WO2016199871A1 - 神経麻痺性角膜症の治療薬 - Google Patents
神経麻痺性角膜症の治療薬 Download PDFInfo
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- WO2016199871A1 WO2016199871A1 PCT/JP2016/067288 JP2016067288W WO2016199871A1 WO 2016199871 A1 WO2016199871 A1 WO 2016199871A1 JP 2016067288 W JP2016067288 W JP 2016067288W WO 2016199871 A1 WO2016199871 A1 WO 2016199871A1
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- corneal
- keratopathy
- neuroparalytic
- therapeutic agent
- diabetes
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- 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 therapeutic agent for neuroparalytic keratopathy, and relates to a novel pharmaceutical use of a PPAR (Peroxisome Proliferator-Activated Receptor) ⁇ agonist as a therapeutic agent for neuroparalytic keratopathy.
- PPAR Peroxisome Proliferator-Activated Receptor
- PPAR is a kind of nuclear receptor expressed in most vertebrates, and is considered to be a group of transcription factors closely related to intracellular sugar / lipid metabolism and cell differentiation. As subtypes, ⁇ , ⁇ , and ⁇ types are known. Note that PPAR ⁇ may be expressed as PPAR ⁇ (Non-Patent Document 1). As for the distribution of PPAR in the eye tissue, it is known that PPAR ⁇ and ⁇ are expressed in rabbit corneal epithelial cells (Non-patent Document 2).
- PPAR ⁇ is known to be distributed in the liver, kidney, etc., and to act on lipid metabolism and transport, and it has also been reported that its agonist can be used as a therapeutic agent for corneal diseases (Patent Document 4).
- Patent Document 4 Regarding PPAR ⁇ agonists, there have been reports on promoting proliferation and differentiation of rat sebaceous gland epithelial cells (Non-patent Document 3) and promoting skin wound healing (Non-patent Document 4).
- Patent Document 5 a method of stimulating the proliferation of ⁇ -cells by administering a non-thiazolidinedione PPAR ligand and a GLP-1 derivative
- Patent Document 6 PPAR ⁇ agonist pioglitazone promotes proliferation of leukemia cells, prostate cancer cells and the like. Inhibiting (Patent Document 6) is known.
- a specific PPAR ⁇ agonist has a corneal epithelial cell proliferation promoting action, and is associated with corneal epithelial disorder and various diseases: Sjogren's syndrome, Stevens-Johnson syndrome, dry eye syndrome (dry) Corneal epithelial disorder associated with endogenous diseases such as eye); postoperative, drug-related, trauma, corneal ulcer, meibomian adenitis, corneal epithelial disorder associated with extrinsic diseases such as wearing contact lenses; spring catarrh, atopic keratoconjunctivitis, etc.
- Patent Document 7 has been found to be useful in the treatment of corneal epithelial disorders associated with ocular allergic diseases with corneal lesions (Patent Document 7).
- Patent Document 7 does not suggest that the PPAR ⁇ agonist has an effect of improving the decrease in corneal perception, and as a result, can be used as a therapeutic agent for neuroparalytic keratopathy.
- Japanese Patent No. 4216266 JP 2006-304611 A Japanese Patent No. 3756313 Japanese Patent No. 4731324 Japanese Patent No. 4383178 Japanese Patent No. 5030998 Japanese Patent No. 5247686 (International Publication No. 2008/143254)
- the problem to be solved by the present invention is to provide a new medical use of a PPAR ⁇ agonist in the ophthalmic field.
- the present invention includes at least the following contents.
- [1] [3- [2- [4-Isopropyl-2- (4-trifluoromethyl) phenyl-5-thiazolyl] ethyl] -5-methyl-1,2-benzisoxazol-6-yl] oxy
- a therapeutic agent for neuroparalytic keratopathy containing acetic acid or a pharmacologically acceptable salt thereof.
- the therapeutic agent according to [1] wherein the neuroparalytic keratopathy is neuroparalytic keratopathy due to diabetes.
- An agent for improving a decrease in corneal sensitivity comprising acetic acid or a pharmacologically acceptable salt thereof.
- the improving agent according to [4] which is for ophthalmic use.
- [5] [3- [2- [4-Isopropyl-2- (4-trifluoromethyl) phenyl-5-thiazolyl] ethyl] -5-methyl- for producing a therapeutic agent for neuroparalytic keratopathy Use of 1,2-benzisoxazol-6-yl] oxyacetic acid or a pharmaceutically acceptable salt thereof.
- [6] The use according to [5], wherein the neuroparalytic keratopathy is neuroparalytic keratopathy due to diabetes.
- [7] The use according to [6], wherein the neuroparalytic keratopathy caused by diabetes is diabetic keratopathy.
- a method of treating neuroparalytic keratopathy comprising administering an effective amount of 1,2-benzisoxazol-6-yl] oxyacetic acid or a pharmaceutically acceptable salt thereof.
- the method according to [9] wherein the neuroparalytic keratopathy is neuroparalytic keratopathy due to diabetes.
- the neuroparalytic keratopathy caused by diabetes is diabetic keratopathy.
- Targets that need to improve the reduction in corneal perception include [3- [2- [4-isopropyl-2- (4-trifluoromethyl) phenyl-5-thiazolyl] ethyl] -5-methyl-1 , 2-benzisoxazol-6-yl] oxyacetic acid or a pharmacologically acceptable salt thereof, a method for improving a decrease in corneal sensitivity.
