RU2776374C2 - Pharmaceutical drug containing pyridylaminoacetic acid - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to the field of medicine and pharmaceutics; it can be used for the treatment or prevention of primary open-angle glaucoma, secondary open-angle glaucoma, glaucoma with normal pressure or ocular hypertension in patients, for whom other treatments are not effective enough, or in whom the specified diseases are resistant to the treatment with other active ingredients, so that, when treated with other remedies for the treatment of glaucoma or ocular hypertension, a value of reduction in intraocular pressure before and after the treatment is 4.5 mmHg or less. The use of a pharmaceutical drug for the preparation of a drug for the treatment or prevention of the specified diseases is proposed, where the pharmaceutical drug contains omidenepag, its composite ester or its salt as the only active ingredient. Options are also proposed of a method for the treatment or prevention of the specified diseases by administration of a pharmaceutical drug containing omidenepag, its ester or its salt as the only active ingredient.

EFFECT: reduction in intraocular pressure is provided in patients, for whom other treatments for glaucoma or ocular hypertension are not effective enough.

19 cl, 1 dwg

Description

The field of technology to which the invention belongs

The present invention relates to a pharmaceutical preparation for the treatment or prevention of glaucoma or ocular hypertension containing omidenepag, an ester thereof or a salt thereof as an active ingredient, wherein the pharmaceutical preparation is administered to a patient for whom other glaucoma or ocular hypertension treatments are not sufficiently effective.

State of the art

Glaucoma is an intractable eye disease in which intraocular pressure rises for various pathological reasons and internal tissues of the eyeball (such as the retina and optic nerve) are destroyed, which can lead to blindness. A common treatment for glaucoma is intraocular pressure lowering therapy, and typical examples thereof include drug therapy, laser therapy, and surgery.

Drugs used in drug therapy include sympathomimetics (nonselective stimulants such as dipivefrine and α ₂ receptor agonists such as brimonidine), sympatholytics (β receptor blockers such as timolol, befunolol, carteolol, nipradilol, betaxolol, levobunolol, and metipranolol, and α1-receptor blockers such as bunazosin hydrochloride), parasympathomimetics (such as pilocarpine), carbonic anhydrase inhibitors (such as acetazolamide), prostaglandins (such as isopropyl unoprostone, latanoprost, travoprost and bimatoprost), Rho kinase inhibitors (ripasudil), etc. . P.

Of these drugs, latanoprost-containing eye drops have been widely used around the world since their first introduction to the world market in 1996 due to their high efficacy in lowering intraocular pressure and good tolerability. However, it is known that there are a number of patients for whom the effect of latanoprost is not effective enough.

In addition, omidenepag is a compound described as one of numerous pyridylaminoacetic acids in Patent Literature 1 and Patent Literature 2. These pyridylaminoacetic acids are said to have EP2 agonist activity (Patent Literature 2) and thus are believed to be effective for lowering intraocular pressure, and may be a treatment for glaucoma (Patent Literature 1).

In addition, Patent Literature 3 and 4 indicate that the effectiveness of lowering intraocular pressure is increased when omidenepag is combined with another glaucoma treatment such as timolol, Patent Literature 5 indicates that omidenepag at a certain content has a particularly high effect on lowering intraocular pressure and Patent Literature 6 indicates that omidenepag is useful as an agent for the treatment of diseases accompanied by markedly elevated intraocular pressure.

In addition, Patent Literature 7-9 describes specific preparations containing omidenepag as an active ingredient.

It should be noted that the entire content of Patent Literature 1-9 and other literature described in this application is included in this application as a disclosure.

However, none of the references described describe the efficacy of omidenepag, its ester or its salt in patients in whom other treatments for glaucoma or ocular hypertension are not sufficiently effective, and there are no other literature or study reports on such efficacy.

Bibliography

Patent Literature

Patent Literature 1: United States Patent Application Publication No. 2012/0190852

Patent Literature 2: Unites States Patent Application Publication No. 2011/0054172

Patent Literature 3: United States Patent Application Publication No. 2014/0018396

Patent Literature 4: United States Patent Application Publication No. 2014/0018350

Patent Literature 5: United States Patent Application Publication No. 2015/0196541

Patent Literature 6: International Publication No. WO2017/006985

Patent Literature 7: United States Patent Application Publication No. 2016/0317512

Patent Literature 8: United States Patent Application Publication No. 2016/0317664

Patent Literature 9: International Publication No. WO2017/002941

The essence of the invention

The challenge of finding a pharmaceutical preparation that treats or prevents glaucoma or ocular hypertension and is effective for patients for whom glaucoma or ocular hypertension treatments are not effective is very attractive.

Problem solving tools

In view of the above, the inventors of the present invention have made a thorough study and as a result found that omidenepag, its ester or its salt has an excellent ability to reduce intraocular pressure in patients who are not sufficiently effective in other treatments for glaucoma or ocular hypertension. Thus, the present invention was completed. More precisely, the present invention relates to the following.

[one]

A pharmaceutical preparation for the treatment or prevention of glaucoma or ocular hypertension, comprising: omidenepag, an ester thereof or a salt thereof as an active ingredient, wherein the pharmaceutical preparation is administered to a patient for whom other glaucoma or ocular hypertension treatments are not sufficiently effective.

[2]

The pharmaceutical preparation according to paragraph [1] described above, wherein the treatment or prevention of glaucoma or ocular hypertension comprises the treatment or prevention of glaucoma or ocular hypertension with other glaucoma or ocular hypertension treatments and the subsequent treatment or prevention of glaucoma or ocular hypertension by lowering intraocular pressure with an active ingredient.

[3]

The pharmaceutical preparation according to paragraph [1] or [2] described above, wherein the active ingredient of other treatments for glaucoma or ocular hypertension is a prostaglandin F _2α derivative.

[four]

The pharmaceutical preparation according to any one of paragraphs [[1]-[3] described above, wherein the active ingredient of other treatments for glaucoma or ocular hypertension is latanoprost.

[5]

The pharmaceutical preparation according to any one of paragraphs [ [1] - [4] described above, in which the content of omidenepag, its ester or its salt is from 0.001 to 0.003% (w/v).

[6]

The pharmaceutical preparation according to any one of [[1] to [5] above, wherein the content of omidenepag, its ester or its salt is 0.002% (w/v).

[7]

The pharmaceutical preparation according to any one of [[1]-[6] above, wherein omidenepag, an ester thereof, or a salt thereof is omidenepag isopropyl.

[eight]

The pharmaceutical preparation according to any of paragraphs [ [1] - [7] described above, which is eye drops.

