Ophthalmic formulations comprising 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 ophthalmic formulations comprising N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide hemihydrate polyethylene glycol and artificial tear solutions, and to processes for preparing said ophthalmic formulations.

Description

Technical Field

[0001] This invention relates to an ophthalmic formulation comprising N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, polyethylene glycol, and an artificial tear solution, and to a method for preparing said ophthalmic formulation. Background Technology

[0002] The synthesis of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide is known from WO 01 / 47904A1, as well as its use in formulating tablets comprising an acidic component including methanesulfonic acid for the treatment of herpes simplex infection. The tablets contain micronized N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide, as disclosed in WO 2006 / 103011 A1.

[0003] The applicant's prior invention, disclosed in WO 2018 / 095576 A1, relates to a topical pharmaceutical formulation for treating or preventing herpesvirus infection, comprising N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide. In one embodiment, the pharmaceutical formulation is applicable to the eye; and in another embodiment, a pharmaceutical formulation containing pregalivir hemihydrate is suitable for treating herpetic keratitis. The topical pharmaceutical formulation of WO 2018 / 095576 A1 comprises a pregalivir reagent, such as a pregalivir hemihydrate, at least one solvent such as PEG, and at least one antioxidant, and has a pH value 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 a formulation as a gel, which contains a gelling agent such as hydroxypropyl methylcellulose (hydroxypropyl methylcellulose). A typical formulation of WO 2018 / 095576 A1 comprises: 5% by weight of a prepirenylvir reagent such as prepirenylvir hemihydrate, 39.1% by weight of SR PEG 400, 9.59% by weight of ethanol, 4.8% by weight of a pH-4 buffer, 23.98% by weight of Transcutol HP, 14.39% by weight of isosorbide dimethyl ether, 1.92% by weight of benzyl alcohol, and 1.25% by weight of hydroxypropyl methylcellulose, wherein the pH of said formulation is in the range of 4.0 to 5.0.

[0005] Herpes infection can also occur in the eye, and in cases where ocular herpes only affects the outermost layer 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 agents.

[0006] N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]-acetamide is known to be an effective antiviral herpes agent, even when herpesviruses are observed to be resistant to other available antiviral herpes agents. Summary of the Invention

[0007] Therefore, the object of the present invention is to provide an ophthalmic formulation containing the compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide, thereby enabling the treatment of drug-resistant herpes infections of the eye.

[0008] The objective of this invention is achieved through the teachings of the independent claims. Other advantageous features, aspects, and details of the invention become apparent from the dependent claims, description, and embodiments of this application. Invention Details

[0010] This invention relates to ophthalmic formulations that comprise or consist of the following:

[0011] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0012] b) Polyethylene glycol, and

[0013] c) An artificial tear solution, wherein the artificial tear solution contains glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0014] This invention also relates to ophthalmic formulations comprising:

[0015] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0016] b) Polyethylene glycol, and

[0017] c) Artificial tear solution containing glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0018] This invention also relates to ophthalmic formulations comprising the following:

[0019] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0020] b) Polyethylene glycol, and

[0021] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0022] The compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide is also known by the International Nonproprietary Name (INN) Prerivir.

[0023] The compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate is also referred to herein as "prerivir free base hemihydrate" or simply "prerivir hemihydrate". The term "free base" in the name "prerivir free base hemihydrate" should be interpreted as meaning that the use of the free base is essential to the invention and that, under the conditions disclosed herein, salts of the compound prerivir should not be used in the preparation of ophthalmic formulations.

[0024] The free base hemihydrate of prepirenylvir has the following chemical structure:

[0025]

[0026] Several salts of prerelivir, such as prerelivir mesylate or maleate, are known. However, in the development of the novel ophthalmic formulations containing prerelivir as described herein, it was surprisingly found that ophthalmic formulations based on the tested prerelivir salts could not be provided under experimental conditions suitable for providing ophthalmic formulations containing the free base hemihydrate of prerelivir as a drug substance (DS) as described herein.

[0027] Furthermore, observations made during the development of the novel ophthalmic formulation described herein indicate that the formation of prerelivir salts should be avoided during the preparation of the ophthalmic formulation. Therefore, this application relates to an ophthalmic formulation that does not contain prerelivir salts and is intended for the treatment of ophthalmic herpes infections, particularly those that have developed resistance to common antiviral herpes medications.

[0028] PEG: Polyethylene Glycol

[0029] An essential component of the ophthalmic formulation of this application is polyethylene glycol, abbreviated as PEG.

[0030] Numerous solvents and components have been studied in compatibility and solubility studies, but surprisingly, only PEG has been found to be suitable and acceptable for ophthalmic formulations of prepillavir free base hemihydrate.

[0031] Polyethylene glycol has the following chemical structure

[0032]

[0033] Where n indicates the number of repeating units.

[0034] The chemical formula is C 2n H 4n+2 O n+1 And its density is 1.125 g / mL.

[0035] Other IUPAC designations for PEG are poly(ethylene oxide) or poly(ethylene oxide). PEG is also marketed under the trademark Carbowax. TM , Polyglycol TM It is known by Ph.Eur. (European Pharmacopoeia) name: polyethylene glycol (Macrogol).

[0036] Several different polyethylene glycols, such as PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 1500, PEG 2000, PEG 3000, PEG 4000, PEG 6000, and PEG 8000, are known.

[0037] The number in the PEG designation indicates its average molecular weight; for example, a PEG with n=9 has an average molecular weight of approximately 400 Daltons and is usually designated as PEG 400. The vast majority of PEGs comprise molecules with a molecular weight distribution, meaning they are polydisperse.

[0038] Scale distribution can be statistically characterized by its weight-average molecular weight (Mw) and its number-average molecular weight (Mn), and their ratio is called the polydispersity index (Mw / Mn). Mw and Mn can be measured by mass spectrometry.

[0039] It has been found that polyethylene glycol with an average molecular weight in the range of 200 g / mol to 400 g / mol is suitable for the ophthalmic formulations of the present invention. The use of PEG 400 is particularly preferred for the ophthalmic formulations of the present invention.

[0040] However, PEG mixtures may also be used in ophthalmic formulations. PEG with an average molecular weight ranging from 200 g / mol to 400 g / mol is a non-volatile liquid at room temperature.

[0041] The terms "range of 'value A' to 'value B'" and "amount of 'value A' to 'value B'" as used throughout this application 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. Values ​​representing the lower and upper ends 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, PEG having an average molecular weight of 400 g / mol, and PEG having an average molecular weight in between.

[0042] The term "room temperature" as used herein is synonymous with the term "standard room temperature" and refers to a temperature in the range of 19°C to 26°C. For example, "PEG is a non-volatile liquid at room temperature" means that the PEG is a non-volatile liquid "at a temperature in the range of 19°C to 26°C".

[0043] Therefore, according to the present invention, mixtures of two, three or more PEGs are also used in ophthalmic formulations. For example, mixtures of PEG 300 and PEG 400, or mixtures of PEG 200 and PEG 400, or mixtures of PEG 200, PEG 300 and PEG 400, etc.

[0044] The average molecular weight of all PEG mixtures used in the ophthalmic formulations of the present invention 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.

[0045] Therefore, this application also relates to ophthalmic preparations that comprise or consist of the following:

[0046] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0047] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0048] c) An artificial tear solution, wherein the artificial tear solution contains glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0049] This invention also relates to ophthalmic formulations comprising:

[0050] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0051] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0052] c) Artificial tear solution containing glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0053] This invention also relates to ophthalmic formulations comprising the following:

[0054] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0055] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0056] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0057] Preferred are ophthalmic preparations that comprise or consist of the following:

[0058] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0059] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0060] c) An artificial tear solution, wherein the artificial tear solution contains glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0061] This invention also relates to ophthalmic formulations comprising:

[0062] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0063] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0064] c) Artificial tear solution containing glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0065] This invention also relates to ophthalmic formulations comprising the following:

[0066] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0067] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0068] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0069] The PEG or PEG mixture used in the ophthalmic formulations of this invention is responsible for the solubility of the prepreg free base hemihydrate. That is, without the use of PEG or PEG mixtures, it is desirable that a certain amount of the prepreg free base hemihydrate cannot dissolve in the ophthalmic formulation and will precipitate. This reduces the amount of active pharmaceutical ingredient (i.e., prepreg free base hemihydrate) in the ophthalmic formulation, thus making it impossible to prepare an ophthalmic formulation with a defined amount of active pharmaceutical ingredient.

[0070] Furthermore, the PEG or PEG mixture used in the ophthalmic formulation of the present invention is responsible for the viscosity of the ophthalmic formulation. Therefore, it is preferable to select PEG or PEG mixture such that the viscosity of the ophthalmic formulation is in the range of 25 cps to 50 cps.

