JP7219476B2 - Therapeutic drug for diseases mainly caused by tenosynovial lesions - Google Patents

Description

TECHNICAL FIELD The present invention relates to a therapeutic agent for diseases mainly caused by tenosynovial lesions (tenosynovitis, etc.) and uses thereof. This application claims priority based on Japanese Patent Application No. 2018-000898 filed on January 7, 2018, the entire contents of which are incorporated by reference.

Tenosynovitis is a disease mainly involving tenosynovial lesions. Administration of steroids and surgical treatment (surgery) are performed for treatment of tendonitis, but there are cases in which sufficient effects are not obtained, and the probability of recurrence is high. In addition, steroids should be carefully administered to diabetic patients because they affect glycemic control.

On the other hand, carpal tunnel syndrome is a disease that causes numbness and pain in the fingers, muscle weakness, etc., and significantly impairs the patient's quality of life (QOL). Median neuropathy is said to occur due to increased pressure in the carpal tunnel due to thickening of the carpal tunnel. Carpal tunnel syndrome is often accompanied by tenosynovitis, which is particularly difficult to treat. Since the effects of drug therapy are limited, carpal tunnel syndrome is generally treated by surgery at present, which is a burden on the patient.

JP-A-2002-255805 Japanese Unexamined Patent Application Publication No. 2011-6406 JP-A-9-278653 WO 97/29744 pamphlet

As described above, the existing treatment methods are not sufficient, and the development of an effective and less burdensome treatment method for diseases mainly composed of tenosynovitis represented by tenosynovitis is desired. An object of the present invention is to meet the needs and to provide effective therapeutic means for various pathological conditions, mainly tenosynovial lesions.

While conducting studies to solve the above problems, the present inventors focused on tranilast, an approved drug. Tranilast is used to treat allergic diseases and improve hypertrophic scars and keloids, and exerts its efficacy by suppressing the action of TGF-β and active oxygen. Tranilast is also being studied for its application to acute respiratory distress syndrome (Patent Document 1), retinal diseases (retinal vascular occlusion, diabetic retinopathy, wet age-related macular degeneration, etc.) (Patent Documents 2 to 4). . The present inventors examined the effect of tranilast on flexor tendon sheath synovial fibroblasts collected from patients with carpal tunnel syndrome, with the expectation that tranilast would also be useful for tendon-synovial lesions. As a result, it was found that tranilast exhibits a cell growth inhibitory effect and suppresses TNF-α/IL-1β-mediated IL-6 production at the gene and protein levels, and is effective against tenosynovial lesions. was shown to be In addition, tranilast does not have cytotoxicity and has favorable properties as a therapeutic drug in terms of side effects. On the other hand, it was found that IL-6 secretion was significantly high in cells derived from cases of carpal tunnel syndrome complicating tenosynovitis. It was suggested that tranilast is effective in treating conditions in which carpal tunnel syndrome is complicated by tenosynovitis.
The following inventions are mainly based on the above results.
[1] A therapeutic agent for diseases mainly caused by tenosynovial lesions, containing tranilast or a pharmaceutically acceptable salt thereof as an active ingredient.
[2] The therapeutic agent of [1], wherein the disease is tenosynovitis.
[3] The therapeutic agent of [1], wherein the disease is trigger finger, de Quervain's tendonitis, intersection syndrome, anterior/posterior tibialis tendonitis, or toe tendonitis.
[4] The therapeutic agent of [1], which is administered to a patient with carpal tunnel syndrome and tendonitis.
[5] The therapeutic drug according to any one of [1] to [4], which is administered to a diabetic patient suffering from the disease.
[6] A therapeutic method comprising administering a therapeutically effective amount of tranilast or a pharmaceutically acceptable salt thereof to a patient suffering from a disease mainly composed of tenosynovial lesions.

MTS assay results. Measurement results after 12 hours (upper right), 24 hours (lower left), and 48 hours (lower right) are shown. ** p < 0.01, * p < 0.05 vs tranilast 0 μM, TNF-α 0 ng/ml) Results of LDH assay (cytotoxicity test). Suppression of IL-6 production by tranilast. Tranilast and TNF-α (10 ng/ml) or IL-1β (10 ng/ml) were simultaneously administered to fibroblasts cultured for 1 hour in the presence of various concentrations of tranilast, and IL-6 production was measured. Examined. **p < 0.01, * p < 0.05 vs tranilast 0 μM, TNF-α or IL-1β 10ng/ml Suppression of IL-6 expression by tranilast. Tranilast and TNF-α (10 ng/ml) or IL-1β (10 ng/ml) were simultaneously administered to fibroblasts cultured for 1 hour in the presence of various concentrations of tranilast, and IL-6 mRNA levels were examined. rice field. **p < 0.01, * p < 0.05 vs tranilast 0 μM Correlation between IL-6 concentrations and patient data. No correlation was observed between IL-6 concentration in the culture supernatant of carpal tunnel syndrome patient-derived fibroblasts and patient data (age, BMI, symptom duration, NCV (Neurophysiological grading scale) grade). . Correlation between IL-6 concentrations and patient data. A correlation was observed between the IL-6 concentration in the culture supernatant of fibroblasts derived from carpal tunnel syndrome patients and the association of trigger finger. **p < 0.01, *p < 0.05 vs control.

