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WO2006073126A1 - Preventif et remede pour la keratoconjonctivite seche associee a la reaction de greffe contre hote - Google Patents

Preventif et remede pour la keratoconjonctivite seche associee a la reaction de greffe contre hote Download PDF

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Publication number
WO2006073126A1
WO2006073126A1 PCT/JP2005/024151 JP2005024151W WO2006073126A1 WO 2006073126 A1 WO2006073126 A1 WO 2006073126A1 JP 2005024151 W JP2005024151 W JP 2005024151W WO 2006073126 A1 WO2006073126 A1 WO 2006073126A1
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WO
WIPO (PCT)
Prior art keywords
transplantation
dry eye
stem cell
hematopoietic stem
cgvhd
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2005/024151
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English (en)
Japanese (ja)
Inventor
Yoko Ogawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kissei Pharmaceutical Co Ltd
Original Assignee
Kissei Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kissei Pharmaceutical Co Ltd filed Critical Kissei Pharmaceutical Co Ltd
Priority to JP2006550866A priority Critical patent/JP4966019B2/ja
Publication of WO2006073126A1 publication Critical patent/WO2006073126A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to a hematopoietic stem cell transplant comprising N- (3,4-dimethoxycinnamoyl) anthralic acid (generic name: tra-last) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention relates to a pharmaceutical composition for the prevention and treatment of dry eye in later chronic graft-versus-host disease (cGVHD, hereinafter referred to as cGVHD).
  • hematopoietic stem cell transplantation such as bone marrow transplantation has been frequently performed as a treatment method for blood diseases caused by abnormalities of hematopoietic stem cells such as leukemia and severe aplastic anemia.
  • cGVHD is a systemic immune response that occurs when a hematopoietic stem cell transplanted from a donor matures in the host, and is diverse in the eyes, mouth, kidney, lung, liver, small intestine, skin, and so on.
  • cGVHD develops in various tissues and organs. Symptoms in the eye include dry eye, meibomian gland dysfunction, retinal hemorrhage, acute conjunctivitis, etc. Among them, dry eye is the most common. Hematopoietic stem cell transplantation is a new treatment, and therefore the mechanism of cGVHD, which is a late complication after transplantation, has not been fully elucidated. In the lacrimal gland, activation of T cells, lymphocytes and other immunocompetent cells, and subsequent repair mechanisms, etc. are observed. Although it is considered to be the center of, there are many unclear points.
  • Dry eye in cGVHD develops in about half of hematopoietic stem cell transplant patients, and moreover, about half of patients who are generally difficult to treat once developed, are said to become severe in a short period of about 3 months.
  • Non-Patent Document 2 Therefore, in the treatment after hematopoietic stem cell transplantation such as bone marrow transplantation, it is important to prevent the onset of dry eye in cGV HD, as well as the improvement and severity of symptoms after onset. Drugs for this purpose are strongly desired.
  • Toralast has antiallergic action and is widely used as an eye drop treatment for allergic conjunctivitis and as an oral treatment for bronchial asthma, allergic rhinitis, atopic dermatitis, keloid and hypertrophic scar It has been confirmed that it is extremely safe with less side effects, even with long-term continuous use.
  • tralastic eye effects include allergic eye diseases, angiogenesis-related diseases such as diabetic retinopathy, subcorneal opacity due to corneal wounds, secondary cataract, retinal pigment epithelial cell proliferative disease, pterygium The effects on eye diseases such as these are known (see Patent Documents 1 to 6).
  • effects on chronic rejection after transplantation of organs such as vascular intimal cell proliferative diseases, keloids, hypertrophic scars, heart and liver are known (see Patent Documents 7 and 8).
  • tranilast is known to have preventive and therapeutic effects on various diseases, but has no known effect on lacrimal glands or dry eye. Therefore, tranilast is not known for dryness in cGVHD after hematopoietic stem cell transplantation. It is described and suggested in the above-mentioned literature that it is useful for the prevention and treatment of eye.
  • Patent Document 1 JP-A 52-65279
  • Patent Document 2 JP-A-2-264716
  • Patent Document 3 International Publication No. 97Z29744 Pamphlet
  • Patent Document 4 Pamphlet of International Publication No. 98Z13038
  • Patent Document 5 Pamphlet of International Publication No. 98Z16214
  • Patent Document 6 Pamphlet of International Publication No. 98Z47504
  • Patent Document 7 Japanese Patent Laid-Open No. 5-163222
  • Patent Document 8 International Publication 2001Z5394 Pamphlet
  • Non-Patent Document 1 Yoko Ogawa, Ophthalmology, 2003, No. 45, p. 309-322
