Oxymetazoline compositions and methods for treating eye diseases

Abstract

To provide compositions comprising oxymetazoline and methods for stabilizing the oxymetazoline compositions for long term storage.SOLUTION: The disclosure relates to a composition comprising oxymetazoline and a method for treating various ophthalmic disorders related to drooping eyelid such as ptosis in a subject, including administration the composition comprising oxymetazoline to the subject. In some aspects, the composition of disclosure relates to an aqueous pharmaceutically stable ophthalmic formulation comprising about 0.1 wt.% of oxymetazoline hydrochloride; about 0.2 to about 1.0 wt.% of sodium chloride; about 0.05 to about 0.10 wt.% of potassium chloride; about 0.02 to about 0.06 wt.% of calcium chloride; about 0.01 to about 0.05 wt.% of magnesium chloride; one or more suitable buffers; about 0.1 to about 0.90 wt.% of hypromellose; and optionally a pH adjuster, where the formulation has a pH range from about 6.3 to about 6.5.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to compositions and methods for treating various eye disorders including drooping of the eyelids or disorders associated with that condition. The present disclosure also relates to compositions containing oxymetazoline, pharmaceutically acceptable salts of oxymetazoline, and methods for preparing and using them.

Background Art

[0002] Ptosis (commonly known as drooping) is an abnormal partial or complete drooping of the upper eyelid and usually results from partial or complete dysfunction of the muscles that lift the upper eyelid, namely the levator palpebrae superioris muscle and / or the Müller muscle. Drooping occurs when the muscles that lift the eyelid (levator palpebrae superioris muscle and / or Müller muscle) are not strong enough to lift it properly. It can occur in one or both eyes and is more common in the elderly as the eyelid muscles begin to deteriorate. It is one of the most common eyelid disorders and occurs in about 12% of adults over the age of 50 (G.V. Sridharan, R.C. Tallis, B. Leatherbarrow, W.M. Forman, A., Community Survey of Ptosis of the Eyelid and Pupil (Size of Elderly People, Age and Ageing, Volume 24, Issue 1, January 1995, pp.21-24). Ptosis is classified as either congenital or acquired. Acquired ptosis has numerous etiologies, but in most cases it is aponeurotic and is the result of degenerative changes to the levator aponeurosis or stretching or tearing as a result of cataract surgery, lens exchange, or long-term contact lens wear with both hard and soft lenses. (Custer P.L., (2008) Blepharoptosis. In: Yanoff M., Duker J.S., editors. Ophthalmology. 3rd ed. St. Louis, MO: Mosby Elsevier; p.1397-1403; van den Bosch WA, Lemij H.G., Blepharoptosis induced by prolonged hard contact lens wear. Ophthalmology. 1992;99:1759‐65; Kersten R.C., Conciliis C., Kulwin D.R., Acquired ptosis in the young and middle-aged adult population. Ophthalmology. 1995;102:924‐8; Reddy A.K., Foroozan R., Arat Y.O., Edmond J.C., Yen M.T., Ptosis in young soft contact lens wearers. Ophthalmology. 2007;114:2370).

[0003] Patients with ptosis may experience significant upper field loss, which can affect daily activities such as driving, crossing the road, and reading. Treatment of acquired ptosis usually involves surgery, which is associated with risks of infection, bleeding, overcorrection or undercorrection, decreased vision, and lagophthalmos (inability to fully close the eyelids) (Finsterer J., Ptosis: causes, presentation, and management. Aesthetic Plast. Surg. 2003;27(3):193-204). Mechanical treatments for ptosis (scleral contact lenses with a bar to lift the eyelid, struts for blepharoptosis attached to glasses, or adhesive tapes or patches that attach the upper eyelid to the supraorbital structure) are limited by patient dissatisfaction with body appearance, contact allergies, or skin irritation. (Shah-Desai S.D., Aslam S.A., Pullum K., Beaconsfield M., Rose G.E., Scleral contact lens usage in patients with complex blepharoptosis. Ophthal. Plast. Reconstr. Surg. 2011 Mar-Apr;27(2):95-8). Pharmacological treatments for ptosis have not been pursued to date because the drugs evaluated (e.g., epinephrine, dipivefrin, apraclonidine, phenylephrine, brimonidine) cause mydriasis, resulting in blurred vision or photophobia, or unacceptable systemic side effects. (Matjucha I.C., The nonsurgical treatment of ptosis. In: Cohen A.J., Weinberg D.A., editors: Evaluation and management of blepharoptosis. New York: Springer, 2011.pp.155-61; Scheinfeld N., The Use of apraclonidine eyedrops to treat ptosis after the administration of botulinum toxin to the upper face. Dermatol. Online J. 2005 Mar 1;11(1):9; Kass M.A., Mandell A.I., Goldberg I., Paine J.M., Becker B., Dipivefrin and epinephrine treatment of elevated intraocular pressure: a comparative study. Arch. Ophthalmol. 1979 Oct;97(10):1865 - 6; Fraunfelder F.T., Scafidi A.F., Possible adverse effects from topical ocular 10% phenylephrine. Am. J. Ophthalmol. 1978;85(4):447 - 53).

[0004] Oxymetazoline hydrochloride, 6 - tert - butyl - 3 - (2 - imidazolin - 2 - ylmethyl)-2,4 - dimethylphenol monohydrochloride or phenol, 3 - [(4,5 - dihydro - 1H - imidazol - 2 - yl)methyl]-6 - (1,1 - dimethylethyl)-2,4 - dimethyl -, monohydrochloride are α - adrenergic agonists. Oxymetazoline is a direct - acting sympathomimetic amine that acts on the α - adrenergic receptors of arterioles in the conjunctiva and nasal mucosa. To address the ongoing challenge of balancing the relative risks of efficacy and adverse events, a novel ophthalmic formulation of oxymetazoline hydrochloride has been developed.

Prior Art Documents

Non - Patent Documents

[0005]

Non - Patent Document 1

Non - Patent Document 2

Summary of the Invention

Means for Solving the Problems

[0006] In one aspect, the composition of the present disclosure comprises about 0.1 wt% of oxymetazoline hydrochloride; about 0.2 wt% to about 1.0 wt% of sodium chloride; about 0.05 wt% to about 0.10 wt% of potassium chloride; about 0.02 wt% to about 0.06 wt% of calcium chloride; about 0.01 wt% to about 0.05 wt% of magnesium chloride; one or more suitable buffers; about 0.1 wt% to about 0.90 wt% of hypromellose; and optionally a pH adjuster, and is a pharmaceutically stable aqueous ophthalmic formulation, wherein the pH of the formulation ranges from about 6.3 to about 6.5. In some aspects, the one or more suitable buffers constitute about 0.05 wt% to about 1.0 wt%. In some aspects, the one or more suitable buffers include sodium acetate trihydrate and sodium citrate. In some aspects, the one or more suitable buffers include about 0.39 wt% of sodium acetate trihydrate and about 0.17 wt% of sodium citrate. In some aspects, the formulation includes about 0.64 wt% of sodium chloride, about 0.075 wt% of potassium chloride, about 0.048 wt% of calcium chloride dihydrate, and about 0.03 wt% of magnesium chloride hexahydrate. In some aspects, the pH adjuster is selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calcium carbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide, ammonium hydroxide, ammonium phosphate, and combinations thereof. In some aspects, the pH adjuster includes hydrochloric acid. In some aspects, the formulation does not contain a preservative. In some aspects, the formulation is stable for 0 to 24 months. In some aspects, the formulation is stable for at least 24 months. In some aspects, the formulation is stable for at least 24 months at 25 °C and 40% relative humidity. In some aspects, the composition is formulated in a disposable container. In some aspects, the volume of the disposable container is about 0.5 mL. In some aspects, the disposable container is packaged in a child-resistant package. In some aspects, the disposable container delivers about 0.035 mg of oxymetazoline hydrochloride per drop.

[0007] The composition of the present disclosure comprises about 0.1% by weight of oxymetazoline hydrochloride; about 0.2% to about 1.0% by weight of sodium chloride; about 0.05% to about 0.10% by weight of potassium chloride; about 0.02% to about 0.06% by weight of calcium chloride; about 0.01% to about 0.05% by weight of magnesium chloride; one or more suitable buffers; about 0.1% to about 0.90% by weight of hypromellose; and optionally, a pH adjuster, and is a pharmaceutically stable aqueous ophthalmic formulation, wherein the pH of the formulation ranges from about 6.3 to about 6.5. In some embodiments, the one or more suitable buffers constitute about 0.05% to about 1.0% by weight. In some embodiments, the one or more suitable buffers include sodium acetate trihydrate and sodium citrate. In some embodiments, the one or more suitable buffers include about 0.39% by weight of sodium acetate trihydrate and about 0.17% by weight of sodium citrate. In some embodiments, the formulation includes about 0.64% by weight of sodium chloride, about 0.075% by weight of potassium chloride, about 0.048% by weight of calcium chloride dihydrate, and about 0.03% by weight of magnesium chloride hexahydrate. In some embodiments, the pH adjuster is selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calcium carbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide, ammonium hydroxide, ammonium phosphate, and combinations thereof. In some embodiments, the pH adjuster includes hydrochloric acid. In some embodiments, the formulation is stable for 0 to 24 months. In some embodiments, the formulation is stable for at least 24 months. In some embodiments, the formulation is stable for at least 24 months at 25°C and a relative humidity of 40%. In some embodiments, the composition is formulated in a disposable container. In some embodiments, the volume of the disposable container is about 0.5 mL. In some embodiments, the disposable container is packaged in a child-resistant package. In some embodiments, the disposable container is packaged in a child-resistant pouch. In some embodiments, the disposable container delivers about 0.035 mg of oxymetazoline hydrochloride per drop.

[0008] The composition of the present disclosure is a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising: about 0.1% by weight of oxymetazoline hydrochloride; about 0.64% by weight of sodium chloride; about 0.075% by weight of potassium chloride; about 0.048% by weight of calcium chloride dihydrate; about 0.03% by weight of magnesium chloride hexahydrate; one or more suitable buffers; about 0.5% by weight of hypromellose; and optionally hydrochloric acid, wherein the pH of the formulation ranges from about 6.3 to about 6.5.

[0009] The method of the present disclosure is a method for treating ptosis of a subject, the method comprising administering to at least one eye of the subject a therapeutically effective amount of a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising: about 0.1% by weight of oxymetazoline hydrochloride; about 0.2% to about 1.0% by weight of sodium chloride; about 0.05% to about 0.10% by weight of potassium chloride; about 0.02% to about 0.06% by weight of calcium chloride; about 0.01% to about 0.05% by weight of magnesium chloride; one or more suitable buffers; about 0.1% to about 0.90% by weight of hypromellose; and optionally hydrochloric acid, wherein the pH range of the pharmaceutically stable aqueous ophthalmic formulation is from about 6.3 to about 6.5. In some embodiments, the ptosis is acquired aponeurotic ptosis. In some embodiments, the pharmaceutically stable aqueous ophthalmic formulation is administered to the subject continuously at a dose of 1 drop per eye, 1 or more days, at a total daily dose of about 0.07 mg of oxymetazoline hydrochloride.

[0010] In some embodiments, the average C max after single-dose administration of the formulation is about 25 to about 35 pg / ml. In some embodiments, the average AUC 0-∞ after single-dose administration of the formulation is about 300 to about 700 pg·h / mL. In some embodiments, the T maxis from about 0.5 to about 6 hours. In some embodiments, the method of the present disclosure relates to a method of treating ptosis using a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising about 0.64 wt% sodium chloride; about 0.075 wt% potassium chloride; about 0.048 wt% calcium chloride dihydrate; about 0.03 wt% magnesium chloride hexahydrate; and about 0.5 wt% hypromellose.

