Degradant compound in a medicament

Abstract

This invention relates to an ophthalmic compound containing carbohydrate, brimonidine, and less than 5% of one or more impurities; a method for preparing an ophthalmic compound containing carbohydrate, brimonidine, and less than 5% of one or more impurities; and a method for treating presbyopia and other ophthalmic conditions by administering an ophthalmic compound containing carbohydrate, brimonidine, and less than 5% of one or more impurities.

Description

Technical Field

[0001] This invention relates to ophthalmic formulations comprising carbohydrate choline, brimonidine, and less than 5% by weight of one or more impurities. The disclosed formulations are suitable for treating ophthalmic conditions such as presbyopia. Prior Technology

[0002] Presbyopia is a common age-related degeneration of the eye. Young, normally functioning eyes can see objects at close range, an ability that declines with age. Presbyopia typically develops with age and is associated with a natural, progressive loss of accommodation. It involves a loss of the ability to quickly and easily focus on near objects. Presbyopia progresses throughout an individual's lifespan, usually becoming noticeable after age 45. By age 65, the lens has typically lost almost all its elasticity and retains only a limited ability to change shape.

[0003] Using over-the-counter reading glasses is a very common way to address vision problems related to presbyopia. Reading glasses allow the eyes to focus on nearby objects and maintain a clear image. This method is similar to the treatment for farsightedness or hyperopia.

[0004] Many presbyopic patients are also prescribed bifocal glasses, where one part of the lens corrects distance vision and the other part corrects near vision. When looking down through the bifocal glasses, the person views objects through the near vision portion of the lens. When observing distant objects, the person views them through the distance vision portion of the bifocal glasses at a higher line of sight. Contact lenses and intraocular lenses (IOLs) have also been used to treat presbyopic vision, for example, by relying on monocular vision (one eye corrects distance vision and the other eye corrects near vision) or by using bifocal or multifocal glasses for bidirectional correction. Laser excision has also been used to treat presbyopic vision. All of these procedures involve drastic steps (surgery, laser excision, etc.) to seek a long-term solution or require the wearing of corrective lenses.

[0005] For patients who do not wish to undergo surgery (IOL, laser eye removal, etc.) or use corrective lenses, new methods for improving or reducing presbyopia are still needed. For those who use corrective lenses, there is still a need for temporary treatment of presbyopia without the use of corrective lenses.

[0006] As with any formulation designed to treat individuals in need, it is crucial to identify and quantify any impurities present in the formulation. Specifically, formulations containing two or more active agents may cause unintended reactivity between these agents, leading to the formation of impurities. Therefore, it is necessary to identify and quantify any impurities present in ophthalmic formulations containing carbohydrate and brimonidine. Summary of the Invention

[0007] This invention provides an ophthalmic formulation containing carbohydrate, brimonidine, and less than 5% by weight of one or more impurities.

[0008] In some formulations, the ophthalmic formulation contains about 2% to about 4% by weight of carbohydrate choline or a pharmaceutically acceptable salt thereof, about 0.05% to about 0.2% by weight of brimonidine or a pharmaceutically acceptable salt thereof, about 0.05% to about 1% by weight of one or more adhesives, and about 0.05% to about 1% by weight of one or more buffers, wherein the pH of the formulation is about 7 to about 7.6, and wherein after about 5 months of storage, the formulation contains less than 5% by weight of impurity A, wherein impurity A has the following structure: , Or its tautomer, wherein the concentration of impurity A was measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity A relative to brimonidine was approximately 0.9.

[0009] In some formulations, ophthalmic preparations can be stored for approximately 5 months at 40°C and a relative humidity not exceeding 25% (NMT).

[0010] In some samples, after storage at 40°C and NMT 25% relative humidity for approximately 3 months, the ophthalmic formulation contained less than 3% by weight of impurity A.

[0011] In some formulations, ophthalmic formulations contain less than 0.25% by weight of impurity A.

[0012] In some samples, after storage at 25°C and 40% relative humidity for about 5 months, the ophthalmic formulation contained less than 1% by weight of impurity A.

[0013] In some formulations, the ophthalmic formulation contains about 2.75% by weight of carbohydrate, about 0.1% by weight of brimonidine, about 0.2% by weight of HPMC, and about 0.05% to about 1% by weight of one or more buffer solutions, wherein the pH is about 7.4, and wherein the formulation contains less than about 5% by weight of impurity A after about 5 months of storage, wherein the concentration of impurity A is measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity A relative to brimonidine is about 0.9.

[0014] In some formulations, the ophthalmic formulation contains about 2.75% by weight of carbohydrate, about 0.1% by weight of brimonidine, about 0.01% by weight of benzalkonium chloride and about 0.2% by weight of HPMC, with a pH of about 7.4.

[0015] In some formulations, the ophthalmic compound further contains impurity B, wherein after approximately 5 months of storage, the compound contains less than 2% by weight of impurity B, wherein impurity B has the following structure: , Or its tautomer, wherein the concentration of impurity B was measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity B relative to brimonidine was approximately 0.67.

[0016] In some samples, ophthalmic formulations contained less than 0.1% by weight of impurity B after approximately 5 months of storage.

[0017] In some samples, after storage at 40°C and 25% NMT relative humidity for approximately 5 months, the ophthalmic formulation contained less than 2% by weight of impurity B.

[0018] In some samples, after storage at 25°C and 40% relative humidity for about 3 months, the ophthalmic formulation contained less than 0.25% by weight of impurity B.

[0019] In some formulations, the ophthalmic formulation contains about 2% to about 4% by weight of carbohydrate choline or a pharmaceutically acceptable salt thereof, about 0.05% to about 0.2% by weight of brimonidine or a pharmaceutically acceptable salt thereof, about 0.05% to about 1% by weight of one or more adhesives, and about 0.05% to about 0.1% by weight of one or more buffer solutions, wherein the pH of the formulation is about 7 to about 7.6, and wherein after about 5 months of storage, the formulation contains less than 5% by weight of impurity B, wherein the concentration of impurity B is measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity B relative to brimonidine is about 0.67.

[0020] In some formulations, the ophthalmic formulation contains about 2.75% by weight of carbohydrate, about 0.1% by weight of brimonidine, about 0.2% by weight of HPMC, and about 0.05% to about 1% by weight of one or more buffer solutions, wherein the pH is about 7.4, and wherein the formulation contains less than about 2% by weight of impurity B after about 5 months of storage, wherein the concentration of impurity B is measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity B relative to brimonidine is about 0.67.

[0021] In some cases, the ophthalmic formulations described herein contain one or more buffers selected from the group consisting of: acetate buffer, borate buffer, citrate-borate buffer, carbonate buffer, citrate buffer, lactate buffer, and phosphate buffer.

[0022] In some cases, the ophthalmic formulations described herein contain one or more buffer solutions, wherein the one or more buffer solutions are phosphate buffers.

[0023] In some samples, phosphate buffer contains sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate heptahydrate.

[0024] In some cases, the ophthalmic formulations described herein contain one or more adhesives selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, and polyvinylpyrrolidone.

[0025] In some cases, the ophthalmic formulations described herein contain HPMC.

[0026] In some formulations, the ophthalmic formulations described herein contain about 0.0025% by weight to about 0.02% by weight of benzalkonium chloride.

[0027] In some cases, the ophthalmic formulations described herein do not contain EDTA.

[0028] The present invention also provides compounds that can be formed as impurities in formulations containing carbohydrate and brimonidine.

[0029] In some samples, the compound is impurity A, which has the following structure: , Or its tautomers, salts or solvates.

[0030] In some samples, the compound is impurity B, which has the following structure: ,

[0031] Or its tautomers, salts or solvates.

[0032] The present invention also provides a method for preparing an ophthalmic formulation containing carbohydrate and brimonidine.

[0033] In some embodiments, the present invention provides a method for manufacturing an ophthalmic formulation comprising about 2% to about 4% by weight of carbohydrate or a medically acceptable salt thereof, about 0.05% to about 0.2% by weight of brimonidine or a medically acceptable salt thereof, about 0.05% to about 1% by weight of one or more viscosity agents and about 0.05% to about 1% by weight of one or more buffer solutions, wherein the pH of the formulation is about 7 to about 7.6, the method comprising adding carbohydrate or a medically acceptable salt thereof, brimonidine or a medically acceptable salt thereof and one or more viscosity agents to water and stirring to obtain the formulation.

[0034] In some samples, one or more buffer solutions contain sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate heptahydrate.

[0035] In some samples, one or more adhesives are hydroxypropyl methylcellulose (HPMC).

[0036] In some samples, the method involves adding benzalkonium chloride.

[0037] In some cases, the method involves adding sodium chloride.

[0038] In some cases, the method involves adding hydrochloric acid.

[0039] In some cases, the method involves adding sodium hydroxide.

[0040] In some cases, the ophthalmic preparation is aseptically filled into vials.

[0041] In some samples, each vial is filled with approximately 0.1 g to approximately 0.3 g of ophthalmic preparation.

[0042] In some samples, each vial is filled with approximately 2 g to approximately 2.7 g of ophthalmic preparation.

[0043] The present invention also provides a method for improving or alleviating presbyopia in an individual, the method comprising administering an ophthalmic compound as described herein.

[0044] The present invention also provides methods for: improving or reducing at least one refractive error in an individual with hyperopia; relaxing the ciliary muscle of an individual under sympathetic stimulation to reduce at least one of headache, migraine, and periorbital pain; preventing myopic conversion induced by parasympathetic effects in presbyopic patients receiving parasympathomimetic drugs or medically acceptable salts thereof; improving or reducing at least one refractive error selected from the group consisting of myopia, hyperopia, and astigmatism in pseudophakic patients; treating at least one refractive error in patients who have undergone eye surgery; and generating multifocality in pseudophakic patients, the methods comprising administering the ophthalmic dressings described herein. Implementation

[0045] definition

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the event of conflict, the application including the definitions shall prevail. Unless the context otherwise requires, singular terms include plural and plural terms include singular. For all purposes, all publications, patents and other references mentioned herein are incorporated herein by full citation as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0047] Suitable methods and materials are described below, but similar or equivalent methods and materials may be used to practice or test the invention. The materials, methods, and examples are illustrative only and are not intended to be limiting. Other features and advantages of the invention will become apparent from the implementation and the scope of the claims.

[0048] To further define this invention, the following terms and definitions are provided.

[0049] Unless the context clearly specifies otherwise, the singular forms “a / an” and “the” include a plural reference. The terms “a / an”, “one or more”, and “at least one” are used interchangeably herein. In some instances, the term “a / an” means “single.” In other instances, the term “a / an” includes “two or more” or “a plurality of”.

[0050] The term "about" is used herein to mean approximately, roughly, or within a range. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the upper and lower limits of the stated value. Generally, the term "about" is used herein to modify values ​​that are greater or less than the stated value, that is, higher or lower (increase or decrease) by 10%.

[0051] The term "and / or" as used herein should be considered as a specific disclosure of each of two specified features or components in the presence or absence of the other. Therefore, the term "and / or" as used in phrases such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of the following states: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0052] As used herein, the term "medically acceptable" means, within the bounds of reasonable medical judgment, a compound, material, composition, formulation, and / or dosage form that is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and whose benefits / risks are commensurate with a reasonable ratio.

[0053] The term "excipient" means any substance that is not itself a therapeutic agent but can be used in a composition to deliver an active therapeutic agent to an individual, or combined with an active therapeutic agent (e.g., to produce a pharmaceutical composition) to improve its handling or storage properties, or to allow or facilitate the formation of a dosage unit of the composition. Excipients can be inert, inactive, and / or non-pharmaceutical active substances.

[0054] As used herein, the terms “effective amount” or “medically effective amount” or “therapeutic effective amount” refer to the amount or quantity of a drug or pharmaceutically active substance that is sufficient to elicit a desired or required therapeutic response, or in other words, the amount that, when administered to a patient, is sufficient to elicit a significant biological response.

[0055] "Administration" or "dosing" refers to the process of giving (i.e., providing) a pharmaceutical composition to an individual. The pharmaceutical compositions disclosed herein can be "topically administered," that is, administered at or near the site where a therapeutic result or outcome is desired. For example, to treat an eye condition such as corneal pain, an ophthalmic preparation can be directly administered topically to an individual's eye, and this is an example of topically administered medication.

[0056] The term "medically acceptable salt" is recognized in this technology and includes relatively non-toxic inorganic and organic acid addition salts and relatively non-toxic inorganic and organic base addition salts of compounds.

[0057] Inorganic acids that can be used to prepare pharmaceutically acceptable salts include (but are not limited to) hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, and similar acids. Organic acids that can be used to prepare pharmaceutically acceptable salts include (but are not limited to) aliphatic monocarboxylic acids and dicarboxylic acids, such as tartaric acid, oxalic acid, carbonic acid, citric acid, succinic acid, phenyl heteroatom-substituted alkyl acids, aliphatic and aromatic sulfuric acids, and similar acids. Therefore, pharmaceutically acceptable salts prepared from inorganic or organic acids include (but are not limited to) hydrochlorides, hydrobromic acids, nitrates, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, hydroiodates, hydrofluoric acids, acetates, propionates, formates, oxalates, tartrates, citrates, lactates, p-toluenesulfonates, methanesulfonates, and maleates. Suitable pharmaceutically acceptable salts can also be formed by reacting the active component with an organic base (such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and analogues). Pharmaceutically acceptable salts include salts formed by reacting carboxyl or sulfonate ions, which can be found on some active components, with inorganic cations (such as sodium, potassium, ammonium, or calcium) or organic cations (such as isopropylammonium, trimethylammonium, tetramethylammonium, and imidazoline). All such salts can be prepared from the active component of the present invention by conventional methods, for example by reacting a suitable acid or base with the active component of the present invention.

[0058] As used herein, the terms “unit dosage form” or “unit dose composition” refer to a quantity of compound, such as a drop or a small drop, that allows one or more predetermined units to be provided in a single therapeutic dose.

[0059] As used herein, "treatment" refers to a reduction or improvement in the progression, severity, and / or duration of a given disease caused by the administration of one or more therapies (including, but not limited to, the administration of ophthalmic preparations). In some contexts, the term refers to the relief of pain associated with one or more diseases or symptoms.

