A TOPICAL ANTI-INFLAMMATORY PHARMACEUTICAL COMPOSITION COMPRISING ZILEUTON

Abstract

The present invention relates to a topical anti-inflammatory pharmaceutical composition comprising Zileuton. Furthermore, the present invention relates to uses of such composition. Moreover, the present invention relates to methods of preparing a topical anti-inflammatory pharmaceutical composition comprising Zileuton.

Claims

1-81. (canceled)

82. A topical anti-inflammatory pharmaceutical composition, comprising Zileuton at a concentration of >2% (w/w).

83. The composition according to claim 82, wherein Zileuton is present at a concentration in the range of from 4.5% (w/w) to 5.5% (w/w).

84. The composition according to claim 82, wherein the pharmaceutical composition is formulated as a topical formulation selected from solution ointment, suspension ointment, solution cream, suspension cream, water/buffer solution cream, gel and lotion.

85. The composition according to claim 82, wherein the pharmaceutical composition is formulated as a gel formulation and comprises an organic solvent, an aqueous solvent, a viscosity controlling agent and an emulsifier.

86. The topical anti-inflammatory pharmaceutical composition according to claim 85, wherein the organic solvent is present in said composition in a range of from 52% (w/w) to 57% (w/w), the aqueous solvent is present in said composition in a range of from 14% (w/w) to 19% (w/w), the viscosity controlling agent is present in said composition in a range of from 2% (w/w) to 6% (w/w) and the emulsifier is present in said composition in a range of from 18% (w/w) to 22% (w/w).

87. The composition according to claim 85, wherein the aqueous solvent is water or a pH buffered solution in a range from pH 2.0 to 8.0.

88. The composition according to claim 87, wherein the pH buffered solution is selected from 0.01N HCl (pH 2.0), sodium citrate buffer (pH 4.0), phosphate buffer (pH 6.0), and phosphate buffer (pH 7.5).

89. The composition according to claim 85, wherein the viscosity controlling agent is selected from acrylic acid polymer, methylcellulose 400 cP, methylcellulose 4000 cP, hydroxypropyl methyl cellulose K4M, hydroxypropyl methyl cellulose K15M, sodium carboxymethyl cellulose, gum acacia, and mixtures of any of the foregoing; and/or wherein the organic solvent is selected from ethanol, diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, N-methyl-2-pyrrolidone, dimethyl formamide, dimethyl acetamide, and mixtures of any of the foregoing; and/or wherein the emulsifier is selected from poly-oxyethylene esters of 12-hydroxystearic acid, triethanolamine, caprylocaproyl polyoxyl glycerides, polyoxyl 35 hydrogenated castor oil, polyethylene glycol-40 hydrogenated castor oil, polyoxy ethylene sorbitan monooleate, d-a-tocopheryl polyethylene glycol 1000 succinate, and mixtures of any of the foregoing.

90. The composition according to claim 82, wherein the pharmaceutical composition is formulated as a water/buffer solution cream formulation and comprises an aqueous solvent and an emulsifier.

91. The composition according to claim 92, wherein said water/buffer solution cream formulation comprises an organic solvent, an aqueous solvent, a thickening agent and an emulsifier.

92. The composition according to claim 90, wherein the aqueous solvent is present in said composition in a range of from 4% (w/w) to 13% (w/w) and the emulsifier is present in said composition in a range of from 7% (w/w) to 67% (w/w).

93. The topical anti-inflammatory pharmaceutical composition according to claim 91, wherein the organic solvent is present in said composition in a range of from 18% (w/w) to 22% (w/w), the aqueous solvent is present in said composition in a range of from 5% (w/w) to 7% (w/w), the thickening agent is present in said composition in a range of from 12% (w/w) to 16% (w/w) and the emulsifier is present in said composition in a range of from 53% (w/w) to 60% (w/w).

94. The composition according to claim 90, wherein the aqueous solvent is water or a pH buffered solution in a range from pH 2.0 to 8.0.

95. The composition according to claim 94, wherein the pH buffered solution is acid phthalate buffer (pH4.0), acetate buffer (pH 4.1), citrate buffer (pH4.0), phosphate buffer (pH6.0), and Merck buffer (pH4.0).

96. The composition according to claim 90, wherein the emulsifier is selected from ethylene glycol palmitostearate, sorbitan monolaurate, sorbitane monooleate, caprylocaproyl polyoxyl glycerides, polyoxyl 35 hydrogenated castor oil, polyethylene glycol-40 hydrogenated castor oil, lecithin from egg, polyethylene glycol sorbitan monolaurate, polyoxy ethylene sorbitan monostearate, polyoxy ethylene sorbitan monooleate, d-a-tocopheryl polyethylene glycol 1000 succinate, poly-oxyethylene esters of 12-hydroxystearic acid, poloxamer 407, triethanolamine, sodium lauryl sulfate, lauroyl polyoxyl-32 glycerides, and mixtures of any of the foregoing; and/or wherein the organic solvent is selected from ethanol, diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, N-methyl-2-pyrrolidone, dimethyl acetamide, dimethyl formamide, hexylene glycol, and mixtures of any of the foregoing; and/or wherein the thickening agent is selected from white wax, beeswax polyethylene glycol-8, cetyl alcohol, stearyl alcohol, glyceryl mono and di stearate, polyethylene glycol 1500, polyethylene glycol 3350, polyethylene glycol 6000, lanolin, white vaseline, and mixtures of any of the foregoing.

97. The composition according to claim 90, comprising an oil wherein the oil is selected from medium chain triglycerides, ethyl oleate, propylene glycol dicaprylate, glyceryl monocaprate type I, propylene glycol monocaprylate type II, caprylocaproyl polyoxylglycerides, caprylic glycerides, isopropyl myristate, corn oil, linoleoyl polyoxyl-6 glycerides, glyceryl monolinoleate, and mixtures of any of the foregoing.

