyl Cellulose, Sodium Alginate, Calcium Carboxymethyl Cellulose, Calcium Citrate, Sodium Lauryl Sulfate, Silicic Anhydride, 1-Hydroxy Propyl cellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum, sodium bicarbonate, polyvinylpyrrolidone, calcium phosphate, gelled starch, gum arabic, disintegrants such as amylopectin, pectin, sodium polyphosphate, ethyl cellulose, white sugar, magnesium aluminum silicate, di-sorbitol solution, and light anhydrous silicic acid; Calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopod, kaolin, petrolatum, sodium stearate, cacao butter, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogen Added soybean oil (Lubri wax), aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, macrogol, synthetic aluminum silicate, silicic anhydride, higher fatty acid, higher alcohol, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, Lubricants such as starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and light anhydrous silicic acid; may be used.

Additives for the liquid formulation according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (tween esters), polyoxyethylene monoalkyl ethers, lanolin ethers, Lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, and the like may be used.

In the syrup according to the present invention, a solution of white sugar, other sugars, or a sweetener may be used, and aromatics, coloring agents, preservatives, stabilizers, suspending agents, emulsifiers, thickeners, etc. may be used as necessary.

Purified water may be used in the emulsion according to the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.

Suspension agents according to the present invention include acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC 1828, HPMC 2906, HPMC 2910, etc. Agents may be used, and surfactants, preservatives, stabilizers, colorants, and fragrances may be used as needed.

Injections according to the present invention include distilled water for injection, 0.9% sodium chloride injection, IV injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated IV injection, ethanol, propylene glycol, non-volatile oil-sesame oil , solvents such as cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate; solubilizing agents such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, twins, nijuntinamide, hexamine, and dimethylacetamide; buffers such as weak acids and their salts (acetic acid and sodium acetate), weak bases and their salts (ammonia and ammonium acetate), organic compounds, proteins, albumin, peptone, and gums; tonicity agents such as sodium chloride; Stabilizers such as sodium bisulfite (NaHSO ₃ ) carbon dioxide gas, sodium metabisulfite (Na ₂ S ₂ O ₅ ), sodium sulfite (Na ₂ SO ₃ ), nitrogen gas (N ₂ ), ethylenediaminetetraacetic acid; Sulfating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, ethylenediamine disodium tetraacetate, acetone sodium bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; Suspending agents such as Siemesis sodium, sodium alginate, Tween 80, aluminum monostearate may be included.

The suppository according to the present invention includes cacao butter, lanolin, witapsol, polyethylene glycol, glycerogelatin, methylcellulose, carboxymethylcellulose, a mixture of stearic acid and oleic acid, subanal, cottonseed oil, peanut oil, palm oil, cacao butter + Cholesterol, Lecithin, Lannet Wax, Glycerol Monostearate, Tween or Span, Imhausen, Monolen (Propylene Glycol Monostearate), Glycerin, Adeps Solidus, Buytyrum Tego-G -G), Cebes Pharma 16, Hexalide Base 95, Cotomar, Hydroxycote SP, S-70-XXA, S-70-XX75 (S-70-XX95), Hyde Hydrokote 25, Hydrokote 711, Idropostal, Massa estrarium (A, AS, B, C, D, E, I, T), Massa-MF, Masupol, Masupol-15, Neosupostal-N, Paramound-B, Suposiro (OSI, OSIX, A, B, C, D, H, L), suppository type IV (AB, B, A, BC, BBG, E, BGF, C, D, 299), Supostal (N, Es), Wecobi (W, R, S, M, Fs), testosterone triglyceride base (TG-95, MA, 57) and The same mechanism can be used.

Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, for example, starch, calcium carbonate, sucrose, etc. ) or by mixing lactose and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. there is. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.