- [13] [3- [2- [4-Isopropyl-2- (4-trifluoromethyl) phenyl-5-thiazolyl] ethyl] -5-methyl-1,2-benzisoxazol-6-yl] oxy
- the therapeutic agent according to [13] wherein the corneal neuropathy is a disorder caused by diabetes.
- the therapeutic agent according to [13] or [13-1] which is for ophthalmic use.
- Neuroparalytic keratopathy is a corneal disease caused by damage, degeneration, paralysis, or other damage to the corneal nerve that governs corneal perception, and decreases corneal perception, corneal epithelial cell damage, and wounds Delayed healing is clinical findings.
- the active ingredient according to the present invention has an action of improving the decrease in corneal perception, it is extremely useful as a therapeutic agent for neuroparalytic keratopathy.
- causes of neuroparalytic keratopathy and corneal hyposensitivity include herpes keratitis, surgical trauma, etc., and keratosis as a diabetic complication, especially for the treatment of diabetic keratopathy. Since it is important not only to proliferate corneal epithelial cells but also to improve corneal hyposensitivity, the medicament of the present invention is useful as a therapeutic agent for diabetic keratopathy.
- FIG. 1 shows an outline of the production of a rabbit cornea flap and the measurement position (1-4) of cornea perception.
- FIG. 2 is a graph of corneal perception at the measurement position 1 after making the corneal flap.
- FIG. 3 is a graph of corneal perception at the measurement position 2 after the corneal flap is produced.
- the present invention relates to [3- [2- [4-isopropyl-2- (4-trifluoromethyl) phenyl-5-thiazolyl] ethyl] -5-methyl-1,2-benzisoxazol-6-yl].
- a therapeutic agent for neuroparalytic keratosis an agent for reducing corneal sensitivity, comprising oxyacetic acid or a pharmacologically acceptable salt thereof (hereinafter collectively referred to as “the compound of the present invention”) as an active ingredient
- the compound of the present invention comprising oxyacetic acid or a pharmacologically acceptable salt thereof (hereinafter collectively referred to as “the compound of the present invention”) as an active ingredient
- the compound of the present invention A therapeutic agent for diabetic keratopathy and a therapeutic agent for corneal neuropathy are provided.
- the “neuroparalytic keratopathy” in the present invention is a corneal disease caused by damage, degeneration, paralysis, or the like of a corneal nerve that controls corneal perception, Clinical findings are cell damage and delayed wound healing.
- the “decreased corneal perception” in the present invention refers to a state in which the perception of the corneal nerve is reduced due to damage, degeneration or paralysis of the corneal nerve.
- the “corneal nerve” in the present invention is controlled by the trigeminal nerve, which is a sensory nerve, and is formed immediately below the Bowman's membrane, the plexus plexus formed around the cornea, the intraparenchymal plexus distributed in a mesh form in the corneal stroma. This refers to the subepithelial plexus, the basal cell plexus and nerve fibers that are formed when the Bowman membrane is penetrated.
- “Treatment” in the present invention is a concept that includes not only improvement of symptoms, delay of progression, prevention of severity but also prevention. Prevention refers to suppressing or delaying the onset of symptoms. Specifically, the corneal nerve is damaged, degenerated, or paralyzed due to various causes, resulting in decreased corneal perception, corneal epithelial cell damage. “Neuroparalytic keratopathy”, which has a clinical finding of disorder and wound healing, means to suppress or delay the onset of clinical findings by restoring the disorder of the corneal nerve. Specifically, prevention of “neuroparalytic keratopathy” refers to the suppression of the onset of clinical findings by administering the compound of the present application to a subject having various causes before the clinical findings are manifested. Means delay. Various causes include diabetes, aging, corneal transplantation, eye surgery, contact lens wearing, corneal herpes, trigeminal nerve palsy and the like.
- the degree of corneal epithelial disorder can be confirmed by observing the corneal epithelium stained with fluorescein using a slit lamp and using AD classification (clinical eyelid 1994, 48, 183-188).
- the degree of decrease in corneal perception can be confirmed by measuring the perception at a specific measurement point on the corneal surface using a Kosch-Bonnet corneal sensor (manufactured by LUNEAU). Since corneal perception decreases with aging, for example, it is not possible to accurately define a normal human value, but it is important to define the measurement point and compare the left and right eyes.
- the compound of the present invention Since the compound of the present invention has an effect of promoting improvement in corneal perception reduction, it is useful for the treatment of neuroparalytic keratopathy.
- the compounds of the present invention are particularly caused by diabetes accompanied by corneal nerve damage, degeneration or paralysis. It is useful for the treatment of neuroparalytic keratopathy, as well as diabetic keratopathy.
- the compound of the present invention since the compound of the present invention has an effect of recovering damaged nerves, it is useful for preventing corneal epithelial disorders caused by neuropathy, particularly diabetic keratopathy.
- the compound of the present invention Since the compound of the present invention has an effect of recovering corneal nerve damage, it is useful for the treatment of corneal nerve damage.
- causes of corneal neuropathy include diabetes, aging, corneal transplantation, eye surgery, contact lens wear, corneal herpes, trigeminal nerve palsy and the like. Among them, it is useful for treating corneal neuropathy caused by diabetes.
- Pharmacologically acceptable salts of the above compounds include alkali metals such as sodium and potassium; metal salts with alkaline earth metals such as calcium and magnesium. Moreover, the solvate is also contained in the compound of this invention.