[9]

A pharmaceutical preparation that treats or prevents glaucoma or ocular hypertension, comprising: omidenepag, an ester thereof, or a salt thereof as an active ingredient, wherein the glaucoma is glaucoma resistant to treatment of glaucoma with other active ingredients other than omidenepag, an ester thereof, or its salt, and where ocular hypertension is ocular hypertension resistant to treatment of ocular hypertension with other active ingredients.

[ten]

A method for treating or preventing glaucoma or ocular hypertension, comprising: administering to a patient a pharmaceutical preparation containing omidenepag, its ester or salt as an active ingredient, where the patient is a patient for whom other treatments for glaucoma or ocular hypertension are not sufficiently effective.

[eleven]

The method according to paragraph [10] described above, wherein the treatment or prevention of glaucoma or ocular hypertension comprises treating or preventing glaucoma or ocular hypertension with other glaucoma or ocular hypertension treatments and subsequently treating or preventing glaucoma or ocular hypertension by lowering intraocular pressure with the active ingredient .

[12]

The method according to paragraph [10] or [11] described above, wherein the active ingredient of other treatments for glaucoma or ocular hypertension is a prostaglandin F _2α derivative.

[13]

The method according to any of paragraphs [10] - [12] described above, wherein the active ingredient of other treatments for glaucoma or ocular hypertension is latanoprost.

[fourteen]

The method according to any of paragraphs [10] to [13] described above, wherein the content of omidenepag, its ester or its salt in the pharmaceutical preparation is from 0.001 to 0.003% (w/v).

[fifteen]

The method according to any of paragraphs [10] - [14] described above, wherein the content of omidenepag, its ester or its salt in the pharmaceutical preparation is 0.002% (w/v).

[16]

The method according to any one of paragraphs [10] - [15] described above, wherein the omidenepag, ester or salt thereof is isopropyl omidenepag.

[17]

The method according to any one of paragraphs [10] - [16] described above, wherein the administration is an administration to the eyes.

[eighteen]

A method for treating or preventing glaucoma or ocular hypertension, comprising: administering to a patient a pharmaceutical preparation containing omidenepag, an ester thereof or a salt thereof as an active ingredient, wherein the glaucoma is glaucoma resistant to treatment of glaucoma with other active ingredients other than omidenepag, its an ester or salt thereof, and wherein the ocular hypertension is ocular hypertension resistant to treatment of ocular hypertension with other active ingredients.

[19]

A method for treating or preventing glaucoma or ocular hypertension, comprising administering to a patient a pharmaceutical preparation containing omidenepag, an ester thereof, or a salt thereof as an active ingredient, the method comprising the following steps:

(1) the first step of administering to the patient another glaucoma or ocular hypertension treatment other than omidenepag, an ester thereof, or a salt thereof;

(2) a step of determining whether the first stage of treatment is not sufficient to cure or not sufficient to provide a warning; and

(3) a second treatment step comprising additionally administering to the patient a pharmaceutical preparation containing omidenepag, an ester thereof or a salt thereof as an active ingredient, if the first treatment step is insufficient to cure or insufficient to provide prevention.

[twenty]

The use of a pharmaceutical preparation according to any of paragraphs [1] to [9] described above for the preparation of a medicament that treats or prevents glaucoma or ocular hypertension.

It should be noted that two or more of these provisions [1] - [20] optionally can be selected and combined.

As detailed in the examples below, omidenepag, an ester thereof, or a salt thereof, has been found to have excellent ability to lower intraocular pressure in patients in whom other treatments for glaucoma or ocular hypertension have not been effective enough. Therefore, omidenepag, an ester thereof, or a salt thereof is useful as a pharmaceutical preparation that treats or prevents glaucoma or ocular hypertension even in patients for whom other glaucoma or ocular hypertension treatments are not sufficiently effective.

Brief description of the drawings

In FIG. Figure 1 shows the time dependence of changes in intraocular pressure obtained in a clinical study.

Description of Embodiments

Embodiments of the present invention are described in detail below.

[Pharmaceutical drug]

Omidenepag contained in the pharmaceutical preparation of the present invention is a compound having the following formula (1) (CAS registration number; 1187451-41-7):

and is also called (6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetic acid.

The omidenepag ester contained in the pharmaceutical preparation of the present invention is preferably an ester obtained by dehydrating condensation of the carboxy group of omidenepag with a monohydric alcohol having 1 to 6 carbon atoms, and preferably is an ester obtained by dehydrating condensation of the carboxy group of omidenepag with a monohydric alcohol, more preferably containing 2 to 5 carbon atoms and more preferably containing 3 or 4 carbon atoms. Specific esters include methyl esters, ethyl esters, n-propyl esters, isopropyl esters, n-butyl esters, isobutyl esters, sec-butyl esters, tert-butyl esters, n-pentyl esters and n-hexyl esters, more preferably ethyl esters, n-propyl esters, isopropyl esters, and more preferably isopropyl esters. Specific omidenepag isopropyl ether is a compound represented by the following formula (2) (CAS registration number; 1187451-19-9):

and is also referred to as omidenepag isopropyl or isopropyl-(6-{[4-(pyrazol-1-yl)benzyl](pyridin-3-ylsulfonyl)aminomethyl}pyridin-2-ylamino)acetate.

The omidenepag salt or omidenepag ester salt contained in the pharmaceutical preparation of the present invention is not particularly limited as long as it is a pharmacologically acceptable salt. Specific examples include inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates and phosphates; organic acid salts such as acetates, trifluoroacetates, benzoates, oxalates, malonates, succinates, maleates, fumarates, tartrates, citrates, methanesulfonates, ethanesulfonates, trifluoromethanesulfonates, benzenesulfonates, p-toluenesulfonates, glutamates and aspartates; metal salts such as sodium salts, potassium salts, calcium salts and magnesium salts; inorganic salts such as ammonium salts; and organic amine salts such as triethylamine salts or guanidine salts, and preferably include hydrochlorides and trifluoroacetates.

Omidenepag, its ester or its salt contained in the pharmaceutical preparation of the present invention can be obtained, for example, according to the usual method used in the art, and according to the methods described in US Patent Publication No. 2012/0190852 (Patent Literature 1) and in US Patent Application Publication No. 2011/0054172 (Patent Literature 2). In preparation procedures, the content of omidenepag, its ester or its salt in the pharmaceutical preparation of the present invention, the type and amount of additive, the route of administration, etc. may be as described in the above literature. It should be noted that the term "omidenepag, ester or salt thereof" as used herein includes (1) omidenepag, (2) omidenepag ester, (3) omidenepag salt, and (4) omidenepag ester salt.