[0071] In addition to the PEG or PEG mixture used in the ophthalmic formulation of this invention, the choice of artificial tear solution also affects the viscosity of the ophthalmic formulation. Considering that artificial tear solution is usually the main component of ophthalmic formulations, the viscosity of the ophthalmic formulation of this application is substantially the same as the viscosity of the artificial tear solution. However, the presence of PEG or PEG mixture in the ophthalmic formulation can alter the viscosity of the artificial tear solution, thus the ophthalmic formulation preferably has a viscosity that differs from the artificial tear solution by more than 20%.

[0072] This means that if the artificial tear solution has a viscosity of, for example, 40 cps, the ophthalmic formulation of this application preferably has a viscosity in the range of 32 cps to 48 cps, and more preferably a viscosity close to 40 cps.

[0073] Typically, 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.

[0074] Many everyday fluids have a viscosity ranging from 0.5 to 1000 cP. For example, water has a viscosity of 1 cP. Tears have a viscosity ranging from 1.0 cP to 6.0 cP. Ophthalmic formulations with a viscosity of up to 20 cP are well tolerated. However, to ensure that ophthalmic formulations remain in the eye for a sufficiently long time, a viscosity of 25 to 50 cP is preferred and generally only results in increased tearing and blinking reflexes in the treated eye.

[0075] Solution viscosity is measured in poise. Poise is the unit of dynamic viscosity (i.e., absolute viscosity). A centipoise (cp or complex cps) is equal to 0.01 poise. The SI unit of viscosity is Pascal-second (Pa*s), equivalent to Newton-second per square meter (N*s*m-). 2 ).

[0076] 1000cp=10p=1Pa*s=1N*s*m- 2 =1kg*m- 1* s- 1

[0077] Therefore, in order to obtain the desired viscosity, a viscosity enhancer may also be added to the ophthalmic formulation of the present invention.

[0078] Suitable viscosity enhancers are hydroxyethyl cellulose, polyvinyl alcohol, hydroxypropyl methylcellulose, methylcellulose, and polyvinylpyrrolidone. Viscosity enhancers should not be used in ophthalmic formulations in amounts exceeding 1.0% by weight.

[0079] Therefore, this application also relates to ophthalmic preparations that comprise or consist of the following:

[0080] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0081] b) Polyethylene glycol, and

[0082] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0083] The ophthalmic formulation described herein has a viscosity in the range of 25 cp to 50 cp.

[0084] This invention also relates to ophthalmic formulations comprising:

[0085] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0086] b) Polyethylene glycol, and

[0087] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0088] The ophthalmic formulation described herein has a viscosity in the range of 25 cp to 50 cp.

[0089] This invention also relates to ophthalmic formulations comprising the following:

[0090] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0091] b) Polyethylene glycol, and

[0092] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0093] The ophthalmic formulation described herein has a viscosity in the range of 25 cp to 50 cp.

[0094] Preferred are ophthalmic preparations that comprise or consist of the following:

[0095] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0096] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0097] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0098] The ophthalmic formulation described herein has a viscosity in the range of 25 cp to 50 cp.

[0099] This invention also relates to ophthalmic formulations comprising:

[0100] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0101] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0102] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0103] The ophthalmic formulation described herein has a viscosity in the range of 25 cp to 50 cp.

[0104] This invention also relates to ophthalmic formulations comprising the following:

[0105] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0106] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0107] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0108] The ophthalmic formulation described herein has a viscosity in the range of 25 cp to 50 cp.

[0109] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0110] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0111] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0112] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0113] The ophthalmic formulation described herein has a viscosity in the range of 25 cp to 50 cp.

[0114] This invention also relates to ophthalmic formulations comprising:

[0115] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0116] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0117] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0118] The ophthalmic formulation described herein has a viscosity in the range of 25 cp to 50 cp.

[0119] This invention also relates to ophthalmic formulations comprising the following:

[0120] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0121] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0122] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0123] The ophthalmic formulation described herein has a viscosity in the range of 25 cp to 50 cp.

[0124] The pH value of the ophthalmic preparations of this application 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.

[0125] Although tears have a physiological pH of approximately 7.4, the experiments revealed in this paper demonstrate that pH values ​​below 7.0 are more beneficial than pH values ​​above 7.0.

[0126] Preferably, the pH of the ophthalmic preparation is determined by adding an aqueous hydrochloric acid solution, or more preferably by adding 0.1M HCl. aq The solution is used for adjustment.

[0127] For pH adjustment, hydrochloric acid or hydrobromic acid is preferred, with hydrochloric acid being particularly preferred.

[0128] Acidic solutions containing 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, ethanedisulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, p-aminobenzenesulfonic acid, camphorsulfonic acid, cinchonaic acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, D-o-tolyltartaric acid, malonic acid, (o,m,p)-toluic acid, naphthylaminesulfonic acid, and trifluoroacetic acid.

[0129] Therefore, this application also relates to ophthalmic preparations that comprise or consist of the following:

[0130] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0131] b) Polyethylene glycol, and

[0132] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0133] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0134] This invention also relates to ophthalmic formulations comprising:

[0135] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0136] b) Polyethylene glycol, and

[0137] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0138] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0139] This invention also relates to ophthalmic formulations comprising the following:

[0140] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0141] b) Polyethylene glycol, and

[0142] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0143] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0144] Preferred are ophthalmic preparations that comprise or consist of the following:

[0145] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0146] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0147] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0148] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0149] This invention also relates to ophthalmic formulations comprising:

[0150] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0151] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0152] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0153] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0154] This invention also relates to ophthalmic formulations comprising the following:

[0155] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0156] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0157] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0158] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0159] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0160] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0161] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0162] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0163] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0164] This invention also relates to ophthalmic formulations comprising:

[0165] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0166] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0167] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0168] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0169] This invention also relates to ophthalmic formulations comprising the following:

[0170] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0171] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0172] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0173] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0174] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0175] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0176] b) Polyethylene glycol, and

[0177] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0178] The ophthalmic formulation described herein 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 5.5 to 6.5.

[0179] This invention also relates to ophthalmic formulations comprising:

[0180] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0181] b) Polyethylene glycol, and

[0182] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0183] The ophthalmic formulation described herein 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 5.5 to 6.5.

[0184] This invention also relates to ophthalmic formulations comprising the following:

[0185] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0186] b) Polyethylene glycol, and

[0187] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0188] The ophthalmic formulation described herein 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 5.5 to 6.5.

[0189] Artificial tear solution

[0190] Artificial tear solutions, also known as tear replacement solutions, are used to dilute or replace tears, and are therefore used in ophthalmic formulations due to their ocular compatibility.

[0191] Artificial tear solutions that can be used in the ophthalmic formulations of this application are, for example... tear solution, tear solution, tear solution, Lac-Ophtal MP, EDO, Dry eyes, Dry eye EDO, Yxin splash MDO / EDO, Bepanthen eye drops (+dexpanshenol), Opticalm eye drops (+hydroxypropyl methylcellulose), etc.

[0192] Artificial tear solutions can be purchased as ready-to-use solutions or can be prepared from commonly used and readily available substances.

[0193] Artificial tear solutions typically consist of glycerin, hydroxypropyl methylcellulose, and polyethylene glycol as lubricants, and also usually contain 10 to all of the following substances: carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and / or sodium lactate. All of these substances are soluble in pure water.

[0194] According to the experiments conducted and published in this article, Tear solutions or equivalent artificial tear solutions are preferred artificial tear solutions for ophthalmic formulations.

[0195] The tear solution contains 0.2% by weight glycerin, 0.2% by weight hydroxypropyl methylcellulose, and 1% by weight PEG 400. In addition to these lubricants, The following substances are also present in tear solution: carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate. Artificial tear solutions, which are equivalent to tear solutions, contain substantially the same components. However, they may lack one or more of the components mentioned above, or additionally contain one or more pharmaceutically acceptable components, provided they exhibit the same characteristics as tear solutions. Tear solutions have essentially the same properties. Artificial tear solutions equivalent to tear solutions can also contain some or all of the components mentioned above in varying amounts, provided that they exhibit the same characteristics as tear solutions. The properties are substantially the same as those of the tear solution. The term "substantially the same properties" as used herein refers to the physicochemical characteristics of a particular formulation that are acceptable for use as an artificial tear solution. For example, having properties similar to... Artificial tear solutions, which have essentially the same properties as tear solutions, have similar properties to... The pH difference of the tear solution does not exceed 5% of the pH, and / or is similar to... The viscosity difference of the tear solution does not exceed 5%, and / or is similar to... The density difference of tear solutions does not exceed 10%.

[0196] This article also discloses ophthalmic preparations that contain or consist of the following:

[0197] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0198] b) Polyethylene glycol, and

[0199] c) Artificial tear solution.

[0200] This article also discloses ophthalmic preparations that contain or consist of the following:

[0201] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0202] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0203] c) Artificial tear solution.

[0204] This article also discloses ophthalmic preparations that contain or consist of the following:

[0205] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0206] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0207] c) Artificial tear solution.

[0208] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0209] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0210] b) Polyethylene glycol, and

[0211] c) Tear solution.

