Ophthalmic preparations containing N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate

Abstract

The present invention relates to N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate [Formula 1] TIFF2023519312000058.tif47169 The present invention relates to an ophthalmic formulation comprising polyethylene glycol and artificial tears, and a method for preparing the ophthalmic formulation.

Description

Detailed Description of the Invention

[0001] The present invention relates to an ophthalmic formulation comprising N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, polyethylene glycol, and artificial tears, and a method for preparing the ophthalmic formulation.

[0002] [Background of the invention] The synthesis of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is known from WO 01 / 47904 A1 and the use of an acidic component including methanesulfonic acid for tablet formulations for the treatment of herpes simplex infections. The tablets contain micronized N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, as disclosed by WO 2006 / 103011 A1.

[0003] The applicant's prior invention, disclosed in WO 2018 / 095576 A1, relates to a topical pharmaceutical formulation for the treatment or prevention of herpes virus infections, comprising N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide. In one embodiment, the pharmaceutical formulation is applicable to the eye, and in another embodiment, the pharmaceutical formulation comprising plitelivir hemihydrate is suitable for the treatment of herpes keratitis. The topical pharmaceutical formulation in WO 2018 / 095576 A1 comprises a plitelivir agent (e.g., plitelivir hemihydrate), at least one solvent such as PEG, and at least one antioxidant, and has a pH of 2.0 to 8.0, preferably 4.0 to 5.0, and more preferably 4.0 to 4.5.

[0004] WO 2018 / 095576 A1 also discloses formulations as gels containing a gelling agent such as hydroxypropyl methylcellulose (hypromellose). A typical formulation in WO 2018 / 095576 A1 contains 5% by weight of a plitelivir agent such as plitelivir hemihydrate, 39.1% by weight of SR PEG 400, 9.59% by weight of ethanol, 4.8% by weight of pH-4 buffer, 23.98% by weight of Transcutol HP, 14.39% by weight of dimethyl isosorbide, 1.92% by weight of benzyl alcohol, and 1.25% by weight of hydroxypropyl methylcellulose, where the pH of the formulation is in the range of 4.0 to 5.0.

[0005] Herpes infections can also occur in the eye, and in cases where ocular herpes affects only the outermost part of the eye, antiviral eye drops containing antiviral agents such as acyclovir can be used for treatment. However, there are known cases of ocular herpes in which the herpes virus is resistant to available antiviral herpes medications.

[0006] N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide is known to be an effective antiviral herpes agent, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide can be administered even when resistance of the herpes virus to other available antiviral herpes agents is observed.

[0007] It is therefore an object of the present invention to provide an ophthalmic formulation comprising the compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, thus capable of treating drug-resistant herpes infections in the eye.

[0008] The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description and the examples of the present application.

[0009] [Description of the Invention] The present invention provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears, wherein the artificial tears comprise glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; The present invention relates to an ophthalmic formulation comprising or consisting of:

[0010] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic formulation comprising:

[0011] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears consisting of glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising:

[0012] The compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is also known by the International Nonproprietary Name (INN) as plitelivir.

[0013] The compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is also named herein as "pritelivir free base hemihydrate," or simply "pritelivir hemihydrate." The term "free base" in the name "pritelivir free base hemihydrate" indicates that the use of the free base is essential to the invention and that salts of the compound plitelivir will not be used under the conditions disclosed herein for the preparation of ophthalmic formulations.

[0014] Priterivir free base hemihydrate has the following chemical structure:

[0015] [ka] It has.

[0016] Several salts of pritelivir are known, such as the mesylate or maleate salt of pritelivir. However, during the course of developing the novel ophthalmic formulations described herein that contain pritelivir, it surprisingly became apparent that it was not possible to provide ophthalmic formulations based on the tested salts of pritelivir under experimental conditions suitable for providing the ophthalmic formulations described herein that contain pritelivir free base hemihydrate as the drug substance (DS).

[0017] Furthermore, observations made during the development of the novel ophthalmic formulations described herein suggest that salt formation of plitelivir should be avoided during preparation of the ophthalmic formulations. Consequently, the present application is directed to ophthalmic formulations that are free of plitelivir salts and that are useful for treating ophthalmic herpes infections, particularly those that have developed resistance to common antiviral herpes medications.

[0018] PEG: polyethylene glycol One of the essential ingredients in the present ophthalmic formulations is polyethylene glycol, abbreviated as PEG.

[0019] Although numerous solvents and components were investigated in compatibility and solubility studies, unexpectedly, only PEG was found to be suitable and acceptable for ophthalmic formulations of plitelivir free base hemihydrate.

[0020] Polyethylene glycol has the following chemical structure:

[0021] [ka]

[0022] In the formula, n represents the number of repeating units. The chemical formula is C 2n H 4n+2 O n+1 and the density is 1.125 g / mL. Other IUPAC names for PEG are poly(oxyethylene), or poly(ethylene oxide). PEG is also known under the trademarks Carbowax™, Kollisolv®, Kolliphor®, Polyglycol™, and the Ph.Eur. (European Pharmacopoeia) name Macrogol.

[0023] A number of different polyethylene glycols are known, for example, PEG200, PEG300, PEG400, PEG600, PEG1000, PEG1500, PEG2000, PEG3000, PEG4000, PEG6000, PEG8000, etc.

[0024] The number in the name of PEG indicates the average molecular weight of the PEG, for example, a PEG with n=9 has an average molecular weight of about 400 daltons and is usually referred to as PEG 400. Most PEGs contain molecules with a distribution of molecular weights, i.e., they are polydisperse.

[0025] The size distribution can be statistically characterized by the weight average molecular weight (Mw) and the number average molecular weight (Mn), the ratio of which is called the polydispersity index (Mw / Mn). Mw and Mn can be measured by mass spectrometry.

[0026] Polyethylene glycols having an average molecular weight in the range of 200 g / mol to 400 g / mol have been found to be suitable for the present ophthalmic formulations. The use of PEG 400 is particularly preferred for the present ophthalmic formulations.

[0027] However, it is also possible to use mixtures of PEGs for ophthalmic formulations. PEGs with average molecular weights ranging from 200 g / mol to 400 g / mol are non-volatile liquids at room temperature.

[0028] As used throughout this application, the terms "within the range of 'value A' to 'value B'" and "amount between 'value A' and 'value B'" refer to a continuous group of possible values, where 'value A' represents the lower end of the group and 'value B' represents the upper end of the group. The lower and upper end values ​​are included in the group of possible values. For example, PEG having an average molecular weight in the range of 200 g / mol to 400 g / mol includes PEG having an average molecular weight of 200 g / mol and PEG having an average molecular weight of 400 g / mol, as well as PEGs having average molecular weights in between.

[0029] As used herein, the term "room temperature" is synonymous with the term "normal room temperature" and refers to a temperature in the range of 19° C. to 26° C. For example, PEG that is a "non-volatile liquid at room temperature" means that the PEG is a non-volatile liquid "at temperatures in the range of 19° C. to 26° C."

[0030] Thus, it is also in accordance with the present invention to use mixtures of two, three, or more PEGs in ophthalmic formulations, such as mixtures of PEG300 and PEG400, or mixtures of PEG200 and PEG400, or mixtures of PEG200, PEG300, and PEG400, etc.

[0031] The average molecular weight of all mixtures of PEG used in the present ophthalmic formulations should be in the range of 200 g / mol to 400 g / mol, preferably in the range of 300 g / mol to 400 g / mol, more preferably in the range of 350 g / mol to 400 g / mol, and most preferably about 400 g / mol.

