Pharmaceutical composition for ophthalmic use

Abstract

To provide a suitable formulation of a drug that activates a cystic fibrosis transmembrane conductance regulator for non-systemic treatment of an eye disease or disorder including a dry eye disorder.SOLUTION: A pharmaceutical composition for ophthalmic use contains a compound of formula I or a pharmaceutically acceptable acid addition salt, (b) water, (c) solubilizer, (d) cosolvent and (e) antioxidant system.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 944,074, filed December 5, 2019, and U.S. Provisional Application No. 63 / 077,196, filed September 11, 2020, the disclosures of both of which are incorporated herein by reference in their entireties.

[0002] Technical Field The present invention relates to an ophthalmic pharmaceutical composition. [Background technology]

[0003] background Compound N 2 -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 the cystic fibrosis transmembrane conductance regulator (CFTR) and is described, for example, in WO2017112951. See also S. Lee, et al., J. Med. Chem. 2017; 60, 3, 1210-1218, which describes ocular administration of the compound of Formula I to increase tear production in mice. WO2017112951 also describes administration of CFTR activators as useful for treating dry eye disorders. [ka] Summary of the Invention [Problem to be solved by the invention]

[0004] There is a need for suitable formulations of drugs that activate the cystic fibrosis transmembrane conductance regulator for the non-systemic treatment of ocular diseases or disorders, including dry eye disorder. In particular, there is a need for storage-stable ophthalmic pharmaceutical compositions of the compound of Formula I and its acid addition salts that are suitable for ocular administration. [Means for solving the problem]

[0005] overview The present invention provides a storage-stable ophthalmic pharmaceutical composition of a pharmaceutically acceptable acid addition salt thereof.

[0006] In one aspect, the present invention provides an ophthalmic pharmaceutical composition, comprising: (a) in said composition a compound of Formula I in a concentration effective to treat an ocular disease or condition; [ka] or a pharmaceutically acceptable acid addition salt thereof, (b) water; (c) solubilizing agents; (d) cosolvents and (e) Antioxidant system The present invention provides a pharmaceutical composition comprising:

[0007] In other embodiments, the present invention provides a composition comprising a compound of Formula I: [ka] and a relative amount of not more than 0.5%, preferably not more than 0.2% (by HPLC) of the compound of formula II to the compound of formula I. [ka] An aqueous ophthalmic composition is provided comprising the compound of formula (I).

[0008] In another aspect, the present invention provides a compound of formula I: [ka] and an antioxidant system, wherein the compound of formula II present in the composition [ka] does not increase by more than 200% as determined 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 a commercially acceptable expiration date for the composition.

[0009] In yet another aspect, the present invention provides a compound of formula I: [ka] and an antioxidant system, wherein the antioxidant system has a 300% or greater amount of the compound of formula II present in the composition relative to the amount of the compound of formula I 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 a commercially acceptable expiration date for the composition. [ka] is present in an amount sufficient to maintain the amount of compound (I) below 0.5%, preferably below 0.2% (by HPLC). DETAILED DESCRIPTION OF THE INVENTION

[0010] Description of Illustrative 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 methodology, conditions, or parameters described and / or illustrated herein, and the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to limit the present invention.

[0011] Scientific and technical terms used in connection with this application shall have meanings commonly understood by those skilled in the art, unless otherwise 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] During the development of the compound of Formula I for ocular administration, an unexpected degradation impurity, N 2 -phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (compound of formula II): [ka]

[0014] Surprisingly, compounds of formula II are not formed during forced degradation tests of compounds of formula I. Instead, compounds of formula II are formed during storage. Formation of compounds of formula II is delayed and / or eliminated in the novel ophthalmic solution compositions described herein by the inclusion of an "antioxidant system," as described herein.

[0015] In one embodiment, the present invention provides a compound of formula I [ka] or a pharmaceutically acceptable acid addition salt thereof. In certain embodiments, the ophthalmic pharmaceutical composition comprises a compound of Formula I. In other embodiments, the ophthalmic pharmaceutical composition comprises a pharmaceutically acceptable acid addition salt of the compound of Formula I.

[0016] As used herein, the pharmaceutically acceptable acid addition salt of the compound of formula I refers to the acid addition salt of the compound of formula I. Pharmaceutically acceptable acid addition salts are known to those skilled in the art. Examples of such salts of the compound of formula I are described in WO2017112951.

[0017] In certain embodiments, the compound of Formula I or a pharmaceutically acceptable acid addition salt thereof is present in the composition at a concentration effective to treat an ophthalmic disease or condition. As used herein, the term "ophthalmic disease or condition" refers to any disease or condition of the eye.

[0018] The compositions of the present invention comprise a concentration of a compound of Formula I that is effective for treating an ocular disease or condition. The concentration of the compound of Formula I that is effective in this regard will vary depending on the characteristics and condition of the subject and the ocular disease or condition.

[0019] In some embodiments, the ocular disease or condition is a dry eye disorder. "Dry eye disorder" (or "dry eye") refers to a heterogeneous group of disorders that share the common characteristics of decreased tear volume and tear hyperosmolarity, leading to inflammation of the ocular surface. Symptoms of dry eye include ocular discomfort and blurred vision. Eye discomfort can include a stinging, burning, or stinging sensation in the eye; stringy mucus in or around the eye; and eye redness. Vision impairment can include sensitivity to light; difficulty wearing contact lenses; and difficulty driving at night. Symptoms of dry eye include damage to corneal epithelial cells. In some embodiments, the dry eye disorder is Sjogren's syndrome.

[0020] In certain embodiments, the ocular disease or condition is allergic conjunctivitis.

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

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

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

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

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

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

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

[0028] In some embodiments, the ophthalmic pharmaceutical composition of the present invention comprises water. In some embodiments, the water is sterile water.

[0029] In certain embodiments, the ophthalmic pharmaceutical composition of the present invention comprises a solubilizing agent, which is an additive that aids in dissolving the compound of Formula I.

[0030] In some embodiments, the solubilizing agent is a surfactant.

[0031] In some embodiments, the solubilizing agent is an anionic surfactant.

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

[0033] In yet another embodiment, the solubilizing agent is a non-ionic surfactant.

[0034] In certain embodiments, the solubilizer is polyoxyethylene fatty ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, polyoxyl hydroxystearate, poloxamer, or povidone.

[0035] In certain embodiments, the solubilizing agent 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, the solubilizer is polyoxyl 40 stearate, polyoxyl 15 hydroxystearate, povidone K30, povidone K90, poloxamer 407, or poloxamer 188.

[0039] In some embodiments, the solubilizer is polyoxyl 40 stearate.

[0040] In other embodiments, the solubilizer is polyoxyl 35 castor oil.

[0041] In certain embodiments, the amount of solubilizing agent in the ophthalmic pharmaceutical composition of the present invention ranges from about 1% (w / v) to about 15% (w / v).

[0042] In another embodiment, the amount of solubilizing agent in the ophthalmic pharmaceutical composition of the present invention ranges from about 4% (w / v) to about 8% (w / v).

[0043] In some embodiments, the ophthalmic pharmaceutical composition comprises polyoxyl 40 stearate. In some embodiments, the ophthalmic pharmaceutical composition comprises about 5% (w / v) polyoxyl 40 stearate. In some embodiments, the ophthalmic pharmaceutical composition comprises 5% (w / v) polyoxyl 40 stearate.

[0044] In certain embodiments, the ophthalmic pharmaceutical composition comprises about 7% (w / v) polyoxyl 40 stearate. In certain embodiments, the ophthalmic pharmaceutical composition comprises 7% (w / v) polyoxyl 40 stearate.

[0045] In some embodiments, the ophthalmic pharmaceutical composition comprises polyoxyl 35 castor oil. In some embodiments, the ophthalmic pharmaceutical composition comprises about 5% (w / v) polyoxyl 35 castor oil. In some embodiments, the ophthalmic pharmaceutical composition comprises 5% (w / v) polyoxyl 35 castor oil.

[0046] In some embodiments, the ophthalmic pharmaceutical composition comprises about 7% (w / v) polyoxyl 35 castor oil. In some embodiments, the ophthalmic pharmaceutical composition comprises 7% (w / v) polyoxyl 35 castor oil.

[0047] In some embodiments, the ophthalmic pharmaceutical composition of the present invention comprises a co-solvent. A co-solvent is a solvent other than water that is suitable for use in an ophthalmic composition.

[0048] In some embodiments, the co-solvent is a water-miscible organic solvent.

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

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

[0051] In certain embodiments, the co-solvent is PEG-300, PEG-400, PEG-4000, PEG-8000, or a mixture thereof.

[0052] In some embodiments, the co-solvent is PEG-400.

