JP2011503061A - Composition for the treatment and prevention of eyelid swelling comprising an osmotically active agent and a vasoconstrictor - Google Patents

Abstract

Eyelid swelling and eyelid inflammation are serious both in the long and short term in terms of tissue effects, patient quality of life, and general patient comfort. The human eyelid is composed of the thinnest skin layer of the body, the clearest layer of tissue and muscle, and the most fragile collagen fibers. Because of these delicate skin layers, eyelids are highly susceptible to swelling, acute inflammation, and possible long-term damage. The invention features topical formulations containing osmotically active agents and / or vasoconstrictors and / or astringents for the treatment and prevention of eyelid swelling and methods of use thereof.

Description

  This application claims priority to US Provisional Patent Application No. 61 / 007,511, filed Nov. 8, 2007. The contents of US Provisional Patent Application No. 61 / 007,511 are hereby incorporated by reference in their entirety.

  The present invention relates to novel ophthalmic compositions and methods useful for the prevention and treatment of eyelid swelling. In particular, the present invention relates to ophthalmic compositions comprising osmotically active agents, astringents, vasoconstrictors, or combinations thereof that are useful in the prevention and treatment of eyelid swelling. The invention further relates to a method of administering such a composition to a subject in need thereof.

  Eyelid swelling and eyelid inflammation are serious both in the long and short term in terms of tissue effects, patient quality of life, and general patient comfort. The human eyelid is composed of the thinnest skin layer of the body, the clearest layer of tissue and muscle, and the most fragile collagen fibers. Because of these delicate skin layers, eyelids are highly susceptible to swelling, acute inflammation, and possible long-term damage.

  Eyelids have several important roles so that the eye performs its function. Eyelids protect the eye by reflex closure and cover the cornea. It is this mechanism that often prevents particles or foreign bodies from entering the eye and possible damage. Eyelids also adjust the amount of light entering the eye, just like a camera shutter. The eyelid further adds components of the tear film (via the eyelid margin) and maintains a smooth liquid distribution throughout the eye by spreading action during blinking. Eyelids play an extremely important role in maintaining not only eye health but also the overall function of the eyeball system. When this extremely important protective mechanism of inflammation occurs, the health of the eyeball of the individual is impaired.

  Eyelid damage as a result of repeated stretching and swelling of various etiologies can cause temporary sagging and the skin layer hangs above and below the eye. This eyelid swelling can be a very undesirable appearance and can even limit the field of view. Although these symptoms are often only temporary, the actual damage that occurs at the physiological and anatomical level can eventually accumulate as it accumulates with each recurrence.

  This symptom of eyelid swelling is rarely seen as a major concern when assessing eye health, but is a significant concern for many patients, physicians and researchers. Morning eyelid swelling is very common. In addition to the patient's health concerns, this is also widely socially concerned. Patient discomfort and general intolerance associated with swollen eyelids, eyelid surgery (229,092) and botulinum toxin injection (1,658,667) were performed by plastic surgeons in the United States in 2002 It is clear from the fact that it was two of the most common procedures. Despite this great desire to reduce the presence of eyelid edema, attention has not been paid to this symptom. Eyelid swelling is often classified among other signs and symptoms, but has rarely been the primary evaluation variable in clinical trials because it has historically been difficult to measure accurately. Various ocular allergic drugs such as 0.1% olopatadine (Patanol) have begun to be used to reduce eyelid swelling associated with allergic conjunctivitis, but directly and effectively specifically combat this symptom. There are no drugs available. There are numerous powerful forms of society in society that require treatment that directly affects the symptoms of eyelid swelling.

  Novel compositions and methods are provided for treating and preventing eyelid swelling, particularly non-allergic eyelid swelling. In certain embodiments, novel topical ophthalmic formulations comprising osmotically active agents and / or vasoconstrictors and / or astringents are provided. In particular, the present invention provides an acceptable topical ophthalmic formulation comprising a combination of osmotically active agents and / or vasoconstrictors and / or astringents that act synergistically to treat and prevent eyelid swelling. To do. The extraordinary efficacy of this formulation is due, inter alia, to the synergistic effect of the combination of each component therein. Combinations of osmotically active agents and / or vasoconstrictors and / or astringents act synergistically to treat signs and symptoms of eyelid swelling. This has not previously been intended to be realized in one product containing each of these separate components.

  In one embodiment, the present invention provides a target osmolarity for formulating an effective ophthalmic composition having an acceptable (ie, tolerable) comfort profile to treat and prevent eyelid swelling. Provide an osmolality range. In order to be osmotic activity, the osmolarity and / or osmolality of the solution must be higher than the osmolarity and / or osmolality of its surrounding environment. Osmolarity is a measure of osmolality of a solute per liter of solution and osmolality is a measure of osmolality of a solute per kilogram of solvent. Since osmolarity and osmolarity are temperature dependent, that is, water is not commonly used for osmotic pressure measurements because its volume changes with temperature. One skilled in the art will recognize that the terms osmolarity and osmolality are equivalent as applied to the compositions of the present invention when the concentration is very low (such as the concentration of the composition of the present invention). It will be easily recognized that it is used interchangeably in the book.

  The osmolality of the human tear film ranges from about 250-350 mOsm / Kg in the average human eye to individuals with eye disease, including but not limited to dry eye disease (having a maximum value above 700 mOsm / Kg) Averages up to about 450 mOsm / Kg. Therefore, in order to exert a therapeutic effect and reduce edema, the osmolality of the ophthalmic solution must be limited to a minimum osmolality of the human eye environment (ie, about 250 to 450 mOsm / Kg). I must. However, with increasing osmolality, discomfort after instillation increases. High concentrations of ions can activate nerve endings and thus cause stinging pain in the eyeball. Through comfort testing, it has now been discovered that ophthalmic solutions have an osmolality of less than 2000 mOsm / Kg, more preferably less than 1050 mOsm / Kg, in order to have an acceptable, or tolerable, comfort profile. Should have. Accordingly, the target osmolality range of drops prescribed for the treatment of eyelid swelling is preferably within 200 and 2000 mOsm / Kg, preferably 250 mOsm / Kg to 1500 mOsm / Kg, more preferably 260 mOsm / Kg to 1250 mOsm. / Kg, more preferably 265 mOsm / Kg to 1200 mOsm / Kg, more preferably 400 mOsm / Kg to 1150 mOsm / Kg, more preferably 500 mOsm / Kg to 1100 mOsm / Kg.

  In some embodiments, the compositions of the present invention include osmotically active agents, including but not limited to colloidal osmotic agents and crystalline osmotic agents. Crystalline osmotic agents suitable for use in the compositions of the present invention include, but are not limited to, sodium chloride (NaCl), dextrose, sucrose, glycerol, mannitol, sorbitol, polyethylene glycol 3350NF, magnesium citrate and lactulose. Not. In certain embodiments, the effective amount of crystalline osmotic agent is about 1% to about 10% w / v sodium chloride, about 1% to about 10% w / v dextrose, about 1% to about 20% w / v. v Glycerol, selected from the group consisting of about 1% to about 20% w / v mannitol, about 1% to about 95% w / v sucrose, and about 1% to about 95% w / v sorbitol. Preferably, the crystalline osmotic agent is sodium chloride and the effective amount is from about 1% to about 10% w / v, more preferably from about 2% to about 5% w / v.

  Colloidal osmotic agents suitable for use in the compositions of the present invention include hetastarch, pentastarch, urea cross-linked gelatin polypeptide, dextran 70, dextran 40, albumin, icodextrin, bentonite USP, MgAl silicate NF type 2A, alginic acid / sodium alginate NF, microcrystalline cellulose and CMC NF, carbomer, and gellan gum, but are not limited thereto.

  In certain embodiments, the effective amount of colloidal osmotic agent is from about 1% to about 10% w / v hetastarch, from about 1% to about 20% w / v pentastarch, from about 1% to about 10% w / v. v Dextran 70, selected from the group consisting of about 1% to about 10% w / v dextran 40, about 1% to about 50% w / v albumin, and about 1% to about 50% w / v microcrystalline cellulose. .

  Other osmotic agents suitable for use in the method of the present invention include magnesium sulfate, magnesium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium sulfate, potassium acid. Potassium acid phosphate, calcium lactate, magnesium succinate, tartaric acid, and raffinose, glucose, caffeine, carbomer 934P, tannic acid, ascorbic acid, dextran-40,000, inulin, menthol, polysorbate 80, mixtures thereof Soluble carbohydrates such as, but not limited to. In certain embodiments, the effective amount of osmotic agent is from about 0.001% to about 10% w / v caffeine, from about 0.001% to about 10% w / v carbomer 934P, from about 0.001%. About 10% w / v tannic acid, about 0.001% to about 10% w / v ascorbic acid, about 0.001% to about 10% w / v dextran-40,000, about 0.001% to about 10 % W / v inulin, from about 0.001% to about 10% w / v menthol, from about 0.001% to about 10% w / v polysorbate-80, or a mixture thereof.

  In some embodiments, the composition of the invention includes a vasoconstrictor. Vasoconstrictors suitable for use in the compositions of the present invention include, but are not limited to, naphazoline, oxymetazoline, phenylephrine, tetrahydrozoline, and other agents that are vasoactive alpha receptor agonists. In one preferred embodiment, the vasoconstrictor is naphazoline and the effective amount is from about 0.01% to about 10% w / v, preferably from about 0.01% to about 1% w / v, more preferably about 0.01% to about 0.5% w / v, even more preferably about 0.01% to about 0.2% w / v, even more preferably about 0.09% to about 0.1% w / v The range of v. In another preferred embodiment, the vasoconstrictor suitable for use in the present invention is oxymetazoline, and the effective amount is from about 0.01% to about 0.2% w / v, more preferably 0.01. % To about 0.1% w / v, even more preferably from about 0.03% to about 0.05% w / v. In yet another preferred embodiment, the vasoconstrictor suitable for use in the present invention is phenylephrine and the effective amount is from about 0.01% to about 10% w / v, preferably from about 0.01% to about It ranges from 1% w / v, more preferably from about 0.01% to about 0.5% w / v, even more preferably from about 0.05% to about 0.2% w / v.

  In yet another embodiment, the composition of the present invention comprises an astringent. Astringents suitable for use in the compositions of the present invention include witch hazel, zinc sulfate, silver sulfate, plant tannin, oak bark extract, pentagalloyl glucose, alum, Burow liquor, hawthorn extract, walnut cherry extract and Examples include, but are not limited to, natural flavanoids. Preferably, the astringent is witch hazel and / or zinc sulfate and an effective amount is about 0.001% to about 10% w / v, preferably about 0.01% to about 5% w / v, more preferably It ranges from about 0.1% to about 1% w / v, even more preferably from about 0.2% to about 0.75% w / v.

  In one embodiment, the composition of the present invention comprises a combination of an osmotically active agent and a vasoconstrictor. In one embodiment, the osmotically active agent is NaCl or glycerol and the vasoconstrictor is naphazoline or oxymetazoline. Preferably, sodium chloride is present in the range of about 1% to about 10% w / v, more preferably about 2% to about 5% w / v, and glycerol is about 1% to about 30% w / v. , Preferably from 1% to about 20% w / v, more preferably from about 1% to about 10% w / v, even more preferably from about 5% to about 8% w / v, Present in the range of about 0.01% to about 0.5% w / v, more preferably about 0.01% to about 0.2% w / v; It is present in the range of 0.2% w / v, more preferably from 0.01% to about 0.1% w / v, even more preferably from about 0.03% to about 0.05% w / v.

  For example, the osmotically active agent is 3% w / v NaCl or 7.5% w / v glycerol and the vasoconstrictor is naphazoline 0.09% w / v or 0.05% w / v oxymetazoline. . In one embodiment, the osmotic agent is 7.5% w / v glycerol and the vasoconstrictor is 0.09% w / v naphazoline. In another embodiment, the osmotic agent is 7.5% w / v glycerol and the vasoconstrictor is 0.05% w / v oxymetazoline. In yet another embodiment, the osmotic agent is 3% w / v NaCl and the vasoconstrictor is 0.09% w / v naphazoline. In yet another embodiment, the osmotic agent is 3% w / v NaCl and the vasoconstrictor is 0.05% w / v oxymetazoline.

  In one particular embodiment, the composition of the invention comprises a pharmaceutically acceptable carrier and naphazoline hydrochloride 0.9 mg / mL, sodium chloride 30 mg / mL, disodium edetate 1 mg / mL, boric acid 5 mg / mL. And benzalkonium chloride 0.1 mg / mL, and the pH of the composition is 6.0.

  In another particular embodiment, the composition of the present invention comprises a pharmaceutically acceptable carrier and naphazoline hydrochloride 0.9 mg / mL, glycerol 75 mg / mL, disodium edetate 1 mg / mL, boric acid 5 mg / mL. mL and 0.1 mg / mL benzalkonium chloride, and the pH of the composition is 6.0.

  In yet another specific embodiment, the composition of the present invention comprises a pharmaceutically acceptable carrier and oxymetazoline hydrochloride 0.5 mg / mL, sodium chloride 30 mg / mL, edetate disodium. 1 mg / mL, boric acid 5 mg / mL and benzalkonium chloride 0.1 mg / mL, and the pH of the composition is 6.0.

  In yet another specific embodiment, the composition of the invention comprises a pharmaceutically acceptable carrier and oxymetazoline hydrochloride 0.5 mg / mL, glycerol 75 mg / mL, disodium edetate 1 mg / mL, boron It contains 5 mg / mL of acid and 0.1 mg / mL of benzalkonium chloride, and the pH of the composition is 6.0.