[0032] Therefore, the present application also provides: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears, wherein the artificial tears comprise glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; The present invention relates to an ophthalmic formulation comprising or consisting of:

[0033] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic formulation comprising:

[0034] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising:

[0035] Preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears, wherein the artificial tears comprise glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of:

[0036] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic formulation comprising:

[0037] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate. The present invention relates to an ophthalmic preparation comprising:

[0038] The PEG or mixture of PEGs used in the ophthalmic formulations of the present application is involved in the solubility of plitelivir free base hemihydrate; i.e., without the use of PEG or mixture of PEGs, the desired amount of plitelivir free base hemihydrate cannot be dissolved in the ophthalmic formulation, and precipitation occurs, reducing the amount of active pharmaceutical ingredient (i.e., plitelivir free base hemihydrate) in the ophthalmic formulation; therefore, it is not possible to prepare an ophthalmic formulation having a specified amount of active pharmaceutical ingredient.

[0039] Furthermore, the PEG or mixture of PEGs used in the present ophthalmic formulations contributes to the viscosity of the ophthalmic formulation, and therefore, the PEG or mixture of PEGs is preferably selected so that the viscosity of the ophthalmic formulation is within the range of 25 cps to 50 cps.

[0040] In addition to the PEG or PEG mixture used in the ophthalmic formulation of the present application, the choice of artificial tears also affects the viscosity of the ophthalmic formulation. Considering that artificial tears are usually the main component of ophthalmic formulations, the viscosity of the ophthalmic formulation of the present application is basically the same as that of the artificial tears. However, the PEG or PEG mixture present in the ophthalmic formulation can change the viscosity of the artificial tears solution, and therefore the ophthalmic formulation preferably has a viscosity that is the same as or at most 20% different from that of the artificial tears.

[0041] This means that if the artificial tears have a viscosity of, for example, 40 cps, the ophthalmic formulations of the present application preferably have a viscosity in the range of 32 cps to 48 cps, and more preferably have a viscosity close to 40 cps.

[0042] Generally, the ophthalmic formulations of the present invention should have a viscosity in the range of 10 cps to 100 cps, preferably in the range of 15 cps to 80 cps, more preferably in the range of 20 cps to 60 cps, even more preferably in the range of 25 cps to 50 cps, and even more preferably in the range of 30 cps to 40 cps.

[0043] Many everyday fluids have viscosities between 0.5 cP and 1000 cP. For example, water has a viscosity of 1 cP. Tears have viscosities ranging from 1.0 cP to 6.0 cP. Ophthalmic formulations with viscosities up to 20 cP are well tolerated. However, ophthalmic formulations with viscosities between 25 cP and 50 cP are preferred to ensure long enough retention in the eye, usually resulting in only an increase in tear flow and blinking reflexes in the treated eye.

[0044] The viscosity of a solution is expressed in poises. Poise is the unit of dynamic viscosity (i.e., absolute viscosity). The unit centipoise (cp or plural cps) is equal to 0.01 poise. The SI unit for viscosity is the Pascal second (Pa*s), which is Newton seconds per square meter (N*s*m -2 ) is equivalent to

[0045]

number

[0046] Thus, viscosity enhancing agents can be added to the ophthalmic formulations of the present invention to achieve the desired viscosity. Suitable viscosity enhancing agents are hydroxyethyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, methylcellulose, and polyvinylpyrrolidone. Viscosity enhancing agents should not be used in ophthalmic formulations in amounts greater than 1.0% by weight.

[0047] Therefore, the present application also a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; The present invention relates to an ophthalmic preparation comprising or consisting of Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp.

[0048] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp.

[0049] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate. The present invention relates to an ophthalmic preparation comprising: Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp.

[0050] Preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) Artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone An ophthalmic formulation comprising or consisting of Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp.

[0051] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp.

[0052] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate. The present invention relates to an ophthalmic preparation comprising: Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp.

[0053] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp.

[0054] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp.

[0055] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp.

[0056] The pH value of the ophthalmic formulations herein should be in the range of 4.0 to 8.5, preferably in the range of 4.2 to 8.0, more preferably in the range of 4.5 to 7.5, even more preferably in the range of 5.0 to 7.0, even more preferably in the range of 5.5 to 6.5, and even more preferably in the range of 5.7 to 6.3.

[0057] Although tears have a physiological pH value of about 7.4, the experiments set forth herein demonstrated that pH values ​​below 7.0 are more beneficial than pH values ​​above pH 7.0.

[0058] Preferably, the pH value of the ophthalmic formulation is adjusted by the addition of an aqueous solution of hydrochloride, preferably 0.1 M HCl. aq It is adjusted by adding a solution. For pH adjustment, hydrochloric acid or hydrobromic acid is preferred, and particularly preferred is hydrochloric acid.

[0059] The use of acidic solutions of acids that tend to form salts, especially sparingly soluble or insoluble salts, should be avoided. Acids to be avoided include, for example, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, do-tolyltartaric acid, tartronic acid, (o,m,p)-toluic acid, naphthylaminesulfonic acid, trifluoroacetic acid, and the like.

[0060] Therefore, the present application also provides: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; The present invention relates to an ophthalmic preparation comprising or consisting of The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0061] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0062] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0063] Preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) Artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone An ophthalmic formulation comprising or consisting of The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0064] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0065] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0066] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0067] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0068] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0069] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp and a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0070] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp and a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0071] The present invention also provides: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: Here, the ophthalmic formulation has a viscosity in the range of 25 cp to 50 cp and a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0072] Artificial tears Artificial tears are also known as tear substitutes that are used to thin or replace tears, and therefore, artificial tears are used in ophthalmic formulations due to their compatibility with the eye.

[0073] Artificial tears that can be used for the ophthalmic formulations of the present application include, for example, Thera® Tears, GenTeal® Tears, Visine® Tears, Lac-Ophtal MP, Protagent®, Vidisept® EDO, WET-Comodo®, Berberil® Dry Eye, Berberil® Dry Eye EDO, Artelac®, Yxin®, and others. Teras®, Hylo-Comod®, Hyabak®, Artelac® splash MDO / EDO, Vislube, Bepanthen eye drops (+ dexpanthenol), Opticalm eye drops (+ hypromellose), etc.

[0074] Artificial tears can be purchased as a ready-to-use solution or can be prepared from commonly used and readily available materials. Common ingredients in artificial tears include glycerin, hypromellose, and polyethylene glycol as lubricants, plus typically from ten to all of the following substances: carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and / or sodium lactate, all of which are dissolved in purified water.

[0075] Based on the experiments performed and disclosed herein, Visine® Tears or equivalent artificial tears are preferred artificial tears for ophthalmic formulations.

[0076] Visine® tears contain 0.2% by weight glycerin, 0.2% by weight hypromellose, and 1% by weight PEG 400. In addition to these lubricants, the following substances are present in Visine® tears: carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate. Artificial tears equivalent to Visine® tears contain substantially the same ingredients. However, artificial tears may lack one or more of the aforementioned ingredients or may further contain one or more pharmaceutically acceptable ingredients, so long as they exhibit substantially the same properties as Visine® tears. Artificial tears equivalent to Visine® tears may contain different amounts of some or all of the aforementioned components, so long as they exhibit substantially the same properties as Visine® tears. As used herein, the term "substantially the same properties" refers to the physicochemical properties of a particular formulation that are acceptable for use as artificial tears. For example, artificial tears having substantially the same properties as Visine® tears have a pH that differs by no more than 5% from that of Visine® tears, a viscosity that differs by no more than 5% from that of Visine® tears, and / or a density that differs by no more than 10% from that of Visine® tears.

