Composite pharmaceutical composition for treating glaucoma and its use

Abstract

The present invention provides a combined ophthalmic pharmaceutical composition of two drugs and a combined composition of three drugs for treating glaucoma and ocular hypertension. The stability of the pharmaceutical composition is greatly improved by salt modification technology. The combined two-drug pharmaceutical composition is produced from netarsudil free base or a pharmaceutically acceptable salt thereof, and an adrenergic β-receptor blocker. The combined three-drug pharmaceutical composition is produced from netarsudil free base or a pharmaceutically acceptable salt thereof, an adrenergic β-receptor blocker, and a prostaglandin analog. The combined pharmaceutical composition of two drugs and three drugs has excellent stability at pH 4.5 to 5.4. By administering an effective amount of the pharmaceutical composition of the present invention once a day to the eyes of patients in need at bedtime or at a time close to bedtime, the intraocular pressure can be effectively and rapidly reduced, and the intraocular pressure can be maintained within the physiological range for a long time. In addition, it has few side effects and high patient compliance.

Description

Technical Field

[0001] The present invention belongs to the field of drugs, and specifically relates to ophthalmic two-component and three-component pharmaceutical compositions, and its use in the manufacture of drugs for preventing or treating glaucoma or reducing intraocular pressure.

Background Art

[0002] Glaucoma is a common ophthalmic disease, and pathological increase in intraocular pressure and insufficient blood supply to the optic nerve are the main risk factors for its onset. The increase in intraocular pressure compresses the optic nerve, causing thinning of the optic nerve fiber layer and damage to photoreceptor cells, resulting in decreased visual acuity, visual field defects, optic nerve atrophy, etc. Severe glaucoma patients may even cause blindness. Therefore, glaucoma has become the leading cause of blindness in humans.

[0003] Currently, the commonly used single preparations have the following types. (1) Rho kinase inhibitor An intraocular pressure-lowering drug that acts directly on the trabecular meshwork mainly changes the cell morphology, cell movement, cytokinesis, smooth muscle contraction, etc. of the trabecular meshwork by affecting the cytoskeleton, thereby increasing the outflow of aqueous humor and reducing intraocular pressure. Rho kinase inhibitors also have the functions of improving retinal vascular perfusion, promoting optic nerve regeneration, protecting the optic nerve, and reducing filtration bleb scarring. The drug commonly used clinically is netarsudil mesylate. (2) Adrenergic β-receptor blocker By blocking the β-receptor, it has a strong and sustained effect of reducing the production of aqueous humor, promoting the drainage and excretion of aqueous humor, and reducing intraocular pressure, effectively controlling intraocular pressure. Drugs commonly used clinically are timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, metipranolol hydrochloride, etc. (3) Prostaglandin analog By relaxing the ciliary muscle, widening the gap between the muscles, and increasing the outflow and drainage of aqueous humor from the uveoscleral pathway to reduce intraocular pressure. It has a strong nocturnal intraocular pressure-lowering effect, especially for patients who cannot tolerate or have low efficacy with other intraocular pressure-lowering drugs. Drugs commonly used clinically are latanoprost, bimatoprost, travoprost, tafluprost, etc.

[0004] Glaucoma is a chronic eye disease in which patients need to take medicine for a long time. However, in many cases, a single preparation cannot effectively control intraocular pressure, so it is necessary to use two drugs in combination. In the case of combining two single preparations or currently commercially available fixed-dose combination products (such as Combigan®, Cosopt®, etc.), the increased dosing frequency significantly increases the exposure amount of preservatives, thereby causing problems such as low safety, many side effects, and low patient compliance. In view of the above, the present invention provides a fixed-dose combination pharmaceutical composition by combining an adrenergic β-receptor blocker (timolol free base or its salt, carteolol free base or its salt, betaxolol free base or its salt, metipranolol free base or its salt) and netarsudil, a representative drug of Rho kinase inhibitor. (1) It can lower intraocular pressure through various mechanisms of action, and the therapeutic effect is remarkable and reliable. (2) It is taken once a day, reducing the dosing frequency and the exposure amount of preservatives, reducing the occurrence of ocular side effects, and significantly improving patient compliance. Therefore, the ophthalmic pharmaceutical composition of the present invention provides a clinically safe and effective possibility for reducing intraocular pressure and treating glaucoma.

[0005] Referring to the prescription information of commercially available netarsudil eye drops (Rhopress (registered trademark)) and related literature reports, it is clear that in a boric acid-sodium borate buffer with a pH exceeding 5.4, netarsudil mesylate is unstable and prone to precipitation. Also, in a boric acid-sodium borate buffer with a pH less than 5.4, netarsudil mesylate at the commercially available dosage is in solution and has good stability. Therefore, combining the eye tolerance to pH, the in vitro stability of netarsudil mesylate, and the pH value range specified for netarsudil eye drops (Rhopress (registered trademark)), the ophthalmic pharmaceutical composition of the present invention was initially designed as a boric acid-sodium borate buffer having a pH value of 4.5 to 5.4. The applicant of the present application surprisingly found in initial studies that netarsudil mesylate at the commercially available dosage and adrenergic β-receptor blockers (timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, metipranolol hydrochloride) are unstable in a boric acid-sodium borate buffer having a pH value of 4.5 to 5.4. That is, netarsudil mesylate separates and white precipitates appear in the solution. To verify the cause of the precipitation of netarsudil mesylate, the inventors mixed commercially available dosages of maleic acid and methanesulfonic acid, hydrochloric acid and methanesulfonic acid, maleic acid and netarsudil mesylate, hydrochloric acid and netarsudil mesylate, timolol maleate and methanesulfonic acid, carteolol hydrochloride and methanesulfonic acid, betaxolol hydrochloride and methanesulfonic acid, metipranolol hydrochloride and methanesulfonic acid, timolol maleate and netarsudil mesylate, carteolol hydrochloride and netarsudil mesylate, betaxolol hydrochloride and netarsudil mesylate, and metipranolol hydrochloride and netarsudil mesylate respectively in a boric acid-sodium borate buffer with a pH value of 4.5 to 5.4. As a result, it was found that netarsudil mesylate is immiscible with any of maleic acid, hydrochloric acid, timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, and metipranolol hydrochloride, and white precipitation occurs. This indicates that netarsudil mesylate is immiscible with both maleic acid and hydrochloric acid.

[0006] Based on this, the present invention improves the compatibility between an adrenergic β-receptor blocker (timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, metipranolol hydrochloride) and netarsudil mesylate by a salt engineering strategy. That is, by controlling the types of salt-forming species between an adrenergic β-receptor blocker (timolol, carteolol, betaxolol, metipranolol) and netarsudil, the adrenergic β-receptor blocker and netarsudil have good compatibility in an aqueous injection solution with a pH value of 4.5 to 5.4. Further, the present invention constructs a triple combination preparation based on netarsudil and an adrenergic β-receptor blocker. For example, a triple combination preparation such as netarsudil, an adrenergic β-receptor blocker (timolol, carteolol, betaxolol, metipranolol), and a prostaglandin analog is constructed. The triple combination preparation has advantages such as a strong intraocular pressure-lowering effect and once-daily administration, and is expected to solve problems such as serious adverse drug reactions and limited intraocular pressure-lowering effects existing in the only triple combination preparation (Krytantek Ofteno (registered trademark), dorzolamide 2% / timolol 0.5% / brimonidine 0.2%) sold in the conventional world.

Summary of the Invention

[0007] In view of the drawbacks of conventional single-agent, dual-agent combination, and triple-agent combination preparations for treating glaucoma, such as poor therapeutic effects, many side effects, and poor patient compliance, the present invention provides a dual-agent combination pharmaceutical composition containing an adrenergic β-receptor blocker and netarsudil at the same time, and a triple-agent combination pharmaceutical composition containing an adrenergic β-receptor blocker, netarsudil, and a prostaglandin analog at the same time, and successfully solves the problem of incompatibility of certain salts of an adrenergic β-receptor blocker (timolol free base or its salt, carteolol free base or its salt, betaxolol free base or its salt, metipranolol free base or its salt) and netarsudil by a salt engineering strategy. Furthermore, the pharmaceutical composition of the present invention can more significantly reduce intraocular pressure compared with commercially available combined ophthalmic preparations.

[0008] That is, the present invention relates to the following content.

[0009] (1) In a first aspect, the present invention provides an ophthalmic two-agent solution composition containing netarsudil free base or a pharmaceutically acceptable salt thereof as a pharmaceutical active ingredient, and an adrenergic β-receptor blocker (timolol free base or a salt thereof, carteolol free base or a salt thereof, betaxolol free base or a salt thereof, metipranolol free base or a salt thereof), and in addition, containing a certain amount of buffer, isotonic agent, preservative, and pH adjuster, and an ophthalmic three-agent solution composition containing netarsudil free base or a pharmaceutically acceptable salt thereof as a pharmaceutical active ingredient, an adrenergic β-receptor blocker (timolol free base or a salt thereof, carteolol free base or a salt thereof, betaxolol free base or a salt thereof, metipranolol free base or a salt thereof), and a prostaglandin analog, and in addition, containing a certain amount of buffer, isotonic agent, preservative, and pH adjuster.

[0010] (2) In the solution composition described in (1) above, when the adrenergic β-receptor blocker is selected from timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, and metipranolol hydrochloride, the netarsudil is in the form of a free base or any pharmaceutically acceptable salt thereof (excluding mesylate). Netarsudil maleate, netarsudil sulfate, netarsudil dihydrobromide, netarsudil dihydrochloride, netarsudil digluconate, netarsudil dinitrate, netarsudil diacetate, netarsudil dibenzoate, netarsudil diphenylacetate, netarsudil succinate, netarsudil oxalate, netarsudil dihydroiodide, or netarsudil dipropionate is preferred.

[0011] (3) In the solution composition according to the above (1), when netaluzil is in the form of dimethylate, timolol is in the form of a free base or any pharmaceutically acceptable salt (excluding maleate), preferably timolol mesylate, timolol sulfate, timolol hydrobromide, timolol phosphate, timolol nitrate, timolol citrate, timolol tartrate, timolol salicylate, timolol malate, timolol lactate, timolol phenylacetate, timolol succinate, timolol hydroiodide, timolol formate, timolol acetate, timolol benzoate, timolol ethanesulfonate, timolol oxalate, or timolol propionate. carteolol is in the form of a free base or any pharmaceutically acceptable salt (excluding hydrochloride), preferably carteolol mesylate, carteolol hydrobromide, carteolol sulfate, carteolol nitrate, carteolol citrate, carteolol tartrate, carteolol salicylate, carteolol malate, carteolol lactate, phenyl acetate carteolol, carteolol succinate, carteolol hydroiodide, carteolol formate, carteolol acetate, carteolol benzoate, carteolol ethanesulfonate, carteolol oxalate, or carteolol propionate. Betaxolol is in the form of a free base or any pharmaceutically acceptable salt (excluding hydrochloride), preferably betaxolol mesylate, betaxolol hydrobromide, betaxolol sulfate, betaxolol nitrate, betaxolol citrate, betaxolol tartrate, betaxolol salicylate, betaxolol malate, betaxolol lactate, phenyl acetate betaxolol, betaxolol succinate, betaxolol hydroiodide, betaxolol formate, betaxolol acetate, betaxolol benzoate, betaxolol ethanesulfonate, betaxolol oxalate, or betaxolol propionate.Metipranolol is in the form of the free base or any pharmaceutically acceptable salt (excluding hydrochloride), preferably metipranolol mesylate, metipranolol hydrobromide, metipranolol sulfate, metipranolol nitrate, metipranolol citrate, metipranolol tartrate, metipranolol salicylate, metipranolol malate, metipranolol lactate, phenyl acetate of metipranolol, metipranolol succinate, metipranolol hydroiodide, metipranolol formate, metipranolol acetate, metipranolol benzoate, metipranolol ethanesulfonate, metipranolol oxalate, or metipranolol propionate.

[0012] (4) In the solution composition according to (1) above, examples of the prostaglandin analog include, but are not limited to, latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol isopropyl ester, 13,14-dihydrocloprostenol isopropyl ester, latanoprostene bunod, unoprostone, PGF1α isopropyl ester, PGF2α isopropyl ester, PGF3α isopropyl ester, and fluoroprostinol isopropyl ester.

[0013] (5) In the solution composition according to (1) above, examples of the isotonic agent include, but are not limited to, glycerin, sorbitol, mannitol, propylene glycol, erythritol, arabitol, xylitol, ribitol, galactitol, polyethylene glycol, lactitol, and other sugar alcohols, sodium chloride, potassium chloride, and calcium chloride, or any combination thereof.

[0014] (6) In the solution composition described in (1) above, examples of the buffer include, but are not limited to, boric acid or its salts, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous sodium phosphate, citric acid or its salts, gluconic acid or its salts, acetate or its salts, phosphate or its salts, various amino acids such as glutamic acid and ε-aminocaproic acid, and Tris buffer, or any combination thereof.

[0015] (7) In the solution composition described in (1) above, examples of the preservative include, but are not limited to, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl parahydroxybenzoate, phenethyl alcohol, disodium edetate, boric acid, sorbic acid, or any combination thereof.

[0016] (8) In the solution composition described in (1) above, examples of the pH adjuster include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, hydrochloric acid, citric acid or its salts, phosphoric acid or its salts, acetic acid or its salts, and tartaric acid or its salts, etc.

[0017] (9) In the solution composition described in (1) to (8) above, the composition contains an adrenergic receptor blocker (timolol free base or its salt, carteolol free base or its salt, betaxolol free base or its salt, metipranolol free base or its salt) at 0.02% w / v to 4.0% w / v.

[0018] (10) In the solution composition described in (1) to (8) above, the composition contains netarsudil free base or its salt at 0.005% w / v to 0.1% w / v.

[0019] (11) In the solution composition described in (1) to (8) above, the composition contains a prostaglandin analog at 0.0005% w / v to 0.05% w / v.

[0020] (12) In the solution composition according to (1) to (8) above, the composition contains 1.0% w / v to 10.0% w / v of mannitol.

[0021] (13) In the solution composition according to (1) to (8) above, the composition contains 0.05% w / v of boric acid.

[0022] (14) In the solution composition according to (1) to (8) above, the composition contains 0.001 to 0.02% w / v of benzalkonium chloride.

[0023] (15) The solution composition according to (1) to (14) above has an osmotic pressure of 280 to 320 mOsmol / kg.

[0024] (16) The solution composition according to (1) to (15) above has a pH of 4.5 to 5.4.

[0025] (17) When the solution composition according to (1) to (16) above was stored at 5°C for 24 months, there was no significant change in the content of each main drug component compared to day 0, and it satisfied the storage conditions before opening of a commercially available eye drop.

[0026] (18) When the solution composition according to (1) to (16) above was stored at 25°C for 6 weeks, there was no significant change in the content of each main drug component compared to day 0, and it satisfied the storage conditions after opening of a commercially available eye drop.

[0027] (19) When the solution composition according to (1) to (16) above was stored at 40°C for 14 days, there was no significant change in the content of each main drug component compared to day 0, and it satisfied the storage conditions when deviating slightly from the storage conditions of a commercially available eye drop.

[0028] (20) As a second aspect, the present invention provides the use of the solution composition according to the first aspect above in the manufacture of a medicament for preventing or treating eye diseases.

[0029] (21) In the use described in (20) above, the eye disease is glaucoma or a symptom related thereto.

[0030] (22) As a third aspect, the present invention provides the use of the solution composition described in the first aspect above in the manufacture of a medicament for reducing intraocular pressure.

Advantages of the Invention

[0031] The present invention has the following beneficial effects over the prior art.

[0032] (1) The problem of incompatibility of some salts of an adrenergic β-receptor blocker (timolol free base or its salt, carteolol free base or its salt, betaxolol free base or its salt, metipranolol free base or its salt) and netarsudil is improved by a salt engineering strategy, whereby a solution excellent in stability containing an adrenergic β-receptor blocker (timolol free base or its salt, carteolol free base or its salt, betaxolol free base or its salt, metipranolol free base or its salt) and netarsudil is obtained.

[0033] (2) In another aspect, the solution pharmaceutical composition provided by the present invention is useful for preventing or treating an eye disease (particularly, glaucoma or a symptom related thereto) and for manufacturing a medicament for reducing intraocular pressure, and the pharmaceutical composition of the present invention can reduce intraocular pressure more significantly as compared with commercially available combined ophthalmic preparations.

Brief Description of the Drawings

[0034]

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Mode for Carrying Out the Invention

[0035] In the ophthalmic pharmaceutical composition of the present invention, when netarsudil is in the form of dimesylate, timolol is preferably in the form of a salt formed from a pharmaceutically acceptable acid (excluding maleic acid). Specific acids include methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid, citric acid, tartaric acid, salicylic acid, malic acid, ethanesulfonic acid, lactic acid, or phenylacetic acid, and more preferably methanesulfonic acid.

[0036] In the ophthalmic pharmaceutical composition of the present invention, when netarsudil is in the form of dimesylate, carteolol is preferably in the form of a salt formed from a pharmaceutically acceptable acid (excluding hydrochloric acid). Specific acids include methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid, citric acid, tartaric acid, salicylic acid, malic acid, ethanesulfonic acid, lactic acid, or phenylacetic acid, and more preferably methanesulfonic acid.

[0037] In the ophthalmic pharmaceutical composition of the present invention, when netarsudil is in the form of dimesylate, betaxolol is preferably in the form of a salt formed from a pharmaceutically acceptable acid (excluding hydrochloric acid). Specific acids include methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid, citric acid, tartaric acid, salicylic acid, malic acid, ethanesulfonic acid, lactic acid, or phenylacetic acid, and more preferably methanesulfonic acid.

[0038] In the ophthalmic pharmaceutical composition of the present invention, when netarsudil is in the form of dimesylate, metipranolol is preferably in the form of a salt formed from a pharmaceutically acceptable acid (excluding hydrochloric acid). Specific acids include methanesulfonic acid, sulfuric acid, hydrobromic acid, phosphoric acid, nitric acid, citric acid, tartaric acid, salicylic acid, malic acid, ethanesulfonic acid, lactic acid, or phenylacetic acid, and more preferably methanesulfonic acid.

[0039] In the ophthalmic solution pharmaceutical composition of the present invention, when timolol is in the form of maleate, carteolol is in the form of hydrochloride, betaxolol is in the form of hydrochloride, or metipranolol is in the form of hydrochloride, netarsudil is preferably in the form of a salt formed from a pharmaceutically acceptable acid (excluding methanesulfonic acid). Specific examples of the acid include maleic acid, sulfuric acid, hydrobromic acid, hydrochloric acid, formic acid, nitric acid, acetic acid, formic acid, phenylacetic acid, succinic acid, oxalic acid, hydroiodic acid, or propionic acid, and more preferably maleic acid and hydrochloric acid.

[0040] In the pharmaceutical composition of the present invention, the salts of timolol, carteolol, betaxolol, metipranolol, and netarsudil are not particularly limited as long as they are pharmaceutically acceptable salts. Specifically, examples of suitable inorganic anions include inorganic anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid, but are not limited thereto. Examples of suitable organic anions include 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethanedisulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, ethanesulfonic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, sulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, and valeric acid, but are not limited thereto. Examples of suitable polymeric organic anions include polymeric organic anions derived from polymeric acids such as tannic acid and carboxymethylcellulose, but are not limited thereto.

[0041] The pharmaceutical composition of the present invention further comprises at least one prostaglandin analog as an active ingredient. Specifically, examples of prostaglandin analogs include, but are not limited to, latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol isopropyl ester, 13,14-dihydrocloprostenol isopropyl ester, latanoprostene bunod, unoprostone, PGF1α isopropyl ester, PGF2α isopropyl ester, PGF3α isopropyl ester, and fluoroprostinol isopropyl ester.

[0042] In the ophthalmic solution pharmaceutical composition of the present invention, the concentration of the adrenergic β-receptor blocker (timolol free base or its salt, carteolol free base or its salt, betaxolol free base or its salt, metipranolol free base or its salt) is 0.02% w / v to 4.0% w / v, and more preferably 0.3% w / v to 2.0% w / v.

[0043] In the ophthalmic solution pharmaceutical composition of the present invention, the concentration of netarsudil free base or its salt is 0.005% w / v to 0.1% w / v, and more preferably 0.02% w / v to 0.04% w / v, and most preferably 0.02% w / v.

