Hydration formulation including brimonidine

Abstract

The present disclosure describes formulations and methods for hydrating dry eyes. The formulations comprise brimonidine, at least one natural humectant, at least one amino acid, and at least one vitamin, wherein the formulation is preservative free, and may provide effective redness reduction, hydration, lubrication, and / or nourishment of the eyes.

Description

INTERNATIONAL PATENT APPLICATIONFORHYDRATION FORMULATION INCLUDING BRIMONIDINEBYERIC PHILLIPS,MARTIN COFFEY andZORA MARLOWE

[0001] The present disclosure is related to formulations comprising brimonidine, at least one natural humectant, at least one amino acid, and at least one vitamin, wherein the formulation is preservative free. The present disclosure also provides methods of treating, improving, and / or ameliorating dryness; removing irritants and / or debris; maintaining eye hygiene; and / or treating, improving, or ameliorating dry eye and symptoms thereof. In some embodiments, the formulations and methods provide for cleansing, cleaning, conditioning, moisturizing, lubricating, hydrating, nourishing, soothing, calming, and / or refreshing ocular surface tissues.

[0002] The formulations of the present disclosure may rebuild and / or nurture the homeostasis of the ocular surface and may provide essential nutrients to a compromised tear fluid to restore tear film integrity.

[0003] Dry eye is defined by the DEWS Definition and Classification Subcommittee as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear instability with potential damage to the ocular surface, accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. (Ubels et al., Curr. Eye Res., 28:437-444, 2002). Dry eye is a disorder of the ocular surface due to tear deficiency, excessive tear evaporation, or incorrect composition of tears. For most patients with mild dry eye symptoms, over-the-counter dry eye drops (OTC-DED) are the first line of therapy. These products offer temporary relief by providing replacement of naturally produced tears in patients with aqueous tear deficiency, acting as lubricants, diluting pro-inflammatory substances, and / or protecting against osmotic stress. Some drops may contain lipids to restore the lipid layer of the tear film.

[0004] A recent study has shown a link between sleep deprivation and dry eye syndrome. Amino acids such as arginine, leucine, and taurine were found to be lower in the tears in a sleep derived model. Leucine is the main component of proteoglycans found in the corneal stroma and aids in corneal healing. Arginine is necessary for the expression of beta-def ensins, which are part of the immune system. Taurine is a transporter necessary for osmoregulatory action. The formulation of the present disclosure assists in replenishing amino acids in tears.

[0005] The present disclosure also provides methods for inducing vasoconstriction to treat, improve, and / or ameliorate an ocular condition. In some embodiments, the ocular condition is red eye (conjunctival hyperemia), including chronic red eye. In some embodiments, theocular condition encompasses aestethic conditions, such as occasional excessive redness of an eye.

[0006] Chronic red eye is a common condition associated with chronic conditions such as dry eye, contact lens wear, or allergic conjunctivitis.

[0007] Occasional excessive eye redness, sometimes referred to as “blood shot”, is a common condition that can be caused by minor eye irritation. Common causes include environmental allergens, excessive use of digital devices, lack of sleep, or dry and / or dusty conditions.

[0008] Common redness relievers act by constricting the artieries in the eye, which deprives the eye of oxygen. This oxygen deprivation works to relieve redness initially, but commonly causes rebound redness. Rebound redness refers to induced vasodilation (instead of intended vasoconstriction) occurring, often with a lag time, after an application or, more typically, repeated applications of vasoconstrictors. Rebound redness is characterized by engorgement of blood vessels (such as those in the conjunctiva), increased capillary permeability and leakage, and, in some cases, inflammatory sequelae (medicamentosa).

[0009] The formulations of the present disclosure induce preferential vasoconstriction of smaller blood vessels, such as capillaries and venules, relative to larger blood vessels, such as arteries and arterioles. While not wishing to be bound to any particular theory, this method of vasoconstriction allows for contstiction of the blood flow to visible surface area, with maximal constriction of microvasculature together with minimal additional vasoconstriction of larger arterioles, to maximize per unit area vasoconstrictive benefit and minimize ischemic consequence, including rebound redness.

[0010] The present disclosure will now be described more fully. However, the disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

[0011] Definitions of certain terms as used in this application are provided below. Unless defined otherwise, all technical and scientific terms used herein have the normal and common meaning that would be commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0012] As used herein, “a,” “an,” and “the” refer to one or more (z.e., to at least one) of the grammatical object of the article.

[0013] As used herein, the terms “hydrating,” “lubricating,” and “nourishing” are used interchangeably and all refer to reduction of dryness, prevention of water loss, tear evaporation protection, restoration of natural moisture balance of the tear film, or any combination of the foregoing.

[0014] The terms “patient,” “subject,” “individual,” and the like, as used herein, are interchangeable and all refer to any animal, which may be a human or a non -human animal.

[0015] As will be understood by one of ordinary skill in the art, when disclosed herein, each range includes all possible subranges as well as individual numerical values within that range. For example, a range of “1.0 to 5.0” includes and would be understood to specifically disclose subranges such as “1.0 to 3.0,” “1.5 to 3.7,” “2.1 to 4.3,” etc., as well as all individual numbers within the disclosed range, for example, 1.0, 1.1, 1.2, 1.3, etc.

[0016] As used herein, a formulation is “stable” if there is no visible appearance of precipitation and / or phase separation.

[0017] As used herein, a formulation is “shelf stable” if, after being stored at 20-25°C for 24 months, there is no visible appearance of precipitation and / or phase separation.

[0018] As used herein, a formulation is “free of’ a compound when said compound is not added during manufacture of the formulation.

[0019] As used herein, an ingredient is “active” if that ingredient provides pharmacological activity or other direct or indirect effect in the treatment, mitigation, or prevention of a disease or condition. As used herein, an ingredient is “inactive” if it is not an active ingredient in a formulation.

[0020] As used herein, an ingredient is “natural” when said ingredient is produced by a living organism or otherwise found in nature, or derived or isolated therefrom.

[0021] As noted above, the present disclosure is related to formulations for hydrating eyes comprising brimonidine, at least one natural humectant, at least one amino acid, and at least one vitamin, wherein the formulation is preservative free. The formulations may be useful fortreating, improving, and / or ameliorating dry eye and symptoms thereof. In some embodiments, the formulations and methods provide for lubricating, hydrating, and / or nourishing ocular surface tissues. The formulations may also be useful for inducing vasoconstriction to treat, improve, and / or ameliorate red eye.

