WO2020166679A1 - Pharmaceutical composition for lowering intraocular pressure - Google Patents

Pharmaceutical composition for lowering intraocular pressure Download PDF

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Publication number
WO2020166679A1
WO2020166679A1 PCT/JP2020/005681 JP2020005681W WO2020166679A1 WO 2020166679 A1 WO2020166679 A1 WO 2020166679A1 JP 2020005681 W JP2020005681 W JP 2020005681W WO 2020166679 A1 WO2020166679 A1 WO 2020166679A1
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intraocular pressure
salt
asp8477
pharmaceutical composition
glaucoma
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PCT/JP2020/005681
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French (fr)
Japanese (ja)
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一己 林
智成 綿引
雄之 谷津
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アステラス製薬株式会社
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to a medicament for lowering intraocular pressure, particularly a pharmaceutical composition useful for preventing or treating glaucoma or ocular hypertension.
  • Glaucoma is always the top cause of blindness in Japan and is a very important social disease. Glaucoma is a disease in which the optic nerve is damaged and the visual field is narrowed, and it is said that an increase in intraocular pressure is one of the etiological factors. Optic neuropathy and visual field impairment in glaucoma are basically progressive and irreversible. Further, in glaucoma, the disorder gradually progresses without any awareness of the patient, and therefore, early detection and prevention or suppression of progression of the disorder by early treatment are important issues.
  • O Ocular hypertension is a condition in which the visual field is normal without any damage to the optic nerve, but the intraocular pressure exceeds the normal value (about 10 to 20 mmHg). It is known that when the intraocular pressure is high, the optic nerve is easily damaged and the risk of glaucoma is increased.
  • benzalkonium which is most widely used as an antiseptic for eye drops, is known to cause corneal damage after repeated eye drops over a long period of time (Ophthalmology Clinical Bulletin 2016, Vol.9, No.5, p. .423-427, new ophthalmology 2017, Vol.34, No.9, p.1263-1267).
  • acetazolamide which is the only oral intraocular pressure-lowering drug, is a carbonic anhydrase inhibitor that suppresses the production of aqueous humor and lowers intraocular pressure, but it has systemic side effects such as metabolic acidosis and hypokalemia. Yes (Glaucoma Practice Guideline, 4th Edition), not used chronically.
  • the main active ingredient of cannabis delta 9 - tetrahydrocannabinol is the intraocular pressure-lowering effect was observed is reported in glaucoma patients.
  • cannabinoid preparations have poor oral absorbability, and there are concerns about central side effects such as dependence and orthostatic hypotension (Pharmacia 2016, Vol.52, No.9, p.850- 854).
  • cannabinoid receptors type 1 and type 2 are the target molecules of THC in vivo, and anandamide (AEA) and anandamide (AEA) and 2-arachidonoylglycerol (2-AG) was discovered, and the major degrading enzymes against them were fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). It is reported that there is (Balkan Med. J. 2014, Vol.31, No.2, p.115-120).
  • Carbamic acid derivatives that inhibit FAAH activity for the treatment of diseases that may be effective by FAAH inhibition including neuropathic pain, vomiting, anxiety, altered feeding behavior, movement disorders, glaucoma, brain injury, and cardiovascular disease It is disclosed that it is useful (WO2003/065989 and WO2004/033422). However, it does not specifically disclose the effect of lowering the intraocular pressure or the effect on the treatment of glaucoma.
  • Patent Document 1 discloses a pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylic acid ester derivative having FAAH inhibitory activity, which is useful for treating frequent urination/urinary incontinence, overactive bladder and/or pain.
  • Example 173 discloses pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate (hereinafter sometimes referred to as ASP8477).
  • ASP8477 pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate
  • Patent Document 1 describes that the compound described in the present specification has an excellent FAAH inhibitory action and is useful as a therapeutic agent for many diseases including psychiatric disorders. One includes glaucoma.
  • Non-patent document 1 discloses a report on the analgesic effect of ASP8477 disclosed in Patent Document 1 (Eur. J. Pharmacol. 2017, Vol.815, p.42-48, and International Publication No. 2011/136308). Furthermore, it has been reported that a clinical test (Non-patent document 1) that verified the analgesic effect in healthy adult women and a clinical test (Non-patent document 2) in patients with neuropathic pain were conducted. .. However, there is no report to date on the effect of ASP8477 on intraocular pressure.
  • Non-Patent Document 3 Chemical name: cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester
  • Non-Patent Document 4 there is a report comparing the intraocular pressure lowering effect in rabbit eye drops between URB597 having FAAH inhibitory activity and a compound having FAAH inhibitory activity as well as a melatonin receptor agonistic action.
  • 4 compounds including URB597 showed significant intraocular pressure-lowering effect by instillation, but other 3 compounds showed no significant effect. It has been reported.
  • An object of the present invention is to provide a prophylactic or therapeutic agent for glaucoma or ocular hypertension, which has a low risk of dependence and central side effects reported for cannabinoid preparations and which can be continuously administered.
  • the present inventors have completed the present invention by finding that ASP8477 or a salt thereof has a good intraocular pressure lowering effect in humans and is useful for the prevention or treatment of glaucoma or ocular hypertension.
  • the present invention relates to a pharmaceutical composition for lowering intraocular pressure, which contains ASP8477 or a salt thereof as an active ingredient, specifically, the above-mentioned pharmaceutical composition for preventing or treating glaucoma or ocular hypertension.
  • the pharmaceutical composition containing ASP8477 or a salt thereof as an active ingredient may further contain a pharmaceutically acceptable excipient.
  • it relates to said pharmaceutical composition for oral administration.
  • the present invention also relates to the above-mentioned pharmaceutical composition for orally administering 3 to 200 mg of ASP8477 or a salt thereof per administration.
  • the present invention also relates to the above-mentioned pharmaceutical composition for oral administration of 10 to 100 mg of ASP8477 or a salt thereof per administration.
  • a method for lowering intraocular pressure comprising administering an effective amount of ASP8477 or a salt thereof to a subject, further, use of ASP8477 or a salt thereof for producing a pharmaceutical composition for lowering intraocular pressure, intraocular pressure It also relates to the use of ASP8477 or a salt thereof for lowering and a pharmaceutical composition containing ASP8477 or a salt thereof for lowering intraocular pressure.
  • a “subject” is a human (patient) or mammal animal in need of treatment, and in one embodiment, a human (patient).
  • the present invention provides a method for preventing or treating glaucoma or ocular hypertension, which comprises administering an effective amount of ASP8477 or a salt thereof to a subject, for producing a pharmaceutical composition for preventing or treating glaucoma or ocular hypertension.
  • a pharmaceutical composition containing ASP8477 or a salt thereof for the prevention or treatment of ocular hypertension is also relates to a pharmaceutical composition containing ASP8477 or a salt thereof for the prevention or treatment of ocular hypertension.
  • the pharmaceutical composition for lowering intraocular pressure of the present invention containing ASP8477 or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a preventive or therapeutic agent for glaucoma or ocular hypertension.
  • FIG. 4 is a graph showing changes in intraocular pressure in a test in which a single post-menopausal healthy adult female subject was orally administered ASP8477 in Example 1.
  • the vertical axis shows intraocular pressure (mmHg)
  • the horizontal axis shows the dose (mg) of placebo or ASP8477, the number of cases (n), and the time elapsed from administration (0, 2 and 4 h (hours)) (left eye: (I), right eye: (II)).
  • P value ⁇ 0.05 the case where there is a statistically significant difference in the amount of change from the value before administration is indicated by *.
