WO2010010939A1 - Agent prophylactique ou thérapeutique pour la dégénérescence maculaire liée à l’âge - Google Patents

Agent prophylactique ou thérapeutique pour la dégénérescence maculaire liée à l’âge Download PDF

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Publication number
WO2010010939A1
WO2010010939A1 PCT/JP2009/063239 JP2009063239W WO2010010939A1 WO 2010010939 A1 WO2010010939 A1 WO 2010010939A1 JP 2009063239 W JP2009063239 W JP 2009063239W WO 2010010939 A1 WO2010010939 A1 WO 2010010939A1
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Prior art keywords
administration
age
macular degeneration
buformin
phenformin
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PCT/JP2009/063239
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English (en)
Japanese (ja)
Inventor
淑起 大橋
康司 大橋
正明 景山
健一 遠藤
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参天製薬株式会社
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Publication of WO2010010939A1 publication Critical patent/WO2010010939A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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

Definitions

  • the present invention relates to a preventive or therapeutic agent for age-related macular degeneration, which contains as an active ingredient at least one compound selected from the group consisting of buformin, phenformin, and salts thereof.
  • Age-related macular degeneration is currently one of the leading causes of blindness in developed countries, and is mainly seen in elderly people over 50 years of age.
  • Age-related macular degeneration is a disease caused by age-related changes in the macula, exudative age-related macular degeneration (extraactive AMD), atrophic age-related macular degeneration (atomic AMD), and early age-related macular degeneration, which are precursor lesions thereof. It is roughly divided into degeneration (early age-related macropathy).
  • wet age-related macular degeneration is a disease in which neovascularization occurs in the macular of the elderly from the choroid, causing bleeding or exudative lesions under the retinal pigment or under the retina, and finally forming scar tissue.
  • atrophic age-related macular degeneration is a disease accompanied by macular atrophy and drusen accumulation.
  • choroidal neovascularization The pathological condition underlying wet age-related macular degeneration is choroidal neovascularization, which is thought to develop on the basis of age-related changes in macular retinal pigment epithelial cells, Bruch's membrane, choroidal blood vessels, and the like.
  • the cause and mechanism of choroidal neovascularization has not yet been elucidated, and this is an area where future development is expected.
  • early age-related macular degeneration and atrophic age-related macular degeneration are not accompanied by choroidal neovascularization.
  • Non-Patent Document 1 In atrophic age-related macular degeneration, it is considered that visual acuity decreases due to photoreceptor cell degeneration (cell death) accompanying atrophy, and photoreceptor cell protection is attracting attention as a new treatment method.
  • biguanide drugs are drugs that have been developed and used clinically as oral diabetes drugs for a long time.
  • biguanides in addition to metformin and buformin marketed in Japan, phenformin, benphosphoformin (Benfosformin), etformin (Etoformin), tiformin (Tiformin) and the like are known.
  • Non-patent Document 2 AMP-activated protein kinase
  • Patent Document 2 it is suggested in Patent Document 2 that metformin, which is one of biguanide drugs, is useful for the treatment of age-related macular degeneration due to its AMPK activation action.
  • Patent Document 2 does not disclose how metformin is used for the treatment of age-related macular degeneration, and it is also disclosed in early age-related macular degeneration, atrophic age-related macular degeneration, or wet age-related macular degeneration. It is not clear which of these types is useful in the treatment of age-related macular degeneration.
  • Patent Document 2 does not describe or suggest any influence of biguanide drugs other than metformin (for example, buformin or phenformin) on age-related macular degeneration.
  • AICAR 5-aminoimidazole-4-carboxamide ribonucleoside
  • VEGF basic endothelial growth factor
  • angiogenesis-promoting factor angiogenesis-promoting factor
  • the inventor of the present application diligently researched to find a new pharmaceutical use of buformin or phenformin.
  • inhibition of choroidal neovascularization was observed by oral administration of buformin or phenformin. And found the present invention.
  • this is a surprising result considering that almost no inhibition of choroidal neovascularization was observed with oral administration of metformin.
  • HREC which is a human retinal vascular endothelial cell
  • metformin did not inhibit cell proliferation at all. That is, it is possible that buformin and phenformin may inhibit choroidal neovascularization due to a heterogeneous action that metformin does not have.