[0212] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0213] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0214] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0215] c) Tear solution.

[0216] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0217] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0218] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0219] c) Tear solution.

[0220] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0221] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0222] b) Polyethylene glycol, and

[0223] c) tear solution,

[0224] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0225] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0226] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0227] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0228] c) tear solution,

[0229] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0230] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0231] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0232] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0233] c) tear solution,

[0234] The ophthalmic formulation described herein has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0235] Preferably, in the ophthalmic formulation of the present invention, polyethylene glycol is included in the ophthalmic formulation in the following amounts: 20 μg per ml of ophthalmic formulation to 100 μg per ml of ophthalmic formulation, more preferably 30 μg per ml of ophthalmic formulation to 90 μg per ml of ophthalmic formulation, more preferably 35 μg per ml of ophthalmic formulation to 80 μg per ml of ophthalmic formulation, more preferably 40 μg per ml of ophthalmic formulation to 70 μg per ml of ophthalmic formulation, even more preferably 45 μg per ml of ophthalmic formulation to 65 μg per ml of ophthalmic formulation, and even more preferably 50 μg per ml of ophthalmic formulation to 60 μg per ml of ophthalmic formulation.

[0236] Therefore, this application also relates to ophthalmic preparations that comprise or consist of the following:

[0237] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0238] b) Polyethylene glycol, and

[0239] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0240] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0241] This invention also relates to ophthalmic formulations comprising:

[0242] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0243] b) Polyethylene glycol, and

[0244] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0245] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0246] This invention also relates to ophthalmic formulations comprising the following:

[0247] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0248] b) Polyethylene glycol, and

[0249] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0250] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0251] All embodiments of the ophthalmic formulations according to the present invention, as disclosed herein, contain glycerin, hydroxypropyl methylcellulose (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 carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0252] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0253] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0254] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0255] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0256] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0257] This invention also relates to ophthalmic formulations comprising:

[0258] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0259] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0260] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0261] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0262] This invention also relates to ophthalmic formulations comprising the following:

[0263] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0264] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0265] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0266] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0267] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0268] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0269] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0270] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0271] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0272] This invention also relates to ophthalmic formulations comprising:

[0273] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0274] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0275] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0276] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0277] This invention also relates to ophthalmic formulations comprising the following:

[0278] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0279] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0280] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0281] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0282] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0283] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0284] b) Polyethylene glycol, and

[0285] c) tear solution,

[0286] Polyethylene glycol is included in ophthalmic preparations at amounts ranging from 40 μg per ml to 70 μg per ml.

[0287] In all embodiments disclosed herein, the amount of polyethylene glycol, if explicitly stated as in the ten embodiments disclosed above, refers to the total amount of polyethylene glycol present in the formulation, which is the cumulative amount of polyethylene glycol in steps b) and c). However, if 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).

[0288] Preferably, the ophthalmic formulation of the present invention contains N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in the ophthalmic formulation in the following amounts: 20 μg per ml of ophthalmic formulation to 100 μg per ml of ophthalmic formulation, more preferably 25 μg per ml of ophthalmic formulation to 90 μg per ml of ophthalmic formulation, more preferably 30 μg per ml of ophthalmic formulation to 80 μg per ml of ophthalmic formulation, more preferably 35 μg per ml of ophthalmic formulation to 70 μg per ml of ophthalmic formulation, even more preferably 40 μg per ml of ophthalmic formulation to 60 μg per ml of ophthalmic formulation, and even more preferably 45 μg per ml of ophthalmic formulation to 55 μg per ml of ophthalmic formulation.

[0289] Therefore, this application also relates to ophthalmic preparations that comprise or consist of the following:

[0290] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0291] b) Polyethylene glycol, and

[0292] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0293] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0294] This invention also relates to ophthalmic formulations comprising:

[0295] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0296] b) Polyethylene glycol, and

[0297] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0298] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0299] This invention also relates to ophthalmic formulations comprising the following:

[0300] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0301] b) Polyethylene glycol, and

[0302] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0303] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0304] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0305] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0306] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0307] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0308] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0309] This invention also relates to ophthalmic formulations comprising:

[0310] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0311] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0312] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0313] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0314] This invention also relates to ophthalmic formulations comprising the following:

[0315] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0316] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0317] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0318] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0319] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0320] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0321] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0322] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0323] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0324] This invention also relates to ophthalmic formulations comprising:

[0325] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0326] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0327] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0328] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0329] This invention also relates to ophthalmic formulations comprising the following:

[0330] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0331] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0332] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0333] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0334] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0335] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0336] b) Polyethylene glycol, and

[0337] c) tear solution,

[0338] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation.

[0339] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0340] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0341] b) Polyethylene glycol, and

[0342] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0343] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0344] This invention also relates to ophthalmic formulations comprising:

[0345] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0346] b) Polyethylene glycol, and

[0347] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0348] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0349] This invention also relates to ophthalmic formulations comprising the following:

[0350] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0351] b) Polyethylene glycol, and

[0352] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0353] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0354] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0355] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0356] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0357] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0358] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0359] This invention also relates to ophthalmic formulations comprising:

[0360] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0361] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0362] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0363] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0364] This invention also relates to ophthalmic formulations comprising the following:

[0365] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0366] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0367] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0368] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0369] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0370] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0371] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0372] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0373] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0374] This invention also relates to ophthalmic formulations comprising:

[0375] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0376] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0377] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0378] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0379] This invention also relates to ophthalmic formulations comprising the following:

[0380] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0381] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0382] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0383] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0384] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0385] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0386] b) Polyethylene glycol, and

[0387] c) tear solution,

[0388] Polyethylene glycol is included in the ophthalmic preparation at an amount of 40 μg per ml to 70 μg per ml of ophthalmic preparation, while N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is included in the ophthalmic preparation at an amount of 40 μg per ml to 60 μg per ml of ophthalmic preparation.

[0389] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0390] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0391] b) Polyethylene glycol, and

[0392] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0393] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0394] This invention also relates to ophthalmic formulations comprising:

[0395] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0396] b) Polyethylene glycol, and

[0397] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0398] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0399] This invention also relates to ophthalmic formulations comprising the following:

[0400] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0401] b) Polyethylene glycol, and

[0402] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0403] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0404] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0405] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0406] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0407] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0408] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0409] This invention also relates to ophthalmic formulations comprising:

[0410] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0411] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0412] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0413] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0414] This invention also relates to ophthalmic formulations comprising the following:

[0415] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0416] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0417] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0418] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0419] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0420] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0421] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0422] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0423] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0424] This invention also relates to ophthalmic formulations comprising:

[0425] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0426] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0427] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0428] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0429] This invention also relates to ophthalmic formulations comprising the following:

[0430] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0431] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0432] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0433] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0434] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0435] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0436] b) Polyethylene glycol, and

[0437] c) tear solution,

[0438] The N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic preparation in an amount of 40 μg per ml of ophthalmic preparation to 60 μg per ml of ophthalmic preparation, and the ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0439] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0440] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0441] b) Polyethylene glycol, and

[0442] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0443] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0444] This invention also relates to ophthalmic formulations comprising:

[0445] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0446] b) Polyethylene glycol, and

[0447] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0448] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0449] This invention also relates to ophthalmic formulations comprising the following:

[0450] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0451] b) Polyethylene glycol, and

[0452] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0453] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0454] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0455] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0456] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0457] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0458] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0459] This invention also relates to ophthalmic formulations comprising:

[0460] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0461] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0462] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0463] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0464] This invention also relates to ophthalmic formulations comprising the following:

[0465] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0466] b) PEG 200, PEG 300, PEG 400, or a mixture of two or more of these PEGs, and

[0467] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0468] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0469] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0470] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0471] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0472] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0473] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0474] This invention also relates to ophthalmic formulations comprising:

[0475] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0476] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0477] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0478] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0479] This invention also relates to ophthalmic formulations comprising the following:

[0480] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0481] b) PEG 200 and / or PEG 400, preferably PEG 400, and

[0482] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0483] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0484] Also preferred are ophthalmic preparations that comprise or consist of the following:

[0485] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0486] b) Polyethylene glycol, and

[0487] c) tear solution,

[0488] The ophthalmic preparation contains polyethylene glycol in an amount of 40 μg to 70 μg per ml of ophthalmic preparation, and N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate in an amount of 40 μg to 60 μg per ml of ophthalmic preparation. The ophthalmic preparation has a pH value in the range of 5.0 to 7.0, preferably in the range of 5.5 to 6.5.

[0489] Preferably, the artificial tear solution is contained in the ophthalmic formulation of the present invention in the following amounts: 0.5 g per ml of ophthalmic formulation to 1.7 g per ml of ophthalmic formulation, more preferably 0.6 g per ml of ophthalmic formulation to 1.6 g per ml of ophthalmic formulation, more preferably 0.7 g per ml of ophthalmic formulation to 1.5 g per ml of ophthalmic formulation, even more preferably 0.8 g per ml of ophthalmic formulation to 1.4 g per ml of ophthalmic formulation, even more preferably 0.9 g per ml of ophthalmic formulation to 1.3 g per ml of ophthalmic formulation, and even more preferably 1.0 g per ml of ophthalmic formulation to 1.2 g per ml of ophthalmic formulation.

