DEGRADANT COMPOUNDIN A MEDICAMENT
`
`FIELD AND BACKGROUND OF THE INVENTION
`
`[0001]
`
`The present disclosure relates to ophthalmic formulations comprising carbachol,
`
`brimonidine, and less than 5 wt % of one or more impurities. The formulations disclosed
`
`maybe useful in treating ophthalmic conditions such as presbyopia.
`
`[0002]
`
`Presbyopiais typically age-related eye deterioration. Young, properly functioning,
`
`eyes are able to see at near distances, an ability that deteriorates as one ages. Presbyopia
`
`normally develops as a person ages, and is associated with a natural progressive loss of
`
`accommodation. A presbyopic eye loses the ability to rapidly and easily focus on objects at
`
`near distances. Presbyopia progresses overthe lifetime of an individual, usually becoming
`
`noticeable after the age of 45 years. By the age of 65 years, the crystalline lens has often lost
`
`almostall elastic properties and has only limited ability to change shape.
`
`[0003]
`
`Use of over the counter reading glasses is a very common wayofaddressing the
`
`vision problemsassociated with presbyopia. Reading glasses allow the eye to focus on near
`
`objects and maintain a clear image. This approachis similar to that of treating hyperopia, or
`
`farsightedness.
`
`[0004]
`
`Manypresbyopesare also prescribed bi-focal eyeglasses, where one portion of the
`
`lens is corrected for distance vision and anotherportion ofthe lens is corrected for near
`
`vision. When peering downthroughthe bifocals, the individual looks throughthe portion of
`
`the lens corrected for near vision. When viewing distant objects, the individual looks higher,
`
`throughthe portion of the bi-focals corrected for distance vision. Contact lenses andintra-
`
`ocular lenses (IOLs) havealso been usedto treat presbyopia, for example, by relying on
`
`monovision (where one eye is corrected for distance-vision, while the other eye is corrected
`
`for near-vision) or bilateral correction with either bi-focal or multi-focal lenses. Laser
`
`ablation has also been usedto treat presbyopia. All these procedures seek to correct the
`
`problem for long term purposesusing drastic steps (surgery, laser ablation, etc) or require
`
`wearing corrective lenses.
`
`[0005]
`
`There remains a need for new ways of ameliorating or reducing presbyopiafor
`
`patients that do not wish to undergo surgery (IOLs,laser ablation, etc.) or use corrective
`
`

`

`-2-
`
`glasses. For people whousecorrective lenses, there remains a need to temporarily treat
`
`presbyopia withoutthe use of corrective lenses.
`
`[0006]
`
`Aswith any formulation designed for treatment of a subject in need thereof, it is
`
`important to identify and quantify the presence of any impurities in the formulation. In
`
`particular, formulations comprising two or more active agents may result in unexpected
`
`reactivity between said agents, resulting in the formation of impurity species. Thus,there is a
`
`need to identify and quantify the presence of any impurity species in ophthalmic
`
`formulations comprising carbachol and brimonidine.
`
`BRIEF SUMMARY OF THE INVENTION
`
`[0007]
`
`The present disclosure provides ophthalmic formulations comprising carbachol,
`
`brimonidine, and less than 5 wt % of one or more impurities.
`
`[0008]
`
`In someaspects, the ophthalmic formulation comprises from about 2 wt % to about 4
`
`wt % carbachol, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about
`
`0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to
`
`about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about 1 wt % of
`
`one or more buffers, wherein the pH of the formulation is from about 7 to about 7.6, and
`
`wherein the formulation comprises less than 5 wt % impurity A after storage for about 5
`
`months, wherein impurity A hasthe structure:
`
`
`
`or a tautomerthereof, wherein the concentration of impurity A is measured by high-
`
`performanceliquid chromatography (HPLC)in pH 3.5 potassium octane sulfonate
`
`buffer:acetonitrile (64:36 v/v) and impurity A hasa relative retention time (RRT)of about
`
`0.9 relative to brimonidine.
`
`Atty. Dkt. No. 4902.0120001
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`

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`-3-
`
`[0009}
`
`In someaspects, the ophthalmic formulation is stored at 40 °C and not more than
`
`(NMT) 25% relative humidity for about 5 months.
`
`[0010}
`
`In someaspects, the ophthalmic formulation comprises less than 3 wt % impurity A
`
`after storage at 40 °C and NMT 25% relative humidity for about 3 months.
`
`[0011]
`
`In someaspects, the ophthalmic formulation comprises less than 0.25 wt % impurity
`
`A.
`
`[0012]
`
`In someaspects, the ophthalmic formulation comprises less than 1 wt % impurity A
`
`after storage at 25 °C and 40% relative humidity for about 5 months.