The content of omidenepag, its ester or its salt in the pharmaceutical preparation of the present invention is not particularly limited and depends on the route of administration, and its lower limit is, for example, 0.000001% (w/v) , preferably 0.00001% (w/v), more preferably 0.00003% (w/v), 0.0001% (w/v), 0.001 (w/v), 0 01% (w/v), 0.1% (w/v) or 1% (w/v). The upper limit value of the above content may be, for example, 30% (w/v), 25% (w/v), 20% (w/v), 15% (w/v) or 12% (w/v), or 0.03% (w/v), 0.01% (w/v), 0.005% (w/v), 0.003% (w/v) ./vol.) or 0.0027% (wt./vol.). More preferably, if the above content can be in the range formed by combining any of the above lower limit values and upper limit values, and is, for example, from 0.000001 to 30% (w/v), preferably from 0, 00001 to 25% (w/v), more preferably 0.00003 to 20% (w/v), more preferably 0.0001 to 15% (w/v), even more preferably from 0.0013 to 12% (w/v) and particularly preferably 0.0015 to 10% (w/v). The expression "% (w/v)" in the present invention means the mass (g) of the active ingredient (omidenepag, its ester or its salt) or additive (such as a surfactant) in 100 ml of a pharmaceutical preparation. For example, omidenepag at 0.01% (w/v) means that the content of omidenepag in 100 ml of a pharmaceutical preparation is 0.01 g.

If the pharmaceutical preparation of the present invention is an eye drop, the lower limit value of the content of omidenepag, its ester or its salt in the pharmaceutical preparation of the present invention is preferably 0.0003% (w/v), more than preferably 0.001% (w/v), more preferably 0.0013% (w/v) and even more preferably 0.0015% (w/v). In addition, the upper limit value of the above content is preferably 0.03% (w/v), more preferably 0.01% (w/v), more preferably 0.005% (w/v), still more preferably 0.003% (w/v) and particularly preferably 0.0027% (w/v). More preferably, if the above content can be in the range formed by combining any lower limit values and upper limit values, and preferably is from 0.0003 to 0.03% (w/v), more preferably from 0.001 to 0, 01% (w/v), more preferably 0.001 to 0.005% (w/v), even more preferably 0.001 to 0.003% (w/v), particularly preferably 0.0013 to 0.003% (w/v) and even more preferably from 0.0015 to 0.0027% (w/v). Especially preferred are 0.0010% (w/v), 0.0011% (w/v), 0.0012% (w/v), 0.0013% (w/v) , 0.0014% (w/v), 0.0015% (w/v), 0.0016% (w/v), 0.0017% (w/v), 0 .0018% (w/v), 0.0019% (w/v), 0.0020% (w/v), 0.0021% (w/v), 0.0022 % (w/v), 0.0023% (w/v), 0.0024% (w/v), 0.0025% (w/v), 0.0026% ( w/v), 0.0027% (w/v), 0.0028% (w/v), 0.0029% (w/v), 0.0030% (w/v) /vol.), 0.005% (wt./vol.), 0.01% (wt./vol.), 0.03% (wt./vol.) and the range including the above values as the upper limit value or lower limit value and 0.002% (w/v) is the most preferred. It should be noted that the above content is a preferred example for eye drops, but is not limited to eye drops.

If the pharmaceutical preparation of the present invention is an eye injection agent, the lower limit value of the content of omidenepag, its ester or its salt in the pharmaceutical preparation of the present invention is preferably 0.000001% (w/v ), more preferably 0.000003 (w/v), more preferably 0.000005% (w/v), even more preferably 0.00001% (w/v), and particularly preferably 0.00003% (w/v). In addition, the upper limit value of the above content is preferably 30% (w/v), more preferably 10% (w/v), more preferably 1% (w/v), even more preferably 0, 1% (w/v) and particularly preferably 0.01% (w/v). More preferably, if the above content can be in the range formed by combining any lower limit values and upper limit values, and is preferably from 0.000001 to 30% (w/v), more preferably from 0.000003 to 10% (w/v), more preferably 0.000005 to 1% (w/v), even more preferably 0.00001 to 0.1% (w/v), and particularly preferably 0, 00003 to 0.01% (w/v). It should be noted that the above content is a preferred example of an eye injection agent, but is not limited to an eye injection agent.

It should be noted that in the case where the pharmaceutical preparation of the present invention contains a salt of omidenepag or an ester thereof, the content of omidenepag or its ester when the salt is released is in the above range.

[Additive]

If necessary, an additive can be used in the pharmaceutical preparation of the present invention. As an additive, for example, surfactants, buffering agents, tonicity agents, stabilizers, preservatives, antioxidants, thickeners, bases, pH adjusters, and the like can be added.

The pharmaceutical preparation of the present invention can be appropriately mixed with a surfactant that can be used as a pharmaceutical additive.

Examples of the surfactant include polyoxyethylene-castor oil systems, polyoxyethylene-hydrogenated castor oil systems, polyoxyethylene sorbitan fatty acid esters, vitamin E TPGS, polyoxyethylene fatty acid esters, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid esters, and the like.

More preferably, if as polyoxyethylene castor oil systems, different polyoxyethylene castor oil systems having different degrees of polymerization of ethylene oxide can be used, and the degree of polymerization of ethylene oxide is preferably from 5 to 100, more preferably from 20 to 50, even more preferably from 30 to 40 and most preferably 35. Specific examples of polyoxyethylene castor oil systems include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, and the like, and polyoxyl 35 castor oil is most preferred. .

As polyoxyethylene-hydrogenated castor oil systems, various polyoxyethylene-hydrogenated castor oil systems having different degrees of polymerization of ethylene oxide can be used, and the degree of polymerization of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, even more preferably 40 to 70 and most preferably 60. Specific examples of the polyoxyethylene-hydrogenated castor oil system include polyoxyethylene-hydrogenated castor oil 10, polyoxyethylene-hydrogenated castor oil 40, polyoxyethylene-hydrogenated castor oil 50, polyoxyethylene-hydrogenated castor oil 60, and polyoxyethylene-hydrogenated castor oil 60 is the most preferred.

The polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65, and the like, and polysorbate 80 is most preferred.

Vitamin E TPGS is also referred to as tocopherol polyethylene glycol 1000 succinate.

Polyoxyethylene fatty acid esters include polyoxyl 40 stearate and the like.

Polyoxyethylene polyoxypropylene glycol includes polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, etc.

Esters of sucrose fatty acids include sucrose stearate.