[0053] In another embodiment, the co-solvent is propylene glycol.

[0054] In some embodiments, the co-solvent is a mixture of PEG-400 and propylene glycol.

[0055] In certain embodiments, the amount of co-solvent in the ophthalmic pharmaceutical composition of the present invention ranges from about 0.5% (w / v) to about 10% (w / v).

[0056] In certain embodiments, the amount of cosolvent in the ophthalmic pharmaceutical composition of the present invention ranges from about 1% (w / v) to about 3% (w / v).

[0057] In some embodiments, the ophthalmic pharmaceutical composition of the present invention comprises PEG, e.g., PEG-400. In some embodiments, the ophthalmic pharmaceutical composition of the present invention comprises about 1% (w / v) PEG-400. In other embodiments, the ophthalmic pharmaceutical composition of the present invention comprises 1% (w / v) PEG-400.

[0058] In some embodiments, the ophthalmic pharmaceutical composition of the present invention comprises propylene glycol. In some embodiments, the ophthalmic pharmaceutical composition of the present invention comprises about 1% (w / v) propylene glycol. In other embodiments, the ophthalmic pharmaceutical composition of the present invention comprises 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, hi another embodiment, the ophthalmic pharmaceutical composition of the present invention comprises 1% (w / v) PEG-400 and 1% (w / v) propylene glycol.

[0060] In certain embodiments, the ophthalmic pharmaceutical compositions of the present invention include an "antioxidant system." An 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 compositions of the present invention upon storage. Without wishing to be bound by any particular mechanistic theory, the antioxidant system of the present invention reduces and / or eliminates the formation of oxidative degradation products of the compound of Formula I in the ophthalmic compositions of the present invention. N-demethylation is an example of an oxidative degradation process.

[0061] In some embodiments, the antioxidant system comprises sodium bisulfite, sodium metabisulfite, sodium thiosulfate or its hydrate, sodium sulfite, sodium sulfate, ascorbyl palmitate, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, citric acid or a salt thereof, ascorbic acid or a salt thereof, or a combination of these compounds.

[0062] In certain embodiments, the antioxidant system comprises EDTA disodium salt or a hydrate thereof, such as, for example, EDTA disodium salt dihydrate.

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

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

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

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

[0067] In certain embodiments, the amount of antioxidant system in the ophthalmic pharmaceutical composition of the present invention ranges from about 0.01% (w / v) to about 0.6% (w / v).

[0068] In certain embodiments, the amount of antioxidant system in the ophthalmic pharmaceutical composition of the present invention ranges from about 0.05% (w / v) to about 0.5% (w / v).

[0069] In certain embodiments, 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 a hydrate thereof.

[0070] In certain embodiments, 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 a hydrate thereof.

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

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

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

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

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

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

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

[0078] In certain embodiments, the antioxidant system in the ophthalmic pharmaceutical composition of the invention comprises about 0.01% (w / v) to about 0.04% (w / v) ascorbyl palmitate.

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

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

[0081] In certain embodiments, 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 certain embodiments, 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 certain embodiments, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.10% (w / v) EDTA disodium salt or its hydrate and about 0.20% (w / v) sodium thiosulfate pentahydrate.

[0084] In certain embodiments, 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 certain embodiments, 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 certain embodiments, 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 certain embodiments, the antioxidant system in the ophthalmic pharmaceutical composition of the present invention comprises about 0.10% (w / v) EDTA disodium salt or its hydrate and about 0.02% (w / v) ascorbyl palmitate.

[0088] In certain embodiments, 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 a tonicity agent, which is an additive that adjusts the osmotic pressure in the ophthalmic composition.

[0090] In some embodiments, the tonicity agent is sodium chloride, potassium chloride, dextrose, mannitol, or glycerin.

[0091] In some embodiments, the tonicity agent is sodium chloride.

[0092] The amount of tonicity agent in the ophthalmic compositions of the present invention is sufficient to adjust the osmolality of the composition to a range of about 200 mOsm / kg to about 600 mOsm / kg. <785> It is measured according to

[0093] In some embodiments, the amount of tonicity agent in the ophthalmic compositions of the present invention is sufficient to cause the osmolality of the composition to be in the range of about 250 mOsm / kg to about 350 mOsm / kg.

[0094] In other embodiments, the amount of tonicity agent in the ophthalmic composition of the present invention is sufficient to adjust the osmolality of the composition to about 280 mOsm / kg to about 320 mOsm / kg.

[0095] In certain embodiments, the amount of tonicity agent present in the ophthalmic compositions of the present invention is from about 0.01% (w / v) to about 0.5% (w / v).

[0096] In some embodiments, the ophthalmic pharmaceutical composition of the present invention further comprises a thickener. A thickener is an additive that increases the viscosity of the composition.

[0097] In some embodiments, the viscosity increasing agent is hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC) (5 cps, 4000 cps, 15000 cps); hypromellose, methylcellulose, sodium carboxymethylcellulose (CMC) (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 some embodiments, the viscosity increasing agent is sodium carboxymethylcellulose (CMC).

[0099] In some embodiments, the amount of thickener present in the ophthalmic compositions 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., a Brookfield viscometer, Model: LVDV-E with a spindle and an extended UL adapter with a water jacket); sample temperature is maintained at 25.0±0.1°C during measurement.

[0100] In other embodiments, the viscosity increasing agent is present in the ophthalmic compositions of the present invention in an amount of about 0.05% (w / v) to about 0.5% (w / v).

[0101] In some embodiments, the ophthalmic pharmaceutical composition of the present invention further comprises a buffer system. A 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 some embodiments, the buffer system is a phosphate buffer, a citrate buffer, an acetate buffer, or a borate buffer.

[0103] In some embodiments, the buffer system is a phosphate buffer.

[0104] In certain embodiments where the buffer system is a phosphate buffer, the buffer system comprises 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 some embodiments, the buffer system is a citrate buffer.

[0106] In certain embodiments where the buffer system is a citrate buffer, the buffer system comprises sodium citrate and citric acid.

[0107] In some embodiments, the buffer system is an acetate buffer.

[0108] In certain embodiments where the buffer system is an acetate buffer, the buffer system comprises sodium acetate and acetic acid.

[0109] In other embodiments, the buffer system is a borate buffer.

[0110] In certain embodiments where the buffer system is a borate buffer, the buffer system comprises sodium borate and boric acid.

[0111] In certain embodiments, the buffer system is present in the ophthalmic compositions 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 within the range of about 4.0 to about 8.0. <791> The measurement is carried out at 25±2°C.

[0113] In another embodiment, the pH of the ophthalmic pharmaceutical composition of the present invention is within 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 within 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 within the range of about 6.8 to about 7.4.

[0116] In some embodiments, the ophthalmic pharmaceutical composition of the present invention may further comprise an antimicrobial agent. An antimicrobial is an additive that inhibits the growth of microorganisms in the ophthalmic pharmaceutical composition.

[0117] In some embodiments, the antimicrobial agent is benzalkonium chloride (BAK), chlorobutanol, benzethonium chloride, phenylmercuric nitrate, phenylmercuric acetate, or thimerosal.

[0118] In certain embodiments, the ophthalmic pharmaceutical compositions of the present invention contain 0.5% or less (by HPLC) of any single impurity relative to the amount of the compound of formula I.

[0119] As used herein, the term "by HPLC" means that the amount indicated was determined using high performance liquid chromatography.

[0120] In certain embodiments, "by HPLC" means "by HPLC area %." In these embodiments, the area under the response curve corresponding to the analyte of interest in an HPLC chromatogram (wherein the HPLC chromatogram is generated 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 in which the detector response to the analyte of interest varies linearly with the analyte concentration in the sample. Furthermore, the HPLC chromatogram is obtained under conditions in which the peaks of the impurities are resolved from each other and from the peak of the compound of Formula I.

[0121] For example, a composition contains 0.2% or less of any single impurity, by HPLC area %, relative to the compound of Formula I, when a sample is analyzed by HPLC as described above and the area under the peak of any single impurity does not exceed 0.2% of the area under the peak 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 analyte of interest in the HPLC chromatogram is compared to the area under the response curve of the compound of Formula I in an HPLC chromatogram prepared from a standard containing a known weight of the compound of Formula I. The HPLC chromatograms of the standard sample and the standard sample are prepared under the same conditions (e.g., 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 analyte of interest varies linearly with the analyte concentration in the sample. Furthermore, the HPLC chromatogram is obtained under conditions in which the peaks of the impurities are resolved from each other and from the peak of the compound of Formula I.

[0123] For example, a composition contains 0.2% or less (by HPLC weight %) of any single impurity when a sample 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.