  • oral administration of buformin or phenformin suppresses photoreceptor cell death in a mouse photodamage model.
  • oral administration of metformin did not inhibit photoreceptor cell death at all.
  • the present invention is a preventive or therapeutic agent for age-related macular degeneration, which contains at least one compound selected from the group consisting of buformin, phenformin and salts thereof as an active ingredient.
  • buformin or phenformin exhibited an excellent choroidal neovascularization inhibitory action in a laser-induced rat choroidal neovascularization model, while suppressing photoreceptor cell death in a mouse photodamage model. Moreover, buformin or phenformin suppressed the proliferation of HREC cells induced by VEGF. That is, buformin or phenformin or a salt thereof (hereinafter also referred to as “the present compound”) is useful as a preventive or therapeutic agent for age-related macular degeneration.
  • Buformin or phenformin is a compound represented by the following chemical structural formula [I] or [II], respectively.
  • the salt of buformin or phenformin is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, or phosphoric acid.
  • Salts with organic acids quaternary ammonium salts with methyl bromide, methyl iodide, , Salts with halogen ions such as chlorine ions and iodine ions, salts with alkali metals such as lithium, sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, metal salts with iron and zinc, ammonia Salt, triethylenediamine, 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, and the like, and hydrochloride is particularly preferable.
  • Buformin or phenformin may take the form of hydrate or solvate.
  • crystal polymorphs and crystal polymorphism groups are also within the scope of the present invention.
  • the crystal polymorph group means that the crystal form changes depending on the conditions and state (including the formulated state in this state) such as production, crystallization, and storage of these crystals. Means the individual crystal forms and the whole process at each stage.
  • age-related macular degeneration means wet age-related macular degeneration, atrophic age-related macular degeneration, and early age-related macular degeneration, which are precursor lesions thereof.
  • Exudative age-related macular degeneration is a disease in which neovascularization occurs in the macular of the elderly from the choroid, causing bleeding or exudative lesions in the subretinal or subretinal area of the retina, and finally scar tissue.
  • atrophic age-related macular degeneration is a disease accompanied by macular atrophy and drusen accumulation.
  • This compound can be formulated by using a technique commonly used as a single preparation or a combination preparation by adding a pharmaceutically acceptable additive as necessary.
  • a pharmaceutical composition “Divetos Tablets 50 mg” containing 50 mg of buformin hydrochloride in one tablet and containing lactose, potato starch, gum arabic powder, magnesium stearate, hypromellose, titanium oxide and carnaubauro as additives. It is marketed as an oral hypoglycemic agent.
  • this compound When this compound is used for the prevention or treatment of the aforementioned eye diseases, it can be administered to patients orally or parenterally.
  • oral administration topical administration to the eye (instillation administration)
  • intravenous administration, transdermal administration, etc. are preferable, and oral administration is particularly preferred.
  • This compound is formulated into a dosage form suitable for administration together with a pharmaceutically acceptable additive as necessary.
  • the dosage form suitable for oral administration include tablets, capsules, granules, powders and the like, and tablets are particularly preferred.
  • dosage forms suitable for parenteral administration include injections, eye drops, eye ointments, patches, gels, inserts and the like. These can be prepared using ordinary techniques widely used in the field. In addition to these preparations, this compound can also be made into preparations for DDS (drug delivery system) such as preparations for intraocular implants and microspheres.
  • DDS drug delivery system
  • tablets are made of excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, starch, partially pregelatinized starch ,
  • Disintegrating agents such as low-substituted hydroxypropylcellulose; binders such as hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol; magnesium stearate, calcium stearate, talc, hydrous silicon dioxide ,
  • Lubricants such as hydrogenated oils; refined sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinyl chloride Coating agents such as Rupiroridon; citric acid, aspartame, using ascorbic acid, appropriately selected and the like flavoring agent such as menthol
  • the injection is selected as necessary from an isotonic agent such as sodium chloride; a buffering agent such as sodium phosphate; a surfactant such as polyoxyethylene sorbitan monooleate; and a thickener such as methylcellulose.
