Hydrating formulations comprising brimonidine

Abstract

The present disclosure describes formulations and methods for dry eye rehydration. The formulations include brimonidine, at least one natural wetting agent, at least one amino acid, and at least one vitamin, wherein the formulation is preservative-free and can provide effective redness reduction, rehydration, lubrication, and / or nourishment of the eye.

Description

[0001] This disclosure relates to formulations comprising brimanidine, at least one natural wetting agent, at least one amino acid, and at least one vitamin, wherein the formulation is free of preservatives. This disclosure also provides methods for treating, improving, and / or alleviating dryness; removing irritants and / or debris; maintaining eye hygiene; and / or treating, improving, or alleviating dry eye syndrome and its symptoms. In some embodiments, the formulations and methods provide for cleaning, washing, conditioning, moisturizing, lubricating, hydrating, nourishing, soothing, calming, and / or refreshing the ocular surface tissue.

[0002] The formulation disclosed herein can rebuild and / or cultivate ocular surface homeostasis and provide essential nutrients to damaged tears to restore tear film integrity.

[0003] Dry eye disease is defined by the DEWS Definition and Classification Subcommittee as a multifactorial disease of the tear film and ocular surface, causing symptoms of discomfort, visual disturbances, and tear instability, with underlying damage to the ocular surface, accompanied by increased tear film osmotic pressure and inflammation of the ocular surface (Ubels et al., Curr. Eye Res., 28:437-444, 2002). Dry eye disease is an ocular surface disorder caused by insufficient tear production, excessive tear evaporation, or an incorrect tear composition. For most patients with mild dry eye symptoms, over-the-counter dry eye drops (OTC-DED) are the first-line treatment. These products provide temporary relief in patients with aqueous tear deficiency by providing a replacement for naturally occurring tears, acting as a lubricant, 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] Recent studies have demonstrated a link between sleep deprivation and dry eye symptoms. In sleep-derived models, amino acids such as arginine, leucine, and taurine have been found to be lower in tears. Leucine is a major component of proteoglycans found in the corneal stroma and contributes to corneal healing. Arginine is essential for the expression of β-defensin, which is part of the immune system. Taurine is a transporter essential for osmotic regulation. The formulation disclosed herein helps replenish amino acids in tears.

[0005] This disclosure also provides methods for inducing vasoconstriction to treat, improve, and / or alleviate eye conditions. In some embodiments, the eye condition is red eye (conjunctival hyperemia), including chronic red eye. In some embodiments, the eye condition includes conditions that affect appearance, such as occasional excessive redness of the eyes.

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

[0007] Occasional excessive redness of the eyes, sometimes referred to as a "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 work by constricting the arteries in the eye, depriving the eye of oxygen. This oxygen deprivation may initially relieve redness, but often leads to rebound redness. Rebound redness refers to induced vasodilation (rather than the intended vasoconstriction) that occurs after the application or, more typically, repeated application of a vasoconstrictor, usually with a lag time. Rebound redness is characterized by congestion of blood vessels (such as those in the conjunctiva), increased capillary permeability and leakage, and in some cases, post-inflammatory sequelae (pharmacological).

[0009] Compared to larger blood vessels, such as arteries and arterioles, the formulations of this disclosure induce preferential vasoconstriction in smaller blood vessels, such as capillaries and venules. While not wishing to be bound by any particular theory, this vasoconstriction approach allows for the contraction of blood flow toward visible surface areas, with maximum contraction of the microvascular system and minimum additional vasoconstriction of larger arterioles, to maximize the vasoconstriction benefit per unit area and minimize ischemic consequences, including rebound redness.

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

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

[0012] As used in this article, “a”, “an” and “the” refer to one or more (i.e., at least one) of the grammatical objects of the article.

[0013] As used herein, the terms “hydration,” “lubrication,” and “nourishment” are used interchangeably and all refer to reducing dryness, preventing moisture loss, protecting against tear evaporation, restoring the natural moisture balance of the tear film, or any combination thereof.

[0014] As used in this article, the terms “patient,” “subject,” and “individual” are interchangeable and refer to any animal, which may be human or non-human.

[0015] As will be understood by those skilled in the art, when disclosed herein, each range includes all possible subranges as well as individual numerical values ​​within that range. For example, the range “1.0 to 5.0” includes and will be understood as a specific disclosed subrange 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, such as 1.0, 1.1, 1.2, 1.3, etc.

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

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

[0018] As used herein, when no compound is added during the manufacture of the formulation, the formulation "does not contain" the compound.

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

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

[0021] As described above, this disclosure relates to a formulation for hydrating the eyes, comprising brimonidine, at least one natural wetting agent, at least one amino acid, and at least one vitamin, wherein the formulation is preservative-free. This formulation can be used to treat, improve, and / or alleviate dry eye syndrome and its symptoms. In some embodiments, the formulation and method provide lubrication, hydration, and / or nourishment of the ocular surface tissue. The formulation can also be used to induce vasoconstriction to treat, improve, and / or alleviate red eye.

