Ophthalmic pharmaceutical composition

Abstract

The present invention relates to a compound of formula I An ophthalmic pharmaceutical composition of the compound JPEG2023505255000045.jpg3263 is provided.

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority based on U.S. Provisional Application No. 62 / 944,074 filed on December 5, 2019 and U.S. Provisional Application No. 63 / 077,196 filed on September 11, 2020. The disclosures of these applications are hereby incorporated herein by reference in their entirety.

[0002] Technical Field The present invention relates to ophthalmic pharmaceutical compositions.

Background Art

[0003] Background Compound N , , , , ,

[0004] , , , , -Methyl - N 4 -Phenyl - 6-(2,2,3,3 - tetrafluoropropoxy)-1,3,5 - triazine - 2,4 - diamine (the compound of formula I) is an activator of cystic fibrosis transmembrane conductance regulator (CFTR), and is described, for example, in WO2017112951. Also refer to S. Lee, et al., J. Med. Chem. 2017; 60, 3, 1210 - 1218 which describes the ocular administration of the compound of formula I for increasing tear volume in mice. WO2017112951 also describes the administration of CFTR activators as useful for treating dry eye disorders.

Chemical Formula

Summary of the Invention

Problems to be Solved by the Invention

[0004] There is a need for a suitable formulation of a drug that activates cystic fibrosis transmembrane conductance regulator for the non - systemic treatment of eye diseases or disorders including dry eye disorders. In particular, there is a need for a storage - stable ophthalmic pharmaceutical composition of the compound of formula I and its acid addition salts suitable for ocular administration.

Means for Solving the Problems

[0005] overview The present invention provides an ophthalmic pharmaceutical composition with pharmaceutically acceptable acid addition salt storage stability.

[0006] In one aspect, the present invention is an ophthalmic pharmaceutical composition, (a) The composition contains a concentration of formula I that is effective for treating an eye disease or condition. [ka] Compounds or pharmaceutically acceptable acid addition salts thereof (b) water; (c) Solubilizer, (d) cosolvent and (e) Antioxidant system The present invention provides a pharmaceutical composition containing [a specific ingredient].

[0007] In another embodiment, the present invention provides a composition that, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains formula I: [ka] The compound and the compound of formula I in a relative amount of 0.5% or less, preferably 0.2% or less (by HPLC) of formula II [ka] The present invention provides an aqueous ophthalmic composition containing the compound.

[0008] In another embodiment, the present invention relates to formula I: [ka] An aqueous ophthalmic composition comprising the compound and antioxidant system of formula II present in the composition. [ka] The amount of the compound does not increase by more than 200% when quantified by HPLC after storage of the composition in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, thereby providing a composition.

[0009] In yet another aspect, the present invention relates to a compound of formula I:

Chemical formula

Chemical formula

Mode for Carrying Out the Invention

[0010] Description of Exemplary Embodiments The present invention can be understood by reference to the following detailed description, which forms a part of this disclosure. The present invention is not limited to the specific methods, conditions or parameters described and / or shown herein, and the terms used herein are for the purpose of describing specific embodiments by way of example only and are not intended to limit the present invention.

[0011] Scientific and technical terms used in connection with this application have meanings commonly understood by those skilled in the art unless specifically defined herein.

[0012] The compound of formula I is a highly lipophilic compound and is poorly water-soluble (<0.01 mg / mL in water).

[0013] In the development of the compound of formula I for ocular administration, unexpected degradation impurities, N 2 -Phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (compound of formula II) is produced: [ka]

[0014] Surprisingly, the compound of formula II is not formed during the forced decomposition test of the compound of formula I. Instead, the compound of formula II is formed during storage. The formation of the compound of formula II is delayed and / or eliminated in the novel ophthalmic solution composition described herein by the inclusion of the “antioxidant system” as described herein.

[0015] In one embodiment, the present invention relates to formula I [ka] The present invention provides an ophthalmic pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. In one embodiment, the ophthalmic pharmaceutical composition comprises a compound of formula I. In another embodiment, the ophthalmic pharmaceutical composition comprises a pharmaceutically acceptable acid addition salt of a compound of formula I.

[0016] The pharmaceutically acceptable acid addition salts of the compounds of formula I used herein refer to the acid addition salts of the compounds of formula I. Pharmaceutically acceptable acid addition salts are known to those skilled in the art. Examples of such salts of the compounds of formula I are described in WO2017112951.

[0017] In one embodiment, a compound of formula I or a pharmaceutically acceptable acid addition salt thereof is present in the composition in a concentration effective for treating an eye disease or condition. The term “eye disease or condition” as used herein means any disease or condition of the eye.

[0018] The composition of the present invention contains a compound of formula I in a concentration effective for treating eye diseases or conditions. In this regard, the effective concentration of the compound of formula I varies depending on the characteristics and condition of the subject, as well as the eye disease or condition.

[0019] In one embodiment, the eye disease or condition is dry eye disorder. "Dry eye disorder" (or "dry eye") refers to a mixed group of disorders having the common characteristics of reduced tear volume and high osmotic pressure of the tear film, leading to inflammation of the ocular surface. Symptoms of dry eye include ocular discomfort and visual impairment. Ocular discomfort may include a tingling, burning, or stinging sensation in the eye; stringy mucus in or around the eye; and conjunctivitis. Visual impairment may include sensitivity to light; difficulty inserting contact lenses; and difficulty driving at night. Signs of dry eye include damage to corneal epithelial cells. In one embodiment, dry eye disorder is Sjögren's syndrome.

[0020] In one embodiment, the eye disease or condition is allergic conjunctivitis.

[0021] In one embodiment, the concentration of the compound of formula I or its pharmaceutically acceptable acid addition salt in the composition of the present invention is about 0.5% (w / v) to about 0.005% (w / v) based on the compound of formula I.

[0022] In other embodiments, the concentration of the compound of formula I or its pharmaceutically acceptable acid addition salt in the composition of the present invention is about 0.2% (w / v) to about 0.01% (w / v) based on the compound of formula I.

[0023] In other embodiments, the concentration of the compound of formula I or its pharmaceutically acceptable acid addition salt in the composition of the present invention is about 0.1% (w / v) to about 0.005% (w / v) based on the compound of formula I.

[0024] In one embodiment, the concentration of the compound of formula I or its pharmaceutically acceptable acid addition salt in the composition of the present invention is about 0.034% (w / v) based on the compound of formula I.

[0025] In other embodiments, the concentration of the compound of formula I or its pharmaceutically acceptable acid addition salt in the composition of the present invention is 0.034% (w / v) based on the compound of formula I.

[0026] In one embodiment, the concentration of the compound of formula I or its pharmaceutically acceptable acid addition salt in the composition of the present invention is about 0.01% (w / v) based on the compound of formula I.

[0027] In other embodiments, the concentration of the compound of formula I or its pharmaceutically acceptable acid addition salt in the composition of the present invention is 0.01% (w / v) based on the compound of formula I.

[0028] In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains water. In one embodiment, the water is sterile water.

[0029] In one embodiment, the ophthalmic pharmaceutical composition of the present invention comprises a solubilizer. The solubilizer is an additive that helps dissolve the compound of formula I.

[0030] In one embodiment, the solubilizer is a surfactant.

[0031] In one embodiment, the solubilizer is an anionic surfactant.

[0032] In other embodiments, the solubilizer is a cationic surfactant.

[0033] In yet another embodiment, the solubilizer is a nonionic surfactant.

[0034] In one embodiment, the solubilizer is a polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, polyoxyl hydroxystearate, poloxamer, or povidone.

[0035] In one embodiment, the solubilizer is poly(oxyethylene)sorbitan monooleate, poly(oxyethylene)sorbitan monostearate, poly(oxyethylene)sorbitan monopalmitate, poly(oxyethylene)sorbitan monolaurate, poly(oxyethylene)sorbitan trioleate, or poly(oxyethylene)sorbitan tristearate.

[0036] In one embodiment, the solubilizer is polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 35 (i.e., polyoxyl 35 castor oil), polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, or polyoxyethylene hydrogenated castor oil 60.

[0037] In one embodiment, the solubilizer is polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, or polyoxyethylene (20) polyoxypropylene (20) glycol.

[0038] In one embodiment, the solubilizer is polyoxyl 40 stearate, polyoxyl 15 hydroxystearate, povidone K30, povidone K90, poloxamer 407, or poloxamer 188.

[0039] In one embodiment, the solubilizer is polyoxyl 40 stearate.

[0040] In another embodiment, the solubilizer is polyoxyl 35 castor oil.

[0041] In one embodiment, the amount of solubilizer in the ophthalmic pharmaceutical composition of the present invention is in the range of about 1% (w / v) to about 15% (w / v).

[0042] In another embodiment, the amount of solubilizer in the ophthalmic pharmaceutical composition of the present invention is in the range of about 4% (w / v) to about 8% (w / v).

[0043] In one embodiment, the ophthalmic pharmaceutical composition contains polyoxyl 40 stearate. In one embodiment, the ophthalmic pharmaceutical composition contains about 5% (w / v) polyoxyl 40 stearate. In one embodiment, the ophthalmic pharmaceutical composition contains 5% (w / v) polyoxyl 40 stearate.

[0044] In one embodiment, the ophthalmic pharmaceutical composition contains about 7% (w / v) polyoxyl 40 stearate.

[0045] In one embodiment, the ophthalmic pharmaceutical composition contains polyoxyl 35 castor oil. In another embodiment, the ophthalmic pharmaceutical composition contains about 5% (w / v) polyoxyl 35 castor oil. In yet another embodiment, the ophthalmic pharmaceutical composition contains 5% (w / v) polyoxyl 35 castor oil.

[0046] In one embodiment, the ophthalmic pharmaceutical composition contains about 7% (w / v) polyoxyl 35 castor oil.

[0047] In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains a co-solvent. The co-solvent is a solvent other than water that is suitable for use in the ophthalmic composition.

[0048] In one embodiment, the cosolvent is a water-soluble organic solvent.

[0049] In other embodiments, the cosolvent is a water-miscible organic solvent.

[0050] In other embodiments, the cosolvent is polyethylene glycol, propylene glycol, glycerin, ethanol, benzyl alcohol, or a mixture thereof.

