RU2820596C2 - Oxymetazoline compositions and methods for treating ophthalmic disorders - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical industry, namely to compositions and methods of treating ophthalmic disorders. Aqueous pharmaceutically stable ophthalmic composition for treating ptosis, comprising: a) 0.1 wt.% of oxymetazoline hydrochloride; b) from 0.2 to 1.0 wt.% of sodium chloride; c) from 0.05 to 0.10 wt.% of potassium chloride; d) from 0.02 to 0.06 wt.% of calcium chloride; e) from 0.01 to 0.05 wt.% of magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90 wt.% of hypromellose; and h) optionally a pH regulator; wherein the composition has a pH in range of 5.8 to 6.8, and the composition is stable for a period of at least 24 months. Aqueous pharmaceutically stable ophthalmic composition for increasing vertical separation of an upper eyelid and a lower eyelid in at least one eye in a subject, comprising said components in said amount, and wherein the composition is stable for a period of at least 24 months. Aqueous pharmaceutically stable ophthalmic composition for improving the upper part of the visual field in a subject, comprising the above substances in the above amount, wherein the composition has a pH in range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. Disposable container containing any of the above compositions. Aqueous pharmaceutically stable ophthalmic composition for treating ptosis, consisting of said substances in said amount, wherein the composition has a pH in range of 5.8 to 6.8, and the composition is stable for a period of at least 24 months. Aqueous pharmaceutically stable ophthalmic composition for increasing vertical separation of an upper eyelid and a lower eyelid in at least one eye in a subject, consisting of said substances in said amount, wherein the composition has a pH in range of 5.8 to 6.8, and the composition is stable for a period of at least 24 months. Aqueous pharmaceutically stable ophthalmic composition for improving the upper part of the visual field in a subject, consisting of the above substances in the above amount, wherein the composition has a pH in range of 5.8 to 6.8, and the composition is stable for a period of at least 24 months. Disposable container containing any of the above composition. Aqueous pharmaceutically stable ophthalmic preservative-free composition for treating ptosis, comprising said substances in said amount, wherein the composition has a pH in range of 5.8 to 6.8, and the composition is stable for a period of at least 24 months. Aqueous pharmaceutically stable ophthalmic preservative-free composition for increasing vertical separation of an upper eyelid and a lower eyelid in at least one eye in a subject, comprising said substances in a specified amount, wherein the composition has a pH in range of 5.8 to 6.8, and the composition is stable for a period of at least 24 months. Method of treating ptosis in a subject, comprising administering into at least one eye of a subject a therapeutically effective amount of an aqueous pharmaceutically stable ophthalmic preservative-free composition comprising said substances in said amount, wherein the composition has a pH in range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. Method for increasing vertical separation of upper eyelid and lower eyelid of at least one eye in a subject, comprising administering to at least one eye of a subject a therapeutically effective amount of an aqueous pharmaceutically stable ophthalmic preservative-free composition comprising said substances in said amount, wherein the composition has a pH in range of 5.8 to 6.8, and the composition is stable for a period of at least 24 months. Method for improving the Lester peripheral visual field test (LPFT) score in a subject, comprising administering to at least one eye of a subject a therapeutically effective amount of an aqueous pharmaceutically stable ophthalmic preservative-free composition comprising said substances in said amount, wherein the composition has a pH in range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months, and whereby the average LPFT score is increased by 5–10 points in 0.1–16 hours after administration. Method for improving the score of the marginal reflex distance 1 (MRD-1) test in a subject, comprising administering to at least one eye of a subject a therapeutically effective amount of an aqueous pharmaceutically stable ophthalmic preservative-free composition comprising said substances in said amount, wherein the composition has a pH in range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months and whereby the average score is increased by 0.2–1.5 points 1–20 minutes after administration or 0.1-16 hours after administration.

EFFECT: use of the group of inventions provides an ophthalmic composition stable for a period of at least 24 months, a disposable container for storing the composition, as well as effective treatment of ptosis, increased vertical separation of upper and lower eyelids, improved Lester peripheral visual field test (LPFT), improved marginal reflex distance test 1 (MRD-1).

52 cl, 5 dwg, 12 tbl, 6 ex

Description

Field to which the invention relates

[0001] The present invention relates to compositions and methods for treating various ophthalmic disorders, including disorders associated with drooping eyelids or such conditions. The present invention also relates to compositions comprising oxymetazoline, pharmaceutically acceptable oxymetazoline salts, and methods for their preparation and use.

Prerequisites for creating the invention

[0002] Blepharoptosis (more commonly known as ptosis) is an abnormal partial or complete drooping of the upper eyelid, which usually occurs due to partial or complete dysfunction of the muscles that elevate the upper eyelid: the levator maxillary eyelid and/or Müller's muscle. Ptosis occurs when the muscles that lift the eyelid (levator superioris and/or Müller's muscles) are not strong enough to do so properly. This can affect one eye or both eyes and is most common in older people as the muscles in the eyelids begin to weaken. It is one of the most common eyelid disorders, occurring in approximately 12% of adults over 50 years of age (GV Sridharan, RC Tallis, B. Leatherbarrow, WM 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 various etiologies, but most often is aponeurotic as a result of involutional changes in the levator aponeurosis, or as a result of stretching or rupture during cataract surgery, lens replacement, or as a result of prolonged wear of contact lenses, both hard and soft lenses. (Custer PL, (2008) Blepharoptosis. In: Yanoff M., Duker JS, editors. Ophthalmology. 3rd ed. St. Louis, MO: Mosby Elsevier; p. 1397-1403; van den Bosch WA, Lemij HG, Blepharoptosis induced by prolonged hard contact lens wear. Ophthalmology. 1992;99:1759-65; Kersten RC, Kulwin DR, Acquired ptosis in the young and middle-aged adult population. AK, Foroozan R, Arat YO, Edmond JC, Yen MT, Ptosis in young soft contact lens wearers. 2007;

[0003] Patients with ptosis may have significant defects in the upper visual field, which can affect activities of daily living such as driving, crossing the street, and reading. Treatment for acquired ptosis usually involves surgery, and there are risks of infection, bleeding, overcorrection, undercorrection, decreased visual acuity, and lagophthalmos (inability to close the eyelids completely) (Finsterer J., Ptosis: causes, presentation, and management. Aesthetic Plast. Surg 2003;27(3):193-204). Mechanical treatments for ptosis (scleral contact lenses with an eyelid lift strip, ptosis eyelid props attached to glasses, or adhesive tape or adhesive to attach the upper eyelid to the supraorbital structures) have limitations such as patient dissatisfaction with 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 treatment for ptosis was not used because the agents that were studied (eg, epinephrine, dipiverphine, apraclonidine, phenylephrine, brimonidine) either caused mydriasis as a result of blurred vision or photophobia or caused 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 elevated intraocular pressure: a comparative study. Arch. Ophthalmol. 1979 (10): 1865-6; 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, is an α-adrenergic agonist. Oxymetazoline is a direct-acting sympathomimetic amine that acts on alpha-adrenergic receptors in the arterioles of the conjunctiva and nasal mucosa.

[0005] To solve the existing problem of balancing effectiveness and relative risk of adverse events, a new ophthalmic composition of oxymetazoline hydrochloride was developed.

The essence of the invention

[0006] In some aspects, the compositions of the present invention relate to an aqueous pharmaceutically stable ophthalmic composition comprising: about 0.1 wt%. oxymetazoline hydrochloride; from about 0.2% wt. up to about 1.0% wt. sodium chloride; from about 0.05% wt. up to about 0.10% wt. potassium chloride; from about 0.02% wt. up to about 0.06% wt. calcium chloride; from about 0.01% wt. up to about 0.05% wt. magnesium chloride; one or more suitable buffers; from about 0.1% wt. up to about 0.90% wt. hypromellose; and optionally a pH regulator; wherein the composition has a pH in the range of about 6.3 to about 6.5. In some aspects, one or more suitable buffers range from about 0.05% by weight. up to about 1.0% wt. In some aspects, one or more suitable buffers include sodium acetate trihydrate and sodium citrate. In some aspects, one or more suitable buffers include about 0.39% by weight. sodium acetate trihydrate and about 0.17% wt. sodium citrate. In some aspects, the composition includes about 0.64 wt.%. sodium chloride, about 0.075% wt. potassium chloride, about 0.048% wt. calcium chloride dihydrate and about 0.03% wt. 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 composition does not include a preservative. In some aspects, the composition is stable for 0-24 months. In some aspects, the composition is stable for at least 24 months. In some aspects, the composition is stable at 25°C and 40% relative humidity for at least 24 months. In some aspects, the composition is provided ready for use 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 presented in child-safe packaging. In some aspects, the disposable container delivers about 0.035 mg of oxymetazoline hydrochloride per drop.

[0007] The compositions of the present invention also relate to an aqueous pharmaceutically stable ophthalmic composition consisting of: about 0.1 wt%. oxymetazoline hydrochloride; from about 0.2% wt. up to about 1.0% wt. sodium chloride; from about 0.05% wt. up to about 0.10% wt. potassium chloride; from about 0.02% wt. up to about 0.06% wt. calcium chloride; from about 0.01% wt. up to about 0.05% wt. magnesium chloride; one or more suitable buffers; from about 0.1% wt. up to about 0.90% wt. hypromellose; and optionally a pH regulator; wherein the composition has a pH in the range of about 6.3 to about 6.5. In some aspects, one or more suitable buffers range from about 0.05 wt%. up to about 1.0% wt. In some aspects, one or more suitable buffers include sodium acetate trihydrate and sodium citrate. In some aspects, one or more suitable buffers include about 0.39% by weight. sodium acetate trihydrate and about 0.17% wt. sodium citrate. In some aspects, the composition includes about 0.64 wt%. sodium chloride, about 0.075% wt. potassium chloride, about 0.048% wt. calcium chloride dihydrate and about 0.03% wt. 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 composition is stable for 0-24 months. In some aspects, the composition is stable for at least 24 months. In some aspects, the composition is stable at 25°C and 40% relative humidity for at least 24 months. In some aspects, the composition is provided ready for use 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 presented in child-safe packaging. In some aspects, the disposable container is presented in a child-safe pouch. In some aspects, the disposable container delivers about 0.035 mg of oxymetazoline hydrochloride per drop.

[0008] The compositions of the present invention also relate to an aqueous pharmaceutically stable ophthalmic preservative-free composition comprising: about 0.1% wt. oxymetazoline hydrochloride; 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; one or more suitable buffers; about 0.5% wt. hypromellose; and optionally hydrochloric acid; wherein the composition has a pH in the range of about 6.3 to about 6.5.

[0009] The methods of the present invention relate to a method of treating ptosis in a subject, comprising administering to at least one eye of the subject a therapeutically effective amount of an aqueous, pharmaceutically stable, preservative-free ophthalmic composition comprising: about 0.1% by weight. oxymetazoline hydrochloride; from about 0.2% wt. up to about 1.0% wt. sodium chloride; from about 0.05% wt. up to about 0.10% wt. potassium chloride; from about 0.02% wt. up to about 0.06% wt. calcium chloride; from about 0.01% wt. up to about 0.05% wt. magnesium chloride; one or more suitable buffers; from about 0.1% wt. up to about 0.90% wt. hypromellose; and optionally hydrochloric acid; wherein the aqueous pharmaceutically stable ophthalmic composition has a pH ranging from about 6.3 to about 6.5. In some aspects, ptosis is acquired blepharoptosis. In some aspects, the composition is administered to a subject over one or more consecutive days at a dose of one drop in each eye for a total daily dose of about 0.07 mg of oxymetazoline hydrochloride.