- the PPAR ⁇ agonist refers to a substance that binds to the ligand binding domain (LBD) of PPAR ⁇ , activates the receptor, and regulates the transcription of the PPAR target gene.
- PPAR ⁇ agonistic activity is determined by a yeast two-hybrid method using a chimeric receptor of LBD and yeast GAL4 and a reporter gene in order to exclude the influence of other nuclear receptors endogenous to mammalian cells. Can be measured.
- the compound of the present invention can be synthesized according to the description in International Publication No. 2003/033493 pamphlet (particularly Example 5). *
- the medicament of the present invention can contain any carrier in addition to the above active ingredients.
- carriers include solvents (eg, water, alcohol, etc.), buffering agents (eg, phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamic acid). , Epsilon aminocaproic acid, etc.), preservatives (eg benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, paraoxybenzoates, sodium edetate, boric acid, etc.), etc.
- examples include tonicity agents (for example, sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, glucose, propylene glycol and the like).
- Examples of the administration target of the medicament of the present invention include mammals (eg, human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, etc.).
- mammals eg, human, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, etc.
- the medicament of the present invention is used in dosage forms such as eye drops, patches, ointments, lotions, creams, oral preparations and the like, and includes any carrier, for example, a pharmaceutically acceptable carrier, in addition to the above active ingredients. be able to.
- the route of administration of the medicament of the present invention is not particularly limited as long as it exhibits the above therapeutic effect, but is preferably administered locally to the eye.
- Examples of the dosage form for topical ocular administration include eye drops and eye ointments.
- a stabilizer for example, sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutylhydroxytoluene, etc.
- a solubilizing agent for example, glycerin, propylene glycol, macrogol, polyoxyethylene hydrogenated castor oil, etc.
- suspending agents for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxymethylcellulose, sodium carboxymethylcellulose, etc.
- emulsifiers for example, polyvinylpyrrolidone, Soybean lecithin, egg yolk lecithin, polyoxyethylene hydrogenated castor
- Tonicity agents eg, sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, glucose, prop Pyrene glycol, etc.
- pH adjusters eg, hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, etc.
- cooling agents eg, l-menthol, d-camphor, d-borneol, mint oil, etc.
- ointment bases For example, white petrolatum, refined lanolin, liquid paraffin, vegetable oil (olive oil, camellia oil, peanut oil, etc.), etc.
- white petrolatum, refined lanolin, liquid paraffin, vegetable oil (olive oil, camellia oil, peanut oil, etc.), etc. can be added as additives.
- the addition amount of these additives varies depending on the type and use of the additive, but may be added so that the concentration can achieve the purpose of the additive.
- the medicament of the present invention is an eye drop or eye ointment, it may be produced according to a method commonly used in the pharmaceutical field. For example, the 16th revised Japanese Pharmacopoeia, General Rules for Preparations, Eye Drops, It can manufacture based on the method described in the item.
- eye drops includes aqueous eye drops (aqueous eye drops, aqueous suspension eye drops, viscous eye drops, etc.), non-aqueous eye drops (non-aqueous eye drops, non-aqueous suspension eye drops, etc.) or emulsion eye drops. Can be mentioned.
- the pH of the eye drop is appropriately set depending on the form of the eye drop, but is usually in the range of 4 to 8.
- the pH is particularly preferably set to 6 to 8 from the viewpoint of solubility of the active ingredient.
- Eye drops are usually preparations sterilized by methods such as filtration sterilization, irradiation sterilization (for example, electron beam sterilization, UV sterilization, gamma ray sterilization), autoclave sterilization, and dry heat sterilization.
- irradiation sterilization for example, electron beam sterilization, UV sterilization, gamma ray sterilization
- autoclave sterilization for example, autoclave sterilization
- dry heat sterilization for example, filtration sterilization sterilization, irradiation sterilization (for example, electron beam sterilization, UV sterilization, gamma ray sterilization), autoclave sterilization, and dry heat sterilization.
- the liquid When formulated as an eye drop, the liquid is preferably contained in an eye drop container having a small-diameter injection hole capable of controlling the amount of liquid droplets for facilitating the dropping to the eye.
- the container is made of synthetic resin, glass, cellulose, pulp, or the like, and is appropriately selected depending on the properties and amount of the active ingredient and base. From the viewpoint of squeeze property and durability, the container is preferably made of a synthetic resin. Specific materials for the synthetic resin include polyethylene resin (for example, low density polyethylene or high density polyethylene), polypropylene resin, ethylene-propylene copolymer resin, polyethylene terephthalate resin, and the like.
- the eye drop container examples include a container in which a separately molded container body and an inner plug member are fitted, and an integrally formed filling container (for example, WO2004 / 006826) in which a liquid agent is hermetically filled simultaneously with the molding of the container. .
- an integrally molded filling container is adopted, the container and the liquid agent are produced in one part, so that cost and hygiene are excellent.
- the eye drop container may be a unit dose type container (for example, JP-A-9-207959) that is disposable once. When this container is employed, it is possible to formulate a preparation that is highly safe for the cornea and does not contain a preservative.
- these containers may be tightly packaged with an ultraviolet blocking film. Further, the container may be colored (brown, green, blue, yellow, etc.) in order to enhance the ultraviolet blocking property.