`
`[0013]
`
`In someaspects, the ophthalmic formulation comprises about 2.75 wt % carbachol,
`
`about 0.1 wt % brimonidine, about 0.2 wt % HPMC,and from about 0.05 wt % to about 1 wt
`
`% of one or more buffers, wherein the pH is about 7.4, and wherein the formulation
`
`comprises less than about 5 wt % impurity A after storage for about 5 months, wherein the
`
`concentration of impurity A is measured by high-performance liquid chromatography
`
`(HPLC)in pH 3.5 potassium octane sulfonate buffer:acetonitrile (64:36 v/v) and impurity A
`
`has a relative retention time (RRT) of about 0.9 relative to brimonidine.
`
`[0014]
`
`In someaspects, the ophthalmic formulation comprises about 2.75 wt % carbachol,
`
`about 0.1 wt % brimonidine, about 0.01 wt % benzalkonium chloride, and about 0.2 wt %
`
`HPMC,wherein the pH is about 7.4.
`
`[0015]
`
`In someaspects, the ophthalmic formulation further comprises impurity B, wherein
`
`the formulation comprises less than 2 wt % impurity B after storage for about 5 months,
`
`wherein impurity B hasthe structure:
`
`
`
`or a tautomer thereof, wherein the concentration of impurity B is measured by high-
`
`performanceliquid chromatography (HPLC) in pH 3.5 potassium octane sulfonate
`
`buffer:acetonitrile (64:36 v/v) and impurity B hasa relative retention time (RRT) of about
`
`0.67 relative to brimonidine.
`
`Atty. Dkt. No. 4902.0120001
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`-4-
`
`[0016]
`
`In someaspects, the ophthalmic formulation comprises less than 0.1 wt % impurity B
`
`after storage for about 5 months.
`
`[0017]
`
`In someaspects, the ophthalmic formulation comprises less than 2 wt % impurity B
`
`after storage at 40 °C and NMT 25% relative humidity for about 5 months.
`
`[0018]
`
`In some aspects, the ophthalmic formulation comprises less than 0.25 wt % impurity
`
`B after storage at 25 °C and 40% relative humidity for about 3 months.
`
`[0019}
`
`In someaspects, the ophthalmic formulation comprises from about 2 wt % to about 4
`
`wt % carbachol, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about
`
`0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to
`
`about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about 0.1 wt % of
`
`one or more buffers, wherein the pH ofthe formulation is from about 7 to about 7.6, and
`
`wherein the formulation comprises less than 5 wt % impurity B after storage for about 5
`
`months, wherein the concentration of impurity B is measured by high-performance liquid
`
`chromatography (HPLC) in pH 3.5 potassium octane sulfonate buffer:acetonitrile (64:36 v/v)
`
`and impurity B hasa relative retention time (RRT) of about 0.67 relative to brimonidine.
`
`[0020}
`
`In someaspects, the ophthalmic formulation comprises about 2.75 wt % carbachol,
`
`about 0.1 wt % brimonidine, about 0.2 wt % HPMC,and from about 0.05 wt % to about 1 wt
`
`% of one or more buffers, wherein the pH is about 7.4, and wherein the formulation
`
`comprises less than about 2 wt % impurity B after storage for about 5 months, wherein the
`
`concentration of impurity B is measured by high-performance liquid chromatography
`
`(HPLC)in pH 3.5 potassium octane sulfonate buffer:acetonitrile (64:36 v/v) and impurity B
`
`has a relative retention time (RRT) of about 0.67 relative to brimonidine.
`
`[0021]
`
`In some aspects, an ophthalmic formulation described herein comprises one or more
`
`buffers selected from the group consisting of acetate buffer, borate buffer, borate citrate
`
`buffer, carbonate buffer, citrate buffer, lactate buffer, and phosphate buffer.
`
`[0022]
`
`In some aspects, an ophthalmic formulation described herein comprises one or more
`
`buffers that is a phosphate buffer.
`
`[0023]
`
`In someaspects, the phosphate buffer comprises sodium phosphate monobasic
`
`monohydrate and sodium phosphate dibasic heptahydrate.
`
`Atty. Dkt. No. 4902.0120001
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`

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`-5-
`
`[0024]
`
`In some aspects, an ophthalmic formulation described herein comprises one or more
`
`viscosity agents selected from the group consisting of hydroxypropylmethyl cellulose
`
`(HPMC), hydroxyethyl cellulose, methyl cellulose, carboxymethy1 cellulose, and polyvinyl
`
`alcohol, and polyvinylpyrrolidone.
`
`In some aspects, an ophthalmic formulation described herein comprises HPMC.
