Composition comprising altiratinib as active ingredient for preventing or treating arthritis

Abstract

The present invention relates to a composition comprising altiratinib as an active ingredient for preventing or treating arthritis. More specifically, the present invention provides a pharmaceutical composition, a health functional food composition, and an animal pharmaceutical composition for preventing or treating arthritis, comprising altiratinib or a pharmaceutically / sitologically acceptable salt thereof as an active ingredient. Effectively inhibiting the expression of inflammatory cytokines and matrix-degrading enzymes, the altiratinib or the salt thereof according to the present invention is able to more effectively prevent, alleviate or treat arthritis diseases.

Description

Composition for preventing or treating arthritis containing altilatinib as an active ingredient

[0001] The present invention relates to a composition for preventing or treating arthritis, and more particularly, to a composition for preventing or treating arthritis comprising altiratinib as an active ingredient.

[0002] Arthritis is a general term for several diseases that cause damage to joints, including osteoarthritis (OA), rheumatoid arthritis, gout, and psoriatic arthritis. 85% of arthritis patients suffer from osteoarthritis.

[0003] Osteoarthritis is a disease that is accompanied by pain, stiffness, swelling, and decreased function. It is known that various factors such as inflammation of the synovium surrounding the cartilage and changes in chondrocytes reduce the production of extracellular matrix and increase the activity of extracellular matrix-degrading enzymes, accelerating their degradation. As a result, the basic structure of cartilage is destroyed, and the joints become unable to withstand the load, resulting in joint deformation. This type of osteoarthritis is known to occur mainly in the knees, hip joints, hands, and spine.

[0004] Rheumatoid arthritis is an autoimmune disease that causes inflammation by attacking the body's own joints due to an abnormality in the immune system. It is a chronic, systemic inflammatory disease that causes pain and swelling in joints such as the fingers, hands, feet, wrists, ankles, and knees, and can also cause abnormalities in various other organs such as the muscles, skin, lungs, and eyes.

[0005] Current clinical treatments include medications such as steroids, non-steroidal anti-inflammatory drugs (NSAIDs), and analgesics, as well as chondroprotectors such as hyaluronic acid, glucosamine, and chondroitin. However, these drug treatments have drawbacks, such as upper gastrointestinal bleeding, cardiovascular toxicity, and addiction, which hinder long-term use, as well as limited anti-inflammatory effects. Furthermore, chondroprotectors only protect joints by providing nutrients to cartilage cells or alleviating septal defects, and do not fundamentally treat arthritis.

[0006] Surgical treatment methods include arthroscopic surgery, high tibial osteotomy, partial joint replacement, and total knee replacement, but they cause significant pain and discomfort to patients. Therefore, there is a continuing demand for the development of treatments that minimize the side effects of drug treatments and minimize patient pain and discomfort while still having a definite effect.

[0007] The purpose of the present invention is to provide a pharmaceutical composition and a health functional food composition having excellent effects in preventing, improving or treating arthritis.

[0008] To achieve the above purpose, the present invention provides a pharmaceutical composition for preventing or treating arthritis, comprising Altiratinib or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] The present invention provides a health functional food composition for preventing or improving arthritis, comprising Altiratinib or a food-related acceptable salt thereof as an active ingredient.

[0010] The present invention provides an animal pharmaceutical composition for preventing or treating arthritis, comprising Altiratinib or a pharmaceutically acceptable salt thereof as an active ingredient.

[0011] In addition, the present invention provides a feed additive composition for preventing or improving arthritis, comprising Altiratinib or a food-related acceptable salt thereof as an active ingredient.

[0012] Altiratinib or a pharmaceutically / foodstuffally acceptable salt thereof according to the present invention effectively suppresses the expression of inflammatory cytokines and substrate-degrading enzymes, which are one of the main causes of arthritis, and thus can be provided as a pharmaceutical composition, a health functional food composition, an animal drug composition, etc. for preventing, improving, or treating arthritis disease.

[0013] By using the composition according to the present invention, arthritis disease can be prevented, improved or treated more safely and effectively.

[0014] Figure 1 shows the effect of inhibiting the expression of inflammatory cytokines by treatment with Altiratinib according to an experimental example of the present invention.

[0015] Figure 2 shows the effect of inhibiting the expression of substrate-degrading enzymes by treatment with altiratinib according to another experimental example of the present invention.

[0016] Hereinafter, the present invention will be described in detail.