[0490] The ophthalmic formulations described in this application are intended for the prevention and / or treatment of diseases caused by herpes simplex virus, and / or the prevention of the spread of one or more herpes viruses.

[0491] Preferably, the ophthalmic formulations of this application are used for the prevention and / or treatment of ocular herpes simplex infection, particularly ocular herpes (i.e., keratitis).

[0492] Therefore, in some preferred embodiments, this application relates to ophthalmic formulations comprising:

[0493] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0494] b) Polyethylene glycol, and

[0495] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0496] Used for the prevention and / or treatment of diseases caused by herpes simplex virus, and / or for the prevention of transmission of one or more herpes viruses. Diseases caused by herpes simplex virus are preferably ocular herpes simplex infections, especially ocular herpes (i.e., keratitis).

[0497] This invention also relates to ophthalmic formulations comprising:

[0498] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0499] b) Polyethylene glycol, and

[0500] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0501] Used for the prevention and / or treatment of diseases caused by herpes simplex virus, and / or for the prevention of transmission of one or more herpes viruses. Diseases caused by herpes simplex virus are preferably ocular herpes simplex infections, especially ocular herpes (i.e., keratitis).

[0502] This invention also relates to ophthalmic formulations comprising the following:

[0503] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0504] b) Polyethylene glycol, and

[0505] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0506] Used for the prevention and / or treatment of diseases caused by herpes simplex virus, and / or for the prevention of transmission of one or more herpes viruses. Diseases caused by herpes simplex virus are preferably ocular herpes simplex infections, especially ocular herpes (i.e., keratitis).

[0507] Therefore, one aspect of this application is the use of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate in the prevention and / or treatment of diseases caused by herpes simplex virus, and / or in the prevention of the spread of one or more herpes viruses. As disclosed herein, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate is preferably administered as an ophthalmic preparation. Preferably, 1 to 5 drops of the ophthalmic preparation disclosed herein are administered twice or three times daily.

[0508] As used herein, the terms “prevention,” “avoidance,” “protection,” or “stopping” mean that a disorder or disease will not progress if it has not occurred, or that a disorder or disease will not progress further if it has already progressed. The ability of a substance to prevent some or all of the symptoms associated with a disorder or disease is also considered. Stopping a disease means preventing the disease, and preventing disease means stopping the disease. Therefore, the terms “prevention” and “stopping” are used interchangeably throughout this application.

[0509] The ophthalmic formulations of this application can also be used together or in combination with other antiviral agents such as antimetabolites and preferably nucleobase analogs, nucleotide analogs, or nucleoside analogs. It is also preferred that the other antiviral agents are effective against herpesviruses and / or against the transmission of one or more herpesviruses and are selected from the group of drugs comprising, but not limited to, or consisting of: acetylsalicylic acid, trifluuridine, idoxuridine, phosphonoformic acid, cidofovir, ganciclovir, acyclovir, penciclovir, or their respective prodrugs valacyclovir, valganciclovir, or famciclovir.

[0510] Another aspect of the present invention relates to a method for preventing or treating diseases caused by herpes simplex virus and / or preventing the spread of one or more herpes viruses, comprising:

[0511] To administer an effective amount of the ophthalmic formulation of the present invention to a patient requiring treatment, comprising...

[0512] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0513] b) Polyethylene glycol, and

[0514] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0515] The most common disease caused by herpes simplex virus is ocular herpes simplex infection, especially ocular herpes (i.e., keratitis).

[0516] Another aspect of the present invention relates to a method for preventing or treating diseases caused by herpes simplex virus and / or preventing the spread of one or more herpes viruses, comprising:

[0517] To administer an effective amount of the ophthalmic formulation of the present invention to a patient requiring treatment, comprising...

[0518] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0519] b) Polyethylene glycol, and

[0520] c) Artificial tear solution containing glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0521] The most common disease caused by herpes simplex virus is ocular herpes simplex infection, especially ocular herpes (i.e., keratitis).

[0522] Another aspect of the present invention relates to a method for preventing or treating diseases caused by herpes simplex virus and / or preventing the spread of one or more herpes viruses, comprising:

[0523] An effective amount of the ophthalmic preparation of the present invention, comprising the following components, is administered to a patient requiring treatment:

[0524] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0525] b) Polyethylene glycol, and

[0526] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0527] The most common disease caused by herpes simplex virus is ocular herpes simplex infection, especially ocular herpes (i.e., keratitis).

[0528] The method can also be used in conjunction with or in combination with other antiviral agents such as antimetabolites and preferably nucleobase analogs, nucleotide analogs, or nucleoside analogs. Preferably, the other antiviral agents are effective against herpesvirus and / or against the spread of herpesvirus and are preferably selected from the group of drugs comprising, but not limited to, or consisting of: acetylsalicylic acid, trifluuridine, idoxuridine, phosphonoformic acid, cidofovir, ganciclovir, acyclovir, penciclovir, or their respective prodrugs valacyclovir, valganciclovir, or famciclovir.

[0529] Therefore, one aspect of this application is a method for preventing or treating diseases caused by herpes simplex virus and / or preventing the spread of one or more herpes viruses, comprising administering an effective amount of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate to a patient in need. As disclosed herein, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate is preferably administered as an ophthalmic preparation. Preferably, 1 to 5 drops of the ophthalmic preparation disclosed herein are administered two or three times daily.

[0530] N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate can also be administered co-administered with other antiviral agents such as antimetabolites and preferably nucleobase analogs, nucleotide analogs, or nucleoside analogs. Preferred drugs are acetylsalicylic acid, trifluuridine, idoxuridine, phosphonoformic acid, cidofovir, ganciclovir, acyclovir, penciclovir, valacyclovir, valganciclovir, or famciclovir. These other drugs can be included in the same ophthalmic formulation or in other ophthalmic formulations administered simultaneously with or at time intervals with N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate.

[0531] Another aspect of the present invention relates to the use of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate in the preparation of ophthalmic formulations, comprising:

[0532] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0533] b) Polyethylene glycol, and

[0534] c) An artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0535] The ophthalmic formulation is used for the prevention and / or treatment of diseases caused by herpes simplex virus, and / or to prevent the spread of one or more herpes viruses. Preferably, the diseases caused by herpes simplex virus are ocular herpes simplex infections, particularly ocular herpes (i.e., keratitis).

[0536] Another aspect of the present invention relates to the use of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate in the preparation of ophthalmic formulations, comprising:

[0537] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0538] b) Polyethylene glycol, and

[0539] c) Artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0540] The ophthalmic formulation is used for the prevention and / or treatment of diseases caused by herpes simplex virus, and / or to prevent the spread of one or more herpes viruses. Preferably, the diseases caused by herpes simplex virus are ocular herpes simplex infections, particularly ocular herpes (i.e., keratitis).

[0541] Another aspect of the present invention relates to the use of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate in the preparation of ophthalmic formulations, comprising the following:

[0542] a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate, and

[0543] b) Polyethylene glycol, and

[0544] c) An artificial tear solution comprising: glycerol, hydroxypropyl methylcellulose, polyethylene glycol 400, water as a solvent, and at least one compound selected from carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0545] The ophthalmic formulation is used for the prevention and / or treatment of diseases caused by herpes simplex virus, and / or to prevent the spread of one or more herpes viruses. Preferably, the diseases caused by herpes simplex virus are ocular herpes simplex infections, particularly ocular herpes (i.e., keratitis).

[0546] As discussed in the introduction, the prior art disclosed in WO 2018 / 095576 A1 by the applicant can be considered the closest prior art, which discloses topical pharmaceutical formulations for the treatment or prevention of herpes virus infection. These topical formulations may contain N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)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, and more preferably 4.0 to 4.5.

[0547] However, WO 2018 / 095576 A1 does not disclose the following ophthalmic formulation: N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate (prerivir free base hemihydrate), PEG (polyethylene glycol), and artificial tear solution containing glycerin, hydroxypropyl methylcellulose, and polyethylene glycol 400 and optionally polyvinylpyrrolidone.

[0548] During the development of the ophthalmic formulation disclosed herein, it was discovered that the prepreg free base hemihydrate is unstable and precipitates in most artificial tear solutions at pH 4.0. Even worse, precipitation was found to increase with increasing pH. Therefore, the object of the present invention is to provide an artificial tear solution of prepreg reagent, wherein the prepreg reagent is stable at a pH of 6.0 to 7.0, which is the optimal and required pH range for ophthalmic application.