[0077] Further disclosed herein is a method for producing a medicament for use in a pharmaceutical composition comprising: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears, An ophthalmic formulation comprising or consisting of:

[0078] Further disclosed herein is a method for producing a medicament for use in a pharmaceutical composition comprising: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears, An ophthalmic formulation comprising or consisting of:

[0079] Further disclosed herein is a method for producing a medicament for use in a pharmaceutical composition comprising: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears, An ophthalmic formulation comprising or consisting of:

[0080] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) Visine® tears; An ophthalmic formulation comprising or consisting of:

[0081] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) Visine® tears; An ophthalmic formulation comprising or consisting of:

[0082] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) Visine® tears; An ophthalmic formulation comprising or consisting of:

[0083] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) Visine® tears; An ophthalmic formulation comprising or consisting of The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0084] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) Visine® tears; An ophthalmic formulation comprising or consisting of The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0085] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) Visine® tears; An ophthalmic formulation comprising or consisting of The ophthalmic formulation herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0086] With respect to the ophthalmic formulations of the present application, polyethylene glycol is preferably present in the ophthalmic formulation in an amount of from 20 μg per ml to 100 μg per ml of ophthalmic formulation, more preferably from 30 μg per ml to 90 μg per ml of ophthalmic formulation, more preferably from 35 μg per ml to 80 μg per ml of ophthalmic formulation, more preferably from 40 μg per ml to 70 μg per ml of ophthalmic formulation, even more preferably from 45 μg per ml to 65 μg per ml of ophthalmic formulation, and even more preferably from 50 μg per ml to 60 μg per ml of ophthalmic formulation.

[0087] Therefore, the present application also a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; The present invention relates to an ophthalmic preparation comprising or consisting of Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0088] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0089] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0090] All embodiments of the ophthalmic formulations of the present invention disclosed herein comprise glycerin, hypromellose (also known as hydroxypropyl methylcellulose), polyethylene glycol 400, and water as a solvent, and preferably one, more preferably two, more preferably three, more preferably four, even more preferably five, even more preferably six, even more preferably seven, even more preferably eight, even more preferably nine, even more preferably ten, even more preferably eleven, even more preferably twelve, even more preferably thirteen, even more preferably fourteen, even more preferably fifteen, even more preferably sixteen, even more preferably seventeen, or most preferably all eighteen compounds selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0091] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) Artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone An ophthalmic formulation comprising or consisting of Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0092] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0093] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0094] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0095] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0096] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0097] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) Visine® tears; An ophthalmic formulation comprising or consisting of Here, polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 70 μg per ml of the ophthalmic formulation.

[0098] In all embodiments disclosed herein, the amount of polyethylene glycol when explicitly stated, such as in the 10 embodiments disclosed above, refers to the total amount of polyethylene glycol present in the formulation, and the total amount of polyethylene glycol present in the formulation is the cumulative amount of polyethylene glycol in steps b) and c). When different polyethylene glycols are used in steps b) and c), such as PEG 200 in step b) and PEG 400 in step c), the stated amount of polyethylene glycol refers to the amount of PEG in step b) plus the amount of PEG in step c).

[0099] With respect to the ophthalmic formulations of the present application, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is preferably present in the ophthalmic formulation in an amount of from 20 μg per ml to 100 μg per ml of the ophthalmic formulation, more preferably from 25 μg per ml to 90 μg per ml of the ophthalmic formulation, more preferably from 30 μg per ml to 80 μg per ml of the ophthalmic formulation, more preferably from 35 μg per ml to 70 μg per ml of the ophthalmic formulation, even more preferably from 40 μg per ml to 65 μg per ml of the ophthalmic formulation, and even more preferably from 45 μg per ml to 55 μg per ml of the ophthalmic formulation.

[0100] Therefore, the present application also provides: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; The present invention relates to an ophthalmic preparation comprising or consisting of wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0101] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0102] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0103] Even more preferably: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) Artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone An ophthalmic formulation comprising or consisting of wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0104] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0105] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0106] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0107] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0108] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0109] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) Visine® tears; An ophthalmic formulation comprising or consisting of wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

[0110] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0111] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0112] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0113] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) Artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone An ophthalmic formulation comprising or consisting of wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0114] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0115] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0116] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0117] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0118] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0119] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) Visine® tears; An ophthalmic formulation comprising or consisting of wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, and the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation.

[0120] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0121] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0122] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0123] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) Artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone An ophthalmic formulation comprising or consisting of wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0124] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0125] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0126] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0127] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0128] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0129] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) Visine® tears; An ophthalmic formulation comprising or consisting of wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is included in the ophthalmic formulation in an amount of 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably a pH value in the range of 5.5 to 6.5.

[0130] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of wherein the polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0131] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and wherein the polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0132] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein the polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0133] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of wherein the polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0134] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and wherein the polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0135] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200, PEG300, PEG400, or a mixture of two or more of these PEGs, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0136] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; An ophthalmic formulation comprising or consisting of wherein the polyethylene glycol is present in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0137] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; and wherein the polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0138] The present invention also provides a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, and b) PEG200 and / or PEG400, preferably PEG400, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The present invention relates to an ophthalmic preparation comprising: wherein the polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0139] More preferably, a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) Visine® Tears An ophthalmic formulation comprising or consisting of wherein the polyethylene glycol is contained in the ophthalmic formulation in an amount of 40 μg per ml to 70 μg per ml of the ophthalmic formulation, the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic formulation in an amount of 40 μg per ml to 60 μg per ml of the ophthalmic formulation, and the ophthalmic formulation has a pH value in the range of 5.0 to 7.0, preferably 5.5 to 6.5.

[0140] With respect to the ophthalmic formulations of the present application, the artificial tears are preferably present in the ophthalmic formulation in an amount of from 0.5 g per ml to 1.7 g per ml of the ophthalmic formulation, more preferably from 0.6 g per ml to 1.6 g per ml of the ophthalmic formulation, more preferably from 0.7 g per ml to 1.5 g per ml of the ophthalmic formulation, even more preferably from 0.8 g per ml to 1.4 g per ml of the ophthalmic formulation, even more preferably from 0.9 g per ml to 1.3 g per ml of the ophthalmic formulation, and even more preferably from 1.0 g per ml to 1.2 g per ml of the ophthalmic formulation.

[0141] The ophthalmic preparations of the present application are used for the prevention and / or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses.

[0142] Preferably, the ophthalmic formulations of the present application are used for the prevention and / or treatment of herpes simplex infections of the eye, particularly ocular herpes (ie, keratitis). Thus, in some preferred embodiments, the present application provides a method for the prevention and / or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses. a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; The disease caused by the herpes simplex virus is preferably a herpes simplex infection of the eye, particularly ocular herpes (i.e., keratitis).

[0143] The present invention also relates to a method for the prevention and / or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses. a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The disease caused by the herpes simplex virus is preferably a herpes simplex infection of the eye, particularly ocular herpes (i.e., keratitis).

[0144] The present invention also relates to a method for the prevention and / or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses. a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; The disease caused by the herpes simplex virus is preferably a herpes simplex infection of the eye, particularly ocular herpes (i.e., keratitis).

