(12) Patent Application Publication (10) Pub. No.: US 2007/0299044 A1 Faring Et Al

US 20070299044A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0299044 A1 Faring et al. (43) Pub. Date: Dec. 27, 2007

(54) CORTICOSTEROID TOPICAL DISPERSION Related U.S. Application Data WITH LOW CONTENT OF SURFACTANT (60) Provisional application No. 60/610,139, filed on Sep. (76) Inventors: Richard K. Farng, East Brunswick, NJ 15, 2004. (US); Chung-Tsin Chiu, Miami, FL (US); Ba Cuong Tu, Miami, FL (US); Publication Classification Kenneth W. Kwochka, St. Joseph, MO (51) Int. Cl. (US) A6II 3/56 (2006.01) A6IP 29/00 (2006.01) Correspondence Address: (52) U.S. Cl...... S14/178 LERNER, DAVID, LITTENBERG, KRUMHOLZ. & MENTLIK (57) ABSTRACT 6OO SOUTHAVENUE WEST The invention provides novel compositions of water-in WESTFIELD, NJ 07090 (US) soluble corticosteroid drug in combination with antimicro (21) Appl. No.: 11/662,538 bial agents and very low concentrations of polymers and Surfactants for topical, otic and ophthalmic treatment. The (22) PCT Filed: Sep. 15, 2005 invention provides stable aqueous Suspension where the ingredients remain in Such a state so as to allow for imme (86). PCT No.: PCT/USOS/32641 diate re-suspension, when desired, even after extended peri ods of settling. The invention provides also a method for S 371(c)(1), treating inflammation with low systemic absorption and (2), (4) Date: Jul. 23, 2007 side-effects of the corticosteroid. US 2007/0299044 A1 Dec. 27, 2007

CORTICOSTEROID TOPCAL DISPERSON WITH provides formulations having ionic polymers and very low LOW CONTENT OF SURFACTANT concentrations of Surfactants. It is Surprisingly found that at the low concentrations of non-ionic polymers (e.g., 0.005% BACKGROUND OF THE INVENTION to 0.2% w/w), the re-suspension of the drug substance is better than the formulation comprising conventional con 0001 Typically topical, otic, or ophthalmic products con centrations (i.e., 0.2-2% w/w) of non-ionic polymers. The taining water insoluble steroid(s) alone or in combination following table shows molar ratios of steroid, polymers, and with antimicrobial agent(s) are very greasy because of surfactant that can be used in this invention. These molar mineral oil or petrolatum present in the Suspension. Such ratios of non-ionic polymer and Surfactant range from about products are very hard to instill and spread into the ear canal 1.7 to more than 1300 fold below the limits of U.S. Pat. No. or skin folds, especially on haired areas. In the case of otic 5,540,930,

U.S. Pat. No. 5,540,930 MW % Wiw mM Molar ratio Molar Ratio Lower limit Etiprednol 485.41 4.120228 1 1 Dicloacetate Methocel (R) 86,000 O.OOS-O.2 O.OOS814-O.O232SS8 OOOO141-0.0056443 O.O1