[0022] In some embodiments, the formulation comprises brimonidine, at least one natural humectant, at least one amino acid, and at least one vitamin, wherein the formulation is preservative free. In some embodiments, the formulation comprises brimonidine. In some embodiments, the formulation comprises at least one natural humectant. In some embodiments, the formulation comprises at least one amino acid. In some embodiments, the formulation comprises at least one vitamin. In some embodiments, the formulation is preservative free. In some embodiments, the formulation comprises brimonidine, at least one natural humectant, and is preservative free. In some embodiments, the formulation comprises brimonidine, at least one amino acid, and is preservative free. In some embodiments, the formulation comprises brimonidine, at least one vitamin and is preservative free.

[0023] In some embodiments, the formulation comprises brimonidine, at least one natural humectant, at least one amino acid, and at least one vitamin, wherein the formulation is borate free. In some embodiments, the formulation comprises brimonidine, at least one natural humectant, and is borate free. In some embodiments, the formulation comprises brimonidine, at least one amino acid, and is borate free. In some embodiments, the formulation comprises brimonidine, at least one vitamin, and is borate free

[0024] In some embodiments, the formulation is free of polyethylene glycol (PEG) and PEG- containing ingredients. In some embodiments, the formulation is free of polyethylene glycol (PEG). In some embodiments, the formulation is free of PEG-containing ingredients.

[0025] In some embodiments, the formulation comprises brimonidine. In some embodiments, the brimonidine is chosen from brimonidine salts and other derivatives. As a non-limiting example, the brimonidine may be brimonidine tartrate, also known as 5-bromo-6-(2- imidazolin-2-ylamino)quinoxaline D-tartrate, Alphagan™, and UK14304.

[0026] In some embodiments, the formulation comprises 0.0001% w / v to 0.05% w / v brimonidine. In some embodiments, the formulation comprises 0.001% w / v to 0.05% w / v brimonidine. In some embodiments, the formulation comprises 0.001% w / v to 0.025% w / v brimonidine. In some embodiments, the formulation comprises 0.01% w / v to 0.02% w / vbrimonidine. In some embodiments, the formulation comprises 0.02% w / v to 0.03% w / v brimonidine. In some embodiments, the formulation comprises 0.03% w / v to 0.04% w / v brimonidine. In some embodiments, the formulation comprises 0.04% w / v to 0.05% w / v brimonidine. In some embodiments, the formulation comprises 0.025% w / v brimonidine.

[0027] In some embodiments, the formulation comprises at least one natural humectant chosen from glycerin, trehalose, sucrose, and sodium hyaluronate. In some embodiments, the formulation comprises glycerin. In some embodiments, the formulation comprises trehalose. In some embodiments, the formulation comprises sucrose. In some embodiments, the formulation comprises sodium hyaluronate. In some embodiments, the formulation comprises glycerin and trehalose. In some embodiments, the formulation comprises glycerin and sodium hyaluronate. In some embodiments, the formulation comprises trehalose and sodium hyaluronate. In some embodiments, the formulation comprises sucrose and glycerin. In some embodiments, the formulation comprises sucrose and trehalose. In some embodiments, the formulation comprises sucrose and sodium hyaluronate. In some embodiments, the formulation comprises glycerin, trehalose, and sodium hyaluronate. In some embodiments, the formulation comprises glycerin, trehalose, sucrose, and sodium hyaluronate.

[0028] In some embodiments, the sodium hyaluronate is a high molecular weight sodium hyaluronate. In some embodiments, the sodium hyaluronate has a molecular weight in the range of 700 kDa to 1500 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 700 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 750 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 800 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 850 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 900 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 950 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1000 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1050 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1100 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1150 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1200 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1250 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1300 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1350 kDa. In someembodiments, the sodium hyaluronate has a molecular weight of 1400 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1450 kDa. In some embodiments, the sodium hyaluronate has a molecular weight of 1500 kDa.

[0029] In some embodiments, the formulation comprises at least one natural humectant chosen from glycerin, trehalose, and a combination of the same. In some embodiments, the formulation comprises up to 2% w / v of glyecerin, trehalose, or a combination of the same. In some embodiments, the formulation comprises up to 1.75% w / v of glyecerin, trehalose, or a combination of the same. In some embodiments, the formulation comprises up to 1.5% w / v of glyecerin, trehalose, or a combination of the same. In some embodiments, the formulation comprises up to 1.25% w / v of glyecerin, trehalose, or a combination of the same. In some embodiments, the formulation comprises an amount of glycerin, trehalose, or a combination of the same that avoids creating a hypertonic formulation.

[0030] In some embodiments, the formulation comprises at least one amino acid chosen from arginine, leucine, taurine, proline, lysine, and methionine. In some embodiments, the formulation comprises arginine. In some embodiments, the formulation comprises leucine. In some embodiments, the formulation comprises taurine. In some embodiments, the formulation comprises proline. In some embodiments, the formulation comprises lysine. In some embodiments, the formulation comprises methinonine. In some embodiments, the formulation comprises arginine and leucine. In some embodiments, the formulation comprises arginine and taurine. In some embodiments, the formulation comprises leucine and taurine. In some embodiments, the formulation arginine, leucine, and taurine.

[0031] In some embodiments, the formulation comprises at least one vitamin chosen from vitamin C and vitamin Bn. In some embodiments, the formulation comprises vitamin C and vitamin Bn.

[0032] In some embodiments, the formulation comprises vitamin C. In some embodiments, the vitamin C is chosen from sodium ascorbyl phosphate, magnesium ascorbyl phosphate, and combination thereof. In some embodiments, the vitamin C is sodium ascorbyl phosphate. In some embodiments, the vitamin C is magnesium ascorbyl phosphate. In some embodiments, the vitamin C is sodium ascorbyl phosphate and magnesium ascorbyl phosphate.

[0033] In some embodiments, the formulation comprises vitamin Bn. In some embodiments,the vitamin B12 is chosen from cyanocobalamin, hydroxy cobalamin, adenosyl cobalamin, methyl cobalamin, and combinations thereof. In some embodiments, the vitamin Bn is chosen from cyanocobalamin, hydroxycobalamin, adenosyl cobalamin, and methyl cobalamin. In some embodiments, the vitamin Bn is cyanocobalamin. In some embodiments, the vitamin B12 is hydroxy cobalamin. In some embodiments, the vitamin B12 is adenosyl cobalamin. In some embodiments, the vitamin Bn is methyl cobalamin. In some embodiments, the vitamin Bn is cyanocobalamin and hydroxycobalamin. In some embodiments, the vitamin Bn is cyanocobalamin and adenosyl cobalamin. In some embodiments, the vitamin Bn is cyanocobalamin and methyl cobalamin. In some embodiments, the vitamin Bn is hydroxycobalamin and adenosyl cobalamin. In some embodiments, the vitamin Bn is hydroxycobalamin and methyl cobalamin. In some embodiments, the vitamin B12 is adenosyl cobalamin and methyl cobalamin.

[0034] In some embodiments, the formulation comprises zinc and / or copper. In some embodiments, the formulation comprises zinc and copper. In some embodiments, the formulation comprises copper. In some embodiments, the formulation comprises zinc. In some embodiments, the amount of copper is below 5 ppm.

