JP7469435B2 - Pharmaceutical Preparations (2) - Google Patents

Description

The present invention relates to pharmaceutical preparations, etc.

It has been known that some isoquinoline-6-amino derivatives are useful for the prevention and treatment of eye diseases such as ocular hypertension and glaucoma.
Specifically, for example, the following structural formula:

The compound represented by the formula (chemical name: {4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl}methyl 2,4-dimethylbenzoate, international generic name: netarsudil. In the following, this compound may be referred to as "netarsudil" in this specification.) is also known as AR-13324, and has pharmacological effects such as Rho kinase inhibitory action and norepinephrine transporter inhibitory action, and has been reported to be useful in the prevention and treatment of eye diseases such as ocular hypertension and glaucoma (for example, Patent Document 1, Non-Patent Documents 1 and 2).

Also, similarly, the following structural formula:

The compound represented by the formula (chemical name: rac-(2R)-2-(dimethylamino)-N-(1-oxo-1,2-dihydroisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide, international generic name: verosudil. In the following, this specification may refer to it as "verosudil") is also known as AR-12286, and has been reported to have a Rho kinase inhibitory effect and to be useful in the prevention and treatment of eye diseases such as ocular hypertension (for example, Patent Document 2, Non-Patent Documents 1 and 3).
Therefore, it would be extremely useful to establish a technique for stably formulating these isoquinoline-6-amino derivatives into, for example, ophthalmic preparations.

Incidentally, Patent Document 3 describes the preparation of compositions containing Netarsudil and Velosudil in 150 mL plastic containers. However, in this document, the preparation of each composition was done for use in pharmacological tests, and there is no description whatsoever of the stability of Netarsudil and Velosudil in the compositions, nor is there any description of the material or characteristics of the container.

JP 2012-525386 A WO2009/091898 Pamphlet JP 2016-515520 A

Bacharach J. et al., Ophthalmology 122 (2) 302-7 (2015) Sturdivant JM. et al., Bioorg Med Chem Lett. 26(10) 2475-80 (2016) Williams RD. et al., Am. J. Ophthalmol. 152(5) 834-41 (2011)

Ophthalmic preparations and the like are usually compositions containing water (aqueous compositions). Therefore, the present inventors prepared an aqueous composition containing an isoquinoline-6-amino derivative such as netarsudil, placed it in a container, and confirmed its storage stability.
However, it has been unexpectedly found that the aqueous composition becomes cloudy and loses clarity over time when stored at high temperatures. The loss of clarity due to clouding of the aqueous composition not only means a loss of quality, but also makes it difficult to check whether or not the aqueous composition is contaminated with foreign matter, which can be a major problem in quality control during production.
Therefore, an object of the present invention is to provide a pharmaceutical preparation which is stable even at high temperatures, even though it is an aqueous composition containing an isoquinoline-6-amino derivative such as Netasudil or Velosudil.

The inventors therefore conducted further intensive research to improve the stability of aqueous compositions containing isoquinoline-6-amino derivatives at high temperatures. They discovered that by adding one or more members selected from the group consisting of polyhydric alcohols and prostaglandins to an aqueous composition containing isoquinoline-6-amino derivatives, the loss of clarity during storage at high temperatures is suppressed, and they also discovered that by storing this aqueous composition in a transparent container, it becomes possible to check for the presence or absence of foreign matter in the aqueous composition by visual observation from outside the container, resulting in a pharmaceutical preparation with improved stability at high temperatures and capable of quality control, thus completing the present invention.

That is, the present invention relates to a composition comprising the following components (A) and (B):
(A) a compound represented by the following general formula (1):

(wherein R ₁ and R ₂ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group;
_R3 represents a hydrogen atom or a hydroxyl group;
A represents -CH(R ₄ )- or -CH ₂ -CH(R ₄ )- (wherein R ₄ represents an optionally substituted C ₆ -C ₁₀ aryl group or an optionally substituted 5-10 membered heteroaryl group),
Furthermore, formula (1) also includes its tautomers.
or a salt thereof, or a solvate thereof;
(B) one or more members selected from the group consisting of polyhydric alcohols and prostaglandins;
The present invention provides a pharmaceutical preparation, comprising an aqueous composition containing the above in a transparent container.

According to the present invention, it is possible to improve the stability at high temperatures of aqueous compositions containing isoquinoline-6-amino derivatives such as netasudil.

1 is a graph showing the light transmittance (%) in the wavelength range of 270 to 800 nm of a transparent polypropylene eye drop container containing a benzotriazole-based ultraviolet absorber used in Test Example 6. 1 is a graph showing the light transmittance (%) in the wavelength range of 270 to 800 nm of the side surface (the portion wrapped with the shrink film) of a transparent polypropylene eye drop container equipped with a shrink film containing an ultraviolet scattering agent, used in Test Example 7.

In this specification, "general formula (1)

(wherein R ₁ and R ₂ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group;
_R3 represents a hydrogen atom or a hydroxyl group;
A represents -CH(R ₄ )- or -CH ₂ -CH(R ₄ )- (wherein R ₄ represents an optionally substituted C ₆ -C ₁₀ aryl group or an optionally substituted 5-10 membered heteroaryl group),
Furthermore, formula (1) also includes its tautomers.
The term "a compound represented by formula (1), a salt thereof, or a solvate thereof" includes not only the compound represented by formula (1) itself, but also its salts and solvates.

Here, the salt of the compound represented by general formula (1) is not particularly limited as long as it is a pharma- ceutically acceptable salt, and specific examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, and hydrobromide; and organic acid salts such as acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, and camphorsulfonate; and the like. Of these, hydrochloride and methanesulfonate are preferred.
Furthermore, examples of solvates of the compound represented by formula (1) or a salt thereof include hydrates and alcohol solvates.
Furthermore, when an asymmetric carbon is present in the chemical structure of the compound represented by general formula (1), various stereoisomers may exist. However, the stereoconfiguration of the compound represented by general formula (1) is not particularly limited, and the compound may be a single stereoisomer or a mixture of various stereoisomers in any ratio.
In this specification, when a compound represented by various formulas has an asymmetric carbon in its chemical structure, unless a steric configuration is particularly specified, such formula includes all of the various stereoisomers alone and mixtures of them in any ratio. Therefore, a compound represented by a formula that does not particularly specify a steric configuration may be a single stereoisomer or a mixture of various stereoisomers in any ratio.

In addition, general formula (1) includes not only the compound directly represented by general formula (1) itself, but also its tautomers. Specifically, for example, in the case of the following general formula (1a) in which R ₃ is a hydroxy group, its tautomer (general formula (1b)) may occur, but "compounds represented by general formula (1)" include not only compounds represented by the following general formula (1a) but also compounds represented by general formula (1b).

In this specification, "C ₁ -C ₄ alkyl group" means a linear, branched or cyclic alkyl group having 1 to 4 carbon atoms. Specific examples of the "C ₁ -C ₄ alkyl group" include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, an n-butyl group, a t-butyl group, an isobutyl group, etc., with a methyl group being preferred.
In this specification, the term "C ₆ -C ₁₀ aryl group" refers to an aryl group having a carbon number of 6 to 10. Specific examples of the "C ₆ -C ₁₀ aryl group" include a phenyl group and a naphthyl group, with a phenyl group being preferred.

In this specification, the term "5- to 10-membered heteroaryl group" refers to a 5- to 10-membered monocyclic, polycyclic or fused-ring aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms as ring-constituting atoms. Specific examples of the "5- to 10-membered heteroaryl group" include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrimidyl group, a pyrazinyl group, a pyridazinyl group, a benzofuranyl group, an isobenzofuranyl group, a benzothienyl group, an indolyl group, an isoindolyl group, an indazolyl group, a benzimidazolyl group, a benzoyl group, a benzo ... Examples of the alkyl group include benzoxazolyl group, benzoisoxazolyl group, benzothiazolyl group, benzoisothiazolyl group, benzoxadiazolyl group, benzothiadiazolyl group, benzotriazolyl group, quinolyl group, isoquinolyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, phthalazinyl group, naphthyridinyl group, purinyl group, pteridinyl group, furopyridyl group, thienopyridyl group, pyrrolopyridyl group, oxazolopyridyl group, thiazolopyridyl group, and imidazopyridyl group, with thienyl group being preferred.

In this specification, specific examples of the "substituent" in the "optionally substituted _C6 - _C10 aryl group" and "optionally substituted 5- to 10-membered heteroaryl group" include a halogen atom and _-CH2 -OC(=O) _-R5 (wherein _R5 means a _C6 - _C10 aryl group which may have 1 to 3 _C1 - _C4 alkyl groups as substituents (for example, a 2,4-dimethylphenyl group)), and a chlorine atom and a 2,4-dimethylphenylcarboxymethyl group are preferred.
In the present specification, the "optionally substituted C ₆ -C ₁₀ aryl group" is preferably a 4-chlorophenyl group or a 4-(2,4-dimethylphenylcarboxymethyl)phenyl group.
In the present specification, the "optionally substituted 5- to 10-membered heteroaryl group" is preferably a 3-thienyl group.
When R ₃ is a hydroxy group, the substitution position of R ₃ is not limited so long as it is on the isoquinoline ring, but the 1-position of the isoquinoline ring is preferred.

In this specification, the term "compound represented by general formula (1) or its salt, or solvate thereof" refers to the compound represented by the following formula (2):

A compound represented by the following formula (3):

The compound represented by the formula (4): (netarsudil) (chemical name: {4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl}methyl 2,4-dimethylbenzoate, international generic name: netarsudil) or its salt or solvate is more preferred.