[0044] In the ophthalmic solution pharmaceutical composition of the present invention, the concentration of the prostaglandin analog is 0.0005% w / v to 0.05% w / v, and more preferably 0.0015% w / v to 0.03% w / v.

[0045] The ophthalmic solution pharmaceutical composition of the present invention may contain an isotonic agent. Examples of the isotonic agent include, but are not limited to, sodium chloride, potassium chloride, mannitol, dextrose, glycerin, and propylene glycol. Preferably, the isotonic agent may be present in the ophthalmic composition in an amount of about 0.01% w / v to about 10% w / v, about 1% w / v to about 10% w / v, about 2.5% w / v to about 7.5% w / v, or about 4% w / v to about 6% w / v. Preferably, the isotonic agent may be present in an amount of at least 0.01% w / v, at least 0.05% w / v, at least 1% w / v, at least 2.5% w / v, at least 4% w / v, or at least 5% w / v. Preferably, the isotonic agent may be present in an amount of 10% w / v or less, 8% w / v or less, or 6% w / v or less. In the examples, the isotonic agent may be present in the ophthalmic composition in an amount of about 3.0% w / v, about 3.1% w / v, about 3.2% w / v, about 3.3% w / v, about 3.4% w / v, about 3.5% w / v, about 3.6% w / v, about 3.7% w / v, about 3.8% w / v, about 3.9% w / v, about 4.0% w / v, about 4.1% w / v, about 4.2% w / v, about 4.3% w / v, about 4.4% w / v, about 4.5% w / v, about 4.6% w / v, about 4.7% w / v, about 4.8% w / v, about 4.9% w / v, about 5.0% w / v, about 5.1% w / v, about 5.2% w / v, about 5.3% w / v, about 5.4% w / v, or about 5.5% w / v. The isotonic agent may preferably be mannitol.

[0046] The ophthalmic solution pharmaceutical composition of the present invention may contain a buffering agent. Suitable buffering agents include, but are not limited to, acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, their pharmaceutically acceptable salts, tromethamine, and combinations thereof. The buffering agent may be present in the ophthalmic composition in an amount of about 0.01% w / v to about 1% w / v, about 0.1% w / v to about 0.9% w / v, about 0.3% w / v to about 0.8% w / v, or about 0.4% w / v to about 0.6% w / v. Preferably, the buffering agent may be present at at least 0.01% w / v, at least 0.05% w / v, at least 0.1% w / v, at least 0.3% w / v, or at least 0.5% w / v. Preferably, the buffering agent may be present in an amount of 1.0% w / v or less, 0.8% w / v or less, or 0.6% w / v or less. In the examples, the buffering agent may be present in the ophthalmic composition in an amount of about 0.01% w / v, about 0.02% w / v, about 0.03% w / v, about 0.04% w / v, about 0.05% w / v, about 0.06% w / v, about 0.07% w / v, about 0.08% w / v, about 0.09% w / v, or about 0.1% w / v. The buffering agent may preferably be boric acid.

[0047] The ophthalmic solution pharmaceutical composition of the present invention may contain a preservative. Suitable preservatives include, but are not limited to, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl parahydroxybenzoate, phenethyl alcohol, disodium edetate, boric acid, sorbic acid, or other reagents known to those skilled in the art. The preservative may be present in the ophthalmic composition in an amount of about 0.001% w / v to about 0.02% w / v. The preservative may preferably be benzalkonium chloride.

[0048] The ophthalmic solution pharmaceutical composition of the present invention may contain a pH adjuster having an amount sufficient to adjust the pH of the composition to about 4 to about 9. Preferably, the pH of the ophthalmic composition may be about 4.5 to about 5.4. Suitable pH adjusters include, but are not limited to, sodium hydroxide.

[0049] Examples The present disclosure has various aspects exemplified by the following non-limiting examples. In each example, the following materials and property evaluation techniques were used.

[0050] <Examples 1 to 5> Formulations containing netarsudil mesylate and carteolol mesylate Table 1 Preparation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure (formulated as follows)

[0051] [Table 1]

[0052] The manufacturing process is as follows. Step 1, Weigh 95% of the amount of water for injection in the prescription, add the active ingredient and adjuvant in the prescription amount, stir until completely dissolved, and adjust the pH to 4.5 - 5.4 with a sodium hydroxide solution (10%). Step 2, Supplement the water for injection to the total prescription amount, stir uniformly and make the volume 100%. Step 3, Put the solution in Step 2 into a low-density polyethylene medicinal eye drop bottle and examine the stability under various storage temperature conditions.

[0053] Table 2 Content of each main drug component in Examples 1 to 5 when stored at 5°C for 24 months

[0054] [Table 2]

[0055] Table 3 Content of each main drug component in commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)) when stored at 5°C for 24 months

[0056] [Table 3]

[0057] According to Examples 1 to 5, the preparations containing netarsudil mesylate and carteolol mesylate showed good stability when stored at 5°C for 24 months, and met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®).

[0058] Table 4 Contents of each active ingredient in Examples 1 - 5 when stored at 25°C for 6 weeks

[0059]

Table 4

[0060] Table 5 Contents of each active ingredient in commercially available eye drops (Mikelan®, Rhopress®) when stored at 25°C for 6 weeks

[0061]

Table 5

[0062] According to Examples 1 to 5, the preparations containing netarsudil mesylate and carteolol mesylate showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®).

[0063] Table 6 Contents of each active ingredient in Examples 1 - 5 when stored at 40°C for 14 days

[0064]

Table 6

[0065] Table 7 Contents of each active ingredient in commercially available eye drops (Mikelan®, Rhopress®) when stored at 40°C for 14 days

[0066]

Table 7

[0067] According to Examples 1 to 5, the preparations containing netarsudil mesylate and carteolol mesylate showed good stability when stored at 40°C for 14 days, and met the storage conditions in the case of short-term deviation of commercially available eye drops (Mikelan®, Rhopress®).

[0068] <Examples 6 to 10> Preparations containing netarsudil dihydrochloride and carteolol hydrochloride Table 8 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0069]

Table 8

[0070] Please refer to the manufacturing processes described in Examples 1 to 5 for the manufacturing process.

[0071] Table 9 Contents of each main drug component in Examples 6 to 10 when stored at 5°C for 24 months

[0072]

Table 9

[0073] According to Examples 6 to 10, the preparations containing netarsudil dihydrochloride and carteolol hydrochloride showed good stability when stored at 5°C for 24 months, and met the requirements of the storage conditions before opening of commercially available eye drops (Mikelan®, Rhopress®).

[0074] Table 10 Contents of each main drug component in Examples 6 to 10 when stored at 25°C for 6 weeks

[0075]

Table 10

[0076] According to Examples 6 to 10, the preparations containing netarsudil dihydrochloride and carteolol hydrochloride showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0077] Table 11. Contents of each active ingredient in Examples 6 to 10 when stored at 40°C for 14 days

[0078] [Table 11]

[0079] According to Examples 6 to 10, the preparations containing netarsudil dihydrochloride and carteolol hydrochloride showed good stability when stored at 40°C for 14 days and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0080] <Example 11> Evaluation of the medicinal effects of the ophthalmic solution pharmaceutical compositions in Examples 1 to 10 using a glaucoma model of Japanese white rabbit species Experimental animals: Healthy male Japanese white rabbits (Shenyang Pharmaceutical University, permit number SYXK (Liao) 2018-0009), initial body weight 2.5 - 3.0 kg, 3 rabbits / group.

[0081] <Grouping of experimental groups> Normal control group: No treatment was performed.

[0082] Model group: A high intraocular pressure model was established and no eye drops were administered.

[0083] Treatment group 1: A high intraocular pressure model was established and commercially available netarsudil eye drops (Rhopress (registered trademark)) were administered.

[0084] Treatment group 2: An ocular hypertension model was established, and commercially available carteolol hydrochloride eye drops (Mikelan (registered trademark)) were administered.

[0085] Example 1: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 1 was administered.

[0086] Example 2: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 2 was administered.

[0087] Example 3: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 3 was administered.

[0088] Example 4: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 4 was administered.

[0089] Example 5: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 5 was administered.

[0090] Example 6: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 6 was administered.

[0091] Example 7: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 7 was administered.

[0092] Example 8: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 8 was administered.

[0093] Example 9: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 9 was administered.

[0094] Example 10: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 10 was administered.

[0095] Establishment of the model: No treatment was given to the rabbits in the normal control group. For the remaining 13 groups of white rabbits, on day 0, urethane at a dose of 0.8 - 1 g / kg was injected into the marginal vein of the earlobe for general anesthesia. Using a 1 mL syringe, 10 μL of aqueous humor was collected from the anterior chamber of each eye, and then 10 μL of a composite carbomer solution (the weight of the main drug carbomer was 0.3% and the weight of dexamethasone was 0.025%) was injected. The intraocular pressure was measured every two days, and the clinical symptoms were observed. In the successfully established model, turbidity occurred in the anterior chamber and the intraocular pressure increased significantly. The establishment of the rabbit model of high intraocular pressure was successful after 10 days.

[0096] Dosing schedule: Based on the clinical dosing schedules of currently commercially available netarsudil eye drops (Rhopress®) and commercially available carteolol hydrochloride eye drops (Mikelan®), this experiment was mainly divided into the following groups. (1) Treatment group 1: Commercially available netarsudil eye drops (Rhopress®) were administered at 50 μL per eye once a day (9:00 PM). (2) Treatment group 2: Commercially available carteolol hydrochloride eye drops (Mikelan®) were administered at 50 μL per eye twice a day (9:00 AM and 9:00 PM). (3) Examples 1 - 10: The eye drops of Examples 1 - 10 were administered at 50 μL per eye once a day (9:00 PM). In all groups, on day 10, the model was successfully established, dosing was started, and dosing continued for 10 days. The normal control group and the model group were not administered eye drops. The dosing schedule is shown in Figure 1.

[0097] Inspection indicators and inspection methods <Intraocular pressure> The intraocular pressure was measured once a day (9:00 PM) on days 0, 2, 4, 6, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of the experiment. The upper and lower eyelids of the rabbit were gently opened, the tonometer was brought close to the rabbit's eye, and after adjusting the distance, the measurement button was gently pressed. During the measurement process, the eyelids were not touched. After completing 6 measurements in sequence, the single measurement value and the average value (mmHg) could be obtained.

[0098] Experimental results At all time points after administration during the <intraocular pressure> study, the IOP values of all treatment groups and example groups were significantly decreased compared with the model group (Student's paired t-test). Also, when using the ophthalmic solution compositions of Examples 4, 5, 9, and 10, the IOP (intraocular pressure) was significantly decreased compared with Treatment Group 1, Treatment Group 2, and Examples 1, 2, 3, 6, 7, and 8. However, there was no significant difference in the measured IOP values and IOP change values of Examples 4, 5, 9, and 10.

[0099] Table 12 Difference between the measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (measured intraocular pressure on the 10th day) after continuous administration for 10 days starting from the 10th day

[0100]

Table 12

[0101] Table 13 Measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days after continuous administration for 10 days starting from the 10th day

[0102]

Table 13

[0103] <Example 12> Preparation containing netarsudil mesylate and carteolol hydrobromide Table 14 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0104]

Table 14

[0105] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0106] Table 15 Content of each main drug component of Example 12 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0107]

Table 15

[0108] According to Example 12, the preparation containing netarsudil mesylate and carteolol hydrobromide showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®).

[0109] <Example 13> Preparation containing netarsudil mesylate and carteolol sulfate Table 16 The following is the formulation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure.

[0110]

Table 16

[0111] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0112] Table 17 Content of each main drug component of Example 13 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0113]

Table 17

[0114] According to Example 13, the preparation containing netarsudil mesylate and carteolol sulfate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®).

[0115] <Example 14> Preparation containing netarsudil mesylate and carteolol ethanesulfonate Table 18 The following is the formulation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure.

[0116]

Table 18

[0117] For the manufacturing process, refer to the manufacturing processes described in Examples 1 - 5.

[0118] Table 19 Contents of each main drug component of Example 14 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0119]

Table 19

[0120] According to Example 14, the preparation containing netarsudil mesylate and carteolol ethanesulfonate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®).

[0121] <Example 15> Preparation containing netarsudil mesylate and carteolol nitrate Table 20 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[0122] [Table 20]

[0123] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0124] Table 21 Contents of each active ingredient in Example 15 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0125] [Table 21]

[0126] According to Example 15, the preparation containing netarsudil mesylate and carteolol nitrate showed good stability when stored at 5°C for 24 months, met the pre-opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post-opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0127] <Example 16> Preparation containing netarsudil mesylate and carteolol citrate Table 22 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[0128] [Table 22]

[0129] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0130] Table 23 Content of each active ingredient of Example 16 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0131] [Table 23]

[0132] According to Example 16, the preparation containing netarsudil mesylate and carteolol citrate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0133] <Example 17> Preparation containing netarsudil mesylate and carteolol tartrate Table 24 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0134] [Table 24]

[0135] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0136] Table 25 Content of each active ingredient of Example 17 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0137] [Table 25]

[0138] According to Example 17, the preparation containing netarsudil mesylate and carteolol tartrate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0139] <Example 18> Preparation containing netarsudil mesylate and carteolol salicylate Table 26 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0140]

Table 26

[0141] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0142] Table 27 Contents of each main drug component of Example 18 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0143]

Table 27

[0144] According to Example 18, the preparation containing netarsudil mesylate and carteolol salicylate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0145] <Example 19> Preparation containing netarsudil mesylate and carteolol malate Table 28 shows the preparation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by formulating as follows.

[0146]

Table 28

[0147] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0148] Table 29 shows the content of each active ingredient in Example 19 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks.

[0149]

Table 29

[0150] According to Example 19, the preparation containing netarsudil mesylate and carteolol malate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0151] <Example 20> A preparation containing netarsudil mesylate and carteolol lactate Table 30 shows the preparation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by formulating as follows.

[0152]

Table 30

[0153] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0154] Table 31 Content of each active ingredient in Example 20 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0155] [Table 31]

[0156] According to Example 20, the preparation containing netarsudil mesylate and carteolol lactate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0157] <Example 21> Preparation containing netarsudil mesylate and phenyl carteolol acetate Table 32 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0158] [Table 32]

[0159] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0160] Table 33 Content of each active ingredient in Example 21 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0161] [Table 33]

[0162] According to Example 21, the preparation containing netarsudil mesylate and phenyl carteolol acetate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®).

[0163] <Example 22> Preparation containing netarsudil dihydrobromide and carteolol hydrochloride Table 34 The following is the formulation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure.

[0164]

Table 34

[0165] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0166] Table 35 Contents of each main drug component of Example 22 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0167]

Table 35

[0168] According to Example 22, the preparation containing netarsudil dihydrobromide and carteolol hydrochloride showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®).

[0169] <Example 23> Preparation containing netarsudil sulfate and carteolol hydrochloride Table 36 describes the preparation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by mixing the components as follows.

[0170] [Table 36]

[0171] Please refer to the manufacturing processes described in Examples 1 to 5 of the manufacturing process.

[0172] Table 37 shows the content of each active ingredient in Example 23 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks.

[0173] [Table 37]

[0174] According to Example 23, the preparation containing netarsudil sulfate and carteolol hydrochloride showed good stability when stored at 5°C for 24 months, meeting the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), and also showed good stability when stored at 25°C for 6 weeks, meeting the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0175] <Example 24> A preparation containing netarsudil diglutamate and carteolol hydrochloride Table 38 describes the preparation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by mixing the components as follows.

[0176] [Table 38]

[0177] Please refer to the manufacturing processes described in Examples 1 to 5 of the manufacturing process.

[0178] Table 39 Content of each active ingredient of Example 24 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0179] [Table 39]

[0180] According to Example 24, the preparation containing netarsudil disulfate and carteolol hydrochloride showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0181] <Example 25> Preparation containing netarsudil nitrate and carteolol hydrochloride Table 40 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0182] [Table 40]

[0183] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0184] Table 41 Content of each active ingredient of Example 25 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0185] [Table 41]

[0186] According to Example 25, the preparation containing netarsudil nitrate and carteolol hydrochloride showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0187] <Example 26> Preparation containing netarsudil diacetate and carteolol hydrochloride Table 42 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0188]

Table 42

[0189] Refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0190] Table 43 Contents of each active ingredient of Example 26 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0191]

Table 43

[0192] According to Example 26, the preparation containing netarsudil diacetate and carteolol hydrochloride showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0193] <Example 27> Preparation containing netarsudil dibenzoate and carteolol hydrochloride Table 44 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0194] [Table 44]

[0195] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0196] Table 45 Contents of each active ingredient in Example 27 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0197] [Table 45]

[0198] According to Example 27, the preparation containing netarsudil mesylate and carteolol salicylate showed good stability when stored at 5°C for 24 months, met the pre-opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post-opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0199] <Example 28> A preparation containing netarsudil oxalate and carteolol hydrochloride Table 46 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0200] [Table 46]

[0201] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0202] Table 47 Content of each active ingredient in Example 28 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0203] [Table 47]

[0204] According to Example 28, the preparation containing netarsudil oxalate and carteolol hydrochloride showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0205] <Example 29> Preparation containing netarsudil succinate and carteolol hydrochloride Table 48 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0206] [Table 48]

[0207] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0208] Table 49 Content of each active ingredient in Example 29 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0209] [Table 49]

[0210] According to Example 29, the preparation containing netarsudil mesylate and carteolol lactate showed good stability when stored at 5°C for 24 months, met the storage conditions before opening of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the storage conditions after opening of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0211] <Example 30> Preparation containing netarsudil diphenylacetate and carteolol hydrochloride Table 50 The following is the formulation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure.

[0212]

Table 50

[0213] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0214] Table 51 Contents of each active ingredient in Example 30 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0215]

Table 51

[0216] According to Example 30, the preparation containing netarsudil diphenylacetate and carteolol hydrochloride showed good stability when stored at 5°C for 24 months, met the storage conditions before opening of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the storage conditions after opening of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0217] <Example 31> Preparation containing netarsudil maleate and carteolol hydrochloride Table 52 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0218] [Table 52]

[0219] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0220] Table 53 Contents of each active ingredient of Example 31 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0221] [Table 53]

[0222] According to Example 31, the preparation containing netarsudil maleate and carteolol hydrochloride showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark)).

[0223] <Comparative Examples 1 - 4> Preparations containing netarsudil mesylate and carteolol hydrochloride Table 54 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0224] [Table 54]

[0225] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0226] Table 55 Contents of each active ingredient of Comparative Examples 1 to 4 stored at 5°C for 7 days

[0227]

Table 55

[0228] According to Comparative Examples 1 to 4, the preparations containing netarsudil mesylate and carteolol hydrochloride were incompatible under storage conditions of 5°C, and netarsudil mesylate precipitated.

[0229] <Comparative Examples 5 to 8> Preparations containing netarsudil mesylate and hydrochloric acid Table 56 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0230]

Table 56

[0231] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0232] Table 57 Contents of each active ingredient in Comparative Examples 5 to 8 when stored at 5°C for 24 hours

[0233]

Table 57

[0234] According to Comparative Examples 5 to 8, the preparations containing netarsudil mesylate and hydrochloric acid were incompatible under storage conditions of 5°C, and netarsudil mesylate precipitated.

[0235] <Examples 32 to 36> Preparations containing netarsudil mesylate and timolol mesylate Table 58 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0236]

Table 58

[0237] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0238] Table 59 Content of each active pharmaceutical ingredient in Examples 32 to 36 when stored at 5°C for 24 months

[0239]

Table 59

[0240] Table 60 Content of each active pharmaceutical ingredient in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)) stored at 5°C for 24 months.

[0241]

Table 60

[0242] According to Examples 32 to 36, the formulations containing netarsudil mesylate and timolol mesylate showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)).

[0243] Table 61 Content of each active pharmaceutical ingredient in Examples 32 to 36 when stored at 25°C for 6 weeks

[0244]

Table 61

[0245] Table 62 Content of each active pharmaceutical ingredient in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)) when stored at 25°C for 6 weeks

[0246]

Table 62

[0247] According to Examples 32 to 36, the preparations containing netarsudil mesylate and timolol mesylate showed good stability when stored at 25°C for 6 weeks, and met the requirements for the storage conditions after opening of commercially available eye drops (Timoptic®, Rhopress®).