Merquat (R) 1,600,000 O.OOS-2 O.OOO313-0.0125 O.OOOOO76-O.OO3O34 Doesn't have non 550 (9% ionic polymers. solid) Tyloxapol 5,000 O.OOS-O.3 O.01-02 O.0024271-0.048.5410 O.S application, the “oily residue” stays in the ear canal after 0006. In addition to the unexpected improvements in application for prolonged periods of time, which is not physical properties, the use of low concentrations of Surfac desirable. tant and non-ionic polymer also surprisingly improves the 0002 There are some aqueous suspensions (for example, pharmacological profile when compared to the formulation Lotemax Suspension, for ophthalmic use) or oil-in-water of drug Suspended in mineral oil or without polymer. This lotion products for topical use. However, many of these second unexpected result is the reduction in Systemic products still leave non-drug residues because of high con absorption of steroid, which is highly desirable given the centrations of Suspending agents (0.2% w/w for example), side effects of steroidal drugs. Furthermore, contrary to U.S. surfactants (2-5% w/w) and/or oily components (2-10% Pat. No. 5,540,930, which is limited to non-ionic polymer w/w) which may cause harmful effects. The ideal topical, only, however, we have also discovered that ionic polymers otic, or ophthalmic formulation should be low in residues, isotonic, aqueous based, and physically and chemically (e.g., Merquat(R) 550 and/or Xanthan gum) also work well in stable. the present steroidal formulations. 0003) In U.S. Pat. No. 5,540,930, the non-ionic polymer 0007 Thus, surprisingly, we have found that by reducing concentration in its steroid composition is about 0.2-2% w/w the concentration of Surfactant (e.g., Tyloxapol) from the and the claimed molar concentration range for the steroid prior art teaching of 0.3-2% w/w to 0.005-0.3% w/w and by :non-ionic-polymer:surfactant is between about 1:20:1 and either adding an ionic polymer or a low concentration, about 1:0.01:0.5. U.S. Pat. No. 5,540,930 indicates that the 0.005-0.2% w/w, of non-ionic polymer, the systemic absorp polymer used in the formulation has to be non-ionic. tion and as a consequence, the systemic (side) effect of 0004. A reduction in amount of polymer and surfactant anti-inflammatory corticosteroids, could be reduced by used in a steroid composition should be beneficial to the approximately 60%. biological membrane. Thus, there exists a need for aqueous Suspensions of water insoluble corticosteroids, which are DETAILED DESCRIPTION OF THE free of problems of prior art formulations which can be INVENTION easily applied. 0008. A soft steroid antimicrobial combination topical and/or otic formulation has broad application for inflamma SUMMARY OF THE INVENTION tory conditions complicated by secondary bacterial and/or 0005 The present invention provides formulations hav fungal infections. In fact, most ear and skin infections in ing very low concentrations of non-ionic polymers and very companion animals are precipitated by an inflammatory low concentrations of Surfactants. The present invention also process. US 2007/0299044 A1 Dec. 27, 2007

0009 Examples of cutaneous and otic inflammatory dis 0030 urinary potassium increase, which leads to eases include but are not limited to: hypokalemia and metabolic alkalosis, 0010 Parasites such as Otodectes cynotis, Demodex 0031 hyperglycemia, spp., Sarcoptes scabiei, Notoedres cati, Cheyletiella spp., Ctenocephalides felis 0032 delay in wound healing, 0011 Foreign bodies such as plant awns 0033 altered calcium metabolism with prolonged 0012 Hypersensitivity and allergic diseases such as treatment, resulting in osteoporosis and bone fractures, atopic dermatitis and otitis, food related dermatitis and otitis, contact allergic and irritant cutaneous and otic 0034 reduction in GI motility, thinning of the gastric reactions, feline eosinophilic dermatitis mucosa, and reduced mucus production, thus resulting in gastrointestinal ulceration. 0013 Autoimmune diseases such as pemphigus folia ceus, pemphigus erythematosus, pemphigus Vulgaris, 0035. Therefore, a significant reduction in systemic pemphigus Vegitans, discoid lupus erythematosus, absorption of steroid from formulation, which results in a cutaneous vasculitis, bullous pemphigoid, and mucous safer long-term use of corticosteroids is highly desirable. membrane pemphigoid 0036). Some of the materials and their sources that can be 0014 Bacterial and fungal infections may present sec used in the current inventions are listed below. The first table ondary to the above inflammatory diseases or as primary lists examples of water insoluble corticosteroids and anti infections. Common canine and feline cutaneous and/or otic microbial agents that can be combined with the steroids. pathogens include but are not limited to: More than one steroid or more than one anti-microbial can 0015 Staphylococcus intermedius be used in the present invention. 0016 Staphylococcus aureus

0017 Staphylococcus Schleiferi Drug Substance Manufacturer Address 0018 Pseudomonas aeruginosa Hydrocortisone Acetate micronized Shandong China 0019 Streptococcus spp. Xinhua Hydrocortisone Acetate micronized Roussel Uclaf Paris, France 0020 Proteus mirabilis Betamethasone dipropionate Sicor Via micronized Terrazzano, 0021) Escherichia coli Italy Betamethasone dipropionate Pfizer Kalamazoo, MI 0022 Corynebacterium spp. Micronized Betamethasone Valerate, Micronized Pfizer Kalamazoo, MI 0023. Enterococcus spp. Triamcinolone acetonide, Micronized Pfizer Kalamazoo, MI Clotrimazole micronized Erregierre, Sovere, Italy 0024 Malassezia pachydermatis S.p.A. Polymyxin B sulfate Alphrama APS Copenhagen, 0.025 Candida spp. Denmark 0026 Systemic side effects are a limiting factor in the long-term use of anti-inflammatory corticosteroids. These side effects are well documented and include 0037)

