WO2019135363A1 - Médicament thérapeutique pour des maladies impliquant principalement des lésions ténosynoviales - Google Patents

Médicament thérapeutique pour des maladies impliquant principalement des lésions ténosynoviales Download PDF

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Publication number
WO2019135363A1
WO2019135363A1 PCT/JP2018/047135 JP2018047135W WO2019135363A1 WO 2019135363 A1 WO2019135363 A1 WO 2019135363A1 JP 2018047135 W JP2018047135 W JP 2018047135W WO 2019135363 A1 WO2019135363 A1 WO 2019135363A1
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Prior art keywords
tranilast
therapeutic agent
disease
tendonitis
acid
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PCT/JP2018/047135
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English (en)
Japanese (ja)
Inventor
平田　仁
祐也 川本
克之 岩月
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国立大学法人名古屋大学
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Priority to JP2019563964A priority Critical patent/JP7219476B2/ja
Publication of WO2019135363A1 publication Critical patent/WO2019135363A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention relates to a therapeutic agent for diseases (teninositis and the like) based on tendon synovial lesion and its use.
  • diseases teninositis and the like
  • tendon synovial lesion tendon synovial lesion and its use.
  • Tendinitis is a disease that is based on tendon synovial lesions. Although steroid administration and surgical treatment (surgery) are performed for the treatment of tendonitis, there are cases where sufficient effects can not be obtained, and the probability of recurrence is also high. In addition, since diabetic patients affect blood sugar control, it is necessary to administer steroids carefully.
  • carpal tunnel syndrome is a disease that causes numbness, pain in the fingers, muscle weakness, etc., and significantly impairs the patient's QOL (quality of life).
  • QOL quality of life
  • the peritendon connective tissue It is said that median nerve damage is caused by an increase in intracarpal pressure due to thickening of Tendonitis is often associated with carpal tunnel syndrome, which makes treatment particularly difficult.
  • surgical treatment is generally generally performed for carpal tunnel syndrome, which places a burden on patients.
  • JP 2002-255805 A JP, 2011-6406, A Japanese Patent Application Laid-Open No. 9-278653 WO 97/29744 pamphlet
  • the object of the present invention is to provide a therapeutic means effective for various pathologies mainly composed of tendon synovial lesion in response to the needs.
  • Tranilast is used for treatment of allergic diseases and improvement of hypertrophic scars and keloids, and exerts its medicinal effect by suppressing the function of TGF- ⁇ and active oxygen.
  • the application of Tranilast to acute respiratory distress syndrome (patent document 1), retinal diseases (retinal vascular occlusion, diabetic retinopathy, wet-type age-related macular degeneration, etc.) (patent documents 2 to 4) is also considered.
  • the present inventors examined the effect of tranilast on flexor tendon tendon sheath synovial fibroblasts collected from a patient with carpal tunnel syndrome, with the expectation that tranilast is also useful for tendon synovial lesions.
  • tranilast exhibits cytostatic activity and suppresses TNF- ⁇ / IL-1 ⁇ mediated IL-6 production at gene level and protein level, which is effective against tendon synovial lesions It was shown to be. In addition, tranilast was non-cytotoxic and had desirable properties as a therapeutic agent in terms of side effects. On the other hand, it is known that IL-6 secretion is significantly high in cells derived from cases in which carpal tunnel syndrome was complicated with tendonitis, preventing patients with carpal tunnel syndrome from developing (combining) tenoritis, or It was suggested that tranilast is effective in treating pathophysiology of carpal tunnel syndrome and tendonitis. The following inventions are mainly based on the above results.
  • the therapeutic agent according to [1] which is administered to a patient with tendonitis in carpal tunnel syndrome.
  • MTS assay results The measurement results after 12 hours (upper right), after 24 hours (lower left), and after 48 hours (lower right) are shown. ** p ⁇ 0.01, * p ⁇ 0.05 vs. tranilast 0 ⁇ M, TNF- ⁇ 0 ng / ml) Results of LDH assay (cytotoxicity test). Suppression of IL-6 production by Tranilast. To fibroblasts cultured for 1 hour in the presence of various concentrations of tranilast, tranilast and TNF- ⁇ (10 ng / ml) or IL-1 ⁇ (10 ng / ml) are simultaneously administered to produce IL-6 production Examined.