[0248] Table 63 Contents of each active ingredient in Examples 32 to 36 when stored at 40°C for 14 days

[0249] [Table 63]

[0250] Table 64 Contents of each active ingredient in commercially available eye drops (Timoptic®, Rhopress®) when stored at 40°C for 14 days

[0251] [Table 64]

[0252] According to Examples 32 to 36, the preparations containing netarsudil mesylate and timolol mesylate showed good stability when stored at 40°C for 14 days, and met the storage conditions when there was a short-term deviation from commercially available eye drops (Timoptic®, Rhopress®).

[0253] <Examples 37 to 41> Preparations containing netarsudil maleate and timolol maleate Table 65 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0254] [Table 65]

[0255] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0256] Table 66 Content of each active ingredient in Examples 37 to 41 when stored at 5°C for 24 months

[0257] [Table 66]

[0258] According to Examples 37 to 41, the preparations containing netarsudil maleate and timolol maleate showed good stability when stored at 5°C for 24 months, meeting the pre - opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)).

[0259] Table 67 Content of each active ingredient in Examples 37 to 41 when stored at 25°C for 6 weeks

[0260] [Table 67]

[0261] According to Examples 37 to 41, the preparations containing netarsudil maleate and timolol maleate showed good stability when stored at 25°C for 6 weeks, meeting the post - opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)).

[0262] Table 68 Content of each active ingredient in Examples 37 to 41 when stored at 40°C for 14 days

[0263] [Table 68]

[0264] According to Examples 37 to 41, the preparation containing netarsudil maleate and timolol maleate showed good stability when stored at 40 °C for 14 days, and met the storage conditions when the deviation from the commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)) was short-term.

[0265] <Example 42> Evaluation of the drug efficacy of the ophthalmic solution pharmaceutical compositions in Examples 32 to 41 using a Japanese white rabbit glaucoma model <Experimental group division> Normal control group: No treatment was performed.

[0266] Model group: A high intraocular pressure model was established, and no eye drops were administered.

[0267] Treatment group 1: A high intraocular pressure model was established, and the commercially available netarsudil eye drops (Rhopress (registered trademark)) were administered.

[0268] Treatment group 3: A high intraocular pressure model was established, and the commercially available timolol eye drops (Timoptic (registered trademark)) were administered.

[0269] Example 32: A high intraocular pressure model was established, and the ophthalmic solution pharmaceutical composition of Example 32 was administered.

[0270] Example 33: A high intraocular pressure model was established, and the ophthalmic solution pharmaceutical composition of Example 33 was administered.

[0271] Example 34: A high intraocular pressure model was established, and the ophthalmic solution pharmaceutical composition of Example 34 was administered.

[0272] Example 35: A high intraocular pressure model was established, and the ophthalmic solution pharmaceutical composition of Example 35 was administered.

[0273] Example 36: A high intraocular pressure model was established, and the ophthalmic solution pharmaceutical composition of Example 36 was administered.

[0274] Example 37: A high intraocular pressure model was established, and the ophthalmic solution pharmaceutical composition of Example 37 was administered.

[0275] Example 38: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 38 was administered.

[0276] Example 39: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 39 was administered.

[0277] Example 40: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 40 was administered.

[0278] Example 41: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 41 was administered.

[0279] Administration plan: Based on the clinical administration plans of currently commercially available netarsudil eye drops (Rhopress®) and commercially available timolol eye drops (Timoptic®), this experiment was mainly divided into the following groups. (1) Treatment group 1: Commercially available netarsudil eye drops (Rhopress®) were administered at 50 μL per eye once a day (9:00 PM). (2) Treatment group 3: Commercially available timolol eye drops (Timoptic®) were administered at 50 μL per eye twice a day (9:00 AM, 9:00 PM). (3) Examples 32 - 41: The eye drops of Examples 32 - 41 were administered at 50 μL per eye once a day (9:00 PM). In all groups, on the 10th day, the model was successfully established, and drug administration was started and continued for 10 days. No treatment was given to the normal control group and the model group. The administration plan is shown in Figure 3.

[0280] For the remaining experimental operation process (experimental animals, model establishment, inspection indicators and inspection methods), please refer to those described in Example 11.

[0281] Experimental results At all time points after administration during the <Intraocular Pressure> study, the IOP values of all treatment groups and example groups were significantly decreased compared to the model group (Student's paired t-test). Also, when using the ophthalmic solution compositions of Examples 35, 36, 40, and 41, the IOP was significantly decreased compared to Treatment Group 1, Treatment Group 3, and Examples 32, 33, 34, 37, 38, and 39. However, there was no significant difference in the measured IOP values and IOP change values of Examples 35, 36, 40, and 41.

[0282] Table 69 Difference between the measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (measured intraocular pressure on the 10th day) after continuous administration for 10 days starting from the 10th day

[0283]

Table 69

[0284] Table 70 Measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days after continuous administration for 10 days starting from the 10th day

[0285]

Table 70

[0286] <Example 43> Preparation containing netarsudil mesylate and timolol hydrobromide Table 71 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0287]

Table 71

[0288] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0289] Table 72 Content of each main drug component of Example 43 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0290]

Table 72

[0291] According to Example 43, the preparation containing netarsudil mesylate and timolol hydrobromide showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0292] <Example 44> Preparation containing netarsudil mesylate and timolol sulfate Table 73 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0293]

Table 73

[0294] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0295] Table 74 Contents of each main drug component of Example 44 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0296]

Table 74

[0297] According to Example 44, a formulation with a pH of 4.5 to 5.4 containing netarsudil mesylate and timolol sulfate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0298] <Example 45> A formulation containing netarsudil mesylate and timolol ethanesulfonate Table 75 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0299]

Table 75

[0300] Please refer to the manufacturing processes described in Examples 1 to 5 of the manufacturing process.

[0301] Table 76 Content of each main drug component of Example 45 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0302]

Table 76

[0303] According to Example 45, a formulation containing netarsudil mesylate and timolol ethanesulfonate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0304] <Example 46> Preparation Containing Netarsudil Mesylate and Timolol Nitrate Table 77 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0305]

Table 77

[0306] For the manufacturing process, refer to the manufacturing processes described in Examples 1 to 5.

[0307] Table 78 Contents of each active ingredient in Example 46 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0308]

Table 78

[0309] According to Example 46, the preparation containing netarsudil mesylate and timolol nitrate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)).

[0310] <Example 47> Preparation Containing Netarsudil Mesylate and Timolol Citrate Table 79 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0311]

Table 79

[0312] For the manufacturing process, refer to the manufacturing processes described in Examples 1 to 5.

[0313] Table 80 Content of each active ingredient of Example 47 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0314] [Table 80]

[0315] According to Example 47, the preparation containing netarsudil mesylate and timolol citrate showed good stability when stored at 5°C for 24 months, met the requirements for the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the requirements for the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0316] <Example 48> Preparation containing netarsudil mesylate and timolol tartrate Table 81 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0317] [Table 81]

[0318] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0319] Table 82 Content of each active ingredient of Example 48 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0320] [Table 82]

[0321] According to Example 48, the preparation containing netarsudil mesylate and timolol tartrate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0322] <Example 49> Preparation containing netarsudil mesylate and timolol salicylate Table 83 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0323]

Table 83

[0324] Please refer to the manufacturing processes described in Examples 1 - 5 of the manufacturing process.

[0325] Table 84 Content of each main drug component of Example 49 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0326]

Table 84

[0327] According to Example 49, the preparation containing netarsudil mesylate and timolol salicylate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0328] <Example 50> Preparation containing netarsudil mesylate and timolol malate Table 85 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[0329] [Table 85]

[0330] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0331] Table 86 Contents of each active ingredient in Example 50 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0332] [Table 86]

[0333] According to Example 50, the preparation containing netarsudil mesylate and timolol malate showed good stability when stored at 5°C for 24 months, met the requirements for the pre - opening storage conditions of commercially available eye drops (Timoptic® and Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the requirements for the post - opening storage conditions of commercially available eye drops (Timoptic® and Rhopress®).

[0334] <Example 51> Preparation containing netarsudil mesylate and timolol lactate Table 87 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[0335] [Table 87]

[0336] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0337] Table 88 Content of each active ingredient of Example 51 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0338] [Table 88]

[0339] According to Example 51, the preparation containing netarsudil mesylate and timolol lactate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)).

[0340] <Example 52> Preparation containing netarsudil mesylate and timolol phenylacetate Table 89 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0341] [Table 89]

[0342] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0343] Table 90 Content of each active ingredient of Example 52 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0344] [Table 90]

[0345] According to Example 52, the preparation containing netarsudil mesylate and timolol phenylacetate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0346] <Example 53> Preparation containing netarsudil dihydrobromide and timolol maleate Table 91 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0347]

Table 91

[0348] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0349] Table 92 Contents of each active ingredient of Example 53 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0350]

Table 92

[0351] According to Example 53, the preparation containing netarsudil dihydrobromide and timolol maleate showed good stability when stored at 5°C for 24 months, met the requirements of the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the requirements of the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0352] <Example 54> Preparation containing netarsudil dihydrochloride and timolol maleate Table 93 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0353]

Table 93

[0354] For the manufacturing process, refer to the manufacturing processes described in Examples 1 to 5.

[0355] Table 94 Contents of each active ingredient in Example 54 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0356]

Table 94

[0357] According to Example 54, the preparation containing netarsudil dihydrochloride and timolol maleate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0358] <Example 55> Preparation containing netarsudil sulfate and timolol maleate Table 95 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0359]

Table 95

[0360] For the manufacturing process, refer to the manufacturing processes described in Examples 1 to 5.

[0361] Table 96 Content of each active ingredient of Example 55 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0362] [Table 96]

[0363] According to Example 55, the preparation containing netarsudil sulfate and timolol maleate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark)).

[0364] <Example 56> Preparation containing netarsudil digalate and timolol maleate Table 97 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0365] [Table 97]

[0366] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0367] Table 98 Content of each active ingredient of Example 56 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0368] [Table 98]

[0369] According to Example 56, a preparation containing netarsudil disulfate and timolol maleate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0370] <Example 57> A preparation containing netarsudil dinitrate and timolol maleate Table 99 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0371]

Table 99

[0372] Refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0373] Table 100 Contents of each active ingredient of Example 57 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0374]

Table 100

[0375] According to Example 57, a preparation containing netarsudil dinitrate and timolol maleate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0376] <Example 58> A preparation containing netarsudil diacetate and timolol maleate Table 101 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[0377] [Table 101]

[0378] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0379] Table 102 Contents of each active ingredient of Example 58 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0380] [Table 102]

[0381] According to Example 58, the preparation containing netarsudil diacetate and timolol maleate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0382] <Example 59> Preparation containing netarsudil dibenzoate and timolol maleate Table 103 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[0383] [Table 103]

[0384] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0385] Table 104 Content of each active ingredient of Example 59 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0386] [Table 104]

[0387] According to Example 59, the preparation containing netarsudil dibenzoate and timolol maleate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic® and Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic® and Rhopress®).

[0388] <Example 60> Preparation containing netarsudil oxalate and timolol maleate Table 105 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0389] [Table 105]

[0390] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0391] Table 106 Content of each active ingredient of Example 60 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0392] [Table 106]

[0393] According to Example 60, a preparation containing netarsudil oxalate and timolol maleate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0394] <Example 61> A preparation containing netarsudil succinate and timolol maleate Table 107 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0395]

Table 107

[0396] Refer to the manufacturing processes described in Manufacturing Process Examples 1 - 5.

[0397] Table 108 Contents of each main drug component of Example 61 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0398]

Table 108

[0399] According to Example 61, a preparation containing netarsudil succinate and timolol maleate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0400] <Example 62> Preparation Containing Netarsudil Diphenylacetate and Timolol Maleate Table 109 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0401] [Table 109]

[0402] For the manufacturing process, refer to the manufacturing processes described in Examples 1 to 5.

[0403] Table 110 Contents of each active ingredient in Example 62 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0404] [Table 110]

[0405] According to Example 62, the preparation containing netarsudil diphenylacetate and timolol maleate showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®).

[0406] <Comparative Examples 9 - 12> Preparation Containing Netarsudil Mesylate and Timolol Maleate Table 111 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0407] [Table 111]

[0408] For the manufacturing process, refer to the manufacturing processes described in Examples 1 to 5.

[0409] Table 112 Content of each main drug component in Comparative Examples 9 to 12 when stored at 5°C for 7 days

[0410] [Table 112]

[0411] According to Comparative Examples 9 to 12, the formulations containing netarsudil mesylate and timolol maleate were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[0412] <Comparative Examples 13 to 16> Formulations containing netarsudil mesylate and maleic acid Table 113 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0413] [Table 113]

[0414] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0415] Table 114 Content of each main drug component in Comparative Examples 13 to 16 when stored at 5°C for 7 days

[0416] [Table 114]

[0417] According to Comparative Examples 13 to 16, the formulations containing netarsudil mesylate and maleic acid were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[0418] <Examples 63 to 67> Formulations containing netarsudil mesylate and betaxolol mesylate Table 115 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing the components as follows.

[0419] [Table 115]

[0420] Refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0421] Table 116 Contents of each active ingredient in Examples 63 to 67 when stored at 5°C for 24 months

[0422] [Table 116]

[0423] Table 117 Contents of each active ingredient in commercially available eye drops (Vetoptic (registered trademark), Rhopress (registered trademark)) when stored at 5°C for 24 months

[0424] [Table 117]

[0425] According to Examples 63 to 67, the preparations containing netarsudil mesylate and betaxolol mesylate showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Vetoptic (registered trademark), Rhopress (registered trademark)).

[0426] Table 118 Contents of each active ingredient in Examples 63 to 67 when stored at 25°C for 6 weeks

[0427] [Table 118]

[0428] Content of each main drug component in commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark)) stored at 25°C for 6 weeks

[0429] [Table 119]

[0430] According to Examples 63 to 67, the preparations containing netarsudil mesylate and betaxolol mesylate showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark)).

[0431] Table 120 Content of each main drug component in Examples 63 to 67 when stored at 40°C for 14 days

[0432] [Table 120]

[0433] Table 121 Content of each main drug component in commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark)) when stored at 40°C for 14 days

[0434] [Table 121]

[0435] According to Examples 63 to 67, the preparations containing netarsudil dihydrochloride and betaxolol hydrochloride showed good stability when stored at 40°C for 14 days and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark)).

[0436] <Examples 68 to 72> Preparations containing netarsudil dihydrochloride and betaxolol hydrochloride Table 122 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0437] [Table 122]

[0438] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0439] Table 123 Contents of each active ingredient in Examples 68 to 72 when stored at 5°C for 24 months

[0440] [Table 123]

[0441] According to Examples 68 to 72, the preparations containing netarsudil dihydrochloride and betaxolol hydrochloride showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark)).

[0442] Table 124 Contents of each active ingredient in Examples 68 to 72 when stored at 25°C for 6 weeks

[0443] [Table 124]

[0444] According to Examples 68 to 72, the preparations containing netarsudil dihydrochloride and betaxolol hydrochloride showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark)).

[0445] Table 125 Contents of each active ingredient in Examples 68 to 72 when stored at 40°C for 14 days

[0446]

Table 125

[0447] According to Examples 68 to 72, the preparations containing netarsudil dihydrochloride and betaxolol hydrochloride showed good stability when stored at 40°C for 14 days, and met the storage conditions in the case of short-term deviation of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark)).

[0448] <Comparative Examples 17 to 20> Preparations containing netarsudil mesylate and betaxolol hydrochloride Table 126 The following is the formulation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure.

[0449]

Table 126

[0450] Please refer to the manufacturing processes described in Examples 1 to 5.

[0451] Table 127 Contents of each main drug component in Comparative Examples 17 to 20 stored at 5°C for 7 days

[0452]

Table 127

[0453] According to Comparative Examples 17 to 20, the preparations containing netarsudil mesylate and betaxolol hydrochloride were incompatible under the storage conditions at 5°C, and netarsudil mesylate precipitated.

[0454] <Examples 73 to 77> Preparations containing netarsudil mesylate and mecipranolol mesylate Table 128 The following is the formulation of a topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure.

[0455]

Table 128

[0456] Refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0457] Table 129 Content of each active pharmaceutical ingredient in Examples 73 to 77 when stored at 5°C for 24 months

[0458]

Table 129

[0459] Table 130 Content of each active pharmaceutical ingredient in a commercially available eye drop (Optipranolol (registered trademark), Rhopress (registered trademark)) stored at 5°C for 24 months

[0460]

Table 130

[0461] According to Examples 73 to 77, the preparations containing netarsudil mesylate and metipranolol mesylate showed good stability when stored at 5°C for 24 months and met the pre - opening storage conditions of the commercially available eye drop (Optipranolol (registered trademark), Rhopress (registered trademark)).

[0462] Table 131 Content of each active pharmaceutical ingredient in Examples 73 to 77 when stored at 25°C for 6 weeks

[0463]

Table 131

[0464] Table 132 Content of each active pharmaceutical ingredient in a commercially available eye drop (Optipranolol (registered trademark), Rhopress (registered trademark)) stored at 25°C for 6 weeks

[0465]

Table 132

[0466] According to Examples 73 to 77, the preparation containing netarsudil mesylate and metipranolol mesylate showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Optipranolol®, Rhopress®).

[0467] Table 133 Content of each main drug component in Examples 73 to 77 when stored at 40°C for 14 days

[0468]

Table 133

[0469] Table 134 Content of each main drug component of commercially available eye drops (Optipranolol®, Rhopress®) when stored at 40°C for 14 days

[0470]

Table 134

[0471] According to Examples 73 to 77, the preparation containing netarsudil mesylate and metipranolol mesylate showed good stability when stored at 40°C for 14 days and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Optipranolol®, Rhopress®).

[0472] <Examples 78 to 82> Preparation containing netarsudil dihydrochloride and metipranolol hydrochloride Table 135 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0473]

Table 135

[0474] Please refer to the manufacturing processes described in Manufacturing Process Examples 1 to 5.

[0475] Table 136 Content of each active ingredient in Examples 78 to 82 when stored at 5°C for 24 months

[0476] [Table 136]

[0477] According to Examples 78 to 82, the preparation containing netarsudil dihydrochloride and metipranolol hydrochloride showed good stability when stored at 5°C for 24 months and met the requirements for the storage conditions before opening of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark)).

[0478] Table 137 Content of each active ingredient in Examples 78 to 82 when stored at 25°C for 6 weeks

[0479] [Table 137]

[0480] According to Examples 78 to 82, the preparation containing netarsudil dihydrochloride and metipranolol hydrochloride showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark)).

[0481] Table 138 Content of each active ingredient in Examples 78 to 82 when stored at 40°C for 14 days

[0482] [Table 138]

[0483] According to Examples 78 to 82, the preparation containing netarsudil dihydrochloride and metipranolol hydrochloride showed good stability when stored at 40°C for 14 days, and met the storage conditions in case of short-term deviation of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark)).

[0484] <Comparative Examples 21 to 24> Preparations containing netarsudil mesylate and metipranolol hydrochloride Table 139 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0485]

Table 139

[0486] Please refer to the manufacturing processes described in Examples 1 to 5 of the manufacturing process.

[0487] Table 140 Contents of each main drug component of Comparative Examples 21 to 24 stored at 5°C for 7 days

[0488]

Table 140

[0489] According to Comparative Examples 21 to 24, the preparation containing netarsudil mesylate and metipranolol hydrochloride was incompatible under the storage conditions at 5°C, and netarsudil mesylate precipitated.

[0490] <Examples 83 to 87> Preparations containing netarsudil mesylate, timolol mesylate and latanoprost Table 141 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0491]

Table 141

[0492] The manufacturing process is as follows. Step 1, weigh 50% of the injection water in the prescription amount, add the prostaglandin active ingredient and benzalkonium chloride in the prescription amount, and heat in a water bath and stir until completely dissolved. Step 2, weigh 45% of the injection water in the prescription amount, add the remaining active ingredients and adjuvants in the prescription amount, and stir until completely dissolved. Step 3, add the solution of Step 2 to the solution of Step 1, stir evenly, and adjust the pH to 4.5 - 5.4 with a sodium hydroxide solution (10%). Step 4, supplement the injection water to the total prescription amount, stir evenly and make the volume 100%. Step 5, put the solution of Step 4 into a low-density polyethylene medicinal eye drop bottle, and examine the stability under various storage temperature conditions.

