Compositions and uses of alpha adrenergic agonists

Abstract

To provide a non-surgical alternative to blepharoplasty for treatment and cosmetic applications.SOLUTION: To provide cosmetic and therapeutic compositions of alpha-adrenergic agents. The compositions of the disclosure may be used for topical, transdermal or parenteral administration to the eye or eyelid. The compositions of the present disclosure may be used cosmetically to improve the appearance of the eye or therapeutically to treat ptosis.SELECTED DRAWING: None

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 62 / 287,391, filed January 26, 2016, which is incorporated by reference in its entirety. [Background technology]

[0002] Background of the Invention Blepharoplasty is a surgical procedure that involves removing excess skin, muscle and fat from the target eyelid.Blepharoplasty can be prescribed as a treatment for drooping eyelids, called ptosis, but can also be used to improve vision or change the cosmetic appearance of the target eye.This procedure was one of the top five most commonly performed cosmetic procedures in the United States, where more than 200,000 surgical procedures were performed in 2014, according to the 2014 Plastic Surgery Report of the American Society of Plastic Surgeons (Non-Patent Document 1).

[0003] Blepharoplasty is an expensive procedure and may not be available to all individuals who need or desire surgery to correct ptosis or improve vision or appearance. The average cost of blepharoplasty in the United States in 2014 was approximately $2,900, according to a report by the American Society of Plastic Surgeons. While the cost may be covered by health insurance carriers in certain circumstances, health insurance carriers generally do not cover the cost of cosmetic surgery or its complications.

[0004] Although non-surgical alternatives to blepharoplasty can be used, such as clutch glasses or special scleral contact lenses to support eyelids, these alternatives are cumbersome to wear and may not provide sufficient symptom relief for patients.Available surgical alternatives are also unsuitable for individuals seeking cosmetic improvement.Therefore, there remains a need for non-surgical alternatives to blepharoplasty for therapeutic and cosmetic use. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] American Society of Plastic Surgeons’ 2014 Plastic Surgery Report Summary of the Invention

[0006] The present disclosure provides an eyeshadow-like composition comprising a dermatologically acceptable carrier, an agent that stimulates the Müller muscle, and at least one cosmetic excipient. In some embodiments of the eyeshadow-like composition, the agent that stimulates the Müller muscle comprises an alpha-adrenergic agonist. In some embodiments of the eyeshadow-like composition, the alpha-adrenergic agonist is selected from natural alpha-adrenergic agonists or synthetic alpha-adrenergic agonists. In some embodiments of the eyeshadow-like composition, the alpha-adrenergic agonist is selected from alpha-1 agonists and alpha-2 agonists. In some embodiments of the eyeshadow composition, the alpha-adrenergic agonist is selected from the group consisting of amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, Selected from oxymetazoline, phenylephrine, phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline, 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a salt of any one of them, and any combination thereof.

[0007] In some embodiments of the eyeshadow-like composition, the alpha-adrenergic agonist is oxymetazoline or a salt thereof. In some embodiments of the eyeshadow-like composition, the alpha-adrenergic agonist is oxymetazoline. In some embodiments of the eyeshadow-like composition, the alpha-adrenergic agonist is not oxymetazoline.

[0008] In some embodiments of the eye shadow-like composition, the dermatologically acceptable carrier is selected from lotions, oils, creams, butters, gels, ointments, sprays, milks, and powders. In some embodiments of the eye shadow-like composition, the dermatologically acceptable carrier is a powder. In some embodiments of the eye shadow-like composition, the cosmetic vehicle is selected from sunscreens, fragrances, pigments, and antioxidants.

[0009] In some aspects, the present disclosure provides dermatological compositions comprising a dermatologically acceptable carrier, an alpha-adrenergic agonist, and at least one permeation enhancer. In some embodiments of the dermatological compositions, the permeation enhancer increases the skin permeation of the alpha-adrenergic agonist by about 2-fold or more. In some embodiments of the dermatological compositions, the permeation enhancer increases the skin permeation of the alpha-adrenergic agonist by about 3-fold or more. In some embodiments of the dermatological compositions, the permeation enhancer increases the skin permeation of the alpha-adrenergic agonist by about 0.5 mm or more. In some embodiments of the dermatological compositions, the permeation enhancer increases the skin permeation of the alpha-adrenergic agonist by about 1.0 mm or more. In some embodiments of the dermatological compositions, the alpha-adrenergic agonist penetrates the skin and septal fat pad and contacts the Müller's muscle. In some embodiments of the dermatological composition, the penetration enhancer is selected from alcohols, sulfoxides, azones, pyrrolidones, ureas, alkyl-N,N-disubstituted aminoacetals, propylene glycol, surfactants, terpenes, terpenoids, fatty acids, esters, cyclodextrins, and any combination thereof. In some embodiments of the dermatological composition, the penetration enhancer is selected from ethanol, propylene glycol, dodecyl-N,N-dimethyl-aminoacetate, ethyl acetate, azones, sodium dodecyl sulfate, d-limonene, oleic acid, 1,3-diphenylurea, N-methyl-2-pyrrolidone, beta-cyclodextrin, dimethyl sulfoxide, and any combination thereof. In some embodiments of the dermatological composition, the composition further comprises one or more cosmetic excipients.

[0010] In one aspect, the present disclosure provides a dermatological composition comprising an alpha-adrenergic agonist, at least one dermatologically acceptable carrier, and at least one cosmetic excipient selected from sunscreens, fragrances, pigments, and antioxidants. In some embodiments of the dermatological composition, the dermatologically acceptable carrier is selected from lotions, oils, creams, butters, gels, ointments, sprays, milks, and powders. In some embodiments of the dermatological composition, the alpha-adrenergic agonist is selected from natural alpha-adrenergic agonists or synthetic alpha-adrenergic agonists. In some embodiments of the dermatological composition, the alpha-adrenergic agonist is selected from alpha-1 agonists and alpha-2 agonists. In certain embodiments of the dermatological composition, the alpha-adrenergic agonist is amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, ointmenthol, ointmenthol, ointmenthol-based steroids ... Selected from ximetazoline, phenylephrine, phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline, 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a salt of any one thereof, and any combination thereof.

[0011] In some embodiments of the dermatological composition, the alpha-adrenergic agonist is oxymetazoline or a salt thereof. In some embodiments of the dermatological composition, the alpha-adrenergic agonist is oxymetazoline. In some embodiments of the dermatological composition, the alpha-adrenergic agonist is not oxymetazoline. In some embodiments of the dermatological composition, the composition contains about 0.5 μg to about 4 mg of the alpha-adrenergic agonist per dose. In some embodiments of the dermatological composition, the composition contains about 0.5 μg to about 2 mg of the alpha-adrenergic agonist per dose.

[0012] Further disclosed herein are controlled-release dermatological compositions comprising an alpha-adrenergic agonist and a delivery system that controls the release of the alpha-adrenergic agonist. In some embodiments of the controlled-release dermatological compositions, the composition is selected from sustained-release compositions, extended-release compositions, pulsed-release compositions, and delayed-release compositions. In some embodiments of the controlled-release dermatological compositions, the delivery system is selected from polymer-based systems, porous matrices, hydrogel release systems, and peptide-based systems. In some embodiments of the controlled-release dermatological compositions, the composition is a sustained-release composition. In some embodiments of the controlled-release dermatological compositions, the composition is formulated for administration to the outer surface of the eyelid. In some embodiments of the controlled-release dermatological compositions, the composition comprises from about 0.2 μg to about 6 mg of alpha-adrenergic agonist per dose. In some embodiments of the controlled-release dermatological compositions, the composition comprises from about 0.5 μg to about 4 mg of alpha-adrenergic agonist per dose. In some embodiments of the controlled-release dermatological composition, the composition comprises from about 0.5 μg to about 3 mg of an alpha-adrenergic agonist per dose.

[0013] In some embodiments of the controlled-release dermatological composition, the composition is formulated as a lotion, cream, butter, gel, ointment, spray, milk, or powder. In some embodiments of the controlled-release dermatological composition, the composition further comprises at least one dermatologically acceptable carrier. In some embodiments of the controlled-release dermatological composition, the composition further comprises one or more cosmetic excipients selected from sunscreens, fragrances, pigments, and antioxidants.

[0014] In some embodiments of the controlled-release dermatological composition, the alpha-adrenergic agonist is selected from a natural alpha-adrenergic agonist or a synthetic alpha-adrenergic agonist. In some embodiments of the controlled-release dermatological composition, the alpha-adrenergic agonist is selected from an alpha-1 agonist and an alpha-2 agonist. In certain embodiments of the controlled-release dermatological composition, the alpha-adrenergic agonist is amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine In some embodiments of the controlled-release dermatological composition, the alpha-adrenergic agonist is selected from oxymetazoline, phenylephrine, phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline, 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a salt of any one thereof, and any combination thereof. In some embodiments of the controlled-release dermatological composition, the alpha-adrenergic agonist is oxymetazoline or a salt thereof.

[0015] Further disclosed herein is a method for treating ptosis in a subject in need thereof, comprising administering a composition comprising an alpha-adrenergic agonist to the outer surface of the eyelid of the subject's eye.In some embodiments of the method for treating ptosis, the composition is administered once, twice, or three times per day.In some embodiments of the method for treating ptosis, the composition is selected from any one of the eyeshadow compositions, dermatological compositions, or controlled-release dermatological compositions described herein.In some embodiments of the method for treating ptosis, the composition is not administered to the eye.

[0016] Further disclosed herein is a method for cosmetic treatment of the eye of a subject, comprising administering a composition comprising an alpha-adrenergic agonist to the outer surface of the eyelid of the eye of the subject.In some embodiments of the method for cosmetic treatment, the composition is administered once, twice or three times per day.In some embodiments of the method for cosmetic treatment, the composition is selected from any one of the eyeshadow compositions, dermatological compositions or controlled-release dermatological compositions described herein.In some embodiments of the method for cosmetic treatment, the composition is not administered to the eye.

[0017] Further disclosed herein is a method for increasing the vertical separation of the upper and lower eyelids of a subject's eye, comprising administering a composition comprising an effective amount of an alpha-adrenergic agonist to the outer surface of the eyelid of the subject's eye. In some embodiments of the method for increasing the vertical separation of the upper and lower eyelids, the method increases the vertical separation of the upper and lower eyelids by about 10 percent or more compared to the separation of the upper and lower eyelids before said administration. In some embodiments of the method for increasing the vertical separation of the upper and lower eyelids, the composition is selected from any one of the eyeshadow-like compositions, dermatological compositions, or controlled-release dermatological compositions described herein. In some embodiments of the method for increasing the vertical separation of the upper and lower eyelids, the subject does not have ptosis. In some embodiments of the method for increasing the vertical separation of the upper and lower eyelids, the composition is not administered to the eye.

[0018] [The present invention 1001] An eyeshadow-like composition comprising a dermatologically acceptable carrier, an agent that stimulates the Muller muscle, and at least one cosmetic excipient. [The present invention 1002] 1001. An eye shadow-like composition according to claim 1001, wherein the agent that stimulates the Muller muscle comprises an alpha-adrenergic agonist. [The present invention 1003] 1002. The eye shadow-like composition of claim 1002, wherein the alpha-adrenergic agonist is selected from natural alpha-adrenergic agonists or synthetic alpha-adrenergic agonists. [The present invention 1004] The eye shadow-like composition of claim 1003, wherein the alpha-adrenergic agent is selected from an alpha-1 agonist and an alpha-2 agonist. [The present invention 1005] Alpha-adrenergic agonists include amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluoronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline, phenylephrine, and phenylephrine. An eye shadow-like composition according to claim 1004, wherein the active ingredient is selected from nylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline, 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a salt of any one of these, and any combination thereof. [The present invention 1006] The eye shadow-like composition of the present invention 1005, wherein the alpha-adrenergic agonist is oxymetazoline or a salt thereof. [The present invention 1007] The eye shadow composition of the present invention 1006, wherein the alpha-adrenergic agonist is oxymetazoline. [The present invention 1008] The eye shadow composition of any one of inventions 1002 to 1005, wherein the alpha-adrenergic agonist is not oxymetazoline. [The present invention 1009] The eye shadow-like composition of any one of inventions 1001 to 1008, wherein the dermatologically acceptable carrier is selected from lotions, oils, creams, butters, gels, ointments, sprays, milks, and powders. [The present invention 1010] 1009. An eye shadow-like composition according to claim 10, wherein the dermatologically acceptable carrier is a powder. [The present invention 1011] The eye shadow-like composition of any one of inventions 1001 to 1010, wherein the cosmetic excipient is selected from a light-blocking agent, a fragrance, a pigment, and an antioxidant. [The present invention 1012] A dermatological composition comprising a dermatologically acceptable carrier, an alpha-adrenergic agonist, and at least one penetration enhancer. [The present invention 1013] The dermatological composition of the present invention 1012, wherein the penetration enhancer increases skin penetration of the alpha-adrenergic agonist by about two-fold or more. [The present invention 1014] The dermatological composition of the present invention 1013, wherein the penetration enhancer increases skin penetration of the alpha-adrenergic agonist by about three-fold or more. [The present invention 1015] The dermatological composition of the present invention 1012, wherein the penetration enhancer increases skin penetration of the alpha-adrenergic agonist by about 0.5 mm or more. [The present invention 1016] The dermatological composition of the present invention 1015, wherein the penetration enhancer increases skin penetration of the alpha-adrenergic agonist by about 1.0 mm or more. [The present invention 1017] The dermatological composition of any of claims 1012 to 1016, wherein the alpha-adrenergic agonist penetrates the skin and septal fat pad to contact the Muller muscle. [The present invention 1018] 18. The dermatological composition of any one of claims 1012 to 1017, wherein the penetration enhancer is selected from an alcohol, a sulfoxide, an azone, a pyrrolidone, a urea, an alkyl-N,N-disubstituted aminoacetal, a propylene glycol, a surfactant, a terpene, a terpenoid, a fatty acid, an ester, a cyclodextrin, and any combination thereof. [The present invention 1019] The dermatological composition of the present invention 1018, wherein the penetration enhancer is selected from ethanol, propylene glycol, dodecyl-N,N-dimethyl-aminoacetate, ethyl acetate, azone, sodium dodecyl sulfate, d-limonene, oleic acid, 1,3-diphenylurea, N-methyl-2-pyrrolidone, beta-cyclodextrin, dimethyl sulfoxide, and any combination thereof. [The present invention 1020] 1020. The dermatological composition of any of claims 1012 to 1019, further comprising one or more cosmetic excipients. [The present invention 1021] A dermatological composition comprising a dermatologically acceptable carrier, an alpha-adrenergic agonist, and at least one cosmetic excipient selected from sunscreens, fragrances, pigments, and antioxidants. [The present invention 1022] The dermatological composition of any one of claims 1012 to 1021, wherein the dermatologically acceptable carrier is selected from lotions, oils, creams, butters, gels, ointments, sprays, milks, and powders. [The present invention 1023] The dermatological composition of any of claims 1012 to 1022, wherein the alpha-adrenergic agonist is selected from natural alpha-adrenergic agonists or synthetic alpha-adrenergic agonists. [The present invention 1024] The dermatological composition of invention 1023, wherein the alpha-adrenergic agent is selected from an alpha-1 agonist and an alpha-2 agonist. [The present invention 1025] Alpha-adrenergic agonists include amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluoronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline, phenylephrine, and phenylproline. The dermatological composition of any of claims 1012 to 1024, wherein the compound is selected from panolamine, pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline, 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a salt of any one thereof, and any combination thereof. [The present invention 1026] The dermatological composition of invention 1025, wherein the alpha-adrenergic agonist is oxymetazoline or a salt thereof. [The present invention 1027] The dermatological composition of claim 1026, wherein the alpha-adrenergic agonist is oxymetazoline. [The present invention 1028] The dermatological composition of any of claims 1012 to 1027, wherein the alpha-adrenergic agonist is not oxymetazoline. [The present invention 1029] 1028. The dermatological composition of any of claims 1012 to 1028, comprising about 0.5 μg to 4 mg of an alpha-adrenergic agonist per dose. [The present invention 1030] 1029. A dermatological composition of the present invention comprising about 0.5 μg to 2 mg of an alpha-adrenergic agonist per dose. [The present invention 1031] A controlled release dermatological composition comprising an alpha-adrenergic agonist and a delivery system that controls the release of the alpha-adrenergic agonist. [The present invention 1032] The controlled release dermatological composition of the present invention 1031 selected from sustained release compositions, extended release compositions, pulsed release compositions, and delayed release compositions. [The present invention 1033] The controlled release dermatological composition of claim 1031 or 1032, wherein the delivery system is selected from a polymer-based system, a porous matrix, a hydrogel release system, a peptide-based system, and any combination thereof. [The present invention 1034] The controlled release dermatological composition of any one of claims 1031 to 1033, which is a sustained release composition. [This invention 1035] 5. The controlled release dermatological composition of any of claims 1031 to 1034, formulated for administration to the outer surface of the eyelid. [The present invention 1036] 6. The controlled-release dermatological composition of any of claims 1031 to 1035, comprising from about 0.2 μg to about 6 mg of an alpha-adrenergic agonist per dose. [This invention 1037] 1036. A controlled-release dermatological composition of the present invention comprising about 0.5 μg to about 4 mg of an alpha-adrenergic agonist per dose. [The present invention 1038] 1037. A controlled release dermatological composition of the present invention comprising about 0.5 μg to about 3 mg of an alpha-adrenergic agonist per dose. [This invention 1039] The controlled-release dermatological composition of any of claims 1031 to 1038, formulated as a lotion, cream, butter, gel, ointment, spray, milk, or powder. [The present invention 1040] 1039. The controlled release dermatological composition of any of claims 1031 to 1039, further comprising at least one dermatologically acceptable carrier. [The present invention 1041] The controlled release dermatological composition of invention 1040 further comprising one or more cosmetic excipients selected from sunscreens, fragrances, pigments, and antioxidants. [The present invention 1042] 1042. The controlled release dermatological composition of any of claims 1031 to 1041, wherein the alpha-adrenergic agonist is selected from natural alpha-adrenergic agonists or synthetic alpha-adrenergic agonists. [This invention 1043] The controlled release dermatological composition of this invention 1042, wherein the alpha-adrenergic agent is selected from an alpha-1 agonist and an alpha-2 agonist. [This invention 1044] Alpha-adrenergic agonists include amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluoronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline, phenylephrine, and phenylpropanol. 10. The controlled-release dermatological composition of any one of claims 1031 to 1043, wherein the compound is selected from the group consisting of benzodiazepine, benzophenone, benzocaine, benzoyl benzoate ... [This invention 1045] The controlled release dermatological composition of the present invention 1044, wherein the alpha-adrenergic agonist is oxymetazoline or a salt thereof. [The present invention 1046] A method for treating ptosis of the eye of a subject in need thereof, comprising administering a composition comprising an alpha-adrenergic agonist to the outer surface of the eyelid of the subject's eye. [This invention 1047] 1046. The method of claim 1046, wherein the composition is administered once, twice, or three times per day. [This invention 1048] The method of claim 1046, wherein the composition is administered every two days. [This invention 1049] The method of claim 1046, wherein the composition is administered every three days. [The present invention 1050] The method of any one of claims 1046 to 1049, wherein the composition is selected from any one of claims 1001 to 1045. [This invention 1051] A method for cosmetic treatment of a subject's eye, comprising administering a composition comprising an alpha-adrenergic agonist to the outer surface of the eyelid of the subject's eye. [This invention 1052] The method of claim 1051, wherein the composition is administered once, twice, or three times per day. [This invention 1053] The method of claim 1051, wherein the composition is administered every two days. [This invention 1054] 1051. The method of claim 1051, wherein the composition is administered every three days. [This invention 1055] The method of any one of claims 1051 to 1054, wherein the composition is selected from any one of claims 1001 to 1045. [This invention 1056] A method for increasing the vertical separation of the upper and lower eyelids of a subject's eye, comprising administering to the outer surface of the eyelid of the subject's eye a composition comprising an effective amount of an alpha-adrenergic agonist. [This invention 1057] 1056. The method of claim 1056, wherein the vertical separation of the upper and lower eyelids is increased by about 10 percent or more compared to the separation of the upper and lower eyelids prior to said administration. [This invention 1058] The method of claim 1056 or 1057, wherein the composition is selected from any one of claims 1001 to 1045. [This invention 1059] The method of any of claims 1051 to 1058, wherein the subject does not have ptosis. [The present invention 1060] The method of any one of claims 1051 to 1059, wherein the composition is not administered to the eyeball. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description The present disclosure provides compositions and uses of alpha-adrenergic agonists. In some embodiments, the compositions of the present disclosure include an alpha-adrenergic agonist and are suitable for topical, transdermal, or parenteral administration. In certain embodiments, the present disclosure provides controlled-release compositions of alpha-adrenergic agonists for topical, transdermal, or parenteral administration. In certain embodiments, the alpha-adrenergic agonist is an alpha-adrenergic agonist, such as oxymetazoline.