  • the present invention relates to a therapeutic agent for diseases mainly composed of tendon synovial lesion and its use.
  • the present invention is based on the surprising finding that Tranilast, which is used to treat allergic diseases and skin diseases, suppresses the production (secretion) of IL-6 and is also useful in the orthopedic field.
  • Tranilast which is used to treat allergic diseases and skin diseases, suppresses the production (secretion) of IL-6 and is also useful in the orthopedic field.
  • 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
  • Tranilast is a chemical mediator release inhibitor and is used for allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis and the like.
  • Tranilast has an effect of suppressing collagen synthesis by suppressing the production or release of TGF- ⁇ 1 or active oxygen, and is also used for the treatment of skin diseases (keloid and hypertrophic scars).
  • salts of tranilast 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 Citric acid, tartaric acid, adipic acid, gluconic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, oleic acid, stearic acid, tannic acid, salts with organic acids such as trifluoromethanesulfonic acid, benzenesulfonic acid, tri Ethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1,3-propanediol , Salts with organic amines such as procaine, N, N-bis
  • Tranilast or a pharmaceutically acceptable salt thereof is known (for example, JP-B-56-40710, JP-B-57-36905, JP-B-58-17186, JP-B-58-48545, JP-B-58) JP-55138, JP-B-58-55139, JP-B-1-28013, JP-B-1-50219, JP-B-3-37539, etc. can be used as a reference.
  • Formulations of tranilast capsule, fine granules, dry syrup
  • Rizaben registered trademark
  • therapeutic agent refers to a medicine that exhibits a therapeutic or prophylactic effect on a disease or condition of a subject.
  • Therapeutic effects include alleviation of symptoms or concomitant symptoms characteristic of the target disease / condition (reduction of symptoms), prevention or delay of deterioration of symptoms, and the like. The latter can be regarded as one of the preventive effects in terms of preventing the aggravation.
  • therapeutic effects and preventive effects are partially overlapping concepts, so it is difficult to distinguish them clearly, and there are few benefits to doing so.
  • a typical preventive effect is to prevent or delay the recurrence of symptoms characteristic of the target disease / condition.
  • it corresponds to a therapeutic drug.
  • the therapeutic agent of the present invention is used for the treatment or prevention of diseases based on tendon synovial lesion.
  • the therapeutic agent of the present invention is administered to a patient suffering from a disease based on tendon synovial lesion.
  • the "dendon synovial lesion-based disease” is a disease in which the tendon periosteum lesion is the central or base of the pathological condition, and a typical disease of interest is tendonitis.
  • spring finger and Dokerban's disease stenotic tenositis
  • the onset site is not particularly limited.
  • hand finger, palm
  • Tendinitis that occurs in can be a treatment target.
  • Preferred target diseases to be treated include spring finger, dokerban tendinitis, intersection syndrome, anterior / posterior tibial tendonitis and toe tendonitis.
  • Formulation of the therapeutic agent of the present invention can be carried out according to a conventional method.
  • other pharmaceutically acceptable ingredients eg, carrier, excipient, disintegrant, buffer, emulsifier, suspending agent, soothing agent, stabilizer, preservative, preservative, physiology
  • Saline solution etc. can be contained.
  • excipient lactose, starch, sorbitol, D-mannitol, sucrose or the like can be used.
  • disintegrant starch, carboxymethylcellulose, calcium carbonate and the like can be used.
  • As a buffer, phosphate, citrate, acetate and the like can be used.
  • As an emulsifier gum arabic, sodium alginate, tragacanth etc.
  • glycerin monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, sodium lauryl sulfate and the like can be used.
  • a soothing agent benzyl alcohol, chlorobutanol, sorbitol or the like can be used.
  • propylene glycol, ascorbic acid and the like can be used.
  • preservatives phenol, benzalkonium chloride, benzyl alcohol, chlorobutanol, methyl paraben and the like can be used.