[0046] In particular, dimethanesulfonate of the compound represented by formula (3) (chemical name: {4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl}methyl 2,4-dimethylbenzoate dimethanesulfonate ([4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate dimethanesulfonate). Hereinafter, in this specification, this may be referred to as "netarsudil dimesylate").
In another embodiment, the "compound represented by general formula (1) or a salt thereof, or a solvate thereof" is a compound represented by the following formula (5) or (5'):

A compound represented by the following formula (6):

The compound represented by formula (7): (Verosudil) (chemical name: rac-(2R)-2-(dimethylamino)-N-(1-oxo-1,2-dihydroisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide, international generic name: verosudil) is more preferred, as is its tautomer, salt, or solvate, which is represented by formula (7):

The monohydrochloride of the compound represented by formula (6) (chemical name: rac-(2R)-2-(dimethylamino)-N-(1-oxo-1,2-dihydroisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide monohydrochloride. In the following, this may be referred to as "Verosudil monohydrochloride" in this specification) is particularly preferred.

In another embodiment, the "compound represented by general formula (1) or its salt, or a solvate thereof" is the compound represented by the following formula (8):

The compound represented by the formula (3-amino-2-(4-chlorophenyl)-N-(isoquinolin-6-yl)propanamide) or a salt thereof, or a solvate thereof is preferred.

The compound represented by formula (1) or a salt thereof, or a solvate thereof is publicly known and can be produced by a publicly known method. Specifically, for example, it can be produced by referring to the methods described in Patent Documents 1 to 3 or the method described in Non-Patent Document 2. The contents of these documents are incorporated herein by reference.
In addition, the compound represented by formula (1) or its salt or solvate thereof is commercially available, and these commercially available products may be used. Specific examples of commercially available products include Netarsudil dimesylate (compound represented by formula (4)) manufactured by Medchemexpress or Chemscene LLS, Netarsudil monohydrochloride (compound represented by formula (3)) manufactured by Shanghai biopharmaleader, and Verosudil (free form of compound represented by formula (6)) manufactured by MedKoo biosciences.

The content of the compound represented by general formula (1) or a salt thereof, or a solvate thereof in the aqueous composition is not particularly limited and may be appropriately determined depending on the applicable disease, the sex, age, symptoms, and the like of the patient. From the viewpoint of obtaining an excellent pharmacological action, the compound represented by general formula (1) is preferably contained in an amount of 0.0001 to 5 w/v %, more preferably 0.001 to 3 w/v %, even more preferably 0.005 to 2 w/v %, and particularly preferably 0.01 to 1 w/v %, calculated as a free form, relative to the total volume of the aqueous composition.
In particular, when netarsudil is used as the compound represented by general formula (1), from the viewpoint of obtaining an excellent pharmacological effect, the aqueous composition contains netarsudil in a free form at 0.0001 to 1 w/v%, more preferably 0.001 to 0.5 w/v%, even more preferably 0.005 to 0.1 w/v%, and particularly preferably 0.01 to 0.04 w/v%, relative to the total volume of the aqueous composition.
Furthermore, when using Velosudil as the compound represented by general formula (1), from the viewpoint of obtaining an excellent pharmacological effect, it is preferable to contain 0.01 to 3.5 w/v% of Velosudil, calculated as a free form, relative to the total volume of the aqueous composition, more preferably 0.1 to 2.5 w/v%, even more preferably 0.2 to 1.5 w/v%, and particularly preferably 0.3 to 0.8 w/v%.
Furthermore, when a compound represented by formula (8) is used as the compound represented by general formula (1), from the viewpoint of obtaining an excellent pharmacological action, the compound represented by formula (8) is contained in an amount of preferably 0.0001 to 3 w/v %, more preferably 0.001 to 2 w/v %, even more preferably 0.005 to 1 w/v %, and particularly preferably 0.01 to 0.5 w/v %, calculated as a free form, relative to the total volume of the aqueous composition.

In this specification, the term "polyhydric alcohol" refers to an alcohol having two or more hydroxy groups in the same molecule, and examples thereof include glycerin; sugars such as fructose and glucose; sugar alcohols such as sorbitol, mannitol, and xylitol; trometamol; propylene glycol; macrogols (polyethylene glycols) such as Macrogol 100, Macrogol 200, Macrogol 300, Macrogol 400, Macrogol 600, Macrogol 1000, Macrogol 1500, Macrogol 1540, Macrogol 4000, Macrogol 6000, Macrogol 20000, and Macrogol 35000. One of these may be used alone, or two or more may be used in combination. Among these, from the viewpoint of suppressing a decrease in clarity of an aqueous composition containing a compound represented by general formula (1) during high-temperature storage, glycerin, sorbitol, propylene glycol, mannitol, and macrogol (among these, from the viewpoint of suppressing a decrease in clarity of an aqueous composition containing a compound represented by general formula (1) during high-temperature storage, those having an average molecular weight of 100 to 10,000 are preferred, and those having an average molecular weight of 200 to 8,000 are more preferred. The average molecular weight of macrogol can be measured by the "Average Molecular Weight Test" described in the section on "Macrogol 400" in the Seventeenth Edition of the Japanese Pharmacopoeia for Pharmaceuticals) are preferred, and D-mannitol, Macrogol 400, Macrogol 4000, and Macrogol 6000 are particularly preferred.
The polyhydric alcohol is known and may be produced by a known method, or a commercially available product may be used.

The content of the polyhydric alcohol in the aqueous composition is not particularly limited and may be determined by appropriate consideration, but from the viewpoint of suppressing the decrease in clarity of the aqueous composition containing the compound represented by formula (1) during high-temperature storage, it is preferable that the content be 0.01 to 30 w/v%, more preferably 0.1 to 20 w/v%, and particularly preferably 0.5 to 5 w/v% relative to the total volume of the aqueous composition. In particular, when mannitol is used as the polyhydric alcohol, from the viewpoint of suppressing the decrease in clarity of the aqueous composition containing the compound represented by formula (1) during high-temperature storage, it is preferable that the content be 0.1 to 25 w/v%, more preferably 1 to 15 w/v%, and particularly preferably 3 to 10 w/v% relative to the total volume of the aqueous composition. Furthermore, when macrogol is used as the polyhydric alcohol, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing a compound represented by general formula (1), the aqueous composition preferably contains macrogol at 0.01 to 20 w/v%, more preferably 0.5 to 7 w/v%, and particularly preferably 1 to 3 w/v%, based on the total volume of the aqueous composition.

The mass ratio of the compound represented by general formula (1) or a salt thereof, or a solvate thereof to the polyhydric alcohol in the aqueous composition is not particularly limited, but from the viewpoint of suppressing a decrease in clarity during high-temperature storage of the aqueous composition containing the compound represented by general formula (1), the aqueous composition preferably contains 0.01 to 2500 parts by mass, more preferably 0.05 to 1500 parts by mass, and particularly preferably 0.5 to 750 parts by mass of the polyhydric alcohol per part by mass of the compound represented by general formula (1) or a salt thereof, or a solvate thereof, in free form.
In particular, when netarsudil is used as the compound represented by general formula (1) and mannitol is used as the polyhydric alcohol, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing netarsudil, it is preferable to contain 10 to 2000 parts by mass of mannitol per part by mass of netarsudil or a salt thereof, or a solvate thereof in free form, more preferably 20 to 1000 parts by mass, and particularly preferably 30 to 500 parts by mass.
In addition, when Velosudil is used as the compound represented by general formula (1) and mannitol is used as the polyhydric alcohol, from the viewpoint of suppressing a decrease in clarity of an aqueous composition containing Velosudil during high-temperature storage, it is preferable to contain 0.1 to 200 parts by mass of mannitol per 1 part by mass of Velosudil or a salt thereof, or a solvate thereof in free form, more preferably 0.5 to 100 parts by mass, and particularly preferably 1 to 50 parts by mass.
Furthermore, in the case where a compound represented by formula (8) is used as the compound represented by general formula (1) and mannitol is used as the polyhydric alcohol, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing the compound represented by formula (8), the composition preferably contains 10 to 2000 parts by mass, more preferably 20 to 1000 parts by mass, and particularly preferably 30 to 500 parts by mass of mannitol per part by mass of the compound represented by formula (8) or a salt thereof, or a solvate thereof in free form.

In addition, when netarsudil is used as the compound represented by general formula (1) and macrogol is used as the polyhydric alcohol, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing netarsudil, it is preferable to contain 10 to 900 parts by mass of macrogol per 1 part by mass of netarsudil or a salt thereof, or a solvate thereof in free form, more preferably 30 to 600 parts by mass, and particularly preferably 50 to 300 parts by mass.
In addition, when Velosudil is used as the compound represented by general formula (1) and Macrogol is used as the polyhydric alcohol, from the viewpoint of suppressing a decrease in clarity of an aqueous composition containing Velosudil during high-temperature storage, it is preferable to contain 0.1 to 40 parts by mass of Macrogol per 1 part by mass of Velosudil or its salt, or a solvate thereof in free form, more preferably 0.5 to 30 parts by mass, and particularly preferably 1 to 20 parts by mass.
Furthermore, when a compound represented by formula (8) is used as the compound represented by general formula (1) and macrogol is used as the polyhydric alcohol, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing the compound represented by formula (8), the composition preferably contains 10 to 900 parts by mass, more preferably 30 to 600 parts by mass, and particularly preferably 50 to 300 parts by mass of macrogol per part by mass of the compound represented by formula (8) or a salt thereof, or a solvate thereof in free form.