[0020] The composition of the present disclosure can be used as an alternative to blepharoplasty to treat ptosis in a subject.In some embodiments, the composition of the present disclosure is used to increase the vertical separation of the upper and lower eyelids of a subject or improve the visual axis of a subject without the need for invasive surgical procedures.In certain embodiments, the composition is administered to a subject who does not suffer from ptosis.The composition of the present disclosure can be used for cosmetic purposes, such as improving the appearance of eyes.

[0021] In some embodiments, the present disclosure provides compositions, e.g., cosmetic compositions, for topical administration to the outer surface of the eyelid, or any portion thereof, wherein the composition comprises an agent that stimulates the Müller muscle. Agents that stimulate the Müller muscle are known in the art and include, for example, alpha-adrenergic agonists.

[0022] Alpha-adrenergic agonists In some embodiments, the present disclosure provides an alpha-adrenergic agonist, which is a compound that modulates alpha-adrenergic receptors. The alpha-adrenergic agonist of the present disclosure can be selected from natural alpha-adrenergic agonists or synthetic alpha-adrenergic agonists. In certain embodiments, the present disclosure provides an alpha-adrenergic agonist that agonizes one or more of alpha-1 and alpha-2 adrenergic receptors. In some embodiments, the alpha-adrenergic agonist agonizes alpha-1 and alpha-2 adrenergic receptors. In certain embodiments, the alpha-adrenergic agonist agonizes alpha-1 and alpha-2 adrenergic receptors and is selected from compounds other than oxymetazoline. In certain embodiments, the present disclosure provides an alpha-adrenergic agonist that antagonizes one or more of alpha-1 and alpha-2 adrenergic receptors.

[0023] In some embodiments, the alpha-adrenergic agonist agonizes alpha-1 adrenergic receptors. In some embodiments, the alpha-adrenergic agonist selectively agonizes alpha-1 adrenergic receptors. In some embodiments, the alpha-adrenergic agonist agonizes alpha-2 adrenergic receptors. In some embodiments, the alpha-adrenergic agonist partially agonizes alpha-1 or alpha-2 adrenergic receptors. In some embodiments, the alpha-adrenergic agonist is oxymetazoline. In certain embodiments, the alpha-adrenergic agonist selectively agonizes alpha-1 adrenergic receptors and partially agonizes alpha-2 adrenergic receptors, and is selected from compounds other than oxymetazoline.

[0024] The terms "agonist," or "agonizing" compound, as used herein, generally refer to a compound that binds to a specific receptor and elicits a response in a cell. Agonists generally mimic the action of an endogenous ligand that binds to the same receptor.

[0025] The term "antagonist" as used herein refers to a molecule, such as a compound, that reduces, inhibits, or blocks the cellular response to a receptor activated by an agonist. Antagonists may include, but are not limited to, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, partial agonists, and inverse agonists. A competitive antagonist can reversibly bind to a receptor at the same binding site (active site) as an endogenous ligand or agonist without necessarily activating the receptor. A non-competitive antagonist (also known as an allosteric antagonist) can bind to a binding site distinct from that of an agonist and exert its effect on the receptor through another binding site. A non-competitive antagonist generally does not compete with an agonist for binding. The binding of a non-competitive antagonist to a receptor can reduce the affinity of an agonist to the receptor. Alternatively, binding of a non-competitive antagonist to a receptor may prevent the conformational changes in the receptor necessary for agonist-mediated receptor activation. Non-competitive antagonists may require receptor activation by an agonist before they can bind to a separate allosteric binding site.

[0026] "Partial agonist" or "partially agonizing" compounds refer to compounds that, at a given receptor, may differ in the magnitude of the functional response they elicit after maximal receptor occupancy. Partial agonists are agonists, but when co-administered with a full agonist, they may act as competitive antagonists by competing with the full agonist for receptor occupancy, resulting in a net decrease in receptor activation observed with the full agonist alone.

[0027] A "full agonist" or a compound that "fully agonizes" an alpha-adrenergic receptor refers to a compound that activates the receptor and exerts full efficacy at that receptor.

[0028] As used herein, the term " selectively " agonize refers to the ability of the compound described herein to agonize target receptor with greater affinity than non-target receptor.The method for determining whether a compound selectively agonizes alpha-1 or alpha-2 adrenergic receptor is well known (for example, A. Megans et al. Eur. J. Pharm. V. 129, I. 1-2, p 57-64 (1996)).

[0029] In some embodiments, the alpha-adrenergic agonist is selected from a long-acting alpha-adrenergic agonist and a short-acting alpha-adrenergic agonist. As used herein, a "long-acting alpha-adrenergic agonist" is an alpha-adrenergic agonist with a systemic half-life of greater than 3 hours in normal adults. Long-acting alpha-adrenergic agonists include, but are not limited to, oxymetazoline, methoxamine, naphazoline, tetrahydrozoline, xylometazoline, and apraclonidine (also known as Iopidine®). In some embodiments, the long-acting alpha-adrenergic agonist is oxymetazoline, which has a reported half-life of 5 to 6 hours. In one embodiment, the long-acting alpha-adrenergic agonist is a pharmaceutically acceptable salt of a long-acting alpha-adrenergic agonist. In some embodiments, the long-acting alpha-adrenergic agonist is oxymetazoline or a pharmaceutically acceptable salt thereof, such as oxymetazoline hydrochloride.

[0030] As used herein, "short-acting alpha-adrenergic agonist" refers to an alpha-adrenergic agonist that has a systemic half-life of 3 hours or less in normal adults.Short-acting alpha-adrenergic agonists include, but are not limited to, phenylephrine and brimonidine.In one embodiment, the short-acting alpha-adrenergic agonist is a pharmaceutically acceptable salt of the short-acting alpha-adrenergic agonist.In some embodiments, the short-acting alpha-adrenergic agonist is phenylephrine or its pharmaceutically acceptable salt, for example, phenylephrine hydrochloride.

[0031] In some embodiments, the alpha-adrenergic agonist selectively agonizes the alpha-1A adrenergic receptor. In some embodiments, the alpha-adrenergic agonist selectively agonizes the alpha-1B adrenergic receptor. In some embodiments, the alpha-adrenergic agonist selectively agonizes the alpha-1D adrenergic receptor. In some embodiments, the alpha-adrenergic agonist selectively agonizes the alpha-2A adrenergic receptor. In some embodiments, the alpha-adrenergic agonist selectively agonizes the alpha-2B adrenergic receptor. In some embodiments, the alpha-adrenergic agonist selectively agonizes the alpha-2C adrenergic receptor.

[0032] In some embodiments, the alpha-1 adrenergic agonist is selected from the group consisting of amidefrin, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, oxaliplatin ... The alpha-1 adrenergic agonist is selected from the group consisting of cimetazoline, phenylephrine, phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline, 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), any one of their salts, and any combination thereof. In some embodiments, the alpha-1 adrenergic agonist is oxymetazoline or its salt.

[0033] In some embodiments, the alpha-1 adrenergic agonist is selected from the group consisting of amidefrin, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine. the benzodiazepine, phenylephrine, phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline, 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a salt of any one thereof, and any combination thereof.

[0034] In some embodiments, the alpha-adrenergic agonist is a selective alpha-1A adrenergic agonist. In some embodiments, the alpha-1A selective adrenergic agonist is 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole or A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide).

[0035] In some embodiments, the alpha-adrenergic agonist is an alpha-2 adrenergic agonist. In some embodiments, the alpha-2 adrenergic agonist is agmatine, amitraz, apraclonidine, brimonidine, cannabigerol, cannabivarin, clonidine, detomidine, dexmedetomidine, dihydroergotamine, dipivefrin, dopamine, ephedrine, ergotamine, epinephrine (adrenaline), esproquine, etilefrine, ethylnorepinephrine, fadolmidine, 6-fluoronorepinephrine, guanabenz, guanfacine, guanoxabenz, levonordefrin, lofexidine, marsanidine. nidine), 7-Me-marsanidine, medetomidine, methamphetamine, methyldopa, mivazerol, naphazoline, 4-NEMD (4-(1-naphthalen-1-ylethyl)-1H-imidazole), (R)-3-nitrobiphenyline, norepinephrine (noradrenaline), phenylpropanolamine, piperoxane, pseudoephedrine, rilmenidine, romifidine, talipexole, tetrahydrozoline, tizanidine, tolonidine, urapidil, xylazine, xylometazoline, a salt of any one of them, and any combination thereof.

[0036] The compositions described herein may contain at least one alpha-adrenergic agonist as an active ingredient in the form of a free acid or free base, or in the form of a pharmaceutically acceptable salt. Included in the present disclosure are salts of the alpha-adrenergic agonists herein, particularly pharmaceutically acceptable salts. Alpha-adrenergic agonists of the present disclosure that have sufficiently acidic, sufficiently basic, or both functional groups can react with any of a number of inorganic bases and inorganic and organic acids to form salts. Alternatively, compounds that are inherently charged, such as those with quaternary nitrogen, can form salts with appropriate counterions, such as halides, e.g., bromide, chloride, or fluoride, particularly bromide.

[0037] The alpha-adrenergic agonists described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as the appropriate mixtures thereof. Separation of stereoisomers can be carried out by chromatography, or by formation of diastereomers and recrystallization or chromatographic separation, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981, the disclosure of which is incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis.

[0038] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). Active metabolites of these compounds having the same type of activity are included within the scope of this disclosure. Furthermore, the compounds described herein can exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. Solvated forms of the alpha-adrenergic agonists presented herein are also considered to be disclosed herein. In some situations, alpha-adrenergic agonists may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0039] In some embodiments, the alpha-adrenergic agonist can be a prodrug, e.g., where a hydroxyl in the parent compound is presented as an ester, carbonate, or a carboxylic acid present in the parent compound is presented as an ester. In some such embodiments, the prodrug is metabolized in vivo to the active parent compound, e.g., an ester is hydrolyzed to the corresponding hydroxyl or acid.

[0040] Cosmetic and pharmaceutical compositions In some embodiments, cosmetic and therapeutic compositions are provided herein, which comprise an agent that stimulates the Müller muscle, such as an alpha-adrenergic agonist, or its cosmetically or pharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide, or isomer, and an excipient. In some embodiments, the alpha-adrenergic agonist is formulated into a pharmaceutical or cosmetic composition. The cosmetic or pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compound into a preparation that can be used pharmaceutical or cosmetically. The appropriate formulation depends on the selected route of administration. Exemplary compositions of the present disclosure include those found in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0041] In some embodiments, provided herein is a pharmaceutical composition comprising an alpha-adrenergic agonist as described herein and at least one cosmetic or pharmaceutically acceptable excipient.In some embodiments, the at least one cosmetic or pharmaceutically acceptable excipient is selected from carriers, buffers, binders, fillers, suspending agents, disintegrants, dispersants, surfactants, lubricants, diluents, solubilizers, plasticizers, stabilizers, humectants, antifoaming agents, antioxidants, preservatives, pigments, or combinations thereof.In some embodiments, the at least one cosmetic or pharmaceutically acceptable excipient is a cosmetic excipient, such as those described herein.

[0042] In certain embodiments, a composition of the present disclosure comprises more than one alpha-adrenergic agonist, for example, two alpha-adrenergic agonists.

[0043] The compositions described herein may be administered to a subject by any suitable route of administration, including, but not limited to, parenteral (e.g., intravenous, subcutaneous, intramuscular), topical, or transdermal routes. The compositions described herein may be in the form of aqueous liquid dispersions, liquids, gels, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, powders, immediate release formulations, controlled release compositions, lyophilized formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and combined immediate and controlled release compositions.

[0044] Compositions containing the alpha-adrenergic agonists described herein can be manufactured in a conventional manner, such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or compressing processes.

[0045] As will be understood by those skilled in the art, the most appropriate method of administering an alpha-adrenergic agonist to a subject depends on many factors. In various embodiments, the alpha-adrenergic agonist is administered topically to the eye or eyelid. In some embodiments, the alpha-adrenergic agonist is administered topically to the eyelid, for example, to the outer surface of the eyelid. In some embodiments, the alpha-adrenergic agonist is formulated for cosmetic application to the eyelid and may contain additional agents, such as sunscreens, vitamins, moisturizers (e.g., hyaluronic acid), antioxidants, pigments, natural oils or butters, or essential fatty acids. In some embodiments, the alpha-adrenergic agonist is formulated as a lotion or cosmetic for topical application to the outer surface of the eyelid, for example, eye shadow or eyeliner.

[0046] In some embodiments, the alpha-adrenergic agonist is administered parenterally, such as by injection into the eyelid. The alpha-adrenergic agonist may be injected intravenously into the eyelid or surrounding area, such as by injection into the canthal vein. The alpha-adrenergic agonist may be administered subcutaneously, such as by subcutaneous injection into the eyelid. In some embodiments, the alpha-adrenergic agonist is administered intramuscularly, such as by injection into the Muller muscle within the eyelid. In some embodiments, the alpha-adrenergic agonist is administered preseptally, postseptally, or into the postseptal fat pad.