  • an isotonic agent such as sodium chloride
  • a buffering agent such as sodium phosphate
  • a surfactant such as polyoxyethylene sorbitan monooleate
  • a thickener such as methylcellulose.
  • Eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surface activity such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil Agents; Stabilizers such as sodium citrate and sodium edetate; can be selected and used as needed from preservatives such as benzalkonium chloride and paraben, and pH is acceptable for ophthalmic preparations Although it may be within the range, it is usually preferably within the range of 4-8.
  • the eye ointment can be prepared using a commonly used base such as white petrolatum or liquid paraffin.
  • the intercalating agent is prepared by pulverizing and mixing a biodegradable polymer, for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, and polyacrylic acid, together with the compound, and compressing the powder. If necessary, an excipient, a binder, a stabilizer, and a pH adjuster can be used.
  • the preparation for intraocular implant can be prepared using a biodegradable polymer, for example, a biodegradable polymer such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose.
  • the dose of this compound can be appropriately changed depending on the dosage form, the severity of the patient's symptoms, age, weight, doctor's judgment, etc. 0.01-5000 mg per day, preferably 0.1-2500 mg, more preferably 0.5-1000 mg can be administered in one or several divided doses.
  • 0.0001 to 2000 mg can be administered once or divided into several times.
  • eye drops or intercalating agents 0.000001 to 10% (w / v), preferably 0.00001 to 1% (w / v), more preferably 0.0001 to 0.1% ( The active ingredient concentration of w / v) can be administered once or several times a day.
  • a patch a patch containing 0.0001 to 2000 mg can be applied to an adult.
  • 0.0001 to 2000 mg is included for an adult.
  • An intraocular implant formulation can be implanted in the eye.
  • Rats were intramuscularly anesthetized with 1 ml / kg of a mixed solution (7: 1) of 5% (W / V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection to give 0.5% (W / V V) Tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriatics, and then photocoagulated with a krypton laser photocoagulator (multicolor laser photocoagulator MC-7000 manufactured by Nidec).
  • a mixed solution 7: 1 of 5% (W / V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection to give 0.5% (W / V V)
  • Tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriatics, and then photocoagulated with a krypton laser photocoagulator (multicolor laser photocoagulator MC-7000 manufactured
  • Photocoagulation was carried out at 8 locations per eye, avoiding thick retinal blood vessels in the posterior region of the fundus, focusing on the deep retina (coagulation conditions: spot size 100 ⁇ m, output 100 Wm, coagulation time 0.1 seconds). . After photocoagulation, fundus photography was performed to confirm the laser irradiation site.
  • Buformin hydrochloride hereinafter also referred to as “compound A” or phenformin hydrochloride (hereinafter also referred to as “compound B”) in a 1% (W / V) methylcellulose solution (prepared by dissolving methylcellulose in purified water) 6 mg / Suspended to be ml or 20 mg / ml, and was orally administered once a day for 7 days from the photocoagulation surgery day, including the surgery day, at a dose of 5 ml / kg each time (30 mg per day) / Kg or 100 mg / kg).
  • metformin hydrochloride (hereinafter also referred to as “compound C”) was suspended in 1% (W / V) methylcellulose solution so as to be 20 mg / ml or 60 mg / ml, and 5 ml / kg each time. The dose was orally administered once a day for 7 days from the photocoagulation surgery day, including the surgery day (100 mg / kg or 300 mg / kg per day).
  • Compounds A, B, and C are respectively “Buformin hydrochloride” (catalog number: 028-10052) purchased from Wako Pure Chemical Industries, “Phenformin hydrochloride” (catalog number: P7045) and Sigma company purchased from Sigma. “Metformin (1,1-Dimethylbihydride Hydrochloride)” (catalog number: D150959) purchased from Japan was used.
  • part with which some fluorescence exposure was recognized was determined to be positive when it existed in two places. Thereafter, the rate of choroidal neovascularization (%) was calculated from the number of positive spots with respect to 8 spots irradiated with laser according to Formula 1, and the rate of inhibition (%) of the evaluation drug was calculated according to Formula 2.
  • the evaluation results of Compounds A, B and C are shown in Table 1. The number of cases in each administration group is 8.
  • Incidence rate of choroidal neovascularization (number of positive spots / total number of photocoagulation sites) ⁇ 100
  • Inhibition rate (%) (A0 ⁇ AX) / A0 ⁇ 100