In the present specification, the term "prostaglandins" refers to one or more selected from the group consisting of prostaglandins, derivatives thereof, and salts thereof (e.g., alkali metal salts such as sodium salts and potassium salts; salts with Group II elements such as calcium salts; ammonium salts, etc.), and solvates thereof (hydrates, etc.). Specific examples of such solvates include isopropyl unoprostone (chemical name: (+)-isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxodecyl) cyclopentyl]hept-5-enoate), tafluprost (chemical name: 1-Methylethyl (5Z)-7-[(1R,2R,3R, 5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-butenyl]-3,5-dihydroxycyclopentyl]-5-heptenoate), travoprost (chemical name: Isopropyl (5Z)-7-((1R,2R ,3R ,5S )-3,5-dihydroxy-2-[(1E ,3R )-3-hydroxy-4-[3-(trifluoromethyl)phenoxy]but-1-enyl]cyclopentyl)hept-5-enoate), bimatoprost (chemical name: (5Z)-7-{(1R,2R,3R,5S)-3,5-Dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenylpent-1-en-1-yl]cyclopentyl}-N-ethylhept-5-enamide), latanoprost (chemical name: (+)-Isopropyl(Z)-7-[(1R,2R,3R,5S)-3, 5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate] and pharma- ceutical acceptable salts thereof, as well as solvates of these compounds or pharma- ceutical acceptable salts with water, alcohol, or the like. These compounds can be used singly or in combination of two or more.
As the prostaglandins, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing a compound represented by general formula (1), one or more types selected from the group consisting of tafluprost, travoprost, bimatoprost, latanoprost, salts thereof, and solvates thereof are preferred, and latanoprost is particularly preferred.
These prostaglandins are all known and may be produced by known methods or may be commercially available products.

The content of prostaglandins in the aqueous composition is not particularly limited and may be determined by appropriate consideration, but from the viewpoint of suppressing a decrease in clarity of an aqueous composition containing a compound represented by formula (1) during high-temperature storage, it is preferable to contain 0.00005 to 3 w/v% of the free form relative to the total volume of the aqueous composition, more preferably 0.00025 to 0.25 w/v%, and particularly preferably 0.00075 to 0.075 w/v%. In particular, when latanoprost or a salt thereof or a solvate thereof is used as the prostaglandin, it is preferable to contain 0.0001 to 0.1 w/v% of latanoprost as a free form relative to the total volume of the aqueous composition, more preferably 0.0005 to 0.05 w/v%, and particularly preferably 0.001 to 0.01 w/v%, from the viewpoint of suppressing a decrease in clarity of an aqueous composition containing a compound represented by formula (1) during high-temperature storage. In addition, when tafluprost or a salt thereof or a solvate thereof is used as the prostaglandin, from the viewpoint of suppressing the decrease in clarity of the aqueous composition containing the compound represented by formula (1) during high-temperature storage, the aqueous composition preferably contains 0.0001-0.02 w/v% of tafluprost as a free form, more preferably 0.0005-0.01 w/v%, and particularly preferably 0.001-0.005 w/v% of tafluprost as a free form, based on the total volume of the aqueous composition. In addition, when travoprost or a salt thereof or a solvate thereof is used as the prostaglandin, from the viewpoint of suppressing the decrease in clarity of the aqueous composition containing the compound represented by formula (1) during high-temperature storage, the aqueous composition preferably contains 0.0001-0.05 w/v% of travoprost as a free form, more preferably 0.0005-0.01 w/v%, and particularly preferably 0.001-0.005 w/v% of travoprost as a free form, based on the total volume of the aqueous composition. Furthermore, when bimatoprost or a salt thereof or a solvate thereof is used as the prostaglandin, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing the compound represented by formula (1), the aqueous composition preferably contains 0.001 to 2 w/v% of free bimatoprost, more preferably 0.005 to 1 w/v%, and particularly preferably 0.01 to 0.5 w/v%, based on the total volume of the aqueous composition.

The content mass ratio of the compound represented by general formula (1) or a salt thereof, or a solvate thereof to prostaglandins in the aqueous composition is not particularly limited, but from the viewpoint of suppressing a decrease in clarity during high-temperature storage of the aqueous composition containing the compound represented by general formula (1), the aqueous composition preferably contains 0.0001 to 50 parts by mass, more preferably 0.0125 to 12.5 parts by mass, and particularly preferably 0.0375 to 3.75 parts by mass of prostaglandins in free form per part by mass of the compound represented by general formula (1) or a salt thereof, or a solvate thereof in free form.
In particular, when using netasudil as the compound represented by the general formula (1) and latanoprost or its salt or their solvates as the prostaglandins, from the viewpoint of suppressing the decrease in clarity of the aqueous composition containing netasudil during high-temperature storage, it is preferable to contain 0.005 to 5 parts by mass of latanoprost as a free form per part by mass of netasudil or its salt or its solvates as a free form, more preferably 0.025 to 2.5 parts by mass, and particularly preferably 0.05 to 0.5 parts by mass. In addition, when using netasudil as the compound represented by the general formula (1) and tafluprost or its salt or their solvates as the prostaglandins, from the viewpoint of suppressing the decrease in clarity of the aqueous composition containing netasudil during high-temperature storage, it is preferable to contain 0.005 to 1 part by mass of tafluprost as a free form per part by mass of netasudil or its salt or its solvates as a free form, more preferably 0.025 to 0.5 parts by mass, and particularly preferably 0.05 to 0.25 parts by mass. In addition, when using netasudil as the compound represented by the general formula (1) and travoprost or its salt or their solvates as the prostaglandins, from the viewpoint of suppressing the decrease in clarity of the aqueous composition containing netasudil during high-temperature storage, it is preferable to contain 0.005 to 2.5 parts by mass of travoprost as a free form per part by mass of netasudil or its salt or its solvates as a free form, more preferably 0.025 to 0.5 parts by mass, and particularly preferably 0.05 to 0.25 parts by mass. Furthermore, when using netasudil as the compound represented by the general formula (1) and bimatoprost or its salt or its solvates as the prostaglandins, from the viewpoint of suppressing the decrease in clarity of the aqueous composition containing netasudil during high-temperature storage, it is preferable to contain 1 to 30 parts by mass of bimatoprost as a free form per part by mass of netasudil or its salt or its solvates as a free form, more preferably 5 to 25 parts by mass, and particularly preferably 10 to 20 parts by mass.

In addition, when Verosudil is used as the compound represented by general formula (1) and latanoprost or a salt thereof, or a solvate thereof is used as the prostaglandin, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing Verosudil, it is preferable to contain 0.001 to 2 parts by mass of latanoprost in free form, more preferably 0.003 to 1 part by mass, and particularly preferably 0.005 to 0.2 parts by mass, per part by mass of Verosudil or a salt thereof, or a solvate thereof in free form. In addition, when Velosudil is used as the compound represented by general formula (1) and Tafluprost or a salt thereof, or a solvate thereof is used as the prostaglandin, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing Velosudil, it is preferable to contain 0.0005 to 3 parts by mass of Tafluprost in free form per part by mass of Velosudil or a salt thereof, or a solvate thereof in free form, more preferably 0.001 to 0.2 parts by mass, and particularly preferably 0.002 to 0.1 parts by mass. In addition, when using Velosudil as the compound represented by the general formula (1) and travoprost or a salt thereof or a solvate thereof as the prostaglandin, from the viewpoint of suppressing the decrease in clarity of the aqueous composition containing Velosudil during high-temperature storage, it is preferable to contain 0.0003 to 0.2 parts by mass of travoprost as a free form per part by mass of Velosudil or a salt thereof or a solvate thereof as a free form, more preferably 0.001 to 0.1 parts by mass, and particularly preferably 0.005 to 0.05 parts by mass. Furthermore, when using Velosudil as the compound represented by the general formula (1) and bimatoprost or a salt thereof or a solvate thereof as the prostaglandin, it is preferable to contain 0.01 to 10 parts by mass of bimatoprost as a free form per part by mass of Velosudil or a salt thereof or a solvate thereof as a free form, more preferably 0.05 to 5 parts by mass, and particularly preferably 0.1 to 2 parts by mass.

Furthermore, when a compound represented by formula (8) is used as the compound represented by general formula (1) and latanoprost or a salt thereof, or a solvate thereof is used as the prostaglandin, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing the compound represented by formula (8), it is preferable to contain 0.005 to 5 parts by mass of latanoprost in free form, more preferably 0.025 to 2.5 parts by mass, and particularly preferably 0.05 to 0.5 parts by mass, per part by mass of the compound represented by formula (8) or a salt thereof, or a solvate thereof in free form. Furthermore, in the case where a compound represented by formula (8) is used as the compound represented by general formula (1) and tafluprost or a salt thereof, or a solvate thereof is used as the prostaglandin, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing the compound represented by formula (8), the aqueous composition preferably contains 0.005 to 1 part by mass, more preferably 0.025 to 0.5 parts by mass, and particularly preferably 0.05 to 0.25 parts by mass of tafluprost in free form per part by mass of the compound represented by formula (8) or a salt thereof, or a solvate thereof in free form. In addition, when a compound represented by formula (8) is used as the compound represented by general formula (1) and travoprost or a salt thereof, or a solvate thereof is used as the prostaglandin, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing the compound represented by formula (8), the aqueous composition preferably contains 0.005 to 2.5 parts by mass, more preferably 0.025 to 0.5 parts by mass, and particularly preferably 0.05 to 0.25 parts by mass of travoprost in free form per part by mass of the compound represented by formula (8) or a salt thereof, or a solvate thereof in free form. Furthermore, when a compound represented by formula (8) is used as the compound represented by general formula (1) and bimatoprost or a salt thereof or a solvate thereof is used as the prostaglandin, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of an aqueous composition containing the compound represented by formula (8), it is preferable to contain 1 to 30 parts by mass of bimatoprost in free form, more preferably 5 to 25 parts by mass, and particularly preferably 10 to 20 parts by mass, per part by mass of the compound represented by formula (8) or a salt thereof or a solvate thereof in free form.