  • Non-Patent Document 1 a clinical test in which the analgesic effect was verified in healthy adult women, It has been reported that a clinical test was conducted on patients with neuropathic pain (Non-patent Document 2).
  • the present inventors have conducted a detailed examination of the results of a phase I clinical trial conducted by oral administration of ASP8477, and since ASP8477 exhibits a good intraocular pressure lowering action, it contains ASP8477 or a salt thereof as an active ingredient. It was found that the above-mentioned pharmaceutical composition is useful as a pharmaceutical composition for lowering intraocular pressure, and thus can be used for prevention or treatment of glaucoma or ocular hypertension. Furthermore, since ASP8477 has low concern about the dependence and central side effects reported in cannabinoid preparations even after oral administration, a pharmaceutical composition for lowering intraocular pressure by systemic administration such as oral administration, and further glaucoma or ocular hypertension. It has been found to be useful as a pharmaceutical composition for the prevention or treatment of.
  • ASP8477 is due to not only good FAAH inhibitory activity but also good transferability of ASP8477 to ocular tissues. Such transferability to ocular tissues has not been observed with other compounds having FAAH inhibitory activity, for example, ASP3652 (Urology 2017, Vol. 103, p. 191-197).
  • a pharmaceutical composition containing ASP8477 or a salt thereof of the present invention as an active ingredient can be expected to have a good action of lowering intraocular pressure based on its good FAAH inhibitory activity. Since ASP8477 or a salt thereof has a good ability to migrate to ocular tissues, it has been confirmed that a good intraocular pressure-lowering effect is obtained even by oral administration, as shown in Examples below. For glaucoma, which is a chronic disease and has few subjective symptoms, the oral administration suitable for continuous administration is highly useful because the adherence of the treatment by eye drops is extremely poor. Furthermore, the oral preparation does not have a concern of corneal damage due to benzalkonium, which is added to many eye drops as a preservative. Therefore, the pharmaceutical composition for oral administration containing ASP8477 or a salt thereof of the present invention as an active ingredient is expected to be a new intraocular pressure lowering drug that can be continuously administered and is not affected by a preservative. To be done.
  • the salt of ASP8477 is a pharmaceutically acceptable salt of ASP8477, and specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid.
  • Acid formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfone
  • acids include acid addition salts with acids, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and the like, salts with various amino acids and amino acid derivatives such as acetylleucine, ammonium salts and the like.
  • no salt is formed, that is, the free form.
  • ASP8477 or a salt thereof according to the present invention includes various hydrates and solvates of ASP8477 and a salt thereof, and crystalline polymorphic substances.
  • ASP8477 or a salt thereof can be produced by the method described in Patent Document 1 or the reaction well known to those skilled in the art. As a certain aspect, it can be manufactured by the method described in Example 173 of Patent Document 1.
  • a pharmaceutical composition containing ASP8477 or a salt thereof as an active ingredient can be prepared by a commonly used method using an excipient that is usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier. It can be prepared.
  • the administration is oral administration by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intravenous and intramuscular, suppositories, eye drops, eye ointments, transdermal solutions, ointments, It may be any form of transdermal patch, transmucosal solution, transmucosal patch, parenteral administration such as inhalant.
  • the administration is oral administration or systemic administration by injection, and in one aspect, oral administration.
  • the solid composition for oral administration tablets, powders, granules and the like are used.
  • ASP8477 or a salt thereof may be combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or metasilicate. Acid mixed with magnesium aluminate etc.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, a stabilizer and a solubilizing agent according to a conventional method. If necessary, the tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and generally used inert diluents such as purified water. Or it contains ethanol.
  • the liquid composition may contain, in addition to the inert diluent, solubilizers, wetting agents, auxiliary agents such as suspending agents, sweeteners, flavors, aromatics and preservatives.
  • the injection contains a sterile aqueous or non-aqueous solution, suspension or emulsion.
  • the aqueous solvent include distilled water for injection or physiological saline.
  • the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (Pharmacopoeia).
  • Such a composition may further contain a tonicity agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • a single dose is about 0.1 to 500 mg, preferably 1 to 200 mg, more preferably 3 to 200 mg, and further preferably 10 to 150 mg in terms of free form ASP8477, Further, it is preferably 10 to 100 mg, and more preferably 10 to 30 mg, and in another embodiment, 60 mg to 100 mg is suitable, and this is administered once a day or twice to four times. It is preferably administered 1 to 3 times a day, more preferably 1 to 2 times a day, even more preferably once a day, and preferably 2 times.
  • the appropriate daily dose is about 0.0001 to 10 mg/kg of body weight, and the daily dose may be administered once or in multiple doses.
  • a transmucosal agent about 0.001 to 100 mg/kg of body weight is to be administered once a day or in divided doses. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex and the like.
  • the pharmaceutical composition of the present invention is 0.01 to 100% by weight, and in one embodiment 0.01 to 50% by weight as an active ingredient. Or more ASP8477 or a salt thereof.
  • ASP8477 can be used in combination with various therapeutic agents or prophylactic agents for the above-mentioned diseases that are considered to be effective, for example, latanaprost or brimonidine.
  • the combination may be administered simultaneously, or separately and continuously, or at desired time intervals.
  • the preparation for co-administration may be a combination drug or separately formulated.
  • the dosage form may be in the form of tablets, pills, capsules, granules, powders, solutions, injections, or eye drops.
  • Example 1 Intraocular pressure lowering effect in a single oral administration clinical study in postmenopausal healthy adult female subjects Postmenopausal healthy adult female subjects (36 subjects in total) were administered with 8 doses of 3, 10, 20, 30, 60, 100, 150 and 200 mg of free ASP8477 as a study drug, and a placebo (placebo) containing no active ingredient. ) was orally administered once to the same subject by a three-stage crossover method in which the test drug and placebo were administered at different times to measure intraocular pressure. The intraocular pressure was measured with a non-contact tonometer.
  • the rate of change from the baseline (measured value before administration on the first day of each test) (100 ⁇ [(value at 2 or 4 hours after administration of the study drug The value at baseline)/the value at baseline]) was calculated, and the rate of change in intraocular pressure at each measurement time point was statistically analyzed using the covariance analysis method.
  • the results of the group having a P value ⁇ 0.05 defined as a value at which a statistically significant difference in the intraocular pressure change was recognized are shown by * in FIG.
  • ASP8477 lowered intraocular pressure in both left and right eyes 2 and 4 hours after administration. Furthermore, at 4 hours after administration, at a dose of 100 mg or higher of ASP8477, a significant intraocular pressure-lowering effect was seen in both left and right eyes compared with placebo (except for the right eye of 200 mg). In the left eye, a significant decrease in intraocular pressure relative to the pre-dose value was observed from the dose of 20 mg at 2 hours and/or 4 hours after administration or at one side. In the right eye, significant intraocular pressure-lowering effects on placebo were observed at doses of 10 mg (4 hours after administration) and 20 mg (2 hours after administration), but doses of 30 and 60 mg and 200 mg ( No statistically significant difference was observed 4 hours after administration.
  • latanoprost which is known as an eye drop of prostaglandin-related drug (latanoprost ophthalmic solution 0.005%, drug interview form 6th edition)
  • latanoprost ophthalmic solution 0.005%
  • instillation the maximum change in intraocular pressure was 3.73 mmHg as compared to before instillation, which was almost the same as the change in ASP8477.
  • the intraocular pressure lowering effect by oral administration of ASP8477 shows the same effect as the intraocular pressure lowering drug known as an existing eye drop, and it is clinically useful. confirmed.