[0124] As used herein, the term "impurity" refers to a compound present in a composition that is (or may be) a degradation product of a compound of Formula I.

[0125] In certain embodiments, the ophthalmic pharmaceutical composition of the present invention contains 0.5% or less (by HPLC) of any single impurity relative to the amount of the compound of formula I.

[0126] In certain embodiments, the ophthalmic pharmaceutical composition of the present invention contains 0.4% or less (by HPLC) of any single impurity relative to the amount of the compound of formula I.

[0127] In certain embodiments, the ophthalmic pharmaceutical composition of the present invention contains 0.3% or less (by HPLC) of any single impurity relative to the amount of the compound of formula I.

[0128] In certain embodiments, the ophthalmic pharmaceutical composition of the present invention contains 0.2% or less (by HPLC) of any single impurity relative to the amount of the compound of formula I.

[0129] In certain embodiments, the ophthalmic pharmaceutical composition of the present invention contains 0.1% or less (by HPLC) of any single impurity relative to the amount of the compound of formula I.

[0130] In other embodiments, the ophthalmic pharmaceutical compositions of the present invention contain 0.5% or less (by HPLC) of any single impurity relative to the compound of Formula I 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.

[0131] In other embodiments, the ophthalmic pharmaceutical compositions of the present invention contain 0.4% or less (by HPLC) of any single impurity relative to the compound of Formula I 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.

[0132] In other embodiments, the ophthalmic pharmaceutical compositions of the invention contain 0.3% or less (by HPLC) of any single impurity relative to the compound of Formula I 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.

[0133] In other embodiments, the ophthalmic pharmaceutical compositions of the invention contain 0.2% or less (by HPLC) of any single impurity relative to the compound of Formula I 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.

[0134] In other embodiments, the ophthalmic pharmaceutical compositions of the present invention contain 0.1% or less (by HPLC) of any single impurity relative to the compound of Formula I 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.

[0135] In some embodiments of the invention described herein, "storage in a closed container" refers to storage in a glass vial with a cap. In other embodiments of the invention described herein, "storage in a closed container" refers to storage in a USP Type 1 glass vial with a Flurotec coated butyl rubber stopper and aluminum seal.

[0136] In some embodiments of the invention described herein, "storage in a sealed container" refers to storage in a low density polyethylene (LDPE) bottle with a lid. In other embodiments of the invention described herein, "storage in a sealed container" refers to storage in an LDPE bottle with an HDPE cap.

[0137] As used herein, the term "expiration date" of a manufacturing lot of a finished pharmaceutical dosage form refers to the end of the period during which a regulatory authority is satisfied that product distribution from that lot can be expected to remain sufficiently stable (i.e., retain sufficient strength, quality, and purity) to be prescribed under specified storage conditions, such that an expiration date can be designated with the product distribution from manufacture.

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

[0139] In certain embodiments, storage of the composition in a sealed container is at a temperature ranging from about 20 to 75°C.

[0140] In other embodiments, storage in a sealed container is at a temperature ranging from about 2-8°C.

[0141] In other embodiments, storage in a sealed container is at a temperature ranging from about 5 to 50°C.

[0142] In yet another embodiment, storage in a sealed container is at a temperature ranging from about 15 to 50°C.

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

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

[0145] In other embodiments, the ophthalmic pharmaceutical compositions of the invention contain no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of any single impurity, based on the amount of the compound of Formula I, after storage 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.

[0146] In other embodiments, the ophthalmic pharmaceutical composition of the present invention has a solubility of 0.5%, 0.4%, 0.3%, or less of the compound of Formula I after storage 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. or less, containing 0.2% or less, or 0.1% or less (by HPLC) of any single impurity.

[0147] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of any single impurity, based on the amount of the compound of Formula I, after storage in a sealed container at a temperature of 25° C. in an atmosphere having a relative humidity of 60% 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.

[0148] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of any single impurity, based on the amount of the compound of Formula I, after storage in a sealed glass vial at a temperature of 25° C. in an atmosphere having a relative humidity of 60% 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.

[0149] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of any single impurity, based on the amount of the compound of Formula I, after storage in a sealed container at a temperature of 40° C. in an atmosphere having a relative humidity of 75% 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.

[0150] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of any single impurity, based on the amount of the compound of Formula I, after storage in a sealed glass vial at a temperature of 40° C. in an atmosphere having a relative humidity of 75% 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.

[0151] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of any single impurity, based on the amount of the compound of Formula I, after storage in a sealed container at a temperature of 25° C. in an atmosphere having a relative humidity of 40% 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.

[0152] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of any single impurity, based on the amount of the compound of Formula I, after storage in a sealed LDPE bottle at a temperature of 25° C. in an atmosphere having a relative humidity of 40% 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.

[0153] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of any single impurity, based on the amount of the compound of Formula I, after storage in a sealed container at a temperature of 40° C. in an atmosphere having 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.

[0154] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of any single impurity, based on the amount of the compound of Formula I, after storage in a sealed LDPE bottle at a temperature of 40° C. in an atmosphere having 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.

[0155] In some embodiments, the ophthalmic compositions of the present invention contain 0.5% or less (by HPLC) of a compound of formula II relative to the amount of a compound of formula I. [ka] This includes compounds of the formula:

[0156] In certain embodiments, the ophthalmic compositions of the present invention contain 0.4% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0157] In certain embodiments, the ophthalmic compositions of the present invention contain 0.3% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0158] In certain embodiments, the ophthalmic compositions of the present invention contain 0.2% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0159] In certain embodiments, the ophthalmic compositions of the present invention contain 0.1% or less (by HPLC) of the compound of formula II relative to the amount of the compound of formula I.

[0160] In certain embodiments, the ophthalmic pharmaceutical composition of the invention contains 0.5% or less (by HPLC) of the compound of formula II relative to the compound of formula I 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.

[0161] In certain embodiments, the ophthalmic pharmaceutical composition of the invention contains 0.4% or less (by HPLC) of the compound of formula II relative to the compound of formula I 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.

[0162] In certain embodiments, the ophthalmic pharmaceutical composition of the invention contains 0.3% or less (by HPLC) of the compound of formula II relative to the compound of formula I 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.

[0163] In certain embodiments, the ophthalmic pharmaceutical composition of the invention contains 0.2% or less (by HPLC) of the compound of formula II relative to the compound of formula I 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.

[0164] In certain embodiments, the ophthalmic pharmaceutical composition of the invention contains 0.1% or less (by HPLC) of the compound of formula II relative to the compound of formula I 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.

[0165] In one embodiment, storage in a sealed container is at a temperature ranging from about 20 to 75°C.

[0166] In other embodiments, storage in a sealed container is at a temperature ranging from about 15 to 50°C.

[0167] In yet another embodiment, storage in a sealed container is at a temperature ranging from about 5 to 50°C.

[0168] In another embodiment, storage in a sealed container is in an atmosphere having a relative humidity of about 25-80%.

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

[0170] In some embodiments, the sealed container is a glass vial with a lid.

[0171] In another embodiment, the closed container is a lidded LDPE bottle.

[0172] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II, relative to the amount of the compound of formula I, 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.

[0173] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of Formula II, relative to the amount of the compound of Formula I, after storage in a sealed container at a temperature in the range of about 20-75° C. in an atmosphere having a relative humidity of about 25-80% 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.

[0174] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II, relative to the amount of the compound of formula I, after storage in a sealed container at a temperature of 25° C. in an atmosphere having a relative humidity of 60% 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.

[0175] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II, relative to the amount of the compound of formula I, after storage in a sealed glass vial at a temperature of 25° C. in an atmosphere having a relative humidity of 60% 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.

[0176] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II, relative to the amount of the compound of formula I, after storage in a sealed container at a temperature of 40° C. in an atmosphere having a relative humidity of 75% 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.

[0177] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II, relative to the amount of the compound of formula I, after storage in a sealed glass vial at a temperature of 40° C. in an atmosphere having a relative humidity of 75% 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.

[0178] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II, relative to the amount of the compound of formula I, after storage in a sealed container at a temperature of 25° C. in an atmosphere having a relative humidity of 40% 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.

[0179] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II, relative to the amount of the compound of formula I, after storage in a sealed LDPE bottle at a temperature of 25° C. in an atmosphere having a relative humidity of 40% 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.

[0180] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II, relative to the amount of the compound of formula I, after storage in a sealed container at a temperature of 40° C. in an atmosphere having 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.

[0181] In other embodiments, the ophthalmic pharmaceutical composition of the invention contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II, relative to the amount of the compound of formula I, after storage in a sealed LDPE bottle at a temperature of 40° C. in an atmosphere having 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.