In this specification, the term "aqueous composition" refers to a composition containing at least water, and its properties are not particularly limited as long as it can be contained in a container described later, and examples thereof include liquid (solution or suspension) and semi-solid (ointment). In addition, when contained in a transparent container, it is preferable that the composition is clear enough to confirm the presence or absence of foreign matter by observation with the naked eye from the outside of the container, and for example, it is preferable that the composition is judged to be clear when the "insoluble foreign matter test method for eye drops" specified in the 17th revised Japanese Pharmacopoeia is performed. In addition, the water in the composition can be, for example, purified water, water for injection, sterilized purified water, etc.
The content of water in the aqueous composition is not particularly limited, but is preferably 5% by mass or more, more preferably 20% by mass or more, even more preferably 50% by mass or more, even more preferably 90% by mass or more, and particularly preferably 90 to 99.99% by mass.

Depending on the dosage form, the aqueous composition may contain additives used in pharmaceuticals and quasi-drugs. Examples of such additives include inorganic salts, isotonicity agents, chelating agents, stabilizers, pH regulators, preservatives, antioxidants, thickening agents, surfactants, solubilizers, suspending agents, cooling agents, dispersants, preservatives, oil-based bases, emulsion bases, and water-soluble bases. In addition, additives that are included in polyhydric alcohols may also be used.

Specific examples of such additives include ascorbic acid, potassium aspartate, sodium hydrogen sulfite, alginic acid, sodium benzoate, benzyl benzoate, epsilon-aminocaproic acid, fennel oil, ethanol, ethylene-vinyl acetate copolymer, sodium edetate, tetrasodium edetate, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, hydrochloric acid, alkyldiaminoethylglycine hydrochloride solution, carboxyvinyl polymer, dry sodium sulfite, dry sodium carbonate, d-camphor, dl-camphor, citric acid hydrate, sodium citrate. Hydrate, L-glutamic acid, Sodium L-glutamate, Creatinine, Chlorobutanol, Crystalline Sodium Dihydrogen Phosphate, Geraniol, Sodium Chondroitin Sulfate, Acetic Acid, Potassium Acetate, Sodium Acetate, Titanium Dioxide, Dibutylhydroxytoluene, Potassium Bromide, Benzododecinium Bromide, Tartaric Acid, Sodium Hydroxide, Polyoxyl 45 Stearate, Purified Lanolin, Sorbic Acid, Potassium Sorbate, Taurine, Sodium Bicarbonate, Sodium Carbonate Hydrate, Sodium Thiosulfate Hydrate, Tyloxapol, Sodium Dehydroacetate, Concentrated Mixed Tocopherols, White Wax Serine, peppermint water, peppermint oil, concentrated benzalkonium chloride solution 50, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl parahydroxybenzoate, human serum albumin, glacial acetic acid, sodium pyrosulfite, phenylethyl alcohol, bergamot oil, benzalkonium chloride, benzalkonium chloride solution, benzyl alcohol, benzethonium chloride, benzethonium chloride solution, borax, boric acid or a salt thereof (e.g., boric acid, ammonium borate), povidone, polyoxyethylene (200), polyoxypropylene glycol (70), polystyrene Examples include sodium methacrylate sulfonate, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, d-borneol, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, methanesulfonic acid, l-menthol, monoethanolamine, aluminum monostearate, polyethylene glycol monostearate, eucalyptus oil, potassium iodide, sulfuric acid, oxyquinoline sulfate, liquid paraffin, ryuuno, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, malic acid, and petrolatum.

Preferred additives include, for example, potassium chloride, calcium chloride hydrate, sodium chloride, magnesium chloride, acetic acid, potassium acetate, sodium acetate hydrate, tartaric acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate hydrate, borax, boric acid or a salt thereof, povidone, polysorbate 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, anhydrous citric acid, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, monoethanolamine, phosphoric acid, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, and l-menthol.

The aqueous composition may further contain other medicinal ingredients in addition to those mentioned above, depending on the disease to which it is applied, etc. Examples of such medicinal ingredients include α1 receptor blockers including bunazosin, such as bunazosin hydrochloride, or a salt thereof, or a solvate thereof; brimonidine, such as brimonidine tartrate, or a salt thereof, or a solvate thereof; α2 receptor agonists including apraclonidine, a salt thereof, or a solvate thereof; carteolol, such as carteolol hydrochloride, or a salt thereof, or a solvate thereof; nipradilol, or a salt thereof, or a solvate thereof; timolol, such as timolol maleate, or a salt thereof, or a solvate thereof; beta-blockers including solvates thereof, betaxolol or a salt thereof or a solvate thereof such as betaxolol hydrochloride, levobunolol or a salt thereof or a solvate thereof such as levobunolol hydrochloride, befunolol or a salt thereof or a solvate thereof, metipranolol or a salt thereof or a solvate thereof; dorzolamide or a salt thereof or a solvate thereof such as dorzolamide hydrochloride, brinzolamide or a salt thereof or a solvate thereof, acetazolamide or a salt thereof or a solvate thereof, dichlorphena carbonic anhydrase inhibitors including methazolamide or a salt thereof or a solvate thereof; ripasudil or a salt thereof or a solvate thereof, Rho kinase inhibitors including Y-39983 and H-1129; sympathomimetics including dipivefrin such as dipivefrin hydrochloride or a salt thereof or a solvate thereof, epinephrine, epinephrine borate, epinephrine hydrochloride or a salt thereof or a solvate thereof; distigmine bromide or a salt thereof or a solvate thereof parasympathomimetics including pilocarpine, pilocarpine hydrochloride, pilocarpine nitrate, or other salts or solvates thereof, and carbachol, a salt or a solvate thereof; calcium antagonists including lomerizine, a salt or a solvate thereof, such as lomerizine hydrochloride; cholinesterase inhibitors including demecarium, a salt or a solvate thereof, echothiophate, a salt or a solvate thereof, and physostigmine, a salt or a solvate thereof; EP2 receptor agonists including omidenepag isopropyl, or other omidenepag, a salt or a solvate thereof, and these can be used alone or in combination.
As the other medicinal ingredient, a β-blocker is preferable, and timolol is preferable.

The aqueous composition may be, for example, one other than the following <A-1> to <A-10>.
<A-1> A composition containing (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride, travoprost, boric acid, D-mannitol, benzalkonium chloride, polyoxyl 40 stearate, polyethylene glycol 400, EDTA, and purified water.
<A-2> A composition comprising (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride, travoprost, boric acid, D-mannitol, benzalkonium chloride, Cremophor RH40, polyethylene glycol 400, EDTA, and purified water.
<A-3> A composition comprising (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride, travoprost, boric acid, D-mannitol, polyoxyl 40 stearate, polyethylene glycol 400, EDTA, and purified water.
<A-4> A composition comprising (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride, latanoprost, sodium phosphate monobasic, sodium phosphate dibasic, benzalkonium chloride, sodium chloride, EDTA, and purified water.
<A-5> A composition comprising (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride, latanoprost, boric acid, D-mannitol, benzalkonium chloride, EDTA, and purified water.
<A-6> A composition comprising (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride, bimatoprost, sodium phosphate monobasic, sodium phosphate dibasic, benzalkonium chloride, sodium chloride, EDTA, and purified water.
<A-7> A composition comprising (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride, bimatoprost, sodium phosphate monobasic, sodium phosphate dibasic, benzalkonium chloride, sodium chloride, EDTA, and purified water.
<A-8> A composition comprising (rac)-2-(dimethylamino)-N-(1-hydroxyisoquinolin-6-yl)-2-(thiophen-3-yl)acetamide hydrochloride, bimatoprost, boric acid, D-mannitol, and purified water.
<A-9> A composition comprising (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, travoprost, boric acid, D-mannitol, benzalkonium chloride, polyoxyl 40 stearate, polyethylene glycol 400, EDTA, and purified water.
<A-10> A composition comprising (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate, latanoprost, boric acid, D-mannitol, benzalkonium chloride, polyoxyl 40 stearate, polyethylene glycol 400, EDTA, and purified water.

The pH (25°C) of the aqueous composition is not particularly limited, but is preferably 3 to 9, more preferably 3.5 to 8, even more preferably 4 to 7, and particularly preferably 5 to 6. The osmotic pressure ratio to physiological saline is not particularly limited, but is preferably 0.6 to 3, and particularly preferably 0.6 to 2.

The pharmaceutical preparation of the present invention uses a transparent container.
In the present specification, the term "container" refers to a container that directly contains the aqueous composition. The term "container" is a concept that encompasses any of "sealed containers,""airtightcontainers," and "sealed containers" defined in the General Rules of the Japanese Pharmacopoeia, 17th Edition.

In this specification, a "transparent container" means a container having a portion that is transparent enough to allow the inside to be observed with the naked eye (internal visibility). By storing an aqueous composition containing an isoquinoline-6-amino derivative in a transparent container, it becomes possible to check the presence or absence of foreign matter in the aqueous composition by observing it with the naked eye from outside the container, thereby enabling appropriate quality control during the manufacture of the pharmaceutical preparation. Note that, during the distribution stage of the pharmaceutical preparation, the transparency of the transparent container may be impaired by the application of a label or shrink film to display the ingredients or product name on the surface. However, from the viewpoint of enabling the user to check the presence or absence of foreign matter and the remaining amount of the aqueous composition when using the pharmaceutical preparation, it is preferable that the portion that is transparent is secured to an extent that the aqueous composition in the transparent container can be observed by the user with the naked eye.

The degree of transparency is not particularly limited as long as the inside of the container can be observed with the naked eye, and may be, for example, transparent enough to allow the "Testing Method for Insoluble Foreign Matter in Eye Drops" as specified in the 17th Revised Japanese Pharmacopoeia. Specifically, for example, the average light transmittance of the transparent portion of the transparent container in the visible light region (400 to 750 nm) may be about 10% or more (more preferably about 20% or more, even more preferably about 30% or more, even more preferably about 40% or more, and particularly preferably about 50% or more), but is not limited thereto.
In this specification, the average value of the transmittance of light in a specific wavelength range can be measured by measuring the transmittance of light through a container in air at 5 nm intervals within that range using a spectrophotometer, and then calculating the average value. An example of a spectrophotometer is the U-3900 (Hitachi High-Technologies Corporation).