  • Example 3 Efficacy evaluation of ASP8477 against intraocular pressure 1) Using 8-year-old, Long-Evans rats (Institute for Animal Reproduction, Ibaraki, Japan) weighing about 270 g, the intraocular pressure was measured by the method of 3) below, and the average intraocular pressure in each group became uniform. Group as follows. 2) The test is performed in a solvent group and a test compound administration group, and the solvent group is orally administered by suspending the test compound in a 0.5% methylcellulose aqueous solution and the test compound administration group in a 0.5% methylcellulose aqueous solution (dose: 3- 30 mg/kg). 3) Measured according to the intraocular pressure measurement method of Wang et al.
  • Tonolab hand-held tonometer (TV02, Icare Finland Oy, Finland) is used as a measuring instrument. Keep the measuring instrument horizontal with the eyeball of the animal and measure the distance between the corneal surface and the measuring instrument probe at about 2 mm. At each point, the intraocular pressure of the right eye is measured twice, and the average value is used as the result value, and the efficacy is judged by the amount of change in intraocular pressure from the value before compound administration.
  • a pharmaceutical composition containing pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof as an active ingredient has an intraocular pressure-lowering effect, and is effective for preventing glaucoma and/or ocular hypertension. It can be used as a therapeutic agent.

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Abstract

[Problem] To provide a prophylactic or therapeutic agent for glaucoma or ocular hypertension, which has an intraocular pressure lowering effect. [Solution] It has been confirmed that pyridin-3-yl 4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof has an intraocular pressure lowering effect. Consequently, the compound or a salt thereof is able to be used for prophylaxis or treatment of glaucoma or ocular hypertension.

Description

眼圧下降用医薬組成物Pharmaceutical composition for lowering intraocular pressure
　本発明は、眼圧下降用医薬、殊に緑内障又は高眼圧症の予防又は治療に有用な医薬組成物に関する。 The present invention relates to a medicament for lowering intraocular pressure, particularly a pharmaceutical composition useful for preventing or treating glaucoma or ocular hypertension.
　緑内障は、日本における失明原因の常に上位を占め、社会的にも非常に重要な疾患である。緑内障とは、視神経が障害され視野が狭くなる病気で、眼圧の上昇がその病因の一つと言われている。緑内障の視神経障害および視野障害は、基本的には進行性であり、非可逆的である。また、緑内障では、患者の自覚なしに障害が徐々に進行するため、その早期発見と早期治療による障害の進行の阻止あるいは抑制が重要課題となっている。 Glaucoma is always the top cause of blindness in Japan and is a very important social disease. Glaucoma is a disease in which the optic nerve is damaged and the visual field is narrowed, and it is said that an increase in intraocular pressure is one of the etiological factors. Optic neuropathy and visual field impairment in glaucoma are basically progressive and irreversible. Further, in glaucoma, the disorder gradually progresses without any awareness of the patient, and therefore, early detection and prevention or suppression of progression of the disorder by early treatment are important issues.
　高眼圧症とは、視神経に障害はなく視野が正常であるものの、眼圧が正常値（約１０～２０ｍｍＨｇ）を超えている病態である。眼圧が高いと、視神経が障害されやすくなり、緑内障になるリスクが高くなることが知られている。 O Ocular hypertension is a condition in which the visual field is normal without any damage to the optic nerve, but the intraocular pressure exceeds the normal value (about 10 to 20 mmHg). It is known that when the intraocular pressure is high, the optic nerve is easily damaged and the risk of glaucoma is increased.
　現在、緑内障に対するエビデンスに基づいた唯一確実な治療法は眼圧下降である。緑内障に対する眼圧下降治療には、薬物治療、レーザー治療、手術治療の選択肢があるが、薬物治療が治療の基本となっている。現在、緑内障治療薬の多くは点眼薬である。眼圧を上げる眼房水の排泄を促進して眼圧を下げるプロスタグランジン関連薬ラタノプロストや、眼房水の産生を抑制して眼圧を下げる交換神経β受容体遮断薬カルテオロールなど、１０種類以上の点眼薬がある。一種類の点眼薬だけで効果が少ないと判断された場合は、複数の点眼薬を組み合わせて処方される。 Currently, the only reliable evidence-based treatment for glaucoma is lowering intraocular pressure. There are drug treatment, laser treatment, and surgery treatment options for intraocular pressure reduction treatment for glaucoma, and drug treatment is the basis of treatment. Currently, most of the therapeutic agents for glaucoma are eye drops. Increases intraocular pressure Latanoprost, a prostaglandin-related drug that promotes excretion of aqueous humor and reduces intraocular pressure, and carteolol, a sympathetic beta-receptor blocker that suppresses aqueous humor production and decreases intraocular pressure There are more than one type of eye drops. When it is determined that one type of eye drops is not effective, multiple eye drops are combined and prescribed.
　点眼は、１回に１滴、複数のときは５分以上空けて点眼する方法が、なるべく副作用を少なくして、確実に効果を得る点眼方法である。しかしながら、慢性疾患で自覚症状に乏しい緑内障においては、点眼による治療のアドヒアランス（即ち、患者が治療方針を納得して自分の意思で正しく治療を受けること）がきわめて悪いことが判明している。例えば、点眼間隔を守らない、点眼の際に、間を開けず連続点眼してしまう、一度に数滴点眼し期間内の点眼薬切れが起きる、瞬目が多くうまく点眼できていない等、効果減弱や副作用増加につながる恐れがある。このような低い点眼のアドヒアランスが、緑内障の進行に関与することが懸念されている。 ▼ For instillation, one drop at a time and 5 or more minutes if more than one is left, it is a method to obtain the effect surely by reducing side effects as much as possible. However, in glaucoma, which is a chronic disease and has few subjective symptoms, it has been found that the adherence of treatment by eye drops (that is, the patient is convinced of the treatment policy and correctly receives the treatment at his own will). For example, do not observe the interval of instillation, when instilling, continuous instillation without opening, instilling several drops at a time and running out of eye drops within the period, there are many blinks and inadequate instillation, etc. May lead to diminishing and increased side effects. It is feared that such low eye drop adherence is involved in the progression of glaucoma.
　さらに、点眼薬の防腐剤として最も汎用されているベンザルコニウムは、長期にわたって何度も点眼すると角膜障害が起こることが知られている（眼科臨床紀要 2016, Vol.9, No.5, p.423-427、あたらしい眼科 2017, Vol.34, No.9, p.1263-1267）。 Furthermore, benzalkonium, which is most widely used as an antiseptic for eye drops, is known to cause corneal damage after repeated eye drops over a long period of time (Ophthalmology Clinical Bulletin 2016, Vol.9, No.5, p. .423-427, new ophthalmology 2017, Vol.34, No.9, p.1263-1267).
　また、唯一の経口眼圧下降薬であるアセタゾラミドは、眼房水の産生を抑制して眼圧を下げる炭酸脱水酵素阻害薬であるが、代謝性アシドーシスや低カリウム血症等の全身性副作用があり(緑内障診療ガイドライン　第4版)、慢性的な使用はされていない。 In addition, acetazolamide, which is the only oral intraocular pressure-lowering drug, is a carbonic anhydrase inhibitor that suppresses the production of aqueous humor and lowers intraocular pressure, but it has systemic side effects such as metabolic acidosis and hypokalemia. Yes (Glaucoma Practice Guideline, 4th Edition), not used chronically.
