KR101388235B1 - Composition for preventing and treating arthritis comprising meclizine - Google Patents

Abstract

The present invention relates to a novel medicinal use of meclizin, and more particularly, the present invention relates to a pharmaceutical composition for preventing and treating arthritis, including meclizin or a pharmaceutically acceptable salt thereof.

Description

Composition for preventing and treating arthritis comprising meclizine

The present invention relates to a novel medicinal use of meclizin, and more particularly, the present invention relates to a pharmaceutical composition for preventing and treating arthritis, including meclizin or a pharmaceutically acceptable salt thereof.

Arthritis-related diseases are representative degenerative and refractory diseases in which about 12% of the world suffers. There are more than 2 million patients in Korea. Arthritis is a disease that collectively refers to the appearance of systemic symptoms in the skeletal system due to inflammatory changes in the body's skeleton and connective tissue. The disease is characterized by chronic inflammation that affects joints, bones, cartilage tissue or spinal cord, often causing permanent tissue damage, malformations, degeneration and disorders (Hofbause, LC, et.al., Arthritis and Rheumatism 44: 253-259, 2001).

Osteoarthritis is the most commonly seen arthritis, also called degenerative arthritis, which causes degenerative changes in articular cartilage, such as pain, stiffness, and gradual dyskinesia in weight-bearing joints such as knee and hip joints as the articular cartilage wears away. Disease. In the past, as a cause of aging caused by the aging of the past, but now it is not a single cause, but the symptoms, such as age, genetic factors, obesity, joint shape, hormones, etc. It is thought.

Rheumatoid arthritis is an inflammatory autoimmune disease that occurs multiple times in multiple joints. The disease indicates persistent inflammatory synovitis, which causes cartilage destruction and bone erosion, causing structural malformations of the surrounding joints. Symptoms associated with rheumatoid arthritis include joint swelling, joint tenderness, inflammation, landscape stiffness and especially pain when bending the joint. This includes.

In addition, arthritis includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, systemic lupus erythematosus, polymyositis or rheumatoid polymyalgia, and the ideal goal for all arthritis treatments is to protect and maintain cartilage and bone tissue in the diseased joints. will be.

Currently used treatment methods for arthritis are as follows. Drugs commonly used in early treatment are nonsteroidal anti-inflammatory drugs (NSAIDs), which may slightly improve symptoms but do not prevent joint cartilage loss or disease progression. This severely manifested case requires about half of patients to stop treatment within a year. Next steps include: drugs modifying anti-rheumatic drugs such as gold drugs (gold sodium thiomalate, gold sodium thiosulfate), penicillamine, anti-malarials; DMARDs) and the like. However, these agents also slightly reduce the progression of arthritis but can have serious side effects, so only 5-15% of patients adhere to the use of these drugs after 5 years of treatment with DMARD. If the above treatments are no longer effective, it may be necessary to replace the joints with rheumatoid joints with external joints (Simon LS, Int. J. Clin. Pract., 54, pp 243-249, 2000).

Therefore, there is an urgent need for the development of new materials effective for the prevention and treatment of arthritis having a new function and skeletal structure that minimize the toxicity and side effects that are the limitations of current therapeutic agents of arthritis.

Meclizin, on the other hand, is a synthetic antihistamine-based drug commercialized as a drug that is effective in nausea, vomiting, motion sickness, dizziness, and the like. The compound name of meclizine is (R / S) -1-[(4-chlorophenyl) (phenyl) methyl] -4- (3-methylbenzyl) piperazine, and has the structure of Formula 1:

[Chemical Formula 1]

In relation to meclizin, US Patent No. 2709169 discloses a method for preparing meclizin, US Patent Publication No. 20090111833 discloses a technique for preparing mecrizine in an injection formulation, and US Patent Publication No. 20110172425 Disclosed is a method for producing mecrizine using water. In addition, International Publication No. 97/48390 discloses the use of meclizin in combination with acetaminophen as an analgesic agent. However, it has not been reported that meclizin can be applied to the treatment of arthritis.

Accordingly, the present inventors have studied to develop a new therapeutic agent effective for arthritis, and thus, the present invention was completed by confirming that meclizin, which was previously used as an anti-emetic agent, has an excellent effect on the treatment of arthritis.

It is an object of the present invention to provide a pharmaceutical composition for preventing and treating arthritis, including meclizin or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a method for treating arthritis comprising administering a pharmaceutical composition comprising meclizin or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention relates to a pharmaceutical composition for preventing and treating arthritis, including meclizin or a pharmaceutically acceptable salt thereof.

Meclizin refers to a compound having the structure of Formula 1, wherein the compound name is (R / S) -1-[(4-chlorophenyl) (phenyl) methyl] -4- (3-methylbenzyl) piperazin

[Chemical Formula 1]

In the present invention, meclizin is not only meclizin of the formula, but also pharmaceutically acceptable salts, racemates, enantiomers, homologues, anhydrides, hydrates (hemihydrate, monohydrate, dihydrate, trihydrate) Cargoes, etc.) and solvates.

Pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases, and salts derived from inorganic acids are preferred. Suitable acids include, for example, 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, , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid.

Preferably, the present invention includes meglizine hydrochloride or a hydrate thereof, more preferably meclizin dihydrochloride or a hydrate thereof.

Meclizin can be prepared by chemical synthesis methods known in the art, for example, reference may be made to the preparation method described in US Patent No. 2709169 and the like.