In addition, the transparent portion of a transparent container may be a part of the container or the entire container. If transparency is ensured in at least a part of the container, the aqueous composition contained inside the container can be observed from that part. For such a transparent container, it is preferable that 10% or more of the total area of the outer surface is transparent, more preferably 30% or more, and particularly preferably 50% or more.

The shape of the transparent container is not particularly limited as long as it can accommodate the aqueous composition, and may be appropriately selected and set depending on the dosage form, the use of the pharmaceutical preparation, etc. Specific examples of such container shapes include containers for injections, containers for inhalants, containers for sprays, bottle-shaped containers, tube-shaped containers, containers for eye drops, containers for nasal drops, containers for ear drops, bag containers, etc.
The container is preferably an eye drop container, from the viewpoint of advantageously utilizing the pharmacological action of the compound represented by formula (1).

The material of the transparent container is not particularly limited, and examples thereof include glass, plastic, and the like. From the viewpoint of suppressing a decrease in the clarity of the aqueous composition containing the compound represented by general formula (1) during high-temperature storage, plastic is preferred, thermoplastic resin is more preferred, and one or more resins selected from the group consisting of polyolefin-based resins and polyester-based resins are particularly preferred.
As specifically shown in the test examples described later, it has become clear that by storing an aqueous composition containing a compound represented by the general formula (1) or a salt thereof, or a solvate thereof and one or more selected from the group consisting of polyhydric alcohols and prostaglandins in a transparent container made of a polyolefin resin or a transparent container made of a polyester resin, the decrease in clarity during storage under high temperature conditions can be further suppressed.

In this specification, the term "transparent container made of polyolefin resin" refers to a transparent container in which at least the portion of the container that comes into contact with the aqueous composition is made of "polyolefin resin". Therefore, for example, a transparent container in which a layer of polyolefin resin is provided in the inner layer that comes into contact with the aqueous composition and a resin of another material is laminated on the outside also falls under the category of "transparent container made of polyolefin resin". Here, the polyolefin resin is not particularly limited, and may be a polymer (homopolymer) of a single type of monomer or a copolymer (copolymer) of multiple types of monomers. In addition, in the case of a copolymer, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited.
Specific examples of such polyolefin resins include polyethylene (more specifically, for example, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, etc.), polypropylene, cyclic polyolefins, poly(4-methylpentene), polytetrafluoroethylene, ethylene-propylene copolymer, ethylene-α-olefin copolymer, ethylene-acrylic acid copolymer, ethylene-methacrylic acid copolymer, ethylene-vinyl acetate copolymer, ethylene-ethyl acrylate copolymer, etc., and one or more of these can be used in combination. As the polyolefin resin, from the viewpoint of suppressing a decrease in clarity during high-temperature storage of the aqueous composition containing the compound represented by formula (1), polyethylene, polypropylene, and cyclic polyolefins are preferred, low-density polyethylene, medium-density polyethylene, high-density polyethylene, and polypropylene are more preferred, low-density polyethylene, high-density polyethylene, and polypropylene are even more preferred, and low-density polyethylene is particularly preferred.
In this specification, "made of polyolefin-based resin" means that at least a portion of the material contains polyolefin-based resin, and for example, a mixture of two or more resins, that is, a polyolefin-based resin and another resin (polymer alloy), is also included in "made of polyolefin-based resin".

In this specification, the term "transparent container made of polyester resin" refers to a transparent container in which at least the portion of the container that comes into contact with the aqueous composition is made of polyester resin. Therefore, for example, a transparent container in which a layer of polyester resin is provided as an inner layer that comes into contact with the aqueous composition and a resin of another material is laminated on the outside of the layer also falls under the category of "transparent container made of polyester resin". Here, the dicarboxylic acid and diol constituting the polyester resin are not particularly limited, and examples of the dicarboxylic acid include phthalic acid, terephthalic acid, and 2,6-naphthalenedicarboxylic acid, and examples of the diol include ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,4-cyclohexanedimethanol, and bisphenol. In addition, the polymer may be a polymer of a single type of polyester unit or a polymer of multiple types of polyester units. In addition, in the case of a polymer of multiple types of polyester units, the polymerization mode is not particularly limited, and may be random polymerization or block polymerization. Furthermore, the stereoregularity (tacticity) is not particularly limited.
Specific examples of such polyester resins include homopolyesters such as polyalkylene terephthalates (e.g., polyethylene terephthalate, polybutylene terephthalate, etc.), polyalkylene naphthalates (e.g., polyethylene naphthalate, polybutylene naphthalate, etc.), polycycloalkylene terephthalates (e.g., poly(1,4-cyclohexylene dimethylene terephthalate)), polyarylates (e.g., resins composed of bisphenol and phthalic acid), copolyesters containing these homopolyester units as the main component, and copolymers of the homopolyesters. One or more of these can be used in combination. As the polyester resin, polyethylene terephthalate is preferred from the viewpoint of suppressing the decrease in clarity during high-temperature storage of the aqueous composition containing the compound represented by formula (1).
In this specification, "made of polyester-based resin" means that at least a part of the material contains polyester-based resin, and for example, a mixture of two or more resins, i.e., a polyester-based resin and another resin (polymer alloy), is also included in "made of polyester-based resin".

A transparent container may block light in a particular wavelength range as long as the container is transparent.
As specifically shown in the Test Examples described later, it has been revealed that by storing an aqueous composition containing a compound represented by general formula (1) or a salt thereof, or a solvate of either of them in a transparent container that blocks light with wavelengths of 320 to 380 nm, the decrease in the content of the compound represented by general formula (1) in the aqueous composition due to exposure to light can be further suppressed.
In addition, the wavelength range of light blocked by the transparent container is sufficient if it is in the range of 320 to 380 nm (preferably 320 to 395 nm) in consideration of the normal storage environment of pharmaceutical preparations, but from the viewpoint of further improving stability against light, it is preferably 300 to 380 nm, more preferably 300 to 395 nm. Furthermore, in consideration of use under storage conditions where there is a high risk of exposure to wavelengths of less than 300 nm, it is preferably 270 to 380 nm, particularly preferably 270 to 395 nm.

In this specification, "blocking light" in the wavelength range means that the average transmittance of light in the wavelength range is 40% or less. Therefore, for example, a "container that blocks light with wavelengths of 320 to 380 nm" means a container with an average transmittance of light with wavelengths of 320 to 380 nm of 40% or less.
In addition, from the viewpoint of further improving stability against light, the average transmittance of the transparent container for light in the above-mentioned wavelength range is preferably 35% or less, more preferably 30% or less, even more preferably 25% or less, even more preferably 20% or less, even more preferably 15% or less, even more preferably 10% or less, and particularly preferably 5% or less.

By storing the composition in a light-blocking transparent container as described above, specifically when light is irradiated to an integrated irradiation amount of 1.2 million lux-hr under a temperature condition of 25±5°C using a D65 fluorescent lamp as a light source, the remaining rate of the compound represented by general formula (1) in the aqueous composition after irradiation can be, for example, 80% or more (preferably 85% or more, more preferably 90% or more, and particularly preferably 95% or more). The remaining rate of the compound represented by general formula (1) in the aqueous composition can be calculated by the following formula from the ratio of the concentrations of the compound in the aqueous composition measured before and after irradiation with light.

Residual rate (%) of the compound represented by general formula (1) = {(Concentration of the compound represented by general formula (1) in the aqueous composition after light irradiation) / (Concentration of the compound represented by general formula (1) in the aqueous composition before light irradiation)} x 100

Specific means for imparting the property of blocking light in the above wavelength range to the transparent container is not particularly limited, but examples thereof include a method of using a substance that blocks light in the above wavelength range. More specifically, for example,
A method of incorporating a substance that blocks light in the above wavelength range into a transparent container (for example, a method of adding a substance that blocks light in the above wavelength range to a resin and molding the resin into a container shape);
A method of providing a surface of a transparent container (at least one of the inner and outer surfaces of the container) with a member (e.g., a film, etc.) containing a substance that blocks light in the above wavelength range (e.g., a method of adding a substance that blocks light in the above wavelength range to a resin to make a heat-shrinkable film, which is then wrapped around the outer surface of the container);
A method of applying a substance that blocks light in the above wavelength range to the surface of a transparent container (at least one of the inner and outer surfaces of the container);
etc.

