Methods for producing dermatological GEL compositions

Abstract

The disclosure provides a method for preparing a gel formulation comprising (a) sterilizing a first portion, wherein the first portion comprises a gelling agent, and (b) filtering a second portion to remove submicron contaminants, wherein the second portion comprises an aqueous carrier, one or more buffers, an antioxidant, an antimicrobial, a humectant, and a penetration enhancer, and following step (a) and step (b), contacting the first portion with the second portion to produce the gel formulation.

Description

METHODS FOR PRODUCING DERMATOLOGICAL GEL COMPOSITIONSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 551,614 filed February 9, 2024, which is incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Blepharoplasty is a surgical procedure that involves removal of excess skin, muscle, and fat from the eyelid of a subject. Blepharoplasty may be prescribed as a treatment for a droopy eyelid, referred to as ptosis, but may also be used to improve the line of vision or change the cosmetic appearance of the eyes of a subject. The procedure was one of the top five most commonly performed cosmetic procedures in the United States with over 200,000 surgeries performed in 2014, according to the 2014 Plastic Surgery Report of the American Society of Plastic Surgeons.

[0003] Blepharoplasty is an expensive procedure and not accessible to all individuals who need or want the surgery to repair ptosis or improve their eyesight or appearance. The average cost of blepharoplasy in the U.S. in 2014 was approximately $2900 as reported by the American Society of Plastic Surgeons. While the cost may be covered by health insurance carriers in particular circumstances, health insurers generally do not cover the cost of cosmetic surgery or its complications. Therefore, there remains a need for non-surgical approaches using therapeutic formulations.SUMMARY OF THE INVENTION

[0004] The disclosure provides a method for preparing a gel formulation comprising (a) sterilizing a first portion, wherein the first portion comprises a gelling agent, and (b) filtering a second portion to remove submicron contaminants, wherein the second portion comprises an aqueous carrier, one or more buffers, an antioxidant, an antimicrobial, a humectant, and a penetration enhancer, and following step (a) and step (b), contacting the first portion with the second portion to produce the gel formulation. In some embodiments, the sterilizing is heat sterilizing. In some embodiments, step (a) occurs at a temperature of at least 120 °C. In some embodiments, step (a) occurs at a temperature of between about 120 °C to about 200 °C. In some embodiments, step (a) occurs at a temperature of at most 200 °C. In some embodiments, the temperature applied during step (a) is between about 5 minutes to about 720 minutes. In some embodiments, the contacting occurs for between about 1 hour to about48 hours. In some embodiments, the contacting comprises mixing the first portion and second portion. In some embodiments, the mixing is for between about 4 hours to about 24 hours.

[0005] In some embodiments, the gelling agent is in solid form. In some embodiments, the gelling agent is a polymer. In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), carbomer, hyaluronic acid, polycarbophil, carboxymethylcellulose (CMC), gellan gum, alginic acid, chitosan, dextran, polyethylene glycol, polypropylene glycol, polysorbate, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), and carboxymethylcellulose (CMC). In some embodiments, the polymer is hydroxy ethylcellulose.

[0006] In some embodiments, the submicron contaminants are microbial contaminants. In some embodiments, the microbial contaminants are selected from bacteria, viruses, and fungi, or a combination thereof. In some embodiments, the microbial contaminants are selected from bacteria and fungi, or a combination thereof. In some embodiments, the microbial contaminants is selected from P. aeruginosa, P. aureus, E.coli, A. brasiliensis, and C. albicans, or a combination thereof. In some embodiments, the filtering comprises at least one filter. In some embodiments, the at least one filter is a micron filter. In some embodiments, the micron filter has a filter size of between about 0.01 um to about 0.5 um.

[0007] In some embodiments, the one or more buffers is selected from 4- Morpholineethanesulfonic acid (MES), 2,2-Bis(hydroxymethyl)-2,2',2"-nitrilotriethanol (BisTris), N-(2-Acetamido)iminodiacetic acid (ADA), 2-[(2-Amino-2- oxoethyl)azaniumyl]ethanesulfonate (ACES), 1,4-Piperazinedi ethanesulfonic acid (PIPES), 3-Morpholino-2-hydroxypropanesulfonic acid (MOPSO), 1,3-Bis[tris(hydroxymethyl) methylamino]propane (Bis-Tris Propane), 2-(bis(2-hydroxyethyl)amino)ethane sulfonic acid (BES), 3-(N-Morpholino)propanesulfonic acid (MOPS), 2-[(2 -Hydroxy- 1,1- bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-Hydroxyethyl)piperazine-l- ethanesulfonic acid (HEPES), 4-(N-Morpholino)butanesulfonic acid (MOBS), N- [Tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropanesulfonic acid (TAPSO), Tris(hydroxymethyl)aminomethane (Tris), Piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) (POPSO), 4-(2 -Hydroxy ethyl)- 1 -piperazinepropanesulfonic acid (EPPS), N- [Tris(hydroxymethyl)methyl]glycine (Tricine), Diglycine (Gly-Gly), N,N-Bis(2- hydroxyethyl)glycine (Bicine), N-(2 -Hydroxy ethyl)piperazine-N'-(4-butanesulfonic acid)(HEPBS), N-[Tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid (TAPS), 2-Amino-2-methyl- 1,3 -propanediol (AMPD), N-(l,l-Dimethyl-2-hydroxyethyl)-3-amino-2- hydroxypropanesulfonic acid (AMPSO), 2-(Cyclohexylamino)ethanesulfonic acid (CHES),3 -(Cyclohexylamino)-2-hydroxy-l -propanesulfonic acid (CAPSO), 3-(Cyclohexylamino)-l- propanesulfonic acid (CAPS), 4-(Cyclohexylamino)-l -butanesulfonic acid (CABS), phosphoric acid, citric acid, acetic acid, carbonic acid, or a salt or hydrate of any one thereof. In some embodiments, the one or more buffers is selected from citric acid monohydrate, sodium phosphate dibasic, monosodium phosphate, sodium acetate, and sodium citrate. In some embodiments, the antioxidant is selected from acetylcamitine, acetylcysteine, allopurinol, amiloxate, ascorbic acid, butylated hydroxanisole (BHA),butylated bydroxytoluene (BHT), t-butyl hydroquinone (TBHQ), Beta-carotene, cholecalciferol, cysteine, dioxybenzone, Ethylenediaminetetraacetic acid (EDTA), erythorbic acid, etidronic acid, 4-hexylresorcinol, idebenone, lipoic acid, melatonin, methionine, niacinamide, pentaoxiflline, probucol, propyl gallate, retinol, selenious acid, sitosterol, and ubiquinone, or a salt of any one thereof.

[0008] In some embodiments, the antioxidant is EDTA or a salt thereof. In some embodiments, the antioxidant is disodium EDTA.

[0009] In some embodiments, the antimicrobial is selected from a quaternary ammonium salts, boric acid, and a borate salt. In some embodiments, the antimicrobial is selected from benzalkonium chloride, polyquartenium-1 (PQ-1), polyquartenium-42 (PQ-42), poly quad, boric acid, and sodium borate. In some embodiments, the antimicrobial is boric acid.

[0010] In some embodiments, the humectant is selected from glycerol, urea, hyaluronic acid, sorbitol, propylene glycol, and hypromellose. In some embodiments, the humectant is glycerol.

[0011] In some embodiments, the permeation enhancer is selected from selected from alcohols, sulfoxides, azones, pyrrolidones, ureas, alkyl-N,N- disubstituted aminoacetals, propylene glycol, surfactants, terpenes, terpenoids, fatty acids, esters, and cyclodextrins. In some embodiments, the permeation enhancer is selected from ethanol, propylene glycol, dodecyl-N,N-dimethyl- amino acetate, ethylacetate, azone, sodium dodecyl sulfate, d- limonene, oleic acid, 1,3-diphenyl-urea, N-methyl-2- pyrrolidone, beta-cyclodextrin, and dimethylsulfoxide. In some embodiments, the permeation enhancer is propylene glycol.

[0012] In some embodiments, the aqueous carrier is purified water. In some embodiments, the gel formulation comprises: about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt toabout 1.0 % wt / wt of an antimicrobial, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent, and an aqueous carrier to reach 100 % wt / wt. In some embodiments, the gel formulation comprises: about 0.10 % wt / wt to about 0.25 % wt / wt of citric acid monohydrate, about 0.25 % wt / wt to about 0.50 % wt / wt of sodium phosphate dibasic, about 0.05 % wt / wt to about 0.15 % wt / wt of disodium EDTA, about 0.5 % wt / wt to about 1.0 % wt / wt of boric acid, about 10.0 % wt / wt to about 25.0 % wt / wt of propylene glycol, about 1.0 % wt / wt to about 5.0 % wt / wt of glycerol, about 0.5 % wt / wt to about 5.0 % wt / wt of hydroxy ethylcellullose, and purified water to reach 100 % wt / wt. In some embodiments, the gel formulation comprises: 0.15 % wt / wt of citric acid monohydrate, 0.35 % wt / wt of sodium phosphate dibasic, 0.13 % wt / wt of di-sodium EDTA, 0.5 % wt / wt of boric acid, 15.0 % wt / wt of propylene glycol, 3.0 % wt / wt of glycerol, 1.5 % wt / wt of hydroxy ethylcellullose, and purified water to reach 100 % wt / wt.

[0013] In some embodiments, the second portion further comprises an alpha-adrenergic agent. In some embodiments, the alpha-adrenergic agent is selected from amidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrine, 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[l,2- a]imidazole, and A-61603 (N-[5-(4,5-dihydro-lH-imidazol-2-yl)-2- hydroxy-5,6,7,8- tetrahydronaphthalen-l-yl]methanesulfonamide), or a salt of any one thereof. In some embodiments, the alpha-adrenergic agent is oxymetazoline or a salt thereof. In some embodiments, the alpha-adrenergic agent is oxymetazoline hydrochloride (HC1). In some embodiments, the gel formulation further comprises about 0.10 % wt / wt to about 5.00 % wt / wt alpha-adrenergic agent. In some embodiments, the gel formulation comprises about 0.10 % wt / wt to about 5.00 % wt / wt oxymetazoline hydrochloride (HC1).

[0014] In some embodiments, the gel formulation comprises: about 0.10 % wt / wt to about 5.00 % wt / wt of an alpha-adrenergic agent, about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent and an aqueous carrier, to reach 100 % wt / wt.In some embodiments, the gel formulation comprises: about 2.0 % wt / wt oxymetazoline HC1, about 0.15 % wt / wt citric acid monohydrate, about 0.35 % wt / wt sodium phosphate dibasic, about 0.13 % wt / wt di-sodium EDTA, about 0.5 % wt / wt boric acid, about 15.0 % wt / wt propylene glycol, about 3.0 % wt / wt glycerol, about 1.5 % wt / wt hydroxyethylcellullose and purified water to reach 100 % wt / wt. In some embodiments, the gel formulation comprises: about 1.0 % wt / wt oxymetazoline HC1, about 0.15 % wt / wt citric acid monohydrate, about 0.35 % wt / wt sodium phosphate dibasic, about 0.13 % wt / wt di-sodium EDTA, about 0.5 % wt / wt boric acid, about 15.0 % wt / wt propylene glycol, about 3.0 % wt / wt glycerol, about 1.5 % wt / wt hydroxyethylcellullose, and purified water to reach 100 % wt / wt.

[0015] In some embodiments, the gel formulation comprises a viscosity of between about 4500 mPa.s to about 6500 mPa.s. In some embodiments, the gel formulation comprises a viscosity of between about 5500 mPa.s to about 6000 mPa.s. In some embodiments, the gel formulation comprises a pH of between about 5 to about 7. In some embodiments, the gel formulation comprises a pH of about 6. In some embodiments, the gel formulation comprises an acceptable USP pathogen count, wherein the pathogen is selected from P. aeruginosa, P. aureus, E.coli, A. brasiliensis, and C. albicans. In some embodiments, the acceptable USP pathogen count is identified using a USP<61> test or USP<62> test. In some embodiments, the acceptable USP pathogen count is less than 1000 CFU / g. In some embodiments, the acceptable USP pathogen count is about 1 CFU / g to about CFU / g 1000. In some embodiments, the acceptable USP pathogen count is about 10 CFU / g to about CFU / g 100.

[0016] The present disclosure provides a dermatological gel composition, comprising: about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent, and purified water to reach 100 % wt / wt.

[0017] The present disclosure provides a dermatological gel composition, consisting of about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial, about 10.0 % wt / wt to about 25.0 % wt / wt of an permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of an humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of an gelling agent; and purified water to reach 100 % wt / wt.

[0018] The present disclosure provides a dermatological gel composition, consisting of: about 0.5 % wt / wt to about 2.5 % wt / wt of an alpha adrenergic agent, about 0.10 % wt / wt toabout 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and purified water to reach 100 % wt / wt. In some embodiments, the dermatological composition consists of about 0.5 % wt / wt to about 1.5 % wt / wt of an alpha adrenergic agent, about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and purified water to reach 100 % wt / wt. In some embodiments, the dermatological composition consists of about 1.5 % wt / wt to about 2.5 % wt / wt of an alpha adrenergic agent, about 0.10 % wt / wt to about 2.00 % wt / wt a one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent, and purified water to reach 100 % wt / wt.

[0019] The present disclosure provides for a dermatological gel composition comprising about 0.5 % wt / wt to about 2.5 % wt / wt of an alpha adrenergic agent, about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent, and purified water to reach 100 % wt / wt.

[0020] In some embodiments, the dermatological gel composition has a viscosity of 4500 mPa.s to 6500 mPa.s measured at 25 °C. In some embodiments, the composition has a viscosity of 5500 mPa.s to about 6000 mPa.s measured at 25 °C. In some embodiments, the composition has a pathogen count of less than 1000 CFU / g as measured by a test selected from USP<61> and USP<62>. In some embodiments, the pathogen is selected from a bacteria, a virus, a fungus, or a combination thereof. In some embodiments, the pathogen is selected from a bacteria, a fungus, or a combination thereof. In some embodiments, the pathogen is selected from P. aeruginosa, P. aureus, E.coli, A. brasiliensis, and C. albicans, or a combination thereof.

[0021] In some embodiments, the dermatological gel composition has a pH from about 5.0 to about 7.0. In some embodiments, the composition has a pH of about 6.0. In some embodiments, the gelling agent is a polymer. In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), carbomer, hyaluronic acid, polycarbophil, carboxymethylcellulose (CMC), gellan gum, alginic acid, chitosan, dextran, polyethylene glycol, polypropylene glycol, polysorbate, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), and carboxymethylcellulose (CMC). In some embodiments, the polymer is hydroxy ethylcellulose.

[0022] In some embodiments, the one or more buffers is selected from 4- Morpholineethanesulfonic acid (MES), 2,2-Bis(hydroxymethyl)-2,2',2"-nitrilotriethanol (BisTris), N-(2-Acetamido)iminodiacetic acid (ADA), 2-[(2-Amino-2- oxoethyl)azaniumyl]ethanesulfonate (ACES), 1,4-Piperazinedi ethanesulfonic acid (PIPES), 3-Morpholino-2-hydroxypropanesulfonic acid (MOPSO), 1,3-Bis[tris(hydroxymethyl) methylamino]propane (Bis-Tris Propane), 2-(bis(2-hydroxyethyl)amino)ethane sulfonic acid (BES), 3-(N-Morpholino)propanesulfonic acid (MOPS), 2-[(2 -Hydroxy- 1,1- bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-Hydroxyethyl)piperazine-l- ethanesulfonic acid (HEPES), 4-(N-Morpholino)butanesulfonic acid (MOBS), N- [Tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropanesulfonic acid (TAPSO), Tris(hydroxymethyl)aminomethane (Tris), Piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) (POPSO), 4-(2 -Hydroxy ethyl)- 1 -piperazinepropanesulfonic acid (EPPS), N- [Tris(hydroxymethyl)methyl]glycine (Tricine), Diglycine (Gly-Gly), N,N-Bis(2- hydroxyethyl)glycine (Bicine), N-(2 -Hydroxy ethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS), N-[Tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid (TAPS), 2-Amino-2-methyl- 1,3 -propanediol (AMPD), N-(l,l-Dimethyl-2-hydroxyethyl)-3-amino-2- hydroxypropanesulfonic acid (AMPSO), 2-(Cyclohexylamino)ethanesulfonic acid (CHES),3 -(Cyclohexylamino)-2-hydroxy-l -propanesulfonic acid (CAPSO), 3-(Cyclohexylamino)-l- propanesulfonic acid (CAPS), 4-(Cyclohexylamino)-l -butanesulfonic acid (CABS), phosphoric acid, citric acid, acetic acid, carbonic acid, or a salt or hydrate of any one thereof. In some embodiments, the one or more buffers is selected from citric acid monohydrate, sodium phosphate dibasic, monosodium phosphate, sodium acetate, and sodium citrate.

