WO2006073126A1

WO2006073126A1 - Preventive and remedy for dry eye associated with chronic graft versus host disease

Info

Publication number: WO2006073126A1
Application number: PCT/JP2005/024151
Authority: WO
Inventors: Yoko Ogawa
Original assignee: Kissei Pharmaceutical Co., Ltd.
Priority date: 2005-01-06
Filing date: 2005-12-29
Publication date: 2006-07-13
Also published as: JPWO2006073126A1; JP4966019B2

Abstract

It is intended to provide a medicinal composition for preventing and treating dye eye associated with chronic graft versus host disease (cGVHD) following the transplantation of hematopoietic stem cells. Namely, a medicinal composition or the like for preventing and treating dye eye associated with GVHD occurring after the transplantation of hematopoietic stem cells such as peripheral blood stem cell transplantation, cord blood transplantation or bone marrow transplantation which contains as the active ingredient N-(3,4-dimethoxycinnamoyl)anthranilic acid (common name: tranilast) or a pharmacologically acceptable salt thereof.

Description

Prevention and treatment of dry eye in chronic graft-versus-host disease

[0001] 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).

Background art

In recent years, 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. While the success rate of hematopoietic stem cell transplantation has increased and the number of long-term survivors has increased, cGVHD, which is a late complication after transplantation, has become a problem (see Non-Patent Document 1). 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. It affects the tissues and organs. In addition, after transplantation, the disease usually occurs in more than half of patients despite the administration of immunosuppressive drugs. Therefore, prevention and treatment of cGV HD is extremely important after hematopoietic stem cell transplantation. is there.

[0003] 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.

[0004] Currently, dry eye in cGVHD is treated with immunosuppressant FK506 eye ointment or steroid eye drops as an immunomodulator. Immunosuppression Since steroid eye drops are problematic for long-term continuous administration, side effects such as increased intraocular pressure and cataracts are feared, making them difficult to use for a long time. A method of changing to a therapeutic agent is common. As such symptomatic therapeutic agents, eye drops such as hyaluronic acid preparations, vitamin A, steroids, serum eye drops, and artificial tears are used, but the effects are not necessarily sufficient. Therefore, there is a demand for new drugs that have high efficacy and can be used continuously. 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. (For example, see 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.

[0005] 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. In addition, 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). In addition to the eyes, 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).

[0006] As described above, 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.

[0007] 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

Disclosure of the invention

Problems to be solved by the invention

[0008] 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.

Means for solving the problem

[0009] 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.

[0010] 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

(1) 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;

(2) The pharmaceutical composition according to the above (1), which is an eye drop;

(3) The pharmaceutical composition according to the above (1) or (2), wherein the hematopoietic stem cell transplantation is a transplant selected from peripheral blood stem cell transplantation, umbilical cord blood transplantation, and bone marrow transplantation;

(4) The pharmaceutical composition according to any one of (1) to (3), wherein the hematopoietic stem cell transplantation is bone marrow transplantation;

(5) The pharmaceutical composition according to any one of (1) to (4) above, which is used in combination with a drug used for the prevention / treatment of dry eye in cGVHD after hematopoietic stem cell transplantation; It is about.

[0011] 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 invention's effect

[0012] The present invention can provide a pharmaceutical composition useful for the prevention and treatment of dry eye in cGVHD after hematopoietic stem cell transplantation.

BEST MODE FOR CARRYING OUT THE INVENTION

[0013] 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. Among these, 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.

[0014] For dry eye diagnosis and evaluation of therapeutic effect, the criteria for diagnosis of dry eye study group using tear layer destruction time and tear volume as an index (Jun Shimashima et al., Ophthalmology, 1995, 37th, p. 765-77 0) is generally used. The diagnostic criteria are reviewed every 10 years and the 1995 criteria are now used. Overseas, the 1995 NIH diagnostic criteria (Lemp et al.) Are commonly used. The standard was revised in 2005. 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. In addition, 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).

[0015] 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).

[0016] 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.

[0017] When the pharmaceutical composition of the present invention is used for actual treatment, various dosage forms are used depending on the usage. Examples of such 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. Can be mentioned. Examples of routes of administration include oral and parenteral administration. Examples of parenteral include eye drops, intravenous injection, transdermal route, etc. In particular, eye drops and oral are preferable.

[0018] 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.

[0019] For example, 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. Depending on the product, 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.

[0020] 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.

[0021] 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.

[0022] 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. Examples of other drugs that can be used in combination include vitamins, methylcellulose eye drops and other artificial tears, serum eye drops, steroids, and immunosuppressants.

[0023] When the pharmaceutical composition of the present invention is used in combination with one or more of the other drugs described above, 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.

[0024] When the pharmaceutical composition of the present invention is used for actual treatment, 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. For example, in the case of ophthalmic administration, adults can generally be administered in the range of ΙΟ / zg ~: LOmg, and in the case of oral administration, the adult single dose is approximately 100 ~ It can be administered in the range of 1000 mg. Examples of the administration method include ophthalmic administration 4 times a day or oral administration 1 to 3 times a day. Further, when used in combination with the above other drugs, the dose of the compound of the present invention can be reduced according to the dose of the other drug.

[0025] When 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. When used for treatment, it is preferable to continue administration after diagnosing dry eye in cGVHD until at least it is confirmed that symptoms will not progress or worsen. The contents of the present invention will be described in more detail with reference to the following examples and comparative examples, but the present invention is not limited to the contents.