[0549] Surprisingly, it was found that prepirenyl hemihydrate, as a prepirenyl reagent, is sufficiently stable for ophthalmic formulations at pH 6.0 to 7.0, provided that the ophthalmic formulation contains glycerin, hydroxypropyl methylcellulose, and polyethylene glycol 400. This ophthalmic formulation is not disclosed or taught in the prior art, including WO 2018 / 095576A1. The above-described composition of the ophthalmic formulation prevents prepirenyl hemihydrate precipitation not only at pH 4.0 (see Example 7) but also at the pH 6.0 to 7.0 required for formulations used in the eye (see Example 8). Furthermore, it was found that not all commercially available artificial tear solutions are suitable. It is essential that an artificial tear solution or commercially available artificial tear solution containing glycerin, hydroxypropyl methylcellulose, and polyethylene glycol 400 be present. Preferably, other components are present in the artificial tear solution. The ingredients are at least one, preferably five, more preferably ten, and even more preferably fifteen compounds from the group consisting of: carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextran, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate, and sodium lactate.

[0550] Regarding the prepirenyl ether reagent, it was surprisingly found that the prepirenyl ether hemihydrate cannot be replaced by prepirenyl ether mesylate or prepirenyl ether maleate due to insolubility and precipitation issues.

[0551] These findings regarding the composition of the prepirenylvita reagent and artificial tear solution were not even inspired by prior art literature, including WO 2018 / 095576A1, thus the ophthalmic formulations disclosed herein are non-obvious and not inspired by prior art.

[0552] Assuming one starts with the gel formulation disclosed in WO 2018 / 095576 A1, a person skilled in the art would have to understand that they would have to select the prepreg hemihydrate from a list of known prepreg reagents, such as free base, hemihydrate, mesylate, sulfate, and maleate. Furthermore, the pH of the gel would have to be adjusted to a pH of 6.0 to 7.0. A person skilled in the art would also have to understand the importance of polyethylene glycol 400 and would have to replace hydroxypropyl cellulose with hydroxypropyl methylcellulose, and ultimately add glycerin to the ophthalmic formulation. Therefore, a person skilled in the art would need to understand several non-obvious steps to reach the ophthalmic formulation disclosed herein from the closest prior art WO 2018 / 095576A1.

[0553] Another aspect of this application relates to a method for preparing ophthalmic formulations, wherein the method comprises the following steps:

[0554] I) Provides N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0555] II) Provide polyethylene glycol,

[0556] III) Provide an artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0557] IV) Preparation of a stock solution of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate in polyethylene glycol.

[0558] V) Dilute the stock solution with artificial tear solution until the desired concentration is achieved.

[0559] VI) Adjust the pH to the desired value by adding an aqueous solution of acid, and

[0560] VII) The ophthalmic preparation is obtained by aseptic filtration through a suitable sterile filter.

[0561] The method preferably includes at least one step: adjusting the pH value to a desired pH value, preferably in the range of 5.5 to 6.5. It is possible to adjust the ophthalmic solution to the desired pH value before and after sterile filtration. However, all pH ranges disclosed herein are similarly acceptable for the preparation of ophthalmic formulations.

[0562] Ophthalmic preparations should be stored at temperatures between 2°C and 8°C, but can also be stored at room temperature without degradation.

[0563] N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate is used in this method at the amounts and concentrations disclosed above.

[0564] The same applies to other components such as polyethylene glycol and artificial tear solutions, which are used in the amounts and concentrations disclosed above. In the methods described herein, PEG 400 and... Tear solution as an artificial tear solution.

[0565] The preparation is sterilized by filtration through a sterile / aseptic filter, resulting in a sterile preparation. Aseptic filtration can be performed at any convenient temperature, such as room temperature. Aseptic filtration is carried out using a filter with a pore size preferably of 0.20 μm or smaller.

[0566] 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).

[0567] However, it was discovered that the sterile filtration step is critical and can only be performed using a specific type of sterile filter, namely the RC filter.

[0568] Regenerated cellulose (RC) is a class of substances prepared by converting natural cellulose into a soluble fibrous derivative and subsequently regenerating it, generally forming fibers (via polymer spinning) or membranes (via polymer casting). RC sterile filters are hydrophilic membrane filters. The RC sterile filters have a thickness in the range of 10 to 500 μm, preferably 50 to 400 μm, more preferably 100 to 300 μm, and most preferably 150 to 200 μm. The RC sterile filters have a flux of greater than 10 mL / min*cm at 0.7 bar at 25°C. 2 Preferably greater than 15 mL / min*cm 2 The flow rate.

[0569] The RC sterile filter was purchased from CZT (Klaus Trott Chromatographie- Kriftel, Germany; item number 802527020).

[0570] The RC sterile filter has a pore size of 0.2 μm and is connected via Luer Lok.

[0571] The specifications of the RC sterile filter are summarized as follows:

[0572]

[0573] Therefore, this application relates to a method for preparing ophthalmic formulations, wherein the method comprises the following steps:

[0574] I) Provides N-[5-(aminosulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate,

[0575] II) Provide polyethylene glycol,

[0576] III) Provide an artificial tear solution containing glycerin, hydroxypropyl methylcellulose, polyethylene glycol 400, and optionally polyvinylpyrrolidone.

[0577] IV) Preparation of a stock solution of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate in polyethylene glycol.

[0578] V) Dilute the stock solution with artificial tear solution until the desired concentration is achieved.

[0579] VI) Adjust the pH to the desired value by adding an aqueous solution of acid, and

[0580] VII) The ophthalmic preparation is obtained by aseptic filtration through an RC aseptic filter. Detailed Implementation

[0581] Example

[0582] 1. Abbreviation List

[0583] PA (polyacetic acid)

[0584] LE (low extractable)

[0585] PFTE (Polytetrafluoroethylene)

[0586] PVDF (Polyvinylidene Fluoride)

[0587] CM cellulose acetate

[0588] RC regenerated cellulose

[0589] PP polypropylene

[0590] PES (polyethersulfone)

[0591] 2. Matter

[0592]

[0593] 3. Equipment

[0594] equipment supplier Climate Chamber Weiβtechnik pH meter 766Calimatic Knick Electrode SE104N Knick

[0595] 4. Analytical equipment

[0596]

[0597] 5. Preparation Scheme HPLC Analysis 5.1 Quantitative Analysis

[0598] 5.1.1 Preparation of eluent

[0599] ● Add 10 mL of HAc to 990 mL of water and mix.

[0600] ● Add 495 mL of methanol to 495 mL of ACN and 10 mL of HAc and mix.

[0601] 5.2 Sample Preparation

[0602] Ophthalmic preparation concentration = 0.05 mg AIC090093 / mL

[0603] related impurities

[0604] ● Dilute 500 μL of each sample with 500 μL of ACN / MeOH / H2O (ratio 25:25:50) + 1% HAc (1:2).

[0605] ● Mix it for 5 seconds using vortex stirring.

[0606] Final concentration

[0607] ● Dilute 250 μL of each sample with 730 μL ACN / MeOH / H2O (ratio 25:25:50) + 1% HAc, and add 20 μL ACN / DMSO 4:1 (1:4).

[0608] ● Mix it for 5 seconds using vortex stirring.

[0609] 5.3 Calibration stock solution 10 mg / ml AIC090093

[0610] ● Weigh AIC090093 and dissolve it in 10 mL DMSO

[0611] ● Mix it in a vortex mixer for 15 minutes.

[0612] Target weight AIC090093 100.0mg DMSO 10mL

[0613] 5.4 Medium Solution

[0614] ●A mixture of PEG 200 and GenTeal tears

[0615] ● Mix it in a vortex mixer for 15 minutes.

[0616] Target volume PEG 0.75mL Visine tears 14.25mL

[0617] 5.5 Preparation of Standard Solutions for Calibration, Qualitative and Testing Work

[0618]

[0619] 5.6 For HPLC dilution

[0620] ● Dilute 20 μl of calibration or QC-solution with 730 μl ACN / MeOH / H2O (ratio 25:25:50) + 1% HAc, and add 250 μl of the corresponding media solution (1:50).