  In some embodiments, the composition of the invention comprises a combination of an osmotically active agent and a vasoconstrictor, wherein the osmotically active agent is caffeine, carbomer 934P, tannic acid, ascorbic acid, dextran 40,000. , Inulin, mannitol, menthol and polysorbate 80, and the vasoconstrictor is selected from the group consisting of naphazoline, oxymetazoline, phenylephrine and tetrahydrozoline.

  In some cases, the osmotically active agent and / or vasoconstrictor and / or astringent may be an additional vasoconstrictor, tear substitute, antiallergic agent, antihistamine, mast cell stabilizer, NSAID, steroid, anti-inflammatory agent In combination with various other agents used to treat and prevent eyelid swelling, including but not limited to, antioxidants, anti-infectives, cholinergic agents and combinations thereof.

  The composition of the present invention can be a solution, suspension, oil, viscous or semi-viscous gel, emulsion, liposome, lotion, ointment, cream, gel, salve, powder, sustained release or slow release Can be formulated for topical administration in a sprayable or nebulized form as a sex preparation or implant, eye lotion, or another type of solid or semi-solid composition. The compositions of the present invention can be formulated for acute or chronic administration for the treatment and / or prevention of eyelid swelling.

  The invention also features novel methods of treating and preventing eyelid swelling using these formulations. In some embodiments, a method of treating and preventing eyelid swelling in a subject comprises topically administering the composition of the present invention to the eyeball surface of the subject to treat and prevent eyelid swelling. In another embodiment, the methods of the present invention comprise topically administering the composition of the present invention to the inner and / or outer eyelids of a subject to treat and prevent eyelid swelling.

  In some embodiments, the method of treating and preventing eyelid swelling in a subject comprises an effective amount of at least one active agent selected from the group consisting of an osmotic active agent, a vasoconstrictor and an astringent. Administration to the eyeball / eyelid surface inside or outside the subject.

  In another embodiment, a method of treating and preventing eyelid swelling in a subject comprises an effective amount of a combination of at least two agents selected from osmotically active agents, vasoconstrictors and astringents. Administration to the inner or outer eyeball / eyelid surface. In one particular embodiment, an effective amount of a combination of an osmotic agent and a vasoconstrictor is administered to the inner or outer eye / eyelid surface of a subject. For example, the osmotically active agent is NaCl or glycerol and the vasoconstrictor is naphazoline or oxymetazoline.

  In one embodiment, the method of the present invention applies a combination of 7.5% w / v glycerol and 0.09% w / v naphazoline to the inner or outer eyeball of a subject to treat and prevent eyelid swelling. / Containing to the surface of the eyelid. In another embodiment, the method of the present invention applies a combination of 7.5% w / v glycerol and 0.05% w / v oxymetazoline to the inside of a subject to treat and prevent eyelid swelling. Or administration to the outer eyeball / eyelid surface. In yet another embodiment, the method of the present invention applies a combination of 3% w / v NaCl and 0.09% w / v naphazoline to the inside or outside of a subject to treat and prevent eyelid swelling. Administration to the eyeball / eyelid surface. In yet another embodiment, the method of the present invention uses a combination of 3% w / v NaCl and 0.05% w / v oxymetazoline inside a subject or to treat and prevent eyelid swelling. Administration to the outer eyeball / eyelid surface.

  In one particular embodiment, the method of the present invention comprises naphazoline hydrochloride 0.9 mg / mL, sodium chloride 30 mg / mL, disodium edetate 1 mg / mL, boric acid 5 mg to treat and prevent eyelid swelling. / ML and benzalkonium chloride 0.1 mg / mL in combination with a pharmaceutically acceptable carrier, pH 6.0 on the inner or outer eyeball / eyelid surface of the subject.

  In another specific embodiment, the method of the present invention comprises naphazoline hydrochloride 0.9 mg / mL, glycerol 75 mg / mL, disodium edetate 1 mg / mL, boric acid to treat and prevent eyelid swelling. Administering a combination of 5 mg / mL and benzalkonium chloride 0.1 mg / mL with a pharmaceutically acceptable carrier (total pH = 6.0) to the inner or outer eyeball / eyelid surface of the subject. Including.

  In yet another specific embodiment, the method of the present invention comprises oxymetazoline hydrochloride 0.5 mg / mL, sodium chloride 30 mg / mL, disodium edetate 1 mg / mL to treat and prevent eyelid swelling. A combination of mL, boric acid 5 mg / mL and benzalkonium chloride 0.1 mg / mL and a pharmaceutically acceptable carrier (total pH = 6.0) on the inner or outer eyeball / eyelid surface of the subject Administration.

  In yet another specific embodiment, the method of the present invention comprises 0.5 mg / mL oxymetazoline hydrochloride, 75 mg / mL glycerol, 1 mg / mL edetate disodium to treat and prevent eyelid swelling. A combination of boric acid 5 mg / mL and benzalkonium chloride 0.1 mg / mL and a pharmaceutically acceptable carrier (total pH = 6.0) on the inner or outer eyeball / eyelid surface of the subject Including doing.

  In some embodiments, the methods of the invention administer a combination of an osmotically active agent and a vasoconstrictor to the inner or outer eyeball / eyelid surface of a subject to treat and prevent eyelid swelling. The osmotically active agent is selected from the group consisting of caffeine, carbomer 934P, tannic acid, ascorbic acid, dextran 40,000, inulin, mannitol, menthol and polysorbate 80, and the vasoconstrictor is naphazoline, oxy Selected from the group consisting of metazoline, phenylephrine and tetrahydrozoline.

  Such preparations are administered during the day, at night, immediately before going to bed and / or immediately after awakening, at doses appropriate to the rate of drug absorption, deactivation and excretion and compound delivery to treat and prevent eyelid swelling. can do. Such formulations can also be administered for short or long term use to treat and prevent eyelid swelling.

  Furthermore, the invention features a method of measuring changes in eyelid swelling using a controlled objective technique that utilizes scanning imaging techniques (eg, 3D scanning techniques). Such a method can objectively and accurately quantify daily fluctuations in eyelid swelling.

  Furthermore, the invention features a kit for transport, storage or use of the formulation, as well as performing the method. Other features and advantages of the invention will be apparent from the following detailed description and from the claims.

FIG. 5 is a table of some of the symptoms of eyelid swelling, details of such presentation of each symptom, and other symptoms of such symptom. It is the figure which showed the effect of the osmotic agent with respect to eyelid swelling. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 5 is a line graph showing the results of a study using 0.1% naphazoline for the treatment of morning eyelid swelling in 11 subjects. Values are expressed relative to baseline and time points represent the time after study drug instillation. For each subject, the right eye (circle, also referred to as “OD”) was treated with naphazoline hydrochloride (0.1%) and the left eye (square, also referred to as “OS”) was untreated. FIG. 4 is a line graph showing the results of a study evaluating 5% NaCl ophthalmic solution for treatment of morning eyelid edema in 6 subjects. Values are expressed relative to baseline, error bars represent 1 standard error, and time points represent time after study drug instillation. For each subject, treatment is not given to either eye at baseline, the right eye (circle, also referred to as “OD”) is treated with 5% NaCl ophthalmic solution, and the left eye (square, “ OS ”) was untreated. FIG. 4 is a line graph showing the results of a study evaluating 5% NaCl ophthalmic solution for treatment of morning eyelid edema in 6 subjects. Values are expressed relative to baseline, error bars represent 1 standard error, and time points represent time after study drug instillation. For each subject, treatment is not given to either eye at baseline, the right eye (circle, also referred to as “OD”) is treated with 5% NaCl ophthalmic solution, and the left eye (square, “ OS ”) was untreated. FIG. 4 is a line graph showing the results of a study evaluating 5% NaCl ophthalmic solution for treatment of morning eyelid edema in 6 subjects. Values are expressed relative to baseline, error bars represent 1 standard error, and time points represent time after study drug instillation. For each subject, treatment is not given to either eye at baseline, the right eye (circle, also referred to as “OD”) is treated with 5% NaCl ophthalmic solution, and the left eye (square, “ OS ”) was untreated. FIG. 4 is a line graph showing the results of a study evaluating 5% NaCl ophthalmic solution for treatment of morning eyelid edema in 6 subjects. Values are expressed relative to baseline, error bars represent 1 standard error, and time points represent time after study drug instillation. For each subject, treatment is not given to either eye at baseline, the right eye (circle, also referred to as “OD”) is treated with 5% NaCl ophthalmic solution, and the left eye (square, “ OS ”) was untreated. FIG. 4 is a line graph showing the results of a study evaluating 5% NaCl ophthalmic solution for treatment of morning eyelid edema in 6 subjects. Values are expressed relative to baseline, error bars represent 1 standard error, and time points represent time after study drug instillation. For each subject, treatment is not given to either eye at baseline, the right eye (circle, also referred to as “OD”) is treated with 5% NaCl ophthalmic solution, and the left eye (square, “ OS ”) was untreated. FIG. 4 is a line graph showing the results of a study evaluating 5% NaCl ophthalmic solution for treatment of morning eyelid edema in 6 subjects. Values are expressed relative to baseline, error bars represent 1 standard error, and time points represent time after study drug instillation. For each subject, treatment is not given to either eye at baseline, the right eye (circle, also referred to as “OD”) is treated with 5% NaCl ophthalmic solution, and the left eye (square, “ OS ”) was untreated. FIG. 4 is a line graph showing the results of a study evaluating 5% NaCl ophthalmic solution for treatment of morning eyelid edema in 6 subjects. Values are expressed relative to baseline, error bars represent 1 standard error, and time points represent time after study drug instillation. For each subject, treatment is not given to either eye at baseline, the right eye (circle, also referred to as “OD”) is treated with 5% NaCl ophthalmic solution, and the left eye (square, “ OS ”) was untreated. For the treatment of eyelid swelling in the morning, the results of a study comparing the efficacy of a combination of 0.1% naphazoline and 5% NaCl solution individually with 0.1% naphazoline or 5% NaCl (and no treatment control) are: It is the shown line graph. 6 is a bar graph showing the results of a combination of 0.1% naphazoline and 5% NaCl in the test shown in FIG. FIG. 7A shows a mixed formulation of 5% NaCl and 0.1% naphazoline compared to the individual components alone (first column), osmolality of each test article (first column), tested for the ability to reduce morning eyelid swelling. Column 2) Reduction rate of morning eyelid swelling by the corresponding test substance (column 3), reduction rate of eyelid swelling in the control eye (no test substance, column 4), normalized reduction of eyelid swelling It is the table | surface which summarized the rate (5th column) and the standard error of a deviation (6th column). FIG. 7B is a bar graph showing the reduction rate of eyelid swelling by each test substance. 4 is a bar graph showing the results of a study evaluating the efficacy of a combination of naphazoline hydrochloride (0.05%) dissolved in 5% NaCl eye ointment for the treatment of morning eyelid swelling in 4 subjects. 6 is a bar graph showing the results of a study evaluating the efficacy of a combination of naphazoline hydrochloride (0.1%) dissolved in 2.5% NaCl ophthalmic solution for the treatment of morning eyelid swelling in 6 subjects. . Error bars represent one standard error. 6 is a bar graph showing the results of a study evaluating the efficacy of a combination of naphazoline hydrochloride (0.1%) in a 50% sucrose solution for the treatment of morning eyelid swelling in 6 subjects. Error bars represent one standard error. FIG. 11A shows a mixed preparation of 50% sucrose and 0.1% naphazoline compared to the individual components alone (column 1), osmolality of each test article (first column) tested for the ability to reduce morning eyelid swelling. Column 2) Reduction rate of morning eyelid swelling by the corresponding test substance (column 3), reduction rate of eyelid swelling in the control eye (no test substance, column 4), normalized reduction of eyelid swelling It is the table | surface which summarized the rate (5th column) and the standard error of a deviation (6th column). FIG. 11B is a bar graph showing the reduction rate of eyelid swelling by each test substance. It is the line graph which showed the natural progression of the eyelid swelling of the morning in a test subject's right eye (OD), left eye (OS), and both eyes (OU). No treatment was given in this experiment. 6 is a bar graph showing the results of a study evaluating the efficacy of topical 0.1% phenylephrine ointment for the treatment of morning eyelid swelling in 6 subjects. Error bars represent one standard error. Results of a study evaluating the efficacy of a combination of naphazoline hydrochloride (0.1%) dissolved in an ophthalmic solution of 5% NaCl and 12.5% mannitol for the treatment of morning eyelid swelling in 6 subjects. It is the shown bar graph. Error bars represent one standard error. Mixed preparation of naphazoline hydrochloride (0.1%) dissolved in ophthalmic solution of 5% NaCl and 12.5% mannitol for the treatment of eyelid swelling in the morning compared to the individual components alone (column 1 ), Osmolality of each test substance (second column), decrease rate of morning eyelid swelling by the corresponding test substance (third column), decrease rate of eyelid swelling in the control eye (no test substance, second column) 4 column), normalized reduction rate of eyelid swelling (5th column), and standard error of deviation (6th column). It is the bar graph which showed the decreasing rate of eyelid swelling by each test substance. 6 is a line graph showing the results of a study evaluating the efficacy of 12.5% mannitol ophthalmic solution for treatment of morning eyelid swelling in 6 subjects. Error bars represent one standard error. FIG. 16A shows 5% NaCl and 0.1% naphazoline, 50% sucrose and 0.1% naphazoline, and 5% NaCl, 12 compared to the individual components tested for the ability to reduce morning eyelid swelling. .5% mannitol and 0.1% naphazoline mixed formulations (first column), osmolality of each test substance (second column), reduction rate of morning eyelid swelling by corresponding test substance (third column) ), Reduction rate of eyelid swelling in control eyes (no test article, column 4), normalized reduction rate of eyelid swelling (column 5), and standard error of deviation (column 6) It is. FIG. 16B is a bar graph showing the reduction rate of eyelid swelling by each test substance. 6 is a bar graph showing the results of a study evaluating the efficacy of 50% sucrose ophthalmic solution for treatment of morning eyelid swelling in 6 subjects. Error bars represent one standard error. FIG. 18A is a table showing osmolality and average comfort level for various ophthalmic solutions. FIG. 18B shows the correlation between osmolality and comfort (for 0-10 grades, where 0 is the most comfortable and 10 is the most comfortable) for six ophthalmic formulations with osmolality of about 800 mOsm / Kg to 2400 mOsm / Kg. It is a line graph showing discomfort. FIG. 2 is a bar graph showing the average comfort level of various ophthalmic formulations (“Oxy” means oxymetazoline and “Naph” means naphazoline). FIG. 5 is a line graph showing the mean baseline eyelid swelling score for 20 subjects based on subjective regional / global eyelid swelling grade. Eyelid swelling was assessed in the evening and the following morning after waking (baseline), followed by 10 minute intervals for up to 1 hour. 6 is a line graph showing the average overall score of eyelid swelling in the evening and morning for 6 days for 19 subjects. Overall eyelid swelling was assessed subjectively on a scale of 0 to 3 (0 = none, 3 = clear swelling). Average eye in region 1 of human eyelids before (baseline) and immediately after (time = 0) instilling 1 drop of 0.09% naphazoline / 3% NaCl in one eye and placebo in the other eye A line showing tendon swelling (N = 12). Eyelid swelling was assessed for 60 minutes. Mean eye in region 2 of human eyelids before (baseline) and immediately after (time = 0) instilling 1 drop of 0.09% naphazoline / 3% NaCl in one eye and placebo in the other eye It is a line graph which showed tendon swelling (N = 10). Eyelid swelling was assessed for 60 minutes. Average eye in region 3 of the human eyelid before (baseline) and immediately after (time = 0) instilling 1 drop of 0.09% naphazoline / 3% NaCl in one eye and placebo in the other eye It is a line graph which showed tendon swelling (N = 15). Eyelid swelling was assessed for 60 minutes. Average eye in region 4 of human eyelids before (baseline) and immediately after (time = 0) instilling 1 drop of 0.09% naphazoline / 3% NaCl in one eye and placebo in the other eye It is a line graph which showed tendon swelling (N = 16). Eyelid swelling was assessed for 60 minutes. FIG. 2 is a line graph showing average overall eyelid swelling before (baseline) and after instillation of 1 drop of 0.09% naphazoline / 3% NaCl in one eye and placebo in the other eye (baseline). N = 10). 6 is a bar graph showing the average comfort score for 0.09% naphazoline / 3% NaCl ophthalmic formulation and placebo. One drop of 0.09% naphazoline / 3% NaCl on one eye and 0.05% oxymetazoline / 3% NaCl on the next eye before (baseline) and immediately after (time = 0). 2 is a line graph showing the average overall eyelid swelling score. Eyelid swelling was assessed for 6 hours (360 minutes). Before applying 1 drop of 0.09% naphazoline / 7.5% glycerol to one eye and 0.05% oxymetazoline / 7.5% glycerol to the other eye (baseline) and immediately after applying (time) = 0) is a line graph showing the average overall eyelid swelling score. Eyelid swelling was assessed for 6 hours (360 minutes). Instill 0.09% naphazoline / 3% NaCl, 0.05% oxymetazoline / 3% NaCl, 0.09% naphazoline / 7.5% glycerol and 0.05% oxymetazoline / 7.5% glycerol. FIG. 6 is a line graph comparing the average overall eyelid swelling score before (baseline) and immediately after instillation (time = 0). Eyelid swelling was assessed for 6 hours (360 minutes). Average comfort of 0.09% naphazoline / 3% NaCl, 0.05% oxymetazoline / 3% NaCl, 0.09% naphazoline / 7.5% glycerol and 0.05% oxymetazoline / 7.5% glycerol It is the bar graph which compared the score.