[0035] In some embodiments, the formulation further comprises at least one natural electrolyte. In some embodiments, the at least one natural electrolyte is chosen from sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. In some embodiments, the formulation further comprises sodium chloride, potassium chloride, calcium chloride and magnesium chloride. In some embodiments, the formulation further comprises sodium chloride. In some embodiments, the formulation further comprises potassium chloride. In some embodiments, the formulation further comprises calcium chloride. In some embodiments, the formulation further comprises magnesium chloride. In some embodiments, the formulation further comprises sodium chloride and potassium chloride. In some embodiments, the formulation further comprises sodium chloride and calcium chloride. In some embodiments, the formulation further comprises sodium chloride and magnesium chloride. In some embodiments, the formulation further comprises potassium chloride and calcium chloride. In some embodiments, the formulation further comprises potassium chloride and magnesium chloride. In some embodiments, the formulation further comprises calcium chloride and magnesium chloride.

[0036] In some embodiments, the formulation further comprises at least one natural bufferagent. In some embodiments, the at least one natural buffer agent is chosen from sodium citrate, citric acid, sodium bicarbonate, and amino acids. In some embodiments, the formulation further comprises sodium citrate, citric acid, sodium bicarbonate, and amino acids. In some embodiments, the formulation further comprises sodium citrate. In some embodiments, the formulation further comprises citric acid. In some embodiments, the formulation further comprises sodium bicarbonate. In some embodiments, the formulation further comprises sodium citrate and citric acid. In some embodiments, the formulation further comprises sodium citrate and sodium bicarbonate. In some embodiments, the formulation further comprises sodium citrate and amino acids. In some embodiments, the formulation further comprises citric acid and sodium bicarbonate. In some embodiments, the formulation further comprises citric acid and amino acids. In some embodiments, the formulation further comprises sodium bicarbonate and amino acids.

[0037] In some embodiments, the formulation further comprises at least one antimicrobial agent. In some embodiments, the antimicrobial agent is poly-e-lysine. In some embodiments, the antimicrobial agent is sodium chlorite. In some embodiments, the antimicrobial agent is alexidine.

[0038] In some embodiments, most or all of the inactive ingredients in the formulation are natural. In some embodiments, most of the inactive ingredients are natural. In some embodiments, all of the inactive ingredients are natural. In some embodiments, most of the ingredients are natural. In some embodiments, all of the ingredients are natural.

[0039] In some embodiments, the pH of the formulation is in a range of 5.5 to 8. In some embodiments, the pH of the formulation is in a range of 6 to 8. In some embodiments, the pH of the formulation is in a range of 5.5 to 6. In some embodiments, the pH of the formulation is in a range of 5.5 to 6.5. In some embodiments the pH of the formulation is in a range of 6 to 7. In some embodiments, the pH of the formulation is in a range of 6.0 to 6.7. In some embodiments, the pH of the formulation is in a range of 6.3 to 6.7. In some embodiments the pH of the formulation is in a range of 7 to 8. In some embodiments, the pH of the formulation is 5.5. In some embodiments the pH of the formulation is 6.0. In some embodiments the pH of the formulation is 6.5. In some embodiments the pH of the formulation is 7.0. In some embodiments the pH of the formulation is 7.5. In some embodiments the pH of the formulation is 8.0.

[0040] In some embodiments, the formulation includes a pH adjuster added to obtain a desired pH. In some embodiments, the pH adjuster is sodium hydroxide. In some embodiments, the pH adjuster is hydrochloric acid.

[0041] In some embodiments, the formulation has an osmolality in a range of 200 mOsm / kg to 300 mOsm / kg. In some embodiments, the formulation has an osmolality of 200 mOsm / kg. In some embodiments, the formulation has an osmolality of 215 mOsm / kg. In some embodiments, the formulation has an osmolality of 230 mOsm / kg. In some embodiments, the formulation has an osmolality of 245 mOsm / kg. In some embodiments, the formulation has an osmolality of 275 mOsm / kg. In some embodiments, the formulation has an osmolality of 300 mOsm / kg.

[0042] In some embodiments, the formulation comprises brimonidine, glycerin, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbyl phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride, sodium bicarbonate, cyanocobalamin, and sodium hydroxide.

[0043] In some embodiments, the formulation comprises 0.001% w / v to 0.05% w / v brimonidine, 0.6 % w / v to 0.8 % w / v glycerin, 0.25 % w / v to 0.5 % w / v trehalose, 0.1 % w / v to 0.3 % w / v sodium hyaluronate, 0.2 % w / v to 0.3 % w / v sodium chloride, 0.01 % w / v to 0.14 % w / v potassium chloride, 0.01 % w / v to 0.1 % w / v magnesium ascorbyl phosphate, 0.02 % w / v to 0.06 % w / v sodium citrate, 0.02 % w / v to 0.05 % w / v L-arginine, 0.01 % w / v to 0.0275 % w / v citric acid, 0.01 % w / v to 0.02 % w / v L-taurine, 0.01 % w / v to 0.02 % w / v L-leucine, 0.01 % w / v to 0.02 % w / v calcium chloride, 0.001 % w / v to 0.015 % w / v sodium bicarbonate, 0.001 % w / v to 0.004 % w / v cyanocobalamin, and qs % w / v sodium hydroxide.

[0044] In some embodiments, the formulation comprises 0.025% w / v brimonidine, 0.75 % w / v glycerin, 0.5 % w / v trehalose, 0.24 % w / v sodium hyaluronate, 0.3 % w / v sodium chloride, 0.14 % w / v potassium chloride, 0.1 % w / v magnesium ascorbyl phosphate, 0.06% w / v sodium citrate, 0.05 % w / v L-arginine, 0.024 % w / v citric acid, 0.02 % w / v L-taurine. 0.02 % w / v L-leucine, 0.02 % w / v calcium chloride, 0.005 % w / v sodium bicarbonate, 0.004 % w / v cyanocobalamin, and qs % w / v sodium hydroxide.

[0045] In some embodiments, the formulation comprises brimonidine, glycerin, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbyl phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride,cyanocobalamin, and hydrochloric acid.

[0046] In some embodiments, the formulation comprises 0.001% w / v to 0.05% w / v brimonidine, 0.6 % w / v to 0.8 % w / v glycerin, 0.25 % w / v to 0.5 % w / v trehalose, 0.1 % w / v to 0.3 % w / v sodium hyaluronate, 0.2 % w / v to 0.3 % w / v sodium chloride, 0.01 % w / v to 0.14 % w / v potassium chloride, 0.01 % w / v to 0.1 % w / v magnesium ascorbyl phosphate, 0.02 % w / v to 0.06 % w / v sodium citrate, 0.02 % w / v to 0.05 % w / v L-arginine, 0.01 % w / v to 0.0275 % w / v citric acid, 0.01 % w / v to 0.02 % w / v L-taurine, 0.01 % w / v to 0.02 % w / v L-leucine, 0.01 % w / v to 0.02 % w / v calcium chloride, 0.001 % w / v to 0.004 % w / v cyanocobalamin, and qs % w / v hydrochloric acid.