  • VEGF is a factor that promotes angiogenesis, and is considered to be one of the causes of the onset and progression of age-related macular degeneration (Prog. Retina Eye Res., 22 (1), 1-29 (2003)). . Therefore, the inhibitory effect of Compound A and Compound B on VEGF-induced cell proliferation was evaluated using HREC, which is a human retinal vascular endothelial cell. In addition, the effects of Compound C were also evaluated and compared.
  • HREC (manufactured by Cell systems, catalog number: ABI-181) was seeded in a 96-well plate at 1.5 ⁇ 10 3 cells / well and cultured overnight under conditions of 37 ° C., 5% CO 2 /95% air. .
  • CSC medium containing 10% fetal bovine serum was used.
  • the culture broth was then removed and replaced with a base broth or a laboratory broth containing 1 mM compound A, B or C.
  • a base culture solution a solution obtained by adding a heparin solution to CSC medium to 50 IU / ml was used.
  • buformin or phenformin inhibited cell proliferation induced by VEGF, whereas metformin did not inhibit cell proliferation at all. This is a surprising result. Further, as described above, buformin and phenformin inhibit choroidal neovascularization by oral administration, unlike metformin. That is, it is considered that the present compound may inhibit choroidal neovascularization through a heterogeneous action that metformin does not have.
  • the mouse photo damage model is a model animal in which cell death of retinal photoreceptor cells is induced by light irradiation, and is widely used as a model animal of retinal degeneration (Invest Ophthalmol Vis Sci., 46 (3), 979-987. (2005)). Further, as described in the background section, photoreceptor cell protection has attracted attention as a new treatment method for atrophic age-related macular degeneration. Therefore, the pharmacological effects of Compound A and Compound B were evaluated using this model. In addition, the effect of Compound C was simultaneously evaluated and compared.
  • Amplitude attenuation suppression rate (%) (V X ⁇ V 0 ) / (V n ⁇ V 0 ) ⁇ 100
  • V 0 amplitude ( ⁇ V) of the base administration group
  • V n amplitude of normal control group ( ⁇ V)
  • V X amplitude of drug administration group ( ⁇ V)
  • this compound has a remarkable prophylactic or therapeutic effect on all types of age-related macular degeneration (early age-related macular degeneration, atrophic age-related macular degeneration and exudative age-related macular degeneration), It is expected to be a very useful oral type preventive or therapeutic agent for age-related macular degeneration.
  • formulation example The pharmaceutical agent of the present invention will be described more specifically with formulation examples, but the present invention is not limited to these formulation examples.
  • Formulation Example 1 Compound A 1 mg in 100 mg tablet Lactose 66.4mg Corn starch 20mg Carboxymethylcellulose calcium 6mg Hydroxypropylcellulose 6mg Magnesium stearate 0.6mg This compound and lactose are mixed in a blender, carboxymethylcellulose calcium and hydroxypropylcellulose are added to the mixture and granulated. The resulting granules are dried and sized, and magnesium stearate is added to the sized granules. Mix and compress with a tableting machine. Moreover, the tablet whose content in 100 mg is 0.1 mg, 10 mg, or 50 mg can be prepared by changing the addition amount of this compound.
  • Formulation Example 2 Eyedrops 10ml Compound A 10mg Sodium chloride 900mg Polysorbate 80 Appropriate amount Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount Add this compound and the other components to sterile purified water, and mix them well to prepare an ophthalmic solution. By changing the addition amount of this compound, the concentration is 0.05% (w / v), 0.1% (w / v), 0.5% (w / v) or 1% (w / v). Eye drops can be prepared.
  • Formulation Example 3 Eye Ointment 100g Compound B 0.3g Liquid paraffin 10.0g Appropriate amount of white petrolatum An ointment is prepared by adding this compound to white petrolatum and liquid paraffin uniformly melted, thoroughly mixing them, and then gradually cooling them. By changing the amount of this compound added, the concentration is 0.05% (w / w), 0.1% (w / w), 0.5% (w / w), 1% (w / w) or A 3% (w / w) eye ointment can be prepared.
  • Formulation Example 4 10 mg of Compound B in 10 ml of injection Sodium chloride 90mg Polysorbate 80 Appropriate amount Sterilized purified water Appropriate amount The compound and sodium chloride are dissolved in sterile purified water to prepare an injection. By changing the addition amount of this compound, an injection with a content of 0.1 mg, 1 mg or 50 mg in 10 ml can be prepared.
  • buformin or phenformin exhibited an excellent inhibitory effect on choroidal neovascularization in a laser-induced rat choroidal neovascularization model, while suppressing photoreceptor cell death in a mouse photodamage model. Moreover, buformin or phenformin suppressed the proliferation of HREC cells induced by VEGF. Therefore, buformin or phenformin or a salt thereof is useful as a preventive or therapeutic agent for age-related macular degeneration.