`
`In some aspects, an ophthalmic formulation described herein comprises from about
`
`0.0025 wt % to about 0.02 wt % benzalkonium chloride.
`
`In some aspects, an ophthalmic formulation described herein does not contain EDTA.
`
`The present disclosure also provides compounds that may be formed as impurities in
`
`formulations comprising carbachol and brimonidine
`
`In some aspects, the compoundis impurity A, having the structure:
`O
`
`NH,
`
`or a tautomer, salt or solvate thereof.
`
`In some aspects, the compoundis impurity B, having the structure:
`
`Br
`
`
`or a tautomer, salt or solvate thereof.
`
`The present disclosure also provides processes for preparing ophthalmic formulations
`
`[0025]
`
`[0026]
`
`[0027]
`
`[0028]
`
`[0029]
`
`[0030]
`
`[0031]
`
`[0032]
`
`comprising carbacholand brimonidine.
`
`[0033]
`
`In someaspects, the disclosure provides a process for manufacturing an ophthalmic
`
`formulation comprising from about 2 wt % to about 4 wt % carbachol, or a pharmaceutically
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`Atty. Dkt. No. 4902.0120001
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`

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`-6-
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`acceptable salt thereof, from about 0.05 wt % to about 0.2 wt % brimonidine,or a
`
`pharmaceutically acceptable salt thereof, from about 0.05 wt % to about 1 wt % of one or
`
`more viscosity agents, and from about 0.05 wt % to about 1 wt % of one or more buffers,
`
`wherein the pH of the formulation is from about 7 to about 7.6, the process comprising
`
`adding carbachol, or a pharmaceutically acceptable salt thereof, brimonidine, or a
`
`pharmaceutically acceptable salt thereof, and one or more viscosity agents to water and
`
`mixing to provide the formulation.
`
`[0034]
`
`In someaspects, the one or more buffers comprise sodium phosphate monobasic
`
`monohydrate and sodium phosphate dibasic heptahydrate.
`
`[0035]
`
`In someaspects, the one or more viscosity agents is hydroxypropylmethyl cellulose
`
`(HPMC).
`
`[0036]
`
`[0037]
`
`[0038]
`
`[0039]
`
`[0040}
`
`[0041]
`
`In some aspects, the process comprises adding benzalkonium chloride.
`
`In someaspects, the process comprises adding sodium chloride.
`
`In someaspects, the process comprises adding hydrochloric acid.
`
`In someaspects, the process comprises adding sodium hydroxide.
`
`In someaspects, the ophthalmic formulationis aseptically filled into vials.
`
`In someaspects, eachvialis filled with from about 0.1 g to about 0.3 g of the
`
`ophthalmic formulation.
`
`[0042]
`
`In someaspects, each vialis filled with from about 2 g to about 2.7 g of the
`
`ophthalmic formulation.
`
`[0043]
`
`The present disclosure also provides methods of ameliorating or reducing presbyopia
`
`in a subject comprising administering an ophthalmic formulation described herein.
`
`[0044]
`
`The present disclosure also provides methods of ameliorating or reducing at least one
`
`refractive error of subject with hyperopia, relaxing a ciliary muscle of a subject stimulated by
`
`sympathetic innervation to reduceat least one of headache, browacheandperiorbital pain,
`
`preventing a parasympathomimetic induced myopic shift in a patient with presbyopia
`
`receiving parasympathomimetic drugs or pharmaceutically acceptable salts thereof,
`
`ameliorating or reducing at least one refractive error of a pseudophakic patient selected from
`
`the group consisting of myopia, hyperopia, and astigmatism,treating at least one refractive
`
`Atty. Dkt. No. 4902.0120001
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`-7-
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`error in a patient that has had ocular surgery, and creating multifocality in a pseudophakic
`
`patient, comprising administering an ophthalmic formulation described herein.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Definitions
`
`[0045]
`
`Unless defined otherwise, all technical and scientific terms used herein have the same
`
`meaning as commonly understood by oneofordinary skill in the art to which this disclosure
`
`belongs. In case of conflict, the present application including the definitions will control.
`
`Unless otherwise required by context, singular terms shall include pluralities and plural terms
`
`shall include the singular. All publications, patents and other references mentioned herein are
`
`incorporated by reference in their entireties for all purposesas if each individual publication
`
`or patent application were specifically and individually indicated to be incorporated by
`
`reference.
`
`[0046]
`
`Although methods and materials similar or equivalent to those described herein can
`
`be used in practice or testing of the present disclosure, suitable methods and materials are
`
`described below. The materials, methods and examplesare illustrative only and are not
`
`intended to be limiting. Other features and advantagesofthe disclosure will be apparent from
`
`the detailed description and from the claims.