[0047] In some embodiments, the formulation comprises 0.025% w / v brimonidine, 0.75 % w / v glycerin, 0.5 % w / v trehalose, 0.24 % w / v sodium hyaluronate, 0.3 % w / v sodium chloride, 0.14 % w / v potassium chloride, 0.1 % w / v magnesium ascorbyl phosphate, 0.06% w / v sodium citrate, 0.05 % w / v L-arginine, 0.024 % w / v citric acid, 0.02 % w / v L-taurine. 0.02 % w / v L-leucine, 0.02 % w / v calcium chloride, 0.004 % w / v cyanocobalamin, and qs % w / v hydrochloric acid.

[0048] In some embodiments, the formulations disclosed herein are stable. In some embodiments, the formulations are shelf-stable.

[0049] In some embodiments, after being stored at 20-25 °C for 24 months, the pH of the formulation does not drop more than 0.75 pH units. In some embodiments, after being stored at 20-25°C for 24 months, the pH of the formulation does not drop more than 0.6 pH units. In some embodiments, after being stored at 20-25°C for 24 months, the pH of the formulation does not drop more than 0.5 pH units. In some embodiments, after being stored at 20-25°C for 24 months, the pH of the formulation does not drop more than 0.4 pH units. In some embodiments, after being stored at 20-25°C for 24 months, the pH of the formulation does not drop more than 0.3 pH units. In some embodiments, after being stored at 20-25°C for 24 months, the pH of the formulation does not drop more than 0.25 pH units. In some embodiments, after being stored at 20-25°C for 24 months, the pH of the formulation does not drop more than 0.2 pH units. In some embodiments, after being stored at 20-25°C for 24 months, the pH of the formulation does not drop more than 0.1 pH units.

[0050] In some embodiments, after being stored at 20-25 °C for 24 months, the osmolality of the formulation does not increase more than 50 mOsm. In some embodiments, after beingstored at 20-25°C for 24 months, the osmolality of the formulation does not increase more than 40 mOsm. In some embodiments, after being stored at 20-25°C for 24 months, the osmolality of the formulation does not increase more than 30 mOsm. In some embodiments, after being stored at 20-25°C for 24 months, the osmolality of the formulation does not increase more than 25 mOsm. In some embodiments, after being stored at 20-25°C for 24 months, the osmolality of the formulation does not increase more than 20 mOsm. In some embodiments, after being stored at 20-25°C for 24 months, the osmolality of the formulation does not increase more than 15 mOsm.

[0051] In some embodiments, the formulation is packaged in a sealed package. In some embodiments, the formulation is sealed in a plastic bottle. In some embodiments, the plastic bottle is made of polyethylene. In some embodiments, the plastic bottle is made of polypropylene. In some embodiments, the plastic bottle is made of polyethylene terephthalate (PET).

[0052] In some embodiments, the formulation is sterilized by filtration, autoclaving, gamma irradiation, and / or electron-beam. In some embodiments, the formulation is sterilized by filtration. In some embodiments, the formulation is sterilized by autoclaving. In some embodiments, the formulation is sterilized by filtration and autoclaving. In some embodiments, the formulation is sterilized by gamma irradiation. In some embodiments, the formulation is sterilized by electron-beam.

[0053] In some embodiments, the formulations disclosed herein are free of parabens, thiazolinones, and formaldehyde-donor preservatives. In some embodiments, formulations disclosed herein are free of polyethylene glycol (PEG) and PEG-containing ingredients. In some embodiments, formulations disclosed herein are preservative free. In some embodiments, formulations disclosed herein are sterile and preservative free. In some embodiments, the formulations disclosed herein are borate free.

[0054] In some embodiments, formulations disclosed herein are pH-balanced and nonirritating.

[0055] The formulations disclosed herein may be prepared according to any known method for the manufacture of cosmetic formulations or preparations. As will be appreciated by those of ordinary skill in the art, a number of methods are known.

[0056] In some embodiments, the formulations disclosed herein are useful for cleansing, cleaning, conditioning, moisturizing, lubricating, hydrating, nourishing, soothing, calming, and / or refreshing, ocular surface tissues. In some embodiments, formulations disclosed herein are useful for treating, improving, and / or ameliorating dryness; removing irritants and / or debris; maintaining eye hygiene; and / or treating, improving, and / or ameliorating dry eye and symptoms thereof. In some embodiments, formulations disclosed herein are suitable for adults and children.

[0057] In some embodiemnts, formulations disclosed herein are suitable for contact-lens wearers. In some embodiments, formulations disclosed herein may be applied to the eye while the contact is in the eye. In some embodiments, contacts are removed for a period of time when applying formulations disclosed herein to the eye.

[0058] Accordingly, provided herein are methods of cleansing, cleaning, conditioning, moisturizing, lubricating, hydrating, nourishing, soothing, calming, and / or refreshing ocular surface tissues, comprising applying to said ocular surface tissues a formulation as disclosed herein. In some embodiments, provided herein are methods of treating, improving, and / or ameliorating dryness; removing irritants and / or debris; maintaining eye hygiene; and / or treating, improving, or ameliorating dry eye and symptoms thereof. The methods comprise applying to ocular surface tissues a formulation as disclosed herein.

[0059] In some embodiments, the formulations disclosed herein are useful for inducing vasoconstriction to treat, improve, and / or ameliorate an ocular condition such as red eye. Accordingly, provided herein are methods of reducing red eye, comprising applying to the ocular surface tissue a formulation as disclosed herein.

[0060] In some embodiments, the formulations disclosed herein for treating, improving, and / or ameliorating red eye and the methods of reducing red eye comprising applying to the ocular surface tissue a formulation as disclosed herein result in at least 3 hours of redness relief. In some embodiments, the formulations and methods disclosed herein result in at least 5 hours of redness relief. In some embodiments, the formulations and methods disclosed herein result in at least 7 hours of redness relief. In some embodiments, the formulations and methods disclosed herein result in redness relief without redness rebound.

[0061] In some embodiments, the formulations disclosed herein include, in addition to brimonidine, at least one selective a-2 adrenergic receptor agonist. In some embodiments, theformulations disclosed herein include, in place of brimonidine, at least one selective a-2 adrenergic receptor agonist. In some embodiments, the at least one selective a-2 adrenergic receptor agonist is chosen from apraclonidine, mivazerol, clonidine, alpha methyl dopa, guanfacine, dexemeditomidine, (+)-(S)-4-[l-(2,3-dimethyl-phenyl)-ethyl]-l,3-dihydro- imidazole-2-thione, l-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.