[0022] In some embodiments, the formulation comprises brimonidine, at least one natural wetting agent, at least one amino acid, and at least one vitamin, wherein the formulation is free of preservatives. In some embodiments, the formulation comprises brimonidine. In some embodiments, the formulation comprises at least one natural wetting agent. 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 free of preservatives. In some embodiments, the formulation comprises brimonidine, at least one natural wetting agent, and is free of preservatives. In some embodiments, the formulation comprises brimonidine, at least one amino acid, and is free of preservatives. In some embodiments, the formulation comprises brimonidine, at least one vitamin, and is free of preservatives.

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

[0024] In some embodiments, the formulation is free of polyethylene glycol (PEG) and free of 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 selected 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 / v brimonidine. 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 wetting agent selected 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, sodium hyaluronate is high molecular weight sodium hyaluronate. In some embodiments, the molecular weight of sodium hyaluronate is in the range of 700 kDa to 1500 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 700 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 750 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 800 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 850 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 900 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 950 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1000 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1050 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1100 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1150 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1200 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1250 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1300 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1350 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1400 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1450 kDa. In some embodiments, the molecular weight of sodium hyaluronate is 1500 kDa.

[0029] In some embodiments, the formulation comprises at least one natural wetting agent selected from glycerol, trehalose, and combinations thereof. In some embodiments, the formulation comprises up to 2% w / v glycerol, trehalose, or a combination thereof. In some embodiments, the formulation comprises up to 1.75% w / v glycerol, trehalose, or a combination thereof. In some embodiments, the formulation comprises up to 1.5% w / v glycerol, trehalose, or a combination thereof. In some embodiments, the formulation comprises up to 1.25% w / v glycerol, trehalose, or a combination thereof. In some embodiments, the formulation comprises an amount of glycerol, trehalose, or a combination thereof to avoid the formation of a hypertonic formulation.

[0030] In some embodiments, the formulation comprises at least one amino acid selected 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 methionine. In some embodiments, the formulation comprises both arginine and leucine. In some embodiments, the formulation comprises both arginine and taurine. In some embodiments, the formulation comprises leucine and taurine. In some embodiments, the formulation comprises arginine, leucine, and taurine.

[0031] In some embodiments, the formulation contains at least one vitamin C and vitamin B. 12 Vitamins 。 In some embodiments, the formulation contains vitamin C and vitamin B. 12 .

[0032] In some embodiments, the formulation comprises vitamin C. In some embodiments, the vitamin C is selected from sodium ascorbate phosphate, magnesium ascorbate phosphate, and combinations thereof. In some embodiments, the vitamin C is sodium ascorbate phosphate. In some embodiments, the vitamin C is magnesium ascorbate phosphate. In some embodiments, the vitamin C is both sodium ascorbate phosphate and magnesium ascorbate phosphate.

[0033] In some implementations, the formulation contains vitamin B. 12 In some implementation schemes, vitamin B... 12 Selected from cyanocobalamin, hydroxocobalamin, adenosylcobalamin, methylcobalamin, and combinations thereof. In some embodiments, vitamin B... 12 It is selected from cyanocobalamin, hydroxocobalamin, adenosylcobalamin, and methylcobalamin. In some embodiments, vitamin B... 12 It is cyanocobalamin. In some implementations, vitamin B... 12 It is hydroxycobalamin. In some implementations, vitamin B... 12 It is adenosylcobalamin. In some implementations, vitamin B... 12 It is methylcobalamin. In some implementations, vitamin B... 12 These are cyanocobalamin and hydroxycoobalamin. In some implementations, vitamin B... 12 These are cyanocobalamin and adenosylcobalamin. In some implementations, vitamin B... 12 These are cyanocobalamin and methylcoobalamin. In some implementations, vitamin B... 12 These are hydroxycobalamin and adenosylcobalamin. In some implementations, vitamin B...12 These are hydroxycobalamin and methylcobalamin. In some implementations, vitamin B... 12 It is adenosylcobalamin and methylcobalamin.

[0034] In some embodiments, the formulation comprises zinc and / or copper. In some embodiments, the formulation comprises both 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 less than 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 selected 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 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 buffer. In some embodiments, the at least one natural buffer is selected 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 alexidin.