Generic name Trade Name Manufacturer Address Hydroxypropylcellulose Klucel GF Pharm Hercules Wilmington DE HydroxyETHYLcellulose Natrosol 25OHHX Hercules Wilmington DE HydroxyETHYLcellulose Natrosol 25OH Hercules Wilmington DE Hydroxypropylmethylcellulose Methocel(R) F4M Prem Dow Chem Midland Michigan Hydroxypropylmethylcellulose Methocel(R) K4M Prem Dow Chem Midland Michigan Polyvinyl alcohol Celwol VS40 Celanese Dallas, Tx Polyethylene glycol Polyox WSR N6OK NF Dow Chem Midland Michigan Xanthan gum Kaltrol CGF Kelco Biopolymers Chicago, IL Polyguaternium 7 series Merquat (R) 550 (9% solid) Nalco Naperville, IL Tyloxapol Tyloxapol, USP Ruger Chemical Co. Irvington, NJ

0027 suppression of the adreno-pituitary axis resulting 0038. Additional surfactants include, but are not limited in Cushing-syndrome, to, polysorbate 80, TWEEN 80 (ICI America Inc., Wilm 0028 immunosuppression by a reduction in cell-me ington, Del.), PLURONIC F-68 (from BASF, Ludwig diated immunity and decreased antibody production, shafen, Germany) and poloxamer Surfactants. Additional non-ionic polymers include, but are not limited to dextrans thus, increasing the risk of infections, and other hydroxypropylmethylcelluloses, hydroxyethylcel 0029 retention of sodium and water and hence edema, luloses, hydroxypropylcelluloses, polyvinyl alcohols, and US 2007/0299044 A1 Dec. 27, 2007 polyethylene glycols not listed above. Additional ionic poly 0040. The molar ratio of water insoluble corticosteroid, mers include, but are not limited to other Xanthan gums and polymer (e.g., non-ionic polymer), and Surfactant can be other highly charged cationic homo- or co-polymers (e.g., between about 1:0.000001:0.001 to about 1:0.01:0.49. other copolymer of diallyl dimethyl ammonium chloride and Another example of this molar ratio is between about acrylamide) not listed above. 1:0.0014:0.002 to about 1:0.006:0.15. These ratios are typi 0.039 The amount of surfactant present can range from cally used when a non-ionic polymer is present, but can also 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, apply when an ionic polymer is present. 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.20, to 0.3% w/w, with other ranges and examples including (a) 0.005, 0.006, 0.007, 0041) Pharmaceutically acceptable excipients, as used 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, herein, include anything that one of ordinary skill in the art 0.09, 0.10, 0.20, to <0.3% w/w, (b) 0.005, 0.006, 0.007, would add to a composition in order to aid in its manufac 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, to 0.05% w/w, and (c) ture, stability, marketing, etc. Examples of excipients 0.01% w/w. When no ionic polymer is present in the include, but are not limited to, preservatives (e.g., EDTA formulation, then the amount of Surfactant present is pref salts), glycerin, mineral oil, additional Surfactants (e.g., erably <0.3% w/w. The amount of non-ionic polymer BrijR 72 and BrijR 721), base (e.g., sodium hydroxide), present can range from 0.005, 0.006, 0.007, 0.008, 0.009, acid (e.g., hydrochloric acid), methyl paraben, and water. 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, to 0.20% w/w 0042. As an example, the present invention includes with other ranges and examples including (a) 0.005, 0.006, oil/lotion based Suspensions. This type of Suspension 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, includes an oil (e.g., mineral oil) and a second Surfactant 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, capable of emulsifying the oil. The second Surfactant can be 0.19, to <0.20% w/w, (b) 0.005, 0.006, 0.007, 0.008, 0.009, two (or more) surfactants. Surfactants capable of emulsify 0.01, 0.02, 0.03, 0.04, to 0.05% w/w, and (c) 0.01% w/w. ing oil in pharmaceutical compositions are well known. When no ionic polymer is present in the formulation, then Examples of Surfactant pairs include, but are not limited to the amount of non-ionic polymer present is preferably BrijR 72/Brij(R 721, BrijR 78/ArlacelSM 60, BrijR 72/Brij(R) <0.2% w/w. The amount of ionic polymer is not specifically 78, and Brij(R) 52/BrijR 58 (Brij(R) surfactants are etherified limited, but can range from 0.005, 0.006, 0.007, 0.008, polyethylene glycols, which are available from Uniqema) 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, (ArlacelTM 60 is a sorbitan stearate surfactant available from 0.10, 0.20, 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 0.20, 0.30, Uniqema). The amount of second surfactant present can be 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, from about 0.1 to 2% w/w. This amount includes the total 1.6, 1.7, 1.8, 1.9, to 2.0% w/w with other ranges and amount of second Surfactant, if the second Surfactant is a examples including (a) 0.005, 0.006, 0.007, 0.008, 0.009, pair (or more). The molar ratio of second Surfactant to 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.20, corticosteroid can be about 1:1.2 to 1:10 and 1:7 to 1:9. This 0.30, 0.40, 0.50, 0.60, 0.70, 0.80, 0.90, 0.20, 0.30, 0.40, 0.50, ratio includes the total amount of second surfactant, if the 0.60, 0.70, 0.80, 0.90, to 1.0% w/w, (b) 0.01, 0.02, 0.03, second Surfactant is a pair (or more). 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.20, 0.30, 0.40, to 0.50, 96 w/w, (c) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, EXAMPLES 0.08, 0.09, 0.10, 0.11, to 0.12% w/w, (d) 0.12% w/w and (e) 0.01% w/w. Both a non-ionic and ionic polymer can be 0043. Formulations in this invention include the follow present in the present invention. ing.