In the present invention, "arthritis" is a disease in which the cartilage of a joint, which is a site where two or more bones come into contact, is destroyed and inflammatory changes occur in the joint, accompanied by symptoms such as pain, fever, swelling, joint stiffness, and the like . There are various types of arthritis depending on the site of occurrence or cause, but it can be largely divided into acute arthritis (serous arthritis, serous fibrinous arthritis, suppurative arthritis, etc.) and chronic arthritis (specific inflammation, polyarthritis, deforming osteoarthritis, hemophilic arthritis). It is generally classified as osteoarthritis (degenerative arthritis) or rheumatoid arthritis. The specific type of arthritis is not limited, but in the present invention, arthritis may be preferably selected from rheumatoid arthritis, osteoarthritis, degenerative arthritis, and polyarthritis.

In the present invention, "Rheumatoid Arthritis" refers to a chronic inflammatory systemic disease caused by a continuous inflammatory response of the synovial (thin film that produces joint fluid) tissue surrounding the joint. If inflammation of the synovial membrane persists, joint cartilage damage (erosion) occurs, and eventually joint destruction occurs, resulting in impaired joint function. Rheumatoid arthritis is one of the representative autoimmune diseases. Lymphocytes abnormally attack synovial membranes in the body and cause inflammation, resulting in rheumatoid arthritis. , rheumatoid inflammation can invade the kidneys. Symptoms of rheumatoid arthritis include inflammation within the joints, swelling, enlargement (enlargement) of the spleen and lymph nodes, and fatigue. Therefore, the pharmaceutical composition according to the present invention is characterized in that it treats at least one selected from the group consisting of edema, enlargement of the spleen, enlargement of the lymph node, and inflammation in the joint, and suppresses, improves, and/or It can be used as a pharmaceutical composition for treatment.

The present invention relates to sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; and fingolimod or a pharmaceutically acceptable salt thereof, thereby maximizing the efficacy of each drug and reducing the excessive dosage of each drug, thereby minimizing side effects such as toxicity.

Therefore, the pharmaceutical composition for concomitant administration according to the present invention comprises a pharmaceutically effective amount of sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; and a mixed agent in which a pharmacologically effective amount of fingolimod or a pharmaceutically acceptable salt thereof is mixed, and may be in a form for simultaneous administration of the two drugs.

Alternatively, the pharmaceutical composition for concomitant administration according to the present invention includes a pharmaceutically effective amount of sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; and fingolimod or a pharmaceutically acceptable salt thereof may be each formulated and administered simultaneously (simultaneously) or sequentially (sequentially). In this case, the pharmaceutical composition for concomitant administration includes a first pharmaceutical composition comprising a pharmaceutically effective amount of sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof as an active ingredient; and a second pharmaceutical composition comprising a pharmaceutically effective amount of fingolimod or a pharmaceutically acceptable salt thereof as an active ingredient, for simultaneous or sequential administration. At this time, in the case of sequential administration, the administration order is not limited, and the administration regimen may be appropriately adjusted according to the condition of the patient.

That is, when the pharmaceutical composition is a pharmaceutical composition for concomitant administration for sequential administration, the composition is administered first with fingolimod or a pharmaceutically acceptable salt thereof (“first component”) and then with sphingosylphosphoryl Choline or a pharmaceutically acceptable salt thereof ("second component") may be administered, and vice versa.

When the pharmaceutical composition is a pharmaceutical composition for combined administration for sequential administration, the time from administration of the first component to administration of the second component is 10 minutes to 72 hours, 10 minutes to 60 hours, and 10 minutes to 60 hours. 48 hours, 10 minutes to 36 hours, 10 minutes to 30 hours, 10 minutes to 24 hours, 30 minutes to 72 hours, 30 minutes to 60 hours, 30 minutes to 48 hours, 30 minutes to 36 hours, 30 minutes to 30 hours , 30 minutes to 24 hours, 1 hour to 72 hours, 1 hour to 60 hours, 1 hour to 48 hours, 1 hour to 36 hours, 1 hour to 30 hours, 1 hour to 24 hours, 3 hours to 72 hours, 3 time to 60 hours, 3 hours to 48 hours, 3 hours to 36 hours, 3 hours to 30 hours, 3 hours to 24 hours, 6 hours to 72 hours, 6 hours to 60 hours, 6 hours to 48 hours, 6 hours to 36 hours, 6 hours to 30 hours, 6 hours to 24 hours, 12 hours to 72 hours, 12 hours to 60 hours, 12 hours to 48 hours, 12 hours to 36 hours, 12 hours to 30 hours, 12 hours to 24 hours , 10 minutes to 24 hours, 10 minutes to 12 hours, 10 minutes to 6 hours, 10 minutes to 3 hours, 10 minutes to 1 hour, 10 minutes to 50 minutes, 10 minutes to 40 minutes, or 10 minutes to 30 minutes. However, it is not limited thereto.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, activity of the drug, It may be determined according to factors including sensitivity to the drug, administration time, route of administration and excretion rate, duration of treatment, drugs used concurrently, and other factors well known in the medical field.