[0182] In other embodiments, the ophthalmic compositions of the present invention contain 2.0% or less (by HPLC) total impurities relative to the amount of the compound of Formula I. A composition contains 2.0% or less (by HPLC) total impurities relative to the amount of the compound of Formula I when, upon sample analysis by HPLC as described above, the area under the peak of the impurity does not exceed 2.0% of the area under the peak of the compound of Formula I.

[0183] In other embodiments, the ophthalmic compositions of the present invention contain 1.5% or less (by HPLC) of total impurities relative to the amount of the compound of Formula I.

[0184] In other embodiments, the ophthalmic compositions of the present invention contain 1.0% or less (by HPLC) of total impurities relative to the amount of the compound of Formula I.

[0185] In other embodiments, the ophthalmic compositions of the present invention contain 0.5% or less (by HPLC) of total impurities relative to the amount of the compound of Formula I.

[0186] In certain embodiments, the ophthalmic compositions of the present invention contain 2.0% or less (by HPLC) total impurities relative to the compound of Formula I 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.

[0187] In certain embodiments, the ophthalmic compositions of the present invention contain 1.5% or less (by HPLC) total impurities relative to the compound of Formula I 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.

[0188] In certain embodiments, the ophthalmic compositions of the present invention contain 1.0% or less (by HPLC) total impurities relative to the compound of Formula I 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.

[0189] In certain embodiments, the ophthalmic compositions of the present invention contain 0.5% or less (by HPLC) total impurities relative to the compound of Formula I 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.

[0190] In one embodiment, storage in a sealed container is at a temperature ranging from about 20 to 75°C.

[0191] In other embodiments, storage in a sealed container is at a temperature ranging from about 2-8°C.

[0192] In other embodiments, storage in a sealed container is at a temperature ranging from about 5 to 50°C.

[0193] In yet another embodiment, storage in a sealed container is at a temperature ranging from about 15 to 50°C.

[0194] In another embodiment, storage in a sealed container is in an atmosphere having a relative humidity of about 25-80%.

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

[0196] In some embodiments, the sealed container is a glass vial with a lid.

[0197] In another embodiment, the closed container is a lidded LDPE bottle.

[0198] In other embodiments, the ophthalmic compositions of the present invention contain less than 2.0%, less than 1.5%, less than 1.0%, or less than 0.5% (by HPLC) of total impurities relative to the amount of compound of Formula I after storage in a sealed container stored at a temperature ranging from about 20 to 75°C until at least 2.0%, less than 1.5%, less than 1.0%, or less than 0.5% (by HPLC) of total impurities.

[0199] In other embodiments, the ophthalmic compositions of the present invention contain no more than 2.0%, no more than 1.5%, no more than 1.0%, or no more than 0.5% (by HPLC) of total impurities based on the amount of the compound of Formula I after storage in a sealed container in an atmosphere having a relative humidity of about 25-80% at a temperature ranging from 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.

[0200] In other embodiments, the ophthalmic compositions of the present invention contain no more than 2.0%, no more than 1.5%, no more than 1.0%, or no more than 0.5% (by HPLC) of total impurities based on the amount of the compound of Formula I after storage 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.

[0201] In other embodiments, the ophthalmic compositions of the invention contain no more than 2.0%, no more than 1.5%, no more than 1.0%, or no more than 0.5% (by HPLC) of total impurities based on the amount of the compound of Formula I after storage in a sealed glass vial at a temperature of 25° C. in an atmosphere having 60% relative humidity 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.

[0202] In other embodiments, the ophthalmic compositions of the present invention contain no more than 2.0%, no more than 1.5%, no more than 1.0%, or no more than 0.5% (by HPLC) of total impurities based on the amount of the compound of Formula I after storage in a sealed container at a temperature of 40° C. and in an atmosphere having 75% relative humidity 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.

[0203] In other embodiments, the ophthalmic compositions of the present invention contain no more than 2.0%, no more than 1.5%, no more than 1.0%, or no more than 0.5% (by HPLC) of total impurities, based on the amount of the compound of Formula I, after storage in a sealed glass vial at a temperature of 40° C. in an atmosphere having 75% relative humidity 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.

[0204] In other embodiments, the ophthalmic compositions of the present invention contain no more than 2.0%, no more than 1.5%, no more than 1.0%, or no more than 0.5% (by HPLC) of total impurities based on the amount of the compound of Formula I after storage in a sealed container stored 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 until the commercially acceptable expiration date of the composition.

[0205] In other embodiments, the ophthalmic compositions of the present invention contain no more than 2.0%, no more than 1.5%, no more than 1.0%, or no more than 0.5% (by HPLC) of total impurities, based on the amount of the compound of Formula I, after storage in a sealed LDPE bottle stored at a temperature of 25° C. in an atmosphere having 40% relative humidity 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.

[0206] In other embodiments, the ophthalmic compositions of the present invention contain no more than 2.0%, no more than 1.5%, no more than 1.0%, or no more than 0.5% (by HPLC) of total impurities based on the amount of the compound of Formula I after storage in a sealed container at a temperature of 40° C. and in an atmosphere having 25% relative humidity 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.

[0207] In other embodiments, the ophthalmic compositions of the present invention contain no more than 2.0%, no more than 1.5%, no more than 1.0%, or no more than 0.5% (by HPLC) of total impurities, based on the amount of the compound of Formula I, after storage in a sealed LDPE bottle stored at a temperature of 40° C. in an atmosphere having 25% relative humidity 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.

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

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

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

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

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

[0213] In certain embodiments, the present invention provides an aqueous ophthalmic pharmaceutical composition, comprising an ophthalmic compound having a structure represented by Formula I: [ka] and a compound of formula II in an amount relative to the amount of compound of formula I of 0.5% or less (by HPLC). [ka] The present invention relates to a composition comprising a compound of formula (I).

[0214] In certain embodiments, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and 0.4% or less (by HPLC) of a compound of formula II relative to the amount of the 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.

[0215] In certain embodiments, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and 0.3% or less (by HPLC) of a compound of formula II relative to the amount of the 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.

[0216] In certain embodiments, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and 0.2% or less (by HPLC) of a compound of formula II relative to the amount of the 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.

[0217] In certain embodiments, the present invention relates to an aqueous ophthalmic pharmaceutical composition comprising a compound of formula I and 0.1% or less (by HPLC) of a compound of formula II relative to the amount of the 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 ranging from about 20 to 75°C.

[0219] In other embodiments, storage in a sealed container is at a temperature ranging from about 2-8°C.

[0220] In other embodiments, storage in a sealed container is at a temperature ranging from about 5 to 50°C.

[0221] In yet another embodiment, storage in a sealed container is at a temperature ranging from about 15 to 50°C.

[0222] In another embodiment, storage in a sealed container is in an atmosphere having a relative humidity of about 25-80%.

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

[0224] In some embodiments, the sealed container is a glass vial with a lid.

[0225] In another embodiment, the closed container is a lidded LDPE bottle.

[0226] In certain embodiments, the aqueous ophthalmic pharmaceutical composition contains the compound of formula I and no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II 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.

[0227] In certain embodiments, the aqueous ophthalmic pharmaceutical composition comprises the compound of Formula I and no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of Formula II after storage 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.

[0228] In certain embodiments, the aqueous ophthalmic pharmaceutical composition contains the compound of formula I and no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II after storage 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.

[0229] In certain embodiments, the aqueous ophthalmic pharmaceutical composition contains the compound of formula I and no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II after storage 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 until the commercially acceptable expiration date of the composition.

[0230] In certain embodiments, the aqueous ophthalmic pharmaceutical composition contains the compound of formula I and no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II after storage in a sealed container in an atmosphere having a relative humidity of 75% 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.

[0231] In certain embodiments, the aqueous ophthalmic pharmaceutical composition contains the compound of formula I and no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II after storage 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 until the commercially acceptable expiration date of the composition.

[0232] In certain embodiments, the aqueous ophthalmic pharmaceutical composition contains the compound of formula I and no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II after storage in a sealed container in an atmosphere having a relative humidity of 40% 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.

[0233] In certain embodiments, the aqueous ophthalmic pharmaceutical composition contains the compound of formula I and no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II after storage in a sealed LDPE bottle stored at a temperature of 25° C. in an atmosphere having a relative humidity of 40% 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.

[0234] In certain embodiments, the aqueous ophthalmic pharmaceutical composition contains the compound of formula I and no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of formula II after storage 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 until the commercially acceptable expiration date of the composition.

[0235] In certain embodiments, the aqueous ophthalmic pharmaceutical composition contains no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% (by HPLC) of the compound of Formula II after storage 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.

[0236] In another aspect, the present invention provides a compound of formula I: [ka] and an antioxidant system, wherein the compound of formula II present in the composition is [ka] does not increase by more than 200%, as determined by HPLC, after storage of the composition in a sealed container prior to the commercially acceptable expiration date of the composition.

