Oxymetazoline composition and method for treating eye diseases

Abstract

To provide a composition containing oxymetazoline, and a method for stabilizing the oxymetazoline composition for long-term storage. [Solution] The disclosure also relates to compositions comprising oxymetazoline, and to methods for treating various eye disorders in subjects that involve ptosis or other eyelid drooping, comprising administering the oxymetazoline-containing composition to a subject. In some embodiments, the compositions of the disclosure relate to pharmaceutically stable aqueous ophthalmic formulations having a pH in the range of about 6.3 to about 6.5, comprising about 0.1% by weight of oxymetazoline hydrochloride; about 0.2 to about 1.0% by weight of sodium chloride; about 0.05 to about 0.10% by weight of potassium chloride; about 0.02 to about 0.06% by weight of calcium chloride; about 0.01 to about 0.05% by weight of magnesium chloride; 1 or more suitable buffer; about 0.1 to about 0.90% by weight of hypromellose; and optionally a pH adjuster.

Description

[Technical Field]

[0001] This disclosure relates to compositions and methods for treating various eye disorders, including eyelid drooping or disorders related to such conditions. This disclosure also relates to compositions comprising oxymetazoline, pharmaceutically acceptable salts of oxymetazoline, and methods for preparing and using them. [Background technology]

[0002] Ptosis (commonly known as ptosis) is an abnormal partial or complete drooping of the upper eyelid, usually resulting from partial or complete dysfunction of the muscles that lift the upper eyelid, namely the levator palpebrae superioris and / or Müller's muscle. Ptosis occurs when the muscles that lift the eyelid (levator palpebrae superioris and / or Müller's muscle) are not strong enough to lift it properly. It can occur in one or both eyes and is more common in older adults as the eyelid muscles begin to deteriorate. It is one of the most common eyelid disorders and occurs in about 12% of adults over 50 years of age (GVSridharan, RCTallis, B. Leatherbarrow, WMForman, A., Community Survey of Ptosis of the Eyelid and Pupil). (Size of Elderly People, Age and Ageing, Volume 24, Issue 1, January 1995, pp. 21-24). Ptosis is classified as either congenital or acquired. Acquired ptosis has numerous etiologies, but in most cases it is aponeurotic, resulting from degenerative changes in the levator aponeurosis or from stretching or tearing as a result of cataract surgery, lens replacement, or long-term wear of both hard and soft contact 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,Conciliis C.,Kulwin DR,Acquired ptosis in the young and middle-aged adult population.Ophthalmology.1995;102:924-8;Reddy AK, Foroozan R., Arat YO, Edmond JC, Yen MT, Ptosis in young soft contact lens wearers.Ophthalmology.2007;114:2370).

[0003] Patients with ptosis may experience significant upper visual field defects, which can affect daily activities such as driving, crossing the road, and reading. Treatment for acquired ptosis typically involves surgery, which carries risks of infection, bleeding, overcorrection or undercorrection, decreased visual acuity, and lagophthalmos (inability to completely close the eyelids) (Finsterer J., Ptosis: Causes, Presentation, and Management. Aesthetic Plast. Surg. 2003;27(3):193-204). Mechanical treatments for ptosis (scleral contact lenses with bars to lift the eyelids, ptosis supports attached to eyeglasses, or adhesive tape or putty to attach the upper eyelid to the supraorbital structure) are limited by patient dissatisfaction with physical appearance, contact allergies, or skin irritation. (Shah-Desai SD, Aslam SA, Pullum K., Beaconsfield M., Rose GE, Scleral contact lens usage in patients with complex blepharoptosis. Ophthal. Plast. Reconstr. Surg. 2011 Mar-Apr;27(2):95-8). Pharmacological treatment of ptosis has not been pursued until now because the drugs evaluated (e.g., epinephrine, dipivefrin, apraclonidine, phenylephrine, brimonidine) cause pupillary dilation, leading to blurred vision or photophobia, or unacceptable systemic side effects. (Matjucha IC, The nonsurgical treatment of ptosis. In: Cohen AJ, Weinberg DA, editors: Evaluation and management of blepharoptosis.New York:Springer,2011.pp.155-61;Scheinfeld N.,The Use of apraclonidine eyedrops to treat ptosis after the administration of botulinum toxin to the upper face.Dermatol.Online J.2005 Mar 1;11(1):9;Kass M.A.,Mandell A.I.,Goldberg I.,Paine J.M.,Becker B.,Dipivefrin and epinephrine treatment of elevated intraocular pressure:a comparative study.Arch.Ophthalmol.1979 Oct;97(10):1865-6;Fraunfelder F.T.,Scafidi A.F.,Possible adverse effects from topical ocular 10% phenylephrine.Am.J.Ophthalmol.1978;85(4):447-53).

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

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

[0006] In some embodiments, the composition of the present disclosure relates to a pharmaceutically stable aqueous ophthalmic formulation comprising: about 0.1% by weight of oxymetazoline hydrochloride; about 0.2% to about 1.0% by weight of sodium chloride; about 0.05% to about 0.10% by weight of potassium chloride; about 0.02% to about 0.06% by weight of calcium chloride; about 0.01% to about 0.05% by weight of magnesium chloride; 1 or more of a suitable buffer; about 0.1% to about 0.90% by weight of hypromellose; and optionally a pH adjuster; wherein the pH of the formulation is in the range of about 6.3 to about 6.5. In some embodiments, the 1 or more of the suitable buffer constitutes about 0.05% to about 1.0% by weight. In some embodiments, the 1 or more of the suitable buffer comprises sodium acetate trihydrate and sodium citrate. In some embodiments, the suitable buffer solution, one or more of the above, comprises about 0.39% by weight of sodium acetate trihydrate and about 0.17% by weight of sodium citrate. In some embodiments, the formulation comprises about 0.64% by weight of sodium chloride, about 0.075% by weight of potassium chloride, about 0.048% by weight of calcium chloride dihydrate, and about 0.03% by weight of magnesium chloride hexahydrate. In some embodiments, the pH adjuster is selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calcium carbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide, ammonium hydroxide, ammonium phosphate, and combinations thereof. In some embodiments, the pH adjuster comprises hydrochloric acid. In some embodiments, the formulation is free of preservatives. In some embodiments, the formulation is stable for 0 to 24 months. In some embodiments, the formulation is stable for at least 24 months. In some embodiments, the formulation is stable for at least 24 months at 25°C and 40% relative humidity. In some embodiments, the composition is formulated in a disposable container containing a volume of approximately 0.5 mL. In some embodiments, the disposable container is in packaging that prevents children from opening it. In some embodiments, the disposable container delivers approximately 0.035 mg of oxymetazoline hydrochloride per drop.