If the pharmaceutical preparation of the present invention is mixed with a surfactant, its content can be appropriately adjusted depending on the type and the like of the surfactant. More precisely, the lower limit value is preferably 0.001% (w/v), more preferably 0.01% (w/v), more preferably 0.1% (w/v), even more preferably 0, 5% (w/v) and most preferably 0.8% (w/v). The upper limit value is preferably 10% (w/v), more preferably 5% (w/v), more preferably 4% (w/v), even more preferably 3% (w/v). ) and most preferably 2% (w/v). More preferably, if the above content can be in the range formed by combining any lower limit values and upper limit values, and is preferably from 0.001 to 10% (wt./vol.), more preferably from 0.01 to 5% (wt. ./vol.), more preferably from 0.03 to 4% (w/v), even more preferably from 0.05 to 3% (w/v), and most preferably from 0.1 to 2% (w/v).

The pharmaceutical preparation of the present invention can be appropriately mixed with a buffer agent that can be used as a pharmaceutical additive.

Examples of the buffering agent include phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol, and the like. More preferably, the phosphates include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate and the like, borates include borax, sodium borate and potassium borate, citric acid or a salt thereof includes citric acid monohydrate, sodium citrate, disodium citrate, trisodium citrate and the like, acetates include sodium acetate, potassium acetate and the like, carbonates include sodium carbonate, sodium bicarbonate and the like, and tartrates include sodium tartrate, potassium tartrate and the like. Of these, boric acid or a salt thereof or citric acid or a salt thereof is preferred.

If the pharmaceutical preparation of the present invention is mixed with a buffering agent, its content can be appropriately adjusted depending on the type and the like of the buffering agent, and is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), more preferably 0.05 to 3% (w/v) and most preferably 0.1 to 2% (w/v).

The pharmaceutical preparation of the present invention can be appropriately mixed with a tonicity agent that can be used as a pharmaceutical additive.

Examples of the tonicity agent include ionic tonicity agents and nonionic tonicity agents.

The ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like, and the nonionic tonicity agents include glycerol, propylene glycol, sorbitol, mannitol, and the like. mixed with the tonicity adjusting agent, its content can be appropriately adjusted depending on the type and the like of the tonicity adjusting agent, it is preferably 0.01 to 10% (w/v), more preferably 0, 02 to 7% (w/v), more preferably 0.1 to 5% (w/v), even more preferably 0.5 to 4% (w/v) and most preferably from 0.8 to 3% (w/v).

The pharmaceutical preparation of the present invention can be appropriately mixed with a stabilizer that can be used as a pharmaceutical additive.

Examples of the stabilizer include EDTA, monosodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, sodium citrate and the like, and disodium ethylenediaminetetraacetate is particularly preferred. Sodium ethylenediaminetetraacetate may be a hydrate. If the pharmaceutical preparation of the present invention is mixed with a stabilizer, its content can be appropriately adjusted depending on the type and the like of the stabilizer, preferably 0.001 to 1% (w/v), more preferably 0.005 to 0 .5% (w/v) and most preferably 0.01 to 0.1% (w/v).

The pharmaceutical preparation of the present invention can be appropriately mixed with a preservative that can be used as a pharmaceutical additive.

Examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, chlorobutanol, and the like. adjusted depending on the type and the like of the preservative, it is preferably 0.0001 to 1% (w/v), more preferably 0.0005 to 0.1% (w/v), more preferably 0.001 to 0.05% (w/v) and most preferably 0.005 to 0.010% (w/v). In addition, the case where no preservative is included is also preferable.

The pharmaceutical preparation of the present invention can be appropriately mixed with an antioxidant that can be used as a pharmaceutical additive.

Examples of the antioxidant include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite, and the like. If the pharmaceutical preparation of the present invention is mixed with an antioxidant, its content can be appropriately adjusted depending on the type, etc. p. antioxidant, it is preferably from 0.0001 to 1% (w/v), more preferably from 0.0005 to 0.1% (w/v), and most preferably from 0.001 to 0.05% (w/v).

The pharmaceutical preparation of the present invention can be appropriately mixed with a thickener that can be used as a pharmaceutical additive.

Examples of the thickener include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, and p.

If the pharmaceutical preparation of the present invention is mixed with a thickener, its content can be appropriately adjusted depending on the type and the like of the thickener, it is preferably 0.001 to 5% (w/v), more preferably 0 01 to 1% (w/v) and most preferably 0.1 to 0.5% (w/v).

The pharmaceutical preparation of the present invention can be appropriately mixed with a base that can be used as a pharmaceutical additive.

Examples of the base include water, saline, dimethyl sulfoxide, polyethylene glycols such as PEG 400, tributyl citrate, acetyl tributyl citrate, benzyl benzoate, white liquid paraffin, liquid paraffin, and the like, and water, saline, dimethyl sulfoxide and PEG 400 are preferred.

The pH value of the pharmaceutical preparation of the present invention is preferably 4.0 to 8.0, more preferably 4.5 to 7.5, even more preferably 5.0 to 7.0, and most preferably 5.5 up to 6.1. In addition, the pH value may be from 6.0 to 8.0. To the pharmaceutical preparation of the present invention, a pH adjuster such as hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide and potassium hydroxide can be added to adjust the pH.

[Application]

The pharmaceutical preparation of the present invention is excellent in lowering intraocular pressure even in patients in whom other treatments for glaucoma or ocular hypertension are not sufficiently effective, and thus it is useful as a treatment or prevention agent for glaucoma and/or a treatment or prevention agent. ocular hypertension and/or intraocular pressure lowering agents. In the present invention, glaucoma includes primary open-angle glaucoma, secondary open-angle glaucoma, normal pressure glaucoma, hypersecretory glaucoma, primary angle-closure glaucoma, secondary angle-closure glaucoma, flat iris glaucoma, mixed glaucoma, congenital glaucoma, steroid glaucoma, exfoliative glaucoma, amyloid glaucoma, revascularization glaucoma, malignant glaucoma, lens capsular glaucoma, flat iris syndrome, and the like, and preferably primary open-angle glaucoma, normal pressure glaucoma and primary angle-closure glaucoma. In particular, the pharmaceutical preparation of the present invention is effective in primary open-angle glaucoma.