There are no particular limitations on the substance that blocks light in the above wavelength range, but substances that prevent the transmission of ultraviolet light, such as ultraviolet absorbers and ultraviolet scattering agents, are preferred. Specific examples of ultraviolet scattering agents include titanium oxide and zinc oxide. Examples of the ultraviolet absorber include 2-(2H-benzotriazol-2-yl)-p-cresol (e.g., Tinuvin P, manufactured by BASF), 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (e.g., Tinuvin 234, manufactured by BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)benzotriazole (e.g., Tinuvin 320, manufactured by BASF), 2-[5-chloro(2H)-benzotriazol-2-yl]-4-methyl-6-(tert-butyl)phenol (e.g., Tinuvin 326, manufactured by BASF), 2-(3,5-di-t-butyl-2-hydroxyphenyl)-5-chlorobenzotriazole (e.g., Tinuvin 327, manufactured by BASF), and 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (e.g., Tinuvin PA328: BASF), 2-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol (e.g., Tinuvin 329: BASF), 2,2'-methylenebis[6-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol (e.g., Tinuvin 360: BASF), reaction products of methyl 3-(3-(2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyphenyl)propionate and polyethylene glycol 300 (e.g., Tinuvin 213: BASF), 2-(2H-benzotriazol-2-yl)-6-dodecyl-4-methylphenol (e.g., Tinuvin 571: BASF), benzotriazole-based ultraviolet absorbers such as 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole, 2-[2'-hydroxy-3'-(3'',4'',5'',6''-tetrahydrophthalimidomethyl)-5'-methylphenyl]benzotriazole, and 2,2'-methylenebis[4-(1,1,3,3-tetramethylbutyl)-6-(2H-benzotriazol-2-yl)phenol]; 2,2-bis{[2-cyano-3,3-diphenylacryloyloxy]methyl}propane-1,3-diyl=bis(2-cyano-3,3-diphenylacrylate) (for example, Uvinul 3030 FF: BASF), and ethyl 2-cyano-3,3-diphenylacrylate (for example, Uvinul 3035: BASF), 2-cyano-3,3-diphenylacrylic acid 2-ethylhexyl (e.g., Uvinul 3039: BASF), and other cyanoacrylate-based ultraviolet absorbers; 2-(4,6-diphenyl-1,3,5-triazin-2-yl)-5-[(hexyl)oxy]-phenol (e.g., Tinuvin 1577 ED: BASF), and other triazine-based ultraviolet absorbers; octabenzone (e.g., Chimassorb 81: BASF), 2,2'-dihydroxy-4,4'-dimethoxybenzophenone (e.g., Uvinul 3049: BASF), 2,2'-4,4'-tetrahydrobenzophenone (e.g., Uvinul 3050: BASF), benzophenone-based ultraviolet absorbers such as oxybenzone, hydroxymethoxybenzophenone sulfonic acid, hydroxymethoxybenzophenone sodium sulfonate, dihydroxydimethoxybenzophenone, dihydroxydimethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, and tetrahydroxybenzophenone; cinnamic acid-based ultraviolet absorbers such as methyl diisopropylcinnamate, cinoxate, di-paramethoxycinnamate mono-2-ethylhexanoate glyceryl, isopropyl paramethoxycinnamate-diisopropylcinnamate mixture, 2-ethylhexyl paramethoxycinnamate, and benzyl cinnamate; paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, and paradimethylaminobenzoate; benzoate ester-based ultraviolet absorbers such as 2-ethylhexyl ethylaminobenzoate and 4-[N,N-di(2-hydroxypropyl)amino]ethyl benzoate; salicylic acid-based ultraviolet absorbers such as ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomenthyl salicylate, and methyl salicylate; guaiazulene; 2-ethylhexyl dimethoxybenzylidene dioxoimidazolidinepropionate; 2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]1,3,5-triazine; parahydroxyanisole; 4-tert-butyl-4'-methoxydibenzoylmethane; phenylbenzimidazole sulfonic acid; and 2-(4-diethylamino-2-hydroxybenzoyl)-hexyl benzoate. As a substance that blocks light in the above wavelength range, for example, one or more of these may be appropriately combined to block light in the above wavelength range. As a substance that blocks light in the above wavelength range, titanium oxide; benzotriazole-based ultraviolet absorbers are preferred.

When a substance that blocks light in the above wavelength range is incorporated into the material or component of a transparent container, the blending ratio will vary depending on the type of substance and the materials of the container and other components, but may be, for example, about 0.001 to 50 mass %, preferably 0.002 to 25 mass %, and particularly preferably 0.01 to 10 mass % in the container material or other component.

In this specification, "containers that block light" also include cases where only a portion of the container blocks light. For such containers, it is preferable that 10% or more of the total area of the inner surface is a light blocking portion, more preferably 30% or more, even more preferably 50% or more, and particularly preferably 70% or more.

There are no particular limitations on the means for storing the aqueous composition in the container, and the container may be filled in a conventional manner according to the shape of the container.

The pharmaceutical preparation or aqueous composition can be made into various dosage forms, for example, according to known methods described in the General Provisions for Preparations of the 17th Revised Japanese Pharmacopoeia. Dosage forms include, for example, injections, inhalation solutions, eye drops, eye ointments, ear drops, nasal drops, enemas, external solutions, sprays, ointments, gels, oral solutions, and syrups. From the viewpoint of advantageously utilizing the pharmacological action of the compound represented by general formula (1), preferred dosage forms are preparations for eye diseases, specifically eye drops and eye ointments, with eye drops being particularly preferred.

The indications for the pharmaceutical preparation are not particularly limited, and may be appropriately selected depending on the pharmacological action of the compound represented by formula (1), etc.
Specifically, for example, the compound represented by formula (1) can be used as a preventive or therapeutic agent for ocular hypertension or glaucoma based on its Rho kinase inhibitory activity, norepinephrine transporter inhibitory activity, and intraocular pressure reducing activity. More specific examples of glaucoma include primary open-angle glaucoma, normal tension glaucoma, aqueous humor hyperproduction glaucoma, acute angle-closure glaucoma, chronic angle-closure glaucoma, plateau iris syndrome, mixed glaucoma, steroid-induced glaucoma, lenticular capsular glaucoma, pigmentary glaucoma, amyloid glaucoma, neovascular glaucoma, and malignant glaucoma.

When the aqueous composition or pharmaceutical preparation is used as a preventive or therapeutic agent for an eye disease (preferably a disease selected from ocular hypertension and glaucoma), an appropriate amount may be administered, for example, about 1 to 3 times a day.

The present specification discloses, for example, embodiments of the following aspects, but is in no way limited thereto.
[1A] The following components (A) and (B):
(A) a compound represented by the following general formula (1):

(wherein R ₁ and R ₂ each independently represent a hydrogen atom or a C ₁ -C ₄ alkyl group;
_R3 represents a hydrogen atom or a hydroxyl group;
A represents -CH(R ₄ )- or -CH ₂ -CH(R ₄ )- (wherein R ₄ represents an optionally substituted C ₆ -C ₁₀ aryl group or an optionally substituted 5-10 membered heteroaryl group),
Furthermore, formula (1) also includes its tautomers.
or a salt thereof, or a solvate thereof;
(B) one or more members selected from the group consisting of polyhydric alcohols and prostaglandins;
A pharmaceutical preparation comprising an aqueous composition containing the above in a transparent container.
[2A] The compound represented by the general formula (1) is represented by the following formula (2), (5), (5') or (8):

The pharmaceutical formulation according to [1A], wherein the compound is represented by the formula:
[3A] The compound represented by the general formula (1) is represented by the following formula (3) or (6):

The pharmaceutical formulation described in [1A] is a compound represented by the formula:

[4A] The compound represented by the general formula (1) is represented by the following formula (4) or (7):

The pharmaceutical formulation described in [1A] is a compound represented by the formula:

[5A] The pharmaceutical preparation according to any one of [1A] to [4A], wherein the polyhydric alcohol is one or more selected from the group consisting of glycerin, sorbitol, propylene glycol, mannitol, and macrogol (preferably, a macrogol having an average molecular weight of 100 to 10,000).
[6A] The pharmaceutical formulation according to any one of [1A] to [5A], wherein the prostaglandin is one or more selected from the group consisting of tafluprost, travoprost, bimatoprost, latanoprost, salts thereof, and solvates thereof.
[7A] The pharmaceutical formulation according to any one of [1A] to [6A], wherein the transparent container is made of one or more resins selected from the group consisting of polyolefin-based resins and polyester-based resins.
[8A] The pharmaceutical formulation according to [7A], wherein the polyolefin resin is polyethylene or polypropylene.
[9A] The pharmaceutical formulation according to [7A], wherein the polyester resin is polyethylene terephthalate.
[10A] The pharmaceutical preparation according to any one of [1A] to [9A], wherein the container is an eye drop container.

[11A] The pharmaceutical preparation according to any one of [1A] to [10A], wherein the container is a container that blocks light having a wavelength of 320 to 380 nm (preferably 320 to 395 nm).
[12A] The pharmaceutical preparation according to any one of [1A] to [10A], wherein the container is a container that blocks light having a wavelength of 300 to 380 nm (preferably 300 to 395 nm).
[13A] The pharmaceutical preparation according to any one of [1A] to [10A], wherein the container is a container that blocks light having a wavelength of 270 to 380 nm (preferably 270 to 395 nm).
[14A] The pharmaceutical preparation according to any one of [1A] to [13A], wherein when light is irradiated at a temperature condition of 25±5° C. using a D65 fluorescent lamp as a light source so as to give an accumulated irradiation amount of 1,200,000 lux hr, the remaining rate of the compound represented by the general formula (1) in the aqueous composition after irradiation is 80% or more (preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, and particularly preferably 97% or more).
[15A] The container comprises the following 1) or 2):
1) A container (preferably a container whose inside can be seen) into which a substance that blocks the transmission of ultraviolet light (more preferably, one or more selected from an ultraviolet scattering agent and an ultraviolet absorbing agent; particularly preferably, one or more selected from zinc oxide, titanium oxide, and a benzotriazole-based ultraviolet absorbing agent) is kneaded;
2) A container (preferably a container whose inside can be seen) with a member (preferably a heat shrink film (shrink film)) kneaded with a substance that blocks the transmission of ultraviolet light (more preferably, one or more selected from an ultraviolet scattering agent and an ultraviolet absorbing agent; particularly preferably, one or more selected from zinc oxide, titanium oxide, and a benzotriazole-based ultraviolet absorbing agent) wrapped around the side thereof;
The pharmaceutical formulation according to any one of [1A] to [14A],

[1B] The following steps (A) to (C):
(A) a step of incorporating the compound represented by the general formula (1) or a salt thereof, or a solvate thereof into an aqueous composition;
(B) a step of adding one or more members selected from the group consisting of polyhydric alcohols and prostaglandins to the aqueous composition;
(C) placing the aqueous composition in a transparent container;
(Here, the "method of improving thermal stability" means a method of suppressing a decrease in clarity when stored at high temperatures. For example, if the decrease in clarity (which can be evaluated, for example, by the transmittance (%) of light at a wavelength of 500 nm) after storage at high temperatures (for example, 80° C.) for a certain period of time (for example, 1 week) is suppressed compared to when the aqueous composition does not contain a polyhydric alcohol and a prostaglandin, then the "thermal stability is improved." In addition, the order of steps (A) to (C) is not particularly limited.)
[2B] The method according to [1B], wherein the compound represented by the general formula (1) is a compound represented by the formula (2), (5), (5') or (8).
[3B] The method according to [1B], wherein the compound represented by the general formula (1) is a compound represented by the formula (3) or (6).
[4B] The method according to [1B], wherein the compound represented by the general formula (1) is a compound represented by the formula (4) or (7).
[5B] The method according to any one of [1B] to [4B], wherein the polyhydric alcohol is one or more selected from the group consisting of glycerin, sorbitol, propylene glycol, mannitol, and macrogol (preferably a macrogol having an average molecular weight of 100 to 10,000).
[6B] The method according to any one of [1B] to [5B], wherein the prostaglandin is one or more selected from the group consisting of tafluprost, travoprost, bimatoprost, latanoprost, salts thereof, and solvates thereof.
[7B] The method according to any one of [1B] to [6B], wherein the transparent container is made of one or more resins selected from the group consisting of polyolefin-based resins and polyester-based resins.
[8B] The method according to [7B], wherein the polyolefin resin is polyethylene or polypropylene.
[9B] The method according to [7B], wherein the polyester resin is polyethylene terephthalate.
[10B] The method according to any one of [1B] to [9B], wherein the container is an eye drop container.