[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 the range of 5.5 to 8. In some embodiments, the pH of the formulation is in the range of 6 to 8. In some embodiments, the pH of the formulation is in the range of 5.5 to 6. In some embodiments, the pH of the formulation is in the range of 5.5 to 6.5. In some embodiments, the pH of the formulation is in the range of 6 to 7. In some embodiments, the pH of the formulation is in the range of 6.0 to 6.7. In some embodiments, the pH of the formulation is in the range of 6.3 to 6.7. In some embodiments, the pH of the formulation is in the 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 an added pH adjuster to achieve the 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 osmotic pressure of the formulation is in the range of 200 mOsm / kg to 300 mOsm / kg. In some embodiments, the osmotic pressure of the formulation is 200 mOsm / kg. In some embodiments, the osmotic pressure of the formulation is 215 mOsm / kg. In some embodiments, the osmotic pressure of the formulation is 230 mOsm / kg. In some embodiments, the osmotic pressure of the formulation is 245 mOsm / kg. In some embodiments, the osmotic pressure of the formulation is 275 mOsm / kg. In some embodiments, the osmotic pressure of the formulation is 300 mOsm / kg.

[0042] In some embodiments, the formulation comprises brimonidine, glycerol, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbate 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 glycerol, 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 ascorbate 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, and 0.01% w / v to 0.02% arginine. L-taurine (w / v), L-leucine (0.01% w / v to 0.02% w / v), calcium chloride (0.01% w / v to 0.02% w / v), sodium bicarbonate (0.001% w / v to 0.015% w / v), cyanocobalamin (0.001% w / v to 0.004% w / v), and sodium hydroxide (qs % w / v).

[0044] In some embodiments, the formulation comprises 0.025% w / v brimonidine, 0.75% w / v glycerol, 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 ascorbate 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, glycerol, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbate 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 glycerol, 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 ascorbate 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, and 0.01% w / v to 0.02% arginine. L-taurine w / v, L-leucine 0.01% w / v to 0.02% w / v, calcium chloride 0.01% w / v to 0.02% w / v, cyanocobalamin 0.001% w / v to 0.004% w / v, and hydrochloric acid qs % w / v.

[0047] In some embodiments, the formulation comprises 0.025% w / v brimonidine, 0.75% w / v glycerol, 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 ascorbate 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 formulation disclosed herein is stable. In some embodiments, the formulation is storage stable.

[0049] In some embodiments, after storage at 20-25°C for 24 months, the pH of the formulation decreases by no more than 0.75 pH units. In some embodiments, the pH of the formulation decreases by no more than 0.6 pH units. In some embodiments, the pH of the formulation decreases by no more than 0.5 pH units. In some embodiments, the pH of the formulation decreases by no more than 0.4 pH units. In some embodiments, the pH of the formulation decreases by no more than 0.3 pH units. In some embodiments, the pH of the formulation decreases by no more than 0.25 pH units. In some embodiments, the pH of the formulation decreases by no more than 0.2 pH units. In some embodiments, the pH of the formulation decreases by no more than 0.1 pH units after storage at 20-25°C for 24 months.

[0050] In some embodiments, the osmotic pressure of the formulation increases by no more than 50 mOsm after 24 months of storage at 20-25°C. In some embodiments, the osmotic pressure increases by no more than 40 mOsm after 24 months of storage at 20-25°C. In some embodiments, the osmotic pressure increases by no more than 30 mOsm after 24 months of storage at 20-25°C. In some embodiments, the osmotic pressure increases by no more than 25 mOsm after 24 months of storage at 20-25°C. In some embodiments, the osmotic pressure increases by no more than 20 mOsm after 24 months of storage at 20-25°C. In some embodiments, the osmotic pressure increases by no more than 15 mOsm after 24 months of storage at 20-25°C.

[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 radiation, 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 a combination of filtration and autoclaving. In some embodiments, the formulation is sterilized by gamma radiation. 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, the formulations disclosed herein are free of polyethylene glycol (PEG) and PEG-containing components. In some embodiments, the formulations disclosed herein are free of preservatives. In some embodiments, the formulations disclosed herein are sterile and preservative-free. In some embodiments, the formulations disclosed herein are free of borates.

[0054] In some implementations, the formulations disclosed herein are pH balanced and non-irritating.

[0055] The formulations disclosed herein can be prepared according to any known method used in the manufacture of cosmetic formulations or preparations. As will be understood by those skilled in the art, many methods are known.

[0056] In some embodiments, the formulations disclosed herein can be used to cleanse, wash, condition, moisturize, lubricate, hydrate, nourish, soothe, calm, and / or refresh the ocular surface tissue. In some embodiments, the formulations disclosed herein can be used to treat, improve, and / or alleviate dryness; remove irritants and / or debris; maintain eye hygiene; and / or treat, improve, and / or alleviate dry eye syndrome and its symptoms. In some embodiments, the formulations disclosed herein are suitable for use in adults and children.

[0057] In some embodiments, the formulations disclosed herein are suitable for use by contact lens wearers. In some embodiments, the formulations disclosed herein can be applied to the eye while the contact lens is in the eye. In some embodiments, the contact lens is removed for a period of time when the formulations disclosed herein are applied to the eye.