[0011] The method of the present disclosure is a method of increasing the vertical separation of the upper and lower eyelids of a subject, the method comprising administering to at least one eye of the subject a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising: about 0.1 wt% oxymetazoline hydrochloride; about 0.2 wt% to about 1.0 wt% sodium chloride; about 0.05 wt% to about 0.10 wt% potassium chloride; about 0.02 wt% to about 0.06 wt% calcium chloride; about 0.01 wt% to about 0.05 wt% magnesium chloride; 1 or more suitable buffers; about 0.1 wt% to about 0.90 wt% hypromellose; and hydrochloric acid as needed, wherein the pH range of the pharmaceutically stable aqueous ophthalmic formulation is from about 6.3 to about 6.5.

[0012] In some embodiments, the formulation is administered to the subject continuously for one day or more at a dose of 1 drop per single eye with a total daily dose of about 0.035 mg of oxymetazoline hydrochloride. In some embodiments, the formulation is administered to the subject continuously for one day or more at a dose of 1 drop per eye with a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. In some embodiments, the average C max is from about 25 to about 35 pg / ml. In some embodiments, the average AUC 0-∞ is from about 300 to about 700 pg·h / mL. In some embodiments, the T max after single-dose administration of the formulation is from about 0.5 to about 6 hours.

[0013] In one aspect, the pharmaceutically stable aqueous ophthalmic preservative-free formulation comprises about 0.64% by weight of sodium chloride; about 0.075% by weight of potassium chloride; about 0.048% by weight of calcium chloride dihydrate; about 0.03% by weight of magnesium chloride hexahydrate; and about 0.5% by weight of hypromellose.

[0014] The method of the present disclosure is a method for improving the Lester perimetric field test (LPFT) score of a subject, the method comprising administering to at least one eye of the subject a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising: about 0.1% by weight of oxymetazoline hydrochloride; about 0.2% to about 1.0% by weight of sodium chloride; about 0.05% to about 0.10% by weight of potassium chloride; about 0.02% to about 0.06% by weight of calcium chloride; about 0.01% to about 0.05% by weight of magnesium chloride; 1 or more suitable buffers; about 0.1% to about 0.90% by weight of hypromellose; and hydrochloric acid as needed, wherein the pH range of the pharmaceutically stable aqueous ophthalmic formulation is about 6.3 to about 6.5, and the average LPFT score increases by about 5 to 10 points about 0.1 to 16 hours after administration. In some aspects, the formulation is administered to the subject continuously for one day or more at a dose of 1 drop per eye, with a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. In some aspects, the average C max is about 25 to about 35 pg / ml. In some aspects, the average AUC 0-∞ after single-dose administration of the formulation is about 300 to about 700 pg·h / mL. In some aspects, the T maxis about 0.5 to about 6 hours. In some embodiments, the median score of the perimetric Lester perimeter field test (LPFT) increases by about 5 to 10 points about 6 hours after administration. In some embodiments, tachyphylaxis is not shown for at least 6 weeks. In some embodiments, the pharmaceutically stable aqueous ophthalmic preservative-free formulation comprises about 0.64 wt% sodium chloride; about 0.075 wt% potassium chloride; about 0.048 wt% calcium chloride dihydrate; about 0.03 wt% magnesium chloride hexahydrate; and about 0.5 wt% hypromellose.

[0015] The method of the present disclosure is a method of improving the medial reflex distance test 1 (MRD-1) score of a subject's eyelid margin corneal reflex, the method comprising administering to at least one eye of the subject a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising: about 0.1 wt% oxymetazoline hydrochloride; about 0.2 wt% to about 1.0 wt% sodium chloride; about 0.05 wt% to about 0.10 wt% potassium chloride; about 0.02 wt% to about 0.06 wt% calcium chloride; about 0.01 wt% to about 0.05 wt% magnesium chloride; 1 or more suitable buffers; about 0.1 wt% to about 0.90 wt% hypromellose; and hydrochloric acid as needed, wherein the pH range of the pharmaceutically stable aqueous ophthalmic formulation is about 6.3 to about 6.5, and the average score increases by about 0.2 to 1.5 points about 1 to 20 minutes after administration or about 1 to 6 hours, e.g., 8 hours after administration. In some embodiments, the pharmaceutically stable aqueous ophthalmic formulation is administered to the subject continuously for 1 day or more at a dose of 1 drop per eye with a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. In some embodiments, the average C max is about 25 to about 35 pg / ml. In some embodiments, the average AUC 0-∞ is about 300 to about 700 pg·h / mL. In some embodiments, the T maxis about 0.5 to about 6 hours. In some embodiments, the average score of the marginal reflex distance test 1 (MRD-1) increases by about 0.2 to 1.0 points about 5 minutes after administration. In some embodiments, tachyphylaxis is not exhibited for at least 6 weeks. In some embodiments, the pharmaceutically stable aqueous ophthalmic preservative-free formulation comprises about 0.64 wt% sodium chloride; about 0.075 wt% potassium chloride; about 0.048 wt% calcium chloride dihydrate; about 0.03 wt% magnesium chloride hexahydrate; and about 0.5 wt% hypromellose. In some embodiments, the use of the compositions and methods of the present invention does not exhibit tachyphylaxis. In some embodiments, tachyphylaxis is not exhibited for 6 weeks. In some embodiments, tachyphylaxis is not exhibited for a period of 6 weeks to 3 months. In some embodiments, tachyphylaxis is not exhibited for a period of 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 1 month, 2 months, or 3 months. In some embodiments, tachyphylaxis is not exhibited during the use of the compositions or methods of the present disclosure. The present disclosure relates to compositions comprising oxymetazoline, and methods of stabilizing oxymetazoline compositions for long-term storage. The present disclosure also relates to methods of treating various eye disorders associated with ptosis of the eyelids, such as drooping, in a subject, comprising administering to the subject a composition comprising oxymetazoline. BRIEF DESCRIPTION OF THE DRAWINGS

[0016]

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Figure 5A

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DETAILED DESCRIPTION OF THE INVENTION

[0021] I. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present application, including the definitions, will control. Unless specifically required otherwise in the context, singular terms shall include the plural and plural terms shall include the singular. All publications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0022] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the present disclosure will be apparent from the detailed description and claims.

[0023] To further define the present disclosure, the following terms and definitions are provided.

[0024] The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), as well as the terms "one or more than one", and "at least one" can be used synonymously herein. In certain embodiments, the term "a" or "an" means "single". In other embodiments, the term "a" or "an" includes "two or more than two" or "plural".

[0025] The term "about" is used herein to mean about, approximately, around, or in the region thereof. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the boundaries above and below the recited numerical values. In general, the term "about" is used herein to modify a numerical value up or down by up to 10 percent of the numerical value recited (higher or lower).

[0026] As used herein, the term "and / or" shall be construed to mean that each of the two specified features or components is specifically disclosed regardless of the presence or absence of the other. Thus, the term "and / or" as used in phrases such as "A and / or B" herein is intended to include "A and B", "A or B", "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to include each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0027] As used herein, "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that is suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0028] The term "pharmaceutically stable" means the ability of a pharmaceutical dosage form to maintain its physical, chemical, therapeutic, and microbiological properties during storage and use by the patient.

[0029] As used herein, the term "effective amount" or "pharmaceutically effective amount" refers to the amount or quantity of a drug or pharmaceutically active substance sufficient to elicit the required or desired therapeutic response, in other words, an amount sufficient to elicit a recognizable biological response when administered to a patient.

[0030] As used herein, the term "unit dosage form" or "unit dose composition" refers to a device containing a quantity of a therapeutic compound, said quantity being such that one or more predetermined units can be provided as a single therapeutic administration.

[0031] As used herein, the terms "weight %" or "weight / volume" refer to the ratio between components with respect to volume. For example, a 5% by weight aqueous ethanol solution represents a solution containing 5 g of ethanol per 100 mL of water.

[0032] As used herein, the term "C max " refers to the maximum plasma concentration of a drug after administration to a subject.

[0033] As used herein, the term "T max " refers to the time required to reach the maximum plasma concentration ("C max ) after administration of a drug.

[0034] As used herein, the term "AUC" refers to the area under the curve of a plot of plasma concentration versus time after administration of a drug.

[0035] As used herein, the term "AUC 0-t " refers to the area under the drug concentration-time curve from time zero to the time of the final measurable concentration (C t ).

[0036] As used herein, the term "AUC 0-∞ " refers to the area under the drug concentration-time curve from time zero to infinity. AUC 0-∞ is calculated with respect to the last measured concentration (AUC 0-T ) and extrapolated to infinity (AUC t-∞ ).

[0037] As used herein, the term "free base equivalent" or "FBE" refers to the amount of oxymetazoline present in oxymetazoline or its salts. In other words, the term "FBE" means either the amount of oxymetazoline free base or the equivalent amount of oxymetazoline free base provided by the salt of oxymetazoline. For example, for the weight of the hydrochloride salt, 100 mg of oxymetazoline hydrochloride provides only as much oxymetazoline as 88 mg of the free base form of oxymetazoline. Other salts are expected to have different conversion factors depending on the molecular weight of the salt.

[0038] The term "Lester Peripheral Field Test" or "LPFT" refers to a customized visual field test specifically designed to evaluate ptosis (Ho S.F., Morawski A., Sampath R., Burns J., Modified visual field test for ptosis surgery (Leicester Peripheral Field Test). Eye (Lond). 2011 Mar;25(3):365-9.doi:10.1038 / eye.2010.210.Epub 2011 Jan 21), which is performed using a Humphrey Visual Field Analyzer. This is an age-corrected screening test in which 35 points are tested in the upper visual field and 14 points are tested in the lower visual field. Up to 48° is tested in the upper visual field. The fixation center is shifted 15° downward to enable the maximum upper visual field test. The lower visual field test serves as a reference but is not used in the analysis.

[0039] The term "Marginal Reflex Distance 1 (MRD)" refers to one of two tests. MRD-1 refers to a test that uses photographic measurement of the distance from the central pupillary light reflex to the central margin of the upper eyelid. External digital photographs are used to measure MRD-1. The measurement is made based on the distance from the central pupillary light reflex to the central margin of the upper eyelid, ≤2 mm (the visible central pupillary light reflex does not default to 0). MRD-2 refers to the measured value of the vertical distance from the center of the pupil and the edge of the lower eyelid.

[0040] As used herein, the term "treat" or "treatment" refers to administering a composition to a subject for therapeutic purposes.

[0041] The term "average" refers to the mean value of a patient population. For example, "average Cmax" refers to the mean of the maximum plasma concentration values of a drug in a patient population.

[0042] The term "adult" refers to a person 18 years of age or older.

[0043] II. Compositions The compositions of the present disclosure comprise an effective amount of an α-adrenergic agonist formulated for ocular administration. The present disclosure provides compositions and methods useful in the treatment of ptosis. In some embodiments, the composition is an eye drop. In some embodiments, oxymetazoline hydrochloride is formulated for topical ocular delivery as a sterile, preservative-free eye drop (ophthalmic solution) prepared aseptically. The eye drop may contain 0.1 wt% oxymetazoline hydrochloride in a balanced salt solution with a viscosity modifier (hypromellose). The eye drop can be filled into clear unit dose 0.5 mL low density polyethylene (LDPE) blow-fill-seal (BFS) vials, which can be individually packaged in foil pouches.