ED-Poly-B-Clo Otic suspension

1578- 1578- 1578- 1578- 1578- 1578- 1578 57A 64 89T 9 OB 90D 90E 90F Ingredients % Wiw % Wiw % Wiw % Wiw % wiw % wiw % wiw

Etiprednol O.2 O.2 O.2 O.2 O.2 O.2 O.2 dicloacetate Polymyxin B O.12S O.12S O.12S O.12S O.12S O.12S O.12S Sulfate 10,000 Ug Clotrimazole 1 1 1 1 1 1 1 Micronized Tyloxapol O.300 O.300 OO1 O.O1 O.O1 O.O1 O.O1 Methocel(R) K4M O.2 O.O1 O.O1 Methocel(R) F4M O.O1 Merquat (R) 550 2 0.556 O.278 O.O1 Methylparaben O.18 O.18 O.18 O.18 O.18 O.18 EDTA disodium O.100 O.1 O.1 O.1 O.1 O.1 O.1 salts US 2007/0299044 A1 Dec. 27, 2007

-continued ED-Poly-B-Clo Otic suspension

1578- 1578- 1578- 1578- 1578- 1578 1578 57A 64 89T 9 OB 90D 90E 90F Ingredients % Wiw % Wiw % Wiw % Wiw % wiw % wiw % Wiw

Glycerin 2.50 2.50 2.50 2.50 2.50 2.50 2.50 NaOH pH 5.0-5.5 QS QS QS QS QS QS QS Purified water 95.775 93.595 95.33 95.775 95.775 95.61 95.775

Total 1OO 100 100 100 1OO 100 100

0044) The following procedures can be used to manufac 0049) 5. Adjust the pH and QS to the final proper ture the formulations of the present invention. The non-ionic weight. polymer, Methocel(R) F4M, is used as a non-limiting example. 0050 Formulation 1578-90D (Methocel(R) F4M 0.01%, 0045 1. Heat the purified water to 57-85°C., dissolve tyloxapol 0.01%) can be re-suspended easily when com disodium edentate and tyloxapol first, then dissolve pared to formulation 1578-57A, which comprises higher methylparaben. Disperse the Methocel(R) F4M and then concentration of non-ionic polymer (0.2%) and Surfactant cool to about 30° C. (Methocel(R) does not dissolve in (0.3%). It takes about 25-30 vigorous shakes to suspend the hot water, so first disperse it in hot water and upon drug substances in formulation 1578-57A. It takes only cooling, the Methocel(R) solution will become clear.) about 4 shakes for formulation 1578-90D. As non-ionic 0046 2. Add glycerin to the vehicle in Step 1 and mix polymer concentration increases, it becomes harder to re to dissolve. suspend the water insoluble corticosteroid. 0047 3. For active drug substances, dissolve the water 0051. The following additional formulations demon soluble drug substance (Polymyxin B sulfate in this strated the applicability of this type of formulation to other example) in the vehicle first. steroids (hydrocortisone acetate, betamethasone dipropi 0048 4. Add and disperse the water insoluble clotri onate, betamethasone Valerate, triamcinolone acetonide) as mazole and etiprednol dicloacetate. High shear mixer well as polymer (Klucel, Natrosol, Methocel(R), polyethylene would facilitate the dispersion for better uniformity. glycol, polyvinyl alcohol. Xanthan gum) combinations,

