KR20210076580A - Composition for preventing and treating arthritis comprising niclosamide - Google Patents

Abstract

The present invention relates to a composition for preventing or treating arthritis comprising niclosamide or a pharmaceutically acceptable salt thereof. The composition comprising niclosamide or the pharmaceutically acceptable salt thereof of the present invention exhibits excellent arthritis treatment and alleviation effects as well as an edema inhibitory effect.

Description

Arthritis prevention and treatment composition comprising niclosamide {COMPOSITION FOR PREVENTING AND TREATING ARTHRITIS COMPRISING NICLOSAMIDE}

The present invention relates to a composition for preventing or treating arthritis comprising niclosamide or a pharmaceutically acceptable salt thereof.

Arthritis is a chronic degenerative disease in which joint cartilage damage and cartilage cell death occur due to inflammation in the joints. As the most common form of joint disease, it has a prevalence of 5% of the world population, and in Korea, the prevalence is 10.7% as of 2008. In particular, as the aging population rapidly increases and the prevalence of obesity increases, the number of arthritis patients also tends to increase, with a prevalence rate of up to 34.5% among those over 80 years of age.

Although the exact cause of arthritis is not yet known, it is known that factors such as physical stress caused by obesity, free radicals, and cytokines are closely involved in the pathogenesis. As a treatment method for degenerative arthritis currently clinically used, analgesics, steroids, nonsteroidal anti-inflammatory drugs, chondroprotectors such as glucosamine, hyaluronic acid, etc., or surgical treatment are used.

In the case of drug treatments, non-specific relief of pain or inflammatory response itself, and chondroprotectors play a role in protecting joints by affecting chondrocytes or alleviating shock. Among these, steroid-based agents have side effects that can cause diseases such as osteoporosis, high blood pressure, and diabetes due to loss of calcium when taken for a long time.

As such, in most cases, drug treatment for arthritis is used only for the purpose of reducing pain, and surgical methods such as permanent artificial joint replacement are mainly used, and there is no drug showing a fundamental therapeutic effect to date.

Korean Patent Publication No. 10-2018-0081936

An object of the present invention is to provide a pharmaceutical composition for preventing or treating arthritis, comprising niclosamide or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for treating arthritis, comprising administering niclosamide or a pharmaceutically acceptable salt thereof.

One aspect of the present invention for achieving the above object relates to a pharmaceutical composition for preventing or treating arthritis, comprising niclosamide.

In the present invention, “niclosamide” is an oral salicylanilide derivative used to treat various parasitic infections for nearly 50 years with FDA approval in 1960. Recently, it can be used for anticancer therapy for various types of cancer. It has been reported that there is, but it has not been reported about the treatment or improvement effect for arthritis.

In the present invention, "arthritis" refers to damage or inflammation caused by various causes in the joint, which is the site where the bone meets the bone, and refers to all inflammatory changes in the joint.

Specifically, the arthritis may be one or more selected from the group consisting of osteoarthritis, rheumatoid arthritis, degenerative arthritis, gouty arthritis, juvenile arthritis, reactive arthritis, and combinations thereof, but is not limited thereto.

In the present invention, 'osteoarthritis', also called degenerative arthritis, is a chronic disease in which damage to the bones, cartilage and ligaments constituting the joint occurs due to damage or degenerative changes in cartilage, and inflammation and pain occur. Osteoarthritis occurs in almost all joints in the body, such as the fingers, knee (knee joint), hip (hip joint), lower back (lumbar joint), and neck (cervical joint). Osteoarthritis has been thought to be caused by overuse of joints or wear and tear of cartilage due to aging, as the occurrence of osteoarthritis is related to age. However, as the development mechanism of osteoarthritis and the response to various stimuli of chondrocytes have recently become known, it is not simply an unavoidable phenomenon associated with aging, but joint damage caused by various causes, such as abnormal chondrocyte metabolic balance, and various systemic factors. It is understood as a joint disease caused by the interaction of and local factors.

In the present invention, 'Rheumatoid Arthritis (RA)' is a chronic, progressive systemic inflammatory disease that mainly invades the synovial membranes of various joints and destroys bones and cartilage. In addition, as an inflammatory autoimmune disease that appears multiple in several joints, the synovial membrane tissue of the joint is hyperplasia and at the same time macrophages, dendritic cells, and activated T lymphocytes and B lymphocytes After moving to the synovial tissue, polymorphonuclear cells accumulate in synovial fluid and on the surface of cartilage, causing inflammation.