98. The composition according to claim 82 wherein the pharmaceutical composition is formulated as a solution ointment and comprises an organic solvent, a thickening agent and a solubilizer.

99. The composition according to claim 98, wherein the organic solvent is present in said composition in a range of from 40% (w/w) to 60% (w/w), the thickening agent is present in said composition in a range of from 35% (w/w) to 55% (w/w) and the solubilizer is present in said composition in a range of from 0.5% (w/w) to 1.5% (w/w).

100. The composition according to claim 98, wherein the organic solvent is selected from diethylene glycol mono ethyl ether, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, propylene glycol, hexylene glycol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethyl formamide, dimethyl acetamide, and mixtures of any of the foregoing; and/or wherein the thickening agent is selected from stearyl alcohol, beeswax polyethylene glycol-8, polyethylene glycol 1500, polyethylene glycol 3350, polyethylene glycol 6000, polyethylene glycol 8000, polyacrylic acid, glyceryl mono and di stearate, stearic acid, cetyl alcohol, mono and diglycerides, lanolin, white vaseline, paraffin, and mixtures of any of the foregoing; and/or wherein the solubilizer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

101. The composition according to claim 98, wherein the composition further comprises an emulsifier selected from ethylene glycol palmitostearate, propylene glycol monolaurate, sorbitan monolaurate, sorbitane monooleate, and mixtures of any of the foregoing.

102. The composition according to claim 98, wherein the composition further comprises an oil selected from corn oil, castor oil, linoleoyl polyoxyl-6 glycerides, medium chain triglycerides, propylene glycol dicaprylate, glyceryl monocaprate type I, propylene glycol monocaprylate type II, caprylocaproyl polyoxyl glycerides, caprylic glycerides, oleic acid, ethyl oleate, liquid paraffin, isopropyl myristate, and mixtures of any of the foregoing.

103. The composition according to claim 82, wherein Zileuton is racemic Zileuton.

104. A method of treatment of a skin disease, wherein said method comprises administering, to a subject in need of such treatment, a composition of claim 82.

105. The method according to claim 104, wherein said disease is selected from atopic dermatitis, acne, urticaria, psoriasis, eczema, a bullous skin disease, collagenoses, Sjogren-Larsson syndrome, or acne in skin lesions of mastocytosis.

106. The method according to 104, wherein the composition is applied topically to human skin.

107. A method of preparing a topical anti-inflammatory pharmaceutical composition according to claim 82, said method comprising the following steps: heating ingredients and solvents, mixing Zileuton and dissolved ingredients as well as cooling mixed Zileuton and ingredients.

108. The method according to claim 107, said method comprising the following steps: heating ingredients and solvents under heating condition of temperature of 50° C. to 70° C., mixing Zileuton and dissolved ingredients under mixing condition of temperature of 50° C. to 70° C. with 1000 rpm to 1500 rpm of mixing speed as well as cooling mixed Zileuton and ingredients to 20° C. to 30° C.

Description

EXAMPLE 1

[0096] Solubility of Zileuton in Various Solvents

[0097] Approximately solubility of the Zileuton was measured in different vehicles. Semi-soild and waxy solid excipients were melted and tested at 50° C. or 70° C.

TABLE-US-00001 Approximate Solubility Vehicle Temp. HLB (mg/mL) Medium chain triglycerides 25° C. 1 S < 5 Linoleoyl polyoxyl-6 glycerides 25° C. 9 S < 5 Oleoyl polyoxyl-6 glycerides 25° C. 4 S < 5 Corn oil 25° C. / S < 5 Castor oil 25° C. / S < 5 Oleic acid 25° C. / S < 5 Olive oil 25° C. / S < 5 Propylene glycol monolaurate 25° C. 3  8.3 < S < 12.5 Peceol 25° C. 1 S < 5 Glyceryl monocaprate type I 25° C. /  8.3 < S < 12.5 Propylene glycol monocaprylate 25° C. / 12.5 < S < 25   type II Hexylene glycol 25° C. / 25 < S < 50 Isopropyl myristate 25° C. / S < 5 Sorbitan monolaurate 25° C. ~8 S < 5 Sorbitane monooleate 25° C. ~4 S < 5 Glyceryl monolinoleate 25° C. ~1 S < 5 Liquid paraffin 25° C. / S < 5 Ethyl oleate 25° C. / S < 5 Propylene glycol dicaprylate 25° C. 1 S < 5 Lauroyl polyoxyl-6 glycerides 50° C. 9  S < 10 Caprylic glycerides 50° C. / 18.2 < S < 28.6 Caprylocaproyl polyoxyl 25° C. ~14   40 < S < 66.7 glycerides Polyoxyl 35 hydrogenated 25° C. ~14 12.5 < S < 14.3 castor oil Polyethylene glycol octadecyl 25° C. ~15   10 < S < 11.1 ether Polyethylene glycol sorbitan 25° C. ~16 12.5 < S < 14.3 monolaurate Polyoxy ethylene sorbitan 25° C. ~15 33.3 < S < 50   monostearate Polyoxy ethylene sorbitan 25° C. ~15 12.5 < S < 14.3 monooleate Triethanolamine 25° C. /  S < 10 Polyethylene glyco-40 50° C. ~14 22.2 < S < 28.6 hydrogenated castor oil Lauroyl polyoxyl-32 glycerides 50° C. ~14  S < 10 d-a-tocopheryl polyethylene 50° C. ~14  S < 10 glycol 1000 succinate Poly-oxyethylene esters of 12- 50° C. ~14  40 < S < 100 hydroxystearic acid 20% Poloxamer 188 water 25° C. / S < 5 20% Sulfobutylether-β- 25° C. /   10 < S < 16.7 cyclodextrin in water 20% 2-Hydroxypropyl-β- 25° C. /   10 < S < 16.7 cyclodextrin in water 20% Sulfobutylether-β- 25° C. /  5 < S < 10 cyclodextrin in pH 4 sodium citrate buffer 20% 2-Hydroxypropyl-β- 25° C. /   10 < S < 16.7 cyclodextrin in pH 4 sodium citrate buffer 25 mM sodium citrate buffer 25° C. / S < 5 solution (pH = 4) Water 25° C. / S < 5 Ethanol 25° C. / 40 < S < 50 Glycerin 25° C. /  S < 10 Diethylene glycol monoethyl ether 25° C. /  S > 200 Propylene glycol 25° C. /   40 < S < 66.7 Polyethylene glycol 200 25° C. /   50 < S < 66.7 Polyethylene glycol 300 25° C. /   40 < S < 66.7 Polyethylene glycol 400 25° C. /   40 < S < 66.7 Dimethyl sulfoxide 25° C. / 100 < S < 200 N-methyl-2-pyrrolidone 25° C. /  S > 200 Dimethyl acetamide 25° C. / 66.7 < S < 100  Dimethyl formamide 25° C. / 100 < S < 200 Polyethylene glycol 1500 70° C. /  50 < S < 100 Polyethylene glycol 3350 70° C. / 25 < S < 50 Polyethylene glycol 6000 70° C. / 25 < S < 50 Glyceryl monostearate 70° C. / 25 < S < 50 White wax 70° C. / S < 5 White vaseline 70° C. / S < 5 Beeswax polyethylene glycol-8 70° C. / 15.7 < S < 25   Glyceryl mono and di stearate 70° C. / 25 < S < 50 Paraffin 70° C. / S < 5 Ethylene glycol palmitostearate 70° C. 9.5  50 < S < 100 Lanolin 70° C. / S < 5