1. Definitions For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood by those of ordinary skill in the art.

  As used herein, the term “acceptable comfort profile” refers to the tolerability of an ophthalmic formulation when administered to the eye and such ophthalmic formulation is administered to the eye to reduce, alleviate, treat and treat ocular disease. The advantage of preventing / or surpassing any risk of discomfort associated with administration of the formulation to the eye, such as increased patient compliance of the patient administering the ophthalmic formulation to the eye.

  The term “antiallergic agent” refers to a molecule or composition that treats or alleviates symptoms of ocular allergy. Examples of antiallergic agents include “antihistamines”, ie drugs that block the binding of histamine to histamine receptors, “mast cell stabilizers”, ie drugs that block the release of histamine and other substances from mast cells. , "Drugs with multiple modes of action", ie drugs that are antiallergic agents with multiple modes of action (eg, drugs that are antihistamines and mast cell stabilizers, antihistamines, mast cell stabilizing and anti-inflammatory activities) Drugs), non-steroidal anti-inflammatory drugs, or “NSAIDs”, as well as steroids.

  The term “aqueous solution” typically means an aqueous solution composition in which the carrier is up to a range of> 50% by weight, more preferably> 75% by weight, in particular> 90% by weight of water.

  The phrase “effective amount” is an art-recognized term that, when included in a pharmaceutical composition of the invention, has any desired effect with a reasonable benefit / risk ratio applicable to any drug therapy. Refers to the amount of drug that results in In certain embodiments, the term refers to an amount necessary or sufficient to eliminate, reduce or maintain eyelid swelling (eg, prevent diffusion) or to prevent or treat eyelid swelling. Point to. The effective amount can vary depending on factors such as the disease or condition being treated, the particular composition being administered, and the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular agent without necessitating undue experimentation. In the treatment of eyelid swelling, an effective amount is a measure, ie, a subjective grade that assesses eyelid swelling (eg, but not limited to mild, moderate, severe, or 0, 1, 2, or 3). Preferably determined at least 2%, at least 5%, at least 10%, at least 15%, at least 2%, as measured by subjective clinical grades, or other suitable grades), and / or 3D scanning techniques 20%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85% at least 90%, Refers to an amount of the therapeutic agent that reduces by at least 95% or at least 100%.

  The term “eyelid swelling” refers to any non-allergic or allergic condition, including eyelid swelling or inflammation, including eye or surrounding edema. For example, but not limited to, all of the symptoms shown in FIG. 1 are encompassed by the term non-allergic “eyelid swelling”. Thus, as defined herein, “eyelid swelling” refers to eyelids ranging from rare disorders such as eyelid skin laxity to more common skin laxity characterized by “sagging under the eyes”. Includes all causes of swelling. In addition to these swelling infections, dermatitis, lymphoma, kidney and endocrine dysfunction (thyroid) caused by rosacea, cosmetics or topical medicines, and even chronic periocular edema can be very useful diagnostic signs There are a number of other non-allergic conditions that can result in eyelid swelling, including but not limited to the infectious disease trichinosis. More common causes of eyelid swelling include age, alcohol use, computer use, reading, fatigue and diurnal variation (morning of eyelids in the morning). Morning eyelid swelling occurs at night and causes eyelid swelling simultaneously with morning awakening. In addition, ocular allergy is one of the most common causes of eyelid inflammation, affecting almost 20% of the general population. In this case, a series of preformed mediators released as a result of IgE-stimulated mast cell degranulation are the clinical features of allergic reactions that cause vasodilation of the vasculature and leakage of fluid from the bloodstream to the tissue. Causes of signs and symptoms.

  As used herein, the term “hyperosmotic solution” refers to any solution that has a higher osmolality than other fluids, eg, contains a higher concentration of osmotic active ingredients than other fluids.

  As used herein, the term “eye allergy” refers to any allergic disease of the eye. Examples of such ocular allergies include, but are not limited to, seasonal / perennial allergic conjunctivitis, spring keratoconjunctivitis, giant papillary conjunctivitis, perennial allergic conjunctivitis and atopic keratoconjunctivitis. Signs and symptoms of ocular allergy include conjunctival edema, itchy eyes, redness, tearing and swelling of the eyelids.

  The term “osmotic active agent” refers to a hydrophilic agent, such as a hygroscopic agent, a hydroscopic agent or other agent, which causes an osmotic flow in a hyperosmotic fluid. To be osmotic activity, the osmolality of the solution must be higher than the osmolality of its surrounding environment.

  A “patient”, “subject” or “host” to be treated by the subject method refers to a human or non-human animal such as a primate, mammal, vertebrate.

  The phrase “pharmaceutically acceptable” is art-recognized and is free of excessive toxicity, irritation, allergic reactions or other problems or disorders for use in contact with human and animal tissues. Refers to compositions, polymers and other materials and / or dosage forms that are appropriate within the scope of sound medical judgment, depending on a reasonable benefit / risk ratio.

  The phrase “pharmaceutically acceptable carrier” is art-recognized and includes, for example, the delivery of any adjuvant or composition or component thereof from one organ or part of the body to another organ or part of the body. Or refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, encapsulating material involved in transport. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the adjuvant and not injurious to the patient. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that can serve as pharmaceutically acceptable carriers include (1) sugars such as lactose, glucose, sucrose, (2) starches such as corn starch, potato starch, (3) cellulose and sodium carboxymethylcellulose , Derivatives thereof such as ethyl cellulose and cellulose acetate, (4) tragacanth powder, (5) malt, (6) gelatin, (7) talc, (8) cocoa butter, excipients such as suppository wax, (9) peanut Oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil and the like, (10) glycols such as propylene glycol, (11) polyols such as glycerol, sorbitol, mannitol, polyethylene glycol, (12) ethyl oleate Esthetics such as ethyl laurate (13) agar, (14) buffer such as magnesium hydroxide, aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, ( 19) ethyl alcohol, (20) phosphate buffer, (21) aqueous solutions, suspensions, ointments, and (22) other non-toxic compatible materials used in pharmaceutical formulations.

  The term “pharmaceutically acceptable salt” is art recognized and includes, but is not limited to, therapeutic agents, excipients, other materials, etc. Refers to the relatively non-toxic inorganic and organic acid addition salts of ingredients. Examples of pharmaceutically acceptable salts include salts derived from mineral acids such as hydrochloric acid and sulfuric acid, salts derived from organic acids such as ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. It is done. Examples of inorganic bases suitable for salt formation include, but are not limited to, hydroxides such as ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, carbonates and bicarbonates. Salts can also be formed using suitable organic bases, including non-toxic and sufficiently strong organic bases to form such salts. For illustrative purposes, such organic base classes include mono-, di-, and trialkylamines such as methylamine, dimethylamine, triethylamine; mono-, di-, triethanolamine, such as mono-, di-, and triethanolamine. Hydroxyalkylamine; amino acids such as arginine and lysine; guanidine; N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; (trihydroxymethyl) aminoethane and the like. Can be mentioned. For example, J. et al. Pharm. Sci. 66: 1-19 (1977).

  The term “prevent” when used in connection with a symptom is art-recognized and reduces or reduces the incidence of symptoms of a medical condition in a subject compared to a subject who does not receive the composition. Refers to administration of the composition that is delayed.

  The term “treat” is an art-recognized term and includes one or more types of diagnostics including, but not limited to, ophthalmic agents such as osmotically active agents, vasoconstrictors, astringents, combinations thereof. It refers to curing and / or ameliorating at least one symptom of any symptom or disease by administering a drug, therapeutic agent or prophylactic agent.

  The term “vasoconstrictor” refers to any drug or agent that causes blood vessels to contract, including but not limited to agents that act on alpha-1 receptors in smooth muscle tissue.

2. Eyelid swelling Eyelid swelling can occur as a result of several different pathological symptoms, including allergies, infections, mild irritation / inflammation, trauma, and morning eyelid swelling. Morning eyelid swelling occurs as a result of reduced tissue tension and inflammation. As the individual ages, the skin around the eyelids loses its elasticity. Collagen fibers that give the dermis stiffness and elasticity begin to break down. This is a natural process that can be exacerbated by excessive exposure to sunlight or other destructive environmental stimuli such as smoking. In addition, the underlying eye or fat breaks down, and also produces tissue that looks like relaxed voids or loses tissue tension.

  When an individual is lying horizontally, body fluid leaks from the underlying vasculature to the empty, unstructured tissue around the eye, particularly the lower eyelid. This may be due to the accumulation of inflammatory mediators in the tear film and conjunctiva. Due to the reduced elasticity of the dermis, the superficial eyelid tissue swells with increasing body fluids. When the individual wakes up, the eyelids appear swollen and swollen as a result of excess fluid flowing into the decomposed eyelid tissue. Indefinite fluid accumulation can occur in tissues overlying the eyes or bones of the eyelids of the lower eyelid. This bodily fluid may appear dark blue or purple, giving it an appearance or tired swollen eyes. After the individual wakes up and takes a standing position, the eyelid swelling gradually decreases as fluid escapes from the eyelid tissue. However, this process can take a considerable amount of time.

  Eyelid swelling and periocular edema are distinguishable from other types of ocular edema, such as corneal edema. As noted above, eyelid swelling occurs as a result of fluid leaking from the eye and the underlying vasculature in the area surrounding the eye. In contrast, the cornea does not contain blood vessels. Corneal edema is typically due to abnormal intraocular pressure, electrolyte imbalance in the corneal stroma, and / or the presence of active metabolic pumps in the endothelium, each of which sends fluid to the cornea.