[0023] In some embodiments, the antioxidant is selected from acetylcarnitine, acetylcysteine, allopurinol, amiloxate, ascorbic acid, butylated hydroxanisole (BHA),butylated bydroxytoluene (BHT), t-butyl hydroquinone (TBHQ), Beta-carotene, cholecalciferol, cysteine, dioxybenzone, Ethylenediaminetetraacetic acid (EDTA), erythorbic acid, etidronic acid, 4-hexylresorcinol, idebenone, lipoic acid, melatonin, methionine, niacinamide, pentaoxiflline, probucol, propyl gallate, retinol, selenious acid, sitosterol, and ubiquinone, or a salt of any one thereof. In some embodiments, the antioxidant is EDTA or a salt thereof. In some embodiments, the antioxidant is disodium EDTA.

[0024] In some embodiments, the antimicrobial is selected from antimicrobial is selected from a quaternary ammonium salt, boric acid, and a borate salt. In some embodiments, the antimicrobial is selected from benzalkonium chloride, polyquartenium-1 (PQ-1), polyquartenium-42 (PQ-42), polyquad, boric acid, and sodium borate. In some embodiments, the antimicrobial is boric acid.

[0025] In some embodiments, the humectant is selected from glycerol, urea, hyaluronic acid, sorbitol, propylene glycol, and hypromellose. In some embodiments, the humectant is glycerol.

[0026] In some embodiments, the permeation enhancer is selected from selected from alcohols, sulfoxides, azones, pyrrolidones, ureas, alkyl-N,N- disubstituted aminoacetals, propylene glycol, surfactants, terpenes, terpenoids, fatty acids, esters, and cyclodextrins. In some embodiments, the permeation enhancer is selected from ethanol, propylene glycol, dodecyl-N,N-dimethyl- amino acetate, ethylacetate, azone, sodium dodecyl sulfate, d- limonene, oleic acid, 1,3-diphenyl-urea, N-methyl-2- pyrrolidone, beta-cyclodextrin, and dimethylsulfoxide. In some embodiments, the permeation enhancer is propylene glycol.

[0027] In some embodiments, the alpha-adrenergic agent is selected from amidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrine, 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[l,2- a]imidazole, and A-61603 (N-[5-(4,5-dihydro-lH-imidazol-2-yl)-2- hydroxy-5,6,7,8- tetrahydronaphthalen-l-yl]methanesulfonamide), or a salt of any one thereof. In some embodiments, the alpha-adrenergic agent is oxymetazoline or a salt thereof. In some embodiments, the alpha-adrenergic agent is oxymetazoline hydrochloride (HC1).

[0028] In some embodiments, the dermatological gel composition comprises 0.15 % wt / wt of citric acid monohydrate, 0.35 % wt / wt of sodium phosphate dibasic, 0.13 % wt / wt of disodium EDTA, 0.5 % wt / wt of boric acid, 15.0 % wt / wt of propylene glycol, 3.0 % wt / wt of glycerol, 1.5 % wt / wt of hydroxy ethylcellullose; and purified water to reach 100 % wt / wt. In some embodiments, the dermatological gel composition consists of 0.15 % wt / wt of citric acid monohydrate, 0.35 % wt / wt of sodium phosphate dibasic, 0.13 % wt / wt of di-sodium EDTA, 0.5 % wt / wt of boric acid, 15.0 % wt / wt of propylene glycol, 3.0 % wt / wt of glycerol, 1.5 % wt / wt of hydroxy ethylcellullose, and purified water to reach 100 % wt / wt. In some embodiments, the dermatological gel composition consists of 2.0 % wt / wt oxymetazoline HC1, 0.15 % wt / wt citric acid monohydrate, 0.35 % wt / wt sodium phosphate dibasic, 0.13 % wt / wt di-sodium EDTA, 0.5 % wt / wt boric acid, 15.0 % wt / wt propylene glycol, 3.0 % wt / wt glycerol, 1.5 % wt / wt hydroxy ethylcellullose, and purified water to reach 100 % wt / wt. In some embodiments, the dermatological gel composition consists of 1.0 % wt / wt oxymetazoline HC1, 0.15 % wt / wt citric acid monohydrate, 0.35 % wt / wt sodium phosphate dibasic, 0.13 % wt / wt di-sodium EDTA, 0.5 % wt / wt boric acid, 15.0 % wt / wt propylene glycol, 3.0 % wt / wt glycerol, 1.5 % wt / wt hydroxyethylcellullose, and purified water to reach 100 % wt / wt. In some embodiments, the dermatological composition comprises 2.0 % wt / wt oxymetazoline HC1, 0.15 % wt / wt citric acid monohydrate, 0.35 % wt / wt sodium phosphate dibasic, 0.13 % wt / wt di-sodium EDTA, 0.5 % wt / wt boric acid, 15.0 % wt / wt propylene glycol, 3.0 % wt / wt glycerol, 1.5 % wt / wt hydroxyethylcellullose, and purified water to reach 100 % wt / wt. In some embodiments, the dermatological composition comprises 1.0 % wt / wt oxymetazoline HC1, 0.15 % wt / wt citric acid monohydrate, 0.35 % wt / wt sodium phosphate dibasic, 0.13 % wt / wt di-sodium EDTA, 0.5 % wt / wt boric acid, 15.0 % wt / wt propylene glycol, 3.0 % wt / wt glycerol, 1.5 % wt / wt hydroxyethylcellullose, and purified water to reach 100 % wt / wt.INCORPORATION BY REFERENCE

[0029] 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will beobtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0031] FIG. 1 illustrates a manufacturing overview for the production of the formulations of the present disclosure at a 250 kg scale.

[0032] FIG. 2 provides the analytical results, such as viscosity and pH, from the dumping samples produced in the 250 kg scale process described herein.DETAILED DESCRIPTION OF THE INVENTION

[0033] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0034] Definitions

[0035] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0036] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0037] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0038] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of thepresent disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 'H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0039] The term “in vivo” refers to an event that takes place in a subject’s body.

[0040] The term “in vitro” refers to an event that takes places outside of a subject’s body. For example, an in vitro assay encompasses any assay run outside of a subject. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[0041] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.

[0042] As described herein the products and intermediates synthesized can be analyzed using a variety of experimental techniques. For example, and not limited to, the method of elicitation can be Karl-fisher titration (KF), 'H-NMR,13C-NMR, Mass Spectroscopy (MS), liquid chromatography (LC), Elemental Analysis, Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-OES), X-ray powder diffraction (XPRD), Differential Scanning Calorimetry (DSC), Gas chromatography (GC), or Thermogravimetric Analysis (TGA).

[0043] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0044] “Pharmaceutically acceptable carrier”, “pharmaceutically acceptable diluent”, or “pharmaceutically acceptable excipient” each includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0045] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and / or cell migration. The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0046] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with theunderlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0047] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic 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, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0048] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0049] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0050] The term "about," as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11.

[0051] Whenever the term “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0052] Whenever the term “no more than,” “at most”, “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “at most”, “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0053] The terms “decreased” or “decrease,” as used herein, generally mean a decrease by a statistically significant amount. In some embodiments, “decreased” or “decrease” means a reduction by at least 10% as compared to a reference level, for example, a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g., absent level or non-detectable level as compared to a reference level), or any decrease from 10% to 100% as compared to a reference level. In the context of a marker or symptom, by these terms is meant a statistically significant decrease in such level. The decrease can be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more.

[0054] Terms such as “composition”, “gel formulation”, “dermatological gel composition”, “gel composition” are meant to describe products formed from the methods and processes described herein.

[0055] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0056] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.

[0057] The present disclosure provides methods of preparing gel formulations and uses thereof. In certain embodiments, the methods disclosed herein are large scale synthetic procedures to produce the gel formulations disclosed herein. In particular, the methods disclosed herein are used to produce sterile gel formulations.

[0058] Methods for Preparing a Gel Formulation

[0059] The present disclosure provides a method for preparing a gel formulation comprising (a) sterilizing a first portion, wherein the first portion comprises a gelling agent, and (b) filtering a second portion to remove submicron contaminants, wherein the second portion comprises an aqueous carrier, one or more buffers, an antioxidant, an antimicrobial, a humectant, and a penetration enhancer, and following step (a) and step (b), contacting the first portion with the second portion to produce the gel formulation.

[0060] In some embodiments, the sterilizing is heat sterilizing. In some embodiments, the sterilizing is UV light sterilizing. In some embodiments, the sterilizing is electromagnetic radiation sterilizing. In some embodiments, the method of sterilizing is one that produces an acceptable pathogen count under the USP<61> test or the USP<62> test. As used herein USP refers to the US Pharmacopeia.

[0061] In some embodiments, step (a) occurs at a temperature of at least 120 °C. In some embodiments, step (a) occurs at a temperature of between about 120 °C to about 200 °C. In some embodiments, step (a) occurs at a temperature of at most 200 °C. In some embodiments, step (a) occurs at a temperature of about 120 °C to about 200 °C. In some embodiments, step (a) occurs at a temperature of about 120 °C to about 130 °C, about 120 °C to about 140 °C, about 120 °C to about 150 °C, about 120 °C to about 160 °C, about 120 °C to about 170 °C, about 120 °C to about 180 °C, about 120 °C to about 190 °C, about 120 °C to about 200 °C, about 130 °C to about 140 °C, about 130 °C to about 150 °C, about 130 °C to about 160 °C, about 130 °C to about 170 °C, about 130 °C to about 180 °C, about 130 °C to about 190 °C, about 130 °C to about 200 °C, about 140 °C to about 150 °C, about 140 °C to about 160 °C, about 140 °C to about 170 °C, about 140 °C to about 180 °C, about 140 °C to about 190 °C, about 140 °C to about 200 °C, about 150 °C to about 160 °C, about 150 °C to about 170 °C, about 150 °C to about 180 °C, about 150 °C to about 190 °C, about 150 °C to about 200 °C, about 160 °C to about 170 °C, about 160 °C to about 180 °C, about 160 °C to about 190 °C, about 160 °C to about 200 °C, about 170 °C to about 180 °C, about 170 °C to about 190 °C, about 170 °C to about 200 °C, about 180 °C to about 190 °C, about 180 °C to about 200 °C, or about 190 °C to about 200 °C. In some embodiments, step (a) occurs at a temperature of about 120 °C, about 130 °C, about 140 °C, about 150 °C, about 160 °C, about 170 °C, about 180 °C, about 190 °C, or about 200 °C. In some embodiments, step (a) occurs at a temperature of at least about 120 °C, about 130 °C, about 140 °C, about 150 °C, about 160 °C, about 170 °C, about 180 °C, or about 190 °C. In some embodiments, step (a) occurs at a temperature of at most about 130 °C, about 140 °C, about 150 °C, about 160 °C, about 170 °C, about 180 °C, about 190 °C, or about 200 °C.

[0062] In some embodiments, the temperature applied during step (a) is between about 5 minutes to about 720 minutes. In some embodiments, the temperature applied during step (a) is about 5 min to about 60 min, about 5 min to about 120 min, about 5 min to about 180 min, about 5 min to about 240 min, about 5 min to about 300 min, about 5 min to about 360 min, about 5 min to about 420 min, about 5 min to about 480 min, about 5 min to about 540 min, about 5 min to about 600 min, about 5 min to about 660 min, about 60 min to about 120 min, about 60 min to about 180 min, about 60 min to about 240 min, about 60 min to about 300 min, about 60 min to about 360 min, about 60 min to about 420 min, about 60 min to about 480 min, about 60 min to about 540 min, about 60 min to about 600 min, about 60 min to about 660 min, about 120 min to about 180 min, about 120 min to about 240 min, about 120 min to about 300 min, about 120 min to about 360 min, about 120 min to about 420 min,about 120 min to about 480 min, about 120 min to about 540 min, about 120 min to about 600 min, about 120 min to about 660 min, about 180 min to about 240 min, about 180 min to about 300 min, about 180 min to about 360 min, about 180 min to about 420 min, about 180 min to about 480 min, about 180 min to about 540 min, about 180 min to about 600 min, about 180 min to about 660 min, about 240 min to about 300 min, about 240 min to about 360 min, about 240 min to about 420 min, about 240 min to about 480 min, about 240 min to about 540 min, about 240 min to about 600 min, about 240 min to about 660 min, about 300 min to about 360 min, about 300 min to about 420 min, about 300 min to about 480 min, about 300 min to about 540 min, about 300 min to about 600 min, about 300 min to about 660 min, about 360 min to about 420 min, about 360 min to about 480 min, about 360 min to about 540 min, about 360 min to about 600 min, about 360 min to about 660 min, about 420 min to about 480 min, about 420 min to about 540 min, about 420 min to about 600 min, about 420 min to about 660 min, about 480 min to about 540 min, about 480 min to about 600 min, about 480 min to about 660 min, about 540 min to about 600 min, about 540 min to about 660 min, or about 600 min to about 660 min. In some embodiments, the temperature applied during step (a) is about 5 min, about 60 min, about 120 min, about 180 min, about 240 min, about 300 min, about 360 min, about 420 min, about 480 min, about 540 min, about 600 min, about 660 min, or about 720 min. In some embodiments, the temperature applied during step (a) is at least about 5 min, about 60 min, about 120 min, about 180 min, about 240 min, about 300 min, about 360 min, about 420 min, about 480 min, about 540 min, about 600 min, or about 660 min, or about 720 min. In some embodiments, the temperature applied during step (a) is at most about 60 min, about 120 min, about 180 min, about 240 min, about 300 min, about 360 min, about 420 min, about 480 min, about 540 min, about 600 min, about 660 min, or about 720 min.

[0063] In some embodiments, the gelling agent is in solid form. In some embodiments, the gelling agent is a polymer. In some embodiments, the polymer is a homopolymer or a copolymer. In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), carbomer, hyaluronic acid, polycarbophil, carboxymethylcellulose (CMC), gellan gum, alginic acid, chitosan, dextran, polyethylene glycol, polypropylene glycol, polysorbate, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), and carboxymethylcellulose (CMC). In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose(HPMC), and hydroxyethylcellulose (HEC). In some embodiments, the polymer is hydroxyethylcellulose. In some embodiments, the polymer is hydroxypropyl cellulose. In some embodiments, the polymer is hydroxypropyl methylcellulose.

[0064] In some aspects, the present disclosure provides a method of minimizing submicron contaminants. In some embodiments, the submicron contaminants are microbial contaminants as described herein.

[0065] In some embodiments, the submicron contaminants are microbial contaminants. In some embodiments, the microbial contaminants are selected from bacteria, viruses, and fungi, or a combination thereof. In some embodiments, the microbial contaminants are selected from bacteria and fungi, or a combination thereof. In some embodiments, the microbial contaminants is bacteria. In some embodiments, the microbial contaminants is fungi. In some embodiments, the microbial contaminants is selected from P. aeruginosa, P. aureus, E.coli, A. brasiliensis, and C. albicans, or a combination thereof. In some embodiments, the microbial contaminants is P. aeruginosa. In some embodiments, the microbial contaminants is P. aureus. In some embodiments, the microbial contaminants is E.coli. In some embodiments, the microbial contaminants is A. brasiliensis. In some embodiments, the microbial contaminants is C. albicans.

[0066] In some embodiments, the filtering comprises at least one filter. In some embodiments, the filtering comprises at least two filters. In some embodiments, the at least one filter is a micron filter. In some embodiments, the micron filter has a filter size of between about 0.01 pm to about 0.5 pm. In some embodiments, the micron filter has a filter size of about 0.22 pm.