　１９７１年に、少数の健康人において、マリファナの喫煙は眼圧を下降させることが報告された（JAMA 1971, Vol.217, No.5, p.1392）。その報告以降、カンナビジオール、カンナビノール、内因性カンナビノイド、およびいくつかの合成カンナビノイドを含む様々なカンナビノイドの全身投与または局所投与により、眼圧を下降させることが報告されている（Biomed. Pharmacother. 2017, Vol.86, p.620-627、Br. J. Ophthalmol. 2004, Vol.88, No.5, p.708-713）。例えば、大麻の主活性成分であるΔ9－テトラヒドロカンナビノール（Δ9-tetrahydrocannabinol:THC）は、緑内障患者において眼圧下降作用が認められたことが報告されている。一方で、カンナビノイド製剤は、経口吸収性が乏しく、さらに依存性や起立性低血圧等の中枢性の副作用の懸念が報告されている（ファルマシア 2016, Vol.52, No.9, p.850-854）。 In 1971, smoking of marijuana was reported to lower intraocular pressure in a small number of healthy people (JAMA 1971, Vol.217, No.5, p.1392). Since that report, systemic or topical administration of various cannabinoids, including cannabidiol, cannabinol, endogenous cannabinoids, and some synthetic cannabinoids, has been reported to lower intraocular pressure (Biomed. Pharmacother. 2017). , Vol.86, p.620-627, Br. J. Ophthalmol. 2004, Vol.88, No.5, p.708-713). For example, the main active ingredient of cannabis delta 9 - tetrahydrocannabinol (Δ 9 -tetrahydrocannabinol: THC) is the intraocular pressure-lowering effect was observed is reported in glaucoma patients. On the other hand, cannabinoid preparations have poor oral absorbability, and there are concerns about central side effects such as dependence and orthostatic hypotension (Pharmacia 2016, Vol.52, No.9, p.850- 854).
　さらに、ＴＨＣの生体内標的分子としてカンナビノイド受容体タイプ１およびタイプ２（cannabinoid receptor type 1 and type 2：CB1 and CB2）が、さらに、当該ＣＢ受容体に対する生体内アゴニストとしてアナンダミド（anandamide：AEA）および２－アラキドノイルグリセロール（2-arachidonoylglycerol：2-AG）が発見され、それらに対する主要分解酵素が、脂肪酸アミド加水分解酵素（fatty acid amide hydrolase：FAAH）およびモノアシルグリセロールリパーゼ（monoacylglycerol lipase：MAGL）であることが報告されている（Balkan Med. J. 2014, Vol.31, No.2, p.115-120）。 Furthermore, cannabinoid receptors type 1 and type 2 (cannabinoid receptor type 1 and and type 2: CB1 and and CB2) are the target molecules of THC in vivo, and anandamide (AEA) and anandamide (AEA) and 2-arachidonoylglycerol (2-AG) was discovered, and the major degrading enzymes against them were fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). It is reported that there is (Balkan Med. J. 2014, Vol.31, No.2, p.115-120).
　ＦＡＡＨ活性を阻害するカルバミン酸誘導体が、神経因性疼痛、嘔吐、不安症、摂食行動の変化、運動障害、緑内障、脳損傷、および循環器病を含むＦＡＡＨ阻害により有効となり得る疾患の処置に有用であると開示されている（国際公開第2003/065989号、及び、国際公開第2004/033422号）。しかしながら、眼圧下降作用、又は緑内障の治療に対する有効性については具体的に開示されていない。 Carbamic acid derivatives that inhibit FAAH activity for the treatment of diseases that may be effective by FAAH inhibition, including neuropathic pain, vomiting, anxiety, altered feeding behavior, movement disorders, glaucoma, brain injury, and cardiovascular disease It is disclosed that it is useful (WO2003/065989 and WO2004/033422). However, it does not specifically disclose the effect of lowering the intraocular pressure or the effect on the treatment of glaucoma.
　また、頻尿・尿失禁、過活動膀胱及び／又は疼痛の治療に有用なＦＡＡＨ阻害作用を有するピリジル 非芳香族含窒素へテロ環－１－カルボン酸エステル誘導体が特許文献１に開示され、その実施例１７３には、ピリジン－３－イル ４－（アニリノカルボニル）ピペリジン－１－カルボキシラート（以下、ASP8477と記載する場合がある）が開示されている。さらに特許文献１には、当該明細書に記載の化合物が優れたＦＡＡＨ阻害作用を有し、精神性疾患をはじめとする多数の疾患の治療薬として有用であることが記載され、その疾患の一つに緑内障が含まれている。また、特許文献１に開示されるASP8477について鎮痛効果に対する報告（Eur. J. Pharmacol. 2017, Vol.815, p.42-48、及び、国際公開第2011/136308号）がある。更に、健康成人女性を対象として鎮痛効果を検証した臨床試験（非特許文献１）や、神経因性疼痛の患者を対象として臨床試験（非特許文献２）が実施されたことが報告されている。しかしながら、ASP8477の眼圧に対する作用については現在まで報告がない。 Further, Patent Document 1 discloses a pyridyl non-aromatic nitrogen-containing heterocyclic-1-carboxylic acid ester derivative having FAAH inhibitory activity, which is useful for treating frequent urination/urinary incontinence, overactive bladder and/or pain. Example 173 discloses pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate (hereinafter sometimes referred to as ASP8477). Further, Patent Document 1 describes that the compound described in the present specification has an excellent FAAH inhibitory action and is useful as a therapeutic agent for many diseases including psychiatric disorders. One includes glaucoma. Further, there is a report on the analgesic effect of ASP8477 disclosed in Patent Document 1 (Eur. J. Pharmacol. 2017, Vol.815, p.42-48, and International Publication No. 2011/136308). Furthermore, it has been reported that a clinical test (Non-patent document 1) that verified the analgesic effect in healthy adult women and a clinical test (Non-patent document 2) in patients with neuropathic pain were conducted. .. However, there is no report to date on the effect of ASP8477 on intraocular pressure.
　ＦＡＡＨ阻害活性を有する化合物であるURB597（化学名：シクロヘキシルカルバミン酸 3'-カルバモイル-ビフェニル-3-イルエステル）が、ラットへの腹腔内投与において、網膜細胞の保護作用を示した報告がある（非特許文献３）。また、ＦＡＡＨ阻害活性を有するURB597と、ＦＡＡＨ阻害活性に加えてメラトニン受容体アゴニスト作用を併せ持つ化合物との、ウサギ点眼における眼圧下降作用を比較した報告がある（非特許文献４）。当該文献では、試験したＦＡＡＨ阻害活性を有する７化合物中、URB597を含む４化合物で点眼による有意な眼圧下降作用が見られたものの、他の3化合物では有意な作用は見られなかったことが報告されている。 It has been reported that URB597 (chemical name: cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester), which is a compound having FAAH inhibitory activity, has a protective effect on retinal cells after intraperitoneal administration to rats ( Non-Patent Document 3). In addition, there is a report comparing the intraocular pressure lowering effect in rabbit eye drops between URB597 having FAAH inhibitory activity and a compound having FAAH inhibitory activity as well as a melatonin receptor agonistic action (Non-Patent Document 4). In this document, among the 7 compounds having FAAH inhibitory activity tested, 4 compounds including URB597 showed significant intraocular pressure-lowering effect by instillation, but other 3 compounds showed no significant effect. It has been reported.