[0621] Concentration [mg / ml] blank 0 K1 0.002 K2 0.005 K3 0.010 K4 0.015 K5 0.020 K6 0.040 K7 0.050 K8 0.075 QC1 0.0056 QC2 0.030 QC3 0.060 AWS 0.0040

[0622] 5.7 Measurement of HPLC-DAD

[0623]

[0624] PAL sampler

[0625]

[0634] PAL Method Information

[0626] PAL loop parameters

[0627] DAD method

[0628] Analog output 1 Simulation 1 Zero Offset: 5%

[0629] Simulation 1 attenuation: 1000mAU Analog output 2 Simulation 2 Zero Offset: 5%

[0630] Simulation 2 attenuation: 1000mAU Signal

[0631] Signal Table

[0632] Line ID get Signal Wavelength (nm) Bandwidth (nm) 1 no Signal A 2 yes Signal B 290 20 3 no Signal C 4 no Signal D 5 no Signal E 6 no Signal F 7 no Signal G 8 no Signal H

[0633] Line ID Use reference Reference wavelength (nm) Reference bandwidth (nm) 1 2 yes 450 50 3 4 5 6 7 8

[0634] Preparation mode

[0635] Boundary for negative absorbance: 100 mAU

[0636] Automatic balance

[0637] Automatic balance pre-run: Yes Automatic balance post-run: Yes

[0638] spectrum Spectral storage: None

[0639] Stop time

[0640] Stop-time mode: such as pump / syringe

[0641] After time

[0642] Post-Time Mode: Off

[0643] Column Comp. method Module display name: Column Comp. Module type: G1316B Sequence: 1

[0644] Left side temperature control Temperature control mode: Temperature group Temperature: 23.0℃ This allows for the analysis of the temperature on the left side. Enables temperature analysis on the left side: Yes This allows us to analyze the temperature value on the left: 1.0℃ Right side temperature control Temperature control mode on the right: Combination

[0645] This allows for the analysis of the temperature on the right side. Enables temperature analysis on the right side: Yes This allows us to analyze the temperature value on the right: 1.0℃ Stop time

[0646] Stop-time mode: such as pump / syringe

[0647] After time

[0648] Post-Time Mode: Off

[0649] Binary pump method

[0650] Flow rate: 0.350 mL / min

[0651] Solvent type used: Yes

[0652] Low pressure limit: 0.00 bar

[0653] High pressure limit: 400.00 bar

[0654] Maximum flow gradient: 100,000 mL / min 2

[0655] Module display name: Binary Pump

[0656] Module type: G1312B

[0657] Sequence: 1

[0658] Solvent Composition

[0659]

[0660] schedule

[0661] Line ID Time (min) A(％) B(％) Flow rate (mL / min) 1 2.00 98.0 2.0 0.350 2 20.00 30.0 70.0 0.350 3 20.10 2.0 98.0 0.350 4 25.00 98.0 2.0 0.350

[0662] Line ID Pressure (Bar) Contact A Contact B Contact C 1 400.00 open open open 2 400.00 open open open 3 400.00 open open open 4 400.00 open open open

[0663]

[0664]

[0665] Itinerary A

[0666] Automatic travel calculation A: Yes

[0667] Itinerary B

[0668] Automatic travel calculation B: Yes

[0669] Stop time Stop Time Mode: Time Group Stop time: 25.00 minutes

[0670] After time

[0671] Post-Time Mode: Off

[0672] External contact Contact A: Open Contact B: Open Contact C: Open

[0673] Contact D: Open

[0674] Method characteristics Equipment Technology: Liquid Chromatography

[0675] 6. Preparation of ophthalmic formulations

[0676] Chemicals and substances:

[0677] Prerivir free base hemihydrate was synthesized from Carbogen amics.

[0678] Prerivir maleate is synthesized from Carbogen amics.

[0679] Prerivir mesylate monohydrate was synthesized by Carbogen amics.

[0680] Polyethylene glycol 200 is derived from Clariant.

[0681] Polyethylene glycol 400 (Kollisolv 400) was purchased from BASF.

[0682] The tear solution was obtained from Alcon.

[0683] The tear solution was obtained from Akron Consumer Health.

[0684] The tear solution was obtained from Johnson & Johnson Healthcare.

[0685] Preparation Experiment

[0686] The following experiments describe the preparation of several different ophthalmic formulations using different drug substances (DS). The term prerelvir hemihydrate, as used herein, refers to the free base hemihydrate of prerelvir and N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate. The term prerelvir maleate, as used herein, refers to N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide maleate, while the term prerelvir methanesulfonate monohydrate, as used herein, refers to N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazo-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide methanesulfonate monohydrate.

[0687] Example 1

[0688] To prepare new ophthalmic formulations, it is necessary to determine the drug substance concentrations of both i) the stock solution and ii) the drug product to be administered to the patient. For this purpose, stock solutions of different concentrations of prepivirine free base hemihydrate in PEG 200 were diluted... It is present in tears, and the sediment is examined over time.

[0689]

[0690] Preparation of stock solutions

[0691] Equilibrate all liquids and DS to ≥20°C. Provide seven 10 mL tubes. In each of these tubes, add 5 mL of PEG 200 and dissolve the required amount of DS to provide the following stock solutions: 30 mg / mL, 25 mg / mL, 20 mg / mL, 10 mg / mL, 5 mg / mL, 1 mg / mL, and 0.05 mg / mL. Mix the solutions as follows: Vortex the tube for 5 seconds and shake until the DS is dissolved.

[0692] Preparation of ophthalmic formulations

[0693] use The stock solution was diluted with tear fluid and the pH was measured. Precipitation in the sample was then examined visually.

[0694] An ophthalmic formulation with a drug loading of 24 mg / mL can be obtained without any visually detectable precipitation.

[0695] Example 2

[0696] To investigate stability over 5 weeks at room temperature (RT) and in a temperature range of 2°C–8°C, stock solutions of DS at a concentration of 1.0 mg / mL were prepared in PEG200 and PEG400. The different stock solutions were diluted with three different artificial tear compositions to achieve a final concentration of 0.05 mg DS per mL in ophthalmic formulations.

[0697]

[0698] Prepare a stock solution of 1 mg / mL

[0699] Equilibrate all liquids and DS to ≥20°C. Add 10 mL of each PEG (PEG 200 or PEG 400) to a 50 mL tube and dissolve 10 mg of DS in each tube. Mix the solutions as follows: Vortex the tube for 5 seconds and shake until the DS dissolves.

[0700] Preparation of ophthalmic formulation 0.05 mg / mL

[0701] In a beaker, add 1.5 mL of the stock solution to 28.5 mL of each artificial tear solution ( tears or tears or Dilute the solution with tears and stir with a magnetic stirrer for 2 min. Determine the pH and take samples before and after aseptic filtration. Filter the solution through a CA (cellulose acetate) 0.22 μm filter system. Drain the contents of the beaker and add 14 mL of the prepared formulation to two empty 50 mL tubes. Additionally, provide an empty 2 mL tube and add 1.5 mL of the prepared formulation to this 2 mL tube. Store the samples at RT and at a temperature range of 2–8 °C for 5 weeks.

[0702] What was observed was that the pH value of ophthalmic formulations depended on the artificial tear solution used. The pH value of artificial tear solutions varied between 7.5 and 8.5.

[0703] Surprisingly, it was noted that after sterile filtration of ophthalmic formulations, DS could no longer be detected by HPLC for any of the prepared formulations.

[0704] Example 3

[0705] To investigate filter compatibility, a stock solution containing 1.0 mg of prepivirine free base hemihydrate per mL of PEG200 was prepared. Dilute in tear film to a concentration of 0.05 mg prepivir free base hemihydrate per eye for the preparation.

[0706] Use different filter materials and pore sizes to filter ophthalmic preparations.

[0707]

[0708] Prepare a stock solution of 1 mg / mL DS

[0709] Equilibrate all liquids and DS to ≥20°C. Add 10 mL of PEG 200 to a 50 mL tube and dissolve 10 mg of DS in it. Mix the solution as follows: Vortex the tube for 5 seconds and shake the tube until the DS dissolves.

[0710] Preparation of ophthalmic formulation 0.05 mg / mL DS

[0711] Add 4.0 mL of the stock solution to 76.0 mL of... Dilute the tear fluid and mix the solution by vortexing for 5 seconds, then stir for 2 minutes until the DS dissolves.

[0712] Filter testing for all syringe filters (e.g., PA 0.2μm).

[0713] Repeat the test once to make duplicate samples (n=2). Draw 6 mL of the ophthalmic preparation using a 10 mL syringe. Determine the final concentration with 1 mL before filtration. Connect the syringe to a PA 0.2 μm filter via Luer Lok and filter the solution. Obtain another sample after filtration to determine the final concentration.

[0714] The filter was then disconnected from the syringe, and 3 mL of DMSO was drawn using the 10 mL syringe. The syringe was then smoothly shaken. After rinsing, 1 mL was used to determine the final concentration. The syringe was then reconnected to the PA 0.2 μm filter used via Luer Lok to filter the DMSO. After washing, a sample was obtained to determine the final concentration.

[0715] Repeat this procedure for all filters tested: PA / Nylon, PALE / Nylon, PTFE , PVDF, CM, CA, RC, PP, PES. Each filter contains filter material with pore sizes of 0.2μm and 0.45μm.

[0716] Surprisingly, only two filters were identified as suitable for sterile filtration of ophthalmic preparations. Test data for the filter materials PFTE 0.2 μm and RC 0.2 μm showed equivalent values ​​before and after filtration.

[0717] Example 4

[0718] To investigate the feasibility of sterile filtration using two grades of PEG and three different artificial tear compositions, the experiment of Example 3 was repeated, and the same conditions as in Example 3 were tested in addition to a stock solution of PEG400 with a concentration of 1.0 mg prepivir free base hemihydrate per mL of stock solution and two other commercially available artificial tears compositions.