[0060] As used herein, the terms "% by weight" or "weight / volume" refer to the ratio of two components in terms of volume. For example, an aqueous solution containing 5% by weight of ethanol means that each 100 mL of water contains a solution of 5 g of ethanol.

[0061] As used herein, the term "mg / mL" refers to the ratio between a solute (usually an active pharmaceutical ingredient or excipient) and a solvent (usually, but not necessarily, water). For example, a 50 mg / mL sodium chloride aqueous solution means a solution containing 50 mg of sodium chloride per 1 mL of water.

[0062] The term "stable" is used herein to describe a composition in which most or all of the active pharmaceutical ingredients do not degrade or transform within a specific time period and under specific conditions. impurity compounds

[0063] The present invention provides a compound that can be formed as an impurity in a formulation containing carbohydrate and brimonidine.

[0064] In some samples, the compound is 2-((5-bromoquinazolin-6-yl)amino)-4,5-dihydro-1H-imidazol-1-methylamine ("Impurity A"), which has the following structure: , Or its tautomers.

[0065] In some samples, when measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, the relative retention time (RRT) of impurity A relative to brimonidine was approximately 0.9.

[0066] In some samples, the compound is 1-(5-bromoquinazolin-6-yl)-3-(2-ureidoethyl)urea ("Impurity B"), which has the following structure: , Or its tautomers.

[0067] In some samples, when measured by HPLC in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, the RRT of impurity B relative to brimonidine was approximately 0.67. ophthalmic preparations

[0068] The present invention also provides ophthalmic formulations comprising carbohydrate, brimonidine, pharmaceutically acceptable excipients, and less than 5% by weight of one or more impurities.

[0069] In some samples, the impurity is 2-((5-bromoquinazolin-6-yl)amino)-4,5-dihydro-1H-imidazol-1-methylamine ("Impurity A"), which has the following structure: , Or its tautomers.

[0070] In some samples, when measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, the relative retention time (RRT) of impurity A relative to brimonidine was approximately 0.9.

[0071] In some samples, the impurity is 1-(5-bromoquinazolin-6-yl)-3-(2-ureidoethyl)urea ("Impurity B"), which has the following structure: , Or its tautomers.

[0072] In some samples, when measured by HPLC in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, the RRT of impurity B relative to brimonidine was approximately 0.67.

[0073] In some formulations, the ophthalmic formulation contains about 2% to about 4% by weight of carbohydrate choline or a pharmaceutically acceptable salt thereof, about 0.05% to about 0.2% by weight of brimonidine or a pharmaceutically acceptable salt thereof, about 0.05% to about 1% by weight of one or more adhesives and about 0.05% to about 1% by weight of one or more buffers, wherein the pH of the formulation is about 7 to about 7.6, and wherein the formulation contains less than 5% by weight of impurity A after about 5 months of storage.

[0074] In some formulations, the ophthalmic formulation contains carbohydrate choline or a pharmaceutically acceptable salt thereof in the following amounts: about 0.25 wt% to about 0.5 wt%, about 0.25 wt% to about 0.75 wt%, about 0.25 wt% to about 1 wt%, about 0.25 wt% to about 1.25 wt%, about 0.25 wt% to about 1.5 wt%, about 0.25 wt% to about 1.75 wt%, about 0.25 wt% to about 2 wt%, about 0.25 wt% to about 2.25 wt%, about 0.25 wt% to about 2.5 wt%, about 0.25 wt% to about 2.75 wt%, about 0.25 wt% to about 3 wt%, about 0.25 wt% to about 3.25 wt%, about 0.25 wt% to about 3.5 wt%, about 0.25 wt% to about 3.75 wt%, about 0.25 wt% to about 4 wt%, about 0.25 wt% to about 4.25 wt%, about 0.25 wt% to about 4.5 wt%, about 0.25 wt% to about 4.75 wt%, about 0.25 wt% to about 5 wt%, about 0.5 wt% to about 0.75 wt%, about 0.5 wt% to about 1 wt%, about 0.5 wt% to about 1.25 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 1.75 wt%, about 0.5 wt% to about 2 wt%, about 0.5 wt% to about 2.25 wt%, about 0.5 wt% to about 2.5 wt%, about 0.5 wt% to about 2.75 wt%. % by weight, about 0.5% by weight to about 3% by weight, about 0.5% by weight to about 3.25% by weight, about 0.5% by weight to about 3.5% by weight, about 0.5% by weight to about 3.75% by weight, about 0.5% by weight to about 4% by weight, about 0.5% by weight to about 4.25% by weight, about 0.5% by weight to about 4.5% by weight, about 0.5% by weight to about 4.75% by weight, about 0.5% by weight to about 5% by weight, about 0.75% by weight to about 1% by weight, about 0.75% by weight to about 1.25% by weight, about 0.75% by weight to about 1.5% by weight, about 0.75% by weight to about 1.75% by weight, about 0.75% by weight to about 2% by weight, about 0.75% by weight to about 2.25% by weight, about 0% by weight 0.75 wt% to about 2.5 wt%, about 0.75 wt% to about 2.75 wt%, about 0.75 wt% to about 3 wt%, about 0.75 wt% to about 3.25 wt%, about 0.75 wt% to about 3.5 wt%, about 0.75 wt% to about 3.75 wt%, about 0.75 wt% to about 4 wt%, about 0.75 wt% to about 4.25 wt%, about 0.75 wt% to about 4.5 wt%, about 0.75 wt% to about 4.75 wt%, about 0.75 wt% to about 5 wt%, about 1 wt% to about 1.25 wt%, about 1 wt% to about 1.5 wt%, about 1 wt% to about 1.75 wt%, about 1 wt% to about 2 wt%, about 1 wt% to about 2.25 wt%, about 1 wt% to about 2.5 wt%, about 1 wt% to about 2.75 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 3.25 wt%, about 1 wt% to about 3.5 wt%, about 1 wt% to about 3.75 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 4.25 wt%, about 1 wt% to about 4.5 wt%, about 1 wt% to about 4.75 wt%, about 1 wt% to about 5 wt%, about 1.25 wt% to about 1.5 wt%, about 1.25 wt% to about 1.75 wt%, about 1.25 wt% to about 2 wt%, about 1.25 wt% to about 2.25 wt%, about 1.25 wt% to about 2.5 wt%, about 1. 25 wt% to about 2.75 wt%, about 1.25 wt% to about 3 wt%, about 1.25 wt% to about 3.25 wt%, about 1.25 wt% to about 3.5 wt%, about 1.25 wt% to about 3.75 wt%, about 1.25 wt% to about 4 wt%, about 1.25 wt% to about 4.25 wt%, about 1.25 wt% to about 4.5 wt%, about 1.25 wt% to about 4.75 wt%, about 1.25 wt% to about 5 wt%, about 1.5 wt% to about 1.75 wt%, about 1.5 wt% to about 2 wt%, about 1.5 wt% to about 2.25 wt%, about 1.5 wt% to about 2.5 wt%, about 1.5 wt% to about 2.75 wt%, about 1.5 wt% to about 3 wt%, about 1.5 wt% to about 3.25 wt%, about 1.5 wt% to about 3.5 wt%, about 1.5 wt% to about 3.75 wt%, about 1.5 wt% to about 4 wt%, about 1.5 wt% to about 4.25 wt%, about 1.5 wt% to about 4.5 wt%, about 1.5 wt% to about 4.75 wt%, about 1.5 wt% to about 5 wt%, about 1.75 wt% to about 2 wt%, about 1.75 wt% to about 2.25 wt%, about 1.75 wt% to about 2.5 wt%, about 1.75 wt% to about 2.75 wt%, about 1.75 wt% to about 3 wt%, about 1.75 wt% to about 3.25 wt%, about 1.75 wt% From approximately 1.75% to approximately 3.75% by weight, from approximately 1.75% to approximately 4% by weight, from approximately 1.75% to approximately 4.25% by weight, from approximately 1.75% to approximately 4.5% by weight, from approximately 1.75% to approximately 4.75% by weight, from approximately 1.75% to approximately 5% by weight, from approximately 2% to approximately 2.25% by weight, from approximately 2% to approximately 2.5% by weight, from approximately 2% to approximately 2.75% by weight, from approximately 2% to approximately 3% by weight, from approximately 2% to approximately 3.25% by weight, from approximately 2% to approximately 3.5% by weight, from approximately 2% to approximately 3.75% by weight, from approximately 2% to approximately 4% by weight, from approximately 2% to approximately 4.25% by weight, from approximately 2% to approximately 4.5 wt%, about 2 wt% to about 4.75 wt%, about 2 wt% to about 5 wt%, about 2.25 wt% to about 2.5 wt%, about 2.25 wt% to about 2.75 wt%, about 2.25 wt% to about 3 wt%, about 2.25 wt% to about 3.25 wt%, about 2.25 wt% to about 3.5 wt%, about 2.25 wt% to about 3.75 wt%, about 2.25 wt% to about 4 wt%, about 2.25 wt% to about 4.25 wt%, about 2.25 wt% to about 4.5 wt%, about 2.25 wt% to about 4.75 wt%, about 2.25 wt% to about 5 wt%, about 2.5 wt% to about 2.75 wt%, about 2.5 wt% to about 3 wt%. Approximately 2.5% by weight to approximately 3.25% by weight, approximately 2.5% by weight to approximately 3.5% by weight, approximately 2.5% by weight to approximately 3.75% by weight, approximately 2.5% by weight to approximately 4% by weight, approximately 2.5% by weight to approximately 4.25% by weight, approximately 2.5% by weight to approximately 4.5% by weight, approximately 2.5% by weight to approximately 4.75% by weight, approximately 2.5% by weight to approximately 5% by weight, approximately 2.75% by weight to approximately 3% by weight, approximately 2.75% by weight to approximately 3.25% by weight, approximately 2.75% by weight to approximately 3.5% by weight, approximately 2.75% by weight to approximately 4% by weight, approximately 2.75% by weight to approximately 4.25% by weight, approximately 2.75% by weight to approximately 4.5% by weight, approximately 2 0.75 wt% to about 4.75 wt%, about 2.75 wt% to about 5 wt%, about 3 wt% to about 3.25 wt%, about 3 wt% to about 3.5 wt%, about 3 wt% to about 3.75 wt%, about 3 wt% to about 4 wt%, about 3 wt% to about 4.25 wt%, about 3 wt% to about 4.5 wt%, about 3 wt% to about 4.75 wt%, about 3 wt% to about 5 wt%, about 3.25 wt% to about 3.5 wt%, about 3.25 wt% to about 3.75 wt%, about 3.25 wt% to about 4 wt%, about 3.25 wt% to about 4.25 wt%, about 3.25 wt% to about 4.5 wt%, about 3.25 wt% to about 4.75 wt%, about 3. 25% by weight to about 5% by weight, about 3.5% by weight to about 3.75% by weight, about 3.5% by weight to about 4% by weight, about 3.5% by weight to about 4.25% by weight, about 3.5% by weight to about 4.5% by weight, about 3.5% by weight to about 4.75% by weight, about 3.5% by weight to about 5% by weight, about 3.75% by weight to about 4% by weight, about 3.75% by weight to about 4.25% by weight, about 3.75% by weight to about 4.5% by weight, about 4% by weight to about 4.75% by weight, about 4% by weight to about 5% by weight, about 4%.From 25% by weight to about 4.5% by weight, from about 4.25% by weight to about 4.75% by weight, from about 4.25% by weight to about 5% by weight, from about 4.5% by weight to about 4.75% by weight, from about 4.5% by weight to about 5% by weight, or from about 4.75% by weight to about 5% by weight. In some formulations, the ophthalmic formulation contains from about 2% by weight to about 4% by weight of carbohydrate choline or a pharmaceutically acceptable salt thereof.

[0075] In some formulations, the ophthalmic compound contains carbohydrate or a pharmaceutically acceptable salt thereof in the following amounts: about 0.25% by weight, about 0.5% by weight, about 0.75% by weight, about 1% by weight, about 1.25% by weight, about 1.5% by weight, about 1.75% by weight, about 2% by weight, about 2.25% by weight, about 2.5% by weight, about 2.75% by weight, about 3% by weight, about 3.25% by weight, about 3.5% by weight, about 3.75% by weight, about 4% by weight, about 4.25% by weight, about 4.5% by weight, about 4.75% by weight, or about 5% by weight. In some formulations, the ophthalmic compound contains about 2.75% by weight of carbohydrate or a pharmaceutically acceptable salt thereof.

[0076] In some formulations, the ophthalmic compound contains the following amounts of brimonidine or its pharmaceutically acceptable salt: about 0.05% to about 0.1% by weight, about 0.05% to about 0.15% by weight, about 0.05% to about 0.2% by weight, about 0.05% to about 0.25% by weight, about 0.05% to about 0.3% by weight, about 0.05% to about 0.35% by weight, about 0.05% to about 0.4% by weight, about 0.05% to about 0.45% by weight, about 0.05% to about 0.5% by weight, and about 0.1% to [amount missing]. About 0.15 wt%, about 0.1 wt% to about 0.2 wt%, about 0.1 wt% to about 0.25 wt%, about 0.1 wt% to about 0.3 wt%, about 0.1 wt% to about 0.35 wt%, about 0.1 wt% to about 0.4 wt%, about 0.1 wt% to about 0.45 wt%, about 0.1 wt% to about 0.5 wt%, about 0.15 wt% to about 0.2 wt%, about 0.15 wt% to about 0.25 wt%, about 0.15 wt% to about 0.3 wt%, about 0.15 wt% to about 0.35 wt%, about 0.15 wt% Amount % to about 0.4 wt%, about 0.15 wt% to about 0.45 wt%, about 0.15 wt% to about 0.5 wt%, about 0.2 wt% to about 0.25 wt%, about 0.2 wt% to about 0.3 wt%, about 0.2 wt% to about 0.35 wt%, about 0.2 wt% to about 0.4 wt%, about 0.2 wt% to about 0.45 wt%, about 0.2 wt% to about 0.5 wt%, about 0.25 wt% to about 0.3 wt%, about 0.25 wt% to about 0.35 wt%, about 0.25 wt% to about 0.4 wt%, about 0. 25% by weight to about 0.45% by weight, about 0.25% by weight to about 0.5% by weight, about 0.3% by weight to about 0.35% by weight, about 0.3% by weight to about 0.4% by weight, about 0.3% by weight to about 0.45% by weight, about 0.3% by weight to about 0.5% by weight, about 0.35% by weight to about 0.45% by weight, about 0.35% by weight to about 0.5% by weight, about 0.4% by weight to about 0.45% by weight, about 0.4% by weight to about 0.5% by weight, or about 0.45% by weight to about 0.5% by weight. In some formulations, the ophthalmic compound contains about 0.05% by weight to about 0.2% by weight of brimonidine or a pharmaceutically acceptable salt thereof.