TECHNICAL FIELD The present invention relates to therapeutic agents for diseases mainly caused by tenosynovial lesions and uses thereof. The present invention is based on the surprising finding that tranilast, which is used for treating allergic diseases and skin diseases, suppresses the production (secretion) of IL-6 and is also useful in the field of orthopedic surgery. Without being bound by theory, the therapeutic agent of the present invention exerts its efficacy by suppressing the production/secretion of IL-6 in the affected area.

Tranilast (N-(3,4-dimethoxycinnamoyl)anthranilic acid) is a chemical mediator release inhibitor and is used for allergic diseases such as bronchial asthma, allergic rhinitis and atopic dermatitis. Tranilast also has the effect of suppressing collagen synthesis by suppressing the production or release of TGF-β1 and reactive oxygen species, and is also used for the treatment of skin diseases (keloids and hypertrophic scars).

Pharmaceutically acceptable salts of tranilast include, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, fumaric acid, maleic acid, succinic acid , salts with organic acids such as citric acid, tartaric acid, adipic acid, gluconic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, oleic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, and benzenesulfonic acid; Ethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol , procaine, salts with organic amines such as N,N-bis(phenylmethyl)-1,2-ethanediamine, salts with amino acids such as glycine, phenylalanine, lysine, aspartic acid, glutamic acid, lithium, sodium, potassium, etc. and salts with alkaline earth metals such as calcium and magnesium.

Tranilast or a pharmaceutically acceptable salt thereof has been reported (e.g., Japanese Patent Publication No. 56-40710, Japanese Patent Publication No. 57-36905, Japanese Patent Publication No. 58-17186, Japanese Patent Publication No. 58-48545, Japanese Patent Publication No. 58 -55138, Japanese Patent Publication No. 58-55139, Japanese Patent Publication No. 1-28013, Japanese Patent Publication No. 1-50219, Japanese Patent Publication No. 3-37539, etc. can be referred to)). . Tranilast preparations (capsules, fine granules, dry syrup) are commercially available under the name of Rizaben (registered trademark).

A “therapeutic agent” refers to a drug that exhibits therapeutic or prophylactic effects on a target disease or condition. Therapeutic effects include mitigation (mitigation) of symptoms characteristic of the target disease/condition or associated symptoms, prevention or delay of exacerbation of symptoms, and the like. The latter can be regarded as one of preventive effects in terms of preventing aggravation. Thus, the therapeutic effect and the prophylactic effect are partially overlapping concepts, and it is difficult to clearly distinguish between them, and there is little practical benefit from doing so. A prophylactic effect is typically to prevent or delay the recurrence of symptoms characteristic of the disease/condition in question. As long as it exhibits some therapeutic or prophylactic effect, or both, on the disease/condition of interest, it is considered a therapeutic agent.

The therapeutic agent of the present invention is used for treatment or prevention of diseases mainly composed of tenosynovial lesions. In other words, the therapeutic agent of the present invention is administered to a patient suffering from a disease mainly composed of tenosynovial lesions. “Disease mainly composed of tenosynovial lesion” means a disease in which a tenoperiosteal lesion is the center or base of the pathology, and a typical corresponding disease is tenosynovitis. Specific examples of tenosynovitis include spring finger and de Quervain's disease (stenotic tenosynovitis), but the site of onset is not particularly limited, for example, hands (fingers, palms), wrist joints, forearms, elbows, feet, knees, etc. Tenosynovitis that occurs in Preferred diseases to be treated include trigger finger, de quervain tendonitis, intersection syndrome, anterior and posterior tibialis tendonitis, and toe tendonitis.

Formulation of the therapeutic agent of the present invention can be carried out according to conventional methods. When formulating, other pharmaceutically acceptable ingredients (e.g., carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives, physiological saline solution, etc.). Lactose, starch, sorbitol, D-mannitol, sucrose and the like can be used as excipients. Starch, carboxymethyl cellulose, calcium carbonate and the like can be used as the disintegrant. Phosphate, citrate, acetate and the like can be used as buffers. Gum arabic, sodium alginate, tragacanth and the like can be used as emulsifiers. As suspending agents, glyceryl monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, sodium lauryl sulfate and the like can be used. Benzyl alcohol, chlorobutanol, sorbitol and the like can be used as analgesics. Propylene glycol, ascorbic acid and the like can be used as stabilizers. Preservatives that can be used include phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methylparaben, and the like. As antiseptics, benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.