  • Non-Patent Document 2 Yoko Ogawa, 11 others, Br. J. Ophthalmol., 1999, 83rd, p. 1125-1130
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating dry eye in cGVHD after hematopoietic stem cell transplantation, which can be used continuously with high effectiveness.
  • the present inventor has conducted extensive research to find a drug that has a high efficacy and can be used continuously, and has an effect on dry eye in cG VHD after hematopoietic stem cell transplantation such as bone marrow transplantation.
  • N-(3, 4-Dimethoxycinnamoyl) anthroleic acid (generic name: tra-last) force cGVHD It is found to significantly suppress the progression of dry eye or bad habits in patients and is extremely useful for the prevention and treatment of the disease As a result, the present invention has been achieved.
  • the present invention relates to a pharmaceutical composition for preventing or treating dry eye in cGVHD after hematopoietic stem cell transplantation. More specifically, the present invention
  • a pharmaceutical composition for preventing and treating dry eye in cGVHD after hematopoietic stem cell transplantation comprising tra-last or a pharmacologically acceptable salt thereof as an active ingredient;
  • hematopoietic stem cell transplantation is a transplant selected from peripheral blood stem cell transplantation, umbilical cord blood transplantation, and bone marrow transplantation;
  • the present inventor examined the effects of various drugs in patients who developed dry eye due to cGVHD after bone marrow transplantation to find a preventive and therapeutic agent for cGVHD that can be used continuously with high efficacy. did. As a result, surprisingly, tralast significantly suppresses the progression of dry eye symptoms in cGVHD, and further has a remarkable effect of improving it to below the diagnostic criteria for dry eye. -The pharmaceutical composition containing last as the active ingredient was found to be extremely useful as a preventive and therapeutic agent for dry eye in cGVHD, which occurs frequently after hematopoietic stem cell transplantation.
  • the present invention can provide a pharmaceutical composition useful for the prevention and treatment of dry eye in cGVHD after hematopoietic stem cell transplantation.
  • Examples of hematopoietic stem cell transplantation include bone marrow transplantation, which is well known, and peripheral blood stem cell transplantation, umbilical cord blood transplantation, autologous transplantation, and the like.
  • bone marrow transplantation has been the most important issue because of the incidence of dry eye caused by conventional cGVHD.
  • the same dry eye caused by cGVHD is also observed in peripheral blood stem cell transplants and umbilical cord blood transplants. Since autotransplantation is a patient's own cell transplantation, dry eye caused by cGVHD rarely develops. Therefore, the pharmaceutical composition of the present invention is useful as an agent for preventing and treating dry eye in cGVHD after bone marrow transplantation, peripheral blood stem cell transplantation and umbilical cord blood transplantation.
  • the subject of application of the pharmaceutical composition of the present invention is an ocular symptom that develops after hematopoietic stem cell transplantation, and is based on the above diagnostic criteria, etc., and qualitative or quantitative abnormalities (decrease) in tears or associated with them Diagnosis of dry eye characterized by keratoconjunctival epithelial disorder, etc. and suspected dry eye Including what is.
  • the severity of dry eye can generally be evaluated by using positive indicators of reflex lacrimation (10 mm or less), Rose Bengal staining findings (1 or more), and fluorescein staining findings (3 or more). (Tsubota K, Am J Ophthalmol, 1991, Vol. Ill, p. 106-108).
  • Tralast which is an active ingredient of the pharmaceutical composition of the present invention, or a pharmacologically acceptable salt thereof can be easily produced by a method described in the literature or a method analogous thereto (for example, see Patent Document 1).
  • Examples of pharmacologically acceptable salts of tralast include salts with inorganic bases such as sodium salt, potassium salt and calcium salt, organic amines such as morpholine, piperazine and pyrrolidine, and amino acids. And the like.
  • dosage forms are used depending on the usage.
  • dosage forms include oral preparations such as powders, granules, fine granules, dry syrups, tablets and capsules, eye drops such as eye drops and eye ointments, injections, patches and the like.
  • routes of administration include oral and parenteral administration.
  • parenteral include eye drops, intravenous injection, transdermal route, etc. In particular, eye drops and oral are preferable.