[0058] Therefore, this document provides methods for cleaning, washing, conditioning, moisturizing, lubricating, hydrating, nourishing, soothing, calming, and / or refreshing ocular surface tissues, comprising applying preparations as disclosed herein to said ocular surface tissues. In some embodiments, this document provides methods for treating, improving, and / or alleviating dryness; removing irritants and / or debris; maintaining eye hygiene; and / or treating, improving, or alleviating dry eye and its symptoms. These methods include applying preparations as disclosed herein to ocular surface tissues.

[0059] In some embodiments, the formulations disclosed herein can be used to induce vasoconstriction to treat, improve, and / or alleviate eye conditions such as conjunctivitis. Therefore, this document provides methods for reducing conjunctivitis, which include applying a formulation as disclosed herein to ocular surface tissue.

[0060] In some embodiments, the formulations disclosed herein for treating, improving, and / or reducing redness, and methods for reducing redness including applying such formulations to ocular surface tissue, result in redness relief for at least 3 hours. In some embodiments, the formulations and methods disclosed herein result in redness relief for at least 5 hours. In some embodiments, the formulations and methods disclosed herein result in redness relief for at least 7 hours. In some embodiments, the formulations and methods disclosed herein result in redness relief without rebound redness.

[0061] In some embodiments, the formulations disclosed herein, in addition to brimonidine, comprise at least one selective α-2 adrenergic receptor agonist. In some embodiments, the formulations disclosed herein comprise at least one selective α-2 adrenergic receptor agonist as an alternative to brimonidine. In some embodiments, the at least one selective α-2 adrenergic receptor agonist is selected from aclomid, mirtazapine, clonidine, α-methyldopa, guanifacin, dexmedetomidine, (+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydroimidazole-2-thione, 1-[(imidazolidine-2-yl)imino]indazole, and mixtures of these compounds.

[0062] In some embodiments, the formulations disclosed herein, in addition to brimonidine, comprise at least one ocular redness reliever listed in a pharmacopoeia monograph. In some embodiments, the formulations disclosed herein comprise at least one ocular redness reliever listed in a pharmacopoeia monograph as an alternative to brimonidine. In some embodiments, the at least one ocular redness reliever listed in a pharmacopoeia monograph is selected from ephedrine, naphazoline, phenylephrine, tetrahydrozoline, pharmaceutically acceptable salts thereof, and mixtures of these compounds. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride salt (i.e., ephedrine hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, and / or tetrahydrozoline hydrochloride).

[0063] In some embodiments, the formulations disclosed herein, in addition to brimonidine, comprise at least one selective α-1 adrenergic receptor antagonist. In some embodiments, the formulations disclosed herein comprise at least one selective α-1 adrenergic receptor antagonist as an alternative to brimonidine. In some embodiments, said at least one selective α-1 adrenergic receptor antagonist is oxymetazoline, a pharmaceutically acceptable salt thereof, or a mixture of these compounds.

[0064] In some embodiments, the formulations disclosed herein, in addition to brimonidine, comprise at least one natural antihistamine. In some embodiments, the formulations disclosed herein comprise at least one antihistamine as an alternative to brimonidine. In some embodiments, said at least one antihistamine is ectoin.

[0065] In an unrestricted manner, some embodiments of this disclosure include:

[0066] Implementation Scheme A: A preparation for hydrating the eyes, comprising brimonidine, at least one natural wetting agent, at least one amino acid and at least one vitamin, wherein the preparation is free of preservatives.

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

[0068] Implementation Scheme C: A formulation according to any one of Implementation Schemes A and B, wherein the formulation is free of polyethylene glycol (PEG) and / or PEG-containing components.

[0069] Implementation Scheme D: The formulation according to any one of Implementation Schemes A and C, wherein the at least one natural wetting agent is selected from glycerin, trehalose, sucrose, sodium hyaluronate, and combinations thereof. For example, the at least one natural wetting agent is glycerin; the at least one natural wetting agent is trehalose; the at least one natural wetting agent is sucrose; the at least one natural wetting agent is sodium hyaluronate; the at least one natural wetting agent is glycerin and trehalose; the at least one natural wetting agent is glycerin and sodium hyaluronate; the at least one natural wetting agent is trehalose and sodium hyaluronate; the at least one natural wetting agent is sucrose and glycerin; the at least one natural wetting agent is sucrose and trehalose; the at least one natural wetting agent is sucrose and sodium hyaluronate; the at least one natural wetting agent is glycerin, trehalose, and sodium hyaluronate; or the at least one natural wetting agent is glycerin, trehalose, sucrose, and sodium hyaluronate.

[0070] Implementation Scheme E: The formulation according to any one of Implementation Schemes A and D, wherein the sodium hyaluronate is selected from high molecular weight sodium hyaluronate.

[0071] Implementation Scheme F: The formulation according to any one of Implementation Schemes A, E, and E, wherein the molecular weight of the sodium hyaluronate is 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] Implementation scheme G: The formulation according to any one of implementation schemes AF, wherein the molecular weight of the sodium hyaluronate is 800 kDa.