[0098] Ointment

EXAMPLE 2

[0099] Formulation of Solution Ointment (S01 to SO20)

TABLE-US-00002 Composition SO1 SO2 SO3 SO4 SO5 SO6 SO7 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Corn oil 34.0% Propylene glycol dicaprylate 20.0% Glyceryl monocaprate type I 54.0% Propylene glycol monocaprylate type II 40.0% Caprylocaproyl polyoxyl glycerides 44.0% Diethylene glycol monoethyl ether 20.0% 20.0% 20.0% 10.0% 10.0% Polyethylene glycol 200 44.0% Polyethylene glycol 400 44.0% Stearyl alcohol 10.0% 14.0% 10.0% 14.0% 10.0% Polyethylene glycol 3350 50.0% Polyethylene glycol 6000 50.0% White vaseline 10.0% 10.0% 10.0% 10.0% 10.0% Sorbitan monolaurate 20.0% Sorbitane monooleate 20.0% Propylene glycol monolaurate 50.0% polyvinyl caprolactam-polyvinyl acetate- 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% polyethylene glycol graft copolymer Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition SO8 SO9 SO10 SO11 SO12 SO13 SO14 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Castor oil 15.0% Linoleoyl polyoxyl-6 glycerides 15.0% Medium chain triglycerides 15.0% Glyceryl monocaprate type I 40.0% Caprylocaproyl polyoxyl glycerides 30.0% Caprylic Glycerides 44.0% Diethylene glycol monoethyl ether 10.0% 10.0% 10.0% 25.0% Polyethylene glycol 200 50.0% Polyethylene glycol 300 29.0% 29.0% N-methyl-2-pyrrolidone 5.0% Dimethyl formamide 5.0% Dimethyl acetamide 10.0% Hexylene glycol 40.0% Stearyl alcohol 10.0% 14.0% 19.0% Beeswax polyethylene glycol-8 15.0% Polyethylene glycol 1500 40.0% 45.0% Polyethylene glycol 6000 25.0% 44.0% Polyethylene glycol 8000 20.0% White vaseline 10.0% 10.0% 14.0% 10.0% polyvinyl caprolactam-polyvinyl acetate- 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% polyethylene glycol graft copolymer Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition SO15 SO16 SO17 SO18 SO19 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% Medium chain triglycerides 20.0% Oleic acid 20.0% Ethyl oleate 20.0% Liquid paraffin 20.0% Isopropyl myristate Diethylene glycol monoethyl ether 20.0% 25.0% 25.0% 25.0% 25.0% Propylene glycol Dimethyl sulfoxide 5.0% Polyacrylic acid Glyceryl mono and di stearate 19.0% Stearic acid 9.0% Cetyl alcohol 19.0% Mono and diglycerides 19.0% Paraffin 10.0% Lanolin 30.0% White vaseline 30.0% 30.0% 30.0% 30.0% Ethylene glycol palmitostearate 19.0% Propylene glycol monolaurate 20.0% polyvinyl caprolactam-polyvinyl acetate- 1.0% 1.0% 1.0% 1.0% 1.0% polyethylene glycol graft copolymer Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0%

[0100] Process of Formulation Preparation for Solution Ointment (SO1 to SO19)

TABLE-US-00003 Formulation Process SO1 to SO7, Step 1: Weigh all excipients except some polar SO8 to SO10 solvent and add into 4 mL vial. And then melt all the excipients at 70° C./1000 rpm until getting a homogeneous solution. Step 2: Weigh 100 mg of Zileuton and add into a 2 mL vial and then add the solvent of formulation to dissolve/dispense it. Step 3: Transfer Step 2 solution to Step 1 and stir for 30 min at ~70° C./1000 rpm. Step 4: Cool down to room temperature. SO11 to SO13 Step 1: Weigh all excipients and add into 4 ml vial. And melt them at 70° C./1000 rpm until getting a homogeneous solution and then cool down to 60° C. Step 2: Weigh 100 mg of Zileuton and add into the 4 mL vial and then stir for 30 min until getting a homogeneous solution. Step 3: Transfer Step 2 solution to Step 1 and stir for 30 min ~60° C./1000 rpm. Step 4: Cool down to room temperature. SO14 to SO19 Step 1: Weigh all excipients and add into 4 ml vial. And melt them at 70° C./1000 rpm until getting a homogeneous solution and then cool down to 50° C. Step 2: Weigh 100 mg of Zileuton and add into the 4 ml vial and then stir for 30 min until getting a homogeneous solution. Step 3: Transfer Step 2 solution to Step 1 and stir for 30 min ~50° C./1000 rpm. Step 4: Cool down to room temperature.