[0044] When administered at 0.1% by weight, oxymetazoline is thought to stimulate the α2 - adrenergic receptors of the Müller muscle, causing the Müller muscle to contract, thereby lifting the upper eyelid and contracting the lower eyelid slightly.

[0045] In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation consisting of about 0.1% by weight of oxymetazoline hydrochloride; about 0.2% to about 1.0% by weight of sodium chloride; about 0.05% to about 0.10% by weight of potassium chloride; about 0.02% to about 0.06% by weight of calcium chloride; about 0.01% to about 0.05% by weight of magnesium chloride; one or more suitable buffers; about 0.1% to about 0.90% by weight of hypromellose; and, optionally, a pH adjuster; the pH range of the formulation is about 6.3 to about 6.5.

[0046] In some embodiments, one or more suitable buffers constitute about 0.05% to about 1.0% by weight. In some embodiments, one or more suitable buffers include sodium acetate trihydrate and sodium citrate. In some embodiments, the formulation contains about 0.64% by weight of sodium chloride, about 0.075% by weight of potassium chloride, about 0.048% by weight of calcium chloride dihydrate, and about 0.03% by weight of magnesium chloride hexahydrate. In some embodiments, the pH adjuster is selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calcium carbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide, ammonium hydroxide, ammonium phosphate, and combinations thereof. In some embodiments, the pH adjuster includes hydrochloric acid.

[0047] In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation consisting essentially of 0.1 wt% oxymetazoline hydrochloride; 0.64 wt% sodium chloride; 0.075 wt% potassium chloride; 0.048 wt% calcium chloride dihydrate; 0.03 wt% magnesium chloride hexahydrate; 1 or more suitable buffers; 0.5 wt% hypromellose; and hydrochloric acid as needed; and the pH range of the formulation is 6.3 - 6.5. In some embodiments, 1 or more suitable buffers include sodium acetate trihydrate, sodium citrate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, tris(hydroxymethyl)aminomethane (TRIS), and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In one embodiment, 1 or more suitable buffers include 0.39 wt% sodium acetate trihydrate and 0.17 wt% sodium citrate.

[0048] In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation consisting essentially of 0.1 wt% oxymetazoline hydrochloride; 0.64 wt% sodium chloride; 0.075 wt% potassium chloride; 0.048 wt% calcium chloride dihydrate; 0.03 wt% magnesium chloride hexahydrate; 1 or more suitable buffers; 0.5 wt% hypromellose; and hydrochloric acid as needed; and the pH range of the formulation is 6.3 - 6.5. In some embodiments, 1 or more suitable buffers include sodium acetate trihydrate, sodium citrate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In one embodiment, 1 or more suitable buffers include 0.39 wt% sodium acetate trihydrate and 0.17 wt% sodium citrate.

[0049] In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation consisting of 0.1 wt% oxymetazoline hydrochloride; 0.64 wt% sodium chloride; 0.075 wt% potassium chloride; 0.048 wt% calcium chloride dihydrate; 0.03 wt% magnesium chloride hexahydrate; 1 or more suitable buffers; 0.5 wt% hypromellose; and optionally hydrochloric acid; the pH range of the formulation is 6.3 - 6.5. In some embodiments, 1 or more suitable buffers include sodium acetate trihydrate, sodium citrate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In one embodiment, 1 or more suitable buffers include 0.39 wt% sodium acetate trihydrate and 0.17 wt% sodium citrate.

[0050] One embodiment of the present disclosure is a method for treating ptosis in a subject. The method includes administering an effective amount of oxymetazoline to an eye of a subject in need of such treatment. In some embodiments, the method includes administering to at least one eye of the subject a therapeutically effective amount of a pharmaceutically stable aqueous ophthalmic formulation comprising 0.1 wt% oxymetazoline hydrochloride; 0.64 wt% sodium chloride; 0.075 wt% potassium chloride; 0.048 wt% calcium chloride dihydrate; 0.03 wt% magnesium chloride hexahydrate; 1 or more suitable buffers; 0.5 wt% hypromellose; and optionally hydrochloric acid; the pH range of the formulation is 6.3 - 6.5. In some embodiments, 1 or more suitable buffers include sodium acetate trihydrate, sodium citrate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In one embodiment, 1 or more suitable buffers include 0.39 wt% sodium acetate trihydrate and 0.17 wt% sodium citrate.

[0051] In some aspects of the present disclosure, the subject is a mammal. In another aspect, the mammal is a human.

[0052] In some aspects, the formulation is administered at a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. In some aspects, the average weight of one drop is 0.035 g. In some aspects, one drop is administered to each eye, and each drop contains approximately 0.035 mg of oxymetazoline hydrochloride (0.0308 mg of free oxymetazoline base).

[0053] In some aspects, the method comprises administering to at least one eye of a subject a therapeutically effective amount of a pharmaceutically stable aqueous ophthalmic formulation consisting essentially of 0.1 wt% oxymetazoline hydrochloride; 0.64 wt% sodium chloride; 0.075 wt% potassium chloride; 0.048 wt% calcium chloride dihydrate; 0.03 wt% magnesium chloride hexahydrate; one or more suitable buffers; 0.5 wt% hypromellose; and optionally hydrochloric acid; the pH range of the formulation is 6.3 - 6.5. In some aspects, one or more suitable buffers include sodium acetate trihydrate, sodium citrate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In some aspects, one or more suitable buffers include 0.39 wt% sodium acetate trihydrate and 0.17 wt% sodium citrate. In some aspects, the formulation is administered in an amount of about 0.07 mg.

[0054] In some embodiments, the method comprises administering to at least one eye of a subject a therapeutically effective amount of a pharmaceutically stable aqueous ophthalmic formulation comprising 0.1% by weight of oxymetazoline hydrochloride; 0.64% by weight of sodium chloride; 0.075% by weight of potassium chloride; 0.048% by weight of calcium chloride dihydrate; 0.03% by weight of magnesium chloride hexahydrate; one or more suitable buffers; 0.5% by weight of hypromellose; and optionally hydrochloric acid; the pH range of the formulation being 6.3 to 6.5. In some embodiments, one or more suitable buffers include sodium acetate trihydrate, sodium citrate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In some embodiments, one or more suitable buffers include 0.39% by weight of sodium acetate trihydrate and 0.17% by weight of sodium citrate.

[0055] In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation comprising 0.1% by weight of oxymetazoline hydrochloride; 0.64% by weight of sodium chloride; 0.075% by weight of potassium chloride; 0.048% by weight of calcium chloride dihydrate; 0.03% by weight of magnesium chloride hexahydrate; one or more suitable buffers; 0.5% by weight of hypromellose; and optionally hydrochloric acid; the pH range of the formulation being 6.3 to 6.5. In other embodiments, one or more suitable buffers include boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In some embodiments, one or more suitable buffers include 0.39% by weight of sodium acetate trihydrate and 0.17% by weight of sodium citrate.

[0056] In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation comprising about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, or about 1.0 wt% of metazoline hydrochloride. In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation comprising about 0.10 wt%, about 0.12 wt%, about 0.13 wt%, about 0.14 wt%, about 0.15 wt%, about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, about 0.19 wt%, or about 0.20 wt% of metazoline hydrochloride. In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation comprising about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, or about 0.09 wt% of metazoline hydrochloride.

[0057] In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation consisting essentially of 0.1 wt% of oxymetazoline hydrochloride; 0.64 wt% of sodium chloride; 0.075 wt% of potassium chloride; 0.048 wt% of calcium chloride dihydrate; 0.03 wt% of magnesium chloride hexahydrate; 1 or more suitable buffers; 0.5 wt% of hypromellose; and optionally hydrochloric acid; the pH range of the formulation is 6.3 - 6.5. In other embodiments, 1 or more suitable buffers include boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In some embodiments, 1 or more suitable buffers include 0.39 wt% of sodium acetate trihydrate and 0.17 wt% of sodium citrate.

[0058] In one embodiment, the solution is a pharmaceutically stable aqueous ophthalmic formulation consisting of 0.1% by weight of oxymetazoline hydrochloride; 0.64% by weight of sodium chloride; 0.075% by weight of potassium chloride; 0.048% by weight of calcium chloride dihydrate; 0.03% by weight of magnesium chloride hexahydrate; 1 or more suitable buffers; 0.5% by weight of hypromellose; and optionally hydrochloric acid; the pH range of the formulation is 6.3 - 6.5. In other embodiments, 1 or more suitable buffers include sodium acetate trihydrate, sodium citrate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In some embodiments, 1 or more suitable buffers include 0.39% by weight of sodium acetate trihydrate and 0.17% by weight of sodium citrate.

[0059] In one embodiment, the formulation contains sodium chloride, and the amount of sodium chloride in the formulation is about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, or about 1.0% by weight.

[0060] In one embodiment, the formulation contains potassium chloride, and the amount of potassium chloride in the formulation is about 0.01% by weight, about 0.02% by weight, about 0.03% by weight, about 0.04% by weight, about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, or about 0.5% by weight.

[0061] In one embodiment, the formulation contains calcium chloride, and the amount of calcium chloride in the formulation is about 0.01% by weight, about 0.02% by weight, about 0.03% by weight, about 0.04% by weight, about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, about 0.1% by weight, or about 0.2% by weight.

[0062] In one aspect, the formulation comprises magnesium chloride, and the amount of magnesium chloride in the formulation is about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, or about 0.2 wt%.

[0063] In one aspect, the formulation comprises hypromellose, and the amount of hypromellose in the formulation is about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1.0 wt%, or about 2.0 wt%.

[0064] In some aspects, oxymetazoline is provided as a pharmaceutically acceptable salt of oxymetazoline. The term "pharmaceutically acceptable salt" is recognized in the art and refers to relatively non-toxic inorganic and organic acid addition salts of the compositions of the present disclosure or any of its components, including, but not limited to, therapeutic agents, excipients, and other materials. Examples of pharmaceutically acceptable salts include those derived from mineral acids such as hydrochloric acid and sulfuric acid, as well as those derived from organic acids such as ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Examples of inorganic bases suitable for salt formation include, but are not limited to, hydroxides, carbonates, and bicarbonates of mania, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, etc. The salt can also be formed with a suitable organic base, including those that are non-toxic and strong enough to form such salts.

[0065] III. Composition Stability The compositions of the present disclosure are stable. Long-term stability is an important attribute to consider when formulating ophthalmic preparations, particularly preservative-free preparations. To ensure the long-term stability of the composition, including assays, mass osmolality, impurities, viscosity, weight loss, and sterility, it is necessary to maintain various important quality attributes over the shelf life of the composition. These attributes are affected by various factors, including temperature, relative humidity, and / or pH.

[0066] Mass osmolality is the concentration of all solutes in a given weight of water, expressed as units of either mass osmolality, and is an important attribute for the maintenance of ophthalmic preparations. Since the mass osmolality of the eyes of most subjects is approximately 300 mOsm, it is important that any preparation administered to the eye be maintained in the vicinity of this range, for example, from about 290 to about 365 mOsm / kg, so that the preparation is well tolerated.

[0067] The stability of the pH of the solution is also important for comfort and safety. If the components of an ophthalmic preparation change the pH over time, the preparation can become unstable. Also, a change in pH can cause the administration of a preparation that can damage the eye. Therefore, it is important that the desired physiological pH be maintained throughout the life of the preparation. Maintaining the pH near neutrality and maintaining the natural pH of the eye is important for safety.