[0067] In some embodiments, the micron filter has a filter size of about 0.01 pm to about 0.6 pm. In some embodiments, the micron filter has a filter size of about 0.01 pm to about 0.05 pm, about 0.01 pm to about 0.1 pm, about 0.01 pm to about 0.2 pm, about 0.01 pm to about 0.3 pm, about 0.01 pm to about 0.4 pm, about 0.01 pm to about 0.5 pm, about 0.01 pm to about 0.6 pm, about 0.05 pm to about 0.1 pm, about 0.05 pm to about 0.2 pm, about 0.05 pm to about 0.3 pm, about 0.05 pm to about 0.4 pm, about 0.05 pm to about 0.5 pm, about 0.05 pm to about 0.6 pm, about 0.1 pm to about 0.2 pm, about 0.1 pm to about 0.3 pm, about 0.1 pm to about 0.4 pm, about 0.1 pm to about 0.5 pm, about 0.1 pm to about 0.6 pm, about 0.2 pm to about 0.3 pm, about 0.2 pm to about 0.4 pm, about 0.2 pm to about 0.5 pm, about 0.2 pm to about 0.6 pm, about 0.3 pm to about 0.4 pm, about 0.3 pm to about 0.5 pm, about 0.3 pm to about 0.6 pm, about 0.4 pm to about 0.5 pm, about 0.4 pm to about 0.6 pm, or about 0.5 pm to about 0.6 pm. In some embodiments, the micron filter has a filter size of about 0.01pm, about 0.05 pm, about 0.1 pm, about 0.2 pm, about 0.3 pm, about 0.4 pm, about 0.5 pm, or about 0.6 pm. In some embodiments, the micron filter has a filter size of at least about 0.01 pm, about 0.05 pm, about 0.1 pm, about 0.2 pm, about 0.3 pm, about 0.4 pm, or about 0.5 pm. In some embodiments, the micron filter has a filter size of at most about 0.05 pm, about 0.1 pm, about 0.2 pm, about 0.3 pm, about 0.4 pm, about 0.5 pm, or about 0.6 pm.

[0068] In some embodiments, the one or more buffers is selected from 4- Morpholineethanesulfonic acid (MES), 2,2-Bis(hydroxymethyl)-2,2',2"-nitrilotriethanol (BisTris), N-(2-Acetamido)iminodiacetic acid (ADA), 2-[(2-Amino-2- oxoethyl)azaniumyl]ethanesulfonate (ACES), 1,4-Piperazinedi ethanesulfonic acid (PIPES), 3-Morpholino-2-hydroxypropanesulfonic acid (MOPSO), 1,3-Bis[tris(hydroxymethyl) methylamino]propane (Bis-Tris Propane), 2-(bis(2-hydroxyethyl)amino)ethane sulfonic acid (BES), 3-(N-Morpholino)propanesulfonic acid (MOPS), 2-[(2 -Hydroxy- 1,1- bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-Hydroxyethyl)piperazine-l- ethanesulfonic acid (HEPES), 4-(N-Morpholino)butanesulfonic acid (MOBS), N- [Tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropanesulfonic acid (TAPSO), Tris(hydroxymethyl)aminomethane (Tris), Piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) (POPSO), 4-(2 -Hydroxy ethyl)- 1 -piperazinepropanesulfonic acid (EPPS), N- [Tris(hydroxymethyl)methyl]glycine (Tricine), Diglycine (Gly-Gly), N,N-Bis(2- hydroxyethyl)glycine (Bicine), N-(2 -Hydroxy ethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS), N-[Tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid (TAPS), 2-Amino-2-methyl- 1,3 -propanediol (AMPD), N-(l,l-Dimethyl-2-hydroxyethyl)-3-amino-2- hydroxypropanesulfonic acid (AMPSO), 2-(Cyclohexylamino)ethanesulfonic acid (CHES),3 -(Cyclohexylamino)-2-hydroxy-l -propanesulfonic acid (CAPSO), 3-(Cyclohexylamino)-l- propanesulfonic acid (CAPS), 4-(Cyclohexylamino)-l -butanesulfonic acid (CABS), phosphoric acid, citric acid, acetic acid, carbonic acid, or a salt or hydrate of any one thereof. In some embodiments, the one or more buffers is selected from 4-Morpholineethanesulfonic acid (MES), 2,2-Bis(hydroxymethyl)-2,2',2"-nitrilotriethanol (Bis-Tris), 4-(2- Hydroxyethyl)piperazine-1 -ethanesulfonic acid (HEPES), 4-(N-Morpholino)butanesulfonic acid (MOBS), Tri s(hydroxymethyl)aminom ethane (Tris), N- [Tris(hydroxymethyl)methyl]glycine (Tricine), Diglycine (Gly-Gly), N,N-Bis(2- hydroxyethyl)glycine (Bicine), N-(2 -Hydroxy ethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS), 2-(Cyclohexylamino)ethanesulfonic acid (CHES), 3-(Cyclohexylamino)-2- hydroxy-1 -propanesulfonic acid (CAPSO), phosphoric acid, citric acid, acetic acid, carbonic acid, or a salt or hydrate of any one thereof.

[0069] In some embodiments, the one or more buffers is selected from citric acid monohydrate, sodium phosphate dibasic, monosodium phosphate, sodium acetate, and sodium citrate. In some embodiments, the one or more buffers is selected from citric acid monohydrate and sodium phosphate dibasic.

[0070] In some embodiments, the antioxidant is selected from acetylcarnitine, acetylcysteine, allopurinol, amiloxate, ascorbic acid, butylated hydroxanisole (BHA),butylated bydroxytoluene (BHT), t-butyl hydroquinone (TBHQ), Beta-carotene, cholecalciferol, cysteine, dioxybenzone, Ethylenediaminetetraacetic acid (EDTA), erythorbic acid, etidronic acid, 4-hexylresorcinol, idebenone, lipoic acid, melatonin, methionine, niacinamide, pentaoxiflline, probucol, propyl gallate, retinol, selenious acid, sitosterol, and ubiquinone, or a salt of any one thereof. In some embodiments, the antioxidant is selected from ascorbic acid, Ethylenediaminetetraacetic acid (EDTA), erythorbic acid, etidronic acid, lipoic acid, selenious acid, or a salt of any one thereof. In some embodiments, the antioxidant is EDTA or a salt thereof. In some embodiments, the antioxidant is disodium EDTA.

[0071] In some embodiments, the antimicrobial is selected from a quaternary ammonium salts, boric acid, and a borate salt. In some embodiments, the antimicrobial is selected from benzalkonium chloride, polyquartenium-1 (PQ-1), polyquartenium-42 (PQ-42), poly quad, boric acid, and sodium borate. In some embodiments, the antimicrobial is boric acid. In some embodiments, the antimicrobial is benzalkonium chloride. In some embodiments, the antimicrobial is polyquartenium-1 (PQ-1). In some embodiments, the antimicrobial is polyquartenium-42 (PQ-42). In some embodiments, the antimicrobial is polyquad. In some embodiments, the antimicrobial is sodium borate.

[0072] In some embodiments, the humectant is selected from glycerol, urea, hyaluronic acid, sorbitol, propylene glycol, and hypromellose. In some embodiments, the humectant is selected from glycerol, propylene glycol, and hypromellose. In some embodiments, the humectant is glycerol. In some embodiments, the humectant is propylene glycol. In some embodiments, the humectant is hypromellose.

[0073] In some embodiments, the permeation enhancer is selected from selected from alcohols, sulfoxides, azones, pyrrolidones, ureas, alkyl-N,N- disubstituted aminoacetals, propylene glycol, surfactants, terpenes, terpenoids, fatty acids, esters, and cyclodextrins. In some embodiments, the permeation enhancer is selected from ethanol, propylene glycol, dodecyl-N,N-dimethyl- amino acetate, ethylacetate, azone, sodium dodecyl sulfate, d- limonene, oleic acid, 1,3-diphenyl-urea, N-methyl-2- pyrrolidone, beta-cyclodextrin, and dimethylsulfoxide. In some embodiments, the permeation enhancer is selected from ethanol,propylene glycol, d-limonene, oleic acid, 1,3-diphenyl-urea, N-methyl-2- pyrrolidone, betacyclodextrin, and dimethylsulfoxide. In some embodiments, the permeation enhancer is propylene glycol.

[0074] In some embodiments, the contacting occurs for between about 1 hour to about 48 hours. In some embodiments, the contacting occurs for about 1 hour to about 8 hours, about 1 hour to about 16 hours, about 1 hour to about 24 hours, about 1 hour to about 32 hours, about 1 hour to about 40 hours, about 1 hour to about 48 hours, about 8 hours to about 16 hours, about 8 hours to about 24 hours, about 8 hours to about 32 hours, about 8 hours to about 40 hours, about 8 hours to about 48 hours, about 16 hours to about 24 hours, about 16 hours to about 32 hours, about 16 hours to about 40 hours, about 16 hours to about 48 hours, about 24 hours to about 32 hours, about 24 hours to about 40 hours, about 24 hours to about 48 hours, about 32 hours to about 40 hours, about 32 hours to about 48 hours, or about 40 hours to about 48 hours. In some embodiments, the contacting occurs for about 1 hour, about 8 hours, about 16 hours, about 24 hours, about 32 hours, about 40 hours, or about 48 hours. In some embodiments, the contacting occurs for at least about 1 hour, about 8 hours, about 16 hours, about 24 hours, about 32 hours, or about 40 hours. In some embodiments, the contacting occurs for at most about 8 hours, about 16 hours, about 24 hours, about 32 hours, about 40 hours, or about 48 hours. In some embodiments, the contacting comprises mixing the first portion and second portion. In some embodiments, the mixing is for between about 4 hours to about 24 hours. In some embodiments, the mixing is for about 4 hours to about 8 hours, about 4 hours to about 12 hours, about 4 hours to about 16 hours, about 4 hours to about 20 hours, about 4 hours to about 24 hours, about 8 hours to about 12 hours, about 8 hours to about 16 hours, about 8 hours to about 20 hours, about 8 hours to about 24 hours, about 12 hours to about 16 hours, about 12 hours to about 20 hours, about 12 hours to about 24 hours, about 16 hours to about 20 hours, about 16 hours to about 24 hours, or about 20 hours to about 24 hours. In some embodiments, the mixing is for about 4 hours, about 8 hours, about 12 hours, about 16 hours, about 20 hours, or about 24 hours. In some embodiments, the mixing is for at least about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 20 hours. In some embodiments, the mixing is for at most about 8 hours, about 12 hours, about 16 hours, about 20 hours, or about 24 hours.

[0075] In some embodiments, the aqueous carrier is water. In some embodiments, the aqueous carrier is purified water. In some embodiments, the aqueous carrier is selected from saline, purified water, aqueous buffer, water and miscible solvent, and a combination of any one thereof.

[0076] In some embodiments, the gel formulation comprises: about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent, and an aqueous carrier to reach 100 % wt / wt.

[0077] In some embodiments, the gel formulation comprises about 0.10 % wt / wt to about 1.50 % wt / wt of one or more buffers, about 0.10 % wt / wt to about 1.00 % wt / wt of one or more buffers, about 0.10 % wt / wt to about 0.80 % wt / wt of one or more buffers, or about 0.10 % wt / wt to about 0.60 % wt / wt of one or more buffers.

[0078] In some embodiments, the gel formulation comprises about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.07 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.09 % wt / wt to about 0.15 % wt / wt of an antioxidant, or about 0.11 % wt / wt to about 0.15 % wt / wt of an antioxidant.

[0079] In some embodiments, the gel formulation comprises about 0.5 % wt / wt to about 0.9 % wt / wt of an antimicrobial, about 0.5 % wt / wt to about 0.8 % wt / wt of an antimicrobial, about 0.5 % wt / wt to about 0.7 % wt / wt of an antimicrobial, or about 0.5 % wt / wt to about 0.6 % wt / wt of an antimicrobial.

[0080] In some embodiments, the gel formulation comprises about 10.0 % wt / wt to about 22.0 % wt / wt of a permeation enhancer, about 10.0 % wt / wt to about 20.0 % wt / wt of a permeation enhancer, about 10.0 % wt / wt to about 18.0 % wt / wt of a permeation enhancer, about 10.0 % wt / wt to about 16.0 % wt / wt of a permeation enhancer, about 10.0 % wt / wt to about 15.0 % wt / wt of a permeation enhancer, about 15.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, or about 15.0 % wt / wt to about 20.0 % wt / wt of a permeation enhancer.

[0081] In some embodiments, the gel formulation comprises about 1.0 % wt / wt to about 4.0 % wt / wt of a humectant, about 1.0 % wt / wt to about 3.0 % wt / wt of a humectant, about 2.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 2.0 % wt / wt to about 4.0 % wt / wt of a humectant, or about 2.0 % wt / wt to about 3.0 % wt / wt of a humectant.

[0082] In some embodiments, the gel formulation comprises about 0.5 % wt / wt to about 4.0 % wt / wt of a gelling agent, about 0.5 % wt / wt to about 3.0 % wt / wt of a gelling agent, about 0.5 % wt / wt to about 2.5 % wt / wt of a gelling agent, about 0.5 % wt / wt to about 2.0 % wt / wt of a gelling agent, or about 1.0 % wt / wt to about 2.0 % wt / wt of a gelling agent.

[0083] In some embodiments, the gel formulation comprises: about 0.10 % wt / wt to about 0.25 % wt / wt of citric acid monohydrate, about 0.25 % wt / wt to about 0.50 % wt / wt ofsodium phosphate dibasic, about 0.05 % wt / wt to about 0.15 % wt / wt of disodium EDTA, about 0.5 % wt / wt to about 1.0 % wt / wt of boric acid, about 10.0 % wt / wt to about 25.0 % wt / wt of propylene glycol, about 1.0 % wt / wt to about 5.0 % wt / wt of glycerol, about 0.5 % wt / wt to about 5.0 % wt / wt of hydroxy ethylcellullose, and purified water to reach 100 % wt / wt.

[0084] In some embodiments, the gel formulation comprises about 0.10 % wt / wt to about 0.25 % wt / wt of citric acid monohydrate, about 0.10 % wt / wt to about 0.20 % wt / wt of citric acid monohydrate, or about 0.10 % wt / wt to about 0.15 % wt / wt of citric acid monohydrate. In some embodiments, the gel formulation comprises about 0.10 % wt / wt, about 0.11 % wt / wt, about 0.12 % wt / wt, about 0.13 % wt / wt, about 0.14 % wt / wt, about 0.15 % wt / wt, or about 0.16 % wt / wt of citric acid monohydrate. In some embodiments, the gel formulation comprises at least about 0.10 % wt / wt, about 0.11 % wt / wt, about 0.12 % wt / wt, about 0.13 % wt / wt, about 0.14 % wt / wt, or about 0.15 % wt / wt of citric acid monohydrate. In some embodiments, the gel formulation comprises at most about 0.11 % wt / wt, about 0.12 % wt / wt, about 0.13 % wt / wt, about 0.14 % wt / wt, about 0.15 % wt / wt, or about 0.16 % wt / wt of citric acid monohydrate.

[0085] In some embodiments, the gel formulation comprises about 0.25 % wt / wt to about 0.45 % wt / wt of sodium phosphate dibasic, about 0.25 % wt / wt to about 0.40 % wt / wt of sodium phosphate dibasic, about 0.25 % wt / wt to about 0.35 % wt / wt of sodium phosphate dibasic, or about 0.30 % wt / wt to about 0.35 % wt / wt of sodium phosphate dibasic. In some embodiments, the gel formulation comprises about 0.31 % wt / wt, about 0.32 % wt / wt, about 0.33 % wt / wt, about 0.34 % wt / wt, about 0.35 % wt / wt, or about 0.36 % wt / wt of sodium phosphate dibasic. In some embodiments, the gel formulation comprises at least about 0.31 % wt / wt, about 0.32 % wt / wt, about 0.33 % wt / wt, about 0.34 % wt / wt, or about 0.35 % wt / wt of sodium phosphate dibasic. In some embodiments, the gel formulation comprises at most about 0.32 % wt / wt, about 0.33 % wt / wt, about 0.34 % wt / wt, about 0.35 % wt / wt, or about 0.36 % wt / wt of sodium phosphate dibasic.