[0010] In some aspects, the average _Cmax after administration of a single dose of the composition is from about 25 to about 35 pg/ml. In some aspects, the average AUC _0-∞ after administration of a single dose of the composition is from about 300 to about 700 pg⋅h/ml. In some aspects, the _Tmax after administration of a single dose of the composition is from about 0.5 to about 6 hours. In some aspects, the methods of the present invention relate to a method of treating ptosis using an aqueous, pharmaceutically stable, ophthalmic, preservative-free composition comprising: about 0.64% by weight. 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 methods of the present invention also relate to a method of increasing the vertical separation of the upper and lower eyelids in a subject, comprising administering to at least one eye of the subject an aqueous pharmaceutically stable ophthalmic preservative-free composition comprising: about 0.1% by weight. oxymetazoline hydrochloride; from about 0.2% wt. up to about 1.0% wt. sodium chloride; from about 0.05% wt. up to about 0.10% wt. potassium chloride; from about 0.02% wt. up to about 0.06% wt. calcium chloride; from about 0.01% wt. up to about 0.05% wt. magnesium chloride; one or more suitable buffers; from about 0.1% wt. up to about 0.90% wt. hypromellose; and optionally hydrochloric acid; wherein the aqueous pharmaceutically stable ophthalmic composition has a pH ranging from about 6.3 to about 6.5.

[0012] In some aspects, the composition is administered to a subject over one or more consecutive days at a dose of one drop per eye, for a total daily dose of about 0.035 mg of oxymetazoline hydrochloride. In some aspects, the composition is administered to a subject over one or more consecutive days at a dose of one drop in each eye, for a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. In some aspects, the average _Cmax after administration of a single dose of the composition is from about 25 to about 35 pg/ml. In some aspects, the average AUC _0-∞ after administration of a single dose of the composition is from about 300 to about 700 pg⋅h/ml. In some aspects, the _Tmax after administration of a single dose of the composition is from about 0.5 to about 6 hours.

[0013] In some aspects, the aqueous pharmaceutically stable ophthalmic preservative-free composition includes: about 0.64% by weight. 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.

[0014] The methods of the present invention are also directed to a method of improving the Lester Peripheral Field Test (LPFT) score of a subject, comprising administering to at least one eye of the subject an aqueous pharmaceutically stable ophthalmic preservative-free composition comprising: about 0.1% wt. oxymetazoline hydrochloride; from about 0.2% wt. up to about 1.0% wt. sodium chloride; from about 0.05% wt. up to about 0.10% wt. potassium chloride; from about 0.02% wt. up to about 0.06% wt. calcium chloride; from about 0.01% wt. up to about 0.05% wt. magnesium chloride; one or more suitable buffers; from about 0.1% wt. up to about 0.90% wt. hypromellose; and optionally hydrochloric acid; wherein the aqueous pharmaceutically stable ophthalmic composition has a pH ranging from about 6.3 to about 6.5, whereby the average LPFT score increases by about 5 to 10 points from about 0.1 to 16 hours after administration. In some aspects, the composition is administered to a subject over one or more consecutive days at a dose of one drop in each eye for a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. In some aspects, the average Cmax after administration of a single dose of the composition is from about 25 to about 35 pg/ml. In some aspects, the average AUC _0-∞ after administration of a single dose of the composition is from about 300 to about 700 pg⋅h/ml. In some aspects, the _Tmax after administration of a single dose of the composition is from about 0.5 to about 6 hours. In some aspects, the median Lester peripheral visual field test (LPFT) score increases by about 5-10 points approximately 6 hours after administration. In some aspects, tachyphylaxis does not appear for at least six weeks. In some aspects, the aqueous pharmaceutically stable ophthalmic preservative-free composition includes: about 0.64% by weight. 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 methods of the present invention also provide a method of improving the marginal reflex distance 1 (MRD-1) test score of a subject, comprising administering to at least one eye of the subject an aqueous pharmaceutically stable ophthalmic preservative-free composition comprising: about 0.1 % wt. oxymetazoline hydrochloride; from about 0.2% wt. up to about 1.0% wt. sodium chloride; from about 0.05% wt. up to about 0.10% wt. potassium chloride; from about 0.02% wt. up to about 0.06% wt. calcium chloride; from about 0.01% wt. up to about 0.05% wt. magnesium chloride; one or more suitable buffers; from about 0.1% wt. up to about 0.90% wt. hypromellose; and optionally hydrochloric acid; wherein the aqueous pharmaceutically stable ophthalmic composition has a pH ranging from about 6.3 to about 6.5, whereby the average score increases by about 0.2 to 1.5 points at about 1 to 20 minutes after administration or at about 1 -6 hours, for example 8 hours, after administration. In some aspects, the aqueous pharmaceutically stable ophthalmic composition is administered to a subject over one or more consecutive days at a dose of one drop in each eye, for a total daily dose of about 0.07 mg of oxymetazoline hydrochloride. In some aspects, the average _Cmax after administration of a single dose of the composition is from about 25 to about 35 pg/ml. In some aspects, the average AUC _0-∞ after administration of a single dose of the composition is from about 300 to about 700 pg⋅h/ml. In some aspects, the _Tmax after administration of a single dose of the composition is from about 0.5 to about 6 hours. In some aspects, the average marginal reflex distance test 1 (MRD-1) score increases by about 0.2 to 1.0 points approximately 5 minutes after administration. In some aspects, tachyphylaxis does not appear for at least six weeks. In some aspects, the aqueous pharmaceutically stable ophthalmic preservative-free composition includes: about 0.64% by weight. 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 aspects, use of the compositions and methods of the present invention does not cause tachyphylaxis. In some aspects, tachyphylaxis does not manifest itself for 6 weeks. In some aspects, tachyphylaxis does not manifest itself for a period of 6 weeks to 3 months. In some aspects, tachyphylaxis does not appear 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 aspects, tachyphylaxis does not occur during use of the compositions or methods of the present disclosure.

Brief description of drawings

[0016] FIG. 1 shows the average concentration achieved after local administration of one dose of an ophthalmic solution of 0.1% by weight. oxymetazoline HCl using one drop in each eye.

[0017] FIG. Figure 2 shows a diagram of the Lester test for testing the peripheral visual field.

[0018] FIG. 3A and 3B show stability data obtained after 24 and 30 months for oxymetazoline formulation, lot R60681.

[0019] FIG. 4A and 4B show stability data obtained after 24 and 30 months for oxymetazoline formulation, lot R60701.

[0020] FIG. 5A and 5B show stability data obtained after 24 and 30 months for oxymetazoline formulation, lot R60711.

Detailed Description of the Invention

I. Definitions

[0021] Unless otherwise specified, all technical and scientific terms used in this application have the same meaning as commonly understood by one skilled in the art to which the present invention relates. In the event of a conflict, this application, including definitions, will control. Unless the context otherwise requires, terms in the singular shall include the plural and terms in the plural shall include the singular. All publications, patents and other references cited in this application are incorporated by reference in their entirety for all purposes as if each individual publication or patent application had been specifically and individually designated for inclusion by reference.

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

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

[0024] Singular forms include plural entities unless the context clearly dictates otherwise. The singular terms, as well as the terms “one or more” and “at least one” may be used interchangeably throughout this application. In some aspects, a term given in the singular means "one and only." In other aspects, the singular term includes "two or more" or "several."

[0025] The term "about" as used herein means about, approximately, rounded or about. When the term "about" is used in conjunction with a numeric range, it modifies that range by extending the boundaries above and below the specified numeric values. Generally, the term "about" in the context of this application modifies a numerical value with a deviation above and below the specified value by 10 percent, up or down (above or below).

[0026] The term “and/or,” when used herein, is to be construed as specifically disclosing each of two definable features or components, with or without the other. Thus, the term “and/or” as used herein in a phrase such as “A and/or B” is intended to include “A and B,” “A or B,” “A” (only) and “B " (only). Likewise, the term “and/or” used in a phrase such as “A, B and/or C” is intended to cover each of the following: 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 (only); B (only); and C (only).

[0027] The term "pharmaceutically acceptable" as used herein refers to those compounds, substances, compositions and/or dosage forms which, based on sound medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problems or complications, in accordance with a reasonable benefit/risk ratio.

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

[0029] The term "effective amount" or "pharmaceutically effective amount" as used herein refers to a dose or amount of a drug or pharmaceutically active substance that is sufficient to produce a required or desired therapeutic response, or in other words, an amount, which is sufficient to produce a significant biological response when administered to a patient.

[0030] The term "unit dosage form" or "unit dose composition" as used herein refers to a device containing an amount of a therapeutic compound, wherein said amount is such that one or more predetermined units can be provided per therapeutic administration.

[0031] The term "% wt." or "weight/volume" as used herein refers to the ratio between components relative to volume. For example, a solution of 5% wt. ethanol in water will be a solution containing 5 g of ethanol for every 100 ml of water.

[0032] The term " _Cmax " as used herein refers to the maximum plasma concentration of a drug following administration to a subject.

[0033] The term "T _max " as used herein refers to the time required to achieve maximum plasma concentration ("C _max ") after drug administration.

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

[0035] The term "AUC _0-t " as used herein refers to the area under the drug concentration-time curve from time zero to the time of the last measured concentration ( _Ct ).

[0036] The term "AUC_0-∞" in the context of this application refers to the area under the drug concentration-time curve from time zero to infinity. AUC_0-∞calculated up to the last measured concentration (AUC_0-T) and extrapolated to infinity (AUC_t-∞), for the degree of absorption of the drug.

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

[0038] The term "Lester peripheral visual 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). . It is an age-adjusted screening test in which thirty-five points are tested in the upper field, with 14 points tested in the lower field. A maximum of 48° is assessed at the top of the visual field. The center of fixation is shifted 15° lower, allowing maximum testing of the upper field. The bottom margin test is used for comparison 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 a photographic measurement of the distance from the central pupillary reflection of light to the central edge of the upper eyelid. External digital images are used to measure MRD-1. Measurements are based on the distance from the central pupillary light reflection to the central edge of the upper eyelid, ≤ 2 mm (no visible central pupillary light reflection is the default value of 0). MRD-2 refers to the measurement of the vertical distance from the center of the pupil and the edge of the lower eyelid.

[0040] The term "treat" or "treat" as used herein refers to administering a composition to a subject for therapeutic purposes.

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

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

II. Composition

[0043] The compositions of the invention include an effective amount of an alpha-adrenergic agonist formulated for ophthalmic administration. The invention provides compositions and methods useful for treating ptosis. In some aspects, the composition is an ophthalmic solution. In some aspects, oxymetazoline hydrochloride is formulated for topical delivery to the eye as an aseptically prepared, sterile, preservative-free ophthalmic solution (eye drops). The ophthalmic solution may contain 0.1% wt. oxymetazoline hydrochloride in balanced salt solution with added viscosity modifier (hypromellose). It can be filled into clear, single-dose 0.5 mL low-density polyethylene (LDPE) vials using blow/fill/seal (BFS) technology, which can be individually packaged in foil pouches.

