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(12) Patent Application Publication (10) Pub. No.: US 2017/0152273 A1 Merchant Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0152273 A1 Merchant Et Al US 20170152273A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0152273 A1 Merchant et al. (43) Pub. Date: Jun. 1, 2017 (54) TOPCAL PHARMACEUTICAL Publication Classification FORMULATIONS FOR TREATING (51) Int. Cl. NFLAMMLATORY-RELATED CONDITIONS C07F 5/02 (2006.01) Applicant: A6II 47/06 (2006.01) (71) Anacor Pharmaceuticals Inc., New A69/06 (2006.01) York, NY (US) A6IR 9/00 (2006.01) (72) Inventors: Tejal Merchant, Cupertino, CA (US); A6II 47/8 (2006.01) Dina Jean Coronado, Danville, CA A6II 45/06 (2006.01) (US); Charles Edward Lee, Union A6II 47/10 (2006.01) City, CA (US); Delphine Caroline A6II 3/69 (2006.01) Imbert, Cupertino, CA (US); Sylvia (52) U.S. Cl. Zarela Yep, Milpitas, CA (US) CPC .............. C07F 5/025 (2013.01); A61K 47/10 (2013.01); A61K 47/06 (2013.01); A61K3I/69 (73) Assignee: Anacor Pharmaceuticals Inc., New (2013.01); A61K 9/0014 (2013.01); A61 K York, NY (US) 47/183 (2013.01); A61K 45/06 (2013.01); A61K 9/06 (2013.01); C07B 2.200/13 (21) Appl. No.: 15/364,347 (2013.01) (22) Filed: Nov. 30, 2016 (57) ABSTRACT Related U.S. Application Data (60) Provisional application No. 62/420,987, filed on Nov. Topical pharmaceutical formulations, and methods of treat 11, 2016, provisional application No. 62/260,716. ing inflammatory conditions with these formulations, are filed on Nov. 30, 2015. disclosed. Patent Application Publication Jun. 1, 2017. Sheet 1 of 4 US 2017/0152273 A1 ?zzzzzzzzzzzzzzzzzzzzzzzzzzzz ????????????????????????????????????????????????????????????????????? S&S&S Šx&N Sssssssssssssssssssssssssssssssssssssss (r) eqn. O. peppy jeeNA go eunO/A Patent Application Publication Jun. 1, 2017. Sheet 2 of 4 US 2017/0152273 A1 gbaehaeolaehaehaeg |6 / | | || ripr ra aarara fry as c o c CSS co 000€ SunOO Patent Application Publication Jun. 1, 2017. Sheet 3 of 4 US 2017/0152273 A1 r; r.r --- **** sur -------firr rry g g d ed C c 0008) E000Z E0006 g SunOO Patent Application Publication Jun. 1, 2017. Sheet 4 of 4 US 2017/0152273 A1 -------------- ----------------------- :------------------ g Co |-000£ SunOO US 2017/0152273 A1 Jun. 1, 2017 TOPCAL PHARMACEUTICAL (0.014 d) a stabilizer; FORMULATIONS FOR TREATING 0.015 e) an emulsifying agent; and NFLAMMLATORY-RELATED CONDITIONS 0016 f) a stiffening agent, wherein the topical pharmaceutical formulation comprises BACKGROUND FOR THE INVENTION the active agent, crisaborole. 0001 Topical pharmaceutical formulations which are 0017. The invention provides additional topical pharma useful in the treatment of inflammatory-related conditions, ceutical formulations, as well as methods for their use and Such as atopic dermatitis and/or psoriasis, are known in the production, and combinations thereof. art. Topical pharmaceutical formulations which more 0018. The present invention also relates to crystalline quickly reduce the condition symptoms and/or resolve the forms or a non-crystalline form of 5-(4-cyanophenoxy)-1, underlying causes of the condition would be a significant 3-dihydro-1-hydroxy-2, 1-benzoxaborole. The present advance in the art. invention also relates to pharmaceutical compositions com 0002 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2, prising a crystalline or non-crystalline form, and to methods for preparing such forms. The invention further relates to the 1-benzoxaborole, use of a crystalline or non-crystalline form in the topical treatment of various diseases. 0019. The invention also contemplates combinations of Nss YOH active ingredients for the treatment of atopic dermatitis. N O, DESCRIPTION OF FIGURES 0020 FIG. 1: The equation to calculate the volume of material that physically separated. is a non-steroidal PDE4 inhibitor useful in the treatment of 0021 FIG. 2: Powder X-ray spectrum of crisaborole Form inflammatory skin diseases, including mild to moderate 1 atopic dermatitis and psoriasis. Crisaborole (tradename) is (0022 FIG. 3: Powder X-ray spectrum of crisaborole 2% 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzo Forms 1 (black), 2 (red) & 3 (blue) Xaborole and is the first topical ointment PDE4 inhibitor for 0023 FIG. 4: Powder X-ray spectrum of crisaborole drug mild to moderate atopic dermatitis (AD) for patients two product placebo lot overlaid with Form 1. years of age and older and is recommended for twice daily DETAILED DESCRIPTION OF THE application to the affected areas for about 28 days and up to INVENTION an additional 48 weeks. 