`
`[0047]
`
`In order to further define this disclosure, the following terms anddefinitions are
`
`provided.
`
`[0048]
`
`The singular forms "a," "an" and "the" include plural referents unless the context
`
`clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more," and
`
`"at least one” can be used interchangeably herein. In certain aspects, the term "a" or "an"
`
`means"single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."
`
`[0049]
`
`The term "about" is used herein to mean approximately, roughly, around,or in the
`
`regions of. When the term "about" is used in conjunction with a numerical range, it modifies
`
`that range by extending the boundaries above and below the numerical valuesset forth. In
`
`general, the term "about" is used herein to modify a numerical value above and below the
`
`stated value by a variance of 10 percent, up or down(higheror lower).
`
`Atty. Dkt. No. 4902.0120001
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`-8-
`
`[0050]
`
`The term "and/or" where used herein is to be taken as specific disclosure of each of
`
`the two specified features or components with or without the other. Thus, the term "and/or"
`
`as used in a phrase such as "A and/or B" herein is intended to include "A and B," "A or B,"”
`
`"A" (alone), and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B,
`
`and/or C"is intended to encompasseachof the following aspects: 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).
`
`[0051]
`
`The term "pharmaceutically acceptable" as used herein refers to those compounds,
`
`materials, compositions, formulations, and/or dosage forms which are, within the scope of
`
`sound medical judgment, suitable for use in contact with the tissues of human beings and
`
`animals without excessive toxicity, irritation, allergic response, or other problem or
`
`complication, commensurate with a reasonable benefit/risk ratio.
`
`[0052]
`
`The term "excipient" refers to any substance,notitself a therapeutic agent, which may
`
`be used in a composition for delivery of an active therapeutic agent to a subject or combined
`
`with an active therapeutic agent (e.g., to create a pharmaceutical composition) to improveits
`
`handling or storage properties or to permit or facilitate formation of a dose unit of the
`
`composition. The excipient can be an inert substance, an inactive substance, and/or a not
`
`medicinally active substance.
`
`[0053]
`
`The terms "effective amount" or "pharmaceutically effective amount” or
`
`"therapeutically effective amount" as used herein refer to the amount or quantity of a drug or
`
`pharmaceutically active substance whichis sufficientto elicit the required or desired
`
`therapeutic response, or in other words, the amount whichis sufficient to elicit an appreciable
`
`biological response when administered to a patient.
`
`[0054]
`
`"Administration", or "to administer" meansthe step of giving (i.e. providing) a
`
`pharmaceutical composition to a subject. The pharmaceutical compositions disclosed herein
`
`can be "locally administered", that is administered at or in the vicinity of the site at which a
`
`therapeutic result or outcomeis desired. For example to treat an ocular condition such as
`
`corneal pain, topical administration, directly to the eye of a subject, of an ophthalmic
`
`formulation can be carried out, and is an example of local administration.
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`Atty. Dkt. No. 4902.0120001
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`-9-
`
`[0055]
`
`The term "pharmaceutically acceptable salts" is art-recognized, and includes
`
`relatively non-toxic, inorganic and organic acid addition salts of compoundsandrelatively
`
`non-toxic, inorganic and organic base addition salts of compounds.
`
`[0056]
`
`Inorganic acids which may be used to prepare pharmaceutically acceptable salts
`
`include, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic
`
`acid, hydroiodic acid, phosphorousacid andthe like. Organic acids which maybe used to
`
`prepare pharmaceutically acceptable salts include, without limitation, aliphatic mono- and
`
`dicarboxylic acids, suchastartaric acid, oxalic acid, carbonic acid, citric acid, succinic acid,
`
`phenyl-heteroatom-substituted alkanoic acids, aliphatic and aromatic sulfuric acids and the
`
`like. Pharmaceutically acceptable salts prepared from inorganic or organic acids thus include,
`
`but are not limited to, hydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate, bisulfate,
`
`sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
`
`pyrophosphate, hydroiodide, hydrofluoride, acetate, propionate, formate, oxalate, tartrate,
`
`citrate, lactate, p-toluenesulfonate, methanesulfonate, and maleate. Suitable pharmaceutically
`
`acceptable salts may also be formed by reacting the active components with an organic base
`
`such as methylamine, ethylamine, ethanolamine, lysine, ornithine andthelike.
`
`Pharmaceutically acceptable salts include the salts formed between carboxylate or sulfonate
`
`groups that may be found on someofthe active components and inorganic cations, such as
`
`sodium, potassium, ammonium,or calcium, or such organic cations as isopropylammonium,
`
`trimethylammonium,tetramethylammonium,and imidazolium. All of these salts may be
`
`prepared by conventional means from the active components ofthe invention by reacting, for
`
`example, the appropriate acid or base with the active components of the invention.