[0047] Parenteral formulations In some embodiments, the agent that stimulates the Müller muscle, for example, an alpha-adrenergic agonist, is administered parenterally, such as by injection.Parenteral administration can involve bolus injection or continuous infusion.The preparation for injection can be presented in a unit dosage form, for example, in an ampule or in a multi-dose container, with preservatives added.The pharmaceutical composition described herein can be in a form suitable for parenteral injection, for example, a sterile suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain additional agents such as suspending agents, stabilizers, and / or dispersing agents.

[0048] Preparations for parenteral administration include aqueous solutions of water-soluble alpha-adrenergic agonists.In addition, suspensions of alpha-adrenergic agonists can be prepared as appropriate oily injection suspensions.Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil; synthetic fatty acid esters, such as ethyl oleate; triglycerides; or liposomes.Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form, which can be reconstituted with a suitable vehicle, such as sterile pyrogen-free water, before use.In some embodiments, systems for pharmaceutical compounds, such as liposomes and emulsions, can be used.

[0049] Preparations suitable for intramuscular, subcutaneous or intravenous injection can include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, cremophor, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.Appropriate fluidity can be maintained, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0050] Preparations suitable for subcutaneous injection may also contain additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial growth can be ensured by various antibacterial and antifungal agents. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin.

[0051] For intravenous injection, alpha-adrenergic agonists may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.

[0052] In various embodiments, the injectable composition contains about 0.1 μg to about 4 mg of alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains about 0.1 mg to about 10 mg of alpha-adrenergic agonist per dose. In some embodiments, the composition contains about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, 2.1 mg, about 2.2 mg, about 2.3 mg, or about 3.0 mg per dose. About 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, 5.1mg, about 5.2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6.0mg, 6.1mg, about 6.2mg, about 6.3mg, About 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7.0mg, 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7 In certain embodiments, any two of the doses in this paragraph may be combined to form a dosage range encompassed within the present disclosure, e.g., an injectable composition containing from about 1.0 mg to about 9.0 mg of alpha-adrenergic agonist per dose.

[0053] In some embodiments, the injectable composition contains about 0.1 mg to about 1 mg of alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains about 0.5 mg to about 1 mg of alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains about 1 mg to about 3 mg of alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains about 3 mg to about 5 mg of alpha-adrenergic agonist per dose.

[0054] In some embodiments, the injectable composition contains 0.5 mg or less, e.g., about 0.05 mg to about 0.4 mg, of an alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains 1 mg or less, e.g., about 0.05 mg to about 0.9 mg, of an alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains 2 mg or less, e.g., about 0.05 mg to about 1.9 mg, of an alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains 4 mg or less, e.g., about 0.05 mg to about 3.9 mg, of an alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains at least 0.5 mg of an alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains at least 1 mg of an alpha-adrenergic agonist per dose. In some embodiments, the injectable composition contains at least 2 mg of an alpha-adrenergic agonist per dose. In some embodiments, the injectable composition comprises at least 4 mg of an alpha-adrenergic agonist per dose.

[0055] In some embodiments, the injectable composition comprises about 0.5 μg to about 1 mg of alpha-adrenergic agonist per dose, e.g., about 0.5 μg to about 10 μg, about 0.5 μg to about 0.1 mg, about 0.5 μg to about 0.5 mg, about 10 μg to about 0.1 mg, about 10 μg to about 0.5 mg, about 0.1 mg to about 0.5 mg, or about 0.1 mg to about 1 mg.

[0056] In various embodiments, the dose of injectable composition is injected daily, weekly, or monthly as needed.In some embodiments, the dose of injectable composition is injected once a day, twice a day, or three times a day as needed.In some embodiments, the dose of injectable composition is injected every other day.In some embodiments, the dose of injectable composition is injected every 3 days, every 4 days, or every 5 days.

[0057] Topical / transdermal formulations In some embodiments, the alpha-adrenergic agonist is formulated into a composition for topical administration. In some embodiments, the topical formulation is administered to the external surface of the eyelid. In some embodiments, the alpha-adrenergic agonist is formulated into a composition for transdermal administration. In some embodiments, the transdermal formulation is administered to the external surface of the eyelid.

[0058] Topical preparations In some embodiments, the alpha-adrenergic agonist is administered topically to a subject. In some embodiments, the topical composition of the present disclosure is a dermatological composition and is applied to the surface of the skin, for example, the outer surface of the eyelid, such as the upper eyelid. In some embodiments, the topical formulation comprises an alpha-adrenergic agonist and one or more excipients. In some embodiments, the topical formulation comprises a dermatologically acceptable carrier, such as a dermatologically acceptable carrier commonly used in the cosmetic, pharmaceutical, or dermatological fields. In some embodiments, the composition of the present disclosure further comprises at least one excipient. As used herein, the term "dermatologically acceptable carrier" refers to vehicles, diluents, and carriers known in the art to be suitable for use in dermatological compositions. Dermatologically acceptable carriers may further comprise auxiliary agents, additives, and excipients that enhance the structure and function of the carrier, such as, but not limited to, buffers, preservatives, gelling agents, rheology adjusters and stabilizers, moisturizers, and humectants. Suitable ingredients are those known in the art to be suitable for use in contact with human skin without undue toxicity, irritation, or allergic reaction. Suitable materials may be selected from the "Inventory of ingredients employed in cosmetic products" provided in European Commission Decision 2006 / 257 / EC of February 9, 2006.

[0059] Dermatologically acceptable carriers can be in the form of aqueous, aqueous / alcoholic or oily solutions; powders; lotion or serum-type dispersions; anhydrous or lipophilic gels; emulsions of liquid or semi-liquid consistency obtained by dispersing a fatty phase in an aqueous phase (O / W) or vice versa (W / O); or cream or gel-type smooth, semi-solid or solid consistency suspensions or emulsions. Dermatologically acceptable carriers can take the physical form of liquids, lotions, creams, butters, gels, ointments or powders. In some embodiments, dermatologically acceptable carriers are selected from carriers that are acceptable for administration to the outer surface of the eyelid.

[0060] Aqueous emulsions in the form of lotions or creams allow for application of an effective amount of the composition to the area of ​​skin in need of treatment, do not dry out quickly, and can maintain contact between the skin and the alpha-adrenergic agonist for an extended period of time. Lotions and creams also improve the penetration rate of the alpha-adrenergic agonist into the epidermis by moisturizing and softening the stratum corneum. In some embodiments, lotion and cream compositions according to the present invention comprise water and an effective amount of an emulsifier.

[0061] In some embodiments, the composition comprises dermatologically acceptable oil.Suitable oils are well known in the field of cosmetics, and include but are not limited to grape seed oil, olive oil, sweet almond oil, avocado oil, sesame oil, canola oil, jojoba oil, etc., and mineral oil and synthetic oil, such as dimethicone.In some embodiments, the composition comprises semi-solid triglycerides, including but not limited to shea butter, cocoa butter, illipe butter, mango butter, avocado butter, etc.In some embodiments, the composition comprises silicone.

[0062] In some embodiments, the composition includes a stiffener, such as stearic acid or 12-hydroxystearic acid. The amount of stiffener can vary depending, for example, on whether a lotion or a cream is desired. In some embodiments, the topical composition includes hyaluronic acid or a salt thereof.

[0063] In some embodiments, the composition includes one or more of an emulsifier, such as emulsifying wax NF, glyceryl stearate, cetearyl alcohol, or sodium stearoyl lactylate, to incorporate water uniformly into the ointment. In some embodiments, the composition includes a humectant, including but not limited to glycerin, a sugar alcohol, or aloe vera gel.

[0064] In some embodiments, the carrier may contain a thickening agent. An exemplary thickening agent is a cross-linked polyacrylic acid material available under the trademark Carbopol. Gums such as xanthan, carrageenan, gelatin, karaya, pectin, and locust bean gum may be used. In some circumstances, the thickening function may be achieved by silicone or a material that also serves as an emollient.

[0065] In some embodiments, the dermatologically acceptable carrier comprises a powder, which may be selected from chalk, talc, kaolin, starch, mica, smectite clay, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, aluminum starch octenyl succinate, and mixtures thereof.

[0066] The compositions of the present invention may contain additives and adjuvants commonly used in the cosmetic, pharmaceutical, or dermatological fields, such as gelling agents, preservatives, antioxidants, solvents, fragrances, fillers, disinfectants, odor absorbers, sunscreens, or pigments. The amounts of these various additives and adjuvants are those commonly used in the art, for example, in the range of about 0.01% to about 90% of the total weight of the composition. In certain embodiments, the compositions of the present disclosure contain one or more cosmetic excipients suitable for administration to the outer surface of the eyelid.

[0067] In some embodiments, the composition of the present disclosure comprises an agent that stimulates the Müller muscle and at least one cosmetic excipient. As used herein, "cosmetic excipient" refers to an excipient used to enhance one or more cosmetic properties of the compositions described herein (e.g., dermatological compositions). In some embodiments, the cosmetic property is the appearance, smell, texture, ease of application, etc. of the composition. In some embodiments, the cosmetic property is the effect of using the composition, such as improving the appearance or texture of the skin, reducing the appearance of wrinkles, protecting the skin from radiation, covering marks or blemishes on the skin, or any combination thereof.

[0068] "Eye shadow-like composition," as used herein, refers to a composition suitable for administration to the outer surface of the eyelid. The eye shadow-like composition is not intended to be limited to any particular type of composition or method of application and may include, for example, liquids, creams, powders, etc., suitable for application to the outer surface of the eyelid or any portion thereof, for example, using an applicator, finger, or brush. The eye shadow-like compositions of the present disclosure may include one or more cosmetic vehicles.

[0069] In some embodiments, the composition comprises an effective amount of one or more preservatives, including but not limited to potassium sorbate, citric acid, propylparaben, methylparaben, glycol, tocopherol, diazolidinyl urea, and imidazolidinyl urea.In some embodiments, the composition comprises any of the above-mentioned oils and triglycerides, and can further comprise hydrocarbon bases, such as solid paraffin, soft paraffin, microcrystalline wax, or ceresin wax.In some embodiments, non-hydrocarbon bases, such as wool fat or beeswax, are also used.

[0070] In some embodiments, the composition comprises a sunscreen, hi some embodiments, the sunscreen is selected from zinc oxide, titanium dioxide, octyl methoxycinnamate, octyl salicylate, avobenzone, menthyl anthranilate, cinoxate, ecamsule, octyl salicylate, octyl methoxycinnamate, sulisobenzone, oxybenzone, and combinations thereof.

[0071] In certain embodiments, the compositions of the present disclosure include one or more of the following: mica, PTFE, zinc stearate, silica, isoeicosane, polyisobutene, lauroyl lysine, dimethicone, boron nitride, polyethylene, phenoxyethanol, nylon-12, caprylic / capric triglyceride, sorbic acid, sodium dehydroacetate, magnesium stearate, talc, ethylhexyl palmitate, ethylene / acrylic acid copolymer, poloxamer, synthetic wax, tin oxide, kaolin, triethylhexanoin, hydrogenated lecithin, tocopheryl acetate, caprylyl glycol, hexylene glycol, calcium sodium borosilicate, ethylhexylglycerin, synthetic sapphire, calcium aluminum borosilicate, C13-16 isoparaffin, octadecene, stearyl dimethicone, titanium dioxide CI 77891, iron oxides CI 77491 CI 77492 CI 77499, Ultramarines CI 77007, Carmine CI 75470, Manganese Violet CI 77742, Yellow 5 Lake CI 19140, Ferric Ferrocyanide CI 77510, Bismuth Oxychloride CI 77163, Chromium Hydroxide Green CI 77289, Chromium Oxide Green CI 77288, Zinc Oxide, Blue 1 Lake CI 42090, Ferric Ammonium Ferrocyanide CI 77510, Bronze Powder, DC Black No. 2 CI 77266, and Red 40 Lake CI 16035.

[0072] In some embodiments, the alpha-adrenergic agonist is formulated as an eyeshadow-like composition suitable for application to the outer surface of the eyelid (e.g., the upper eyelid). In some embodiments, the eyeshadow comprises a powder. Suitable powders generally comprise dry particulate matter having a particle size of about 0.02 to about 200 microns, preferably about 0.5 to about 100 microns. In some embodiments, the particulate matter is pigmented. Suitable powders that can be used in eyeshadow-like compositions include, for example, bismuth oxychloride, mica titanium, fumed silica, spherical silica, polymethyl methacrylate, micronized Teflon, boron nitride, acrylate polymers, aluminum silicate, aluminum starch octenylsuccinate, bentonite, calcium silicate, cellulose, chalk, corn starch, diatomaceous earth, fuller's earth, glyceryl starch, hectorite, silicic acid, kaolin, magnesium aluminum silicate, magnesium carbonate, magnesium hydroxide, and magnesium oxide. Examples of suitable powders include sucrose, magnesium silicate, magnesium trisilicate, maltodextrin, montmorillonite, microcrystalline cellulose, rice starch, silica, talc, mica, titanium dioxide, zinc laurate, zinc myristate, zinc neodecanoate, zinc rosinate, zinc stearate, polyethylene, alumina, attapulgite, calcium carbonate, calcium silicate, dextran, kaolin, nylon, silica silylate, silk powder, sericite, soy flour, tin oxide, titanium hydroxide, trimagnesium phosphate, walnut kernels, and mixtures thereof. In some embodiments, the powder is surface treated with lecithin, amino acids, mineral oil, silicone oil, or various other agents, either alone or in combination, to coat the powder surface and render the particles hydrophobic.

[0073] In some embodiments, the powder of the eyeshadow-like composition described herein contains an organic or inorganic pigment. Organic pigments may be selected from aromatic compounds, including azo, indigoid, triphenylmethane, anthraquinone, and xanthine dyes, such as those called D&C and FD&C blue, brown, green, orange, red, and yellow. Organic pigments may be selected from insoluble metal salts of certified color additives, known as lakes. Inorganic pigments include iron oxide, ultramarine, and chromium or chromium hydroxide colorants, as well as mixtures thereof. The percentage of pigment used in the powder component depends on the type of cosmetic product being formulated and typically ranges from about 5 to about 50% of the total cosmetic composition. In some embodiments, the pigment:powder weight ratio ranges from about 1:20 to about 20:1 or from about 1:10 to about 1:2.

[0074] In some embodiments, the topical composition comprises about 0.1 μg to about 5 mg of an alpha-adrenergic agonist per dose. In some embodiments, the topical composition comprises about 0.5 μg to about 4 mg of an alpha-adrenergic agonist per dose. In some embodiments, the topical composition comprises about 1 μg to about 3 mg of an alpha-adrenergic agonist per dose. In some embodiments, the topical composition comprises about 3 μg to about 5 mg of an alpha-adrenergic agonist per dose.

[0075] In some embodiments, the topical composition comprises about 0.5 μg to about 1 mg of an alpha-adrenergic agonist per dose, e.g., about 0.5 μg to about 10 μg, about 0.5 μg to about 0.1 mg, about 0.5 μg to about 0.5 mg, about 10 μg to about 0.1 mg, about 10 μg to about 0.5 mg, about 0.1 mg to about 0.5 mg, or about 0.1 mg to about 1 mg per dose.

[0076] In some embodiments, the topical composition contains about 0.5 mg or less, e.g., about 0.5 μg to about 0.4 mg, of an alpha-adrenergic agonist per dose. In some embodiments, the topical composition contains about 1 mg or less, e.g., about 0.5 μg to about 0.9 mg, of an alpha-adrenergic agonist per dose. In some embodiments, the topical / transdermal composition contains about 2 mg or less, e.g., about 0.5 μg to about 1.9 mg, of an alpha-adrenergic agonist per dose. In some embodiments, the topical composition contains about 4 mg or less, e.g., about 0.5 μg to about 3.9 mg, of an alpha-adrenergic agonist per dose.

[0077] In some embodiments, the topical composition comprises at least about 0.5 μg of an alpha-adrenergic agonist per dose. In some embodiments, the topical composition comprises at least about 1 μg of an alpha-adrenergic agonist per dose. In some embodiments, the topical composition comprises at least about 2 μg of an alpha-adrenergic agonist per dose. In some embodiments, the topical composition comprises at least about 4 μg of an alpha-adrenergic agonist per dose.

[0078] In various embodiments, a dose of topical composition is applied to the outer surface of the subject's eyelid as needed.In some embodiments, a dose of topical composition is applied once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day.A dose of topical composition can be applied to the subject's eyelid 1 to 10 times a day, for example, 1 to 5 times a day.In some embodiments, a dose of topical composition is applied once every two days, once every three days, once every four days, once every five days, once every six days, or even once every seven days.

[0079] In some embodiments, the topical composition provides sustained release of the alpha-adrenergic agonist. In some embodiments, the topical composition includes a delivery system that controls the release of the alpha-adrenergic agonist to the subject. In various embodiments, the release of the alpha-adrenergic agonist is sustained for a period of 4 hours or more after application, 5 hours or more after application, 6 hours or more after application, 7 hours or more after application, 8 hours or more after application, 9 hours or more after application, 10 hours or more after application, 11 hours or more after application, 12 hours or more after application, 14 hours or more after application, 16 hours or more after application, 18 hours or more after application, 20 hours or more after application, 22 hours or more after application, or even 24 hours or more after application.