  Accordingly, a pharmaceutical composition formulated for the eye comprising an effective amount of an active agent selected from an osmotically active agent, a vasoconstrictor, an astringent, or a combination thereof that is dropped directly into the eye is an underlying pulse. It is effective in treating eyelid swelling by “drying” the tube structure to treat and prevent leakage to the eyelid tissue and the eye or surrounding area. A pharmaceutical composition formulated for the eye comprising an effective amount of an active agent selected from osmotically active agents, vasoconstrictors, astringents or combinations thereof applied to the ocular surface / inner surface and / or outer surface of the eyelid The object is also effective in treating and preventing eyelid swelling.

3. Pharmaceutical Compositions A novel topical pharmaceutical composition comprising an effective amount of one or more active agents in a pharmaceutically acceptable carrier for the treatment and prevention of eyelid swelling and periocular edema. The one or more active agents can include, but are not limited to, osmotically active agents, vasoconstrictors, astringents, or combinations thereof. Astringents or osmotically active agents help drain fluid from swollen or inflamed tissue (Figure 2), and vasoconstrictors prevent further leakage from the underlying vasculature into the eyelid tissue To help. In one particular embodiment, the pharmaceutical composition of the present invention comprises at least two active agents, including but not limited to osmotically active agents, vasoconstrictors, astringents or combinations thereof.

  In one preferred embodiment, the pharmaceutical composition of the present invention comprises 200 and 2000 mOsm / Kg, preferably 250 mOsm / Kg to 1500 mOsm / Kg, more preferably 260 mOsm / Kg to 1250 mOsm / Kg, more preferably 265 mOsm / Kg to 1200 mOsm. / Kg, more preferably 400 mOsm / Kg to 1150 mOsm / Kg, more preferably 500 mOsm / Kg to 1100 mOsm / Kg osmolality. Such formulations give drops with an acceptable comfort profile when dropped on the eye.

  In one embodiment, the active agent is an osmotically active agent. In certain embodiments, the pharmaceutical composition comprises a hyperosmotic solution containing an osmotically active agent. The hyperosmotic solution contains a higher concentration of electrolyte than the surrounding environment.

  In certain embodiments, the osmotically active agent is a crystalline osmotic agent. Examples of crystalline osmotic agents include, but are not limited to, sodium chloride (NaCl), dextrose, glycerol, mannitol, sorbitol, sucrose, polyethylene glycol 3350NF, magnesium citrate and lactulose.

  In some embodiments, the crystalline osmotic agent is mannitol. Mannitol is a sugar alcohol body of mannose that occurs naturally in many fruits and vegetables.

  In another embodiment, the crystalline osmotic agent is glycerol. Glycerol is obtained from oils and fats as a by-product of saponification and is frequently used as a solvent in many ophthalmic products and as a component of various products including cosmetics, soaps and lubricants.

  In one particular embodiment, the crystalline osmotic agent is sodium chloride (solution, gel, suspension, or other pharmaceutically acceptable vehicle). In another particular embodiment, the crystalline osmotic agent is glycerol (solution, gel, suspension, or other pharmaceutically acceptable vehicle).

  In yet another embodiment, the crystalline osmotic agent is dextrose. Dextrose is approved for injection in adult and pediatric patients as an electrolyte source, calorie source and hydration water source.

  In yet another embodiment, the crystalline osmotic agent is polyethylene glycol 3350NF.

  In yet another embodiment, the crystalline osmotic agent is magnesium citrate.

  In yet another embodiment, the crystalline osmotic agent is lactulose. Lactulose is a synthetic sugar.

  In certain embodiments, the osmotically active agent is a colloidal osmotic agent. Examples of colloidal osmotic agents include hetastarch, pentastarch, urea cross-linked gelatin polypeptide, dextran 70, dextran 40, albumin, icodextrin, bentonite USP, MgAl silicate NF type 2A, alginic acid / sodium alginate NF, These include, but are not limited to, microcrystalline cellulose and CMC NF, carbomer, and gellan gum.

  In some embodiments, the colloidal osmotic agent is hetastarch. Hetastarch is a plasma extender that is required for the treatment of shock due to fluid loss.

  In yet another embodiment, the colloidal osmotic agent is pentastarch. Like hetastarch, pentastarch is a plasma extender that is needed to treat shock due to fluid loss.

  In yet another embodiment, the colloidal osmotic agent is a combined product of urea cross-linked gelatin polypeptides.

  In yet another embodiment, the colloidal osmotic agent is dextran 70.

  In another embodiment, the colloidal osmotic agent is dextran 40. Like dextran 70, dextran 40 is required for fluid replacement in shock.

  In yet another embodiment, the colloidal osmotic agent is albumin.

  In yet another embodiment, the colloidal osmotic agent is icodextrin. Icodextran is a sucrose derivative that is frequently used for osmotic applications as an alternative to glucose.

  In yet another embodiment, the colloidal osmotic agent is MgAl silicate NF type 2A.

  In yet another embodiment, the colloidal osmotic agent is alginic acid. Alginic acid is a sticky gum isolated from seaweed and can be used as an osmotic agent.

  In yet another embodiment, the colloidal osmotic agent is sodium carboxymethyl cellulose (CMC) NF.

  In yet another embodiment, the colloidal osmotic agent is gellan gum.

  In yet another embodiment, the colloidal osmotic agent is sodium carbomer.

  In yet another embodiment, the colloidal osmotic agent is microcrystalline cellulose.

  There are fundamental differences between colloids and crystalloids in the formulation. Crystalloids are mainly based on sterile aqueous solutions with added electrolytes. Crystalloids are provided in a variety of formulations, ranging from formulations that are hypotonic to plasma to formulations that are isotonic or hypertonic. Colloids are often based on crystalline solutions and thus contain components of water and electrolytes, but colloidal materials (eg, suspensions of particles smaller than 1 millimicron in diameter that do not freely diffuse through a semipermeable membrane) including.

  Other exemplary osmotically active agents contemplated for use in the pharmaceutical compositions of the present invention include magnesium sulfate, magnesium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, calcium bicarbonate, sodium sulfate. , Calcium sulfate, potassium phosphate, calcium lactate, magnesium succinate, tartaric acid, and raffinose, glucose, caffeine, carbomer 934P, tannic acid, ascorbic acid, dextran-40,000, inulin, menthol, polysorbate 80, Compounds such as soluble carbohydrates such as mixtures. In certain embodiments, the effective amount of osmotic agent is from about 0.001% to about 10% w / v caffeine, from about 0.001% to about 10% w / v carbomer 934P, from about 0.001%. About 10% w / v tannic acid, about 0.001% to about 10% w / v ascorbic acid, about 0.001% to about 10% w / v dextran-40,000, about 0.001% to about 10 % W / v inulin, from about 0.001% to about 10% w / v menthol, from about 0.001% to about 10% w / v polysorbate-80, or mixtures thereof.

  In another embodiment, the active agent is an astringent (ie, an agent that specifically contracts tissue). Examples of astringents contemplated for use in the topical pharmaceutical compositions of the present invention include witch hazel, zinc sulfate, silver sulfate, plant tannin, oak bark extract, pentagalloyl glucose, alum, Burow liquid, hawthorn extract , Walnut cherry extract and natural flavonoids, but not limited to.

  In one particular embodiment, the astringent is a witch hazel. Witch hazel is an isolated from herb found in Central and Southern Europe.

  In another particular embodiment, the astringent is zinc sulfate.

  In yet another specific embodiment, the astringent is silver sulfate.

  In yet another embodiment, the active agent is a vasoconstrictor. In certain embodiments, the vasoconstrictor is an alpha-1 adrenergic agent. In another embodiment, the vasoconstrictor is any agent that reduces the vessel diameter and thus prevents leakage. Alpha-1 adrenergic agonists contemplated for use in the topical pharmaceutical compositions of the present invention include, but are not limited to, naphazoline, oxymetazoline, phenylephrine and tetrahydrozoline. In one particular embodiment, the vasoconstrictor contemplated for use in the present invention is naphazoline and the effective amount is from about 0.01% to about 10% w / v, preferably from about 0.01% to about 1 % V, more preferably from about 0.01% to about 0.5% w / v, even more preferably from about 0.01% to about 0.2% w / v, even more preferably from about 0.09%. The range is about 0.1% w / v. In another particular embodiment, the vasoconstrictor contemplated for use in the present invention is oxymetazoline, and the effective amount is from about 0.01% to about 0.2% w / v, more preferably 0. 0.01% to about 0.1% w / v, even more preferably about 0.03% to about 0.05% w / v. In yet another specific embodiment, the vasoconstrictor contemplated for use in the present invention is phenylephrine, and the effective amount is from about 0.01% to about 10% w / v, preferably about 0.01%. To about 1% w / v, more preferably about 0.01% to about 0.5% w / v, even more preferably about 0.05% to about 0.2% w / v.

  In one embodiment, the pharmaceutical composition of the present invention includes both a vasoconstrictor and an osmotically active agent. In one particular embodiment, the pharmaceutical composition of the invention comprises both naphazoline and NaCl. In another specific embodiment, the pharmaceutical composition of the present invention comprises both oxymetazoline and NaCl. In yet another specific embodiment, the pharmaceutical composition of the invention comprises both naphazoline and glycerol. In yet another specific embodiment, the pharmaceutical composition of the present invention comprises both oxymetazoline and glycerol. The extraordinary efficacy of such formulations is due, inter alia, to the synergistic effect of the combination of each component therein, as described in the examples below.

  An effective amount of the active agent can be present in the composition at a dose ranging from about 0.001% to about 100.0% w / v. For example, an effective amount of each active agent is about 0.001% to about 0.01% w / v, about 0.01% to about 0.100% w / v, about 0.100% to about 1.0. % W / v, about 1.00% to about 10.00% w / v, or about 10% to about 100% w / v.

  The effective amount of active agent present in the formulations of the present invention depends on the nature of the active agent (s) used, i.e., drug absorption, deactivation and elimination rates, compound delivery rates, and drug One skilled in the art will recognize that it can vary depending on factors including, but not limited to, one or more combinations. For example, an effective amount of sodium chloride ranges from about 1% to about 10% w / v, preferably from about 1% to about 6% w / v, more preferably from about 2% to about 5% w / v. . Effective amounts of dextrose range from about 1% to about 10% w / v, preferably from about 1% to about 6% w / v, more preferably from about 2% to about 5% w / v. An effective amount of sucrose is about 1% to about 95% w / v, preferably about 10% to about 90% w / v, more preferably about 20% to about 80% w / v, even more preferably about 30 % To about 70% w / v. An effective amount of glycerol is about 1% to about 30% w / v, preferably 1% to about 20% w / v, more preferably about 1% to about 10% w / v, even more preferably about 5%. To about 8% w / v. Effective amounts of mannitol range from about 1% to about 30% w / v, preferably from about 1% to about 20% w / v, more preferably from about 10% to about 15% w / v. An effective amount of sorbitol is about 1% to about 100% w / v, preferably about 10% to about 90% w / v, more preferably about 20% to about 80% w / v, even more preferably about 30 % To about 70% w / v. An effective amount of hetastarch ranges from about 1% to about 20% w / v, preferably from about 1% to about 10% w / v, more preferably from about 4% to about 6% w / v. Effective amounts of pentastarch range from about 1% to about 20% w / v, preferably from about 5% to about 15% w / v, more preferably from about 5% to about 10% w / v. Effective amounts of dextran 70 range from about 1% to about 20% w / v, preferably from about 1% to about 10% w / v, more preferably from about 4% to about 6% w / v. An effective amount of dextran 40 ranges from about 1% to about 20% w / v, preferably from about 1% to about 10% w / v, more preferably from about 4% to about 6% w / v. An effective amount of albumin ranges from about 10% to about 50% w / v, preferably from about 15% to about 30% w / v, more preferably from about 20% to 30% w / v albumin.

  The initial excess of solid solute can be in any suitable physical form such as particles, crystals, pellets, tablets, strips, films, granules and the like.

  In certain embodiments, the pharmaceutical composition of the present invention comprises a combination of one or more active agents selected from osmotic agents, vasoconstrictors and / or astringents, and additional vasoconstrictors, tear substitutes. An effective amount of another agent or agents, such as an antiallergic agent, antihistamine, mast cell stabilizer, NSAID, steroid, anti-inflammatory agent, antioxidant, anti-infective agent, cholinergic agent, or combinations thereof Including. The drug combination acts synergistically to reduce eyelid swelling.

  Exemplary vasoconstrictors contemplated for use in the pharmaceutical compositions of the present invention include, but are not limited to, naphazoline, antolazine, tetrahydrazoline, oxymetazoline, and phenylephrine. In addition to reducing eyelid swelling, vasoconstrictors can also act as decongestants. In certain embodiments, the effective amount of vasoconstrictor is about 0.01% to about 10% w / v, preferably about 0.01% to about 1% w / v, more preferably about 0.01%. To about 0.5% w / v, even more preferably in the range of about 0.01% to about 0.2% w / v. In one particular embodiment, the vasoconstrictor contemplated for use in the present invention is naphazoline and the effective amount is from about 0.01% to about 10% w / v, preferably from about 0.01% to about 1% w / v, more preferably from about 0.01% to about 0.5% w / v, even more preferably from about 0.01% to about 0.2% w / v, even more preferably from about 0. The range is 09% to about 0.1% w / v. In another particular embodiment, the vasoconstrictor contemplated for use in the present invention is oxymetazoline, and the effective amount is from about 0.01% to about 0.2% w / v, more preferably 0. 0.01% to about 0.1% w / v, even more preferably about 0.03% to about 0.05% w / v. In yet another specific embodiment, the vasoconstrictor contemplated for use in the present invention is phenylephrine, and the effective amount is from about 0.01% to about 10% w / v, preferably about 0.01%. To about 1% w / v, more preferably about 0.01% to about 0.5% w / v, even more preferably about 0.05% to about 0.2% w / v.