- the present invention relates to a method for treating neuroparalytic keratopathy or diabetic keratopathy, comprising administering an effective amount of the compound of the present invention to a subject in need of treatment for neuroparalytic keratopathy or diabetic keratopathy.
- I will provide a.
- the present invention relates to a neuroparalytic cornea comprising administering an effective amount of a compound of the present invention to a subject at risk of or expected to suffer from neuroparalytic keratopathy or diabetic keratopathy.
- a subject at risk of or expected to suffer from neuroparalytic keratopathy or diabetic keratopathy.
- the disease or diabetic keratopathy is provided.
- the subject include subjects suffering from diabetes and subjects having risk factors such as corneal herpes, contact lens wearing, eye surgery, and aging.
- the present invention comprises administering an effective amount of a compound of the present invention to a subject in need of improvement in the decrease in corneal sensitivity. Provide a way to improve perceptual decline.
- the present invention provides a method for preventing a decrease in corneal sensitivity, comprising administering an effective amount of a compound of the present invention to a subject at risk of or expected to decrease the corneal sensitivity.
- a subject examples include a subject suffering from diabetes.
- the present invention provides a method for treating corneal neuropathy, comprising administering an effective amount of the compound of the present invention to a subject in need of treatment for corneal neuropathy.
- the effective amount of the compound of the present invention cannot be generally defined depending on the age, weight, condition, therapeutic purpose, etc. of the administration subject, but when administering the pharmaceutical of the present invention to humans, it is usually 0.0001 to 0.1 w / v%, preferably 0.001 to 0.01 w / v%, most preferably 0.005 w / v% of a solution containing a compound of the invention 3 to 4 times a day, 1 per eye per eye An amount of ⁇ 2 drops, that is, about 10 to 100 ⁇ L per one time is exemplified, and the amount of the compound contained in the solution within the concentration and volume range can be exemplified as an effective amount.
- Test Example 1 Effect of compound A on rabbit cornea perception reduction 1.
- Animals used Male Japanese white rabbits (weight 2.80-3.32 kg) purchased from Kitayama Labes were used. The animals were kept in the breeding room set at room temperature 23 ° C ⁇ 3 ° C, humidity 55% ⁇ 10% RH, and 12-hour lighting (08:00 on, 20:00 off) from the arrival to the end of the test. Animals were fed 100-120 g of solid feed (Lab R Stock, Nippon Agricultural Industry) daily, and the city water passed through the animal beverage sterilizer was freely ingested by the automatic water feeder. The test shall be approved by the Animal Experimentation Ethics Committee based on the Act on the Protection and Control of Animals (Law No. 105, October 1, 1973, final revision: Law No. 38, June 12, 2013). Received and implemented.
- Test substance As a test substance, [3- [2- [4-isopropyl-2- (4-trifluoromethyl) phenyl-5-thiazolyl] ethyl] -5-methyl-1,2-benzisoxazole- 6-yl] oxyacetic acid (hereinafter referred to as Compound A) was used. Compound A dissolved in the base shown in Table 1 so as to be 0.005% was used as an ophthalmic solution. Moreover, the base ophthalmic solution which consists only of bases (Table 1) which does not contain the compound A was used as a control group. The corneal sensory measurer encoded the ophthalmic solution label so that the rabbit to be measured did not know which ophthalmic solution was administered (single-blind method).
- 3.Test method 1 Grouping Before corneal flap preparation, the rabbit's anterior eye was observed with the naked eye, and rabbits with no abnormalities were selected. Next, using a Koche-Bonnet corneal sensor (manufactured by LUNEAU), measure the corneal sensitivity at measurement positions 1 and 2 in FIG. 1, and select a rabbit whose corneal sensitivity threshold at measurement positions 1 and 2 is 15 mm or more. Selected. Sixteen selected rabbits were assigned to two groups of Compound A ophthalmic solution administration group and base ophthalmic solution administration group so that the cornea perception threshold of each group was uniform.
- a Koche-Bonnet corneal sensor manufactured by LUNEAU
- a corneal flap having a thickness of 130 ⁇ m and a diameter of 8.6 mm was prepared using a microkeratome (MK-2000, manufactured by Nidec Corp.). After repositioning the flap under a surgical microscope, the rabbit was laid down with the surgical site up until anesthesia and awakening. After awakening, 0.3% gatifloxacin ophthalmic solution (Gatiflo ophthalmic solution (registered trademark), Senju Pharmaceutical) was administered by eye drops. 3) Administration The day after flap preparation, Compound A ophthalmic solution or base ophthalmic solution was applied to rabbits who did not have flap detachment or corneal infection, nor perceived at any of measurement positions 1 to 4 (Fig. 1). Was instilled for 17 days.
- Eye drops are administered 4 times a day with an interval of 2 hours or longer (however, the next day, 14 days, 16 days and 21 days after surgery, twice a day, and 4 days after surgery 3 times a day). Instilled with a micropipette, 50 ⁇ L at a time. 1, 2, 4, 5 and 6 days after the operation, 0.3% gatifloxacin ophthalmic solution was instilled into the treated eye at least 10 minutes before administration of Compound A ophthalmic solution or base ophthalmic solution. 4) Corneal perception measurement Using the Kosch-Bonnet cornea perception meter, the cornea perception at the measurement positions 1 and 2 (Fig. 1) was measured on the day after the flap was produced, and 1, 2, 3 and 4 weeks after production.