Steroid-antimicrobial Suspensions

2170-96- 217O-96 2170-90 2170-93-3 TRM10 TRM17 ngredients % Wiw % Wiw % Wiw % Wiw Hydrocortisone Acetate, Microniced 1.12 Etiprednol dicloacetate Micronized O.1 Triamcinolone acetonide Micronized O.1 O.1 Clotrimazole Micronized 1.OO 1.OO 1.OO 1.OO Tyloxapol O.O10 O.O1 O.O1 O.O1 Hydroxypropyl methylcellulose O.O10 O.O1 (Methocel (R) F4M) Hydroxypropyl cellulose, Klucel GF O.O1 Polyethylene glycol, Polyox WSR N60K O.O1 Methylparaben O.18 O.18 O.18 O.18 EDTA disodium Salts O.100 O.1 O.1 O.1 Glycerin 2.50 2.50 2.50 2.50 NaOH pH 5.0-5.5 QS QS QS QS Purified Water 95.775 95.775 95.775 95.775

Total 100 100 100 100 Steroid-antimicrobial Suspensions

2170-96- 2170-96- 217O-96- 2170-96- 2170-96 BDS BD-15 BV4 BV15 BV2O Ingredients % Wiw % Wiw % Wiw % Wiw % Wiw Betamethasone dipropionate, O.10 O.10 Micronized Btamethasone valerate, Micronize O.10 O.10 O.10 Clotrimazole Micronized 1.00 1.OO 1.00 1.OO 1.00 US 2007/0299044 A1 Dec. 27, 2007

-continued

Tyloxapol O.O1 O.O1 O.O1 O.O1 O.O1 Hydroxyethylcellulose, Natrosol O.O1 2SOH Hydroxyethylcellulose, O.O1 Natrosol 25OHHX Polyvinal alcohol O.O1 0.01– (Celvol V540) Xanthan gum (Kaltrol) O.O1 Methylparaben O.18 O.18 O.18 O.18 O.18 EDTA disodium Salts O.10 O.1 O.1 O.1 O.1 Glycerin 2.50 2.50 2.50 2.SO 2.50 Purified Water 95.775 95.775 95.775 95.775 95.775

Total 100 1OO 100 1OO 100

0.052 The formulation with low concentration of surfac 0055 Systemic effect of two aqueous suspensions on the tant (for example Tyloxapol at 0.01%) and non-ionic poly opposite non-treated ear, mer (for example Methocel(R) F4M at 0.01% w/w) also reduced the systemic absorption of anti-inflammatory cor ticosteroids when applied topically. This was demonstrated Ear weight (mg) mean +/- Sd in a validated mouse model as follows. N = 40 N = 20 N = 20 0053. In the following experiment, the irritant, croton oil, Untreated control Etiprednol dicloacetate Etiprednol dicloacetate group 0.2% in aqueous 0.2% in aqueous was applied to one earlobe of the mice in the untreated Suspension 2170-79* Suspension 2170-20* control group and to both earlobes of the mice in the with 0.01% polymer with. no polymer treatment groups to induce inflammation. The control group 46.51 +f- 4.77 39.34 +f- 6.27 35.75 f- 3.27a,b was left untreated after induction of inflammation. In the Reduction in (39.34–46.51)/(35.75-46.51) x 100 = 67% systemic effect treatment group, the anti-inflammatory treatment was Earthickness (x102mm)) mean +/- sc applied to one ear, one hour after croton oil application; the opposite ear was left untreated. Assessment of the reduction N = 40 N = 20 N = 20 Untreated control Etiprednol dicloacetate Etiprednol dicloacetate in ear-weight and ear-thickness on the non-treated earlobe group 0.2% in aqueous 0.2% in aqueous was performed 3 hours after treatment application. Since the Suspension 2170-79* Suspension 2170-20* measurement is performed on the untreated ear, the reduc with 0.01% polymer with. no polymer 34.58 +f- 4.58 28.60 +f- 3.95 25.40 +/- 3.23. tion of ear weight or thickness is due to the drug that reached Reduction in (28.60-34.58)/(25.40-34.58) x 100 = 65% the untreated ear from systemic circulation after absorption systemic effect of drug at the area of treatment. Results showed statistical significance (p<0.05) when the aqueous formulation with *See below for formulation. ANOVA (p < 0.05: Two-sides) low concentration of Surfactant and non-ionic polymer (For Statistically significant when compared to the untreated control group mulation 2170-79 & 2170-64) was compared to pure min Statistically significant when compared to the formulation 2170-64 or eral oil formulation or aqueous formulation with no polymer 2170-79 (Formulation 2170-20). 0054 Systemic effect of aqueous suspension and oil 0056) Suspension on the opposite non-treated ear,