  Various tear substitutes are known in the art, including but not limited to the following, and can be used in the compositions of the present invention: glycerol, glycerol, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, Propylene glycol and polyols such as ethylene glycol, polyvinyl alcohol, povidone, polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose (also known as hypromellose); Dextran; water-soluble protein such as gelatin; carbomer 934P, carbomer 941, carbomer 9 And HP- rubbers such as guar; 0, carbomer, such as Carbomer 974P. A number of such tear substitutes are commercially available, such as Bion Tears (R), Cellubisc (R), Geneal (R), OccuCoat (R), Refresh (R) ), Teargen II (registered trademark), Tears Naturale (registered trademark), Tears Naturale 118 (registered trademark), Tears Naturale Free (registered trademark), TeraTears (registered trademark), and ester esters of Akwa Tears (registered trademark). Polyvinyl alcohol such as HypoTears (registered trademark), Moisture Eyes (registered trademark), Murine Lubricatin (registered trademark), Visine Tears (registered trademark) But is not limited to that. The tear substitute can also be composed of paraffin such as a commercially available Lacri-Lube® ointment. Other commercially available ointments used as tear substitutes include Lubrfresh PM®, Moisture Eyes PM® and Refresh PM®.

  In a preferred embodiment, the tear substitute or one or more components thereof has a viscosity in a range that optimizes the ability to support the tear film while minimizing blurring, lid caking, and the like. An aqueous solution having Preferably, the viscosity of the tear substitute or one or more of its components is in the range of 30 to 150 centipoise (cpi), preferably 30 to 130 cpi, more preferably 50 to 120 cpi, and even more preferably 60 to 115 cpi (or Any particular value within that range). In one particular embodiment, the viscosity of the tear substitute or one or more components thereof is about 70-90 cpi, or any particular value within the range (eg, but not limited to, 85 cpi). .

The viscosity of the ophthalmic formulation of the present invention can be measured according to standard methods known in the art such as the use of viscometers or rheometers. One skilled in the art will recognize that factors such as temperature, shear rate, etc. can result in viscosity measurements. In one particular embodiment, the ophthalmic formulation of the present invention has a viscosity of 20 ° C. + / − 1 ° C. using a Brookfield Cone and Plate Viscometer Model VDV-III Ultra ⁺ using CP40 or an equivalent spindle. Using a SC4-18 or equivalent spindle at a shear rate of about 22.50 +/− about 10 (1 / sec) or using a Brookfield Viscometer Model LVDV-E. (1 / sec)).

  In some embodiments, the tear substitute or one or more components thereof is pH 5.0 to 9.0, preferably pH 5.5 to 8. using a suitable salt (eg, phosphate). 5, more preferably buffered to pH 6 to 8 (or any specific value within the range). In some embodiments, the tear substitute further comprises one or more ingredients, including but not limited to glycerol, propylene glycerol, glycine, sodium borate, magnesium chloride, and zinc chloride.

  In one preferred embodiment of the invention, the tear substitute comprises hydroxypropylmethylcellulose. For example, but not limited to, a tear substitute containing hydroxypropyl methylcellulose is GenTeal® lubricating eye drops. GenTeal® (CibaVision-Novatis) is a sterile lubricating eye drop containing 3 mg / g of hydroxypropylmethylcellulose and stored with sodium perborate. Another example of HPMC tears is described.

  In another preferred embodiment, the tear substitute comprises sodium carboxymethylcellulose. For example, but not limited to, a tear substitute containing sodium carboxymethylcellulose is Refresh® Tears. Refresh (R) Tears can be applied to normal tears, including a stabilized oxychloro complex (Purite (TM)), which is a mild non-sensitizing preservative that eventually transforms into a natural tear component upon use. Similar lubricant formulation.

  Exemplary NSAIDs suitable for use in the compositions of the present invention include all esters and pharmaceutically acceptable salts thereof, including ampenac, propionic acids (naproxen, flurbiprofen, oxaprozin, ibuprofen, ketoprofen. , Phenoprofen, etc.); ketorolac tromethamine (Acular®) (and its related parts, incorporated herein by reference, Waterbury, U.S. Pat. No. 4, issued June 12, 1984). Other compounds described as ophthalmologically effective in US Pat. No. 454,151); acetic acid derivatives such as sulindac, indomethacin, etodolac; diclofenac (Voltaren®) (and related parts herein by reference) Issued on October 2, 1990. agy, other compounds described as ophthalmologically effective in US Pat. No. 4,960,799), phenylacetic acids such as bromfenac, suprofen; arylacetic acid prodrugs such as nepafenac; aspirin, salsalate, diflunisal, Salicylic acid such as choline magnesium trisalicylate (CMT); para-aminophenol derivatives such as acetaminophen; naphthyl alkanones such as nabumetone; enolic acid derivatives such as piroxicam and meloxicam; mefenamic acid, meclofenamic acid, flufenam Femanates such as acids; pyrrole acetic acids such as tolmetine; and pyrazolones such as phenylbutazone; celecoxib, valdecoxib, parecoxib, etoroxixib, ruari COX-2 selective inhibitors such as Kishibu (luaricoxib) include but are but are not limited to.

  Exemplary antihistamines include, but are not limited to, pheniramine, antazoline, emedastine fumarate, ebastine, calebastine, levocabastine, cetirizine and pharmaceutically active salts thereof.

  Exemplary mast cell stabilizers include, but are not limited to, nedocromil, rhodoxamide, pemirolast, cromolyn, cromolyn sodium and pharmaceutically active salts thereof.

  Exemplary drugs having multiple modes of action include, but are not limited to, azelastine, epinastine, olopatadine, ketotifen fumarate, bilastine, bepotastine, mizolastine, and pharmaceutically active salts thereof.

  The one or more active agents of the pharmaceutical composition can be in the form of a pharmaceutically acceptable salt.

  Pharmaceutical compositions include solutions, suspensions, oils, viscous or semi-viscous gels, emulsions, liposomes, lotions, ointments, including the formulations described in US Pat. No. 6,806,364. Creams, gels, salves, powders, and sustained or slow release as well as eye lotions or other types of solid or semi-solid compositions can be formulated for topical administration. The composition can also be administered topically in a sprayable or nebulizer form.

  Preferably, the pharmaceutical composition is a gel for controlled or sustained release of one or more pharmaceutically active agents (eg, osmotically active agents or vasoconstrictors or combinations thereof). The preparation can be an aqueous preparation that can be gelled in situ. Such formulations comprise a gelling agent at a concentration effective to promote gelation immediately after contact with the eye or with tears outside the eye. Suitable gelling agents include thermosetting polymers such as tetrasubstituted ethylenediamine block copolymers of ethylene oxide and propylene oxide (eg, poloxamine), polycarbophil, and gellan, carrageenan (eg, kappa-carrageenan and iota-carrageenan). ), Polysaccharides such as chitosan and alginic acid gum, but are not limited thereto.

  As used herein, the phrase “in situ gelable” refers to not only the low viscosity liquid that forms a gel immediately after contact with the eye, or tears outside the eye, but also the viscosity or Also included are more viscous liquids such as semi-fluid gels, thixotropic gels, where the gel stiffness is significantly increased. Such formulations preferably have a further increase in viscosity or gel stiffness after administration, which is sufficiently resistant to disintegration of the initial gel by tearing resulting in an effective residence time as specified herein. If it is sex, it is not absolutely necessary.

  Sustained release ophthalmic formulations of highly viscous gels are described in US Pat. Nos. 4,271,143 and 4,407,792. In addition, GB-A-2007091 (A) describes an ophthalmic composition in the form of a gel comprising a carboxyvinyl polymer, a water-soluble basic substance and an aqueous solution of an ophthalmic drug. Alternatively, US Pat. No. 4,615,697 discloses controlled release compositions and methods of use based on bioadhesives and therapeutic agents.

  In certain embodiments, the pharmaceutical composition according to the invention can be formulated as a hyperosmotic solution for topical administration. Aqueous solutions are easy to formulate and are easily administered by the patient by dropping one or two drops of solution into the affected eye.

  Water, mixtures of water and water miscible solvents such as, but not limited to, C1 to C7 alkanols, vegetable or mineral oils containing 0.5 to 5% non-toxic water soluble polymers, gelatin, alginate, pectin, tragacanth, karaya gum, xanthan gum Natural products such as carrageenin, agar, and gum arabic, starch derivatives such as starch acetate and hydroxypropyl starch, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid such as neutral Carbopol, etc. Any of a variety of carriers can be used in the formulations of the present invention, including other synthetic products such as mixtures of polymers. The carrier concentration is typically 1 to 100,000 times the active ingredient concentration.

  Additional ingredients that can be included in the formulation include tonicity enhancing agents, preservatives, solubilizers, non-toxic excipients, demulcents, sequestering agents, pH adjusting agents, cosolvents and viscosity increasing agents. .

Buffers may be particularly useful for pH adjustment, preferably to adjust to physiological pH. The pH of the solution should be maintained within the range of 4.0 to 8.0, more preferably about 4.0 to 6.0, more preferably about 6.5 to 7.8. Boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, various mixed phosphate buffers (including combinations of Na ₂ HPO ₄ , NaH ₂ PO ₄ and KH ₂ PO ₄ ), Appropriate buffers such as, but not limited to, mixtures can be added. Generally, the buffering agent is used in an amount of about 0.05 to 2.5 weight percent, preferably 0.1 to 1.5 percent.

Tonicity is adjusted as needed, typically by tonicity enhancing agents. Such agents can be, for example, ionic and / or non-ionic types. Examples of ionic tonicity enhancing agents are, for _{example, CaCl 2, KBr, KCl,} LiCl, NaI, NaBr, or an alkali metal or alkaline earth metal halides such as _NaCl, is a Na 2 SO4 or boric acid include, but limited Not. Nonionic tonicity enhancing agents are, for example, urea, glycerol, sorbitol, mannitol, propylene glycol or dextrose. These agents can also serve as active agents in certain embodiments. In certain embodiments, these agents may also help regulate osmolality.

  To be osmotic activity, the osmolality of the solution must be higher than the osmolality of its surrounding environment. The osmolality of the human tear film ranges from about 250-350 mOsm / Kg in the average human eye to individuals with eye disease, including but not limited to dry eye disease (having a maximum value above 700 mOsm / Kg) Averages up to about 450 mOsm / Kg. Therefore, in order to exert a therapeutic effect and suppress edema, the osmolality of the ophthalmic solution must be limited to the minimum osmolality of the human eye environment (ie, about 250 to 450 mOsm / Kg). I must. However, with increasing osmolality, discomfort after instillation increases. High concentrations of ions can activate nerve endings and thus cause stinging pain in the eyeball. Through comfort testing, it has been discovered that in order to have an acceptable or tolerable comfort profile, the ophthalmic solution should have an osmolality from less than 2000 mOsm / Kg, more preferably from less than 1050 mOsm / Kg. It was done. Accordingly, the target osmolality range of drops prescribed for the treatment of eyelid swelling is preferably within 200 and 2000 mOsm / Kg, preferably 250 mOsm / Kg to 1500 mOsm / Kg, more preferably 260 mOsm / Kg to 1250 mOsm. / Kg, more preferably 265 mOsm / Kg to 1200 mOsm / Kg, more preferably 400 mOsm / Kg to 1150 mOsm / Kg, more preferably 500 mOsm / Kg to 1100 mOsm / Kg.

In certain embodiments, the topical formulation further comprises a preservative. Preservatives are typically benzalkonium chloride (N- Benzyl _-N- (C 8 _{-C 18} alkyl) -N, N-dimethyl ammonium chloride), the quaternary ammonium compounds such as chlorides benzoxonium bromide You can choose. Examples of preservatives different from quaternary ammonium salts are alkyl-mercury salts of thiosalicylic acid, such as thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, sodium perborate, sodium chlorite, parabens. For example, methylparaben or propylparaben, alcohols such as chlorobutanol, benzyl alcohol or phenylethanol, guanidine derivatives such as chlorohexidine or polyhexamethylene biguanide, sodium perborate, Germal® II, or sorbic acid . Preferred preservatives are quaternary ammonium compounds, especially benzalkonium chloride or its derivatives such as Polyquad (see US Pat. No. 4,407,791), alkyl-mercury salts and parabens. If necessary, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection against secondary contamination during use due to bacteria and fungi.

  In another embodiment, the topical formulations of the present invention do not contain preservatives. Such formulations can be used for patients wearing contact lenses, or patients using some topical eye drops, and / or already impaired ocular surfaces where it may be more desirable to limit exposure to preservatives (e.g. Useful for patients with dry eye).

  Topical formulations may further require the presence of solubilizers, particularly where the active or inactive ingredients tend to form suspensions or emulsions. Suitable solubilizers for the above composition are, for example, tyloxapol, fatty acid glycerol polyethylene glycol ester, fatty acid polyethylene glycol ester, polyethylene glycol, glycerol ether, cyclodextrin (eg alpha-, beta- or gamma-cyclodextrin, eg Alkylated, hydroxyalkylated, carboxyalkylated or alkyloxycarbonyl-alkylated derivatives, or mono- or diglycosyl-alpha-, beta- or gamma-cyclodextrin, mono- or dimaltosyl-alpha-, beta- or gamma-cyclo Dextrin or panosyl-cyclodextrin), polysorbate 20, polysorbate 80 or a mixture of these compounds It is selected from. Specific examples of particularly preferred solubilizers are the reaction products of castor oil and ethylene oxide, such as the commercial product Cremophor EL® or Cremophor RH40®. The reaction product of castor oil and ethylene oxide has been found to be a particularly good solubilizer that is very well tolerated by the eye. Another preferred solubilizer is selected from tyloxapol and cyclodextrin. The concentration used depends in particular on the active ingredient concentration. The amount added is typically sufficient to solubilize the active ingredient. For example, the solubilizer concentration is 0.1 to 5000 times the active ingredient concentration.