[0068] Viscosity is an important quality of ophthalmic preparations for maintaining the residence time of the preparation in the eye. It is important that the viscosity of the preparation be maintained over the life of the preparation so that the viscosity is constant and the delivery and residence time of the active ingredient are maintained. For example, in one aspect, the viscosity is from about 15 to about 35 cPs to maintain the residence time in the eye and the comfort of the eye.

[0069] Unstable solutions can decompose over time and produce undesirable degradation products. These products can be the result of unwanted chemical reactions involving the active ingredient, including hydrolysis and oxidation. The instability of the solution with respect to degradation products can cause both the toxicity resulting from the formation of these impurities and the decrease in the concentration of the active ingredient due to degradation. Undesirable degradation products include N-(2-aminoethyl)-2-[4-(1,1-dimethylethyl)-3-hydroxy-2,6-dimethylphenyl]acetamide, hydroxylated imidazoline derivatives, hydroxylamine, and N-oxide derivatives. Non-limiting examples of degradation products resulting from oxymetazoline decomposition include the following:

Chemical Structure

[0070] Therefore, the presence of these degradation products must be restricted and monitored as the formulation ages to prevent potential loss of the activity of the active ingredient and to prevent potential undesirable toxicity resulting from the degradation products that occur.

[0071] Maintaining the sterility of the formulation is also important. The sterility test ensures that there is no contamination of the ophthalmic formulation by microorganisms that can cause infection or other complications.

[0072] Maintaining the water content in the formulation is important to maintain the desired concentration of the components present in the formulation. Therefore, loss of weight of water will affect the concentration of the components. Degradation products can also affect the concentration of the components and the pH of the solution, and can introduce undesirable contaminants that can pose a risk to eye safety. Therefore, maintaining and monitoring the degradation of the components is also important. Limiting degradation products is important for the safety of the drug product, and formulation and process variables can affect degradation products.

[0073] In some embodiments, the compositions of the present disclosure are stable for about 3 months, about 6 months, about 9 months, about 12 months, about 14 months, about 18 months, about 21 months, about 24 months, about 30 months, about 36 months, about 42 months, about 48 months, about 54 months, or about 60 months. In some embodiments, the compositions of the present disclosure are stable for about 3 months. In some embodiments, the compositions of the present disclosure are stable for about 6 months. In some embodiments, the compositions of the present disclosure are stable for at least about 9 months. In some embodiments, the compositions of the present disclosure are stable for at least about 12 months. In some embodiments, the compositions of the present disclosure are stable for about 14 months. In some embodiments, the compositions of the present disclosure are stable for at least about 18 months. In some embodiments, the compositions of the present disclosure are stable for about 21 months. In some embodiments, the compositions of the present disclosure are stable for at least about 24 months. In some embodiments, the compositions of the present disclosure are stable for at least about 30 months. In some embodiments, the compositions of the present disclosure are stable for at least about 36 months. In some embodiments, the compositions of the present disclosure are stable for at least about 42 months. In some embodiments, the compositions of the present disclosure are stable for at least about 48 months. In some embodiments, the compositions of the present disclosure are stable for at least about 54 months. In some embodiments, the compositions of the present disclosure are stable for at least about 60 months.

[0074] Stability is also affected by the environmental conditions present during storage. For example, ambient temperature and / or humidity can affect the long-term stability of ophthalmic preparations. In some embodiments, the compositions of the present disclosure are stable at a temperature of about 4°C to about 30°C, about 4°C to about 25°C, about 4°C to about 20°C, about 10°C to about 20°C, about 15°C to about 20°C, or about 20°C to about 30°C. In some embodiments, the compositions of the present disclosure are stable at a temperature of about 15°C, about 16°C, about 17°C, about 18°C, about 19°C, about 20°C, about 21°C, about 22°C, about 23°C, about 24°C, about 25°C, about 26°C, about 27°C, about 28°C, about 29°C, or about 30°C.

[0075] In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 10% to about 70%, about 20% to about 60%, about 30% to about 50%, about 20% to about 80%, about 30% to about 70%, about 40% to about 60%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 10% to about 70%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 40% to about 60%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 10%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 20%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 30%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 40%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 50%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 60%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 70%. In some embodiments, the compositions of the present disclosure are stable at a relative humidity of about 80%.

[0076] IV. Treatment Methods The upper eyelid is normally lifted by the contraction of the levator palpebrae superioris muscle (levator muscle) and the Müller's muscle. Ptosis creates a tired appearance, which may be cosmetically undesirable; in more severe cases, ptosis can interfere with the vision of one or more affected eyes. In addition to fatigue and age-related weakening of the levator and Müller muscles, which are the underlying causes of ptosis, there are a number of other conditions that are recognized to cause ptosis. For example, ptosis can be caused by myogenic, neurogenic, aponeurotic, mechanical, or traumatic causes; ptosis usually occurs in isolation, but it can also be associated with various other conditions such as genetic diseases, immune diseases, or degenerative diseases, tumors, and infections. The methods of the present disclosure are useful for the treatment of ptosis. In some embodiments, a therapeutically effective amount of oxymetazoline hydrochloride is delivered in an ophthalmically acceptable carrier. In some embodiments, the carrier is an emulsion, suspension, gel, ointment, or solution.

[0077] In certain embodiments, the solution is a topical eye drop administered as an eye medicine. The myogenic causes of ptosis can include diseases that can cause muscle weakness or nerve damage, such as myasthenia gravis and chronic progressive external ophthalmoplegia. Dystrophy or hypoplasia of the levator and / or Müller muscles are the most common causes of congenital ptosis. Ptosis can be caused by damage to the third cranial nerve (oculomotor nerve) that controls the muscle that elevates the upper eyelid. Congenital neurogenic ptosis is thought to be caused by Horner syndrome (also known as Horner’s syndrome), in which mild ptosis due to incomplete paralysis of the Müller muscle can be associated with ipsilateral miosis (pupil constriction) and anhidrosis. Acquired Horner syndrome can occur even after trauma, neoplastic invasion, or vascular disease. Acquired ptosis is generally caused by aponeurotic ptosis. This can occur as a result of aging, tearing, or detachment of the levator aponeurosis.

[0078] Furthermore, the same effect can be obtained with chronic inflammation or intraocular surgery. Ptosis due to trauma can occur following eyelid laceration due to transection of the levator muscle or disruption of the nerve input. Other causes of ptosis include eyelid neoplasms, neurofibromas, or inflammatory or postoperative scarring. Mild ptosis can occur with aging. Surprisingly, through the process of evaluating many agents over a range of concentrations of such agents, certain α-adrenergic agents, particularly those containing 0.1% by weight of oxymetazoline hydrochloride, have been found to provide highly effective compositions that result in surprising treatment outcomes as measured by the results of the Lester Peripheral Field Test (LPFT). This composition can be used for the treatment of ptosis, and it has been found to persist for 4 - 10 hours, or in one embodiment 6 hours, after a single drop topical administration of such an agent to the affected eye.

[0079] Also, surprisingly, through the process of evaluating many agents over such a concentration range of such agents, it has also been found that a particular alpha - adrenergic agent containing 0.1% by weight of oxymetazoline hydrochloride provides a highly effective composition that results in a surprising treatment outcome as measured by the results of the marginal reflex distance test (MRD - 1). Further, this composition can be used for the treatment of ptosis, and it has also been found that it persists for 4 - 10 hours, or 6 hours, after a single drop of such an agent is topically administered to the affected eye. A rapid onset of the effect of 0.1% by weight of oxymetazoline hydrochloride has also been found, and improvement of ptosis was demonstrated 5 minutes after administration of the composition of the present disclosure. It has also been found that the improvement in the results of MRD - 1 continued for at least 6 hours after dose administration. It has also been found that the improvement in the results of MRD - 1 continued for at least 8 hours. The compounds and methods of the present disclosure did not exhibit tachyphylaxis, which rapidly reduces the response to sequential doses of a drug and diminishes the effect of the drug. In some embodiments, tachyphylaxis is not exhibited for 6 weeks. In some embodiments, tachyphylaxis is not exhibited for a period of 6 weeks to 3 months. In some embodiments, tachyphylaxis is not exhibited for periods of 6 weeks, 7 weeks, 9 weeks, 10 weeks, 11 weeks, 1 month, 2 months, or 3 months. In some embodiments, tachyphylaxis is not exhibited during the use of the composition or method of the present disclosure. In some embodiments, tachyphylaxis is not exhibited for a period of about 1 week, about 90 days, about 180 days, or about 1 year. In some embodiments, tachyphylaxis is not exhibited for periods of about 1 year, about 2 years, about 3 years, about 5 years, or about 10 years.

[0080] One aspect of the present disclosure is a method for treating ptosis in a subject. The method includes topically administering an effective amount of oxymetazoline to the outer surface of the eye of a subject in need of such treatment. As used herein, "treating" means reducing the severity of a condition or disease in a subject having such a condition or disease, even if only temporarily. In one aspect, reducing, even if only temporarily, means eliminating. For example, ptosis in a subject is said to be treated according to this method if, even if only temporarily, the ptosis is reduced or eliminated.

[0081] The method of the present disclosure is also related to treating other eyelid disorders or non-specific conditions in which the condition is treated by lifting the eyelid. Other conditions that can be treated by the formulations of the present disclosure include Horner's syndrome and myasthenia gravis. The method of the present disclosure can be used to treat other clinical conditions related to the eye, such as eye disorders or eye diseases. The method includes administering a therapeutically effective amount of the composition of the present disclosure to at least one eye of a subject in need of such treatment. In some aspects, clinical conditions related to the eye include dry eye syndrome (e.g., keratoconjunctivitis sicca), Sjogren's syndrome, congenital alacrimia, xerophthalmia (dry eye due to vitamin A deficiency), keratomalacia, thyroid eye disease, ophthalmic rosacea, eyelid disorders, meibomian gland disorders, meibomian gland dysfunction, ectropion, blepharitis, blepharochalasis, sarcoidosis, stye, hordeolum, chalazion, ptosis, pterygium, eyelid edema, eyelid dermatitis, trichiasis, madarosis, dacryadenitis, Stevens-Johnson syndrome, ocular graft-versus-host disease, dacryocystitis, conjunctivitis, keratoconjunctivitis, eyelid conjunctivitis, eyelid keratoconjunctivitis, allergic conjunctivitis, vernal catarrh, conjunctival suffusion), conjunctivochalasis, subconjunctival hemorrhage, pterygium, pinguecula, chemosis, iritis, iridocyclitis, glaucoma, ocular hypertension, red eye, keratitis, scleritis, episcleritis, peripheral ulcerative keratitis, neurotrophic keratitis, neurotrophic eye diseases, corneal ulcer, ulcerative keratitis, corneal abrasion, photokeratitis, ultraviolet keratitis, rabbit eye keratitis, and corneal dystrophy are included.

[0082] Other conditions include postoperative inflammation after ophthalmic surgery (e.g., eyelid surgery, cataract surgery, corneal surgery, refractive corrective surgery including photorefractive keratectomy, glaucoma surgery, lacrimal gland surgery, conjunctival surgery, eye muscle surgery, physical trauma, eye conditions caused by the following autoimmune or vascular disorders: rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Reiter's syndrome, enteropathic arthritis, psoriatic arthritis, discoid and systemic lupus erythematosus, multiple sclerosis, Graves' disease, antiphospholipid antibody syndrome, sarcoidosis, Wegener's granulomatosis, Behcet's syndrome, polyarteritis nodosa, Takayasu arteritis, dermatomyositis, psoriasis, relapsing polychondritis, vasculitis, sickle cell anemia, type II diabetes, diabetic retinopathy, and combinations thereof.