[0017]

[0018] The present inventors completed the present invention by confirming that Altiratinib effectively suppresses the expression of inflammatory cytokines and matrix-degrading enzymes that are causes or characteristics of arthritis.

[0019]

[0020] The present invention provides a pharmaceutical composition for preventing or treating arthritis, comprising Altiratinib or a pharmaceutically acceptable salt thereof as an active ingredient.

[0021] In this specification, "Altiratinib" is a compound represented by the following chemical formula 1, and is known as a multi-target kinase inhibitor including hepatocyte growth factor receptor (c-MET) / TEK tyrosine kinase (TIE-2) / vascular endothelial growth factor receptor (VEGFR):

[0022] <Chemical Formula 1>

[0023]

[0024] The above-mentioned altiratinib can be synthesized by a method well known in the art, and a commercially available one can be selected and used, but the method or material is not particularly limited.

[0025]

[0026] The above-mentioned altiratinib can be used in the form of a pharmaceutically or food-wise acceptable salt within the range of efficacy.

[0027] As used herein, “pharmaceutically or food-wise acceptable salt” means a salt that is non-toxic to cells or humans exposed to the composition and has a safety and efficacy profile suitable for administration to humans.

[0028] The above salt may be used in the form of either a basic salt or an acid salt that is pharmaceutically or food-wise acceptable. The basic salt may be used in the form of either an organic basic salt or an inorganic basic salt, and may be selected from the group consisting of sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethylaminium salt, and pyridinium salt. The acid salt is useful as an acid addition salt formed by a free acid. Inorganic acids and organic acids can be used as free acids, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, diphosphoric acid, nitric acid, etc. can be used, and organic acids such as citric acid, acetic acid, maleic acid, malic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, stearic acid, etc. can be used, but are not limited thereto, and all salts formed using various inorganic acids and organic acids commonly used in the art can be included.

[0029] In addition, the above-mentioned altiratinib may include not only the above-mentioned salts, but also all salts, hydrates, solvates, derivatives, etc. that can be prepared by conventional methods. The addition salt may be prepared by dissolving in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of organic base, or adding an aqueous base solution of an inorganic base, and then precipitating or crystallizing. Alternatively, the addition salt may be obtained by evaporating the solvent or the excess base from the mixture and then drying, or the precipitated salt may be prepared by suction filtration.

[0030]

[0031] The composition according to the present invention can suppress the expression of any one or more inflammatory cytokines selected from the group consisting of IL-1β, IL-6, and IL-8, which are one of the main causes of arthritis.

[0032] Additionally, the composition according to the present invention can inhibit the expression of one or more substrate-degrading enzymes selected from MMP-1 or MMP-3.

[0033] As used herein, "matrix metalloproteinase (MMP)" refers to a zinc-dependent endopeptidase that degrades extracellular matrix (ECM) proteins. MMPs are known to play a crucial role in tissue remodeling associated with various physiological and pathological processes, such as morphogenesis, angiogenesis, tissue repair, cirrhosis, arthritis, and cancer metastasis.

[0034]

[0035] The above arthritis may be selected from the group consisting of, but is not limited to, degenerative arthritis (osteoarthritis), rheumatoid arthritis, gout, psoriatic arthritis, ankylosing spondylitis, septic arthritis, and lupus arthritis.

[0036]

[0037] The composition may contain 0.01 to 50 parts by weight of the altiratinib or its salt relative to 100 parts by weight of the total pharmaceutical composition, but is not limited thereto.

[0038]

[0039] In this specification, "pharmaceutical composition" means a composition administered for the purpose of preventing or treating a specific disease, and for the purpose of the present invention, means administered to prevent or treat arthritis disease or at least one symptom thereof.

[0040] The pharmaceutical composition according to the present invention can be prepared according to conventional methods in the pharmaceutical field. The pharmaceutical composition can be combined with an appropriate pharmaceutically acceptable carrier depending on the formulation, and, if necessary, can be prepared by further including excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc. The appropriate carrier, etc., can be selected differently depending on the dosage form and formulation as long as it does not inhibit the activity and properties of altiratinib or a pharmaceutically acceptable salt thereof according to the present invention.

[0041] The above pharmaceutical composition can be applied in any dosage form, and more specifically, it can be formulated and used as an oral dosage form and a parenteral dosage form such as an external preparation, a transdermal patch, a suppository, an injection, and an intra-articular implant according to a conventional method.

