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(12) Patent Application Publication (10) Pub. No.: US 2010/0029602 A1 Arkin Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0029602 A1 Arkin Et Al US 2010.0029602A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0029602 A1 Arkin et al. (43) Pub. Date: Feb. 4, 2010 (54) LOW-DOSE MOMETASONE (60) Provisional application No. 60/911, 185, filed on Apr. FORMULATIONS 11, 2007. (75) Inventors: Moshe Arkin, Kfar Shmaryahu Publication Classification (IL); Amira Zeevi, Omer (IL); Stephen Cherkez, Caesarea (IL); (51) Int. Cl. Eilon Asculai, Lehavim (IL); Rina A6II 3/58 (2006.01) Uzan, Beer Sheva (IL); Bella A6IP 7/02 (2006.01) Braghinski, Beer Sheva (IL) A6IP 7/06 (2006.01) (52) U.S. Cl. ........................................................ S14f172 Correspondence Address: LEYDIG VOIT & MAYER, LTD (57) ABSTRACT TWO PRUDENTIAL PLAZA, SUITE 4900, 180 Provided is a topical cream composition for the delivery of NORTH STETSONAVENUE mometasone furoate comprising low dose mometasone CHICAGO, IL 60601-6731 (US) furoate for the treatment of corticosteroid responsive derma toses. The composition of the present invention can be safely (73) Assignee: Perrigo Israel Pharmaceuticals applied over large Surface areas of the skin (including areas Ltd., Bnei Brak (IL) with wrinkles and/or hair), and can be used therapeutically for extended periods of time (e.g., greater than 3 weeks). Treat (21) Appl. No.: 12/535,406 ment with the composition of the present invention carries reduced and/or fewer side effects compared with commer (22) Filed: Aug. 4, 2009 cially available mometaSone furoate cream products. The cream composition of the present invention is safe for the use Related U.S. Application Data ofbabies and infants under 2 years old. Additionally provided (63) Continuation-in-part of application No. PCT/IL2008/ are methods of preparing and using the composition of the 000485, filed on Apr. 9, 2008. invention. 25 20 i O 0.00 0.25 0.50 0.75 100 125 150 1.75 2.00 2.25 2.50 Sqrt(t), hrs' 3NGF401 MMO21 Patent Application Publication Feb. 4, 2010 Sheet 1 of 3 US 2010/002.9602 A1 0.00 0.25 0.50 0.75 1.00 125 150 1.75 2.00 2.25 2.50 Sqrt(t), hrs 12 -3NGF401 MM021 FIG. 1 Patent Application Publication Feb. 4, 2010 Sheet 2 of 3 US 2010/002.9602 A1 12 10 O.O O.3 O.5 0.8 1.0 3 - 1. 18 2.0 2.3 2.5 Sqrt(t), hrs' - - FIG. 2 Patent Application Publication Feb. 4, 2010 Sheet 3 of 3 US 2010/002.9602 A1 500 s Score of dermal inflammatory - . cell infiltration 3 4.00 – Score of epidermal hyperplasia 3 2. 2 3.00 ...or 3a 9 as 2.00 5 S E 1.00 Z E I OOO Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 FIG. 3 US 2010/0029602 A1 Feb. 4, 2010 LOW-DOSE MOMETASONE ent properties of Elocon R. Cream 0.1% may discourage FORMULATIONS patient compliance with the prescribed treatment regimen. 0006. As such, there is a need for topical mometasone CROSS-REFERENCE TO RELATED furoate compositions that are relatively non-toxic, yet safe APPLICATIONS and effective for treating corticosteroid-responsive skin con ditions, particularly in pediatric patients under 2 years of age. 0001. This patent application is a continuation-in-part of There is also need for topical mometasone furoate composi copending International Application No. PCT/IL2008/ tions that can be safely applied over large Surface areas of the 000485, filed Apr. 9, 2008, which is incorporated by refer skin (e.g., greater than 20% of the total skin Surface) and/or ence, and claims the benefit of U.S. Provisional Patent Appli for a significant duration of time (e.g., greater than 3 weeks), cation No. 60/911,185, filed Apr. 11, 2007, which is with reduced side effects and toxicity as compared to treat incorporated by reference. ment with Elocon R. Cream 0.1%. There is also a need for cosmetically elegant mometaSone furoate compositions that BACKGROUND OF THE INVENTION are pleasant, easy to apply, leave fewer residues, are easy to 0002 Mometasone furoate is a corticosteroid compound wash off, and less adherent or irritating to damaged skin. The that is useful as a topical anti-inflammatory compound. See, present invention provides Such compositions, and methods e.g., U.S. Pat. No. 4,472.393 (“the 393 patent”), which dis for preparing and using such compositions. closes topical compositions that include, interalia, mometa sone furoate for the treatment and control of inflammatory BRIEF SUMMARY OF THE INVENTION conditions. MometaSone furoate is practically insoluble in 0007. The present invention provides a unique, elegant, water, slightly soluble in octanol, and moderately soluble in safe and effective composition for the topical delivery of ethyl alcohol. mometasone furoate. The composition of the present inven 0003 Mometasone furoate cream is currently manufac tion includes from about 0.05 wt % to less than 0.1 wt % tured and sold as a topical cream under the trademark Elo mometasone furoate (e.g., from about 