- the animals were kept in the breeding room set at room temperature 23 ° C ⁇ 3 ° C, humidity 55% ⁇ 10% RH, and 12-hour lighting (08:00 on, 20:00 off) from the arrival to the end of the test.
- Animals were allowed to ingest solid feed (Lab MR Stock, Nippon Agricultural Industry) freely, and city water through an animal beverage sterilizer was freely ingested by an automatic water feeder.
- the test shall be approved by the Animal Experimentation Ethics Committee based on the Act on the Protection and Control of Animals (Law No. 105, October 1, 1973, final revision: Law No. 38, June 12, 2013). Received and implemented.
- Test substance Compound A was used as a test substance. Compound A dissolved in the base (Table 2) so as to be 0.005% was used as an ophthalmic solution. Moreover, the base ophthalmic solution which consists only of bases (Table 2) which does not contain the compound A was used as a control group.
- Observation of corneal epithelial disorder The degree of corneal epithelial disorder was determined by administering 5 ⁇ L of 0.1% sodium fluorescein (Wako Pure Chemical Industries) and observing fluorescein staining of the corneal epithelium using a slit lamp. In order to show the degree of abnormal findings in detail, one item was added to the criteria for the McDonald-Shadduck method, and this was used as the criteria for the test (Table 3). The score of corneal epithelial disorder was scored for each of the upper, middle, and lower areas, and the scores for the three areas were combined. Observation of corneal epithelial injury was performed 2, 4, 6, 8, 11, and 15 days after instillation.
- Diabetic keratopathy is a disease involving a decrease in corneal perception with the background of diabetes.
- substance P-positive nerve fibers ii) presence of substance P or substance P metabolites in tears even in healthy subjects
- substance P acts as a neurotrophic factor for corneal epithelial cells because substance P in the medium is decreased.
- substance P a neurotransmitter of the sensory nervous system, promotes corneal epithelial wound healing in cooperation with growth factors (Takeo Nishida, Corneal Text, page 164, March 30, 2010) Issued by Elsevier Japan).
- Compound A improves the decrease in corneal perception and promotes the secretion of neurotrophic factor, so that it is a diabetic that is a typical example of corneal epithelial disorder accompanied by corneal nerve damage, degeneration or paralysis. Particularly useful for keratopathy.
- the medicament of the present invention has an effect of improving the decrease in corneal sensitivity, it is useful as a therapeutic agent for neuroparalytic keratopathy and a therapeutic agent for diabetic keratopathy, which is a complication of diabetes.
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Abstract
Description
PPARの眼組織における分布としては、PPARα及びβがウサギの角膜上皮細胞に発現していることが知られている(非特許文献2)。