[0080] Transdermal preparations In some embodiments, alpha-adrenergic agonist is administered by transdermal formulation.In some embodiments, the transdermal formulation of the present disclosure is the topical formulation as described in the previous section, with one or more additional excipients that facilitate transport across the skin.The transdermal formulation described herein is the same as that described in U.S. Patent Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069 The compositions may be administered using a variety of devices, including but not limited to, those described in US Pat. Nos. 4,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801, and 6,946,144.

[0081] The transdermal dosage forms described herein incorporate certain pharmaceutically acceptable excipients conventional in the art. The transdermal formulations of the present disclosure may include one or more of the carriers, excipients, and additives discussed in the previous section. In one embodiment, the transdermal formulations described herein include an alpha-adrenergic agonist and a permeation enhancer. In addition, the transdermal formulations may include additional components, such as, but not limited to, aqueous adjuvants, gelling agents, cream and ointment bases, etc. In some embodiments, the transdermal formulations may further include a woven or nonwoven backing material to enhance absorption and prevent the transdermal formulation from peeling off the skin. In other embodiments, the transdermal formulations described herein may maintain a saturated or supersaturated state to promote diffusion into the skin.

[0082] The term "permeation enhancer" refers to a substance used to alter, and generally increase, the rate of penetration of an alpha-adrenergic agonist in a composition through the skin or other body tissue. Most known permeation enhancers fall into the following categories: alcohols (ethanol, pentanol, benzyl alcohol, lauryl alcohol, propylene glycol, and glycerol), fatty acids (oleic acid, linoleic acid, valeric acid, and lauric acid), amines (diethanolamine and triethanolamine), esters (isopropyl palmitate, isopropyl myristate, and ethyl acetate), amides (1-dodecylazacycloheptan-2-one [Azone®], urea, dimethylacetamide, dimethylformamide, and pyrrolidone derivatives), hydrocarbons (alkanes and squalene), surfactants (sodium laureate, cetyltrimethylammonium bromide, Brij®, Tween®, and sodium cholate), terpenes (D-limonene, carvone, and anise oil), sulfoxides (dimethyl sulfoxide), and phospholipids (lecithin). Other examples of permeation enhancers include amine oxides, unsaturated fatty acids, alpha-terpineol, and sorbitan monooleate. Amine oxides include, for example, lauramine oxide and 2-hexadecyldimethylamine oxide. Unsaturated fatty acids include, for example, oleic acid, linoleic acid, and linolenic acid. Sorbitan esters include, for example, sorbitan monooleate, sorbitan laurate, and sorbitan stearate. Isopropyl myristate and lauroglycol are also suitable for use as permeation enhancers. In some embodiments, the permeation enhancers of the compositions described herein enhance the permeation of alpha-adrenergic agonists through healthy skin, for example, skin that is not affected by diseases or conditions such as rosacea, eczema, acne, psoriasis, etc. In general, healthy skin forms a robust barrier against the penetration of pharmaceutical agents such as alpha-adrenergic agonists, while unhealthy skin is more permeable to such agents.A penetration enhancer that can enhance the penetration of an alpha-adrenergic agonist into unhealthy skin may be insufficient to affect the penetration of such an agent into healthy skin, or to the same depth. In some embodiments, the penetration enhancer of the compositions described herein may be characterized by significant penetration of the alpha-adrenergic agonist into healthy skin, for example, about 2-fold or more, about 3-fold or more, about 4-fold or more, about 5-fold or more, or about 6-fold or more compared to the penetration of such an agent without the penetration enhancer. In some embodiments, the penetration enhancer of the compositions described herein may penetrate the stratum corneum and septal fat pads, allowing contact with the Müller muscle. In some embodiments, the penetration enhancer of the compositions described herein may allow the alpha-adrenergic agonist, such as oxymetazoline or a salt thereof, to penetrate healthy skin to a depth of up to about 3 mm, for example, up to about 2.5 mm, for example, up to about 2 mm.

[0083] In some embodiments, the amount of permeation enhancer in the compositions of the present disclosure is less than the amount used in compositions for unhealthy skin. For example, the compositions of the present disclosure may have an amount of permeation enhancer that is up to about 10% less, up to about 20% less, up to about 30% less, up to about 40% less, up to about 50% less, up to about 60% less, up to about 70% less, or even up to about 80% less than the amount required to permeate the same drug to the same depth into unhealthy skin.

[0084] Examples of permeation enhancers can be found in Pathan et al. (“Chemical Penetration Enhancers for Transdermal Drug Delivery Systems” Tropical Journal of Pharmaceutical Research, April 2009; 8 (2): 173-179); Som et al. (“Status of Surfactants as Penetration Enhancers in Transdermal Drug Delivery” J Pharm Bioallied Sci. 2012; 4(1): 2-9); and Trommer at al. (“Overcoming the Stratum Corneum: The Modulation of Skin Penetration” Skin Pharmacol Physiol 2006; 19:106-121), all of which are incorporated by reference in their entireties. In some embodiments, skin permeation is measured as set forth in Franz TJ “Percutaneous absorption. On the relevance of in vitro data” J. Invest. Dermatol 1975, 64:190-195, which is incorporated by reference in its entirety. In the experimental setup for measuring skin permeation, a skin fragment (approximately 2.5 cm x 2.5 cm square) is placed on a receptor well, which is completely filled with solvent to ensure uniform contact with the underside of the skin fragment. A donor well is secured to the top of the skin fragment, and the test formulation is introduced into the donor well. Fluid samples are withdrawn from the receptor at given time intervals, and the active agent concentration can then be analyzed. The retention of the active agent in the skin, or in the separate epidermal and dermal skin compartments, is then measured.Animal models utilizing pig skin are used to measure the penetration of active agents (e.g., Barbero et al. 2009 “Pig and guinea pig skin as surrogates for human in vitro penetration studies: a quantitative review” Toxicol. In Vitro 23, 1-13; Godin et al. 2007 “Transdermal skin delivery: predictions for humans from in vivo, ex vivo and animal models” Adv. Drug Deliv. Rev. 59, 1152-1161; Mahl et al. 2006 “The minipig in dermatotoxicology: methods and challenges” Exp. Toxicol. Pathol. 57, 341-345; Yu et al. 2013 “Topical skin targeting effect of penetration modifiers on hairless mouse skin, pig abdominal skin and pig ear skin” Drug Delivery Vol. 22, Iss. 8, 2015; and Simon et al. “The pig as an experimental animal model” of per-cutaneous permeation in man: qualitative and quantitative observations - an overview” Skin Pharmacol. Appl. Skin Physiol. 200, 13, 229-234; all of which are incorporated by reference in their entireties.

[0085] The permeation enhancer should be present in an amount sufficient to allow penetration of a sufficient amount of the alpha-adrenergic agonist across the skin to produce the desired therapeutic effect. The amount of permeation enhancer is typically less than about 40% by weight of the total composition, or less than about 39%, less than about 38%, less than about 37%, less than about 36%, less than about 35%, less than about 34%, less than about 33%, less than about 32%, less than about 31%, less than about 30%, less than about 29%, less than about 28%, less than about 27%, less than about 26%, less than about 25%, less than about 24%, less than about 23%, less than about 22%, less than about 21%, less than about 20%, less than about 19%, less than about 18%, less than about 17%, less than about 16%, less than about 15%, less than about 14%, less than about 13%, less than about 12%, less than about 11%, or less than about 10% by weight of the total composition.

[0086] In some embodiments, formulations suitable for transdermal administration of alpha-adrenergic agonists use transdermal delivery devices and transdermal delivery patches. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents. The absorption rate can be slowed by using a rate-controlling membrane or by trapping the compound in a polymer matrix or gel. For example, a transdermal device is in the form of a bandage, comprising a backing member, a reservoir containing the compound, optionally with a carrier, and optionally a rate-controlling barrier for delivering the compound to the host's skin at a controlled, predetermined rate over a long period of time, and a means for fixing the device to the skin.

[0087] In some embodiments, the transdermal compositions containing alpha-adrenergic agonists are incorporated into various makeup products, such as makeup foundations, liquid and compact foundations, makeup removal lotions, makeup removal milks, eye shadows, and powders.

[0088] In some embodiments, the transdermal composition comprises about 0.1 μg to about 1 mg of an alpha-adrenergic agonist per dose. In some embodiments, the transdermal composition comprises about 0.5 μg to about 1 mg of an alpha-adrenergic agonist per dose. In some embodiments, the transdermal composition comprises about 1 μg to about 3 mg of an alpha-adrenergic agonist per dose. In some embodiments, the transdermal composition comprises about 3 μg to about 5 mg of an alpha-adrenergic agonist per dose.

[0089] In some embodiments, the transdermal composition comprises from about 0.5 μg to about 1 mg of an alpha-adrenergic agonist per dose, e.g., from about 0.5 μg to about 10 μg, from about 0.5 μg to about 0.1 mg, from about 0.5 μg to about 0.5 mg, from about 10 μg to about 0.1 mg, from about 10 μg to about 0.5 mg, from about 0.1 mg to about 0.5 mg, or from about 0.1 mg to about 1 mg.

[0090] In some embodiments, the transdermal composition contains about 0.5 mg or less of an alpha-adrenergic agonist per dose, e.g., about 0.5 μg to about 0.4 mg. In some embodiments, the transdermal composition contains about 1 mg or less of an alpha-adrenergic agonist per dose, e.g., about 0.5 μg to about 0.9 mg. In some embodiments, the topical / transdermal composition contains about 2 mg or less of an alpha-adrenergic agonist per dose, e.g., about 0.5 μg to about 1.9 mg. In some embodiments, the transdermal composition contains about 4 mg or less of an alpha-adrenergic agonist per dose, e.g., about 0.5 μg to about 3.9 mg.

[0091] In some embodiments, the transdermal composition comprises at least about 0.5 μg of an alpha-adrenergic agonist per dose. In some embodiments, the transdermal composition comprises at least about 1 μg of an alpha-adrenergic agonist per dose. In some embodiments, the transdermal composition comprises at least about 2 μg of an alpha-adrenergic agonist per dose. In some embodiments, the topical / transdermal composition comprises at least about 4 μg of an alpha-adrenergic agonist per dose.

[0092] In various embodiments, the transdermal composition dose is applied to the outer surface of the subject's eyelid as needed. In some embodiments, the transdermal composition dose is applied once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day. The topical / transdermal composition dose may be applied to the subject's eyelid 1 to 10 times a day, for example, 1 to 5 times a day. In some embodiments, the transdermal composition dose is applied once every two days, once every three days, once every four days, once every five days, once every six days, or even once every seven days.

[0093] In some embodiments, the transdermal composition provides sustained release of the alpha-adrenergic agonist. In some embodiments, the transdermal composition includes a delivery system that controls the release of the alpha-adrenergic agonist to the subject. In various embodiments, the release of the alpha-adrenergic agonist is sustained for a period of 4 hours or more after application, 5 hours or more after application, 6 hours or more after application, 7 hours or more after application, 8 hours or more after application, 9 hours or more after application, 10 hours or more after application, 11 hours or more after application, 12 hours or more after application, 14 hours or more after application, 16 hours or more after application, 18 hours or more after application, 20 hours or more after application, 22 hours or more after application, or even 24 hours or more after application.

[0094] Controlled Release Composition In some embodiments, the alpha-adrenergic agonist is administered to a subject as a controlled-release composition. In some embodiments, the controlled-release composition comprises an alpha-adrenergic agonist and a delivery system that controls the release of the alpha-adrenergic agonist. In some embodiments, the controlled-release composition comprises a delivery system and any of the alpha-adrenergic agonist compositions described herein. In some embodiments, the controlled-release composition comprises a topical or transdermal formulation described in the previous section. Examples of delivery systems include, for example, polymer-based systems, such as implants or inserts; porous matrices; hydrogel release systems; transdermal patches; peptide-based systems; and contact lenses.

[0095] In some embodiments, the delivery system is a polymer-based implant. A polymer-based implant, such as a biodegradable implant, can be implanted into the eyelid or surrounding area, where the polymer-based implant provides a controlled release of the alpha-adrenergic agonist over a period of time. In some embodiments, the polymer-based implant is surgically implanted. In some embodiments, the implant is injected without the need for surgery. The polymer-based implant can be implanted subcutaneously or intramuscularly. In some embodiments, the polymer-based implant can be implanted in close proximity to the Müller muscle, such as within about 1 mm, about 2 mm, about 3 mm, about 4 mm, or about 5 mm of the Müller muscle.

[0096] In some embodiments, the delivery system of the controlled release composition comprises PLGA microparticles. PLGA is a biocompatible biodegradable polymer that can be used to encapsulate compounds for sustained release administration. In some embodiments, the lactic acid-glycolic acid copolymer is a PLGA-PEG-PLGA triblock copolymer. Methods for preparing PLGA microparticles and encapsulating compounds in microparticles are well known in the art (e.g., MH Lee et al., Biomaterials Research (2009) 13(1):11-15).

[0097] Generally, water-soluble forms of alpha-adrenergic agonists elute faster from a delivery system than less water-soluble forms of the same drug. In some embodiments, the present disclosure provides a composition that allows for the rate of in vivo local delivery of an alpha-adrenergic agonist from a delivery system to be adjusted. In particular, the local delivery rate can be adjusted by controlling the relative proportion of a slower-eluting form of the alpha-adrenergic agonist to a faster-eluting form of the alpha-adrenergic agonist. Controlling the water solubility of the delivered agent can be achieved in a number of ways, such as by using salt or non-salt forms of the alpha-adrenergic agonist. To control the release kinetics of an alpha-adrenergic agonist from a delivery system, two or more forms of the alpha-adrenergic agonist with different solubilities can be combined in a ratio selected to achieve a desired kinetic profile.

[0098] To increase the water solubility of an alpha-adrenergic agonist, the drug may be converted from a neutral or non-salt form to a salt form. A salt form of an alpha-adrenergic agonist is likely to be more water soluble than a non-salt or neutral form of the same alpha-adrenergic agonist. In general, a soluble salt form of an alpha-adrenergic agonist will elute from the delivery system of the present disclosure at a faster rate than a neutral form of the alpha-adrenergic agonist. By controlling the relative proportions of the salt and non-salt forms of the alpha-adrenergic agonist in the delivery system of the present disclosure, the rate and duration of drug delivery from the delivery system can be controlled.

[0099] In addition to controlling release through the combination of salt and non-salt forms of alpha-adrenergic agonists, the solubility of the alpha-adrenergic agonist can also be adjusted by the choice of counterion for the salt form of the alpha-adrenergic agonist. Counterions with greater hydrophilicity generally increase the dissolution rate, while more hydrophobic counterions decrease the dissolution rate. For example, alkali metal counterions are likely to provide greater water solubility and faster dissolution rates than quaternary ammonium counterions.

[0100] In certain embodiments, the delivery systems of the present disclosure, such as polymer-based implants, have properties that help slow the elution of the non-salt form of the alpha-adrenergic agonist from the delivery system. Generally, the non-salt form of the alpha-adrenergic agonist has a stronger intermolecular attraction to the polymeric material of the delivery system, thereby slowing the elution rate of the non-salt form of the alpha-adrenergic agonist from the delivery system.

[0101] In some embodiments, the controlled-release composition of the present disclosure comprises a delivery system, a first alpha-adrenergic agonist in free base or acid form, and a second alpha-adrenergic agonist in salt form. In some embodiments, the first alpha-adrenergic agonist is an alpha-adrenergic agonist. In some embodiments, the second alpha-adrenergic agonist is an alpha-adrenergic agonist. In some embodiments, the first alpha-adrenergic agonist is a non-salt form, such as a free base or acid, of the second alpha-adrenergic agonist. For example, the first alpha-adrenergic agonist is oxymetazoline, and the second alpha-adrenergic agonist is a salt of oxymetazoline. Alternatively, the second alpha-adrenergic agonist can be a salt of an alpha-adrenergic agonist different from the first alpha-adrenergic agonist. For example, the first alpha-adrenergic agonist can be oxymetazoline and the second alpha-adrenergic agonist can be a salt of phenylephrine.

[0102] In some embodiments, the composition comprises a first alpha-adrenergic agonist in non-salt form and a second alpha-adrenergic agonist in salt form in a weight ratio of about 95:5 to about 30:70, e.g., about 95:5 to about 50:50, e.g., about 95:5 to about 60:40.

[0103] Other methods for controlling the elution rate of an alpha-adrenergic agonist from a delivery system include, for example, using a biodegradable delivery system that releases the alpha-adrenergic agonist as it degrades in vivo, using an inclusion complex in the composition, using a solubilizing agent in the composition, and selecting a crystalline or amorphous form of the alpha-adrenergic agonist for the composition.

[0104] A. Polymer-based implants In some embodiments, the polymer-based implant is a solid polymeric implant. In some embodiments, the polymer-based implant is a liquid or semi-solid that solidifies in situ, e.g., upon injection into tissue, thereby forming an implant. The polymer-based implant can be implanted into the eyelid or surrounding area by surgical implantation or by injection.