[0007] The compositions of the present disclosure also relate to pharmaceutically stable aqueous ophthalmic formulations comprising: about 0.1% by weight of oxymetazoline hydrochloride; about 0.2% to about 1.0% by weight of sodium chloride; about 0.05% to about 0.10% by weight of potassium chloride; about 0.02% to about 0.06% by weight of calcium chloride; about 0.01% to about 0.05% by weight of magnesium chloride; 1 or more of a suitable buffer; about 0.1% to about 0.90% by weight of hypromellose; and optionally a pH adjuster; wherein the pH of the formulation is in the range of about 6.3 to about 6.5. In some embodiments, the 1 or more of the suitable buffer constitutes about 0.05% to about 1.0% by weight. In some embodiments, the 1 or more of the suitable buffer contains sodium acetate trihydrate and sodium citrate. In some embodiments, a suitable buffer solution, one or more of the above, comprises about 0.39% by weight of sodium acetate trihydrate and about 0.17% by weight of sodium citrate. In some embodiments, the formulation comprises about 0.64% by weight of sodium chloride, about 0.075% by weight of potassium chloride, about 0.048% by weight of calcium chloride dihydrate, and about 0.03% by weight of magnesium chloride hexahydrate. In some embodiments, the pH adjuster is selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, fumaric acid, phosphoric acid, calcium acetate, calcium carbonate, ammonium bicarbonate, ammonium sulfate, sodium hydroxide, ammonium hydroxide, ammonium phosphate, and combinations thereof. In some embodiments, the pH adjuster comprises hydrochloric acid. In some embodiments, the formulation is stable for 0 to 24 months. In some embodiments, the formulation is stable for at least 24 months. In some embodiments, the formulation is stable for at least 24 months at 25°C and 40% relative humidity. In some embodiments, the composition is formulated in disposable containers. In some embodiments, the volume of the disposable container is approximately 0.5 mL. In some embodiments, the disposable container is in packaging that cannot be opened by children. In some embodiments, the disposable container is in a pouch that cannot be opened by children. In some embodiments, the disposable container delivers approximately 0.035 mg of oxymetazoline hydrochloride per drop.

[0008] The composition of the present disclosure also relates to a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising: about 0.1% by weight of oxymetazoline hydrochloride; about 0.64% by weight of sodium chloride; about 0.075% by weight of potassium chloride; about 0.048% by weight of calcium chloride dihydrate; about 0.03% by weight of magnesium chloride hexahydrate; 1 or more of a suitable buffer; about 0.5% by weight of hypromellose; and optionally of hydrochloric acid; wherein the pH of the formulation is in the range of about 6.3 to about 6.5.

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

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

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

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

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

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

[0015] The present disclosure is a method for improving the palpebral margin corneal reflection distance 1 (MRD-1) score of a subject, the method comprising administering to at least one eye of the subject a pharmaceutically stable aqueous ophthalmic preservative-free formulation comprising: about 0.1 wt% oxymetazoline hydrochloride; about 0.2 wt% to about 1.0 wt% sodium chloride; about 0.05 wt% to about 0.10 wt% potassium chloride; about 0.02 wt% to about 0.06 wt% calcium chloride; about 0.01 wt% to about 0.05 wt% magnesium chloride; 1 or more suitable buffer; about 0.1 wt% to about 0.90 wt% hypromellose; and hydrochloric acid if necessary, the present disclosure The present invention also relates to a method wherein the pharmaceutically stable aqueous ophthalmic preparation has a pH range of approximately 6.3 to approximately 6.5, and the average score increases by approximately 0.2 to 1.5 points approximately 1 to 20 minutes after administration or approximately 1 to 6 hours after administration, for example, 8 hours later. In some embodiments, the pharmaceutically stable aqueous ophthalmic preparation is administered to the subject as a total daily dose of approximately 0.07 mg of oxymetazoline hydrochloride, in a dose of one drop per eye, for one day or more consecutively. In some embodiments, the average C after a single dose of the preparation is measured. max The concentration is approximately 25 to 35 pg / ml. In some embodiments, the average AUC after a single dose administration of the formulation is approximately 25 to 35 pg / ml. 0-∞ The concentration is approximately 300 to 700 pg·h / mL. In some embodiments, the T after a single dose of the formulation is administered. maxThe time interval is approximately 0.5 to 6 hours. In some embodiments, the mean score of the eyelid margin corneal reflection distance test 1 (MRD-1) increases by approximately 0.2 to 1.0 points about 5 minutes after administration. In some embodiments, tachyphylaxis is not shown for at least 6 weeks. In some embodiments, the pharmaceutically stable aqueous ophthalmic preservative-free formulation comprises approximately 0.64% by weight of sodium chloride; approximately 0.075% by weight of potassium chloride; approximately 0.048% by weight of calcium chloride dihydrate; approximately 0.03% by weight of magnesium chloride hexahydrate; and approximately 0.5% by weight of hypromellose. In some embodiments, the use of the compositions and methods of the present invention does not result in tachyphylaxis. In some embodiments, tachyphylaxis is not shown for 6 weeks. In some embodiments, tachyphylaxis is not shown for a period of 6 weeks to 3 months. In some embodiments, tachyphylaxis is not shown for a period of 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 1 month, 2 months, or 3 months. In some embodiments, tachyphylaxis is not shown during use of the compositions or methods of the Disclosure. This disclosure relates to compositions comprising oxymetazoline and methods for stabilizing oxymetazoline compositions for long-term storage. This disclosure also relates to compositions comprising oxymetazoline and methods for treating various eye disorders in subjects that involve ptosis or other eyelid drooping, including administering compositions comprising oxymetazoline to subjects. [Brief explanation of the drawing]

[0016] [Figure 1] Figure 1 shows the average concentration reached after a single-dose topical administration of 0.1% by weight oxymetazoline hydrochloride eye drops, one drop per eye.