国際公開第２００６／０８８０７５号International Publication No. 2006/088075
本発明の課題は、カンナビノイド製剤に報告される依存性や中枢性の副作用の懸念が低く、継続的な投与が可能な、緑内障又は高眼圧症の予防又は治療剤の提供である。 An object of the present invention is to provide a prophylactic or therapeutic agent for glaucoma or ocular hypertension, which has a low risk of dependence and central side effects reported for cannabinoid preparations and which can be continuously administered.
　本発明者らは、ASP8477又はその塩が、ヒトにおいて良好な眼圧下降作用を有し、緑内障又は高眼圧症の予防又は治療に有用であることを知見して本発明を完成した。 The present inventors have completed the present invention by finding that ASP8477 or a salt thereof has a good intraocular pressure lowering effect in humans and is useful for the prevention or treatment of glaucoma or ocular hypertension.
　即ち、本発明は、ASP8477又はその塩を有効成分として含有する、眼圧下降用医薬組成物、具体的には、緑内障又は高眼圧症の予防又は治療用である前記医薬組成物に関する。ASP8477又はその塩を有効成分として含有する前記医薬組成物は、さらに製薬学的に許容される賦形物を含んでもよい。更に、経口投与用である前記医薬組成物に関する。また更に、投与１回あたり３～２００ｍｇのASP8477又はその塩を経口投与するための、前記医薬組成物にも関する。また更に、投与１回あたり１０～１００ｍｇのASP8477又はその塩を経口投与するための、前記医薬組成物にも関する。 That is, the present invention relates to a pharmaceutical composition for lowering intraocular pressure, which contains ASP8477 or a salt thereof as an active ingredient, specifically, the above-mentioned pharmaceutical composition for preventing or treating glaucoma or ocular hypertension. The pharmaceutical composition containing ASP8477 or a salt thereof as an active ingredient may further contain a pharmaceutically acceptable excipient. Furthermore, it relates to said pharmaceutical composition for oral administration. Furthermore, the present invention also relates to the above-mentioned pharmaceutical composition for orally administering 3 to 200 mg of ASP8477 or a salt thereof per administration. Furthermore, the present invention also relates to the above-mentioned pharmaceutical composition for oral administration of 10 to 100 mg of ASP8477 or a salt thereof per administration.
　また、本発明は、ASP8477又はその塩の有効量を対象に投与することからなる眼圧下降方法、更に、眼圧下降用医薬組成物の製造のためのASP8477又はその塩の使用、眼圧を下降させるためのASP8477又はその塩の使用、及び、眼圧を下降させるために使用するためのASP8477又はその塩を含有する医薬組成物にも関する。ここに「対象」とは処置を必要とするヒト（患者）又は哺乳類の動物であり、ある態様としてはヒト（患者）である。 Further, the present invention, a method for lowering intraocular pressure comprising administering an effective amount of ASP8477 or a salt thereof to a subject, further, use of ASP8477 or a salt thereof for producing a pharmaceutical composition for lowering intraocular pressure, intraocular pressure It also relates to the use of ASP8477 or a salt thereof for lowering and a pharmaceutical composition containing ASP8477 or a salt thereof for lowering intraocular pressure. As used herein, a “subject” is a human (patient) or mammal animal in need of treatment, and in one embodiment, a human (patient).
　更にまた、本発明は、ASP8477又はその塩の有効量を対象に投与することからなる緑内障又は高眼圧症の予防又は治療方法、緑内障又は高眼圧症の予防又は治療用医薬組成物の製造のためのASP8477又はその塩の使用、緑内障又は高眼圧症の予防又は治療のためのASP8477又はその塩の使用、及び、緑内障又は高眼圧症の予防又は治療の使用のためのASP8477又はその塩、緑内障又は高眼圧症の予防又は治療のためのASP8477又はその塩を含有する医薬組成物にも関する。 Furthermore, the present invention provides a method for preventing or treating glaucoma or ocular hypertension, which comprises administering an effective amount of ASP8477 or a salt thereof to a subject, for producing a pharmaceutical composition for preventing or treating glaucoma or ocular hypertension. Use of ASP8477 or a salt thereof, use of ASP8477 or a salt thereof for the prevention or treatment of glaucoma or ocular hypertension, and ASP8477 or a salt thereof for the use of the prevention or treatment of glaucoma or ocular hypertension, glaucoma or It also relates to a pharmaceutical composition containing ASP8477 or a salt thereof for the prevention or treatment of ocular hypertension.
　ASP8477又はその製薬学的に許容される塩を有効成分として含有する、本発明の眼圧下降用医薬組成物は、緑内障又は高眼圧症の予防又は治療剤として使用できる。 The pharmaceutical composition for lowering intraocular pressure of the present invention containing ASP8477 or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a preventive or therapeutic agent for glaucoma or ocular hypertension.
実施例１において、閉経後健康成人女性の被験者にASP8477を単回経口投与した試験の眼圧の変化を示すグラフである。縦軸に眼圧（mmHg）を、横軸にプラセボ又はASP8477の投与用量（mg）、例数（n）並びに投与からの経過時間（0，2及び4h（時間））を示す（左眼：（Ｉ）、右眼：（ＩＩ））。なお、投与前値からの変化量において、統計学的に有意な差（P値<0.05）がある場合を*で示す。4 is a graph showing changes in intraocular pressure in a test in which a single post-menopausal healthy adult female subject was orally administered ASP8477 in Example 1. The vertical axis shows intraocular pressure (mmHg), and the horizontal axis shows the dose (mg) of placebo or ASP8477, the number of cases (n), and the time elapsed from administration (0, 2 and 4 h (hours)) (left eye: (I), right eye: (II)). In addition, the case where there is a statistically significant difference (P value <0.05) in the amount of change from the value before administration is indicated by *.
　以下、本発明の実施の形態について、詳細に説明する。 Hereinafter, embodiments of the present invention will be described in detail.
　本発明の有効成分であるASP8477又はその塩は、特許文献１の実施例１７３に記載される公知化合物であり、健康成人女性を対象として鎮痛効果を検証した臨床試験（非特許文献１）や、神経因性疼痛の患者を対象として臨床試験が実施されたことが報告されている（非特許文献２）。 ASP8477 or a salt thereof, which is the active ingredient of the present invention, is a known compound described in Example 173 of Patent Document 1, and a clinical test (Non-Patent Document 1) in which the analgesic effect was verified in healthy adult women, It has been reported that a clinical test was conducted on patients with neuropathic pain (Non-patent Document 2).
　本発明者らは、ASP8477の経口投与により行われた第一相臨床試験の結果を詳細に検討した結果、ASP8477が良好な眼圧下降作用を示すことから、ASP8477又はその塩を有効成分として含有する医薬組成物が眼圧下降用医薬組成物として有用であること、よって、緑内障又は高眼圧症の予防又は治療に使用できることを見出した。さらに、ASP8477は経口投与においてもカンナビノイド製剤に報告される依存性や中枢性の副作用の懸念が低いことから、経口投与等の全身投与による眼圧下降用医薬組成物、さらに、緑内障又は高眼圧症の予防又は治療用医薬組成物として有用であることを見出したものである。 The present inventors have conducted a detailed examination of the results of a phase I clinical trial conducted by oral administration of ASP8477, and since ASP8477 exhibits a good intraocular pressure lowering action, it contains ASP8477 or a salt thereof as an active ingredient. It was found that the above-mentioned pharmaceutical composition is useful as a pharmaceutical composition for lowering intraocular pressure, and thus can be used for prevention or treatment of glaucoma or ocular hypertension. Furthermore, since ASP8477 has low concern about the dependence and central side effects reported in cannabinoid preparations even after oral administration, a pharmaceutical composition for lowering intraocular pressure by systemic administration such as oral administration, and further glaucoma or ocular hypertension. It has been found to be useful as a pharmaceutical composition for the prevention or treatment of.