  • the pharmaceutical composition of the present invention comprises an appropriate excipient, a disintegrant, a binder, a lubricant, a diluent, a buffer, and an isotonic agent according to the method used in pharmacology depending on the dosage form. It can be prepared by mixing or diluting and dissolving appropriately with pharmaceutical additives such as preservatives, wetting agents, milking agents, dispersants, stabilizers, solubilizing agents, etc., and dispensing according to conventional methods. When other drugs are used in combination, they can be produced by formulating the respective active ingredients simultaneously or separately in the same manner as described above.
  • eye drops are prepared by heating and dissolving tralast or a pharmacologically acceptable salt thereof and a basic substance in a suitable amount of sterile purified water together with a solubilizing agent such as polyvinylpyrrolidone.
  • a solubilizing agent such as polyvinylpyrrolidone.
  • pharmaceutical additives such as surfactants, preservatives, stabilizers, buffers, isotonic agents, antioxidants, thickeners, etc. are added as appropriate, and sterilized by filtration through membrane filters. can do.
  • the tablet is made of, for example, tralast or a salt thereof, if necessary, an appropriate excipient, a disintegrant. Then, a binder, a lubricant and the like can be added and compressed into tablets according to a conventional method. Tablets may be coated as necessary to form film-coated tablets, sugar-coated tablets, enteric-coated skin tablets, etc.
  • the capsule can be, for example, added to Tralast with an appropriate excipient, lubricant, etc., if necessary, and mixed well, and then filled into an appropriate capsule to form a capsule. . Furthermore, it may be filled after granulation or fine granulation by a conventional method.
  • the pharmaceutical composition of the present invention can also be used in appropriate combination with other drugs having an effect of suppressing dry eye in cGVHD.
  • other drugs that can be used in combination include vitamins, methylcellulose eye drops and other artificial tears, serum eye drops, steroids, and immunosuppressants.
  • the present invention may be administered simultaneously as a single formulation, identical or different as separate formulations Both forms of administration, including simultaneous administration by administration route and spaced administration by the same or different administration routes as separate formulations are included.
  • the dose of tralast which is an active ingredient, or a pharmacologically acceptable salt thereof depends on the patient's body weight, age, sex, and disease.
  • the adult single dose is approximately 100 ⁇ It can be administered in the range of 1000 mg.
  • the administration method include ophthalmic administration 4 times a day or oral administration 1 to 3 times a day.
  • the dose of the compound of the present invention can be reduced according to the dose of the other drug.
  • the pharmaceutical composition of the present invention is used prophylactically, at least 3 to 6 months after the hematopoietic stem cell transplantation, which is generally regarded as a period of high risk of developing dry eye in cGVHD, or It is preferable to continue administration for at least 3 to 6 months or more after gradual reduction or cessation of systemic immunosuppressant administration, or after confirming the onset of cGVHD at a site other than the eye.
  • the pharmaceutical composition of the present invention has an effect of preventing onset, an effect of suppressing the progression of the disease state, and a therapeutic effect on dry eye in cGVHD after bone marrow transplantation, and frequently occurs after hematopoietic stem cell transplantation. It has been shown to be extremely useful for the prevention or treatment of dry eye in cGVHD.
  • the pharmaceutical composition of the present invention is extremely useful as a prophylactic and therapeutic agent for dry eye in cGVHD after hematopoietic stem cell transplantation.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition médicinale destinée à prévenir et à traiter la kératoconjonctivite sèche associée à la réaction de greffe contre hôte (cGVHD) suite à la transplantation de cellules souches hématopoïétiques. En fait, la présente invention concerne une composition médicinale ou similaire destinée à prévenir et à traiter la kératoconjonctivite sèche associée à la GVHD se produisant après la transplantation de cellules souches hématopoïétiques telles que la transplantation de cellules souches du sang périphérique, la transplantation de sang de cordon ombilical ou la transplantation de moelle osseuse contenant en tant que principe actif de l’acide N-(3,4-diméthoxycinnamoyl) anthranilique (dont le nom commun est le tranilast) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2005/024151 2005-01-06 2005-12-29 Preventif et remede pour la keratoconjonctivite seche associee a la reaction de greffe contre hote Ceased WO2006073126A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2006550866A JP4966019B2 (ja) 2005-01-06 2005-12-29 慢性移植片対宿主症におけるドライアイの予防および治療剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2005-001600 2005-01-06
JP2005001600 2005-01-06