[0105] In some embodiments, release of the alpha-adrenergic agonist is sustained for a specified amount of time after implantation of the polymer-based implant, hi various embodiments, release of the alpha-adrenergic agonist is sustained for up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, up to 7 days, up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, up to 1 month, up to 2 months, up to 3 months, up to 4 months, up to 5 months, up to 6 months, up to 7 months, up to 8 months, up to 9 months, up to 10 months, up to 11 months, up to 12 months, or up to 1 year after implantation.

[0106] In various embodiments, the implant comprises about 0.1 mg to about 10 mg of an alpha-adrenergic agonist. In some embodiments, the implant comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6.0 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, about 6.5 mg, about 6.6 mg, about 6.7 mg, about 6.8 mg, about 6.9 0.4mg, about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3.0mg, 3.1mg, about 3.2mg, about 3.3mg, about 3.4mg, about 3.5mg, about 3.6mg, about 3.7mg, about 3.8mg, about 3.9mg, about 4.0mg, 4.1mg, about 4.2mg, about 4.3mg, about 4.4mg, about 4.5mg, about 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5.0 mg, 5.1mg, about 5.2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6.0mg, 6.1mg, about 6.2mg, about 6.3mg , about 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7.0mg, 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg, about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10 mg of alpha-adrenergic agonist. In some embodiments, any two of the doses in this paragraph may be combined to form a dosage range encompassed within the present disclosure, e.g., the implant contains from about 1.0 mg to about 8.0 mg of alpha-adrenergic agonist.

[0107] In some embodiments, the implant comprises about 0.1 mg to about 10 mg of an alpha-adrenergic agonist. In some embodiments, the implant comprises about 0.5 mg to about 8 mg of an alpha-adrenergic agonist. In some embodiments, the implant comprises about 2 mg to about 5 mg of an alpha-adrenergic agonist. In some embodiments, the implant comprises about 3 mg to about 5 mg of an alpha-adrenergic agonist.

[0108] In some embodiments, the implant contains about 10 mg or less of an alpha-adrenergic agonist. In some embodiments, the implant contains about 8 mg or less of an alpha-adrenergic agonist. In some embodiments, the implant contains about 6 mg or less of an alpha-adrenergic agonist. In some embodiments, the implant contains about 4 mg or less of an alpha-adrenergic agonist.

[0109] In some embodiments, the implant comprises at least about 1 mg of an alpha-adrenergic agonist. In some embodiments, the implant comprises at least about 2 mg of an alpha-adrenergic agonist. In some embodiments, the implant comprises at least about 3 mg of an alpha-adrenergic agonist. In some embodiments, the implant comprises at least about 4 mg of an alpha-adrenergic agonist.

[0110] 1. Solid polymeric implants In some embodiments, a solid polymer-based implant is used to administer an alpha-adrenergic agonist. In some embodiments, the solid polymer-based implant is surgically implanted into the eyelid, such as in close proximity to the Muller muscle. In some embodiments, the polymer-based implant comprises an alpha-adrenergic agonist.

[0111] In various embodiments, the polymer of the polymer-based implant is selected from any polymer suitable for implantation into animals. In some embodiments, the polymer-based implant comprises a biodegradable polymer. "Biodegradable" is used to refer to any substance or object that can be decomposed by bacteria or another organism. In some embodiments, the polymer is a biocompatible polymer. The terms "biocompatible polymer" and "biocompatibility" when used in reference to a polymer are recognized in the art. For example, biocompatible polymers include polymers that are not themselves toxic to the host (e.g., cells, animals, or humans) and do not decompose at a rate that produces toxic concentrations of monomeric or oligomeric subunits or other by-products in the host (when the polymer decomposes).

[0112] In some embodiments, the toxicological behavior of biodegradable polymers intended for intracellular or in vivo use, such as implantation or injection into a patient, can be determined after one or more toxicity analyses. To be considered biocompatible, the composition does not need to have 100% purity. Thus, the composition can contain 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or even less biocompatible polymers, for example, the polymers described herein and other materials and excipients, and still be biocompatible. Exemplary polymers that may be used in polymer-based implants include poly(caprolactone) (PCL), ethylene vinyl acetate polymer (EVA), poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(L-lactic-co-glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA), poly(L-lactide) (PLLA), poly(D,L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone-co-glycolide), poly(D,L-lactide-co-PEO-co-D,L-lactide), poly(D,L-lactide-co-PPO-co-D,L-lactide), polyalkyl cyanoacrylates (polyalkyl cyanoacrylates), polyalkyl ... cyanoacralate), polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA), polyethylene glycol, poly-L-glutamic acid, poly(hydroxy acid), polyanhydride, polyorthoester, poly(ester amide), polyamide, poly(ester ether), polycarbonate, silicone, polyalkylene, e.g., polyethylene, polypropylene, and polytetrafluoroethylene, polyalkylene glycol, e.g., poly(ethylene glycol) (PEG), polyalkylene oxide (PEO), polyalkylene terephthalate, e.g., poly(ethylene terephthalate), polyvinyl alcohol (PVA), polyvinyl ether, polyvinyl ester, e.g., poly(vinyl acetate), polyvinyl halides, e.g., poly(vinyl chloride) (PVC), polyvinylpyrrolidone, polysiloxane, polystyrene (PS), polyurethane,Derivatized celluloses, such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitrocellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polymers of acrylic acid, such as poly(methyl(meth)acrylate) (PMMA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), ), poly(octadecyl acrylate) (collectively referred to herein as "polyacrylic acid") and copolymers and blends thereof, polydioxanone and copolymers thereof, polyhydroxyalkanoates, poly(propylene fumarate), polyoxymethylene, poloxamer, poly(ortho)esters, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), trimethylene carbonate, polyvinylpyrrolidone, polyalkyl cyanoacrylates, polyethyleneimine, dioleyltrimethiammoniumpropane / dioleyl-sn-glycerolphosphoethanolamine, polysebacic anhydride, polyurethanes, nylons, or copolymers thereof, and Shieh et al., 1994, J. Biomed. Mater. Res., 28, 1465-1475, and U.S. Patent No. 4,757,128, Hubbell et al., U.S. Patent Nos. 5,654,381; 5,627,233; 5,628,863; 5,567,440; and 5,567,435. Other suitable polymers include polyorthoesters (e.g., as disclosed in Heller et al., 2000, Eur. J. Pharm. Biopharn., 50:121-128), polyphosphazenes (e.g., as disclosed in Vandorpe et al., 1997, Biomaterials, 18:1147-1152), and polyphosphoesters (e.g.,Encyclopedia of Controlled Drug Delivery, pp. 45-60, Ed. E. Mathiowitz, John Wiley & Sons, Inc. New York, 1999), as well as blends and / or block copolymers of two or more such polymers. The carboxyl termini of lactide- and glycolide-containing polymers can be optionally capped, for example, by esterification, and the hydroxyl termini can be optionally capped, for example, by etherification or esterification. In some embodiments, the polymer comprises or consists essentially of polyvinyl chloride (PVC), polymethyl methacrylate (PMMA), and decyl methacrylate, or copolymers or any combination thereof. In polymers containing lactic acid monomers, the lactic acid can be the D-isomer, the L-isomer, or any mixture of the D- and L-isomers.

[0113] The polymer of the polymer-based implant may contain a plasticizer, such as dioctyl sebacate (DOS), o-nitrophenyl-octyl ether, dimethyl phthalate, dioctyl phenylphosphonate, dibutyl phthalate, hexamethylphosphoramide, dibutyl adipate, dioctyl phthalate, diundecyl phthalate, dioctyl adipate, dioctyl sebacate, or other suitable plasticizer. In some embodiments, the plasticizer is poly(glycerol sebacate) (PGS). In some embodiments, the plasticizer includes those disclosed in U.S. Patent Nos. 2,784,127 and 4,444,933.

[0114] 2. Injectable polymeric implants The injectable polymeric implant of the present disclosure refers to a liquid polymeric delivery system that can be injected into the eyelid, forming a solid or semi-solid implant that releases an alpha-adrenergic agonist in a controlled manner.In some embodiments, the solid or semi-solid implant formed from the liquid polymeric delivery system is biodegradable.In some embodiments, the liquid polymeric system is selected from thermoplastic polymers dissolved in biocompatible solvents and thermosetting polymers that are liquid without the use of solvents.Thermosetting and thermoplastic formulations incorporate the advantages of implants while avoiding the need for surgery for implantation.

[0115] Thermoplastic systems In some embodiments, the liquid polymeric delivery system is a thermoplastic system. A solid linear polymer can be dissolved in a biocompatible solvent to obtain a liquid thermoplastic system, which can then be combined with an alpha-adrenergic agonist and administered via syringe. In some embodiments, the thermoplastic system is prepared from a formulation containing one or more polymers. In some embodiments, the polymer comprises a biodegradable polymer. Examples of biodegradable polymers that can be used in the present application include polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers, or combinations or mixtures of the above materials. In some embodiments, the polymer has lower crystallinity and is more hydrophobic. These polymers and copolymers may be more soluble in biocompatible solvents than highly crystalline polymers such as polyglycolide and chitin, which also have a high degree of hydrogen bonding. In some embodiments, the polymer is polylactide, polycaprolactone, and copolymers thereof with glycolide, which have more amorphous regions to enhance solubility.

[0116] In some embodiments, the solvent for the polymer is non-toxic, water-miscible, and otherwise biocompatible. The solvent must also be biocompatible so that it does not cause severe tissue irritation or necrosis at the implantation site. Furthermore, the solvent should be water-miscible so that it rapidly diffuses into body fluids, allowing water to penetrate into the polymer solution and cause it to coagulate or solidify. Examples of such solvents include, but are not limited to, N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, oleic acid, and 1-dodecylazacycloheptan-2-one. In some embodiments, the solvent is N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, or acetone due to their solvating ability and compatibility.

[0117] The solubility of polymers in various solvents varies depending on their crystallinity, hydrophilicity, hydrogen bonding, and molecular weight. Therefore, not all polymers are soluble in the same solvent, but each polymer or copolymer should have its optimal solvent. Lower molecular weight polymers can dissolve in a solvent more easily than higher molecular weight polymers. As a result, the concentration of polymers dissolved in various solvents varies depending on the type of polymer and its molecular weight. Conversely, higher molecular weight polymers may tend to solidify or solidify more quickly than very low molecular weight polymers. Furthermore, higher molecular weight polymers tend to give higher solution viscosity than low molecular weight materials. Therefore, for optimal injection efficiency, the molecular weight and concentration of the polymer in the solvent should be controlled.

[0118] For example, low molecular weight polylactic acid, formed by the condensation of lactic acid, dissolves in N-methyl-2-pyrrolidone (NMP) to give a 73 wt % solution that still flows easily through a 23-gauge syringe needle, while higher molecular weight poly(DL-lactide) (DL-PLA), formed by the addition polymerization of DL-lactide, gives the same solution viscosity when dissolved in NMP at only 50 wt %. Higher molecular weight polymer solutions solidify immediately when placed in water. Low molecular weight polymer solutions, although more concentrated, tend to solidify very slowly when placed in water.

[0119] For polymers that tend to solidify slowly, solvent mixtures can be used to increase the solidification rate. For example, one liquid component of the mixture can be a good solvent for the polymer, while the other component is a poor solvent or non-solvent. The two liquids can be mixed in a ratio such that the polymer remains soluble but precipitates with only a small increase in the amount of non-solvent, such as water, in a physiological environment. Necessarily, the solvent system must be miscible with both the polymer and water. An example of such a binary solvent system is the use of NMP and ethanol for low molecular weight DL-PLA. The addition of ethanol to the NMP / polymer solution significantly increases its solidification rate.

[0120] It has also been found that solutions containing very high concentrations of high molecular weight polymers can coagulate or solidify more slowly than more dilute solutions. It is believed that the high concentration of polymer hinders the diffusion of solvent from within the polymer matrix, thereby preventing the penetration of water into the matrix, where it can precipitate the polymer chains.

[0121] In some embodiments, the polymer comprises a block copolymer. In some embodiments, the block copolymer comprises a hydrophilic poly(ethylene oxide) block and a hydrophobic poly(propylene oxide) block. In some embodiments, the block copolymer is a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock (commercially available under the tradenames Pluronic™ or Poloxamer™). In some embodiments, the triblock copolymer is dissolved in an aqueous solution. In some embodiments, the triblock copolymer absorbs water to form a gel. In some embodiments, the block copolymer is a surface-active block copolymer that exhibits inverse thermogelation behavior and has drug release characteristics.

[0122] Pluronic™, Poloxamer™-type triblock copolymers solidify or gel as the solution temperature is raised above a critical temperature (gelation temperature). These polymers form micelles (microscopic spheres containing trapped water) at low concentrations and transform into thick, continuous gels at high concentrations and temperatures (approximately 30°C).

[0123] In some embodiments, the polymer comprises a lactic acid-glycolic acid copolymer. In some embodiments, the lactic acid-glycolic acid copolymer is a PLGA-PEG-PLGA triblock copolymer. Suitable PLGA-PEG-PLGA triblock copolymers are commercially available from PolySciTech (a division of Akina, Inc.) located in West Lafayette, Ind. Thermosensitive PLGA-PEG-PLGA triblock copolymers have been well described in the art. These polymers can have a molecular weight of about 2000 Da to about 40,000 Da, but can have any molecular weight as long as they have the requisite inverse thermosensitive properties. In some embodiments, the PLGA-PEG-PLGA triblock polymer can have a molecular weight of about 30,000 Da. In some other embodiments, the PLGA-PEG-PLGA triblock polymer can have a molecular weight of about 4000 Da. In some other embodiments, the PLGA-PEG-PLGA triblock copolymer may have a molecular weight distribution of 1500:1000:1500, although as one skilled in the art will recognize, other molecular weight distributions may be possible and are within the scope of the present disclosure. The ratio of lactic acid to glycolic acid in the PLGA segment of the polymer may not be important as long as the polymer has the required thermosensitive properties. In some embodiments, the PLGA segment of the copolymer has a lactic acid to glycolic acid ratio of about 1:1, and in some other embodiments, the PLGA segment of the copolymer has a lactic acid to glycolic acid ratio of about 3:1.

[0124] In some embodiments, the alpha-adrenergic agonist described herein is added to a polymer solution prior to injection, and the polymer / solvent / drug mixture is then injected into the eyelid. In some embodiments, the formulation is injected intradermally, subcutaneously, preseptally, postseptally, into the postseptal fat pad, or intramuscularly. In some cases, the alpha-adrenergic agonist is soluble in the solvent, and a homogeneous solution of the polymer and alpha-adrenergic agonist can be used for injection. In other cases, the alpha-adrenergic agonist is not soluble in the solvent, resulting in a suspension or dispersion of the drug. In some embodiments, the suspension or dispersion is injected into the eyelid. In some embodiments, upon injection, the solvent dissipates and the polymer solidifies, encapsulating or encasing the alpha-adrenergic agonist within a solid or semi-solid matrix. Drug release from these solid or semi-solid in-situ forming implants can follow the same general rules as drug release from monolithic polymeric devices. Drug release can be affected by the size and shape of the implant, the loading of the drug within the implant, permeability factors including the drug and the particular polymer, and the degradability of the polymer.

[0125] The amount of alpha-adrenergic agonist incorporated into the injectable in situ solid-forming implant depends on the desired release profile, the concentration of drug required for biological effect, and the length of time the drug must be released for treatment. The lower limit of the alpha-adrenergic agonist incorporated into the delivery system depends on the activity of the alpha-adrenergic agonist and the length of time required for treatment.

[0126] B. Thermosetting Systems In some embodiments, the liquid polymeric delivery system is a thermosetting system. In some embodiments, the thermosetting system comprises one or more biocompatible polymers. In some embodiments, the thermosetting system comprises a crosslinkable polymer that can be formed and cured in situ with the use of a curing agent. The polymer can be formed by first forming a polyol-terminated prepolymer using a polyol initiator and a catalyst, and then converting this to an acrylate-terminated prepolymer. Just prior to injection, a curing agent such as benzoyl peroxide or azobisisobutyronitrile is added to the acrylic prepolymer solution. Upon injection, the crosslinking reaction proceeds until sufficient molecular weight is achieved, solidifying the polymer. In some embodiments, the curing reaction is rapid, and injection must occur almost immediately after the addition of the curing agent. These polymers can be formed primarily by the polymerization or copolymerization of biodegradable hydrophobic polylactides, polyglycolides, polycaprolactones, and the like. In some embodiments, the biodegradable system comprises a bifunctional polyester synthesized from a bifunctional chain initiator such as ethylene glycol. In some embodiments, the biodegradable system comprises a trifunctional polyester synthesized from a trifunctional initiator such as trimethylolpropane. The amount of chain initiator can determine the resulting molecular weight of the polymer or copolymer. In some embodiments, the gel matrix, once formed, releases the drug in a controlled manner and degrades into products that are easily metabolized and excreted.