[0083] V. Dosage Frequency and Dose Escalation According to the present disclosure, any of the pharmaceutical compositions described herein is administered to a subject (e.g., a human) having or at risk of having ptosis. In some embodiments, the pharmaceutical composition is administered at a constant therapeutically effective amount from the start of treatment. The therapeutically effective amount may include 0.1 wt% oxymetazoline hydrochloride and be 1 drop per eye. In one embodiment, the dose includes 2 drops of a 0.1 wt% solution of about 0.035 g / drop with a total dose of about 0.07 mg, and the pharmaceutical composition includes about 0.035 mg of oxymetazoline hydrochloride per drop.

[0084] The pharmaceutical composition can be administered once, twice, or three times a day in unit doses, and the total daily dose of the composition is about 0.005 g, about 0.01 g, about 0.02 g, about 0.03 g, about 0.04 g, about 0.05 g, about 0.06 g, about 0.07 g, about 0.08 g, about 0.09 g, or about 0.10 g. A pharmaceutical composition containing 0.1% by weight of oxymetazoline hydrochloride can be administered once, twice, or three times a day in unit doses, and the total daily dose of oxymetazoline hydrochloride is about 0.050 mg, about 0.010 mg, about 0.020 mg, about 0.030 mg, about 0.035 mg, about 0.040 mg, about 0.050 mg, about 0.060 mg, about 0.070 mg, about 0.080 mg, about 0.090 mg, about 0.1 mg, about 0.14 mg, or about 0.21 mg. In some embodiments, the pharmaceutical composition is administered once, twice, or three times a day in unit doses to each eye. In some embodiments, the total daily dose of the composition is about 0.07 mg, about 0.14 mg, or about 0.21 mg.

[0085] In some embodiments, the formulation is administered in an amount of about 0.07 mg. In some embodiments, the formulation is administered in a single drop dose to a single eye once or for consecutive days exceeding one day with a total daily dose of about 0.035 mg. In some embodiments, the formulation is administered in a single drop dose to each eye once or for consecutive days exceeding one day with a total daily dose of about 0.07 mg of oxymetazoline hydrochloride.

[0086] In one embodiment, the pharmaceutical composition is administered once a day to one or both eyes. In one embodiment, the pharmaceutical composition is administered in the morning. In one embodiment, the pharmaceutical composition is administered in the afternoon. In one embodiment, the pharmaceutical composition is administered at night. In one embodiment, the pharmaceutical composition is administered before 4 hours before bedtime. In some embodiments, a pharmaceutical composition containing oxymetazoline or a pharmaceutically acceptable salt thereof is administered once or twice a day in unit doses containing about 0.015 mg, about 0.035 mg, or about 0.07 mg. In some embodiments, one drop is administered to each eye during each dose administration. In some embodiments, one drop is administered only to one eye during each dose administration.

[0087] VI. Pharmaceutical Compositions Another aspect of the present disclosure relates to a pharmaceutical composition comprising oxymetazoline hydrochloride. For ophthalmic applications, preferably, the solution is prepared using a physiological saline solution as a vehicle. The pH of such eye drops is preferably maintained from 4.5 to 8.0 by a suitable buffer system. Ideally, the pH of such a solution is maintained from 6.3 to 6.5. The formulation can also include conventional pharmaceutically acceptable stabilizers and surfactants. A tonicity adjusting agent can be added as needed or conveniently. This includes, but is not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjusting agent. As long as the resulting preparation is ophthalmically acceptable, various buffers and means for adjusting the pH can be used. Thus, buffers include acetate buffer, citrate buffer, phosphate buffer and borate buffer. In some aspects, the pharmaceutical composition is in an ophthalmic dosage form. The present disclosure is not limited to a particular ophthalmic dosage form, and any dosage form capable of delivering oxymetazoline hydrochloride to a patient is suitable for the present disclosure as long as the dosage form achieves the pharmacokinetics and therapeutic effects described in the present disclosure.

[0088] In one aspect, the formulation does not contain one or more preservatives.

[0089] In some aspects, the pharmaceutical composition includes an adsorbent, an antioxidant, a buffering agent, and / or a diluent.

[0090] As used herein, the term "adsorbent" is intended to mean an agent capable of retaining other molecules on its surface by physical or chemical (chemisorption) means. Such compounds include, by way of example and not limitation, powdered charcoal and activated charcoal, and other materials known to those skilled in the art.

[0091] As used herein, the term "antioxidant" means an agent that inhibits oxidation and is thus intended to be used to prevent degradation of a preparation by an oxidation process. Such compounds include, by way of example and not limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium citrate, sodium formaldehyde sulfoxylate and sodium metabisulfite, and other materials known to those skilled in the art.

[0092] As used herein, the term "buffering agent" is intended to mean a compound used to resist changes in pH upon dilution or addition of an acid or an alkali. Such compounds include, by way of example and not limitation, potassium metaphosphate, potassium phosphate, sodium acetate monobasic and anhydrous and dihydrate sodium citrate, and other materials known to those skilled in the art.

[0093] VII. LESTER PERIPHERAL FIELD TEST (LPFT) The effectiveness of the compositions of the present disclosure can be evaluated using a variety of tests to assess patient improvement. In some aspects, the Lester Peripheral Field Test (LPFT) is used to evaluate patient improvement outcomes. In some aspects, the Lester Peripheral Field Test (LPFT) is used for evaluation and the Lester Peripheral Field Test (LPFT) average score and the Lester Peripheral Field Test (LPFT) median score are determined. In some aspects, the Lester Peripheral Field Test (LPFT) average score increases by about 5 to 10 points about 0.1 to 16 hours later. In some aspects, the Lester Peripheral Field Test (LPFT) average score increases by about 5.2 points or about 6.3 points about 0.1 to 16 hours later. In some aspects, the Lester Peripheral Field Test (LPFT) average score increases by about 5.2 points or about 6.3 points about 6 hours later. In some aspects, the Lester Peripheral Field Test (LPFT) average score increases by about 5 to 10 points about 10 to 15 days later. In some aspects, the Lester Peripheral Field Test (LPFT) average score increases by about 6 to about 8 points about 10 to 15 days later. In some aspects, the Lester Peripheral Field Test (LPFT) average score increases by about 6.4 points or about 7.7 points about 10 to 15 days later. In some aspects, the Lester Peripheral Field Test (LPFT) average score increases by about 6.4 points or about 7.7 points about 14 days later.

[0094] In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points about 0.1 to 16 hours later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points about 5 to about 10 minutes later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 5.2 points or about 6.3 points about 0.1 to 16 hours later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 5.2 points or about 6.3 points about 6 hours later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 5.2 points about 6 hours later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 6.3 points about 6 hours later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 7.7 points about 2 hours later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 6.4 points about 2 hours later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points about 10 to 15 days later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 6 to about 8 points about 10 to 15 days later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 6.4 points or about 7.7 points about 10 to 15 days later. In some embodiments, the mean score of the Lester Peripheral Field Test (LPFT) increases by about 6.4 points or about 7.7 points about 14 days later.

[0095] In some embodiments, the median score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points after about 0.1 to 16 hours. In some embodiments, the median score of the Lester Peripheral Field Test (LPFT) increases by about 7 points after about 0.1 to 16 hours. In some embodiments, the Lester Peripheral Field Test (LPFT) is used for evaluation, and the average score and median score of the Lester Peripheral Field Test (LPFT) are determined. In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points after about 2 hours or about 6 hours. In some embodiments, the median score of the Lester Peripheral Field Test (LPFT) increases by about 7 points after about 6 hours. In some embodiments, the median score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points after about 10 to 15 days. In some embodiments, the median score of the Lester Peripheral Field Test (LPFT) increases by about 9 points after about 10 to 15 days. In some embodiments, the median score of the Lester Peripheral Field Test (LPFT) increases by about 9 points after about 14 days.

[0096] In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 20 points after about 1 to 9 hours. In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 15 points after about 0.1 to 16 hours. In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 10 to 15 points after about 0.1 to 16 hours. In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 15 points after about 2 to about 6 hours. In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 15 points after about 1 to 14 days. In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points after about 1 day. In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points after about 14 days. In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points after about 14 days. In some embodiments, the average score of the Lester Peripheral Field Test (LPFT) increases by about 5 to 10 points after about 0.1 to 16 hours.

[0097] In some embodiments, the mean score on the Lester Peripheral Field Test (LPFT) increases by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 points at about 0.1 to 16 hours. In some embodiments, the mean score on the Lester Peripheral Field Test (LPFT) increases by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 points at about 6 hours. In some embodiments, the mean score on the Lester Peripheral Field Test (LPFT) increases by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 points at about 10 to 15 days. In some embodiments, the mean score on the Lester Peripheral Field Test (LPFT) increases by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 points at about 14 days.

[0098] In some embodiments, the Lester Peripheral Field Test (LPFT) median score increases by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 points at about 0.1 - 16 hours. In some embodiments, the Lester Peripheral Field Test (LPFT) median score increases by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 points at about 6 hours. In some embodiments, the Lester Peripheral Field Test (LPFT) median score increases by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 points at about 10 - 15 days. In some embodiments, the Lester Peripheral Field Test (LPFT) median score increases by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 points at about 14 days.

[0099] In some embodiments, the Lester Peripheral Field Test (LPFT) median score maintains an increase over a period of about 10 minutes, about 20 minutes, about 1 hour, about 6 hours, about 8 hours, about 12 hours, or about 24 hours.

[0100] VIII. Margin Reflex Distance - 1 (MRD - 1) Test The Margin Reflex Distance - 1 (MRD - 1) test is performed using photographic measurement to evaluate the distance from the central pupillary light reflex to the central edge of the upper eyelid. External digital photographs are used to measure MRD - 1. The measurement is based on the distance from the central pupillary light reflex to the central edge of the upper eyelid, ≤2 mm (the visible central pupillary light reflex does not default to 0). The MRD - 1 test is useful for evaluating the effectiveness of treatment.

[0101] In some embodiments, the margin to reflex distance 1 test (MRD-1) is used to evaluate the improved outcome of a patient. In some embodiments, the margin to reflex distance 1 test (MRD-1) is used for the evaluation, and the margin to reflex distance 1 test (MRD-1) average score and the margin to reflex distance 1 test (MRD-1) median score are determined. In some embodiments, the margin to reflex distance 1 test (MRD-1) is performed, whereby the average score increases by about 0.2 to 1.0 points about 1 to 10 minutes later. In some embodiments, the margin to reflex distance 1 test (MRD-1) average score increases by about 0.2 to 1.0 points about 5 minutes later. In some embodiments, the margin to reflex distance 1 test (MRD-1) average score increases by about 0.6 points about 5 minutes later. In some embodiments, the margin to reflex distance 1 test (MRD-1) average score increases by about 0.5 to 1.5 points about 10 to 20 minutes later. In some embodiments, the margin to reflex distance 1 test (MRD-1) average score increases by about 0.5 to 1.5 points about 15 minutes later. In some embodiments, the margin to reflex distance 1 test (MRD-1) average score increases by about 0.9 points about 15 minutes later.