[0086] In some embodiments, the gel formulation comprises about 0.05 % wt / wt to about 0.15 % wt / wt of disodium EDTA, about 0.07 % wt / wt to about 0.15 % wt / wt of disodium EDTA, about 0.09 % wt / wt to about 0.15 % wt / wt of disodium EDTA, or about 0.11 % wt / wt to about 0.15 % wt / wt of disodium EDTA. In some embodiments, the gel formulation comprises about 0.10 % wt / wt, about 0.11 % wt / wt, about 0.12 % wt / wt, about 0.13 % wt / wt, about 0.14 % wt / wt, or about 0.15 % wt / wt of disodium EDTA. In some embodiments, the gel formulation comprises at least about 0.10 % wt / wt, about 0.11 % wt / wt, about 0.12 %wt / wt, about 0.13 % wt / wt, or about 0.14 % wt / wt of disodium EDTA. In some embodiments, the gel formulation comprises at most about 0.11 % wt / wt, about 0.12 % wt / wt, about 0.13 % wt / wt, about 0.14 % wt / wt, or about 0.15 % wt / wt of disodium EDTA.

[0087] In some embodiments, the gel formulation comprises about 0.5 % wt / wt to about 0.9 % wt / wt of boric acid, about 0.5 % wt / wt to about 0.8 % wt / wt of boric acid, about 0.5 % wt / wt to about 0.7 % wt / wt of boric acid, or about 0.5 % wt / wt to about 0.6 % wt / wt of boric acid. In some embodiments, the gel formulation comprises about 0.3 % wt / wt, about 0.4 % wt / wt, about 0.5 % wt / wt, about 0.6 % wt / wt, or about 0.7 % wt / wt of boric acid. In some embodiments, the gel formulation comprises at least about 0.3 % wt / wt, about 0.4 % wt / wt, about 0.5 % wt / wt, or about 0.6 % wt / wt of boric acid. In some embodiments, the gel formulation comprises at most about 0.4 % wt / wt, about 0.5 % wt / wt, about 0.6 % wt / wt, or about 0.7 % wt / wt of boric acid.

[0088] In some embodiments, the gel formulation comprises about 10.0 % wt / wt to about 22.0 % wt / wt of propylene glycol, about 10.0 % wt / wt to about 20.0 % wt / wt of propylene glycol, about 10.0 % wt / wt to about 18.0 % wt / wt of propylene glycol, about 10.0 % wt / wt to about 16.0 % wt / wt of propylene glycol, about 10.0 % wt / wt to about 15.0 % wt / wt of propylene glycol, about 15.0 % wt / wt to about 25.0 % wt / wt of propylene glycol, or about 15.0 % wt / wt to about 20.0 % wt / wt of propylene glycol. In some embodiments, the gel formulation comprises about 13 % wt / wt, about 14 % wt / wt, about 15 % wt / wt, about 16 % wt / wt, or about 17 % wt / wt of propylene glycol. In some embodiments, the gel formulation comprises at least about 13 % wt / wt, about 14 % wt / wt, about 15 % wt / wt, or about 16 % wt / wt of propylene glycol. In some embodiments, the gel formulation comprises at most about 14 % wt / wt, about 15 % wt / wt, about 16 % wt / wt, or about 17 % wt / wt of propylene glycol.

[0089] In some embodiments, the gel formulation comprises about 1.0 % wt / wt to about 4.0 % wt / wt of glycerol, about 1.0 % wt / wt to about 3.0 % wt / wt of glycerol, about 2.0 % wt / wt to about 5.0 % wt / wt of glycerol, about 2.0 % wt / wt to about 4.0 % wt / wt of glycerol, or about 2.0 % wt / wt to about 3.0 % wt / wt of glycerol. In some embodiments, the gel formulation comprises about 2.8 % wt / wt, about 2.9 % wt / wt, about 3 % wt / wt, about 3.1 % wt / wt, or about 3.2 % wt / wt of glycerol. In some embodiments, the gel formulation comprises at least about 2.8 % wt / wt, about 2.9 % wt / wt, about 3 % wt / wt, or about 3.1 % wt / wt of glycerol. In some embodiments, the gel formulation comprises at most about 2.9 % wt / wt, about 3 % wt / wt, about 3.1 % wt / wt, or about 3.2 % wt / wt of glycerol.

[0090] In some embodiments, the gel formulation comprises about 0.5 % wt / wt to about 4.0 % wt / wt of hydroxy ethylcellullose, about 0.5 % wt / wt to about 3.0 % wt / wt of hydroxyethylcellullose, about 0.5 % wt / wt to about 2.5 % wt / wt of hydroxy ethylcellullose, about 0.5 % wt / wt to about 2.0 % wt / wt of hydroxyethylcellullose, or about 1.0 % wt / wt to about 2.0 % wt / wt of hydroxyethylcellullose. In some embodiments, the gel formulation comprises about 1.2 % wt / wt, about 1.3 % wt / wt, about 1.4 % wt / wt, about 1.5 % wt / wt, about 1.6 % wt / wt, about 1.7 % wt / wt, or about 1.8 % wt / wt of hydroxyethylcellullose. In some embodiments, the gel formulation comprises at least about 1.2 % wt / wt, about 1.3 % wt / wt, about 1.4 % wt / wt, about 1.5 % wt / wt, about 1.6 % wt / wt, or about 1.7 % wt / wt of hydroxyethylcellullose. In some embodiments, the gel formulation comprises at most about 1.3 % wt / wt, about 1.4 % wt / wt, about 1.5 % wt / wt, about 1.6 % wt / wt, about 1.7 % wt / wt, or about 1.8 % wt / wt of hydroxyethylcellullose.

[0091] In some embodiments, the gel formulation comprises: about 0.15 % wt / wt of citric acid monohydrate, about 0.35 % wt / wt of sodium phosphate dibasic, about 0.13 % wt / wt of di-sodium EDTA, about 0.5 % wt / wt of boric acid, about 15.0 % wt / wt of propylene glycol, about 3.0 % wt / wt of glycerol, about 1.5 % wt / wt of hydroxyethylcellullose, and purified water to reach 100 % wt / wt.

[0092] In some embodiments, the gel formulation comprises: 0.15 % wt / wt of citric acid monohydrate, 0.35 % wt / wt of sodium phosphate dibasic, 0.13 % wt / wt of di-sodium EDTA, 0.5 % wt / wt of boric acid, 15.0 % wt / wt of propylene glycol, 3.0 % wt / wt of glycerol, 1.5 % wt / wt of hydroxyethylcellullose, and purified water to reach 100 % wt / wt.

[0093] In some embodiments, the second portion further comprises an alpha-adrenergic agent. In some embodiments, the alpha-adrenergic agent is selected from amidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrine, 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[l,2- a]imidazole, and A-61603 (N-[5-(4,5-dihydro-lH-imidazol-2-yl)-2- hydroxy-5,6,7,8- tetrahydronaphthalen-l-yl]methanesulfonamide), or a salt of any one thereof. In some embodiments, the alpha-adrenergic agent is selected from amidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrine, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5-fluronorepinephrine, 6-fluoronorepinephrine, indanidine, levonordefrin, methoxamine, midodrine, naphazoline, norepinephrine (noradrenaline), octopamine, oxymetazoline, phenylephrine, phenylpropanolamine, pseudoephedrine, synephrine, tetrahydrozoline, and xylometazoline, or a salt of any one thereof. In some embodiments, the alpha-adrenergic agent is selected from cirazoline, naphazoline, norepinephrine (noradrenaline), oxymetazoline, tetrahydrozoline, and xylometazoline, or a salt of any one thereof. In some embodiments, the alpha-adrenergic agent is oxymetazoline or a salt thereof. In some embodiments, the alpha-adrenergic agent is oxymetazoline hydrochloride (HC1).

[0094] In some embodiments, the gel formulation further comprises about 0.10 % wt / wt to about 5.00 % wt / wt alpha-adrenergic agent. In some embodiments, the gel formulation further comprises about 0.10 % wt / wt to about 4.00 % wt / wt, about 0.10 % wt / wt to about 3.00 % wt / wt, about 0.10 % wt / wt to about 2.50 % wt / wt, about 1.0 % wt / wt to about 4.00 % wt / wt, about 1.0 % wt / wt to about 3.00 % wt / wt, about 1.0 % wt / wt to about 2.50 % wt / wt, about 1.0 % wt / wt to about 2.0 % wt / wt alpha-adrenergic agent. In some embodiments, the gel formulation further comprises about 0.1 % wt / wt, about 0.5 % wt / wt, about 1 % wt / wt, about 1.5 % wt / wt, about 2 % wt / wt, about 2.5 % wt / wt, about 3 % wt / wt, about 3.5 % wt / wt, about 4 % wt / wt, about 4.5 % wt / wt, or about 5 % wt / wt alpha-adrenergic agent. In some embodiments, the gel formulation further comprises at least about 0.1 % wt / wt, about 0.5 % wt / wt, about 1 % wt / wt, about 1.5 % wt / wt, about 2 % wt / wt, about 2.5 % wt / wt, about 3 % wt / wt, about 3.5 % wt / wt, about 4 % wt / wt, or about 4.5 % wt / wt alpha-adrenergic agent. In some embodiments, the gel formulation further comprises at most about 0.5 % wt / wt, about 1 % wt / wt, about 1.5 % wt / wt, about 2 % wt / wt, about 2.5 % wt / wt, about 3 % wt / wt, about 3.5 % wt / wt, about 4 % wt / wt, about 4.5 % wt / wt, or about 5 % wt / wt alpha-adrenergic agent.

[0095] In some embodiments, the gel formulation comprises about 0.10 % wt / wt to about 5.00 % wt / wt oxymetazoline hydrochloride (HC1). In some embodiments, the gel formulation further comprises about 0.10 % wt / wt to about 4.00 % wt / wt, about 0.10 % wt / wt to about 3.00 % wt / wt, about 0.10 % wt / wt to about 2.50 % wt / wt, about 1.0 % wt / wt to about 4.00 % wt / wt, about 1.0 % wt / wt to about 3.00 % wt / wt, about 1.0 % wt / wt to about 2.50 % wt / wt, about 1.0 % wt / wt to about 2.0 % wt / wt oxymetazoline HC1. In some embodiments, the gel formulation further comprises about 0.1 % wt / wt, about 0.5 % wt / wt, about 1 % wt / wt, about 1.5 % wt / wt, about 2 % wt / wt, about 2.5 % wt / wt, about 3 % wt / wt, about 3.5 % wt / wt, about 4 % wt / wt, about 4.5 % wt / wt, or about 5 % wt / wt oxymetazoline HC1. In some embodiments, the gel formulation further comprises at least about 0.1 % wt / wt, about 0.5 % wt / wt, about 1 % wt / wt, about 1.5 % wt / wt, about 2 % wt / wt, about 2.5 % wt / wt, about 3 %wt / wt, about 3.5 % wt / wt, about 4 % wt / wt, or about 4.5 % wt / wt oxymetazoline HC1. In some embodiments, the gel formulation further comprises at most about 0.5 % wt / wt, about 1 % wt / wt, about 1.5 % wt / wt, about 2 % wt / wt, about 2.5 % wt / wt, about 3 % wt / wt, about 3.5 % wt / wt, about 4 % wt / wt, about 4.5 % wt / wt, or about 5 % wt / wt oxymetazoline HC1.

[0096] In some embodiments, the gel formulation comprises: about 0.10 % wt / wt to about 5.00 % wt / wt of an alpha-adrenergic agent, about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent and an aqueous carrier, to reach 100 % wt / wt.

[0097] In some embodiments, the gel formulation comprises: about 2.0 % wt / wt oxymetazoline HC1, about 0.15 % wt / wt citric acid monohydrate, about 0.35 % wt / wt sodium phosphate dibasic, about 0.13 % wt / wt di-sodium EDTA, about 0.5 % wt / wt boric acid, about 15.0 % wt / wt propylene glycol, about 3.0 % wt / wt glycerol, about 1.5 % wt / wt hydroxy ethylcellullose and purified water to reach 100 % wt / wt.

[0098] In some embodiments, the gel formulation comprises: about 1.0 % wt / wt oxymetazoline HC1, about 0.15 % wt / wt citric acid monohydrate, about 0.35 % wt / wt sodium phosphate dibasic, about 0.13 % wt / wt di-sodium EDTA, about 0.5 % wt / wt boric acid, about 15.0 % wt / wt propylene glycol, about 3.0 % wt / wt glycerol, about 1.5 % wt / wt hydroxy ethylcellullose, and purified water to reach 100 % wt / wt.

[0099] In some embodiments, the gel formulation comprises a viscosity of between about 4500 mPa.s to about 6500 mPa.s. In some embodiments, the composition has a viscosity of about 4,500 mPa.s to about 6,750 mPa.s measured at 25 °C. In some embodiments, the gel formulation has a viscosity of about 4,500 mPa.s to about 4,750 mPa.s, about 4,500 mPa.s to about 5,000 mPa.s, about 4,500 mPa.s to about 5,250 mPa.s, about 4,500 mPa.s to about 5,500 mPa.s, about 4,500 mPa.s to about 5,750 mPa.s, about 4,500 mPa.s to about 6,000 mPa.s, about 4,500 mPa.s to about 6,250 mPa.s, about 4,500 mPa.s to about 6,500 mPa.s, about 4,500 mPa.s to about 6,750 mPa.s, about 4,750 mPa.s to about 5,000 mPa.s, about4.750 mPa.s to about 5,250 mPa.s, about 4,750 mPa.s to about 5,500 mPa.s, about 4,750 mPa.s to about 5,750 mPa.s, about 4,750 mPa.s to about 6,000 mPa.s, about 4,750 mPa.s to about 6,250 mPa.s, about 4,750 mPa.s to about 6,500 mPa.s, about 4,750 mPa.s to about6.750 mPa.s, about 5,000 mPa.s to about 5,250 mPa.s, about 5,000 mPa.s to about 5,500 mPa.s, about 5,000 mPa.s to about 5,750 mPa.s, about 5,000 mPa.s to about 6,000 mPa.s, about 5,000 mPa.s to about 6,250 mPa.s, about 5,000 mPa.s to about 6,500 mPa.s, about5,000 mPa.s to about 6,750 mPa.s, about 5,250 mPa.s to about 5,500 mPa.s, about 5,250 mPa.s to about 5,750 mPa.s, about 5,250 mPa.s to about 6,000 mPa.s, about 5,250 mPa.s to about 6,250 mPa.s, about 5,250 mPa.s to about 6,500 mPa.s, about 5,250 mPa.s to about6.750 mPa.s, about 5,500 mPa.s to about 5,750 mPa.s, about 5,500 mPa.s to about 6,000 mPa.s, about 5,500 mPa.s to about 6,250 mPa.s, about 5,500 mPa.s to about 6,500 mPa.s, about 5,500 mPa.s to about 6,750 mPa.s, about 5,750 mPa.s to about 6,000 mPa.s, about5.750 mPa.s to about 6,250 mPa.s, about 5,750 mPa.s to about 6,500 mPa.s, about 5,750 mPa.s to about 6,750 mPa.s, about 6,000 mPa.s to about 6,250 mPa.s, about 6,000 mPa.s to about 6,500 mPa.s, about 6,000 mPa.s to about 6,750 mPa.s, about 6,250 mPa.s to about6.500 mPa.s, about 6,250 mPa.s to about 6,750 mPa.s, or about 6,500 mPa.s to about 6,750 mPa.s measured at 25 °C. In some embodiments, the gel formulation has a viscosity of about4.500 mPa.s, about 4,750 mPa.s, about 5,000 mPa.s, about 5,250 mPa.s, about 5,500 mPa.s, about 5,750 mPa.s, about 6,000 mPa.s, about 6,250 mPa.s, about 6,500 mPa.s, or about 6,750 mPa.s measured at 25 °C. In some embodiments, the gel formulation has a viscosity of at least about 4,500 mPa.s, about 4,750 mPa.s, about 5,000 mPa.s, about 5,250 mPa.s, about5.500 mPa.s, about 5,750 mPa.s, about 6,000 mPa.s, about 6,250 mPa.s, or about 6,500 mPa.s measured at 25 °C. In some embodiments, the gel formulation has a viscosity of at most about 4,750 mPa.s, about 5,000 mPa.s, about 5,250 mPa.s, about 5,500 mPa.s, about 5,750 mPa.s, about 6,000 mPa.s, about 6,250 mPa.s, about 6,500 mPa.s, or about 6,750 mPa.s measured at 25 °C.