EXAMPLE 3

[0101] Formulation of Suspension Ointment (SPO1 to SPO17)

TABLE-US-00004 Composition SPO1 SPO2 SPO3 SPO4 SPO5 SPO6 SPO7 Ziluton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Castor oil 40.0% Oleic acid 40.0% Linoleoyl polyoxyl-6 glycerides 40.0% Medium chain triglycerides 40.0% 40.0% Ethyl oleate 40.0% Propylene glycol dicaprylate 40.0% Cetyl alcohol 10.0% Stearyl alcohol 10.0% Paraffin 10.0% Beeswax polyethylene glycol-8 10.0% White wax 10.0% Lanolin 15.0% White vaseline 40.0% 45.0% 45.0% 45.0% 45.0% 45.0% 45.0% Ethylene glycol palmitostearate 10.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition SPO8 SPO9 SPO10 SPO11 SPO12 SPO13 SPO14 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Castor oil 40.0% Medium chain triglycerides 40.0% 40.0% Glyceryl monolinoleate 40.0% Liquid paraffin 40.0% Peceol 40.0% Isopropyl myristate 40.0% Polyacrylic acid 10.0% Cetyl alcohol 10.0% Paraffin 10.0% 10.0% Mono and diglycerides 10.0% Stearic acid 10.0% Glyceryl mono and di stearate 10.0% Lanolin 45.0% White vaseline 45.0% 45.0% 45.0% 45.0% 45.0% 45.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition SPO15 SPO16 SPO17 Zileuton 5.0% 5.0% 5.0% Olive Oil 40.0% Oleoyl polyoxyl-6 glycerides 40.0% Lauroyl polyoxyl-6 glycerides 30.0% Glyceryl monocaprate type I 20.0% Stearyl alcohol 10.0% 10.0% Paraffin Mono and diglycerides Glyceryl mono and di stearate Lanolin 45.0% White vaseline 45.0% 45.0% Sorbitan monolaurate Sorbitane monooleate Propylene glycol monolaurate Total weight (mg) 100.0% 100.0% 100.0%

[0102] Process of Formulation Preparation for Suspension Ointment (SPO1 to SPO17)

TABLE-US-00005 Formulation Process SPO1 to SPO13 Step 1: Mill Zileuton using mortar into ~10 micrometer of particle size observed by polarized light microscope (PLM). Step 2: Weigh all excipients and add into 4 mL vial. And then melt all the excipients at 70° C./ 1000 rpm until getting a homogeneous solution. Step 3: Weigh 100 mg of milled Zileuton into the 4 mL vial and then stir 15 min at ~70° C./ 1000 rpm. Step 4: Transfer Step 3 solution to Step 2 and stir for 30 min at ~70° C./1000 rpm. Step 5: Cool down to room temperature. SPO14 to SPO17 Step 1: Mill Zileuton using mortar into ~10 micrometer of particle size observed by PLM. Step 2: Weigh all excipients and add into 4 mL vial. And melt all the excipients at 70° C./ 1000 rpm until getting a homogeneous solution and then cool down to 50° C. Step 3: Weigh 100 mg of milled Zileuton into the 4 mL vial and then stir 30 min at ~50° C./ 1000 rpm. Step 4: Transfer Step 3 solution to Step 2 and stir for 30 min at ~50° C./1000 rpm. Step 5: Cool down to room temperature.

[0103] Cream

EXAMPLE 4

[0104] Formulation of Solution Cream (SC1 to SC20)