[0493] Table 142 Contents of each main drug component in Examples 83 - 87 when stored at 5°C for 24 months

[0494]

Table 142

[0495] Table 143 Contents of each main drug component in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) when stored at 5°C for 24 months

[0496]

Table 143

[0497] According to Examples 83 - 87, the preparations containing netarsudil mesylate, timolol mesylate and latanoprost showed good stability when stored at 5°C for 24 months and met the pre-opening storage conditions of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)).

[0498] Table 144 Contents of each main drug component in Examples 83 - 87 when stored at 25°C for 6 weeks

[0499]

Table 144

[0500] Content of each main drug component in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) stored at 25°C for 6 weeks

[0501]

Table 145

[0502] According to Examples 83 to 87, the preparations containing netarsudil mesylate, timolol mesylate and latanoprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)).

[0503] Content of each main drug component in Examples 83 to 87 when stored at 40°C for 14 days

[0504]

Table 146

[0505] Content of each main drug component in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) when stored at 40°C for 14 days

[0506]

Table 147

[0507] According to Examples 83 to 87, the preparations containing netarsudil mesylate, timolol mesylate, and latanoprost showed good stability when stored at 40 °C for 14 days, and met the storage conditions in the case of short-term deviation of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0508] <Examples 88 to 92> Preparations containing netarsudil maleate, timolol maleate, and latanoprost Table 148 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0509]

Table 148

[0510] For the manufacturing process, refer to the process described in Examples 83 to 87.

[0511] Table 149 Contents of each active ingredient in Examples 88 to 92 when stored at 5 °C for 24 months

[0512]

Table 149

[0513] According to Examples 88 to 92, the preparations containing netarsudil maleate, timolol maleate, and latanoprost showed good stability when stored at 5 °C for 24 months, and met the storage conditions before opening of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0514] Table 150 Contents of each active ingredient in Examples 88 to 92 when stored at 25 °C for 6 weeks

[0515]

Table 150

[0516] According to Examples 88 to 92, the preparations containing netarsudil maleate, timolol maleate, and latanoprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0517] Table 151 Content of each active ingredient in Examples 88 to 92 when stored at 40°C for 14 days

[0518] [Table 151]

[0519] According to Examples 88 to 92, the preparations containing netarsudil maleate, timolol maleate, and latanoprost showed good stability when stored at 40°C for 14 days and met the storage conditions when deviating slightly in the short term from commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0520] <Example 93> Evaluation of the efficacy of ophthalmic solution pharmaceutical compositions in Examples 83 to 92 using a Japanese white rabbit glaucoma model <Experimental group division> Normal control group: No treatment was performed.

[0521] Model group: A high intraocular pressure model was established, and no eye drops were administered.

[0522] Treatment group 4: A high intraocular pressure model was established, and a commercially available latanoprost - timolol maleate combination eye drop (Xalacom®) was administered.

[0523] Treatment group 5: A high intraocular pressure model was established, and a commercially available netarsudil / latanoprost eye drop (Rocklatan®) was administered.

[0524] Example 83: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 83 was administered.

[0525] Example 84: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 84 was administered.

[0526] Example 85: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 85 was administered.

[0527] Example 86: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 86 was administered.

[0528] Example 87: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 87 was administered.

[0529] Example 88: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 88 was administered.

[0530] Example 89: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 89 was administered.

[0531] Example 90: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 90 was administered.

[0532] Example 91: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 91 was administered.

[0533] Example 92: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 92 was administered.

[0534] Administration Plan: Based on the clinical administration plans of currently marketed latanoprost / timolol maleate combination eye drops (Xalacom®) and currently marketed netarsudil / latanoprost eye drops (Rocklatan®), this experiment was mainly divided into the following groups. (1) Treatment Group 4: The currently marketed latanoprost / timolol maleate combination eye drops (Xalacom®) were administered at 50 μL per eye once a day (9:00 PM). (2) Treatment Group 5: The currently marketed netarsudil / latanoprost eye drops (Rocklatan®) were administered at 50 μL per eye once a day (9:00 PM). (3) Examples 83 - 92: The eye drops of Examples 83 - 92 were administered at 50 μL per eye once a day (9:00 PM). In all groups, on the 10th day, the model was successfully established, and dosing was initiated and continued for 10 days. No treatment was given to the normal control group and the model group. The administration plan is shown in Figure 5.

[0535] For the remaining experimental operation process (experimental animals, model establishment, inspection indicators and inspection methods), please refer to those described in Example 11.

[0536] Experimental Results <Intraocular Pressure> At all post - administration time points during the study, the IOP values of all treatment groups and example groups were significantly decreased compared to the model group (Student's paired t - test). Also, when using the ophthalmic solution compositions of Examples 86, 87, 91, and 92, the IOP was significantly decreased compared to Treatment Group 4, Treatment Group 5, and Examples 83, 84, 85, 88, 89, and 90. However, there was no significant difference in the measured IOP values and IOP change values of Examples 86, 87, 91, and 92.

[0537] Table 152 Differences between the measured intraocular pressure values of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (the measured intraocular pressure value on the 10th day) after continuous administration for 10 days starting from the 10th day

[0538]

Table 152

[0539] Table 153 Measured intraocular pressure values of rabbits in each group on the 10th, 15th, and 20th days after continuous administration for 10 days starting from the 10th day

[0540]

Table 153

[0541] <Examples 94 - 98> Preparations containing netarsudil mesylate, timolol mesylate, and bimatoprost Table 154 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0542]

Table 154

[0543] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[0544] Table 155 Contents of each main drug component in Examples 94 - 98 when stored at 5°C for 24 months

[0545]

Table 155

[0546] Table 156 Contents of each main drug component in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) when stored at 5°C for 24 months

[0547]

Table 156

[0548] According to Examples 94 to 98, the preparations containing netarsudil mesylate, timolol mesylate and bimatoprost showed good stability when stored at 5°C for 24 months, and met the requirements for the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Lumigan®).

[0549] Table 157 Contents of each active ingredient in Examples 94 - 98 when stored at 25°C for 6 weeks

[0550]

Table 157

[0551] Table 158 Contents of each active ingredient in commercially available eye drops (Timoptic®, Rhopress®, Lumigan®) when stored at 25°C for 6 weeks

[0552]

Table 158

[0553] According to Examples 94 to 98, the preparations containing netarsudil mesylate, timolol mesylate and bimatoprost showed good stability when stored at 25°C for 6 weeks, and met the storage conditions after opening of commercially available eye drops (Timoptic®, Rhopress®, Lumigan®).

[0554] Table 159 Contents of each active ingredient in Examples 94 - 98 when stored at 40°C for 14 days

[0555]

Table 159

[0556] Table 160 Content of each main drug component of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) when stored at 40°C for 14 days

[0557]

Table 160

[0558] According to Examples 94 to 98, the preparations containing netarsudil mesylate, timolol mesylate and bimatoprost showed good stability when stored at 40°C for 14 days and met the storage conditions when the commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) deviated slightly in the short term.

[0559] <Examples 99 to 103> Preparations containing netarsudil maleate, timolol maleate and bimatoprost Table 161 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0560]

Table 161

[0561] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[0562] Table 162 Content of each main drug component in Examples 99 to 103 when stored at 5°C for 24 months

[0563]

Table 162

[0564] According to Examples 99 to 103, the preparations containing netarsudil maleate, timolol maleate and bimatoprost showed good stability when stored at 5°C for 24 months, and met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Lumigan®).

[0565] Table 163 Content of each active ingredient in Examples 99 - 103 when stored at 25°C for 6 weeks

[0566]

Table 163

[0567] According to Examples 99 to 103, the preparations containing netarsudil maleate, timolol maleate and bimatoprost showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Lumigan®).

[0568] Table 164 Content of each active ingredient when stored at 40°C for 14 days

[0569]

Table 164

[0570] According to Examples 99 to 103, the preparations containing netarsudil maleate, timolol maleate and bimatoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when deviating slightly in the short - term of commercially available eye drops (Timoptic®, Rhopress®, Lumigan®).

[0571] <Example 104> Evaluation of the efficacy of ophthalmic solution pharmaceutical compositions in Examples 94 - 103 using a Japanese white rabbit glaucoma model <Experimental group division> Normal control group: No treatment was performed.

[0572] Model group: An ocular hypertension model was established and no eye drops were administered.

[0573] Treatment group 6: An ocular hypertension model was established and a commercially available bimatoprost / timolol maleate eye drop (Ganfort (registered trademark)) was administered.

[0574] Example 94: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 94 was administered.

[0575] Example 95: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 95 was administered.

[0576] Example 96: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 96 was administered.

[0577] Example 97: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 97 was administered.

[0578] Example 98: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 98 was administered.

[0579] Example 99: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 99 was administered.

[0580] Example 100: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 100 was administered.

[0581] Example 101: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 101 was administered.

[0582] Example 102: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 102 was administered.

[0583] Example 103: An ocular hypertension model was established and the ophthalmic solution pharmaceutical composition of Example 103 was administered.

[0584] Administration plan: Based on the clinical administration plan of the currently marketed bimatoprost / timolol maleate eye drops Ganfort (registered trademark), this experiment was mainly divided into the following groups. (1) Treatment group 6: The bimatoprost / timolol maleate eye drops (Ganfort (registered trademark)) were administered at 50 μL per eye once a day (9:00 PM). (2) Examples 94 to 103: The eye drops of Examples 94 to 103 were administered at 50 μL per eye once a day (9:00 PM). In all groups, on the 10th day, the model was successfully established, and drug administration was started and continued for 10 days. No treatment was given to the normal control group and the model group. The administration plan is shown in Figure 7.

[0585] For the remaining experimental operation process (experimental animals, model establishment, inspection indicators and inspection methods), please refer to those described in Example 11.

[0586] Experimental results <Intraocular pressure> At all post-administration time points during the study, the IOP values of all treatment groups and example groups were significantly decreased compared with the model group (Student's paired t-test). Also, compared with treatment group 6 and Examples 94, 95, 96, 99, 100, 101, the IOP was significantly decreased when using the ophthalmic solution compositions of Examples 97, 98, 102, 103, but there was no significant difference in the measured IOP values and IOP change values of Examples 97, 98, 102, 103.

[0587] Table 165 Differences between the measured intraocular pressure values of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (measured intraocular pressure value on the 10th day) after continuous administration for 10 days starting from the 10th day

[0588] [Table 165]

[0589] Table 166 Measured intraocular pressure values of rabbits in each group on the 10th, 15th, and 20th days after continuous administration for 10 days starting from the 10th day

[0590]

Table 166

[0591] <Examples 105 - 109>Preparations containing netarsudil mesylate, timolol mesylate and travoprost Table 167 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[0592]

Table 167

[0593] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[0594] Table 168 Contents of each active ingredient in Examples 105 - 109 when stored at 5°C for 24 months

[0595]

Table 168

[0596] Table 169 Contents of each active ingredient in commercially available eye drops (Timoptic®, Rhopress®, Travatan®) stored at 5°C for 24 months

[0597]

Table 169

[0598] According to Examples 105 - 109, the preparations containing netarsudil mesylate, timolol mesylate and travoprost showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Travatan®).

[0599] Table 170 Content of each main drug component in Examples 105 to 109 when stored at 25°C for 6 weeks

[0600] [Table 170]

[0601] Table 171 Content of each main drug component in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) when stored at 25°C for 6 weeks

[0602] [Table 171]

[0603] According to Examples 105 to 109, the preparations containing netarsudil mesylate, timolol mesylate and travoprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)).

[0604] Table 172 Content of each main drug component in Examples 105 to 109 when stored at 40°C for 14 days

[0605] [Table 172]

[0606] Table 173 Content of each main drug component in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) when stored at 40°C for 14 days

[0607] [Table 173]

[0608] According to Examples 105 to 109, the preparation containing netarsudil mesylate, timolol mesylate, and travoprost showed good stability when stored at 40 °C for 14 days, and met the storage conditions when the commercially available eye drops (Timoptic®, Rhopress®, Travatan®) deviated slightly in the short term.

[0609] <Examples 110 to 114> Preparation containing netarsudil maleate, timolol maleate, and travoprost Table 174 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0610]

Table 174

[0611] Refer to the processes described in Examples 83 to 87 for the manufacturing process.

[0612] Table 175 Contents of each main drug component in Examples 110 to 114 when stored at 5 °C for 24 months

[0613]

Table 175

[0614] According to Examples 110 to 114, the preparation containing netarsudil maleate, timolol maleate, and travoprost showed good stability when stored at 5 °C for 24 months, and met the storage conditions before opening of the commercially available eye drops (Timoptic®, Rhopress®, Travatan®).

[0615] Table 176 Contents of each main drug component in Examples 110 to 114 when stored at 25 °C for 6 weeks

[0616]

Table 176

[0617] According to Examples 110 to 114, the preparation containing netarsudil maleate, timolol maleate and travoprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Timoptic®, Rhopress®, Travatan®).

[0618] Table 177 Content of each active ingredient in Examples 110 to 114 when stored at 40°C for 14 days

[0619] [Table 177]

[0620] According to Examples 110 to 114, the preparation containing netarsudil maleate, timolol maleate and travoprost showed good stability when stored at 40°C for 14 days and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Timoptic®, Rhopress®, Travatan®).

[0621] <Example 115> Evaluation of the efficacy of ophthalmic solution pharmaceutical compositions in Examples 105 to 114 using a Japanese white rabbit glaucoma model <Experimental group division> Normal control group: No treatment was performed.

[0622] Model group: A high intraocular pressure model was established and no eye drops were administered.

[0623] Treatment group 7: A high intraocular pressure model was established and a commercially available travoprost / timolol maleate combination eye drop (DuoTrav®) was administered.

[0624] Example 105: A high intraocular pressure model was established and the ophthalmic solution pharmaceutical composition of Example 105 was administered.

[0625] Example 106. An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 106 was administered.

[0626] Example 107. An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 107 was administered.

[0627] Example 108. An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 108 was administered.

[0628] Example 109. An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 109 was administered.

[0629] Example 110. An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 110 was administered.

[0630] Example 111. An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 111 was administered.

[0631] Example 112. An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 112 was administered.

[0632] Example 113. An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 113 was administered.

[0633] Example 114. An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 114 was administered.

[0634] Administration Plan: Based on the clinical administration plan of the currently marketed travoprost / timolol maleate combination eye drops (DuoTrav®), this experiment was mainly divided into the following groups. (1) Treatment Group 7: The marketed travoprost / timolol maleate combination eye drops (DuoTrav®) were administered at 50 μL per eye once a day (9:00 PM). (2) Examples 105 - 114: The eye drops of Examples 105 - 114 were administered at 50 μL per eye once a day (9:00 PM). In all groups, the model was successfully established on the 10th day, and dosing was started and continued for 10 days. No treatment was given to the normal control group and the model group. The administration plan is shown in Figure 9.

[0635] For the remaining experimental operation process (experimental animals, model establishment, inspection indicators and inspection methods), please refer to those described in Example 11.

[0636] Experimental Results <Intraocular Pressure> At all post - administration time points during the study, the IOP values of all treatment groups and example groups were significantly decreased compared with the model group (Student's paired t - test). Also, compared with Treatment Group 7 and Examples 105, 106, 107, 110, 111, 112, the IOP was significantly decreased when using the ophthalmic solution compositions of Examples 108, 109, 113, 114, but there was no significant difference in the measured IOP values and IOP change values of Examples 108, 109, 113, 114.

[0637] Table 178 Differences between the measured intraocular pressure values of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (measured intraocular pressure value on the 10th day) after continuous administration for 10 days starting from the 10th day

[0638]

Table 178

[0639] Table 179 Measured intraocular pressure values of rabbits in each group on the 10th, 15th, and 20th days after continuous administration for 10 days starting from the 10th day

[0640]

Table 179

[0641] <Examples 116 - 120>Preparations containing netarsudil mesylate, timolol mesylate and tafluprost Table 180 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by mixing as follows.

[0642]

Table 180

[0643] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[0644] Table 181 Contents of each main drug component in Examples 116 - 120 when stored at 5°C for 24 months

[0645]

Table 181

[0646] Table 182 Contents of each main drug component in commercially available eye drops (Timoptic®, Rhopress®, Tapros®) stored at 5°C for 24 months

[0647]

Table 182

[0648] According to Examples 116 - 120, the preparations containing netarsudil mesylate, timolol mesylate and tafluprost showed good stability when stored at 5°C for 24 months and met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Tapros®).

[0649] Table 183 Contents of each active ingredient in Examples 116 to 120 when stored at 25°C for 6 weeks

[0650] [Table 183]

[0651] Table 184 Contents of each active ingredient in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) when stored at 25°C for 6 weeks

[0652] [Table 184]

[0653] According to Examples 116 to 120, the preparations containing netarsudil mesylate, timolol mesylate, and tafluprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[0654] Table 185 Contents of each active ingredient in Examples 116 to 120 when stored at 40°C for 14 days

[0655] [Table 185]

[0656] Table 186 Contents of each active ingredient in commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) when stored at 40°C for 14 days

[0657] [Table 186]

[0658] According to Examples 116 to 120, the preparation containing netarsudil mesylate, timolol mesylate, and tafluprost showed good stability when stored at 40°C for 14 days and met the storage conditions in the case of short-term deviation of commercially available eye drops (Timoptic®, Rhopress®, Tapros®).

[0659] <Examples 121 to 125> A preparation containing netarsudil maleate, timolol maleate, and tafluprost Table 187 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0660]

Table 187

[0661] For the manufacturing process, refer to the process described in Examples 83 to 87.

[0662] Table 188 Contents of each main drug component in Examples 121 to 125 when stored at 5°C for 24 months

[0663]

Table 188

[0664] According to Examples 121 to 125, the preparation containing netarsudil maleate, timolol maleate, and tafluprost showed good stability when stored at 5°C for 24 months and met the storage conditions before opening of commercially available eye drops (Timoptic®, Rhopress®, Tapro®).

[0665] Table 189 Contents of each main drug component in Examples 121 to 125 when stored at 25°C for 6 weeks

[0666]

Table 189

[0667] According to Examples 121 to 125, the preparations containing netarsudil maleate, timolol maleate and tafluprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[0668] Table 190 Contents of each active ingredient in Examples 121 to 125 when stored at 40°C for 14 days

[0669] [Table 190]

[0670] According to Examples 121 to 125, the preparations containing netarsudil maleate, timolol maleate and tafluprost showed good stability when stored at 40°C for 14 days and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Timoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[0671] <Example 126> Evaluation of the efficacy of ophthalmic solution pharmaceutical compositions in Examples 116 to 125 using a Japanese white rabbit glaucoma model <Experimental group division> Normal control group: No treatment was performed.

[0672] Model group: A high intraocular pressure model was established and no eye drops were administered.

[0673] Treatment group 8: A high intraocular pressure model was established and commercially available tafluprost - timolol maleate eye drops (Tapcom (registered trademark)) were administered.

[0674] Example 116: A high intraocular pressure model was established and the ophthalmic solution pharmaceutical composition of Example 116 was administered.

[0675] Example 117: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 117 was administered.

[0676] Example 118: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 118 was administered.

[0677] Example 119: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 119 was administered.

[0678] Example 120: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 120 was administered.

[0679] Example 121: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 121 was administered.

[0680] Example 122: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 122 was administered.

[0681] Example 123: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 123 was administered.

[0682] Example 124: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 124 was administered.

[0683] Example 125: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 125 was administered.

[0684] Administration Plan: Based on the clinical administration plan of the currently marketed Tafluprost Timolol Maleate Eye Drops (Tapcom (registered trademark)), this experiment was mainly divided into the following groups. (1) Treatment Group 8: The marketed Tafluprost Timolol Maleate Eye Drops (Tapcom (registered trademark)) were administered at 50 μL per eye once a day (9:00 PM). (2) Examples 116 - 125: The eye drops of Examples 116 - 125 were administered at 50 μL per eye once a day (9:00 PM). In all groups, the model was successfully established on the 10th day, and drug administration was started and continued for 10 days. No treatment was given to the normal control group and the model group. The administration plan is shown in Figure 11.

[0685] For the remaining experimental operation process (experimental animals, model establishment, inspection indicators and inspection methods), please refer to those described in Example 11.

[0686] Experimental Results <Intraocular Pressure> At all post - administration time points during the study, the IOP values of all treatment groups and example groups were significantly decreased compared with the model group (Student's paired t - test). Also, when using the ophthalmic solution compositions of Examples 119, 120, 124, and 125, the IOP was significantly decreased compared with Treatment Group 8 and Examples 116, 117, 118, 121, 122, and 123. However, there was no significant difference in the measured IOP values and IOP change values of Examples 119, 120, 124, and 125.