The pharmaceutical preparation of the present invention is preferably administered to patients who are not sufficiently effective in other treatments for glaucoma or ocular hypertension. Other glaucoma or ocular hypertension treatment is any glaucoma or ocular hypertension treatment containing an active ingredient other than omidenepag, an ester or salt thereof (another active ingredient), and specific examples of an active ingredient other than omidenepag, its ester or salt thereof include non-selective sympathomimetics, α 2 receptor agonists, α ₁ receptor blockers, β receptor blockers, parasympathomimetics, carbonic anhydrase inhibitors, prostaglandins, and Rho kinase inhibitors.

Specific examples of non-selective sympathomimetics include dipivefrine, specific examples of _α2 receptor agonists include brimonidine and apraclonidine, specific examples of α1 receptor blockers include bunazosin, specific examples of β receptor blockers include timolol, befunolol, cartolol, nipradilol, betaxolol, levobunolol and metipranolol, specific examples of parasympathomimetics include pilocarpine, specific examples of carbonic anhydrase inhibitors include dorzolamide, brinzolamide and acetazolamide, specific examples of prostaglandins include latanoprost, isopropyl unoprostone, bimatoprost and travoprost, and specific examples of Rho kinase inhibitors include fazudil. Of these, prostaglandins are preferred, prostaglandin F _2α derivatives are more preferred, latanoprost is also preferred, latanoprost ophthalmic solution is particularly preferred, and latanoprost ophthalmic solution 0.005% is most preferred.

Patients for whom other treatments for glaucoma or ocular hypertension are not sufficiently effective are patients for whom the advantage of sufficient efficacy in the treatment of other treatments for glaucoma or ocular hypertension cannot be provided. More precisely, the patients are preferably those in whom, when treated with other glaucoma or ocular hypertension treatments, the degree of reduction in intraocular pressure after treatment compared with intraocular pressure before treatment (the degree of reduction in intraocular pressure: [intraocular pressure before treatment (mm Hg) - intraocular pressure after treatment (mmHg)]/[intraocular pressure before treatment (mmHg)]×100) is 18% or less, preferably 17% or less, more preferably 16% or less, more preferably 15% or less, even more preferably 14% or less, particularly preferably 13% or less, even more preferably 12% or less, and most preferably 10% or less. In addition, patients are also preferably those who, when treated with other treatments for glaucoma or ocular hypertension, have a value of lowering intraocular pressure after treatment compared to intraocular pressure before treatment (=change in intraocular pressure: [intraocular pressure before treatment (mmHg ) - intraocular pressure after treatment (mm Hg)]) is equal to 4.5 mm Hg. or less, preferably 4.2 mmHg. or less, more preferably 4 mm Hg. or less, more preferably 3.7 mmHg. or less, even more preferably 3.5 mmHg. or less, particularly preferably 3.2 mmHg. or less, even more preferably 3 mmHg. or less and most preferably 2.5 mm Hg. or less. This treatment with other treatments for glaucoma or ocular hypertension is usually carried out by administering to the eye 1 to 3 drops at a time and 1 to 3 drops per day for 1 week or more, preferably 2 weeks or more, more preferably 4 weeks or more, more preferably 2 months or more, even more preferably 6 months or more, and most preferably 1 year or more. In addition, patients for whom other treatments for glaucoma or ocular hypertension are not sufficiently effective include patients who cannot be treated with other treatments for glaucoma or ocular hypertension or who cannot use them due to side effects, etc. It should be noted that patients for which the pharmaceutical preparation of the present invention is intended are mammals, including domestic animals such as cows and pigs, rabbits, monkeys, dogs, cats, and humans, and preferably humans.

On the other hand, the pharmaceutical preparation of the present invention makes it possible to further reduce intraocular pressure in a patient who is treated with other treatments for glaucoma or ocular hypertension, even if the degree of reduction in intraocular pressure and changes in intraocular pressure to such an extent that the effectiveness is considered insufficient. as described above. The degree of reduction in intraocular pressure after treatment compared with intraocular pressure before treatment (intraocular pressure reduction rate) attributed to the pharmaceutical preparation of the present invention is preferably not less than 5%, such as 6% or more, preferably 7% or more, more preferably 8% or more, more preferably 9% or more, even more preferably 10% or more, particularly preferably 11% or more, even more preferably 12% or more, and most preferably 13% or more. The upper limit value of the degree of reduction in intraocular pressure attributed to the pharmaceutical preparation of the present invention may be, for example, 40% or less, preferably 35% or less, more preferably 30% or less, more preferably 28% or less, even more preferably 26% or less, particularly preferably 24% or less, even more preferably 22% or less, and most preferably 20% or less. You can suitably select a range obtained by suitably combining any of the above upper limit values and lower limit values. The preferred degree of intraocular pressure reduction attributed to the pharmaceutical preparation of the present invention is, for example, 5 to 40%, preferably 7 to 35%, and more preferably 9 to 30%.

In addition, when using the pharmaceutical preparation of the present invention, the value of reduction in intraocular pressure after treatment compared with intraocular pressure before treatment (change in intraocular pressure) attributed to the pharmaceutical preparation of the present invention is preferably not less than 1.0 mm Hg. .st. or more, preferably 1.2 mmHg. or more, more preferably 1.4 mmHg. or more, more preferably 1.6 mmHg. or more, even more preferably 1.8 mmHg. or more, particularly preferably 2.0 mmHg. or more, even more preferably 2.5 mmHg. or more and most preferably 2.9 mmHg. or more. The upper limit value of intraocular pressure change attributed to the pharmaceutical preparation of the present invention may be, for example, 10.0 mmHg. or less, preferably 8.0 mmHg. or less, more preferably 6.0 mmHg. or less, more preferably 5.5 mmHg. or less, even more preferably 5.0 mmHg. or less, particularly preferably 4.5 mm Hg. or less, even more preferably 4.0 mmHg. or less and most preferably 3.2 mmHg. or less. You can suitably select a range obtained by suitably combining any of the above upper limit values and lower limit values. The preferred change in intraocular pressure attributed to the pharmaceutical preparation of the present invention is, for example, from 1.0 to 10.0 mmHg, preferably from 1.4 to 8.0 mmHg. and more preferably from 1.8 to 6.0 mmHg.

It should be noted that the "degree of reduction in intraocular pressure after treatment compared with intraocular pressure before treatment (degree of reduction in intraocular pressure) attributed to the pharmaceutical preparation of the present invention" and "reduction value (change in intraocular pressure)" defined in the present invention, means the degree of reduction and the value of reduction in intraocular pressure in the second stage of treatment, as indicated in paragraph (3) of the section [Method of administration] described below, but does not include the degree of reduction in intraocular pressure and change in intraocular pressure due to treatment with other glaucoma or ocular hypertension treatment, as in the first stage of treatment, as indicated in paragraph (1) of the section [Method of administration]. Therefore, the pharmaceutical preparation of the present invention containing omidenepag and the like as an active ingredient can reduce intraocular pressure in addition to the therapeutic effects of other glaucoma or ocular hypertension treatments containing latanoprost and the like as active ingredients.