[0017] [Figure 2] Figure 2 shows a diagram of the Leicester Peripheral Field Test.

[0018] [Figure 3A]Figures 3A and 3B show the 24-month and 30-month stability data for oxymetazoline composition batch R60681. [Figure 3B] Figures 3A and 3B show the 24-month and 30-month stability data for oxymetazoline composition batch R60681.

[0019] [Figure 4A] Figures 4A and 4B show the 24-month and 30-month stability data for oxymetazoline composition batch R60701. [Figure 4B] Figures 4A and 4B show the 24-month and 30-month stability data for oxymetazoline composition batch R60701.

[0020] [Figure 5A] Figures 5A and 5B show the 24-month and 30-month stability data for oxymetazoline composition batch R60711. [Figure 5B] Figures 5A and 5B show the 24-month and 30-month stability data for oxymetazoline composition batch R60711. [Modes for carrying out the invention]

[0021] I. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure belongs. In case of any conflict, the definitions provided in this application shall prevail. Unless specifically required by context, singular terms shall be accompanied by plural forms, and plural terms shall be accompanied by singular forms. All publications, patents, and other references referenced herein are incorporated by reference in their entirety for any purpose as if it were specifically and individually indicated that each publication or patent application is incorporated by reference.

[0022] Similar or equivalent methods and materials may be used in the implementation or testing of this disclosure, but suitable methods and materials are listed below. The materials, methods, and examples are illustrative and not intended to limit the scope. Other features and advantages of this disclosure will be apparent from the detailed description and the claims.

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

[0024] The singular forms “a,” “an,” and “the” include multiple referents unless the context makes this clear. The terms “a” (or “an”), as well as “one or more,” and “at least one,” can be used synonymously herein. In certain embodiments, the terms “a” or “an” mean “single.” In other embodiments, the terms “a” or “an” include “two or more” or “plural.”

[0025] The term "about" is used herein to mean approximately, roughly, around, or within the area thereof. When the term "about" is used with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical value. Generally, the term "about" is used herein to modify the numerical values ​​above and below the stated value by a variation of 10 percent (higher or lower).

[0026] As used herein, the term "and / or" should be interpreted as meaning that each of the two specified features or components is specifically disclosed, whether or not the other is present. Accordingly, as used herein in phrases such as "A and / or B," the term "and / or" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, as used in phrases such as "A, B, and / or C," the term "and / or" is intended to include each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

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

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

[0029] As used herein, the terms “effective dose” or “pharmaceutical effective dose” refer to the amount or quantity of a drug or pharmacoactive substance sufficient to elicit the required or desired therapeutic response, in other words, the amount sufficient to elicit a recognizable biological response when administered to a patient.

[0030] As used herein, the terms “unit dosage form” or “unit dose composition” refer to a device containing a certain amount of a therapeutic compound, such that one or more predetermined units can be provided as a single therapeutic dose.

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

[0032] The term "C" as used herein max The term "maximum plasma concentration" refers to the highest plasma concentration of a drug after it has been administered to a subject.

[0033] The term "T" as used herein max The term "C" refers to the maximum plasma concentration after drug administration. max This refers to the time required to reach a certain point.

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

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

[0036] The term "AUC" as used herein 0-∞ The term "AUC" refers to the area under the drug concentration-time curve from time zero to infinity. 0-∞ This refers to the degree of drug absorption, measured by the last measured concentration (AUC). 0-T (AUC) is calculated for ) and extrapolated to infinity. t-∞ ).

[0037] As used herein, the terms “free base equivalent” or “FBE” refer 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 equivalent amount of oxymetazoline free base provided by a salt of oxymetazoline. For example, due to the weight of the hydrochloride, 100 mg of oxymetazoline hydrochloride provides only about 88 mg of oxymetazoline in the free base form. Other salts are expected to have different conversion factors depending on the molecular weight of the salt.

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

[0039] The term "Marginal Reflex Distance (MRD)" refers to one of two tests. MRD-1 refers to a test that uses photographic measurement of the distance from the central pupillary light reflex to the central margin of the upper eyelid. MRD-1 is measured using an external digital photograph. The measurement is based on the distance from the central pupillary light reflex to the central margin of the upper eyelid, ≤2 mm (the visible central pupillary light reflex is not 0 by default). MRD-2 refers to a measurement of the vertical distance from the center of the pupil to the margin of the lower eyelid.

[0040] As used herein, the terms “to treat” or “to treat” refer to administering a composition to a subject for therapeutic purposes.

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

[0042] The term "adult" refers to a person aged 18 or older.

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

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

[0045] In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic preparation comprising about 0.1% by weight of oxymetazoline hydrochloride; about 0.2% to about 1.0% by weight of sodium chloride; about 0.05% to about 0.10% by weight of potassium chloride; about 0.02% to about 0.06% by weight of calcium chloride; about 0.01% to about 0.05% by weight of magnesium chloride; 1 or more of a suitable buffer; about 0.1% to about 0.90% by weight of hypromellose; and a pH adjuster as needed; the pH range of the preparation is about 6.3 to about 6.5.

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

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

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

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

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

[0051] In some aspects of this disclosure, the subject is a mammal. In other aspects, the mammal is a human.