　殊に、本発明者らは、ASP8477の上記作用が、良好なＦＡＡＨ阻害活性のみならず、ASP8477の良好な眼組織への移行性によるものであることを知見した。このような眼組織への移行性は、他のＦＡＡＨ阻害活性を有する化合物、例えばASP3652（Urology 2017, Vol.103, p.191-197）では観察されていない。 In particular, the present inventors have found that the above-mentioned action of ASP8477 is due to not only good FAAH inhibitory activity but also good transferability of ASP8477 to ocular tissues. Such transferability to ocular tissues has not been observed with other compounds having FAAH inhibitory activity, for example, ASP3652 (Urology 2017, Vol. 103, p. 191-197).
　本発明のASP8477又はその塩を有効成分として含む医薬組成物は、その良好なＦＡＡＨ阻害活性に基づき良好な眼圧下降作用が期待できる。ASP8477又はその塩は良好な眼組織への移行性を有することから、後記実施例に示す様に、経口投与によっても良好な眼圧下降作用が確認されている。慢性疾患で自覚症状に乏しい緑内障においては、点眼による治療のアドヒアランスがきわめて悪いことから、継続的な投与に適する経口剤の有用性は高い。さらに、経口剤は、多くの点眼薬に防腐剤として添加されているベンザルコニウムによる角膜障害等の懸念もない。よって、本発明のASP8477又はその塩を有効成分として含む経口投与用である医薬組成物は、継続的な投与が可能であり、防腐剤の影響がない新たな眼圧下降薬となり得ることが期待される。 A pharmaceutical composition containing ASP8477 or a salt thereof of the present invention as an active ingredient can be expected to have a good action of lowering intraocular pressure based on its good FAAH inhibitory activity. Since ASP8477 or a salt thereof has a good ability to migrate to ocular tissues, it has been confirmed that a good intraocular pressure-lowering effect is obtained even by oral administration, as shown in Examples below. For glaucoma, which is a chronic disease and has few subjective symptoms, the oral administration suitable for continuous administration is highly useful because the adherence of the treatment by eye drops is extremely poor. Furthermore, the oral preparation does not have a concern of corneal damage due to benzalkonium, which is added to many eye drops as a preservative. Therefore, the pharmaceutical composition for oral administration containing ASP8477 or a salt thereof of the present invention as an active ingredient is expected to be a new intraocular pressure lowering drug that can be continuously administered and is not affected by a preservative. To be done.
　本明細書において、ASP8477の塩とは、ASP8477の製薬学的に許容される塩であり、具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、マンデル酸、酒石酸、ジベンゾイル酒石酸、ジトルオイル酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、グルタミン酸等の有機酸との酸付加塩、アセチルロイシン等の各種アミノ酸及びアミノ酸誘導体との塩やアンモニウム塩等が挙げられる。ASP8477のある態様としては、塩を形成していない、即ち、フリー体である。 In the present specification, the salt of ASP8477 is a pharmaceutically acceptable salt of ASP8477, and specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid. Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfone Examples thereof include acid addition salts with acids, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid and the like, salts with various amino acids and amino acid derivatives such as acetylleucine, ammonium salts and the like. In one embodiment of ASP8477, no salt is formed, that is, the free form.
　更に、本発明に係るASP8477又はその塩には、ASP8477及びその塩の各種の水和物や溶媒和物、及び結晶多形の物質も包含する。 Further, ASP8477 or a salt thereof according to the present invention includes various hydrates and solvates of ASP8477 and a salt thereof, and crystalline polymorphic substances.
　ASP8477又はその塩は、特許文献１に記載の方法、或いは当業者に周知の反応を用いて製造することができる。ある態様としては、特許文献１の実施例１７３に記載の方法により製造することができる。 ASP8477 or a salt thereof can be produced by the method described in Patent Document 1 or the reaction well known to those skilled in the art. As a certain aspect, it can be manufactured by the method described in Example 173 of Patent Document 1.
　ASP8477又はその塩を有効成分として含有する医薬組成物は、当分野において通常用いられている賦形剤、即ち、薬剤用賦形剤や薬剤用担体等を用いて、通常使用されている方法によって調製することができる。 A pharmaceutical composition containing ASP8477 or a salt thereof as an active ingredient can be prepared by a commonly used method using an excipient that is usually used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier. It can be prepared.
　投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。ある態様としては、投与は経口投与又は注射剤による全身投与であり、ある態様としては経口投与である。 The administration is oral administration by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intravenous and intramuscular, suppositories, eye drops, eye ointments, transdermal solutions, ointments, It may be any form of transdermal patch, transmucosal solution, transmucosal patch, parenteral administration such as inhalant. In one aspect, the administration is oral administration or systemic administration by injection, and in one aspect, oral administration.
　経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、ASP8477又はその塩を、少なくとも1種の不活性な賦形剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、及び／又はメタケイ酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な添加剤、例えばステアリン酸マグネシウムのような滑沢剤やカルボキシメチルスターチナトリウム等のような崩壊剤、安定剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要により糖衣又は胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。 As the solid composition for oral administration, tablets, powders, granules and the like are used. In such solid compositions, ASP8477 or a salt thereof may be combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or metasilicate. Acid mixed with magnesium aluminate etc. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, a stabilizer and a solubilizing agent according to a conventional method. If necessary, the tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
　経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤又はエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水又はエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。 Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and generally used inert diluents such as purified water. Or it contains ethanol. The liquid composition may contain, in addition to the inert diluent, solubilizers, wetting agents, auxiliary agents such as suspending agents, sweeteners, flavors, aromatics and preservatives.
　注射剤は、無菌の水性又は非水性の溶液剤、懸濁剤又は乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水又は生理食塩液が含まれる。非水性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコール又はオリーブ油のような植物油、エタノールのようなアルコール類、又はポリソルベート８０（局方名）等がある。このような組成物は、さらに等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、又は溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解又は懸濁して使用することもできる。 ∙ The injection contains a sterile aqueous or non-aqueous solution, suspension or emulsion. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (Pharmacopoeia). Such a composition may further contain a tonicity agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
　通常経口投与の場合、１回の投与量は、フリー体のASP8477換算で約０．１～５００ ｍｇ、好ましくは１～２００ ｍｇ、更に好ましくは３～２００ｍｇ、また更に好ましくは１０～１５０ ｍｇ、また好ましくは１０～１００ ｍｇ、また更に好ましくは１０～３０ ｍｇが適当であり、また別の態様として６０ｍｇ～１００ｍｇが適当であり、これを１日１回、あるいは２回～４回投与する。好ましくは１日１～３回、更に好ましくは１日１～２回、また更に好ましくは１日１回、また好ましくは２回投与する。静脈内投与される場合は、１日の投与量は、体重当たり約０．０００１～１０ ｍｇ／ｋｇが適当で、１日１回～複数回に分けて投与する。また、経粘膜剤としては、体重当たり約０．００１～１００ ｍｇ／ｋｇを１日１回～複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。 Normally, in the case of oral administration, a single dose is about 0.1 to 500 mg, preferably 1 to 200 mg, more preferably 3 to 200 mg, and further preferably 10 to 150 mg in terms of free form ASP8477, Further, it is preferably 10 to 100 mg, and more preferably 10 to 30 mg, and in another embodiment, 60 mg to 100 mg is suitable, and this is administered once a day or twice to four times. It is preferably administered 1 to 3 times a day, more preferably 1 to 2 times a day, even more preferably once a day, and preferably 2 times. In the case of intravenous administration, the appropriate daily dose is about 0.0001 to 10 mg/kg of body weight, and the daily dose may be administered once or in multiple doses. As a transmucosal agent, about 0.001 to 100 mg/kg of body weight is to be administered once a day or in divided doses. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex and the like.