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

[0238] In certain embodiments, 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 upon storage of the composition in a sealed container prior to the commercially acceptable expiration date of the composition.

[0239] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, as determined 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 until the commercially acceptable expiration date of the composition.

[0240] In other embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, as determined 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 until the commercially acceptable expiration date of the composition.

[0241] In one embodiment, storage in a sealed container is at a temperature ranging from about 20 to 75°C.

[0242] In other embodiments, storage in a sealed container is at a temperature ranging from about 2-8°C.

[0243] In other embodiments, storage in a sealed container is at a temperature ranging from about 5 to 50°C.

[0244] In yet another embodiment, storage in a sealed container is at a temperature ranging from about 15 to 50°C.

[0245] In another embodiment, storage in a sealed container is in an atmosphere having a relative humidity of about 25-80%.

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

[0247] In some embodiments, the sealed container is a glass vial with a lid.

[0248] In another embodiment, the closed container is a lidded LDPE bottle.

[0249] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, upon storage of the composition in a sealed container at a temperature ranging from 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, as determined by HPLC.

[0250] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, upon storage of the composition in a sealed container in an atmosphere having a relative humidity of about 25-80% at a temperature ranging from 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.

[0251] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, upon storage of the composition in a sealed container in an atmosphere having a relative humidity of 60% 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, as determined by HPLC.

[0252] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, upon storage of 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 until the commercially acceptable expiration date of the composition.

[0253] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, upon storage of the composition in a sealed container in an atmosphere having a relative humidity of 75% 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.

[0254] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, upon storage of 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 until the commercially acceptable expiration date of the composition.

[0255] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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 by more than 100% upon storage of the composition in a sealed container stored at a temperature of 25° C. in an atmosphere having a relative humidity of 40% 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, as measured by HPLC.

[0256] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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 does not increase by more than 100%, upon storage of the composition in a sealed glass vial 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 until the commercially acceptable expiration date of the composition, as determined by HPLC.

[0257] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, upon storage of the composition in a sealed container in an atmosphere having a relative humidity of 25% 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, as determined by HPLC.

[0258] In certain embodiments, an aqueous ophthalmic pharmaceutical composition of the 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%, upon storage of the composition in a sealed LDPE bottle at a temperature of 40° C. in an atmosphere having a relative humidity of 25% for at least 6 months, at least 12 months, at least 18 months, at least 24 months, or until before the commercially acceptable expiration date of the composition, as determined by HPLC.

[0259] In one embodiment, the present invention provides a compound of formula I: [ka] and an antioxidant system, wherein the antioxidant system is such that upon storage of the composition in a closed container, a compound of formula II present in the composition relative to the amount of the compound of formula I is present in the composition. [ka] is present in an amount sufficient to maintain the amount of hydroxybenzoates at 0.5% or less (by HPLC).

[0260] In certain embodiments, 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 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 upon storage of the composition in a sealed container.

[0261] In certain embodiments, 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 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 upon storage of the composition in a sealed container.

[0262] In certain embodiments, 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 the compound of formula II present in the composition at 0.2% or less (by HPLC) relative to the amount of the compound of formula I upon storage of the composition in a sealed container.

[0263] In certain embodiments, 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 the compound of formula II present in the composition at 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.

[0264] In certain embodiments, storage is 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.

[0265] In one embodiment, storage in a sealed container is at a temperature ranging from about 20 to 75°C.

[0266] In other embodiments, storage in a sealed container is at a temperature ranging from about 2-8°C.

[0267] In another embodiment, storage in a sealed container is at a temperature ranging from about 5 to 50°C.

[0268] In yet another embodiment, storage in a sealed container is at a temperature ranging from about 15 to 50°C.

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

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

[0271] In some embodiments, the sealed container is a glass vial with a lid.

[0272] In another embodiment, the closed container is a lidded LDPE bottle.

[0273] 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 stored 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 before the commercially acceptable expiration date of the composition.

[0274] 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 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 before the commercially acceptable expiration date of the composition.

[0275] 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 in an atmosphere having a relative humidity of 60% 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 before the commercially acceptable expiration date of the composition.

[0276] 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 glass vial stored at a temperature of 25° C. in an atmosphere having a relative humidity of 60% 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.

[0277] 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 stored at a temperature of 40° C. in an atmosphere having a relative humidity of 75% 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.

[0278] 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 glass vial stored at a temperature of 40° C. in an atmosphere having a relative humidity of 75% 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.

[0279] 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 stored at a temperature of 25° C. in an atmosphere having a relative humidity of 40% 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.

[0280] 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 stored at a temperature of 25° C. in an atmosphere having a relative humidity of 40% 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.

[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 stored at a temperature of 40° C. in an atmosphere having 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.

[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 stored at a temperature of 40° C. in an atmosphere having 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.

[0283] In one embodiment, the aqueous ophthalmic pharmaceutical compositions of the invention are individually packaged in sterile, clear, 30 μL to 50 μL droppers, for example, 40 μL droppers.

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

[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 certain embodiments, the dosage of the aqueous ophthalmic pharmaceutical composition of the present invention is 1 drop per eye per day. [Example]

[0287] The following examples are presented to provide a better understanding of the subject matter described herein. These examples should not be construed as limiting the subject matter described. It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or variations therein will be apparent to those skilled in the art and fall within the scope of the present invention and can be made without departing from it.

[0288] HPLC method : HPLC analysis is performed on an Agilent HPLC system equipped with a UV detector monitoring at 264 nm.

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

[0290] Samples were eluted using a gradient comprising 0–20% eluent B over 13 min, followed by 20–90% eluent B over 27 min, followed by a linear gradient from 90–0% eluent B over 5 min and a 5-min hold at 100% A, with a total run time of 50 min.

[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), prepared by mixing 800 mL of acetonitrile (HPLC grade) with 200 mL of methanol (HPLC grade).

[0293] A blank solution is prepared by mixing 740 mL of DI water and 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 weighing approximately 34.0±3 mg of Formula I standard into a 100 mL volumetric flask, adding approximately 50 mL of ACN to dissolve, sonicating if necessary to dissolve the compound of Formula (I), and then diluting to the mark with ACN.

[0296] A working standard solution of Formula I is prepared by adding 5.0 mL of the standard stock solution to a 25 mL volumetric flask and diluting to the mark with diluent. 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 standard stock solution (Wstd (mg) / 100 mL) by (1) the weight percent purity of the Formula (I) compound standard used to prepare the standard stock solution (purity), (2) the dilution factor of 5 mL / 25 mL, which is the volume of the standard stock solution divided by the volume of the working standard solution, and (3) the μg to mg conversion factor of 1000 μg / mg. This relationship is shown in the following equation:

number

[0297] The reference standard solutions are prepared in the same manner as the working standard solutions.

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

[0299] A 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 to the mark with diluent. The sample solution has a nominal concentration of 68 μg / mL of the compound of Formula (I).

[0300] Sample solution injections are sandwiched between injections of working standard solutions.

[0301] Calculate the % of label statement (where label statement is the concentration at the label in Equation 1) as follows:

number

[0302] Calculate % impurities (wt%) as follows:

number

[0303] % Total Impurities = Sum of % of individual impurities.

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

[0305] These studies demonstrated that Formula I is poorly water soluble (<0.01 mg / mL in water), and of the solvents tested, solubility was highest in polyethylene glycol 400 (14.5 mg / mL), followed by propylene glycol (4.96 mg / mL), castor oil (1.09 mg / mL), 7% Polyoxyl 140 stearate in water (0.62 mg / mL), and 5% Polyoxyl 35 in castor oil (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 Experiments are carried out using various amounts of ascorbyl palmitate and EDTA.

[0308] Polyoxyl 40 stearate is also evaluated as a solubilizer of Formula I [Table 2]

[0309] Accelerated stability data at 50°C shows that in these compositions, the combination of ascorbyl palmitate and EDTA improves the stability of the composition.

[0310] Compositions containing both ascorbyl palmitate (0.02% w / v) and EDTA disodium salt dihydrate (0.25% w / v) in the composition are found to be stable 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) for up to 3 months of the tested period.

[0311] Example 3 Sodium thiosulfate pentahydrate (STS) (i.e., 0.0% to 0.2% w / v) is evaluated along 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%) is found to be stable for up to 3 months of 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 composition 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 a portion of the water used in the composition. The resulting solution is mixed with a solution of water, sodium dihydrogen phosphate monohydrate, disodium phosphate anhydrous, 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 aseptic conditions and sealed. The composition is packaged in a 5 mL, 20 mm, USP Type I, clear glass vial (silica coating) with a 20 mm gray stopper and a 20 mm flip-off seal.