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

[0053] In some embodiments, the method comprises the step of administering to at least one eye of a subject a therapeutically effective amount of a pharmaceutically stable aqueous ophthalmic preparation essentially consisting of 0.1 wt% oxymetazoline hydrochloride; 0.64 wt% sodium chloride; 0.075 wt% potassium chloride; 0.048 wt% calcium chloride dihydrate; 0.03 wt% magnesium chloride hexahydrate; 1 or more suitable buffer; 0.5 wt% hypromellose; and optionally hydrochloric acid; the pH range of the preparation is 6.3 to 6.5. In some embodiments, 1 or more suitable buffers include sodium acetate trihydrate, sodium citrate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In some embodiments, a suitable buffer, in one or more units, comprises 0.39% by weight of sodium acetate trihydrate and 0.17% by weight of sodium citrate. In some embodiments, the formulation is administered in an amount of about 0.07 mg.

[0054] In some embodiments, the method comprises the step of administering a therapeutically effective amount of a pharmaceutically stable aqueous ophthalmic preparation to at least one eye of a subject, comprising 0.1 wt% oxymetazoline hydrochloride; 0.64 wt% sodium chloride; 0.075 wt% potassium chloride; 0.048 wt% calcium chloride dihydrate; 0.03 wt% magnesium chloride hexahydrate; 1 or more suitable buffer; 0.5 wt% hypromellose; and optionally hydrochloric acid; the pH range of the preparation is 6.3 to 6.5. In some embodiments, 1 or more suitable buffers include sodium acetate trihydrate, sodium citrate, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In some embodiments, one or more suitable buffers comprise 0.39% by weight of sodium acetate trihydrate and 0.17% by weight of sodium citrate.

[0055] In some embodiments, the solution is a pharmaceutically stable aqueous ophthalmic formulation comprising 0.1 wt% oxymetazoline hydrochloride; 0.64 wt% sodium chloride; 0.075 wt% potassium chloride; 0.048 wt% calcium chloride dihydrate; 0.03 wt% magnesium chloride hexahydrate; 1 or more suitable buffers; 0.5 wt% hypromellose; and hydrochloric acid as an option; the pH range of the formulation is 6.3 to 6.5. In other embodiments, 1 or more suitable buffers include boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4) and mixtures thereof. In some embodiments, 1 or more suitable buffers include 0.39 wt% sodium acetate trihydrate and 0.17 wt% sodium citrate.

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

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

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

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

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

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

[0062] In one embodiment, the preparation contains magnesium chloride, and the amount of magnesium chloride in the preparation is approximately 0.01% by weight, approximately 0.02% by weight, approximately 0.03% by weight, approximately 0.04% by weight, approximately 0.05% by weight, approximately 0.06% by weight, approximately 0.07% by weight, approximately 0.08% by weight, approximately 0.09% by weight, approximately 0.1% by weight, or approximately 0.2% by weight.

[0063] In one embodiment, the preparation contains hypromellose, and the amount of hypromellose in the preparation is approximately 0.08% by weight, approximately 0.09% by weight, approximately 0.1% by weight, approximately 0.2% by weight, approximately 0.3% by weight, approximately 0.4% by weight, approximately 0.5% by weight, approximately 0.6% by weight, approximately 0.7% by weight, approximately 0.8% by weight, approximately 0.9% by weight, approximately 1.0% by weight, or approximately 2.0% by weight.

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

[0065] III. Composition stability The compositions disclosed herein are stable. Long-term stability is an important attribute to consider when preparing ophthalmic formulations, particularly those without preservatives. To ensure the long-term stability of a composition, various important quality attributes, including assays, mass osmolality, impurities, viscosity, weight loss, and sterility, must be maintained throughout the composition's shelf life. These attributes are affected by various factors, including temperature, relative humidity, and / or pH.

[0066] Mass osmolality is the concentration of all solutes in a given weight of water and is expressed in units of either mass osmolality. It is an important attribute for maintaining ophthalmic formulations. Since the mass osmolality of the eyes of most subjects is approximately 300 mOsm, it is important that any formulation administered to the eye be maintained near this range, for example, approximately 290 to 365 mOsm / kg, so that the formulation is well tolerable.

[0067] The pH stability of a solution is crucial for both comfort and safety. If the components of an ophthalmic formulation change pH over time, the formulation can become unstable. Furthermore, pH changes can lead to the administration of formulations that may damage the eye. Therefore, it is important that the desired physiological pH is maintained throughout the formulation's lifespan. Maintaining a near-neutral pH, and thus maintaining the eye's natural pH, is essential for safety.

[0068] Viscosity is an important quality of ophthalmic formulations for maintaining the intraocular residence time of the formulation. It is important that the viscosity of the formulation is maintained throughout its lifespan so that the viscosity is constant and the delivery and residence time of the active ingredient are maintained. For example, in one embodiment, the viscosity is approximately 15 to approximately 35 cPs to maintain intraocular residence time and eye comfort.

[0069] Unstable solutions can decompose over time, producing undesirable degradation products. These products may be the result of undesirable chemical reactions involving the active ingredient, including hydrolysis and oxidation. Instability of the solution with respect to degradation products can lead to both toxicity as a result of the formation of these impurities and a decrease in the concentration of the active ingredient due to the decomposition. Undesirable degradation products include N-(2-aminoethyl)-2-[4-(1,1-dimethylethyl)-3-hydroxy-2,6-dimethylphenyl]acetamide, hydroxylated imidazoline derivatives, hydroxylamines, and N-oxide derivatives. Not limited to the following, degradation products generated from oxymetazoline decomposition include: [ka]

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

[0071] Maintaining the sterility of the formulation is also important. Sterility testing ensures that the ophthalmic formulation is free from contamination by microorganisms that could cause infection or other complications.

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

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

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

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

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

[0077] In certain embodiments, the solution is a topical eye drop administered as eye drops. Myopathic causes of ptosis may include diseases that can cause muscle weakness or nerve damage, such as myasthenia gravis and chronic progressive extraocular muscle palsy. Dystrophy or hypoplasia of the levator supra and / or Müller's muscle is the most common cause of congenital ptosis. Ptosis may be caused by damage to the third cranial nerve (oculomotor nerve), which controls the muscles that elevate the upper eyelid. Congenital neurogenic ptosis is thought to be caused by Horner's syndrome (also known as Horner's syndrome), in which mild ptosis resulting from paresis of Müller's muscle may be associated with ipsilateral miosis (pupillary constriction) and anhidrosis. Acquired Homer syndromes can occur after trauma, neoplastic invasion, or even after vascular disease. Acquired ptosis is generally caused by aponeurotic ptosis. This can occur as a result of aging, tearing, or rupture of the levator aponeurosis.