[0687] Table 191 Difference between the measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (measured intraocular pressure on the 10th day) after continuous administration for 10 days starting from the 10th day

[0688]

Table 191

[0689] Table 192 Measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days after continuous administration for 10 days starting from the 10th day

[0690]

Table 192

[0691] <Example 127> Preparation containing netarsudil mesylate, timolol hydrobromide and latanoprost Table 193 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0692]

Table 193

[0693] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[0694] Table 194 Content of each main drug component in Example 127 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0695]

Table 194

[0696] According to Example 127, the preparation containing netarsudil mesylate, timolol hydrobromide and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0697] <Example 128> Preparation containing netarsudil mesylate, timolol sulfate and latanoprost Table 195 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0698]

Table 195

[0699] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[0700] Table 196 Content of each active ingredient in Example 128 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0701]

Table 196

[0702] According to Example 128, the preparation containing netarsudil mesylate, timolol sulfate, and latanoprost showed good stability when stored at 5°C for 24 months, meeting the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), and showed good stability when stored at 25°C for 6 weeks, meeting the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0703] <Example 129> Preparation containing netarsudil mesylate, timolol ethanesulfonate, and latanoprost Table 197 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0704]

Table 197

[0705] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[0706] Table 198 Content of each active ingredient in Example 129 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0707] [Table 198]

[0708] According to Example 129, the preparation containing netarsudil mesylate, timolol ethanesulfonate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0709] <Example 130> Preparation containing netarsudil mesylate, timolol nitrate, and latanoprost Table 199 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0710] [Table 199]

[0711] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[0712] Table 200 Content of each active ingredient in Example 130 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0713] [Table 200]

[0714] According to Example 130, a preparation containing netarsudil mesylate, timolol nitrate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0715] <Example 131> A preparation containing netarsudil mesylate, timolol citrate, and latanoprost Table 201 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0716]

Table 201

[0717] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[0718] Table 202 The contents of each main drug component in Example 131 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0719]

Table 202

[0720] According to Example 131, a formulation containing netarsudil mesylate, timolol citrate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0721] <Example 132> A formulation containing netarsudil mesylate, timolol tartrate, and latanoprost Table 203 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0722]

Table 203

[0723] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[0724] Table 204 Content of each active ingredient in Example 132 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0725]

Table 204

[0726] According to Example 132, a preparation containing netarsudil mesylate, timolol tartrate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0727] <Example 133> A preparation containing netarsudil mesylate, timolol salicylate, and latanoprost Table 205 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0728]

Table 205

[0729] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[0730] Table 206 Contents of each main drug component in Example 133 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0731]

Table 206

[0732] According to Example 133, a formulation containing netarsudil mesylate, timolol salicylate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0733] <Example 134> A formulation containing netarsudil mesylate, timolol malate, and latanoprost Table 207 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0734]

Table 207

[0735] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[0736] Table 208 Contents of each main drug component in Example 134 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0737]

Table 208

[0738] According to Example 134, a formulation containing netarsudil mesylate, timolol malate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0739] <Example 135> A formulation containing netarsudil mesylate, timolol lactate, and latanoprost Table 209 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0740]

Table 209

[0741] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[0742] Table 210 Contents of each main drug component in Example 135 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0743]

Table 210

[0744] According to Example 135, a preparation containing netarsudil mesylate, timolol lactate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0745] <Example 136> A preparation containing netarsudil mesylate, timolol phenylacetate, and latanoprost Table 211 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0746]

Table 211

[0747] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[0748] Table 212 The contents of each main drug component in Example 136 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0749]

Table 212

[0750] According to Example 136, a preparation containing netarsudil mesylate, timolol phenylacetate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0751] <Example 137>A preparation containing netarsudil dihydrobromide, timolol maleate, and latanoprost Table 213 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0752]

Table 213

[0753] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[0754] Table 214 Contents of each main drug component in Example 137 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0755]

Table 214

[0756] According to Example 137, a preparation containing netarsudil hydrobromide, timolol maleate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0757] <Example 138> A preparation containing netarsudil dihydrochloride, timolol maleate, and latanoprost Table 215 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0758]

Table 215

[0759] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[0760] Table 216 The content of each main drug component in Example 138 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0761]

Table 216

[0762] According to Example 138, a preparation containing netarsudil dihydrochloride, timolol maleate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0763] <Example 139> A preparation containing netarsudil sulfate, timolol maleate, and latanoprost Table 217 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0764]

Table 217

[0765] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[0766] Table 218 Contents of each main drug component in Example 139 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0767]

Table 218

[0768] According to Example 139, a preparation containing netarsudil sulfate, timolol maleate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0769] <Example 140> A preparation containing netarsudil diglate, timolol maleate, and latanoprost Table 219 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0770]

Table 219

[0771] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[0772] Table 220 Contents of each main drug component in Example 140 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0773]

Table 220

[0774] According to Example 140, a formulation containing netarsudil disulfate, timolol maleate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0775] <Example 141> A formulation containing netarsudil dinitrate, timolol maleate, and latanoprost Table 221 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by blending as follows.

[0776]

Table 221

[0777] Please refer to the processes described in Examples 83 - 87 for the manufacturing process.

[0778] Table 222 The content of each main drug component in Example 141 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0779]

Table 222

[0780] According to Example 141, a preparation containing netarsudil dinitrate, timolol maleate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0781] <Example 142> A preparation containing netarsudil diacetate, timolol maleate, and latanoprost Table 223 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0782]

Table 223

[0783] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[0784] Table 224 The content of each main drug component in Example 142 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0785]

Table 224

[0786] According to Example 142, a formulation containing netarsudil diacetate, timolol maleate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0787] <Example 143> A formulation containing netarsudil dibenzoate, timolol maleate, and latanoprost Table 225 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0788]

Table 225

[0789] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[0790] Table 226 Contents of each main drug component in Example 143 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0791]

Table 226

[0792] According to Example 143, a formulation containing netarsudil dibenzoate, timolol maleate and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0793] <Example 144> A formulation containing netarsudil oxalate, timolol maleate and latanoprost Table 227 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0794]

Table 227

[0795] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[0796] Table 228 Contents of each main drug component in Example 144 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0797]

Table 228

[0798] According to Example 144, a formulation containing netarsudil oxalate, timolol maleate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0799] <Example 145> A formulation containing netarsudil succinate, timolol maleate, and latanoprost Table 229 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0800]

Table 229

[0801] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[0802] Table 230 Contents of each main drug component in Example 145 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0803]

Table 230

[0804] According to Example 145, a formulation containing netarsudil succinate, timolol maleate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0805] <Example 146> A formulation containing netarsudil diphenylacetate, timolol maleate, and latanoprost Table 231 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0806]

Table 231

[0807] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[0808] Table 232 Contents of each main drug component in Example 146 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[0809]

Table 232

[0810] According to Example 146, a preparation containing netarsudil diphenylacetate, timolol maleate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Timoptic®, Rhopress®, Xalatan®).

[0811] <Comparative Examples 25 - 28> Preparations containing netarsudil mesylate, timolol maleate, and latanoprost Table 233 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0812]

Table 233

[0813] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[0814] Table 234 Contents of each main drug component in Comparative Examples 25 - 28 when stored at 5°C for 7 days

[0815]

Table 234

[0816] According to Comparative Examples 25 - 28, preparations containing netarsudil mesylate, timolol maleate, and latanoprost were incompatible under storage conditions of 5°C, and netarsudil mesylate precipitated.

[0817] <Comparative Examples 29 - 32> Preparations containing netarsudil mesylate, maleic acid, and latanoprost Table 235 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0818]

Table 235

[0819] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[0820] Table 236 Contents of each active ingredient in Comparative Examples 29 to 32 when stored at 5°C for 7 days

[0821]

Table 236

[0822] According to Comparative Examples 29 to 32, the formulations containing netarsudil mesylate, maleic acid, and latanoprost were incompatible under storage conditions of 5°C, and netarsudil mesylate precipitated.

[0823] <Comparative Examples 33 to 36> Formulations containing netarsudil mesylate, timolol maleate, and bimatoprost Table 237 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0824]

Table 237

[0825] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[0826] Table 238 Contents of each active ingredient in Comparative Examples 33 to 36 when stored at 5°C for 7 days

[0827]

Table 238

[0828] According to Comparative Examples 33 to 36, the preparation containing netarsudil mesylate, timolol maleate and bimatoprost was incompatible under the storage condition at 5°C, and netarsudil mesylate precipitated.

[0829] <Comparative Examples 37 to 40> Preparation containing netarsudil mesylate, maleic acid and bimatoprost Table 239 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0830]

Table 239

[0831] Please refer to the processes described in Production Process Examples 83 to 87.

[0832] Table 240 Contents of each active ingredient in Comparative Examples 37 to 40 when stored at 5°C for 7 days

[0833]

Table 240

[0834] According to Comparative Examples 37 to 40, the preparation containing netarsudil mesylate, maleic acid and bimatoprost was incompatible under the storage condition at 5°C, and netarsudil mesylate precipitated.

[0835] <Comparative Examples 41 to 44> Preparation containing netarsudil mesylate, timolol maleate and travoprost Table 241 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[0836]

Table 241

[0837] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[0838] Table 242 Contents of each active ingredient in Comparative Examples 41 to 44 when stored at 5°C for 7 days

[0839] [Table 242]

[0840] According to Comparative Examples 41 to 44, the formulations containing netarsudil mesylate, timolol maleate and travoprost were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[0841] <Comparative Examples 45 to 48> Formulations containing netarsudil mesylate, maleic acid and travoprost Table 243 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0842] [Table 243]

[0843] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[0844] Table 244 Contents of each active ingredient in Comparative Examples 45 to 48 when stored at 5°C for 7 days

[0845] [Table 244]

[0846] According to Comparative Examples 45 to 48, the formulations containing netarsudil mesylate, maleic acid and travoprost were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[0847] <Comparative Examples 49 to 52> Formulations containing netarsudil mesilate, timolol maleate, and tafluprost Table 245 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0848] [Table 245]

[0849] Refer to the processes described in Manufacturing Process Examples 83 to 87.

[0850] Table 246 Contents of each active ingredient in Comparative Examples 49 to 52 when stored at 5°C for 7 days

[0851] [Table 246]

[0852] According to Comparative Examples 49 to 52, the formulations containing netarsudil mesilate, timolol maleate, and tafluprost were incompatible under storage conditions at 5°C, and netarsudil mesilate precipitated.

[0853] <Comparative Examples 53 to 56> Formulations containing netarsudil mesilate, maleic acid, and tafluprost Table 247 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[0854] [Table 247]

[0855] Refer to the processes described in Manufacturing Process Examples 83 to 87.

[0856] Table 248 Contents of each active ingredient in Comparative Examples 53 to 56 when stored at 5°C for 7 days

[0857]

Table 248

[0858] According to Comparative Examples 53 to 56, the preparation containing netarsudil mesylate, maleic acid, and tafluprost was incompatible under the storage condition at 5°C, and netarsudil mesylate precipitated.

[0859] <Examples 147 to 151> Preparations containing netarsudil mesylate, carteolol mesylate, and latanoprost Table 249 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure by the conventional method were prepared by formulating as follows.

[0860]

Table 249

[0861] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[0862] Table 250 Contents of each main drug component in Examples 147 to 151 when stored at 5°C for 24 months

[0863]

Table 250

[0864] Table 251 Contents of each main drug component in commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) when stored at 5°C for 24 months

[0865]

Table 251

[0866] According to Examples 147 to 151, the preparation containing netarsudil mesylate, carteolol mesylate and latanoprost showed good storage stability at 5°C for 24 months and satisfied the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[0867] Table 252 Content of each main drug component in Examples 147 - 151 when stored at 25°C for 6 weeks

[0868] [Table 252]

[0869] Table 253 Content of each main drug component in commercially available eye drops (Mikelan®, Rhopress®, Xalatan®) when stored at 25°C for 6 weeks

[0870] [Table 253]

[0871] According to Examples 147 to 151, the preparation containing netarsudil mesylate, carteolol mesylate and latanoprost showed good stability when stored at 25°C for 6 weeks and satisfied the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress® and Xalatan®).

[0872] Table 254 Content of each main drug component in Examples 147 - 151 when stored at 40°C for 14 days

[0873] [Table 254]

[0874] Table 255 Content of each active ingredient of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) when stored at 40°C for 14 days

[0875] [Table 255]

[0876] According to Examples 147 to 151, the preparations containing netarsudil mesylate, carteolol mesylate and latanoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when the commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) deviated slightly in the short term.

[0877] <Examples 152 to 156> Preparations containing netarsudil dihydrochloride, carteolol hydrochloride and latanoprost Table 256 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows according to the conventional method.

[0878] [Table 256]

[0879] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[0880] Table 257 Content of each active ingredient in Examples 152 to 156 when stored at 5°C for 24 months

[0881] [Table 257]

[0882] According to Examples 152 to 156, the preparation containing netarsudil dihydrochloride, carteolol hydrochloride and latanoprost showed good stability when stored at 5°C for 24 months, and met the requirements for the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)).

[0883] Table 258 Content of each main drug component in Examples 152 to 156 when stored at 25°C for 6 weeks

[0884]

Table 258

[0885] According to Examples 152 to 156, the preparation containing netarsudil dihydrochloride, carteolol hydrochloride and latanoprost showed good stability when stored at 25°C for 6 weeks, and met the requirements for the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)).

[0886] Table 259 Content of each main drug component in Examples 152 to 156 when stored at 40°C for 14 days

[0887]

Table 259

[0888] According to Examples 152 to 156, the preparation containing netarsudil dihydrochloride, carteolol hydrochloride and latanoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)).

[0889] <Example 157> Evaluation of the efficacy of ophthalmic solution pharmaceutical compositions in Examples 147 to 156 using a Japanese white rabbit glaucoma model <Experimental group division> Normal control group: No treatment was performed.

[0890] Model group: An ocular hypertension model was established, and no eye drops were administered.

[0891] Treatment group 5: An ocular hypertension model was established, and a commercially available netarsudil / latanoprost eye drop (Rocklatan (registered trademark)) was administered.

[0892] Treatment group 9: An ocular hypertension model was established, and a commercially available carteolol hydrochloride / latanoprost combination eye drop (Mikeluna (registered trademark)) was administered.

[0893] Example 147: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 147 was administered.

[0894] Example 148: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 148 was administered.

[0895] Example 149: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 149 was administered.

[0896] Example 150: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 150 was administered.

[0897] Example 151: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 151 was administered.

[0898] Example 152: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 152 was administered.

[0899] Example 153: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 153 was administered.

[0900] Example 154: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 154 was administered.

[0901] Example 155: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 155 was administered.

[0902] Example 156: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 156 was administered.

[0903] Administration plan: Based on the clinical administration plans of currently marketed netarsudil / latanoprost eye drops (Rocklatan®) and commercially available carteolol hydrochloride / latanoprost combination eye drops (Mikeluna®), this experiment was mainly divided into the following groups. (1) Treatment group 5: Commercially available netarsudil / latanoprost eye drops (Rocklatan®) were administered at 50 μL per eye once a day (9:00 PM). (2) Treatment group 9: Commercially available carteolol hydrochloride / latanoprost combination eye drops (Mikeluna®) were administered at 50 μL per eye once a day (9:00 PM). (3) Examples 147 - 156: The eye drops of Examples 147 - 156 were administered at 50 μL per eye once a day (9:00 PM). In all groups, the model was successfully established on the 10th day, and dosing was started and continued for 10 days. No eye drops were administered to the normal control group and the model group. The administration plan is shown in Figure 13.

[0904] For the remaining experimental operation process (experimental animals, model establishment, inspection indicators, and inspection methods), refer to those described in Example 11.

[0905] Experimental results <Intraocular pressure> At all post - administration time points during the study, the IOP values of all treatment groups and example groups were significantly decreased compared with the model group (Student's paired t - test). Also, when using the ophthalmic solution compositions of Examples 150, 151, 155, and 156, the IOPs were all significantly decreased compared with Treatment group 5, Treatment group 9, and Examples 147, 148, 149, 152, 153, and 154. However, there was no significant difference in the measured IOP values and IOP change values of Examples 150, 151, 155, and 156.

[0906] Table 260. Difference between the measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (measured intraocular pressure on the 10th day) after continuous administration for 10 days starting from the 10th day

[0907] [Table 260]

[0908] Table 261. Measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days after continuous administration for 10 days starting from the 10th day

[0909] [Table 261]

[0910] <Examples 158 - 162> Preparations containing netarsudil mesylate, carteolol mesylate, and bimatoprost Table 262. A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[0911] [Table 262]

[0912] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[0913] Table 263. Content of each main drug component in Examples 158 - 162 when stored at 5°C for 24 months

[0914] [Table 263]

[0915] Table 264. Content of each main drug component in commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) when stored at 5°C for 24 months

[0916]

Table 264

[0917] According to Examples 158 to 162, the preparations containing netarsudil mesylate, carteolol mesylate and bimatoprost showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Lumigan®).

[0918] Table 265 Contents of each main drug component in Examples 158 to 162 when stored at 25°C for 6 weeks

[0919]

Table 265

[0920] Table 266 Contents of each main drug component in commercially available eye drops (Mikelan®, Rhopress®, Lumigan®) when stored at 25°C for 6 weeks

[0921]

Table 266

[0922] According to Examples 158 to 162, the preparations containing netarsudil mesylate, carteolol mesylate and bimatoprost showed good stability when stored at 25°C for 6 weeks and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Lumigan®).

[0923] Table 267 Contents of each main drug component in Examples 158 to 162 when stored at 40°C for 14 days

[0924]

Table 267

[0925] Table 268 Content of each active ingredient of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) when stored at 40°C for 14 days

[0926]

Table 268

[0927] According to Examples 158 to 162, the preparations containing netarsudil mesylate, carteolol mesylate and bimatoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when the commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) deviated slightly in the short term.

[0928] <Examples 163 to 167> Preparations containing netarsudil dihydrochloride, carteolol hydrochloride and bimatoprost Table 269 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows according to the conventional method.

[0929]

Table 269

[0930] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[0931] Table 270 Content of each active ingredient in Examples 163 to 167 when stored at 5°C for 24 months

[0932]

Table 270

[0933] According to Examples 163 to 167, the preparation containing netarsudil dihydrochloride, carteolol hydrochloride and bimatoprost showed good stability when stored at 5°C for 24 months, and met the requirements for the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)).

[0934] Table 271 Content of each main drug component in Examples 163 to 167 when stored at 25°C for 6 weeks

[0935]

Table 271

[0936] According to Examples 163 to 167, the preparation containing netarsudil dihydrochloride, carteolol hydrochloride and bimatoprost showed good stability when stored at 25°C for 6 weeks, and met the storage conditions after opening of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)).

[0937] Table 272 Content of each main drug component in Examples 163 to 167 when stored at 40°C for 14 days

[0938]

Table 272

[0939] According to Examples 163 to 167, the preparation containing netarsudil dihydrochloride, carteolol hydrochloride and bimatoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions in case of short - term deviation of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)).

[0940] <Example 168> Evaluation of the medicinal effects of the ophthalmic solution pharmaceutical composition in Examples 158 to 167 using a Japanese white rabbit glaucoma model <Experimental Grouping> Normal control group: No treatment was performed.

[0941] Model group: An ocular hypertension model was established, and no eye drops were administered.

[0942] Treatment group 5: An ocular hypertension model was established, and a commercially available netarsudil / latanoprost eye drop (Rocklatan (registered trademark)) was administered.

[0943] Treatment group 6: An ocular hypertension model was established, and a commercially available bimatoprost / timolol maleate eye drop (Ganfort (registered trademark)) was administered.

[0944] Example 158: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 158 was administered.

[0945] Example 159: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 159 was administered.

[0946] Example 160: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 160 was administered.

[0947] Example 161: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 161 was administered.

[0948] Example 162: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 162 was administered.

[0949] Example 163: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 163 was administered.

[0950] Example 164: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 164 was administered.

[0951] Example 165: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 165 was administered.

[0952] Example 166: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 166 was administered.

[0953] Example 167: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 167 was administered.