[0062] In some embodiments, the formulations disclosed herein include, in addition to brimonidine, at least one monographed ophthalmic redness reducer. In some embodiments, the formulations disclosed herein include, in place of brimonidine, at least one monographed ophthalmic redness reducer. In some embodiments, the at least one monographed ophthalmic redness reducer is chosen from of ephedrine, naphazoline, phenylephrine, tetrahydrozoline, pharmaceutically acceptable salts thereof, and mixtures of these compounds. In some embodiments, the pharmaceutically acceptable salts are hydrochlorides (z.e., ephedrine hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, and / or tetrahydrozoline hydrochloride).

[0063] In some embodiments, the formulations disclosed herein include, in addition to brimonidine, at least one selective a-1 adrenergic receptor antagonist. In some embodiments, the formulations disclosed herein include, in place of brimonidine, at least one selective a-1 adrenergic receptor antagonist. In some embodiment, the at least one selective a-1 adrenergic receptor antagonist is oxymetazoline, pharmaceutically acceptable salts thereof, and mixtures of these compounds.

[0064] In some embodiments, the formulations disclosed herein include, in addition to brimonidine, at least one natural antihistamine. In some embodiments, the formulations disclosed herein include, in place of brimonidine, at least one antihistamine. In some embodiments, the at least one antihistamine is ectoin.

[0065] Without limitation, some embodiments of the disclosure include:

[0066] Embodiment A: A formulation for hydrating eyes comprising brimonidine, at least one natural humectant, at least one amino acid, and at least one vitamin, wherein the formulation is preservative free.

[0067] Embodiment B: The formulation according to Embodiment A, wherein the formulation is borate free.

[0068] Embodiment C: The formulation according to any of Embodiments A-B, wherein the formulation is free of polyethylene glycol (PEG) and / or PEG-containing ingredients.

[0069] Embodiment D: The formulation according to any of Embodiments A-C, wherein the at least one natural humectant is chosen from glycerin, trehalose, sucrose, sodium hyaluronate, and combinations thereof, for example, wherein the at least one natural humectant is glycerin, wherein the at least one natural humectant is trehalose, wherein the at least one natural humectant is sucrose, wherein the at least one natural humectant is sodium hyaluronate, wherein the at least one natural humectant is glycerin and trehalose, wherein the at least one natural humectant is glycerin and sodium hyaluronate, wherein the at least one natural humectant is trehalose and sodium hyaluronate, wherein the at least one natural humectant is sucrose and glycerin, wherein the at least one natural humectant is sucrose and trehalose, wherein the at least one natural humectant is sucrose and sodium hyaluronate, wherein the at least one natural humectant is glycerin, trehalose, and sodium hyaluronate, or wherein the at least one natural humectant is glycerin, trehalose, sucrose, and sodium hyaluronate.

[0070] Embodiment E: The formulation according to any of Embodiments A-D, wherein the sodium hyaluronate is chosen from high molecular weight sodium hyaluronates.

[0071] Embodiment F: The formulation according to any of Embodiments A-E, wherein the sodium hyaluronate has a molecular weight in the range of 700 kDa to 1500 kDa, for example, 700 kDa, 750 kDa, 800 kDa, 850 kDa, 900 kDa, 950 kDa, 1000 kDa, 1050 kDa, 1100 kDa, 1150 kDa,, 1200 kDa, 1250 kDa, 1300 kDa, 1350 kDa, 1400 kDa, 1450 kDa, or 1500 kDa.

[0072] Embodiment G: The formulation according to any of Embodiments A-F, wherein the sodium hyaluronate has a molecular weight of 800 kDa.

[0073] Embodiment H: The formulation according to any of Embodiments A-G, wherein the at least one amino acid is chosen from arginine, leucine, taurine, proline, lysine, methionine, and combinations thereof, for example, wherein the at least one amino acid is arginine, wherein the at least one amino acid is leucine, wherein the at least one amino acid is taurine, wherein the at least one amino acid is proline, wherein the at least one amino acid is lysine wherein the at least one amino acid is methinonine, wherein the at least one amino acid is arginine and leucine, wherein the at least one amino acid is arginine and taurine, wherein theat least one amino acid is leucine and taurine, or wherein the at least one amino acid is arginine, leucine, and taurine.

[0074] Embodiment I: The formulation according to any of Embodiments A-H, wherein the at least one vitamin is chosen from vitamin C, vitamin B12, and combinations thereof, for example wherein the at least one vitamin is vitamin C, wherein the at least one vitamin is vitamin B12, or wherein the at least one vitamin is vitamin C and vitamin B12.

[0075] Embodiment J: The formulation according to any of Embodiments A-I, wherein the vitamin C is chosen from sodium ascorbyl phosphate, magnesium ascorbyl phosphate, and a combination thereof, for example, wherein the vitamin C is sodium ascorbyl phosphate, wherein the vitamin C is magnesium ascorbyl phosphate, or wherein the vitamin C is sodium ascorbyl phosphate and magnesium ascorbyl phosphate.

[0076] Embodiment K: The formulation according to any of Embodiments A- J, wherein the vitamin C is magnesium ascorbyl phosphate.

[0077] Embodiment L: The formulation according to any of Embodiments A-K, wherein the vitamin B12 is chosen from cyanocobalamin, hydroxy cobalamin, adenosyl cobalamin, methyl cobalamin, and combinations thereof, for example, wherein the vitamin B12 is cyanocobalamin, wherein the vitamin B12 is hydroxy cobalamin, wherein the vitamin B12 is adenosyl cobalamin, wherein the vitamin B12 is methyl cobalamin, wherein the vitamin B12 is cyanocobalamin and hydroxy cobalamin, wherein the vitamin Bn is cyanocobalamin and adenosyl cobalamin, wherein the vitamin Bn is cyanocobalamin and methyl cobalamin, wherein the vitamin Bn is hydroxy cobalamin and adenosyl cobalamin, wherein the vitamin B12 is hydroxy cobalamin and methyl cobalamin, or wherein the vitamin B12 is adenosyl cobalamin and methyl cobalamin.

[0078] Embodiment M: The formulation according to any of Embodiments A-L, wherein the vitamin B12 is cyanocobalamin.

[0079] Embodiment N: The formulation according to any of Embodiments A-M, wherein the formulation further comprises at least one natural electrolyte.