[0314] The composition comprises the following ingredients: [Table 4]

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

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

[0317] In some embodiments, the present invention relates to the following aspects: Aspect 1. (a) in said composition a compound of Formula I in a concentration effective to treat an ocular disease or condition; [ka] or a pharmaceutically acceptable acid addition salt thereof, (b) water; (c) solubilizing agents; (d) cosolvents and (e) An ophthalmic pharmaceutical composition comprising an antioxidant system. Embodiment 2. The ophthalmic composition of embodiment 1, wherein said composition comprises a compound of formula I. Embodiment 3. The ophthalmic composition of embodiment 1, wherein said composition comprises a pharmaceutically acceptable acid addition salt of a compound of formula I. Embodiment 4. The ophthalmic composition of any of the previous embodiments, wherein the solubilizing agent is a surfactant. Embodiment 5. The ophthalmic composition of any of the previous embodiments, wherein the solubilizing agent is a non-ionic surfactant. Embodiment 6. The ophthalmic composition of any of the previous embodiments, wherein the solubilizing agent is a polyoxyethylene fatty ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, polyoxyl hydroxystearate, poloxamer, povidone, or a combination thereof. Aspect 7. The solubilizing agent 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 ... 10. The ophthalmic composition of any of the preceding aspects, wherein the hydroxypropyl hydroxypropyl ester is selected from the group consisting of 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 solubilizing agent is polyoxyl 35 castor oil, polyoxyl 40 stearate, or a combination thereof. Embodiment 9. The ophthalmic composition of embodiment 8, wherein the solubilizing agent is polyoxyl 35 castor oil. Embodiment 10. The ophthalmic composition of embodiment 8, wherein the solubilizing agent is polyoxyl 40 stearate. Embodiment 11. The ophthalmic composition of any of the previous embodiments, wherein the co-solvent is a water-miscible organic solvent. Embodiment 12. The ophthalmic composition of any of the previous embodiments, wherein the co-solvent is one or more of propylene glycol, polyethylene glycol, glycerin, ethanol, or benzyl alcohol. Embodiment 13 The ophthalmic composition of embodiment 12, wherein the polyethylene glycol is one or more of PEG-400, PEG-300, PEG-4000, or PEG-8000. Embodiment 14. The ophthalmic composition of any of the previous embodiments, wherein the co-solvent is one or more of propylene glycol or PEG-400. Embodiment 15 The ophthalmic composition of embodiment 14, wherein the co-solvent is propylene glycol. Embodiment 16 The ophthalmic composition of embodiment 14, wherein the co-solvent is PEG-400. Embodiment 17. The ophthalmic composition of any of the previous embodiments, wherein the antioxidant system comprises one or more of sodium bisulfite, sodium metabisulfite, sodium thiosulfate or a hydrate thereof, sodium sulfite, sodium sulfate, ascorbyl palmitate, ethylenediaminetetraacetic acid (EDTA) or a salt thereof, citric acid or a salt thereof, or ascorbic acid or a salt thereof. Embodiment 18 The ophthalmic composition of embodiment 17, wherein the antioxidant system comprises EDTA. Embodiment 19. The ophthalmic composition of embodiment 17, wherein the antioxidant system comprises sodium thiosulfate pentahydrate. Embodiment 20 The ophthalmic composition of embodiment 17, wherein the antioxidant system comprises ascorbyl palmitate. Embodiment 21 The ophthalmic composition of embodiment 17, wherein the antioxidant system comprises ascorbyl palmitate and EDTA disodium salt or a hydrate thereof. Embodiment 22 The ophthalmic composition of embodiment 17, wherein the antioxidant system comprises sodium thiosulfate pentahydrate and EDTA disodium salt or a hydrate thereof. Aspect 23 The ophthalmic composition of any of the previous aspects, further comprising a tonicity agent. Embodiment 24 The ophthalmic composition of embodiment 23, wherein the tonicity agent is sodium chloride, potassium chloride, dextrose, mannitol, or glycerin. Embodiment 25 The ophthalmic composition of embodiment 24, wherein the tonicity agent is sodium chloride. Aspect 26. The ophthalmic composition of any of the previous aspects, further comprising a viscosity increasing agent. Embodiment 27. The ophthalmic composition of embodiment 26, wherein the viscosity increasing agent is hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC) (5 cps, 4000 cps, 15000 cps); hypromellose, methylcellulose, sodium carboxymethylcellulose (CMC) (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. Embodiment 28 The ophthalmic composition of embodiment 27, wherein the viscosity increasing agent is sodium carboxymethylcellulose (CMC). Embodiment 29. The ophthalmic composition of any of the previous embodiments, further comprising a buffering agent. Embodiment 30 The ophthalmic composition of embodiment 29, wherein the buffer is a phosphate buffer, a citrate buffer, an acetate buffer, or a borate buffer. Embodiment 31 The ophthalmic composition of embodiment 30, wherein the buffer 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. The ophthalmic composition of any of the previous embodiments, wherein the composition has a pH in the range of 4.0 to 8.0. Embodiment 34. The ophthalmic composition of embodiment 33, wherein the composition has a pH in the range of 6.5 to 7.5. Embodiment 35. The ophthalmic composition of any of the previous embodiments, wherein the composition has an osmotic pressure in the range of 200 to 600 (mOsm / kg). Embodiment 36. The ophthalmic composition of embodiment 35, wherein the composition has an osmotic pressure in the range of 250 to 350 (mOsm / kg). Embodiment 37. The ophthalmic composition of any of the previous embodiments, wherein the compound of Formula (I) or a pharmaceutically acceptable acid addition salt thereof is present in a concentration of 0.005 to 0.1% (w / v) based on the compound of Formula I. Embodiment 38. The ophthalmic composition of any of the previous embodiments, wherein the antioxidant system is present in a concentration of 0.01 to 0.6% (w / v). Embodiment 39 The ophthalmic composition of any of the previous embodiments, wherein the composition contains 0.2% or less (by HPLC) of any single impurity relative to the compound of Formula I 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. Embodiment 40. The ophthalmic pharmaceutical composition of embodiment 39, wherein the composition contains 0.2% or less (by HPLC) of any single impurity relative to the compound of Formula I after storage in a sealed container until the commercially acceptable expiration date of the composition. Embodiment 41. The ophthalmic pharmaceutical composition of embodiment 40, wherein the storage temperature is in the range of about 20 to 75°C in a sealed container. Embodiment 42. The ophthalmic pharmaceutical composition of embodiment 40 or embodiment 41, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%. Embodiment 43. The ophthalmic pharmaceutical composition of any one of Embodiments 40 to 42, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C. Embodiment 44. The ophthalmic pharmaceutical composition of any one of Embodiments 40 to 43, wherein the sealed container is a glass vial with a lid. Embodiment 45. The ophthalmic pharmaceutical composition of any one of Embodiments 40 to 43, wherein the sealed container is an LDPE bottle with a lid. Embodiment 46. The composition contains no more than 0.5%, preferably no more than 0.2% (by HPLC) of the compound of Formula II relative to the compound of Formula I 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. [ka] 2. The ophthalmic composition of any of the previous aspects, comprising a compound of formula (I). Embodiment 47. The ophthalmic pharmaceutical composition of embodiment 46, wherein the composition 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 after storage in a sealed container until the commercially acceptable expiration date of the composition. Embodiment 48. The ophthalmic pharmaceutical composition of embodiment 47, wherein the storage temperature is in the range of about 20 to 75°C in a sealed container. Embodiment 49. The ophthalmic pharmaceutical composition of embodiment 47 or embodiment 48, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%. Embodiment 50. The ophthalmic pharmaceutical composition of any one of embodiments 47 to 49, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C. Embodiment 51. The ophthalmic pharmaceutical composition of any one of Embodiments 47 to 50, wherein the sealed container is a glass vial with a lid. Embodiment 52. The ophthalmic pharmaceutical composition of any one of embodiments 47 to 50, wherein the sealed container is an LDPE bottle with a lid. Embodiment 53 The ophthalmic composition of any of the previous embodiments, wherein the composition contains no more than 2.0%, preferably no more than 1.0% (by HPLC) total impurities relative to the compound of Formula I 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 a commercially acceptable expiration date for the composition. Embodiment 54. The ophthalmic pharmaceutical composition of embodiment 53, wherein the composition contains 2.0% or less, preferably 1.0% or less (by HPLC) total impurities relative to the compound of Formula I after storage in a sealed container until the commercially acceptable expiration date of the composition. Embodiment 55. The ophthalmic pharmaceutical composition of embodiment 54, wherein the storage temperature is in the range of about 20 to 75°C in a sealed container. Embodiment 56. The ophthalmic pharmaceutical composition of embodiment 54 or embodiment 55, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%. Embodiment 57. The ophthalmic pharmaceutical composition of any one of embodiments 54 to 56, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C. Embodiment 58. The ophthalmic pharmaceutical composition of any one of Embodiments 54 to 57, wherein the sealed container is a glass vial with a lid. Embodiment 59. The ophthalmic pharmaceutical composition of any one of embodiments 54 to 57, wherein the sealed container is an LDPE bottle with a lid. Embodiment 60. A composition comprising a compound of Formula I: [ka] and a relative amount of not more than 0.5%, preferably not more than 0.2% (by HPLC) of the compound of formula II to the compound of formula I. [ka] An aqueous ophthalmic composition comprising the compound of formula (I). Embodiment 61. The aqueous ophthalmic composition of embodiment 60, wherein 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 after storage in a sealed container until before the commercially acceptable expiration date of the composition. Embodiment 62. The aqueous ophthalmic composition of embodiment 61, wherein the storage is in a sealed container at a temperature ranging from about 20 to 75°C. Embodiment 63. The aqueous ophthalmic composition of embodiment 61 or embodiment 62, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%. Embodiment 64. The aqueous ophthalmic composition of any of Embodiments 61 to 63, wherein the aqueous ophthalmic composition is stored in a sealed container in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C. Embodiment 65. The aqueous ophthalmic composition of any one of Embodiments 61 to 64, wherein the sealed container is a glass vial with a lid. Embodiment 66. The aqueous ophthalmic composition of any one of Embodiments 61 to 64, wherein the sealed container is an LDPE bottle with a lid. Aspect 67. Formula I: [ka] and an antioxidant system, wherein the compound of formula II present in the composition [ka] does not increase by more than 200% as 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 a commercially acceptable expiration date for the composition. Embodiment 68 The aqueous ophthalmic composition of embodiment 67, wherein the storage of the composition in a sealed container is prior to the commercially acceptable expiration date of the composition. Embodiment 69 The aqueous ophthalmic composition of embodiment 67 or embodiment 68, wherein storage of the composition in a sealed container is at a temperature in the range of about 20 to 75°C. Embodiment 70. The aqueous ophthalmic composition of any of Embodiments 67 to 69, wherein storage of the composition in a sealed container is in an atmosphere having a relative humidity of about 25 to 80%. Embodiment 71. The aqueous ophthalmic composition of any of embodiments 67 to 70, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C. Embodiment 72. The ophthalmic pharmaceutical composition of any one of embodiments 67 to 71, wherein the sealed container is a glass vial with a lid. Embodiment 73. The ophthalmic pharmaceutical composition of any one of embodiments 67 to 71, wherein the sealed container is an LDPE bottle with a lid. Embodiment 74. Formula I: [ka] and an antioxidant system, wherein the antioxidant system provides a 100% to 150% aqueous ophthalmic composition containing a compound of formula II present in the composition relative to the amount of the compound of formula I 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 a commercially acceptable expiration date for the composition. [ka] is present in an amount sufficient to maintain the amount of compound (I) below 0.5%, preferably below 0.2% (by HPLC). Embodiment 75. The aqueous ophthalmic composition of embodiment 74, wherein the storage of the composition in a sealed container is prior to the commercially acceptable expiration date of the composition. Embodiment 76 The aqueous ophthalmic composition of embodiment 74 or embodiment 75, wherein storage of the composition in a sealed container is at a temperature in the range of about 20 to 75°C. Embodiment 77. The aqueous ophthalmic composition of any of Embodiments 74 to 76, wherein storage of the composition in a sealed container is in an atmosphere having a relative humidity of about 25 to 80%. Embodiment 78. The aqueous ophthalmic composition of any of embodiments 74 to 77, wherein the aqueous ophthalmic composition is stored in a sealed container in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C. Embodiment 79. The ophthalmic pharmaceutical composition of any one of Embodiments 74 to 78, wherein the sealed container is a glass vial with a lid. Embodiment 80. The ophthalmic pharmaceutical composition of any one of embodiments 74 to 78, wherein the sealed container is an LDPE bottle with a lid. Aspect 81. The ophthalmic pharmaceutical composition of any one of Aspects 39 to 80, wherein the value by HPLC is determined by HPLC area %. Aspect 82. The ophthalmic pharmaceutical composition of any one of Aspects 39 to 80, wherein the value by HPLC is by HPLC weight %.