`
`[0057]
`
`The term "unit dosage form” or "unit dose composition" as used herein refers to a
`
`quantity of a compound, such as a drop or a droplet, said quantity being such that one or
`
`more predetermined units may be provided as a single therapeutic administration.
`
`[0058]
`
`Asused herein, "treat," "treatment", and "treating" refer to the reduction or
`
`amelioration of the progression, severity, and/or duration of a given disease resulting from
`
`the administration of one or more therapies (including, but not limited to, the administration
`
`of an ophthalmic formulation). In certain aspects, the terms refer to the reduction of pain
`
`associated with one or more diseases or conditions.
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`-1]0-
`
`[0059]
`
`The term "wt %" or "weight/volume"as used herein refers to the ratio between two
`
`components with respect to volume. For example, a 5 wt % ethanol in water solution would
`
`represent a solution comprising 5 g ethanol for every 100 mL water.
`
`[0060]
`
`The term "mg/mL"as used herein refers to the ratio between a solute, generally an
`
`active pharmaceutical ingredient or excipient, and a solvent, generally but not necessarily
`
`water. For example, a 50 mg/mL sodium chloride aqueous solution would represent a
`
`solution comprising 50 mg sodium chloride for every 1 mL water.
`
`[0061]
`
`The term "stable" is used herein to describe a composition in which mostorall of the
`
`active pharmaceutical ingredient does not degrade or transform over a specific time period
`
`and underspecific conditions.
`
`Impurity Compounds
`
`[0062]
`
`The present disclosure provides compoundsthat may be formed as impurities in
`
`formulations comprising carbachol and brimonidine.
`
`[0063]
`
`In some aspects, the compoundis 2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-
`
`1H-imidazole-1-carboxamide("impurity A"), having the structure:
`
`
`
`or a tautomerthereof.
`
`[0064]
`
`In some aspects, impurity A has a relative retention time (RRT) of about 0.9 relative
`
`to brimonidine when measured by high performance liquid chromatography (HPLC)in pH
`
`3.5 potassium octane sulfonate buffer:acetonitrile (64:36 v/v).
`
`[0065]
`
`In some aspects, the compoundis 1-(5-bromoquinoxalin-6-yl)-3-(2-ureidoethyl)urea
`
`("impurity B"), having the structure:
`
`Atty. Dkt. No. 4902.0120001
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`-jl-
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`Br
`
`Oo
`
`Ss N yo NH,
`
`ZA
`
`N
`
`ZA
`
`O
`
`or a tautomerthereof.
`
`[0066]
`
`In some aspects, impurity B has a RRT of about 0.67 relative to brimonidine when
`
`measured by HPLC in pH 3.5 potassium octane sulfonate buffer:acetonitrile (64:36 v/v).
`
`Ophthalmic Formulations
`
`[0067]
`
`The present disclosure also provides ophthalmic formulations comprising carbachol,
`
`brimonidine, pharmaceutically acceptable excipients, and less than 5 wt % of one or more
`
`impurities.
`
`[0068]
`
`In someaspects, the impurity is 2-((5-bromoquinoxalin-6-yl)amino)-4,5-dihydro-1H-
`
`imidazole-1-carboxamide ("impurity A"), having the structure:
`O
`
`NH,
`
`or a tautomerthereof.
`
`[0069]
`
`In some aspects, impurity A has a relative retention time (RRT) of about 0.9 relative
`
`to brimonidine when measured by high performance liquid chromatography (HPLC)in pH
`
`3.5 potassium octane sulfonate buffer:acetonitrile (64:36 v/v).
`
`[0070}
`
`In some aspects, the impurity is 1-(5-bromoquinoxalin-6-yl)-3-(2-ureidoethyl)urea
`
`("impurity B"), having the structure:
`
`Atty. Dkt. No. 4902.0120001
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`-|2-
`
`Br
`
`O
`
`( Sy
`
`ra a
`
`“SS TT SS NH,
`
`i.
`
`or a tautomerthereof.
`
`[0071]
`
`In some aspects, impurity B has a RRT of about 0.67 relative to brimonidine when
`
`measured by HPLC in pH 3.5 potassium octane sulfonate buffer:acetonitrile (64:36 v/v).