これまでに、主としてPPARγ活性化作用を有すると考えられる5-[4-(6-メトキシ-1-メチル-1H-ベンゾイミダゾール-2-イルメトキシ)ベンジル]チアゾリジン-2,4-ジオンが、角結膜障害の治療剤として利用できること(特許文献1及び2)、眼疾患(結膜炎、ドライアイ症候群、角膜炎等)の治療においてPPARα、δ又はγアゴニストが投与されること(特許文献3)が報告されている。また、PPARαに関しては、肝臓、腎臓などに分布し、脂質代謝・輸送に作用することが知られており、さらに、そのアゴニストが角膜疾患の治療剤として利用できることも報告されている(特許文献4)。PPARδアゴニストについては、これまで、ラット皮脂腺上皮細胞の増殖及び分化を促進すること(非特許文献3)、皮膚の創傷治癒を促進すること(非特許文献4)についての報告がある。その他にも、非チアゾリジンジオンPPARリガンドとGLP-1誘導体を投与することによりβ-細胞の増殖を刺激する方法(特許文献5)、PPARγアゴニストであるピオグリタゾンが白血病細胞や前立腺癌細胞などの増殖を阻害すること(特許文献6)などが知られている。
本発明者らは、特定のPPARδアゴニストが、角膜上皮細胞の増殖促進作用を有し、角膜上皮障害及び種々の疾患に伴う角膜上皮障害:シェーグレン症候群、スティーブンス・ジョンソン症候群、眼球乾燥症候群(ドライアイ)等の内因性疾患に伴う角膜上皮障害;術後、薬剤性、外傷、角膜潰瘍、マイボーム腺炎、コンタクトレンズ装用等における外因性疾患に伴う角膜上皮障害;春季カタルやアトピー性角結膜炎等の角膜病変を伴う眼アレルギー性疾患に伴う角膜上皮障害の治療に有用であることを見出している(特許文献7)。しかし、特許文献7には、PPARδアゴニストが角膜知覚低下の改善作用を有すること、その結果、神経麻痺性角膜症の治療剤としての利用が可能であることの示唆はされていない。
したがって、本発明は以下の内容を少なくとも含む。
〔1〕 [3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩を含有する神経麻痺性角膜症の治療剤。
〔2〕 神経麻痺性角膜症が糖尿病に起因する神経麻痺性角膜症である、〔1〕に記載の治療剤。
〔3〕 糖尿病に起因する神経麻痺性角膜症が糖尿病性角膜症である、〔2〕に記載の治療剤。
〔3-1〕 眼局所用である[1]~〔3〕に記載の治療剤。
〔4〕 [3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩を含有する角膜知覚低下の改善剤。
〔4-1〕 眼局所用である[4]に記載の改善剤。
〔5〕 神経麻痺性角膜症の治療剤を製造するための、[3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩の使用。
〔6〕 神経麻痺性角膜症が糖尿病に起因する神経麻痺性角膜症である、〔5〕に記載の使用。
〔7〕 糖尿病に起因する神経麻痺性角膜症が糖尿病性角膜症である、〔6〕に記載の使用。
〔8〕 角膜知覚低下の改善剤を製造するための、[3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩の使用。
〔9〕 神経麻痺性角膜症の治療を必要とする対象に、[3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩の有効量を投与することを含む、神経麻痺性角膜症を治療する方法。
〔10〕 神経麻痺性角膜症が糖尿病に起因する神経麻痺性角膜症である、〔9〕に記載の方法。
〔11〕 糖尿病に起因する神経麻痺性角膜症が糖尿病性角膜症である、〔10〕に記載の方法。
〔12〕 角膜知覚の低下の改善を必要とする対象に、[3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩の有効量を投与することを含む、角膜知覚の低下を改善する方法。
〔13〕 [3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩を含有する角膜神経障害の治療剤。
〔13-1〕角膜神経障害が糖尿病による障害である〔13〕に記載の治療剤。
〔13-2〕 眼局所用である〔13〕又は〔13-1〕に記載の治療剤。
本発明における「角膜知覚の低下」とは、角膜神経が損傷、変性又は麻痺により角膜神経の知覚が低下した状態をいう。
本発明における「角膜神経」とは、知覚神経である三叉神経の支配を受け、角膜周囲に形成される輪状神経叢、角膜実質に網目状に分布する実質内神経叢、ボーマン膜直下で形成される上皮下神経叢、ボーマン膜を貫通したところで形成される基底細胞神経叢および神経線維をいう。
具体的には、「神経麻痺性角膜症」の予防とは、上記臨床所見が顕在化する前に、種々の原因を有する対象に本願の化合物を投与することにより、臨床所見の発症を抑制又は遅延させることを意味する。
種々の原因としては、糖尿病、加齢、角膜移植、眼手術、コンタクトレンズ装用、角膜ヘルペス、三叉神経麻痺などが挙げられる。
角膜神経障害の原因としては、糖尿病、加齢、角膜移植、眼手術、コンタクトレンズ装用、角膜ヘルペス、三叉神経麻痺などが挙げられる。なかでも糖尿病に起因する角膜神経障害を治療するのに有用である。
例えば、本発明の医薬を点眼剤又は眼軟膏剤として用いる場合、安定剤(例えば、亜硫酸水素ナトリウム、チオ硫酸ナトリウム、エデト酸ナトリウム、クエン酸ナトリウム、アスコルビン酸、ジブチルヒドロキシトルエン等)、溶解補助剤(例えば、グリセリン、プロピレングリコール、マクロゴール、ポリオキシエチレン硬化ヒマシ油等)、懸濁化剤(例えば、ポリビニルピロリドン、ヒドロキシプロピルメチルセルロース、ヒドロキシメチルセルロース、カルボキシメチルセルロースナトリウム等)、乳化剤(例えば、ポリビニルピロリドン、大豆レシチン、卵黄レシチン、ポリオキシエチレン硬化ヒマシ油、ポリソルベート80等)、緩衝剤(例えば、リン酸緩衝液、酢酸緩衝液、ホウ酸緩衝液、炭酸緩衝液、クエン酸緩衝液、トリス緩衝液、グルタミン酸、イプシロンアミノカプロン酸等)、粘稠剤(例えば、メチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース等の水溶性セルロース誘導体、コンドロイチン硫酸ナトリウム、ヒアルロン酸ナトリウム、カルボキシビニルポリマー、ポリビニルアルコール、ポリビニルピロリドン、マクロゴール等)、保存剤(例えば、塩化ベンザルコニウム、塩化ベンゼトニウム、グルコン酸クロルヘキシジン、クロロブタノール、ベンジルアルコール、デヒドロ酢酸ナトリウム、パラオキシ安息香酸エステル類、エデト酸ナトリウム、ホウ酸等)、等張化剤(例えば、塩化ナトリウム、塩化カリウム、グリセリン、マンニトール、ソルビトール、ホウ酸、ブドウ糖、プロピレングリコール等)、pH調整剤(例えば、塩酸、水酸化ナトリウム、リン酸、酢酸等)、清涼化剤(例えば、l-メントール、d-カンフル、d-ボルネオール、ハッカ油等)、軟膏基剤(例えば、白色ワセリン、精製ラノリン、流動パラフィン、植物油(オリーブ油、椿油、落花生油等)等)などを添加剤として加えることができる。これら添加剤の添加量は、添加剤の種類、用途などによって異なるが、添加剤の目的を達成し得る濃度となるように添加すればよい。