[0077] In some formulations, the ophthalmic compound contains about 0.05% by weight, about 0.15% by weight, about 0.2% by weight, about 0.25% by weight, about 0.30% by weight, about 0.35% by weight, about 0.40% by weight, about 0.45% by weight, or about 0.5% by weight of brimonidine or a pharmaceutically acceptable salt thereof. In some formulations, the ophthalmic compound contains about 0.1% by weight of brimonidine or a pharmaceutically acceptable salt thereof.

[0078] In some formulations, the pharmaceutically acceptable salt of brimonidine is brimonidine tartrate.

[0079] In some formulations, ophthalmic formulations contain one or more adhesives. Non-limiting examples of adhesives include hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium chondroitin sulfate, and sodium hyaluronate. Other acceptable adhesives include (but are not limited to) acacia / gum arabic, agar, magnesium aluminum silicate, sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer, carrageenan, carbopol, xanthan, cellulose, microcrystalline cellulose (MCC), carob, chitin, carboxymethyl chitosan, carrageenan, dextrose, red algae gum, gelatin, ghatti gum, guar gum, lithium saponite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, guizitan gum, xanthum gum, and tragacanth gum. tragacanth), ethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), oxidized polygelatin, pectin, polygelatin peptide, povidone, propyl carbonate, ethylene methyl ether / maleic anhydride copolymer (PVM / MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), silicon dioxide, polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrin and sucralose) and combinations thereof.

[0080] In some formulations, ophthalmic formulations contain hydroxypropyl methylcellulose or carboxymethyl cellulose.

[0081] In some formulations, the ophthalmic compound contains one or more of the following adhesives in amounts: about 0.05 wt% to about 0.1 wt%, about 0.05 wt% to about 0.25 wt%, about 0.05 wt% to about 0.5 wt%, about 0.05 wt% to about 0.75 wt%, about 0.05 wt% to about 1 wt%, about 0.1 wt% to about 0.25 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 0.75 wt%, about 0.1 wt% to about 1 wt%, about 0.25 wt% to about 0.5 wt%, about 0.25 wt% to about 0.75 wt%, about 0.25 wt% to about 1 wt%, about 0.5 wt% to about 0.75 wt%, about 0.5 wt% to about 1 wt%, or about 0.75 wt% to about 1 wt%. In some formulations, the ophthalmic compound contains one or more adhesives in amounts from about 0.05 wt% to about 1 wt%.

[0082] In some formulations, the ophthalmic formulation contains one or more of the following adhesives in amounts: about 0.05% by weight, about 0.1% by weight, about 0.15% by weight, about 0.2% by weight, about 0.25% by weight, about 0.5% by weight, about 0.75% by weight, or about 1% by weight. In some formulations, the ophthalmic formulation contains about 0.2% by weight of one or more adhesives.

[0083] In some samples, the viscosity of the ophthalmic formulation is about 1 cP to about 5 cP, about 1 cP to about 10 cP, about 1 cP to about 15 cP, about 1 cP to about 20 cP, about 1 cP to about 30 cP, about 1 cP to about 40 cP, about 1 cP to about 50 cP, about 1 cP to about 60 cP, about 1 cP to about 80 cP, about 1 cP to about 100 cP, about 1 cP to about 125 cP, about 1 cP to about 150 cP, about 1 cP to about 175 cP, about 1 cP to about 200 cP, about 1 cP to about 400 cP, about 5 cP to about 10 cP, about 5 cP to about 15 cP, about 5 cP to about 20 cP, about 5 cP to about 30 cP, about 5 cP to about 40 cP, about 5 cP to about 50 cP, about 5 cP to about 60 cP, about 5 cP to about 5 cP. cP to about 80 cP, about 5 cP to about 100 cP, about 5 cP to about 125 cP, about 5 cP to about 150 cP, about 5 cP to about 175 cP, about 5 cP to about 200 cP, about 5 cP to about 400 cP, about 10 cP to about 15 cP, about 10 cP to about 20 cP, about 10 cP to about 30 cP, about 10 cP to about 40 cP, about 10 cP to about 50 cP, about 10 cP to about 60 cP, about 10 cP to about 80 cP, about 10 cP to about 100 cP, about 10 cP to about 125 cP, about 10 cP to about 150 cP, about 10 cP to about 175 cP, about 10 cP to about 200 cP, about 10 cP to about 400 cP, about 15 cP to about 20 cP, about 15 cP to about 30 cP cP, approximately 15 cP to approximately 40 cP, approximately 15 cP to approximately 50 cP, approximately 15 cP to approximately 60 cP, approximately 15 cP to approximately 80 cP, approximately 15 cP to approximately 100 cP, approximately 15 cP to approximately 125 cP, approximately 15 cP to approximately 150 cP, approximately 15 cP to approximately 175 cP, approximately 15 cP to approximately 200 cP, approximately 15 cP to approximately 400 cP, approximately 20 cP to approximately 30 cP, approximately 20 cP to approximately 40 cP, approximately 20 cP to approximately 50 cP, approximately 20 cP to approximately 60 cP, approximately 20 cP to approximately 80 cP, approximately 20 cP to approximately 100 cP, approximately 20 cP to approximately 125 cP, approximately 20 cP to approximately 150 cP, approximately 20 cP to approximately 175 cP, approximately 20 cP to approximately 200 cP, approximately 20 cP to approximately 400 cP cP, approximately 30 cP to approximately 40 cP, approximately 30 cP to approximately 50 cP, approximately 30 cP to approximately 60 cP, approximately 30 cP to approximately 80 cP, approximately 30 cP to approximately 100 cP, approximately 30cP to approximately 125 cP, approximately 30 cP to approximately 150 cP, approximately 30 cP to approximately 175 cP, approximately 30 cP to approximately 200 cP, approximately 30 cP to approximately 400 cP, approximately 40 cP to approximately 50 cP, approximately 40 cP to approximately 60 cP, approximately 40 cP to approximately 80 cP, approximately 40 cP to approximately 100 cP, approximately 40 cP to approximately 125 cP, approximately 40 cP to approximately 150 cP, approximately 40 cP to approximately 175 cP, approximately 40 cP to approximately 200 cP, approximately 40 cP to approximately 400 cP, approximately 50 cP to approximately 60 cP, approximately 50 cP to approximately 80 cP, approximately 50 cP to approximately 100 cP, approximately 50 cP to approximately 125 cP, approximately 50 cP to approximately 150 cP, approximately 50 cP to approximately 175 cP, approximately 50 cP to approximately 200 cP, approximately 50 cP to approximately 400 cP, approximately 60 cP to approximately 80 cP, approximately 60 cP to approximately 100 cP, approximately 60 cP to approximately 125 cP, approximately 60 cP to approximately 150 cP, approximately 60 cP to approximately 175 cP, approximately 60 cP to approximately 200 cP, approximately 60 cP to approximately 400 cP, approximately 80 cP to approximately 100 cP, approximately 80 cP to approximately 125 cP, approximately 80 cP to approximately 150 cP, approximately 80 cP to approximately 175 cP, approximately 80 cP to approximately 200 cP, approximately 80 cP to approximately 400 cP, approximately 100 cP to approximately 125 cP, approximately 100 cP to approximately 150 cP, approximately 100 cP to approximately 175 cP, approximately 100 cP to approximately 200 cP, approximately 100 cP to approximately 400 cP, approximately 125 cP to approximately 150 cP, approximately 125 cP to about 175 cP, about 125 cP to about 200 cP, about 125 cP to about 400 cP, about 150 cP to about 175 cP, about 150 cP to about 200 cP, about 150 cP to about 400 cP, about 175 cP to about 200 cP, about 175 cP to about 400 cP, or about 200 cP to about 400 cP. In some formulations, the viscosity of the ophthalmic formulation is about 10 cP to about 30 cP.

[0084] In some samples, the viscosity of the ophthalmic formulation is about 1 cP, about 5 cP, about 10 cP, about 15 cP, about 20 cP, about 30 cP, about 40 cP, about 50 cP, about 60 cP, about 80 cP, about 100 cP, about 125 cP, about 150 cP, about 175 cP, about 200 cP, or about 400 cP. In some samples, the viscosity of the ophthalmic formulation is about 30 cP.

[0085] In some formulations, ophthalmic preparations contain one or more buffer solutions. Non-limiting examples of buffer solutions include acetate buffer, borate buffer, citrate-borate buffer, citrate buffer, lactate buffer, phosphate buffer, succinate buffer, borate-polyol complex buffer, carbonate buffer, organic buffer, amino acid buffer, and combinations thereof. In some formulations, ophthalmic preparations contain one or more buffer solutions, wherein the one or more buffer solutions are phosphate buffers.

[0086] In some formulations, phosphate buffer contains phosphate; alkali metal phosphates, such as disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate, disodium hydrogen phosphate heptahydrate, trisodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and tripotassium phosphate; alkaline earth metal phosphates, such as calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, monomagnesium phosphate, dimagnesium phosphate (magnesium hydrogen phosphate), and trimagnesium phosphate; ammonium phosphate, such as diammonium hydrogen phosphate and ammonium dihydrogen phosphate; or combinations thereof. In some formulations, phosphate buffer contains one or more acid anhydrides. In some formulations, phosphate buffer contains one or more hydrates.

[0087] Organic buffers include (but are not limited to) Good's Buffers, such as 2-(N-α-phosphoryl)ethanesulfonic acid (MES), N-(2-acetamino)iminodiacetic acid, N-(aminomethoxymethyl)iminodiacetic acid (ADA), piperidine-N,N'-bis(2-ethanesulfonic acid) (PIPES), N-(2-acetamino)-2-aminoethanesulfonic acid (ACES), β-hydroxy-4-phosphorylpropanesulfonic acid, 3-phosphoryl-2-phosphorylpropanesulfonic acid, etc. 3-Hydroxypropanesulfonic acid (MOPSO), choline chloride, 3-(N-hydroxylinyl)propanesulfonic acid (MOPS), N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), 3-(N,N-bis... [2-hydroxyethyl]amino)-2-hydroxypropanesulfonic acid (DIPSO), acetaminoglycolic acid, 3-{[1,3-dihydroxy-2-(hydroxymethyl)-2-propane]amino}-2-hydroxy-1-propanesulfonic acid (TAPSO), piper-1,4,-bis(2-hydroxypropanesulfonic acid) (POPSO), 4-(2-hydroxyethyl)piperazine-1-(2-hydroxypropanesulfonic acid) hydrate (HEPPSO), 3-[4-(2-hydroxyethyl)-1-piperazine]propanesulfonic acid (HEPPS), tris(hydroxymethyl)methylglycine (tricine), glycine, N,N-dihydroxyethylglycine (bicine) or N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid sodium salt (TAPS); glycine; diethanolamine (DEA); and combinations thereof.

[0088] Amino acid buffers include (but are not limited to) taurine, aspartic acid and its salts (e.g., potassium salts), ε-aminohexanoic acid and combinations thereof.

[0089] In some formulations, the ophthalmic formulation contains one or more of the following buffer solutions in amounts: about 0.05 wt% to about 0.1 wt%, about 0.05 wt% to about 0.25 wt%, about 0.05 wt% to about 0.5 wt%, about 0.05 wt% to about 0.75 wt%, about 0.1 wt% to about 0.25 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 0.75 wt%, about 0.1 wt% to about 1 wt%, about 0.25 wt% to about 0.5 wt%, about 0.25 wt% to about 0.75 wt%, about 0.25 wt% to about 1 wt%, about 0.3 wt% to about 0.4 wt%, about 0.3 wt% to about 0.35 wt%, about 0.5 wt% to about 0.75 wt%, about 0.5 wt% to about 1 wt%, or about 0.75 wt% to about 1 wt%. In some formulations, ophthalmic preparations contain about 0.05% by weight to about 1% by weight of one or more buffer solutions.

[0090] In some formulations, the ophthalmic preparation contains one or more of the following buffer solutions in amounts: about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, or about 1 wt%. In some formulations, the ophthalmic preparation contains about 0.3 wt% of one or more buffer solutions. In some formulations, the ophthalmic preparation contains about 0.35 wt% of one or more buffer solutions.

[0091] In some samples, the pH of the ophthalmic formulation is about 6 to about 6.5, about 6 to about 7, about 6 to about 7.2, about 6 to about 7.4, about 6 to about 7.6, about 6 to about 7.8, about 6 to about 8, about 6.5 to about 7, about 6.5 to about 7.2, about 6.5 to about 7.4, about 6.5 to about 7.6, about 6.5 to about 7.8, about 6.5 to about 8, about 7 to about 7.2, about 7 to about 7.4, about 7 to about 7.8, about 7 to about 8, about 7.2 to about 7.4, about 7.2 to about 7.6, about 7.2 to about 7.8, about 7.4 to about 7.6, about 7.4 to about 7.8, or about 7.6 to about 7.8. In some samples, the pH of the ophthalmic formulation is about 7 to about 7.6.

[0092] In some samples, the pH of the ophthalmic formulation was approximately 6, 6.5, 7, 7.2, 7.6, or 8. In other samples, the pH of the ophthalmic formulation was approximately 7.4.

[0093] In some formulations, the pH of the ophthalmic preparation is adjusted by a strong acid or a strong base. Examples of strong acids and bases are well known in the art and include (but are not limited to) NaOH, KOH, HCl, and H₂SO₄. In some formulations, the strong acid or base is HCl or NaOH.

[0094] In some formulations, ophthalmic formulations contain preservatives. Non-limiting examples of preservatives include benzalkonium chloride, stable oxychloride complex (Purite®), phenylmercuric acetate, chlorobutanol, benzyl alcohol, parabens, EDTA, and thimerosal.

[0095] In some formulations, ophthalmic formulations do not contain preservatives.

[0096] In some formulations, the ophthalmic formulation does not contain ethylenediaminetetraacetic acid (EDTA).