For a more significant reduction in intraocular pressure, the pharmaceutical preparation of the present invention can be used in combination (for example, can be used as a set in combination) with one or more, preferably with one to three, and more preferably with one or two additional glaucoma treatments. or ocular hypertension or it may contain an additional active ingredient. Additional treatments for glaucoma or ocular hypertension are not particularly limited. In particular, commercially available or developing treatments for glaucoma or ocular hypertension and the like are preferred, commercially available treatments for glaucoma or ocular hypertension, and the like are more preferred, and commercially available treatments for glaucoma or ocular hypertension, having a mechanism of action different from the mechanism of action of the compounds proposed in the present invention are particularly preferred. More specific examples include agents for the treatment of glaucoma or ocular hypertension containing as active ingredients non-selective sympathomimetics, α 2 receptor agonists, α ₁ receptor blockers, β receptor blockers, parasympathomimetics, carbonic anhydrase inhibitors, prostaglandins, Rho kinase inhibitors, and the like. Specific examples of the additional active ingredient include non-selective sympathomimetics, α2 receptor agonists, _α1 receptor blockers, β receptor blockers, parasympathomimetics, carbonic anhydrase inhibitors, prostaglandins, Rho kinase inhibitors, and the like. in the present invention, used in combination with an additional agent for the treatment of glaucoma or ocular hypertension, or it contains an additional active ingredient, "the degree of reduction in intraocular pressure after treatment compared with intraocular pressure before treatment (degree of intraocular pressure reduction) attributed by the pharmaceutical the present invention" and "lowering value (change in intraocular pressure)" described above mean the part of the effect excluding the effect of the additional glaucoma or ocular hypertension treatment agent or the additional active ingredient.

Specific examples of non-selective sympathomimetics include dipivefrine, specific examples of _α2 receptor agonists include brimonidine and apraclonidine, specific examples of α1 receptor blockers include bunazosin, specific examples of β receptor blockers include timolol, befunolol, cartolol, nipradilol, betaxolol, levobunolol and metipranolol, specific examples of parasympathomimetics include pilocarpine, specific examples of carbonic anhydrase inhibitors include dorzolamide, brinzolamide and acetazolamide, specific examples of prostaglandins include isopropyl unoprostone, bimatoprost and travoprost, and specific examples of Rho kinase inhibitors include fazudil.

[Way of introduction]

The pharmaceutical preparation of the present invention may be administered orally or parenterally, for example, by ophthalmic administration, vitreous administration, conjunctival sac administration, intracameral administration, subconjunctival administration, Tenon's capsule administration, or punctal plug administration. The dosage form of the pharmaceutical preparation of the present invention includes eye drops, eye ointments, injections, punctal inserts, tablets, capsules, granules, powders, and the like, and eye drops, eye injections, and eye inserts. puncta is particularly preferred. Ocular injections include intracameral, intracameral, conjunctival sac, intracameral, subconjunctival, or Tenon capsule injection. The dosage form of the pharmaceutical preparation of the present invention can be prepared according to conventional methods used in the field of medicines. In addition to the additives described above, oral preparations such as tablets, capsules, granules and powders can be prepared, if necessary, using bulking agents such as lactose, crystalline cellulose, starch and vegetable oil, lubricants such as magnesium stearate and talc. , binders such as hydroxypropylcellulose and polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose calcium salt and low substituted hydroxypropylmethylcellulose, coating agents such as hydroxypropyl methylcellulose, macrogol and silicone resin, film-like materials such as gelatin coating, and the like.

The pharmaceutical preparation of the present invention can be stored in containers made from different materials. For example, containers made of polyethylene, polypropylene, and the like can be used, and in the case of eye drops, the pharmaceutical preparation of the present invention is preferably stored in a polyethylene container, which allows, for example, ease of dropwise administration (container stiffness ) and the stability of the compound of the present invention.

[Dose and administration]

The dosage and administration of the pharmaceutical preparation of the present invention is not particularly limited as long as the dosage and administration are sufficient to provide the desired efficacy and can be properly selected according to the symptoms of the disease, the age and weight of the patient, the dosage form of the pharmaceutical preparation, etc. .

Particularly in the case of eye drops, 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 or 2 drops, and even more preferably 1 drop per dose may be administered to the eyes 1 to 4 times a day, preferably 1 to 3 times a day, more preferably 1 or 2 times a day, and particularly preferably 1 time a day and with a frequency of daily to weekly administration. Preferably, the eye drops are administered 1 drop per day daily. In this case, the volume of 1 drop is usually from about 0.01 to about 0.1 ml, preferably from about 0.015 to about 0.07 ml, more preferably from about 0.02 to about 0.05 ml, and even more preferably about 0 .03 ml.

In the case of an ophthalmic injection, it is preferable to simultaneously administer 1 to 1000 µl, more preferably 5 to 700 µl, more preferably 10 to 500 µl, and most preferably 20 to 300 µl. The dose of drug is preferably 0.0001 to 30,000 µg/eye, more preferably 0.0005 to 10,000 µg/eye, and most preferably 0.001 to 5000 µg/eye. If the pharmaceutical preparation of the present invention is continuously administered to the eye by injection, there are no particular restrictions on the interval between administrations as long as it is sufficient to provide the desired efficacy. However, the interval between administrations is preferably 1 week to 3 years, more preferably if the interval between administrations is 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years. or 3 years and most preferably 2 months, 3 months, 4 months, 5 months or 6 months. In addition, the interval between injections can be changed accordingly.

In the case of an oral preparation, it may be administered at a dose of 0.01 to 5000 mg and preferably 0.1 to 1000 mg/day one to several times singly (1 to 5 times, preferably 2 or 3 times).

[Introduction Method]

The pharmaceutical preparation of the present invention is administered thereafter if sufficient efficacy is not provided or expected to be obtained by treating or preventing other treatments for glaucoma or ocular hypertension described above. More specifically, the method of administering the pharmaceutical preparation of the present invention includes

(1) the first step in the treatment or prevention of glaucoma or ocular hypertension with other active ingredients as described above other than omidenepag, an ester thereof or a salt thereof,

(2) an optional step of determining whether the first treatment step is insufficient to cure or insufficient to provide a warning, and

(3) after the first stage of treatment, the second stage of treatment or prevention of glaucoma or ocular hypertension by administering a pharmaceutical preparation containing omidenepag, an ester thereof or a salt thereof as an active ingredient.