本発明の医薬を点眼剤又は眼軟膏剤とする場合、製剤分野で通常用いられている方法に従って製造すればよく、例えば第16改正日本薬局方、製剤総則、点眼剤の項及び眼軟膏剤の項に記載された方法に基づき製造することができる。
ウサギ角膜知覚低下に対する化合物Aの効果
1.使用動物
北山ラベスより購入した雄性日本白色種ウサギ(体重2.80~3.32 kg)を使用した。動物は入荷後から試験終了日まで、室温23℃ ± 3℃、湿度55% ± 10% RH、12時間照明(08:00点灯、20:00消灯)に設定された飼育室内で飼育した。動物には固型飼料(ラボRストック、日本農産工業)を1日100~120 g与え、動物飲料滅菌装置を通した市水を自動給水装置により自由に摂取させた。当該試験は、動物の愛護及び管理に関する法律(昭和48年10月1日法律第105号、最終改正:平成25年6月12日法律第38号)等に基づく動物実験倫理委員会の承認を受けて実施した。
被験物質として、[3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸(以下、化合物Aと称する)を用いた。化合物Aは、0.005%となるように表1に示す基剤に溶解したものを点眼液として使用した。また、対照群として化合物Aを含まない基剤(表1)のみからなる基剤点眼液を用いた。なお、角膜知覚測定者には、測定するウサギがいずれの点眼液を投与しているのかわからないように点眼液のラベルを暗号化した(単盲検法)。
1)群分け
角膜フラップ作製前にウサギの前眼部を肉眼観察し、異常を認めないウサギを選定した。次に、コシュ・ボネ角膜知覚計(LUNEAU社製)を用いて、図1の測定位置1及び2の角膜知覚を測定し、測定位置1及び2の角膜知覚閾値が共に15 mm以上のウサギを選定した。選定されたウサギ16匹を各群の角膜知覚閾値が均一になるように、化合物A点眼液投与群及び基剤点眼液投与群の2群に8匹ずつ割り付けた。
2)角膜フラップの作製
キシラジン塩酸塩注射液(セラクタール2%注射液(登録商標)、バイエル薬品)とケタミン塩酸塩注射液(ケタラール筋注用500 mg(登録商標)、第一三共)の1:2混合液(0.9mL/kg)の筋肉内注射によりウサギに全身麻酔を施した後、0.4%オキシブプロカイン塩酸塩点眼液(ベノキシール点眼液0.4%(登録商標)、参天製薬)を用いて局所麻酔を施した。眼球を充分に露出させた後、マイクロケラトーム(MK-2000、ニデック社製)を用いて、130μm厚で直径8.6 mmの角膜フラップを作製した。手術顕微鏡下でフラップを復位させた後、麻酔から覚醒するまでの間、術部を上にしてウサギを横臥させた。覚醒後、0.3%ガチフロキサシン点眼液(ガチフロ点眼液(登録商標)、千寿製薬)を点眼投与した。
3)投与
フラップ作製翌日、フラップの剥離や角膜の感染症を認めず、また測定位置1~4(図1)のいずれの位置でも知覚を認めないウサギに、化合物A点眼液又は基剤点眼液を17日間点眼投与した。点眼投与は2時間以上の間隔をあけて1日4回(ただし、術翌日、術14、16及び21日後は1日2回、術4日後は1日3回とした。)、それぞれ処置眼に対して1回50μLずつ、マイクロピペットを用いて点眼した。術1、2、4、5及び6日後、化合物A点眼液又は基剤点眼液の点眼投与10分以上前に、0.3%ガチフロキサシン点眼液を処置眼に点眼投与した。
4)角膜知覚測定
コシュ・ボネ角膜知覚計を用いて、フラップ作製翌日、作製1、2、3及び4週後に測定位置1及び2(図1)の角膜知覚を測定した。
試験の結果を図2及び図3に示す。化合物A点眼液投与群の知覚は、基剤点眼液投与群の知覚よりも速やかに回復した。以上のことから、化合物Aはフラップ作製によって損傷された神経の回復を促進し、神経障害に伴う角膜知覚の低下を早期に回復させることが明らかになった。
自然発症糖尿病ラット(Goto-Kakizaki(GK)ラット)に生じる角膜上皮障害に対する化合物Aの効果
1.使用動物
日本クレアから購入した雄性GKラット(Wakuta M., et al., Invest. Ophthalmol. Vis. Sci. 2007 48 590-596)を使用した(20匹)。GKラットは神経障害に伴う角膜上皮障害の所見が認められている動物である(Wang F., et al., Am J Pathol. 2012 181 2058-2066)。GKラットは、Wistarラットを起源としていることから、正常対照群としてWistarラットを使用した(7匹)。動物は入荷後から試験終了日まで、室温23℃ ± 3℃、湿度55% ± 10% RH、12時間照明(08:00点灯、20:00消灯)に設定された飼育室内で飼育した。動物には固型飼料(ラボMRストック、日本農産工業)を自由に摂取させ、また、動物飲料滅菌装置を通した市水を自動給水装置により自由に摂取させた。当該試験は、動物の愛護及び管理に関する法律(昭和48年10月1日法律第105号、最終改正:平成25年6月12日法律第38号)等に基づく動物実験倫理委員会の承認を受けて実施した。
被験物質には化合物Aを用いた。化合物Aは、0.005%となるように基剤(表2)に溶解したものを点眼液として使用した。また、対照群として化合物Aを含まない基剤(表2)のみからなる基剤点眼液を用いた。
1) 群分け
点眼投与前に測定した血中グルコース濃度の平均値及び角膜上皮障害スコアの平均値が均一になるように、統計解析ソフトウェア(SAS clinical package ver. 5.0, SAS Institute Japan)を用いて、GKラットを化合物A点眼液投与群に4匹、非投与群及び基剤点眼液投与群に8匹ずつ、3群に割り付けた。
2) 投与
化合物A点眼液又は基剤点眼液を14日間点眼投与した。点眼投与は1日4回、それぞれ両眼に対して1回10 μLずつ、マイクロピペットを用いて実施した。なお、非投与群及びWistarラットについては投与を実施しなかった。
3) 血中グルコース濃度の測定
点眼投与前にグルコースCIIテストワコー(和光純薬工業)を用いて血中グルコース濃度を測定した。
4) 角膜上皮障害の観察
0.1%フルオレセインナトリウム(和光純薬工業)を5μL点眼投与し、スリットランプを用いて角膜上皮のフルオレセイン染色を観察することにより、角膜上皮障害の程度を判定した。異常所見の程度を詳細に示すため、McDonald-Shadduck法の判定基準に1項目追加し、これを当該試験の判定基準とした(表3)。角膜上皮障害のスコアは上・中・下3つの領域につきそれぞれ採点し、3つの領域のスコアを合算した。角膜上皮障害の観察は点眼投与2、4、6、8、11及び15日後に実施した。