`
`[0072]
`
`In someaspects, the ophthalmic formulation comprises from about 2 wt % to about 4
`
`wt % carbachol, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to about
`
`0.2 wt % brimonidine, or a pharmaceutically acceptable salt thereof, from about 0.05 wt % to
`
`about 1 wt % of one or more viscosity agents, and from about 0.05 wt % to about 1 wt % of
`
`one or more buffers, wherein the pH of the formulation is from about 7 to about 7.6, and
`
`wherein the formulation comprises less than 5 wt % impurity A after storage for about 5
`
`months.
`
`[0073]
`
`In someaspects, the ophthalmic formulation comprises from about 0.25 wt % to
`
`about 0.5 wt %, from about 0.25 wt % to about 0.75 wt %, from about 0.25 wt % to about 1
`
`wt %, from about 0.25 wt % to about 1.25 wt %, from about 0.25 wt % to about 1.5 wt %,
`
`from about 0.25 wt % to about 1.75 wt %, from about 0.25 wt % to about 2 wt %, from about
`
`0.25 wt % to about 2.25 wt %, from about 0.25 wt % to about 2.5 wt %, from about 0.25 wt
`
`% to about 2.75 wt %, from about 0.25 wt % to about 3 wt %, from about 0.25 wt % to about
`
`3.25 wt %, from about 0.25 wt % to about 3.5 wt %, from about 0.25 wt % to about 3.75 wt
`
`%, from about 0.25 wt % to about 4 wt %, from about 0.25 wt % to about 4.25 wt %, from
`
`about 0.25 wt % to about 4.5 wt %, from about 0.25 wt % to about 4.75 wt %, from about
`
`0.25 wt % to about 5 wt %, from about 0.5 wt % to about 0.75 wt %, from about 0.5 wt % to
`
`about 1 wt %, from about 0.5 wt % to about 1.25 wt %, from about 0.5 wt % to about 1.5 wt
`
`%, from about 0.5 wt % to about 1.75 wt %, from about 0.5 wt % to about 2 wt %, from
`
`about 0.5 wt % to about 2.25 wt %, from about 0.5 wt % to about 2.5 wt %, from about 0.5
`
`wt % to about 2.75 wt %, from about 0.5 wt % to about 3 wt %, from about 0.5 wt % to about
`
`3.25 wt %, from about 0.5 wt % to about 3.5 wt %, from about 0.5 wt % to about 3.75 wt %,
`
`Atty. Dkt. No. 4902.0120001
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`-13-
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`from about 0.5 wt % to about 4 wt %, from about 0.5 wt % to about 4.25 wt %, from about
`
`0.5 wt % to about 4.5 wt %, from about 0.5 wt % to about 4.75 wt %, from about 0.5 wt % to
`
`about 5 wt %, from about 0.75 wt % to about 1 wt %, from about 0.75 wt % to about 1.25 wt
`
`%, from about 0.75 wt % to about 1.5 wt %, from about 0.75 wt % to about 1.75 wt %, from
`
`about 0.75 wt % to about 2 wt %, from about 0.75 wt % to about 2.25 wt %, from about 0.75
`
`wt % to about 2.5 wt %, from about 0.75 wt % to about 2.75 wt %, from about 0.75 wt % to
`
`about 3 wt %, from about 0.75 wt % to about 3.25 wt %, from about 0.75 wt % to about 3.5
`
`wt %, from about 0.75 wt % to about 3.75 wt %, from about 0.75 wt % to about 4 wt %, from
`
`about 0.75 wt % to about 4.25 wt %, from about 0.75 wt % to about 4.5 wt %, from about
`
`0.75 wt % to about 4.75 wt %, from about 0.75 wt % to about 5 wt %, from about 1 wt % to
`
`about 1.25 wt %, from about 1 wt % to about 1.5 wt %, from about 1 wt % to about 1.75 wt
`
`%, from about 1 wt % to about 2 wt %, from about 1 wt % to about 2.25 wt %, from about 1
`
`wt % to about 2.5 wt %, from about 1 wt % to about 2.75 wt %, from about 1 wt % to about 3
`
`wt %, from about | wt % to about 3.25 wt %, from about 1 wt % to about 3.5 wt %, from
`
`about 1 wt % to about 3.75 wt %, from about | wt % to about 4 wt %, from about 1 wt % to
`
`about 4.25 wt %, from about 1 wt % to about 4.5 wt %, from about 1 wt % to about 4.75 wt
`
`%, from about 1 wt % to about 5 wt %, carbachol, from about 1.25 wt % to about 1.5 wt %,