ED-Otic suspension Ear weight (mg) mean +/- Sd 2170-20 2170-79 2170-64 with Betamethasone Series series betamethasone in mineral oil N = 20 N = 20 N = 20 Ingredients % Wiw % wiw % Wiw % Wiw Untreated control Betamethasone 0.1% in Betamethasone 0.1% in group aqueous formulation pure mineral oil group Etiprednol O.2-0.8 O.OS-O.2 2170-64* group dicloacetate 47.53 +f- 5.66 40.18 +f- 4.29 34.93 +/- 3.09. Betamethasone O.1 O.1 Reduction in (40.18-47.53)/(34.93-47.53) x 100 = 58% Tyloxapol O.300 O.O1 O.O1 systemic effect= Methocel(R) F4M O.O1 O.O1 Earthickness (x10 mm)) mean +/- sci Methylparaben O.18 O.18 O.18 EDTA disodium O.OSO 0.1 O.1 N = 20 N = 20 N = 20 Salts Untreated control Betamethasone 0.1% in Betamethasone 0.1% in Glycerin 2. SOO 2.50 2.50 group aqueous formulation pure mineral oil group Mineral oil QS 2170-64* group NaOH pH 5.0-5.5 QS QS QS 36.4 +/- 4.85 28.95 -f- 3.97 24.92 +/- 2.20. Purified Water 95.775 95.775 95.775 Reduction in (28.95-36.4)/(24.92-36.4) x 100 = 65% systemic effect= Total 1OO 100 100 1OO US 2007/0299044 A1 Dec. 27, 2007