[0044] When introduced at 0.1% wt. Oxymetazoline is thought to stimulate α2 adrenergic receptors in the Müller muscle, causing it to contract, thereby lifting the upper eyelid with less retraction of the lower eyelid.

[0045] In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition consisting of: about 0.1 wt%. oxymetazoline hydrochloride; from about 0.2% wt. up to about 1.0% wt. sodium chloride; from about 0.05% wt. up to about 0.10% wt. potassium chloride; from about 0.02% wt. up to about 0.06% wt. calcium chloride; from about 0.01% wt. up to about 0.05% wt. magnesium chloride; one or more suitable buffers; from about 0.1% wt. up to about 0.90% wt. hypromellose; and optionally a pH regulator; wherein the composition has a pH in the range of about 6.3 to about 6.5.

[0046] In some aspects, one or more suitable buffers range from about 0.05 wt%. up to about 1.0% wt. In some aspects, one or more suitable buffers include sodium acetate trihydrate and sodium citrate. In some aspects, the composition includes about 0.64 wt.%. sodium chloride, about 0.075% wt. potassium chloride, about 0.048% wt. calcium chloride dihydrate and about 0.03% wt. 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.

[0047] In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition 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; one or more suitable buffers; 0.5% wt. hypromellose; and optionally hydrochloric acid; wherein the composition has a pH in the range from 6.3 to 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(hydroxymethyl)aminomethane (TRIS), and various mixed phosphate buffers (including combinations of Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), and mixtures thereof. In one aspect, one or more suitable buffers include 0.39 wt%. sodium acetate trihydrate and 0.17% wt. sodium citrate.

[0048] In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition 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; wherein the composition has a pH in the range from 6.3 to 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 Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), and mixtures thereof. In one aspect, one or more suitable buffers include 0.39 wt%. sodium acetate trihydrate and 0.17% wt. sodium citrate.

[0049] In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition 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; one or more suitable buffers; 0.5% wt. hypromellose; and optionally hydrochloric acid; wherein the composition has a pH in the range from 6.3 to 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 Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), and mixtures thereof. In one aspect, one or more suitable buffers include 0.39 wt%. sodium acetate trihydrate and 0.17% wt. sodium citrate.

[0050] One aspect of the invention is a method for treating ptosis in a subject. The method includes the step of administering an effective amount of oxymetazoline to the eye of a subject in need of such treatment. In some aspects, the method includes administering to at least one eye of the subject a therapeutically effective amount of an aqueous pharmaceutically stable ophthalmic composition 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; one or more suitable buffers; 0.5% wt. hypromellose; and optionally hydrochloric acid; wherein the composition has a pH in the range from 6.3 to 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 Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), and mixtures thereof. In one aspect, one or more suitable buffers include 0.39 wt%. sodium acetate trihydrate and 0.17% wt. sodium citrate.

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

[0052] In some aspects, the composition 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 about 0.035 mg of oxymetazoline hydrochloride (0.0308 mg of oxymetazoline free base).

[0053] In some aspects, the method includes administering to at least one eye a therapeutically effective amount of an aqueous pharmaceutically stable ophthalmic composition consisting essentially of: 0.1% by weight. 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; wherein the composition has a pH in the range from 6.3 to 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 Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), 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 composition is administered in an amount of about 0.07 mg.

[0054] In some aspects, the method includes administering to at least one eye a therapeutically effective amount of an aqueous pharmaceutically stable ophthalmic composition 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; one or more suitable buffers; 0.5% wt. hypromellose; and optionally hydrochloric acid; wherein the composition has a pH in the range from 6.3 to 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 Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), and mixtures thereof. In some aspects, one or more suitable buffers include 0.39 wt%. sodium acetate trihydrate and 0.17% wt. sodium citrate.

[0055] In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition 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; one or more suitable buffers; 0.5% wt. hypromellose; and optionally hydrochloric acid; wherein the composition has a pH in the range from 6.3 to 6.5. In other aspects, 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 Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), and mixtures thereof. In some aspects, one or more suitable buffers include 0.39 wt%. sodium acetate trihydrate and 0.17% wt. sodium citrate.

[0056] In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition 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. oxymetazoline hydrochloride. In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition comprising about 0.10 wt%, about 0.12 wt%, about 0.13 wt%, about 0.14 wt%, about 0.15 wt%. wt., about 0.16% wt., about 0.17% wt., about 0.18% wt., about 0.19% wt. or about 0.20% wt. oxymetazoline hydrochloride. In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition 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. oxymetazoline hydrochloride.

[0057] In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition 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; wherein the composition has a pH in the range from 6.3 to 6.5. In other aspects, 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 Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), and mixtures thereof. In some aspects, one or more suitable buffers include 0.39 wt%. sodium acetate trihydrate and 0.17% wt. sodium citrate.

[0058] In some aspects, the solution is an aqueous pharmaceutically stable ophthalmic composition 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; one or more suitable buffers; 0.5% wt. hypromellose; and optionally hydrochloric acid; wherein the composition has a pH in the range from 6.3 to 6.5. In other aspects, 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 Na ₂ HPO ₄ , NaH ₂ PO ₄ , and KH ₂ PO ₄ ), and mixtures thereof. In some aspects, one or more suitable buffers include 0.39 wt%. sodium acetate trihydrate and 0.17% wt. sodium citrate.

[0059] In one aspect, the composition includes sodium chloride, and the amount of sodium chloride in the composition is 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.

[0060] In one aspect, the composition includes potassium chloride, and the amount of potassium chloride in the composition 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%, about 0 .2% wt., about 0.3% wt., about 0.4% wt. or about 0.5% wt.

[0061] In one aspect, the composition includes calcium chloride, and the amount of calcium chloride in the composition 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.

[0062] In one aspect, the composition includes magnesium chloride, and the amount of magnesium chloride in the composition 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 composition includes hypromellose, and the amount of hypromellose in the composition 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 oxymetazoline salt. The term "pharmaceutically acceptable salt" is as accepted in the art and refers to the relatively non-toxic addition salts of inorganic and organic acids of the compositions of the present invention or any components thereof, including, without limitation, therapeutic agents, excipients, other substances, and the like. Examples of pharmaceutically acceptable salts include salts formed from mineral acids such as hydrochloric acid and sulfuric acid, and salts formed from organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Examples of suitable inorganic bases for forming salts include, but are not limited to, hydroxides, carbonates and bicarbonates of mania, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc and the like. Salts can also be formed with suitable organic bases, including bases that are non-toxic and strong enough to form such salts.

III. Composition stability

[0065] The compositions of the present invention are stable. Long-term stability is an important property to consider when preparing ophthalmic compositions, especially those compositions that do not contain preservatives. Various critical quality characteristics must be maintained during the shelf life of the composition to ensure long-term stability of the composition, including quantity, osmolality, impurities, viscosity, weight loss, and sterility. These characteristics are influenced by various factors including temperature, relative humidity and/or pH.

[0066] Osmolality is the concentration of all solutes in a given body of water, which is expressed in osmolality units and is a property important for the preservation of an ophthalmic composition. The eyes of most subjects have an osmolality of about 300 mOsm, and it is therefore important that any composition administered to the eye is maintained within approximately this range, for example, from about 290 to about 365 mOsm/kg, for the composition to be well tolerated.

[0067] Stability of the pH of the solution is also important for comfort and safety. If the elements of an ophthalmic composition change pH over time, the composition may become unstable. In addition, changes in pH may result in the introduction of a composition that may cause damage to the eye. Therefore, it is important that the desired physiological pH is maintained throughout the life of the composition. Maintaining a pH close to neutral and the natural pH of the eye is important for safety.

[0068] Viscosity is a quality of an ophthalmic composition that is critical to prolonging the retention time of the composition in the eye. It is important that the viscosity of the composition is maintained throughout the life of the composition so that the viscosity is constant and the delivery time and retention time of the active ingredient is maintained. For example, in one aspect, the viscosity is from about 15 to about 35 cP to maintain eye retention time and ocular comfort.

[0069] Unstable solutions may decompose over time to form undesirable decomposition products. These products may result from unwanted chemical reactions involving the active ingredient, including hydrolysis and oxidation. Instability of the solution, taking into account degradation products, can lead to both toxicity due to the formation of these impurities and lower concentrations 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 the degradation of oxymetazoline include:

[0070] Therefore, the presence of these degradation products must be limited and controlled as the composition ages to prevent potential loss of activity of the active ingredient and to prevent potential unwanted toxicity arising from any degradation products that are formed.

[0071] It is also important to maintain the sterility of the composition. Sterility testing ensures that the ophthalmic composition is not contaminated with microorganisms that could potentially lead to infection or other complications.

[0072] Maintaining the water content of the composition is important to maintain the desired concentration of the components present in the composition, and therefore loss of water mass will affect the concentration of the components. Likewise, maintaining and monitoring component degradation is also important as degradation products can also affect component concentrations, solution pH, and may introduce unwanted contaminants that may pose a risk to eye safety. Limiting degradation products is critical to drug product safety, and composition and route variables can influence degradation products.

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

[0074] Stability is also affected by environmental conditions during storage. For example, ambient temperature and/or humidity may affect the long-term stability of an ophthalmic drug. In some aspects, the compositions of the present invention are stable at temperatures from about 4°C to about 30°C, from about 4°C to about 25°C, from about 4°C to about 20°C, from about 10°C to about 20°C, from about 15°C to about 20°C, or from about 20°C to about 30°C. In some aspects, the compositions of the present invention are stable at 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 aspects, the compositions of the present invention are stable at relative humidity of from about 10% to about 70%, from about 20% to about 60%, from about 30% to about 50%, from about 20% to about 80%, from about 30% to about 70%, from about 40% to about 60%. In some aspects, the compositions of the present invention are stable at relative humidity from about 10% to about 70%. In some aspects, the compositions of the present invention are stable at relative humidity from about 40% to about 60%. In some aspects, the compositions of the present invention 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 aspects, the compositions of the present invention are stable at a relative humidity of about 10%. In some aspects, the compositions of the present invention are stable at a relative humidity of about 20%. In some aspects, the compositions of the present invention are stable at a relative humidity of about 30%. In some aspects, the compositions of the present invention are stable at a relative humidity of about 40%. In some aspects, the compositions of the present invention are stable at a relative humidity of about 50%. In some aspects, the compositions of the present invention are stable at a relative humidity of about 60%. In some aspects, the compositions of the present invention are stable at a relative humidity of about 70%. In some aspects, the compositions of the present invention are stable at a relative humidity of about 80%.

IV. Treatment methods

[0076] The upper eyelids are typically raised by contraction of the levator muscle (levator) and Müller muscles. Ptosis creates a tired appearance that may be cosmetically undesirable; In more severe cases, ptosis can interfere with vision in the affected eye(s). Besides fatigue and age-related weakening of the levator and Müller muscles as the main causes of ptosis, there are a number of other conditions that are known to cause ptosis. For example, causes of ptosis can also be myogenic, neurogenic, aponeurotic, mechanical or traumatic causes; it usually occurs alone but may be associated with various other conditions such as hereditary, immunological or degenerative disorders, tumors and infections. The methods of the present invention are useful for the treatment of ptosis. In some aspects, a therapeutically effective amount of oxymetazoline hydrochloride is delivered in an ophthalmologically acceptable carrier. In some aspects, the carrier is an emulsion, suspension, gel, ointment, or solution.