[0097] In some formulations, the ophthalmic compound contains a penetration enhancer. Non-limiting examples of penetration enhancers include benzalkonium chloride, laurocapram (azone), bile acids and their alkali metal salts (including chenodeoxycholic acid, cholic acid, taurocholic acid, taurodeoxycholic acid, taurodesoxycholic acid, taurodesoxycholic acid, or ursodeoxycholic acid, glycocholate), n-dodecyl-β-D-maltose glycoside, sucrose dodecanoate, octylmaltose glycoside, decylmaltose glycoside, tridecaylmaltose glycoside, tetradecaylmaltose glycoside, hexamethylene laurylamine, hexamethylene octylamine, glyceryl monolaurate, PGML (polyethylene glycol monolaurate), dimethyl sulfoxide, methanesulfonylmethane, sodium thiocyanate, saponins, or any combination thereof. In some formulations, the ophthalmic compound contains benzalkonium chloride.

[0098] In some formulations, the ophthalmic formulation contains the following amounts of a penetration enhancer: about 0.0025 wt% to about 0.005 wt%, about 0.0025 wt% to about 0.0075 wt%, about 0.0025 wt% to about 0.01 wt%, about 0.0025 wt% to about 0.0125 wt%, about 0.0025 wt% to about 0.02 wt%, about 0.005 wt% to about 0.0075 wt%, about 0. 0.005 wt% to about 0.01 wt%, about 0.005 wt% to about 0.0125 wt%, about 0.005 wt% to about 0.02 wt%, about 0.0075 wt% to about 0.01 wt%, about 0.0075 wt% to about 0.02 wt%, about 0.01 wt% to about 0.0125 wt%, about 0.01 wt% to about 0.02 wt%, or about 0.0125 wt% to about 0.02 wt%. In some formulations, the ophthalmic formulation contains about 0.0075 wt% to about 0.0125 wt% of a penetration enhancer.

[0099] In some formulations, the ophthalmic compound contains about 0.0025% by weight, about 0.005% by weight, about 0.0075% by weight, about 0.0110% by weight, about 0.0115% by weight, about 0.0125% by weight, or about 0.02% by weight of a penetration enhancer. In some formulations, the ophthalmic compound contains about 0.01% by weight of a penetration enhancer.

[0100] In some formulations, the ophthalmic compound contains the following amounts of benzalkonium chloride: about 0.0025 wt% to about 0.005 wt%, about 0.0025 wt% to about 0.0075 wt%, about 0.0025 wt% to about 0.01 wt%, about 0.0025 wt% to about 0.0125 wt%, about 0.0025 wt% to about 0.02 wt%, about 0.005 wt% to about 0.0075 wt%, about 0.0 0.05 wt% to about 0.01 wt%, about 0.005 wt% to about 0.0125 wt%, about 0.005 wt% to about 0.02 wt%, about 0.0075 wt% to about 0.01 wt%, about 0.0075 wt% to about 0.02 wt%, about 0.01 wt% to about 0.0125 wt%, about 0.01 wt% to about 0.02 wt%, or about 0.0125 wt% to about 0.02 wt%. In some formulations, the ophthalmic compound contains about 0.0075 wt% to about 0.0125 wt% benzalkonium chloride.

[0101] In some formulations, the ophthalmic compound contains about 0.0025% by weight, about 0.005% by weight, about 0.0075% by weight, about 0.0110% by weight, about 0.0115% by weight, about 0.0125% by weight, or about 0.02% by weight of benzalkonium chloride. In some formulations, the ophthalmic compound contains about 0.01% by weight of benzalkonium chloride.

[0102] In some formulations, ophthalmic formulations do not contain penetration enhancers.

[0103] In some formulations, the ophthalmic formulation does not contain benzalkonium chloride.

[0104] In some formulations, ophthalmic formulations contain one or more stabilizers. Stabilizers include (but are not limited to) fatty acids, fatty alcohols, alcohols, long-chain fatty acid esters, long-chain ethers, hydrophilic derivatives of fatty acids, polyvinylpyrrolidone, polyvinyl ether, polyvinyl alcohol, hydrocarbons, hydrophobic polymers, water-absorbing polymers, and combinations thereof. In some formulations, amide analogs of stabilizers are also used. In some formulations, the selected stabilizers alter the hydrophobicity of the formulation, improve the mixing of the various components in the formulation, control the water content in the formulation, or control the mobility of the phase.

[0105] In some formulations, ophthalmic formulations contain one or more stabilizers in amounts sufficient to inhibit the degradation of the active agent. Examples of such stabilizers include (but are not limited to): glycerol, methionine, monothioglycerol, EDTA, ascorbic acid, polysorbate 80, polysorbate 20, arginine, heparin, dextran sulfate, cyclodextrin, pentosan polysulfate and other heparin-like substances, divalent cations (such as magnesium and zinc), or combinations thereof.

[0106] In some formulations, the ophthalmic formulation does not contain ethylenediaminetetraacetic acid (EDTA).

[0107] In some formulations, the ophthalmic compound contains about 0.01 wt% to about 5 wt% of impurity A. In some formulations, the ophthalmic compound contains impurity A in the following amounts: about 0.01 wt% to about 0.1 wt%, about 0.01 wt% to about 0.5 wt%, about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 1.5 wt%, about 0.01 wt% to about 2 wt%, about 0.01 wt% to about 2.5 wt%, about 0.01 wt% to about 3 wt%, about 0.01 wt% to about 3.5 wt%, about 0.01 wt% to about 4 wt%, about 0.01 wt% to about 4.5 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 1.5 wt%, about 0.1 wt% to about 2 wt%. Weight%, about 0.1 wt% to about 2.5 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 3.5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 4.5 wt%, about 0.1 wt% to about 5 wt%, about 0.5 wt% to about 1 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 2 wt%, about 0.5 wt% to about 2.5 wt%, about 0.5 wt% to about 3 wt%, about 0.5 wt% to about 3.5 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 4.5 wt%, about 0.5 wt% to about 5 wt%, about 1 wt% to about 1.5 wt%. About 1 wt% to about 2 wt%, about 1 wt% to about 2.5 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 3.5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 4.5 wt%, about 1 wt% to about 5 wt%, about 1.5 wt% to about 2 wt%, about 1.5 wt% to about 2.5 wt%, about 1.5 wt% to about 3 wt%, about 1.5 wt% to about 3.5 wt%, about 1.5 wt% to about 4 wt%, about 1.5 wt% to about 4.5 wt%, about 1.5 wt% to about 5 wt%, about 2 wt% to about 2.5 wt%, about 2 wt% to about 3 wt%, about 2 wt% to about 3.5 wt%, about 2 wt% to about 4 wt%, about 2 wt% to about 4.5 wt%, about 2 wt% to about 5 wt%, about 2.5 wt% to about 3 wt%, about 2.5 wt% to about 3.5 wt%, about 2.5 wt% to about 4 wt%, about 2.5 wt% to about 4.5 wt%, about 2.5 wt% to about 5 wt%, about 3 wt% to about 3.5 wt%, about 3 wt% to about 4 wt%, about 3 wt% to about 4.5 wt%, about 3 wt% to about 5 wt%, about 3.5 wt% to about 4 wt%, about 3.5 wt% to about 4.5 wt%, about 3.5 wt% to about 5 wt%, or about 4.5 wt% to about 5 wt%.

[0108] In some formulations, the ophthalmic compound contains about 5% by weight of impurity A. In some formulations, the ophthalmic compound contains impurity A in the following amounts: about 4.5% by weight, about 4% by weight, about 3.5% by weight, about 3% by weight, about 2.5% by weight, about 2% by weight, about 1.5% by weight, about 1% by weight, about 0.5% by weight, about 0.1% by weight, or about 0.01% by weight.

[0109] In some samples, the ophthalmic formulation does not contain impurity A.

[0110] In some samples, the ophthalmic compound contains less than 5% by weight of impurity A after approximately 5 months of storage. In some samples, the ophthalmic compound contains the following amounts of impurity A after approximately 5 months of storage: less than 4.5% by weight, less than 4% by weight, less than 3.5% by weight, less than 3% by weight, less than 2.5% by weight, less than 2% by weight, less than 1.5% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.1% by weight, or less than 0.01% by weight.

[0111] In some formulations, the ophthalmic compound contains about 0.01 wt% to about 5 wt% of impurity B. In some formulations, the ophthalmic compound contains impurity B in the following amounts: about 0.01 wt% to about 0.1 wt%, about 0.01 wt% to about 0.5 wt%, about 0.01 wt% to about 1 wt%, about 0.01 wt% to about 1.5 wt%, about 0.01 wt% to about 2 wt%, about 0.01 wt% to about 2.5 wt%, about 0.01 wt% to about 3 wt%, about 0.01 wt% to about 3.5 wt%, about 0.01 wt% to about 4 wt%, about 0.01 wt% to about 4.5 wt%, about 0.1 wt% to about 0.5 wt%, about 0.1 wt% to about 1 wt%, about 0.1 wt% to about 1.5 wt%, about 0.1 wt% to about 2 wt%. Weight%, about 0.1 wt% to about 2.5 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 3.5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 4.5 wt%, about 0.1 wt% to about 5 wt%, about 0.5 wt% to about 1 wt%, about 0.5 wt% to about 1.5 wt%, about 0.5 wt% to about 2 wt%, about 0.5 wt% to about 2.5 wt%, about 0.5 wt% to about 3 wt%, about 0.5 wt% to about 3.5 wt%, about 0.5 wt% to about 4 wt%, about 0.5 wt% to about 4.5 wt%, about 0.5 wt% to about 5 wt%, about 1 wt% to about 1.5 wt%. About 1 wt% to about 2 wt%, about 1 wt% to about 2.5 wt%, about 1 wt% to about 3 wt%, about 1 wt% to about 3.5 wt%, about 1 wt% to about 4 wt%, about 1 wt% to about 4.5 wt%, about 1 wt% to about 5 wt%, about 1.5 wt% to about 2 wt%, about 1.5 wt% to about 2.5 wt%, about 1.5 wt% to about 3 wt%, about 1.5 wt% to about 3.5 wt%, about 1.5 wt% to about 4 wt%, about 1.5 wt% to about 4.5 wt%, about 1.5 wt% to about 5 wt%, about 2 wt% to about 2.5 wt%, about 2 wt% to about 3 wt%, about 2 wt% to about 3.5 wt%, about 2 wt% to about 4 wt%, about 2 wt% to about 4.5 wt%, about 2 wt% to about 5 wt%, about 2.5 wt% to about 3 wt%, about 2.5 wt% to about 3.5 wt%, about 2.5 wt% to about 4 wt%, about 2.5 wt% to about 4.5 wt%, about 2.5 wt% to about 5 wt%, about 3 wt% to about 3.5 wt%, about 3 wt% to about 4 wt%, about 3 wt% to about 4.5 wt%, about 3 wt% to about 5 wt%, about 3.5 wt% to about 4 wt%, about 3.5 wt% to about 4.5 wt%, about 3.5 wt% to about 5 wt%, or about 4.5 wt% to about 5 wt%.

[0112] In some formulations, the ophthalmic compound contains about 5% by weight of impurity B. In some formulations, the ophthalmic compound contains impurity B in the following amounts: about 4.5% by weight, about 4% by weight, about 3.5% by weight, about 3% by weight, about 2.5% by weight, about 2% by weight, about 1.5% by weight, about 1% by weight, about 0.5% by weight, about 0.1% by weight, or about 0.01% by weight.

[0113] In some samples, the ophthalmic formulation does not contain impurity B.

[0114] In some samples, the ophthalmic compound contains less than 5% by weight of impurity B after approximately 5 months of storage. In some samples, the ophthalmic compound contains the following amounts of impurity B after approximately 5 months of storage: less than 4.5% by weight, less than 4% by weight, less than 3.5% by weight, less than 3% by weight, less than 2.5% by weight, less than 2% by weight, less than 1.5% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.1% by weight, or less than 0.01% by weight.

[0115] In some samples, ophthalmic preparations are stored at 40°C and 25% NMT relative humidity. In other samples, ophthalmic preparations are stored at 25°C and 40% NMT relative humidity. In still other samples, ophthalmic preparations are stored for approximately 1 day, approximately 7 days, approximately 21 days, approximately 1 month, approximately 2 months, approximately 3 months, approximately 4 months, approximately 5 months, approximately 6 months, or approximately 12 months.

[0116] In some formulations, the ophthalmic formulation contains about 2.75% by weight of carbohydrate, about 0.1% by weight of brimonidine, about 0.2% by weight of HPMC and about 0.05% by weight to about 1% by weight of one or more buffer solutions, wherein the pH is about 7.4, and wherein the formulation contains less than about 5% by weight of impurity A after about 5 months of storage.

[0117] In some formulations, the ophthalmic formulation contains about 2.75% by weight of carbohydrate, about 0.1% by weight of brimonidine, about 0.2% by weight of HPMC and about 0.05% by weight to about 1% by weight of one or more buffer solutions, wherein the pH is about 7.4, and wherein the formulation contains less than about 2% by weight of impurity B after about 5 months of storage.

[0118] In some samples, the total impurity concentration of the ophthalmic compound was less than 1% by weight. In other samples, the total impurity concentration of the ophthalmic compound was less than 0.5% by weight, less than 0.1% by weight, less than 0.05% by weight, less than 0.01% by weight, or less than 0.005% by weight.

[0119] In some formulations, the solubility of the components of the ophthalmic formulation may be enhanced by surfactants or other suitable co-solvents in the composition. Such co-solvents include polysorbate 20, polysorbate 60 and polysorbate 80, Pluronic F68, Pluronic F-84 and Pluronic P-103, cyclodextrin or other agents known to those skilled in the art. In some formulations, the concentration of the co-solvent is from 0.01% by weight to about 2% by weight.

[0120] In some formulations, ophthalmic formulations contain one or more polyols. As used herein, the term "polyol" includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms, which are not in a cis configuration relative to each other. Polyols may be linear or cyclic, substituted or unsubstituted, or mixtures thereof, provided that the resulting complex is water-soluble and pharmaceutically acceptable. Examples of such compounds include sugars, sugar alcohols, sugar acids, and uronic acids. Preferred polyols are sugars, sugar alcohols, and sugar acids, including (but not limited to): mannitol, glycerol, xylitol, sorbitol, and propylene glycol. It is considered that a polyol may consist of two or more different polyols.