0003 U.S. Pat. Nos. 8,039,451, 8,168,614, 8,501,712 I. Definitions and Abbreviations cover the compound and various method of treatments thereof. All references cited herein are incorporated in its 0024. As used herein, the singular forms “a,” “an', and entirety and for all purposes. “the include plural references unless the context clearly 0004 Formulation development of Crisaborole began dictates otherwise. For example, reference to “an active with ointment and cream formulations for Phase I and Phase agent includes a single active agent as well as two or more 2 clinical studies. It was determined that an ointment for different active agents in combination. It is to be understood mulation was preferable for the treatment of inflammatory that present teaching is not limited to the specific dosage skin diseases, in part due to the beneficial emollient prop forms, carriers, or the like, disclosed herein and as such may erties of an ointment. Early formulations were comprised of vary. a partial Suspension of Crisaborole, but chemical and physi 0025. The abbreviations used herein generally have their cal stability issues became problematic requiring a different conventional meaning within the chemical and biological approach. artS. 0005. The present invention is directed to pharmaceutical compositions containing crisaborole, combinations of crisa II. Introduction borole and other active agents, and methods of using thereof. 0026. The present invention relates to topical pharma ceutical formulations. These formulations can be useful in SUMMARY OF THE INVENTION the treatment of inflammatory-related conditions. In one 0006. In a first aspect, the invention provides a topical aspect, the formulation contains an active agent. In another pharmaceutical formulation comprising: aspect, the formulation does not contain an active agent. 0007 a) an active agent which treats an inflammatory These formulations are useful in the treatment and/or pre related condition, or a pharmaceutically acceptable salt, vention of atopic dermatitis and/or psoriasis. or a hydrate or a solvate thereof; 0008 b) from about 5% (w/w) to about 15% (w/w) IIa. Topical Pharmaceutical Formulations propylene glycol, and 0027. In a first aspect, the invention comprises: a) an 0009 c) petrolatum. active agent, or a pharmaceutically acceptable salt, or a 0010. In a second aspect, the invention provides a topical hydrate or a solvate thereof; b) from about 5% (w/w) to pharmaceutical formulation comprising: about 15% (w/w) of a solvent; and c) a base. In an exemplary (0011) a) from about 5% (w/w) to about 15% (w/w) embodiment, the topical pharmaceutical formulation further propylene glycol, comprises up to about 0.5% (w/w) water. In an exemplary (0012 b) petrolatum; embodiment, the topical pharmaceutical formulation further 0013 c) an antioxidant; comprises up to about 0.1% (w/w) water. In an exemplary US 2017/0152273 A1 Jun. 1, 2017 embodiment, the topical pharmaceutical formulation further 0033. In an exemplary embodiment, the invention pro comprises up to about 0.01% (w/w) water. vides an active agent described herein, or a salt, hydrate or 0028. In an exemplary embodiment, all of the compo solvate thereof, or a combination thereof. An exemplary nents of pharmaceutical formulations are pharmaceutically embodiment is a combination of crisaborole as one active acceptable. agent and a second active agent useful for the treatment of atopic dermatitis or psoriasis. The combination may be II. a. i. Active Agent comprised of an admixture or co-formulation of the two active ingredients. Alternatively, the combination may be 0029. In an exemplary embodiment, the topical pharma packaged in a dispenser wherein one active agent is in one ceutical formulation comprises an active pharmaceutical chamber and another active ingredient is in a second cham ingredient ("active agent'). In an exemplary embodiment, ber, but upon dispensing the two active agents are simulta the active agent is an anti-inflammatory agent. In an exem neously delivered together such that administration of the plary embodiment, the active agent is an anti-pruritic agent. combination may occur in one application. Alternatively, the In an exemplary embodiment, the active agent treats atopic active agents may individually be administered with the dermatitis. In an exemplary embodiment, the active agent other active agent, wherein the second active agent may be treats psoriasis. In an exemplary embodiment, the active administered either orally or topically. agent is a compound described herein. In an exemplary 0034 Examples of second active agents that are contem embodiment, the active agent is a benzoxaborole. plated in combination with crisaborole include but are not 0030. In an exemplary embodiment, the active agent is limited to: disclosed in: PCT/US07/062350; Ser. No. 1 1/676,120 (now 0035 Topical corticosteroids such as Fluocinonide, Des U.S. Pat. No. 8,168,614); 60/823,888; 60/774,532. PCT/ Oximetasone, Mometasone, Triamcinolone, Betamethasone, US09/036250; Ser. No. 12/399,015 (now U.S. Pat. No. Alclometasone, DeSonide, Hydrocortisone and Mapracorat; 8,039,450); 61/148,731: 61/143,700: 61/110,903: 61/105, 0036 Topical Calcineurin inhibitors such as Tacrolimus, 990: 61/094,406; 61/052,637; 61/034,371; PCT/US11/ pimecrolimus and cyclosporine; 022780: Ser. No. 13/015.487 (now U.S. Pat. No. 8,716.478); 0037 Topical formulations of PDE4 inhibitors such as 61/298.860: 61/354,187: 61/368,211; PCT/US14/056800; apremilast, E-6005, OPA-15406, LEO 2.9102, DRM02, and and 61/881,343, the content of each of which is herein Roflumilast; incorporated by reference for all purposes.
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