Claims

1. (a) a compound of Formula I at a concentration effective to treat an ocular disease or condition; 【Chemical 1】 or a pharmaceutically acceptable acid addition salt thereof, (b) water; (c) a solubilizing agent; (d) co-solvents and (e) Antioxidant system 1. An ophthalmic pharmaceutical composition comprising:

2. 2. The ophthalmic pharmaceutical composition of claim 1, wherein said composition comprises a compound of Formula I.

3. 2. The ophthalmic pharmaceutical composition of claim 1, wherein said composition comprises a pharmaceutically acceptable acid addition salt of a compound of Formula I.

4. The ophthalmic pharmaceutical composition of claim 1 , wherein the solubilizing agent is a surfactant.

5. 5. The ophthalmic pharmaceutical composition of claim 4, wherein the solubilizing agent is a non-ionic surfactant.

6. 2. The ophthalmic pharmaceutical composition of claim 1, wherein the solubilizing agent is a polyoxyethylene fatty ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, polyoxyl hydroxystearate, poloxamer, povidone, or a combination thereof.

7. The solubilizing agent may be 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, The ophthalmic pharmaceutical composition of claim 1, 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.

8. 8. The ophthalmic pharmaceutical composition of claim 7, wherein the solubilizer is polyoxyl 35 castor oil, polyoxyl 40 stearate, or a combination thereof.

9. 9. The ophthalmic pharmaceutical composition of claim 8, wherein the solubilizing agent is polyoxyl 35 castor oil.

10. 9. The ophthalmic pharmaceutical composition of claim 8, wherein the solubilizing agent is polyoxyl 40 stearate.

11. 2. The ophthalmic pharmaceutical composition of claim 1, wherein the co-solvent is a water-soluble organic solvent.

12. 2. The ophthalmic pharmaceutical composition of claim 1, wherein the co-solvent is one or more of propylene glycol, polyethylene glycol, glycerin, ethanol, or benzyl alcohol.

13. 13. The ophthalmic pharmaceutical composition of claim 12, wherein the polyethylene glycol is one or more of PEG-400, PEG-300, PEG-4000, or PEG-8000.

14. 2. The ophthalmic pharmaceutical composition of claim 1, wherein the co-solvent is one or more of propylene glycol or PEG-400.

15. 15. The ophthalmic pharmaceutical composition of claim 14, wherein the co-solvent is propylene glycol.

16. 15. The ophthalmic pharmaceutical composition of claim 14, wherein the co-solvent is PEG-400.

17. 2. The ophthalmic pharmaceutical composition of claim 1, wherein the antioxidant system comprises one or more of 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.

18. 18. The ophthalmic pharmaceutical composition of claim 17, wherein the antioxidant system comprises EDTA.

19. 18. The ophthalmic pharmaceutical composition of claim 17, wherein the antioxidant system comprises sodium thiosulfate pentahydrate.

20. 18. The ophthalmic pharmaceutical composition of claim 17, wherein the antioxidant system comprises ascorbyl palmitate.

21. 18. The ophthalmic pharmaceutical composition of claim 17, wherein the antioxidant system comprises ascorbyl palmitate and EDTA disodium salt or a hydrate thereof.

22. 18. The ophthalmic pharmaceutical composition of claim 17, wherein the antioxidant system comprises sodium thiosulfate pentahydrate and EDTA disodium salt or a hydrate thereof.

23. The ophthalmic pharmaceutical composition of claim 1, further comprising a tonicity agent.

24. 24. The ophthalmic composition of claim 23, wherein the tonicity agent is sodium chloride, potassium chloride, dextrose, mannitol, or glycerin.

25. 25. The ophthalmic pharmaceutical composition of claim 24, wherein the tonicity agent is sodium chloride.

26. The ophthalmic pharmaceutical composition of claim 1 further comprising a viscosity increasing agent.

27. The ophthalmic pharmaceutical composition of claim 26, wherein the viscosity increasing agent is hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC) (5 cps, 4000 cps, 15000 cps); hypromellose, methylcellulose, sodium carboxymethylcellulose (CMC) (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.

28. 28. The ophthalmic pharmaceutical composition of claim 27, wherein the viscosity increasing agent is sodium carboxymethylcellulose (CMC).