[0102] In some embodiments, the margin to reflex distance 1 test (MRD-1) average score increases by about 0.5 to 1.5 points about 5 minutes to about 16 hours later. In some embodiments, the margin to reflex distance 1 test (MRD-1) average score increases by about 0.5 to 1.5 points about 15 minutes to about 16 hours later. In some embodiments, the margin to reflex distance 1 test (MRD-1) average score increases by about 0.5 to 1.5 points about 15 minutes later. In some embodiments, the average score increases by about 0.2 to 1.0 points about 5 minutes to about 16 hours later. In some embodiments, the average score increases by about 0.5 to 1.5 points about 5 minutes to about 42 days later.

[0103] In some embodiments, the mean score of the margin-reflex distance 1 test (MRD-1) increases by about 1.5 points, about 1.4 points, about 1.3 points, about 1.2 points, about 1.1 points, about 1.0 point, about 0.9 point, about 0.8 point, about 0.7 point, about 0.6 point, about 0.5 point, about 0.4 point, or about 0.3 point at about 5 minutes to about 16 hours later. In some embodiments, the mean score of the margin-reflex distance 1 test (MRD-1) increases by about 1.5 points, about 1.4 points, about 1.3 points, about 1.2 points, about 1.1 points, about 1.0 point, about 0.9 point, about 0.8 point, about 0.7 point, about 0.6 point, about 0.5 point, about 0.4 point, or about 0.3 point at about 5 minutes later. In some embodiments, the mean score of the margin-reflex distance 1 test (MRD-1) increases by about 1.5 points, about 1.4 points, about 1.3 points, about 1.2 points, about 1.1 points, about 1.0 point, about 0.9 point, about 0.8 point, about 0.7 point, about 0.6 point, about 0.5 point, about 0.4 point, or about 0.3 point at about 15 minutes later. In some embodiments, the mean score of the margin-reflex distance 1 test (MRD-1) increases by about 1.5 points, about 1.4 points, about 1.3 points, about 1.2 points, about 1.1 points, about 1.0 point, about 0.9 point, about 0.8 point, about 0.7 point, about 0.6 point, about 0.5 point, about 0.4 point, or about 0.3 point at about 16 hours later.

[0104] In some embodiments, the mean score of the margin-reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 1 to 20 minutes later. In some embodiments, the mean score of the margin-reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 5 minutes later.

[0105] In some embodiments, the mean score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 10 to 20 minutes later. In some embodiments, the mean score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 15 minutes later.

[0106] In some embodiments, the mean score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 2 to 12 hours later. In some embodiments, the mean score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 2 hours later. In some embodiments, the mean score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 6 hours later.

[0107] In some embodiments, the average score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 5 to 20 days later. In some embodiments, the average score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 14 days later.

[0108] In some embodiments, the average score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 30 to 60 days later. In some embodiments, the average score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 42 days later.

[0109] In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 1 to 20 minutes. In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 0.1 to 16 hours, for example, after 8 hours. In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 5 minutes.

[0110] In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 10 to 20 minutes. In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 15 minutes.

[0111] In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 2 to 12 hours. In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 2 hours. In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 6 hours.

[0112] In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 5 to 20 days. In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points after about 14 days.

[0113] In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 30 to 60 days. In some embodiments, the median score of the marginal reflex distance 1 (MRD-1) increases by about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points at about 42 days.

[0114] IX. Pharmacokinetics In one embodiment, the dosage comprises two drops of a 0.1 wt% composition at a total dosage of about 0.070 mg, or about 0.035 mg / drop, and the pharmaceutical composition comprises about 0.035 mg of oxymetazoline hydrochloride per drop. In another embodiment, each drop of the eye drop solution comprises 0.035 mg (0.1% oxymetazoline hydrochloride, which is equivalent to 0.031 mg (0.088% of the oxymetazoline free base equivalent)).

[0115] The compositions and methods of the present disclosure are useful for minimizing systemic exposure of a patient to oxymetazoline hydrochloride. In some embodiments, the average AUC 0-∞ of the pharmaceutical composition after single-dose administration is about 300 to about 700 pg·h / mL. In some embodiments, the average AUC 0-∞ of the pharmaceutical composition after single-dose administration is about 468 pg·h / mL.

[0116] In some embodiments, the T max of the pharmaceutical composition after single-dose administration is about 0.5 to about 6 hours. In some embodiments, the T max of the pharmaceutical composition after single-dose administration is about 2 to 4 hours. In some embodiments, the T max of the pharmaceutical composition after single-dose administration is about 0.5 to 4 hours. In some embodiments, the T max of the pharmaceutical composition after single-dose administration is about 2 hours.

[0117] In some embodiments, the average T of the pharmaceutical composition after a single-dose administration to a patient max is from about 0.5 hours to about 12 hours, from about 0.5 hours to about 10 hours, from about 0.5 hours to about 8 hours, from about 0.5 hours to about 6 hours, from about 6 hours to about 12 hours, from about 6 hours to about 10 hours, from about 6 hours to about 8 hours, from about 7 hours to about 12 hours, from about 7 hours to about 10 hours, from about 7 hours to about 8 hours, from about 8 hours to about 12 hours, from about 8 hours to about 10 hours, from about 9 hours to about 12 hours, from about 9 hours to about 10 hours, or from about 10 hours to about 12 hours. In some embodiments, the average T of the pharmaceutical composition max is from about 0 hours to about 6 hours, from about 1 hour to about 6 hours, from about 1 hour to about 5 hours, from about 2 hours to about 5 hours, from about 2 hours to about 4 hours, or from about 2 hours to about 3 hours. In one embodiment, the average T of the pharmaceutical composition max is about 2.5 hours. In some embodiments, the median T of the pharmaceutical composition max is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours.

[0118] In some embodiments, the average C of the pharmaceutical composition after a single-dose administration max is from about 25 pg / ml to about 35 pg / ml. In some embodiments, the average C of the pharmaceutical composition after a single-dose administration max is from about 28 to 32 pg / ml. In some embodiments, the average C of the pharmaceutical composition after a single-dose administration max is about 30.5 pg / ml.

[0119] In one embodiment, the dose comprises 2 drops of a 0.1 wt% composition at about 0.035 g / drop with a total dose of about 0.070 mg, and the pharmaceutical composition comprises about 0.035 mg of oxymetazoline hydrochloride per drop. In some embodiments, the average C of the pharmaceutical composition after a single-dose administration to a patient max is from about 10 pg / ml to about 40 pg / ml, from about 12 pg / ml to about 38 pg / ml, from about 14 pg / ml to about 36 pg / ml, from about 16 pg / ml to about 34 pg / ml, from about 18 pg / ml to about 32 pg / ml, or from about 20 pg / ml to about 30 pg / ml. In some embodiments, the average C of the pharmaceutical composition after a single-dose administrationmax is about 20 pg / ml, about 21 pg / ml, about 22 pg / ml, about 22 pg / ml, about 23 pg / ml, about 24 pg / ml, about 25 pg / ml, about 26 pg / ml, about 27 pg / ml, about 28 pg / ml, about 29 pg / ml, about 30 pg / ml, about 31 pg / ml, about 32 pg / ml, about 33 pg / ml, about 34 pg / ml, about 35 pg / ml, about 36 pg / ml, about 37 pg / ml, about 38 pg / ml, about 39 pg / ml, or about 40 pg / ml. In some embodiments, the average C of the pharmaceutical composition after single-dose administration max is from about 25 pg / ml to about 35 pg / ml. In some embodiments, the average C of the pharmaceutical composition after single-dose administration max is from about 28 to 32 pg / ml. In some embodiments, the average C of the pharmaceutical composition after single-dose administration max is about 30.5 pg / ml. In some embodiments, the average C of the pharmaceutical composition after single-dose administration max is about 30.5 pg / ml and the geometric mean Cmax is about 28.3 pg / mL.

[0120] In some embodiments, the area under the mean plasma concentration-time curve (AUC 0-∞ ) is measured. In some embodiments, the average AUC of the pharmaceutical composition after single-dose administration 0-∞is from about 0 pg·h / mL to about 800 pg·h / mL, from about 50 pg·h / mL to about 800 pg·h / mL, from about 50 pg·h / mL to about 750 pg·h / mL, from about 100 pg·h / mL to about 750 pg·h / mL, from about 100 pg·h / mL to about 700 pg·h / mL, from about 150 pg·h / mL to about 700 pg·h / mL, from about 150 pg·h / mL to about 650 pg·h / mL, from about 200 pg·h / mL to about 650 pg·h / mL, from about 200 pg·h / mL to about 600 pg·h / mL, from about 250 pg·h / mL to about 600 pg·h / mL, from about 250 pg·h / mL to about 550 pg·h / mL, from about 300 pg·h / mL to about 550 pg·h / mL, from about 300 pg·h / mL to about 500 pg·h / mL, from about 350 pg·h / mL to about 500 pg·h / mL, from about 400 pg·h / mL to about 500 pg·h / mL, or from about 420 pg·h / mL to about 480 pg·h / mL. In some embodiments, the average AUC of the pharmaceutical composition after single-dose administration 0-∞ is about 468 pg·h / mL.

[0121] In some embodiments, the geometric mean AUC of the pharmaceutical composition after single-dose administration 0-∞ is from about 0 pg·h / mL to about 800 pg·h / mL, from about 50 pg·h / mL to about 800 pg·h / mL, from about 50 pg·h / mL to about 750 pg·h / mL, from about 100 pg·h / mL to about 750 pg·h / mL, from about 100 pg·h / mL to about 700 pg·h / mL, from about 150 pg·h / mL to about 700 pg·h / mL, from about 150 pg·h / mL to about 650 pg·h / mL, from about 200 pg·h / mL to about 650 pg·h / mL, from about 200 pg·h / mL to about 600 pg·h / mL, from about 250 pg·h / mL to about 600 pg·h / mL, from about 250 pg·h / mL to about 550 pg·h / mL, from about 300 pg·h / mL to about 550 pg·h / mL, from about 300 pg·h / mL to about 500 pg·h / mL, from about 350 pg·h / mL to about 500 pg·h / mL, from about 400 pg·h / mL to about 500 pg·h / mL, or from about 420 pg·h / mL to about 480 pg·h / mL. In some embodiments, the geometric mean AUC of the pharmaceutical composition after single-dose administration 0-∞ is about 439 pg·h / mL.

[0122] X. Packaging The storage form and packaging of the formulation are also important for maintaining and delivering a consistent product. The packaging method of the present disclosure may involve the use of a single unit dose container formed from a transparent low density polyethylene (LDPE) resin. In some embodiments, the disposable container is formed by a blow / fill / seal (“B / F / S” or “BFS”) process. In some embodiments, the BFS process is performed in a sterile environment. The BFS process is a process of forming, filling, and sealing a container in one continuous automated system, wherein the contents are kept sterile. BFS vials are continuously manufactured on a machine that extrudes plastic resin at high temperature, rendering the resin sterile. Pellets are fed via gravity from a hopper at the top of the BFS machine into an extruder. The extruder heats the resin pellets to about 170°C to about 230°C, melting the plastic granules to produce a sterile extruded plastic tube (parison). The process begins by melting and extruding a low density polyethylene (LDPE) resin to form a parison (a hot resin in a hollow tubular form). Next, the seal mold closes to seal the vial, and the filled and sealed vial is released from the mold. Since the entire process is performed without human intervention, the risk of contamination is reduced. BFS vials can be filled and sealed upside down to form a “card” containing multiple vials to ensure consistent filling. Sterile packaging techniques are important when the contents do not contain a preservative or antimicrobial agent. In some embodiments, the volume of the BFS vial is about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, or about 1.0 mL. In some embodiments, the volume of the BFS vial is about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, or about 10 mL. In some embodiments, the volume of the BFS vial is about 0.5 mL. In some embodiments, the volume of the BFS vial is 0.34 mL.