[0077] In a specific aspect, the solution is a topical ophthalmic solution administered as eye drops. Myogenic causes of ptosis may include diseases that can cause muscle weakness or nerve damage, such as myasthenia gravis and chronic progressive external ophthalmoplegia. Dystrophy or dysgenesis 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), which controls the muscles that lift the upper eyelid. The cause of congenital neurogenic ptosis is thought to be Horner's syndrome (also known as Horner's syndrome), in which mild ptosis due to Müller muscle paresis may be associated with ipsilateral miosis (constriction of the pupil) and anhidrosis. Acquired Horner's syndrome can occur after trauma, neoplastic lesion, or even vascular disease. Acquired ptosis is usually caused by aponeurotic ptosis. This may occur as a result of aging, dehiscence, or avulsion of the levator aponeurosis.

[0078] Moreover, chronic inflammation or intraocular surgery can lead to the same effect. Ptosis due to trauma can occur after an eyelid tear with dissection of the levator palpebral muscles or disruption of neural input. Other causes of ptosis include eyelid tumors, neurofibromas, or scarring from inflammation or surgery. Mild ptosis may occur with age. Surprisingly, it has been discovered that in evaluating a number of agents over a range of concentrations of such agents, certain alpha-adrenergic agonists, including in particular Oxymetazoline HCl 0.1 wt%, provide a highly effective formulation that produces unexpected treatment results as measured using a test Lester for assessment of peripheral visual field (LPFT). It has been found that this composition can be used to treat ptosis lasting for 4-10 hours, or 6 hours in one aspect, after topical administration of one drop of such agent to the affected eye.

[0079] It was also unexpectedly discovered, in the course of evaluating a number of agents over a range of concentrations of such agents, that certain alpha-adrenergic agonists, including in particular oxymetazoline hydrochloride 0.1% by weight, provide a highly effective composition that produces unexpected treatment results, as measured using the marginal reflex distance test (MRD-1). It has been found that this composition can be used to treat ptosis lasting for 4-10 hours, or 6 hours, after topical administration of one drop of such agent to the affected eye. The rapid effects of oxymetazoline hydrochloride 0.1 wt% were also observed, with demonstrated improvement in ptosis 5 minutes after administration of the compositions of the present invention. It was also found that the improvement in MRD-1 outcome lasted at least 6 hours after dosing. It was also found that the improvement in MRD-1 score lasted for at least 8 hours. The compounds and methods of the present invention do not exhibit tachyphylaxis, which is a rapidly declining response to successive doses of a drug, making it less effective. In some aspects, tachyphylaxis does not appear for six weeks. In some aspects, tachyphylaxis does not appear for a period of six weeks to three months. In some aspects, tachyphylaxis does not appear for a period of 6 weeks, 7 weeks, 9 weeks, 10 weeks, 11 weeks, 1 month, 2 months, or 3 months. In some aspects, tachyphylaxis does not occur during use of the compositions or methods of the present invention. In some aspects, tachyphylaxis does not appear for a period of about 1 week, about 90 days, about 180 days, or about one year. In some aspects, tachyphylaxis does not appear for a period of about 1 year, about 2 years, about 3 years, about 5 years, or about 10 years.

[0080] One An aspect of the invention is a method of treating ptosis in a subject. The method includes the step of locally administering an effective amount of oxymetazoline to the outer surface of the eye of a subject in need of such treatment. As used herein, the term “treating” means reducing, even if only temporarily, the severity of a condition or disease in a subject having such condition or disease. In one aspect, reduction means elimination, even if only temporarily. For example, ptosis in a subject is considered to be treated in accordance with a given method if the ptosis is reduced or eliminated, even if only temporarily.

[0081] The methods of the present invention also relate to the treatment of other eyelid diseases or non-specific conditions, wherein the condition is treated by eyelid elevation. Other conditions that can be treated using the compositions of the present invention include Horner's syndrome and myasthenia gravis. The methods of the present invention can be used to treat other clinical conditions associated with the eyes, such as an ocular disorder or ocular disease. The method includes administering to at least one eye of a subject in need of such treatment a therapeutically effective amount of a composition of the present invention. In some aspects, the clinical condition associated with the eye includes dry eye syndrome (eg, keratoconjunctivitis sicca), Sjögren's syndrome, congenital alacryma, xerophthalmia (dry eye due to vitamin A deficiency), keratomalacia, thyroid-related eye disease, ocular rosacea, eyelid pathologies, meibomian gland disease, meibomian gland dysfunction, ectropion, blepharitis, blepharochalasis, sarcoidosis, stye, hordeolum, chalazion, ptosis, pterygium, eyelid edema, eyelid dermatitis, trichiasis, madarosis, dacryoadenitis, Stevens-Johnson syndrome, eye graft disease against the host”, dacryocystitis, conjunctivitis, keratoconjunctivitis, blepharoconjunctivitis, blepharokeratoconjunctivitis, allergic conjunctivitis, vernal conjunctivitis, conjunctival hyperemia, conjunctivochalasis, subconjunctival hemorrhage, pterygium, pinguculu, chemosis, iritis, and ridocyclitis, glaucoma, ocular hypertension, red eye, keratitis, scleritis, episcleritis, peripheral ulcerative keratitis, neurotrophic keratitis, neurotrophic eye disease, corneal ulcer, ulcerative keratitis, corneal abrasion, ultraviolet keratitis, palpebral fissure keratitis, and corneal dystrophy.

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

V. Frequency of administration and dose escalation

[0083] In accordance with the present invention, a subject (eg, a human) having ptosis or at risk of ptosis is administered any of the pharmaceutical compositions described herein. In some aspects, the pharmaceutical compositions are administered at a constant therapeutically effective dose from the start of treatment. A therapeutically effective dose may contain 0.1 wt%. oxymetazoline HCl and can be one drop per eye. In one aspect, the dose includes two drops of about 0.035 g/drop of 0.1 wt%. solution at a total dose of about 0.07 mg, and wherein the pharmaceutical composition comprises about 0.035 mg of oxymetazoline hydrochloride in each drop.

[0084] The pharmaceutical composition can be administered three times a day, twice a day, or once a day at a unit dose, with a total daily dose of the composition of 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 Oxymetazoline hydrochloride 0.1% wt., can be administered three times a day, twice a day or once a day at a standard dose, with a total daily dose of oxymetazoline hydrochloride being 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 aspects, the pharmaceutical composition is administered three times daily, twice daily, or once daily at a unit dose to each eye. In some aspects, the total daily dose of the composition is about 0.07 mg, about 0.14 mg, or about 0.21 mg.

[0085] In some aspects, the composition is administered in an amount of about 0.07 mg. In some aspects, the composition is administered over one or more consecutive days at a dose of one drop per eye for a total daily dose of about 0.035 mg. In some aspects, the composition is administered over one or more consecutive days at a dose of one drop in each eye for a total daily dose of about 0.07 mg of oxymetazoline hydrochloride.

[0086] In one aspect, the pharmaceutical composition is administered once daily to one or both eyes. In one aspect, the pharmaceutical composition is administered in the morning. In one aspect, the pharmaceutical composition is administered during the day. In one aspect, the pharmaceutical composition is administered in the evening. In one aspect, the pharmaceutical composition is administered more than 4 hours before bedtime. In some aspects, a pharmaceutical composition comprising oxymetazoline or a pharmaceutically acceptable salt thereof is administered twice daily or once daily at a unit dose comprising about 0.015 mg, about 0.035 mg, or about 0.07 mg. In some aspects, one drop is administered to each eye during each dosage administration. In some aspects, one drop is administered to only one eye during each dosage.

VI. Pharmaceutical compositions

[0087] Another aspect of the present invention relates to a pharmaceutical composition comprising oxymetazoline hydrochloride. For ophthalmic use, preferably the solutions are prepared using physiological saline as a carrier. The pH of such ophthalmic solutions is preferably maintained between 4.5 and 8.0 using an appropriate buffer system. Ideally, the pH of such solutions is maintained between 6.3 and 6.5. The compositions may also contain conventional pharmaceutically acceptable stabilizers and surfactants. If necessary or for convenience, you can add tonicity controls. These include, but are not limited to, salts, in particular sodium chloride, potassium chloride, mannitol and glycerol or any other suitable ophthalmologically acceptable tonicity regulator. Various buffers and pH adjusters can be used, provided the resulting formulation is acceptable for ophthalmic use. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. In some aspects, the pharmaceutical composition is an ophthalmic dosage form. The present invention 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 invention, provided that the dosage form achieves the pharmacokinetic and therapeutic effects described in the present invention.

[0088] In one aspect, the composition does not contain preservative(s).

[0089] In some aspects, the pharmaceutical composition contains 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 without limitation, powdered and activated carbon and other substances known to one of ordinary skill in the art.

[0091] As used herein, the term "antioxidant" is intended to mean an agent that inhibits oxidation and is thus used to prevent drug deterioration due to the oxidative process. Such compounds include, by way of example and without 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 substances known to those of ordinary skill in the art. in this area.

[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 alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, sodium acetate monobasic and sodium citrate anhydrous and dihydrate and other substances known to one of ordinary skill in the art.

VII. Lester peripheral visual field test (LPFT)

[0093] The effectiveness of the compositions of the present invention can be assessed using various tests to assess improvement in a patient. In some aspects, Lester's peripheral visual field test (LPFT) is used to assess improvement in a patient's performance. In some aspects, the Lester Peripheral Field Test (LPFT) is used to evaluate and the mean Lester Peripheral Field Test (LPFT) score and the median Lester Peripheral Field Test (LPFT) score are determined. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 5-10 points after approximately 0.1-16 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by about 5.2 points or about 6.3 points after about 0.1 to 16 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by about 5.2 points or about 6.3 points after about 6 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by about 5 to 10 points after about 10 to 15 days. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by about 6 points to about 8 points after about 10 to 15 days. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 6.4 points or approximately 7.7 points after approximately 10 to 15 days. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by about 6.4 points or about 7.7 points after about 14 days.

[0094] In some aspects, the average Lester Peripheral Field Test (LPFT) score increases by about 5 to 10 points after about 0.1 to 16 hours. In some aspects, the average Lester Peripheral Field Test (LPFT) score increases by about 5 to 10 points after about 5 to 10 minutes. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by about 5.2 points or about 6.3 points after about 0.1 to 16 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 5.2 points or approximately 6.3 points after approximately 6 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 5.2 points after approximately 6 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 6.3 points after approximately 6 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 7.7 points after approximately 2 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 6.4 points after approximately 2 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by about 5 to 10 points after about 10 to 15 days. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by about 6 points to about 8 points after about 10 to 15 days. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 6.4 points or approximately 7.7 points after approximately 10 to 15 days. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 6.4 points or approximately 7.7 points after approximately 14 days.

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

[0096] In some aspects, the average Lester Peripheral Field Test (LPFT) score increases by about 5 to 20 points after about 1 to 9 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 5-15 points after approximately 0.1-16 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 10-15 points after approximately 0.1-16 hours. In some aspects, the average Lester Peripheral Field Test (LPFT) score increases by about 5 to 15 points from about 2 to about 6 hours. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 5 to 15 points after approximately 1 to 14 days. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by about 5 to 10 points after about 1 day. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 5 to 10 points after approximately 14 days. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 5 to 10 points after approximately 14 days. In some aspects, the average Lester peripheral visual field test (LPFT) score increases by approximately 5-10 points after approximately 0.1-16 hours.