The dosage form for formulation is also not particularly limited. Examples of dosage forms are tablets, powders, fine granules, granules, capsules, dry syrups, injections, and external preparations. The therapeutic agent of the present invention is administered orally or parenterally (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, intraperitoneal injection, transdermal, nasal, transmucosal injection, etc.) depending on its dosage form. Applies to Systemic administration and local administration are also indicated by the subject. These administration routes are not mutually exclusive, and two or more arbitrarily selected routes can be used in combination (for example, intravenous injection or the like is performed at the same time as oral administration or after a predetermined period of time has elapsed). The therapeutic agent of the present invention contains an amount of active ingredient necessary to obtain the expected therapeutic effect (ie, a therapeutically effective amount). Although the amount of the active ingredient in the therapeutic agent of the present invention generally varies depending on the dosage form, the amount of the active ingredient is set, for example, within the range of about 0.1% to about 99% by weight so as to achieve the desired dosage.

The dosage of the therapeutic agent of the present invention is set to obtain the expected therapeutic effect. In setting a therapeutically effective dose, symptoms, age, sex and weight of the patient are generally taken into consideration. A person skilled in the art can take these matters into consideration and set an appropriate dosage. For example, for adults (body weight of about 60 kg), the daily dose of the active ingredient can be set to 10 mg to 1000 mg, preferably 50 mg to 800 mg, particularly preferably 200 mg to 500 mg. As an administration schedule, for example, once to several times a day, once every two days, or once every three days can be adopted. In preparing the dosing schedule, the patient's condition and duration of effect of the active ingredient can be taken into consideration.

In parallel with treatment with the therapeutic agent of the present invention, treatment with other drugs (for example, existing therapeutic agents such as steroids) may be performed, or treatment with the therapeutic agent of the present invention may be combined with existing therapeutic procedures. good.

By the way, steroid administration (typically intramyelin injection) is generally used for treatment of tendonitis. However, since administration of steroids to diabetic patients may cause an increase in blood sugar level, treatment of tendonitis in diabetic patients is often difficult. According to the therapeutic drug of the present invention, it is possible to overcome such a situation. Therefore, in a preferred embodiment, the therapeutic agent of the present invention is used to treat tendonitis in diabetic patients as an alternative to conventional steroid therapy. However, even in this case, concomitant use of steroids is not prohibited (when the therapeutic agent of the present invention is used in combination with steroids, the amount of steroids used can be reduced).

On the other hand, studies by the present inventors (see Examples below) have revealed that the IL-6 level in the affected area is significantly higher in patients with carpal tunnel syndrome and tendonitis. Therefore, it is suitable for treatment with the therapeutic agent of the present invention, which exerts its efficacy through inhibition of IL-6 production/secretion. That is, the patient is also a preferred therapeutic target.

As is clear from the above description, the present application also provides a therapeutic method of administering a therapeutically effective amount of tranilast or a pharmaceutically acceptable salt thereof to a patient suffering from a disease mainly composed of tenosynovial lesions. .

We investigated the efficacy of the approved drug tranilast for tenosynovial lesions. Specifically, we examined the effect of tranilast on flexor tendon sheath synovial fibroblasts collected from patients with carpal tunnel syndrome.

1. Method (1) Cells Fibroblasts were collected from tenosynovial tissue obtained when carpal tunnel release and tenosynovectomy were performed. The cells were proliferated and maintained by subculture, and cells at passages 2 to 5 were used for the following experiments.

(2) MTS assay The effect of tranilast on cell proliferation was examined by MTS assay. The MTS assay is an assay that utilizes the change in absorbance in proportion to the number of cells. After the prepared fibroblasts were seeded in a 96-well plate, various concentrations of tranilast were added. MTS was administered after a predetermined time (12 hours, 24 hours or 48 hours) after the addition of tranilast, and the absorbance was measured with a microplate reader.

(3) Cytotoxicity test An LDH assay was used for the cytotoxicity test. Since LDH is released when cell death occurs, the presence or absence of cytotoxicity can be determined by measuring the amount of LDH. After the prepared fibroblasts were seeded in a 96-well plate, various concentrations of tranilast were added. Twenty-four hours after the addition of tranilast, the amount of LDH in the culture supernatant was measured.