That is, in the composition according to the present invention, sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; And the pharmacologically effective amount (i.e., the dose) of fingolimod or a pharmaceutically acceptable salt thereof is not limited and may vary depending on the condition of the patient and the severity of the disease, but preferably once for the subject of SPC The dosage is 1 to 10 mg/kg, 1 to 8 mg/kg, 2 to 8 mg/kg, 3 to 7 mg/kg, 3 to 6 mg/kg, 3 to 5 mg/kg, 4 to 7 mg/kg. kg, or 5 to 7 mg/kg, but is not limited thereto. In addition, a single dose of FTY720 for an individual is 1 to 10 mg/kg, 1 to 8 mg/kg, 1 to 7 mg/kg, 1 to 6 mg/kg, 2 to 6 mg/kg, 2 to 5 It may be mg/kg, 3 to 6 mg/kg, or 4 to 6 mg/kg, but is not limited thereto.

In summary, the composition for combined administration according to the present invention is not limited in the method and order of administration, but includes sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; and fingolimod or a pharmaceutically acceptable salt thereof, and although each component is administered sequentially, that is, separately, there is only a difference in the timing of administration, and as a result, it is characterized in that they are administered in combination. . Therefore, the pharmaceutical composition for combined administration according to the present invention includes sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; and fingolimod or a pharmaceutically acceptable salt thereof, characterized in that the preventive, ameliorative, and/or therapeutic effect of rheumatoid arthritis is more excellent than that of single administration of each of the above components through the combined administration.

Accordingly, the present invention provides a method for preventing or treating arthritis, comprising administering the pharmaceutical composition according to the present invention to a subject in need thereof. That is, the present invention relates to sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; and jointly administering fingolimod or a pharmaceutically acceptable salt thereof to a subject in need thereof, providing a method for preventing or treating arthritis.

The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art to which the present invention belongs.

The pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be envisaged, eg oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intrathecal) injection, sublingual administration, buccal administration, intrarectal insertion, vaginal It can be administered by intraoral insertion, ocular administration, otic administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, and the like.

The pharmaceutical composition of the present invention is determined according to the type of drug as an active ingredient together with various related factors such as the disease to be treated, the route of administration, the age, sex, weight and severity of the disease of the patient.

In the present invention, "subject" means a subject in need of treatment of a disease, and more specifically, a human or non-human primate, mouse, rat, dog, cat, horse, cow, etc. of mammals.

In the present invention, "administration" means providing a given composition of the present invention to a subject by any suitable method.

In the present invention, "prevention" refers to any action that suppresses or delays the onset of a desired disease, and "treatment" means that a desired disease and its associated metabolic abnormalities are improved or treated by administration of the pharmaceutical composition according to the present invention. All actions that are beneficially altered are meant, and "improvement" means any action that reduces a parameter related to a desired disease, for example, the severity of a symptom, by administration of the composition according to the present invention.

In addition, the pharmaceutical composition according to the present invention is characterized in that it satisfies one or more of the following characteristics, but is not limited thereto:

(a) promote activation of regulatory T cells;

(b) inhibits the activation of T helper 17 cells; or

(c) Inhibits activation of T helper 1 cells.