29. The ophthalmic pharmaceutical composition of claim 1 , further comprising a buffering agent.

30. 30. The ophthalmic pharmaceutical composition of claim 29, wherein the buffer is a phosphate buffer, a citrate buffer, an acetate buffer, or a borate buffer.

31. 31. The ophthalmic pharmaceutical composition of claim 30, wherein the buffer is a phosphate buffer.

32. 32. The ophthalmic pharmaceutical composition of claim 31, wherein the phosphate buffer comprises sodium dihydrogen phosphate and disodium phosphate.

33. 33. The ophthalmic pharmaceutical composition of any of claims 1 to 32, wherein the composition has a pH in the range of 4.0 to 8.

0.

34. 34. The ophthalmic pharmaceutical composition of claim 33, wherein the composition has a pH in the range of 6.5 to 7.

5.

35. 33. The ophthalmic pharmaceutical composition of any one of claims 1 to 32, wherein the composition has an osmotic pressure in the range of 200 to 600 (mOsm / kg).

36. 36. The ophthalmic pharmaceutical composition of claim 35, wherein the composition has an osmolality in the range of 250 to 350 (mOsm / kg).

37. 33. The ophthalmic pharmaceutical composition of any one of claims 1 to 32, wherein the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof is present in a concentration of 0.005 to 0.1% (w / v) based on the compound of formula I.

38. 33. The ophthalmic pharmaceutical composition of any one of claims 1 to 32, wherein the antioxidant system is present in a concentration of 0.01 to 0.6% (w / v).

39. 33. The ophthalmic pharmaceutical composition of any of claims 1 to 32, wherein the composition contains 0.2% or less (by HPLC) of any single impurity relative to the compound of Formula I 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.

40. 40. The ophthalmic pharmaceutical composition of claim 39, wherein the composition contains 0.2% or less (by HPLC) of any single impurity relative to the compound of formula I after storage in a sealed container until before the commercially acceptable expiration date of the composition.

41. 41. The ophthalmic pharmaceutical composition of claim 40, wherein the composition is stored in a sealed container at a temperature ranging from about 20 to 75°C.

42. 42. The ophthalmic pharmaceutical composition of claim 40 or claim 41, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%.

43. 42. The ophthalmic pharmaceutical composition of claim 40 or 41, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C.

44. 44. The ophthalmic pharmaceutical composition of claim 43, wherein the sealed container is a glass vial with a lid.

45. 44. The ophthalmic pharmaceutical composition of claim 43, wherein the sealed container is a lidded LDPE bottle.

46. The composition contains no more than 0.5%, preferably no more than 0.2% (by HPLC) of a compound of formula II relative to a compound of formula I 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. 【Chemistry 2】 33. The ophthalmic pharmaceutical composition of any one of claims 1 to 32, comprising a compound of formula (I):

47. 47. The ophthalmic pharmaceutical composition of claim 46, wherein the composition contains no more than 0.5%, preferably no more than 0.2% (by HPLC) of the compound of formula II relative to the compound of formula I after storage in a sealed container until before the commercially acceptable expiration date of the composition.

48. 48. The ophthalmic pharmaceutical composition of claim 47, wherein the composition is stored in a sealed container at a temperature ranging from about 20 to 75°C.

49. 49. The ophthalmic pharmaceutical composition of claim 47 or claim 48, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%.

50. 49. The ophthalmic pharmaceutical composition of claim 47 or claim 48, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C.

51. 51. The ophthalmic pharmaceutical composition of claim 50, wherein the sealed container is a glass vial with a lid.

52. 51. The ophthalmic pharmaceutical composition of claim 50, wherein the sealed container is a lidded LDPE bottle.

53. 33. The ophthalmic pharmaceutical composition of any of claims 1 to 32, wherein the composition contains no more than 2.0%, preferably no more than 1.0% (by HPLC) total impurities relative to the compound of formula I 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.

54. 54. The ophthalmic pharmaceutical composition of claim 53, wherein the composition contains less than 2.0%, preferably less than 1.0% (by HPLC) of total impurities relative to the compound of formula I after storage in a sealed container until before the commercially acceptable expiration date of the composition.

55. 55. The ophthalmic pharmaceutical composition of claim 54, wherein the storage temperature is in the range of about 20 to 75°C in a sealed container.

56. 56. The ophthalmic pharmaceutical composition of claim 54 or claim 55, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%.

57. 56. The ophthalmic pharmaceutical composition of claim 54 or 55, wherein the storage in a sealed container is in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C.

58. 58. The ophthalmic pharmaceutical composition of claim 57, wherein the sealed container is a glass vial with a lid.

59. 58. The ophthalmic pharmaceutical composition of claim 57, wherein the sealed container is a lidded LDPE bottle.

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, a compound of Formula I: 【Chemistry 3】 and a relative amount of not more than 0.5%, preferably not more than 0.2% (by HPLC) of the compound of formula II to the compound of formula I. 【Chemistry 4】 10. An ophthalmic pharmaceutical composition comprising a compound of formula (I).

61. 61. The ophthalmic pharmaceutical composition of claim 60, wherein 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 after storage in a sealed container until before the commercially acceptable expiration date of the composition.

62. 62. The ophthalmic pharmaceutical composition of claim 61, wherein the composition is stored in a sealed container at a temperature ranging from about 20 to 75°C.

63. 63. The ophthalmic pharmaceutical composition of claim 61 or claim 62, wherein the composition is stored in a sealed container in an atmosphere having a relative humidity of about 25 to 80%.

64. 63. The ophthalmic pharmaceutical composition of claim 61 or 62, wherein the storage in a sealed container is in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C.

65. 65. The ophthalmic pharmaceutical composition of claim 64, wherein the sealed container is a glass vial with a lid.

66. 65. The ophthalmic pharmaceutical composition of claim 64, wherein the sealed container is a lidded LDPE bottle.

67. Formula I: 【Chemistry 5】 and an antioxidant system, wherein the compound of formula II present in the composition 【Chemistry 6】 does not increase by more than 200% as determined by HPLC 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 a commercially acceptable expiration date for the composition.

68. 68. The ophthalmic pharmaceutical composition of claim 67, wherein the storage of the composition in a sealed container is prior to the commercially acceptable expiration date of the composition.

69. 69. The ophthalmic pharmaceutical composition of claim 67 or claim 68, wherein storage of the composition in a sealed container is at a temperature in the range of about 20 to 75°C.

70. 69. The ophthalmic pharmaceutical composition of claim 67 or claim 68, wherein storage of the composition in a sealed container is in an atmosphere having a relative humidity of about 25 to 80%.

71. The ophthalmic pharmaceutical composition of claim 67 or claim 68, wherein the storage in a sealed container is in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C.

72. 72. The ophthalmic pharmaceutical composition of claim 71, wherein the sealed container is a glass vial with a lid.

73. 72. The ophthalmic pharmaceutical composition of claim 71, wherein the sealed container is a lidded LDPE bottle.

74. Formula I: 【Chemistry 7】 and an antioxidant system, wherein the antioxidant system provides a 500mg / mL or greater amount of a compound of formula II present in the composition relative to the amount of the compound of formula I 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 a commercially acceptable expiration date for the composition. 【Chemistry 8】 is present in an amount sufficient to maintain the amount of compound of formula (I) below 0.5%, preferably below 0.2% (by HPLC).

75. 75. The ophthalmic pharmaceutical composition of claim 74, wherein the storage of the composition in a sealed container is prior to the commercially acceptable expiration date of the composition.

76. 76. The ophthalmic pharmaceutical composition of claim 74 or claim 75, wherein storage of the composition in a sealed container is at a temperature in the range of about 20 to 75°C.

77. 76. The ophthalmic pharmaceutical composition of claim 74 or claim 75, wherein storage of the composition in a sealed container is in an atmosphere having a relative humidity of about 25 to 80%.

78. 76. The ophthalmic pharmaceutical composition of claim 74 or claim 75, wherein the storage in a sealed container is in an atmosphere having a relative humidity of 60% at a temperature of 25°C; or an atmosphere having a relative humidity of 75% at a temperature of 40°C; or an atmosphere having a relative humidity of 40% at a temperature of 25°C; or an atmosphere having a relative humidity of 25% at a temperature of 40°C.

79. 79. The ophthalmic pharmaceutical composition of claim 78, wherein the sealed container is a glass vial with a lid.

80. 79. The ophthalmic pharmaceutical composition of claim 78, wherein the sealed container is a lidded LDPE bottle.

81. 75. The ophthalmic pharmaceutical composition of claim 60, 67 or 74, wherein the HPLC analysis is by HPLC area %.

82. 75. The ophthalmic pharmaceutical composition of claim 60, 67 or 74, wherein the HPLC analysis is by HPLC weight percent.

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