TABLE-US-00006 Composition SC1 SC2 SC3 SC4 SC5 SC6 SC7 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Corn oil 20.0% Linoleoyl polyoxyl-6 glycerides 20.0% Glyceryl monocaprate type I 20.0% Propylene glycol monocaprylate type II 20.0% Caprylocaproyl polyoxyl glycerides 20.0% Caprylic glyceride 24.0% Ethanol 20.0% Diethylene glycol monoethyl ether 25.0% 20.0% 9.0% 14.0% 20.0% N-methyl-2-pyrrolidone 10.0% Dimethyl formamide 10.0% Dimethyl acetamide 10.0% Hexylene glycol 20.0% Cetyl alcohol 24.0% 25.0% Stearyl alcohol 20.0% 20.0% Beeswax polyethylene glycol-8 20.0% 20.0% 14.0% Lanolin 25.0% 25.0% 30.0% White vaseline 10.0% 25.0% 20.0% Ethylene glycol palmitostearate 15.0% Caprylocaproyl polyoxyl glycerides 9.0% 10.0% Polyoxyl 35 hydrogenated castor oil 14.0% Polyethylene glycol-40 hydrogenated 10.0% castor oil Sodium lauryl sulfate 10.0% d-a-tocopheryl polyethylene glycol 1000 10.0% succinate Propylene glycol monolaurate 20.0% Polyvinyl caprolactam-polyvinyl acetate- 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% polyethylene glycol graft copolymer Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition SC8 SC9 SC10 SC11 SC12 SC13 SC14 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Medium chain triglycerides 20.0% 10.0% 20.0% Ethyl oleate 20.0% Propylene glycol dicaprylate 20.0% Caprylic glyceride 20.0% Diethylene glycol monoethyl ether 25.0% 25.0% 20.0% Propylene glycol 20.0% Polyethylene glycol 200 30.0% Polyethylene glycol 300 30.0% Polyethylene glycol 400 30.0% Mono and diglycerides 9.0% 14.0% Glyceryl mono and di stearate 14.0% 14.0% Polyethylene glycol 3350 14.0% 14.0% 14.0% Ethylene glycol palmitostearate 20.0% 20.0% 15.0% 20.0% 30.0% 20.0% 20.0% Sorbitan monolaurate 10.0% Sorbitane monooleate 20.0% Polyethylene glycol sorbitan 20.0% monolaurate Polyoxyethylene sorbitan monooleate 20.0% d-a-tocopheryl polyethylene glycol 1000 20.0% succinate Triethanolamine 10.0% 10.0% Lecithin from egg 10.0% Poly-oxyethylene esters of 12- 10.0% hydroxystearic acid Polyvinyl caprolactam-polyvinyl acetate- 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% polyethylene glycol graft copolymer Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition SC15 SC16 SC17 SC18 SC19 SC20 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Medium chain triglycerides 20.0% 20.0% Glyceryl monolinoleate 20.0% Peceol 20.0% Isopropyl myristate 20.0% Ethanol 30.0% Diethylene glycol monoethyl ether 20.0% 30.0% 30.0% 20.0% 30.0% Beeswax polyethylene glycol-8 14.0% White wax 14.0% 14.0% Stearic acid 15.0% Glyceryl mono and di stearate 20.0% Polyethylene glycol 1500 10.0% Polyethylene glycol 6000 10.0% Lanolin 20.0% 34.0% White vaseline 20.0% 20.0% Ethylene glycol palmitostearate 24.0% 20.0% Sorbitan monolaurate 9.0% Polyethylene glycol octadecyl ether 10.0% Polyoxy ethylene sorbitan monooleate 10.0% d-a-tocopheryl polyethylene glycol 1000 10.0% succinate Lecithin from soybean 10.0% Poloxamer 407 10.0% Poloxamer 188 10.0% Polyvinyl caprolactam-polyvinyl acetate- 1.0% 1.0% 1.0% 1.0% 1.0% 1.0% polyethylene glycol graft copolymer Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

[0105] Process of Formulation Preparation for Solution Cream (SC1 to SC20)

TABLE-US-00007 Formulation Process SC1, SC3, SC4, SC5, Step 1: Weigh all excipients and add into SC8, SC9, SC10, SC11, 4 mL vial and then melt them at 70° C./ SC12, SC14, SC15, 1000 rpm until getting a homogeneous solution. SC18, SC19 Step 2: Weigh 100 mg of Zileuton and add into the 4 mL vial and then stir for 15 min at ~50° C./1000 rpm. Step 3: Transfer Step 2 solution to Step 1 and stir for 30 min at ~50° C./1000 rpm. Step 4: Cool down to room temperature. SC2, SC6, SC7, SC13, Step 1: Weigh all excipients and add into SC16, SC17 4 mL vial and then melt them at 70° C./ 1000 rpm until getting a homogeneous solution. Step 2: Weigh 100 mg of Zileuton and add into the 4 mL vial and then stir for 15 min at ~70° C./1000 rpm. Step 3: Transfer Step 2 solution to Step 1 and stir for 30 min at ~70° C./1000 rpm. Step 4: Cool down to room temperature. SC20 Step 1: Weigh all excipients and add into 4 mL vial and then melt them at 70° C./ 1000 rpm until getting a homogeneous solution. Step 2: Weigh 100 mg of Zileuton and add into the 4 mL vial and then stir for overnight at ~50° C./1000 rpm. Step 3: Transfer Step 2 solution to Step 1 and stir for 30 min at ~50° C./1000 rpm. Step 4: Cool down to room temperature.

EXAMPLE 5

[0106] Formulation of Suspension Cream (SPC1 to SPC20)

TABLE-US-00008 Composition SPC1 SPC2 SPC3 SPC4 SPC5 SPC6 SPC7 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Medium chain triglycerides 20.0% Liquid paraffin 20.0% Peceol 20.0% Caprylic glycerides 20.0% Isopropyl myristate 20.0% Glycerin 25.0% 25.0% 25.0% 25.0% 25.0% 25.0% 25.0% Cetyl alcohol 20.0% 20.0% Stearyl alcohol 20.0% Paraffin 20.0% Beeswax polyethylene glycol-8 20.0% White wax 20.0% Mono and diglycerides 20.0% Lanolin 20.0% 20.0% 20.0% White vaseline 20.0% 20.0% 20.0% 20.0% Sorbitan monolaurate 20.0% Sorbitane monooleate 20.0% Polyoxyl 35 hydrogenated castor oil 10.0% Polyethylene glycol-40 hydrogenated 10.0% castor oil Sodium lauryl sulfate 10.0% Polyethylene glycol octadecyl ether 10.0% Lauroyl poloxyl-32 glycerides 10.0% Lecithin from egg 10.0% Polyoxy ethylene sorbitan monooleate 10.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition SPC8 SPC9 SPC10 SPC11 SPC12 SPC13 SPC14 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Medium chain triglycerides 20.0% 20.0% 20.0% Glyceryl monolinoleate 20.0% Lauroyl polyoxyl-6 glycerides 20.0% Ethyl oleate 20.0% Propylene glycol dicaprylate 20.0% Glycerin 25.0% 25.0% 25.0% 25.0% 25.0% 25.0% 25.0% Cetyl alcohol 20.0% Stearyl alcohol 10.0% Stearic acid 20.0% Glyceryl mono and di stearate 20.0% 10.0% 20.0% Lanolin 20.0% 20.0% 20.0% White vaseline 20.0% 20.0% 20.0% 20.0% Lecithin from soybean 10.0% Polyethylene glycol sorbitan 10.0% monolaurate Polyoxy ethylene sorbitan monostearate 10.0% d-a-tocopheryl polyethylene glycol 1000 10.0% succinate 2-Hydroxypropyl-β-cyclodextrin 10.0% Sulfobutylether-β-cyclodextrin 20.0% Poloxamer 407 20.0% Poly-oxyethylene esters of 12- 10.0% hydroxystearic acid Triethanolamine 10.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition SPC15 SPC16 SPC17 SPC18 SPC19 SPC20 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Castor oil 20.0% Oleic acid 20.0% Olive oil 20.0% Linoleoyl polyoxyl-6 glycerides 20.0% Oleoyl polyoxyl-6 glycerides 20.0% Glycerin 25.0% 25.0% 25.0% 25.0% 25.0% 25.0% Cetyl alcohol 20.0% 20.0% Stearyl alcohol 20.0% Paraffin 20.0% Beeswax polyethylene glycol-8 20.0% 20.0% White wax 20.0% Mono and diglycerides 20.0% Stearic acid 10.0% Glyceryl mono and di stearate 10.0% Lanolin 20.0% White vaseline 20.0% 20.0% Lecithin from egg 10.0% Lecithin from soybean 10.0% d-a-tocopheryl polyethylene glycol 1000 10.0% succinate Poloxamer 407 10.0% Poloxamer 188 10.0% Triethanolamine 10.0% Propylene glycol monolaurate 20.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