0.075 wt % to less than conR. Cream 0.1%. According to the product label, each gram 0.1 wt % mometaSone furoate) and a pharmaceutically of Elocon R. Cream 0.1% contains mometasone furoate, USP acceptable vehicle that includes an oily phase and at least (1 mg) in a cream base of hexylene glycol, NF; phosphoric about 30 wt % water (e.g., from about 30 wt % to about 65 wt acid, NF: propylene glycol stearate (55% monoester); stearyl % water). Preferably, the composition further includes a alcohol and ceteareth-20; titanium dioxide, USP, aluminum polyol (which can include one or more polyols) and a gelling starch octenylsuccinate (Gamma Irradiated); white wax, NF: agent (which can include one or more gelling agents). In a white petrolatum, USP; and purified water, USP preferred embodiment, the composition of the present inven 0004 Elocon R. Cream 0.1% is indicated for the relief of tion is formulated as a topical cream. Exemplary composi the inflammatory and pruritic manifestations of corticoster tions of the present invention include about 0.075 wt % oid-responsive dermatoses. According to the prescribing mometasone furoate, a polyol, a gelling agent, at least about information, however, Elocon R. Cream 0.1% caused HPA 30 wt % water (e.g., about 60 wt % water), and an oily phase axis Suppression in approximately 16% of pediatric patients (e.g., about 20 wt % of an oily phase). ages 6 to 23 months and is not recommended for patients 0008. The composition of the present invention is effective under 2 years of age. Although the prescribing information for treating corticosteroid responsive dermatoses. The com for Elocon R. Cream 0.1% indicates that it may be used “with position of the present invention can be safely applied over caution' in patients 2 years of age or older, the prescribing large surface areas of the skin (including areas with wrinkles information also warns that pediatric patients may be more and/or hair), and can be used therapeutically for extended Susceptible to systemic toxicity, including HPA axis Suppres periods of time (e.g., greater than 3 weeks). sion and Cushing's syndrome due to their larger skin Surface 0009 Moreover, treatment with the composition of the to body mass ratios. Pediatric patients also are at greater risk present invention carries reduced and/or fewer side effects of adrenal insufficiency during and/or after withdrawal of compared with treatment with Elocon R. Cream. Side effects treatment, and skin atrophy. The prescribing information for that are decreased and/or avoided by the compositions of the Elocon R. Cream 0.1% also states that pediatric patients present invention can include Steroid rosacea, atrophy (skin applying topical corticosteroids to greater than 20% of body thinning) and striae (stretch marks), easy bruising and tearing skin area are at greater risk of HPA axis Suppression. of the skin, perioral dermatitis (rash around the mouth), 0005 Elocon R. Cream 0.1% (like most conventional oil telangiectasia (enlarged blood vessels), Susceptibility to skin based-containing topical corticosteroid creams) is formu infections, tinea incognito (disguising infection). Withdrawal lated with relatively low concentrations of water. For symptoms that have been associated with cessation of instance, U.S. Pat. No. 4,808,610, which describes Elocon R mometasone treatment, including glucocorticosteroid insuf Cream 0.1%, teaches formulating mometaSone furoate in a ficiency, can also be reduced or avoided. The compositions of vehicle that contains relatively low concentrations of water the present invention are associated with decreased HPA axis (1.0 to 5.0 percent). Elocon R. Cream 0.1% tends to have an suppression, a common side effect of Elocon R. Cream which oily texture and tends to be rather difficult to wash off the skin. can lead to increased risk of Cushing's syndrome, hypergly Oily compositions like Elocon R. Cream 0.1% also can cemia, and glucosuria. become tacky or Sticky. Nevertheless, oily compositions are 0010 Without wishing to be bound by any particular used conventionally to provide the occlusiveness needed for theory, it is believed that the composition of the present inven topical efficacy. See, e.g., McKenzie A W. et al., Arch Der tion has a relatively low systemic steroid absorption, as com matol 86:608-10 (1962), which teaches the importance of pared with Elocon R. Cream. hydration on skin in cortico Steroid therapy as demonstrated 0011. In addition, the composition of the present invention by employing an occlusive plastic film. The oily and/or adher has a pleasant texture, is easy to apply, leaves fewer residues US 2010/0029602 A1 Feb. 4, 2010 on the treated area after application, is much easierto washoff DETAILED DESCRIPTION OF THE INVENTION and remove from the skin, and is less tacky and less adherent to damaged skin than conventional oily compositions, yet 0018.
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