[0100] In some embodiments, the gel formulation comprises a viscosity of between about 5500 mPa.s to about 6000 mPa.s. In some embodiments, the gel formulation has a viscosity of about 5,500 mPa.s to about 5,600 mPa.s, about 5,500 mPa.s to about 5,700 mPa.s, about5,500 mPa.s to about 5,800 mPa.s, about 5,500 mPa.s to about 5,900 mPa.s, about 5,500 mPa.s to about 6,000 mPa.s, about 5,600 mPa.s to about 5,700 mPa.s, about 5,600 mPa.s to about 5,800 mPa.s, about 5,600 mPa.s to about 5,900 mPa.s, about 5,600 mPa.s to about 6,000 mPa.s, about 5,700 mPa.s to about 5,800 mPa.s, about 5,700 mPa.s to about 5,900 mPa.s, about 5,700 mPa.s to about 6,000 mPa.s, about 5,800 mPa.s to about 5,900 mPa.s, about 5,800 mPa.s to about 6,000 mPa.s, or about 5,900 mPa.s to about 6,000 mPa.s measured at 25 °C. In some embodiments, the gel formulation has a viscosity of about 5,500 mPa.s, about 5,600 mPa.s, about 5,700 mPa.s, about 5,800 mPa.s, about 5,900 mPa.s, or about 6,000 mPa.s measured at 25 °C. In some embodiments, the gel formulation has a viscosity of at least about 5,500 mPa.s, about 5,600 mPa.s, about 5,700 mPa.s, about 5,800 mPa.s, or about 5,900 mPa.s measured at 25 °C. In some embodiments, the gel formulationhas a viscosity of at most about 5,600 mPa.s, about 5,700 mPa.s, about 5,800 mPa.s, about 5,900 mPa.s, or about 6,000 mPa.s measured at 25 °C.

[0101] In some embodiments, the gel formulation comprises a pH of between about 5 to about 7. In some embodiments, the gel formulation comprises a pH of about 6. In some embodiments, the gel formulation has a pH from about 5 to about 7.2. In some embodiments, the gel formulation has a pH from about 5 to about 5.2, about 5 to about 5.4, about 5 to about 5.6, about 5 to about 5.8, about 5 to about 6, about 5 to about 6.2, about 5 to about 6.4, about 5 to about 6.6, about 5 to about 6.8, about 5 to about 7, about 5 to about 7.2, about 5.2 to about 5.4, about 5.2 to about 5.6, about 5.2 to about 5.8, about 5.2 to about 6, about 5.2 to about 6.2, about 5.2 to about 6.4, about 5.2 to about 6.6, about 5.2 to about 6.8, about 5.2 to about 7, about 5.2 to about 7.2, about 5.4 to about 5.6, about 5.4 to about 5.8, about 5.4 to about 6, about 5.4 to about 6.2, about 5.4 to about 6.4, about 5.4 to about 6.6, about 5.4 to about 6.8, about 5.4 to about 7, about 5.4 to about 7.2, about 5.6 to about 5.8, about 5.6 to about 6, about 5.6 to about 6.2, about 5.6 to about 6.4, about 5.6 to about 6.6, about 5.6 to about 6.8, about 5.6 to about 7, about 5.6 to about 7.2, about 5.8 to about 6, about 5.8 to about6.2, about 5.8 to about 6.4, about 5.8 to about 6.6, about 5.8 to about 6.8, about 5.8 to about 7, about 5.8 to about 7.2, about 6 to about 6.2, about 6 to about 6.4, about 6 to about 6.6, about 6 to about 6.8, about 6 to about 7, about 6 to about 7.2, about 6.2 to about 6.4, about 6.2 to about 6.6, about 6.2 to about 6.8, about 6.2 to about 7, about 6.2 to about 7.2, about 6.4 to about 6.6, about 6.4 to about 6.8, about 6.4 to about 7, about 6.4 to about 7.2, about 6.6 to about 6.8, about 6.6 to about 7, about 6.6 to about 7.2, about 6.8 to about 7, about 6.8 to about7.2, or about 7 to about 7.2. In some embodiments, the gel formulation has a pH from about 5, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 6, about6.2, about 6.4, about 6.6, about 6.8, about 7, or about 7.2. In some embodiments, the gel formulation has a pH from at least about 5, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 6, about 6.2, about 6.4, about 6.6, about 6.8, or about 7. In some embodiments, the gel formulation has a pH from at most about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 6, about 6.2, about 6.4, about 6.6, about 6.8, about 7, or about 7.2.In some embodiments, the gel formulation comprises an acceptable USP pathogen count, wherein the pathogen is selected from P. aeruginosa, P. aureus, E.coli, A. brasiliensis, and C. albicans. In some embodiments, the acceptable USP pathogen count is identified using a USP<61> test or a USP<62> test. In some embodiments, the acceptable USP pathogen count is identified using a USP<61> test. In some embodiments, the acceptable USP pathogencount is identified using a USP<62> test. In some embodiments, the acceptable USP pathogen count is less than 1000 CFU / g. In some embodiments, the acceptable USP pathogen count is less than about 950 CFU / g, 900 CFU / g, 850 CFU / g, 800 CFU / g, 750 CFU / g, 700 CFU / g, 650 CFU / g, 600 CFU / g, 550 CFU / g, 500 CFU / g, 450 CFU / g, 400 CFU / g, 350 CFU / g, 300 CFU / g, 250 CFU / g, 200 CFU / g, 150 CFU / g, or 100 CFU / g. In some embodiments, the acceptable USP pathogen count is about 1 CFU / g to about 1000 CFU / g. In some embodiments, the acceptable USP pathogen count is about 10 CFU / g to about 100 CFU / g. In some embodiments, the acceptable USP pathogen count is about 1 CFU / g to about 10 CFU / g, about 1 CFU / g to about 100 CFU / g, about 1 CFU / g to about 250 CFU / g, about 1 CFU / g to about 500 CFU / g, about 1 CFU / g to about 750 CFU / g, about 1 CFU / g to about 1,000 CFU / g, about 10 CFU / g to about 100 CFU / g, about 10 CFU / g to about 250 CFU / g, about 10 CFU / g to about 500 CFU / g, about 10 CFU / g to about 750 CFU / g, about 10 CFU / g to about 1,000 CFU / g, about 100 CFU / g to about 250 CFU / g, about 100 CFU / g to about 500 CFU / g, about 100 CFU / g to about 750 CFU / g, about 100 CFU / g to about 1,000 CFU / g, about 250 CFU / g to about 500 CFU / g, about 250 CFU / g to about 750 CFU / g, about 250 CFU / g to about 1,000 CFU / g, about 500 CFU / g to about 750 CFU / g, about 500 CFU / g to about 1,000 CFU / g, or about 750 CFU / g to about 1,000 CFU / g. In some embodiments, the acceptable USP pathogen count is about 1 CFU / g, about 10 CFU / g, about 100 CFU / g, about 250 CFU / g, about 500 CFU / g, about 750 CFU / g, or about 1,000 CFU / g.

[0102] Dermatological Gel Composition

[0103] In certain aspects, the present disclosure provides dermatological gel composition. In some embodiments, the dermatological gel composition is produced using the methods described herein. The present disclosure provides a dermatological gel composition, comprising: about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent, and purified water to reach 100 % wt / wt.

[0104] In some embodiments, the dermatological gel composition comprises about 0.10 % wt / wt to about 1.50 % wt / wt of one or more buffers, about 0.10 % wt / wt to about 1.00 % wt / wt of one or more buffers, about 0.10 % wt / wt to about 0.80 % wt / wt of one or more buffers, or about 0.10 % wt / wt to about 0.60 % wt / wt of one or more buffers.

[0105] In some embodiments, the dermatological gel composition comprises about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.07 % wt / wt to about 0.15 % wt / wt ofan antioxidant, about 0.09 % wt / wt to about 0.15 % wt / wt of an antioxidant, or about 0.11 % wt / wt to about 0.15 % wt / wt of an antioxidant.

[0106] In some embodiments, the dermatological gel composition comprises about 0.5 % wt / wt to about 0.9 % wt / wt of an antimicrobial, about 0.5 % wt / wt to about 0.8 % wt / wt of an antimicrobial, about 0.5 % wt / wt to about 0.7 % wt / wt of an antimicrobial, or about 0.5 % wt / wt to about 0.6 % wt / wt of an antimicrobial.

[0107] In some embodiments, the dermatological gel composition comprises about 10.0 % wt / wt to about 22.0 % wt / wt of a permeation enhancer, about 10.0 % wt / wt to about 20.0 % wt / wt of a permeation enhancer, about 10.0 % wt / wt to about 18.0 % wt / wt of a permeation enhancer, about 10.0 % wt / wt to about 16.0 % wt / wt of a permeation enhancer, about 10.0 % wt / wt to about 15.0 % wt / wt of a permeation enhancer, about 15.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, or about 15.0 % wt / wt to about 20.0 % wt / wt of a permeation enhancer.

[0108] In some embodiments, the dermatological gel composition comprises about 1.0 % wt / wt to about 4.0 % wt / wt of a humectant, about 1.0 % wt / wt to about 3.0 % wt / wt of a humectant, about 2.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 2.0 % wt / wt to about 4.0 % wt / wt of a humectant, or about 2.0 % wt / wt to about 3.0 % wt / wt of a humectant.

[0109] In some embodiments, the dermatological gel composition comprises about 0.5 % wt / wt to about 4.0 % wt / wt of a gelling agent, about 0.5 % wt / wt to about 3.0 % wt / wt of a gelling agent, about 0.5 % wt / wt to about 2.5 % wt / wt of a gelling agent, about 0.5 % wt / wt to about 2.0 % wt / wt of a gelling agent, or about 1.0 % wt / wt to about 2.0 % wt / wt of a gelling agent.

[0110] The present disclosure provides a dermatological gel composition, consisting of about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial, about 10.0 % wt / wt to about 25.0 % wt / wt of an permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of an humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of an gelling agent, and purified water to reach 100 % wt / wt.[OHl] The present disclosure provides a dermatological gel composition, consisting of: about 0.5 % wt / wt to about 2.5 % wt / wt of an alpha adrenergic agent, about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 %wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent, and purified water to reach 100 % wt / wt.

[0112] In some embodiments, the dermatological composition comprises about 0.50 % wt / wt to about 2.00 % wt / wt, about 0.50 % wt / wt to about 1.50 % wt / wt, about 1.0 % wt / wt to about 2.50 % wt / wt, about 1.0 % wt / wt to about 2.0 % wt / wt, or about 1.0 % wt / wt to about1.5 % wt / wt of an alpha-adrenergic agent. In some embodiments, the dermatological composition comprises about 0.8 % wt / wt, about 0.9 % wt / wt, about 1 % wt / wt, about 1.1 % wt / wt, about 1.2 % wt / wt, about 1.3 % wt / wt, about 1.4 % wt / wt, about 1.5 % wt / wt, about1.6 % wt / wt, about 1.7 % wt / wt, about 1.8 % wt / wt, about 1.9 % wt / wt, about 2.0 % wt / wt, about 2.1 % wt / wt, about 2.2 % wt / wt, about 2.3 % wt / wt, or about 2.4 % wt / wt of an alpha- adrenergic agent. In some embodiments, the dermatological composition comprises at least about 0.8 % wt / wt, about 0.9 % wt / wt, about 1 % wt / wt, about 1.1 % wt / wt, about 1.2 % wt / wt, about 1.3 % wt / wt, about 1.4 % wt / wt, about 1.5 % wt / wt, about 1.6 % wt / wt, about1.7 % wt / wt, about 1.8 % wt / wt, about 1.9 % wt / wt, about 2 % wt / wt, about 2.1 % wt / wt, about 2.2 % wt / wt, about 2.3 % wt / wt, or about 2.4 % wt / wt of an alpha-adrenergic agent. In some embodiments, the dermatological composition comprises at most about 0.9 % wt / wt, about 1 % wt / wt, about 1.1 % wt / wt, about 1.2 % wt / wt, about 1.3 % wt / wt, about 1.4 % wt / wt, about 1.5 % wt / wt, about 1.6 % wt / wt, about 1.7 % wt / wt, about 1.8 % wt / wt, about 1.9 % wt / wt, about 2 % wt / wt, about 2.1 % wt / wt, about 2.2 % wt / wt, about 2.3 % wt / wt, or about 2.4 % wt / wt of an alpha-adrenergic agent.

[0113] In some embodiments, the dermatological composition consists of about 0.5 % wt / wt to about 1.5 % wt / wt of an alpha adrenergic agent, about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and purified water to reach 100 % wt / wt.

[0114] In some embodiments, the dermatological composition consists of about 1.5 % wt / wt to about 2.5 % wt / wt of an alpha adrenergic agent, about 0.10 % wt / wt to about 2.00 % wt / wt a one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent, and purified water to reach 100 % wt / wt.

[0115] The present disclosure provides for a dermatological gel composition comprising about 0.5 % wt / wt to about 2.5 % wt / wt of an alpha adrenergic agent, about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers, about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant, about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent, about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer, about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant, about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent, and purified water to reach 100 % wt / wt.

[0116] In some embodiments, the dermatological composition has a viscosity of 4500 mPa.s to 6500 mPa.s measured at 25 °C. In some embodiments, the composition has a viscosity of about 4,500 mPa.s to about 6,750 mPa.s measured at 25 °C. In some embodiments, the composition has a viscosity of about 4,500 mPa.s to about 4,750 mPa.s, about 4,500 mPa.s to about 5,000 mPa.s, about 4,500 mPa.s to about 5,250 mPa.s, about 4,500 mPa.s to about5.500 mPa.s, about 4,500 mPa.s to about 5,750 mPa.s, about 4,500 mPa.s to about 6,000 mPa.s, about 4,500 mPa.s to about 6,250 mPa.s, about 4,500 mPa.s to about 6,500 mPa.s, about 4,500 mPa.s to about 6,750 mPa.s, about 4,750 mPa.s to about 5,000 mPa.s, about4.750 mPa.s to about 5,250 mPa.s, about 4,750 mPa.s to about 5,500 mPa.s, about 4,750 mPa.s to about 5,750 mPa.s, about 4,750 mPa.s to about 6,000 mPa.s, about 4,750 mPa.s to about 6,250 mPa.s, about 4,750 mPa.s to about 6,500 mPa.s, about 4,750 mPa.s to about6.750 mPa.s, about 5,000 mPa.s to about 5,250 mPa.s, about 5,000 mPa.s to about 5,500 mPa.s, about 5,000 mPa.s to about 5,750 mPa.s, about 5,000 mPa.s to about 6,000 mPa.s, about 5,000 mPa.s to about 6,250 mPa.s, about 5,000 mPa.s to about 6,500 mPa.s, about 5,000 mPa.s to about 6,750 mPa.s, about 5,250 mPa.s to about 5,500 mPa.s, about 5,250 mPa.s to about 5,750 mPa.s, about 5,250 mPa.s to about 6,000 mPa.s, about 5,250 mPa.s to about 6,250 mPa.s, about 5,250 mPa.s to about 6,500 mPa.s, about 5,250 mPa.s to about6.750 mPa.s, about 5,500 mPa.s to about 5,750 mPa.s, about 5,500 mPa.s to about 6,000 mPa.s, about 5,500 mPa.s to about 6,250 mPa.s, about 5,500 mPa.s to about 6,500 mPa.s, about 5,500 mPa.s to about 6,750 mPa.s, about 5,750 mPa.s to about 6,000 mPa.s, about5.750 mPa.s to about 6,250 mPa.s, about 5,750 mPa.s to about 6,500 mPa.s, about 5,750 mPa.s to about 6,750 mPa.s, about 6,000 mPa.s to about 6,250 mPa.s, about 6,000 mPa.s to about 6,500 mPa.s, about 6,000 mPa.s to about 6,750 mPa.s, about 6,250 mPa.s to about6.500 mPa.s, about 6,250 mPa.s to about 6,750 mPa.s, or about 6,500 mPa.s to about 6,750 mPa.s measured at 25 °C. In some embodiments, the dermatological composition has a viscosity of about 4,500 mPa.s, about 4,750 mPa.s, about 5,000 mPa.s, about 5,250 mPa.s, about 5,500 mPa.s, about 5,750 mPa.s, about 6,000 mPa.s, about 6,250 mPa.s, about 6,500mPa.s, or about 6,750 mPa.s measured at 25 °C. In some embodiments, the dermatological composition has a viscosity of at least about 4,500 mPa.s, about 4,750 mPa.s, about 5,000 mPa.s, about 5,250 mPa.s, about 5,500 mPa.s, about 5,750 mPa.s, about 6,000 mPa.s, about 6,250 mPa.s, or about 6,500 mPa.s measured at 25 °C. In some embodiments, the composition has a viscosity of at most about 4,750 mPa.s, about 5,000 mPa.s, about 5,250 mPa.s, about 5,500 mPa.s, about 5,750 mPa.s, about 6,000 mPa.s, about 6,250 mPa.s, about 6,500 mPa.s, or about 6,750 mPa.s measured at 25 °C.