[0073] Implementation Scheme H: In the formulation according to any one of Implementation Schemes A and B, wherein the at least one amino acid is selected 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 methionine, wherein the at least one amino acid is arginine and leucine, wherein the at least one amino acid is arginine and taurine, wherein the at least one amino acid is leucine and taurine, or wherein the at least one amino acid is arginine, leucine, and taurine.

[0074] Implementation Scheme I: The preparation according to any one of Implementation Schemes A and H, wherein the at least one vitamin is selected from vitamin C and vitamin B. 12 Combinations thereof, for example, wherein the at least one vitamin is vitamin C, wherein the at least one vitamin is vitamin B. 12 Or, wherein the at least one vitamin is vitamin C and vitamin B. 12 .

[0075] Implementation Scheme J: The formulation according to any one of Implementation Scheme A1, wherein vitamin C is selected from sodium ascorbate phosphate, magnesium ascorbate phosphate, and combinations thereof, for example, wherein vitamin C is sodium ascorbate phosphate, wherein vitamin C is magnesium ascorbate phosphate, or wherein vitamin C is sodium ascorbate phosphate and magnesium ascorbate phosphate.

[0076] Implementation scheme K: The formulation according to any one of implementation schemes A and J, wherein vitamin C is magnesium ascorbate phosphate.

[0077] Implementation Scheme L: A formulation according to any one of Implementation Schemes A and B, wherein vitamin B 12 Selected from cyanocobalamin, hydrocobalamin, adenosylcobalamin, methylcobalamin, and combinations thereof, for example, vitamin B... 12 It is cyanocobalamin, which contains vitamin B. 12 It is hydroxycobalamin, which contains vitamin B. 12 It is adenosylcobalamin, which contains vitamin B. 12 It is methylcobalamin, containing vitamin B. 12 It consists of cyanocobalamin and hydroxocobalamin, among which vitamin B... 12 It consists of cyanocobalamin and adenosylcobalamin, among which vitamin B... 12 It consists of cyanocobalamin and methylcoobalamin, among which vitamin B... 12 It consists of hydroxycobalamin and adenosylcobalamin, among which vitamin B... 12It is either hydroxycobalamin and methylcobalamin, or vitamin B11 among them. 12 It consists of adenosylcobalamin and methylcobalamin.

[0078] Implementation Scheme M: A preparation according to any one of Implementation Scheme A1, wherein vitamin B 12 It is cyanocobalamin.

[0079] Implementation Scheme N: The formulation according to any one of Implementation Scheme AM, wherein the formulation further comprises at least one natural electrolyte.

[0080] Implementation Scheme O: In the formulation according to any one of Implementation Schemes A and B, the at least one natural electrolyte is selected from sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and combinations thereof. For example, the at least one natural electrolyte is sodium chloride, potassium chloride, calcium chloride, and magnesium chloride; the at least one natural electrolyte is sodium chloride; the at least one natural electrolyte is potassium chloride; the at least one natural electrolyte is calcium chloride; the at least one natural electrolyte is magnesium chloride; the at least one natural electrolyte is sodium chloride and potassium chloride; the at least one natural electrolyte is sodium chloride and calcium chloride; the at least one natural electrolyte is sodium chloride and magnesium chloride; the at least one natural electrolyte is potassium chloride and calcium chloride; the at least one natural electrolyte is potassium chloride and magnesium chloride; and the at least one natural electrolyte is calcium chloride and magnesium chloride.

[0081] Implementation scheme P: The formulation according to any one of implementation schemes A and B, wherein the formulation further comprises at least one natural buffer.

[0082] Implementation Scheme Q: In the formulation according to any one of Implementation Schemes AP, the at least one natural buffer is selected from sodium citrate, citric acid, sodium bicarbonate, amino acids, and combinations thereof. For example, the at least one natural buffer is sodium citrate, citric acid, sodium bicarbonate, and amino acids; the at least one natural buffer is sodium citrate; the at least one natural buffer is citric acid; the at least one natural buffer is sodium bicarbonate; the at least one natural buffer is sodium citrate and citric acid; the at least one natural buffer is sodium citrate and sodium bicarbonate; the at least one natural buffer is sodium citrate and amino acids; the at least one natural buffer is citric acid and sodium bicarbonate; the at least one natural buffer is citric acid and amino acids; and the at least one natural buffer is sodium bicarbonate and amino acids.

[0083] Implementation Scheme R: The formulation according to any one of Implementation Schemes AQ, wherein the pH of the formulation is in the range of 5.5 to 8, for example, pH in the range of 6 to 8, pH in the range of 5.5 to 6, pH in the range of 5.5 to 6.5, pH in the range of 6 to 7, pH in the range of 6.0 to 6.7, pH in the range of 6.3 to 6.7, pH in the range of 7 to 8, pH of 5.5, pH of 6.0, pH of 7.0, pH of 7.5, or pH of 8.0.