In the present invention, 'degenerative arthritis' refers to a disease in which inflammation and pain occur due to damage to the cartilage protecting the joint or damage to the bones and ligaments constituting the joint due to degenerative changes. Primary or idiopathic arthritis that occurs due to factors such as age, sex, genetic factors, obesity, and specific joint sites without cause, and secondary or idiopathic arthritis that occurs due to trauma, disease or deformity that can damage articular cartilage secondary arthritis. One of the differences from rheumatoid arthritis is that the initial symptom is local pain in the joint area where arthritis occurs, and there are usually no systemic symptoms.

In the present invention, 'gouty arthritis' is a form of acute arthritis in which uric acid crystals adhere to tissues around the joint and cause severe inflammation in the joint. In addition to treatment that suppresses the production of uric acid, anti-inflammatory treatment for joints is performed to prevent joint deformation and damage.

In the present invention, 'juvenile arthritis' refers to arthritis occurring in children under 16 years of age, and includes juvenile idiopathic arthritis, juvenile rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthritis, and appendicitis. It mainly appears in the form of chronic inflammatory arthritis, and joint fever, swelling, and pain appear together. The scope and severity of symptoms of juvenile arthritis vary from person to person, and if not treated properly, joint deformities may occur.

In the present invention, 'reactive arthritis' refers to an inflammatory joint disease caused by an abnormality in the immune system due to bacterial infection in the body. It is one of the inflammatory arthropathy that occurs after infection of the gastrointestinal tract or genitourinary system, and it is known that the immune system activated to fight the infectious bacteria attacks not only the infectious bacteria but also the joints and tissues around the joints in a normal body. Reactive arthritis usually develops acutely, but may become chronic or recurrent.

The composition of the present invention treats and improves joint stiffness, edema, pain, etc. for acute or chronic arthritis caused by various causes, and exhibits excellent pharmacological effects on inflammatory diseases occurring in the joints.

In one embodiment of the present invention, it was confirmed that when niclosamide was administered, it exhibited an excellent effect compared to tofacitinib, a positive control. Specifically, in the case of oral administration of niclosamide, it exhibited a superior arthritic score reduction effect compared to the low-dose tofacitinib group, and the parenteral injection of niclosamide showed a significantly superior arthritis reduction effect compared to the tofacitinib high-dose group. shown (FIG. 2).

For administration, the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier, excipient or diluent in addition to the niclosamide of the present invention. The carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In addition, the pharmaceutical composition of the present invention can be applied in any dosage form, specifically, it can be applied as an oral dosage form or a parenteral dosage form. The oral dosage form can be applied in the form of a liquid or tablet, and the parenteral dosage form can be in the form of injection, application, spray, such as aerosol. More specifically, it may be in the form of an injection. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

Specifically, the pharmaceutical composition of the present invention may be a parenteral formulation, and more specifically, a sustained release injection. In addition, it may be specifically for subcutaneous or intramuscular injection.

More specifically, the composition may further include polyvinylpyrrolidone and mannitol. Polyvinylpyrrolidone and mannitol can be mixed and suspended with niclosamide or a pharmaceutically acceptable salt thereof and used in the form of an injection, and the route of injection is not limited.

In one embodiment of the present invention, when administered in the form of an injection, it was confirmed that it exhibits an edema inhibitory effect as well as an excellent arthritis reduction effect ( FIGS. 2 and 3 ). As a parenteral formulation, it can be applied in the form of subcutaneous or intramuscular injection, However, the present invention is not limited thereto.

In addition, the pharmaceutical composition of the present invention may be applied in a pharmaceutically effective amount, and "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and effective Dosage levels depend on the patient's sex, age, type of disease, severity, drug activity, drug sensitivity, administration time, administration route and excretion rate, duration of treatment, factors including concomitant drugs, and other factors well known in the medical field. It may depend on factors.

Furthermore, the pharmaceutical composition of the present invention may be administered in combination with another therapeutic agent, and may be administered sequentially or simultaneously with other conventional therapeutic agents. In addition, the pharmaceutical composition of the present invention may be administered single or multiple. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art as needed.

Another aspect of the present invention relates to a kit for preventing or treating arthritis comprising the pharmaceutical composition.

The type of the kit of the present invention is not particularly limited, and a kit of a type commonly used in the art may be used. The kit of the present invention may be packaged in a form in which niclosamide is contained in an individual container, or in a form in which niclosamide is contained in one container divided into one or more compartments with other drugs or excipients, wherein each of the niclosamide is administered in a single dose It may be packaged in a unit dose form, but is not limited thereto.

Niclosamide or a pharmaceutically acceptable salt thereof in the kit may be administered at an appropriate time according to the health condition of the subject to be administered, etc., and may be administered concurrently, sequentially, or in reverse order with other drugs as needed.