(4) Suppression of IL-6 production It was verified whether IL-6 is suppressed by administering tranilast to carpal tunnel syndrome patient-derived fibroblasts activated with TNF-α or IL-1β. . Tranilast and TNF-α (10 ng/ml) or IL-1β (10 ng/ml) were simultaneously administered to fibroblasts cultured for 1 hour in the presence of various concentrations of tranilast. After 12 hours or 24 hours of culture, the culture supernatant was collected. The IL-6 concentration in the recovered culture supernatant was measured by ELISA.

On the other hand, we also investigated whether tranilast suppresses IL-6 at the gene level. In the same manner as above, tranilast and TNF-α (10 ng/ml) or IL-1β (10 ng/ml) were simultaneously administered to fibroblasts cultured for 1 hour in the presence of various concentrations of tranilast. After 24 hours, RNA was extracted from the cells, and using cDNA obtained by reverse transcription reaction, the expression level of IL-6 mRNA was measured by real-time RT-PCR.

Next, IL-6 concentration in the culture supernatant of carpal tunnel syndrome patient-derived fibroblasts and patient data (age, BMI, duration of symptoms, NCV (Neurophysiological grading scale) grade, presence or absence of complication of trigger finger, etc.) ) was investigated for any correlation between

2. result
As a result of the MTS assay, the number of cells in the tranilast administration group (10-250 μM) was significantly higher than that in the control (0 μM) in a concentration-dependent manner at all measurement time points after 12 hours, 24 hours, and 48 hours. (Fig. 1).

Cytotoxicity studies showed no significant difference in LDH levels, indicating that tranilast was not cytotoxic (Figure 2).

In addition, the amount of IL-6 protein secreted by carpal tunnel syndrome patient-derived fibroblasts was significantly increased by administration of TNF-α or IL-1β, and administration of tranilast significantly suppressed IL-6 secretion. (Fig. 3). Tranilast also exhibited an inhibitory effect on IL-6 at the gene level (Fig. 4).

No correlation was observed between the IL-6 concentration in the culture supernatant of carpal tunnel syndrome patient-derived fibroblasts and the patient's age, BMI, symptom duration and NCV (Fig. 5). On the other hand, it was shown that the amount of IL-6 secreted by the cells was higher (the concentration in the culture supernatant was higher) in cases complicated by trigger fingers (Fig. 6).

3. DISCUSSION We found that IL-6 secretion was significantly higher in patients with carpal tunnel syndrome accompanied by tenosynovitis. Tenosynovitis frequently complicates carpal tunnel syndrome patients (30-60%). Therefore, it is considered that cases with high inflammation in the synovium (that is, cases with high IL-6 secretion) are more likely to develop symptoms of trigger finger.

Tranilast exerted a cytostatic effect on carpal tunnel syndrome patient-derived fibroblasts without showing cytotoxicity. It was also shown to suppress IL-6 secretion (protein level) and expression (gene level).

The above results show that tranilast is a promising therapeutic drug for diseases mainly involving tenosynovial lesions. In addition, tranilast can be expected to exhibit excellent efficacy in cases of carpal tunnel syndrome complicating tenosynovitis.

The therapeutic agent of the present invention contains the approved drug tranilast or a pharmaceutically acceptable salt thereof as an active ingredient. Tranilast has a long track record of use, and its safety, including side effects and contraindications, has been established. This point is a great advantage when the therapeutic agent of the present invention is applied clinically. The therapeutic agent of the present invention can be used as an alternative to steroid agents frequently used in conventional treatments. Therefore, it is good news for diabetic patients who have had to be cautious about using steroids and who often struggle with treatment.

The present invention is by no means limited to the description of the above embodiments and examples of the invention. Various modifications are also included in the present invention within the scope of those skilled in the art without departing from the description of the claims. The contents of articles, published patent publications, patent publications, etc., identified herein are incorporated by reference in their entirety.

Claims (4)

A remedy for tenosynovitis selected from the group consisting of spring finger, de Quervain's tenosynovitis, intersection syndrome, anterior/posterior tibialis tendonitis, and toe tenosynovitis, containing tranilast or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The therapeutic agent according to claim 1, which is administered to a patient with carpal tunnel syndrome complicated by trigger finger, de Quervain's tenosynovitis or intersection syndrome. 3. The therapeutic drug according to claim 1 or 2 , which is administered to a diabetic patient suffering from said tenosynovitis. A therapeutically effective amount of tranilast or a pharmaceutically acceptable drug thereof for patients suffering from tendonitis selected from the group consisting of trigger finger, dequervain tendonitis, intersection syndrome, anterior/posterior tibialis tendonitis and toe tendonitis 11. The therapeutic agent of claim 1, used to administer a salt.

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