[0127] In some embodiments, solid implants formed in an injectable polymer solution gradually biodegrade in the body, allowing natural tissue to grow in and replace the implant as it dissolves. In some embodiments, solid implants formed from injectable systems release the alpha-adrenergic agonist contained within their matrix at a controlled rate until the drug is depleted. In some embodiments, the polymer degrades after the drug is completely released. In some other embodiments, the drug is completely released only after the polymer degrades, exposing the non-diffusible drug to bodily fluids.

[0128] In various embodiments, the choice of polymer determines the release rate of the alpha-adrenergic agonist.

[0129] Microneedles In some embodiments, the alpha-adrenergic agonist is packaged in or on a microneedle. Microneedles are typically micrometer- to millimeter-sized structures designed to penetrate the skin and deliver the composition to the epidermis or dermis of a subject. In some embodiments, the skin penetrated by the microneedle is the eyelid or around the eyelid. Microneedles offer several advantages over traditional subcutaneous or intramuscular injections. First, a smaller amount of alpha-adrenergic agonist may be required for administration, reducing production costs and time. Second, microneedles can be self-administered. Third, the alpha-adrenergic agonist can be dried onto the microneedle, which greatly increases the stability of the composition at room temperature. Furthermore, microneedle administration is typically painless, which may make it a more acceptable form of administration.

[0130] Microneedles are typically solid or hollow structures. When used as solid supports, the alpha-adrenergic agonist for delivery can be coated on the microneedles (typically in a dry form) or can be released through the hollow structure (e.g., a liquid composition is injected or injected into the skin). The composition can be on the microneedles (e.g., coated onto the surface of the microneedles after formation) or in the microneedles (e.g., formed as part of the microneedles themselves, such as by deposition inside the microneedles or by being included in the mixture used to form the microneedles). In some embodiments, the alpha-adrenergic agonist is dissolved in the skin compartment or injected into the skin. Microneedles are often formed in an array containing multiple needle-like structures, such as on a patch. In some embodiments, the microneedle array is then directly applied to the skin for intradermal administration of the composition.

[0131] In some embodiments, the microneedle array patch can be designed to be any shape or size. For example, a microneedle array patch for cosmetic delivery of alpha-adrenergic agonists can be shaped to mimic facial features, such as eyelids. In some embodiments, the microneedle array patch can be any size, but preferably the smallest size capable of delivering a selected amount of alpha-adrenergic agonist.

[0132] The size and shape of the microneedles can also vary as desired. In some embodiments, the microneedles include a cylindrical portion on which a conical portion having a tip is disposed. In other embodiments, the microneedles have an overall pyramidal or overall conical shape. In general, microneedles typically include a base and a tip. In some embodiments, the tip has a radius of about 1 micrometer or less. Microneedles are typically of sufficient length to penetrate the stratum corneum and into the epidermis or dermis. In some embodiments, the microneedles have a length (from their tip to base) of about 0.1 micrometers to about 5 millimeters, e.g., about 5 millimeters or less, 4 millimeters or less, about 1 millimeter to about 4 millimeters, about 500 micrometers to about 1 millimeter, about 10 micrometers to about 500 micrometers, about 30 micrometers to about 200 micrometers, or about 250 micrometers to about 1500 micrometers.

[0133] In some embodiments, the size of individual microneedles is optimized depending on the desired target depth, the strength requirements of the injection needle to avoid breakage in a particular tissue type, etc. In some embodiments, the cross-sectional dimensions of the transdermal microneedle are about 10 nm to about 1 mm, or about 1 micrometer to about 200 micrometers, or about 10 micrometers to about 100 micrometers. The outer diameter can be about 10 micrometers to about 100 micrometers, and the inner diameter of the hollow injection needle can be about 3 micrometers to about 80 micrometers.

[0134] In some embodiments, the microneedles are arranged on the substrate in various patterns, such as designed for a particular application. In some embodiments, the microneedles are uniformly spaced, such as in a rectangular or square grid or concentric circles. The spacing can depend on a number of factors, including the height and width of the microneedles, the properties of the film applied to the surface of the microneedles, and the amount and type of material intended to be transferred through the microneedles. Exemplary microneedle arrangements have a "tip-to-tip" spacing of about 50 micrometers or more, in some embodiments, about 100 to about 800 micrometers, and in some embodiments, about 200 to about 600 micrometers.

[0135] In some embodiments, the microneedle composition is made of any suitable material. Exemplary materials include metals, ceramics, semiconductors, organics, polymers, and composites. In some embodiments, construction materials include pharmaceutical-grade stainless steel, gold, titanium, nickel, iron, gold, tin, chromium, copper, alloys of these or other metals, silicon, silicon dioxide, and polymers. Representative biodegradable polymers include polymers of hydroxy acids such as lactic acid and glycolic acid, polylactide, polyglycolide, polylactide-co-glycolide, and copolymers with PEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone). Representative non-biodegradable polymers include polycarbonate, polymethacrylic acid, ethylene vinyl acetate, polytetrafluoroethylene, and polyester. In some embodiments, the microneedles are dissolvable, biodissolvable, or biodegradable, or a combination thereof. Various dissolvable and / or biodissolvable microneedles can be used (see, for example, US20140200509 and WO2009021048, which are incorporated herein by reference in their entireties). Briefly, dissolvable microneedles can be made of water-soluble materials. These materials can include, for example, chitosan, collagen, gelatin, maltose, dextrose, galactose, alginate, agarose, cellulose (e.g., carboxymethylcellulose or hydroxypropylcellulose), starch, and hyaluronic acid. Generally, the material selected is sufficiently elastic to allow penetration of the skin. Preferably, the dissolving microneedles dissolve in the skin within a few seconds, e.g., within about 5, 10, 15, 20, 25, 30, 45, 50, 60, 120, 180 seconds or more; or within a few minutes, e.g., within about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 60, 120 minutes or more.The dissolvable microneedles may include the entire microneedle, such that the entire microneedle structure dissolves in the skin, or the dissolvable coating may be formed on a non-dissolvable support structure, such that only the coating dissolves in the skin. The microneedles may be coated with a polymer that is dissolvable, biodegradable, biodissolvable, or a combination thereof.

[0136] In some embodiments, the alpha-adrenergic agonist composition is coated onto the dissolvable microneedles or is contained within the dissolvable microneedles themselves (e.g., by forming part of a dissolvable polymer matrix). In some embodiments, the alpha-adrenergic agonist composition is coated directly onto the microneedle structure or mixed with a polymer matrix prior to molding and polymerizing the microneedle structure.

[0137] For examples of biodegradable microneedles, see, for example, WO200801068 and US6334856, each of which is incorporated herein by reference.

[0138] A variety of suitable methods for making microneedles are available (see, for example, US6312612, US6334856, US7182747, US7226439, and WO2013137831). In some embodiments, microneedles are manufactured using a variety of methods, including, but not limited to, molding (e.g., self-molding, micromolding, microembossing, microinjection, etc.), casting (e.g., die-casting), etching (e.g., soft microlithography techniques), etc. The manufacturing method used typically depends on the material used.

[0139] In some embodiments, the microneedle composition comprises one or more alpha-adrenergic agonists.

[0140] In various embodiments, the release of the alpha-adrenergic agonist is sustained for a specified amount of time. In various embodiments, the release of the alpha-adrenergic agonist is sustained for a period of 4 hours or more. In various embodiments, the release of the alpha-adrenergic agonist is sustained for a period of 8 hours or more. In various embodiments, the release of the alpha-adrenergic agonist is sustained for a period of 12 hours or more. In various embodiments, the release of the alpha-adrenergic agonist is sustained for up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, up to 7 days, up to 1 week, up to 2 weeks, up to 3 weeks, up to 4 weeks, up to 1 month, or up to 2 months.

[0141] In various embodiments, the microneedle array comprises about 0.1 mg to about 10 mg of an alpha-adrenergic agonist. In some embodiments, the microneedle array comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, 2.1 mg, about 2.2 mg, or about 2.3 mg of an alpha-adrenergic agonist. g, about 2.4mg, about 2.5mg, about 2.6mg, about 2.7mg, about 2.8mg, about 2.9mg, about 3.0mg, 3.1mg, about 3.2mg, about 3.3mg, about 3.4mg, about 3.5mg, about 3.6mg, About 3.7mg, about 3.8mg, about 3.9mg, about 4.0mg, 4.1mg, about 4.2mg, about 4.3mg, about 4.4mg, about 4.5mg, about 4.6mg, about 4.7mg, about 4.8mg, about 4.9mg, about 5 0.0mg, 5.1mg, about 5.2mg, about 5.3mg, about 5.4mg, about 5.5mg, about 5.6mg, about 5.7mg, about 5.8mg, about 5.9mg, about 6.0mg, 6.1mg, about 6.2mg, about 6.3mg, about 6.4mg, about 6.5mg, about 6.6mg, about 6.7mg, about 6.8mg, about 6.9mg, about 7.0mg, 7.1mg, about 7.2mg, about 7.3mg, about 7.4mg, about 7.5mg, about 7.6mg , about 7.7 mg, about 7.8 mg, about 7.9 mg, about 8.0 mg, 8.1 mg, about 8.2 mg, about 8.3 mg, about 8.4 mg, about 8.5 mg, about 8.6 mg, about 8.7 mg, about 8.8 mg, about 8.9 mg, about 9.0 mg, 9.1 mg, about 9.2 mg, about 9.3 mg, about 9.4 mg, about 9.5 mg, about 9.6 mg, about 9.7 mg, about 9.8 mg, about 9.9 mg, or about 10 mg of alpha-adrenergic agonist. In some embodiments, any two of the doses in this paragraph may be combined to form a dosage range encompassed within the present disclosure, for example, the microneedle array contains from about 1.0 mg to about 8.0 mg of alpha-adrenergic agonist.

[0142] In some embodiments, the microneedle array comprises between about 0.1 mg and about 10 mg of an alpha-adrenergic agonist. In some embodiments, the microneedle array comprises between about 0.5 mg and about 8 mg of an alpha-adrenergic agonist. In some embodiments, the microneedle array comprises between about 2 mg and about 5 mg of an alpha-adrenergic agonist. In some embodiments, the microneedle array comprises between about 3 mg and about 5 mg of an alpha-adrenergic agonist.

[0143] In some embodiments, the microneedle array comprises about 10 mg or less of an alpha-adrenergic agonist. In some embodiments, the microneedle array comprises about 8 mg or less of an alpha-adrenergic agonist. In some embodiments, the microneedle array comprises about 6 mg or less of an alpha-adrenergic agonist. In some embodiments, the microneedle array comprises about 4 mg or less of an alpha-adrenergic agonist.

[0144] In some embodiments, the microneedle array comprises at least about 1 mg of alpha-adrenergic agonist. In some embodiments, the microneedle array comprises at least about 2 mg of alpha-adrenergic agonist. In some embodiments, the microneedle array comprises at least about 3 mg of alpha-adrenergic agonist. In some embodiments, the microneedle array comprises at least about 4 mg of alpha-adrenergic agonist.

[0145] How to use In some aspects, any of the compositions described herein can be used in the treatment of ptosis, for cosmetic changes to eyelids, or other related applications. The compositions of the present disclosure are preferably applied topically to the eye or eyelid, injected into the eyelid, or released from an implant in or near the eyelid. In some embodiments, the controlled-release compositions of the present disclosure are used to treat ptosis, or for cosmetic changes to eyelids, or other related applications. The compositions used in the methods described herein can be selected from parenteral compositions, topical compositions, controlled-release compositions, microneedle formulations, transdermal formulations, and any other compositions described herein. In some embodiments, the alpha-adrenergic agonist of the methods described herein is an alpha-adrenergic agonist, such as oxymetazoline or its salt.

[0146] As used herein, the terms "treatment" or "treating" are used interchangeably herein. These terms refer to an approach to obtaining beneficial or desired results, including, but not limited to, therapeutic benefit, cosmetic benefit, and / or preventive benefit. A therapeutic benefit can refer to the eradication or improvement of the underlying disease being treated. Furthermore, a therapeutic benefit can be achieved by eradicating or improving one or more of the physiological symptoms associated with the underlying disease, resulting in an improvement observed in the subject, even though the subject may still suffer from the underlying disease. A preventive effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof. For a preventive benefit, the composition can be administered to a subject who is at risk of developing a particular disease, even if the disease has not been diagnosed, or to a subject who reports one or more physiological symptoms of the disease. A cosmetic benefit can refer to affecting a physical change in a subject that is desired by the subject.

[0147] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound sufficient to affect the intended application, including but not limited to cosmetic treatment and disease treatment, as defined below. The therapeutically effective amount may vary depending on the intended therapeutic application (in vivo), or the subject and disease state to be treated, such as the severity of the disease state, the mode of administration, etc., and can be easily determined by those skilled in the art. The term also applies to a dose that induces a specific response in target cells. The specific dose will vary depending on the specific compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system by which it is delivered.

[0148] In one aspect, the present disclosure provides a method for treating ptosis in a subject, comprising administering an effective amount of an alpha-adrenergic agonist into the subject's eyelid, such as by injection into the eyelid. In some embodiments, the injection is intradermal, subcutaneous, preseptal, postseptal, into the postseptal fat pad, or intramuscular. In certain embodiments, the injection is intramuscular into the Müller muscle or levator muscle, or both. In some embodiments, the injection is subcutaneous, adjacent to the Müller muscle or levator muscle.

[0149] In some embodiments, a method for treating ptosis in a subject comprises administering a controlled-release composition into the eyelid of the subject. The controlled-release composition may be administered into the eyelid by surgical implantation, or the controlled-release composition may be administered into the eyelid by injection. In some embodiments, a controlled-release implant is injected into the eyelid of the subject. For example, a solid polymer-based implant may be injected into the eyelid of the subject.

[0150] In some embodiments, the controlled release implant is formed by injection of an injectable polymeric composition, such as a thermosetting or thermoplastic composition, hi some such embodiments, the injectable polymeric composition forms a solid or semi-solid implant once injected into the tissue of a subject.

[0151] In some embodiments, the present disclosure provides a method for treating ptosis in a subject, comprising contacting one or more muscles in the eyelid with an effective amount of an alpha-adrenergic agonist. In some embodiments, the method for treating ptosis in a subject comprises contacting any one or more of the superior tarsus muscle, the orbital muscle, and the levator palpebrae superioris muscle. In some embodiments, the method comprises directly contacting the muscles in the eyelid, for example, by injecting an alpha-adrenergic composition into the eyelid or implanting an alpha-adrenergic agonist-containing implant into the eyelid. The method can also comprise indirectly contacting the muscles in the eyelid, for example, by applying a topical composition that penetrates the skin of the eyelid. In some such embodiments, the topical composition can be a transdermal formulation.

[0152] In some embodiments, the disclosed methods include contacting the subject's Müller muscle and / or levator muscle with an effective amount of an alpha-adrenergic agonist. The Müller muscle, also known as the orbital muscle, is a smooth muscle that extends from the infraorbital groove and inferior orbital fissure and is tightly connected to the periosteum of the orbit. The Müller muscle is located at the back of the orbit and extends into the inferior orbital fissure.

[0153] In some embodiments, contact with a muscle (e.g., Müller's muscle) of the subject occurs by parenteral administration of an alpha-adrenergic agonist, for example, by injection of an alpha-adrenergic agonist into the eyelid of the subject. In some embodiments, parenteral administration is injection of an alpha-adrenergic agonist in an area on the face adjacent to the eyelid, for example, injection into the canthal vein.

[0154] In some embodiments, the alpha-adrenergic agonist is administered in a controlled-release composition. In some embodiments, contact with the subject's muscle (e.g., Müller's muscle) occurs by release of the alpha-adrenergic agonist from a controlled-release composition, such as a polymer-based implant described herein, implanted into the subject's eyelid. In some embodiments, contact with the subject's muscle (e.g., Müller's muscle) occurs by release of the alpha-adrenergic agonist from an insert placed in contact with or under the subject's eyelid.

[0155] In one aspect, the present disclosure provides a method for treating ptosis in a subject, comprising administering a controlled-release composition into, in contact with, or in close proximity to the subject's eyelid, wherein the controlled-release composition releases a therapeutically effective amount of an alpha-adrenergic agonist to the subject. In some embodiments, the controlled-release composition is selected from any of the controlled-release compositions described herein. In certain embodiments, the method comprises administering the controlled-release composition as an implant in the subject's eyelid. In certain embodiments, the implant is biodegradable in vivo. In certain embodiments, the method comprises administering an effective amount of an alpha-adrenergic agonist controlled-release composition to the subject as an injectable polymeric implant. In certain embodiments, the alpha-adrenergic agonist of the method is oxymetazoline or a salt thereof.

[0156] In one aspect, the present disclosure provides a method for cosmetic treatment of a subject, comprising administering an effective amount of an alpha-adrenergic agonist into the subject's eyelid, such as by injection into the eyelid. In some embodiments, the injection is intradermal, subcutaneous, preseptal, postseptal, into the postseptal fat pad, or intramuscular. In certain embodiments, the injection is intramuscular into the Müller muscle or levator muscle, or both. In some embodiments, the injection is subcutaneous, adjacent to the Müller muscle or levator muscle.