Representative pathological changes of arthritis include thickening of the synovial membrane, protruding into the chorionic form, and hyperproliferation of fibrolast like synoviocytes (FLS), which constitute the synovial membrane. FLS derived from arthritis patients is morphologically different from normal synovial cells and may exhibit anchorage independent growth or loss of adhesion inhibition, which is characteristic of tumor cells. In addition, through many experiments, FLS mainly plays a role of destroying cartilage by secreting proteolytic enzymes, inducing inflammatory cells through interaction with other cells in the synovial membrane, increasing lymphocyte survival, and continuing inflammation, Differentiation of osteoclasts has been found to play an important role in indirectly affecting bone destruction.

Therefore, in a specific embodiment of the present invention, synovial cells (FLS) extracted from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), arthritis synovial cells by introducing a change in telomerase into the synovial cells To retain the traits of As a result of measuring the effect of inhibiting cell proliferation after treatment of meclizin to tRA-FLS and tOA-FLS cells, it was confirmed that meclizin exhibited excellent proliferation inhibitory effect in all of the arthritis-derived cells (FIG. 1). Therefore, it can be seen that meclizin is effective in the treatment of arthritis by inhibiting arthritis cell proliferation.

In the present invention, the term "treatment or prophylaxis" is any action that inhibits, alleviates or beneficially alters the clinical situation associated with arthritis by using a pharmaceutical composition comprising meclizin or a pharmaceutically acceptable salt thereof as an active ingredient. Means. Preferably the composition comprising meclizin or a pharmaceutically acceptable salt thereof can protect and maintain cartilage and bone tissue of the diseased joint by inhibiting hyperproliferation of synovial cells causing arthritis.

In the present invention, the arthritis is osteoarthritis, rheumatoid arthrits, ankylosing spondylitis, reactive arthritis, psoriatic arthritis, systemic lupus erythematosus, polymyositis Or polymyalgia rheumatica and the like, preferably, rheumatoid arthritis or degenerative arthritis.

Pharmaceutical compositions comprising the meglizine of the present invention or a pharmaceutically acceptable salt thereof may be formulated further comprising a pharmaceutically acceptable carrier. At this time, the concentration of meclizin or a pharmaceutically acceptable salt thereof is preferably 100 uM or more, but is not limited thereto.

As used herein, the term "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not significantly stimulate the organism and does not interfere with the biological activity and properties of the administered compound. The pharmaceutically acceptable carrier in the present invention may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, If desired, other conventional additives such as antioxidants, buffers and bacteriostatic agents can be added. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to formulate injectable formulations, pills, capsules, or tablets such as aqueous solutions, suspensions, emulsions and the like.

Also, preferably, the pharmaceutical composition of the present invention may further include a filler, an excipient, a disintegrant, a binder, a lubricant, and the like. The pharmaceutical composition of the present invention may also be formulated using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. The formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable drugs, sterile powders.

As another aspect, the invention relates to a method for treating arthritis comprising administering a pharmaceutical composition comprising meclizin or a pharmaceutically acceptable salt thereof.

As used herein, the term "administration" means introducing a pharmaceutical composition of the present invention to a patient in any suitable manner, and the route of administration of the composition of the present invention may be various oral or parenteral routes as long as it can reach the desired tissue. It can be administered through.

The method of treatment of the present invention comprises administering medicine or a pharmaceutically acceptable salt thereof in a pharmaceutically effective amount. It will be apparent to those skilled in the art that a suitable total daily dose may be determined by the practitioner within the correct medical judgment. Preferably the dosage of the pharmaceutical composition may be used in the range of about 10 mg to about 200 mg per kg, and may be administered one time or divided into several times. For purposes of the present invention, however, the specific therapeutically effective amount for a particular patient will depend upon the nature and extent of the reaction to be achieved, the particular composition, including whether or not other agents are used, the age, weight, Sex and diet of the patient, the time of administration, the route of administration and the rate of administration of the composition, the duration of the treatment, the drugs used or concurrently used with the specific composition, and similar factors well known in the medical arts.

The pharmaceutical composition comprising the meglizine of the present invention or a pharmaceutically acceptable salt thereof may be usefully used for preventing and treating arthritis by inhibiting hyperproliferation of synovial cells causing arthritis and protecting cartilage and bone tissue of the diseased joint. .

Figure 1 shows the degree of inhibition of cell proliferation when treated with meclizin to synovial cells (cho-FLS), tRA-FLS and tOA-FLS cells derived from arthritis patients.

Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Example  One. Meclizin  Inhibitory Effect of Arthritis-derived Cells

In order to confirm the effect of meclizin as a therapeutic agent for arthritis, the degree of cell proliferation was measured by treating meclizin with CCK8 assay for cell lines of arthritis origin.

Synovial cells (fibroblast-like synoviocytes, FLS) extracted from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), to the synovial cells After incorporating changes in telomerase and incubating the tRA-FLS and tOA-FLS cells, which retain the traits of arthritis synovial cells, respectively, the cells were cultured in 96 well plates at 5 X 10 ³ and cultured for 12-16 hours. .

Treatment with meclizin (Pavis hydrochloric acid, Korea Fabis Biotech) by concentration (0 uM, 1 uM, 10 uM, 100 uM) in the culture medium of each cell and incubated again for 48 hours, CCK8 assay kit The experiment was performed as instructed by (CK04, DOJINDO Laboratories). 96 well plates were analyzed with SoftMax Pro5 software after reading VERSA MAX (BNR 06620, Molecular Devices) at 450 nm and 550 nm.

As a result, as shown in Figure 1, all the FLS, tRA-FLS and tOA-FLS cells derived from arthritis patients showed the effect of inhibiting cell proliferation after the treatment with mecrizine, especially the treatment with high concentration (100uM) When the growth inhibition effect was excellent. Therefore, it can be seen that meclizin is effective in the treatment of arthritis by inhibiting arthritis cell proliferation.

Claims (4)

A pharmaceutical composition for preventing and treating degenerative arthritis, comprising a pharmaceutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

The composition of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
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