[0123] After BFS packaging, the container can be enclosed in a foil laminate pouch for individual packaging and / or a child-resistant zipper bag to prevent unwanted access. Pharmaceuticals usually require product packaging compliant with government regulations to include child-safe features to prevent children, for example those under 5 years old, from accessing products that can cause serious illness or injury. Alternatively, the container can be enclosed in a child-resistant foil laminate pouch. The child-resistant pouch material can include PET, aluminum foil, and / or a sealant.

[0124] The present disclosure is further illustrated by the following examples, which should not be construed as further limitations. The content of all references cited throughout this application is hereby expressly incorporated herein by reference.

Example

[0125] Example 1 Formulation Oxymetazoline hydrochloride eye drops, 0.1 wt%, were manufactured at a batch size of 200 kg. The batch formulation of the drug product is shown in Table 1.

Table 1

[0126] To improve the overall absorption of oxymetazoline in the eye without using preservatives, formulation enhancement was pursued. The vehicle formulation is a balanced salt solution for eye irrigation made to physiological pH and isotonic salt concentration. The addition of the excipient hypromellose, a viscosity modifier, helps to add retention time in the eye and improve eye comfort. Eight development batches were tested using either hypromellose (HPMC) or sodium carboxymethylcellulose (Na CMC). The effect of this change on pH was also measured. Stability tests were conducted at 25°C ± 2°C / 40% RH, 40°C ± 2°C / NMT 25% RH, and 55°C / ambient RH. The composition and results of these tests, including 3-month stability test data, can be seen in Tables 2 and 3 below.

Table 2

Table 3

[0127] Example 2 PK Analysis The following pharmacokinetic data were generated based on a single-drop dose in each eye, with each drop containing approximately 0.035 mg of oxymetazoline hydrochloride, for a total of 0.07 mg of oxymetazoline hydrochloride.

[0128] Parameter C max , AUC 0-∞ , and T max were evaluated based on a study population of 24 patients.

[0129] A study was conducted to determine the mean plasma oxymetazoline concentration after a single-dose administration of 0.1 wt% of oxymetazoline hydrochloride eye drops. The results of the study are detailed in Figure 1, Tables 4, and 5.

Table 4

Table 5

[0130] Example 3 Phase 3 Data, Study 1 Study 1: This study was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial of the safety and efficacy of oxymetazoline hydrochloride ophthalmic solution, 0.1%, administered once daily (QD) (one drop in each eye), compared to vehicle in subjects with acquired ptosis. A total of 140 subjects were randomized in an approximate 2:1 ratio, i.e., 94 to oxymetazoline hydrochloride 0.1 wt% QD at 16 sites (N = 94); vehicle (N = 46). Oxymetazoline hydrochloride was administered topically for 42 days (6 weeks). The study was conducted in two periods, i.e., Period 1 (safety and efficacy) had a duration of 2 weeks and Period 2 (long-term safety and comfort) had a duration of 4 weeks. The mean age of the subjects was 64.2 years.

[0131] 3.2 Efficacy Efficacy was evaluated by photographic measurement of LPFT (primary) and MRD-1. The primary efficacy assessment was stratified to compare oxymetazoline hydrochloride to vehicle with respect to the mean increase from baseline (Day 1, Time 0) in the number of points seen in the upper 4 rows of the LPFT of the test eye as follows: 1. Day 1, Time 6 2. Day 14, Time 2 This study was completed and the results are shown below. The increase in the number of points seen in the upper visual field (change in LPFT) in the oxymetazoline hydrochloride group compared to the vehicle group was statistically significant at both time points. This indicates that improvement in the upper visual field was evident at 6 hours after dosing on Day 1 and 2 hours after dosing on Day 14, as shown in Table 6. The mean change from baseline in visual field data at the time points of Day 14, Time 6, Day 14, Time 8, and Day 42 can be seen in Table 7. [Table 6] [Table 7]

[0132] Example 4 Phase 3 Data, Study 2 Study 2: This study was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial of the safety and efficacy of once-daily (QD) treatment (1 drop per eye) with oxymetazoline hydrochloride compared to vehicle in subjects with acquired ptosis. A total of 164 subjects were randomized in an approximately 2:1 ratio, i.e., QD of 0.1 wt% oxymetazoline hydrochloride (N = 109) at 27 sites; vehicle (N = 55). 0.1 wt% oxymetazoline hydrochloride was administered topically for 42 days (6 weeks). This study was conducted in two periods, i.e., the duration of Period 1 (safety and efficacy) was 2 weeks and the duration of Period 2 (long-term safety and comfort) was 4 weeks. The mean age of the subjects was 63.5 years. One subject was less than 18 years old.

[0133] 4.1 Efficacy Efficacy was evaluated by photographic measurement of LPFT (primary) and MRD-1. The primary efficacy assessment was stratified to compare oxymetazoline hydrochloride with vehicle with respect to the mean increase from baseline (Day 1, Time 0) in the number of points seen in the top 4 rows of the LPFT of the test eye as follows: 1. 6 hours on Day 1 2. 2 hours on Day 14 The results are shown below. The increase in the number of points seen in the superior visual field (change in LPFT) in the oxymetazoline hydrochloride group compared to the vehicle group at both time points was statistically significant. This indicates that improvement in the superior visual field was evident at 6 hours after dosing on Day 1 and 2 hours after dosing on Day 14 in Table 8.

[0134] Even in the photographic measurement of MRD-1, a positive effect by oxymetazoline hydrochloride treatment was shown. The increase in LPFT was numerically greater in the oxymetazoline hydrochloride group than in the vehicle group at all time points after administration. A greater increase in MRD-1 was observed for the oxymetazoline hydrochloride group than for the vehicle group at all time points after 6 weeks of administration, Table 9. The increase in the MRD-1 value observed 5 minutes after dosing indicated that the action had started by 5 minutes.

[0135] 4.2 Safety Oxymetazoline hydrochloride had high tolerance, and the intensity of the observed AEs was mainly mild.

[0136] 4.3 Results LPFT was performed using a Humphrey visual field analyzer. This is an age-corrected screening test using a 3-zone strategy. 35 points are tested in the upper visual field and 14 points are tested in the lower visual field. A maximum of 48° is tested in the upper visual field. The fixation center is shifted 15° downward to enable a maximum upper visual field test (Ho et al., 2011). The lower visual field test serves as a reference but is not used in the analysis. A representative grid of a Lester perimetry test can be seen in Figure 2. The subject holds the head in front of the chin and below the chin, keeps the head stationary, and relaxes the forehead. The subject views the fixation target throughout the test. Correction lenses are not required for LPFT unless the subject has difficulty seeing the target without correction lenses (e.g., severe myopes, severe hyperopes, or severe astigmatics). [Table 8] [Table 9]

[0137] Example 5 Stability of Oxymetazoline Hydrochloride Preparation The stability test was carried out on the oxymetazoline hydrochloride preparation for 24 months at a relative humidity of 40%. The results of the stability test are shown in Table 10 below, and the vehicle stability data can be found in Table 11.

Table 10

Table 11

[0138] The oxymetazoline hydrochloride solution was stable over five measurement time points of 0 months, 6 months, 12 months, 18 months, and 24 months, indicating good stability and shelf life of the formulated preparation.

[0139] Example 6 Study on the Clinical Supply Stability of Oxymetazoline Hydrochloride The oxymetazoline hydrochloride formulation was prepared according to Table 12. The stability test was carried out on the oxymetazoline preparation for 24 to 30 months.

Table 12

[0140] Three commercial-scale one-step process batches (R60681, R60701, and R60711) were tested at the end of the shelf life. The results support the proposed 24-month shelf life. The stability data at 24 months and 30 months are shown in Figures 3A - 3B, Figures 4A - 4B, and Figures 5A - 5B for each batch (R60681, R60701, and R60711) respectively.