[0084] Implementation S: The formulation according to any one of Implementation S, AR, wherein the pH of the formulation is 6.5.

[0085] Implementation scheme T: The formulation according to any one of implementation schemes A and B, wherein the pH of the formulation is 7.5.

[0086] Implementation scheme U: The formulation according to any one of implementation schemes A and B, wherein the osmotic pressure of the formulation is in the range of 200 mOsm / kg to 300 mOsm / kg, for example, the osmotic pressure of the formulation is 215 mOsm / kg, 230 mOsm / kg, 245 mOsm / kg, 275 mOsm / kg or 300 mOsm / kg.

[0087] Implementation scheme V: The formulation according to any one of implementation schemes A and B, wherein the osmotic pressure of the formulation is 275 mOsm / kg.

[0088] Implementation scheme W: The formulation according to any one of implementation schemes A and B, wherein the formulation is stable.

[0089] Implementation Scheme X: A formulation according to any one of Implementation Schemes A, W, and E, wherein the formulation comprises brimonidine, glycerol, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbate phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride, sodium bicarbonate, cyanocobalamin, and sodium hydroxide.

[0090] Implementation Scheme Y: The formulation according to any one of Implementation Schemes A and B, wherein the formulation comprises:

[0091] Brimonidine, ranging from 0.001% w / v to 0.05% w / v;

[0092] Glycerin at 0.6% w / v to 0.8% w / v;

[0093] Trehalose, 0.25% w / v to 0.5% w / v;

[0094] Sodium hyaluronate, 0.1% w / v to 0.3% w / v;

[0095] Sodium chloride at 0.2% w / v to 0.3% w / v;

[0096] Potassium chloride ranging from 0.01% w / v to 0.14% w / v;

[0097] Magnesium ascorbate phosphate, 0.01% w / v to 0.1% w / v;

[0098] Sodium citrate, ranging from 0.02% w / v to 0.06% w / v;

[0099] L-arginine at 0.02% w / v to 0.05% w / v;

[0100] Citric acid from 0.01% w / v to 0.0275% w / v;

[0101] L-taurine at 0.01% w / v to 0.02% w / v;

[0102] L-Leucine, 0.01% w / v to 0.02% w / v;

[0103] Calcium chloride, 0.01% w / v to 0.02% w / v;

[0104] Sodium bicarbonate from 0.001% w / v to 0.015% w / v;

[0105] 0.001% w / v to 0.004% w / v cyanocobalamin; and

[0106] qs % w / v of sodium hydroxide.

[0107] Implementation Scheme Z: The formulation according to any one of Implementation Schemes A, B, and C, wherein the formulation comprises:

[0108] 0.025% w / v brimonidine;

[0109] 0.75% w / v glycerin;

[0110] 0.5% w / v trehalose;

[0111] 0.24% w / v sodium hyaluronate;

[0112] 0.3% w / v sodium chloride;

[0113] 0.14% w / v potassium chloride;

[0114] 0.1% w / v magnesium ascorbate phosphate;

[0115] 0.06% w / v sodium citrate;

[0116] 0.05% w / v L-arginine;

[0117] 0.024% w / v citric acid;

[0118] 0.02% w / v L-taurine;

[0119] 0.02% w / v L-leucine;

[0120] 0.02% w / v calcium chloride;

[0121] 0.005% w / v sodium bicarbonate;

[0122] 0.004% w / v cyanocobalamin; and

[0123] qs % w / v of sodium hydroxide.

[0124] Implementation Scheme AA: The formulation according to any one of Implementation Schemes AZ, wherein the pH of the formulation is 7.5.

[0125] Implementation Scheme BB: A formulation according to any one of Implementation Schemes A-AA, wherein the formulation comprises brimonidine, glycerol, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbate phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride, cyanocobalamin, and hydrochloric acid.

[0126] Implementation Scheme CC: A formulation according to any one of Implementation Schemes A-BB, wherein the formulation comprises:

[0127] Brimonidine, ranging from 0.001% w / v to 0.05% w / v;

[0128] Glycerin at 0.6% w / v to 0.8% w / v;

[0129] Trehalose, 0.25% w / v to 0.5% w / v;

[0130] Sodium hyaluronate, 0.1% w / v to 0.3% w / v;

[0131] Sodium chloride at 0.2% w / v to 0.3% w / v;

[0132] Potassium chloride ranging from 0.01% w / v to 0.14% w / v;

[0133] Magnesium ascorbate phosphate, 0.01% w / v to 0.1% w / v;

[0134] Sodium citrate, ranging from 0.02% w / v to 0.06% w / v;

[0135] L-arginine at 0.02% w / v to 0.05% w / v;

[0136] Citric acid from 0.01% w / v to 0.0275% w / v;

[0137] L-taurine at 0.01% w / v to 0.02% w / v;

[0138] L-Leucine, 0.01% w / v to 0.02% w / v;

[0139] Calcium chloride, 0.01% w / v to 0.02% w / v;

[0140] 0.001% w / v to 0.004% w / v cyanocobalamin; and

[0141] qs % w / v of hydrochloric acid.