[0078] Furthermore, the same effect can be obtained in cases of chronic inflammation or intraocular surgery. Traumatic ptosis can occur following eyelid laceration due to severance of the levator muscle or destruction of nerve input. Other causes of ptosis include eyelid neoplasms, neurofibromas, or scar formation after inflammation or surgery. Mild ptosis can occur with age. Surprisingly, through the process of evaluating many drugs across a range of such drug concentrations, it was found that certain alpha-adrenergic agonists, particularly 0.1 wt% oxymetazoline hydrochloride, provide a highly effective composition that yields remarkable treatment outcomes, such as those measured by Lester peripheral visual field testing (LPFT). This composition can be used to treat ptosis, and it was found to last for 4 to 10 hours, or in one embodiment 6 hours, after topical administration of one drop of such drug to the affected eye.

[0079] Furthermore, surprisingly, through the process of evaluating many drugs across a range of such drug concentrations, it was also found that certain α-adrenergic agonists, particularly 0.1 wt% oxymetazoline hydrochloride, provide a highly effective composition that yields remarkable treatment outcomes, such as those measured by the palpebral margin-corneal reflection distance test (MRD-1). This composition can also be used to treat ptosis, and it was found that the effect lasts for 4–10 hours, or even 6 hours, after topical administration of one drop of such drug to the affected eye. Rapid onset of effect of 0.1 wt% oxymetazoline hydrochloride was also observed, with improvement in ptosis demonstrated within 5 minutes after administration of the composition of this disclosure. Improvement in MRD-1 results was also found to last for at least 6 hours after dose administration. Furthermore, improvement in MRD-1 results was also found to last for at least 8 hours. The compounds and methods of this disclosure did not exhibit tachyphylaxis, which rapidly reduces the response to sequential doses of drugs and diminishes the effect of the drugs. In some embodiments, tachyphylaxis is not shown for 6 weeks. In some embodiments, tachyphylaxis is not shown for a period of 6 weeks to 3 months. In some embodiments, tachyphylaxis is not shown for a period of 6 weeks, 7 weeks, 9 weeks, 10 weeks, 11 weeks, 1 month, 2 months, or 3 months. In some embodiments, tachyphylaxis is not shown during use of the composition or method of the Disclosure. In some embodiments, tachyphylaxis is not shown for a period of about 1 week, about 90 days, about 180 days, or about 1 year. In some embodiments, tachyphylaxis is not shown for a period of about 1 year, about 2 years, about 3 years, about 5 years, or about 10 years.

[0080] One aspect of this disclosure is a method for treating ptosis in a subject. This method involves topically administering an effective amount of oxymetazoline to the outer surface of the eye of a subject requiring such treatment. As used herein, “treat” means to alleviate the severity of a condition or disease in a subject having such a condition or disease, even if only temporarily. In one aspect, alleviation, even if only temporarily, is equivalent to elimination. For example, ptosis in a subject is said to be treated according to this method if the ptosis is reduced or eliminated, even if only temporarily.

[0081] The methods of the present disclosure are also relating to the treatment of other eyelid disorders or nonspecific conditions in which the condition is treated by raising the eyelids. Other conditions that can be treated with the formulations of the present disclosure include Horner's syndrome and myasthenia gravis. The methods of the present disclosure can be used to treat other eye-related clinical conditions, such as eye disorders or eye diseases. The method comprises administering a therapeutically effective amount of the composition of the present disclosure to at least one eye of a subject requiring such treatment. In some cases, eye-related clinical conditions include dry eye syndrome (e.g., keratoconjunctivitis sicca), Sjögren's syndrome, congenital anlacrimation, xerophthalmos (dry eye due to vitamin A deficiency), corneal malacia, thyroid eye disease, ocular rosacea, eyelid disorders, meibomian gland disease, meibomian gland dysfunction, ectropion, blepharitis, blepharochalasis, sarcoidosis, stye, hordeolum, chalazion, ptosis, pterygium, eyelid edema, eyelid dermatitis, trichiasis, eyelash loss, dacryoadenitis, Stevens-Johnson syndrome, ocular graft-versus-host disease, dacryocystitis, conjunctivitis, keratoconjunctivitis, blepharoconjunctivitis, blepharoconjunctivitis, allergic conjunctivitis, vernal keratoconjunctivitis, and conjunctival hyperemia. This includes suffusion, conjunctival laxity, subconjunctival hemorrhage, pterygium, pinguecula, conjunctival edema, iritis, iridocyclitis, glaucoma, ocular hypertension, red eye, keratitis, scleritis, episcleritis, peripheral ulcerative keratitis, neurotrophic keratitis, neurotrophic eye diseases, corneal ulcer, ulcerative keratitis, corneal abrasion, photokeratitis, ultraviolet keratitis, lagophthalmos, and corneal dystrophy.

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

[0083] V. Medication frequency and dose escalation According to this disclosure, subjects (e.g., humans) who have or are at risk of having ptosis are administered one of the pharmaceutical compositions described herein. In some embodiments, the pharmaceutical composition is administered in a constant therapeutically effective dose from the start of treatment. The therapeutically effective dose may be one drop per eye containing 0.1% by weight of oxymetazoline hydrochloride. In one embodiment, the dose comprises two drops of a 0.1% by weight solution at approximately 0.035 g / drop, with a total dose of approximately 0.07 mg, and the pharmaceutical composition contains approximately 0.035 mg of oxymetazoline hydrochloride in each drop.

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

[0085] In some embodiments, the formulation is administered in an amount of approximately 0.07 mg. In some embodiments, the formulation is administered as one drop to a single eye daily or more consecutively, with a total daily dose of approximately 0.035 mg. In some embodiments, the formulation is administered as one drop to each eye daily or more consecutively, with a total daily dose of approximately 0.07 mg of oxymetazoline hydrochloride.