[0121] In some formulations, ophthalmic formulations contain one or more anti-aggregation additives. Anti-aggregation additives enhance the stability of ophthalmic formulations by reducing protein aggregation rates. Anti-aggregation additives include (but are not limited to) urea, guanidine hydrochloride, simple amino acids (such as glycine or arginine), sugars, polyols, polysorbates, polymers (such as polyethylene glycol and dextran), alkyl sugars (such as alkyl glycosides), and surfactants.

[0122] In some formulations, ophthalmic formulations contain one or more antioxidants. Antioxidants include (but are not limited to) ascorbic acid, methionine, sodium thiosulfate, sodium metabisulfite, and combinations thereof. Metal chelators, thiol compounds, and other general stabilizers may be acceptable antioxidants.

[0123] In some formulations, ophthalmic formulations contain one or more osmotic agents. Osmotic agents include (but are not limited to) salts, especially sodium chloride or potassium chloride; organic compounds such as propylene glycol, mannitol, sorbitol, dextrose, and glycerol.

[0124] In some formulations, the weight molar osmotic concentration of the ophthalmic formulation was approximately 260 mOsm / kg to approximately 365 mOsm / kg. In some formulations, the weight molar osmotic concentration of the ophthalmic compound was approximately 285 mOsm / kg to approximately 295 mOsm / kg, approximately 285 mOsm / kg to approximately 305 mOsm / kg, approximately 285 mOsm / kg to approximately 315 mOsm / kg, approximately 285 mOsm / kg to approximately 325 mOsm / kg, approximately 285 mOsm / kg to approximately 335 mOsm / kg, approximately 285 mOsm / kg to approximately 345 mOsm / kg, approximately 285 mOsm / kg to approximately 355 mOsm / kg, approximately 285 mOsm / kg to approximately 365 mOsm / kg, approximately 295 mOsm / kg to approximately 305 mOsm / kg, approximately 295 mOsm / kg to approximately 315 mOsm / kg, approximately 295 mOsm / kg to approximately 325 mOsm / kg. mOsm / kg, about 295 mOsm / kg to about 335 mOsm / kg, about 295 mOsm / kg to about 345 mOsm / kg, about 295 mOsm / kg to about 355 mOsm / kg, about 295 mOsm / kg to about 365 mOsm / kg, about 305 mOsm / kg to about 315 mOsm / kg, about 305 mOsm / kg to about 325 mOsm / kg, about 305 mOsm / kg to about 335 mOsm / kg, about 305 mOsm / kg to about 345 mOsm / kg, about 305 mOsm / kg to about 355 mOsm / kg, about 305 mOsm / kg to about 365 mOsm / kg, about 315 mOsm / kg to about 325 mOsm / kg, about 315 mOsm / kg to about 335 mOsm / kg, about 315 mOsm / kg to about 345 mOsm / kg, about 315 mOsm / kg to about 355 mOsm / kg, about 315 mOsm / kg to about 365 mOsm / kg, about 325 mOsm / kg to about 335 mOsm / kg, about 325 mOsm / kg to about 345 mOsm / kg, about 325 mOsm / kg to about 355 mOsm / kg, about 325 mOsm / kg to about 345 mOsm / kg, about 325 mOsm / kg to about 355 mOsm / kg, about 325 mOsm / kg to about 345 mOsm / kg, about 335 mOsm / kg to about 355 mOsm / kg, about 335 mOsm / kg to about 365 mOsm / kg, about 345 mOsm / kg to about 355 mOsm / kg mOsm / kg, approximately 345 mOsm / kg to approximately 365 mOsm / kg, approximately 355 mOsm / kg to approximately 365mOsm / kg, about 260 mOsm / kg to about 265 mOsm / kg, about 260 mOsm / kg to about 275 mOsm / kg, about 260 mOsm / kg to about 285 mOsm / kg, about 260 mOsm / kg to about 295 mOsm / kg, about 260 mOsm / kg to about 305 mOsm / kg, about 260 mOsm / kg to about 315 mOsm / kg, about 260 mOsm / kg to about 325 mOsm / kg, about 260 mOsm / kg to about 335 mOsm / kg, about 260 mOsm / kg to about 345 mOsm / kg, about 260 mOsm / kg to about 355 mOsm / kg, about 260 mOsm / kg to about 365 mOsm / kg, about 265 mOsm / kg to about 275 mOsm / kg, about 265 mOsm / kg to about 285 mOsm / kg, about 265 mOsm / kg to about 295 mOsm / kg, about 265 mOsm / kg to about 305 mOsm / kg, about 265 mOsm / kg to about 315 mOsm / kg, about 265 mOsm / kg to about 325 mOsm / kg, about 265 mOsm / kg to about 335 mOsm / kg, about 265 mOsm / kg to about 345 mOsm / kg, about 265 mOsm / kg to about 355 mOsm / kg, about 265 mOsm / kg to about 365 mOsm / kg, about 275 mOsm / kg to about 285 mOsm / kg, about 275 mOsm / kg to about 295 mOsm / kg mOsm / kg, about 275 mOsm / kg to about 305 mOsm / kg, about 275 mOsm / kg to about 315 mOsm / kg, about 275 mOsm / kg to about 325 mOsm / kg, about 275 mOsm / kg to about 335 mOsm / kg, about 275 mOsm / kg to about 345 mOsm / kg, about 275 mOsm / kg to about 355 mOsm / kg, about 275 mOsm / kg to about 365 mOsm / kg.

[0125] In some formulations, the weight molar osmotic concentration of the ophthalmic formulation was approximately 260 mOsm / kg, approximately 265 mOsm / kg, approximately 275 mOsm / kg, approximately 285 mOsm / kg, approximately 295 mOsm / kg, approximately 305 mOsm / kg, approximately 315 mOsm / kg, approximately 325 mOsm / kg, approximately 335 mOsm / kg, approximately 345 mOsm / kg, approximately 355 mOsm / kg, approximately 365 mOsm / kg, approximately 370 mOsm / kg, or approximately 375 mOsm / kg.

[0126] In some samples, the ophthalmic compound was isotonic. In some samples, the ophthalmic compound was hypotonic. In some samples, the ophthalmic compound was hypertonic.

[0127] In some formulations, ophthalmic formulations may include a variety of additional ingredients. Such ingredients include (but are not limited to) additional therapeutic agents, additional or alternative antimicrobial agents, suspending agents, surfactants, additional or alternative tension agents, additional or alternative buffers, antioxidants, additional or alternative viscosity modifiers, chelating agents, or any combination thereof. Treatment

[0128] This invention provides a method for treating ocular conditions in individuals in need, comprising administering a topical ocular composition comprising carbohydrate and brimonidine. As used herein, the term "ocular condition" may refer to any symptom, disease, or injury affecting or involving the eye or a part or region of the eye, and includes visual problems causing refractive errors in the eye. Ocular symptoms include (but are not limited to) presbyopia, myopia, progressive myopia, pathological myopia, amblyopia, cycloplegia, mydriasis, allergic conjunctivitis, conjunctival hyperemia, red eye, glaucoma, ocular hypertension, post-refractive surgery night vision symptoms (e.g., halos, glows, or starbursts), accommodative esotropia, glaucoma, ocular hypertension, accommodative dysfunction, hyperopia, asymmetrical pupils, astigmatism, amblyopia, Adie's tonic pupil or other parasympathetic denervation causes, and complications following refractive surgery (such as eccentric resection after LASIK or PRK, undercorrection of LASIK, overcorrection of LASIK, corneal scarring, opacity, and refractive errors). In some cases, the ocular symptom is presbyopia.

[0129] Presbyopia, or farsightedness, is a condition typically caused by the loss of elasticity in the lens of the eye, usually occurring in middle and old age. It is a progressive deterioration of the ability to focus clearly, especially at near distances. Symptoms include difficulty reading small print, the need to maintain a greater distance from reading materials, headaches, and eye strain. Most people begin to notice the effects of presbyopia after age 40 when they start having difficulty seeing small print (including text messages on their mobile phones). In these individuals, the use of cholinergic agonists (miotics) is beneficial because the pupillary constriction caused by sphincter contraction creates a "pinhole effect," which can potentially improve near and intermediate vision by increasing the depth of field. Therefore, these cholinergic agonists can be used to treat presbyopia, but the most effective frequency and concentration of administration have not yet been defined.

[0130] Pinhole cameras reduce the amount of light entering the eye. Since more light enters, more focusing is required, so users hardly need to focus when using a pinhole camera. The pinhole effect removes peripheral vision. The treatment methods and compositions described herein use drugs to achieve the pinhole effect, thereby significantly increasing the depth of focus. The eye contains two types of muscles: contractile muscles and dilators. By acting on these two muscles, the unique drug combination described herein achieves the pinhole effect, thereby correcting refractive errors.

[0131] A pharmacological pinhole effect is induced in at least the non-dominant eye of any patient with refractive error. In some cases, treatment can be administered to both eyes. In some cases, treatment is administered only to the non-dominant eye of patients with emmetropic presbyopia and myopic presbyopia, and to both eyes of patients with hyperopic presbyopia and hyperopia. For pure myopia, a pinhole effect can be induced in the non-dominant eye or both eyes of the myopic patient.

[0132] More specifically, carbohydrate choline causes the pupil to constrict (constrict), while brimonidine acts as a blocker (preventing dilation). Brimonidine prevents pupillary dilation that occurs at night to minimize visual distortions such as halos and glare in some patients after refractive surgery, and in the treatment of glaucoma.

[0133] For some refractive errors, including (but not limited to) presbyopia, the dressing is placed in only one eye to reduce the likelihood of blurred vision caused by treatment. For other refractive errors, including (but not limited to) hyperopia, it is preferable to place the drops in both eyes during treatment, but it may also be placed in only one eye. In patients with myopia, pseudophakia, or astigmatism, the dressing may be placed in one or both eyes.

[0134] For some refractive errors, administering the pharmaceutical preparations described herein to only one eye may be beneficial. In some cases, when the combination is administered to both eyes, blurred farsightedness (a result of focusing accommodation) and blurred vision (a result of pupillary constriction) may occur. When administered to only one eye, the benefit of improving presbyopia is obtained, and blurred vision and blurred vision are reduced or completely relieved. It was initially believed that the patient's brain would correct between the treated and untreated eyes, thereby reducing unwanted effects. Therefore, when only one eye is treated, the combination of pupillary constriction and increased visual depth in the treated eye with normal distance vision and brightness in the untreated eye will cause the brain to ignore any monocular blurred vision, whether near or far. However, when the pharmaceutical preparations are administered to both eyes, distance visual sensitivity is preserved, but parasympathomimetic drugs or their medically acceptable salts (such as pirocarpine and carbohydrate alone) can still induce myopic conversion, inducing myopia while impairing distance vision, and simultaneously causing increased focusing depth. When applied to both eyes, the addition of an α-2 agonist (such as brimonidine or its medically acceptable salt) can prevent myopic conversion and maintain distance visual acuity.

[0135] Presbyopia can be diagnosed using one or more types of eye examination procedures, which may include visual acuity (e.g., by using the Snellen chart, Jaeger chart, Rosenbaum chart, or ETDRS near vision chart), refractive power, binocular visual acuity and accommodation, convex lenses for near vision, balance of accommodation range, accommodation amplitude, cross cylinder test, accommodative convergence / accommodation, heterophoria and convergence, and one or more of the following tests: vertical balance disorder.

[0136] The present invention also provides a method for improving or alleviating presbyopia in an individual, the method comprising administering an ophthalmic formulation described herein. In some formulations, the ophthalmic formulation comprises about 2.75 wt% carbohydrate, about 0.1 wt% brimonidine, about 0.2 wt% HPMC, and about 0.05 wt% to about 1 wt% of one or more buffer solutions, wherein the pH is about 7.4, and wherein after storage for about 5 months the formulation contains less than about 5 wt% impurity A, wherein the concentration of impurity A is measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity A relative to brimonidine is about 0.9. In some samples, after approximately 5 months of storage, the formulation further contained less than 2% by weight of impurity B, the concentration of which was measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity B relative to brimonidine was approximately 0.67. In some formulations, the ophthalmic formulation contains about 2.75 wt% carbohydrate, about 0.1 wt% brimonidine, about 0.2 wt% HPMC, and about 0.05 wt% to about 1 wt% of one or more buffer solutions, wherein the pH is about 7.4, and wherein the formulation contains less than 2 wt% impurity B after about 5 months of storage, wherein the concentration of impurity B is measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity B relative to brimonidine is about 0.67.

[0137] When used to treat presbyopia, the methods described herein can improve one or more features of presbyopia. In some cases, administration of the ophthalmic compound described herein to an individual can cause a reduction in pupil diameter compared to the reduction observed before administration of the ophthalmic compound. The magnitude of the reduction may vary. In some cases, the reduction is about 0.25 mm to about 10 mm, about 1 mm to about 9 mm, or about 2 mm to about 8 mm. In some cases, the reduction is about 0.25 mm to about 3.0 mm, about 0.5 mm to about 1.5 mm, or about 0.5 mm to about 1.0 mm. In some cases, the method can improve uncorrected near visual acuity or other measures of visual function (including uncorrected intermediate or distance visual acuity, contrast sensitivity, or depth of focus) and other measures. When measuring visual acuity using eye charts such as the Jaeger or Rosenbaum near vision chart, the Snellen chart, or the ETDRS near vision chart, the methods described herein may result in improvements reflected in one or more columns of the chart, such as columns 1 to 8 or 2 to 6. In some cases, the improvement is approximately 5 feet or more, approximately 10 feet or more, or approximately 15 feet or more, relative to letters that can be read at approximately 20 feet. In some cases, the improvement is approximately 5 feet to approximately 60 feet, approximately 5 feet to approximately 30 feet, or approximately 10 feet to approximately 25 feet, relative to letters that can be read at approximately 20 feet. In some cases, the visual acuity improvement is approximately 20 / 40 to approximately 20 / 25 or approximately 20 / 40 to approximately 20 / 20.

[0138] In some cases, effective improvement or reduction of presbyopia is achieved for at least 8 hours. In other cases, effective improvement or reduction of presbyopia is achieved for at least 0.5 hours, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, at least 3 hours, at least 3.5 hours, at least 4 hours, at least 4.5 hours, at least 5 hours, at least 5.5 hours, at least 6 hours, at least 6.5 hours, at least 7 hours, at least 7.5 hours, at least 8.5 hours, at least 9 hours, at least 9.5 hours, at least 10 hours, at least 12 hours, at least 16 hours, at least 20 hours, or at least 24 hours.