[0954] Dosing schedule: Based on the clinical dosing schedules of currently marketed netarsudil / latanoprost eye drops (Rocklatan®) and marketed bimatoprost / timolol maleate eye drops (Ganfort®), this experiment was mainly divided into the following groups. (1) Treatment group 5: Commercially available netarsudil / latanoprost eye drops (Rocklatan®) were administered at 50 μL per eye once a day (9:00 PM). (2) Treatment group 6: Commercially available bimatoprost / timolol maleate eye drops (Ganfort®) were administered at 50 μL per eye once a day (9:00 PM). (3) Examples 158 - 167: The eye drops of Examples 158 - 167 were administered at 50 μL per eye once a day (9:00 PM). In all groups, on the 10th day, the model was successfully established, dosing was started, and dosing was continued for 10 days. No eye drops were administered to the normal control group and the model group. The dosing schedule is shown in Figure 15.

[0955] For the remaining experimental operation process (experimental animals, model establishment, inspection indicators and inspection methods), please refer to those described in Example 11.

[0956] Experimental results <Intraocular pressure> At all post - dosing time points during the study, the IOP values of all treatment groups and example groups were significantly decreased compared to the model group (Student's paired t - test). Also, when using the ophthalmic solution compositions of Examples 161, 162, 166, and 167, the IOP was significantly decreased compared to Treatment group 5, Treatment group 6, and Examples 158, 159, 160, 163, 164, and 165. However, there was no significant difference in the measured IOP values and IOP change values of Examples 161, 162, 166, and 167.

[0957] Table 273. Difference between the measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (measured intraocular pressure on the 10th day) after continuous administration for 10 days starting from the 10th day

[0958]

Table 273

[0959] Table 274. Measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days after continuous administration for 10 days starting from the 10th day

[0960]

Table 274

[0961] <Examples 169 - 173> Preparations containing netarsudil mesylate, carteolol mesylate, and travoprost Table 275. A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[0962]

Table 275

[0963] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[0964] Table 276. Content of each main drug component in Examples 169 - 173 when stored at 5°C for 24 months

[0965]

Table 276

[0966] Table 277. Content of each main drug component in commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) when stored at 5°C for 24 months

[0967]

Table 277

[0968] According to Examples 169 to 173, the preparations containing netarsudil mesylate, carteolol mesylate and travoprost showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Travatan®).

[0969] Table 278 Content of each main drug component in Examples 169 to 173 when stored at 25°C for 6 weeks

[0970]

Table 278

[0971] Table 279 Content of each main drug component in commercially available eye drops (Mikelan®, Rhopress®, Travatan®) when stored at 25°C for 6 weeks

[0972]

Table 279

[0973] According to Examples 169 to 173, the preparations containing netarsudil mesylate, carteolol mesylate and travoprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Mikelan®, Rhopress®, Travatan®).

[0974] Table 280 Content of each main drug component in Examples 169 to 173 when stored at 40°C for 14 days

[0975]

Table 280

[0976] Table 281 Content of each main drug component of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) when stored at 40°C for 14 days

[0977]

Table 281

[0978] According to Examples 169 to 173, the preparations containing netarsudil mesylate, carteolol mesylate and travoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when the commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) deviated slightly in the short term.

[0979] <Examples 174 to 178> Preparations containing netarsudil dihydrochloride, carteolol hydrochloride and travoprost Table 282 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[0980]

Table 282

[0981] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[0982] Table 283 Content of each main drug component in Examples 174 to 178 when stored at 5°C for 24 months

[0983]

Table 283

[0984] According to Examples 174 to 178, the preparation containing netarsudil dihydrochloride, carteolol hydrochloride and travoprost showed good stability when stored at 5°C for 24 months, and met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)).

[0985] Table 284 Content of each active ingredient in Examples 174 to 178 when stored at 25°C for 6 weeks

[0986]

Table 284

[0987] According to Examples 174 to 178, the preparation containing netarsudil dihydrochloride, carteolol hydrochloride and travoprost showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)).

[0988] Table 285 Content of each active ingredient in Examples 174 to 178 when stored at 40°C for 14 days

[0989]

Table 285

[0990] According to Examples 174 to 178, the preparation containing netarsudil dihydrochloride, carteolol hydrochloride and travoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) deviated slightly in the short term.

[0991] <Example 179> Evaluation of the efficacy of ophthalmic solution pharmaceutical compositions in Examples 169 to 178 using a Japanese white rabbit glaucoma model <Experimental Group Division> Normal control group: No treatment was performed.

[0992] Model group: An ocular hypertension model was established, and no eye drops were administered.

[0993] Treatment group 5: An ocular hypertension model was established, and a commercially available netarsudil / latanoprost eye drop (Rocklatan (registered trademark)) was administered.

[0994] Treatment group 7: An ocular hypertension model was established, and a commercially available travoprost / timolol maleate combination eye drop (DuoTrav (registered trademark)) was administered.

[0995] Example 169: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 169 was administered.

[0996] Example 170: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 170 was administered.

[0997] Example 171: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 171 was administered.

[0998] Example 172: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 172 was administered.

[0999] Example 173: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 173 was administered.

[1000] Example 174: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 174 was administered.

[1001] Example 175: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 175 was administered.

[1002] Example 176: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 176 was administered.

[1003] Example 177: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 177 was administered.

[1004] Example 178: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 178 was administered.

[1005] Administration plan: Based on the clinical administration plans of currently marketed netarsudil / latanoprost eye drops (Rocklatan®) and commercially available travoprost / timolol maleate combination eye drops (DuoTrav®), this experiment was mainly divided into the following groups. (1) Treatment group 5: Commercially available netarsudil / latanoprost eye drops (Rocklatan®) were administered at 50 μL per eye once a day (9:00 PM). (2) Treatment group 7: Commercially available travoprost / timolol maleate combination eye drops (DuoTrav®) were administered at 50 μL per eye once a day (9:00 PM). (3) Examples 169 - 178: The eye drops of Examples 169 - 178 were administered at 50 μL per eye once a day (9:00 PM). In all groups, the model was successfully established on the 10th day, and drug administration was started and continued for 10 days. The normal control group and the model group were not administered eye drops. The administration plan is shown in Figure 17.

[1006] For the remaining experimental operation process (experimental animals, model establishment, inspection indicators and inspection methods), please refer to those described in Example 11.

[1007] Experimental results <Intraocular pressure> At all post - administration time points during the study, the IOP values of all treatment groups and example groups were significantly decreased compared with the model group (Student's paired t - test). Also, when comparing with treatment group 5, treatment group 7, and Examples 169, 170, 171, 174, 175, 176, the IOP was significantly decreased when using the ophthalmic solution compositions of Examples 172, 173, 177, 178, but there was no significant difference in the measured IOP values and IOP change values of Examples 172, 173, 177, 178.

[1008] Table 286. Difference between the actually measured intraocular pressure values of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (the actually measured intraocular pressure value on the 10th day), after continuous administration for 10 days starting from the 10th day

[1009]

Table 286

[1010] Table 287. Actually measured intraocular pressure values of rabbits in each group on the 10th, 15th, and 20th days, after continuous administration for 10 days starting from the 10th day

[1011]

Table 287

[1012] <Examples 180 to 184> Preparations containing netarsudil mesylate, carteolol mesylate, and tafluprost Table 288. A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1013]

Table 288

[1014] Refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1015] Table 289. Content of each main drug component in Examples 180 to 184 when stored at 5°C for 24 months

[1016]

Table 289

[1017] Table 290. Content of each main drug component in commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) when stored at 5°C for 24 months

[1018]

Table 290

[1019] According to Examples 180 to 184, the preparations containing netarsudil mesylate, carteolol mesylate and tafluprost showed good stability when stored at 5°C for 24 months, and met the storage conditions before opening of commercially available eye drops (Mikelan®, Rhopress®, Tapros®).

[1020] Table 291 Contents of each active ingredient in Examples 180 to 184 when stored at 25°C for 6 weeks

[1021]

Table 291

[1022] Table 292 Contents of each active ingredient in commercially available eye drops (Mikelan®, Rhopress®, Tapros®) when stored at 25°C for 6 weeks

[1023]

Table 292

[1024] According to Examples 180 to 184, the preparations containing netarsudil mesylate, carteolol mesylate and tafluprost showed good stability when stored at 25°C for 6 weeks, and met the storage conditions after opening of commercially available eye drops (Mikelan®, Rhopress®, Tapros®).

[1025] Table 293 Contents of each active ingredient in Examples 180 to 184 when stored at 40°C for 14 days

[1026]

Table 293

[1027] Table 294 Content of each main drug component of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) when stored at 40 °C for 14 days

[1028]

Table 294

[1029] According to Examples 180 to 184, the preparations containing netarsudil mesylate, carteolol mesylate and tafluprost showed good stability when stored at 40 °C for 14 days and met the storage conditions when the commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) deviated slightly in the short term.

[1030] <Examples 185 to 189> Preparations containing netarsudil dihydrochloride, carteolol hydrochloride and tafluprost Table 295 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows according to the conventional method.

[1031]

Table 295

[1032] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1033] Table 296 Content of each main drug component in Examples 185 to 189 when stored at 5 °C for 24 months

[1034]

Table 296

[1035] According to Examples 185 to 189, the preparations containing netarsudil dihydrochloride, carteolol hydrochloride, and tafluprost showed good stability when stored at 5°C for 24 months, and met the pre - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Tapro (registered trademark)).

[1036] Table 297 Content of each active ingredient in Examples 185 to 189 when stored at 25°C for 6 weeks

[1037]

Table 297

[1038] According to Examples 185 to 189, the preparations containing netarsudil dihydrochloride, carteolol hydrochloride, and tafluprost showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1039] Table 298 Content of each active ingredient in Examples 185 to 189 when stored at 40°C for 14 days

[1040]

Table 298

[1041] According to Examples 185 to 189, the preparations containing netarsudil dihydrochloride, carteolol hydrochloride, and tafluprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when commercially available eye drops (Mikelan (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) deviated slightly in the short term.

[1042] <Example 190> Evaluation of the efficacy of ophthalmic solution pharmaceutical compositions in Examples 180 to 189 using a Japanese white rabbit glaucoma model <Experimental group division> Normal control group: No treatment was performed.

[1043] Model group: An ocular hypertension model was established, and no eye drops were administered.

[1044] Treatment group 5: An ocular hypertension model was established, and a commercially available netarsudil / latanoprost eye drop (Rocklatan (registered trademark)) was administered.

[1045] Treatment group 8: An ocular hypertension model was established, and a commercially available tafluprost timolol maleate eye drop (Tapcom (registered trademark)) was administered.

[1046] Example 180: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 180 was administered.

[1047] Example 181: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 181 was administered.

[1048] Example 182: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 182 was administered.

[1049] Example 183: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 183 was administered.

[1050] Example 184: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 184 was administered.

[1051] Example 185: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 185 was administered.

[1052] Example 186: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 186 was administered.

[1053] Example 187: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 187 was administered.

[1054] Example 188: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 188 was administered.

[1055] Example 189: An ocular hypertension model was established, and the ophthalmic solution pharmaceutical composition of Example 189 was administered.

[1056] Administration plan: Based on the clinical administration plans of currently commercially available netarsudil / latanoprost eye drops (Rocklatan®) and commercially available tafluprost / timolol maleate eye drops (Tapcom®), this experiment was mainly divided into the following groups. (1) Treatment group 5: Commercially available netarsudil / latanoprost eye drops (Rocklatan®) were administered at 50 μL per eye once a day (9:00 PM). (2) Treatment group 8: Commercially available tafluprost / timolol maleate eye drops (Tapcom®) were administered at 50 μL per eye once a day (9:00 PM). (3) Examples 180 - 189: The eye drops of Examples 180 - 189 were administered at 50 μL per eye once a day (9:00 PM). In all groups, the model was successfully established on the 10th day, and drug administration was started and continued for 10 days. No eye drops were administered to the normal control group and the model group. No eye drops were administered to the normal control group and the model group. The administration plan is shown in Figure 19.

[1057] For the remaining experimental operation process (experimental animals, model establishment, inspection indicators and inspection methods), refer to those described in Example 11.

[1058] Experimental results <Intraocular pressure> At all post - administration time points during the study, the IOP values of all treatment groups and example groups were significantly decreased compared to the model group (Student's paired t - test). Also, compared with treatment group 5, treatment group 8, and Examples 180, 181, 182, 185, 186, 187, the IOP was significantly decreased when using the ophthalmic solution compositions of Examples 183, 184, 188, 189, but there was no significant difference in the measured IOP values and IOP change values of Examples 183, 184, 188, 189.

[1059] Table 299. Difference between the measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days and the initial intraocular pressure (measured intraocular pressure on the 10th day), after continuous administration for 10 days starting from the 10th day

[1060] [Table 299]

[1061] Table 300. Measured intraocular pressure of rabbits in each group on the 10th, 15th, and 20th days, after continuous administration for 10 days starting from the 10th day

[1062] [Table 300]

[1063] <Example 191> Preparation containing netarsudil mesilate, carteolol hydrobromide, and latanoprost Table 301. A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1064] [Table 301]

[1065] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[1066] Table 302. Content of each main drug component in Example 191 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1067] [Table 302]

[1068] According to Example 191, a preparation containing netarsudil mesylate, carteolol hydrobromide, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), and showed good stability when stored at 25°C for 6 weeks, meeting the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1069] <Example 192> A preparation containing netarsudil mesylate, carteolol sulfate, and latanoprost Table 303 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1070]

Table 303

[1071] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1072] Table 304 Contents of each main drug component in Example 192 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1073]

Table 304

[1074] According to Example 192, a preparation containing netarsudil mesylate, carteolol sulfate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), and showed good stability when stored at 25°C for 6 weeks, meeting the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1075] <Example 193> A preparation containing netarsudil mesylate, carteolol ethanesulfonate, and latanoprost Table 305 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1076]

Table 305

[1077] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[1078] Table 306 Contents of each main drug component in Example 193 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1079]

Table 306

[1080] According to Example 193, a preparation containing netarsudil mesylate, carteolol ethanesulfonate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1081] <Example 194> A preparation containing netarsudil mesylate, carteolol nitrate, and latanoprost Table 307 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1082]

Table 307

[1083] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1084] Table 308 Contents of each main drug component in Example 194 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1085]

Table 308

[1086] According to Example 194, a formulation containing netarsudil mesylate, carteolol nitrate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1087] <Example 195> A formulation containing netarsudil mesylate, carteolol citrate, and latanoprost Table 309 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1088]

Table 309

[1089] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[1090] Table 310 Contents of each main drug component in Example 195 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1091]

Table 310

[1092] According to Example 195, a preparation containing netarsudil mesylate, carteolol citrate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1093] <Example 196> A preparation containing netarsudil mesylate, carteolol tartrate, and latanoprost Table 311 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1094]

Table 311

[1095] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1096] Table 312 Contents of each main drug component in Example 196 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1097]

Table 312

[1098] According to Example 196, the preparation containing netarsudil mesylate, carteolol tartrate and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1099] <Example 197> A preparation containing netarsudil mesylate, carteolol salicylate and latanoprost Table 313 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1100]

Table 313

[1101] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1102] Table 314 Contents of each main drug component in Example 197 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1103]

Table 314

[1104] According to Example 197, a preparation containing netarsudil mesylate, carteolol salicylate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1105] <Example 198>A preparation containing netarsudil mesylate, carteolol malate, and latanoprost Table 315 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1106]

Table 315

[1107] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[1108] Table 316 Contents of each main drug component in Example 198 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1109]

Table 316

[1110] According to Example 198, a formulation containing netarsudil mesylate, carteolol malate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1111] <Example 199> A formulation containing netarsudil mesylate, carteolol lactate, and latanoprost Table 317 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1112]

Table 317

[1113] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[1114] Table 318 Contents of each main drug component in Example 199 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1115]

Table 318

[1116] According to Example 199, a preparation containing netarsudil mesylate, carteolol lactate, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1117] <Example 200>A preparation containing netarsudil mesylate, phenyl carteolol acetate, and latanoprost Table 319 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1118]

Table 319

[1119] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1120] Table 320 Content of each main drug component in Example 200 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1121]

Table 320

[1122] According to Example 200, a preparation containing netarsudil mesylate, phenyl carteolol acetate and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1123] <Example 201>A preparation containing netarsudil dihydrobromide, carteolol hydrochloride and latanoprost Table 321 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1124]

Table 321

[1125] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1126] Table 322 The content of each main drug component in Example 201 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1127]

Table 322

[1128] According to Example 201, a preparation containing netarsudil hydrobromide, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1129] <Example 202>A preparation containing netarsudil sulfate, carteolol hydrochloride, and latanoprost Table 323 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1130]

Table 323

[1131] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1132] Table 324 Contents of each main drug component in Example 202 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1133]

Table 324

[1134] According to Example 202, a preparation containing netarsudil sulfate, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), and showed good stability when stored at 25°C for 6 weeks, meeting the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1135] <Example 203> A preparation containing netarsudil diglate, carteolol hydrochloride, and latanoprost Table 325 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1136]

Table 325

[1137] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[1138] Table 326 Contents of each main drug component in Example 203 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1139]

Table 326

[1140] According to Example 203, a preparation containing netarsudil disulfate, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1141] <Example 204> A preparation containing netarsudil dinitrate, carteolol hydrochloride, and latanoprost Table 327 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1142]

Table 327

[1143] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1144] Table 328 Contents of each main drug component in Example 204 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1145]

Table 328

[1146] According to Example 204, a preparation containing netarsudil dinitrate, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1147] <Example 205> A preparation containing netarsudil diacetate, carteolol hydrochloride, and latanoprost Table 329 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1148]

Table 329

[1149] Refer to the processes described in Manufacturing Process Examples 83 - 87.

[1150] Table 330 Contents of each main drug component in Example 205 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1151]

Table 330

[1152] According to Example 205, a preparation containing netarsudil diacetate, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1153] <Example 206> A preparation containing netarsudil dibenzoate, carteolol hydrochloride, and latanoprost Table 331 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1154]

Table 331

[1155] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1156] Table 332 Content of each main drug component in Example 206 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1157]

Table 332

[1158] According to Example 206, a formulation containing netarsudil mesylate, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1159] <Example 207> A formulation containing netarsudil oxalate, carteolol hydrochloride, and latanoprost Table 333 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1160]

Table 333

[1161] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1162] Table 334 Contents of each active ingredient in Example 207 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1163]

Table 334

[1164] According to Example 207, a preparation containing netarsudil oxalate, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1165] <Example 208> A preparation containing netarsudil succinate, carteolol hydrochloride, and latanoprost Table 335 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1166]

Table 335

[1167] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1168] Table 336 Contents of each main drug component in Example 208 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1169]

Table 336

[1170] According to Example 208, a formulation containing netarsudil mesylate, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1171] <Example 209> A formulation containing netarsudil diphenylacetate, carteolol hydrochloride, and latanoprost Table 337 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1172]

Table 337

[1173] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[1174] Table 338 Contents of each main drug component in Example 209 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1175]

Table 338

[1176] According to Example 209, the preparation containing netarsudil diphenylacetate, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1177] <Example 210> A preparation containing netarsudil maleate, carteolol hydrochloride, and latanoprost Table 339 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by the conventional method was prepared by formulating as follows.

[1178]

Table 339

[1179] Please refer to the processes described in Manufacturing Process Examples 83 - 87.

[1180] Table 340 Content of each main drug component in Example 210 when stored at 5°C for 24 months and when stored at 25°C for 6 weeks

[1181]

Table 340

[1182] According to Example 210, a preparation containing netarsudil diphenylacetate, carteolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, met the pre - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®), showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Mikelan®, Rhopress®, Xalatan®).

[1183] <Comparative Examples 57 - 60> Preparations containing netarsudil mesylate and carteolol hydrochloride Table 341 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure by the conventional method were prepared by formulating as follows.

[1184]

Table 341

[1185] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[1186] Table 342 Contents of each main drug component in Comparative Examples 57 - 60 when stored at 5°C for 7 days

[1187]

Table 342

[1188] According to Comparative Examples 57 - 60, preparations containing netarsudil mesylate, carteolol hydrochloride, and latanoprost were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1189] <Comparative Examples 61 - 64> Preparations containing netarsudil mesylate and hydrochloric acid Table 343 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure by the conventional method were prepared by formulating as follows.

[1190]

Table 343

[1191] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1192] Table 344 Content of each main drug component in Comparative Examples 61 to 64 when stored at 5°C for 7 days

[1193]

Table 344

[1194] According to Comparative Examples 61 to 64, the preparation containing netarsudil mesylate, hydrochloric acid and latanoprost was incompatible under the storage condition of 5°C, and netarsudil mesylate precipitated.