[0097] In some aspects, the average Lester Peripheral Field Test (LPFT) score is increased by about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8 , approximately 9, approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, approximately 19 or approximately 20 points approximately in 0.1-16 hours. In some aspects, the average Lester Peripheral Field Test (LPFT) score increases by about 1, by about 2, by about 3, by about 4, by about 5, by about 6, by about 7, by about 8, by 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 after about 6 hours . In some aspects, the average Lester Peripheral Field Test (LPFT) score increases by about 1, by about 2, by about 3, by about 4, by about 5, by about 6, by about 7, by about 8, by 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 after about 10- 15 days. In some aspects, the average Lester Peripheral Field Test (LPFT) score increases by about 1, by about 2, by about 3, by about 4, by about 5, by about 6, by about 7, by about 8, by 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 in about 14 days .

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

[0099] In some aspects, the median Lester peripheral visual field test (LPFT) score remains elevated for 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. .

VIII. Marginal Reflex Distance 1 (MRD-1) Test

[0100] Test for determining marginal reflex distance 1 (MRD-1) is performed using photographic measurement to estimate the distance from the central pupillary light reflection to the central edge of the upper eyelid. External digital images are used to measure MRD-1. Measurements are based on the distance from the central pupillary light reflection to the central edge of the upper eyelid, ≤ 2 mm (no visible central pupillary light reflection is the default value of 0). The MRD-1 test is useful for assessing the effectiveness of treatment.

[0101] In some aspects, the marginal reflex distance 1 (MRD-1) test is used to assess improvement in a patient's performance. In some aspects, the marginal reflex distance 1 (MRD-1) test is used to evaluate and the mean marginal reflex distance 1 (MRD-1) test score and the median marginal reflex distance 1 (MRD-1) test score are determined. In some aspects, the marginal reflex distance 1 (MRD-1) test is administered and the result is that the average score increases by about 0.2 to 1.0 points in about 1 to 10 minutes. In some aspects, the average marginal reflex distance test 1 (MRD-1) score increases by approximately 0.2 to 1.0 points after approximately 5 minutes. In some aspects, the average marginal reflex distance test 1 (MRD-1) score increases by about 0.6 points after about 5 minutes. In some aspects, the average marginal reflex distance test 1 (MRD-1) score increases by approximately 0.5 to 1.5 points after approximately 10 to 20 minutes. In some aspects, the average marginal reflex distance test 1 (MRD-1) score increases by approximately 0.5 to 1.5 points after approximately 15 minutes. In some aspects, the average marginal reflex distance test 1 (MRD-1) score increases by about 0.9 points after about 15 minutes.

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

[0103] In some aspects, the average marginal reflex distance 1 (MRD-1) test score is increased by about 1.5 points, by about 1.4 points, by about 1.3 points, by about 1.2 points, by about 1 ,1 point, approximately 1.0 point, approximately 0.9 point, approximately 0.8 point, approximately 0.7 point, approximately 0.6 point, approximately 0.5 point, approximately 0, 4 points or about 0.3 points from about 5 minutes to about 16 hours. In some aspects, the average marginal reflex distance 1 (MRD-1) test score increases by about 1.5 points, by about 1.4 points, by about 1.3 points, by about 1.2 points, by about 1.1 points , approximately 1.0 point, approximately 0.9 point, approximately 0.8 point, approximately 0.7 point, approximately 0.6 point, approximately 0.5 point, approximately 0.4 point or by about 0.3 points in about 5 minutes. In some aspects, the average marginal reflex distance 1 (MRD-1) test score increases by about 1.5 points, by about 1.4 points, by about 1.3 points, by about 1.2 points, by about 1.1 points , approximately 1.0 point, approximately 0.9 point, approximately 0.8 point, approximately 0.7 point, approximately 0.6 point, approximately 0.5 point, approximately 0.4 point or by about 0.3 points in about 15 minutes. In some aspects, the average marginal reflex distance 1 (MRD-1) test score increases by about 1.5 points, by about 1.4 points, by about 1.3 points, by about 1.2 points, by about 1.1 points , approximately 1.0 point, approximately 0.9 point, approximately 0.8 point, approximately 0.7 point, approximately 0.6 point, approximately 0.5 point, approximately 0.4 point or by about 0.3 points after about 16 hours.

[0104] In some aspects, the average marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 1-20 minutes. In some aspects, the average marginal reflex distance 1 (MRD-1) test score increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by 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 in about 5 minutes.

[0105] In some aspects, the average marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9 or about 2.0 points in about 10-20 minutes. In some aspects, the average marginal reflex distance 1 (MRD-1) test score increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 15 minutes.

[0106] In some aspects, the average marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 2-12 hours. In some aspects, the average marginal reflex distance 1 (MRD-1) test score increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, by about 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or by about 2.0 points in about 2 hours. In some aspects, the average marginal reflex distance 1 (MRD-1) test score increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 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.

[0107] In some aspects, the average marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 5-20 days. In some aspects, the average marginal reflex distance 1 (MRD-1) test score increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, by about 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or by about 2.0 points in about 14 days.

[0108] In some aspects, the average marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 30-60 days. In some aspects, the average marginal reflex distance 1 (MRD-1) test score increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, by about 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or by about 2.0 points in about 42 days.

[0109] In some aspects, the median marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 1-20 minutes. In some aspects, the median score of the Marginal Reflex Distance 1 (MRD-1) test increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, by about 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or by about 2.0 points after about 0.1 to 16 hours, such as 8 hours. In some aspects, the median score of the Marginal Reflex Distance 1 (MRD-1) test increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 5 minutes.

[0110] In some aspects, the median marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9 or about 2.0 points in about 10-20 minutes. In some aspects, the median score of the Marginal Reflex Distance 1 (MRD-1) test increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 15 minutes.

[0111] In some aspects, the median marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 2-12 hours. In some aspects, the median score of the Marginal Reflex Distance 1 (MRD-1) test increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, by about 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or by about 2.0 points in about 2 hours. In some aspects, the median score of the Marginal Reflex Distance 1 (MRD-1) test increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 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 aspects, the median marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 5-20 days. In some aspects, the median score of the Marginal Reflex Distance 1 (MRD-1) test increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, by about 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or by about 2.0 points in about 14 days.

[0113] In some aspects, the median marginal reflex distance 1 (MRD-1) test score is increased by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about by 0.6, by about 0.7, by about 0.8, by about 0.9, by about 1.0, by about 1.1, by about 1.2, by about 1.3, by about 1 ,4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 points in about 30-60 days. In some aspects, the median score of the Marginal Reflex Distance 1 (MRD-1) test increases by about 0.1, by about 0.2, by about 0.3, by about 0.4, by about 0.5, by about 0. 6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1.0, approximately 1.1, approximately 1.2, approximately 1.3, approximately 1.4, by about 1.5, by about 1.6, by about 1.7, by about 1.8, by about 1.9, or by about 2.0 points in about 42 days.

IX. Pharmacokinetics

[0114] In one aspect, the dose includes two drops of about 0.035 g/drop of 0.1 wt%. composition at a total dose of about 0.070 mg, and wherein the pharmaceutical composition includes about 0.035 mg of oxymetazoline hydrochloride in each drop. In another aspect, each drop of the ophthalmic solution contains 0.035 mg (0.1% oxymetazoline hydrochloride, equivalent to 0.031 mg (equivalents to 0.088% oxymetazoline free base).

[0115] The compositions and methods of the present invention are useful for minimizing the systemic exposure of a patient to oxymetazoline hydrochloride. In some aspects, the average AUC _0-∞ of the pharmaceutical composition after a single dose is from about 300 to about 700 pg⋅h/ml. In some aspects, the average AUC _0-∞ value of the pharmaceutical composition after administration of a single dose is about 468 pg⋅h/ml.

[0116] In some aspects, the T _max of the pharmaceutical composition after administration of a single dose is from about 0.5 to about 6 hours. In some aspects, the _Tmax of the pharmaceutical composition after administration of a single dose is about 2-4 hours. In some aspects, the _Tmax of the pharmaceutical composition after administration of a single dose is about 0.5-4 hours. In some aspects, the _Tmax of the pharmaceutical composition after administration of a single dose is about 2 hours.

[0117] In some aspects, the average _Tmax of the pharmaceutical composition after administration of a single dose to a patient is from about 0.5 hour to about 12 hours, from about 0.5 hour to about 10 hours, from about 0.5 hour 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 aspects, the average T _max of the pharmaceutical composition 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 aspect, the average _Tmax of the pharmaceutical composition is about 2.5 hours. In some aspects, the median T _max of the pharmaceutical composition 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 aspects, the average C _max of the pharmaceutical composition after administration of a single dose is from about 25 pg/ml to about 35 pg/ml. In some aspects, the average _Cmax of the pharmaceutical composition after administration of a single dose is about 28-32 pg/ml. In some aspects, the average C _max of the pharmaceutical composition after administration of a single dose is about 30.5 pg/ml.

[0119] In one aspect, the dose includes two drops of about 0.035 g/drop of 0.1 wt%. composition for a total amount of about 0.070 g, and wherein the pharmaceutical composition includes about 0.035 mg of oxymetazoline hydrochloride in each drop. In some aspects, the average C _max of the pharmaceutical composition after administration of a single dose to a patient 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 aspects, the average _Cmax of the pharmaceutical composition after a single dose 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 aspects, the average C _max of the pharmaceutical composition after administration of a single dose is from about 25 pg/ml to about 35 pg/ml. In some aspects, the average _Cmax of the pharmaceutical composition after administration of a single dose is about 28-32 pg/ml. In some aspects, the average C _max of the pharmaceutical composition after administration of a single dose is about 30.5 pg/ml. In some aspects, the mean _Cmax of the pharmaceutical composition after a single dose is about 30.5 pg/ml, and the geometric mean Cmax is about 28.3 pg/ml.

[0120] In some aspects, the average area under the plasma concentration versus time curve (AUC _0-∞ ) is measured. In some aspects, the average AUC _0-∞ value of the pharmaceutical composition after administration of a single dose 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 aspects, the average AUC _0-∞ value of the pharmaceutical composition after administration of a single dose is about 468 pg⋅h/ml.

[0121] In some aspects, the geometric mean AUC _0-∞ of the pharmaceutical composition after administration of a single dose 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 aspects, the geometric mean AUC _0-∞ of the pharmaceutical composition after a single dose is about 439 pg⋅h/ml.

X. Packaging

[0122] The storage format and packaging of the composition are also important to preserve and deliver a uniform product. The packaging methods of the present invention may include the use of a unit dose container made of transparent low-density polyethylene (LDPE). In some aspects, disposable containers are manufactured by a blow/fill/seal (“B/F/S” or “BFS”) process. In some aspects, the BFS method is carried out in an aseptic environment. The BFS method is a method in which a container is formed, filled and sealed in one continuous automated system while keeping the contents sterile. BFS vials are continuously produced on a machine that extrudes plastic resin at high temperature, making it sterile. The pellets are fed from a hopper at the top of the BFS machine into the extruder by gravity. The extruder heats the resin pellets to about 170°C - about 230°C, melting the plastic granules to produce a sterile extruded plastic tube (preform). The process begins by melting and extruding low-density polyethylene (LDPE) resin to form a preform (a hollow, tubular mold of hot resin). The sealing molds are then closed, sealing the vials, and the molds release the filled and sealed vials. The entire process takes place without human intervention, which reduces the risk of infection. BFS vials can be filled upside down to ensure uniform filling and sealed to form a “card” containing multiple vials. Sterile packaging techniques are important if the contents do not contain preservatives or antimicrobials. In some aspects, the BFS vial has a volume of 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 aspects, the BFS vial has a volume of 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 aspects, the BFS vial has a volume of about 0.5 ml. In some aspects, the BFS vial has a volume of 0.34 ml.