[0139] In some cases, administration of ophthalmic dressings can alleviate periorbital pain in individuals.

[0140] The present invention also provides methods for: improving or reducing at least one refractive error in an individual with hyperopia; relaxing the ciliary muscle of an individual under sympathetic stimulation to reduce at least one of headache, migraine, and periorbital pain; preventing myopic conversion induced by parasympathetic effects in presbyopic patients receiving parasympathomimetic drugs or their medically acceptable salts; improving or reducing at least one refractive error selected from the group consisting of myopia, hyperopia, and astigmatism in patients with pseudophacsis; treating at least one refractive error in patients who have undergone eye surgery; and generating multifocality in patients with pseudophacsis, the methods comprising administering the ophthalmic compound described herein. In some formulations, the ophthalmic formulation contains about 2.75% by weight of carbohydrate, about 0.1% by weight of brimonidine, about 0.2% by weight of HPMC, and about 0.05% to about 1% by weight of one or more buffer solutions, wherein the pH is about 7.4, and wherein the formulation contains less than about 5% by weight of impurity A after about 5 months of storage, wherein the concentration of impurity A is measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity A relative to brimonidine is about 0.9. In some samples, after approximately 5 months of storage, the formulation further contained less than 2% by weight of impurity B, the concentration of which was measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity B relative to brimonidine was approximately 0.67. In some formulations, the ophthalmic formulation contains about 2.75 wt% carbohydrate, about 0.1 wt% brimonidine, about 0.2 wt% HPMC, and about 0.05 wt% to about 1 wt% of one or more buffer solutions, wherein the pH is about 7.4, and wherein the formulation contains less than 2 wt% impurity B after about 5 months of storage, wherein the concentration of impurity B is measured by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity B relative to brimonidine is about 0.67.

[0141] In some samples, administration of ophthalmic dressings to individuals with hyperopia resulted in a visual improvement of at least 20% compared to no treatment. In other samples, administration of ophthalmic dressings to individuals with hyperopia resulted in a visual improvement of at least 5%, at least 10%, at least 15%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to no treatment.

[0142] In some cases, administration of ocular conditioning agents can cause an increase in the depth of focus of an individual's vision.

[0143] In some cases, administering eye-care formulations can maintain an individual's visual acuity.

[0144] Ophthalmic preparations can typically be administered as needed to individuals with myopia, hyperopia, astigmatism, presbyopia, or other visual impairments to induce pupillary constriction sufficient to temporarily treat, improve, or alleviate these visual impairments, as well as to temporarily generate multifocal focus. These refractive errors can benefit from these medications to a clinically and practically usable level, allowing patients who have always needed to wear glasses to completely eliminate the need for them. Therefore, the present invention further provides a method for temporarily treating, improving, or alleviating these visual impairments and temporarily generating multifocal focus by inducing pupillary constriction.

[0145] As defined in this article, "visual impairment" or "refractive error," also known as ammetropia (visual acuity), refers to a visual defect or impairment that prevents the eye from focusing light properly, causing blurred vision. The main refractive errors are myopia (nearsightedness), hyperopia (farsightedness, blurred vision), presbyopia (when the lens of the eye loses its flexibility), pseudophakia (near vision impairment caused by the implantation of an artificial lens), and astigmatism (including regular astigmatism, irregular astigmatism, and highly regular astigmatism). Some refractive errors occur after cataract surgery or laser surgery.

[0146] As used herein, the term "ameliorate / ameorating / amelioration" is intended to refer to a reduction in the severity of refractive error. Ambience can be complete, such as eliminating one or more refractive errors entirely. Ambience can also be partial, such that the amount of refractive error is less than that present without treatment. For example, the degree of refractive error when using the methods of the present invention can be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% less than the amount of refractive error present without using such methods.

[0147] The method described herein improves refractive errors, including (but not limited to) myopia, hyperopia, astigmatism, presbyopia, pseudophagia (e.g., after cataract surgery, replacing the natural lens with an artificial lens), and post-laser surgery distortion, by administering a therapeutically effective amount of an ophthalmic preparation to at least one eye of a patient. The ophthalmic preparation contains one or more parasympathomimetic drugs or medically acceptable salts thereof, and one or more alpha agonists or antagonists or medically acceptable salts thereof.

[0148] The present invention further provides a method for improving at least one visual acuity parameter in an individual in need, comprising administering to the individual the ophthalmic dressings described herein. As used herein, the term "visual acuity parameter" refers to any characteristic of an individual's visual acuity that is measurable and readily modifiable by the ophthalmic dressings and methods described herein. Visual acuity parameters include (but are not limited to) near visual acuity, intermediate visual acuity, distance visual acuity, night vision, daytime vision, visual distortions (e.g., glare, light scattering), and uncorrected refractive errors. Other examples of visual acuity parameters include (but are not limited to) nighttime glare, "starburst" glare after LASIK, visual "halos" visible around light sources, and accommodative dysfunction.

[0149] "Improved visual acuity parameters" include (but are not limited to) near vision, intermediate vision and / or far vision acuity, and may be reflected, for example, as an increase in the number of letters correctly read at any time point after administration, an increase in the average change in letters, or an improvement of 2 or 3 columns compared to baseline (i.e., before treatment).

[0150] Improved night vision can be reflected as an individual's vision improvement in dim or low light conditions (e.g., in dim or low-light conditions). Improved daytime vision can be reflected as an individual's vision improvement in sufficient light conditions, such as during the day or in sunlight conditions (e.g., in bright light conditions). Vision improvements using the methods described herein can also be achieved in combination with or while using other visual aids and devices, including (but not limited to) reading glasses, crystalline lens accommodative drugs, and refractive surgery options.

[0151] In some cases, treatment with the ophthalmic adjuvants described herein resulted in at least two columns of improvement in uncorrected near visual acuity (UNVA) under bright, high-contrast conditions compared to baseline. As used herein, the term "bright visual acuity" refers to visual acuity of the eye under adequate lighting conditions (luminance level of 10 to 10⁸ cd / m²). In humans and other animals, bright visual acuity enables cone-mediated color perception and significantly higher visual acuity and temporal resolution compared to low-light visual acuity (visual acuity of the eye under dim lighting conditions; luminance level of 10⁻³ to 10⁻⁶ cd / m²). As used herein, the term "uncorrected near visual acuity" (UNVA) refers to the ability of an individual to see details of objects within an arm's length of the body (e.g., at a distance of 33–41 cm from the eye) in the absence of any visual aids (such as eyeglasses or contact lenses).

[0152] In some samples, the treatment method using the ophthalmic formulations described herein resulted in at least three improvements compared to baseline under bright, high-contrast UNVA conditions. In other samples, the method described herein resulted in an increase in mean letter change compared to baseline under bright, high-contrast UNVA conditions.

[0153] The term "improvement compared to baseline" refers to an increase in the number of letters read correctly at a post-treatment time point compared to before treatment. As used herein, the terms "improvement of 2 columns compared to baseline," "improvement of 3 columns compared to baseline," or similar improvements compared to baseline refer to an individual's ability to read 2 or 3 more columns of letters on a standard visual acuity chart (e.g., Snellen, ETDRS, logarithmic visual acuity chart, etc.) after treatment with the topical ophthalmic composition of the present invention, compared to the number of columns they could read before treatment.

[0154] In some cases, treatment with the ophthalmic formulations described herein resulted in at least two columns of improvement compared to baseline under dim, high-contrast UNVA conditions. As used herein, the term "dim" vision refers to a combination of bright and dim vision in low-light but not complete darkness. Dim light levels range from approximately 0.001 to 3 cd / m². Most nighttime outdoor and traffic lighting conditions fall within the dim range. The human eye uses dim vision in low-light conditions and dim vision in moderate-light conditions. Humans perceive differently at different light levels. This is because at high light levels (bright vision) (typically during the day), the eye uses cone cells to process light. At very low light levels, corresponding to moonless nights without electrical lighting (dim vision), the eye uses rod cells to process light. At many nighttime levels, a combination of cone and rod cells maintains vision. Bright light vision promotes excellent color discrimination, while low light vision fails to distinguish colors. Dim vision lies somewhere in between these two extremes. In most nighttime environments, there is sufficient ambient light to prevent true dim vision.

[0155] In some samples, the treatment method using the ophthalmic composition described herein resulted in at least three improvements compared to baseline under dim, high-contrast UNVA conditions. In other samples, the method described herein resulted in an increase in mean letter change compared to baseline under dim, high-contrast UNVA conditions.

[0156] In some cases, treatment with the ophthalmic adjuvants described herein resulted in at least two columns of improvement in uncorrected distance visual acuity (UDVA) under bright, high-contrast conditions compared to baseline. As used herein, the term "uncorrected distance visual acuity" (UDVA) refers to an individual's ability to see details of objects at an arm's length away (e.g., at least 4 meters from the eyes) in the absence of any visual aids (such as eyeglasses or contact lenses).

[0157] In some embodiments, the treatment method using the ophthalmic formulations described herein resulted in at least three improvements compared to baseline under bright, high-contrast UDVA conditions. In other embodiments, the method described herein resulted in an increase in the average letter change compared to baseline under bright, high-contrast UDVA conditions.

[0158] In some cases, treatment with the ophthalmic adjuvants described herein resulted in at least two columns of improvement in near visual acuity with distance correction (DCNVA) under dim, high-contrast conditions compared to baseline. As used herein, the term “near visual acuity with distance correction” (DCNVA) refers to an individual’s ability to see details of objects within an arm’s length of the body (e.g., 33–41 cm from the eyes) when using visual aids such as glasses or contact lenses to correct distance vision problems.

[0159] In some samples, the treatment method using the ophthalmic formulation described herein resulted in at least three improvements compared to baseline under dim, high-contrast, DCNVA conditions. In other samples, the method described herein resulted in an increase in mean letter change compared to baseline under dim, high-contrast, DCNVA conditions. In other samples, the method described herein resulted in at least three improvements compared to baseline under bright, high-contrast, DCNVA conditions. In other samples, the method described herein resulted in at least two improvements compared to baseline under bright, high-contrast, DCNVA conditions. In other samples, the method described herein resulted in an increase in mean letter change compared to baseline under bright, high-contrast, DCNVA conditions.

[0160] In certain cases, treatment with the ophthalmic adjuvants described herein resulted in at least two columns of improvement in distance corrected intermediate visual acuity (DCIVA) compared to baseline under dim, high-contrast, distance vision-corrected conditions. As used herein, the term "distance corrected intermediate visual acuity" (DCIVA) can be used to refer to an individual's ability to see details of objects at intermediate distances when using visual aids such as eyeglasses or contact lenses to correct distance vision problems.

[0161] In some samples, the treatment method using the ophthalmic formulation described herein resulted in at least three improvements compared to baseline under dim, high-contrast, DCIVA conditions. In other samples, the method described herein resulted in an increase in mean letter change compared to baseline under dim, high-contrast, DCIVA conditions. In other samples, the method described herein resulted in at least two improvements compared to baseline under bright, high-contrast, DCIVA conditions. In other samples, the method described herein resulted in at least three improvements compared to baseline under bright, high-contrast, DCIVA conditions. In other samples, the method described herein resulted in an increase in mean letter change compared to baseline under bright, high-contrast, DCIVA conditions. Method for preparing ophthalmic compound

[0162] The present invention also provides a method for preparing an ophthalmic formulation containing carbohydrate and brimonidine.

[0163] In some formulations, an ophthalmic formulation is prepared by adding carbohydrate or a medically acceptable salt thereof, brimonidine or a medically acceptable salt thereof, and one or more viscous agents to water and stirring to obtain a formulation. The ophthalmic formulation comprises about 2% to about 4% by weight of carbohydrate or a medically acceptable salt thereof, about 0.05% to about 0.2% by weight of brimonidine or a medically acceptable salt thereof, about 0.05% to about 1% by weight of one or more viscous agents, and about 0.05% to about 1% by weight of one or more buffer solutions, wherein the pH of the formulation is about 7 to about 7.6.

[0164] In some samples, the buffer solution is a phosphate buffer. In some samples, the phosphate buffer solution contains sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate heptahydrate.

[0165] In some samples, one or more adhesives are HPMC.

[0166] In some samples, the method involves adding benzalkonium chloride.

[0167] In some cases, the method involves adding sodium chloride.

[0168] In some cases, the method involves adding hydrochloric acid.

[0169] In some cases, the method involves adding sodium hydroxide.

[0170] In some cases, the ophthalmic preparation is aseptically filled into vials.

[0171] In some formulations, each vial contains the following amounts of ophthalmic preparation: about 0.01 g to about 0.1 g, about 0.05 g to about 0.15 g, about 0.2 g to about 0.4 g, about 0.3 g to about 0.5 g, about 1 g to about 2 g, about 1.5 g to about 2.5 g, about 2.5 g to about 3.5 g, about 3 g to about 4 g, or about 3.5 g to about 5 g.

[0172] In some samples, each vial is filled with approximately 0.1 g to approximately 0.3 g of ophthalmic preparation.

[0173] In some samples, each vial is filled with approximately 2 g to approximately 2.7 g of ophthalmic preparation.