[0141] Throughout this application, various publications are indicated in parentheses and are referenced by author name and date, or patent number or patent publication number. The disclosures of these publications are hereby incorporated by reference in their entirety into this application to more fully describe the state of the art known to those of ordinary skill in the art as of the date of the present disclosure described and claimed herein. However, the citation of references in this specification should not be construed as an admission that such references are prior art to the present disclosure. In embodiments of the present invention, for example, the following items are provided. (Item 1) a) about 0.1% by weight of oxymetazoline hydrochloride; b) about 0.2% to about 1.0% by weight of sodium chloride; c) about 0.05% to about 0.10% by weight of potassium chloride; d) about 0.02% to about 0.06% by weight of calcium chloride; e) about 0.01% to about 0.05% by weight of magnesium chloride; f) one or more suitable buffers; g) about 0.1% to about 0.90% by weight of hypromellose; h) optionally, a pH adjuster; A pharmaceutically stable aqueous ophthalmic preparation comprising wherein the pH of the preparation is in the range of about 6.3 to about 6.5. (Item 2) The preparation according to item 1, wherein the one or more suitable buffers constitute about 0.05% to about 1.0% by weight. (Item 3) The preparation according to item 2, wherein the one or more suitable buffers comprise sodium acetate trihydrate and sodium citrate. (Item 4) The preparation according to item 3, wherein the one or more suitable buffers comprise about 0.39% by weight of sodium acetate trihydrate and about 0.17% by weight of sodium citrate. (Item 5) The preparation according to item 1, wherein the preparation contains about 0.64% by weight of sodium chloride, about 0.075% by weight of potassium chloride, about 0.048% by weight of calcium chloride dihydrate, and about 0.03% by weight of magnesium chloride hexahydrate. (Item 6) The preparation according to item 1, wherein the pH adjuster is selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calcium carbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide, ammonium hydroxide, ammonium phosphate, and combinations thereof. (Item 7) The preparation according to item 6, wherein the pH adjuster contains hydrochloric acid. (Item 8) The preparation according to item 1, wherein the preparation does not contain a preservative. (Item 9) The preparation according to item 8, wherein the preparation is stable for 0 to 24 months. (Item 10) The preparation according to item 8, wherein the preparation is stable for at least 24 months. (Item 11) The preparation according to item 10, wherein the preparation is stable for at least 24 months at 25 °C and a relative humidity of 40%. (Item 12) A disposable container containing the preparation according to item 8. (Item 13) The disposable container according to item 12, wherein the volume of the disposable container is about 0.5 mL. (Item 14) The disposable container according to item 13, wherein the disposable container is contained in a pouch that cannot be opened by children. (Item 15) The disposable container according to item 12, wherein the disposable container delivers about 0.035 mg of oxymetazoline hydrochloride per drop. (Item 16) a) about 0.1% by weight of oxymetazoline hydrochloride; and b) about 0.2% to about 1.0% by weight of sodium chloride; and c) about 0.05% to about 0.10% by weight of potassium chloride; and d) about 0.02% to about 0.06% by weight of calcium chloride; e) about 0.01% to about 0.05% by weight of magnesium chloride; f) one or more suitable buffers; g) about 0.1% to about 0.90% by weight of hypromellose; h) optionally, a pH adjuster; A pharmaceutically stable aqueous ophthalmic preparation comprising: wherein the pH of the preparation is in the range of about 6.3 to about 6.5. (Item 17) The preparation according to Item 16, wherein the one or more suitable buffers constitute about 0.05% to about 1.0% by weight. (Item 18) The preparation according to Item 17, wherein the one or more suitable buffers contain sodium acetate trihydrate and sodium citrate. (Item 19) The preparation according to Item 18, wherein the one or more suitable buffers contain about 0.39% by weight of sodium acetate trihydrate and about 0.17% by weight of sodium citrate. (Item 20) The preparation according to Item 16, wherein the preparation contains about 0.64% by weight of sodium chloride, about 0.075% by weight of potassium chloride, about 0.048% by weight of calcium chloride dihydrate, and about 0.03% by weight of magnesium chloride hexahydrate. (Item 21) The preparation according to Item 16, wherein the pH adjuster is selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calcium carbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide, ammonium hydroxide, ammonium phosphate, and combinations thereof. (Item 22) The preparation according to Item 21, wherein the pH adjuster contains hydrochloric acid. (Item 23) The preparation according to Item 16, wherein the preparation is stable for 0 to 24 months. (Item 24) The preparation according to item 16, wherein the preparation is stable for at least 24 months. (Item 25) The preparation according to item 24, wherein the preparation is stable for at least 24 months at 25 °C and a relative humidity of 40%. (Item 26) A disposable container containing the preparation according to item 16. (Item 27) The disposable container according to item 26, wherein the volume of the disposable container is about 0.5 mL. (Item 28) The disposable container according to item 26, wherein the disposable container is in a packaging that cannot be opened by children. (Item 29) The disposable container according to item 26, wherein the disposable container delivers about 0.035 mg of oxymetazoline hydrochloride per drop. (Item 30) A pharmaceutically stable aqueous ophthalmic preparation free of preservatives, comprising: a) about 0.1% by weight of oxymetazoline hydrochloride; b) about 0.64% by weight of sodium chloride; c) about 0.075% by weight of potassium chloride; d) about 0.048% by weight of calcium chloride dihydrate; e) about 0.03% by weight of magnesium chloride hexahydrate; f) one or more suitable buffer solutions; g) about 0.5% by weight of hypromellose; h) hydrochloric acid if necessary; and i) the pH of the preparation is in the range of about 6.3 to about 6.5. (Item 31) A method for treating ptosis of a subject, the method comprising administering to at least one eye of the subject: a) about 0.1% by weight of oxymetazoline hydrochloride; b) about 0.2% to about 1.0% by weight of sodium chloride; c) about 0.05% to about 0.10% by weight of potassium chloride; d) from about 0.02% to about 0.06% by weight of calcium chloride; e) from about 0.01% to about 0.05% by weight of magnesium chloride; f) one or more suitable buffers; g) from about 0.1% to about 0.90% by weight of hypromellose; h) hydrochloric acid, if necessary; administering a therapeutically effective amount of a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising: wherein the pH range of the pharmaceutically stable aqueous ophthalmic formulation is from about 6.3 to about 6.5. (Item 32) The method according to Item 31, wherein the ptosis is acquired aponeurotic ptosis. (Item 33) The method according to Item 31, wherein the pharmaceutically stable aqueous ophthalmic formulation is administered to the subject continuously for one day or more at a dose of one drop per eye, with a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. (Item 34) The average C max after single-dose administration of the formulation is from about 25 to about 35 pg / ml. (Item 35) The average AUC 0-∞ after single-dose administration of the formulation is from about 300 to about 700 pg·h / mL. (Item 36) The T max after single-dose administration of the formulation is from about 0.5 to about 6 hours. (Item 37) The pharmaceutically stable aqueous ophthalmic preservative-free formulation comprises a) about 0.64% by weight of sodium chloride; b) about 0.075% by weight of potassium chloride; c) about 0.048% by weight of calcium chloride dihydrate; d) about 0.03% by weight of magnesium chloride hexahydrate; e) about 0.5% by weight of hypromellose The method according to item 31, comprising (Item 38) A method for increasing the vertical separation between the upper and lower eyelids of at least one eye of a subject, the method comprising administering to at least one eye of the subject the following: f) about 0.1% by weight of oxymetazoline hydrochloride; g) about 0.2% to about 1.0% by weight of sodium chloride; h) about 0.05% to about 0.10% by weight of potassium chloride; i) about 0.02% to about 0.06% by weight of calcium chloride; j) about 0.01% to about 0.05% by weight of magnesium chloride; k) one or more suitable buffers; l) about 0.1% to about 0.90% by weight of hypromellose; m) hydrochloric acid, if necessary; comprising administering a pharmaceutically stable aqueous ophthalmic preservative-free formulation, wherein the pH range of the pharmaceutically stable aqueous ophthalmic formulation is about 6.3 to about 6.5. (Item 39) The method according to item 38, wherein the formulation is administered to the subject continuously for one day or more at a dose of one drop per single eye, with a total daily dose of about 0.035 mg of oxymetazoline hydrochloride. (Item 40) The method according to item 38, wherein the formulation is administered to the subject continuously for one day or more at a dose of one drop per each eye, with a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. (Item 41) The average C max after single-dose administration of the formulation is about 25 to about 35 pg / ml. The method according to item 40. (Item 42) The average AUC 0-∞ after single-dose administration of the formulation is about 300 to about 700 pg·h / mL. The method according to item 40. (Item 43) The T maxThe method according to item 40, which is about 0.5 to about 6 hours. (Item 44) The pharmaceutically stable aqueous ophthalmic preservative-free formulation is a) about 0.64% by weight of sodium chloride; b) about 0.075% by weight of potassium chloride; c) about 0.048% by weight of calcium chloride dihydrate; d) about 0.03% by weight of magnesium chloride hexahydrate; e) about 0.5% by weight of hypromellose The method according to item 38, comprising (Item 45) A method for improving the Lester perimetric field test (LPFT) score of a subject, the method comprising administering to at least one eye of the subject the following: a) about 0.1% by weight of oxymetazoline hydrochloride; b) about 0.2% to about 1.0% by weight of sodium chloride; c) about 0.05% to about 0.10% by weight of potassium chloride; d) about 0.02% to about 0.06% by weight of calcium chloride; e) about 0.01% to about 0.05% by weight of magnesium chloride; f) 1 or more suitable buffers; g) about 0.1% to about 0.90% by weight of hypromellose; h) hydrochloric acid as required; The method according to item 45, comprising administering a pharmaceutically stable aqueous ophthalmic preservative-free formulation, wherein the pH range of the pharmaceutically stable aqueous ophthalmic formulation is about 6.3 to about 6.5, and the average LPFT score increases by about 5 to 10 points about 0.1 to 16 hours after administration. (Item 46) The method according to item 45, wherein the formulation is administered to the subject continuously for 1 day or more at a dose of 1 drop per eye, with a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. (Item 47) The average C after single-dose administration of the formulation maxThe method according to item 46, wherein it is about 25 to about 35 pg / ml. (Item 48) The average AUC after single-dose administration of the preparation 0-∞ The method according to item 46, wherein it is about 300 to about 700 pg·h / mL. (Item 49) The T after single-dose administration of the preparation max The method according to item 46, wherein it is about 0.5 to about 6 hours. (Item 50) The method according to item 45, wherein the median score of the perimetric test (LPFT) increases by about 5 to 10 points about 6 hours after administration. (Item 51) The method according to item 45, wherein tachyphylaxis is not shown for at least 6 weeks. (Item 52) The pharmaceutically stable aqueous ophthalmic preservative-free preparation is a) about 0.64% by weight of sodium chloride and; b) about 0.075% by weight of potassium chloride and; c) about 0.048% by weight of calcium chloride dihydrate and; d) about 0.03% by weight of magnesium chloride hexahydrate and; e) about 0.5% by weight of hypromellose and The method according to item 45, comprising (Item 53) A method for improving the margin reflex distance test 1 (MRD-1) score of a subject, the method comprising administering to at least one eye of the subject the following: a) about 0.1% by weight of oxymetazoline hydrochloride and; b) about 0.2% to about 1.0% by weight of sodium chloride and; c) about 0.05% to about 0.10% by weight of potassium chloride and; d) about 0.02% to about 0.06% by weight of calcium chloride and; e) about 0.01% to about 0.05% by weight of magnesium chloride and; f) 1 or more suitable buffers and; g) about 0.1% to about 0.90% by weight of hypromellose and; h) hydrochloric acid as necessary; administering a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising wherein the pH range of the pharmaceutically stable aqueous ophthalmic formulation is from about 6.3 to about 6.5, and the average score increases by about 0.2 to 1.5 points about 1 to 20 minutes after administration or about 0.1 to 16 hours after administration. (Item 54) The method according to item 53, wherein the pharmaceutically stable aqueous ophthalmic formulation is administered to the subject continuously for 1 day or more at a dose of 1 drop per eye as about 0.07 mg of oxymetazoline hydrochloride per day. (Item 55) The average C max after single-dose administration of the formulation is from about 25 to about 35 pg / ml, according to the method of item 54. (Item 56) The average AUC 0-∞ after single-dose administration of the formulation is from about 300 to about 700 pg·h / mL, according to the method of item 54. (Item 57) The T max after single-dose administration of the formulation is from about 0.5 to about 6 hours, according to the method of item 54. (Item 58) The method according to item 53, wherein the average score of the marginal reflex distance test 1 (MRD-1) increases by about 0.2 to 1.0 points about 5 minutes after administration. (Item 59) The method according to item 53, wherein tachyphylaxis is not exhibited for at least 6 weeks. (Item 60) The pharmaceutically stable aqueous ophthalmic preservative-free formulation comprises a) about 0.64% by weight of sodium chloride; and b) about 0.075% by weight of potassium chloride; and c) about 0.048% by weight of calcium chloride dihydrate; and d) about 0.03% by weight of magnesium chloride hexahydrate; and e) about 0.5% by weight of hypromellose The method according to item 53, including

Claims

1. A product comprising an aqueous ophthalmic sterile preparation filled in a container, wherein the preparation comprises: a) about 0.1% by weight of oxymetazoline hydrochloride; b) about 0.2% to about 1.0% by weight of sodium chloride; c) about 0.05% to about 0.10% by weight of potassium chloride; d) about 0.02% to about 0.06% by weight of calcium chloride or its hydrate; e) about 0.01% to about 0.05% by weight of magnesium chloride or its hydrate; f) one or more suitable buffer solutions; g) about 0.5% to about 0.9% by weight of hypromellose; h) optionally, a pH adjuster; and the buffer solution contains sodium acetate or its hydrate and sodium citrate or its hydrate, the pH of the preparation is in the range of about 5.8 to about 6.6, the viscosity of the preparation is about 15 cPs to about 35 cPs, the mass osmolality of the preparation is about 290 to about 365 mOsm / kg, product.

2. The product according to claim 1, wherein the calcium chloride or its hydrate is calcium chloride dihydrate, and the magnesium chloride or its hydrate is magnesium chloride hexahydrate.

3. The product according to claim 1, wherein the preparation contains the one or more suitable buffer solutions at a total concentration of about 0.05% to about 1.0% by weight.

4. The product according to claim 1, wherein the buffer solution contains sodium acetate trihydrate and sodium citrate dihydrate.

5. The product according to claim 1, wherein the pH adjuster is selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calcium carbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide, ammonium hydroxide, ammonium phosphate, and combinations thereof.

6. The product according to claim 5, wherein the pH adjuster contains hydrochloric acid.

7. The product according to claim 1, wherein the preparation does not contain a preservative.

8. The product according to claim 1, wherein the pH of the preparation is in the range of about 6.3 to about 6.

5.

9. The product according to claim 1, wherein the viscosity of the preparation is about 25 cPs.

10. The product according to claim 1, wherein the mass osmolality of the preparation is about 301 to about 326 mOsm / kg.

11. The product according to claim 1, wherein the container is a single-use container.

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