[0123] After BFS packaging, the containers may be enclosed in a foil laminate pouch for individual packaging and/or enclosed in a child-resistant zip-lock bag to prevent unwanted access. Pharmaceuticals typically require that product packaging meets government regulations and includes child-safe features to ensure that young children, such as those 5 years of age and younger, cannot access products that could cause serious illness or injury. Alternatively, the containers can be enclosed in a child-safe foil laminate pouch. Child resistant bags may include PET, aluminum foil and/or a seal that can provide puncture resistance, processability, integrity and child resistance.

[0124] The present invention will be further illustrated by the following examples, which should not be construed as further limiting. The contents of all referenced documents cited in this application are expressly incorporated herein by reference.

Examples

Example 1

Composition

[0125] Oxymetazoline hydrochloride ophthalmic solution, 0.1 wt%, was prepared with a batch size of 200 kg. The batch composition for the drug product is presented in Table 1.

Table 1
Batch composition for oxymetazoline HCl ophthalmic solution, 0.1% wt Component Quality standard Function Quantity per lot Amount (mg/ml) Quantity
(mg/dose unit) Oxymetazoline hydrochloride USP Active substance 200.00 g* 1.00 0.34 Sodium chloride USP Excipient 1280.00 g 6.40 2.18 Potassium chloride USP Excipient 150.00 g 0.75 0.26 Calcium chloride, dihydrate USP Excipient 96.00 g 0.48 0.16 Magnesium chloride hexahydrate USP Excipient 60.00 g 0.30 0.10 Sodium acetate trihydrate USP Excipient 780.00 g 3.90 1.33 Sodium citrate NF Excipient 340.00 g 1.70 0.58 Hypromellose** (Methocel E4M) USP Excipient 1000.00 g 5.00 1.70 Hydrochloric acid NF pH regulator 25 ml To bring the pH to 6.3-6.5 To bring the pH to 6.3-6.5 Water for injections USP Diluent How much will it take up to 200 kg How much will it take How much will it take up to 0.34 ml Nitrogen (sterile filtered) NF Filling and supporting gas N/A N/A N/A *Adjusted based on analysis results
**Adjust to compensate for 5kg purge

[0126]

Attempts have been made to improve the composition to improve the overall absorption of oxymetazoline into the eye, without the use of preservatives. The carrier composition is a balanced salt solution intended for ocular irrigation, which is adjusted to physiological pH and isotonic salt concentration. The addition of the excipient hypromellose, which is a viscosity modifier, promotes longer retention time in the eye as well as greater ocular comfort. Eight pilot batches were tested using either hypromellose (HPMC) or sodium carboxymethylcellulose (NA CMC). The effect of this change on pH was also determined. Stability studies were performed at 25°C ± 2°C/40% RH, 40°C ± 2°C/NMT 25% RH, and 55°C/RH ambient. The compositions and results of these tests, including 3-month stability test data, can be seen in Table 2 and Table 3 below:

table 2
Composition (% w/w) of eight pilot batches (batch sizes ~91-172 g) Ingredient Batch EPS- 352-057 Batch EPS-352-059 Lot EPS-352-060 Lot EPS-352-061 Batch EPS-352-062 Batch EPS-352-065 Batch EPS-357-036 Batch EPS-357-039 Sodium chloride 0.64% 0.64% 0.64% 0.64% 0.64% 0.64% 0.64% 0.64% Potassium chloride 0.075% 0.075% 0.075% 0.075% 0.075% 0.075% 0.075% 0.075% Calcium chloride 0.048% 0.048% 0.048% 0.048% 0.048% 0.048% 0.048% 0.048% Magnesium chloride 0.030% 0.030% 0.030% 0.030% 0.030% 0.030% 0.030% 0.030% Sodium acetate 0.39% 0.39% 0.39% 0.39% 0.39% 0.39% 0.39% 0.39% Sodium citrate 0.17% 0.17% 0.17% 0.17% 0.17% 0.17% 0.17% 0.17% HPMC
(Hypromellose) - 1.0% - 0.5% - - - - Sodium carboxymethylcellulose 1.0% - 0.5% - 0.25% 0.25% 0.25% 0.25% pH 7.2 7.2 7.2 7.2 5.5 6.0 6.5 7.0 Water for injections how much is needed how much is needed how much is needed how much is needed how much is needed how much is needed how much is needed how much is needed

Table 3
Initial data from eight pilot batches (batch sizes ~91-172g) Song ID Oxymetazoline concentration (mg/ml) pH Osmolality (mOsm/kg) Oxymetazoline concentration (mg/ml)
3 month stability test at 25 ° C±2°C/40%RH Oxymetazoline concentration (mg/ml)
3 month stability test at 40 ° C±2°C/ NMT 25% RH EPS-352-057 (1% Na CMC) 0.99 6.6 326 0.99 0.97 EPS-352-059 (1% HPMC) 0.90 6.5 314 0.94 0.91 EPS-352-060 (0.5% Na CMC) 0.99 6.5 313 0.98 0.99 EPS-352-061 (0.5% HPMC) 0.95 6.5 308 0.96 0.95 EPS-352-062 (0.25% Na CMC; pH 5.5) 0.97 5.6 301 0.98 1.00 EPS-352-065 (0.25% Na CMC; pH 6.0) 0.99 5.8 309 0.99 1.00 EPS-357-036 (0.25% Na CMC; pH 6.5) 0.97 6.0 302 0.98 0.95 EPS-357-039 (0.25% Na CMC; pH 7.0) 1.00 6.6 305 0.99 0.97

Example 2

PK analysis

[0127] The following pharmacokinetic (PK) data were obtained when a dose of one drop was administered to each eye, with each drop containing approximately 0.035 mg of oxymetazoline HCl, for a total amount of 0.07 mg of oxymetazoline HCl.

[0128] The parameters C _max , AUC _0-∞ and T _max were estimated based on a test population of 24 patients.

[0129] The test was carried out to determine the average concentrations of oxymetazoline in plasma after administration of a single dose of oxymetazoline HCl ophthalmic solution, 0.1 wt%. The test results are shown in Fig. 1, Table 4 and Table 5.

Table 4
Pharmacokinetic parameters following ocular administration of oxymetazoline to healthy male and female volunteers, PK study Parameter Test product n Average value SD CV% Geometric mean tmax(h) ^a 23 2.00 (0.500-12.0) - Cmax (pg/ml) 23 30.5 12.7 41.8 28.3184 AUC0-tldc (h*pg/ml) 23 400 188 47.1 367.5829 AUCinf (h*pg/ml) 19 468 214 45.7 438.9934 AUC%ext. 21 12.4 5.41 43.7 - kel(h-1) 21 0.0841 0.0190 22.6 - t1/2 (h) ^b 21 8.25 - - - Treatment A: One drop of oxymetazoline HCl (ophthalmic solution, 0.1% wt) in each eye (Test)
Note: PK parameters are presented as arithmetic mean, standard deviation (SD) and coefficient of variation (CV%) unless otherwise noted.
AUCinf values with extrapolation >20% were excluded from the summary data.
^a tmax is presented as the median value (min - max)
^b t½ is represented as the harmonic mean

Table 5

Oxymetazoline concentration-time data after administration of a single dose of oxymetazoline HCl ophthalmic solution, 0.1%; Treatment A

Example 3

Data from Phase 3 Study 1

[0130] Study 1 : This study was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study to determine the safety and efficacy of treatment administered once daily (QD) (one drop per eye) oxymetazoline hydrochloride ophthalmic solution, 0.1% , compared with vehicle in subjects with acquired ptosis. A total of 140 subjects were randomly assigned to a ratio of approximately 2:1: oxymetazoline hydrochloride 0.1% wt. QD (N=94); Carrier (N=46) in 16 centers. Oxymetazoline hydrochloride was administered topically for 42 days (6 weeks). The study was carried out over 2 periods; Period 1 (safety and efficacy assessment) was 2 weeks, and Period 2 (continued safety assessment and comfort assessment) was 4 weeks. The mean age of the subjects was 64.2 years.

3.2 Efficiency

[0131] Efficacy was assessed using LPFT (primary) and photographic measurement of MRD-1. The primary efficacy endpoints were ranked hierarchically to compare oxymetazoline hydrochloride with vehicle by the mean increase from baseline (Day 1 Hour 0) in the number of spots observed in the top 4 rows of the LPFT in the study eye at time point:

1. Hour 6 on Day 1.

2. Hour 2 on Day 14.

This study has been completed and the results are presented below. At both time points, the increase in the number of points visible in the upper visual field (LPFT change) in the oxymetazoline hydrochloride group compared with the vehicle group was statistically significant, indicating that improvement in the upper visual field was evident 6 hours after dosing on Day 1 and 2 hours post-dose on Day 14, Table 6. Mean change from baseline in visual field data at time points Day 14, hour 6, Day 14, hour 8, and Day 42 are shown in Table 7.

Table 6
Observed and change from baseline in mean number of dots visible in the upper visual field using LPFT in the study eye at primary efficacy time points (ITT population), Study 1 Parameter Points visible at the top of the field of view Average difference
P -Value ^a
[95% CI]
P -value ^b Test product
N=94 Carrier
N=46 Test product vs Vehicle Average number of points at baseline (SD) 17 (4.41) 1(5.21) - Average number of points at primary efficacy assessment time points N 94 46 Day 1, Hour 6, observed mean (SD) 22.2 (6.18) 18.4 (6.01) Mean change from baseline (SD) 5.2 (5.97) 1.5 (3.93) 3.67, <0.0001a ^,
[2.00, 5.34]
0.0002b ^​ N 91 46 Day 14, Hour 2, observed mean (SD) 23.4 (5.60) 19.1 (6.13) Mean change from baseline (SD) 6.4 (5.04) 2.2 (5.80) 4.20 ,< 0.0001 ^a ,
[2.30, 6.10]
< ^0.0001b CI=confidence interval; ITT=intention to treat; LPFT=Lester peripheral visual field test; SD=standard deviation
^a P- value=2-sided t-test
^b P- value=Wilcoxon test