`
`from about 1.25 wt % to about 1.75 wt %, from about 1.25 wt % to about 2 wt %, from about
`
`1.25 wt % to about 2.25 wt %, from about 1.25 wt % to about 2.5 wt %, from about 1.25 wt
`
`% to about 2.75 wt %, from about 1.25 wt % to about 3 wt %, from about 1.25 wt % to about
`
`3.25 wt %, from about 1.25 wt % to about 3.5 wt %, from about 1.25 wt % to about 3.75 wt
`
`%, from about 1.25 wt % to about 4 wt %, from about 1.25 wt % to about 4.25 wt %, from
`
`about 1.25 wt % to about 4.5 wt %, from about 1.25 wt % to about 4.75 wt %, from about
`
`1.25 wt % to about 5 wt %, from about 1.5 wt % to about 1.75 wt %, from about 1.5 wt % to
`
`about 2 wt %, from about 1.5 wt % to about 2.25 wt %, from about 1.5 wt % to about 2.5 wt
`
`%, from about 1.5 wt % to about 2.75 wt %, from about 1.5 wt % to about 3 wt %, from
`
`about 1.5 wt % to about 3.25 wt %, from about 1.5 wt % to about 3.5 wt %, from about 1.5
`
`wt % to about 3.75 wt %, from about 1.5 wt % to about 4 wt %, from about 1.5 wt % to about
`
`4.25 wt %, from about 1.5 wt % to about 4.5 wt %, from about 1.5 wt % to about 4.75 wt %,
`
`from about 1.5 wt % to about 5 wt %, from about 1.75 wt % to about 2 wt %, from about
`
`Atty. Dkt. No. 4902.0120001
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`-14-
`
`1.75 wt % to about 2.25 wt %, from about 1.75 wt % to about 2.5 wt %, from about 1.75 wt
`
`% to about 2.75 wt %, from about 1.75 wt % to about 3 wt %, from about 1.75 wt % to about
`
`3.25 wt %, from about 1.75 wt % to about 3.5 wt %, from about 1.75 wt % to about 3.75 wt
`
`%, from about 1.75 wt % to about 4 wt %, from about 1.75 wt % to about 4.25 wt %, from
`
`about 1.75 wt % to about 4.5 wt %, from about 1.75 wt % to about 4.75 wt %, from about
`
`1.75 wt % to about 5 wt %, from about 2 wt % to about 2.25 wt %, from about 2 wt % to
`
`about 2.5 wt %, from about 2 wt % to about 2.75 wt %, from about 2 wt % to about 3 wt %,
`
`from about 2 wt % to about 3.25 wt %, from about 2 wt % to about 3.5 wt %, from about 2
`
`wt % to about 3.75 wt %, from about 2 wt % to about 4 wt %, from about 2 wt % to about
`
`4.25 wt %, from about 2 wt % to about 4.5 wt %, from about 2 wt % to about 4.75 wt %,
`
`from about 2 wt % to about 5 wt %, from about 2.25 wt % to about 2.5 wt %, from about
`
`2.25 wt % to about 2.75 wt %, from about 2.25 wt % to about 3 wt %, from about 2.25 wt %
`
`to about 3.25 wt %, from about 2.25 wt % to about 3.5 wt %, from about 2.25 wt % to about
`
`3.75 wt %, from about 2.25 wt % to about 4 wt %, from about 2.25 wt % to about 4.25 wt %,
`
`from about 2.25 wt % to about 4.5 wt %, from about 2.25 wt % to about 4.75 wt %, from
`
`about 2.25 wt % to about 5 wt %, from about 2.5 wt % to about 2.75 wt %, from about 2.5 wt
`
`% to about 3 wt %, from about 2.5 wt % to about 3.25 wt %, from about 2.5 wt % to about
`
`3.5 wt %, from about 2.5 wt % to about 3.75 wt %, from about 2.5 wt % to about 4 wt %,
`
`from about 2.5 wt % to about 4.25 wt %, from about 2.5 wt % to about 4.5 wt %, from about
`
`2.5 wt % to about 4.75 wt %, from about 2.5 wt % to about 5 wt %, from about 2.75 wt % to
`
`about 3 wt %, from about 2.75 wt % to about 3.25 wt %, from about 2.75 wt % to about 3.5
`
`wt %, from about 2.75 wt % to about 3.75 wt %, from about 2.75 wt % to about 4 wt %, from
`
`about 2.75 wt % to about 4.25 wt %, from about 2.75 wt % to about 4.5 wt %, from about
`
`2.75 wt % to about 4.75 wt %, from about 2.75 wt % to about 5 wt %, from about 3 wt % to
`
`about 3.25 wt %, from about 3 wt % to about 3.5 wt %, from about 3 wt % to about 3.75 wt
`
`%, from about 3 wt % to about 4 wt %, from about 3 wt % to about 4.25 wt %, from about3