If the pharmaceutical preparation of the present invention is administered to a patient by the administration method described above, the pharmaceutical preparation of the present invention further effectively reduces intraocular pressure and the like, and further makes it possible to treat or prevent glaucoma or ocular hypertension regardless of the effectiveness of the treatment or prevention of the other active ingredients described above, or if the effectiveness is insufficient.

The above method of administration is described in more detail. First, other glaucoma or ocular hypertension treatments (other active ingredients) other than omidenepag, an ester thereof, or a salt thereof of the present invention are administered to treat or prevent glaucoma or ocular hypertension. Then, if other active ingredients are expected to have insufficient curative effect or insufficient preventive effect, glaucoma is considered "glaucoma resistant to treatment of glaucoma with other active ingredients" or "ocular hypertension resistant to treatment of ocular hypertension with other active ingredients". Omidenepag, its ester or its salt according to the present invention is then introduced. In this case, the situation "expected to have insufficient curative effect or insufficient preventive effect" includes the case of an approximate degree of reduction in intraocular pressure and the value of reduction in intraocular pressure for the above "patients for whom the advantage due to sufficient efficacy cannot be provided with treatment by other means. treatment of glaucoma or ocular hypertension" as well as the case when the absolute value of intraocular pressure is high enough to conclude the presence of glaucoma or ocular hypertension, for example, equal to 22 mm Hg. or more, preferably 21.5 mmHg. or more, more preferably 21 mmHg. or more, more preferably 20.5 mmHg. or more and even more preferably 20 mmHg. or more. If glaucoma or ocular hypertension is still not cured or the potential risk of recurrence remains even after administration of the other active ingredients described above, it is reasonable to use the pharmaceutical preparation of the present invention as a secondary agent. As shown above, in the case where the treatment and the like of glaucoma or ocular hypertension with the above-described other active ingredients such as latanoprost is not sufficient, and even in the case where, based on ordinary knowledge, it is believed that other active ingredients have led to a sufficient completion treatment or prevention, the pharmaceutical preparation of the present invention provides unexpected effects, this treatment or prevention may lead to additional completion and provides a solution to a problem different from the usual.

For example, if we consider latanoprost as another active ingredient. In the event that glaucoma or ocular hypertension is treated or prevented with latanoprost and then additional reduction in intraocular pressure is required, or in the case where a return of increased intraocular pressure occurs or is expected after treatment or prevention with latanoprost, it can be assumed that the pharmaceutical preparation of the present invention, will have an impact on the necessary reduction in intraocular pressure or on the prevention of the return of increased intraocular pressure.

Examples relating to production examples and results of the clinical study conducted in the present invention are given below. It should be noted that these examples are intended to provide a better understanding of the present invention and do not limit the scope of the present invention.

[Examples]

[Receiving example]

Omidenepag, an ester thereof or a salt thereof according to the present invention can be used to prepare the pharmaceutical preparation described above. Below in the present invention are typical examples of obtaining a pharmaceutical preparation proposed in the present invention. It should be noted that, in the preparation examples below, the amount of each of the ingredients is the content in 100 ml of the preparation.

[Receiving Example 1]

Eye drops 1 (in an amount equal to 100 ml)

Omidenepag isopropyl Boric acid Glycerol Polysorbate 80 Disodiumethylenediaminetetraacetate Benzalkonium chloride Dilute hydrochloric acid how much do you need Sodium hydroxide how much do you need Purified water how much do you need

[Receiving Example 2]

Eye drops 2 (in an amount equal to 100 ml)

Omidenepag isopropyl Sodium dihydrogen phosphate Glycerol Vitamin E TPGS Disodiumethylenediaminetetraacetate Benzalkonium chloride Dilute hydrochloric acid how much do you need Sodium hydroxide how much do you need Purified water how much do you need

[Receiving Example 3]

Eye drops 3 (in an amount equal to 100 ml)

Omidenepag isopropyl Trisodium citrate Glycerol Polyoxyethylene - hydrogenated castor oil 60 Disodiumethylenediaminetetraacetate Benzalkonium chloride Dilute hydrochloric acid how much do you need Sodium hydroxide how much do you need Purified water how much do you need

[Receiving Example 4]

Injection 1 (in an amount equal to 100 ml)

Omidenepag PEG400 how much do you need

[Receiving Example 5]

Injection 2 (in an amount equal to 100 ml)

Omidenepag PEG400 how much do you need

It should be noted that in Preparation Examples 1-5, the desired pharmaceutical preparation can be prepared by appropriate selection of the type and/or amount of omidenepag and/or additive to be mixed. In particular, the desired pharmaceutical preparation can be prepared by using the amount of miscible omidenepag indicated in Preparation Examples 1 to 5 equal to 0.001 g, 0.0011 g, 0.0012 g, 0.0013 g, 0.0014 g, 0.0015 g 0.0016 g 0.0017 g 0.0018 g 0.0019 g 0.0021 g 0.0022 g 0.0023 g 0.0024 g 0.0025 g 0.0026 g , 0.0027 g, 0.0028 g, 0.0029 g or 0.003 g.

[Clinical study]

Omidenepag isopropyl has been studied in patients who are not sufficiently effective with other treatments for glaucoma or ocular hypertension.

1. Preparation of eye drops

Omidenepag isopropyl, polyoxyl 35 castor oil, glycerin, citric acid, sodium citrate, sodium ethylenediaminetetraacetate and benzalkonium chloride were dissolved in purified water to adjust the pH. Purified water was then added to establish the full volume and thus 0.002% (w/v) omidenepag isopropyl eye drops A was obtained.

2. Research methodology

For patients with primary open-angle glaucoma or ocular hypertension, a washout period of 1 to 4 weeks was used, and then 0.005% latanoprost ophthalmic solution was dropped into both eyes in an amount equal to 1 drop 1 time per day for 8 weeks as induction phase (week -8 to baseline). Patients with primary open-angle glaucoma (21 subjects) or ocular hypertension (5 subjects) who were resistant to treatment with latanoprost ophthalmic solution and whose IOP reduction from the start of the drops was 15% or less by the end of the induction phase were referred to the treatment phase (from 0.002% (w/v) omidenepag isopropyl eye drops A as described above in an amount equal to 1 drop (about 0.03 ml) once daily for 4 weeks at baseline until week 4) and were administered in both eyes .

3. Research results and discussion

The results are shown in FIG. one.