  The formulation comprises further non-toxic excipients, for example emulsifiers, wetting agents or fillers, for example polyethylene glycols designated 200, 300, 400 and 600 or Carbowax designated 1000, 1500, 4000, 6000 and 10000. be able to. The amount and type of excipient added is generally in the range of about 0.0001 to about 90% by weight, according to individual requirements.

Other compounds can also be added to the formulations of the present invention to increase the carrier viscosity. Examples of viscosity increasing agents include, but are not limited to, hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, polysaccharides such as various polymers of the cellulose family, vinyl polymers, and acrylic acid polymers. Method of Use The present invention features a method of treating and preventing eyelid swelling in a subject comprising the use of the novel formulation described above. For example, a method of treating eyelid swelling involves administering a pharmaceutical composition comprising an effective amount of an osmotically active agent and / or a vasoconstrictor and / or an astringent to the ocular surface of a subject in a pharmaceutically acceptable carrier. Including doing. As another example, a method of treating eyelid swelling may include a pharmaceutical composition comprising an effective amount of an osmotically active agent and / or a vasoconstrictor and / or an astringent in a pharmaceutically acceptable carrier. And / or administration to the inner eyelid surface or the eyeball surface. In one particular embodiment, a method of treating eyelid swelling comprises applying a pharmaceutical composition comprising an effective amount of a combination of an osmotically active agent and a vasoconstrictor to the outer and / or inner eyelid surface or eyeball surface of a subject. Administration. Various embodiments of such formulations suitable for use in the methods of the present invention are described above.

  In various embodiments, the composition comprises an emulsion or suspension, liposome, lotion, ointment, cream, gel, salve or powder, including the formulations described in US Pat. No. 6,806,364. And can be administered in the form of sustained or slow release, as well as an eye lotion, or another type of solid or semi-solid composition. The composition can also be used as an eye wash or rinse to irrigate the eye. The composition can also be administered in a sprayable form.

  The effective amount of osmotically active agent and / or vasoconstrictor and / or astringent in the formulation depends on the rate of drug absorption, deactivation and excretion, and the delivery rate of the compound from the formulation. In certain embodiments comprising an osmotically active agent, the effective amount also depends on the concentration of drug required to make the formulation a highly osmotic solution.

  The present invention provides target osmolarity and / or osmolality ranges of ophthalmic compositions for treating eyelid swelling. One skilled in the art will recognize that the terms osmolarity and osmolality are essentially equivalent as applied to the composition of the present invention when the composition concentration, such as the concentration of the composition of the present invention, is very low. It will be readily recognized that they are used interchangeably herein. In order to have an acceptable or tolerable comfort profile throughout the comfort test, the ophthalmic solution has an osmolality and / or osmolality from less than 2000 mOsm / Kg, more preferably less than 1050 mOsm / Kg. It was discovered that it should be. Accordingly, the target osmolality range of drops prescribed for the treatment of eyelid swelling is preferably within 200 and 2000 mOsm / Kg, preferably 250 mOsm / Kg to 1500 mOsm / Kg, more preferably 260 mOsm / Kg to 1250 mOsm. / Kg, more preferably 265 mOsm / Kg to 1200 mOsm / Kg, more preferably 400 mOsm / Kg to 1150 mOsm / Kg, more preferably 500 mOsm / Kg to 1100 mOsm / Kg.

  Note that the dosage may also vary depending on the severity of the symptoms to be alleviated. In addition, for any particular subject, it should be understood that the specific dosage regimen should be adjusted over time according to individual requirements and the professional judgment of the person administering or administering the composition. Typically, dosing is determined using techniques known to those skilled in the art.

  The dosage of any compound of the present invention depends on the patient's symptoms, age and other physical characteristics, the nature and severity of the disorder to be treated or prevented, the desired comfort, the route of administration, and the form of the adjuvant. change. Any of the subject formulations can be administered in a single dose or in divided doses. The dosage of the formulations of the present invention can be readily determined by techniques known to those skilled in the art or according to the teachings herein.

  Any possible effect on the effective amount or amount and timing of administration of the formulation may need to be confirmed for any particular formulation of the invention. This can be done by routine experiment as described herein. The effectiveness of any formulation and method of treatment or prevention may be determined by administering the formulation and measuring one or more indices related to drug efficacy and patient comfort, as described herein. And by comparing the post-treatment values of these indices with the same index values before treatment, or by comparing the post-treatment values of these indices with the same index values using different formulations Can be evaluated.

  The exact time and amount of any particular formulation that gives the most effective treatment in a given patient depends on the activity, pharmacokinetics and bioavailability of the particular compound (age, gender, disease type and It depends on the patient's physiological conditions (including stage, general physical condition, responsiveness to a given dose and type of drug), route of administration, etc. The guidelines provided herein can be used to optimize treatment, eg, determine the optimal time and / or amount of administration. This requires only routine experimentation consisting of monitoring the subject and adjusting dose and / or timing.

  The combination of several drugs formulated in the composition of the present invention can reduce the required dosage of any individual component, since the onset and duration of the effects of the different components can be complimentary. it can. In such combination therapy, different drugs can be delivered together or separately, simultaneously or at different times of the day.

  The efficacy of the formulations and compositions of the present invention in the treatment and prevention of eyelid swelling can be measured by ruler, subjective grade (eg, but not limited to mild, moderate, severe, or 0, 1, 2, or 3 or subjective clinical grade determined as another suitable grade), and assessment by measuring changes in eyelid swelling using various methods, including but not limited to scanning techniques it can. In a preferred embodiment, changes in eyelid swelling are assessed using 3D scanning techniques. By using 3D scanning techniques, daily variations in eyelid swelling that were not accurately measured previously can be quantified to assess the reduction in eyelid swelling using the various formulations of the present invention. .

5. Packaging The formulations of the present invention can be packaged as either a single dose product or a multiple dose product. Single dose products are sterile before opening the package, and all of the compositions in the package are intended to be consumed in a single dose in one or both eyes of the patient. The use of antimicrobial preservatives that maintain the sterility of the composition after opening the package is generally unnecessary.

Multi-dose products are also sterile before opening the package. However, since the container of the composition can be opened many times before all of the composition in the container is consumed, a multi-dose product ensures that the composition is microbial as a result of repeated opening and handling of the container. Must have sufficient antibacterial activity to prevent contamination. The level of antibacterial activity required for this purpose is well known to those skilled in the art and is published in official publications such as the US Pharmacopoeia ("USP"), other publications by the US Food and Drug Administration, and corresponding in other countries. It is clearly stated in the publication. Detailed descriptions of storage specifications for ophthalmic pharmaceuticals against microbial contamination and procedures for assessing the preservative efficacy of specific formulations are described in these publications. In the United States, preservative efficacy standards are commonly referred to as “USP PET” requirements. (The acronym “PET (preservative efficacy testing)” stands for “preservative efficacy test”.)
By using a single dose packaging system, antimicrobial preservatives in the composition are not required. This is a considerable advantage from a medical point of view. This is because conventional antibacterial agents (eg, benzalkonium chloride) used to preserve ophthalmic compositions can cause ocular inflammation, particularly in patients with dry eye symptoms or previous ocular inflammation. It is. However, currently available single dose packaging systems such as small plastic vials prepared by a process known as “molding, filling and sealing” have several drawbacks for manufacturers and consumers. A major drawback of single dose packaging systems is that they require much larger amounts of packaging material and are inconvenient for the consumer. Larger amounts of packaging material are wasteful and expensive. In addition, there is a risk that the consumer will not discard the single dose container after administering one or two drops to the eye. The consumer is instructed to discard, but instead saves the open container and the composition remaining therein for later use. This improper use of single dose products creates the risk of microbial contamination of single dose products and the associated risk of eye infection when contaminated compositions are administered to the eye.

  The formulations of the present invention are preferably formulated as “ready-to-use” aqueous solutions, although other formulations are contemplated within the scope of the present invention. Thus, for example, the active ingredients, surfactants, salts, chelating agents or other ingredients of ophthalmic solutions, or mixtures thereof can be lyophilized or provided with dissolved (eg, deionized or distilled) water Can be provided as a dry powder or tablet. Sterile water is not required due to the self-preserving nature of the solution.

6). Kits In yet another embodiment, the present invention provides kits for packaging and / or storing and / or using the formulations described herein, and kits for performing the methods described herein. I will provide a. Thus, for example, a kit can include one or more containers containing one or more ophthalmic preparations, tablets, or capsules of the present invention. The kit can be designed to facilitate one or more aspects of transport, use and storage.

  The kit can optionally include instructional material including guidance (ie, a protocol) that indicates how to use the formulation provided therein. The instructional materials typically include, but are not limited to, written or printed materials. Any medium capable of storing such instructions and communicating them to the end user is contemplated by the present invention. Such media include, but are not limited to, electronic storage media (eg, magnetic disks, tapes, cartridges, chips) and optical media (eg, CD ROM). Such media may include addresses to internal sites that provide such instructional materials.

  The invention as outlined can be more easily understood by reference to the following examples. The following examples are merely illustrative of certain aspects and embodiments of the present invention and are not intended to limit the present invention in any way.

Example 1
Use of 0.1% Naphazoline Ophthalmic Solution as a Treatment for Morning Eyelid Edema This study evaluated the efficacy of 0.1% naphazoline ophthalmic solution for the treatment of eyelid edema. The eyelid volume of the 11 subjects who participated in the study was recorded in the afternoon of the first day and also immediately after arrival at the clinic the next morning (second day). All subjects showed increased eyelid swelling on the second morning scan of the visit. The natural progression of eyelid swelling in the morning measured using 3D scanning technique is shown in FIG. Increase was in the range of 14mm ³ of 659mm ^3. Then, 0.1% naphazoline (vasoconstrictor) was administered to the subject's right eye, and eyelid volume was evaluated using a 3D scanner at 5, 10, 15, 30, and 120 minutes after treatment. As shown in FIG. 3, two drops of 0.1% naphazoline solution reduced eyelid swelling in most subjects. Nine of the eleven subjects showed a greater volume reduction in treated eyes (0.1% naphazoline) than untreated eyes up to 30 minutes (FIGS. 3B-E, G-K). Up to 120 minutes, 7 out of 11 subjects showed a greater volume reduction in the right eye than in the left eye (FIGS. 3B, C, E, GI, K). A summary of all patient data is shown in FIG. 3L.

  Overall, these results reduce eyelid swelling in patients with morning eyelid swelling rather than diseased eyes or eyes with ongoing vasodilation where vasoconstrictors are typically used The efficacy of 0.1% naphazoline on ability was demonstrated.

(Example 2)
Use of colloidal osmotic agent, 5% NaCl ophthalmic solution for treatment of morning eyelid edema Evaluate 5% NaCl ophthalmic solution as a candidate for treatment of eyelid edema in a preliminary study with a design similar to the above did. Topical administration of 2 drops of drug reduced eyelid swelling in several patients (FIG. 4). Eyelid swelling was assessed using a 3D scanner at 5, 10, 15, 20, 30 and 120 minutes after treatment. In three patients, eyelid swelling decreased for 15 minutes after instillation. In one subject, this decrease was significant and existed until the 120 minute evaluation time point. The treatment was not effective in the remaining 3 patients.

  Overall, these results demonstrated some efficacy of 5% NaCl on the ability to reduce eyelid swelling in certain patients. Assessment of mean change from baseline (Figure 4G) suggests that NaCl treatment was numerically superior to the negative control, but that the difference was not statistically significant in this small trial. .

  Furthermore, 0.1% naphazoline in combination with 5% NaCl exhibits superior efficacy in reducing eyelid swelling in patients compared to the individual components 0.1% naphazoline alone and 5% NaCl alone (FIG. 5). 7).

(Example 3)
Use of 0.05% naphazoline / 5% NaCl ointment for the treatment of morning eyelid edema The efficacy of 0.05% naphazoline hydrochloride eye ointment dissolved in 5% NaCl in preventing morning eyelid swelling Of patients. Each patient and each eye was scanned 3D from 4:30 PM to 5:30 PM. Each patient was asked to bring home a vial containing 5% NaCl eye ointment containing 0.05% naphazoline hydrochloride and apply the ointment to the conjunctival sac of the right eye just before sleep. The next morning, from 7:30 am to 8:00 am, each patient eye was scanned again. The average volume of the upper and lower eyelid area was calculated for both afternoon and morning scans for each patient. The difference between each average was also calculated. As a result, the treated eye was about half as swollen as the untreated eye (FIG. 8).

  The final formulation used in this study was 5% sodium chloride in lanolin, mineral oil, purified water, white petrolatum, and 0.05% naphazoline hydrochloride.

Example 4
Use of sodium chloride (2.5%) / naphazoline (0.1%) and sodium chloride (5%) / naphazoline (0.1%) for the treatment of morning eyelid edema Treatment of morning eyelid swelling The efficacy of 0.1% naphazoline in combination with 2.5% sodium chloride solution in and / or prevention was evaluated by measuring by 3D scanning technique.