[0157] In some embodiments, a method for cosmetic treatment of a subject comprises administering a controlled-release composition into the eyelid of the subject. The controlled-release composition may be administered into the eyelid by surgical implantation, or the controlled-release composition may be administered into the eyelid by injection. In some embodiments, a controlled-release implant is injected into the eyelid of the subject. For example, a solid polymer-based implant may be injected into the eyelid of the subject.

[0158] In some embodiments, the controlled release implant for the cosmetic method is formed by injection of an injectable polymeric composition, such as a thermosetting or thermoplastic composition, hi some such embodiments, the injectable polymeric composition forms a solid or semi-solid implant once injected into the tissue of a subject.

[0159] In some embodiments, the present disclosure provides a method for cosmetic therapy of a subject, comprising contacting one or more muscles in the eyelid with an effective amount of an alpha-adrenergic agonist.In some embodiments, the method for cosmetic therapy of a subject comprises contacting any one or more of the following muscles: superior tarsus muscle, orbital muscle, and levator palpebrae superioris muscle.In some embodiments, the method comprises directly contacting the muscles in the eyelid, for example, by injecting an alpha-adrenergic composition into the eyelid or implanting an alpha-adrenergic agonist-containing implant into the eyelid.The method can also comprise indirectly contacting the muscles in the eyelid, for example, by applying a topical composition that penetrates the skin of the eyelid.In some such embodiments, the topical composition can be a transdermal formulation.

[0160] In some embodiments, the cosmetic treatment method comprises contacting the subject's Müller muscle and / or levator muscle with an effective amount of an alpha-adrenergic agonist. In some embodiments, contacting the subject's muscle (e.g., Müller muscle) occurs by parenteral administration of the alpha-adrenergic agonist, for example, by injection of the alpha-adrenergic agonist into the subject's eyelid. In some embodiments, parenteral administration is injection of the alpha-adrenergic agonist into the facial area adjacent to the eyelid, for example, injection into the canthal vein.

[0161] In some embodiments, a subject's cosmetic treatment method includes administering an alpha-adrenergic agonist in a controlled-release composition. In some embodiments, direct contact with a subject's muscle, such as the Müller muscle, occurs through release of the alpha-adrenergic agonist from a controlled-release composition, such as a polymer-based implant described herein, implanted into the subject's eyelid. In some embodiments, indirect contact with a subject's muscle, such as the Müller muscle, occurs through release of the alpha-adrenergic agonist from an insert placed in contact with or under the subject's eyelid.

[0162] In one aspect, the present disclosure provides a method for cosmetic therapy of a subject, comprising administering a controlled-release composition into, in contact with, or in close proximity to the subject's eyelid, wherein the controlled-release composition releases a therapeutically effective amount of an alpha-adrenergic agonist to the subject. In some embodiments, the controlled-release composition is selected from any of the controlled-release compositions described herein. In certain embodiments, the cosmetic therapy method comprises administering the controlled-release composition as an implant in the subject's eyelid. In certain embodiments, the implant is biodegradable in vivo. In certain embodiments, the method comprises administering an effective amount of an alpha-adrenergic agonist controlled-release composition to the subject as an injectable polymeric implant. In certain embodiments, the alpha-adrenergic agonist of the method is oxymetazoline or a salt thereof.

[0163] In certain embodiments, the controlled release compositions of the present disclosure provide sustained release of the alpha-adrenergic agonist over a period of 2 weeks or more, such as 3 weeks or more, for example 4 weeks or more, such as 5 weeks or more, for example 6 weeks or more, such as 7 weeks or more, for example 8 weeks or more, such as 9 weeks or more, for example 10 weeks or more, such as 11 weeks or more, for example 12 weeks or more, such as 13 weeks or more, for example 14 weeks or more, such as 15 weeks or more, or even such as 16 weeks or more.

[0164] In some embodiments, the controlled-release compositions of the present disclosure provide sustained release of an alpha-adrenergic agonist for a period of about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, or even about 16 weeks. In some embodiments, the controlled-release compositions of the present disclosure provide sustained release of an alpha-adrenergic agonist for a period of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or even about 12 months. In some embodiments, any two of the time frames in this paragraph may be combined to form a range of time frames encompassed within the present disclosure; for example, the controlled-release compositions of the present disclosure provide sustained release of an alpha-adrenergic agonist for a period of about 3 weeks to about 4 months.

[0165] The term "controlled release," as used herein, refers to the release of a predetermined amount of an alpha-adrenergic agonist into the body over a specific period of time. Controlled release compositions include sustained release compositions, delayed release compositions, targeted release formulations, and the like. The term "sustained release," as used herein, refers to the release of an alpha-adrenergic agonist at a predetermined rate to maintain a constant or near-constant drug concentration for a period of time.

[0166] In one aspect, the present disclosure provides a method for increasing the vertical separation of a subject's upper and lower eyelids compared to the pre-treatment separation, the method comprising administering an effective amount of an alpha-adrenergic agonist to the subject's eye or eyelid. In certain embodiments, the subject does not have ptosis. In some embodiments, the alpha-adrenergic agonist is administered as a controlled-release composition. In some embodiments, the alpha-adrenergic agonist is administered topically to the eye or eyelid. In certain embodiments, the alpha-adrenergic agonist is administered to the subject's eyelid, e.g., into the subject's eyelid. In some embodiments, the vertical separation of the upper and lower eyelids is increased by 10 percent or more compared to the pre-treatment separation.

[0167] In certain embodiments, the methods of the present disclosure achieve about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 11% or more, about 12% or more, about 13% or more, about 14% or more, about 15% or more, about 16% or more, about 17% or more, about 18% or more, about 19% or more, about 20% or more, about 21% or more, about 22% or more, about 23% or more, about 24% or more, about 25% or more, about 26% or more, about 27% or more, about 28% or more, about 29% or more, about 30% or more, about 31% or more, about 32% or more, about 33% or more, about 34% or more, about 35% or more, about 36% or more, about 37% or more, about 38% or more compared to pre-treatment vertical separation of the upper and lower eyelids. Increase the vertical separation of the upper and lower eyelids by about 39% or more, about 40% or more, about 41% or more, about 42% or more, about 43% or more, about 44% or more, about 45% or more, about 46% or more, about 47% or more, about 48% or more, about 49% or more, about 50% or more.

[0168] In some embodiments, the disclosed methods increase the distance of the upper eyelid from the midpupil. A drooping or ptotic eyelid can have a distance between the upper eyelid and the midpupil of about 2 mm or less. In certain embodiments, the methods of the present disclosure increase the distance between the upper eyelid and the pupil center to about 2 mm or more, about 2.1 mm or more, about 2.2 mm or more, about 2.3 mm or more, about 2.4 mm or more, about 2.5 mm or more, about 2.6 mm or more, about 2.7 mm or more, about 2.8 mm or more, about 2.9 mm or more, about 3.0 mm or more, about 3.1 mm or more, about 3.2 mm or more, about 3.3 mm or more, about 3.4 mm or more, about 3.5 mm or more, about 3.6 mm or more, about 3.7 mm or more, about 3.8 mm or more, about 3.9 mm or more, or even about 4.0 mm or more compared to the pre-treatment distance of the upper eyelid from the pupil center.

[0169] In some embodiments, the methods of the present disclosure reduce asymmetry between the upper eyelids.

[0170] In some embodiments, the present disclosure provides a method for altering the position of a subject's visual axis, the method comprising administering an effective amount of an alpha-adrenergic agonist to the eye or into the eyelid of the subject. In certain embodiments, the subject does not have ptosis. In some embodiments, the alpha-adrenergic agonist is administered as a controlled-release composition. In some embodiments, the alpha-adrenergic agonist is administered topically to the eye or eyelid. In certain embodiments, the alpha-adrenergic agonist is administered to, e.g., into, the subject's eyelid. In some embodiments, altering the position of the visual axis improves the subject's vision. The improvement in the subject's vision can include any of the following: improved visual acuity, improved contrast sensitivity, reduced glare and halos, and an increase in the amount of open mouth through which the subject has good vision.

[0171] Diagnostic methods In some embodiments, the present disclosure provides a method for screening subjects who will benefit from the methods disclosed herein using alpha-adrenergic agonists. In certain embodiments, to determine whether the subject's eyelids respond to the administration of alpha-adrenergic agonists, the alpha-adrenergic agonist is administered locally to the subject's eye or eyelid as a screening dose. In some embodiments, if the subject's eyelids respond to the topical administration of alpha-adrenergic agonists, the subject can be administered a treatment regimen of alpha-adrenergic agonists in the form of topical or parenteral administration. In certain embodiments, the subject is administered a topical alpha-adrenergic agonist, and if the eyelids respond to the administration, the subject is administered one or more doses of alpha-adrenergic agonists by injection into the eyelid, as described in the methods disclosed herein.

[0172] In some embodiments, the eyelid responds to administration by contracting, resulting in an increase in the vertical separation of the lower and upper eyelids of the treated eye. For example, a topical alpha-adrenergic agonist (e.g., oxymetazoline eye drops) is administered intraocularly to a subject, and the upper eyelid of the eye contracts upward, resulting in an increase in the vertical separation of the lower and upper eyelids of about 0.5 mm or more, such as about 1 mm or more, or even about 2 mm or more.

[0173] If the upper eyelid of the eye treated with alpha-adrenergic agonist responds to the screening dose, any of the methods of use described in the previous section can be used on the subject.For example, if the upper eyelid of the eye treated with alpha-adrenergic agonist responds to the screening dose, the subject can receive an injection of alpha-adrenergic agonist, the subject can apply a topical composition of alpha-adrenergic agonist into the eye or on the eyelid, or any combination thereof.

[0174] In some embodiments, the screening method provides information regarding the appropriate dosage or administration method of an alpha-adrenergic agonist. For example, a subject's eyelids may not constrict or only minimally constrict upon administration of a screening dose of an alpha-adrenergic agonist. As used herein, "minimally constrict" may refer to an increase in the vertical separation of the upper and lower eyelids of less than 2 mm, e.g., about 0.1 mm to about 2 mm, about 0.1 mm to about 1.5 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 0.8 mm, or even about 0.1 mm to about 0.5 mm, compared to the position of the eyelids before administration of the alpha-adrenergic agonist. If the subject's eyelids do not constrict or only minimally constrict upon administration of a topical alpha-adrenergic agonist screening dose, the subject may be given a second screening dose higher than the first screening dose to determine whether the subject's eyelids respond to a higher dose.

[0175] In some embodiments, a subject's response to a topical screening dose of an alpha-adrenergic agonist can be used to determine the dose or frequency of administration of the alpha-adrenergic agonist to the subject. For example, the subject's eyelid may show a large contractile response upon administration of the topical screening dose, and therefore the subject may be prescribed a lower dose of the alpha-adrenergic agonist. Alternatively, the subject's eyelid may show a small contractile response upon administration of the screening dose, and therefore the subject may be prescribed a higher dose of the alpha-adrenergic agonist.

[0176] In some embodiments, the administration method of the alpha-adrenergic agonist can be prescribed based on the subject's response to the screening dose. For example, the subject's eyelids may show a large contractile response upon administration of the topical screening dose, and therefore the subject may be prescribed a topical treatment regimen. Alternatively, the subject's eyelids may show a small contractile response upon administration of the screening dose, and therefore the subject may be prescribed a parenteral treatment regimen, alone or in combination with a topical treatment regimen.

[0177] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0178] The present invention will be described in further detail by reference to the following examples. These examples are provided for illustrative purposes only and are not intended as limiting unless otherwise specified. Therefore, the present invention should in no way be construed as being limited to the following examples, but rather should be construed to encompass any variations that become evident as a result of the teachings provided herein.

[0179] Embodiments contemplated herein include embodiments P1 through P48.

[0180] Aspect P1. A controlled release composition comprising an alpha-adrenergic agonist and a delivery system that controls the release of the alpha-adrenergic agonist.

[0181] Aspect P2. A controlled release composition according to aspect P1, selected from a sustained release composition, an extended release composition, a pulsed release composition, and a delayed release composition.

[0182] Embodiment P3. The controlled release composition of embodiment P1 or P2, wherein the delivery system is selected from a polymer-based system, a porous matrix, a hydrogel release system, and a peptide-based system.

[0183] Aspect P4. The controlled release composition of any of Aspects P1-P3, which is a sustained release composition.

[0184] Aspect P5. The controlled release composition of aspect P4, wherein the sustained release composition is formulated for injection.

[0185] Aspect P6. The controlled release composition of aspect P6, which is formulated for intradermal, subcutaneous, preseptal, postseptal, into the postseptal fat pad, or intramuscular injection.

[0186] Aspect P7. The controlled release composition of any one of Aspects P1-P6 comprising 0.2-10 mg of an alpha-adrenergic agonist.

[0187] Aspect P8. The controlled release composition of aspect P7 comprising 0.5 to 8 mg of an alpha-adrenergic agonist.

[0188] Aspect P9. The controlled release composition of aspect P7 comprising 0.5 to 3 mg of an alpha-adrenergic agonist.

[0189] Aspect P10. The controlled release composition of aspect P7 comprising 3-6 mg of an alpha-adrenergic agonist.

[0190] Aspect P11. The controlled release composition of aspect P4, wherein the sustained release composition is formulated for topical administration.

[0191] Aspect P12. The controlled release composition of aspect P1 formulated for administration to the eyelid.

[0192] Aspect P13. The controlled-release composition of aspect P11 or P12 comprising 0.2 to 6 mg of alpha-adrenergic agonist per dose.

[0193] Aspect P14. The controlled release composition of aspect P13 comprising 0.5 to 4 mg of alpha-adrenergic agonist per dose.

[0194] Aspect P15. The controlled release composition of aspect P14 comprising 0.5 to 3 mg of alpha-adrenergic agonist per dose.

[0195] Aspect P16. The controlled-release composition of any one of Aspects P1-P15, wherein the alpha-adrenergic agonist is selected from a natural alpha-adrenergic agonist or a synthetic alpha-adrenergic agonist.

[0196] Aspect P17. The controlled release composition of any one of Aspects P1-P16, wherein the alpha-adrenergic agent is selected from an alpha-1 agonist and an alpha-2 agonist.

[0197] Aspect P18. The alpha-adrenergic agonist is selected from the group consisting of amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline, phenylephrine. , phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline, 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), and a salt of any one thereof.

[0198] Aspect P19. The controlled-release composition of aspect P18, wherein the alpha-adrenergic agonist is oxymetazoline or a salt thereof.

[0199] Aspect P20. A method for treating ptosis in a subject, comprising injecting a therapeutically effective amount of an alpha-adrenergic agonist into the eyelid of the subject.

[0200] Aspect P21. A method for cosmetic treatment of a subject, comprising injecting a therapeutically effective amount of an alpha-adrenergic agonist into the eyelid of the subject.

[0201] Embodiment 22 The method of embodiment P20 or P21, wherein the injection is intradermal, subcutaneous, preseptal, postseptal, into the postseptal fat pad, or intramuscular.

[0202] Embodiment P23. The method of embodiment P22, wherein the alpha-adrenergic agonist is administered intramuscularly.

[0203] Aspect P24. The method of Aspect P23, wherein the intramuscular injection is into the Muller muscle or the levator muscle or both.

[0204] Embodiment P25. The method of embodiment P21, wherein the injection is adjacent to the Muller's muscle or the levator muscle, or both.

[0205] Aspect P26. The method of any one of Aspects P20-P25, wherein the alpha-adrenergic agonist is formulated as a controlled-release composition according to any one of Aspects P1-P10.

[0206] Embodiment P27. The method of any one of embodiments P20-P26, wherein the alpha-adrenergic agonist is oxymetazoline or a salt thereof.

[0207] Aspect P28. A method for treating ptosis in a subject comprising directly contacting Muller's muscle with an effective amount of an alpha-adrenergic agonist.

[0208] Aspect P29. A method for cosmetic treatment of a subject comprising directly contacting the Muller muscle with an effective amount of an alpha-adrenergic agonist.

[0209] Embodiment P30. The method of embodiment P28 or P29, wherein the direct contact occurs by release of the alpha-adrenergic agonist from an implant in the subject's eyelid.

[0210] Embodiment P31. The method of embodiment P28 or P29, wherein the direct contact occurs by injection of an alpha-adrenergic agonist into the Muller muscle.

[0211] Aspect P32. The method of any one of Aspects P28-P31, wherein the alpha-adrenergic agonist is formulated as a controlled-release composition according to any one of Aspects P1-P10.

[0212] Aspect P33. The method of any one of Aspects P28-P32, wherein the alpha-adrenergic agonist is oxymetazoline or a salt thereof.

[0213] Aspect P34. A method for treating ptosis in a subject, comprising administering to an eyelid of the subject a controlled-release composition of an alpha-adrenergic agonist, wherein the controlled-release composition releases an effective amount of the alpha-adrenergic agonist to the subject over a period of time.