[0107] Process of Formulation Preparation for Suspension Cream (SPC1 to SPC20)

TABLE-US-00009 Formulation Process SPC1 to SPC9; Step 1: Mill Zileuton using mortar into ~10 SPC14 micrometer of particle size observed by PLM. Step 2: Weigh all excipients and add into 4 mL vial. And then melt all the excipients at 70° C./ 1000 rpm until getting a homogeneous solution. Step 3: Weigh 100 mg of milled Zileuton into the 4 mL vial and then stir 15 min at ~60° C./ 1000 rpm. Step 4: Transfer Step 3 solution to Step 2 and stir for 30 min at ~60° C./1000 rpm. Step 5: Cool down to room temperature. SPC10 to SPC11; Step 1: Mill Zileuton using mortar into ~10 SPC13, SPC15, micrometer of particle size observed by PLM. SPC16, SPC17 Step 2: Weigh all excipients and add into 4 mL to SPC20 vial. And then melt all the excipients at 70° C./ 1000 rpm until getting a homogeneous solution. Step 3: Weigh 100 mg of milled Zileuton into the 4 mL vial and then stir 15 min at ~70° C./ 1000 rpm. Step 4: Transfer Step 3 solution to Step 2 and stir for 30 min at ~70° C./1000 rpm. Step 5: Cool down to room temperature.

EXAMPLE 6

[0108] Formulation of Water/Buffer solution Cream (WB1 to WB20)

TABLE-US-00010 Composition WB1 WB2 WB3 WB4 WB5 WB6 WB7 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Medium chain triglycerides 7.5% Propylene glycol dicaprylate 15.0% Glyceryl monocaprate type I 20.0% Propylene glycol monocaprylate type II 20.0% Caprylic glycerides 15.0% Diethylene glycol monoethyl ether 20.0% 20.0% 9.0% 25.0% 25.0% 20.0% Propylene glycol 20.0% Dimethyl formamide 10.0% Hexylene glycol 15.0% Cetyl alcohol 20.0% Stearyl alcohol 20.0% 20.0% Glyceryl mono and di stearate 9.0% 14.0% 14.0% 14.0% Lanolin 20.0% White vaseline 20.0% 20.0% Ethylene glycol palmitostearate 20.0% 15.0% 20.0% 30.0% Sorbitan monolaurate 7.5% Sorbitane monooleate 15.0% Caprylocaproyl polyoxyl glycerides 9.0% 9.0% Polyethylene glycol-40 hydrogenated 10.0% castor oil Lecithin from egg 10.0% Polyethylene glycol sorbitan 20.0% monolaurate Polyoxy ethylene sorbitan monooleate 20.0% d-a-tocopheryl polyethylene glycol 1000 20.0% succinate Pure water 6.0% 6.0% Acid Phthalate buffer (pH4.0) 6.0% Acetate buffer (pH 4.1) 11.0% Citrate buffer (pH4.0) 6.0% Phosphate buffer (pH6.0) 6.0% Merck buffer pH4.0 6.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition WB8 WB9 WB10 WB11 WB12 WB13 WB14 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Medium chain triglycerides 15.0% 15.0% 15.0% Ethyl oleate 15.0% Glyceryl monocaprate type I 15.0% Caprylocaproyl polyoxyl glycerides 15.0% Glyceryl monolinoleate 15.0% Ethanol 30.0% 20.0% Diethylene glycol monoethyl ether 20.0% 30.0% Polyethylene glycol 200 30.0% Polyethylene glycol 300 30.0% N-methyl-2-pyrrolidone 10.0% White wax 14.0% Beeswax polyethylene glycol-8 14.0% 20.0% Cetyl alcohol 24.0% 25.0% Polyethylene glycol 1500 10.0% Polyethylene glycol 3350 14.0% 14.0% Polyethylene glycol 6000 10.0% Lanolin 25.0% White vaseline 20.0% Ethylene glycol palmitostearate 20.0% 20.0% 24.0% 20.0% Polyoxyl 35 hydrogenated castor oil 14.0% Polyoxy ethylene sorbitan monooleate 10.0% d-a-tocopheryl polyethylene glycol 1000 10.0% succinate Poly-oxyethylene esters of 12- 10.0% hydroxystearic acid Poloxamer 407 10.0% Triethanolamine 10.0% 10.0% Pure water 6.0% Acid phthalate buffer (pH4.0) 6.0% 6.0% Acetate buffer (pH 4.1) 6.0% Citrate buffer (pH4.0) 6.0% Phosphate buffer (pH6.0) 6.0% Merck buffer pH4.0 6.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition WB15 WB16 WB17 WB18 WB19 WB20 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Medium chain triglycerides 15.0% Caprylocaproyl polyoxyl glycerides 10.0% 15.0% Corn oil 15.0% Linoleoyl polyoxyl-6 glycerides 15.0% Diethylene glycol monoethyl ether 14.0% 20.0% 15.0% Polyethylene glycol 400 30.0% Dimethyl acetamide 10.0% Hexylene glycol 15.0% Beeswax polyethylene glycol-8 20.0% 14.0% Cetyl alcohol 25.0% Polyethylene glycol 3350 14.0% Lanolin 30.0% 9.0% White vaseline 20.0% Ethylene glycol palmitostearate 20.0% 15.0% 50.0% 50.0% Poly-oxyethylene esters of 12- 50.0% hydroxystearic acid Triethanolamine 10.0% Sodium lauryl sulfate 10.0% Lauroyl polyoxyl-32 glycerides 5.0% Acid phthalate buffer (pH4.0) 6.0% Acetate buffer (pH 4.1) 6.0% Citrate buffer (pH4.0) 6.0% Phosphate buffer (pH6.0) 6.0% Merck buffer pH4.0 10.0% 20.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