[0080] Embodiment O: The formulation according to any of Embodiments A-N, wherein the at least one natural electrolyte is chosen from sodium chloride, potassium chloride, calciumchloride, magnesium chloride, and combinations thereof, for example, wherein the at least one natural electrolyte is sodium chloride, potassium chloride, calcium chloride and magnesium chloride, wherein the at least one natural electrolyte is sodium chloride, wherein the at least one natural electrolyte is potassium chloride, wherein the at least one natural electrolyte is calcium chloride, wherein the at least one natural electrolyte is magnesium chloride, wherein the at least one natural electrolyte is sodium chloride and potassium chloride, wherein the at least one natural electrolyte is sodium chloride and calcium chloride, wherein the at least one natural electrolyte is sodium chloride and magnesium chloride, wherein the at least one natural electrolyte is potassium chloride and calcium chloride, wherein the at least one natural electrolyte is potassium chloride and magnesium chloride, wherein the at least one natural electrolyte is calcium chloride and magnesium chloride.

[0081] Embodiment P: The formulation according to any of Embodiments A-O, wherein the formulation further comprises at least one natural buffer agent.

[0082] Embodiment Q: The formulation according to any of Embodiments A-P, wherein the at least one natural buffer agent is chosen from sodium citrate, citric acid, sodium bicarbonate, amino acids, and combinations thereof, for example, wherein the at least one natural buffer agent is sodium citrate, citric acid, sodium bicarbonate, and amino acids, wherein the at least one natural buffer agent is sodium citrate, wherein the at least one natural buffer agent is citric acid, wherein the at least one natural buffer agent is sodium bicarbonate, wherein the at least one natural buffer agent is sodium citrate and citric acid, wherein the at least one natural buffer agent is sodium citrate and sodium bicarbonate, wherein the at least one natural buffer agent is sodium citrate and amino acids, wherein the at least one natural buffer agent is citric acid and sodium bicarbonate, wherein the at least one natural buffer agent is citric acid and amino acids, wherein the at least one natural buffer agent is sodium bicarbonate and amino acids.

[0083] Embodiment R: The formulation according to any of Embodiments A-Q, wherein the pH of the formulation is in a range of 5.5 to 8, for example, the pH is in a range of 6 to 8, the pH is in a range of 5.5 to 6, the pH is in a range of 5.5 to 6.5, the pH is in a range of 6 to 7, the pH is in a range of 6.0 to 6.7, the pH is in a range of 6.3 to 6.7, the pH is in a range of 7 to 8, the pH is 5.5, the pH is 6.0, the pH is 7.0, the pH is 7.5, or the pH is 8.0.

[0084] Embodiment S: The formulation according to any of Embodiments A-R, wherein thepH of the formulation is 6.5.

[0085] Embodiment T: The formulation according to any of Embodiments A-S, wherein the pH of the formulation is 7.5.

[0086] Embodiment U: The formulation according to any of Embodiments A-T, wherein the osmolality of the formulation is in a range of 200 mOsm / kg to 300 mOsm / kg, for example, the formulation has an osmolality 215 mOsm / kg, 230 mOsm / kg, 245 mOsm / kg, 275 mOsm / kg, or 300 mOsm / kg.

[0087] Embodiment V: The formulation according to any of Embodiments A-U, wherein the osmolality of the formulation is 275 mOsm / kg.

[0088] Embodiment W: The formulation according to any of Embodiments A-V, wherein the formulation is stable.

[0089] Embodiment X: The formulation according to any of Embodiments A-W, wherein the formulation comprises brimonidine, glycerin, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbyl phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride, sodium bicarbonate, cyanocobalamin, and sodium hydroxide.

[0090] Embodiment Y: The formulation according to any of Embodiments A-X, wherein the formulation comprises:0.001% w / v to 0.05% w / v brimonidine;0.6 % w / v to 0.8 % w / v glycerin;0.25 % w / v to 0.5 % w / v trehalose;0.1 % w / v to 0.3 % w / v sodium hyaluronate;0.2 % w / v to 0.3 % w / v sodium chloride;0.01 % w / v to 0.14 % w / v potassium chloride;0.01 % w / v to 0.1 % w / v magnesium ascorbyl phosphate;0.02 % w / v to 0.06% w / v sodium citrate;0.02 % w / v to 0.05 % w / v L-arginine;0.01 % w / v to 0.0275 % w / v citric acid;0.01 % w / v to 0.02 % w / v L-taurine;0.01 % w / v to 0.02 % w / v L-leucine;0.01 % w / v to 0.02 % w / v calcium chloride;0.001 % w / v to 0.015 % w / v sodium bicarbonate;0.001 % w / v to 0.004 % w / v cyanocobalamin; and qs % w / v sodium hydroxide.

[0091] Embodiment Z: The formulation according to any of Embodiments A-Y, wherein the formulation comprises:0.025% w / v brimonidine;0.75 % w / v glycerin;0.5 % w / v trehalose;0.24 % w / v sodium hyaluronate;0.3 % w / v sodium chloride;0.14 % w / v potassium chloride;0.1 % w / v magnesium ascorbyl phosphate;0.06% w / v sodium citrate;0.05 % w / v L-arginine;0.024 % w / v citric acid;0.02 % w / v L-taurine;0.02 % w / v L-leucine;0.02 % w / v calcium chloride;0.005 % w / v sodium bicarbonate;0.004 % w / v cyanocobalamin; and qs % w / v sodium hydroxide.

[0092] Embodiment AA: The formulation according to any of Embodiments A-Z, wherein the pH of the formulation is 7.5.

[0093] Embodiment BB: The formulation according to any of Embodiments A-AA, wherein the formulation comprises brimonidine, glycerin, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbyl phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride, cyanocobalamin, and hydrochloric acid.

[0094] Embodiment CC: The formulation according to any of Embodiments A-BB, wherein the formulation comprises:0.001% w / v to 0.05% w / v brimonidine;0.6 % w / v to 0.8 % w / v glycerin;0.25 % w / v to 0.5 % w / v trehalose;0.1 % w / v to 0.3 % w / v sodium hyaluronate;0.2 % w / v to 0.3 % w / v sodium chloride;0.01 % w / v to 0.14 % w / v potassium chloride;0.01 % w / v to 0.1 % w / v magnesium ascorbyl phosphate;0.02 % w / v to 0.06% w / v sodium citrate;0.02 % w / v to 0.05 % w / v L-arginine;0.01 % w / v to 0.0275 % w / v citric acid;0.01 % w / v to 0.02 % w / v L-taurine;0.01 % w / v to 0.02 % w / v L-leucine;0.01 % w / v to 0.02 % w / v calcium chloride;0.001 % w / v to 0.004 % w / v cyanocobalamin; and qs % w / v hydrochloric acid.

[0095] Embodiment DD: The formulation according to any of Embodiments A-CC, wherein the formulation comprises:0.025% w / v brimonidine;0.75 % w / v glycerin;0.5 % w / v trehalose;0.24 % w / v sodium hyaluronate;0.3 % w / v sodium chloride;0.14 % w / v potassium chloride;0.1 % w / v magnesium ascorbyl phosphate;0.06% w / v sodium citrate;0.05 % w / v L-arginine;0.024 % w / v citric acid;0.02 % w / v L-taurine;0.02 % w / v L-leucine;0.02 % w / v calcium chloride;0.004 % w / v cyanocobalamin; and qs % w / v hydrochloric acid.