The present invention will now be described in further detail with reference to examples, but the present invention is not limited to these in any way.
In addition, in the following test examples, the measurement of netarosidil using HPLC was performed using an ODS column as the column, 0.01 mol/L phosphate buffer and acetonitrile as the mobile phase, and an ultraviolet absorption photometer (wavelength: 254 nm) as the detector.

[Test Example 1] Clarity test Part 1
The presence or absence of a decrease in transparency (presence or absence of turbidity) of an aqueous composition containing netarsudil after high-temperature storage was evaluated by measuring the transmittance of light at a wavelength of 500 nm through the aqueous composition, and also by visual inspection.
That is, aqueous compositions of formulations 1 to 3 shown in Table 1 were prepared by a conventional method. All the aqueous compositions were clear at the time of preparation, and no turbidity was observed by naked eye. Then, they were placed in the following transparent glass containers to prepare pharmaceutical preparations of Examples 1 and 2 (corresponding to formulations 1 and 2, respectively) and Comparative Example 1 (corresponding to formulation 3).
The obtained pharmaceutical preparations were stored at 80° C. for one week. In order to evaluate the presence or absence of a decrease in the clarity of the aqueous composition in the pharmaceutical preparation after storage, the aqueous composition was removed from each transparent container, and the transmittance of light at a wavelength of 500 nm was measured using a spectrophotometer (U-3900: Hitachi High-Technologies). In addition, the presence or absence of turbidity in the aqueous composition in each pharmaceutical preparation was evaluated according to the following evaluation criteria by visual observation from the outside of the transparent container.
<Evaluation criteria>
◯: The aqueous composition is clear, and even if a foreign matter is mixed in, it can be clearly seen.
×: The aqueous composition is clouded, and if a foreign matter is mixed in, it is difficult to visually recognize the foreign matter.

<Transparent glass container>
A glass container was used. The container was almost transparent except for the cap, and the inside of the container could be observed with the naked eye (for example, the light transmittance in the visible light region (400 to 750 nm) was more than 70% at all wavelengths, with an average of 75.1%).
A spectrophotometer (U-3900: Hitachi High-Technologies) was used to measure the light transmittance of the container. Specifically, the container was cut into plate-like pieces, which were then set on the light path so that the light was incident on the plate-like pieces approximately perpendicularly, and measurements were taken every 5 nm. The average light transmittance was calculated as the average value of the light transmittance every 5 nm within a specified wavelength range.
The results are shown in Table 2.

As shown in the results in Table 2, when an aqueous composition containing only netasudil was stored in a transparent glass container, it became cloudy when stored under high temperature conditions, and the transmittance of light at a wavelength of 500 nm decreased due to a decrease in transparency (Comparative Example 1). In contrast, when an aqueous composition containing netasudil was further added with macrogol 400 or latanoprost and stored in a transparent glass container, the decrease in transparency was suppressed, and it was found that even if a foreign object was mixed in, it was possible to clearly see the foreign object with the naked eye from outside the container (Examples 1-2).

From the results of Test Example 1 above, it has become clear that by further adding a polyhydric alcohol such as macrogol 400 and/or a prostaglandin such as latanoprost to an aqueous composition containing a compound represented by the general formula (1) such as netasudil or a salt thereof or a solvate thereof and storing this in a transparent container, the decrease in clarity when stored under high temperature conditions is relatively low, and even if a foreign matter is mixed in, it is possible to confirm the presence of the foreign matter by visual observation from outside the container.

[Test Example 2] Clarity test Part 2
In order to confirm the degree to which the decrease in transparency can be suppressed when the material of the transparent container is changed, the following test was carried out.
That is, the aqueous composition of Formulation 1 shown in Table 1 was prepared by a conventional method, and then placed in a transparent container made of low-density polyethylene (LDPE) or a transparent container made of polypropylene (PP) as described below to prepare the pharmaceutical preparations of Examples 3 and 4, respectively.
Each of the obtained pharmaceutical preparations was tested in the same manner as in Test Example 1.

<Transparent container made of low-density polyethylene (LDPE)>
An eye drop container made of low-density polyethylene was used. The container was almost transparent except for the cap, and the inside of the container could be observed with the naked eye (for example, the light transmittance in the visible light region (400-750 nm) exceeded 30% at all wavelengths, with an average of 52.0%).
The light transmittance was measured in the same manner as in Test Example 1 for the transparent glass container.

<Transparent container made of polypropylene (PP)>
A polypropylene eye drop container was used. The container was almost transparent except for the cap, and the inside of the container could be observed with the naked eye (for example, the light transmittance in the visible light region (400-750 nm) was more than 70% at all wavelengths, with an average of 80.9%).
The light transmittance was measured in the same manner as in Test Example 1 for the transparent glass container.

The results are shown in Table 3 together with the results of Example 1.

As shown in the results in Table 3, when the aqueous composition containing Netasudil and Macrogol 400 was contained in a transparent container made of low-density polyethylene (Example 3) or a transparent container made of polypropylene (Example 4), the decrease in clarity was further suppressed compared to when it was contained in a transparent container made of glass (Example 1), and even if a foreign object was mixed in, it was possible to clearly see the foreign object by observing it with the naked eye from outside the container.

[Test Example 3] Clarity test No. 3
In order to confirm the degree to which the decrease in transparency can be suppressed when the material of the transparent container is changed, the following test was carried out.
That is, the aqueous composition of Formulation 2 shown in Table 1 was prepared by a conventional method, and then placed in the transparent container made of low-density polyethylene (LDPE) used in Test Example 2, a transparent container made of polypropylene (PP), or a transparent container made of polyethylene terephthalate (PET) described below, to prepare the pharmaceutical preparations of Examples 5 to 7, respectively.
Each of the obtained pharmaceutical preparations was tested in the same manner as in Test Example 1.

<Transparent container made of polyethylene terephthalate (PET)>
An eye drop container made of polyethylene terephthalate was used. The container was almost transparent except for the cap, and the inside of the container could be observed with the naked eye (for example, the light transmittance in the visible light region (400-750 nm) exceeded 75% at all wavelengths, with an average of 80.5%).
The light transmittance was measured in the same manner as in Test Example 1 for the transparent glass container.

The results are shown in Table 4 together with the results of Example 2.

As shown in the results in Table 4, when the aqueous composition containing netasudil and latanoprost was contained in a transparent container made of low-density polyethylene (Example 5), a transparent container made of polypropylene (Example 6), or a transparent container made of polyethylene terephthalate (Example 7), the decrease in clarity was further suppressed compared to when it was contained in a transparent container made of glass (Example 2), and even if a foreign object was mixed in, it was possible to clearly see the foreign object by observing it with the naked eye from outside the container.

From the results of Test Examples 2 and 3 above, it was confirmed that by storing an aqueous composition containing a compound represented by the general formula (1) or a salt thereof, or a solvate thereof, such as netasudil, and a polyhydric alcohol, such as macrogol 400, or a prostaglandin, such as latanoprost, in a transparent container made of a polyolefin resin, such as polypropylene or low-density polyethylene, or a transparent container made of a polyester resin, such as polyethylene terephthalate, the decrease in clarity during storage under high temperature conditions is further suppressed, and even if a foreign matter is mixed in, it is possible to confirm the presence of the foreign matter by visual observation from outside the container.

[Test Example 4] Photostability test Part 1
The stability of Netarsudil against light when incorporated into an aqueous composition was evaluated by checking whether or not the content of Netarsudil decreased due to exposure to light.
That is, an aqueous composition having the formulation shown in Table 5 was prepared and placed in a transparent polypropylene container for eye drops. Thereafter, using a photostability tester (LT-120A: Nagano Science Co., Ltd.), the composition was irradiated with light of 4,000 lux at 25° C. for 300 hours using a D65 fluorescent lamp as the light source so that the cumulative irradiation amount was 1.2 million lux hr.

In order to confirm whether the content of netarsudil is reduced by exposure to light, the concentration of netarsudil in the aqueous composition before and after exposure to light is measured.The concentration of netarsudil in the aqueous composition is calculated by measuring the ratio of the peak area in the aqueous composition to the peak area of the netarsudil solution of known concentration using HPLC.
Then, based on the concentration of Netarsudil in the obtained aqueous composition, the residual rate (%) of Netarsudil was evaluated according to the following formula.

Residual rate (%) = [(concentration of netarsudil in the aqueous composition after exposure) / (concentration of netarsudil in the aqueous composition before exposure)] x 100

The results are shown in Table 6.