[0145] As a result, an aspect of the present application is the use of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate in the prevention and / or treatment of diseases caused by herpes simplex viruses and / or the prevention of herpes virus or herpes virus transmission. N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is preferably administered as an ophthalmic formulation disclosed herein. Preferably, one to five drops of the ophthalmic formulation disclosed herein are administered two or three times daily.

[0146] As used herein, the terms "prevent," "preventing," "prevention," or "prophylaxis" refer to the absence of a disorder or disease if nothing occurs, or the absence of further onset of a disorder or disease if onset of a disorder or disease has already occurred. Also considered is the ability of the ophthalmic formulations disclosed herein to prevent some or all of the symptoms associated with a disorder or disease. Disease prevention refers to prophylaxis, and disease prophylaxis refers to the prevention of a disease. Thus, the terms "prophylaxis" and "prevention" are used interchangeably throughout this application.

[0147] The present ophthalmic formulations can also be used with or in combination with an additional antiviral agent, such as an antimetabolite, and preferably a nucleobase analog, nucleotide analog, or nucleoside analog drug, that is useful against herpes viruses and / or against the transmission of herpes viruses and is selected from drugs including, but not limited to, acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acyclovir, penciclovir, or their respective prodrugs valacyclovir, valganciclovir, or famciclovir.

[0148] Another aspect of the invention is directed to a method for the prevention or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses, comprising: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; to a patient in need of such treatment. Preferably, the disease caused by herpes simplex virus is herpes simplex infection of the eye, particularly ocular herpes (i.e., keratitis).

[0149] Another aspect of the invention is directed to a method for the prevention or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses, comprising: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; to a patient in need of such treatment. Preferably, the disease caused by herpes simplex virus is herpes simplex infection of the eye, particularly ocular herpes (i.e., keratitis).

[0150] Another aspect of the invention is directed to a method for the prevention or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses, comprising: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; to a patient in need of said treatment. Preferably, the disease caused by herpes simplex virus is herpes simplex infection of the eye, particularly ocular herpes (i.e., keratitis).

[0151] The method can also be used with or in combination with an additional antiviral agent, such as an antimetabolite, and preferably a nucleobase analog, nucleotide analog, or nucleoside analog drug. Preferably, the additional antiviral agent is useful against herpes viruses and / or against herpes viruses or the transmission of herpes viruses, and is preferably selected from the group of drugs including, but not limited to, acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acyclovir, penciclovir, or the respective prodrugs valacyclovir, valganciclovir, or famciclovir.

[0152] Accordingly, an embodiment of the present application is a method for preventing or treating a disease caused by herpes simplex virus and / or preventing the transmission of herpes virus or herpes viruses, comprising administering an effective amount of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate to a patient in need thereof. N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is preferably administered as an ophthalmic formulation disclosed herein. Preferably, one to five drops of the ophthalmic formulation disclosed herein are administered two or three times daily.

[0153] N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate can also be administered together with an antiviral agent, such as an antimetabolite, and preferably a nucleobase analog, nucleotide analog, or nucleoside analog drug. Preferably, the drug is acetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acyclovir, penciclovir, valacyclovir, valganciclovir, or famciclovir. The additional drug is contained in the same ophthalmic formulation or in an additional ophthalmic formulation, which is administered simultaneously or within a specific time interval with respect to the administration of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate.

[0154] Another aspect of the invention is directed to the use of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate for the preparation of an ophthalmic formulation for the prevention and / or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses, the ophthalmic formulation comprising a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; Preferably, the disease caused by herpes simplex virus is an ocular herpes simplex infection, particularly ocular herpes (i.e., keratitis).

[0155] Another aspect of the invention is directed to the use of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate for the preparation of an ophthalmic formulation for the prevention and / or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses, the ophthalmic formulation comprising a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears containing glycerin, hypromellose, polyethylene glycol 400, carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; Preferably, the disease caused by herpes simplex virus is an ocular herpes simplex infection, particularly ocular herpes (i.e., keratitis).

[0156] Another aspect of the invention is directed to the use of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate for the preparation of an ophthalmic formulation for the prevention and / or treatment of diseases caused by herpes simplex viruses and / or for the prevention of herpes viruses or the transmission of herpes viruses, the ophthalmic formulation comprising a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol, and c) artificial tears comprising glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; Preferably, the disease caused by herpes simplex virus is an ocular herpes simplex infection, particularly ocular herpes (i.e., keratitis).

[0157] As mentioned in the introduction, the applicant's earlier invention disclosed in WO2018 / 095576A1 can be considered the closest prior art disclosing topical pharmaceutical preparations for the treatment or prevention of herpes virus infections. These topical preparations comprise N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, at least one solvent, such as PEG, and at least one antioxidant, and have a pH value of 2.0 to 8.0, preferably 4.0 to 5.0, more preferably 4.0 to 4.5.

[0158] However, WO2018 / 095576A1 does not disclose an ophthalmic formulation of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate (priterivir free base hemihydrate), PEG (polyethylene glycol), and artificial tears, which contain glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone.

[0159] During development of the ophthalmic formulations disclosed herein, it was discovered that plitelivir free base hemihydrate is unstable and precipitates at pH 4.0 in most artificial tears. Worse yet, it was discovered that precipitation increases with increasing pH. Consequently, it is an object of the present invention to develop an artificial tear of plitelivir, wherein plitelivir is stable at a pH of 6.0 to 7.0, the optimal and required pH range for ocular application.

[0160] Surprisingly, it has been found that plitelivir hemihydrate as a plitelivir agent is sufficiently stable at pH values ​​between 6.0 and 7.0 in ophthalmic formulations containing glycerin, hypromellose, and polyethylene glycol 400. This ophthalmic formulation is neither disclosed nor suggested by the state of the art, including WO 2018 / 095576 A1. This composition in an ophthalmic formulation not only prevents precipitation of plitelivir hemihydrate at pH 4.0 (see Example 7) but also at pH 6.0 to 7.0 (see Example 8), which is required for formulations used on and in the eye. Furthermore, it has been found that any commercially available artificial tears cannot be used. It is essential that the artificial tears or commercially available artificial tears contain glycerin, hypromellose, and polyethylene glycol 400. Preferably, additional components can be present in the artificial tears. The component is at least one compound, preferably five, more preferably ten, and even more preferably fifteen compounds from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0161] With regard to the plitelivir drug, it has surprisingly been found that plitelivir hemihydrate cannot be replaced by plitelivir mesylate or plitelivir maleate due to insolubility and precipitation problems.

[0162] These findings regarding the components of pritelivir and artificial tears are not even suggested by the state of the art literature, including WO2018 / 095576A1, and therefore the ophthalmic formulations disclosed herein are not obvious and are not suggested by the state of the art.

[0163] Therefore, starting from the gel formulation disclosed in WO2018 / 095576A1, a person skilled in the art would have to recognize that hemihydrate plitelivir must be selected from a list of known plitelivir formulations, such as plitelivir free base, hemihydrate, mesylate, sulfate, maleate, etc. Furthermore, the pH value of the gel must be adjusted to a pH value between 6.0 and 7.0. Here, a person skilled in the art would have to recognize that polyethylene glycol 400 is important, that hydroxypropyl cellulose must be replaced by hypromellose, and finally, that glycerin must be added to the ophthalmic formulation. As a result, a person skilled in the art would have to recognize multiple non-obvious steps to arrive at the ophthalmic formulation disclosed herein, starting from WO2018 / 095576A1 as the closest prior art.