[0117] In some embodiments, the dermatological composition has a viscosity of 5500 mPa.s to about 6000 mPa.s measured at 25 °C. In some embodiments, the dermatological composition has a viscosity of about 5,500 mPa.s to about 5,600 mPa.s, about 5,500 mPa.s to about 5,700 mPa.s, about 5,500 mPa.s to about 5,800 mPa.s, about 5,500 mPa.s to about 5,900 mPa.s, about 5,500 mPa.s to about 6,000 mPa.s, about 5,600 mPa.s to about 5,700 mPa.s, about 5,600 mPa.s to about 5,800 mPa.s, about 5,600 mPa.s to about 5,900 mPa.s, about 5,600 mPa.s to about 6,000 mPa.s, about 5,700 mPa.s to about 5,800 mPa.s, about 5,700 mPa.s to about 5,900 mPa.s, about 5,700 mPa.s to about 6,000 mPa.s, about 5,800 mPa.s to about 5,900 mPa.s, about 5,800 mPa.s to about 6,000 mPa.s, or about 5,900 mPa.s to about 6,000 mPa.s measured at 25 °C. In some embodiments, the dermatological composition has a viscosity of about 5,500 mPa.s, about 5,600 mPa.s, about 5,700 mPa.s, about 5,800 mPa.s, about 5,900 mPa.s, or about 6,000 mPa.s measured at 25 °C. In some embodiments, the dermatological composition has a viscosity of at least about 5,500 mPa.s, about 5,600 mPa.s, about 5,700 mPa.s, about 5,800 mPa.s, or about 5,900 mPa.s measured at 25 °C. In some embodiments, the dermatological composition has a viscosity of at most about 5,600 mPa.s, about 5,700 mPa.s, about 5,800 mPa.s, about 5,900 mPa.s, or about 6,000 mPa.s measured at 25 °C.

[0118] In some embodiments, the dermatological composition has a pathogen count of less than 1000 CFU / g as measured by a test selected from USP<61> and USP<62>. In some embodiments, the dermatological composition has a pathogen count of less than 950 CFU / g, 900 CFU / g, 850 CFU / g, 800 CFU / g, 750 CFU / g, 700 CFU / g, 650 CFU / g, 600 CFU / g, 550 CFU / g, or 500 CFU / g as measured by a test selected from USP<61> and USP<62>.

[0119] In some embodiments, the pathogen is selected from a bacteria, a virus, a fungus, and a combination thereof. In some embodiments, the pathogen is selected from a bacteria, a fungus, and a combination thereof. In some embodiments, the pathogen is a bacteria. In some embodiments, the pathogen is a fungus. In some embodiments, the pathogen is selected from P. aeruginosa, P. aureus, E.coli, A. brasiliensis, C. albicans, and a combination thereof. Insome embodiments, the pathogen is P. aeruginosa. In some embodiments, the pathogen is P. aureus, E.coli. In some embodiments, the pathogen is A. brasiliensis. In some embodiments, the pathogen is C. albicans.

[0120] In some embodiments, the composition has a pH from about 5.0 to about 7.0. In some embodiments, the pathogen in the pathogen count is selected from a bacteria, a virus, a fungus, and a combination thereof.

[0121] embodiments, the composition has a pH of about 6.0. In some embodiments, the composition has a pH from about 5 to about 7.2. In some embodiments, the composition has a pH from about 5 to about 5.2, about 5 to about 5.4, about 5 to about 5.6, about 5 to about 5.8, about 5 to about 6, about 5 to about 6.2, about 5 to about 6.4, about 5 to about 6.6, about 5 to about 6.8, about 5 to about 7, about 5 to about 7.2, about 5.2 to about 5.4, about 5.2 to about 5.6, about 5.2 to about 5.8, about 5.2 to about 6, about 5.2 to about 6.2, about 5.2 to about 6.4, about 5.2 to about 6.6, about 5.2 to about 6.8, about 5.2 to about 7, about 5.2 to about 7.2, about 5.4 to about 5.6, about 5.4 to about 5.8, about 5.4 to about 6, about 5.4 to about 6.2, about 5.4 to about 6.4, about 5.4 to about 6.6, about 5.4 to about 6.8, about 5.4 to about 7, about 5.4 to about 7.2, about 5.6 to about 5.8, about 5.6 to about 6, about 5.6 to about6.2, about 5.6 to about 6.4, about 5.6 to about 6.6, about 5.6 to about 6.8, about 5.6 to about 7, about 5.6 to about 7.2, about 5.8 to about 6, about 5.8 to about 6.2, about 5.8 to about 6.4, about 5.8 to about 6.6, about 5.8 to about 6.8, about 5.8 to about 7, about 5.8 to about 7.2, about 6 to about 6.2, about 6 to about 6.4, about 6 to about 6.6, about 6 to about 6.8, about 6 to about 7, about 6 to about 7.2, about 6.2 to about 6.4, about 6.2 to about 6.6, about 6.2 to about 6.8, about 6.2 to about 7, about 6.2 to about 7.2, about 6.4 to about 6.6, about 6.4 to about 6.8, about 6.4 to about 7, about 6.4 to about 7.2, about 6.6 to about 6.8, about 6.6 to about 7, about 6.6 to about 7.2, about 6.8 to about 7, about 6.8 to about 7.2, or about 7 to about 7.2. In some embodiments, the composition has a pH from about 5, about 5.2, about5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 6, about 6.2, about 6.4, about 6.6, about 6.8, about 7, or about 7.2. In some embodiments, the composition has a pH from at least about 5, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 6, about 6.2, about 6.4, about 6.6, about 6.8, or about 7. In some embodiments, the composition has a pH from at most about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 6, about 6.2, about 6.4, about 6.6, about 6.8, about 7, or about 7.2.

[0122] In some embodiments, the gelling agent is a polymer. In some embodiments, the polymer is a homopolymer or a copolymer. In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC),hydroxyethylcellulose (HEC), carbomer, hyaluronic acid, polycarbophil, carboxymethylcellulose (CMC), gellan gum, alginic acid, chitosan, dextran, polyethylene glycol, polypropylene glycol, polysorbate, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), and carboxymethylcellulose (CMC). In some embodiments, the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and hydroxyethylcellulose (HEC). In some embodiments, the polymer is hydroxypropyl cellulose (HPC). In some embodiments, the polymer is hydroxypropyl methylcellulose (HPMC). In some embodiments, the polymer is hydroxy ethylcellulose.

[0123] In some embodiments, the one or more buffers is selected from 4- Morpholineethanesulfonic acid (MES), 2,2-Bis(hydroxymethyl)-2,2',2"-nitrilotriethanol (BisTris), N-(2-Acetamido)iminodiacetic acid (ADA), 2-[(2-Amino-2- oxoethyl)azaniumyl]ethanesulfonate (ACES), 1,4-Piperazinedi ethanesulfonic acid (PIPES), 3-Morpholino-2-hydroxypropanesulfonic acid (MOPSO), 1,3-Bis[tris(hydroxymethyl) methylamino]propane (Bis-Tris Propane), 2-(bis(2-hydroxyethyl)amino)ethane sulfonic acid (BES), 3-(N-Morpholino)propanesulfonic acid (MOPS), 2-[(2 -Hydroxy- 1,1- bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-Hydroxyethyl)piperazine-l- ethanesulfonic acid (HEPES), 4-(N-Morpholino)butanesulfonic acid (MOBS), N- [Tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropanesulfonic acid (TAPSO), Tris(hydroxymethyl)aminomethane (Tris), Piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) (POPSO), 4-(2 -Hydroxy ethyl)- 1 -piperazinepropanesulfonic acid (EPPS), N- [Tris(hydroxymethyl)methyl]glycine (Tricine), Diglycine (Gly-Gly), N,N-Bis(2- hydroxyethyl)glycine (Bicine), N-(2 -Hydroxy ethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS), N-[Tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid (TAPS), 2-Amino-2-methyl- 1,3 -propanediol (AMPD), N-(l,l-Dimethyl-2-hydroxyethyl)-3-amino-2- hydroxypropanesulfonic acid (AMPSO), 2-(Cyclohexylamino)ethanesulfonic acid (CHES),3 -(Cyclohexylamino)-2-hydroxy-l -propanesulfonic acid (CAPSO), 3-(Cyclohexylamino)-l- propanesulfonic acid (CAPS), 4-(Cyclohexylamino)-l -butanesulfonic acid (CABS), phosphoric acid, citric acid, acetic acid, carbonic acid, or a salt or hydrate of any one thereof.

[0124] In some embodiments, the one or more buffers is selected from citric acid monohydrate, sodium phosphate dibasic, monosodium phosphate, sodium acetate, and sodium citrate. In some embodiments, the one or more buffers is citric acid monohydrate. In some embodiments, the one or more buffers is citric acid monohydrate and sodium phosphatedibasic. In some embodiments, the one or more buffers is sodium phosphate dibasic. In some embodiments, the one or more buffers is monosodium phosphate. In some embodiments, the one or more buffers is sodium acetate. In some embodiments, the one or more buffers is sodium citrate.

[0125] In some embodiments, the antioxidant is selected from acetylcarnitine, acetylcysteine, allopurinol, amiloxate, ascorbic acid, butylated hydroxanisole (BHA),butylated bydroxytoluene (BHT), t-butyl hydroquinone (TBHQ), Beta-carotene, cholecalciferol, cysteine, dioxybenzone, Ethylenediaminetetraacetic acid (EDTA), erythorbic acid, etidronic acid, 4-hexylresorcinol, idebenone, lipoic acid, melatonin, methionine, niacinamide, pentaoxiflline, probucol, propyl gallate, retinol, selenious acid, sitosterol, and ubiquinone, or a salt of any one thereof. In some embodiments, the antioxidant is selected from ascorbic acid, butylated hydroxanisole (BHA), butylated bydroxytoluene (BHT), t-butyl hydroquinone (TBHQ), Beta-carotene, cholecalciferol, cysteine, dioxybenzone, Ethylenediaminetetraacetic acid (EDTA), erythorbic acid, lipoic acid, melatonin, methionine, niacinamide, pentaoxiflline, probucol, propyl gallate, retinol, selenious acid, sitosterol, and ubiquinone, or a salt of any one thereof. In some embodiments, the antioxidant is selected from ascorbic acid, butylated hydroxanisole (BHA), Ethylenediaminetetraacetic acid (EDTA), erythorbic acid, lipoic acid, selenious acid, or a salt of any one thereof. In some embodiments, the antioxidant is EDTA or a salt thereof. In some embodiments, the antioxidant is disodium EDTA.

[0126] In some embodiments, the antimicrobial is selected from antimicrobial is selected from a quaternary ammonium salt, boric acid, and a borate salt. In some embodiments, the antimicrobial is selected from benzalkonium chloride, polyquartenium-1 (PQ-1), polyquartenium-42 (PQ-42), polyquad, boric acid, and sodium borate. In some embodiments, the antimicrobial is selected from boric acid, and sodium borate. In some embodiments, the antimicrobial is boric acid. In some embodiments, the antimicrobial is a borate salt.

[0127] In some embodiments, the humectant is selected from glycerol, urea, hyaluronic acid, sorbitol, propylene glycol, and hypromellose. In some embodiments, the humectant is selected from glycerol, sorbitol, propylene glycol, and Hypromellose. In some embodiments, the humectant is selected from glycerol and propylene glycol. In some embodiments, the humectant is glycerol. In some embodiments, the humectant is propylene glycol.

[0128] In some embodiments, the permeation enhancer is selected from selected from alcohols, sulfoxides, azones, pyrrolidones, ureas, alkyl-N,N- disubstituted aminoacetals, propylene glycol, surfactants, terpenes, terpenoids, fatty acids, esters, and cyclodextrins. Insome embodiments, the permeation enhancer is selected from ethanol, propylene glycol, dodecyl-N,N-dimethyl- amino acetate, ethylacetate, azone, sodium dodecyl sulfate, d- limonene, oleic acid, 1,3-diphenyl-urea, N-methyl-2- pyrrolidone, beta-cyclodextrin, and dimethylsulfoxide. In some embodiments, the permeation enhancer is selected from ethanol, propylene glycol, d-limonene, oleic acid, 1,3-diphenyl-urea, N-methyl-2- pyrrolidone, beta- cyclodextrin, and dimethylsulfoxide. In some embodiments, the permeation enhancer is propylene glycol.

[0129] In some embodiments, the alpha-adrenergic agent is selected from amidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrine, 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[l,2- a]imidazole, and A-61603 (N-[5-(4,5-dihydro-lH-imidazol-2-yl)-2- hydroxy-5,6,7,8- tetrahydronaphthalen-l-yl]methanesulfonamide), or a salt of any one thereof. In some embodiments, the alpha-adrenergic agent is selected cirazoline, naphazoline, norepinephrine (noradrenaline), oxymetazoline, tetrahydrozoline, xylometazoline, or a salt of any one thereof. In some embodiments, the alpha-adrenergic agent is oxymetazoline or a salt thereof. In some embodiments, the alpha-adrenergic agent is oxymetazoline hydrochloride (HC1).

[0130] In some embodiments, the dermatological gel composition comprises 0.15 % wt / wt of citric acid monohydrate, 0.35 % wt / wt of sodium phosphate dibasic, 0.13 % wt / wt of disodium EDTA, 0.5 % wt / wt of boric acid, 15.0 % wt / wt of propylene glycol, 3.0 % wt / wt of glycerol, 1.5 % wt / wt of hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

[0131] In some embodiments, the dermatological gel composition consists of 0.15 % wt / wt of citric acid monohydrate, 0.35 % wt / wt of sodium phosphate dibasic, 0.13 % wt / wt of disodium EDTA, 0.5 % wt / wt of boric acid, 15.0 % wt / wt of propylene glycol, 3.0 % wt / wt of glycerol, 1.5 % wt / wt of hydroxy ethylcellullose, and purified water to reach 100 % wt / wt.

[0132] In some embodiments, the dermatological gel composition consists of 2.0 % wt / wt oxymetazoline HC1, 0.15 % wt / wt citric acid monohydrate, 0.35 % wt / wt sodium phosphate dibasic, 0.13 % wt / wt di-sodium EDTA, 0.5 % wt / wt boric acid, 15.0 % wt / wt propylene glycol, 3.0 % wt / wt glycerol, 1.5 % wt / wt hydroxyethylcellullose, and purified water to reach 100 % wt / wt.

[0133] In some embodiments, the dermatological composition comprises 2.0 % wt / wt oxymetazoline HC1, 0.15 % wt / wt citric acid monohydrate, 0.35 % wt / wt sodium phosphate dibasic, 0.13 % wt / wt di-sodium EDTA, 0.5 % wt / wt boric acid, 15.0 % wt / wt propylene glycol, 3.0 % wt / wt glycerol, 1.5 % wt / wt hydroxyethylcellullose, and purified water to reach 100 % wt / wt.

[0134] In some embodiments, the dermatological gel composition consists of 1.0 % wt / wt oxymetazoline HC1, 0.15 % wt / wt citric acid monohydrate, 0.35 % wt / wt sodium phosphate dibasic, 0.13 % wt / wt di-sodium EDTA, 0.5 % wt / wt boric acid, 15.0 % wt / wt propylene glycol, 3.0 % wt / wt glycerol, 1.5 % wt / wt hydroxyethylcellullose, and purified water to reach 100 % wt / wt.

[0135] In some embodiments, the dermatological composition comprises 1.0 % wt / wt oxymetazoline HC1, 0.15 % wt / wt citric acid monohydrate, 0.35 % wt / wt sodium phosphate dibasic, 0.13 % wt / wt di-sodium EDTA, 0.5 % wt / wt boric acid, 15.0 % wt / wt propylene glycol, 3.0 % wt / wt glycerol, 1.5 % wt / wt hydroxyethylcellullose, and purified water to reach 100 % wt / wt.EXAMPLES

[0136] The invention now being generally described, will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.