Change in intraocular pressure (mean ± standard error) 4 weeks after the administration of the drops, which is the time point (week 4) at the end of the treatment phase, from the time point (baseline) with the transition from administration of 0.005% latanoprost ophthalmic solution in the induction phase to administration of 0.002% (w/v) omidenepag isopropyl eye drops in the treatment phase was -2.99 ± 0.43 mmHg. Thus, there was a statistically significant decrease in intraocular pressure (P < 0.0001). In addition, the degree of reduction in intraocular pressure at the end of the treatment phase (week 4) compared to baseline intraocular pressure was 13.2%. Thus, it became clear that in patients resistant to treatment with latanoprost, omidenepag isopropyl reduces intraocular pressure to a greater extent than latanoprost drops.

Based on the above data, omidenepag, an ester thereof or a salt thereof, is found to have an excellent ability to reduce intraocular pressure in patients who are not sufficiently effective in other treatments for glaucoma or ocular hypertension.

Claims (22)

1. The use of a pharmaceutical preparation for the preparation of a medicament for the treatment or prevention of primary open-angle glaucoma, secondary open-angle glaucoma, normal pressure glaucoma or ocular hypertension, wherein the pharmaceutical preparation contains omidenepag, an ester thereof, or a salt thereof as the sole active ingredient, wherein the pharmaceutical preparation is intended for administration to a patient for whom other treatments for glaucoma or ocular hypertension are not sufficiently effective, so that when treated with other agents for the treatment of glaucoma or ocular hypertension, the value of intraocular pressure reduction before treatment and after treatment is 4.5 mm Hg. Art. or less. 2. Use according to claim 1, wherein the treatment or prevention of glaucoma or ocular hypertension comprises the treatment or prevention of glaucoma or ocular hypertension with other glaucoma or ocular hypertension treatments and subsequent treatment or prevention of glaucoma or ocular hypertension by lowering intraocular pressure with omidenepag, its compound ether or its salt. 3. Use according to claim 1 or 2, wherein the active ingredient of the other treatments for glaucoma or ocular hypertension is a prostaglandin F _2α derivative. 4. Application according to any one of paragraphs. 1-3, wherein the active ingredient in other treatments for glaucoma or ocular hypertension is latanoprost. 5. Application according to any one of paragraphs. 1-4, in which the content of omidenepag, its ester or its salt is from 0.001 to 0.003% (w/v). 6. Application according to any one of paragraphs. 1-5, wherein the content of omidenepag, its ester or its salt is 0.002% (w/v). 7. Application according to any one of paragraphs. 1-6, wherein the omidenepag, ester or salt thereof is omidenepag isopropyl. 8. Application according to any one of paragraphs. 1-7, wherein the pharmaceutical preparation is an eye drop. 9. The use of a pharmaceutical preparation for the preparation of a medicament for the treatment or prevention of primary open-angle glaucoma, secondary open-angle glaucoma, normal pressure glaucoma or ocular hypertension, wherein the pharmaceutical preparation contains: omidenepag, an ester thereof, or a salt thereof as the sole active ingredient, where glaucoma is glaucoma resistant to treatment of glaucoma with other active ingredients other than omidenepag, its ester or salt thereof, and where ocular hypertension is ocular hypertension resistant to treatment of ocular hypertension with other active ingredients, so that when treated with other treatments glaucoma or ocular hypertension, the value of lowering intraocular pressure before and after treatment is 4.5 mm Hg. Art. or less. 10. A method for treating or preventing primary open-angle glaucoma, secondary open-angle glaucoma, normal pressure glaucoma, or ocular hypertension, comprising: administering to a patient a pharmaceutical preparation containing omidenepag, an ester thereof, or a salt thereof as the sole active ingredient, where the patient is the patient, for which other treatments for glaucoma or ocular hypertension are not sufficiently effective, so that when treated with other drugs for the treatment of glaucoma or ocular hypertension, the value of reducing intraocular pressure before treatment and after treatment is 4.5 mm Hg. Art. or less. 11. The method of claim 10 wherein treating or preventing glaucoma or ocular hypertension comprises treating or preventing glaucoma or ocular hypertension with other glaucoma or ocular hypertension treatments and then treating or preventing glaucoma or ocular hypertension by lowering intraocular pressure with omidenepag, its compound ether or its salt. 12. The method according to claim 10 or 11, wherein the active ingredient of other treatments for glaucoma or ocular hypertension is a prostaglandin F _2α derivative. 13. The method according to any one of paragraphs. 10-12, where the active ingredient in other treatments for glaucoma or ocular hypertension is latanoprost. 14. The method according to any one of paragraphs. 10-13, in which the content of omidenepag, its ester or its salt in the pharmaceutical preparation is from 0.001 to 0.003% (w/v). 15. The method according to any one of paragraphs. 10-14, in which the content of omidenepag, its ester or its salt in the pharmaceutical preparation is 0.002% (w/v). 16. The method according to any one of paragraphs. 10-15, wherein omidenepag, its ester or its salt is omidenepag isopropyl. 17. The method according to any one of paragraphs. 10-16, wherein the administration is an administration to the eyes. 18. A method for treating or preventing primary open-angle glaucoma, secondary open-angle glaucoma, normal pressure glaucoma or ocular hypertension, comprising: administering to a patient a pharmaceutical preparation containing omidenepag, an ester thereof or a salt thereof as the sole active ingredient, wherein the glaucoma is glaucoma, resistant to treatment of glaucoma with other active ingredients other than omidenepag, its ester or salt thereof, and where the ocular hypertension is ocular hypertension resistant to the treatment of ocular hypertension with other active ingredients, so that when treated with other agents for the treatment of glaucoma or ocular hypertension the value of reducing intraocular pressure before treatment and after treatment is 4.5 mm Hg. Art. or less. 19. A method for treating or preventing primary open-angle glaucoma, secondary open-angle glaucoma, normal pressure glaucoma or ocular hypertension, comprising administering to a patient a pharmaceutical preparation containing omidenepag, an ester thereof, or a salt thereof as the sole active ingredient, the method comprising the following steps: (1) the first step of administering to the patient another glaucoma or ocular hypertension treatment other than omidenepag, an ester thereof, or a salt thereof; (2) a step of determining whether the first stage of treatment is not sufficient to cure or not sufficient to provide a warning; and (3) the second stage of treatment, including further administration to the patient of a pharmaceutical preparation containing omidenepag, its ester or its salt as an active ingredient, if the first stage of treatment is insufficient to cure or insufficient to provide a warning, so that the value of lowering intraocular pressure before treatment and after treatment is 4.5 mm Hg. Art. or less.

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