`
`wt % to about 4.5 wt %, from about 3 wt % to about 4.75 wt %, from about 3 wt % to about 5
`
`wt %, from about 3.25 wt % to about 3.5 wt %, from about 3.25 wt % to about 3.75 wt %,
`
`from about 3.25 wt % to about 4 wt %, from about 3.25 wt % to about 4.25 wt %, from about
`
`3.25 wt % to about 4.5 wt %, from about 3.25 wt % to about 4.75 wt %, from about 3.25 wt
`
`Atty. Dkt. No. 4902.0120001
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`-1]5-
`
`% to about 5 wt %, from about 3.5 wt % to about 3.75 wt %, from about 3.5 wt % to about 4
`
`wt %, from about 3.5 wt % to about 4.25 wt %, from about 3.5 wt % to about 4.5 wt %, from
`
`about 3.5 wt % to about 4.75 wt %, from about 3.5 wt % to about 5 wt %, from about 3.75 wt
`
`% to about 4 wt %, from about 3.75 wt % to about 4.25 wt %, from about 3.75 wt % to about
`
`4.5 wt %, from about 3.75 wt % to about 4.75 wt %, from about 3.75 wt % to about 5 wt %,
`
`from about 4 wt % to about 4.25 wt %, from about 4 wt % to about 4.5 wt %, from about 4
`
`wt % to about 4.75 wt %, from about 4 wt % to about 5 wt %, from about 4.25 wt % to about
`
`4.5 wt %, from about 4.25 wt % to about 4.75 wt %, from about 4.25 wt % to about 5 wt %,
`
`from about 4.5 wt % to about 4.75 wt %, from about 4.5 wt % to about 5 wt %, or from about
`
`4.75 wt % to about 5 wt % carbachol, or a pharmaceutically acceptable salt thereof. In some
`
`aspects, the ophthalmic formulation comprises from about 2 wt % to about 4 wt % carbachol,
`
`or a pharmaceutically acceptable salt thereof.
`
`[0074]
`
`In some aspects, the ophthalmic formulation comprises about 0.25 wt %, about 0.5
`
`wt %, about 0.75 wt %, about 1 wt %, about 1.25 wt %, about 1.5 wt %, about 1.75 wt %,
`
`about 2 wt %, about 2.25 wt %, about 2.5 wt %, about 2.75 wt %, about 3 wt %, about 3.25
`
`wt %, about 3.5 wt %, about 3.75 wt %, about 4 wt %, about 4.25 wt %, about 4.5 wt %,
`
`about 4.75 wt %, or about 5 wt % carbachol, or a pharmaceutically acceptable salt thereof.
`
`In someaspects, the ophthalmic formulation comprises about 2.75 wt % carbachol, or a
`
`pharmaceutically acceptable salt thereof.
`
`[0075]
`
`In someaspects, the ophthalmic formulation comprises from about 0.05 wt % to
`
`about 0.1 wt %, from about 0.05 wt % to about 0.15 wt %, from about 0.05 wt % to about 0.2
`
`wt %, from about 0.05 wt % to about 0.25 wt %, from about 0.05 wt % to about 0.3 wt %,
`
`from about 0.05 wt % to about 0.35 wt %, from about 0.05 wt % to about 0.4 wt %, from
`
`about 0.05 wt % to about 0.45 wt %, from about 0.05 wt % to about 0.5 wt %, from about 0.1
`
`wt % to about 0.15 wt %, from about 0.1 wt % to about 0.2 wt %, from about 0.1 wt % to
`
`about 0.25 wt %, from about 0.1 wt % to about 0.3 wt %, from about 0.1 wt % to about 0.35
`
`wt %, from about 0.1 wt % to about 0.4 wt %, from about 0.1 wt % to about 0.45 wt %, from
`
`about 0.1 wt % to about 0.5 wt %, from about 0.15 wt % to about 0.2 wt %, from about 0.15
`
`wt % to about 0.25 wt %, from about 0.15 wt % to about 0.3 wt %, from about 0.15 wt % to
`
`about 0.35 wt %, from about 0.15 wt % to about 0.4 wt %, from about 0.15 wt % to about
`
`Atty. Dkt. No. 4902.0120001
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`-16-
`
`0.45 wt %, from about 0.15 wt % to about 0.5 wt %, from about 0.2 wt % to about 0.25 wt %,
`
`from about 0.2 wt % to about 0.3 wt %, from about 0.2 wt % to about 0.35 wt %, from about
`
`0.2 wt % to about 0.4 wt %, from about 0.2 wt % to about 0.45 wt %, from about 0.2 wt % to
`
`about 0.5 wt %, from about 0.25 wt % to about 0.3 wt %, from about 0.25 wt % to about 0.