WO2003028442A1 - Procede de criblage de remedes contre le glaucome - Google Patents

Procede de criblage de remedes contre le glaucome Download PDF

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Publication number
WO2003028442A1
WO2003028442A1 PCT/JP2002/008789 JP0208789W WO03028442A1 WO 2003028442 A1 WO2003028442 A1 WO 2003028442A1 JP 0208789 W JP0208789 W JP 0208789W WO 03028442 A1 WO03028442 A1 WO 03028442A1
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WO
WIPO (PCT)
Prior art keywords
polymer
crosslinked
cross
intraocular pressure
glaucoma
Prior art date
Application number
PCT/JP2002/008789
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English (en)
Japanese (ja)
Inventor
Takashi Ota
Yukiko Sugihara
Fumio Nakazawa
Mitsuaki Kuwano
Hideaki Hara
Original Assignee
Santen 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 Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO2003028442A1 publication Critical patent/WO2003028442A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms

Definitions

  • the present invention relates to a method for screening a therapeutic agent for glaucoma using an animal in which ocular hypertension and an optic nerve disorder have been induced, and a method for producing an experimental animal thereof.
  • Glaucoma is an intractable eye disease in which the optic nerve is damaged by high intraocular pressure exceeding normal intraocular pressure, causing visual impairment such as loss of visual field or reduced visual acuity, and leading to blindness.
  • Glaucoma patients have chronic ocular hypertension symptoms, which are considered to be one of the causes of ganglion cell death. Therefore, screening of drugs using chronic ocular hypertension model animals is extremely important for research and development of glaucoma therapeutics. .
  • the anterior chamber of the eye is filled with aqueous humor, and aqueous humor production and aqueous humor outflow resistance contribute to the determination of intraocular pressure.
  • the aqueous humor produced by the ciliary process passes between the iris and the lens and reaches the anterior chamber via the pupil. Most of the aqueous humor in the anterior chamber flows out of the trabecular meshwork into the superior scleral vein.
  • the present inventors have conducted intensive studies on polymers capable of solving the above-mentioned problems. It has been found that intraocular pressure can be induced with a small amount of a crosslinked polymer-containing solution without requiring replacement.
  • the present invention relates to a pharmacological screening method for a therapeutic agent for glaucoma using an experimental animal in which ocular hypertension and optic nerve damage have been induced by injecting a solution containing a crosslinked polymer into the anterior chamber.
  • the present invention also relates to a method for producing an experimental animal in which ocular hypertension and optic nerve damage have been induced by injecting a solution containing a crosslinked polymer into the anterior chamber.
  • the crosslinked polymer is preferably a crosslinkable lipoxyvinyl polymer or a crosslinked polyvinyl alcohol.
  • the polymer When the crosslinked polymer of the present invention is used, the polymer is crosslinked to form a three-dimensional structure, so that it is harder to pass through the mesh of the trabecular meshwork than a linear polymer, and the effect of causing clogging is increased. Therefore, only a small amount of polymer is injected, and there is no need to drain the aqueous humor prior to injecting the polymer solution.
  • the animal used in the present invention is usually used as an experimental animal. .
  • the cross-linked polymer used in the present invention refers to a polymer obtained by cross-linking a linear polymer with a cross-linking agent, radiation irradiation or the like.
  • These crosslinked polymers can be produced by a known method.
  • linear polymers are carboxyvinyl polymer (hereinafter abbreviated as CVP), polymethacrylic acid, polyglutamic acid, polyvinyl alcohol (abbreviated as PVA), hyaluronic acid, polyallylamine, polyethyleneimine, collagen and polyvinylpyridine. And the like.
  • Methods for cross-linking these linear polymers include a method using a cross-linking agent, a method of irradiating light, and a method of irradiating radiation, and a method suitable for each polymer may be selected.
  • the cross-linking agent include ethylene glycol, glycerin, ethylene diamine, polyallylphenol erythryl, divinyl diol, dartalaldehyde, glutaric acid, and dibumohexane, and the like.
  • the cross-linking agent depends on the functional group of the polymer. You can choose
  • crosslinked polymers are commercially available, sold under the trade name Kyrupopol by Goodlitsch Chemical Co., Ltd., a CVP crosslinked with polyallylpenyl erythritol, and a commercial product of Hibis Co., Ltd. by Wako Pure Chemical Industries, Ltd. CVP, etc. cross-linked with divinyl dalicol, sold under the product name, is available.
  • Crosslinked polymers are preferably crosslinked CVP and crosslinked PVA.
  • the crosslinked CVP can be obtained as a commercial product as described above.
  • the crosslinked PVA is described in detail in the Examples section, and can be obtained by crosslinking commercially available PVA by irradiation.
  • the concentration of the crosslinked polymer in the liquid containing the crosslinked polymer used in the present invention can be appropriately increased or decreased, but is preferably 0.01% to 5%.
  • the crosslinked polymer dissolves or disperses it in a base that can be administered to a living body.
  • a liquid containing a crosslinked polymer Purified as base Water is preferred.
  • An anti-inflammatory agent or an antibacterial agent can be added to the crosslinked polymer-containing liquid in order to prevent inflammation and infection accompanying the injection of the crosslinked polymer-containing liquid.
  • a buffer such as disodium hydrogen phosphate, an isotonic agent such as sodium chloride or glycerin
  • PH adjusters such as hydrochloric acid, sodium hydroxide and the like can be added. It is characterized in that the crosslinked polymer-containing liquid can be injected into the anterior chamber without draining the aqueous humor.