[0142] Implementation Scheme DD: A formulation according to any one of Implementation Schemes A-CC, wherein the formulation comprises:

[0143] 0.025% w / v brimonidine;

[0144] 0.75% w / v glycerin;

[0145] 0.5% w / v trehalose;

[0146] 0.24% w / v sodium hyaluronate;

[0147] 0.3% w / v sodium chloride;

[0148] 0.14% w / v potassium chloride;

[0149] 0.1% w / v magnesium ascorbate phosphate;

[0150] 0.06% w / v sodium citrate;

[0151] 0.05% w / v L-arginine;

[0152] 0.024% w / v citric acid;

[0153] 0.02% w / v L-taurine;

[0154] 0.02% w / v L-leucine;

[0155] 0.02% w / v calcium chloride;

[0156] 0.004% w / v cyanocobalamin; and

[0157] qs % w / v of hydrochloric acid.

[0158] Implementation scheme EE: The formulation according to any one of implementation schemes A-DD, wherein the pH of the formulation is 6.5.

[0159] Implementation Scheme FF: The formulation according to any one of Implementation Schemes A-EE, wherein the formulation comprises:

[0160] 0.025% w / v brimonidine;

[0161] 0.75% w / v glycerin;

[0162] 0.5% w / v trehalose;

[0163] 0.24% w / v sodium hyaluronate;

[0164] 0.3% w / v sodium chloride;

[0165] 0.14% w / v potassium chloride;

[0166] 0.1% w / v magnesium ascorbate phosphate;

[0167] 0.06% w / v sodium citrate;

[0168] 0.05% w / v L-arginine;

[0169] 0.024% w / v citric acid;

[0170] 0.02% w / v L-taurine;

[0171] 0.02% w / v L-leucine;

[0172] 0.02% w / v calcium chloride;

[0173] 0.005% w / v sodium bicarbonate;

[0174] 0.004% w / v cyanocobalamin;

[0175] 0.0015% w / v poly-e-lysine; and

[0176] qs % w / v of sodium hydroxide.

[0177] Implementation Scheme GG: The formulation according to any one of Implementation Schemes A-FF, wherein the formulation comprises:

[0178] 0.025% w / v brimonidine;

[0179] 0.75% w / v glycerin;

[0180] 0.5% w / v trehalose;

[0181] 0.24% w / v sodium hyaluronate;

[0182] 0.3% w / v sodium chloride;

[0183] 0.14% w / v potassium chloride;

[0184] 0.06% w / v sodium citrate;

[0185] 0.05% w / v L-arginine;

[0186] 0.024% w / v citric acid;

[0187] 0.02% w / v L-taurine;

[0188] 0.02% w / v L-leucine;

[0189] 0.02% w / v calcium chloride;

[0190] 0.005% w / v sodium bicarbonate;

[0191] 0.004% w / v cyanocobalamin;

[0192] 0.011% w / v magnesium chloride;

[0193] 0.011% w / v sodium chlorite; and

[0194] qs % w / v of sodium hydroxide. Example

[0195] Example 1: Exemplary Formulation

[0196] The formulation disclosed herein can be prepared using the ingredients listed in Table 1 below.

[0197] Table 1

[0198]

[0199] Formulations containing the ingredients listed above can be prepared by mixing the listed ingredients, for example, according to the manufacturing process described below:

[0200] 1. In a suitable mixing container, add water equal to 80% of the total batch weight by volume.

[0201] 2. Sprinkle in sodium hyaluronate while mixing until the polymer is fully hydrated, NLT 1 hour to ensure uniform dispersion.

[0202] 3. Slowly add the remaining ingredients in batches to the solution. Mix NLT for 30 minutes to ensure complete dissolution. For example, one possible order of addition could be: brimonidine tartrate, glycerin, trehalose, sodium chloride, potassium chloride, calcium chloride, magnesium ascorbate phosphate, sodium citrate, citric acid, sodium bicarbonate, amino acids, and vitamin B. 12 (Cyanocobalamin).

[0203] 4. Use purified water to QS up to 100% batch weight.

[0204] 5. The formulation is sterilely filtered using a suitable sterile filter (0.2 µm PES).

[0205] Assess the pH, osmotic pressure, and color of the formulation.

[0206] A pH adjuster can be added. For example, sodium hydroxide can be added to obtain the desired pH. As a non-limiting example, 1N sodium hydroxide can be added to obtain a pH of 7.5.

[0207] Other ingredients may be added. For example, at least one amino acid may be selected from L-proline, L-lysine, and L-methionine, or combinations thereof. Propylene glycol may also be used as an additional humectant, and sucrose may be used as a sugar substitute. Copper and / or zinc may be added as additional nutrients. These metals are added to vitamin supplements and function as vitamin cofactors. For example, copper may be added in an amount of about 5 pmm, and zinc may be added in higher levels.