[0109] Process of Formulation Preparation for Water/Buffer solution Cream (WB1 to WB20)

TABLE-US-00011 Formulation Process WB1 to WB20 Step1: Weight all excipients (except Zileuton and water/buffer) and add into a 4 mL vial. Step 2: Stir all the excipient at 70° C./1500 rpm until getting a homogeneous solution and then cool it to 50-60° C. Step3: Weight Zileuton and water/buffer and add to Step 2 vial and stir at 1500 rpm until getting a homogeneous solution. Step 4: Cool down to room temperature.

[0110] Gel

EXAMPLE 7

[0111] Formulation of Gel (Gel-1 to Ge1-20)

TABLE-US-00012 Composition Gel-1 Gel-2 Gel-3 Gel-4 Gel-5 Gel-6 Gel-7 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Ethanol 80.0% Diethylene glycol monoethyl ether 75.0% 57.0% Propylene glycol 80.0% Polyethylene glycol 200 80.0% Polyethylene glycol 300 80.0% Polyethylene glycol 400 80.0% N-methyl-2-pyrrolidone 5.0% Acrylic acid polymer 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 8.0% Triethanolamine 5.0% Pure water 10.0% 15.0% 10.0% 10.0% 10.0% 0.01N HCl (pH 2.0) 20.0% Phosphate buffer (pH 7.5) 10.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition Gel-8 Gel-9 Gel-10 Gel-11 Gel-12 Gel-13 Gel-14 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Diethylene glycol monoethyl ether 55.0% 55.0% 55.0% 55.0% 55.0% Propylene glycol 57.0% Polyethylene glycol 400 57.0% Dimethyl formamid 5.0% Dimethyl acetamide 5.0% Acrylic acid polymer 8.0% 8.0% 3.0% 5.0% 5.0% 5.0% 5.0% Poly-oxyethylene esters of 12- 20.0% hydroxystearic acid Triethanolamine 5.0% 5.0% Caprylocaproyl polyoxy lglycerides 20.0% Polyethylene glycol-40 hydrogenated 20.0% castor oil Polyoxy ethylene sorbitan monooleate 20.0% d-a-tocopheryl polyethylene glycol 1000 20.0% succinate Pure water 17.0% 15.0% 15.0% 15.0% 15.0% Sodium citrate buffer (pH 4.0) 20.0% Phosphate buffer (pH 6.0) 20.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition Gel-15 Gel-16 Gel-17 Gel-18 Gel-19 Gel-20 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Diethylene glycol monoethyl ether 50.0% 50.0% Propylene glycol 25.0% Polyethylene glycol 200 25.0% Methylcellulose 400 cP 10.0% Methylcellulose 4000 cP 10.0% Hydroxy propyl methyl cellulose K4M 5.0% Hydroxy propyl methyl cellulose K15M 10.0% Sodium carboxymethyl cellulose 20.0% Gum acacia 30.0% Caprylocaproyl polyoxyl glycerides 20.0% Polyoxyl 35 hydrogenated castor oil 20.0% Pure water 60.0% 45.0% 0.01N HCl (pH 2.0) 60.0% Sodium citrate buffer (pH 4.0) 40.0% Phosphate buffer (pH 6.0) 35.0% Phosphate buffer (pH 7.5) 55.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

[0112] Process of Formulation Preparation for Gel (Gel-1 to Gel-20)

TABLE-US-00013 Formulation Process Gel-1 to Gel-14 Step 1: Weight Zileuton, solvent and surfactant and add into 4 mL vail Step 2: Vortex and sonicate until Zileuton is fully dissolved at room temperature. Step 3: Add gel material and water/buffer solution to Step 2 and then stir manually for 15 min at room temperature. Gel-15 to Gel 20 Step 1: Weight Zileuton, solvent and surfactant and add into 4 mL vail Step 2: Vortex and sonicate until getting a homogeneous solution. Step 3: Add gel material and water/buffer solution to Step 2 and then stir manually for 15 min at room temperature.