  • benzalkonium chloride, p-hydroxybenzoic acid, chlorobutanol and the like can be used.
  • the dosage form for formulation is also not particularly limited.
  • dosage forms are tablets, powders, fine granules, granules, capsules, dry syrups, injections, and external preparations.
  • the therapeutic agent of the present invention is administered by oral or parenteral administration (intravenous, intraarterial, subcutaneous, intradermal, intramuscular, or intraperitoneal injection, transdermal, transnasal, transmucosal etc.) according to its dosage form.
  • parenteral administration intravenous, intraarterial, subcutaneous, intradermal, intramuscular, or intraperitoneal injection, transdermal, transnasal, transmucosal etc.
  • systemic administration and local administration are also adapted by the subject. These administration routes are not mutually exclusive, and two or more optionally selected can be used in combination (for example, intravenous injection or the like simultaneously with oral administration or after a predetermined time has elapsed).
  • the therapeutic agent of the present invention contains the active ingredient in an amount necessary to obtain the expected therapeutic effect (ie, a therapeutically effective amount).
  • a therapeutically effective amount ie, a therapeutically effective amount.
  • 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% by weight to about 99% by weight to achieve the desired dose.
  • the dose of the therapeutic agent of the present invention is set so as to obtain the expected therapeutic effect.
  • the condition, age, sex, and weight of the patient, etc. are generally considered. Those skilled in the art can set appropriate dosages in consideration of these matters.
  • the dose can be set such that the daily dose of the active ingredient is 10 mg to 1000 mg, preferably 50 mg to 800 mg, and particularly preferably 200 mg to 500 mg for adults (body weight of about 60 kg).
  • the administration schedule may be, for example, once to several times a day, once every two days, or once every three days. In preparation of the administration schedule, the patient's medical condition, the duration of the effect of the active ingredient and the like can be considered.
  • treatment with the therapeutic agent of the present invention treatment with another drug (for example, existing therapeutic agents such as steroids) may be performed, or the treatment with the therapeutic agent of the present invention may be combined with existing therapeutic procedures. Good.
  • another drug for example, existing therapeutic agents such as steroids
  • the therapeutic agent of the present invention is used to treat tendinitis in diabetic patients as an alternative to conventional steroid therapy.
  • the combination use of steroids is not hindered (when the therapeutic agent of the present invention and a steroid are used in combination, the amount of steroid used can be suppressed).
  • the patients with carpal tunnel syndrome and tendonitis have a significantly higher IL-6 level in the affected area. Therefore, it is suitable for treatment with the therapeutic agent of the present invention that exerts its efficacy via suppression of IL-6 production / secretion. That is, the patient is also a preferred treatment target.
  • the present application also provides a therapeutic method for administering a therapeutically effective amount of tranilast or a pharmaceutically acceptable salt thereof to a patient suffering from a disease based on tendon synovial lesion. .
  • Tranilast for tendon synovial lesions. Specifically, the effect of tranilast on flexor tendon tendon sheath intrasynovial fibroblasts collected from patients with carpal tunnel syndrome was examined.
  • 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 preparing the prepared fibroblasts 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.
  • Tranilast and TNF- ⁇ (10 ng / ml) or IL-1 ⁇ (10 ng / ml) were simultaneously administered to fibroblasts cultured for 1 hour in the presence of various concentrations of tranilast. After culture for 12 hours or 24 hours, the culture supernatant was recovered. The IL-6 concentration in the collected culture supernatant was measured by ELISA.
  • Tranilast suppresses IL-6 at the gene level.
  • tranilast and TNF- ⁇ (10 ng / ml) or IL-1 ⁇ (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 the expression level of IL-6 mRNA was measured by real-time RT-PCR using cDNA obtained by reverse transcription reaction.
  • IL-6 concentration in the culture supernatant of carpal tunnel syndrome patient-derived fibroblasts and patient data (age, BMI, symptom duration, grade of NCV (neurophysiological grading scale), presence or absence of spring finger, etc. ) was examined for correlation.