[0096] Embodiment EE: The formulation according to any of Embodiments A-DD, wherein the pH of the formulation is 6.5.

[0097] Embodiment FF : The formulation according to any of Embodiments A-EE, wherein the formulation comprises:0.025% w / v brimonidine;0.75 % w / v glycerin;0.5 % w / v trehalose;0.24 % w / v sodium hyaluronate;0.3 % w / v sodium chloride;0.14 % w / v potassium chloride;0.1 % w / v magnesium ascorbyl phosphate;0.06% w / v sodium citrate;0.05 % w / v L-arginine;0.024 % w / v citric acid;0.02 % w / v L-taurine;0.02 % w / v L-leucine;0.02 % w / v calcium chloride;0.005 % w / v sodium bicarbonate;0.004 % w / v cyanocobalamin;0.0015 % w / v poly-e-lysine; and qs % w / v sodium hydroxide.

[0098] Embodiment GG: The formulation according to any of Embodiments A-FF, wherein the formulation comprises:0.025% w / v brimonidine;0.75 % w / v glycerin;0.5 % w / v trehalose;0.24 % w / v sodium hyaluronate;0.3 % w / v sodium chloride;0.14 % w / v potassium chloride;0.06% w / v sodium citrate;0.05 % w / v L-arginine;0.024 % w / v citric acid;0.02 % w / v L-taurine;0.02 % w / v L-leucine;0.02 % w / v calcium chloride;0.005 % w / v sodium bicarbonate;0.004 % w / v cyanocobalamin;0.011 % w / v magnesium chloride;0.011 sodium chlorite; and qs % w / v sodium hydroxide.EXAMPLESEXAMPLE 1 : Exemplary formulation

[0099] Formulations of the present disclosure can be prepared with ingredients as listed in the following Table 1.Table 1

[0100] Formulations with the ingredients listed above can be prepared by mixing the recited ingredients, for example according to the proposed manufacturing process below:1. In an appropriate mixing vessel, add volume of water equivalent to 80 % of the total batch weight.2. Sprinkle in sodium hyaluronate while mixing, until the polymer is fully hydrated, NLT 1 hour to ensure homogenous dispersing.3. Slowly add batch quantities of the remaining ingredients to the solution. Mix NLT 30 minutes to ensure complete dissolution. For example, one order of addition could be: brimonidine tartrate, glycerin, trehalose, sodium chloride, potassium chloride, calcium chloride, magnesium ascorbyl phosphate, sodium citrate, citric acid, sodium bicarbonate, amino acids, and vitamin Bn (cyanocobalamin).4. Q.S. to 100% batch weight with purified water.5. Sterile filter the formulation with an appropriate sterilizing filter (0.2 pm PES).

[0101] The pH, osmolality, and color of the formulations are assessed.

[0102] A pH adjuster could be added. For example, sodium hydroxide could be added to obtain the desired pH. As a non-limiting example, IN sodium hydroxide could be added to obtain a pH of 7.5.

[0103] Other ingredients could be added. For example, at least one amino acid chosen from L-proline, L-lysine, and L-methionine, or combinations thereof. Propylene glycol could also be used as an additional humectant, and sucrose could be used as an alternative saccharide. Copper and / or zinc could be added as as an additional nutritional component. These metals are added to vitamin supplements and operate as vitamin co-factors. For example, copper could be added in an amount of about 5 pmm and zinc could be added at higher levels.EXAMPLE 2: Additional exemplary formulation

[0104] Formulations of the present disclosure can be prepared with ingredients as listed in the following Table 2.Table 2

[0105] Formulations with the ingredients listed above can be prepared by mixing the recited ingredients, for example according to the proposed manufacturing process below:1. In an appropriate mixing vessel, add volume of water equivalent to 80 % of the total batch weight.2. Sprinkle in sodium hyaluronate while mixing, until the polymer is fully hydrated, NLT 1 hour to ensure homogenous dispersing.3. Slowly add batch quantities of the remaining ingredients to the solution. Mix NLT 30 minutes to ensure complete dissolution. For example, one order of addition could be: brimonidine tartrate, glycerin, trehalose, sodium chloride, potassium chloride, calcium chloride, magnesium ascorbyl phosphate, sodium citrate, citric acid, amino acids, and vitamin Bn (cyanocobalamin).4. Q.S. to 100% batch weight with purified water.5. Sterile filter the formulation with an appropriate sterilizing filter (0.2 pm PES).

[0106] The pH, osmolality, and color of the formulations are assessed.

[0107] A pH adjuster could be added. For example, hydrochloric acid could be added to obtain the desired pH. As a non-limiting example, IN hydrochloric acid could be added to obtain a pH of 6.5.

[0108] Other ingredients could be added. For example, at least one amino acid chosen from L-proline, L-lysine, and L-methionine, or combinations thereof. Propylene glycol could also be used as an additional humectant, and sucrose could be used as an alternative saccharide. Copper and / or zinc could be added as as an additional nutritional component. These metals are added to vitamin supplements and operate as vitamin co-factors. For example, copper could be added in an amount of about 5 pmm and zinc could be added at higher levels.EXAMPLE 3 : Additional exemplary formulations

[0109] Other exemplary formulations of the present disclosure are listed in the following Table 3.Table 3

Claims

What is claimed:

1. A formulation for hydrating eyes comprising brimonidine, at least one natural humectant, at least one amino acid, and at least one vitamin, wherein the formulation is preservative free.

2. The formulation according to claim 1, wherein the formulation is borate free.

3. The formulation according to claim 1 or 2, wherein the formulation is free of polyethylene glycol (PEG) and PEG-containing ingredients.

4. The formulation according to any one of claims 1-3, wherein the at least one natural humectant is chosen from glycerin, trehalose, sucrose, and sodium hyaluronate.

5. The formulation according to claim 4, wherein the sodium hyaluronate is chosen from high molecular weight sodium hyaluronates.

6. The formulation according to claim 4 or 5, wherein the sodium hyaluronate has a molecular weight in the range of 700 kDa to 1500 kDa.

7. The formulation according to any one of claims 4-6, wherein the sodium hyaluronate has a molecular weight of 800 kDa.

8. The formulation according to any one of claims 1-7, wherein the at least one amino acid is chosen from arginine, leucine, and taurine.

9. The formulation according to any one of claims 1-8, wherein the at least one vitamin is chosen from vitamin C and vitamin Bn.