[0051] In one embodiment, the cosolvent is PEG-300, PEG-400, PEG-4000, PEG-8000, or a mixture thereof.

[0052] In one embodiment, the cosolvent is PEG-400.

[0053] In other embodiments, the cosolvent is propylene glycol.

[0054] In one embodiment, the cosolvent is a mixture of PEG-400 and propylene glycol.

[0055] In one embodiment, the amount of cosolvent in the ophthalmic pharmaceutical composition of the present invention is in the range of about 0.5% (w / v) to about 10% (w / v).

[0056] In one embodiment, the amount of cosolvent in the ophthalmic pharmaceutical composition of the present invention is in the range of about 1% (w / v) to about 3% (w / v).

[0057] In one embodiment, the ophthalmic pharmaceutical composition of the present invention comprises PEG, for example, PEG-400. In one embodiment, the ophthalmic pharmaceutical composition of the present invention comprises about 1% (w / v) of PEG-400. In another embodiment, the ophthalmic pharmaceutical composition of the present invention comprises 1% (w / v) of PEG-400.

[0058] In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains propylene glycol. In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains about 1% (w / v) propylene glycol. In another embodiment, the ophthalmic pharmaceutical composition of the present invention contains 1% (w / v) propylene glycol.

[0059] In one embodiment, the ophthalmic pharmaceutical composition of the present invention comprises about 1% (w / v) PEG-400 and about 1% (w / v) propylene glycol. In another embodiment, the ophthalmic pharmaceutical composition of the present invention comprises 1% (w / v) PEG-400 and 1% (w / v) propylene glycol.

[0060] In one embodiment, the ophthalmic pharmaceutical composition of the present invention comprises an "antioxidant system." The antioxidant system is an additive or combination of additives that reduces and / or eliminates the formation of degradation products of the compound of formula I in the ophthalmic composition of the present invention due to storage. While we do not wish to be bound by any particular mechanistic theory, the antioxidant system of the present invention reduces and / or eliminates the reduction of oxidative degradation products of the compound of formula I in the ophthalmic composition of the present invention. N-demethylation is an example of an oxidative degradation process.

[0061] In one embodiment, the antioxidant system includes sodium bisulfite, sodium metabisulfite, sodium thiosulfate or its hydrate, sodium sulfite, sodium sulfate, ascorbyl palmitate, ethylenediaminetetraacetic acid (EDTA) or its salts or citric acid or its salts, ascorbic acid or its salts or combinations thereof.

[0062] In one embodiment, the antioxidant system includes EDTA disodium salt or a hydrate thereof, such as EDTA disodium salt dihydrate.

[0063] In another embodiment, the antioxidant system includes sodium thiosulfate pentahydrate.

[0064] In another embodiment, the antioxidant system includes ascorbyl palmitate.

[0065] In one embodiment, the antioxidant system comprises a combination of EDTA disodium salt or its hydrate and sodium thiosulfate pentahydrate.

[0066] In other embodiments, the antioxidant system comprises a combination of EDTA disodium salt or its hydrate and ascorbyl palmitate.

[0067] In one embodiment, the amount of antioxidants in the ophthalmic pharmaceutical composition of the present invention is in the range of about 0.01% (w / v) to about 0.6% (w / v).

[0068] In one embodiment, the amount of antioxidants in the ophthalmic pharmaceutical composition of the present invention is in the range of about 0.05% (w / v) to about 0.5% (w / v).

[0069] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.01% (w / v) to about 0.40% (w / v) of EDTA disodium salt or its hydrate.

[0070] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.05% (w / v) to about 0.20% (w / v) of EDTA disodium salt or its hydrate.

[0071] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.10% (w / v) of EDTA disodium salt or its hydrate.

[0072] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises 0.10% (w / v) of EDTA disodium salt or its hydrate.

[0073] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention contains about 0.01% (w / v) to about 0.40% (w / v) of sodium thiosulfate pentahydrate.

[0074] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention contains about 0.05% (w / v) to about 0.25% (w / v) of sodium thiosulfate pentahydrate.

[0075] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention contains about 0.20% (w / v) sodium thiosulfate pentahydrate.

[0076] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises 0.20% (w / v) sodium thiosulfate pentahydrate.

[0077] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention contains about 0.01% (w / v) to about 0.10% (w / v) of ascorbyl palmitate.

[0078] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention contains about 0.01% (w / v) to about 0.04% (w / v) of ascorbyl palmitate.

[0079] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention contains about 0.02% (w / v) ascorbyl palmitate.

[0080] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention contains 0.02% (w / v) ascorbyl palmitate.

[0081] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.01% (w / v) to about 0.40% (w / v) of EDTA disodium salt or its hydrate and about 0.01% (w / v) to about 0.40% (w / v) of sodium thiosulfate pentahydrate.

[0082] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.05% (w / v) to about 0.20% (w / v) of EDTA disodium salt or its hydrate and about 0.05% (w / v) to about 0.25% (w / v) of sodium thiosulfate pentahydrate.

[0083] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.10% (w / v) of EDTA disodium salt or its hydrate and about 0.20% (w / v) of sodium thiosulfate pentahydrate.

[0084] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises 0.10% (w / v) EDTA disodium salt or its hydrate and 0.20% (w / v) sodium thiosulfate pentahydrate.

[0085] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.01% (w / v) to about 0.40% (w / v) of EDTA disodium salt or its hydrate and about 0.01% (w / v) to about 0.10% (w / v) of ascorbyl palmitate.

[0086] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.05% (w / v) to about 0.20% (w / v) of EDTA disodium salt or its hydrate and about 0.01% (w / v) to about 0.04% (w / v) of ascorbyl palmitate.

[0087] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.10% (w / v) of EDTA disodium salt or its hydrate and about 0.02% (w / v) of ascorbyl palmitate.

[0088] In one embodiment, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises 0.10% (w / v) EDTA disodium salt or its hydrate and 0.02% (w / v) ascorbyl palmitate.

[0089] In one embodiment, the ophthalmic pharmaceutical composition of the present invention further comprises an isotonic agent. The isotonic agent is an additive that adjusts the osmotic pressure in the ophthalmic composition.

[0090] In one embodiment, the isotonic agent is sodium chloride, potassium chloride, dextrose, mannitol, or glycerin.

[0091] In one embodiment, the isotonic agent is sodium chloride.

[0092] The amount of isotonic agent in the ophthalmic composition of the present invention is sufficient to adjust the osmotic pressure of the composition to a range of approximately 200 mOsm / kg to approximately 600 mOsm / kg. Osmotic pressure is defined in accordance with the United States Pharmacopeia (USP). <785> It is measured according to the following.

[0093] In one embodiment, the amount of isotonic agent in the ophthalmic composition of the present invention is sufficient to cause the osmotic pressure of the composition to fall in the range of approximately 250 mOsm / kg to approximately 350 mOsm / kg.

[0094] In other embodiments, the amount of isotonic agent in the ophthalmic composition of the present invention is sufficient to adjust the osmotic pressure of the composition to approximately 280 mOsm / kg to approximately 320 mOsm / kg.

[0095] In one embodiment, the amount of isotonic agent present in the ophthalmic composition of the present invention is approximately 0.01% (w / v) to approximately 0.5% (w / v).

[0096] In one embodiment, the ophthalmic pharmaceutical composition of the present invention further comprises a thickening agent. The thickening agent is an additive that increases the viscosity of the composition.

[0097] In one embodiment, the thickener is hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) (5 cps, 4000 cps, 15000 cps); hypromellose, methylcellulose, carboxymethylcellulose (CMC) sodium (i.e., sodium CMC; e.g., Cekol 150), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP; or povidone), povidone K30, povidone K90, carbomer 940, carbomer 974P, carbomer 980, povidone K30, povidone K90, gellan gum, or xanthan gum.

[0098] In one embodiment, the thickener is sodium carboxymethylcellulose (CMC).

[0099] In one embodiment, the amount of thickener present in the ophthalmic composition of the present invention is sufficient to adjust the viscosity of the composition to about 2 cP to about 60 cP. Viscosity is measured using a rotational rheometer / viscometer (e.g., Brookfield viscometer, model: LVDV-E with spindle and extended UL adapter with water jacket); the sample temperature is maintained at 25.0 ± 0.1 °C during measurement.

[0100] In another embodiment, the thickening agent is present in the ophthalmic composition of the present invention in an amount of about 0.05% (w / v) to about 0.5% (w / v).

[0101] In one embodiment, the ophthalmic pharmaceutical composition of the present invention further comprises a buffer system. The buffer system is an additive or combination of additives that buffers the pH of the composition. The buffer system comprises an acid and its conjugate base.

[0102] In one embodiment, the buffer system is a phosphate buffer, a citrate buffer, an acetate buffer, or a borate buffer.

[0103] In one embodiment, the buffer system is a phosphate buffer.

[0104] In one embodiment, where the buffer system is a phosphate buffer, the buffer system includes sodium dihydrogen phosphate (also known as monosodium phosphate or monobasic sodium phosphate) and disodium phosphate (also known as disodium hydrogen phosphate or dibasic sodium phosphate).

[0105] In one embodiment, the buffer system is a citrate buffer.

[0106] In one embodiment, where the buffer system is a citrate buffer, the buffer system comprises sodium citrate and citrate.

[0107] In one embodiment, the buffer system is an acetate buffer.

[0108] In one embodiment, where the buffer system is an acetate buffer, the buffer system includes sodium acetate and acetic acid.

[0109] In another embodiment, the buffer system is a borate buffer.

[0110] In one embodiment, where the buffer system is a borate buffer, the buffer system includes sodium borate and boric acid.

[0111] In one embodiment, the buffer system is present in the ophthalmic composition of the present invention in an amount of about 0.01% (w / v) to about 0.5% (w / v).

[0112] In one embodiment, the pH of the ophthalmic pharmaceutical composition of the present invention is in the range of about 4.0 to about 8.0. pH is defined in accordance with the United States Pharmacopeia (USP) standards. <791> Measurements are taken according to the specified method. Measurements are performed at 25±2℃.

[0113] In another embodiment, the pH of the ophthalmic pharmaceutical composition of the present invention is in the range of about 6.0 to about 8.0.

[0114] In another embodiment, the pH of the ophthalmic pharmaceutical composition of the present invention is in the range of about 6.5 to about 7.5.