[0042] Among the oral dosage forms, the solid dosage forms are in the form of tablets, pills, powders, granules, capsules, etc., and can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, gelatin, etc., and in addition to simple excipients, lubricants such as magnesium stearate and talc may also be included. In addition, in the case of capsule dosage forms, in addition to the above-mentioned substances, a liquid carrier such as fatty oil may be further included. Among the oral dosage forms, the liquid dosage forms include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. may be included.

[0043] The above parenteral formulations may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, patches, suppositories, implants, etc. Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin, etc. Intra-articular implants may be formulated including carriers such as hyaluronic acid, PLGA [poly(lactic-co-glycolic acid)], caprolactone, liposomes, etc. Without being limited thereto, any suitable agent known in the art may be used.

[0044]

[0045] The pharmaceutical composition according to the present invention can be administered in a pharmaceutically effective amount.

[0046] As used herein, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing adverse effects.

[0047] The effective dosage level of the pharmaceutical composition may vary depending on the intended use, the patient's age, sex, weight, and health condition, the type and severity of the disease, the activity and sensitivity of the drug, the method of administration, the time of administration, the route of administration, and the excretion rate, the duration of treatment, the drugs used in combination or concurrently, and other factors well known in the medical field. For example, although not fixed, it may generally be administered once or several times daily at a dosage of 0.001 to 1000 mg / kg, preferably 0.01 to 100 mg / kg. The above dosage does not limit the scope of the present invention in any way.

[0048]

[0049] The pharmaceutical composition according to the present invention can be administered to any animal that can develop arthritis, and the animal can include, for example, humans and primates, as well as livestock such as cows, pigs, horses, and dogs.

[0050] The pharmaceutical composition according to the present invention can be administered via an appropriate route of administration depending on the formulation form, and can be administered via various routes, either oral or parenteral, as long as it can reach the target tissue. The method of administration is not particularly limited, and can be administered by conventional methods such as oral, transdermal, subcutaneous, rectal, intravenous, intramuscular, skin application, respiratory inhalation, intrauterine epidural, or intracerebroventricular injection.

[0051] The pharmaceutical composition according to the present invention can be used alone for the prevention or treatment of arthritis, or can be used in combination with surgery or other drug treatments.

[0052]

[0053] The present invention provides a health functional food composition for preventing or improving arthritis, comprising Altiratinib or a food-related acceptable salt thereof as an active ingredient.

[0054] The above-mentioned altiratinib or a salt thereof can suppress the expression of one or more inflammatory cytokines selected from the group consisting of IL-1β, IL-6, and IL-8, which are one of the main causes of arthritis, and can suppress the expression of one or more substrate-degrading enzymes selected from MMP-1 or MMP-3, and thus can be utilized as a health functional food composition for preventing or improving arthritis.

[0055] Corresponding features can be substituted in the above-described part.

[0056]

[0057] In this specification, "health functional food" includes food manufactured and processed using raw materials or ingredients with functionality useful to the human body according to Act No. 6727 on Health Functional Foods, and means a food with high medical or healthcare effects that is processed to efficiently exhibit bioregulatory functions such as prevention of arthritis or its symptoms, biodefense, immunity, and recovery for the purpose of the present invention in addition to nutritional supply.

[0058] In the health functional food composition according to the present invention, the health functional food may be manufactured in the form of powder, granules, tablets, capsules, syrup, or beverage, etc., for the purpose of preventing or improving arthritis. There is no limitation on the form that the health functional food may take, and it may be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods.

[0059] The above health functional foods may include all foods in the conventional sense. For example, they may include beverages and various drinks, fruits and their processed foods (canned fruits, jams, etc.), fish, meats and their processed foods (ham, bacon, etc.), breads and noodles, cookies and snacks, dairy products (butter, cheese, etc.), and all functional foods in the conventional sense. They may also include foods used as animal feed.

[0060] The above health functional food composition may be manufactured by further including food additives (food additives) commonly used in the art and other appropriate auxiliary ingredients that are acceptable in terms of food science. Unless otherwise specified, suitability as a food additive may be determined by the specifications and standards for the relevant item in accordance with the general provisions and general test methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety. Items listed in the above 'Food Additives Codex' include, for example, chemical synthetics such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, sucrose pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, alkaline agents for noodles, preservative preparations, and tar color preparations.