In addition, the pharmaceutical composition according to the present invention is characterized in that it satisfies one or more of the following characteristics, but is not limited thereto:

(a) reducing the level of inflammatory cytokines in the blood; or

(b) increase the level of anti-inflammatory cytokines in the blood.

In this case, the inflammatory cytokine may be selected from TNF-α, IL-6, IL-1β, IFN-γ, and IL-17a, but any cytokine known to induce inflammation may be included without limitation. In addition, the anti-inflammatory cytokine may be IL-10, but any cytokine known to inhibit inflammation may be included without limitation.

Hereinafter, a preferred embodiment is presented to aid understanding of the present invention. However, the following examples are provided to more easily understand the present invention, and the content of the present invention is not limited by the following examples.

[Example]

Example 1. CD4 by co-administration of SPC and FTY720 ⁺ T lymphocyte immunomodulatory effect

Regulatory T cells (Treg) are lymphocytes that induce an immune response by activating other immune cells such as B cells and cytotoxic T cells, and are important regulators of the immune system. Therefore, in order to confirm the immunomodulatory improvement effect of the combined administration of sphingosylphosphorylcholine (SPC) and fingolimod (FTY720), the present inventors investigated immunomodulation according to the combined administration of SPC and FTY720 during the activation of CD4 ⁺ T lymphocytes. Changes in cells (Treg) were observed.

Specifically, total CD4 ⁺ T lymphocytes were isolated from the spleen of DBA1/J mice, treated with a cell division marker (CFSE Cell Division Tracker Kit), ^and then expressed through αCD3e/αCD28. The cells were treated with 1 μg/ml of FTY720 while inducing activation, and then treated with 10 μM of SPC after 30 minutes to confirm changes in immunoregulatory cells according to the combined administration of FTY720 and SPC. As an inactivation control group, a group treated with IL-2 (2 ng/ml), a cytokine necessary for the survival of T lymphocytes, was set ("IL-2 control group"), and PBS (Vehicle) was used as a positive control group for T lymphocyte activation. The administered group was set ("PBS control group"), and Foxp3 was set as a marker for immunoregulatory cells (Treg). The weight ratio of SPC:FTY720 co-administered in in vitro experiments was 4.462:1.

Experimental results are shown in Figures 1 and 2. First, as a result of comparing the PBS control group to the IL-2 control group, it was confirmed that CD4 ⁺ T lymphocytes were effectively activated and divided through a leftward decrease in CFSE intensity as T lymphocytes were activated. In addition, it was confirmed that the ratio of Treg cells increased when SPC or FTY720 was treated alone compared to the PBS control group, in which the ratio of Treg decreased, but the ratio of Treg cells increased more remarkably when SPC and FTY720 were co-administered. The above results show that the combined administration induces the activation of regulatory T cells and achieves a more excellent immunomodulatory effect than the single administration of SPC or FTY720.

Example 2. Effect of joint administration of SPC and FTY720 to alleviate the symptoms of rheumatoid arthritis

Subsequently, it was confirmed whether the combined administration of sphingosylphosphorylcholine and fingolimod actually showed superior preventive and therapeutic effects of rheumatoid arthritis compared to the single administration of each drug using a rheumatoid arthritis animal model. A collagen-induced arthritis (CIA) model was used as an animal model for rheumatoid arthritis, and the clinical score for CIA was 0 (no symptoms) or 1 (slight on the soles or toes), depending on the severity. edema), 2 (severe edema of the sole and toes), 3 (severe to severe edema of the entire foot), and 4 (severe edema and twisting of the entire foot), and the 4 feet were integrated. SPC was administered 30 minutes after administration of FTY720, and administration was continued for 3 weeks. In the in vivo experiment, the weight ratio of co-administered SPC:FTY720 was 1.2:1.

Specifically, after administering PBS, SPC (6 mg/kg), FTY720 (5 mg/kg), or SPC+FTY720 (combined administration) to mice with pathogenesis index 4 to 6 among CIA mice with rheumatoid arthritis, Changes in the onset index over time were confirmed.