0057 When comparing re-suspensions of (1) an aqueous 12. The composition of claim 11, wherein the non-ionic based Suspension and (2) an oil/lotion based Suspension, it polymer is Methocel(R) F4M. was found that the better choice was the oil/lotion based Suspension. Surprisingly, the Suspension in oil/lotion 13. The composition of claim 1, further comprising: improved upon aging as it stayed Suspended for a longer pharmaceutically acceptable excipients. period than the non-lotion Suspension (i.e., no mineral oil or 14. The composition of claim 1, wherein the composition Brij(R) surfactants). Oil/lotion based suspension have an oil is an oil/lotion based suspension. (e.g., mineral) that is suspended by the presence of a 15. The composition of claim 14, wherein the oil/lotion surfactant (e.g., BrijR 72 and 721). The surfactant of the based suspension, further comprises a second Surfactant in a oil/lotion based suspension is in addition to the first surfac molar ratio of steroid to second surfactant of from 1:1.2 to tant discussed previously. An example of an oil/lotion for 1:10. mulation is shown below. 16. The composition of claim 15, wherein oil/lotion based Suspension, further comprises: mineral oil, and wherein the second Surfactant is a pair of Surfactants that are capable of Oil/lotion based Suspension emulsifying mineral oil ngredient % Wiw 17. The composition of claim 16, wherein the second Etidprednol dicloacetate, micronized O.2 surfactant is a pair of surfactants, BrijR 72 and BrijR 721. Clotrimazole, micronized 1 18. The composition of claim 1, wherein the steroid is Polymyxin B sulfate USP 0.1375 etidprednol dicloacetate and 0.2% w/w is present, the ionic Tyloxapol USP O.O1 disodium Edetate, USP O.1 polymer is of MerquatR 550 (9% solids) and 0.12% w/w is Glycerine USP 2.5 present, and the surfactant is tyloxapol and 0.01% w/w is Hypromellose USP 2906 (Methocel (R) F4M) O.O1 present. Merquat (R) 5509% O.12 Light mineral oil 2 19. The composition of claim 18, further comprising: 1% Brij (R) 72 (Polyethylene Glycol 2 Sterayl ether)* O45 w/w clotrimazole, 0.01% w/w of Methocel(R) F4M, 2% w/w Brij (R 721 (Polyethylene Glycol 21 Sterayl ether)* 0.55 Sodium hydroxide NF O.OO1 mineral oil, 0.45% w/w BrijR 72, and 0.55% w/w Brij(R) Sodium hydroxide NF adjust pH to 5.0-5.5 QS 721. Hydrochloric acid, adjust pH to 5.0-5.5 QS 20. An aqueous composition for topical application, com Purified water USP, QS QS prising: *Brij (R) 72 and Brij (R 721 are surfactants the act in combination as the Second Surfactants of the present invention. a. a water insoluble corticosteroid, b. a non-ionic polymer, What is claim is: 1. An aqueous topical composition for the treatment of c. and from 0.005 to <0.3% w/w surfactant, inflammation, comprising: wherein the molar ratio of steroid to polymer to surfactant a. a water insoluble corticosteroid, of about 1:0.000001:0.001 to about 1:0.01:0.49. 21. The composition in claim 20, wherein the molar ratio b. an ionic polymer, and of corticosteroid, polymer, and Surfactant is between about c. from 0.005 to 0.3% w/w of a Surfactant. 1:0.0014:0.002 to about 1:0.006:0.15. 2. The composition of claim 1 wherein the corticosteroid 22. The composition of claim 20, wherein the corticos is a soft steroid having anti-inflammatory activity. teroid is soft steroid having anti-inflammatory activity. 3. The composition of claim 2 wherein the soft steroid is loteprednol etabonate or etiprednol dichloacetate or a mix 23. The composition of claim 22, wherein the soft steroid ture thereof. is loteprednol etabonate or etiprednol dichloacetate or a 4. The composition of claim 1, further comprising: a first mixture thereof. antimicrobial agent. 24. The composition of claim 20, further comprising: a 5. The composition of claim 4, further comprising: a first antimicrobial agent. second antimicrobial agent. 25. The composition of claim 24, further comprising: a 6. The composition of claim 1, wherein the surfactant is second antimicrobial agent. tyloxapol. 26. The composition of claim 20, wherein the surfactant 7. The composition of claim 6, wherein 0.01% w/w of is tyloxapol. tyloxapol is present. 27. The composition of claim 26, wherein 0.01% w/w of 8. The composition of claim 1, wherein 0.005 to 2% w/w tyloxapol is present. of the ionic polymer is present. 9. The composition of claim 8, wherein from 0.01 to 1% 28. The composition of claim 20, wherein 0.005 to <0.2% W/w of the ionic polymer is present and the ionic polymer is W/w of the non-ionic polymer is present. MerquatR 550 (9% solid). 29. The composition of claim 28, wherein 0.01% w/w of 10. The composition of claim 1, further comprising: from the non-ionic polymer is present and the non-ionic polymer 0.005 to 0.2% w/w of a non-ionic polymer. is Methocel(R) F4M. 11. The composition of claim 10, wherein 0.01% w/w of 30. The composition of claim 20, further comprising: the non-ionic polymer is present. from 0.005 to 0.2% w/w of an ionic polymer. US 2007/0299044 A1 Dec. 27, 2007

31. The composition of claim 30, wherein from 0.01 to 36. The composition of claim 35, wherein oil/lotion based 0.2% w/w of the ionic polymer is present. Suspension, further comprises: mineral oil, and wherein the 32. The composition of claim 31, wherein the ionic second Surfactant is a pair of Surfactants that are capable of polymer is MerquatR 550 (9% solid). emulsifying mineral oil 33. The composition of claim 20, further comprising: 37. The composition of claim 36, wherein the second pharmaceutically acceptable excipients. surfactant is a pair of surfactants, BrijR 72 and BrijR 721. 34. The composition of claim 20, wherein the composi 38. A method for reducing inflammation, comprising: tion is an oil/lotion based suspension. contacting the inflamed area with a composition of claim 1. 35. The composition of claim 34, wherein the oil/lotion 39. A method for reducing inflammation, comprising: based suspension, further comprises a second Surfactant in a contacting the inflamed area with a composition of claim 20. molar ratio of steroid to second surfactant of from 1:1.2 to 1:10. k k k k k