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

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

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

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

[0090] As used herein, the term “adsorbent” is intended to mean an agent capable of retaining other molecules on its surface by physical or chemical (chemiadsorption) means. Such compounds include, but are not limited to, powdered carbon and activated carbon, and other materials known to those skilled in the art.

[0091] As used herein, the term “antioxidant” means an agent that inhibits oxidation and is therefore intended to be used to prevent deterioration of preparations due to oxidation processes. Examples of such compounds include, but are not limited to, 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, as well as other materials known to those skilled in the art.

[0092] As used herein, the term “buffering agent” is intended to mean a compound used to resist changes in pH due to the dilution or addition of an acid or alkali. Such compounds include, but are not limited to, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate, as well as other materials known to those skilled in the art.

[0093] VII. Lester Peripheral Visual Field Test (LPFT) The efficacy of the compositions of this disclosure can be evaluated using a variety of tests to assess patient improvement. In some embodiments, the Lester Perimeter Test (LPFT) is used to assess patient improvement outcomes. In some embodiments, the Lester Perimeter Test (LPFT) is used for evaluation and the Lester Perimeter Test (LPFT) mean score and Lester Perimeter Test (LPFT) median score are determined. In some embodiments, the Lester Perimeter Test (LPFT) mean score increases by approximately 5 to 10 points after approximately 0.1 to 16 hours. In some embodiments, the Lester Perimeter Test (LPFT) mean score increases by approximately 5.2 or 6.3 points after approximately 0.1 to 16 hours. In some embodiments, the Lester Perimeter Test (LPFT) mean score increases by approximately 5.2 or 6.3 points after approximately 6 hours. In some embodiments, the Lester Perimeter Test (LPFT) mean score increases by approximately 5 to 10 points after approximately 10 to 15 days. In some embodiments, the average Lester Perimeter Test (LPFT) score increases by approximately 6 to 8 points after about 10 to 15 days. In some embodiments, the average Lester Perimeter Test (LPFT) score increases by approximately 6.4 points or 7.7 points after about 10 to 15 days. In some embodiments, the average Lester Perimeter Test (LPFT) score increases by approximately 6.4 points or 7.7 points after about 14 days.

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

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

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

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

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

[0099] In some embodiments, the Lester Peripheral Field Test (LPFT) median score remains elevated for periods of approximately 10 minutes, 20 minutes, 1 hour, 6 hours, 8 hours, 12 hours, or 24 hours.

[0100] VIII. Marginal Corneal Reflectance Distance 1 (MRD-1) Test The Marginal Distance-Corneal Reflection Distance 1 (MRD-1) test is performed using photographic measurement to assess the distance from the central pupillary light reflex to the central margin of the upper eyelid. MRD-1 is measured using external digital photographs. Measurements are based on the distance from the central pupillary light reflex to the central margin of the upper eyelid, ≤2 mm (visible central pupillary light reflex is not 0 by default). The MRD-1 test is useful for evaluating the effectiveness of treatment.

[0101] In some embodiments, the Marginal Corneal Reflex Distance 1 (MRD-1) test is used to assess the patient's improvement outcome. In some embodiments, the Marginal Corneal Reflex Distance 1 (MRD-1) test is used for assessment, and the mean and median scores of the Marginal Corneal Reflex Distance 1 (MRD-1) test are determined. In some embodiments, the Marginal Corneal Reflex Distance 1 (MRD-1) test is performed, resulting in an increase of approximately 0.2 to 1.0 points in the mean score after approximately 1 to 10 minutes. In some embodiments, the mean score of the Marginal Corneal Reflex Distance 1 (MRD-1) test increases by approximately 0.2 to 1.0 points after approximately 5 minutes. In some embodiments, the mean score of the Marginal Corneal Reflex Distance 1 (MRD-1) test increases by approximately 0.6 points after approximately 5 minutes. In some embodiments, the average score of the Marginal Corneal Reflectance Distance 1 (MRD-1) test increases by approximately 0.5 to 1.5 points after approximately 10 to 20 minutes. In some embodiments, the average score of the Marginal Corneal Reflectance Distance 1 (MRD-1) test increases by approximately 0.5 to 1.5 points after approximately 15 minutes. In some embodiments, the average score of the Marginal Corneal Reflectance Distance 1 (MRD-1) test increases by approximately 0.9 points after approximately 15 minutes.

[0102] In some embodiments, the average score of the Marginal Resonance Distance 1 (MRD-1) test increases by approximately 0.5 to 1.5 points between approximately 5 minutes and 16 hours later. In some embodiments, the average score of the Marginal Resonance Distance 1 (MRD-1) test increases by approximately 0.5 to 1.5 points between approximately 15 minutes and 16 hours later. In some embodiments, the average score of the Marginal Resonance Distance 1 (MRD-1) test increases by approximately 0.5 to 1.5 points after approximately 15 minutes. In some embodiments, the average score increases by approximately 0.2 to 1.0 points between approximately 5 minutes and 16 hours later. In some embodiments, the average score increases by approximately 0.5 to 1.5 points between approximately 5 minutes and 42 days later.

[0103] In some embodiments, the mean Marginal Distance-1 (MRD-1) score increases by approximately 1.5 points, 1.4 points, 1.3 points, 1.2 points, 1.1 points, 1.0 points, 0.9 points, 0.8 points, 0.7 points, 0.6 points, 0.5 points, 0.4 points, or 0.3 points between approximately 5 minutes and 16 hours later. In some embodiments, the mean Marginal Distance-1 (MRD-1) score increases by approximately 1.5 points, 1.4 points, 1.3 points, 1.2 points, 1.1 points, 1.0 points, 0.9 points, 0.8 points, 0.7 points, 0.6 points, 0.5 points, 0.4 points, or 0.3 points after approximately 5 minutes. In some embodiments, the mean Marginal Corneal Reflectance Distance 1 (MRD-1) score increases by approximately 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, or 0.3 points after approximately 15 minutes. In some embodiments, the mean Marginal Corneal Reflectance 1 (MRD-1) score increases by approximately 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, or 0.3 points after approximately 16 hours.