As a result, as shown in Figure 3, compared to the control group administered with PBS, even in the group administered with SPC or FTY720 alone, it was found that the progress and onset of rheumatoid arthritis were reduced, but when SPC and FTY720 were administered in combination, alone Compared to the administration group, the incidence index of rheumatoid arthritis decreased significantly, and in particular, it was found that the incidence index was lower than before administration of the drug. The above results show that the combined administration can achieve a more excellent rheumatoid arthritis symptom relief effect than the single administration of SPC or FTY720.

Example 3. Effect of inhibiting edema by combined administration of SPC and FTY720

Next, it was confirmed whether the combined administration of sphingosylphosphorylcholine and fingolimod effectively inhibits foot swelling, which is one of the representative symptoms of rheumatoid arthritis.

Specifically, after administering PBS, SPC (6 mg/kg), FTY720 (5 mg/kg), or SPC+FTY720 (combined administration) to mice with an onset index of 4 to 6 among CIA mice with rheumatoid arthritis, It was confirmed whether the edema of the feet was improved. For clear measurement and comparison of paw edema, the most swollen part of the paw was measured multiple times to record and compare the value of convergent thickness, and DBA/1J mice (disease-free) without antigen administration were used as negative control. used

As shown in FIGS. 4 and 5, the degree of edema of the foot decreased in the group administered with SPC or FTY720 alone compared to the group administered with PBS, but the thickness of the foot was the lowest when SPC and FTY720 were co-administered, that is, It was confirmed that edema was most suppressed. The above results show that the combined administration can achieve a more excellent anti-edema effect than the single administration of SPC or FTY720.

Example 4. Inhibitory effect on spleen and lymph node enlargement by combined administration of SPC and FTY720

Next, it was confirmed whether the combined administration of sphingosylphosphorylcholine and fingolimod effectively inhibits spleen and lymph node enlargement, another representative symptom of rheumatoid arthritis.

DBA/1J mice (disease-free) without antigen administration were used as negative controls, and inguinal and popliteal lymph nodes were compared as draining lymph nodes (DLN) that migrated to the foot tissue. .

As a result of comparing the sizes of the spleen and lymph nodes, respectively, it was confirmed that the spleen and lymph nodes of the PBS-administered control group were enlarged compared to the negative control group. It was relatively small. However, compared to all the groups, the size of the spleen and lymph node was the smallest in the group administered with SPC and FTY720 (FIG. 6). The above results show that the combined administration is superior to the single administration of SPC or FTY720 in suppressing spleen and lymph node activation (enlargement).

Example 5. Immunomodulatory effect in inflamed tissues by combined administration of SPC and FTY720

Rheumatoid arthritis occurs due to inflammation of the synovial tissue surrounding the joint, and when activated immune cells (eg, CD4 ⁺ lymphocytes) infiltrate into the inflamed tissue, the inflammation may further intensify due to an excessive immune response. Therefore, it was confirmed whether the combined administration of SPC and FTY720 in a rheumatoid arthritis animal model has an effect of regulating the migration of immune cells to inflamed tissues.

Specifically, after administering PBS, SPC (6 mg/kg), FTY720 (5 mg/kg), or SPC+FTY720 (combined administration) to mice with an onset index of 4 to 6 among CIA mice with rheumatoid arthritis, Immune cells were isolated from inflamed tissue of paws at the time of mouse sacrifice using collagenase, etc., and the levels of CD4 ⁺ lymphocytes and immune regulatory cells (Treg) were analyzed by flow cytometry. . In addition, DBA/1J mice (disease-free) without antigen administration were used as a negative control group in order to clearly compare and analyze changes in immune cells infiltrating tissues.

