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WO2020166679A1 - Composition pharmaceutique pour abaisser la pression intraoculaire - Google Patents

Composition pharmaceutique pour abaisser la pression intraoculaire 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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WO
WIPO (PCT)
Prior art keywords
intraocular pressure
salt
asp8477
pharmaceutical composition
glaucoma
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Ceased
Application number
PCT/JP2020/005681
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English (en)
Japanese (ja)
Inventor
一己 林
智成 綿引
雄之 谷津
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Astellas Pharma Inc
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Astellas Pharma Inc
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Publication date
Application filed by Astellas Pharma Inc filed Critical Astellas Pharma Inc
Publication of WO2020166679A1 publication Critical patent/WO2020166679A1/fr
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Ceased legal-status Critical Current

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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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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Ophthalmology & Optometry (AREA)
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Abstract

Le problème décrit ar la présente invention est de fournir un agent prophylactique ou thérapeutique pour le glaucome ou l'hypertension oculaire, qui a un effet d'abaissement de pression intraoculaire. Il a été confirmé que pyridine-3-yl 4-(anilinocarbonyl)pipéridine-1-carboxylate ou un sel de celui-ci a un effet d'abaissement de la pression intraoculaire. Par conséquent, le composé ou un sel de celui-ci peut être utilisé pour la prophylaxie ou le traitement du glaucome ou de l'hypertension oculaire.
PCT/JP2020/005681 2019-02-15 2020-02-14 Composition pharmaceutique pour abaisser la pression intraoculaire Ceased WO2020166679A1 (fr)

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JP2019-025472 2019-02-15
JP2019025472A JP2022059092A (ja) 2019-02-15 2019-02-15 眼圧下降用医薬組成物

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06192071A (ja) * 1987-03-19 1994-07-12 Nikken Chem Co Ltd 眼圧降下剤
JPH0820531A (ja) * 1994-07-06 1996-01-23 Mitsubishi Chem Corp 緑内障治療剤及び眼圧降下剤
JPH09316002A (ja) * 1995-10-25 1997-12-09 Mitsubishi Chem Corp 眼疾患用薬剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06192071A (ja) * 1987-03-19 1994-07-12 Nikken Chem Co Ltd 眼圧降下剤
JPH0820531A (ja) * 1994-07-06 1996-01-23 Mitsubishi Chem Corp 緑内障治療剤及び眼圧降下剤
JPH09316002A (ja) * 1995-10-25 1997-12-09 Mitsubishi Chem Corp 眼疾患用薬剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
NUCCI, CARLO, GASPERI VALERIA, TARTAGLIONE ROSANNA, CERULLI ANGELICA, TERRINONI ALESSANDRO, BARI MONICA, DE SIMONE CHIARA, AGRO` A: "Involvement of the Endocannabinoid System in Retinal Damage after High Intraocular Pressure-Induced Ischemia in Rats", IOVS, vol. 48, no. 7, 2007, pages 2997 - 3004, XP055737476, DOI: 10.1167/iovs.06-1355 *
SPADONI, GILBERTO, BEDINI ANNALIDA, FURIASSI LUCIA, MARI MICHELE, MOR MARCO, SCALVINI LAURA, LODOLA ALESSIO, GHIDINI ANDREA, LUCIN: "Identification of Bivalent Ligands with Melatonin Receptor Agonist and Fatty Acid Amide Hydrolase (FAAH) Inhibitory Activity That Exhibit Ocular Hypotensive Effect in the Rabbit", J. MED. CHEM., vol. 61, no. 17, September 2018 (2018-09-01), pages 7902 - 7916, XP055737478, DOI: 10.1021/acs.jmedchem.8b00893 *
WATABIKI, TOMONARI ET AL.: "In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 815, 2017, pages 42 - 48, XP085245785, DOI: 10.1016/j.ejphar.2017.10.007 *

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