[0164] A further aspect of the present application relates to a method for preparing an ophthalmic formulation, wherein the method comprises the steps of: I) providing N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate; II) providing polyethylene glycol; III) providing an artificial tear solution comprising glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; IV) preparing a stock solution of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate in polyethylene glycol; V) diluting the stock solution with artificial tears until the desired concentration is achieved; VI) adjusting the pH value to the desired pH value by adding an aqueous solution of an acid; VII) Sterile filtration using a suitable sterilizing filter to obtain an ophthalmic preparation; Includes.

[0165] The method preferably includes at least one step of adjusting the pH to a desired pH value, preferably in the range of 5.5 to 6.5. The ophthalmic solution can be adjusted to the desired pH value before or after sterile filtration. However, all pH ranges disclosed herein will be equally acceptable for preparing ophthalmic formulations.

[0166] Ophthalmic formulations should be stored at temperatures ranging from 2°C to 8°C, but can be stored at room temperature without deterioration. N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate is used in this method in the amounts and concentrations disclosed above.

[0167] The same applies to other components, such as polyethylene glycol and artificial tears, both of which are used in the amounts and concentrations disclosed above. In the methods described herein, the use of PEG 400 and Visine® tears as artificial tears is preferred.

[0168] The formulation is sterilized by filtration through a sterile / aseptic filter to produce a sterile formulation. Sterile filtration may be performed at any convenient temperature, such as room temperature. Sterile filtration is preferably through a filter having a pore size of 0.20 μm or less.

[0169] Sterile filter materials include, but are not limited to, polyvinylidene fluoride (PVDF), polypropylene (PE), polyphenylene oxide, polytetrafluoroethylene (PTFE), ethylene-tetrafluoroethylene copolymer, polysulfone, polyethersulfone (PES), polyacetate (PA) / nylon, PA-LE / nylon, polyethersulfone, cellulose acetate (CA), and regenerated cellulose (RC).

[0170] However, it has become clear that the sterile filtration step is critical and can only be performed using a specific type of sterile filter, namely an RC filter.

[0171] Regenerated cellulose (RC) is a class of material produced by converting natural cellulose to a soluble cellulose derivative and subsequent regeneration, usually forming either fibers (by polymer spinning) or films (by polymer casting). RC sterilizing filters are hydrophilic membrane filters. The RC sterilizing filters have a thickness ranging from 10 μm to 500 μm, preferably 50 μm to 400 μm, more preferably 100 μm to 300 μm, and most preferably 150 μm to 200 μm. RC sterilizing filters have a flow rate of 10 mL / min*cm at 25°C and 0.7 bar. 2 or more, preferably 15mL / min*cm 2 It has a flow rate of more than 1000kJ / s.

[0172] RC sterile filters were purchased from CZT (Klaus Trott Chromatographie-Zubehor, Kriftel, Germany; product number 802527020).

[0173] The RC sterilizing filter had a pore size of 0.2 μm and was connected via a Luer Lok. The specifications of the RC sterilizing filters are summarized below:

[0174] [Table 1]

[0175] Consequently, the present application relates to a method for preparing an ophthalmic formulation, wherein the method comprises the following steps: I) providing N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate; II) providing polyethylene glycol; III) providing an artificial tear solution comprising glycerin, hypromellose, and polyethylene glycol 400, and optionally povidone; IV) preparing a stock solution of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate in polyethylene glycol; V) diluting the stock solution with artificial tears until the desired concentration is achieved; VI) adjusting the pH value to the desired pH value by adding an aqueous solution of an acid; and VII) Sterile filtration using an RC sterilizing filter to obtain an ophthalmic preparation; Includes. DETAILED DESCRIPTION OF THE INVENTION

[0176] [Example] 1. List of Abbreviations

[0177] [Table 2]

[0178] 2.Material

[0179] [Table 3] TIFF0007798784000007.tif62170

[0180] 3. Equipment

[0181] [Table 4]

[0182] 4.Analyzer

[0183] [Table 5]

[0184] 5. HPLC Analysis Preparation Protocol 5.1 Quantification 5.1.1 Preparation of eluent · Add 10 mL of HAc to 990 mL of water and mix it. Add 495 mL of methanol to 495 mL of ACN and 10 mL of HAc and mix it.

[0185] 5.2 Sample preparation Ophthalmic formulation concentration = 0.05 mg AIC090093 / mL Related Impurities Dilute 500 μL of each sample with 500 μL of ACN / MeOH / H2O 25:25:50 + 1% HAc (1:2). Mix it by vortexing for 5 seconds. final concentration Dilute 250 μL of each sample with 730 μL of ACN / MeOH / HO 25:25:50 + 1% HAc and add 20 μL of ACN / DMSO 4:1 (1:4). Mix it by vortexing for 5 seconds.

[0186] 5.3 Calibration stock solution 10mg / ml AIC090093 Weigh out AIC090093 and dissolve it in 10 mL of DMSO. Mix it by vortexing for 15 minutes.

[0187] [Table 6]

[0188] 5.4 Vehicle solution Mix PEG200 and GenTeal tears. Mix it by vortexing for 15 minutes.

[0189] [Table 7]

[0190] 5.5 Calibration, Qualification, and Analytical Working Standard Preparation

[0191] [Table 8]

[0192] 5.6 HPLC Diluent · 20 μl of calibration or QC solution is diluted with 730 μl of ACN / MeOH / H2O 25:25:50 + 1% HAc and 250 μL of the corresponding vehicle solution (1:50) is added.

[0193] [Table 9]

[0194] 5.7 HPLC-DAD Measurement

[0195] [Table 10] PAL Sampler

[0196] [Table 11] PAL method information PAL Cycle Parameters

[0197] [Table 12] DAD method

[0198] [Table 13] Analog Output 1

[0199] [Table 14] Analog Output 2

[0200] [Table 15] signal Signal Table

[0201] [Table 16] Preparation method

[0202] [Table 17] automatic balancing

[0203] [Table 18] Spectrum

[0204] [Table 19] Downtime

[0205] [Table 20] Post Time

[0206] [Table 21] Column Comp. Method

[0207] [Table 22] Left temperature control

[0208] [Table 23] Effective analysis temperature

[0209] [Table 24] Right Temperature Control

[0210] [Table 25] Effective analysis temperature

[0211] [Table 26] Downtime

[0212] [Table 27] Post Time

[0213] [Table 28] Binary Pump Method

[0214] [Table 29] Solvent Composition

[0215] [Table 30] Timetable

[0216] [Table 31] Stroke A

[0217] [Table 32] Stroke B

[0218] [Table 33] Downtime

[0219] [Table 34] Post Time

[0220] [Table 35] external contact

[0221] [Table 36] method characteristics

[0222] [Table 37]

[0223] 6. Preparation of Ophthalmic Formulations Chemicals and Materials: Priterivir free base hemihydrate was synthesized by Carbogen Amics.

[0224] Priterivil maleate was synthesized by Carbogen Amics. Priterivir mesylate monohydrate was synthesized by Carbogen Amics.

[0225] Polyethylene glycol 200 (Polyglycol 200) was obtained from Clariant. Polyethylene glycol 400 (Kollisolv 400) was purchased from BASF.

[0226] GenTeal® tears were obtained from Alcon. Thera® Tears were obtained from Akron Consumer Health.

[0227] Visine® tears were obtained from Johnson & Johnson Healthcare.

[0228] Preparatory experiment The following experiments describe the preparation of several different ophthalmic formulations using different drug substances (DS). As used herein, the term pritelivir hemihydrate refers to pritelivir free base hemihydrate and N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate. As used herein, the term pritelivir maleate refers to N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide maleate, and the term pritelivir mesylate monohydrate refers to N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mesylate monohydrate.