Table 7
Mean change from baseline in marginal reflex distance 1 in study eye (ITT population), Study 1 Parameter Test product
N=94 Carrier
N=46 Mean difference, P -value ^a
[95%CI]
P -value ^b Test product
vs Carrier Mean MRD-1 value at baseline, mm (SD) 1.16 (0.661) 1.03 (0.678) - Mean change in MRD-1 from baseline at primary efficacy time points, mm (SD) Day 1, Hour 6 n=94
0.94 (0.924) n=46
0.67 (1.001) 0.27, 0.1198 ^a , [-0.07, 0.61]
^0.0276b Day 14, Hour 2 n=91
1.09 (0.799) n=46
0.58 (0.875) 0.52, 0.0007 ^a , [0.22, 0.81]
^0.0004b Average change in MRD-1 from baseline at other time points after administration, mm (SD) Day 1, Hour 2 n=94
0.99 (0.776) n=46
0.50 (0.803) 0.49, 0.0007 ^a , [0.21, 0.77]
<0.0001 ^b Day 1, Hour 8 n=94
0.93 (0.958) n=46
0.70 (0.771) 0.24, ^0.1491a ,
[-0.09, 0.56]
0.1701 ^b Day 14, Hour 6 n=92
1.03 (0.856) n=45
0.70 (0.985) 0.33, ^0.0477a ,
[0.00, 0.65]
^0.0101b Day 14, Hour 8 n=91
0.88 (0.857) n=45
0.68 (1.023) 0.20, ^0.2295a
[-0.13, 0.53]
^0.1511b day 42 n=91
1.25 (1.036) n=45
0.79 (1.020) 0.46, ^0.0160a ,
[0.09, 0.83]
0.0113 ^b CI=confidence interval; ITT=intention to treat; MRD -1=marginal reflex distance -1; SD=standard deviation
^a P- value=2-sided t-test
^b P- value=Wilcoxon test

Example 4

Data from Phase 3, Study 2

[0132] Study 2: This study was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 study to determine the safety and efficacy of treatment administered once daily (QD) (one drop per eye) of oxymetazoline hydrochloride compared with vehicle in subjects with acquired ptosis. A total of 164 subjects were randomly administered at a ratio of approximately 2:1: oxymetazoline hydrochloride 0.1% wt. QD (N=109); Carrier (N=55) in 27 centers. Oxymetazoline hydrochloride was administered topically for 42 days (6 weeks). The study was carried out over 2 periods; Period 1 (safety and efficacy assessment) was 2 weeks, and Period 2 (continued safety assessment and comfort assessment) was 4 weeks. The average age of the subjects was 63.5 years. One subject was under 18 years of age.

4.1 Efficiency

[0133] Efficacy was assessed using LPFT (primary) and photographic measurement of MRD-1. The primary efficacy endpoints were ranked hierarchically to compare oxymetazoline hydrochloride with vehicle by the mean increase from baseline (Day 1 Hour 0) in the number of spots observed in the top 4 rows of the LPFT in the study eye at time point:

1. Hour 6 on Day 1

2. Hour 2 on Day 14

The results are presented below. At both time points, the increase in the number of points visible in the upper visual field (LPFT change) in the oxymetazoline hydrochloride group compared with the vehicle group was statistically significant, indicating that improvement in the upper visual field was evident 6 hours after dosing on Day 1 and 2 hours after dosing on Day 14, Table 8.

[0134] Photographic measurement of MRD-1 also showed a beneficial effect upon treatment with oxymetazoline hydrochloride. The increases in LPFT were numerically greater in the oxymetazoline hydrochloride group than in the vehicle group at all post-administration time points. Larger MRD-1 increases were observed for the oxymetazoline hydrochloride administration group compared with the vehicle group at all time points post-administration for 6 weeks, Table 9. Increased MRD-1 values observed at 5 minutes after administration indicated onset of action after 5 weeks. minutes.

4.2 Security

[0135] Oxymetazoline hydrochloride was well tolerated and adverse events observed were predominantly mild.

4.3 Results

[0136] LPFT was performed using a Humphrey visual field analyzer. It is an age-adjusted screening test using a three-zone strategy. Thirty-five points are checked in the top box, while 14 points are checked in the bottom box. A maximum of 48° is checked at the top of the visual field. The center of fixation is shifted 15° lower, allowing maximum testing of the superior field (Ho et al., 2011). The bottom margin test is used for comparison but is not used in the analysis. In FIG. In Figure 2A, a representative grid of the Lester test for assessing peripheral visual field can be seen. Subjects rest their chin and forehead against the chin and forehead rests and keep their eyebrows relaxed. Subjects look at the fixation point throughout the test. A corrective lens is not required for LPFT unless the subject would be unable to see the target for a period of time without it (eg, high myopia, high farsightedness, or high astigmatism).

Table 8
Observed and change from baseline in the mean number of dots visible in the upper visual field using LPFT in the study eye at the primary efficacy time points (ITT population), Study 2 Parameter Points visible at the top of the field of view Average difference
(95% CL), p-value ^a
p-value ^b Oxymetazoline hydrochloride N=109 Carrier N=55 Oxymetazoline hydrochloride vs Carrier Average number of points at baseline (SD) 17.6 (4.92) 17.6 (5.48) Average number of points at primary efficacy assessment time points Day 1, Hour 6, observed mean (SD) 23.9 (6.67) 19.7 (6.16) Mean change from baseline (SD) 6.3 (6.72) 2.1 (4.28) 4.23 (2.36, 6.09), <0.0001^a
<0.0003^b Day 14, Hour 2, observed mean (SD) 25.3 (6.35) 20.0 (5.84) Mean change from baseline (SD) 7.7 (6.41) 2.4 (5.26) 5.30 (3.45, 7.14), <0.0001^a
<0.0003^b CL=confidence limit; ITT=intention to treat; SD=standard deviation
^a p - value (2-tailed t-test) obtained from an ANCOVA model, with treatment as a fixed factor and baseline score as a variable
^b p - value (Wilcoxon rank sum test)

Additional data from the above LPFT is shown below in Table 9:

Table 9
Mean change from baseline in marginal reflex distance 1 in study eye (ITT population), Study 2 Parameter Oxymetazoline hydrochloride
N=109 Carrier
N=55 Mean difference, (95% CL), p-value ^a p-value ^b Oxymetazoline hydrochloride vs Carrier Mean MRD-1 value at baseline, mm (SD) 1.04 (0.735) 1.07 (0.697) - Mean change in MRD-1 from baseline at primary efficacy time points, mm (SD) Day 1, 5 minutes 0.59 (0.721) 0.20 (0.571) 0.38, (0.16, 0.59), 0.0007 ^a
0.0007 ^b Day 1, 15 minutes 0.93 (0.811) 0.32 (0.641) 0.60, (0.36, 0.84), <0.0001 ^a
<0.0001 ^b Day 1, 2 hours 1.05 (0.903) 0.33 (0.555) 0.71, (0.45, 0.96), <0.0001 ^a
<0.0001 ^b Day 1, 6 hours 0.98 (0.867) 0.35 (0.567) 0.61, (0.37, 0.86), <0.0001 ^a
<0.0001 ^b Day 14, 0 hours 0.37 (0.805) 0.40 (0.743) -0.04, (-0.29, 0.22), 0.7800 ^a
0.9648b Day 14, 5 minutes 0.77 (0.853) 0.42 (0.775) 0.33, (0.07, 0.60), 0.0151 ^a
0.0115 ^b Day 14, 15 minutes 1.11 (0.0.922) 0.41 (0.833) 0.68, (0.39, 0.97), <0.0001 ^a
<0.0001 ^b Day 14, 2 hours 1.22 (0.926) 0.43 (0.734) 0.78, (0.50, 1.06), <0.0001 ^a
<0.0001 ^b Day 14, 6 hours 1.06 (0.902) 0.47 (0.737) 0.58, (0.31, 0.85), <0.0001 ^a
<0.0001 ^b Day 42, 5 minutes 0.86 (0.849) 0.42 (0.799) 0.42, (0.15, 0.68), 0.0020 ^a
0.0033b Day 42, 15 minutes 1.04 (0.912) 0.47 (0.926) 0.55, (0.26, 0.84), 0.0003 ^a
0.0005b CL=confidence limit; ITT=intention to treat; MRD-1=marginal reflex distance 1; SD=standard deviation
^a p - value (2-tailed t-test) obtained from an ANCOVA model, with treatment as a fixed factor and baseline score as a variable
^b p - value (Wilcoxon rank sum test)

Example 5

Stability of Oxymetazoline HCl Composition

[0137] Stability testing was performed on oxymetazoline hydrochloride formulations for 24 months at 40% relative humidity. The stability test results are shown below in Table 10, stability data in the vehicle group can be found in Table 11.

Table 10
Stability assessment results every 6 months at 25°C/40% RH Analysis Method Recommended rate Time points (months) 0 6 12 18 24 Appearance EPS TP-042 Transparent colorless solution
free of any particulate matter or crystallization Compliant Compliant Compliant Compliant Compliant pH EPS SOP
SAS-013 5.8-6.8 6.5 6.4 6.5 6.5 6.4 Osmolality EPS SOP SAS-005 290-330 mOsm/kg 315 304 320 300 318 Viscosity EPS SOP SAS-057 5-25 cps 24.9 NT NT NT NT Main substance content EPS TP-101 90.0-110.0% of the declared content (1.0 mg/ml) 99.1% 96.5% 95.9% 95.2% 93.9% HPLC ID EPS TP-101 (USP) Compliant Compliant NT NT NT NT Related impurities EPS TP-113 TBD (0.05% reporting limit) Single unidentified impurity
RRT=0.42 NT NT ND 0.13% ND Single unidentified impurity
RRT=0.50 NT NT 0.46% 0.73% 0.13% Single unidentified impurity
RRT=0.54-0.57 NT NT 0.53% 0.79% 0.87% Single unidentified impurity
RRT=0.61-62 NT NT ND ND 0.90 Single unidentified impurity
RRT=0.81-0.86 NT NT 0.60% 0.79% ND Single unidentified impurity
RRT=1.2 NT NT 0.07% ND 1.01% Single unidentified impurity
RRT=1.9 NT NT 0.09% 0.10% 0.10% Total Related Impurities (Reporting Results) NT NT 1.68% 2.61% 3.07% Mechanical inclusions EPS TP-034
microscopic ≥ 10µm NMT 50
per ml 1 NT NT NT NT ≥ 25µm NMT 50 per ml 0 NT NT NT NT ≥ 50µm NMT 50 per ml 0 NT NT NT NT NT=not determined

Table 11
Stability results every 6 months at 25°C/40% RH (Carrier) Analysis Method Recommended rate Time points (months) 0 6 12 18 24 Appearance EPS TP-042 A clear, colorless solution free of any solid particles or crystallization Compliant Compliant Compliant Compliant Compliant pH EPS SOP SAS-013 5.8-6.8 6.5 6.2 6.4 6.4 6.5 Osmolality EPS SOP
SAS-005 290-330 mOsm/kg 312 306 313 296 311 Viscosity EPS SOP
SAS-057 5-25 cP 18.4 NT NT NT NT Main substance content EPS TP-101 90.0-110.0% of the declared content (1.0 mg/ml) 0.0% NT NT NT NT HPLC ID EPS TP-101 (USP) Matches (not found) Compliant NT NT NT NT Mechanical inclusions EPS TP-034
Microscopic ≥ 10µm NMT 50 per ml 1 NT NT NT NT ≥ 25µm NMT 5 per ml 0 NT NT NT NT ≥ 50µm NMT 2 per ml 0 NT NT NT NT NT=not determined

[0138] Oxymetazoline hydrochloride solutions were stable at five time points when measured at 0 months, 6 months, 12 months, 18 months and 24 months, showing good stability and shelf life of the formulated formulations.

Example 6

Study of the stability of oxymetazoline HCl in a clinical setting

[0139] Oxymetazoline hydrochloride formulations were prepared according to Table 12. Stability testing was performed on oxymetazoline formulations over a 24- and 30-month time period.