　投与経路、剤形、投与部位、賦形剤や添加剤の種類によって異なるが、本発明の医薬組成物は0.01～100重量%、ある態様としては0.01～50重量%の有効成分である１種又はそれ以上のASP8477又はその塩を含有する。 Depending on the route of administration, dosage form, site of administration, kind of excipients and additives, the pharmaceutical composition of the present invention is 0.01 to 100% by weight, and in one embodiment 0.01 to 50% by weight as an active ingredient. Or more ASP8477 or a salt thereof.
　ASP8477は、前述のASP8477が有効性を示すと考えられる疾患の種々の治療剤又は予防剤、例えばラタナプロスト又はブリモニジンと併用することができる。当該併用は、同時投与、或いは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。投与製剤は、錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤、注射剤、又は、点眼剤のいずれの形態であってもよい。 ASP8477 can be used in combination with various therapeutic agents or prophylactic agents for the above-mentioned diseases that are considered to be effective, for example, latanaprost or brimonidine. The combination may be administered simultaneously, or separately and continuously, or at desired time intervals. The preparation for co-administration may be a combination drug or separately formulated. The dosage form may be in the form of tablets, pills, capsules, granules, powders, solutions, injections, or eye drops.
実施例１
閉経後健康成人女性の被験者を用いた単回経口投与臨床試験における眼圧降下作用
（方法）
　閉経後健康成人女性の被験者（計36人）に、被験薬物としてフリー体のASP8477の3, 10, 20, 30, 60, 100, 150及び200 mgの8用量及び有効成分を含まないプラセボ（偽薬）を、同一の被験者に時期を変えて被験薬物とプラセボを投与する3時期クロスオーバー法により、単回経口投与して眼圧を測定した。
　眼圧は非接触眼圧計にて測定した。さらに、被験薬物投与後2時間又は4時間における眼圧から、ベースライン（各試験の1日目の投与前測定値）に対する変化率（100×［（被験薬物投与後2又は4時間における値 － ベースライン時の値）／ベースライン時の値］）を計算し、共分散分析法を用いて、各測定時点での眼圧の変化率を統計解析した。眼圧の変化率に統計学的な有意差が認められた値として定めたP値<0.05であった群の結果を、図１に*で示した。 Example 1
Intraocular pressure lowering effect in a single oral administration clinical study in postmenopausal healthy adult female subjects (method)
Postmenopausal healthy adult female subjects (36 subjects in total) were administered with 8 doses of 3, 10, 20, 30, 60, 100, 150 and 200 mg of free ASP8477 as a study drug, and a placebo (placebo) containing no active ingredient. ) Was orally administered once to the same subject by a three-stage crossover method in which the test drug and placebo were administered at different times to measure intraocular pressure.
The intraocular pressure was measured with a non-contact tonometer. Furthermore, from the intraocular pressure at 2 hours or 4 hours after the administration of the study drug, the rate of change from the baseline (measured value before administration on the first day of each test) (100 × [(value at 2 or 4 hours after administration of the study drug The value at baseline)/the value at baseline]) was calculated, and the rate of change in intraocular pressure at each measurement time point was statistically analyzed using the covariance analysis method. The results of the group having a P value <0.05 defined as a value at which a statistically significant difference in the intraocular pressure change was recognized are shown by * in FIG.
（結果）
　ASP8477は、投与後2時間および4時間のいずれにおいても、左右眼の両方で眼圧を下降させた。さらに投与後4時間では、ASP8477の100 mgまたはそれ以上の用量において、左右両眼でプラセボと比較して有意な眼圧下降作用が見られた（200 mgの右眼を除く）。また左眼では、投与後2時間および4時間の両方又は一方で20 mgの用量から、投与前値に対する眼圧の有意な下降が観察された。右眼では、10 mg（投与後4時間）および20 mg（投与後2時間）の用量で、プラセボに対する有意な眼圧下降作用が観察されたが、30および60 mgの用量、及び200 mg（投与後4時間）では統計的に有意な差は観察されなかった。 (result)
ASP8477 lowered intraocular pressure in both left and right eyes 2 and 4 hours after administration. Furthermore, at 4 hours after administration, at a dose of 100 mg or higher of ASP8477, a significant intraocular pressure-lowering effect was seen in both left and right eyes compared with placebo (except for the right eye of 200 mg). In the left eye, a significant decrease in intraocular pressure relative to the pre-dose value was observed from the dose of 20 mg at 2 hours and/or 4 hours after administration or at one side. In the right eye, significant intraocular pressure-lowering effects on placebo were observed at doses of 10 mg (4 hours after administration) and 20 mg (2 hours after administration), but doses of 30 and 60 mg and 200 mg ( No statistically significant difference was observed 4 hours after administration.
　なお、本臨床試験において、死亡、重篤な有害事象及び中止に至った有害事象は認められなかった。また、重度の有害事象として、本剤200 mgを投与した被験者1例（59歳白人女性）で意識消失を伴う低血圧が認められ、被験薬物との関連性は否定されなかった。その他の有害事象の程度はいずれも軽度又は中等度であった。 In this clinical study, no deaths, serious adverse events, or adverse events leading to discontinuation were observed. As a serious adverse event, hypotension accompanied by loss of consciousness was observed in one subject (59 year old Caucasian female) who received 200 mg of this drug, and its association with the study drug could not be ruled out. All other adverse events were mild or moderate in severity.
（考察）
　β遮断薬の点眼薬として知られるカルテオロールの臨床試験結果（カルテオロール塩酸塩 LA点眼液1%、カルテオロール塩酸塩 LA点眼液2％ 医薬品インタビューフォーム 第４版）によれば、カルテオロール（LA点眼液2％）を健康成人男子に1回1滴点眼した結果、点眼前に比して有意な眼圧下降作用が認められたことが記載されている。その眼圧最大変化値は3.49 mmHgであり、上記ASP8477を右眼に100 mg点眼した際の変化値と比較した結果、ほぼ同等であった。また、プロスタグランジン関連薬の点眼薬として知られるラタノプロストの臨床試験結果（ラタノプロスト点眼液0.005% 医薬品インタビューフォーム 第６版）によれば、ラタノプロスト（点眼液0.005%）を健康成人男子に1回1滴点眼した結果、点眼前に比してその眼圧最大変化値は3.73 mmHgであり、前記ASP8477の変化値とほぼ同等であった。 (Discussion)
According to the results of clinical trials of carteolol, which is known as a β-blocker eye drop (carteolol hydrochloride LA ophthalmic solution 1%, carteolol hydrochloride LA ophthalmic solution 2%, drug interview form 4th edition), It has been described that as a result of instilling 1 drop of eye drops (2%) on healthy adult males once, a significant lowering effect of intraocular pressure was observed as compared to before instillation. The maximum change in intraocular pressure was 3.49 mmHg, and as a result of comparison with the change when ASP8477 was instilled at 100 mg in the right eye, it was almost the same. In addition, according to the clinical test results of latanoprost, which is known as an eye drop of prostaglandin-related drug (latanoprost ophthalmic solution 0.005%, drug interview form 6th edition), latanoprost (ophthalmic solution 0.005%) was given to healthy adult males once a time. As a result of instillation, the maximum change in intraocular pressure was 3.73 mmHg as compared to before instillation, which was almost the same as the change in ASP8477.