[0208] Example 2: Another exemplary formulation

[0209] The formulation disclosed herein can be prepared using the ingredients listed in Table 2 below.

[0210] Table 2

[0211]

[0212] Formulations containing the ingredients listed above can be prepared by mixing the listed ingredients, for example, according to the manufacturing process described below:

[0213] 1. In a suitable mixing container, add water equal to 80% of the total batch weight by volume.

[0214] 2. Sprinkle in sodium hyaluronate while mixing until the polymer is fully hydrated, NLT 1 hour to ensure uniform dispersion.

[0215] 3. Slowly add the remaining ingredients in batches to the solution. Mix NLT for 30 minutes to ensure complete dissolution. For example, one possible order of addition could be: brimonidine tartrate, glycerin, trehalose, sodium chloride, potassium chloride, calcium chloride, magnesium ascorbate phosphate, sodium citrate, citric acid, amino acids, and vitamin B. 12 (Cyanocobalamin).

[0216] 4. Use purified water to QS up to 100% batch weight.

[0217] 5. The formulation is sterilely filtered using a suitable sterile filter (0.2 µm PES).

[0218] Assess the pH, osmotic pressure, and color of the formulation.

[0219] A pH adjuster can be added. For example, hydrochloric acid can be added to obtain the desired pH. As a non-limiting example, 1N hydrochloric acid can be added to obtain a pH of 6.5.

[0220] Other ingredients may be added. For example, at least one amino acid may be selected from L-proline, L-lysine, and L-methionine, or combinations thereof. Propylene glycol may also be used as an additional humectant, and sucrose may be used as a sugar substitute. Copper and / or zinc may be added as additional nutrients. These metals are added to vitamin supplements and function as vitamin cofactors. For example, copper may be added in an amount of about 5 pmm, and zinc may be added in higher levels.

[0221] Example 3: Another exemplary formulation

[0222] Other exemplary formulations disclosed herein are listed in Table 3 below.

[0223] Table 3

[0224]

Claims

1. A preparation for hydrating the eyes, comprising brimonidine, at least one natural wetting agent, at least one amino acid and at least one vitamin, wherein the preparation is free of preservatives.

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

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

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

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

6. The formulation according to claim 4 or 5, wherein the molecular weight of the sodium hyaluronate is 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 selected from arginine, leucine and taurine.

9. The formulation according to any one of claims 1-8, wherein the at least one vitamin is selected from vitamin C and vitamin B. 12 .

10. The formulation according to claim 9, wherein the vitamin C is selected from sodium ascorbate phosphate, magnesium ascorbate phosphate, and combinations thereof.

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

12. The formulation according to claim 9, wherein the vitamin B 12 It is selected from cyanocobalamin, hydroxycobalamin, adenosylcobalamin, methylcobalamin and combinations thereof.

13. The formulation according to claim 9 or 12, wherein the vitamin B 12 It 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 selected 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.

17. The formulation according to claim 16, wherein the at least one natural buffer is selected 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 the 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 osmotic pressure of the formulation is in the range of 200 mOsm / kg to 300 mOsm / kg.

22. The formulation according to any one of claims 1-21, wherein the osmotic pressure 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, glycerol, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbate phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride, sodium bicarbonate, cyanocobalamin, and sodium hydroxide.

25. The formulation of claim 1, wherein the formulation comprises: 0.001% w / v to 0.05% w / v brimonidine; Glycerin at 0.6% w / v to 0.8% w / v; 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 ascorbate 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 of claim 1, wherein the formulation comprises: 0.025% w / v brimonidine; 0.75% w / v glycerol; 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 ascorbate 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, glycerol, trehalose, sodium hyaluronate, sodium chloride, potassium chloride, magnesium ascorbate phosphate, sodium citrate, L-arginine, citric acid, L-taurine, L-leucine, calcium chloride, cyanocobalamin, and hydrochloric acid.

29. The formulation of claim 1, wherein the formulation comprises: 0.001% w / v to 0.05% w / v brimonidine; Glycerin at 0.6% w / v to 0.8% w / v; 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 ascorbate 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 of claim 1, wherein the formulation comprises: 0.025% w / v brimonidine; 0.75% w / v glycerol; 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 ascorbate 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.

31. The formulation according to any one of claims 28-30, wherein the pH of the formulation is 6.

5.

32. The formulation of claim 1, wherein the formulation comprises: 0.025% w / v brimonidine; 0.75% w / v glycerol; 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 ascorbate 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.

33. The formulation of claim 1, wherein the formulation comprises: 0.025% w / v brimonidine; 0.75% w / v glycerol; 0.5% w / v trehalose; and 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% w / v sodium chlorite; and qs % w / v sodium hydroxide.

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