[0137] Example 1. Evaluation of Radiation Sterilization for Formulation A

[0138] To investigate the effects of autoclave sterilization on the chemical and physical characteristics of the aqueous gel, neat finished samples of Formulation A (Table 1) were subjected to e-beam radiation sterilization under five conditions (i.e. levels in Table 2), both under air and under nitrogen (to reduce potential for oxidation), and dosing either in one steady pulse or dividing the radiation exposure into two equal pulses at a total dosage of either 15 kGy (kiloGray), 20 kGy or 25 kGy.

[0139] Table 1. Dermatological Gel Formulation A

[0140] Table 2 below describes the macroscopic observations of formulations presterilization and following sterilization at different radiation levels (in kiloGray - kGy). After radiation exposure under all five conditions the viscosity of resultant aqueous gel was reduced to an unsatisfactory low viscosity level. Even at the lowest feasible dose to achieve sterility (15 kGy), sample viscosity was reduced to an unacceptable level. Thus radiation sterilization was shown not to be a suitable method to sterilize aqueous gel formulations containing HEC.

[0141] Table 2. Macroscopic observations of Formulation A: pre-sterilization and poststerilization at various radiation levels.

[0142] Example 2. Evaluation of autoclave thermal sterilization of Formulation B and Formulation C.

[0143] Formulation B and Formulation C (Table 3) were prepared on a 100-gram scale for investigating the effects of autoclave sterilization on the chemical and physical characteristics of the aqueous gel. Following manufacture, the formulations were aliquoted, with one aliquot of the Formulation B and Formulation C gels being directly analyzed (pre-sterilization) and another subjected to autoclaving at 123 °C ± 2 °C for 15 minutes (with delayed cooling at 100 °C). The following parameters were assessed for both pre-sterilization and poststerilization samples (i) oxymetazoline HC1 content and related substances; and (ii) rheology.

[0144] Table 3. Dermatological Gel Formulation B and Formulation C

[0145] Table 4 describes the percentage recovery (%), percentage peak purity (% a / a) and related substances of oxymetazoline HC1 in Formulation C pre-sterilization and poststerilization. The thermal sterilization procedure was found to reduce the oxymetazoline HC1 concentration in neat finished Formulation C to an unsatisfactory level. Oxymetazoline HC1 degradation was as much as 5% with a concomitant generation of about 5% reportable impurities, which is undesirable. Thus, thermal autoclave sterilization is not suitable for aqueous gel formulations.

[0146] Table 4: Oxymetazoline HC1 measurements of Formulation C at pre-sterilization and post-sterilization using autoclave thermal sterilization.

[0147] Table 5 describes the rheological attributes of Formulation B and Formulation C presterilization and post-sterilization. No obvious changes in the visual viscosity of the formulations were observed following autoclave sterilization. This is in contrast to the observations post e-beam sterilization where a notable drop in the apparent viscosity of the aqueous gel was reported. Following sterilization minor changes in the rheological profile of the formulations were observed. The average complex modulus, apparent yield stress and phase angle stress at 45° decreased for both the Formulation B and Formulation C following sterilization, while the low frequency crossover was observed to increase. This was indicative of a potential breakdown in the polymer constituents. Thermal sterilization of the finished fluid product reduced product viscosity. Thus, terminal thermal sterilization of the fully completed Formulation B and Formulation C is not feasible nor suitable for aqueous gel formulations.

[0148] Table 5. Rheological observations of Formulation B and Formulation C at presterilization and post-sterilization using autoclave thermal sterilization.

[0149] Example 3: Manufacturing Process - 250 kg Scale

[0150] As provided in Examples 1 and 2, conventional methods for sterilizing gel formulations of the present disclosure are insufficient. Example 1 provides that irradiation of the gel formulation at various radiation exposures resulted in a substantial decrease in the gel formulation viscosity. Example 2 provides that thermal methods such as autoclaving, resulted in oxymetazoline degradation.

[0151] Sterile Formulations Description

[0152] Dermatological Gel Formulations: Formulation 1, Formulation 2 and Formulation 3. Table 6 provides a description of the dermatological gel formulations produced using the methods described herein. Tables 7-9 provide the dermatological gel formulations produced using the methods described herein. Figure 1 provides a manufacturing overview for the production of the dermatological gel formulations of the present disclosure at a 250 kg scale. The manufacturing overview in Figure 1 is described below.

[0153] Table 6: Description Of The Exemplary Dermatological Gel Formulations

[0154] Table 7: Exemplary Dermatological Gel - Formulation 1

[0155] Table 8: Exemplary Dermatological Gel - Formulation 2

[0156] Table 9: Exemplary Dermatological Gel - Formulation 3

[0157] Dispensing: The raw materials were dispensed and packaged in a grade C clean room. All materials were released for use at the time of dispensing. Dry materials were double bagged in LDPE bags, while liquids were stored in HDPE containers with screw lid. The dispensed materials were stored in non-translucent plastic boxes during transfer to the manufacturing area.

[0158] Manufacture of the Filtered Fraction: The filtered fraction was prepared in vessel 1 in a grade C clean room. 120 L of purified water was brought into vessel 1 and cooled to < 25°C while stirring at 350 rpm. The indicated amount of each excipient was then added sequentially to the vessel (addition order: see Figure 1), stirring was continued at 350 rpm, ensuring complete dissolution of the previous raw material before adding the next. A maximum of an additional 32L purified water was used to rinse the raw material recipients. The aqueous solution was filtered into the pre-sterilized vessel 2 through a filtration assembly consisting of two 0.22 pm sterilizing product filters (Pall N66 Posidyne AB1NFZ7PH4). Finally, cooled purified water was filtered through the sterilizing product filters into vessel 2 until the required weight was reached to bring total weight to 246.25 kg, thereby rinsing vessel 1 and flushing the filtration assembly.

[0159] Gelling Agent Sterilization: The total required amount of HEC was divided into six equal fractions of 625g, which were double bagged in heat-sealed polyamide bags before being presented for dry heat sterilization. The sterilization cycle of 480 minutes at 130°C was applied to the batch. (Alternative HEC sterilization conditions: 180 minutes at 160° or 6 minutes 190° C). Prior to incorporation, clumping of the HEC occurred after sterilization, which impacted the aseptic incorporation into vessel 2.

[0160] Gelling Agent Incorporation: The aseptic incorporation of the dry heat sterilized HEC 250 HHX into vessel 2 was performed in a clean room of grade A / B. Incorporation was achieved by introducing the raw material into a pre-sterilized stainless steel incorporation funnel, which was connected to vessel 2 in a grade C clean room via a sterile incorporation piping. By applying a vacuum, the material was introduced into vessel 2, in which the filtered fraction was being stirred. Before the incorporation, the HEC material had clumped together and was reduced to a clump size of < 1.5 cm by manually manipulating the bags. Incorporation was resumed and completed successfully by setting the vacuum to -400 mbar and introducing the remaining Natrosol 250 HHX HEC into the funnel in 200-300 gram increments. The contents of vessel 2 were continuously stirred at 900 rpm during the incorporation.

[0161] Homogenization and Transfer: After incorporation of HEC 250 HHX, the contents of vessel 2 were homogenized for 16 hours at 600 rpm. The scrapers were set at 15 rpm. After 8 and 16 hours of mixing, a bulk sample of the gel was taken for physicochemical analysis. After the last bulk sample was taken, a portion of the gel was transferred to a transfer tank pending filling. The remaining gel (approximately 190 kg) was dumped through the product exit line. During dumping, 10 bulk samples were collected to assess homogeneity of the bulk by measuring viscosity and pH.

[0162] Filling: The gel was filled into 15 g laminate tubes. During start-up, the 15 g filling needle caused excess gel to form a string in between filled units, thereby soiling the outside and interfering with heat sealing of the tubes. It was change to a 10 g filling needle, which resulted in desirable filling dynamics. About 2000 tubes were successfully filled with 15 g of product.

[0163] Analytical Results: Samples were analyzed according to viscosity, pH, appearance, and particulate matter. Results are summarized in the Tables below. Generally, the pH was higher than the specified range, and viscosity was lower than the ±11000 mPa.s that was initially expected. The gel was not completely colorless, nor clear, as was observed during bulk sampling.

[0164] Bulk Samples: The results for the bulk samples taken after 8 and 16 hours of homogenization are summarized in Table 10.

[0165] Table 10: Analysis Results For the Bulk Samples

[0166] Dumping Samples: The analysis results for the dumping samples are summarized in Table 11 and illustrated in Figure 2.

[0167] Table 11: Analysis Results For The Dumping Samples

[0168] Filled Units: The analysis results for the filled units are summarized in Table 12 below.

[0169] Table 12: Analysis Results Of The Filled Units

[0170] Sterility Testing: Following manufacture, Formulation 2 (1.0 % wt / wt oxymetazoline) was tested to confirm if the formulation has the ability to prevent microbial growth. The formulation was also manufactured with 10% less boric acid (Formulation 2-90%) to demonstrate that the boric acid content drop would still effectively prevent microbial growth. The result of this testing is provided in Table 13 and provides that the formulations tested pass USP and EP sterility standards. Accordingly, the methods provided herein effective at removing submicron contaminants.

[0171] Table 13: Sterility Testing

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method for preparing a gel formulation comprising:(a) sterilizing a first portion, wherein the first portion comprises a gelling agent;(b) filtering a second portion to remove submicron contaminants, wherein the second portion comprises an aqueous carrier, one or more buffers, an antioxidant, an antimicrobial, a humectant, and a penetration enhancer; and following step (a) and step (b), contacting the first portion with the second portion to produce the gel formulation.

2. The method of claim 1, wherein the sterilizing is heat sterilizing.

3. The method of claim 1 or claim 2, wherein step (a) occurs at a temperature of at least 120 C.

4. The method of claim 1 or claim 2, wherein step (a) occurs at a temperature of between about 120 C to about 200 C.

5. The method of claim 1 or claim 2, wherein step (a) occurs at a temperature of at most 200 C.

6. The method of any one of claims 1 to 5, wherein the temperature applied during step(a) is between about 5 minutes to about 720 minutes.

7. The method of any one of claims 1 to 6, wherein the gelling agent is in solid form.

8. The method of any one of claims 1 to 7, wherein the gelling agent is a polymer.

9. The method of claim 8, wherein the polymer is selected from hydroxypropyl cellulose(HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), carbomer, hyaluronic acid, polycarbophil, carboxymethylcellulose (CMC), gellan gum, alginic acid, chitosan, dextran, polyethylene glycol, polypropylene glycol, polysorbate, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).

10. The method of claim 9, wherein the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), and carboxymethylcellulose (CMC).

11. The method of claim 10, wherein the polymer is hydroxy ethylcellulose.

12. The method of any one of claims 1 to 11, wherein the submicron contaminants are microbial contaminants.

13. The method of claim 12, wherein the microbial contaminants are selected from bacteria, viruses, and fungi, or a combination thereof.

14. The method of claim 13, wherein the microbial contaminants are selected from bacteria and fungi, or a combination thereof.

15. The method of claim 14, wherein the microbial contaminants is selected from P. aeruginosa, P. aureus, E.coli, A. brasiliensis, and C. albicans, or a combination thereof.

16. The method of any one of claims 1 to 15, wherein the filtering comprises at least one filter.

17. The method of claim 16, wherein the at least one filter is a micron filter.

18. The method of claim 17, wherein the micron filter has a filter size of between about 0.01 um to about 0.5 um.

19. The method of any one of claims 1 to 18, wherein the one or more buffers is selected from 4-Morpholineethanesulfonic acid (MES), 2,2-Bis(hydroxymethyl)-2,2',2"- nitrilotriethanol (Bis-Tris), N-(2-Acetamido)iminodiacetic acid (ADA), 2-[(2-Amino-2- oxoethyl)azaniumyl]ethanesulfonate (ACES), 1,4-Piperazinedi ethanesulfonic acid (PIPES), 3-Morpholino-2-hydroxypropanesulfonic acid (MOPSO), 1,3-Bis[tris(hydroxymethyl) methylamino]propane (Bis-Tris Propane), 2-(bis(2-hydroxyethyl)amino)ethane sulfonic acid (BES), 3-(N-Morpholino)propanesulfonic acid (MOPS), 2-[(2 -Hydroxy- 1,1- bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid (TES), 4-(2-Hydroxyethyl)piperazine-l- ethanesulfonic acid (HEPES), 4-(N-Morpholino)butanesulfonic acid (MOBS), N- [Tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropanesulfonic acid (TAPSO), Tris(hydroxymethyl)aminomethane (Tris), Piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) (POPSO), 4-(2 -Hydroxy ethyl)- 1 -piperazinepropanesulfonic acid (EPPS), N- [Tris(hydroxymethyl)methyl]glycine (Tricine), Diglycine (Gly-Gly), N,N-Bis(2- hydroxyethyl)glycine (Bicine), N-(2 -Hydroxy ethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS), N-[Tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid (TAPS), 2-Amino-2-methyl- 1,3 -propanediol (AMPD), N-(l,l-Dimethyl-2-hydroxyethyl)-3-amino-2- hydroxypropanesulfonic acid (AMPSO), 2-(Cyclohexylamino)ethanesulfonic acid (CHES),3 -(Cyclohexylamino)-2-hydroxy-l -propanesulfonic acid (CAPSO), 3-(Cyclohexylamino)-l- propanesulfonic acid (CAPS), 4-(Cyclohexylamino)-l -butanesulfonic acid (CABS), phosphoric acid, citric acid, acetic acid, carbonic acid, or a salt or hydrate of any one thereof.

20. The method of claim 19, wherein the one or more buffers is selected from citric acid monohydrate, sodium phosphate dibasic, monosodium phosphate, sodium acetate, and sodium citrate.

21. The method of any of claims 1 to 20, wherein the antioxidant is selected from acetylcarnitine, acetylcysteine, allopurinol, amiloxate, ascorbic acid, butylated hydroxanisole (BHA),butylated bydroxytoluene (BHT), t-butyl hydroquinone (TBHQ), Beta-carotene, cholecalciferol, cysteine, dioxybenzone, Ethylenediaminetetraacetic acid (EDTA), erythorbic acid, etidronic acid, 4-hexylresorcinol, idebenone, lipoic acid, melatonin, methionine, niacinamide, pentaoxiflline, probucol, propyl gallate, retinol, selenious acid, sitosterol, and ubiquinone, or a salt of any one thereof.

22. The method of claim 21, wherein the antioxidant is EDTA or a salt thereof.

23. The method of claim 22, wherein the antioxidant is disodium EDTA.

24. The method of any of claims 1 to 23, wherein the antimicrobial is selected from a quaternary ammonium salts, boric acid, and a borate salt.

25. The method of claim 24, wherein the antimicrobial is selected from benzalkonium chloride, polyquartenium-1 (PQ-1), polyquartenium-42 (PQ-42), poly quad, boric acid, and sodium borate.

26. The method of claim 25, wherein the antimicrobial is boric acid.

27. The method of any of claims 1 to 26, wherein the humectant is selected from glycerol, urea, hyaluronic acid, sorbitol, propylene glycol, and hypromellose.

28. The method of claim 27, wherein the humectant is glycerol.

29. The method of any of claims 1 to 28, wherein the permeation enhancer is selected from selected from alcohols, sulfoxides, azones, pyrrolidones, ureas, alkyl-N,N- disubstitutedaminoacetals, propylene glycol, surfactants, terpenes, terpenoids, fatty acids, esters, and cyclodextrins.

30. The method of claim 29, wherein the permeation enhancer is selected from ethanol, propylene glycol, dodecyl-N,N-dimethyl- amino acetate, ethylacetate, azone, sodium dodecyl sulfate, d-limonene, oleic acid, 1,3-diphenyl-urea, N-methyl-2- pyrrolidone, betacyclodextrin, and dimethylsulfoxide.

31. The method of claim 30, wherein the permeation enhancer is propylene glycol.

32. The method of any one of claims 1 to 31, wherein the contacting occurs for between about 1 hour to about 48 hours.

33. The method of any one of claims 1 to 32, wherein the contacting comprises mixing the first portion and second portion.

34. The method of claim 33, wherein the mixing is for between about 4 hours to about 24 hours.

35. The method of any one of claims 1 to 34, wherein the aqueous carrier is purified water.

36. The method of any one of claims 1 to 35, wherein the gel formulation comprises: about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers; about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant; about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial; about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer; about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant; about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and an aqueous carrier to reach 100 % wt / wt.