[0115] In another embodiment, the pH of the ophthalmic pharmaceutical composition of the present invention is in the range of about 6.8 to about 7.4.

[0116] In one embodiment, the ophthalmic pharmaceutical composition of the present invention may further contain an antimicrobial agent. The antimicrobial agent is an additive that inhibits the growth of microorganisms in the ophthalmic pharmaceutical composition.

[0117] In one embodiment, the antimicrobial agent is benzalkonium chloride (BAK), chlorobutanol, benzethonium chloride, phenylmercury nitrate, phenylmercury acetate, or thimerosal.

[0118] In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains some single impurity in an amount of 0.5% or less (by HPLC) relative to the amount of the compound of formula I.

[0119] The term "by HPLC" used here means that the indicated quantities were determined using high-performance liquid chromatography.

[0120] In some embodiments, "by HPLC" means "by HPLC area %". In these embodiments, the area under the response curve corresponding to the sample in question in the HPLC chromatogram (where the HPLC chromatogram is prepared using a UV detector monitoring a wavelength of 264 nm) is compared to the area under the response curve corresponding to the compound of formula I. In these embodiments, the HPLC chromatogram is obtained under conditions where the detector response to the sample of interest changes linearly with the sample concentration in the sample. Furthermore, the HPLC chromatogram is obtained under conditions where the impurity peaks are decomposed from each other and from the peaks of the compound of formula I.

[0121] For example, when a sample is analyzed by HPLC as described above, the composition contains 0.2% or less of some single impurity relative to the compound of formula I, in terms of HPLC area percentage, if the sub-peak area of ​​any single impurity does not exceed 0.2% of the sub-peak area of ​​the compound of formula I.

[0122] In other embodiments, “by HPLC” means “by HPLC wt%”. In these embodiments, the area under the response curve corresponding to the sample in question in the HPLC chromatogram is compared to the area under the response curve of the compound of formula I in the HPLC chromatogram prepared from a standard containing a known weight of the compound of formula I. The HPLC chromatograms of the sample and the standard sample are prepared under the same conditions (for example, the HPLC chromatogram is prepared using a UV detector monitoring a wavelength of 264 nm). Furthermore, in these embodiments, the HPLC chromatogram is obtained under conditions in which the detector response to the sample of interest changes linearly with the sample concentration in the sample. Furthermore, the HPLC chromatogram is obtained under conditions in which the impurity peaks are decomposed from each other and from the peaks of the compound of formula I.

[0123] For example, when a composition is analyzed by HPLC as described above, and the weight of any single impurity does not exceed 0.2% of the amount of the compound of formula I, it contains any single impurity in an amount of 0.2% or less (by HPLC wt%).

[0124] The term "impurity" as used herein refers to a compound present in the composition that is (or potentially is) a decomposition product of the compound of formula I.

[0125] In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains some single impurity in an amount of 0.5% or less (by HPLC) relative to the amount of the compound of formula I.

[0126] In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains some single impurity in an amount of 0.4% or less (by HPLC) relative to the amount of the compound of formula I.

[0127] In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains some single impurity in an amount of 0.3% or less (by HPLC) relative to the amount of the compound of formula I.

[0128] In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains some single impurity in an amount of 0.2% or less (by HPLC) relative to the amount of the compound of formula I.

[0129] In one embodiment, the ophthalmic pharmaceutical composition of the present invention contains some single impurity in an amount of 0.1% or less (by HPLC) relative to the amount of the compound of formula I.

[0130] In another embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5% or less (by HPLC) relative to the compound of formula I.

[0131] In another embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.4% or less (by HPLC) relative to the compound of formula I.

[0132] In another embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.3% or less (by HPLC) relative to the compound of formula I.

[0133] In another embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.2% or less (by HPLC) relative to the compound of formula I.

[0134] In another embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.1% or less (by HPLC) relative to the compound of formula I.

[0135] In one embodiment of the present invention described herein, “storage in a sealed container” means storage in a glass vial with a lid. In another embodiment of the present invention described herein, “storage in a sealed container” means storage in a USP Type 1 glass vial with a Flurotec-coated butyl rubber stopper and an aluminum seal.

[0136] In one embodiment of the present invention described herein, “storage in a sealed container” means storage in a low-density polyethylene (LDPE) bottle with a lid. In another embodiment of the present invention described herein, “storage in a sealed container” means storage in an LDPE bottle with an HDPE cap.

[0137] The term "expiration date" as used herein for a manufacturing lot of a finished drug dosage form refers to the end of the period during which the regulatory authority is convinced that the product from that lot will remain sufficiently stable for prescription (i.e., maintain sufficient strength, quality, and purity) under certain storage conditions, so that the expiration date may be indicated along with the distribution of the product from manufacture.

[0138] The term "commercially acceptable expiration date" as used herein refers to an expiration date that is sufficient to facilitate the efficient distribution of a pharmaceutical product, generally a period of 6 to 12 months or more, more preferably 18 to 24 months. Methods for determining stability and convincing regulatory authorities that the finished pharmaceutical product will remain sufficiently stable until its expiration date are known in this field.

[0139] In one embodiment, the composition is stored in a sealed container at a temperature in the range of about 20 to 75°C.

[0140] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 2 to 8°C.

[0141] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 5 to 50°C.

[0142] In yet another embodiment, storage in a sealed container is at a temperature in the range of approximately 15 to 50°C.

[0143] In another embodiment, the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25-80%.

[0144] In other embodiments, storage in a sealed container is in an atmosphere having 60% relative humidity at a temperature of 25°C; or an atmosphere having 75% relative humidity at a temperature of 40°C; or an atmosphere having 40% relative humidity at a temperature of 25°C; or an atmosphere having 25% relative humidity at a temperature of 40°C.

[0145] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after storage in a sealed container at a temperature in the range of about 20 to 75°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound I.

[0146] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container in an atmosphere having a relative humidity of about 25-80% at a temperature in the range of about 20-75°C, for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains 0.5% or less, 0.4% or less, or 0.3% or less of the compound of formula I. The following may contain any single impurity at a concentration of 0.2% or less, or 0.1% or less (by HPLC).

[0147] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after storage in a sealed container in an atmosphere with 60% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound I.

[0148] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed glass vial in an atmosphere with 60% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I.

[0149] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container in an atmosphere with 75% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound I.

[0150] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed glass vial in an atmosphere with 75% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I.

[0151] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container in an atmosphere with 40% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound I.

[0152] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed LDPE bottle in an atmosphere with 40% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I.

[0153] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container in an atmosphere with 25% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I.

[0154] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed LDPE bottle in an atmosphere with 25% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains any single impurity in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I.

[0155] In one embodiment, the ophthalmic composition of the present invention contains 0.5% or less (by HPLC) of compound I of formula II. [ka] It contains the compound.

[0156] In one embodiment, the ophthalmic composition of the present invention contains 0.4% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0157] In one embodiment, the ophthalmic composition of the present invention contains 0.3% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0158] In one embodiment, the ophthalmic composition of the present invention contains 0.2% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0159] In one embodiment, the ophthalmic composition of the present invention contains 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0160] In one embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains 0.5% or less (by HPLC) of the compound of formula II relative to the compound of formula I.

[0161] In one embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains 0.4% or less (by HPLC) of the compound of formula II relative to the compound of formula I.

[0162] In one embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains 0.3% or less (by HPLC) of the compound of formula II relative to the compound of formula I.

[0163] In one embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains 0.2% or less (by HPLC) of the compound of formula II relative to the compound of formula I.

[0164] In one embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains 0.1% or less (by HPLC) of the compound of formula II relative to the compound of formula I.

[0165] In one embodiment, storage in a sealed container is at a temperature in the range of approximately 20 to 75°C.

[0166] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 15 to 50°C.

[0167] In yet another embodiment, storage in a sealed container is at a temperature in the range of approximately 5 to 50°C.

[0168] In another embodiment, storage in a sealed container takes place in an atmosphere with a relative humidity of approximately 25-80%.

[0169] In other embodiments, storage in a sealed container is in an atmosphere having 60% relative humidity at a temperature of 25°C; or an atmosphere having 75% relative humidity at a temperature of 40°C; or an atmosphere having 40% relative humidity at a temperature of 25°C; or an atmosphere having 25% relative humidity at a temperature of 40°C.

[0170] In one embodiment, the sealed container is a glass vial with a lid.

[0171] In another embodiment, the airtight container is an LDPE bottle with a lid.

[0172] In other embodiments, the ophthalmic pharmaceutical composition of the present invention contains, after being stored in a sealed container at a temperature in the range of about 20 to 75°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0173] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container in an atmosphere having a relative humidity of about 25-80% at a temperature in the range of about 20-75°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0174] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container in an atmosphere with 60% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0175] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed glass vial in an atmosphere with 60% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0176] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container in an atmosphere with 75% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0177] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed glass vial in an atmosphere with 75% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0178] In other embodiments, the ophthalmic pharmaceutical composition of the present invention contains, after being stored in a sealed container in an atmosphere with 40% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0179] In another embodiment, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed LDPE bottle in an atmosphere with 40% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0180] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed container in an atmosphere with 25% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0181] In other embodiments, the ophthalmic pharmaceutical composition of the present invention, after being stored in a sealed LDPE bottle in an atmosphere with 25% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, contains 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0182] In another embodiment, the ophthalmic composition of the present invention contains 2.0% or less (by HPLC) of total impurities relative to the amount of compound I. The composition contains 2.0% or less (by HPLC) of total impurities relative to the amount of compound I, when the area under the peak of the impurities does not exceed 2.0% of the area under the peak of the compound I, as described above by sample analysis by HPLC.

[0183] In another embodiment, the ophthalmic composition of the present invention contains 1.5% or less of total impurities (by HPLC) relative to the amount of compound of formula I.

[0184] In another embodiment, the ophthalmic composition of the present invention contains 1.0% or less of total impurities (by HPLC) relative to the amount of the compound of formula I.

[0185] In another embodiment, the ophthalmic composition of the present invention contains 0.5% or less of total impurities (by HPLC) relative to the amount of compound I.

[0186] In one embodiment, the ophthalmic composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains no more than 2.0% (by HPLC) of total impurities relative to the compound of formula I.