[0174] The following examples are illustrative and do not limit the scope of the claimed states. Example Example 1 Example carbocholine / brimonidine formulations

[0175] Table 1 lists exemplary ophthalmic formulations prepared for further testing, which include carbocholine and brimonidine. Table 1: Carbohydrate / Bromidine Blends [] [Ingredients] [1] [Ingredients] [2] [Ingredients] [3] [Ingredients] [4] [Ingredients] [5] [Ingredients] [6] [Ingredients] [7] [Ingredients] [8] [Ingredients] [9] [Ingredients]

[10] [Components] [level] [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) Carbocholine USP 3.0% 2.75% 2.75% 2.75% 2.75% 2.75% NA 2.75% 2.25% 2.75% bromonidin tartrate Non-Pharmacopoeia 0.2% 0.1% 0.1% 0.1% NA 0.1% 0.1% NA NA NA CMC USP / Ph Eur 1.0% NA NA NA NA NA NA NA NA NA Hydroxypropyl methylcellulose (HPMC) USP / Ph Eur NA 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% 0.2% benzalkonium chloride NF / Ph Eur 100 ppm 100 ppm NA NA 100 ppm 100 ppm NA NA NA NA Disodium ethylenediaminetetraacetate USP 0.05% 0.05% 0.05% NA NA NA 0.05% 0.05% NA NA Example 2 Additional illustrative examples of carbocholine / brimonidine formulations

[0176] Table 2 lists additional illustrative ophthalmic formulations prepared for further testing, including carbocholine and brimonidine. Table 2: Additional Carbohydrate / Bromidine Blends [Ingredients] [#] [Ingredients]

[11] [Ingredients]

[12] [Ingredients]

[13] [Ingredients]

[14] [Ingredients]

[15] [Ingredients]

[16] [Ingredients]

[17] [Ingredients]

[18] [Ingredients]

[19] [Ingredients]

[20] [Ingredients] [twenty one] [Components] [level] [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) [concentration] [(] [weight] [%) Carbocholine USP 3% 2.75% 3% 2.75% 2.75% 2.75% 2.75% 2.75% 2.75% 2.75% 2.75% bromonidin tartrate Non-Pharmacopoeia 0.2% 0.1% 0.2% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% Sodium carboxymethyl cellulose (NaCMC, 7M8SFPH grade) USP / Ph Eur 1.0% 1.0% 1.0% - - - - - 1.0% - - Hydroxypropyl methylcellulose (HPMC, Methocel E50 Premium LY grade) USP / Ph Eur - - - 0.2% 0.2% 1.0% 1.0% 0.2% - 0.2% 0.2% benzalkonium chloride NF / Ph Eur 0.01% 0.01% - 0.01% 0.02% 0.01% 0.01% 0.01% 0.01% 0.01% 0.01% Disodium ethylenediaminetetraacetate USP 0.05% 0.05% 0.05% - - - 0.05% 0.05% - - 0.05% Polyvinylpyrrolidone (PYPJ) USP - - - - - - - - - 2.0% 2.0% Sodium dihydrogen phosphate monohydrate USP 0.0137% 0.0137% 0.0137% 0.00171% 0.00171% 0.00171% 0.00171% 0.00171% 0.001 71% 0.00171% 0.00171% Sodium hydrogen phosphate heptahydrate USP 0.108% 0.108% 0.108% 0.332% 0.332% 0.332% 0.332% 0.332% 0.332% 0.332% 0.332% Hydrochloric acid / sodium hydroxide (in stock solution form) NF Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Appropriate amount, to achieve pH 7.4. Purified water USP / Ph Eur Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Expected initial pH value 5.5* 5.5* 5.5* 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4 Total buffer concentration 5 mM 5 mM 5 mM 12.5 mM 12.5 mM 12.5 mM 12.5 mM 12.5 mM 12.5 mM 12.5 mM 12.5 mM Expected osmotic concentration (mOsm / Kg) 369 314 369 314 314 314 314 314 314 314 314 pH adjustment is required. Example 3 Quantification of impurity concentrations in carbohydrate / brimonidine formulations after storage

[0177] Ophthalmic formulations containing carbohydrate and brimonidine, namely formulations 4, 6, 2, and 3, were prepared as described in Table 1 above. Samples were stored at 25°C and 40% relative humidity (RH), or at 40°C and no more than 25% RH (NMT). After 2, 3, and / or 5 months of storage, impurities in the samples were tested using the high-performance liquid chromatography (HPLC) method shown in Table 3. The results are shown in Table 4. Table 3: HPLC Methods tubular GL Sciences Inertsil ODS-3V column, 5 μm, 4.6 × 250 mm, part number 5020-01801 Column temperature 25℃ Diluent / Mobile Phase (MP) Potassium octanesulfonate buffer at pH 3.5:acetonitrile (64:36 v / v) Flow rate 1.0 ml / min Detection UV 254 nm Automatic sampler temperature Ambient temperature Injection volume 20 μL Needle washing solution Acetonitrile:water (50:50 v / v) Runtime 10 minutes Table 4: Quantitative analysis of impurity concentrations in carbamate / brimonidine formulations stored for 5 months at 25°C and 40% RH or at 40°C and NMT 25% RH. impurities 4 ingredients 6 ingredients Blend 2 3 ingredients 25 ℃, 40% RH 40 ℃, NMT 25% RH 25 ℃, 40% RH 40 ℃, NMT 25% RH 25 ℃, 40% RH 40 ℃, NMT 25% RH 25 ℃, 40% RH 40 ℃, NMT 25% RH choline ND 5.1-5.4% (0.19%, at 3 months) ND 5.0-5.4% (0.17%, at 3 months) ND 4.7-4.8% (0.11%, at 3 months) ND 5.9% (0.2%, at 3 months) Impurity B (RRT 0.67) ND (0.09%, at 3 months) 1.2-1.3% (0.6%, at 3 months) ND (0.09% @ months) 1.2-1.3% (0.5% at 3 months) ND (0.08%, at 3 months) 1.5% (0.53%, at 3 months) ND (0.11%, at 3 months) 1.7% (0.58%, at 3 months) Impurity A (RRT 0.91) 0.23-0.25% (0.16%, at 3 months) 2.6-2.9% (1.2%, at 3 months) 0.25% (0.16%, at 3 months) 2.3-2.9% (1.1%, at 3 months) 0.2% (0.15%, at 3 months) 2.9-3.0% (1.1%, at 3 months) 0.14-16% (0.18% at 3 months) 3.3% (1.2%, at 3 months) ND = Data does not exist Example 4 Identification of unknown impurities in carbohydrate / brimonidine formulations

[0178] Three identical samples containing carbohydrate and brimonidine were prepared as Samples I, II, and III and stored at 40°C and 25% relative humidity (RH) at NMT for six months. The observed impurities were identified by HPLC and mass spectrometry (MS). The EP impurity F and EP impurity G standards of brimonidine were also analyzed by HPLC and MS for comparison with the carbohydrate / brimonidine formulation. A summary of the studied samples is shown in Table 5. Table 5: Samples prepared for LC-PDA analysis Sample Name Stability Information purity Carbohydrate / brimonidine sample (I) 6 months, at 40℃ / NMT 25% RH N / A Carbohydrate / brimonidine sample (II) 6 months, at 40℃ / NMT 25% RH N / A Carbohydrate / brimonidine sample (III) 6 months, at 40℃ / NMT 25% RH N / A EP impurity G standard N / A 98.3% EP impurity F standard N / A 95% LC-PDA analysis based on the method in Example 3

[0179] The mobile phase (MP), diluent, and syringe wash solution were prepared according to the method described in Table 3 of Example 3, except that the ion-pairing agent potassium 1-octanesulfonate used in the MP was replaced with sodium 1-octanesulfonate because potassium salts were unavailable. Additionally, impurities G and F, as described in Table 5, and three carbohydrate / brimonidine samples were prepared into solutions with an impurity concentration of approximately 0.2 mg / mL and a sample concentration of 0.1 mg / mL. All solutions were analyzed using a liquid chromatography-photodiode array (LC-PDA) according to the method described in Table 3 of Example 3, except that the injection volume was increased from 20 μL to 30 μL for better observation of the impurity peaks. All three sample solutions showed a similar chromatographic profile to that obtained in Example 3, with two major impurities (RRT 0.67 and RRT 0.91) and brimonidine API observed in the chromatograms at 2.81 min, 4.03 min, and 4.39 min at room temperature, respectively. Furthermore, EP impurity G was observed at the same retention time as the target impurity RRT 0.91, and EP impurity F dissociated at the same retention time as brimonidine API. The UV spectra of all major peaks (peak area % approximately 0.05) in each chromatogram were extracted and examined. Because all three samples contained similar major impurities, only one sample was studied in the remaining studies, rather than all three. Since the chromatogram of carbohydrate / brimonidine sample I did not have a placebo peak at 1.8 min at room temperature, it was used for subsequent analysis to reduce matrix interference. The UV spectra of all main peaks in the extracted carbocholine / brimonidine formulation sample revealed that the impurities exhibited unique UV spectra at RRT 0.91. These characteristics included a relatively flat and broad second UV absorption band at 240–260 nm and a less dense third UV absorption band at 320 nm. These features distinguish the impurities at RRT 0.91 from all other impurities and brimonidine API, which is crucial for subsequent LC-PDA-MS analysis. The peak at RRT 0.91 was confirmed by LC-PDA analysis using low organic matter MP.

[0180] To further confirm that the impurity observed at RRT 0.91 in the above analysis was the target impurity and that its UV spectrum possessed the unique characteristics mentioned above, carbohydrate / brimonidine sample I was prepared in 10% acetonitrile at the same concentration used in the previous analysis, and the solution was analyzed according to the same method, but the MP was adjusted to contain a lower percentage of organic matter (30% mobile phase B (MPB) plus 70% mobile phase A (MPA)) and the injection volume was increased to 30 μL. The resulting 254 nm UV chromatography showed that, with the adjusted low organic matter MP, the target impurity at RRT 0.91 (at room temperature, 5.62 min) was better separated from the previously almost co-dissolved brimonidine API peak (at room temperature, 6.82 min), and a small amount of previously unobserved impurity was observed at room temperature, which co-dissolved with either the target impurity or brimonidine API in the previous analysis. However, the UV spectrum of the better separated RRT 0.91 peak still exhibits characteristics similar to those previously observed. The distinctive UV features of the RRT 0.91 impurity are reaffirmed (a relatively flat and broad second UV absorption band at 240–260 nm, and a less dense third UV absorption band at 320 nm).

[0181] LC-PDA analysis using low organic matter MP also confirmed that EP impurity G was not the target impurity RRT 0.91, because the UV curves of the two peaks were different and their residence times were also different; RRT 0.91 impurity dissociated at 5.62 minutes at room temperature, while EP impurity G dissociated together with the adjusted mobile phase at a residence time of 2 minutes. Development of LC-PDA Methods for LC-PDA-MS Analysis

[0182] With the UV spectrum of the target impurity RRT 0.91 confirmed, LC-MS compatible MPA (20 mM ammonium formate solution with pH adjusted to 3.5 using formic acid), MPB (acetonitrile), and a new diluent (water containing 10% acetonitrile) were prepared for the development of an LC-MS compatible method. The sample solution concentration was kept the same as previously used; the standard solution was diluted sufficiently to avoid UV detector saturation. These solutions were injected with the new MP through different columns (including the column previously specified in Table 3 of Example 3). However, all test results were unsatisfactory because the MP lacked an ion-pairing agent, resulting in insufficient retention time for the observed peak. Finally, analysis was attempted using a Phenomenex Kinetex XB C-18 column (2.6 μm, 4.6 × 100 mm, catalog number 00F-4496-E0), achieving good retention time and separation of the target RRT 0.91 peak. The final developed LC-PDA method is summarized in Table 6. This method was used to analyze the standards and the sample solutions prepared above. In the resulting chromatograms, the RRT 0.91 impurity dissociated at room temperature in 3.4 minutes, while brimonidine API dissociated at room temperature in 2.1 minutes, confirming good separation between the two. The UV spectrum of the extracted RRT 0.91 was also consistent with previously observed results. Table 6: LC-PDA-TOFMS conditions used for identification analysis HPLC tubular Phenomenex Kinetex XB C-18 column, 2.6 μm, 4.6 × 100 mm, part number 00F-4496-E0 Column temperature 25℃ Moving phase A (MPA) 20 mM ammonium formate buffer at pH 3.5 Moving phase B (MPB) Degassed acetonitrile Standard diluent 10% acetonitrile Injection volume 30 μL Needle washing solution 50:50 Acetonitrile:Water, v / v Runtime 10 minutes Flow rate 0.8 ml / min Dissolution Isocratic 20% MPB + 80% MPA Automatic sampler temperature Ambient temperature MS ionization Positive ESI atomized gas Nitrogen (35 psig) Dry gas Nitrogen (325°C, 11 liters / minute) V frag 100 volts V cap 3500 volts Quality scan rate 1 spectrum / second Scan range 110-950 m / z LC material flow into MSD time window 3.1-4.5 minutes LC-PDA-MS analysis

[0183] Using the LC-PDA method developed in previous chapters, along with corresponding mass spectrometry parameters (lower half of Table 6), EP impurity G, EP impurity F, and carbohydrate / brimonidine sample A solution were analyzed by LC-PDA-MS. In the UV chromatography, the target impurity was observed at 3.5 minutes at room temperature, and in all ion chromatography sequences, at 3.57 minutes at room temperature (RRT 0.91). The two peaks generated in the UV and mass spectra were extracted, revealing a clear monoisotope [M+H]+ peak at m / z 335.0252; high-resolution mass matching indicated its molecular formula as C12H11BrN6O, with a mass matching error of only 0.48 ppm, as shown in Table 7. Compared to brimonidine API (C11H10BrN5), the former has an additional CONH group in its molecule. Table 7: High-resolution mass spectrometry analysis results of RRT 0.91 impurities Impurity Name The discovered monoisotope ions (m / z) Ionic form The theoretical monoisotopic mass of M Molecular formula of M Absolute quality matching error (ppm) Overall quality match score (%) generated by Masshunter software Impurity A (RRT 0.91) 335.0252 [M+H] + 334.0178 Da C 12H 11BrN 6O 0.48 96.75 Example 5 Forced Degradation Study of Carbohydrate / Bromidine Compound Materials

[0184] The materials used in this forced degradation study are shown in Table 8 below. Table 8: Materials used in forced degradation studies [Material Name] Brimonidine Tartrate API Carbohydrate choline API Carbohydrate / brimonidine formulation (6-month accelerated stability sample) Drug mediator Preparation of pressure sample solution (Phase I)