[0229] Example 1 To prepare novel ophthalmic formulations, it is necessary to determine the concentration of the active ingredient in both i) the stock solution and ii) the drug product administered to patients. To this end, stock solutions with different concentrations of pritelivir free base hemihydrate in PEG 200 were diluted with GenTeal® tears and examined for precipitation over time.

[0230] [Table 38]

[0231] Preparation of stock solutions All liquids and DS were equilibrated to above 20°C. Seven 10 mL tubes were provided. In each of these tubes, 5 ml of PEG200 was added and the required amount of DS was dissolved in solution to provide the following stock solutions: 30 mg / mL, 25 mg / mL, 20 mg / mL, 10 mg / mL, 5 mg / mL, 1 mg / mL, 0.05 mg / mL. The solutions were mixed by vortexing the tubes for 5 seconds and the tubes were shaken until the DS was dissolved.

[0232] Preparation of ophthalmic formulations The stock solution was diluted with GenTeal® tear fluid and the pH was measured, after which the samples were inspected for precipitation by visual inspection.

[0233] An ophthalmic formulation with a drug load of 24 mg / mL was obtained without any visually detectable precipitate. Example 2 Stock solutions with a DS concentration of 1.0 mg / mL were prepared in PEG 200 and PEG 400 to study in-use stability over a 5-week period at room temperature (RT) and temperatures ranging from 2°C to 8°C. The different stock solutions were diluted with artificial tears of three different compositions to a final concentration of 0.05 mg DS per mL of ophthalmic preparation.

[0234] [Table 39]

[0235] Preparation of 1 mg / mL stock solution All liquids and DS were equilibrated to above 20°C. A 10 ml volume of each PEG (either PEG 200 or PEG 400) was added to a 50 mL tube, and 10 mg of DS was dissolved in each tube. The solution was mixed by vortexing the tube for 5 seconds, and the tube was shaken until the DS was dissolved.

[0236] Preparation of 0.05 mg / mL ophthalmic formulation A 1.5 mL volume of the stock solution was diluted with 28.5 mL of the respective artificial tears (either GenTeal®, Thera®, or Visine®) in a beaker and stirred for 2 minutes using a magnetic stirrer. The pH was measured, and samples were taken before and after sterile filtration. The solution was filtered through a CA (cellulose acetate) 0.22 μm filter system. The contents of the beaker were collected, and 14 mL of the prepared formulation was added to each of two empty 50 mL tubes. In addition, one empty 2 mL tube was provided, and 1.5 mL of the prepared formulation was added to the 2 mL tube. The samples were stored at room temperature and at temperatures ranging from 2°C to 8°C for 5 weeks.

[0237] The pH value of the ophthalmic formulations was observed to depend on the artificial tears used, with the pH value of the artificial tears varying between 7.5 and 8.5. However, it was very surprising to find that after sterile filtration of the ophthalmic formulations, DS could no longer be detected by HPLC for all prepared formulations.

[0238] Example 3 To determine filter compatibility, a stock solution of 1.0 mg pritelivir free base hemihydrate per mL of stock solution in PEG200 was diluted with GenTeal® tear solution to a concentration of 0.05 mg pritelivir free base hemihydrate per ophthalmic formulation.

[0239] The ophthalmic formulations were filtered using different filter materials and pore sizes.

[0240] [Table 40]

[0241] Preparation of 1 mg / mL DS stock solution All liquids and DS were equilibrated to above 20°C. A 10 ml volume of PEG200 was added to a 50 mL tube and 10 mg of DS was dissolved in the tube. The solution was mixed by vortexing the tube for 5 seconds and the tube was shaken until the DS was dissolved.

[0242] Preparation of 0.05 mg / mL DS for ophthalmic use A 4.0 mL volume of stock solution was diluted with 76.0 mL of GenTeal® tear solution and mixed by vortexing for 5 seconds with stirring for 2 minutes until the DS was dissolved.

[0243] Filter testing for all syringe filters (e.g. PA 0.2 μm) The test was repeated once, and samples were prepared in duplicate (n=2). A 6 mL volume of the ophthalmic formulation was drawn using a 10 mL syringe. A 1 mL volume was used to measure the final concentration before filtration. The syringe was connected to a PA 0.2 μm filter via a Luer Lok, and the solution was filtered. Another sample was taken to measure the final concentration after filtration.

[0244] The filter was then removed from the syringe, and a 3 mL amount of DMSO was removed using a used 10 mL syringe. The syringe was then gently shaken. A 1 mL amount was used to measure the final concentration after rinsing. The syringe was reconnected to a used PA 0.2 μm filter via a Luer Lok, and the DMSO was filtered. A sample was taken to measure the final concentration after rinsing.

[0245] This protocol was repeated for all tested filters: PA / Nylon, PALE / Nylon, PTFE, PVDF, CM, CA, RC, PP, PES. Each filter contained filter material with pore sizes of 0.2 μm and 0.45 μm.

[0246] Surprisingly, only two filters were identified as suitable for the sterile filtration of ophthalmic formulations: the analytical data before and after filtration for the filter materials PFTE 0.2 μm and RC 0.2 μm showed identical values.

[0247] Example 4 To investigate the feasibility of sterile filtration using two grades of PEG and three different compositions of artificial tears, the experiment in Example 3 was repeated, and the same conditions as those in Example 3 were also tested using a stock solution of PEG 400 at a concentration of 1.0 mg of pritelivir free base hemihydrate per mL of stock solution, and two other compositions of commercially available artificial tears.

[0248] [Table 41]

[0249] Preparation of PEG200 stock solution 1 mg / mL DS All liquids and DS were equilibrated to above 20°C. A 10 ml volume of PEG200 was added to a 50 mL tube and 10 mg of DS was dissolved in the tube. The solution was mixed by vortexing the tube for 5 seconds and the tube was shaken until the DS was dissolved.

[0250] Preparation of PEG400 stock solution 1 mg / mL DS All liquids and DS were equilibrated to above 20°C. A 10 ml volume of PEG400 was added to a 50 mL tube and 10 mg of DS was dissolved in the tube. The solution was mixed by vortexing the tube for 5 seconds and the tube was shaken until the DS was dissolved.

[0251] Preparation of 0.05 mg / mL DS for ophthalmic use A 2.0 mL volume of each stock solution was diluted with 38.0 mL of each artificial tear solution (either GenTeal® tears, Thera® tears, or Visine® tears), and the solution was mixed by vortexing for 5 seconds while stirring for 2 minutes.

[0252] Filter testing for all syringe filters The test was repeated with triplicate samples (n=3). A 6 mL volume of the ophthalmic formulation was drawn using a 10 mL syringe. A 1 mL volume was used to measure the final concentration before filtration. The syringe was connected to a filter via a Luer Lok, and the solution was filtered. Another sample was taken to measure the final concentration after filtration.

[0253] The filter was removed from the syringe and a 2 mL volume of DMSO was removed using a fresh 10 mL syringe. The syringe was reconnected to the used filter via a Luer Lok and the DMSO was filtered. A sample was taken to determine the final concentration after washing.

[0254] This protocol was repeated for all tested filters. The following filter materials were tested: PTFE, PVDF, and RC, each with a pore size of 0.2 μm.

[0255] A stock solution of PEG 400 diluted with Thera® tear fluid showed identical results before and after filtration using the filter material PVDF 0.2 μm (syringe filter). For all other formulations, the PVDF filter was not suitable. The PVDF filter was suitable for only one of the six formulations.