[0187] In one embodiment, the ophthalmic composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains no more than 1.5% (by HPLC) of total impurities relative to the compound of formula I.

[0188] In one embodiment, the ophthalmic composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains no more than 1.0% (by HPLC) of total impurities relative to the compound of formula I.

[0189] In one embodiment, the ophthalmic composition of the present invention, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains no more than 0.5% (by HPLC) of total impurities relative to the compound of formula I.

[0190] In one embodiment, storage in a sealed container is at a temperature in the range of approximately 20 to 75°C.

[0191] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 2 to 8°C.

[0192] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 5 to 50°C.

[0193] In yet another embodiment, storage in a sealed container is at a temperature in the range of approximately 15 to 50°C.

[0194] In another embodiment, storage in a sealed container takes place in an atmosphere with a relative humidity of approximately 25-80%.

[0195] In other embodiments, storage in a sealed container is in an atmosphere having 60% relative humidity at a temperature of 25°C; or an atmosphere having 75% relative humidity at a temperature of 40°C; or an atmosphere having 40% relative humidity at a temperature of 25°C; or an atmosphere having 25% relative humidity at a temperature of 40°C.

[0196] In one embodiment, the sealed container is a glass vial with a lid.

[0197] In another embodiment, the airtight container is an LDPE bottle with a lid.

[0198] In another embodiment, the ophthalmic composition of the present invention is stored in a sealed container at a temperature in the range of about 20 to 75°C until it contains at least 2.0%, 1.5%, 1.0%, or 0.5% (by HPLC) of total impurities relative to the amount of compound I.

[0199] In other embodiments, the ophthalmic composition of the present invention, after being stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80% at a temperature in the range of about 20 to 75°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, contains a total impurity content of 2.0%, 1.5%, 1.0%, or 0.5% or less (by HPLC) relative to the amount of compound of formula I.

[0200] In other embodiments, the ophthalmic composition of the present invention, after being stored in a sealed container in an atmosphere having 60% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains a total impurity content of 2.0%, 1.5%, 1.0%, or 0.5% or less (by HPLC) relative to the amount of compound of formula I.

[0201] In other embodiments, the ophthalmic composition of the present invention, after being stored in a sealed glass vial in an atmosphere having 60% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, contains 2.0%, 1.5%, 1.0%, or 0.5% or less of total impurities (by HPLC) relative to the amount of compound I.

[0202] In other embodiments, the ophthalmic composition of the present invention, after being stored in a sealed container in an atmosphere having 75% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, contains a total impurity content of 2.0%, 1.5%, 1.0%, or 0.5% or less (by HPLC) relative to the amount of compound of formula I.

[0203] In other embodiments, the ophthalmic composition of the present invention, after being stored in a sealed glass vial at a temperature of 40°C in an atmosphere of 75% relative humidity for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, contains a total impurity content of 2.0%, 1.5%, 1.0%, or 0.5% or less (by HPLC) relative to the amount of compound of formula I.

[0204] In other embodiments, the ophthalmic composition of the present invention, after being stored in a sealed container in an atmosphere having 40% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, contains a total impurity content of 2.0%, 1.5%, 1.0%, or 0.5% or less (by HPLC) relative to the amount of compound of formula I.

[0205] In another embodiment, the ophthalmic composition of the present invention, after being stored in a sealed LDPE bottle at a temperature of 25°C in an atmosphere with 40% relative humidity for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, contains a total impurity content of 2.0%, 1.5%, 1.0%, or 0.5% or less (by HPLC) relative to the amount of compound of formula I.

[0206] In other embodiments, the ophthalmic composition of the present invention, after being stored in a sealed container in an atmosphere having 25% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, contains a total impurity content of 2.0%, 1.5%, 1.0%, or 0.5% or less (by HPLC) relative to the amount of compound of formula I.

[0207] In another embodiment, the ophthalmic composition of the present invention, after being stored in a sealed LDPE bottle at a temperature of 40°C in an atmosphere with a relative humidity of 25%, for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains a total impurity content of 2.0%, 1.5%, 1.0%, or 0.5% or less (by HPLC) relative to the amount of compound of formula I.

[0208] In one embodiment, the present invention is an aqueous ophthalmic pharmaceutical composition comprising formula I: [ka] Compounds of formula I and compounds of formula II in a relative amount of 0.5% or less (by HPLC) [ka] This relates to a composition containing the compound.

[0209] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and a compound of formula II in an amount of 0.4% or less (by HPLC) relative to the amount of compound of formula I.

[0210] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and a compound of formula II in an amount of 0.3% or less (by HPLC) relative to the amount of compound of formula I.

[0211] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and a compound of formula II in an amount of 0.2% or less (by HPLC) relative to the amount of compound of formula I.

[0212] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and a compound of formula II in an amount of 0.1% or less (by HPLC) relative to the amount of compound of formula I.

[0213] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition, which, after storage in a sealed container, can be stored for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, for a period of [ka] The compound of formula I, and formula II in an amount of 0.5% or less relative to the compound of formula I (by HPLC). [ka] This relates to a composition containing the compound.

[0214] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition that, after storage of the composition in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains a compound of formula I and a compound of formula II in an amount of 0.4% or less (by HPLC) relative to the amount of compound of formula I.

[0215] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition that, after storage of the composition in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains a compound of formula I and a compound of formula II in an amount of 0.3% or less (by HPLC) relative to the amount of compound of formula I.

[0216] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition that, after storage of the composition in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, contains a compound of formula I and a compound of formula II in an amount of 0.2% or less (by HPLC) relative to the amount of compound of formula I.

[0217] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and a compound of formula II in an amount of 0.1% or less (by HPLC) relative to the amount of compound of formula I, after storage of the composition in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition.

[0218] In one embodiment, storage in a sealed container is at a temperature in the range of approximately 20 to 75°C.

[0219] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 2 to 8°C.

[0220] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 5 to 50°C.

[0221] In yet another embodiment, storage in a sealed container is at a temperature in the range of approximately 15 to 50°C.

[0222] In another embodiment, storage in a sealed container takes place in an atmosphere with a relative humidity of approximately 25-80%.

[0223] In other embodiments, storage in a sealed container is in an atmosphere having 60% relative humidity at a temperature of 25°C; or an atmosphere having 75% relative humidity at a temperature of 40°C; or an atmosphere having 40% relative humidity at a temperature of 25°C; or an atmosphere having 25% relative humidity at a temperature of 40°C.

[0224] In one embodiment, the sealed container is a glass vial with a lid.

[0225] In another embodiment, the airtight container is an LDPE bottle with a lid.

[0226] In one embodiment, an aqueous ophthalmic pharmaceutical composition contains a compound of formula I and a compound of formula II in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% (by HPLC) or less, after being stored in a sealed container at a temperature in the range of about 20–75°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition.

[0227] In one embodiment, an aqueous ophthalmic pharmaceutical composition contains a compound of formula I and a compound of formula II in an atmosphere having a relative humidity of about 25-80% at a temperature in the range of about 20-75°C, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, up to 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% (by HPLC).

[0228] In one embodiment, the aqueous ophthalmic pharmaceutical composition contains a compound of formula I and a compound of formula II in an atmosphere of 60% relative humidity at a temperature of 25°C, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, up to 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% (by HPLC).

[0229] In one embodiment, the aqueous ophthalmic pharmaceutical composition contains a compound of formula I and a compound of formula II in an atmosphere with 60% relative humidity at a temperature of 25°C, after being stored in a sealed glass vial for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC).

[0230] In one embodiment, an aqueous ophthalmic pharmaceutical composition contains a compound of formula I and a compound of formula II in an atmosphere of 75% relative humidity at a temperature of 40°C, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, at a concentration of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% (by HPLC).

[0231] In one embodiment, the aqueous ophthalmic pharmaceutical composition contains a compound of formula I and a compound of formula II in an atmosphere of 75% relative humidity at a temperature of 40°C, after being stored in a sealed glass vial for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC).

[0232] In one embodiment, an aqueous ophthalmic pharmaceutical composition contains a compound of formula I and a compound of formula II in an atmosphere of 40% relative humidity at a temperature of 25°C, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition.

[0233] In one embodiment, the aqueous ophthalmic pharmaceutical composition contains a compound of formula I and a compound of formula II in an atmosphere with 40% relative humidity at a temperature of 25°C, after being stored in a sealed LDPE bottle for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, in an amount of 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC).

[0234] In one embodiment, the aqueous ophthalmic pharmaceutical composition contains a compound of formula I and a compound of formula II in an atmosphere of 25% relative humidity at a temperature of 40°C, after being stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition.

[0235] In one embodiment, an aqueous ophthalmic pharmaceutical composition contains, after being stored in a sealed LDPE bottle in an atmosphere with 25% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less (by HPLC) of the compound of formula II.

[0236] In another embodiment, the present invention relates to a compound of formula I: [ka] and an aqueous ophthalmic pharmaceutical composition comprising an antioxidant, wherein the composition contains formula II [ka] The present invention relates to a composition in which the amount of compound does not increase by more than 200% when quantified by HPLC after storage of the composition in a sealed container until the commercially acceptable expiration date of the composition.

[0237] The term "not increasing by more than 200% as determined by HPLC" used herein means that, as determined by HPLC, the amount of compound II relative to the amount of compound I does not increase by more than 200% from the beginning of storage of the composition until the end of the commercially acceptable expiration date of the stored composition. Whether the amount of compound II increases during storage can be determined by analyzing the composition by HPLC before storage and after storage, and comparing the amount of compound II before storage with the amount of compound II after storage. Furthermore, as previously described, the HPLC chromatogram is prepared using a UV detector monitored at a wavelength of 264 nm. Furthermore, the HPLC chromatogram is obtained under conditions where the detector response to the sample of interest changes linearly with the sample concentration in the sample. Furthermore, the HPLC chromatogram is obtained under conditions where the impurity peaks are separated from each other and from the peak of compound I.

[0238] In one embodiment, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not exceed 100% as measured by HPLC by storing the composition in a sealed container until the commercially acceptable expiration date of the composition.

[0239] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 200% by quantification by HPLC upon storage of the composition in a sealed container for at least 6 months; at least 12 months; at least 18 months; at least 24 months or before the commercially acceptable expiration date of the composition.