[0061] The above other auxiliary ingredients may additionally contain, for example, flavoring agents, natural carbohydrates, sweeteners, vitamins, electrolytes, coloring agents, pectic acid, alginic acid, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonating agents, etc. In particular, as the natural carbohydrates, monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol, and erythritol can be used, and as the sweetener, natural sweeteners such as thaumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame can be used.

[0062]

[0063] The effective dose of the altiratinib or its salt contained in the health functional food composition according to the present invention can be appropriately adjusted depending on the purpose of use, such as prevention or improvement of arthritis.

[0064] The above health functional food composition has the advantage of not having side effects that may occur with long-term use of general medicines as it is made from food, and is highly portable, so it can be taken as a supplement for preventing or improving arthritis.

[0065]

[0066] The present invention provides an animal pharmaceutical composition for preventing or treating arthritis, comprising Altiratinib or a pharmaceutically acceptable salt thereof as an active ingredient.

[0067] The above animal pharmaceutical composition can be formulated in the same manner as the pharmaceutical composition described above, and the corresponding features can be replaced in the above-described part.

[0068]

[0069] The present invention provides a feed additive composition for preventing or improving arthritis, comprising Altiratinib or a food-related acceptable salt thereof as an active ingredient.

[0070] In this specification, “feed additive” is a general term for a substance added in small amounts to feed for nutritional or specific purposes, and in the present invention, it means a substance added for the purpose of preventing or improving arthritis disease.

[0071] In the feed additive composition according to the present invention, the feed is a substance that supplies organic or inorganic nutrients necessary for maintaining the life of an individual and raising the individual, and may include nutrients such as energy, protein, lipid, vitamins, and minerals required by the individual consuming the feed.

[0072] The above feed is a feed of a known composition generally used for livestock breeding, and may include all commercially available general feeds, and is not particularly limited thereto, but may include plant feeds such as grains, roots, food processing by-products, algae, fibers, oils, starches, meal, and grain by-products, or animal feeds such as proteins, inorganic substances, oils, minerals, single-cell proteins, zooplankton, and fish meal. Examples thereof may include, but are not limited to, rice bran, corn, soybean meal, beans, sorghum, rice, barley, wheat, oats, rye, millet, buckwheat, triticale, sweet potato, tapioca, wheat bran, barley germ, soybean hull, corn bran, malt germ, starch meal, coffee grounds, silkworm meal, silkworm cod, seaweed meal, cottonseed meal, rapeseed meal, canola meal, sesame meal, hemp meal, flax meal, sunflower seed meal, peanut meal, palm meal, corn gluten, distillers' meal, corn germ meal, pepper seed meal, lupine seeds, fish meal, feather meal, and meat meal.

[0073] The above feed additives may include general feed additives, for example, feed additives for special purposes such as salt, bone meal, calcium phosphate, mineral mixtures, vitamins, amino acids, antibiotics, and hormones.

[0074]

[0075] The feed additive composition according to the present invention can be added to feed of animals selected from the group consisting of, but not limited to, pigs, cows, chickens, goats, sheep, horses, fish, dogs, and cats.

[0076] In the above feed additive composition, the effective dose of the compound may be used in accordance with the effective dose of the animal pharmaceutical composition, but may be below the above range in the case of long-term intake for the purpose of health and hygiene or health control, and the effective ingredient may be used in an amount above the above range as there is no problem in terms of safety.

[0077] The dosage of the above feed additive composition can be appropriately adjusted by an expert in the field according to the type of animal to be administered, the age of the animal, the weight of the animal, the disease to be prevented in the animal, the desired effect, etc.

[0078]

[0079] In addition, the present invention provides a reagent composition for suppressing inflammatory cytokine expression, comprising altiratinib or a pharmaceutically acceptable salt thereof as an active ingredient.

[0080] In addition, the present invention provides a reagent composition for inhibiting substrate decomposition enzyme expression, comprising altiratinib or a pharmaceutically acceptable salt thereof as an active ingredient.

[0081] Hereinafter, to aid understanding of the present invention, examples will be given in detail. However, the following examples are intended only to illustrate the scope of the present invention and are not intended to limit its scope. These examples are provided to more fully explain the present invention to those of average skill in the art.

[0082]

[0083] <Experimental Method>

[0084] 1. Cell culture

[0085] MH7A cells, a human synovial fibroblast cell line, were cultured in RPMI (Roswell Park Memorial Institute) 1640 medium containing 10% FBS, 120 μg / mL penicillin, and 200 μg / mL streptomycin at 37°C in a humidified incubator with 5% CO2.