表4に示すとおり、非投与群及び基剤点眼液投与群と比較して、化合物A点眼液投与群はGKラットの角膜上皮障害を改善させることが明らかとなった。以上のことから、化合物Aは糖尿病性角膜症の治療に有用である。
Claims (12)
- [3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩を含有する神経麻痺性角膜症の治療剤。
- 神経麻痺性角膜症が糖尿病に起因する神経麻痺性角膜症である、請求項1に記載の治療剤。
- 糖尿病に起因する神経麻痺性角膜症が糖尿病性角膜症である、請求項2に記載の治療剤。
- [3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩を含有する角膜知覚低下の改善剤。
- 神経麻痺性角膜症の治療剤を製造するための、[3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩の使用。
- 神経麻痺性角膜症が糖尿病に起因する神経麻痺性角膜症である、請求項5に記載の使用。
- 糖尿病に起因する神経麻痺性角膜症が糖尿病性角膜症である、請求項6に記載の使用。
- 角膜知覚低下の改善剤を製造するための、[3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩の使用。
- 神経麻痺性角膜症の治療を必要とする対象に、[3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩の有効量を投与することを含む、神経麻痺性角膜症を治療する方法。
- 神経麻痺性角膜症が糖尿病に起因する神経麻痺性角膜症である、請求項9に記載の方法。
- 糖尿病に起因する神経麻痺性角膜症が糖尿病性角膜症である、請求項10に記載の方法。
- 角膜知覚の低下の改善を必要とする対象に、[3-[2-[4-イソプロピル-2-(4-トリフルオロメチル)フェニル-5-チアゾリル]エチル]-5-メチル-1,2-ベンズイソキサゾール-6-イル]オキシ酢酸又はその薬理学的に許容される塩の有効量を投与することを含む、角膜知覚の低下を改善する方法。
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Publication number | Priority date | Publication date | Assignee | Title |
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JPH08231549A (ja) * | 1994-12-28 | 1996-09-10 | Sanwa Kagaku Kenkyusho Co Ltd | 糖尿病性角膜症の治療剤 |
JPH11279062A (ja) * | 1998-01-30 | 1999-10-12 | Fujisawa Pharmaceut Co Ltd | 眼科用剤 |
WO2004091662A1 (ja) * | 2003-04-18 | 2004-10-28 | Senju Pharmaceutical Co. Ltd. | 角膜知覚回復剤 |
WO2008143254A1 (ja) * | 2007-05-21 | 2008-11-27 | Senju Pharmaceutical Co., Ltd. | PPARδアゴニスト含有医薬 |
-
2016
- 2016-06-09 WO PCT/JP2016/067288 patent/WO2016199871A1/ja active Application Filing
- 2016-06-09 US US15/580,979 patent/US20180177766A1/en not_active Abandoned
- 2016-06-09 EP EP16807577.8A patent/EP3308784A4/en not_active Withdrawn
- 2016-06-09 JP JP2017523703A patent/JPWO2016199871A1/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08231549A (ja) * | 1994-12-28 | 1996-09-10 | Sanwa Kagaku Kenkyusho Co Ltd | 糖尿病性角膜症の治療剤 |
JPH11279062A (ja) * | 1998-01-30 | 1999-10-12 | Fujisawa Pharmaceut Co Ltd | 眼科用剤 |
WO2004091662A1 (ja) * | 2003-04-18 | 2004-10-28 | Senju Pharmaceutical Co. Ltd. | 角膜知覚回復剤 |
WO2008143254A1 (ja) * | 2007-05-21 | 2008-11-27 | Senju Pharmaceutical Co., Ltd. | PPARδアゴニスト含有医薬 |
Non-Patent Citations (3)
Title |
---|
NAKAMURA, YOSHIKUNI ET AL.: "Function Role of PPARdelta in Corneal Epithelial Wound Healing", EPITHELIAL AND MESENCHYMAL CELL BIOLOGY, vol. 180, no. 2, 2012, pages 583 - 598, XP009507778 * |
See also references of EP3308784A4 * |
TAIICHIRO CHIKAMA: "A New Treatment for Neurotrophic Keratopathy", YAMAGUCHI MEDICAL JOURNAL, vol. 49, no. 6, 2000, pages 519 - 525, XP009507759 * |
Also Published As
Publication number | Publication date |
---|---|
US20180177766A1 (en) | 2018-06-28 |
EP3308784A4 (en) | 2019-02-06 |
JPWO2016199871A1 (ja) | 2018-03-29 |
EP3308784A1 (en) | 2018-04-18 |
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