[0256] The PFTE filters were suitable for all formulations diluted with GenTeal® and Visine® tears.

[0257] The RC filters were suitable for all formulations, including any artificial tears, and for PEG200 and PEG400 stock solutions. Example 5 To examine the in-use stability of two grades of PEG and three different artificial tear compositions in combination with the use of RC filter materials for sterile filtration over a 5-week period at room temperature (RT) and 2°C to 8°C, stock solutions of pritelivir free base hemihydrate in PEG at a concentration of 1.0 mg / mL were prepared using either PEG 200 or PEG 400. The stock solutions were diluted to a concentration of 0.05 mg / mL with three different artificial tear compositions and filtered through appropriate sterile filters.

[0258] [Table 42]

[0259] Preparation of PEG200 stock solution 1 mg / mL DS All liquids and DS were equilibrated to above 20°C. A 20 ml volume of PEG200 was added to a 50 mL tube and 20 mg of DS was dissolved in the tube. The solution was mixed by vortexing the tube for 5 seconds and the tube was shaken until the DS was dissolved.

[0260] Preparation of PEG400 stock solution 1 mg / mL DS All liquids and DS were equilibrated to above 20°C. A 20 ml volume of PEG400 was added to a 50 mL tube and 20 mg of DS was dissolved in the tube. The solution was mixed by vortexing the tube for 5 seconds and the tube was shaken until the DS was dissolved.

[0261] Preparation of 0.05 mg / mL ophthalmic formulation Each stock solution was diluted with artificial tears in a beaker.

[0262] [Table 43]

[0263] Samples were taken from the top, middle, and bottom of each beaker to determine the final concentration. Sterile filtration A 50 mL amount of the ophthalmic formulation was withdrawn using a 50 mL syringe. The syringe was then connected to each filter via a Luer Lock, and the solution was filtered into a beaker. This step was repeated as needed by using the same filter and the same syringe for the corresponding batch number, and the solution was then refilled into the same beaker. Samples were taken to measure the final concentration after filtration. Three empty 50 mL tubes and one 5 mL tube were provided, and the contents of one beaker were withdrawn. A 15 mL amount of the prepared formulation was added to each of the three empty 50 mL tubes, and 5 mL was added to the empty 5 mL tube. The samples were stored at room temperature and at temperatures ranging from 2°C to 8°C for 5 weeks.

[0264] Only the ophthalmic formulation prepared by using a 1 mg / mL stock solution with PEG200 and diluted with GenTeal® tear solution could be evaluated. In all other formulations, precipitation occurred, which is believed to have occurred before the filtration step using PTFE and RC filters with 0.2 μm pore size, respectively.

[0265] Example 6 To further investigate the stability of the ophthalmic formulation, plitelivir free base hemihydrate was provided as a 1 mg / mL stock solution in PEG 400 and diluted with GenTeal® tear solution.

[0266] [Table 44]

[0267] Preparation of 1 mg / mL stock solution PEG400 All liquids and DS were equilibrated to above 20°C. A 20 ml volume of PEG400 was added to a 50 mL tube and 20 mg of DS was dissolved in the tube. The solution was mixed by vortexing the tube for 5 seconds and the tube was shaken until the DS was dissolved.

[0268] Preparation of 0.05 mg / mL ophthalmic formulation All samples were prepared in 6x. Ophthalmic formulations were prepared in a beaker from a 1 mg / mL plitelivir free base hemihydrate stock solution in PEG 400 and GenTeal® tear solution.

[0269] [Table 45]

[0270] Samples were taken from the top, middle, and bottom of each beaker to determine the final concentration. Sterile filtration The ophthalmic formulation was withdrawn using a 20 mL syringe. The syringe was then connected to a RC 0.2 μm filter via a Luer Lock, and the solution was filtered into the tubing. Samples were taken to measure the final concentration after filtration, and the samples were stored at room temperature and at temperatures ranging from 2°C to 8°C for 5 weeks.

[0271] A total of six samples were prepared sequentially. Each sample took approximately 5 minutes. All formulations showed comparable assays before and after filtration. Therefore, preparation time is a critical process parameter. After one week, samples stored at room temperature showed an increase in impurities. Samples stored at temperatures ranging from 2°C to 8°C were stable over one week.

[0272] Example 7 To investigate the effect of pH on the tendency of ophthalmic formulations to decompose and precipitate, three different compositions of artificial tears were adjusted to pH 4.0, pH 5.0, and pH 6.0. A stock solution of pritelivir free base hemihydrate in PEG 400 was prepared at a concentration of 1.0 mg / mL. The stock solution was diluted with pH-adjusted artificial tears to a pritelivir free base hemihydrate concentration of 0.05 mg / mL and filtered through a RC 0.2 μm sterile filter. It was found preferable to perform the dilution steps for each sample one after the other to keep the time before the filtration step short.

[0273] [Table 46]

[0274] Preparation of 1 mg / mL stock solution PEG400 All liquids and DS were equilibrated to above 20°C. A 40 ml volume of PEG400 was added to a 50 mL tube and 40 mg of DS was dissolved in the tube. The solution was mixed by vortexing the tube for 5 seconds and the tube was shaken until the DS was dissolved.

[0275] Preparation of pH-adjusted artificial tears The following pH values ​​4.0, 5.0 and 6.0 were adjusted by adding various amounts of hydrochloric acid to the artificial tears.

[0276] Preparation of 0.05 mg / mL ophthalmic formulation All samples were prepared in triplicate. To keep preparation time short and minimize the risk of precipitation, samples were prepared one after the other. The stock solution was diluted with pH-adjusted artificial tears in a tube and gently mixed. A sample was taken to measure the final concentration. A 20 mL volume in the tube was removed using a 20 mL syringe. The syringe was then connected to a RC 0.2 mm filter via a Luer Lock, and the solution was filtered in two 10 mL portions into two 50 mL tubes. Another sample was taken to measure the final concentration after filtration.

[0277] [Table 47]

[0278] Samples were stored at room temperature and at temperatures ranging from 2°C to 8°C for 4 weeks. None of the formulations showed a significant change in pH level over the 4-week period. A higher risk of precipitation was observed for formulations with higher pH values. The most stable ophthalmic formulation was Visine® Tears adjusted to a pH of 4. The formulations were stable over 3 weeks of storage at room temperature and at temperatures ranging from 2°C to 8°C.

[0279] Example 8 To determine an ophthalmically acceptable pH value, a stock solution of pritelivir free base hemihydrate in PEG 400 was prepared at a concentration of 1.0 mg / mL. The stock solution was diluted with Visine® tear solution to a concentration of pritelivir free base hemihydrate of 0.05 mg / mL. The ophthalmic formulations were adjusted to pH 6.0, 6.5, and 7.0 and then filtered through a RC 0.2 μm sterile filter.

[0280] [Table 48]

[0281] Preparation of 1 mg / mL stock solution PEG400 All liquids and DS were equilibrated to above 20°C. A 20 ml volume of PEG400 was added to a 50 mL tube and 20 mg of DS was dissolved in the tube. The solution was mixed by vortexing the tube for 5 seconds and the tube was shaken until the DS was dissolved.

[0282] Preliminary test for pH adjustment The stock solution was diluted with Visine® tear fluid in a 50 mL tube and the resulting solution was mixed gently.