[0240] In other embodiments, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 100% by HPLC upon storage of the composition in a sealed container for at least 6 months; at least 12 months; at least 18 months; at least 24 months or before the commercially acceptable expiration date of the composition.

[0241] In one embodiment, storage in a sealed container is at a temperature in the range of approximately 20 to 75°C.

[0242] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 2 to 8°C.

[0243] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 5 to 50°C.

[0244] In yet another embodiment, storage in a sealed container is at a temperature in the range of approximately 15 to 50°C.

[0245] In another embodiment, storage in a sealed container takes place in an atmosphere with a relative humidity of approximately 25-80%.

[0246] In other embodiments, storage in a sealed container is in an atmosphere having 60% relative humidity at a temperature of 25°C; or an atmosphere having 75% relative humidity at a temperature of 40°C; or an atmosphere having 40% relative humidity at a temperature of 25°C; or an atmosphere having 25% relative humidity at a temperature of 40°C.

[0247] In one embodiment, the sealed container is a glass vial with a lid.

[0248] In another embodiment, the airtight container is an LDPE bottle with a lid.

[0249] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 200% or more than 100% when quantified by HPLC for at least 6 months, at least 12 months, at least 18 months, at least 24 months or before the commercially acceptable expiration date of the composition, upon storage of the composition in a sealed container at a temperature in the range of about 20 to 75°C.

[0250] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 200% or more than 100% when quantified by HPLC for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, by storage of the composition in a sealed container in an atmosphere having a relative humidity of about 25 to 80% at a temperature in the range of about 20 to 75°C.

[0251] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 200% or more than 100% when quantified by HPLC for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, upon storage of the composition in a sealed container in an atmosphere having 60% relative humidity at a temperature of 25°C.

[0252] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 200% or more than 100% when quantified by HPLC for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, upon storage of the composition in a sealed glass vial in an atmosphere having 60% relative humidity at a temperature of 25°C.

[0253] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 200% or more than 100% when quantified by HPLC for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, by storage of the composition in a sealed container in an atmosphere having 75% relative humidity at a temperature of 40°C.

[0254] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 200% or more than 100% when quantified by HPLC for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, upon storage of the composition in a sealed glass vial at a temperature of 40°C and an atmosphere of 75% relative humidity.

[0255] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 200% or more than 100% as measured by HPLC for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, by storage of the composition in a sealed container at a temperature of 25°C and an atmosphere of 40% relative humidity.

[0256] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by 200% or more, or by 100% or more, as determined by HPLC, for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, upon storage of the composition in a sealed glass vial at a temperature of 25°C and an atmosphere of 40% relative humidity.

[0257] In one embodiment, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of formula I and an antioxidant system, wherein the amount of the compound of formula II present in the composition does not increase by more than 200% or more than 100% when quantified by HPLC for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition, by storage of the composition in a sealed container in an atmosphere having 25% relative humidity at a temperature of 40°C.

[0258] In certain embodiments, the aqueous ophthalmic pharmaceutical composition of the present invention comprises a compound of Formula I and an antioxidant system, wherein the amount of the compound of Formula II present in the composition does not increase by more than 200% or does not increase by more than 100% as determined by HPLC upon storage of the composition in a sealed LDPE bottle in an atmosphere having 25% relative humidity at a temperature of 40 °C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition.

[0259] In one aspect, the present invention provides a compound of Formula I:

Chemical formula

Chemical formula

[0260] In certain embodiments, the present invention provides an aqueous ophthalmic composition comprising a compound of Formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain, upon storage of the composition in a sealed container, the amount of the compound of Formula II present in the composition at 0.4% or less (by HPLC) relative to the amount of the compound of Formula I.

[0261] In certain embodiments, the present invention provides an aqueous ophthalmic composition comprising a compound of Formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain, upon storage of the composition in a sealed container, the amount of the compound of Formula II present in the composition at 0.3% or less (by HPLC) relative to the amount of the compound of Formula I.

[0262] In one embodiment, the present invention relates to an aqueous ophthalmic composition comprising a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of compound of formula II in the composition at 0.2% or less (by HPLC) relative to the amount of compound of formula I, when the composition is stored in a sealed container.

[0263] In one embodiment, the present invention relates to an aqueous ophthalmic composition comprising a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of compound of formula II in the composition at 0.1% or less (by HPLC) relative to the amount of compound of formula I, when the composition is stored in a sealed container.

[0264] In one embodiment, storage is at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition.

[0265] In one embodiment, storage in a sealed container is at a temperature in the range of approximately 20 to 75°C.

[0266] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 2 to 8°C.

[0267] In another embodiment, storage in a sealed container is at a temperature in the range of approximately 5 to 50°C.

[0268] In yet another embodiment, storage in a sealed container is at a temperature in the range of approximately 15 to 50°C.

[0269] In another embodiment, storage in a sealed container is in an atmosphere with a relative humidity of approximately 25-80%.

[0270] In other embodiments, storage in a sealed container is in an atmosphere having 60% relative humidity at a temperature of 25°C; or an atmosphere having 75% relative humidity at a temperature of 40°C; or an atmosphere having 40% relative humidity at a temperature of 25°C; or an atmosphere having 25% relative humidity at a temperature of 40°C.

[0271] In one embodiment, the sealed container is a glass vial with a lid.

[0272] In another embodiment, the airtight container is an LDPE bottle with a lid.

[0273] In one embodiment, an aqueous ophthalmic pharmaceutical composition comprises a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of compound of formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I, by storing the composition in a sealed container at a temperature in the range of about 20–75°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition.

[0274] In one embodiment, an aqueous ophthalmic pharmaceutical composition comprises a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of compound of formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I, by storing the composition in a sealed container in an atmosphere having a relative humidity of about 25–80% at a temperature in the range of about 20–75°C, for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition.

[0275] In one embodiment, an aqueous ophthalmic pharmaceutical composition comprises a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of compound of formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I, by storing the composition in a sealed container in an atmosphere having 60% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition.

[0276] In one embodiment, an aqueous ophthalmic pharmaceutical composition comprises a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of compound of formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I, by storing the composition in a sealed glass vial in an atmosphere having 60% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition.

[0277] In one embodiment, an aqueous ophthalmic pharmaceutical composition comprises a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of compound of formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I, by storing the composition in a sealed container in an atmosphere having 75% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition.

[0278] In one embodiment, an aqueous ophthalmic pharmaceutical composition comprises a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of compound of formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I, by storing the composition in a sealed glass vial in an atmosphere having 75% relative humidity at a temperature of 40°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition.

[0279] In one embodiment, an aqueous ophthalmic pharmaceutical composition comprises a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of compound of formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) relative to the amount of compound of formula I, by storing the composition in a sealed container in an atmosphere having 40% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition.

[0280] In one embodiment, an aqueous ophthalmic pharmaceutical composition comprises a compound of formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the compound of formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% or less (by HPLC) by storing the composition in a sealed LDPE bottle in an atmosphere having 40% relative humidity at a temperature of 25°C for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or before the commercially acceptable expiration date of the composition.

[0281] In certain embodiments, the aqueous ophthalmic pharmaceutical composition comprises a compound of Formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the amount of the compound of Formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2% or 0.1% or less (by HPLC) relative to the amount of the compound of Formula I, upon storage of the composition in a sealed container having 25% relative humidity at a temperature of 40 °C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition.

[0282] In certain embodiments, the aqueous ophthalmic pharmaceutical composition comprises a compound of Formula I and an antioxidant system, wherein the antioxidant system is present in an amount sufficient to maintain the compound of Formula II present in the composition at 0.5%, 0.4%, 0.3%, 0.2% or 0.1% or less (by HPLC), upon storage of the composition in a sealed LDPE bottle having 25% relative humidity at a temperature of 40 °C for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition.

[0283] In certain embodiments, the aqueous ophthalmic pharmaceutical composition of the present invention is individually packaged in a sterile, transparent, 30 μL to 50 μL dropper, such as a 40 μL dropper.

[0284] In certain embodiments, the aqueous ophthalmic pharmaceutical composition of the present invention is provided in a kit comprising vials of an ophthalmic solution of the compound of Formula (I). In certain embodiments, the kit comprises 3 to 10 vials, such as 4 or 5 vials, containing 2 to 5 mL (e.g., 3 or 4 mL) of the compound of (I) as an ophthalmic solution at 0.03 to 0.04% (e.g., 0.034%). Each vial is used for once-daily dosing.

[0285] In certain embodiments, the aqueous ophthalmic pharmaceutical composition of the present invention is stored at 15 °C to 30 °C (59 °F to 86 °F).

[0286] In one embodiment, the dose of the aqueous ophthalmic pharmaceutical composition of the present invention is one drop per eye per day. [Examples]

[0287] The following embodiments are provided to offer a better understanding of the subject matter described herein. These embodiments should not be construed as limiting the subject matter described herein. The embodiments and examples described herein are for illustrative purposes only, and it should be understood that various modifications or changes based thereon will be apparent to those skilled in the art, fall within the scope of the invention, and can be made without departing therefrom.

[0288] HPLC method : HPLC analysis will be performed using an Agilent HPLC system equipped with a UV detector that monitors at 264 nm.

[0289] Chromatographic separation will be performed using a Welch 4.6 mm × 50 mm ghostbuster column, a Phenomenex C8 4.0 mm × 3.0 mm pre-column, and a Halo C8 4.6 mm × 150 mm, 2.7 μm analytical column. The column heater will be maintained at 40°C and the flow rate will be 1.0 mL / min.

[0290] The samples were eluted over a total runtime of 50 minutes using a gradient that included a linear gradient of 0–20% eluent B over 13 minutes, followed by 20–90% eluent B over 27 minutes, followed by 90–0% eluent B over 5 minutes, and a 5-minute maintenance at 100% A.

[0291] Eluent A is 0.05% perchloric acid in deionized water. Eluent A is prepared by mixing 0.5 mL of perchloric acid (70% ACS reagent grade) with 1000 mL of deionized water. The solution is degassed before use.

[0292] Eluent B is acetonitrile / methanol (80 / 20), which is prepared by mixing 800 mL of acetonitrile (HPLC grade) and 200 mL of methanol (HPLC grade).

[0293] A blank solution is prepared by mixing 740 mL of DI water with 260 mL of ACN.