Another aspect of the present invention relates to a method for treating arthritis, comprising administering the pharmaceutical composition to a subject. 'Arthritis' is the same as described above.

The term "individual" of the present invention includes an animal or human having arthritis whose symptoms can be improved by administration of the pharmaceutical composition according to the present invention. By administering the composition for treatment according to the present invention to an individual, arthritis can be effectively prevented and treated.

The term "administration" of the present invention means introducing a predetermined substance into a human or animal by any suitable method, and the administration route of the therapeutic composition according to the present invention is through any general route as long as it can reach the target tissue. It may be administered orally or parenterally. In addition, the therapeutic composition according to the present invention may be administered by any device capable of moving the active ingredient to the target cell.

The preferred dosage of the pharmaceutical composition according to the present invention varies depending on the patient's condition and body weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art.

The composition comprising niclosamide or a pharmaceutically acceptable salt thereof of the present invention exhibits excellent arthritis treatment and improvement effects as well as an edema inhibitory effect, but unlike steroids that are difficult to maintain due to side effects, it is more effective for maintaining remission. By allowing long-term administration, excellent therapeutic effects can be maintained for a longer period of time.

It should be understood that the effects of the present invention are not limited to the above-described effects, and include all effects that can be inferred from the configuration of the invention described in the detailed description or claims of the present invention.

1 shows the weight change results after administering the drugs of Comparative Examples 1 to 3, Examples 1 and 2 for 14 days to the arthritis-induced model (*P<0.05 vs Vehicle (Comparative Example 1), ** P<0.01 vs Vehicle).
Figure 2 shows the results of measuring the arthritis score after administering the drugs of Comparative Examples 1 to 3, Examples 1 and 2 for 14 days to the arthritis-induced model (* P<0.05 vs Vehicle (Comparative Example 1) , **P<0.05 vs Comparative Example 2, ***P<0.05 vs Example 1).
Figure 3 shows the results of comparing the edema before (0 days) and 14 days after administration of the drug to the arthritis animal model (** P<0.05 vs Vehicle (Comparative Example 1)).

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

Example 1. Niclosamide Powder

Niclosamide powder was purchased from Sigma-aldrich, USA, and niclosamide was dispersed in 0.5% (w/v) polyvinylpyrrolidone solution and then orally administered.

Example 2. Niclosamide Injection

Niclosamide is poorly soluble and has a very low bioavailability. A suspension injection was prepared using the poor solubility of niclosamide as described above.

Specifically, a suspension injection formulation was prepared by mixing niclosamide with Kollidon 17PF (BASF, Polyvinylpyrrolidone molecular weight 70 to 10,000) and D-mannitol. The particle size range of the main component particles of the suspension was d(0.5) = 4-5 um, d(0.9) = 12-13 um.

Experimental Example 1. Preparation of arthritis disease model

1-1. Arthritis causes disease

DBA/1J mice were purchased from Japan SLC, Inc. and used. 6-week-old male DBA/1J mice were bred in an SPF facility and acclimatized for 1 week before the experiment, and water and feed were allowed to be freely consumed. Temperature 23±3 ℃, relative humidity 55±15%, ventilation frequency 10-20 times/hr, illumination time 12 hours, and illumination intensity 150-300 Lux were set for breeding. Temperature/humidity of the animal room, number of ventilations during breeding period and environmental conditions such as illuminance were measured regularly. Breeding boxes, rugs, and water bottles were exchanged at least once a week, and the weights of animals determined to be healthy during the acclimatization period were measured and distributed randomly so that the average weight of each group was distributed as evenly as possible according to the ranked weights.

After that, 2 mg/mL Bovine Type II collagen was emulsified 1:1 in 4 mg/mL Complete Freund's adjuvant in DBA/1J mice (n = 8 for each group), and first intradermal injection at 100 μL/head at the base of the mouse tail to induce arthritis, and 3 weeks later, 2 mg/mL Bovine Type II collagen was emulsified 1:1 in 4 mg/mL Incomplete Freund's adjuvant and additionally injected in the same way to induce arthritis. As a control, an animal model administered with a vehicle under the same conditions was used.

1-2. Arthritis Efficacy Assessment

The clinical symptoms are divided from no edema or swelling (0 points) to cases where there is swelling and redness from the ankle to the entire leg and stiffness of the joints (4 points), from immediately before and after administration of the test substance to twice a week during the test period. The degree was measured by scoring (Arthritis score). The scores of the extremities were summed up and the highest score was 16 points. For paw edema, the animals were anesthetized using ether before test substance administration and on the day of autopsy, and the changed hind paw edema was measured.