[0185] Following the procedure shown in Table 9, the two combined APIs were pressurized for 66 hours under the following conditions: humid heat (Sample A), 0.1 M HCl at room temperature (Sample B), 0.1 M NaOH at room temperature (Sample C), mordant and heating (Sample D), 1 M HCl at room temperature (Sample E), and 1 M NaOH at room temperature (Sample F). A control (Sample G) was prepared by pressurizing the drug mordant at room temperature for 66 hours. After pressure treatment, all samples were removed from the treatment conditions, cooled to room temperature, and then neutralized and brought to similar concentration levels as appropriate. The samples were capped and shaken until all material in each sample was dissolved. The sample solutions were then diluted and thoroughly mixed with the diluent used in the HPLC method described in Table 6 of Example 4. Reference sample solutions were also prepared using a six-month accelerated stability sample of carbohydrate / brimonidine for the purpose of verifying retention time (Table 8). The analytical concentration of brimonidine tartrate in all degradation and reference sample solutions was 0.1 mg / mL. Table 9: Sample Preparation for Forced Degradation (Phase I) sample VF volume Added API* pressurization conditions program A 50 mL 5.0 mg brimonidine tartrate and 137.5 mg carbocholine Hot and humid (50℃) Add 5.0 mL of water to a flask containing both APIs, seal the flask, and place it in a 50°C oven for 66 hours. B 50 mL 5.0 mg brimonidine tartrate and 137.5 mg carbocholine 0.1 M HCl, room temperature Add 5.0 mL of 0.1 M HCl to a flask containing both APIs, seal the flask, place it on a stirring plate, and stir the solution at room temperature for 66 hours. C 50 mL 5.0 mg brimonidine tartrate and 137.5 mg carbocholine 0.1 M NaOH, room temperature Add 5.0 mL of 0.1 M NaOH to a flask containing both APIs, seal the flask, place it on a stirring plate, and stir the solution at room temperature for 66 hours. D 50 mL 5.0 mg brimonidine tartrate and 137.5 mg carbocholine Media and high temperature (50 ℃) Add 1.0 mL of the mediator to a flask containing both APIs, seal the flask, and place it in a 50°C oven for 66 hours. E 50 mL 5.0 mg brimonidine tartrate and 137.5 mg carbocholine 1 M HCl, room temperature Add 5.0 mL of 1 M HCl to a flask containing both APIs, seal the flask, place it on a stirring plate, and stir the solution at room temperature for 66 hours. F 50 mL 5.0 mg brimonidine tartrate and 137.5 mg carbocholine 1 M NaOH, room temperature Add 5.0 mL of 1 M NaOH to a flask containing both APIs, seal the flask, place it on a stirring plate, and stir the solution at room temperature for 66 hours. G 10 mL none Medium, heating (50℃, as a control). Add 0.2 mL of the agent to an API-free flask, seal the flask, and place it in a 50°C oven for 66 hours. *The API w / w ratio is the same as the ratio in Table 8. LC-PDA Analysis of Forced Degradation Sample Solutions

[0186] All sample solutions prepared as described in Table 9 were analyzed according to the HPLC-PDA method shown in Table 6 of Example 4. The RRT 0.91 impurity was observed at 3.4 minutes at room temperature only in the reference sample and the alkaline pressurized samples (Sample C, Sample F, and Sample G). The impurity content in the two alkaline pressurized samples was approximately 0.02% relative to the brimonidine peak. The UV spectra of the extracted RRT 0.91 impurity from the carbohydrate / brimonidine formulation (6-month accelerated stability sample) and the two alkaline pressurized samples were similar to each other. Quality verification of RRT 0.91 impurities was performed by HPLC-MS (Phase I).

[0187] Using the method shown in Table 6 of Example 4, the reference sample solution and two alkaline pressurized API sample solutions were analyzed by HPLC-PDA-MS. In the resulting chromatograms, the RRT 0.91 ion peak was clearly observed in each sample at 3.63 minutes at room temperature. The extracted mass spectra of the ion peaks in all three samples appeared similar, confirming that the molecular formula of the RRT 0.91 peak was C12H11BrN6O. Preparation of pressure sample solution (Phase II)

[0188] Phase I forced degradation studies confirmed that when the two APIs were combined under alkaline conditions (0.1 M NaOH or 1 M NaOH) and pressurized at room temperature, an RRT 0.91 impurity was formed. To investigate the effect of temperature on the reaction, the two APIs (brimonidine tartrate and carbohydrate choline) were combined and simultaneously pressurized under alkaline and heating (45°C) conditions.

[0189] Furthermore, to further confirm that the formation of the RRT 0.91 peak requires the presence of two APIs, individual API samples were pressurized in the same manner. Table 10 shows the degradation sample preparation procedure used. After pressure treatment, the processing conditions of all samples (HM) were removed, and they were allowed to cool to room temperature, neutralized where appropriate, and brought to similar concentration levels. The samples were capped and shaken until all materials in each flask were dissolved. Subsequently, each sample solution was diluted with HPLC diluent (Example 4, Table 6) and thoroughly mixed. Table 10: Sample Preparation for Forced Degradation (Phase II) sample API used Pressure conditions program H 5.0 mg brimonidine tartrate 0.1 M NaOH and heating (45℃) Add 5.0 mL of 0.1 M NaOH to a flask containing brimonidine tartrate, shake to disperse the material, add to a small stir bar, seal the flask, and place it on a 45°C heating plate. Stir the solution at 50 rpm for 66 hours. I 5.0 mg brimonidine tartrate 1 M NaOH and heating (45℃) Add 5.0 mL of 1 M NaOH to a flask containing brimonidine tartrate, shake to disperse the material, add to a small stir bar, seal the flask, and place it on a 45°C heating plate. Stir the solution at 50 rpm for 66 hours. J 137.5 mg carbocholine 0.1 M NaOH and heating (45℃) Add 5.0 mL of 0.1 M NaOH to a flask containing carbocholine, shake to disperse the material, add to a small stir bar, seal the flask, and place it on a 45°C heating plate. Stir the solution at 50 rpm for 66 hours. K 137.5 mg carbocholine 1 M NaOH and heating (45℃) Add 5.0 mL of 1 M NaOH to a flask containing carbocholine, shake to disperse the material, add to a small stir bar, seal the flask, and place it on a 45°C heating plate. Stir the solution at 50 rpm for 66 hours. L 5.0 mg brimonidine tartrate and 137.5 mg carbocholine 0.1 M NaOH and heating (45℃) Add 5.0 mL of 0.1 M NaOH to a flask containing both APIs, shake to disperse the material, add to a small stir bar, seal the flask, and place it on a 45°C heating plate. Stir the solution at 50 rpm for 66 hours. M 5.0 mg brimonidine tartrate and 137.5 mg carbocholine 1 M NaOH and heating (45℃) Add 5.0 mL of 1 M NaOH to a flask containing both APIs, shake to disperse the material, add to a small stir bar, seal the flask, and place it on a 45°C heating plate. Stir the solution at 50 rpm for 66 hours. LC-PDA Analysis of Alkaline and Heated / Pressurized Sample Solutions

[0190] Following the method shown in Table 6 of Example 4, all alkaline and heated / pressurized sample solutions prepared as described in Table 10 were analyzed by LC-PDA. In the resulting 254 nm UV chromatograms, the target impurity RRT 0.91 was observed in both heated and alkaline / pressurized sample solutions when both APIs were present, but not in the individual alkaline and heated / pressurized API solutions. This further confirms that the RRT 0.91 impurity is a reaction product of the two APIs.

[0191] Table 11 shows the relative peak area % (compared to the brimonidine API peak) of the RRT 0.91 peak in each alkaline pressurized API combination with or without relevant heating. The higher peak area % values ​​of impurities in heated and alkaline pressurized samples indicate that heating promotes the formation of RRT 0.91 impurities under alkaline conditions. Table 11: Comparison of relative peak area % of RRT 0.91 impurities formed under alkaline conditions at room temperature and at higher temperatures (45°C). Pressure conditions RRT 0.91 Relative peak area % of impurities (compared to the peak area of ​​brimonidine) 0.1 M NaOH, room temperature 0.02% 1 M NaOH, room temperature 0.02% 0.1 M NaOH, 45℃ 0.15% 1 M NaOH, 45℃ 0.03% HPLC-PDA analysis of all pressurized sample solutions performed according to the prototype method.

[0192] A new prototype HPLC method has been developed to investigate early dissociation peaks that were not well separated by the method described in Table 3 of Example 3. This method better separates early dissociation of brimonidine-related impurities. Conditions are shown in Table 12. All sample solutions from the Phase I and Phase II pressure studies were analyzed using the prototype method. In the resulting 254 nm chromatograms, with or without heating, an RRT 0.91 impurity of the basic pressurized API combination was observed at 13.4 min at room temperature; however, the RRT 0.91 impurity was not observed in other pressurized samples without alkali. This is consistent with the analytical results obtained according to the method described in Table 6 of Example 4. Another unknown impurity (impurity B) of the 0.1 M NaOH and heated pressurized API combination samples was also observed in the chromatogram at 3.44 min at room temperature, with a content of approximately 0.05% relative to the brimonidine peak area. The UV spectrum of the extracted impurity B was consistent with the UV spectra previously observed in stable samples. Impurity B was also observed in other alkaline pressurized API combinations, but at extremely low levels. Table 12: Prototype HPLC Methods tubular GL Sciences Inertsil ODS-3V column, 5 μm, 4.6 × 250 mm, part number 5020-01801 Column temperature 25℃ Diluent / Mobile Phase (MP) Potassium octanesulfonate buffer at pH 3.5:acetonitrile (80:20 v / v) Flow rate 2.0 ml / min Detection UV 254 nm Automatic sampler temperature Ambient temperature Injection volume 20 μL Needle washing solution Acetonitrile:water (50:50 v / v) Runtime 30 minutes Example 6 Other illustrative examples of carbocholine / brimonidine formulations

[0193] An ophthalmic formulation containing carbohydrate and brimonidine was prepared by dissolving the components in an aqueous solution within the concentration ranges shown in Table 13. Table 13: Examples of carbocholine / brimonidine formulations Components 22 ingredients 23 ingredients 24 ingredients 25 ingredients 26 ingredients 27 ingredients Carbocholine 2.25% - 3% by weight 2.25% - 3% by weight 2.25% - 3% by weight 2.25% - 3% by weight 2.25% - 3% by weight 2.25% - 3% by weight bromonidin 0.1% to 0.3% by weight 0.1% to 0.3% by weight 0.1% to 0.3% by weight 0.1% to 0.3% by weight 0.1% to 0.3% by weight 0.1% to 0.3% by weight Sodium carboxymethyl cellulose 0.8% to 1.2% by weight 0.8% to 1.2% by weight 0.8% to 1.2% by weight - - - Hydroxypropyl methylcellulose - - - 0.1% by weight to 1.2% by weight 0.1% by weight to 1.2% by weight 0.1% by weight to 1.2% by weight benzalkonium chloride 0.0075% by weight to 0.025% by weight 0.0075% by weight to 0.025% by weight - 0.0075% by weight to 0.025% by weight 0.0075% by weight to 0.025% by weight - Polyvinylpyrrolidone (PVP) - 1.5% to 2.5% by weight - - 1.5% to 2.5% by weight - Phosphate buffer* 0.1% by weight to 0.2% by weight 0.1% by weight to 0.2% by weight 0.1% by weight to 0.2% by weight 0.1% by weight to 0.2% by weight 0.1% by weight to 0.2% by weight 0.1% by weight to 0.2% by weight Purified water Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. *Total concentration of phosphate buffer containing sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate heptahydrate

[0194] Other ophthalmic formulations containing carbohydrate and brimonidine were prepared by dissolving the components in aqueous solutions within the concentration ranges shown in Table 14. Table 14: Other exemplary carbocholine / brimonidine formulations Components 28 ingredients 29 ingredients 30g of ingredients 31 ingredients 32 ingredients 33 ingredients Carbocholine 2.75% by weight 2.75% by weight 2.75% by weight 2.75% by weight 2.75% by weight 2.75% by weight bromonidin 0.1% by weight 0.1% by weight 0.1% by weight 0.1% by weight 0.1% by weight 0.1% by weight Sodium carboxymethyl cellulose 1% by weight 1% by weight 1% by weight - - - Hydroxypropyl methylcellulose - - - 0.2% by weight 0.2% by weight 0.2% by weight benzalkonium chloride 0.01% by weight 0.01% by weight - 0.01% by weight 0.01% by weight - Polyvinylpyrrolidone (PVP) - 2% by weight - - 2% by weight - Phosphate buffer* 0.12% by weight 0.12% by weight 0.12% by weight 0.12% by weight 0.12% by weight 0.12% by weight Purified water Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. Appropriate amount, reaching 100%. *Total concentration of phosphate buffer containing sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate heptahydrate

[0195] Although the invention has been described in conjunction with specific embodiments thereof, it will be apparent to those skilled in the art that many alternatives, modifications, and variations will be readily apparent. Therefore, it is intended to cover all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0196] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety, as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated herein by reference. Furthermore, any reference or identification of any reference in this application should not be construed as an admission that such reference is prior art to this invention. The section headings used should not be construed as necessarily restrictive.

Claims

1. An ophthalmic formulation comprising 2.75% by weight of carbohydrate choline or a pharmaceutically acceptable salt thereof, 0.1% by weight of brimonidine or a pharmaceutically acceptable salt thereof, 0.2% by weight of hydroxypropyl methylcellulose (HPMC), and 0.05% to 1% by weight of one or more buffer solutions, wherein the pH is 7.4, and wherein the formulation comprises: (i) less than 5% by weight of impurity A after storage at 40°C and relative humidity not exceeding 25% (NMT) for 5 months, wherein impurity A has the following structure: , or its tautomer, wherein the concentration of impurity A is determined by high performance liquid chromatography (HPLC) in potassium octanesulfonate buffer:acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time (RRT) of impurity A relative to brimonidine is 0.9; and / or (ii) After storage at 40°C and no more than 25% relative humidity for 5 months, less than 2% by weight of impurity B, wherein impurity B has the following structure: , or its tautomer, wherein the concentration of impurity B is measured by high performance liquid chromatography in potassium octanesulfonate buffer: acetonitrile (64:36 v / v) at pH 3.5, and the relative retention time of impurity B relative to brimonidine is 0.

67.

2. The ophthalmic compound as requested in item 1, wherein the ophthalmic compound is free of benzalkonium chloride (BAK).

3. The ophthalmic compound as requested in item 1, wherein the compound is free of ethylenediaminetetraacetic acid (EDTA).

4. As in request item 1, the ophthalmic preparation wherein one or more buffer solutions are phosphate buffers.

5. The ophthalmic preparation as claimed in claim 4, wherein the phosphate buffer comprises sodium dihydrogen phosphate monohydrate and disodium hydrogen phosphate heptahydrate.

6. The ophthalmic compound of claim 1, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate.

7. Use of an ophthalmic compound as claimed in any one of claims 1 to 6, wherein the compound is used to prepare a medicine for improving or alleviating presbyopia in at least one eye of an individual.

8. As requested in item 7, wherein it effectively improves or reduces presbyopia for at least 9 hours.