[0294] The diluent is prepared by mixing 900 mL of deionized water (DI water) and 100 mL of acetonitrile (ACN).

[0295] A standard stock solution of the compound of formula I is prepared by accurately measuring approximately 34.0 ± 3 mg of the formula I standard into a 100 mL volumetric flask, dissolving it in approximately 50 mL of ACN, performing ultrasonic treatment if necessary to dissolve the compound of formula (I), and then diluting it with ACN to the indicated level.

[0296] A working standard solution of formula I is prepared by adding 5.0 mL of the stock solution to a 25 mL volumetric flask and diluting it with a diluent to the indicated level. This standard has a nominal concentration of formula I of approximately 68 μg / mL. The concentration of formula I in the working standard solution or Cstd (micrograms / milliliter) is calculated by multiplying the concentration of formula I in the stock solution (Wstd (mg) / 100 mL) by (1) the weight % purity of the compound standard of formula (I) used in the preparation of the stock solution (purity), (2) the dilution factor of 5 mL / 25 mL, which is the volume of the stock solution divided by the volume of the working standard solution, and (3) the conversion factor from μg to mg of 1000 μg / mg. This relationship is shown by the following formula.

number

[0297] The reference standard solution is prepared using the same method as the working standard solution.

[0298] The limit of quantification (LOQ) solution is prepared by adding 2.0 mL of the working standard to a 100 mL volumetric flask and diluting it to the mark with the blank solution. Add 2.5 mL of the resulting mixture to a 50 mL volumetric flask and dilute it to the mark with the blank solution.

[0299] The sample solution is prepared by adding 4.0 mL of the composition of the present invention to a 20 mL volumetric flask, adding 4 mL of ACN, sonicating for 10 minutes, and then diluting with a diluent to the indicated level. The sample solution has a nominal concentration of 68 μg / mL of the compound of formula (I).

[0300] The injection of the sample solution is sandwiched between injections of the working standard solution.

[0301] The percentage of the label indication (the label indication is the concentration on the label in Equation 1) is calculated as follows:

number

[0302] The percentage of impurities (by weight) is calculated as follows:

number

[0303] % Total impurities = the sum of the percentages of each individual impurity.

[0304] Example 1 The solubility of the compound of formula I in various materials is determined.

[0305] These tests showed that Formula I is poorly water-soluble (<0.01 mg / mL in water). In the solvents tested, polyethylene glycol 400 had the highest solubility (14.5 mg / mL), followed by propylene glycol (4.96 mg / mL), castor oil (1.09 mg / mL), 7% polyoxyl 40 stearate aqueous solution (0.62 mg / mL), and 5% polyoxyl 35 castor oil aqueous solution (0.48 mg / mL). The solubility results are shown in the table below:

[0306] [Table 1] *ND - Not detected (HPLC with UV detector)

[0307] Example 2 The experiment will be conducted using various amounts of ascorbyl palmitate and EDTA.

[0308] Polyoxyl 40 stearate is also evaluated as a solubilizing agent for formula I. [Table 2]

[0309] The accelerated stability data at 50°C indicates that the combination of ascorbyl palmitate and EDTA improves the stability of these compositions.

[0310] Compositions containing both ascorbyl palmitate (0.02% w / v) and EDTA disodium salt dihydrate (0.25% w / v) were found to be stable for up to 3 months of the test period under all storage conditions (i.e., 25°C / 60%RH and 40°C / 75%RH) and packaging forms [i.e., glass vials and LDPE containers].

[0311] Example 3 Sodium thiosulfate pentahydrate (STS) (i.e., 0.0% to 0.2% w / v) is evaluated together with various levels of EDTA disodium salt dihydrate (0.05% to 0.20%) in the formulation. [Table 3]

[0312] The composition containing sodium thiosulfate pentahydrate (0.2%) and EDTA disodium salt dihydrate (0.1%) was found to be stable for up to 3 months during the test period under all storage conditions in glass vials (i.e., 2-8°C, 25°C / 60%RH, 40°C / 75%RH) and LDPE (i.e., 2-8°C, 25°C / 40%RH, 40°C / 25%RH) packaging containers.

[0313] Example 4 The compositions of the present invention can be prepared using conventional techniques. For example, a solution of the compound of formula I in PEG-400 and propylene glycol is prepared by adding formula I to a mixture of PEG-400 and propylene glycol while stirring. The resulting solution is mixed with a solution of polyoxyl 40 stearate and some of the water used in the composition. The resulting solution is mixed with a solution of water, sodium dihydrogen phosphate monohydrate, anhydrous disodium phosphate, sodium CMC, sodium chloride, sodium thiosulfate pentahydrate, and EDTA disodium salt dihydrate to obtain a final solution, which is sterilized by filtration (0.2 μm PES filter). The filtered solution is filled into vials under sterile conditions and sealed. The compositions are packaged in 5 mL, 20 mm, USP type I, clear glass vials (silica coated) equipped with a 20 mm gray stopper and a 20 mm flip-off seal.

[0314] The composition contains the following components: [Table 4]

[0315] The compound of formula I used in this composition is supplemented with approximately 2% of the compound of formula II.

[0316] The composition is stable, as shown in the table below. [Table 5]