As a result, as shown in FIGS. 7 to 9 , it was confirmed that FTY720 decreased the ratio of CD4 ⁺ lymphocytes in the inflamed tissue, while SPC further increased the ratio of Treg cells in the inflamed tissue. These results suggest that fingolimod inhibits infiltration of CD4 ⁺ lymphocytes into inflamed tissues to prevent excessive immune responses, and sphingosylphosphocholine induces an increase in Tregs, thereby achieving effective immunomodulation for the treatment of rheumatoid arthritis. show what

Example 6. Autoimmunity induced T in the gateway lymph node by combined administration of SPC and FTY720 _H 17 Cell regulation

T helper 17 cells (T _H 17) are a type of T helper cells that produce interleukin 17 (IL-17), and are involved in the activation of neutrophils and the production of inflammatory cytokines, especially inducing autoimmunity. It is known. Therefore, it was confirmed whether the combined administration of SPC and FTY720 has an effect on T _H 17 in a rheumatoid arthritis animal model.

Specifically, after administering PBS, SPC (6 mg/kg), FTY720 (5 mg/kg), or SPC+FTY720 (combined administration) to mice with an onset index of 4 to 6 among CIA mice with rheumatoid arthritis, At the time of mouse sacrifice, inguinal lymph node and popliteal lymph node cells, which are draining LNs, were isolated, treated with PMA/ _Inomycin , and then the T 17 cell level was confirmed.

As a result, as shown in FIGS. 10 and 11, T _H 17 cells, which are autoimmune induced T lymphocytes, were significantly increased in CIA mice compared to DBA/1J mice (disease-free), a negative control group to which antigen was not administered. When SPC or _FTY720 was administered alone, the percentage of _TH 17 cells in the gateway lymph node slightly decreased. could confirm that These results show that the remarkable therapeutic effect of rheumatoid arthritis by the combined administration of FTY720 and SPC is derived from the effective inhibition of autoimmunity-induced T _H 17 lymphocytes.

Example 7. Autoimmunity induced T by combined administration of SPC and FTY720 _H 1 Cell regulatory effect

Finally, in order to further verify the effect of regulating inflammation by the combined administration of SPC and FTY720, autoimmunity-induced cell T _H 1 (T helper 1 cell) cell level was examined after the combined administration of SPC and FTY720 to an animal model of rheumatoid arthritis. The change in was confirmed.

Specifically, after administering PBS, SPC (6 mg/kg), FTY720 (5 mg/kg), or SPC+FTY720 (combined administration) to mice with an onset index of 4 to 6 among CIA mice with rheumatoid arthritis, At the time of mouse sacrifice, inguinal and popliteal lymph node cells, which are draining LNs, were isolated and treated with PMA/Ionomycin to form autoimmune-induced CD4 lymphocytes, IFN-gamma (IFN-γ) T _H 1 was compared.

As a result, as shown in FIGS. 12 and 13, compared to DBA/1J mice (Disease-free), a negative control group to which antigen was not administered, CIA mice had a significant increase in T _H 1 cells, which are autoimmune-induced CD4 lymphocytes. , Even in the group administered with SPC or FTY720 alone, TH 1 lymphocytes were slightly decreased in the gateway lymph node, but in the experimental group administered with FTY720 and SPC in combination, it was confirmed that _TH 1 cells were effectively inhibited to a similar extent to the _DBA1 /J negative control group. did These results suggest that the therapeutic effect of rheumatoid arthritis caused by the combined use of FTY720 and SPC is derived from effective inhibition of autoimmune-induced T _H 1 lymphocytes.

Example 8. Modulating effects of inflammatory and anti-inflammatory cytokines in peripheral blood by co-administration of SPC and FTY720

Next, in order to more specifically confirm the inflammatory control effect of the combined administration of SPC and FTY720, the levels of various inflammatory and anti-inflammatory cytokines were measured after co-administration of SPC and FTY720 to a rheumatoid arthritis animal model.

Specifically, after administering PBS, SPC (6 mg/kg), FTY720 (5 mg/kg), or SPC+FTY720 (combined administration) to mice with an onset index of 4 to 6 among CIA mice with rheumatoid arthritis, Representative immune responses of TNF-α, IL-6, IL-1β, and T _H 1, key inflammatory cytokines of rheumatoid arthritis, in peripheral blood at the time of mouse sacrifice. Representative immune responses of cytokines IFN-γ and T _H 17 IL-17a, a cytokine, and IL-10, an anti-inflammatory cytokine, were comparatively analyzed by ELISA. In addition, DBA / 1J mice (Disease-free) to which no antigen was administered were used as a negative control group to compare changes in cytokines in peripheral blood caused by the onset of rheumatoid arthritis.