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

[0105] In some embodiments, the mean palpebral corneal distance-1 (MRD-1) score increases by approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 points after approximately 10–20 minutes. In some embodiments, the mean palpebral corneal distance-1 (MRD-1) score increases by approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 points after approximately 15 minutes.

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

[0107] In some embodiments, the mean palpebral corneal distance 1 (MRD-1) score increases by approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 points after approximately 5–20 days. In some embodiments, the mean palpebral corneal distance 1 (MRD-1) score increases by approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 points after approximately 14 days.

[0108] In some embodiments, the mean palpebral corneal distance 1 (MRD-1) score increases by approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 points after approximately 30–60 days. In some embodiments, the mean palpebral corneal distance 1 (MRD-1) score increases by approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 points after approximately 42 days.

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

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

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

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

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

[0114] IX. Pharmacokinetics In one embodiment, the dose comprises two drops of a composition containing approximately 0.035 g / drop, or 0.1% by weight, with a total dose of approximately 0.070 mg, and the pharmaceutical composition contains approximately 0.035 mg of oxymetazoline hydrochloride in each drop. In another embodiment, each drop of the eye drop solution contains 0.035 mg (0.1% oxymetazoline hydrochloride, which corresponds to 0.031 mg (0.088%) of the oxymetazoline free base equivalent).

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

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

[0117] In some embodiments, the average T of the pharmaceutical composition after a single dose administration to the patient. max The average time interval for the pharmaceutically active ingredient is approximately 0.5 to 12 hours, approximately 0.5 to 10 hours, approximately 0.5 to 8 hours, approximately 0.5 to 6 hours, approximately 6 to 12 hours, approximately 6 to 10 hours, approximately 6 to 8 hours, approximately 7 to 12 hours, approximately 7 to 10 hours, approximately 7 to 8 hours, approximately 8 to 12 hours, approximately 8 to 10 hours, approximately 9 to 12 hours, approximately 9 to 10 hours, or approximately 10 to 12 hours. In some embodiments, the average time interval for the pharmaceutically active ingredient is approximately 0.5 to 12 hours. max The average time intervals are approximately 0 to 6 hours, 1 to 6 hours, 1 to 5 hours, 2 to 5 hours, 2 to 4 hours, or 2 to 3 hours. In one embodiment, the average time interval of the pharmaceutical composition is approximately 0 to 6 hours, 1 to 6 hours, 1 to 5 hours, 2 to 5 hours, 2 to 4 hours, or 2 to 3 hours. max This is approximately 2.5 hours. In some embodiments, the median T of the pharmaceutical composition is max These times are approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.

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

[0119] In one embodiment, the dose comprises two drops of a composition of approximately 0.035 g / drop, or 0.1% by weight, with a total dose of approximately 0.070 mg, and the pharmaceutical composition contains approximately 0.035 mg of oxymetazoline hydrochloride in each drop. In some embodiments, the mean C of the pharmaceutical composition after a single dose administration to a patient is measured. max The concentrations are approximately 10 pg / ml to 40 pg / ml, 12 pg / ml to 38 pg / ml, 14 pg / ml to 36 pg / ml, 16 pg / ml to 34 pg / ml, 18 pg / ml to 32 pg / ml, or 20 pg / ml to 30 pg / ml. In some embodiments, the average C of the pharmaceutical composition after single-dose administration is...max This is approximately 20 pg / ml, approximately 21 pg / ml, approximately 22 pg / ml, approximately 22 pg / ml, approximately 23 pg / ml, approximately 24 pg / ml, approximately 25 pg / ml, approximately 26 pg / ml, approximately 27 pg / ml, approximately 28 pg / ml, approximately 29 pg / ml, approximately 30 pg / ml, approximately 31 pg / ml, approximately 32 pg / ml, approximately 33 pg / ml, approximately 34 pg / ml, approximately 35 pg / ml, approximately 36 pg / ml, approximately 37 pg / ml, approximately 38 pg / ml, approximately 39 pg / ml, or approximately 40 pg / ml. In some embodiments, the average C of the pharmaceutical composition after single-dose administration. max The concentration is approximately 25 pg / ml to approximately 35 pg / ml. In some embodiments, the average C of the pharmaceutical composition after single-dose administration is max The concentration is approximately 28-32 pg / ml. In some embodiments, the average C of the pharmaceutical composition after single-dose administration is max This is approximately 30.5 pg / ml. In some embodiments, the average C of the pharmaceutical composition after single-dose administration is max The concentration is approximately 30.5 pg / ml, and the geometric mean Cmax is approximately 28.3 pg / ml.

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

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

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

[0123] After BFS packaging, the containers can be sealed in foil-laminated pouches for individual packaging and / or in child-proof zipper bags to prevent unwanted access. Pharmaceuticals typically require product packaging compliant with government regulations to include child-safe features to prevent, for example, children under 5 years of age from accessing products that could cause serious illness or injury. Alternatively, the containers can be sealed in child-proof foil-laminated pouches. Child-proof pouch materials can provide PET, which offers resistance to breakage, machinability, integrity, and child resistance. This may include aluminum foil and / or sealant.

[0124] This disclosure is further illustrated by the following embodiments, which should not be construed as further limitations. The contents of all references cited throughout this application are expressly incorporated herein by reference. [Examples]

[0125] Example 1 formulation Oxymetazoline hydrochloride ophthalmic solution, 0.1% by weight, was manufactured in a 200 kg batch size. The batch formulation of the drug product is shown in Table 1. [Table 1]

[0126] Formulation enhancement was pursued to improve the overall absorption of oxymetazoline in the eye without the use of preservatives. The vehicle formulation is an equilibrium salt solution intended for eye washing, formulated to have physiological pH and isotonic salt concentration. The addition of the excipient hypromellose, a viscosity modifier, helps to increase the retention time in the eye and improve eye comfort. Eight development batches were tested using either hypromellose (HPMC) or sodium carboxymethylcellulose (NA CMC). The effect of this change on pH was also measured. Stability tests were performed at 25°C±2°C / 40%RH, 40°C±2°C / NMT25%RH, and 55°C / ambient RH. The composition and results of these tests, including 3-month stability test data, can be seen in Tables 2 and 3 below. [Table 2] [Table 3]