[0317] In one embodiment, the present invention relates to the following aspects: Appearance 1. (a) The composition contains a concentration of formula I that is effective for treating an eye disease or condition. [ka] Compounds or pharmaceutically acceptable acid addition salts thereof (b) water; (c) Solubilizer, (d) cosolvent and (e) An ophthalmic pharmaceutical composition containing antioxidants. Embodiment 2. The ophthalmic composition according to Embodiment 1, wherein the composition comprises a compound of formula I. Embodiment 3. The ophthalmic composition according to Embodiment 1, wherein the composition comprises a pharmaceutically acceptable acid addition salt of a compound of formula I. Embodiment 4. An ophthalmic composition according to any of the preceding embodiments, wherein the solubilizer is a surfactant. Embodiment 5. An ophthalmic composition according to any of the preceding embodiments, wherein the solubilizer is a nonionic surfactant. Embodiment 6. An ophthalmic composition according to any of the preceding embodiments, wherein the solubilizer is a polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, polyoxyl hydroxystearate, poloxamer, povidone, or a combination thereof. Apparatus 7. The solubilizer is poly(oxyethylene)sorbitan monooleate, poly(oxyethylene)sorbitan monostearate, poly(oxyethylene)sorbitan monopalmitate, poly(oxyethylene)sorbitan monolaurate, poly(oxyethylene)sorbitan trioleate, poly(oxyethylene)sorbitan tristearate, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 35 (i.e., polyoxyl 35 castor oil), polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, An ophthalmic composition according to any of the preceding embodiments, which is polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyl 40 stearate, polyoxyl 15 hydroxystearate, povidone K30, povidone K90, poloxamer 407, poloxamer 188, or a combination thereof. Embodiment 8. The ophthalmic composition of Embodiment 7, wherein the solubilizer is polyoxyl 35 castor oil, polyoxyl 40 stearate, or a combination thereof. Embodiment 9. The ophthalmic composition according to Embodiment 8, wherein the solubilizer is polyoxyl 35 castor oil. Embodiment 10. The ophthalmic composition according to Embodiment 8, wherein the solubilizer is polyoxyl 40 stearate. Embodiment 11. An ophthalmic composition according to any of the preceding embodiments, wherein the cosolvent is a water-soluble organic solvent. Embodiment 12. An ophthalmic composition according to any of the previous embodiments, wherein the cosolvent is one or more of propylene glycol, polyethylene glycol, glycerin, ethanol, or benzyl alcohol. Embodiment 13. The ophthalmic composition according to Embodiment 12, wherein the polyethylene glycol is one or more of PEG-400, PEG-300, PEG-4000, or PEG-8000. Embodiment 14. An ophthalmic composition according to any of the preceding embodiments, wherein the cosolvent is propylene glycol or one or more PEG-400s. Embodiment 15. The ophthalmic composition of Embodiment 14, wherein the cosolvent is propylene glycol. Embodiment 16. The ophthalmic composition of Embodiment 14, wherein the cosolvent is PEG-400. Embodiment 17. An ophthalmic composition according to any of the preceding embodiments, wherein the antioxidant system comprises one or more of the following: sodium bisulfite, sodium metabisulfite, sodium thiosulfate or its hydrate, sodium sulfite, sodium sulfate, ascorbyl palmitate, ethylenediaminetetraacetic acid (EDTA) or its salt, citric acid or its salt, or ascorbic acid or its salt. Embodiment 18. The ophthalmic composition of Embodiment 17, wherein the antioxidant system contains EDTA. Embodiment 19. The ophthalmic composition of Embodiment 17, wherein the antioxidant system comprises sodium thiosulfate pentahydrate. Embodiment 20. The ophthalmic composition according to Embodiment 17, wherein the antioxidant system comprises ascorbyl palmitate. Embodiment 21. The ophthalmic composition according to Embodiment 17, wherein the antioxidant system comprises ascorbyl palmitate and EDTA disodium salt or its hydrate. Embodiment 22. The ophthalmic composition of Embodiment 17, wherein the antioxidant system comprises sodium thiosulfate pentahydrate and EDTA disodium salt or its hydrate. Embodiment 23. An ophthalmic composition according to any of the preceding embodiments, further comprising an isotonic agent. Embodiment 24. The ophthalmic composition of Embodiment 23, wherein the isotonic agent is sodium chloride, potassium chloride, dextrose, mannitol, or glycerin. Embodiment 25. The ophthalmic composition of Embodiment 24, wherein the isotonic agent is sodium chloride. Embodiment 26. An ophthalmic composition according to any of the preceding embodiments, further comprising a thickening agent. Appearance 27. An ophthalmic composition of Appearance 26, wherein the thickener is hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) (5 cps, 4000 cps, 15000 cps); hypromellose, methylcellulose, carboxymethylcellulose (CMC) sodium (i.e., sodium CMC), polyvinyl alcohol (PVA), polyvinylpyrrolidione (PVP; or povidone), povidone K30, povidone K90, carbomer 940, carbomer 974P, carbomer 980, povidone K30, povidone K90, gellan gum, or xanthan gum. Embodiment 28. The ophthalmic composition according to Embodiment 27, wherein the thickening agent is carboxymethylcellulose (CMC) sodium. Embodiment 29. An ophthalmic composition according to any of the preceding embodiments, further comprising a buffering agent. Embodiment 30. The ophthalmic composition according to Embodiment 29, wherein the buffering agent is a phosphate buffer, a citrate buffer, an acetate buffer, or a borate buffer. Embodiment 31. The ophthalmic composition according to Embodiment 30, wherein the buffering agent is a phosphate buffer. Embodiment 32. The ophthalmic composition of Embodiment 31, wherein the phosphate buffer comprises sodium dihydrogen phosphate and disodium phosphate. Embodiment 33. An ophthalmic composition according to any of the preceding embodiments, wherein the composition has a pH in the range of 4.0 to 8.0. Embodiment 34. The ophthalmic composition according to Embodiment 33, wherein the composition has a pH in the range of 6.5 to 7.5. Embodiment 35. An ophthalmic composition according to any of the preceding embodiments, wherein the composition has an osmotic pressure in the range of 200 to 600 (mOsm / kg). Embodiment 36. The ophthalmic composition according to Embodiment 35, wherein the composition has an osmotic pressure in the range of 250 to 350 (mOsm / kg). Embodiment 37. An ophthalmic composition according to any of the preceding embodiments, wherein a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof is present at a concentration of 0.005 to 0.1% (w / v) based on the compound of formula I. Embodiment 38. An ophthalmic composition according to any of the preceding embodiments, wherein an antioxidant system is present at a concentration of 0.01 to 0.6% (w / v). Embodiment 39. An ophthalmic composition of any of the preceding embodiments, wherein, after storage for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, the composition contains 0.2% or less of any single impurity (by HPLC) relative to the compound of formula I. Embodiment 40. The ophthalmic pharmaceutical composition of Embodiment 39, wherein, after the composition is stored in a sealed container until before the commercially acceptable expiration date of the composition, it contains any single impurity in an amount of 0.2% or less (by HPLC) relative to the compound of Formula I. Embodiment 41. The ophthalmic pharmaceutical composition according to Embodiment 40, which is stored in a sealed container at a temperature in the range of approximately 20 to 75°C. Embodiment 42. An ophthalmic pharmaceutical composition according to Embodiment 40 or Embodiment 41, which is stored in a sealed container in an atmosphere having a relative humidity of approximately 25-80%. Embodiment 43. An ophthalmic pharmaceutical composition according to any of Embodiments 40 to 42, wherein the composition is stored in a sealed container in an atmosphere having a temperature of 25°C and a relative humidity of 60%; or an atmosphere having a temperature of 40°C and a relative humidity of 75%; or an atmosphere having a temperature of 25°C and a relative humidity of 40%; or an atmosphere having a temperature of 40°C and a relative humidity of 25%. Embodiment 44. An ophthalmic pharmaceutical composition according to any of Embodiments 40 to 43, wherein the sealed container is a glass vial with a lid. Embodiment 45. An ophthalmic pharmaceutical composition according to any of Embodiments 40 to 43, wherein the sealed container is an LDPE bottle with a lid. Apparatus 46. After the composition has been stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, 0.5% or less, preferably 0.2% or less (by HPLC) of the compound of formula II relative to the compound of formula I. [ka] An ophthalmic composition according to any of the preceding embodiments, comprising the compound. Embodiment 47. The ophthalmic pharmaceutical composition of Embodiment 46, wherein, after the composition is stored in a sealed container until before the commercially acceptable expiration date of the composition, it contains 0.5% or less, preferably 0.2% or less (by HPLC) of the compound of Formula II relative to the compound of Formula I. Embodiment 48. The ophthalmic pharmaceutical composition according to Embodiment 47, which is stored in a sealed container at a temperature in the range of approximately 20 to 75°C. Embodiment 49. An ophthalmic pharmaceutical composition according to Embodiment 47 or Embodiment 48, which is stored in a sealed container in an atmosphere having a relative humidity of approximately 25-80%. Embodiment 50. An ophthalmic pharmaceutical composition according to any of Embodiments 47 to 49, wherein the composition is stored in a sealed container in an atmosphere having a temperature of 25°C and a relative humidity of 60%; or an atmosphere having a temperature of 40°C and a relative humidity of 75%; or an atmosphere having a temperature of 25°C and a relative humidity of 40%; or an atmosphere having a temperature of 40°C and a relative humidity of 25%. Embodiment 51. An ophthalmic pharmaceutical composition according to any one of Embodiments 47 to 50, wherein the sealed container is a glass vial with a lid. Embodiment 52. An ophthalmic pharmaceutical composition according to any one of Embodiments 47 to 50, wherein the sealed container is an LDPE bottle with a lid. Embodiment 53. An ophthalmic composition according to any of the preceding embodiments, wherein, after storage in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, the composition contains 2.0% or less, preferably 1.0% or less (by HPLC) of total impurities relative to the compound of formula I. Embodiment 54. The ophthalmic pharmaceutical composition of Embodiment 53, wherein, after storage in a sealed container until before the commercially acceptable expiration date of the composition, the composition contains 2.0% or less, preferably 1.0% or less (by HPLC) of total impurities relative to the compound of Formula I. Embodiment 55. The ophthalmic pharmaceutical composition according to Embodiment 54, which is stored in a sealed container at a temperature in the range of approximately 20 to 75°C. Embodiment 56. An ophthalmic pharmaceutical composition according to Embodiment 54 or Embodiment 55, which is stored in a sealed container in an atmosphere having a relative humidity of approximately 25-80%. Embodiment 57. An ophthalmic pharmaceutical composition according to any of Embodiments 54 to 56, wherein the composition is stored in a sealed container in an atmosphere having a temperature of 25°C and a relative humidity of 60%; or an atmosphere having a temperature of 40°C and a relative humidity of 75%; or an atmosphere having a temperature of 25°C and a relative humidity of 40%; or an atmosphere having a temperature of 40°C and a relative humidity of 25%. Embodiment 58. An ophthalmic pharmaceutical composition according to any of Embodiments 54 to 57, wherein the sealed container is a glass vial with a lid. Embodiment 59. An ophthalmic pharmaceutical composition according to any of Embodiments 54 to 57, wherein the sealed container is an LDPE bottle with a lid. Embodiment 60. After storage in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, Formula I: [ka] The compound and the compound of formula I in a relative amount of 0.5% or less, preferably 0.2% or less (by HPLC) of formula II [ka] An aqueous ophthalmic composition containing the compound. Embodiment 61. The aqueous ophthalmic composition of Embodiment 60, wherein the composition, after being stored in a sealed container until before the commercially acceptable expiration date of the composition, contains 0.5% or less, preferably 0.2% or less (by HPLC) of the compound of Formula II relative to the amount of the compound of Formula I. Embodiment 62. The aqueous ophthalmic composition according to Embodiment 61, which is stored in a sealed container at a temperature in the range of approximately 20 to 75°C. Embodiment 63. An aqueous ophthalmic composition according to Embodiment 61 or Embodiment 62, which is stored in a sealed container in an atmosphere with a relative humidity of approximately 25-80%. Embodiment 64. An aqueous ophthalmic composition according to any one of Embodiments 61 to 63, which is stored in a sealed container in an atmosphere having a temperature of 25°C and a relative humidity of 60%; or an atmosphere having a temperature of 40°C and a relative humidity of 75%; or an atmosphere having a temperature of 25°C and a relative humidity of 40%; or an atmosphere having a temperature of 40°C and a relative humidity of 25%. Embodiment 65. An aqueous ophthalmic composition according to any one of Embodiments 61 to 64, wherein the sealed container is a glass vial with a lid. Embodiment 66. An aqueous ophthalmic composition according to any of Embodiments 61 to 64, wherein the sealed container is an LDPE bottle with a lid. Appearance 67. Formula I: [ka] An aqueous ophthalmic composition comprising the compound and antioxidant system of formula II present in the composition. [ka] A composition in which the amount of compound does not increase by more than 200% when measured by HPLC after storage of the composition in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition. Embodiment 68. The aqueous ophthalmic composition according to Embodiment 67, wherein the composition is stored in a sealed container until the commercially permissible expiration date of the composition. Embodiment 69. An aqueous ophthalmic composition according to Embodiment 67 or Embodiment 68, wherein the composition is stored in a sealed container at a temperature in the range of approximately 20 to 75°C. Embodiment 70. An aqueous ophthalmic composition according to any one of Embodiments 67 to 69, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%. Embodiment 71. An aqueous ophthalmic composition according to any one of Embodiments 67 to 70, which is stored in a sealed container in an atmosphere having a temperature of 25°C and a relative humidity of 60%; or an atmosphere having a temperature of 40°C and a relative humidity of 75%; or an atmosphere having a temperature of 25°C and a relative humidity of 40%; or an atmosphere having a temperature of 40°C and a relative humidity of 25%. Embodiment 72. An ophthalmic pharmaceutical composition according to any of Embodiments 67 to 71, wherein the sealed container is a glass vial with a lid. Embodiment 73. An ophthalmic pharmaceutical composition according to any one of Embodiments 67 to 71, wherein the sealed container is an LDPE bottle with a lid. Appearance 74. Formula I: [ka] An aqueous ophthalmic composition comprising a compound and an antioxidant system, wherein the antioxidant system, after the composition has been stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months or until the commercially acceptable expiration date of the composition, is present in the composition in proportion to the amount of compound of formula I and formula II [ka] The compound is present in an amount sufficient to maintain the amount of the compound at 0.5% or less, preferably 0.2% or less (by HPLC). Embodiment 75. The aqueous ophthalmic composition according to Embodiment 74, wherein the composition is stored in a sealed container until the commercially permissible expiration date of the composition. Embodiment 76. An aqueous ophthalmic composition according to Embodiment 74 or Embodiment 75, wherein the composition is stored in a sealed container at a temperature in the range of approximately 20 to 75°C. Embodiment 77. An aqueous ophthalmic composition according to any one of Embodiments 74 to 76, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%. Embodiment 78. An aqueous ophthalmic composition according to any of Embodiments 74 to 77, wherein the storage in a sealed container is in an atmosphere having a temperature of 25°C and a relative humidity of 60%; or an atmosphere having a temperature of 40°C and a relative humidity of 75%; or an atmosphere having a temperature of 25°C and a relative humidity of 40%; or an atmosphere having a temperature of 40°C and a relative humidity of 25%. Embodiment 79. An ophthalmic pharmaceutical composition according to any of Embodiments 74 to 78, wherein the sealed container is a glass vial with a lid. Embodiment 80. An ophthalmic pharmaceutical composition according to any of Embodiments 74 to 78, wherein the sealed container is an LDPE bottle with a lid. Embodiment 81. An ophthalmic pharmaceutical composition according to any one of Embodiments 39 to 80, wherein the measurement is obtained by HPLC or by HPLC area percentage. Embodiment 82. An ophthalmic pharmaceutical composition according to any one of Embodiments 39 to 80, wherein the determination is by HPLC in weight percent.