As a result of measuring the arthritis score of the arthritis disease model and comparing the arthritis score with the vehicle-administered animal model, it was confirmed that arthritis was effectively induced.

Experimental Example 2. Confirmation of pharmacological effect on arthritis

2-1. Composition and dosage setting of the test group

The composition and dosage settings of the test group are summarized in Table 1 below.

Tofacitinib, a JAK inhibitor class drug, was used as a positive control. The tofacitinib is an oral arthritis treatment for rheumatoid arthritis and psoriatic arthritis, and in the present invention, a low-dose group of 10 mg/kg (Comparative Example 2), and a high-dose group of 50 mg/kg (Comparative Example 3) The pharmacological effects of the niclosamide-administered group and arthritis were compared.

2-2. Check weight change

The drugs of Comparative Examples 1 to 3 and Examples 1 and 2 were administered to the arthritis animal model prepared in Experimental Example 1 for 14 days, and the change in body weight at the end of the test was measured.

As a result, as shown in FIG. 1 , in Comparative Examples 1 and 2, no significant weight change was observed, however, a weight loss of about 5% was observed in the tofacitinib high-dose group. In Examples 1 and 2 groups administered with niclosamide, the body weight increased, and in particular, when the injection was administered, the body weight increased by about 10%, indicating that the individual's vital signs were the most excellent.

2-3. Arthritis score measurement

The drugs of Comparative Examples 1 to 3 and Examples 1 and 2 were administered to the arthritis animal model prepared in Experimental Example 1 for 14 days, and the arthritis score at the end of the test was measured.

As a result, as shown in FIG. 2, the vehicle administration group of Comparative Example 1 compared to the low-dose tofacitinib administration group of Comparative Example 2 showed a decrease in arthritis score of about 15%, but was not statistically significant. On the other hand, the high-dose tofacitinib administration group of Comparative Example 3 decreased the arthritis score by 36% (p<0.05).

In addition, the oral administration group of niclosamide of Example 1 showed a 27% reduction in arthritis score (p<0.05), and the niclosamide injection group of Example 2 showed a decrease in arthritis score of 45%, showing the most excellent showed medicinal effect.

In the case of the oral administration group of niclosamide of Example 1, limited efficacy was shown due to the relatively low bioavailability compared to the intramuscular injection of Example 2, but superior effect compared to the tofacitinib low-dose group (Comparative Example 2), which is a positive control group was shown.

In the case of Example 2, a significant improvement in drug efficacy was further exhibited compared to the oral administration group of Example 1 (P<0.05), which was determined to be an effect due to an increase in exposure to the body through administration of an injection and maintenance of a continuous blood drug concentration. .

2-4. Confirmation of Paw edema inhibitory effect

In the arthritic animal model prepared in Experimental Example 1, edema before (0 days) and 14 days after administration of the drug 　 administration 　 　 was compared.

As a result, as shown in FIG. 3, edema increased in all test groups, but in the group administered with the injection of Example 2, compared to Vehicle (Comparative Example 1), left hind ankle edema (HL), right hind ankle edema (HR) All showed an inhibitory effect.

Through the above results, it was confirmed that niclosamide of the present invention can exhibit a therapeutic effect on arthritis disease, and in particular, it was confirmed that it can exhibit an edema inhibitory effect together with arthritis treatment.

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains 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. For example, each component described as a single type may be implemented in a dispersed form, and likewise components described as distributed may be implemented in a combined form.

The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included in the scope of the present invention.

Claims (7)

A pharmaceutical composition for preventing or treating arthritis, comprising niclosamide or a pharmaceutically acceptable salt thereof.
According to claim 1,
The arthritis is one or more selected from the group consisting of osteoarthritis, rheumatoid arthritis, degenerative arthritis, gouty arthritis, juvenile arthritis, reactive arthritis, and combinations thereof, a pharmaceutical composition for the prevention or treatment of arthritis.
According to claim 1,
The composition is a pharmaceutical composition for the prevention or treatment of arthritis, which is a parenteral formulation.
4. The method of claim 3,
The composition is for subcutaneous or intramuscular injection, a pharmaceutical composition for the prevention or treatment of arthritis.
5. The method of claim 4,
The composition is a pharmaceutical composition for preventing or treating arthritis, which further comprises polyvinylpyrrolidone and mannitol.
A kit for preventing or treating arthritis, comprising the composition of claim 1.
A method of treating arthritis, comprising administering the composition of claim 1 to a subject other than a human.

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