  2.5% sodium chloride was formulated with water. Naphazoline was then dissolved in 2.5% NaCl solution to formulate 0.1% naphazoline.

  A total of 6 subjects (men aged 25 to 29) were evaluated. At the start of the test, 5 baseline scans were performed using a 3D scanner per subject and eye. The next day, the subject was then asked to take 5 scans of each eye, the same as the first visit.

  Subjects received 2 drops (40 μl each) of combination therapy at 1 minute intervals in one eye and the other eye was untreated. 20 minutes after the second instillation, each eye was scanned 5 times as in the first visit. Subjects were asked to grade their eyelid swelling after treatment subjectively based on a comfort rating of 0 to 10 (0 being most comfortable and 10 being most uncomfortable). ). Digital photographs were also taken at baseline and 20 minutes after treatment.

The average comfort level immediately after instillation was 3.3. The average mean eyelid volume increase in the morning was 243 and 309 mm ³ for the right and left eyes, respectively. The mean reduction of 20 minutes after treatment was −100 and −14 mm ³ for the treated and untreated eyes, respectively.

  These results suggest that 2.5% NaCl in combination with 0.1% naphazoline indeed reduced morning eyelid swelling (FIG. 9). 2.5% NaCl was less effective (about half) compared to 5% NaCl combined with 0.1% naphazoline (see FIGS. 6 and 9). This suggests that the efficacy of NaCl in the treatment of morning eyelid swelling is directly related to concentration.

  In terms of comfort level, 2.5% NaCl was more comfortable than 5% NaCl. This is an improvement. The average comfort level (3.3) for this study was more comfortable than the 5% NaCl / 0.1% naphazoline combination (5.8).

(Example 5)
Use of 50% sucrose and naphazoline (0.1%) for the treatment of morning eyelid edema of naphazoline (0.1%) in combination with a 50% sucrose solution in the treatment and / or prevention of morning eyelid swelling Efficacy was measured and evaluated by 3D scanning technique.

  Sucrose was formulated with water to a 50% concentration. Naphazoline was then dissolved in the sucrose solution to formulate a naphazoline (0.1%) concentration.

  A total of 6 subjects were evaluated. The method was similar to the above experiment. At the start of the test, 5 baseline scans were performed using a 3D scanner per subject and eye. The next day, the subject was then asked to take 5 scans of each eye, the same as the first visit.

  Subjects received 2 drops (40 μl each) of combination therapy at 1 minute intervals in one eye and the other eye was untreated. 20 minutes after the second instillation, each eye was scanned 5 times as in the first visit. Subjects were asked to grade their eyelid swelling after treatment subjectively based on a comfort rating of 0 to 10 (0 being most comfortable and 10 being most uncomfortable). ). Digital photographs were also taken at baseline and 20 minutes after treatment.

  These results suggest that the 50% sucrose / 0.1% naphazoline formulation indeed reduced morning eyelid swelling (FIG. 10). Furthermore, 50% sucrose in combination with 0.1% naphazoline shows superior efficacy in reducing eyelid swelling in patients compared to the individual components 50% sucrose alone and 0.1% naphazoline alone (FIGS. 11A and 11A). 11B). The average comfort of the test group was 5.2.

(Example 6)
Use of topical 0.25% phenylephrine ointment for treatment of morning eyelid edema The efficacy of topical 0.25% phenylephrine ointment to treat and / or prevent morning eyelid swelling was measured by 3D scanning technique. And evaluated.

  A total of 6 subjects were evaluated. The method was similar to the above experiment. At the start of the test, 5 baseline scans were performed using a 3D scanner per subject and eye. The next day, the subject was then asked to take 5 scans of each eye, the same as the first visit.

  Subjects received 2 drops (40 μl each) of combination therapy at 1 minute intervals in one eye and the other eye was untreated. 20 minutes after the second instillation, each eye was scanned 5 times as in the first visit. Subjects were asked to grade eyelid swelling after treatment. Digital photographs were also taken at baseline and 20 minutes after treatment.

  These results suggest that 0.25% phenylephrine ointment topically applied to the lower eyelid did indeed reduce morning eyelid swelling (FIG. 13).

(Example 7)
Use of 12.5% mannitol and 0.1% naphazoline and 5% NaCl solution for the treatment of morning eyelid edema 12. In 5% NaCl solution to treat and / or prevent morning eyelid swelling. The efficacy of 5% mannitol and 0.1% naphazoline was assessed by measuring by 3D scanning technique.

  A total of 6 subjects were evaluated. The method was similar to the above experiment. At the start of the test, 5 baseline scans were performed using a 3D scanner per subject and eye. The next day, the subject was then asked to take 5 scans of each eye, the same as the first visit.

  Subjects received 2 drops (40 μl each) of combination therapy at 1 minute intervals in one eye and the other eye was untreated. 20 minutes after the second instillation, each eye was scanned 5 times as in the first visit. Subjects were asked to grade eyelid swelling after treatment. Digital photographs were also taken at baseline and 20 minutes after treatment.

  These results suggest that the mannitol / naphazoline / NaCl combination indeed reduced morning eyelid swelling (FIG. 14).

(Example 8)
Use of 12.5% mannitol solution for the treatment of morning eyelid edema The efficacy of 12.5% mannitol solution for treating and / or preventing morning eyelid swelling is measured and measured by 3D scanning technique did.

  A total of 6 subjects were evaluated. The method was similar to the above experiment. At the start of the test, 5 baseline scans were performed using a 3D scanner per subject and eye. The next day, the subject was then asked to take 5 scans of each eye, the same as the first visit.

  Subjects received 2 drops (40 μl each) of combination therapy at 1 minute intervals in one eye and the other eye was untreated. 20 minutes after the second instillation, each eye was scanned 5 times as in the first visit. Subjects were asked to grade eyelid swelling after treatment. Digital photographs were also taken at baseline and 20 minutes after treatment.

  These results suggest that the 12.5% mannitol solution indeed reduced morning eyelid swelling (FIG. 15).

  16A and 16B summarize the test results described in Examples 1-8, as described in Examples 1-8 compared to the individual drugs used alone in the treatment of morning eyelid swelling. It shows the excellent efficacy of the mixed preparation. According to these results, the mixed preparations were each effective in reducing eyelid swelling, and in most cases, the mixed preparations produced synergistic effects compared to the individual drugs alone.

Example 9
Use of 50% sucrose solution for the treatment of morning eyelid edema The efficacy of sucrose (50%) to treat and / or prevent morning eyelid swelling was measured and measured by a 3D scanning technique.

  A total of 6 subjects were evaluated. The method was similar to the above experiment. At the start of the test, 5 baseline scans were performed using a 3D scanner per subject and eye. The next day, the subject was then asked to take 5 scans of each eye, the same as the first visit.

  Subjects received 2 drops (40 μl each) of combination therapy at 1 minute intervals in one eye and the other eye was untreated. 20 minutes after the second instillation, each eye was scanned 5 times as in the first visit. The subjects were also asked to grade their eyelid swelling after treatment subjectively based on a comfort rating of 0 to 10 (0 indicates the most comfortable and 10 indicates the most uncomfortable) .) These results suggest that the 50% sucrose solution minimized morning eyelid swelling (FIG. 17). The average comfort of the test group was 4.5.

(Example 10)
Osmolality and comfort The correlation between the osmolality of the test substance and the comfort was evaluated, and any relationship was found. The table shown in FIG. 18A shows the corresponding osmolality values and the average comfort level immediately after instillation of each test article (0 indicates the most comfortable based on a subjective rating of 0 to 10, 10 indicates Shows the most unpleasant.)

  Without being bound by any theory, these results suggest a direct relationship between osmolality and comfort, with higher osmolality increasing discomfort (FIG. 18B). Based on this data, the maximum ideal osmolality of the test substance that reduces morning eyelid swelling without causing significant discomfort ranges from less than 2000 mOsm / Kg, preferably from 200 mOsm / Kg to 2000 mOsm. / Kg, more preferably 250 mOsm / Kg to 1500 mOsm / Kg, more preferably 260 mOsm / Kg to 1250 mOsm / Kg, and even more preferably 265 mOsm / Kg to 1200 mOsm / Kg.

  FIG. 19 shows naphazoline (0.1% and 0.09%) and 3% NaCl, oxymetazoline (0.03%, 0.04%, 0.05%) and mannitol (12.5%, 6% And 3%), 0.05% oxymetazoline, 6% mannitol and 3% NaCl, 0.05% oxymetazoline and 3% NaCl, 0.05% oxymetazoline and 7.5% glycerol, And comfort data for yet another ophthalmic formulation comprising 0.05% oxymetazoline alone. The comfort level was measured immediately after the instillation of each test substance based on the above-mentioned subjective rating of 0-10. The osmolality of each of these formulations is expected to be within the target range of acceptable comfort profiles (ie, 500 mOsm / Kg to 1100 mOsm / Kg).

(Example 11)
Use of naphazoline (0.09%) / sodium chloride (3%) to treat morning eyelid edema Evaluate the pattern of morning eyelid swelling after waking up daily for 6 days in a hotel environment and at home. Single-center, double-blind, randomized, contralateral (evaluating the efficacy of dose 0.09% naphazoline / 3% NaCl ophthalmic solution in reducing morning eyelid swelling compared to placebo a control, a placebo-controlled study was designed.

  A 0.09% naphazoline / 3% NaCl ophthalmic solution was prepared as shown in Table 1.

０．５Ｎ水酸化ナトリウム又は０．５Ｎ塩酸を使用してｐＨを６．０に調節し、精製水（ＵＳＰ）を用いて製剤を１ｍＬにした。

The pH was adjusted to 6.0 using 0.5N sodium hydroxide or 0.5N hydrochloric acid and the formulation was made up to 1 mL with purified water (USP).

  A total of 20 male subjects with an average age of 50 were evaluated as follows. Screening in the hotel environment in the evening (1st visit, evening (pm)) and after the next morning awakening (2nd visit, baseline), then 10 minutes apart for up to 1 hour by regional / global eyelid swelling grade Baseline eyelid swelling was assessed. For subjective evaluation of eyelid swelling, the eyelids and surrounding areas include the upper and lower eyelids (regions 1 and 2, respectively) and the region immediately above and below the upper and lower eyelids (regions 3 and 4 respectively). It was divided into four different eyeball regions. Subjects were asked to subjectively score eyelid swelling in each area on a scale of 0-3. Subjects were asked to score their eyelid swelling subjectively, even based on the whole (ie gross). A score of zero (“0”) is used to indicate that the subject has not detected any swelling in the assessment area or globally, and a score of “3” is used to indicate that the subject is in the assessment area or globally clear It was shown that a large swelling was detected. The average score of each of the four eyelid areas during baseline measurements at Visits 1 and 2 is shown in FIG. As shown in FIG. 20, the maximum amount of eyelid swelling was detected in region 3 and globally.

  After baseline assessment at Visits 1 and 2, the subject had a diary and returned home for 6 days, and subjectively graded and recorded eyelid swelling daily in the morning and evening by regional / global eyelid swelling grade Asked to do. The average overall score for each 6-day time zone is shown in FIG. As shown in FIG. 21, the subject consistently experienced increased eyelid swelling the following morning compared to the evening of the previous day throughout all six days.

  At the end of 6 days, subjects returned to the hotel for the study treatment group. In the evening (Visit 3rd) and in the morning (Visit 4), subjective eyelid swelling assessments were performed again in the hotel environment with the regional / global eyelid swelling rating described above. Immediately after the evaluation of eyelid swelling in the morning of the fourth visit, subjects received 1 drop of 0.09% naphazoline / 3% NaCl in one eye and Tears Natural II artificial tears (placebo) in the other eye. Evaluation of eyelid swelling after subjective treatment by regional / global eyelid swelling grade and objective assessment of eyelid swelling improvement (ie, reduction) using digital photographs was performed at 10 minute intervals for 1 hour. In the objective evaluation, a masked grader was asked to evaluate the digital photographs to assess whether eyelid swelling was better, worse or the same as baseline measurements. The evaluation results of eyelid swelling after subjective treatment are shown in FIGS. As shown in FIGS. 22-26, 0.09% naphazoline / NaCl was more effective than placebo in reducing morning eyelid swelling in each and all of the four designated eyelid areas evaluated.

  The average comfort of treatment was also evaluated. After instillation of 0.09% naphazoline / 3% NaCl, subjects were asked to grade their instillation comfort based on a subjective rating of 0-10 (0 indicates the most comfortable, 10 is Shows the most unpleasant.) The results are shown in FIG. As shown in FIG. 27, the treatment group had an average comfort score of 4.0 compared to the more comfortable placebo (average comfort score of 1.5). The osmolality of 0.09% naphazoline / 3% NaCl ophthalmic solution is predicted to be within the target range of acceptable comfort profile (ie, 500 mOsm / Kg to 1100 mOsm / Kg). Only 3 subjects reported transient stinging pain after instillation of 0.09% naphazoline / 3% NaCl in active treated eyes.

  In summary, 0.09% naphazoline / 3% NaCl treated eyes showed lower eyelid swelling scores across all areas after 40 minutes of instillation. All subjects reported the same or better overall score for the treated eye compared to placebo (p value = 0.001). The overall treatment effect was a 0.4 unit decrease. A single 0.09% naphazoline / 3% NaCl was safe and well tolerated with an average comfort score of 4.0. The diary data showed a consistent pattern of morning and evening eyelid swelling between the baseline hotel environment and the treatment environment for 6 days.