[0719]

[0720]

[0721] Preparation of PEG200 stock solution 1 mg / mL DS

[0722] Equilibrate all liquids and DS to ≥20°C. Add 10 mL of PEG 200 to a 50 mL tube and dissolve 10 mg of DS in it. Mix the solution as follows: Vortex the tube for 5 seconds and shake the tube until the DS dissolves.

[0723] Preparation of PEG400 stock solution 1 mg / mL DS

[0724] Equilibrate all liquids and DS to ≥20°C. Add 10 mL of PEG 400 to a 50 mL tube and dissolve 10 mg of DS in it. Mix the solution as follows: Vortex the tube for 5 seconds and shake the tube until the DS dissolves.

[0725] Preparation of ophthalmic formulation 0.05 mg / mL DS

[0726] Add 2.0 mL of each stock solution to 38.0 mL of each artificial tear solution. Tears, or Tears, or Dilute the tear fluid and mix the solution as follows: vortex for 5 seconds or stir for 2 minutes.

[0727] Filter testing for all syringe filters

[0728] Repeat the test to ensure the sample is replicated three times (n=3). Draw 6 mL of the ophthalmic preparation using a 10 mL syringe. Determine the final concentration with 1 mL before filtration. Connect the syringe to the filter via Luer Lok and filter the solution. Obtain another sample after filtration to determine the final concentration.

[0729] Disconnect the filter from the syringe and draw 2 mL of DMSO using a new 10 mL syringe. Reconnect the syringe to the filter used via Luer Lok and filter the DMSO. Obtain a sample after washing to determine the final concentration.

[0730] Repeat this procedure for all tested filters. Test the following filter materials: PTFE, PVDF, and RC, each with a pore size of 0.2 μm.

[0731] use Stock solutions of PEG400 diluted with tears showed equivalent results before and after filtration with 0.2 μm PVDF (syringe filter). PVDF filters are not suitable for all other formulations. PVDF filters are suitable for only one of the six formulations.

[0732] PFTE filters are suitable for use and All preparations for tear dilution.

[0733] RC filters are suitable for all formulations containing any artificial tear solution, as well as PEG200 and PEG400 stock solutions.

[0734] Example 5

[0735] To investigate the stability of two grades of PEG and three different compositions of artificial tears in a sterile filtration combination using RC filter materials over 5 weeks at room temperature (RT) and 2°C–8°C, stock solutions of prepivirine free base hemihydrate at a concentration of 1.0 mg / mL in PEG200 or PEG400 were prepared. The stock solutions were diluted to a concentration of 0.05 mg / mL in the three different compositions of artificial tears and filtered through suitable sterile filters.

[0736]

[0737] Preparation of PEG200 stock solution 1 mg / mL DS

[0738] Equilibrate all liquids and DS to ≥20°C. Add 20 mL of PEG 200 to a 50 mL tube and dissolve 20 mg of DS in it. Mix the solution as follows: Vortex the tube for 5 seconds and shake the tube until the DS dissolves.

[0739] Preparation of PEG400 stock solution 1 mg / mL DS

[0740] Equilibrate all liquids and DS to ≥20°C. Add 20 mL of PEG 400 to a 50 mL tube and dissolve 20 mg of DS in it. Mix the solution as follows: Vortex the tube for 5 seconds and shake the tube until the DS dissolves.

[0741] Preparation of ophthalmic formulation 0.05 mg / mL

[0742] Dilute each stock solution with artificial tear solution in a beaker.

[0743]

[0744] Samples were taken from the top, middle, and bottom of each beaker to determine the final concentration.

[0745] Aseptic filtration

[0746] Draw 50 mL of the ophthalmic preparation using a 50 mL syringe. Then, connect the syringe to each filter via Luer Lok and filter the solution into a beaker. Repeat this procedure as needed: use the same filter and syringe for each batch number, and then fill the same beaker with the solution. Obtain a sample after filtration to determine the final concentration. Provide three empty 50 mL tubes and one 5 mL tube, and draw the contents of one beaker. Add 15 mL of the prepared preparation to each of the three empty 50 mL tubes, and add 5 mL to the empty 5 mL tube. Store the sample at room temperature and within the range of 2°C–8°C for 5 weeks.

[0747] Only those prepared using a stock solution of 1 mg / mL PEG200 and used can be evaluated. Tear-diluted ophthalmic formulations. Precipitation occurs in all other formulations, which may begin before the filtration step using PTFE and RC filters, each with a pore size of 0.2 μm.

[0748] Example 6

[0749] To further investigate the stability of ophthalmic formulations, prepirenylvir free base hemihydrate, a 1 mg / mL stock solution in PEG400, was provided and used... Tears are diluted.

[0750]

[0751] Preparation of 1 mg / mL stock solution of PEG400

[0752] Equilibrate all liquids and DS to ≥20°C. Add 20 mL of PEG 400 to a 50 mL tube and dissolve 20 mg of DS in it. Mix the solution as follows: Vortex the tube for 5 seconds and shake the tube until the DS dissolves.

[0753] Preparation of ophthalmic formulation 0.05 mg / mL

[0754] All samples were prepared at a ratio of six. The stock solution of 1 mg / mL prepirimib free base hemihydrate in PEG400 was prepared in a beaker and... Tear preparation ophthalmic formulations:

[0755]

[0756] Samples were taken from the top, middle, and bottom of each beaker to determine the final concentration.

[0757] Aseptic filtration

[0758] Draw the ophthalmic preparation into a 20 mL syringe. Then connect the syringe to an RC 0.2 μm filter via Luer Lok and filter the solution into the tube. After filtration, obtain a sample to determine the final concentration and store the sample at room temperature and within the range of 2 °C–8 °C for 5 weeks.

[0759] Six samples were prepared sequentially. Each sample took approximately 5 minutes. All preparations showed comparable test content before and after filtration. Therefore, preparation time is a critical process parameter. After one week, samples stored at room temperature showed increased impurities. Samples stored at temperatures ranging from 2 to 8°C were stable within one week.

[0760] Example 7

[0761] To investigate the effect of pH on the degradation and precipitation tendency of ophthalmic formulations, three artificial tears with different compositions were adjusted to pH 4.0, 5.0, and 6.0. A stock solution of prepirenzeb free base hemihydrate at a concentration of 1.0 mg / mL in PEG400 was prepared. The stock solution was diluted in pH-adjusted artificial tears at a concentration of 0.05 mg / mL prepirenzeb free base hemihydrate and filtered through an RC 0.2 μm sterile filter. As a result, it was preferable to perform the dilution steps one after another for each sample to keep the time before filtration short.

[0762]

[0763] Preparation of 1 mg / mL stock solution of PEG400

[0764] Equilibrate all liquids and DS to ≥20°C. Add 40 mL of PEG 400 to a 50 mL tube and dissolve 40 mg of DS in it. Mix the solution as follows: Vortex the tube for 5 seconds and shake the tube until the DS dissolves.

[0765] Preparation of pH-adjusted artificial tear solution

[0766] The pH values ​​of 4.0, 5.0, and 6.0 were adjusted by adding appropriate amounts of hydrochloric acid to the artificial tear solution.

[0767] Preparation of ophthalmic formulation 0.05 mg / mL

[0768] All samples were prepared in triplicate. Samples were prepared one after another to keep preparation time short and minimize the risk of precipitation. The stock solution was diluted in the tube with pH-adjusted artificial tear solution and gently mixed. Samples were obtained to determine the final concentration. A 20 mL volume was drawn from the tube using a 20 mL syringe. The syringe was then connected to an RC 0.2 mm filter via Luer Lok, and the solution was filtered in two 10 mL batches into two separate 50 mL tubes. Another sample was obtained after filtration to determine the final concentration.

[0769]

[0770] The samples were stored at room temperature and at a temperature ranging from 2°C to 8°C for 4 weeks.

[0771] No formulations showed significant changes in pH level over 4 weeks. A higher risk of precipitation was observed in formulations with higher pH values. The most stable ophthalmic formulations were those adjusted to pH 4. Tears. The formulation is stable for up to 3 weeks when stored at room temperature and in the range of 2°C–8°C.

[0772] Example 8

[0773] To determine the acceptable pH for ophthalmic use, a stock solution of prepillamivir free base hemihydrate in PEG400 was prepared at a concentration of 1.0 mg / mL. The stock solution was then... Dilute to a concentration of 0.05 mg / mL prepirenzeb free base hemihydrate in tear solution. Adjust ophthalmic formulations to pH 6.0, 6.5, and 7.0, then filter through an RC 0.2 μm sterile filter.

[0774]

[0775] Preparation of 1 mg / mL stock solution of PEG400

[0776] Equilibrate all liquids and DS to ≥20°C. Add 20 mL of PEG 400 to a 50 mL tube and dissolve 20 mg of DS in it. Mix the solution as follows: Vortex the tube for 5 seconds and shake the tube until the DS dissolves.

[0777] Pre-test for pH adjustment

[0778] Use the stock solution The tears were diluted in a 50 mL tube and the resulting solution was gently mixed.