Example

[0027] Example 1

(Growth inhibition) effect on dry eye in cGVHD after hematopoietic stem cell transplantation (1) We confirmed the therapeutic effect of tranilast instillation in cases where dry eye developed in cGVHD after bone marrow transplantation. The target cases, administration methods, and treatment courses are as follows.

[0028] Case 1:

A 49-year-old man.

Administration method and course of treatment:

After bone marrow transplantation, periodic observations were made every 3 months, and after 1 year and 1 month, the onset of dry eye was confirmed by Schirmer test I and keratoconjunctival findings. CGVHD in other organs was found in the skin and gastrointestinal tract. From the 1st and 3rd month, treatment was started with sodium hyaluronate 0.3% ophthalmic solution 5 times daily and tranilast 0.5% ophthalmic solution 4 times daily. As a result of continuing treatment for 1 year and 10 months, the progression of dry eye, which usually worsens rapidly in about 3 months, was suppressed, and further, a mild type that reduced subjective symptoms and hindered daily life. Table 1 shows the ophthalmic examination findings before, at the time of onset (1 year and 1 month after transplantation) and after treatment (1 year and 10 months after the start of treatment) in Case 1.

[0029] [Table 1] Case 1 ophthalmological findings

(1: normal +: positive) [0030] Case 2:

39-year-old woman.

Administration method and course of treatment:

Periodic observations were made every 3 months after transplantation, and after 11 months, the onset of dry eye was confirmed by Schirmer test I and keratoconjunctival findings. Two months later, a biopsy of the left lacrimal gland confirmed a dry eye due to cGVHD. After 1 year and 3 months after transplantation, artificial tears and fluorometholone 0.1% instillation once daily are administered, and then trastol 0.5% instillation 4 times a day. Changed to dosing. As a result of continuing the treatment for about 3 years, the progress of dry eye, bad habits, recovery to the extent that it did not meet the diagnostic criteria for dry eye, and the patient's subjective symptoms were very good. Table 2 shows the ophthalmic examination findings before, at the time of onset (11 months after transplantation) and after treatment (2 years and 9 months after the start of treatment) in Case 2.

[0031] [Table 2] Table 2 Case 2 ophthalmological findings

(-: Normal +: Positive)

[0032] Example 2

(Growth inhibition) effect on dry eye in cGVHD after hematopoietic stem cell transplantation (2) In 11 patients who received hematopoietic stem cell transplantation, as a result of regular follow-up, 9 patients developed dry eye. It was. These nine patients started to receive 0.5% instillation of Tralust 4 times a day from the time of diagnosis of dry eye, and then followed up. As for dry eye onset power, 7 cases whose findings were observed after 3 months, sex, age, type of transplanted stem cells, period until onset of dry eye (number of months passed until diagnosis), onset Eye examination findings at diagnosis after 3 months (fluorescein staining, rose bengal staining, tear film destruction time, Schirmer test Test I method, cotton thread method, reflex tear secretion (hereinafter referred to as NST) and concomitant drugs (in the table, SST-D is Soft Santia® eye drop; INT-D is sodium cromoglycate eye drop; HYA —D Table 1 shows 1% sodium hyaluronate instillation; VA means vitamin A instillation, respectively). All seven cases were markedly prevented from becoming severe, and one of them (case 9) showed improvement in dry eye. Since about half of the cases of dry eye in cGVHD are said to become severe in about 3 months, this result clearly shows that Trust has the effect of preventing the severity of dry eye in cGVHD. Is shown. This result also suggests that tralast has the effect of preventing the development of dry eye in cGVHD.

[0033] [Table 3]

Comparative example

[0034] Case 10:

47 years old woman.

Administration method and course of treatment:

After transplantation, perform periodic observation every 3 months, and after 7 months, Schirmer test method I and keratosis Membrane findings confirmed the onset of dry eye. Vitamin A instillation (1000V. A. unit ZmL) and sodium hyaluronate 0.3% instillation was performed. After 10 months, a left eye lacrimal gland biopsy was performed. Atrophy was observed, and severe dry eye was diagnosed. The same treatment was continued, but at 2 years and 6 months after transplantation, progression and worsening of dry eye due to cGVHD were observed in both eyes. In this case, punctal plug treatment was finally performed and follow-up is underway. Table 4 shows ophthalmic examination findings before transplantation, onset (10 months after transplantation) and after treatment (1 year and 11 months after treatment start) in Case 3.

[0035] [Table 4]

(1: Normal +: Positive)

[0036] As described above, 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.

Industrial applicability

[0037] 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.

Claims

The scope of the claims

[1] A pharmaceutical composition for preventing and treating dry eye in chronic graft-versus-host disease after hematopoietic stem cell transplantation, comprising tralast or a pharmacologically acceptable salt thereof as an active ingredient.

[2] The pharmaceutical composition according to claim 1, which is an eye drop.

[3] The pharmaceutical composition according to claim 1 or 2, wherein the hematopoietic stem cell transplantation is a transplant selected from peripheral blood stem cell transplantation, hemorrhoid cord blood transplantation, and bone marrow transplantation.

[4] The hematopoietic stem cell transplant is a bone marrow transplant, according to claims 1 to 3! Or the pharmaceutical composition according to any one of

[5] The pharmaceutical composition according to any one of claims 1 to 4, which is combined with a drug for the prevention of dry eye in chronic graft-versus-host disease after hematopoietic stem cell transplantation.