  • a method for injecting the liquid containing the crosslinked polymer a known method for injecting into the anterior chamber may be used.
  • the liquid may be injected into the anterior chamber from the limbus of the cornea using an injection needle.
  • the number of injections of the crosslinked polymer-containing liquid is not particularly limited, it can be injected one to several times in consideration of the intraocular pressure and the state of inflammation of the eye.
  • the amount of the crosslinked polymer-containing liquid to be injected is preferably 5 to 15%, more preferably 1.0%, of the aqueous humor of the animal to be injected.
  • the amount to be injected differs depending on the animal to be injected.
  • the amount of aqueous humor is 200 1 ⁇ , so that 10 to 30 L is preferable, and about 20 L is particularly preferable.
  • the amount of aqueous humor is 100 / zL, so that it is preferably 5 to 15 L, particularly preferably 10 L.
  • the model animal used in the present invention can be bred under the same general breeding conditions as the breeding conditions before the injection of the liquid containing the crosslinked polymer.
  • Screening of a therapeutic agent for glaucoma using the model animal of the present invention is performed by administering a test agent to a model animal and determining whether a decrease in intraocular pressure is observed or a decrease in retinal ganglion cells is suppressed. To do. BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a graph showing the relationship between RGC and AUC in a cross-linked CVP-injected ⁇ sagi ocular hypertension model.
  • the injection solution was injected at 2 O L using a micro syringe connected to a 30 G injection needle.
  • the eyeball was paraffin-embedded using an embedding device, and four 3-thick sections were prepared using a microtome along a vertical line passing through the optic papilla and attached to a slide glass.
  • the number of cells in the retinal ganglion cell layer on the photograph was counted, and the number of cells per 1 mm of the retina was calculated.
  • the same treatment was carried out using a separately prepared untreated egret eyeball (normal eye), and the number of cells per lmm of the retina was calculated.
  • the area under the curve (hereinafter abbreviated as AUC) and the maximum intraocular pressure were calculated from the measured intraocular pressure, and the correlation between the number of cells in the ganglion cell layer and AUC was examined.
  • Intraocular pressure measurement results in a cross-linked CVP-injected ⁇ heron ocular hypertension model.
  • the injection of cross-linked CVP increased intraocular pressure, which lasted 28 days after injection compared to the contralateral eye.
  • the average intraocular pressure up to 28 days after injection was 35.2 mmHg, and the maximum intraocular pressure (average of the maximum intraocular pressure of each individual) was 65. OmmHg.
  • Table 2 shows the number of retinal ganglion cells. The number of cells in the ganglion cell layer is
  • Fig. 1 shows the correlation between the number of cells in the ganglion cell layer (hereinafter abbreviated as RGC) and .AUC. AUC showed a good correlation with ganglion cell loss, indicating that ganglion cell death was dependent on sustained increases in intraocular pressure.
  • RGC ganglion cell layer
  • the value of eyes with cross-linked CVP is the average of 9 eyes
  • Intraocular pressure measurement results in cross-linked PVA-injected ⁇ heron ocular hypertension model The injection of cross-linked PVA increased intraocular pressure, which persisted for 11 days after injection compared to the contralateral eye. After injection The average intraocular pressure up to 11 days was 40.9 mmHg, and the maximum intraocular pressure (average of the maximum intraocular pressure of each individual) was 55. OmmHg.
  • high intraocular pressure can be induced by injecting a bridge polymer-containing solution of about 10% of the aqueous humor into the anterior chamber of an experimental animal without replacing aqueous humor. Therefore, the procedure for preparing an experimental animal can be simplified and the irritation to the animal can be reduced.
  • the screening method for a glaucoma drug using this model animal is a useful tool in the development of a glaucoma drug. .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Cell Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Toxicology (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur un procédé pharmacologique de criblage de remèdes contre le glaucome au moyen d'un animal d'expérience chez lequel on a provoqué de l'hypertension oculaire et des lésions du nerf optique par injection dans le protomérite d'une solution contenant un polymère réticulé, de préférence de carboxyvinyle ou d'alcool de polyvinyle, à raison de 10 % de l'humeur aqueuse et sans remplacer cette dernière. On peut ainsi élaborer par une procédure simplifiée réduisant le stimulus de l'animal, un animal d'expérience utile pour le développement de remèdes contre le glaucome.
PCT/JP2002/008789 2001-08-30 2002-08-30 Procede de criblage de remedes contre le glaucome WO2003028442A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2001-260809 2001-08-30
JP2001260809 2001-08-30

Publications (1)

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WO2003028442A1 true WO2003028442A1 (fr) 2003-04-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113273546A (zh) * 2021-02-25 2021-08-20 中南大学 聚桂醇在制备慢性高眼压动物模型中的应用及动物模型

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002112664A (ja) * 2000-10-04 2002-04-16 Koken Co Ltd 緑内障モデル動物の作成方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002112664A (ja) * 2000-10-04 2002-04-16 Koken Co Ltd 緑内障モデル動物の作成方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DONG M. ET AL., AUSTRALIAN AND NEW ZEALAND JOURNAL OF OPHTHALMOLOGY, vol. 20, no. 3, 1992, pages 225 - 234, XP002961343 *
KAREL I. ET AL., GRAEFE'S ARCH. CLIN. EXP. OPHTHALMOL., vol. 235, 1997, pages 186 - 189, XP002961342 *
UEDA J. ET AL., JPN. J. OPHTHALMOL., vol. 42, 1998, pages 337 - 344, XP002961344 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113273546A (zh) * 2021-02-25 2021-08-20 中南大学 聚桂醇在制备慢性高眼压动物模型中的应用及动物模型

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