37. The method of claim 36, wherein the gel formulation comprises: about 0.10 % wt / wt to about 0.25 % wt / wt of citric acid monohydrate; about 0.25 % wt / wt to about 0.50 % wt / wt of sodium phosphate dibasic; about 0.05 % wt / wt to about 0.15 % wt / wt of disodium EDTA;about 0.5 % wt / wt to about 1.0 % wt / wt of boric acid; about 10.0 % wt / wt to about 25.0 % wt / wt of propylene glycol; about 1.0 % wt / wt to about 5.0 % wt / wt of glycerol; about 0.5 % wt / wt to about 5.0 % wt / wt of hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

38. The method of claim 37, wherein the gel formulation comprises:0.15 % wt / wt of citric acid monohydrate;0.35 % wt / wt of sodium phosphate dibasic;0.13 % wt / wt of di-sodium EDTA;0.5 % wt / wt of boric acid;15.0 % wt / wt of propylene glycol;3.0 % wt / wt of glycerol;1.5 % wt / wt of hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

39. The method of any one of claims 1 to 35, wherein the second portion further comprises an alpha-adrenergic agent.

40. The method of claim 39, wherein the alpha-adrenergic agent is selected from amidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrine, dopamine, ephedrine, epinephrine (adrenaline), etilefrine, ethylnorepinephrine, 5- fhironorepinephrine, 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[l,2- a]imidazole, and A-61603 (N-[5-(4,5-dihydro-lH-imidazol-2-yl)-2- hydroxy-5,6,7,8- tetrahydronaphthalen-l-yl]methanesulfonamide), or a salt of any one thereof.

41. The method of claim 40, wherein the alpha-adrenergic agent is oxymetazoline or a salt thereof.

42. The method of claim 41, wherein the alpha-adrenergic agent is oxymetazoline hydrochloride (HC1).

43. The method of any of claims 1 to 42, wherein the gel formulation further comprises about 0.10 % wt / wt to about 5.00 % wt / wt alpha-adrenergic agent.

44. The method of claim 43, wherein the gel formulation comprises about 0.10 % wt / wt to about 5.00 % wt / wt oxymetazoline hydrochloride (HC1).

45. The method of any one of claims 1 to 44, wherein the gel formulation comprises: about 0.10 % wt / wt to about 5.00 % wt / wt of an alpha-adrenergic agent; about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers; about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant; about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial; about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer; about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant; about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and an aqueous carrier, to reach 100 % wt / wt.

46. The method of claim 44, wherein the gel formulation comprises: about 2.0 % wt / wt oxymetazoline HC1; about 0.15 % wt / wt citric acid monohydrate; about 0.35 % wt / wt sodium phosphate dibasic; about 0.13 % wt / wt di-sodium EDTA; about 0.5 % wt / wt boric acid; about 15.0 % wt / wt propylene glycol; about 3.0 % wt / wt glycerol; about 1.5 % wt / wt hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

47. The method of claim 46, wherein the gel formulation comprises: about 1.0 % wt / wt oxymetazoline HC1;about 0.15 % wt / wt citric acid monohydrate; about 0.35 % wt / wt sodium phosphate dibasic; about 0.13 % wt / wt di-sodium EDTA; about 0.5 % wt / wt boric acid; about 15.0 % wt / wt propylene glycol; about 3.0 % wt / wt glycerol; about 1.5 % wt / wt hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

48. The method of any one of claims 1 to 47, wherein the gel formulation comprises a viscosity of between about 4500 mPa.s to about 6500 mPa.s.

49. The method of claim 48, wherein the gel formulation comprises a viscosity of between about 5500 mPa.s to about 6000 mPa.s.

50. The method of any one of claims 1 to 49, wherein the gel formulation comprises a pH of between about 5 to about 7.

51. The method of claim 50, wherein the gel formulation comprises a pH of about 6.

52. The method of any one of claims 1 to 51, wherein the gel formulation comprises an acceptable USP pathogen count, wherein the pathogen is selected from P. aeruginosa, P. aureus, E.coli, A. brasiliensis, and C. albicans.

53. The method of claim 52, wherein the acceptable USP pathogen count is identified using a USP<61> test or USP<62> test.

54. The method of claim 52, wherein the acceptable USP pathogen count is less than 1000 CFU / g.

55. The method of claim 52, wherein the acceptable USP pathogen count is about 1 CFU / g to about CFU / g 1000.

56. The method of claim 55, wherein the acceptable USP pathogen count is about 10 CFU / g to about CFU / g 100.

57. A dermatological gel composition, comprising: about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers; about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant; about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial; about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer; about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant; about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and purified water to reach 100 % wt / wt.

58. A dermatological gel composition, consisting of: about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers; about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant; about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial; about 10.0 % wt / wt to about 25.0 % wt / wt of an permeation enhancer; about 1.0 % wt / wt to about 5.0 % wt / wt of an humectant; about 0.5 % wt / wt to about 5.0 % wt / wt of an gelling agent; and purified water to reach 100 % wt / wt.

59. A dermatological gel composition, consisting of: about 0.5 % wt / wt to about 2.5 % wt / wt of an alpha adrenergic agent; about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers; about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant; about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent; about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer; about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant; about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and purified water to reach 100 % wt / wt.

60. The dermatological gel composition of claim 59, consisting of: about 0.5 % wt / wt to about 1.5 % wt / wt of an alpha adrenergic agent; about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers; about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant; about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent; about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer; about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant; about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and purified water to reach 100 % wt / wt.

61. The dermatological gel composition of claim 60, consisting of: about 1.5 % wt / wt to about 2.5 % wt / wt of an alpha adrenergic agent; about 0.10 % wt / wt to about 2.00 % wt / wt a one or more buffers; about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant; about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent; about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer; about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant; about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and purified water to reach 100 % wt / wt.

62. A dermatological gel composition, comprising: about 0.5 % wt / wt to about 2.5 % wt / wt of an alpha adrenergic agent; about 0.10 % wt / wt to about 2.00 % wt / wt of one or more buffers; about 0.05 % wt / wt to about 0.15 % wt / wt of an antioxidant; about 0.5 % wt / wt to about 1.0 % wt / wt of an antimicrobial agent; about 10.0 % wt / wt to about 25.0 % wt / wt of a permeation enhancer; about 1.0 % wt / wt to about 5.0 % wt / wt of a humectant;about 0.5 % wt / wt to about 5.0 % wt / wt of a gelling agent; and purified water to reach 100 % wt / wt.

63. The dermatological gel composition of any one of claims 57 to 62, wherein the composition has a viscosity of 4500 mPa.s to 6500 mPa.s measured at 25 °C.

64. The dermatological gel composition of claim 63, wherein the composition has a viscosity of 5500 mPa.s to about 6000 mPa.s measured at 25 °C.

65. The dermatological gel composition of any one of claims 57 to 64, wherein the composition has a pathogen count of less than 1000 CFU / g as measured by a test selected from USP<61> and USP<62>.

66. The dermatological gel composition of claim 65, wherein the pathogen is selected from a bacteria, a virus, a fungus, or a combination thereof.

67. The dermatological gel composition of claim 66, wherein the pathogen is selected from a bacteria, a fungus, or a combination thereof.

68. The dermatological gel composition of claim 67, wherein the pathogen is selected from P. aeruginosa, P. aureus, E.coli, A. brasiliensis, and C. albicans, or a combination thereof.

69. The dermatological gel composition of any one of claims 57 to 68, wherein the composition has a pH from about 5.0 to about 7.0.

70. The dermatological gel composition of claim 69, wherein the composition has a pH of about 6.0.

71. The dermatological gel composition of any one of claims 57 to 70, wherein the gelling agent is a polymer.

72. The dermatological gel composition of claim 71, wherein the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), carbomer, hyaluronic acid, polycarbophil, carboxymethylcellulose (CMC), gellan gum, alginic acid, chitosan, dextran, polyethyleneglycol, polypropylene glycol, polysorbate, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).

73. The dermatological gel composition of claim 72, wherein the polymer is selected from hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), and carboxymethylcellulose (CMC).

74. The dermatological gel composition of claim 73, wherein the polymer is hydroxy ethylcellulose.

75. The dermatological gel composition of any one of claims 57 to 74, wherein the one or more buffers is selected from 4-Morpholineethanesulfonic acid (MES), 2,2- Bis(hydroxymethyl)-2,2',2"-nitrilotriethanol (Bis-Tris), N-(2-Acetamido)iminodiacetic acid (ADA), 2-[(2-Amino-2-oxoethyl)azaniumyl]ethanesulfonate (ACES), 1,4-Piperazinedi ethanesulfonic acid (PIPES), 3-Morpholino-2-hydroxypropanesulfonic acid (MOPSO), 1,3-Bis[tris(hydroxymethyl) methylamino]propane (Bis-Tris Propane), 2-(bis(2- hydroxyethyl)amino)ethane sulfonic acid (BES), 3-(N-Morpholino)propanesulfonic acid (MOPS), 2- [(2 -Hydroxy- 1,1 -bi s(hydroxymethyl)ethyl)amino] ethanesulfonic acid (TES), 4- (2-Hydroxyethyl)piperazine-l -ethanesulfonic acid (HEPES), 4-(N- Morpholino)butanesulfonic acid (MOBS), N-[Tris(hydroxymethyl)methyl]-3-amino-2- hydroxypropanesulfonic acid (TAPSO), Tri s(hydroxymethyl)aminom ethane (Tris), Piperazine-N,N'-bis(2 -hydroxypropanesulfonic acid) (POPSO), 4-(2 -Hydroxy ethyl)- 1- piperazinepropanesulfonic acid (EPPS), N-[Tris(hydroxymethyl)methyl]glycine (Tricine), Diglycine (Gly-Gly), N,N-Bis(2 -hydroxy ethyl)glycine (Bicine), N-(2- Hydroxyethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS), N- [Tris(hydroxymethyl)methyl]-3-aminopropanesulfonic acid (TAPS), 2-Amino-2-methyl-l,3- propanediol (AMPD), N-(l,l-Dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid (AMP SO), 2-(Cyclohexylamino)ethanesulfonic acid (CHES), 3-(Cyclohexylamino)-2- hydroxy-1 -propanesulfonic acid (CAPSO), 3 -(Cyclohexylamino)- 1 -propanesulfonic acid (CAPS), 4-(Cyclohexylamino)-l -butanesulfonic acid (CABS), phosphoric acid, citric acid, acetic acid, carbonic acid, or a salt or hydrate of any one thereof.

76. The dermatological gel composition of claim 75, wherein the one or more buffers is selected from citric acid monohydrate, sodium phosphate dibasic, monosodium phosphate, sodium acetate, and sodium citrate.

77. The dermatological gel composition of any of claims 57 to 76, wherein the antioxidant is selected from acetylcarnitine, acetylcysteine, allopurinol, amiloxate, ascorbic acid, butylated hydroxanisole (BHA),butylated by droxy toluene (BHT), t-butyl hydroquinone (TBHQ), Beta-carotene, cholecalciferol, cysteine, dioxybenzone, Ethylenediaminetetraacetic acid (EDTA), erythorbic acid, etidronic acid, 4-hexylresorcinol, idebenone, lipoic acid, melatonin, methionine, niacinamide, pentaoxiflline, probucol, propyl gallate, retinol, selenious acid, sitosterol, and ubiquinone, or a salt of any one thereof.

78. The dermatological gel composition of claim 77, wherein the antioxidant is EDTA or a salt thereof.

79. The dermatological gel composition of claim 78, wherein the antioxidant is disodium EDTA.

80. The dermatological gel composition of any of claims 57 to 79, wherein the antimicrobial is selected from antimicrobial is selected from a quaternary ammonium salt, boric acid, and a borate salt.

81. The dermatological gel composition of claim 80, wherein the antimicrobial is selected from benzalkonium chloride, polyquartenium-1 (PQ-1), polyquartenium-42 (PQ-42), polyquad, boric acid, and sodium borate.

82. The dermatological gel composition of claim 81, wherein the antimicrobial is boric acid.

83. The dermatological gel composition of any of claims 57 to 82, wherein the humectant is selected from glycerol, urea, hyaluronic acid, sorbitol, propylene glycol, and hypromellose.

84. The dermatological gel composition of claim 83, wherein the humectant is glycerol.

85. The dermatological gel composition of any of claims 57 to 84, wherein the permeation enhancer is selected from selected from alcohols, sulfoxides, azones, pyrrolidones, ureas, alkyl-N,N- disubstituted aminoacetals, propylene glycol, surfactants, terpenes, terpenoids, fatty acids, esters, and cyclodextrins.

86. The dermatological gel composition of claim 85, wherein the permeation enhancer is selected from ethanol, propylene glycol, dodecyl-N,N-dimethyl- amino acetate, ethylacetate,azone, sodium dodecyl sulfate, d-limonene, oleic acid, 1,3-diphenyl-urea, N-methyl-2- pyrrolidone, beta-cyclodextrin, and dimethylsulfoxide.

87. The dermatological gel composition of claim 86, wherein the permeation enhancer is propylene glycol.

88. The dermatological gel composition of any one of claims 59 to 86, wherein the alpha- adrenergic agent is selected from amidephrine, anisodamine, anisodine, chloroethylclonidine, cirazoline, desvenlafaxine, dipivefrine, 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[l,2- a]imidazole, and A-61603 (N- [5-(4,5-dihydro-lH-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1- yl]methanesulfonamide), or a salt of any one thereof.

89. The dermatological gel composition of claim 87, wherein the alpha-adrenergic agent is oxymetazoline or a salt thereof.

90. The dermatological gel composition of claim 88, wherein the alpha-adrenergic agent is oxymetazoline hydrochloride (HC1).

91. The dermatological gel composition of any one of claims 57 or 63-87, comprising:0.15 % wt / wt of citric acid monohydrate;0.35 % wt / wt of sodium phosphate dibasic;0.13 % wt / wt of di-sodium EDTA;0.5 % wt / wt of boric acid;15.0 % wt / wt of propylene glycol;3.0 % wt / wt of glycerol;1.5 % wt / wt of hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

92. The dermatological gel compositions of any one of claims 58 or 63-87, consisting of:0.15 % wt / wt of citric acid monohydrate;0.35 % wt / wt of sodium phosphate dibasic;0.13 % wt / wt of di-sodium EDTA;0.5 % wt / wt of boric acid;15.0 % wt / wt of propylene glycol3.0 % wt / wt of glycerol;1.5 % wt / wt of hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

93. The dermatological gel composition of any one of claims 59-61 or 63-90, consisting of:2.0 % wt / wt oxymetazoline HC1;0.15 % wt / wt citric acid monohydrate;0.35 % wt / wt sodium phosphate dibasic;0.13 % wt / wt di-sodium EDTA;0.5 % wt / wt boric acid;15.0 % wt / wt propylene glycol;3.0 % wt / wt glycerol;1.5 % wt / wt hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

94. The dermatological gel composition of any one of claims 59-61 or 63-90, consisting of:1.0 % wt / wt oxymetazoline HC1;0.15 % wt / wt citric acid monohydrate;0.35 % wt / wt sodium phosphate dibasic;0.13 % wt / wt di-sodium EDTA;0.5 % wt / wt boric acid;15.0 % wt / wt propylene glycol;3.0 % wt / wt glycerol;1.5 % wt / wt hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

95. The dermatological gel composition of any one of claims 62 to 90, comprising:2.0 % wt / wt oxymetazoline HC1;0.15 % wt / wt citric acid monohydrate;0.35 % wt / wt sodium phosphate dibasic;0.13 % wt / wt di-sodium EDTA;0.5 % wt / wt boric acid;15.0 % wt / wt propylene glycol;3.0 % wt / wt glycerol;1.5 % wt / wt hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

96. The dermatological gel composition of any one of claims 62 to 90, comprising:1.0 % wt / wt oxymetazoline HC1;0.15 % wt / wt citric acid monohydrate;0.35 % wt / wt sodium phosphate dibasic;0.13 % wt / wt di-sodium EDTA;0.5 % wt / wt boric acid;15.0 % wt / wt propylene glycol;3.0 % wt / wt glycerol;1.5 % wt / wt hydroxy ethylcellullose; and purified water to reach 100 % wt / wt.

Images