Table 12
Clinical Study Lots, Oxymetazoline Hydrochloride Ophthalmic Solution, 0.1% (RVL-1201) Batch number Active substance or carrier Batch size Container/Closing/Filling 1680614 Active substance 3 l drop 1 cm ³ ,
filling 0.7 ml 1680615 Carrier 3 l drop 1 cm ³ ,
filling 0.7 ml RD427 Active substance 150 kg 0.5 ml BFS in foil pouch, filling 0.34 ml RD425 Carrier 150 kg 0.5 ml BFS in foil pouch, filling 0.34 ml R80261 Active substance 200 kg 0.5 ml BFS in foil pouch, filling 0.34 ml R80251 Carrier 200 kg 0.5 ml BFS in foil pouch, filling 0.34 ml

[0140] Three commercially produced single-step batches (R60681, R60701, and R60711) were tested at the end of shelf life and the results supported the stated 24-month shelf life. Stability data obtained at 24 months and 30 months are presented in FIG. 3A-3B, 4A-4B and 5A-5B for each batch (R60681, R60701 and R60711, respectively).

[0141] In this application, the various publications referenced are indicated in parentheses by the author's name and the date, patent number, or patent publication number. The disclosures of these publications are incorporated herein by reference in their entirety to more fully describe the state of the art known to those skilled in the art at the date of the invention described and claimed herein. However, the citation of a reference should not be construed as an admission that such reference is prior art to the present invention.

Claims (189)

1. An aqueous pharmaceutically stable ophthalmic composition for the treatment of ptosis, including: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally a pH regulator; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 2. An aqueous, pharmaceutically stable ophthalmic composition for increasing the vertical separation of the upper eyelid and lower eyelid of at least one eye in a subject, comprising: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally a pH regulator; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 3. An aqueous pharmaceutically stable ophthalmic composition for improving the upper visual field of a subject, comprising: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally a pH regulator; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 4. Composition according to any one of paragraphs. 1-3, where one or more suitable buffers range from 0.05 to 1.0 wt.%. 5. The composition of claim 4, wherein one or more suitable buffers include sodium acetate trihydrate and sodium citrate. 6. The composition of claim 5, wherein one or more suitable buffers include 0.39% by weight sodium acetate trihydrate and 0.17% by weight sodium citrate. 7. Composition according to any one of paragraphs. 1-3, where the composition includes 0.64 wt.% sodium chloride, 0.075 wt.% potassium chloride, 0.048 wt.% calcium chloride and 0.03 wt.% magnesium chloride. 8. The composition according to claim 7, wherein the calcium chloride is calcium chloride dihydrate and the magnesium chloride is magnesium chloride hexahydrate. 9. Composition according to any one of paragraphs. 1-3, 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. 10. The composition according to claim 9, where the pH regulator includes hydrochloric acid. 11. Composition according to any one of paragraphs. 1-3, where the composition does not include a preservative. 12. Composition according to any one of paragraphs. 1-3, where the composition is stable at 25°C and 40% relative humidity for a period of at least 24 months. 13. A disposable container comprising the composition of claim 11. 14. Disposable container according to claim 13, where the volume of the disposable container is 0.5 ml. 15. Disposable container according to claim 14, where the disposable container is presented in a child-safe bag. 16. The disposable container of claim 13, wherein the disposable container delivers 0.035 mg of oxymetazoline hydrochloride per drop. 17. Aqueous pharmaceutically stable ophthalmic composition for the treatment of ptosis, consisting of: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally a pH regulator; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 18. An aqueous, pharmaceutically stable ophthalmic composition for increasing the vertical separation of the upper eyelid and lower eyelid of at least one eye in a subject, consisting of: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally a pH regulator; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 19. An aqueous pharmaceutically stable ophthalmic composition for improving the upper visual field of a subject, consisting of: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally a pH regulator; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 20. Composition according to any one of paragraphs. 17-19, where one or more suitable buffers range from 0.05 to 1.0 wt.%. 21. The composition of claim 20, wherein one or more suitable buffers include sodium acetate trihydrate and sodium citrate. 22. The composition of claim 21, wherein the one or more suitable buffers comprise 0.39% by weight sodium acetate trihydrate and 0.17% by weight sodium citrate. 23. Composition according to any one of paragraphs. 17-19, where the composition includes 0.64 wt.% sodium chloride, 0.075 wt.% potassium chloride, 0.048 wt.% calcium chloride dihydrate and 0.03 wt.% magnesium chloride hexahydrate. 24. The composition according to claim 23, wherein the calcium chloride is calcium chloride dihydrate and the magnesium chloride is magnesium chloride hexahydrate. 25. Composition according to any one of paragraphs. 17-19, 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 their combinations. 26. The composition according to claim 25, where the pH regulator includes hydrochloric acid. 27. Composition according to any one of paragraphs. 17-19, where the composition is stable at 25°C and 40% relative humidity for a period of at least 24 months. 28. A disposable container, comprising the composition according to any one of paragraphs. 17-19. 29. Disposable container according to claim 28, where the volume of the disposable container is 0.5 ml. 30. Disposable container according to claim 28, where the disposable container is presented in child-safe packaging. 31. The disposable container of claim 28, wherein the disposable container delivers 0.035 mg of oxymetazoline hydrochloride per drop. 32. An aqueous pharmaceutically stable ophthalmic preservative-free composition for the treatment of ptosis, including: a) 0.1 wt.% oxymetazoline hydrochloride; b) 0.64% by weight sodium chloride; c) 0.075 wt.% potassium chloride; d) 0.048 wt.% calcium chloride dihydrate; e) 0.03 wt.% magnesium chloride hexahydrate; f) one or more suitable buffers; g) 0.5 wt.% hypromellose; And h) optionally hydrochloric acid; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 33. An aqueous, pharmaceutically stable, ophthalmic, preservative-free composition for increasing the vertical separation of the upper eyelid and lower eyelid of at least one eye in a subject, comprising: a) 0.1 wt.% oxymetazoline hydrochloride; b) 0.64% by weight sodium chloride; c) 0.075 wt.% potassium chloride; d) 0.048 wt.% calcium chloride dihydrate; e) 0.03 wt.% magnesium chloride hexahydrate; f) one or more suitable buffers; g) 0.5 wt.% hypromellose; And h) optionally hydrochloric acid; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 34. An aqueous, pharmaceutically stable, preservative-free ophthalmic composition for improving the upper visual field of a subject, comprising: a) 0.1 wt.% oxymetazoline hydrochloride; b) 0.64% by weight sodium chloride; c) 0.075 wt.% potassium chloride; d) 0.048 wt.% calcium chloride dihydrate; e) 0.03 wt.% magnesium chloride hexahydrate; f) one or more suitable buffers; g) 0.5 wt.% hypromellose; And h) optionally hydrochloric acid; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 35. A method of treating ptosis in a subject, comprising administering to at least one eye of the subject a therapeutically effective amount of an aqueous, pharmaceutically stable, preservative-free ophthalmic composition comprising: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally hydrochloric acid; wherein the composition has a pH ranging from 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 36. The method according to claim 35, where the ptosis is acquired blepharoptosis. 37. The method of claim 35, wherein the composition is administered to the subject over one or more consecutive days at a dose of one drop in each eye for a total daily dose of 0.07 mg of oxymetazoline hydrochloride. 38. The method according to claim 35, where the aqueous pharmaceutically stable ophthalmic preservative-free composition includes: a) 0.64% by weight sodium chloride; b) 0.075 wt.% potassium chloride; c) 0.048% by weight calcium chloride; d) 0.03% by weight magnesium chloride; And e) 0.5 wt.% hypromellose. 39. The method according to claim 38, wherein the calcium chloride is calcium chloride dihydrate and the magnesium chloride is magnesium chloride hexahydrate. 40. A method of increasing the vertical separation of the upper eyelid and lower eyelid of at least one eye in a subject, comprising administering to at least one eye of the subject a therapeutically effective amount of an aqueous, pharmaceutically stable, preservative-free ophthalmic composition comprising: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally hydrochloric acid; wherein the composition has a pH in the range of 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months. 41. The method of claim 40, wherein the composition is administered to the subject over one or more consecutive days at a dose of one drop in one eye for a total daily dose of 0.035 mg of oxymetazoline hydrochloride. 42. The method of claim 40, wherein the composition is administered to the subject over one or more consecutive days at a dose of one drop in each eye for a total daily dose of 0.07 mg of oxymetazoline hydrochloride. 43. The method according to claim 40, where the aqueous pharmaceutically stable ophthalmic preservative-free composition includes: a) 0.64% by weight sodium chloride; b) 0.075 wt.% potassium chloride; c) 0.048% by weight calcium chloride; d) 0.03 wt.% magnesium chloride; And e) 0.5 wt.% hypromellose. 44. The method according to claim 43, wherein the calcium chloride is calcium chloride dihydrate and the magnesium chloride is magnesium chloride hexahydrate. 45. A method of improving the Leicester Peripheral Field Test (LPFT) score in a subject, comprising administering to at least one eye of the subject a therapeutically effective amount of an aqueous, pharmaceutically stable, preservative-free ophthalmic composition comprising: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally hydrochloric acid; wherein the composition has a pH ranging from 5.8 to 6.8, and wherein the composition is stable for a period of at least 24 months, and whereby the average LPFT score increases by 5-10 points after 0.1-16 hours after introduction. 46. The method of claim 45, wherein the composition is administered to the subject over one or more consecutive days at a dose of one drop in each eye for a total daily dose of 0.07 mg of oxymetazoline hydrochloride. 47. The method according to claim 45, where the aqueous pharmaceutically stable ophthalmic preservative-free composition includes: a) 0.64% by weight sodium chloride; b) 0.075 wt.% potassium chloride; c) 0.048% by weight calcium chloride; d) 0.03 wt.% magnesium chloride; And e) 0.5 wt.% hypromellose. 48. The method according to claim 47, wherein the calcium chloride is calcium chloride dihydrate and the magnesium chloride is magnesium chloride hexahydrate. 49. A method of improving the marginal reflex distance 1 (MRD-1) test score in a subject, comprising administering to at least one eye of the subject a therapeutically effective amount of an aqueous, pharmaceutically stable, ophthalmic, preservative-free composition comprising: a) 0.1 wt.% oxymetazoline hydrochloride; b) from 0.2 to 1.0% by weight sodium chloride; c) from 0.05 to 0.10 wt.% potassium chloride; d) from 0.02 to 0.06% by weight calcium chloride; e) from 0.01 to 0.05 wt.% magnesium chloride; f) one or more suitable buffers; g) from 0.1 to 0.90% by weight hypromellose; And h) optionally hydrochloric acid; wherein the composition has a pH ranging from 5.8 to 6.8, and wherein the composition is stable over a period of at least 24 months, whereby the average score increases by 0.2 to 1.5 points after 1 to 20 minutes after administration or 0.1-16 hours after administration. 50. The method of claim 49, wherein the composition is administered to the subject over one or more consecutive days at a dose of one drop in each eye for a total daily dose of 0.07 mg of oxymetazoline hydrochloride. 51. The method according to claim 49, where the aqueous pharmaceutically stable ophthalmic preservative-free composition includes: a) 0.64% by weight sodium chloride; b) 0.075 wt.% potassium chloride; c) 0.048% by weight calcium chloride; d) 0.03% by weight magnesium chloride; And e) 0.5 wt.% hypromellose. 52. The method according to claim 51, wherein the calcium chloride is calcium chloride dihydrate and the magnesium chloride is magnesium chloride hexahydrate.

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