[1195] <Comparative Examples 65 to 68> Preparation containing netarsudil mesylate, carteolol hydrochloride and bimatoprost Table 345 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[1196]

Table 345

[1197] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1198] Table 346 Content of each main drug component in Comparative Examples 65 to 68 when stored at 5°C for 7 days

[1199]

Table 346

[1200] According to Comparative Examples 65 to 68, the preparation containing netarsudil mesylate, carteolol hydrochloride, and bimatoprost was incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1201] <Comparative Examples 69 to 72> Preparation containing netarsudil mesylate, hydrochloric acid, and bimatoprost Table 347 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[1202]

Table 347

[1203] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1204] Table 348 Contents of each main drug component in Comparative Examples 69 to 72 when stored at 5°C for 7 days

[1205]

Table 348

[1206] According to Comparative Examples 69 to 72, the preparation containing netarsudil mesylate, hydrochloric acid, and bimatoprost was incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1207] <Comparative Examples 73 to 76> Preparation containing netarsudil mesylate, carteolol hydrochloride, and travoprost Table 349 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[1208]

Table 349

[1209] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1210] Table 350 Content of each main drug component in Comparative Examples 73 to 76 when stored at 5°C for 7 days

[1211]

Table 350

[1212] According to Comparative Examples 73 to 76, the preparation containing netarsudil mesylate, carteolol hydrochloride and travoprost is incompatible under storage conditions at 5°C, and netarsudil mesylate has precipitated.

[1213] <Comparative Examples 77 - 80> Preparation containing netarsudil mesylate, hydrochloric acid and travoprost Table 351 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[1214]

Table 351

[1215] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1216] Table 352 Content of each main drug component in Comparative Examples 77 to 80 when stored at 5°C for 7 days

[1217]

Table 352

[1218] According to Comparative Examples 77 to 80, the preparation containing netarsudil mesylate, hydrochloric acid and travoprost is incompatible under storage conditions at 5°C, and netarsudil mesylate has precipitated.

[1219] <Comparative Examples 81 - 84> Preparation containing netarsudil mesylate, carteolol hydrochloride and tafluprost Table 353 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[1220] [Table 353]

[1221] Refer to the processes described in Manufacturing Process Examples 83 to 87.

[1222] Table 354 Content of each main drug component in Comparative Examples 81 to 84 when stored at 5°C for 7 days

[1223] [Table 354]

[1224] According to Comparative Examples 81 to 84, the preparations containing netarsudil mesylate, carteolol hydrochloride, and tafluprost were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1225] <Comparative Examples 85 to 88> Preparations containing netarsudil mesylate, hydrochloric acid, and tafluprost Table 355 The topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[1226] [Table 355]

[1227] Refer to the processes described in Manufacturing Process Examples 83 to 87.

[1228] Table 356 Content of each main drug component in Comparative Examples 85 to 88 when stored at 5°C for 7 days

[1229] [Table 356]

[1230] According to Comparative Examples 85 to 88, the preparation containing netarsudil mesylate, hydrochloric acid, and tafluprost was incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1231] <Examples 211 to 215> Preparation containing netarsudil mesylate, bexolol mesylate, and latanoprost Table 357 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure by the conventional method were prepared by formulating as follows.

[1232]

Table 357

[1233] Refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1234] Table 358 Contents of each active ingredient in Examples 211 to 215 when stored at 5°C for 24 months

[1235]

Table 358

[1236] Table 359 Contents of each active ingredient in commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) when stored at 5°C for 24 months

[1237]

Table 359

[1238] According to Examples 211 to 215, the preparations containing netarsudil mesylate, betaxolol mesylate and latanoprost showed good stability when stored at 5°C for 24 months, and met the pre - opening storage conditions of commercially available eye drops (Betoptic®, Rhopress®, Xalatan®).

[1239] Table 360 Contents of each active ingredient in Examples 211 to 215 when stored at 25°C for 6 weeks

[1240] [Table 360]

[1241] Table 361 Contents of each active ingredient in commercially available eye drops (Betoptic®, Rhopress®, Xalatan®) when stored at 25°C for 6 weeks

[1242] [Table 361]

[1243] According to Examples 211 to 215, the preparations containing netarsudil mesylate, betaxolol mesylate and latanoprost showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Betoptic®, Rhopress®, Xalatan®).

[1244] Table 362 Contents of each active ingredient in Examples 211 to 215 when stored at 40°C for 14 days

[1245] [Table 362]

[1246] Table 363 Content of each main drug component of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) when stored at 40 °C for 14 days

[1247]

Table 363

[1248] According to Examples 211 to 215, the preparations containing netarsudil mesylate, betaxolol mesylate and latanoprost showed good stability when stored at 40 °C for 14 days, and met the storage conditions when the commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) deviated slightly in the short term.

[1249] <Examples 216 to 220> Preparations containing netarsudil dihydrochloride, betaxolol hydrochloride and latanoprost Table 364 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows according to the conventional method.

[1250]

Table 364

[1251] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1252] Table 365 Content of each main drug component in Examples 216 to 220 when stored at 5 °C for 24 months

[1253]

Table 365

[1254] According to Examples 216 to 220, the preparation containing netarsudil dihydrochloride, betaxolol hydrochloride, and latanoprost showed good stability when stored at 5°C for 24 months, and met the pre - opening storage conditions of commercially available eye drops (Betoptic®, Rhopress®, Xalatan®).

[1255] Table 366 Contents of each active ingredient in Examples 216 to 220 when stored at 25°C for 6 weeks

[1256]

Table 366

[1257] According to Examples 216 to 220, the preparation containing netarsudil dihydrochloride, betaxolol hydrochloride, and latanoprost showed good stability when stored at 25°C for 6 weeks, and met the requirements of the pre - opening storage conditions of commercially available eye drops (Betoptic®, Rhopress®, Xalatan®).

[1258] Table 367 Contents of each active ingredient in Examples 216 to 220 when stored at 40°C for 14 days

[1259]

Table 367

[1260] According to Examples 216 to 220, the preparation containing netarsudil dihydrochloride, betaxolol hydrochloride, and latanoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when commercially available eye drops (Betoptic®, Rhopress®, Xalatan®) deviated slightly in the short term.

[1261] <Examples 221 - 225> Preparation containing netarsudil mesylate, betaxolol mesylate, and bimatoprost Table 368 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by mixing as follows.

[1262]

Table 368

[1263] Refer to the processes described in Manufacturing Process Examples 83 to 87.

[1264] Table 369 Contents of each active ingredient in Examples 221 to 225 when stored at 5°C for 24 months

[1265]

Table 369

[1266] Table 370 Contents of each active ingredient in commercially available eye drops (Betoptic®, Rhopress®, Lumigan®) when stored at 5°C for 24 months

[1267]

Table 370

[1268] According to Examples 221 to 225, the preparations containing netarsudil mesylate, betaxolol mesylate, and bimatoprost showed good stability when stored at 5°C for 24 months and met the pre - opening storage conditions of commercially available eye drops (Betoptic®, Rhopress®, Lumigan®).

[1269] Table 371 Contents of each active ingredient in Examples 221 to 225 when stored at 25°C for 6 weeks

[1270]

Table 371

[1271] Table 372 Content of each main drug component in commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) when stored at 25°C for 6 weeks

[1272] [Table 372]

[1273] According to Examples 221 to 225, the preparations containing netarsudil mesylate, betaxolol mesylate and bimatoprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)).

[1274] Table 373 Content of each main drug component in Examples 221 to 225 when stored at 40°C for 14 days

[1275] [Table 373]

[1276] Table 374 Content of each main drug component in commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) when stored at 40°C for 14 days

[1277] [Table 374]

[1278] According to Examples 221 to 225, the preparations containing netarsudil mesylate, betaxolol mesylate and bimatoprost showed good stability when stored at 40°C for 14 days and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)).

[1279] <Examples 226 - 230> Preparations containing netarsudil dihydrochloride, betaxolol hydrochloride, and bimatoprost Table 375 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure by conventional methods were prepared by formulating as follows.

[1280]

Table 375

[1281] Please refer to the processes described in Examples 83 - 87 of the manufacturing process.

[1282] Table 376 Contents of each active ingredient in Examples 226 - 230 when stored at 5°C for 24 months

[1283]

Table 376

[1284] According to Examples 226 - 230, preparations containing netarsudil dihydrochloride, betaxolol hydrochloride, and bimatoprost showed good stability when stored at 5°C for 24 months and met the requirements for pre - opening storage conditions of commercially available eye drops (Betoptic®, Rhopress®, Lumigan®).

[1285] Table 377 Contents of each active ingredient in Examples 226 - 230 when stored at 25°C for 6 weeks

[1286]

Table 377

[1287] According to Examples 266 to 270, the preparations containing netarsudil dihydrochloride, betaxolol hydrochloride and bimatoprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Betoptic®, Rhopress®, Lumigan®).

[1288] Table 378 Content of each active ingredient in Examples 226 to 230 when stored at 40°C for 14 days

[1289] [Table 378]

[1290] According to Examples 266 to 270, the preparations containing netarsudil dihydrochloride, betaxolol hydrochloride and bimatoprost showed good stability when stored at 40°C for 14 days and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Betoptic®, Rhopress®, Lumigan®).

[1291] <Examples 231 to 235> Preparations containing netarsudil mesylate, betaxolol mesylate and travoprost Table 379 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows according to the conventional method.

[1292] [Table 379]

[1293] Please refer to the process described in Examples 83 to 87 of the manufacturing process.

[1294] Table 380 Content of each active ingredient in Examples 231 to 235 when stored at 5°C for 24 months

[1295] [Table 380]

[1296] Table 381 Content of each main drug component in commercially available eye drops (Betoptic®, Rhopress®, Travatan®) when stored at 5°C for 24 months

[1297] [Table 381]

[1298] According to Examples 231 to 235, the preparations containing netarsudil mesylate, betaxolol mesylate and travoprost showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Betoptic®, Rhopress®, Travatan®).

[1299] Table 382 Content of each main drug component in Examples 231 to 235 when stored at 25°C for 6 weeks

[1300] [Table 382]

[1301] Table 383 Content of each main drug component in commercially available eye drops (Betoptic®, Rhopress®, Travatan®) when stored at 25°C for 6 weeks

[1302] [Table 383]

[1303] According to Examples 231 to 235, the preparations containing netarsudil mesylate, betaxolol mesylate and travoprost showed good stability when stored at 25°C for 6 weeks, and met the storage conditions after opening of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)).

[1304] Table 384 Content of each active ingredient in Examples 231 to 235 when stored at 40°C for 14 days

[1305]

Table 384

[1306] Table 385 Content of each active ingredient in commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) when stored at 40°C for 14 days

[1307]

Table 385

[1308] According to Examples 231 to 235, the preparations containing netarsudil mesylate, betaxolol mesylate and travoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)).

[1309] <Examples 236 to 240> Preparations containing netarsudil dihydrochloride, betaxolol hydrochloride and travoprost Table 386 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows according to the conventional method.

[1310]

Table 386

[1311] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1312] Table 387 Content of each active ingredient in Examples 236 to 240 when stored at 5°C for 24 months

[1313] [Table 387]

[1314] According to Examples 236 to 240, the preparations containing netarsudil dihydrochloride, betaxolol hydrochloride, and travoprost showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Betoptic®, Rhopress®, Travatan®).

[1315] Table 388 Content of each active ingredient in Examples 236 to 240 when stored at 25°C for 6 weeks

[1316] [Table 388]

[1317] According to Examples 236 to 240, the preparations containing netarsudil dihydrochloride, betaxolol hydrochloride, and travoprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Betoptic®, Rhopress®, Travatan®).

[1318] Table 389 Content of each active ingredient in Examples 236 to 240 when stored at 40°C for 14 days

[1319] [Table 389]

[1320] According to Examples 236 to 240, the preparation containing netarsudil dihydrochloride, betaxolol hydrochloride, and travoprost showed good stability when stored at 40°C for 14 days, and satisfied the storage conditions in the case of short-term deviation of commercially available eye drops (Betoptic®, Rhopress®, Travatan®).

[1321] <Examples 241 to 245> Preparations containing netarsudil mesylate, betaxolol mesylate, and tafluprost Table 390 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1322]

Table 390

[1323] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1324] Table 391 Contents of each main drug component in Examples 241 to 245 when stored at 5°C for 24 months

[1325]

Table 391

[1326] Table 392 Contents of each main drug component in commercially available eye drops (Betoptic®, Rhopress®, Tapros®) when stored at 5°C for 24 months

[1327]

Table 392

[1328] According to Examples 241 to 245, the preparations containing netarsudil mesylate, bepotastine besilate, and tafluprost showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1329] Table 393 Content of each active ingredient in Examples 241 to 245 when stored at 25°C for 6 weeks

[1330]

Table 393

[1331] Table 394 Content of each active ingredient in commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) when stored at 5°C for 6 weeks

[1332]

Table 394

[1333] According to Examples 241 to 245, the preparations containing netarsudil mesylate, bepotastine besilate, and tafluprost showed good stability when stored at 25°C for 6 weeks and met the post - opening storage conditions of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1334] Table 395 Content of each active ingredient in Examples 241 to 245 when stored at 40°C for 14 days

[1335]

Table 395

[1336] Table 396 Content of each active ingredient in commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) when stored at 40°C for 14 days

[1337] [Table 396]

[1338] According to Examples 241 to 245, the preparations containing netarsudil mesylate, betaxolol mesylate and tafluprost showed good stability when stored at 40°C for 14 days and met the storage conditions in the case of short-term deviation of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1339] <Examples 246 to 250> Preparations containing netarsudil dihydrochloride, betaxolol hydrochloride and tafluprost Table 397 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows according to the conventional method.

[1340] [Table 397]

[1341] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1342] Table 398 Content of each active ingredient in Examples 246 to 250 when stored at 5°C for 24 months

[1343] [Table 398]

[1344] According to Examples 246 to 250, the preparation containing netarsudil dihydrochloride, betaxolol hydrochloride and tafluprost showed good stability when stored at 5°C for 24 months, and met the storage conditions before opening of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1345] Table 399 Content of each active ingredient in Examples 246 to 250 when stored at 25°C for 6 weeks

[1346]

Table 399

[1347] According to Examples 246 to 250, the preparation containing netarsudil dihydrochloride, betaxolol hydrochloride and tafluprost showed good stability when stored at 25°C for 6 weeks, and met the storage conditions after opening of commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1348] Table 400 Content of each active ingredient in Examples 246 to 250 when stored at 40°C for 14 days

[1349]

Table 400

[1350] According to Examples 246 to 250, the preparation containing netarsudil dihydrochloride, betaxolol hydrochloride and tafluprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when deviating short - term from commercially available eye drops (Betoptic (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1351] <Comparative Examples 89 to 92> Preparation containing netarsudil mesylate, betaxolol hydrochloride and latanoprost Table 401 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[1352] [Table 401]

[1353] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1354] Table 402 Contents of each main drug component in Comparative Examples 89 to 92 when stored at 5°C for 7 days

[1355] [Table 402]

[1356] According to Comparative Examples 89 to 92, the preparations containing netarsudil mesylate, betaxolol hydrochloride and latanoprost were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1357] <Comparative Examples 93 to 96> Preparations containing netarsudil mesylate, betaxolol hydrochloride and bimatoprost Table 403 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows.

[1358] [Table 403]

[1359] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1360] Table 404 Contents of each main drug component in Comparative Examples 93 to 96 when stored at 5°C for 7 days

[1361] [Table 404]

[1362] According to Comparative Examples 93 to 96, the preparations containing netarsudil mesylate, betaxolol hydrochloride, and bimatoprost were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1363] <Comparative Examples 97 to 100> Preparations containing netarsudil mesylate, betaxolol hydrochloride, and travoprost Table 405 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[1364]

Table 405

[1365] Please refer to the processes described in Production Process Examples 83 to 87.

[1366] Table 406 Contents of each main drug component in Comparative Examples 97 to 100 when stored at 5°C for 7 days

[1367]

Table 406

[1368] According to Comparative Examples 97 to 100, the preparations containing netarsudil mesylate, betaxolol hydrochloride, and travoprost were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1369] <Comparative Examples 101 to 104> Preparations containing netarsudil mesylate, betaxolol hydrochloride, and tafluprost Table 407 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[1370]

Table 407

[1371] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1372] Table 408 Contents of each active ingredient in Comparative Examples 101 to 104 when stored at 5°C for 7 days

[1373] [Table 408]

[1374] According to Comparative Examples 101 to 104, the formulations containing netarsudil mesylate, betaxolol hydrochloride, and tafluprost were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1375] <Examples 251 to 255> Formulations containing netarsudil mesylate, meptanolol mesylate, and latanoprost Table 409 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1376] [Table 409]

[1377] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1378] Table 410 Contents of each active ingredient in Examples 251 to 255 when stored at 5°C for 24 months

[1379] [Table 410]

[1380] Content of each main drug component in commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) when stored at 5°C for 24 months

[1381]

Table 411

[1382] According to Examples 251 to 255, the preparations containing netarsudil mesylate, metipranolol mesylate and latanoprost showed good stability when stored at 5°C for 24 months and met the storage conditions before opening of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)).

[1383] Content of each main drug component in Examples 251 to 255 when stored at 25°C for 6 weeks

[1384]

Table 412

[1385] Content of each main drug component in commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) when stored at 25°C for 6 weeks

[1386]

Table 413

[1387] According to Examples 251 to 255, the preparations containing netarsudil mesylate, metipranolol mesylate and latanoprost showed good stability when stored at 25°C for 6 weeks and met the requirements of the storage conditions after opening of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)).

[1388] Table 414 Content of each active pharmaceutical ingredient in Examples 251 to 255 when stored at 40 °C for 14 days

[1389] [Table 414]

[1390] Table 415 Content of each active pharmaceutical ingredient in commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)) when stored at 40 °C for 14 days

[1391] [Table 415]

[1392] According to Examples 251 to 255, the formulations containing netarsudil mesylate, metipranolol mesylate and latanoprost showed good stability when stored at 40 °C for 14 days and met the storage conditions in the case of short-term deviation of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)).

[1393] <Examples 256 to 260> Formulations containing netarsudil dihydrochloride, metipranolol hydrochloride and latanoprost Table 416 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows according to the conventional method.

[1394] [Table 416]

[1395] Please refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1396] Table 417 Content of each active pharmaceutical ingredient in Examples 256 to 260 when stored at 5 °C for 24 months

[1397]

Table 417

[1398] According to Examples 256 to 260, the preparation containing netarsudil dihydrochloride, metipranolol hydrochloride and latanoprost showed good stability when stored at 5°C for 24 months and met the pre - opening storage conditions of commercially available eye drops (Optipranolol®, Rhopress®, Xalatan®).

[1399] Table 418 Content of each main drug component in Examples 256 to 260 when stored at 25°C for 6 weeks

[1400]

Table 418

[1401] According to Examples 256 to 260, the preparation containing netarsudil dihydrochloride, metipranolol hydrochloride and latanoprost showed good stability when stored at 25°C for 6 weeks and met the pre - opening storage conditions of commercially available eye drops (Optipranolol®, Rhopress®, Xalatan®).

[1402] Table 419 Content of each main drug component in Examples 256 to 260 when stored at 40°C for 14 days

[1403]

Table 419

[1404] According to Examples 256 to 260, the preparation containing netarsudil dihydrochloride, metipranolol hydrochloride, and latanoprost showed good stability when stored at 40°C for 14 days and met the storage conditions in the case of short-term deviation of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Xalatan (registered trademark)).

[1405] <Examples 261 to 265> Preparation containing netarsudil mesylate, metipranolol mesylate, and bimatoprost Table 420 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by formulating as follows.

[1406]

Table 420

[1407] For the manufacturing process, refer to the process described in Examples 83 to 87.

[1408] Table 421 Contents of each main drug component in Examples 261 to 265 when stored at 5°C for 24 months

[1409]

Table 421

[1410] Table 422 Contents of each main drug component in commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) when stored at 5°C for 24 months

[1411]

Table 422

[1412] According to Examples 261 to 265, the preparations containing netarsudil mesylate, metipranolol mesylate, and bimatoprost showed good stability when stored at 5°C for 24 months, and met the requirements for the pre - opening storage conditions of commercially available eye drops (Optipranolol®, Rhopress®, Lumigan®).