As a result, as shown in FIG. 14, the major inflammatory cytokines of rheumatoid arthritis, TNF-α, IL-6, and IL-1β, were increased in CIA model mice compared to negative control mice; autoimmune inducible T _H 1 and T _H 17; and immune response cytokines, IFN-γ and IL-17a, were increased, and the level of inflammatory cytokines decreased in the group administered with SPC or FTY720 alone, but when SPC and FTY720 were administered in combination, the level was comparable to that of the negative control group. It was confirmed that inflammatory cytokines were suppressed. In addition, it was confirmed that IL-10, an anti-inflammatory cytokine in peripheral blood, was significantly increased when SPC and FTY720 were co-administered than when each was administered alone. The above results show that the combined administration of SPC and FTY720 suppresses the level of inflammatory cytokines and increases the level of anti-inflammatory cytokines, thereby achieving a more effective rheumatoid arthritis treatment effect than the single administration of SPC or FTY720.

As described above, the present inventors have demonstrated that the combined administration of sphingosylphosphorylcholine (SPC) and fingolimod (FTY720) is effective in the soles and joints through in vitro experiments using immune cells and in vivo experiments using animal models of rheumatoid arthritis. It was confirmed that the above two drugs exerted more remarkable effects than when the two drugs were administered alone in terms of inhibition of edema, inhibition of enlargement of the spleen and lymph nodes, inhibition of inflammatory cytokines in the blood, and increase of anti-inflammatory cytokines. Therefore, the combined administration of sphingosylphosphorylcholine and fingolimod is expected to be usefully used in the field of preventing and treating rheumatoid arthritis as a more effective therapeutic agent.

The above description of the present invention is for illustrative purposes, and those skilled in the art can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (8)

sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; And Fingolimod (Fingolimod) or a pharmaceutical composition for concomitant administration for the prevention or treatment of arthritis, containing as an active ingredient a pharmaceutically acceptable salt thereof.
According to claim 1,
The pharmaceutical composition for concomitant administration may include sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; And fingolimod or a pharmaceutically acceptable salt thereof, characterized in that in the form of a mixed agent mixed, a pharmaceutical composition for concomitant administration.
According to claim 1,
The pharmaceutical composition for concomitant administration may include sphingosylphosphorylcholine or a pharmaceutically acceptable salt thereof; Alternatively, a pharmaceutical composition for concomitant administration characterized in that each of fingolimod or a pharmaceutically acceptable salt thereof is formulated and administered simultaneously (simultaneously) or sequentially (sequentially).
According to claim 1,
The arthritis is a pharmaceutical composition for combined administration, characterized in that at least one selected from the group consisting of rheumatoid arthritis, osteoarthritis, degenerative arthritis, and polyarthritis.
According to claim 1,
The pharmaceutical composition for concomitant administration, characterized in that it satisfies at least one of the following characteristics:
(a) promote activation of regulatory T cells;
(b) inhibits the activation of T helper 17 cells; or
(c) Inhibits activation of T helper 1 cells.
According to claim 1,
The pharmaceutical composition for combined administration, characterized in that the suppression of at least one selected from the group consisting of edema, enlargement of the spleen, enlargement of the lymph node, and inflammation in the joint.
According to claim 1,
The pharmaceutical composition for concomitant administration, characterized in that it satisfies at least one of the following characteristics:
(a) reducing the level of inflammatory cytokines in the blood; or
(b) increase the level of anti-inflammatory cytokines in the blood.
According to claim 7,
the inflammatory cytokine is at least one selected from the group consisting of TNF-α, IL-6, IL-1β, IFN-γ, and IL-17a; The anti-inflammatory cytokine is IL-10, characterized in that, the pharmaceutical composition for combined administration.

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