[0283] [Table 49]

[0284] Appropriate amounts of hydrochloric acid were added to adjust the pH values ​​to 6.0, 6.5 and 7.0, and the resulting solutions were mixed gently. Preparation of 0.05 mg / mL ophthalmic formulation All samples were prepared in sextuplicate. Samples were prepared one after the other to keep preparation time short and minimize the risk of precipitation. The stock solution was diluted with Visine® tear solution in a 50 mL tube and the resulting solution was mixed gently.

[0285] [Table 50]

[0286] The amount of hydrochloric acid determined in the preliminary test was added to adjust the pH to 6.0, and samples were taken to measure the final concentration before filtration. The entire contents of one tube were removed using a 20 mL syringe. The syringe was then connected to an RC 0.2 μm filter via a Luer Lock, and the solution was filtered into a 50 mL tube. Samples were taken to measure the final concentration after filtration in each tube. Additionally, samples with corresponding pH values ​​of 6.5 and 7.0 were prepared. All samples were stored at room temperature and at temperatures ranging from 2°C to 8°C for 2 weeks.

[0287] A higher risk of precipitation was observed for formulations with higher pH values. The lower the pH value, the better the stability over two weeks. No significant change in pH value was observed for any sample over two weeks. The most stable ophthalmic formulation was the one adjusted to pH 6.0. The formulation was stable at room temperature for one week. The ophthalmic formulation adjusted to pH 6.5 was nearly as stable as the one adjusted to pH 6.0. The ophthalmic formulation adjusted to pH 7.0 showed decreased stability after one week.

[0288] Comparative Example 1 To determine whether plitelivir free base hemihydrate could be replaced by plitelivir mesylate, Example 8 was repeated using plitelivir mesylate monohydrate as the DS.

[0289] [Table 51]

[0290] The preparation protocol of Example 8 was also followed for ophthalmic formulations containing pliterivir mesylate monohydrate as the drug substance. However, surprisingly, plitelivir mesylate monohydrate was found to be insoluble in PEG 400 at a concentration of 1 mg / mL. Precipitation was observed and analytical levels were significantly reduced after filtration.

[0291] Comparative Example 2 To determine whether plitelivir free base hemihydrate could be substituted with plitelivir maleate, Example 8 was repeated using plitelivir maleate as the DS.

[0292] [Table 52]

[0293] However, it surprisingly turned out that it was not possible to prepare a 1 mg / mL stock solution. Conclusion: Of the three tested drug substances, only plitelivir hemihydrate was suitable for preparation of an ophthalmic formulation. Experiments 1-10 above suggest that a suitable ophthalmic formulation is obtained from a 1 mg / mL PEG 400 stock solution diluted with Visine® Tears (also named Visine® Tears) and adjusted to pH 6.0.

[0294] Examples of ophthalmic preparations Formulation 1: Prepared according to Example 8. Stock solution: 1 mg plitelivir free base hemihydrate in 1 ml PEG400. Ophthalmic preparations: 0.4 ml of stock solution and 7.6 ml of Visine® tear solution to obtain 8.0 ml of ophthalmic formulation. The pH was adjusted to 6.0.

[0295] Formulation 2: Prepared according to Example 8. Stock solution: 1 mg plitelivir free base hemihydrate in 1 ml PEG400. Ophthalmic preparations: 0.4 ml of stock solution and 7.6 ml of Visine® tear solution to obtain 8.0 ml of ophthalmic formulation. The pH was adjusted to 6.5.

[0296] Formulation 3: Prepared according to Example 8. Stock solution: 1 mg plitelivir free base hemihydrate in 1 ml PEG400. Ophthalmic preparations: 0.4 ml of stock solution and 7.6 ml of Visine® tear solution to obtain 8.0 ml of ophthalmic formulation. The pH was adjusted to 7.0.

[0297] Formulation 4: Prepared according to Example 5. Stock solution: 1 mg plitelivir free base hemihydrate in 1 ml PEG200. Ophthalmic preparations: 8 ml of stock solution and 152 ml of GenTeal® tear solution to obtain 160.0 ml of ophthalmic formulation, and the pH was adjusted to 6.0.

[0298] Formulation 5: Prepared according to Example 5. Stock solution: 1 mg plitelivir free base hemihydrate in 1 ml PEG200. Ophthalmic preparations: 2.5 ml of stock solution and 47.5 ml of GenTeal® tear solution to obtain 50.0 ml of ophthalmic formulation, and the pH was adjusted to 6.8.

[0299] Formulation 6: Prepared according to Example 4. Stock solution: 1 mg plitelivir free base hemihydrate in a solution with 0.5 ml PEG200 and 0.5 ml PEG400. Ophthalmic preparations: 8 ml of stock solution and 152 ml of Thera® tear solution to obtain 160.0 ml of ophthalmic formulation, and the pH was adjusted to 7.0.

[0300] Formulation 7: Stock solution: 1.5 mg plitelivir free base hemihydrate in 1 ml PEG300. Artificial tears: 2.5 g / L glycerin, 2 g / L hypromellose, and 11.28 g / L polyethylene glycol 400 in purified water with polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and / or sodium lactate.

[0301] Ophthalmic preparations: 1 ml of stock solution and 15 ml of artificial tears to obtain 16.0 ml of ophthalmic formulation. The pH was adjusted to 6.5.

Claims

1. a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate, b) polyethylene glycol 400, and c) artificial tears, wherein the artificial tears contain glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; 1. An ophthalmic formulation comprising: The ophthalmic formulation has a pH value in the range of 6.0 to 7.

0.

2. 10. The ophthalmic formulation of claim 1, wherein the ophthalmic formulation has a viscosity of between 25 cps and 50 cps.

3. 3. The ophthalmic formulation of claim 1 or claim 2, wherein b) polyethylene glycol 400 is present in the ophthalmic formulation in an amount ranging from 40 μg per ml of ophthalmic formulation to 70 μg per ml of ophthalmic formulation.

4. 4. The ophthalmic formulation of any one of claims 1 to 3, wherein the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide hemihydrate is present in the ophthalmic formulation in an amount ranging from 40 μg per ml of the ophthalmic formulation to 60 μg per ml of the ophthalmic formulation.

5. 5. The ophthalmic formulation of claim 1, wherein the artificial tear is present in the ophthalmic formulation in an amount ranging from 0.9 g per ml of ophthalmic formulation to 1.3 g per ml of ophthalmic formulation.

6. 6. The ophthalmic formulation of claim 1, wherein the artificial tears comprise 0.2% by weight glycerin, 0.2% by weight hypromellose, and 1% by weight PEG 400.

7. 10. A method for producing an ophthalmic formulation as defined in claim 1, comprising the steps of: I) providing N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate; II) providing polyethylene glycol 400; III) providing an artificial tear solution, wherein the artificial tear solution comprises glycerin, hypromellose, polyethylene glycol 400, water as a solvent, and at least one compound selected from the group consisting of carboxymethylcellulose, dextran, polysorbate, polyvinyl alcohol, povidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate; IV) preparing a stock solution of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate in polyethylene glycol 400; V) diluting the stock solution with artificial tears until a desired concentration is reached; VI) adjusting the pH value to the range of 6.0 to 7.0 by adding an aqueous solution of acid; VII) sterile filtration using a suitable sterile filter to obtain the ophthalmic formulation; A method comprising:

8. 8. The method of claim 7, wherein the sterile filtration is performed using a regenerated cellulose (RC) 0.2 μm filter.

9. The method described in claim 7 or claim 8, wherein the artificial tear solution comprises 0.2 wt% glycerin, 0.2 wt% hypromellose, and 1 wt% PEG 400.

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