[1413] Table 423 Contents of each active ingredient in Examples 261 to 265 when stored at 25°C for 6 weeks

[1414]

Table 423

[1415] Table 424 Contents of each active ingredient in commercially available eye drops (Optipranolol®, Rhopress®, Lumigan®) when stored at 25°C for 6 weeks

[1416]

Table 424

[1417] According to Examples 261 to 265, the preparations containing netarsudil mesylate, metipranolol mesylate, and bimatoprost showed good stability when stored at 25°C for 6 weeks, and met the post - opening storage conditions of commercially available eye drops (Optipranolol®, Rhopress®, Lumigan®).

[1418] Table 425 Contents of each active ingredient in Examples 261 to 265 when stored at 40°C for 14 days

[1419]

Table 425

[1420] Table 426 Content of each active ingredient of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) when stored at 40°C for 14 days

[1421] [Table 426]

[1422] According to Examples 261 to 265, the preparations containing netarsudil mesylate, metipranolol mesylate and bimatoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when the commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)) deviated slightly in the short term.

[1423] <Examples 266 to 270> Preparations containing netarsudil dihydrochloride, metipranolol hydrochloride and bimatoprost Table 427 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows according to the conventional method.

[1424] [Table 427]

[1425] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1426] Table 428 Content of each active ingredient in Examples 266 to 270 when stored at 5°C for 24 months

[1427] [Table 428]

[1428] According to Examples 266 to 270, a preparation containing netarsudil dihydrochloride, metipranolol hydrochloride, and bimatoprost showed good stability when stored at 5°C for 24 months and met the storage conditions before opening of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)).

[1429] Table 429 Content of each active ingredient in Examples 266 to 270 when stored at 25°C for 6 weeks

[1430] [Table 429]

[1431] According to Examples 266 to 270, a preparation containing netarsudil dihydrochloride, metipranolol hydrochloride, and bimatoprost showed good stability when stored at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)).

[1432] Table 430 Content of each active ingredient in Examples 266 to 270 when stored at 40°C for 14 days

[1433] [Table 430]

[1434] According to Examples 266 to 270, a preparation containing netarsudil dihydrochloride, metipranolol hydrochloride, and bimatoprost showed good stability when stored at 40°C for 14 days and met the storage conditions when deviating temporarily from commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Lumigan (registered trademark)).

[1435] <Examples 271 to 275> A preparation containing netarsudil mesylate, metipranolol mesylate, and travoprost Table 431 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure by a conventional method was prepared by blending as follows.

[1436] [Table 431]

[1437] Refer to the processes described in Manufacturing Process Examples 83 to 87.

[1438] Table 432 Contents of each active ingredient in Examples 271 to 275 when stored at 5°C for 24 months

[1439] [Table 432]

[1440] Table 433 Contents of each active ingredient in commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) when stored at 5°C for 24 months

[1441] [Table 433]

[1442] According to Examples 271 to 275, the preparations containing netarsudil mesylate, metipranolol mesylate, and travoprost showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)).

[1443] Table 434 Contents of each active ingredient in Examples 271 to 275 when stored at 25°C for 6 weeks

[1444] [Table 434]

[1445] Table 435 Content of each main drug component in commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) when stored at 25°C for 6 weeks

[1446]

Table 435

[1447] According to Examples 271 to 275, the preparations containing netarsudil mesylate, metipranolol mesylate and travoprost showed good stability when stored at 25°C for 6 weeks and met the requirements for the storage conditions after opening of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)).

[1448] Table 436 Content of each main drug component in Examples 271 to 275 when stored at 40°C for 14 days

[1449]

Table 436

[1450] Table 437 Content of each main drug component in commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Travatan (registered trademark)) when stored at 40°C for 14 days

[1451]

Table 437

[1452] According to Examples 271 to 275, the preparations containing netarsudil mesylate, metipranolol mesylate and travoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions in the case of short-term deviation of commercially available eye drops (Optipranolol®, Rhopress®, Travatan®).

[1453] <Examples 276 to 280> Preparations containing netarsudil dihydrochloride, metipranolol hydrochloride and travoprost Table 438 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure by the conventional method were prepared by formulating as follows.

[1454]

Table 438

[1455] Refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1456] Table 439 Contents of each main drug component in Examples 276 to 280 when stored at 5°C for 24 months

[1457]

Table 439

[1458] According to Examples 276 to 280, the preparations containing netarsudil dihydrochloride, metipranolol hydrochloride and travoprost showed good stability when stored at 5°C for 24 months, and met the storage conditions before opening of commercially available eye drops (Optipranolol®, Rhopress®, Travatan®).

[1459] Table 440 Contents of each main drug component in Examples 276 to 280 when stored at 25°C for 6 weeks

[1460]

Table 440

[1461] According to Examples 276 to 280, the preparations containing netarsudil dihydrochloride, metipranolol hydrochloride and travoprost showed good stability when stored at 25°C for 6 weeks, and met the requirements for the storage conditions after opening of commercially available eye drops (Optipranolol®, Rhopress®, Travatan®).

[1462] Table 441 Content of each active ingredient in Examples 276 to 280 when stored at 40°C for 14 days

[1463] [Table 441]

[1464] According to Examples 276 to 280, the preparations containing netarsudil dihydrochloride, metipranolol hydrochloride and travoprost showed good stability when stored at 40°C for 14 days, and met the storage conditions when deviating slightly in the short term of commercially available eye drops (Optipranolol®, Rhopress®, Travatan®).

[1465] <Examples 281 to 285> Preparations containing netarsudil mesylate, metipranolol mesylate, and tafluprost Table 442 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by formulating as follows according to the conventional method.

[1466] [Table 442]

[1467] Please refer to the process described in Manufacturing Process Examples 83 to 87.

[1468] Table 443 Contents of Each Active Pharmaceutical Ingredient in Examples 281 to 285 When Stored at 5°C for 24 Months

[1469] [Table 443]

[1470] Table 444 Contents of Each Active Pharmaceutical Ingredient in Commercially Available Eye Drops (Optipranolol (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) When Stored at 5°C for 24 Months

[1471] [Table 444]

[1472] According to Examples 281 to 285, the preparations containing netarsudil mesylate, metipranolol mesylate, and tafluprost showed good stability when stored at 5°C for 24 months and met the requirements for the pre - opening storage conditions of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1473] Table 445 Contents of Each Active Pharmaceutical Ingredient in Examples 281 to 285 When Stored at 25°C for 6 Weeks

[1474] [Table 445]

[1475] Table 446 Contents of Each Active Pharmaceutical Ingredient in Commercially Available Eye Drops (Optipranolol (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)) When Stored at 25°C for 6 Weeks

[1476] [Table 446]

[1477] According to Examples 281 to 285, the preparations containing netarsudil mesylate, metipranolol mesylate and tafluprost were good under storage conditions at 25°C for 6 weeks and met the storage conditions after opening of commercially available eye drops (Optipranolol®, Rhopress®, Tapros®).

[1478] Table 447 Content of each active ingredient in Examples 281 to 285 when stored at 40°C for 14 days

[1479] [Table 447]

[1480] Table 448 Content of each active ingredient in commercially available eye drops (Optipranolol®, Rhopress®, Tapros®) when stored at 40°C for 14 days

[1481] [Table 448]

[1482] According to Examples 281 to 285, the preparations containing netarsudil mesylate, metipranolol mesylate and tafluprost showed good stability when stored at 40°C for 14 days and met the storage conditions when the commercially available eye drops (Optipranolol®, Rhopress®, Tapros®) deviated slightly in the short term.

[1483] <Examples 286 to 290> Preparations containing netarsudil dihydrochloride, metipranolol hydrochloride and tafluprost Table 449 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows according to the conventional method.

[1484] [Table 449]

[1485] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1486] Content of each active ingredient in Examples 286 to 290 when stored at 5°C for 24 months

[1487] [Table 450]

[1488] According to Examples 286 to 290, the preparations containing netarsudil dihydrochloride, metipranolol hydrochloride and tafluprost showed good stability when stored at 5°C for 24 months, and met the requirements for the pre - opening storage conditions of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Tapro (registered trademark)).

[1489] Content of each active ingredient in Examples 286 to 290 when stored at 25°C for 6 weeks

[1490] [Table 451]

[1491] According to Examples 286 to 290, the preparations containing netarsudil dihydrochloride, metipranolol hydrochloride and tafluprost showed good stability when stored at 25°C for 6 weeks, and met the storage conditions after opening of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1492] Content of each active ingredient in Examples 286 to 290 when stored at 40°C for 14 days

[1493] [Table 452]

[1494] According to Examples 286 to 290, the preparation containing netarsudil dihydrochloride, metipranolol hydrochloride and tafluprost showed good stability when stored at 40°C for 14 days, and satisfied the storage conditions in the case of short-term deviation of commercially available eye drops (Optipranolol (registered trademark), Rhopress (registered trademark), Tapros (registered trademark)).

[1495] <Comparative Examples 105 to 108> Preparations containing netarsudil mesylate, metipranolol hydrochloride and latanoprost Table 453 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[1496]

Table 453

[1497] Refer to the processes described in Examples 83 to 87 of the manufacturing process.

[1498] Table 454 Contents of each main drug component in Comparative Examples 105 to 108 when stored at 5°C for 7 days

[1499]

Table 454

[1500] According to Comparative Examples 105 to 108, the preparation containing netarsudil mesylate, metipranolol hydrochloride and latanoprost was incompatible under the storage conditions at 5°C, and netarsudil mesylate precipitated.

[1501] <Comparative Examples 109 to 112> Preparations containing netarsudil mesylate, metipranolol hydrochloride and bimatoprost Table 455 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[1502]

Table 455

[1503] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1504] Table 456 Contents of each active ingredient in Comparative Examples 109 to 112 when stored at 5°C for 7 days

[1505]

Table 456

[1506] According to Comparative Examples 109 to 112, the formulations containing netarsudil mesylate, meptoprolol hydrochloride and bimatoprost were incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1507] <Comparative Examples 113 - 116> Formulations containing netarsudil mesylate, meptoprolol hydrochloride and travoprost Table 457 A topical ophthalmic solution pharmaceutical composition for reducing intraocular pressure was prepared by mixing as follows.

[1508]

Table 457

[1509] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1510] Table 458 Contents of each active ingredient in Comparative Examples 113 to 116 when stored at 5°C for 7 days

[1511]

Table 458

[1512] According to Comparative Examples 113 to 116, the preparation containing netarsudil mesylate, metipranolol hydrochloride, and travoprost was incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

[1513] <Comparative Examples 117 to 120> Preparations containing netarsudil mesylate, metipranolol hydrochloride, and tafluprost Table 459 Topical ophthalmic solution pharmaceutical compositions for reducing intraocular pressure were prepared by formulating as follows.

[1514]

Table 459

[1515] Please refer to the processes described in Manufacturing Process Examples 83 to 87.

[1516] Table 460 Contents of each main drug component in Comparative Examples 117 to 120 when stored at 5°C for 7 days

[1517]

Table 460

[1518] According to Comparative Examples 117 to 120, the preparation containing netarsudil mesylate, metipranolol hydrochloride, and tafluprost was incompatible under storage conditions at 5°C, and netarsudil mesylate precipitated.

Claims

1. An ophthalmic two-component composite pharmaceutical composition, wherein the pharmaceutical composition comprises: (1) an adrenergic β-receptor blocker selected from (S)-1-(tert-butylamino)-3-[(4-morpholinyl-1,2,5-thiadiazol-3-yl)oxy]-2-propanol (timolol) or a pharmaceutically acceptable salt thereof, 5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydro-2(1H)-quinolone (carteolol) or a pharmaceutically acceptable salt thereof, (RS)-1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-[(1-methylethyl)-amino]-2-propanol (betaxolol) or a pharmaceutically acceptable salt thereof, or 4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]-2,3,6-trimethyl-phenol 1-acetate (metipranolol) or a pharmaceutically acceptable salt thereof; and (2) (S)-2,4-dimethylbenzoic acid 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxoprop-2-yl)benzyl ester (netarsudil) or a pharmaceutically acceptable salt thereof; and (3) a preservative selected from benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl parahydroxybenzoate, phenethyl alcohol, disodium edetate, boric acid, sorbic acid, or any combination thereof; and (4) a buffer selected from boric acid or a salt thereof, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous sodium phosphate, citric acid or a salt thereof, gluconic acid or a salt thereof, acetic acid or a salt thereof, phosphoric acid or a salt thereof, various amino acids such as glutamic acid and ε-aminocaproic acid, and Tris buffer, or any combination thereof; and (5) an isotonicity agent selected from glycerin, sorbitol, mannitol, propylene glycol, erythritol, arabitol, xylitol, ribitol, galactitol, polyethylene glycol, lactitol, and other sugar alcohols, sodium chloride, potassium chloride, and calcium chloride, or any combination thereof. (6) A pH adjuster selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, hydrochloric acid, citric acid or its salts, phosphoric acid or its salts, acetic acid or its salts, and tartaric acid and / or hydrochloric acid or its salts, and (7) An ophthalmic two-component pharmaceutical composition containing water for injection.

2. An ophthalmic three-component pharmaceutical composition, wherein the pharmaceutical composition is (1) An adrenergic β-receptor blocker selected from (S)-1-(tert-butylamino)-3-[(4-morpholinyl-1,2,5-thiadiazol-3-yl)oxy]-2-propanol (timolol) or a pharmaceutically acceptable salt thereof, 5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydro-2(1H)-quinolone ( carteolol) or a pharmaceutically acceptable salt thereof, (RS)-1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]3-[(1-methylethyl)-amino]-2-propanol (betaxolol) or a pharmaceutically acceptable salt thereof, or 4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]-2,3,6-trimethyl-phenol 1-acetate (metipranolol) or a pharmaceutically acceptable salt thereof, and (2) (S)-2,4-dimethylbenzoic acid 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxoprop-2-yl)benzyl ester (netarsudil) or a pharmaceutically acceptable salt thereof, and (3) A prostaglandin analog selected from latanoprost, bimatoprost, travoprost, tafluprost, AR-102, cloprostenol isopropyl ester, 13,14-dihydrocloprostenol isopropyl ester, latanoprostene bunod, unoprostone, PGF1α isopropyl ester, PGF2α isopropyl ester, PGF3α isopropyl ester or fluoroprostene isopropyl ester, and (4) A preservative selected from benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl parahydroxybenzoate, phenethyl alcohol, disodium edetate, boric acid, sorbic acid, or any combination thereof, and (5) A buffer selected from boric acid or its salts, sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous sodium phosphate, citric acid or its salts, gluconic acid or its salts, acetic acid or its salts, phosphoric acid or its salts, various amino acids such as glutamic acid and ε-aminocaproic acid, and Tris buffer, or any combination thereof, (6) An isotonic agent selected from glycerin, sorbitol, mannitol, propylene glycol, erythritol, arabitol, xylitol, ribitol, galactitol, polyethylene glycol, lactitol, and other sugar alcohols, sodium chloride, potassium chloride, and calcium chloride, or any combination thereof, (7) A pH adjuster selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, hydrochloric acid, citric acid or its salts, phosphoric acid or its salts, acetic acid or its salts, and tartaric acid and / or hydrochloric acid or its salts, (8) An ophthalmic triple-combination pharmaceutical composition containing water for injection. (Claim 3) (5) When the netalsujil is the dimesylate, (6) Timolol is in the form of the free base or any pharmaceutically acceptable salt thereof (excluding the maleate), preferably timolol mesylate, timolol sulfate, timolol hydrobromide, timolol phosphate, timolol nitrate, timolol citrate, timolol tartrate, timolol salicylate, timolol malate, timolol lactate, timolol phenylacetate, timolol succinate, timolol hydroiodide, timolol formate, timolol phenylacetate, timolol benzoate, timolol ethanesulfonate, timolol oxalate, or timolol propionate, Carteolol is in the form of a free base or any of its pharmaceutically acceptable salts (excluding hydrochloride), preferably carteolol mesylate, carteolol hydrobromide, carteolol sulfate, carteolol nitrate, carteolol citrate, carteolol tartrate, carteolol salicylate, carteolol malate, carteolol lactate, phenyl acetate carteolol, carteolol succinate, carteolol hydroiodide, carteolol formate, carteolol acetate, carteolol benzoate, carteolol ethanesulfonate, carteolol oxalate, or carteolol propionate, Betaxolol is in the form of a free base or any of its pharmaceutically acceptable salts (excluding hydrochloride), preferably betaxolol mesylate, betaxolol hydrobromide, betaxolol sulfate, betaxolol nitrate, betaxolol citrate, betaxolol tartrate, betaxolol salicylate, betaxolol malate, betaxolol lactate, phenyl acetate betaxolol, betaxolol succinate, betaxolol hydroiodide, betaxolol formate, betaxolol acetate, betaxolol benzoate, betaxolol ethanesulfonate, betaxolol oxalate, or betaxolol propionate, Metipranolol is in the form of a free base or any of its pharmaceutically acceptable salts (excluding hydrochloride), preferably metipranolol mesylate, metipranolol hydrobromide, metipranolol sulfate, metipranolol nitrate, metipranolol citrate, metipranolol tartrate, metipranolol salicylate, metipranolol malate, metipranolol lactate, phenyl acetate metipranolol, metipranolol succinate, metipranolol hydroiodide, metipranolol formate, metipranolol acetate, metipranolol benzoate, metipranolol ethanesulfonate, metipranolol oxalate, or metipranolol propionate, and the combined pharmaceutical composition according to claim 1 or 2, characterized in that.

4. When the adrenergic β-receptor blocker is timolol maleate, carteolol hydrochloride, betaxolol hydrochloride, or metipranolol hydrochloride, the netarsudil is in the form of a free base or any pharmaceutically acceptable salt thereof (excluding mesylate), preferably netarsudil maleate, netarsudil sulfate, netarsudil dihydrobromide, netarsudil dihydrochloride, netarsudil digluconate, netarsudil dinitrate, netarsudil diacetate, netarsudil dibenzoate, netarsudil diphenylacetate, netarsudil succinate, netarsudil oxalate, netarsudil dihydroiodide, or netarsudil dipropionate. The combined pharmaceutical composition according to claim 1 or 2, characterized in that it is as described above.

5. (1) 0.02% w / v to 4.0% w / v of an adrenergic β-receptor blocker, preferably timolol free base or its salt, carteolol free base or its salt, betaxolol free base or its salt, or metipranolol free base or its salt, and (2) 0.005% w / v to 0.1% w / v of netarsudil free base or its salt, and (3) 0.01% w / v to 10.0% w / v of an isotonic agent, and (4) 0.01% w / v to 1.0% w / v of a buffering agent, and (5) 0.001% w / v to 0.02% w / v of a preservative, and (6) having a pH of 4.5 to 5.4, and (7) having an osmotic pressure of 280 to 320 mOsmol / kg. The combined pharmaceutical composition according to any one of claims 1, 3, and 4, characterized in that it is as described above.

6. A combined pharmaceutical composition according to any one of claims 2 to 4, wherein the pharmaceutical composition comprises (1) 0.02% w / v to 4.0% w / v of an adrenergic β-receptor blocker, preferably timolol free base or its salt, carteolol free base or its salt, betaxolol free base or its salt, or metipranolol free base or its salt, and (2) 0.005% w / v to 0.1% w / v of netarsudil free base or its salt, and (3) 0.0005% w / v to 0.05% w / v of a prostaglandin analog, and (4) 0.01% w / v to 10.0% w / v of an isotonic agent, and (5) 0.01% w / v to 1.0% w / v of a buffering agent, and (6) 0.001% w / v to 0.02% w / v of a preservative, and (7) having a pH of 4.5 to 5.4, and A composite pharmaceutical composition characterized in that the osmotic pressure is 280 to 320 mOsmol / kg.

7. The composite pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition does not contain a precipitate after being stored at 5°C for 24 months, and the content of each main drug component has no significant change compared with that on the 0th day; does not contain a precipitate after being stored at 25°C for 6 weeks, and the content of each main drug component has no significant change compared with that on the 0th day; and does not contain a precipitate after being stored at 40°C for 14 days, and the content of each main drug component has no significant change compared with that on the 0th day.

8. Use of the composite pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament for preventing or treating an eye disease.

9. The use according to claim 8, wherein the eye disease is glaucoma or a symptom related thereto.

10. Use of the composite pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament for reducing intraocular pressure.

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