　これらの比較結果から、上記ASP8477の経口投与による眼圧下降作用は、既存の点眼薬として知られている眼圧下降薬と同等の効果を示しており、臨床的に有用な効果であることが確認された。 From these comparative results, the intraocular pressure lowering effect by oral administration of ASP8477 shows the same effect as the intraocular pressure lowering drug known as an existing eye drop, and it is clinically useful. confirmed.
実施例２
健康成人女性を被験者とする反復経口投与臨床試験 Example 2
Repeated oral dose clinical study in healthy adult women
　健康成人女性に、フリー体のASP8477の3用量（20, 60, 100 mg）またはプラセボを1日1回、同一の被験者に７日間ごとに用量を20, 60, 100 mgと増量しながら、合計21日間反復経口投与した。本試験において、ASP8477投与群の被験者では投与前値に比して有意な眼圧下降作用が観察された。 For healthy adult women, 3 doses of free ASP8477 (20, 60, 100 mg) or placebo once a day, increasing to 20, 60, 100 mg every 7 days for the same subject, totaling Oral administration was repeated for 21 days. In this test, a significant intraocular pressure lowering effect was observed in the subjects of the ASP8477-administered group as compared with the pre-administration value.
実施例３　眼内圧に対するASP8477の有効性評価
1)　8週令、体重約270gのLong-Evans rats (Institute for Animal Reproduction, Ibaraki, Japan)を用い、下記3)の方法にて眼圧を測定し各群の眼圧平均値が均一になるように群分けを行う。
2)　試験は溶媒群および被験化合物投与群で行い、溶媒群には0.5%メチルセルロース水溶液を、被験化合物投与群には0.5%メチルセルロース水溶液に被験化合物を懸濁して経口投与する(投与量：3-30mg/kg)。
3)　試験化合物投与前および投与後1, 2, 3, 4時間目にWangらの眼圧測定方法に従って測定する（Invest. Ophthalmol. Vis. Sci. 2005, Vol.46, No.12, p.4617-4621、 Invest. Ophthalmol. Vis. Sci. 2009, Vol.50, No.6, p.2802-2808）。測定器具としてトノラボ 手持眼圧計（TV02, Icare Finland Oy, Finland）を使用する。測定器具を動物の眼球と水平に保ち、角膜表面と測定器具プローブの距離は約2 mmの条件にて測定する。各ポイントにおいて、右眼の眼圧を2回測定し、この平均値を結果値とし、化合物投与前値からの眼圧変化量にて薬効を判定する。 Example 3 Efficacy evaluation of ASP8477 against intraocular pressure
1) Using 8-year-old, Long-Evans rats (Institute for Animal Reproduction, Ibaraki, Japan) weighing about 270 g, the intraocular pressure was measured by the method of 3) below, and the average intraocular pressure in each group became uniform. Group as follows.
2) The test is performed in a solvent group and a test compound administration group, and the solvent group is orally administered by suspending the test compound in a 0.5% methylcellulose aqueous solution and the test compound administration group in a 0.5% methylcellulose aqueous solution (dose: 3- 30 mg/kg).
3) Measured according to the intraocular pressure measurement method of Wang et al. before the administration of the test compound and 1, 2, 3, and 4 hours after the administration (Invest. Ophthalmol. Vis. Sci. 2005, Vol. 46, No. 12, p. 4617-4621, Invest. Ophthalmol. Vis. Sci. 2009, Vol.50, No.6, p.2802-2808). Tonolab hand-held tonometer (TV02, Icare Finland Oy, Finland) is used as a measuring instrument. Keep the measuring instrument horizontal with the eyeball of the animal and measure the distance between the corneal surface and the measuring instrument probe at about 2 mm. At each point, the intraocular pressure of the right eye is measured twice, and the average value is used as the result value, and the efficacy is judged by the amount of change in intraocular pressure from the value before compound administration.
　ピリジン－３－イル ４－（アニリノカルボニル）ピペリジン－１－カルボキシラート又はその塩を有効成分として含有する医薬組成物は、眼圧下降作用を有し、緑内障及び／又は高眼圧症の予防又は治療剤として使用できる。 A pharmaceutical composition containing pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof as an active ingredient has an intraocular pressure-lowering effect, and is effective for preventing glaucoma and/or ocular hypertension. It can be used as a therapeutic agent.

Claims (9)

  1. ピリジン－３－イル ４－（アニリノカルボニル）ピペリジン－１－カルボキシラート又はその塩を有効成分として含有する、眼圧下降用医薬組成物。 A pharmaceutical composition for lowering intraocular pressure, which contains pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof as an active ingredient.
  2. 緑内障又は高眼圧症の予防又は治療用である請求項１記載の医薬組成物。 The pharmaceutical composition according to claim 1, which is used for preventing or treating glaucoma or ocular hypertension.
  3. 経口投与用である請求項１又は２記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, which is for oral administration.
  4. 投与１回あたり３～２００ｍｇのピリジン－３－イル ４－（アニリノカルボニル）ピペリジン－１－カルボキシラート又はその塩を経口投与するための、請求項３記載の医薬組成物。 The pharmaceutical composition according to claim 3, for orally administering 3 to 200 mg of pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof once per administration.
  5. 投与１回あたり１０～１００ｍｇのピリジン－３－イル ４－（アニリノカルボニル）ピペリジン－１－カルボキシラート又はその塩を経口投与するための、請求項３記載の医薬組成物。 The pharmaceutical composition according to claim 3, for orally administering 10 to 100 mg of pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof per administration.
  6. 緑内障又は高眼圧症の予防又は治療用医薬組成物の製造のための、ピリジン－３－イル ４－（アニリノカルボニル）ピペリジン－１－カルボキシラート又はその塩の使用。 Use of pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof for the manufacture of a pharmaceutical composition for preventing or treating glaucoma or ocular hypertension.
  7. 緑内障又は高眼圧症の予防又は治療のための、ピリジン－３－イル ４－（アニリノカルボニル）ピペリジン－１－カルボキシラート又はその塩の使用。 Use of pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof for the prevention or treatment of glaucoma or ocular hypertension.
  8. 緑内障又は高眼圧症の予防又は治療の使用のための、ピリジン－３－イル ４－（アニリノカルボニル）ピペリジン－１－カルボキシラート又はその塩。 Pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof for use in prevention or treatment of glaucoma or ocular hypertension.
  9. ピリジン－３－イル ４－（アニリノカルボニル）ピペリジン－１－カルボキシラート又はその塩の有効量を対象に投与することからなる、緑内障又は高眼圧症の予防又は治療方法。 A method for preventing or treating glaucoma or ocular hypertension, which comprises administering an effective amount of pyridin-3-yl-4-(anilinocarbonyl)piperidine-1-carboxylate or a salt thereof to a subject.
PCT/JP2020/005681 2019-02-15 2020-02-14 Pharmaceutical composition for lowering intraocular pressure WO2020166679A1 (en)

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JPH06192071A (en) * 1987-03-19 1994-07-12 Nikken Chem Co Ltd Intraocular pressure-lowering agent
JPH0820531A (en) * 1994-07-06 1996-01-23 Mitsubishi Chem Corp Glaucoma-treating agent and intraocular pressurelowering agent
JPH09316002A (en) * 1995-10-25 1997-12-09 Mitsubishi Chem Corp Preparation for ophthalmic disease

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