  • Tranilast also showed an inhibitory effect on IL-6 at the gene level (FIG. 4).
  • Tranilast exhibited a cytostatic effect without exhibiting cytotoxicity against fibroblasts derived from patients with carpal tunnel syndrome. It has also been shown to suppress the secretion (protein level) and expression (gene level) of IL-6.
  • Tranilast is promising as a therapeutic agent for diseases mainly composed of tendon synovial lesions.
  • tranilast exerts excellent medicinal effects in cases where tendonitis is complicated with carpal tunnel syndrome.
  • the therapeutic agent of the present invention comprises, as an active ingredient, tranilast, which is an approved drug, or a pharmaceutically acceptable salt thereof. Tranilast has a wealth of use and safety has been established, including side effects and contraindications. This point is a great advantage in clinical application of the therapeutic agent of the present invention.
  • the therapeutic agent of the present invention can be used as an alternative to steroids frequently used in conventional treatments. Therefore, it is the gospel to diabetic patients who have to be cautious about the use of steroids and often have difficulty in treatment.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'objectif de la présente invention est de fournir un médicament thérapeutique efficace contre des pathologies variées, principalement impliquant des lésions ténosynoviales. L'invention concerne un médicament thérapeutique comprenant comme principe actif du tranilast ou un sel pharmaceutiquement acceptable de ce dernier.
PCT/JP2018/047135 2018-01-07 2018-12-21 Médicament thérapeutique pour des maladies impliquant principalement des lésions ténosynoviales WO2019135363A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2019563964A JP7219476B2 (ja) 2018-01-07 2018-12-21 腱滑膜病変を主体とした疾患の治療薬

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JP2018-000898 2018-01-07
JP2018000898 2018-01-07

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WO2019135363A1 true WO2019135363A1 (fr) 2019-07-11

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Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
KAIBARA, NOBUTAKA ET AL.: "A comparative review of tendinous synovitis and joint synovitis of rheumatoid arthritis", CONNECTIVE TISSUE, vol. 36, no. 2, 2004, pages 98, ISSN: 0916-572X *
KATO, YOSHIYUKI ET AL.: "Tenosynovitis Diagnosed as Sarcoidosis of the Finger: A Case Report", THE JOURNAL OF THE CHUGOKU-SHIKOKU ORTHOPAEDIC ASSOCIATION, vol. 11, no. 1, 1999, pages 137 - 140, ISSN: 0915-2695 *
MIZUTANI, TAKAYA ET AL.: "Results of synovectomy for rheumatoid flexor tendon synovitis", THE JOURNAL OF JAPANESE ORTHOPAEDIC SURGICAL SOCIETY, vol. 75, no. 2, 2001, pages 314, ISSN: 0021-5325 *
SHIOTA, N. ET AL.: "The anti-allergic compound tranilast attenuates inflammation and inhibits bone destruction in collagen-induced arthritis in mice", BRITISH JOURNAL OF PHARMACOLOGY, vol. 159, no. 3, February 2010 (2010-02-01), pages 626 - 635, XP055620299, ISSN: 0007-1188 *
WANG, S. ET AL.: "Gene expression of transforming growth factor beta-1 in tendon healing", JOURNAL OF CLINICAL REHABILITATIVE TISSUE ENGINEERING RESEARCH, vol. 12, no. 7, 2008, pages 1372 - 1375, ISSN: 1673-8225 *
XIA, C. ET AL.: "Effects of Antisense Transforming Growth Factor-beta1 Gene Transfer on the Biological Activities of Tendon Sheath Fibroblasts", ORTHOPEDICS, vol. 33, no. 8, August 2010 (2010-08-01), ISSN: 0147-7447, Retrieved from the Internet <URL:https://doi.org/10.3928/01477447-20100625-06> *
YAMANAKA, Y. ET AL.: "Blocking fibrotic signaling in fibroblasts from patients with carpal tunnel syndrome", JOURNAL OF CELLULAR PHYSIOLOGY, vol. 233, no. 3, 10 March 2018 (2018-03-10), pages 2067 - 2074, XP055620304, ISSN: 1097-4652 *

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