As shown in Table 6, it was revealed that the content of netarsudil in the aqueous composition was decreased by exposure to light. The light source, the D65 fluorescent lamp, irradiates light with a wavelength of 300 nm or more.
From the above test results, it became clear that the compound represented by the general formula (1), represented by netarsudil, or its salt or solvate thereof is unstable to light in an aqueous composition.

[Test Example 5] Photostability test Part 2
Regarding the decrease in content of Netarsudil in the aqueous composition due to exposure to light, as confirmed in Test Example 4, the wavelength of light causing this was confirmed by irradiating the composition with light having a specific range of wavelengths and evaluating whether or not there was a decrease in content due to exposure to light.
That is, an aqueous composition having the formulation shown in Table 5 was prepared and placed in a transparent glass container to obtain a pharmaceutical preparation. Then, using a spectral irradiation device equipped with an optical filter (spectroscopic unit: HSU-100S, light source: MAX-302FBD, both manufactured by Asahi Spectroscopy Co., Ltd.), the pharmaceutical preparation was irradiated with light having a wavelength in the range of approximately 270 to 335 nm, 320 to 395 nm, 380 to 410 nm, 430 to 475 nm, 470 to 535 nm, or 350 to 800 nm under the condition of 25°C. Note that the irradiation energy of the light of each wavelength was set to approximately 200 W·h/ ^m2 .

In order to confirm whether the content of Netarsudil decreased due to exposure to light, the remaining rate (%) of Netarsudil was evaluated using the same method as in Test Example 4.
The results are shown in Table 7.

As shown in the results in Table 7, almost no decrease in content was observed when irradiated with light having a wavelength of 380 nm or more, but a significant decrease in content was observed when irradiated with light having a shorter wavelength, particularly 320 to 380 nm.
One of the tests to confirm the storage stability of pharmaceuticals is a photostability test, and the guidelines for this test stipulate that the D65 light source should be used. The D65 light source is internationally recognized as the standard for outdoor daylight, as specified in ISO 10977 (1993), and is specified by the value of the spectral distribution in the wavelength range of 300 to 830 nm. For these reasons, it is considered sufficient to consider light with a wavelength of 300 nm or more under the storage conditions normally assumed for pharmaceuticals.
From the above, it has been concluded that in order to ensure the photostability of an aqueous composition containing a compound represented by general formula (1) or a salt thereof, or a solvate of either or both, such as netarsudil, it is particularly important to block light with a wavelength of 320 to 380 nm.

[Test Example 6] Photostability Test No. 3
Based on the results obtained in Test Example 5, an attempt was made to stabilize an aqueous composition containing Netasudil by placing it in a transparent container containing an ultraviolet absorber.
That is, an aqueous composition having the formulation shown in Table 5 was prepared and placed in a transparent polypropylene container for eye drops containing the following ultraviolet absorbent to obtain a pharmaceutical preparation. The obtained pharmaceutical preparation was irradiated with 4,000 lux of light using a photostability tester (LT-120A: Nagano Science Co., Ltd.) at 25°C for 300 hours using a D65 fluorescent lamp as the light source so that the cumulative irradiation amount was 1.2 million lux hr.

To confirm whether the content of netarsudil decreased due to exposure to light, the remaining rate (%) of netarsudil was evaluated using the same method as in Test Example 4.

<Transparent polypropylene container containing UV absorbent>
A polypropylene eye drop container with a benzotriazole-based UV absorber kneaded in was used. The average light transmittance of the container was 18.6% at 320-380 nm (18.2% average at 300-380 nm; 21.5% average at 270-380 nm; 23.7% average at 320-395 nm; 22.3% average at 300-395 nm; 24.3% average at 270-395 nm).
The container was almost transparent in appearance, and the inside of the container could be observed with the naked eye (for example, the light transmittance in the visible light region (400 to 750 nm) exceeded 60% at all wavelengths, averaging 80.5%).
The light transmittance was measured every 5 nm using a spectrophotometer (U-3900: Hitachi High-Technologies) by cutting the container into plate-like pieces, setting them on the light path so that the light was incident almost perpendicularly, and measuring the light transmittance every 5 nm. The average light transmittance was calculated as the average value of the light transmittance every 5 nm within a specified wavelength range.
FIG. 1 is a graph showing the relationship between the wavelength of light and the transmittance (%) in the range of 270 nm to 800 nm in the container.

The results are shown in Table 8. For comparison, the results are also shown alongside the test results (results of Test Example 4) using a polypropylene eye drop container that does not contain an ultraviolet absorbent (average light transmittance of 320 to 380 nm: 68.4%).

The results shown in Table 8 reveal that by storing an aqueous composition containing netarsudil in a transparent container with an average light transmittance of 18.6% at 320 to 380 nm, the decrease in the netarsudil content in the aqueous composition is significantly suppressed and the photostability is improved.

[Test Example 7] Photostability Test No. 4
As in Test Example 6, an attempt was made to stabilize an aqueous composition containing netarsudil by placing it in a polypropylene container containing an ultraviolet scattering agent.
That is, the test was conducted in the same manner as in Test Example 6, except that a transparent polypropylene container equipped with a shrink film containing the following ultraviolet scattering agent was used instead of a transparent polypropylene container containing an ultraviolet absorbing agent.

<Polypropylene container with shrink film containing UV scattering agent>
A white shrink film (heat shrink film) (Iwata Label Co., Ltd.) containing 40-45% by mass of titanium oxide as an ultraviolet scattering agent was wrapped in the usual manner around the side of the transparent polypropylene eye drop container used in Test Example 2. The average light transmittance of the shrink film containing titanium oxide was 0% at 320-380 nm (average 0% for all of 300-380 nm, 270-380 nm, 320-395 nm, 300-395 nm, and 270-395 nm).
Since the shrink film was not transparent, the contents could not be seen from the side of the container as it was. Therefore, a slit about 5 mm wide was made in the lower half of the side of the container so that the inside of the container could be observed with the naked eye (light could not be blocked in this part). In addition, since the shrink film was not wrapped around the bottom of the container, the inside of the container could be observed with the naked eye from the bottom (the light transmittance in the visible light region (400 to 750 nm) at the slit part and the bottom was the same as that of the transparent polypropylene container used in Test Example 2).
The light transmittance was measured at 5 nm intervals using a spectrophotometer (U-3900: Hitachi High-Technologies Corporation). The average light transmittance was calculated as the average value of the light transmittance at 5 nm intervals within a given wavelength range.
FIG. 2 is a graph showing the relationship between the wavelength of light and the transmittance (%) of the container side surface (where the shrink film is wrapped) in the range of 270 nm to 800 nm.

The results are shown in Table 9.

The results shown in Table 9 reveal that by storing an aqueous composition containing netarsudil in a transparent polypropylene container with an average light transmittance of 0% at 320 to 380 nm, the decrease in the netarsudil content in the aqueous composition is almost completely suppressed, and the photostability is further improved.

The results of Test Examples 6 and 7 confirmed that by storing an aqueous composition containing a compound represented by general formula (1), such as netarthudil, or a salt thereof, or a solvate thereof, in a container that blocks light with wavelengths of 320 to 380 nm, the photostability of the compound represented by general formula (1) in the aqueous composition is improved.

[Production Examples 1 to 32]
Aqueous compositions containing the components and amounts (amounts (g) per 100 mL of the aqueous composition) shown in Tables 10 to 17 are prepared by a conventional method, and then placed in a transparent container for eye drops made of low-density polyethylene to produce the pharmaceutical preparations of Preparation Examples 1 to 32.

[Production Examples 33 to 64]
The pharmaceutical preparations of Preparation Examples 33 to 64 can be produced by using a polypropylene transparent container for eye drops instead of the low-density polyethylene transparent container for eye drops in Preparation Examples 1 to 32.

[Production Examples 65 to 96]
The pharmaceutical preparations of Preparation Examples 65 to 96 can be produced by using a transparent container for eye drops made of cyclic polyolefin in place of the transparent container for eye drops made of low-density polyethylene in Preparation Examples 1 to 32.

[Production Examples 97 to 128]
The pharmaceutical preparations of Preparation Examples 97 to 128 can be produced by using a transparent container for eye drops made of high density polyethylene instead of the transparent container for eye drops made of low density polyethylene in Preparation Examples 1 to 32.

[Production Examples 129 to 256]
In Preparation Examples 1 to 128, 0.5 g of verosudil monohydrochloride as a free form was used instead of netasudil dimesylate, and the pharmaceutical preparations of Preparation Examples 129 to 256 can be prepared by conventional methods.

[Manufacturing Examples 257 to 384]
In Preparation Examples 1 to 128, 0.02 g of the compound represented by formula (8) was used instead of netasudil dimesylate, and the pharmaceutical preparations of Preparation Examples 257 to 384 can be prepared by conventional methods.

The present invention provides a pharmaceutical preparation with excellent stability, which can be suitably used in the pharmaceutical industry, etc.

Claims (6)

The following components (A) and (B):
(A) Formula (4) below

A compound represented by the formula:
(B) one or more selected from the group consisting of latanoprost, a salt thereof, and a solvate thereof;
The pharmaceutical preparation comprises an aqueous composition contained in a transparent container, the aqueous composition having a content of component (A) of 0.02 g in terms of free form per 100 mL of the aqueous composition and a content of component (B) of 0.005 g per 100 mL of the aqueous composition. 2. The pharmaceutical preparation according to claim 1, wherein the transparent container is made of polyethylene resin. 3. The pharmaceutical preparation according to claim 1, wherein the transparent container has an average transmittance of 10% or more for light having a wavelength of 400 to 750 nm in the transparent portion. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the transparent container blocks light having a wavelength of 320 to 380 nm. 5. The pharmaceutical preparation according to claim 4, wherein the transparent container contains a substance that blocks the transmission of ultraviolet light. 6. The pharmaceutical preparation according to claim 4, wherein the transparent container is provided with a material that contains a substance that blocks the transmission of ultraviolet light.