Claims

1. (a) Equation (I) 【Chemistry 1】 The compound or a pharmaceutically acceptable acid addition salt thereof is added at a concentration of 0.005 to 0.1% (w / v) based on the compound of formula (I). (b) water; (c) Solubilizers which are polyoxyethylene fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, polyoxyl hydroxystearate, poloxamer, povidone, or combinations thereof. (d) one or more cosolvents of propylene glycol, polyethylene glycol, glycerin, ethanol, and benzyl alcohol and (e) (i) Ascorbyl palmitate and disodium EDTA salt or its hydrate; or (ii) Antioxidant system comprising sodium thiosulfate pentahydrate and disodium EDTA salt or its hydrate An ophthalmic pharmaceutical composition containing [the specified ingredient].

2. The ophthalmic composition according to claim 1, wherein the composition comprises a compound of formula I.

3. The ophthalmic composition according to claim 1, wherein the composition comprises a pharmaceutically acceptable acid addition salt of a compound of formula I.

4. An ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein the solubilizer is a surfactant.

5. The ophthalmic pharmaceutical composition according to claim 4, wherein the solubilizer is a nonionic surfactant.

6. The solubilizer is poly(oxyethylene)sorbitan monooleate, poly(oxyethylene)sorbitan monostearate, poly(oxyethylene)sorbitan monopalmitate, poly(oxyethylene)sorbitan monolaurate, poly(oxyethylene)sorbitan trioleate or poly(oxyethylene)sorbitan tristearate, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 35 (i.e., polyoxyl 35 castor oil), polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50 or polyoxyethylene hydrogenated castor oil The ophthalmic composition according to claim 1, wherein the composition is 60, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, polyoxyl 40 stearate, polyoxyl 15 hydroxystearate, povidone K30, povidone K90, poloxamer 407, poloxamer 188, or a combination thereof.

7. The ophthalmic composition according to claim 6, wherein the solubilizer is polyoxyl 40 stearate, polyoxyl 35 castor oil, or a combination thereof.

8. The ophthalmic composition according to claim 6, wherein the solubilizer is polyoxyl 35 castor oil.

9. The ophthalmic composition according to claim 6, wherein the solubilizer is polyoxyl 40 stearate.

10. The ophthalmic composition according to claim 1, wherein the polyethylene glycol is one or more of PEG-400, PEG-300, PEG-4000, or PEG-8000.

11. The ophthalmic composition according to claim 1, wherein the cosolvent is propylene glycol or PEG-400, one or more of the above.

12. The ophthalmic composition according to claim 11, wherein the cosolvent is propylene glycol.

13. The ophthalmic composition according to claim 11, wherein the cosolvent is PEG-400.

14. An ophthalmic composition according to any one of claims 1 to 13, wherein the antioxidant system comprises (i) ascorbyl palmitate and EDTA disodium salt or its hydrate.

15. An ophthalmic composition according to any one of claims 1 to 13, wherein the antioxidant system comprises (ii) sodium thiosulfate pentahydrate and EDTA disodium salt or its hydrate.

16. An ophthalmic pharmaceutical composition according to any one of claims 1 to 15, further comprising an isotonic agent.

17. The ophthalmic pharmaceutical composition according to claim 16, wherein the isotonic agent is sodium chloride, potassium chloride, dextrose, mannitol, or glycerin.

18. The ophthalmic pharmaceutical composition according to claim 17, wherein the isotonic agent is sodium chloride.

19. An ophthalmic pharmaceutical composition according to any one of claims 1 to 18, further comprising a thickening agent.

20. The ophthalmic pharmaceutical composition of claim 19, wherein the thickener is hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) (5 cps, 4000 cps, 15000 cps); hypromellose, methylcellulose, carboxymethylcellulose (CMC) sodium (i.e., sodium CMC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP; or povidone), povidone K30, povidone K90, carbomer 940, carbomer 974P, carbomer 980, povidone K30, povidone K90, gellan gum, or xanthan gum.

21. The ophthalmic pharmaceutical composition according to claim 20, wherein the thickening agent is carboxymethylcellulose (CMC) sodium.

22. An ophthalmic pharmaceutical composition according to any one of claims 1 to 21, further comprising a buffering agent.

23. The ophthalmic pharmaceutical composition according to claim 22, wherein the buffer system is a phosphate buffer, a citrate buffer, an acetate buffer, or a borate buffer.

24. The ophthalmic pharmaceutical composition according to claim 23, wherein the buffer system is a phosphate buffer.

25. The ophthalmic pharmaceutical composition according to claim 24, wherein the phosphate buffer comprises sodium dihydrogen phosphate and disodium phosphate.

26. An ophthalmic pharmaceutical composition according to any one of claims 1 to 25, wherein the composition has a pH in the range of 4.0 to 8.

0.

27. The ophthalmic pharmaceutical composition according to claim 26, wherein the composition has a pH in the range of 6.5 to 7.

5.

28. An ophthalmic composition according to any one of claims 1 to 27, wherein the composition has an osmotic pressure in the range of 200 to 600 (mOsm / kg).

29. The ophthalmic composition according to claim 28, wherein the composition has an osmotic pressure in the range of 250 to 350 (mOsm / kg).

30. An ophthalmic pharmaceutical composition according to any one of claims 1 to 29, wherein an antioxidant system is present at a concentration of 0.01 to 0.6% (w / v).

31. The ophthalmic pharmaceutical composition according to claim 1, wherein, after storage in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, the composition contains any single impurity in an amount of 0.2% or less (by area or weight in HPLC) relative to the compound of formula (I).

32. The ophthalmic pharmaceutical composition of claim 31, wherein, after the composition is stored in a sealed container until before the commercially acceptable expiration date of the composition, it contains any single impurity in an amount of 0.2% or less (by area or weight in HPLC) relative to the compound of formula I.

33. The ophthalmic pharmaceutical composition according to claim 32, wherein the composition is stored in a sealed container at a temperature in the range of 20 to 75°C.

34. The ophthalmic pharmaceutical composition according to claim 32, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of 25 to 80%.

35. The ophthalmic pharmaceutical composition according to claim 32, wherein storage in a sealed container is in an atmosphere having a temperature of 25°C and a relative humidity of 60%; or an atmosphere having a temperature of 40°C and a relative humidity of 75%; or an atmosphere having a temperature of 25°C and a relative humidity of 40%; or an atmosphere having a temperature of 40°C and a relative humidity of 25%.

36. The ophthalmic pharmaceutical composition according to claim 32, wherein the sealed container is a glass vial with a lid.

37. The ophthalmic pharmaceutical composition according to claim 32, wherein the sealed container is an LDPE bottle with a lid.

38. After the composition is stored in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, 0.5% or less (by area or weight in HPLC) of compound (II) of compound (I) is added to the compound (II). 【Chemistry 2】 An ophthalmic pharmaceutical composition according to claim 1, comprising the compound.

39. The ophthalmic pharmaceutical composition of claim 38, wherein, after the composition is stored in a sealed container until before the commercially acceptable expiration date of the composition, it contains 0.5% or less (by area or weight in HPLC) of the compound of formula (II) relative to the compound of formula (I).

40. The ophthalmic pharmaceutical composition according to claim 38, wherein the storage temperature in a sealed container is in the range of approximately 20 to 75°C.

41. The ophthalmic pharmaceutical composition according to claim 39 or claim 40, which is stored in a sealed container in an atmosphere having a relative humidity of approximately 25 to 80%.

42. The ophthalmic pharmaceutical composition according to claim 39, wherein storage in a sealed container is in an atmosphere having a temperature of 25°C and a relative humidity of 60%; or an atmosphere having a temperature of 40°C and a relative humidity of 75%; or an atmosphere having a temperature of 25°C and a relative humidity of 40%; or an atmosphere having a temperature of 40°C and a relative humidity of 25%.

43. The ophthalmic pharmaceutical composition according to claim 39, wherein the sealed container is a glass vial with a lid.

44. The ophthalmic pharmaceutical composition according to claim 39, wherein the sealed container is an LDPE bottle with a lid.

45. The ophthalmic pharmaceutical composition according to claim 1, wherein after storage in a sealed container for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until the commercially acceptable expiration date of the composition, the composition contains no more than 2.0% (by area or weight in HPLC) of total impurities relative to the compound of formula (I).

46. The ophthalmic pharmaceutical composition of claim 45, wherein, after the composition is stored in a sealed container until before the commercially acceptable expiration date of the composition, it contains 2.0% or less of total impurities (by area or weight in HPLC) relative to the compound of formula (I).

47. The ophthalmic pharmaceutical composition according to claim 46, which is stored in a sealed container at a temperature in the range of approximately 20 to 75°C.

48. The ophthalmic pharmaceutical composition according to claim 45 or claim 46, which is stored in a sealed container in an atmosphere having a relative humidity of approximately 25 to 80%.

49. The ophthalmic pharmaceutical composition according to claim 38, wherein storage in a sealed container is in an atmosphere having a temperature of 25°C and a relative humidity of 60%; or an atmosphere having a temperature of 40°C and a relative humidity of 75%; or an atmosphere having a temperature of 25°C and a relative humidity of 40%; or an atmosphere having a temperature of 40°C and a relative humidity of 25%.

50. The ophthalmic pharmaceutical composition according to claim 46, wherein the sealed container is a glass vial with a lid.

51. The ophthalmic pharmaceutical composition according to claim 46, wherein the sealed container is an LDPE bottle with a lid.

52. An ophthalmic pharmaceutical composition according to any one of claims 31, 38, or 45, wherein the measurement by HPLC is expressed as HPLC area percentage.

53. An ophthalmic pharmaceutical composition according to any one of claims 31, 38, or 45, wherein the HPLC method is based on HPLC by weight %.

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