Publications (1)

Publication Number Publication Date
WO2006073126A1 true WO2006073126A1 (fr) 2006-07-13

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JP (1) JP4966019B2 (fr)
WO (1) WO2006073126A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105007981A (zh) * 2013-02-20 2015-10-28 诺华股份有限公司 在移植患者中治疗移植物抗宿主病
US10695353B2 (en) 2010-11-24 2020-06-30 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09176003A (ja) * 1995-12-28 1997-07-08 Tsumura & Co 角膜治療剤
WO1997037650A1 (fr) * 1996-04-05 1997-10-16 Santen Pharmaceutical Co., Ltd. Medicaments contre les maladies retiniennes
WO1998013038A1 (fr) * 1996-09-28 1998-04-02 Kissei Pharmaceutical Co., Ltd. Inhibiteur de turbidite sous-epitheliale
WO1998016214A1 (fr) * 1996-10-14 1998-04-23 Kissei Pharmaceutical Co., Ltd. Inhibiteur de la cataracte secondaire
WO1998035668A1 (fr) * 1997-02-14 1998-08-20 Kissei Pharmaceutical Co., Ltd. Medicaments entravant l'evolution du pterygion et sa recurrence postoperatoire
WO1998047504A1 (fr) * 1997-04-18 1998-10-29 Kissei Pharmaceutical Co., Ltd. Remedes pour la prophylaxie ou le traitement de maladies se traduisant par une proliferation excessive des cellules epitheliales pigmentaires de la retine
WO2001005394A1 (fr) * 1999-07-16 2001-01-25 Kissei Pharmaceutical Co., Ltd. Agents inhibant les reactions de rejet chronique faisant suite a une greffe d'organe

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09176003A (ja) * 1995-12-28 1997-07-08 Tsumura & Co 角膜治療剤
WO1997037650A1 (fr) * 1996-04-05 1997-10-16 Santen Pharmaceutical Co., Ltd. Medicaments contre les maladies retiniennes
WO1998013038A1 (fr) * 1996-09-28 1998-04-02 Kissei Pharmaceutical Co., Ltd. Inhibiteur de turbidite sous-epitheliale
WO1998016214A1 (fr) * 1996-10-14 1998-04-23 Kissei Pharmaceutical Co., Ltd. Inhibiteur de la cataracte secondaire
WO1998035668A1 (fr) * 1997-02-14 1998-08-20 Kissei Pharmaceutical Co., Ltd. Medicaments entravant l'evolution du pterygion et sa recurrence postoperatoire
WO1998047504A1 (fr) * 1997-04-18 1998-10-29 Kissei Pharmaceutical Co., Ltd. Remedes pour la prophylaxie ou le traitement de maladies se traduisant par une proliferation excessive des cellules epitheliales pigmentaires de la retine
WO2001005394A1 (fr) * 1999-07-16 2001-01-25 Kissei Pharmaceutical Co., Ltd. Agents inhibant les reactions de rejet chronique faisant suite a une greffe d'organe

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ISAJI M. ET AL.: "Selective inhibition of collagen accumulation by N-(3,4-dimethoxycin namoyl)anthranilic acid (N-5') in granulation tissue", BIOCHEMICAL PHARMACOLOGY, vol. 36, no. 4, 1987, pages 469 - 474, XP000995000 *
KUWANA M.: "Zenshinsei Jiko Men'eki Shikkan ni Okeru Nanjisei Byotai no Shindan to Chiryoho ni Kansuru Kenkyu Sen'ika Byotai ni Okeru Seniga Saibo to T Saibo no Kyocho Sayo ni Kansuru Kenkyu", ZENSHINSEI JIKO MEN'EKI SHIKKAN NI OKERU NANJISEI BYOTAI NO SHINDAN TO CHIRYOHO NI KANSURU KENKYU HEISEI 14 NENDO SOKATSU, 2003, pages 21 - 23, XP003000551 *
MATSUMOTO Y.: "Graft-versus-host disease (GVHD) no me no Chiryo", SHIKAGAKUHO, vol. 104, no. 2, 2004, pages 121 - 123, XP003000552 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10695353B2 (en) 2010-11-24 2020-06-30 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
US10786510B2 (en) 2010-11-24 2020-09-29 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
US11583535B2 (en) 2010-11-24 2023-02-21 Occurx Pty Ltd Methods of treating eye diseases associated with inflammation and vascular proliferation
CN105007981A (zh) * 2013-02-20 2015-10-28 诺华股份有限公司 在移植患者中治疗移植物抗宿主病
US11224604B2 (en) 2013-02-20 2022-01-18 Priothera Limited Treatment of graft versus host disease in transplant patients
US11014873B2 (en) 2017-02-03 2021-05-25 Certa Therapeutics Pty Ltd. Anti-fibrotic compounds
US11603349B2 (en) 2017-02-03 2023-03-14 Certa Therapeutics Pty Ltd Anti-fibrotic compounds

Also Published As

Publication number Publication date
JPWO2006073126A1 (ja) 2008-06-12
JP4966019B2 (ja) 2012-07-04

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