[0086]

[0087] 2. Enzyme-linked immunosorbent assay (ELISA)

[0088] To determine the effects of altiratinib on the expression of inflammatory cytokines and substrate-degrading enzymes, enzyme-linked immunosorbent assay (ELISA) was performed. MH7A cells were seeded in 12-well plates at a density of 5 × 10 per well. 4 After dividing the cells, they were cultured for 24 hours. After treatment with 2.5, 5, and 10 μM of altiratinib together with tumor necrosis factor-α (TNF-α) (10 ng / mL) for 24 hours, the culture medium was collected, centrifuged at 4°C and 8,000 rpm for 5 minutes to remove cell debris, and the supernatant was used for analysis.

[0089] ELISA kits for IL-1β, IL-6, IL-8, MMP-1, and MMP-3 were purchased from ThermoFisher Scientific and enzyme-linked immunosorbent assays were performed according to the manufacturer's instructions. First, the plates coated with each antibody were washed, and the culture medium supernatant and standard substances were dispensed and reacted at room temperature for 2 hours. Then, the color reaction was induced by sequential reaction with the detection antibody (HRP-conjugated antibody) and the detection substrate (TMB). After the reaction was terminated with 0.16 M sulfuric acid, the absorbance was measured at 450 nm using a plate reader. The concentrations were calculated using a standard curve generated with the standard solutions for IL-1β, IL-6, IL-8, MMP-1, and MMP-3, respectively.

[0090]

[0091] <Experimental Example 1> Confirmation of the inhibitory effect of inflammatory cytokine expression following treatment with Altiratinib.

[0092] Increased expression of inflammatory cytokines is a major cause of arthritis. Therefore, the effect of altiratinib on the expression of inflammatory cytokines induced by tumor necrosis factor-alpha (TNF-α) in MH7A cells, a synovial cell line derived from arthritis patients, was analyzed using ELISA.

[0093] As a result, as shown in Fig. 1, it was confirmed that the expression of inflammatory cytokines IL-1β, IL-6, and IL-8 increased by TNF-α was reduced by altiratinib.

[0094]

[0095] <Example 2> Confirmation of the inhibitory effect of altiratinib on substrate-degrading enzyme expression

[0096] Cartilage matrix degradation by activation of matrix-degrading enzymes is known to be a hallmark of arthritis. Therefore, the effect of altiratinib on the expression of matrix metalloproteinases (MMP-1) and matrix metalloproteinase (MMP-3) induced by tumor necrosis factor-alpha (TNF-α) in MH7A cells, a synovial cell line derived from arthritis patients, was analyzed using ELISA.

[0097] As a result, as shown in Fig. 2, it was confirmed that the expression of MMP-1 and MMP-3 substrate-degrading enzymes increased by TNF-α was reduced by altiratinib.

[0098]

[0099] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. In other words, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for preventing or treating arthritis, comprising Altiratinib or a pharmaceutically acceptable salt thereof as an active ingredient.

2. In paragraph 1, The above composition, A pharmaceutical composition characterized in that it inhibits the expression of any one or more inflammatory cytokines selected from the group consisting of IL-1β, IL-6, and IL-8.

3. In paragraph 1, The above composition, A pharmaceutical composition characterized in that it inhibits the expression of one or more substrate-degrading enzymes selected from MMP-1 or MMP-3.

4. In paragraph 1, The above composition, A pharmaceutical composition characterized in that the altiratinib or its salt is contained in an amount of 0.01 to 50 parts by weight based on 100 parts by weight of the total pharmaceutical composition.

5. In paragraph 1, The above arthritis is, A pharmaceutical composition characterized in that the disease is selected from the group consisting of degenerative arthritis (osteoarthritis), rheumatoid arthritis, gout, psoriatic arthritis, ankylosing spondylitis, septic arthritis, and lupus arthritis.

6. In paragraph 1, The above composition, A pharmaceutical composition characterized in that it is formulated as an oral dosage form, an external preparation, a transdermal patch, an injection, or an intra-articular implant.

7. A health functional food composition for preventing or improving arthritis, comprising Altiratinib or a food-related acceptable salt thereof as an active ingredient.

8. An animal pharmaceutical composition for preventing or treating arthritis, comprising Altiratinib or a pharmaceutically acceptable salt thereof as an active ingredient.

9. A feed additive composition for preventing or improving arthritis, comprising Altiratinib or a food-based acceptable salt thereof as an active ingredient.

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