10. The formulation according to claim 9, wherein the vitamin C is chosen from sodium ascorbyl phosphate, magnesium ascorbyl phosphate, and a combination thereof.

11. The formulation according to claim 9 or 10, wherein the vitamin C is magnesium ascorbyl phosphate.

12. The formulation according to claim 9, wherein the vitamin Bn is chosen from cyanocobalamin, hydroxycobalamin, adenosyl cobalamin, methyl cobalamin, and combinations thereof.

13. The formulation according to claim 9 or 12, wherein the vitamin Bn is cyanocobalamin.

14. The formulation according to any one of claims 1-13, wherein the formulation further comprises at least one natural electrolyte.

15. The formulation according to claim 14, wherein the at least one natural electrolyte is chosen from sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

16. The formulation according to any one of claims 1-15, wherein the formulation further comprises at least one natural buffer agent.

17. The formulation according to claim 16, wherein the at least one natural buffer agent is chosen from sodium citrate, citric acid, sodium bicarbonate, and amino acids.

18. The formulation according to any one of claims 1-17, wherein the pH of the formulation is in a range of 6 to 8.

19. The formulation according to any one of claims 1-18, wherein the pH of the formulation is 6.5.

20. The formulation according to any one of claims 1-19, wherein the pH of the formulation is 7.5.

21. The formulation according to any one of claims 1-20, wherein the osmolality of the formulation is in a range of 200 mOsm / kg to 300 mOsm / kg.

22. The formulation according to any one of claims 1-21, wherein the osmolality of the formulation is 275 mOsm / kg.

23. The formulation according to any one of claims 1-22, wherein the formulation is stable.

24. The formulation according to claim 1, wherein the formulation comprises brimonidine, glycerin, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbyl phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride, sodium bicarbonate, cyanocobalamin, and sodium hydroxide.

25. The formulation according to claim 1, wherein the formulation comprises:0.001% w / v to 0.05% w / v brimonidine;0.6 % w / v to 0.8 % w / v glycerin;0.25 % w / v to 0.5 % w / v trehalose;0.1 % w / v to 0.3 % w / v sodium hyaluronate;0.2 % w / v to 0.3 % w / v sodium chloride;0.01 % w / v to 0.14 % w / v potassium chloride;0.01 % w / v to 0.1 % w / v magnesium ascorbyl phosphate;0.02 % w / v to 0.06% w / v sodium citrate;0.02 % w / v to 0.05 % w / v L-arginine;0.01 % w / v to 0.0275 % w / v citric acid;0.01 % w / v to 0.02 % w / v L-taurine;0.01 % w / v to 0.02 % w / v L-leucine;0.01 % w / v to 0.02 % w / v calcium chloride;0.001 % w / v to 0.015 % w / v sodium bicarbonate;0.001 % w / v to 0.004 % w / v cyanocobalamin; and qs % w / v sodium hydroxide.

26. The formulation according to claim 1, wherein the formulation comprises:0.025% w / v brimonidine;0.75 % w / v glycerin;0.5 % w / v trehalose;0.24 % w / v sodium hyaluronate;0.3 % w / v sodium chloride;0.14 % w / v potassium chloride;0.1 % w / v magnesium ascorbyl phosphate;0.06% w / v sodium citrate;0.05 % w / v L-arginine;0.024 % w / v citric acid;0.02 % w / v L-taurine;0.02 % w / v L-leucine;0.02 % w / v calcium chloride;0.005 % w / v sodium bicarbonate;0.004 % w / v cyanocobalamin; and qs % w / v sodium hydroxide.

27. The formulation according to any one of claims 24-26, wherein the pH of the formulation is 7.5.

28. The formulation according to claim 1, wherein the formulation comprises brimonidine, glycerin, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbyl phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride, cyanocobalamin, and hydrochloric acid.

29. The formulation according to claim 1, wherein the formulation comprises:0.001% w / v to 0.05% w / v brimonidine;0.6 % w / v to 0.8 % w / v glycerin;0.25 % w / v to 0.5 % w / v trehalose;0.1 % w / v to 0.3 % w / v sodium hyaluronate;0.2 % w / v to 0.3 % w / v sodium chloride;0.01 % w / v to 0.14 % w / v potassium chloride;0.01 % w / v to 0.1 % w / v magnesium ascorbyl phosphate;0.02 % w / v to 0.06% w / v sodium citrate;0.02 % w / v to 0.05 % w / v L-arginine;0.01 % w / v to 0.0275 % w / v citric acid;0.01 % w / v to 0.02 % w / v L-taurine;0.01 % w / v to 0.02 % w / v L-leucine;0.01 % w / v to 0.02 % w / v calcium chloride;0.001 % w / v to 0.004 % w / v cyanocobalamin; and qs % w / v hydrochloric acid.

30. The formulation according to claim 1, wherein the formulation comprises:0.025% w / v brimonidine;0.75 % w / v glycerin;0.5 % w / v trehalose;0.24 % w / v sodium hyaluronate;0.3 % w / v sodium chloride;0.14 % w / v potassium chloride;0.1 % w / v magnesium ascorbyl phosphate;0.06% w / v sodium citrate;0.05 % w / v L-arginine;0.024 % w / v citric acid;0.02 % w / v L-taurine;0.02 % w / v L-leucine;0.02 % w / v calcium chloride;0.004 % w / v cyanocobalamin; qs % w / v hydrochloric acid.

31. The formulation according to any one of claims 28-30, wherein the pH of the formulation is 6.5.

32. The formulation according to claim 1, wherein the formulation comprises:0.025% w / v brimonidine;0.75 % w / v glycerin;0.5 % w / v trehalose;0.24 % w / v sodium hyaluronate;0.3 % w / v sodium chloride;0.14 % w / v potassium chloride;0.1 % w / v magnesium ascorbyl phosphate;0.06% w / v sodium citrate;0.05 % w / v L-arginine;0.024 % w / v citric acid;0.02 % w / v L-taurine;0.02 % w / v L-leucine;0.02 % w / v calcium chloride;0.005 % w / v sodium bicarbonate;0.004 % w / v cyanocobalamin;0.0015 % w / v poly-e-lysine; and qs % w / v sodium hydroxide.

3. The formulation according to claim 1, wherein the formulation comprises:0.025% w / v brimonidine;0.75 % w / v glycerin;0.5 % w / v trehalose;0.24 % w / v sodium hyaluronate;0.3 % w / v sodium chloride;0.14 % w / v potassium chloride;0.06% w / v sodium citrate;0.05 % w / v L-arginine;0.024 % w / v citric acid;0.02 % w / v L-taurine;0.02 % w / v L-leucine;0.02 % w / v calcium chloride;0.005 % w / v sodium bicarbonate;0.004 % w / v cyanocobalamin;0.011 % w / v magnesium chloride; 0.011 sodium chlorite; and qs % w / v sodium hydroxide.

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