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Abstract

La présente invention a pour objet une nouvelle application d’utilisation de la buformine, de la phenformine ou d’un sel de la buformine ou de la phenformine pour des objectifs médicaux. La buformine, la phenformine ou un sel de la buformine ou de la phenformine peut présenter une excellente activité antiangiogénique dans une choroïde et peut également prévenir la mort des cellules des photorécepteurs provoquée par un endommagement par la lumière. Par conséquent, la buformine, la phenformine ou un sel de la buformine ou de la phenformine est utile en tant qu’agent prophylactique ou thérapeutique pour la dégénérescence maculaire liée à l’âge.
PCT/JP2009/063239 2008-07-24 2009-07-24 Agent prophylactique ou thérapeutique pour la dégénérescence maculaire liée à l’âge WO2010010939A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2016171282A1 (ja) * 2015-04-24 2018-02-22 学校法人慶應義塾 近視予防剤及び近視進行抑制剤
CN115068456A (zh) * 2022-05-18 2022-09-20 中山大学中山眼科中心 二甲双胍在制备预防、治疗眼部疾病的药物中的用途及其剂型和制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001082916A2 (fr) * 2000-05-03 2001-11-08 Tularik Inc. Compositions therapeutiques combinees et leurs methodes d'utilisation
WO2005049014A1 (fr) * 2003-11-18 2005-06-02 Pharmacia Corporation Methodes de traitement ou de prevention de troubles oculaires lies au diabete par des inhibiteurs cox-2 seuls ou en association avec des agents anti-diabete classiques
WO2008022256A2 (fr) * 2006-08-16 2008-02-21 Blagosklonny Mikhail V Procédés et compositions de prévention ou de traitement de maladies liées au vieillissement

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001082916A2 (fr) * 2000-05-03 2001-11-08 Tularik Inc. Compositions therapeutiques combinees et leurs methodes d'utilisation
WO2005049014A1 (fr) * 2003-11-18 2005-06-02 Pharmacia Corporation Methodes de traitement ou de prevention de troubles oculaires lies au diabete par des inhibiteurs cox-2 seuls ou en association avec des agents anti-diabete classiques
WO2008022256A2 (fr) * 2006-08-16 2008-02-21 Blagosklonny Mikhail V Procédés et compositions de prévention ou de traitement de maladies liées au vieillissement

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
NAOKO TAJIMA: "Topics B. Tonyobyo 3. UKPDS-NIDDM no Tashisetsu Choki Daikibo Shiken", ANNUAL REVIEW NAIBUNPITSU, vol. 2000, 2000, TAISHA, pages 40 - 45 *
ONUMA YAMASHITA: "Naibunpitsu Taisha Evidence ni Motozuita Tonyobyo Gappeisho no Management Tonyobyo Momakusho no Management", MEBIO, vol. 20, no. 5, 2003, pages 48 - 53 *
OTA TAKASAKI ISHIDA: "Buformin Choki Toyo no Yukosei to Anzensei no Hyoka", THE JOURNAL OF THE JAPAN DIABETIC SOCIETY, vol. 46, no. SUP.5, 2003, pages 2 - 272 *
SUGAWARA-KANAZAWA ET AL.: "Tonyobyo no Keikachu, Yonkagetsu Kankaku de Sayu Kotaisei ni Massho Shinkei Mahi o Okoshita Ichirei", THE JOURNAL OF THE JAPAN DIABETIC SOCIETY, vol. 144, no. 7, 2001, pages 594 - 596 *
TANAKA-SAITO ET AL.: "Kiken Inshi no Guidline C. Tonyobyo 2. Tonyobyo Chiryo no Guidline", JUNKANKI SHIKKAN KISO CHOSA SEISEKI NI MOTOZUKU IRYO NO GUIDLINE SAKUSEI JIGYO HOKOKUSHO, HEISEI 7 NENDO, 1996, pages 309 - 322 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2016171282A1 (ja) * 2015-04-24 2018-02-22 学校法人慶應義塾 近視予防剤及び近視進行抑制剤
CN115068456A (zh) * 2022-05-18 2022-09-20 中山大学中山眼科中心 二甲双胍在制备预防、治疗眼部疾病的药物中的用途及其剂型和制备方法

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