[0113] Lotion

EXAMPLE 8

[0114] Formulation of Lotion (LO1 to LO20)

TABLE-US-00014 Composition LO1 LO2 LO3 LO4 LO5 LO6 LO7 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Diethylene glycol monoethyl ether 75.0% 25.0% 50.0% 10.0% Propylene glycol 45.0% Polyethylene glycol 200 45.0% Polyethylene glycol 300 45.0% Polyethylene glycol 400 45.0% N-methyl-2-pyrrolidone 5.0% Dimethyl formamide 5.0% Dimethyl acetamide 5.0% Caprylocaproyl polyoxyl glycerides 50.0% 25.0% Poly-oxyethylene esters of 12- 25.0% hydroxystearic acid Polyoxy ethylene sorbitan monooleate 25.0% d-a-tocopheryl polyethylene glycol 1000 25.0% succinate Triethanolamine 25.0% Pure water 20.0% 15.0% Acid phthalate buffer (pH4.0) 20.0% Acetate buffer (pH 4.1) 20.0% Citrate buffer (pH4.0) 20.0% Phosphate buffer (pH6.0) 20.0% Merck buffer pH4.0 20.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition LO8 LO9 LO10 LO11 LO12 LO13 LO14 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Caprylocaproyl polyoxyl glycerides 10.0% 50.0% Ethanol 45.0% 50.0% Diethylene glycol monoethyl ether 10.0% 10.0% 10.0% 10.0% 20.0% Propylene glycol 50.0% Hexylene glycol 10.0% Polyethylene glycol 200 50.0% Polyethylene glycol 300 50.0% Polyethylene glycol 1500 20.0% Sodium lauryl sulfate 20.0% Polyethylene glycol octadecyl ether 20.0% Lecithin from soybean 25.0% Polyoxyl 35 hydrogenated castor oil 20.0% Polyethylene glycol-40 hydrogenated 20.0% castor oil Poly-oxyethylene esters of 12- 50.0% hydroxystearic acid Pure water 15.0% Acid phthalate buffer (pH4.0) 15.0% 15.0% Acetate buffer (pH 4.1) 15.0% Citrate buffer (pH4.0) 15.0% Phosphate buffer (pH6.0) 15.0% Merck buffer pH4.0 15.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% Composition LO15 LO16 LO17 LO18 LO19 LO20 Zileuton 5.0% 5.0% 5.0% 5.0% 5.0% 5.0% Glyceryl monocaprate Type I 10.0% Propylene glycol monocaprylate type II 10.0% Ethanol 15.0% 15.0% Polyethylene glycol 200 30.0% Polyethylene glycol 400 20.0% Polyethylene glycol 1500 55.0% Polyethylene glycol 3350 20.0% 25.0% Dimethyl formamide 10.0% Sorbitan monolaurate 20.0% Caprylocaproyl polyoxyl glycerides 50.0% Polyoxy ethylene sorbitan monostearate 20.0% Poly-oxyethylene esters of 12- 50.0% 50.0% 65.0% hydroxystearic acid Polyoxy ethylene sorbitan monooleate Propylene glycol monolaurate 10.0% Acetate buffer (pH 4.1) 15.0% Citrate buffer (pH4.0) 20.0% Phosphate buffer (pH6.0) 20.0% Merck buffer (pH4.0) 20.0% 20.0% Total weight (mg) 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

[0115] Process of Formulation Preparation for Lotion (LO1 to LO20)

TABLE-US-00015 Formulation Process LO1 to LO3, LO5 to Step 1: Weigh all excipients except Zileuton LO6, LO12 and add into 4 mL vial and then melt them at 70° C./1000 rpm until getting a homogeneous solution and then cool to room temperature. Step 2: Weigh 100 mg of Zileuton and add into the 4 mL vial and then vortex and sonicate until getting homogeneous solution at room temperature. LO4, LO7 to LO11, Step 1: Weight all excipients including Zileuton LO13 to LO20 and add into 4 mL vial Step 2: Vortex and sonicate until getting homogeneous solution at room temperature.

EXAMPLE 9

[0116] Phorbol Ester Induced Ear Edema Test

[0117] The effect of Zileuton-containing formulations on phorbol ester induced ear edema in ICR mice was evaluated. One hundred and twenty (120) female ICR mice were assigned to eleven (11) groups by randomization with BioBook software to achieve similar mean weight and right ear thickness baseline among groups. Mice were terminated by 95% CO.sub.2 asphyxiation and then cervical dislocation.

[0118] Totally nine (9) Zileuton-containing formulations which are SO13, SO17, WB6, Gel-10, Gel-11, LO3, LO13, SPC19 and Zileuton 1.0% cream were selected for the tests Dexamethasone were used for the reference and Acetone was treated to the vehicle group.

[0119] Mice were anesthetized with 2-5 isoflurane. The mice were sensitized by painting 5 μg of phorbol ester dissolved in 0.02 mL of Acetone on ear inside and out. For dosing of test compounds and positive controls, animals were anesthetized with 2-5% isoflurane for about 5 minutes to ensure that the test compounds and positive controls were well given to the skin and not licking by the mice. Six (6) hours after the modeling, the both side's ear thickness were measured after anesthetized by isoflurane (2-3%), respectively. Ear swelling response was determined by ear thickness measured with a micrometer before challenge and 6 hours after challenge and reported as the mean change in ear thickness (ΔT±S.E.M.). Percent suppression of ear swelling response was calculated as % suppression=[1−(ΔT of sensitized mice exposed to experimental treatment/ΔT of sensitized mice exposed to vehicle treatment)]×100.

[0120] Results are shown in FIG. 1.

[0121] Phorbol ester (5 μg/ear) induced an edematogenic response as evidenced by a marked increase in ear thickness. As the treatment with positive control Dexamethasone showed significant decrease in ear swelling. And the test compounds which are nine (9) Zileuton-containing formulations showed good disease inhibition ration. In comparison to Zileuton 1.0% cream, 5013, WB6, Gel-10 and Gel-11 showed significant disease inhibition, especially test article 4 which is Gel-10 showed most strong disease inhibition which presented as the highest suppression rate.

TABLE-US-00016 TABLE Suppression Rate % suppression Group Vs G1-right ear PMA-Dex 27.14 PMA-Test article 1 SO13 29.15 PMA-Test article 2 SO17 25.13 PMA-Test article 3 WB6 32.16 PMA-Test article 4 Gel-10 36.68 PMA-Test article 5 Gel-11 26.63 PMA-Test article 6 LO3 23.62 PMA-Test article 7 LO13 21.11 PMA-Test article 8 SPC19 22.11 PMA-Test article 9 Zileuton 1.0% cream 15.08