(Example 12)
Naphazoline (0.09%) / sodium chloride (3%), 0.05% oxymetazoline / 3% NaCl, 0.09% naphazoline / 7.5% glycerol for the treatment of morning eyelid edema, and 0.05% Oxymetazoline / 7.5% Glycerol Single dose 0.09% Naphazoline / 3% NaCl Ophthalmic Solution, 0.05% Oxymetazoline / 3% NaCl Ophthalmic Solution, 0.09 Single-center opposition to evaluate and compare the efficacy of% naphazoline / 7.5% glycerol ophthalmic solution and 0.05% oxymetazoline / 7.5% glycerol ophthalmic solution in reducing morning eyelid swelling A side test was designed.

  Ophthalmic solutions were prepared as shown in Tables 2-5.

上記製剤の各々について、０．５Ｎ水酸化ナトリウム又は０．５Ｎ塩酸を用いてｐＨを６．０に調節し、精製水（ＵＳＰ）を用いて各製剤を１ｍＬにした。

About each of the said formulation, pH was adjusted to 6.0 using 0.5N sodium hydroxide or 0.5N hydrochloric acid, and each formulation was made into 1 mL using purified water (USP).

  Similar to the test described in Example 11, the test was performed in a hotel environment. Subjects were screened in the evening and subjectively assessed for eyelid swelling. Morning baseline eyelid swelling was assessed immediately after waking by the overall eyelid swelling rating described in Example 11. Immediately after assessing morning baseline measurements, each subject was instilled as follows. Eleven subjects received one drop of 0.09% naphazoline / NaCl ophthalmic solution and the other eye received one drop of 0.05% oxymetazoline / NaCl solution. One eye of another 11 subjects received 1 drop of 0.09% naphazoline / 7.5% glycerol and the other eye received 1 drop of 0.05% oxymetazoline / 7.5% glycerol. During the first hour after treatment, eyelid swelling is assessed at 20 minute intervals according to the overall eyelid swelling grade, then the next hour after treatment, 30 minute intervals, followed by 1 hour interval up to 6 hours after treatment. It was evaluated with.

  The results are shown in FIGS. As shown in FIG. 28, both 0.09% naphazoline / 3% NaCl and 0.05% oxymetazoline / 3% NaCl were effective in reducing morning eyelid swelling for 6 hours after treatment. . 0.05% oxymetazoline / 3% NaCl showed a slightly better reduction in overall eyelid swelling. However, when asked to choose 0.09% naphazoline / 3% NaCl or 0.05% oxymetazoline / 3% NaCl, 66.6% of subjects who received both treatments had 0.09% naphazoline. / 3% NaCl ophthalmic solution preferred.

  As shown in FIG. 29, both 0.09% naphazoline / 75% glycerol and 0.05% oxymetazoline / 7.5% glycerol are effective in reducing morning eyelid swelling for 6 hours after treatment. Yes, 0.09% naphazoline / 7.5% glycerol showed a slightly better decrease. When asked to choose between two ophthalmic solutions, 66.6% of subjects said that they prefer 0.09% naphazoline / 7.5% glycerol solution.

  FIG. 30 is a comparison of the efficacy of all four ophthalmic solutions tested in reducing morning eyelid swelling (for comparison, different treatment groups were brought to the same baseline (ie pre-instillation) values. As shown in Figure 30, 7.5% glycerol solutions (ie 0.09% naphazoline / 7.5% glycerol and 0.05% oxymetazoline / 7.5% glycerol) Was more effective than 3% NaCl-based solutions (ie 0.09% naphazoline / 3% NaCl and 0.05% oxymetazoline / 3% NaCl), which was a surprising and unexpected. One skilled in the art would expect that NaCl, a higher tonicity agent than glycerol, would be more effective in reducing morning eyelid swelling, but the results were more effective with glycerol solutions. Was Tsu.

  Again, subjects were asked to grade their eye drop comfort based on a subjective rating of 0 to 10 (0 indicates the most comfortable and 10 indicates the most uncomfortable). The results are shown in FIG. As shown in FIG. 31, 7.5% glycerol-based ophthalmic solution was found to be more comfortable than 3% NaCl-based ophthalmic solution, but the 7.5% glycerol-based and 3% NaCl-based solutions Each was within the target osmolality range of acceptable comfort profile. Five subjects reported a stinging / burning sensation after instillation of NaCl solution.

  In summary, 7.5% glycerol ophthalmic solutions (ie 0.09% naphazoline / 7.5% glycerol and 0.05% oxymetazoline / 7.5% glycerol) are more likely to cause morning eyelid swelling. It was effective in reducing, and was larger and faster decreased from baseline eyelid swelling measurements. Furthermore, glycerol-based solutions were found to be more comfortable and no adverse effects were reported. Of the test formulations, 0.09% naphazoline / 7.5% glycerol was numerically slightly more effective in reducing overall morning eyelid swelling, but the difference was slight. The 0.09% naphazoline / 7.5% glycerol solution was also found to be more comfortable and preferred by the subject over the 0.05% oxymetazoline / 7.5% glycerol solution.

(Example 13)
0.05% oxymetazoline / 7.5% glycerol ophthalmic solution for the treatment of morning eyelid edema In reducing morning eyelid swelling in a hotel environment, a single dose of 0.05% oxymetazoline / A single center contralateral study was designed to evaluate and compare the efficacy of 7.5% glycerol ophthalmic solutions.

  4 visits will be held for about 1 week. During the first visit, as described in Example 11, evening baseline eyelid swelling is assessed using subjective regional / global eyelid swelling grades, scoring systems and digital photographs. Further, the grading of the eyeball redness evaluated by the inspector is finished at intervals of 1 hour from 6pm to 9pm.

  During the second visit, morning baseline eyelid swelling will be assessed using subjective regional / global eyelid swelling grade, scoring system and digital photographs. The grading of eye redness as assessed by the inspector is also assessed at 20, 40 and 60 minutes immediately after awakening, and then every hour for 6 hours after awakening.

  During the third visit, evening eyelid swelling and eye redness are assessed by the same procedure as the first visit.

  During the fourth visit, morning eyelid swelling is assessed according to the procedure used for the second visit. Patients are then randomized into one of the treatment groups and a drop of study drug is administered to both eyes. After the instillation, the same test evaluation and time as the second visit will be completed. The comfort of the formulation is also subjectively assessed as described above (0-10 grade, 0 being more comfortable and 10 being more uncomfortable).

  The treatment groups are as follows.

Formulation 1: 0.05% Oxymetazoline Ophthalmic Solution Formulation 2: 0.05% Oxymetazoline / 7.5% Glycerol Ophthalmic Solution Formulation 3: Vehicle of Formula 1 (no oxymetazoline, no glycerol)
Formula 4: Vehicle of Formula 2 (7.5% glycerol, no oxymetazoline)
A 3D scanning technique is also used to evaluate and compare the efficacy of these four formulations in reducing morning eyelid swelling. Baseline scans are performed for each subject and eye using a 3D scanner in the evening and the following morning before treatment. Patients are then randomized into one of the treatment groups and a drop of test drug is administered to both eyes. Immediately after instillation, 3D scans of each eye are taken at regular intervals.

(Example 14)
Novel osmotic / vasoconstrictor combination formulation for the treatment of morning eyelid edema About 0.5 grams of the following chemicals were added to separate 50 mL polypropylene tubes. The process was performed in duplicate.

1. Caffeine 2. Carbomer 934P
3. Tannic acid 4. Ascorbic acid Dextran 40,000
6). Inulin 7. Mannitol 8. Menthol (0.05 grams)
9. Menthol (0.05 grams), polysorbate 80 (0.50 grams)
To each of tubes 1-9, 50 mL of oxymetazoline hydrochloride sample was added and vortexed. To the remaining nine tubes, a 50 mL sample of naphazoline hydrochloride was added and vortexed. The pH and osmolality of each solution was tested. The results are shown in Table 6 below.

上記製剤の各々を朝の眼けん腫脹の減少における効力について、上記実施例１〜９に記載のように３Ｄ走査技術によって、さらに、実施例１１及び１２で上述したように主観的領域的／全体的眼けん腫脹等級及びスコア化システムを用いて、試験する。製剤の快適さを前述のように主観的に評価する（０〜１０等級、０はより快適であり、１０はより不快である。）。

Each of the above formulations was tested for efficacy in reducing morning eyelid swelling by 3D scanning techniques as described in Examples 1-9 above, and further by subjective regional / total as described above in Examples 11 and 12. Test using an eyelid swelling grade and scoring system. The comfort of the formulation is assessed subjectively as described above (0-10 grade, 0 being more comfortable and 10 being more uncomfortable).

Equivalent Form The present invention provides, in part, a topical ophthalmic formulation for use in the treatment of eyelid swelling. While specific embodiments of the invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The accompanying claims are not intended to claim all such embodiments and variations, and the full scope of the invention is defined by the claims and their generic equivalents, and the specification. It should be determined by reference to such variants.

  All publications and patents mentioned in this specification, including the items listed below, are by reference as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. The entirety of which is incorporated herein by reference. In case of conflict, the present application, including all definitions herein, will control.

Claims (18)

  A topical pharmaceutical composition for the treatment and prevention of eyelid swelling in a subject comprising a pharmaceutically acceptable carrier and an effective amount of an osmotically active agent and a vasoconstrictor, wherein the osmotically active agent is 3% w / V NaCl or 7.5% w / v glycerol and the vasoconstrictor is 0.09% w / v naphazoline or 0.05% w / v oxymetazoline.   2. The composition of claim 1 wherein the osmotic agent is 7.5% w / v glycerol and the vasoconstrictor is 0.09% w / v naphazoline.   The composition of claim 1, wherein the osmotic agent is 7.5% w / v glycerol and the vasoconstrictor is 0.05% w / v oxymetazoline.   The composition of claim 1, wherein the osmotic agent is 3% w / v NaCl and the vasoconstrictor is 0.09% w / v naphazoline.   The composition of claim 1 wherein the osmotic agent is 3% w / v NaCl and the vasoconstrictor is 0.05% w / v oxymetazoline.   The composition according to claim 1, wherein the composition has an osmolality of 500 mOsm / Kg to 1050 mOsm / Kg.   A topical pharmaceutical composition for the treatment and prevention of eyelid swelling in a subject comprising a pharmaceutically acceptable carrier and naphazoline hydrochloride 0.9 mg / mL, sodium chloride 30 mg / mL, edetate disodium 1 mg / mL, boric acid A topical pharmaceutical composition comprising 5 mg / mL and benzalkonium chloride 0.1 mg / mL, wherein the pH of the composition is 6.0.   Topical pharmaceutical composition for the treatment and prevention of eyelid swelling in a subject, comprising a pharmaceutically acceptable carrier and naphazoline hydrochloride 0.9 mg / mL, glycerol 75 mg / mL, edetate disodium 1 mg / mL, boric acid 5 mg / ML and benzalkonium chloride 0.1 mg / mL, wherein the pH of the composition is 6.0.   A topical pharmaceutical composition for the treatment and prevention of eyelid swelling in a subject comprising a pharmaceutically acceptable carrier and oxymetazoline hydrochloride 0.5 mg / mL, sodium chloride 30 mg / mL, edetate disodium 1 mg / mL, A topical pharmaceutical composition comprising 5 mg / mL boric acid and 0.1 mg / mL benzalkonium chloride, wherein the pH of the composition is 6.0.   A topical pharmaceutical composition for the treatment and prevention of eyelid swelling in a subject comprising a pharmaceutically acceptable carrier and oxymetazoline hydrochloride 0.5 mg / mL, glycerol 75 mg / mL, edetate disodium 1 mg / mL, boro A topical pharmaceutical composition comprising 5 mg / mL of acid and 0.1 mg / mL of benzalkonium chloride, wherein the pH of the composition is 6.0.   A topical pharmaceutical composition for the treatment and prevention of eyelid swelling in a subject comprising a pharmaceutically acceptable carrier and an effective amount of an osmotic active agent and a vasoconstrictor, wherein the osmotic active agent comprises caffeine , Carbomer 934P, tannic acid, ascorbic acid, dextran 40,000, inulin, mannitol, menthol and polysorbate 80, and the vasoconstrictor is selected from the group consisting of naphazoline, oxymetazoline, phenylephrine and tetrahydrozoline A topical pharmaceutical composition.   A method of treating and preventing eyelid swelling in a subject comprising administering to the surface of the subject's eye a composition comprising an effective amount of an osmotically active agent and a vasoconstrictor, wherein the osmotically active agent is 3 % W / v NaCl or 7.5% w / v glycerol and the vasoconstrictor is 0.09% w / v naphazoline or 0.05% w / v oxymetazoline.   13. The method of claim 12, wherein the osmotic agent is 7.5% w / v glycerol and the vasoconstrictor is 0.09% w / v naphazoline.   13. The method of claim 12, wherein the osmotic agent is 7.5% w / v glycerol and the vasoconstrictor is 0.05% w / v oxymetazoline.   13. The method of claim 12, wherein the osmotic agent is 3% w / v NaCl and the vasoconstrictor is 0.09% w / v naphazoline.   13. The method of claim 12, wherein the osmotic agent is 3% w / v NaCl and the vasoconstrictor is 0.05% w / v oxymetazoline.   A method of treating and preventing eyelid swelling in a subject comprising administering to the eyeball surface of the subject an effective amount of an osmotically active agent and a composition comprising a vasoconstrictor, the osmotically active agent comprising: A group selected from the group consisting of caffeine, carbomer 934P, tannic acid, ascorbic acid, dextran 40,000, inulin, mannitol, menthol and polysorbate 80, and the vasoconstrictor is a group consisting of naphazoline, oxymetazoline, phenylephrine and tetrahydrozoline A method selected from.   A kit comprising the pharmaceutical composition according to claim 1 or 7 to 11.

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