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

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

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

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

[0131] 3.2 Effectiveness Efficacy was assessed by photographic measurements of LPFT (primary) and MRD-1. The primary efficacy endpoint was hierarchically ranked to compare oxymetazoline hydrochloride and the vehicle in terms of the mean increase from baseline (day 1, time 0) in the top four rows of LPFT scores for the tested eyes: 1. Day 1 Time 6 2.14th day time 2 This study is complete, and the results are shown below. The increase in the number of points observed in the upper visual field (LPFT change) in the oxymetazoline hydrochloride group compared to the vehicle group at both time points was statistically significant. This shows a clear improvement in the upper visual field at 6 hours post-dose on day 1 and 2 hours post-dose on day 14, as shown in Table 6. The mean change from baseline in visual field data at time points 6 hours post-dose on day 14, 8 hours post-dose on day 14, and 42 can be seen in Table 7. [Table 6] [Table 7]

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

[0133] 4.1 Effectiveness Efficacy was assessed by photographic measurements of LPFT (primary) and MRD-1. The primary efficacy endpoint was hierarchically ranked to compare oxymetazoline hydrochloride and the vehicle in terms of the mean increase from baseline (day 1, time 0) in the top four rows of LPFT scores for the tested eyes: 1. Day 1 Time 6 2.14th day time 2 The results are shown below. The increase in the number of points observed in the upper visual field (LPFT change) in the oxymetazoline hydrochloride group compared to the vehicle group at both time points was statistically significant. This indicates a clear improvement in the upper visual field at 6 hours post-dose on day 1 and 2 hours post-dose on day 14, as shown in Table 8.

[0134] Photometric measurements of MRD-1 also showed a positive effect of oxymetazoline hydrochloride treatment. The increase in LPFT was numerically greater in the oxymetazoline hydrochloride group than in the vehicle group at all time points after administration. A larger increase in MRD-1 was observed in the oxymetazoline hydrochloride group than in the vehicle group at all time points after 6 weeks of administration, Table 9. The increase in MRD-1 values ​​observed at 5 minutes post-dose indicated that the effect began by 5 minutes.

[0135] 4.2 Safety Oxymetazoline hydrochloride was well-tolerated, and the observed adverse events were mostly mild.

[0136] 4.3 Results The LPFT was performed using a Humphrey visual field analyzer. This is an age-corrected screening test using a three-zone strategy. 35 points are tested in the upper visual field and 14 points in the lower visual field. A maximum of 48° is tested in the upper visual field. The fixation center is shifted 15° downward to allow for maximum upper visual field testing (Ho et al., 2011). The lower visual field test serves as a reference but is not used for analysis. A typical Lester peripheral visual field test grid can be seen in Figure 2. The subject holds the forehead against the chin and keeps the forehead still and the forehead relaxed. The subject views the fixation target throughout the test. Corrective lenses are not required in the LPFT unless the subject has difficulty viewing the target without corrective lenses (e.g., high myopia, high hyperopia, or high astigmatism). [Table 8] [Table 9]

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

[0138] The oxymetazoline hydrochloride solution remained stable across five measurement time points: 0 months, 6 months, 12 months, 18 months, and 24 months, demonstrating good stability and shelf life of the prescribed preparation.

[0139] Example 6 Study on the clinical supply stability of oxymetazoline hydrochloride Oxymetazoline hydrochloride preparations were prepared according to Table 12. Stability tests were conducted on the oxymetazoline preparations over a period of 24 to 30 months. [Table 12]

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

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

Claims

1. a) about 0.1% by weight of oxymetazoline hydrochloride; b) With one or more tension adjusters; c) One or more suitable buffers comprising sodium acetate or its hydrate and sodium citrate or its hydrate; d) with approximately 0.1% to 0.90% by weight of hypromellose; e) pH adjuster as needed; f) Water for injection and A pharmaceutically stable aqueous ophthalmic preparation containing, The pH of the aforementioned formulation is in the range of approximately 5.8 to approximately 6.

8. formulation.

2. The formulation according to claim 1, wherein the formulation comprises about 0.5% by weight of hypromellose.

3. The formulation according to claim 1, wherein the one or more tonicity adjusting agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, or a combination thereof.

4. The tension adjusting agent described in item 1 or more thereof, Approximately 0.2% to 1.0% by weight of sodium chloride; Approximately 0.05% to 0.10% by weight of potassium chloride; Approximately 0.02% to approximately 0.06% by weight of calcium chloride or its hydrate; Approximately 0.01% to approximately 0.05% by weight of magnesium chloride or its hydrate The formulation according to claim 3, including the formulation described in claim 3.

5. The formulation according to claim 4, wherein the calcium chloride or its hydrate is calcium chloride dihydrate, and the magnesium chloride or its hydrate is magnesium chloride hexahydrate.

6. The formulation according to claim 1, wherein the 1 or more suitable buffer comprises about 0.39% by weight of sodium acetate or its hydrate and about 0.17% by weight of sodium citrate or its hydrate.

7. The formulation according to claim 1, wherein the suitable buffer solution 1 or more comprises sodium acetate trihydrate and sodium citrate dihydrate.

8. The formulation according to claim 1, wherein the pH adjusting agent 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.

9. The formulation according to claim 8, wherein the pH adjusting agent comprises hydrochloric acid.

10. The formulation according to claim 1, wherein the formulation does not contain a preservative.

11. The formulation according to claim 1, wherein the viscosity of the formulation is about 15 cPs to about 35 cPs.

12. The formulation according to claim 1, wherein the viscosity of the formulation is about 15 cPs to about 25 cPs.

13. The formulation according to claim 1, wherein the mass osmolality of the formulation is about 290 to about 365 mOsm / kg.

14. The formulation according to claim 1, wherein the mass osmolality of the formulation is about 290 to about 330 mOsm / kg.

15. The formulation according to claim 1, wherein the formulation is filled into a disposable container.

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