[0779]

[0780] Add appropriate amounts of hydrochloric acid to adjust the pH to 6.0, 6.5, and 7.0. Gently mix the resulting solutions.

[0781] Preparation of ophthalmic formulation 0.05 mg / mL

[0782] Prepare all samples at a rate of six times. Prepare samples one after another to keep preparation time short and minimize the risk of precipitation. Use the stock solution... The tear solution was diluted in a 50 mL tube and the resulting solution was gently mixed.

[0783]

[0784] Hydrochloric acid was added to adjust the pH to 6.0 according to the amount determined in the pre-test, and samples were obtained before filtration to determine the final concentration. The entire contents of one tube were drawn using a 20 mL syringe. The syringe was then connected to an RC 0.2 μm filter via Luer Lok, and the solution was filtered into a 50 mL tube. Samples were obtained after filtration of each tube to determine the final concentration. Additionally, samples with corresponding pH values ​​of 6.5 and 7.0 were prepared. All samples were stored at room temperature and within the range of 2 °C–8 °C for 2 weeks.

[0785] A higher risk of precipitation was observed in formulations with higher pH values. Lower pH values ​​generally resulted in better stability over two weeks. No significant pH changes were observed in any of the samples over two weeks. The most stable ophthalmic formulation was the one adjusted to pH 6.0. The formulation was stable for one week when stored at room temperature. The ophthalmic formulation adjusted to pH 6.5 was almost as stable as that adjusted to pH 6.0. The ophthalmic formulation adjusted to pH 7.0 showed reduced stability after one week.

[0786] Comparative Example 1

[0787] To investigate whether prepillavir free base hemihydrate could be replaced by prepillavir mesylate, prepillavir mesylate monohydrate was used as the DS repeat experiment 8.

[0788]

[0789] The ophthalmic formulations containing prerivir mesylate monohydrate as a pharmaceutical substance also follow the preparation method of Example 8.

[0790] Surprisingly, it was found that prepillavir mesylate monohydrate could not be dissolved in PEG400 at a concentration of 1 mg / mL. Precipitation was observed, and the test level decreased significantly after filtration.

[0791] Comparative Example 2

[0792] To investigate whether prepillavir free base hemihydrate can be replaced by prepillavir maleate, prepillavir maleate was used as the DS repeat experiment 8.

[0793]

[0794] Surprisingly, it was found that a 1 mg / mL stock solution could not be prepared.

[0795] in conclusion:

[0796] Of the three drug substances tested, only prepirenylvir hemihydrate was suitable for preparing ophthalmic formulations. Experiments 1-10 discussed above indicate that the preferred ophthalmic formulation is derived from a 1 mg / mL PEG 400 stock solution. Tear solution (also known as The tears were diluted and adjusted to pH 6.0.

[0797] Examples of ophthalmic formulations

[0798] Formulation 1:

[0799] Prepared according to Example 8

[0800] Stock solution: 1 mg prepirenylvir free base hemihydrate / 1 ml PEG 400.

[0801] Ophthalmic preparations:

[0802] Use 0.4 ml of stock solution and 7.6 ml of... Prepare 8.0 ml ophthalmic preparation from the tear solution. Adjust the pH to 6.0.

[0803] Formulation 2:

[0804] Prepared according to Example 8.

[0805] Stock solution: 1 mg prepirenylvir free base hemihydrate / 1 ml PEG 400.

[0806] Ophthalmic preparations:

[0807] Use 0.4 ml of stock solution and 7.6 ml of... Prepare 8.0 ml ophthalmic formulation from the tear solution. Adjust the pH to 6.5.

[0808] Formulation 3:

[0809] Prepared according to Example 8.

[0810] Stock solution: 1 mg prepirenylvir free base hemihydrate / 1 ml PEG 400.

[0811] Ophthalmic preparations:

[0812] Use 0.4 ml of stock solution and 7.6 ml of... Prepare 8.0 ml ophthalmic preparation from the tear solution. Adjust the pH to 7.0.

[0813] Formulation 4:

[0814] Prepared according to Example 5.

[0815] Stock solution: 1 mg prepirenylvir free base hemihydrate / 1 ml PEG 200.

[0816] Ophthalmic preparations:

[0817] Use 8 ml of stock solution and 152 ml The tear solution yielded 160.0 ml of ophthalmic preparation. Additionally, the pH was adjusted to 6.0.

[0818] Formulation 5:

[0819] Prepared according to Example 5.

[0820] Stock solution: 1 mg prepirenylvir free base hemihydrate / 1 ml PEG 200.

[0821] Ophthalmic preparations:

[0822] Use 2.5 ml of stock solution and 47.5 ml The tear solution yielded 50.0 ml of ophthalmic preparation. Additionally, the pH was adjusted to 6.8.

[0823] Formulation 6:

[0824] Prepared according to Example 4.

[0825] Stock solutions: 1 mg prepirenzeb free base hemihydrate / 0.5 ml PEG 200 and 0.5 ml PEG 400.

[0826] Ophthalmic preparations:

[0827] Use 8 ml of stock solution and 152 ml The tear solution yielded 160.0 ml of ophthalmic preparation. Additionally, the pH was adjusted to 7.0.

[0828] Preparation 7:

[0829] Stock solution: 1.5 mg prepirenzeb free base hemihydrate / 1 ml PEG 300.

[0830] Artificial tear solution: 2.5 g / L glycerin, 2 g / L hydroxypropyl methylcellulose and 11.28 g / L polyethylene glycol 400 / pure water, containing polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, magnesium chloride, potassium chloride, sodium borate, sodium chloride, sodium citrate and / or sodium lactate.

[0831] Ophthalmic preparations:

[0832] Prepare 16.0 ml of ophthalmic preparation by mixing 1 ml of stock solution and 15 ml of artificial tear solution. Adjust the pH to 6.5.

Claims

1. Ophthalmic preparations, comprising: a) N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate b) Polyethylene glycol having an average molecular weight ranging from 200 g / mol to 400 g / mol, and c) An artificial tear solution, wherein the artificial tear solution contains glycerin, hydroxypropyl methylcellulose, and polyethylene glycol 400. The ophthalmic formulation has a pH value in the range of 6.0 to 7.0, and the artificial tear solution contains 0.2% by weight of glycerin, 0.2% by weight of hydroxypropyl methylcellulose, and 1% by weight of polyethylene glycol 400. Polyethylene glycol is included in the ophthalmic preparation in an amount ranging from 40 µg per ml of ophthalmic preparation to 70 µg per ml of ophthalmic preparation. The artificial tear solution is included in the ophthalmic preparation in an amount ranging from 0.9 g per ml of ophthalmic preparation to 1.3 g per ml of ophthalmic preparation; The artificial tear solution also contains carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, purified water, sodium borate, sodium chloride, sodium citrate, and / or sodium lactate.

2. The ophthalmic formulation according to claim 1, wherein the ophthalmic formulation has a viscosity of 25 cps to 50 cps.

3. The ophthalmic formulation according to claim 1 or 2, wherein N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)-phenyl]acetamide hemihydrate is contained in the ophthalmic formulation in an amount ranging from 40 µg per ml of ophthalmic formulation to 60 µg per ml of ophthalmic formulation.

4. A method for preparing an ophthalmic formulation as defined in claim 1, the method comprising the following steps: I) Provides N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate. II) Provide polyethylene glycol having an average molecular weight ranging from 200 g / mol to 400 g / mol. III) Provide an artificial tear solution, wherein the artificial tear solution contains glycerin, hydroxypropyl methylcellulose, and polyethylene glycol 400. IV) Preparation of a stock solution of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazolyl-2-yl]-N-methyl-2-[4-(2-pyridyl)phenyl]acetamide hemihydrate in polyethylene glycol. V) Dilute the stock solution with artificial tears solution until the desired concentration is achieved. VI) Adjust the pH to the desired range of 6.0 to 7.0 by adding an aqueous solution of acid. VII) The ophthalmic preparation is obtained by aseptic filtration through a suitable sterile filter. The artificial tear solution contains 0.2% by weight glycerin, 0.2% by weight hydroxypropyl methylcellulose, and 1% by weight polyethylene glycol 400. Polyethylene glycol is included in the ophthalmic preparation in an amount ranging from 40 µg per ml of ophthalmic preparation to 70 µg per ml of ophthalmic preparation. The artificial tear solution is included in the ophthalmic preparation in an amount ranging from 0.9 g per ml of ophthalmic preparation to 1.3 g per ml of ophthalmic preparation; The artificial tear solution also contains carboxymethyl cellulose, dextran, polysorbate, polyvinyl alcohol, polyvinylpyrrolidone, propylene glycol, ascorbic acid, benzalkonium chloride, boric acid, dextrose, disodium hydrogen phosphate, glycine, magnesium chloride, potassium chloride, purified water, sodium borate, sodium chloride, sodium citrate, and / or sodium lactate.

5. The method of claim 4, wherein the aseptic filtration is performed using a regenerated cellulose (RC) 0.2µm filter.

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