[0214] Aspect P35. A method for cosmetic treatment of a subject, comprising administering to an eyelid of the subject a controlled-release composition of an alpha-adrenergic agonist, wherein the controlled-release composition releases an effective amount of the alpha-adrenergic agonist to the subject over a period of time.

[0215] Aspect P36. The method of aspect P34 or P35, wherein the controlled release composition is selected from any one of aspects P1-P19.

[0216] Aspect P37. The method of Aspect P35, wherein the controlled release composition is administered topically to the eyelid.

[0217] Aspect P38. The method of Aspect P37, wherein the controlled-release composition releases an effective amount of the alpha-adrenergic agonist to the subject over a period of 6 hours or more.

[0218] Aspect P39. The method of Aspect P35, wherein the controlled release composition is administered by injection into the eyelid.

[0219] Embodiment P40. The method of embodiment P39, wherein the controlled release composition is administered as an injectable polymeric implant.

[0220] Embodiment P41. The method of embodiment P39 or P40, wherein the controlled-release composition releases an effective amount of the alpha-adrenergic agonist to the subject over a period of two weeks or more.

[0221] Aspect P42. A method for increasing the vertical separation of a subject's upper and lower eyelids, comprising administering an effective amount of an alpha-adrenergic agonist to the subject's eye or eyelid.

[0222] Embodiment P43. The method of embodiment P42, wherein the subject does not have ptosis.

[0223] Aspect P44. The method of aspect P42 or P43, wherein the alpha-adrenergic agonist is administered in a controlled release composition selected from any one of aspects P1-P14.

[0224] Embodiment P45. The method of embodiment P42 or P43, wherein the alpha-adrenergic agonist is administered topically to the eye or eyelid.

[0225] Aspect P46. The method of Aspect P45, wherein the alpha-adrenergic agonist is administered to the eyelid of the subject.

[0226] Aspect P47. The method of Aspect P42 or P43, wherein the alpha-adrenergic agonist is injected into the eyelid of the subject.

[0227] Embodiment P48. The method of any one of embodiments P42-P47, wherein the vertical separation of the upper and lower eyelids is increased by 10 percent or more compared to pre-treatment separation of the upper and lower eyelids. [Example]

[0228] Example 1. Evaluation of the effect of oxymetazoline solution on eyelid contraction after administration in rabbits Rabbits without ocular disease were given oxymetazoline solution via ocular injection. Treatment was followed by examination for progression at 1, 2, 3, 7, 10, and 14 days after administration of oxymetazoline solution. Eyelids were analyzed histologically at the end of the experiment. Endpoints included inflammation, fibrosis, pre- and post-septal fat, the status of the levator and Müller muscles, and the presence of vascular damage or necrosis or ischemic damage to eyelid tissue.

[0229] material Animal: Female New Zealand rabbit (2.5-3 kg) Sedation: Atropine sulfate and midazolam IV (ear vein) Anesthesia: Induction with propofol 1% (10 mg / kg) via ear vein Maintenance with isoflurane (inhalation anesthesia) Oxymetazoline solution Slit lamp

[0230] method Baseline measurements (phase 1) I. Animals (n=2): 2.5-3 kg New Zealand rabbits II. No sedation or anesthesia III. Photographic recording, accompanied by a ruler (to provide a standard measure of distance). Three sets of photographs per measurement were taken in dim lighting to avoid the rabbits squinting. IV. 50 μl of 10% phenylephrine was administered topically to the right eye (RE). V. Photographic record with ruler. 3 sets of photos per measurement. 20-30 minutes after administration. VI. The animals were returned to their animal housing.

[0231] Test substance (oxymetazoline solution) (Phase 2) I. Animals (n=3 / group): 2.5-3 kg New Zealand rabbits II. Photographic recording, accompanied by a ruler (to provide a standard measure of distance). Three sets of photographs per measurement were taken in dim lighting to avoid the rabbits squinting. III. Sedation with Atropine Sulfate and Midazolam IV. Propofol induction V. Maintenance with Isoflurane VI. Ocular injection of oxymetazoline solution or PBS (phosphate-buffered saline) a. Group A: Oxymetazoline 1 mg / ml in PBS (RE) and PBS (LE) b. Group B: Oxymetazoline 3 mg / ml in PBS (RE) and PBS (LE) c. Group C: Oxymetazoline 10 mg / ml in PBS (RE) and PBS (LE)

[0232] On day 0, all animals received 100 μL (0.1 ml) of oxymetazoline solution (RE) or PBS vehicle control (LE) via injection into the retroseptal fat pad adjacent to the Müller muscle of both eyelids. A 30G needle was used for this injection; the test article was administered at least 4 mm from the needle entry site to prevent backflow of fluid through the hole. VII. Follow-up VIII. 14 days after injection of oxymetazoline solution, the animals were euthanized and the eyelid tissues were processed. a. Both eyelids are collected from each animal and stored in formalin. b.Histology (H / E staining)

[0233] Follow-up Follow-up included: - Eyelid retraction / ptosis measurements and digital photographs with the eyes looking directly into the camera and a ruler in the photograph frame to standardize distances. Three sets of photographs per measurement were taken in dim lighting to avoid the rabbits squinting. - Slit lamp biomicroscopy - Daily health monitoring - Pre-medication and pre-slaughter body weight

[0234] Study variables I. Palpebral fissure distance II. Margin Reflection Distance 1

[0235] result Group A (1 mg / ml) Note: Before injection. Oxygen injection, no incidents; Day 2: Apply pressure to close the right eyelid (3 hours after injection). The animal will show ocular discomfort. Day 3 AM: Apply pressure to close the right eyelid TIFF2026001122000001.tif153167TIFF2026001122000002.tif243167TIFF2026001122000003.tif187167

[0236] Group B (3mg / ml) Note: Before injection. Oxygen injection, no incidents; Day 2: Apply pressure to close the right eyelid (3 hours after injection). The animal will show ocular discomfort. Day 3 AM: Apply pressure to close the right eyelid Day 3, afternoon: Apply pressure to close the right eyelid Day 4 AM: Apply pressure to close the right eyelid TIFF2026001122000004.tif243167TIFF2026001122000005.tif243167TIFF2026001122000006.tif76167

[0237] Example 2. Diagnostic method A drop of phenylephrine 2.5% or 10% is administered to the eye of a subject with ptosis or a subject who wishes to elevate the upper eyelid for cosmetic or other purposes. The treated eye is observed to determine how the eyelid responds to the administration. The eyelid response to phenylephrine can be used to determine whether the patient will respond to treatment with an alpha-adrenergic agonist to treat ptosis or elevate the upper eyelid for cosmetic or other purposes. The dosage, frequency, and method of administration of the alpha-adrenergic agonist to treat ptosis or elevate the upper eyelid for cosmetic or other purposes can also be determined.

[0238] Example 3. Treatment of ptosis A sustained-release composition of oxymetazoline, for example, about 0.5 mg to about 4 mg, is injected into one eyelid for unilateral ptosis or into both eyelids for bilateral ptosis of a subject suffering from ptosis. The subject receives the injection as part of a treatment regimen that includes biweekly, monthly, or bimonthly injections of oxymetazoline. The subject may also apply a topical pharmaceutical composition of oxymetazoline, for example, 0.5 mg to 2 mg per dose, if desired.

[0239] Example 4: Injectable Cosmetic Treatment A sustained-release composition of oxymetazoline, e.g., about 0.5 mg to about 4 mg, is injected into a subject's eyelid for cosmetic purposes. The subject receives the injection as part of a treatment regimen that includes biweekly, monthly, or bimonthly injections of oxymetazoline. The subject may also apply a topical pharmaceutical composition of oxymetazoline as needed.

[0240] Example 4: Cosmetic treatment by topical application to the outer surface of the eyelid A dermatological composition of oxymetazoline formulated for administration to the outer surface of the upper eyelid is applied to the eyelids of a subject in need thereof.The composition can be formulated as a lotion, cream, or makeup, such as eyeshadow or eyeliner.The subject applies the composition as needed, for example, once or twice a day.

Claims

1. An eyeshadow-like composition comprising a dermatologically acceptable carrier, an agent that stimulates the Muller muscle, and at least one cosmetic excipient.

2. 2. The eyeshadow composition of claim 1, wherein the agent that stimulates the Muller muscle comprises an alpha-adrenergic agonist.

3. 3. The eyeshadow composition of claim 2, wherein the alpha-adrenergic agonist is selected from natural alpha-adrenergic agonists or synthetic alpha-adrenergic agonists.

4. 4. The eyeshadow composition of claim 3, wherein the alpha-adrenergic agent is selected from an alpha-1 agonist and an alpha-2 agonist.

5. Alpha-adrenergic agonists include amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline, phenylephrine, and phenylephrine.

5. The eye shadow-like composition according to claim 4, wherein the hydroxybenzoate is selected from the group consisting of nylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline, xylometazoline, 6-(5-fluoro-2-pyrimidin-5-yl-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, A-61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a salt thereof, and any combination thereof.

6. 6. The eyeshadow composition according to claim 5, wherein the alpha-adrenergic agonist is oxymetazoline or a salt thereof.

7. 7. The eyeshadow composition of claim 6, wherein the alpha-adrenergic agonist is oxymetazoline.

8. 6. An eyeshadow composition according to claim 2, wherein the alpha-adrenergic agonist is not oxymetazoline.

9. 9. An eye shadow-like composition according to claim 1, wherein the dermatologically acceptable carrier is selected from the group consisting of lotions, oils, creams, butters, gels, ointments, sprays, milks, and powders.

10. 10. The eye shadow composition according to claim 9, wherein the dermatologically acceptable carrier is a powder.

11. 11. The eyeshadow-like composition according to claim 1, wherein the cosmetic excipient is selected from the group consisting of sunscreens, fragrances, pigments, and antioxidants.

12. A dermatological composition comprising a dermatologically acceptable carrier, an alpha-adrenergic agonist, and at least one penetration enhancer.

13. 13. The dermatological composition of claim 12, wherein the penetration enhancer increases skin penetration of the alpha-adrenergic agonist by about 2-fold or more.

14. 14. The dermatological composition of claim 13, wherein the penetration enhancer increases skin penetration of the alpha-adrenergic agonist by about 3-fold or more.

15. 13. The dermatological composition of claim 12, wherein the permeation enhancer increases skin penetration of the alpha-adrenergic agonist by about 0.5 mm or more.

16. 16. The dermatological composition of claim 15, wherein the permeation enhancer increases skin penetration of the alpha-adrenergic agonist by about 1.0 mm or more.

17. 17. The dermatological composition of any one of claims 12 to 16, wherein the alpha-adrenergic agonist penetrates the skin and septal fat pad to contact the Müller muscle.

18. 18. The dermatological composition of any one of claims 12 to 17, wherein the penetration enhancer is selected from alcohols, sulfoxides, azones, pyrrolidones, ureas, alkyl-N,N-disubstituted aminoacetals, propylene glycol, surfactants, terpenes, terpenoids, fatty acids, esters, cyclodextrins, and any combination thereof.

19. 19. The dermatological composition of claim 18, wherein the penetration enhancer is selected from ethanol, propylene glycol, dodecyl-N,N-dimethyl-aminoacetate, ethyl acetate, azone, sodium dodecyl sulfate, d-limonene, oleic acid, 1,3-diphenylurea, N-methyl-2-pyrrolidone, beta-cyclodextrin, dimethyl sulfoxide, and any combination thereof.

20. Dermatological composition according to any one of claims 12 to 19, further comprising one or more cosmetic excipients.

21. A dermatological composition comprising a dermatologically acceptable carrier, an alpha-adrenergic agonist, and at least one cosmetic excipient selected from sunscreens, fragrances, pigments, and antioxidants.

22. Dermatological composition according to any one of claims 12 to 21, wherein the dermatologically acceptable carrier is selected from lotions, oils, creams, butters, gels, ointments, sprays, milks and powders.

23. 23. The dermatological composition according to any one of claims 12 to 22, wherein the alpha-adrenergic agonist is selected from natural or synthetic alpha-adrenergic agonists.

24. 24. The dermatological composition of claim 23, wherein the alpha-adrenergic agent is selected from an alpha-1 agonist and an alpha-2 agonist.

25. Alpha-adrenergic agonists include amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluoronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline, phenylephrine, and phenylpropional.

25. The dermatological composition of any one of claims 12 to 24, wherein the hydroxybenzoates are selected from the group consisting of benzoyl benzoates, ...

26. 26. The dermatological composition of claim 25, wherein the alpha-adrenergic agonist is oxymetazoline or a salt thereof.

27. 27. The dermatological composition of claim 26, wherein the alpha-adrenergic agonist is oxymetazoline.

28. 28. The dermatological composition of any one of claims 12 to 27, wherein the alpha-adrenergic agonist is not oxymetazoline.

29. 29. The dermatological composition of any one of claims 12 to 28, comprising about 0.5 μg to 4 mg of alpha-adrenergic agonist per dose.

30. 30. The dermatological composition of claim 29, comprising about 0.5 μg to 2 mg of an alpha-adrenergic agonist per dose.

31. A controlled release dermatological composition comprising an alpha-adrenergic agonist and a delivery system that controls the release of the alpha-adrenergic agonist.

32. 32. The controlled release dermatological composition of claim 31, selected from a sustained release composition, an extended release composition, a pulsed release composition, and a delayed release composition.

33. 33. The controlled release dermatological composition of claim 31 or 32, wherein the delivery system is selected from a polymer-based system, a porous matrix, a hydrogel release system, a peptide-based system, and any combination thereof.

34. 34. The controlled release dermatological composition of any one of claims 31 to 33, which is a sustained release composition.

35. 35. The controlled release dermatological composition of any one of claims 31 to 34, formulated for administration to the outer surface of the eyelid.

36. 36. The controlled release dermatological composition of any one of claims 31 to 35, comprising from about 0.2 μg to about 6 mg of alpha-adrenergic agonist per dose.

37. 37. The controlled release dermatological composition of claim 36, comprising about 0.5 μg to about 4 mg of alpha-adrenergic agonist per dose.

38. 38. The controlled release dermatological composition of claim 37, comprising about 0.5 μg to about 3 mg of alpha-adrenergic agonist per dose.

39. 39. The controlled release dermatological composition of any one of claims 31 to 38, formulated as a lotion, cream, butter, gel, ointment, spray, milk, or powder.

40. 40. The controlled release dermatological composition of any one of claims 31 to 39, further comprising at least one dermatologically acceptable carrier.

41. 41. The controlled release dermatological composition of claim 40, further comprising one or more cosmetic excipients selected from sunscreens, fragrances, pigments, and antioxidants.

42. 42. The controlled release dermatological composition of any one of claims 31 to 41, wherein the alpha-adrenergic agonist is selected from natural alpha-adrenergic agonists or synthetic alpha-adrenergic agonists.

43. 43. The controlled release dermatological composition of claim 42, wherein the alpha-adrenergic agent is selected from an alpha-1 agonist and an alpha-2 agonist.

44. Alpha-adrenergic agonists include amidefrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrin, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluoronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, metaraminol, methoxamine, methyldopa, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline, phenylephrine, and phenylpropanol.

44. The controlled release dermatological composition of any one of claims 31 to 43, wherein the active ingredient is selected from the group consisting of benzodiazepine, benzophenone, benzoyl benzoate ...

45. 45. The controlled-release dermatological composition of claim 44, wherein the alpha-adrenergic agonist is oxymetazoline or a salt thereof.

46. A method for treating ptosis of the eye of a subject in need thereof, comprising administering a composition comprising an alpha-adrenergic agonist to the outer surface of the eyelid of the subject's eye.

47. 47. The method of claim 46, wherein the composition is administered once, twice, or three times per day.

48. 47. The method of claim 46, wherein the composition is administered every two days.

49. 47. The method of claim 46, wherein the composition is administered every three days.

50. 50. The method of any one of claims 46 to 49, wherein the composition is selected from any one of claims 1 to 45.

51. A method for cosmetic treatment of a subject's eye, comprising administering a composition comprising an alpha-adrenergic agonist to the outer surface of the eyelid of the subject's eye.

52. 52. The method of claim 51, wherein the composition is administered once, twice, or three times per day.

53. 52. The method of claim 51, wherein the composition is administered every two days.

54. 52. The method of claim 51, wherein the composition is administered every three days.

55. 55. The method of any one of claims 51 to 54, wherein the composition is selected from any one of claims 1 to 45.

56. A method for increasing the vertical separation of the upper and lower eyelids of a subject's eye, comprising administering to the outer surface of the eyelid of the subject's eye a composition comprising an effective amount of an alpha-adrenergic agonist.

57. 57. The method of claim 56, wherein the method increases the vertical separation of the upper and lower eyelids by about 10 percent or more compared to the separation of the upper and lower eyelids before said administration.

58. 58. The method of claim 56 or 57, wherein the composition is selected from any one of claims 1 to 45.

59. 59. The method of any one of claims 51 to 58, wherein the subject does not have ptosis.

60. 60. The method of any one of claims 51 to 59, wherein the composition is not administered to the eye.

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